Materi presentasi dr.Ari Djatikusumo,SpM(K) pd RTD Perdami Bekasi

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The Role of anti-VEGF therapy in retina diseases associated with macular edema :

The Role of anti-VEGF therapy in retina diseases associated with macular edema Ari Djatikusumo , MD

Neovascular AMD and DME have distinct disease profiles:

2 Neovascular AMD and DME have distinct disease profiles Neovascular AMD DME Driver Ageing Diabetes mellitus Prevalence Affects 2.3% of people ≥65 years of age in Europe 1 (~2.5 million people worldwide) DME with visual impairment affects 1–3% of diabetes patients 2 (~3.6 million people worldwide) Primary macular site of pathology Choroid Intraretinal layers 3 Key elements in pathogenesis Changes in aging eye, upregulation of VEGF, neovascularization, breakdown of outer BRB Sustained hyperglycaemia, upregulation of VEGF, hyperpermeability, breakdown of inner BRB 3 Progression Rapid loss of VA 4,5 Gradual loss of VA 6 Diagnosis & evaluation FA (CNV) 5 Slit-lamp biomicroscopy, ICGA, OCT, ETDRS score 5,7 Fundus contact lens biomicroscopy (retinal thickening) 3 FA, OCT, ETDRS score 3 Classification By location and appearance on FA By location and extent of leakage observed on FA 3 Current standard of care Ranibizumab IVI Laser photocoagulation 5. Sickenberg M. Ophthalmologica 2001;215:247–253 6. Cunningham E at al. Ophthalmology 2005;112:1747–1757 7. The Royal College of Ophthalmologists. AMD: guidelines for management 2009. http://www.rcophth.ac.uk/docs/publications/AMD_GUIDELINES_FINAL_VERSION_Feb_09.pdf [accessed Sep 2009 1. Augood CA et al . Arch Ophthalmol 2006;124:529–535 2. WESDR/ETDRS extrapolation and RNIB studies 3. Bhagat N et al . Surv Ophthalmol 2009;54:1–32 4. Rosenfeld B et al . N Engl J Med 2006;355:1419–1431

Neovascular AMD and DME primarily affect different vascular systems:

3 Neovascular AMD and DME primarily affect different vascular systems Primarily associated with breakdown of the inner BRB 2 Primarily associated with breakdown of the outer BRB 1 1. Cummings M, Cunha-Vaz J. Clin Ophthalmol 2008;2:369–375 2. Bhagat N et al. Surv Ophthalmol 2009;54:1–32 Neovascular AMD DME RPE layer Retinal capillary Microaneurysm Fovea Fovea Choroid Drusen PRL ONL INL IPL OPL IPL, inner plexiform layer; INL, inner nuclear layer; OPL, outer plexiform layer; ONL, outer nuclear layer; PRL, photoreceptor layer Choroidal neovascularization (CNV) Edema Retina Hard exudate

Differences in neovascular AMD and DME are evident from OCT images:

4 Structural changes observed 1,2 Retinal thickening Subretinal fluid accumulation Cystoid spaces Pigment epithelial detachment CNV OCT of neovascular AMD Structural changes observed 3,4 Retinal swelling (thickening) Cystoid macular edema Serous retinal detachment Vitreomacular traction Hard exudates OCT of DME Differences in neovascular AMD and DME are evident from OCT images 1. Liakopoulos S et al. Invest Ophthalmol Vis Sci 2008;49:5048–5054 2. The Royal College of Ophthalmologists. AMD: guidelines for management. 2009. http://www.rcophth.ac.uk/docs/publications/AMD_GUIDELINES_FINAL_VERSION_Feb_09.pdf [accessed Sep 2009] 3. Bhagat N et al. Surv Ophthalmol 2009;54:1–32 4. Lang GE. In Developments in ophthalmology . 2007. p31–47 Retina RPE layer Choroid

Different gold standard diagnostics with common ancillary tests:

5 Early detection of neovascular AMD is possible with an Amsler grid 1 FA is essential to confirm diagnosis of neovascular AMD, and to identify the location and composition of the CNV 1 Ancillary tests: 2 ICGA – delineation of choroidal vessel morphology OCT – measurement of retinal thickness Neovascular AMD DME is diagnosed stereoscopically as retinal thickening in the macula using fundus contact lens biomicroscopy 3 Ancillary tests: 3 FA – identification and evaluation of fluid leakage from lesions OCT – measurement of retinal thickness DME Different gold standard diagnostics with common ancillary tests 1. Sickenberg M. Ophthalmologica 2001;215:247–253 2. The Royal College of Ophthalmologists. AMD: guidelines for management. 2009. http://www.rcophth.ac.uk/docs/publications/AMD_GUIDELINES_FINAL_VERSION_Feb_09.pdf [accessed Sep 2009] 3. Bhagat N et al. Surv Ophthalmol 2009;54:1–32

Pathogenesis of neovascular AMD:

6 Pathogenesis of neovascular AMD Augustin AJ, Kirchhoff J . Expert Opin Ther Targets 2009;13:641–651 Kijlstra A et al . In Uveitis and immunological disorders. 2009. p73–85 CFH, complement factor H; IL, interleukin; MCP, monocyte chemoattractant protein; RPE, retinal pigment epithelium Thinning choriocapillaris UV light exposure Thickening Bruch’s membrane Advanced AMD and vision loss The ageing eye Oxidative stress and related tissue damage RPE dysfunction Drusen formation Complement activation  VEGF  IL-1, IL-6, IL-8, MCP-1  Macrophages  Inflammatory mediators (C3a and C5a) Associated with genetic polymorphism in CFH Stimulation of C5a receptor Disruption of Bruch’s membrane Neovascularization and invasion of subretinal space

Pathogenesis of DME:

7 Pathogenesis of DME Bhagat N et al. Surv Ophthalmol 2009;54:1–32 AII, angiotensin II; AGE, advanced glycation end; BRB, blood–retinal barrier; DAG, diacylglycerol; ET, endothelin; LPO, lypoxygenase; MMP, matrix metallo-proteinases; NO, nitric oxide; PKC, protein kinase C; PPVP, posterior precortical vitreous pocket; RAS, renin-angiotensin system Role of genetic factors? Sustained hyperglycaemia Macular edema AGE ET  VEGF Hypoxia IL-6 Destabilization of vitreous Abnormalities in collagen cross-linking MMP activity  PPVP DAG PKC Vasoconstriction  Histamine ET-receptors on pericytes Oxidative damage  LPO, NO, NADH/NAD + Antioxidant enzymes RAS activation Vitreomacular traction Accumulation of cytokeratin and glial fibrillary acidic protein Phosphorylation of tight junction proteins Disorganization of BRB AII

Common rationale for targeting VEGF:

8 Common rationale for targeting VEGF Augustin AJ, Kirchhoff J . Expert Opin Ther Targets 2009;13:641–651 Kijlstra A et al . In Uveitis and immunological disorders. 2009. p73–85 Bhagat N et al. Surv Ophthalmol 2009;54:1–32 Upregulation in expression of VEGF Changes in the ageing eye Sustained hyperglycaemia Neovascularization Neovascular AMD Hyperpermeability Macular edema Phosphorylation of tight junction proteins Disorganization of BRB

VEGF-A levels are increased in many ocular neovascular diseases:

VEGF-A levels are increased in many ocular neovascular diseases Age-related macular degeneration (AMD) Proliferative diabetic retinopathy Diabetic macular edema Rubeosis iridis associated with retinoblastoma Central and branch retinal vein occlusion von Hippel-Lindau syndrome Ocular melanomas and retinoblastomas Pe'er et al. Ophthalmology 1997; 104: 1251-1258 Pe'er et al. Ophthalmology 1998; 105: 412-416 Harris. Oncologist 2000; 5 Suppl 1: 32-36 Stitt et al. J Pathol 1998; 186: 306-312 VEGF, vascular endothelial growth factor Otani et al. Microvasc Res 2002; 64: 162-169 Wilkinson- Berka et al. J Vasc Res 2001; 38: 527-535 Funatsu et al. Ophthalmology 2003; 110: 1690-1696

