“Beyond anti-VEGF-A for Retinal Diseases” New York City, KOL Forum, November 6 2018 Megan Baldwin PhD, CEO & Managing Director NEOVASCULAR AMD CURRENT TREATMENT PARADIGMS AND UNMET NEEDS ARSHAD M. KHANANI MD,MA MANAGING PARTNER, DIRECTOR OF CLINICAL RESEARCH, DIRECTOR OF FEL LOWSHIP SIERRA EYE ASSOCIATES CLINICAL ASSOCIATE PROFESSOR UNIVERSITY OF NEVADA - RENO OBJECTIVES ▪ PRACTICE SETTING ▪ STANDARD OF CARE DOSING STRATEGIES ▪ CLINICAL TRIALS DATA HIGHLIGHTING UNMET NEEDS ▪ NEW TREATMENTS ON THE HORIZON PRACTICE SETTING ▪ PRIVATE OFFICE BASED PRACTICE ▪ MULTISPECIALTY WITH 2 RETINAL PHYSICIANS ▪ 55 EMPLOYEES TOTAL ▪ 7 TECHNICIANS, 3 RESEARCH COORDINATORS ▪ 15-20 ACTIVE CLINICAL TRIALS ▪ 70 PATIENTS A DAY ON AVERAGE ▪ APPROXIMATELY 500 INJECTIONS A MONTH ANGIOGENESIS IN AGE-RELATED MACULAR DEGENERATION COMPLEX CASCADE OF EVENTS VEGF Vascular Endothelial Growth Factor Tube formation + remodeling Endothelial cell activation Basement membrane degradation Endothelial cell proliferation, migration Griffioen AW, et al. Pharmacol Rev. 2000;52(2):237-68; Das A, et al. Prog Retin Eye Res. 2003;22(6):721-48; Davis GE, et al. Circ Res. 2005;97(11):1093-107. CURRENT PARADIGM – BLOCK VEGF-A VEGF Vascular Endothelial Growth Factor Tube formation + remodeling Endothelial cell activation Basement membrane Endothelial cell proliferation, degradation migration Griffioen AW, et al. Pharmacol Rev. 2000;52(2):237-68; Das A, et al. Prog Retin Eye Res. 2003;22(6):721-48; Davis GE, et al. Circ Res. 2005;97(11):1093-107. CURRENT ANTI-VEGF-A THERAPIES FOR nAMD ▪ ANTI-VEGF-A THERAPY HAS REVOLUTIONIZED THE MANAGEMENT OF nAMD IN THE PAST 10-15 YEARS ▪ THREE MOLECULES CURRENTLY USED: ▪ RANIBIZUMAB (LUCENTIS) ▪ BEVACIZUMAB (AVASTIN) ▪ AFLIBERCEPT (EYLEA) ANTI-VEGF-A DOSING STRATEGIES USED IN CLINICAL TRIALS TO OPTIMIZE OUTCOMES AND MANAGE nAMD DISEASE MONTHLY - ANCHOR - MARINA - CATT - HARBOR PRN TREAT AND - SAILOR EXTEND - CATT - LUCAS - HARBOR - TREX - ALTAIR CONTINUOUS FIXED MONTHLY DOSING: VISUAL ACUITY FROM BASELINE THROUGH MONTH 24 MARINA1 MONTHS MONTHS ANCHOR2 VIEW 1 and 23 1. Rosenfeld PJ et al. N Engl J Med. 2006;355:1419-1431. 2. Brown DM et al. N Engl J Med. 2006;355:1432-1444. 3. Heier JS et al. Ophthalmology. 