65
Treatment pathways for Intravitreal therapies in Diabetic Macular Oedema (DMO) Louise Downey Consultant Ophthalmologist MBChB BSc PhD FRCOphth

Treatment pathways for Intravitreal therapies in Diabetic ...yorkshireretinasociety.com/pdfs/talks pdf/Louise Downey Pathways... · Treatment pathways for Intravitreal therapies in

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Treatment pathways for Intravitreal therapies in

Diabetic Macular Oedema (DMO)

Louise DowneyConsultant OphthalmologistMBChB BSc PhD FRCOphth

Disclosures and acknowledgements

bull Financial disclosuresbull Alcon Alimera Allergan Bayer Novartis Thrombogenics Orayabull Advisory board work travel grants speakers fees research studies

bull Elements of this slide deck were taken from Bayer published slide deck (UK DMO slide deck v 13) plus Allergan Alimera and Novartis slide decks

Plan for this presentation helliphellipa long list

bull What treatment options are available for DMO (evidence base)

bull What treatment should I start with at baselinebull Re-treatment algorithms for intravitreal DMO therapiesbull When should I switchcombine therapiesbull The bigger picture

bull Other eyebull The patient as a wholebull The service -coping with capacity

Plan for this presentation helliphellipa long list

bull What treatment options are available for DMO (evidence base)

bull 1)What treatment should I start with at baselinebull 2)Re-treatment algorithms for intravitreal DMO

therapiesbull 3)When should I switchcombine therapiesbull 4)The bigger picture

bull Other eyeperipheral retinopathybull The patient as a wholebull The service -coping with capacity ndash compromises

DMO ndash treatment options1)What treatments should I use at baseline

bull ETDRS based laser therapies

bull ADJUNCT

bull Surgery ndash VMTERM

bull Pan-retinal photocoagulation

bull INTRAVITREAL

bull ANTI-VEGF

bull Lucentis (Ranibizumab)

bull Eylea (Aflibercept)

bull Avastin (Bevacizumab)

bull STEROIDS

bull Iluvien (Fluocinolone)

bull Ozurdex (Dexamethasone)

RCO recommendations for the treatment of CSMO

The Royal College of Ophthalmologists Diabetic Retinopathy Guidelines 2012

CSMO

No centre involvement

Photocoagulation

Centre involvement

gt 78 letters(normalminimally reduced VA)

Photocoagulation

VA 78ndash24 letters

Phakic

Anti-VEGF

Pseudophakic

Anti-VEGF

Fluocinolone is an option for eyes unresponsive to other treatments but potential side effects must be considered Triamcinolone +- adjunctive laser or fluocinolone may be considered for eyes unresponsive to other treatments

6

ETDRS based laser therapies = Clinically significant macular oedema (CSMO)

bull The ETDRS defined CSMO as DMO that threatens the centre of the macula (fovea)1 and forms the basis of current recommendations for the treatment of CSMO2

bull CSMO is diagnosed if any of the following parameters are met1

1 ETDRS Research Group Arch Ophthalmol 19851031796ndash1806 2 Bandello F et al Eye (Lond) 201226(4)485ndash493

1 Retinal thickening within 500 microm of the centre of the macula

2 Hard exudates within 500 microm of the centre of the macula if associated with thickening of the adjacent retina

3 Retinal thickening of gt1 disc area in size any part of which is located within 1 disc diameter of the centre of the macula

500 microm

500 microm

1 discdiameter

ge 1 discdiameter

Fovea

7

ETDRS = Early Treatment Diabetic Retinopathy Study

Date of Prep Jan 2015 LGB0820157252f

DMO ndash treatment optionsWhat treatments should I use at baseline

ETDRS based laser therapies = Clinically significant macular oedema (CSMO)

bull The ETDRS defined CSMO as DMO that threatens the centre of the macula (fovea)1 and forms the basis of current recommendations for the treatment of CSMO2

bull CSMO is diagnosed if any of the following parameters are met1

1 ETDRS Research Group Arch Ophthalmol 19851031796ndash1806 2 Bandello F et al Eye (Lond) 201226(4)485ndash493

1 Retinal thickening within 500 microm of the centre of the macula

2 Hard exudates within 500 microm of the centre of the macula if associated with thickening of the adjacent retina

3 Retinal thickening of gt1 disc area in size any part of which is located within 1 disc diameter of the centre of the macula

500 microm

500 microm

1 discdiameter

ge 1 discdiameter

Fovea

8

ETDRS = Early Treatment Diabetic Retinopathy Study

LASER

RCO recommendations for the treatment of CSMO

The Royal College of Ophthalmologists Diabetic Retinopathy Guidelines 2012

CSMO

No centre involvement

Photocoagulation

Centre involvement

gt 78 letters(normalminimally reduced VA)

Photocoagulation

VA 78ndash24 letters

Phakic

Anti-VEGF

Pseudophakic

Anti-VEGF

9

ILUVIEN (chronicunresponsive)

OZURXEX (no improvement)

DMO ndash treatment optionsWhat treatments should I use at baseline

bull ETDRS based laser therapies

bull ADJUNCT

bull Surgery ndash VMTERM

bull Pan-retinal photocoagulation

bull INTRAVITREAL

bull ANTI-VEGF

bull Lucentis (Ranibizumab)

bull Eylea (Aflibercept)

bull Avastin (Bevacizumab)

bull STEROIDS

bull Iluvien (Fluocinolone)

bull Ozurdex (Dexamethasone)

11

BOLT

RESOLVERISE and RIDERELIGHT

DA VINCI

VIVID and VISTA

vs laser

vs sham

Steroids

(in combination

with laser)

Anti-VEGF

(in combination

with laser)

DRCRnet (Protocol I)

ETDRS

READ-2

RESTORE

RETAIN

REVEAL

DRCRnet (Protocol B)

FAMEMEAD

vs laser

vs sham

RanibizumabAflibercept

Bevacizumab

Triamcinolone

Fluocinolone acetonide Dexamethasone

Anti-VEGF Laser Steroids

DRCRnet PROTOCOL T

DMO ndash treatment optionsWhat treatments should I use at baseline ndash based on evidence from RCT data

What therapy do I choose for my patient at baselineWhich treatments can I access

NICE TA 274 Lucentis for DMO April 2013NICE TA 346 Eylea for DMO July 2015

NICE TA 301 Iluvien for DMO Nov 2013NICE TA 349 Ozurdex for DMO July 2015

OCT gt400um1st line if OCT suitable

bull Chronic DMObull PSEUDOPHAKICbull Patients ldquoinsufficiently responsive

to existing therapiesrdquo

bull PSEUDOPHAKICbull ldquoNot improved with non-

corticosteroid or such treatment is not suitable for themrdquo

What therapy do I choose for my patient at baseline

bull ANTI-VEGF

bull Superior to ETDRS argon laser in terms of efficacy

RESTORE 36 month Lucentis prn extension studyLucentis monotherapy vs Lucentis plus laser vs laser aloneSchmidt-Erfuth U et al Ophthalmology 2014 121(5) 1045-1053

23

Months

12

10

8

6

4

2

0

minus22 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36

Extension study (ranibizumab 05 mg PRN)Core study

Me

an o

f th

e c

han

ge in

ETD

RS

BC

VA

Prior ranibizumab 05 mg + active laser (n=83)

Prior sham injections + active laser (n=74)

Prior ranibizumab 05 mg + sham laser (n=83)

79

71 606780

Core study assessment

Full analysisstudy completionInterim analysis

RIDE

RISE

Mea

n ch

ange

in B

CVA

(E

TDR

S le

tters

)M

ean

chan

ge in

BC

VA

(ETD

RS

lette

rs)

Time (months)

RISE and RIDE (Lucentis monthly dosing) Mean change in BCVA over 36 months

Brown DM et al Ophthalmology 2013120(10)2013ndash2022

15

Ranibizumab 03 mgRanibizumab 05 mgShamranibizumab 05 mg

RISE amp RIDE

Date of Prep Dec 2014 LGB0820147252X

02 Laser

125 2q4

107 2q8

0

Mea

n ch

ange

in B

CVA

lette

r sco

re

2

101214

02

6

10

14

4

8

12

468

09 Laser

115 2q4

111 2q8

VISTA Week 100

100928068645652403628201240 8 16 24 32 44 48 60 72 76 84 88 96

12 Laser

100928068645652403628201240 8 16 24 32 44 48 60 72 76 84 88 96

105 2q4

107 2q8VIVID Week 100

Week Laser 2q4 2q8

07 Laser

114 2q4

94 2q8

Eylea =VIVID and VISTA Mean change in BCVA to week 100Korobelnik J-F et al Ophthalmology 2014 121 (11) 2247ndash2254 Brown DM et al Ophthalmology 2015 Jul 18 [Epub ahead of print]

Plt00001 vs laser VIVID Laser n=132 2q4 n=136 2q8 n=135 VISTA Laser n=154 2q4 n=154 2q8 n=151Full analysis set 2q4 2 mg every 4 weeks 2q8 2 mg every 8 weeks BCVA best corrected visual acuity ETDRS Early Treatment Diabetic Retinopathy Study

What therapy do I choose for my patient at baseline

bull ANTI-VEGF helliphellipif OCT gt 400um

bull Sohellip Which one

Key trials in DMO

18

BOLT

RESOLVERISE and RIDE

DA VINCI

VIVID and VISTA

vs laser

vs sham

Steroids

(in combination

with laser)

Anti-VEGF

(in combination

with laser)

DRCRnet (Protocol I)

ETDRS

READ-2

RESTORE

RETAIN

REVEAL

DRCRnet (Protocol B)

FAMEMEAD

vs laser

vs sham

RanibizumabAflibercept

Bevacizumab

Triamcinolone

Fluocinolone acetonide Dexamethasone

Anti-VEGF Laser Steroids

DRCRnet PROTOCOL T

PROTOCOL T (DRCRnet)

bull Aflibercept Bevacizumab or Ranibizumab for Diabetic Macular Edema

bull N Engl J Med 2015 Mar 26372(13)1193-203

The Diabetic retinopathy Clinical Research Network February 18 2015

USA study NIHR funded

n=660

Lucentis 03mg not 05mg Eylea 2mg Avastin 125mg

Eylea protocol not the licensed regime

Avastin unlicensed

RETREATMENT protocol

First 6 months ndash inject every month 95 of patients UNLESS VA=66 AND OCT DRY

Then 2nd six months ndash if no change after 3 visits DEFER otherwise keep injecting monthly

Recurs ndash need at least 2 injections ie 3 months of stability

STABILITY = 10 Oct change or VA 5 letter change

STABILITY and residual OCT thickness gt250um LASER

Protocol T 1 year visual acuity outcomes

0

5

10

15

20

0 8 16 24 32 40 48

Visit Week

2032-2040 = 696 ndash 612= 78-69

0

5

10

15

20

0 8 16 24 32 40 48

Visit Week

2050 = 615 or worse = lt69

Mea

n ch

ange

in B

CV

A

Mea

n ch

ange

in B

CV

A

Aflibercept Bevacizumab Ranibizumab

+189

+142

+118+75

+8+83

Protocol T OCT outcomes year 1

-250

-200

-150

-100

-50

0

0 4 8 12 16 20 24 28 32 36 40 44 48 52

Visit Week

Aflibercept Bevacizumab Ranibizumab

Mea

n ch

ange

in C

ST

Conclusions ndash Protocol T year 1 data

bull Eylea was statistically superior in terms of visual acuity to 03mg Lucentisand to Avastin FOR PATIENTS WITH VA worse than 69 letters

bull Eylea and Lucentis were statistically superior in terms of OCT CRT reduction to Avastin for all patients regardless of baseline vision

bull No safety differences between the three drugs

SUMMARY What do I choose for my patient at baselineOCT central retinal thickness (CRT)PseudophakicAttempts at prior treatment duration of DMO

bull lt 400um

bull IFR licensed anti-VEGF or Avastin

+-ETDRS laser

PSEUDOPHAKIC

Iluvien

Ozurdex

bull gt 400um = Anti-VEGF

Which one

Depends on

bull baseline vision lt615 Eylea

bull Fixed dosing attractive (Eylea)bull Chronic DMO

bull PSEUDOPHAKICbull Patients ldquoinsufficiently

responsive to existing therapiesrdquo

bull ldquoNot improved with non-corticosteroid or such treatment is not suitable for themrdquo

Which steroid ndash Ozurdex or Iluvien

bull No head to head data

bull Revisit this when we think about switching from ANTI-VEGF to steroid

Assuming we have started with an anti-VEGF agent ndash what are the re-treatment algorithms in DMO

Treatment posologies

ldquoTreatment is initiated with one injection per month until maximum VA is achieved andor there are no signs of disease activity ie no change in VA and in other signs and

symptoms of the disease under continued treatment

In patients withhellipDMOhellip initially three or more consecutive monthly injections may be needed Thereafter monitoring and treatment intervals

should be determined by the physician and should be based on disease activity as

assessed by VA andor anatomical parametershellip

If patients are being treated according to a treat-and-extend regimen once maximum VA is achieved andor there are no

signs of disease activity the treatment intervals can be extended stepwise until signs of

disease activity or visual impairment recur The treatment intervalhellipmay be extended by up to one month

at a time for DMOrdquo

1 Novartis Pharmaceuticals UK Ltd 30 October 2014 Available at httpwwwmedicinesorgukemcmedicine19409 Accessed 04 September 2015

2 Bayer Pharma AG February 2015 Available at httpwwwmedicinesorgukemcmedicine27224 Accessed 04 September 2015

Ranibizumab1 Aflibercept2

ldquohelliptreatment is initiated with one injection per month for five consecutive doses followed by

one injection every two months There is no requirement for monitoring between injectionshellip

After the first 12 months of treatmenthellipthe treatment interval may be extended based

on visual andor anatomic outcomes The schedule for monitoring should

be determined by the treating physicianrdquo

DMO diabetic macular oedema VA visual acuity

Re-treatment algorithms for anti-VEGF agents in DMO

bull LOADING PHASE

bull Lucentis label = monthly until stability

bull Eylea label = 5 x 112 then every 8 weeks ie fixed regime year 1

bull DRCRnet protocol T = effectively 6 x112 for majority (95) BUT actually only mandated for first 3 months then prn

bull helliphellip likely that majority will receive injections monthly for first 6 months

bull INDIVIDUALISED PHASE

bull Once ldquostablerdquo ndash based on VA and OCT

bull NB May never get a ldquodryrdquo OCT so treat to stability

bull THEN

bull Treat and extend

bull prn

What does Treat and Extend mean

Pathway overview = Lucentis prn

Jan

Loading phase = injections every 4 weeks until ldquostablerdquo for 3 visits

helliphelliphellip

Feb OctSepAugJulJunMayAprMar

MarFebJan

DecNov

DecNovOctSepAugJulJunMayApr

Then observe UNTIL VA decreases or OCT increase = prn

Once reactivates need at least 2 injections until stable again over 3 visits

Pathway overview = Treat and Extend

Jan

Loading phase = injections every 4 weeks until ldquostablerdquo for 3 visits or Eyleayear 1

helliphelliphellip

Feb OctSepAugJulJunMayAprMar

MarFebJan

DecNov

DecNovOctSepAugJulJunMayApr

Then keep injecting but extend the interval between injections gradually ie keep treating even if perfect

If reactivates need at least 2 injections until stable again over 3 visits

Pathway overview = Eylea fixed dosing year 1

Jan

Eylea = 5 x 112 injection then every 8 weeks

Average 6 injections yr 2 Beyond that

helliphelliphellip

Feb OctSepAugJulJunMayAprMar

MarFebJan

DecNov

DecNovOctSepAugJulJunMayApr

Then individualised UNTIL VA decreases or OCT increase = prn

Once reactivates need at least 2 injections until stable again over 3 visits

Pros and cons of Treat and Extend vs Prn

T+E PRN

PROS bull Proactive patient and service get advance warning of injection ndash capacity and demand planning easier

bull One ndashstopbull Fewer visits than prnbull Overtreatment

advantageous for peripheral retinopathy

bull Only treated when active ieno overtreatment

bull Aggressive year 1 protocols (DRCRN I ndash few injections needed thereafter

bull DMO tolerant of reactivations ()

CONS bull Overtreatment = riskexpenseinconvenience

bull Evidence base scantbull Bilateral disease tricky

bull Reactive so need enoughemergency capacity to inject when disease flares up

bull No advance warning to patientservice that injection needed

bull NEED TO DO IT WELL ndashNHS real life audits prn based regimes not good resultsUndertreatment in year 1 Affects long term prognosis and treatment burden

Pros and cons of Treat and Extend vs Prn

T+E PRN

PROS bull Proactive patient and service get advance warning of injection ndash capacity and demand planning easier

bull One ndashstopbull Fewer visits than prnbull Overtreatment

advantageous for peripheral retinopathy

bull Only treated when active ieno overtreatment

bull Aggressive year 1 protocols (DRCRN I ndash few injections needed thereafter

bull DMO tolerant of reactivations ()

CONS bull Overtreatment = riskexpenseinconvenience

bull Evidence base scantbull Bilateral disease tricky

bull Reactive so need enoughemergency capacity to inject when disease flares up

bull No advance warning to patientservice that injection needed

bull NEED TO DO IT WELL ndashNHS real life audits prn based regimes not good resultsUndertreatment in year 1 Affects long term prognosis and treatment burden

DMO ndash anti-VEGF Treat and Extend

bull Retain study ndash the only RCT data

bull Br J Ophthalmol 2015 Oct 9 pii bjophthalmol-2015-307249 doi 101136bjophthalmol-2015-307249 [Epub ahead of print]

bull Ranibizumab 05 mg treat-and-extend regimen for diabetic macular oedema the RETAIN study

bull Pruumlnte C1 Fajnkuchen F2 Mahmood S3 Ricci F4 Hatz K5 Studnička J6 Bezlyak V7 Parikh S7 Stubbings WJ7 Wenzel A7 Figueira J8 and the RETAIN Study Group

RETAIN Phase III trial evaluating the efficacy of lsquotreat and extendrsquo regimen (ARVO 2014)

bull Patients with DMO and visual impairment (n = 372) were randomised 111

to one of three groups for 24 months

bull Two phases to dosing schedule

bull Phase A

bull Patients in all groups were initially treated with monthly ranibizumab until BCVA remained

stable

bull Phase B

bull Patients in the TampE groups whose vision remained stable had treatment- free intervals

that were increased incrementally by 1 month for a maximum of 3 months

bull Patients in the PRN group had ongoing monthly monitoring

bull In all groups Phase A was resumed if a decrease in BCVA was observed at a visit

Ranibizumab 05 mg monotherapy

in TampE regimen

Ranibizumab 05 mg in TampE regimen

plus laser

Ranibizumab 05 mg PRN

35

RETAIN Visual acuity endpoints

Pruumlnte C ARVO 2014 Annual Meeting Abstracts Abstract 1700

Mean average change in BCVAat 12 months (primary endpoint)

Mean change in BCVA at 24 months

Mea

n av

erag

e ch

ange

in B

CVA

(ETD

RS

lette

rs)

RanibizumabTampE

RanibizumabTampE + laser

RanibizumabPRN

RanibizumabTampE

RanibizumabTampE + laser

RanibizumabPRN

Mea

n ch

ange

in B

CVA

(ETD

RS

lette

rs)

plt00001 for both ranibizumab TampE groups versus PRN for primary endpoint

36

RETAIN Patient visits and monitoring with TampE regimen over 24 months

bull The TampE regimen provided an approximately 40 reduction in the number of treatment visits required compared with the ranibizumab PRN regimen

bull Approximately 70 of patients receiving TampE regimens had monitoring intervals ge2 months compared with ongoing monthly monitoring in the ranibizumab PRN group

bull Informed the license for Lucentis in DMO (extend by 1 month at a time)

37

INTRAVITREAL STEROIDSWhich intravitreal steroid is better

bull Licensed steroids ndash Ozurdex (Dexamethasone) and Iluvien (Fluocinoloneacetonide

bull Which steroid is best in terms of VA outcomes hellipWE DONrsquoT KNOW FOR SURE ndash no head to head studies for licensed drugs either between steroids or between anti-VEGF and steroids

bull STEROIDS ARE efficacious in DMO

bull MEAD

bull FAME

bull DRCRnet protocol I

bull NICE ndash Ozurdex and Iluvien ndash second-line agents

Ozurdex

bull A biodegradable co-polymer implant ndash degrades in time to lactic and glycolic acid releasing Dexamethasone

bull 22gauge injectionbull MEAD study

bull N=1048

bull Dex 07mg vs 035mg vs sham

bull No rescue therapy

bull 3 year follow up max 6 monthly dosing ie 7 over 3 years

Gan IM et al Greafes Acrh Clin Exp Ophthalmol 2005

MEAD studyMean BCVA change from baseline based on baseline lens status

-2

0

2

4

6

8

10

0 3 6 9 12 15 18 21 24 27 30 33 36 39

Mea

n C

hang

e Fr

om

Bas

elin

e B

CVA

(Let

ters

)

Month

DEX Implant 07 mg (n = 86)

Sham (n = 101)

Boyer DS et al Ophthalmology 20141211904ndash14

Results analyzed in the ITT population with LOCF for missing values

Pseudophakic

Total

0

5

10

0 3 6 9 12 15 18 21 24 27 30 33 36 39

DEX 700 (n=351)

Sham (n=350)

10

8

6

4

2

0

Mea

n C

hang

e fr

om

Bas

elin

e B

CVA

(Let

ters

)

Month

07mg dose is approved as Ozurdexreg by the FDA and EMA 035mg dose not commercially available

1 Boyer DS et al Ophthalmology 2014 121 1904-1914

bull Nonbioerodible micro implant (polyimide) containing 190microg of fluocinolone acetonide (FAc)

bull Consistent daily submicrogram delivery of 02 microgd FAc for up to 36 months

bull Posterior point of release

bull 35 mm times 037 mm non-bioerodable micro implant

bull 25-gauge injector creates self-sealing wound

bull No measurable systemic exposure

ILUVIEN Implant Technology

FAcimplant

ILUVIEN SPC httpwwwmedicinesorgukemcmedicine27636

0 6 12 18 24 30 36

ILUVIEN 02 microgd FAc(n = 376)05 microgd FAc (n = 395)Control sham injection(n = 185)

Design of Phase 3 FAME Study (FAME A and B = same protocol)

Additional laser therapy allowed after week 6a

Retreatment any time after month 12 (if eligibleb)

Study ends

N = 956Randomisation

221Primary readout

Patients with DMO and

bull At least 1 previous laser tx

bull BCVA ge19 and le68 letters

bull TD-OCT FTH ge250 μm

Month

BCVA = best corrected visual acuity DMO = diabetic macular oedema TD-OCT=time domain optical coherence tomography FTH = foveal thicknessa At masked investigatorrsquos discretion b If BCVA loss ge5 letters or retinal thickening ge50 microm from best reading in previous 12 months

ge15 letter Gain is Greater in Chronic DMO Patients

ge 15

-Let

ter I

mpr

ovem

ent

in B

CVA

Fro

m B

asel

ine

Δ = 98

Months

Full Population Patients With Chronic DMO

Months

Δ = 206

287

189134

34

Steroid re-treatments

bullOzurdexbull Longer half-life than anti-VEGF in the eye

bull Redosing regimes not very helpful from RCT data eg MEAD study only 612 dosing

bull In reality re-treatment interval may be shorter

bull POSOLOGY

bull Patients treated with OZURDEX who have experienced an initial response and in the physicians opinion may benefit from retreatment without being exposed to significant risk should be considered for retreatment Retreatment may be performed after approximately 6 months if the patient experiences decreased vision andor an increase in retinal thickness secondary to recurrent or worsening diabetic macular oedema

bullIluvienbull 70 of patients in FAE only needed 1

injection over 3 years

bull BUT additional rescue treatments allowed

bull POSOLOGY

bull Each ILUVIEN implant releases fluocinolone acetonide for up to 36 months An additional implant may be administered after 12 months if the patient experiences decreased vision or an increase in retinal thickness secondary to recurrent or worsening diabetic macular oedema

bull Patients receiving escape medication were exited from MEAD before administration1

bull Macular laser rescue treatment allowed in RISERIDE (Lucentisreg) from 3 months2

bull Focalgrid laser allowed in FAME (Iluvienreg) from 6 weeks3

MEAD TREATMENT PROTOCOL

bull First treatment given at randomisation (day 0) bull Patients assessed for retreatment eligibility every 3 months from

months 6ndash36bull Patients were eligible for retreatment if

OCT optical coherence tomography

ge6 months since most recent

study treatment

Retinal thickness in 1 mm central macular

subfield by OCT gt175 microm

Evidence of residual retinal oedema (intraretinal cysts or

any regions of increased retinal thickening) as assessed by

investigator from OCT

AND OR

MEA

D

Amendment in May 2010 revised anatomic criterion for retreatment before this time the threshold was gt225 microm1Boyer DS et al Ophthalmology 2014 121 1904-19142Nguyen QD et al Ophthalmology 20121191064minus10773Campochiaro PA et al Ophthalmology 2011118626ndash635

Treatment burdenILUVIEN

Control(n =112)

02 microgd FAc(n =209)

Study Treatments(sham injection or ILUVIEN 02 microgday or FAc 05microgday)

1 treatment 661 761

2 treatments 277 187

ge 3 treatments 63 53

Rescue Laser Treatments (at masked physicianrsquos discretion after week 6)

Patients 607 407

Off-Protocol Treatments (IVTA bevacizumab ranibizumab intravitreal dexamethasone)

Patients 295 115

OZURDEX = 23injections year 1 41 by year 3

No other Rx

Summary of side effects with intravitreal steroids

Drug device Evidence base Cataract risk IOP rise (requiring drops)

Glaucoma surgery

endophthalmitis

ILUVIEN FAME studies 80 cat surgery(273 sham)

384(14 control)

48 0

Ozurdex MEAD 592 had cataract surgery(72 sham)

215 (end of study)(34 sham)

06 0

Trivaris+ laser vs Luc+laserx2 vs laser

Protocol IOphthalmology 2010

15 42(ONE OFgt10mmHg risegt30mmHGStart drops)

2186 0

NICE guidance for intravitreal steroids in DMO

bull Iluvien

bull NICE TA 301 Iluvien for DMO Nov 2013

bull hellipfor treating chronic diabetic macular oedema that is insufficiently responsive to available therapies only if

bull the implant is to be used in an eye with an intraocular

(pseudophakic) lens and

bull the manufacturer provides fluocinolone acetonide intravitreal implant with the discount agreed in the patient access scheme

NICE guidance for intravitreal steroids in DMO

bull Ozurdex

bull NICE TA 349 Ozurdex for DMO July 2015

bull there is an artificial lens in the eye to be treated and

bull their diabetic macular oedema has not improved with

non-corticosteroid treatment or such treatment is not suitable for them

Steroids = second line therapyWhen do I switch

bull Anti-VEGF first line for centre involving DMObull NICE TA ndash ldquoinsufficiently responsiverdquo ldquo ldquonot improvedrdquo ldquonot suitablerdquo ndash

OTHER TREATMENTS

bull 2 scenariosbull 1) Anti-VEGF canrsquot be funded ie OCTlt400um + PSEUDOPHAKIC

bull 2) Already had a course of treatment with laseranti-VEGF + PSEUDOPHAKIC ie SWITCHING from anti-VEGF to steroid

bull Plus

bull ldquochronicrdquo DMO ndash 3 years duration in FAME (18months) for ILUVIEN

bull Chronic DMO not essential for Ozurdex

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

Protocol T ndash patients may not improve in first 6 months

RIDE

RISE

Mea

n ch

ange

in B

CVA

(E

TDR

S le

tters

)M

ean

chan

ge in

BC

VA

(ETD

RS

lette

rs)

Time (months)

RISE and RIDE (Lucentis monthly dosing) Mean change in BCVA over 36 months

Brown DM et al Ophthalmology 2013120(10)2013ndash2022

54

Ranibizumab 03 mgRanibizumab 05 mgShamranibizumab 05 mg

Date of Prep Dec 2014 LGB0820147252X

VA improvement continues throughout year 1 with monthly dosing

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user ndash more than protocol

I

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

DRCRN protocol I5 year outcomesInjections 8-9 in year 1Year 2 = 2-3Year 3= 1-2Year 4 = 0-1Year 5 = 0

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

Wait for plateau = stability in protocol T laserPatient factors again

Judgement of response to anti-VEGF ndashtimeframe

bull Wait 6 months in poor responders

bull Wait 1 year for heavy users

bull Tempting to try steroids earlier than this ifbull No glaucoma ndash not a deal breaker Ozurdex better short term optionbull Pseudophakic

bull Clues from the diseasebull chronic

bull PATIENT FACTORS

bull Any eyes avoid steroids ndash advanced glaucomaCSCR Or prior viral retinitis RARE

bull Any eyes avoid anti-VEGF pregnancytrying to concieve recent CVA

BIOMARKERS AT BASELINE WOULD BE USEFULRESTORE subgroup analysis of OCT features

bull Andreas Pollreisz EURETINA 2015

bull OCT biomarkers (RESTORE data)

bull Better effects with anti-VEGF ifbull Small rather than large intra-retinal cyst

bull Sub-retinal fluid present

bull Vitreo-macular adhesion at baseline

bull No disruption of ELM and ISOS junction

bull No disorganisation of inner retinal layers (DRIL)

RESTORE subgroup analysis of OCT features

bull Andreas Pollreisz EURETINA 2015

bull OCT biomarkers (RESTORE data)

bull Better effects with anti-VEGF ifbull Small rather than large intra-retinal cyst

bull Sub-retinal fluid present

bull Vitreo-macular adhesion at baseline

bull No disruption of ELM and ISOS junction

bull No disorganisation of inner retinal layers (DRIL)

Better baseline characterisationclassificationERG Contrast sensitivityOCT AngiographyMicroperimetry= clues as to who responds best to which drug

Plan for this presentation helliphellipa long list

bull What treatment options are available for DMO (evidence base)

bull What treatment should I start with at baselinebull Re-treatment algorithms for intravitreal DMO therapiesbull When should I switchcombine therapiesbull The bigger picture

bull Other eyebull The patient as a wholebull The service -coping with capacity ndash compromises

The bigger pictureOther eyeThe patient as a wholeThe service -coping with capacity ndash compromises

bull OTHER EYE ndash may create problems

bull Treat and extend ndash ldquoreduce of visitsrdquo plus Eylea license ndash ldquono need for monitoringrdquo may not benefit if lots of visits due to PDR other eye

bull PERIPHERAL RETINA anti-VEGF supresses proliferative disease - Rebound on stopping Rx

bull PATIENT

bull Anti-VEGF ndash heavy user - Will comply

bull One stop much better than two stop for patient ndash Treat and extend

bull SERVICE

bull Capacity and demand planning = fixedT+E more predictable at least 1 month in advance ndash flexible nurse injectors

bull Steroids ndash even if well controlled (Iluvien for 3 years) need IOP check

bull Need pan-retinal examination both eyes ndash separate visits

Summary

CSMO

No centre involvement

Photocoagulation

Centre involvement

gt 78 letters(normalminimally reduced VA)

Photocoagulation

VA 78ndash24 letters

Phakic

Anti-VEGF

Pseudophakic

Anti-VEGF

SWITCHglaucoma

Injection tolerance

Medical issuesrecent CVA

Peripheral diseaseBilateral Rx

CSMO

No centre involvement

LASER

Centre involvement

gt 78 letters(normalminimally

reduced VA)

VA 78ndash24 letters

EYLEA OR LUCENTIS OR AVASTIN

Funding issues

Protocol T ndash poor VA lt 65 letters (615)

LOADING

Monthly injections until stability OR 5 x 112 (EYLEA) = 6 MONTHS then 8 weeks

RETREATMENT1

TREAT AND EXTEND - PRN

PRN

PSEUDOPHAKIC

Prior Rx

ILUVIEN

Chronic disease

OZURDEX

RETREATMENT

OZURDEX

OCT gt175um or any residual oedema

ILUVIEN after 12 months if risksltbenefits

OCT

gt400um

bull FACE TO FACE CLINICS RUNNING IN PARALLEL

bull = MAC002 every 6 months (optom or doctor) routine check for cataracttolerance of injectionsglaucoma issues etc

bull =MAC003 (DOCTOR) for problems as needed no fixed intervalDischargestop treatmentDeclines treatment diagnosis CSR overlay etcswitch drugs

bull =RV002- (DOCTOR) every 6 months

bull =DM002 ndash (DOCTOR) variable interval determined by last assessing doctor

bull First visit at 6 months from 1st injection if mild NPDR

bull Otherwise determined by retinopathy generally

LOADING PHASE

EyleaLucentis 1 within 48hrs of baseline

EyleaLucentis 2 (and LogMAR VA plus OCT same visit)

EyleaLucentis 3 (and LogMAR VA plus OCT same visit)

EyleaLucentis 4 (TEinj)(and Logmar VA plus OCT same visit

AFTER INJECTION 4 data goes off to be reviewed immediately as a hellip

TREAT AND EXTEND assessment ndash the next interval will depend on the response to the loading phase

NB -DMO patients ndash majority (95) will need 6 injctions x 112 of Lucentis

OR Eylea 5 x 112 then 8 weekly

ONCE STABLE for 3 x injection in TE phase

VIRTUAL CLINIC MONITORING OF MACULOPATHY AND PRN RETREATMENT

ANTI-VEGF INJECTION PATHWAYS Baseline visitMAC001 for wet AMDRV001 for CRVOBRVOMed ret clinic for DMO

Pathways ndash too many directions

Better that thanhellip

Thank you

Disclosures and acknowledgements

bull Financial disclosuresbull Alcon Alimera Allergan Bayer Novartis Thrombogenics Orayabull Advisory board work travel grants speakers fees research studies

bull Elements of this slide deck were taken from Bayer published slide deck (UK DMO slide deck v 13) plus Allergan Alimera and Novartis slide decks

Plan for this presentation helliphellipa long list

bull What treatment options are available for DMO (evidence base)

bull What treatment should I start with at baselinebull Re-treatment algorithms for intravitreal DMO therapiesbull When should I switchcombine therapiesbull The bigger picture

bull Other eyebull The patient as a wholebull The service -coping with capacity

Plan for this presentation helliphellipa long list

bull What treatment options are available for DMO (evidence base)

bull 1)What treatment should I start with at baselinebull 2)Re-treatment algorithms for intravitreal DMO

therapiesbull 3)When should I switchcombine therapiesbull 4)The bigger picture

bull Other eyeperipheral retinopathybull The patient as a wholebull The service -coping with capacity ndash compromises

DMO ndash treatment options1)What treatments should I use at baseline

bull ETDRS based laser therapies

bull ADJUNCT

bull Surgery ndash VMTERM

bull Pan-retinal photocoagulation

bull INTRAVITREAL

bull ANTI-VEGF

bull Lucentis (Ranibizumab)

bull Eylea (Aflibercept)

bull Avastin (Bevacizumab)

bull STEROIDS

bull Iluvien (Fluocinolone)

bull Ozurdex (Dexamethasone)

RCO recommendations for the treatment of CSMO

The Royal College of Ophthalmologists Diabetic Retinopathy Guidelines 2012

CSMO

No centre involvement

Photocoagulation

Centre involvement

gt 78 letters(normalminimally reduced VA)

Photocoagulation

VA 78ndash24 letters

Phakic

Anti-VEGF

Pseudophakic

Anti-VEGF

Fluocinolone is an option for eyes unresponsive to other treatments but potential side effects must be considered Triamcinolone +- adjunctive laser or fluocinolone may be considered for eyes unresponsive to other treatments

6

ETDRS based laser therapies = Clinically significant macular oedema (CSMO)

bull The ETDRS defined CSMO as DMO that threatens the centre of the macula (fovea)1 and forms the basis of current recommendations for the treatment of CSMO2

bull CSMO is diagnosed if any of the following parameters are met1

1 ETDRS Research Group Arch Ophthalmol 19851031796ndash1806 2 Bandello F et al Eye (Lond) 201226(4)485ndash493

1 Retinal thickening within 500 microm of the centre of the macula

2 Hard exudates within 500 microm of the centre of the macula if associated with thickening of the adjacent retina

3 Retinal thickening of gt1 disc area in size any part of which is located within 1 disc diameter of the centre of the macula

500 microm

500 microm

1 discdiameter

ge 1 discdiameter

Fovea

7

ETDRS = Early Treatment Diabetic Retinopathy Study

Date of Prep Jan 2015 LGB0820157252f

DMO ndash treatment optionsWhat treatments should I use at baseline

ETDRS based laser therapies = Clinically significant macular oedema (CSMO)

bull The ETDRS defined CSMO as DMO that threatens the centre of the macula (fovea)1 and forms the basis of current recommendations for the treatment of CSMO2

bull CSMO is diagnosed if any of the following parameters are met1

1 ETDRS Research Group Arch Ophthalmol 19851031796ndash1806 2 Bandello F et al Eye (Lond) 201226(4)485ndash493

1 Retinal thickening within 500 microm of the centre of the macula

2 Hard exudates within 500 microm of the centre of the macula if associated with thickening of the adjacent retina

3 Retinal thickening of gt1 disc area in size any part of which is located within 1 disc diameter of the centre of the macula

500 microm

500 microm

1 discdiameter

ge 1 discdiameter

Fovea

8

ETDRS = Early Treatment Diabetic Retinopathy Study

LASER

RCO recommendations for the treatment of CSMO

The Royal College of Ophthalmologists Diabetic Retinopathy Guidelines 2012

CSMO

No centre involvement

Photocoagulation

Centre involvement

gt 78 letters(normalminimally reduced VA)

Photocoagulation

VA 78ndash24 letters

Phakic

Anti-VEGF

Pseudophakic

Anti-VEGF

9

ILUVIEN (chronicunresponsive)

OZURXEX (no improvement)

DMO ndash treatment optionsWhat treatments should I use at baseline

bull ETDRS based laser therapies

bull ADJUNCT

bull Surgery ndash VMTERM

bull Pan-retinal photocoagulation

bull INTRAVITREAL

bull ANTI-VEGF

bull Lucentis (Ranibizumab)

bull Eylea (Aflibercept)

bull Avastin (Bevacizumab)

bull STEROIDS

bull Iluvien (Fluocinolone)

bull Ozurdex (Dexamethasone)

11

BOLT

RESOLVERISE and RIDERELIGHT

DA VINCI

VIVID and VISTA

vs laser

vs sham

Steroids

(in combination

with laser)

Anti-VEGF

(in combination

with laser)

DRCRnet (Protocol I)

ETDRS

READ-2

RESTORE

RETAIN

REVEAL

DRCRnet (Protocol B)

FAMEMEAD

vs laser

vs sham

RanibizumabAflibercept

Bevacizumab

Triamcinolone

Fluocinolone acetonide Dexamethasone

Anti-VEGF Laser Steroids

DRCRnet PROTOCOL T

DMO ndash treatment optionsWhat treatments should I use at baseline ndash based on evidence from RCT data

What therapy do I choose for my patient at baselineWhich treatments can I access

NICE TA 274 Lucentis for DMO April 2013NICE TA 346 Eylea for DMO July 2015

NICE TA 301 Iluvien for DMO Nov 2013NICE TA 349 Ozurdex for DMO July 2015

OCT gt400um1st line if OCT suitable

bull Chronic DMObull PSEUDOPHAKICbull Patients ldquoinsufficiently responsive

to existing therapiesrdquo

bull PSEUDOPHAKICbull ldquoNot improved with non-

corticosteroid or such treatment is not suitable for themrdquo

What therapy do I choose for my patient at baseline

bull ANTI-VEGF

bull Superior to ETDRS argon laser in terms of efficacy

RESTORE 36 month Lucentis prn extension studyLucentis monotherapy vs Lucentis plus laser vs laser aloneSchmidt-Erfuth U et al Ophthalmology 2014 121(5) 1045-1053

23

Months

12

10

8

6

4

2

0

minus22 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36

Extension study (ranibizumab 05 mg PRN)Core study

Me

an o

f th

e c

han

ge in

ETD

RS

BC

VA

Prior ranibizumab 05 mg + active laser (n=83)

Prior sham injections + active laser (n=74)

Prior ranibizumab 05 mg + sham laser (n=83)

79

71 606780

Core study assessment

Full analysisstudy completionInterim analysis

RIDE

RISE

Mea

n ch

ange

in B

CVA

(E

TDR

S le

tters

)M

ean

chan

ge in

BC

VA

(ETD

RS

lette

rs)

Time (months)

RISE and RIDE (Lucentis monthly dosing) Mean change in BCVA over 36 months

Brown DM et al Ophthalmology 2013120(10)2013ndash2022

15

Ranibizumab 03 mgRanibizumab 05 mgShamranibizumab 05 mg

RISE amp RIDE

Date of Prep Dec 2014 LGB0820147252X

02 Laser

125 2q4

107 2q8

0

Mea

n ch

ange

in B

CVA

lette

r sco

re

2

101214

02

6

10

14

4

8

12

468

09 Laser

115 2q4

111 2q8

VISTA Week 100

100928068645652403628201240 8 16 24 32 44 48 60 72 76 84 88 96

12 Laser

100928068645652403628201240 8 16 24 32 44 48 60 72 76 84 88 96

105 2q4

107 2q8VIVID Week 100

Week Laser 2q4 2q8

07 Laser

114 2q4

94 2q8

Eylea =VIVID and VISTA Mean change in BCVA to week 100Korobelnik J-F et al Ophthalmology 2014 121 (11) 2247ndash2254 Brown DM et al Ophthalmology 2015 Jul 18 [Epub ahead of print]

Plt00001 vs laser VIVID Laser n=132 2q4 n=136 2q8 n=135 VISTA Laser n=154 2q4 n=154 2q8 n=151Full analysis set 2q4 2 mg every 4 weeks 2q8 2 mg every 8 weeks BCVA best corrected visual acuity ETDRS Early Treatment Diabetic Retinopathy Study

What therapy do I choose for my patient at baseline

bull ANTI-VEGF helliphellipif OCT gt 400um

bull Sohellip Which one

Key trials in DMO

18

BOLT

RESOLVERISE and RIDE

DA VINCI

VIVID and VISTA

vs laser

vs sham

Steroids

(in combination

with laser)

Anti-VEGF

(in combination

with laser)

DRCRnet (Protocol I)

ETDRS

READ-2

RESTORE

RETAIN

REVEAL

DRCRnet (Protocol B)

FAMEMEAD

vs laser

vs sham

RanibizumabAflibercept

Bevacizumab

Triamcinolone

Fluocinolone acetonide Dexamethasone

Anti-VEGF Laser Steroids

DRCRnet PROTOCOL T

PROTOCOL T (DRCRnet)

bull Aflibercept Bevacizumab or Ranibizumab for Diabetic Macular Edema

bull N Engl J Med 2015 Mar 26372(13)1193-203

The Diabetic retinopathy Clinical Research Network February 18 2015

USA study NIHR funded

n=660

Lucentis 03mg not 05mg Eylea 2mg Avastin 125mg

Eylea protocol not the licensed regime

Avastin unlicensed

RETREATMENT protocol

First 6 months ndash inject every month 95 of patients UNLESS VA=66 AND OCT DRY

Then 2nd six months ndash if no change after 3 visits DEFER otherwise keep injecting monthly

Recurs ndash need at least 2 injections ie 3 months of stability

STABILITY = 10 Oct change or VA 5 letter change

STABILITY and residual OCT thickness gt250um LASER

Protocol T 1 year visual acuity outcomes

0

5

10

15

20

0 8 16 24 32 40 48

Visit Week

2032-2040 = 696 ndash 612= 78-69

0

5

10

15

20

0 8 16 24 32 40 48

Visit Week

2050 = 615 or worse = lt69

Mea

n ch

ange

in B

CV

A

Mea

n ch

ange

in B

CV

A

Aflibercept Bevacizumab Ranibizumab

+189

+142

+118+75

+8+83

Protocol T OCT outcomes year 1

-250

-200

-150

-100

-50

0

0 4 8 12 16 20 24 28 32 36 40 44 48 52

Visit Week

Aflibercept Bevacizumab Ranibizumab

Mea

n ch

ange

in C

ST

Conclusions ndash Protocol T year 1 data

bull Eylea was statistically superior in terms of visual acuity to 03mg Lucentisand to Avastin FOR PATIENTS WITH VA worse than 69 letters

bull Eylea and Lucentis were statistically superior in terms of OCT CRT reduction to Avastin for all patients regardless of baseline vision

bull No safety differences between the three drugs

SUMMARY What do I choose for my patient at baselineOCT central retinal thickness (CRT)PseudophakicAttempts at prior treatment duration of DMO

bull lt 400um

bull IFR licensed anti-VEGF or Avastin

+-ETDRS laser

PSEUDOPHAKIC

Iluvien

Ozurdex

bull gt 400um = Anti-VEGF

Which one

Depends on

bull baseline vision lt615 Eylea

bull Fixed dosing attractive (Eylea)bull Chronic DMO

bull PSEUDOPHAKICbull Patients ldquoinsufficiently

responsive to existing therapiesrdquo

bull ldquoNot improved with non-corticosteroid or such treatment is not suitable for themrdquo

Which steroid ndash Ozurdex or Iluvien

bull No head to head data

bull Revisit this when we think about switching from ANTI-VEGF to steroid

Assuming we have started with an anti-VEGF agent ndash what are the re-treatment algorithms in DMO

Treatment posologies

ldquoTreatment is initiated with one injection per month until maximum VA is achieved andor there are no signs of disease activity ie no change in VA and in other signs and

symptoms of the disease under continued treatment

In patients withhellipDMOhellip initially three or more consecutive monthly injections may be needed Thereafter monitoring and treatment intervals

should be determined by the physician and should be based on disease activity as

assessed by VA andor anatomical parametershellip

If patients are being treated according to a treat-and-extend regimen once maximum VA is achieved andor there are no

signs of disease activity the treatment intervals can be extended stepwise until signs of

disease activity or visual impairment recur The treatment intervalhellipmay be extended by up to one month

at a time for DMOrdquo

1 Novartis Pharmaceuticals UK Ltd 30 October 2014 Available at httpwwwmedicinesorgukemcmedicine19409 Accessed 04 September 2015

2 Bayer Pharma AG February 2015 Available at httpwwwmedicinesorgukemcmedicine27224 Accessed 04 September 2015

Ranibizumab1 Aflibercept2

ldquohelliptreatment is initiated with one injection per month for five consecutive doses followed by

one injection every two months There is no requirement for monitoring between injectionshellip

After the first 12 months of treatmenthellipthe treatment interval may be extended based

on visual andor anatomic outcomes The schedule for monitoring should

be determined by the treating physicianrdquo

DMO diabetic macular oedema VA visual acuity

Re-treatment algorithms for anti-VEGF agents in DMO

bull LOADING PHASE

bull Lucentis label = monthly until stability

bull Eylea label = 5 x 112 then every 8 weeks ie fixed regime year 1

bull DRCRnet protocol T = effectively 6 x112 for majority (95) BUT actually only mandated for first 3 months then prn

bull helliphellip likely that majority will receive injections monthly for first 6 months

bull INDIVIDUALISED PHASE

bull Once ldquostablerdquo ndash based on VA and OCT

bull NB May never get a ldquodryrdquo OCT so treat to stability

bull THEN

bull Treat and extend

bull prn

What does Treat and Extend mean

Pathway overview = Lucentis prn

Jan

Loading phase = injections every 4 weeks until ldquostablerdquo for 3 visits

helliphelliphellip

Feb OctSepAugJulJunMayAprMar

MarFebJan

DecNov

DecNovOctSepAugJulJunMayApr

Then observe UNTIL VA decreases or OCT increase = prn

Once reactivates need at least 2 injections until stable again over 3 visits

Pathway overview = Treat and Extend

Jan

Loading phase = injections every 4 weeks until ldquostablerdquo for 3 visits or Eyleayear 1

helliphelliphellip

Feb OctSepAugJulJunMayAprMar

MarFebJan

DecNov

DecNovOctSepAugJulJunMayApr

Then keep injecting but extend the interval between injections gradually ie keep treating even if perfect

If reactivates need at least 2 injections until stable again over 3 visits

Pathway overview = Eylea fixed dosing year 1

Jan

Eylea = 5 x 112 injection then every 8 weeks

Average 6 injections yr 2 Beyond that

helliphelliphellip

Feb OctSepAugJulJunMayAprMar

MarFebJan

DecNov

DecNovOctSepAugJulJunMayApr

Then individualised UNTIL VA decreases or OCT increase = prn

Once reactivates need at least 2 injections until stable again over 3 visits

Pros and cons of Treat and Extend vs Prn

T+E PRN

PROS bull Proactive patient and service get advance warning of injection ndash capacity and demand planning easier

bull One ndashstopbull Fewer visits than prnbull Overtreatment

advantageous for peripheral retinopathy

bull Only treated when active ieno overtreatment

bull Aggressive year 1 protocols (DRCRN I ndash few injections needed thereafter

bull DMO tolerant of reactivations ()

CONS bull Overtreatment = riskexpenseinconvenience

bull Evidence base scantbull Bilateral disease tricky

bull Reactive so need enoughemergency capacity to inject when disease flares up

bull No advance warning to patientservice that injection needed

bull NEED TO DO IT WELL ndashNHS real life audits prn based regimes not good resultsUndertreatment in year 1 Affects long term prognosis and treatment burden

Pros and cons of Treat and Extend vs Prn

T+E PRN

PROS bull Proactive patient and service get advance warning of injection ndash capacity and demand planning easier

bull One ndashstopbull Fewer visits than prnbull Overtreatment

advantageous for peripheral retinopathy

bull Only treated when active ieno overtreatment

bull Aggressive year 1 protocols (DRCRN I ndash few injections needed thereafter

bull DMO tolerant of reactivations ()

CONS bull Overtreatment = riskexpenseinconvenience

bull Evidence base scantbull Bilateral disease tricky

bull Reactive so need enoughemergency capacity to inject when disease flares up

bull No advance warning to patientservice that injection needed

bull NEED TO DO IT WELL ndashNHS real life audits prn based regimes not good resultsUndertreatment in year 1 Affects long term prognosis and treatment burden

DMO ndash anti-VEGF Treat and Extend

bull Retain study ndash the only RCT data

bull Br J Ophthalmol 2015 Oct 9 pii bjophthalmol-2015-307249 doi 101136bjophthalmol-2015-307249 [Epub ahead of print]

bull Ranibizumab 05 mg treat-and-extend regimen for diabetic macular oedema the RETAIN study

bull Pruumlnte C1 Fajnkuchen F2 Mahmood S3 Ricci F4 Hatz K5 Studnička J6 Bezlyak V7 Parikh S7 Stubbings WJ7 Wenzel A7 Figueira J8 and the RETAIN Study Group

RETAIN Phase III trial evaluating the efficacy of lsquotreat and extendrsquo regimen (ARVO 2014)

bull Patients with DMO and visual impairment (n = 372) were randomised 111

to one of three groups for 24 months

bull Two phases to dosing schedule

bull Phase A

bull Patients in all groups were initially treated with monthly ranibizumab until BCVA remained

stable

bull Phase B

bull Patients in the TampE groups whose vision remained stable had treatment- free intervals

that were increased incrementally by 1 month for a maximum of 3 months

bull Patients in the PRN group had ongoing monthly monitoring

bull In all groups Phase A was resumed if a decrease in BCVA was observed at a visit

Ranibizumab 05 mg monotherapy

in TampE regimen

Ranibizumab 05 mg in TampE regimen

plus laser

Ranibizumab 05 mg PRN

35

RETAIN Visual acuity endpoints

Pruumlnte C ARVO 2014 Annual Meeting Abstracts Abstract 1700

Mean average change in BCVAat 12 months (primary endpoint)

Mean change in BCVA at 24 months

Mea

n av

erag

e ch

ange

in B

CVA

(ETD

RS

lette

rs)

RanibizumabTampE

RanibizumabTampE + laser

RanibizumabPRN

RanibizumabTampE

RanibizumabTampE + laser

RanibizumabPRN

Mea

n ch

ange

in B

CVA

(ETD

RS

lette

rs)

plt00001 for both ranibizumab TampE groups versus PRN for primary endpoint

36

RETAIN Patient visits and monitoring with TampE regimen over 24 months

bull The TampE regimen provided an approximately 40 reduction in the number of treatment visits required compared with the ranibizumab PRN regimen

bull Approximately 70 of patients receiving TampE regimens had monitoring intervals ge2 months compared with ongoing monthly monitoring in the ranibizumab PRN group

bull Informed the license for Lucentis in DMO (extend by 1 month at a time)

37

INTRAVITREAL STEROIDSWhich intravitreal steroid is better

bull Licensed steroids ndash Ozurdex (Dexamethasone) and Iluvien (Fluocinoloneacetonide

bull Which steroid is best in terms of VA outcomes hellipWE DONrsquoT KNOW FOR SURE ndash no head to head studies for licensed drugs either between steroids or between anti-VEGF and steroids

bull STEROIDS ARE efficacious in DMO

bull MEAD

bull FAME

bull DRCRnet protocol I

bull NICE ndash Ozurdex and Iluvien ndash second-line agents

Ozurdex

bull A biodegradable co-polymer implant ndash degrades in time to lactic and glycolic acid releasing Dexamethasone

bull 22gauge injectionbull MEAD study

bull N=1048

bull Dex 07mg vs 035mg vs sham

bull No rescue therapy

bull 3 year follow up max 6 monthly dosing ie 7 over 3 years

Gan IM et al Greafes Acrh Clin Exp Ophthalmol 2005

MEAD studyMean BCVA change from baseline based on baseline lens status

-2

0

2

4

6

8

10

0 3 6 9 12 15 18 21 24 27 30 33 36 39

Mea

n C

hang

e Fr

om

Bas

elin

e B

CVA

(Let

ters

)

Month

DEX Implant 07 mg (n = 86)

Sham (n = 101)

Boyer DS et al Ophthalmology 20141211904ndash14

Results analyzed in the ITT population with LOCF for missing values

Pseudophakic

Total

0

5

10

0 3 6 9 12 15 18 21 24 27 30 33 36 39

DEX 700 (n=351)

Sham (n=350)

10

8

6

4

2

0

Mea

n C

hang

e fr

om

Bas

elin

e B

CVA

(Let

ters

)

Month

07mg dose is approved as Ozurdexreg by the FDA and EMA 035mg dose not commercially available

1 Boyer DS et al Ophthalmology 2014 121 1904-1914

bull Nonbioerodible micro implant (polyimide) containing 190microg of fluocinolone acetonide (FAc)

bull Consistent daily submicrogram delivery of 02 microgd FAc for up to 36 months

bull Posterior point of release

bull 35 mm times 037 mm non-bioerodable micro implant

bull 25-gauge injector creates self-sealing wound

bull No measurable systemic exposure

ILUVIEN Implant Technology

FAcimplant

ILUVIEN SPC httpwwwmedicinesorgukemcmedicine27636

0 6 12 18 24 30 36

ILUVIEN 02 microgd FAc(n = 376)05 microgd FAc (n = 395)Control sham injection(n = 185)

Design of Phase 3 FAME Study (FAME A and B = same protocol)

Additional laser therapy allowed after week 6a

Retreatment any time after month 12 (if eligibleb)

Study ends

N = 956Randomisation

221Primary readout

Patients with DMO and

bull At least 1 previous laser tx

bull BCVA ge19 and le68 letters

bull TD-OCT FTH ge250 μm

Month

BCVA = best corrected visual acuity DMO = diabetic macular oedema TD-OCT=time domain optical coherence tomography FTH = foveal thicknessa At masked investigatorrsquos discretion b If BCVA loss ge5 letters or retinal thickening ge50 microm from best reading in previous 12 months

ge15 letter Gain is Greater in Chronic DMO Patients

ge 15

-Let

ter I

mpr

ovem

ent

in B

CVA

Fro

m B

asel

ine

Δ = 98

Months

Full Population Patients With Chronic DMO

Months

Δ = 206

287

189134

34

Steroid re-treatments

bullOzurdexbull Longer half-life than anti-VEGF in the eye

bull Redosing regimes not very helpful from RCT data eg MEAD study only 612 dosing

bull In reality re-treatment interval may be shorter

bull POSOLOGY

bull Patients treated with OZURDEX who have experienced an initial response and in the physicians opinion may benefit from retreatment without being exposed to significant risk should be considered for retreatment Retreatment may be performed after approximately 6 months if the patient experiences decreased vision andor an increase in retinal thickness secondary to recurrent or worsening diabetic macular oedema

bullIluvienbull 70 of patients in FAE only needed 1

injection over 3 years

bull BUT additional rescue treatments allowed

bull POSOLOGY

bull Each ILUVIEN implant releases fluocinolone acetonide for up to 36 months An additional implant may be administered after 12 months if the patient experiences decreased vision or an increase in retinal thickness secondary to recurrent or worsening diabetic macular oedema

bull Patients receiving escape medication were exited from MEAD before administration1

bull Macular laser rescue treatment allowed in RISERIDE (Lucentisreg) from 3 months2

bull Focalgrid laser allowed in FAME (Iluvienreg) from 6 weeks3

MEAD TREATMENT PROTOCOL

bull First treatment given at randomisation (day 0) bull Patients assessed for retreatment eligibility every 3 months from

months 6ndash36bull Patients were eligible for retreatment if

OCT optical coherence tomography

ge6 months since most recent

study treatment

Retinal thickness in 1 mm central macular

subfield by OCT gt175 microm

Evidence of residual retinal oedema (intraretinal cysts or

any regions of increased retinal thickening) as assessed by

investigator from OCT

AND OR

MEA

D

Amendment in May 2010 revised anatomic criterion for retreatment before this time the threshold was gt225 microm1Boyer DS et al Ophthalmology 2014 121 1904-19142Nguyen QD et al Ophthalmology 20121191064minus10773Campochiaro PA et al Ophthalmology 2011118626ndash635

Treatment burdenILUVIEN

Control(n =112)

02 microgd FAc(n =209)

Study Treatments(sham injection or ILUVIEN 02 microgday or FAc 05microgday)

1 treatment 661 761

2 treatments 277 187

ge 3 treatments 63 53

Rescue Laser Treatments (at masked physicianrsquos discretion after week 6)

Patients 607 407

Off-Protocol Treatments (IVTA bevacizumab ranibizumab intravitreal dexamethasone)

Patients 295 115

OZURDEX = 23injections year 1 41 by year 3

No other Rx

Summary of side effects with intravitreal steroids

Drug device Evidence base Cataract risk IOP rise (requiring drops)

Glaucoma surgery

endophthalmitis

ILUVIEN FAME studies 80 cat surgery(273 sham)

384(14 control)

48 0

Ozurdex MEAD 592 had cataract surgery(72 sham)

215 (end of study)(34 sham)

06 0

Trivaris+ laser vs Luc+laserx2 vs laser

Protocol IOphthalmology 2010

15 42(ONE OFgt10mmHg risegt30mmHGStart drops)

2186 0

NICE guidance for intravitreal steroids in DMO

bull Iluvien

bull NICE TA 301 Iluvien for DMO Nov 2013

bull hellipfor treating chronic diabetic macular oedema that is insufficiently responsive to available therapies only if

bull the implant is to be used in an eye with an intraocular

(pseudophakic) lens and

bull the manufacturer provides fluocinolone acetonide intravitreal implant with the discount agreed in the patient access scheme

NICE guidance for intravitreal steroids in DMO

bull Ozurdex

bull NICE TA 349 Ozurdex for DMO July 2015

bull there is an artificial lens in the eye to be treated and

bull their diabetic macular oedema has not improved with

non-corticosteroid treatment or such treatment is not suitable for them

Steroids = second line therapyWhen do I switch

bull Anti-VEGF first line for centre involving DMObull NICE TA ndash ldquoinsufficiently responsiverdquo ldquo ldquonot improvedrdquo ldquonot suitablerdquo ndash

OTHER TREATMENTS

bull 2 scenariosbull 1) Anti-VEGF canrsquot be funded ie OCTlt400um + PSEUDOPHAKIC

bull 2) Already had a course of treatment with laseranti-VEGF + PSEUDOPHAKIC ie SWITCHING from anti-VEGF to steroid

bull Plus

bull ldquochronicrdquo DMO ndash 3 years duration in FAME (18months) for ILUVIEN

bull Chronic DMO not essential for Ozurdex

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

Protocol T ndash patients may not improve in first 6 months

RIDE

RISE

Mea

n ch

ange

in B

CVA

(E

TDR

S le

tters

)M

ean

chan

ge in

BC

VA

(ETD

RS

lette

rs)

Time (months)

RISE and RIDE (Lucentis monthly dosing) Mean change in BCVA over 36 months

Brown DM et al Ophthalmology 2013120(10)2013ndash2022

54

Ranibizumab 03 mgRanibizumab 05 mgShamranibizumab 05 mg

Date of Prep Dec 2014 LGB0820147252X

VA improvement continues throughout year 1 with monthly dosing

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user ndash more than protocol

I

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

DRCRN protocol I5 year outcomesInjections 8-9 in year 1Year 2 = 2-3Year 3= 1-2Year 4 = 0-1Year 5 = 0

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

Wait for plateau = stability in protocol T laserPatient factors again

Judgement of response to anti-VEGF ndashtimeframe

bull Wait 6 months in poor responders

bull Wait 1 year for heavy users

bull Tempting to try steroids earlier than this ifbull No glaucoma ndash not a deal breaker Ozurdex better short term optionbull Pseudophakic

bull Clues from the diseasebull chronic

bull PATIENT FACTORS

bull Any eyes avoid steroids ndash advanced glaucomaCSCR Or prior viral retinitis RARE

bull Any eyes avoid anti-VEGF pregnancytrying to concieve recent CVA

BIOMARKERS AT BASELINE WOULD BE USEFULRESTORE subgroup analysis of OCT features

bull Andreas Pollreisz EURETINA 2015

bull OCT biomarkers (RESTORE data)

bull Better effects with anti-VEGF ifbull Small rather than large intra-retinal cyst

bull Sub-retinal fluid present

bull Vitreo-macular adhesion at baseline

bull No disruption of ELM and ISOS junction

bull No disorganisation of inner retinal layers (DRIL)

RESTORE subgroup analysis of OCT features

bull Andreas Pollreisz EURETINA 2015

bull OCT biomarkers (RESTORE data)

bull Better effects with anti-VEGF ifbull Small rather than large intra-retinal cyst

bull Sub-retinal fluid present

bull Vitreo-macular adhesion at baseline

bull No disruption of ELM and ISOS junction

bull No disorganisation of inner retinal layers (DRIL)

Better baseline characterisationclassificationERG Contrast sensitivityOCT AngiographyMicroperimetry= clues as to who responds best to which drug

Plan for this presentation helliphellipa long list

bull What treatment options are available for DMO (evidence base)

bull What treatment should I start with at baselinebull Re-treatment algorithms for intravitreal DMO therapiesbull When should I switchcombine therapiesbull The bigger picture

bull Other eyebull The patient as a wholebull The service -coping with capacity ndash compromises

The bigger pictureOther eyeThe patient as a wholeThe service -coping with capacity ndash compromises

bull OTHER EYE ndash may create problems

bull Treat and extend ndash ldquoreduce of visitsrdquo plus Eylea license ndash ldquono need for monitoringrdquo may not benefit if lots of visits due to PDR other eye

bull PERIPHERAL RETINA anti-VEGF supresses proliferative disease - Rebound on stopping Rx

bull PATIENT

bull Anti-VEGF ndash heavy user - Will comply

bull One stop much better than two stop for patient ndash Treat and extend

bull SERVICE

bull Capacity and demand planning = fixedT+E more predictable at least 1 month in advance ndash flexible nurse injectors

bull Steroids ndash even if well controlled (Iluvien for 3 years) need IOP check

bull Need pan-retinal examination both eyes ndash separate visits

Summary

CSMO

No centre involvement

Photocoagulation

Centre involvement

gt 78 letters(normalminimally reduced VA)

Photocoagulation

VA 78ndash24 letters

Phakic

Anti-VEGF

Pseudophakic

Anti-VEGF

SWITCHglaucoma

Injection tolerance

Medical issuesrecent CVA

Peripheral diseaseBilateral Rx

CSMO

No centre involvement

LASER

Centre involvement

gt 78 letters(normalminimally

reduced VA)

VA 78ndash24 letters

EYLEA OR LUCENTIS OR AVASTIN

Funding issues

Protocol T ndash poor VA lt 65 letters (615)

LOADING

Monthly injections until stability OR 5 x 112 (EYLEA) = 6 MONTHS then 8 weeks

RETREATMENT1

TREAT AND EXTEND - PRN

PRN

PSEUDOPHAKIC

Prior Rx

ILUVIEN

Chronic disease

OZURDEX

RETREATMENT

OZURDEX

OCT gt175um or any residual oedema

ILUVIEN after 12 months if risksltbenefits

OCT

gt400um

bull FACE TO FACE CLINICS RUNNING IN PARALLEL

bull = MAC002 every 6 months (optom or doctor) routine check for cataracttolerance of injectionsglaucoma issues etc

bull =MAC003 (DOCTOR) for problems as needed no fixed intervalDischargestop treatmentDeclines treatment diagnosis CSR overlay etcswitch drugs

bull =RV002- (DOCTOR) every 6 months

bull =DM002 ndash (DOCTOR) variable interval determined by last assessing doctor

bull First visit at 6 months from 1st injection if mild NPDR

bull Otherwise determined by retinopathy generally

LOADING PHASE

EyleaLucentis 1 within 48hrs of baseline

EyleaLucentis 2 (and LogMAR VA plus OCT same visit)

EyleaLucentis 3 (and LogMAR VA plus OCT same visit)

EyleaLucentis 4 (TEinj)(and Logmar VA plus OCT same visit

AFTER INJECTION 4 data goes off to be reviewed immediately as a hellip

TREAT AND EXTEND assessment ndash the next interval will depend on the response to the loading phase

NB -DMO patients ndash majority (95) will need 6 injctions x 112 of Lucentis

OR Eylea 5 x 112 then 8 weekly

ONCE STABLE for 3 x injection in TE phase

VIRTUAL CLINIC MONITORING OF MACULOPATHY AND PRN RETREATMENT

ANTI-VEGF INJECTION PATHWAYS Baseline visitMAC001 for wet AMDRV001 for CRVOBRVOMed ret clinic for DMO

Pathways ndash too many directions

Better that thanhellip

Thank you

Plan for this presentation helliphellipa long list

bull What treatment options are available for DMO (evidence base)

bull What treatment should I start with at baselinebull Re-treatment algorithms for intravitreal DMO therapiesbull When should I switchcombine therapiesbull The bigger picture

bull Other eyebull The patient as a wholebull The service -coping with capacity

Plan for this presentation helliphellipa long list

bull What treatment options are available for DMO (evidence base)

bull 1)What treatment should I start with at baselinebull 2)Re-treatment algorithms for intravitreal DMO

therapiesbull 3)When should I switchcombine therapiesbull 4)The bigger picture

bull Other eyeperipheral retinopathybull The patient as a wholebull The service -coping with capacity ndash compromises

DMO ndash treatment options1)What treatments should I use at baseline

bull ETDRS based laser therapies

bull ADJUNCT

bull Surgery ndash VMTERM

bull Pan-retinal photocoagulation

bull INTRAVITREAL

bull ANTI-VEGF

bull Lucentis (Ranibizumab)

bull Eylea (Aflibercept)

bull Avastin (Bevacizumab)

bull STEROIDS

bull Iluvien (Fluocinolone)

bull Ozurdex (Dexamethasone)

RCO recommendations for the treatment of CSMO

The Royal College of Ophthalmologists Diabetic Retinopathy Guidelines 2012

CSMO

No centre involvement

Photocoagulation

Centre involvement

gt 78 letters(normalminimally reduced VA)

Photocoagulation

VA 78ndash24 letters

Phakic

Anti-VEGF

Pseudophakic

Anti-VEGF

Fluocinolone is an option for eyes unresponsive to other treatments but potential side effects must be considered Triamcinolone +- adjunctive laser or fluocinolone may be considered for eyes unresponsive to other treatments

6

ETDRS based laser therapies = Clinically significant macular oedema (CSMO)

bull The ETDRS defined CSMO as DMO that threatens the centre of the macula (fovea)1 and forms the basis of current recommendations for the treatment of CSMO2

bull CSMO is diagnosed if any of the following parameters are met1

1 ETDRS Research Group Arch Ophthalmol 19851031796ndash1806 2 Bandello F et al Eye (Lond) 201226(4)485ndash493

1 Retinal thickening within 500 microm of the centre of the macula

2 Hard exudates within 500 microm of the centre of the macula if associated with thickening of the adjacent retina

3 Retinal thickening of gt1 disc area in size any part of which is located within 1 disc diameter of the centre of the macula

500 microm

500 microm

1 discdiameter

ge 1 discdiameter

Fovea

7

ETDRS = Early Treatment Diabetic Retinopathy Study

Date of Prep Jan 2015 LGB0820157252f

DMO ndash treatment optionsWhat treatments should I use at baseline

ETDRS based laser therapies = Clinically significant macular oedema (CSMO)

bull The ETDRS defined CSMO as DMO that threatens the centre of the macula (fovea)1 and forms the basis of current recommendations for the treatment of CSMO2

bull CSMO is diagnosed if any of the following parameters are met1

1 ETDRS Research Group Arch Ophthalmol 19851031796ndash1806 2 Bandello F et al Eye (Lond) 201226(4)485ndash493

1 Retinal thickening within 500 microm of the centre of the macula

2 Hard exudates within 500 microm of the centre of the macula if associated with thickening of the adjacent retina

3 Retinal thickening of gt1 disc area in size any part of which is located within 1 disc diameter of the centre of the macula

500 microm

500 microm

1 discdiameter

ge 1 discdiameter

Fovea

8

ETDRS = Early Treatment Diabetic Retinopathy Study

LASER

RCO recommendations for the treatment of CSMO

The Royal College of Ophthalmologists Diabetic Retinopathy Guidelines 2012

CSMO

No centre involvement

Photocoagulation

Centre involvement

gt 78 letters(normalminimally reduced VA)

Photocoagulation

VA 78ndash24 letters

Phakic

Anti-VEGF

Pseudophakic

Anti-VEGF

9

ILUVIEN (chronicunresponsive)

OZURXEX (no improvement)

DMO ndash treatment optionsWhat treatments should I use at baseline

bull ETDRS based laser therapies

bull ADJUNCT

bull Surgery ndash VMTERM

bull Pan-retinal photocoagulation

bull INTRAVITREAL

bull ANTI-VEGF

bull Lucentis (Ranibizumab)

bull Eylea (Aflibercept)

bull Avastin (Bevacizumab)

bull STEROIDS

bull Iluvien (Fluocinolone)

bull Ozurdex (Dexamethasone)

11

BOLT

RESOLVERISE and RIDERELIGHT

DA VINCI

VIVID and VISTA

vs laser

vs sham

Steroids

(in combination

with laser)

Anti-VEGF

(in combination

with laser)

DRCRnet (Protocol I)

ETDRS

READ-2

RESTORE

RETAIN

REVEAL

DRCRnet (Protocol B)

FAMEMEAD

vs laser

vs sham

RanibizumabAflibercept

Bevacizumab

Triamcinolone

Fluocinolone acetonide Dexamethasone

Anti-VEGF Laser Steroids

DRCRnet PROTOCOL T

DMO ndash treatment optionsWhat treatments should I use at baseline ndash based on evidence from RCT data

What therapy do I choose for my patient at baselineWhich treatments can I access

NICE TA 274 Lucentis for DMO April 2013NICE TA 346 Eylea for DMO July 2015

NICE TA 301 Iluvien for DMO Nov 2013NICE TA 349 Ozurdex for DMO July 2015

OCT gt400um1st line if OCT suitable

bull Chronic DMObull PSEUDOPHAKICbull Patients ldquoinsufficiently responsive

to existing therapiesrdquo

bull PSEUDOPHAKICbull ldquoNot improved with non-

corticosteroid or such treatment is not suitable for themrdquo

What therapy do I choose for my patient at baseline

bull ANTI-VEGF

bull Superior to ETDRS argon laser in terms of efficacy

RESTORE 36 month Lucentis prn extension studyLucentis monotherapy vs Lucentis plus laser vs laser aloneSchmidt-Erfuth U et al Ophthalmology 2014 121(5) 1045-1053

23

Months

12

10

8

6

4

2

0

minus22 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36

Extension study (ranibizumab 05 mg PRN)Core study

Me

an o

f th

e c

han

ge in

ETD

RS

BC

VA

Prior ranibizumab 05 mg + active laser (n=83)

Prior sham injections + active laser (n=74)

Prior ranibizumab 05 mg + sham laser (n=83)

79

71 606780

Core study assessment

Full analysisstudy completionInterim analysis

RIDE

RISE

Mea

n ch

ange

in B

CVA

(E

TDR

S le

tters

)M

ean

chan

ge in

BC

VA

(ETD

RS

lette

rs)

Time (months)

RISE and RIDE (Lucentis monthly dosing) Mean change in BCVA over 36 months

Brown DM et al Ophthalmology 2013120(10)2013ndash2022

15

Ranibizumab 03 mgRanibizumab 05 mgShamranibizumab 05 mg

RISE amp RIDE

Date of Prep Dec 2014 LGB0820147252X

02 Laser

125 2q4

107 2q8

0

Mea

n ch

ange

in B

CVA

lette

r sco

re

2

101214

02

6

10

14

4

8

12

468

09 Laser

115 2q4

111 2q8

VISTA Week 100

100928068645652403628201240 8 16 24 32 44 48 60 72 76 84 88 96

12 Laser

100928068645652403628201240 8 16 24 32 44 48 60 72 76 84 88 96

105 2q4

107 2q8VIVID Week 100

Week Laser 2q4 2q8

07 Laser

114 2q4

94 2q8

Eylea =VIVID and VISTA Mean change in BCVA to week 100Korobelnik J-F et al Ophthalmology 2014 121 (11) 2247ndash2254 Brown DM et al Ophthalmology 2015 Jul 18 [Epub ahead of print]

Plt00001 vs laser VIVID Laser n=132 2q4 n=136 2q8 n=135 VISTA Laser n=154 2q4 n=154 2q8 n=151Full analysis set 2q4 2 mg every 4 weeks 2q8 2 mg every 8 weeks BCVA best corrected visual acuity ETDRS Early Treatment Diabetic Retinopathy Study

What therapy do I choose for my patient at baseline

bull ANTI-VEGF helliphellipif OCT gt 400um

bull Sohellip Which one

Key trials in DMO

18

BOLT

RESOLVERISE and RIDE

DA VINCI

VIVID and VISTA

vs laser

vs sham

Steroids

(in combination

with laser)

Anti-VEGF

(in combination

with laser)

DRCRnet (Protocol I)

ETDRS

READ-2

RESTORE

RETAIN

REVEAL

DRCRnet (Protocol B)

FAMEMEAD

vs laser

vs sham

RanibizumabAflibercept

Bevacizumab

Triamcinolone

Fluocinolone acetonide Dexamethasone

Anti-VEGF Laser Steroids

DRCRnet PROTOCOL T

PROTOCOL T (DRCRnet)

bull Aflibercept Bevacizumab or Ranibizumab for Diabetic Macular Edema

bull N Engl J Med 2015 Mar 26372(13)1193-203

The Diabetic retinopathy Clinical Research Network February 18 2015

USA study NIHR funded

n=660

Lucentis 03mg not 05mg Eylea 2mg Avastin 125mg

Eylea protocol not the licensed regime

Avastin unlicensed

RETREATMENT protocol

First 6 months ndash inject every month 95 of patients UNLESS VA=66 AND OCT DRY

Then 2nd six months ndash if no change after 3 visits DEFER otherwise keep injecting monthly

Recurs ndash need at least 2 injections ie 3 months of stability

STABILITY = 10 Oct change or VA 5 letter change

STABILITY and residual OCT thickness gt250um LASER

Protocol T 1 year visual acuity outcomes

0

5

10

15

20

0 8 16 24 32 40 48

Visit Week

2032-2040 = 696 ndash 612= 78-69

0

5

10

15

20

0 8 16 24 32 40 48

Visit Week

2050 = 615 or worse = lt69

Mea

n ch

ange

in B

CV

A

Mea

n ch

ange

in B

CV

A

Aflibercept Bevacizumab Ranibizumab

+189

+142

+118+75

+8+83

Protocol T OCT outcomes year 1

-250

-200

-150

-100

-50

0

0 4 8 12 16 20 24 28 32 36 40 44 48 52

Visit Week

Aflibercept Bevacizumab Ranibizumab

Mea

n ch

ange

in C

ST

Conclusions ndash Protocol T year 1 data

bull Eylea was statistically superior in terms of visual acuity to 03mg Lucentisand to Avastin FOR PATIENTS WITH VA worse than 69 letters

bull Eylea and Lucentis were statistically superior in terms of OCT CRT reduction to Avastin for all patients regardless of baseline vision

bull No safety differences between the three drugs

SUMMARY What do I choose for my patient at baselineOCT central retinal thickness (CRT)PseudophakicAttempts at prior treatment duration of DMO

bull lt 400um

bull IFR licensed anti-VEGF or Avastin

+-ETDRS laser

PSEUDOPHAKIC

Iluvien

Ozurdex

bull gt 400um = Anti-VEGF

Which one

Depends on

bull baseline vision lt615 Eylea

bull Fixed dosing attractive (Eylea)bull Chronic DMO

bull PSEUDOPHAKICbull Patients ldquoinsufficiently

responsive to existing therapiesrdquo

bull ldquoNot improved with non-corticosteroid or such treatment is not suitable for themrdquo

Which steroid ndash Ozurdex or Iluvien

bull No head to head data

bull Revisit this when we think about switching from ANTI-VEGF to steroid

Assuming we have started with an anti-VEGF agent ndash what are the re-treatment algorithms in DMO

Treatment posologies

ldquoTreatment is initiated with one injection per month until maximum VA is achieved andor there are no signs of disease activity ie no change in VA and in other signs and

symptoms of the disease under continued treatment

In patients withhellipDMOhellip initially three or more consecutive monthly injections may be needed Thereafter monitoring and treatment intervals

should be determined by the physician and should be based on disease activity as

assessed by VA andor anatomical parametershellip

If patients are being treated according to a treat-and-extend regimen once maximum VA is achieved andor there are no

signs of disease activity the treatment intervals can be extended stepwise until signs of

disease activity or visual impairment recur The treatment intervalhellipmay be extended by up to one month

at a time for DMOrdquo

1 Novartis Pharmaceuticals UK Ltd 30 October 2014 Available at httpwwwmedicinesorgukemcmedicine19409 Accessed 04 September 2015

2 Bayer Pharma AG February 2015 Available at httpwwwmedicinesorgukemcmedicine27224 Accessed 04 September 2015

Ranibizumab1 Aflibercept2

ldquohelliptreatment is initiated with one injection per month for five consecutive doses followed by

one injection every two months There is no requirement for monitoring between injectionshellip

After the first 12 months of treatmenthellipthe treatment interval may be extended based

on visual andor anatomic outcomes The schedule for monitoring should

be determined by the treating physicianrdquo

DMO diabetic macular oedema VA visual acuity

Re-treatment algorithms for anti-VEGF agents in DMO

bull LOADING PHASE

bull Lucentis label = monthly until stability

bull Eylea label = 5 x 112 then every 8 weeks ie fixed regime year 1

bull DRCRnet protocol T = effectively 6 x112 for majority (95) BUT actually only mandated for first 3 months then prn

bull helliphellip likely that majority will receive injections monthly for first 6 months

bull INDIVIDUALISED PHASE

bull Once ldquostablerdquo ndash based on VA and OCT

bull NB May never get a ldquodryrdquo OCT so treat to stability

bull THEN

bull Treat and extend

bull prn

What does Treat and Extend mean

Pathway overview = Lucentis prn

Jan

Loading phase = injections every 4 weeks until ldquostablerdquo for 3 visits

helliphelliphellip

Feb OctSepAugJulJunMayAprMar

MarFebJan

DecNov

DecNovOctSepAugJulJunMayApr

Then observe UNTIL VA decreases or OCT increase = prn

Once reactivates need at least 2 injections until stable again over 3 visits

Pathway overview = Treat and Extend

Jan

Loading phase = injections every 4 weeks until ldquostablerdquo for 3 visits or Eyleayear 1

helliphelliphellip

Feb OctSepAugJulJunMayAprMar

MarFebJan

DecNov

DecNovOctSepAugJulJunMayApr

Then keep injecting but extend the interval between injections gradually ie keep treating even if perfect

If reactivates need at least 2 injections until stable again over 3 visits

Pathway overview = Eylea fixed dosing year 1

Jan

Eylea = 5 x 112 injection then every 8 weeks

Average 6 injections yr 2 Beyond that

helliphelliphellip

Feb OctSepAugJulJunMayAprMar

MarFebJan

DecNov

DecNovOctSepAugJulJunMayApr

Then individualised UNTIL VA decreases or OCT increase = prn

Once reactivates need at least 2 injections until stable again over 3 visits

Pros and cons of Treat and Extend vs Prn

T+E PRN

PROS bull Proactive patient and service get advance warning of injection ndash capacity and demand planning easier

bull One ndashstopbull Fewer visits than prnbull Overtreatment

advantageous for peripheral retinopathy

bull Only treated when active ieno overtreatment

bull Aggressive year 1 protocols (DRCRN I ndash few injections needed thereafter

bull DMO tolerant of reactivations ()

CONS bull Overtreatment = riskexpenseinconvenience

bull Evidence base scantbull Bilateral disease tricky

bull Reactive so need enoughemergency capacity to inject when disease flares up

bull No advance warning to patientservice that injection needed

bull NEED TO DO IT WELL ndashNHS real life audits prn based regimes not good resultsUndertreatment in year 1 Affects long term prognosis and treatment burden

Pros and cons of Treat and Extend vs Prn

T+E PRN

PROS bull Proactive patient and service get advance warning of injection ndash capacity and demand planning easier

bull One ndashstopbull Fewer visits than prnbull Overtreatment

advantageous for peripheral retinopathy

bull Only treated when active ieno overtreatment

bull Aggressive year 1 protocols (DRCRN I ndash few injections needed thereafter

bull DMO tolerant of reactivations ()

CONS bull Overtreatment = riskexpenseinconvenience

bull Evidence base scantbull Bilateral disease tricky

bull Reactive so need enoughemergency capacity to inject when disease flares up

bull No advance warning to patientservice that injection needed

bull NEED TO DO IT WELL ndashNHS real life audits prn based regimes not good resultsUndertreatment in year 1 Affects long term prognosis and treatment burden

DMO ndash anti-VEGF Treat and Extend

bull Retain study ndash the only RCT data

bull Br J Ophthalmol 2015 Oct 9 pii bjophthalmol-2015-307249 doi 101136bjophthalmol-2015-307249 [Epub ahead of print]

bull Ranibizumab 05 mg treat-and-extend regimen for diabetic macular oedema the RETAIN study

bull Pruumlnte C1 Fajnkuchen F2 Mahmood S3 Ricci F4 Hatz K5 Studnička J6 Bezlyak V7 Parikh S7 Stubbings WJ7 Wenzel A7 Figueira J8 and the RETAIN Study Group

RETAIN Phase III trial evaluating the efficacy of lsquotreat and extendrsquo regimen (ARVO 2014)

bull Patients with DMO and visual impairment (n = 372) were randomised 111

to one of three groups for 24 months

bull Two phases to dosing schedule

bull Phase A

bull Patients in all groups were initially treated with monthly ranibizumab until BCVA remained

stable

bull Phase B

bull Patients in the TampE groups whose vision remained stable had treatment- free intervals

that were increased incrementally by 1 month for a maximum of 3 months

bull Patients in the PRN group had ongoing monthly monitoring

bull In all groups Phase A was resumed if a decrease in BCVA was observed at a visit

Ranibizumab 05 mg monotherapy

in TampE regimen

Ranibizumab 05 mg in TampE regimen

plus laser

Ranibizumab 05 mg PRN

35

RETAIN Visual acuity endpoints

Pruumlnte C ARVO 2014 Annual Meeting Abstracts Abstract 1700

Mean average change in BCVAat 12 months (primary endpoint)

Mean change in BCVA at 24 months

Mea

n av

erag

e ch

ange

in B

CVA

(ETD

RS

lette

rs)

RanibizumabTampE

RanibizumabTampE + laser

RanibizumabPRN

RanibizumabTampE

RanibizumabTampE + laser

RanibizumabPRN

Mea

n ch

ange

in B

CVA

(ETD

RS

lette

rs)

plt00001 for both ranibizumab TampE groups versus PRN for primary endpoint

36

RETAIN Patient visits and monitoring with TampE regimen over 24 months

bull The TampE regimen provided an approximately 40 reduction in the number of treatment visits required compared with the ranibizumab PRN regimen

bull Approximately 70 of patients receiving TampE regimens had monitoring intervals ge2 months compared with ongoing monthly monitoring in the ranibizumab PRN group

bull Informed the license for Lucentis in DMO (extend by 1 month at a time)

37

INTRAVITREAL STEROIDSWhich intravitreal steroid is better

bull Licensed steroids ndash Ozurdex (Dexamethasone) and Iluvien (Fluocinoloneacetonide

bull Which steroid is best in terms of VA outcomes hellipWE DONrsquoT KNOW FOR SURE ndash no head to head studies for licensed drugs either between steroids or between anti-VEGF and steroids

bull STEROIDS ARE efficacious in DMO

bull MEAD

bull FAME

bull DRCRnet protocol I

bull NICE ndash Ozurdex and Iluvien ndash second-line agents

Ozurdex

bull A biodegradable co-polymer implant ndash degrades in time to lactic and glycolic acid releasing Dexamethasone

bull 22gauge injectionbull MEAD study

bull N=1048

bull Dex 07mg vs 035mg vs sham

bull No rescue therapy

bull 3 year follow up max 6 monthly dosing ie 7 over 3 years

Gan IM et al Greafes Acrh Clin Exp Ophthalmol 2005

MEAD studyMean BCVA change from baseline based on baseline lens status

-2

0

2

4

6

8

10

0 3 6 9 12 15 18 21 24 27 30 33 36 39

Mea

n C

hang

e Fr

om

Bas

elin

e B

CVA

(Let

ters

)

Month

DEX Implant 07 mg (n = 86)

Sham (n = 101)

Boyer DS et al Ophthalmology 20141211904ndash14

Results analyzed in the ITT population with LOCF for missing values

Pseudophakic

Total

0

5

10

0 3 6 9 12 15 18 21 24 27 30 33 36 39

DEX 700 (n=351)

Sham (n=350)

10

8

6

4

2

0

Mea

n C

hang

e fr

om

Bas

elin

e B

CVA

(Let

ters

)

Month

07mg dose is approved as Ozurdexreg by the FDA and EMA 035mg dose not commercially available

1 Boyer DS et al Ophthalmology 2014 121 1904-1914

bull Nonbioerodible micro implant (polyimide) containing 190microg of fluocinolone acetonide (FAc)

bull Consistent daily submicrogram delivery of 02 microgd FAc for up to 36 months

bull Posterior point of release

bull 35 mm times 037 mm non-bioerodable micro implant

bull 25-gauge injector creates self-sealing wound

bull No measurable systemic exposure

ILUVIEN Implant Technology

FAcimplant

ILUVIEN SPC httpwwwmedicinesorgukemcmedicine27636

0 6 12 18 24 30 36

ILUVIEN 02 microgd FAc(n = 376)05 microgd FAc (n = 395)Control sham injection(n = 185)

Design of Phase 3 FAME Study (FAME A and B = same protocol)

Additional laser therapy allowed after week 6a

Retreatment any time after month 12 (if eligibleb)

Study ends

N = 956Randomisation

221Primary readout

Patients with DMO and

bull At least 1 previous laser tx

bull BCVA ge19 and le68 letters

bull TD-OCT FTH ge250 μm

Month

BCVA = best corrected visual acuity DMO = diabetic macular oedema TD-OCT=time domain optical coherence tomography FTH = foveal thicknessa At masked investigatorrsquos discretion b If BCVA loss ge5 letters or retinal thickening ge50 microm from best reading in previous 12 months

ge15 letter Gain is Greater in Chronic DMO Patients

ge 15

-Let

ter I

mpr

ovem

ent

in B

CVA

Fro

m B

asel

ine

Δ = 98

Months

Full Population Patients With Chronic DMO

Months

Δ = 206

287

189134

34

Steroid re-treatments

bullOzurdexbull Longer half-life than anti-VEGF in the eye

bull Redosing regimes not very helpful from RCT data eg MEAD study only 612 dosing

bull In reality re-treatment interval may be shorter

bull POSOLOGY

bull Patients treated with OZURDEX who have experienced an initial response and in the physicians opinion may benefit from retreatment without being exposed to significant risk should be considered for retreatment Retreatment may be performed after approximately 6 months if the patient experiences decreased vision andor an increase in retinal thickness secondary to recurrent or worsening diabetic macular oedema

bullIluvienbull 70 of patients in FAE only needed 1

injection over 3 years

bull BUT additional rescue treatments allowed

bull POSOLOGY

bull Each ILUVIEN implant releases fluocinolone acetonide for up to 36 months An additional implant may be administered after 12 months if the patient experiences decreased vision or an increase in retinal thickness secondary to recurrent or worsening diabetic macular oedema

bull Patients receiving escape medication were exited from MEAD before administration1

bull Macular laser rescue treatment allowed in RISERIDE (Lucentisreg) from 3 months2

bull Focalgrid laser allowed in FAME (Iluvienreg) from 6 weeks3

MEAD TREATMENT PROTOCOL

bull First treatment given at randomisation (day 0) bull Patients assessed for retreatment eligibility every 3 months from

months 6ndash36bull Patients were eligible for retreatment if

OCT optical coherence tomography

ge6 months since most recent

study treatment

Retinal thickness in 1 mm central macular

subfield by OCT gt175 microm

Evidence of residual retinal oedema (intraretinal cysts or

any regions of increased retinal thickening) as assessed by

investigator from OCT

AND OR

MEA

D

Amendment in May 2010 revised anatomic criterion for retreatment before this time the threshold was gt225 microm1Boyer DS et al Ophthalmology 2014 121 1904-19142Nguyen QD et al Ophthalmology 20121191064minus10773Campochiaro PA et al Ophthalmology 2011118626ndash635

Treatment burdenILUVIEN

Control(n =112)

02 microgd FAc(n =209)

Study Treatments(sham injection or ILUVIEN 02 microgday or FAc 05microgday)

1 treatment 661 761

2 treatments 277 187

ge 3 treatments 63 53

Rescue Laser Treatments (at masked physicianrsquos discretion after week 6)

Patients 607 407

Off-Protocol Treatments (IVTA bevacizumab ranibizumab intravitreal dexamethasone)

Patients 295 115

OZURDEX = 23injections year 1 41 by year 3

No other Rx

Summary of side effects with intravitreal steroids

Drug device Evidence base Cataract risk IOP rise (requiring drops)

Glaucoma surgery

endophthalmitis

ILUVIEN FAME studies 80 cat surgery(273 sham)

384(14 control)

48 0

Ozurdex MEAD 592 had cataract surgery(72 sham)

215 (end of study)(34 sham)

06 0

Trivaris+ laser vs Luc+laserx2 vs laser

Protocol IOphthalmology 2010

15 42(ONE OFgt10mmHg risegt30mmHGStart drops)

2186 0

NICE guidance for intravitreal steroids in DMO

bull Iluvien

bull NICE TA 301 Iluvien for DMO Nov 2013

bull hellipfor treating chronic diabetic macular oedema that is insufficiently responsive to available therapies only if

bull the implant is to be used in an eye with an intraocular

(pseudophakic) lens and

bull the manufacturer provides fluocinolone acetonide intravitreal implant with the discount agreed in the patient access scheme

NICE guidance for intravitreal steroids in DMO

bull Ozurdex

bull NICE TA 349 Ozurdex for DMO July 2015

bull there is an artificial lens in the eye to be treated and

bull their diabetic macular oedema has not improved with

non-corticosteroid treatment or such treatment is not suitable for them

Steroids = second line therapyWhen do I switch

bull Anti-VEGF first line for centre involving DMObull NICE TA ndash ldquoinsufficiently responsiverdquo ldquo ldquonot improvedrdquo ldquonot suitablerdquo ndash

OTHER TREATMENTS

bull 2 scenariosbull 1) Anti-VEGF canrsquot be funded ie OCTlt400um + PSEUDOPHAKIC

bull 2) Already had a course of treatment with laseranti-VEGF + PSEUDOPHAKIC ie SWITCHING from anti-VEGF to steroid

bull Plus

bull ldquochronicrdquo DMO ndash 3 years duration in FAME (18months) for ILUVIEN

bull Chronic DMO not essential for Ozurdex

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

Protocol T ndash patients may not improve in first 6 months

RIDE

RISE

Mea

n ch

ange

in B

CVA

(E

TDR

S le

tters

)M

ean

chan

ge in

BC

VA

(ETD

RS

lette

rs)

Time (months)

RISE and RIDE (Lucentis monthly dosing) Mean change in BCVA over 36 months

Brown DM et al Ophthalmology 2013120(10)2013ndash2022

54

Ranibizumab 03 mgRanibizumab 05 mgShamranibizumab 05 mg

Date of Prep Dec 2014 LGB0820147252X

VA improvement continues throughout year 1 with monthly dosing

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user ndash more than protocol

I

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

DRCRN protocol I5 year outcomesInjections 8-9 in year 1Year 2 = 2-3Year 3= 1-2Year 4 = 0-1Year 5 = 0

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

Wait for plateau = stability in protocol T laserPatient factors again

Judgement of response to anti-VEGF ndashtimeframe

bull Wait 6 months in poor responders

bull Wait 1 year for heavy users

bull Tempting to try steroids earlier than this ifbull No glaucoma ndash not a deal breaker Ozurdex better short term optionbull Pseudophakic

bull Clues from the diseasebull chronic

bull PATIENT FACTORS

bull Any eyes avoid steroids ndash advanced glaucomaCSCR Or prior viral retinitis RARE

bull Any eyes avoid anti-VEGF pregnancytrying to concieve recent CVA

BIOMARKERS AT BASELINE WOULD BE USEFULRESTORE subgroup analysis of OCT features

bull Andreas Pollreisz EURETINA 2015

bull OCT biomarkers (RESTORE data)

bull Better effects with anti-VEGF ifbull Small rather than large intra-retinal cyst

bull Sub-retinal fluid present

bull Vitreo-macular adhesion at baseline

bull No disruption of ELM and ISOS junction

bull No disorganisation of inner retinal layers (DRIL)

RESTORE subgroup analysis of OCT features

bull Andreas Pollreisz EURETINA 2015

bull OCT biomarkers (RESTORE data)

bull Better effects with anti-VEGF ifbull Small rather than large intra-retinal cyst

bull Sub-retinal fluid present

bull Vitreo-macular adhesion at baseline

bull No disruption of ELM and ISOS junction

bull No disorganisation of inner retinal layers (DRIL)

Better baseline characterisationclassificationERG Contrast sensitivityOCT AngiographyMicroperimetry= clues as to who responds best to which drug

Plan for this presentation helliphellipa long list

bull What treatment options are available for DMO (evidence base)

bull What treatment should I start with at baselinebull Re-treatment algorithms for intravitreal DMO therapiesbull When should I switchcombine therapiesbull The bigger picture

bull Other eyebull The patient as a wholebull The service -coping with capacity ndash compromises

The bigger pictureOther eyeThe patient as a wholeThe service -coping with capacity ndash compromises

bull OTHER EYE ndash may create problems

bull Treat and extend ndash ldquoreduce of visitsrdquo plus Eylea license ndash ldquono need for monitoringrdquo may not benefit if lots of visits due to PDR other eye

bull PERIPHERAL RETINA anti-VEGF supresses proliferative disease - Rebound on stopping Rx

bull PATIENT

bull Anti-VEGF ndash heavy user - Will comply

bull One stop much better than two stop for patient ndash Treat and extend

bull SERVICE

bull Capacity and demand planning = fixedT+E more predictable at least 1 month in advance ndash flexible nurse injectors

bull Steroids ndash even if well controlled (Iluvien for 3 years) need IOP check

bull Need pan-retinal examination both eyes ndash separate visits

Summary

CSMO

No centre involvement

Photocoagulation

Centre involvement

gt 78 letters(normalminimally reduced VA)

Photocoagulation

VA 78ndash24 letters

Phakic

Anti-VEGF

Pseudophakic

Anti-VEGF

SWITCHglaucoma

Injection tolerance

Medical issuesrecent CVA

Peripheral diseaseBilateral Rx

CSMO

No centre involvement

LASER

Centre involvement

gt 78 letters(normalminimally

reduced VA)

VA 78ndash24 letters

EYLEA OR LUCENTIS OR AVASTIN

Funding issues

Protocol T ndash poor VA lt 65 letters (615)

LOADING

Monthly injections until stability OR 5 x 112 (EYLEA) = 6 MONTHS then 8 weeks

RETREATMENT1

TREAT AND EXTEND - PRN

PRN

PSEUDOPHAKIC

Prior Rx

ILUVIEN

Chronic disease

OZURDEX

RETREATMENT

OZURDEX

OCT gt175um or any residual oedema

ILUVIEN after 12 months if risksltbenefits

OCT

gt400um

bull FACE TO FACE CLINICS RUNNING IN PARALLEL

bull = MAC002 every 6 months (optom or doctor) routine check for cataracttolerance of injectionsglaucoma issues etc

bull =MAC003 (DOCTOR) for problems as needed no fixed intervalDischargestop treatmentDeclines treatment diagnosis CSR overlay etcswitch drugs

bull =RV002- (DOCTOR) every 6 months

bull =DM002 ndash (DOCTOR) variable interval determined by last assessing doctor

bull First visit at 6 months from 1st injection if mild NPDR

bull Otherwise determined by retinopathy generally

LOADING PHASE

EyleaLucentis 1 within 48hrs of baseline

EyleaLucentis 2 (and LogMAR VA plus OCT same visit)

EyleaLucentis 3 (and LogMAR VA plus OCT same visit)

EyleaLucentis 4 (TEinj)(and Logmar VA plus OCT same visit

AFTER INJECTION 4 data goes off to be reviewed immediately as a hellip

TREAT AND EXTEND assessment ndash the next interval will depend on the response to the loading phase

NB -DMO patients ndash majority (95) will need 6 injctions x 112 of Lucentis

OR Eylea 5 x 112 then 8 weekly

ONCE STABLE for 3 x injection in TE phase

VIRTUAL CLINIC MONITORING OF MACULOPATHY AND PRN RETREATMENT

ANTI-VEGF INJECTION PATHWAYS Baseline visitMAC001 for wet AMDRV001 for CRVOBRVOMed ret clinic for DMO

Pathways ndash too many directions

Better that thanhellip

Thank you

Plan for this presentation helliphellipa long list

bull What treatment options are available for DMO (evidence base)

bull 1)What treatment should I start with at baselinebull 2)Re-treatment algorithms for intravitreal DMO

therapiesbull 3)When should I switchcombine therapiesbull 4)The bigger picture

bull Other eyeperipheral retinopathybull The patient as a wholebull The service -coping with capacity ndash compromises

DMO ndash treatment options1)What treatments should I use at baseline

bull ETDRS based laser therapies

bull ADJUNCT

bull Surgery ndash VMTERM

bull Pan-retinal photocoagulation

bull INTRAVITREAL

bull ANTI-VEGF

bull Lucentis (Ranibizumab)

bull Eylea (Aflibercept)

bull Avastin (Bevacizumab)

bull STEROIDS

bull Iluvien (Fluocinolone)

bull Ozurdex (Dexamethasone)

RCO recommendations for the treatment of CSMO

The Royal College of Ophthalmologists Diabetic Retinopathy Guidelines 2012

CSMO

No centre involvement

Photocoagulation

Centre involvement

gt 78 letters(normalminimally reduced VA)

Photocoagulation

VA 78ndash24 letters

Phakic

Anti-VEGF

Pseudophakic

Anti-VEGF

Fluocinolone is an option for eyes unresponsive to other treatments but potential side effects must be considered Triamcinolone +- adjunctive laser or fluocinolone may be considered for eyes unresponsive to other treatments

6

ETDRS based laser therapies = Clinically significant macular oedema (CSMO)

bull The ETDRS defined CSMO as DMO that threatens the centre of the macula (fovea)1 and forms the basis of current recommendations for the treatment of CSMO2

bull CSMO is diagnosed if any of the following parameters are met1

1 ETDRS Research Group Arch Ophthalmol 19851031796ndash1806 2 Bandello F et al Eye (Lond) 201226(4)485ndash493

1 Retinal thickening within 500 microm of the centre of the macula

2 Hard exudates within 500 microm of the centre of the macula if associated with thickening of the adjacent retina

3 Retinal thickening of gt1 disc area in size any part of which is located within 1 disc diameter of the centre of the macula

500 microm

500 microm

1 discdiameter

ge 1 discdiameter

Fovea

7

ETDRS = Early Treatment Diabetic Retinopathy Study

Date of Prep Jan 2015 LGB0820157252f

DMO ndash treatment optionsWhat treatments should I use at baseline

ETDRS based laser therapies = Clinically significant macular oedema (CSMO)

bull The ETDRS defined CSMO as DMO that threatens the centre of the macula (fovea)1 and forms the basis of current recommendations for the treatment of CSMO2

bull CSMO is diagnosed if any of the following parameters are met1

1 ETDRS Research Group Arch Ophthalmol 19851031796ndash1806 2 Bandello F et al Eye (Lond) 201226(4)485ndash493

1 Retinal thickening within 500 microm of the centre of the macula

2 Hard exudates within 500 microm of the centre of the macula if associated with thickening of the adjacent retina

3 Retinal thickening of gt1 disc area in size any part of which is located within 1 disc diameter of the centre of the macula

500 microm

500 microm

1 discdiameter

ge 1 discdiameter

Fovea

8

ETDRS = Early Treatment Diabetic Retinopathy Study

LASER

RCO recommendations for the treatment of CSMO

The Royal College of Ophthalmologists Diabetic Retinopathy Guidelines 2012

CSMO

No centre involvement

Photocoagulation

Centre involvement

gt 78 letters(normalminimally reduced VA)

Photocoagulation

VA 78ndash24 letters

Phakic

Anti-VEGF

Pseudophakic

Anti-VEGF

9

ILUVIEN (chronicunresponsive)

OZURXEX (no improvement)

DMO ndash treatment optionsWhat treatments should I use at baseline

bull ETDRS based laser therapies

bull ADJUNCT

bull Surgery ndash VMTERM

bull Pan-retinal photocoagulation

bull INTRAVITREAL

bull ANTI-VEGF

bull Lucentis (Ranibizumab)

bull Eylea (Aflibercept)

bull Avastin (Bevacizumab)

bull STEROIDS

bull Iluvien (Fluocinolone)

bull Ozurdex (Dexamethasone)

11

BOLT

RESOLVERISE and RIDERELIGHT

DA VINCI

VIVID and VISTA

vs laser

vs sham

Steroids

(in combination

with laser)

Anti-VEGF

(in combination

with laser)

DRCRnet (Protocol I)

ETDRS

READ-2

RESTORE

RETAIN

REVEAL

DRCRnet (Protocol B)

FAMEMEAD

vs laser

vs sham

RanibizumabAflibercept

Bevacizumab

Triamcinolone

Fluocinolone acetonide Dexamethasone

Anti-VEGF Laser Steroids

DRCRnet PROTOCOL T

DMO ndash treatment optionsWhat treatments should I use at baseline ndash based on evidence from RCT data

What therapy do I choose for my patient at baselineWhich treatments can I access

NICE TA 274 Lucentis for DMO April 2013NICE TA 346 Eylea for DMO July 2015

NICE TA 301 Iluvien for DMO Nov 2013NICE TA 349 Ozurdex for DMO July 2015

OCT gt400um1st line if OCT suitable

bull Chronic DMObull PSEUDOPHAKICbull Patients ldquoinsufficiently responsive

to existing therapiesrdquo

bull PSEUDOPHAKICbull ldquoNot improved with non-

corticosteroid or such treatment is not suitable for themrdquo

What therapy do I choose for my patient at baseline

bull ANTI-VEGF

bull Superior to ETDRS argon laser in terms of efficacy

RESTORE 36 month Lucentis prn extension studyLucentis monotherapy vs Lucentis plus laser vs laser aloneSchmidt-Erfuth U et al Ophthalmology 2014 121(5) 1045-1053

23

Months

12

10

8

6

4

2

0

minus22 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36

Extension study (ranibizumab 05 mg PRN)Core study

Me

an o

f th

e c

han

ge in

ETD

RS

BC

VA

Prior ranibizumab 05 mg + active laser (n=83)

Prior sham injections + active laser (n=74)

Prior ranibizumab 05 mg + sham laser (n=83)

79

71 606780

Core study assessment

Full analysisstudy completionInterim analysis

RIDE

RISE

Mea

n ch

ange

in B

CVA

(E

TDR

S le

tters

)M

ean

chan

ge in

BC

VA

(ETD

RS

lette

rs)

Time (months)

RISE and RIDE (Lucentis monthly dosing) Mean change in BCVA over 36 months

Brown DM et al Ophthalmology 2013120(10)2013ndash2022

15

Ranibizumab 03 mgRanibizumab 05 mgShamranibizumab 05 mg

RISE amp RIDE

Date of Prep Dec 2014 LGB0820147252X

02 Laser

125 2q4

107 2q8

0

Mea

n ch

ange

in B

CVA

lette

r sco

re

2

101214

02

6

10

14

4

8

12

468

09 Laser

115 2q4

111 2q8

VISTA Week 100

100928068645652403628201240 8 16 24 32 44 48 60 72 76 84 88 96

12 Laser

100928068645652403628201240 8 16 24 32 44 48 60 72 76 84 88 96

105 2q4

107 2q8VIVID Week 100

Week Laser 2q4 2q8

07 Laser

114 2q4

94 2q8

Eylea =VIVID and VISTA Mean change in BCVA to week 100Korobelnik J-F et al Ophthalmology 2014 121 (11) 2247ndash2254 Brown DM et al Ophthalmology 2015 Jul 18 [Epub ahead of print]

Plt00001 vs laser VIVID Laser n=132 2q4 n=136 2q8 n=135 VISTA Laser n=154 2q4 n=154 2q8 n=151Full analysis set 2q4 2 mg every 4 weeks 2q8 2 mg every 8 weeks BCVA best corrected visual acuity ETDRS Early Treatment Diabetic Retinopathy Study

What therapy do I choose for my patient at baseline

bull ANTI-VEGF helliphellipif OCT gt 400um

bull Sohellip Which one

Key trials in DMO

18

BOLT

RESOLVERISE and RIDE

DA VINCI

VIVID and VISTA

vs laser

vs sham

Steroids

(in combination

with laser)

Anti-VEGF

(in combination

with laser)

DRCRnet (Protocol I)

ETDRS

READ-2

RESTORE

RETAIN

REVEAL

DRCRnet (Protocol B)

FAMEMEAD

vs laser

vs sham

RanibizumabAflibercept

Bevacizumab

Triamcinolone

Fluocinolone acetonide Dexamethasone

Anti-VEGF Laser Steroids

DRCRnet PROTOCOL T

PROTOCOL T (DRCRnet)

bull Aflibercept Bevacizumab or Ranibizumab for Diabetic Macular Edema

bull N Engl J Med 2015 Mar 26372(13)1193-203

The Diabetic retinopathy Clinical Research Network February 18 2015

USA study NIHR funded

n=660

Lucentis 03mg not 05mg Eylea 2mg Avastin 125mg

Eylea protocol not the licensed regime

Avastin unlicensed

RETREATMENT protocol

First 6 months ndash inject every month 95 of patients UNLESS VA=66 AND OCT DRY

Then 2nd six months ndash if no change after 3 visits DEFER otherwise keep injecting monthly

Recurs ndash need at least 2 injections ie 3 months of stability

STABILITY = 10 Oct change or VA 5 letter change

STABILITY and residual OCT thickness gt250um LASER

Protocol T 1 year visual acuity outcomes

0

5

10

15

20

0 8 16 24 32 40 48

Visit Week

2032-2040 = 696 ndash 612= 78-69

0

5

10

15

20

0 8 16 24 32 40 48

Visit Week

2050 = 615 or worse = lt69

Mea

n ch

ange

in B

CV

A

Mea

n ch

ange

in B

CV

A

Aflibercept Bevacizumab Ranibizumab

+189

+142

+118+75

+8+83

Protocol T OCT outcomes year 1

-250

-200

-150

-100

-50

0

0 4 8 12 16 20 24 28 32 36 40 44 48 52

Visit Week

Aflibercept Bevacizumab Ranibizumab

Mea

n ch

ange

in C

ST

Conclusions ndash Protocol T year 1 data

bull Eylea was statistically superior in terms of visual acuity to 03mg Lucentisand to Avastin FOR PATIENTS WITH VA worse than 69 letters

bull Eylea and Lucentis were statistically superior in terms of OCT CRT reduction to Avastin for all patients regardless of baseline vision

bull No safety differences between the three drugs

SUMMARY What do I choose for my patient at baselineOCT central retinal thickness (CRT)PseudophakicAttempts at prior treatment duration of DMO

bull lt 400um

bull IFR licensed anti-VEGF or Avastin

+-ETDRS laser

PSEUDOPHAKIC

Iluvien

Ozurdex

bull gt 400um = Anti-VEGF

Which one

Depends on

bull baseline vision lt615 Eylea

bull Fixed dosing attractive (Eylea)bull Chronic DMO

bull PSEUDOPHAKICbull Patients ldquoinsufficiently

responsive to existing therapiesrdquo

bull ldquoNot improved with non-corticosteroid or such treatment is not suitable for themrdquo

Which steroid ndash Ozurdex or Iluvien

bull No head to head data

bull Revisit this when we think about switching from ANTI-VEGF to steroid

Assuming we have started with an anti-VEGF agent ndash what are the re-treatment algorithms in DMO

Treatment posologies

ldquoTreatment is initiated with one injection per month until maximum VA is achieved andor there are no signs of disease activity ie no change in VA and in other signs and

symptoms of the disease under continued treatment

In patients withhellipDMOhellip initially three or more consecutive monthly injections may be needed Thereafter monitoring and treatment intervals

should be determined by the physician and should be based on disease activity as

assessed by VA andor anatomical parametershellip

If patients are being treated according to a treat-and-extend regimen once maximum VA is achieved andor there are no

signs of disease activity the treatment intervals can be extended stepwise until signs of

disease activity or visual impairment recur The treatment intervalhellipmay be extended by up to one month

at a time for DMOrdquo

1 Novartis Pharmaceuticals UK Ltd 30 October 2014 Available at httpwwwmedicinesorgukemcmedicine19409 Accessed 04 September 2015

2 Bayer Pharma AG February 2015 Available at httpwwwmedicinesorgukemcmedicine27224 Accessed 04 September 2015

Ranibizumab1 Aflibercept2

ldquohelliptreatment is initiated with one injection per month for five consecutive doses followed by

one injection every two months There is no requirement for monitoring between injectionshellip

After the first 12 months of treatmenthellipthe treatment interval may be extended based

on visual andor anatomic outcomes The schedule for monitoring should

be determined by the treating physicianrdquo

DMO diabetic macular oedema VA visual acuity

Re-treatment algorithms for anti-VEGF agents in DMO

bull LOADING PHASE

bull Lucentis label = monthly until stability

bull Eylea label = 5 x 112 then every 8 weeks ie fixed regime year 1

bull DRCRnet protocol T = effectively 6 x112 for majority (95) BUT actually only mandated for first 3 months then prn

bull helliphellip likely that majority will receive injections monthly for first 6 months

bull INDIVIDUALISED PHASE

bull Once ldquostablerdquo ndash based on VA and OCT

bull NB May never get a ldquodryrdquo OCT so treat to stability

bull THEN

bull Treat and extend

bull prn

What does Treat and Extend mean

Pathway overview = Lucentis prn

Jan

Loading phase = injections every 4 weeks until ldquostablerdquo for 3 visits

helliphelliphellip

Feb OctSepAugJulJunMayAprMar

MarFebJan

DecNov

DecNovOctSepAugJulJunMayApr

Then observe UNTIL VA decreases or OCT increase = prn

Once reactivates need at least 2 injections until stable again over 3 visits

Pathway overview = Treat and Extend

Jan

Loading phase = injections every 4 weeks until ldquostablerdquo for 3 visits or Eyleayear 1

helliphelliphellip

Feb OctSepAugJulJunMayAprMar

MarFebJan

DecNov

DecNovOctSepAugJulJunMayApr

Then keep injecting but extend the interval between injections gradually ie keep treating even if perfect

If reactivates need at least 2 injections until stable again over 3 visits

Pathway overview = Eylea fixed dosing year 1

Jan

Eylea = 5 x 112 injection then every 8 weeks

Average 6 injections yr 2 Beyond that

helliphelliphellip

Feb OctSepAugJulJunMayAprMar

MarFebJan

DecNov

DecNovOctSepAugJulJunMayApr

Then individualised UNTIL VA decreases or OCT increase = prn

Once reactivates need at least 2 injections until stable again over 3 visits

Pros and cons of Treat and Extend vs Prn

T+E PRN

PROS bull Proactive patient and service get advance warning of injection ndash capacity and demand planning easier

bull One ndashstopbull Fewer visits than prnbull Overtreatment

advantageous for peripheral retinopathy

bull Only treated when active ieno overtreatment

bull Aggressive year 1 protocols (DRCRN I ndash few injections needed thereafter

bull DMO tolerant of reactivations ()

CONS bull Overtreatment = riskexpenseinconvenience

bull Evidence base scantbull Bilateral disease tricky

bull Reactive so need enoughemergency capacity to inject when disease flares up

bull No advance warning to patientservice that injection needed

bull NEED TO DO IT WELL ndashNHS real life audits prn based regimes not good resultsUndertreatment in year 1 Affects long term prognosis and treatment burden

Pros and cons of Treat and Extend vs Prn

T+E PRN

PROS bull Proactive patient and service get advance warning of injection ndash capacity and demand planning easier

bull One ndashstopbull Fewer visits than prnbull Overtreatment

advantageous for peripheral retinopathy

bull Only treated when active ieno overtreatment

bull Aggressive year 1 protocols (DRCRN I ndash few injections needed thereafter

bull DMO tolerant of reactivations ()

CONS bull Overtreatment = riskexpenseinconvenience

bull Evidence base scantbull Bilateral disease tricky

bull Reactive so need enoughemergency capacity to inject when disease flares up

bull No advance warning to patientservice that injection needed

bull NEED TO DO IT WELL ndashNHS real life audits prn based regimes not good resultsUndertreatment in year 1 Affects long term prognosis and treatment burden

DMO ndash anti-VEGF Treat and Extend

bull Retain study ndash the only RCT data

bull Br J Ophthalmol 2015 Oct 9 pii bjophthalmol-2015-307249 doi 101136bjophthalmol-2015-307249 [Epub ahead of print]

bull Ranibizumab 05 mg treat-and-extend regimen for diabetic macular oedema the RETAIN study

bull Pruumlnte C1 Fajnkuchen F2 Mahmood S3 Ricci F4 Hatz K5 Studnička J6 Bezlyak V7 Parikh S7 Stubbings WJ7 Wenzel A7 Figueira J8 and the RETAIN Study Group

RETAIN Phase III trial evaluating the efficacy of lsquotreat and extendrsquo regimen (ARVO 2014)

bull Patients with DMO and visual impairment (n = 372) were randomised 111

to one of three groups for 24 months

bull Two phases to dosing schedule

bull Phase A

bull Patients in all groups were initially treated with monthly ranibizumab until BCVA remained

stable

bull Phase B

bull Patients in the TampE groups whose vision remained stable had treatment- free intervals

that were increased incrementally by 1 month for a maximum of 3 months

bull Patients in the PRN group had ongoing monthly monitoring

bull In all groups Phase A was resumed if a decrease in BCVA was observed at a visit

Ranibizumab 05 mg monotherapy

in TampE regimen

Ranibizumab 05 mg in TampE regimen

plus laser

Ranibizumab 05 mg PRN

35

RETAIN Visual acuity endpoints

Pruumlnte C ARVO 2014 Annual Meeting Abstracts Abstract 1700

Mean average change in BCVAat 12 months (primary endpoint)

Mean change in BCVA at 24 months

Mea

n av

erag

e ch

ange

in B

CVA

(ETD

RS

lette

rs)

RanibizumabTampE

RanibizumabTampE + laser

RanibizumabPRN

RanibizumabTampE

RanibizumabTampE + laser

RanibizumabPRN

Mea

n ch

ange

in B

CVA

(ETD

RS

lette

rs)

plt00001 for both ranibizumab TampE groups versus PRN for primary endpoint

36

RETAIN Patient visits and monitoring with TampE regimen over 24 months

bull The TampE regimen provided an approximately 40 reduction in the number of treatment visits required compared with the ranibizumab PRN regimen

bull Approximately 70 of patients receiving TampE regimens had monitoring intervals ge2 months compared with ongoing monthly monitoring in the ranibizumab PRN group

bull Informed the license for Lucentis in DMO (extend by 1 month at a time)

37

INTRAVITREAL STEROIDSWhich intravitreal steroid is better

bull Licensed steroids ndash Ozurdex (Dexamethasone) and Iluvien (Fluocinoloneacetonide

bull Which steroid is best in terms of VA outcomes hellipWE DONrsquoT KNOW FOR SURE ndash no head to head studies for licensed drugs either between steroids or between anti-VEGF and steroids

bull STEROIDS ARE efficacious in DMO

bull MEAD

bull FAME

bull DRCRnet protocol I

bull NICE ndash Ozurdex and Iluvien ndash second-line agents

Ozurdex

bull A biodegradable co-polymer implant ndash degrades in time to lactic and glycolic acid releasing Dexamethasone

bull 22gauge injectionbull MEAD study

bull N=1048

bull Dex 07mg vs 035mg vs sham

bull No rescue therapy

bull 3 year follow up max 6 monthly dosing ie 7 over 3 years

Gan IM et al Greafes Acrh Clin Exp Ophthalmol 2005

MEAD studyMean BCVA change from baseline based on baseline lens status

-2

0

2

4

6

8

10

0 3 6 9 12 15 18 21 24 27 30 33 36 39

Mea

n C

hang

e Fr

om

Bas

elin

e B

CVA

(Let

ters

)

Month

DEX Implant 07 mg (n = 86)

Sham (n = 101)

Boyer DS et al Ophthalmology 20141211904ndash14

Results analyzed in the ITT population with LOCF for missing values

Pseudophakic

Total

0

5

10

0 3 6 9 12 15 18 21 24 27 30 33 36 39

DEX 700 (n=351)

Sham (n=350)

10

8

6

4

2

0

Mea

n C

hang

e fr

om

Bas

elin

e B

CVA

(Let

ters

)

Month

07mg dose is approved as Ozurdexreg by the FDA and EMA 035mg dose not commercially available

1 Boyer DS et al Ophthalmology 2014 121 1904-1914

bull Nonbioerodible micro implant (polyimide) containing 190microg of fluocinolone acetonide (FAc)

bull Consistent daily submicrogram delivery of 02 microgd FAc for up to 36 months

bull Posterior point of release

bull 35 mm times 037 mm non-bioerodable micro implant

bull 25-gauge injector creates self-sealing wound

bull No measurable systemic exposure

ILUVIEN Implant Technology

FAcimplant

ILUVIEN SPC httpwwwmedicinesorgukemcmedicine27636

0 6 12 18 24 30 36

ILUVIEN 02 microgd FAc(n = 376)05 microgd FAc (n = 395)Control sham injection(n = 185)

Design of Phase 3 FAME Study (FAME A and B = same protocol)

Additional laser therapy allowed after week 6a

Retreatment any time after month 12 (if eligibleb)

Study ends

N = 956Randomisation

221Primary readout

Patients with DMO and

bull At least 1 previous laser tx

bull BCVA ge19 and le68 letters

bull TD-OCT FTH ge250 μm

Month

BCVA = best corrected visual acuity DMO = diabetic macular oedema TD-OCT=time domain optical coherence tomography FTH = foveal thicknessa At masked investigatorrsquos discretion b If BCVA loss ge5 letters or retinal thickening ge50 microm from best reading in previous 12 months

ge15 letter Gain is Greater in Chronic DMO Patients

ge 15

-Let

ter I

mpr

ovem

ent

in B

CVA

Fro

m B

asel

ine

Δ = 98

Months

Full Population Patients With Chronic DMO

Months

Δ = 206

287

189134

34

Steroid re-treatments

bullOzurdexbull Longer half-life than anti-VEGF in the eye

bull Redosing regimes not very helpful from RCT data eg MEAD study only 612 dosing

bull In reality re-treatment interval may be shorter

bull POSOLOGY

bull Patients treated with OZURDEX who have experienced an initial response and in the physicians opinion may benefit from retreatment without being exposed to significant risk should be considered for retreatment Retreatment may be performed after approximately 6 months if the patient experiences decreased vision andor an increase in retinal thickness secondary to recurrent or worsening diabetic macular oedema

bullIluvienbull 70 of patients in FAE only needed 1

injection over 3 years

bull BUT additional rescue treatments allowed

bull POSOLOGY

bull Each ILUVIEN implant releases fluocinolone acetonide for up to 36 months An additional implant may be administered after 12 months if the patient experiences decreased vision or an increase in retinal thickness secondary to recurrent or worsening diabetic macular oedema

bull Patients receiving escape medication were exited from MEAD before administration1

bull Macular laser rescue treatment allowed in RISERIDE (Lucentisreg) from 3 months2

bull Focalgrid laser allowed in FAME (Iluvienreg) from 6 weeks3

MEAD TREATMENT PROTOCOL

bull First treatment given at randomisation (day 0) bull Patients assessed for retreatment eligibility every 3 months from

months 6ndash36bull Patients were eligible for retreatment if

OCT optical coherence tomography

ge6 months since most recent

study treatment

Retinal thickness in 1 mm central macular

subfield by OCT gt175 microm

Evidence of residual retinal oedema (intraretinal cysts or

any regions of increased retinal thickening) as assessed by

investigator from OCT

AND OR

MEA

D

Amendment in May 2010 revised anatomic criterion for retreatment before this time the threshold was gt225 microm1Boyer DS et al Ophthalmology 2014 121 1904-19142Nguyen QD et al Ophthalmology 20121191064minus10773Campochiaro PA et al Ophthalmology 2011118626ndash635

Treatment burdenILUVIEN

Control(n =112)

02 microgd FAc(n =209)

Study Treatments(sham injection or ILUVIEN 02 microgday or FAc 05microgday)

1 treatment 661 761

2 treatments 277 187

ge 3 treatments 63 53

Rescue Laser Treatments (at masked physicianrsquos discretion after week 6)

Patients 607 407

Off-Protocol Treatments (IVTA bevacizumab ranibizumab intravitreal dexamethasone)

Patients 295 115

OZURDEX = 23injections year 1 41 by year 3

No other Rx

Summary of side effects with intravitreal steroids

Drug device Evidence base Cataract risk IOP rise (requiring drops)

Glaucoma surgery

endophthalmitis

ILUVIEN FAME studies 80 cat surgery(273 sham)

384(14 control)

48 0

Ozurdex MEAD 592 had cataract surgery(72 sham)

215 (end of study)(34 sham)

06 0

Trivaris+ laser vs Luc+laserx2 vs laser

Protocol IOphthalmology 2010

15 42(ONE OFgt10mmHg risegt30mmHGStart drops)

2186 0

NICE guidance for intravitreal steroids in DMO

bull Iluvien

bull NICE TA 301 Iluvien for DMO Nov 2013

bull hellipfor treating chronic diabetic macular oedema that is insufficiently responsive to available therapies only if

bull the implant is to be used in an eye with an intraocular

(pseudophakic) lens and

bull the manufacturer provides fluocinolone acetonide intravitreal implant with the discount agreed in the patient access scheme

NICE guidance for intravitreal steroids in DMO

bull Ozurdex

bull NICE TA 349 Ozurdex for DMO July 2015

bull there is an artificial lens in the eye to be treated and

bull their diabetic macular oedema has not improved with

non-corticosteroid treatment or such treatment is not suitable for them

Steroids = second line therapyWhen do I switch

bull Anti-VEGF first line for centre involving DMObull NICE TA ndash ldquoinsufficiently responsiverdquo ldquo ldquonot improvedrdquo ldquonot suitablerdquo ndash

OTHER TREATMENTS

bull 2 scenariosbull 1) Anti-VEGF canrsquot be funded ie OCTlt400um + PSEUDOPHAKIC

bull 2) Already had a course of treatment with laseranti-VEGF + PSEUDOPHAKIC ie SWITCHING from anti-VEGF to steroid

bull Plus

bull ldquochronicrdquo DMO ndash 3 years duration in FAME (18months) for ILUVIEN

bull Chronic DMO not essential for Ozurdex

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

Protocol T ndash patients may not improve in first 6 months

RIDE

RISE

Mea

n ch

ange

in B

CVA

(E

TDR

S le

tters

)M

ean

chan

ge in

BC

VA

(ETD

RS

lette

rs)

Time (months)

RISE and RIDE (Lucentis monthly dosing) Mean change in BCVA over 36 months

Brown DM et al Ophthalmology 2013120(10)2013ndash2022

54

Ranibizumab 03 mgRanibizumab 05 mgShamranibizumab 05 mg

Date of Prep Dec 2014 LGB0820147252X

VA improvement continues throughout year 1 with monthly dosing

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user ndash more than protocol

I

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

DRCRN protocol I5 year outcomesInjections 8-9 in year 1Year 2 = 2-3Year 3= 1-2Year 4 = 0-1Year 5 = 0

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

Wait for plateau = stability in protocol T laserPatient factors again

Judgement of response to anti-VEGF ndashtimeframe

bull Wait 6 months in poor responders

bull Wait 1 year for heavy users

bull Tempting to try steroids earlier than this ifbull No glaucoma ndash not a deal breaker Ozurdex better short term optionbull Pseudophakic

bull Clues from the diseasebull chronic

bull PATIENT FACTORS

bull Any eyes avoid steroids ndash advanced glaucomaCSCR Or prior viral retinitis RARE

bull Any eyes avoid anti-VEGF pregnancytrying to concieve recent CVA

BIOMARKERS AT BASELINE WOULD BE USEFULRESTORE subgroup analysis of OCT features

bull Andreas Pollreisz EURETINA 2015

bull OCT biomarkers (RESTORE data)

bull Better effects with anti-VEGF ifbull Small rather than large intra-retinal cyst

bull Sub-retinal fluid present

bull Vitreo-macular adhesion at baseline

bull No disruption of ELM and ISOS junction

bull No disorganisation of inner retinal layers (DRIL)

RESTORE subgroup analysis of OCT features

bull Andreas Pollreisz EURETINA 2015

bull OCT biomarkers (RESTORE data)

bull Better effects with anti-VEGF ifbull Small rather than large intra-retinal cyst

bull Sub-retinal fluid present

bull Vitreo-macular adhesion at baseline

bull No disruption of ELM and ISOS junction

bull No disorganisation of inner retinal layers (DRIL)

Better baseline characterisationclassificationERG Contrast sensitivityOCT AngiographyMicroperimetry= clues as to who responds best to which drug

Plan for this presentation helliphellipa long list

bull What treatment options are available for DMO (evidence base)

bull What treatment should I start with at baselinebull Re-treatment algorithms for intravitreal DMO therapiesbull When should I switchcombine therapiesbull The bigger picture

bull Other eyebull The patient as a wholebull The service -coping with capacity ndash compromises

The bigger pictureOther eyeThe patient as a wholeThe service -coping with capacity ndash compromises

bull OTHER EYE ndash may create problems

bull Treat and extend ndash ldquoreduce of visitsrdquo plus Eylea license ndash ldquono need for monitoringrdquo may not benefit if lots of visits due to PDR other eye

bull PERIPHERAL RETINA anti-VEGF supresses proliferative disease - Rebound on stopping Rx

bull PATIENT

bull Anti-VEGF ndash heavy user - Will comply

bull One stop much better than two stop for patient ndash Treat and extend

bull SERVICE

bull Capacity and demand planning = fixedT+E more predictable at least 1 month in advance ndash flexible nurse injectors

bull Steroids ndash even if well controlled (Iluvien for 3 years) need IOP check

bull Need pan-retinal examination both eyes ndash separate visits

Summary

CSMO

No centre involvement

Photocoagulation

Centre involvement

gt 78 letters(normalminimally reduced VA)

Photocoagulation

VA 78ndash24 letters

Phakic

Anti-VEGF

Pseudophakic

Anti-VEGF

SWITCHglaucoma

Injection tolerance

Medical issuesrecent CVA

Peripheral diseaseBilateral Rx

CSMO

No centre involvement

LASER

Centre involvement

gt 78 letters(normalminimally

reduced VA)

VA 78ndash24 letters

EYLEA OR LUCENTIS OR AVASTIN

Funding issues

Protocol T ndash poor VA lt 65 letters (615)

LOADING

Monthly injections until stability OR 5 x 112 (EYLEA) = 6 MONTHS then 8 weeks

RETREATMENT1

TREAT AND EXTEND - PRN

PRN

PSEUDOPHAKIC

Prior Rx

ILUVIEN

Chronic disease

OZURDEX

RETREATMENT

OZURDEX

OCT gt175um or any residual oedema

ILUVIEN after 12 months if risksltbenefits

OCT

gt400um

bull FACE TO FACE CLINICS RUNNING IN PARALLEL

bull = MAC002 every 6 months (optom or doctor) routine check for cataracttolerance of injectionsglaucoma issues etc

bull =MAC003 (DOCTOR) for problems as needed no fixed intervalDischargestop treatmentDeclines treatment diagnosis CSR overlay etcswitch drugs

bull =RV002- (DOCTOR) every 6 months

bull =DM002 ndash (DOCTOR) variable interval determined by last assessing doctor

bull First visit at 6 months from 1st injection if mild NPDR

bull Otherwise determined by retinopathy generally

LOADING PHASE

EyleaLucentis 1 within 48hrs of baseline

EyleaLucentis 2 (and LogMAR VA plus OCT same visit)

EyleaLucentis 3 (and LogMAR VA plus OCT same visit)

EyleaLucentis 4 (TEinj)(and Logmar VA plus OCT same visit

AFTER INJECTION 4 data goes off to be reviewed immediately as a hellip

TREAT AND EXTEND assessment ndash the next interval will depend on the response to the loading phase

NB -DMO patients ndash majority (95) will need 6 injctions x 112 of Lucentis

OR Eylea 5 x 112 then 8 weekly

ONCE STABLE for 3 x injection in TE phase

VIRTUAL CLINIC MONITORING OF MACULOPATHY AND PRN RETREATMENT

ANTI-VEGF INJECTION PATHWAYS Baseline visitMAC001 for wet AMDRV001 for CRVOBRVOMed ret clinic for DMO

Pathways ndash too many directions

Better that thanhellip

Thank you

DMO ndash treatment options1)What treatments should I use at baseline

bull ETDRS based laser therapies

bull ADJUNCT

bull Surgery ndash VMTERM

bull Pan-retinal photocoagulation

bull INTRAVITREAL

bull ANTI-VEGF

bull Lucentis (Ranibizumab)

bull Eylea (Aflibercept)

bull Avastin (Bevacizumab)

bull STEROIDS

bull Iluvien (Fluocinolone)

bull Ozurdex (Dexamethasone)

RCO recommendations for the treatment of CSMO

The Royal College of Ophthalmologists Diabetic Retinopathy Guidelines 2012

CSMO

No centre involvement

Photocoagulation

Centre involvement

gt 78 letters(normalminimally reduced VA)

Photocoagulation

VA 78ndash24 letters

Phakic

Anti-VEGF

Pseudophakic

Anti-VEGF

Fluocinolone is an option for eyes unresponsive to other treatments but potential side effects must be considered Triamcinolone +- adjunctive laser or fluocinolone may be considered for eyes unresponsive to other treatments

6

ETDRS based laser therapies = Clinically significant macular oedema (CSMO)

bull The ETDRS defined CSMO as DMO that threatens the centre of the macula (fovea)1 and forms the basis of current recommendations for the treatment of CSMO2

bull CSMO is diagnosed if any of the following parameters are met1

1 ETDRS Research Group Arch Ophthalmol 19851031796ndash1806 2 Bandello F et al Eye (Lond) 201226(4)485ndash493

1 Retinal thickening within 500 microm of the centre of the macula

2 Hard exudates within 500 microm of the centre of the macula if associated with thickening of the adjacent retina

3 Retinal thickening of gt1 disc area in size any part of which is located within 1 disc diameter of the centre of the macula

500 microm

500 microm

1 discdiameter

ge 1 discdiameter

Fovea

7

ETDRS = Early Treatment Diabetic Retinopathy Study

Date of Prep Jan 2015 LGB0820157252f

DMO ndash treatment optionsWhat treatments should I use at baseline

ETDRS based laser therapies = Clinically significant macular oedema (CSMO)

bull The ETDRS defined CSMO as DMO that threatens the centre of the macula (fovea)1 and forms the basis of current recommendations for the treatment of CSMO2

bull CSMO is diagnosed if any of the following parameters are met1

1 ETDRS Research Group Arch Ophthalmol 19851031796ndash1806 2 Bandello F et al Eye (Lond) 201226(4)485ndash493

1 Retinal thickening within 500 microm of the centre of the macula

2 Hard exudates within 500 microm of the centre of the macula if associated with thickening of the adjacent retina

3 Retinal thickening of gt1 disc area in size any part of which is located within 1 disc diameter of the centre of the macula

500 microm

500 microm

1 discdiameter

ge 1 discdiameter

Fovea

8

ETDRS = Early Treatment Diabetic Retinopathy Study

LASER

RCO recommendations for the treatment of CSMO

The Royal College of Ophthalmologists Diabetic Retinopathy Guidelines 2012

CSMO

No centre involvement

Photocoagulation

Centre involvement

gt 78 letters(normalminimally reduced VA)

Photocoagulation

VA 78ndash24 letters

Phakic

Anti-VEGF

Pseudophakic

Anti-VEGF

9

ILUVIEN (chronicunresponsive)

OZURXEX (no improvement)

DMO ndash treatment optionsWhat treatments should I use at baseline

bull ETDRS based laser therapies

bull ADJUNCT

bull Surgery ndash VMTERM

bull Pan-retinal photocoagulation

bull INTRAVITREAL

bull ANTI-VEGF

bull Lucentis (Ranibizumab)

bull Eylea (Aflibercept)

bull Avastin (Bevacizumab)

bull STEROIDS

bull Iluvien (Fluocinolone)

bull Ozurdex (Dexamethasone)

11

BOLT

RESOLVERISE and RIDERELIGHT

DA VINCI

VIVID and VISTA

vs laser

vs sham

Steroids

(in combination

with laser)

