AMD Trials and Treatments: AAO Media Briefing AMD Trials and Treatments: An Evolving Landscape ABDHISH R. BHAVSAR, M.D. Chair

Financial Disclosures Abdhish R. Bhavsar, MD Research support - clinical trials: DRCR, Regeneron, Genentech

Agenda Abdhish R. Bhavsar, MD: Welcome/Introductions Pravin Dugel, MD: Fovista 2b clinical trial results Q/A Abdhish R. Bhavsar, MD: Update CATT and Eylea Susan Bressler, MD: Cataract sugery/AMD - no inc risk Paul Mitchell, MD: Cataract surgery/AMD – inc risk Edwin Stone, MD: Update on genetic testing for AMD Media Q & A

Study Disclosures This study does include research conducted on human subjects IRB approval has been obtained for each of the studies discussed.

Investigation of Efficacy and Safety of Intravitreal Aflibercept Injection in Wet Age-Related Macular Degeneration (AMD) VIEW 1 Integrated VIEW 2 Abdhish R. Bhavsar, MD

Purpose The following has been developed in response to an unsolicited request for slides on the intravitreal aflibercept injection (IAI)* VIEW 1 and VIEW 2 Year 1 and 2 data The slides may be used by the requesting physician for scientific presentation at a medical meeting. NOTE: The slides may not be used for any program supported by Regeneron Pharmaceuticals, Inc. through an educational grant and accredited by the ACCME This presentation may not be duplicated or distributed Intravitreal aflibercept injection has been approved by the FDA for the treatment of patients with neovascular (Wet) Age-related Macular Degeneration and Macular Edema following Central Retinal Vein Occlusion under the trade name EYLEA® (aflibercept) Injection. Please see the Important Product Information at the end of this deck, and the full Prescribing Information for EYLEA accompanying this presentation *also known as VEGF-Trap Eye in the scientific literature

Study Design Multi-center, active controlled, double masked trial VIEW 1 N=1217; VIEW 2 N=1240 Patients randomized 1:1:1:1 Intravitreal Aflibercept Ranibizumab 2 mg q4 wks 0.5 mg q4 wks 2 mg q8 wks 0.5 mg q4 wks Primary endpoint: Maintenance of Vision Dosing through Week 52 Modified quarterly dosing through Week 96 Secondary endpoint: Mean change in BCVA *After 3 initial monthly doses

KEY SECONDARY ENDPOINTS Study Endpoints Proportion of patients who maintained BCVA (%) (losing <15 ETDRS letters from baseline) PRIMARY ENDPOINT Mean change in BCVA as measured by ETDRS letter score from baseline Proportion of patients who gained at least 15 letters of BCVA from baseline Central Retinal Thickness KEY SECONDARY ENDPOINTS BCVA: Best-Corrected Visual Acuity ETDRS: Early Treatment Diabetic Retinopathy Study 10 10

VIEW 1 Integrated VIEW 2 Results Week 52

VIEW 1 Integrated VIEW 2 Results Week 52 – Week 96

Treatment Schedule Re-treatment Criteria – 12 weeks since previous injection New or persistent fluid on OCT Increase in CRT of ≥100 μm compared to the lowest previous value Loss of ≥5 ETDRS letters from the best previous score in conjunction with recurrent fluid on OCT New onset classic neovascularization New or persistent leak on FA New macular hemorrhage Solid = Injection Outline = Sham Hatched = Modified Quarterly Dosing 24

VIEW 1 Integrated VIEW 2 Safety

Summary Aflibercept noninferior to ranibizumab Safety and efficacy was similar amongst the treatment groups

Important Product Information 42 42

EYLEA® (aflibercept) Injection Important Prescribing Information EYLEA® (aflibercept) Injection is indicated for the treatment of patients with neovascular (Wet) Age-related Macular Degeneration (AMD). The recommended dose for EYLEA is 2 mg administered by intravitreal injection every 4 weeks (monthly) for the first 12 weeks (3 months), followed by 2 mg once every 8 weeks (2 months). Although EYLEA may be dosed as frequently as 2 mg every 4 weeks (monthly), additional efficacy was not demonstrated when EYLEA was dosed every 4 weeks compared to every 8 weeks. EYLEA is indicated for the treatment of patients with Macular Edema following Central Retinal Vein Occlusion (CRVO). The recommended dose for EYLEA is 2 mg administered by intravitreal injection every 4 weeks (monthly).

