Macugen (pegaptanib sodium injection) Advisory Committee Meeting August 27, 2004 Jennifer D. Harris, MD Medical Officer Division of Anti-Inflammatory, Analgesic, and Ophthalmic Drug Products Food and Drug Administration

Overview Study Design Efficacy Results (individual study) Efficacy Conclusions Safety Overview (combined studies) Specific Safety Concerns Safety Conclusions Questions

Studies EOP1003 – International EOP1004 – North American

Study Randomized, Double-Masked, Controlled, Dose- Ranging, Multi-center trials Intravitreous injections of either 0.3, 1 or 3 mg every 6 weeks for 54 weeks Re-randomization at 54 weeks Study Duration 2 years

Study Schedule Week 54 Re-randomization Primary efficacy endpoint 2 years Study End treatment Randomization 1

Subjects > 50 years old Subfoveal CNV secondary to AMD Total lesion size < 12 disc areas ≥ 50% active CNV BCVA between 20/40 and 20/320 ≤ 1 prior PDT treatment No previous subfoveal laser treatment

Endpoints Primary efficacy endpoint Proportion of patients losing < 15 letters of VA from baseline to 54 weeks (responders) Secondary efficacy endpoint Proportion of patients gaining > 15 letters of VA Proportion of patients gaining > 0 letters Mean change in VA

Subject Disposition EOP1003

Subject Disposition EOP1004

Subject Demographics EOP1003

Subject Demographics EOP1004

Hochberg’s Procedure P 3 <0.05 P 2 <0.025 P 1 < active doses 2 active doses 1 active dose No dose active No Yes No

Primary Efficacy Endpoint EOP1004

Primary Efficacy Endpoint EOP1003

Visual Acuity EOP1004

Visual Acuity EOP1003

Subgroup Analyses EOP1004

Subgroup Analysis EOP1003

Lesion Size EOP1004

Lesion Size EOP1003

On-Study PDT Treatment EOP1004

On-Study PDT Treatment EOP1003

Number of PDT Treatments EOP1004

Number of PDT Treatments EOP1003

PDT Treatment Responder Analysis at Month 12 EOP mg1 mg3 mgSham No PDT65/101 (64%)70/99 (71%)65/99 (66%)54/93 (58%) Pre-study PDT only 4/5 (80%)3/8 (38%)3/5 (60%)2/4 (50%) On-study PDT only 18/25 (72%)16/28 (57%)15/29 (52%)18/39 (46%) Pre and On- study PDT 10/13 (77%)9/12 (75%)8/14 (57%)5/12 (42%) All Patients97/144 (67%)98/147 (67%)91/147 (62%)79/148 (53%) The impact of concomitant PDT can not be determined due to small numbers

PDT Treatment Responder Analysis at Month 12 EOP mg1 mg3 mgSham No PDT97/131 (74%)103/132 (78%)92/127 (72%)78/127 (61%) Pre-study PDT only 2/2 (100%)3/5 (60 %)5/6 (83%)3/4 (75%) On-study PDT only 9/16 (56%)9/17 (53%)10/20 (50%)12/25 (48%) Pre and On- study PDT 4/4 (100%) 1/2 (50%)0 All Patients112/153 (73%)119/158 (75%)108/155 (70%)93/156 (60%) The impact of concomitant PDT can not be determined due to small numbers

Vision Gain ≥ 15 letters

Efficacy Conclusions Pegaptanib sodium (0.3mg) reduces the risk of vision loss in patient with neovascular AMD Approximately 15% treatment effect over sham No clinically meaningful increase in vision

Overall Safety Similar events seen in all treatment groups –No dose dependent adverse events Most are likely to be related to intraocular injection –e.g. eye pain, SPK, floaters, iritis, etc.

Specific Safety Concerns Endophthalmitis Systemic VEGF Inhibition

Endophthalmitis 16 pegaptanib sodium-treated patients All 16 cases occurred with in one week of injection No cases in the sham-treated patients

Organisms OrganismNumber of Cases (N=16) Coagulase negative Staphylococcus5 Coagulase positive Staphylococcus1 Staphylococcus Epidermidis2 Staphylococcus lugdunensis1 Micrococcus species1 Negative6

Endophthalmitis Original Procedure: 2-3 drops of 50% saline diluted 10% povidone-iodine Or 1 drop of topical antibiotic

Endophthalmitis Protocol amendment: Sterile preparation and drape similar to intraocular surgery Use of either pre-injection topical antibiotics for 3 days prior to injection Or 5% povidone-iodine flush immediately prior to injection

Endophthalmitis 13/16 cases occurred before protocol amendment 3/16 cases occurred within 3 months after protocol amendment No additional cases

Systemic VEGF Cardiac angiogenesis –Collateral formation in myocardial ischemia Vasodilation –Maintain coronary artery blood flow

Theoretical Anti-VEGF Adverse Events Pooled Studies Preferred Term0.3 mg N=295 1 mg N=301 3 mg N=296 Sham N=298 Arrhythmia1 (<1%)3 (1%)5 (2%)0 Atrial fibrillation4 (1%)2 (1%) Bradycardia2 (1%)1 (<1%)4 (1%)2 (1%) Chest Pain7 (2%)3 (1%)5 (2%)4 (1%) Coronary artery disease1 (<1%)0 3 (1%) Myocardial infarction3 (1%)2 (1%) 3 (1%)

Death Rate Majority of Causes: Cardiovascular, Malignancy, CVA

Safety Conclusions Similar events seen in all treatment groups Most frequently occurring AE’s related to intraocular injection Risk of endophthalmitis appears to be minimized by sterile technique No apparent increased risk associated with systemic anti-VEGF activity

Questions 1.Based on the Inclusion/Exclusion Criteria, are there patients excluded from the studies that you believe need to be studied? 2.Visual acuity measurements were conducted using the ETDRS scale placed at 2 meters from the patient. The validity of the ETDRS scale was established based on readings at 4 meters. Are the visual acuity findings sufficiently robust to overcome the potential bias introduced by visual acuity measurements at 2 meters?

Questions (cont) 3.Has sufficient data been submitted to evaluate the efficacy and safety profile of pegaptanib sodium for the treatment of the neovascular form of AMD? If not, what additional data are needed? 4.Are additional analyses of the current data needed to understand the efficacy or safety of pegaptanib sodium for the treatment of the neovascular form of AMD? 5.Has the concomitant use of PDT therapy with pegaptanib been explored sufficiently? Are there concerns with using this product concomitantly with PDT therapy?

Questions (cont) 6.Do the route and/or frequency of administration of the drug raise any concerns that are not addressed by the studies? 7.Endophthalmitis was observed in approximately 2% of patients in these studies. What is the optimal follow-up needed to minimize the impact of potential endophthalmitis cases? 8. Are there any other adverse experiences that are of particular concern for this product?

Questions (cont) 9.Vascular Endothelial Growth Factor (VEGF) has been shown to be an important component in the development of collateral vessels in ischemic heart disease. Inhibition of VEGF in the systemic circulation could present a theoretical increased risk of symptomatic cardiovascular disease in the target population of elderly patients with AMD. Has the adverse event profile of the two randomized phase 3 trials raised any concern over the possible systemic effects of this therapy? Is there additional monitoring that should be in place for patients on pegaptanib sodium therapy?