Intravitreal Injections for

Diabetic Retinopathy

Nawat WatanachaiVR Fellow

SCGH

What to inject into the vitreous of diabetic eyes?

CorticosteroidAnti-Vascular endothelial growth factors (anti-VEGF)Avastin (Bevacizumab)Lucentis (Ranibizumab)Macugen(Pegaptanib)

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In which eyes?I. Diabetic macular edemaII. Adjunctive therapy

PDR with NV that not response to laserPDR with cataract/ VH, unable to add laser

III. Eyes with active NV and/or VH, planned for Vx

DR

Leakage/ occlusion of small vesselsWide spread of ischemic retinaImbalance between PG/IL/pro-angiogenic factor VEGF & anti-angiogenic factor PEDF, AngiostatinVEGF-A + other factors NV

Corticosteroids

extravasation from leaking blood vessels (inhibit archidonic pathway that produce IL/PG)

proliferation of fibroblasts and granulation tissue

breakdown of the blood-retinal barrier

production of vascular endothelial growth factor (VEGF)

AntiVEGF : Targeting VEGF pathway

antiVEGF Structure Target Vitreous (wk)

Macugen (Pegaptanib

)

RNA aptamer

VEGF165 isoform

6

Lucentis (Ranibizuma

b)

Fab portion

All VEGF-A isoforms

4-8

Avastin (Bevacizuma

b)

Full-length Ab

All VEGF-A isoforms

8-12

Anti-VEGF

In which eyes?

I. Diabetic macular edema

II. Adjunctive therapyPDR with NV that not response to laserPDR with VH, unable to add laser

Eyes with active NV and/or VH, planned for Vx

Diabetic Macula Edema

- ETDRS- Repeated macular laser for focal/diffuse DME may do more damage to the vision

- Diffuse DME is much less responsive to laser than focal DME

I. DME: Intravitreal Triamcinolone (IVTA)Intravitreal triamcinolone acetonide for diabetic macular edema: A prospective randomized study. Jonas JB et al. J Ocul Pharmacol Ther. 2006; 22.

Unilateral 20 mg IVTA injection in bilateral DME. 33 casesVA improvement by 3 lines: 39% in the IVTA (20mg) eyes vs. 0% in the control eyes at 6 months.Big dose

Effect lasts approximately 7-8 mthsIIOP ~52%

I. DME : Avastin - persistent DME

- Intravitreal Avastin therapy for persistent diffuse diabetic macular edema

- Christos Haritoglou et al, Retina 2006;26.

- 51 patients with diffuse CSME (age 23-79 yrs)

- Persistent DME after any treatment (beyond 6 mths period)- Laser 18 eyes/ IVTA 17 eyes/ Vitrectomy 6 eyes

- Avastin 1.25 mg/0.05 ml- 6 wks follow up

- Intravitreal Avastin therapy for persistent diffuse diabetic macular edema

- Christos Haritoglou et al, Retina 2006;26.

- 51 patients with diffuse CSME (age 23-79 yrs)

- Persistent DME after any treatment (beyond 6 mths period)- Laser 18 eyes/ IVTA 17 eyes/ Vitrectomy 6 eyes

- Avastin 1.25 mg/0.05 ml- 6 wks follow up

I. DME : Avastin - persistent DME

baseline 6 wks 12 wks

VA(ETDRS letters)

25.88+/-14.43

31.32+/-14.33(P=0.001)

27.05+/-14.83(not sig)

CRT(Microns)

501+/-163

416+/-180(P=0.001)

377+/-117(P=0.001)-Intravitreal Avastin therapy for

persistent diffuse diabetic macular edema.-Christos Haritoglou et al, Retina

2006;26.

I. DME : Avastin - persistent DME

- 15 eyes (29%) increased in VA of at least 3 lines

- 70% received a second injection at 12 wks

- Factors influencing treatment success- Baseline VA +++- Macular ischemia --- - CRT +- Age, previous treatment, area of peripheral ischemia +/--Intravitreal Avastin therapy for

persistent diffuse diabetic macular edema.-Christos Haritoglou et al, Retina

2006;26.

I. DME : Avastin - primary RxPrimary intravitreal Avastin for DME

, Results from the Pan-American Collaborative Retina Study Group at 6-mth follow up.

J.Arevalo et al. Ophthalmology 2007 April, 114(4).

