World's First CRISPR/RNA-Targeting Therapy (HG202) for Patients with Neovascular Age-Related Macular Degeneration

Abstract

Purpose : Although anti-vascular endothelial growth factor (VEGF) agents are approved to treat neovascular age-related macular degeneration (nAMD), repeated invasive injections lead to serious complications and reduce patient adherence to treatment, resulting in vision loss over time. Additionally, up to 40% of patients fail to respond or only partially respond to anti-VEGF therapies. HG202 is designed as a CRISPR RNA-targeting therapy to partially knock down the VEGFA mRNA expression in the retina. Here, we conducted the SIGHT-I study (NCT06031727) to investigate HG202 as the potential treatment for nAMD.

Methods : SIGHT-I is an open-label trial that evaluates the safety, tolerability, and efficacy of subretinal injection of HG202 which is a single adeno-associated viral (AAV) vector packaging novel high-fidelity CRISPR/Cas13 RNA targeting technology to reduce the expression of VEGFA and thus inhibit choroidal neovascularization (CNV) formation. A total of 9 nAMD patients who are either non-responsive and resistant to anti-VEGF therapies or responsive to anti-VEGF therapies but require frequent injections will be randomized to one of the three doses of HG202. The primary objectives are the safety and tolerability of HG202 at different doses. Secondary objectives include mean change in best-corrected visual acuity (BCVA), central retinal thickness (CRT), and other efficacy endpoints.

Results : As of Dec-2023, 3 subjects have been enrolled in the low-dose cohort. Subject #001, a non-responsive and resistant to anti-VEGF therapies patient, had a history of 6 anti-VEGF injections within 8 months and with persistent macular fluid, CRT of 233 µm, and BCVA of 29 letters before the injection. Retinal fluid was significantly eliminated post-injection, and CRT was recovered to 162 µm and 155 µm at 4- and 8-week post-injection, respectively. The BCVA improvement of nearly 15 letters was observed starting at 4 weeks and sustained at 8 weeks post-injection visit. No serious adverse event or dose-limiting toxicity has been observed.

Conclusions : Current anti-VEGF therapies have significantly changed the landscape to treat nAMD but require life-long repeated invasive injections. HG202 as a novel therapy has the potential to provide safe and effective RNA-targeting therapy to treat nAMD patients who are responsive and non-responsive or develop tachyphylaxis to anti-VEGF agents with a one-time treatment.

This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.