Safety of the Subretinal Delivery of RGX-314 AAV8-anti-VEGF Fab Gene Therapy in NHP: Retinal Structure Over One Year

Abstract

Purpose : To evaluate the long-term (one year) safety and define an upper dose limit of subretinally delivered RGX-314 AAV8-anti-VEGF Fab as a treatment for wet AMD in non-human primates (NHP).

Methods : Cynomolgus monkeys, ages 3-5 years, received a single, unilateral, subretinal injection of 1e10 (‘low’, n=6), 1e12 (‘high’, n=6) AAV8 GC/eye, or of a vehicle-control (n=4). The contralateral eye served as an uninjected control. Retinal structure was evaluated with spectral domain optical coherence tomography (SD-OCT) at 3 months post-injection; a subset of these animals (high-dose, n=2; low-dose, n=3; injected-control, n=2) were evaluated every 3 months for 12 months post-injection. Overlapping SD-OCT scans were performed to ensure coverage of the treated retina. SD-OCT cross-sections within injected regions were co-registered to baseline cross-sections. The thickness of the total retina (TRT), inner retina (IRT), and outer nuclear layer (ONL) within injected regions were compared to the same retinal locations pre-injection.

Results : Retinal demelanization separated the injected regions from uninjected retina in all injected (including vehicle-injected) eyes from the earliest visit and remained unchanged in extent over time. There were no signs of intraocular inflammation. No significant SD-OCT changes were observed in vehicle-injected compared to uninjected eyes (99 percentile limits for change: TRT=14%, IRT= 31%, ONL=18%) at 3 months, or during the 12-month follow-up. Eyes injected with the low-dose vector showed no significant differences during the entire observation period in TRT, IRT or ONL thickness compared to baseline values. Four of six eyes from the high-dose vector group showed significant ONL thinning within the injected regions at 3 months accompanied by non-significant thickening of the inner retina. One of two animals of the high-dose group who were followed for 12 months had normal ONL thickness at 3 months but showed ONL progressive thinning over time.

Conclusions : Subretinal injections of AAV8-anti-VEGF Fab in NHP demonstrated long-term safety in the low dose group with no apparent changes on main SD-OCT structural parameters out to 12 months and notable structural changes in the high dose group in the area of injection. Findings from this study support the long-term safety of the low dose and help establish the upper dose limit for future RGX-314 clinical trials.

This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.