EYLEA® (aflibercept) Injection Important Safety Information EYLEA® (aflibercept) Injection is contraindicated in patients with ocular or periocular infections, active intraocular inflammation, or known hypersensitivity to aflibercept or to any of the excipients in EYLEA. Intravitreal injections, including those with EYLEA, have been associated with endophthalmitis and retinal detachments. Proper aseptic injection technique must always be used when administering EYLEA. Patients should be instructed to report any symptoms suggestive of endophthalmitis or retinal detachment without delay and should be managed appropriately. Intraocular inflammation has been reported during the post approval use of EYLEA. Acute increases in intraocular pressure have been seen within 60 minutes of intravitreal injection, including with EYLEA. Sustained increases in intraocular pressure have also been reported after repeated intravitreal dosing with VEGF inhibitors. Intraocular pressure and the perfusion of the optic nerve head should be monitored and managed appropriately.

EYLEA® (aflibercept) Injection Important Safety Information (Continued) There is a potential risk of arterial thromboembolic events (ATEs) following use of intravitreal VEGF inhibitors, including EYLEA, defined as nonfatal stroke, nonfatal myocardial infarction, or vascular death (including deaths of unknown cause). The incidence of ATEs in the VIEW 1 and VIEW 2 wet AMD studies in patients treated with EYLEA was 1.8% during the first year. The incidence of ATEs in the COPERNICUS and GALILEO CRVO studies was 0% in patients treated with EYLEA compared with 1.4% in patients receiving sham control during the first six months. The most common adverse reactions (≥5%) reported in patients receiving EYLEA were conjunctival hemorrhage, eye pain, cataract, vitreous detachment, vitreous floaters, and increased intraocular pressure. Serious adverse reactions related to the injection procedure have occurred in <0.1% of intravitreal injections with EYLEA including endophthalmitis, traumatic cataract, increased intraocular pressure, and vitreous detachment. 

Comparison of AMD Treatments Trials (CATT): Two Year Results Abdhish R. Bhavsar, MD for the Comparison of AMD Treatments Trials (CATT) Research Group Supported by Cooperative Agreements from the National Eye Institute, National Institutes of Health, DHHS

Objectives To determine the relative efficacy and safety of intravitreal ranibizumab and bevacizumab for treatment of neovascular AMD To determine if less than monthly dosing of either drug compromises long term visual outcomes - Designed as two-year study with primary outcome at one year

CATT Clinical Sites 1185 patients with neovascular AMD enrolled at 43 sites in the United States 48

Enrollment Criteria More Inclusive than Previous AMD Trials CNV not required to be subfoveal as long as center involved by some component such as SRF, PED, or blood. Allowed RAP lesions, juxtafoveal, and extrafoveal CNV Allowed eyes with VA 20/25-20/320 No limit on size of lesion

Enrollment Criteria More Inclusive than Previous AMD Trials Allowed eyes with >50% blood. All other entry criteria had to be met (VA 20/320 or better and can identify CNV on FA and fluid on OCT) 50

} CATT Treatment Year 1 Year 2 Retreat if fluid on OCT or (Months) Year 1 Year 2 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 ranibizumab Monthly bevacizumab Monthly ranibizumab PRN bevacizumab PRN } Retreat if fluid on OCT or other signs of active CNV Primary Endpoint Final visit

Treatment in PRN Arms Treat to a dry OCT – zero tolerance for intraretinal, subretinal, or sub-RPE fluid. May also treat if there is other evidence of CNV activity New subretinal or intraretinal hemorrhage Leakage or increased lesion size on FA Unexplained decrease in visual acuity with no obvious atrophy or subretinal fibrosis. No retinal thickness threshold (100 microns) as used in many neovascular AMD treatment studies.