Anti-VEGF

(in combination

with laser)

DRCRnet (Protocol I)

ETDRS

READ-2

RESTORE

RETAIN

REVEAL

DRCRnet (Protocol B)

FAMEMEAD

vs laser

vs sham

RanibizumabAflibercept

Bevacizumab

Triamcinolone

Fluocinolone acetonide Dexamethasone

Anti-VEGF Laser Steroids

DRCRnet PROTOCOL T

DMO ndash treatment optionsWhat treatments should I use at baseline ndash based on evidence from RCT data

What therapy do I choose for my patient at baselineWhich treatments can I access

NICE TA 274 Lucentis for DMO April 2013NICE TA 346 Eylea for DMO July 2015

NICE TA 301 Iluvien for DMO Nov 2013NICE TA 349 Ozurdex for DMO July 2015

OCT gt400um1st line if OCT suitable

bull Chronic DMObull PSEUDOPHAKICbull Patients ldquoinsufficiently responsive

to existing therapiesrdquo

bull PSEUDOPHAKICbull ldquoNot improved with non-

corticosteroid or such treatment is not suitable for themrdquo

What therapy do I choose for my patient at baseline

bull ANTI-VEGF

bull Superior to ETDRS argon laser in terms of efficacy

RESTORE 36 month Lucentis prn extension studyLucentis monotherapy vs Lucentis plus laser vs laser aloneSchmidt-Erfuth U et al Ophthalmology 2014 121(5) 1045-1053

23

Months

12

10

8

6

4

2

0

minus22 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36

Extension study (ranibizumab 05 mg PRN)Core study

Me

an o

f th

e c

han

ge in

ETD

RS

BC

VA

Prior ranibizumab 05 mg + active laser (n=83)

Prior sham injections + active laser (n=74)

Prior ranibizumab 05 mg + sham laser (n=83)

79

71 606780

Core study assessment

Full analysisstudy completionInterim analysis

RIDE

RISE

Mea

n ch

ange

in B

CVA

(E

TDR

S le

tters

)M

ean

chan

ge in

BC

VA

(ETD

RS

lette

rs)

Time (months)

RISE and RIDE (Lucentis monthly dosing) Mean change in BCVA over 36 months

Brown DM et al Ophthalmology 2013120(10)2013ndash2022

15

Ranibizumab 03 mgRanibizumab 05 mgShamranibizumab 05 mg

RISE amp RIDE

Date of Prep Dec 2014 LGB0820147252X

02 Laser

125 2q4

107 2q8

0

Mea

n ch

ange

in B

CVA

lette

r sco

re

2

101214

02

6

10

14

4

8

12

468

09 Laser

115 2q4

111 2q8

VISTA Week 100

100928068645652403628201240 8 16 24 32 44 48 60 72 76 84 88 96

12 Laser

100928068645652403628201240 8 16 24 32 44 48 60 72 76 84 88 96

105 2q4

107 2q8VIVID Week 100

Week Laser 2q4 2q8

07 Laser

114 2q4

94 2q8

Eylea =VIVID and VISTA Mean change in BCVA to week 100Korobelnik J-F et al Ophthalmology 2014 121 (11) 2247ndash2254 Brown DM et al Ophthalmology 2015 Jul 18 [Epub ahead of print]

Plt00001 vs laser VIVID Laser n=132 2q4 n=136 2q8 n=135 VISTA Laser n=154 2q4 n=154 2q8 n=151Full analysis set 2q4 2 mg every 4 weeks 2q8 2 mg every 8 weeks BCVA best corrected visual acuity ETDRS Early Treatment Diabetic Retinopathy Study

What therapy do I choose for my patient at baseline

bull ANTI-VEGF helliphellipif OCT gt 400um

bull Sohellip Which one

Key trials in DMO

18

BOLT

RESOLVERISE and RIDE

DA VINCI

VIVID and VISTA

vs laser

vs sham

Steroids

(in combination

with laser)

Anti-VEGF

(in combination

with laser)

DRCRnet (Protocol I)

ETDRS

READ-2

RESTORE

RETAIN

REVEAL

DRCRnet (Protocol B)

FAMEMEAD

vs laser

vs sham

RanibizumabAflibercept

Bevacizumab

Triamcinolone

Fluocinolone acetonide Dexamethasone

Anti-VEGF Laser Steroids

DRCRnet PROTOCOL T

PROTOCOL T (DRCRnet)

bull Aflibercept Bevacizumab or Ranibizumab for Diabetic Macular Edema

bull N Engl J Med 2015 Mar 26372(13)1193-203

The Diabetic retinopathy Clinical Research Network February 18 2015

USA study NIHR funded

n=660

Lucentis 03mg not 05mg Eylea 2mg Avastin 125mg

Eylea protocol not the licensed regime

Avastin unlicensed

RETREATMENT protocol

First 6 months ndash inject every month 95 of patients UNLESS VA=66 AND OCT DRY

Then 2nd six months ndash if no change after 3 visits DEFER otherwise keep injecting monthly

Recurs ndash need at least 2 injections ie 3 months of stability

STABILITY = 10 Oct change or VA 5 letter change

STABILITY and residual OCT thickness gt250um LASER

Protocol T 1 year visual acuity outcomes

0

5

10

15

20

0 8 16 24 32 40 48

Visit Week

2032-2040 = 696 ndash 612= 78-69

0

5

10

15

20

0 8 16 24 32 40 48

Visit Week

2050 = 615 or worse = lt69

Mea

n ch

ange

in B

CV

A

Mea

n ch

ange

in B

CV

A

Aflibercept Bevacizumab Ranibizumab

+189

+142

+118+75

+8+83

Protocol T OCT outcomes year 1

-250

-200

-150

-100

-50

0

0 4 8 12 16 20 24 28 32 36 40 44 48 52

Visit Week

Aflibercept Bevacizumab Ranibizumab

Mea

n ch

ange

in C

ST

Conclusions ndash Protocol T year 1 data

bull Eylea was statistically superior in terms of visual acuity to 03mg Lucentisand to Avastin FOR PATIENTS WITH VA worse than 69 letters

bull Eylea and Lucentis were statistically superior in terms of OCT CRT reduction to Avastin for all patients regardless of baseline vision

bull No safety differences between the three drugs

SUMMARY What do I choose for my patient at baselineOCT central retinal thickness (CRT)PseudophakicAttempts at prior treatment duration of DMO

bull lt 400um

bull IFR licensed anti-VEGF or Avastin

+-ETDRS laser

PSEUDOPHAKIC

Iluvien

Ozurdex

bull gt 400um = Anti-VEGF

Which one

Depends on

bull baseline vision lt615 Eylea

bull Fixed dosing attractive (Eylea)bull Chronic DMO

bull PSEUDOPHAKICbull Patients ldquoinsufficiently

responsive to existing therapiesrdquo

bull ldquoNot improved with non-corticosteroid or such treatment is not suitable for themrdquo

Which steroid ndash Ozurdex or Iluvien

bull No head to head data

bull Revisit this when we think about switching from ANTI-VEGF to steroid

Assuming we have started with an anti-VEGF agent ndash what are the re-treatment algorithms in DMO

Treatment posologies

ldquoTreatment is initiated with one injection per month until maximum VA is achieved andor there are no signs of disease activity ie no change in VA and in other signs and

symptoms of the disease under continued treatment

In patients withhellipDMOhellip initially three or more consecutive monthly injections may be needed Thereafter monitoring and treatment intervals

should be determined by the physician and should be based on disease activity as

assessed by VA andor anatomical parametershellip

If patients are being treated according to a treat-and-extend regimen once maximum VA is achieved andor there are no

signs of disease activity the treatment intervals can be extended stepwise until signs of

disease activity or visual impairment recur The treatment intervalhellipmay be extended by up to one month

at a time for DMOrdquo

1 Novartis Pharmaceuticals UK Ltd 30 October 2014 Available at httpwwwmedicinesorgukemcmedicine19409 Accessed 04 September 2015

2 Bayer Pharma AG February 2015 Available at httpwwwmedicinesorgukemcmedicine27224 Accessed 04 September 2015

Ranibizumab1 Aflibercept2

ldquohelliptreatment is initiated with one injection per month for five consecutive doses followed by

one injection every two months There is no requirement for monitoring between injectionshellip

After the first 12 months of treatmenthellipthe treatment interval may be extended based

on visual andor anatomic outcomes The schedule for monitoring should

be determined by the treating physicianrdquo

DMO diabetic macular oedema VA visual acuity

Re-treatment algorithms for anti-VEGF agents in DMO

bull LOADING PHASE

bull Lucentis label = monthly until stability

bull Eylea label = 5 x 112 then every 8 weeks ie fixed regime year 1

bull DRCRnet protocol T = effectively 6 x112 for majority (95) BUT actually only mandated for first 3 months then prn

bull helliphellip likely that majority will receive injections monthly for first 6 months

bull INDIVIDUALISED PHASE

bull Once ldquostablerdquo ndash based on VA and OCT

bull NB May never get a ldquodryrdquo OCT so treat to stability

bull THEN

bull Treat and extend

bull prn

What does Treat and Extend mean

Pathway overview = Lucentis prn

Jan

Loading phase = injections every 4 weeks until ldquostablerdquo for 3 visits

helliphelliphellip

Feb OctSepAugJulJunMayAprMar

MarFebJan

DecNov

DecNovOctSepAugJulJunMayApr

Then observe UNTIL VA decreases or OCT increase = prn

Once reactivates need at least 2 injections until stable again over 3 visits

Pathway overview = Treat and Extend

Jan

Loading phase = injections every 4 weeks until ldquostablerdquo for 3 visits or Eyleayear 1

helliphelliphellip

Feb OctSepAugJulJunMayAprMar

MarFebJan

DecNov

DecNovOctSepAugJulJunMayApr

Then keep injecting but extend the interval between injections gradually ie keep treating even if perfect

If reactivates need at least 2 injections until stable again over 3 visits

Pathway overview = Eylea fixed dosing year 1

Jan

Eylea = 5 x 112 injection then every 8 weeks

Average 6 injections yr 2 Beyond that

helliphelliphellip

Feb OctSepAugJulJunMayAprMar

MarFebJan

DecNov

DecNovOctSepAugJulJunMayApr

Then individualised UNTIL VA decreases or OCT increase = prn

Once reactivates need at least 2 injections until stable again over 3 visits

Pros and cons of Treat and Extend vs Prn

T+E PRN

PROS bull Proactive patient and service get advance warning of injection ndash capacity and demand planning easier

bull One ndashstopbull Fewer visits than prnbull Overtreatment

advantageous for peripheral retinopathy

bull Only treated when active ieno overtreatment

bull Aggressive year 1 protocols (DRCRN I ndash few injections needed thereafter

bull DMO tolerant of reactivations ()

CONS bull Overtreatment = riskexpenseinconvenience

bull Evidence base scantbull Bilateral disease tricky

bull Reactive so need enoughemergency capacity to inject when disease flares up

bull No advance warning to patientservice that injection needed

bull NEED TO DO IT WELL ndashNHS real life audits prn based regimes not good resultsUndertreatment in year 1 Affects long term prognosis and treatment burden

Pros and cons of Treat and Extend vs Prn

T+E PRN

PROS bull Proactive patient and service get advance warning of injection ndash capacity and demand planning easier

bull One ndashstopbull Fewer visits than prnbull Overtreatment

advantageous for peripheral retinopathy

bull Only treated when active ieno overtreatment

bull Aggressive year 1 protocols (DRCRN I ndash few injections needed thereafter

bull DMO tolerant of reactivations ()

CONS bull Overtreatment = riskexpenseinconvenience

bull Evidence base scantbull Bilateral disease tricky

bull Reactive so need enoughemergency capacity to inject when disease flares up

bull No advance warning to patientservice that injection needed

bull NEED TO DO IT WELL ndashNHS real life audits prn based regimes not good resultsUndertreatment in year 1 Affects long term prognosis and treatment burden

DMO ndash anti-VEGF Treat and Extend

bull Retain study ndash the only RCT data

bull Br J Ophthalmol 2015 Oct 9 pii bjophthalmol-2015-307249 doi 101136bjophthalmol-2015-307249 [Epub ahead of print]

bull Ranibizumab 05 mg treat-and-extend regimen for diabetic macular oedema the RETAIN study

bull Pruumlnte C1 Fajnkuchen F2 Mahmood S3 Ricci F4 Hatz K5 Studnička J6 Bezlyak V7 Parikh S7 Stubbings WJ7 Wenzel A7 Figueira J8 and the RETAIN Study Group

RETAIN Phase III trial evaluating the efficacy of lsquotreat and extendrsquo regimen (ARVO 2014)

bull Patients with DMO and visual impairment (n = 372) were randomised 111

to one of three groups for 24 months

bull Two phases to dosing schedule

bull Phase A

bull Patients in all groups were initially treated with monthly ranibizumab until BCVA remained

stable

bull Phase B

bull Patients in the TampE groups whose vision remained stable had treatment- free intervals

that were increased incrementally by 1 month for a maximum of 3 months

bull Patients in the PRN group had ongoing monthly monitoring

bull In all groups Phase A was resumed if a decrease in BCVA was observed at a visit

Ranibizumab 05 mg monotherapy

in TampE regimen

Ranibizumab 05 mg in TampE regimen

plus laser

Ranibizumab 05 mg PRN

35

RETAIN Visual acuity endpoints

Pruumlnte C ARVO 2014 Annual Meeting Abstracts Abstract 1700

Mean average change in BCVAat 12 months (primary endpoint)

Mean change in BCVA at 24 months

Mea

n av

erag

e ch

ange

in B

CVA

(ETD

RS

lette

rs)

RanibizumabTampE

RanibizumabTampE + laser

RanibizumabPRN

RanibizumabTampE

RanibizumabTampE + laser

RanibizumabPRN

Mea

n ch

ange

in B

CVA

(ETD

RS

lette

rs)

plt00001 for both ranibizumab TampE groups versus PRN for primary endpoint

36

RETAIN Patient visits and monitoring with TampE regimen over 24 months

bull The TampE regimen provided an approximately 40 reduction in the number of treatment visits required compared with the ranibizumab PRN regimen

bull Approximately 70 of patients receiving TampE regimens had monitoring intervals ge2 months compared with ongoing monthly monitoring in the ranibizumab PRN group

bull Informed the license for Lucentis in DMO (extend by 1 month at a time)

37

INTRAVITREAL STEROIDSWhich intravitreal steroid is better

bull Licensed steroids ndash Ozurdex (Dexamethasone) and Iluvien (Fluocinoloneacetonide

bull Which steroid is best in terms of VA outcomes hellipWE DONrsquoT KNOW FOR SURE ndash no head to head studies for licensed drugs either between steroids or between anti-VEGF and steroids

bull STEROIDS ARE efficacious in DMO

bull MEAD

bull FAME

bull DRCRnet protocol I

bull NICE ndash Ozurdex and Iluvien ndash second-line agents

Ozurdex

bull A biodegradable co-polymer implant ndash degrades in time to lactic and glycolic acid releasing Dexamethasone

bull 22gauge injectionbull MEAD study

bull N=1048

bull Dex 07mg vs 035mg vs sham

bull No rescue therapy

bull 3 year follow up max 6 monthly dosing ie 7 over 3 years

Gan IM et al Greafes Acrh Clin Exp Ophthalmol 2005

MEAD studyMean BCVA change from baseline based on baseline lens status

-2

0

2

4

6

8

10

0 3 6 9 12 15 18 21 24 27 30 33 36 39

Mea

n C

hang

e Fr

om

Bas

elin

e B

CVA

(Let

ters

)

Month

DEX Implant 07 mg (n = 86)

Sham (n = 101)

Boyer DS et al Ophthalmology 20141211904ndash14

Results analyzed in the ITT population with LOCF for missing values

Pseudophakic

Total

0

5

10

0 3 6 9 12 15 18 21 24 27 30 33 36 39

DEX 700 (n=351)

Sham (n=350)

10

8

6

4

2

0

Mea

n C

hang

e fr

om

Bas

elin

e B

CVA

(Let

ters

)

Month

07mg dose is approved as Ozurdexreg by the FDA and EMA 035mg dose not commercially available

1 Boyer DS et al Ophthalmology 2014 121 1904-1914

bull Nonbioerodible micro implant (polyimide) containing 190microg of fluocinolone acetonide (FAc)

bull Consistent daily submicrogram delivery of 02 microgd FAc for up to 36 months

bull Posterior point of release

bull 35 mm times 037 mm non-bioerodable micro implant

bull 25-gauge injector creates self-sealing wound

bull No measurable systemic exposure

ILUVIEN Implant Technology

FAcimplant

ILUVIEN SPC httpwwwmedicinesorgukemcmedicine27636

0 6 12 18 24 30 36

ILUVIEN 02 microgd FAc(n = 376)05 microgd FAc (n = 395)Control sham injection(n = 185)

Design of Phase 3 FAME Study (FAME A and B = same protocol)

Additional laser therapy allowed after week 6a

Retreatment any time after month 12 (if eligibleb)

Study ends

N = 956Randomisation

221Primary readout

Patients with DMO and

bull At least 1 previous laser tx

bull BCVA ge19 and le68 letters

bull TD-OCT FTH ge250 μm

Month

BCVA = best corrected visual acuity DMO = diabetic macular oedema TD-OCT=time domain optical coherence tomography FTH = foveal thicknessa At masked investigatorrsquos discretion b If BCVA loss ge5 letters or retinal thickening ge50 microm from best reading in previous 12 months

ge15 letter Gain is Greater in Chronic DMO Patients

ge 15

-Let

ter I

mpr

ovem

ent

in B

CVA

Fro

m B

asel

ine

Δ = 98

Months

Full Population Patients With Chronic DMO

Months

Δ = 206

287

189134

34

Steroid re-treatments

bullOzurdexbull Longer half-life than anti-VEGF in the eye

bull Redosing regimes not very helpful from RCT data eg MEAD study only 612 dosing

bull In reality re-treatment interval may be shorter

bull POSOLOGY

bull Patients treated with OZURDEX who have experienced an initial response and in the physicians opinion may benefit from retreatment without being exposed to significant risk should be considered for retreatment Retreatment may be performed after approximately 6 months if the patient experiences decreased vision andor an increase in retinal thickness secondary to recurrent or worsening diabetic macular oedema

bullIluvienbull 70 of patients in FAE only needed 1

injection over 3 years

bull BUT additional rescue treatments allowed

bull POSOLOGY

bull Each ILUVIEN implant releases fluocinolone acetonide for up to 36 months An additional implant may be administered after 12 months if the patient experiences decreased vision or an increase in retinal thickness secondary to recurrent or worsening diabetic macular oedema

bull Patients receiving escape medication were exited from MEAD before administration1

bull Macular laser rescue treatment allowed in RISERIDE (Lucentisreg) from 3 months2

bull Focalgrid laser allowed in FAME (Iluvienreg) from 6 weeks3

MEAD TREATMENT PROTOCOL

bull First treatment given at randomisation (day 0) bull Patients assessed for retreatment eligibility every 3 months from

months 6ndash36bull Patients were eligible for retreatment if

OCT optical coherence tomography

ge6 months since most recent

study treatment

Retinal thickness in 1 mm central macular

subfield by OCT gt175 microm

Evidence of residual retinal oedema (intraretinal cysts or

any regions of increased retinal thickening) as assessed by

investigator from OCT

AND OR

MEA

D

Amendment in May 2010 revised anatomic criterion for retreatment before this time the threshold was gt225 microm1Boyer DS et al Ophthalmology 2014 121 1904-19142Nguyen QD et al Ophthalmology 20121191064minus10773Campochiaro PA et al Ophthalmology 2011118626ndash635

Treatment burdenILUVIEN

Control(n =112)

02 microgd FAc(n =209)

Study Treatments(sham injection or ILUVIEN 02 microgday or FAc 05microgday)

1 treatment 661 761

2 treatments 277 187

ge 3 treatments 63 53

Rescue Laser Treatments (at masked physicianrsquos discretion after week 6)

Patients 607 407

Off-Protocol Treatments (IVTA bevacizumab ranibizumab intravitreal dexamethasone)

Patients 295 115

OZURDEX = 23injections year 1 41 by year 3

No other Rx

Summary of side effects with intravitreal steroids

Drug device Evidence base Cataract risk IOP rise (requiring drops)

Glaucoma surgery

endophthalmitis

ILUVIEN FAME studies 80 cat surgery(273 sham)

384(14 control)

48 0

Ozurdex MEAD 592 had cataract surgery(72 sham)

215 (end of study)(34 sham)

06 0

Trivaris+ laser vs Luc+laserx2 vs laser

Protocol IOphthalmology 2010

15 42(ONE OFgt10mmHg risegt30mmHGStart drops)

2186 0

NICE guidance for intravitreal steroids in DMO

bull Iluvien

bull NICE TA 301 Iluvien for DMO Nov 2013

bull hellipfor treating chronic diabetic macular oedema that is insufficiently responsive to available therapies only if

bull the implant is to be used in an eye with an intraocular

(pseudophakic) lens and

bull the manufacturer provides fluocinolone acetonide intravitreal implant with the discount agreed in the patient access scheme

NICE guidance for intravitreal steroids in DMO

bull Ozurdex

bull NICE TA 349 Ozurdex for DMO July 2015

bull there is an artificial lens in the eye to be treated and

bull their diabetic macular oedema has not improved with

non-corticosteroid treatment or such treatment is not suitable for them

Steroids = second line therapyWhen do I switch

bull Anti-VEGF first line for centre involving DMObull NICE TA ndash ldquoinsufficiently responsiverdquo ldquo ldquonot improvedrdquo ldquonot suitablerdquo ndash

OTHER TREATMENTS

bull 2 scenariosbull 1) Anti-VEGF canrsquot be funded ie OCTlt400um + PSEUDOPHAKIC

bull 2) Already had a course of treatment with laseranti-VEGF + PSEUDOPHAKIC ie SWITCHING from anti-VEGF to steroid

bull Plus

bull ldquochronicrdquo DMO ndash 3 years duration in FAME (18months) for ILUVIEN

bull Chronic DMO not essential for Ozurdex

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

Protocol T ndash patients may not improve in first 6 months

RIDE

RISE

Mea

n ch

ange

in B

CVA

(E

TDR

S le

tters

)M

ean

chan

ge in

BC

VA

(ETD

RS

lette

rs)

Time (months)

RISE and RIDE (Lucentis monthly dosing) Mean change in BCVA over 36 months

Brown DM et al Ophthalmology 2013120(10)2013ndash2022

54

Ranibizumab 03 mgRanibizumab 05 mgShamranibizumab 05 mg

Date of Prep Dec 2014 LGB0820147252X

VA improvement continues throughout year 1 with monthly dosing

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user ndash more than protocol

I

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

DRCRN protocol I5 year outcomesInjections 8-9 in year 1Year 2 = 2-3Year 3= 1-2Year 4 = 0-1Year 5 = 0

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

Wait for plateau = stability in protocol T laserPatient factors again

Judgement of response to anti-VEGF ndashtimeframe

bull Wait 6 months in poor responders

bull Wait 1 year for heavy users

bull Tempting to try steroids earlier than this ifbull No glaucoma ndash not a deal breaker Ozurdex better short term optionbull Pseudophakic

bull Clues from the diseasebull chronic

bull PATIENT FACTORS

bull Any eyes avoid steroids ndash advanced glaucomaCSCR Or prior viral retinitis RARE

bull Any eyes avoid anti-VEGF pregnancytrying to concieve recent CVA

BIOMARKERS AT BASELINE WOULD BE USEFULRESTORE subgroup analysis of OCT features

bull Andreas Pollreisz EURETINA 2015

bull OCT biomarkers (RESTORE data)

bull Better effects with anti-VEGF ifbull Small rather than large intra-retinal cyst

bull Sub-retinal fluid present

bull Vitreo-macular adhesion at baseline

bull No disruption of ELM and ISOS junction

bull No disorganisation of inner retinal layers (DRIL)

RESTORE subgroup analysis of OCT features

bull Andreas Pollreisz EURETINA 2015

bull OCT biomarkers (RESTORE data)

bull Better effects with anti-VEGF ifbull Small rather than large intra-retinal cyst

bull Sub-retinal fluid present

bull Vitreo-macular adhesion at baseline

bull No disruption of ELM and ISOS junction

bull No disorganisation of inner retinal layers (DRIL)

Better baseline characterisationclassificationERG Contrast sensitivityOCT AngiographyMicroperimetry= clues as to who responds best to which drug

Plan for this presentation helliphellipa long list

bull What treatment options are available for DMO (evidence base)

bull What treatment should I start with at baselinebull Re-treatment algorithms for intravitreal DMO therapiesbull When should I switchcombine therapiesbull The bigger picture

bull Other eyebull The patient as a wholebull The service -coping with capacity ndash compromises

The bigger pictureOther eyeThe patient as a wholeThe service -coping with capacity ndash compromises

bull OTHER EYE ndash may create problems

bull Treat and extend ndash ldquoreduce of visitsrdquo plus Eylea license ndash ldquono need for monitoringrdquo may not benefit if lots of visits due to PDR other eye

bull PERIPHERAL RETINA anti-VEGF supresses proliferative disease - Rebound on stopping Rx

bull PATIENT

bull Anti-VEGF ndash heavy user - Will comply

bull One stop much better than two stop for patient ndash Treat and extend

bull SERVICE

bull Capacity and demand planning = fixedT+E more predictable at least 1 month in advance ndash flexible nurse injectors

bull Steroids ndash even if well controlled (Iluvien for 3 years) need IOP check

bull Need pan-retinal examination both eyes ndash separate visits

Summary

CSMO

No centre involvement

Photocoagulation

Centre involvement

gt 78 letters(normalminimally reduced VA)

Photocoagulation

VA 78ndash24 letters

Phakic

Anti-VEGF

Pseudophakic

Anti-VEGF

SWITCHglaucoma

Injection tolerance

Medical issuesrecent CVA

Peripheral diseaseBilateral Rx

CSMO

No centre involvement

LASER

Centre involvement

gt 78 letters(normalminimally

reduced VA)

VA 78ndash24 letters

EYLEA OR LUCENTIS OR AVASTIN

Funding issues

Protocol T ndash poor VA lt 65 letters (615)

LOADING

Monthly injections until stability OR 5 x 112 (EYLEA) = 6 MONTHS then 8 weeks

RETREATMENT1

TREAT AND EXTEND - PRN

PRN

PSEUDOPHAKIC

Prior Rx

ILUVIEN

Chronic disease

OZURDEX

RETREATMENT

OZURDEX

OCT gt175um or any residual oedema

ILUVIEN after 12 months if risksltbenefits

OCT

gt400um

bull FACE TO FACE CLINICS RUNNING IN PARALLEL

bull = MAC002 every 6 months (optom or doctor) routine check for cataracttolerance of injectionsglaucoma issues etc

bull =MAC003 (DOCTOR) for problems as needed no fixed intervalDischargestop treatmentDeclines treatment diagnosis CSR overlay etcswitch drugs

bull =RV002- (DOCTOR) every 6 months

bull =DM002 ndash (DOCTOR) variable interval determined by last assessing doctor

bull First visit at 6 months from 1st injection if mild NPDR

bull Otherwise determined by retinopathy generally

LOADING PHASE

EyleaLucentis 1 within 48hrs of baseline

EyleaLucentis 2 (and LogMAR VA plus OCT same visit)

EyleaLucentis 3 (and LogMAR VA plus OCT same visit)

EyleaLucentis 4 (TEinj)(and Logmar VA plus OCT same visit

AFTER INJECTION 4 data goes off to be reviewed immediately as a hellip

TREAT AND EXTEND assessment ndash the next interval will depend on the response to the loading phase

NB -DMO patients ndash majority (95) will need 6 injctions x 112 of Lucentis

OR Eylea 5 x 112 then 8 weekly

ONCE STABLE for 3 x injection in TE phase

VIRTUAL CLINIC MONITORING OF MACULOPATHY AND PRN RETREATMENT

ANTI-VEGF INJECTION PATHWAYS Baseline visitMAC001 for wet AMDRV001 for CRVOBRVOMed ret clinic for DMO

Pathways ndash too many directions

Better that thanhellip

Thank you

RCO recommendations for the treatment of CSMO

The Royal College of Ophthalmologists Diabetic Retinopathy Guidelines 2012

CSMO

No centre involvement

Photocoagulation

Centre involvement

gt 78 letters(normalminimally reduced VA)

Photocoagulation

VA 78ndash24 letters

Phakic

Anti-VEGF

Pseudophakic

Anti-VEGF

Fluocinolone is an option for eyes unresponsive to other treatments but potential side effects must be considered Triamcinolone +- adjunctive laser or fluocinolone may be considered for eyes unresponsive to other treatments

6

ETDRS based laser therapies = Clinically significant macular oedema (CSMO)

bull The ETDRS defined CSMO as DMO that threatens the centre of the macula (fovea)1 and forms the basis of current recommendations for the treatment of CSMO2

bull CSMO is diagnosed if any of the following parameters are met1

1 ETDRS Research Group Arch Ophthalmol 19851031796ndash1806 2 Bandello F et al Eye (Lond) 201226(4)485ndash493

1 Retinal thickening within 500 microm of the centre of the macula

2 Hard exudates within 500 microm of the centre of the macula if associated with thickening of the adjacent retina

3 Retinal thickening of gt1 disc area in size any part of which is located within 1 disc diameter of the centre of the macula

500 microm

500 microm

1 discdiameter

ge 1 discdiameter

Fovea

7

ETDRS = Early Treatment Diabetic Retinopathy Study

Date of Prep Jan 2015 LGB0820157252f

DMO ndash treatment optionsWhat treatments should I use at baseline

ETDRS based laser therapies = Clinically significant macular oedema (CSMO)

bull The ETDRS defined CSMO as DMO that threatens the centre of the macula (fovea)1 and forms the basis of current recommendations for the treatment of CSMO2

bull CSMO is diagnosed if any of the following parameters are met1

1 ETDRS Research Group Arch Ophthalmol 19851031796ndash1806 2 Bandello F et al Eye (Lond) 201226(4)485ndash493

1 Retinal thickening within 500 microm of the centre of the macula

2 Hard exudates within 500 microm of the centre of the macula if associated with thickening of the adjacent retina

3 Retinal thickening of gt1 disc area in size any part of which is located within 1 disc diameter of the centre of the macula

500 microm

500 microm

1 discdiameter

ge 1 discdiameter

Fovea

8

ETDRS = Early Treatment Diabetic Retinopathy Study

LASER

RCO recommendations for the treatment of CSMO

The Royal College of Ophthalmologists Diabetic Retinopathy Guidelines 2012

CSMO

No centre involvement

Photocoagulation

Centre involvement

gt 78 letters(normalminimally reduced VA)

Photocoagulation

VA 78ndash24 letters

Phakic

Anti-VEGF

Pseudophakic

Anti-VEGF

9

ILUVIEN (chronicunresponsive)

OZURXEX (no improvement)

DMO ndash treatment optionsWhat treatments should I use at baseline

bull ETDRS based laser therapies

bull ADJUNCT

bull Surgery ndash VMTERM

bull Pan-retinal photocoagulation

bull INTRAVITREAL

bull ANTI-VEGF

bull Lucentis (Ranibizumab)

bull Eylea (Aflibercept)

bull Avastin (Bevacizumab)

bull STEROIDS

bull Iluvien (Fluocinolone)

bull Ozurdex (Dexamethasone)

11

BOLT

RESOLVERISE and RIDERELIGHT

DA VINCI

VIVID and VISTA

vs laser

vs sham

Steroids

(in combination

with laser)

Anti-VEGF

(in combination

with laser)

DRCRnet (Protocol I)

ETDRS

READ-2

RESTORE

RETAIN

REVEAL

DRCRnet (Protocol B)

FAMEMEAD

vs laser

vs sham

RanibizumabAflibercept

Bevacizumab

Triamcinolone

Fluocinolone acetonide Dexamethasone

Anti-VEGF Laser Steroids

DRCRnet PROTOCOL T

DMO ndash treatment optionsWhat treatments should I use at baseline ndash based on evidence from RCT data

What therapy do I choose for my patient at baselineWhich treatments can I access

NICE TA 274 Lucentis for DMO April 2013NICE TA 346 Eylea for DMO July 2015

NICE TA 301 Iluvien for DMO Nov 2013NICE TA 349 Ozurdex for DMO July 2015

OCT gt400um1st line if OCT suitable

bull Chronic DMObull PSEUDOPHAKICbull Patients ldquoinsufficiently responsive

to existing therapiesrdquo

bull PSEUDOPHAKICbull ldquoNot improved with non-

corticosteroid or such treatment is not suitable for themrdquo

What therapy do I choose for my patient at baseline

bull ANTI-VEGF

bull Superior to ETDRS argon laser in terms of efficacy

RESTORE 36 month Lucentis prn extension studyLucentis monotherapy vs Lucentis plus laser vs laser aloneSchmidt-Erfuth U et al Ophthalmology 2014 121(5) 1045-1053

23

Months

12

10

8

6

4

2

0

minus22 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36

Extension study (ranibizumab 05 mg PRN)Core study

Me

an o

f th

e c

han

ge in

ETD

RS

BC

VA

Prior ranibizumab 05 mg + active laser (n=83)

Prior sham injections + active laser (n=74)

Prior ranibizumab 05 mg + sham laser (n=83)

79

71 606780

Core study assessment

Full analysisstudy completionInterim analysis

RIDE

RISE

Mea

n ch

ange

in B

CVA

(E

TDR

S le

tters

)M

ean

chan

ge in

BC

VA

(ETD

RS

lette

rs)

Time (months)

RISE and RIDE (Lucentis monthly dosing) Mean change in BCVA over 36 months

Brown DM et al Ophthalmology 2013120(10)2013ndash2022

15

Ranibizumab 03 mgRanibizumab 05 mgShamranibizumab 05 mg

RISE amp RIDE

Date of Prep Dec 2014 LGB0820147252X

02 Laser

125 2q4

107 2q8

0

Mea

n ch

ange

in B

CVA

lette

r sco

re

2

101214

02

6

10

14

4

8

12

468

09 Laser

115 2q4

111 2q8

VISTA Week 100

100928068645652403628201240 8 16 24 32 44 48 60 72 76 84 88 96

12 Laser

100928068645652403628201240 8 16 24 32 44 48 60 72 76 84 88 96

105 2q4

107 2q8VIVID Week 100

Week Laser 2q4 2q8

07 Laser

114 2q4

94 2q8

Eylea =VIVID and VISTA Mean change in BCVA to week 100Korobelnik J-F et al Ophthalmology 2014 121 (11) 2247ndash2254 Brown DM et al Ophthalmology 2015 Jul 18 [Epub ahead of print]

Plt00001 vs laser VIVID Laser n=132 2q4 n=136 2q8 n=135 VISTA Laser n=154 2q4 n=154 2q8 n=151Full analysis set 2q4 2 mg every 4 weeks 2q8 2 mg every 8 weeks BCVA best corrected visual acuity ETDRS Early Treatment Diabetic Retinopathy Study

What therapy do I choose for my patient at baseline

bull ANTI-VEGF helliphellipif OCT gt 400um

bull Sohellip Which one

Key trials in DMO

18

BOLT

RESOLVERISE and RIDE

DA VINCI

VIVID and VISTA

vs laser

vs sham

Steroids

(in combination

with laser)

Anti-VEGF

(in combination

with laser)

DRCRnet (Protocol I)

ETDRS

READ-2

RESTORE

RETAIN

REVEAL

DRCRnet (Protocol B)

FAMEMEAD

vs laser

vs sham

RanibizumabAflibercept

Bevacizumab

Triamcinolone

Fluocinolone acetonide Dexamethasone

Anti-VEGF Laser Steroids

DRCRnet PROTOCOL T

PROTOCOL T (DRCRnet)

bull Aflibercept Bevacizumab or Ranibizumab for Diabetic Macular Edema

bull N Engl J Med 2015 Mar 26372(13)1193-203

The Diabetic retinopathy Clinical Research Network February 18 2015

USA study NIHR funded

n=660

Lucentis 03mg not 05mg Eylea 2mg Avastin 125mg

Eylea protocol not the licensed regime

Avastin unlicensed

RETREATMENT protocol

First 6 months ndash inject every month 95 of patients UNLESS VA=66 AND OCT DRY

Then 2nd six months ndash if no change after 3 visits DEFER otherwise keep injecting monthly

Recurs ndash need at least 2 injections ie 3 months of stability

STABILITY = 10 Oct change or VA 5 letter change

STABILITY and residual OCT thickness gt250um LASER

Protocol T 1 year visual acuity outcomes

0

5

10

15

20

0 8 16 24 32 40 48

Visit Week

2032-2040 = 696 ndash 612= 78-69

0

5

10

15

20

0 8 16 24 32 40 48

Visit Week

2050 = 615 or worse = lt69

Mea

n ch

ange

in B

CV

A

Mea

n ch

ange

in B

CV

A

Aflibercept Bevacizumab Ranibizumab

+189

+142

+118+75

+8+83

Protocol T OCT outcomes year 1

-250

-200

-150

-100

-50

0

0 4 8 12 16 20 24 28 32 36 40 44 48 52

Visit Week

Aflibercept Bevacizumab Ranibizumab

Mea

n ch

ange

in C

ST

Conclusions ndash Protocol T year 1 data

bull Eylea was statistically superior in terms of visual acuity to 03mg Lucentisand to Avastin FOR PATIENTS WITH VA worse than 69 letters

bull Eylea and Lucentis were statistically superior in terms of OCT CRT reduction to Avastin for all patients regardless of baseline vision

bull No safety differences between the three drugs

SUMMARY What do I choose for my patient at baselineOCT central retinal thickness (CRT)PseudophakicAttempts at prior treatment duration of DMO

bull lt 400um

bull IFR licensed anti-VEGF or Avastin

+-ETDRS laser

PSEUDOPHAKIC

Iluvien

Ozurdex

bull gt 400um = Anti-VEGF

Which one

Depends on

bull baseline vision lt615 Eylea

bull Fixed dosing attractive (Eylea)bull Chronic DMO

bull PSEUDOPHAKICbull Patients ldquoinsufficiently

responsive to existing therapiesrdquo

bull ldquoNot improved with non-corticosteroid or such treatment is not suitable for themrdquo

Which steroid ndash Ozurdex or Iluvien

bull No head to head data

bull Revisit this when we think about switching from ANTI-VEGF to steroid

Assuming we have started with an anti-VEGF agent ndash what are the re-treatment algorithms in DMO

Treatment posologies

ldquoTreatment is initiated with one injection per month until maximum VA is achieved andor there are no signs of disease activity ie no change in VA and in other signs and

symptoms of the disease under continued treatment

In patients withhellipDMOhellip initially three or more consecutive monthly injections may be needed Thereafter monitoring and treatment intervals

should be determined by the physician and should be based on disease activity as

assessed by VA andor anatomical parametershellip

If patients are being treated according to a treat-and-extend regimen once maximum VA is achieved andor there are no

signs of disease activity the treatment intervals can be extended stepwise until signs of

disease activity or visual impairment recur The treatment intervalhellipmay be extended by up to one month

at a time for DMOrdquo

1 Novartis Pharmaceuticals UK Ltd 30 October 2014 Available at httpwwwmedicinesorgukemcmedicine19409 Accessed 04 September 2015

2 Bayer Pharma AG February 2015 Available at httpwwwmedicinesorgukemcmedicine27224 Accessed 04 September 2015

Ranibizumab1 Aflibercept2

ldquohelliptreatment is initiated with one injection per month for five consecutive doses followed by

one injection every two months There is no requirement for monitoring between injectionshellip

After the first 12 months of treatmenthellipthe treatment interval may be extended based

on visual andor anatomic outcomes The schedule for monitoring should

be determined by the treating physicianrdquo

DMO diabetic macular oedema VA visual acuity

Re-treatment algorithms for anti-VEGF agents in DMO

bull LOADING PHASE

bull Lucentis label = monthly until stability

bull Eylea label = 5 x 112 then every 8 weeks ie fixed regime year 1

bull DRCRnet protocol T = effectively 6 x112 for majority (95) BUT actually only mandated for first 3 months then prn

bull helliphellip likely that majority will receive injections monthly for first 6 months

bull INDIVIDUALISED PHASE

bull Once ldquostablerdquo ndash based on VA and OCT

bull NB May never get a ldquodryrdquo OCT so treat to stability

bull THEN

bull Treat and extend

bull prn

What does Treat and Extend mean

Pathway overview = Lucentis prn

Jan

Loading phase = injections every 4 weeks until ldquostablerdquo for 3 visits

helliphelliphellip

Feb OctSepAugJulJunMayAprMar

MarFebJan

DecNov

DecNovOctSepAugJulJunMayApr

Then observe UNTIL VA decreases or OCT increase = prn

Once reactivates need at least 2 injections until stable again over 3 visits

Pathway overview = Treat and Extend

Jan

Loading phase = injections every 4 weeks until ldquostablerdquo for 3 visits or Eyleayear 1

helliphelliphellip

Feb OctSepAugJulJunMayAprMar

MarFebJan

DecNov

DecNovOctSepAugJulJunMayApr

Then keep injecting but extend the interval between injections gradually ie keep treating even if perfect

If reactivates need at least 2 injections until stable again over 3 visits

Pathway overview = Eylea fixed dosing year 1

Jan

Eylea = 5 x 112 injection then every 8 weeks

Average 6 injections yr 2 Beyond that

helliphelliphellip

Feb OctSepAugJulJunMayAprMar

MarFebJan

DecNov

DecNovOctSepAugJulJunMayApr

Then individualised UNTIL VA decreases or OCT increase = prn

Once reactivates need at least 2 injections until stable again over 3 visits

Pros and cons of Treat and Extend vs Prn

T+E PRN

PROS bull Proactive patient and service get advance warning of injection ndash capacity and demand planning easier

bull One ndashstopbull Fewer visits than prnbull Overtreatment

advantageous for peripheral retinopathy

bull Only treated when active ieno overtreatment

bull Aggressive year 1 protocols (DRCRN I ndash few injections needed thereafter

bull DMO tolerant of reactivations ()

CONS bull Overtreatment = riskexpenseinconvenience

bull Evidence base scantbull Bilateral disease tricky

bull Reactive so need enoughemergency capacity to inject when disease flares up

bull No advance warning to patientservice that injection needed

bull NEED TO DO IT WELL ndashNHS real life audits prn based regimes not good resultsUndertreatment in year 1 Affects long term prognosis and treatment burden

Pros and cons of Treat and Extend vs Prn

T+E PRN

PROS bull Proactive patient and service get advance warning of injection ndash capacity and demand planning easier

bull One ndashstopbull Fewer visits than prnbull Overtreatment

advantageous for peripheral retinopathy

bull Only treated when active ieno overtreatment

bull Aggressive year 1 protocols (DRCRN I ndash few injections needed thereafter

bull DMO tolerant of reactivations ()

CONS bull Overtreatment = riskexpenseinconvenience

bull Evidence base scantbull Bilateral disease tricky

bull Reactive so need enoughemergency capacity to inject when disease flares up

bull No advance warning to patientservice that injection needed

bull NEED TO DO IT WELL ndashNHS real life audits prn based regimes not good resultsUndertreatment in year 1 Affects long term prognosis and treatment burden

DMO ndash anti-VEGF Treat and Extend

bull Retain study ndash the only RCT data

bull Br J Ophthalmol 2015 Oct 9 pii bjophthalmol-2015-307249 doi 101136bjophthalmol-2015-307249 [Epub ahead of print]

bull Ranibizumab 05 mg treat-and-extend regimen for diabetic macular oedema the RETAIN study

bull Pruumlnte C1 Fajnkuchen F2 Mahmood S3 Ricci F4 Hatz K5 Studnička J6 Bezlyak V7 Parikh S7 Stubbings WJ7 Wenzel A7 Figueira J8 and the RETAIN Study Group

RETAIN Phase III trial evaluating the efficacy of lsquotreat and extendrsquo regimen (ARVO 2014)

bull Patients with DMO and visual impairment (n = 372) were randomised 111

to one of three groups for 24 months

bull Two phases to dosing schedule

bull Phase A

bull Patients in all groups were initially treated with monthly ranibizumab until BCVA remained

stable

bull Phase B

bull Patients in the TampE groups whose vision remained stable had treatment- free intervals

that were increased incrementally by 1 month for a maximum of 3 months

bull Patients in the PRN group had ongoing monthly monitoring

bull In all groups Phase A was resumed if a decrease in BCVA was observed at a visit

Ranibizumab 05 mg monotherapy

in TampE regimen

Ranibizumab 05 mg in TampE regimen

plus laser

Ranibizumab 05 mg PRN

35

RETAIN Visual acuity endpoints

Pruumlnte C ARVO 2014 Annual Meeting Abstracts Abstract 1700

Mean average change in BCVAat 12 months (primary endpoint)

Mean change in BCVA at 24 months

Mea

n av

erag

e ch

ange

in B

CVA

(ETD

RS

lette

rs)

RanibizumabTampE

RanibizumabTampE + laser

RanibizumabPRN

RanibizumabTampE

RanibizumabTampE + laser

RanibizumabPRN

Mea

n ch

ange

in B

CVA

(ETD

RS

lette

rs)

plt00001 for both ranibizumab TampE groups versus PRN for primary endpoint

36

RETAIN Patient visits and monitoring with TampE regimen over 24 months

bull The TampE regimen provided an approximately 40 reduction in the number of treatment visits required compared with the ranibizumab PRN regimen

bull Approximately 70 of patients receiving TampE regimens had monitoring intervals ge2 months compared with ongoing monthly monitoring in the ranibizumab PRN group

bull Informed the license for Lucentis in DMO (extend by 1 month at a time)

37

INTRAVITREAL STEROIDSWhich intravitreal steroid is better

bull Licensed steroids ndash Ozurdex (Dexamethasone) and Iluvien (Fluocinoloneacetonide

bull Which steroid is best in terms of VA outcomes hellipWE DONrsquoT KNOW FOR SURE ndash no head to head studies for licensed drugs either between steroids or between anti-VEGF and steroids

bull STEROIDS ARE efficacious in DMO

bull MEAD

bull FAME

bull DRCRnet protocol I

bull NICE ndash Ozurdex and Iluvien ndash second-line agents

Ozurdex

bull A biodegradable co-polymer implant ndash degrades in time to lactic and glycolic acid releasing Dexamethasone

bull 22gauge injectionbull MEAD study

bull N=1048

bull Dex 07mg vs 035mg vs sham

bull No rescue therapy

bull 3 year follow up max 6 monthly dosing ie 7 over 3 years

Gan IM et al Greafes Acrh Clin Exp Ophthalmol 2005

MEAD studyMean BCVA change from baseline based on baseline lens status

-2

0

2

4

6

8

10

0 3 6 9 12 15 18 21 24 27 30 33 36 39

Mea

n C

hang

e Fr

om

Bas

elin

e B

CVA

(Let

ters

)

Month

DEX Implant 07 mg (n = 86)

Sham (n = 101)

Boyer DS et al Ophthalmology 20141211904ndash14

Results analyzed in the ITT population with LOCF for missing values

Pseudophakic

Total

0

5

10

0 3 6 9 12 15 18 21 24 27 30 33 36 39

DEX 700 (n=351)

Sham (n=350)

10

8

6

4

2

0

Mea

n C

hang

e fr

om

Bas

elin

e B

CVA

(Let

ters

)

Month

07mg dose is approved as Ozurdexreg by the FDA and EMA 035mg dose not commercially available

1 Boyer DS et al Ophthalmology 2014 121 1904-1914

bull Nonbioerodible micro implant (polyimide) containing 190microg of fluocinolone acetonide (FAc)

bull Consistent daily submicrogram delivery of 02 microgd FAc for up to 36 months

bull Posterior point of release

bull 35 mm times 037 mm non-bioerodable micro implant

bull 25-gauge injector creates self-sealing wound

bull No measurable systemic exposure

ILUVIEN Implant Technology

FAcimplant

ILUVIEN SPC httpwwwmedicinesorgukemcmedicine27636

0 6 12 18 24 30 36

ILUVIEN 02 microgd FAc(n = 376)05 microgd FAc (n = 395)Control sham injection(n = 185)

Design of Phase 3 FAME Study (FAME A and B = same protocol)

Additional laser therapy allowed after week 6a

Retreatment any time after month 12 (if eligibleb)

Study ends

N = 956Randomisation

221Primary readout

Patients with DMO and

bull At least 1 previous laser tx

bull BCVA ge19 and le68 letters

bull TD-OCT FTH ge250 μm

Month

BCVA = best corrected visual acuity DMO = diabetic macular oedema TD-OCT=time domain optical coherence tomography FTH = foveal thicknessa At masked investigatorrsquos discretion b If BCVA loss ge5 letters or retinal thickening ge50 microm from best reading in previous 12 months

ge15 letter Gain is Greater in Chronic DMO Patients

ge 15

-Let

ter I

mpr

ovem

ent

in B

CVA

Fro

m B

asel

ine

Δ = 98

Months

Full Population Patients With Chronic DMO

Months

Δ = 206

287

189134

34

Steroid re-treatments

bullOzurdexbull Longer half-life than anti-VEGF in the eye

bull Redosing regimes not very helpful from RCT data eg MEAD study only 612 dosing

bull In reality re-treatment interval may be shorter

bull POSOLOGY

bull Patients treated with OZURDEX who have experienced an initial response and in the physicians opinion may benefit from retreatment without being exposed to significant risk should be considered for retreatment Retreatment may be performed after approximately 6 months if the patient experiences decreased vision andor an increase in retinal thickness secondary to recurrent or worsening diabetic macular oedema

bullIluvienbull 70 of patients in FAE only needed 1

injection over 3 years

bull BUT additional rescue treatments allowed

bull POSOLOGY

bull Each ILUVIEN implant releases fluocinolone acetonide for up to 36 months An additional implant may be administered after 12 months if the patient experiences decreased vision or an increase in retinal thickness secondary to recurrent or worsening diabetic macular oedema

bull Patients receiving escape medication were exited from MEAD before administration1

bull Macular laser rescue treatment allowed in RISERIDE (Lucentisreg) from 3 months2

bull Focalgrid laser allowed in FAME (Iluvienreg) from 6 weeks3

MEAD TREATMENT PROTOCOL

bull First treatment given at randomisation (day 0) bull Patients assessed for retreatment eligibility every 3 months from

months 6ndash36bull Patients were eligible for retreatment if

OCT optical coherence tomography

ge6 months since most recent

study treatment

Retinal thickness in 1 mm central macular

subfield by OCT gt175 microm

Evidence of residual retinal oedema (intraretinal cysts or

any regions of increased retinal thickening) as assessed by

investigator from OCT

AND OR

MEA

D

Amendment in May 2010 revised anatomic criterion for retreatment before this time the threshold was gt225 microm1Boyer DS et al Ophthalmology 2014 121 1904-19142Nguyen QD et al Ophthalmology 20121191064minus10773Campochiaro PA et al Ophthalmology 2011118626ndash635

Treatment burdenILUVIEN

Control(n =112)

02 microgd FAc(n =209)

Study Treatments(sham injection or ILUVIEN 02 microgday or FAc 05microgday)

1 treatment 661 761

2 treatments 277 187

ge 3 treatments 63 53

Rescue Laser Treatments (at masked physicianrsquos discretion after week 6)

Patients 607 407

Off-Protocol Treatments (IVTA bevacizumab ranibizumab intravitreal dexamethasone)

Patients 295 115

OZURDEX = 23injections year 1 41 by year 3

No other Rx

Summary of side effects with intravitreal steroids

Drug device Evidence base Cataract risk IOP rise (requiring drops)

Glaucoma surgery

endophthalmitis

ILUVIEN FAME studies 80 cat surgery(273 sham)

384(14 control)

48 0

Ozurdex MEAD 592 had cataract surgery(72 sham)

215 (end of study)(34 sham)

06 0

Trivaris+ laser vs Luc+laserx2 vs laser

Protocol IOphthalmology 2010

15 42(ONE OFgt10mmHg risegt30mmHGStart drops)

2186 0

NICE guidance for intravitreal steroids in DMO

bull Iluvien

bull NICE TA 301 Iluvien for DMO Nov 2013

bull hellipfor treating chronic diabetic macular oedema that is insufficiently responsive to available therapies only if

bull the implant is to be used in an eye with an intraocular

(pseudophakic) lens and

bull the manufacturer provides fluocinolone acetonide intravitreal implant with the discount agreed in the patient access scheme

NICE guidance for intravitreal steroids in DMO

bull Ozurdex

bull NICE TA 349 Ozurdex for DMO July 2015

bull there is an artificial lens in the eye to be treated and

bull their diabetic macular oedema has not improved with

non-corticosteroid treatment or such treatment is not suitable for them

Steroids = second line therapyWhen do I switch

bull Anti-VEGF first line for centre involving DMObull NICE TA ndash ldquoinsufficiently responsiverdquo ldquo ldquonot improvedrdquo ldquonot suitablerdquo ndash

OTHER TREATMENTS

bull 2 scenariosbull 1) Anti-VEGF canrsquot be funded ie OCTlt400um + PSEUDOPHAKIC

bull 2) Already had a course of treatment with laseranti-VEGF + PSEUDOPHAKIC ie SWITCHING from anti-VEGF to steroid

bull Plus

bull ldquochronicrdquo DMO ndash 3 years duration in FAME (18months) for ILUVIEN

bull Chronic DMO not essential for Ozurdex

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

Protocol T ndash patients may not improve in first 6 months

RIDE

RISE

Mea

n ch

ange

in B

CVA

(E

TDR

S le

tters

)M

ean

chan

ge in

BC

VA

(ETD

RS

lette

rs)

Time (months)

RISE and RIDE (Lucentis monthly dosing) Mean change in BCVA over 36 months

Brown DM et al Ophthalmology 2013120(10)2013ndash2022

54

Ranibizumab 03 mgRanibizumab 05 mgShamranibizumab 05 mg

Date of Prep Dec 2014 LGB0820147252X

VA improvement continues throughout year 1 with monthly dosing

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user ndash more than protocol

I

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

DRCRN protocol I5 year outcomesInjections 8-9 in year 1Year 2 = 2-3Year 3= 1-2Year 4 = 0-1Year 5 = 0

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

Wait for plateau = stability in protocol T laserPatient factors again

Judgement of response to anti-VEGF ndashtimeframe

bull Wait 6 months in poor responders

bull Wait 1 year for heavy users

bull Tempting to try steroids earlier than this ifbull No glaucoma ndash not a deal breaker Ozurdex better short term optionbull Pseudophakic

bull Clues from the diseasebull chronic

bull PATIENT FACTORS

bull Any eyes avoid steroids ndash advanced glaucomaCSCR Or prior viral retinitis RARE

bull Any eyes avoid anti-VEGF pregnancytrying to concieve recent CVA

BIOMARKERS AT BASELINE WOULD BE USEFULRESTORE subgroup analysis of OCT features

bull Andreas Pollreisz EURETINA 2015

bull OCT biomarkers (RESTORE data)

bull Better effects with anti-VEGF ifbull Small rather than large intra-retinal cyst

bull Sub-retinal fluid present

bull Vitreo-macular adhesion at baseline

bull No disruption of ELM and ISOS junction

bull No disorganisation of inner retinal layers (DRIL)

RESTORE subgroup analysis of OCT features

bull Andreas Pollreisz EURETINA 2015

bull OCT biomarkers (RESTORE data)

bull Better effects with anti-VEGF ifbull Small rather than large intra-retinal cyst

bull Sub-retinal fluid present

bull Vitreo-macular adhesion at baseline

bull No disruption of ELM and ISOS junction

bull No disorganisation of inner retinal layers (DRIL)

Better baseline characterisationclassificationERG Contrast sensitivityOCT AngiographyMicroperimetry= clues as to who responds best to which drug

Plan for this presentation helliphellipa long list

bull What treatment options are available for DMO (evidence base)

bull What treatment should I start with at baselinebull Re-treatment algorithms for intravitreal DMO therapiesbull When should I switchcombine therapiesbull The bigger picture

bull Other eyebull The patient as a wholebull The service -coping with capacity ndash compromises

The bigger pictureOther eyeThe patient as a wholeThe service -coping with capacity ndash compromises

bull OTHER EYE ndash may create problems

bull Treat and extend ndash ldquoreduce of visitsrdquo plus Eylea license ndash ldquono need for monitoringrdquo may not benefit if lots of visits due to PDR other eye

bull PERIPHERAL RETINA anti-VEGF supresses proliferative disease - Rebound on stopping Rx

bull PATIENT

bull Anti-VEGF ndash heavy user - Will comply

bull One stop much better than two stop for patient ndash Treat and extend

bull SERVICE

bull Capacity and demand planning = fixedT+E more predictable at least 1 month in advance ndash flexible nurse injectors

bull Steroids ndash even if well controlled (Iluvien for 3 years) need IOP check

bull Need pan-retinal examination both eyes ndash separate visits

Summary

CSMO

No centre involvement

Photocoagulation

Centre involvement

gt 78 letters(normalminimally reduced VA)

Photocoagulation

VA 78ndash24 letters

Phakic

Anti-VEGF

Pseudophakic

Anti-VEGF

SWITCHglaucoma

Injection tolerance

Medical issuesrecent CVA

Peripheral diseaseBilateral Rx

CSMO

No centre involvement

LASER

Centre involvement

gt 78 letters(normalminimally

reduced VA)

VA 78ndash24 letters

EYLEA OR LUCENTIS OR AVASTIN

Funding issues

Protocol T ndash poor VA lt 65 letters (615)

LOADING

Monthly injections until stability OR 5 x 112 (EYLEA) = 6 MONTHS then 8 weeks

RETREATMENT1

TREAT AND EXTEND - PRN

PRN

PSEUDOPHAKIC

Prior Rx

ILUVIEN

Chronic disease

OZURDEX

RETREATMENT

OZURDEX

OCT gt175um or any residual oedema

ILUVIEN after 12 months if risksltbenefits

OCT

gt400um

bull FACE TO FACE CLINICS RUNNING IN PARALLEL

bull = MAC002 every 6 months (optom or doctor) routine check for cataracttolerance of injectionsglaucoma issues etc

bull =MAC003 (DOCTOR) for problems as needed no fixed intervalDischargestop treatmentDeclines treatment diagnosis CSR overlay etcswitch drugs

bull =RV002- (DOCTOR) every 6 months

bull =DM002 ndash (DOCTOR) variable interval determined by last assessing doctor

bull First visit at 6 months from 1st injection if mild NPDR

bull Otherwise determined by retinopathy generally

LOADING PHASE

EyleaLucentis 1 within 48hrs of baseline

EyleaLucentis 2 (and LogMAR VA plus OCT same visit)

EyleaLucentis 3 (and LogMAR VA plus OCT same visit)

EyleaLucentis 4 (TEinj)(and Logmar VA plus OCT same visit

AFTER INJECTION 4 data goes off to be reviewed immediately as a hellip

TREAT AND EXTEND assessment ndash the next interval will depend on the response to the loading phase

NB -DMO patients ndash majority (95) will need 6 injctions x 112 of Lucentis

OR Eylea 5 x 112 then 8 weekly

ONCE STABLE for 3 x injection in TE phase

VIRTUAL CLINIC MONITORING OF MACULOPATHY AND PRN RETREATMENT

ANTI-VEGF INJECTION PATHWAYS Baseline visitMAC001 for wet AMDRV001 for CRVOBRVOMed ret clinic for DMO

Pathways ndash too many directions

Better that thanhellip

Thank you

ETDRS based laser therapies = Clinically significant macular oedema (CSMO)

bull The ETDRS defined CSMO as DMO that threatens the centre of the macula (fovea)1 and forms the basis of current recommendations for the treatment of CSMO2

bull CSMO is diagnosed if any of the following parameters are met1

1 ETDRS Research Group Arch Ophthalmol 19851031796ndash1806 2 Bandello F et al Eye (Lond) 201226(4)485ndash493

1 Retinal thickening within 500 microm of the centre of the macula

2 Hard exudates within 500 microm of the centre of the macula if associated with thickening of the adjacent retina

3 Retinal thickening of gt1 disc area in size any part of which is located within 1 disc diameter of the centre of the macula

500 microm

500 microm

1 discdiameter

ge 1 discdiameter

Fovea

7

ETDRS = Early Treatment Diabetic Retinopathy Study

Date of Prep Jan 2015 LGB0820157252f

DMO ndash treatment optionsWhat treatments should I use at baseline

ETDRS based laser therapies = Clinically significant macular oedema (CSMO)

bull The ETDRS defined CSMO as DMO that threatens the centre of the macula (fovea)1 and forms the basis of current recommendations for the treatment of CSMO2

bull CSMO is diagnosed if any of the following parameters are met1

1 ETDRS Research Group Arch Ophthalmol 19851031796ndash1806 2 Bandello F et al Eye (Lond) 201226(4)485ndash493

1 Retinal thickening within 500 microm of the centre of the macula

2 Hard exudates within 500 microm of the centre of the macula if associated with thickening of the adjacent retina

3 Retinal thickening of gt1 disc area in size any part of which is located within 1 disc diameter of the centre of the macula

500 microm

500 microm

1 discdiameter

ge 1 discdiameter

Fovea

8

ETDRS = Early Treatment Diabetic Retinopathy Study

LASER

RCO recommendations for the treatment of CSMO

The Royal College of Ophthalmologists Diabetic Retinopathy Guidelines 2012

CSMO

No centre involvement

Photocoagulation

Centre involvement

gt 78 letters(normalminimally reduced VA)

Photocoagulation

VA 78ndash24 letters

Phakic

Anti-VEGF

Pseudophakic

Anti-VEGF

9

ILUVIEN (chronicunresponsive)

OZURXEX (no improvement)

DMO ndash treatment optionsWhat treatments should I use at baseline

bull ETDRS based laser therapies

bull ADJUNCT

bull Surgery ndash VMTERM

bull Pan-retinal photocoagulation

bull INTRAVITREAL

bull ANTI-VEGF

bull Lucentis (Ranibizumab)

bull Eylea (Aflibercept)

bull Avastin (Bevacizumab)

bull STEROIDS

bull Iluvien (Fluocinolone)

bull Ozurdex (Dexamethasone)

11

BOLT

RESOLVERISE and RIDERELIGHT

DA VINCI

VIVID and VISTA

vs laser

vs sham

Steroids

(in combination

with laser)

Anti-VEGF

(in combination

with laser)

DRCRnet (Protocol I)

ETDRS

READ-2

RESTORE

RETAIN

REVEAL

DRCRnet (Protocol B)

FAMEMEAD

vs laser

vs sham

RanibizumabAflibercept

Bevacizumab

Triamcinolone

Fluocinolone acetonide Dexamethasone

Anti-VEGF Laser Steroids

DRCRnet PROTOCOL T

DMO ndash treatment optionsWhat treatments should I use at baseline ndash based on evidence from RCT data

What therapy do I choose for my patient at baselineWhich treatments can I access

NICE TA 274 Lucentis for DMO April 2013NICE TA 346 Eylea for DMO July 2015

NICE TA 301 Iluvien for DMO Nov 2013NICE TA 349 Ozurdex for DMO July 2015

OCT gt400um1st line if OCT suitable

bull Chronic DMObull PSEUDOPHAKICbull Patients ldquoinsufficiently responsive

to existing therapiesrdquo

bull PSEUDOPHAKICbull ldquoNot improved with non-

corticosteroid or such treatment is not suitable for themrdquo

What therapy do I choose for my patient at baseline

bull ANTI-VEGF

bull Superior to ETDRS argon laser in terms of efficacy

RESTORE 36 month Lucentis prn extension studyLucentis monotherapy vs Lucentis plus laser vs laser aloneSchmidt-Erfuth U et al Ophthalmology 2014 121(5) 1045-1053

23

Months

12

10

8

6

4

2

0

minus22 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36

Extension study (ranibizumab 05 mg PRN)Core study

Me

an o

f th

e c

han

ge in

ETD

RS

BC

VA

Prior ranibizumab 05 mg + active laser (n=83)

Prior sham injections + active laser (n=74)

Prior ranibizumab 05 mg + sham laser (n=83)

79

71 606780

Core study assessment

Full analysisstudy completionInterim analysis

RIDE

RISE

Mea

n ch

ange

in B

CVA

(E

TDR

S le

tters

)M

ean

chan

ge in

BC

VA

(ETD

RS

lette

rs)

Time (months)

RISE and RIDE (Lucentis monthly dosing) Mean change in BCVA over 36 months

Brown DM et al Ophthalmology 2013120(10)2013ndash2022

15

Ranibizumab 03 mgRanibizumab 05 mgShamranibizumab 05 mg

RISE amp RIDE

Date of Prep Dec 2014 LGB0820147252X

02 Laser

125 2q4

107 2q8

0

Mea

n ch

ange

in B

CVA

lette

r sco

re

2

101214

02

6

10

14

4

8

12

468

09 Laser

115 2q4

111 2q8

VISTA Week 100

100928068645652403628201240 8 16 24 32 44 48 60 72 76 84 88 96

12 Laser

100928068645652403628201240 8 16 24 32 44 48 60 72 76 84 88 96

105 2q4

107 2q8VIVID Week 100

Week Laser 2q4 2q8

07 Laser

114 2q4

94 2q8

Eylea =VIVID and VISTA Mean change in BCVA to week 100Korobelnik J-F et al Ophthalmology 2014 121 (11) 2247ndash2254 Brown DM et al Ophthalmology 2015 Jul 18 [Epub ahead of print]

Plt00001 vs laser VIVID Laser n=132 2q4 n=136 2q8 n=135 VISTA Laser n=154 2q4 n=154 2q8 n=151Full analysis set 2q4 2 mg every 4 weeks 2q8 2 mg every 8 weeks BCVA best corrected visual acuity ETDRS Early Treatment Diabetic Retinopathy Study

What therapy do I choose for my patient at baseline

bull ANTI-VEGF helliphellipif OCT gt 400um

bull Sohellip Which one

Key trials in DMO

18

BOLT

RESOLVERISE and RIDE

DA VINCI

VIVID and VISTA

vs laser

vs sham

Steroids

(in combination

with laser)

Anti-VEGF

(in combination

with laser)

DRCRnet (Protocol I)

ETDRS

READ-2

RESTORE

RETAIN

REVEAL

DRCRnet (Protocol B)

FAMEMEAD

vs laser

vs sham

RanibizumabAflibercept

Bevacizumab

Triamcinolone

Fluocinolone acetonide Dexamethasone

Anti-VEGF Laser Steroids

DRCRnet PROTOCOL T

PROTOCOL T (DRCRnet)

bull Aflibercept Bevacizumab or Ranibizumab for Diabetic Macular Edema

bull N Engl J Med 2015 Mar 26372(13)1193-203

The Diabetic retinopathy Clinical Research Network February 18 2015

USA study NIHR funded

n=660

Lucentis 03mg not 05mg Eylea 2mg Avastin 125mg

Eylea protocol not the licensed regime

Avastin unlicensed

RETREATMENT protocol

First 6 months ndash inject every month 95 of patients UNLESS VA=66 AND OCT DRY

Then 2nd six months ndash if no change after 3 visits DEFER otherwise keep injecting monthly

Recurs ndash need at least 2 injections ie 3 months of stability

STABILITY = 10 Oct change or VA 5 letter change

STABILITY and residual OCT thickness gt250um LASER

Protocol T 1 year visual acuity outcomes

0

5

10

15

20

0 8 16 24 32 40 48

Visit Week

2032-2040 = 696 ndash 612= 78-69

0

5

10

15

20

0 8 16 24 32 40 48

Visit Week

2050 = 615 or worse = lt69

Mea

n ch

ange

in B

CV

A

Mea

n ch

ange

in B

CV

A

Aflibercept Bevacizumab Ranibizumab

+189

+142

+118+75

+8+83

Protocol T OCT outcomes year 1

-250

-200

-150

-100

-50

0

0 4 8 12 16 20 24 28 32 36 40 44 48 52

Visit Week

Aflibercept Bevacizumab Ranibizumab

Mea

n ch

ange

in C

ST

Conclusions ndash Protocol T year 1 data

bull Eylea was statistically superior in terms of visual acuity to 03mg Lucentisand to Avastin FOR PATIENTS WITH VA worse than 69 letters

bull Eylea and Lucentis were statistically superior in terms of OCT CRT reduction to Avastin for all patients regardless of baseline vision

bull No safety differences between the three drugs

SUMMARY What do I choose for my patient at baselineOCT central retinal thickness (CRT)PseudophakicAttempts at prior treatment duration of DMO

bull lt 400um

bull IFR licensed anti-VEGF or Avastin

+-ETDRS laser

PSEUDOPHAKIC

Iluvien

Ozurdex

bull gt 400um = Anti-VEGF

Which one

Depends on

bull baseline vision lt615 Eylea

bull Fixed dosing attractive (Eylea)bull Chronic DMO

bull PSEUDOPHAKICbull Patients ldquoinsufficiently

responsive to existing therapiesrdquo

bull ldquoNot improved with non-corticosteroid or such treatment is not suitable for themrdquo

Which steroid ndash Ozurdex or Iluvien

bull No head to head data

bull Revisit this when we think about switching from ANTI-VEGF to steroid

Assuming we have started with an anti-VEGF agent ndash what are the re-treatment algorithms in DMO

Treatment posologies

ldquoTreatment is initiated with one injection per month until maximum VA is achieved andor there are no signs of disease activity ie no change in VA and in other signs and

symptoms of the disease under continued treatment

In patients withhellipDMOhellip initially three or more consecutive monthly injections may be needed Thereafter monitoring and treatment intervals

should be determined by the physician and should be based on disease activity as

assessed by VA andor anatomical parametershellip

If patients are being treated according to a treat-and-extend regimen once maximum VA is achieved andor there are no

signs of disease activity the treatment intervals can be extended stepwise until signs of

disease activity or visual impairment recur The treatment intervalhellipmay be extended by up to one month

at a time for DMOrdquo

1 Novartis Pharmaceuticals UK Ltd 30 October 2014 Available at httpwwwmedicinesorgukemcmedicine19409 Accessed 04 September 2015

2 Bayer Pharma AG February 2015 Available at httpwwwmedicinesorgukemcmedicine27224 Accessed 04 September 2015

Ranibizumab1 Aflibercept2

ldquohelliptreatment is initiated with one injection per month for five consecutive doses followed by

one injection every two months There is no requirement for monitoring between injectionshellip

After the first 12 months of treatmenthellipthe treatment interval may be extended based

on visual andor anatomic outcomes The schedule for monitoring should

be determined by the treating physicianrdquo

DMO diabetic macular oedema VA visual acuity

Re-treatment algorithms for anti-VEGF agents in DMO

bull LOADING PHASE

bull Lucentis label = monthly until stability

bull Eylea label = 5 x 112 then every 8 weeks ie fixed regime year 1

bull DRCRnet protocol T = effectively 6 x112 for majority (95) BUT actually only mandated for first 3 months then prn

bull helliphellip likely that majority will receive injections monthly for first 6 months

bull INDIVIDUALISED PHASE

bull Once ldquostablerdquo ndash based on VA and OCT

bull NB May never get a ldquodryrdquo OCT so treat to stability

bull THEN

bull Treat and extend

bull prn

What does Treat and Extend mean

Pathway overview = Lucentis prn

Jan

Loading phase = injections every 4 weeks until ldquostablerdquo for 3 visits

helliphelliphellip

Feb OctSepAugJulJunMayAprMar

MarFebJan

DecNov

DecNovOctSepAugJulJunMayApr

Then observe UNTIL VA decreases or OCT increase = prn

Once reactivates need at least 2 injections until stable again over 3 visits

Pathway overview = Treat and Extend

Jan

Loading phase = injections every 4 weeks until ldquostablerdquo for 3 visits or Eyleayear 1

helliphelliphellip

Feb OctSepAugJulJunMayAprMar

MarFebJan

DecNov

DecNovOctSepAugJulJunMayApr

Then keep injecting but extend the interval between injections gradually ie keep treating even if perfect

If reactivates need at least 2 injections until stable again over 3 visits

Pathway overview = Eylea fixed dosing year 1

Jan

Eylea = 5 x 112 injection then every 8 weeks

Average 6 injections yr 2 Beyond that

helliphelliphellip

Feb OctSepAugJulJunMayAprMar

MarFebJan

DecNov

DecNovOctSepAugJulJunMayApr

Then individualised UNTIL VA decreases or OCT increase = prn

Once reactivates need at least 2 injections until stable again over 3 visits

Pros and cons of Treat and Extend vs Prn

T+E PRN

PROS bull Proactive patient and service get advance warning of injection ndash capacity and demand planning easier

bull One ndashstopbull Fewer visits than prnbull Overtreatment

advantageous for peripheral retinopathy

bull Only treated when active ieno overtreatment

bull Aggressive year 1 protocols (DRCRN I ndash few injections needed thereafter

bull DMO tolerant of reactivations ()

CONS bull Overtreatment = riskexpenseinconvenience

bull Evidence base scantbull Bilateral disease tricky

bull Reactive so need enoughemergency capacity to inject when disease flares up

bull No advance warning to patientservice that injection needed

bull NEED TO DO IT WELL ndashNHS real life audits prn based regimes not good resultsUndertreatment in year 1 Affects long term prognosis and treatment burden

Pros and cons of Treat and Extend vs Prn

T+E PRN

PROS bull Proactive patient and service get advance warning of injection ndash capacity and demand planning easier

bull One ndashstopbull Fewer visits than prnbull Overtreatment

advantageous for peripheral retinopathy

bull Only treated when active ieno overtreatment

bull Aggressive year 1 protocols (DRCRN I ndash few injections needed thereafter

bull DMO tolerant of reactivations ()

CONS bull Overtreatment = riskexpenseinconvenience

bull Evidence base scantbull Bilateral disease tricky

bull Reactive so need enoughemergency capacity to inject when disease flares up

bull No advance warning to patientservice that injection needed

bull NEED TO DO IT WELL ndashNHS real life audits prn based regimes not good resultsUndertreatment in year 1 Affects long term prognosis and treatment burden

DMO ndash anti-VEGF Treat and Extend

bull Retain study ndash the only RCT data

bull Br J Ophthalmol 2015 Oct 9 pii bjophthalmol-2015-307249 doi 101136bjophthalmol-2015-307249 [Epub ahead of print]

bull Ranibizumab 05 mg treat-and-extend regimen for diabetic macular oedema the RETAIN study

bull Pruumlnte C1 Fajnkuchen F2 Mahmood S3 Ricci F4 Hatz K5 Studnička J6 Bezlyak V7 Parikh S7 Stubbings WJ7 Wenzel A7 Figueira J8 and the RETAIN Study Group

RETAIN Phase III trial evaluating the efficacy of lsquotreat and extendrsquo regimen (ARVO 2014)

bull Patients with DMO and visual impairment (n = 372) were randomised 111

to one of three groups for 24 months

bull Two phases to dosing schedule

bull Phase A

bull Patients in all groups were initially treated with monthly ranibizumab until BCVA remained

stable

bull Phase B

bull Patients in the TampE groups whose vision remained stable had treatment- free intervals

that were increased incrementally by 1 month for a maximum of 3 months

bull Patients in the PRN group had ongoing monthly monitoring

bull In all groups Phase A was resumed if a decrease in BCVA was observed at a visit

Ranibizumab 05 mg monotherapy

in TampE regimen

Ranibizumab 05 mg in TampE regimen

plus laser

Ranibizumab 05 mg PRN

35

RETAIN Visual acuity endpoints

Pruumlnte C ARVO 2014 Annual Meeting Abstracts Abstract 1700

Mean average change in BCVAat 12 months (primary endpoint)

Mean change in BCVA at 24 months

Mea

n av

erag

e ch

ange

in B

CVA

(ETD

RS

lette

rs)

RanibizumabTampE

RanibizumabTampE + laser

RanibizumabPRN

RanibizumabTampE

RanibizumabTampE + laser

RanibizumabPRN

Mea

n ch

ange

in B

CVA

(ETD

RS

lette

rs)

plt00001 for both ranibizumab TampE groups versus PRN for primary endpoint

36

RETAIN Patient visits and monitoring with TampE regimen over 24 months

bull The TampE regimen provided an approximately 40 reduction in the number of treatment visits required compared with the ranibizumab PRN regimen

bull Approximately 70 of patients receiving TampE regimens had monitoring intervals ge2 months compared with ongoing monthly monitoring in the ranibizumab PRN group

bull Informed the license for Lucentis in DMO (extend by 1 month at a time)

37

INTRAVITREAL STEROIDSWhich intravitreal steroid is better

bull Licensed steroids ndash Ozurdex (Dexamethasone) and Iluvien (Fluocinoloneacetonide

bull Which steroid is best in terms of VA outcomes hellipWE DONrsquoT KNOW FOR SURE ndash no head to head studies for licensed drugs either between steroids or between anti-VEGF and steroids

bull STEROIDS ARE efficacious in DMO

bull MEAD

bull FAME

bull DRCRnet protocol I

bull NICE ndash Ozurdex and Iluvien ndash second-line agents

Ozurdex

bull A biodegradable co-polymer implant ndash degrades in time to lactic and glycolic acid releasing Dexamethasone

bull 22gauge injectionbull MEAD study

bull N=1048

bull Dex 07mg vs 035mg vs sham

bull No rescue therapy

bull 3 year follow up max 6 monthly dosing ie 7 over 3 years

Gan IM et al Greafes Acrh Clin Exp Ophthalmol 2005

MEAD studyMean BCVA change from baseline based on baseline lens status

-2

0

2

4

6

8

10

0 3 6 9 12 15 18 21 24 27 30 33 36 39

Mea

n C

hang

e Fr

om

Bas

elin

e B

CVA

(Let

ters

)

Month

DEX Implant 07 mg (n = 86)

Sham (n = 101)

Boyer DS et al Ophthalmology 20141211904ndash14

Results analyzed in the ITT population with LOCF for missing values

Pseudophakic

Total

0

5

10

0 3 6 9 12 15 18 21 24 27 30 33 36 39

DEX 700 (n=351)

Sham (n=350)

10

8

6

4

2

0

Mea

n C

hang

e fr

om

Bas

elin

e B

CVA

(Let

ters

)

Month

07mg dose is approved as Ozurdexreg by the FDA and EMA 035mg dose not commercially available

1 Boyer DS et al Ophthalmology 2014 121 1904-1914

bull Nonbioerodible micro implant (polyimide) containing 190microg of fluocinolone acetonide (FAc)

bull Consistent daily submicrogram delivery of 02 microgd FAc for up to 36 months

bull Posterior point of release

bull 35 mm times 037 mm non-bioerodable micro implant

bull 25-gauge injector creates self-sealing wound

bull No measurable systemic exposure

ILUVIEN Implant Technology

FAcimplant

ILUVIEN SPC httpwwwmedicinesorgukemcmedicine27636

0 6 12 18 24 30 36

ILUVIEN 02 microgd FAc(n = 376)05 microgd FAc (n = 395)Control sham injection(n = 185)

Design of Phase 3 FAME Study (FAME A and B = same protocol)

Additional laser therapy allowed after week 6a

Retreatment any time after month 12 (if eligibleb)

Study ends

N = 956Randomisation

221Primary readout

Patients with DMO and

bull At least 1 previous laser tx

bull BCVA ge19 and le68 letters

bull TD-OCT FTH ge250 μm

Month

BCVA = best corrected visual acuity DMO = diabetic macular oedema TD-OCT=time domain optical coherence tomography FTH = foveal thicknessa At masked investigatorrsquos discretion b If BCVA loss ge5 letters or retinal thickening ge50 microm from best reading in previous 12 months

ge15 letter Gain is Greater in Chronic DMO Patients

ge 15

-Let

ter I

mpr

ovem

ent

in B

CVA

Fro

m B

asel

ine

Δ = 98

Months

Full Population Patients With Chronic DMO

Months

Δ = 206

287

189134

34

Steroid re-treatments

bullOzurdexbull Longer half-life than anti-VEGF in the eye

bull Redosing regimes not very helpful from RCT data eg MEAD study only 612 dosing

bull In reality re-treatment interval may be shorter

bull POSOLOGY

bull Patients treated with OZURDEX who have experienced an initial response and in the physicians opinion may benefit from retreatment without being exposed to significant risk should be considered for retreatment Retreatment may be performed after approximately 6 months if the patient experiences decreased vision andor an increase in retinal thickness secondary to recurrent or worsening diabetic macular oedema

bullIluvienbull 70 of patients in FAE only needed 1

injection over 3 years

bull BUT additional rescue treatments allowed

bull POSOLOGY

bull Each ILUVIEN implant releases fluocinolone acetonide for up to 36 months An additional implant may be administered after 12 months if the patient experiences decreased vision or an increase in retinal thickness secondary to recurrent or worsening diabetic macular oedema

bull Patients receiving escape medication were exited from MEAD before administration1

bull Macular laser rescue treatment allowed in RISERIDE (Lucentisreg) from 3 months2

bull Focalgrid laser allowed in FAME (Iluvienreg) from 6 weeks3

MEAD TREATMENT PROTOCOL

bull First treatment given at randomisation (day 0) bull Patients assessed for retreatment eligibility every 3 months from

months 6ndash36bull Patients were eligible for retreatment if

OCT optical coherence tomography

ge6 months since most recent

study treatment

Retinal thickness in 1 mm central macular

subfield by OCT gt175 microm

Evidence of residual retinal oedema (intraretinal cysts or

any regions of increased retinal thickening) as assessed by

investigator from OCT

AND OR

MEA

D

Amendment in May 2010 revised anatomic criterion for retreatment before this time the threshold was gt225 microm1Boyer DS et al Ophthalmology 2014 121 1904-19142Nguyen QD et al Ophthalmology 20121191064minus10773Campochiaro PA et al Ophthalmology 2011118626ndash635

Treatment burdenILUVIEN

Control(n =112)

02 microgd FAc(n =209)

Study Treatments(sham injection or ILUVIEN 02 microgday or FAc 05microgday)

1 treatment 661 761

2 treatments 277 187

ge 3 treatments 63 53

Rescue Laser Treatments (at masked physicianrsquos discretion after week 6)

Patients 607 407

Off-Protocol Treatments (IVTA bevacizumab ranibizumab intravitreal dexamethasone)

Patients 295 115

OZURDEX = 23injections year 1 41 by year 3

No other Rx

Summary of side effects with intravitreal steroids

Drug device Evidence base Cataract risk IOP rise (requiring drops)

Glaucoma surgery

endophthalmitis

ILUVIEN FAME studies 80 cat surgery(273 sham)

384(14 control)

48 0

Ozurdex MEAD 592 had cataract surgery(72 sham)

215 (end of study)(34 sham)

06 0

Trivaris+ laser vs Luc+laserx2 vs laser

Protocol IOphthalmology 2010

15 42(ONE OFgt10mmHg risegt30mmHGStart drops)

2186 0

NICE guidance for intravitreal steroids in DMO

bull Iluvien

bull NICE TA 301 Iluvien for DMO Nov 2013

bull hellipfor treating chronic diabetic macular oedema that is insufficiently responsive to available therapies only if

bull the implant is to be used in an eye with an intraocular

(pseudophakic) lens and

bull the manufacturer provides fluocinolone acetonide intravitreal implant with the discount agreed in the patient access scheme

NICE guidance for intravitreal steroids in DMO

bull Ozurdex

bull NICE TA 349 Ozurdex for DMO July 2015

bull there is an artificial lens in the eye to be treated and

bull their diabetic macular oedema has not improved with

non-corticosteroid treatment or such treatment is not suitable for them

Steroids = second line therapyWhen do I switch

bull Anti-VEGF first line for centre involving DMObull NICE TA ndash ldquoinsufficiently responsiverdquo ldquo ldquonot improvedrdquo ldquonot suitablerdquo ndash

OTHER TREATMENTS

bull 2 scenariosbull 1) Anti-VEGF canrsquot be funded ie OCTlt400um + PSEUDOPHAKIC

bull 2) Already had a course of treatment with laseranti-VEGF + PSEUDOPHAKIC ie SWITCHING from anti-VEGF to steroid

bull Plus

bull ldquochronicrdquo DMO ndash 3 years duration in FAME (18months) for ILUVIEN

bull Chronic DMO not essential for Ozurdex

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

Protocol T ndash patients may not improve in first 6 months

RIDE

RISE

Mea

n ch

ange

in B

CVA

(E

TDR

S le

tters

)M

ean

chan

ge in

BC

VA

(ETD

RS

lette

rs)

Time (months)

RISE and RIDE (Lucentis monthly dosing) Mean change in BCVA over 36 months

Brown DM et al Ophthalmology 2013120(10)2013ndash2022

54

Ranibizumab 03 mgRanibizumab 05 mgShamranibizumab 05 mg

Date of Prep Dec 2014 LGB0820147252X

VA improvement continues throughout year 1 with monthly dosing

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user ndash more than protocol

I

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

DRCRN protocol I5 year outcomesInjections 8-9 in year 1Year 2 = 2-3Year 3= 1-2Year 4 = 0-1Year 5 = 0

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

Wait for plateau = stability in protocol T laserPatient factors again

Judgement of response to anti-VEGF ndashtimeframe

bull Wait 6 months in poor responders

bull Wait 1 year for heavy users

bull Tempting to try steroids earlier than this ifbull No glaucoma ndash not a deal breaker Ozurdex better short term optionbull Pseudophakic

bull Clues from the diseasebull chronic

bull PATIENT FACTORS

bull Any eyes avoid steroids ndash advanced glaucomaCSCR Or prior viral retinitis RARE

bull Any eyes avoid anti-VEGF pregnancytrying to concieve recent CVA

BIOMARKERS AT BASELINE WOULD BE USEFULRESTORE subgroup analysis of OCT features

bull Andreas Pollreisz EURETINA 2015

bull OCT biomarkers (RESTORE data)

bull Better effects with anti-VEGF ifbull Small rather than large intra-retinal cyst

bull Sub-retinal fluid present

bull Vitreo-macular adhesion at baseline

bull No disruption of ELM and ISOS junction

bull No disorganisation of inner retinal layers (DRIL)

RESTORE subgroup analysis of OCT features

bull Andreas Pollreisz EURETINA 2015

bull OCT biomarkers (RESTORE data)

bull Better effects with anti-VEGF ifbull Small rather than large intra-retinal cyst

bull Sub-retinal fluid present

bull Vitreo-macular adhesion at baseline

bull No disruption of ELM and ISOS junction

bull No disorganisation of inner retinal layers (DRIL)

Better baseline characterisationclassificationERG Contrast sensitivityOCT AngiographyMicroperimetry= clues as to who responds best to which drug

Plan for this presentation helliphellipa long list

bull What treatment options are available for DMO (evidence base)

bull What treatment should I start with at baselinebull Re-treatment algorithms for intravitreal DMO therapiesbull When should I switchcombine therapiesbull The bigger picture

bull Other eyebull The patient as a wholebull The service -coping with capacity ndash compromises

The bigger pictureOther eyeThe patient as a wholeThe service -coping with capacity ndash compromises

bull OTHER EYE ndash may create problems

bull Treat and extend ndash ldquoreduce of visitsrdquo plus Eylea license ndash ldquono need for monitoringrdquo may not benefit if lots of visits due to PDR other eye

bull PERIPHERAL RETINA anti-VEGF supresses proliferative disease - Rebound on stopping Rx

bull PATIENT

bull Anti-VEGF ndash heavy user - Will comply

bull One stop much better than two stop for patient ndash Treat and extend

bull SERVICE

bull Capacity and demand planning = fixedT+E more predictable at least 1 month in advance ndash flexible nurse injectors

bull Steroids ndash even if well controlled (Iluvien for 3 years) need IOP check

bull Need pan-retinal examination both eyes ndash separate visits

Summary

CSMO

No centre involvement

Photocoagulation

Centre involvement

gt 78 letters(normalminimally reduced VA)

Photocoagulation

VA 78ndash24 letters

Phakic

Anti-VEGF

Pseudophakic

Anti-VEGF

SWITCHglaucoma

Injection tolerance

Medical issuesrecent CVA

Peripheral diseaseBilateral Rx

CSMO

No centre involvement

LASER

Centre involvement

gt 78 letters(normalminimally

reduced VA)

VA 78ndash24 letters

EYLEA OR LUCENTIS OR AVASTIN

Funding issues

Protocol T ndash poor VA lt 65 letters (615)

LOADING

Monthly injections until stability OR 5 x 112 (EYLEA) = 6 MONTHS then 8 weeks

RETREATMENT1

TREAT AND EXTEND - PRN

PRN

PSEUDOPHAKIC

Prior Rx

ILUVIEN

Chronic disease

OZURDEX

RETREATMENT

OZURDEX

OCT gt175um or any residual oedema

ILUVIEN after 12 months if risksltbenefits

OCT

gt400um

bull FACE TO FACE CLINICS RUNNING IN PARALLEL

bull = MAC002 every 6 months (optom or doctor) routine check for cataracttolerance of injectionsglaucoma issues etc

bull =MAC003 (DOCTOR) for problems as needed no fixed intervalDischargestop treatmentDeclines treatment diagnosis CSR overlay etcswitch drugs

bull =RV002- (DOCTOR) every 6 months

bull =DM002 ndash (DOCTOR) variable interval determined by last assessing doctor

bull First visit at 6 months from 1st injection if mild NPDR

bull Otherwise determined by retinopathy generally

LOADING PHASE

EyleaLucentis 1 within 48hrs of baseline

EyleaLucentis 2 (and LogMAR VA plus OCT same visit)

EyleaLucentis 3 (and LogMAR VA plus OCT same visit)

EyleaLucentis 4 (TEinj)(and Logmar VA plus OCT same visit

AFTER INJECTION 4 data goes off to be reviewed immediately as a hellip

TREAT AND EXTEND assessment ndash the next interval will depend on the response to the loading phase

NB -DMO patients ndash majority (95) will need 6 injctions x 112 of Lucentis

OR Eylea 5 x 112 then 8 weekly

ONCE STABLE for 3 x injection in TE phase

VIRTUAL CLINIC MONITORING OF MACULOPATHY AND PRN RETREATMENT

ANTI-VEGF INJECTION PATHWAYS Baseline visitMAC001 for wet AMDRV001 for CRVOBRVOMed ret clinic for DMO

Pathways ndash too many directions

Better that thanhellip

Thank you

ETDRS based laser therapies = Clinically significant macular oedema (CSMO)

bull The ETDRS defined CSMO as DMO that threatens the centre of the macula (fovea)1 and forms the basis of current recommendations for the treatment of CSMO2

bull CSMO is diagnosed if any of the following parameters are met1

1 ETDRS Research Group Arch Ophthalmol 19851031796ndash1806 2 Bandello F et al Eye (Lond) 201226(4)485ndash493

1 Retinal thickening within 500 microm of the centre of the macula

2 Hard exudates within 500 microm of the centre of the macula if associated with thickening of the adjacent retina

3 Retinal thickening of gt1 disc area in size any part of which is located within 1 disc diameter of the centre of the macula

500 microm

500 microm

1 discdiameter

ge 1 discdiameter

Fovea

8

ETDRS = Early Treatment Diabetic Retinopathy Study

LASER

RCO recommendations for the treatment of CSMO

The Royal College of Ophthalmologists Diabetic Retinopathy Guidelines 2012

CSMO

No centre involvement

Photocoagulation

Centre involvement

gt 78 letters(normalminimally reduced VA)

Photocoagulation

VA 78ndash24 letters

Phakic

Anti-VEGF

Pseudophakic

Anti-VEGF

9

ILUVIEN (chronicunresponsive)

OZURXEX (no improvement)

DMO ndash treatment optionsWhat treatments should I use at baseline

bull ETDRS based laser therapies

bull ADJUNCT

bull Surgery ndash VMTERM

bull Pan-retinal photocoagulation

bull INTRAVITREAL

bull ANTI-VEGF

bull Lucentis (Ranibizumab)

bull Eylea (Aflibercept)

bull Avastin (Bevacizumab)

bull STEROIDS

bull Iluvien (Fluocinolone)

bull Ozurdex (Dexamethasone)

11

BOLT

RESOLVERISE and RIDERELIGHT

DA VINCI

VIVID and VISTA

vs laser

vs sham

Steroids

(in combination

with laser)

Anti-VEGF

(in combination

with laser)

DRCRnet (Protocol I)

ETDRS

READ-2

RESTORE

RETAIN

REVEAL

DRCRnet (Protocol B)

FAMEMEAD

vs laser

vs sham

RanibizumabAflibercept

Bevacizumab

Triamcinolone

Fluocinolone acetonide Dexamethasone

Anti-VEGF Laser Steroids

DRCRnet PROTOCOL T

DMO ndash treatment optionsWhat treatments should I use at baseline ndash based on evidence from RCT data

What therapy do I choose for my patient at baselineWhich treatments can I access

NICE TA 274 Lucentis for DMO April 2013NICE TA 346 Eylea for DMO July 2015

NICE TA 301 Iluvien for DMO Nov 2013NICE TA 349 Ozurdex for DMO July 2015

OCT gt400um1st line if OCT suitable

bull Chronic DMObull PSEUDOPHAKICbull Patients ldquoinsufficiently responsive

to existing therapiesrdquo

bull PSEUDOPHAKICbull ldquoNot improved with non-

corticosteroid or such treatment is not suitable for themrdquo

What therapy do I choose for my patient at baseline

bull ANTI-VEGF

bull Superior to ETDRS argon laser in terms of efficacy

RESTORE 36 month Lucentis prn extension studyLucentis monotherapy vs Lucentis plus laser vs laser aloneSchmidt-Erfuth U et al Ophthalmology 2014 121(5) 1045-1053

23

Months

12

10

8

6

4

2

0

minus22 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36

Extension study (ranibizumab 05 mg PRN)Core study

Me

an o

f th

e c

han

ge in

ETD

RS

BC

VA

Prior ranibizumab 05 mg + active laser (n=83)

Prior sham injections + active laser (n=74)

Prior ranibizumab 05 mg + sham laser (n=83)

79

71 606780

Core study assessment

Full analysisstudy completionInterim analysis

RIDE

RISE

Mea

n ch

ange

in B

CVA

(E

TDR

S le

tters

)M

ean

chan

ge in

BC

VA

(ETD

RS

lette

rs)

Time (months)

RISE and RIDE (Lucentis monthly dosing) Mean change in BCVA over 36 months

Brown DM et al Ophthalmology 2013120(10)2013ndash2022

15

Ranibizumab 03 mgRanibizumab 05 mgShamranibizumab 05 mg

RISE amp RIDE

Date of Prep Dec 2014 LGB0820147252X

02 Laser

125 2q4

107 2q8

0

Mea

n ch

ange

in B

CVA

lette

r sco

re

2

101214

02

6

10

14

4

8

12

468

09 Laser

115 2q4

111 2q8

VISTA Week 100

100928068645652403628201240 8 16 24 32 44 48 60 72 76 84 88 96

12 Laser

100928068645652403628201240 8 16 24 32 44 48 60 72 76 84 88 96

105 2q4

107 2q8VIVID Week 100

Week Laser 2q4 2q8

07 Laser

114 2q4

94 2q8

Eylea =VIVID and VISTA Mean change in BCVA to week 100Korobelnik J-F et al Ophthalmology 2014 121 (11) 2247ndash2254 Brown DM et al Ophthalmology 2015 Jul 18 [Epub ahead of print]

Plt00001 vs laser VIVID Laser n=132 2q4 n=136 2q8 n=135 VISTA Laser n=154 2q4 n=154 2q8 n=151Full analysis set 2q4 2 mg every 4 weeks 2q8 2 mg every 8 weeks BCVA best corrected visual acuity ETDRS Early Treatment Diabetic Retinopathy Study

What therapy do I choose for my patient at baseline

bull ANTI-VEGF helliphellipif OCT gt 400um

bull Sohellip Which one

Key trials in DMO

18

BOLT

RESOLVERISE and RIDE

DA VINCI

VIVID and VISTA

vs laser

vs sham

Steroids

(in combination

with laser)

Anti-VEGF

(in combination

with laser)

DRCRnet (Protocol I)

ETDRS

READ-2

RESTORE

RETAIN

REVEAL

DRCRnet (Protocol B)

FAMEMEAD

vs laser

vs sham

RanibizumabAflibercept

Bevacizumab

Triamcinolone

Fluocinolone acetonide Dexamethasone

Anti-VEGF Laser Steroids

DRCRnet PROTOCOL T

PROTOCOL T (DRCRnet)

bull Aflibercept Bevacizumab or Ranibizumab for Diabetic Macular Edema

bull N Engl J Med 2015 Mar 26372(13)1193-203

The Diabetic retinopathy Clinical Research Network February 18 2015

USA study NIHR funded

n=660

Lucentis 03mg not 05mg Eylea 2mg Avastin 125mg

Eylea protocol not the licensed regime

Avastin unlicensed

RETREATMENT protocol

First 6 months ndash inject every month 95 of patients UNLESS VA=66 AND OCT DRY

Then 2nd six months ndash if no change after 3 visits DEFER otherwise keep injecting monthly

Recurs ndash need at least 2 injections ie 3 months of stability

STABILITY = 10 Oct change or VA 5 letter change

STABILITY and residual OCT thickness gt250um LASER

Protocol T 1 year visual acuity outcomes

0

5

10

15

20

0 8 16 24 32 40 48

Visit Week

2032-2040 = 696 ndash 612= 78-69

0

5

10

15

20

0 8 16 24 32 40 48

Visit Week

2050 = 615 or worse = lt69

Mea

n ch

ange

in B

CV

A

Mea

n ch

ange

in B

CV

A

Aflibercept Bevacizumab Ranibizumab

+189

+142

+118+75

+8+83

Protocol T OCT outcomes year 1

-250

-200

-150

-100

-50

0

0 4 8 12 16 20 24 28 32 36 40 44 48 52

Visit Week

Aflibercept Bevacizumab Ranibizumab

Mea

n ch

ange

in C

ST

Conclusions ndash Protocol T year 1 data

bull Eylea was statistically superior in terms of visual acuity to 03mg Lucentisand to Avastin FOR PATIENTS WITH VA worse than 69 letters

bull Eylea and Lucentis were statistically superior in terms of OCT CRT reduction to Avastin for all patients regardless of baseline vision

bull No safety differences between the three drugs

SUMMARY What do I choose for my patient at baselineOCT central retinal thickness (CRT)PseudophakicAttempts at prior treatment duration of DMO

bull lt 400um

bull IFR licensed anti-VEGF or Avastin

+-ETDRS laser

PSEUDOPHAKIC

Iluvien

Ozurdex

bull gt 400um = Anti-VEGF

Which one

Depends on

bull baseline vision lt615 Eylea

bull Fixed dosing attractive (Eylea)bull Chronic DMO

bull PSEUDOPHAKICbull Patients ldquoinsufficiently

responsive to existing therapiesrdquo

bull ldquoNot improved with non-corticosteroid or such treatment is not suitable for themrdquo

Which steroid ndash Ozurdex or Iluvien

bull No head to head data

bull Revisit this when we think about switching from ANTI-VEGF to steroid

Assuming we have started with an anti-VEGF agent ndash what are the re-treatment algorithms in DMO

Treatment posologies

ldquoTreatment is initiated with one injection per month until maximum VA is achieved andor there are no signs of disease activity ie no change in VA and in other signs and

symptoms of the disease under continued treatment

In patients withhellipDMOhellip initially three or more consecutive monthly injections may be needed Thereafter monitoring and treatment intervals

should be determined by the physician and should be based on disease activity as

assessed by VA andor anatomical parametershellip

If patients are being treated according to a treat-and-extend regimen once maximum VA is achieved andor there are no

signs of disease activity the treatment intervals can be extended stepwise until signs of

disease activity or visual impairment recur The treatment intervalhellipmay be extended by up to one month

at a time for DMOrdquo

1 Novartis Pharmaceuticals UK Ltd 30 October 2014 Available at httpwwwmedicinesorgukemcmedicine19409 Accessed 04 September 2015

2 Bayer Pharma AG February 2015 Available at httpwwwmedicinesorgukemcmedicine27224 Accessed 04 September 2015

Ranibizumab1 Aflibercept2

ldquohelliptreatment is initiated with one injection per month for five consecutive doses followed by

one injection every two months There is no requirement for monitoring between injectionshellip

After the first 12 months of treatmenthellipthe treatment interval may be extended based

on visual andor anatomic outcomes The schedule for monitoring should

be determined by the treating physicianrdquo

DMO diabetic macular oedema VA visual acuity

Re-treatment algorithms for anti-VEGF agents in DMO

bull LOADING PHASE

bull Lucentis label = monthly until stability

bull Eylea label = 5 x 112 then every 8 weeks ie fixed regime year 1

bull DRCRnet protocol T = effectively 6 x112 for majority (95) BUT actually only mandated for first 3 months then prn

bull helliphellip likely that majority will receive injections monthly for first 6 months

bull INDIVIDUALISED PHASE

bull Once ldquostablerdquo ndash based on VA and OCT

bull NB May never get a ldquodryrdquo OCT so treat to stability

bull THEN

bull Treat and extend

bull prn

What does Treat and Extend mean

Pathway overview = Lucentis prn

Jan

Loading phase = injections every 4 weeks until ldquostablerdquo for 3 visits

helliphelliphellip

Feb OctSepAugJulJunMayAprMar

MarFebJan

DecNov

DecNovOctSepAugJulJunMayApr

Then observe UNTIL VA decreases or OCT increase = prn

Once reactivates need at least 2 injections until stable again over 3 visits

Pathway overview = Treat and Extend

Jan

Loading phase = injections every 4 weeks until ldquostablerdquo for 3 visits or Eyleayear 1

helliphelliphellip

Feb OctSepAugJulJunMayAprMar

MarFebJan

DecNov

DecNovOctSepAugJulJunMayApr

Then keep injecting but extend the interval between injections gradually ie keep treating even if perfect

If reactivates need at least 2 injections until stable again over 3 visits

Pathway overview = Eylea fixed dosing year 1

Jan

Eylea = 5 x 112 injection then every 8 weeks

Average 6 injections yr 2 Beyond that

helliphelliphellip

Feb OctSepAugJulJunMayAprMar

MarFebJan

DecNov

DecNovOctSepAugJulJunMayApr

Then individualised UNTIL VA decreases or OCT increase = prn

Once reactivates need at least 2 injections until stable again over 3 visits

Pros and cons of Treat and Extend vs Prn

T+E PRN

PROS bull Proactive patient and service get advance warning of injection ndash capacity and demand planning easier

bull One ndashstopbull Fewer visits than prnbull Overtreatment

advantageous for peripheral retinopathy

bull Only treated when active ieno overtreatment

bull Aggressive year 1 protocols (DRCRN I ndash few injections needed thereafter

bull DMO tolerant of reactivations ()

CONS bull Overtreatment = riskexpenseinconvenience

bull Evidence base scantbull Bilateral disease tricky

bull Reactive so need enoughemergency capacity to inject when disease flares up

bull No advance warning to patientservice that injection needed

bull NEED TO DO IT WELL ndashNHS real life audits prn based regimes not good resultsUndertreatment in year 1 Affects long term prognosis and treatment burden

Pros and cons of Treat and Extend vs Prn

T+E PRN

PROS bull Proactive patient and service get advance warning of injection ndash capacity and demand planning easier

bull One ndashstopbull Fewer visits than prnbull Overtreatment

advantageous for peripheral retinopathy

bull Only treated when active ieno overtreatment

bull Aggressive year 1 protocols (DRCRN I ndash few injections needed thereafter

bull DMO tolerant of reactivations ()

CONS bull Overtreatment = riskexpenseinconvenience

bull Evidence base scantbull Bilateral disease tricky

bull Reactive so need enoughemergency capacity to inject when disease flares up

bull No advance warning to patientservice that injection needed

bull NEED TO DO IT WELL ndashNHS real life audits prn based regimes not good resultsUndertreatment in year 1 Affects long term prognosis and treatment burden

DMO ndash anti-VEGF Treat and Extend

bull Retain study ndash the only RCT data

bull Br J Ophthalmol 2015 Oct 9 pii bjophthalmol-2015-307249 doi 101136bjophthalmol-2015-307249 [Epub ahead of print]

bull Ranibizumab 05 mg treat-and-extend regimen for diabetic macular oedema the RETAIN study

bull Pruumlnte C1 Fajnkuchen F2 Mahmood S3 Ricci F4 Hatz K5 Studnička J6 Bezlyak V7 Parikh S7 Stubbings WJ7 Wenzel A7 Figueira J8 and the RETAIN Study Group

RETAIN Phase III trial evaluating the efficacy of lsquotreat and extendrsquo regimen (ARVO 2014)

bull Patients with DMO and visual impairment (n = 372) were randomised 111

to one of three groups for 24 months

bull Two phases to dosing schedule

bull Phase A

bull Patients in all groups were initially treated with monthly ranibizumab until BCVA remained

stable

bull Phase B

bull Patients in the TampE groups whose vision remained stable had treatment- free intervals

that were increased incrementally by 1 month for a maximum of 3 months

bull Patients in the PRN group had ongoing monthly monitoring

bull In all groups Phase A was resumed if a decrease in BCVA was observed at a visit

Ranibizumab 05 mg monotherapy

in TampE regimen

Ranibizumab 05 mg in TampE regimen

plus laser

Ranibizumab 05 mg PRN

35

RETAIN Visual acuity endpoints

Pruumlnte C ARVO 2014 Annual Meeting Abstracts Abstract 1700

Mean average change in BCVAat 12 months (primary endpoint)

Mean change in BCVA at 24 months

Mea

n av

erag

e ch

ange

in B

CVA

(ETD

RS

lette

rs)

RanibizumabTampE

RanibizumabTampE + laser

RanibizumabPRN

RanibizumabTampE

RanibizumabTampE + laser

RanibizumabPRN

Mea

n ch

ange

in B

CVA

(ETD

RS

lette

rs)

plt00001 for both ranibizumab TampE groups versus PRN for primary endpoint

36

RETAIN Patient visits and monitoring with TampE regimen over 24 months

bull The TampE regimen provided an approximately 40 reduction in the number of treatment visits required compared with the ranibizumab PRN regimen

bull Approximately 70 of patients receiving TampE regimens had monitoring intervals ge2 months compared with ongoing monthly monitoring in the ranibizumab PRN group

bull Informed the license for Lucentis in DMO (extend by 1 month at a time)

37

INTRAVITREAL STEROIDSWhich intravitreal steroid is better

bull Licensed steroids ndash Ozurdex (Dexamethasone) and Iluvien (Fluocinoloneacetonide

bull Which steroid is best in terms of VA outcomes hellipWE DONrsquoT KNOW FOR SURE ndash no head to head studies for licensed drugs either between steroids or between anti-VEGF and steroids

bull STEROIDS ARE efficacious in DMO

bull MEAD

bull FAME

bull DRCRnet protocol I

bull NICE ndash Ozurdex and Iluvien ndash second-line agents

Ozurdex

bull A biodegradable co-polymer implant ndash degrades in time to lactic and glycolic acid releasing Dexamethasone

bull 22gauge injectionbull MEAD study

bull N=1048

bull Dex 07mg vs 035mg vs sham

bull No rescue therapy

bull 3 year follow up max 6 monthly dosing ie 7 over 3 years

Gan IM et al Greafes Acrh Clin Exp Ophthalmol 2005

MEAD studyMean BCVA change from baseline based on baseline lens status

-2

0

2

4

6

8

10

0 3 6 9 12 15 18 21 24 27 30 33 36 39

Mea

n C

hang

e Fr

om

Bas

elin

e B

CVA

(Let

ters

)

Month

DEX Implant 07 mg (n = 86)

Sham (n = 101)

Boyer DS et al Ophthalmology 20141211904ndash14

Results analyzed in the ITT population with LOCF for missing values

Pseudophakic

Total

0

5

10

0 3 6 9 12 15 18 21 24 27 30 33 36 39

DEX 700 (n=351)

Sham (n=350)

10

8

6

4

2

0

Mea

n C

hang

e fr

om

Bas

elin

e B

CVA

(Let

ters

)

Month

07mg dose is approved as Ozurdexreg by the FDA and EMA 035mg dose not commercially available

1 Boyer DS et al Ophthalmology 2014 121 1904-1914

bull Nonbioerodible micro implant (polyimide) containing 190microg of fluocinolone acetonide (FAc)

bull Consistent daily submicrogram delivery of 02 microgd FAc for up to 36 months

bull Posterior point of release

bull 35 mm times 037 mm non-bioerodable micro implant

bull 25-gauge injector creates self-sealing wound

bull No measurable systemic exposure

ILUVIEN Implant Technology

FAcimplant

ILUVIEN SPC httpwwwmedicinesorgukemcmedicine27636

0 6 12 18 24 30 36

ILUVIEN 02 microgd FAc(n = 376)05 microgd FAc (n = 395)Control sham injection(n = 185)

Design of Phase 3 FAME Study (FAME A and B = same protocol)

Additional laser therapy allowed after week 6a

Retreatment any time after month 12 (if eligibleb)

Study ends

N = 956Randomisation

221Primary readout

Patients with DMO and

bull At least 1 previous laser tx

bull BCVA ge19 and le68 letters

bull TD-OCT FTH ge250 μm

Month

BCVA = best corrected visual acuity DMO = diabetic macular oedema TD-OCT=time domain optical coherence tomography FTH = foveal thicknessa At masked investigatorrsquos discretion b If BCVA loss ge5 letters or retinal thickening ge50 microm from best reading in previous 12 months

ge15 letter Gain is Greater in Chronic DMO Patients

ge 15

-Let

ter I

mpr

ovem

ent

in B

CVA

Fro

m B

asel

ine

Δ = 98

Months

Full Population Patients With Chronic DMO

Months

Δ = 206

287

189134

34

Steroid re-treatments

bullOzurdexbull Longer half-life than anti-VEGF in the eye

bull Redosing regimes not very helpful from RCT data eg MEAD study only 612 dosing

bull In reality re-treatment interval may be shorter

bull POSOLOGY

bull Patients treated with OZURDEX who have experienced an initial response and in the physicians opinion may benefit from retreatment without being exposed to significant risk should be considered for retreatment Retreatment may be performed after approximately 6 months if the patient experiences decreased vision andor an increase in retinal thickness secondary to recurrent or worsening diabetic macular oedema

bullIluvienbull 70 of patients in FAE only needed 1

injection over 3 years

bull BUT additional rescue treatments allowed

bull POSOLOGY

bull Each ILUVIEN implant releases fluocinolone acetonide for up to 36 months An additional implant may be administered after 12 months if the patient experiences decreased vision or an increase in retinal thickness secondary to recurrent or worsening diabetic macular oedema

bull Patients receiving escape medication were exited from MEAD before administration1

bull Macular laser rescue treatment allowed in RISERIDE (Lucentisreg) from 3 months2

bull Focalgrid laser allowed in FAME (Iluvienreg) from 6 weeks3

MEAD TREATMENT PROTOCOL

bull First treatment given at randomisation (day 0) bull Patients assessed for retreatment eligibility every 3 months from

months 6ndash36bull Patients were eligible for retreatment if

OCT optical coherence tomography

ge6 months since most recent

study treatment

Retinal thickness in 1 mm central macular

subfield by OCT gt175 microm

Evidence of residual retinal oedema (intraretinal cysts or

any regions of increased retinal thickening) as assessed by

investigator from OCT

AND OR

MEA

D

Amendment in May 2010 revised anatomic criterion for retreatment before this time the threshold was gt225 microm1Boyer DS et al Ophthalmology 2014 121 1904-19142Nguyen QD et al Ophthalmology 20121191064minus10773Campochiaro PA et al Ophthalmology 2011118626ndash635

Treatment burdenILUVIEN

Control(n =112)

02 microgd FAc(n =209)

Study Treatments(sham injection or ILUVIEN 02 microgday or FAc 05microgday)

1 treatment 661 761

2 treatments 277 187

ge 3 treatments 63 53

Rescue Laser Treatments (at masked physicianrsquos discretion after week 6)

Patients 607 407

Off-Protocol Treatments (IVTA bevacizumab ranibizumab intravitreal dexamethasone)

Patients 295 115

OZURDEX = 23injections year 1 41 by year 3

No other Rx

Summary of side effects with intravitreal steroids

Drug device Evidence base Cataract risk IOP rise (requiring drops)

Glaucoma surgery

endophthalmitis

ILUVIEN FAME studies 80 cat surgery(273 sham)

384(14 control)

48 0

Ozurdex MEAD 592 had cataract surgery(72 sham)

215 (end of study)(34 sham)

06 0

Trivaris+ laser vs Luc+laserx2 vs laser

Protocol IOphthalmology 2010

15 42(ONE OFgt10mmHg risegt30mmHGStart drops)

2186 0

NICE guidance for intravitreal steroids in DMO

bull Iluvien

bull NICE TA 301 Iluvien for DMO Nov 2013

bull hellipfor treating chronic diabetic macular oedema that is insufficiently responsive to available therapies only if

bull the implant is to be used in an eye with an intraocular

(pseudophakic) lens and

bull the manufacturer provides fluocinolone acetonide intravitreal implant with the discount agreed in the patient access scheme

NICE guidance for intravitreal steroids in DMO

bull Ozurdex

bull NICE TA 349 Ozurdex for DMO July 2015

bull there is an artificial lens in the eye to be treated and

bull their diabetic macular oedema has not improved with

non-corticosteroid treatment or such treatment is not suitable for them

Steroids = second line therapyWhen do I switch

bull Anti-VEGF first line for centre involving DMObull NICE TA ndash ldquoinsufficiently responsiverdquo ldquo ldquonot improvedrdquo ldquonot suitablerdquo ndash

OTHER TREATMENTS

bull 2 scenariosbull 1) Anti-VEGF canrsquot be funded ie OCTlt400um + PSEUDOPHAKIC

bull 2) Already had a course of treatment with laseranti-VEGF + PSEUDOPHAKIC ie SWITCHING from anti-VEGF to steroid

bull Plus

bull ldquochronicrdquo DMO ndash 3 years duration in FAME (18months) for ILUVIEN

bull Chronic DMO not essential for Ozurdex

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

Protocol T ndash patients may not improve in first 6 months

RIDE

RISE

Mea

n ch

ange

in B

CVA

(E

TDR

S le

tters

)M

ean

chan

ge in

BC

VA

(ETD

RS

lette

rs)

Time (months)

RISE and RIDE (Lucentis monthly dosing) Mean change in BCVA over 36 months

Brown DM et al Ophthalmology 2013120(10)2013ndash2022

54

Ranibizumab 03 mgRanibizumab 05 mgShamranibizumab 05 mg

Date of Prep Dec 2014 LGB0820147252X

VA improvement continues throughout year 1 with monthly dosing

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user ndash more than protocol

I

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

DRCRN protocol I5 year outcomesInjections 8-9 in year 1Year 2 = 2-3Year 3= 1-2Year 4 = 0-1Year 5 = 0

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

Wait for plateau = stability in protocol T laserPatient factors again

Judgement of response to anti-VEGF ndashtimeframe

bull Wait 6 months in poor responders

bull Wait 1 year for heavy users

bull Tempting to try steroids earlier than this ifbull No glaucoma ndash not a deal breaker Ozurdex better short term optionbull Pseudophakic

bull Clues from the diseasebull chronic

bull PATIENT FACTORS

bull Any eyes avoid steroids ndash advanced glaucomaCSCR Or prior viral retinitis RARE

bull Any eyes avoid anti-VEGF pregnancytrying to concieve recent CVA

BIOMARKERS AT BASELINE WOULD BE USEFULRESTORE subgroup analysis of OCT features

bull Andreas Pollreisz EURETINA 2015

bull OCT biomarkers (RESTORE data)

bull Better effects with anti-VEGF ifbull Small rather than large intra-retinal cyst

bull Sub-retinal fluid present

bull Vitreo-macular adhesion at baseline

bull No disruption of ELM and ISOS junction

bull No disorganisation of inner retinal layers (DRIL)

RESTORE subgroup analysis of OCT features

bull Andreas Pollreisz EURETINA 2015

bull OCT biomarkers (RESTORE data)

bull Better effects with anti-VEGF ifbull Small rather than large intra-retinal cyst

bull Sub-retinal fluid present

bull Vitreo-macular adhesion at baseline

bull No disruption of ELM and ISOS junction

bull No disorganisation of inner retinal layers (DRIL)

Better baseline characterisationclassificationERG Contrast sensitivityOCT AngiographyMicroperimetry= clues as to who responds best to which drug

Plan for this presentation helliphellipa long list

bull What treatment options are available for DMO (evidence base)

bull What treatment should I start with at baselinebull Re-treatment algorithms for intravitreal DMO therapiesbull When should I switchcombine therapiesbull The bigger picture

bull Other eyebull The patient as a wholebull The service -coping with capacity ndash compromises

The bigger pictureOther eyeThe patient as a wholeThe service -coping with capacity ndash compromises

bull OTHER EYE ndash may create problems

bull Treat and extend ndash ldquoreduce of visitsrdquo plus Eylea license ndash ldquono need for monitoringrdquo may not benefit if lots of visits due to PDR other eye

bull PERIPHERAL RETINA anti-VEGF supresses proliferative disease - Rebound on stopping Rx

bull PATIENT

bull Anti-VEGF ndash heavy user - Will comply

bull One stop much better than two stop for patient ndash Treat and extend

bull SERVICE

bull Capacity and demand planning = fixedT+E more predictable at least 1 month in advance ndash flexible nurse injectors

bull Steroids ndash even if well controlled (Iluvien for 3 years) need IOP check

bull Need pan-retinal examination both eyes ndash separate visits

Summary

CSMO

No centre involvement

Photocoagulation

Centre involvement

gt 78 letters(normalminimally reduced VA)

Photocoagulation

VA 78ndash24 letters

Phakic

Anti-VEGF

Pseudophakic

Anti-VEGF

SWITCHglaucoma

Injection tolerance

Medical issuesrecent CVA

Peripheral diseaseBilateral Rx

CSMO

No centre involvement

LASER

Centre involvement

gt 78 letters(normalminimally

reduced VA)

VA 78ndash24 letters

EYLEA OR LUCENTIS OR AVASTIN

Funding issues

Protocol T ndash poor VA lt 65 letters (615)

LOADING

Monthly injections until stability OR 5 x 112 (EYLEA) = 6 MONTHS then 8 weeks

RETREATMENT1

TREAT AND EXTEND - PRN

PRN

PSEUDOPHAKIC

Prior Rx

ILUVIEN

Chronic disease

OZURDEX

RETREATMENT

OZURDEX

OCT gt175um or any residual oedema

ILUVIEN after 12 months if risksltbenefits

OCT

gt400um

bull FACE TO FACE CLINICS RUNNING IN PARALLEL

bull = MAC002 every 6 months (optom or doctor) routine check for cataracttolerance of injectionsglaucoma issues etc

bull =MAC003 (DOCTOR) for problems as needed no fixed intervalDischargestop treatmentDeclines treatment diagnosis CSR overlay etcswitch drugs

bull =RV002- (DOCTOR) every 6 months

bull =DM002 ndash (DOCTOR) variable interval determined by last assessing doctor

bull First visit at 6 months from 1st injection if mild NPDR

bull Otherwise determined by retinopathy generally

LOADING PHASE

EyleaLucentis 1 within 48hrs of baseline

EyleaLucentis 2 (and LogMAR VA plus OCT same visit)

EyleaLucentis 3 (and LogMAR VA plus OCT same visit)

EyleaLucentis 4 (TEinj)(and Logmar VA plus OCT same visit

AFTER INJECTION 4 data goes off to be reviewed immediately as a hellip

TREAT AND EXTEND assessment ndash the next interval will depend on the response to the loading phase

NB -DMO patients ndash majority (95) will need 6 injctions x 112 of Lucentis

OR Eylea 5 x 112 then 8 weekly

ONCE STABLE for 3 x injection in TE phase

VIRTUAL CLINIC MONITORING OF MACULOPATHY AND PRN RETREATMENT

ANTI-VEGF INJECTION PATHWAYS Baseline visitMAC001 for wet AMDRV001 for CRVOBRVOMed ret clinic for DMO

Pathways ndash too many directions

Better that thanhellip

Thank you

RCO recommendations for the treatment of CSMO

The Royal College of Ophthalmologists Diabetic Retinopathy Guidelines 2012

CSMO

No centre involvement

Photocoagulation

Centre involvement

gt 78 letters(normalminimally reduced VA)

Photocoagulation

VA 78ndash24 letters

Phakic

Anti-VEGF

Pseudophakic

Anti-VEGF

9

ILUVIEN (chronicunresponsive)

OZURXEX (no improvement)

DMO ndash treatment optionsWhat treatments should I use at baseline

bull ETDRS based laser therapies

bull ADJUNCT

bull Surgery ndash VMTERM

bull Pan-retinal photocoagulation

bull INTRAVITREAL

bull ANTI-VEGF

bull Lucentis (Ranibizumab)

bull Eylea (Aflibercept)

bull Avastin (Bevacizumab)

bull STEROIDS

bull Iluvien (Fluocinolone)

bull Ozurdex (Dexamethasone)

11

BOLT

RESOLVERISE and RIDERELIGHT

DA VINCI

VIVID and VISTA

vs laser

vs sham

Steroids

(in combination

with laser)

Anti-VEGF

(in combination

with laser)

DRCRnet (Protocol I)

ETDRS

READ-2

RESTORE

RETAIN

REVEAL

DRCRnet (Protocol B)

FAMEMEAD

vs laser

vs sham

RanibizumabAflibercept

Bevacizumab

Triamcinolone

Fluocinolone acetonide Dexamethasone

Anti-VEGF Laser Steroids

DRCRnet PROTOCOL T

DMO ndash treatment optionsWhat treatments should I use at baseline ndash based on evidence from RCT data

What therapy do I choose for my patient at baselineWhich treatments can I access

NICE TA 274 Lucentis for DMO April 2013NICE TA 346 Eylea for DMO July 2015

NICE TA 301 Iluvien for DMO Nov 2013NICE TA 349 Ozurdex for DMO July 2015

OCT gt400um1st line if OCT suitable

bull Chronic DMObull PSEUDOPHAKICbull Patients ldquoinsufficiently responsive

to existing therapiesrdquo

bull PSEUDOPHAKICbull ldquoNot improved with non-

corticosteroid or such treatment is not suitable for themrdquo

What therapy do I choose for my patient at baseline

bull ANTI-VEGF

bull Superior to ETDRS argon laser in terms of efficacy

RESTORE 36 month Lucentis prn extension studyLucentis monotherapy vs Lucentis plus laser vs laser aloneSchmidt-Erfuth U et al Ophthalmology 2014 121(5) 1045-1053

23

Months

12

10

8

6

4

2

0

minus22 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36

Extension study (ranibizumab 05 mg PRN)Core study

Me

an o

f th

e c

han

ge in

ETD

RS

BC

VA

Prior ranibizumab 05 mg + active laser (n=83)

Prior sham injections + active laser (n=74)

Prior ranibizumab 05 mg + sham laser (n=83)

79

71 606780

Core study assessment

Full analysisstudy completionInterim analysis

RIDE

RISE

Mea

n ch

ange

in B

CVA

(E

TDR

S le

tters

)M

ean

chan

ge in

BC

VA

(ETD

RS

lette

rs)

Time (months)

RISE and RIDE (Lucentis monthly dosing) Mean change in BCVA over 36 months

Brown DM et al Ophthalmology 2013120(10)2013ndash2022

15

Ranibizumab 03 mgRanibizumab 05 mgShamranibizumab 05 mg

RISE amp RIDE

Date of Prep Dec 2014 LGB0820147252X

02 Laser

125 2q4

107 2q8

0

Mea

n ch

ange

in B

CVA

lette

r sco

re

2

101214

02

6

10

14

4

8

12

468

09 Laser

115 2q4

111 2q8

VISTA Week 100

100928068645652403628201240 8 16 24 32 44 48 60 72 76 84 88 96

12 Laser

100928068645652403628201240 8 16 24 32 44 48 60 72 76 84 88 96

105 2q4

107 2q8VIVID Week 100

Week Laser 2q4 2q8

07 Laser

114 2q4

94 2q8

Eylea =VIVID and VISTA Mean change in BCVA to week 100Korobelnik J-F et al Ophthalmology 2014 121 (11) 2247ndash2254 Brown DM et al Ophthalmology 2015 Jul 18 [Epub ahead of print]

Plt00001 vs laser VIVID Laser n=132 2q4 n=136 2q8 n=135 VISTA Laser n=154 2q4 n=154 2q8 n=151Full analysis set 2q4 2 mg every 4 weeks 2q8 2 mg every 8 weeks BCVA best corrected visual acuity ETDRS Early Treatment Diabetic Retinopathy Study

What therapy do I choose for my patient at baseline

bull ANTI-VEGF helliphellipif OCT gt 400um

bull Sohellip Which one

Key trials in DMO

18

BOLT

RESOLVERISE and RIDE

DA VINCI

VIVID and VISTA

vs laser

vs sham

Steroids

(in combination

with laser)

Anti-VEGF

(in combination

with laser)

DRCRnet (Protocol I)

ETDRS

READ-2

RESTORE

RETAIN

REVEAL

DRCRnet (Protocol B)

FAMEMEAD

vs laser

vs sham

RanibizumabAflibercept

Bevacizumab

Triamcinolone

Fluocinolone acetonide Dexamethasone

Anti-VEGF Laser Steroids

DRCRnet PROTOCOL T

PROTOCOL T (DRCRnet)

bull Aflibercept Bevacizumab or Ranibizumab for Diabetic Macular Edema

bull N Engl J Med 2015 Mar 26372(13)1193-203

The Diabetic retinopathy Clinical Research Network February 18 2015

USA study NIHR funded

n=660

Lucentis 03mg not 05mg Eylea 2mg Avastin 125mg

Eylea protocol not the licensed regime

Avastin unlicensed

RETREATMENT protocol

First 6 months ndash inject every month 95 of patients UNLESS VA=66 AND OCT DRY

Then 2nd six months ndash if no change after 3 visits DEFER otherwise keep injecting monthly

Recurs ndash need at least 2 injections ie 3 months of stability

STABILITY = 10 Oct change or VA 5 letter change

STABILITY and residual OCT thickness gt250um LASER

Protocol T 1 year visual acuity outcomes

0

5

10

15

20

0 8 16 24 32 40 48

Visit Week

2032-2040 = 696 ndash 612= 78-69

0

5

10

15

20

0 8 16 24 32 40 48

Visit Week

2050 = 615 or worse = lt69

Mea

n ch

ange

in B

CV

A

Mea

n ch

ange

in B

CV

A

Aflibercept Bevacizumab Ranibizumab

+189

+142

+118+75

+8+83

Protocol T OCT outcomes year 1

-250

-200

-150

-100

-50

0

0 4 8 12 16 20 24 28 32 36 40 44 48 52

Visit Week

Aflibercept Bevacizumab Ranibizumab

Mea

n ch

ange

in C

ST

Conclusions ndash Protocol T year 1 data

bull Eylea was statistically superior in terms of visual acuity to 03mg Lucentisand to Avastin FOR PATIENTS WITH VA worse than 69 letters

bull Eylea and Lucentis were statistically superior in terms of OCT CRT reduction to Avastin for all patients regardless of baseline vision

bull No safety differences between the three drugs

SUMMARY What do I choose for my patient at baselineOCT central retinal thickness (CRT)PseudophakicAttempts at prior treatment duration of DMO

bull lt 400um

bull IFR licensed anti-VEGF or Avastin

+-ETDRS laser

PSEUDOPHAKIC

Iluvien

Ozurdex

bull gt 400um = Anti-VEGF

Which one

Depends on

bull baseline vision lt615 Eylea

bull Fixed dosing attractive (Eylea)bull Chronic DMO

bull PSEUDOPHAKICbull Patients ldquoinsufficiently

responsive to existing therapiesrdquo

bull ldquoNot improved with non-corticosteroid or such treatment is not suitable for themrdquo

Which steroid ndash Ozurdex or Iluvien

bull No head to head data

bull Revisit this when we think about switching from ANTI-VEGF to steroid

Assuming we have started with an anti-VEGF agent ndash what are the re-treatment algorithms in DMO

Treatment posologies

ldquoTreatment is initiated with one injection per month until maximum VA is achieved andor there are no signs of disease activity ie no change in VA and in other signs and

symptoms of the disease under continued treatment

In patients withhellipDMOhellip initially three or more consecutive monthly injections may be needed Thereafter monitoring and treatment intervals

should be determined by the physician and should be based on disease activity as

assessed by VA andor anatomical parametershellip

If patients are being treated according to a treat-and-extend regimen once maximum VA is achieved andor there are no

signs of disease activity the treatment intervals can be extended stepwise until signs of

disease activity or visual impairment recur The treatment intervalhellipmay be extended by up to one month

at a time for DMOrdquo

1 Novartis Pharmaceuticals UK Ltd 30 October 2014 Available at httpwwwmedicinesorgukemcmedicine19409 Accessed 04 September 2015

2 Bayer Pharma AG February 2015 Available at httpwwwmedicinesorgukemcmedicine27224 Accessed 04 September 2015

Ranibizumab1 Aflibercept2

ldquohelliptreatment is initiated with one injection per month for five consecutive doses followed by

one injection every two months There is no requirement for monitoring between injectionshellip

After the first 12 months of treatmenthellipthe treatment interval may be extended based

on visual andor anatomic outcomes The schedule for monitoring should

be determined by the treating physicianrdquo

DMO diabetic macular oedema VA visual acuity

Re-treatment algorithms for anti-VEGF agents in DMO

bull LOADING PHASE

bull Lucentis label = monthly until stability

bull Eylea label = 5 x 112 then every 8 weeks ie fixed regime year 1

bull DRCRnet protocol T = effectively 6 x112 for majority (95) BUT actually only mandated for first 3 months then prn

bull helliphellip likely that majority will receive injections monthly for first 6 months

bull INDIVIDUALISED PHASE

bull Once ldquostablerdquo ndash based on VA and OCT

bull NB May never get a ldquodryrdquo OCT so treat to stability

bull THEN

bull Treat and extend

bull prn

What does Treat and Extend mean

Pathway overview = Lucentis prn

Jan

Loading phase = injections every 4 weeks until ldquostablerdquo for 3 visits

helliphelliphellip

Feb OctSepAugJulJunMayAprMar

MarFebJan

DecNov

DecNovOctSepAugJulJunMayApr

Then observe UNTIL VA decreases or OCT increase = prn

Once reactivates need at least 2 injections until stable again over 3 visits

Pathway overview = Treat and Extend

Jan

Loading phase = injections every 4 weeks until ldquostablerdquo for 3 visits or Eyleayear 1

helliphelliphellip

Feb OctSepAugJulJunMayAprMar

MarFebJan

DecNov

DecNovOctSepAugJulJunMayApr

Then keep injecting but extend the interval between injections gradually ie keep treating even if perfect

If reactivates need at least 2 injections until stable again over 3 visits

Pathway overview = Eylea fixed dosing year 1

Jan

Eylea = 5 x 112 injection then every 8 weeks

Average 6 injections yr 2 Beyond that

helliphelliphellip

Feb OctSepAugJulJunMayAprMar

MarFebJan

DecNov

DecNovOctSepAugJulJunMayApr

Then individualised UNTIL VA decreases or OCT increase = prn

Once reactivates need at least 2 injections until stable again over 3 visits

Pros and cons of Treat and Extend vs Prn

T+E PRN

PROS bull Proactive patient and service get advance warning of injection ndash capacity and demand planning easier

bull One ndashstopbull Fewer visits than prnbull Overtreatment

advantageous for peripheral retinopathy

bull Only treated when active ieno overtreatment

bull Aggressive year 1 protocols (DRCRN I ndash few injections needed thereafter

bull DMO tolerant of reactivations ()

CONS bull Overtreatment = riskexpenseinconvenience

bull Evidence base scantbull Bilateral disease tricky

bull Reactive so need enoughemergency capacity to inject when disease flares up

bull No advance warning to patientservice that injection needed

bull NEED TO DO IT WELL ndashNHS real life audits prn based regimes not good resultsUndertreatment in year 1 Affects long term prognosis and treatment burden

Pros and cons of Treat and Extend vs Prn

T+E PRN

PROS bull Proactive patient and service get advance warning of injection ndash capacity and demand planning easier

bull One ndashstopbull Fewer visits than prnbull Overtreatment

advantageous for peripheral retinopathy

bull Only treated when active ieno overtreatment

bull Aggressive year 1 protocols (DRCRN I ndash few injections needed thereafter

bull DMO tolerant of reactivations ()

CONS bull Overtreatment = riskexpenseinconvenience

bull Evidence base scantbull Bilateral disease tricky

bull Reactive so need enoughemergency capacity to inject when disease flares up

bull No advance warning to patientservice that injection needed

bull NEED TO DO IT WELL ndashNHS real life audits prn based regimes not good resultsUndertreatment in year 1 Affects long term prognosis and treatment burden

DMO ndash anti-VEGF Treat and Extend

bull Retain study ndash the only RCT data

bull Br J Ophthalmol 2015 Oct 9 pii bjophthalmol-2015-307249 doi 101136bjophthalmol-2015-307249 [Epub ahead of print]

bull Ranibizumab 05 mg treat-and-extend regimen for diabetic macular oedema the RETAIN study

bull Pruumlnte C1 Fajnkuchen F2 Mahmood S3 Ricci F4 Hatz K5 Studnička J6 Bezlyak V7 Parikh S7 Stubbings WJ7 Wenzel A7 Figueira J8 and the RETAIN Study Group

RETAIN Phase III trial evaluating the efficacy of lsquotreat and extendrsquo regimen (ARVO 2014)

bull Patients with DMO and visual impairment (n = 372) were randomised 111

to one of three groups for 24 months

bull Two phases to dosing schedule

bull Phase A

bull Patients in all groups were initially treated with monthly ranibizumab until BCVA remained

stable

bull Phase B

bull Patients in the TampE groups whose vision remained stable had treatment- free intervals

that were increased incrementally by 1 month for a maximum of 3 months

bull Patients in the PRN group had ongoing monthly monitoring

bull In all groups Phase A was resumed if a decrease in BCVA was observed at a visit

Ranibizumab 05 mg monotherapy

in TampE regimen

Ranibizumab 05 mg in TampE regimen

plus laser

Ranibizumab 05 mg PRN

35

RETAIN Visual acuity endpoints

Pruumlnte C ARVO 2014 Annual Meeting Abstracts Abstract 1700

Mean average change in BCVAat 12 months (primary endpoint)

Mean change in BCVA at 24 months

Mea

n av

erag

e ch

ange

in B

CVA

(ETD

RS

lette

rs)

