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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

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12/2/2016 1

Disclosures

Title

Late-Stage Management of Macular Edema Secondary to Retinal Vein

Occlusion: Collective Analyses of the BRAVO, CRUISE, HORIZON, and SHORE Studies Financial Disclosures

Robert B. Bhisitkul, MD, PhD: Grant support, speakers bureau, and

consultant: Genentech/Roche; consultant: Santen, Inc.; advisory boards: Allergan; Bausch & Lomb.

Late-Stage Management of Macular Edema Secondary to Retinal Vein Occlusion: Collective Analyses of the BRAVO, CRUISE, HORIZON, and SHORE Studies

Robert B. Bhisitkul, MD, PhD Professor of Clinical Ophthalmology University of California San Francisco School of Medicine

Key Clinical Questions

In the initial stage of monthly ranibizumab treatment, how quickly did patients with RVO respond? In the later stage of PRN ranibizumab treatment, were the vision gains maintained? In the later stage of PRN ranibizumab treatment, what dosing frequency was required to maintain vision gains and anatomic stability?

BRAVO/CRUISE: Ranibizumab for the Treatment of BRVO and CRVO

* 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.

Primary endpoint

Monthly injections

1:1:1 randomization

Monthly sham injection Monthly ranibizumab 0.3 mg

Month 6

Monthly ranibizumab 0.5 mg

Macular edema secondary to retinal vein occlusion

BRAVO* (BRVO, N = 397) CRUISE (CRVO, N = 392)

HORIZON open-label extension PRN ranibizumab 0.5 mg†

Secondary endpoint Month 12

PRN ranibizumab 0.5 mg Crossover PRN ranibizumab 0.3 mg PRN ranibizumab 0.5 mg

PRN injections

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Stable disease? Monthly RBZ dosing Stable disease? Monthly RBZ dosing PRN RBZ Yes Stable disease? No

SHORE: Evaluation of Individualized PRN Ranibizumab Dosing for RVO Disease Stability Maintenance

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 discontinuations prior to month 7, n = 12; number of discontinuations between months 7‒15, n = 6. R, randomized; RBZ, ranibizumab.

2 3 4 5 6 7 8 9 10 11 12 13 14 15 1

Fixed treatment: monthly dosing

All patients (N = 202)

Rolling randomization

First month of eligibility for randomization 7 monthly RBZ injections Yes No Monthly RBZ dosing

R R

Yes No Monthly RBZ dosing

R 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

n = 85* n = 86† n = 31‡

R R R R R

Non-randomized (monthly RBZ dosing)

In the initial stage of monthly ranibizumab treatment, how quickly did patients with RVO respond?

Visual Gains in the Initial 6-Month Treatment Period: Ranibizumab Injections Every Month

5 10 15 20 25 1 2 3 4 5 6

Mean BCVA Change From Baseline, Letters

+18.3 +7.9 +15.0 +19.3 +2.2 Month

BRAVO/CRUISE SHORE

Month

Sham Monthly RBZ 0.5 mg BRAVO (n = 131) CRUISE (n = 130) BRAVO (n = 132) CRUISE (n = 130)

5 10 15 20 25 1 2 3 4 5 6

Monthly RBZ 0.5 mg All patients

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.

In the later stage of PRN ranibizumab treatment, were the vision gains maintained?

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5 10 15 20 25 1 2 3 4 5 6 7 8 9 10 11 12

Maintenance of Vision Gains During Later-Stage Treatment With PRN Ranibizumab Dosing

Mean BCVA Change From Baseline, Letters

+12.9 +14.7 +19.2 +9.6

BRAVO/CRUISE

Monthly PRN

5 10 15 20 25 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 +18.7 +21.0

SHORE

Monthly Individualized Dosing

Observed data; vertical bars represent +/‒ 1 SE. RBZ, ranibizumab.

Month

Monthly RBZ 0.5 mg/PRN RBZ 0.5 mg BRAVO (n = 131) CRUISE (n = 130) Sham/PRN RBZ 0.5 mg BRAVO (n = 132) CRUISE (n = 130)

Month

RBZ 0.5 mg Monthly (n = 85) PRN (n = 86) 10

Maintenance of Vision Gains During Later-Stage Treatment With PRN Ranibizumab Dosing

a Difference is calculated as change from randomization at M15.

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.