CATT Study Drugs Ranibizumab supplied locally similar to patients outside of the study Bevacizumab supplied by CATT repackaged in glass vials under IND Multiple Lines of Evidence Support a Role for VEGF in Choroidal Neovascularization Surgical removal and staining of subfoveal fibrovascular membranes from patients with AMD reveal the increased expression of VEGF protein and mRNA. VEGF mRNA expression was highest in membranes with an inflammatory response. VEGF expression was concentrated in areas containing fibroblasts and inflammatory cells.1 Increased VEGF levels are present in the vitreous of eyes with subfoveal neovascularization. Vitreous samples obtained from patients undergoing vitrectomy were compared with vitreous samples from patients who did not display subfoveal neovascularization.2 Compared with healthy controls, VEGF is overexpressed in the retinal pigmented epithelium and choroidal blood vessels of early and neovascular AMD lesions.3 In animal studies, overexpression of VEGF165 in retinal pigment epithelial cells led to choroidal neovascularization.4,5 Anti-VEGF drugs may improve vision in patients with CNV and lead to resolution of fluorescein leakage. 1. Kvanta et al. Invest Ophthalmol Vis Sci. 1996;37:1929. 2. Wells et al. Br J Ophthalmol. 1996;80:363. 3. Kliffen et al. Br J Ophthalmol. 1997;81:154. 4. Baffi et al. Invest Ophthalmol Vis Sci. 2000;41:3582. 5. Spilsbury et al. Am J Path. 2000;157:135.

Mean Change in Visual Acuity All Groups

Distribution of Visual Acuity at 1 Year

Mean Change in Total Retinal Thickness Over Time All Groups

Percent with No Fluid at 1 Year

Year 1 Adverse Events No difference between drugs in rates of death, stroke, or myocardial infarction Imbalance in total SAE’s (mostly hospitalizations): 24% bevacizumab vs 19% ranibizumab (p=0.04) SAEs broadly distributed across all organ systems with differences present in areas not previously identified as areas of concern in systemic bevacizumab trials.

Questions at End of Year 1 Would ranibizumab and bevacizumab remain equivalent for visual acuity in Year 2? Would wider visual acuity differences emerge between monthly and PRN dosing in Year 2? Would the fluid differences between treatments noted in year 1 impact visual acuity with longer follow-up? Would switching to PRN dosing after one year of monthly treatment maintain or adversely effect vision? Would important safety differences emerge with longer follow-up?

Two Year Results

Design CATT is non-inferiority trial with its primary outcome at 1 year. Objectives of Year 2: To evaluate outcomes in patients who maintain the same regimen for two years To determine the effects of switching to as-needed treatment after 1 year of monthly dosing.

Patients 1107 patients alive who continued in Year 2 All available monthly treated patients in Year 1 (n=549) were successfully randomized to monthly or PRN treatment in Year 2 Masking remained robust in Year 2 with identity of assigned drug known to ophthalmologist in only 66 of 12,645 evaluations (11 patients)

Statistical Features Little evidence that dosing regimen affects drug effects in Year 1 (no interaction) Because no interaction and 6 groups in Year 2, we report results by drug and by dosing regimen Data analysis 2-way ANOVA & linear regression - continuous variables Χ2 tests & logistic regression - categorical variables Cox model - incidence of serious adverse events

Visual Acuity Results Same Regimen for Two Years

Mean Change in Visual Acuity Same Regimen for Two years This is what the second click of the animation should look like (with black font for the 4 ending average VAs

Patients Without 15 Letter Decrease Same Regimen for 2 Years The colors here are not as saturated or intense as the colors (blue and red) on other slides so far – is there a way for the colors to match exactly across all slides? Is there a fill pattern that is denser or larger dots so there is not so much white space in the PRN Always bars? This applies to a number of bar graphs, not just this one. Decrease the size of the legend at the top to the size used on the slide 15

15 Letter Change from Baseline Same Regimen for 2 Years Same note about color Move the percentages in the bottom segment up so that they are farther from the x axis. Decrease the size of the legend at the top to the size used on the next slide (slide 15)

Distribution of Visual Acuity Same Regimen for 2 Years

Anatomical Results Same Regimen for Two Years

Mean Change in Total Retinal Thickness Same Regimen for 2 Years Make Legend just a little smaller Add p-values for drug and regimen over to the right “P=0.xx Drug”