RanibizumabTampE

RanibizumabTampE + laser

RanibizumabPRN

RanibizumabTampE

RanibizumabTampE + laser

RanibizumabPRN

Mea

n ch

ange

in B

CVA

(ETD

RS

lette

rs)

plt00001 for both ranibizumab TampE groups versus PRN for primary endpoint

36

RETAIN Patient visits and monitoring with TampE regimen over 24 months

bull The TampE regimen provided an approximately 40 reduction in the number of treatment visits required compared with the ranibizumab PRN regimen

bull Approximately 70 of patients receiving TampE regimens had monitoring intervals ge2 months compared with ongoing monthly monitoring in the ranibizumab PRN group

bull Informed the license for Lucentis in DMO (extend by 1 month at a time)

37

INTRAVITREAL STEROIDSWhich intravitreal steroid is better

bull Licensed steroids ndash Ozurdex (Dexamethasone) and Iluvien (Fluocinoloneacetonide

bull Which steroid is best in terms of VA outcomes hellipWE DONrsquoT KNOW FOR SURE ndash no head to head studies for licensed drugs either between steroids or between anti-VEGF and steroids

bull STEROIDS ARE efficacious in DMO

bull MEAD

bull FAME

bull DRCRnet protocol I

bull NICE ndash Ozurdex and Iluvien ndash second-line agents

Ozurdex

bull A biodegradable co-polymer implant ndash degrades in time to lactic and glycolic acid releasing Dexamethasone

bull 22gauge injectionbull MEAD study

bull N=1048

bull Dex 07mg vs 035mg vs sham

bull No rescue therapy

bull 3 year follow up max 6 monthly dosing ie 7 over 3 years

Gan IM et al Greafes Acrh Clin Exp Ophthalmol 2005

MEAD studyMean BCVA change from baseline based on baseline lens status

-2

0

2

4

6

8

10

0 3 6 9 12 15 18 21 24 27 30 33 36 39

Mea

n C

hang

e Fr

om

Bas

elin

e B

CVA

(Let

ters

)

Month

DEX Implant 07 mg (n = 86)

Sham (n = 101)

Boyer DS et al Ophthalmology 20141211904ndash14

Results analyzed in the ITT population with LOCF for missing values

Pseudophakic

Total

0

5

10

0 3 6 9 12 15 18 21 24 27 30 33 36 39

DEX 700 (n=351)

Sham (n=350)

10

8

6

4

2

0

Mea

n C

hang

e fr

om

Bas

elin

e B

CVA

(Let

ters

)

Month

07mg dose is approved as Ozurdexreg by the FDA and EMA 035mg dose not commercially available

1 Boyer DS et al Ophthalmology 2014 121 1904-1914

bull Nonbioerodible micro implant (polyimide) containing 190microg of fluocinolone acetonide (FAc)

bull Consistent daily submicrogram delivery of 02 microgd FAc for up to 36 months

bull Posterior point of release

bull 35 mm times 037 mm non-bioerodable micro implant

bull 25-gauge injector creates self-sealing wound

bull No measurable systemic exposure

ILUVIEN Implant Technology

FAcimplant

ILUVIEN SPC httpwwwmedicinesorgukemcmedicine27636

0 6 12 18 24 30 36

ILUVIEN 02 microgd FAc(n = 376)05 microgd FAc (n = 395)Control sham injection(n = 185)

Design of Phase 3 FAME Study (FAME A and B = same protocol)

Additional laser therapy allowed after week 6a

Retreatment any time after month 12 (if eligibleb)

Study ends

N = 956Randomisation

221Primary readout

Patients with DMO and

bull At least 1 previous laser tx

bull BCVA ge19 and le68 letters

bull TD-OCT FTH ge250 μm

Month

BCVA = best corrected visual acuity DMO = diabetic macular oedema TD-OCT=time domain optical coherence tomography FTH = foveal thicknessa At masked investigatorrsquos discretion b If BCVA loss ge5 letters or retinal thickening ge50 microm from best reading in previous 12 months

ge15 letter Gain is Greater in Chronic DMO Patients

ge 15

-Let

ter I

mpr

ovem

ent

in B

CVA

Fro

m B

asel

ine

Δ = 98

Months

Full Population Patients With Chronic DMO

Months

Δ = 206

287

189134

34

Steroid re-treatments

bullOzurdexbull Longer half-life than anti-VEGF in the eye

bull Redosing regimes not very helpful from RCT data eg MEAD study only 612 dosing

bull In reality re-treatment interval may be shorter

bull POSOLOGY

bull Patients treated with OZURDEX who have experienced an initial response and in the physicians opinion may benefit from retreatment without being exposed to significant risk should be considered for retreatment Retreatment may be performed after approximately 6 months if the patient experiences decreased vision andor an increase in retinal thickness secondary to recurrent or worsening diabetic macular oedema

bullIluvienbull 70 of patients in FAE only needed 1

injection over 3 years

bull BUT additional rescue treatments allowed

bull POSOLOGY

bull Each ILUVIEN implant releases fluocinolone acetonide for up to 36 months An additional implant may be administered after 12 months if the patient experiences decreased vision or an increase in retinal thickness secondary to recurrent or worsening diabetic macular oedema

bull Patients receiving escape medication were exited from MEAD before administration1

bull Macular laser rescue treatment allowed in RISERIDE (Lucentisreg) from 3 months2

bull Focalgrid laser allowed in FAME (Iluvienreg) from 6 weeks3

MEAD TREATMENT PROTOCOL

bull First treatment given at randomisation (day 0) bull Patients assessed for retreatment eligibility every 3 months from

months 6ndash36bull Patients were eligible for retreatment if

OCT optical coherence tomography

ge6 months since most recent

study treatment

Retinal thickness in 1 mm central macular

subfield by OCT gt175 microm

Evidence of residual retinal oedema (intraretinal cysts or

any regions of increased retinal thickening) as assessed by

investigator from OCT

AND OR

MEA

D

Amendment in May 2010 revised anatomic criterion for retreatment before this time the threshold was gt225 microm1Boyer DS et al Ophthalmology 2014 121 1904-19142Nguyen QD et al Ophthalmology 20121191064minus10773Campochiaro PA et al Ophthalmology 2011118626ndash635

Treatment burdenILUVIEN

Control(n =112)

02 microgd FAc(n =209)

Study Treatments(sham injection or ILUVIEN 02 microgday or FAc 05microgday)

1 treatment 661 761

2 treatments 277 187

ge 3 treatments 63 53

Rescue Laser Treatments (at masked physicianrsquos discretion after week 6)

Patients 607 407

Off-Protocol Treatments (IVTA bevacizumab ranibizumab intravitreal dexamethasone)

Patients 295 115

OZURDEX = 23injections year 1 41 by year 3

No other Rx

Summary of side effects with intravitreal steroids

Drug device Evidence base Cataract risk IOP rise (requiring drops)

Glaucoma surgery

endophthalmitis

ILUVIEN FAME studies 80 cat surgery(273 sham)

384(14 control)

48 0

Ozurdex MEAD 592 had cataract surgery(72 sham)

215 (end of study)(34 sham)

06 0

Trivaris+ laser vs Luc+laserx2 vs laser

Protocol IOphthalmology 2010

15 42(ONE OFgt10mmHg risegt30mmHGStart drops)

2186 0

NICE guidance for intravitreal steroids in DMO

bull Iluvien

bull NICE TA 301 Iluvien for DMO Nov 2013

bull hellipfor treating chronic diabetic macular oedema that is insufficiently responsive to available therapies only if

bull the implant is to be used in an eye with an intraocular

(pseudophakic) lens and

bull the manufacturer provides fluocinolone acetonide intravitreal implant with the discount agreed in the patient access scheme

NICE guidance for intravitreal steroids in DMO

bull Ozurdex

bull NICE TA 349 Ozurdex for DMO July 2015

bull there is an artificial lens in the eye to be treated and

bull their diabetic macular oedema has not improved with

non-corticosteroid treatment or such treatment is not suitable for them

Steroids = second line therapyWhen do I switch

bull Anti-VEGF first line for centre involving DMObull NICE TA ndash ldquoinsufficiently responsiverdquo ldquo ldquonot improvedrdquo ldquonot suitablerdquo ndash

OTHER TREATMENTS

bull 2 scenariosbull 1) Anti-VEGF canrsquot be funded ie OCTlt400um + PSEUDOPHAKIC

bull 2) Already had a course of treatment with laseranti-VEGF + PSEUDOPHAKIC ie SWITCHING from anti-VEGF to steroid

bull Plus

bull ldquochronicrdquo DMO ndash 3 years duration in FAME (18months) for ILUVIEN

bull Chronic DMO not essential for Ozurdex

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

Protocol T ndash patients may not improve in first 6 months

RIDE

RISE

Mea

n ch

ange

in B

CVA

(E

TDR

S le

tters

)M

ean

chan

ge in

BC

VA

(ETD

RS

lette

rs)

Time (months)

RISE and RIDE (Lucentis monthly dosing) Mean change in BCVA over 36 months

Brown DM et al Ophthalmology 2013120(10)2013ndash2022

54

Ranibizumab 03 mgRanibizumab 05 mgShamranibizumab 05 mg

Date of Prep Dec 2014 LGB0820147252X

VA improvement continues throughout year 1 with monthly dosing

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user ndash more than protocol

I

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

DRCRN protocol I5 year outcomesInjections 8-9 in year 1Year 2 = 2-3Year 3= 1-2Year 4 = 0-1Year 5 = 0

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

Wait for plateau = stability in protocol T laserPatient factors again

Judgement of response to anti-VEGF ndashtimeframe

bull Wait 6 months in poor responders

bull Wait 1 year for heavy users

bull Tempting to try steroids earlier than this ifbull No glaucoma ndash not a deal breaker Ozurdex better short term optionbull Pseudophakic

bull Clues from the diseasebull chronic

bull PATIENT FACTORS

bull Any eyes avoid steroids ndash advanced glaucomaCSCR Or prior viral retinitis RARE

bull Any eyes avoid anti-VEGF pregnancytrying to concieve recent CVA

BIOMARKERS AT BASELINE WOULD BE USEFULRESTORE subgroup analysis of OCT features

bull Andreas Pollreisz EURETINA 2015

bull OCT biomarkers (RESTORE data)

bull Better effects with anti-VEGF ifbull Small rather than large intra-retinal cyst

bull Sub-retinal fluid present

bull Vitreo-macular adhesion at baseline

bull No disruption of ELM and ISOS junction

bull No disorganisation of inner retinal layers (DRIL)

RESTORE subgroup analysis of OCT features

bull Andreas Pollreisz EURETINA 2015

bull OCT biomarkers (RESTORE data)

bull Better effects with anti-VEGF ifbull Small rather than large intra-retinal cyst

bull Sub-retinal fluid present

bull Vitreo-macular adhesion at baseline

bull No disruption of ELM and ISOS junction

bull No disorganisation of inner retinal layers (DRIL)

Better baseline characterisationclassificationERG Contrast sensitivityOCT AngiographyMicroperimetry= clues as to who responds best to which drug

Plan for this presentation helliphellipa long list

bull What treatment options are available for DMO (evidence base)

bull What treatment should I start with at baselinebull Re-treatment algorithms for intravitreal DMO therapiesbull When should I switchcombine therapiesbull The bigger picture

bull Other eyebull The patient as a wholebull The service -coping with capacity ndash compromises

The bigger pictureOther eyeThe patient as a wholeThe service -coping with capacity ndash compromises

bull OTHER EYE ndash may create problems

bull Treat and extend ndash ldquoreduce of visitsrdquo plus Eylea license ndash ldquono need for monitoringrdquo may not benefit if lots of visits due to PDR other eye

bull PERIPHERAL RETINA anti-VEGF supresses proliferative disease - Rebound on stopping Rx

bull PATIENT

bull Anti-VEGF ndash heavy user - Will comply

bull One stop much better than two stop for patient ndash Treat and extend

bull SERVICE

bull Capacity and demand planning = fixedT+E more predictable at least 1 month in advance ndash flexible nurse injectors

bull Steroids ndash even if well controlled (Iluvien for 3 years) need IOP check

bull Need pan-retinal examination both eyes ndash separate visits

Summary

CSMO

No centre involvement

Photocoagulation

Centre involvement

gt 78 letters(normalminimally reduced VA)

Photocoagulation

VA 78ndash24 letters

Phakic

Anti-VEGF

Pseudophakic

Anti-VEGF

SWITCHglaucoma

Injection tolerance

Medical issuesrecent CVA

Peripheral diseaseBilateral Rx

CSMO

No centre involvement

LASER

Centre involvement

gt 78 letters(normalminimally

reduced VA)

VA 78ndash24 letters

EYLEA OR LUCENTIS OR AVASTIN

Funding issues

Protocol T ndash poor VA lt 65 letters (615)

LOADING

Monthly injections until stability OR 5 x 112 (EYLEA) = 6 MONTHS then 8 weeks

RETREATMENT1

TREAT AND EXTEND - PRN

PRN

PSEUDOPHAKIC

Prior Rx

ILUVIEN

Chronic disease

OZURDEX

RETREATMENT

OZURDEX

OCT gt175um or any residual oedema

ILUVIEN after 12 months if risksltbenefits

OCT

gt400um

bull FACE TO FACE CLINICS RUNNING IN PARALLEL

bull = MAC002 every 6 months (optom or doctor) routine check for cataracttolerance of injectionsglaucoma issues etc

bull =MAC003 (DOCTOR) for problems as needed no fixed intervalDischargestop treatmentDeclines treatment diagnosis CSR overlay etcswitch drugs

bull =RV002- (DOCTOR) every 6 months

bull =DM002 ndash (DOCTOR) variable interval determined by last assessing doctor

bull First visit at 6 months from 1st injection if mild NPDR

bull Otherwise determined by retinopathy generally

LOADING PHASE

EyleaLucentis 1 within 48hrs of baseline

EyleaLucentis 2 (and LogMAR VA plus OCT same visit)

EyleaLucentis 3 (and LogMAR VA plus OCT same visit)

EyleaLucentis 4 (TEinj)(and Logmar VA plus OCT same visit

AFTER INJECTION 4 data goes off to be reviewed immediately as a hellip

TREAT AND EXTEND assessment ndash the next interval will depend on the response to the loading phase

NB -DMO patients ndash majority (95) will need 6 injctions x 112 of Lucentis

OR Eylea 5 x 112 then 8 weekly

ONCE STABLE for 3 x injection in TE phase

VIRTUAL CLINIC MONITORING OF MACULOPATHY AND PRN RETREATMENT

ANTI-VEGF INJECTION PATHWAYS Baseline visitMAC001 for wet AMDRV001 for CRVOBRVOMed ret clinic for DMO

Pathways ndash too many directions

Better that thanhellip

Thank you

DMO ndash treatment optionsWhat treatments should I use at baseline

bull ETDRS based laser therapies

bull ADJUNCT

bull Surgery ndash VMTERM

bull Pan-retinal photocoagulation

bull INTRAVITREAL

bull ANTI-VEGF

bull Lucentis (Ranibizumab)

bull Eylea (Aflibercept)

bull Avastin (Bevacizumab)

bull STEROIDS

bull Iluvien (Fluocinolone)

bull Ozurdex (Dexamethasone)

11

BOLT

RESOLVERISE and RIDERELIGHT

DA VINCI

VIVID and VISTA

vs laser

vs sham

Steroids

(in combination

with laser)

Anti-VEGF

(in combination

with laser)

DRCRnet (Protocol I)

ETDRS

READ-2

RESTORE

RETAIN

REVEAL

DRCRnet (Protocol B)

FAMEMEAD

vs laser

vs sham

RanibizumabAflibercept

Bevacizumab

Triamcinolone

Fluocinolone acetonide Dexamethasone

Anti-VEGF Laser Steroids

DRCRnet PROTOCOL T

DMO ndash treatment optionsWhat treatments should I use at baseline ndash based on evidence from RCT data

What therapy do I choose for my patient at baselineWhich treatments can I access

NICE TA 274 Lucentis for DMO April 2013NICE TA 346 Eylea for DMO July 2015

NICE TA 301 Iluvien for DMO Nov 2013NICE TA 349 Ozurdex for DMO July 2015

OCT gt400um1st line if OCT suitable

bull Chronic DMObull PSEUDOPHAKICbull Patients ldquoinsufficiently responsive

to existing therapiesrdquo

bull PSEUDOPHAKICbull ldquoNot improved with non-

corticosteroid or such treatment is not suitable for themrdquo

What therapy do I choose for my patient at baseline

bull ANTI-VEGF

bull Superior to ETDRS argon laser in terms of efficacy

RESTORE 36 month Lucentis prn extension studyLucentis monotherapy vs Lucentis plus laser vs laser aloneSchmidt-Erfuth U et al Ophthalmology 2014 121(5) 1045-1053

23

Months

12

10

8

6

4

2

0

minus22 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36

Extension study (ranibizumab 05 mg PRN)Core study

Me

an o

f th

e c

han

ge in

ETD

RS

BC

VA

Prior ranibizumab 05 mg + active laser (n=83)

Prior sham injections + active laser (n=74)

Prior ranibizumab 05 mg + sham laser (n=83)

79

71 606780

Core study assessment

Full analysisstudy completionInterim analysis

RIDE

RISE

Mea

n ch

ange

in B

CVA

(E

TDR

S le

tters

)M

ean

chan

ge in

BC

VA

(ETD

RS

lette

rs)

Time (months)

RISE and RIDE (Lucentis monthly dosing) Mean change in BCVA over 36 months

Brown DM et al Ophthalmology 2013120(10)2013ndash2022

15

Ranibizumab 03 mgRanibizumab 05 mgShamranibizumab 05 mg

RISE amp RIDE

Date of Prep Dec 2014 LGB0820147252X

02 Laser

125 2q4

107 2q8

0

Mea

n ch

ange

in B

CVA

lette

r sco

re

2

101214

02

6

10

14

4

8

12

468

09 Laser

115 2q4

111 2q8

VISTA Week 100

100928068645652403628201240 8 16 24 32 44 48 60 72 76 84 88 96

12 Laser

100928068645652403628201240 8 16 24 32 44 48 60 72 76 84 88 96

105 2q4

107 2q8VIVID Week 100

Week Laser 2q4 2q8

07 Laser

114 2q4

94 2q8

Eylea =VIVID and VISTA Mean change in BCVA to week 100Korobelnik J-F et al Ophthalmology 2014 121 (11) 2247ndash2254 Brown DM et al Ophthalmology 2015 Jul 18 [Epub ahead of print]

Plt00001 vs laser VIVID Laser n=132 2q4 n=136 2q8 n=135 VISTA Laser n=154 2q4 n=154 2q8 n=151Full analysis set 2q4 2 mg every 4 weeks 2q8 2 mg every 8 weeks BCVA best corrected visual acuity ETDRS Early Treatment Diabetic Retinopathy Study

What therapy do I choose for my patient at baseline

bull ANTI-VEGF helliphellipif OCT gt 400um

bull Sohellip Which one

Key trials in DMO

18

BOLT

RESOLVERISE and RIDE

DA VINCI

VIVID and VISTA

vs laser

vs sham

Steroids

(in combination

with laser)

Anti-VEGF

(in combination

with laser)

DRCRnet (Protocol I)

ETDRS

READ-2

RESTORE

RETAIN

REVEAL

DRCRnet (Protocol B)

FAMEMEAD

vs laser

vs sham

RanibizumabAflibercept

Bevacizumab

Triamcinolone

Fluocinolone acetonide Dexamethasone

Anti-VEGF Laser Steroids

DRCRnet PROTOCOL T

PROTOCOL T (DRCRnet)

bull Aflibercept Bevacizumab or Ranibizumab for Diabetic Macular Edema

bull N Engl J Med 2015 Mar 26372(13)1193-203

The Diabetic retinopathy Clinical Research Network February 18 2015

USA study NIHR funded

n=660

Lucentis 03mg not 05mg Eylea 2mg Avastin 125mg

Eylea protocol not the licensed regime

Avastin unlicensed

RETREATMENT protocol

First 6 months ndash inject every month 95 of patients UNLESS VA=66 AND OCT DRY

Then 2nd six months ndash if no change after 3 visits DEFER otherwise keep injecting monthly

Recurs ndash need at least 2 injections ie 3 months of stability

STABILITY = 10 Oct change or VA 5 letter change

STABILITY and residual OCT thickness gt250um LASER

Protocol T 1 year visual acuity outcomes

0

5

10

15

20

0 8 16 24 32 40 48

Visit Week

2032-2040 = 696 ndash 612= 78-69

0

5

10

15

20

0 8 16 24 32 40 48

Visit Week

2050 = 615 or worse = lt69

Mea

n ch

ange

in B

CV

A

Mea

n ch

ange

in B

CV

A

Aflibercept Bevacizumab Ranibizumab

+189

+142

+118+75

+8+83

Protocol T OCT outcomes year 1

-250

-200

-150

-100

-50

0

0 4 8 12 16 20 24 28 32 36 40 44 48 52

Visit Week

Aflibercept Bevacizumab Ranibizumab

Mea

n ch

ange

in C

ST

Conclusions ndash Protocol T year 1 data

bull Eylea was statistically superior in terms of visual acuity to 03mg Lucentisand to Avastin FOR PATIENTS WITH VA worse than 69 letters

bull Eylea and Lucentis were statistically superior in terms of OCT CRT reduction to Avastin for all patients regardless of baseline vision

bull No safety differences between the three drugs

SUMMARY What do I choose for my patient at baselineOCT central retinal thickness (CRT)PseudophakicAttempts at prior treatment duration of DMO

bull lt 400um

bull IFR licensed anti-VEGF or Avastin

+-ETDRS laser

PSEUDOPHAKIC

Iluvien

Ozurdex

bull gt 400um = Anti-VEGF

Which one

Depends on

bull baseline vision lt615 Eylea

bull Fixed dosing attractive (Eylea)bull Chronic DMO

bull PSEUDOPHAKICbull Patients ldquoinsufficiently

responsive to existing therapiesrdquo

bull ldquoNot improved with non-corticosteroid or such treatment is not suitable for themrdquo

Which steroid ndash Ozurdex or Iluvien

bull No head to head data

bull Revisit this when we think about switching from ANTI-VEGF to steroid

Assuming we have started with an anti-VEGF agent ndash what are the re-treatment algorithms in DMO

Treatment posologies

ldquoTreatment is initiated with one injection per month until maximum VA is achieved andor there are no signs of disease activity ie no change in VA and in other signs and

symptoms of the disease under continued treatment

In patients withhellipDMOhellip initially three or more consecutive monthly injections may be needed Thereafter monitoring and treatment intervals

should be determined by the physician and should be based on disease activity as

assessed by VA andor anatomical parametershellip

If patients are being treated according to a treat-and-extend regimen once maximum VA is achieved andor there are no

signs of disease activity the treatment intervals can be extended stepwise until signs of

disease activity or visual impairment recur The treatment intervalhellipmay be extended by up to one month

at a time for DMOrdquo

1 Novartis Pharmaceuticals UK Ltd 30 October 2014 Available at httpwwwmedicinesorgukemcmedicine19409 Accessed 04 September 2015

2 Bayer Pharma AG February 2015 Available at httpwwwmedicinesorgukemcmedicine27224 Accessed 04 September 2015

Ranibizumab1 Aflibercept2

ldquohelliptreatment is initiated with one injection per month for five consecutive doses followed by

one injection every two months There is no requirement for monitoring between injectionshellip

After the first 12 months of treatmenthellipthe treatment interval may be extended based

on visual andor anatomic outcomes The schedule for monitoring should

be determined by the treating physicianrdquo

DMO diabetic macular oedema VA visual acuity

Re-treatment algorithms for anti-VEGF agents in DMO

bull LOADING PHASE

bull Lucentis label = monthly until stability

bull Eylea label = 5 x 112 then every 8 weeks ie fixed regime year 1

bull DRCRnet protocol T = effectively 6 x112 for majority (95) BUT actually only mandated for first 3 months then prn

bull helliphellip likely that majority will receive injections monthly for first 6 months

bull INDIVIDUALISED PHASE

bull Once ldquostablerdquo ndash based on VA and OCT

bull NB May never get a ldquodryrdquo OCT so treat to stability

bull THEN

bull Treat and extend

bull prn

What does Treat and Extend mean

Pathway overview = Lucentis prn

Jan

Loading phase = injections every 4 weeks until ldquostablerdquo for 3 visits

helliphelliphellip

Feb OctSepAugJulJunMayAprMar

MarFebJan

DecNov

DecNovOctSepAugJulJunMayApr

Then observe UNTIL VA decreases or OCT increase = prn

Once reactivates need at least 2 injections until stable again over 3 visits

Pathway overview = Treat and Extend

Jan

Loading phase = injections every 4 weeks until ldquostablerdquo for 3 visits or Eyleayear 1

helliphelliphellip

Feb OctSepAugJulJunMayAprMar

MarFebJan

DecNov

DecNovOctSepAugJulJunMayApr

Then keep injecting but extend the interval between injections gradually ie keep treating even if perfect

If reactivates need at least 2 injections until stable again over 3 visits

Pathway overview = Eylea fixed dosing year 1

Jan

Eylea = 5 x 112 injection then every 8 weeks

Average 6 injections yr 2 Beyond that

helliphelliphellip

Feb OctSepAugJulJunMayAprMar

MarFebJan

DecNov

DecNovOctSepAugJulJunMayApr

Then individualised UNTIL VA decreases or OCT increase = prn

Once reactivates need at least 2 injections until stable again over 3 visits

Pros and cons of Treat and Extend vs Prn

T+E PRN

PROS bull Proactive patient and service get advance warning of injection ndash capacity and demand planning easier

bull One ndashstopbull Fewer visits than prnbull Overtreatment

advantageous for peripheral retinopathy

bull Only treated when active ieno overtreatment

bull Aggressive year 1 protocols (DRCRN I ndash few injections needed thereafter

bull DMO tolerant of reactivations ()

CONS bull Overtreatment = riskexpenseinconvenience

bull Evidence base scantbull Bilateral disease tricky

bull Reactive so need enoughemergency capacity to inject when disease flares up

bull No advance warning to patientservice that injection needed

bull NEED TO DO IT WELL ndashNHS real life audits prn based regimes not good resultsUndertreatment in year 1 Affects long term prognosis and treatment burden

Pros and cons of Treat and Extend vs Prn

T+E PRN

PROS bull Proactive patient and service get advance warning of injection ndash capacity and demand planning easier

bull One ndashstopbull Fewer visits than prnbull Overtreatment

advantageous for peripheral retinopathy

bull Only treated when active ieno overtreatment

bull Aggressive year 1 protocols (DRCRN I ndash few injections needed thereafter

bull DMO tolerant of reactivations ()

CONS bull Overtreatment = riskexpenseinconvenience

bull Evidence base scantbull Bilateral disease tricky

bull Reactive so need enoughemergency capacity to inject when disease flares up

bull No advance warning to patientservice that injection needed

bull NEED TO DO IT WELL ndashNHS real life audits prn based regimes not good resultsUndertreatment in year 1 Affects long term prognosis and treatment burden

DMO ndash anti-VEGF Treat and Extend

bull Retain study ndash the only RCT data

bull Br J Ophthalmol 2015 Oct 9 pii bjophthalmol-2015-307249 doi 101136bjophthalmol-2015-307249 [Epub ahead of print]

bull Ranibizumab 05 mg treat-and-extend regimen for diabetic macular oedema the RETAIN study

bull Pruumlnte C1 Fajnkuchen F2 Mahmood S3 Ricci F4 Hatz K5 Studnička J6 Bezlyak V7 Parikh S7 Stubbings WJ7 Wenzel A7 Figueira J8 and the RETAIN Study Group

RETAIN Phase III trial evaluating the efficacy of lsquotreat and extendrsquo regimen (ARVO 2014)

bull Patients with DMO and visual impairment (n = 372) were randomised 111

to one of three groups for 24 months

bull Two phases to dosing schedule

bull Phase A

bull Patients in all groups were initially treated with monthly ranibizumab until BCVA remained

stable

bull Phase B

bull Patients in the TampE groups whose vision remained stable had treatment- free intervals

that were increased incrementally by 1 month for a maximum of 3 months

bull Patients in the PRN group had ongoing monthly monitoring

bull In all groups Phase A was resumed if a decrease in BCVA was observed at a visit

Ranibizumab 05 mg monotherapy

in TampE regimen

Ranibizumab 05 mg in TampE regimen

plus laser

Ranibizumab 05 mg PRN

35

RETAIN Visual acuity endpoints

Pruumlnte C ARVO 2014 Annual Meeting Abstracts Abstract 1700

Mean average change in BCVAat 12 months (primary endpoint)

Mean change in BCVA at 24 months

Mea

n av

erag

e ch

ange

in B

CVA

(ETD

RS

lette

rs)

RanibizumabTampE

RanibizumabTampE + laser

RanibizumabPRN

RanibizumabTampE

RanibizumabTampE + laser

RanibizumabPRN

Mea

n ch

ange

in B

CVA

(ETD

RS

lette

rs)

plt00001 for both ranibizumab TampE groups versus PRN for primary endpoint

36

RETAIN Patient visits and monitoring with TampE regimen over 24 months

bull The TampE regimen provided an approximately 40 reduction in the number of treatment visits required compared with the ranibizumab PRN regimen

bull Approximately 70 of patients receiving TampE regimens had monitoring intervals ge2 months compared with ongoing monthly monitoring in the ranibizumab PRN group

bull Informed the license for Lucentis in DMO (extend by 1 month at a time)

37

INTRAVITREAL STEROIDSWhich intravitreal steroid is better

bull Licensed steroids ndash Ozurdex (Dexamethasone) and Iluvien (Fluocinoloneacetonide

bull Which steroid is best in terms of VA outcomes hellipWE DONrsquoT KNOW FOR SURE ndash no head to head studies for licensed drugs either between steroids or between anti-VEGF and steroids

bull STEROIDS ARE efficacious in DMO

bull MEAD

bull FAME

bull DRCRnet protocol I

bull NICE ndash Ozurdex and Iluvien ndash second-line agents

Ozurdex

bull A biodegradable co-polymer implant ndash degrades in time to lactic and glycolic acid releasing Dexamethasone

bull 22gauge injectionbull MEAD study

bull N=1048

bull Dex 07mg vs 035mg vs sham

bull No rescue therapy

bull 3 year follow up max 6 monthly dosing ie 7 over 3 years

Gan IM et al Greafes Acrh Clin Exp Ophthalmol 2005

MEAD studyMean BCVA change from baseline based on baseline lens status

-2

0

2

4

6

8

10

0 3 6 9 12 15 18 21 24 27 30 33 36 39

Mea

n C

hang

e Fr

om

Bas

elin

e B

CVA

(Let

ters

)

Month

DEX Implant 07 mg (n = 86)

Sham (n = 101)

Boyer DS et al Ophthalmology 20141211904ndash14

Results analyzed in the ITT population with LOCF for missing values

Pseudophakic

Total

0

5

10

0 3 6 9 12 15 18 21 24 27 30 33 36 39

DEX 700 (n=351)

Sham (n=350)

10

8

6

4

2

0

Mea

n C

hang

e fr

om

Bas

elin

e B

CVA

(Let

ters

)

Month

07mg dose is approved as Ozurdexreg by the FDA and EMA 035mg dose not commercially available

1 Boyer DS et al Ophthalmology 2014 121 1904-1914

bull Nonbioerodible micro implant (polyimide) containing 190microg of fluocinolone acetonide (FAc)

bull Consistent daily submicrogram delivery of 02 microgd FAc for up to 36 months

bull Posterior point of release

bull 35 mm times 037 mm non-bioerodable micro implant

bull 25-gauge injector creates self-sealing wound

bull No measurable systemic exposure

ILUVIEN Implant Technology

FAcimplant

ILUVIEN SPC httpwwwmedicinesorgukemcmedicine27636

0 6 12 18 24 30 36

ILUVIEN 02 microgd FAc(n = 376)05 microgd FAc (n = 395)Control sham injection(n = 185)

Design of Phase 3 FAME Study (FAME A and B = same protocol)

Additional laser therapy allowed after week 6a

Retreatment any time after month 12 (if eligibleb)

Study ends

N = 956Randomisation

221Primary readout

Patients with DMO and

bull At least 1 previous laser tx

bull BCVA ge19 and le68 letters

bull TD-OCT FTH ge250 μm

Month

BCVA = best corrected visual acuity DMO = diabetic macular oedema TD-OCT=time domain optical coherence tomography FTH = foveal thicknessa At masked investigatorrsquos discretion b If BCVA loss ge5 letters or retinal thickening ge50 microm from best reading in previous 12 months

ge15 letter Gain is Greater in Chronic DMO Patients

ge 15

-Let

ter I

mpr

ovem

ent

in B

CVA

Fro

m B

asel

ine

Δ = 98

Months

Full Population Patients With Chronic DMO

Months

Δ = 206

287

189134

34

Steroid re-treatments

bullOzurdexbull Longer half-life than anti-VEGF in the eye

bull Redosing regimes not very helpful from RCT data eg MEAD study only 612 dosing

bull In reality re-treatment interval may be shorter

bull POSOLOGY

bull Patients treated with OZURDEX who have experienced an initial response and in the physicians opinion may benefit from retreatment without being exposed to significant risk should be considered for retreatment Retreatment may be performed after approximately 6 months if the patient experiences decreased vision andor an increase in retinal thickness secondary to recurrent or worsening diabetic macular oedema

bullIluvienbull 70 of patients in FAE only needed 1

injection over 3 years

bull BUT additional rescue treatments allowed

bull POSOLOGY

bull Each ILUVIEN implant releases fluocinolone acetonide for up to 36 months An additional implant may be administered after 12 months if the patient experiences decreased vision or an increase in retinal thickness secondary to recurrent or worsening diabetic macular oedema

bull Patients receiving escape medication were exited from MEAD before administration1

bull Macular laser rescue treatment allowed in RISERIDE (Lucentisreg) from 3 months2

bull Focalgrid laser allowed in FAME (Iluvienreg) from 6 weeks3

MEAD TREATMENT PROTOCOL

bull First treatment given at randomisation (day 0) bull Patients assessed for retreatment eligibility every 3 months from

months 6ndash36bull Patients were eligible for retreatment if

OCT optical coherence tomography

ge6 months since most recent

study treatment

Retinal thickness in 1 mm central macular

subfield by OCT gt175 microm

Evidence of residual retinal oedema (intraretinal cysts or

any regions of increased retinal thickening) as assessed by

investigator from OCT

AND OR

MEA

D

Amendment in May 2010 revised anatomic criterion for retreatment before this time the threshold was gt225 microm1Boyer DS et al Ophthalmology 2014 121 1904-19142Nguyen QD et al Ophthalmology 20121191064minus10773Campochiaro PA et al Ophthalmology 2011118626ndash635

Treatment burdenILUVIEN

Control(n =112)

02 microgd FAc(n =209)

Study Treatments(sham injection or ILUVIEN 02 microgday or FAc 05microgday)

1 treatment 661 761

2 treatments 277 187

ge 3 treatments 63 53

Rescue Laser Treatments (at masked physicianrsquos discretion after week 6)

Patients 607 407

Off-Protocol Treatments (IVTA bevacizumab ranibizumab intravitreal dexamethasone)

Patients 295 115

OZURDEX = 23injections year 1 41 by year 3

No other Rx

Summary of side effects with intravitreal steroids

Drug device Evidence base Cataract risk IOP rise (requiring drops)

Glaucoma surgery

endophthalmitis

ILUVIEN FAME studies 80 cat surgery(273 sham)

384(14 control)

48 0

Ozurdex MEAD 592 had cataract surgery(72 sham)

215 (end of study)(34 sham)

06 0

Trivaris+ laser vs Luc+laserx2 vs laser

Protocol IOphthalmology 2010

15 42(ONE OFgt10mmHg risegt30mmHGStart drops)

2186 0

NICE guidance for intravitreal steroids in DMO

bull Iluvien

bull NICE TA 301 Iluvien for DMO Nov 2013

bull hellipfor treating chronic diabetic macular oedema that is insufficiently responsive to available therapies only if

bull the implant is to be used in an eye with an intraocular

(pseudophakic) lens and

bull the manufacturer provides fluocinolone acetonide intravitreal implant with the discount agreed in the patient access scheme

NICE guidance for intravitreal steroids in DMO

bull Ozurdex

bull NICE TA 349 Ozurdex for DMO July 2015

bull there is an artificial lens in the eye to be treated and

bull their diabetic macular oedema has not improved with

non-corticosteroid treatment or such treatment is not suitable for them

Steroids = second line therapyWhen do I switch

bull Anti-VEGF first line for centre involving DMObull NICE TA ndash ldquoinsufficiently responsiverdquo ldquo ldquonot improvedrdquo ldquonot suitablerdquo ndash

OTHER TREATMENTS

bull 2 scenariosbull 1) Anti-VEGF canrsquot be funded ie OCTlt400um + PSEUDOPHAKIC

bull 2) Already had a course of treatment with laseranti-VEGF + PSEUDOPHAKIC ie SWITCHING from anti-VEGF to steroid

bull Plus

bull ldquochronicrdquo DMO ndash 3 years duration in FAME (18months) for ILUVIEN

bull Chronic DMO not essential for Ozurdex

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

Protocol T ndash patients may not improve in first 6 months

RIDE

RISE

Mea

n ch

ange

in B

CVA

(E

TDR

S le

tters

)M

ean

chan

ge in

BC

VA

(ETD

RS

lette

rs)

Time (months)

RISE and RIDE (Lucentis monthly dosing) Mean change in BCVA over 36 months

Brown DM et al Ophthalmology 2013120(10)2013ndash2022

54

Ranibizumab 03 mgRanibizumab 05 mgShamranibizumab 05 mg

Date of Prep Dec 2014 LGB0820147252X

VA improvement continues throughout year 1 with monthly dosing

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user ndash more than protocol

I

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

DRCRN protocol I5 year outcomesInjections 8-9 in year 1Year 2 = 2-3Year 3= 1-2Year 4 = 0-1Year 5 = 0

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

Wait for plateau = stability in protocol T laserPatient factors again

Judgement of response to anti-VEGF ndashtimeframe

bull Wait 6 months in poor responders

bull Wait 1 year for heavy users

bull Tempting to try steroids earlier than this ifbull No glaucoma ndash not a deal breaker Ozurdex better short term optionbull Pseudophakic

bull Clues from the diseasebull chronic

bull PATIENT FACTORS

bull Any eyes avoid steroids ndash advanced glaucomaCSCR Or prior viral retinitis RARE

bull Any eyes avoid anti-VEGF pregnancytrying to concieve recent CVA

BIOMARKERS AT BASELINE WOULD BE USEFULRESTORE subgroup analysis of OCT features

bull Andreas Pollreisz EURETINA 2015

bull OCT biomarkers (RESTORE data)

bull Better effects with anti-VEGF ifbull Small rather than large intra-retinal cyst

bull Sub-retinal fluid present

bull Vitreo-macular adhesion at baseline

bull No disruption of ELM and ISOS junction

bull No disorganisation of inner retinal layers (DRIL)

RESTORE subgroup analysis of OCT features

bull Andreas Pollreisz EURETINA 2015

bull OCT biomarkers (RESTORE data)

bull Better effects with anti-VEGF ifbull Small rather than large intra-retinal cyst

bull Sub-retinal fluid present

bull Vitreo-macular adhesion at baseline

bull No disruption of ELM and ISOS junction

bull No disorganisation of inner retinal layers (DRIL)

Better baseline characterisationclassificationERG Contrast sensitivityOCT AngiographyMicroperimetry= clues as to who responds best to which drug

Plan for this presentation helliphellipa long list

bull What treatment options are available for DMO (evidence base)

bull What treatment should I start with at baselinebull Re-treatment algorithms for intravitreal DMO therapiesbull When should I switchcombine therapiesbull The bigger picture

bull Other eyebull The patient as a wholebull The service -coping with capacity ndash compromises

The bigger pictureOther eyeThe patient as a wholeThe service -coping with capacity ndash compromises

bull OTHER EYE ndash may create problems

bull Treat and extend ndash ldquoreduce of visitsrdquo plus Eylea license ndash ldquono need for monitoringrdquo may not benefit if lots of visits due to PDR other eye

bull PERIPHERAL RETINA anti-VEGF supresses proliferative disease - Rebound on stopping Rx

bull PATIENT

bull Anti-VEGF ndash heavy user - Will comply

bull One stop much better than two stop for patient ndash Treat and extend

bull SERVICE

bull Capacity and demand planning = fixedT+E more predictable at least 1 month in advance ndash flexible nurse injectors

bull Steroids ndash even if well controlled (Iluvien for 3 years) need IOP check

bull Need pan-retinal examination both eyes ndash separate visits

Summary

CSMO

No centre involvement

Photocoagulation

Centre involvement

gt 78 letters(normalminimally reduced VA)

Photocoagulation

VA 78ndash24 letters

Phakic

Anti-VEGF

Pseudophakic

Anti-VEGF

SWITCHglaucoma

Injection tolerance

Medical issuesrecent CVA

Peripheral diseaseBilateral Rx

CSMO

No centre involvement

LASER

Centre involvement

gt 78 letters(normalminimally

reduced VA)

VA 78ndash24 letters

EYLEA OR LUCENTIS OR AVASTIN

Funding issues

Protocol T ndash poor VA lt 65 letters (615)

LOADING

Monthly injections until stability OR 5 x 112 (EYLEA) = 6 MONTHS then 8 weeks

RETREATMENT1

TREAT AND EXTEND - PRN

PRN

PSEUDOPHAKIC

Prior Rx

ILUVIEN

Chronic disease

OZURDEX

RETREATMENT

OZURDEX

OCT gt175um or any residual oedema

ILUVIEN after 12 months if risksltbenefits

OCT

gt400um

bull FACE TO FACE CLINICS RUNNING IN PARALLEL

bull = MAC002 every 6 months (optom or doctor) routine check for cataracttolerance of injectionsglaucoma issues etc

bull =MAC003 (DOCTOR) for problems as needed no fixed intervalDischargestop treatmentDeclines treatment diagnosis CSR overlay etcswitch drugs

bull =RV002- (DOCTOR) every 6 months

bull =DM002 ndash (DOCTOR) variable interval determined by last assessing doctor

bull First visit at 6 months from 1st injection if mild NPDR

bull Otherwise determined by retinopathy generally

LOADING PHASE

EyleaLucentis 1 within 48hrs of baseline

EyleaLucentis 2 (and LogMAR VA plus OCT same visit)

EyleaLucentis 3 (and LogMAR VA plus OCT same visit)

EyleaLucentis 4 (TEinj)(and Logmar VA plus OCT same visit

AFTER INJECTION 4 data goes off to be reviewed immediately as a hellip

TREAT AND EXTEND assessment ndash the next interval will depend on the response to the loading phase

NB -DMO patients ndash majority (95) will need 6 injctions x 112 of Lucentis

OR Eylea 5 x 112 then 8 weekly

ONCE STABLE for 3 x injection in TE phase

VIRTUAL CLINIC MONITORING OF MACULOPATHY AND PRN RETREATMENT

ANTI-VEGF INJECTION PATHWAYS Baseline visitMAC001 for wet AMDRV001 for CRVOBRVOMed ret clinic for DMO

Pathways ndash too many directions

Better that thanhellip

Thank you

11

BOLT

RESOLVERISE and RIDERELIGHT

DA VINCI

VIVID and VISTA

vs laser

vs sham

Steroids

(in combination

with laser)

Anti-VEGF

(in combination

with laser)

DRCRnet (Protocol I)

ETDRS

READ-2

RESTORE

RETAIN

REVEAL

DRCRnet (Protocol B)

FAMEMEAD

vs laser

vs sham

RanibizumabAflibercept

Bevacizumab

Triamcinolone

Fluocinolone acetonide Dexamethasone

Anti-VEGF Laser Steroids

DRCRnet PROTOCOL T

DMO ndash treatment optionsWhat treatments should I use at baseline ndash based on evidence from RCT data

What therapy do I choose for my patient at baselineWhich treatments can I access

NICE TA 274 Lucentis for DMO April 2013NICE TA 346 Eylea for DMO July 2015

NICE TA 301 Iluvien for DMO Nov 2013NICE TA 349 Ozurdex for DMO July 2015

OCT gt400um1st line if OCT suitable

bull Chronic DMObull PSEUDOPHAKICbull Patients ldquoinsufficiently responsive

to existing therapiesrdquo

bull PSEUDOPHAKICbull ldquoNot improved with non-

corticosteroid or such treatment is not suitable for themrdquo

What therapy do I choose for my patient at baseline

bull ANTI-VEGF

bull Superior to ETDRS argon laser in terms of efficacy

RESTORE 36 month Lucentis prn extension studyLucentis monotherapy vs Lucentis plus laser vs laser aloneSchmidt-Erfuth U et al Ophthalmology 2014 121(5) 1045-1053

23

Months

12

10

8

6

4

2

0

minus22 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36

Extension study (ranibizumab 05 mg PRN)Core study

Me

an o

f th

e c

han

ge in

ETD

RS

BC

VA

Prior ranibizumab 05 mg + active laser (n=83)

Prior sham injections + active laser (n=74)

Prior ranibizumab 05 mg + sham laser (n=83)

79

71 606780

Core study assessment

Full analysisstudy completionInterim analysis

RIDE

RISE

Mea

n ch

ange

in B

CVA

(E

TDR

S le

tters

)M

ean

chan

ge in

BC

VA

(ETD

RS

lette

rs)

Time (months)

RISE and RIDE (Lucentis monthly dosing) Mean change in BCVA over 36 months

Brown DM et al Ophthalmology 2013120(10)2013ndash2022

15

Ranibizumab 03 mgRanibizumab 05 mgShamranibizumab 05 mg

RISE amp RIDE

Date of Prep Dec 2014 LGB0820147252X

02 Laser

125 2q4

107 2q8

0

Mea

n ch

ange

in B

CVA

lette

r sco

re

2

101214

02

6

10

14

4

8

12

468

09 Laser

115 2q4

111 2q8

VISTA Week 100

100928068645652403628201240 8 16 24 32 44 48 60 72 76 84 88 96

12 Laser

100928068645652403628201240 8 16 24 32 44 48 60 72 76 84 88 96

105 2q4

107 2q8VIVID Week 100

Week Laser 2q4 2q8

07 Laser

114 2q4

94 2q8

Eylea =VIVID and VISTA Mean change in BCVA to week 100Korobelnik J-F et al Ophthalmology 2014 121 (11) 2247ndash2254 Brown DM et al Ophthalmology 2015 Jul 18 [Epub ahead of print]

Plt00001 vs laser VIVID Laser n=132 2q4 n=136 2q8 n=135 VISTA Laser n=154 2q4 n=154 2q8 n=151Full analysis set 2q4 2 mg every 4 weeks 2q8 2 mg every 8 weeks BCVA best corrected visual acuity ETDRS Early Treatment Diabetic Retinopathy Study

What therapy do I choose for my patient at baseline

bull ANTI-VEGF helliphellipif OCT gt 400um

bull Sohellip Which one

Key trials in DMO

18

BOLT

RESOLVERISE and RIDE

DA VINCI

VIVID and VISTA

vs laser

vs sham

Steroids

(in combination

with laser)

Anti-VEGF

(in combination

with laser)

DRCRnet (Protocol I)

ETDRS

READ-2

RESTORE

RETAIN

REVEAL

DRCRnet (Protocol B)

FAMEMEAD

vs laser

vs sham

RanibizumabAflibercept

Bevacizumab

Triamcinolone

Fluocinolone acetonide Dexamethasone

Anti-VEGF Laser Steroids

DRCRnet PROTOCOL T

PROTOCOL T (DRCRnet)

bull Aflibercept Bevacizumab or Ranibizumab for Diabetic Macular Edema

bull N Engl J Med 2015 Mar 26372(13)1193-203

The Diabetic retinopathy Clinical Research Network February 18 2015

USA study NIHR funded

n=660

Lucentis 03mg not 05mg Eylea 2mg Avastin 125mg

Eylea protocol not the licensed regime

Avastin unlicensed

RETREATMENT protocol

First 6 months ndash inject every month 95 of patients UNLESS VA=66 AND OCT DRY

Then 2nd six months ndash if no change after 3 visits DEFER otherwise keep injecting monthly

Recurs ndash need at least 2 injections ie 3 months of stability

STABILITY = 10 Oct change or VA 5 letter change

STABILITY and residual OCT thickness gt250um LASER

Protocol T 1 year visual acuity outcomes

0

5

10

15

20

0 8 16 24 32 40 48

Visit Week

2032-2040 = 696 ndash 612= 78-69

0

5

10

15

20

0 8 16 24 32 40 48

Visit Week

2050 = 615 or worse = lt69

Mea

n ch

ange

in B

CV

A

Mea

n ch

ange

in B

CV

A

Aflibercept Bevacizumab Ranibizumab

+189

+142

+118+75

+8+83

Protocol T OCT outcomes year 1

-250

-200

-150

-100

-50

0

0 4 8 12 16 20 24 28 32 36 40 44 48 52

Visit Week

Aflibercept Bevacizumab Ranibizumab

Mea

n ch

ange

in C

ST

Conclusions ndash Protocol T year 1 data

bull Eylea was statistically superior in terms of visual acuity to 03mg Lucentisand to Avastin FOR PATIENTS WITH VA worse than 69 letters

bull Eylea and Lucentis were statistically superior in terms of OCT CRT reduction to Avastin for all patients regardless of baseline vision

bull No safety differences between the three drugs

SUMMARY What do I choose for my patient at baselineOCT central retinal thickness (CRT)PseudophakicAttempts at prior treatment duration of DMO

bull lt 400um

bull IFR licensed anti-VEGF or Avastin

+-ETDRS laser

PSEUDOPHAKIC

Iluvien

Ozurdex

bull gt 400um = Anti-VEGF

Which one

Depends on

bull baseline vision lt615 Eylea

bull Fixed dosing attractive (Eylea)bull Chronic DMO

bull PSEUDOPHAKICbull Patients ldquoinsufficiently

responsive to existing therapiesrdquo

bull ldquoNot improved with non-corticosteroid or such treatment is not suitable for themrdquo

Which steroid ndash Ozurdex or Iluvien

bull No head to head data

bull Revisit this when we think about switching from ANTI-VEGF to steroid

Assuming we have started with an anti-VEGF agent ndash what are the re-treatment algorithms in DMO

Treatment posologies

ldquoTreatment is initiated with one injection per month until maximum VA is achieved andor there are no signs of disease activity ie no change in VA and in other signs and

symptoms of the disease under continued treatment

In patients withhellipDMOhellip initially three or more consecutive monthly injections may be needed Thereafter monitoring and treatment intervals

should be determined by the physician and should be based on disease activity as

assessed by VA andor anatomical parametershellip

If patients are being treated according to a treat-and-extend regimen once maximum VA is achieved andor there are no

signs of disease activity the treatment intervals can be extended stepwise until signs of

disease activity or visual impairment recur The treatment intervalhellipmay be extended by up to one month

at a time for DMOrdquo

1 Novartis Pharmaceuticals UK Ltd 30 October 2014 Available at httpwwwmedicinesorgukemcmedicine19409 Accessed 04 September 2015

2 Bayer Pharma AG February 2015 Available at httpwwwmedicinesorgukemcmedicine27224 Accessed 04 September 2015

Ranibizumab1 Aflibercept2

ldquohelliptreatment is initiated with one injection per month for five consecutive doses followed by

one injection every two months There is no requirement for monitoring between injectionshellip

After the first 12 months of treatmenthellipthe treatment interval may be extended based

on visual andor anatomic outcomes The schedule for monitoring should

be determined by the treating physicianrdquo

DMO diabetic macular oedema VA visual acuity

Re-treatment algorithms for anti-VEGF agents in DMO

bull LOADING PHASE

bull Lucentis label = monthly until stability

bull Eylea label = 5 x 112 then every 8 weeks ie fixed regime year 1

bull DRCRnet protocol T = effectively 6 x112 for majority (95) BUT actually only mandated for first 3 months then prn

bull helliphellip likely that majority will receive injections monthly for first 6 months

bull INDIVIDUALISED PHASE

bull Once ldquostablerdquo ndash based on VA and OCT

bull NB May never get a ldquodryrdquo OCT so treat to stability

bull THEN

bull Treat and extend

bull prn

What does Treat and Extend mean

Pathway overview = Lucentis prn

Jan

Loading phase = injections every 4 weeks until ldquostablerdquo for 3 visits

helliphelliphellip

Feb OctSepAugJulJunMayAprMar

MarFebJan

DecNov

DecNovOctSepAugJulJunMayApr

Then observe UNTIL VA decreases or OCT increase = prn

Once reactivates need at least 2 injections until stable again over 3 visits

Pathway overview = Treat and Extend

Jan

Loading phase = injections every 4 weeks until ldquostablerdquo for 3 visits or Eyleayear 1

helliphelliphellip

Feb OctSepAugJulJunMayAprMar

MarFebJan

DecNov

DecNovOctSepAugJulJunMayApr

Then keep injecting but extend the interval between injections gradually ie keep treating even if perfect

If reactivates need at least 2 injections until stable again over 3 visits

Pathway overview = Eylea fixed dosing year 1

Jan

Eylea = 5 x 112 injection then every 8 weeks

Average 6 injections yr 2 Beyond that

helliphelliphellip

Feb OctSepAugJulJunMayAprMar

MarFebJan

DecNov

DecNovOctSepAugJulJunMayApr

Then individualised UNTIL VA decreases or OCT increase = prn

Once reactivates need at least 2 injections until stable again over 3 visits

Pros and cons of Treat and Extend vs Prn

T+E PRN

PROS bull Proactive patient and service get advance warning of injection ndash capacity and demand planning easier

bull One ndashstopbull Fewer visits than prnbull Overtreatment

advantageous for peripheral retinopathy

bull Only treated when active ieno overtreatment

bull Aggressive year 1 protocols (DRCRN I ndash few injections needed thereafter

bull DMO tolerant of reactivations ()

CONS bull Overtreatment = riskexpenseinconvenience

bull Evidence base scantbull Bilateral disease tricky

bull Reactive so need enoughemergency capacity to inject when disease flares up

bull No advance warning to patientservice that injection needed

bull NEED TO DO IT WELL ndashNHS real life audits prn based regimes not good resultsUndertreatment in year 1 Affects long term prognosis and treatment burden

Pros and cons of Treat and Extend vs Prn

T+E PRN

PROS bull Proactive patient and service get advance warning of injection ndash capacity and demand planning easier

bull One ndashstopbull Fewer visits than prnbull Overtreatment

advantageous for peripheral retinopathy

bull Only treated when active ieno overtreatment

bull Aggressive year 1 protocols (DRCRN I ndash few injections needed thereafter

bull DMO tolerant of reactivations ()

CONS bull Overtreatment = riskexpenseinconvenience

bull Evidence base scantbull Bilateral disease tricky

bull Reactive so need enoughemergency capacity to inject when disease flares up

bull No advance warning to patientservice that injection needed

bull NEED TO DO IT WELL ndashNHS real life audits prn based regimes not good resultsUndertreatment in year 1 Affects long term prognosis and treatment burden

DMO ndash anti-VEGF Treat and Extend

bull Retain study ndash the only RCT data

bull Br J Ophthalmol 2015 Oct 9 pii bjophthalmol-2015-307249 doi 101136bjophthalmol-2015-307249 [Epub ahead of print]

bull Ranibizumab 05 mg treat-and-extend regimen for diabetic macular oedema the RETAIN study

bull Pruumlnte C1 Fajnkuchen F2 Mahmood S3 Ricci F4 Hatz K5 Studnička J6 Bezlyak V7 Parikh S7 Stubbings WJ7 Wenzel A7 Figueira J8 and the RETAIN Study Group

RETAIN Phase III trial evaluating the efficacy of lsquotreat and extendrsquo regimen (ARVO 2014)

bull Patients with DMO and visual impairment (n = 372) were randomised 111

to one of three groups for 24 months

bull Two phases to dosing schedule

bull Phase A

bull Patients in all groups were initially treated with monthly ranibizumab until BCVA remained

stable

bull Phase B

bull Patients in the TampE groups whose vision remained stable had treatment- free intervals

that were increased incrementally by 1 month for a maximum of 3 months

bull Patients in the PRN group had ongoing monthly monitoring

bull In all groups Phase A was resumed if a decrease in BCVA was observed at a visit

Ranibizumab 05 mg monotherapy

in TampE regimen

Ranibizumab 05 mg in TampE regimen

plus laser

Ranibizumab 05 mg PRN

35

RETAIN Visual acuity endpoints

Pruumlnte C ARVO 2014 Annual Meeting Abstracts Abstract 1700

Mean average change in BCVAat 12 months (primary endpoint)

Mean change in BCVA at 24 months

Mea

n av

erag

e ch

ange

in B

CVA

(ETD

RS

lette

rs)

RanibizumabTampE

RanibizumabTampE + laser

RanibizumabPRN

RanibizumabTampE

RanibizumabTampE + laser

RanibizumabPRN

Mea

n ch

ange

in B

CVA

(ETD

RS

lette

rs)

plt00001 for both ranibizumab TampE groups versus PRN for primary endpoint

36

RETAIN Patient visits and monitoring with TampE regimen over 24 months

bull The TampE regimen provided an approximately 40 reduction in the number of treatment visits required compared with the ranibizumab PRN regimen

bull Approximately 70 of patients receiving TampE regimens had monitoring intervals ge2 months compared with ongoing monthly monitoring in the ranibizumab PRN group

bull Informed the license for Lucentis in DMO (extend by 1 month at a time)

37

INTRAVITREAL STEROIDSWhich intravitreal steroid is better

bull Licensed steroids ndash Ozurdex (Dexamethasone) and Iluvien (Fluocinoloneacetonide

bull Which steroid is best in terms of VA outcomes hellipWE DONrsquoT KNOW FOR SURE ndash no head to head studies for licensed drugs either between steroids or between anti-VEGF and steroids

bull STEROIDS ARE efficacious in DMO

bull MEAD

bull FAME

bull DRCRnet protocol I

bull NICE ndash Ozurdex and Iluvien ndash second-line agents

Ozurdex

bull A biodegradable co-polymer implant ndash degrades in time to lactic and glycolic acid releasing Dexamethasone

bull 22gauge injectionbull MEAD study

bull N=1048

bull Dex 07mg vs 035mg vs sham

bull No rescue therapy

bull 3 year follow up max 6 monthly dosing ie 7 over 3 years

Gan IM et al Greafes Acrh Clin Exp Ophthalmol 2005

MEAD studyMean BCVA change from baseline based on baseline lens status

-2

0

2

4

6

8

10

0 3 6 9 12 15 18 21 24 27 30 33 36 39

Mea

n C

hang

e Fr

om

Bas

elin

e B

CVA

(Let

ters

)

Month

DEX Implant 07 mg (n = 86)

Sham (n = 101)

Boyer DS et al Ophthalmology 20141211904ndash14

Results analyzed in the ITT population with LOCF for missing values

Pseudophakic

Total

0

5

10

0 3 6 9 12 15 18 21 24 27 30 33 36 39

DEX 700 (n=351)

Sham (n=350)

10

8

6

4

2

0

Mea

n C

hang

e fr

om

Bas

elin

e B

CVA

(Let

ters

)

Month

07mg dose is approved as Ozurdexreg by the FDA and EMA 035mg dose not commercially available

1 Boyer DS et al Ophthalmology 2014 121 1904-1914

bull Nonbioerodible micro implant (polyimide) containing 190microg of fluocinolone acetonide (FAc)

bull Consistent daily submicrogram delivery of 02 microgd FAc for up to 36 months

bull Posterior point of release

bull 35 mm times 037 mm non-bioerodable micro implant

bull 25-gauge injector creates self-sealing wound

bull No measurable systemic exposure

ILUVIEN Implant Technology

FAcimplant

ILUVIEN SPC httpwwwmedicinesorgukemcmedicine27636

0 6 12 18 24 30 36

ILUVIEN 02 microgd FAc(n = 376)05 microgd FAc (n = 395)Control sham injection(n = 185)

Design of Phase 3 FAME Study (FAME A and B = same protocol)

Additional laser therapy allowed after week 6a

Retreatment any time after month 12 (if eligibleb)

Study ends

N = 956Randomisation

221Primary readout

Patients with DMO and

bull At least 1 previous laser tx

bull BCVA ge19 and le68 letters

bull TD-OCT FTH ge250 μm

Month

BCVA = best corrected visual acuity DMO = diabetic macular oedema TD-OCT=time domain optical coherence tomography FTH = foveal thicknessa At masked investigatorrsquos discretion b If BCVA loss ge5 letters or retinal thickening ge50 microm from best reading in previous 12 months

ge15 letter Gain is Greater in Chronic DMO Patients

ge 15

-Let

ter I

mpr

ovem

ent

in B

CVA

Fro

m B

asel

ine

Δ = 98

Months

Full Population Patients With Chronic DMO

Months

Δ = 206

287

189134

34

Steroid re-treatments

bullOzurdexbull Longer half-life than anti-VEGF in the eye

bull Redosing regimes not very helpful from RCT data eg MEAD study only 612 dosing

bull In reality re-treatment interval may be shorter

bull POSOLOGY

bull Patients treated with OZURDEX who have experienced an initial response and in the physicians opinion may benefit from retreatment without being exposed to significant risk should be considered for retreatment Retreatment may be performed after approximately 6 months if the patient experiences decreased vision andor an increase in retinal thickness secondary to recurrent or worsening diabetic macular oedema

bullIluvienbull 70 of patients in FAE only needed 1

injection over 3 years

bull BUT additional rescue treatments allowed

bull POSOLOGY

bull Each ILUVIEN implant releases fluocinolone acetonide for up to 36 months An additional implant may be administered after 12 months if the patient experiences decreased vision or an increase in retinal thickness secondary to recurrent or worsening diabetic macular oedema

bull Patients receiving escape medication were exited from MEAD before administration1

bull Macular laser rescue treatment allowed in RISERIDE (Lucentisreg) from 3 months2

bull Focalgrid laser allowed in FAME (Iluvienreg) from 6 weeks3

MEAD TREATMENT PROTOCOL

bull First treatment given at randomisation (day 0) bull Patients assessed for retreatment eligibility every 3 months from

months 6ndash36bull Patients were eligible for retreatment if

OCT optical coherence tomography

ge6 months since most recent

study treatment

Retinal thickness in 1 mm central macular

subfield by OCT gt175 microm

Evidence of residual retinal oedema (intraretinal cysts or

any regions of increased retinal thickening) as assessed by

investigator from OCT

AND OR

MEA

D

Amendment in May 2010 revised anatomic criterion for retreatment before this time the threshold was gt225 microm1Boyer DS et al Ophthalmology 2014 121 1904-19142Nguyen QD et al Ophthalmology 20121191064minus10773Campochiaro PA et al Ophthalmology 2011118626ndash635

Treatment burdenILUVIEN

Control(n =112)

02 microgd FAc(n =209)

Study Treatments(sham injection or ILUVIEN 02 microgday or FAc 05microgday)

1 treatment 661 761

2 treatments 277 187

ge 3 treatments 63 53

Rescue Laser Treatments (at masked physicianrsquos discretion after week 6)

Patients 607 407

Off-Protocol Treatments (IVTA bevacizumab ranibizumab intravitreal dexamethasone)

Patients 295 115

OZURDEX = 23injections year 1 41 by year 3

No other Rx

Summary of side effects with intravitreal steroids

Drug device Evidence base Cataract risk IOP rise (requiring drops)

Glaucoma surgery

endophthalmitis

ILUVIEN FAME studies 80 cat surgery(273 sham)

384(14 control)

48 0

Ozurdex MEAD 592 had cataract surgery(72 sham)

215 (end of study)(34 sham)

06 0

Trivaris+ laser vs Luc+laserx2 vs laser

Protocol IOphthalmology 2010

15 42(ONE OFgt10mmHg risegt30mmHGStart drops)

2186 0

NICE guidance for intravitreal steroids in DMO

bull Iluvien

bull NICE TA 301 Iluvien for DMO Nov 2013

bull hellipfor treating chronic diabetic macular oedema that is insufficiently responsive to available therapies only if

bull the implant is to be used in an eye with an intraocular

(pseudophakic) lens and

bull the manufacturer provides fluocinolone acetonide intravitreal implant with the discount agreed in the patient access scheme

NICE guidance for intravitreal steroids in DMO

bull Ozurdex

bull NICE TA 349 Ozurdex for DMO July 2015

bull there is an artificial lens in the eye to be treated and

bull their diabetic macular oedema has not improved with

non-corticosteroid treatment or such treatment is not suitable for them

Steroids = second line therapyWhen do I switch

bull Anti-VEGF first line for centre involving DMObull NICE TA ndash ldquoinsufficiently responsiverdquo ldquo ldquonot improvedrdquo ldquonot suitablerdquo ndash

OTHER TREATMENTS

bull 2 scenariosbull 1) Anti-VEGF canrsquot be funded ie OCTlt400um + PSEUDOPHAKIC

bull 2) Already had a course of treatment with laseranti-VEGF + PSEUDOPHAKIC ie SWITCHING from anti-VEGF to steroid

bull Plus

bull ldquochronicrdquo DMO ndash 3 years duration in FAME (18months) for ILUVIEN

bull Chronic DMO not essential for Ozurdex

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

Protocol T ndash patients may not improve in first 6 months

RIDE

RISE

Mea

n ch

ange

in B

CVA

(E

TDR

S le

tters

)M

ean

chan

ge in

BC

VA

(ETD

RS

lette

rs)

Time (months)

RISE and RIDE (Lucentis monthly dosing) Mean change in BCVA over 36 months

Brown DM et al Ophthalmology 2013120(10)2013ndash2022

54

Ranibizumab 03 mgRanibizumab 05 mgShamranibizumab 05 mg

Date of Prep Dec 2014 LGB0820147252X

VA improvement continues throughout year 1 with monthly dosing

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user ndash more than protocol

I

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

DRCRN protocol I5 year outcomesInjections 8-9 in year 1Year 2 = 2-3Year 3= 1-2Year 4 = 0-1Year 5 = 0

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

Wait for plateau = stability in protocol T laserPatient factors again

Judgement of response to anti-VEGF ndashtimeframe

bull Wait 6 months in poor responders

bull Wait 1 year for heavy users

bull Tempting to try steroids earlier than this ifbull No glaucoma ndash not a deal breaker Ozurdex better short term optionbull Pseudophakic

bull Clues from the diseasebull chronic

bull PATIENT FACTORS

bull Any eyes avoid steroids ndash advanced glaucomaCSCR Or prior viral retinitis RARE

bull Any eyes avoid anti-VEGF pregnancytrying to concieve recent CVA

BIOMARKERS AT BASELINE WOULD BE USEFULRESTORE subgroup analysis of OCT features

bull Andreas Pollreisz EURETINA 2015

bull OCT biomarkers (RESTORE data)

bull Better effects with anti-VEGF ifbull Small rather than large intra-retinal cyst

bull Sub-retinal fluid present

bull Vitreo-macular adhesion at baseline

bull No disruption of ELM and ISOS junction

bull No disorganisation of inner retinal layers (DRIL)

RESTORE subgroup analysis of OCT features

bull Andreas Pollreisz EURETINA 2015

bull OCT biomarkers (RESTORE data)

bull Better effects with anti-VEGF ifbull Small rather than large intra-retinal cyst

bull Sub-retinal fluid present

bull Vitreo-macular adhesion at baseline

bull No disruption of ELM and ISOS junction

bull No disorganisation of inner retinal layers (DRIL)

Better baseline characterisationclassificationERG Contrast sensitivityOCT AngiographyMicroperimetry= clues as to who responds best to which drug

Plan for this presentation helliphellipa long list

bull What treatment options are available for DMO (evidence base)

bull What treatment should I start with at baselinebull Re-treatment algorithms for intravitreal DMO therapiesbull When should I switchcombine therapiesbull The bigger picture

bull Other eyebull The patient as a wholebull The service -coping with capacity ndash compromises

The bigger pictureOther eyeThe patient as a wholeThe service -coping with capacity ndash compromises

bull OTHER EYE ndash may create problems

bull Treat and extend ndash ldquoreduce of visitsrdquo plus Eylea license ndash ldquono need for monitoringrdquo may not benefit if lots of visits due to PDR other eye

bull PERIPHERAL RETINA anti-VEGF supresses proliferative disease - Rebound on stopping Rx

bull PATIENT

bull Anti-VEGF ndash heavy user - Will comply

bull One stop much better than two stop for patient ndash Treat and extend

bull SERVICE

bull Capacity and demand planning = fixedT+E more predictable at least 1 month in advance ndash flexible nurse injectors

bull Steroids ndash even if well controlled (Iluvien for 3 years) need IOP check

bull Need pan-retinal examination both eyes ndash separate visits

Summary

CSMO

No centre involvement

Photocoagulation

Centre involvement

gt 78 letters(normalminimally reduced VA)

Photocoagulation

VA 78ndash24 letters

Phakic

Anti-VEGF

Pseudophakic

Anti-VEGF

SWITCHglaucoma

Injection tolerance

Medical issuesrecent CVA

Peripheral diseaseBilateral Rx

CSMO

No centre involvement

LASER

Centre involvement

gt 78 letters(normalminimally

reduced VA)

VA 78ndash24 letters

EYLEA OR LUCENTIS OR AVASTIN

Funding issues

Protocol T ndash poor VA lt 65 letters (615)

LOADING

Monthly injections until stability OR 5 x 112 (EYLEA) = 6 MONTHS then 8 weeks

RETREATMENT1

TREAT AND EXTEND - PRN

PRN

PSEUDOPHAKIC

Prior Rx

ILUVIEN

Chronic disease

OZURDEX

RETREATMENT

OZURDEX

OCT gt175um or any residual oedema

ILUVIEN after 12 months if risksltbenefits

OCT

gt400um

bull FACE TO FACE CLINICS RUNNING IN PARALLEL

bull = MAC002 every 6 months (optom or doctor) routine check for cataracttolerance of injectionsglaucoma issues etc

bull =MAC003 (DOCTOR) for problems as needed no fixed intervalDischargestop treatmentDeclines treatment diagnosis CSR overlay etcswitch drugs

bull =RV002- (DOCTOR) every 6 months

bull =DM002 ndash (DOCTOR) variable interval determined by last assessing doctor

bull First visit at 6 months from 1st injection if mild NPDR

bull Otherwise determined by retinopathy generally

LOADING PHASE

EyleaLucentis 1 within 48hrs of baseline

EyleaLucentis 2 (and LogMAR VA plus OCT same visit)

EyleaLucentis 3 (and LogMAR VA plus OCT same visit)

EyleaLucentis 4 (TEinj)(and Logmar VA plus OCT same visit

AFTER INJECTION 4 data goes off to be reviewed immediately as a hellip

TREAT AND EXTEND assessment ndash the next interval will depend on the response to the loading phase

NB -DMO patients ndash majority (95) will need 6 injctions x 112 of Lucentis

OR Eylea 5 x 112 then 8 weekly

ONCE STABLE for 3 x injection in TE phase

VIRTUAL CLINIC MONITORING OF MACULOPATHY AND PRN RETREATMENT

ANTI-VEGF INJECTION PATHWAYS Baseline visitMAC001 for wet AMDRV001 for CRVOBRVOMed ret clinic for DMO

Pathways ndash too many directions

Better that thanhellip

Thank you

What therapy do I choose for my patient at baselineWhich treatments can I access

NICE TA 274 Lucentis for DMO April 2013NICE TA 346 Eylea for DMO July 2015

NICE TA 301 Iluvien for DMO Nov 2013NICE TA 349 Ozurdex for DMO July 2015

OCT gt400um1st line if OCT suitable

bull Chronic DMObull PSEUDOPHAKICbull Patients ldquoinsufficiently responsive

to existing therapiesrdquo

bull PSEUDOPHAKICbull ldquoNot improved with non-

corticosteroid or such treatment is not suitable for themrdquo

What therapy do I choose for my patient at baseline

bull ANTI-VEGF

bull Superior to ETDRS argon laser in terms of efficacy

RESTORE 36 month Lucentis prn extension studyLucentis monotherapy vs Lucentis plus laser vs laser aloneSchmidt-Erfuth U et al Ophthalmology 2014 121(5) 1045-1053

23

Months

12

10

8

6

4

2

0

minus22 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36

Extension study (ranibizumab 05 mg PRN)Core study

Me

an o

f th

e c

han

ge in

ETD

RS

BC

VA

Prior ranibizumab 05 mg + active laser (n=83)

Prior sham injections + active laser (n=74)

Prior ranibizumab 05 mg + sham laser (n=83)

79

71 606780

Core study assessment

Full analysisstudy completionInterim analysis

RIDE

RISE

Mea

n ch

ange

in B

CVA

(E

TDR

S le

tters

)M

ean

chan

ge in

BC

VA

(ETD

RS

lette

rs)

Time (months)

RISE and RIDE (Lucentis monthly dosing) Mean change in BCVA over 36 months

Brown DM et al Ophthalmology 2013120(10)2013ndash2022

15

Ranibizumab 03 mgRanibizumab 05 mgShamranibizumab 05 mg

RISE amp RIDE

Date of Prep Dec 2014 LGB0820147252X

02 Laser

125 2q4

107 2q8

0

Mea

n ch

ange

in B

CVA

lette

r sco

re

2

101214

02

6

10

14

4

8

12

468

09 Laser

115 2q4

111 2q8

VISTA Week 100

100928068645652403628201240 8 16 24 32 44 48 60 72 76 84 88 96

12 Laser

100928068645652403628201240 8 16 24 32 44 48 60 72 76 84 88 96

105 2q4

107 2q8VIVID Week 100

Week Laser 2q4 2q8

07 Laser

114 2q4

94 2q8

Eylea =VIVID and VISTA Mean change in BCVA to week 100Korobelnik J-F et al Ophthalmology 2014 121 (11) 2247ndash2254 Brown DM et al Ophthalmology 2015 Jul 18 [Epub ahead of print]

Plt00001 vs laser VIVID Laser n=132 2q4 n=136 2q8 n=135 VISTA Laser n=154 2q4 n=154 2q8 n=151Full analysis set 2q4 2 mg every 4 weeks 2q8 2 mg every 8 weeks BCVA best corrected visual acuity ETDRS Early Treatment Diabetic Retinopathy Study

What therapy do I choose for my patient at baseline

bull ANTI-VEGF helliphellipif OCT gt 400um

bull Sohellip Which one

Key trials in DMO

18

BOLT

RESOLVERISE and RIDE

DA VINCI

VIVID and VISTA

vs laser

vs sham

Steroids

(in combination

with laser)

Anti-VEGF

(in combination

with laser)

DRCRnet (Protocol I)

ETDRS

READ-2

RESTORE

RETAIN

REVEAL

DRCRnet (Protocol B)

FAMEMEAD

vs laser

vs sham

RanibizumabAflibercept

Bevacizumab

Triamcinolone

Fluocinolone acetonide Dexamethasone

Anti-VEGF Laser Steroids

DRCRnet PROTOCOL T

PROTOCOL T (DRCRnet)

bull Aflibercept Bevacizumab or Ranibizumab for Diabetic Macular Edema

bull N Engl J Med 2015 Mar 26372(13)1193-203

The Diabetic retinopathy Clinical Research Network February 18 2015

USA study NIHR funded

n=660

Lucentis 03mg not 05mg Eylea 2mg Avastin 125mg

Eylea protocol not the licensed regime

Avastin unlicensed

RETREATMENT protocol

First 6 months ndash inject every month 95 of patients UNLESS VA=66 AND OCT DRY

Then 2nd six months ndash if no change after 3 visits DEFER otherwise keep injecting monthly

Recurs ndash need at least 2 injections ie 3 months of stability

STABILITY = 10 Oct change or VA 5 letter change

STABILITY and residual OCT thickness gt250um LASER

Protocol T 1 year visual acuity outcomes

0

5

10

15

20

0 8 16 24 32 40 48

Visit Week

2032-2040 = 696 ndash 612= 78-69

0

5

10

15

20

0 8 16 24 32 40 48

Visit Week

2050 = 615 or worse = lt69

Mea

n ch

ange

in B

CV

A

Mea

n ch

ange

in B

CV

A

Aflibercept Bevacizumab Ranibizumab

+189

+142

+118+75

+8+83

Protocol T OCT outcomes year 1

-250

-200

-150

-100

-50

0

0 4 8 12 16 20 24 28 32 36 40 44 48 52

Visit Week

Aflibercept Bevacizumab Ranibizumab

Mea

n ch

ange

in C

ST

Conclusions ndash Protocol T year 1 data

bull Eylea was statistically superior in terms of visual acuity to 03mg Lucentisand to Avastin FOR PATIENTS WITH VA worse than 69 letters

bull Eylea and Lucentis were statistically superior in terms of OCT CRT reduction to Avastin for all patients regardless of baseline vision

bull No safety differences between the three drugs

SUMMARY What do I choose for my patient at baselineOCT central retinal thickness (CRT)PseudophakicAttempts at prior treatment duration of DMO

bull lt 400um

bull IFR licensed anti-VEGF or Avastin

+-ETDRS laser

PSEUDOPHAKIC

Iluvien

Ozurdex

bull gt 400um = Anti-VEGF

Which one

Depends on

bull baseline vision lt615 Eylea

bull Fixed dosing attractive (Eylea)bull Chronic DMO

bull PSEUDOPHAKICbull Patients ldquoinsufficiently

responsive to existing therapiesrdquo

bull ldquoNot improved with non-corticosteroid or such treatment is not suitable for themrdquo

Which steroid ndash Ozurdex or Iluvien

bull No head to head data

bull Revisit this when we think about switching from ANTI-VEGF to steroid

Assuming we have started with an anti-VEGF agent ndash what are the re-treatment algorithms in DMO

Treatment posologies

ldquoTreatment is initiated with one injection per month until maximum VA is achieved andor there are no signs of disease activity ie no change in VA and in other signs and

symptoms of the disease under continued treatment

In patients withhellipDMOhellip initially three or more consecutive monthly injections may be needed Thereafter monitoring and treatment intervals

should be determined by the physician and should be based on disease activity as

assessed by VA andor anatomical parametershellip

If patients are being treated according to a treat-and-extend regimen once maximum VA is achieved andor there are no

signs of disease activity the treatment intervals can be extended stepwise until signs of

disease activity or visual impairment recur The treatment intervalhellipmay be extended by up to one month

at a time for DMOrdquo

1 Novartis Pharmaceuticals UK Ltd 30 October 2014 Available at httpwwwmedicinesorgukemcmedicine19409 Accessed 04 September 2015

2 Bayer Pharma AG February 2015 Available at httpwwwmedicinesorgukemcmedicine27224 Accessed 04 September 2015

Ranibizumab1 Aflibercept2

ldquohelliptreatment is initiated with one injection per month for five consecutive doses followed by

one injection every two months There is no requirement for monitoring between injectionshellip

After the first 12 months of treatmenthellipthe treatment interval may be extended based

on visual andor anatomic outcomes The schedule for monitoring should

be determined by the treating physicianrdquo

DMO diabetic macular oedema VA visual acuity

Re-treatment algorithms for anti-VEGF agents in DMO

bull LOADING PHASE

bull Lucentis label = monthly until stability

bull Eylea label = 5 x 112 then every 8 weeks ie fixed regime year 1

bull DRCRnet protocol T = effectively 6 x112 for majority (95) BUT actually only mandated for first 3 months then prn

bull helliphellip likely that majority will receive injections monthly for first 6 months

bull INDIVIDUALISED PHASE

bull Once ldquostablerdquo ndash based on VA and OCT

bull NB May never get a ldquodryrdquo OCT so treat to stability

bull THEN

bull Treat and extend

bull prn

What does Treat and Extend mean

Pathway overview = Lucentis prn

Jan

Loading phase = injections every 4 weeks until ldquostablerdquo for 3 visits

helliphelliphellip

Feb OctSepAugJulJunMayAprMar

MarFebJan

DecNov

DecNovOctSepAugJulJunMayApr

Then observe UNTIL VA decreases or OCT increase = prn

Once reactivates need at least 2 injections until stable again over 3 visits

Pathway overview = Treat and Extend

Jan

Loading phase = injections every 4 weeks until ldquostablerdquo for 3 visits or Eyleayear 1

helliphelliphellip

Feb OctSepAugJulJunMayAprMar

MarFebJan

DecNov

DecNovOctSepAugJulJunMayApr

Then keep injecting but extend the interval between injections gradually ie keep treating even if perfect

If reactivates need at least 2 injections until stable again over 3 visits

Pathway overview = Eylea fixed dosing year 1

Jan

Eylea = 5 x 112 injection then every 8 weeks

Average 6 injections yr 2 Beyond that

helliphelliphellip

Feb OctSepAugJulJunMayAprMar

MarFebJan

DecNov

DecNovOctSepAugJulJunMayApr

Then individualised UNTIL VA decreases or OCT increase = prn

Once reactivates need at least 2 injections until stable again over 3 visits

Pros and cons of Treat and Extend vs Prn

T+E PRN

PROS bull Proactive patient and service get advance warning of injection ndash capacity and demand planning easier

bull One ndashstopbull Fewer visits than prnbull Overtreatment

advantageous for peripheral retinopathy

bull Only treated when active ieno overtreatment

bull Aggressive year 1 protocols (DRCRN I ndash few injections needed thereafter

bull DMO tolerant of reactivations ()

CONS bull Overtreatment = riskexpenseinconvenience

bull Evidence base scantbull Bilateral disease tricky

bull Reactive so need enoughemergency capacity to inject when disease flares up

bull No advance warning to patientservice that injection needed

bull NEED TO DO IT WELL ndashNHS real life audits prn based regimes not good resultsUndertreatment in year 1 Affects long term prognosis and treatment burden

Pros and cons of Treat and Extend vs Prn

T+E PRN

PROS bull Proactive patient and service get advance warning of injection ndash capacity and demand planning easier

bull One ndashstopbull Fewer visits than prnbull Overtreatment

advantageous for peripheral retinopathy

bull Only treated when active ieno overtreatment

bull Aggressive year 1 protocols (DRCRN I ndash few injections needed thereafter

bull DMO tolerant of reactivations ()

CONS bull Overtreatment = riskexpenseinconvenience

bull Evidence base scantbull Bilateral disease tricky

bull Reactive so need enoughemergency capacity to inject when disease flares up

bull No advance warning to patientservice that injection needed

bull NEED TO DO IT WELL ndashNHS real life audits prn based regimes not good resultsUndertreatment in year 1 Affects long term prognosis and treatment burden

DMO ndash anti-VEGF Treat and Extend

bull Retain study ndash the only RCT data

bull Br J Ophthalmol 2015 Oct 9 pii bjophthalmol-2015-307249 doi 101136bjophthalmol-2015-307249 [Epub ahead of print]

bull Ranibizumab 05 mg treat-and-extend regimen for diabetic macular oedema the RETAIN study

bull Pruumlnte C1 Fajnkuchen F2 Mahmood S3 Ricci F4 Hatz K5 Studnička J6 Bezlyak V7 Parikh S7 Stubbings WJ7 Wenzel A7 Figueira J8 and the RETAIN Study Group

RETAIN Phase III trial evaluating the efficacy of lsquotreat and extendrsquo regimen (ARVO 2014)

bull Patients with DMO and visual impairment (n = 372) were randomised 111

to one of three groups for 24 months

bull Two phases to dosing schedule

bull Phase A

bull Patients in all groups were initially treated with monthly ranibizumab until BCVA remained

stable

bull Phase B

bull Patients in the TampE groups whose vision remained stable had treatment- free intervals

that were increased incrementally by 1 month for a maximum of 3 months

bull Patients in the PRN group had ongoing monthly monitoring

bull In all groups Phase A was resumed if a decrease in BCVA was observed at a visit

Ranibizumab 05 mg monotherapy

in TampE regimen

Ranibizumab 05 mg in TampE regimen

plus laser

Ranibizumab 05 mg PRN

35

RETAIN Visual acuity endpoints

Pruumlnte C ARVO 2014 Annual Meeting Abstracts Abstract 1700

Mean average change in BCVAat 12 months (primary endpoint)

Mean change in BCVA at 24 months

Mea

n av

erag

e ch

ange

in B

CVA

(ETD

RS

lette

rs)

RanibizumabTampE

RanibizumabTampE + laser

RanibizumabPRN

RanibizumabTampE

RanibizumabTampE + laser

RanibizumabPRN

Mea

n ch

ange

in B

CVA

(ETD

RS

lette

rs)

plt00001 for both ranibizumab TampE groups versus PRN for primary endpoint

36

RETAIN Patient visits and monitoring with TampE regimen over 24 months

bull The TampE regimen provided an approximately 40 reduction in the number of treatment visits required compared with the ranibizumab PRN regimen

bull Approximately 70 of patients receiving TampE regimens had monitoring intervals ge2 months compared with ongoing monthly monitoring in the ranibizumab PRN group

bull Informed the license for Lucentis in DMO (extend by 1 month at a time)

37

INTRAVITREAL STEROIDSWhich intravitreal steroid is better

bull Licensed steroids ndash Ozurdex (Dexamethasone) and Iluvien (Fluocinoloneacetonide

bull Which steroid is best in terms of VA outcomes hellipWE DONrsquoT KNOW FOR SURE ndash no head to head studies for licensed drugs either between steroids or between anti-VEGF and steroids

bull STEROIDS ARE efficacious in DMO

bull MEAD

bull FAME

bull DRCRnet protocol I

bull NICE ndash Ozurdex and Iluvien ndash second-line agents

Ozurdex

bull A biodegradable co-polymer implant ndash degrades in time to lactic and glycolic acid releasing Dexamethasone

bull 22gauge injectionbull MEAD study

bull N=1048

bull Dex 07mg vs 035mg vs sham

bull No rescue therapy

bull 3 year follow up max 6 monthly dosing ie 7 over 3 years

Gan IM et al Greafes Acrh Clin Exp Ophthalmol 2005

MEAD studyMean BCVA change from baseline based on baseline lens status

-2

0

2

4

6

8

10

0 3 6 9 12 15 18 21 24 27 30 33 36 39

Mea

n C

hang

e Fr

om

Bas

elin

e B

CVA

(Let

ters

)

Month

DEX Implant 07 mg (n = 86)

Sham (n = 101)

Boyer DS et al Ophthalmology 20141211904ndash14

Results analyzed in the ITT population with LOCF for missing values

Pseudophakic

Total

0

5

10

0 3 6 9 12 15 18 21 24 27 30 33 36 39

DEX 700 (n=351)

Sham (n=350)

10

8

6

4

2

0

Mea

n C

hang

e fr

om

Bas

elin

e B

CVA

(Let

ters

)

Month

07mg dose is approved as Ozurdexreg by the FDA and EMA 035mg dose not commercially available

1 Boyer DS et al Ophthalmology 2014 121 1904-1914

bull Nonbioerodible micro implant (polyimide) containing 190microg of fluocinolone acetonide (FAc)

bull Consistent daily submicrogram delivery of 02 microgd FAc for up to 36 months

bull Posterior point of release

bull 35 mm times 037 mm non-bioerodable micro implant

bull 25-gauge injector creates self-sealing wound

bull No measurable systemic exposure

ILUVIEN Implant Technology

FAcimplant

ILUVIEN SPC httpwwwmedicinesorgukemcmedicine27636

0 6 12 18 24 30 36

ILUVIEN 02 microgd FAc(n = 376)05 microgd FAc (n = 395)Control sham injection(n = 185)

Design of Phase 3 FAME Study (FAME A and B = same protocol)

Additional laser therapy allowed after week 6a

Retreatment any time after month 12 (if eligibleb)

Study ends

N = 956Randomisation

221Primary readout

Patients with DMO and

bull At least 1 previous laser tx

bull BCVA ge19 and le68 letters

bull TD-OCT FTH ge250 μm

Month

BCVA = best corrected visual acuity DMO = diabetic macular oedema TD-OCT=time domain optical coherence tomography FTH = foveal thicknessa At masked investigatorrsquos discretion b If BCVA loss ge5 letters or retinal thickening ge50 microm from best reading in previous 12 months

ge15 letter Gain is Greater in Chronic DMO Patients

ge 15

-Let

ter I

mpr

ovem

ent

in B

CVA

Fro

m B

asel

ine

Δ = 98

Months

Full Population Patients With Chronic DMO

Months

Δ = 206

287

189134

34

Steroid re-treatments

bullOzurdexbull Longer half-life than anti-VEGF in the eye

bull Redosing regimes not very helpful from RCT data eg MEAD study only 612 dosing

bull In reality re-treatment interval may be shorter

bull POSOLOGY

bull Patients treated with OZURDEX who have experienced an initial response and in the physicians opinion may benefit from retreatment without being exposed to significant risk should be considered for retreatment Retreatment may be performed after approximately 6 months if the patient experiences decreased vision andor an increase in retinal thickness secondary to recurrent or worsening diabetic macular oedema

bullIluvienbull 70 of patients in FAE only needed 1

injection over 3 years

bull BUT additional rescue treatments allowed

bull POSOLOGY

bull Each ILUVIEN implant releases fluocinolone acetonide for up to 36 months An additional implant may be administered after 12 months if the patient experiences decreased vision or an increase in retinal thickness secondary to recurrent or worsening diabetic macular oedema

bull Patients receiving escape medication were exited from MEAD before administration1

bull Macular laser rescue treatment allowed in RISERIDE (Lucentisreg) from 3 months2

bull Focalgrid laser allowed in FAME (Iluvienreg) from 6 weeks3

MEAD TREATMENT PROTOCOL

bull First treatment given at randomisation (day 0) bull Patients assessed for retreatment eligibility every 3 months from

months 6ndash36bull Patients were eligible for retreatment if

OCT optical coherence tomography

ge6 months since most recent

study treatment

Retinal thickness in 1 mm central macular

subfield by OCT gt175 microm

Evidence of residual retinal oedema (intraretinal cysts or

any regions of increased retinal thickening) as assessed by

investigator from OCT

AND OR

MEA

D

Amendment in May 2010 revised anatomic criterion for retreatment before this time the threshold was gt225 microm1Boyer DS et al Ophthalmology 2014 121 1904-19142Nguyen QD et al Ophthalmology 20121191064minus10773Campochiaro PA et al Ophthalmology 2011118626ndash635

Treatment burdenILUVIEN

Control(n =112)

02 microgd FAc(n =209)

Study Treatments(sham injection or ILUVIEN 02 microgday or FAc 05microgday)

1 treatment 661 761

2 treatments 277 187

ge 3 treatments 63 53

Rescue Laser Treatments (at masked physicianrsquos discretion after week 6)

Patients 607 407

Off-Protocol Treatments (IVTA bevacizumab ranibizumab intravitreal dexamethasone)

Patients 295 115

OZURDEX = 23injections year 1 41 by year 3

No other Rx

Summary of side effects with intravitreal steroids

Drug device Evidence base Cataract risk IOP rise (requiring drops)

Glaucoma surgery

endophthalmitis

ILUVIEN FAME studies 80 cat surgery(273 sham)

384(14 control)

48 0

Ozurdex MEAD 592 had cataract surgery(72 sham)

215 (end of study)(34 sham)

06 0

Trivaris+ laser vs Luc+laserx2 vs laser

Protocol IOphthalmology 2010

15 42(ONE OFgt10mmHg risegt30mmHGStart drops)

2186 0

NICE guidance for intravitreal steroids in DMO

bull Iluvien

bull NICE TA 301 Iluvien for DMO Nov 2013

bull hellipfor treating chronic diabetic macular oedema that is insufficiently responsive to available therapies only if

bull the implant is to be used in an eye with an intraocular

(pseudophakic) lens and

bull the manufacturer provides fluocinolone acetonide intravitreal implant with the discount agreed in the patient access scheme

NICE guidance for intravitreal steroids in DMO

bull Ozurdex

bull NICE TA 349 Ozurdex for DMO July 2015

bull there is an artificial lens in the eye to be treated and

bull their diabetic macular oedema has not improved with

non-corticosteroid treatment or such treatment is not suitable for them

Steroids = second line therapyWhen do I switch

bull Anti-VEGF first line for centre involving DMObull NICE TA ndash ldquoinsufficiently responsiverdquo ldquo ldquonot improvedrdquo ldquonot suitablerdquo ndash

OTHER TREATMENTS

bull 2 scenariosbull 1) Anti-VEGF canrsquot be funded ie OCTlt400um + PSEUDOPHAKIC

bull 2) Already had a course of treatment with laseranti-VEGF + PSEUDOPHAKIC ie SWITCHING from anti-VEGF to steroid

bull Plus

bull ldquochronicrdquo DMO ndash 3 years duration in FAME (18months) for ILUVIEN

bull Chronic DMO not essential for Ozurdex

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

Protocol T ndash patients may not improve in first 6 months

RIDE

RISE

Mea

n ch

ange

in B

CVA

(E

TDR

S le

tters

)M

ean

chan

ge in

BC

VA

(ETD

RS

lette

rs)

Time (months)

RISE and RIDE (Lucentis monthly dosing) Mean change in BCVA over 36 months

Brown DM et al Ophthalmology 2013120(10)2013ndash2022

54

Ranibizumab 03 mgRanibizumab 05 mgShamranibizumab 05 mg

Date of Prep Dec 2014 LGB0820147252X

VA improvement continues throughout year 1 with monthly dosing

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user ndash more than protocol

I

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

DRCRN protocol I5 year outcomesInjections 8-9 in year 1Year 2 = 2-3Year 3= 1-2Year 4 = 0-1Year 5 = 0

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

Wait for plateau = stability in protocol T laserPatient factors again

Judgement of response to anti-VEGF ndashtimeframe

bull Wait 6 months in poor responders

bull Wait 1 year for heavy users

bull Tempting to try steroids earlier than this ifbull No glaucoma ndash not a deal breaker Ozurdex better short term optionbull Pseudophakic

bull Clues from the diseasebull chronic

bull PATIENT FACTORS

bull Any eyes avoid steroids ndash advanced glaucomaCSCR Or prior viral retinitis RARE

bull Any eyes avoid anti-VEGF pregnancytrying to concieve recent CVA

BIOMARKERS AT BASELINE WOULD BE USEFULRESTORE subgroup analysis of OCT features

bull Andreas Pollreisz EURETINA 2015

bull OCT biomarkers (RESTORE data)

bull Better effects with anti-VEGF ifbull Small rather than large intra-retinal cyst

bull Sub-retinal fluid present

bull Vitreo-macular adhesion at baseline

bull No disruption of ELM and ISOS junction

bull No disorganisation of inner retinal layers (DRIL)

RESTORE subgroup analysis of OCT features

bull Andreas Pollreisz EURETINA 2015

bull OCT biomarkers (RESTORE data)

bull Better effects with anti-VEGF ifbull Small rather than large intra-retinal cyst

bull Sub-retinal fluid present

bull Vitreo-macular adhesion at baseline

bull No disruption of ELM and ISOS junction

bull No disorganisation of inner retinal layers (DRIL)

Better baseline characterisationclassificationERG Contrast sensitivityOCT AngiographyMicroperimetry= clues as to who responds best to which drug

Plan for this presentation helliphellipa long list

bull What treatment options are available for DMO (evidence base)

bull What treatment should I start with at baselinebull Re-treatment algorithms for intravitreal DMO therapiesbull When should I switchcombine therapiesbull The bigger picture

bull Other eyebull The patient as a wholebull The service -coping with capacity ndash compromises

The bigger pictureOther eyeThe patient as a wholeThe service -coping with capacity ndash compromises

bull OTHER EYE ndash may create problems

bull Treat and extend ndash ldquoreduce of visitsrdquo plus Eylea license ndash ldquono need for monitoringrdquo may not benefit if lots of visits due to PDR other eye

bull PERIPHERAL RETINA anti-VEGF supresses proliferative disease - Rebound on stopping Rx

bull PATIENT

bull Anti-VEGF ndash heavy user - Will comply

bull One stop much better than two stop for patient ndash Treat and extend

bull SERVICE

bull Capacity and demand planning = fixedT+E more predictable at least 1 month in advance ndash flexible nurse injectors

bull Steroids ndash even if well controlled (Iluvien for 3 years) need IOP check

bull Need pan-retinal examination both eyes ndash separate visits

Summary

CSMO

No centre involvement

Photocoagulation

Centre involvement

gt 78 letters(normalminimally reduced VA)

Photocoagulation

VA 78ndash24 letters

Phakic

Anti-VEGF

Pseudophakic

Anti-VEGF

SWITCHglaucoma

Injection tolerance

Medical issuesrecent CVA

Peripheral diseaseBilateral Rx

CSMO

No centre involvement

LASER

Centre involvement

gt 78 letters(normalminimally

reduced VA)

VA 78ndash24 letters

EYLEA OR LUCENTIS OR AVASTIN

Funding issues

Protocol T ndash poor VA lt 65 letters (615)

LOADING

Monthly injections until stability OR 5 x 112 (EYLEA) = 6 MONTHS then 8 weeks

RETREATMENT1

TREAT AND EXTEND - PRN

PRN

PSEUDOPHAKIC

Prior Rx

ILUVIEN

Chronic disease

OZURDEX

RETREATMENT

OZURDEX

OCT gt175um or any residual oedema

ILUVIEN after 12 months if risksltbenefits

OCT

gt400um

bull FACE TO FACE CLINICS RUNNING IN PARALLEL

bull = MAC002 every 6 months (optom or doctor) routine check for cataracttolerance of injectionsglaucoma issues etc

bull =MAC003 (DOCTOR) for problems as needed no fixed intervalDischargestop treatmentDeclines treatment diagnosis CSR overlay etcswitch drugs

bull =RV002- (DOCTOR) every 6 months

bull =DM002 ndash (DOCTOR) variable interval determined by last assessing doctor

bull First visit at 6 months from 1st injection if mild NPDR

bull Otherwise determined by retinopathy generally

LOADING PHASE

EyleaLucentis 1 within 48hrs of baseline

EyleaLucentis 2 (and LogMAR VA plus OCT same visit)

EyleaLucentis 3 (and LogMAR VA plus OCT same visit)

EyleaLucentis 4 (TEinj)(and Logmar VA plus OCT same visit

AFTER INJECTION 4 data goes off to be reviewed immediately as a hellip

TREAT AND EXTEND assessment ndash the next interval will depend on the response to the loading phase

NB -DMO patients ndash majority (95) will need 6 injctions x 112 of Lucentis

OR Eylea 5 x 112 then 8 weekly

ONCE STABLE for 3 x injection in TE phase

VIRTUAL CLINIC MONITORING OF MACULOPATHY AND PRN RETREATMENT

ANTI-VEGF INJECTION PATHWAYS Baseline visitMAC001 for wet AMDRV001 for CRVOBRVOMed ret clinic for DMO

Pathways ndash too many directions

Better that thanhellip

Thank you

What therapy do I choose for my patient at baseline

bull ANTI-VEGF

bull Superior to ETDRS argon laser in terms of efficacy

RESTORE 36 month Lucentis prn extension studyLucentis monotherapy vs Lucentis plus laser vs laser aloneSchmidt-Erfuth U et al Ophthalmology 2014 121(5) 1045-1053

23

Months

12

10

8

6

4

2

0

minus22 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36

Extension study (ranibizumab 05 mg PRN)Core study

Me

an o

f th

e c

han

ge in

ETD

RS

BC

VA

Prior ranibizumab 05 mg + active laser (n=83)

Prior sham injections + active laser (n=74)

Prior ranibizumab 05 mg + sham laser (n=83)

79

71 606780

Core study assessment

Full analysisstudy completionInterim analysis

RIDE

RISE

Mea

n ch

ange

in B

CVA

(E

TDR

S le

tters

)M

ean

chan

ge in

BC

VA

(ETD

RS

lette

rs)

Time (months)

RISE and RIDE (Lucentis monthly dosing) Mean change in BCVA over 36 months

Brown DM et al Ophthalmology 2013120(10)2013ndash2022

15

Ranibizumab 03 mgRanibizumab 05 mgShamranibizumab 05 mg

RISE amp RIDE

Date of Prep Dec 2014 LGB0820147252X

02 Laser

125 2q4

107 2q8

0

Mea

n ch

ange

in B

CVA

lette

r sco

re

2

101214

02

6

10

14

4

8

12

468

09 Laser

115 2q4

111 2q8

VISTA Week 100

100928068645652403628201240 8 16 24 32 44 48 60 72 76 84 88 96

12 Laser

100928068645652403628201240 8 16 24 32 44 48 60 72 76 84 88 96

105 2q4

107 2q8VIVID Week 100

Week Laser 2q4 2q8

07 Laser

114 2q4

94 2q8

Eylea =VIVID and VISTA Mean change in BCVA to week 100Korobelnik J-F et al Ophthalmology 2014 121 (11) 2247ndash2254 Brown DM et al Ophthalmology 2015 Jul 18 [Epub ahead of print]

Plt00001 vs laser VIVID Laser n=132 2q4 n=136 2q8 n=135 VISTA Laser n=154 2q4 n=154 2q8 n=151Full analysis set 2q4 2 mg every 4 weeks 2q8 2 mg every 8 weeks BCVA best corrected visual acuity ETDRS Early Treatment Diabetic Retinopathy Study

What therapy do I choose for my patient at baseline

bull ANTI-VEGF helliphellipif OCT gt 400um

bull Sohellip Which one

Key trials in DMO

18

BOLT

RESOLVERISE and RIDE

DA VINCI

VIVID and VISTA

vs laser

vs sham

Steroids

(in combination

with laser)

Anti-VEGF

(in combination

with laser)

DRCRnet (Protocol I)

ETDRS

READ-2

RESTORE

RETAIN

REVEAL

DRCRnet (Protocol B)

FAMEMEAD

vs laser

vs sham

RanibizumabAflibercept

Bevacizumab

Triamcinolone

Fluocinolone acetonide Dexamethasone

Anti-VEGF Laser Steroids

DRCRnet PROTOCOL T

PROTOCOL T (DRCRnet)

bull Aflibercept Bevacizumab or Ranibizumab for Diabetic Macular Edema

bull N Engl J Med 2015 Mar 26372(13)1193-203

The Diabetic retinopathy Clinical Research Network February 18 2015

USA study NIHR funded

n=660

Lucentis 03mg not 05mg Eylea 2mg Avastin 125mg

Eylea protocol not the licensed regime

Avastin unlicensed

RETREATMENT protocol

First 6 months ndash inject every month 95 of patients UNLESS VA=66 AND OCT DRY

Then 2nd six months ndash if no change after 3 visits DEFER otherwise keep injecting monthly

Recurs ndash need at least 2 injections ie 3 months of stability

STABILITY = 10 Oct change or VA 5 letter change

STABILITY and residual OCT thickness gt250um LASER

Protocol T 1 year visual acuity outcomes

0

5

10

15

20

0 8 16 24 32 40 48

Visit Week

2032-2040 = 696 ndash 612= 78-69

0

5

10

15

20

0 8 16 24 32 40 48

Visit Week

2050 = 615 or worse = lt69

Mea

n ch

ange

in B

CV

A

Mea

n ch

ange

in B

CV

A

Aflibercept Bevacizumab Ranibizumab

+189

+142

+118+75

+8+83

Protocol T OCT outcomes year 1

-250

-200

-150

-100

-50

0

0 4 8 12 16 20 24 28 32 36 40 44 48 52

Visit Week

Aflibercept Bevacizumab Ranibizumab

Mea

n ch

ange

in C

ST

Conclusions ndash Protocol T year 1 data

bull Eylea was statistically superior in terms of visual acuity to 03mg Lucentisand to Avastin FOR PATIENTS WITH VA worse than 69 letters

bull Eylea and Lucentis were statistically superior in terms of OCT CRT reduction to Avastin for all patients regardless of baseline vision

bull No safety differences between the three drugs

SUMMARY What do I choose for my patient at baselineOCT central retinal thickness (CRT)PseudophakicAttempts at prior treatment duration of DMO

bull lt 400um

bull IFR licensed anti-VEGF or Avastin

+-ETDRS laser

PSEUDOPHAKIC

Iluvien

Ozurdex

bull gt 400um = Anti-VEGF

Which one

Depends on

bull baseline vision lt615 Eylea

bull Fixed dosing attractive (Eylea)bull Chronic DMO

bull PSEUDOPHAKICbull Patients ldquoinsufficiently

responsive to existing therapiesrdquo

bull ldquoNot improved with non-corticosteroid or such treatment is not suitable for themrdquo

Which steroid ndash Ozurdex or Iluvien

bull No head to head data

bull Revisit this when we think about switching from ANTI-VEGF to steroid

Assuming we have started with an anti-VEGF agent ndash what are the re-treatment algorithms in DMO

Treatment posologies

ldquoTreatment is initiated with one injection per month until maximum VA is achieved andor there are no signs of disease activity ie no change in VA and in other signs and

symptoms of the disease under continued treatment

In patients withhellipDMOhellip initially three or more consecutive monthly injections may be needed Thereafter monitoring and treatment intervals

should be determined by the physician and should be based on disease activity as

assessed by VA andor anatomical parametershellip

If patients are being treated according to a treat-and-extend regimen once maximum VA is achieved andor there are no

signs of disease activity the treatment intervals can be extended stepwise until signs of

disease activity or visual impairment recur The treatment intervalhellipmay be extended by up to one month

at a time for DMOrdquo

1 Novartis Pharmaceuticals UK Ltd 30 October 2014 Available at httpwwwmedicinesorgukemcmedicine19409 Accessed 04 September 2015

2 Bayer Pharma AG February 2015 Available at httpwwwmedicinesorgukemcmedicine27224 Accessed 04 September 2015

Ranibizumab1 Aflibercept2

ldquohelliptreatment is initiated with one injection per month for five consecutive doses followed by

one injection every two months There is no requirement for monitoring between injectionshellip

After the first 12 months of treatmenthellipthe treatment interval may be extended based

on visual andor anatomic outcomes The schedule for monitoring should

be determined by the treating physicianrdquo

DMO diabetic macular oedema VA visual acuity

Re-treatment algorithms for anti-VEGF agents in DMO

bull LOADING PHASE

bull Lucentis label = monthly until stability

bull Eylea label = 5 x 112 then every 8 weeks ie fixed regime year 1

bull DRCRnet protocol T = effectively 6 x112 for majority (95) BUT actually only mandated for first 3 months then prn

bull helliphellip likely that majority will receive injections monthly for first 6 months

bull INDIVIDUALISED PHASE

bull Once ldquostablerdquo ndash based on VA and OCT

bull NB May never get a ldquodryrdquo OCT so treat to stability

bull THEN

bull Treat and extend

bull prn

What does Treat and Extend mean

Pathway overview = Lucentis prn

Jan

Loading phase = injections every 4 weeks until ldquostablerdquo for 3 visits

helliphelliphellip

Feb OctSepAugJulJunMayAprMar

MarFebJan

DecNov

DecNovOctSepAugJulJunMayApr

Then observe UNTIL VA decreases or OCT increase = prn

Once reactivates need at least 2 injections until stable again over 3 visits

Pathway overview = Treat and Extend

Jan

Loading phase = injections every 4 weeks until ldquostablerdquo for 3 visits or Eyleayear 1

helliphelliphellip

Feb OctSepAugJulJunMayAprMar

MarFebJan

DecNov

DecNovOctSepAugJulJunMayApr

Then keep injecting but extend the interval between injections gradually ie keep treating even if perfect

If reactivates need at least 2 injections until stable again over 3 visits

Pathway overview = Eylea fixed dosing year 1

Jan

Eylea = 5 x 112 injection then every 8 weeks

Average 6 injections yr 2 Beyond that

helliphelliphellip

Feb OctSepAugJulJunMayAprMar

MarFebJan

DecNov

DecNovOctSepAugJulJunMayApr

Then individualised UNTIL VA decreases or OCT increase = prn

Once reactivates need at least 2 injections until stable again over 3 visits

Pros and cons of Treat and Extend vs Prn

T+E PRN

PROS bull Proactive patient and service get advance warning of injection ndash capacity and demand planning easier

bull One ndashstopbull Fewer visits than prnbull Overtreatment

advantageous for peripheral retinopathy

bull Only treated when active ieno overtreatment

bull Aggressive year 1 protocols (DRCRN I ndash few injections needed thereafter

bull DMO tolerant of reactivations ()

CONS bull Overtreatment = riskexpenseinconvenience

bull Evidence base scantbull Bilateral disease tricky

bull Reactive so need enoughemergency capacity to inject when disease flares up

bull No advance warning to patientservice that injection needed

bull NEED TO DO IT WELL ndashNHS real life audits prn based regimes not good resultsUndertreatment in year 1 Affects long term prognosis and treatment burden

Pros and cons of Treat and Extend vs Prn

T+E PRN

PROS bull Proactive patient and service get advance warning of injection ndash capacity and demand planning easier

bull One ndashstopbull Fewer visits than prnbull Overtreatment

advantageous for peripheral retinopathy

bull Only treated when active ieno overtreatment

bull Aggressive year 1 protocols (DRCRN I ndash few injections needed thereafter

bull DMO tolerant of reactivations ()

CONS bull Overtreatment = riskexpenseinconvenience

bull Evidence base scantbull Bilateral disease tricky

bull Reactive so need enoughemergency capacity to inject when disease flares up

bull No advance warning to patientservice that injection needed

bull NEED TO DO IT WELL ndashNHS real life audits prn based regimes not good resultsUndertreatment in year 1 Affects long term prognosis and treatment burden

DMO ndash anti-VEGF Treat and Extend

bull Retain study ndash the only RCT data

bull Br J Ophthalmol 2015 Oct 9 pii bjophthalmol-2015-307249 doi 101136bjophthalmol-2015-307249 [Epub ahead of print]

bull Ranibizumab 05 mg treat-and-extend regimen for diabetic macular oedema the RETAIN study

bull Pruumlnte C1 Fajnkuchen F2 Mahmood S3 Ricci F4 Hatz K5 Studnička J6 Bezlyak V7 Parikh S7 Stubbings WJ7 Wenzel A7 Figueira J8 and the RETAIN Study Group

RETAIN Phase III trial evaluating the efficacy of lsquotreat and extendrsquo regimen (ARVO 2014)

bull Patients with DMO and visual impairment (n = 372) were randomised 111

to one of three groups for 24 months

bull Two phases to dosing schedule

bull Phase A

bull Patients in all groups were initially treated with monthly ranibizumab until BCVA remained

stable

bull Phase B

bull Patients in the TampE groups whose vision remained stable had treatment- free intervals

that were increased incrementally by 1 month for a maximum of 3 months

bull Patients in the PRN group had ongoing monthly monitoring

bull In all groups Phase A was resumed if a decrease in BCVA was observed at a visit

Ranibizumab 05 mg monotherapy

in TampE regimen

Ranibizumab 05 mg in TampE regimen

plus laser

Ranibizumab 05 mg PRN

35

RETAIN Visual acuity endpoints

Pruumlnte C ARVO 2014 Annual Meeting Abstracts Abstract 1700

Mean average change in BCVAat 12 months (primary endpoint)

Mean change in BCVA at 24 months

Mea

n av

erag

e ch

ange

in B

CVA

(ETD

RS

lette

rs)

RanibizumabTampE

RanibizumabTampE + laser

RanibizumabPRN

RanibizumabTampE

RanibizumabTampE + laser

RanibizumabPRN

Mea

n ch

ange

in B

CVA

(ETD

RS

lette

rs)

plt00001 for both ranibizumab TampE groups versus PRN for primary endpoint

36

RETAIN Patient visits and monitoring with TampE regimen over 24 months

bull The TampE regimen provided an approximately 40 reduction in the number of treatment visits required compared with the ranibizumab PRN regimen

bull Approximately 70 of patients receiving TampE regimens had monitoring intervals ge2 months compared with ongoing monthly monitoring in the ranibizumab PRN group

bull Informed the license for Lucentis in DMO (extend by 1 month at a time)

37

INTRAVITREAL STEROIDSWhich intravitreal steroid is better

bull Licensed steroids ndash Ozurdex (Dexamethasone) and Iluvien (Fluocinoloneacetonide

bull Which steroid is best in terms of VA outcomes hellipWE DONrsquoT KNOW FOR SURE ndash no head to head studies for licensed drugs either between steroids or between anti-VEGF and steroids

bull STEROIDS ARE efficacious in DMO

bull MEAD

bull FAME

bull DRCRnet protocol I

bull NICE ndash Ozurdex and Iluvien ndash second-line agents

Ozurdex

bull A biodegradable co-polymer implant ndash degrades in time to lactic and glycolic acid releasing Dexamethasone

bull 22gauge injectionbull MEAD study

bull N=1048

bull Dex 07mg vs 035mg vs sham

bull No rescue therapy

bull 3 year follow up max 6 monthly dosing ie 7 over 3 years

Gan IM et al Greafes Acrh Clin Exp Ophthalmol 2005

MEAD studyMean BCVA change from baseline based on baseline lens status

-2

0

2

4

6

8

10

0 3 6 9 12 15 18 21 24 27 30 33 36 39

Mea

n C

hang

e Fr

om

Bas

elin

e B

CVA

(Let

ters

)

Month

DEX Implant 07 mg (n = 86)

Sham (n = 101)

Boyer DS et al Ophthalmology 20141211904ndash14

Results analyzed in the ITT population with LOCF for missing values

Pseudophakic

Total

0

5

10

0 3 6 9 12 15 18 21 24 27 30 33 36 39

DEX 700 (n=351)

Sham (n=350)

10

8

6

4

2

0

Mea

n C

hang

e fr

om

Bas

elin

e B

CVA

(Let

ters

)

Month

07mg dose is approved as Ozurdexreg by the FDA and EMA 035mg dose not commercially available

1 Boyer DS et al Ophthalmology 2014 121 1904-1914

bull Nonbioerodible micro implant (polyimide) containing 190microg of fluocinolone acetonide (FAc)

bull Consistent daily submicrogram delivery of 02 microgd FAc for up to 36 months

bull Posterior point of release

bull 35 mm times 037 mm non-bioerodable micro implant

bull 25-gauge injector creates self-sealing wound

bull No measurable systemic exposure

ILUVIEN Implant Technology

FAcimplant

ILUVIEN SPC httpwwwmedicinesorgukemcmedicine27636

0 6 12 18 24 30 36

ILUVIEN 02 microgd FAc(n = 376)05 microgd FAc (n = 395)Control sham injection(n = 185)

Design of Phase 3 FAME Study (FAME A and B = same protocol)

Additional laser therapy allowed after week 6a

Retreatment any time after month 12 (if eligibleb)

Study ends

N = 956Randomisation

221Primary readout

Patients with DMO and

bull At least 1 previous laser tx

bull BCVA ge19 and le68 letters

bull TD-OCT FTH ge250 μm

Month

BCVA = best corrected visual acuity DMO = diabetic macular oedema TD-OCT=time domain optical coherence tomography FTH = foveal thicknessa At masked investigatorrsquos discretion b If BCVA loss ge5 letters or retinal thickening ge50 microm from best reading in previous 12 months

ge15 letter Gain is Greater in Chronic DMO Patients

ge 15

-Let

ter I

mpr

ovem

ent

in B

CVA

Fro

m B

asel

ine

Δ = 98

Months

Full Population Patients With Chronic DMO

Months

Δ = 206

287

189134

34

Steroid re-treatments

bullOzurdexbull Longer half-life than anti-VEGF in the eye

bull Redosing regimes not very helpful from RCT data eg MEAD study only 612 dosing

bull In reality re-treatment interval may be shorter

bull POSOLOGY

bull Patients treated with OZURDEX who have experienced an initial response and in the physicians opinion may benefit from retreatment without being exposed to significant risk should be considered for retreatment Retreatment may be performed after approximately 6 months if the patient experiences decreased vision andor an increase in retinal thickness secondary to recurrent or worsening diabetic macular oedema

bullIluvienbull 70 of patients in FAE only needed 1

injection over 3 years

bull BUT additional rescue treatments allowed

bull POSOLOGY

bull Each ILUVIEN implant releases fluocinolone acetonide for up to 36 months An additional implant may be administered after 12 months if the patient experiences decreased vision or an increase in retinal thickness secondary to recurrent or worsening diabetic macular oedema

bull Patients receiving escape medication were exited from MEAD before administration1

bull Macular laser rescue treatment allowed in RISERIDE (Lucentisreg) from 3 months2

bull Focalgrid laser allowed in FAME (Iluvienreg) from 6 weeks3

MEAD TREATMENT PROTOCOL

bull First treatment given at randomisation (day 0) bull Patients assessed for retreatment eligibility every 3 months from

months 6ndash36bull Patients were eligible for retreatment if

OCT optical coherence tomography

ge6 months since most recent

study treatment

Retinal thickness in 1 mm central macular

subfield by OCT gt175 microm

Evidence of residual retinal oedema (intraretinal cysts or

any regions of increased retinal thickening) as assessed by

investigator from OCT

AND OR

MEA

D

Amendment in May 2010 revised anatomic criterion for retreatment before this time the threshold was gt225 microm1Boyer DS et al Ophthalmology 2014 121 1904-19142Nguyen QD et al Ophthalmology 20121191064minus10773Campochiaro PA et al Ophthalmology 2011118626ndash635

Treatment burdenILUVIEN

Control(n =112)

02 microgd FAc(n =209)

Study Treatments(sham injection or ILUVIEN 02 microgday or FAc 05microgday)

1 treatment 661 761

2 treatments 277 187

ge 3 treatments 63 53

Rescue Laser Treatments (at masked physicianrsquos discretion after week 6)

Patients 607 407

Off-Protocol Treatments (IVTA bevacizumab ranibizumab intravitreal dexamethasone)

Patients 295 115

OZURDEX = 23injections year 1 41 by year 3

No other Rx

Summary of side effects with intravitreal steroids

Drug device Evidence base Cataract risk IOP rise (requiring drops)

Glaucoma surgery

endophthalmitis

ILUVIEN FAME studies 80 cat surgery(273 sham)

384(14 control)

48 0

Ozurdex MEAD 592 had cataract surgery(72 sham)

215 (end of study)(34 sham)

06 0

Trivaris+ laser vs Luc+laserx2 vs laser

Protocol IOphthalmology 2010

15 42(ONE OFgt10mmHg risegt30mmHGStart drops)

2186 0

NICE guidance for intravitreal steroids in DMO

bull Iluvien

bull NICE TA 301 Iluvien for DMO Nov 2013

bull hellipfor treating chronic diabetic macular oedema that is insufficiently responsive to available therapies only if

bull the implant is to be used in an eye with an intraocular

(pseudophakic) lens and

bull the manufacturer provides fluocinolone acetonide intravitreal implant with the discount agreed in the patient access scheme

NICE guidance for intravitreal steroids in DMO

bull Ozurdex

bull NICE TA 349 Ozurdex for DMO July 2015

bull there is an artificial lens in the eye to be treated and

bull their diabetic macular oedema has not improved with

non-corticosteroid treatment or such treatment is not suitable for them

Steroids = second line therapyWhen do I switch

bull Anti-VEGF first line for centre involving DMObull NICE TA ndash ldquoinsufficiently responsiverdquo ldquo ldquonot improvedrdquo ldquonot suitablerdquo ndash

OTHER TREATMENTS

bull 2 scenariosbull 1) Anti-VEGF canrsquot be funded ie OCTlt400um + PSEUDOPHAKIC

bull 2) Already had a course of treatment with laseranti-VEGF + PSEUDOPHAKIC ie SWITCHING from anti-VEGF to steroid

bull Plus

bull ldquochronicrdquo DMO ndash 3 years duration in FAME (18months) for ILUVIEN

bull Chronic DMO not essential for Ozurdex

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

Protocol T ndash patients may not improve in first 6 months

RIDE

RISE

Mea

n ch

ange

in B

CVA

(E

TDR

S le

tters

)M

ean

chan

ge in

BC

VA

(ETD

RS

lette

rs)

Time (months)

RISE and RIDE (Lucentis monthly dosing) Mean change in BCVA over 36 months

Brown DM et al Ophthalmology 2013120(10)2013ndash2022

54

Ranibizumab 03 mgRanibizumab 05 mgShamranibizumab 05 mg

Date of Prep Dec 2014 LGB0820147252X

VA improvement continues throughout year 1 with monthly dosing

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user ndash more than protocol

I

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

DRCRN protocol I5 year outcomesInjections 8-9 in year 1Year 2 = 2-3Year 3= 1-2Year 4 = 0-1Year 5 = 0

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

Wait for plateau = stability in protocol T laserPatient factors again

Judgement of response to anti-VEGF ndashtimeframe

bull Wait 6 months in poor responders

bull Wait 1 year for heavy users

bull Tempting to try steroids earlier than this ifbull No glaucoma ndash not a deal breaker Ozurdex better short term optionbull Pseudophakic

bull Clues from the diseasebull chronic

bull PATIENT FACTORS

bull Any eyes avoid steroids ndash advanced glaucomaCSCR Or prior viral retinitis RARE

bull Any eyes avoid anti-VEGF pregnancytrying to concieve recent CVA

BIOMARKERS AT BASELINE WOULD BE USEFULRESTORE subgroup analysis of OCT features

bull Andreas Pollreisz EURETINA 2015

bull OCT biomarkers (RESTORE data)

bull Better effects with anti-VEGF ifbull Small rather than large intra-retinal cyst

bull Sub-retinal fluid present

bull Vitreo-macular adhesion at baseline

bull No disruption of ELM and ISOS junction

bull No disorganisation of inner retinal layers (DRIL)

RESTORE subgroup analysis of OCT features

bull Andreas Pollreisz EURETINA 2015

bull OCT biomarkers (RESTORE data)

bull Better effects with anti-VEGF ifbull Small rather than large intra-retinal cyst

bull Sub-retinal fluid present

bull Vitreo-macular adhesion at baseline

bull No disruption of ELM and ISOS junction

bull No disorganisation of inner retinal layers (DRIL)

Better baseline characterisationclassificationERG Contrast sensitivityOCT AngiographyMicroperimetry= clues as to who responds best to which drug

Plan for this presentation helliphellipa long list

bull What treatment options are available for DMO (evidence base)

bull What treatment should I start with at baselinebull Re-treatment algorithms for intravitreal DMO therapiesbull When should I switchcombine therapiesbull The bigger picture

bull Other eyebull The patient as a wholebull The service -coping with capacity ndash compromises

The bigger pictureOther eyeThe patient as a wholeThe service -coping with capacity ndash compromises

bull OTHER EYE ndash may create problems

bull Treat and extend ndash ldquoreduce of visitsrdquo plus Eylea license ndash ldquono need for monitoringrdquo may not benefit if lots of visits due to PDR other eye

bull PERIPHERAL RETINA anti-VEGF supresses proliferative disease - Rebound on stopping Rx

bull PATIENT

bull Anti-VEGF ndash heavy user - Will comply

bull One stop much better than two stop for patient ndash Treat and extend

bull SERVICE

bull Capacity and demand planning = fixedT+E more predictable at least 1 month in advance ndash flexible nurse injectors

bull Steroids ndash even if well controlled (Iluvien for 3 years) need IOP check

bull Need pan-retinal examination both eyes ndash separate visits

Summary

CSMO

No centre involvement

Photocoagulation

Centre involvement

gt 78 letters(normalminimally reduced VA)

Photocoagulation

VA 78ndash24 letters

Phakic

Anti-VEGF

Pseudophakic

Anti-VEGF

SWITCHglaucoma

Injection tolerance

Medical issuesrecent CVA

Peripheral diseaseBilateral Rx

CSMO

No centre involvement

LASER

Centre involvement

gt 78 letters(normalminimally

reduced VA)

VA 78ndash24 letters

EYLEA OR LUCENTIS OR AVASTIN

Funding issues

Protocol T ndash poor VA lt 65 letters (615)

LOADING

Monthly injections until stability OR 5 x 112 (EYLEA) = 6 MONTHS then 8 weeks

RETREATMENT1

TREAT AND EXTEND - PRN

PRN

PSEUDOPHAKIC

Prior Rx

ILUVIEN

Chronic disease

OZURDEX

RETREATMENT

OZURDEX

OCT gt175um or any residual oedema

ILUVIEN after 12 months if risksltbenefits

OCT

gt400um

bull FACE TO FACE CLINICS RUNNING IN PARALLEL

bull = MAC002 every 6 months (optom or doctor) routine check for cataracttolerance of injectionsglaucoma issues etc

bull =MAC003 (DOCTOR) for problems as needed no fixed intervalDischargestop treatmentDeclines treatment diagnosis CSR overlay etcswitch drugs

bull =RV002- (DOCTOR) every 6 months

bull =DM002 ndash (DOCTOR) variable interval determined by last assessing doctor

bull First visit at 6 months from 1st injection if mild NPDR

bull Otherwise determined by retinopathy generally

LOADING PHASE

EyleaLucentis 1 within 48hrs of baseline

EyleaLucentis 2 (and LogMAR VA plus OCT same visit)

EyleaLucentis 3 (and LogMAR VA plus OCT same visit)

EyleaLucentis 4 (TEinj)(and Logmar VA plus OCT same visit

AFTER INJECTION 4 data goes off to be reviewed immediately as a hellip

TREAT AND EXTEND assessment ndash the next interval will depend on the response to the loading phase

NB -DMO patients ndash majority (95) will need 6 injctions x 112 of Lucentis

OR Eylea 5 x 112 then 8 weekly

ONCE STABLE for 3 x injection in TE phase

VIRTUAL CLINIC MONITORING OF MACULOPATHY AND PRN RETREATMENT

ANTI-VEGF INJECTION PATHWAYS Baseline visitMAC001 for wet AMDRV001 for CRVOBRVOMed ret clinic for DMO

Pathways ndash too many directions

Better that thanhellip

Thank you

RESTORE 36 month Lucentis prn extension studyLucentis monotherapy vs Lucentis plus laser vs laser aloneSchmidt-Erfuth U et al Ophthalmology 2014 121(5) 1045-1053

23

Months

12

10

8

6

4

2

0

minus22 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36

Extension study (ranibizumab 05 mg PRN)Core study

Me

an o

f th

e c

han

ge in

ETD

RS

BC

VA

Prior ranibizumab 05 mg + active laser (n=83)

Prior sham injections + active laser (n=74)

Prior ranibizumab 05 mg + sham laser (n=83)

79

71 606780

Core study assessment

Full analysisstudy completionInterim analysis

RIDE

RISE

Mea

n ch

ange

in B

CVA

(E

TDR

S le

tters

)M

ean

chan

ge in

BC

VA

(ETD

RS

lette

rs)

Time (months)

RISE and RIDE (Lucentis monthly dosing) Mean change in BCVA over 36 months

Brown DM et al Ophthalmology 2013120(10)2013ndash2022

15

Ranibizumab 03 mgRanibizumab 05 mgShamranibizumab 05 mg

RISE amp RIDE

Date of Prep Dec 2014 LGB0820147252X

02 Laser

125 2q4

107 2q8

0

Mea

n ch

ange

in B

CVA

lette

r sco

re

2

101214

02

6

10

14

4

8

12

468

09 Laser

115 2q4

111 2q8

VISTA Week 100

100928068645652403628201240 8 16 24 32 44 48 60 72 76 84 88 96

12 Laser

100928068645652403628201240 8 16 24 32 44 48 60 72 76 84 88 96

105 2q4

107 2q8VIVID Week 100

Week Laser 2q4 2q8

07 Laser

114 2q4

94 2q8

Eylea =VIVID and VISTA Mean change in BCVA to week 100Korobelnik J-F et al Ophthalmology 2014 121 (11) 2247ndash2254 Brown DM et al Ophthalmology 2015 Jul 18 [Epub ahead of print]

Plt00001 vs laser VIVID Laser n=132 2q4 n=136 2q8 n=135 VISTA Laser n=154 2q4 n=154 2q8 n=151Full analysis set 2q4 2 mg every 4 weeks 2q8 2 mg every 8 weeks BCVA best corrected visual acuity ETDRS Early Treatment Diabetic Retinopathy Study

What therapy do I choose for my patient at baseline

bull ANTI-VEGF helliphellipif OCT gt 400um

bull Sohellip Which one

Key trials in DMO

18

BOLT

RESOLVERISE and RIDE

DA VINCI

VIVID and VISTA

vs laser

vs sham

Steroids

(in combination

with laser)

Anti-VEGF

(in combination

with laser)

DRCRnet (Protocol I)

ETDRS

READ-2

RESTORE

RETAIN

REVEAL

DRCRnet (Protocol B)

FAMEMEAD

vs laser

vs sham

RanibizumabAflibercept

Bevacizumab

Triamcinolone

Fluocinolone acetonide Dexamethasone

Anti-VEGF Laser Steroids

DRCRnet PROTOCOL T

PROTOCOL T (DRCRnet)

bull Aflibercept Bevacizumab or Ranibizumab for Diabetic Macular Edema

bull N Engl J Med 2015 Mar 26372(13)1193-203

The Diabetic retinopathy Clinical Research Network February 18 2015

USA study NIHR funded

n=660

Lucentis 03mg not 05mg Eylea 2mg Avastin 125mg

Eylea protocol not the licensed regime

Avastin unlicensed

RETREATMENT protocol

First 6 months ndash inject every month 95 of patients UNLESS VA=66 AND OCT DRY

Then 2nd six months ndash if no change after 3 visits DEFER otherwise keep injecting monthly

Recurs ndash need at least 2 injections ie 3 months of stability

STABILITY = 10 Oct change or VA 5 letter change

STABILITY and residual OCT thickness gt250um LASER

Protocol T 1 year visual acuity outcomes

0

5

10

15

20

0 8 16 24 32 40 48

Visit Week

2032-2040 = 696 ndash 612= 78-69

0

5

10

15

20

0 8 16 24 32 40 48

Visit Week

2050 = 615 or worse = lt69

Mea

n ch

ange

in B

CV

A

Mea

n ch

ange

in B

CV

A

Aflibercept Bevacizumab Ranibizumab

+189

+142

+118+75

+8+83

Protocol T OCT outcomes year 1

-250

-200

-150

-100

-50

0

0 4 8 12 16 20 24 28 32 36 40 44 48 52

Visit Week

Aflibercept Bevacizumab Ranibizumab

Mea

n ch

ange

in C

ST

Conclusions ndash Protocol T year 1 data

bull Eylea was statistically superior in terms of visual acuity to 03mg Lucentisand to Avastin FOR PATIENTS WITH VA worse than 69 letters

bull Eylea and Lucentis were statistically superior in terms of OCT CRT reduction to Avastin for all patients regardless of baseline vision

bull No safety differences between the three drugs

SUMMARY What do I choose for my patient at baselineOCT central retinal thickness (CRT)PseudophakicAttempts at prior treatment duration of DMO

bull lt 400um

bull IFR licensed anti-VEGF or Avastin

+-ETDRS laser

PSEUDOPHAKIC

Iluvien

Ozurdex

bull gt 400um = Anti-VEGF

Which one

Depends on

bull baseline vision lt615 Eylea

bull Fixed dosing attractive (Eylea)bull Chronic DMO

bull PSEUDOPHAKICbull Patients ldquoinsufficiently

responsive to existing therapiesrdquo

bull ldquoNot improved with non-corticosteroid or such treatment is not suitable for themrdquo

Which steroid ndash Ozurdex or Iluvien

bull No head to head data

bull Revisit this when we think about switching from ANTI-VEGF to steroid

Assuming we have started with an anti-VEGF agent ndash what are the re-treatment algorithms in DMO

Treatment posologies

ldquoTreatment is initiated with one injection per month until maximum VA is achieved andor there are no signs of disease activity ie no change in VA and in other signs and

symptoms of the disease under continued treatment

In patients withhellipDMOhellip initially three or more consecutive monthly injections may be needed Thereafter monitoring and treatment intervals

should be determined by the physician and should be based on disease activity as

assessed by VA andor anatomical parametershellip

If patients are being treated according to a treat-and-extend regimen once maximum VA is achieved andor there are no

signs of disease activity the treatment intervals can be extended stepwise until signs of

disease activity or visual impairment recur The treatment intervalhellipmay be extended by up to one month

at a time for DMOrdquo

1 Novartis Pharmaceuticals UK Ltd 30 October 2014 Available at httpwwwmedicinesorgukemcmedicine19409 Accessed 04 September 2015

2 Bayer Pharma AG February 2015 Available at httpwwwmedicinesorgukemcmedicine27224 Accessed 04 September 2015

Ranibizumab1 Aflibercept2

ldquohelliptreatment is initiated with one injection per month for five consecutive doses followed by

one injection every two months There is no requirement for monitoring between injectionshellip

After the first 12 months of treatmenthellipthe treatment interval may be extended based

on visual andor anatomic outcomes The schedule for monitoring should

be determined by the treating physicianrdquo

DMO diabetic macular oedema VA visual acuity

Re-treatment algorithms for anti-VEGF agents in DMO

bull LOADING PHASE

bull Lucentis label = monthly until stability

bull Eylea label = 5 x 112 then every 8 weeks ie fixed regime year 1

bull DRCRnet protocol T = effectively 6 x112 for majority (95) BUT actually only mandated for first 3 months then prn

bull helliphellip likely that majority will receive injections monthly for first 6 months

bull INDIVIDUALISED PHASE

bull Once ldquostablerdquo ndash based on VA and OCT

bull NB May never get a ldquodryrdquo OCT so treat to stability

bull THEN

bull Treat and extend

bull prn

What does Treat and Extend mean

Pathway overview = Lucentis prn

Jan

Loading phase = injections every 4 weeks until ldquostablerdquo for 3 visits

helliphelliphellip

Feb OctSepAugJulJunMayAprMar

MarFebJan

DecNov

DecNovOctSepAugJulJunMayApr

Then observe UNTIL VA decreases or OCT increase = prn

Once reactivates need at least 2 injections until stable again over 3 visits

Pathway overview = Treat and Extend

Jan

Loading phase = injections every 4 weeks until ldquostablerdquo for 3 visits or Eyleayear 1

helliphelliphellip

Feb OctSepAugJulJunMayAprMar

MarFebJan

DecNov

DecNovOctSepAugJulJunMayApr

Then keep injecting but extend the interval between injections gradually ie keep treating even if perfect

If reactivates need at least 2 injections until stable again over 3 visits

Pathway overview = Eylea fixed dosing year 1

Jan

Eylea = 5 x 112 injection then every 8 weeks

Average 6 injections yr 2 Beyond that

helliphelliphellip

Feb OctSepAugJulJunMayAprMar

MarFebJan

DecNov

DecNovOctSepAugJulJunMayApr

Then individualised UNTIL VA decreases or OCT increase = prn

Once reactivates need at least 2 injections until stable again over 3 visits

Pros and cons of Treat and Extend vs Prn

T+E PRN

PROS bull Proactive patient and service get advance warning of injection ndash capacity and demand planning easier

bull One ndashstopbull Fewer visits than prnbull Overtreatment

advantageous for peripheral retinopathy

bull Only treated when active ieno overtreatment

bull Aggressive year 1 protocols (DRCRN I ndash few injections needed thereafter

bull DMO tolerant of reactivations ()

CONS bull Overtreatment = riskexpenseinconvenience

bull Evidence base scantbull Bilateral disease tricky

bull Reactive so need enoughemergency capacity to inject when disease flares up

bull No advance warning to patientservice that injection needed

bull NEED TO DO IT WELL ndashNHS real life audits prn based regimes not good resultsUndertreatment in year 1 Affects long term prognosis and treatment burden

