Abstract
Purpose :
Brimonidine (brimo) DDS is under clinical evaluation as a long-acting therapy for the treatment of GA secondary to AMD. Our objective was to examine the cyto- and neuro-protective effects of brimo DDS in a nonhuman primate model of progressive retinal degeneration.
Methods :
Both eyes of 6 cynomolgus monkeys received 3 parafoveal lesions using a light source (470nm filter) with three exposure times (ET) (5min (low), 15min (medium) or 30min (high)) generating a graded insult to the RPE. Fundus autofluorescence (FAF) and optical coherence tomography (OCT) imaging were performed at baseline, and up to 20 weeks post-induction. FAF images were used to determine extent of RPE disruption via quantification of area of hypofluorescence, and loss of outer nuclear layer (ONL) thickness was quantified from OCT images. Five weeks post-induction, eyes of N=4 monkeys were injected with 132ug brimo DDS, while fellow eyes received placebo DDS. Two additional animals served as untreated controls. A linear mixed effects model was used to determine treatment differences and multiple comparisons were conducted with Dunnett’s test at each time point. In a separate pharmacokinetic study, brimo concentrations were measured up to 25 weeks post-injection of 132 µg brimo DDS (N=3/timepoint).
Results :
No significant differences in hypofluorescence area or ONL thickness were observed prior to dosing. Treatment differences were observed earliest in high ET lesions, with significantly less change from baseline in hypofluorescence area at week 12 (p<0.05) followed by medium (p<0.01) and low (p<0.05) at 16 weeks. ONL thickness differences were seen as early as 16 weeks (p<0.01) in the high ET lesions with significantly less change from baseline, followed by medium at 20 weeks (p<0.05). No significant changes were detected in low ET lesions. Effects on both RPE and ONL were maintained up to week 20. Brimo concentrations in retina were ≥ 1000 ng/g and were sustained for 25 weeks.
Conclusions :
Our results demonstrate the cyto- and neuro-protective effects of brimo DDS in a large eye model of progressive outer retinal degeneration. Analogous to recent clinical results, it took longer to reach statistical significance in lesions of lesser severity, although sustained beneficial effects were observed in all lesions.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.