Mean BCVA Change From Baseline 6 months 12 months Difference BRAVO 19.3 19.2 – 0.1 CRUISE 15 14.7 – 0.3 Mean BCVA Change From Baseline Randomization 15 months Differencea Monthly 18.8 18.7 – 0.1 PRN 20.6 21.0 + 0.3

5 10 15 20 25 1 2 3 4 5 6 7 8 9 10 11 12 +14.7 +19.2 Month

BRAVO/CRUISE

Monthly RBZ 0.5 mg/PRN RBZ 0.5 mg BRAVO (n = 131) CRUISE (n = 130) Sham/PRN RBZ 0.5 mg BRAVO (n = 132) CRUISE (n = 130)

5 10 15 20 25 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15

SHORE

Month

RBZ 0.5 mg Monthly (n = 85) PRN (n = 86) P = 0.81 P = 0.20

Monthly PRN Monthly Individualized Dosing

Mean BCVA Change From Baseline, Letters

Mean slope change from baseline P = 0.509

+18.7 +21.0

20 40 60 80 100 1 2 3 4 5 6 7 8 9 10 11 12

Proportion of Patients With ≥ 15-Letter Gains: PRN Ranibizumab Dosing

20 40 60 80 100 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15

Patients With ≥ 15-Letter Gains From Baseline, %

66.3% 70.7% 46.5% 56.1% 62.6% 37.4%

BRAVO/CRUISE SHORE

Observed data. RBZ, ranibizumab.

Monthly PRN Monthly Individualized Dosing Month

Monthly RBZ 0.5 mg/PRN RBZ 0.5 mg BRAVO (n = 131) CRUISE (n = 130) Sham/PRN RBZ 0.5 mg BRAVO (n = 132) CRUISE (n = 130)

Month

RBZ 0.5 mg Monthly (n = 85) PRN (n = 86) 12

Proportion of Patients With ≥ 15-Letter Gains: PRN Ranibizumab Dosing

Observed data. P-values are from the Chi-square test. RBZ, ranibizumab.

% Patients With ≥ 15 ETDRS-Letter Gains From Baseline 6 months 12 months Difference BRAVO 63.4 62.6 – 0.8 CRUISE 50.5 56.1 + 5.7 % Patients With ≥ 15 ETDRS-Letter Gains From Baseline Randomization 15 months Difference Monthly 64.7 66.3 + 1.5 PRN 75.6 70.7 – 4.9 20 40 60 80 100 1 2 3 4 5 6 7 8 9 10 11 12 20 40 60 80 100 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 66.3% 70.7% 56.1% 62.6%

BRAVO/CRUISE SHORE

Monthly PRN Monthly Individualized Dosing Month

Monthly RBZ 0.5 mg/PRN RBZ 0.5 mg BRAVO (n = 131) CRUISE (n = 130) Sham/PRN RBZ 0.5 mg BRAVO (n = 132) CRUISE (n = 130)

Month

RBZ 0.5 mg Monthly (n = 85) PRN (n = 86)

Patients With ≥ 15-Letter Gains From Baseline, %

P = 0.89 P = 0.39 P = 0.48 P = 0.83

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In the later stage of PRN ranibizumab treatment, what dosing frequency was required to maintain vision gains and anatomic stability?

BRAVO and CRUISE: PRN Ranibizumab Treatment Phase Injection Frequency

Observed data. Data are from patients randomized to the ranibizumab 0.5 mg treatment arm. Inj, injection; RBZ, ranibizumab; Tx, treatment.

BRAVO

(n = 125) PRN Tx: 6 months Mean PRN inj: 2.8

CRUISE

(n = 119) PRN Tx: 6 months Mean PRN inj: 3.6 Less-than-monthly Monthly Less-than- monthly Monthly

Less-than-monthly 0–4 inj per 6 months Monthly 5–6 inj per 6 months

20.0% 21.6% 40.8% 17.6% 25.6% 74.4% 25.2% 6.7% 27.7% 40.3% 39.5% 60.5%

0 inj per 6 months 1–3 inj per 6 months 4–5 inj per 6 months 6 inj per 6 months PRN RBZ injections

BRAVO and CRUISE: PRN Ranibizumab Treatment Phase Monthly vs Less-Than-Monthly Subgroups

5 10 15 20 25 BRAVO: Less-than-monthly (n = 93) BRAVO: Monthly (n = 32) CRUISE: Less-than-monthly (n = 72) CRUISE: Monthly (n = 47) Baseline Month 6 Month 12 Mean BCVA Change From Baseline, Letters

15 ETDRS letters

17.1 letters 14.2 letters Monthly RBZ Dosing PRN RBZ Dosing

Observed data. Data are from patients randomized to the ranibizumab 0.5 mg treatment arm. Inj, injection; RBZ, ranibizumab; Tx, treatment.