Pros and cons of Treat and Extend vs Prn

T+E PRN

PROS bull Proactive patient and service get advance warning of injection ndash capacity and demand planning easier

bull One ndashstopbull Fewer visits than prnbull Overtreatment

advantageous for peripheral retinopathy

bull Only treated when active ieno overtreatment

bull Aggressive year 1 protocols (DRCRN I ndash few injections needed thereafter

bull DMO tolerant of reactivations ()

CONS bull Overtreatment = riskexpenseinconvenience

bull Evidence base scantbull Bilateral disease tricky

bull Reactive so need enoughemergency capacity to inject when disease flares up

bull No advance warning to patientservice that injection needed

bull NEED TO DO IT WELL ndashNHS real life audits prn based regimes not good resultsUndertreatment in year 1 Affects long term prognosis and treatment burden

DMO ndash anti-VEGF Treat and Extend

bull Retain study ndash the only RCT data

bull Br J Ophthalmol 2015 Oct 9 pii bjophthalmol-2015-307249 doi 101136bjophthalmol-2015-307249 [Epub ahead of print]

bull Ranibizumab 05 mg treat-and-extend regimen for diabetic macular oedema the RETAIN study

bull Pruumlnte C1 Fajnkuchen F2 Mahmood S3 Ricci F4 Hatz K5 Studnička J6 Bezlyak V7 Parikh S7 Stubbings WJ7 Wenzel A7 Figueira J8 and the RETAIN Study Group

RETAIN Phase III trial evaluating the efficacy of lsquotreat and extendrsquo regimen (ARVO 2014)

bull Patients with DMO and visual impairment (n = 372) were randomised 111

to one of three groups for 24 months

bull Two phases to dosing schedule

bull Phase A

bull Patients in all groups were initially treated with monthly ranibizumab until BCVA remained

stable

bull Phase B

bull Patients in the TampE groups whose vision remained stable had treatment- free intervals

that were increased incrementally by 1 month for a maximum of 3 months

bull Patients in the PRN group had ongoing monthly monitoring

bull In all groups Phase A was resumed if a decrease in BCVA was observed at a visit

Ranibizumab 05 mg monotherapy

in TampE regimen

Ranibizumab 05 mg in TampE regimen

plus laser

Ranibizumab 05 mg PRN

35

RETAIN Visual acuity endpoints

Pruumlnte C ARVO 2014 Annual Meeting Abstracts Abstract 1700

Mean average change in BCVAat 12 months (primary endpoint)

Mean change in BCVA at 24 months

Mea

n av

erag

e ch

ange

in B

CVA

(ETD

RS

lette

rs)

RanibizumabTampE

RanibizumabTampE + laser

RanibizumabPRN

RanibizumabTampE

RanibizumabTampE + laser

RanibizumabPRN

Mea

n ch

ange

in B

CVA

(ETD

RS

lette

rs)

plt00001 for both ranibizumab TampE groups versus PRN for primary endpoint

36

RETAIN Patient visits and monitoring with TampE regimen over 24 months

bull The TampE regimen provided an approximately 40 reduction in the number of treatment visits required compared with the ranibizumab PRN regimen

bull Approximately 70 of patients receiving TampE regimens had monitoring intervals ge2 months compared with ongoing monthly monitoring in the ranibizumab PRN group

bull Informed the license for Lucentis in DMO (extend by 1 month at a time)

37

INTRAVITREAL STEROIDSWhich intravitreal steroid is better

bull Licensed steroids ndash Ozurdex (Dexamethasone) and Iluvien (Fluocinoloneacetonide

bull Which steroid is best in terms of VA outcomes hellipWE DONrsquoT KNOW FOR SURE ndash no head to head studies for licensed drugs either between steroids or between anti-VEGF and steroids

bull STEROIDS ARE efficacious in DMO

bull MEAD

bull FAME

bull DRCRnet protocol I

bull NICE ndash Ozurdex and Iluvien ndash second-line agents

Ozurdex

bull A biodegradable co-polymer implant ndash degrades in time to lactic and glycolic acid releasing Dexamethasone

bull 22gauge injectionbull MEAD study

bull N=1048

bull Dex 07mg vs 035mg vs sham

bull No rescue therapy

bull 3 year follow up max 6 monthly dosing ie 7 over 3 years

Gan IM et al Greafes Acrh Clin Exp Ophthalmol 2005

MEAD studyMean BCVA change from baseline based on baseline lens status

-2

0

2

4

6

8

10

0 3 6 9 12 15 18 21 24 27 30 33 36 39

Mea

n C

hang

e Fr

om

Bas

elin

e B

CVA

(Let

ters

)

Month

DEX Implant 07 mg (n = 86)

Sham (n = 101)

Boyer DS et al Ophthalmology 20141211904ndash14

Results analyzed in the ITT population with LOCF for missing values

Pseudophakic

Total

0

5

10

0 3 6 9 12 15 18 21 24 27 30 33 36 39

DEX 700 (n=351)

Sham (n=350)

10

8

6

4

2

0

Mea

n C

hang

e fr

om

Bas

elin

e B

CVA

(Let

ters

)

Month

07mg dose is approved as Ozurdexreg by the FDA and EMA 035mg dose not commercially available

1 Boyer DS et al Ophthalmology 2014 121 1904-1914

bull Nonbioerodible micro implant (polyimide) containing 190microg of fluocinolone acetonide (FAc)

bull Consistent daily submicrogram delivery of 02 microgd FAc for up to 36 months

bull Posterior point of release

bull 35 mm times 037 mm non-bioerodable micro implant

bull 25-gauge injector creates self-sealing wound

bull No measurable systemic exposure

ILUVIEN Implant Technology

FAcimplant

ILUVIEN SPC httpwwwmedicinesorgukemcmedicine27636

0 6 12 18 24 30 36

ILUVIEN 02 microgd FAc(n = 376)05 microgd FAc (n = 395)Control sham injection(n = 185)

Design of Phase 3 FAME Study (FAME A and B = same protocol)

Additional laser therapy allowed after week 6a

Retreatment any time after month 12 (if eligibleb)

Study ends

N = 956Randomisation

221Primary readout

Patients with DMO and

bull At least 1 previous laser tx

bull BCVA ge19 and le68 letters

bull TD-OCT FTH ge250 μm

Month

BCVA = best corrected visual acuity DMO = diabetic macular oedema TD-OCT=time domain optical coherence tomography FTH = foveal thicknessa At masked investigatorrsquos discretion b If BCVA loss ge5 letters or retinal thickening ge50 microm from best reading in previous 12 months

ge15 letter Gain is Greater in Chronic DMO Patients

ge 15

-Let

ter I

mpr

ovem

ent

in B

CVA

Fro

m B

asel

ine

Δ = 98

Months

Full Population Patients With Chronic DMO

Months

Δ = 206

287

189134

34

Steroid re-treatments

bullOzurdexbull Longer half-life than anti-VEGF in the eye

bull Redosing regimes not very helpful from RCT data eg MEAD study only 612 dosing

bull In reality re-treatment interval may be shorter

bull POSOLOGY

bull Patients treated with OZURDEX who have experienced an initial response and in the physicians opinion may benefit from retreatment without being exposed to significant risk should be considered for retreatment Retreatment may be performed after approximately 6 months if the patient experiences decreased vision andor an increase in retinal thickness secondary to recurrent or worsening diabetic macular oedema

bullIluvienbull 70 of patients in FAE only needed 1

injection over 3 years

bull BUT additional rescue treatments allowed

bull POSOLOGY

bull Each ILUVIEN implant releases fluocinolone acetonide for up to 36 months An additional implant may be administered after 12 months if the patient experiences decreased vision or an increase in retinal thickness secondary to recurrent or worsening diabetic macular oedema

bull Patients receiving escape medication were exited from MEAD before administration1

bull Macular laser rescue treatment allowed in RISERIDE (Lucentisreg) from 3 months2

bull Focalgrid laser allowed in FAME (Iluvienreg) from 6 weeks3

MEAD TREATMENT PROTOCOL

bull First treatment given at randomisation (day 0) bull Patients assessed for retreatment eligibility every 3 months from

months 6ndash36bull Patients were eligible for retreatment if

OCT optical coherence tomography

ge6 months since most recent

study treatment

Retinal thickness in 1 mm central macular

subfield by OCT gt175 microm

Evidence of residual retinal oedema (intraretinal cysts or

any regions of increased retinal thickening) as assessed by

investigator from OCT

AND OR

MEA

D

Amendment in May 2010 revised anatomic criterion for retreatment before this time the threshold was gt225 microm1Boyer DS et al Ophthalmology 2014 121 1904-19142Nguyen QD et al Ophthalmology 20121191064minus10773Campochiaro PA et al Ophthalmology 2011118626ndash635

Treatment burdenILUVIEN

Control(n =112)

02 microgd FAc(n =209)

Study Treatments(sham injection or ILUVIEN 02 microgday or FAc 05microgday)

1 treatment 661 761

2 treatments 277 187

ge 3 treatments 63 53

Rescue Laser Treatments (at masked physicianrsquos discretion after week 6)

Patients 607 407

Off-Protocol Treatments (IVTA bevacizumab ranibizumab intravitreal dexamethasone)

Patients 295 115

OZURDEX = 23injections year 1 41 by year 3

No other Rx

Summary of side effects with intravitreal steroids

Drug device Evidence base Cataract risk IOP rise (requiring drops)

Glaucoma surgery

endophthalmitis

ILUVIEN FAME studies 80 cat surgery(273 sham)

384(14 control)

48 0

Ozurdex MEAD 592 had cataract surgery(72 sham)

215 (end of study)(34 sham)

06 0

Trivaris+ laser vs Luc+laserx2 vs laser

Protocol IOphthalmology 2010

15 42(ONE OFgt10mmHg risegt30mmHGStart drops)

2186 0

NICE guidance for intravitreal steroids in DMO

bull Iluvien

bull NICE TA 301 Iluvien for DMO Nov 2013

bull hellipfor treating chronic diabetic macular oedema that is insufficiently responsive to available therapies only if

bull the implant is to be used in an eye with an intraocular

(pseudophakic) lens and

bull the manufacturer provides fluocinolone acetonide intravitreal implant with the discount agreed in the patient access scheme

NICE guidance for intravitreal steroids in DMO

bull Ozurdex

bull NICE TA 349 Ozurdex for DMO July 2015

bull there is an artificial lens in the eye to be treated and

bull their diabetic macular oedema has not improved with

non-corticosteroid treatment or such treatment is not suitable for them

Steroids = second line therapyWhen do I switch

bull Anti-VEGF first line for centre involving DMObull NICE TA ndash ldquoinsufficiently responsiverdquo ldquo ldquonot improvedrdquo ldquonot suitablerdquo ndash

OTHER TREATMENTS

bull 2 scenariosbull 1) Anti-VEGF canrsquot be funded ie OCTlt400um + PSEUDOPHAKIC

bull 2) Already had a course of treatment with laseranti-VEGF + PSEUDOPHAKIC ie SWITCHING from anti-VEGF to steroid

bull Plus

bull ldquochronicrdquo DMO ndash 3 years duration in FAME (18months) for ILUVIEN

bull Chronic DMO not essential for Ozurdex

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

Protocol T ndash patients may not improve in first 6 months

RIDE

RISE

Mea

n ch

ange

in B

CVA

(E

TDR

S le

tters

)M

ean

chan

ge in

BC

VA

(ETD

RS

lette

rs)

Time (months)

RISE and RIDE (Lucentis monthly dosing) Mean change in BCVA over 36 months

Brown DM et al Ophthalmology 2013120(10)2013ndash2022

54

Ranibizumab 03 mgRanibizumab 05 mgShamranibizumab 05 mg

Date of Prep Dec 2014 LGB0820147252X

VA improvement continues throughout year 1 with monthly dosing

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user ndash more than protocol

I

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

DRCRN protocol I5 year outcomesInjections 8-9 in year 1Year 2 = 2-3Year 3= 1-2Year 4 = 0-1Year 5 = 0

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

Wait for plateau = stability in protocol T laserPatient factors again

Judgement of response to anti-VEGF ndashtimeframe

bull Wait 6 months in poor responders

bull Wait 1 year for heavy users

bull Tempting to try steroids earlier than this ifbull No glaucoma ndash not a deal breaker Ozurdex better short term optionbull Pseudophakic

bull Clues from the diseasebull chronic

bull PATIENT FACTORS

bull Any eyes avoid steroids ndash advanced glaucomaCSCR Or prior viral retinitis RARE

bull Any eyes avoid anti-VEGF pregnancytrying to concieve recent CVA

BIOMARKERS AT BASELINE WOULD BE USEFULRESTORE subgroup analysis of OCT features

bull Andreas Pollreisz EURETINA 2015

bull OCT biomarkers (RESTORE data)

bull Better effects with anti-VEGF ifbull Small rather than large intra-retinal cyst

bull Sub-retinal fluid present

bull Vitreo-macular adhesion at baseline

bull No disruption of ELM and ISOS junction

bull No disorganisation of inner retinal layers (DRIL)

RESTORE subgroup analysis of OCT features

bull Andreas Pollreisz EURETINA 2015

bull OCT biomarkers (RESTORE data)

bull Better effects with anti-VEGF ifbull Small rather than large intra-retinal cyst

bull Sub-retinal fluid present

bull Vitreo-macular adhesion at baseline

bull No disruption of ELM and ISOS junction

bull No disorganisation of inner retinal layers (DRIL)

Better baseline characterisationclassificationERG Contrast sensitivityOCT AngiographyMicroperimetry= clues as to who responds best to which drug

Plan for this presentation helliphellipa long list

bull What treatment options are available for DMO (evidence base)

bull What treatment should I start with at baselinebull Re-treatment algorithms for intravitreal DMO therapiesbull When should I switchcombine therapiesbull The bigger picture

bull Other eyebull The patient as a wholebull The service -coping with capacity ndash compromises

The bigger pictureOther eyeThe patient as a wholeThe service -coping with capacity ndash compromises

bull OTHER EYE ndash may create problems

bull Treat and extend ndash ldquoreduce of visitsrdquo plus Eylea license ndash ldquono need for monitoringrdquo may not benefit if lots of visits due to PDR other eye

bull PERIPHERAL RETINA anti-VEGF supresses proliferative disease - Rebound on stopping Rx

bull PATIENT

bull Anti-VEGF ndash heavy user - Will comply

bull One stop much better than two stop for patient ndash Treat and extend

bull SERVICE

bull Capacity and demand planning = fixedT+E more predictable at least 1 month in advance ndash flexible nurse injectors

bull Steroids ndash even if well controlled (Iluvien for 3 years) need IOP check

bull Need pan-retinal examination both eyes ndash separate visits

Summary

CSMO

No centre involvement

Photocoagulation

Centre involvement

gt 78 letters(normalminimally reduced VA)

Photocoagulation

VA 78ndash24 letters

Phakic

Anti-VEGF

Pseudophakic

Anti-VEGF

SWITCHglaucoma

Injection tolerance

Medical issuesrecent CVA

Peripheral diseaseBilateral Rx

CSMO

No centre involvement

LASER

Centre involvement

gt 78 letters(normalminimally

reduced VA)

VA 78ndash24 letters

EYLEA OR LUCENTIS OR AVASTIN

Funding issues

Protocol T ndash poor VA lt 65 letters (615)

LOADING

Monthly injections until stability OR 5 x 112 (EYLEA) = 6 MONTHS then 8 weeks

RETREATMENT1

TREAT AND EXTEND - PRN

PRN

PSEUDOPHAKIC

Prior Rx

ILUVIEN

Chronic disease

OZURDEX

RETREATMENT

OZURDEX

OCT gt175um or any residual oedema

ILUVIEN after 12 months if risksltbenefits

OCT

gt400um

bull FACE TO FACE CLINICS RUNNING IN PARALLEL

bull = MAC002 every 6 months (optom or doctor) routine check for cataracttolerance of injectionsglaucoma issues etc

bull =MAC003 (DOCTOR) for problems as needed no fixed intervalDischargestop treatmentDeclines treatment diagnosis CSR overlay etcswitch drugs

bull =RV002- (DOCTOR) every 6 months

bull =DM002 ndash (DOCTOR) variable interval determined by last assessing doctor

bull First visit at 6 months from 1st injection if mild NPDR

bull Otherwise determined by retinopathy generally

LOADING PHASE

EyleaLucentis 1 within 48hrs of baseline

EyleaLucentis 2 (and LogMAR VA plus OCT same visit)

EyleaLucentis 3 (and LogMAR VA plus OCT same visit)

EyleaLucentis 4 (TEinj)(and Logmar VA plus OCT same visit

AFTER INJECTION 4 data goes off to be reviewed immediately as a hellip

TREAT AND EXTEND assessment ndash the next interval will depend on the response to the loading phase

NB -DMO patients ndash majority (95) will need 6 injctions x 112 of Lucentis

OR Eylea 5 x 112 then 8 weekly

ONCE STABLE for 3 x injection in TE phase

VIRTUAL CLINIC MONITORING OF MACULOPATHY AND PRN RETREATMENT

ANTI-VEGF INJECTION PATHWAYS Baseline visitMAC001 for wet AMDRV001 for CRVOBRVOMed ret clinic for DMO

Pathways ndash too many directions

Better that thanhellip

Thank you

RIDE

RISE

Mea

n ch

ange

in B

CVA

(E

TDR

S le

tters

)M

ean

chan

ge in

BC

VA

(ETD

RS

lette

rs)

Time (months)

RISE and RIDE (Lucentis monthly dosing) Mean change in BCVA over 36 months

Brown DM et al Ophthalmology 2013120(10)2013ndash2022

15

Ranibizumab 03 mgRanibizumab 05 mgShamranibizumab 05 mg

RISE amp RIDE

Date of Prep Dec 2014 LGB0820147252X

02 Laser

125 2q4

107 2q8

0

Mea

n ch

ange

in B

CVA

lette

r sco

re

2

101214

02

6

10

14

4

8

12

468

09 Laser

115 2q4

111 2q8

VISTA Week 100

100928068645652403628201240 8 16 24 32 44 48 60 72 76 84 88 96

12 Laser

100928068645652403628201240 8 16 24 32 44 48 60 72 76 84 88 96

105 2q4

107 2q8VIVID Week 100

Week Laser 2q4 2q8

07 Laser

114 2q4

94 2q8

Eylea =VIVID and VISTA Mean change in BCVA to week 100Korobelnik J-F et al Ophthalmology 2014 121 (11) 2247ndash2254 Brown DM et al Ophthalmology 2015 Jul 18 [Epub ahead of print]

Plt00001 vs laser VIVID Laser n=132 2q4 n=136 2q8 n=135 VISTA Laser n=154 2q4 n=154 2q8 n=151Full analysis set 2q4 2 mg every 4 weeks 2q8 2 mg every 8 weeks BCVA best corrected visual acuity ETDRS Early Treatment Diabetic Retinopathy Study

What therapy do I choose for my patient at baseline

bull ANTI-VEGF helliphellipif OCT gt 400um

bull Sohellip Which one

Key trials in DMO

18

BOLT

RESOLVERISE and RIDE

DA VINCI

VIVID and VISTA

vs laser

vs sham

Steroids

(in combination

with laser)

Anti-VEGF

(in combination

with laser)

DRCRnet (Protocol I)

ETDRS

READ-2

RESTORE

RETAIN

REVEAL

DRCRnet (Protocol B)

FAMEMEAD

vs laser

vs sham

RanibizumabAflibercept

Bevacizumab

Triamcinolone

Fluocinolone acetonide Dexamethasone

Anti-VEGF Laser Steroids

DRCRnet PROTOCOL T

PROTOCOL T (DRCRnet)

bull Aflibercept Bevacizumab or Ranibizumab for Diabetic Macular Edema

bull N Engl J Med 2015 Mar 26372(13)1193-203

The Diabetic retinopathy Clinical Research Network February 18 2015

USA study NIHR funded

n=660

Lucentis 03mg not 05mg Eylea 2mg Avastin 125mg

Eylea protocol not the licensed regime

Avastin unlicensed

RETREATMENT protocol

First 6 months ndash inject every month 95 of patients UNLESS VA=66 AND OCT DRY

Then 2nd six months ndash if no change after 3 visits DEFER otherwise keep injecting monthly

Recurs ndash need at least 2 injections ie 3 months of stability

STABILITY = 10 Oct change or VA 5 letter change

STABILITY and residual OCT thickness gt250um LASER

Protocol T 1 year visual acuity outcomes

0

5

10

15

20

0 8 16 24 32 40 48

Visit Week

2032-2040 = 696 ndash 612= 78-69

0

5

10

15

20

0 8 16 24 32 40 48

Visit Week

2050 = 615 or worse = lt69

Mea

n ch

ange

in B

CV

A

Mea

n ch

ange

in B

CV

A

Aflibercept Bevacizumab Ranibizumab

+189

+142

+118+75

+8+83

Protocol T OCT outcomes year 1

-250

-200

-150

-100

-50

0

0 4 8 12 16 20 24 28 32 36 40 44 48 52

Visit Week

Aflibercept Bevacizumab Ranibizumab

Mea

n ch

ange

in C

ST

Conclusions ndash Protocol T year 1 data

bull Eylea was statistically superior in terms of visual acuity to 03mg Lucentisand to Avastin FOR PATIENTS WITH VA worse than 69 letters

bull Eylea and Lucentis were statistically superior in terms of OCT CRT reduction to Avastin for all patients regardless of baseline vision

bull No safety differences between the three drugs

SUMMARY What do I choose for my patient at baselineOCT central retinal thickness (CRT)PseudophakicAttempts at prior treatment duration of DMO

bull lt 400um

bull IFR licensed anti-VEGF or Avastin

+-ETDRS laser

PSEUDOPHAKIC

Iluvien

Ozurdex

bull gt 400um = Anti-VEGF

Which one

Depends on

bull baseline vision lt615 Eylea

bull Fixed dosing attractive (Eylea)bull Chronic DMO

bull PSEUDOPHAKICbull Patients ldquoinsufficiently

responsive to existing therapiesrdquo

bull ldquoNot improved with non-corticosteroid or such treatment is not suitable for themrdquo

Which steroid ndash Ozurdex or Iluvien

bull No head to head data

bull Revisit this when we think about switching from ANTI-VEGF to steroid

Assuming we have started with an anti-VEGF agent ndash what are the re-treatment algorithms in DMO

Treatment posologies

ldquoTreatment is initiated with one injection per month until maximum VA is achieved andor there are no signs of disease activity ie no change in VA and in other signs and

symptoms of the disease under continued treatment

In patients withhellipDMOhellip initially three or more consecutive monthly injections may be needed Thereafter monitoring and treatment intervals

should be determined by the physician and should be based on disease activity as

assessed by VA andor anatomical parametershellip

If patients are being treated according to a treat-and-extend regimen once maximum VA is achieved andor there are no

signs of disease activity the treatment intervals can be extended stepwise until signs of

disease activity or visual impairment recur The treatment intervalhellipmay be extended by up to one month

at a time for DMOrdquo

1 Novartis Pharmaceuticals UK Ltd 30 October 2014 Available at httpwwwmedicinesorgukemcmedicine19409 Accessed 04 September 2015

2 Bayer Pharma AG February 2015 Available at httpwwwmedicinesorgukemcmedicine27224 Accessed 04 September 2015

Ranibizumab1 Aflibercept2

ldquohelliptreatment is initiated with one injection per month for five consecutive doses followed by

one injection every two months There is no requirement for monitoring between injectionshellip

After the first 12 months of treatmenthellipthe treatment interval may be extended based

on visual andor anatomic outcomes The schedule for monitoring should

be determined by the treating physicianrdquo

DMO diabetic macular oedema VA visual acuity

Re-treatment algorithms for anti-VEGF agents in DMO

bull LOADING PHASE

bull Lucentis label = monthly until stability

bull Eylea label = 5 x 112 then every 8 weeks ie fixed regime year 1

bull DRCRnet protocol T = effectively 6 x112 for majority (95) BUT actually only mandated for first 3 months then prn

bull helliphellip likely that majority will receive injections monthly for first 6 months

bull INDIVIDUALISED PHASE

bull Once ldquostablerdquo ndash based on VA and OCT

bull NB May never get a ldquodryrdquo OCT so treat to stability

bull THEN

bull Treat and extend

bull prn

What does Treat and Extend mean

Pathway overview = Lucentis prn

Jan

Loading phase = injections every 4 weeks until ldquostablerdquo for 3 visits

helliphelliphellip

Feb OctSepAugJulJunMayAprMar

MarFebJan

DecNov

DecNovOctSepAugJulJunMayApr

Then observe UNTIL VA decreases or OCT increase = prn

Once reactivates need at least 2 injections until stable again over 3 visits

Pathway overview = Treat and Extend

Jan

Loading phase = injections every 4 weeks until ldquostablerdquo for 3 visits or Eyleayear 1

helliphelliphellip

Feb OctSepAugJulJunMayAprMar

MarFebJan

DecNov

DecNovOctSepAugJulJunMayApr

Then keep injecting but extend the interval between injections gradually ie keep treating even if perfect

If reactivates need at least 2 injections until stable again over 3 visits

Pathway overview = Eylea fixed dosing year 1

Jan

Eylea = 5 x 112 injection then every 8 weeks

Average 6 injections yr 2 Beyond that

helliphelliphellip

Feb OctSepAugJulJunMayAprMar

MarFebJan

DecNov

DecNovOctSepAugJulJunMayApr

Then individualised UNTIL VA decreases or OCT increase = prn

Once reactivates need at least 2 injections until stable again over 3 visits

Pros and cons of Treat and Extend vs Prn

T+E PRN

PROS bull Proactive patient and service get advance warning of injection ndash capacity and demand planning easier

bull One ndashstopbull Fewer visits than prnbull Overtreatment

advantageous for peripheral retinopathy

bull Only treated when active ieno overtreatment

bull Aggressive year 1 protocols (DRCRN I ndash few injections needed thereafter

bull DMO tolerant of reactivations ()

CONS bull Overtreatment = riskexpenseinconvenience

bull Evidence base scantbull Bilateral disease tricky

bull Reactive so need enoughemergency capacity to inject when disease flares up

bull No advance warning to patientservice that injection needed

bull NEED TO DO IT WELL ndashNHS real life audits prn based regimes not good resultsUndertreatment in year 1 Affects long term prognosis and treatment burden

Pros and cons of Treat and Extend vs Prn

T+E PRN

PROS bull Proactive patient and service get advance warning of injection ndash capacity and demand planning easier

bull One ndashstopbull Fewer visits than prnbull Overtreatment

advantageous for peripheral retinopathy

bull Only treated when active ieno overtreatment

bull Aggressive year 1 protocols (DRCRN I ndash few injections needed thereafter

bull DMO tolerant of reactivations ()

CONS bull Overtreatment = riskexpenseinconvenience

bull Evidence base scantbull Bilateral disease tricky

bull Reactive so need enoughemergency capacity to inject when disease flares up

bull No advance warning to patientservice that injection needed

bull NEED TO DO IT WELL ndashNHS real life audits prn based regimes not good resultsUndertreatment in year 1 Affects long term prognosis and treatment burden

DMO ndash anti-VEGF Treat and Extend

bull Retain study ndash the only RCT data

bull Br J Ophthalmol 2015 Oct 9 pii bjophthalmol-2015-307249 doi 101136bjophthalmol-2015-307249 [Epub ahead of print]

bull Ranibizumab 05 mg treat-and-extend regimen for diabetic macular oedema the RETAIN study

bull Pruumlnte C1 Fajnkuchen F2 Mahmood S3 Ricci F4 Hatz K5 Studnička J6 Bezlyak V7 Parikh S7 Stubbings WJ7 Wenzel A7 Figueira J8 and the RETAIN Study Group

RETAIN Phase III trial evaluating the efficacy of lsquotreat and extendrsquo regimen (ARVO 2014)

bull Patients with DMO and visual impairment (n = 372) were randomised 111

to one of three groups for 24 months

bull Two phases to dosing schedule

bull Phase A

bull Patients in all groups were initially treated with monthly ranibizumab until BCVA remained

stable

bull Phase B

bull Patients in the TampE groups whose vision remained stable had treatment- free intervals

that were increased incrementally by 1 month for a maximum of 3 months

bull Patients in the PRN group had ongoing monthly monitoring

bull In all groups Phase A was resumed if a decrease in BCVA was observed at a visit

Ranibizumab 05 mg monotherapy

in TampE regimen

Ranibizumab 05 mg in TampE regimen

plus laser

Ranibizumab 05 mg PRN

35

RETAIN Visual acuity endpoints

Pruumlnte C ARVO 2014 Annual Meeting Abstracts Abstract 1700

Mean average change in BCVAat 12 months (primary endpoint)

Mean change in BCVA at 24 months

Mea

n av

erag

e ch

ange

in B

CVA

(ETD

RS

lette

rs)

RanibizumabTampE

RanibizumabTampE + laser

RanibizumabPRN

RanibizumabTampE

RanibizumabTampE + laser

RanibizumabPRN

Mea

n ch

ange

in B

CVA

(ETD

RS

lette

rs)

plt00001 for both ranibizumab TampE groups versus PRN for primary endpoint

36

RETAIN Patient visits and monitoring with TampE regimen over 24 months

bull The TampE regimen provided an approximately 40 reduction in the number of treatment visits required compared with the ranibizumab PRN regimen

bull Approximately 70 of patients receiving TampE regimens had monitoring intervals ge2 months compared with ongoing monthly monitoring in the ranibizumab PRN group

bull Informed the license for Lucentis in DMO (extend by 1 month at a time)

37

INTRAVITREAL STEROIDSWhich intravitreal steroid is better

bull Licensed steroids ndash Ozurdex (Dexamethasone) and Iluvien (Fluocinoloneacetonide

bull Which steroid is best in terms of VA outcomes hellipWE DONrsquoT KNOW FOR SURE ndash no head to head studies for licensed drugs either between steroids or between anti-VEGF and steroids

bull STEROIDS ARE efficacious in DMO

bull MEAD

bull FAME

bull DRCRnet protocol I

bull NICE ndash Ozurdex and Iluvien ndash second-line agents

Ozurdex

bull A biodegradable co-polymer implant ndash degrades in time to lactic and glycolic acid releasing Dexamethasone

bull 22gauge injectionbull MEAD study

bull N=1048

bull Dex 07mg vs 035mg vs sham

bull No rescue therapy

bull 3 year follow up max 6 monthly dosing ie 7 over 3 years

Gan IM et al Greafes Acrh Clin Exp Ophthalmol 2005

MEAD studyMean BCVA change from baseline based on baseline lens status

-2

0

2

4

6

8

10

0 3 6 9 12 15 18 21 24 27 30 33 36 39

Mea

n C

hang

e Fr

om

Bas

elin

e B

CVA

(Let

ters

)

Month

DEX Implant 07 mg (n = 86)

Sham (n = 101)

Boyer DS et al Ophthalmology 20141211904ndash14

Results analyzed in the ITT population with LOCF for missing values

Pseudophakic

Total

0

5

10

0 3 6 9 12 15 18 21 24 27 30 33 36 39

DEX 700 (n=351)

Sham (n=350)

10

8

6

4

2

0

Mea

n C

hang

e fr

om

Bas

elin

e B

CVA

(Let

ters

)

Month

07mg dose is approved as Ozurdexreg by the FDA and EMA 035mg dose not commercially available

1 Boyer DS et al Ophthalmology 2014 121 1904-1914

bull Nonbioerodible micro implant (polyimide) containing 190microg of fluocinolone acetonide (FAc)

bull Consistent daily submicrogram delivery of 02 microgd FAc for up to 36 months

bull Posterior point of release

bull 35 mm times 037 mm non-bioerodable micro implant

bull 25-gauge injector creates self-sealing wound

bull No measurable systemic exposure

ILUVIEN Implant Technology

FAcimplant

ILUVIEN SPC httpwwwmedicinesorgukemcmedicine27636

0 6 12 18 24 30 36

ILUVIEN 02 microgd FAc(n = 376)05 microgd FAc (n = 395)Control sham injection(n = 185)

Design of Phase 3 FAME Study (FAME A and B = same protocol)

Additional laser therapy allowed after week 6a

Retreatment any time after month 12 (if eligibleb)

Study ends

N = 956Randomisation

221Primary readout

Patients with DMO and

bull At least 1 previous laser tx

bull BCVA ge19 and le68 letters

bull TD-OCT FTH ge250 μm

Month

BCVA = best corrected visual acuity DMO = diabetic macular oedema TD-OCT=time domain optical coherence tomography FTH = foveal thicknessa At masked investigatorrsquos discretion b If BCVA loss ge5 letters or retinal thickening ge50 microm from best reading in previous 12 months

ge15 letter Gain is Greater in Chronic DMO Patients

ge 15

-Let

ter I

mpr

ovem

ent

in B

CVA

Fro

m B

asel

ine

Δ = 98

Months

Full Population Patients With Chronic DMO

Months

Δ = 206

287

189134

34

Steroid re-treatments

bullOzurdexbull Longer half-life than anti-VEGF in the eye

bull Redosing regimes not very helpful from RCT data eg MEAD study only 612 dosing

bull In reality re-treatment interval may be shorter

bull POSOLOGY

bull Patients treated with OZURDEX who have experienced an initial response and in the physicians opinion may benefit from retreatment without being exposed to significant risk should be considered for retreatment Retreatment may be performed after approximately 6 months if the patient experiences decreased vision andor an increase in retinal thickness secondary to recurrent or worsening diabetic macular oedema

bullIluvienbull 70 of patients in FAE only needed 1

injection over 3 years

bull BUT additional rescue treatments allowed

bull POSOLOGY

bull Each ILUVIEN implant releases fluocinolone acetonide for up to 36 months An additional implant may be administered after 12 months if the patient experiences decreased vision or an increase in retinal thickness secondary to recurrent or worsening diabetic macular oedema

bull Patients receiving escape medication were exited from MEAD before administration1

bull Macular laser rescue treatment allowed in RISERIDE (Lucentisreg) from 3 months2

bull Focalgrid laser allowed in FAME (Iluvienreg) from 6 weeks3

MEAD TREATMENT PROTOCOL

bull First treatment given at randomisation (day 0) bull Patients assessed for retreatment eligibility every 3 months from

months 6ndash36bull Patients were eligible for retreatment if

OCT optical coherence tomography

ge6 months since most recent

study treatment

Retinal thickness in 1 mm central macular

subfield by OCT gt175 microm

Evidence of residual retinal oedema (intraretinal cysts or

any regions of increased retinal thickening) as assessed by

investigator from OCT

AND OR

MEA

D

Amendment in May 2010 revised anatomic criterion for retreatment before this time the threshold was gt225 microm1Boyer DS et al Ophthalmology 2014 121 1904-19142Nguyen QD et al Ophthalmology 20121191064minus10773Campochiaro PA et al Ophthalmology 2011118626ndash635

Treatment burdenILUVIEN

Control(n =112)

02 microgd FAc(n =209)

Study Treatments(sham injection or ILUVIEN 02 microgday or FAc 05microgday)

1 treatment 661 761

2 treatments 277 187

ge 3 treatments 63 53

Rescue Laser Treatments (at masked physicianrsquos discretion after week 6)

Patients 607 407

Off-Protocol Treatments (IVTA bevacizumab ranibizumab intravitreal dexamethasone)

Patients 295 115

OZURDEX = 23injections year 1 41 by year 3

No other Rx

Summary of side effects with intravitreal steroids

Drug device Evidence base Cataract risk IOP rise (requiring drops)

Glaucoma surgery

endophthalmitis

ILUVIEN FAME studies 80 cat surgery(273 sham)

384(14 control)

48 0

Ozurdex MEAD 592 had cataract surgery(72 sham)

215 (end of study)(34 sham)

06 0

Trivaris+ laser vs Luc+laserx2 vs laser

Protocol IOphthalmology 2010

15 42(ONE OFgt10mmHg risegt30mmHGStart drops)

2186 0

NICE guidance for intravitreal steroids in DMO

bull Iluvien

bull NICE TA 301 Iluvien for DMO Nov 2013

bull hellipfor treating chronic diabetic macular oedema that is insufficiently responsive to available therapies only if

bull the implant is to be used in an eye with an intraocular

(pseudophakic) lens and

bull the manufacturer provides fluocinolone acetonide intravitreal implant with the discount agreed in the patient access scheme

NICE guidance for intravitreal steroids in DMO

bull Ozurdex

bull NICE TA 349 Ozurdex for DMO July 2015

bull there is an artificial lens in the eye to be treated and

bull their diabetic macular oedema has not improved with

non-corticosteroid treatment or such treatment is not suitable for them

Steroids = second line therapyWhen do I switch

bull Anti-VEGF first line for centre involving DMObull NICE TA ndash ldquoinsufficiently responsiverdquo ldquo ldquonot improvedrdquo ldquonot suitablerdquo ndash

OTHER TREATMENTS

bull 2 scenariosbull 1) Anti-VEGF canrsquot be funded ie OCTlt400um + PSEUDOPHAKIC

bull 2) Already had a course of treatment with laseranti-VEGF + PSEUDOPHAKIC ie SWITCHING from anti-VEGF to steroid

bull Plus

bull ldquochronicrdquo DMO ndash 3 years duration in FAME (18months) for ILUVIEN

bull Chronic DMO not essential for Ozurdex

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

Protocol T ndash patients may not improve in first 6 months

RIDE

RISE

Mea

n ch

ange

in B

CVA

(E

TDR

S le

tters

)M

ean

chan

ge in

BC

VA

(ETD

RS

lette

rs)

Time (months)

RISE and RIDE (Lucentis monthly dosing) Mean change in BCVA over 36 months

Brown DM et al Ophthalmology 2013120(10)2013ndash2022

54

Ranibizumab 03 mgRanibizumab 05 mgShamranibizumab 05 mg

Date of Prep Dec 2014 LGB0820147252X

VA improvement continues throughout year 1 with monthly dosing

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user ndash more than protocol

I

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

DRCRN protocol I5 year outcomesInjections 8-9 in year 1Year 2 = 2-3Year 3= 1-2Year 4 = 0-1Year 5 = 0

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

Wait for plateau = stability in protocol T laserPatient factors again

Judgement of response to anti-VEGF ndashtimeframe

bull Wait 6 months in poor responders

bull Wait 1 year for heavy users

bull Tempting to try steroids earlier than this ifbull No glaucoma ndash not a deal breaker Ozurdex better short term optionbull Pseudophakic

bull Clues from the diseasebull chronic

bull PATIENT FACTORS

bull Any eyes avoid steroids ndash advanced glaucomaCSCR Or prior viral retinitis RARE

bull Any eyes avoid anti-VEGF pregnancytrying to concieve recent CVA

BIOMARKERS AT BASELINE WOULD BE USEFULRESTORE subgroup analysis of OCT features

bull Andreas Pollreisz EURETINA 2015

bull OCT biomarkers (RESTORE data)

bull Better effects with anti-VEGF ifbull Small rather than large intra-retinal cyst

bull Sub-retinal fluid present

bull Vitreo-macular adhesion at baseline

bull No disruption of ELM and ISOS junction

bull No disorganisation of inner retinal layers (DRIL)

RESTORE subgroup analysis of OCT features

bull Andreas Pollreisz EURETINA 2015

bull OCT biomarkers (RESTORE data)

bull Better effects with anti-VEGF ifbull Small rather than large intra-retinal cyst

bull Sub-retinal fluid present

bull Vitreo-macular adhesion at baseline

bull No disruption of ELM and ISOS junction

bull No disorganisation of inner retinal layers (DRIL)

Better baseline characterisationclassificationERG Contrast sensitivityOCT AngiographyMicroperimetry= clues as to who responds best to which drug

Plan for this presentation helliphellipa long list

bull What treatment options are available for DMO (evidence base)

bull What treatment should I start with at baselinebull Re-treatment algorithms for intravitreal DMO therapiesbull When should I switchcombine therapiesbull The bigger picture

bull Other eyebull The patient as a wholebull The service -coping with capacity ndash compromises

The bigger pictureOther eyeThe patient as a wholeThe service -coping with capacity ndash compromises

bull OTHER EYE ndash may create problems

bull Treat and extend ndash ldquoreduce of visitsrdquo plus Eylea license ndash ldquono need for monitoringrdquo may not benefit if lots of visits due to PDR other eye

bull PERIPHERAL RETINA anti-VEGF supresses proliferative disease - Rebound on stopping Rx

bull PATIENT

bull Anti-VEGF ndash heavy user - Will comply

bull One stop much better than two stop for patient ndash Treat and extend

bull SERVICE

bull Capacity and demand planning = fixedT+E more predictable at least 1 month in advance ndash flexible nurse injectors

bull Steroids ndash even if well controlled (Iluvien for 3 years) need IOP check

bull Need pan-retinal examination both eyes ndash separate visits

Summary

CSMO

No centre involvement

Photocoagulation

Centre involvement

gt 78 letters(normalminimally reduced VA)

Photocoagulation

VA 78ndash24 letters

Phakic

Anti-VEGF

Pseudophakic

Anti-VEGF

SWITCHglaucoma

Injection tolerance

Medical issuesrecent CVA

Peripheral diseaseBilateral Rx

CSMO

No centre involvement

LASER

Centre involvement

gt 78 letters(normalminimally

reduced VA)

VA 78ndash24 letters

EYLEA OR LUCENTIS OR AVASTIN

Funding issues

Protocol T ndash poor VA lt 65 letters (615)

LOADING

Monthly injections until stability OR 5 x 112 (EYLEA) = 6 MONTHS then 8 weeks

RETREATMENT1

TREAT AND EXTEND - PRN

PRN

PSEUDOPHAKIC

Prior Rx

ILUVIEN

Chronic disease

OZURDEX

RETREATMENT

OZURDEX

OCT gt175um or any residual oedema

ILUVIEN after 12 months if risksltbenefits

OCT

gt400um

bull FACE TO FACE CLINICS RUNNING IN PARALLEL

bull = MAC002 every 6 months (optom or doctor) routine check for cataracttolerance of injectionsglaucoma issues etc

bull =MAC003 (DOCTOR) for problems as needed no fixed intervalDischargestop treatmentDeclines treatment diagnosis CSR overlay etcswitch drugs

bull =RV002- (DOCTOR) every 6 months

bull =DM002 ndash (DOCTOR) variable interval determined by last assessing doctor

bull First visit at 6 months from 1st injection if mild NPDR

bull Otherwise determined by retinopathy generally

LOADING PHASE

EyleaLucentis 1 within 48hrs of baseline

EyleaLucentis 2 (and LogMAR VA plus OCT same visit)

EyleaLucentis 3 (and LogMAR VA plus OCT same visit)

EyleaLucentis 4 (TEinj)(and Logmar VA plus OCT same visit

AFTER INJECTION 4 data goes off to be reviewed immediately as a hellip

TREAT AND EXTEND assessment ndash the next interval will depend on the response to the loading phase

NB -DMO patients ndash majority (95) will need 6 injctions x 112 of Lucentis

OR Eylea 5 x 112 then 8 weekly

ONCE STABLE for 3 x injection in TE phase

VIRTUAL CLINIC MONITORING OF MACULOPATHY AND PRN RETREATMENT

ANTI-VEGF INJECTION PATHWAYS Baseline visitMAC001 for wet AMDRV001 for CRVOBRVOMed ret clinic for DMO

Pathways ndash too many directions

Better that thanhellip

Thank you

02 Laser

125 2q4

107 2q8

0

Mea

n ch

ange

in B

CVA

lette

r sco

re

2

101214

02

6

10

14

4

8

12

468

09 Laser

115 2q4

111 2q8

VISTA Week 100

100928068645652403628201240 8 16 24 32 44 48 60 72 76 84 88 96

12 Laser

100928068645652403628201240 8 16 24 32 44 48 60 72 76 84 88 96

105 2q4

107 2q8VIVID Week 100

Week Laser 2q4 2q8

07 Laser

114 2q4

94 2q8

Eylea =VIVID and VISTA Mean change in BCVA to week 100Korobelnik J-F et al Ophthalmology 2014 121 (11) 2247ndash2254 Brown DM et al Ophthalmology 2015 Jul 18 [Epub ahead of print]

Plt00001 vs laser VIVID Laser n=132 2q4 n=136 2q8 n=135 VISTA Laser n=154 2q4 n=154 2q8 n=151Full analysis set 2q4 2 mg every 4 weeks 2q8 2 mg every 8 weeks BCVA best corrected visual acuity ETDRS Early Treatment Diabetic Retinopathy Study

What therapy do I choose for my patient at baseline

bull ANTI-VEGF helliphellipif OCT gt 400um

bull Sohellip Which one

Key trials in DMO

18

BOLT

RESOLVERISE and RIDE

DA VINCI

VIVID and VISTA

vs laser

vs sham

Steroids

(in combination

with laser)

Anti-VEGF

(in combination

with laser)

DRCRnet (Protocol I)

ETDRS

READ-2

RESTORE

RETAIN

REVEAL

DRCRnet (Protocol B)

FAMEMEAD

vs laser

vs sham

RanibizumabAflibercept

Bevacizumab

Triamcinolone

Fluocinolone acetonide Dexamethasone

Anti-VEGF Laser Steroids

DRCRnet PROTOCOL T

PROTOCOL T (DRCRnet)

bull Aflibercept Bevacizumab or Ranibizumab for Diabetic Macular Edema

bull N Engl J Med 2015 Mar 26372(13)1193-203

The Diabetic retinopathy Clinical Research Network February 18 2015

USA study NIHR funded

n=660

Lucentis 03mg not 05mg Eylea 2mg Avastin 125mg

Eylea protocol not the licensed regime

Avastin unlicensed

RETREATMENT protocol

First 6 months ndash inject every month 95 of patients UNLESS VA=66 AND OCT DRY

Then 2nd six months ndash if no change after 3 visits DEFER otherwise keep injecting monthly

Recurs ndash need at least 2 injections ie 3 months of stability

STABILITY = 10 Oct change or VA 5 letter change

STABILITY and residual OCT thickness gt250um LASER

Protocol T 1 year visual acuity outcomes

0

5

10

15

20

0 8 16 24 32 40 48

Visit Week

2032-2040 = 696 ndash 612= 78-69

0

5

10

15

20

0 8 16 24 32 40 48

Visit Week

2050 = 615 or worse = lt69

Mea

n ch

ange

in B

CV

A

Mea

n ch

ange

in B

CV

A

Aflibercept Bevacizumab Ranibizumab

+189

+142

+118+75

+8+83

Protocol T OCT outcomes year 1

-250

-200

-150

-100

-50

0

0 4 8 12 16 20 24 28 32 36 40 44 48 52

Visit Week

Aflibercept Bevacizumab Ranibizumab

Mea

n ch

ange

in C

ST

Conclusions ndash Protocol T year 1 data

bull Eylea was statistically superior in terms of visual acuity to 03mg Lucentisand to Avastin FOR PATIENTS WITH VA worse than 69 letters

bull Eylea and Lucentis were statistically superior in terms of OCT CRT reduction to Avastin for all patients regardless of baseline vision

bull No safety differences between the three drugs

SUMMARY What do I choose for my patient at baselineOCT central retinal thickness (CRT)PseudophakicAttempts at prior treatment duration of DMO

bull lt 400um

bull IFR licensed anti-VEGF or Avastin

+-ETDRS laser

PSEUDOPHAKIC

Iluvien

Ozurdex

bull gt 400um = Anti-VEGF

Which one

Depends on

bull baseline vision lt615 Eylea

bull Fixed dosing attractive (Eylea)bull Chronic DMO

bull PSEUDOPHAKICbull Patients ldquoinsufficiently

responsive to existing therapiesrdquo

bull ldquoNot improved with non-corticosteroid or such treatment is not suitable for themrdquo

Which steroid ndash Ozurdex or Iluvien

bull No head to head data

bull Revisit this when we think about switching from ANTI-VEGF to steroid

Assuming we have started with an anti-VEGF agent ndash what are the re-treatment algorithms in DMO

Treatment posologies

ldquoTreatment is initiated with one injection per month until maximum VA is achieved andor there are no signs of disease activity ie no change in VA and in other signs and

symptoms of the disease under continued treatment

In patients withhellipDMOhellip initially three or more consecutive monthly injections may be needed Thereafter monitoring and treatment intervals

should be determined by the physician and should be based on disease activity as

assessed by VA andor anatomical parametershellip

If patients are being treated according to a treat-and-extend regimen once maximum VA is achieved andor there are no

signs of disease activity the treatment intervals can be extended stepwise until signs of

disease activity or visual impairment recur The treatment intervalhellipmay be extended by up to one month

at a time for DMOrdquo

1 Novartis Pharmaceuticals UK Ltd 30 October 2014 Available at httpwwwmedicinesorgukemcmedicine19409 Accessed 04 September 2015

2 Bayer Pharma AG February 2015 Available at httpwwwmedicinesorgukemcmedicine27224 Accessed 04 September 2015

Ranibizumab1 Aflibercept2

ldquohelliptreatment is initiated with one injection per month for five consecutive doses followed by

one injection every two months There is no requirement for monitoring between injectionshellip

After the first 12 months of treatmenthellipthe treatment interval may be extended based

on visual andor anatomic outcomes The schedule for monitoring should

be determined by the treating physicianrdquo

DMO diabetic macular oedema VA visual acuity

Re-treatment algorithms for anti-VEGF agents in DMO

bull LOADING PHASE

bull Lucentis label = monthly until stability

bull Eylea label = 5 x 112 then every 8 weeks ie fixed regime year 1

bull DRCRnet protocol T = effectively 6 x112 for majority (95) BUT actually only mandated for first 3 months then prn

bull helliphellip likely that majority will receive injections monthly for first 6 months

bull INDIVIDUALISED PHASE

bull Once ldquostablerdquo ndash based on VA and OCT

bull NB May never get a ldquodryrdquo OCT so treat to stability

bull THEN

bull Treat and extend

bull prn

What does Treat and Extend mean

Pathway overview = Lucentis prn

Jan

Loading phase = injections every 4 weeks until ldquostablerdquo for 3 visits

helliphelliphellip

Feb OctSepAugJulJunMayAprMar

MarFebJan

DecNov

DecNovOctSepAugJulJunMayApr

Then observe UNTIL VA decreases or OCT increase = prn

Once reactivates need at least 2 injections until stable again over 3 visits

Pathway overview = Treat and Extend

Jan

Loading phase = injections every 4 weeks until ldquostablerdquo for 3 visits or Eyleayear 1

helliphelliphellip

Feb OctSepAugJulJunMayAprMar

MarFebJan

DecNov

DecNovOctSepAugJulJunMayApr

Then keep injecting but extend the interval between injections gradually ie keep treating even if perfect

If reactivates need at least 2 injections until stable again over 3 visits

Pathway overview = Eylea fixed dosing year 1

Jan

Eylea = 5 x 112 injection then every 8 weeks

Average 6 injections yr 2 Beyond that

helliphelliphellip

Feb OctSepAugJulJunMayAprMar

MarFebJan

DecNov

DecNovOctSepAugJulJunMayApr

Then individualised UNTIL VA decreases or OCT increase = prn

Once reactivates need at least 2 injections until stable again over 3 visits

Pros and cons of Treat and Extend vs Prn

T+E PRN

PROS bull Proactive patient and service get advance warning of injection ndash capacity and demand planning easier

bull One ndashstopbull Fewer visits than prnbull Overtreatment

advantageous for peripheral retinopathy

bull Only treated when active ieno overtreatment

bull Aggressive year 1 protocols (DRCRN I ndash few injections needed thereafter

bull DMO tolerant of reactivations ()

CONS bull Overtreatment = riskexpenseinconvenience

bull Evidence base scantbull Bilateral disease tricky

bull Reactive so need enoughemergency capacity to inject when disease flares up

bull No advance warning to patientservice that injection needed

bull NEED TO DO IT WELL ndashNHS real life audits prn based regimes not good resultsUndertreatment in year 1 Affects long term prognosis and treatment burden

Pros and cons of Treat and Extend vs Prn

T+E PRN

PROS bull Proactive patient and service get advance warning of injection ndash capacity and demand planning easier

bull One ndashstopbull Fewer visits than prnbull Overtreatment

advantageous for peripheral retinopathy

bull Only treated when active ieno overtreatment

bull Aggressive year 1 protocols (DRCRN I ndash few injections needed thereafter

bull DMO tolerant of reactivations ()

CONS bull Overtreatment = riskexpenseinconvenience

bull Evidence base scantbull Bilateral disease tricky

bull Reactive so need enoughemergency capacity to inject when disease flares up

bull No advance warning to patientservice that injection needed

bull NEED TO DO IT WELL ndashNHS real life audits prn based regimes not good resultsUndertreatment in year 1 Affects long term prognosis and treatment burden

DMO ndash anti-VEGF Treat and Extend

bull Retain study ndash the only RCT data

bull Br J Ophthalmol 2015 Oct 9 pii bjophthalmol-2015-307249 doi 101136bjophthalmol-2015-307249 [Epub ahead of print]

bull Ranibizumab 05 mg treat-and-extend regimen for diabetic macular oedema the RETAIN study

bull Pruumlnte C1 Fajnkuchen F2 Mahmood S3 Ricci F4 Hatz K5 Studnička J6 Bezlyak V7 Parikh S7 Stubbings WJ7 Wenzel A7 Figueira J8 and the RETAIN Study Group

RETAIN Phase III trial evaluating the efficacy of lsquotreat and extendrsquo regimen (ARVO 2014)

bull Patients with DMO and visual impairment (n = 372) were randomised 111

to one of three groups for 24 months

bull Two phases to dosing schedule

bull Phase A

bull Patients in all groups were initially treated with monthly ranibizumab until BCVA remained

stable

bull Phase B

bull Patients in the TampE groups whose vision remained stable had treatment- free intervals

that were increased incrementally by 1 month for a maximum of 3 months

bull Patients in the PRN group had ongoing monthly monitoring

bull In all groups Phase A was resumed if a decrease in BCVA was observed at a visit

Ranibizumab 05 mg monotherapy

in TampE regimen

Ranibizumab 05 mg in TampE regimen

plus laser

Ranibizumab 05 mg PRN

35

RETAIN Visual acuity endpoints

Pruumlnte C ARVO 2014 Annual Meeting Abstracts Abstract 1700

Mean average change in BCVAat 12 months (primary endpoint)

Mean change in BCVA at 24 months

Mea

n av

erag

e ch

ange

in B

CVA

(ETD

RS

lette

rs)

RanibizumabTampE

RanibizumabTampE + laser

RanibizumabPRN

RanibizumabTampE

RanibizumabTampE + laser

RanibizumabPRN

Mea

n ch

ange

in B

CVA

(ETD

RS

lette

rs)

plt00001 for both ranibizumab TampE groups versus PRN for primary endpoint

36

RETAIN Patient visits and monitoring with TampE regimen over 24 months

bull The TampE regimen provided an approximately 40 reduction in the number of treatment visits required compared with the ranibizumab PRN regimen

bull Approximately 70 of patients receiving TampE regimens had monitoring intervals ge2 months compared with ongoing monthly monitoring in the ranibizumab PRN group

bull Informed the license for Lucentis in DMO (extend by 1 month at a time)

37

INTRAVITREAL STEROIDSWhich intravitreal steroid is better

bull Licensed steroids ndash Ozurdex (Dexamethasone) and Iluvien (Fluocinoloneacetonide

bull Which steroid is best in terms of VA outcomes hellipWE DONrsquoT KNOW FOR SURE ndash no head to head studies for licensed drugs either between steroids or between anti-VEGF and steroids

bull STEROIDS ARE efficacious in DMO

bull MEAD

bull FAME

bull DRCRnet protocol I

bull NICE ndash Ozurdex and Iluvien ndash second-line agents

Ozurdex

bull A biodegradable co-polymer implant ndash degrades in time to lactic and glycolic acid releasing Dexamethasone

bull 22gauge injectionbull MEAD study

bull N=1048

bull Dex 07mg vs 035mg vs sham

bull No rescue therapy

bull 3 year follow up max 6 monthly dosing ie 7 over 3 years

Gan IM et al Greafes Acrh Clin Exp Ophthalmol 2005

MEAD studyMean BCVA change from baseline based on baseline lens status

-2

0

2

4

6

8

10

0 3 6 9 12 15 18 21 24 27 30 33 36 39

Mea

n C

hang

e Fr

om

Bas

elin

e B

CVA

(Let

ters

)

Month

DEX Implant 07 mg (n = 86)

Sham (n = 101)

Boyer DS et al Ophthalmology 20141211904ndash14

Results analyzed in the ITT population with LOCF for missing values

Pseudophakic

Total

0

5

10

0 3 6 9 12 15 18 21 24 27 30 33 36 39

DEX 700 (n=351)

Sham (n=350)

10

8

6

4

2

0

Mea

n C

hang

e fr

om

Bas

elin

e B

CVA

(Let

ters

)

Month

07mg dose is approved as Ozurdexreg by the FDA and EMA 035mg dose not commercially available

1 Boyer DS et al Ophthalmology 2014 121 1904-1914

bull Nonbioerodible micro implant (polyimide) containing 190microg of fluocinolone acetonide (FAc)

bull Consistent daily submicrogram delivery of 02 microgd FAc for up to 36 months

bull Posterior point of release

bull 35 mm times 037 mm non-bioerodable micro implant

bull 25-gauge injector creates self-sealing wound

bull No measurable systemic exposure

ILUVIEN Implant Technology

FAcimplant

ILUVIEN SPC httpwwwmedicinesorgukemcmedicine27636

0 6 12 18 24 30 36

ILUVIEN 02 microgd FAc(n = 376)05 microgd FAc (n = 395)Control sham injection(n = 185)

Design of Phase 3 FAME Study (FAME A and B = same protocol)

Additional laser therapy allowed after week 6a

Retreatment any time after month 12 (if eligibleb)

Study ends

N = 956Randomisation

221Primary readout

Patients with DMO and

bull At least 1 previous laser tx

bull BCVA ge19 and le68 letters

bull TD-OCT FTH ge250 μm

Month

BCVA = best corrected visual acuity DMO = diabetic macular oedema TD-OCT=time domain optical coherence tomography FTH = foveal thicknessa At masked investigatorrsquos discretion b If BCVA loss ge5 letters or retinal thickening ge50 microm from best reading in previous 12 months

ge15 letter Gain is Greater in Chronic DMO Patients

ge 15

-Let

ter I

mpr

ovem

ent

in B

CVA

Fro

m B

asel

ine

Δ = 98

Months

Full Population Patients With Chronic DMO

Months

Δ = 206

287

189134

34

Steroid re-treatments

bullOzurdexbull Longer half-life than anti-VEGF in the eye

bull Redosing regimes not very helpful from RCT data eg MEAD study only 612 dosing

bull In reality re-treatment interval may be shorter

bull POSOLOGY

bull Patients treated with OZURDEX who have experienced an initial response and in the physicians opinion may benefit from retreatment without being exposed to significant risk should be considered for retreatment Retreatment may be performed after approximately 6 months if the patient experiences decreased vision andor an increase in retinal thickness secondary to recurrent or worsening diabetic macular oedema

bullIluvienbull 70 of patients in FAE only needed 1

injection over 3 years

bull BUT additional rescue treatments allowed

bull POSOLOGY

bull Each ILUVIEN implant releases fluocinolone acetonide for up to 36 months An additional implant may be administered after 12 months if the patient experiences decreased vision or an increase in retinal thickness secondary to recurrent or worsening diabetic macular oedema

bull Patients receiving escape medication were exited from MEAD before administration1

bull Macular laser rescue treatment allowed in RISERIDE (Lucentisreg) from 3 months2

bull Focalgrid laser allowed in FAME (Iluvienreg) from 6 weeks3

MEAD TREATMENT PROTOCOL

bull First treatment given at randomisation (day 0) bull Patients assessed for retreatment eligibility every 3 months from

months 6ndash36bull Patients were eligible for retreatment if

OCT optical coherence tomography

ge6 months since most recent

study treatment

Retinal thickness in 1 mm central macular

subfield by OCT gt175 microm

Evidence of residual retinal oedema (intraretinal cysts or

any regions of increased retinal thickening) as assessed by

investigator from OCT

AND OR

MEA

D

Amendment in May 2010 revised anatomic criterion for retreatment before this time the threshold was gt225 microm1Boyer DS et al Ophthalmology 2014 121 1904-19142Nguyen QD et al Ophthalmology 20121191064minus10773Campochiaro PA et al Ophthalmology 2011118626ndash635

Treatment burdenILUVIEN

Control(n =112)

02 microgd FAc(n =209)

Study Treatments(sham injection or ILUVIEN 02 microgday or FAc 05microgday)

1 treatment 661 761

2 treatments 277 187

ge 3 treatments 63 53

Rescue Laser Treatments (at masked physicianrsquos discretion after week 6)

Patients 607 407

Off-Protocol Treatments (IVTA bevacizumab ranibizumab intravitreal dexamethasone)

Patients 295 115

OZURDEX = 23injections year 1 41 by year 3

No other Rx

Summary of side effects with intravitreal steroids

Drug device Evidence base Cataract risk IOP rise (requiring drops)

Glaucoma surgery

endophthalmitis

ILUVIEN FAME studies 80 cat surgery(273 sham)

384(14 control)

48 0

Ozurdex MEAD 592 had cataract surgery(72 sham)

215 (end of study)(34 sham)

06 0

Trivaris+ laser vs Luc+laserx2 vs laser

Protocol IOphthalmology 2010

15 42(ONE OFgt10mmHg risegt30mmHGStart drops)

2186 0

NICE guidance for intravitreal steroids in DMO

bull Iluvien

bull NICE TA 301 Iluvien for DMO Nov 2013

bull hellipfor treating chronic diabetic macular oedema that is insufficiently responsive to available therapies only if

bull the implant is to be used in an eye with an intraocular

(pseudophakic) lens and

bull the manufacturer provides fluocinolone acetonide intravitreal implant with the discount agreed in the patient access scheme

NICE guidance for intravitreal steroids in DMO

bull Ozurdex

bull NICE TA 349 Ozurdex for DMO July 2015

bull there is an artificial lens in the eye to be treated and

bull their diabetic macular oedema has not improved with

non-corticosteroid treatment or such treatment is not suitable for them

Steroids = second line therapyWhen do I switch

bull Anti-VEGF first line for centre involving DMObull NICE TA ndash ldquoinsufficiently responsiverdquo ldquo ldquonot improvedrdquo ldquonot suitablerdquo ndash

OTHER TREATMENTS

bull 2 scenariosbull 1) Anti-VEGF canrsquot be funded ie OCTlt400um + PSEUDOPHAKIC

bull 2) Already had a course of treatment with laseranti-VEGF + PSEUDOPHAKIC ie SWITCHING from anti-VEGF to steroid

bull Plus

bull ldquochronicrdquo DMO ndash 3 years duration in FAME (18months) for ILUVIEN

bull Chronic DMO not essential for Ozurdex

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

Protocol T ndash patients may not improve in first 6 months

RIDE

RISE

Mea

n ch

ange

in B

CVA

(E

TDR

S le

tters

)M

ean

chan

ge in

BC

VA

(ETD

RS

lette

rs)

Time (months)

RISE and RIDE (Lucentis monthly dosing) Mean change in BCVA over 36 months

Brown DM et al Ophthalmology 2013120(10)2013ndash2022

54

Ranibizumab 03 mgRanibizumab 05 mgShamranibizumab 05 mg

Date of Prep Dec 2014 LGB0820147252X

VA improvement continues throughout year 1 with monthly dosing

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user ndash more than protocol

I

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

DRCRN protocol I5 year outcomesInjections 8-9 in year 1Year 2 = 2-3Year 3= 1-2Year 4 = 0-1Year 5 = 0

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

Wait for plateau = stability in protocol T laserPatient factors again

Judgement of response to anti-VEGF ndashtimeframe

bull Wait 6 months in poor responders

bull Wait 1 year for heavy users

bull Tempting to try steroids earlier than this ifbull No glaucoma ndash not a deal breaker Ozurdex better short term optionbull Pseudophakic

bull Clues from the diseasebull chronic

bull PATIENT FACTORS

bull Any eyes avoid steroids ndash advanced glaucomaCSCR Or prior viral retinitis RARE

bull Any eyes avoid anti-VEGF pregnancytrying to concieve recent CVA

BIOMARKERS AT BASELINE WOULD BE USEFULRESTORE subgroup analysis of OCT features

bull Andreas Pollreisz EURETINA 2015

bull OCT biomarkers (RESTORE data)

bull Better effects with anti-VEGF ifbull Small rather than large intra-retinal cyst

bull Sub-retinal fluid present

bull Vitreo-macular adhesion at baseline

bull No disruption of ELM and ISOS junction

bull No disorganisation of inner retinal layers (DRIL)

RESTORE subgroup analysis of OCT features

bull Andreas Pollreisz EURETINA 2015

bull OCT biomarkers (RESTORE data)

bull Better effects with anti-VEGF ifbull Small rather than large intra-retinal cyst

bull Sub-retinal fluid present

bull Vitreo-macular adhesion at baseline

bull No disruption of ELM and ISOS junction

bull No disorganisation of inner retinal layers (DRIL)

Better baseline characterisationclassificationERG Contrast sensitivityOCT AngiographyMicroperimetry= clues as to who responds best to which drug

Plan for this presentation helliphellipa long list

bull What treatment options are available for DMO (evidence base)

bull What treatment should I start with at baselinebull Re-treatment algorithms for intravitreal DMO therapiesbull When should I switchcombine therapiesbull The bigger picture

bull Other eyebull The patient as a wholebull The service -coping with capacity ndash compromises

The bigger pictureOther eyeThe patient as a wholeThe service -coping with capacity ndash compromises

bull OTHER EYE ndash may create problems

bull Treat and extend ndash ldquoreduce of visitsrdquo plus Eylea license ndash ldquono need for monitoringrdquo may not benefit if lots of visits due to PDR other eye

bull PERIPHERAL RETINA anti-VEGF supresses proliferative disease - Rebound on stopping Rx

bull PATIENT

bull Anti-VEGF ndash heavy user - Will comply

bull One stop much better than two stop for patient ndash Treat and extend

bull SERVICE

bull Capacity and demand planning = fixedT+E more predictable at least 1 month in advance ndash flexible nurse injectors

bull Steroids ndash even if well controlled (Iluvien for 3 years) need IOP check

bull Need pan-retinal examination both eyes ndash separate visits

Summary

CSMO

No centre involvement

Photocoagulation

Centre involvement

gt 78 letters(normalminimally reduced VA)

Photocoagulation

VA 78ndash24 letters

Phakic

Anti-VEGF

Pseudophakic

Anti-VEGF

SWITCHglaucoma

Injection tolerance

Medical issuesrecent CVA

Peripheral diseaseBilateral Rx

CSMO

No centre involvement

LASER

Centre involvement

gt 78 letters(normalminimally

reduced VA)

VA 78ndash24 letters

EYLEA OR LUCENTIS OR AVASTIN

Funding issues

Protocol T ndash poor VA lt 65 letters (615)

LOADING

Monthly injections until stability OR 5 x 112 (EYLEA) = 6 MONTHS then 8 weeks

RETREATMENT1

TREAT AND EXTEND - PRN

PRN

PSEUDOPHAKIC

Prior Rx

ILUVIEN

Chronic disease

OZURDEX

RETREATMENT

OZURDEX

OCT gt175um or any residual oedema

ILUVIEN after 12 months if risksltbenefits

OCT

gt400um

bull FACE TO FACE CLINICS RUNNING IN PARALLEL

bull = MAC002 every 6 months (optom or doctor) routine check for cataracttolerance of injectionsglaucoma issues etc

bull =MAC003 (DOCTOR) for problems as needed no fixed intervalDischargestop treatmentDeclines treatment diagnosis CSR overlay etcswitch drugs

bull =RV002- (DOCTOR) every 6 months

bull =DM002 ndash (DOCTOR) variable interval determined by last assessing doctor

bull First visit at 6 months from 1st injection if mild NPDR

bull Otherwise determined by retinopathy generally

LOADING PHASE

EyleaLucentis 1 within 48hrs of baseline

EyleaLucentis 2 (and LogMAR VA plus OCT same visit)

EyleaLucentis 3 (and LogMAR VA plus OCT same visit)

EyleaLucentis 4 (TEinj)(and Logmar VA plus OCT same visit

AFTER INJECTION 4 data goes off to be reviewed immediately as a hellip

TREAT AND EXTEND assessment ndash the next interval will depend on the response to the loading phase

NB -DMO patients ndash majority (95) will need 6 injctions x 112 of Lucentis

OR Eylea 5 x 112 then 8 weekly

ONCE STABLE for 3 x injection in TE phase

VIRTUAL CLINIC MONITORING OF MACULOPATHY AND PRN RETREATMENT

ANTI-VEGF INJECTION PATHWAYS Baseline visitMAC001 for wet AMDRV001 for CRVOBRVOMed ret clinic for DMO

Pathways ndash too many directions

Better that thanhellip

Thank you

What therapy do I choose for my patient at baseline

bull ANTI-VEGF helliphellipif OCT gt 400um

bull Sohellip Which one

Key trials in DMO

18

BOLT

RESOLVERISE and RIDE

DA VINCI

VIVID and VISTA

vs laser

vs sham

Steroids

(in combination

with laser)

Anti-VEGF

(in combination

with laser)

DRCRnet (Protocol I)

ETDRS

READ-2

RESTORE

RETAIN

REVEAL

DRCRnet (Protocol B)

FAMEMEAD

vs laser

vs sham

RanibizumabAflibercept

Bevacizumab

Triamcinolone

Fluocinolone acetonide Dexamethasone

Anti-VEGF Laser Steroids

DRCRnet PROTOCOL T

PROTOCOL T (DRCRnet)

bull Aflibercept Bevacizumab or Ranibizumab for Diabetic Macular Edema

bull N Engl J Med 2015 Mar 26372(13)1193-203

The Diabetic retinopathy Clinical Research Network February 18 2015

USA study NIHR funded

n=660

Lucentis 03mg not 05mg Eylea 2mg Avastin 125mg

Eylea protocol not the licensed regime

Avastin unlicensed

RETREATMENT protocol

First 6 months ndash inject every month 95 of patients UNLESS VA=66 AND OCT DRY

Then 2nd six months ndash if no change after 3 visits DEFER otherwise keep injecting monthly

Recurs ndash need at least 2 injections ie 3 months of stability

STABILITY = 10 Oct change or VA 5 letter change

STABILITY and residual OCT thickness gt250um LASER

Protocol T 1 year visual acuity outcomes

0

5

10

15

20

0 8 16 24 32 40 48

Visit Week

2032-2040 = 696 ndash 612= 78-69

0

5

10

15

20

0 8 16 24 32 40 48

Visit Week

2050 = 615 or worse = lt69

Mea

n ch

ange

in B

CV

A

Mea

n ch

ange

in B

CV

A

Aflibercept Bevacizumab Ranibizumab

+189

+142

+118+75

+8+83

Protocol T OCT outcomes year 1

-250

-200

-150

-100

-50

0

0 4 8 12 16 20 24 28 32 36 40 44 48 52

Visit Week

Aflibercept Bevacizumab Ranibizumab

Mea

n ch

ange

in C

ST

Conclusions ndash Protocol T year 1 data

bull Eylea was statistically superior in terms of visual acuity to 03mg Lucentisand to Avastin FOR PATIENTS WITH VA worse than 69 letters

bull Eylea and Lucentis were statistically superior in terms of OCT CRT reduction to Avastin for all patients regardless of baseline vision

bull No safety differences between the three drugs

SUMMARY What do I choose for my patient at baselineOCT central retinal thickness (CRT)PseudophakicAttempts at prior treatment duration of DMO

bull lt 400um

bull IFR licensed anti-VEGF or Avastin

+-ETDRS laser

PSEUDOPHAKIC

Iluvien

Ozurdex

bull gt 400um = Anti-VEGF

Which one

Depends on

bull baseline vision lt615 Eylea

bull Fixed dosing attractive (Eylea)bull Chronic DMO

bull PSEUDOPHAKICbull Patients ldquoinsufficiently

responsive to existing therapiesrdquo

bull ldquoNot improved with non-corticosteroid or such treatment is not suitable for themrdquo

Which steroid ndash Ozurdex or Iluvien

bull No head to head data

bull Revisit this when we think about switching from ANTI-VEGF to steroid

Assuming we have started with an anti-VEGF agent ndash what are the re-treatment algorithms in DMO

Treatment posologies

ldquoTreatment is initiated with one injection per month until maximum VA is achieved andor there are no signs of disease activity ie no change in VA and in other signs and

symptoms of the disease under continued treatment

In patients withhellipDMOhellip initially three or more consecutive monthly injections may be needed Thereafter monitoring and treatment intervals

should be determined by the physician and should be based on disease activity as

assessed by VA andor anatomical parametershellip

If patients are being treated according to a treat-and-extend regimen once maximum VA is achieved andor there are no

signs of disease activity the treatment intervals can be extended stepwise until signs of

disease activity or visual impairment recur The treatment intervalhellipmay be extended by up to one month

at a time for DMOrdquo

1 Novartis Pharmaceuticals UK Ltd 30 October 2014 Available at httpwwwmedicinesorgukemcmedicine19409 Accessed 04 September 2015

2 Bayer Pharma AG February 2015 Available at httpwwwmedicinesorgukemcmedicine27224 Accessed 04 September 2015

Ranibizumab1 Aflibercept2

ldquohelliptreatment is initiated with one injection per month for five consecutive doses followed by

one injection every two months There is no requirement for monitoring between injectionshellip

After the first 12 months of treatmenthellipthe treatment interval may be extended based

on visual andor anatomic outcomes The schedule for monitoring should

be determined by the treating physicianrdquo

DMO diabetic macular oedema VA visual acuity

Re-treatment algorithms for anti-VEGF agents in DMO

bull LOADING PHASE

bull Lucentis label = monthly until stability

bull Eylea label = 5 x 112 then every 8 weeks ie fixed regime year 1

bull DRCRnet protocol T = effectively 6 x112 for majority (95) BUT actually only mandated for first 3 months then prn

bull helliphellip likely that majority will receive injections monthly for first 6 months

bull INDIVIDUALISED PHASE

bull Once ldquostablerdquo ndash based on VA and OCT

bull NB May never get a ldquodryrdquo OCT so treat to stability

bull THEN

bull Treat and extend

bull prn

What does Treat and Extend mean

Pathway overview = Lucentis prn

Jan

Loading phase = injections every 4 weeks until ldquostablerdquo for 3 visits

helliphelliphellip

Feb OctSepAugJulJunMayAprMar

MarFebJan

DecNov

DecNovOctSepAugJulJunMayApr

Then observe UNTIL VA decreases or OCT increase = prn

Once reactivates need at least 2 injections until stable again over 3 visits

Pathway overview = Treat and Extend

Jan

Loading phase = injections every 4 weeks until ldquostablerdquo for 3 visits or Eyleayear 1

helliphelliphellip

Feb OctSepAugJulJunMayAprMar

MarFebJan

DecNov

DecNovOctSepAugJulJunMayApr

Then keep injecting but extend the interval between injections gradually ie keep treating even if perfect

If reactivates need at least 2 injections until stable again over 3 visits

Pathway overview = Eylea fixed dosing year 1

Jan

Eylea = 5 x 112 injection then every 8 weeks

Average 6 injections yr 2 Beyond that

helliphelliphellip

Feb OctSepAugJulJunMayAprMar

MarFebJan

DecNov

DecNovOctSepAugJulJunMayApr

Then individualised UNTIL VA decreases or OCT increase = prn

Once reactivates need at least 2 injections until stable again over 3 visits

Pros and cons of Treat and Extend vs Prn

T+E PRN

PROS bull Proactive patient and service get advance warning of injection ndash capacity and demand planning easier

bull One ndashstopbull Fewer visits than prnbull Overtreatment

advantageous for peripheral retinopathy

bull Only treated when active ieno overtreatment

bull Aggressive year 1 protocols (DRCRN I ndash few injections needed thereafter

bull DMO tolerant of reactivations ()

CONS bull Overtreatment = riskexpenseinconvenience

bull Evidence base scantbull Bilateral disease tricky

bull Reactive so need enoughemergency capacity to inject when disease flares up

bull No advance warning to patientservice that injection needed

bull NEED TO DO IT WELL ndashNHS real life audits prn based regimes not good resultsUndertreatment in year 1 Affects long term prognosis and treatment burden

Pros and cons of Treat and Extend vs Prn

T+E PRN

PROS bull Proactive patient and service get advance warning of injection ndash capacity and demand planning easier

bull One ndashstopbull Fewer visits than prnbull Overtreatment

advantageous for peripheral retinopathy

bull Only treated when active ieno overtreatment

bull Aggressive year 1 protocols (DRCRN I ndash few injections needed thereafter

bull DMO tolerant of reactivations ()

CONS bull Overtreatment = riskexpenseinconvenience

bull Evidence base scantbull Bilateral disease tricky

bull Reactive so need enoughemergency capacity to inject when disease flares up

bull No advance warning to patientservice that injection needed

bull NEED TO DO IT WELL ndashNHS real life audits prn based regimes not good resultsUndertreatment in year 1 Affects long term prognosis and treatment burden

DMO ndash anti-VEGF Treat and Extend

bull Retain study ndash the only RCT data

bull Br J Ophthalmol 2015 Oct 9 pii bjophthalmol-2015-307249 doi 101136bjophthalmol-2015-307249 [Epub ahead of print]

bull Ranibizumab 05 mg treat-and-extend regimen for diabetic macular oedema the RETAIN study

bull Pruumlnte C1 Fajnkuchen F2 Mahmood S3 Ricci F4 Hatz K5 Studnička J6 Bezlyak V7 Parikh S7 Stubbings WJ7 Wenzel A7 Figueira J8 and the RETAIN Study Group

RETAIN Phase III trial evaluating the efficacy of lsquotreat and extendrsquo regimen (ARVO 2014)

bull Patients with DMO and visual impairment (n = 372) were randomised 111

to one of three groups for 24 months

bull Two phases to dosing schedule

bull Phase A

bull Patients in all groups were initially treated with monthly ranibizumab until BCVA remained

stable

bull Phase B

bull Patients in the TampE groups whose vision remained stable had treatment- free intervals

that were increased incrementally by 1 month for a maximum of 3 months

bull Patients in the PRN group had ongoing monthly monitoring

bull In all groups Phase A was resumed if a decrease in BCVA was observed at a visit

Ranibizumab 05 mg monotherapy

in TampE regimen

Ranibizumab 05 mg in TampE regimen

plus laser

Ranibizumab 05 mg PRN

35

RETAIN Visual acuity endpoints

Pruumlnte C ARVO 2014 Annual Meeting Abstracts Abstract 1700

Mean average change in BCVAat 12 months (primary endpoint)

Mean change in BCVA at 24 months

Mea

n av

erag

e ch

ange

in B

CVA

(ETD

RS

lette

rs)

RanibizumabTampE

RanibizumabTampE + laser

RanibizumabPRN

RanibizumabTampE

RanibizumabTampE + laser

RanibizumabPRN

Mea

n ch

ange

in B

CVA

(ETD

RS

lette

rs)

plt00001 for both ranibizumab TampE groups versus PRN for primary endpoint

36

RETAIN Patient visits and monitoring with TampE regimen over 24 months

bull The TampE regimen provided an approximately 40 reduction in the number of treatment visits required compared with the ranibizumab PRN regimen

bull Approximately 70 of patients receiving TampE regimens had monitoring intervals ge2 months compared with ongoing monthly monitoring in the ranibizumab PRN group

bull Informed the license for Lucentis in DMO (extend by 1 month at a time)

37

INTRAVITREAL STEROIDSWhich intravitreal steroid is better

bull Licensed steroids ndash Ozurdex (Dexamethasone) and Iluvien (Fluocinoloneacetonide

bull Which steroid is best in terms of VA outcomes hellipWE DONrsquoT KNOW FOR SURE ndash no head to head studies for licensed drugs either between steroids or between anti-VEGF and steroids

bull STEROIDS ARE efficacious in DMO

bull MEAD

bull FAME

bull DRCRnet protocol I

bull NICE ndash Ozurdex and Iluvien ndash second-line agents

Ozurdex

bull A biodegradable co-polymer implant ndash degrades in time to lactic and glycolic acid releasing Dexamethasone

bull 22gauge injectionbull MEAD study

bull N=1048

bull Dex 07mg vs 035mg vs sham

bull No rescue therapy

bull 3 year follow up max 6 monthly dosing ie 7 over 3 years

Gan IM et al Greafes Acrh Clin Exp Ophthalmol 2005

MEAD studyMean BCVA change from baseline based on baseline lens status

-2

0

2

4

6

8

10

0 3 6 9 12 15 18 21 24 27 30 33 36 39

Mea

n C

hang

e Fr

om

Bas

elin

e B

CVA

(Let

ters

)

Month

DEX Implant 07 mg (n = 86)

Sham (n = 101)

Boyer DS et al Ophthalmology 20141211904ndash14

Results analyzed in the ITT population with LOCF for missing values

Pseudophakic

Total

0

5

10

0 3 6 9 12 15 18 21 24 27 30 33 36 39

DEX 700 (n=351)

Sham (n=350)

10

8

6

4

2

0

Mea

n C

hang

e fr

om

Bas

elin

e B

CVA

(Let

ters

)

Month

07mg dose is approved as Ozurdexreg by the FDA and EMA 035mg dose not commercially available

1 Boyer DS et al Ophthalmology 2014 121 1904-1914

bull Nonbioerodible micro implant (polyimide) containing 190microg of fluocinolone acetonide (FAc)

bull Consistent daily submicrogram delivery of 02 microgd FAc for up to 36 months

bull Posterior point of release

bull 35 mm times 037 mm non-bioerodable micro implant

bull 25-gauge injector creates self-sealing wound

bull No measurable systemic exposure

ILUVIEN Implant Technology

FAcimplant

ILUVIEN SPC httpwwwmedicinesorgukemcmedicine27636

0 6 12 18 24 30 36

ILUVIEN 02 microgd FAc(n = 376)05 microgd FAc (n = 395)Control sham injection(n = 185)

Design of Phase 3 FAME Study (FAME A and B = same protocol)

Additional laser therapy allowed after week 6a

Retreatment any time after month 12 (if eligibleb)

Study ends

N = 956Randomisation

221Primary readout

Patients with DMO and

bull At least 1 previous laser tx

bull BCVA ge19 and le68 letters

bull TD-OCT FTH ge250 μm

Month

BCVA = best corrected visual acuity DMO = diabetic macular oedema TD-OCT=time domain optical coherence tomography FTH = foveal thicknessa At masked investigatorrsquos discretion b If BCVA loss ge5 letters or retinal thickening ge50 microm from best reading in previous 12 months

ge15 letter Gain is Greater in Chronic DMO Patients

ge 15

-Let

ter I

mpr

ovem

ent

in B

CVA

Fro

m B

asel

ine

Δ = 98

Months

Full Population Patients With Chronic DMO

Months

Δ = 206

287

189134

34

Steroid re-treatments

bullOzurdexbull Longer half-life than anti-VEGF in the eye

bull Redosing regimes not very helpful from RCT data eg MEAD study only 612 dosing

bull In reality re-treatment interval may be shorter

bull POSOLOGY

bull Patients treated with OZURDEX who have experienced an initial response and in the physicians opinion may benefit from retreatment without being exposed to significant risk should be considered for retreatment Retreatment may be performed after approximately 6 months if the patient experiences decreased vision andor an increase in retinal thickness secondary to recurrent or worsening diabetic macular oedema

bullIluvienbull 70 of patients in FAE only needed 1

injection over 3 years

bull BUT additional rescue treatments allowed

bull POSOLOGY

bull Each ILUVIEN implant releases fluocinolone acetonide for up to 36 months An additional implant may be administered after 12 months if the patient experiences decreased vision or an increase in retinal thickness secondary to recurrent or worsening diabetic macular oedema

bull Patients receiving escape medication were exited from MEAD before administration1

bull Macular laser rescue treatment allowed in RISERIDE (Lucentisreg) from 3 months2

bull Focalgrid laser allowed in FAME (Iluvienreg) from 6 weeks3

MEAD TREATMENT PROTOCOL

bull First treatment given at randomisation (day 0) bull Patients assessed for retreatment eligibility every 3 months from

months 6ndash36bull Patients were eligible for retreatment if

OCT optical coherence tomography

ge6 months since most recent

study treatment

Retinal thickness in 1 mm central macular

subfield by OCT gt175 microm

Evidence of residual retinal oedema (intraretinal cysts or

any regions of increased retinal thickening) as assessed by

investigator from OCT

AND OR

MEA

D

Amendment in May 2010 revised anatomic criterion for retreatment before this time the threshold was gt225 microm1Boyer DS et al Ophthalmology 2014 121 1904-19142Nguyen QD et al Ophthalmology 20121191064minus10773Campochiaro PA et al Ophthalmology 2011118626ndash635

Treatment burdenILUVIEN

Control(n =112)

02 microgd FAc(n =209)

Study Treatments(sham injection or ILUVIEN 02 microgday or FAc 05microgday)

1 treatment 661 761

2 treatments 277 187

ge 3 treatments 63 53

Rescue Laser Treatments (at masked physicianrsquos discretion after week 6)

Patients 607 407

Off-Protocol Treatments (IVTA bevacizumab ranibizumab intravitreal dexamethasone)

Patients 295 115

OZURDEX = 23injections year 1 41 by year 3

No other Rx

Summary of side effects with intravitreal steroids

Drug device Evidence base Cataract risk IOP rise (requiring drops)

Glaucoma surgery

endophthalmitis

ILUVIEN FAME studies 80 cat surgery(273 sham)

384(14 control)

48 0

Ozurdex MEAD 592 had cataract surgery(72 sham)

215 (end of study)(34 sham)

06 0

Trivaris+ laser vs Luc+laserx2 vs laser

Protocol IOphthalmology 2010

15 42(ONE OFgt10mmHg risegt30mmHGStart drops)

2186 0

NICE guidance for intravitreal steroids in DMO

bull Iluvien

bull NICE TA 301 Iluvien for DMO Nov 2013

bull hellipfor treating chronic diabetic macular oedema that is insufficiently responsive to available therapies only if

bull the implant is to be used in an eye with an intraocular

(pseudophakic) lens and

bull the manufacturer provides fluocinolone acetonide intravitreal implant with the discount agreed in the patient access scheme

NICE guidance for intravitreal steroids in DMO

bull Ozurdex

bull NICE TA 349 Ozurdex for DMO July 2015

bull there is an artificial lens in the eye to be treated and

bull their diabetic macular oedema has not improved with

non-corticosteroid treatment or such treatment is not suitable for them

Steroids = second line therapyWhen do I switch

bull Anti-VEGF first line for centre involving DMObull NICE TA ndash ldquoinsufficiently responsiverdquo ldquo ldquonot improvedrdquo ldquonot suitablerdquo ndash

OTHER TREATMENTS

bull 2 scenariosbull 1) Anti-VEGF canrsquot be funded ie OCTlt400um + PSEUDOPHAKIC

bull 2) Already had a course of treatment with laseranti-VEGF + PSEUDOPHAKIC ie SWITCHING from anti-VEGF to steroid

bull Plus

bull ldquochronicrdquo DMO ndash 3 years duration in FAME (18months) for ILUVIEN

bull Chronic DMO not essential for Ozurdex

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

Protocol T ndash patients may not improve in first 6 months

RIDE

RISE

Mea

n ch

ange

in B

CVA

(E

TDR

S le

tters

)M

ean

chan

ge in

BC

VA

(ETD

RS

lette

rs)

Time (months)

RISE and RIDE (Lucentis monthly dosing) Mean change in BCVA over 36 months

Brown DM et al Ophthalmology 2013120(10)2013ndash2022

54

Ranibizumab 03 mgRanibizumab 05 mgShamranibizumab 05 mg

Date of Prep Dec 2014 LGB0820147252X

VA improvement continues throughout year 1 with monthly dosing

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user ndash more than protocol

I

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

DRCRN protocol I5 year outcomesInjections 8-9 in year 1Year 2 = 2-3Year 3= 1-2Year 4 = 0-1Year 5 = 0

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

Wait for plateau = stability in protocol T laserPatient factors again

Judgement of response to anti-VEGF ndashtimeframe

bull Wait 6 months in poor responders

bull Wait 1 year for heavy users

bull Tempting to try steroids earlier than this ifbull No glaucoma ndash not a deal breaker Ozurdex better short term optionbull Pseudophakic

bull Clues from the diseasebull chronic

bull PATIENT FACTORS

bull Any eyes avoid steroids ndash advanced glaucomaCSCR Or prior viral retinitis RARE

bull Any eyes avoid anti-VEGF pregnancytrying to concieve recent CVA

BIOMARKERS AT BASELINE WOULD BE USEFULRESTORE subgroup analysis of OCT features

bull Andreas Pollreisz EURETINA 2015

bull OCT biomarkers (RESTORE data)

bull Better effects with anti-VEGF ifbull Small rather than large intra-retinal cyst

bull Sub-retinal fluid present

bull Vitreo-macular adhesion at baseline

bull No disruption of ELM and ISOS junction

bull No disorganisation of inner retinal layers (DRIL)

RESTORE subgroup analysis of OCT features

bull Andreas Pollreisz EURETINA 2015

bull OCT biomarkers (RESTORE data)

bull Better effects with anti-VEGF ifbull Small rather than large intra-retinal cyst

bull Sub-retinal fluid present

bull Vitreo-macular adhesion at baseline

bull No disruption of ELM and ISOS junction

bull No disorganisation of inner retinal layers (DRIL)

Better baseline characterisationclassificationERG Contrast sensitivityOCT AngiographyMicroperimetry= clues as to who responds best to which drug

Plan for this presentation helliphellipa long list

bull What treatment options are available for DMO (evidence base)

bull What treatment should I start with at baselinebull Re-treatment algorithms for intravitreal DMO therapiesbull When should I switchcombine therapiesbull The bigger picture

bull Other eyebull The patient as a wholebull The service -coping with capacity ndash compromises

The bigger pictureOther eyeThe patient as a wholeThe service -coping with capacity ndash compromises

bull OTHER EYE ndash may create problems

bull Treat and extend ndash ldquoreduce of visitsrdquo plus Eylea license ndash ldquono need for monitoringrdquo may not benefit if lots of visits due to PDR other eye

bull PERIPHERAL RETINA anti-VEGF supresses proliferative disease - Rebound on stopping Rx

bull PATIENT

bull Anti-VEGF ndash heavy user - Will comply

bull One stop much better than two stop for patient ndash Treat and extend

bull SERVICE

bull Capacity and demand planning = fixedT+E more predictable at least 1 month in advance ndash flexible nurse injectors

bull Steroids ndash even if well controlled (Iluvien for 3 years) need IOP check

bull Need pan-retinal examination both eyes ndash separate visits

Summary

CSMO

No centre involvement

Photocoagulation

Centre involvement

gt 78 letters(normalminimally reduced VA)

Photocoagulation

VA 78ndash24 letters

Phakic

Anti-VEGF

Pseudophakic

Anti-VEGF

SWITCHglaucoma

Injection tolerance

Medical issuesrecent CVA

Peripheral diseaseBilateral Rx

CSMO

No centre involvement

LASER

Centre involvement

gt 78 letters(normalminimally

reduced VA)

VA 78ndash24 letters

EYLEA OR LUCENTIS OR AVASTIN

Funding issues

Protocol T ndash poor VA lt 65 letters (615)

LOADING

Monthly injections until stability OR 5 x 112 (EYLEA) = 6 MONTHS then 8 weeks

RETREATMENT1

TREAT AND EXTEND - PRN

PRN

PSEUDOPHAKIC

Prior Rx

ILUVIEN

Chronic disease

OZURDEX

RETREATMENT

OZURDEX

OCT gt175um or any residual oedema

ILUVIEN after 12 months if risksltbenefits

OCT

gt400um

bull FACE TO FACE CLINICS RUNNING IN PARALLEL

bull = MAC002 every 6 months (optom or doctor) routine check for cataracttolerance of injectionsglaucoma issues etc

bull =MAC003 (DOCTOR) for problems as needed no fixed intervalDischargestop treatmentDeclines treatment diagnosis CSR overlay etcswitch drugs

bull =RV002- (DOCTOR) every 6 months

bull =DM002 ndash (DOCTOR) variable interval determined by last assessing doctor

bull First visit at 6 months from 1st injection if mild NPDR

bull Otherwise determined by retinopathy generally

LOADING PHASE

EyleaLucentis 1 within 48hrs of baseline

EyleaLucentis 2 (and LogMAR VA plus OCT same visit)

EyleaLucentis 3 (and LogMAR VA plus OCT same visit)

EyleaLucentis 4 (TEinj)(and Logmar VA plus OCT same visit

AFTER INJECTION 4 data goes off to be reviewed immediately as a hellip

TREAT AND EXTEND assessment ndash the next interval will depend on the response to the loading phase

NB -DMO patients ndash majority (95) will need 6 injctions x 112 of Lucentis

OR Eylea 5 x 112 then 8 weekly

ONCE STABLE for 3 x injection in TE phase

VIRTUAL CLINIC MONITORING OF MACULOPATHY AND PRN RETREATMENT

ANTI-VEGF INJECTION PATHWAYS Baseline visitMAC001 for wet AMDRV001 for CRVOBRVOMed ret clinic for DMO

Pathways ndash too many directions

Better that thanhellip

Thank you

Key trials in DMO

18

BOLT

RESOLVERISE and RIDE

DA VINCI

VIVID and VISTA

vs laser

vs sham

Steroids

(in combination

with laser)

Anti-VEGF

(in combination

with laser)

DRCRnet (Protocol I)

ETDRS

READ-2

RESTORE

RETAIN

REVEAL

DRCRnet (Protocol B)

FAMEMEAD

vs laser

vs sham

RanibizumabAflibercept

Bevacizumab

Triamcinolone

Fluocinolone acetonide Dexamethasone

Anti-VEGF Laser Steroids

DRCRnet PROTOCOL T

PROTOCOL T (DRCRnet)

bull Aflibercept Bevacizumab or Ranibizumab for Diabetic Macular Edema

bull N Engl J Med 2015 Mar 26372(13)1193-203

The Diabetic retinopathy Clinical Research Network February 18 2015

USA study NIHR funded

n=660

Lucentis 03mg not 05mg Eylea 2mg Avastin 125mg

Eylea protocol not the licensed regime

Avastin unlicensed

RETREATMENT protocol

First 6 months ndash inject every month 95 of patients UNLESS VA=66 AND OCT DRY

Then 2nd six months ndash if no change after 3 visits DEFER otherwise keep injecting monthly

Recurs ndash need at least 2 injections ie 3 months of stability

STABILITY = 10 Oct change or VA 5 letter change

STABILITY and residual OCT thickness gt250um LASER

Protocol T 1 year visual acuity outcomes

0

5

10

15

20

0 8 16 24 32 40 48

Visit Week

2032-2040 = 696 ndash 612= 78-69

0

5

10

15

20

0 8 16 24 32 40 48

Visit Week

2050 = 615 or worse = lt69

Mea

n ch

ange

in B

CV

A

Mea

n ch

ange

in B

CV

A

Aflibercept Bevacizumab Ranibizumab

+189

+142

+118+75

+8+83

Protocol T OCT outcomes year 1

-250

-200

-150

-100

-50

0

0 4 8 12 16 20 24 28 32 36 40 44 48 52

Visit Week

Aflibercept Bevacizumab Ranibizumab

Mea

n ch

ange

in C

ST

Conclusions ndash Protocol T year 1 data

bull Eylea was statistically superior in terms of visual acuity to 03mg Lucentisand to Avastin FOR PATIENTS WITH VA worse than 69 letters

bull Eylea and Lucentis were statistically superior in terms of OCT CRT reduction to Avastin for all patients regardless of baseline vision

bull No safety differences between the three drugs

SUMMARY What do I choose for my patient at baselineOCT central retinal thickness (CRT)PseudophakicAttempts at prior treatment duration of DMO

bull lt 400um

bull IFR licensed anti-VEGF or Avastin

+-ETDRS laser

PSEUDOPHAKIC

Iluvien

Ozurdex

bull gt 400um = Anti-VEGF

Which one

Depends on

bull baseline vision lt615 Eylea

bull Fixed dosing attractive (Eylea)bull Chronic DMO

bull PSEUDOPHAKICbull Patients ldquoinsufficiently

responsive to existing therapiesrdquo

bull ldquoNot improved with non-corticosteroid or such treatment is not suitable for themrdquo

Which steroid ndash Ozurdex or Iluvien

bull No head to head data

bull Revisit this when we think about switching from ANTI-VEGF to steroid

Assuming we have started with an anti-VEGF agent ndash what are the re-treatment algorithms in DMO

Treatment posologies

ldquoTreatment is initiated with one injection per month until maximum VA is achieved andor there are no signs of disease activity ie no change in VA and in other signs and

symptoms of the disease under continued treatment

In patients withhellipDMOhellip initially three or more consecutive monthly injections may be needed Thereafter monitoring and treatment intervals

should be determined by the physician and should be based on disease activity as

assessed by VA andor anatomical parametershellip

If patients are being treated according to a treat-and-extend regimen once maximum VA is achieved andor there are no

signs of disease activity the treatment intervals can be extended stepwise until signs of

disease activity or visual impairment recur The treatment intervalhellipmay be extended by up to one month

at a time for DMOrdquo

1 Novartis Pharmaceuticals UK Ltd 30 October 2014 Available at httpwwwmedicinesorgukemcmedicine19409 Accessed 04 September 2015

2 Bayer Pharma AG February 2015 Available at httpwwwmedicinesorgukemcmedicine27224 Accessed 04 September 2015

Ranibizumab1 Aflibercept2

ldquohelliptreatment is initiated with one injection per month for five consecutive doses followed by

one injection every two months There is no requirement for monitoring between injectionshellip

After the first 12 months of treatmenthellipthe treatment interval may be extended based

on visual andor anatomic outcomes The schedule for monitoring should

be determined by the treating physicianrdquo

DMO diabetic macular oedema VA visual acuity

Re-treatment algorithms for anti-VEGF agents in DMO

bull LOADING PHASE

bull Lucentis label = monthly until stability

bull Eylea label = 5 x 112 then every 8 weeks ie fixed regime year 1

bull DRCRnet protocol T = effectively 6 x112 for majority (95) BUT actually only mandated for first 3 months then prn

bull helliphellip likely that majority will receive injections monthly for first 6 months

bull INDIVIDUALISED PHASE

bull Once ldquostablerdquo ndash based on VA and OCT

bull NB May never get a ldquodryrdquo OCT so treat to stability

bull THEN

bull Treat and extend

bull prn

What does Treat and Extend mean

Pathway overview = Lucentis prn

Jan

Loading phase = injections every 4 weeks until ldquostablerdquo for 3 visits

helliphelliphellip

Feb OctSepAugJulJunMayAprMar

MarFebJan

DecNov

DecNovOctSepAugJulJunMayApr

Then observe UNTIL VA decreases or OCT increase = prn

Once reactivates need at least 2 injections until stable again over 3 visits

Pathway overview = Treat and Extend

Jan

Loading phase = injections every 4 weeks until ldquostablerdquo for 3 visits or Eyleayear 1

helliphelliphellip

Feb OctSepAugJulJunMayAprMar

MarFebJan

DecNov

DecNovOctSepAugJulJunMayApr

Then keep injecting but extend the interval between injections gradually ie keep treating even if perfect

If reactivates need at least 2 injections until stable again over 3 visits

Pathway overview = Eylea fixed dosing year 1

Jan

Eylea = 5 x 112 injection then every 8 weeks

Average 6 injections yr 2 Beyond that

helliphelliphellip

Feb OctSepAugJulJunMayAprMar

MarFebJan

DecNov

DecNovOctSepAugJulJunMayApr

Then individualised UNTIL VA decreases or OCT increase = prn

Once reactivates need at least 2 injections until stable again over 3 visits

Pros and cons of Treat and Extend vs Prn

T+E PRN

PROS bull Proactive patient and service get advance warning of injection ndash capacity and demand planning easier

bull One ndashstopbull Fewer visits than prnbull Overtreatment

advantageous for peripheral retinopathy

bull Only treated when active ieno overtreatment

bull Aggressive year 1 protocols (DRCRN I ndash few injections needed thereafter

bull DMO tolerant of reactivations ()

CONS bull Overtreatment = riskexpenseinconvenience

bull Evidence base scantbull Bilateral disease tricky

bull Reactive so need enoughemergency capacity to inject when disease flares up

bull No advance warning to patientservice that injection needed

bull NEED TO DO IT WELL ndashNHS real life audits prn based regimes not good resultsUndertreatment in year 1 Affects long term prognosis and treatment burden

Pros and cons of Treat and Extend vs Prn

T+E PRN

PROS bull Proactive patient and service get advance warning of injection ndash capacity and demand planning easier

bull One ndashstopbull Fewer visits than prnbull Overtreatment

advantageous for peripheral retinopathy

bull Only treated when active ieno overtreatment

bull Aggressive year 1 protocols (DRCRN I ndash few injections needed thereafter

bull DMO tolerant of reactivations ()

CONS bull Overtreatment = riskexpenseinconvenience

bull Evidence base scantbull Bilateral disease tricky

bull Reactive so need enoughemergency capacity to inject when disease flares up

bull No advance warning to patientservice that injection needed

bull NEED TO DO IT WELL ndashNHS real life audits prn based regimes not good resultsUndertreatment in year 1 Affects long term prognosis and treatment burden

DMO ndash anti-VEGF Treat and Extend

bull Retain study ndash the only RCT data

bull Br J Ophthalmol 2015 Oct 9 pii bjophthalmol-2015-307249 doi 101136bjophthalmol-2015-307249 [Epub ahead of print]

bull Ranibizumab 05 mg treat-and-extend regimen for diabetic macular oedema the RETAIN study

bull Pruumlnte C1 Fajnkuchen F2 Mahmood S3 Ricci F4 Hatz K5 Studnička J6 Bezlyak V7 Parikh S7 Stubbings WJ7 Wenzel A7 Figueira J8 and the RETAIN Study Group

RETAIN Phase III trial evaluating the efficacy of lsquotreat and extendrsquo regimen (ARVO 2014)

bull Patients with DMO and visual impairment (n = 372) were randomised 111

to one of three groups for 24 months

bull Two phases to dosing schedule

bull Phase A

bull Patients in all groups were initially treated with monthly ranibizumab until BCVA remained

stable

bull Phase B

bull Patients in the TampE groups whose vision remained stable had treatment- free intervals

that were increased incrementally by 1 month for a maximum of 3 months

bull Patients in the PRN group had ongoing monthly monitoring

bull In all groups Phase A was resumed if a decrease in BCVA was observed at a visit

Ranibizumab 05 mg monotherapy

in TampE regimen

Ranibizumab 05 mg in TampE regimen

plus laser

Ranibizumab 05 mg PRN

35

RETAIN Visual acuity endpoints

Pruumlnte C ARVO 2014 Annual Meeting Abstracts Abstract 1700

Mean average change in BCVAat 12 months (primary endpoint)

Mean change in BCVA at 24 months

Mea

n av

erag

e ch

ange

in B

CVA

(ETD

RS

lette

rs)

RanibizumabTampE

RanibizumabTampE + laser

RanibizumabPRN

RanibizumabTampE

RanibizumabTampE + laser

RanibizumabPRN

Mea

n ch

ange

in B

CVA

(ETD

RS

lette

rs)

plt00001 for both ranibizumab TampE groups versus PRN for primary endpoint

36

RETAIN Patient visits and monitoring with TampE regimen over 24 months

bull The TampE regimen provided an approximately 40 reduction in the number of treatment visits required compared with the ranibizumab PRN regimen

bull Approximately 70 of patients receiving TampE regimens had monitoring intervals ge2 months compared with ongoing monthly monitoring in the ranibizumab PRN group

bull Informed the license for Lucentis in DMO (extend by 1 month at a time)

37

INTRAVITREAL STEROIDSWhich intravitreal steroid is better

bull Licensed steroids ndash Ozurdex (Dexamethasone) and Iluvien (Fluocinoloneacetonide

bull Which steroid is best in terms of VA outcomes hellipWE DONrsquoT KNOW FOR SURE ndash no head to head studies for licensed drugs either between steroids or between anti-VEGF and steroids

bull STEROIDS ARE efficacious in DMO

bull MEAD

bull FAME

bull DRCRnet protocol I

bull NICE ndash Ozurdex and Iluvien ndash second-line agents

Ozurdex

bull A biodegradable co-polymer implant ndash degrades in time to lactic and glycolic acid releasing Dexamethasone

bull 22gauge injectionbull MEAD study

bull N=1048

bull Dex 07mg vs 035mg vs sham

bull No rescue therapy

bull 3 year follow up max 6 monthly dosing ie 7 over 3 years

Gan IM et al Greafes Acrh Clin Exp Ophthalmol 2005

MEAD studyMean BCVA change from baseline based on baseline lens status

-2

0

2

4

6

8

10

0 3 6 9 12 15 18 21 24 27 30 33 36 39

Mea

n C

hang

e Fr

om

Bas

elin

e B

CVA

(Let

ters

)

Month

DEX Implant 07 mg (n = 86)

Sham (n = 101)

Boyer DS et al Ophthalmology 20141211904ndash14

Results analyzed in the ITT population with LOCF for missing values

Pseudophakic

Total

0

5

10

0 3 6 9 12 15 18 21 24 27 30 33 36 39

DEX 700 (n=351)

Sham (n=350)

10

8

6

4

2

0

Mea

n C

hang

e fr

om

Bas

elin

e B

CVA

(Let

ters

)

Month

07mg dose is approved as Ozurdexreg by the FDA and EMA 035mg dose not commercially available

1 Boyer DS et al Ophthalmology 2014 121 1904-1914

bull Nonbioerodible micro implant (polyimide) containing 190microg of fluocinolone acetonide (FAc)

bull Consistent daily submicrogram delivery of 02 microgd FAc for up to 36 months

bull Posterior point of release

bull 35 mm times 037 mm non-bioerodable micro implant

bull 25-gauge injector creates self-sealing wound

bull No measurable systemic exposure

ILUVIEN Implant Technology

FAcimplant

ILUVIEN SPC httpwwwmedicinesorgukemcmedicine27636

0 6 12 18 24 30 36

ILUVIEN 02 microgd FAc(n = 376)05 microgd FAc (n = 395)Control sham injection(n = 185)

Design of Phase 3 FAME Study (FAME A and B = same protocol)

Additional laser therapy allowed after week 6a

Retreatment any time after month 12 (if eligibleb)

Study ends

N = 956Randomisation

221Primary readout

Patients with DMO and

bull At least 1 previous laser tx

bull BCVA ge19 and le68 letters

bull TD-OCT FTH ge250 μm

Month

BCVA = best corrected visual acuity DMO = diabetic macular oedema TD-OCT=time domain optical coherence tomography FTH = foveal thicknessa At masked investigatorrsquos discretion b If BCVA loss ge5 letters or retinal thickening ge50 microm from best reading in previous 12 months

ge15 letter Gain is Greater in Chronic DMO Patients

ge 15

-Let

ter I

mpr

ovem

ent

in B

CVA

Fro

m B

asel

ine

Δ = 98

Months

Full Population Patients With Chronic DMO

Months

Δ = 206

287

189134

34

Steroid re-treatments

bullOzurdexbull Longer half-life than anti-VEGF in the eye

bull Redosing regimes not very helpful from RCT data eg MEAD study only 612 dosing

bull In reality re-treatment interval may be shorter

bull POSOLOGY

bull Patients treated with OZURDEX who have experienced an initial response and in the physicians opinion may benefit from retreatment without being exposed to significant risk should be considered for retreatment Retreatment may be performed after approximately 6 months if the patient experiences decreased vision andor an increase in retinal thickness secondary to recurrent or worsening diabetic macular oedema

bullIluvienbull 70 of patients in FAE only needed 1

injection over 3 years

bull BUT additional rescue treatments allowed

bull POSOLOGY

bull Each ILUVIEN implant releases fluocinolone acetonide for up to 36 months An additional implant may be administered after 12 months if the patient experiences decreased vision or an increase in retinal thickness secondary to recurrent or worsening diabetic macular oedema

bull Patients receiving escape medication were exited from MEAD before administration1

bull Macular laser rescue treatment allowed in RISERIDE (Lucentisreg) from 3 months2

bull Focalgrid laser allowed in FAME (Iluvienreg) from 6 weeks3

MEAD TREATMENT PROTOCOL

bull First treatment given at randomisation (day 0) bull Patients assessed for retreatment eligibility every 3 months from

months 6ndash36bull Patients were eligible for retreatment if

OCT optical coherence tomography

ge6 months since most recent

study treatment

Retinal thickness in 1 mm central macular

subfield by OCT gt175 microm

Evidence of residual retinal oedema (intraretinal cysts or

any regions of increased retinal thickening) as assessed by

investigator from OCT

AND OR

MEA

D

Amendment in May 2010 revised anatomic criterion for retreatment before this time the threshold was gt225 microm1Boyer DS et al Ophthalmology 2014 121 1904-19142Nguyen QD et al Ophthalmology 20121191064minus10773Campochiaro PA et al Ophthalmology 2011118626ndash635

Treatment burdenILUVIEN

Control(n =112)

02 microgd FAc(n =209)

Study Treatments(sham injection or ILUVIEN 02 microgday or FAc 05microgday)

1 treatment 661 761

2 treatments 277 187

ge 3 treatments 63 53

Rescue Laser Treatments (at masked physicianrsquos discretion after week 6)

Patients 607 407

Off-Protocol Treatments (IVTA bevacizumab ranibizumab intravitreal dexamethasone)

Patients 295 115

OZURDEX = 23injections year 1 41 by year 3

No other Rx

Summary of side effects with intravitreal steroids

Drug device Evidence base Cataract risk IOP rise (requiring drops)

Glaucoma surgery

endophthalmitis

ILUVIEN FAME studies 80 cat surgery(273 sham)

384(14 control)

48 0

Ozurdex MEAD 592 had cataract surgery(72 sham)

215 (end of study)(34 sham)

06 0

Trivaris+ laser vs Luc+laserx2 vs laser

Protocol IOphthalmology 2010

15 42(ONE OFgt10mmHg risegt30mmHGStart drops)

2186 0

NICE guidance for intravitreal steroids in DMO

bull Iluvien

bull NICE TA 301 Iluvien for DMO Nov 2013

bull hellipfor treating chronic diabetic macular oedema that is insufficiently responsive to available therapies only if

bull the implant is to be used in an eye with an intraocular

(pseudophakic) lens and

bull the manufacturer provides fluocinolone acetonide intravitreal implant with the discount agreed in the patient access scheme

NICE guidance for intravitreal steroids in DMO

bull Ozurdex

bull NICE TA 349 Ozurdex for DMO July 2015

bull there is an artificial lens in the eye to be treated and

bull their diabetic macular oedema has not improved with

non-corticosteroid treatment or such treatment is not suitable for them

Steroids = second line therapyWhen do I switch

bull Anti-VEGF first line for centre involving DMObull NICE TA ndash ldquoinsufficiently responsiverdquo ldquo ldquonot improvedrdquo ldquonot suitablerdquo ndash

OTHER TREATMENTS

bull 2 scenariosbull 1) Anti-VEGF canrsquot be funded ie OCTlt400um + PSEUDOPHAKIC

bull 2) Already had a course of treatment with laseranti-VEGF + PSEUDOPHAKIC ie SWITCHING from anti-VEGF to steroid

bull Plus

bull ldquochronicrdquo DMO ndash 3 years duration in FAME (18months) for ILUVIEN

bull Chronic DMO not essential for Ozurdex

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

Protocol T ndash patients may not improve in first 6 months

RIDE

RISE

Mea

n ch

ange

in B

CVA

(E

TDR

S le

tters

)M

ean

chan

ge in

BC

VA

(ETD

RS

lette

rs)

Time (months)

RISE and RIDE (Lucentis monthly dosing) Mean change in BCVA over 36 months

Brown DM et al Ophthalmology 2013120(10)2013ndash2022

54

Ranibizumab 03 mgRanibizumab 05 mgShamranibizumab 05 mg

Date of Prep Dec 2014 LGB0820147252X

VA improvement continues throughout year 1 with monthly dosing

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user ndash more than protocol

I

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

DRCRN protocol I5 year outcomesInjections 8-9 in year 1Year 2 = 2-3Year 3= 1-2Year 4 = 0-1Year 5 = 0

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

Wait for plateau = stability in protocol T laserPatient factors again

Judgement of response to anti-VEGF ndashtimeframe

bull Wait 6 months in poor responders

bull Wait 1 year for heavy users

bull Tempting to try steroids earlier than this ifbull No glaucoma ndash not a deal breaker Ozurdex better short term optionbull Pseudophakic

bull Clues from the diseasebull chronic

bull PATIENT FACTORS

bull Any eyes avoid steroids ndash advanced glaucomaCSCR Or prior viral retinitis RARE

bull Any eyes avoid anti-VEGF pregnancytrying to concieve recent CVA

BIOMARKERS AT BASELINE WOULD BE USEFULRESTORE subgroup analysis of OCT features

bull Andreas Pollreisz EURETINA 2015

bull OCT biomarkers (RESTORE data)

bull Better effects with anti-VEGF ifbull Small rather than large intra-retinal cyst

bull Sub-retinal fluid present

bull Vitreo-macular adhesion at baseline

bull No disruption of ELM and ISOS junction

bull No disorganisation of inner retinal layers (DRIL)

RESTORE subgroup analysis of OCT features

bull Andreas Pollreisz EURETINA 2015

bull OCT biomarkers (RESTORE data)

bull Better effects with anti-VEGF ifbull Small rather than large intra-retinal cyst

bull Sub-retinal fluid present

bull Vitreo-macular adhesion at baseline

bull No disruption of ELM and ISOS junction

bull No disorganisation of inner retinal layers (DRIL)

Better baseline characterisationclassificationERG Contrast sensitivityOCT AngiographyMicroperimetry= clues as to who responds best to which drug

Plan for this presentation helliphellipa long list

bull What treatment options are available for DMO (evidence base)

bull What treatment should I start with at baselinebull Re-treatment algorithms for intravitreal DMO therapiesbull When should I switchcombine therapiesbull The bigger picture

bull Other eyebull The patient as a wholebull The service -coping with capacity ndash compromises

The bigger pictureOther eyeThe patient as a wholeThe service -coping with capacity ndash compromises

bull OTHER EYE ndash may create problems

bull Treat and extend ndash ldquoreduce of visitsrdquo plus Eylea license ndash ldquono need for monitoringrdquo may not benefit if lots of visits due to PDR other eye

bull PERIPHERAL RETINA anti-VEGF supresses proliferative disease - Rebound on stopping Rx

bull PATIENT

bull Anti-VEGF ndash heavy user - Will comply

bull One stop much better than two stop for patient ndash Treat and extend

bull SERVICE

bull Capacity and demand planning = fixedT+E more predictable at least 1 month in advance ndash flexible nurse injectors

bull Steroids ndash even if well controlled (Iluvien for 3 years) need IOP check

bull Need pan-retinal examination both eyes ndash separate visits

Summary

CSMO

No centre involvement

Photocoagulation

Centre involvement

gt 78 letters(normalminimally reduced VA)

Photocoagulation

VA 78ndash24 letters

Phakic

Anti-VEGF

Pseudophakic

Anti-VEGF

SWITCHglaucoma

Injection tolerance

Medical issuesrecent CVA

Peripheral diseaseBilateral Rx

CSMO

No centre involvement

LASER

Centre involvement

gt 78 letters(normalminimally

reduced VA)

VA 78ndash24 letters

EYLEA OR LUCENTIS OR AVASTIN

Funding issues

Protocol T ndash poor VA lt 65 letters (615)

LOADING

Monthly injections until stability OR 5 x 112 (EYLEA) = 6 MONTHS then 8 weeks

RETREATMENT1

TREAT AND EXTEND - PRN

PRN

PSEUDOPHAKIC

Prior Rx

ILUVIEN

Chronic disease

OZURDEX

RETREATMENT

OZURDEX

OCT gt175um or any residual oedema

ILUVIEN after 12 months if risksltbenefits

OCT

gt400um

bull FACE TO FACE CLINICS RUNNING IN PARALLEL

bull = MAC002 every 6 months (optom or doctor) routine check for cataracttolerance of injectionsglaucoma issues etc

bull =MAC003 (DOCTOR) for problems as needed no fixed intervalDischargestop treatmentDeclines treatment diagnosis CSR overlay etcswitch drugs

bull =RV002- (DOCTOR) every 6 months

bull =DM002 ndash (DOCTOR) variable interval determined by last assessing doctor

bull First visit at 6 months from 1st injection if mild NPDR

bull Otherwise determined by retinopathy generally

LOADING PHASE

EyleaLucentis 1 within 48hrs of baseline

EyleaLucentis 2 (and LogMAR VA plus OCT same visit)

EyleaLucentis 3 (and LogMAR VA plus OCT same visit)

EyleaLucentis 4 (TEinj)(and Logmar VA plus OCT same visit

AFTER INJECTION 4 data goes off to be reviewed immediately as a hellip

TREAT AND EXTEND assessment ndash the next interval will depend on the response to the loading phase

NB -DMO patients ndash majority (95) will need 6 injctions x 112 of Lucentis

OR Eylea 5 x 112 then 8 weekly

ONCE STABLE for 3 x injection in TE phase

VIRTUAL CLINIC MONITORING OF MACULOPATHY AND PRN RETREATMENT

ANTI-VEGF INJECTION PATHWAYS Baseline visitMAC001 for wet AMDRV001 for CRVOBRVOMed ret clinic for DMO

Pathways ndash too many directions

Better that thanhellip

Thank you

PROTOCOL T (DRCRnet)

bull Aflibercept Bevacizumab or Ranibizumab for Diabetic Macular Edema

bull N Engl J Med 2015 Mar 26372(13)1193-203

The Diabetic retinopathy Clinical Research Network February 18 2015

USA study NIHR funded

n=660

Lucentis 03mg not 05mg Eylea 2mg Avastin 125mg

Eylea protocol not the licensed regime

Avastin unlicensed

RETREATMENT protocol

First 6 months ndash inject every month 95 of patients UNLESS VA=66 AND OCT DRY

Then 2nd six months ndash if no change after 3 visits DEFER otherwise keep injecting monthly

Recurs ndash need at least 2 injections ie 3 months of stability

STABILITY = 10 Oct change or VA 5 letter change

STABILITY and residual OCT thickness gt250um LASER

Protocol T 1 year visual acuity outcomes

0

5

10

15

20

0 8 16 24 32 40 48

Visit Week

2032-2040 = 696 ndash 612= 78-69

0

5

10

15

20

0 8 16 24 32 40 48

Visit Week

2050 = 615 or worse = lt69

Mea

n ch

ange

in B

CV

A

Mea

n ch

ange

in B

CV

A

Aflibercept Bevacizumab Ranibizumab

+189

+142

+118+75

+8+83

Protocol T OCT outcomes year 1

-250

-200

-150

-100

-50

0

0 4 8 12 16 20 24 28 32 36 40 44 48 52

Visit Week

Aflibercept Bevacizumab Ranibizumab

Mea

n ch

ange

in C

ST

Conclusions ndash Protocol T year 1 data

bull Eylea was statistically superior in terms of visual acuity to 03mg Lucentisand to Avastin FOR PATIENTS WITH VA worse than 69 letters

bull Eylea and Lucentis were statistically superior in terms of OCT CRT reduction to Avastin for all patients regardless of baseline vision

bull No safety differences between the three drugs

SUMMARY What do I choose for my patient at baselineOCT central retinal thickness (CRT)PseudophakicAttempts at prior treatment duration of DMO

bull lt 400um

bull IFR licensed anti-VEGF or Avastin

+-ETDRS laser

PSEUDOPHAKIC

Iluvien

Ozurdex

bull gt 400um = Anti-VEGF

Which one

Depends on

bull baseline vision lt615 Eylea

bull Fixed dosing attractive (Eylea)bull Chronic DMO

bull PSEUDOPHAKICbull Patients ldquoinsufficiently

responsive to existing therapiesrdquo

bull ldquoNot improved with non-corticosteroid or such treatment is not suitable for themrdquo

Which steroid ndash Ozurdex or Iluvien

bull No head to head data

bull Revisit this when we think about switching from ANTI-VEGF to steroid

Assuming we have started with an anti-VEGF agent ndash what are the re-treatment algorithms in DMO

Treatment posologies

ldquoTreatment is initiated with one injection per month until maximum VA is achieved andor there are no signs of disease activity ie no change in VA and in other signs and

symptoms of the disease under continued treatment

In patients withhellipDMOhellip initially three or more consecutive monthly injections may be needed Thereafter monitoring and treatment intervals

should be determined by the physician and should be based on disease activity as

assessed by VA andor anatomical parametershellip

If patients are being treated according to a treat-and-extend regimen once maximum VA is achieved andor there are no

signs of disease activity the treatment intervals can be extended stepwise until signs of

disease activity or visual impairment recur The treatment intervalhellipmay be extended by up to one month

at a time for DMOrdquo

1 Novartis Pharmaceuticals UK Ltd 30 October 2014 Available at httpwwwmedicinesorgukemcmedicine19409 Accessed 04 September 2015

2 Bayer Pharma AG February 2015 Available at httpwwwmedicinesorgukemcmedicine27224 Accessed 04 September 2015

Ranibizumab1 Aflibercept2

ldquohelliptreatment is initiated with one injection per month for five consecutive doses followed by

one injection every two months There is no requirement for monitoring between injectionshellip

After the first 12 months of treatmenthellipthe treatment interval may be extended based

on visual andor anatomic outcomes The schedule for monitoring should

be determined by the treating physicianrdquo

DMO diabetic macular oedema VA visual acuity

Re-treatment algorithms for anti-VEGF agents in DMO

bull LOADING PHASE

bull Lucentis label = monthly until stability

bull Eylea label = 5 x 112 then every 8 weeks ie fixed regime year 1

bull DRCRnet protocol T = effectively 6 x112 for majority (95) BUT actually only mandated for first 3 months then prn

bull helliphellip likely that majority will receive injections monthly for first 6 months

bull INDIVIDUALISED PHASE

bull Once ldquostablerdquo ndash based on VA and OCT

bull NB May never get a ldquodryrdquo OCT so treat to stability

bull THEN

bull Treat and extend

bull prn

What does Treat and Extend mean

Pathway overview = Lucentis prn

Jan

Loading phase = injections every 4 weeks until ldquostablerdquo for 3 visits

helliphelliphellip

Feb OctSepAugJulJunMayAprMar

MarFebJan

DecNov

DecNovOctSepAugJulJunMayApr

Then observe UNTIL VA decreases or OCT increase = prn

Once reactivates need at least 2 injections until stable again over 3 visits

Pathway overview = Treat and Extend

Jan

Loading phase = injections every 4 weeks until ldquostablerdquo for 3 visits or Eyleayear 1

helliphelliphellip

Feb OctSepAugJulJunMayAprMar

MarFebJan

DecNov

DecNovOctSepAugJulJunMayApr

Then keep injecting but extend the interval between injections gradually ie keep treating even if perfect

If reactivates need at least 2 injections until stable again over 3 visits

Pathway overview = Eylea fixed dosing year 1

Jan

Eylea = 5 x 112 injection then every 8 weeks

Average 6 injections yr 2 Beyond that

helliphelliphellip

Feb OctSepAugJulJunMayAprMar

MarFebJan

DecNov

DecNovOctSepAugJulJunMayApr

Then individualised UNTIL VA decreases or OCT increase = prn

Once reactivates need at least 2 injections until stable again over 3 visits

Pros and cons of Treat and Extend vs Prn

T+E PRN

PROS bull Proactive patient and service get advance warning of injection ndash capacity and demand planning easier

bull One ndashstopbull Fewer visits than prnbull Overtreatment

advantageous for peripheral retinopathy

bull Only treated when active ieno overtreatment

bull Aggressive year 1 protocols (DRCRN I ndash few injections needed thereafter

bull DMO tolerant of reactivations ()

CONS bull Overtreatment = riskexpenseinconvenience

bull Evidence base scantbull Bilateral disease tricky

bull Reactive so need enoughemergency capacity to inject when disease flares up

bull No advance warning to patientservice that injection needed

bull NEED TO DO IT WELL ndashNHS real life audits prn based regimes not good resultsUndertreatment in year 1 Affects long term prognosis and treatment burden

Pros and cons of Treat and Extend vs Prn

T+E PRN

PROS bull Proactive patient and service get advance warning of injection ndash capacity and demand planning easier

bull One ndashstopbull Fewer visits than prnbull Overtreatment

advantageous for peripheral retinopathy

bull Only treated when active ieno overtreatment

bull Aggressive year 1 protocols (DRCRN I ndash few injections needed thereafter

bull DMO tolerant of reactivations ()

CONS bull Overtreatment = riskexpenseinconvenience

bull Evidence base scantbull Bilateral disease tricky

bull Reactive so need enoughemergency capacity to inject when disease flares up

bull No advance warning to patientservice that injection needed

bull NEED TO DO IT WELL ndashNHS real life audits prn based regimes not good resultsUndertreatment in year 1 Affects long term prognosis and treatment burden

DMO ndash anti-VEGF Treat and Extend

bull Retain study ndash the only RCT data

bull Br J Ophthalmol 2015 Oct 9 pii bjophthalmol-2015-307249 doi 101136bjophthalmol-2015-307249 [Epub ahead of print]

bull Ranibizumab 05 mg treat-and-extend regimen for diabetic macular oedema the RETAIN study

bull Pruumlnte C1 Fajnkuchen F2 Mahmood S3 Ricci F4 Hatz K5 Studnička J6 Bezlyak V7 Parikh S7 Stubbings WJ7 Wenzel A7 Figueira J8 and the RETAIN Study Group

RETAIN Phase III trial evaluating the efficacy of lsquotreat and extendrsquo regimen (ARVO 2014)

bull Patients with DMO and visual impairment (n = 372) were randomised 111

to one of three groups for 24 months

bull Two phases to dosing schedule

bull Phase A

bull Patients in all groups were initially treated with monthly ranibizumab until BCVA remained

stable

bull Phase B

bull Patients in the TampE groups whose vision remained stable had treatment- free intervals

that were increased incrementally by 1 month for a maximum of 3 months

bull Patients in the PRN group had ongoing monthly monitoring

bull In all groups Phase A was resumed if a decrease in BCVA was observed at a visit

Ranibizumab 05 mg monotherapy

in TampE regimen

Ranibizumab 05 mg in TampE regimen

plus laser

Ranibizumab 05 mg PRN

35

RETAIN Visual acuity endpoints

Pruumlnte C ARVO 2014 Annual Meeting Abstracts Abstract 1700

Mean average change in BCVAat 12 months (primary endpoint)

Mean change in BCVA at 24 months

Mea

n av

erag

e ch

ange

in B

CVA

(ETD

RS

lette

rs)

RanibizumabTampE

RanibizumabTampE + laser

RanibizumabPRN

RanibizumabTampE

RanibizumabTampE + laser

RanibizumabPRN

Mea

n ch

ange

in B

CVA

(ETD

RS

lette

rs)

plt00001 for both ranibizumab TampE groups versus PRN for primary endpoint

36

RETAIN Patient visits and monitoring with TampE regimen over 24 months

bull The TampE regimen provided an approximately 40 reduction in the number of treatment visits required compared with the ranibizumab PRN regimen

bull Approximately 70 of patients receiving TampE regimens had monitoring intervals ge2 months compared with ongoing monthly monitoring in the ranibizumab PRN group

bull Informed the license for Lucentis in DMO (extend by 1 month at a time)

37

INTRAVITREAL STEROIDSWhich intravitreal steroid is better

bull Licensed steroids ndash Ozurdex (Dexamethasone) and Iluvien (Fluocinoloneacetonide

bull Which steroid is best in terms of VA outcomes hellipWE DONrsquoT KNOW FOR SURE ndash no head to head studies for licensed drugs either between steroids or between anti-VEGF and steroids

bull STEROIDS ARE efficacious in DMO

bull MEAD

bull FAME

bull DRCRnet protocol I

bull NICE ndash Ozurdex and Iluvien ndash second-line agents

Ozurdex

bull A biodegradable co-polymer implant ndash degrades in time to lactic and glycolic acid releasing Dexamethasone

bull 22gauge injectionbull MEAD study

bull N=1048

bull Dex 07mg vs 035mg vs sham

bull No rescue therapy

bull 3 year follow up max 6 monthly dosing ie 7 over 3 years

Gan IM et al Greafes Acrh Clin Exp Ophthalmol 2005

MEAD studyMean BCVA change from baseline based on baseline lens status

-2

0

2

4

6

8

10

0 3 6 9 12 15 18 21 24 27 30 33 36 39

Mea

n C

hang

e Fr

om

Bas

elin

e B

CVA

(Let

ters

)

Month

DEX Implant 07 mg (n = 86)

Sham (n = 101)

Boyer DS et al Ophthalmology 20141211904ndash14

Results analyzed in the ITT population with LOCF for missing values

Pseudophakic

Total

0

5

10

0 3 6 9 12 15 18 21 24 27 30 33 36 39

DEX 700 (n=351)

Sham (n=350)

10

8

6

4

2

0

Mea

n C

hang

e fr

om

Bas

elin

e B

CVA

(Let

ters

)

Month

07mg dose is approved as Ozurdexreg by the FDA and EMA 035mg dose not commercially available

1 Boyer DS et al Ophthalmology 2014 121 1904-1914

bull Nonbioerodible micro implant (polyimide) containing 190microg of fluocinolone acetonide (FAc)

bull Consistent daily submicrogram delivery of 02 microgd FAc for up to 36 months

bull Posterior point of release

bull 35 mm times 037 mm non-bioerodable micro implant

bull 25-gauge injector creates self-sealing wound

bull No measurable systemic exposure

ILUVIEN Implant Technology

FAcimplant

ILUVIEN SPC httpwwwmedicinesorgukemcmedicine27636

0 6 12 18 24 30 36

ILUVIEN 02 microgd FAc(n = 376)05 microgd FAc (n = 395)Control sham injection(n = 185)

Design of Phase 3 FAME Study (FAME A and B = same protocol)

Additional laser therapy allowed after week 6a

Retreatment any time after month 12 (if eligibleb)

Study ends

N = 956Randomisation

221Primary readout

Patients with DMO and

bull At least 1 previous laser tx

bull BCVA ge19 and le68 letters

bull TD-OCT FTH ge250 μm

Month

BCVA = best corrected visual acuity DMO = diabetic macular oedema TD-OCT=time domain optical coherence tomography FTH = foveal thicknessa At masked investigatorrsquos discretion b If BCVA loss ge5 letters or retinal thickening ge50 microm from best reading in previous 12 months

ge15 letter Gain is Greater in Chronic DMO Patients

ge 15

-Let

ter I

mpr

ovem

ent

in B

CVA

Fro

m B

asel

ine

Δ = 98

Months

Full Population Patients With Chronic DMO

Months

Δ = 206

287

189134

34

Steroid re-treatments

bullOzurdexbull Longer half-life than anti-VEGF in the eye

bull Redosing regimes not very helpful from RCT data eg MEAD study only 612 dosing

bull In reality re-treatment interval may be shorter

bull POSOLOGY

bull Patients treated with OZURDEX who have experienced an initial response and in the physicians opinion may benefit from retreatment without being exposed to significant risk should be considered for retreatment Retreatment may be performed after approximately 6 months if the patient experiences decreased vision andor an increase in retinal thickness secondary to recurrent or worsening diabetic macular oedema

bullIluvienbull 70 of patients in FAE only needed 1

injection over 3 years

bull BUT additional rescue treatments allowed

bull POSOLOGY

bull Each ILUVIEN implant releases fluocinolone acetonide for up to 36 months An additional implant may be administered after 12 months if the patient experiences decreased vision or an increase in retinal thickness secondary to recurrent or worsening diabetic macular oedema

bull Patients receiving escape medication were exited from MEAD before administration1

bull Macular laser rescue treatment allowed in RISERIDE (Lucentisreg) from 3 months2

bull Focalgrid laser allowed in FAME (Iluvienreg) from 6 weeks3

MEAD TREATMENT PROTOCOL

bull First treatment given at randomisation (day 0) bull Patients assessed for retreatment eligibility every 3 months from

months 6ndash36bull Patients were eligible for retreatment if

OCT optical coherence tomography

ge6 months since most recent

study treatment

Retinal thickness in 1 mm central macular

subfield by OCT gt175 microm

Evidence of residual retinal oedema (intraretinal cysts or

any regions of increased retinal thickening) as assessed by

investigator from OCT

AND OR

MEA

D

Amendment in May 2010 revised anatomic criterion for retreatment before this time the threshold was gt225 microm1Boyer DS et al Ophthalmology 2014 121 1904-19142Nguyen QD et al Ophthalmology 20121191064minus10773Campochiaro PA et al Ophthalmology 2011118626ndash635

Treatment burdenILUVIEN

Control(n =112)

02 microgd FAc(n =209)

Study Treatments(sham injection or ILUVIEN 02 microgday or FAc 05microgday)

1 treatment 661 761

2 treatments 277 187

ge 3 treatments 63 53

Rescue Laser Treatments (at masked physicianrsquos discretion after week 6)

Patients 607 407

Off-Protocol Treatments (IVTA bevacizumab ranibizumab intravitreal dexamethasone)

Patients 295 115

OZURDEX = 23injections year 1 41 by year 3

No other Rx

Summary of side effects with intravitreal steroids

Drug device Evidence base Cataract risk IOP rise (requiring drops)

Glaucoma surgery

endophthalmitis

ILUVIEN FAME studies 80 cat surgery(273 sham)

384(14 control)

48 0

Ozurdex MEAD 592 had cataract surgery(72 sham)

215 (end of study)(34 sham)

06 0

Trivaris+ laser vs Luc+laserx2 vs laser

Protocol IOphthalmology 2010

15 42(ONE OFgt10mmHg risegt30mmHGStart drops)

2186 0

NICE guidance for intravitreal steroids in DMO

bull Iluvien

bull NICE TA 301 Iluvien for DMO Nov 2013

bull hellipfor treating chronic diabetic macular oedema that is insufficiently responsive to available therapies only if

bull the implant is to be used in an eye with an intraocular

(pseudophakic) lens and

bull the manufacturer provides fluocinolone acetonide intravitreal implant with the discount agreed in the patient access scheme

NICE guidance for intravitreal steroids in DMO

bull Ozurdex

bull NICE TA 349 Ozurdex for DMO July 2015

bull there is an artificial lens in the eye to be treated and

bull their diabetic macular oedema has not improved with

non-corticosteroid treatment or such treatment is not suitable for them

Steroids = second line therapyWhen do I switch

bull Anti-VEGF first line for centre involving DMObull NICE TA ndash ldquoinsufficiently responsiverdquo ldquo ldquonot improvedrdquo ldquonot suitablerdquo ndash