2012;119:2537-2548. CONTINUOUS MONTHLY DOSING WHY DO IT? ▪ EVIDENCE OF IMPROVING VISION ▪ MAINTAIN VISION AND RETINAL DRYING ▪ AVOIDS UNDER-TREATMENT WHY NOT DO IT? ▪ NOT INDIVIDUALIZED ▪ nAMD IS HETEROGENEOUS ▪ VARIABLE NATURAL HISTORY AND TREATMENT RESPONSE ▪ MANY PATIENTS DO WELL WITHOUT MONTHLY TREATMENT ▪ VEGF-A SUPPRESSION VARIES BETWEEN PATIENTS ▪ RESULTS BEYOND 2 YEARS LARGELY UNKNOWN CONSEQUENCES OF OVERTREATMENT ▪ EXPENSE: DIRECT AND INDIRECT COSTS ▪ INCONVENIENCE: FREQUENT VISITS ▪ INCREASED RISK (CUMULATIVE) ▪ INFECTION ▪ SUSTAINED IOP ELEVATION/GLAUCOMA INDIVIDUALIZED ANTI-VEGF TREATMENT WHY? HOW? GOALS AVOID OVERTREATMENT SUPPRESS CNV PRN (AS NEEDED) GROWTH, EXUDATION SAFER FREQUENT OCT MORE TREAT-AND-EXTEND IMAGING WITH “ZERO TOLERANCE” COST-EFFECTIVE PRN DOSING IN HARBOR DISTRIBUTION OF THE NUMBER OF RANIBIZUMAB INJECTIONS OVER 2 YEARS Ho AC, Busbee BG, Regillo CD, et al. Ophthalmology. 2014;121(11):2181-2192. UNDERTREATMENT COMPROMISES VISUAL ACUITY POSITIVE CORRELATION OF VA GAINS AND NUMBER OF MANY PATIENTS RECEIVE FEWER INJECTIONS ANTI-VEGF-A INJECTIONS OVER 12 MONTHS IN REAL-WORLD VS CLINICAL STUDIES US medical claims database: Patients received a mean of only 4.6 and 6.9 injections of bevacizumab & ranibizumab over 12 mo, respectively Hussain RM et al. Ophthalmic Surg Lasers Imaging Retina. 2017;48:780-784. PRO RE NATA (PRN) DOSING PATIENTS RECEIVE: ▪ A SERIES OF MONTHLY LOADING INJECTIONS OF ANTI -VEGF THERAPY ▪ REGULAR OFFICE VISITS FOR ASSESSMENT OF VISUAL ACUITY ▪ ANATOMIC MEASURES BASED ON OCT, FA OR OTHER IMAGING MODALITIES POTENTIAL LIMITATIONS OF DISCONTINUOUS PRN ▪ ALLOWS FOR RECURRENCE OF NEOVASCULAR LEAKAGE AND GROWTH ▪ MULTIPLE RECURRENCES LEADS TO PROGRESSION OF DISEASE ▪ POORER LONG-TERM VISUAL OUTCOMES IN SOME PATIENTS Wai KM et al. Am J Ophthalmic Clin Trials. 2018;1:1. TREAT-AND-EXTEND DOSING: WHAT IS IT? ▪ SERIES OF LOADING ANTI-VEGF INJECTIONS, (TYPICALLY 4-WK INTERVALS), WITH VA AND ANATOMIC ASSESSMENT ▪ WHEN CRITERIA INDICATING NO DISEASE ACTIVITY ARE MET, PATIENTS RECEIVE AN INJECTION; TREATMENT INTERVAL IS EXTENDED, USUALLY BY 2 WEEKS AT A TIME, UNTIL MAXIMUM INTERVAL OF 12 –16 WEEKS IS REACHED ▪ IF CNV LESIONS ARE REACTIVATED, TREATMENT INTERVAL IS REDUCED Spaide R. Am J Ophthalmol. 2007;144:679-680 BENEFITS OF TREAT-AND-EXTEND DOSING ▪ CONTINUOUS (PROACTIVE) ▪ MINIMIZES RECURRENCES/SETBACKS ▪ VARIABLE (INDIVIDUALIZED) ▪ MINIMIZES OVERTREATMENT ▪ MINIMIZES TREATMENT BURDEN ▪ MAXIMIZES SAFETY ▪ COST-EFFECTIVE ▪ MINIMIZES DRUG USE, TESTING, AND OFFICE Spaide R. Am J Ophthalmol. 