VEGF-A has a key role in the angiogenic cascade leading to neovascularization and permeability:

VEGF-A has a key role in the angiogenic cascade leading to neovascularization and permeability VEGF-A Aiello et al. N Engl J Med 1994; 331: 1480-1487 Campochiaro et al. Mol Vis 1999; 5: 34 Dvorak et al. Am J Pathol 1995; 146: 1029-1039 Ferrara. Recent Prog Horm Res 2000; 55: 15-35 Miller. Am J Pathol 1997; 151: 13-23 Miller et al. Am J Pathol 1994; 145: 574-584 Pe’er et al. Lab Invest 1995; 72: 638-645 Spilsbury et al. Am J Pathol 2000; 157: 135-144 Migrating endothelial cells form new blood vessels in formerly avascular space Hypoxia Proliferation Migration Proteolysis Vascular endothelial cell Other angiogenic growth factors Basement membrane

Development of Ranibizumab:

Development of Ranibizumab Six amino acid change increases binding affinity rhu Fab v1 Insertion of murine anti-VEGF-A sequences into a human Fab framework Humanization Ranibizumab (48 kDa) ( E.coli vector used to mass produce; no glycosylation) Anti-VEGF-A murine MAb (~150 kDa) Ferrara et al. Retina 2006; 26: 859-870 Chen et al. J Mol Biol 1999; 293: 865-881 Presta et al. Cancer Res 1997; 57: 4593-4599 Selective mutation

Ranibizumab inhibits all biologically active VEGF-A isoforms :

Ranibizumab inhibits all biologically active VEGF-A isoforms Adapted from Ferrara et al. Nat Med 2003; 9: 669-676 165 1 Most abundant isoform expressed in humans Sequestered in the extracellular matrix 1 189 Highly diffusible and bioactive isoform VEGF-A 121 86–89 1 121 1 206 Highest molecular weight isoform bound to extracellular matrix VEGFR binding domain Heparin binding domain Ranibizumab binding site VEGF-A 206 86–89 VEGF-A 189 86–89 VEGF-A 165 86–89 Pegaptanib binding site

Ranibizumab mechanism of action:

Ranibizumab mechanism of action Acts early in the cascade Attacks disease in 3 ways inhibits vascular permeability inhibits endothelial cell proliferation inhibits endothelial cell migration Penetrates retina to block all tested isoforms of VEGF-A Lowe et al. Invest Ophthalmol Vis Sci 2003; 44: ARVO E-abstract 1828 Gaudreault et al. Invest Ophthalmol Vis Sci 2003; 44: ARVO E-abstract 3942 Krzystolik et al. Arch Ophthalmol 2002; 120: 338-346 Mordenti et al. Toxicol Pathol 1999; 27: 536-544 Ranibizumab VEGF-A VEGF-A receptor

Ranibizumab for wet-AMD Marina Study:

Ranibizumab for wet-AMD Marina Study Randomized 1:1:1 Sham (n = 238) Ranibizumab 0.3 mg (n = 238) Ranibizumab 0.5 mg (n = 240) Minimally classic or occult with no classic lesions secondary to AMD (N = 716) Investigator identifies potential patients Rosenfeld et al. N Engl J Med 2006; 355: 1419-1431 Reading center confirms angiographic eligibility Phase III, multicenter, double-masked, 24-month study AMD, age-related macular degeneration

Primary efficacy endpoint: patients losing <15 letters from baseline:

Primary efficacy endpoint: patients losing <15 letters from baseline *p<0.001 vs sham Patients (%) 100 50 0 * * * * Month 12 Month 24 Sham (n = 238) Ranibizumab 0.3 mg (n = 238) Ranibizumab 0.5 mg (n = 240) Rosenfeld et al. N Engl J Med 2006; 355: 1419-1431

