Diabetic retinopathy ranibizumab : A disease modifying therapy

Diabetic Retinopathy: Ranizizumab

Somdutt Prasad MS FRCSEd FRCOphth FACSSenior Consultant Ophthalmologist

AMRI Medical Centre & Fortis Medical CentreKolkata, India

[email protected] www.somduttprasad.com +91 7044 06 7754

A tale of two protocols

Protocol T

Protocol S

A tale

• a story about imaginary events : an exciting or dramatic story

• a story about someone's actual experiences

• an exciting story that may not be completely true

Diabetes

• 1550 BC - Ebers Papyrus of ancient Egypt

• 171 million worldwide• India – 2000 - 31.7 million• 366 million in 2030

– Maximum increase in India– 79.4 million India– 42.3 million China

Avastin Ziv –Aflibercept or Zaltrap

Aflibercept or EyeLeaRanibizumabLucentis / Accentrix

BMJ Open 2014;4:e004015 doi:10.1136/bmjopen-2013-004015

For the first time in at least five decades, diabetic retinopathy/maculopathy is no longer the leading cause of certifiable blindness among working age adults in England and Wales, having been overtaken by inherited retinal disorders

Main causes of severe sight impairment (blindness) in England and Wales in working age adults (age 16–64): certifications 2009–2010.

Liew G et al. BMJ Open 2014;4:e004015

©2014 by British Medical Journal Publishing Group

This change may be related to factors including the introduction of nationwide diabetic retinopathy screening programmes in England and Wales and improved glycaemic control

Ranibizumab 0.5 mg clinical use in DME supported by extensive

scientific evidence

PROTOCOL-IRETAIN

REVEALRESPOND

RESTORE

RESOLVE

RISE

RIDE

8 randomized controlled trials

1800patients

Sham and laser as control

Monthly, PRN and

T&E regimens

Duration* of up to 5

years

*Duration ranged from 1 to 5 years for the different studies

DME patient population is younger than nAMD patients, and has many associated co-morbid

conditions

1. Petrella RJ, et al. J Ophthalmol 2012;1591672. Bandello F. Presented at COPHy 2014, Lisbon,

Portugal

Average age at diagnosis

DME patients are of working age and require long-term

management80

years2

AMD

50-60 years1,2

DME

Disease driven by Age Diabetes2

DME patients often present with

co-morbidities

FDA approval - drugs for DME

• Ranibizumab - August 2012• Aflibercept – March 2015• Bevacizumab - unlicensed

Key points

• Ranibizumab injections – monthly for 3 visits – then as needed depending on VA (with

OCT) stability• Follow-up monthly for 6-12 months• Once visual stability maintained for

3 consecutive visits, follow-up intervals can be prolonged to between 2 and 4 months

Key points…Laser

• If response to anti-VEGF treatment is unsatisfactory – ‘rescue’

• DME not involving center

Key points…Vitrectomy

• IF VMT shown on spectral domain OCT AND Vision affected

• Role of adjunctive antiVEGF, steroid, laser

Steroids

• Triamcinolone– Pseudophakic eyes– Resistant cases

• Dexamethasone– Ozurdex

• Fluocinolone Acetonide– Iluvien, Retisert

American Journal of Ophthalmology 2014 157, 505-513.e8DOI: (10.1016/j.ajo.2013.11.012)

DRCR.net Protocol T: First head to head study in DME with three anti-VEGF agents

Study objective: compare the efficacy and safety of intravitreal aflibercept, intravitreal bevacizumab, and intravitreal ranibizumab for the treatment of

DME in eyes of 660 patients with VA between 20/32 and 20/320

ClinicalTrials.gov. Available from: http://clinicaltrials.gov/ct2/show/NCT01627249 [Accessed 27 October 2014]; Wells JA, et al. NEJM 2015, epub ahead of print

DME, diabetic macular edema; DRCR.net, Diabetic Retinopathy Clinical Research Network; NEI, National Eye Institute; VA, visual acuity; VEGF, vascular endothelial growth factor

Randomization

22

Bevacizumab (1.25 mg)N = 218

Aflibercept (2.0 mg)N = 224

Ranibizumab(0.3 mg)N = 218

Randomly Assigned Eyes(one per participant):

