12/2/2016 Disclosures Late-Stage Management of Macular Edema - PowerPoint PPT Presentation

12/2/2016 Disclosures Late-Stage Management of Macular Edema Secondary to Retinal Vein Occlusion: Title Collective Analyses of the BRAVO, CRUISE, • Late-Stage Management of Macular Edema Secondary to Retinal Vein HORIZON, and SHORE Studies Occlusion: Collective Analyses of the BRAVO, CRUISE, HORIZON, and SHORE Studies Financial Disclosures Robert B. Bhisitkul, MD, PhD • Robert B. Bhisitkul, MD, PhD: Grant support, speakers bureau, and Professor of Clinical Ophthalmology consultant: Genentech/Roche; consultant: Santen, Inc.; advisory boards: University of California San Francisco School of Medicine Allergan; Bausch & Lomb. 1 BRAVO/CRUISE: Ranibizumab for the Treatment of BRVO and CRVO Key Clinical Questions Macular edema secondary to retinal vein occlusion BRAVO* (BRVO, N = 397) CRUISE (CRVO, N = 392) In the initial stage of monthly ranibizumab treatment, 1:1:1 randomization how quickly did patients with RVO respond? Monthly Monthly Monthly Monthly injections sham injection ranibizumab 0.3 mg ranibizumab 0.5 mg In the later stage of PRN ranibizumab treatment, Month 6 Primary endpoint were the vision gains maintained? Crossover PRN PRN PRN In the later stage of PRN ranibizumab treatment, PRN injections ranibizumab 0.5 mg ranibizumab 0.3 mg ranibizumab 0.5 mg what dosing frequency was required to maintain Secondary endpoint Month 12 vision gains and anatomic stability? HORIZON open-label extension PRN ranibizumab 0.5 mg † * BRAVO patients were eligible for laser treatment once during the treatment period and once during the observation period, beginning at months 3 and 9, respectively, if they met the prespecified visual and anatomic criteria. † Patients were monitored at least every 3 months. 3 4 1

12/2/2016 SHORE: Evaluation of Individualized PRN Ranibizumab Dosing for RVO Disease Stability Maintenance Fixed treatment: monthly dosing Rolling randomization In the initial stage of monthly ranibizumab treatment, Monthly RBZ dosing n = 85* how quickly did patients with RVO respond? Yes R R R R R R R R First month of eligibility for n = 86 † randomization PRN RBZ 7 monthly RBZ injections Stable disease? Yes Yes All patients (N = 202) Stable disease? Monthly RBZ dosing Stable disease? No n = 31 ‡ Non-randomized (monthly RBZ dosing) No Monthly RBZ dosing No Monthly RBZ dosing 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 From month 7 to month 14, patients were assessed monthly for disease stability • VA stability criteria: No change in BCVA, or change in BCVA within a pre-specified magnitude from previous month • SD-OCT stability criteria: No disease activity as determined by clinical investigator Patients received 7 monthly RBZ 0.5-mg injections from month 0 to month 6. Rolling randomization began at month 7. * Premature discontinuations, n = 5. † Premature discontinuations, n = 4. ‡ Premature 5 discontinuations prior to month 7, n = 12; number of discontinuations between months 7 ‒ 15, n = 6. R, randomized; RBZ, ranibizumab. Visual Gains in the Initial 6-Month Treatment Period: Ranibizumab Injections Every Month BRAVO/CRUISE SHORE 25 25 From Baseline, Letters In the later stage of PRN ranibizumab treatment, Mean BCVA Change 20 20 +19.3 +18.3 were the vision gains maintained? 15 +15.0 15 10 10 +7.9 5 5 +2.2 0 0 -5 -5 0 1 2 3 4 5 6 0 1 2 3 4 5 6 Month Month Monthly RBZ 0.5 mg Sham Monthly RBZ 0.5 mg BRAVO CRUISE BRAVO CRUISE All patients (n = 131) (n = 130) (n = 132) (n = 130) Median Time in Months to First Gain of ≥ 15 ETDRS Letters From Baseline Ranibizumab 0.5 mg-Treated Patients BRAVO: 4 CRUISE: 5.2 SHORE: 2.1 Observed data; vertical bars represent +/ ‒ 1 SE. RBZ, ranibizumab. 7 2