PowerPoint Presentation:

mean change in VA over time Sham (n = 238) Ranibizumab 0.3 mg (n = 238) Ranibizumab 0.5 mg (n = 240) ETDRS letters Month +7.2 +6.5 -10.4 21.4-letter difference* 20.3-letter difference* *p<0.001 vs sham for all comparisons between each Ranibizumab group and sham group ETDRS, Early Treatment Diabetic Retinopathy Study +6.6 +5.4 -14.9 Rosenfeld et al. N Engl J Med 2006; 355: 1419-1431 +5.9 +5.1 -3.7

Secondary efficacy endpoint: patients with 20 / 200 or worse Snellen equivalent:

Secondary efficacy endpoint: patients with 20 / 200 or worse Snellen equivalent Rosenfeld et al. N Engl J Med 2006; 355: 1419-1431 100 50 0 * * Baseline Month 24 Sham (n = 238) Ranibizumab 0.3 mg (n = 238) Ranibizumab 0.5 mg (n = 240) *p<0.001 vs sham Patients (%)

Secondary efficacy endpoint: patients improving ≥15 letters at Month 24:

Secondary efficacy endpoint: patients improving ≥ 15 letters at Month 24 100 50 0 ≥15 letters gained Sham (n = 238) Ranibizumab 0.3 mg (n = 238) Ranibizumab 0.5 mg (n = 240) *p<0.0001 vs sham * Patients (%) * Rosenfeld et al. N Engl J Med 2006; 355: 1419-1431

Conclusions MARINA study:

Conclusions MARINA study The results from MARINA demonstrate that intravitreal Ranibizumab is associated with clinically and statistically significant benefits with respect to VA in patients with minimally classic or occult lesions with no classic CNV associated with neovascular AMD over a 2-year period In patients treated with Ranibizumab , efficacy was maintained throughout the 2-year period whereas patients in the sham group continued to experience a decline in vision Rosenfeld et al. N Engl J Med 2006; 355: 1419-1431

Conclusions (2):

Conclusions (2) Ranibizumab was well tolerated over a 2-year period Efficacy outcomes were achieved with a low rate of serious ocular AEs and no clear difference from the sham-treated group in the rate of non-ocular AEs Subsequent to the results of the ANCHOR and MARINA trials, Ranibizumab was licensed for the treatment of neovascular AMD by the US Food and Drug Administration in 2006 and in the European Union in 2007 AE, adverse event Rosenfeld et al. N Engl J Med 2006; 355: 1419-1431

Ranibizumab for wet-AMD ANCHOR Study:

Ranibizumab for wet-AMD ANCHOR Study Randomized 1:1:1 Verteporfin PDT Sham PDT Sham PDT Sham injection (n = 143) Ranibizumab 0.3 mg (n = 140) Ranibizumab 0.5 mg (n = 140) Predominantly classic lesions secondary to AMD (N = 423) Brown et al. N Engl J Med 2006; 355: 1432-1444 Investigator identifies potential patients Reading center confirms angiographic eligibility Phase III, multicenter, double-masked, 24-month study AMD, age-related macular degeneration PDT, photodynamic therapy

Patients losing <15 letters from baseline (primary and secondary endpoints):

Patients losing <15 letters from baseline (primary and secondary endpoints) Verteporfin PDT (n = 143) Ranibizumab 0.3 mg (n = 140) Ranibizumab 0.5 mg (n = 139) ***p<0.0001 vs verteporfin PDT; randomized patients Patients (%) 100 Month 12 Month 24 50 0 *** *** *** *** Brown et al. N Engl J Med 2006; 355: 1432-1444 Brown et al. Ophthalmology 2009; 116: 57-65

Mean change in VA from baseline over time (secondary endpoint):

20.5-letter benefit -15 -10 -5 0 5 10 15 24 22 20 18 16 14 12 10 8 6 4 2 0 Mean change in VA from baseline over time (secondary endpoint) Verteporfin (n = 143) Ranibizumab 0.3 mg (n = 140) Ranibizumab 0.5 mg (n = 139) **p<0.001 vs verteporfin PDT at each month; r andomized patients ETDRS, Early Treatment Diabetic Retinopathy Study ETDRS letters Month +10.7 +8.1 -9.8 ** 17.9-letter benefit ** +11.3 +8.5 -9.6 Brown et al. Ophthalmology 2009; 116: 57-65 +10.0 +6.8 -2.5