N = 660

N = 206 (94%)N = 208 (93%) N = 206 (94%)One Year

97%94% 96%One Year Excluding

Deaths

Baseline

Study design: RZB 0.3 mg / Aflibercept 2.0mg / BZB 1.25mg in a PRN regimen

660 patients with DME randomized 1:1:1

OCT, optical coherence tomography; PRN, pro re nata (as needed)Wells JA, et al. NEJM 2015;372:1193-203; Wells JA, et al. Ophthalmology 2016

Visits every 4 ± 1 weeks* Treatment at baseline and thereafter using defined retreatment criteria

Year 1

Year 2Visits every 4–16 weeks, depending on treatment course

*A minimum of 21 days between visits

At or after Week 24, focal/grid laser was initiated if OCT ≥250 μm or edema threatened the fovea and the eye was not improved on OCT or visual acuity from the last two consecutive injections

2.0 mg intravitreal aflibercept(n = 224)

1.25 mg intravitreal bevacizumab (n = 218)

0.3 mg intravitreal ranibizumab (n = 218)

1st year - Topline results

• Clinically meaningful VA improvement with all three medications– +13.3 letters with Aflibercept, – +11.2 with Ranibizumab, – +9.7 with Bevacizumab

1st year - Topline results…2

• When the initial visual-acuity loss was mild, there were no apparent differences, on average, among study groups.

• At worse levels of initial visual acuity, Aflibercept was more effective at improving vision

Recommendations

• If Bevacizumab (& Ranibizumab / Aflibercept are not affordable) is available appropriately compounded it should be used for eyes with good VA

• For eyes with poor VA at presentation Aflibercept is preferred

Discussion

• Bevacizumab used in trials (CATT, IVAN, Protocol T) – is Avastin +

• Same preparation not available to most ophthalmologists

Similar VA gains in overall population between aflibercept and ranibizumab at 2

years

Mea

n ch

ange

from

bas

elin

e in

vi

sual

acu

ity le

tter s

core

25

20

25

10

5

00 4 8 12 16 20 24 28 32 36 40 44 48 52 68 84 104

Aflibercept Bevacizumab Ranibizumab

Week

+12.8+12.3+10.0

At Year 1, the improvement was greater, but not clinically meaningful, with aflibercept than with the other two drugs.1 At Year 2, the difference in VA gain between aflibercept and ranibizumab was no longer significant (p = 0.47), indicating that a dose of ranibizumab

that is 60% of the 0.5 mg ex-U.S. approved dose produced equivalent VA gains over 2 years to the full aflibercept 2.0 mg dose.2

1. Wells JA, et al. NEJM 2015;372:1193-203; 2. Wells JA, et al. . Ophthalmology 2016

+13.5+11.5+10.0

No significant difference in the proportion of patients with ≥10- or ≥ 15-letter gains between aflibercept and ranibizumab at 2

years

≥10-letter gain ≥15-letter gain ≥10-letter loss ≥15-letter loss0

10

20

30

40

50

60

70

Aflibercept(n = 201)

Bevacizumab(n = 185)

Ranibizumab(n = 191)

Pro

porti

on o

f pat

ient

s (%

)

p = 0.22 p = 0.50

p = 0.51

p = 0.49 p = 0.15

p = 0.39

p = 0.70 p = 0.70

p = 0.70

p = 0.84 p = 0.84

p = 0.84

There were no significant differences in the proportion of patients that had a ≥10 or

≥15-letter improvementor worsening

Proportion of patients with ≥10- or ≥15-letter gain or loss

Wells JA, et al. Ophthalmology 2016;XX:1-9

OCT outcomes: bevacizumab less efficacious reducing macular edema compared with ranibizumab and aflibercept at 2 years

CSFT, central subfield thicknessWells JA, et al. Ophthalmology 2016;XX:1-9

Bevacizumab -126 µm

Ranibizumab -149 µmAflibercept -171 µm

p < 0.001*

p = 0.08

0 4 8 12 16 20 24 28 32 36 40 44 48 52 68 84 104

Mea

n ch

ange

from

ba

selin

e in

CS

FT (μ

m)

0

–50

–100

–150

–200

–250


Week

*Also for aflibercept vs. bevacizumab

The difference in CSFT change from baseline between aflibercept and ranibizumab was no longer significant at Year 2

No difference in injection frequency over 2 yearsacross the three treatment arms

Aflibercept Bevacizumab

Ranibizumab

p valueaflibercept–ranibizumab

Total no. of injections in Year 11*

(maximum = 13) N = 208 N = 206 N = 206

Mean (standard deviation) 9.2 (2.0) 9.7 (2.3) 9.4 (2.1)

