Key Developments From Recent Clinical Trials nAMD – A Year in Review Key Developments From Recent Clinical Trials Moderator Panelist Timothy Y. Lai, MD, FRCS, FRCOphth Director, 2010 Retina & Macula Centre Honorary Clinical Associate Professor Department of Ophthalmology & Visual Sciences The Chinese University of Hong Kong Kowloon, Hong Kong SAR Annabelle A. Okada, MD, DMSc Professor of Ophthalmology Department of Ophthalmology Kyorin University School of Medicine Tokyo, Japan

This program may include a discussion of data that were presented in abstract form. These data should be considered preliminary until published in a peer-reviewed journal

Challenges With Current Therapy: Administration High injection frequency leads to high patient volume Creates backlog of patients Burden to staff Burden to patient Financial burden Treatment not covered by insurance in some countries

Challenges With Current Therapy: Regimens Treat and extend (T&E) Proactive treatment Compared to reactive PRN PRN leads to more visits, more injections Patients relapse, need to start over from 4-week injection interval Reduces patient volume Patients are treated at every visit Upper limit of extend period is unclear Some patients extended to 12, 14, or 16 weeks T&E = treat and extend PRN = pro re nata (ie, "as needed")

Polypoidal Choroidal Vasculopathy 22.3% to 61.6% of nAMD in Asia are PCV[a] Two important trials in PCV EVEREST II[b] Intravitreal ranibizumab ± vPDT At 12 months compared with ranibizumab monotherapy: Significantly better VA Fewer intravitreal ranibizumab injections PLANET[c] Aflibercept ± rescue vPDT for patients with PCV Study Start Date: May 2014 Estimated Study Completion Date: July 2017 nAMD = neovascular age-related macular degeneration PCV = polypoidal choroidal vasculopathy VA = visual acuity vPDT = verteporfin photodynamic therapy a. Wong CW, et al. J Clin Med. 2015;4:782-821; b. Koh A, et al. JAMA Ophthalmol. 2017;135:1206-1213; c. Lee WK, et al. ARVO 2017. Oral presentation.

EVEREST II: Ranibizumab ± vPDT in Patients With PCV Study Design[a] BCVA = best corrected visual acuity PCV = polypoidal choroidal vasculopathy PRN = pro re nata (ie, "as needed") vPDT = verteporfin photodynamic therapy Results at 12 months[b] BCVA, letters Complete Polyp Regression, % Ranibizumab + vPDT 8.3 69.3 Ranibizumab (single) 5.1 34.7 a. Koh A, et al. AAO 2016. b. Koh A, et al. JAMA Ophthalmol. 2017;135:1206-1213.

PCV: Safety With PDT PCV first described as a hemorrhagic exudative macular degeneration Polypoidal lesions by indocyanine green angiography PDT results in complete regression in 71% to 95% of cases Stable or improved vision in up to 95% of cases PDT associated with 2.2% to 31% hemorrhagic complications PCV = polypoidal choroidal vasculopathy PDT = photodynamic therapy Rishi P, et al. Indian J Ophthalmol. 2017;65:712-718.

PLANET: Aflibercept ± Rescue vPDT Patients not requiring vPDT, P = .84 BCVA (letters) Absence of active polyps 89.7% 10.7 38.9% 85.7% 10.8 44.8% Patients with PCV (N = 318) 3 monthly injections Aflibercept ± vPDT (rescue) Aflibercept with sham PDT (PRN) was noninferior to aflibercept with rescue vPDT at 52 weeks Similar incidence of ocular treatment-emergent AEs between groups (31.2% vs 29.2% sham PDT and rescue vPDT groups, respectively) Ongoing study AEs = adverse events BCVA = best corrected visual acuity PCV = polypoidal choroidal vasculopathy PRN = pro re nata (ie, "as needed") vPDT = verteporfin photodynamic therapy Lee WK, et al. ARVO 2017. Oral presentation.

ALTAIR: Aflibercept T&E by 2- or 4-Week Increments Patients with nAMD (N = 255) Injections Weeks 0, 4, 8, 16 Aflibercept, adjust by 2-week intervals Aflibercept, adjust by 4-week intervals Weeks 24 to 96 Patients: Japanese adults, ≥ 50 y of age, treatment-naïve nAMD, active CNV, baseline BCVA 25 to 73 letters PCV: 37.4% 2-week interval, 35.8% 4-week interval Primary endpoint: Change from baseline BCVA at 52 weeks nAMD = non-age-related macular degeneration BCVA = best corrected visual acuity CNV = choroidal neovascularization T&E = treat and extend Okada AA, et al. AAO 2017. Oral presentation.

ALTAIR: T&E Criteria Dry macula extend interval Extension Maintenance Shortening No fluid on OCT AND Loss < 5 letters Increase < 100 μm CRT No new neovascularization No new macular hemorrhage Fluid decrease on OCT New fluid on OCT OR Fluid ≥ baseline on OCT Loss ≥ 5 letters Increase ≥ 100 μm CRT New neovascularization New macular hemorrhage CRT = central retinal thickness OCT = optical coherence tomography T&E = treat and extend Dry macula extend interval Trending toward dry maintain current interval Worsening shortening interval Minimum extension: 8 weeks Maximum extension: 16 weeks Okada AA, et al. AAO 2017. Oral presentation.