Patients improving by ≥0 and ≥15 letters (secondary endpoint) at Month 24:

Patients improving by ≥0 and ≥15 letters (secondary endpoint) at Month 24 Verteporfin PDT (n = 143) Ranibizumab 0.3 mg (n = 140) Ranibizumab 0.5 mg (n = 139) Patients (%) ≥ 0 ≥ 15 28.7 77.9 77.7 6.3 34.3 41.0 100 50 0 Letters gained *** *** ***p<0.0001 vs verteporfin Brown et al. Ophthalmology 2009; 116: 57-65 *** ***

Patients with VA 20 / 200 Snellen equivalent or worse (secondary endpoint) at Month 24:

Patients with VA 20 / 200 Snellen equivalent or worse (secondary endpoint) at Month 24 ***p<0.0001 vs verteporfin † n = 139 for Ranibizumab 0.5 mg at baseline Verteporfin PDT (n = 143) Ranibizumab 0.3 mg (n = 140) Ranibizumab 0.5 mg (n = 140) Patients (%) Baseline Month 24 32.2 25.0 23.0 † 60.8 22.9 20.0 100 50 0 *** *** Brown et al. Ophthalmology 2009; 116: 57-65

Key serious ocular adverse events:

Key serious ocular adverse events Safety population Footnotes are presented in the notes section Preferred term n (%) Key serious ocular adverse events Presumed endophthalmitis* Uveitis Rhegmatogenous retinal detachment Retinal tear Vitreous hemorrhage Lens damage Most severe ocular inflammation, regardless of cause (slit-lamp examination) 1+ 2+ 3+ 4+ Brown et al. Ophthalmology 2009; 116: 57-65 Verteporfin PDT (n = 143) 0 0 1 (0.7) † 0 0 0 1 (0.7) 0 0 0 Ranibizumab 0.3 mg (n = 137) 0 0 2 (1.5) 0 2 (1.5) 0 3 (2.2) 2 (1.5) 2 (1.5) 1 (0.7) Ranibizumab 0.5 mg (n = 140) 3 (2.1) 1 (0.7)* 0 1 (0.7) 0 0 9 (6.4) 0 4 (2.9) 1 (0.7)

Conclusions ANCHOR study:

Conclusions ANCHOR study Ranibizumab demonstrated efficacy in patients with subfoveal , predominantly classic CNV associated with neovascular AMD over a 2-year period treatment with monthly intravitreal Ranibizumab prevented central vision loss and improved mean VA VA benefit from Ranibizumab was both rapid (within one month) and sustained (over the 2-year study period) Ranibizumab was superior to treatment with verteporfin PDT for patients losing <15 letters from baseline and mean change in VA over time Brown et al. Ophthalmology 2009; 116: 57-65

Conclusions:

Conclusions Improvements in VA from baseline seen (2-year) are greater in ANCHOR than MARINA ANCHOR patients had predominantly classic CNV lesions; MARINA patients had minimally classic or occult with no classic CNV lesions average CNV lesion size was smaller in ANCHOR; however, predominantly classic lesions are typically more aggressive and lead to more rapid loss of VA than minimally classic lesions, therefore the potential for improvement is greater predominantly classic lesions are typically diagnosed early and therefore treated earlier than occult lesions which may account for the greater improved VA outcomes observed recent VA loss associated with rapidly progressing predominantly classic CNV may be partially reversible whereas earlier VA loss due to slowly progressing occult CNV may be irreversible, providing little opportunity for VA improvement with treatment Brown et al. Ophthalmology 2009; 116: 57-65 Rosenfeld et al. N Engl J Med 2006; 355: 1419-1431

Ranibizumab for DME RESOLVE Study design:

Ranibizumab for DME RESOLVE Study design Randomized 1:1:1 Sham (n=49), 50 µl Baseline fundus photograph, FA, and OCT (reading center) Investigator identifies potential patients with DME with center involvement* Photocoagulation after 3 injections if needed Increase to 100 µl if needed Ranibizumab 0.6 mg (100 µl) if needed Ranibizumab 0.3 mg (n=51), 50 µl Ranibizumab 0.5 mg (n=51), 50 µl Ranibizumab 1.0 mg (100 µl) if needed Phase II, double-masked, multicenter study (N=151) * OCT images, FA, and stereoscopic fundus photographs collected at Visit 1 were sent to a central reading center to confirm diagnosis of DME with center involvement DME: diabetic macular edema; FA: fluorescein angiography; OCT: optical coherence tomography 29 Massin P et al. Diabetes Care 2010;33:2399-2405 Data on file CRFB002D2201, Novartis

PowerPoint Presentation:

Randomization (N=151) Completed (n=46; 90.2%) Completed (n=46; 90.2%) Completed (n=40; 81.6%) 5 (9.8%) patients discontinued study due to the following reasons, n (%) AEs: 1.0 (2.0) Unsatisfactory therapeutic effect: None Protocol deviation: None Consent withdrawal: 2.0 (3.9) Lost to follow-up: 1.0 (2.0) Death: 1.0 (2.0) Sham (n=49) Ranibizumab 0.5 mg (n=51) Ranibizumab 0.3 mg (n=51) 5 (9.8%) patients discontinued study due to the following reasons, n (%) AEs: 1.0 (2.0) Unsatisfactory therapeutic effect: 1.0 (2.0) Protocol deviation: 1.0 (2.0) Consent withdrawal: 2.0 (3.9) Lost to follow-up: 0.0 Death: None 9 (18.4%) patients discontinued study due to the following reasons, n (%) AEs: 1.0 (2.0) Unsatisfactory therapeutic effect: 3.0 (6.1) Protocol deviation: 2.0 (4.1) Consent withdrawal: 2.0 (4.1) Lost to follow-up: 1.0 (2.0) Death: None AEs: adverse events Overall, 12.6% patients discontinued the study before Month 12 mainly due to consent withdrawal or unsatisfactory therapeutic effect 30 Massin P et al. Diabetes Care 2010;33:2399-2405

Mean change in BCVA from baseline to Month 12:

Mean change in BCVA from baseline to Month 12 P value from the two-sided stratified Cochran-Mantel-Haenszel test First VA value post-baseline was assessed at Day 8 Groups A+B, full analysis set/LOCF BCVA: best-corrected visual acuity; D: day; ETDRS: early treatment diabetic retinopathy study; LOCF: last observation carried forward; SE: standard error; VA: visual acuity p<0.0001 Month Treatment initiation Ranibizumab treatment led to superior and rapid improvements in mean BCVA of 11.9 letters (P<0.0001) compared to sham therapy at Month 12 31 Massin P et al. Diabetes Care 2010;33:2399-2405 Day 8

Mean average change in BCVA from baseline to Month 1-12 :

Mean average change in BCVA from baseline to Month 1-12 First VA value post-baseline was assessed at Day 8 Groups A+B, full analysis set/LOCF BCVA: best-corrected visual acuity; D: day; ETDRS: early treatment diabetic retinopathy study; LOCF; last observation carried forward; SE: standard error; VA: visual acuity Treatment initiation Day 8 Mean average change in BCVA from baseline to Month 1 through Month 12 was statistically superior with ranibizumab treatment compared with sham treatment Massin P et al. Diabetes Care 2010;33:2399-2405

Rapid and sustained decrease in CRT with ranibizumab:

Rapid and sustained decrease in CRT with ranibizumab First CRT value post-baseline was assessed at Day 8 Groups A+B, full analysis set/LOCF, P value from the two-sided stratified Cochran-Mantel-Haenszel test CRT: central retinal thickness; D: day; LOCF: last observation carried forward; SE: standard error Month p<0.001 Ranibizumab treatment led to rapid and significant decrease in CRT from baseline to Month 12 as compared with sham (p<0.001) 33 Massin P et al. Diabetes Care 2010;33:2399-2405 Data on file CRFB002D2201, Novartis Day 8