2007;144:679-680 CURRENT UNMET NEEDS IN nAMD NEOVASCULAR AMD ANTI-VEGF A BLOCKADE 15 10 20/63 5 0 20/100 0 6 12 18 24 +25 -5 -10 Mean Changei in ETDRS BCVA ETDRS in Changei Mean -15 -20 Months ANCHOR, MARINA, HARBOR, CATT, VIEW1/2 Brown DM, et al. Ophthalmology. 2009 Jan;116(1):57-65.e5; Rosenfeld PJ, et al; N Engl J Med. 2006;355:1419-1431; Ho AC, et al. Ophthalmology. 2014 Nov;121(11):2181-92; Martin DF, et al. Ophthalmology. 2012; 119(7):1388-98; Heier JS, et al. Ophthalmology. 2012 Dec;119(12):2537-48 NEOVASCULAR AMD – SHORTCOMINGS OF VEGF-A BLOCKADE 20/20 35 >70% VA REMAINS TO BE GAINED 25 15 20/100 5 0 6 12 18 24 -5 Mean Changei in ETDRS BCVA ETDRS in Changei Mean -15 #1 EFFICACY -25 MONTHS Brown DM, et al. Ophthalmology. 2009 Jan;116(1):57-65.e5; Rosenfeld PJ, et al; N Engl J Med. 2006;355:1419-1431; Ho AC, et al. Ophthalmology. 2014 Nov;121(11):2181-92; Martin DF, et al. Ophthalmology. 2012; 119(7):1388-98; Heier JS, et al. Ophthalmology. 2012 Dec;119(12):2537-48 20/200 20/200 #2 Durability X 8 20/40 ANTI-VEGF-A TREATMENT OF nAMD - PROSPECTIVE FIXED OR PRN DOSING ANCHOR, MARINA, HARBOR, CATT, VIEW1/2 Injections 15 Mean = 10.2 Range = 6.6-12.3 11.3 MARINA 0.5 mg 10 ANCHOR (0.5 mg) HARBOR 0.5 mg Monthly Mean = 8.4 CATT Ranibizumab Monthly HARBOR 0.5 mg PRN 5 5.9 CATT Bevacizumab Monthly CATT Ranibizumab PRN Mean Change in ETDRS BCVA ETDRS in Change Mean CATT Bevacizumab PRN VIEW1 (0.5q4) VIEW1 (2q8) 0 VIEW1 (2q4) 0 3 6 9 12 VIEW2 (0.5q4) Months VIEW2 (2q8) Brown DM, et al. Ophthalmology. 2009 Jan;116(1):57-65.e5; Rosenfeld PJ, et al; N Engl J Med. 2006;355:1419-1431; Ho AC, et al. Ophthalmology. 2014 Nov;121(11):2181-92; Martin DF, et al. VIEW2 (2q4) Ophthalmology. 2012; 119(7):1388-98; Heier JS, et al. Ophthalmology. 2012 Dec;119(12):2537-48 ANTI-VEGF-A TREATMENT OF nAMD - PROSPECTIVE TREAT & EXTEND DOSING LUCAS, TREND, TREX-AMD 15 Injections Mean = 8.9 Range = 8.0-10.1 10 10.5 Mean = 8.6 6.6 5 Mean Changei in ETDRS BCVA ETDRS in Changei Mean LUCAS Ranibizumab 0 LUCAS Bevacizumab 0 3 6 9 12 TREND Months TREX AMD Berg K, et al. Ophthalmology. 2015 Jan;122(1):146-52; Silva R, et al. Ophthalmology. 2018 Jan;125(1):57-65; Wykoff CC, et al. Ophthalmology. 