Percent with No Fluid on OCT Same Regimen for 2 Years Try moving p-values to the right of the last bar (bevacizumab PRN) Change label on y-axis to “% of Patients” and drop the “%” from the labels on the y- axis

Typical Amount of Residual Fluid

Percent with Geographic Atrophy Same Regimen for 2 Years Same comment on color Retain the two shades for foveal and non-foveal Remove the current percentages like 4.7% and 21.1% Add the total percentage on top of the bar – like 25.8%

Percent with No Leakage on FA Same Regimen for 2 Years Add the notations “Drug” and “Regimen” for the p values Change label on y-axis to “% of Patients” and drop the “%” from the labels on the y-axis

Mean Change in Lesion Area Same Regimen for 2 Years

Mean Number of Injections Same Regimen for 2 Years

Effect of Switching to PRN after One Year of Monthly Dosing

Mean Change in Visual Acuity after Week 52 Monthly Always and Switched to PRN

Mean Change in Total Retinal Thickness from Week 52 Monthly Always and Switched to PRN Change y-axis scale to -100 to +100 You may need to move the legend to above the lines

15-Letter Change from Baseline at 2 Years Monthly Always and Switched to PRN Same comment on colors Change the size of the legend (4 color patterns) to the size on Slide 15 Move the number of the % in the bottom segment up from the x-axis Make N numbers (134, 129 etc) a little smaller

Percent with No Fluid on OCT Monthly Always and Switched to PRN Try moving p-values to the right of the last bar (bevacizumab PRN) Change label on y-axis to “% of Patients” and drop the “%” from the labels on the y- axis

Percent with Geographic Atrophy Monthly Always and Switched to PRN Same comment on color Retain the two shades for foveal and non-foveal Remove the current percentages like 4.7% and 21.1% Add the total percentage on top of the bar – like 25.8%

Percent with No Leakage on FA Monthly Always and Switched to PRN Add the notations “Drug” and “Regimen” for the p values Change label on y-axis to “% of Patients” and drop the “%” from the labels on the y-axis

Monthly Always and Switched to PRN Mean Change in Lesion Area from Year 1 Monthly Always and Switched to PRN

Mean Number of Injections in Year 2 Monthly Always and Switched to PRN

Mean Change in Visual Acuity By Regimen within Drug

Mean Change in Total Retinal Thickness By Regimen within Drug

Distribution of Visual Acuity at 2 Years

Adverse Events

Death and APTC Events ranibizumab bevacizumab (N=599) (N=586) Difference 95% CI P Death 32 (5.3%) 36 (6.1%) 0.8% (-1.9%, 3.5%) 0.62 APTC* 28 (4.7%) 29 (5.0%) 0.3% (-2.2%, 2.8%) 0.89 *Includes nonfatal myocardial infarction, nonfatal stroke, and vascular deaths

Cumulative Proportion with a Systemic Serious Adverse Event

Any Systemic Serious Adverse Event Drug Difference 95% CI P Unadjusted 2-year rates ranibizumab 190 /599 (31.7%) bevacizumab 234 /586 (39.9%) 8.2% (2.8%, 13.6%) 0.004 Adjusted Risk Ratio 1.30 (1.07, 1.57) 0.009 Regimen Unadjusted 2-year rates* Monthly 199 /587 (33.9%) PRN 225 /598 (37.6%) 3.7% (-1.7%, 9.1%) 0.18 Adjusted Risk Ratio§ 1.20 (0.98, 1.47) 0.08 *Regimen as originally assigned §PRN a time dependent covariate in Cox model After adjustment for demographic features and coexisting illnesses at baseline, the risk ratio for all systemic serious adverse events within 2 years for bevacizumab was 1.30 (95% CI, 1.071.57; P 0.009). Patients treated as needed had higher rates than patients treated monthly (risk ratio, 1.20; 95% CI, 0.981.47; P 0.08).