OTHER TREATMENTS

bull 2 scenariosbull 1) Anti-VEGF canrsquot be funded ie OCTlt400um + PSEUDOPHAKIC

bull 2) Already had a course of treatment with laseranti-VEGF + PSEUDOPHAKIC ie SWITCHING from anti-VEGF to steroid

bull Plus

bull ldquochronicrdquo DMO ndash 3 years duration in FAME (18months) for ILUVIEN

bull Chronic DMO not essential for Ozurdex

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

Protocol T ndash patients may not improve in first 6 months

RIDE

RISE

Mea

n ch

ange

in B

CVA

(E

TDR

S le

tters

)M

ean

chan

ge in

BC

VA

(ETD

RS

lette

rs)

Time (months)

RISE and RIDE (Lucentis monthly dosing) Mean change in BCVA over 36 months

Brown DM et al Ophthalmology 2013120(10)2013ndash2022

54

Ranibizumab 03 mgRanibizumab 05 mgShamranibizumab 05 mg

Date of Prep Dec 2014 LGB0820147252X

VA improvement continues throughout year 1 with monthly dosing

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user ndash more than protocol

I

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

DRCRN protocol I5 year outcomesInjections 8-9 in year 1Year 2 = 2-3Year 3= 1-2Year 4 = 0-1Year 5 = 0

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

Wait for plateau = stability in protocol T laserPatient factors again

Judgement of response to anti-VEGF ndashtimeframe

bull Wait 6 months in poor responders

bull Wait 1 year for heavy users

bull Tempting to try steroids earlier than this ifbull No glaucoma ndash not a deal breaker Ozurdex better short term optionbull Pseudophakic

bull Clues from the diseasebull chronic

bull PATIENT FACTORS

bull Any eyes avoid steroids ndash advanced glaucomaCSCR Or prior viral retinitis RARE

bull Any eyes avoid anti-VEGF pregnancytrying to concieve recent CVA

BIOMARKERS AT BASELINE WOULD BE USEFULRESTORE subgroup analysis of OCT features

bull Andreas Pollreisz EURETINA 2015

bull OCT biomarkers (RESTORE data)

bull Better effects with anti-VEGF ifbull Small rather than large intra-retinal cyst

bull Sub-retinal fluid present

bull Vitreo-macular adhesion at baseline

bull No disruption of ELM and ISOS junction

bull No disorganisation of inner retinal layers (DRIL)

RESTORE subgroup analysis of OCT features

bull Andreas Pollreisz EURETINA 2015

bull OCT biomarkers (RESTORE data)

bull Better effects with anti-VEGF ifbull Small rather than large intra-retinal cyst

bull Sub-retinal fluid present

bull Vitreo-macular adhesion at baseline

bull No disruption of ELM and ISOS junction

bull No disorganisation of inner retinal layers (DRIL)

Better baseline characterisationclassificationERG Contrast sensitivityOCT AngiographyMicroperimetry= clues as to who responds best to which drug

Plan for this presentation helliphellipa long list

bull What treatment options are available for DMO (evidence base)

bull What treatment should I start with at baselinebull Re-treatment algorithms for intravitreal DMO therapiesbull When should I switchcombine therapiesbull The bigger picture

bull Other eyebull The patient as a wholebull The service -coping with capacity ndash compromises

The bigger pictureOther eyeThe patient as a wholeThe service -coping with capacity ndash compromises

bull OTHER EYE ndash may create problems

bull Treat and extend ndash ldquoreduce of visitsrdquo plus Eylea license ndash ldquono need for monitoringrdquo may not benefit if lots of visits due to PDR other eye

bull PERIPHERAL RETINA anti-VEGF supresses proliferative disease - Rebound on stopping Rx

bull PATIENT

bull Anti-VEGF ndash heavy user - Will comply

bull One stop much better than two stop for patient ndash Treat and extend

bull SERVICE

bull Capacity and demand planning = fixedT+E more predictable at least 1 month in advance ndash flexible nurse injectors

bull Steroids ndash even if well controlled (Iluvien for 3 years) need IOP check

bull Need pan-retinal examination both eyes ndash separate visits

Summary

CSMO

No centre involvement

Photocoagulation

Centre involvement

gt 78 letters(normalminimally reduced VA)

Photocoagulation

VA 78ndash24 letters

Phakic

Anti-VEGF

Pseudophakic

Anti-VEGF

SWITCHglaucoma

Injection tolerance

Medical issuesrecent CVA

Peripheral diseaseBilateral Rx

CSMO

No centre involvement

LASER

Centre involvement

gt 78 letters(normalminimally

reduced VA)

VA 78ndash24 letters

EYLEA OR LUCENTIS OR AVASTIN

Funding issues

Protocol T ndash poor VA lt 65 letters (615)

LOADING

Monthly injections until stability OR 5 x 112 (EYLEA) = 6 MONTHS then 8 weeks

RETREATMENT1

TREAT AND EXTEND - PRN

PRN

PSEUDOPHAKIC

Prior Rx

ILUVIEN

Chronic disease

OZURDEX

RETREATMENT

OZURDEX

OCT gt175um or any residual oedema

ILUVIEN after 12 months if risksltbenefits

OCT

gt400um

bull FACE TO FACE CLINICS RUNNING IN PARALLEL

bull = MAC002 every 6 months (optom or doctor) routine check for cataracttolerance of injectionsglaucoma issues etc

bull =MAC003 (DOCTOR) for problems as needed no fixed intervalDischargestop treatmentDeclines treatment diagnosis CSR overlay etcswitch drugs

bull =RV002- (DOCTOR) every 6 months

bull =DM002 ndash (DOCTOR) variable interval determined by last assessing doctor

bull First visit at 6 months from 1st injection if mild NPDR

bull Otherwise determined by retinopathy generally

LOADING PHASE

EyleaLucentis 1 within 48hrs of baseline

EyleaLucentis 2 (and LogMAR VA plus OCT same visit)

EyleaLucentis 3 (and LogMAR VA plus OCT same visit)

EyleaLucentis 4 (TEinj)(and Logmar VA plus OCT same visit

AFTER INJECTION 4 data goes off to be reviewed immediately as a hellip

TREAT AND EXTEND assessment ndash the next interval will depend on the response to the loading phase

NB -DMO patients ndash majority (95) will need 6 injctions x 112 of Lucentis

OR Eylea 5 x 112 then 8 weekly

ONCE STABLE for 3 x injection in TE phase

VIRTUAL CLINIC MONITORING OF MACULOPATHY AND PRN RETREATMENT

ANTI-VEGF INJECTION PATHWAYS Baseline visitMAC001 for wet AMDRV001 for CRVOBRVOMed ret clinic for DMO

Pathways ndash too many directions

Better that thanhellip

Thank you

Protocol T 1 year visual acuity outcomes

0

5

10

15

20

0 8 16 24 32 40 48

Visit Week

2032-2040 = 696 ndash 612= 78-69

0

5

10

15

20

0 8 16 24 32 40 48

Visit Week

2050 = 615 or worse = lt69

Mea

n ch

ange

in B

CV

A

Mea

n ch

ange

in B

CV

A

Aflibercept Bevacizumab Ranibizumab

+189

+142

+118+75

+8+83

Protocol T OCT outcomes year 1

-250

-200

-150

-100

-50

0

0 4 8 12 16 20 24 28 32 36 40 44 48 52

Visit Week

Aflibercept Bevacizumab Ranibizumab

Mea

n ch

ange

in C

ST

Conclusions ndash Protocol T year 1 data

bull Eylea was statistically superior in terms of visual acuity to 03mg Lucentisand to Avastin FOR PATIENTS WITH VA worse than 69 letters

bull Eylea and Lucentis were statistically superior in terms of OCT CRT reduction to Avastin for all patients regardless of baseline vision

bull No safety differences between the three drugs

SUMMARY What do I choose for my patient at baselineOCT central retinal thickness (CRT)PseudophakicAttempts at prior treatment duration of DMO

bull lt 400um

bull IFR licensed anti-VEGF or Avastin

+-ETDRS laser

PSEUDOPHAKIC

Iluvien

Ozurdex

bull gt 400um = Anti-VEGF

Which one

Depends on

bull baseline vision lt615 Eylea

bull Fixed dosing attractive (Eylea)bull Chronic DMO

bull PSEUDOPHAKICbull Patients ldquoinsufficiently

responsive to existing therapiesrdquo

bull ldquoNot improved with non-corticosteroid or such treatment is not suitable for themrdquo

Which steroid ndash Ozurdex or Iluvien

bull No head to head data

bull Revisit this when we think about switching from ANTI-VEGF to steroid

Assuming we have started with an anti-VEGF agent ndash what are the re-treatment algorithms in DMO

Treatment posologies

ldquoTreatment is initiated with one injection per month until maximum VA is achieved andor there are no signs of disease activity ie no change in VA and in other signs and

symptoms of the disease under continued treatment

In patients withhellipDMOhellip initially three or more consecutive monthly injections may be needed Thereafter monitoring and treatment intervals

should be determined by the physician and should be based on disease activity as

assessed by VA andor anatomical parametershellip

If patients are being treated according to a treat-and-extend regimen once maximum VA is achieved andor there are no

signs of disease activity the treatment intervals can be extended stepwise until signs of

disease activity or visual impairment recur The treatment intervalhellipmay be extended by up to one month

at a time for DMOrdquo

1 Novartis Pharmaceuticals UK Ltd 30 October 2014 Available at httpwwwmedicinesorgukemcmedicine19409 Accessed 04 September 2015

2 Bayer Pharma AG February 2015 Available at httpwwwmedicinesorgukemcmedicine27224 Accessed 04 September 2015

Ranibizumab1 Aflibercept2

ldquohelliptreatment is initiated with one injection per month for five consecutive doses followed by

one injection every two months There is no requirement for monitoring between injectionshellip

After the first 12 months of treatmenthellipthe treatment interval may be extended based

on visual andor anatomic outcomes The schedule for monitoring should

be determined by the treating physicianrdquo

DMO diabetic macular oedema VA visual acuity

Re-treatment algorithms for anti-VEGF agents in DMO

bull LOADING PHASE

bull Lucentis label = monthly until stability

bull Eylea label = 5 x 112 then every 8 weeks ie fixed regime year 1

bull DRCRnet protocol T = effectively 6 x112 for majority (95) BUT actually only mandated for first 3 months then prn

bull helliphellip likely that majority will receive injections monthly for first 6 months

bull INDIVIDUALISED PHASE

bull Once ldquostablerdquo ndash based on VA and OCT

bull NB May never get a ldquodryrdquo OCT so treat to stability

bull THEN

bull Treat and extend

bull prn

What does Treat and Extend mean

Pathway overview = Lucentis prn

Jan

Loading phase = injections every 4 weeks until ldquostablerdquo for 3 visits

helliphelliphellip

Feb OctSepAugJulJunMayAprMar

MarFebJan

DecNov

DecNovOctSepAugJulJunMayApr

Then observe UNTIL VA decreases or OCT increase = prn

Once reactivates need at least 2 injections until stable again over 3 visits

Pathway overview = Treat and Extend

Jan

Loading phase = injections every 4 weeks until ldquostablerdquo for 3 visits or Eyleayear 1

helliphelliphellip

Feb OctSepAugJulJunMayAprMar

MarFebJan

DecNov

DecNovOctSepAugJulJunMayApr

Then keep injecting but extend the interval between injections gradually ie keep treating even if perfect

If reactivates need at least 2 injections until stable again over 3 visits

Pathway overview = Eylea fixed dosing year 1

Jan

Eylea = 5 x 112 injection then every 8 weeks

Average 6 injections yr 2 Beyond that

helliphelliphellip

Feb OctSepAugJulJunMayAprMar

MarFebJan

DecNov

DecNovOctSepAugJulJunMayApr

Then individualised UNTIL VA decreases or OCT increase = prn

Once reactivates need at least 2 injections until stable again over 3 visits

Pros and cons of Treat and Extend vs Prn

T+E PRN

PROS bull Proactive patient and service get advance warning of injection ndash capacity and demand planning easier

bull One ndashstopbull Fewer visits than prnbull Overtreatment

advantageous for peripheral retinopathy

bull Only treated when active ieno overtreatment

bull Aggressive year 1 protocols (DRCRN I ndash few injections needed thereafter

bull DMO tolerant of reactivations ()

CONS bull Overtreatment = riskexpenseinconvenience

bull Evidence base scantbull Bilateral disease tricky

bull Reactive so need enoughemergency capacity to inject when disease flares up

bull No advance warning to patientservice that injection needed

bull NEED TO DO IT WELL ndashNHS real life audits prn based regimes not good resultsUndertreatment in year 1 Affects long term prognosis and treatment burden

Pros and cons of Treat and Extend vs Prn

T+E PRN

PROS bull Proactive patient and service get advance warning of injection ndash capacity and demand planning easier

bull One ndashstopbull Fewer visits than prnbull Overtreatment

advantageous for peripheral retinopathy

bull Only treated when active ieno overtreatment

bull Aggressive year 1 protocols (DRCRN I ndash few injections needed thereafter

bull DMO tolerant of reactivations ()

CONS bull Overtreatment = riskexpenseinconvenience

bull Evidence base scantbull Bilateral disease tricky

bull Reactive so need enoughemergency capacity to inject when disease flares up

bull No advance warning to patientservice that injection needed

bull NEED TO DO IT WELL ndashNHS real life audits prn based regimes not good resultsUndertreatment in year 1 Affects long term prognosis and treatment burden

DMO ndash anti-VEGF Treat and Extend

bull Retain study ndash the only RCT data

bull Br J Ophthalmol 2015 Oct 9 pii bjophthalmol-2015-307249 doi 101136bjophthalmol-2015-307249 [Epub ahead of print]

bull Ranibizumab 05 mg treat-and-extend regimen for diabetic macular oedema the RETAIN study

bull Pruumlnte C1 Fajnkuchen F2 Mahmood S3 Ricci F4 Hatz K5 Studnička J6 Bezlyak V7 Parikh S7 Stubbings WJ7 Wenzel A7 Figueira J8 and the RETAIN Study Group

RETAIN Phase III trial evaluating the efficacy of lsquotreat and extendrsquo regimen (ARVO 2014)

bull Patients with DMO and visual impairment (n = 372) were randomised 111

to one of three groups for 24 months

bull Two phases to dosing schedule

bull Phase A

bull Patients in all groups were initially treated with monthly ranibizumab until BCVA remained

stable

bull Phase B

bull Patients in the TampE groups whose vision remained stable had treatment- free intervals

that were increased incrementally by 1 month for a maximum of 3 months

bull Patients in the PRN group had ongoing monthly monitoring

bull In all groups Phase A was resumed if a decrease in BCVA was observed at a visit

Ranibizumab 05 mg monotherapy

in TampE regimen

Ranibizumab 05 mg in TampE regimen

plus laser

Ranibizumab 05 mg PRN

35

RETAIN Visual acuity endpoints

Pruumlnte C ARVO 2014 Annual Meeting Abstracts Abstract 1700

Mean average change in BCVAat 12 months (primary endpoint)

Mean change in BCVA at 24 months

Mea

n av

erag

e ch

ange

in B

CVA

(ETD

RS

lette

rs)

RanibizumabTampE

RanibizumabTampE + laser

RanibizumabPRN

RanibizumabTampE

RanibizumabTampE + laser

RanibizumabPRN

Mea

n ch

ange

in B

CVA

(ETD

RS

lette

rs)

plt00001 for both ranibizumab TampE groups versus PRN for primary endpoint

36

RETAIN Patient visits and monitoring with TampE regimen over 24 months

bull The TampE regimen provided an approximately 40 reduction in the number of treatment visits required compared with the ranibizumab PRN regimen

bull Approximately 70 of patients receiving TampE regimens had monitoring intervals ge2 months compared with ongoing monthly monitoring in the ranibizumab PRN group

bull Informed the license for Lucentis in DMO (extend by 1 month at a time)

37

INTRAVITREAL STEROIDSWhich intravitreal steroid is better

bull Licensed steroids ndash Ozurdex (Dexamethasone) and Iluvien (Fluocinoloneacetonide

bull Which steroid is best in terms of VA outcomes hellipWE DONrsquoT KNOW FOR SURE ndash no head to head studies for licensed drugs either between steroids or between anti-VEGF and steroids

bull STEROIDS ARE efficacious in DMO

bull MEAD

bull FAME

bull DRCRnet protocol I

bull NICE ndash Ozurdex and Iluvien ndash second-line agents

Ozurdex

bull A biodegradable co-polymer implant ndash degrades in time to lactic and glycolic acid releasing Dexamethasone

bull 22gauge injectionbull MEAD study

bull N=1048

bull Dex 07mg vs 035mg vs sham

bull No rescue therapy

bull 3 year follow up max 6 monthly dosing ie 7 over 3 years

Gan IM et al Greafes Acrh Clin Exp Ophthalmol 2005

MEAD studyMean BCVA change from baseline based on baseline lens status

-2

0

2

4

6

8

10

0 3 6 9 12 15 18 21 24 27 30 33 36 39

Mea

n C

hang

e Fr

om

Bas

elin

e B

CVA

(Let

ters

)

Month

DEX Implant 07 mg (n = 86)

Sham (n = 101)

Boyer DS et al Ophthalmology 20141211904ndash14

Results analyzed in the ITT population with LOCF for missing values

Pseudophakic

Total

0

5

10

0 3 6 9 12 15 18 21 24 27 30 33 36 39

DEX 700 (n=351)

Sham (n=350)

10

8

6

4

2

0

Mea

n C

hang

e fr

om

Bas

elin

e B

CVA

(Let

ters

)

Month

07mg dose is approved as Ozurdexreg by the FDA and EMA 035mg dose not commercially available

1 Boyer DS et al Ophthalmology 2014 121 1904-1914

bull Nonbioerodible micro implant (polyimide) containing 190microg of fluocinolone acetonide (FAc)

bull Consistent daily submicrogram delivery of 02 microgd FAc for up to 36 months

bull Posterior point of release

bull 35 mm times 037 mm non-bioerodable micro implant

bull 25-gauge injector creates self-sealing wound

bull No measurable systemic exposure

ILUVIEN Implant Technology

FAcimplant

ILUVIEN SPC httpwwwmedicinesorgukemcmedicine27636

0 6 12 18 24 30 36

ILUVIEN 02 microgd FAc(n = 376)05 microgd FAc (n = 395)Control sham injection(n = 185)

Design of Phase 3 FAME Study (FAME A and B = same protocol)

Additional laser therapy allowed after week 6a

Retreatment any time after month 12 (if eligibleb)

Study ends

N = 956Randomisation

221Primary readout

Patients with DMO and

bull At least 1 previous laser tx

bull BCVA ge19 and le68 letters

bull TD-OCT FTH ge250 μm

Month

BCVA = best corrected visual acuity DMO = diabetic macular oedema TD-OCT=time domain optical coherence tomography FTH = foveal thicknessa At masked investigatorrsquos discretion b If BCVA loss ge5 letters or retinal thickening ge50 microm from best reading in previous 12 months

ge15 letter Gain is Greater in Chronic DMO Patients

ge 15

-Let

ter I

mpr

ovem

ent

in B

CVA

Fro

m B

asel

ine

Δ = 98

Months

Full Population Patients With Chronic DMO

Months

Δ = 206

287

189134

34

Steroid re-treatments

bullOzurdexbull Longer half-life than anti-VEGF in the eye

bull Redosing regimes not very helpful from RCT data eg MEAD study only 612 dosing

bull In reality re-treatment interval may be shorter

bull POSOLOGY

bull Patients treated with OZURDEX who have experienced an initial response and in the physicians opinion may benefit from retreatment without being exposed to significant risk should be considered for retreatment Retreatment may be performed after approximately 6 months if the patient experiences decreased vision andor an increase in retinal thickness secondary to recurrent or worsening diabetic macular oedema

bullIluvienbull 70 of patients in FAE only needed 1

injection over 3 years

bull BUT additional rescue treatments allowed

bull POSOLOGY

bull Each ILUVIEN implant releases fluocinolone acetonide for up to 36 months An additional implant may be administered after 12 months if the patient experiences decreased vision or an increase in retinal thickness secondary to recurrent or worsening diabetic macular oedema

bull Patients receiving escape medication were exited from MEAD before administration1

bull Macular laser rescue treatment allowed in RISERIDE (Lucentisreg) from 3 months2

bull Focalgrid laser allowed in FAME (Iluvienreg) from 6 weeks3

MEAD TREATMENT PROTOCOL

bull First treatment given at randomisation (day 0) bull Patients assessed for retreatment eligibility every 3 months from

months 6ndash36bull Patients were eligible for retreatment if

OCT optical coherence tomography

ge6 months since most recent

study treatment

Retinal thickness in 1 mm central macular

subfield by OCT gt175 microm

Evidence of residual retinal oedema (intraretinal cysts or

any regions of increased retinal thickening) as assessed by

investigator from OCT

AND OR

MEA

D

Amendment in May 2010 revised anatomic criterion for retreatment before this time the threshold was gt225 microm1Boyer DS et al Ophthalmology 2014 121 1904-19142Nguyen QD et al Ophthalmology 20121191064minus10773Campochiaro PA et al Ophthalmology 2011118626ndash635

Treatment burdenILUVIEN

Control(n =112)

02 microgd FAc(n =209)

Study Treatments(sham injection or ILUVIEN 02 microgday or FAc 05microgday)

1 treatment 661 761

2 treatments 277 187

ge 3 treatments 63 53

Rescue Laser Treatments (at masked physicianrsquos discretion after week 6)

Patients 607 407

Off-Protocol Treatments (IVTA bevacizumab ranibizumab intravitreal dexamethasone)

Patients 295 115

OZURDEX = 23injections year 1 41 by year 3

No other Rx

Summary of side effects with intravitreal steroids

Drug device Evidence base Cataract risk IOP rise (requiring drops)

Glaucoma surgery

endophthalmitis

ILUVIEN FAME studies 80 cat surgery(273 sham)

384(14 control)

48 0

Ozurdex MEAD 592 had cataract surgery(72 sham)

215 (end of study)(34 sham)

06 0

Trivaris+ laser vs Luc+laserx2 vs laser

Protocol IOphthalmology 2010

15 42(ONE OFgt10mmHg risegt30mmHGStart drops)

2186 0

NICE guidance for intravitreal steroids in DMO

bull Iluvien

bull NICE TA 301 Iluvien for DMO Nov 2013

bull hellipfor treating chronic diabetic macular oedema that is insufficiently responsive to available therapies only if

bull the implant is to be used in an eye with an intraocular

(pseudophakic) lens and

bull the manufacturer provides fluocinolone acetonide intravitreal implant with the discount agreed in the patient access scheme

NICE guidance for intravitreal steroids in DMO

bull Ozurdex

bull NICE TA 349 Ozurdex for DMO July 2015

bull there is an artificial lens in the eye to be treated and

bull their diabetic macular oedema has not improved with

non-corticosteroid treatment or such treatment is not suitable for them

Steroids = second line therapyWhen do I switch

bull Anti-VEGF first line for centre involving DMObull NICE TA ndash ldquoinsufficiently responsiverdquo ldquo ldquonot improvedrdquo ldquonot suitablerdquo ndash

OTHER TREATMENTS

bull 2 scenariosbull 1) Anti-VEGF canrsquot be funded ie OCTlt400um + PSEUDOPHAKIC

bull 2) Already had a course of treatment with laseranti-VEGF + PSEUDOPHAKIC ie SWITCHING from anti-VEGF to steroid

bull Plus

bull ldquochronicrdquo DMO ndash 3 years duration in FAME (18months) for ILUVIEN

bull Chronic DMO not essential for Ozurdex

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

Protocol T ndash patients may not improve in first 6 months

RIDE

RISE

Mea

n ch

ange

in B

CVA

(E

TDR

S le

tters

)M

ean

chan

ge in

BC

VA

(ETD

RS

lette

rs)

Time (months)

RISE and RIDE (Lucentis monthly dosing) Mean change in BCVA over 36 months

Brown DM et al Ophthalmology 2013120(10)2013ndash2022

54

Ranibizumab 03 mgRanibizumab 05 mgShamranibizumab 05 mg

Date of Prep Dec 2014 LGB0820147252X

VA improvement continues throughout year 1 with monthly dosing

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user ndash more than protocol

I

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

DRCRN protocol I5 year outcomesInjections 8-9 in year 1Year 2 = 2-3Year 3= 1-2Year 4 = 0-1Year 5 = 0

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

Wait for plateau = stability in protocol T laserPatient factors again

Judgement of response to anti-VEGF ndashtimeframe

bull Wait 6 months in poor responders

bull Wait 1 year for heavy users

bull Tempting to try steroids earlier than this ifbull No glaucoma ndash not a deal breaker Ozurdex better short term optionbull Pseudophakic

bull Clues from the diseasebull chronic

bull PATIENT FACTORS

bull Any eyes avoid steroids ndash advanced glaucomaCSCR Or prior viral retinitis RARE

bull Any eyes avoid anti-VEGF pregnancytrying to concieve recent CVA

BIOMARKERS AT BASELINE WOULD BE USEFULRESTORE subgroup analysis of OCT features

bull Andreas Pollreisz EURETINA 2015

bull OCT biomarkers (RESTORE data)

bull Better effects with anti-VEGF ifbull Small rather than large intra-retinal cyst

bull Sub-retinal fluid present

bull Vitreo-macular adhesion at baseline

bull No disruption of ELM and ISOS junction

bull No disorganisation of inner retinal layers (DRIL)

RESTORE subgroup analysis of OCT features

bull Andreas Pollreisz EURETINA 2015

bull OCT biomarkers (RESTORE data)

bull Better effects with anti-VEGF ifbull Small rather than large intra-retinal cyst

bull Sub-retinal fluid present

bull Vitreo-macular adhesion at baseline

bull No disruption of ELM and ISOS junction

bull No disorganisation of inner retinal layers (DRIL)

Better baseline characterisationclassificationERG Contrast sensitivityOCT AngiographyMicroperimetry= clues as to who responds best to which drug

Plan for this presentation helliphellipa long list

bull What treatment options are available for DMO (evidence base)

bull What treatment should I start with at baselinebull Re-treatment algorithms for intravitreal DMO therapiesbull When should I switchcombine therapiesbull The bigger picture

bull Other eyebull The patient as a wholebull The service -coping with capacity ndash compromises

The bigger pictureOther eyeThe patient as a wholeThe service -coping with capacity ndash compromises

bull OTHER EYE ndash may create problems

bull Treat and extend ndash ldquoreduce of visitsrdquo plus Eylea license ndash ldquono need for monitoringrdquo may not benefit if lots of visits due to PDR other eye

bull PERIPHERAL RETINA anti-VEGF supresses proliferative disease - Rebound on stopping Rx

bull PATIENT

bull Anti-VEGF ndash heavy user - Will comply

bull One stop much better than two stop for patient ndash Treat and extend

bull SERVICE

bull Capacity and demand planning = fixedT+E more predictable at least 1 month in advance ndash flexible nurse injectors

bull Steroids ndash even if well controlled (Iluvien for 3 years) need IOP check

bull Need pan-retinal examination both eyes ndash separate visits

Summary

CSMO

No centre involvement

Photocoagulation

Centre involvement

gt 78 letters(normalminimally reduced VA)

Photocoagulation

VA 78ndash24 letters

Phakic

Anti-VEGF

Pseudophakic

Anti-VEGF

SWITCHglaucoma

Injection tolerance

Medical issuesrecent CVA

Peripheral diseaseBilateral Rx

CSMO

No centre involvement

LASER

Centre involvement

gt 78 letters(normalminimally

reduced VA)

VA 78ndash24 letters

EYLEA OR LUCENTIS OR AVASTIN

Funding issues

Protocol T ndash poor VA lt 65 letters (615)

LOADING

Monthly injections until stability OR 5 x 112 (EYLEA) = 6 MONTHS then 8 weeks

RETREATMENT1

TREAT AND EXTEND - PRN

PRN

PSEUDOPHAKIC

Prior Rx

ILUVIEN

Chronic disease

OZURDEX

RETREATMENT

OZURDEX

OCT gt175um or any residual oedema

ILUVIEN after 12 months if risksltbenefits

OCT

gt400um

bull FACE TO FACE CLINICS RUNNING IN PARALLEL

bull = MAC002 every 6 months (optom or doctor) routine check for cataracttolerance of injectionsglaucoma issues etc

bull =MAC003 (DOCTOR) for problems as needed no fixed intervalDischargestop treatmentDeclines treatment diagnosis CSR overlay etcswitch drugs

bull =RV002- (DOCTOR) every 6 months

bull =DM002 ndash (DOCTOR) variable interval determined by last assessing doctor

bull First visit at 6 months from 1st injection if mild NPDR

bull Otherwise determined by retinopathy generally

LOADING PHASE

EyleaLucentis 1 within 48hrs of baseline

EyleaLucentis 2 (and LogMAR VA plus OCT same visit)

EyleaLucentis 3 (and LogMAR VA plus OCT same visit)

EyleaLucentis 4 (TEinj)(and Logmar VA plus OCT same visit

AFTER INJECTION 4 data goes off to be reviewed immediately as a hellip

TREAT AND EXTEND assessment ndash the next interval will depend on the response to the loading phase

NB -DMO patients ndash majority (95) will need 6 injctions x 112 of Lucentis

OR Eylea 5 x 112 then 8 weekly

ONCE STABLE for 3 x injection in TE phase

VIRTUAL CLINIC MONITORING OF MACULOPATHY AND PRN RETREATMENT

ANTI-VEGF INJECTION PATHWAYS Baseline visitMAC001 for wet AMDRV001 for CRVOBRVOMed ret clinic for DMO

Pathways ndash too many directions

Better that thanhellip

Thank you

Protocol T OCT outcomes year 1

-250

-200

-150

-100

-50

0

0 4 8 12 16 20 24 28 32 36 40 44 48 52

Visit Week

Aflibercept Bevacizumab Ranibizumab

Mea

n ch

ange

in C

ST

Conclusions ndash Protocol T year 1 data

bull Eylea was statistically superior in terms of visual acuity to 03mg Lucentisand to Avastin FOR PATIENTS WITH VA worse than 69 letters

bull Eylea and Lucentis were statistically superior in terms of OCT CRT reduction to Avastin for all patients regardless of baseline vision

bull No safety differences between the three drugs

SUMMARY What do I choose for my patient at baselineOCT central retinal thickness (CRT)PseudophakicAttempts at prior treatment duration of DMO

bull lt 400um

bull IFR licensed anti-VEGF or Avastin

+-ETDRS laser

PSEUDOPHAKIC

Iluvien

Ozurdex

bull gt 400um = Anti-VEGF

Which one

Depends on

bull baseline vision lt615 Eylea

bull Fixed dosing attractive (Eylea)bull Chronic DMO

bull PSEUDOPHAKICbull Patients ldquoinsufficiently

responsive to existing therapiesrdquo

bull ldquoNot improved with non-corticosteroid or such treatment is not suitable for themrdquo

Which steroid ndash Ozurdex or Iluvien

bull No head to head data

bull Revisit this when we think about switching from ANTI-VEGF to steroid

Assuming we have started with an anti-VEGF agent ndash what are the re-treatment algorithms in DMO

Treatment posologies

ldquoTreatment is initiated with one injection per month until maximum VA is achieved andor there are no signs of disease activity ie no change in VA and in other signs and

symptoms of the disease under continued treatment

In patients withhellipDMOhellip initially three or more consecutive monthly injections may be needed Thereafter monitoring and treatment intervals

should be determined by the physician and should be based on disease activity as

assessed by VA andor anatomical parametershellip

If patients are being treated according to a treat-and-extend regimen once maximum VA is achieved andor there are no

signs of disease activity the treatment intervals can be extended stepwise until signs of

disease activity or visual impairment recur The treatment intervalhellipmay be extended by up to one month

at a time for DMOrdquo

1 Novartis Pharmaceuticals UK Ltd 30 October 2014 Available at httpwwwmedicinesorgukemcmedicine19409 Accessed 04 September 2015

2 Bayer Pharma AG February 2015 Available at httpwwwmedicinesorgukemcmedicine27224 Accessed 04 September 2015

Ranibizumab1 Aflibercept2

ldquohelliptreatment is initiated with one injection per month for five consecutive doses followed by

one injection every two months There is no requirement for monitoring between injectionshellip

After the first 12 months of treatmenthellipthe treatment interval may be extended based

on visual andor anatomic outcomes The schedule for monitoring should

be determined by the treating physicianrdquo

DMO diabetic macular oedema VA visual acuity

Re-treatment algorithms for anti-VEGF agents in DMO

bull LOADING PHASE

bull Lucentis label = monthly until stability

bull Eylea label = 5 x 112 then every 8 weeks ie fixed regime year 1

bull DRCRnet protocol T = effectively 6 x112 for majority (95) BUT actually only mandated for first 3 months then prn

bull helliphellip likely that majority will receive injections monthly for first 6 months

bull INDIVIDUALISED PHASE

bull Once ldquostablerdquo ndash based on VA and OCT

bull NB May never get a ldquodryrdquo OCT so treat to stability

bull THEN

bull Treat and extend

bull prn

What does Treat and Extend mean

Pathway overview = Lucentis prn

Jan

Loading phase = injections every 4 weeks until ldquostablerdquo for 3 visits

helliphelliphellip

Feb OctSepAugJulJunMayAprMar

MarFebJan

DecNov

DecNovOctSepAugJulJunMayApr

Then observe UNTIL VA decreases or OCT increase = prn

Once reactivates need at least 2 injections until stable again over 3 visits

Pathway overview = Treat and Extend

Jan

Loading phase = injections every 4 weeks until ldquostablerdquo for 3 visits or Eyleayear 1

helliphelliphellip

Feb OctSepAugJulJunMayAprMar

MarFebJan

DecNov

DecNovOctSepAugJulJunMayApr

Then keep injecting but extend the interval between injections gradually ie keep treating even if perfect

If reactivates need at least 2 injections until stable again over 3 visits

Pathway overview = Eylea fixed dosing year 1

Jan

Eylea = 5 x 112 injection then every 8 weeks

Average 6 injections yr 2 Beyond that

helliphelliphellip

Feb OctSepAugJulJunMayAprMar

MarFebJan

DecNov

DecNovOctSepAugJulJunMayApr

Then individualised UNTIL VA decreases or OCT increase = prn

Once reactivates need at least 2 injections until stable again over 3 visits

Pros and cons of Treat and Extend vs Prn

T+E PRN

PROS bull Proactive patient and service get advance warning of injection ndash capacity and demand planning easier

bull One ndashstopbull Fewer visits than prnbull Overtreatment

advantageous for peripheral retinopathy

bull Only treated when active ieno overtreatment

bull Aggressive year 1 protocols (DRCRN I ndash few injections needed thereafter

bull DMO tolerant of reactivations ()

CONS bull Overtreatment = riskexpenseinconvenience

bull Evidence base scantbull Bilateral disease tricky

bull Reactive so need enoughemergency capacity to inject when disease flares up

bull No advance warning to patientservice that injection needed

bull NEED TO DO IT WELL ndashNHS real life audits prn based regimes not good resultsUndertreatment in year 1 Affects long term prognosis and treatment burden

Pros and cons of Treat and Extend vs Prn

T+E PRN

PROS bull Proactive patient and service get advance warning of injection ndash capacity and demand planning easier

bull One ndashstopbull Fewer visits than prnbull Overtreatment

advantageous for peripheral retinopathy

bull Only treated when active ieno overtreatment

bull Aggressive year 1 protocols (DRCRN I ndash few injections needed thereafter

bull DMO tolerant of reactivations ()

CONS bull Overtreatment = riskexpenseinconvenience

bull Evidence base scantbull Bilateral disease tricky

bull Reactive so need enoughemergency capacity to inject when disease flares up

bull No advance warning to patientservice that injection needed

bull NEED TO DO IT WELL ndashNHS real life audits prn based regimes not good resultsUndertreatment in year 1 Affects long term prognosis and treatment burden

DMO ndash anti-VEGF Treat and Extend

bull Retain study ndash the only RCT data

bull Br J Ophthalmol 2015 Oct 9 pii bjophthalmol-2015-307249 doi 101136bjophthalmol-2015-307249 [Epub ahead of print]

bull Ranibizumab 05 mg treat-and-extend regimen for diabetic macular oedema the RETAIN study

bull Pruumlnte C1 Fajnkuchen F2 Mahmood S3 Ricci F4 Hatz K5 Studnička J6 Bezlyak V7 Parikh S7 Stubbings WJ7 Wenzel A7 Figueira J8 and the RETAIN Study Group

RETAIN Phase III trial evaluating the efficacy of lsquotreat and extendrsquo regimen (ARVO 2014)

bull Patients with DMO and visual impairment (n = 372) were randomised 111

to one of three groups for 24 months

bull Two phases to dosing schedule

bull Phase A

bull Patients in all groups were initially treated with monthly ranibizumab until BCVA remained

stable

bull Phase B

bull Patients in the TampE groups whose vision remained stable had treatment- free intervals

that were increased incrementally by 1 month for a maximum of 3 months

bull Patients in the PRN group had ongoing monthly monitoring

bull In all groups Phase A was resumed if a decrease in BCVA was observed at a visit

Ranibizumab 05 mg monotherapy

in TampE regimen

Ranibizumab 05 mg in TampE regimen

plus laser

Ranibizumab 05 mg PRN

35

RETAIN Visual acuity endpoints

Pruumlnte C ARVO 2014 Annual Meeting Abstracts Abstract 1700

Mean average change in BCVAat 12 months (primary endpoint)

Mean change in BCVA at 24 months

Mea

n av

erag

e ch

ange

in B

CVA

(ETD

RS

lette

rs)

RanibizumabTampE

RanibizumabTampE + laser

RanibizumabPRN

RanibizumabTampE

RanibizumabTampE + laser

RanibizumabPRN

Mea

n ch

ange

in B

CVA

(ETD

RS

lette

rs)

plt00001 for both ranibizumab TampE groups versus PRN for primary endpoint

36

RETAIN Patient visits and monitoring with TampE regimen over 24 months

bull The TampE regimen provided an approximately 40 reduction in the number of treatment visits required compared with the ranibizumab PRN regimen

bull Approximately 70 of patients receiving TampE regimens had monitoring intervals ge2 months compared with ongoing monthly monitoring in the ranibizumab PRN group

bull Informed the license for Lucentis in DMO (extend by 1 month at a time)

37

INTRAVITREAL STEROIDSWhich intravitreal steroid is better

bull Licensed steroids ndash Ozurdex (Dexamethasone) and Iluvien (Fluocinoloneacetonide

bull Which steroid is best in terms of VA outcomes hellipWE DONrsquoT KNOW FOR SURE ndash no head to head studies for licensed drugs either between steroids or between anti-VEGF and steroids

bull STEROIDS ARE efficacious in DMO

bull MEAD

bull FAME

bull DRCRnet protocol I

bull NICE ndash Ozurdex and Iluvien ndash second-line agents

Ozurdex

bull A biodegradable co-polymer implant ndash degrades in time to lactic and glycolic acid releasing Dexamethasone

bull 22gauge injectionbull MEAD study

bull N=1048

bull Dex 07mg vs 035mg vs sham

bull No rescue therapy

bull 3 year follow up max 6 monthly dosing ie 7 over 3 years

Gan IM et al Greafes Acrh Clin Exp Ophthalmol 2005

MEAD studyMean BCVA change from baseline based on baseline lens status

-2

0

2

4

6

8

10

0 3 6 9 12 15 18 21 24 27 30 33 36 39

Mea

n C

hang

e Fr

om

Bas

elin

e B

CVA

(Let

ters

)

Month

DEX Implant 07 mg (n = 86)

Sham (n = 101)

Boyer DS et al Ophthalmology 20141211904ndash14

Results analyzed in the ITT population with LOCF for missing values

Pseudophakic

Total

0

5

10

0 3 6 9 12 15 18 21 24 27 30 33 36 39

DEX 700 (n=351)

Sham (n=350)

10

8

6

4

2

0

Mea

n C

hang

e fr

om

Bas

elin

e B

CVA

(Let

ters

)

Month

07mg dose is approved as Ozurdexreg by the FDA and EMA 035mg dose not commercially available

1 Boyer DS et al Ophthalmology 2014 121 1904-1914

bull Nonbioerodible micro implant (polyimide) containing 190microg of fluocinolone acetonide (FAc)

bull Consistent daily submicrogram delivery of 02 microgd FAc for up to 36 months

bull Posterior point of release

bull 35 mm times 037 mm non-bioerodable micro implant

bull 25-gauge injector creates self-sealing wound

bull No measurable systemic exposure

ILUVIEN Implant Technology

FAcimplant

ILUVIEN SPC httpwwwmedicinesorgukemcmedicine27636

0 6 12 18 24 30 36

ILUVIEN 02 microgd FAc(n = 376)05 microgd FAc (n = 395)Control sham injection(n = 185)

Design of Phase 3 FAME Study (FAME A and B = same protocol)

Additional laser therapy allowed after week 6a

Retreatment any time after month 12 (if eligibleb)

Study ends

N = 956Randomisation

221Primary readout

Patients with DMO and

bull At least 1 previous laser tx

bull BCVA ge19 and le68 letters

bull TD-OCT FTH ge250 μm

Month

BCVA = best corrected visual acuity DMO = diabetic macular oedema TD-OCT=time domain optical coherence tomography FTH = foveal thicknessa At masked investigatorrsquos discretion b If BCVA loss ge5 letters or retinal thickening ge50 microm from best reading in previous 12 months

ge15 letter Gain is Greater in Chronic DMO Patients

ge 15

-Let

ter I

mpr

ovem

ent

in B

CVA

Fro

m B

asel

ine

Δ = 98

Months

Full Population Patients With Chronic DMO

Months

Δ = 206

287

189134

34

Steroid re-treatments

bullOzurdexbull Longer half-life than anti-VEGF in the eye

bull Redosing regimes not very helpful from RCT data eg MEAD study only 612 dosing

bull In reality re-treatment interval may be shorter

bull POSOLOGY

bull Patients treated with OZURDEX who have experienced an initial response and in the physicians opinion may benefit from retreatment without being exposed to significant risk should be considered for retreatment Retreatment may be performed after approximately 6 months if the patient experiences decreased vision andor an increase in retinal thickness secondary to recurrent or worsening diabetic macular oedema

bullIluvienbull 70 of patients in FAE only needed 1

injection over 3 years

bull BUT additional rescue treatments allowed

bull POSOLOGY

bull Each ILUVIEN implant releases fluocinolone acetonide for up to 36 months An additional implant may be administered after 12 months if the patient experiences decreased vision or an increase in retinal thickness secondary to recurrent or worsening diabetic macular oedema

bull Patients receiving escape medication were exited from MEAD before administration1

bull Macular laser rescue treatment allowed in RISERIDE (Lucentisreg) from 3 months2

bull Focalgrid laser allowed in FAME (Iluvienreg) from 6 weeks3

MEAD TREATMENT PROTOCOL

bull First treatment given at randomisation (day 0) bull Patients assessed for retreatment eligibility every 3 months from

months 6ndash36bull Patients were eligible for retreatment if

OCT optical coherence tomography

ge6 months since most recent

study treatment

Retinal thickness in 1 mm central macular

subfield by OCT gt175 microm

Evidence of residual retinal oedema (intraretinal cysts or

any regions of increased retinal thickening) as assessed by

investigator from OCT

AND OR

MEA

D

Amendment in May 2010 revised anatomic criterion for retreatment before this time the threshold was gt225 microm1Boyer DS et al Ophthalmology 2014 121 1904-19142Nguyen QD et al Ophthalmology 20121191064minus10773Campochiaro PA et al Ophthalmology 2011118626ndash635

Treatment burdenILUVIEN

Control(n =112)

02 microgd FAc(n =209)

Study Treatments(sham injection or ILUVIEN 02 microgday or FAc 05microgday)

1 treatment 661 761

2 treatments 277 187

ge 3 treatments 63 53

Rescue Laser Treatments (at masked physicianrsquos discretion after week 6)

Patients 607 407

Off-Protocol Treatments (IVTA bevacizumab ranibizumab intravitreal dexamethasone)

Patients 295 115

OZURDEX = 23injections year 1 41 by year 3

No other Rx

Summary of side effects with intravitreal steroids

Drug device Evidence base Cataract risk IOP rise (requiring drops)

Glaucoma surgery

endophthalmitis

ILUVIEN FAME studies 80 cat surgery(273 sham)

384(14 control)

48 0

Ozurdex MEAD 592 had cataract surgery(72 sham)

215 (end of study)(34 sham)

06 0

Trivaris+ laser vs Luc+laserx2 vs laser

Protocol IOphthalmology 2010

15 42(ONE OFgt10mmHg risegt30mmHGStart drops)

2186 0

NICE guidance for intravitreal steroids in DMO

bull Iluvien

bull NICE TA 301 Iluvien for DMO Nov 2013

bull hellipfor treating chronic diabetic macular oedema that is insufficiently responsive to available therapies only if

bull the implant is to be used in an eye with an intraocular

(pseudophakic) lens and

bull the manufacturer provides fluocinolone acetonide intravitreal implant with the discount agreed in the patient access scheme

NICE guidance for intravitreal steroids in DMO

bull Ozurdex

bull NICE TA 349 Ozurdex for DMO July 2015

bull there is an artificial lens in the eye to be treated and

bull their diabetic macular oedema has not improved with

non-corticosteroid treatment or such treatment is not suitable for them

Steroids = second line therapyWhen do I switch

bull Anti-VEGF first line for centre involving DMObull NICE TA ndash ldquoinsufficiently responsiverdquo ldquo ldquonot improvedrdquo ldquonot suitablerdquo ndash

OTHER TREATMENTS

bull 2 scenariosbull 1) Anti-VEGF canrsquot be funded ie OCTlt400um + PSEUDOPHAKIC

bull 2) Already had a course of treatment with laseranti-VEGF + PSEUDOPHAKIC ie SWITCHING from anti-VEGF to steroid

bull Plus

bull ldquochronicrdquo DMO ndash 3 years duration in FAME (18months) for ILUVIEN

bull Chronic DMO not essential for Ozurdex

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

Protocol T ndash patients may not improve in first 6 months

RIDE

RISE

Mea

n ch

ange

in B

CVA

(E

TDR

S le

tters

)M

ean

chan

ge in

BC

VA

(ETD

RS

lette

rs)

Time (months)

RISE and RIDE (Lucentis monthly dosing) Mean change in BCVA over 36 months

Brown DM et al Ophthalmology 2013120(10)2013ndash2022

54

Ranibizumab 03 mgRanibizumab 05 mgShamranibizumab 05 mg

Date of Prep Dec 2014 LGB0820147252X

VA improvement continues throughout year 1 with monthly dosing

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user ndash more than protocol

I

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

DRCRN protocol I5 year outcomesInjections 8-9 in year 1Year 2 = 2-3Year 3= 1-2Year 4 = 0-1Year 5 = 0

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

Wait for plateau = stability in protocol T laserPatient factors again

Judgement of response to anti-VEGF ndashtimeframe

bull Wait 6 months in poor responders

bull Wait 1 year for heavy users

bull Tempting to try steroids earlier than this ifbull No glaucoma ndash not a deal breaker Ozurdex better short term optionbull Pseudophakic

bull Clues from the diseasebull chronic

bull PATIENT FACTORS

bull Any eyes avoid steroids ndash advanced glaucomaCSCR Or prior viral retinitis RARE

bull Any eyes avoid anti-VEGF pregnancytrying to concieve recent CVA

BIOMARKERS AT BASELINE WOULD BE USEFULRESTORE subgroup analysis of OCT features

bull Andreas Pollreisz EURETINA 2015

bull OCT biomarkers (RESTORE data)

bull Better effects with anti-VEGF ifbull Small rather than large intra-retinal cyst

bull Sub-retinal fluid present

bull Vitreo-macular adhesion at baseline

bull No disruption of ELM and ISOS junction

bull No disorganisation of inner retinal layers (DRIL)

RESTORE subgroup analysis of OCT features

bull Andreas Pollreisz EURETINA 2015

bull OCT biomarkers (RESTORE data)

bull Better effects with anti-VEGF ifbull Small rather than large intra-retinal cyst

bull Sub-retinal fluid present

bull Vitreo-macular adhesion at baseline

bull No disruption of ELM and ISOS junction

bull No disorganisation of inner retinal layers (DRIL)

Better baseline characterisationclassificationERG Contrast sensitivityOCT AngiographyMicroperimetry= clues as to who responds best to which drug

Plan for this presentation helliphellipa long list

bull What treatment options are available for DMO (evidence base)

bull What treatment should I start with at baselinebull Re-treatment algorithms for intravitreal DMO therapiesbull When should I switchcombine therapiesbull The bigger picture

bull Other eyebull The patient as a wholebull The service -coping with capacity ndash compromises

The bigger pictureOther eyeThe patient as a wholeThe service -coping with capacity ndash compromises

bull OTHER EYE ndash may create problems

bull Treat and extend ndash ldquoreduce of visitsrdquo plus Eylea license ndash ldquono need for monitoringrdquo may not benefit if lots of visits due to PDR other eye

bull PERIPHERAL RETINA anti-VEGF supresses proliferative disease - Rebound on stopping Rx

bull PATIENT

bull Anti-VEGF ndash heavy user - Will comply

bull One stop much better than two stop for patient ndash Treat and extend

bull SERVICE

bull Capacity and demand planning = fixedT+E more predictable at least 1 month in advance ndash flexible nurse injectors

bull Steroids ndash even if well controlled (Iluvien for 3 years) need IOP check

bull Need pan-retinal examination both eyes ndash separate visits

Summary

CSMO

No centre involvement

Photocoagulation

Centre involvement

gt 78 letters(normalminimally reduced VA)

Photocoagulation

VA 78ndash24 letters

Phakic

Anti-VEGF

Pseudophakic

Anti-VEGF

SWITCHglaucoma

Injection tolerance

Medical issuesrecent CVA

Peripheral diseaseBilateral Rx

CSMO

No centre involvement

LASER

Centre involvement

gt 78 letters(normalminimally

reduced VA)

VA 78ndash24 letters

EYLEA OR LUCENTIS OR AVASTIN

Funding issues

Protocol T ndash poor VA lt 65 letters (615)

LOADING

Monthly injections until stability OR 5 x 112 (EYLEA) = 6 MONTHS then 8 weeks

RETREATMENT1

TREAT AND EXTEND - PRN

PRN

PSEUDOPHAKIC

Prior Rx

ILUVIEN

Chronic disease

OZURDEX

RETREATMENT

OZURDEX

OCT gt175um or any residual oedema

ILUVIEN after 12 months if risksltbenefits

OCT

gt400um

bull FACE TO FACE CLINICS RUNNING IN PARALLEL

bull = MAC002 every 6 months (optom or doctor) routine check for cataracttolerance of injectionsglaucoma issues etc

bull =MAC003 (DOCTOR) for problems as needed no fixed intervalDischargestop treatmentDeclines treatment diagnosis CSR overlay etcswitch drugs

bull =RV002- (DOCTOR) every 6 months

bull =DM002 ndash (DOCTOR) variable interval determined by last assessing doctor

bull First visit at 6 months from 1st injection if mild NPDR

bull Otherwise determined by retinopathy generally

LOADING PHASE

EyleaLucentis 1 within 48hrs of baseline

EyleaLucentis 2 (and LogMAR VA plus OCT same visit)

EyleaLucentis 3 (and LogMAR VA plus OCT same visit)

EyleaLucentis 4 (TEinj)(and Logmar VA plus OCT same visit

AFTER INJECTION 4 data goes off to be reviewed immediately as a hellip

TREAT AND EXTEND assessment ndash the next interval will depend on the response to the loading phase

NB -DMO patients ndash majority (95) will need 6 injctions x 112 of Lucentis

OR Eylea 5 x 112 then 8 weekly

ONCE STABLE for 3 x injection in TE phase

VIRTUAL CLINIC MONITORING OF MACULOPATHY AND PRN RETREATMENT

ANTI-VEGF INJECTION PATHWAYS Baseline visitMAC001 for wet AMDRV001 for CRVOBRVOMed ret clinic for DMO

Pathways ndash too many directions

Better that thanhellip

Thank you

Conclusions ndash Protocol T year 1 data

bull Eylea was statistically superior in terms of visual acuity to 03mg Lucentisand to Avastin FOR PATIENTS WITH VA worse than 69 letters

bull Eylea and Lucentis were statistically superior in terms of OCT CRT reduction to Avastin for all patients regardless of baseline vision

bull No safety differences between the three drugs

SUMMARY What do I choose for my patient at baselineOCT central retinal thickness (CRT)PseudophakicAttempts at prior treatment duration of DMO

bull lt 400um

bull IFR licensed anti-VEGF or Avastin

+-ETDRS laser

PSEUDOPHAKIC

Iluvien

Ozurdex

bull gt 400um = Anti-VEGF

Which one

Depends on

bull baseline vision lt615 Eylea

bull Fixed dosing attractive (Eylea)bull Chronic DMO

bull PSEUDOPHAKICbull Patients ldquoinsufficiently

responsive to existing therapiesrdquo

bull ldquoNot improved with non-corticosteroid or such treatment is not suitable for themrdquo

Which steroid ndash Ozurdex or Iluvien

bull No head to head data

bull Revisit this when we think about switching from ANTI-VEGF to steroid

Assuming we have started with an anti-VEGF agent ndash what are the re-treatment algorithms in DMO

Treatment posologies

ldquoTreatment is initiated with one injection per month until maximum VA is achieved andor there are no signs of disease activity ie no change in VA and in other signs and

symptoms of the disease under continued treatment

In patients withhellipDMOhellip initially three or more consecutive monthly injections may be needed Thereafter monitoring and treatment intervals

should be determined by the physician and should be based on disease activity as

assessed by VA andor anatomical parametershellip

If patients are being treated according to a treat-and-extend regimen once maximum VA is achieved andor there are no

signs of disease activity the treatment intervals can be extended stepwise until signs of

disease activity or visual impairment recur The treatment intervalhellipmay be extended by up to one month

at a time for DMOrdquo

1 Novartis Pharmaceuticals UK Ltd 30 October 2014 Available at httpwwwmedicinesorgukemcmedicine19409 Accessed 04 September 2015

2 Bayer Pharma AG February 2015 Available at httpwwwmedicinesorgukemcmedicine27224 Accessed 04 September 2015

Ranibizumab1 Aflibercept2

ldquohelliptreatment is initiated with one injection per month for five consecutive doses followed by

one injection every two months There is no requirement for monitoring between injectionshellip

After the first 12 months of treatmenthellipthe treatment interval may be extended based

on visual andor anatomic outcomes The schedule for monitoring should

be determined by the treating physicianrdquo

DMO diabetic macular oedema VA visual acuity

Re-treatment algorithms for anti-VEGF agents in DMO

bull LOADING PHASE

bull Lucentis label = monthly until stability

bull Eylea label = 5 x 112 then every 8 weeks ie fixed regime year 1

bull DRCRnet protocol T = effectively 6 x112 for majority (95) BUT actually only mandated for first 3 months then prn

bull helliphellip likely that majority will receive injections monthly for first 6 months

bull INDIVIDUALISED PHASE

bull Once ldquostablerdquo ndash based on VA and OCT

bull NB May never get a ldquodryrdquo OCT so treat to stability

bull THEN

bull Treat and extend

bull prn

What does Treat and Extend mean

Pathway overview = Lucentis prn

Jan

Loading phase = injections every 4 weeks until ldquostablerdquo for 3 visits

helliphelliphellip

Feb OctSepAugJulJunMayAprMar

MarFebJan

DecNov

DecNovOctSepAugJulJunMayApr

Then observe UNTIL VA decreases or OCT increase = prn

Once reactivates need at least 2 injections until stable again over 3 visits

Pathway overview = Treat and Extend

Jan

Loading phase = injections every 4 weeks until ldquostablerdquo for 3 visits or Eyleayear 1

helliphelliphellip

Feb OctSepAugJulJunMayAprMar

MarFebJan

DecNov

DecNovOctSepAugJulJunMayApr

Then keep injecting but extend the interval between injections gradually ie keep treating even if perfect

If reactivates need at least 2 injections until stable again over 3 visits

Pathway overview = Eylea fixed dosing year 1

Jan

Eylea = 5 x 112 injection then every 8 weeks

Average 6 injections yr 2 Beyond that

helliphelliphellip

Feb OctSepAugJulJunMayAprMar

MarFebJan

DecNov

DecNovOctSepAugJulJunMayApr

Then individualised UNTIL VA decreases or OCT increase = prn

Once reactivates need at least 2 injections until stable again over 3 visits

Pros and cons of Treat and Extend vs Prn

T+E PRN

PROS bull Proactive patient and service get advance warning of injection ndash capacity and demand planning easier

bull One ndashstopbull Fewer visits than prnbull Overtreatment

advantageous for peripheral retinopathy

bull Only treated when active ieno overtreatment

bull Aggressive year 1 protocols (DRCRN I ndash few injections needed thereafter

bull DMO tolerant of reactivations ()

CONS bull Overtreatment = riskexpenseinconvenience

bull Evidence base scantbull Bilateral disease tricky

bull Reactive so need enoughemergency capacity to inject when disease flares up

bull No advance warning to patientservice that injection needed

bull NEED TO DO IT WELL ndashNHS real life audits prn based regimes not good resultsUndertreatment in year 1 Affects long term prognosis and treatment burden

Pros and cons of Treat and Extend vs Prn

T+E PRN

PROS bull Proactive patient and service get advance warning of injection ndash capacity and demand planning easier

bull One ndashstopbull Fewer visits than prnbull Overtreatment

advantageous for peripheral retinopathy

bull Only treated when active ieno overtreatment

bull Aggressive year 1 protocols (DRCRN I ndash few injections needed thereafter

bull DMO tolerant of reactivations ()

CONS bull Overtreatment = riskexpenseinconvenience

bull Evidence base scantbull Bilateral disease tricky

bull Reactive so need enoughemergency capacity to inject when disease flares up

bull No advance warning to patientservice that injection needed

bull NEED TO DO IT WELL ndashNHS real life audits prn based regimes not good resultsUndertreatment in year 1 Affects long term prognosis and treatment burden

DMO ndash anti-VEGF Treat and Extend

bull Retain study ndash the only RCT data

bull Br J Ophthalmol 2015 Oct 9 pii bjophthalmol-2015-307249 doi 101136bjophthalmol-2015-307249 [Epub ahead of print]

bull Ranibizumab 05 mg treat-and-extend regimen for diabetic macular oedema the RETAIN study

bull Pruumlnte C1 Fajnkuchen F2 Mahmood S3 Ricci F4 Hatz K5 Studnička J6 Bezlyak V7 Parikh S7 Stubbings WJ7 Wenzel A7 Figueira J8 and the RETAIN Study Group

RETAIN Phase III trial evaluating the efficacy of lsquotreat and extendrsquo regimen (ARVO 2014)

bull Patients with DMO and visual impairment (n = 372) were randomised 111

to one of three groups for 24 months

bull Two phases to dosing schedule

bull Phase A

bull Patients in all groups were initially treated with monthly ranibizumab until BCVA remained

stable

bull Phase B

bull Patients in the TampE groups whose vision remained stable had treatment- free intervals

that were increased incrementally by 1 month for a maximum of 3 months

bull Patients in the PRN group had ongoing monthly monitoring

bull In all groups Phase A was resumed if a decrease in BCVA was observed at a visit

Ranibizumab 05 mg monotherapy

in TampE regimen

Ranibizumab 05 mg in TampE regimen

plus laser

Ranibizumab 05 mg PRN

35

RETAIN Visual acuity endpoints

Pruumlnte C ARVO 2014 Annual Meeting Abstracts Abstract 1700

Mean average change in BCVAat 12 months (primary endpoint)

Mean change in BCVA at 24 months

Mea

n av

erag

e ch

ange

in B

CVA

(ETD

RS

lette

rs)

RanibizumabTampE

RanibizumabTampE + laser

RanibizumabPRN

RanibizumabTampE

RanibizumabTampE + laser

RanibizumabPRN

Mea

n ch

ange

in B

CVA

(ETD

RS

lette

rs)

plt00001 for both ranibizumab TampE groups versus PRN for primary endpoint

36

RETAIN Patient visits and monitoring with TampE regimen over 24 months

bull The TampE regimen provided an approximately 40 reduction in the number of treatment visits required compared with the ranibizumab PRN regimen

bull Approximately 70 of patients receiving TampE regimens had monitoring intervals ge2 months compared with ongoing monthly monitoring in the ranibizumab PRN group

bull Informed the license for Lucentis in DMO (extend by 1 month at a time)

37

INTRAVITREAL STEROIDSWhich intravitreal steroid is better

bull Licensed steroids ndash Ozurdex (Dexamethasone) and Iluvien (Fluocinoloneacetonide

bull Which steroid is best in terms of VA outcomes hellipWE DONrsquoT KNOW FOR SURE ndash no head to head studies for licensed drugs either between steroids or between anti-VEGF and steroids

bull STEROIDS ARE efficacious in DMO

bull MEAD

bull FAME

bull DRCRnet protocol I

bull NICE ndash Ozurdex and Iluvien ndash second-line agents

Ozurdex

bull A biodegradable co-polymer implant ndash degrades in time to lactic and glycolic acid releasing Dexamethasone

bull 22gauge injectionbull MEAD study

bull N=1048

bull Dex 07mg vs 035mg vs sham

bull No rescue therapy

bull 3 year follow up max 6 monthly dosing ie 7 over 3 years

Gan IM et al Greafes Acrh Clin Exp Ophthalmol 2005

MEAD studyMean BCVA change from baseline based on baseline lens status

-2

0

2

4

6

8

10

0 3 6 9 12 15 18 21 24 27 30 33 36 39

Mea

n C

hang

e Fr

om

Bas

elin

e B

CVA

(Let

ters

)

Month

DEX Implant 07 mg (n = 86)

Sham (n = 101)

Boyer DS et al Ophthalmology 20141211904ndash14

Results analyzed in the ITT population with LOCF for missing values

Pseudophakic

Total

0

5

10

0 3 6 9 12 15 18 21 24 27 30 33 36 39

DEX 700 (n=351)

Sham (n=350)

10

8

6

4

2

0

Mea

n C

hang

e fr

om

Bas

elin

e B

CVA

(Let

ters

)

Month

07mg dose is approved as Ozurdexreg by the FDA and EMA 035mg dose not commercially available

1 Boyer DS et al Ophthalmology 2014 121 1904-1914

bull Nonbioerodible micro implant (polyimide) containing 190microg of fluocinolone acetonide (FAc)

bull Consistent daily submicrogram delivery of 02 microgd FAc for up to 36 months

bull Posterior point of release

bull 35 mm times 037 mm non-bioerodable micro implant

bull 25-gauge injector creates self-sealing wound

bull No measurable systemic exposure

ILUVIEN Implant Technology

FAcimplant

ILUVIEN SPC httpwwwmedicinesorgukemcmedicine27636

0 6 12 18 24 30 36

ILUVIEN 02 microgd FAc(n = 376)05 microgd FAc (n = 395)Control sham injection(n = 185)

Design of Phase 3 FAME Study (FAME A and B = same protocol)

Additional laser therapy allowed after week 6a

Retreatment any time after month 12 (if eligibleb)

Study ends

N = 956Randomisation

221Primary readout

Patients with DMO and

bull At least 1 previous laser tx

bull BCVA ge19 and le68 letters

bull TD-OCT FTH ge250 μm

Month

BCVA = best corrected visual acuity DMO = diabetic macular oedema TD-OCT=time domain optical coherence tomography FTH = foveal thicknessa At masked investigatorrsquos discretion b If BCVA loss ge5 letters or retinal thickening ge50 microm from best reading in previous 12 months

ge15 letter Gain is Greater in Chronic DMO Patients

ge 15

-Let

ter I

mpr

ovem

ent

in B

CVA

Fro

m B

asel

ine

Δ = 98

Months

Full Population Patients With Chronic DMO

Months

Δ = 206

287

189134

34

Steroid re-treatments

bullOzurdexbull Longer half-life than anti-VEGF in the eye

bull Redosing regimes not very helpful from RCT data eg MEAD study only 612 dosing

bull In reality re-treatment interval may be shorter

bull POSOLOGY

bull Patients treated with OZURDEX who have experienced an initial response and in the physicians opinion may benefit from retreatment without being exposed to significant risk should be considered for retreatment Retreatment may be performed after approximately 6 months if the patient experiences decreased vision andor an increase in retinal thickness secondary to recurrent or worsening diabetic macular oedema

bullIluvienbull 70 of patients in FAE only needed 1

injection over 3 years

bull BUT additional rescue treatments allowed

bull POSOLOGY

bull Each ILUVIEN implant releases fluocinolone acetonide for up to 36 months An additional implant may be administered after 12 months if the patient experiences decreased vision or an increase in retinal thickness secondary to recurrent or worsening diabetic macular oedema

bull Patients receiving escape medication were exited from MEAD before administration1

bull Macular laser rescue treatment allowed in RISERIDE (Lucentisreg) from 3 months2

bull Focalgrid laser allowed in FAME (Iluvienreg) from 6 weeks3

MEAD TREATMENT PROTOCOL

bull First treatment given at randomisation (day 0) bull Patients assessed for retreatment eligibility every 3 months from

months 6ndash36bull Patients were eligible for retreatment if

OCT optical coherence tomography

ge6 months since most recent

study treatment

Retinal thickness in 1 mm central macular

subfield by OCT gt175 microm

Evidence of residual retinal oedema (intraretinal cysts or

any regions of increased retinal thickening) as assessed by

investigator from OCT

AND OR

MEA

D

Amendment in May 2010 revised anatomic criterion for retreatment before this time the threshold was gt225 microm1Boyer DS et al Ophthalmology 2014 121 1904-19142Nguyen QD et al Ophthalmology 20121191064minus10773Campochiaro PA et al Ophthalmology 2011118626ndash635

Treatment burdenILUVIEN

Control(n =112)

02 microgd FAc(n =209)

Study Treatments(sham injection or ILUVIEN 02 microgday or FAc 05microgday)

1 treatment 661 761

2 treatments 277 187

ge 3 treatments 63 53

Rescue Laser Treatments (at masked physicianrsquos discretion after week 6)

Patients 607 407

Off-Protocol Treatments (IVTA bevacizumab ranibizumab intravitreal dexamethasone)

Patients 295 115

OZURDEX = 23injections year 1 41 by year 3

No other Rx

Summary of side effects with intravitreal steroids

Drug device Evidence base Cataract risk IOP rise (requiring drops)

Glaucoma surgery

endophthalmitis

ILUVIEN FAME studies 80 cat surgery(273 sham)

384(14 control)

48 0

Ozurdex MEAD 592 had cataract surgery(72 sham)

215 (end of study)(34 sham)

06 0

Trivaris+ laser vs Luc+laserx2 vs laser

Protocol IOphthalmology 2010

15 42(ONE OFgt10mmHg risegt30mmHGStart drops)

2186 0

NICE guidance for intravitreal steroids in DMO

bull Iluvien

bull NICE TA 301 Iluvien for DMO Nov 2013

bull hellipfor treating chronic diabetic macular oedema that is insufficiently responsive to available therapies only if

bull the implant is to be used in an eye with an intraocular

(pseudophakic) lens and

bull the manufacturer provides fluocinolone acetonide intravitreal implant with the discount agreed in the patient access scheme

NICE guidance for intravitreal steroids in DMO

bull Ozurdex

bull NICE TA 349 Ozurdex for DMO July 2015

bull there is an artificial lens in the eye to be treated and

bull their diabetic macular oedema has not improved with

non-corticosteroid treatment or such treatment is not suitable for them

Steroids = second line therapyWhen do I switch

bull Anti-VEGF first line for centre involving DMObull NICE TA ndash ldquoinsufficiently responsiverdquo ldquo ldquonot improvedrdquo ldquonot suitablerdquo ndash

OTHER TREATMENTS

bull 2 scenariosbull 1) Anti-VEGF canrsquot be funded ie OCTlt400um + PSEUDOPHAKIC

bull 2) Already had a course of treatment with laseranti-VEGF + PSEUDOPHAKIC ie SWITCHING from anti-VEGF to steroid

bull Plus

bull ldquochronicrdquo DMO ndash 3 years duration in FAME (18months) for ILUVIEN

bull Chronic DMO not essential for Ozurdex

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

Protocol T ndash patients may not improve in first 6 months

RIDE

RISE

Mea

n ch

ange

in B

CVA

(E

TDR

S le

tters

)M

ean

chan

ge in

BC

VA

(ETD

RS

lette

rs)

Time (months)

RISE and RIDE (Lucentis monthly dosing) Mean change in BCVA over 36 months

Brown DM et al Ophthalmology 2013120(10)2013ndash2022

54

Ranibizumab 03 mgRanibizumab 05 mgShamranibizumab 05 mg

Date of Prep Dec 2014 LGB0820147252X

VA improvement continues throughout year 1 with monthly dosing

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user ndash more than protocol

I

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

DRCRN protocol I5 year outcomesInjections 8-9 in year 1Year 2 = 2-3Year 3= 1-2Year 4 = 0-1Year 5 = 0

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

Wait for plateau = stability in protocol T laserPatient factors again

Judgement of response to anti-VEGF ndashtimeframe

bull Wait 6 months in poor responders

bull Wait 1 year for heavy users

bull Tempting to try steroids earlier than this ifbull No glaucoma ndash not a deal breaker Ozurdex better short term optionbull Pseudophakic

bull Clues from the diseasebull chronic

bull PATIENT FACTORS

bull Any eyes avoid steroids ndash advanced glaucomaCSCR Or prior viral retinitis RARE

bull Any eyes avoid anti-VEGF pregnancytrying to concieve recent CVA

BIOMARKERS AT BASELINE WOULD BE USEFULRESTORE subgroup analysis of OCT features

bull Andreas Pollreisz EURETINA 2015

bull OCT biomarkers (RESTORE data)

bull Better effects with anti-VEGF ifbull Small rather than large intra-retinal cyst

bull Sub-retinal fluid present

bull Vitreo-macular adhesion at baseline

bull No disruption of ELM and ISOS junction

bull No disorganisation of inner retinal layers (DRIL)

RESTORE subgroup analysis of OCT features

bull Andreas Pollreisz EURETINA 2015

bull OCT biomarkers (RESTORE data)

bull Better effects with anti-VEGF ifbull Small rather than large intra-retinal cyst

bull Sub-retinal fluid present

bull Vitreo-macular adhesion at baseline

bull No disruption of ELM and ISOS junction

bull No disorganisation of inner retinal layers (DRIL)

Better baseline characterisationclassificationERG Contrast sensitivityOCT AngiographyMicroperimetry= clues as to who responds best to which drug

Plan for this presentation helliphellipa long list

bull What treatment options are available for DMO (evidence base)

bull What treatment should I start with at baselinebull Re-treatment algorithms for intravitreal DMO therapiesbull When should I switchcombine therapiesbull The bigger picture

bull Other eyebull The patient as a wholebull The service -coping with capacity ndash compromises

The bigger pictureOther eyeThe patient as a wholeThe service -coping with capacity ndash compromises

bull OTHER EYE ndash may create problems

bull Treat and extend ndash ldquoreduce of visitsrdquo plus Eylea license ndash ldquono need for monitoringrdquo may not benefit if lots of visits due to PDR other eye

bull PERIPHERAL RETINA anti-VEGF supresses proliferative disease - Rebound on stopping Rx

bull PATIENT

bull Anti-VEGF ndash heavy user - Will comply

bull One stop much better than two stop for patient ndash Treat and extend

bull SERVICE

bull Capacity and demand planning = fixedT+E more predictable at least 1 month in advance ndash flexible nurse injectors

bull Steroids ndash even if well controlled (Iluvien for 3 years) need IOP check

bull Need pan-retinal examination both eyes ndash separate visits

Summary

CSMO

No centre involvement

Photocoagulation

Centre involvement

gt 78 letters(normalminimally reduced VA)

Photocoagulation

VA 78ndash24 letters

Phakic

Anti-VEGF

Pseudophakic

Anti-VEGF

SWITCHglaucoma

Injection tolerance

Medical issuesrecent CVA

Peripheral diseaseBilateral Rx

CSMO

No centre involvement

LASER

Centre involvement

gt 78 letters(normalminimally

reduced VA)

VA 78ndash24 letters

EYLEA OR LUCENTIS OR AVASTIN

Funding issues

Protocol T ndash poor VA lt 65 letters (615)

LOADING

Monthly injections until stability OR 5 x 112 (EYLEA) = 6 MONTHS then 8 weeks

RETREATMENT1

TREAT AND EXTEND - PRN

PRN

PSEUDOPHAKIC

Prior Rx

ILUVIEN

Chronic disease

OZURDEX

RETREATMENT

OZURDEX

OCT gt175um or any residual oedema

ILUVIEN after 12 months if risksltbenefits

OCT

gt400um

bull FACE TO FACE CLINICS RUNNING IN PARALLEL

bull = MAC002 every 6 months (optom or doctor) routine check for cataracttolerance of injectionsglaucoma issues etc

bull =MAC003 (DOCTOR) for problems as needed no fixed intervalDischargestop treatmentDeclines treatment diagnosis CSR overlay etcswitch drugs

bull =RV002- (DOCTOR) every 6 months

bull =DM002 ndash (DOCTOR) variable interval determined by last assessing doctor

bull First visit at 6 months from 1st injection if mild NPDR

bull Otherwise determined by retinopathy generally

LOADING PHASE

EyleaLucentis 1 within 48hrs of baseline

EyleaLucentis 2 (and LogMAR VA plus OCT same visit)

EyleaLucentis 3 (and LogMAR VA plus OCT same visit)

EyleaLucentis 4 (TEinj)(and Logmar VA plus OCT same visit

AFTER INJECTION 4 data goes off to be reviewed immediately as a hellip

TREAT AND EXTEND assessment ndash the next interval will depend on the response to the loading phase

NB -DMO patients ndash majority (95) will need 6 injctions x 112 of Lucentis

OR Eylea 5 x 112 then 8 weekly

ONCE STABLE for 3 x injection in TE phase

VIRTUAL CLINIC MONITORING OF MACULOPATHY AND PRN RETREATMENT

ANTI-VEGF INJECTION PATHWAYS Baseline visitMAC001 for wet AMDRV001 for CRVOBRVOMed ret clinic for DMO

Pathways ndash too many directions

Better that thanhellip

Thank you

SUMMARY What do I choose for my patient at baselineOCT central retinal thickness (CRT)PseudophakicAttempts at prior treatment duration of DMO

bull lt 400um

bull IFR licensed anti-VEGF or Avastin

+-ETDRS laser

PSEUDOPHAKIC

Iluvien

Ozurdex

bull gt 400um = Anti-VEGF

Which one

Depends on

bull baseline vision lt615 Eylea

bull Fixed dosing attractive (Eylea)bull Chronic DMO

bull PSEUDOPHAKICbull Patients ldquoinsufficiently

responsive to existing therapiesrdquo

bull ldquoNot improved with non-corticosteroid or such treatment is not suitable for themrdquo

Which steroid ndash Ozurdex or Iluvien

bull No head to head data

bull Revisit this when we think about switching from ANTI-VEGF to steroid

Assuming we have started with an anti-VEGF agent ndash what are the re-treatment algorithms in DMO

Treatment posologies

ldquoTreatment is initiated with one injection per month until maximum VA is achieved andor there are no signs of disease activity ie no change in VA and in other signs and

symptoms of the disease under continued treatment

In patients withhellipDMOhellip initially three or more consecutive monthly injections may be needed Thereafter monitoring and treatment intervals

should be determined by the physician and should be based on disease activity as

assessed by VA andor anatomical parametershellip

If patients are being treated according to a treat-and-extend regimen once maximum VA is achieved andor there are no

signs of disease activity the treatment intervals can be extended stepwise until signs of

disease activity or visual impairment recur The treatment intervalhellipmay be extended by up to one month

at a time for DMOrdquo

1 Novartis Pharmaceuticals UK Ltd 30 October 2014 Available at httpwwwmedicinesorgukemcmedicine19409 Accessed 04 September 2015

2 Bayer Pharma AG February 2015 Available at httpwwwmedicinesorgukemcmedicine27224 Accessed 04 September 2015

Ranibizumab1 Aflibercept2

ldquohelliptreatment is initiated with one injection per month for five consecutive doses followed by

one injection every two months There is no requirement for monitoring between injectionshellip

After the first 12 months of treatmenthellipthe treatment interval may be extended based

on visual andor anatomic outcomes The schedule for monitoring should

be determined by the treating physicianrdquo

DMO diabetic macular oedema VA visual acuity

Re-treatment algorithms for anti-VEGF agents in DMO

bull LOADING PHASE

bull Lucentis label = monthly until stability

bull Eylea label = 5 x 112 then every 8 weeks ie fixed regime year 1

bull DRCRnet protocol T = effectively 6 x112 for majority (95) BUT actually only mandated for first 3 months then prn

bull helliphellip likely that majority will receive injections monthly for first 6 months

bull INDIVIDUALISED PHASE

bull Once ldquostablerdquo ndash based on VA and OCT

bull NB May never get a ldquodryrdquo OCT so treat to stability

bull THEN

bull Treat and extend

bull prn

What does Treat and Extend mean

Pathway overview = Lucentis prn

Jan

Loading phase = injections every 4 weeks until ldquostablerdquo for 3 visits

helliphelliphellip

Feb OctSepAugJulJunMayAprMar

MarFebJan

DecNov

DecNovOctSepAugJulJunMayApr

Then observe UNTIL VA decreases or OCT increase = prn

Once reactivates need at least 2 injections until stable again over 3 visits

Pathway overview = Treat and Extend

Jan

Loading phase = injections every 4 weeks until ldquostablerdquo for 3 visits or Eyleayear 1

helliphelliphellip

Feb OctSepAugJulJunMayAprMar

MarFebJan

DecNov

DecNovOctSepAugJulJunMayApr

Then keep injecting but extend the interval between injections gradually ie keep treating even if perfect

If reactivates need at least 2 injections until stable again over 3 visits

Pathway overview = Eylea fixed dosing year 1

Jan

Eylea = 5 x 112 injection then every 8 weeks

Average 6 injections yr 2 Beyond that

helliphelliphellip

Feb OctSepAugJulJunMayAprMar

MarFebJan

DecNov

DecNovOctSepAugJulJunMayApr

Then individualised UNTIL VA decreases or OCT increase = prn

Once reactivates need at least 2 injections until stable again over 3 visits

Pros and cons of Treat and Extend vs Prn

T+E PRN

PROS bull Proactive patient and service get advance warning of injection ndash capacity and demand planning easier

bull One ndashstopbull Fewer visits than prnbull Overtreatment

advantageous for peripheral retinopathy

bull Only treated when active ieno overtreatment

bull Aggressive year 1 protocols (DRCRN I ndash few injections needed thereafter

bull DMO tolerant of reactivations ()

CONS bull Overtreatment = riskexpenseinconvenience

bull Evidence base scantbull Bilateral disease tricky

bull Reactive so need enoughemergency capacity to inject when disease flares up

bull No advance warning to patientservice that injection needed

bull NEED TO DO IT WELL ndashNHS real life audits prn based regimes not good resultsUndertreatment in year 1 Affects long term prognosis and treatment burden

Pros and cons of Treat and Extend vs Prn

T+E PRN

PROS bull Proactive patient and service get advance warning of injection ndash capacity and demand planning easier

bull One ndashstopbull Fewer visits than prnbull Overtreatment

advantageous for peripheral retinopathy

bull Only treated when active ieno overtreatment

bull Aggressive year 1 protocols (DRCRN I ndash few injections needed thereafter

bull DMO tolerant of reactivations ()

CONS bull Overtreatment = riskexpenseinconvenience

bull Evidence base scantbull Bilateral disease tricky

bull Reactive so need enoughemergency capacity to inject when disease flares up

bull No advance warning to patientservice that injection needed

bull NEED TO DO IT WELL ndashNHS real life audits prn based regimes not good resultsUndertreatment in year 1 Affects long term prognosis and treatment burden

DMO ndash anti-VEGF Treat and Extend

bull Retain study ndash the only RCT data

bull Br J Ophthalmol 2015 Oct 9 pii bjophthalmol-2015-307249 doi 101136bjophthalmol-2015-307249 [Epub ahead of print]

bull Ranibizumab 05 mg treat-and-extend regimen for diabetic macular oedema the RETAIN study

bull Pruumlnte C1 Fajnkuchen F2 Mahmood S3 Ricci F4 Hatz K5 Studnička J6 Bezlyak V7 Parikh S7 Stubbings WJ7 Wenzel A7 Figueira J8 and the RETAIN Study Group

RETAIN Phase III trial evaluating the efficacy of lsquotreat and extendrsquo regimen (ARVO 2014)

bull Patients with DMO and visual impairment (n = 372) were randomised 111

to one of three groups for 24 months

bull Two phases to dosing schedule

bull Phase A

bull Patients in all groups were initially treated with monthly ranibizumab until BCVA remained

stable

bull Phase B

bull Patients in the TampE groups whose vision remained stable had treatment- free intervals

that were increased incrementally by 1 month for a maximum of 3 months

bull Patients in the PRN group had ongoing monthly monitoring

bull In all groups Phase A was resumed if a decrease in BCVA was observed at a visit

Ranibizumab 05 mg monotherapy

in TampE regimen

Ranibizumab 05 mg in TampE regimen

plus laser

Ranibizumab 05 mg PRN

35

RETAIN Visual acuity endpoints

Pruumlnte C ARVO 2014 Annual Meeting Abstracts Abstract 1700

Mean average change in BCVAat 12 months (primary endpoint)

Mean change in BCVA at 24 months

Mea

n av

erag

e ch

ange

in B

CVA

(ETD

RS

lette

rs)

RanibizumabTampE

RanibizumabTampE + laser

RanibizumabPRN

RanibizumabTampE

RanibizumabTampE + laser

RanibizumabPRN

Mea

n ch

ange

in B

CVA

(ETD

RS

lette

rs)

plt00001 for both ranibizumab TampE groups versus PRN for primary endpoint

36

RETAIN Patient visits and monitoring with TampE regimen over 24 months

bull The TampE regimen provided an approximately 40 reduction in the number of treatment visits required compared with the ranibizumab PRN regimen

bull Approximately 70 of patients receiving TampE regimens had monitoring intervals ge2 months compared with ongoing monthly monitoring in the ranibizumab PRN group

bull Informed the license for Lucentis in DMO (extend by 1 month at a time)

37

INTRAVITREAL STEROIDSWhich intravitreal steroid is better

bull Licensed steroids ndash Ozurdex (Dexamethasone) and Iluvien (Fluocinoloneacetonide

bull Which steroid is best in terms of VA outcomes hellipWE DONrsquoT KNOW FOR SURE ndash no head to head studies for licensed drugs either between steroids or between anti-VEGF and steroids

bull STEROIDS ARE efficacious in DMO

bull MEAD

bull FAME

bull DRCRnet protocol I

bull NICE ndash Ozurdex and Iluvien ndash second-line agents

Ozurdex

bull A biodegradable co-polymer implant ndash degrades in time to lactic and glycolic acid releasing Dexamethasone

bull 22gauge injectionbull MEAD study

bull N=1048

bull Dex 07mg vs 035mg vs sham

bull No rescue therapy

bull 3 year follow up max 6 monthly dosing ie 7 over 3 years

Gan IM et al Greafes Acrh Clin Exp Ophthalmol 2005

MEAD studyMean BCVA change from baseline based on baseline lens status

-2

0

2

4

6

8

10

0 3 6 9 12 15 18 21 24 27 30 33 36 39

Mea

n C

hang

e Fr

om

Bas

elin

e B

CVA

(Let

ters

)

Month

DEX Implant 07 mg (n = 86)

Sham (n = 101)

Boyer DS et al Ophthalmology 20141211904ndash14

Results analyzed in the ITT population with LOCF for missing values

Pseudophakic

Total

0

5

10

0 3 6 9 12 15 18 21 24 27 30 33 36 39

DEX 700 (n=351)

Sham (n=350)

10

8

6

4

2

0

Mea

n C

hang

e fr

om

Bas

elin

e B

CVA

(Let

ters

)

Month

07mg dose is approved as Ozurdexreg by the FDA and EMA 035mg dose not commercially available

1 Boyer DS et al Ophthalmology 2014 121 1904-1914

bull Nonbioerodible micro implant (polyimide) containing 190microg of fluocinolone acetonide (FAc)

bull Consistent daily submicrogram delivery of 02 microgd FAc for up to 36 months

bull Posterior point of release

bull 35 mm times 037 mm non-bioerodable micro implant

bull 25-gauge injector creates self-sealing wound

bull No measurable systemic exposure

ILUVIEN Implant Technology

FAcimplant

ILUVIEN SPC httpwwwmedicinesorgukemcmedicine27636

0 6 12 18 24 30 36

ILUVIEN 02 microgd FAc(n = 376)05 microgd FAc (n = 395)Control sham injection(n = 185)

Design of Phase 3 FAME Study (FAME A and B = same protocol)

Additional laser therapy allowed after week 6a

Retreatment any time after month 12 (if eligibleb)

Study ends

N = 956Randomisation

221Primary readout

Patients with DMO and

bull At least 1 previous laser tx

bull BCVA ge19 and le68 letters

bull TD-OCT FTH ge250 μm

Month

BCVA = best corrected visual acuity DMO = diabetic macular oedema TD-OCT=time domain optical coherence tomography FTH = foveal thicknessa At masked investigatorrsquos discretion b If BCVA loss ge5 letters or retinal thickening ge50 microm from best reading in previous 12 months

ge15 letter Gain is Greater in Chronic DMO Patients

ge 15

-Let

ter I

mpr

ovem

ent

in B

CVA

Fro

m B

asel

ine

Δ = 98

Months

Full Population Patients With Chronic DMO

Months

Δ = 206

287

189134

34

Steroid re-treatments

bullOzurdexbull Longer half-life than anti-VEGF in the eye

bull Redosing regimes not very helpful from RCT data eg MEAD study only 612 dosing

bull In reality re-treatment interval may be shorter

bull POSOLOGY

bull Patients treated with OZURDEX who have experienced an initial response and in the physicians opinion may benefit from retreatment without being exposed to significant risk should be considered for retreatment Retreatment may be performed after approximately 6 months if the patient experiences decreased vision andor an increase in retinal thickness secondary to recurrent or worsening diabetic macular oedema

bullIluvienbull 70 of patients in FAE only needed 1

injection over 3 years

bull BUT additional rescue treatments allowed

bull POSOLOGY

bull Each ILUVIEN implant releases fluocinolone acetonide for up to 36 months An additional implant may be administered after 12 months if the patient experiences decreased vision or an increase in retinal thickness secondary to recurrent or worsening diabetic macular oedema

bull Patients receiving escape medication were exited from MEAD before administration1

bull Macular laser rescue treatment allowed in RISERIDE (Lucentisreg) from 3 months2

bull Focalgrid laser allowed in FAME (Iluvienreg) from 6 weeks3

MEAD TREATMENT PROTOCOL

bull First treatment given at randomisation (day 0) bull Patients assessed for retreatment eligibility every 3 months from

months 6ndash36bull Patients were eligible for retreatment if

OCT optical coherence tomography

ge6 months since most recent

study treatment

Retinal thickness in 1 mm central macular

subfield by OCT gt175 microm

Evidence of residual retinal oedema (intraretinal cysts or

any regions of increased retinal thickening) as assessed by

investigator from OCT

AND OR

MEA

D

Amendment in May 2010 revised anatomic criterion for retreatment before this time the threshold was gt225 microm1Boyer DS et al Ophthalmology 2014 121 1904-19142Nguyen QD et al Ophthalmology 20121191064minus10773Campochiaro PA et al Ophthalmology 2011118626ndash635

Treatment burdenILUVIEN

Control(n =112)

02 microgd FAc(n =209)

Study Treatments(sham injection or ILUVIEN 02 microgday or FAc 05microgday)

1 treatment 661 761

2 treatments 277 187

ge 3 treatments 63 53

Rescue Laser Treatments (at masked physicianrsquos discretion after week 6)

Patients 607 407

Off-Protocol Treatments (IVTA bevacizumab ranibizumab intravitreal dexamethasone)

Patients 295 115

OZURDEX = 23injections year 1 41 by year 3

No other Rx

Summary of side effects with intravitreal steroids

Drug device Evidence base Cataract risk IOP rise (requiring drops)

Glaucoma surgery

endophthalmitis

ILUVIEN FAME studies 80 cat surgery(273 sham)

384(14 control)

48 0

Ozurdex MEAD 592 had cataract surgery(72 sham)

215 (end of study)(34 sham)

06 0

Trivaris+ laser vs Luc+laserx2 vs laser

Protocol IOphthalmology 2010

15 42(ONE OFgt10mmHg risegt30mmHGStart drops)

2186 0

NICE guidance for intravitreal steroids in DMO

bull Iluvien

bull NICE TA 301 Iluvien for DMO Nov 2013

bull hellipfor treating chronic diabetic macular oedema that is insufficiently responsive to available therapies only if

bull the implant is to be used in an eye with an intraocular

(pseudophakic) lens and

bull the manufacturer provides fluocinolone acetonide intravitreal implant with the discount agreed in the patient access scheme

NICE guidance for intravitreal steroids in DMO

bull Ozurdex

bull NICE TA 349 Ozurdex for DMO July 2015

bull there is an artificial lens in the eye to be treated and

bull their diabetic macular oedema has not improved with

non-corticosteroid treatment or such treatment is not suitable for them

Steroids = second line therapyWhen do I switch

bull Anti-VEGF first line for centre involving DMObull NICE TA ndash ldquoinsufficiently responsiverdquo ldquo ldquonot improvedrdquo ldquonot suitablerdquo ndash

OTHER TREATMENTS

bull 2 scenariosbull 1) Anti-VEGF canrsquot be funded ie OCTlt400um + PSEUDOPHAKIC

bull 2) Already had a course of treatment with laseranti-VEGF + PSEUDOPHAKIC ie SWITCHING from anti-VEGF to steroid

bull Plus

bull ldquochronicrdquo DMO ndash 3 years duration in FAME (18months) for ILUVIEN

bull Chronic DMO not essential for Ozurdex

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

Protocol T ndash patients may not improve in first 6 months

RIDE

RISE

Mea

n ch

ange

in B

CVA

(E

TDR

S le

tters

)M

ean

chan

ge in

BC

VA

(ETD

RS

lette

rs)

Time (months)

RISE and RIDE (Lucentis monthly dosing) Mean change in BCVA over 36 months

Brown DM et al Ophthalmology 2013120(10)2013ndash2022

54

Ranibizumab 03 mgRanibizumab 05 mgShamranibizumab 05 mg

Date of Prep Dec 2014 LGB0820147252X

VA improvement continues throughout year 1 with monthly dosing

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user ndash more than protocol

I

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

DRCRN protocol I5 year outcomesInjections 8-9 in year 1Year 2 = 2-3Year 3= 1-2Year 4 = 0-1Year 5 = 0

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

Wait for plateau = stability in protocol T laserPatient factors again

Judgement of response to anti-VEGF ndashtimeframe

bull Wait 6 months in poor responders

bull Wait 1 year for heavy users

bull Tempting to try steroids earlier than this ifbull No glaucoma ndash not a deal breaker Ozurdex better short term optionbull Pseudophakic

bull Clues from the diseasebull chronic

bull PATIENT FACTORS

bull Any eyes avoid steroids ndash advanced glaucomaCSCR Or prior viral retinitis RARE

bull Any eyes avoid anti-VEGF pregnancytrying to concieve recent CVA

BIOMARKERS AT BASELINE WOULD BE USEFULRESTORE subgroup analysis of OCT features

bull Andreas Pollreisz EURETINA 2015

bull OCT biomarkers (RESTORE data)

bull Better effects with anti-VEGF ifbull Small rather than large intra-retinal cyst

bull Sub-retinal fluid present

bull Vitreo-macular adhesion at baseline

bull No disruption of ELM and ISOS junction

bull No disorganisation of inner retinal layers (DRIL)

RESTORE subgroup analysis of OCT features

bull Andreas Pollreisz EURETINA 2015

bull OCT biomarkers (RESTORE data)

bull Better effects with anti-VEGF ifbull Small rather than large intra-retinal cyst

bull Sub-retinal fluid present

bull Vitreo-macular adhesion at baseline

bull No disruption of ELM and ISOS junction

bull No disorganisation of inner retinal layers (DRIL)

Better baseline characterisationclassificationERG Contrast sensitivityOCT AngiographyMicroperimetry= clues as to who responds best to which drug

Plan for this presentation helliphellipa long list

bull What treatment options are available for DMO (evidence base)

bull What treatment should I start with at baselinebull Re-treatment algorithms for intravitreal DMO therapiesbull When should I switchcombine therapiesbull The bigger picture

bull Other eyebull The patient as a wholebull The service -coping with capacity ndash compromises

The bigger pictureOther eyeThe patient as a wholeThe service -coping with capacity ndash compromises

bull OTHER EYE ndash may create problems

bull Treat and extend ndash ldquoreduce of visitsrdquo plus Eylea license ndash ldquono need for monitoringrdquo may not benefit if lots of visits due to PDR other eye

bull PERIPHERAL RETINA anti-VEGF supresses proliferative disease - Rebound on stopping Rx

bull PATIENT

bull Anti-VEGF ndash heavy user - Will comply

bull One stop much better than two stop for patient ndash Treat and extend

bull SERVICE

bull Capacity and demand planning = fixedT+E more predictable at least 1 month in advance ndash flexible nurse injectors

bull Steroids ndash even if well controlled (Iluvien for 3 years) need IOP check

bull Need pan-retinal examination both eyes ndash separate visits

Summary

CSMO

No centre involvement

Photocoagulation

Centre involvement

gt 78 letters(normalminimally reduced VA)

Photocoagulation

VA 78ndash24 letters

Phakic

Anti-VEGF

Pseudophakic

Anti-VEGF

SWITCHglaucoma

Injection tolerance

Medical issuesrecent CVA

Peripheral diseaseBilateral Rx

CSMO

No centre involvement

LASER

Centre involvement

gt 78 letters(normalminimally

reduced VA)

VA 78ndash24 letters

EYLEA OR LUCENTIS OR AVASTIN

Funding issues

Protocol T ndash poor VA lt 65 letters (615)

LOADING

Monthly injections until stability OR 5 x 112 (EYLEA) = 6 MONTHS then 8 weeks

RETREATMENT1

TREAT AND EXTEND - PRN

PRN

PSEUDOPHAKIC

Prior Rx

ILUVIEN

Chronic disease

OZURDEX

RETREATMENT

OZURDEX

OCT gt175um or any residual oedema

ILUVIEN after 12 months if risksltbenefits

OCT

gt400um

bull FACE TO FACE CLINICS RUNNING IN PARALLEL

bull = MAC002 every 6 months (optom or doctor) routine check for cataracttolerance of injectionsglaucoma issues etc

bull =MAC003 (DOCTOR) for problems as needed no fixed intervalDischargestop treatmentDeclines treatment diagnosis CSR overlay etcswitch drugs

bull =RV002- (DOCTOR) every 6 months

bull =DM002 ndash (DOCTOR) variable interval determined by last assessing doctor

bull First visit at 6 months from 1st injection if mild NPDR

bull Otherwise determined by retinopathy generally

LOADING PHASE

EyleaLucentis 1 within 48hrs of baseline

EyleaLucentis 2 (and LogMAR VA plus OCT same visit)

EyleaLucentis 3 (and LogMAR VA plus OCT same visit)

EyleaLucentis 4 (TEinj)(and Logmar VA plus OCT same visit

AFTER INJECTION 4 data goes off to be reviewed immediately as a hellip

TREAT AND EXTEND assessment ndash the next interval will depend on the response to the loading phase

NB -DMO patients ndash majority (95) will need 6 injctions x 112 of Lucentis

OR Eylea 5 x 112 then 8 weekly

ONCE STABLE for 3 x injection in TE phase

VIRTUAL CLINIC MONITORING OF MACULOPATHY AND PRN RETREATMENT

ANTI-VEGF INJECTION PATHWAYS Baseline visitMAC001 for wet AMDRV001 for CRVOBRVOMed ret clinic for DMO

Pathways ndash too many directions

Better that thanhellip

Thank you

Which steroid ndash Ozurdex or Iluvien

bull No head to head data

bull Revisit this when we think about switching from ANTI-VEGF to steroid

Assuming we have started with an anti-VEGF agent ndash what are the re-treatment algorithms in DMO

Treatment posologies

ldquoTreatment is initiated with one injection per month until maximum VA is achieved andor there are no signs of disease activity ie no change in VA and in other signs and

symptoms of the disease under continued treatment

In patients withhellipDMOhellip initially three or more consecutive monthly injections may be needed Thereafter monitoring and treatment intervals

should be determined by the physician and should be based on disease activity as

assessed by VA andor anatomical parametershellip

If patients are being treated according to a treat-and-extend regimen once maximum VA is achieved andor there are no

signs of disease activity the treatment intervals can be extended stepwise until signs of

disease activity or visual impairment recur The treatment intervalhellipmay be extended by up to one month

at a time for DMOrdquo

1 Novartis Pharmaceuticals UK Ltd 30 October 2014 Available at httpwwwmedicinesorgukemcmedicine19409 Accessed 04 September 2015

2 Bayer Pharma AG February 2015 Available at httpwwwmedicinesorgukemcmedicine27224 Accessed 04 September 2015

Ranibizumab1 Aflibercept2

ldquohelliptreatment is initiated with one injection per month for five consecutive doses followed by

one injection every two months There is no requirement for monitoring between injectionshellip

After the first 12 months of treatmenthellipthe treatment interval may be extended based

on visual andor anatomic outcomes The schedule for monitoring should

be determined by the treating physicianrdquo

DMO diabetic macular oedema VA visual acuity

Re-treatment algorithms for anti-VEGF agents in DMO

bull LOADING PHASE

bull Lucentis label = monthly until stability

bull Eylea label = 5 x 112 then every 8 weeks ie fixed regime year 1

bull DRCRnet protocol T = effectively 6 x112 for majority (95) BUT actually only mandated for first 3 months then prn

bull helliphellip likely that majority will receive injections monthly for first 6 months

bull INDIVIDUALISED PHASE

bull Once ldquostablerdquo ndash based on VA and OCT

bull NB May never get a ldquodryrdquo OCT so treat to stability

bull THEN

bull Treat and extend

bull prn

What does Treat and Extend mean

Pathway overview = Lucentis prn

Jan

Loading phase = injections every 4 weeks until ldquostablerdquo for 3 visits

helliphelliphellip

Feb OctSepAugJulJunMayAprMar

MarFebJan

DecNov

DecNovOctSepAugJulJunMayApr

Then observe UNTIL VA decreases or OCT increase = prn

Once reactivates need at least 2 injections until stable again over 3 visits

Pathway overview = Treat and Extend

Jan

Loading phase = injections every 4 weeks until ldquostablerdquo for 3 visits or Eyleayear 1

helliphelliphellip

Feb OctSepAugJulJunMayAprMar

MarFebJan

DecNov

DecNovOctSepAugJulJunMayApr

Then keep injecting but extend the interval between injections gradually ie keep treating even if perfect

If reactivates need at least 2 injections until stable again over 3 visits

Pathway overview = Eylea fixed dosing year 1

Jan

Eylea = 5 x 112 injection then every 8 weeks

Average 6 injections yr 2 Beyond that

helliphelliphellip

Feb OctSepAugJulJunMayAprMar

MarFebJan

DecNov

DecNovOctSepAugJulJunMayApr

Then individualised UNTIL VA decreases or OCT increase = prn

Once reactivates need at least 2 injections until stable again over 3 visits

Pros and cons of Treat and Extend vs Prn

T+E PRN

PROS bull Proactive patient and service get advance warning of injection ndash capacity and demand planning easier

bull One ndashstopbull Fewer visits than prnbull Overtreatment

advantageous for peripheral retinopathy

bull Only treated when active ieno overtreatment

bull Aggressive year 1 protocols (DRCRN I ndash few injections needed thereafter

bull DMO tolerant of reactivations ()

CONS bull Overtreatment = riskexpenseinconvenience

bull Evidence base scantbull Bilateral disease tricky

bull Reactive so need enoughemergency capacity to inject when disease flares up

bull No advance warning to patientservice that injection needed

bull NEED TO DO IT WELL ndashNHS real life audits prn based regimes not good resultsUndertreatment in year 1 Affects long term prognosis and treatment burden

Pros and cons of Treat and Extend vs Prn

T+E PRN

PROS bull Proactive patient and service get advance warning of injection ndash capacity and demand planning easier

bull One ndashstopbull Fewer visits than prnbull Overtreatment

advantageous for peripheral retinopathy

bull Only treated when active ieno overtreatment

bull Aggressive year 1 protocols (DRCRN I ndash few injections needed thereafter

bull DMO tolerant of reactivations ()

CONS bull Overtreatment = riskexpenseinconvenience

bull Evidence base scantbull Bilateral disease tricky

bull Reactive so need enoughemergency capacity to inject when disease flares up

bull No advance warning to patientservice that injection needed

bull NEED TO DO IT WELL ndashNHS real life audits prn based regimes not good resultsUndertreatment in year 1 Affects long term prognosis and treatment burden

DMO ndash anti-VEGF Treat and Extend

bull Retain study ndash the only RCT data

bull Br J Ophthalmol 2015 Oct 9 pii bjophthalmol-2015-307249 doi 101136bjophthalmol-2015-307249 [Epub ahead of print]

bull Ranibizumab 05 mg treat-and-extend regimen for diabetic macular oedema the RETAIN study

bull Pruumlnte C1 Fajnkuchen F2 Mahmood S3 Ricci F4 Hatz K5 Studnička J6 Bezlyak V7 Parikh S7 Stubbings WJ7 Wenzel A7 Figueira J8 and the RETAIN Study Group

RETAIN Phase III trial evaluating the efficacy of lsquotreat and extendrsquo regimen (ARVO 2014)

bull Patients with DMO and visual impairment (n = 372) were randomised 111

to one of three groups for 24 months

bull Two phases to dosing schedule

bull Phase A

bull Patients in all groups were initially treated with monthly ranibizumab until BCVA remained

stable

bull Phase B

bull Patients in the TampE groups whose vision remained stable had treatment- free intervals

that were increased incrementally by 1 month for a maximum of 3 months

bull Patients in the PRN group had ongoing monthly monitoring

bull In all groups Phase A was resumed if a decrease in BCVA was observed at a visit

Ranibizumab 05 mg monotherapy

in TampE regimen

Ranibizumab 05 mg in TampE regimen

plus laser

Ranibizumab 05 mg PRN

35

RETAIN Visual acuity endpoints

Pruumlnte C ARVO 2014 Annual Meeting Abstracts Abstract 1700

Mean average change in BCVAat 12 months (primary endpoint)

Mean change in BCVA at 24 months

Mea

n av

erag

e ch

ange

in B

CVA

(ETD

RS

lette

rs)

RanibizumabTampE

RanibizumabTampE + laser

RanibizumabPRN

RanibizumabTampE

RanibizumabTampE + laser

RanibizumabPRN

Mea

n ch

ange

in B

CVA

(ETD

RS

lette

rs)

plt00001 for both ranibizumab TampE groups versus PRN for primary endpoint

36

RETAIN Patient visits and monitoring with TampE regimen over 24 months

bull The TampE regimen provided an approximately 40 reduction in the number of treatment visits required compared with the ranibizumab PRN regimen

bull Approximately 70 of patients receiving TampE regimens had monitoring intervals ge2 months compared with ongoing monthly monitoring in the ranibizumab PRN group

bull Informed the license for Lucentis in DMO (extend by 1 month at a time)

37

INTRAVITREAL STEROIDSWhich intravitreal steroid is better

bull Licensed steroids ndash Ozurdex (Dexamethasone) and Iluvien (Fluocinoloneacetonide

bull Which steroid is best in terms of VA outcomes hellipWE DONrsquoT KNOW FOR SURE ndash no head to head studies for licensed drugs either between steroids or between anti-VEGF and steroids

bull STEROIDS ARE efficacious in DMO

bull MEAD

bull FAME

bull DRCRnet protocol I

bull NICE ndash Ozurdex and Iluvien ndash second-line agents

Ozurdex

bull A biodegradable co-polymer implant ndash degrades in time to lactic and glycolic acid releasing Dexamethasone

bull 22gauge injectionbull MEAD study

bull N=1048

bull Dex 07mg vs 035mg vs sham

bull No rescue therapy

bull 3 year follow up max 6 monthly dosing ie 7 over 3 years

Gan IM et al Greafes Acrh Clin Exp Ophthalmol 2005

MEAD studyMean BCVA change from baseline based on baseline lens status

-2

0

2

4

6

8

10

0 3 6 9 12 15 18 21 24 27 30 33 36 39

Mea

n C

hang

e Fr

om

Bas

elin

e B

CVA

(Let

ters

)

Month

DEX Implant 07 mg (n = 86)

Sham (n = 101)

Boyer DS et al Ophthalmology 20141211904ndash14

Results analyzed in the ITT population with LOCF for missing values

Pseudophakic

Total

0

5

10

0 3 6 9 12 15 18 21 24 27 30 33 36 39

DEX 700 (n=351)

Sham (n=350)

10

8

6

4

2

0

Mea

n C

hang

e fr

om

Bas

elin

e B

CVA

(Let

ters

)

Month

07mg dose is approved as Ozurdexreg by the FDA and EMA 035mg dose not commercially available

1 Boyer DS et al Ophthalmology 2014 121 1904-1914

bull Nonbioerodible micro implant (polyimide) containing 190microg of fluocinolone acetonide (FAc)

bull Consistent daily submicrogram delivery of 02 microgd FAc for up to 36 months

bull Posterior point of release

bull 35 mm times 037 mm non-bioerodable micro implant

bull 25-gauge injector creates self-sealing wound

bull No measurable systemic exposure

ILUVIEN Implant Technology

FAcimplant

ILUVIEN SPC httpwwwmedicinesorgukemcmedicine27636

0 6 12 18 24 30 36

ILUVIEN 02 microgd FAc(n = 376)05 microgd FAc (n = 395)Control sham injection(n = 185)

Design of Phase 3 FAME Study (FAME A and B = same protocol)

Additional laser therapy allowed after week 6a

Retreatment any time after month 12 (if eligibleb)

Study ends

N = 956Randomisation

221Primary readout

Patients with DMO and

bull At least 1 previous laser tx

bull BCVA ge19 and le68 letters

bull TD-OCT FTH ge250 μm

Month

BCVA = best corrected visual acuity DMO = diabetic macular oedema TD-OCT=time domain optical coherence tomography FTH = foveal thicknessa At masked investigatorrsquos discretion b If BCVA loss ge5 letters or retinal thickening ge50 microm from best reading in previous 12 months

ge15 letter Gain is Greater in Chronic DMO Patients

ge 15

-Let

ter I

mpr

ovem

ent

in B

CVA

Fro

m B

asel

ine

Δ = 98

Months

Full Population Patients With Chronic DMO

Months

Δ = 206

287

189134

34

Steroid re-treatments

bullOzurdexbull Longer half-life than anti-VEGF in the eye

bull Redosing regimes not very helpful from RCT data eg MEAD study only 612 dosing

bull In reality re-treatment interval may be shorter

bull POSOLOGY

bull Patients treated with OZURDEX who have experienced an initial response and in the physicians opinion may benefit from retreatment without being exposed to significant risk should be considered for retreatment Retreatment may be performed after approximately 6 months if the patient experiences decreased vision andor an increase in retinal thickness secondary to recurrent or worsening diabetic macular oedema

bullIluvienbull 70 of patients in FAE only needed 1

injection over 3 years

bull BUT additional rescue treatments allowed

bull POSOLOGY

bull Each ILUVIEN implant releases fluocinolone acetonide for up to 36 months An additional implant may be administered after 12 months if the patient experiences decreased vision or an increase in retinal thickness secondary to recurrent or worsening diabetic macular oedema

bull Patients receiving escape medication were exited from MEAD before administration1

bull Macular laser rescue treatment allowed in RISERIDE (Lucentisreg) from 3 months2

bull Focalgrid laser allowed in FAME (Iluvienreg) from 6 weeks3

MEAD TREATMENT PROTOCOL

bull First treatment given at randomisation (day 0) bull Patients assessed for retreatment eligibility every 3 months from

months 6ndash36bull Patients were eligible for retreatment if

OCT optical coherence tomography

ge6 months since most recent

study treatment

Retinal thickness in 1 mm central macular

subfield by OCT gt175 microm

Evidence of residual retinal oedema (intraretinal cysts or

any regions of increased retinal thickening) as assessed by

investigator from OCT

AND OR

MEA

D

Amendment in May 2010 revised anatomic criterion for retreatment before this time the threshold was gt225 microm1Boyer DS et al Ophthalmology 2014 121 1904-19142Nguyen QD et al Ophthalmology 20121191064minus10773Campochiaro PA et al Ophthalmology 2011118626ndash635

Treatment burdenILUVIEN

Control(n =112)

02 microgd FAc(n =209)

Study Treatments(sham injection or ILUVIEN 02 microgday or FAc 05microgday)

1 treatment 661 761

2 treatments 277 187

ge 3 treatments 63 53

Rescue Laser Treatments (at masked physicianrsquos discretion after week 6)

Patients 607 407

Off-Protocol Treatments (IVTA bevacizumab ranibizumab intravitreal dexamethasone)

Patients 295 115

OZURDEX = 23injections year 1 41 by year 3

No other Rx

Summary of side effects with intravitreal steroids

Drug device Evidence base Cataract risk IOP rise (requiring drops)

Glaucoma surgery

endophthalmitis

ILUVIEN FAME studies 80 cat surgery(273 sham)

384(14 control)

48 0

Ozurdex MEAD 592 had cataract surgery(72 sham)

215 (end of study)(34 sham)

06 0

Trivaris+ laser vs Luc+laserx2 vs laser

Protocol IOphthalmology 2010

15 42(ONE OFgt10mmHg risegt30mmHGStart drops)

2186 0

NICE guidance for intravitreal steroids in DMO

bull Iluvien

bull NICE TA 301 Iluvien for DMO Nov 2013

bull hellipfor treating chronic diabetic macular oedema that is insufficiently responsive to available therapies only if

bull the implant is to be used in an eye with an intraocular

(pseudophakic) lens and

bull the manufacturer provides fluocinolone acetonide intravitreal implant with the discount agreed in the patient access scheme

NICE guidance for intravitreal steroids in DMO

bull Ozurdex

bull NICE TA 349 Ozurdex for DMO July 2015

bull there is an artificial lens in the eye to be treated and

bull their diabetic macular oedema has not improved with

non-corticosteroid treatment or such treatment is not suitable for them

Steroids = second line therapyWhen do I switch

bull Anti-VEGF first line for centre involving DMObull NICE TA ndash ldquoinsufficiently responsiverdquo ldquo ldquonot improvedrdquo ldquonot suitablerdquo ndash

OTHER TREATMENTS

bull 2 scenariosbull 1) Anti-VEGF canrsquot be funded ie OCTlt400um + PSEUDOPHAKIC

bull 2) Already had a course of treatment with laseranti-VEGF + PSEUDOPHAKIC ie SWITCHING from anti-VEGF to steroid

bull Plus

bull ldquochronicrdquo DMO ndash 3 years duration in FAME (18months) for ILUVIEN

bull Chronic DMO not essential for Ozurdex

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

Protocol T ndash patients may not improve in first 6 months

RIDE

RISE

Mea

n ch

ange

in B

CVA

(E

TDR

S le

tters

)M

ean

chan

ge in

BC

VA

(ETD

RS

lette

rs)

Time (months)

RISE and RIDE (Lucentis monthly dosing) Mean change in BCVA over 36 months

Brown DM et al Ophthalmology 2013120(10)2013ndash2022

54

Ranibizumab 03 mgRanibizumab 05 mgShamranibizumab 05 mg

Date of Prep Dec 2014 LGB0820147252X

VA improvement continues throughout year 1 with monthly dosing

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user ndash more than protocol

I

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

DRCRN protocol I5 year outcomesInjections 8-9 in year 1Year 2 = 2-3Year 3= 1-2Year 4 = 0-1Year 5 = 0

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

Wait for plateau = stability in protocol T laserPatient factors again

Judgement of response to anti-VEGF ndashtimeframe

bull Wait 6 months in poor responders

bull Wait 1 year for heavy users

bull Tempting to try steroids earlier than this ifbull No glaucoma ndash not a deal breaker Ozurdex better short term optionbull Pseudophakic

bull Clues from the diseasebull chronic

bull PATIENT FACTORS

bull Any eyes avoid steroids ndash advanced glaucomaCSCR Or prior viral retinitis RARE

bull Any eyes avoid anti-VEGF pregnancytrying to concieve recent CVA

BIOMARKERS AT BASELINE WOULD BE USEFULRESTORE subgroup analysis of OCT features

bull Andreas Pollreisz EURETINA 2015

bull OCT biomarkers (RESTORE data)

bull Better effects with anti-VEGF ifbull Small rather than large intra-retinal cyst

bull Sub-retinal fluid present

bull Vitreo-macular adhesion at baseline

bull No disruption of ELM and ISOS junction

bull No disorganisation of inner retinal layers (DRIL)

RESTORE subgroup analysis of OCT features

bull Andreas Pollreisz EURETINA 2015

bull OCT biomarkers (RESTORE data)

bull Better effects with anti-VEGF ifbull Small rather than large intra-retinal cyst

bull Sub-retinal fluid present

bull Vitreo-macular adhesion at baseline

bull No disruption of ELM and ISOS junction

bull No disorganisation of inner retinal layers (DRIL)

Better baseline characterisationclassificationERG Contrast sensitivityOCT AngiographyMicroperimetry= clues as to who responds best to which drug

Plan for this presentation helliphellipa long list

bull What treatment options are available for DMO (evidence base)

bull What treatment should I start with at baselinebull Re-treatment algorithms for intravitreal DMO therapiesbull When should I switchcombine therapiesbull The bigger picture

bull Other eyebull The patient as a wholebull The service -coping with capacity ndash compromises

The bigger pictureOther eyeThe patient as a wholeThe service -coping with capacity ndash compromises

bull OTHER EYE ndash may create problems

bull Treat and extend ndash ldquoreduce of visitsrdquo plus Eylea license ndash ldquono need for monitoringrdquo may not benefit if lots of visits due to PDR other eye

bull PERIPHERAL RETINA anti-VEGF supresses proliferative disease - Rebound on stopping Rx

bull PATIENT

bull Anti-VEGF ndash heavy user - Will comply

bull One stop much better than two stop for patient ndash Treat and extend

bull SERVICE

bull Capacity and demand planning = fixedT+E more predictable at least 1 month in advance ndash flexible nurse injectors

bull Steroids ndash even if well controlled (Iluvien for 3 years) need IOP check

bull Need pan-retinal examination both eyes ndash separate visits

Summary

CSMO

No centre involvement

Photocoagulation

Centre involvement

gt 78 letters(normalminimally reduced VA)

Photocoagulation

VA 78ndash24 letters

Phakic

Anti-VEGF

Pseudophakic

Anti-VEGF

SWITCHglaucoma

Injection tolerance

Medical issuesrecent CVA

Peripheral diseaseBilateral Rx

CSMO

No centre involvement

LASER

Centre involvement

gt 78 letters(normalminimally

reduced VA)

VA 78ndash24 letters

EYLEA OR LUCENTIS OR AVASTIN

Funding issues

Protocol T ndash poor VA lt 65 letters (615)

LOADING

Monthly injections until stability OR 5 x 112 (EYLEA) = 6 MONTHS then 8 weeks

RETREATMENT1

TREAT AND EXTEND - PRN

PRN

PSEUDOPHAKIC

Prior Rx

ILUVIEN

Chronic disease

OZURDEX

RETREATMENT

OZURDEX

OCT gt175um or any residual oedema

ILUVIEN after 12 months if risksltbenefits

OCT

gt400um

bull FACE TO FACE CLINICS RUNNING IN PARALLEL

bull = MAC002 every 6 months (optom or doctor) routine check for cataracttolerance of injectionsglaucoma issues etc

bull =MAC003 (DOCTOR) for problems as needed no fixed intervalDischargestop treatmentDeclines treatment diagnosis CSR overlay etcswitch drugs

bull =RV002- (DOCTOR) every 6 months

bull =DM002 ndash (DOCTOR) variable interval determined by last assessing doctor

bull First visit at 6 months from 1st injection if mild NPDR

bull Otherwise determined by retinopathy generally

LOADING PHASE

EyleaLucentis 1 within 48hrs of baseline

EyleaLucentis 2 (and LogMAR VA plus OCT same visit)

EyleaLucentis 3 (and LogMAR VA plus OCT same visit)

EyleaLucentis 4 (TEinj)(and Logmar VA plus OCT same visit

AFTER INJECTION 4 data goes off to be reviewed immediately as a hellip

TREAT AND EXTEND assessment ndash the next interval will depend on the response to the loading phase

NB -DMO patients ndash majority (95) will need 6 injctions x 112 of Lucentis

OR Eylea 5 x 112 then 8 weekly

ONCE STABLE for 3 x injection in TE phase

VIRTUAL CLINIC MONITORING OF MACULOPATHY AND PRN RETREATMENT

ANTI-VEGF INJECTION PATHWAYS Baseline visitMAC001 for wet AMDRV001 for CRVOBRVOMed ret clinic for DMO

Pathways ndash too many directions

Better that thanhellip

Thank you

Assuming we have started with an anti-VEGF agent ndash what are the re-treatment algorithms in DMO

Treatment posologies

ldquoTreatment is initiated with one injection per month until maximum VA is achieved andor there are no signs of disease activity ie no change in VA and in other signs and

symptoms of the disease under continued treatment

In patients withhellipDMOhellip initially three or more consecutive monthly injections may be needed Thereafter monitoring and treatment intervals

should be determined by the physician and should be based on disease activity as

assessed by VA andor anatomical parametershellip

If patients are being treated according to a treat-and-extend regimen once maximum VA is achieved andor there are no

signs of disease activity the treatment intervals can be extended stepwise until signs of

disease activity or visual impairment recur The treatment intervalhellipmay be extended by up to one month

at a time for DMOrdquo

1 Novartis Pharmaceuticals UK Ltd 30 October 2014 Available at httpwwwmedicinesorgukemcmedicine19409 Accessed 04 September 2015

2 Bayer Pharma AG February 2015 Available at httpwwwmedicinesorgukemcmedicine27224 Accessed 04 September 2015

Ranibizumab1 Aflibercept2

ldquohelliptreatment is initiated with one injection per month for five consecutive doses followed by

one injection every two months There is no requirement for monitoring between injectionshellip

After the first 12 months of treatmenthellipthe treatment interval may be extended based

on visual andor anatomic outcomes The schedule for monitoring should

be determined by the treating physicianrdquo

DMO diabetic macular oedema VA visual acuity

Re-treatment algorithms for anti-VEGF agents in DMO

bull LOADING PHASE

bull Lucentis label = monthly until stability

bull Eylea label = 5 x 112 then every 8 weeks ie fixed regime year 1

bull DRCRnet protocol T = effectively 6 x112 for majority (95) BUT actually only mandated for first 3 months then prn

bull helliphellip likely that majority will receive injections monthly for first 6 months

bull INDIVIDUALISED PHASE

bull Once ldquostablerdquo ndash based on VA and OCT

bull NB May never get a ldquodryrdquo OCT so treat to stability

bull THEN

bull Treat and extend

bull prn

What does Treat and Extend mean

Pathway overview = Lucentis prn

Jan

Loading phase = injections every 4 weeks until ldquostablerdquo for 3 visits

helliphelliphellip

Feb OctSepAugJulJunMayAprMar

MarFebJan

DecNov

DecNovOctSepAugJulJunMayApr

Then observe UNTIL VA decreases or OCT increase = prn

Once reactivates need at least 2 injections until stable again over 3 visits

Pathway overview = Treat and Extend

Jan

Loading phase = injections every 4 weeks until ldquostablerdquo for 3 visits or Eyleayear 1

helliphelliphellip

Feb OctSepAugJulJunMayAprMar

MarFebJan

DecNov

DecNovOctSepAugJulJunMayApr

Then keep injecting but extend the interval between injections gradually ie keep treating even if perfect

If reactivates need at least 2 injections until stable again over 3 visits

Pathway overview = Eylea fixed dosing year 1

Jan

Eylea = 5 x 112 injection then every 8 weeks

Average 6 injections yr 2 Beyond that

helliphelliphellip

Feb OctSepAugJulJunMayAprMar

MarFebJan

DecNov

DecNovOctSepAugJulJunMayApr

Then individualised UNTIL VA decreases or OCT increase = prn

Once reactivates need at least 2 injections until stable again over 3 visits

Pros and cons of Treat and Extend vs Prn

T+E PRN

PROS bull Proactive patient and service get advance warning of injection ndash capacity and demand planning easier

bull One ndashstopbull Fewer visits than prnbull Overtreatment

advantageous for peripheral retinopathy

bull Only treated when active ieno overtreatment

bull Aggressive year 1 protocols (DRCRN I ndash few injections needed thereafter

bull DMO tolerant of reactivations ()

CONS bull Overtreatment = riskexpenseinconvenience

bull Evidence base scantbull Bilateral disease tricky

bull Reactive so need enoughemergency capacity to inject when disease flares up

bull No advance warning to patientservice that injection needed

bull NEED TO DO IT WELL ndashNHS real life audits prn based regimes not good resultsUndertreatment in year 1 Affects long term prognosis and treatment burden

Pros and cons of Treat and Extend vs Prn

T+E PRN

PROS bull Proactive patient and service get advance warning of injection ndash capacity and demand planning easier

bull One ndashstopbull Fewer visits than prnbull Overtreatment

advantageous for peripheral retinopathy

bull Only treated when active ieno overtreatment

bull Aggressive year 1 protocols (DRCRN I ndash few injections needed thereafter

bull DMO tolerant of reactivations ()

CONS bull Overtreatment = riskexpenseinconvenience

bull Evidence base scantbull Bilateral disease tricky

bull Reactive so need enoughemergency capacity to inject when disease flares up

bull No advance warning to patientservice that injection needed

bull NEED TO DO IT WELL ndashNHS real life audits prn based regimes not good resultsUndertreatment in year 1 Affects long term prognosis and treatment burden

DMO ndash anti-VEGF Treat and Extend

bull Retain study ndash the only RCT data

bull Br J Ophthalmol 2015 Oct 9 pii bjophthalmol-2015-307249 doi 101136bjophthalmol-2015-307249 [Epub ahead of print]

bull Ranibizumab 05 mg treat-and-extend regimen for diabetic macular oedema the RETAIN study

bull Pruumlnte C1 Fajnkuchen F2 Mahmood S3 Ricci F4 Hatz K5 Studnička J6 Bezlyak V7 Parikh S7 Stubbings WJ7 Wenzel A7 Figueira J8 and the RETAIN Study Group

RETAIN Phase III trial evaluating the efficacy of lsquotreat and extendrsquo regimen (ARVO 2014)

bull Patients with DMO and visual impairment (n = 372) were randomised 111

to one of three groups for 24 months

bull Two phases to dosing schedule

bull Phase A

bull Patients in all groups were initially treated with monthly ranibizumab until BCVA remained

stable

bull Phase B

bull Patients in the TampE groups whose vision remained stable had treatment- free intervals

that were increased incrementally by 1 month for a maximum of 3 months

bull Patients in the PRN group had ongoing monthly monitoring

bull In all groups Phase A was resumed if a decrease in BCVA was observed at a visit

Ranibizumab 05 mg monotherapy

in TampE regimen

Ranibizumab 05 mg in TampE regimen

plus laser

Ranibizumab 05 mg PRN

35

RETAIN Visual acuity endpoints

Pruumlnte C ARVO 2014 Annual Meeting Abstracts Abstract 1700

Mean average change in BCVAat 12 months (primary endpoint)

Mean change in BCVA at 24 months

Mea

n av

erag

e ch

ange

in B

CVA

(ETD

RS

lette

rs)

RanibizumabTampE

RanibizumabTampE + laser

RanibizumabPRN

RanibizumabTampE

RanibizumabTampE + laser

RanibizumabPRN

Mea

n ch

ange

in B

CVA

(ETD

RS

lette

rs)

plt00001 for both ranibizumab TampE groups versus PRN for primary endpoint

36

RETAIN Patient visits and monitoring with TampE regimen over 24 months

bull The TampE regimen provided an approximately 40 reduction in the number of treatment visits required compared with the ranibizumab PRN regimen

bull Approximately 70 of patients receiving TampE regimens had monitoring intervals ge2 months compared with ongoing monthly monitoring in the ranibizumab PRN group

bull Informed the license for Lucentis in DMO (extend by 1 month at a time)

37

INTRAVITREAL STEROIDSWhich intravitreal steroid is better

bull Licensed steroids ndash Ozurdex (Dexamethasone) and Iluvien (Fluocinoloneacetonide

bull Which steroid is best in terms of VA outcomes hellipWE DONrsquoT KNOW FOR SURE ndash no head to head studies for licensed drugs either between steroids or between anti-VEGF and steroids

bull STEROIDS ARE efficacious in DMO

bull MEAD

bull FAME

bull DRCRnet protocol I

bull NICE ndash Ozurdex and Iluvien ndash second-line agents

Ozurdex

bull A biodegradable co-polymer implant ndash degrades in time to lactic and glycolic acid releasing Dexamethasone

bull 22gauge injectionbull MEAD study

bull N=1048

bull Dex 07mg vs 035mg vs sham

bull No rescue therapy

bull 3 year follow up max 6 monthly dosing ie 7 over 3 years

Gan IM et al Greafes Acrh Clin Exp Ophthalmol 2005

MEAD studyMean BCVA change from baseline based on baseline lens status

-2

0

2

4

6

8

10

0 3 6 9 12 15 18 21 24 27 30 33 36 39

Mea

n C

hang

e Fr

om

Bas

elin

e B

CVA

(Let

ters

)

Month

DEX Implant 07 mg (n = 86)

Sham (n = 101)

Boyer DS et al Ophthalmology 20141211904ndash14

Results analyzed in the ITT population with LOCF for missing values

Pseudophakic

Total

0

5

10

0 3 6 9 12 15 18 21 24 27 30 33 36 39

DEX 700 (n=351)

Sham (n=350)

10

8

6

4

2

0

Mea

n C

hang

e fr

om

Bas

elin

e B

CVA

(Let

ters

)

Month

07mg dose is approved as Ozurdexreg by the FDA and EMA 035mg dose not commercially available

1 Boyer DS et al Ophthalmology 2014 121 1904-1914

bull Nonbioerodible micro implant (polyimide) containing 190microg of fluocinolone acetonide (FAc)

bull Consistent daily submicrogram delivery of 02 microgd FAc for up to 36 months

bull Posterior point of release

bull 35 mm times 037 mm non-bioerodable micro implant

bull 25-gauge injector creates self-sealing wound

bull No measurable systemic exposure

ILUVIEN Implant Technology

FAcimplant

ILUVIEN SPC httpwwwmedicinesorgukemcmedicine27636

0 6 12 18 24 30 36

ILUVIEN 02 microgd FAc(n = 376)05 microgd FAc (n = 395)Control sham injection(n = 185)

Design of Phase 3 FAME Study (FAME A and B = same protocol)

Additional laser therapy allowed after week 6a

Retreatment any time after month 12 (if eligibleb)

Study ends

N = 956Randomisation

221Primary readout

Patients with DMO and

bull At least 1 previous laser tx

bull BCVA ge19 and le68 letters

bull TD-OCT FTH ge250 μm

Month

BCVA = best corrected visual acuity DMO = diabetic macular oedema TD-OCT=time domain optical coherence tomography FTH = foveal thicknessa At masked investigatorrsquos discretion b If BCVA loss ge5 letters or retinal thickening ge50 microm from best reading in previous 12 months

ge15 letter Gain is Greater in Chronic DMO Patients

ge 15

-Let

ter I

mpr

ovem

ent

in B

CVA

Fro

m B

asel

ine

Δ = 98

Months

Full Population Patients With Chronic DMO

Months

Δ = 206

287

189134

34

Steroid re-treatments

bullOzurdexbull Longer half-life than anti-VEGF in the eye

bull Redosing regimes not very helpful from RCT data eg MEAD study only 612 dosing

bull In reality re-treatment interval may be shorter

bull POSOLOGY

bull Patients treated with OZURDEX who have experienced an initial response and in the physicians opinion may benefit from retreatment without being exposed to significant risk should be considered for retreatment Retreatment may be performed after approximately 6 months if the patient experiences decreased vision andor an increase in retinal thickness secondary to recurrent or worsening diabetic macular oedema

bullIluvienbull 70 of patients in FAE only needed 1

injection over 3 years

bull BUT additional rescue treatments allowed

bull POSOLOGY

bull Each ILUVIEN implant releases fluocinolone acetonide for up to 36 months An additional implant may be administered after 12 months if the patient experiences decreased vision or an increase in retinal thickness secondary to recurrent or worsening diabetic macular oedema

bull Patients receiving escape medication were exited from MEAD before administration1

bull Macular laser rescue treatment allowed in RISERIDE (Lucentisreg) from 3 months2

bull Focalgrid laser allowed in FAME (Iluvienreg) from 6 weeks3

MEAD TREATMENT PROTOCOL

bull First treatment given at randomisation (day 0) bull Patients assessed for retreatment eligibility every 3 months from

months 6ndash36bull Patients were eligible for retreatment if

OCT optical coherence tomography

ge6 months since most recent

study treatment

Retinal thickness in 1 mm central macular

subfield by OCT gt175 microm

Evidence of residual retinal oedema (intraretinal cysts or

any regions of increased retinal thickening) as assessed by

investigator from OCT

AND OR

MEA

D

Amendment in May 2010 revised anatomic criterion for retreatment before this time the threshold was gt225 microm1Boyer DS et al Ophthalmology 2014 121 1904-19142Nguyen QD et al Ophthalmology 20121191064minus10773Campochiaro PA et al Ophthalmology 2011118626ndash635

Treatment burdenILUVIEN

Control(n =112)

02 microgd FAc(n =209)

Study Treatments(sham injection or ILUVIEN 02 microgday or FAc 05microgday)

1 treatment 661 761

2 treatments 277 187

ge 3 treatments 63 53

Rescue Laser Treatments (at masked physicianrsquos discretion after week 6)

Patients 607 407

Off-Protocol Treatments (IVTA bevacizumab ranibizumab intravitreal dexamethasone)

Patients 295 115

OZURDEX = 23injections year 1 41 by year 3

No other Rx

Summary of side effects with intravitreal steroids

Drug device Evidence base Cataract risk IOP rise (requiring drops)

Glaucoma surgery

endophthalmitis

ILUVIEN FAME studies 80 cat surgery(273 sham)

384(14 control)

48 0

Ozurdex MEAD 592 had cataract surgery(72 sham)

215 (end of study)(34 sham)

06 0

Trivaris+ laser vs Luc+laserx2 vs laser

Protocol IOphthalmology 2010

15 42(ONE OFgt10mmHg risegt30mmHGStart drops)

2186 0

NICE guidance for intravitreal steroids in DMO

bull Iluvien

bull NICE TA 301 Iluvien for DMO Nov 2013

bull hellipfor treating chronic diabetic macular oedema that is insufficiently responsive to available therapies only if

bull the implant is to be used in an eye with an intraocular

(pseudophakic) lens and

bull the manufacturer provides fluocinolone acetonide intravitreal implant with the discount agreed in the patient access scheme

NICE guidance for intravitreal steroids in DMO

bull Ozurdex

bull NICE TA 349 Ozurdex for DMO July 2015

bull there is an artificial lens in the eye to be treated and

bull their diabetic macular oedema has not improved with

non-corticosteroid treatment or such treatment is not suitable for them

Steroids = second line therapyWhen do I switch

bull Anti-VEGF first line for centre involving DMObull NICE TA ndash ldquoinsufficiently responsiverdquo ldquo ldquonot improvedrdquo ldquonot suitablerdquo ndash

OTHER TREATMENTS

bull 2 scenariosbull 1) Anti-VEGF canrsquot be funded ie OCTlt400um + PSEUDOPHAKIC

bull 2) Already had a course of treatment with laseranti-VEGF + PSEUDOPHAKIC ie SWITCHING from anti-VEGF to steroid

bull Plus

bull ldquochronicrdquo DMO ndash 3 years duration in FAME (18months) for ILUVIEN

bull Chronic DMO not essential for Ozurdex

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

Protocol T ndash patients may not improve in first 6 months

RIDE

RISE

Mea

n ch

ange

in B

CVA

(E

TDR

S le

tters

)M

ean

chan

ge in

BC

VA

(ETD

RS

lette

rs)

Time (months)

RISE and RIDE (Lucentis monthly dosing) Mean change in BCVA over 36 months

Brown DM et al Ophthalmology 2013120(10)2013ndash2022

54

Ranibizumab 03 mgRanibizumab 05 mgShamranibizumab 05 mg

Date of Prep Dec 2014 LGB0820147252X

VA improvement continues throughout year 1 with monthly dosing

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user ndash more than protocol

I

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

DRCRN protocol I5 year outcomesInjections 8-9 in year 1Year 2 = 2-3Year 3= 1-2Year 4 = 0-1Year 5 = 0

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

Wait for plateau = stability in protocol T laserPatient factors again

Judgement of response to anti-VEGF ndashtimeframe

bull Wait 6 months in poor responders

bull Wait 1 year for heavy users

bull Tempting to try steroids earlier than this ifbull No glaucoma ndash not a deal breaker Ozurdex better short term optionbull Pseudophakic

bull Clues from the diseasebull chronic

bull PATIENT FACTORS

bull Any eyes avoid steroids ndash advanced glaucomaCSCR Or prior viral retinitis RARE

bull Any eyes avoid anti-VEGF pregnancytrying to concieve recent CVA

BIOMARKERS AT BASELINE WOULD BE USEFULRESTORE subgroup analysis of OCT features

bull Andreas Pollreisz EURETINA 2015

bull OCT biomarkers (RESTORE data)

bull Better effects with anti-VEGF ifbull Small rather than large intra-retinal cyst

bull Sub-retinal fluid present

bull Vitreo-macular adhesion at baseline

bull No disruption of ELM and ISOS junction

bull No disorganisation of inner retinal layers (DRIL)

RESTORE subgroup analysis of OCT features

bull Andreas Pollreisz EURETINA 2015

bull OCT biomarkers (RESTORE data)

bull Better effects with anti-VEGF ifbull Small rather than large intra-retinal cyst

bull Sub-retinal fluid present

bull Vitreo-macular adhesion at baseline

bull No disruption of ELM and ISOS junction

bull No disorganisation of inner retinal layers (DRIL)