ALTAIR: Change in BCVA With Time Mean change in BCVA from baseline (letters) 10 12 8 6 4 2 16 20 24 28 32 36 40 44 48 52 5.0 6.7 8.4 9.1 9.4 9.6 9.2 9.0 4.3 8.8 8.3 8.1 LS mean (95% CI) difference at Week 52: -0.4 (-3.8 to 3.0) 2-week intervals 4-week intervals BCVA = best corrected visual acuity Weeks Okada AA, et al. AAO 2017. Oral presentation.

ALTAIR: Central Retinal Thickness Mean change in CRT (UM) from baseline -50 -100 -150 4 8 12 16 20 24 28 32 36 40 44 48 52 LS mean (95% CI) difference at Week 52: -5.8 (-24.3 to 12.7) 2-week intervals 4-week intervals -99.7 -100.1 -105.7 -104.0 -116.1 -117.6 -121.3 -126.1 -106.2 BCVA = best corrected visual acuity -123.7 -127.1 -130.8 -130.9 -132.4 -129.5 -134.4 Weeks Okada AA, et al. AAO 2017. Oral presentation.

ALTAIR: Injection Intervals 2-week Interval (n = 123) 4-week Interval (n = 123) Number of injections, mean (SD) 7.2 (0.9) 6.9 (1.0) Last interval before Week 52 Mean (SD) 10.7 (2.7) 11.8 (3.7) > 8 weeks, n (%) 72 (58.5) 74 (60.2) ≥ 12 weeks, n (%) 52 (42.3) 61 (49.6) 16 weeks, n (%) 50 (40.7) Next scheduled interval determined at the last visit n = 111 n = 116 12.0 (3.4) 12.1 (3.5) 76 (68.5) 76 (65.5) 63 (56.8) 67 (57.8) 39 (35.1) 47 (40.5) Okada AA, et al. AAO 2017. Oral presentation.

ALTAIR: Adverse Events IAI-2W, n (%) (n = 124) IAI-4W, n (%) (n = 123) Any TEAE 67 (54.0) 59 (48.0) Ocular TEAE (study eye) 14 (11.3) 19 (15.4) Conjunctival hemorrhage 3 (2.4) 7 (5.7) Retinal pigment epithelial tear Nonocular TEAE 52 (41.9) 49 (39.8) Nasopharyngitis (study eye) 16 (12.9) 13 (10.6) Serious TEAEs 12 (9.7) 12 (9.8) Ocular serious TEAE (study eye) Nonocular serious TEAEs 11 (8.9) Death 2 (1.6) BCVA = best corrected visual acuity Okada AA, et al. AAO 2017. Oral presentation.

ALTAIR: Summary Both T&E regimens improve BCVA and anatomic outcomes[a] Similar improvement through week 52 55% had achieved an interval of ≥ 12 weeks 40% achieved 16 weeks (maximum allowed interval) Findings in line with Asia-Pacific recommendations[b] Aflibercept dosing intervals can be extended by 4 weeks at a time after 3-month loading dose May be extended to 8- or 12-week intervals in patients with inactive disease BCVA = best corrected visual acuity T&E = treat and extend a. Okada AA, et al. AAO 2017. Oral presentation; b. Koh A, et al. Asia Pac J Ophthalmol (Phila). 2017;6:296-302.

Treatment in the Real World: LUMINOUS Real-world data is not usually as dramatic as seen in the clinical setting Patients need to keep up with injections LD = loading dose (n = 537) (n = 1,924) (n = 918) (n = 224) Holz FG, et al. EURETINA 2017. Oral Presentation.

Emerging Agents: Brolucizumab Noninferior to aflibercept 26 kDa, single chain antibody fragment (scFv) Molar dose equivalent to 11.2- to 13.3-fold aflibercept Superior anatomic changes compared to aflibercept HAWK trial Mean change in BCVA, letters (SE) P Value for Noninferiority Brolucizumab 3 mg (n = 358) 6.1 (0.69) 0.0003 Brolucizumab 6 mg (n = 360) 6.6 (0.71) < .0001 Aflibercept 2 mg (n = 360) 6.8 (0.71) HARRIER trial Brolucizumab 6 mg (n = 370) 6.9 (0.61) Aflibercept 2 mg (n = 369) 7.6 (0.61) BCVA = best corrected visual acuity kDa = kilodaltons scFv = single chain antibody fragment SE = standard error a Noninferiority with a 4.0 letter margin vs aflibercept. b Noninferiority for change in BCVA from baseline averaged over period of Week 36-48 in HAWK (brolucizumab 3 mg, P = .0001; brolucizumab 6 mg, P <.0001) and HARRIER (P = .0003) vs aflibercept. Dugel P, et al. AAO 2017. Oral presentation.

Emerging Agents: Early Stage Angiopoietins Key regulator of adult vascular homeostasis[a] Regulates vascular remodeling and maturation[a] Agents under investigation[b] RG7716, ARP-1536, and nesvacumab Other agents and therapies[b] Anti-VEGF: abicipar pegol, OPT-302, topicals Anti-PDGF: pegpleranib and rinucumab Both failed to show consistently improved visual outcomes compared to anti-VEGF monotherapy Sustained-release anti-VEGF delivery treatments a. Bolinger MT, et al. Int J Mol Sci. 2016;17:1498; b. Hussain RM, et al. Expert Opin Emerg Drugs. 2017;22:235-246.

Summary Anti-VEGF improves visual acuity in patients with PCV EVEREST II and PLANET T&E is a clinically useful approach Possible to extend treatment intervals faster Reduces burden on office staff and patients New agents Brolucizumab Angiopoietins PCV = polypoidal choroidal vasculopathy T&E = treat and extend

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