Systemic Serious Adverse Events ranibizumab bevacizumab (N=599) (N=586) Difference (95% CI) P Associated w/ Anti-VEGF* Yes 45 ( 7.5%) 62 ( 10.6%) 3.1% (-0.2%, 6.4%) 0.07 No 170 (28.4%) 202 (34.5%) 6.1% (0.8%,11.3%) 0.02 * Arteriothrombotic events (myocardial infarction, stroke), systemic hemorrhage, congestive heart failure, venous thrombotic events, hypertension, vascular death.

Ocular Adverse Events Endophthalmitis – 0.06% (11 /18,509 injections) - 11 cases (4 ranibizumab, 7 bevacizumab) - 10 of 11 cases in monthly treatment group; PRN case had received 22 injections Pseudo-endophthalmitis Ocular HTN or Glaucoma ranibizumab 1 bevacizumab - 1 ranibizumab - 15 bevacizumab - 14

2-Year Drug Cost Per Patient 95

Distribution of Visual Acuity at 2 Years

Summary Ranibizumab and bevacizumab were equivalent for visual acuity at all time points over a 2-year period. PRN treatment resulted in less gain in visual acuity (-2.4 letters) at 2 years but vision for all groups was similar at end of 2 years. PRN dosing resulted in mean of 10 fewer injections over 2 years than monthly dosing. Bevacizumab patients received mean 1.5 more injections than ranibizumab. More eyes were completely dry on OCT with monthly dosing with the highest rate in eyes receiving ranibizumab monthly. More eyes developed geographic atrophy with monthly dosing with the highest rate in eyes receiving ranibizumab monthly.

Summary PRN groups had more leakage on FA and more lesion growth than monthly groups. Switching to PRN after one year of monthly treatment produced visual and anatomical results that were similar to PRN-always. There were no differences between drugs in rates of death or arteriothrombotic events. Bevacizumab treated patients had higher rates of systemic SAEs than ranibizumab treated patients. The reason for this difference remains unclear given the lack of specificity to conditions associated with inhibition of VEGF.

Organization Daniel F. Martin MD - Study Chair (Cleveland Clinic) CATT: ranibizumab-bevacizumab Trial Daniel F. Martin MD - Study Chair (Cleveland Clinic) Stuart L. Fine MD - Study Vice-Chair (U Colorado) Maureen G. Maguire PhD - Coordinating Center (Penn) Glenn J. Jaffe MD - OCT Reading Center (Duke) Juan E. Grunwald MD - Photo Reading Center (Penn) Maryann Redford DDS, MPH – NEI Project Officer

Participating CATT Centers Phoenix, AZ Retinal Consultants of AZ Pravin V. Dugel, MD Tucson, AZ Retina Associates Southwest April E. Harris, MD Beverly Hills, CA Retina-Vitreous Associates Firas Rahhal, MD Sacramento, CA University of CA – Davis Susanna S. Park, MD, PhD Sacramento, CA Retinal Consultants Medical Group Joel A. Pearlman, MD, PhD San Francisco, CA West Coast Retina Medical Group Richard McDonald, MD Santa Barbara, CA California Retina Consultants Robert L. Avery, MD Denver, CO Colorado Retina John D. Zilis, MD Fort Meyers, FL National Ophthalmic Research Inst Joseph P. Walker, MD

Participating CATT Centers Fort Lauderdale, FL Retina Group of Florida Larry Halperin, MD Atlanta, GA Emory Eye Center Baker Hubbard, MD Iowa City, IA University of Iowa Hospitals/Clinics James C. Folk, MD Harvey, IL Ingalls Memorial – IL Retina Assoc. David H. Orth, MD and Sohail Hasan MD Indianapolis, IN Midwest Eye Institute Thomas A. Ciulla, MD Lexington, KY Retina Associates of Kentucky Thomas W. Stone, MD Louisville, KY Univ of Louisville – Lions Eye Ctr Charles C. Barr, MD Boston, MA Massachusetts Eye & Ear Infirmary Ivana Kim, MD Ophthalmic Consultants of Boston Trexler M. Topping, MD Baltimore, MD Elman Retina Group, P.A. Michael Elman, MD