Better baseline characterisationclassificationERG Contrast sensitivityOCT AngiographyMicroperimetry= clues as to who responds best to which drug

Plan for this presentation helliphellipa long list

bull What treatment options are available for DMO (evidence base)

bull What treatment should I start with at baselinebull Re-treatment algorithms for intravitreal DMO therapiesbull When should I switchcombine therapiesbull The bigger picture

bull Other eyebull The patient as a wholebull The service -coping with capacity ndash compromises

The bigger pictureOther eyeThe patient as a wholeThe service -coping with capacity ndash compromises

bull OTHER EYE ndash may create problems

bull Treat and extend ndash ldquoreduce of visitsrdquo plus Eylea license ndash ldquono need for monitoringrdquo may not benefit if lots of visits due to PDR other eye

bull PERIPHERAL RETINA anti-VEGF supresses proliferative disease - Rebound on stopping Rx

bull PATIENT

bull Anti-VEGF ndash heavy user - Will comply

bull One stop much better than two stop for patient ndash Treat and extend

bull SERVICE

bull Capacity and demand planning = fixedT+E more predictable at least 1 month in advance ndash flexible nurse injectors

bull Steroids ndash even if well controlled (Iluvien for 3 years) need IOP check

bull Need pan-retinal examination both eyes ndash separate visits

Summary

CSMO

No centre involvement

Photocoagulation

Centre involvement

gt 78 letters(normalminimally reduced VA)

Photocoagulation

VA 78ndash24 letters

Phakic

Anti-VEGF

Pseudophakic

Anti-VEGF

SWITCHglaucoma

Injection tolerance

Medical issuesrecent CVA

Peripheral diseaseBilateral Rx

CSMO

No centre involvement

LASER

Centre involvement

gt 78 letters(normalminimally

reduced VA)

VA 78ndash24 letters

EYLEA OR LUCENTIS OR AVASTIN

Funding issues

Protocol T ndash poor VA lt 65 letters (615)

LOADING

Monthly injections until stability OR 5 x 112 (EYLEA) = 6 MONTHS then 8 weeks

RETREATMENT1

TREAT AND EXTEND - PRN

PRN

PSEUDOPHAKIC

Prior Rx

ILUVIEN

Chronic disease

OZURDEX

RETREATMENT

OZURDEX

OCT gt175um or any residual oedema

ILUVIEN after 12 months if risksltbenefits

OCT

gt400um

bull FACE TO FACE CLINICS RUNNING IN PARALLEL

bull = MAC002 every 6 months (optom or doctor) routine check for cataracttolerance of injectionsglaucoma issues etc

bull =MAC003 (DOCTOR) for problems as needed no fixed intervalDischargestop treatmentDeclines treatment diagnosis CSR overlay etcswitch drugs

bull =RV002- (DOCTOR) every 6 months

bull =DM002 ndash (DOCTOR) variable interval determined by last assessing doctor

bull First visit at 6 months from 1st injection if mild NPDR

bull Otherwise determined by retinopathy generally

LOADING PHASE

EyleaLucentis 1 within 48hrs of baseline

EyleaLucentis 2 (and LogMAR VA plus OCT same visit)

EyleaLucentis 3 (and LogMAR VA plus OCT same visit)

EyleaLucentis 4 (TEinj)(and Logmar VA plus OCT same visit

AFTER INJECTION 4 data goes off to be reviewed immediately as a hellip

TREAT AND EXTEND assessment ndash the next interval will depend on the response to the loading phase

NB -DMO patients ndash majority (95) will need 6 injctions x 112 of Lucentis

OR Eylea 5 x 112 then 8 weekly

ONCE STABLE for 3 x injection in TE phase

VIRTUAL CLINIC MONITORING OF MACULOPATHY AND PRN RETREATMENT

ANTI-VEGF INJECTION PATHWAYS Baseline visitMAC001 for wet AMDRV001 for CRVOBRVOMed ret clinic for DMO

Pathways ndash too many directions

Better that thanhellip

Thank you

Treatment posologies

ldquoTreatment is initiated with one injection per month until maximum VA is achieved andor there are no signs of disease activity ie no change in VA and in other signs and

symptoms of the disease under continued treatment

In patients withhellipDMOhellip initially three or more consecutive monthly injections may be needed Thereafter monitoring and treatment intervals

should be determined by the physician and should be based on disease activity as

assessed by VA andor anatomical parametershellip

If patients are being treated according to a treat-and-extend regimen once maximum VA is achieved andor there are no

signs of disease activity the treatment intervals can be extended stepwise until signs of

disease activity or visual impairment recur The treatment intervalhellipmay be extended by up to one month

at a time for DMOrdquo

1 Novartis Pharmaceuticals UK Ltd 30 October 2014 Available at httpwwwmedicinesorgukemcmedicine19409 Accessed 04 September 2015

2 Bayer Pharma AG February 2015 Available at httpwwwmedicinesorgukemcmedicine27224 Accessed 04 September 2015

Ranibizumab1 Aflibercept2

ldquohelliptreatment is initiated with one injection per month for five consecutive doses followed by

one injection every two months There is no requirement for monitoring between injectionshellip

After the first 12 months of treatmenthellipthe treatment interval may be extended based

on visual andor anatomic outcomes The schedule for monitoring should

be determined by the treating physicianrdquo

DMO diabetic macular oedema VA visual acuity

Re-treatment algorithms for anti-VEGF agents in DMO

bull LOADING PHASE

bull Lucentis label = monthly until stability

bull Eylea label = 5 x 112 then every 8 weeks ie fixed regime year 1

bull DRCRnet protocol T = effectively 6 x112 for majority (95) BUT actually only mandated for first 3 months then prn

bull helliphellip likely that majority will receive injections monthly for first 6 months

bull INDIVIDUALISED PHASE

bull Once ldquostablerdquo ndash based on VA and OCT

bull NB May never get a ldquodryrdquo OCT so treat to stability

bull THEN

bull Treat and extend

bull prn

What does Treat and Extend mean

Pathway overview = Lucentis prn

Jan

Loading phase = injections every 4 weeks until ldquostablerdquo for 3 visits

helliphelliphellip

Feb OctSepAugJulJunMayAprMar

MarFebJan

DecNov

DecNovOctSepAugJulJunMayApr

Then observe UNTIL VA decreases or OCT increase = prn

Once reactivates need at least 2 injections until stable again over 3 visits

Pathway overview = Treat and Extend

Jan

Loading phase = injections every 4 weeks until ldquostablerdquo for 3 visits or Eyleayear 1

helliphelliphellip

Feb OctSepAugJulJunMayAprMar

MarFebJan

DecNov

DecNovOctSepAugJulJunMayApr

Then keep injecting but extend the interval between injections gradually ie keep treating even if perfect

If reactivates need at least 2 injections until stable again over 3 visits

Pathway overview = Eylea fixed dosing year 1

Jan

Eylea = 5 x 112 injection then every 8 weeks

Average 6 injections yr 2 Beyond that

helliphelliphellip

Feb OctSepAugJulJunMayAprMar

MarFebJan

DecNov

DecNovOctSepAugJulJunMayApr

Then individualised UNTIL VA decreases or OCT increase = prn

Once reactivates need at least 2 injections until stable again over 3 visits

Pros and cons of Treat and Extend vs Prn

T+E PRN

PROS bull Proactive patient and service get advance warning of injection ndash capacity and demand planning easier

bull One ndashstopbull Fewer visits than prnbull Overtreatment

advantageous for peripheral retinopathy

bull Only treated when active ieno overtreatment

bull Aggressive year 1 protocols (DRCRN I ndash few injections needed thereafter

bull DMO tolerant of reactivations ()

CONS bull Overtreatment = riskexpenseinconvenience

bull Evidence base scantbull Bilateral disease tricky

bull Reactive so need enoughemergency capacity to inject when disease flares up

bull No advance warning to patientservice that injection needed

bull NEED TO DO IT WELL ndashNHS real life audits prn based regimes not good resultsUndertreatment in year 1 Affects long term prognosis and treatment burden

Pros and cons of Treat and Extend vs Prn

T+E PRN

PROS bull Proactive patient and service get advance warning of injection ndash capacity and demand planning easier

bull One ndashstopbull Fewer visits than prnbull Overtreatment

advantageous for peripheral retinopathy

bull Only treated when active ieno overtreatment

bull Aggressive year 1 protocols (DRCRN I ndash few injections needed thereafter

bull DMO tolerant of reactivations ()

CONS bull Overtreatment = riskexpenseinconvenience

bull Evidence base scantbull Bilateral disease tricky

bull Reactive so need enoughemergency capacity to inject when disease flares up

bull No advance warning to patientservice that injection needed

bull NEED TO DO IT WELL ndashNHS real life audits prn based regimes not good resultsUndertreatment in year 1 Affects long term prognosis and treatment burden

DMO ndash anti-VEGF Treat and Extend

bull Retain study ndash the only RCT data

bull Br J Ophthalmol 2015 Oct 9 pii bjophthalmol-2015-307249 doi 101136bjophthalmol-2015-307249 [Epub ahead of print]

bull Ranibizumab 05 mg treat-and-extend regimen for diabetic macular oedema the RETAIN study

bull Pruumlnte C1 Fajnkuchen F2 Mahmood S3 Ricci F4 Hatz K5 Studnička J6 Bezlyak V7 Parikh S7 Stubbings WJ7 Wenzel A7 Figueira J8 and the RETAIN Study Group

RETAIN Phase III trial evaluating the efficacy of lsquotreat and extendrsquo regimen (ARVO 2014)

bull Patients with DMO and visual impairment (n = 372) were randomised 111

to one of three groups for 24 months

bull Two phases to dosing schedule

bull Phase A

bull Patients in all groups were initially treated with monthly ranibizumab until BCVA remained

stable

bull Phase B

bull Patients in the TampE groups whose vision remained stable had treatment- free intervals

that were increased incrementally by 1 month for a maximum of 3 months

bull Patients in the PRN group had ongoing monthly monitoring

bull In all groups Phase A was resumed if a decrease in BCVA was observed at a visit

Ranibizumab 05 mg monotherapy

in TampE regimen

Ranibizumab 05 mg in TampE regimen

plus laser

Ranibizumab 05 mg PRN

35

RETAIN Visual acuity endpoints

Pruumlnte C ARVO 2014 Annual Meeting Abstracts Abstract 1700

Mean average change in BCVAat 12 months (primary endpoint)

Mean change in BCVA at 24 months

Mea

n av

erag

e ch

ange

in B

CVA

(ETD

RS

lette

rs)

RanibizumabTampE

RanibizumabTampE + laser

RanibizumabPRN

RanibizumabTampE

RanibizumabTampE + laser

RanibizumabPRN

Mea

n ch

ange

in B

CVA

(ETD

RS

lette

rs)

plt00001 for both ranibizumab TampE groups versus PRN for primary endpoint

36

RETAIN Patient visits and monitoring with TampE regimen over 24 months

bull The TampE regimen provided an approximately 40 reduction in the number of treatment visits required compared with the ranibizumab PRN regimen

bull Approximately 70 of patients receiving TampE regimens had monitoring intervals ge2 months compared with ongoing monthly monitoring in the ranibizumab PRN group

bull Informed the license for Lucentis in DMO (extend by 1 month at a time)

37

INTRAVITREAL STEROIDSWhich intravitreal steroid is better

bull Licensed steroids ndash Ozurdex (Dexamethasone) and Iluvien (Fluocinoloneacetonide

bull Which steroid is best in terms of VA outcomes hellipWE DONrsquoT KNOW FOR SURE ndash no head to head studies for licensed drugs either between steroids or between anti-VEGF and steroids

bull STEROIDS ARE efficacious in DMO

bull MEAD

bull FAME

bull DRCRnet protocol I

bull NICE ndash Ozurdex and Iluvien ndash second-line agents

Ozurdex

bull A biodegradable co-polymer implant ndash degrades in time to lactic and glycolic acid releasing Dexamethasone

bull 22gauge injectionbull MEAD study

bull N=1048

bull Dex 07mg vs 035mg vs sham

bull No rescue therapy

bull 3 year follow up max 6 monthly dosing ie 7 over 3 years

Gan IM et al Greafes Acrh Clin Exp Ophthalmol 2005

MEAD studyMean BCVA change from baseline based on baseline lens status

-2

0

2

4

6

8

10

0 3 6 9 12 15 18 21 24 27 30 33 36 39

Mea

n C

hang

e Fr

om

Bas

elin

e B

CVA

(Let

ters

)

Month

DEX Implant 07 mg (n = 86)

Sham (n = 101)

Boyer DS et al Ophthalmology 20141211904ndash14

Results analyzed in the ITT population with LOCF for missing values

Pseudophakic

Total

0

5

10

0 3 6 9 12 15 18 21 24 27 30 33 36 39

DEX 700 (n=351)

Sham (n=350)

10

8

6

4

2

0

Mea

n C

hang

e fr

om

Bas

elin

e B

CVA

(Let

ters

)

Month

07mg dose is approved as Ozurdexreg by the FDA and EMA 035mg dose not commercially available

1 Boyer DS et al Ophthalmology 2014 121 1904-1914

bull Nonbioerodible micro implant (polyimide) containing 190microg of fluocinolone acetonide (FAc)

bull Consistent daily submicrogram delivery of 02 microgd FAc for up to 36 months

bull Posterior point of release

bull 35 mm times 037 mm non-bioerodable micro implant

bull 25-gauge injector creates self-sealing wound

bull No measurable systemic exposure

ILUVIEN Implant Technology

FAcimplant

ILUVIEN SPC httpwwwmedicinesorgukemcmedicine27636

0 6 12 18 24 30 36

ILUVIEN 02 microgd FAc(n = 376)05 microgd FAc (n = 395)Control sham injection(n = 185)

Design of Phase 3 FAME Study (FAME A and B = same protocol)

Additional laser therapy allowed after week 6a

Retreatment any time after month 12 (if eligibleb)

Study ends

N = 956Randomisation

221Primary readout

Patients with DMO and

bull At least 1 previous laser tx

bull BCVA ge19 and le68 letters

bull TD-OCT FTH ge250 μm

Month

BCVA = best corrected visual acuity DMO = diabetic macular oedema TD-OCT=time domain optical coherence tomography FTH = foveal thicknessa At masked investigatorrsquos discretion b If BCVA loss ge5 letters or retinal thickening ge50 microm from best reading in previous 12 months

ge15 letter Gain is Greater in Chronic DMO Patients

ge 15

-Let

ter I

mpr

ovem

ent

in B

CVA

Fro

m B

asel

ine

Δ = 98

Months

Full Population Patients With Chronic DMO

Months

Δ = 206

287

189134

34

Steroid re-treatments

bullOzurdexbull Longer half-life than anti-VEGF in the eye

bull Redosing regimes not very helpful from RCT data eg MEAD study only 612 dosing

bull In reality re-treatment interval may be shorter

bull POSOLOGY

bull Patients treated with OZURDEX who have experienced an initial response and in the physicians opinion may benefit from retreatment without being exposed to significant risk should be considered for retreatment Retreatment may be performed after approximately 6 months if the patient experiences decreased vision andor an increase in retinal thickness secondary to recurrent or worsening diabetic macular oedema

bullIluvienbull 70 of patients in FAE only needed 1

injection over 3 years

bull BUT additional rescue treatments allowed

bull POSOLOGY

bull Each ILUVIEN implant releases fluocinolone acetonide for up to 36 months An additional implant may be administered after 12 months if the patient experiences decreased vision or an increase in retinal thickness secondary to recurrent or worsening diabetic macular oedema

bull Patients receiving escape medication were exited from MEAD before administration1

bull Macular laser rescue treatment allowed in RISERIDE (Lucentisreg) from 3 months2

bull Focalgrid laser allowed in FAME (Iluvienreg) from 6 weeks3

MEAD TREATMENT PROTOCOL

bull First treatment given at randomisation (day 0) bull Patients assessed for retreatment eligibility every 3 months from

months 6ndash36bull Patients were eligible for retreatment if

OCT optical coherence tomography

ge6 months since most recent

study treatment

Retinal thickness in 1 mm central macular

subfield by OCT gt175 microm

Evidence of residual retinal oedema (intraretinal cysts or

any regions of increased retinal thickening) as assessed by

investigator from OCT

AND OR

MEA

D

Amendment in May 2010 revised anatomic criterion for retreatment before this time the threshold was gt225 microm1Boyer DS et al Ophthalmology 2014 121 1904-19142Nguyen QD et al Ophthalmology 20121191064minus10773Campochiaro PA et al Ophthalmology 2011118626ndash635

Treatment burdenILUVIEN

Control(n =112)

02 microgd FAc(n =209)

Study Treatments(sham injection or ILUVIEN 02 microgday or FAc 05microgday)

1 treatment 661 761

2 treatments 277 187

ge 3 treatments 63 53

Rescue Laser Treatments (at masked physicianrsquos discretion after week 6)

Patients 607 407

Off-Protocol Treatments (IVTA bevacizumab ranibizumab intravitreal dexamethasone)

Patients 295 115

OZURDEX = 23injections year 1 41 by year 3

No other Rx

Summary of side effects with intravitreal steroids

Drug device Evidence base Cataract risk IOP rise (requiring drops)

Glaucoma surgery

endophthalmitis

ILUVIEN FAME studies 80 cat surgery(273 sham)

384(14 control)

48 0

Ozurdex MEAD 592 had cataract surgery(72 sham)

215 (end of study)(34 sham)

06 0

Trivaris+ laser vs Luc+laserx2 vs laser

Protocol IOphthalmology 2010

15 42(ONE OFgt10mmHg risegt30mmHGStart drops)

2186 0

NICE guidance for intravitreal steroids in DMO

bull Iluvien

bull NICE TA 301 Iluvien for DMO Nov 2013

bull hellipfor treating chronic diabetic macular oedema that is insufficiently responsive to available therapies only if

bull the implant is to be used in an eye with an intraocular

(pseudophakic) lens and

bull the manufacturer provides fluocinolone acetonide intravitreal implant with the discount agreed in the patient access scheme

NICE guidance for intravitreal steroids in DMO

bull Ozurdex

bull NICE TA 349 Ozurdex for DMO July 2015

bull there is an artificial lens in the eye to be treated and

bull their diabetic macular oedema has not improved with

non-corticosteroid treatment or such treatment is not suitable for them

Steroids = second line therapyWhen do I switch

bull Anti-VEGF first line for centre involving DMObull NICE TA ndash ldquoinsufficiently responsiverdquo ldquo ldquonot improvedrdquo ldquonot suitablerdquo ndash

OTHER TREATMENTS

bull 2 scenariosbull 1) Anti-VEGF canrsquot be funded ie OCTlt400um + PSEUDOPHAKIC

bull 2) Already had a course of treatment with laseranti-VEGF + PSEUDOPHAKIC ie SWITCHING from anti-VEGF to steroid

bull Plus

bull ldquochronicrdquo DMO ndash 3 years duration in FAME (18months) for ILUVIEN

bull Chronic DMO not essential for Ozurdex

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

Protocol T ndash patients may not improve in first 6 months

RIDE

RISE

Mea

n ch

ange

in B

CVA

(E

TDR

S le

tters

)M

ean

chan

ge in

BC

VA

(ETD

RS

lette

rs)

Time (months)

RISE and RIDE (Lucentis monthly dosing) Mean change in BCVA over 36 months

Brown DM et al Ophthalmology 2013120(10)2013ndash2022

54

Ranibizumab 03 mgRanibizumab 05 mgShamranibizumab 05 mg

Date of Prep Dec 2014 LGB0820147252X

VA improvement continues throughout year 1 with monthly dosing

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user ndash more than protocol

I

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

DRCRN protocol I5 year outcomesInjections 8-9 in year 1Year 2 = 2-3Year 3= 1-2Year 4 = 0-1Year 5 = 0

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

Wait for plateau = stability in protocol T laserPatient factors again

Judgement of response to anti-VEGF ndashtimeframe

bull Wait 6 months in poor responders

bull Wait 1 year for heavy users

bull Tempting to try steroids earlier than this ifbull No glaucoma ndash not a deal breaker Ozurdex better short term optionbull Pseudophakic

bull Clues from the diseasebull chronic

bull PATIENT FACTORS

bull Any eyes avoid steroids ndash advanced glaucomaCSCR Or prior viral retinitis RARE

bull Any eyes avoid anti-VEGF pregnancytrying to concieve recent CVA

BIOMARKERS AT BASELINE WOULD BE USEFULRESTORE subgroup analysis of OCT features

bull Andreas Pollreisz EURETINA 2015

bull OCT biomarkers (RESTORE data)

bull Better effects with anti-VEGF ifbull Small rather than large intra-retinal cyst

bull Sub-retinal fluid present

bull Vitreo-macular adhesion at baseline

bull No disruption of ELM and ISOS junction

bull No disorganisation of inner retinal layers (DRIL)

RESTORE subgroup analysis of OCT features

bull Andreas Pollreisz EURETINA 2015

bull OCT biomarkers (RESTORE data)

bull Better effects with anti-VEGF ifbull Small rather than large intra-retinal cyst

bull Sub-retinal fluid present

bull Vitreo-macular adhesion at baseline

bull No disruption of ELM and ISOS junction

bull No disorganisation of inner retinal layers (DRIL)

Better baseline characterisationclassificationERG Contrast sensitivityOCT AngiographyMicroperimetry= clues as to who responds best to which drug

Plan for this presentation helliphellipa long list

bull What treatment options are available for DMO (evidence base)

bull What treatment should I start with at baselinebull Re-treatment algorithms for intravitreal DMO therapiesbull When should I switchcombine therapiesbull The bigger picture

bull Other eyebull The patient as a wholebull The service -coping with capacity ndash compromises

The bigger pictureOther eyeThe patient as a wholeThe service -coping with capacity ndash compromises

bull OTHER EYE ndash may create problems

bull Treat and extend ndash ldquoreduce of visitsrdquo plus Eylea license ndash ldquono need for monitoringrdquo may not benefit if lots of visits due to PDR other eye

bull PERIPHERAL RETINA anti-VEGF supresses proliferative disease - Rebound on stopping Rx

bull PATIENT

bull Anti-VEGF ndash heavy user - Will comply

bull One stop much better than two stop for patient ndash Treat and extend

bull SERVICE

bull Capacity and demand planning = fixedT+E more predictable at least 1 month in advance ndash flexible nurse injectors

bull Steroids ndash even if well controlled (Iluvien for 3 years) need IOP check

bull Need pan-retinal examination both eyes ndash separate visits

Summary

CSMO

No centre involvement

Photocoagulation

Centre involvement

gt 78 letters(normalminimally reduced VA)

Photocoagulation

VA 78ndash24 letters

Phakic

Anti-VEGF

Pseudophakic

Anti-VEGF

SWITCHglaucoma

Injection tolerance

Medical issuesrecent CVA

Peripheral diseaseBilateral Rx

CSMO

No centre involvement

LASER

Centre involvement

gt 78 letters(normalminimally

reduced VA)

VA 78ndash24 letters

EYLEA OR LUCENTIS OR AVASTIN

Funding issues

Protocol T ndash poor VA lt 65 letters (615)

LOADING

Monthly injections until stability OR 5 x 112 (EYLEA) = 6 MONTHS then 8 weeks

RETREATMENT1

TREAT AND EXTEND - PRN

PRN

PSEUDOPHAKIC

Prior Rx

ILUVIEN

Chronic disease

OZURDEX

RETREATMENT

OZURDEX

OCT gt175um or any residual oedema

ILUVIEN after 12 months if risksltbenefits

OCT

gt400um

bull FACE TO FACE CLINICS RUNNING IN PARALLEL

bull = MAC002 every 6 months (optom or doctor) routine check for cataracttolerance of injectionsglaucoma issues etc

bull =MAC003 (DOCTOR) for problems as needed no fixed intervalDischargestop treatmentDeclines treatment diagnosis CSR overlay etcswitch drugs

bull =RV002- (DOCTOR) every 6 months

bull =DM002 ndash (DOCTOR) variable interval determined by last assessing doctor

bull First visit at 6 months from 1st injection if mild NPDR

bull Otherwise determined by retinopathy generally

LOADING PHASE

EyleaLucentis 1 within 48hrs of baseline

EyleaLucentis 2 (and LogMAR VA plus OCT same visit)

EyleaLucentis 3 (and LogMAR VA plus OCT same visit)

EyleaLucentis 4 (TEinj)(and Logmar VA plus OCT same visit

AFTER INJECTION 4 data goes off to be reviewed immediately as a hellip

TREAT AND EXTEND assessment ndash the next interval will depend on the response to the loading phase

NB -DMO patients ndash majority (95) will need 6 injctions x 112 of Lucentis

OR Eylea 5 x 112 then 8 weekly

ONCE STABLE for 3 x injection in TE phase

VIRTUAL CLINIC MONITORING OF MACULOPATHY AND PRN RETREATMENT

ANTI-VEGF INJECTION PATHWAYS Baseline visitMAC001 for wet AMDRV001 for CRVOBRVOMed ret clinic for DMO

Pathways ndash too many directions

Better that thanhellip

Thank you

Re-treatment algorithms for anti-VEGF agents in DMO

bull LOADING PHASE

bull Lucentis label = monthly until stability

bull Eylea label = 5 x 112 then every 8 weeks ie fixed regime year 1

bull DRCRnet protocol T = effectively 6 x112 for majority (95) BUT actually only mandated for first 3 months then prn

bull helliphellip likely that majority will receive injections monthly for first 6 months

bull INDIVIDUALISED PHASE

bull Once ldquostablerdquo ndash based on VA and OCT

bull NB May never get a ldquodryrdquo OCT so treat to stability

bull THEN

bull Treat and extend

bull prn

What does Treat and Extend mean

Pathway overview = Lucentis prn

Jan

Loading phase = injections every 4 weeks until ldquostablerdquo for 3 visits

helliphelliphellip

Feb OctSepAugJulJunMayAprMar

MarFebJan

DecNov

DecNovOctSepAugJulJunMayApr

Then observe UNTIL VA decreases or OCT increase = prn

Once reactivates need at least 2 injections until stable again over 3 visits

Pathway overview = Treat and Extend

Jan

Loading phase = injections every 4 weeks until ldquostablerdquo for 3 visits or Eyleayear 1

helliphelliphellip

Feb OctSepAugJulJunMayAprMar

MarFebJan

DecNov

DecNovOctSepAugJulJunMayApr

Then keep injecting but extend the interval between injections gradually ie keep treating even if perfect

If reactivates need at least 2 injections until stable again over 3 visits

Pathway overview = Eylea fixed dosing year 1

Jan

Eylea = 5 x 112 injection then every 8 weeks

Average 6 injections yr 2 Beyond that

helliphelliphellip

Feb OctSepAugJulJunMayAprMar

MarFebJan

DecNov

DecNovOctSepAugJulJunMayApr

Then individualised UNTIL VA decreases or OCT increase = prn

Once reactivates need at least 2 injections until stable again over 3 visits

Pros and cons of Treat and Extend vs Prn

T+E PRN

PROS bull Proactive patient and service get advance warning of injection ndash capacity and demand planning easier

bull One ndashstopbull Fewer visits than prnbull Overtreatment

advantageous for peripheral retinopathy

bull Only treated when active ieno overtreatment

bull Aggressive year 1 protocols (DRCRN I ndash few injections needed thereafter

bull DMO tolerant of reactivations ()

CONS bull Overtreatment = riskexpenseinconvenience

bull Evidence base scantbull Bilateral disease tricky

bull Reactive so need enoughemergency capacity to inject when disease flares up

bull No advance warning to patientservice that injection needed

bull NEED TO DO IT WELL ndashNHS real life audits prn based regimes not good resultsUndertreatment in year 1 Affects long term prognosis and treatment burden

Pros and cons of Treat and Extend vs Prn

T+E PRN

PROS bull Proactive patient and service get advance warning of injection ndash capacity and demand planning easier

bull One ndashstopbull Fewer visits than prnbull Overtreatment

advantageous for peripheral retinopathy

bull Only treated when active ieno overtreatment

bull Aggressive year 1 protocols (DRCRN I ndash few injections needed thereafter

bull DMO tolerant of reactivations ()

CONS bull Overtreatment = riskexpenseinconvenience

bull Evidence base scantbull Bilateral disease tricky

bull Reactive so need enoughemergency capacity to inject when disease flares up

bull No advance warning to patientservice that injection needed

bull NEED TO DO IT WELL ndashNHS real life audits prn based regimes not good resultsUndertreatment in year 1 Affects long term prognosis and treatment burden

DMO ndash anti-VEGF Treat and Extend

bull Retain study ndash the only RCT data

bull Br J Ophthalmol 2015 Oct 9 pii bjophthalmol-2015-307249 doi 101136bjophthalmol-2015-307249 [Epub ahead of print]

bull Ranibizumab 05 mg treat-and-extend regimen for diabetic macular oedema the RETAIN study

bull Pruumlnte C1 Fajnkuchen F2 Mahmood S3 Ricci F4 Hatz K5 Studnička J6 Bezlyak V7 Parikh S7 Stubbings WJ7 Wenzel A7 Figueira J8 and the RETAIN Study Group

RETAIN Phase III trial evaluating the efficacy of lsquotreat and extendrsquo regimen (ARVO 2014)

bull Patients with DMO and visual impairment (n = 372) were randomised 111

to one of three groups for 24 months

bull Two phases to dosing schedule

bull Phase A

bull Patients in all groups were initially treated with monthly ranibizumab until BCVA remained

stable

bull Phase B

bull Patients in the TampE groups whose vision remained stable had treatment- free intervals

that were increased incrementally by 1 month for a maximum of 3 months

bull Patients in the PRN group had ongoing monthly monitoring

bull In all groups Phase A was resumed if a decrease in BCVA was observed at a visit

Ranibizumab 05 mg monotherapy

in TampE regimen

Ranibizumab 05 mg in TampE regimen

plus laser

Ranibizumab 05 mg PRN

35

RETAIN Visual acuity endpoints

Pruumlnte C ARVO 2014 Annual Meeting Abstracts Abstract 1700

Mean average change in BCVAat 12 months (primary endpoint)

Mean change in BCVA at 24 months

Mea

n av

erag

e ch

ange

in B

CVA

(ETD

RS

lette

rs)

RanibizumabTampE

RanibizumabTampE + laser

RanibizumabPRN

RanibizumabTampE

RanibizumabTampE + laser

RanibizumabPRN

Mea

n ch

ange

in B

CVA

(ETD

RS

lette

rs)

plt00001 for both ranibizumab TampE groups versus PRN for primary endpoint

36

RETAIN Patient visits and monitoring with TampE regimen over 24 months

bull The TampE regimen provided an approximately 40 reduction in the number of treatment visits required compared with the ranibizumab PRN regimen

bull Approximately 70 of patients receiving TampE regimens had monitoring intervals ge2 months compared with ongoing monthly monitoring in the ranibizumab PRN group

bull Informed the license for Lucentis in DMO (extend by 1 month at a time)

37

INTRAVITREAL STEROIDSWhich intravitreal steroid is better

bull Licensed steroids ndash Ozurdex (Dexamethasone) and Iluvien (Fluocinoloneacetonide

bull Which steroid is best in terms of VA outcomes hellipWE DONrsquoT KNOW FOR SURE ndash no head to head studies for licensed drugs either between steroids or between anti-VEGF and steroids

bull STEROIDS ARE efficacious in DMO

bull MEAD

bull FAME

bull DRCRnet protocol I

bull NICE ndash Ozurdex and Iluvien ndash second-line agents

Ozurdex

bull A biodegradable co-polymer implant ndash degrades in time to lactic and glycolic acid releasing Dexamethasone

bull 22gauge injectionbull MEAD study

bull N=1048

bull Dex 07mg vs 035mg vs sham

bull No rescue therapy

bull 3 year follow up max 6 monthly dosing ie 7 over 3 years

Gan IM et al Greafes Acrh Clin Exp Ophthalmol 2005

MEAD studyMean BCVA change from baseline based on baseline lens status

-2

0

2

4

6

8

10

0 3 6 9 12 15 18 21 24 27 30 33 36 39

Mea

n C

hang

e Fr

om

Bas

elin

e B

CVA

(Let

ters

)

Month

DEX Implant 07 mg (n = 86)

Sham (n = 101)

Boyer DS et al Ophthalmology 20141211904ndash14

Results analyzed in the ITT population with LOCF for missing values

Pseudophakic

Total

0

5

10

0 3 6 9 12 15 18 21 24 27 30 33 36 39

DEX 700 (n=351)

Sham (n=350)

10

8

6

4

2

0

Mea

n C

hang

e fr

om

Bas

elin

e B

CVA

(Let

ters

)

Month

07mg dose is approved as Ozurdexreg by the FDA and EMA 035mg dose not commercially available

1 Boyer DS et al Ophthalmology 2014 121 1904-1914

bull Nonbioerodible micro implant (polyimide) containing 190microg of fluocinolone acetonide (FAc)

bull Consistent daily submicrogram delivery of 02 microgd FAc for up to 36 months

bull Posterior point of release

bull 35 mm times 037 mm non-bioerodable micro implant

bull 25-gauge injector creates self-sealing wound

bull No measurable systemic exposure

ILUVIEN Implant Technology

FAcimplant

ILUVIEN SPC httpwwwmedicinesorgukemcmedicine27636

0 6 12 18 24 30 36

ILUVIEN 02 microgd FAc(n = 376)05 microgd FAc (n = 395)Control sham injection(n = 185)

Design of Phase 3 FAME Study (FAME A and B = same protocol)

Additional laser therapy allowed after week 6a

Retreatment any time after month 12 (if eligibleb)

Study ends

N = 956Randomisation

221Primary readout

Patients with DMO and

bull At least 1 previous laser tx

bull BCVA ge19 and le68 letters

bull TD-OCT FTH ge250 μm

Month

BCVA = best corrected visual acuity DMO = diabetic macular oedema TD-OCT=time domain optical coherence tomography FTH = foveal thicknessa At masked investigatorrsquos discretion b If BCVA loss ge5 letters or retinal thickening ge50 microm from best reading in previous 12 months

ge15 letter Gain is Greater in Chronic DMO Patients

ge 15

-Let

ter I

mpr

ovem

ent

in B

CVA

Fro

m B

asel

ine

Δ = 98

Months

Full Population Patients With Chronic DMO

Months

Δ = 206

287

189134

34

Steroid re-treatments

bullOzurdexbull Longer half-life than anti-VEGF in the eye

bull Redosing regimes not very helpful from RCT data eg MEAD study only 612 dosing

bull In reality re-treatment interval may be shorter

bull POSOLOGY

bull Patients treated with OZURDEX who have experienced an initial response and in the physicians opinion may benefit from retreatment without being exposed to significant risk should be considered for retreatment Retreatment may be performed after approximately 6 months if the patient experiences decreased vision andor an increase in retinal thickness secondary to recurrent or worsening diabetic macular oedema

bullIluvienbull 70 of patients in FAE only needed 1

injection over 3 years

bull BUT additional rescue treatments allowed

bull POSOLOGY

bull Each ILUVIEN implant releases fluocinolone acetonide for up to 36 months An additional implant may be administered after 12 months if the patient experiences decreased vision or an increase in retinal thickness secondary to recurrent or worsening diabetic macular oedema

bull Patients receiving escape medication were exited from MEAD before administration1

bull Macular laser rescue treatment allowed in RISERIDE (Lucentisreg) from 3 months2

bull Focalgrid laser allowed in FAME (Iluvienreg) from 6 weeks3

MEAD TREATMENT PROTOCOL

bull First treatment given at randomisation (day 0) bull Patients assessed for retreatment eligibility every 3 months from

months 6ndash36bull Patients were eligible for retreatment if

OCT optical coherence tomography

ge6 months since most recent

study treatment

Retinal thickness in 1 mm central macular

subfield by OCT gt175 microm

Evidence of residual retinal oedema (intraretinal cysts or

any regions of increased retinal thickening) as assessed by

investigator from OCT

AND OR

MEA

D

Amendment in May 2010 revised anatomic criterion for retreatment before this time the threshold was gt225 microm1Boyer DS et al Ophthalmology 2014 121 1904-19142Nguyen QD et al Ophthalmology 20121191064minus10773Campochiaro PA et al Ophthalmology 2011118626ndash635

Treatment burdenILUVIEN

Control(n =112)

02 microgd FAc(n =209)

Study Treatments(sham injection or ILUVIEN 02 microgday or FAc 05microgday)

1 treatment 661 761

2 treatments 277 187

ge 3 treatments 63 53

Rescue Laser Treatments (at masked physicianrsquos discretion after week 6)

Patients 607 407

Off-Protocol Treatments (IVTA bevacizumab ranibizumab intravitreal dexamethasone)

Patients 295 115

OZURDEX = 23injections year 1 41 by year 3

No other Rx

Summary of side effects with intravitreal steroids

Drug device Evidence base Cataract risk IOP rise (requiring drops)

Glaucoma surgery

endophthalmitis

ILUVIEN FAME studies 80 cat surgery(273 sham)

384(14 control)

48 0

Ozurdex MEAD 592 had cataract surgery(72 sham)

215 (end of study)(34 sham)

06 0

Trivaris+ laser vs Luc+laserx2 vs laser

Protocol IOphthalmology 2010

15 42(ONE OFgt10mmHg risegt30mmHGStart drops)

2186 0

NICE guidance for intravitreal steroids in DMO

bull Iluvien

bull NICE TA 301 Iluvien for DMO Nov 2013

bull hellipfor treating chronic diabetic macular oedema that is insufficiently responsive to available therapies only if

bull the implant is to be used in an eye with an intraocular

(pseudophakic) lens and

bull the manufacturer provides fluocinolone acetonide intravitreal implant with the discount agreed in the patient access scheme

NICE guidance for intravitreal steroids in DMO

bull Ozurdex

bull NICE TA 349 Ozurdex for DMO July 2015

bull there is an artificial lens in the eye to be treated and

bull their diabetic macular oedema has not improved with

non-corticosteroid treatment or such treatment is not suitable for them

Steroids = second line therapyWhen do I switch

bull Anti-VEGF first line for centre involving DMObull NICE TA ndash ldquoinsufficiently responsiverdquo ldquo ldquonot improvedrdquo ldquonot suitablerdquo ndash

OTHER TREATMENTS

bull 2 scenariosbull 1) Anti-VEGF canrsquot be funded ie OCTlt400um + PSEUDOPHAKIC

bull 2) Already had a course of treatment with laseranti-VEGF + PSEUDOPHAKIC ie SWITCHING from anti-VEGF to steroid

bull Plus

bull ldquochronicrdquo DMO ndash 3 years duration in FAME (18months) for ILUVIEN

bull Chronic DMO not essential for Ozurdex

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

Protocol T ndash patients may not improve in first 6 months

RIDE

RISE

Mea

n ch

ange

in B

CVA

(E

TDR

S le

tters

)M

ean

chan

ge in

BC

VA

(ETD

RS

lette

rs)

Time (months)

RISE and RIDE (Lucentis monthly dosing) Mean change in BCVA over 36 months

Brown DM et al Ophthalmology 2013120(10)2013ndash2022

54

Ranibizumab 03 mgRanibizumab 05 mgShamranibizumab 05 mg

Date of Prep Dec 2014 LGB0820147252X

VA improvement continues throughout year 1 with monthly dosing

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user ndash more than protocol

I

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

DRCRN protocol I5 year outcomesInjections 8-9 in year 1Year 2 = 2-3Year 3= 1-2Year 4 = 0-1Year 5 = 0

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

Wait for plateau = stability in protocol T laserPatient factors again

Judgement of response to anti-VEGF ndashtimeframe

bull Wait 6 months in poor responders

bull Wait 1 year for heavy users

bull Tempting to try steroids earlier than this ifbull No glaucoma ndash not a deal breaker Ozurdex better short term optionbull Pseudophakic

bull Clues from the diseasebull chronic

bull PATIENT FACTORS

bull Any eyes avoid steroids ndash advanced glaucomaCSCR Or prior viral retinitis RARE

bull Any eyes avoid anti-VEGF pregnancytrying to concieve recent CVA

BIOMARKERS AT BASELINE WOULD BE USEFULRESTORE subgroup analysis of OCT features

bull Andreas Pollreisz EURETINA 2015

bull OCT biomarkers (RESTORE data)

bull Better effects with anti-VEGF ifbull Small rather than large intra-retinal cyst

bull Sub-retinal fluid present

bull Vitreo-macular adhesion at baseline

bull No disruption of ELM and ISOS junction

bull No disorganisation of inner retinal layers (DRIL)

RESTORE subgroup analysis of OCT features

bull Andreas Pollreisz EURETINA 2015

bull OCT biomarkers (RESTORE data)

bull Better effects with anti-VEGF ifbull Small rather than large intra-retinal cyst

bull Sub-retinal fluid present

bull Vitreo-macular adhesion at baseline

bull No disruption of ELM and ISOS junction

bull No disorganisation of inner retinal layers (DRIL)

Better baseline characterisationclassificationERG Contrast sensitivityOCT AngiographyMicroperimetry= clues as to who responds best to which drug

Plan for this presentation helliphellipa long list

bull What treatment options are available for DMO (evidence base)

bull What treatment should I start with at baselinebull Re-treatment algorithms for intravitreal DMO therapiesbull When should I switchcombine therapiesbull The bigger picture

bull Other eyebull The patient as a wholebull The service -coping with capacity ndash compromises

The bigger pictureOther eyeThe patient as a wholeThe service -coping with capacity ndash compromises

bull OTHER EYE ndash may create problems

bull Treat and extend ndash ldquoreduce of visitsrdquo plus Eylea license ndash ldquono need for monitoringrdquo may not benefit if lots of visits due to PDR other eye

bull PERIPHERAL RETINA anti-VEGF supresses proliferative disease - Rebound on stopping Rx

bull PATIENT

bull Anti-VEGF ndash heavy user - Will comply

bull One stop much better than two stop for patient ndash Treat and extend

bull SERVICE

bull Capacity and demand planning = fixedT+E more predictable at least 1 month in advance ndash flexible nurse injectors

bull Steroids ndash even if well controlled (Iluvien for 3 years) need IOP check

bull Need pan-retinal examination both eyes ndash separate visits

Summary

CSMO

No centre involvement

Photocoagulation

Centre involvement

gt 78 letters(normalminimally reduced VA)

Photocoagulation

VA 78ndash24 letters

Phakic

Anti-VEGF

Pseudophakic

Anti-VEGF

SWITCHglaucoma

Injection tolerance

Medical issuesrecent CVA

Peripheral diseaseBilateral Rx

CSMO

No centre involvement

LASER

Centre involvement

gt 78 letters(normalminimally

reduced VA)

VA 78ndash24 letters

EYLEA OR LUCENTIS OR AVASTIN

Funding issues

Protocol T ndash poor VA lt 65 letters (615)

LOADING

Monthly injections until stability OR 5 x 112 (EYLEA) = 6 MONTHS then 8 weeks

RETREATMENT1

TREAT AND EXTEND - PRN

PRN

PSEUDOPHAKIC

Prior Rx

ILUVIEN

Chronic disease

OZURDEX

RETREATMENT

OZURDEX

OCT gt175um or any residual oedema

ILUVIEN after 12 months if risksltbenefits

OCT

gt400um

bull FACE TO FACE CLINICS RUNNING IN PARALLEL

bull = MAC002 every 6 months (optom or doctor) routine check for cataracttolerance of injectionsglaucoma issues etc

bull =MAC003 (DOCTOR) for problems as needed no fixed intervalDischargestop treatmentDeclines treatment diagnosis CSR overlay etcswitch drugs

bull =RV002- (DOCTOR) every 6 months

bull =DM002 ndash (DOCTOR) variable interval determined by last assessing doctor

bull First visit at 6 months from 1st injection if mild NPDR

bull Otherwise determined by retinopathy generally

LOADING PHASE

EyleaLucentis 1 within 48hrs of baseline

EyleaLucentis 2 (and LogMAR VA plus OCT same visit)

EyleaLucentis 3 (and LogMAR VA plus OCT same visit)

EyleaLucentis 4 (TEinj)(and Logmar VA plus OCT same visit

AFTER INJECTION 4 data goes off to be reviewed immediately as a hellip

TREAT AND EXTEND assessment ndash the next interval will depend on the response to the loading phase

NB -DMO patients ndash majority (95) will need 6 injctions x 112 of Lucentis

OR Eylea 5 x 112 then 8 weekly

ONCE STABLE for 3 x injection in TE phase

VIRTUAL CLINIC MONITORING OF MACULOPATHY AND PRN RETREATMENT

ANTI-VEGF INJECTION PATHWAYS Baseline visitMAC001 for wet AMDRV001 for CRVOBRVOMed ret clinic for DMO

Pathways ndash too many directions

Better that thanhellip

Thank you

What does Treat and Extend mean

Pathway overview = Lucentis prn

Jan

Loading phase = injections every 4 weeks until ldquostablerdquo for 3 visits

helliphelliphellip

Feb OctSepAugJulJunMayAprMar

MarFebJan

DecNov

DecNovOctSepAugJulJunMayApr

Then observe UNTIL VA decreases or OCT increase = prn

Once reactivates need at least 2 injections until stable again over 3 visits

Pathway overview = Treat and Extend

Jan

Loading phase = injections every 4 weeks until ldquostablerdquo for 3 visits or Eyleayear 1

helliphelliphellip

Feb OctSepAugJulJunMayAprMar

MarFebJan

DecNov

DecNovOctSepAugJulJunMayApr

Then keep injecting but extend the interval between injections gradually ie keep treating even if perfect

If reactivates need at least 2 injections until stable again over 3 visits

Pathway overview = Eylea fixed dosing year 1

Jan

Eylea = 5 x 112 injection then every 8 weeks

Average 6 injections yr 2 Beyond that

helliphelliphellip

Feb OctSepAugJulJunMayAprMar

MarFebJan

DecNov

DecNovOctSepAugJulJunMayApr

Then individualised UNTIL VA decreases or OCT increase = prn

Once reactivates need at least 2 injections until stable again over 3 visits

Pros and cons of Treat and Extend vs Prn

T+E PRN

PROS bull Proactive patient and service get advance warning of injection ndash capacity and demand planning easier

bull One ndashstopbull Fewer visits than prnbull Overtreatment

advantageous for peripheral retinopathy

bull Only treated when active ieno overtreatment

bull Aggressive year 1 protocols (DRCRN I ndash few injections needed thereafter

bull DMO tolerant of reactivations ()

CONS bull Overtreatment = riskexpenseinconvenience

bull Evidence base scantbull Bilateral disease tricky

bull Reactive so need enoughemergency capacity to inject when disease flares up

bull No advance warning to patientservice that injection needed

bull NEED TO DO IT WELL ndashNHS real life audits prn based regimes not good resultsUndertreatment in year 1 Affects long term prognosis and treatment burden

Pros and cons of Treat and Extend vs Prn

T+E PRN

PROS bull Proactive patient and service get advance warning of injection ndash capacity and demand planning easier

bull One ndashstopbull Fewer visits than prnbull Overtreatment

advantageous for peripheral retinopathy

bull Only treated when active ieno overtreatment

bull Aggressive year 1 protocols (DRCRN I ndash few injections needed thereafter

bull DMO tolerant of reactivations ()

CONS bull Overtreatment = riskexpenseinconvenience

bull Evidence base scantbull Bilateral disease tricky

bull Reactive so need enoughemergency capacity to inject when disease flares up

bull No advance warning to patientservice that injection needed

bull NEED TO DO IT WELL ndashNHS real life audits prn based regimes not good resultsUndertreatment in year 1 Affects long term prognosis and treatment burden

DMO ndash anti-VEGF Treat and Extend

bull Retain study ndash the only RCT data

bull Br J Ophthalmol 2015 Oct 9 pii bjophthalmol-2015-307249 doi 101136bjophthalmol-2015-307249 [Epub ahead of print]

bull Ranibizumab 05 mg treat-and-extend regimen for diabetic macular oedema the RETAIN study

bull Pruumlnte C1 Fajnkuchen F2 Mahmood S3 Ricci F4 Hatz K5 Studnička J6 Bezlyak V7 Parikh S7 Stubbings WJ7 Wenzel A7 Figueira J8 and the RETAIN Study Group

RETAIN Phase III trial evaluating the efficacy of lsquotreat and extendrsquo regimen (ARVO 2014)

bull Patients with DMO and visual impairment (n = 372) were randomised 111

to one of three groups for 24 months

bull Two phases to dosing schedule

bull Phase A

bull Patients in all groups were initially treated with monthly ranibizumab until BCVA remained

stable

bull Phase B

bull Patients in the TampE groups whose vision remained stable had treatment- free intervals

that were increased incrementally by 1 month for a maximum of 3 months

bull Patients in the PRN group had ongoing monthly monitoring

bull In all groups Phase A was resumed if a decrease in BCVA was observed at a visit

Ranibizumab 05 mg monotherapy

in TampE regimen

Ranibizumab 05 mg in TampE regimen

plus laser

Ranibizumab 05 mg PRN

35

RETAIN Visual acuity endpoints

Pruumlnte C ARVO 2014 Annual Meeting Abstracts Abstract 1700

Mean average change in BCVAat 12 months (primary endpoint)

Mean change in BCVA at 24 months

Mea

n av

erag

e ch

ange

in B

CVA

(ETD

RS

lette

rs)

RanibizumabTampE

RanibizumabTampE + laser

RanibizumabPRN

RanibizumabTampE

RanibizumabTampE + laser

RanibizumabPRN

Mea

n ch

ange

in B

CVA

(ETD

RS

lette

rs)

plt00001 for both ranibizumab TampE groups versus PRN for primary endpoint

36

RETAIN Patient visits and monitoring with TampE regimen over 24 months

bull The TampE regimen provided an approximately 40 reduction in the number of treatment visits required compared with the ranibizumab PRN regimen

bull Approximately 70 of patients receiving TampE regimens had monitoring intervals ge2 months compared with ongoing monthly monitoring in the ranibizumab PRN group

bull Informed the license for Lucentis in DMO (extend by 1 month at a time)

37

INTRAVITREAL STEROIDSWhich intravitreal steroid is better

bull Licensed steroids ndash Ozurdex (Dexamethasone) and Iluvien (Fluocinoloneacetonide

bull Which steroid is best in terms of VA outcomes hellipWE DONrsquoT KNOW FOR SURE ndash no head to head studies for licensed drugs either between steroids or between anti-VEGF and steroids

bull STEROIDS ARE efficacious in DMO

bull MEAD

bull FAME

bull DRCRnet protocol I

bull NICE ndash Ozurdex and Iluvien ndash second-line agents

Ozurdex

bull A biodegradable co-polymer implant ndash degrades in time to lactic and glycolic acid releasing Dexamethasone

bull 22gauge injectionbull MEAD study

bull N=1048

bull Dex 07mg vs 035mg vs sham

bull No rescue therapy

bull 3 year follow up max 6 monthly dosing ie 7 over 3 years

Gan IM et al Greafes Acrh Clin Exp Ophthalmol 2005

MEAD studyMean BCVA change from baseline based on baseline lens status

-2

0

2

4

6

8

10

0 3 6 9 12 15 18 21 24 27 30 33 36 39

Mea

n C

hang

e Fr

om

Bas

elin

e B

CVA

(Let

ters

)

Month

DEX Implant 07 mg (n = 86)

Sham (n = 101)

Boyer DS et al Ophthalmology 20141211904ndash14

Results analyzed in the ITT population with LOCF for missing values

Pseudophakic

Total

0

5

10

0 3 6 9 12 15 18 21 24 27 30 33 36 39

DEX 700 (n=351)

Sham (n=350)

10

8

6

4

2

0

Mea

n C

hang

e fr

om

Bas

elin

e B

CVA

(Let

ters

)

Month

07mg dose is approved as Ozurdexreg by the FDA and EMA 035mg dose not commercially available

1 Boyer DS et al Ophthalmology 2014 121 1904-1914

bull Nonbioerodible micro implant (polyimide) containing 190microg of fluocinolone acetonide (FAc)

bull Consistent daily submicrogram delivery of 02 microgd FAc for up to 36 months

bull Posterior point of release

bull 35 mm times 037 mm non-bioerodable micro implant

bull 25-gauge injector creates self-sealing wound

bull No measurable systemic exposure

ILUVIEN Implant Technology

FAcimplant

ILUVIEN SPC httpwwwmedicinesorgukemcmedicine27636

0 6 12 18 24 30 36

ILUVIEN 02 microgd FAc(n = 376)05 microgd FAc (n = 395)Control sham injection(n = 185)

Design of Phase 3 FAME Study (FAME A and B = same protocol)

Additional laser therapy allowed after week 6a

Retreatment any time after month 12 (if eligibleb)

Study ends

N = 956Randomisation

221Primary readout

Patients with DMO and

bull At least 1 previous laser tx

bull BCVA ge19 and le68 letters

bull TD-OCT FTH ge250 μm

Month

BCVA = best corrected visual acuity DMO = diabetic macular oedema TD-OCT=time domain optical coherence tomography FTH = foveal thicknessa At masked investigatorrsquos discretion b If BCVA loss ge5 letters or retinal thickening ge50 microm from best reading in previous 12 months

ge15 letter Gain is Greater in Chronic DMO Patients

ge 15

-Let

ter I

mpr

ovem

ent

in B

CVA

Fro

m B

asel

ine

Δ = 98

Months

Full Population Patients With Chronic DMO

Months

Δ = 206

287

189134

34

Steroid re-treatments

bullOzurdexbull Longer half-life than anti-VEGF in the eye

bull Redosing regimes not very helpful from RCT data eg MEAD study only 612 dosing

bull In reality re-treatment interval may be shorter

bull POSOLOGY

bull Patients treated with OZURDEX who have experienced an initial response and in the physicians opinion may benefit from retreatment without being exposed to significant risk should be considered for retreatment Retreatment may be performed after approximately 6 months if the patient experiences decreased vision andor an increase in retinal thickness secondary to recurrent or worsening diabetic macular oedema

bullIluvienbull 70 of patients in FAE only needed 1

injection over 3 years

bull BUT additional rescue treatments allowed

bull POSOLOGY

bull Each ILUVIEN implant releases fluocinolone acetonide for up to 36 months An additional implant may be administered after 12 months if the patient experiences decreased vision or an increase in retinal thickness secondary to recurrent or worsening diabetic macular oedema

bull Patients receiving escape medication were exited from MEAD before administration1

bull Macular laser rescue treatment allowed in RISERIDE (Lucentisreg) from 3 months2

bull Focalgrid laser allowed in FAME (Iluvienreg) from 6 weeks3

MEAD TREATMENT PROTOCOL

bull First treatment given at randomisation (day 0) bull Patients assessed for retreatment eligibility every 3 months from

months 6ndash36bull Patients were eligible for retreatment if

OCT optical coherence tomography

ge6 months since most recent

study treatment

Retinal thickness in 1 mm central macular

subfield by OCT gt175 microm

Evidence of residual retinal oedema (intraretinal cysts or

any regions of increased retinal thickening) as assessed by

investigator from OCT

AND OR

MEA

D

Amendment in May 2010 revised anatomic criterion for retreatment before this time the threshold was gt225 microm1Boyer DS et al Ophthalmology 2014 121 1904-19142Nguyen QD et al Ophthalmology 20121191064minus10773Campochiaro PA et al Ophthalmology 2011118626ndash635

Treatment burdenILUVIEN

Control(n =112)

02 microgd FAc(n =209)

Study Treatments(sham injection or ILUVIEN 02 microgday or FAc 05microgday)

1 treatment 661 761

2 treatments 277 187

ge 3 treatments 63 53

Rescue Laser Treatments (at masked physicianrsquos discretion after week 6)

Patients 607 407

Off-Protocol Treatments (IVTA bevacizumab ranibizumab intravitreal dexamethasone)

Patients 295 115

OZURDEX = 23injections year 1 41 by year 3

No other Rx

Summary of side effects with intravitreal steroids

Drug device Evidence base Cataract risk IOP rise (requiring drops)

Glaucoma surgery

endophthalmitis

ILUVIEN FAME studies 80 cat surgery(273 sham)

384(14 control)

48 0

Ozurdex MEAD 592 had cataract surgery(72 sham)

215 (end of study)(34 sham)

06 0

Trivaris+ laser vs Luc+laserx2 vs laser

Protocol IOphthalmology 2010

15 42(ONE OFgt10mmHg risegt30mmHGStart drops)

2186 0

NICE guidance for intravitreal steroids in DMO

bull Iluvien

bull NICE TA 301 Iluvien for DMO Nov 2013

bull hellipfor treating chronic diabetic macular oedema that is insufficiently responsive to available therapies only if

bull the implant is to be used in an eye with an intraocular

(pseudophakic) lens and

bull the manufacturer provides fluocinolone acetonide intravitreal implant with the discount agreed in the patient access scheme

NICE guidance for intravitreal steroids in DMO

bull Ozurdex

bull NICE TA 349 Ozurdex for DMO July 2015

bull there is an artificial lens in the eye to be treated and

bull their diabetic macular oedema has not improved with

non-corticosteroid treatment or such treatment is not suitable for them

Steroids = second line therapyWhen do I switch

bull Anti-VEGF first line for centre involving DMObull NICE TA ndash ldquoinsufficiently responsiverdquo ldquo ldquonot improvedrdquo ldquonot suitablerdquo ndash

OTHER TREATMENTS

bull 2 scenariosbull 1) Anti-VEGF canrsquot be funded ie OCTlt400um + PSEUDOPHAKIC

bull 2) Already had a course of treatment with laseranti-VEGF + PSEUDOPHAKIC ie SWITCHING from anti-VEGF to steroid

bull Plus

bull ldquochronicrdquo DMO ndash 3 years duration in FAME (18months) for ILUVIEN

bull Chronic DMO not essential for Ozurdex

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

Protocol T ndash patients may not improve in first 6 months

RIDE

RISE

Mea

n ch

ange

in B

CVA

(E

TDR

S le

tters

)M

ean

chan

ge in

BC

VA

(ETD

RS

lette

rs)

Time (months)

RISE and RIDE (Lucentis monthly dosing) Mean change in BCVA over 36 months

Brown DM et al Ophthalmology 2013120(10)2013ndash2022

54

Ranibizumab 03 mgRanibizumab 05 mgShamranibizumab 05 mg

Date of Prep Dec 2014 LGB0820147252X

VA improvement continues throughout year 1 with monthly dosing

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user ndash more than protocol

I

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

DRCRN protocol I5 year outcomesInjections 8-9 in year 1Year 2 = 2-3Year 3= 1-2Year 4 = 0-1Year 5 = 0

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

Wait for plateau = stability in protocol T laserPatient factors again

Judgement of response to anti-VEGF ndashtimeframe

bull Wait 6 months in poor responders

bull Wait 1 year for heavy users

bull Tempting to try steroids earlier than this ifbull No glaucoma ndash not a deal breaker Ozurdex better short term optionbull Pseudophakic

bull Clues from the diseasebull chronic

bull PATIENT FACTORS

bull Any eyes avoid steroids ndash advanced glaucomaCSCR Or prior viral retinitis RARE

bull Any eyes avoid anti-VEGF pregnancytrying to concieve recent CVA

BIOMARKERS AT BASELINE WOULD BE USEFULRESTORE subgroup analysis of OCT features

bull Andreas Pollreisz EURETINA 2015

bull OCT biomarkers (RESTORE data)

bull Better effects with anti-VEGF ifbull Small rather than large intra-retinal cyst

bull Sub-retinal fluid present

bull Vitreo-macular adhesion at baseline

bull No disruption of ELM and ISOS junction

bull No disorganisation of inner retinal layers (DRIL)

RESTORE subgroup analysis of OCT features

bull Andreas Pollreisz EURETINA 2015

bull OCT biomarkers (RESTORE data)

bull Better effects with anti-VEGF ifbull Small rather than large intra-retinal cyst

bull Sub-retinal fluid present

bull Vitreo-macular adhesion at baseline

bull No disruption of ELM and ISOS junction

bull No disorganisation of inner retinal layers (DRIL)

Better baseline characterisationclassificationERG Contrast sensitivityOCT AngiographyMicroperimetry= clues as to who responds best to which drug

Plan for this presentation helliphellipa long list

bull What treatment options are available for DMO (evidence base)

bull What treatment should I start with at baselinebull Re-treatment algorithms for intravitreal DMO therapiesbull When should I switchcombine therapiesbull The bigger picture

bull Other eyebull The patient as a wholebull The service -coping with capacity ndash compromises

The bigger pictureOther eyeThe patient as a wholeThe service -coping with capacity ndash compromises

bull OTHER EYE ndash may create problems

bull Treat and extend ndash ldquoreduce of visitsrdquo plus Eylea license ndash ldquono need for monitoringrdquo may not benefit if lots of visits due to PDR other eye

bull PERIPHERAL RETINA anti-VEGF supresses proliferative disease - Rebound on stopping Rx

bull PATIENT

bull Anti-VEGF ndash heavy user - Will comply

bull One stop much better than two stop for patient ndash Treat and extend

bull SERVICE

bull Capacity and demand planning = fixedT+E more predictable at least 1 month in advance ndash flexible nurse injectors

bull Steroids ndash even if well controlled (Iluvien for 3 years) need IOP check

bull Need pan-retinal examination both eyes ndash separate visits

Summary

CSMO

No centre involvement

Photocoagulation

Centre involvement

gt 78 letters(normalminimally reduced VA)

Photocoagulation

VA 78ndash24 letters

Phakic

Anti-VEGF

Pseudophakic

Anti-VEGF

SWITCHglaucoma

Injection tolerance

Medical issuesrecent CVA

Peripheral diseaseBilateral Rx

CSMO

No centre involvement

LASER

Centre involvement

gt 78 letters(normalminimally

reduced VA)

VA 78ndash24 letters

EYLEA OR LUCENTIS OR AVASTIN

Funding issues

Protocol T ndash poor VA lt 65 letters (615)

LOADING

Monthly injections until stability OR 5 x 112 (EYLEA) = 6 MONTHS then 8 weeks

RETREATMENT1

TREAT AND EXTEND - PRN

PRN

PSEUDOPHAKIC

Prior Rx

ILUVIEN

Chronic disease

OZURDEX

RETREATMENT

OZURDEX

OCT gt175um or any residual oedema

ILUVIEN after 12 months if risksltbenefits

OCT

gt400um

bull FACE TO FACE CLINICS RUNNING IN PARALLEL

bull = MAC002 every 6 months (optom or doctor) routine check for cataracttolerance of injectionsglaucoma issues etc

bull =MAC003 (DOCTOR) for problems as needed no fixed intervalDischargestop treatmentDeclines treatment diagnosis CSR overlay etcswitch drugs

bull =RV002- (DOCTOR) every 6 months

bull =DM002 ndash (DOCTOR) variable interval determined by last assessing doctor

bull First visit at 6 months from 1st injection if mild NPDR

bull Otherwise determined by retinopathy generally

LOADING PHASE

EyleaLucentis 1 within 48hrs of baseline

EyleaLucentis 2 (and LogMAR VA plus OCT same visit)

EyleaLucentis 3 (and LogMAR VA plus OCT same visit)

EyleaLucentis 4 (TEinj)(and Logmar VA plus OCT same visit

AFTER INJECTION 4 data goes off to be reviewed immediately as a hellip

TREAT AND EXTEND assessment ndash the next interval will depend on the response to the loading phase

NB -DMO patients ndash majority (95) will need 6 injctions x 112 of Lucentis

OR Eylea 5 x 112 then 8 weekly

ONCE STABLE for 3 x injection in TE phase

VIRTUAL CLINIC MONITORING OF MACULOPATHY AND PRN RETREATMENT

ANTI-VEGF INJECTION PATHWAYS Baseline visitMAC001 for wet AMDRV001 for CRVOBRVOMed ret clinic for DMO

Pathways ndash too many directions

Better that thanhellip

Thank you

Pathway overview = Lucentis prn

Jan

Loading phase = injections every 4 weeks until ldquostablerdquo for 3 visits

helliphelliphellip

Feb OctSepAugJulJunMayAprMar

MarFebJan

DecNov

DecNovOctSepAugJulJunMayApr

Then observe UNTIL VA decreases or OCT increase = prn

Once reactivates need at least 2 injections until stable again over 3 visits

Pathway overview = Treat and Extend

Jan

Loading phase = injections every 4 weeks until ldquostablerdquo for 3 visits or Eyleayear 1

helliphelliphellip

Feb OctSepAugJulJunMayAprMar

MarFebJan

DecNov

DecNovOctSepAugJulJunMayApr

Then keep injecting but extend the interval between injections gradually ie keep treating even if perfect

If reactivates need at least 2 injections until stable again over 3 visits

Pathway overview = Eylea fixed dosing year 1

Jan

Eylea = 5 x 112 injection then every 8 weeks

Average 6 injections yr 2 Beyond that

helliphelliphellip

Feb OctSepAugJulJunMayAprMar

MarFebJan

DecNov

DecNovOctSepAugJulJunMayApr

Then individualised UNTIL VA decreases or OCT increase = prn

Once reactivates need at least 2 injections until stable again over 3 visits

Pros and cons of Treat and Extend vs Prn

T+E PRN

PROS bull Proactive patient and service get advance warning of injection ndash capacity and demand planning easier

bull One ndashstopbull Fewer visits than prnbull Overtreatment

advantageous for peripheral retinopathy

bull Only treated when active ieno overtreatment

bull Aggressive year 1 protocols (DRCRN I ndash few injections needed thereafter

bull DMO tolerant of reactivations ()

CONS bull Overtreatment = riskexpenseinconvenience

bull Evidence base scantbull Bilateral disease tricky

bull Reactive so need enoughemergency capacity to inject when disease flares up

bull No advance warning to patientservice that injection needed

bull NEED TO DO IT WELL ndashNHS real life audits prn based regimes not good resultsUndertreatment in year 1 Affects long term prognosis and treatment burden

Pros and cons of Treat and Extend vs Prn

T+E PRN

PROS bull Proactive patient and service get advance warning of injection ndash capacity and demand planning easier

bull One ndashstopbull Fewer visits than prnbull Overtreatment

advantageous for peripheral retinopathy

bull Only treated when active ieno overtreatment

bull Aggressive year 1 protocols (DRCRN I ndash few injections needed thereafter

bull DMO tolerant of reactivations ()

CONS bull Overtreatment = riskexpenseinconvenience

bull Evidence base scantbull Bilateral disease tricky

bull Reactive so need enoughemergency capacity to inject when disease flares up

bull No advance warning to patientservice that injection needed

bull NEED TO DO IT WELL ndashNHS real life audits prn based regimes not good resultsUndertreatment in year 1 Affects long term prognosis and treatment burden

DMO ndash anti-VEGF Treat and Extend

bull Retain study ndash the only RCT data

bull Br J Ophthalmol 2015 Oct 9 pii bjophthalmol-2015-307249 doi 101136bjophthalmol-2015-307249 [Epub ahead of print]

bull Ranibizumab 05 mg treat-and-extend regimen for diabetic macular oedema the RETAIN study

bull Pruumlnte C1 Fajnkuchen F2 Mahmood S3 Ricci F4 Hatz K5 Studnička J6 Bezlyak V7 Parikh S7 Stubbings WJ7 Wenzel A7 Figueira J8 and the RETAIN Study Group

RETAIN Phase III trial evaluating the efficacy of lsquotreat and extendrsquo regimen (ARVO 2014)

bull Patients with DMO and visual impairment (n = 372) were randomised 111

to one of three groups for 24 months

bull Two phases to dosing schedule

bull Phase A

bull Patients in all groups were initially treated with monthly ranibizumab until BCVA remained

stable

bull Phase B

bull Patients in the TampE groups whose vision remained stable had treatment- free intervals

that were increased incrementally by 1 month for a maximum of 3 months

bull Patients in the PRN group had ongoing monthly monitoring

bull In all groups Phase A was resumed if a decrease in BCVA was observed at a visit

Ranibizumab 05 mg monotherapy

in TampE regimen

Ranibizumab 05 mg in TampE regimen

plus laser

Ranibizumab 05 mg PRN

35

RETAIN Visual acuity endpoints

Pruumlnte C ARVO 2014 Annual Meeting Abstracts Abstract 1700

Mean average change in BCVAat 12 months (primary endpoint)

Mean change in BCVA at 24 months

Mea

n av

erag

e ch

ange

in B

CVA

(ETD

RS

lette

rs)

RanibizumabTampE

RanibizumabTampE + laser

RanibizumabPRN

RanibizumabTampE

RanibizumabTampE + laser

RanibizumabPRN

Mea

n ch

ange

in B

CVA

(ETD

RS

lette

rs)

plt00001 for both ranibizumab TampE groups versus PRN for primary endpoint

36

RETAIN Patient visits and monitoring with TampE regimen over 24 months

bull The TampE regimen provided an approximately 40 reduction in the number of treatment visits required compared with the ranibizumab PRN regimen

bull Approximately 70 of patients receiving TampE regimens had monitoring intervals ge2 months compared with ongoing monthly monitoring in the ranibizumab PRN group

bull Informed the license for Lucentis in DMO (extend by 1 month at a time)

37

INTRAVITREAL STEROIDSWhich intravitreal steroid is better

bull Licensed steroids ndash Ozurdex (Dexamethasone) and Iluvien (Fluocinoloneacetonide

bull Which steroid is best in terms of VA outcomes hellipWE DONrsquoT KNOW FOR SURE ndash no head to head studies for licensed drugs either between steroids or between anti-VEGF and steroids

bull STEROIDS ARE efficacious in DMO

bull MEAD

bull FAME

bull DRCRnet protocol I

bull NICE ndash Ozurdex and Iluvien ndash second-line agents

Ozurdex

bull A biodegradable co-polymer implant ndash degrades in time to lactic and glycolic acid releasing Dexamethasone

bull 22gauge injectionbull MEAD study

bull N=1048

bull Dex 07mg vs 035mg vs sham

bull No rescue therapy

bull 3 year follow up max 6 monthly dosing ie 7 over 3 years

Gan IM et al Greafes Acrh Clin Exp Ophthalmol 2005

MEAD studyMean BCVA change from baseline based on baseline lens status

-2

0

2

4

6

8

10

0 3 6 9 12 15 18 21 24 27 30 33 36 39

Mea

n C

hang

e Fr

om

Bas

elin

e B

CVA

(Let

ters

)

Month

DEX Implant 07 mg (n = 86)

Sham (n = 101)

Boyer DS et al Ophthalmology 20141211904ndash14

Results analyzed in the ITT population with LOCF for missing values

Pseudophakic

Total

0

5

10

0 3 6 9 12 15 18 21 24 27 30 33 36 39

DEX 700 (n=351)

Sham (n=350)

10

8

6

4

2

0

Mea

n C

hang

e fr

om

Bas

elin

e B

CVA

(Let

ters

)

Month

07mg dose is approved as Ozurdexreg by the FDA and EMA 035mg dose not commercially available

1 Boyer DS et al Ophthalmology 2014 121 1904-1914

bull Nonbioerodible micro implant (polyimide) containing 190microg of fluocinolone acetonide (FAc)

bull Consistent daily submicrogram delivery of 02 microgd FAc for up to 36 months

bull Posterior point of release

bull 35 mm times 037 mm non-bioerodable micro implant

bull 25-gauge injector creates self-sealing wound

bull No measurable systemic exposure

ILUVIEN Implant Technology

FAcimplant

ILUVIEN SPC httpwwwmedicinesorgukemcmedicine27636

0 6 12 18 24 30 36

ILUVIEN 02 microgd FAc(n = 376)05 microgd FAc (n = 395)Control sham injection(n = 185)

Design of Phase 3 FAME Study (FAME A and B = same protocol)

Additional laser therapy allowed after week 6a

Retreatment any time after month 12 (if eligibleb)

Study ends

N = 956Randomisation

221Primary readout

Patients with DMO and

bull At least 1 previous laser tx

bull BCVA ge19 and le68 letters

bull TD-OCT FTH ge250 μm

Month

BCVA = best corrected visual acuity DMO = diabetic macular oedema TD-OCT=time domain optical coherence tomography FTH = foveal thicknessa At masked investigatorrsquos discretion b If BCVA loss ge5 letters or retinal thickening ge50 microm from best reading in previous 12 months

ge15 letter Gain is Greater in Chronic DMO Patients

ge 15

-Let

ter I

mpr

ovem

ent

in B

CVA

Fro

m B

asel

ine

Δ = 98

Months

Full Population Patients With Chronic DMO

Months

Δ = 206

287

189134

34

Steroid re-treatments

bullOzurdexbull Longer half-life than anti-VEGF in the eye

bull Redosing regimes not very helpful from RCT data eg MEAD study only 612 dosing

bull In reality re-treatment interval may be shorter

bull POSOLOGY

bull Patients treated with OZURDEX who have experienced an initial response and in the physicians opinion may benefit from retreatment without being exposed to significant risk should be considered for retreatment Retreatment may be performed after approximately 6 months if the patient experiences decreased vision andor an increase in retinal thickness secondary to recurrent or worsening diabetic macular oedema

bullIluvienbull 70 of patients in FAE only needed 1

injection over 3 years

bull BUT additional rescue treatments allowed

bull POSOLOGY

bull Each ILUVIEN implant releases fluocinolone acetonide for up to 36 months An additional implant may be administered after 12 months if the patient experiences decreased vision or an increase in retinal thickness secondary to recurrent or worsening diabetic macular oedema

bull Patients receiving escape medication were exited from MEAD before administration1

bull Macular laser rescue treatment allowed in RISERIDE (Lucentisreg) from 3 months2

bull Focalgrid laser allowed in FAME (Iluvienreg) from 6 weeks3

MEAD TREATMENT PROTOCOL

bull First treatment given at randomisation (day 0) bull Patients assessed for retreatment eligibility every 3 months from

months 6ndash36bull Patients were eligible for retreatment if

OCT optical coherence tomography

ge6 months since most recent

study treatment

Retinal thickness in 1 mm central macular

subfield by OCT gt175 microm

Evidence of residual retinal oedema (intraretinal cysts or

any regions of increased retinal thickening) as assessed by

investigator from OCT

AND OR

MEA

D

Amendment in May 2010 revised anatomic criterion for retreatment before this time the threshold was gt225 microm1Boyer DS et al Ophthalmology 2014 121 1904-19142Nguyen QD et al Ophthalmology 20121191064minus10773Campochiaro PA et al Ophthalmology 2011118626ndash635

Treatment burdenILUVIEN

Control(n =112)

02 microgd FAc(n =209)

Study Treatments(sham injection or ILUVIEN 02 microgday or FAc 05microgday)

1 treatment 661 761

2 treatments 277 187

ge 3 treatments 63 53

Rescue Laser Treatments (at masked physicianrsquos discretion after week 6)

Patients 607 407

Off-Protocol Treatments (IVTA bevacizumab ranibizumab intravitreal dexamethasone)

Patients 295 115

OZURDEX = 23injections year 1 41 by year 3

No other Rx

Summary of side effects with intravitreal steroids

Drug device Evidence base Cataract risk IOP rise (requiring drops)

Glaucoma surgery

endophthalmitis

ILUVIEN FAME studies 80 cat surgery(273 sham)

384(14 control)

48 0

Ozurdex MEAD 592 had cataract surgery(72 sham)

215 (end of study)(34 sham)

06 0

Trivaris+ laser vs Luc+laserx2 vs laser

Protocol IOphthalmology 2010

15 42(ONE OFgt10mmHg risegt30mmHGStart drops)

2186 0

NICE guidance for intravitreal steroids in DMO

bull Iluvien

bull NICE TA 301 Iluvien for DMO Nov 2013

bull hellipfor treating chronic diabetic macular oedema that is insufficiently responsive to available therapies only if

bull the implant is to be used in an eye with an intraocular

(pseudophakic) lens and

bull the manufacturer provides fluocinolone acetonide intravitreal implant with the discount agreed in the patient access scheme

NICE guidance for intravitreal steroids in DMO

bull Ozurdex

bull NICE TA 349 Ozurdex for DMO July 2015

bull there is an artificial lens in the eye to be treated and

bull their diabetic macular oedema has not improved with

non-corticosteroid treatment or such treatment is not suitable for them

Steroids = second line therapyWhen do I switch

bull Anti-VEGF first line for centre involving DMObull NICE TA ndash ldquoinsufficiently responsiverdquo ldquo ldquonot improvedrdquo ldquonot suitablerdquo ndash

OTHER TREATMENTS

bull 2 scenariosbull 1) Anti-VEGF canrsquot be funded ie OCTlt400um + PSEUDOPHAKIC

bull 2) Already had a course of treatment with laseranti-VEGF + PSEUDOPHAKIC ie SWITCHING from anti-VEGF to steroid

bull Plus

bull ldquochronicrdquo DMO ndash 3 years duration in FAME (18months) for ILUVIEN

bull Chronic DMO not essential for Ozurdex

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

Protocol T ndash patients may not improve in first 6 months

RIDE

RISE

Mea

n ch

ange

in B

CVA

(E

TDR

S le

tters

)M

ean

chan

ge in

BC

VA

(ETD

RS

lette

rs)

Time (months)

RISE and RIDE (Lucentis monthly dosing) Mean change in BCVA over 36 months

Brown DM et al Ophthalmology 2013120(10)2013ndash2022

54

Ranibizumab 03 mgRanibizumab 05 mgShamranibizumab 05 mg

Date of Prep Dec 2014 LGB0820147252X

VA improvement continues throughout year 1 with monthly dosing

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user ndash more than protocol

I

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

DRCRN protocol I5 year outcomesInjections 8-9 in year 1Year 2 = 2-3Year 3= 1-2Year 4 = 0-1Year 5 = 0

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

Wait for plateau = stability in protocol T laserPatient factors again

Judgement of response to anti-VEGF ndashtimeframe

bull Wait 6 months in poor responders

bull Wait 1 year for heavy users

bull Tempting to try steroids earlier than this ifbull No glaucoma ndash not a deal breaker Ozurdex better short term optionbull Pseudophakic

bull Clues from the diseasebull chronic

bull PATIENT FACTORS

bull Any eyes avoid steroids ndash advanced glaucomaCSCR Or prior viral retinitis RARE

bull Any eyes avoid anti-VEGF pregnancytrying to concieve recent CVA

BIOMARKERS AT BASELINE WOULD BE USEFULRESTORE subgroup analysis of OCT features

bull Andreas Pollreisz EURETINA 2015

bull OCT biomarkers (RESTORE data)

bull Better effects with anti-VEGF ifbull Small rather than large intra-retinal cyst

bull Sub-retinal fluid present

bull Vitreo-macular adhesion at baseline

bull No disruption of ELM and ISOS junction

bull No disorganisation of inner retinal layers (DRIL)

RESTORE subgroup analysis of OCT features

bull Andreas Pollreisz EURETINA 2015

bull OCT biomarkers (RESTORE data)

bull Better effects with anti-VEGF ifbull Small rather than large intra-retinal cyst

bull Sub-retinal fluid present

bull Vitreo-macular adhesion at baseline

bull No disruption of ELM and ISOS junction

bull No disorganisation of inner retinal layers (DRIL)

Better baseline characterisationclassificationERG Contrast sensitivityOCT AngiographyMicroperimetry= clues as to who responds best to which drug

Plan for this presentation helliphellipa long list

bull What treatment options are available for DMO (evidence base)

bull What treatment should I start with at baselinebull Re-treatment algorithms for intravitreal DMO therapiesbull When should I switchcombine therapiesbull The bigger picture

bull Other eyebull The patient as a wholebull The service -coping with capacity ndash compromises

The bigger pictureOther eyeThe patient as a wholeThe service -coping with capacity ndash compromises

bull OTHER EYE ndash may create problems

bull Treat and extend ndash ldquoreduce of visitsrdquo plus Eylea license ndash ldquono need for monitoringrdquo may not benefit if lots of visits due to PDR other eye

bull PERIPHERAL RETINA anti-VEGF supresses proliferative disease - Rebound on stopping Rx

bull PATIENT

bull Anti-VEGF ndash heavy user - Will comply

bull One stop much better than two stop for patient ndash Treat and extend

bull SERVICE

bull Capacity and demand planning = fixedT+E more predictable at least 1 month in advance ndash flexible nurse injectors

bull Steroids ndash even if well controlled (Iluvien for 3 years) need IOP check

bull Need pan-retinal examination both eyes ndash separate visits

Summary

CSMO

No centre involvement

Photocoagulation

Centre involvement

gt 78 letters(normalminimally reduced VA)

Photocoagulation

VA 78ndash24 letters

Phakic

Anti-VEGF

Pseudophakic

Anti-VEGF

SWITCHglaucoma

Injection tolerance

Medical issuesrecent CVA

Peripheral diseaseBilateral Rx

CSMO

No centre involvement

LASER

Centre involvement

gt 78 letters(normalminimally

reduced VA)

VA 78ndash24 letters

EYLEA OR LUCENTIS OR AVASTIN

Funding issues

Protocol T ndash poor VA lt 65 letters (615)

LOADING

Monthly injections until stability OR 5 x 112 (EYLEA) = 6 MONTHS then 8 weeks

RETREATMENT1

TREAT AND EXTEND - PRN

PRN

PSEUDOPHAKIC

Prior Rx

ILUVIEN

Chronic disease

OZURDEX

RETREATMENT

OZURDEX

OCT gt175um or any residual oedema

ILUVIEN after 12 months if risksltbenefits

OCT

gt400um

bull FACE TO FACE CLINICS RUNNING IN PARALLEL

bull = MAC002 every 6 months (optom or doctor) routine check for cataracttolerance of injectionsglaucoma issues etc

bull =MAC003 (DOCTOR) for problems as needed no fixed intervalDischargestop treatmentDeclines treatment diagnosis CSR overlay etcswitch drugs

bull =RV002- (DOCTOR) every 6 months

bull =DM002 ndash (DOCTOR) variable interval determined by last assessing doctor

bull First visit at 6 months from 1st injection if mild NPDR

bull Otherwise determined by retinopathy generally

LOADING PHASE

EyleaLucentis 1 within 48hrs of baseline

EyleaLucentis 2 (and LogMAR VA plus OCT same visit)

EyleaLucentis 3 (and LogMAR VA plus OCT same visit)

EyleaLucentis 4 (TEinj)(and Logmar VA plus OCT same visit

AFTER INJECTION 4 data goes off to be reviewed immediately as a hellip

TREAT AND EXTEND assessment ndash the next interval will depend on the response to the loading phase

NB -DMO patients ndash majority (95) will need 6 injctions x 112 of Lucentis

OR Eylea 5 x 112 then 8 weekly

ONCE STABLE for 3 x injection in TE phase

VIRTUAL CLINIC MONITORING OF MACULOPATHY AND PRN RETREATMENT

ANTI-VEGF INJECTION PATHWAYS Baseline visitMAC001 for wet AMDRV001 for CRVOBRVOMed ret clinic for DMO

Pathways ndash too many directions

Better that thanhellip

Thank you

Pathway overview = Treat and Extend

Jan

Loading phase = injections every 4 weeks until ldquostablerdquo for 3 visits or Eyleayear 1

helliphelliphellip

Feb OctSepAugJulJunMayAprMar

MarFebJan

DecNov

DecNovOctSepAugJulJunMayApr

Then keep injecting but extend the interval between injections gradually ie keep treating even if perfect

If reactivates need at least 2 injections until stable again over 3 visits

Pathway overview = Eylea fixed dosing year 1

Jan

Eylea = 5 x 112 injection then every 8 weeks

Average 6 injections yr 2 Beyond that

helliphelliphellip

Feb OctSepAugJulJunMayAprMar

MarFebJan

DecNov

DecNovOctSepAugJulJunMayApr

Then individualised UNTIL VA decreases or OCT increase = prn

Once reactivates need at least 2 injections until stable again over 3 visits

Pros and cons of Treat and Extend vs Prn

T+E PRN

PROS bull Proactive patient and service get advance warning of injection ndash capacity and demand planning easier

bull One ndashstopbull Fewer visits than prnbull Overtreatment

advantageous for peripheral retinopathy

bull Only treated when active ieno overtreatment

bull Aggressive year 1 protocols (DRCRN I ndash few injections needed thereafter

bull DMO tolerant of reactivations ()

CONS bull Overtreatment = riskexpenseinconvenience

bull Evidence base scantbull Bilateral disease tricky

bull Reactive so need enoughemergency capacity to inject when disease flares up

bull No advance warning to patientservice that injection needed

bull NEED TO DO IT WELL ndashNHS real life audits prn based regimes not good resultsUndertreatment in year 1 Affects long term prognosis and treatment burden

Pros and cons of Treat and Extend vs Prn

T+E PRN

PROS bull Proactive patient and service get advance warning of injection ndash capacity and demand planning easier

bull One ndashstopbull Fewer visits than prnbull Overtreatment

advantageous for peripheral retinopathy

bull Only treated when active ieno overtreatment

bull Aggressive year 1 protocols (DRCRN I ndash few injections needed thereafter

bull DMO tolerant of reactivations ()

CONS bull Overtreatment = riskexpenseinconvenience

bull Evidence base scantbull Bilateral disease tricky

bull Reactive so need enoughemergency capacity to inject when disease flares up

bull No advance warning to patientservice that injection needed

bull NEED TO DO IT WELL ndashNHS real life audits prn based regimes not good resultsUndertreatment in year 1 Affects long term prognosis and treatment burden

DMO ndash anti-VEGF Treat and Extend

bull Retain study ndash the only RCT data

bull Br J Ophthalmol 2015 Oct 9 pii bjophthalmol-2015-307249 doi 101136bjophthalmol-2015-307249 [Epub ahead of print]

bull Ranibizumab 05 mg treat-and-extend regimen for diabetic macular oedema the RETAIN study

bull Pruumlnte C1 Fajnkuchen F2 Mahmood S3 Ricci F4 Hatz K5 Studnička J6 Bezlyak V7 Parikh S7 Stubbings WJ7 Wenzel A7 Figueira J8 and the RETAIN Study Group

RETAIN Phase III trial evaluating the efficacy of lsquotreat and extendrsquo regimen (ARVO 2014)

bull Patients with DMO and visual impairment (n = 372) were randomised 111

to one of three groups for 24 months

bull Two phases to dosing schedule

bull Phase A

bull Patients in all groups were initially treated with monthly ranibizumab until BCVA remained

stable

bull Phase B

bull Patients in the TampE groups whose vision remained stable had treatment- free intervals

that were increased incrementally by 1 month for a maximum of 3 months

bull Patients in the PRN group had ongoing monthly monitoring

bull In all groups Phase A was resumed if a decrease in BCVA was observed at a visit

Ranibizumab 05 mg monotherapy

in TampE regimen

Ranibizumab 05 mg in TampE regimen

plus laser

Ranibizumab 05 mg PRN

35

RETAIN Visual acuity endpoints

Pruumlnte C ARVO 2014 Annual Meeting Abstracts Abstract 1700

Mean average change in BCVAat 12 months (primary endpoint)

Mean change in BCVA at 24 months

Mea

n av

erag

e ch

ange

in B

CVA

(ETD

RS

lette

rs)

RanibizumabTampE

RanibizumabTampE + laser

RanibizumabPRN

RanibizumabTampE

RanibizumabTampE + laser

RanibizumabPRN

Mea

n ch

ange

in B

CVA

(ETD

RS

lette

rs)

plt00001 for both ranibizumab TampE groups versus PRN for primary endpoint

36

RETAIN Patient visits and monitoring with TampE regimen over 24 months

bull The TampE regimen provided an approximately 40 reduction in the number of treatment visits required compared with the ranibizumab PRN regimen

bull Approximately 70 of patients receiving TampE regimens had monitoring intervals ge2 months compared with ongoing monthly monitoring in the ranibizumab PRN group

bull Informed the license for Lucentis in DMO (extend by 1 month at a time)

37

INTRAVITREAL STEROIDSWhich intravitreal steroid is better

bull Licensed steroids ndash Ozurdex (Dexamethasone) and Iluvien (Fluocinoloneacetonide

bull Which steroid is best in terms of VA outcomes hellipWE DONrsquoT KNOW FOR SURE ndash no head to head studies for licensed drugs either between steroids or between anti-VEGF and steroids

bull STEROIDS ARE efficacious in DMO

bull MEAD

bull FAME

bull DRCRnet protocol I

bull NICE ndash Ozurdex and Iluvien ndash second-line agents

Ozurdex

bull A biodegradable co-polymer implant ndash degrades in time to lactic and glycolic acid releasing Dexamethasone

bull 22gauge injectionbull MEAD study

bull N=1048

bull Dex 07mg vs 035mg vs sham

bull No rescue therapy

bull 3 year follow up max 6 monthly dosing ie 7 over 3 years

Gan IM et al Greafes Acrh Clin Exp Ophthalmol 2005

MEAD studyMean BCVA change from baseline based on baseline lens status

-2

0

2

4

6

8

10

0 3 6 9 12 15 18 21 24 27 30 33 36 39

Mea

n C

hang

e Fr

om

Bas

elin

e B

CVA

(Let

ters

)

Month

DEX Implant 07 mg (n = 86)

Sham (n = 101)

Boyer DS et al Ophthalmology 20141211904ndash14

Results analyzed in the ITT population with LOCF for missing values

Pseudophakic

Total

0

5

10

0 3 6 9 12 15 18 21 24 27 30 33 36 39

DEX 700 (n=351)

Sham (n=350)

10

8

6

4

2

0

Mea

n C

hang

e fr

om

Bas

elin

e B

CVA

(Let

ters

)

Month

07mg dose is approved as Ozurdexreg by the FDA and EMA 035mg dose not commercially available

1 Boyer DS et al Ophthalmology 2014 121 1904-1914

bull Nonbioerodible micro implant (polyimide) containing 190microg of fluocinolone acetonide (FAc)

bull Consistent daily submicrogram delivery of 02 microgd FAc for up to 36 months

bull Posterior point of release

bull 35 mm times 037 mm non-bioerodable micro implant

bull 25-gauge injector creates self-sealing wound

bull No measurable systemic exposure

ILUVIEN Implant Technology

FAcimplant

ILUVIEN SPC httpwwwmedicinesorgukemcmedicine27636

0 6 12 18 24 30 36

ILUVIEN 02 microgd FAc(n = 376)05 microgd FAc (n = 395)Control sham injection(n = 185)

Design of Phase 3 FAME Study (FAME A and B = same protocol)

Additional laser therapy allowed after week 6a

Retreatment any time after month 12 (if eligibleb)

Study ends

N = 956Randomisation

221Primary readout

Patients with DMO and

bull At least 1 previous laser tx

bull BCVA ge19 and le68 letters

bull TD-OCT FTH ge250 μm

Month

BCVA = best corrected visual acuity DMO = diabetic macular oedema TD-OCT=time domain optical coherence tomography FTH = foveal thicknessa At masked investigatorrsquos discretion b If BCVA loss ge5 letters or retinal thickening ge50 microm from best reading in previous 12 months

ge15 letter Gain is Greater in Chronic DMO Patients

ge 15

-Let

ter I

mpr

ovem

ent

in B

CVA

Fro

m B

asel

ine

Δ = 98

Months

Full Population Patients With Chronic DMO

Months

Δ = 206

287

189134

34

Steroid re-treatments

bullOzurdexbull Longer half-life than anti-VEGF in the eye

bull Redosing regimes not very helpful from RCT data eg MEAD study only 612 dosing

bull In reality re-treatment interval may be shorter

bull POSOLOGY

bull Patients treated with OZURDEX who have experienced an initial response and in the physicians opinion may benefit from retreatment without being exposed to significant risk should be considered for retreatment Retreatment may be performed after approximately 6 months if the patient experiences decreased vision andor an increase in retinal thickness secondary to recurrent or worsening diabetic macular oedema

bullIluvienbull 70 of patients in FAE only needed 1

injection over 3 years

bull BUT additional rescue treatments allowed

bull POSOLOGY

bull Each ILUVIEN implant releases fluocinolone acetonide for up to 36 months An additional implant may be administered after 12 months if the patient experiences decreased vision or an increase in retinal thickness secondary to recurrent or worsening diabetic macular oedema

bull Patients receiving escape medication were exited from MEAD before administration1

bull Macular laser rescue treatment allowed in RISERIDE (Lucentisreg) from 3 months2

bull Focalgrid laser allowed in FAME (Iluvienreg) from 6 weeks3

MEAD TREATMENT PROTOCOL

bull First treatment given at randomisation (day 0) bull Patients assessed for retreatment eligibility every 3 months from

months 6ndash36bull Patients were eligible for retreatment if

OCT optical coherence tomography

ge6 months since most recent

study treatment

Retinal thickness in 1 mm central macular

subfield by OCT gt175 microm

Evidence of residual retinal oedema (intraretinal cysts or

any regions of increased retinal thickening) as assessed by

investigator from OCT

AND OR

MEA

D

Amendment in May 2010 revised anatomic criterion for retreatment before this time the threshold was gt225 microm1Boyer DS et al Ophthalmology 2014 121 1904-19142Nguyen QD et al Ophthalmology 20121191064minus10773Campochiaro PA et al Ophthalmology 2011118626ndash635

Treatment burdenILUVIEN

Control(n =112)

02 microgd FAc(n =209)

Study Treatments(sham injection or ILUVIEN 02 microgday or FAc 05microgday)

1 treatment 661 761

2 treatments 277 187

ge 3 treatments 63 53

Rescue Laser Treatments (at masked physicianrsquos discretion after week 6)

Patients 607 407

Off-Protocol Treatments (IVTA bevacizumab ranibizumab intravitreal dexamethasone)

Patients 295 115

OZURDEX = 23injections year 1 41 by year 3

No other Rx

Summary of side effects with intravitreal steroids

Drug device Evidence base Cataract risk IOP rise (requiring drops)

Glaucoma surgery

endophthalmitis

ILUVIEN FAME studies 80 cat surgery(273 sham)

384(14 control)

48 0

Ozurdex MEAD 592 had cataract surgery(72 sham)

215 (end of study)(34 sham)

06 0

Trivaris+ laser vs Luc+laserx2 vs laser

Protocol IOphthalmology 2010

15 42(ONE OFgt10mmHg risegt30mmHGStart drops)

2186 0

NICE guidance for intravitreal steroids in DMO

bull Iluvien

bull NICE TA 301 Iluvien for DMO Nov 2013

bull hellipfor treating chronic diabetic macular oedema that is insufficiently responsive to available therapies only if

bull the implant is to be used in an eye with an intraocular

(pseudophakic) lens and

bull the manufacturer provides fluocinolone acetonide intravitreal implant with the discount agreed in the patient access scheme

NICE guidance for intravitreal steroids in DMO

bull Ozurdex

bull NICE TA 349 Ozurdex for DMO July 2015

bull there is an artificial lens in the eye to be treated and

bull their diabetic macular oedema has not improved with

non-corticosteroid treatment or such treatment is not suitable for them

Steroids = second line therapyWhen do I switch

bull Anti-VEGF first line for centre involving DMObull NICE TA ndash ldquoinsufficiently responsiverdquo ldquo ldquonot improvedrdquo ldquonot suitablerdquo ndash

OTHER TREATMENTS

bull 2 scenariosbull 1) Anti-VEGF canrsquot be funded ie OCTlt400um + PSEUDOPHAKIC

bull 2) Already had a course of treatment with laseranti-VEGF + PSEUDOPHAKIC ie SWITCHING from anti-VEGF to steroid

bull Plus

bull ldquochronicrdquo DMO ndash 3 years duration in FAME (18months) for ILUVIEN

bull Chronic DMO not essential for Ozurdex

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

Protocol T ndash patients may not improve in first 6 months

RIDE

RISE

Mea

n ch

ange

in B

CVA

(E

TDR

S le

tters

)M

ean

chan

ge in

BC

VA

(ETD

RS

lette

rs)

Time (months)

RISE and RIDE (Lucentis monthly dosing) Mean change in BCVA over 36 months

Brown DM et al Ophthalmology 2013120(10)2013ndash2022

54

Ranibizumab 03 mgRanibizumab 05 mgShamranibizumab 05 mg

Date of Prep Dec 2014 LGB0820147252X

VA improvement continues throughout year 1 with monthly dosing

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user ndash more than protocol

I

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

DRCRN protocol I5 year outcomesInjections 8-9 in year 1Year 2 = 2-3Year 3= 1-2Year 4 = 0-1Year 5 = 0

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

Wait for plateau = stability in protocol T laserPatient factors again

Judgement of response to anti-VEGF ndashtimeframe

bull Wait 6 months in poor responders

bull Wait 1 year for heavy users

bull Tempting to try steroids earlier than this ifbull No glaucoma ndash not a deal breaker Ozurdex better short term optionbull Pseudophakic

bull Clues from the diseasebull chronic

bull PATIENT FACTORS

bull Any eyes avoid steroids ndash advanced glaucomaCSCR Or prior viral retinitis RARE

bull Any eyes avoid anti-VEGF pregnancytrying to concieve recent CVA

BIOMARKERS AT BASELINE WOULD BE USEFULRESTORE subgroup analysis of OCT features

bull Andreas Pollreisz EURETINA 2015

bull OCT biomarkers (RESTORE data)

bull Better effects with anti-VEGF ifbull Small rather than large intra-retinal cyst

bull Sub-retinal fluid present

bull Vitreo-macular adhesion at baseline

bull No disruption of ELM and ISOS junction

bull No disorganisation of inner retinal layers (DRIL)

RESTORE subgroup analysis of OCT features

bull Andreas Pollreisz EURETINA 2015

bull OCT biomarkers (RESTORE data)

bull Better effects with anti-VEGF ifbull Small rather than large intra-retinal cyst

bull Sub-retinal fluid present

bull Vitreo-macular adhesion at baseline

bull No disruption of ELM and ISOS junction

bull No disorganisation of inner retinal layers (DRIL)

Better baseline characterisationclassificationERG Contrast sensitivityOCT AngiographyMicroperimetry= clues as to who responds best to which drug

Plan for this presentation helliphellipa long list

bull What treatment options are available for DMO (evidence base)

bull What treatment should I start with at baselinebull Re-treatment algorithms for intravitreal DMO therapiesbull When should I switchcombine therapiesbull The bigger picture

bull Other eyebull The patient as a wholebull The service -coping with capacity ndash compromises

The bigger pictureOther eyeThe patient as a wholeThe service -coping with capacity ndash compromises

bull OTHER EYE ndash may create problems

bull Treat and extend ndash ldquoreduce of visitsrdquo plus Eylea license ndash ldquono need for monitoringrdquo may not benefit if lots of visits due to PDR other eye

bull PERIPHERAL RETINA anti-VEGF supresses proliferative disease - Rebound on stopping Rx

bull PATIENT

bull Anti-VEGF ndash heavy user - Will comply

bull One stop much better than two stop for patient ndash Treat and extend

bull SERVICE

bull Capacity and demand planning = fixedT+E more predictable at least 1 month in advance ndash flexible nurse injectors

bull Steroids ndash even if well controlled (Iluvien for 3 years) need IOP check

bull Need pan-retinal examination both eyes ndash separate visits

Summary

CSMO

No centre involvement

Photocoagulation

Centre involvement

gt 78 letters(normalminimally reduced VA)

Photocoagulation

VA 78ndash24 letters

Phakic

Anti-VEGF

Pseudophakic

Anti-VEGF

SWITCHglaucoma

Injection tolerance

Medical issuesrecent CVA

Peripheral diseaseBilateral Rx

CSMO

No centre involvement

LASER

Centre involvement

gt 78 letters(normalminimally

reduced VA)

VA 78ndash24 letters

EYLEA OR LUCENTIS OR AVASTIN

Funding issues

Protocol T ndash poor VA lt 65 letters (615)

LOADING

Monthly injections until stability OR 5 x 112 (EYLEA) = 6 MONTHS then 8 weeks

RETREATMENT1

TREAT AND EXTEND - PRN

PRN

PSEUDOPHAKIC

Prior Rx

ILUVIEN

Chronic disease

OZURDEX

RETREATMENT

OZURDEX

OCT gt175um or any residual oedema

ILUVIEN after 12 months if risksltbenefits

OCT

gt400um

bull FACE TO FACE CLINICS RUNNING IN PARALLEL

bull = MAC002 every 6 months (optom or doctor) routine check for cataracttolerance of injectionsglaucoma issues etc

bull =MAC003 (DOCTOR) for problems as needed no fixed intervalDischargestop treatmentDeclines treatment diagnosis CSR overlay etcswitch drugs

bull =RV002- (DOCTOR) every 6 months

bull =DM002 ndash (DOCTOR) variable interval determined by last assessing doctor

bull First visit at 6 months from 1st injection if mild NPDR

bull Otherwise determined by retinopathy generally

LOADING PHASE

EyleaLucentis 1 within 48hrs of baseline

EyleaLucentis 2 (and LogMAR VA plus OCT same visit)

EyleaLucentis 3 (and LogMAR VA plus OCT same visit)

EyleaLucentis 4 (TEinj)(and Logmar VA plus OCT same visit

AFTER INJECTION 4 data goes off to be reviewed immediately as a hellip

TREAT AND EXTEND assessment ndash the next interval will depend on the response to the loading phase

NB -DMO patients ndash majority (95) will need 6 injctions x 112 of Lucentis

OR Eylea 5 x 112 then 8 weekly

ONCE STABLE for 3 x injection in TE phase

VIRTUAL CLINIC MONITORING OF MACULOPATHY AND PRN RETREATMENT

ANTI-VEGF INJECTION PATHWAYS Baseline visitMAC001 for wet AMDRV001 for CRVOBRVOMed ret clinic for DMO

Pathways ndash too many directions

Better that thanhellip

Thank you

Pathway overview = Eylea fixed dosing year 1

Jan

Eylea = 5 x 112 injection then every 8 weeks

Average 6 injections yr 2 Beyond that

helliphelliphellip

Feb OctSepAugJulJunMayAprMar

MarFebJan

DecNov

DecNovOctSepAugJulJunMayApr

Then individualised UNTIL VA decreases or OCT increase = prn

Once reactivates need at least 2 injections until stable again over 3 visits

Pros and cons of Treat and Extend vs Prn

T+E PRN

PROS bull Proactive patient and service get advance warning of injection ndash capacity and demand planning easier

bull One ndashstopbull Fewer visits than prnbull Overtreatment

advantageous for peripheral retinopathy

bull Only treated when active ieno overtreatment

bull Aggressive year 1 protocols (DRCRN I ndash few injections needed thereafter

bull DMO tolerant of reactivations ()

CONS bull Overtreatment = riskexpenseinconvenience

bull Evidence base scantbull Bilateral disease tricky

bull Reactive so need enoughemergency capacity to inject when disease flares up

bull No advance warning to patientservice that injection needed

bull NEED TO DO IT WELL ndashNHS real life audits prn based regimes not good resultsUndertreatment in year 1 Affects long term prognosis and treatment burden

Pros and cons of Treat and Extend vs Prn

T+E PRN

PROS bull Proactive patient and service get advance warning of injection ndash capacity and demand planning easier

bull One ndashstopbull Fewer visits than prnbull Overtreatment

advantageous for peripheral retinopathy

bull Only treated when active ieno overtreatment

bull Aggressive year 1 protocols (DRCRN I ndash few injections needed thereafter

bull DMO tolerant of reactivations ()

CONS bull Overtreatment = riskexpenseinconvenience

bull Evidence base scantbull Bilateral disease tricky

bull Reactive so need enoughemergency capacity to inject when disease flares up

bull No advance warning to patientservice that injection needed

bull NEED TO DO IT WELL ndashNHS real life audits prn based regimes not good resultsUndertreatment in year 1 Affects long term prognosis and treatment burden

DMO ndash anti-VEGF Treat and Extend

bull Retain study ndash the only RCT data

bull Br J Ophthalmol 2015 Oct 9 pii bjophthalmol-2015-307249 doi 101136bjophthalmol-2015-307249 [Epub ahead of print]

bull Ranibizumab 05 mg treat-and-extend regimen for diabetic macular oedema the RETAIN study

bull Pruumlnte C1 Fajnkuchen F2 Mahmood S3 Ricci F4 Hatz K5 Studnička J6 Bezlyak V7 Parikh S7 Stubbings WJ7 Wenzel A7 Figueira J8 and the RETAIN Study Group

RETAIN Phase III trial evaluating the efficacy of lsquotreat and extendrsquo regimen (ARVO 2014)

bull Patients with DMO and visual impairment (n = 372) were randomised 111

to one of three groups for 24 months

bull Two phases to dosing schedule

bull Phase A

bull Patients in all groups were initially treated with monthly ranibizumab until BCVA remained

stable

bull Phase B

bull Patients in the TampE groups whose vision remained stable had treatment- free intervals

that were increased incrementally by 1 month for a maximum of 3 months

bull Patients in the PRN group had ongoing monthly monitoring

bull In all groups Phase A was resumed if a decrease in BCVA was observed at a visit

Ranibizumab 05 mg monotherapy

in TampE regimen

Ranibizumab 05 mg in TampE regimen

plus laser

Ranibizumab 05 mg PRN

35

RETAIN Visual acuity endpoints

Pruumlnte C ARVO 2014 Annual Meeting Abstracts Abstract 1700

Mean average change in BCVAat 12 months (primary endpoint)

Mean change in BCVA at 24 months

Mea

n av

erag

e ch

ange

in B

CVA

(ETD

RS

lette

rs)

RanibizumabTampE

RanibizumabTampE + laser

RanibizumabPRN

RanibizumabTampE

RanibizumabTampE + laser

RanibizumabPRN

Mea

n ch

ange

in B

CVA

(ETD

RS

lette

rs)

plt00001 for both ranibizumab TampE groups versus PRN for primary endpoint

36

RETAIN Patient visits and monitoring with TampE regimen over 24 months

bull The TampE regimen provided an approximately 40 reduction in the number of treatment visits required compared with the ranibizumab PRN regimen

bull Approximately 70 of patients receiving TampE regimens had monitoring intervals ge2 months compared with ongoing monthly monitoring in the ranibizumab PRN group

bull Informed the license for Lucentis in DMO (extend by 1 month at a time)

37

INTRAVITREAL STEROIDSWhich intravitreal steroid is better

bull Licensed steroids ndash Ozurdex (Dexamethasone) and Iluvien (Fluocinoloneacetonide

bull Which steroid is best in terms of VA outcomes hellipWE DONrsquoT KNOW FOR SURE ndash no head to head studies for licensed drugs either between steroids or between anti-VEGF and steroids

bull STEROIDS ARE efficacious in DMO

bull MEAD

bull FAME

bull DRCRnet protocol I

bull NICE ndash Ozurdex and Iluvien ndash second-line agents

Ozurdex

bull A biodegradable co-polymer implant ndash degrades in time to lactic and glycolic acid releasing Dexamethasone

bull 22gauge injectionbull MEAD study

bull N=1048

bull Dex 07mg vs 035mg vs sham

bull No rescue therapy

bull 3 year follow up max 6 monthly dosing ie 7 over 3 years

Gan IM et al Greafes Acrh Clin Exp Ophthalmol 2005

MEAD studyMean BCVA change from baseline based on baseline lens status

-2

0

2

4

6

8

10

0 3 6 9 12 15 18 21 24 27 30 33 36 39

Mea

n C

hang

e Fr

om

Bas

elin

e B

CVA

(Let

ters

)

Month

DEX Implant 07 mg (n = 86)

Sham (n = 101)

Boyer DS et al Ophthalmology 20141211904ndash14

Results analyzed in the ITT population with LOCF for missing values

Pseudophakic

Total

0

5

10

0 3 6 9 12 15 18 21 24 27 30 33 36 39

DEX 700 (n=351)

Sham (n=350)

10

8

6

4

2

0

Mea

n C

hang

e fr

om

Bas

elin

e B

CVA

(Let

ters

)

Month

07mg dose is approved as Ozurdexreg by the FDA and EMA 035mg dose not commercially available

1 Boyer DS et al Ophthalmology 2014 121 1904-1914

bull Nonbioerodible micro implant (polyimide) containing 190microg of fluocinolone acetonide (FAc)

bull Consistent daily submicrogram delivery of 02 microgd FAc for up to 36 months

bull Posterior point of release

bull 35 mm times 037 mm non-bioerodable micro implant

bull 25-gauge injector creates self-sealing wound

bull No measurable systemic exposure

ILUVIEN Implant Technology

FAcimplant

ILUVIEN SPC httpwwwmedicinesorgukemcmedicine27636

0 6 12 18 24 30 36

ILUVIEN 02 microgd FAc(n = 376)05 microgd FAc (n = 395)Control sham injection(n = 185)

Design of Phase 3 FAME Study (FAME A and B = same protocol)

Additional laser therapy allowed after week 6a

Retreatment any time after month 12 (if eligibleb)

Study ends

N = 956Randomisation

221Primary readout

Patients with DMO and

bull At least 1 previous laser tx

bull BCVA ge19 and le68 letters

bull TD-OCT FTH ge250 μm

Month

BCVA = best corrected visual acuity DMO = diabetic macular oedema TD-OCT=time domain optical coherence tomography FTH = foveal thicknessa At masked investigatorrsquos discretion b If BCVA loss ge5 letters or retinal thickening ge50 microm from best reading in previous 12 months

ge15 letter Gain is Greater in Chronic DMO Patients

ge 15

-Let

ter I

mpr

ovem

ent

in B

CVA

Fro

m B

asel

ine

Δ = 98

Months

Full Population Patients With Chronic DMO

Months

Δ = 206

287

189134

34

Steroid re-treatments

bullOzurdexbull Longer half-life than anti-VEGF in the eye

bull Redosing regimes not very helpful from RCT data eg MEAD study only 612 dosing

bull In reality re-treatment interval may be shorter

bull POSOLOGY

bull Patients treated with OZURDEX who have experienced an initial response and in the physicians opinion may benefit from retreatment without being exposed to significant risk should be considered for retreatment Retreatment may be performed after approximately 6 months if the patient experiences decreased vision andor an increase in retinal thickness secondary to recurrent or worsening diabetic macular oedema

bullIluvienbull 70 of patients in FAE only needed 1

injection over 3 years

bull BUT additional rescue treatments allowed

bull POSOLOGY

bull Each ILUVIEN implant releases fluocinolone acetonide for up to 36 months An additional implant may be administered after 12 months if the patient experiences decreased vision or an increase in retinal thickness secondary to recurrent or worsening diabetic macular oedema

bull Patients receiving escape medication were exited from MEAD before administration1

bull Macular laser rescue treatment allowed in RISERIDE (Lucentisreg) from 3 months2

bull Focalgrid laser allowed in FAME (Iluvienreg) from 6 weeks3

MEAD TREATMENT PROTOCOL

bull First treatment given at randomisation (day 0) bull Patients assessed for retreatment eligibility every 3 months from

months 6ndash36bull Patients were eligible for retreatment if

OCT optical coherence tomography

ge6 months since most recent

study treatment

Retinal thickness in 1 mm central macular

subfield by OCT gt175 microm

Evidence of residual retinal oedema (intraretinal cysts or

any regions of increased retinal thickening) as assessed by

investigator from OCT

AND OR

MEA

D

Amendment in May 2010 revised anatomic criterion for retreatment before this time the threshold was gt225 microm1Boyer DS et al Ophthalmology 2014 121 1904-19142Nguyen QD et al Ophthalmology 20121191064minus10773Campochiaro PA et al Ophthalmology 2011118626ndash635

Treatment burdenILUVIEN

Control(n =112)

02 microgd FAc(n =209)

Study Treatments(sham injection or ILUVIEN 02 microgday or FAc 05microgday)

1 treatment 661 761

2 treatments 277 187

ge 3 treatments 63 53

Rescue Laser Treatments (at masked physicianrsquos discretion after week 6)

Patients 607 407

Off-Protocol Treatments (IVTA bevacizumab ranibizumab intravitreal dexamethasone)

Patients 295 115

OZURDEX = 23injections year 1 41 by year 3

No other Rx

Summary of side effects with intravitreal steroids

Drug device Evidence base Cataract risk IOP rise (requiring drops)

Glaucoma surgery

endophthalmitis

ILUVIEN FAME studies 80 cat surgery(273 sham)

384(14 control)

48 0

Ozurdex MEAD 592 had cataract surgery(72 sham)

215 (end of study)(34 sham)

06 0

Trivaris+ laser vs Luc+laserx2 vs laser

Protocol IOphthalmology 2010

15 42(ONE OFgt10mmHg risegt30mmHGStart drops)

2186 0

NICE guidance for intravitreal steroids in DMO

bull Iluvien

bull NICE TA 301 Iluvien for DMO Nov 2013

bull hellipfor treating chronic diabetic macular oedema that is insufficiently responsive to available therapies only if

bull the implant is to be used in an eye with an intraocular

(pseudophakic) lens and

bull the manufacturer provides fluocinolone acetonide intravitreal implant with the discount agreed in the patient access scheme

NICE guidance for intravitreal steroids in DMO

bull Ozurdex

bull NICE TA 349 Ozurdex for DMO July 2015

bull there is an artificial lens in the eye to be treated and

bull their diabetic macular oedema has not improved with

non-corticosteroid treatment or such treatment is not suitable for them

Steroids = second line therapyWhen do I switch

bull Anti-VEGF first line for centre involving DMObull NICE TA ndash ldquoinsufficiently responsiverdquo ldquo ldquonot improvedrdquo ldquonot suitablerdquo ndash

OTHER TREATMENTS

bull 2 scenariosbull 1) Anti-VEGF canrsquot be funded ie OCTlt400um + PSEUDOPHAKIC

bull 2) Already had a course of treatment with laseranti-VEGF + PSEUDOPHAKIC ie SWITCHING from anti-VEGF to steroid

bull Plus

bull ldquochronicrdquo DMO ndash 3 years duration in FAME (18months) for ILUVIEN

bull Chronic DMO not essential for Ozurdex

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

Protocol T ndash patients may not improve in first 6 months

RIDE

RISE

Mea

n ch

ange

in B

CVA

(E

TDR

S le

tters

)M

ean

chan

ge in

BC

VA

(ETD

RS

lette

rs)

Time (months)

RISE and RIDE (Lucentis monthly dosing) Mean change in BCVA over 36 months

Brown DM et al Ophthalmology 2013120(10)2013ndash2022

54

Ranibizumab 03 mgRanibizumab 05 mgShamranibizumab 05 mg

Date of Prep Dec 2014 LGB0820147252X

VA improvement continues throughout year 1 with monthly dosing

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user ndash more than protocol

I

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

DRCRN protocol I5 year outcomesInjections 8-9 in year 1Year 2 = 2-3Year 3= 1-2Year 4 = 0-1Year 5 = 0

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

Wait for plateau = stability in protocol T laserPatient factors again

Judgement of response to anti-VEGF ndashtimeframe

bull Wait 6 months in poor responders

bull Wait 1 year for heavy users

bull Tempting to try steroids earlier than this ifbull No glaucoma ndash not a deal breaker Ozurdex better short term optionbull Pseudophakic

bull Clues from the diseasebull chronic

bull PATIENT FACTORS

bull Any eyes avoid steroids ndash advanced glaucomaCSCR Or prior viral retinitis RARE

bull Any eyes avoid anti-VEGF pregnancytrying to concieve recent CVA

BIOMARKERS AT BASELINE WOULD BE USEFULRESTORE subgroup analysis of OCT features

bull Andreas Pollreisz EURETINA 2015

bull OCT biomarkers (RESTORE data)

bull Better effects with anti-VEGF ifbull Small rather than large intra-retinal cyst

bull Sub-retinal fluid present

bull Vitreo-macular adhesion at baseline

bull No disruption of ELM and ISOS junction

bull No disorganisation of inner retinal layers (DRIL)

RESTORE subgroup analysis of OCT features

bull Andreas Pollreisz EURETINA 2015

bull OCT biomarkers (RESTORE data)

bull Better effects with anti-VEGF ifbull Small rather than large intra-retinal cyst

bull Sub-retinal fluid present

bull Vitreo-macular adhesion at baseline

bull No disruption of ELM and ISOS junction

bull No disorganisation of inner retinal layers (DRIL)

Better baseline characterisationclassificationERG Contrast sensitivityOCT AngiographyMicroperimetry= clues as to who responds best to which drug

Plan for this presentation helliphellipa long list

bull What treatment options are available for DMO (evidence base)

bull What treatment should I start with at baselinebull Re-treatment algorithms for intravitreal DMO therapiesbull When should I switchcombine therapiesbull The bigger picture

bull Other eyebull The patient as a wholebull The service -coping with capacity ndash compromises

The bigger pictureOther eyeThe patient as a wholeThe service -coping with capacity ndash compromises

bull OTHER EYE ndash may create problems

bull Treat and extend ndash ldquoreduce of visitsrdquo plus Eylea license ndash ldquono need for monitoringrdquo may not benefit if lots of visits due to PDR other eye

bull PERIPHERAL RETINA anti-VEGF supresses proliferative disease - Rebound on stopping Rx

bull PATIENT

bull Anti-VEGF ndash heavy user - Will comply

bull One stop much better than two stop for patient ndash Treat and extend

bull SERVICE

bull Capacity and demand planning = fixedT+E more predictable at least 1 month in advance ndash flexible nurse injectors

bull Steroids ndash even if well controlled (Iluvien for 3 years) need IOP check

bull Need pan-retinal examination both eyes ndash separate visits

Summary

CSMO

No centre involvement

Photocoagulation

Centre involvement

gt 78 letters(normalminimally reduced VA)

Photocoagulation

VA 78ndash24 letters

Phakic

Anti-VEGF

Pseudophakic

Anti-VEGF

SWITCHglaucoma

Injection tolerance

Medical issuesrecent CVA

Peripheral diseaseBilateral Rx

CSMO

No centre involvement

LASER

Centre involvement

gt 78 letters(normalminimally

reduced VA)

VA 78ndash24 letters

EYLEA OR LUCENTIS OR AVASTIN

Funding issues

Protocol T ndash poor VA lt 65 letters (615)

LOADING

Monthly injections until stability OR 5 x 112 (EYLEA) = 6 MONTHS then 8 weeks

RETREATMENT1

TREAT AND EXTEND - PRN

PRN

PSEUDOPHAKIC

Prior Rx

ILUVIEN

Chronic disease

OZURDEX

RETREATMENT

OZURDEX

OCT gt175um or any residual oedema

ILUVIEN after 12 months if risksltbenefits

OCT

gt400um

bull FACE TO FACE CLINICS RUNNING IN PARALLEL

bull = MAC002 every 6 months (optom or doctor) routine check for cataracttolerance of injectionsglaucoma issues etc

bull =MAC003 (DOCTOR) for problems as needed no fixed intervalDischargestop treatmentDeclines treatment diagnosis CSR overlay etcswitch drugs

bull =RV002- (DOCTOR) every 6 months

bull =DM002 ndash (DOCTOR) variable interval determined by last assessing doctor

bull First visit at 6 months from 1st injection if mild NPDR

bull Otherwise determined by retinopathy generally

LOADING PHASE

EyleaLucentis 1 within 48hrs of baseline

EyleaLucentis 2 (and LogMAR VA plus OCT same visit)

EyleaLucentis 3 (and LogMAR VA plus OCT same visit)

EyleaLucentis 4 (TEinj)(and Logmar VA plus OCT same visit

AFTER INJECTION 4 data goes off to be reviewed immediately as a hellip

TREAT AND EXTEND assessment ndash the next interval will depend on the response to the loading phase

NB -DMO patients ndash majority (95) will need 6 injctions x 112 of Lucentis

OR Eylea 5 x 112 then 8 weekly

ONCE STABLE for 3 x injection in TE phase

VIRTUAL CLINIC MONITORING OF MACULOPATHY AND PRN RETREATMENT

ANTI-VEGF INJECTION PATHWAYS Baseline visitMAC001 for wet AMDRV001 for CRVOBRVOMed ret clinic for DMO

Pathways ndash too many directions

Better that thanhellip

Thank you

Pros and cons of Treat and Extend vs Prn

T+E PRN

PROS bull Proactive patient and service get advance warning of injection ndash capacity and demand planning easier

bull One ndashstopbull Fewer visits than prnbull Overtreatment

advantageous for peripheral retinopathy

bull Only treated when active ieno overtreatment

bull Aggressive year 1 protocols (DRCRN I ndash few injections needed thereafter

bull DMO tolerant of reactivations ()

CONS bull Overtreatment = riskexpenseinconvenience

bull Evidence base scantbull Bilateral disease tricky

bull Reactive so need enoughemergency capacity to inject when disease flares up

bull No advance warning to patientservice that injection needed

bull NEED TO DO IT WELL ndashNHS real life audits prn based regimes not good resultsUndertreatment in year 1 Affects long term prognosis and treatment burden

Pros and cons of Treat and Extend vs Prn

T+E PRN

PROS bull Proactive patient and service get advance warning of injection ndash capacity and demand planning easier

bull One ndashstopbull Fewer visits than prnbull Overtreatment

advantageous for peripheral retinopathy

bull Only treated when active ieno overtreatment

bull Aggressive year 1 protocols (DRCRN I ndash few injections needed thereafter

bull DMO tolerant of reactivations ()

CONS bull Overtreatment = riskexpenseinconvenience

bull Evidence base scantbull Bilateral disease tricky

bull Reactive so need enoughemergency capacity to inject when disease flares up

bull No advance warning to patientservice that injection needed

bull NEED TO DO IT WELL ndashNHS real life audits prn based regimes not good resultsUndertreatment in year 1 Affects long term prognosis and treatment burden

DMO ndash anti-VEGF Treat and Extend

bull Retain study ndash the only RCT data

bull Br J Ophthalmol 2015 Oct 9 pii bjophthalmol-2015-307249 doi 101136bjophthalmol-2015-307249 [Epub ahead of print]

bull Ranibizumab 05 mg treat-and-extend regimen for diabetic macular oedema the RETAIN study

bull Pruumlnte C1 Fajnkuchen F2 Mahmood S3 Ricci F4 Hatz K5 Studnička J6 Bezlyak V7 Parikh S7 Stubbings WJ7 Wenzel A7 Figueira J8 and the RETAIN Study Group

RETAIN Phase III trial evaluating the efficacy of lsquotreat and extendrsquo regimen (ARVO 2014)

bull Patients with DMO and visual impairment (n = 372) were randomised 111

to one of three groups for 24 months

bull Two phases to dosing schedule

bull Phase A

bull Patients in all groups were initially treated with monthly ranibizumab until BCVA remained

stable

bull Phase B

bull Patients in the TampE groups whose vision remained stable had treatment- free intervals

that were increased incrementally by 1 month for a maximum of 3 months

bull Patients in the PRN group had ongoing monthly monitoring

bull In all groups Phase A was resumed if a decrease in BCVA was observed at a visit

Ranibizumab 05 mg monotherapy

in TampE regimen

Ranibizumab 05 mg in TampE regimen

plus laser

Ranibizumab 05 mg PRN

35

RETAIN Visual acuity endpoints

Pruumlnte C ARVO 2014 Annual Meeting Abstracts Abstract 1700

Mean average change in BCVAat 12 months (primary endpoint)

Mean change in BCVA at 24 months

Mea

n av

erag

e ch

ange

in B

CVA

(ETD

RS

lette

rs)

RanibizumabTampE

RanibizumabTampE + laser

RanibizumabPRN

RanibizumabTampE

RanibizumabTampE + laser

RanibizumabPRN

Mea

n ch

ange

in B

CVA

(ETD

RS

lette

rs)

plt00001 for both ranibizumab TampE groups versus PRN for primary endpoint

36

RETAIN Patient visits and monitoring with TampE regimen over 24 months

bull The TampE regimen provided an approximately 40 reduction in the number of treatment visits required compared with the ranibizumab PRN regimen

bull Approximately 70 of patients receiving TampE regimens had monitoring intervals ge2 months compared with ongoing monthly monitoring in the ranibizumab PRN group

bull Informed the license for Lucentis in DMO (extend by 1 month at a time)

37

INTRAVITREAL STEROIDSWhich intravitreal steroid is better

bull Licensed steroids ndash Ozurdex (Dexamethasone) and Iluvien (Fluocinoloneacetonide

bull Which steroid is best in terms of VA outcomes hellipWE DONrsquoT KNOW FOR SURE ndash no head to head studies for licensed drugs either between steroids or between anti-VEGF and steroids

bull STEROIDS ARE efficacious in DMO

bull MEAD

bull FAME

bull DRCRnet protocol I

bull NICE ndash Ozurdex and Iluvien ndash second-line agents

Ozurdex

bull A biodegradable co-polymer implant ndash degrades in time to lactic and glycolic acid releasing Dexamethasone

bull 22gauge injectionbull MEAD study

bull N=1048

bull Dex 07mg vs 035mg vs sham

bull No rescue therapy

bull 3 year follow up max 6 monthly dosing ie 7 over 3 years

Gan IM et al Greafes Acrh Clin Exp Ophthalmol 2005

MEAD studyMean BCVA change from baseline based on baseline lens status

-2

0

2

4

6

8

10

0 3 6 9 12 15 18 21 24 27 30 33 36 39

Mea

n C

hang

e Fr

om

Bas

elin

e B

CVA

(Let

ters

)

Month

DEX Implant 07 mg (n = 86)

Sham (n = 101)

Boyer DS et al Ophthalmology 20141211904ndash14

Results analyzed in the ITT population with LOCF for missing values

Pseudophakic

Total

0

5

10

0 3 6 9 12 15 18 21 24 27 30 33 36 39

DEX 700 (n=351)

Sham (n=350)

10

8

6

4

2

0

Mea

n C

hang

e fr

om

Bas

elin

e B

CVA

(Let

ters

)

Month

07mg dose is approved as Ozurdexreg by the FDA and EMA 035mg dose not commercially available

1 Boyer DS et al Ophthalmology 2014 121 1904-1914

bull Nonbioerodible micro implant (polyimide) containing 190microg of fluocinolone acetonide (FAc)

bull Consistent daily submicrogram delivery of 02 microgd FAc for up to 36 months

bull Posterior point of release

bull 35 mm times 037 mm non-bioerodable micro implant

bull 25-gauge injector creates self-sealing wound

bull No measurable systemic exposure

ILUVIEN Implant Technology

FAcimplant

ILUVIEN SPC httpwwwmedicinesorgukemcmedicine27636

0 6 12 18 24 30 36

ILUVIEN 02 microgd FAc(n = 376)05 microgd FAc (n = 395)Control sham injection(n = 185)

Design of Phase 3 FAME Study (FAME A and B = same protocol)

Additional laser therapy allowed after week 6a

Retreatment any time after month 12 (if eligibleb)

Study ends

N = 956Randomisation

221Primary readout

Patients with DMO and

bull At least 1 previous laser tx

bull BCVA ge19 and le68 letters

bull TD-OCT FTH ge250 μm

Month

BCVA = best corrected visual acuity DMO = diabetic macular oedema TD-OCT=time domain optical coherence tomography FTH = foveal thicknessa At masked investigatorrsquos discretion b If BCVA loss ge5 letters or retinal thickening ge50 microm from best reading in previous 12 months

ge15 letter Gain is Greater in Chronic DMO Patients

ge 15

-Let

ter I

mpr

ovem

ent

in B

CVA

Fro

m B

asel

ine

Δ = 98

Months

Full Population Patients With Chronic DMO

Months

Δ = 206

287

189134

34

Steroid re-treatments

bullOzurdexbull Longer half-life than anti-VEGF in the eye

bull Redosing regimes not very helpful from RCT data eg MEAD study only 612 dosing

bull In reality re-treatment interval may be shorter

bull POSOLOGY

bull Patients treated with OZURDEX who have experienced an initial response and in the physicians opinion may benefit from retreatment without being exposed to significant risk should be considered for retreatment Retreatment may be performed after approximately 6 months if the patient experiences decreased vision andor an increase in retinal thickness secondary to recurrent or worsening diabetic macular oedema

bullIluvienbull 70 of patients in FAE only needed 1

injection over 3 years

bull BUT additional rescue treatments allowed

bull POSOLOGY

bull Each ILUVIEN implant releases fluocinolone acetonide for up to 36 months An additional implant may be administered after 12 months if the patient experiences decreased vision or an increase in retinal thickness secondary to recurrent or worsening diabetic macular oedema

bull Patients receiving escape medication were exited from MEAD before administration1

bull Macular laser rescue treatment allowed in RISERIDE (Lucentisreg) from 3 months2

bull Focalgrid laser allowed in FAME (Iluvienreg) from 6 weeks3

MEAD TREATMENT PROTOCOL

bull First treatment given at randomisation (day 0) bull Patients assessed for retreatment eligibility every 3 months from

months 6ndash36bull Patients were eligible for retreatment if

OCT optical coherence tomography

ge6 months since most recent

study treatment

Retinal thickness in 1 mm central macular

subfield by OCT gt175 microm

Evidence of residual retinal oedema (intraretinal cysts or

any regions of increased retinal thickening) as assessed by

investigator from OCT

AND OR

MEA

D

Amendment in May 2010 revised anatomic criterion for retreatment before this time the threshold was gt225 microm1Boyer DS et al Ophthalmology 2014 121 1904-19142Nguyen QD et al Ophthalmology 20121191064minus10773Campochiaro PA et al Ophthalmology 2011118626ndash635

Treatment burdenILUVIEN

Control(n =112)

02 microgd FAc(n =209)

Study Treatments(sham injection or ILUVIEN 02 microgday or FAc 05microgday)

1 treatment 661 761

2 treatments 277 187

ge 3 treatments 63 53

Rescue Laser Treatments (at masked physicianrsquos discretion after week 6)

Patients 607 407

Off-Protocol Treatments (IVTA bevacizumab ranibizumab intravitreal dexamethasone)

Patients 295 115

OZURDEX = 23injections year 1 41 by year 3

No other Rx

Summary of side effects with intravitreal steroids

Drug device Evidence base Cataract risk IOP rise (requiring drops)

Glaucoma surgery

endophthalmitis

ILUVIEN FAME studies 80 cat surgery(273 sham)

384(14 control)

48 0

Ozurdex MEAD 592 had cataract surgery(72 sham)

215 (end of study)(34 sham)

06 0

Trivaris+ laser vs Luc+laserx2 vs laser

Protocol IOphthalmology 2010

15 42(ONE OFgt10mmHg risegt30mmHGStart drops)

2186 0

NICE guidance for intravitreal steroids in DMO

bull Iluvien

bull NICE TA 301 Iluvien for DMO Nov 2013

bull hellipfor treating chronic diabetic macular oedema that is insufficiently responsive to available therapies only if

bull the implant is to be used in an eye with an intraocular

(pseudophakic) lens and

bull the manufacturer provides fluocinolone acetonide intravitreal implant with the discount agreed in the patient access scheme

NICE guidance for intravitreal steroids in DMO

bull Ozurdex

bull NICE TA 349 Ozurdex for DMO July 2015

bull there is an artificial lens in the eye to be treated and

bull their diabetic macular oedema has not improved with

non-corticosteroid treatment or such treatment is not suitable for them

Steroids = second line therapyWhen do I switch

bull Anti-VEGF first line for centre involving DMObull NICE TA ndash ldquoinsufficiently responsiverdquo ldquo ldquonot improvedrdquo ldquonot suitablerdquo ndash

OTHER TREATMENTS

bull 2 scenariosbull 1) Anti-VEGF canrsquot be funded ie OCTlt400um + PSEUDOPHAKIC

bull 2) Already had a course of treatment with laseranti-VEGF + PSEUDOPHAKIC ie SWITCHING from anti-VEGF to steroid

bull Plus

bull ldquochronicrdquo DMO ndash 3 years duration in FAME (18months) for ILUVIEN

bull Chronic DMO not essential for Ozurdex

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

Protocol T ndash patients may not improve in first 6 months

RIDE

RISE

Mea

n ch

ange

in B

CVA

(E

TDR

S le

tters

)M

ean

chan

ge in

BC

VA

(ETD

RS

lette

rs)

Time (months)

RISE and RIDE (Lucentis monthly dosing) Mean change in BCVA over 36 months

Brown DM et al Ophthalmology 2013120(10)2013ndash2022

54

Ranibizumab 03 mgRanibizumab 05 mgShamranibizumab 05 mg

Date of Prep Dec 2014 LGB0820147252X

VA improvement continues throughout year 1 with monthly dosing

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user ndash more than protocol

I

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

DRCRN protocol I5 year outcomesInjections 8-9 in year 1Year 2 = 2-3Year 3= 1-2Year 4 = 0-1Year 5 = 0

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

Wait for plateau = stability in protocol T laserPatient factors again

Judgement of response to anti-VEGF ndashtimeframe

bull Wait 6 months in poor responders

bull Wait 1 year for heavy users

bull Tempting to try steroids earlier than this ifbull No glaucoma ndash not a deal breaker Ozurdex better short term optionbull Pseudophakic

bull Clues from the diseasebull chronic

bull PATIENT FACTORS

bull Any eyes avoid steroids ndash advanced glaucomaCSCR Or prior viral retinitis RARE

bull Any eyes avoid anti-VEGF pregnancytrying to concieve recent CVA

BIOMARKERS AT BASELINE WOULD BE USEFULRESTORE subgroup analysis of OCT features

bull Andreas Pollreisz EURETINA 2015

bull OCT biomarkers (RESTORE data)

bull Better effects with anti-VEGF ifbull Small rather than large intra-retinal cyst

bull Sub-retinal fluid present

bull Vitreo-macular adhesion at baseline

bull No disruption of ELM and ISOS junction

bull No disorganisation of inner retinal layers (DRIL)

RESTORE subgroup analysis of OCT features

bull Andreas Pollreisz EURETINA 2015

bull OCT biomarkers (RESTORE data)

bull Better effects with anti-VEGF ifbull Small rather than large intra-retinal cyst

bull Sub-retinal fluid present

bull Vitreo-macular adhesion at baseline

bull No disruption of ELM and ISOS junction

bull No disorganisation of inner retinal layers (DRIL)

Better baseline characterisationclassificationERG Contrast sensitivityOCT AngiographyMicroperimetry= clues as to who responds best to which drug

Plan for this presentation helliphellipa long list

bull What treatment options are available for DMO (evidence base)

bull What treatment should I start with at baselinebull Re-treatment algorithms for intravitreal DMO therapiesbull When should I switchcombine therapiesbull The bigger picture

bull Other eyebull The patient as a wholebull The service -coping with capacity ndash compromises

The bigger pictureOther eyeThe patient as a wholeThe service -coping with capacity ndash compromises

bull OTHER EYE ndash may create problems

bull Treat and extend ndash ldquoreduce of visitsrdquo plus Eylea license ndash ldquono need for monitoringrdquo may not benefit if lots of visits due to PDR other eye

bull PERIPHERAL RETINA anti-VEGF supresses proliferative disease - Rebound on stopping Rx

bull PATIENT

bull Anti-VEGF ndash heavy user - Will comply

bull One stop much better than two stop for patient ndash Treat and extend

bull SERVICE

bull Capacity and demand planning = fixedT+E more predictable at least 1 month in advance ndash flexible nurse injectors

bull Steroids ndash even if well controlled (Iluvien for 3 years) need IOP check

bull Need pan-retinal examination both eyes ndash separate visits

Summary

CSMO

No centre involvement

Photocoagulation

Centre involvement

gt 78 letters(normalminimally reduced VA)