20.0 letters 15.0 letters Less-than-monthly: 0–4 RBZ injections during 6-month PRN treatment period Monthly: 5–6 RBZ injections during 6-month PRN treatment period

SHORE: PRN Treatment Phase Injection Frequency (Patients Randomized by Month 8)

SHORE

(n = 69) PRN Tx: variable (7-8 months) Mean PRN inj: 3.2

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 patients randomized at month 8. Inj, injection; RBZ, ranibizumab; Tx, treatment.

0 inj per 7–8 M PRN 1–5 inj per 7-8 M PRN 6-7 inj per 7–8 M PRN Less-than-monthly 0–5 inj per 7–8 months PRN Monthly 6–7 inj per 6-7 months PRN

Monthly Less-than-monthly 84.1% 8.7% 7.2% 92.8% 7.2%

PRN RBZ injections

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SHORE: PRN Ranibizumab Treatment Phase Monthly vs Less-Than-Monthly Subgroups (Patients Randomized by Month 8)

5 10 15 20 25 SHORE: Less-than-monthly (n = 64) SHORE: Monthly (n = 5) Baseline Month of Randomization (Month 7 or 8) Month 15 Median BCVA Change From Baseline, Letters

15 ETDRS letters

18.0 letters Monthly RBZ Dosing PRN RBZ Dosing 23.0 letters Less-than-monthly: 0–5 RBZ injections during 7–8-month PRN treatment period Monthly: 6–7 RBZ injections during 7–8-month PRN treatment period

HORIZON open-label extension Patient population

Enrolled patients from BRAVO and CRUISE
Patients had previously received

– 6 months of monthly RBZ – 6 months of PRN RBZ

Treatment regimen

Criteria-based PRN RBZ 0.5 mg at

physician discretion

Patients were seen at least every 3 months

Disease quiescence

0 injections during study treatment

Long-Term Follow-up in HORIZON OLE─Year 2 of Ranibizumab Treatment: Patients Receiving No Further Treatment

Observed data. Data are for patients who completed the month 12 study visit excluding the injection at month 12. RBZ, ranibizumab.

35.6 20.4 10 20 30 40 50

BRVO CRVO Patients With Disease Quiescence, %

n/N 73/205 37/181

HORIZON OLE Patients With Disease Quiescence at Month 12

18.3 18.8 18.6 14.5

5 10 15 20 25 30 BRVO (n = 73) CRVO (n = 37)

VA Gains in HORIZON OLE Patients With Disease Quiescence at Month 12

Baseline HORIZON Month 12 Mean BCVA Change From Baseline, Letters HORIZON Entry

Conclusions

RBZ, ranibizumab.

After one injection, monthly RBZ 0.5 mg treatment resulted in mean gains of ≥ 10 ETDRS letters from baseline in

patients in BRAVO, CRUISE, and SHORE

Median time to first gain of ≥ 15 ETDRS letters from baseline was 4.0, 5.2, and 2.1 months in BRAVO, CRUISE, and

SHORE, respectively

After one injection, monthly RBZ 0.5 mg treatment resulted in mean gains of ≥ 10 ETDRS letters from baseline in

patients in BRAVO, CRUISE, and SHORE

Median time to first gain of ≥ 15 ETDRS letters from baseline was 4.0, 5.2, and 2.1 months in BRAVO, CRUISE, and

SHORE, respectively

Ranibizumab treatment resulted in rapid vision gains in patients with RVO

Majority of patients received less-than-monthly dosing and maintained disease stability during PRN treatment
A small percentage of patients achieved disease quiescence with monthly dosing and received no additional RBZ

injections during PRN treatment

Majority of patients received less-than-monthly dosing and maintained disease stability during PRN treatment
A small percentage of patients achieved disease quiescence with monthly dosing and received no additional RBZ

injections during PRN treatment

Vision gains maintained in later PRN stage with less-than-monthly ranibizumab treatment

Monthly RBZ 0.5 mg treatment resulted in mean BCVA gains of 19.3 and 15.0 letters at 6 months in BRAVO and

CRUISE and 18.3 letters at 7 months in SHORE

These gains were maintained with a mean –0.1, –0.3, and 0.3-letter change from the start of PRN treatment through

the end of each trial in BRAVO, CRUISE, and SHORE, respectively

Monthly RBZ 0.5 mg treatment resulted in mean BCVA gains of 19.3 and 15.0 letters at 6 months in BRAVO and

CRUISE and 18.3 letters at 7 months in SHORE

These gains were maintained with a mean –0.1, –0.3, and 0.3-letter change from the start of PRN treatment through

the end of each trial in BRAVO, CRUISE, and SHORE, respectively

Vision gains were maintained with criteria-based PRN ranibizumab treatment