Phase 2 study of the brimonidine drug delivery system (DDS) generation 1 in patients with geographic atrophy: Primary and supplementary analyses

Session Details

Session Title: Free Paper Session 14: AMD IV

Session Date/Time: Friday 08/09/2017 | 16:30-18:00

Paper Time: 16:54

Venue: Room 111

First Author: : B.Kuppermann USA

Co Author(s): :    S. Patel   D. Boyer   A. Augustin   W. Freeman   T. Kim   K. Kerr              

Abstract Details

Purpose:

Geographic atrophy (GA) secondary to age-related macular degeneration (AMD) is blinding and has a complex pathogenesis. Protection of retinal pigment epithelium (RPE) and photoreceptors may slow retinal degeneration and preserve visual function. Brimonidine, an alpha2-adrenergic agonist, shows cytoprotective activity in animal models and in human RPE and Müller cells in vitro. In the Low-Pressure Glaucoma Treatment Study, brimonidine treatment reduced visual field loss, suggesting a potential neuroprotective effect in humans. The effectiveness and safety of Brimonidine Drug Delivery System (Brimo DDS), an intravitreal implant of brimonidine in a slow-release matrix, is under evaluation in the treatment of GA.

Setting:

Twenty-five retina specialty practices and centres in Asia, Australia, Europe and the USA.

Methods:

This phase 2, double-masked, parallel-group comparison study (NCT00658619) enrolled patients with bilateral GA secondary to AMD. Best-corrected visual acuity in the worse eye (treated eye) was between 70 and 35 ETDRS letters. Patients were randomized in a 2:2:1 ratio to Brimo DDS 132 µg (n=49), Brimo DDS 264 μg (n=41), or sham (n=21) in the treated eye at Baseline and Month 6. Patients were evaluated at study visits through Month 24 (18 months after the last study treatment). The main efficacy variable was change from Baseline (CFB) in the area of GA, measured using fundus photography and fluorescein angiography. The primary endpoint was GA area CFB at Month 12. A post-hoc sensitivity analysis using a mixed-effects model with repeated measures (MMRM) was also conducted. In addition, a post-hoc subgroup analysis conducted using an MMRM model evaluated the effects of Brimo DDS on GA lesion progression rate (calculated as the CFB in effective lesion diameter [2*√((GA lesion area)/π)]) in the subgroup of patients with Baseline lesion area of >9 mm2.

Results:

GA area CFB was consistently reduced by Brimo DDS 132 and 264 μg. Statistically significant (P=0.032) differences between Brimo DDS and sham were observed at Month 3. Sensitivity analysis using observed data and an MMRM model with covariate of Baseline GA area confirmed that Brimo DDS reduced GA progression with nearly significant (P=0.059) effect of Brimo DDS 264 μg at year 2. In sham-treated patients, there was a significant positive association between GA area CFB at Month 12 and Baseline lesion area (P=0.004), which was dose-dependently reduced by Brimo DDS. Patients with Baseline lesion area >9 mm2 (two-thirds of patients) showed significantly reduced GA effective diameter CFB after Brimo DDS 132 and 264 μg at Months 12, 18, and 24 (P<0.05). Reductions of 33.0% and 37.4% GA progression rate over year 1 were observed in Brimo DDS 132 and 264 μg arms. Treatment-related ocular adverse events (AEs) in treated eyes, mostly attributed to the injection procedure, were reported in 17/48 (35%), 11/40 (28%), and 2/23 (9%) of patients in the 132 and 264 μg and sham arms, respectively. Serious AEs (SAEs) occurred with similar frequency across groups. AEs and SAEs were mostly mild or moderate and resolved with treatment.

Conclusions:

Brimo DDS demonstrated a favorable safety profile in this study. At Month 3, GA progression rate was significantly reduced in the Brimo DDS-treated groups. Sensitivity analysis confirmed the observation that Brimo DDS reduced lesion growth, nearing statistical significance with the higher dose at year 2 (P=0.059), 18 months after the last study treatment. Supplementary analysis showed a positive correlation between Baseline GA lesion area and the progression rate at year 1. For patients in the upper 2 tertiles of Baseline GA lesion area (Baseline lesion size >9 mm2), Brimo DDS significantly reduced lesion growth compared with sham at Months 12, 18, and 24. A Phase 2b study is ongoing.

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