Photocoagulation

VA 78ndash24 letters

Phakic

Anti-VEGF

Pseudophakic

Anti-VEGF

SWITCHglaucoma

Injection tolerance

Medical issuesrecent CVA

Peripheral diseaseBilateral Rx

CSMO

No centre involvement

LASER

Centre involvement

gt 78 letters(normalminimally

reduced VA)

VA 78ndash24 letters

EYLEA OR LUCENTIS OR AVASTIN

Funding issues

Protocol T ndash poor VA lt 65 letters (615)

LOADING

Monthly injections until stability OR 5 x 112 (EYLEA) = 6 MONTHS then 8 weeks

RETREATMENT1

TREAT AND EXTEND - PRN

PRN

PSEUDOPHAKIC

Prior Rx

ILUVIEN

Chronic disease

OZURDEX

RETREATMENT

OZURDEX

OCT gt175um or any residual oedema

ILUVIEN after 12 months if risksltbenefits

OCT

gt400um

bull FACE TO FACE CLINICS RUNNING IN PARALLEL

bull = MAC002 every 6 months (optom or doctor) routine check for cataracttolerance of injectionsglaucoma issues etc

bull =MAC003 (DOCTOR) for problems as needed no fixed intervalDischargestop treatmentDeclines treatment diagnosis CSR overlay etcswitch drugs

bull =RV002- (DOCTOR) every 6 months

bull =DM002 ndash (DOCTOR) variable interval determined by last assessing doctor

bull First visit at 6 months from 1st injection if mild NPDR

bull Otherwise determined by retinopathy generally

LOADING PHASE

EyleaLucentis 1 within 48hrs of baseline

EyleaLucentis 2 (and LogMAR VA plus OCT same visit)

EyleaLucentis 3 (and LogMAR VA plus OCT same visit)

EyleaLucentis 4 (TEinj)(and Logmar VA plus OCT same visit

AFTER INJECTION 4 data goes off to be reviewed immediately as a hellip

TREAT AND EXTEND assessment ndash the next interval will depend on the response to the loading phase

NB -DMO patients ndash majority (95) will need 6 injctions x 112 of Lucentis

OR Eylea 5 x 112 then 8 weekly

ONCE STABLE for 3 x injection in TE phase

VIRTUAL CLINIC MONITORING OF MACULOPATHY AND PRN RETREATMENT

ANTI-VEGF INJECTION PATHWAYS Baseline visitMAC001 for wet AMDRV001 for CRVOBRVOMed ret clinic for DMO

Pathways ndash too many directions

Better that thanhellip

Thank you

Pros and cons of Treat and Extend vs Prn

T+E PRN

PROS bull Proactive patient and service get advance warning of injection ndash capacity and demand planning easier

bull One ndashstopbull Fewer visits than prnbull Overtreatment

advantageous for peripheral retinopathy

bull Only treated when active ieno overtreatment

bull Aggressive year 1 protocols (DRCRN I ndash few injections needed thereafter

bull DMO tolerant of reactivations ()

CONS bull Overtreatment = riskexpenseinconvenience

bull Evidence base scantbull Bilateral disease tricky

bull Reactive so need enoughemergency capacity to inject when disease flares up

bull No advance warning to patientservice that injection needed

bull NEED TO DO IT WELL ndashNHS real life audits prn based regimes not good resultsUndertreatment in year 1 Affects long term prognosis and treatment burden

DMO ndash anti-VEGF Treat and Extend

bull Retain study ndash the only RCT data

bull Br J Ophthalmol 2015 Oct 9 pii bjophthalmol-2015-307249 doi 101136bjophthalmol-2015-307249 [Epub ahead of print]

bull Ranibizumab 05 mg treat-and-extend regimen for diabetic macular oedema the RETAIN study

bull Pruumlnte C1 Fajnkuchen F2 Mahmood S3 Ricci F4 Hatz K5 Studnička J6 Bezlyak V7 Parikh S7 Stubbings WJ7 Wenzel A7 Figueira J8 and the RETAIN Study Group

RETAIN Phase III trial evaluating the efficacy of lsquotreat and extendrsquo regimen (ARVO 2014)

bull Patients with DMO and visual impairment (n = 372) were randomised 111

to one of three groups for 24 months

bull Two phases to dosing schedule

bull Phase A

bull Patients in all groups were initially treated with monthly ranibizumab until BCVA remained

stable

bull Phase B

bull Patients in the TampE groups whose vision remained stable had treatment- free intervals

that were increased incrementally by 1 month for a maximum of 3 months

bull Patients in the PRN group had ongoing monthly monitoring

bull In all groups Phase A was resumed if a decrease in BCVA was observed at a visit

Ranibizumab 05 mg monotherapy

in TampE regimen

Ranibizumab 05 mg in TampE regimen

plus laser

Ranibizumab 05 mg PRN

35

RETAIN Visual acuity endpoints

Pruumlnte C ARVO 2014 Annual Meeting Abstracts Abstract 1700

Mean average change in BCVAat 12 months (primary endpoint)

Mean change in BCVA at 24 months

Mea

n av

erag

e ch

ange

in B

CVA

(ETD

RS

lette

rs)

RanibizumabTampE

RanibizumabTampE + laser

RanibizumabPRN

RanibizumabTampE

RanibizumabTampE + laser

RanibizumabPRN

Mea

n ch

ange

in B

CVA

(ETD

RS

lette

rs)

plt00001 for both ranibizumab TampE groups versus PRN for primary endpoint

36

RETAIN Patient visits and monitoring with TampE regimen over 24 months

bull The TampE regimen provided an approximately 40 reduction in the number of treatment visits required compared with the ranibizumab PRN regimen

bull Approximately 70 of patients receiving TampE regimens had monitoring intervals ge2 months compared with ongoing monthly monitoring in the ranibizumab PRN group

bull Informed the license for Lucentis in DMO (extend by 1 month at a time)

37

INTRAVITREAL STEROIDSWhich intravitreal steroid is better

bull Licensed steroids ndash Ozurdex (Dexamethasone) and Iluvien (Fluocinoloneacetonide

bull Which steroid is best in terms of VA outcomes hellipWE DONrsquoT KNOW FOR SURE ndash no head to head studies for licensed drugs either between steroids or between anti-VEGF and steroids

bull STEROIDS ARE efficacious in DMO

bull MEAD

bull FAME

bull DRCRnet protocol I

bull NICE ndash Ozurdex and Iluvien ndash second-line agents

Ozurdex

bull A biodegradable co-polymer implant ndash degrades in time to lactic and glycolic acid releasing Dexamethasone

bull 22gauge injectionbull MEAD study

bull N=1048

bull Dex 07mg vs 035mg vs sham

bull No rescue therapy

bull 3 year follow up max 6 monthly dosing ie 7 over 3 years

Gan IM et al Greafes Acrh Clin Exp Ophthalmol 2005

MEAD studyMean BCVA change from baseline based on baseline lens status

-2

0

2

4

6

8

10

0 3 6 9 12 15 18 21 24 27 30 33 36 39

Mea

n C

hang

e Fr

om

Bas

elin

e B

CVA

(Let

ters

)

Month

DEX Implant 07 mg (n = 86)

Sham (n = 101)

Boyer DS et al Ophthalmology 20141211904ndash14

Results analyzed in the ITT population with LOCF for missing values

Pseudophakic

Total

0

5

10

0 3 6 9 12 15 18 21 24 27 30 33 36 39

DEX 700 (n=351)

Sham (n=350)

10

8

6

4

2

0

Mea

n C

hang

e fr

om

Bas

elin

e B

CVA

(Let

ters

)

Month

07mg dose is approved as Ozurdexreg by the FDA and EMA 035mg dose not commercially available

1 Boyer DS et al Ophthalmology 2014 121 1904-1914

bull Nonbioerodible micro implant (polyimide) containing 190microg of fluocinolone acetonide (FAc)

bull Consistent daily submicrogram delivery of 02 microgd FAc for up to 36 months

bull Posterior point of release

bull 35 mm times 037 mm non-bioerodable micro implant

bull 25-gauge injector creates self-sealing wound

bull No measurable systemic exposure

ILUVIEN Implant Technology

FAcimplant

ILUVIEN SPC httpwwwmedicinesorgukemcmedicine27636

0 6 12 18 24 30 36

ILUVIEN 02 microgd FAc(n = 376)05 microgd FAc (n = 395)Control sham injection(n = 185)

Design of Phase 3 FAME Study (FAME A and B = same protocol)

Additional laser therapy allowed after week 6a

Retreatment any time after month 12 (if eligibleb)

Study ends

N = 956Randomisation

221Primary readout

Patients with DMO and

bull At least 1 previous laser tx

bull BCVA ge19 and le68 letters

bull TD-OCT FTH ge250 μm

Month

BCVA = best corrected visual acuity DMO = diabetic macular oedema TD-OCT=time domain optical coherence tomography FTH = foveal thicknessa At masked investigatorrsquos discretion b If BCVA loss ge5 letters or retinal thickening ge50 microm from best reading in previous 12 months

ge15 letter Gain is Greater in Chronic DMO Patients

ge 15

-Let

ter I

mpr

ovem

ent

in B

CVA

Fro

m B

asel

ine

Δ = 98

Months

Full Population Patients With Chronic DMO

Months

Δ = 206

287

189134

34

Steroid re-treatments

bullOzurdexbull Longer half-life than anti-VEGF in the eye

bull Redosing regimes not very helpful from RCT data eg MEAD study only 612 dosing

bull In reality re-treatment interval may be shorter

bull POSOLOGY

bull Patients treated with OZURDEX who have experienced an initial response and in the physicians opinion may benefit from retreatment without being exposed to significant risk should be considered for retreatment Retreatment may be performed after approximately 6 months if the patient experiences decreased vision andor an increase in retinal thickness secondary to recurrent or worsening diabetic macular oedema

bullIluvienbull 70 of patients in FAE only needed 1

injection over 3 years

bull BUT additional rescue treatments allowed

bull POSOLOGY

bull Each ILUVIEN implant releases fluocinolone acetonide for up to 36 months An additional implant may be administered after 12 months if the patient experiences decreased vision or an increase in retinal thickness secondary to recurrent or worsening diabetic macular oedema

bull Patients receiving escape medication were exited from MEAD before administration1

bull Macular laser rescue treatment allowed in RISERIDE (Lucentisreg) from 3 months2

bull Focalgrid laser allowed in FAME (Iluvienreg) from 6 weeks3

MEAD TREATMENT PROTOCOL

bull First treatment given at randomisation (day 0) bull Patients assessed for retreatment eligibility every 3 months from

months 6ndash36bull Patients were eligible for retreatment if

OCT optical coherence tomography

ge6 months since most recent

study treatment

Retinal thickness in 1 mm central macular

subfield by OCT gt175 microm

Evidence of residual retinal oedema (intraretinal cysts or

any regions of increased retinal thickening) as assessed by

investigator from OCT

AND OR

MEA

D

Amendment in May 2010 revised anatomic criterion for retreatment before this time the threshold was gt225 microm1Boyer DS et al Ophthalmology 2014 121 1904-19142Nguyen QD et al Ophthalmology 20121191064minus10773Campochiaro PA et al Ophthalmology 2011118626ndash635

Treatment burdenILUVIEN

Control(n =112)

02 microgd FAc(n =209)

Study Treatments(sham injection or ILUVIEN 02 microgday or FAc 05microgday)

1 treatment 661 761

2 treatments 277 187

ge 3 treatments 63 53

Rescue Laser Treatments (at masked physicianrsquos discretion after week 6)

Patients 607 407

Off-Protocol Treatments (IVTA bevacizumab ranibizumab intravitreal dexamethasone)

Patients 295 115

OZURDEX = 23injections year 1 41 by year 3

No other Rx

Summary of side effects with intravitreal steroids

Drug device Evidence base Cataract risk IOP rise (requiring drops)

Glaucoma surgery

endophthalmitis

ILUVIEN FAME studies 80 cat surgery(273 sham)

384(14 control)

48 0

Ozurdex MEAD 592 had cataract surgery(72 sham)

215 (end of study)(34 sham)

06 0

Trivaris+ laser vs Luc+laserx2 vs laser

Protocol IOphthalmology 2010

15 42(ONE OFgt10mmHg risegt30mmHGStart drops)

2186 0

NICE guidance for intravitreal steroids in DMO

bull Iluvien

bull NICE TA 301 Iluvien for DMO Nov 2013

bull hellipfor treating chronic diabetic macular oedema that is insufficiently responsive to available therapies only if

bull the implant is to be used in an eye with an intraocular

(pseudophakic) lens and

bull the manufacturer provides fluocinolone acetonide intravitreal implant with the discount agreed in the patient access scheme

NICE guidance for intravitreal steroids in DMO

bull Ozurdex

bull NICE TA 349 Ozurdex for DMO July 2015

bull there is an artificial lens in the eye to be treated and

bull their diabetic macular oedema has not improved with

non-corticosteroid treatment or such treatment is not suitable for them

Steroids = second line therapyWhen do I switch

bull Anti-VEGF first line for centre involving DMObull NICE TA ndash ldquoinsufficiently responsiverdquo ldquo ldquonot improvedrdquo ldquonot suitablerdquo ndash

OTHER TREATMENTS

bull 2 scenariosbull 1) Anti-VEGF canrsquot be funded ie OCTlt400um + PSEUDOPHAKIC

bull 2) Already had a course of treatment with laseranti-VEGF + PSEUDOPHAKIC ie SWITCHING from anti-VEGF to steroid

bull Plus

bull ldquochronicrdquo DMO ndash 3 years duration in FAME (18months) for ILUVIEN

bull Chronic DMO not essential for Ozurdex

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

Protocol T ndash patients may not improve in first 6 months

RIDE

RISE

Mea

n ch

ange

in B

CVA

(E

TDR

S le

tters

)M

ean

chan

ge in

BC

VA

(ETD

RS

lette

rs)

Time (months)

RISE and RIDE (Lucentis monthly dosing) Mean change in BCVA over 36 months

Brown DM et al Ophthalmology 2013120(10)2013ndash2022

54

Ranibizumab 03 mgRanibizumab 05 mgShamranibizumab 05 mg

Date of Prep Dec 2014 LGB0820147252X

VA improvement continues throughout year 1 with monthly dosing

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user ndash more than protocol

I

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

DRCRN protocol I5 year outcomesInjections 8-9 in year 1Year 2 = 2-3Year 3= 1-2Year 4 = 0-1Year 5 = 0

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

Wait for plateau = stability in protocol T laserPatient factors again

Judgement of response to anti-VEGF ndashtimeframe

bull Wait 6 months in poor responders

bull Wait 1 year for heavy users

bull Tempting to try steroids earlier than this ifbull No glaucoma ndash not a deal breaker Ozurdex better short term optionbull Pseudophakic

bull Clues from the diseasebull chronic

bull PATIENT FACTORS

bull Any eyes avoid steroids ndash advanced glaucomaCSCR Or prior viral retinitis RARE

bull Any eyes avoid anti-VEGF pregnancytrying to concieve recent CVA

BIOMARKERS AT BASELINE WOULD BE USEFULRESTORE subgroup analysis of OCT features

bull Andreas Pollreisz EURETINA 2015

bull OCT biomarkers (RESTORE data)

bull Better effects with anti-VEGF ifbull Small rather than large intra-retinal cyst

bull Sub-retinal fluid present

bull Vitreo-macular adhesion at baseline

bull No disruption of ELM and ISOS junction

bull No disorganisation of inner retinal layers (DRIL)

RESTORE subgroup analysis of OCT features

bull Andreas Pollreisz EURETINA 2015

bull OCT biomarkers (RESTORE data)

bull Better effects with anti-VEGF ifbull Small rather than large intra-retinal cyst

bull Sub-retinal fluid present

bull Vitreo-macular adhesion at baseline

bull No disruption of ELM and ISOS junction

bull No disorganisation of inner retinal layers (DRIL)

Better baseline characterisationclassificationERG Contrast sensitivityOCT AngiographyMicroperimetry= clues as to who responds best to which drug

Plan for this presentation helliphellipa long list

bull What treatment options are available for DMO (evidence base)

bull What treatment should I start with at baselinebull Re-treatment algorithms for intravitreal DMO therapiesbull When should I switchcombine therapiesbull The bigger picture

bull Other eyebull The patient as a wholebull The service -coping with capacity ndash compromises

The bigger pictureOther eyeThe patient as a wholeThe service -coping with capacity ndash compromises

bull OTHER EYE ndash may create problems

bull Treat and extend ndash ldquoreduce of visitsrdquo plus Eylea license ndash ldquono need for monitoringrdquo may not benefit if lots of visits due to PDR other eye

bull PERIPHERAL RETINA anti-VEGF supresses proliferative disease - Rebound on stopping Rx

bull PATIENT

bull Anti-VEGF ndash heavy user - Will comply

bull One stop much better than two stop for patient ndash Treat and extend

bull SERVICE

bull Capacity and demand planning = fixedT+E more predictable at least 1 month in advance ndash flexible nurse injectors

bull Steroids ndash even if well controlled (Iluvien for 3 years) need IOP check

bull Need pan-retinal examination both eyes ndash separate visits

Summary

CSMO

No centre involvement

Photocoagulation

Centre involvement

gt 78 letters(normalminimally reduced VA)

Photocoagulation

VA 78ndash24 letters

Phakic

Anti-VEGF

Pseudophakic

Anti-VEGF

SWITCHglaucoma

Injection tolerance

Medical issuesrecent CVA

Peripheral diseaseBilateral Rx

CSMO

No centre involvement

LASER

Centre involvement

gt 78 letters(normalminimally

reduced VA)

VA 78ndash24 letters

EYLEA OR LUCENTIS OR AVASTIN

Funding issues

Protocol T ndash poor VA lt 65 letters (615)

LOADING

Monthly injections until stability OR 5 x 112 (EYLEA) = 6 MONTHS then 8 weeks

RETREATMENT1

TREAT AND EXTEND - PRN

PRN

PSEUDOPHAKIC

Prior Rx

ILUVIEN

Chronic disease

OZURDEX

RETREATMENT

OZURDEX

OCT gt175um or any residual oedema

ILUVIEN after 12 months if risksltbenefits

OCT

gt400um

bull FACE TO FACE CLINICS RUNNING IN PARALLEL

bull = MAC002 every 6 months (optom or doctor) routine check for cataracttolerance of injectionsglaucoma issues etc

bull =MAC003 (DOCTOR) for problems as needed no fixed intervalDischargestop treatmentDeclines treatment diagnosis CSR overlay etcswitch drugs

bull =RV002- (DOCTOR) every 6 months

bull =DM002 ndash (DOCTOR) variable interval determined by last assessing doctor

bull First visit at 6 months from 1st injection if mild NPDR

bull Otherwise determined by retinopathy generally

LOADING PHASE

EyleaLucentis 1 within 48hrs of baseline

EyleaLucentis 2 (and LogMAR VA plus OCT same visit)

EyleaLucentis 3 (and LogMAR VA plus OCT same visit)

EyleaLucentis 4 (TEinj)(and Logmar VA plus OCT same visit

AFTER INJECTION 4 data goes off to be reviewed immediately as a hellip

TREAT AND EXTEND assessment ndash the next interval will depend on the response to the loading phase

NB -DMO patients ndash majority (95) will need 6 injctions x 112 of Lucentis

OR Eylea 5 x 112 then 8 weekly

ONCE STABLE for 3 x injection in TE phase

VIRTUAL CLINIC MONITORING OF MACULOPATHY AND PRN RETREATMENT

ANTI-VEGF INJECTION PATHWAYS Baseline visitMAC001 for wet AMDRV001 for CRVOBRVOMed ret clinic for DMO

Pathways ndash too many directions

Better that thanhellip

Thank you

DMO ndash anti-VEGF Treat and Extend

bull Retain study ndash the only RCT data

bull Br J Ophthalmol 2015 Oct 9 pii bjophthalmol-2015-307249 doi 101136bjophthalmol-2015-307249 [Epub ahead of print]

bull Ranibizumab 05 mg treat-and-extend regimen for diabetic macular oedema the RETAIN study

bull Pruumlnte C1 Fajnkuchen F2 Mahmood S3 Ricci F4 Hatz K5 Studnička J6 Bezlyak V7 Parikh S7 Stubbings WJ7 Wenzel A7 Figueira J8 and the RETAIN Study Group

RETAIN Phase III trial evaluating the efficacy of lsquotreat and extendrsquo regimen (ARVO 2014)

bull Patients with DMO and visual impairment (n = 372) were randomised 111

to one of three groups for 24 months

bull Two phases to dosing schedule

bull Phase A

bull Patients in all groups were initially treated with monthly ranibizumab until BCVA remained

stable

bull Phase B

bull Patients in the TampE groups whose vision remained stable had treatment- free intervals

that were increased incrementally by 1 month for a maximum of 3 months

bull Patients in the PRN group had ongoing monthly monitoring

bull In all groups Phase A was resumed if a decrease in BCVA was observed at a visit

Ranibizumab 05 mg monotherapy

in TampE regimen

Ranibizumab 05 mg in TampE regimen

plus laser

Ranibizumab 05 mg PRN

35

RETAIN Visual acuity endpoints

Pruumlnte C ARVO 2014 Annual Meeting Abstracts Abstract 1700

Mean average change in BCVAat 12 months (primary endpoint)

Mean change in BCVA at 24 months

Mea

n av

erag

e ch

ange

in B

CVA

(ETD

RS

lette

rs)

RanibizumabTampE

RanibizumabTampE + laser

RanibizumabPRN

RanibizumabTampE

RanibizumabTampE + laser

RanibizumabPRN

Mea

n ch

ange

in B

CVA

(ETD

RS

lette

rs)

plt00001 for both ranibizumab TampE groups versus PRN for primary endpoint

36

RETAIN Patient visits and monitoring with TampE regimen over 24 months

bull The TampE regimen provided an approximately 40 reduction in the number of treatment visits required compared with the ranibizumab PRN regimen

bull Approximately 70 of patients receiving TampE regimens had monitoring intervals ge2 months compared with ongoing monthly monitoring in the ranibizumab PRN group

bull Informed the license for Lucentis in DMO (extend by 1 month at a time)

37

INTRAVITREAL STEROIDSWhich intravitreal steroid is better

bull Licensed steroids ndash Ozurdex (Dexamethasone) and Iluvien (Fluocinoloneacetonide

bull Which steroid is best in terms of VA outcomes hellipWE DONrsquoT KNOW FOR SURE ndash no head to head studies for licensed drugs either between steroids or between anti-VEGF and steroids

bull STEROIDS ARE efficacious in DMO

bull MEAD

bull FAME

bull DRCRnet protocol I

bull NICE ndash Ozurdex and Iluvien ndash second-line agents

Ozurdex

bull A biodegradable co-polymer implant ndash degrades in time to lactic and glycolic acid releasing Dexamethasone

bull 22gauge injectionbull MEAD study

bull N=1048

bull Dex 07mg vs 035mg vs sham

bull No rescue therapy

bull 3 year follow up max 6 monthly dosing ie 7 over 3 years

Gan IM et al Greafes Acrh Clin Exp Ophthalmol 2005

MEAD studyMean BCVA change from baseline based on baseline lens status

-2

0

2

4

6

8

10

0 3 6 9 12 15 18 21 24 27 30 33 36 39

Mea

n C

hang

e Fr

om

Bas

elin

e B

CVA

(Let

ters

)

Month

DEX Implant 07 mg (n = 86)

Sham (n = 101)

Boyer DS et al Ophthalmology 20141211904ndash14

Results analyzed in the ITT population with LOCF for missing values

Pseudophakic

Total

0

5

10

0 3 6 9 12 15 18 21 24 27 30 33 36 39

DEX 700 (n=351)

Sham (n=350)

10

8

6

4

2

0

Mea

n C

hang

e fr

om

Bas

elin

e B

CVA

(Let

ters

)

Month

07mg dose is approved as Ozurdexreg by the FDA and EMA 035mg dose not commercially available

1 Boyer DS et al Ophthalmology 2014 121 1904-1914

bull Nonbioerodible micro implant (polyimide) containing 190microg of fluocinolone acetonide (FAc)

bull Consistent daily submicrogram delivery of 02 microgd FAc for up to 36 months

bull Posterior point of release

bull 35 mm times 037 mm non-bioerodable micro implant

bull 25-gauge injector creates self-sealing wound

bull No measurable systemic exposure

ILUVIEN Implant Technology

FAcimplant

ILUVIEN SPC httpwwwmedicinesorgukemcmedicine27636

0 6 12 18 24 30 36

ILUVIEN 02 microgd FAc(n = 376)05 microgd FAc (n = 395)Control sham injection(n = 185)

Design of Phase 3 FAME Study (FAME A and B = same protocol)

Additional laser therapy allowed after week 6a

Retreatment any time after month 12 (if eligibleb)

Study ends

N = 956Randomisation

221Primary readout

Patients with DMO and

bull At least 1 previous laser tx

bull BCVA ge19 and le68 letters

bull TD-OCT FTH ge250 μm

Month

BCVA = best corrected visual acuity DMO = diabetic macular oedema TD-OCT=time domain optical coherence tomography FTH = foveal thicknessa At masked investigatorrsquos discretion b If BCVA loss ge5 letters or retinal thickening ge50 microm from best reading in previous 12 months

ge15 letter Gain is Greater in Chronic DMO Patients

ge 15

-Let

ter I

mpr

ovem

ent

in B

CVA

Fro

m B

asel

ine

Δ = 98

Months

Full Population Patients With Chronic DMO

Months

Δ = 206

287

189134

34

Steroid re-treatments

bullOzurdexbull Longer half-life than anti-VEGF in the eye

bull Redosing regimes not very helpful from RCT data eg MEAD study only 612 dosing

bull In reality re-treatment interval may be shorter

bull POSOLOGY

bull Patients treated with OZURDEX who have experienced an initial response and in the physicians opinion may benefit from retreatment without being exposed to significant risk should be considered for retreatment Retreatment may be performed after approximately 6 months if the patient experiences decreased vision andor an increase in retinal thickness secondary to recurrent or worsening diabetic macular oedema

bullIluvienbull 70 of patients in FAE only needed 1

injection over 3 years

bull BUT additional rescue treatments allowed

bull POSOLOGY

bull Each ILUVIEN implant releases fluocinolone acetonide for up to 36 months An additional implant may be administered after 12 months if the patient experiences decreased vision or an increase in retinal thickness secondary to recurrent or worsening diabetic macular oedema

bull Patients receiving escape medication were exited from MEAD before administration1

bull Macular laser rescue treatment allowed in RISERIDE (Lucentisreg) from 3 months2

bull Focalgrid laser allowed in FAME (Iluvienreg) from 6 weeks3

MEAD TREATMENT PROTOCOL

bull First treatment given at randomisation (day 0) bull Patients assessed for retreatment eligibility every 3 months from

months 6ndash36bull Patients were eligible for retreatment if

OCT optical coherence tomography

ge6 months since most recent

study treatment

Retinal thickness in 1 mm central macular

subfield by OCT gt175 microm

Evidence of residual retinal oedema (intraretinal cysts or

any regions of increased retinal thickening) as assessed by

investigator from OCT

AND OR

MEA

D

Amendment in May 2010 revised anatomic criterion for retreatment before this time the threshold was gt225 microm1Boyer DS et al Ophthalmology 2014 121 1904-19142Nguyen QD et al Ophthalmology 20121191064minus10773Campochiaro PA et al Ophthalmology 2011118626ndash635

Treatment burdenILUVIEN

Control(n =112)

02 microgd FAc(n =209)

Study Treatments(sham injection or ILUVIEN 02 microgday or FAc 05microgday)

1 treatment 661 761

2 treatments 277 187

ge 3 treatments 63 53

Rescue Laser Treatments (at masked physicianrsquos discretion after week 6)

Patients 607 407

Off-Protocol Treatments (IVTA bevacizumab ranibizumab intravitreal dexamethasone)

Patients 295 115

OZURDEX = 23injections year 1 41 by year 3

No other Rx

Summary of side effects with intravitreal steroids

Drug device Evidence base Cataract risk IOP rise (requiring drops)

Glaucoma surgery

endophthalmitis

ILUVIEN FAME studies 80 cat surgery(273 sham)

384(14 control)

48 0

Ozurdex MEAD 592 had cataract surgery(72 sham)

215 (end of study)(34 sham)

06 0

Trivaris+ laser vs Luc+laserx2 vs laser

Protocol IOphthalmology 2010

15 42(ONE OFgt10mmHg risegt30mmHGStart drops)

2186 0

NICE guidance for intravitreal steroids in DMO

bull Iluvien

bull NICE TA 301 Iluvien for DMO Nov 2013

bull hellipfor treating chronic diabetic macular oedema that is insufficiently responsive to available therapies only if

bull the implant is to be used in an eye with an intraocular

(pseudophakic) lens and

bull the manufacturer provides fluocinolone acetonide intravitreal implant with the discount agreed in the patient access scheme

NICE guidance for intravitreal steroids in DMO

bull Ozurdex

bull NICE TA 349 Ozurdex for DMO July 2015

bull there is an artificial lens in the eye to be treated and

bull their diabetic macular oedema has not improved with

non-corticosteroid treatment or such treatment is not suitable for them

Steroids = second line therapyWhen do I switch

bull Anti-VEGF first line for centre involving DMObull NICE TA ndash ldquoinsufficiently responsiverdquo ldquo ldquonot improvedrdquo ldquonot suitablerdquo ndash

OTHER TREATMENTS

bull 2 scenariosbull 1) Anti-VEGF canrsquot be funded ie OCTlt400um + PSEUDOPHAKIC

bull 2) Already had a course of treatment with laseranti-VEGF + PSEUDOPHAKIC ie SWITCHING from anti-VEGF to steroid

bull Plus

bull ldquochronicrdquo DMO ndash 3 years duration in FAME (18months) for ILUVIEN

bull Chronic DMO not essential for Ozurdex

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

Protocol T ndash patients may not improve in first 6 months

RIDE

RISE

Mea

n ch

ange

in B

CVA

(E

TDR

S le

tters

)M

ean

chan

ge in

BC

VA

(ETD

RS

lette

rs)

Time (months)

RISE and RIDE (Lucentis monthly dosing) Mean change in BCVA over 36 months

Brown DM et al Ophthalmology 2013120(10)2013ndash2022

54

Ranibizumab 03 mgRanibizumab 05 mgShamranibizumab 05 mg

Date of Prep Dec 2014 LGB0820147252X

VA improvement continues throughout year 1 with monthly dosing

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user ndash more than protocol

I

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

DRCRN protocol I5 year outcomesInjections 8-9 in year 1Year 2 = 2-3Year 3= 1-2Year 4 = 0-1Year 5 = 0

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

Wait for plateau = stability in protocol T laserPatient factors again

Judgement of response to anti-VEGF ndashtimeframe

bull Wait 6 months in poor responders

bull Wait 1 year for heavy users

bull Tempting to try steroids earlier than this ifbull No glaucoma ndash not a deal breaker Ozurdex better short term optionbull Pseudophakic

bull Clues from the diseasebull chronic

bull PATIENT FACTORS

bull Any eyes avoid steroids ndash advanced glaucomaCSCR Or prior viral retinitis RARE

bull Any eyes avoid anti-VEGF pregnancytrying to concieve recent CVA

BIOMARKERS AT BASELINE WOULD BE USEFULRESTORE subgroup analysis of OCT features

bull Andreas Pollreisz EURETINA 2015

bull OCT biomarkers (RESTORE data)

bull Better effects with anti-VEGF ifbull Small rather than large intra-retinal cyst

bull Sub-retinal fluid present

bull Vitreo-macular adhesion at baseline

bull No disruption of ELM and ISOS junction

bull No disorganisation of inner retinal layers (DRIL)

RESTORE subgroup analysis of OCT features

bull Andreas Pollreisz EURETINA 2015

bull OCT biomarkers (RESTORE data)

bull Better effects with anti-VEGF ifbull Small rather than large intra-retinal cyst

bull Sub-retinal fluid present

bull Vitreo-macular adhesion at baseline

bull No disruption of ELM and ISOS junction

bull No disorganisation of inner retinal layers (DRIL)

Better baseline characterisationclassificationERG Contrast sensitivityOCT AngiographyMicroperimetry= clues as to who responds best to which drug

Plan for this presentation helliphellipa long list

bull What treatment options are available for DMO (evidence base)

bull What treatment should I start with at baselinebull Re-treatment algorithms for intravitreal DMO therapiesbull When should I switchcombine therapiesbull The bigger picture

bull Other eyebull The patient as a wholebull The service -coping with capacity ndash compromises

The bigger pictureOther eyeThe patient as a wholeThe service -coping with capacity ndash compromises

bull OTHER EYE ndash may create problems

bull Treat and extend ndash ldquoreduce of visitsrdquo plus Eylea license ndash ldquono need for monitoringrdquo may not benefit if lots of visits due to PDR other eye

bull PERIPHERAL RETINA anti-VEGF supresses proliferative disease - Rebound on stopping Rx

bull PATIENT

bull Anti-VEGF ndash heavy user - Will comply

bull One stop much better than two stop for patient ndash Treat and extend

bull SERVICE

bull Capacity and demand planning = fixedT+E more predictable at least 1 month in advance ndash flexible nurse injectors

bull Steroids ndash even if well controlled (Iluvien for 3 years) need IOP check

bull Need pan-retinal examination both eyes ndash separate visits

Summary

CSMO

No centre involvement

Photocoagulation

Centre involvement

gt 78 letters(normalminimally reduced VA)

Photocoagulation

VA 78ndash24 letters

Phakic

Anti-VEGF

Pseudophakic

Anti-VEGF

SWITCHglaucoma

Injection tolerance

Medical issuesrecent CVA

Peripheral diseaseBilateral Rx

CSMO

No centre involvement

LASER

Centre involvement

gt 78 letters(normalminimally

reduced VA)

VA 78ndash24 letters

EYLEA OR LUCENTIS OR AVASTIN

Funding issues

Protocol T ndash poor VA lt 65 letters (615)

LOADING

Monthly injections until stability OR 5 x 112 (EYLEA) = 6 MONTHS then 8 weeks

RETREATMENT1

TREAT AND EXTEND - PRN

PRN

PSEUDOPHAKIC

Prior Rx

ILUVIEN

Chronic disease

OZURDEX

RETREATMENT

OZURDEX

OCT gt175um or any residual oedema

ILUVIEN after 12 months if risksltbenefits

OCT

gt400um

bull FACE TO FACE CLINICS RUNNING IN PARALLEL

bull = MAC002 every 6 months (optom or doctor) routine check for cataracttolerance of injectionsglaucoma issues etc

bull =MAC003 (DOCTOR) for problems as needed no fixed intervalDischargestop treatmentDeclines treatment diagnosis CSR overlay etcswitch drugs

bull =RV002- (DOCTOR) every 6 months

bull =DM002 ndash (DOCTOR) variable interval determined by last assessing doctor

bull First visit at 6 months from 1st injection if mild NPDR

bull Otherwise determined by retinopathy generally

LOADING PHASE

EyleaLucentis 1 within 48hrs of baseline

EyleaLucentis 2 (and LogMAR VA plus OCT same visit)

EyleaLucentis 3 (and LogMAR VA plus OCT same visit)

EyleaLucentis 4 (TEinj)(and Logmar VA plus OCT same visit

AFTER INJECTION 4 data goes off to be reviewed immediately as a hellip

TREAT AND EXTEND assessment ndash the next interval will depend on the response to the loading phase

NB -DMO patients ndash majority (95) will need 6 injctions x 112 of Lucentis

OR Eylea 5 x 112 then 8 weekly

ONCE STABLE for 3 x injection in TE phase

VIRTUAL CLINIC MONITORING OF MACULOPATHY AND PRN RETREATMENT

ANTI-VEGF INJECTION PATHWAYS Baseline visitMAC001 for wet AMDRV001 for CRVOBRVOMed ret clinic for DMO

Pathways ndash too many directions

Better that thanhellip

Thank you

RETAIN Phase III trial evaluating the efficacy of lsquotreat and extendrsquo regimen (ARVO 2014)

bull Patients with DMO and visual impairment (n = 372) were randomised 111

to one of three groups for 24 months

bull Two phases to dosing schedule

bull Phase A

bull Patients in all groups were initially treated with monthly ranibizumab until BCVA remained

stable

bull Phase B

bull Patients in the TampE groups whose vision remained stable had treatment- free intervals

that were increased incrementally by 1 month for a maximum of 3 months

bull Patients in the PRN group had ongoing monthly monitoring

bull In all groups Phase A was resumed if a decrease in BCVA was observed at a visit

Ranibizumab 05 mg monotherapy

in TampE regimen

Ranibizumab 05 mg in TampE regimen

plus laser

Ranibizumab 05 mg PRN

35

RETAIN Visual acuity endpoints

Pruumlnte C ARVO 2014 Annual Meeting Abstracts Abstract 1700

Mean average change in BCVAat 12 months (primary endpoint)

Mean change in BCVA at 24 months

Mea

n av

erag

e ch

ange

in B

CVA

(ETD

RS

lette

rs)

RanibizumabTampE

RanibizumabTampE + laser

RanibizumabPRN

RanibizumabTampE

RanibizumabTampE + laser

RanibizumabPRN

Mea

n ch

ange

in B

CVA

(ETD

RS

lette

rs)

plt00001 for both ranibizumab TampE groups versus PRN for primary endpoint

36

RETAIN Patient visits and monitoring with TampE regimen over 24 months

bull The TampE regimen provided an approximately 40 reduction in the number of treatment visits required compared with the ranibizumab PRN regimen

bull Approximately 70 of patients receiving TampE regimens had monitoring intervals ge2 months compared with ongoing monthly monitoring in the ranibizumab PRN group

bull Informed the license for Lucentis in DMO (extend by 1 month at a time)

37

INTRAVITREAL STEROIDSWhich intravitreal steroid is better

bull Licensed steroids ndash Ozurdex (Dexamethasone) and Iluvien (Fluocinoloneacetonide

bull Which steroid is best in terms of VA outcomes hellipWE DONrsquoT KNOW FOR SURE ndash no head to head studies for licensed drugs either between steroids or between anti-VEGF and steroids

bull STEROIDS ARE efficacious in DMO

bull MEAD

bull FAME

bull DRCRnet protocol I

bull NICE ndash Ozurdex and Iluvien ndash second-line agents

Ozurdex

bull A biodegradable co-polymer implant ndash degrades in time to lactic and glycolic acid releasing Dexamethasone

bull 22gauge injectionbull MEAD study

bull N=1048

bull Dex 07mg vs 035mg vs sham

bull No rescue therapy

bull 3 year follow up max 6 monthly dosing ie 7 over 3 years

Gan IM et al Greafes Acrh Clin Exp Ophthalmol 2005

MEAD studyMean BCVA change from baseline based on baseline lens status

-2

0

2

4

6

8

10

0 3 6 9 12 15 18 21 24 27 30 33 36 39

Mea

n C

hang

e Fr

om

Bas

elin

e B

CVA

(Let

ters

)

Month

DEX Implant 07 mg (n = 86)

Sham (n = 101)

Boyer DS et al Ophthalmology 20141211904ndash14

Results analyzed in the ITT population with LOCF for missing values

Pseudophakic

Total

0

5

10

0 3 6 9 12 15 18 21 24 27 30 33 36 39

DEX 700 (n=351)

Sham (n=350)

10

8

6

4

2

0

Mea

n C

hang

e fr

om

Bas

elin

e B

CVA

(Let

ters

)

Month

07mg dose is approved as Ozurdexreg by the FDA and EMA 035mg dose not commercially available

1 Boyer DS et al Ophthalmology 2014 121 1904-1914

bull Nonbioerodible micro implant (polyimide) containing 190microg of fluocinolone acetonide (FAc)

bull Consistent daily submicrogram delivery of 02 microgd FAc for up to 36 months

bull Posterior point of release

bull 35 mm times 037 mm non-bioerodable micro implant

bull 25-gauge injector creates self-sealing wound

bull No measurable systemic exposure

ILUVIEN Implant Technology

FAcimplant

ILUVIEN SPC httpwwwmedicinesorgukemcmedicine27636

0 6 12 18 24 30 36

ILUVIEN 02 microgd FAc(n = 376)05 microgd FAc (n = 395)Control sham injection(n = 185)

Design of Phase 3 FAME Study (FAME A and B = same protocol)

Additional laser therapy allowed after week 6a

Retreatment any time after month 12 (if eligibleb)

Study ends

N = 956Randomisation

221Primary readout

Patients with DMO and

bull At least 1 previous laser tx

bull BCVA ge19 and le68 letters

bull TD-OCT FTH ge250 μm

Month

BCVA = best corrected visual acuity DMO = diabetic macular oedema TD-OCT=time domain optical coherence tomography FTH = foveal thicknessa At masked investigatorrsquos discretion b If BCVA loss ge5 letters or retinal thickening ge50 microm from best reading in previous 12 months

ge15 letter Gain is Greater in Chronic DMO Patients

ge 15

-Let

ter I

mpr

ovem

ent

in B

CVA

Fro

m B

asel

ine

Δ = 98

Months

Full Population Patients With Chronic DMO

Months

Δ = 206

287

189134

34

Steroid re-treatments

bullOzurdexbull Longer half-life than anti-VEGF in the eye

bull Redosing regimes not very helpful from RCT data eg MEAD study only 612 dosing

bull In reality re-treatment interval may be shorter

bull POSOLOGY

bull Patients treated with OZURDEX who have experienced an initial response and in the physicians opinion may benefit from retreatment without being exposed to significant risk should be considered for retreatment Retreatment may be performed after approximately 6 months if the patient experiences decreased vision andor an increase in retinal thickness secondary to recurrent or worsening diabetic macular oedema

bullIluvienbull 70 of patients in FAE only needed 1

injection over 3 years

bull BUT additional rescue treatments allowed

bull POSOLOGY

bull Each ILUVIEN implant releases fluocinolone acetonide for up to 36 months An additional implant may be administered after 12 months if the patient experiences decreased vision or an increase in retinal thickness secondary to recurrent or worsening diabetic macular oedema

bull Patients receiving escape medication were exited from MEAD before administration1

bull Macular laser rescue treatment allowed in RISERIDE (Lucentisreg) from 3 months2

bull Focalgrid laser allowed in FAME (Iluvienreg) from 6 weeks3

MEAD TREATMENT PROTOCOL

bull First treatment given at randomisation (day 0) bull Patients assessed for retreatment eligibility every 3 months from

months 6ndash36bull Patients were eligible for retreatment if

OCT optical coherence tomography

ge6 months since most recent

study treatment

Retinal thickness in 1 mm central macular

subfield by OCT gt175 microm

Evidence of residual retinal oedema (intraretinal cysts or

any regions of increased retinal thickening) as assessed by

investigator from OCT

AND OR

MEA

D

Amendment in May 2010 revised anatomic criterion for retreatment before this time the threshold was gt225 microm1Boyer DS et al Ophthalmology 2014 121 1904-19142Nguyen QD et al Ophthalmology 20121191064minus10773Campochiaro PA et al Ophthalmology 2011118626ndash635

Treatment burdenILUVIEN

Control(n =112)

02 microgd FAc(n =209)

Study Treatments(sham injection or ILUVIEN 02 microgday or FAc 05microgday)

1 treatment 661 761

2 treatments 277 187

ge 3 treatments 63 53

Rescue Laser Treatments (at masked physicianrsquos discretion after week 6)

Patients 607 407

Off-Protocol Treatments (IVTA bevacizumab ranibizumab intravitreal dexamethasone)

Patients 295 115

OZURDEX = 23injections year 1 41 by year 3

No other Rx

Summary of side effects with intravitreal steroids

Drug device Evidence base Cataract risk IOP rise (requiring drops)

Glaucoma surgery

endophthalmitis

ILUVIEN FAME studies 80 cat surgery(273 sham)

384(14 control)

48 0

Ozurdex MEAD 592 had cataract surgery(72 sham)

215 (end of study)(34 sham)

06 0

Trivaris+ laser vs Luc+laserx2 vs laser

Protocol IOphthalmology 2010

15 42(ONE OFgt10mmHg risegt30mmHGStart drops)

2186 0

NICE guidance for intravitreal steroids in DMO

bull Iluvien

bull NICE TA 301 Iluvien for DMO Nov 2013

bull hellipfor treating chronic diabetic macular oedema that is insufficiently responsive to available therapies only if

bull the implant is to be used in an eye with an intraocular

(pseudophakic) lens and

bull the manufacturer provides fluocinolone acetonide intravitreal implant with the discount agreed in the patient access scheme

NICE guidance for intravitreal steroids in DMO

bull Ozurdex

bull NICE TA 349 Ozurdex for DMO July 2015

bull there is an artificial lens in the eye to be treated and

bull their diabetic macular oedema has not improved with

non-corticosteroid treatment or such treatment is not suitable for them

Steroids = second line therapyWhen do I switch

bull Anti-VEGF first line for centre involving DMObull NICE TA ndash ldquoinsufficiently responsiverdquo ldquo ldquonot improvedrdquo ldquonot suitablerdquo ndash

OTHER TREATMENTS

bull 2 scenariosbull 1) Anti-VEGF canrsquot be funded ie OCTlt400um + PSEUDOPHAKIC

bull 2) Already had a course of treatment with laseranti-VEGF + PSEUDOPHAKIC ie SWITCHING from anti-VEGF to steroid

bull Plus

bull ldquochronicrdquo DMO ndash 3 years duration in FAME (18months) for ILUVIEN

bull Chronic DMO not essential for Ozurdex

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

Protocol T ndash patients may not improve in first 6 months

RIDE

RISE

Mea

n ch

ange

in B

CVA

(E

TDR

S le

tters

)M

ean

chan

ge in

BC

VA

(ETD

RS

lette

rs)

Time (months)

RISE and RIDE (Lucentis monthly dosing) Mean change in BCVA over 36 months

Brown DM et al Ophthalmology 2013120(10)2013ndash2022

54

Ranibizumab 03 mgRanibizumab 05 mgShamranibizumab 05 mg

Date of Prep Dec 2014 LGB0820147252X

VA improvement continues throughout year 1 with monthly dosing

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user ndash more than protocol

I

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

DRCRN protocol I5 year outcomesInjections 8-9 in year 1Year 2 = 2-3Year 3= 1-2Year 4 = 0-1Year 5 = 0

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

Wait for plateau = stability in protocol T laserPatient factors again

Judgement of response to anti-VEGF ndashtimeframe

bull Wait 6 months in poor responders

bull Wait 1 year for heavy users

bull Tempting to try steroids earlier than this ifbull No glaucoma ndash not a deal breaker Ozurdex better short term optionbull Pseudophakic

bull Clues from the diseasebull chronic

bull PATIENT FACTORS

bull Any eyes avoid steroids ndash advanced glaucomaCSCR Or prior viral retinitis RARE

bull Any eyes avoid anti-VEGF pregnancytrying to concieve recent CVA

BIOMARKERS AT BASELINE WOULD BE USEFULRESTORE subgroup analysis of OCT features

bull Andreas Pollreisz EURETINA 2015

bull OCT biomarkers (RESTORE data)

bull Better effects with anti-VEGF ifbull Small rather than large intra-retinal cyst

bull Sub-retinal fluid present

bull Vitreo-macular adhesion at baseline

bull No disruption of ELM and ISOS junction

bull No disorganisation of inner retinal layers (DRIL)

RESTORE subgroup analysis of OCT features

bull Andreas Pollreisz EURETINA 2015

bull OCT biomarkers (RESTORE data)

bull Better effects with anti-VEGF ifbull Small rather than large intra-retinal cyst

bull Sub-retinal fluid present

bull Vitreo-macular adhesion at baseline

bull No disruption of ELM and ISOS junction

bull No disorganisation of inner retinal layers (DRIL)

Better baseline characterisationclassificationERG Contrast sensitivityOCT AngiographyMicroperimetry= clues as to who responds best to which drug

Plan for this presentation helliphellipa long list

bull What treatment options are available for DMO (evidence base)

bull What treatment should I start with at baselinebull Re-treatment algorithms for intravitreal DMO therapiesbull When should I switchcombine therapiesbull The bigger picture

bull Other eyebull The patient as a wholebull The service -coping with capacity ndash compromises

The bigger pictureOther eyeThe patient as a wholeThe service -coping with capacity ndash compromises

bull OTHER EYE ndash may create problems

bull Treat and extend ndash ldquoreduce of visitsrdquo plus Eylea license ndash ldquono need for monitoringrdquo may not benefit if lots of visits due to PDR other eye

bull PERIPHERAL RETINA anti-VEGF supresses proliferative disease - Rebound on stopping Rx

bull PATIENT

bull Anti-VEGF ndash heavy user - Will comply

bull One stop much better than two stop for patient ndash Treat and extend

bull SERVICE

bull Capacity and demand planning = fixedT+E more predictable at least 1 month in advance ndash flexible nurse injectors

bull Steroids ndash even if well controlled (Iluvien for 3 years) need IOP check

bull Need pan-retinal examination both eyes ndash separate visits

Summary

CSMO

No centre involvement

Photocoagulation

Centre involvement

gt 78 letters(normalminimally reduced VA)

Photocoagulation

VA 78ndash24 letters

Phakic

Anti-VEGF

Pseudophakic

Anti-VEGF

SWITCHglaucoma

Injection tolerance

Medical issuesrecent CVA

Peripheral diseaseBilateral Rx

CSMO

No centre involvement

LASER

Centre involvement

gt 78 letters(normalminimally

reduced VA)

VA 78ndash24 letters

EYLEA OR LUCENTIS OR AVASTIN

Funding issues

Protocol T ndash poor VA lt 65 letters (615)

LOADING

Monthly injections until stability OR 5 x 112 (EYLEA) = 6 MONTHS then 8 weeks

RETREATMENT1

TREAT AND EXTEND - PRN

PRN

PSEUDOPHAKIC

Prior Rx

ILUVIEN

Chronic disease

OZURDEX

RETREATMENT

OZURDEX

OCT gt175um or any residual oedema

ILUVIEN after 12 months if risksltbenefits

OCT

gt400um

bull FACE TO FACE CLINICS RUNNING IN PARALLEL

bull = MAC002 every 6 months (optom or doctor) routine check for cataracttolerance of injectionsglaucoma issues etc

bull =MAC003 (DOCTOR) for problems as needed no fixed intervalDischargestop treatmentDeclines treatment diagnosis CSR overlay etcswitch drugs

bull =RV002- (DOCTOR) every 6 months

bull =DM002 ndash (DOCTOR) variable interval determined by last assessing doctor

bull First visit at 6 months from 1st injection if mild NPDR

bull Otherwise determined by retinopathy generally

LOADING PHASE

EyleaLucentis 1 within 48hrs of baseline

EyleaLucentis 2 (and LogMAR VA plus OCT same visit)

EyleaLucentis 3 (and LogMAR VA plus OCT same visit)

EyleaLucentis 4 (TEinj)(and Logmar VA plus OCT same visit

AFTER INJECTION 4 data goes off to be reviewed immediately as a hellip

TREAT AND EXTEND assessment ndash the next interval will depend on the response to the loading phase

NB -DMO patients ndash majority (95) will need 6 injctions x 112 of Lucentis

OR Eylea 5 x 112 then 8 weekly

ONCE STABLE for 3 x injection in TE phase

VIRTUAL CLINIC MONITORING OF MACULOPATHY AND PRN RETREATMENT

ANTI-VEGF INJECTION PATHWAYS Baseline visitMAC001 for wet AMDRV001 for CRVOBRVOMed ret clinic for DMO

Pathways ndash too many directions

Better that thanhellip

Thank you

RETAIN Visual acuity endpoints

Pruumlnte C ARVO 2014 Annual Meeting Abstracts Abstract 1700

Mean average change in BCVAat 12 months (primary endpoint)

Mean change in BCVA at 24 months

Mea

n av

erag

e ch

ange

in B

CVA

(ETD

RS

lette

rs)

RanibizumabTampE

RanibizumabTampE + laser

RanibizumabPRN

RanibizumabTampE

RanibizumabTampE + laser

RanibizumabPRN

Mea

n ch

ange

in B

CVA

(ETD

RS

lette

rs)

plt00001 for both ranibizumab TampE groups versus PRN for primary endpoint

36

RETAIN Patient visits and monitoring with TampE regimen over 24 months

bull The TampE regimen provided an approximately 40 reduction in the number of treatment visits required compared with the ranibizumab PRN regimen

bull Approximately 70 of patients receiving TampE regimens had monitoring intervals ge2 months compared with ongoing monthly monitoring in the ranibizumab PRN group

bull Informed the license for Lucentis in DMO (extend by 1 month at a time)

37

INTRAVITREAL STEROIDSWhich intravitreal steroid is better

bull Licensed steroids ndash Ozurdex (Dexamethasone) and Iluvien (Fluocinoloneacetonide

bull Which steroid is best in terms of VA outcomes hellipWE DONrsquoT KNOW FOR SURE ndash no head to head studies for licensed drugs either between steroids or between anti-VEGF and steroids

bull STEROIDS ARE efficacious in DMO

bull MEAD

bull FAME

bull DRCRnet protocol I

bull NICE ndash Ozurdex and Iluvien ndash second-line agents

Ozurdex

bull A biodegradable co-polymer implant ndash degrades in time to lactic and glycolic acid releasing Dexamethasone

bull 22gauge injectionbull MEAD study

bull N=1048

bull Dex 07mg vs 035mg vs sham

bull No rescue therapy

bull 3 year follow up max 6 monthly dosing ie 7 over 3 years

Gan IM et al Greafes Acrh Clin Exp Ophthalmol 2005

MEAD studyMean BCVA change from baseline based on baseline lens status

-2

0

2

4

6

8

10

0 3 6 9 12 15 18 21 24 27 30 33 36 39

Mea

n C

hang

e Fr

om

Bas

elin

e B

CVA

(Let

ters

)

Month

DEX Implant 07 mg (n = 86)

Sham (n = 101)

Boyer DS et al Ophthalmology 20141211904ndash14

Results analyzed in the ITT population with LOCF for missing values

Pseudophakic

Total

0

5

10

0 3 6 9 12 15 18 21 24 27 30 33 36 39

DEX 700 (n=351)

Sham (n=350)

10

8

6

4

2

0

Mea

n C

hang

e fr

om

Bas

elin

e B

CVA

(Let

ters

)

Month

07mg dose is approved as Ozurdexreg by the FDA and EMA 035mg dose not commercially available

1 Boyer DS et al Ophthalmology 2014 121 1904-1914

bull Nonbioerodible micro implant (polyimide) containing 190microg of fluocinolone acetonide (FAc)

bull Consistent daily submicrogram delivery of 02 microgd FAc for up to 36 months

bull Posterior point of release

bull 35 mm times 037 mm non-bioerodable micro implant

bull 25-gauge injector creates self-sealing wound

bull No measurable systemic exposure

ILUVIEN Implant Technology

FAcimplant

ILUVIEN SPC httpwwwmedicinesorgukemcmedicine27636

0 6 12 18 24 30 36

ILUVIEN 02 microgd FAc(n = 376)05 microgd FAc (n = 395)Control sham injection(n = 185)

Design of Phase 3 FAME Study (FAME A and B = same protocol)

Additional laser therapy allowed after week 6a

Retreatment any time after month 12 (if eligibleb)

Study ends

N = 956Randomisation

221Primary readout

Patients with DMO and

bull At least 1 previous laser tx

bull BCVA ge19 and le68 letters

bull TD-OCT FTH ge250 μm

Month

BCVA = best corrected visual acuity DMO = diabetic macular oedema TD-OCT=time domain optical coherence tomography FTH = foveal thicknessa At masked investigatorrsquos discretion b If BCVA loss ge5 letters or retinal thickening ge50 microm from best reading in previous 12 months

ge15 letter Gain is Greater in Chronic DMO Patients

ge 15

-Let

ter I

mpr

ovem

ent

in B

CVA

Fro

m B

asel

ine

Δ = 98

Months

Full Population Patients With Chronic DMO

Months

Δ = 206

287

189134

34

Steroid re-treatments

bullOzurdexbull Longer half-life than anti-VEGF in the eye

bull Redosing regimes not very helpful from RCT data eg MEAD study only 612 dosing

bull In reality re-treatment interval may be shorter

bull POSOLOGY

bull Patients treated with OZURDEX who have experienced an initial response and in the physicians opinion may benefit from retreatment without being exposed to significant risk should be considered for retreatment Retreatment may be performed after approximately 6 months if the patient experiences decreased vision andor an increase in retinal thickness secondary to recurrent or worsening diabetic macular oedema

bullIluvienbull 70 of patients in FAE only needed 1

injection over 3 years

bull BUT additional rescue treatments allowed

bull POSOLOGY

bull Each ILUVIEN implant releases fluocinolone acetonide for up to 36 months An additional implant may be administered after 12 months if the patient experiences decreased vision or an increase in retinal thickness secondary to recurrent or worsening diabetic macular oedema

bull Patients receiving escape medication were exited from MEAD before administration1

bull Macular laser rescue treatment allowed in RISERIDE (Lucentisreg) from 3 months2

bull Focalgrid laser allowed in FAME (Iluvienreg) from 6 weeks3

MEAD TREATMENT PROTOCOL

bull First treatment given at randomisation (day 0) bull Patients assessed for retreatment eligibility every 3 months from

months 6ndash36bull Patients were eligible for retreatment if

OCT optical coherence tomography

ge6 months since most recent

study treatment

Retinal thickness in 1 mm central macular

subfield by OCT gt175 microm

Evidence of residual retinal oedema (intraretinal cysts or

any regions of increased retinal thickening) as assessed by

investigator from OCT

AND OR

MEA

D

Amendment in May 2010 revised anatomic criterion for retreatment before this time the threshold was gt225 microm1Boyer DS et al Ophthalmology 2014 121 1904-19142Nguyen QD et al Ophthalmology 20121191064minus10773Campochiaro PA et al Ophthalmology 2011118626ndash635

Treatment burdenILUVIEN

Control(n =112)

02 microgd FAc(n =209)

Study Treatments(sham injection or ILUVIEN 02 microgday or FAc 05microgday)

1 treatment 661 761

2 treatments 277 187

ge 3 treatments 63 53

Rescue Laser Treatments (at masked physicianrsquos discretion after week 6)

Patients 607 407

Off-Protocol Treatments (IVTA bevacizumab ranibizumab intravitreal dexamethasone)

Patients 295 115

OZURDEX = 23injections year 1 41 by year 3

No other Rx

Summary of side effects with intravitreal steroids

Drug device Evidence base Cataract risk IOP rise (requiring drops)

Glaucoma surgery

endophthalmitis

ILUVIEN FAME studies 80 cat surgery(273 sham)

384(14 control)

48 0

Ozurdex MEAD 592 had cataract surgery(72 sham)

215 (end of study)(34 sham)

06 0

Trivaris+ laser vs Luc+laserx2 vs laser

Protocol IOphthalmology 2010

15 42(ONE OFgt10mmHg risegt30mmHGStart drops)

2186 0

NICE guidance for intravitreal steroids in DMO

bull Iluvien

bull NICE TA 301 Iluvien for DMO Nov 2013

bull hellipfor treating chronic diabetic macular oedema that is insufficiently responsive to available therapies only if

bull the implant is to be used in an eye with an intraocular

(pseudophakic) lens and

bull the manufacturer provides fluocinolone acetonide intravitreal implant with the discount agreed in the patient access scheme

NICE guidance for intravitreal steroids in DMO

bull Ozurdex

bull NICE TA 349 Ozurdex for DMO July 2015

bull there is an artificial lens in the eye to be treated and

bull their diabetic macular oedema has not improved with

non-corticosteroid treatment or such treatment is not suitable for them

Steroids = second line therapyWhen do I switch

bull Anti-VEGF first line for centre involving DMObull NICE TA ndash ldquoinsufficiently responsiverdquo ldquo ldquonot improvedrdquo ldquonot suitablerdquo ndash

OTHER TREATMENTS

bull 2 scenariosbull 1) Anti-VEGF canrsquot be funded ie OCTlt400um + PSEUDOPHAKIC

bull 2) Already had a course of treatment with laseranti-VEGF + PSEUDOPHAKIC ie SWITCHING from anti-VEGF to steroid

bull Plus

bull ldquochronicrdquo DMO ndash 3 years duration in FAME (18months) for ILUVIEN

bull Chronic DMO not essential for Ozurdex

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

Protocol T ndash patients may not improve in first 6 months

RIDE

RISE

Mea

n ch

ange

in B

CVA

(E

TDR

S le

tters

)M

ean

chan

ge in

BC

VA

(ETD

RS

lette

rs)

Time (months)

RISE and RIDE (Lucentis monthly dosing) Mean change in BCVA over 36 months

Brown DM et al Ophthalmology 2013120(10)2013ndash2022

54

Ranibizumab 03 mgRanibizumab 05 mgShamranibizumab 05 mg

Date of Prep Dec 2014 LGB0820147252X

VA improvement continues throughout year 1 with monthly dosing

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user ndash more than protocol

I

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

DRCRN protocol I5 year outcomesInjections 8-9 in year 1Year 2 = 2-3Year 3= 1-2Year 4 = 0-1Year 5 = 0

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

Wait for plateau = stability in protocol T laserPatient factors again

Judgement of response to anti-VEGF ndashtimeframe

bull Wait 6 months in poor responders

bull Wait 1 year for heavy users

bull Tempting to try steroids earlier than this ifbull No glaucoma ndash not a deal breaker Ozurdex better short term optionbull Pseudophakic

bull Clues from the diseasebull chronic

bull PATIENT FACTORS

bull Any eyes avoid steroids ndash advanced glaucomaCSCR Or prior viral retinitis RARE

bull Any eyes avoid anti-VEGF pregnancytrying to concieve recent CVA

BIOMARKERS AT BASELINE WOULD BE USEFULRESTORE subgroup analysis of OCT features

bull Andreas Pollreisz EURETINA 2015

bull OCT biomarkers (RESTORE data)

bull Better effects with anti-VEGF ifbull Small rather than large intra-retinal cyst

bull Sub-retinal fluid present

bull Vitreo-macular adhesion at baseline

bull No disruption of ELM and ISOS junction

bull No disorganisation of inner retinal layers (DRIL)

RESTORE subgroup analysis of OCT features

bull Andreas Pollreisz EURETINA 2015

bull OCT biomarkers (RESTORE data)

bull Better effects with anti-VEGF ifbull Small rather than large intra-retinal cyst

bull Sub-retinal fluid present

bull Vitreo-macular adhesion at baseline

bull No disruption of ELM and ISOS junction

bull No disorganisation of inner retinal layers (DRIL)

Better baseline characterisationclassificationERG Contrast sensitivityOCT AngiographyMicroperimetry= clues as to who responds best to which drug

Plan for this presentation helliphellipa long list

bull What treatment options are available for DMO (evidence base)

bull What treatment should I start with at baselinebull Re-treatment algorithms for intravitreal DMO therapiesbull When should I switchcombine therapiesbull The bigger picture

bull Other eyebull The patient as a wholebull The service -coping with capacity ndash compromises

The bigger pictureOther eyeThe patient as a wholeThe service -coping with capacity ndash compromises

bull OTHER EYE ndash may create problems

bull Treat and extend ndash ldquoreduce of visitsrdquo plus Eylea license ndash ldquono need for monitoringrdquo may not benefit if lots of visits due to PDR other eye

bull PERIPHERAL RETINA anti-VEGF supresses proliferative disease - Rebound on stopping Rx

bull PATIENT

bull Anti-VEGF ndash heavy user - Will comply

bull One stop much better than two stop for patient ndash Treat and extend

bull SERVICE

bull Capacity and demand planning = fixedT+E more predictable at least 1 month in advance ndash flexible nurse injectors

bull Steroids ndash even if well controlled (Iluvien for 3 years) need IOP check

bull Need pan-retinal examination both eyes ndash separate visits

Summary

CSMO

No centre involvement

Photocoagulation

Centre involvement

gt 78 letters(normalminimally reduced VA)

Photocoagulation

VA 78ndash24 letters

Phakic

Anti-VEGF

Pseudophakic

Anti-VEGF

SWITCHglaucoma

Injection tolerance

Medical issuesrecent CVA

Peripheral diseaseBilateral Rx

CSMO

No centre involvement

LASER

Centre involvement

gt 78 letters(normalminimally

reduced VA)

VA 78ndash24 letters

EYLEA OR LUCENTIS OR AVASTIN

Funding issues

Protocol T ndash poor VA lt 65 letters (615)

LOADING

Monthly injections until stability OR 5 x 112 (EYLEA) = 6 MONTHS then 8 weeks

RETREATMENT1

TREAT AND EXTEND - PRN

PRN

PSEUDOPHAKIC

Prior Rx

ILUVIEN

Chronic disease

OZURDEX

RETREATMENT

OZURDEX

OCT gt175um or any residual oedema

ILUVIEN after 12 months if risksltbenefits

OCT

gt400um

bull FACE TO FACE CLINICS RUNNING IN PARALLEL

bull = MAC002 every 6 months (optom or doctor) routine check for cataracttolerance of injectionsglaucoma issues etc

bull =MAC003 (DOCTOR) for problems as needed no fixed intervalDischargestop treatmentDeclines treatment diagnosis CSR overlay etcswitch drugs

bull =RV002- (DOCTOR) every 6 months

bull =DM002 ndash (DOCTOR) variable interval determined by last assessing doctor

bull First visit at 6 months from 1st injection if mild NPDR

bull Otherwise determined by retinopathy generally

LOADING PHASE

EyleaLucentis 1 within 48hrs of baseline

EyleaLucentis 2 (and LogMAR VA plus OCT same visit)

EyleaLucentis 3 (and LogMAR VA plus OCT same visit)

EyleaLucentis 4 (TEinj)(and Logmar VA plus OCT same visit

AFTER INJECTION 4 data goes off to be reviewed immediately as a hellip

TREAT AND EXTEND assessment ndash the next interval will depend on the response to the loading phase

NB -DMO patients ndash majority (95) will need 6 injctions x 112 of Lucentis

OR Eylea 5 x 112 then 8 weekly

ONCE STABLE for 3 x injection in TE phase

VIRTUAL CLINIC MONITORING OF MACULOPATHY AND PRN RETREATMENT

ANTI-VEGF INJECTION PATHWAYS Baseline visitMAC001 for wet AMDRV001 for CRVOBRVOMed ret clinic for DMO

Pathways ndash too many directions

Better that thanhellip

Thank you

RETAIN Patient visits and monitoring with TampE regimen over 24 months

bull The TampE regimen provided an approximately 40 reduction in the number of treatment visits required compared with the ranibizumab PRN regimen

bull Approximately 70 of patients receiving TampE regimens had monitoring intervals ge2 months compared with ongoing monthly monitoring in the ranibizumab PRN group

bull Informed the license for Lucentis in DMO (extend by 1 month at a time)

37

INTRAVITREAL STEROIDSWhich intravitreal steroid is better

bull Licensed steroids ndash Ozurdex (Dexamethasone) and Iluvien (Fluocinoloneacetonide

bull Which steroid is best in terms of VA outcomes hellipWE DONrsquoT KNOW FOR SURE ndash no head to head studies for licensed drugs either between steroids or between anti-VEGF and steroids

bull STEROIDS ARE efficacious in DMO

bull MEAD

bull FAME

bull DRCRnet protocol I

bull NICE ndash Ozurdex and Iluvien ndash second-line agents

Ozurdex

bull A biodegradable co-polymer implant ndash degrades in time to lactic and glycolic acid releasing Dexamethasone

bull 22gauge injectionbull MEAD study

bull N=1048

bull Dex 07mg vs 035mg vs sham

bull No rescue therapy

bull 3 year follow up max 6 monthly dosing ie 7 over 3 years

Gan IM et al Greafes Acrh Clin Exp Ophthalmol 2005

MEAD studyMean BCVA change from baseline based on baseline lens status

-2

0

2

4

6

8

10

0 3 6 9 12 15 18 21 24 27 30 33 36 39

Mea

n C

hang

e Fr

om

Bas

elin

e B

CVA

(Let

ters

)

Month

DEX Implant 07 mg (n = 86)

Sham (n = 101)

Boyer DS et al Ophthalmology 20141211904ndash14

Results analyzed in the ITT population with LOCF for missing values

Pseudophakic

Total

0

5

10

0 3 6 9 12 15 18 21 24 27 30 33 36 39

DEX 700 (n=351)

Sham (n=350)

10

8

6

4

2

0

Mea

n C

hang

e fr

om

Bas

elin

e B

CVA

(Let

ters

)

Month

07mg dose is approved as Ozurdexreg by the FDA and EMA 035mg dose not commercially available

1 Boyer DS et al Ophthalmology 2014 121 1904-1914

bull Nonbioerodible micro implant (polyimide) containing 190microg of fluocinolone acetonide (FAc)

bull Consistent daily submicrogram delivery of 02 microgd FAc for up to 36 months

bull Posterior point of release

bull 35 mm times 037 mm non-bioerodable micro implant

bull 25-gauge injector creates self-sealing wound

bull No measurable systemic exposure

ILUVIEN Implant Technology

FAcimplant

ILUVIEN SPC httpwwwmedicinesorgukemcmedicine27636

0 6 12 18 24 30 36

ILUVIEN 02 microgd FAc(n = 376)05 microgd FAc (n = 395)Control sham injection(n = 185)

Design of Phase 3 FAME Study (FAME A and B = same protocol)

Additional laser therapy allowed after week 6a

Retreatment any time after month 12 (if eligibleb)

Study ends

N = 956Randomisation

221Primary readout

Patients with DMO and

bull At least 1 previous laser tx

bull BCVA ge19 and le68 letters

bull TD-OCT FTH ge250 μm

Month

BCVA = best corrected visual acuity DMO = diabetic macular oedema TD-OCT=time domain optical coherence tomography FTH = foveal thicknessa At masked investigatorrsquos discretion b If BCVA loss ge5 letters or retinal thickening ge50 microm from best reading in previous 12 months

ge15 letter Gain is Greater in Chronic DMO Patients

ge 15

-Let

ter I

mpr

ovem

ent

in B

CVA

Fro

m B

asel

ine

Δ = 98

Months

Full Population Patients With Chronic DMO

Months

Δ = 206

287

189134

34

Steroid re-treatments

bullOzurdexbull Longer half-life than anti-VEGF in the eye

bull Redosing regimes not very helpful from RCT data eg MEAD study only 612 dosing

bull In reality re-treatment interval may be shorter

bull POSOLOGY

bull Patients treated with OZURDEX who have experienced an initial response and in the physicians opinion may benefit from retreatment without being exposed to significant risk should be considered for retreatment Retreatment may be performed after approximately 6 months if the patient experiences decreased vision andor an increase in retinal thickness secondary to recurrent or worsening diabetic macular oedema

bullIluvienbull 70 of patients in FAE only needed 1

injection over 3 years

bull BUT additional rescue treatments allowed

bull POSOLOGY

bull Each ILUVIEN implant releases fluocinolone acetonide for up to 36 months An additional implant may be administered after 12 months if the patient experiences decreased vision or an increase in retinal thickness secondary to recurrent or worsening diabetic macular oedema

bull Patients receiving escape medication were exited from MEAD before administration1

bull Macular laser rescue treatment allowed in RISERIDE (Lucentisreg) from 3 months2

bull Focalgrid laser allowed in FAME (Iluvienreg) from 6 weeks3

MEAD TREATMENT PROTOCOL

bull First treatment given at randomisation (day 0) bull Patients assessed for retreatment eligibility every 3 months from

months 6ndash36bull Patients were eligible for retreatment if

OCT optical coherence tomography

ge6 months since most recent

study treatment

Retinal thickness in 1 mm central macular

subfield by OCT gt175 microm

Evidence of residual retinal oedema (intraretinal cysts or

any regions of increased retinal thickening) as assessed by

investigator from OCT

AND OR

MEA

D

Amendment in May 2010 revised anatomic criterion for retreatment before this time the threshold was gt225 microm1Boyer DS et al Ophthalmology 2014 121 1904-19142Nguyen QD et al Ophthalmology 20121191064minus10773Campochiaro PA et al Ophthalmology 2011118626ndash635

Treatment burdenILUVIEN

Control(n =112)

02 microgd FAc(n =209)

Study Treatments(sham injection or ILUVIEN 02 microgday or FAc 05microgday)

1 treatment 661 761

2 treatments 277 187

ge 3 treatments 63 53

Rescue Laser Treatments (at masked physicianrsquos discretion after week 6)

Patients 607 407

Off-Protocol Treatments (IVTA bevacizumab ranibizumab intravitreal dexamethasone)

Patients 295 115

OZURDEX = 23injections year 1 41 by year 3

No other Rx

Summary of side effects with intravitreal steroids

Drug device Evidence base Cataract risk IOP rise (requiring drops)

Glaucoma surgery

endophthalmitis

ILUVIEN FAME studies 80 cat surgery(273 sham)

384(14 control)

48 0

Ozurdex MEAD 592 had cataract surgery(72 sham)

215 (end of study)(34 sham)

06 0

Trivaris+ laser vs Luc+laserx2 vs laser

Protocol IOphthalmology 2010

15 42(ONE OFgt10mmHg risegt30mmHGStart drops)

2186 0

NICE guidance for intravitreal steroids in DMO

bull Iluvien

bull NICE TA 301 Iluvien for DMO Nov 2013

bull hellipfor treating chronic diabetic macular oedema that is insufficiently responsive to available therapies only if

bull the implant is to be used in an eye with an intraocular

(pseudophakic) lens and

bull the manufacturer provides fluocinolone acetonide intravitreal implant with the discount agreed in the patient access scheme

NICE guidance for intravitreal steroids in DMO

bull Ozurdex

bull NICE TA 349 Ozurdex for DMO July 2015

bull there is an artificial lens in the eye to be treated and

bull their diabetic macular oedema has not improved with

non-corticosteroid treatment or such treatment is not suitable for them

Steroids = second line therapyWhen do I switch

bull Anti-VEGF first line for centre involving DMObull NICE TA ndash ldquoinsufficiently responsiverdquo ldquo ldquonot improvedrdquo ldquonot suitablerdquo ndash

OTHER TREATMENTS

bull 2 scenariosbull 1) Anti-VEGF canrsquot be funded ie OCTlt400um + PSEUDOPHAKIC

bull 2) Already had a course of treatment with laseranti-VEGF + PSEUDOPHAKIC ie SWITCHING from anti-VEGF to steroid

bull Plus

bull ldquochronicrdquo DMO ndash 3 years duration in FAME (18months) for ILUVIEN

bull Chronic DMO not essential for Ozurdex

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

Protocol T ndash patients may not improve in first 6 months

RIDE

RISE

Mea

n ch

ange

in B

CVA

(E

TDR

S le

tters

)M

ean

chan

ge in

BC

VA

(ETD

RS

lette

rs)

Time (months)

RISE and RIDE (Lucentis monthly dosing) Mean change in BCVA over 36 months

Brown DM et al Ophthalmology 2013120(10)2013ndash2022

54

Ranibizumab 03 mgRanibizumab 05 mgShamranibizumab 05 mg

Date of Prep Dec 2014 LGB0820147252X

VA improvement continues throughout year 1 with monthly dosing

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user ndash more than protocol

I

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

DRCRN protocol I5 year outcomesInjections 8-9 in year 1Year 2 = 2-3Year 3= 1-2Year 4 = 0-1Year 5 = 0

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

Wait for plateau = stability in protocol T laserPatient factors again

Judgement of response to anti-VEGF ndashtimeframe

bull Wait 6 months in poor responders

bull Wait 1 year for heavy users

bull Tempting to try steroids earlier than this ifbull No glaucoma ndash not a deal breaker Ozurdex better short term optionbull Pseudophakic

bull Clues from the diseasebull chronic

bull PATIENT FACTORS

bull Any eyes avoid steroids ndash advanced glaucomaCSCR Or prior viral retinitis RARE

bull Any eyes avoid anti-VEGF pregnancytrying to concieve recent CVA

BIOMARKERS AT BASELINE WOULD BE USEFULRESTORE subgroup analysis of OCT features

bull Andreas Pollreisz EURETINA 2015

bull OCT biomarkers (RESTORE data)

bull Better effects with anti-VEGF ifbull Small rather than large intra-retinal cyst

bull Sub-retinal fluid present

bull Vitreo-macular adhesion at baseline

bull No disruption of ELM and ISOS junction

bull No disorganisation of inner retinal layers (DRIL)

RESTORE subgroup analysis of OCT features

bull Andreas Pollreisz EURETINA 2015

bull OCT biomarkers (RESTORE data)

bull Better effects with anti-VEGF ifbull Small rather than large intra-retinal cyst

bull Sub-retinal fluid present

bull Vitreo-macular adhesion at baseline

bull No disruption of ELM and ISOS junction

bull No disorganisation of inner retinal layers (DRIL)

Better baseline characterisationclassificationERG Contrast sensitivityOCT AngiographyMicroperimetry= clues as to who responds best to which drug

Plan for this presentation helliphellipa long list

bull What treatment options are available for DMO (evidence base)

bull What treatment should I start with at baselinebull Re-treatment algorithms for intravitreal DMO therapiesbull When should I switchcombine therapiesbull The bigger picture

bull Other eyebull The patient as a wholebull The service -coping with capacity ndash compromises

The bigger pictureOther eyeThe patient as a wholeThe service -coping with capacity ndash compromises

bull OTHER EYE ndash may create problems

bull Treat and extend ndash ldquoreduce of visitsrdquo plus Eylea license ndash ldquono need for monitoringrdquo may not benefit if lots of visits due to PDR other eye

bull PERIPHERAL RETINA anti-VEGF supresses proliferative disease - Rebound on stopping Rx

bull PATIENT

bull Anti-VEGF ndash heavy user - Will comply

bull One stop much better than two stop for patient ndash Treat and extend

bull SERVICE

bull Capacity and demand planning = fixedT+E more predictable at least 1 month in advance ndash flexible nurse injectors

bull Steroids ndash even if well controlled (Iluvien for 3 years) need IOP check

bull Need pan-retinal examination both eyes ndash separate visits

Summary

CSMO

No centre involvement

Photocoagulation

Centre involvement

gt 78 letters(normalminimally reduced VA)

Photocoagulation

VA 78ndash24 letters

Phakic

Anti-VEGF

Pseudophakic

Anti-VEGF

SWITCHglaucoma

Injection tolerance

Medical issuesrecent CVA

Peripheral diseaseBilateral Rx

CSMO

No centre involvement

LASER

Centre involvement

gt 78 letters(normalminimally

reduced VA)

VA 78ndash24 letters

EYLEA OR LUCENTIS OR AVASTIN

Funding issues

Protocol T ndash poor VA lt 65 letters (615)

LOADING

Monthly injections until stability OR 5 x 112 (EYLEA) = 6 MONTHS then 8 weeks

RETREATMENT1

TREAT AND EXTEND - PRN

PRN

PSEUDOPHAKIC

Prior Rx

ILUVIEN

Chronic disease

OZURDEX

RETREATMENT

OZURDEX

OCT gt175um or any residual oedema

ILUVIEN after 12 months if risksltbenefits

OCT

gt400um

bull FACE TO FACE CLINICS RUNNING IN PARALLEL

bull = MAC002 every 6 months (optom or doctor) routine check for cataracttolerance of injectionsglaucoma issues etc

bull =MAC003 (DOCTOR) for problems as needed no fixed intervalDischargestop treatmentDeclines treatment diagnosis CSR overlay etcswitch drugs

bull =RV002- (DOCTOR) every 6 months

bull =DM002 ndash (DOCTOR) variable interval determined by last assessing doctor

bull First visit at 6 months from 1st injection if mild NPDR

bull Otherwise determined by retinopathy generally

LOADING PHASE

EyleaLucentis 1 within 48hrs of baseline

EyleaLucentis 2 (and LogMAR VA plus OCT same visit)

EyleaLucentis 3 (and LogMAR VA plus OCT same visit)

EyleaLucentis 4 (TEinj)(and Logmar VA plus OCT same visit

AFTER INJECTION 4 data goes off to be reviewed immediately as a hellip

TREAT AND EXTEND assessment ndash the next interval will depend on the response to the loading phase

NB -DMO patients ndash majority (95) will need 6 injctions x 112 of Lucentis

OR Eylea 5 x 112 then 8 weekly

ONCE STABLE for 3 x injection in TE phase

VIRTUAL CLINIC MONITORING OF MACULOPATHY AND PRN RETREATMENT

ANTI-VEGF INJECTION PATHWAYS Baseline visitMAC001 for wet AMDRV001 for CRVOBRVOMed ret clinic for DMO

Pathways ndash too many directions

Better that thanhellip

Thank you

INTRAVITREAL STEROIDSWhich intravitreal steroid is better

bull Licensed steroids ndash Ozurdex (Dexamethasone) and Iluvien (Fluocinoloneacetonide

bull Which steroid is best in terms of VA outcomes hellipWE DONrsquoT KNOW FOR SURE ndash no head to head studies for licensed drugs either between steroids or between anti-VEGF and steroids

bull STEROIDS ARE efficacious in DMO

bull MEAD

bull FAME

bull DRCRnet protocol I

bull NICE ndash Ozurdex and Iluvien ndash second-line agents

Ozurdex

bull A biodegradable co-polymer implant ndash degrades in time to lactic and glycolic acid releasing Dexamethasone

bull 22gauge injectionbull MEAD study

bull N=1048

bull Dex 07mg vs 035mg vs sham

bull No rescue therapy

bull 3 year follow up max 6 monthly dosing ie 7 over 3 years

Gan IM et al Greafes Acrh Clin Exp Ophthalmol 2005

MEAD studyMean BCVA change from baseline based on baseline lens status

-2

0

2

4

6

8

10

0 3 6 9 12 15 18 21 24 27 30 33 36 39

Mea

n C

hang

e Fr

om

Bas

elin

e B

CVA

(Let

ters

)

Month

DEX Implant 07 mg (n = 86)

Sham (n = 101)

Boyer DS et al Ophthalmology 20141211904ndash14

Results analyzed in the ITT population with LOCF for missing values

Pseudophakic

Total

0

5

10

0 3 6 9 12 15 18 21 24 27 30 33 36 39

DEX 700 (n=351)

Sham (n=350)

10

8

6

4

2

0

Mea

n C

hang

e fr

om

Bas

elin

e B

CVA

(Let

ters

)

Month

07mg dose is approved as Ozurdexreg by the FDA and EMA 035mg dose not commercially available

1 Boyer DS et al Ophthalmology 2014 121 1904-1914

bull Nonbioerodible micro implant (polyimide) containing 190microg of fluocinolone acetonide (FAc)

bull Consistent daily submicrogram delivery of 02 microgd FAc for up to 36 months

bull Posterior point of release

bull 35 mm times 037 mm non-bioerodable micro implant

bull 25-gauge injector creates self-sealing wound

bull No measurable systemic exposure

ILUVIEN Implant Technology

FAcimplant

ILUVIEN SPC httpwwwmedicinesorgukemcmedicine27636

0 6 12 18 24 30 36

ILUVIEN 02 microgd FAc(n = 376)05 microgd FAc (n = 395)Control sham injection(n = 185)

Design of Phase 3 FAME Study (FAME A and B = same protocol)

Additional laser therapy allowed after week 6a

Retreatment any time after month 12 (if eligibleb)

Study ends

N = 956Randomisation

221Primary readout

Patients with DMO and

bull At least 1 previous laser tx

bull BCVA ge19 and le68 letters

bull TD-OCT FTH ge250 μm

Month

BCVA = best corrected visual acuity DMO = diabetic macular oedema TD-OCT=time domain optical coherence tomography FTH = foveal thicknessa At masked investigatorrsquos discretion b If BCVA loss ge5 letters or retinal thickening ge50 microm from best reading in previous 12 months

ge15 letter Gain is Greater in Chronic DMO Patients

ge 15

-Let

ter I

mpr

ovem

ent

in B

CVA

Fro

m B

asel

ine

Δ = 98

Months

Full Population Patients With Chronic DMO

Months

Δ = 206

287

189134

34

Steroid re-treatments

bullOzurdexbull Longer half-life than anti-VEGF in the eye

bull Redosing regimes not very helpful from RCT data eg MEAD study only 612 dosing

bull In reality re-treatment interval may be shorter

bull POSOLOGY

bull Patients treated with OZURDEX who have experienced an initial response and in the physicians opinion may benefit from retreatment without being exposed to significant risk should be considered for retreatment Retreatment may be performed after approximately 6 months if the patient experiences decreased vision andor an increase in retinal thickness secondary to recurrent or worsening diabetic macular oedema

bullIluvienbull 70 of patients in FAE only needed 1

injection over 3 years

bull BUT additional rescue treatments allowed

bull POSOLOGY

bull Each ILUVIEN implant releases fluocinolone acetonide for up to 36 months An additional implant may be administered after 12 months if the patient experiences decreased vision or an increase in retinal thickness secondary to recurrent or worsening diabetic macular oedema

bull Patients receiving escape medication were exited from MEAD before administration1

bull Macular laser rescue treatment allowed in RISERIDE (Lucentisreg) from 3 months2

bull Focalgrid laser allowed in FAME (Iluvienreg) from 6 weeks3

MEAD TREATMENT PROTOCOL

bull First treatment given at randomisation (day 0) bull Patients assessed for retreatment eligibility every 3 months from

months 6ndash36bull Patients were eligible for retreatment if

OCT optical coherence tomography

ge6 months since most recent

study treatment

Retinal thickness in 1 mm central macular

subfield by OCT gt175 microm

Evidence of residual retinal oedema (intraretinal cysts or

any regions of increased retinal thickening) as assessed by

investigator from OCT

AND OR

MEA

D

Amendment in May 2010 revised anatomic criterion for retreatment before this time the threshold was gt225 microm1Boyer DS et al Ophthalmology 2014 121 1904-19142Nguyen QD et al Ophthalmology 20121191064minus10773Campochiaro PA et al Ophthalmology 2011118626ndash635

Treatment burdenILUVIEN

Control(n =112)

02 microgd FAc(n =209)

Study Treatments(sham injection or ILUVIEN 02 microgday or FAc 05microgday)

1 treatment 661 761

2 treatments 277 187

ge 3 treatments 63 53

Rescue Laser Treatments (at masked physicianrsquos discretion after week 6)

Patients 607 407

Off-Protocol Treatments (IVTA bevacizumab ranibizumab intravitreal dexamethasone)

Patients 295 115

OZURDEX = 23injections year 1 41 by year 3

No other Rx

Summary of side effects with intravitreal steroids

Drug device Evidence base Cataract risk IOP rise (requiring drops)

Glaucoma surgery

endophthalmitis

ILUVIEN FAME studies 80 cat surgery(273 sham)

384(14 control)

48 0

Ozurdex MEAD 592 had cataract surgery(72 sham)

215 (end of study)(34 sham)

06 0

Trivaris+ laser vs Luc+laserx2 vs laser

Protocol IOphthalmology 2010

15 42(ONE OFgt10mmHg risegt30mmHGStart drops)

2186 0

NICE guidance for intravitreal steroids in DMO

bull Iluvien

bull NICE TA 301 Iluvien for DMO Nov 2013

bull hellipfor treating chronic diabetic macular oedema that is insufficiently responsive to available therapies only if

bull the implant is to be used in an eye with an intraocular

(pseudophakic) lens and

bull the manufacturer provides fluocinolone acetonide intravitreal implant with the discount agreed in the patient access scheme

NICE guidance for intravitreal steroids in DMO

bull Ozurdex

bull NICE TA 349 Ozurdex for DMO July 2015

bull there is an artificial lens in the eye to be treated and

bull their diabetic macular oedema has not improved with

non-corticosteroid treatment or such treatment is not suitable for them

Steroids = second line therapyWhen do I switch

bull Anti-VEGF first line for centre involving DMObull NICE TA ndash ldquoinsufficiently responsiverdquo ldquo ldquonot improvedrdquo ldquonot suitablerdquo ndash

OTHER TREATMENTS

bull 2 scenariosbull 1) Anti-VEGF canrsquot be funded ie OCTlt400um + PSEUDOPHAKIC

bull 2) Already had a course of treatment with laseranti-VEGF + PSEUDOPHAKIC ie SWITCHING from anti-VEGF to steroid

bull Plus

bull ldquochronicrdquo DMO ndash 3 years duration in FAME (18months) for ILUVIEN

bull Chronic DMO not essential for Ozurdex

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

Protocol T ndash patients may not improve in first 6 months

RIDE

RISE

Mea

n ch

ange

in B

CVA

(E

TDR

S le

tters

)M

ean

chan

ge in

BC

VA

(ETD

RS

lette

rs)

Time (months)

RISE and RIDE (Lucentis monthly dosing) Mean change in BCVA over 36 months

Brown DM et al Ophthalmology 2013120(10)2013ndash2022

54

Ranibizumab 03 mgRanibizumab 05 mgShamranibizumab 05 mg

Date of Prep Dec 2014 LGB0820147252X

VA improvement continues throughout year 1 with monthly dosing

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user ndash more than protocol

I

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

DRCRN protocol I5 year outcomesInjections 8-9 in year 1Year 2 = 2-3Year 3= 1-2Year 4 = 0-1Year 5 = 0

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

Wait for plateau = stability in protocol T laserPatient factors again

Judgement of response to anti-VEGF ndashtimeframe

bull Wait 6 months in poor responders

bull Wait 1 year for heavy users

bull Tempting to try steroids earlier than this ifbull No glaucoma ndash not a deal breaker Ozurdex better short term optionbull Pseudophakic

bull Clues from the diseasebull chronic

bull PATIENT FACTORS

bull Any eyes avoid steroids ndash advanced glaucomaCSCR Or prior viral retinitis RARE

bull Any eyes avoid anti-VEGF pregnancytrying to concieve recent CVA

BIOMARKERS AT BASELINE WOULD BE USEFULRESTORE subgroup analysis of OCT features

bull Andreas Pollreisz EURETINA 2015

bull OCT biomarkers (RESTORE data)

bull Better effects with anti-VEGF ifbull Small rather than large intra-retinal cyst

bull Sub-retinal fluid present

bull Vitreo-macular adhesion at baseline

bull No disruption of ELM and ISOS junction

bull No disorganisation of inner retinal layers (DRIL)

RESTORE subgroup analysis of OCT features

bull Andreas Pollreisz EURETINA 2015

bull OCT biomarkers (RESTORE data)

bull Better effects with anti-VEGF ifbull Small rather than large intra-retinal cyst

bull Sub-retinal fluid present

bull Vitreo-macular adhesion at baseline

bull No disruption of ELM and ISOS junction

bull No disorganisation of inner retinal layers (DRIL)

Better baseline characterisationclassificationERG Contrast sensitivityOCT AngiographyMicroperimetry= clues as to who responds best to which drug

Plan for this presentation helliphellipa long list

bull What treatment options are available for DMO (evidence base)

bull What treatment should I start with at baselinebull Re-treatment algorithms for intravitreal DMO therapiesbull When should I switchcombine therapiesbull The bigger picture

bull Other eyebull The patient as a wholebull The service -coping with capacity ndash compromises

The bigger pictureOther eyeThe patient as a wholeThe service -coping with capacity ndash compromises

bull OTHER EYE ndash may create problems

bull Treat and extend ndash ldquoreduce of visitsrdquo plus Eylea license ndash ldquono need for monitoringrdquo may not benefit if lots of visits due to PDR other eye

bull PERIPHERAL RETINA anti-VEGF supresses proliferative disease - Rebound on stopping Rx

bull PATIENT

bull Anti-VEGF ndash heavy user - Will comply

bull One stop much better than two stop for patient ndash Treat and extend

bull SERVICE

bull Capacity and demand planning = fixedT+E more predictable at least 1 month in advance ndash flexible nurse injectors

bull Steroids ndash even if well controlled (Iluvien for 3 years) need IOP check

bull Need pan-retinal examination both eyes ndash separate visits

Summary

CSMO

No centre involvement

Photocoagulation

Centre involvement

gt 78 letters(normalminimally reduced VA)

Photocoagulation

VA 78ndash24 letters

Phakic

Anti-VEGF

Pseudophakic

Anti-VEGF

SWITCHglaucoma

Injection tolerance

Medical issuesrecent CVA

Peripheral diseaseBilateral Rx

CSMO

No centre involvement

LASER

Centre involvement

gt 78 letters(normalminimally

reduced VA)

VA 78ndash24 letters

EYLEA OR LUCENTIS OR AVASTIN

Funding issues

Protocol T ndash poor VA lt 65 letters (615)

LOADING

Monthly injections until stability OR 5 x 112 (EYLEA) = 6 MONTHS then 8 weeks

RETREATMENT1

TREAT AND EXTEND - PRN

PRN

PSEUDOPHAKIC

Prior Rx

ILUVIEN

Chronic disease

OZURDEX

RETREATMENT

OZURDEX

OCT gt175um or any residual oedema

ILUVIEN after 12 months if risksltbenefits

OCT

gt400um

bull FACE TO FACE CLINICS RUNNING IN PARALLEL

bull = MAC002 every 6 months (optom or doctor) routine check for cataracttolerance of injectionsglaucoma issues etc

bull =MAC003 (DOCTOR) for problems as needed no fixed intervalDischargestop treatmentDeclines treatment diagnosis CSR overlay etcswitch drugs

bull =RV002- (DOCTOR) every 6 months

bull =DM002 ndash (DOCTOR) variable interval determined by last assessing doctor

bull First visit at 6 months from 1st injection if mild NPDR

bull Otherwise determined by retinopathy generally

LOADING PHASE

EyleaLucentis 1 within 48hrs of baseline

EyleaLucentis 2 (and LogMAR VA plus OCT same visit)

EyleaLucentis 3 (and LogMAR VA plus OCT same visit)

EyleaLucentis 4 (TEinj)(and Logmar VA plus OCT same visit

AFTER INJECTION 4 data goes off to be reviewed immediately as a hellip

TREAT AND EXTEND assessment ndash the next interval will depend on the response to the loading phase

NB -DMO patients ndash majority (95) will need 6 injctions x 112 of Lucentis

OR Eylea 5 x 112 then 8 weekly

ONCE STABLE for 3 x injection in TE phase

VIRTUAL CLINIC MONITORING OF MACULOPATHY AND PRN RETREATMENT

ANTI-VEGF INJECTION PATHWAYS Baseline visitMAC001 for wet AMDRV001 for CRVOBRVOMed ret clinic for DMO

Pathways ndash too many directions

Better that thanhellip

Thank you

Ozurdex

bull A biodegradable co-polymer implant ndash degrades in time to lactic and glycolic acid releasing Dexamethasone

bull 22gauge injectionbull MEAD study

bull N=1048

bull Dex 07mg vs 035mg vs sham

bull No rescue therapy

bull 3 year follow up max 6 monthly dosing ie 7 over 3 years

Gan IM et al Greafes Acrh Clin Exp Ophthalmol 2005

MEAD studyMean BCVA change from baseline based on baseline lens status

-2

0

2

4

6

8

10

0 3 6 9 12 15 18 21 24 27 30 33 36 39

Mea

n C

hang

e Fr

om

Bas

elin

e B

CVA

(Let

ters

)

Month

DEX Implant 07 mg (n = 86)

Sham (n = 101)

Boyer DS et al Ophthalmology 20141211904ndash14

Results analyzed in the ITT population with LOCF for missing values

Pseudophakic

Total

0

5

10

0 3 6 9 12 15 18 21 24 27 30 33 36 39

DEX 700 (n=351)

Sham (n=350)

10

8

6

4

2

0

Mea

n C

hang

e fr

om

Bas

elin

e B

CVA

(Let

ters

)

Month

07mg dose is approved as Ozurdexreg by the FDA and EMA 035mg dose not commercially available

1 Boyer DS et al Ophthalmology 2014 121 1904-1914

bull Nonbioerodible micro implant (polyimide) containing 190microg of fluocinolone acetonide (FAc)

bull Consistent daily submicrogram delivery of 02 microgd FAc for up to 36 months

bull Posterior point of release

bull 35 mm times 037 mm non-bioerodable micro implant

bull 25-gauge injector creates self-sealing wound

bull No measurable systemic exposure

ILUVIEN Implant Technology

FAcimplant

ILUVIEN SPC httpwwwmedicinesorgukemcmedicine27636

0 6 12 18 24 30 36

ILUVIEN 02 microgd FAc(n = 376)05 microgd FAc (n = 395)Control sham injection(n = 185)

Design of Phase 3 FAME Study (FAME A and B = same protocol)

Additional laser therapy allowed after week 6a

Retreatment any time after month 12 (if eligibleb)

Study ends

N = 956Randomisation

221Primary readout

Patients with DMO and

bull At least 1 previous laser tx

bull BCVA ge19 and le68 letters

bull TD-OCT FTH ge250 μm

Month

BCVA = best corrected visual acuity DMO = diabetic macular oedema TD-OCT=time domain optical coherence tomography FTH = foveal thicknessa At masked investigatorrsquos discretion b If BCVA loss ge5 letters or retinal thickening ge50 microm from best reading in previous 12 months

ge15 letter Gain is Greater in Chronic DMO Patients

ge 15

-Let

ter I

mpr

ovem

ent

in B

CVA

Fro

m B

asel

ine

Δ = 98

Months

Full Population Patients With Chronic DMO

Months

Δ = 206

287

189134

34

Steroid re-treatments

bullOzurdexbull Longer half-life than anti-VEGF in the eye

bull Redosing regimes not very helpful from RCT data eg MEAD study only 612 dosing

bull In reality re-treatment interval may be shorter

bull POSOLOGY

bull Patients treated with OZURDEX who have experienced an initial response and in the physicians opinion may benefit from retreatment without being exposed to significant risk should be considered for retreatment Retreatment may be performed after approximately 6 months if the patient experiences decreased vision andor an increase in retinal thickness secondary to recurrent or worsening diabetic macular oedema

bullIluvienbull 70 of patients in FAE only needed 1

injection over 3 years

bull BUT additional rescue treatments allowed

bull POSOLOGY

bull Each ILUVIEN implant releases fluocinolone acetonide for up to 36 months An additional implant may be administered after 12 months if the patient experiences decreased vision or an increase in retinal thickness secondary to recurrent or worsening diabetic macular oedema

bull Patients receiving escape medication were exited from MEAD before administration1

bull Macular laser rescue treatment allowed in RISERIDE (Lucentisreg) from 3 months2

bull Focalgrid laser allowed in FAME (Iluvienreg) from 6 weeks3

MEAD TREATMENT PROTOCOL

bull First treatment given at randomisation (day 0) bull Patients assessed for retreatment eligibility every 3 months from

months 6ndash36bull Patients were eligible for retreatment if

OCT optical coherence tomography

ge6 months since most recent

study treatment

Retinal thickness in 1 mm central macular

subfield by OCT gt175 microm

Evidence of residual retinal oedema (intraretinal cysts or

any regions of increased retinal thickening) as assessed by

investigator from OCT

AND OR

MEA

D

Amendment in May 2010 revised anatomic criterion for retreatment before this time the threshold was gt225 microm1Boyer DS et al Ophthalmology 2014 121 1904-19142Nguyen QD et al Ophthalmology 20121191064minus10773Campochiaro PA et al Ophthalmology 2011118626ndash635

Treatment burdenILUVIEN

Control(n =112)

02 microgd FAc(n =209)

Study Treatments(sham injection or ILUVIEN 02 microgday or FAc 05microgday)

1 treatment 661 761

2 treatments 277 187

ge 3 treatments 63 53

Rescue Laser Treatments (at masked physicianrsquos discretion after week 6)

Patients 607 407

Off-Protocol Treatments (IVTA bevacizumab ranibizumab intravitreal dexamethasone)

Patients 295 115

OZURDEX = 23injections year 1 41 by year 3

No other Rx

Summary of side effects with intravitreal steroids

Drug device Evidence base Cataract risk IOP rise (requiring drops)

Glaucoma surgery

endophthalmitis

ILUVIEN FAME studies 80 cat surgery(273 sham)

384(14 control)

48 0

Ozurdex MEAD 592 had cataract surgery(72 sham)

215 (end of study)(34 sham)

06 0

Trivaris+ laser vs Luc+laserx2 vs laser

Protocol IOphthalmology 2010

15 42(ONE OFgt10mmHg risegt30mmHGStart drops)

2186 0

NICE guidance for intravitreal steroids in DMO

bull Iluvien

bull NICE TA 301 Iluvien for DMO Nov 2013

bull hellipfor treating chronic diabetic macular oedema that is insufficiently responsive to available therapies only if

bull the implant is to be used in an eye with an intraocular

(pseudophakic) lens and

bull the manufacturer provides fluocinolone acetonide intravitreal implant with the discount agreed in the patient access scheme

NICE guidance for intravitreal steroids in DMO

bull Ozurdex

bull NICE TA 349 Ozurdex for DMO July 2015

bull there is an artificial lens in the eye to be treated and

bull their diabetic macular oedema has not improved with

non-corticosteroid treatment or such treatment is not suitable for them

Steroids = second line therapyWhen do I switch

bull Anti-VEGF first line for centre involving DMObull NICE TA ndash ldquoinsufficiently responsiverdquo ldquo ldquonot improvedrdquo ldquonot suitablerdquo ndash

OTHER TREATMENTS

bull 2 scenariosbull 1) Anti-VEGF canrsquot be funded ie OCTlt400um + PSEUDOPHAKIC

bull 2) Already had a course of treatment with laseranti-VEGF + PSEUDOPHAKIC ie SWITCHING from anti-VEGF to steroid

bull Plus

bull ldquochronicrdquo DMO ndash 3 years duration in FAME (18months) for ILUVIEN

bull Chronic DMO not essential for Ozurdex

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

Protocol T ndash patients may not improve in first 6 months

RIDE

RISE

Mea

n ch

ange

in B

CVA

(E

TDR

S le

tters

)M

ean

chan

ge in

BC

VA

(ETD

RS

lette

rs)

Time (months)

RISE and RIDE (Lucentis monthly dosing) Mean change in BCVA over 36 months

Brown DM et al Ophthalmology 2013120(10)2013ndash2022

54

Ranibizumab 03 mgRanibizumab 05 mgShamranibizumab 05 mg

Date of Prep Dec 2014 LGB0820147252X

VA improvement continues throughout year 1 with monthly dosing

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user ndash more than protocol

I

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

DRCRN protocol I5 year outcomesInjections 8-9 in year 1Year 2 = 2-3Year 3= 1-2Year 4 = 0-1Year 5 = 0

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

Wait for plateau = stability in protocol T laserPatient factors again

Judgement of response to anti-VEGF ndashtimeframe

bull Wait 6 months in poor responders

bull Wait 1 year for heavy users

bull Tempting to try steroids earlier than this ifbull No glaucoma ndash not a deal breaker Ozurdex better short term optionbull Pseudophakic

bull Clues from the diseasebull chronic

bull PATIENT FACTORS

bull Any eyes avoid steroids ndash advanced glaucomaCSCR Or prior viral retinitis RARE

bull Any eyes avoid anti-VEGF pregnancytrying to concieve recent CVA

BIOMARKERS AT BASELINE WOULD BE USEFULRESTORE subgroup analysis of OCT features

bull Andreas Pollreisz EURETINA 2015

bull OCT biomarkers (RESTORE data)

bull Better effects with anti-VEGF ifbull Small rather than large intra-retinal cyst

bull Sub-retinal fluid present

bull Vitreo-macular adhesion at baseline

bull No disruption of ELM and ISOS junction

bull No disorganisation of inner retinal layers (DRIL)

RESTORE subgroup analysis of OCT features

bull Andreas Pollreisz EURETINA 2015

bull OCT biomarkers (RESTORE data)

bull Better effects with anti-VEGF ifbull Small rather than large intra-retinal cyst

bull Sub-retinal fluid present

bull Vitreo-macular adhesion at baseline

bull No disruption of ELM and ISOS junction

bull No disorganisation of inner retinal layers (DRIL)

Better baseline characterisationclassificationERG Contrast sensitivityOCT AngiographyMicroperimetry= clues as to who responds best to which drug

Plan for this presentation helliphellipa long list

bull What treatment options are available for DMO (evidence base)

bull What treatment should I start with at baselinebull Re-treatment algorithms for intravitreal DMO therapiesbull When should I switchcombine therapiesbull The bigger picture

bull Other eyebull The patient as a wholebull The service -coping with capacity ndash compromises

The bigger pictureOther eyeThe patient as a wholeThe service -coping with capacity ndash compromises

bull OTHER EYE ndash may create problems

bull Treat and extend ndash ldquoreduce of visitsrdquo plus Eylea license ndash ldquono need for monitoringrdquo may not benefit if lots of visits due to PDR other eye

bull PERIPHERAL RETINA anti-VEGF supresses proliferative disease - Rebound on stopping Rx

bull PATIENT

bull Anti-VEGF ndash heavy user - Will comply

bull One stop much better than two stop for patient ndash Treat and extend

bull SERVICE

bull Capacity and demand planning = fixedT+E more predictable at least 1 month in advance ndash flexible nurse injectors

bull Steroids ndash even if well controlled (Iluvien for 3 years) need IOP check

bull Need pan-retinal examination both eyes ndash separate visits

Summary

CSMO

No centre involvement

Photocoagulation

Centre involvement

gt 78 letters(normalminimally reduced VA)

Photocoagulation

VA 78ndash24 letters

Phakic

Anti-VEGF

Pseudophakic

Anti-VEGF

SWITCHglaucoma

Injection tolerance

Medical issuesrecent CVA

Peripheral diseaseBilateral Rx

CSMO

No centre involvement

LASER

Centre involvement

gt 78 letters(normalminimally

reduced VA)

VA 78ndash24 letters

EYLEA OR LUCENTIS OR AVASTIN

Funding issues

Protocol T ndash poor VA lt 65 letters (615)

LOADING

Monthly injections until stability OR 5 x 112 (EYLEA) = 6 MONTHS then 8 weeks

RETREATMENT1

TREAT AND EXTEND - PRN

PRN

PSEUDOPHAKIC

Prior Rx

ILUVIEN

Chronic disease

OZURDEX

RETREATMENT

OZURDEX

OCT gt175um or any residual oedema

ILUVIEN after 12 months if risksltbenefits

OCT

gt400um

bull FACE TO FACE CLINICS RUNNING IN PARALLEL

bull = MAC002 every 6 months (optom or doctor) routine check for cataracttolerance of injectionsglaucoma issues etc

bull =MAC003 (DOCTOR) for problems as needed no fixed intervalDischargestop treatmentDeclines treatment diagnosis CSR overlay etcswitch drugs

bull =RV002- (DOCTOR) every 6 months

bull =DM002 ndash (DOCTOR) variable interval determined by last assessing doctor

bull First visit at 6 months from 1st injection if mild NPDR

bull Otherwise determined by retinopathy generally

LOADING PHASE

EyleaLucentis 1 within 48hrs of baseline

EyleaLucentis 2 (and LogMAR VA plus OCT same visit)

EyleaLucentis 3 (and LogMAR VA plus OCT same visit)

EyleaLucentis 4 (TEinj)(and Logmar VA plus OCT same visit

AFTER INJECTION 4 data goes off to be reviewed immediately as a hellip

TREAT AND EXTEND assessment ndash the next interval will depend on the response to the loading phase

NB -DMO patients ndash majority (95) will need 6 injctions x 112 of Lucentis

OR Eylea 5 x 112 then 8 weekly

ONCE STABLE for 3 x injection in TE phase

VIRTUAL CLINIC MONITORING OF MACULOPATHY AND PRN RETREATMENT

ANTI-VEGF INJECTION PATHWAYS Baseline visitMAC001 for wet AMDRV001 for CRVOBRVOMed ret clinic for DMO

Pathways ndash too many directions

Better that thanhellip

Thank you

MEAD studyMean BCVA change from baseline based on baseline lens status

-2

0

2

4

6

8

10

0 3 6 9 12 15 18 21 24 27 30 33 36 39

Mea

n C

hang

e Fr

om

Bas

elin

e B

CVA

(Let

ters

)

Month

DEX Implant 07 mg (n = 86)

Sham (n = 101)

Boyer DS et al Ophthalmology 20141211904ndash14

Results analyzed in the ITT population with LOCF for missing values

Pseudophakic

Total

0

5

10

0 3 6 9 12 15 18 21 24 27 30 33 36 39

DEX 700 (n=351)

Sham (n=350)

10

8

6

4

2

0

Mea

n C

hang

e fr

om

Bas

elin

e B

CVA

(Let

ters

)

Month

07mg dose is approved as Ozurdexreg by the FDA and EMA 035mg dose not commercially available

1 Boyer DS et al Ophthalmology 2014 121 1904-1914

bull Nonbioerodible micro implant (polyimide) containing 190microg of fluocinolone acetonide (FAc)

bull Consistent daily submicrogram delivery of 02 microgd FAc for up to 36 months

bull Posterior point of release

bull 35 mm times 037 mm non-bioerodable micro implant

bull 25-gauge injector creates self-sealing wound

bull No measurable systemic exposure

ILUVIEN Implant Technology

FAcimplant

ILUVIEN SPC httpwwwmedicinesorgukemcmedicine27636

0 6 12 18 24 30 36

ILUVIEN 02 microgd FAc(n = 376)05 microgd FAc (n = 395)Control sham injection(n = 185)

Design of Phase 3 FAME Study (FAME A and B = same protocol)

Additional laser therapy allowed after week 6a

Retreatment any time after month 12 (if eligibleb)

Study ends

N = 956Randomisation

221Primary readout

Patients with DMO and

bull At least 1 previous laser tx

bull BCVA ge19 and le68 letters

bull TD-OCT FTH ge250 μm

Month

BCVA = best corrected visual acuity DMO = diabetic macular oedema TD-OCT=time domain optical coherence tomography FTH = foveal thicknessa At masked investigatorrsquos discretion b If BCVA loss ge5 letters or retinal thickening ge50 microm from best reading in previous 12 months

ge15 letter Gain is Greater in Chronic DMO Patients

ge 15

-Let

ter I

mpr

ovem

ent

in B

CVA

Fro

m B

asel

ine

Δ = 98

Months

Full Population Patients With Chronic DMO

Months

Δ = 206

287

189134

34

Steroid re-treatments

bullOzurdexbull Longer half-life than anti-VEGF in the eye

bull Redosing regimes not very helpful from RCT data eg MEAD study only 612 dosing

bull In reality re-treatment interval may be shorter

bull POSOLOGY

bull Patients treated with OZURDEX who have experienced an initial response and in the physicians opinion may benefit from retreatment without being exposed to significant risk should be considered for retreatment Retreatment may be performed after approximately 6 months if the patient experiences decreased vision andor an increase in retinal thickness secondary to recurrent or worsening diabetic macular oedema

bullIluvienbull 70 of patients in FAE only needed 1

injection over 3 years

bull BUT additional rescue treatments allowed

bull POSOLOGY

bull Each ILUVIEN implant releases fluocinolone acetonide for up to 36 months An additional implant may be administered after 12 months if the patient experiences decreased vision or an increase in retinal thickness secondary to recurrent or worsening diabetic macular oedema

bull Patients receiving escape medication were exited from MEAD before administration1

bull Macular laser rescue treatment allowed in RISERIDE (Lucentisreg) from 3 months2

bull Focalgrid laser allowed in FAME (Iluvienreg) from 6 weeks3

MEAD TREATMENT PROTOCOL

bull First treatment given at randomisation (day 0) bull Patients assessed for retreatment eligibility every 3 months from

months 6ndash36bull Patients were eligible for retreatment if

OCT optical coherence tomography

ge6 months since most recent

study treatment

Retinal thickness in 1 mm central macular

subfield by OCT gt175 microm

Evidence of residual retinal oedema (intraretinal cysts or

any regions of increased retinal thickening) as assessed by

investigator from OCT

AND OR

MEA

D

Amendment in May 2010 revised anatomic criterion for retreatment before this time the threshold was gt225 microm1Boyer DS et al Ophthalmology 2014 121 1904-19142Nguyen QD et al Ophthalmology 20121191064minus10773Campochiaro PA et al Ophthalmology 2011118626ndash635

Treatment burdenILUVIEN

Control(n =112)

02 microgd FAc(n =209)

Study Treatments(sham injection or ILUVIEN 02 microgday or FAc 05microgday)

1 treatment 661 761

2 treatments 277 187

ge 3 treatments 63 53

Rescue Laser Treatments (at masked physicianrsquos discretion after week 6)

Patients 607 407

Off-Protocol Treatments (IVTA bevacizumab ranibizumab intravitreal dexamethasone)

Patients 295 115

OZURDEX = 23injections year 1 41 by year 3

No other Rx

Summary of side effects with intravitreal steroids

Drug device Evidence base Cataract risk IOP rise (requiring drops)

Glaucoma surgery

endophthalmitis

ILUVIEN FAME studies 80 cat surgery(273 sham)

384(14 control)

48 0

Ozurdex MEAD 592 had cataract surgery(72 sham)

215 (end of study)(34 sham)

06 0

Trivaris+ laser vs Luc+laserx2 vs laser

Protocol IOphthalmology 2010

15 42(ONE OFgt10mmHg risegt30mmHGStart drops)

2186 0

NICE guidance for intravitreal steroids in DMO

bull Iluvien

bull NICE TA 301 Iluvien for DMO Nov 2013

bull hellipfor treating chronic diabetic macular oedema that is insufficiently responsive to available therapies only if

bull the implant is to be used in an eye with an intraocular

(pseudophakic) lens and

bull the manufacturer provides fluocinolone acetonide intravitreal implant with the discount agreed in the patient access scheme

NICE guidance for intravitreal steroids in DMO

bull Ozurdex

bull NICE TA 349 Ozurdex for DMO July 2015

bull there is an artificial lens in the eye to be treated and

bull their diabetic macular oedema has not improved with

non-corticosteroid treatment or such treatment is not suitable for them

Steroids = second line therapyWhen do I switch

bull Anti-VEGF first line for centre involving DMObull NICE TA ndash ldquoinsufficiently responsiverdquo ldquo ldquonot improvedrdquo ldquonot suitablerdquo ndash

OTHER TREATMENTS

bull 2 scenariosbull 1) Anti-VEGF canrsquot be funded ie OCTlt400um + PSEUDOPHAKIC

bull 2) Already had a course of treatment with laseranti-VEGF + PSEUDOPHAKIC ie SWITCHING from anti-VEGF to steroid

bull Plus

bull ldquochronicrdquo DMO ndash 3 years duration in FAME (18months) for ILUVIEN

bull Chronic DMO not essential for Ozurdex

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

Protocol T ndash patients may not improve in first 6 months

RIDE

RISE

Mea

n ch

ange

in B

CVA

(E

TDR

S le

tters

)M

ean

chan

ge in

BC

VA

(ETD

RS

lette

rs)

Time (months)

RISE and RIDE (Lucentis monthly dosing) Mean change in BCVA over 36 months

Brown DM et al Ophthalmology 2013120(10)2013ndash2022

54

Ranibizumab 03 mgRanibizumab 05 mgShamranibizumab 05 mg

Date of Prep Dec 2014 LGB0820147252X

VA improvement continues throughout year 1 with monthly dosing

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user ndash more than protocol

I

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

DRCRN protocol I5 year outcomesInjections 8-9 in year 1Year 2 = 2-3Year 3= 1-2Year 4 = 0-1Year 5 = 0

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

Wait for plateau = stability in protocol T laserPatient factors again

Judgement of response to anti-VEGF ndashtimeframe

bull Wait 6 months in poor responders

bull Wait 1 year for heavy users

bull Tempting to try steroids earlier than this ifbull No glaucoma ndash not a deal breaker Ozurdex better short term optionbull Pseudophakic

bull Clues from the diseasebull chronic

bull PATIENT FACTORS

bull Any eyes avoid steroids ndash advanced glaucomaCSCR Or prior viral retinitis RARE

bull Any eyes avoid anti-VEGF pregnancytrying to concieve recent CVA

BIOMARKERS AT BASELINE WOULD BE USEFULRESTORE subgroup analysis of OCT features

bull Andreas Pollreisz EURETINA 2015

bull OCT biomarkers (RESTORE data)

bull Better effects with anti-VEGF ifbull Small rather than large intra-retinal cyst

bull Sub-retinal fluid present

bull Vitreo-macular adhesion at baseline

bull No disruption of ELM and ISOS junction

bull No disorganisation of inner retinal layers (DRIL)

RESTORE subgroup analysis of OCT features

bull Andreas Pollreisz EURETINA 2015

bull OCT biomarkers (RESTORE data)

bull Better effects with anti-VEGF ifbull Small rather than large intra-retinal cyst

bull Sub-retinal fluid present

bull Vitreo-macular adhesion at baseline

bull No disruption of ELM and ISOS junction

bull No disorganisation of inner retinal layers (DRIL)

Better baseline characterisationclassificationERG Contrast sensitivityOCT AngiographyMicroperimetry= clues as to who responds best to which drug

Plan for this presentation helliphellipa long list

bull What treatment options are available for DMO (evidence base)

bull What treatment should I start with at baselinebull Re-treatment algorithms for intravitreal DMO therapiesbull When should I switchcombine therapiesbull The bigger picture

bull Other eyebull The patient as a wholebull The service -coping with capacity ndash compromises

The bigger pictureOther eyeThe patient as a wholeThe service -coping with capacity ndash compromises

bull OTHER EYE ndash may create problems

bull Treat and extend ndash ldquoreduce of visitsrdquo plus Eylea license ndash ldquono need for monitoringrdquo may not benefit if lots of visits due to PDR other eye

bull PERIPHERAL RETINA anti-VEGF supresses proliferative disease - Rebound on stopping Rx

bull PATIENT

bull Anti-VEGF ndash heavy user - Will comply

bull One stop much better than two stop for patient ndash Treat and extend

bull SERVICE

bull Capacity and demand planning = fixedT+E more predictable at least 1 month in advance ndash flexible nurse injectors

bull Steroids ndash even if well controlled (Iluvien for 3 years) need IOP check

bull Need pan-retinal examination both eyes ndash separate visits

Summary

CSMO

No centre involvement

Photocoagulation

Centre involvement

gt 78 letters(normalminimally reduced VA)

Photocoagulation

VA 78ndash24 letters

Phakic

Anti-VEGF

Pseudophakic

Anti-VEGF

SWITCHglaucoma

Injection tolerance

Medical issuesrecent CVA

Peripheral diseaseBilateral Rx

CSMO

No centre involvement

LASER

Centre involvement

gt 78 letters(normalminimally

reduced VA)

VA 78ndash24 letters

EYLEA OR LUCENTIS OR AVASTIN

Funding issues

Protocol T ndash poor VA lt 65 letters (615)

LOADING

Monthly injections until stability OR 5 x 112 (EYLEA) = 6 MONTHS then 8 weeks

RETREATMENT1

TREAT AND EXTEND - PRN

PRN

PSEUDOPHAKIC

Prior Rx

ILUVIEN

Chronic disease

OZURDEX

RETREATMENT

OZURDEX

OCT gt175um or any residual oedema

ILUVIEN after 12 months if risksltbenefits

OCT

gt400um

bull FACE TO FACE CLINICS RUNNING IN PARALLEL

bull = MAC002 every 6 months (optom or doctor) routine check for cataracttolerance of injectionsglaucoma issues etc

bull =MAC003 (DOCTOR) for problems as needed no fixed intervalDischargestop treatmentDeclines treatment diagnosis CSR overlay etcswitch drugs

bull =RV002- (DOCTOR) every 6 months

bull =DM002 ndash (DOCTOR) variable interval determined by last assessing doctor

bull First visit at 6 months from 1st injection if mild NPDR

bull Otherwise determined by retinopathy generally

LOADING PHASE

EyleaLucentis 1 within 48hrs of baseline

EyleaLucentis 2 (and LogMAR VA plus OCT same visit)

EyleaLucentis 3 (and LogMAR VA plus OCT same visit)

EyleaLucentis 4 (TEinj)(and Logmar VA plus OCT same visit

AFTER INJECTION 4 data goes off to be reviewed immediately as a hellip

TREAT AND EXTEND assessment ndash the next interval will depend on the response to the loading phase

NB -DMO patients ndash majority (95) will need 6 injctions x 112 of Lucentis

OR Eylea 5 x 112 then 8 weekly

ONCE STABLE for 3 x injection in TE phase

VIRTUAL CLINIC MONITORING OF MACULOPATHY AND PRN RETREATMENT

ANTI-VEGF INJECTION PATHWAYS Baseline visitMAC001 for wet AMDRV001 for CRVOBRVOMed ret clinic for DMO

Pathways ndash too many directions

Better that thanhellip

Thank you

bull Nonbioerodible micro implant (polyimide) containing 190microg of fluocinolone acetonide (FAc)

bull Consistent daily submicrogram delivery of 02 microgd FAc for up to 36 months

bull Posterior point of release

bull 35 mm times 037 mm non-bioerodable micro implant

bull 25-gauge injector creates self-sealing wound

bull No measurable systemic exposure

ILUVIEN Implant Technology

FAcimplant

ILUVIEN SPC httpwwwmedicinesorgukemcmedicine27636

0 6 12 18 24 30 36

ILUVIEN 02 microgd FAc(n = 376)05 microgd FAc (n = 395)Control sham injection(n = 185)

Design of Phase 3 FAME Study (FAME A and B = same protocol)

Additional laser therapy allowed after week 6a

Retreatment any time after month 12 (if eligibleb)

Study ends

N = 956Randomisation

221Primary readout

Patients with DMO and

bull At least 1 previous laser tx

bull BCVA ge19 and le68 letters

bull TD-OCT FTH ge250 μm

Month

BCVA = best corrected visual acuity DMO = diabetic macular oedema TD-OCT=time domain optical coherence tomography FTH = foveal thicknessa At masked investigatorrsquos discretion b If BCVA loss ge5 letters or retinal thickening ge50 microm from best reading in previous 12 months

ge15 letter Gain is Greater in Chronic DMO Patients

ge 15

-Let

ter I

mpr

ovem

ent

in B

CVA

Fro

m B

asel

ine

Δ = 98

Months

Full Population Patients With Chronic DMO

Months

Δ = 206

287

189134

34

Steroid re-treatments

bullOzurdexbull Longer half-life than anti-VEGF in the eye

bull Redosing regimes not very helpful from RCT data eg MEAD study only 612 dosing

bull In reality re-treatment interval may be shorter

bull POSOLOGY

bull Patients treated with OZURDEX who have experienced an initial response and in the physicians opinion may benefit from retreatment without being exposed to significant risk should be considered for retreatment Retreatment may be performed after approximately 6 months if the patient experiences decreased vision andor an increase in retinal thickness secondary to recurrent or worsening diabetic macular oedema

bullIluvienbull 70 of patients in FAE only needed 1

injection over 3 years

bull BUT additional rescue treatments allowed

bull POSOLOGY

bull Each ILUVIEN implant releases fluocinolone acetonide for up to 36 months An additional implant may be administered after 12 months if the patient experiences decreased vision or an increase in retinal thickness secondary to recurrent or worsening diabetic macular oedema

bull Patients receiving escape medication were exited from MEAD before administration1

bull Macular laser rescue treatment allowed in RISERIDE (Lucentisreg) from 3 months2

bull Focalgrid laser allowed in FAME (Iluvienreg) from 6 weeks3

MEAD TREATMENT PROTOCOL

bull First treatment given at randomisation (day 0) bull Patients assessed for retreatment eligibility every 3 months from

months 6ndash36bull Patients were eligible for retreatment if

OCT optical coherence tomography

ge6 months since most recent

study treatment

Retinal thickness in 1 mm central macular

subfield by OCT gt175 microm

Evidence of residual retinal oedema (intraretinal cysts or

any regions of increased retinal thickening) as assessed by

investigator from OCT

AND OR

MEA

D

Amendment in May 2010 revised anatomic criterion for retreatment before this time the threshold was gt225 microm1Boyer DS et al Ophthalmology 2014 121 1904-19142Nguyen QD et al Ophthalmology 20121191064minus10773Campochiaro PA et al Ophthalmology 2011118626ndash635

Treatment burdenILUVIEN

Control(n =112)

02 microgd FAc(n =209)

Study Treatments(sham injection or ILUVIEN 02 microgday or FAc 05microgday)

1 treatment 661 761

2 treatments 277 187

ge 3 treatments 63 53

Rescue Laser Treatments (at masked physicianrsquos discretion after week 6)

Patients 607 407

Off-Protocol Treatments (IVTA bevacizumab ranibizumab intravitreal dexamethasone)

Patients 295 115

OZURDEX = 23injections year 1 41 by year 3

No other Rx

Summary of side effects with intravitreal steroids

Drug device Evidence base Cataract risk IOP rise (requiring drops)

Glaucoma surgery

endophthalmitis

ILUVIEN FAME studies 80 cat surgery(273 sham)

384(14 control)

48 0

Ozurdex MEAD 592 had cataract surgery(72 sham)

215 (end of study)(34 sham)

06 0

Trivaris+ laser vs Luc+laserx2 vs laser

Protocol IOphthalmology 2010

15 42(ONE OFgt10mmHg risegt30mmHGStart drops)

2186 0

NICE guidance for intravitreal steroids in DMO

bull Iluvien

bull NICE TA 301 Iluvien for DMO Nov 2013

bull hellipfor treating chronic diabetic macular oedema that is insufficiently responsive to available therapies only if

bull the implant is to be used in an eye with an intraocular

(pseudophakic) lens and

bull the manufacturer provides fluocinolone acetonide intravitreal implant with the discount agreed in the patient access scheme

NICE guidance for intravitreal steroids in DMO

bull Ozurdex

bull NICE TA 349 Ozurdex for DMO July 2015

bull there is an artificial lens in the eye to be treated and

bull their diabetic macular oedema has not improved with

non-corticosteroid treatment or such treatment is not suitable for them

Steroids = second line therapyWhen do I switch

bull Anti-VEGF first line for centre involving DMObull NICE TA ndash ldquoinsufficiently responsiverdquo ldquo ldquonot improvedrdquo ldquonot suitablerdquo ndash

OTHER TREATMENTS

bull 2 scenariosbull 1) Anti-VEGF canrsquot be funded ie OCTlt400um + PSEUDOPHAKIC

bull 2) Already had a course of treatment with laseranti-VEGF + PSEUDOPHAKIC ie SWITCHING from anti-VEGF to steroid

bull Plus

bull ldquochronicrdquo DMO ndash 3 years duration in FAME (18months) for ILUVIEN

bull Chronic DMO not essential for Ozurdex

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

Protocol T ndash patients may not improve in first 6 months

RIDE

RISE

Mea

n ch

ange

in B

CVA

(E

TDR

S le

tters

)M

ean

chan

ge in

BC

VA

(ETD

RS

lette

rs)

Time (months)

RISE and RIDE (Lucentis monthly dosing) Mean change in BCVA over 36 months

Brown DM et al Ophthalmology 2013120(10)2013ndash2022

54

Ranibizumab 03 mgRanibizumab 05 mgShamranibizumab 05 mg

Date of Prep Dec 2014 LGB0820147252X

VA improvement continues throughout year 1 with monthly dosing

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user ndash more than protocol

I

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

DRCRN protocol I5 year outcomesInjections 8-9 in year 1Year 2 = 2-3Year 3= 1-2Year 4 = 0-1Year 5 = 0

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

Wait for plateau = stability in protocol T laserPatient factors again

Judgement of response to anti-VEGF ndashtimeframe

bull Wait 6 months in poor responders

bull Wait 1 year for heavy users

bull Tempting to try steroids earlier than this ifbull No glaucoma ndash not a deal breaker Ozurdex better short term optionbull Pseudophakic

bull Clues from the diseasebull chronic

bull PATIENT FACTORS

bull Any eyes avoid steroids ndash advanced glaucomaCSCR Or prior viral retinitis RARE

bull Any eyes avoid anti-VEGF pregnancytrying to concieve recent CVA

BIOMARKERS AT BASELINE WOULD BE USEFULRESTORE subgroup analysis of OCT features

bull Andreas Pollreisz EURETINA 2015

bull OCT biomarkers (RESTORE data)

bull Better effects with anti-VEGF ifbull Small rather than large intra-retinal cyst

bull Sub-retinal fluid present

bull Vitreo-macular adhesion at baseline

bull No disruption of ELM and ISOS junction

bull No disorganisation of inner retinal layers (DRIL)

RESTORE subgroup analysis of OCT features

bull Andreas Pollreisz EURETINA 2015

bull OCT biomarkers (RESTORE data)

bull Better effects with anti-VEGF ifbull Small rather than large intra-retinal cyst

bull Sub-retinal fluid present

bull Vitreo-macular adhesion at baseline

bull No disruption of ELM and ISOS junction

bull No disorganisation of inner retinal layers (DRIL)

Better baseline characterisationclassificationERG Contrast sensitivityOCT AngiographyMicroperimetry= clues as to who responds best to which drug

Plan for this presentation helliphellipa long list

bull What treatment options are available for DMO (evidence base)

bull What treatment should I start with at baselinebull Re-treatment algorithms for intravitreal DMO therapiesbull When should I switchcombine therapiesbull The bigger picture

bull Other eyebull The patient as a wholebull The service -coping with capacity ndash compromises

The bigger pictureOther eyeThe patient as a wholeThe service -coping with capacity ndash compromises

bull OTHER EYE ndash may create problems

bull Treat and extend ndash ldquoreduce of visitsrdquo plus Eylea license ndash ldquono need for monitoringrdquo may not benefit if lots of visits due to PDR other eye

bull PERIPHERAL RETINA anti-VEGF supresses proliferative disease - Rebound on stopping Rx

bull PATIENT

bull Anti-VEGF ndash heavy user - Will comply

bull One stop much better than two stop for patient ndash Treat and extend

bull SERVICE

bull Capacity and demand planning = fixedT+E more predictable at least 1 month in advance ndash flexible nurse injectors

bull Steroids ndash even if well controlled (Iluvien for 3 years) need IOP check

bull Need pan-retinal examination both eyes ndash separate visits

Summary

CSMO

No centre involvement

Photocoagulation

Centre involvement

gt 78 letters(normalminimally reduced VA)

Photocoagulation

VA 78ndash24 letters

Phakic

Anti-VEGF

Pseudophakic

Anti-VEGF

SWITCHglaucoma

Injection tolerance

Medical issuesrecent CVA

Peripheral diseaseBilateral Rx

CSMO

No centre involvement

LASER

Centre involvement

gt 78 letters(normalminimally

reduced VA)

VA 78ndash24 letters

EYLEA OR LUCENTIS OR AVASTIN

Funding issues

Protocol T ndash poor VA lt 65 letters (615)

LOADING

Monthly injections until stability OR 5 x 112 (EYLEA) = 6 MONTHS then 8 weeks

RETREATMENT1

TREAT AND EXTEND - PRN

PRN

PSEUDOPHAKIC

Prior Rx

ILUVIEN

Chronic disease

OZURDEX

RETREATMENT

OZURDEX

OCT gt175um or any residual oedema

ILUVIEN after 12 months if risksltbenefits

OCT

gt400um

bull FACE TO FACE CLINICS RUNNING IN PARALLEL

bull = MAC002 every 6 months (optom or doctor) routine check for cataracttolerance of injectionsglaucoma issues etc

bull =MAC003 (DOCTOR) for problems as needed no fixed intervalDischargestop treatmentDeclines treatment diagnosis CSR overlay etcswitch drugs

bull =RV002- (DOCTOR) every 6 months

bull =DM002 ndash (DOCTOR) variable interval determined by last assessing doctor

bull First visit at 6 months from 1st injection if mild NPDR

bull Otherwise determined by retinopathy generally

LOADING PHASE

EyleaLucentis 1 within 48hrs of baseline

EyleaLucentis 2 (and LogMAR VA plus OCT same visit)

EyleaLucentis 3 (and LogMAR VA plus OCT same visit)

EyleaLucentis 4 (TEinj)(and Logmar VA plus OCT same visit

AFTER INJECTION 4 data goes off to be reviewed immediately as a hellip

TREAT AND EXTEND assessment ndash the next interval will depend on the response to the loading phase

NB -DMO patients ndash majority (95) will need 6 injctions x 112 of Lucentis

OR Eylea 5 x 112 then 8 weekly

ONCE STABLE for 3 x injection in TE phase

VIRTUAL CLINIC MONITORING OF MACULOPATHY AND PRN RETREATMENT

ANTI-VEGF INJECTION PATHWAYS Baseline visitMAC001 for wet AMDRV001 for CRVOBRVOMed ret clinic for DMO

Pathways ndash too many directions

Better that thanhellip

Thank you

0 6 12 18 24 30 36

ILUVIEN 02 microgd FAc(n = 376)05 microgd FAc (n = 395)Control sham injection(n = 185)

Design of Phase 3 FAME Study (FAME A and B = same protocol)

Additional laser therapy allowed after week 6a

Retreatment any time after month 12 (if eligibleb)

Study ends

N = 956Randomisation

221Primary readout

Patients with DMO and

bull At least 1 previous laser tx

bull BCVA ge19 and le68 letters

bull TD-OCT FTH ge250 μm

Month

BCVA = best corrected visual acuity DMO = diabetic macular oedema TD-OCT=time domain optical coherence tomography FTH = foveal thicknessa At masked investigatorrsquos discretion b If BCVA loss ge5 letters or retinal thickening ge50 microm from best reading in previous 12 months

ge15 letter Gain is Greater in Chronic DMO Patients

ge 15

-Let

ter I

mpr

ovem

ent

in B

CVA

Fro

m B

asel

ine

Δ = 98

Months

Full Population Patients With Chronic DMO

Months

Δ = 206

287

189134

34

Steroid re-treatments

bullOzurdexbull Longer half-life than anti-VEGF in the eye

bull Redosing regimes not very helpful from RCT data eg MEAD study only 612 dosing

bull In reality re-treatment interval may be shorter

bull POSOLOGY

bull Patients treated with OZURDEX who have experienced an initial response and in the physicians opinion may benefit from retreatment without being exposed to significant risk should be considered for retreatment Retreatment may be performed after approximately 6 months if the patient experiences decreased vision andor an increase in retinal thickness secondary to recurrent or worsening diabetic macular oedema

bullIluvienbull 70 of patients in FAE only needed 1

injection over 3 years

bull BUT additional rescue treatments allowed

bull POSOLOGY

bull Each ILUVIEN implant releases fluocinolone acetonide for up to 36 months An additional implant may be administered after 12 months if the patient experiences decreased vision or an increase in retinal thickness secondary to recurrent or worsening diabetic macular oedema

bull Patients receiving escape medication were exited from MEAD before administration1

bull Macular laser rescue treatment allowed in RISERIDE (Lucentisreg) from 3 months2

bull Focalgrid laser allowed in FAME (Iluvienreg) from 6 weeks3

MEAD TREATMENT PROTOCOL

bull First treatment given at randomisation (day 0) bull Patients assessed for retreatment eligibility every 3 months from

months 6ndash36bull Patients were eligible for retreatment if

OCT optical coherence tomography

ge6 months since most recent

study treatment

Retinal thickness in 1 mm central macular

subfield by OCT gt175 microm

Evidence of residual retinal oedema (intraretinal cysts or

any regions of increased retinal thickening) as assessed by

investigator from OCT

AND OR

MEA

D

Amendment in May 2010 revised anatomic criterion for retreatment before this time the threshold was gt225 microm1Boyer DS et al Ophthalmology 2014 121 1904-19142Nguyen QD et al Ophthalmology 20121191064minus10773Campochiaro PA et al Ophthalmology 2011118626ndash635