6 centers from 6 contries110 diffuse DME eyes/ 88 ptsMean age 59.7+/-9.3 yrs1.25 mg of Avastin injectionFollow up 6.31 mths (6-9)

I. DME : Avastin - primary RxVABaseline 6/48 or 0.87 logMARFinal 6/24 or 0.6 logMAR (P<0.0001)

Improved >/= 2 snellen lines 43 eyes (55.1%)Stable 32 eyes (41.1%)Decreased >/= 2 snellen lines 3 eyes (3.8%)

Mean CRTBaseline 387.0 +/- 182.8 micronsFinal 275.7 +/- 108.3 microns (P<0.0001)

16 eyes(20.5%) needed 2nd injection Primary intravitreal Avastin for DME.

J.Arevalo et al. Ophthalmology 2007 April, 114(4).

I. I. DME : Lucentis

- VEGF is a critical stimulus for DME,

- Nguyen QD et al. Am J Ophthalmol. 2006 Dec; 142(6).

- 10 pts with chronic DME- Lucentis 0.5 mg at 0, 1, 2 ,4 ,6 mth

I. DME : Lucentis

VA improved in all 10 ptsCRT decreased in all 10 pts

mean VA Mean CRT

baseline 20/80 503

7 mth 20/40P=0.005

257P=0.005

VEGF is a critical stimulus for DME, Nguyen QD et al. Am J Ophthalmol. 2006 Dec; 142(6).

I. DME : Macugen

A Phase II randomized double-masked trial of pegaptanib an anti-VEGF aptamer, for DME; The Macugen Diabetic Retinopathy Study Group; Ophthalmology 2006; 113:23.

Eyes with CSME involving the center of macula corresponding leakage from FA172 subjects, VA 20/50-20/320Inject 0.3/1/ 3mg q 6 wks for 12-30 wks (3-6 injections)

I. DME : MacugenResult at 36 wk, 0.3 mgMedian VA 20/50 vs 20/63 (P=0.04)

Gain VA>10 letters 34% vs 10% (P=0.003)Gain VA>15 letters 18% vs 7 % (P=0.12)

Mean decrease thickness 68 vs -4 microns Decrease thickness>100 microns 42% vs 6% (P=0.02)

Need laser 25% VS 48% (P=0.04)result at 82 wks (1 yr after last possible injection)Decrease thickness 122 vs 49 micronsRequired less frequency of laser treatment1 endophthalmitis from 652 injections

A Phase II randomized double-masked trial of pegaptanib an anti-VEGF aptamer, for DME;

The Macugen Diabetic Retinopathy Study Group; Ophthalmology 2006; 113:23

DME

- Focal DME with microaneurysms --> focal laser

- Diffuse DME which do not response to grid laser --> IVTA or antiVEGF

- DME with vitreous traction --> PPV/ combination

DME : diffuse type

- Predicting factors- Younger age- Lower degree of maculr ischemia- Better pre-injection VA- Shorter duration of ME- Thicker CRT

In which eyes?I. Diabetic macular edema

II. Adjunctive therapyPDR with NV that not response to laserPDR with cataract/VH/etc, unable to add laser

III.Eyes with active NV and/or VH, planned for Vx

II. Adjunctive treatment for PDR : Avastin

-Intravitreal avastin for persistent new vessels in DR (IBEPE Study)-Rodrigo Jorge et al. 200RETINA6 ;26.

- tt ttt ttt tttt ttttt tttt tttttt15 20/40.- 6008age . +/- 775 49 7. yrs ( –3 ).- 15. mg of Avastin

II. Adjunctive treatment for P

DR : Avastin1 week

6 weeks

12 weeks

persistent active NV 5½ months after PRP

II. Adjunctive treatmen t for PDR : Avastin

baseline 1 wk

6 wk 12 wk

II. Adjunctive treatmen t for PDR : Avastin

12 wk

1 wk

6 wk

baseline

II. Adjunctive treatment for PDR : Avastin

Baseline

1 wk 6wk 12wk

Mean NV leakage area (mm2)

27.79+/-6.29

5.43 +/- 2.18

5.65 +/- 1.76

5.50+/-1.24

VA 20/160 20/125P=.05

20/125P=.05

20/125P=.05

IOP (mmHg)

14.93 +/- 0.77

15.33 +/-0.84

15.20 +/- 0.78

15.26 +/-0.81

Recurrence of NV observed in 14/15 eyes at wk12

II. Adjunctive treatment for PDR : Macugen

Changes i n r et i nal neovascul ar i zat i on af t er pegapt ani b ( Macugen) t her apy i n di abet i c i ndi vi dual s.