2015 Dec;122(12):2514-22. REAL-WORLD DATA: MAJORITY OF nAMD PATIENTS LIKELY UNDERTREATED 1ST YEAR OF MANAGEMENT ≈73% ≤ 5 injections LUMINOUS 19.6 20 15 13.5 12.2 11.7 9.5 10 8.5 7.4 5.9 5.1 Proportion of patients (%) patients of Proportion 5 2.9 2.1 1.0 0.5 0.1 0.0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 (n=250) (n=287) (n=661) (n=412) (n=455) (n=396) (n=322) (n=199) (n=173) (n=97) (n=72) (n=35) (n=17) (n=2) (n=1) Number of ranibizumab injections up to Month 12 Holz FG, et al. Presented at: EURetina 2017; September 7-10, 2017; Barcelona, Spain. KEY POINTS & ISSUES WITH CURRENT ANTI-VEGF-A THERAPY ▪ UPPER LIMIT FOR VA ~9 LETTERS FOR nAMD ▪ IMPROVEMENTS IN VA APPEAR DEPENDENT UPON ▪ NUMBER OF INTRAVITREAL INJECTIONS ▪ CLOSE MANAGEMENT OF ANATOMICAL CHANGES ▪ AVOID UNDERTREATMENT ▪ UNDER-TREATMENT IS COMMON AND PROHIBITS PATIENTS FROM ACHIEVING EXPECTED VA GAINS ▪ “MORE IS BETTER” BUT MAY COME AT A PRICE IN nAMD WHICH IS A CHRONIC DISEASE ▪ POSSIBILITY TO INDIVIDUALIZE TREATMENT WITH PRN OR TAE ▪ >12 WEEK TREATMENT INTERVAL POSSIBLE IN ~25-50% OF PATIENTS ▪ NEW TREATMENT MODALITIES INCLUDING COMBINATION THERAPY ARE NEEDED TO IMPROVE VISION AND/OR DURABILITY OF RESPONSE ▪ VEGF-A JUST ONE MOLECULAR PATHWAY IN THE PATHOGENESIS OF nAMD Wai KM et al. Am J Ophthalmic Clin Trials. 2018;1:1. ADDITIONAL ANTI-VEGF AGENTS DUAL-TARGETING BROLUCIZUMAB & ABICIPAR FARICIMAB INTO THE (RG7716) FUTURE VEGF-C/D BLOCKADE: OPT-302 MOONSHOTS C/D C/D Extra-Cellular - - Domains 1-3 DRUG DELIVERY VEGF ▪ GENE THERAPY VEGF hVEGFR-3 APPROACHES ▪ STEM CELLS ▪ DROPS ▪ PILLS hIgG1 Fc COMPARISON OF CURRENT VS EMERGING ANTI-VEGF-A AGENTS Bevacizumaba Ranibizumab Aflibercept Brolucizumabb Abicipar pegolb Monoclonal Single-chain Designed ankyrin Full antibody VEGFR-1/2-Fc Format humanized antibody fragment repeat protein (IgG1) fusion protein antibody fragment (scFv) (DARPin)1 Molecular structure Molecular weight 149 kDa 48 kDa 115 kDa 26 kDa 34 kDa Clinical dose 1.25 mg 0.5 mg 2.0 mg 6.0 mg 2.0 mg for nAMD (unlicensed use) aOff-label; not FDA-approved for any ocular indications bUnder investigation for treatment of nAMD 1. Molecular Partners. www.molecularpartners.com/our-products/abicipar/. Accessed 7/17/18. BROLUCIZUMAB: PHASE 3 STUDY DESIGN Dugel PU et al. Oral Presentation at the American Academy of Ophthalmology Meeting, Chicago, USA, October 2018. BROLUCIZUMAB WAS NON-INFERIOR TO AFLIBERCEPT Dugel PU et al. Oral Presentation at the American Academy of Ophthalmology Meeting, Chicago, USA, October 2018 BROLUCIZUMAB ACHIEVED SUPERIOR REDUCTIONS IN CENTRAL SUBFIELD THICKNESS (CST) AT WEEKS 16, 48 and 96.