Intravitreal Brimonidine Drug delivery system (DDS) slows optic nerve degeneration in a non-human primate model of experimental glaucoma

Abstract

Purpose : Glaucoma is a multifactorial optic neuropathy that results in progressive retinal ganglion cell death and vision loss. Clinically, topical brimonidine reduced visual field progression in low tension glaucoma patients more effectively than timolol despite similar intraocular pressure (IOP) lowering effects. Our objective was to evaluate the neuroprotective efficacy of intravitreal Brimonidine DDS in a non-human primate (NHP) model of glaucoma.

Methods : Unilateral experimental glaucoma was induced in N=30 NHPs and confirmed by bi-weekly IOP assessments. Structural measurements included minimum rim width (MRW), retinal nerve fiber layer (RNFL), and macular ganglion cell inner-plexiform layer thickness (GCIPL). The functional measurement included photopic negative response (PhNR) amplitude. Following model induction, animals were assigned to 3 groups (Brimonidine DDS 200 µg, Brimonidine DDS 67 µg, sham control) based on two criteria: I) A reduction in MRW by ≥1 standard deviation from the non-study eye at 2 consecutive sessions; II) an increase in IOP in the study eye of >5 mmHg relative to the average pre-induction IOP. Six additional animals were assigned to study pharmacokinetics (PK) of Brimonidine DDS (200 µg) at 4, 8 and 12 weeks (n=2/timepoint). The change of various structural and functional endpoints over time in the different treatment groups was computed and analyzed. At the end of the study, ocular tissues were harvested for histological assessments.

Results : Both doses of Brimonidine DDS (67 µg and 200 µg) significantly reduced the RNFL thinning compared to sham (p<0.05, LME). A similar trend was observed for MRW and GCIPL. PhNR amplitude showed significantly less reduction in the 67 µg and 200 µg groups compared to the sham control (p<0.05, LME) from 8 to 12 weeks. Both treatment groups (67 µg and 200 µg) exhibited significantly higher RGC counts relative to sham (p<0.01, GLM). Mean brimonidine concentrations at 200 µg dose was at least 100-fold above EC₅₀ at alpha 2 receptors up to 3 months in the retina (macula and periphery).

Conclusions : This study demonstrated that Brimonidine DDS treatment slows the progressive thinning of MRW, RNFL, GCIPL, and inner retinal functional deficit and prevents progressive RGC loss in the OHT NHP model.

This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.