Macugen Diabetic Retinopathy Group. Ophthalmology 2006;113:23–28.

t egr essi on of ocul ar neovascul ar i z 81362ation occurred in / ( %) of tttt

ents in the pegaptanib treatment group 36at weeks.

38 52/ NV pr ogr essed at wk af t er cess 30at i on of Macugen at wk

03/ i n shamgr oup

II. Adjunctive treatm ent for PDR : Macugen

In which eyes?

I. Diabetic macular edemaII. Adjunctive therapy

PDR with NV that not response to laserPDR with VH, unable to add laser

III. Eyes with active NV and/or VH, planned for Vx

III. Eyes with active NV and/or VH, planned for Vx : Avastin

Intravitreal Avastin : An Adjunctive Therapy for Proliferative Diabetic VitrectomyC. Saovaprut et al,Thai J Ophthalmol 2006; 20(1)

intravitreal bevacizumab 1 mg/0.04 ml.Vitrectomy in 1-4 weeks after injection.Intraoperative homeostasis, postoperative bleeding and retinal reattachment were observed.

1CASE : Avastin

VA 6/400 VA of 20/200, 12 wks after injection.

C. Saovaprut et al,Thai J Ophthalmol 2006; 20(1):20-26.

2CASE : Avastin

Preoperative intravitreal injection of Avastin

Postoperative at 1 week

C. Saovaprut et al,Thai J Ophthalmol 2006; 20(1):20-26.

tttt 3 : Avastin

C. Saovaprut et al,Thai J Ophthalmol 2006; 20(1):20-26.

30 eyes in 28 patientsThe regression of NV was noted as early as 24-48 hours and completed at average 1 week.Significantly less intraoperative bleeding, intraocular diathermy was used only 4 times in 30 surgeriesNo immediately or late postoperative bleeding and anatomical retinal reattachment in all patients at last follow-up. (1-10 months; mean 5.6 months).

III. Eyes with active NV and/or VH, planned for Vx : Avastin -result

C. Saovaprut et al,Thai J Ophthalmol 2006; 20(1):20-26.

In which eyes?I. Diabetic macular edemaII. Adjunctive therapy

PDR with NV that not response to laserPDR with cataract/ VH, unable to add laser

III. Eyes with active NV and/or VH, planned for Vx

Adverse effects : IVTA

Infectious/ non infectious endophthalmitis 1:1000Glaucoma, transient IIOP 25-50% of cases

Need glaucoma surgery 1-2%RD in eyes with previously treated RBCataract

50-90% in 2 yrs esp PSCSignificant cataract that need surgery 15-20% in 1 yr

Reported : MH, persistent unsealed scleral wound(30G)

Adverse effects : IVTA

Glaucoma/ OHTStart ~1wk after injectionRisk factors

Younger agePre-op IOP > 16 mmHGRepeated injectionPre-op glaucoma

Adverse Effects : Anti-VEGF

Foreign body sensationSubconjunctival hemorrhageTransient IIOP/ pain/ floatersUveitis (esp Lucentis)Worsening of preexisting PRHRPE tearEndophthalmitisAllergic reaction Others eg. MI, hypertension

Ongoing StudiesA phase 2 evaluation of anti-VEGF therapy for DME : Avastin/ US NIH (laser/ avastin/ avastin+laser)READ2 study : avastin+laser VS Lucentis+laser for DMEMulticenter randomised clinical trial of laser treatment plus IVTA for DME (Phase III, AUS, 2005-2008)Macugen compared to sham injection in patients with DME involving the center of the macula (Phase III,2005-2010)Efficacy study of Lucentis in the treatment of DMELaser-Lucentis-triamcinolone for PDRLaser-Lucentis-triamcinolone for DMERESOLVE : safety and efficacy of avastin in DME with center involvementIntravitreal avastin vs photocoagulation for PDRIntravitreal avastin for treatment of NVGEffect of macugen on surgical outcomes and VEGF levels in diavetic patients with PDR or CSMEStudy for the treatment of iris NV with Macugen (2006-2007)Macugen to prevent worsening of macular edema following cataract surgery in diabeticLucentis VS Avastin for DME/ US NIH