Treatment burdenILUVIEN

Control(n =112)

02 microgd FAc(n =209)

Study Treatments(sham injection or ILUVIEN 02 microgday or FAc 05microgday)

1 treatment 661 761

2 treatments 277 187

ge 3 treatments 63 53

Rescue Laser Treatments (at masked physicianrsquos discretion after week 6)

Patients 607 407

Off-Protocol Treatments (IVTA bevacizumab ranibizumab intravitreal dexamethasone)

Patients 295 115

OZURDEX = 23injections year 1 41 by year 3

No other Rx

Summary of side effects with intravitreal steroids

Drug device Evidence base Cataract risk IOP rise (requiring drops)

Glaucoma surgery

endophthalmitis

ILUVIEN FAME studies 80 cat surgery(273 sham)

384(14 control)

48 0

Ozurdex MEAD 592 had cataract surgery(72 sham)

215 (end of study)(34 sham)

06 0

Trivaris+ laser vs Luc+laserx2 vs laser

Protocol IOphthalmology 2010

15 42(ONE OFgt10mmHg risegt30mmHGStart drops)

2186 0

NICE guidance for intravitreal steroids in DMO

bull Iluvien

bull NICE TA 301 Iluvien for DMO Nov 2013

bull hellipfor treating chronic diabetic macular oedema that is insufficiently responsive to available therapies only if

bull the implant is to be used in an eye with an intraocular

(pseudophakic) lens and

bull the manufacturer provides fluocinolone acetonide intravitreal implant with the discount agreed in the patient access scheme

NICE guidance for intravitreal steroids in DMO

bull Ozurdex

bull NICE TA 349 Ozurdex for DMO July 2015

bull there is an artificial lens in the eye to be treated and

bull their diabetic macular oedema has not improved with

non-corticosteroid treatment or such treatment is not suitable for them

Steroids = second line therapyWhen do I switch

bull Anti-VEGF first line for centre involving DMObull NICE TA ndash ldquoinsufficiently responsiverdquo ldquo ldquonot improvedrdquo ldquonot suitablerdquo ndash

OTHER TREATMENTS

bull 2 scenariosbull 1) Anti-VEGF canrsquot be funded ie OCTlt400um + PSEUDOPHAKIC

bull 2) Already had a course of treatment with laseranti-VEGF + PSEUDOPHAKIC ie SWITCHING from anti-VEGF to steroid

bull Plus

bull ldquochronicrdquo DMO ndash 3 years duration in FAME (18months) for ILUVIEN

bull Chronic DMO not essential for Ozurdex

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

Protocol T ndash patients may not improve in first 6 months

RIDE

RISE

Mea

n ch

ange

in B

CVA

(E

TDR

S le

tters

)M

ean

chan

ge in

BC

VA

(ETD

RS

lette

rs)

Time (months)

RISE and RIDE (Lucentis monthly dosing) Mean change in BCVA over 36 months

Brown DM et al Ophthalmology 2013120(10)2013ndash2022

54

Ranibizumab 03 mgRanibizumab 05 mgShamranibizumab 05 mg

Date of Prep Dec 2014 LGB0820147252X

VA improvement continues throughout year 1 with monthly dosing

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user ndash more than protocol

I

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

DRCRN protocol I5 year outcomesInjections 8-9 in year 1Year 2 = 2-3Year 3= 1-2Year 4 = 0-1Year 5 = 0

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

Wait for plateau = stability in protocol T laserPatient factors again

Judgement of response to anti-VEGF ndashtimeframe

bull Wait 6 months in poor responders

bull Wait 1 year for heavy users

bull Tempting to try steroids earlier than this ifbull No glaucoma ndash not a deal breaker Ozurdex better short term optionbull Pseudophakic

bull Clues from the diseasebull chronic

bull PATIENT FACTORS

bull Any eyes avoid steroids ndash advanced glaucomaCSCR Or prior viral retinitis RARE

bull Any eyes avoid anti-VEGF pregnancytrying to concieve recent CVA

BIOMARKERS AT BASELINE WOULD BE USEFULRESTORE subgroup analysis of OCT features

bull Andreas Pollreisz EURETINA 2015

bull OCT biomarkers (RESTORE data)

bull Better effects with anti-VEGF ifbull Small rather than large intra-retinal cyst

bull Sub-retinal fluid present

bull Vitreo-macular adhesion at baseline

bull No disruption of ELM and ISOS junction

bull No disorganisation of inner retinal layers (DRIL)

RESTORE subgroup analysis of OCT features

bull Andreas Pollreisz EURETINA 2015

bull OCT biomarkers (RESTORE data)

bull Better effects with anti-VEGF ifbull Small rather than large intra-retinal cyst

bull Sub-retinal fluid present

bull Vitreo-macular adhesion at baseline

bull No disruption of ELM and ISOS junction

bull No disorganisation of inner retinal layers (DRIL)

Better baseline characterisationclassificationERG Contrast sensitivityOCT AngiographyMicroperimetry= clues as to who responds best to which drug

Plan for this presentation helliphellipa long list

bull What treatment options are available for DMO (evidence base)

bull What treatment should I start with at baselinebull Re-treatment algorithms for intravitreal DMO therapiesbull When should I switchcombine therapiesbull The bigger picture

bull Other eyebull The patient as a wholebull The service -coping with capacity ndash compromises

The bigger pictureOther eyeThe patient as a wholeThe service -coping with capacity ndash compromises

bull OTHER EYE ndash may create problems

bull Treat and extend ndash ldquoreduce of visitsrdquo plus Eylea license ndash ldquono need for monitoringrdquo may not benefit if lots of visits due to PDR other eye

bull PERIPHERAL RETINA anti-VEGF supresses proliferative disease - Rebound on stopping Rx

bull PATIENT

bull Anti-VEGF ndash heavy user - Will comply

bull One stop much better than two stop for patient ndash Treat and extend

bull SERVICE

bull Capacity and demand planning = fixedT+E more predictable at least 1 month in advance ndash flexible nurse injectors

bull Steroids ndash even if well controlled (Iluvien for 3 years) need IOP check

bull Need pan-retinal examination both eyes ndash separate visits

Summary

CSMO

No centre involvement

Photocoagulation

Centre involvement

gt 78 letters(normalminimally reduced VA)

Photocoagulation

VA 78ndash24 letters

Phakic

Anti-VEGF

Pseudophakic

Anti-VEGF

SWITCHglaucoma

Injection tolerance

Medical issuesrecent CVA

Peripheral diseaseBilateral Rx

CSMO

No centre involvement

LASER

Centre involvement

gt 78 letters(normalminimally

reduced VA)

VA 78ndash24 letters

EYLEA OR LUCENTIS OR AVASTIN

Funding issues

Protocol T ndash poor VA lt 65 letters (615)

LOADING

Monthly injections until stability OR 5 x 112 (EYLEA) = 6 MONTHS then 8 weeks

RETREATMENT1

TREAT AND EXTEND - PRN

PRN

PSEUDOPHAKIC

Prior Rx

ILUVIEN

Chronic disease

OZURDEX

RETREATMENT

OZURDEX

OCT gt175um or any residual oedema

ILUVIEN after 12 months if risksltbenefits

OCT

gt400um

bull FACE TO FACE CLINICS RUNNING IN PARALLEL

bull = MAC002 every 6 months (optom or doctor) routine check for cataracttolerance of injectionsglaucoma issues etc

bull =MAC003 (DOCTOR) for problems as needed no fixed intervalDischargestop treatmentDeclines treatment diagnosis CSR overlay etcswitch drugs

bull =RV002- (DOCTOR) every 6 months

bull =DM002 ndash (DOCTOR) variable interval determined by last assessing doctor

bull First visit at 6 months from 1st injection if mild NPDR

bull Otherwise determined by retinopathy generally

LOADING PHASE

EyleaLucentis 1 within 48hrs of baseline

EyleaLucentis 2 (and LogMAR VA plus OCT same visit)

EyleaLucentis 3 (and LogMAR VA plus OCT same visit)

EyleaLucentis 4 (TEinj)(and Logmar VA plus OCT same visit

AFTER INJECTION 4 data goes off to be reviewed immediately as a hellip

TREAT AND EXTEND assessment ndash the next interval will depend on the response to the loading phase

NB -DMO patients ndash majority (95) will need 6 injctions x 112 of Lucentis

OR Eylea 5 x 112 then 8 weekly

ONCE STABLE for 3 x injection in TE phase

VIRTUAL CLINIC MONITORING OF MACULOPATHY AND PRN RETREATMENT

ANTI-VEGF INJECTION PATHWAYS Baseline visitMAC001 for wet AMDRV001 for CRVOBRVOMed ret clinic for DMO

Pathways ndash too many directions

Better that thanhellip

Thank you

ge15 letter Gain is Greater in Chronic DMO Patients

ge 15

-Let

ter I

mpr

ovem

ent

in B

CVA

Fro

m B

asel

ine

Δ = 98

Months

Full Population Patients With Chronic DMO

Months

Δ = 206

287

189134

34

Steroid re-treatments

bullOzurdexbull Longer half-life than anti-VEGF in the eye

bull Redosing regimes not very helpful from RCT data eg MEAD study only 612 dosing

bull In reality re-treatment interval may be shorter

bull POSOLOGY

bull Patients treated with OZURDEX who have experienced an initial response and in the physicians opinion may benefit from retreatment without being exposed to significant risk should be considered for retreatment Retreatment may be performed after approximately 6 months if the patient experiences decreased vision andor an increase in retinal thickness secondary to recurrent or worsening diabetic macular oedema

bullIluvienbull 70 of patients in FAE only needed 1

injection over 3 years

bull BUT additional rescue treatments allowed

bull POSOLOGY

bull Each ILUVIEN implant releases fluocinolone acetonide for up to 36 months An additional implant may be administered after 12 months if the patient experiences decreased vision or an increase in retinal thickness secondary to recurrent or worsening diabetic macular oedema

bull Patients receiving escape medication were exited from MEAD before administration1

bull Macular laser rescue treatment allowed in RISERIDE (Lucentisreg) from 3 months2

bull Focalgrid laser allowed in FAME (Iluvienreg) from 6 weeks3

MEAD TREATMENT PROTOCOL

bull First treatment given at randomisation (day 0) bull Patients assessed for retreatment eligibility every 3 months from

months 6ndash36bull Patients were eligible for retreatment if

OCT optical coherence tomography

ge6 months since most recent

study treatment

Retinal thickness in 1 mm central macular

subfield by OCT gt175 microm

Evidence of residual retinal oedema (intraretinal cysts or

any regions of increased retinal thickening) as assessed by

investigator from OCT

AND OR

MEA

D

Amendment in May 2010 revised anatomic criterion for retreatment before this time the threshold was gt225 microm1Boyer DS et al Ophthalmology 2014 121 1904-19142Nguyen QD et al Ophthalmology 20121191064minus10773Campochiaro PA et al Ophthalmology 2011118626ndash635

Treatment burdenILUVIEN

Control(n =112)

02 microgd FAc(n =209)

Study Treatments(sham injection or ILUVIEN 02 microgday or FAc 05microgday)

1 treatment 661 761

2 treatments 277 187

ge 3 treatments 63 53

Rescue Laser Treatments (at masked physicianrsquos discretion after week 6)

Patients 607 407

Off-Protocol Treatments (IVTA bevacizumab ranibizumab intravitreal dexamethasone)

Patients 295 115

OZURDEX = 23injections year 1 41 by year 3

No other Rx

Summary of side effects with intravitreal steroids

Drug device Evidence base Cataract risk IOP rise (requiring drops)

Glaucoma surgery

endophthalmitis

ILUVIEN FAME studies 80 cat surgery(273 sham)

384(14 control)

48 0

Ozurdex MEAD 592 had cataract surgery(72 sham)

215 (end of study)(34 sham)

06 0

Trivaris+ laser vs Luc+laserx2 vs laser

Protocol IOphthalmology 2010

15 42(ONE OFgt10mmHg risegt30mmHGStart drops)

2186 0

NICE guidance for intravitreal steroids in DMO

bull Iluvien

bull NICE TA 301 Iluvien for DMO Nov 2013

bull hellipfor treating chronic diabetic macular oedema that is insufficiently responsive to available therapies only if

bull the implant is to be used in an eye with an intraocular

(pseudophakic) lens and

bull the manufacturer provides fluocinolone acetonide intravitreal implant with the discount agreed in the patient access scheme

NICE guidance for intravitreal steroids in DMO

bull Ozurdex

bull NICE TA 349 Ozurdex for DMO July 2015

bull there is an artificial lens in the eye to be treated and

bull their diabetic macular oedema has not improved with

non-corticosteroid treatment or such treatment is not suitable for them

Steroids = second line therapyWhen do I switch

bull Anti-VEGF first line for centre involving DMObull NICE TA ndash ldquoinsufficiently responsiverdquo ldquo ldquonot improvedrdquo ldquonot suitablerdquo ndash

OTHER TREATMENTS

bull 2 scenariosbull 1) Anti-VEGF canrsquot be funded ie OCTlt400um + PSEUDOPHAKIC

bull 2) Already had a course of treatment with laseranti-VEGF + PSEUDOPHAKIC ie SWITCHING from anti-VEGF to steroid

bull Plus

bull ldquochronicrdquo DMO ndash 3 years duration in FAME (18months) for ILUVIEN

bull Chronic DMO not essential for Ozurdex

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

Protocol T ndash patients may not improve in first 6 months

RIDE

RISE

Mea

n ch

ange

in B

CVA

(E

TDR

S le

tters

)M

ean

chan

ge in

BC

VA

(ETD

RS

lette

rs)

Time (months)

RISE and RIDE (Lucentis monthly dosing) Mean change in BCVA over 36 months

Brown DM et al Ophthalmology 2013120(10)2013ndash2022

54

Ranibizumab 03 mgRanibizumab 05 mgShamranibizumab 05 mg

Date of Prep Dec 2014 LGB0820147252X

VA improvement continues throughout year 1 with monthly dosing

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user ndash more than protocol

I

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

DRCRN protocol I5 year outcomesInjections 8-9 in year 1Year 2 = 2-3Year 3= 1-2Year 4 = 0-1Year 5 = 0

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

Wait for plateau = stability in protocol T laserPatient factors again

Judgement of response to anti-VEGF ndashtimeframe

bull Wait 6 months in poor responders

bull Wait 1 year for heavy users

bull Tempting to try steroids earlier than this ifbull No glaucoma ndash not a deal breaker Ozurdex better short term optionbull Pseudophakic

bull Clues from the diseasebull chronic

bull PATIENT FACTORS

bull Any eyes avoid steroids ndash advanced glaucomaCSCR Or prior viral retinitis RARE

bull Any eyes avoid anti-VEGF pregnancytrying to concieve recent CVA

BIOMARKERS AT BASELINE WOULD BE USEFULRESTORE subgroup analysis of OCT features

bull Andreas Pollreisz EURETINA 2015

bull OCT biomarkers (RESTORE data)

bull Better effects with anti-VEGF ifbull Small rather than large intra-retinal cyst

bull Sub-retinal fluid present

bull Vitreo-macular adhesion at baseline

bull No disruption of ELM and ISOS junction

bull No disorganisation of inner retinal layers (DRIL)

RESTORE subgroup analysis of OCT features

bull Andreas Pollreisz EURETINA 2015

bull OCT biomarkers (RESTORE data)

bull Better effects with anti-VEGF ifbull Small rather than large intra-retinal cyst

bull Sub-retinal fluid present

bull Vitreo-macular adhesion at baseline

bull No disruption of ELM and ISOS junction

bull No disorganisation of inner retinal layers (DRIL)

Better baseline characterisationclassificationERG Contrast sensitivityOCT AngiographyMicroperimetry= clues as to who responds best to which drug

Plan for this presentation helliphellipa long list

bull What treatment options are available for DMO (evidence base)

bull What treatment should I start with at baselinebull Re-treatment algorithms for intravitreal DMO therapiesbull When should I switchcombine therapiesbull The bigger picture

bull Other eyebull The patient as a wholebull The service -coping with capacity ndash compromises

The bigger pictureOther eyeThe patient as a wholeThe service -coping with capacity ndash compromises

bull OTHER EYE ndash may create problems

bull Treat and extend ndash ldquoreduce of visitsrdquo plus Eylea license ndash ldquono need for monitoringrdquo may not benefit if lots of visits due to PDR other eye

bull PERIPHERAL RETINA anti-VEGF supresses proliferative disease - Rebound on stopping Rx

bull PATIENT

bull Anti-VEGF ndash heavy user - Will comply

bull One stop much better than two stop for patient ndash Treat and extend

bull SERVICE

bull Capacity and demand planning = fixedT+E more predictable at least 1 month in advance ndash flexible nurse injectors

bull Steroids ndash even if well controlled (Iluvien for 3 years) need IOP check

bull Need pan-retinal examination both eyes ndash separate visits

Summary

CSMO

No centre involvement

Photocoagulation

Centre involvement

gt 78 letters(normalminimally reduced VA)

Photocoagulation

VA 78ndash24 letters

Phakic

Anti-VEGF

Pseudophakic

Anti-VEGF

SWITCHglaucoma

Injection tolerance

Medical issuesrecent CVA

Peripheral diseaseBilateral Rx

CSMO

No centre involvement

LASER

Centre involvement

gt 78 letters(normalminimally

reduced VA)

VA 78ndash24 letters

EYLEA OR LUCENTIS OR AVASTIN

Funding issues

Protocol T ndash poor VA lt 65 letters (615)

LOADING

Monthly injections until stability OR 5 x 112 (EYLEA) = 6 MONTHS then 8 weeks

RETREATMENT1

TREAT AND EXTEND - PRN

PRN

PSEUDOPHAKIC

Prior Rx

ILUVIEN

Chronic disease

OZURDEX

RETREATMENT

OZURDEX

OCT gt175um or any residual oedema

ILUVIEN after 12 months if risksltbenefits

OCT

gt400um

bull FACE TO FACE CLINICS RUNNING IN PARALLEL

bull = MAC002 every 6 months (optom or doctor) routine check for cataracttolerance of injectionsglaucoma issues etc

bull =MAC003 (DOCTOR) for problems as needed no fixed intervalDischargestop treatmentDeclines treatment diagnosis CSR overlay etcswitch drugs

bull =RV002- (DOCTOR) every 6 months

bull =DM002 ndash (DOCTOR) variable interval determined by last assessing doctor

bull First visit at 6 months from 1st injection if mild NPDR

bull Otherwise determined by retinopathy generally

LOADING PHASE

EyleaLucentis 1 within 48hrs of baseline

EyleaLucentis 2 (and LogMAR VA plus OCT same visit)

EyleaLucentis 3 (and LogMAR VA plus OCT same visit)

EyleaLucentis 4 (TEinj)(and Logmar VA plus OCT same visit

AFTER INJECTION 4 data goes off to be reviewed immediately as a hellip

TREAT AND EXTEND assessment ndash the next interval will depend on the response to the loading phase

NB -DMO patients ndash majority (95) will need 6 injctions x 112 of Lucentis

OR Eylea 5 x 112 then 8 weekly

ONCE STABLE for 3 x injection in TE phase

VIRTUAL CLINIC MONITORING OF MACULOPATHY AND PRN RETREATMENT

ANTI-VEGF INJECTION PATHWAYS Baseline visitMAC001 for wet AMDRV001 for CRVOBRVOMed ret clinic for DMO

Pathways ndash too many directions

Better that thanhellip

Thank you

Steroid re-treatments

bullOzurdexbull Longer half-life than anti-VEGF in the eye

bull Redosing regimes not very helpful from RCT data eg MEAD study only 612 dosing

bull In reality re-treatment interval may be shorter

bull POSOLOGY

bull Patients treated with OZURDEX who have experienced an initial response and in the physicians opinion may benefit from retreatment without being exposed to significant risk should be considered for retreatment Retreatment may be performed after approximately 6 months if the patient experiences decreased vision andor an increase in retinal thickness secondary to recurrent or worsening diabetic macular oedema

bullIluvienbull 70 of patients in FAE only needed 1

injection over 3 years

bull BUT additional rescue treatments allowed

bull POSOLOGY

bull Each ILUVIEN implant releases fluocinolone acetonide for up to 36 months An additional implant may be administered after 12 months if the patient experiences decreased vision or an increase in retinal thickness secondary to recurrent or worsening diabetic macular oedema

bull Patients receiving escape medication were exited from MEAD before administration1

bull Macular laser rescue treatment allowed in RISERIDE (Lucentisreg) from 3 months2

bull Focalgrid laser allowed in FAME (Iluvienreg) from 6 weeks3

MEAD TREATMENT PROTOCOL

bull First treatment given at randomisation (day 0) bull Patients assessed for retreatment eligibility every 3 months from

months 6ndash36bull Patients were eligible for retreatment if

OCT optical coherence tomography

ge6 months since most recent

study treatment

Retinal thickness in 1 mm central macular

subfield by OCT gt175 microm

Evidence of residual retinal oedema (intraretinal cysts or

any regions of increased retinal thickening) as assessed by

investigator from OCT

AND OR

MEA

D

Amendment in May 2010 revised anatomic criterion for retreatment before this time the threshold was gt225 microm1Boyer DS et al Ophthalmology 2014 121 1904-19142Nguyen QD et al Ophthalmology 20121191064minus10773Campochiaro PA et al Ophthalmology 2011118626ndash635

Treatment burdenILUVIEN

Control(n =112)

02 microgd FAc(n =209)

Study Treatments(sham injection or ILUVIEN 02 microgday or FAc 05microgday)

1 treatment 661 761

2 treatments 277 187

ge 3 treatments 63 53

Rescue Laser Treatments (at masked physicianrsquos discretion after week 6)

Patients 607 407

Off-Protocol Treatments (IVTA bevacizumab ranibizumab intravitreal dexamethasone)

Patients 295 115

OZURDEX = 23injections year 1 41 by year 3

No other Rx

Summary of side effects with intravitreal steroids

Drug device Evidence base Cataract risk IOP rise (requiring drops)

Glaucoma surgery

endophthalmitis

ILUVIEN FAME studies 80 cat surgery(273 sham)

384(14 control)

48 0

Ozurdex MEAD 592 had cataract surgery(72 sham)

215 (end of study)(34 sham)

06 0

Trivaris+ laser vs Luc+laserx2 vs laser

Protocol IOphthalmology 2010

15 42(ONE OFgt10mmHg risegt30mmHGStart drops)

2186 0

NICE guidance for intravitreal steroids in DMO

bull Iluvien

bull NICE TA 301 Iluvien for DMO Nov 2013

bull hellipfor treating chronic diabetic macular oedema that is insufficiently responsive to available therapies only if

bull the implant is to be used in an eye with an intraocular

(pseudophakic) lens and

bull the manufacturer provides fluocinolone acetonide intravitreal implant with the discount agreed in the patient access scheme

NICE guidance for intravitreal steroids in DMO

bull Ozurdex

bull NICE TA 349 Ozurdex for DMO July 2015

bull there is an artificial lens in the eye to be treated and

bull their diabetic macular oedema has not improved with

non-corticosteroid treatment or such treatment is not suitable for them

Steroids = second line therapyWhen do I switch

bull Anti-VEGF first line for centre involving DMObull NICE TA ndash ldquoinsufficiently responsiverdquo ldquo ldquonot improvedrdquo ldquonot suitablerdquo ndash

OTHER TREATMENTS

bull 2 scenariosbull 1) Anti-VEGF canrsquot be funded ie OCTlt400um + PSEUDOPHAKIC

bull 2) Already had a course of treatment with laseranti-VEGF + PSEUDOPHAKIC ie SWITCHING from anti-VEGF to steroid

bull Plus

bull ldquochronicrdquo DMO ndash 3 years duration in FAME (18months) for ILUVIEN

bull Chronic DMO not essential for Ozurdex

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

Protocol T ndash patients may not improve in first 6 months

RIDE

RISE

Mea

n ch

ange

in B

CVA

(E

TDR

S le

tters

)M

ean

chan

ge in

BC

VA

(ETD

RS

lette

rs)

Time (months)

RISE and RIDE (Lucentis monthly dosing) Mean change in BCVA over 36 months

Brown DM et al Ophthalmology 2013120(10)2013ndash2022

54

Ranibizumab 03 mgRanibizumab 05 mgShamranibizumab 05 mg

Date of Prep Dec 2014 LGB0820147252X

VA improvement continues throughout year 1 with monthly dosing

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user ndash more than protocol

I

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

DRCRN protocol I5 year outcomesInjections 8-9 in year 1Year 2 = 2-3Year 3= 1-2Year 4 = 0-1Year 5 = 0

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

Wait for plateau = stability in protocol T laserPatient factors again

Judgement of response to anti-VEGF ndashtimeframe

bull Wait 6 months in poor responders

bull Wait 1 year for heavy users

bull Tempting to try steroids earlier than this ifbull No glaucoma ndash not a deal breaker Ozurdex better short term optionbull Pseudophakic

bull Clues from the diseasebull chronic

bull PATIENT FACTORS

bull Any eyes avoid steroids ndash advanced glaucomaCSCR Or prior viral retinitis RARE

bull Any eyes avoid anti-VEGF pregnancytrying to concieve recent CVA

BIOMARKERS AT BASELINE WOULD BE USEFULRESTORE subgroup analysis of OCT features

bull Andreas Pollreisz EURETINA 2015

bull OCT biomarkers (RESTORE data)

bull Better effects with anti-VEGF ifbull Small rather than large intra-retinal cyst

bull Sub-retinal fluid present

bull Vitreo-macular adhesion at baseline

bull No disruption of ELM and ISOS junction

bull No disorganisation of inner retinal layers (DRIL)

RESTORE subgroup analysis of OCT features

bull Andreas Pollreisz EURETINA 2015

bull OCT biomarkers (RESTORE data)

bull Better effects with anti-VEGF ifbull Small rather than large intra-retinal cyst

bull Sub-retinal fluid present

bull Vitreo-macular adhesion at baseline

bull No disruption of ELM and ISOS junction

bull No disorganisation of inner retinal layers (DRIL)

Better baseline characterisationclassificationERG Contrast sensitivityOCT AngiographyMicroperimetry= clues as to who responds best to which drug

Plan for this presentation helliphellipa long list

bull What treatment options are available for DMO (evidence base)

bull What treatment should I start with at baselinebull Re-treatment algorithms for intravitreal DMO therapiesbull When should I switchcombine therapiesbull The bigger picture

bull Other eyebull The patient as a wholebull The service -coping with capacity ndash compromises

The bigger pictureOther eyeThe patient as a wholeThe service -coping with capacity ndash compromises

bull OTHER EYE ndash may create problems

bull Treat and extend ndash ldquoreduce of visitsrdquo plus Eylea license ndash ldquono need for monitoringrdquo may not benefit if lots of visits due to PDR other eye

bull PERIPHERAL RETINA anti-VEGF supresses proliferative disease - Rebound on stopping Rx

bull PATIENT

bull Anti-VEGF ndash heavy user - Will comply

bull One stop much better than two stop for patient ndash Treat and extend

bull SERVICE

bull Capacity and demand planning = fixedT+E more predictable at least 1 month in advance ndash flexible nurse injectors

bull Steroids ndash even if well controlled (Iluvien for 3 years) need IOP check

bull Need pan-retinal examination both eyes ndash separate visits

Summary

CSMO

No centre involvement

Photocoagulation

Centre involvement

gt 78 letters(normalminimally reduced VA)

Photocoagulation

VA 78ndash24 letters

Phakic

Anti-VEGF

Pseudophakic

Anti-VEGF

SWITCHglaucoma

Injection tolerance

Medical issuesrecent CVA

Peripheral diseaseBilateral Rx

CSMO

No centre involvement

LASER

Centre involvement

gt 78 letters(normalminimally

reduced VA)

VA 78ndash24 letters

EYLEA OR LUCENTIS OR AVASTIN

Funding issues

Protocol T ndash poor VA lt 65 letters (615)

LOADING

Monthly injections until stability OR 5 x 112 (EYLEA) = 6 MONTHS then 8 weeks

RETREATMENT1

TREAT AND EXTEND - PRN

PRN

PSEUDOPHAKIC

Prior Rx

ILUVIEN

Chronic disease

OZURDEX

RETREATMENT

OZURDEX

OCT gt175um or any residual oedema

ILUVIEN after 12 months if risksltbenefits

OCT

gt400um

bull FACE TO FACE CLINICS RUNNING IN PARALLEL

bull = MAC002 every 6 months (optom or doctor) routine check for cataracttolerance of injectionsglaucoma issues etc

bull =MAC003 (DOCTOR) for problems as needed no fixed intervalDischargestop treatmentDeclines treatment diagnosis CSR overlay etcswitch drugs

bull =RV002- (DOCTOR) every 6 months

bull =DM002 ndash (DOCTOR) variable interval determined by last assessing doctor

bull First visit at 6 months from 1st injection if mild NPDR

bull Otherwise determined by retinopathy generally

LOADING PHASE

EyleaLucentis 1 within 48hrs of baseline

EyleaLucentis 2 (and LogMAR VA plus OCT same visit)

EyleaLucentis 3 (and LogMAR VA plus OCT same visit)

EyleaLucentis 4 (TEinj)(and Logmar VA plus OCT same visit

AFTER INJECTION 4 data goes off to be reviewed immediately as a hellip

TREAT AND EXTEND assessment ndash the next interval will depend on the response to the loading phase

NB -DMO patients ndash majority (95) will need 6 injctions x 112 of Lucentis

OR Eylea 5 x 112 then 8 weekly

ONCE STABLE for 3 x injection in TE phase

VIRTUAL CLINIC MONITORING OF MACULOPATHY AND PRN RETREATMENT

ANTI-VEGF INJECTION PATHWAYS Baseline visitMAC001 for wet AMDRV001 for CRVOBRVOMed ret clinic for DMO

Pathways ndash too many directions

Better that thanhellip

Thank you

bull Patients receiving escape medication were exited from MEAD before administration1

bull Macular laser rescue treatment allowed in RISERIDE (Lucentisreg) from 3 months2

bull Focalgrid laser allowed in FAME (Iluvienreg) from 6 weeks3

MEAD TREATMENT PROTOCOL

bull First treatment given at randomisation (day 0) bull Patients assessed for retreatment eligibility every 3 months from

months 6ndash36bull Patients were eligible for retreatment if

OCT optical coherence tomography

ge6 months since most recent

study treatment

Retinal thickness in 1 mm central macular

subfield by OCT gt175 microm

Evidence of residual retinal oedema (intraretinal cysts or

any regions of increased retinal thickening) as assessed by

investigator from OCT

AND OR

MEA

D

Amendment in May 2010 revised anatomic criterion for retreatment before this time the threshold was gt225 microm1Boyer DS et al Ophthalmology 2014 121 1904-19142Nguyen QD et al Ophthalmology 20121191064minus10773Campochiaro PA et al Ophthalmology 2011118626ndash635

Treatment burdenILUVIEN

Control(n =112)

02 microgd FAc(n =209)

Study Treatments(sham injection or ILUVIEN 02 microgday or FAc 05microgday)

1 treatment 661 761

2 treatments 277 187

ge 3 treatments 63 53

Rescue Laser Treatments (at masked physicianrsquos discretion after week 6)

Patients 607 407

Off-Protocol Treatments (IVTA bevacizumab ranibizumab intravitreal dexamethasone)

Patients 295 115

OZURDEX = 23injections year 1 41 by year 3

No other Rx

Summary of side effects with intravitreal steroids

Drug device Evidence base Cataract risk IOP rise (requiring drops)

Glaucoma surgery

endophthalmitis

ILUVIEN FAME studies 80 cat surgery(273 sham)

384(14 control)

48 0

Ozurdex MEAD 592 had cataract surgery(72 sham)

215 (end of study)(34 sham)

06 0

Trivaris+ laser vs Luc+laserx2 vs laser

Protocol IOphthalmology 2010

15 42(ONE OFgt10mmHg risegt30mmHGStart drops)

2186 0

NICE guidance for intravitreal steroids in DMO

bull Iluvien

bull NICE TA 301 Iluvien for DMO Nov 2013

bull hellipfor treating chronic diabetic macular oedema that is insufficiently responsive to available therapies only if

bull the implant is to be used in an eye with an intraocular

(pseudophakic) lens and

bull the manufacturer provides fluocinolone acetonide intravitreal implant with the discount agreed in the patient access scheme

NICE guidance for intravitreal steroids in DMO

bull Ozurdex

bull NICE TA 349 Ozurdex for DMO July 2015

bull there is an artificial lens in the eye to be treated and

bull their diabetic macular oedema has not improved with

non-corticosteroid treatment or such treatment is not suitable for them

Steroids = second line therapyWhen do I switch

bull Anti-VEGF first line for centre involving DMObull NICE TA ndash ldquoinsufficiently responsiverdquo ldquo ldquonot improvedrdquo ldquonot suitablerdquo ndash

OTHER TREATMENTS

bull 2 scenariosbull 1) Anti-VEGF canrsquot be funded ie OCTlt400um + PSEUDOPHAKIC

bull 2) Already had a course of treatment with laseranti-VEGF + PSEUDOPHAKIC ie SWITCHING from anti-VEGF to steroid

bull Plus

bull ldquochronicrdquo DMO ndash 3 years duration in FAME (18months) for ILUVIEN

bull Chronic DMO not essential for Ozurdex

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

Protocol T ndash patients may not improve in first 6 months

RIDE

RISE

Mea

n ch

ange

in B

CVA

(E

TDR

S le

tters

)M

ean

chan

ge in

BC

VA

(ETD

RS

lette

rs)

Time (months)

RISE and RIDE (Lucentis monthly dosing) Mean change in BCVA over 36 months

Brown DM et al Ophthalmology 2013120(10)2013ndash2022

54

Ranibizumab 03 mgRanibizumab 05 mgShamranibizumab 05 mg

Date of Prep Dec 2014 LGB0820147252X

VA improvement continues throughout year 1 with monthly dosing

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user ndash more than protocol

I

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

DRCRN protocol I5 year outcomesInjections 8-9 in year 1Year 2 = 2-3Year 3= 1-2Year 4 = 0-1Year 5 = 0

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

Wait for plateau = stability in protocol T laserPatient factors again

Judgement of response to anti-VEGF ndashtimeframe

bull Wait 6 months in poor responders

bull Wait 1 year for heavy users

bull Tempting to try steroids earlier than this ifbull No glaucoma ndash not a deal breaker Ozurdex better short term optionbull Pseudophakic

bull Clues from the diseasebull chronic

bull PATIENT FACTORS

bull Any eyes avoid steroids ndash advanced glaucomaCSCR Or prior viral retinitis RARE

bull Any eyes avoid anti-VEGF pregnancytrying to concieve recent CVA

BIOMARKERS AT BASELINE WOULD BE USEFULRESTORE subgroup analysis of OCT features

bull Andreas Pollreisz EURETINA 2015

bull OCT biomarkers (RESTORE data)

bull Better effects with anti-VEGF ifbull Small rather than large intra-retinal cyst

bull Sub-retinal fluid present

bull Vitreo-macular adhesion at baseline

bull No disruption of ELM and ISOS junction

bull No disorganisation of inner retinal layers (DRIL)

RESTORE subgroup analysis of OCT features

bull Andreas Pollreisz EURETINA 2015

bull OCT biomarkers (RESTORE data)

bull Better effects with anti-VEGF ifbull Small rather than large intra-retinal cyst

bull Sub-retinal fluid present

bull Vitreo-macular adhesion at baseline

bull No disruption of ELM and ISOS junction

bull No disorganisation of inner retinal layers (DRIL)

Better baseline characterisationclassificationERG Contrast sensitivityOCT AngiographyMicroperimetry= clues as to who responds best to which drug

Plan for this presentation helliphellipa long list

bull What treatment options are available for DMO (evidence base)

bull What treatment should I start with at baselinebull Re-treatment algorithms for intravitreal DMO therapiesbull When should I switchcombine therapiesbull The bigger picture

bull Other eyebull The patient as a wholebull The service -coping with capacity ndash compromises

The bigger pictureOther eyeThe patient as a wholeThe service -coping with capacity ndash compromises

bull OTHER EYE ndash may create problems

bull Treat and extend ndash ldquoreduce of visitsrdquo plus Eylea license ndash ldquono need for monitoringrdquo may not benefit if lots of visits due to PDR other eye

bull PERIPHERAL RETINA anti-VEGF supresses proliferative disease - Rebound on stopping Rx

bull PATIENT

bull Anti-VEGF ndash heavy user - Will comply

bull One stop much better than two stop for patient ndash Treat and extend

bull SERVICE

bull Capacity and demand planning = fixedT+E more predictable at least 1 month in advance ndash flexible nurse injectors

bull Steroids ndash even if well controlled (Iluvien for 3 years) need IOP check

bull Need pan-retinal examination both eyes ndash separate visits

Summary

CSMO

No centre involvement

Photocoagulation

Centre involvement

gt 78 letters(normalminimally reduced VA)

Photocoagulation

VA 78ndash24 letters

Phakic

Anti-VEGF

Pseudophakic

Anti-VEGF

SWITCHglaucoma

Injection tolerance

Medical issuesrecent CVA

Peripheral diseaseBilateral Rx

CSMO

No centre involvement

LASER

Centre involvement

gt 78 letters(normalminimally

reduced VA)

VA 78ndash24 letters

EYLEA OR LUCENTIS OR AVASTIN

Funding issues

Protocol T ndash poor VA lt 65 letters (615)

LOADING

Monthly injections until stability OR 5 x 112 (EYLEA) = 6 MONTHS then 8 weeks

RETREATMENT1

TREAT AND EXTEND - PRN

PRN

PSEUDOPHAKIC

Prior Rx

ILUVIEN

Chronic disease

OZURDEX

RETREATMENT

OZURDEX

OCT gt175um or any residual oedema

ILUVIEN after 12 months if risksltbenefits

OCT

gt400um

bull FACE TO FACE CLINICS RUNNING IN PARALLEL

bull = MAC002 every 6 months (optom or doctor) routine check for cataracttolerance of injectionsglaucoma issues etc

bull =MAC003 (DOCTOR) for problems as needed no fixed intervalDischargestop treatmentDeclines treatment diagnosis CSR overlay etcswitch drugs

bull =RV002- (DOCTOR) every 6 months

bull =DM002 ndash (DOCTOR) variable interval determined by last assessing doctor

bull First visit at 6 months from 1st injection if mild NPDR

bull Otherwise determined by retinopathy generally

LOADING PHASE

EyleaLucentis 1 within 48hrs of baseline

EyleaLucentis 2 (and LogMAR VA plus OCT same visit)

EyleaLucentis 3 (and LogMAR VA plus OCT same visit)

EyleaLucentis 4 (TEinj)(and Logmar VA plus OCT same visit

AFTER INJECTION 4 data goes off to be reviewed immediately as a hellip

TREAT AND EXTEND assessment ndash the next interval will depend on the response to the loading phase

NB -DMO patients ndash majority (95) will need 6 injctions x 112 of Lucentis

OR Eylea 5 x 112 then 8 weekly

ONCE STABLE for 3 x injection in TE phase

VIRTUAL CLINIC MONITORING OF MACULOPATHY AND PRN RETREATMENT

ANTI-VEGF INJECTION PATHWAYS Baseline visitMAC001 for wet AMDRV001 for CRVOBRVOMed ret clinic for DMO

Pathways ndash too many directions

Better that thanhellip

Thank you

Treatment burdenILUVIEN

Control(n =112)

02 microgd FAc(n =209)

Study Treatments(sham injection or ILUVIEN 02 microgday or FAc 05microgday)

1 treatment 661 761

2 treatments 277 187

ge 3 treatments 63 53

Rescue Laser Treatments (at masked physicianrsquos discretion after week 6)

Patients 607 407

Off-Protocol Treatments (IVTA bevacizumab ranibizumab intravitreal dexamethasone)

Patients 295 115

OZURDEX = 23injections year 1 41 by year 3

No other Rx

Summary of side effects with intravitreal steroids

Drug device Evidence base Cataract risk IOP rise (requiring drops)

Glaucoma surgery

endophthalmitis

ILUVIEN FAME studies 80 cat surgery(273 sham)

384(14 control)

48 0

Ozurdex MEAD 592 had cataract surgery(72 sham)

215 (end of study)(34 sham)

06 0

Trivaris+ laser vs Luc+laserx2 vs laser

Protocol IOphthalmology 2010

15 42(ONE OFgt10mmHg risegt30mmHGStart drops)

2186 0

NICE guidance for intravitreal steroids in DMO

bull Iluvien

bull NICE TA 301 Iluvien for DMO Nov 2013

bull hellipfor treating chronic diabetic macular oedema that is insufficiently responsive to available therapies only if

bull the implant is to be used in an eye with an intraocular

(pseudophakic) lens and

bull the manufacturer provides fluocinolone acetonide intravitreal implant with the discount agreed in the patient access scheme

NICE guidance for intravitreal steroids in DMO

bull Ozurdex

bull NICE TA 349 Ozurdex for DMO July 2015

bull there is an artificial lens in the eye to be treated and

bull their diabetic macular oedema has not improved with

non-corticosteroid treatment or such treatment is not suitable for them

Steroids = second line therapyWhen do I switch

bull Anti-VEGF first line for centre involving DMObull NICE TA ndash ldquoinsufficiently responsiverdquo ldquo ldquonot improvedrdquo ldquonot suitablerdquo ndash

OTHER TREATMENTS

bull 2 scenariosbull 1) Anti-VEGF canrsquot be funded ie OCTlt400um + PSEUDOPHAKIC

bull 2) Already had a course of treatment with laseranti-VEGF + PSEUDOPHAKIC ie SWITCHING from anti-VEGF to steroid

bull Plus

bull ldquochronicrdquo DMO ndash 3 years duration in FAME (18months) for ILUVIEN

bull Chronic DMO not essential for Ozurdex

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

Protocol T ndash patients may not improve in first 6 months

RIDE

RISE

Mea

n ch

ange

in B

CVA

(E

TDR

S le

tters

)M

ean

chan

ge in

BC

VA

(ETD

RS

lette

rs)

Time (months)

RISE and RIDE (Lucentis monthly dosing) Mean change in BCVA over 36 months

Brown DM et al Ophthalmology 2013120(10)2013ndash2022

54

Ranibizumab 03 mgRanibizumab 05 mgShamranibizumab 05 mg

Date of Prep Dec 2014 LGB0820147252X

VA improvement continues throughout year 1 with monthly dosing

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user ndash more than protocol

I

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

DRCRN protocol I5 year outcomesInjections 8-9 in year 1Year 2 = 2-3Year 3= 1-2Year 4 = 0-1Year 5 = 0

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

Wait for plateau = stability in protocol T laserPatient factors again

Judgement of response to anti-VEGF ndashtimeframe

bull Wait 6 months in poor responders

bull Wait 1 year for heavy users

bull Tempting to try steroids earlier than this ifbull No glaucoma ndash not a deal breaker Ozurdex better short term optionbull Pseudophakic

bull Clues from the diseasebull chronic

bull PATIENT FACTORS

bull Any eyes avoid steroids ndash advanced glaucomaCSCR Or prior viral retinitis RARE

bull Any eyes avoid anti-VEGF pregnancytrying to concieve recent CVA

BIOMARKERS AT BASELINE WOULD BE USEFULRESTORE subgroup analysis of OCT features

bull Andreas Pollreisz EURETINA 2015

bull OCT biomarkers (RESTORE data)

bull Better effects with anti-VEGF ifbull Small rather than large intra-retinal cyst

bull Sub-retinal fluid present

bull Vitreo-macular adhesion at baseline

bull No disruption of ELM and ISOS junction

bull No disorganisation of inner retinal layers (DRIL)

RESTORE subgroup analysis of OCT features

bull Andreas Pollreisz EURETINA 2015

bull OCT biomarkers (RESTORE data)

bull Better effects with anti-VEGF ifbull Small rather than large intra-retinal cyst

bull Sub-retinal fluid present

bull Vitreo-macular adhesion at baseline

bull No disruption of ELM and ISOS junction

bull No disorganisation of inner retinal layers (DRIL)

Better baseline characterisationclassificationERG Contrast sensitivityOCT AngiographyMicroperimetry= clues as to who responds best to which drug

Plan for this presentation helliphellipa long list

bull What treatment options are available for DMO (evidence base)

bull What treatment should I start with at baselinebull Re-treatment algorithms for intravitreal DMO therapiesbull When should I switchcombine therapiesbull The bigger picture

bull Other eyebull The patient as a wholebull The service -coping with capacity ndash compromises

The bigger pictureOther eyeThe patient as a wholeThe service -coping with capacity ndash compromises

bull OTHER EYE ndash may create problems

bull Treat and extend ndash ldquoreduce of visitsrdquo plus Eylea license ndash ldquono need for monitoringrdquo may not benefit if lots of visits due to PDR other eye

bull PERIPHERAL RETINA anti-VEGF supresses proliferative disease - Rebound on stopping Rx

bull PATIENT

bull Anti-VEGF ndash heavy user - Will comply

bull One stop much better than two stop for patient ndash Treat and extend

bull SERVICE

bull Capacity and demand planning = fixedT+E more predictable at least 1 month in advance ndash flexible nurse injectors

bull Steroids ndash even if well controlled (Iluvien for 3 years) need IOP check

bull Need pan-retinal examination both eyes ndash separate visits

Summary

CSMO

No centre involvement

Photocoagulation

Centre involvement

gt 78 letters(normalminimally reduced VA)

Photocoagulation

VA 78ndash24 letters

Phakic

Anti-VEGF

Pseudophakic

Anti-VEGF

SWITCHglaucoma

Injection tolerance

Medical issuesrecent CVA

Peripheral diseaseBilateral Rx

CSMO

No centre involvement

LASER

Centre involvement

gt 78 letters(normalminimally

reduced VA)

VA 78ndash24 letters

EYLEA OR LUCENTIS OR AVASTIN

Funding issues

Protocol T ndash poor VA lt 65 letters (615)

LOADING

Monthly injections until stability OR 5 x 112 (EYLEA) = 6 MONTHS then 8 weeks

RETREATMENT1

TREAT AND EXTEND - PRN

PRN

PSEUDOPHAKIC

Prior Rx

ILUVIEN

Chronic disease

OZURDEX

RETREATMENT

OZURDEX

OCT gt175um or any residual oedema

ILUVIEN after 12 months if risksltbenefits

OCT

gt400um

bull FACE TO FACE CLINICS RUNNING IN PARALLEL

bull = MAC002 every 6 months (optom or doctor) routine check for cataracttolerance of injectionsglaucoma issues etc

bull =MAC003 (DOCTOR) for problems as needed no fixed intervalDischargestop treatmentDeclines treatment diagnosis CSR overlay etcswitch drugs

bull =RV002- (DOCTOR) every 6 months

bull =DM002 ndash (DOCTOR) variable interval determined by last assessing doctor

bull First visit at 6 months from 1st injection if mild NPDR

bull Otherwise determined by retinopathy generally

LOADING PHASE

EyleaLucentis 1 within 48hrs of baseline

EyleaLucentis 2 (and LogMAR VA plus OCT same visit)

EyleaLucentis 3 (and LogMAR VA plus OCT same visit)

EyleaLucentis 4 (TEinj)(and Logmar VA plus OCT same visit

AFTER INJECTION 4 data goes off to be reviewed immediately as a hellip

TREAT AND EXTEND assessment ndash the next interval will depend on the response to the loading phase

NB -DMO patients ndash majority (95) will need 6 injctions x 112 of Lucentis

OR Eylea 5 x 112 then 8 weekly

ONCE STABLE for 3 x injection in TE phase

VIRTUAL CLINIC MONITORING OF MACULOPATHY AND PRN RETREATMENT

ANTI-VEGF INJECTION PATHWAYS Baseline visitMAC001 for wet AMDRV001 for CRVOBRVOMed ret clinic for DMO

Pathways ndash too many directions

Better that thanhellip

Thank you

Summary of side effects with intravitreal steroids

Drug device Evidence base Cataract risk IOP rise (requiring drops)

Glaucoma surgery

endophthalmitis

ILUVIEN FAME studies 80 cat surgery(273 sham)

384(14 control)

48 0

Ozurdex MEAD 592 had cataract surgery(72 sham)

215 (end of study)(34 sham)

06 0

Trivaris+ laser vs Luc+laserx2 vs laser

Protocol IOphthalmology 2010

15 42(ONE OFgt10mmHg risegt30mmHGStart drops)

2186 0

NICE guidance for intravitreal steroids in DMO

bull Iluvien

bull NICE TA 301 Iluvien for DMO Nov 2013

bull hellipfor treating chronic diabetic macular oedema that is insufficiently responsive to available therapies only if

bull the implant is to be used in an eye with an intraocular

(pseudophakic) lens and

bull the manufacturer provides fluocinolone acetonide intravitreal implant with the discount agreed in the patient access scheme

NICE guidance for intravitreal steroids in DMO

bull Ozurdex

bull NICE TA 349 Ozurdex for DMO July 2015

bull there is an artificial lens in the eye to be treated and

bull their diabetic macular oedema has not improved with

non-corticosteroid treatment or such treatment is not suitable for them

Steroids = second line therapyWhen do I switch

bull Anti-VEGF first line for centre involving DMObull NICE TA ndash ldquoinsufficiently responsiverdquo ldquo ldquonot improvedrdquo ldquonot suitablerdquo ndash

OTHER TREATMENTS

bull 2 scenariosbull 1) Anti-VEGF canrsquot be funded ie OCTlt400um + PSEUDOPHAKIC

bull 2) Already had a course of treatment with laseranti-VEGF + PSEUDOPHAKIC ie SWITCHING from anti-VEGF to steroid

bull Plus

bull ldquochronicrdquo DMO ndash 3 years duration in FAME (18months) for ILUVIEN

bull Chronic DMO not essential for Ozurdex

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

Protocol T ndash patients may not improve in first 6 months

RIDE

RISE

Mea

n ch

ange

in B

CVA

(E

TDR

S le

tters

)M

ean

chan

ge in

BC

VA

(ETD

RS

lette

rs)

Time (months)

RISE and RIDE (Lucentis monthly dosing) Mean change in BCVA over 36 months

Brown DM et al Ophthalmology 2013120(10)2013ndash2022

54

Ranibizumab 03 mgRanibizumab 05 mgShamranibizumab 05 mg

Date of Prep Dec 2014 LGB0820147252X

VA improvement continues throughout year 1 with monthly dosing

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user ndash more than protocol

I

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

DRCRN protocol I5 year outcomesInjections 8-9 in year 1Year 2 = 2-3Year 3= 1-2Year 4 = 0-1Year 5 = 0

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

Wait for plateau = stability in protocol T laserPatient factors again

Judgement of response to anti-VEGF ndashtimeframe

bull Wait 6 months in poor responders

bull Wait 1 year for heavy users

bull Tempting to try steroids earlier than this ifbull No glaucoma ndash not a deal breaker Ozurdex better short term optionbull Pseudophakic

bull Clues from the diseasebull chronic

bull PATIENT FACTORS

bull Any eyes avoid steroids ndash advanced glaucomaCSCR Or prior viral retinitis RARE

bull Any eyes avoid anti-VEGF pregnancytrying to concieve recent CVA

BIOMARKERS AT BASELINE WOULD BE USEFULRESTORE subgroup analysis of OCT features

bull Andreas Pollreisz EURETINA 2015

bull OCT biomarkers (RESTORE data)

bull Better effects with anti-VEGF ifbull Small rather than large intra-retinal cyst

bull Sub-retinal fluid present

bull Vitreo-macular adhesion at baseline

bull No disruption of ELM and ISOS junction

bull No disorganisation of inner retinal layers (DRIL)

RESTORE subgroup analysis of OCT features

bull Andreas Pollreisz EURETINA 2015

bull OCT biomarkers (RESTORE data)

bull Better effects with anti-VEGF ifbull Small rather than large intra-retinal cyst

bull Sub-retinal fluid present

bull Vitreo-macular adhesion at baseline

bull No disruption of ELM and ISOS junction

bull No disorganisation of inner retinal layers (DRIL)

Better baseline characterisationclassificationERG Contrast sensitivityOCT AngiographyMicroperimetry= clues as to who responds best to which drug

Plan for this presentation helliphellipa long list

bull What treatment options are available for DMO (evidence base)

bull What treatment should I start with at baselinebull Re-treatment algorithms for intravitreal DMO therapiesbull When should I switchcombine therapiesbull The bigger picture

bull Other eyebull The patient as a wholebull The service -coping with capacity ndash compromises

The bigger pictureOther eyeThe patient as a wholeThe service -coping with capacity ndash compromises

bull OTHER EYE ndash may create problems

bull Treat and extend ndash ldquoreduce of visitsrdquo plus Eylea license ndash ldquono need for monitoringrdquo may not benefit if lots of visits due to PDR other eye

bull PERIPHERAL RETINA anti-VEGF supresses proliferative disease - Rebound on stopping Rx

bull PATIENT

bull Anti-VEGF ndash heavy user - Will comply

bull One stop much better than two stop for patient ndash Treat and extend

bull SERVICE

bull Capacity and demand planning = fixedT+E more predictable at least 1 month in advance ndash flexible nurse injectors

bull Steroids ndash even if well controlled (Iluvien for 3 years) need IOP check

bull Need pan-retinal examination both eyes ndash separate visits

Summary

CSMO

No centre involvement

Photocoagulation

Centre involvement

gt 78 letters(normalminimally reduced VA)

Photocoagulation

VA 78ndash24 letters

Phakic

Anti-VEGF

Pseudophakic

Anti-VEGF

SWITCHglaucoma

Injection tolerance

Medical issuesrecent CVA

Peripheral diseaseBilateral Rx

CSMO

No centre involvement

LASER

Centre involvement

gt 78 letters(normalminimally

reduced VA)

VA 78ndash24 letters

EYLEA OR LUCENTIS OR AVASTIN

Funding issues

Protocol T ndash poor VA lt 65 letters (615)

LOADING

Monthly injections until stability OR 5 x 112 (EYLEA) = 6 MONTHS then 8 weeks

RETREATMENT1

TREAT AND EXTEND - PRN

PRN

PSEUDOPHAKIC

Prior Rx

ILUVIEN

Chronic disease

OZURDEX

RETREATMENT

OZURDEX

OCT gt175um or any residual oedema

ILUVIEN after 12 months if risksltbenefits

OCT

gt400um

bull FACE TO FACE CLINICS RUNNING IN PARALLEL

bull = MAC002 every 6 months (optom or doctor) routine check for cataracttolerance of injectionsglaucoma issues etc

bull =MAC003 (DOCTOR) for problems as needed no fixed intervalDischargestop treatmentDeclines treatment diagnosis CSR overlay etcswitch drugs

bull =RV002- (DOCTOR) every 6 months

bull =DM002 ndash (DOCTOR) variable interval determined by last assessing doctor

bull First visit at 6 months from 1st injection if mild NPDR

bull Otherwise determined by retinopathy generally

LOADING PHASE

EyleaLucentis 1 within 48hrs of baseline

EyleaLucentis 2 (and LogMAR VA plus OCT same visit)

EyleaLucentis 3 (and LogMAR VA plus OCT same visit)

EyleaLucentis 4 (TEinj)(and Logmar VA plus OCT same visit

AFTER INJECTION 4 data goes off to be reviewed immediately as a hellip

TREAT AND EXTEND assessment ndash the next interval will depend on the response to the loading phase

NB -DMO patients ndash majority (95) will need 6 injctions x 112 of Lucentis

OR Eylea 5 x 112 then 8 weekly

ONCE STABLE for 3 x injection in TE phase

VIRTUAL CLINIC MONITORING OF MACULOPATHY AND PRN RETREATMENT

ANTI-VEGF INJECTION PATHWAYS Baseline visitMAC001 for wet AMDRV001 for CRVOBRVOMed ret clinic for DMO

Pathways ndash too many directions

Better that thanhellip

Thank you

NICE guidance for intravitreal steroids in DMO

bull Iluvien

bull NICE TA 301 Iluvien for DMO Nov 2013

bull hellipfor treating chronic diabetic macular oedema that is insufficiently responsive to available therapies only if

bull the implant is to be used in an eye with an intraocular

(pseudophakic) lens and

bull the manufacturer provides fluocinolone acetonide intravitreal implant with the discount agreed in the patient access scheme

NICE guidance for intravitreal steroids in DMO

bull Ozurdex

bull NICE TA 349 Ozurdex for DMO July 2015

bull there is an artificial lens in the eye to be treated and

bull their diabetic macular oedema has not improved with

non-corticosteroid treatment or such treatment is not suitable for them

Steroids = second line therapyWhen do I switch

bull Anti-VEGF first line for centre involving DMObull NICE TA ndash ldquoinsufficiently responsiverdquo ldquo ldquonot improvedrdquo ldquonot suitablerdquo ndash

OTHER TREATMENTS

bull 2 scenariosbull 1) Anti-VEGF canrsquot be funded ie OCTlt400um + PSEUDOPHAKIC

bull 2) Already had a course of treatment with laseranti-VEGF + PSEUDOPHAKIC ie SWITCHING from anti-VEGF to steroid

bull Plus

bull ldquochronicrdquo DMO ndash 3 years duration in FAME (18months) for ILUVIEN

bull Chronic DMO not essential for Ozurdex

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

Protocol T ndash patients may not improve in first 6 months

RIDE

RISE

Mea

n ch

ange

in B

CVA

(E

TDR

S le

tters

)M

ean

chan

ge in

BC

VA

(ETD

RS

lette

rs)

Time (months)

RISE and RIDE (Lucentis monthly dosing) Mean change in BCVA over 36 months

Brown DM et al Ophthalmology 2013120(10)2013ndash2022

54

Ranibizumab 03 mgRanibizumab 05 mgShamranibizumab 05 mg

Date of Prep Dec 2014 LGB0820147252X

VA improvement continues throughout year 1 with monthly dosing

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user ndash more than protocol

I

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

DRCRN protocol I5 year outcomesInjections 8-9 in year 1Year 2 = 2-3Year 3= 1-2Year 4 = 0-1Year 5 = 0

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

Wait for plateau = stability in protocol T laserPatient factors again

Judgement of response to anti-VEGF ndashtimeframe

bull Wait 6 months in poor responders

bull Wait 1 year for heavy users

bull Tempting to try steroids earlier than this ifbull No glaucoma ndash not a deal breaker Ozurdex better short term optionbull Pseudophakic

bull Clues from the diseasebull chronic

bull PATIENT FACTORS

bull Any eyes avoid steroids ndash advanced glaucomaCSCR Or prior viral retinitis RARE

bull Any eyes avoid anti-VEGF pregnancytrying to concieve recent CVA

BIOMARKERS AT BASELINE WOULD BE USEFULRESTORE subgroup analysis of OCT features

bull Andreas Pollreisz EURETINA 2015

bull OCT biomarkers (RESTORE data)

bull Better effects with anti-VEGF ifbull Small rather than large intra-retinal cyst

bull Sub-retinal fluid present

bull Vitreo-macular adhesion at baseline

bull No disruption of ELM and ISOS junction

bull No disorganisation of inner retinal layers (DRIL)

RESTORE subgroup analysis of OCT features

bull Andreas Pollreisz EURETINA 2015

bull OCT biomarkers (RESTORE data)

bull Better effects with anti-VEGF ifbull Small rather than large intra-retinal cyst

bull Sub-retinal fluid present

bull Vitreo-macular adhesion at baseline

bull No disruption of ELM and ISOS junction

bull No disorganisation of inner retinal layers (DRIL)

Better baseline characterisationclassificationERG Contrast sensitivityOCT AngiographyMicroperimetry= clues as to who responds best to which drug

Plan for this presentation helliphellipa long list

bull What treatment options are available for DMO (evidence base)

bull What treatment should I start with at baselinebull Re-treatment algorithms for intravitreal DMO therapiesbull When should I switchcombine therapiesbull The bigger picture

bull Other eyebull The patient as a wholebull The service -coping with capacity ndash compromises

The bigger pictureOther eyeThe patient as a wholeThe service -coping with capacity ndash compromises

bull OTHER EYE ndash may create problems

bull Treat and extend ndash ldquoreduce of visitsrdquo plus Eylea license ndash ldquono need for monitoringrdquo may not benefit if lots of visits due to PDR other eye

bull PERIPHERAL RETINA anti-VEGF supresses proliferative disease - Rebound on stopping Rx

bull PATIENT

bull Anti-VEGF ndash heavy user - Will comply

bull One stop much better than two stop for patient ndash Treat and extend

bull SERVICE

bull Capacity and demand planning = fixedT+E more predictable at least 1 month in advance ndash flexible nurse injectors

bull Steroids ndash even if well controlled (Iluvien for 3 years) need IOP check

bull Need pan-retinal examination both eyes ndash separate visits

Summary

CSMO

No centre involvement

Photocoagulation

Centre involvement

gt 78 letters(normalminimally reduced VA)

Photocoagulation

VA 78ndash24 letters

Phakic

Anti-VEGF

Pseudophakic

Anti-VEGF

SWITCHglaucoma

Injection tolerance

Medical issuesrecent CVA

Peripheral diseaseBilateral Rx

CSMO

No centre involvement

LASER

Centre involvement

gt 78 letters(normalminimally

reduced VA)

VA 78ndash24 letters

EYLEA OR LUCENTIS OR AVASTIN

Funding issues

Protocol T ndash poor VA lt 65 letters (615)

LOADING

Monthly injections until stability OR 5 x 112 (EYLEA) = 6 MONTHS then 8 weeks

RETREATMENT1

TREAT AND EXTEND - PRN

PRN

PSEUDOPHAKIC

Prior Rx

ILUVIEN

Chronic disease

OZURDEX

RETREATMENT

OZURDEX

OCT gt175um or any residual oedema

ILUVIEN after 12 months if risksltbenefits

OCT

gt400um

bull FACE TO FACE CLINICS RUNNING IN PARALLEL

bull = MAC002 every 6 months (optom or doctor) routine check for cataracttolerance of injectionsglaucoma issues etc

bull =MAC003 (DOCTOR) for problems as needed no fixed intervalDischargestop treatmentDeclines treatment diagnosis CSR overlay etcswitch drugs

bull =RV002- (DOCTOR) every 6 months

bull =DM002 ndash (DOCTOR) variable interval determined by last assessing doctor

bull First visit at 6 months from 1st injection if mild NPDR

bull Otherwise determined by retinopathy generally

LOADING PHASE

EyleaLucentis 1 within 48hrs of baseline

EyleaLucentis 2 (and LogMAR VA plus OCT same visit)

EyleaLucentis 3 (and LogMAR VA plus OCT same visit)

EyleaLucentis 4 (TEinj)(and Logmar VA plus OCT same visit

AFTER INJECTION 4 data goes off to be reviewed immediately as a hellip

TREAT AND EXTEND assessment ndash the next interval will depend on the response to the loading phase

NB -DMO patients ndash majority (95) will need 6 injctions x 112 of Lucentis

OR Eylea 5 x 112 then 8 weekly

ONCE STABLE for 3 x injection in TE phase

VIRTUAL CLINIC MONITORING OF MACULOPATHY AND PRN RETREATMENT

ANTI-VEGF INJECTION PATHWAYS Baseline visitMAC001 for wet AMDRV001 for CRVOBRVOMed ret clinic for DMO

Pathways ndash too many directions

Better that thanhellip

Thank you

NICE guidance for intravitreal steroids in DMO

bull Ozurdex

bull NICE TA 349 Ozurdex for DMO July 2015

bull there is an artificial lens in the eye to be treated and

bull their diabetic macular oedema has not improved with

non-corticosteroid treatment or such treatment is not suitable for them

Steroids = second line therapyWhen do I switch

bull Anti-VEGF first line for centre involving DMObull NICE TA ndash ldquoinsufficiently responsiverdquo ldquo ldquonot improvedrdquo ldquonot suitablerdquo ndash

OTHER TREATMENTS

bull 2 scenariosbull 1) Anti-VEGF canrsquot be funded ie OCTlt400um + PSEUDOPHAKIC

bull 2) Already had a course of treatment with laseranti-VEGF + PSEUDOPHAKIC ie SWITCHING from anti-VEGF to steroid

bull Plus

bull ldquochronicrdquo DMO ndash 3 years duration in FAME (18months) for ILUVIEN

bull Chronic DMO not essential for Ozurdex

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

Protocol T ndash patients may not improve in first 6 months

RIDE

RISE

Mea

n ch

ange

in B

CVA

(E

TDR

S le

tters

)M

ean

chan

ge in

BC

VA

(ETD

RS

lette

rs)

Time (months)

RISE and RIDE (Lucentis monthly dosing) Mean change in BCVA over 36 months

Brown DM et al Ophthalmology 2013120(10)2013ndash2022

54

Ranibizumab 03 mgRanibizumab 05 mgShamranibizumab 05 mg

Date of Prep Dec 2014 LGB0820147252X

VA improvement continues throughout year 1 with monthly dosing

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user ndash more than protocol

I

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

DRCRN protocol I5 year outcomesInjections 8-9 in year 1Year 2 = 2-3Year 3= 1-2Year 4 = 0-1Year 5 = 0

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

Wait for plateau = stability in protocol T laserPatient factors again

Judgement of response to anti-VEGF ndashtimeframe

bull Wait 6 months in poor responders

bull Wait 1 year for heavy users

bull Tempting to try steroids earlier than this ifbull No glaucoma ndash not a deal breaker Ozurdex better short term optionbull Pseudophakic

bull Clues from the diseasebull chronic

bull PATIENT FACTORS

bull Any eyes avoid steroids ndash advanced glaucomaCSCR Or prior viral retinitis RARE

bull Any eyes avoid anti-VEGF pregnancytrying to concieve recent CVA

BIOMARKERS AT BASELINE WOULD BE USEFULRESTORE subgroup analysis of OCT features

bull Andreas Pollreisz EURETINA 2015

bull OCT biomarkers (RESTORE data)

bull Better effects with anti-VEGF ifbull Small rather than large intra-retinal cyst

bull Sub-retinal fluid present

bull Vitreo-macular adhesion at baseline

bull No disruption of ELM and ISOS junction

bull No disorganisation of inner retinal layers (DRIL)

RESTORE subgroup analysis of OCT features

bull Andreas Pollreisz EURETINA 2015

bull OCT biomarkers (RESTORE data)

bull Better effects with anti-VEGF ifbull Small rather than large intra-retinal cyst

bull Sub-retinal fluid present

bull Vitreo-macular adhesion at baseline

bull No disruption of ELM and ISOS junction

bull No disorganisation of inner retinal layers (DRIL)

Better baseline characterisationclassificationERG Contrast sensitivityOCT AngiographyMicroperimetry= clues as to who responds best to which drug

Plan for this presentation helliphellipa long list

bull What treatment options are available for DMO (evidence base)

bull What treatment should I start with at baselinebull Re-treatment algorithms for intravitreal DMO therapiesbull When should I switchcombine therapiesbull The bigger picture

bull Other eyebull The patient as a wholebull The service -coping with capacity ndash compromises

The bigger pictureOther eyeThe patient as a wholeThe service -coping with capacity ndash compromises

bull OTHER EYE ndash may create problems

bull Treat and extend ndash ldquoreduce of visitsrdquo plus Eylea license ndash ldquono need for monitoringrdquo may not benefit if lots of visits due to PDR other eye

bull PERIPHERAL RETINA anti-VEGF supresses proliferative disease - Rebound on stopping Rx

bull PATIENT

bull Anti-VEGF ndash heavy user - Will comply

bull One stop much better than two stop for patient ndash Treat and extend

bull SERVICE

bull Capacity and demand planning = fixedT+E more predictable at least 1 month in advance ndash flexible nurse injectors

bull Steroids ndash even if well controlled (Iluvien for 3 years) need IOP check

bull Need pan-retinal examination both eyes ndash separate visits

Summary

CSMO

No centre involvement

Photocoagulation

Centre involvement

gt 78 letters(normalminimally reduced VA)

Photocoagulation

VA 78ndash24 letters

Phakic

Anti-VEGF

Pseudophakic

Anti-VEGF

SWITCHglaucoma

Injection tolerance

Medical issuesrecent CVA

Peripheral diseaseBilateral Rx

CSMO

No centre involvement

LASER

Centre involvement

gt 78 letters(normalminimally

reduced VA)

VA 78ndash24 letters

EYLEA OR LUCENTIS OR AVASTIN

Funding issues

Protocol T ndash poor VA lt 65 letters (615)

LOADING

Monthly injections until stability OR 5 x 112 (EYLEA) = 6 MONTHS then 8 weeks

RETREATMENT1

TREAT AND EXTEND - PRN

PRN

PSEUDOPHAKIC

Prior Rx

ILUVIEN

Chronic disease

OZURDEX

RETREATMENT

OZURDEX

OCT gt175um or any residual oedema

ILUVIEN after 12 months if risksltbenefits

OCT

gt400um

bull FACE TO FACE CLINICS RUNNING IN PARALLEL

bull = MAC002 every 6 months (optom or doctor) routine check for cataracttolerance of injectionsglaucoma issues etc

bull =MAC003 (DOCTOR) for problems as needed no fixed intervalDischargestop treatmentDeclines treatment diagnosis CSR overlay etcswitch drugs

bull =RV002- (DOCTOR) every 6 months

bull =DM002 ndash (DOCTOR) variable interval determined by last assessing doctor

bull First visit at 6 months from 1st injection if mild NPDR

bull Otherwise determined by retinopathy generally

LOADING PHASE

EyleaLucentis 1 within 48hrs of baseline

EyleaLucentis 2 (and LogMAR VA plus OCT same visit)

EyleaLucentis 3 (and LogMAR VA plus OCT same visit)

EyleaLucentis 4 (TEinj)(and Logmar VA plus OCT same visit

AFTER INJECTION 4 data goes off to be reviewed immediately as a hellip

TREAT AND EXTEND assessment ndash the next interval will depend on the response to the loading phase

NB -DMO patients ndash majority (95) will need 6 injctions x 112 of Lucentis

OR Eylea 5 x 112 then 8 weekly

ONCE STABLE for 3 x injection in TE phase

VIRTUAL CLINIC MONITORING OF MACULOPATHY AND PRN RETREATMENT

ANTI-VEGF INJECTION PATHWAYS Baseline visitMAC001 for wet AMDRV001 for CRVOBRVOMed ret clinic for DMO

Pathways ndash too many directions

Better that thanhellip

Thank you

Steroids = second line therapyWhen do I switch

bull Anti-VEGF first line for centre involving DMObull NICE TA ndash ldquoinsufficiently responsiverdquo ldquo ldquonot improvedrdquo ldquonot suitablerdquo ndash

OTHER TREATMENTS

bull 2 scenariosbull 1) Anti-VEGF canrsquot be funded ie OCTlt400um + PSEUDOPHAKIC

bull 2) Already had a course of treatment with laseranti-VEGF + PSEUDOPHAKIC ie SWITCHING from anti-VEGF to steroid

bull Plus

bull ldquochronicrdquo DMO ndash 3 years duration in FAME (18months) for ILUVIEN

bull Chronic DMO not essential for Ozurdex

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

Protocol T ndash patients may not improve in first 6 months

RIDE

RISE

Mea

n ch

ange

in B

CVA

(E

TDR

S le

tters

)M

ean

chan

ge in

BC

VA

(ETD

RS

lette

rs)

Time (months)

RISE and RIDE (Lucentis monthly dosing) Mean change in BCVA over 36 months

Brown DM et al Ophthalmology 2013120(10)2013ndash2022

54

Ranibizumab 03 mgRanibizumab 05 mgShamranibizumab 05 mg

Date of Prep Dec 2014 LGB0820147252X

VA improvement continues throughout year 1 with monthly dosing

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user ndash more than protocol

I

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

DRCRN protocol I5 year outcomesInjections 8-9 in year 1Year 2 = 2-3Year 3= 1-2Year 4 = 0-1Year 5 = 0

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

Wait for plateau = stability in protocol T laserPatient factors again

Judgement of response to anti-VEGF ndashtimeframe

bull Wait 6 months in poor responders

bull Wait 1 year for heavy users

bull Tempting to try steroids earlier than this ifbull No glaucoma ndash not a deal breaker Ozurdex better short term optionbull Pseudophakic

bull Clues from the diseasebull chronic

bull PATIENT FACTORS

bull Any eyes avoid steroids ndash advanced glaucomaCSCR Or prior viral retinitis RARE

bull Any eyes avoid anti-VEGF pregnancytrying to concieve recent CVA

BIOMARKERS AT BASELINE WOULD BE USEFULRESTORE subgroup analysis of OCT features

bull Andreas Pollreisz EURETINA 2015

bull OCT biomarkers (RESTORE data)

bull Better effects with anti-VEGF ifbull Small rather than large intra-retinal cyst

bull Sub-retinal fluid present

bull Vitreo-macular adhesion at baseline

bull No disruption of ELM and ISOS junction

bull No disorganisation of inner retinal layers (DRIL)

RESTORE subgroup analysis of OCT features

bull Andreas Pollreisz EURETINA 2015

bull OCT biomarkers (RESTORE data)

bull Better effects with anti-VEGF ifbull Small rather than large intra-retinal cyst

bull Sub-retinal fluid present

bull Vitreo-macular adhesion at baseline

bull No disruption of ELM and ISOS junction

bull No disorganisation of inner retinal layers (DRIL)

Better baseline characterisationclassificationERG Contrast sensitivityOCT AngiographyMicroperimetry= clues as to who responds best to which drug

Plan for this presentation helliphellipa long list

bull What treatment options are available for DMO (evidence base)

bull What treatment should I start with at baselinebull Re-treatment algorithms for intravitreal DMO therapiesbull When should I switchcombine therapiesbull The bigger picture

bull Other eyebull The patient as a wholebull The service -coping with capacity ndash compromises

The bigger pictureOther eyeThe patient as a wholeThe service -coping with capacity ndash compromises

bull OTHER EYE ndash may create problems

bull Treat and extend ndash ldquoreduce of visitsrdquo plus Eylea license ndash ldquono need for monitoringrdquo may not benefit if lots of visits due to PDR other eye

bull PERIPHERAL RETINA anti-VEGF supresses proliferative disease - Rebound on stopping Rx

bull PATIENT

bull Anti-VEGF ndash heavy user - Will comply

bull One stop much better than two stop for patient ndash Treat and extend

bull SERVICE

bull Capacity and demand planning = fixedT+E more predictable at least 1 month in advance ndash flexible nurse injectors

bull Steroids ndash even if well controlled (Iluvien for 3 years) need IOP check

bull Need pan-retinal examination both eyes ndash separate visits

Summary

CSMO

No centre involvement

Photocoagulation

Centre involvement

gt 78 letters(normalminimally reduced VA)

Photocoagulation

VA 78ndash24 letters

Phakic

Anti-VEGF

Pseudophakic

Anti-VEGF

SWITCHglaucoma

Injection tolerance

Medical issuesrecent CVA

Peripheral diseaseBilateral Rx

CSMO

No centre involvement

LASER

Centre involvement

gt 78 letters(normalminimally

reduced VA)

VA 78ndash24 letters

EYLEA OR LUCENTIS OR AVASTIN

Funding issues

Protocol T ndash poor VA lt 65 letters (615)

LOADING

Monthly injections until stability OR 5 x 112 (EYLEA) = 6 MONTHS then 8 weeks

RETREATMENT1

TREAT AND EXTEND - PRN

PRN

PSEUDOPHAKIC

Prior Rx

ILUVIEN

Chronic disease

OZURDEX

RETREATMENT

OZURDEX

OCT gt175um or any residual oedema

ILUVIEN after 12 months if risksltbenefits

OCT

gt400um

bull FACE TO FACE CLINICS RUNNING IN PARALLEL

bull = MAC002 every 6 months (optom or doctor) routine check for cataracttolerance of injectionsglaucoma issues etc

bull =MAC003 (DOCTOR) for problems as needed no fixed intervalDischargestop treatmentDeclines treatment diagnosis CSR overlay etcswitch drugs

bull =RV002- (DOCTOR) every 6 months

bull =DM002 ndash (DOCTOR) variable interval determined by last assessing doctor

bull First visit at 6 months from 1st injection if mild NPDR

bull Otherwise determined by retinopathy generally

LOADING PHASE

EyleaLucentis 1 within 48hrs of baseline

EyleaLucentis 2 (and LogMAR VA plus OCT same visit)

EyleaLucentis 3 (and LogMAR VA plus OCT same visit)

EyleaLucentis 4 (TEinj)(and Logmar VA plus OCT same visit

AFTER INJECTION 4 data goes off to be reviewed immediately as a hellip

TREAT AND EXTEND assessment ndash the next interval will depend on the response to the loading phase

NB -DMO patients ndash majority (95) will need 6 injctions x 112 of Lucentis

OR Eylea 5 x 112 then 8 weekly

ONCE STABLE for 3 x injection in TE phase

VIRTUAL CLINIC MONITORING OF MACULOPATHY AND PRN RETREATMENT

ANTI-VEGF INJECTION PATHWAYS Baseline visitMAC001 for wet AMDRV001 for CRVOBRVOMed ret clinic for DMO

Pathways ndash too many directions

Better that thanhellip

Thank you

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

Protocol T ndash patients may not improve in first 6 months

RIDE

RISE

Mea

n ch

ange

in B

CVA

(E

TDR

S le

tters

)M

ean

chan

ge in

BC

VA

(ETD

RS

lette

rs)

Time (months)

RISE and RIDE (Lucentis monthly dosing) Mean change in BCVA over 36 months

Brown DM et al Ophthalmology 2013120(10)2013ndash2022

54

Ranibizumab 03 mgRanibizumab 05 mgShamranibizumab 05 mg

Date of Prep Dec 2014 LGB0820147252X

VA improvement continues throughout year 1 with monthly dosing

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user ndash more than protocol

I

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

DRCRN protocol I5 year outcomesInjections 8-9 in year 1Year 2 = 2-3Year 3= 1-2Year 4 = 0-1Year 5 = 0

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

Wait for plateau = stability in protocol T laserPatient factors again

Judgement of response to anti-VEGF ndashtimeframe

bull Wait 6 months in poor responders

bull Wait 1 year for heavy users

bull Tempting to try steroids earlier than this ifbull No glaucoma ndash not a deal breaker Ozurdex better short term optionbull Pseudophakic

bull Clues from the diseasebull chronic

bull PATIENT FACTORS

bull Any eyes avoid steroids ndash advanced glaucomaCSCR Or prior viral retinitis RARE

bull Any eyes avoid anti-VEGF pregnancytrying to concieve recent CVA

BIOMARKERS AT BASELINE WOULD BE USEFULRESTORE subgroup analysis of OCT features

bull Andreas Pollreisz EURETINA 2015

bull OCT biomarkers (RESTORE data)

bull Better effects with anti-VEGF ifbull Small rather than large intra-retinal cyst

bull Sub-retinal fluid present

bull Vitreo-macular adhesion at baseline

bull No disruption of ELM and ISOS junction

bull No disorganisation of inner retinal layers (DRIL)

RESTORE subgroup analysis of OCT features

bull Andreas Pollreisz EURETINA 2015

bull OCT biomarkers (RESTORE data)

bull Better effects with anti-VEGF ifbull Small rather than large intra-retinal cyst

bull Sub-retinal fluid present

bull Vitreo-macular adhesion at baseline

bull No disruption of ELM and ISOS junction

bull No disorganisation of inner retinal layers (DRIL)

Better baseline characterisationclassificationERG Contrast sensitivityOCT AngiographyMicroperimetry= clues as to who responds best to which drug

Plan for this presentation helliphellipa long list

bull What treatment options are available for DMO (evidence base)

bull What treatment should I start with at baselinebull Re-treatment algorithms for intravitreal DMO therapiesbull When should I switchcombine therapiesbull The bigger picture

bull Other eyebull The patient as a wholebull The service -coping with capacity ndash compromises

The bigger pictureOther eyeThe patient as a wholeThe service -coping with capacity ndash compromises

bull OTHER EYE ndash may create problems

bull Treat and extend ndash ldquoreduce of visitsrdquo plus Eylea license ndash ldquono need for monitoringrdquo may not benefit if lots of visits due to PDR other eye

bull PERIPHERAL RETINA anti-VEGF supresses proliferative disease - Rebound on stopping Rx

bull PATIENT

bull Anti-VEGF ndash heavy user - Will comply

bull One stop much better than two stop for patient ndash Treat and extend

bull SERVICE

bull Capacity and demand planning = fixedT+E more predictable at least 1 month in advance ndash flexible nurse injectors

bull Steroids ndash even if well controlled (Iluvien for 3 years) need IOP check

bull Need pan-retinal examination both eyes ndash separate visits

Summary

CSMO

No centre involvement

Photocoagulation

Centre involvement

gt 78 letters(normalminimally reduced VA)

Photocoagulation

VA 78ndash24 letters

Phakic

Anti-VEGF

Pseudophakic

Anti-VEGF

SWITCHglaucoma

Injection tolerance

Medical issuesrecent CVA

Peripheral diseaseBilateral Rx

CSMO

No centre involvement

LASER

Centre involvement

gt 78 letters(normalminimally

reduced VA)

VA 78ndash24 letters

EYLEA OR LUCENTIS OR AVASTIN

Funding issues

Protocol T ndash poor VA lt 65 letters (615)

LOADING

Monthly injections until stability OR 5 x 112 (EYLEA) = 6 MONTHS then 8 weeks

RETREATMENT1

TREAT AND EXTEND - PRN

PRN

PSEUDOPHAKIC

Prior Rx

ILUVIEN

Chronic disease

OZURDEX

RETREATMENT

OZURDEX

OCT gt175um or any residual oedema

ILUVIEN after 12 months if risksltbenefits

OCT

gt400um

bull FACE TO FACE CLINICS RUNNING IN PARALLEL

bull = MAC002 every 6 months (optom or doctor) routine check for cataracttolerance of injectionsglaucoma issues etc

bull =MAC003 (DOCTOR) for problems as needed no fixed intervalDischargestop treatmentDeclines treatment diagnosis CSR overlay etcswitch drugs

bull =RV002- (DOCTOR) every 6 months

bull =DM002 ndash (DOCTOR) variable interval determined by last assessing doctor

bull First visit at 6 months from 1st injection if mild NPDR

bull Otherwise determined by retinopathy generally

LOADING PHASE

EyleaLucentis 1 within 48hrs of baseline

EyleaLucentis 2 (and LogMAR VA plus OCT same visit)

EyleaLucentis 3 (and LogMAR VA plus OCT same visit)

EyleaLucentis 4 (TEinj)(and Logmar VA plus OCT same visit

AFTER INJECTION 4 data goes off to be reviewed immediately as a hellip

TREAT AND EXTEND assessment ndash the next interval will depend on the response to the loading phase

NB -DMO patients ndash majority (95) will need 6 injctions x 112 of Lucentis

OR Eylea 5 x 112 then 8 weekly

ONCE STABLE for 3 x injection in TE phase

VIRTUAL CLINIC MONITORING OF MACULOPATHY AND PRN RETREATMENT

ANTI-VEGF INJECTION PATHWAYS Baseline visitMAC001 for wet AMDRV001 for CRVOBRVOMed ret clinic for DMO

Pathways ndash too many directions

Better that thanhellip

Thank you

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

Protocol T ndash patients may not improve in first 6 months

RIDE

RISE

Mea

n ch

ange

in B

CVA

(E

TDR

S le

tters

)M

ean

chan

ge in

BC

VA

(ETD

RS

lette

rs)

Time (months)

RISE and RIDE (Lucentis monthly dosing) Mean change in BCVA over 36 months

Brown DM et al Ophthalmology 2013120(10)2013ndash2022

54

Ranibizumab 03 mgRanibizumab 05 mgShamranibizumab 05 mg

Date of Prep Dec 2014 LGB0820147252X

VA improvement continues throughout year 1 with monthly dosing

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user ndash more than protocol

I

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

DRCRN protocol I5 year outcomesInjections 8-9 in year 1Year 2 = 2-3Year 3= 1-2Year 4 = 0-1Year 5 = 0

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

Wait for plateau = stability in protocol T laserPatient factors again

Judgement of response to anti-VEGF ndashtimeframe

bull Wait 6 months in poor responders

bull Wait 1 year for heavy users

bull Tempting to try steroids earlier than this ifbull No glaucoma ndash not a deal breaker Ozurdex better short term optionbull Pseudophakic

bull Clues from the diseasebull chronic

bull PATIENT FACTORS

bull Any eyes avoid steroids ndash advanced glaucomaCSCR Or prior viral retinitis RARE

bull Any eyes avoid anti-VEGF pregnancytrying to concieve recent CVA

BIOMARKERS AT BASELINE WOULD BE USEFULRESTORE subgroup analysis of OCT features

bull Andreas Pollreisz EURETINA 2015

bull OCT biomarkers (RESTORE data)

bull Better effects with anti-VEGF ifbull Small rather than large intra-retinal cyst

bull Sub-retinal fluid present

bull Vitreo-macular adhesion at baseline

bull No disruption of ELM and ISOS junction

bull No disorganisation of inner retinal layers (DRIL)

RESTORE subgroup analysis of OCT features

bull Andreas Pollreisz EURETINA 2015

bull OCT biomarkers (RESTORE data)

bull Better effects with anti-VEGF ifbull Small rather than large intra-retinal cyst

bull Sub-retinal fluid present

bull Vitreo-macular adhesion at baseline

bull No disruption of ELM and ISOS junction

bull No disorganisation of inner retinal layers (DRIL)

Better baseline characterisationclassificationERG Contrast sensitivityOCT AngiographyMicroperimetry= clues as to who responds best to which drug

Plan for this presentation helliphellipa long list

bull What treatment options are available for DMO (evidence base)

bull What treatment should I start with at baselinebull Re-treatment algorithms for intravitreal DMO therapiesbull When should I switchcombine therapiesbull The bigger picture

bull Other eyebull The patient as a wholebull The service -coping with capacity ndash compromises

The bigger pictureOther eyeThe patient as a wholeThe service -coping with capacity ndash compromises

bull OTHER EYE ndash may create problems

bull Treat and extend ndash ldquoreduce of visitsrdquo plus Eylea license ndash ldquono need for monitoringrdquo may not benefit if lots of visits due to PDR other eye

bull PERIPHERAL RETINA anti-VEGF supresses proliferative disease - Rebound on stopping Rx

bull PATIENT

bull Anti-VEGF ndash heavy user - Will comply

bull One stop much better than two stop for patient ndash Treat and extend

bull SERVICE

bull Capacity and demand planning = fixedT+E more predictable at least 1 month in advance ndash flexible nurse injectors

bull Steroids ndash even if well controlled (Iluvien for 3 years) need IOP check

bull Need pan-retinal examination both eyes ndash separate visits

Summary

CSMO

No centre involvement

Photocoagulation

Centre involvement

gt 78 letters(normalminimally reduced VA)

Photocoagulation

VA 78ndash24 letters

Phakic

Anti-VEGF

Pseudophakic

Anti-VEGF

SWITCHglaucoma

Injection tolerance

Medical issuesrecent CVA

Peripheral diseaseBilateral Rx

CSMO

No centre involvement

LASER

Centre involvement

gt 78 letters(normalminimally

reduced VA)

VA 78ndash24 letters

EYLEA OR LUCENTIS OR AVASTIN

Funding issues

Protocol T ndash poor VA lt 65 letters (615)

LOADING

Monthly injections until stability OR 5 x 112 (EYLEA) = 6 MONTHS then 8 weeks

RETREATMENT1

TREAT AND EXTEND - PRN

PRN

PSEUDOPHAKIC

Prior Rx

ILUVIEN

Chronic disease

OZURDEX

RETREATMENT

OZURDEX

OCT gt175um or any residual oedema

ILUVIEN after 12 months if risksltbenefits

OCT

gt400um

bull FACE TO FACE CLINICS RUNNING IN PARALLEL

bull = MAC002 every 6 months (optom or doctor) routine check for cataracttolerance of injectionsglaucoma issues etc

bull =MAC003 (DOCTOR) for problems as needed no fixed intervalDischargestop treatmentDeclines treatment diagnosis CSR overlay etcswitch drugs

bull =RV002- (DOCTOR) every 6 months

bull =DM002 ndash (DOCTOR) variable interval determined by last assessing doctor

bull First visit at 6 months from 1st injection if mild NPDR

bull Otherwise determined by retinopathy generally

LOADING PHASE

EyleaLucentis 1 within 48hrs of baseline

EyleaLucentis 2 (and LogMAR VA plus OCT same visit)

EyleaLucentis 3 (and LogMAR VA plus OCT same visit)

EyleaLucentis 4 (TEinj)(and Logmar VA plus OCT same visit

AFTER INJECTION 4 data goes off to be reviewed immediately as a hellip

TREAT AND EXTEND assessment ndash the next interval will depend on the response to the loading phase

NB -DMO patients ndash majority (95) will need 6 injctions x 112 of Lucentis

OR Eylea 5 x 112 then 8 weekly

ONCE STABLE for 3 x injection in TE phase

VIRTUAL CLINIC MONITORING OF MACULOPATHY AND PRN RETREATMENT

ANTI-VEGF INJECTION PATHWAYS Baseline visitMAC001 for wet AMDRV001 for CRVOBRVOMed ret clinic for DMO

Pathways ndash too many directions

Better that thanhellip

Thank you

RIDE

RISE

Mea

n ch

ange

in B

CVA

(E

TDR

S le

tters

)M

ean

chan

ge in

BC

VA

(ETD

RS

lette

rs)

Time (months)

RISE and RIDE (Lucentis monthly dosing) Mean change in BCVA over 36 months

Brown DM et al Ophthalmology 2013120(10)2013ndash2022

54

Ranibizumab 03 mgRanibizumab 05 mgShamranibizumab 05 mg

Date of Prep Dec 2014 LGB0820147252X

VA improvement continues throughout year 1 with monthly dosing

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user ndash more than protocol

I

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

DRCRN protocol I5 year outcomesInjections 8-9 in year 1Year 2 = 2-3Year 3= 1-2Year 4 = 0-1Year 5 = 0

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

Wait for plateau = stability in protocol T laserPatient factors again

Judgement of response to anti-VEGF ndashtimeframe

bull Wait 6 months in poor responders

bull Wait 1 year for heavy users

bull Tempting to try steroids earlier than this ifbull No glaucoma ndash not a deal breaker Ozurdex better short term optionbull Pseudophakic

bull Clues from the diseasebull chronic

bull PATIENT FACTORS

bull Any eyes avoid steroids ndash advanced glaucomaCSCR Or prior viral retinitis RARE

bull Any eyes avoid anti-VEGF pregnancytrying to concieve recent CVA

BIOMARKERS AT BASELINE WOULD BE USEFULRESTORE subgroup analysis of OCT features

bull Andreas Pollreisz EURETINA 2015

bull OCT biomarkers (RESTORE data)

bull Better effects with anti-VEGF ifbull Small rather than large intra-retinal cyst

bull Sub-retinal fluid present

bull Vitreo-macular adhesion at baseline

bull No disruption of ELM and ISOS junction

bull No disorganisation of inner retinal layers (DRIL)

RESTORE subgroup analysis of OCT features

bull Andreas Pollreisz EURETINA 2015

bull OCT biomarkers (RESTORE data)

bull Better effects with anti-VEGF ifbull Small rather than large intra-retinal cyst

bull Sub-retinal fluid present

bull Vitreo-macular adhesion at baseline

bull No disruption of ELM and ISOS junction

bull No disorganisation of inner retinal layers (DRIL)

Better baseline characterisationclassificationERG Contrast sensitivityOCT AngiographyMicroperimetry= clues as to who responds best to which drug

Plan for this presentation helliphellipa long list

bull What treatment options are available for DMO (evidence base)

bull What treatment should I start with at baselinebull Re-treatment algorithms for intravitreal DMO therapiesbull When should I switchcombine therapiesbull The bigger picture

bull Other eyebull The patient as a wholebull The service -coping with capacity ndash compromises

The bigger pictureOther eyeThe patient as a wholeThe service -coping with capacity ndash compromises

bull OTHER EYE ndash may create problems

bull Treat and extend ndash ldquoreduce of visitsrdquo plus Eylea license ndash ldquono need for monitoringrdquo may not benefit if lots of visits due to PDR other eye

bull PERIPHERAL RETINA anti-VEGF supresses proliferative disease - Rebound on stopping Rx

bull PATIENT

bull Anti-VEGF ndash heavy user - Will comply

bull One stop much better than two stop for patient ndash Treat and extend

bull SERVICE

bull Capacity and demand planning = fixedT+E more predictable at least 1 month in advance ndash flexible nurse injectors

bull Steroids ndash even if well controlled (Iluvien for 3 years) need IOP check

bull Need pan-retinal examination both eyes ndash separate visits

Summary

CSMO

No centre involvement

Photocoagulation

Centre involvement

gt 78 letters(normalminimally reduced VA)

Photocoagulation

VA 78ndash24 letters

Phakic

Anti-VEGF

Pseudophakic

Anti-VEGF

SWITCHglaucoma

Injection tolerance

Medical issuesrecent CVA

Peripheral diseaseBilateral Rx

CSMO

No centre involvement

LASER

Centre involvement

gt 78 letters(normalminimally

reduced VA)

VA 78ndash24 letters

EYLEA OR LUCENTIS OR AVASTIN

Funding issues

Protocol T ndash poor VA lt 65 letters (615)

LOADING

Monthly injections until stability OR 5 x 112 (EYLEA) = 6 MONTHS then 8 weeks

RETREATMENT1

TREAT AND EXTEND - PRN

PRN

PSEUDOPHAKIC

Prior Rx

ILUVIEN

Chronic disease

OZURDEX

RETREATMENT

OZURDEX

OCT gt175um or any residual oedema

ILUVIEN after 12 months if risksltbenefits

OCT

gt400um

bull FACE TO FACE CLINICS RUNNING IN PARALLEL

bull = MAC002 every 6 months (optom or doctor) routine check for cataracttolerance of injectionsglaucoma issues etc

bull =MAC003 (DOCTOR) for problems as needed no fixed intervalDischargestop treatmentDeclines treatment diagnosis CSR overlay etcswitch drugs

bull =RV002- (DOCTOR) every 6 months

bull =DM002 ndash (DOCTOR) variable interval determined by last assessing doctor

bull First visit at 6 months from 1st injection if mild NPDR

bull Otherwise determined by retinopathy generally

LOADING PHASE

EyleaLucentis 1 within 48hrs of baseline

EyleaLucentis 2 (and LogMAR VA plus OCT same visit)

EyleaLucentis 3 (and LogMAR VA plus OCT same visit)

EyleaLucentis 4 (TEinj)(and Logmar VA plus OCT same visit

AFTER INJECTION 4 data goes off to be reviewed immediately as a hellip

TREAT AND EXTEND assessment ndash the next interval will depend on the response to the loading phase

NB -DMO patients ndash majority (95) will need 6 injctions x 112 of Lucentis

OR Eylea 5 x 112 then 8 weekly

ONCE STABLE for 3 x injection in TE phase

VIRTUAL CLINIC MONITORING OF MACULOPATHY AND PRN RETREATMENT

ANTI-VEGF INJECTION PATHWAYS Baseline visitMAC001 for wet AMDRV001 for CRVOBRVOMed ret clinic for DMO

Pathways ndash too many directions

Better that thanhellip

Thank you

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user ndash more than protocol

I

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

DRCRN protocol I5 year outcomesInjections 8-9 in year 1Year 2 = 2-3Year 3= 1-2Year 4 = 0-1Year 5 = 0

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

Wait for plateau = stability in protocol T laserPatient factors again

Judgement of response to anti-VEGF ndashtimeframe

bull Wait 6 months in poor responders

bull Wait 1 year for heavy users

bull Tempting to try steroids earlier than this ifbull No glaucoma ndash not a deal breaker Ozurdex better short term optionbull Pseudophakic

bull Clues from the diseasebull chronic

bull PATIENT FACTORS

bull Any eyes avoid steroids ndash advanced glaucomaCSCR Or prior viral retinitis RARE

bull Any eyes avoid anti-VEGF pregnancytrying to concieve recent CVA

BIOMARKERS AT BASELINE WOULD BE USEFULRESTORE subgroup analysis of OCT features

bull Andreas Pollreisz EURETINA 2015

bull OCT biomarkers (RESTORE data)

bull Better effects with anti-VEGF ifbull Small rather than large intra-retinal cyst

bull Sub-retinal fluid present

bull Vitreo-macular adhesion at baseline

bull No disruption of ELM and ISOS junction

bull No disorganisation of inner retinal layers (DRIL)

RESTORE subgroup analysis of OCT features

bull Andreas Pollreisz EURETINA 2015

bull OCT biomarkers (RESTORE data)

bull Better effects with anti-VEGF ifbull Small rather than large intra-retinal cyst

bull Sub-retinal fluid present

bull Vitreo-macular adhesion at baseline

bull No disruption of ELM and ISOS junction

bull No disorganisation of inner retinal layers (DRIL)

Better baseline characterisationclassificationERG Contrast sensitivityOCT AngiographyMicroperimetry= clues as to who responds best to which drug

Plan for this presentation helliphellipa long list

bull What treatment options are available for DMO (evidence base)

bull What treatment should I start with at baselinebull Re-treatment algorithms for intravitreal DMO therapiesbull When should I switchcombine therapiesbull The bigger picture

bull Other eyebull The patient as a wholebull The service -coping with capacity ndash compromises

The bigger pictureOther eyeThe patient as a wholeThe service -coping with capacity ndash compromises

bull OTHER EYE ndash may create problems

bull Treat and extend ndash ldquoreduce of visitsrdquo plus Eylea license ndash ldquono need for monitoringrdquo may not benefit if lots of visits due to PDR other eye

bull PERIPHERAL RETINA anti-VEGF supresses proliferative disease - Rebound on stopping Rx

bull PATIENT

bull Anti-VEGF ndash heavy user - Will comply

bull One stop much better than two stop for patient ndash Treat and extend

bull SERVICE

bull Capacity and demand planning = fixedT+E more predictable at least 1 month in advance ndash flexible nurse injectors

bull Steroids ndash even if well controlled (Iluvien for 3 years) need IOP check

bull Need pan-retinal examination both eyes ndash separate visits

Summary

CSMO

No centre involvement

Photocoagulation

Centre involvement

gt 78 letters(normalminimally reduced VA)

Photocoagulation

VA 78ndash24 letters

Phakic

Anti-VEGF

Pseudophakic

Anti-VEGF

SWITCHglaucoma

Injection tolerance

Medical issuesrecent CVA

Peripheral diseaseBilateral Rx

CSMO

No centre involvement

LASER

Centre involvement

gt 78 letters(normalminimally

reduced VA)

VA 78ndash24 letters

EYLEA OR LUCENTIS OR AVASTIN

Funding issues

Protocol T ndash poor VA lt 65 letters (615)

LOADING

Monthly injections until stability OR 5 x 112 (EYLEA) = 6 MONTHS then 8 weeks

RETREATMENT1

TREAT AND EXTEND - PRN

PRN

PSEUDOPHAKIC

Prior Rx

ILUVIEN

Chronic disease

OZURDEX

RETREATMENT

OZURDEX

OCT gt175um or any residual oedema

ILUVIEN after 12 months if risksltbenefits

OCT

gt400um

bull FACE TO FACE CLINICS RUNNING IN PARALLEL

bull = MAC002 every 6 months (optom or doctor) routine check for cataracttolerance of injectionsglaucoma issues etc

bull =MAC003 (DOCTOR) for problems as needed no fixed intervalDischargestop treatmentDeclines treatment diagnosis CSR overlay etcswitch drugs

bull =RV002- (DOCTOR) every 6 months

bull =DM002 ndash (DOCTOR) variable interval determined by last assessing doctor

bull First visit at 6 months from 1st injection if mild NPDR

bull Otherwise determined by retinopathy generally

LOADING PHASE

EyleaLucentis 1 within 48hrs of baseline

EyleaLucentis 2 (and LogMAR VA plus OCT same visit)

EyleaLucentis 3 (and LogMAR VA plus OCT same visit)

EyleaLucentis 4 (TEinj)(and Logmar VA plus OCT same visit

AFTER INJECTION 4 data goes off to be reviewed immediately as a hellip

TREAT AND EXTEND assessment ndash the next interval will depend on the response to the loading phase

NB -DMO patients ndash majority (95) will need 6 injctions x 112 of Lucentis

OR Eylea 5 x 112 then 8 weekly

ONCE STABLE for 3 x injection in TE phase

VIRTUAL CLINIC MONITORING OF MACULOPATHY AND PRN RETREATMENT

ANTI-VEGF INJECTION PATHWAYS Baseline visitMAC001 for wet AMDRV001 for CRVOBRVOMed ret clinic for DMO

Pathways ndash too many directions

Better that thanhellip

Thank you

FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID

bull Drug response bull Patient factorsbull Heavy user

bull VA improved but ldquonot far enoughrdquo ie needs to regain driving license

bull Struggles with intra-vitrealtechnique

NO RESPONSEVA no changeOCT no change

SUBOPTIMALVA bettersameOCT improved but plateau

GOODBut frequent recurrences and re-dosing at 1 month intervals

Wait for plateau = stability in protocol T laserPatient factors again

Judgement of response to anti-VEGF ndashtimeframe

bull Wait 6 months in poor responders

bull Wait 1 year for heavy users

bull Tempting to try steroids earlier than this ifbull No glaucoma ndash not a deal breaker Ozurdex better short term optionbull Pseudophakic

bull Clues from the diseasebull chronic

bull PATIENT FACTORS

bull Any eyes avoid steroids ndash advanced glaucomaCSCR Or prior viral retinitis RARE

bull Any eyes avoid anti-VEGF pregnancytrying to concieve recent CVA

BIOMARKERS AT BASELINE WOULD BE USEFULRESTORE subgroup analysis of OCT features

bull Andreas Pollreisz EURETINA 2015

bull OCT biomarkers (RESTORE data)

bull Better effects with anti-VEGF ifbull Small rather than large intra-retinal cyst

bull Sub-retinal fluid present

bull Vitreo-macular adhesion at baseline

bull No disruption of ELM and ISOS junction

bull No disorganisation of inner retinal layers (DRIL)

RESTORE subgroup analysis of OCT features

bull Andreas Pollreisz EURETINA 2015

bull OCT biomarkers (RESTORE data)

bull Better effects with anti-VEGF ifbull Small rather than large intra-retinal cyst

bull Sub-retinal fluid present

bull Vitreo-macular adhesion at baseline

bull No disruption of ELM and ISOS junction

bull No disorganisation of inner retinal layers (DRIL)

Better baseline characterisationclassificationERG Contrast sensitivityOCT AngiographyMicroperimetry= clues as to who responds best to which drug

Plan for this presentation helliphellipa long list

bull What treatment options are available for DMO (evidence base)

bull What treatment should I start with at baselinebull Re-treatment algorithms for intravitreal DMO therapiesbull When should I switchcombine therapiesbull The bigger picture

bull Other eyebull The patient as a wholebull The service -coping with capacity ndash compromises

The bigger pictureOther eyeThe patient as a wholeThe service -coping with capacity ndash compromises

bull OTHER EYE ndash may create problems

bull Treat and extend ndash ldquoreduce of visitsrdquo plus Eylea license ndash ldquono need for monitoringrdquo may not benefit if lots of visits due to PDR other eye

bull PERIPHERAL RETINA anti-VEGF supresses proliferative disease - Rebound on stopping Rx

bull PATIENT

bull Anti-VEGF ndash heavy user - Will comply

bull One stop much better than two stop for patient ndash Treat and extend

bull SERVICE

bull Capacity and demand planning = fixedT+E more predictable at least 1 month in advance ndash flexible nurse injectors

bull Steroids ndash even if well controlled (Iluvien for 3 years) need IOP check

bull Need pan-retinal examination both eyes ndash separate visits

Summary

CSMO

No centre involvement

Photocoagulation

Centre involvement

gt 78 letters(normalminimally reduced VA)

Photocoagulation

VA 78ndash24 letters

Phakic

Anti-VEGF

Pseudophakic

Anti-VEGF

SWITCHglaucoma

Injection tolerance

Medical issuesrecent CVA

Peripheral diseaseBilateral Rx

CSMO

No centre involvement

LASER

Centre involvement

gt 78 letters(normalminimally

reduced VA)

VA 78ndash24 letters

EYLEA OR LUCENTIS OR AVASTIN

Funding issues

Protocol T ndash poor VA lt 65 letters (615)

LOADING

Monthly injections until stability OR 5 x 112 (EYLEA) = 6 MONTHS then 8 weeks

RETREATMENT1

TREAT AND EXTEND - PRN

PRN

PSEUDOPHAKIC

Prior Rx

ILUVIEN

Chronic disease

OZURDEX

RETREATMENT

OZURDEX

OCT gt175um or any residual oedema

ILUVIEN after 12 months if risksltbenefits

OCT

gt400um

bull FACE TO FACE CLINICS RUNNING IN PARALLEL

bull = MAC002 every 6 months (optom or doctor) routine check for cataracttolerance of injectionsglaucoma issues etc

bull =MAC003 (DOCTOR) for problems as needed no fixed intervalDischargestop treatmentDeclines treatment diagnosis CSR overlay etcswitch drugs

bull =RV002- (DOCTOR) every 6 months

bull =DM002 ndash (DOCTOR) variable interval determined by last assessing doctor

bull First visit at 6 months from 1st injection if mild NPDR

bull Otherwise determined by retinopathy generally

LOADING PHASE

EyleaLucentis 1 within 48hrs of baseline

EyleaLucentis 2 (and LogMAR VA plus OCT same visit)

EyleaLucentis 3 (and LogMAR VA plus OCT same visit)

EyleaLucentis 4 (TEinj)(and Logmar VA plus OCT same visit

AFTER INJECTION 4 data goes off to be reviewed immediately as a hellip

TREAT AND EXTEND assessment ndash the next interval will depend on the response to the loading phase

NB -DMO patients ndash majority (95) will need 6 injctions x 112 of Lucentis

OR Eylea 5 x 112 then 8 weekly

ONCE STABLE for 3 x injection in TE phase

VIRTUAL CLINIC MONITORING OF MACULOPATHY AND PRN RETREATMENT

ANTI-VEGF INJECTION PATHWAYS Baseline visitMAC001 for wet AMDRV001 for CRVOBRVOMed ret clinic for DMO

Pathways ndash too many directions

Better that thanhellip

Thank you

Judgement of response to anti-VEGF ndashtimeframe

bull Wait 6 months in poor responders

bull Wait 1 year for heavy users

bull Tempting to try steroids earlier than this ifbull No glaucoma ndash not a deal breaker Ozurdex better short term optionbull Pseudophakic

bull Clues from the diseasebull chronic

bull PATIENT FACTORS

bull Any eyes avoid steroids ndash advanced glaucomaCSCR Or prior viral retinitis RARE

bull Any eyes avoid anti-VEGF pregnancytrying to concieve recent CVA

BIOMARKERS AT BASELINE WOULD BE USEFULRESTORE subgroup analysis of OCT features

bull Andreas Pollreisz EURETINA 2015

bull OCT biomarkers (RESTORE data)

bull Better effects with anti-VEGF ifbull Small rather than large intra-retinal cyst

bull Sub-retinal fluid present

bull Vitreo-macular adhesion at baseline

bull No disruption of ELM and ISOS junction

bull No disorganisation of inner retinal layers (DRIL)

RESTORE subgroup analysis of OCT features

bull Andreas Pollreisz EURETINA 2015

bull OCT biomarkers (RESTORE data)

bull Better effects with anti-VEGF ifbull Small rather than large intra-retinal cyst

bull Sub-retinal fluid present

bull Vitreo-macular adhesion at baseline

bull No disruption of ELM and ISOS junction

bull No disorganisation of inner retinal layers (DRIL)

Better baseline characterisationclassificationERG Contrast sensitivityOCT AngiographyMicroperimetry= clues as to who responds best to which drug

Plan for this presentation helliphellipa long list

bull What treatment options are available for DMO (evidence base)

bull What treatment should I start with at baselinebull Re-treatment algorithms for intravitreal DMO therapiesbull When should I switchcombine therapiesbull The bigger picture

bull Other eyebull The patient as a wholebull The service -coping with capacity ndash compromises

The bigger pictureOther eyeThe patient as a wholeThe service -coping with capacity ndash compromises

bull OTHER EYE ndash may create problems

bull Treat and extend ndash ldquoreduce of visitsrdquo plus Eylea license ndash ldquono need for monitoringrdquo may not benefit if lots of visits due to PDR other eye

bull PERIPHERAL RETINA anti-VEGF supresses proliferative disease - Rebound on stopping Rx

bull PATIENT

bull Anti-VEGF ndash heavy user - Will comply

bull One stop much better than two stop for patient ndash Treat and extend

bull SERVICE

bull Capacity and demand planning = fixedT+E more predictable at least 1 month in advance ndash flexible nurse injectors

bull Steroids ndash even if well controlled (Iluvien for 3 years) need IOP check

bull Need pan-retinal examination both eyes ndash separate visits

Summary

CSMO

No centre involvement

Photocoagulation

Centre involvement

gt 78 letters(normalminimally reduced VA)

Photocoagulation

VA 78ndash24 letters

Phakic

Anti-VEGF

Pseudophakic

Anti-VEGF

SWITCHglaucoma

Injection tolerance

Medical issuesrecent CVA

Peripheral diseaseBilateral Rx

CSMO

No centre involvement

LASER

Centre involvement

gt 78 letters(normalminimally

reduced VA)

VA 78ndash24 letters

EYLEA OR LUCENTIS OR AVASTIN

Funding issues

Protocol T ndash poor VA lt 65 letters (615)

LOADING

Monthly injections until stability OR 5 x 112 (EYLEA) = 6 MONTHS then 8 weeks

RETREATMENT1

TREAT AND EXTEND - PRN

PRN

PSEUDOPHAKIC

Prior Rx

ILUVIEN

Chronic disease

OZURDEX

RETREATMENT

OZURDEX

OCT gt175um or any residual oedema

ILUVIEN after 12 months if risksltbenefits

OCT

gt400um

bull FACE TO FACE CLINICS RUNNING IN PARALLEL

bull = MAC002 every 6 months (optom or doctor) routine check for cataracttolerance of injectionsglaucoma issues etc

bull =MAC003 (DOCTOR) for problems as needed no fixed intervalDischargestop treatmentDeclines treatment diagnosis CSR overlay etcswitch drugs

bull =RV002- (DOCTOR) every 6 months

bull =DM002 ndash (DOCTOR) variable interval determined by last assessing doctor

bull First visit at 6 months from 1st injection if mild NPDR

bull Otherwise determined by retinopathy generally

LOADING PHASE

EyleaLucentis 1 within 48hrs of baseline

EyleaLucentis 2 (and LogMAR VA plus OCT same visit)

EyleaLucentis 3 (and LogMAR VA plus OCT same visit)

EyleaLucentis 4 (TEinj)(and Logmar VA plus OCT same visit

AFTER INJECTION 4 data goes off to be reviewed immediately as a hellip

TREAT AND EXTEND assessment ndash the next interval will depend on the response to the loading phase

NB -DMO patients ndash majority (95) will need 6 injctions x 112 of Lucentis

OR Eylea 5 x 112 then 8 weekly

ONCE STABLE for 3 x injection in TE phase

VIRTUAL CLINIC MONITORING OF MACULOPATHY AND PRN RETREATMENT

ANTI-VEGF INJECTION PATHWAYS Baseline visitMAC001 for wet AMDRV001 for CRVOBRVOMed ret clinic for DMO

Pathways ndash too many directions

Better that thanhellip

Thank you

BIOMARKERS AT BASELINE WOULD BE USEFULRESTORE subgroup analysis of OCT features

bull Andreas Pollreisz EURETINA 2015

bull OCT biomarkers (RESTORE data)

bull Better effects with anti-VEGF ifbull Small rather than large intra-retinal cyst

bull Sub-retinal fluid present

bull Vitreo-macular adhesion at baseline

bull No disruption of ELM and ISOS junction

bull No disorganisation of inner retinal layers (DRIL)

RESTORE subgroup analysis of OCT features

bull Andreas Pollreisz EURETINA 2015

bull OCT biomarkers (RESTORE data)

bull Better effects with anti-VEGF ifbull Small rather than large intra-retinal cyst

bull Sub-retinal fluid present

bull Vitreo-macular adhesion at baseline

bull No disruption of ELM and ISOS junction

bull No disorganisation of inner retinal layers (DRIL)

Better baseline characterisationclassificationERG Contrast sensitivityOCT AngiographyMicroperimetry= clues as to who responds best to which drug

Plan for this presentation helliphellipa long list

bull What treatment options are available for DMO (evidence base)

bull What treatment should I start with at baselinebull Re-treatment algorithms for intravitreal DMO therapiesbull When should I switchcombine therapiesbull The bigger picture

bull Other eyebull The patient as a wholebull The service -coping with capacity ndash compromises

The bigger pictureOther eyeThe patient as a wholeThe service -coping with capacity ndash compromises

bull OTHER EYE ndash may create problems

bull Treat and extend ndash ldquoreduce of visitsrdquo plus Eylea license ndash ldquono need for monitoringrdquo may not benefit if lots of visits due to PDR other eye

bull PERIPHERAL RETINA anti-VEGF supresses proliferative disease - Rebound on stopping Rx

bull PATIENT

bull Anti-VEGF ndash heavy user - Will comply

bull One stop much better than two stop for patient ndash Treat and extend

bull SERVICE

bull Capacity and demand planning = fixedT+E more predictable at least 1 month in advance ndash flexible nurse injectors

bull Steroids ndash even if well controlled (Iluvien for 3 years) need IOP check

bull Need pan-retinal examination both eyes ndash separate visits

Summary

CSMO

No centre involvement

Photocoagulation

Centre involvement

gt 78 letters(normalminimally reduced VA)

Photocoagulation

VA 78ndash24 letters

Phakic

Anti-VEGF

Pseudophakic

Anti-VEGF

SWITCHglaucoma

Injection tolerance

Medical issuesrecent CVA

Peripheral diseaseBilateral Rx

CSMO

No centre involvement

LASER

Centre involvement

gt 78 letters(normalminimally

reduced VA)

VA 78ndash24 letters

EYLEA OR LUCENTIS OR AVASTIN

Funding issues

Protocol T ndash poor VA lt 65 letters (615)

LOADING

Monthly injections until stability OR 5 x 112 (EYLEA) = 6 MONTHS then 8 weeks

RETREATMENT1

TREAT AND EXTEND - PRN

PRN

PSEUDOPHAKIC

Prior Rx

ILUVIEN

Chronic disease

OZURDEX

RETREATMENT

OZURDEX

OCT gt175um or any residual oedema

ILUVIEN after 12 months if risksltbenefits

OCT

gt400um

bull FACE TO FACE CLINICS RUNNING IN PARALLEL

bull = MAC002 every 6 months (optom or doctor) routine check for cataracttolerance of injectionsglaucoma issues etc

bull =MAC003 (DOCTOR) for problems as needed no fixed intervalDischargestop treatmentDeclines treatment diagnosis CSR overlay etcswitch drugs

bull =RV002- (DOCTOR) every 6 months

bull =DM002 ndash (DOCTOR) variable interval determined by last assessing doctor

bull First visit at 6 months from 1st injection if mild NPDR

bull Otherwise determined by retinopathy generally

LOADING PHASE

EyleaLucentis 1 within 48hrs of baseline

EyleaLucentis 2 (and LogMAR VA plus OCT same visit)

EyleaLucentis 3 (and LogMAR VA plus OCT same visit)

EyleaLucentis 4 (TEinj)(and Logmar VA plus OCT same visit

AFTER INJECTION 4 data goes off to be reviewed immediately as a hellip

TREAT AND EXTEND assessment ndash the next interval will depend on the response to the loading phase

NB -DMO patients ndash majority (95) will need 6 injctions x 112 of Lucentis

OR Eylea 5 x 112 then 8 weekly

ONCE STABLE for 3 x injection in TE phase

VIRTUAL CLINIC MONITORING OF MACULOPATHY AND PRN RETREATMENT

ANTI-VEGF INJECTION PATHWAYS Baseline visitMAC001 for wet AMDRV001 for CRVOBRVOMed ret clinic for DMO

Pathways ndash too many directions

Better that thanhellip

Thank you

RESTORE subgroup analysis of OCT features

bull Andreas Pollreisz EURETINA 2015

bull OCT biomarkers (RESTORE data)

bull Better effects with anti-VEGF ifbull Small rather than large intra-retinal cyst

bull Sub-retinal fluid present

bull Vitreo-macular adhesion at baseline

bull No disruption of ELM and ISOS junction

bull No disorganisation of inner retinal layers (DRIL)

Better baseline characterisationclassificationERG Contrast sensitivityOCT AngiographyMicroperimetry= clues as to who responds best to which drug

Plan for this presentation helliphellipa long list

bull What treatment options are available for DMO (evidence base)

bull What treatment should I start with at baselinebull Re-treatment algorithms for intravitreal DMO therapiesbull When should I switchcombine therapiesbull The bigger picture

bull Other eyebull The patient as a wholebull The service -coping with capacity ndash compromises

The bigger pictureOther eyeThe patient as a wholeThe service -coping with capacity ndash compromises

bull OTHER EYE ndash may create problems

bull Treat and extend ndash ldquoreduce of visitsrdquo plus Eylea license ndash ldquono need for monitoringrdquo may not benefit if lots of visits due to PDR other eye

bull PERIPHERAL RETINA anti-VEGF supresses proliferative disease - Rebound on stopping Rx

bull PATIENT

bull Anti-VEGF ndash heavy user - Will comply

bull One stop much better than two stop for patient ndash Treat and extend

bull SERVICE

bull Capacity and demand planning = fixedT+E more predictable at least 1 month in advance ndash flexible nurse injectors

bull Steroids ndash even if well controlled (Iluvien for 3 years) need IOP check

bull Need pan-retinal examination both eyes ndash separate visits

Summary

CSMO

No centre involvement

Photocoagulation

Centre involvement

gt 78 letters(normalminimally reduced VA)

Photocoagulation

VA 78ndash24 letters

Phakic

Anti-VEGF

Pseudophakic

Anti-VEGF

SWITCHglaucoma

Injection tolerance

Medical issuesrecent CVA

Peripheral diseaseBilateral Rx

CSMO

No centre involvement

LASER

Centre involvement

gt 78 letters(normalminimally

reduced VA)

VA 78ndash24 letters

EYLEA OR LUCENTIS OR AVASTIN

Funding issues

Protocol T ndash poor VA lt 65 letters (615)

LOADING

Monthly injections until stability OR 5 x 112 (EYLEA) = 6 MONTHS then 8 weeks

RETREATMENT1

TREAT AND EXTEND - PRN

PRN

PSEUDOPHAKIC

Prior Rx

ILUVIEN

Chronic disease

OZURDEX

RETREATMENT

OZURDEX

OCT gt175um or any residual oedema

ILUVIEN after 12 months if risksltbenefits

OCT

gt400um

bull FACE TO FACE CLINICS RUNNING IN PARALLEL

bull = MAC002 every 6 months (optom or doctor) routine check for cataracttolerance of injectionsglaucoma issues etc

bull =MAC003 (DOCTOR) for problems as needed no fixed intervalDischargestop treatmentDeclines treatment diagnosis CSR overlay etcswitch drugs

bull =RV002- (DOCTOR) every 6 months

bull =DM002 ndash (DOCTOR) variable interval determined by last assessing doctor

bull First visit at 6 months from 1st injection if mild NPDR

bull Otherwise determined by retinopathy generally

LOADING PHASE

EyleaLucentis 1 within 48hrs of baseline

EyleaLucentis 2 (and LogMAR VA plus OCT same visit)

EyleaLucentis 3 (and LogMAR VA plus OCT same visit)

EyleaLucentis 4 (TEinj)(and Logmar VA plus OCT same visit

AFTER INJECTION 4 data goes off to be reviewed immediately as a hellip

TREAT AND EXTEND assessment ndash the next interval will depend on the response to the loading phase

NB -DMO patients ndash majority (95) will need 6 injctions x 112 of Lucentis

OR Eylea 5 x 112 then 8 weekly

ONCE STABLE for 3 x injection in TE phase

VIRTUAL CLINIC MONITORING OF MACULOPATHY AND PRN RETREATMENT

ANTI-VEGF INJECTION PATHWAYS Baseline visitMAC001 for wet AMDRV001 for CRVOBRVOMed ret clinic for DMO

Pathways ndash too many directions

Better that thanhellip

Thank you

Plan for this presentation helliphellipa long list

bull What treatment options are available for DMO (evidence base)

bull What treatment should I start with at baselinebull Re-treatment algorithms for intravitreal DMO therapiesbull When should I switchcombine therapiesbull The bigger picture

bull Other eyebull The patient as a wholebull The service -coping with capacity ndash compromises

The bigger pictureOther eyeThe patient as a wholeThe service -coping with capacity ndash compromises

bull OTHER EYE ndash may create problems

bull Treat and extend ndash ldquoreduce of visitsrdquo plus Eylea license ndash ldquono need for monitoringrdquo may not benefit if lots of visits due to PDR other eye

bull PERIPHERAL RETINA anti-VEGF supresses proliferative disease - Rebound on stopping Rx

bull PATIENT

bull Anti-VEGF ndash heavy user - Will comply

bull One stop much better than two stop for patient ndash Treat and extend

bull SERVICE

bull Capacity and demand planning = fixedT+E more predictable at least 1 month in advance ndash flexible nurse injectors

bull Steroids ndash even if well controlled (Iluvien for 3 years) need IOP check

bull Need pan-retinal examination both eyes ndash separate visits

Summary

CSMO

No centre involvement

Photocoagulation

Centre involvement

gt 78 letters(normalminimally reduced VA)

Photocoagulation

VA 78ndash24 letters

Phakic

Anti-VEGF

Pseudophakic

Anti-VEGF

SWITCHglaucoma

Injection tolerance

Medical issuesrecent CVA

Peripheral diseaseBilateral Rx

CSMO

No centre involvement

LASER

Centre involvement

gt 78 letters(normalminimally

reduced VA)

VA 78ndash24 letters

EYLEA OR LUCENTIS OR AVASTIN

Funding issues

Protocol T ndash poor VA lt 65 letters (615)

LOADING

Monthly injections until stability OR 5 x 112 (EYLEA) = 6 MONTHS then 8 weeks

RETREATMENT1

TREAT AND EXTEND - PRN

PRN

PSEUDOPHAKIC

Prior Rx

ILUVIEN

Chronic disease

OZURDEX

RETREATMENT

OZURDEX

OCT gt175um or any residual oedema

ILUVIEN after 12 months if risksltbenefits

OCT

gt400um

bull FACE TO FACE CLINICS RUNNING IN PARALLEL

bull = MAC002 every 6 months (optom or doctor) routine check for cataracttolerance of injectionsglaucoma issues etc

bull =MAC003 (DOCTOR) for problems as needed no fixed intervalDischargestop treatmentDeclines treatment diagnosis CSR overlay etcswitch drugs

bull =RV002- (DOCTOR) every 6 months

bull =DM002 ndash (DOCTOR) variable interval determined by last assessing doctor

bull First visit at 6 months from 1st injection if mild NPDR

bull Otherwise determined by retinopathy generally

LOADING PHASE

EyleaLucentis 1 within 48hrs of baseline

EyleaLucentis 2 (and LogMAR VA plus OCT same visit)

EyleaLucentis 3 (and LogMAR VA plus OCT same visit)

EyleaLucentis 4 (TEinj)(and Logmar VA plus OCT same visit

AFTER INJECTION 4 data goes off to be reviewed immediately as a hellip

TREAT AND EXTEND assessment ndash the next interval will depend on the response to the loading phase

NB -DMO patients ndash majority (95) will need 6 injctions x 112 of Lucentis

OR Eylea 5 x 112 then 8 weekly

ONCE STABLE for 3 x injection in TE phase

VIRTUAL CLINIC MONITORING OF MACULOPATHY AND PRN RETREATMENT

ANTI-VEGF INJECTION PATHWAYS Baseline visitMAC001 for wet AMDRV001 for CRVOBRVOMed ret clinic for DMO

Pathways ndash too many directions

Better that thanhellip

Thank you

The bigger pictureOther eyeThe patient as a wholeThe service -coping with capacity ndash compromises

bull OTHER EYE ndash may create problems

bull Treat and extend ndash ldquoreduce of visitsrdquo plus Eylea license ndash ldquono need for monitoringrdquo may not benefit if lots of visits due to PDR other eye

bull PERIPHERAL RETINA anti-VEGF supresses proliferative disease - Rebound on stopping Rx

bull PATIENT

bull Anti-VEGF ndash heavy user - Will comply

bull One stop much better than two stop for patient ndash Treat and extend

bull SERVICE

bull Capacity and demand planning = fixedT+E more predictable at least 1 month in advance ndash flexible nurse injectors

bull Steroids ndash even if well controlled (Iluvien for 3 years) need IOP check

bull Need pan-retinal examination both eyes ndash separate visits

Summary

CSMO

No centre involvement

Photocoagulation

Centre involvement

gt 78 letters(normalminimally reduced VA)

Photocoagulation

VA 78ndash24 letters

Phakic

Anti-VEGF

Pseudophakic

Anti-VEGF

SWITCHglaucoma

Injection tolerance

Medical issuesrecent CVA

Peripheral diseaseBilateral Rx

CSMO

No centre involvement

LASER

Centre involvement

gt 78 letters(normalminimally

reduced VA)

VA 78ndash24 letters

EYLEA OR LUCENTIS OR AVASTIN

Funding issues

Protocol T ndash poor VA lt 65 letters (615)

LOADING

Monthly injections until stability OR 5 x 112 (EYLEA) = 6 MONTHS then 8 weeks

RETREATMENT1

TREAT AND EXTEND - PRN

PRN

PSEUDOPHAKIC

Prior Rx

ILUVIEN

Chronic disease

OZURDEX

RETREATMENT

OZURDEX

OCT gt175um or any residual oedema

ILUVIEN after 12 months if risksltbenefits

OCT

gt400um

bull FACE TO FACE CLINICS RUNNING IN PARALLEL

bull = MAC002 every 6 months (optom or doctor) routine check for cataracttolerance of injectionsglaucoma issues etc

bull =MAC003 (DOCTOR) for problems as needed no fixed intervalDischargestop treatmentDeclines treatment diagnosis CSR overlay etcswitch drugs

bull =RV002- (DOCTOR) every 6 months

bull =DM002 ndash (DOCTOR) variable interval determined by last assessing doctor

bull First visit at 6 months from 1st injection if mild NPDR

bull Otherwise determined by retinopathy generally

LOADING PHASE

EyleaLucentis 1 within 48hrs of baseline

EyleaLucentis 2 (and LogMAR VA plus OCT same visit)

EyleaLucentis 3 (and LogMAR VA plus OCT same visit)

EyleaLucentis 4 (TEinj)(and Logmar VA plus OCT same visit

AFTER INJECTION 4 data goes off to be reviewed immediately as a hellip

TREAT AND EXTEND assessment ndash the next interval will depend on the response to the loading phase

NB -DMO patients ndash majority (95) will need 6 injctions x 112 of Lucentis

OR Eylea 5 x 112 then 8 weekly

ONCE STABLE for 3 x injection in TE phase

VIRTUAL CLINIC MONITORING OF MACULOPATHY AND PRN RETREATMENT

ANTI-VEGF INJECTION PATHWAYS Baseline visitMAC001 for wet AMDRV001 for CRVOBRVOMed ret clinic for DMO

Pathways ndash too many directions

Better that thanhellip

Thank you

Summary

CSMO

No centre involvement

Photocoagulation

Centre involvement

gt 78 letters(normalminimally reduced VA)

Photocoagulation

VA 78ndash24 letters

Phakic

Anti-VEGF

Pseudophakic

Anti-VEGF

SWITCHglaucoma

Injection tolerance

Medical issuesrecent CVA

Peripheral diseaseBilateral Rx

CSMO

No centre involvement

LASER

Centre involvement

gt 78 letters(normalminimally

reduced VA)

VA 78ndash24 letters

EYLEA OR LUCENTIS OR AVASTIN

Funding issues

Protocol T ndash poor VA lt 65 letters (615)

LOADING

Monthly injections until stability OR 5 x 112 (EYLEA) = 6 MONTHS then 8 weeks

RETREATMENT1

TREAT AND EXTEND - PRN

PRN

PSEUDOPHAKIC

Prior Rx

ILUVIEN

Chronic disease

OZURDEX

RETREATMENT

OZURDEX

OCT gt175um or any residual oedema

ILUVIEN after 12 months if risksltbenefits

OCT

gt400um

bull FACE TO FACE CLINICS RUNNING IN PARALLEL

bull = MAC002 every 6 months (optom or doctor) routine check for cataracttolerance of injectionsglaucoma issues etc

bull =MAC003 (DOCTOR) for problems as needed no fixed intervalDischargestop treatmentDeclines treatment diagnosis CSR overlay etcswitch drugs

bull =RV002- (DOCTOR) every 6 months

bull =DM002 ndash (DOCTOR) variable interval determined by last assessing doctor

bull First visit at 6 months from 1st injection if mild NPDR

bull Otherwise determined by retinopathy generally

LOADING PHASE

EyleaLucentis 1 within 48hrs of baseline

EyleaLucentis 2 (and LogMAR VA plus OCT same visit)

EyleaLucentis 3 (and LogMAR VA plus OCT same visit)

EyleaLucentis 4 (TEinj)(and Logmar VA plus OCT same visit

AFTER INJECTION 4 data goes off to be reviewed immediately as a hellip

TREAT AND EXTEND assessment ndash the next interval will depend on the response to the loading phase

NB -DMO patients ndash majority (95) will need 6 injctions x 112 of Lucentis

OR Eylea 5 x 112 then 8 weekly

ONCE STABLE for 3 x injection in TE phase

VIRTUAL CLINIC MONITORING OF MACULOPATHY AND PRN RETREATMENT

ANTI-VEGF INJECTION PATHWAYS Baseline visitMAC001 for wet AMDRV001 for CRVOBRVOMed ret clinic for DMO

Pathways ndash too many directions

Better that thanhellip

Thank you

SWITCHglaucoma

Injection tolerance

Medical issuesrecent CVA

Peripheral diseaseBilateral Rx

CSMO

No centre involvement

LASER

Centre involvement

gt 78 letters(normalminimally

reduced VA)

VA 78ndash24 letters

EYLEA OR LUCENTIS OR AVASTIN

Funding issues

Protocol T ndash poor VA lt 65 letters (615)

LOADING

Monthly injections until stability OR 5 x 112 (EYLEA) = 6 MONTHS then 8 weeks

RETREATMENT1

TREAT AND EXTEND - PRN

PRN

PSEUDOPHAKIC

Prior Rx

ILUVIEN

Chronic disease

OZURDEX

RETREATMENT

OZURDEX

OCT gt175um or any residual oedema

ILUVIEN after 12 months if risksltbenefits

OCT

gt400um

bull FACE TO FACE CLINICS RUNNING IN PARALLEL

bull = MAC002 every 6 months (optom or doctor) routine check for cataracttolerance of injectionsglaucoma issues etc

bull =MAC003 (DOCTOR) for problems as needed no fixed intervalDischargestop treatmentDeclines treatment diagnosis CSR overlay etcswitch drugs

bull =RV002- (DOCTOR) every 6 months

bull =DM002 ndash (DOCTOR) variable interval determined by last assessing doctor

bull First visit at 6 months from 1st injection if mild NPDR

bull Otherwise determined by retinopathy generally

LOADING PHASE

EyleaLucentis 1 within 48hrs of baseline

EyleaLucentis 2 (and LogMAR VA plus OCT same visit)

EyleaLucentis 3 (and LogMAR VA plus OCT same visit)

EyleaLucentis 4 (TEinj)(and Logmar VA plus OCT same visit

AFTER INJECTION 4 data goes off to be reviewed immediately as a hellip

TREAT AND EXTEND assessment ndash the next interval will depend on the response to the loading phase

NB -DMO patients ndash majority (95) will need 6 injctions x 112 of Lucentis

OR Eylea 5 x 112 then 8 weekly

ONCE STABLE for 3 x injection in TE phase

VIRTUAL CLINIC MONITORING OF MACULOPATHY AND PRN RETREATMENT

ANTI-VEGF INJECTION PATHWAYS Baseline visitMAC001 for wet AMDRV001 for CRVOBRVOMed ret clinic for DMO

Pathways ndash too many directions

Better that thanhellip

Thank you

bull FACE TO FACE CLINICS RUNNING IN PARALLEL

bull = MAC002 every 6 months (optom or doctor) routine check for cataracttolerance of injectionsglaucoma issues etc

bull =MAC003 (DOCTOR) for problems as needed no fixed intervalDischargestop treatmentDeclines treatment diagnosis CSR overlay etcswitch drugs

bull =RV002- (DOCTOR) every 6 months

bull =DM002 ndash (DOCTOR) variable interval determined by last assessing doctor

bull First visit at 6 months from 1st injection if mild NPDR

bull Otherwise determined by retinopathy generally

LOADING PHASE

EyleaLucentis 1 within 48hrs of baseline

EyleaLucentis 2 (and LogMAR VA plus OCT same visit)

EyleaLucentis 3 (and LogMAR VA plus OCT same visit)

EyleaLucentis 4 (TEinj)(and Logmar VA plus OCT same visit

AFTER INJECTION 4 data goes off to be reviewed immediately as a hellip

TREAT AND EXTEND assessment ndash the next interval will depend on the response to the loading phase

NB -DMO patients ndash majority (95) will need 6 injctions x 112 of Lucentis

OR Eylea 5 x 112 then 8 weekly

ONCE STABLE for 3 x injection in TE phase

VIRTUAL CLINIC MONITORING OF MACULOPATHY AND PRN RETREATMENT

ANTI-VEGF INJECTION PATHWAYS Baseline visitMAC001 for wet AMDRV001 for CRVOBRVOMed ret clinic for DMO

Pathways ndash too many directions

Better that thanhellip

Thank you

Pathways ndash too many directions

Better that thanhellip

Thank you

Thank you