Participating CATT Centers St. Louis, MO Barnes Retina Institute Daniel P. Joseph, MD, PhD Chapel Hill, NC University of North Carolina Chapel Hill Travis A. Meredith, MD Charlotte, NC Charlotte, Eye, ENT Associates Andrew N. Antoszyk, MD Durham, NC Duke University Eye Center Srilaxmi Bearelly, MD New Brunswick, NJ Retina Vitreous Center Daniel B. Roth, MD Chevy Chase, MD Retina Group of Washington Daniel M. Berinstein, MD Towson, MD Retina Specialists John T. Thompson, MD Royal Oak, MI Associated Retinal Consultants Michael T. Trese, MD Edina, MN VitreoRetinal Surgery David F. Williams, MD Rochester, MN Mayo Clinic Sophie J. Bakri, MD

Participating CATT Centers Great Neck, NY Long Island Vitreoretinal Consult Philip J. Ferrone, MD Beachwood, OH Retina Associates of Cleveland Lawrence J. Singerman, MD Dublin, OH Ohio State – Retina Division Frederick H. Davidorf, MD Oklahoma City, OK Dean A. McGee Eye Institute Reagan H. Bradford, MD Portland, OR Retina Northwest Richard F. Dreyer, MD Portland, OR Casey Eye Institute Christina J. Flaxel, MD Philadelphia, PA Wills Eye Hospital Retina Assoc Richard Kaiser, MD Pittsburgh, PA Retina Vitreous Consultants Bernard H. Doft, MD West Columbia, SC Palmetto Retina Center John A. Wells, MD Knoxville, TN Southeastern Retina Associates Stephen L. Perkins, MD

Participating CATT Centers Nashville, TN Tennessee Retina, P.C. Carl C. Awh, MD Dallas, TX Texas Retina Associates Gary Edd Fish, MD Houston, TX Retinal Consultants of Houston David M. Brown, MD Houston, TX Retina and Vitreous of Texas Michael Lambert, MD Madison, WI Univ of Wisconsin – Visual Sci Suresh R. Chandra, MD

Committees Executive Committee: Daniel F. Martin, MD (chair); Robert L. Avery, MD; Sophie J. Bakri, MD; Ebenezer Daniel, MBBS, MS, MPH; Stuart L. Fine, MD; Juan E. Grunwald, MD; Glenn Jaffe, MD, Marcia R. Kopfer, BS, COT; Maureen G. Maguire, PhD; Travis A. Meredith, MD; Ellen Peskin, MA, CCRP; Maryann Redford, DDS, MPH; David F. Williams, MD Data and Safety Monitoring Committee: Lawrence M. Friedman, MD (chair); Susan B. Bressler, MD; David L. DeMets, PhD; Martin Friedlander, MD, PhD; Mark W. Johnson, MD; Anne Lindblad, PhD; Douglas W. Losordo, MD, FACC; Franklin G. Miller, PhD.  

Committees Clinic Monitoring Committee: Ellen Peskin, MA, CCRP (chair); Mary Brightwell-Arnold, SCP; Joan DuPont; Maureen G. Maguire, PhD; Kathy McWilliams, CCRP; Susan K. Nolte.   Operations Committee: Daniel F. Martin, MD (chair); Ebenezer Daniel, MBBS, MS, MPH; Frederick L. Ferris III, MD; Stuart L. Fine, MD; Juan E. Grunwald, MD; Glenn Jaffe, MD; Katie Hall; Maureen G. Maguire, PhD; Ellen Peskin, MA, CCRP; Maryann Redford, DDS, MPH; Cynthia Toth, MD.

VIEW 1 & 2 Mean Change in Visual Acuity to 1 year Compared to Baseline 10.9* 2q4 (n=304) 8.1 Rq4 (n=304) 7.9† 2q8 (n=301) 6.9† 0.5q4 (n=301) VIEW 2 9.7† 0.5q4 (n=296) 9.4 Rq4 (n=291) 8.9† 2q8 (n=306) 7.6† 2q4 (n=309) *P = 0.0054 †P = NS vs. Rq4 Week 108

Distribution of number of injections PRN Always and Switched to PRN

Future Improved drug delivery systems Treatments for non-exudative AMD Targeted treatments with combinations of drugs Better prevention strategies

Additional Questions Mary Wade, Academy Science and International PR Manager mwade@aao.org Cell: 510-725-5677

Thank You!