12/2/2016 Maintenance of Vision Gains During Later-Stage Treatment Maintenance of Vision Gains During Later-Stage Treatment With PRN Ranibizumab Dosing With PRN Ranibizumab Dosing BRAVO/CRUISE SHORE BRAVO/CRUISE SHORE Monthly PRN Monthly Individualized Dosing Monthly PRN Monthly Individualized Dosing 25 25 25 25 From Baseline, Letters From Baseline, Letters P = 0.81 Mean BCVA Change Mean BCVA Change +21.0 +21.0 20 20 20 20 +19.2 +19.2 +18.7 +18.7 15 +14.7 15 15 +14.7 15 Mean slope change +12.9 from baseline 10 10 10 10 P = 0.509 +9.6 P = 0.20 5 5 5 5 0 0 0 0 -5 -5 -5 -5 0 1 2 3 4 5 6 7 8 9 10 11 12 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 0 1 2 3 4 5 6 7 8 9 10 11 12 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 Month Month Month Month Monthly RBZ 0.5 mg/PRN RBZ 0.5 mg Sham/PRN RBZ 0.5 mg RBZ 0.5 mg Monthly RBZ 0.5 mg/PRN RBZ 0.5 mg Sham/PRN RBZ 0.5 mg RBZ 0.5 mg BRAVO CRUISE BRAVO CRUISE Monthly PRN BRAVO CRUISE BRAVO CRUISE Monthly PRN (n = 131) (n = 130) (n = 132) (n = 130) (n = 85) (n = 86) (n = 131) (n = 130) (n = 132) (n = 130) (n = 85) (n = 86) Mean BCVA Change From Baseline Mean BCVA Change From Baseline 6 months 12 months Difference Randomization 15 months Difference a BRAVO 19.3 19.2 – 0.1 Monthly 18.8 18.7 – 0.1 CRUISE 15 14.7 – 0.3 PRN 20.6 21.0 + 0.3 a Difference is calculated as change from randomization at M15. 9 10 Observed data; vertical bars represent +/ ‒ 1 SE. RBZ, ranibizumab. Observed data; vertical bars represent +/ ‒ 1 SE. Paired sample t-test was used to compare M6 and M12 BCVA change from baseline for BRAVO and CRUISE study, respectively. RBZ, ranibizumab. Proportion of Patients With ≥ 15-Letter Gains: Proportion of Patients With ≥ 15-Letter Gains: PRN Ranibizumab Dosing PRN Ranibizumab Dosing BRAVO/CRUISE SHORE BRAVO/CRUISE SHORE Patients With ≥ 15-Letter Patients With ≥ 15-Letter Monthly PRN Monthly Individualized Dosing Monthly PRN Monthly Individualized Dosing Gains From Baseline, % Gains From Baseline, % 100 100 100 100 P = 0.48 80 80 80 P = 0.89 80 70.7% 70.7% 62.6% 66.3% 62.6% 66.3% 60 60 60 60 56.1% 56.1% P = 0.83 46.5% 40 40 40 40 37.4% P = 0.39 20 20 20 20 0 0 0 0 0 1 2 3 4 5 6 7 8 9 10 11 12 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 0 1 2 3 4 5 6 7 8 9 10 11 12 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 Month Month Month Month Monthly RBZ 0.5 mg/PRN RBZ 0.5 mg Sham/PRN RBZ 0.5 mg RBZ 0.5 mg Monthly RBZ 0.5 mg/PRN RBZ 0.5 mg Sham/PRN RBZ 0.5 mg RBZ 0.5 mg BRAVO CRUISE BRAVO CRUISE Monthly PRN BRAVO CRUISE BRAVO CRUISE Monthly PRN (n = 131) (n = 130) (n = 132) (n = 130) (n = 85) (n = 86) (n = 131) (n = 130) (n = 132) (n = 130) (n = 85) (n = 86) % Patients With ≥ 15 ETDRS-Letter Gains From Baseline % Patients With ≥ 15 ETDRS-Letter Gains From Baseline 6 months 12 months Difference Randomization 15 months Difference BRAVO 63.4 62.6 – 0.8 Monthly 64.7 66.3 + 1.5 CRUISE 50.5 56.1 + 5.7 PRN 75.6 70.7 – 4.9 Observed data. P -values are from the Chi-square test. RBZ, ranibizumab. Observed data. RBZ, ranibizumab. 11 12 3

12/2/2016 BRAVO and CRUISE: PRN Ranibizumab Treatment Phase Injection Frequency In the later stage of PRN ranibizumab treatment, BRAVO CRUISE what dosing frequency was required to maintain (n = 125) (n = 119) PRN Tx: 6 months PRN Tx: 6 months vision gains and anatomic stability? Mean PRN inj: 2.8 Mean PRN inj: 3.6 PRN RBZ injections 6.7% 25.6% Less-than-monthly 0 inj per 6 months 17.6% 20.0% Monthly 25.2% 0–4 inj per 6 months 39.5% 1–3 inj per 6 months 60.5% Monthly 40.3% Less-than- 4–5 inj per 6 months Monthly 21.6% monthly 74.4% 5–6 inj per 6 months 40.8% 6 inj per 6 months Less-than-monthly 27.7% 14 Observed data. Data are from patients randomized to the ranibizumab 0.5 mg treatment arm. Inj, injection; RBZ, ranibizumab; Tx, treatment. BRAVO and CRUISE: PRN Ranibizumab Treatment Phase SHORE: PRN Treatment Phase Monthly vs Less-Than-Monthly Subgroups Injection Frequency (Patients Randomized by Month 8) SHORE Monthly RBZ Dosing PRN RBZ Dosing (n = 69) 25 BRAVO: Less-than-monthly (n = 93) PRN Tx: variable (7-8 months) Mean BCVA Change From Mean PRN inj: 3.2 BRAVO: Monthly (n = 32) 20 20.0 letters CRUISE: Less-than-monthly (n = 72) Monthly Baseline, Letters 17.1 letters PRN RBZ injections CRUISE: Monthly (n = 47) 7.2% 7.2% 8.7% 15.0 letters 15 15 ETDRS letters 14.2 letters 0 inj per 7–8 M PRN Less-than-monthly 10 0–5 inj per 7–8 months PRN 1–5 inj per 7-8 M PRN Monthly 5 84.1% 6-7 inj per 7–8 M PRN 92.8% 6–7 inj per 6-7 months PRN Less-than-monthly 0 Baseline Month 6 Month 12 Less-than-monthly: 0–4 RBZ injections during 6-month PRN treatment period Monthly: 5–6 RBZ injections during 6-month PRN treatment period Observed data. Data are from patients randomized by month 8 (69 out of 86 PRN patients). Maximum number of RBZ injections during PRN treatment period was 7 for patients randomized at month 7 and 6 for Observed data. Data are from patients randomized to the ranibizumab 0.5 mg treatment arm. Inj, injection; RBZ, ranibizumab; Tx, treatment. 15 patients randomized at month 8. Inj, injection; RBZ, ranibizumab; Tx, treatment. 16 4