RESTORE extension study design:

24-month, open-label, multi-center extension study in patients who completed 12 months of the RESTORE study core phase Patients with a history of stroke or transient ischemic attack, hypersensitivity to ranibizumab or any component of the ranibizumab formulation were excluded from the extension study 34 RESTORE extension s tudy d esign Interim analysis Full analysis RESTORE extension Patients with visual impairment due to DME, randomized 1:1:1 (N=345) Sham Injection* + active laser # (n=111) Open-label, multi-center, 24-month study (N=240) Ranibizumab 0.5 mg PRN* § RESTORE core n=83 (81%) n=83 (81%) n=74 (76%) n=102 (completed) n=103 (completed) n=98 (completed) Day 1 Month 12 ǂ Month 24 Month 36 *Intravitreal injection: monthly on Day 1-Month 2, then PRN based on BCVA stability, treatment futility, and DME; # Laser: on Day 1, then PRN based on investigator‘s discretion in accordance with ETDRS guidelines; § Active laser: PRN at investigator’s discretion in accordance with ETDRS guidelines (recorded as concomitant medication in extension); ǂ Eligibility confirmation for patients entering the extension study Ranibizumab 0.5 mg* + active laser # (n=118) Ranibizumab 0.5 mg * + sham laser # (n=116) BCVA: best-corrected visual acuity; PRN: pro-re- nata ; DME: diabetic macular edema; ETDRS: early treatment diabetic retinopathy study

Patient disposition:

35 Patient disposition Completing RESTORE core study: N=303 Enrolled in extension study receiving open-label ranibizumab 0.5 mg: N=240 10 ( 12.0%) discontinued from the study, n (%): AEs: 2 (2.4) Consent withdrawal: 3 ( 3.6) Lost to follow-up: 2 (2.4) Administrative problems: 1 (1.2) Death: 2 (2.4) 11 ( 13.3%) discontinued from the study, n (%): AEs: 2 (2.4) Consent withdrawal: 4 (4.8) Lost to follow-up: 1 (1.2) Administrative problems: 1 (1.2) Death: 3 (3.6) 11 ( 14.9%) discontinued from the study, n (%): AEs: 2 ( 2.7) Consent withdrawal: 4 (5.4) Lost to follow-up: 2 ( 2.7) Administrative problems: 0 (0.0) Death: 3 (4.1) Prior ranibizumab 0.5 mg n=83 Prior ranibizumab 0.5 mg + laser n=83 Prior laser n=74 Study completion, n (%) Month 36: 73 (88.0) Study completion, n (%) Month 36: 72 (86.7) Study completion, n (%) Month 36: 63 (85.1) Safety set : consisted of all patients who received at least one active application of study treatment and had at least one post-baseline safety assessment; AE: adverse event Patient completion and discontinuation rates were similar across the treatment groups

Mean change in BCVA from baseline over time:

+8.0 +6.7 +6.0 36 Mean change in BCVA from baseline over time Safety set (last observation carried forward ) BCVA: best-corrected visual acuity; ETDRS: early treatment diabetic retinopathy study; SE: standard error Core phase Extension phase (Ranibizumab 0.5 mg PRN)

Mean change in CRT from baseline over time:

37 Mean change in CRT from baseline over time Safety set (last observation carried forward ) CRT: central retinal thickness; SE: standard error Core phase Extension phase (Ranibizumab 0.5 mg PRN) -127.8 -139.7 -63.3 -142.1 -145.9 -142.7 -140.6 -129.1 -126.6

SAILOR Study design:

SAILOR Study design Ranibizumab 0.3 mg (n = 1169) Ranibizumab 0.5 mg (n = 1209) Subfoveal CNV (all lesion types) secondary to AMD Randomized 1:1 Investigator determines eligibility AMD, age-related macular degeneration CNV, choroidal neovascularization Cohort 1 (n = 2378) Single-masked Ranibizumab 0.5 mg (n = 1922) Cohort 2 (n = 1922) Open-label; enrollment after the majority of cohort 1 had been enrolled Phase IIIb , 12-month, multicenter trial (N = 4300) Boyer et al. Ophthalmology 2009;116(9):1731-9