Median (25th, 75th percentile) 9 (8, 11) 10 (8, 12) 10 (8, 11) 0.19

Total no. of injections in Year 22 N = 201 N = 185 N = 192**


Median (25th, 75th percentile) 5 (2, 7) 6 (2, 9) 6 (2, 9) 0.32

Total no. of injections over 2 years2 N = 201 N = 185 N = 192


Median (25th, 75th percentile) 15 (11, 17) 16 (12, 20) 15 (11, 19) 0.081. Wells JA, et al. NEJM 2015;372:1193-2032. Wells JA, et al. . Ophthalmology 2016;XX:1-9

Percentage of laser treatments over 2 years

Aflibercept Bevacizumab Ranibizumabp value

aflibercept–ranibizumab

N = 208 N = 206 N = 206†

At least one focal/grid photocoagulation laser treatment between 24 weeks and 1 year1*, %

37% 56% 46% 0.058

N = 201 N = 185 N = 192At least one focal/grid photocoagulation laser treatment in Year 22, %

20% 31% 27% 0.12

At least one focal/grid photocoagulation laser treatment over 2 years2, %

41% 64% 52% 0.04

1. Wells JA, et al. NEJM 2015;372:1193-203;2. Wells JA, et al. . Ophthalmology 2016;XX:1-9

≥15 Letter Improvement at 2 YearsBaseline Visual Acuity 20/32 to 20/40

36Aflib

ercep

t

Bevac

izumab

Ranibizu

mab

20% 17% 19%

Observed Data

Perc

ent

Treatment Group Comparisons*

Adjusted Difference CIP-

Value

Aflibercept vs

Bevacizumab+1% -10% to +11% 0.89

Aflibercept vs

Ranibizumab+2% -8% to +11% 0.89

Ranibizumab vs

Bevacizumab-1% -11% to +10% 0.89

* P-values adjusted for baseline visual acuity and multiple comparisons

≥10 Letter Worsening at 2 YearsBaseline Visual Acuity 20/32 to 20/40

37Aflib

ercep

t

Bevac

izumab

Ranibizu

mab

4% 4% 1%

Observed Data

Perc

ent



Value

Aflibercept vs

Bevacizumab0 -6% to +5% 0.96

Aflibercept vs


Ranibizumab vs



≥15 Letter Improvement at 2 YearsBaseline Visual Acuity 20/50 or worse

38Afliberc

ept

Bevac

izumab

Ranibizu

mab

58%52% 55%

Observed Data

Perc

ent



ValueAflibercept

vs Bevacizumab

+8% -9% to +25% 0.74

Aflibercept vs


Ranibizumab vs

Bevacizumab+6% -8% to +20% 0.75


≥10 Letter Worsening at 2 YearsBaseline Visual Acuity 20/50 or worse

39Afliberc

ept

Bevac

izumab

Ranibizu

mab

5% 9%2%

Observed Data

Perc

ent



ValueAflibercept

vs Bevacizumab

-3% -10% to +3% 0.49

Aflibercept vs


Ranibizumab vs



RBZ 0.3 mg versus RBZ 0.5 mg?

Trend towards higher VA gain with ranibizumab 0.5 mg than 0.3 mg in patients with worst baseline

vision

(~20/80–20/160) (<20/200)

n = 112 n = 106 n = 119 n = 116 n = 21 n = 28

Zarbin M, Macular Society 2015

(≥ ~20/62.5)

Mea

n ch

ange

in B

CVA

fro

m b

asel

ine

to 1

2 m

onth

s (le

tters

)

Difference in VA gains between aflibercept and ranibizumab at

1 year predominantly driven by worst baseline VA patient group

Change in VA from baseline to Year 1 according to baseline VA

Visual acuity letter score(approximate Snellen equivalent)

Mea

n ch

ange

in v

isua

l acu

ity

lette

r sco

re a

t 1 y

ear

30

10

5

0

15

20

25

74–78(20/32)

69–73(20/40)

64–68(20/50)

54–63(20/63–20/80)

24–53(20/100–20/320)