Study objective and endpoints:

Study objective and endpoints Primary objective : to evaluate the safety and tolerability of intravitreal Ranibizumab in neovascular AMD Primary endpoint: incidence of ocular and non-ocular serious adverse events ( SAEs ) Key secondary endpoints incidence of ocular and non-ocular AEs change from baseline in visual acuity Boyer et al. Ophthalmology 2009;116(9):1731-9

Key serious ocular adverse events:

Key serious ocular adverse events Presumed endophthalmitis a Uveitis Retinal detachment Retinal tear Retinal hemorrhage Detachment of retinal pigment epithelium Vitreous hemorrhage Cataract 0.3 mg (n = 1169) 0.5 mg (n = 1209) 0.5 mg (n = 1922) Cohort 1 Cohort 2 2 (0.2) 1 (0.1) 1 (0.1) 0 11 (0.9) 0 4 (0.3) 1 (0.1) 5 (0.4) 2 (0.2) 0 1 (0.1) 11 (0.9) 2 (0.2) 1 (0.1) 1 (0.1) 1 (0.1) 1 (0.1) 1 (0.1) 0 6 (0.3) 2 (0.1) 3 (0.2) 1 (0.1) a Cohort 1 includes 2 cases of uveitis and 1 case of iridocyclitis that were treated with antibiotics Event, n (%) Boyer et al. Ophthalmology 2009;116(9):1731-9

Key non-ocular serious adverse events:

Key non-ocular serious adverse events a Includes death of unknown cause; APTC ATE, Anti-Platelet Trialists’ Collaboration arterial thromboembolic event Rate, % Any death Vascular death a Stroke Myocardial infarction APTC ATEs Non-vascular death 0 1 2 3 4 Rate, % 0.3 mg (n = 1169) 0.5 mg (n = 1209) Cohort 1 0.5 mg (n = 1922) Cohort 2 1.7 20 2.4 29 1.7 33 0.7 8 1.5 18 0.9 17 1.0 12 0.9 11 0.8 16 1.2 14 1.2 15 0.5 9 0.7 8 1.2 15 0.6 12 2.6 30 2.8 34 1.6 30 No. events Boyer et al. Ophthalmology 2009;116(9):1731-9

Stroke rate by risk factor for stroke:

Stroke rate by risk factor for stroke Rate, % (n) 2.7 2/73 9.6 7/73 0.0 0/95 Rate, % 0 2 4 6 8 10 12 14 16 18 20 0.5 6/1096 0.7 8/1136 0.7 12/1827 3.3 2/60 3.1 2/65 0.8 1/119 0.5 6/1109 1.1 13/1144 0.6 11/1803 0.5 1/214 3.5 7/200 0.9 3/318 0.7 7/955 0.8 8/1009 0.6 9/1604 Yes No Yes No Yes No Prior stroke Congestive heart failure Arrhythmias Error bars are 95% confidence intervals (Blyth-Still-Casella exact method); additional risk factors examined included angioplasty and valve malfunction 0.3 mg (n = 1169) 0.5 mg (n = 1209) Cohort 1 0.5 mg (n = 1922) Cohort 2 Boyer et al. Ophthalmology 2009;116(9):1731-9

Safety conclusions:

Safety conclusions Similar rates of APTC events overall, or individually for myocardial infarction and vascular deaths between doses A trend was seen toward higher stroke and non-vascular death in the 0.5 mg arm; this was not statistically significant and the number of events was small (cohort 1) Prior stroke was the most significant risk factor identified for stroke in cohort 1, independent of treatment the number of patients with a history of stroke was small; however, in this subgroup there was a non-significant trend toward higher stroke rate in the 0.5 mg group than in the 0.3 mg group Ocular safety was consistent between doses and with prior Ranibizumab studies Boyer et al. Ophthalmology 2009;116(9):1731-9

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