Aflibercept 54 52 36 29 37

Bevacizumab 41 63 35 38 29

Ranibizumab 46 59 32 37 32

N =

Wells JA, et al. NEJM 2015;372:1193–203

RISE and RIDE pooled data: time to first macular laser treatment by Month 36

0 5 10 15 20 25 30 4035

Pro

porti

on o

f pat

ient

s w

ith

mac

ular

lase

r tre

atm

ent

0.8

0.6

0.4

0.2

0.0

Time to first macular laser treatment (months)

Sham/0.5 mg Ranibizumab 0.3 mg Ranibizumab 0.5 mgTreatment Group:

Adamis AP, FDA advisory committee presentation. Available at http://www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/drugs/dermatologicandophthalmicdrugsadvisorycommittee/ucm314199.pdf

Sham/0.5mg 257 123 78 62 49 46 43 41 0Ranibizumab 0.3

mg250 189 159 149 136 125 123 118 0

Ranibizumab 0.5 mg

252 199 181 173 160 151 145 132 0

Subjects at risk

67.7%

31.0%

22.4%

72.0%

37.6%

27.4%

73.2%

38.8%

29.4%

Safety• Systemic APTC rates were higher in the

ranibizumab group, with a greater number of nonfatal strokes and vascular deaths in the ranibizumab group– Once adjusted for baseline

characteristics, the p-values shifted from p=0.047 to p=0.09 for aflibercept versus ranibizumab

– These findings are not consistent with previously reported clinical trials.

• Patient characteristics were, overall, well-balanced at baseline– No substantial differences were observed between

patients who did and did not complete the 2-year follow-up

• Compared with previous DME studies, Protocol T included patients with a higher baseline BCVA and lower CSFT– Median BCVA range: 68–69 letters (69 letters in patients

who completed Year 2 visit)– Median OCT central subfield thickness range: 376–390

µm (377–387 µm in patients who completed Year 2 visit)• Numerically more patients in the ranibizumab arm than the

aflibercept arm had a history of coronary artery disease at enrolment into the study– 34 (16%) versus 22 (10%), respectively

Participant baseline characteristics

Wells JA, et al. NEJM 2015;372:1193-203; Wells JA, et al. Ophthalmology 2016;XX:1-9

Summary Y2 Protocol T• Differences in VA gains observed at 1

year in the overall population and the subgroup of patients treated with ranibizumab or aflibercept with worse baseline BCVA were no longer statistically significant at 2 years

• The mean/median number of injections was similar of aflibercept (14.2/15) and ranibizumab (14.8/15).

Variabilty

DRCR.net Protocol S

Prompt PRP vs.

Ranibizumab 0.5 mg + Deferred PRP for PDR Study

Protocol S 2 year resultsRanibizumab• a viable treatment option for people

with proliferative diabetic retinopathy

• especially for individuals needing anti-VEGF for diabetic macular edema

Study:Protocol S

• 55 sites– 203 eyes PRP group– 109 eyes RZB

• 2 years –VA– 0.2 letters in PRP group– 2.8 letters in RZB group

• Vitrectomies– 15% PRP group– 4% RZB group

51

0 16 32 52 68 84 104

Without “Baseline DME”

Visit Week

0 16 32 52 68 84 104-4-202468

101214

With “Baseline DME”

Ranibizumab Group PRP Group

Visit Week

Mea

n Vi

sual

Acu

ity C

hang

e(L

ette

r Sco

re)

+2

+7.9

- 0.5

+1.8

N = 42 N = 33 N = 147N = 46 N = 37 N = 155 N = 130

N = 126

*Outlying values were truncated to 3 SD from the mean

Mean Change in Visual AcuityStratified by Baseline DME

Advantages of PRP• Completed in one or two visits • Often long-lasting effect requiring no

additional treatment However, study suggests approximately

45% given additional PRP after initial full PRP was completed

From completion of initial full PRP, median time to additional PRP ~7 months

• Cost less than ranibizumab injections• No risk of endophthalmitis• No risk of systemic exposure to anti-VEGF

Advantages of RanibizumabMean change in VA from baseline to 2-

years no worse than with PRPSuperior mean visual acuity over course

of 2-years (area under the curve analysis)Superior mean visual field outcomesDecreased chance of vitrectomies Decreased chance of developing DMEPRP rarely given for futility or failure Unknown if similar outcomes with other

anti-VEGF agents (bevacizumab or aflibercept)

Thank You Somdutt PrasadKolkata +917044067754

www.somduttprasad.com

Healthcare

Diabetic retinopathy ranibizumab : A disease modifying therapy