HG004 Gene Therapy for Patients with Leber Congenital Amaurosis

Abstract

Purpose : The safety and efficacy of adeno-associated virus serotype 2 (AAV2) gene therapy for Leber Congenital Amaurosis caused by mutations in the RPE65 gene (LCA2) have been validated in humans. However, transduction of retinal pigment epithelial (RPE) cells with AAV2 has partially corrected LCA2 in animals while AAV serotype 9 (AAV9) is an ideal AAV vector to restore cone-photoreceptor function than AAV2. We conducted the LIGHT (Leber congenital amaurosis Inherited blindness of Gene tHerapy Trial) study (NCT06088992) to evaluate the safety and efficacy of a single injection of HG004 (AAV9-RPE65) in LCA2 patients.

Methods : After completing the informed consent process and confirming the eligibility criteria, the eye with the worst visual function was selected for subretinal injection of one of the three doses of HG004. Patients were evaluated before and after surgery at designated follow-up visits up to 5 years by complete ophthalmic examination. Efficacy for each treated patient was monitored with best-corrected visual acuity (BCVA), full-field stimulus threshold (FST), and kinetic visual field (KVF) assessments.

Results : Six adults or children (aged 20.00±10.75, 8-35 years) with RPE65-associated LCA have enrolled in the low and middle-dose cohorts. The average BCVA, FST-white light, and KVF improvements are +11 letters, -2.268 log cd.s/m², and +554.25 deg² (III4e), respectively, at 6 months post-injection in the low dose and +7.5 letters, -1.408 log cd.s/m², and +691.77 deg² (III4e), respectively, at 3 months post-injection in the middle dose. 60% of evaluable patients in these doses reached nearly 15 (14-18) letters of BCVA improvement at either 6- or 3-month visits. No serious adverse event or dose-limiting toxicity has been observed. Most adverse events were mild and transient which have resolved without any intervention.

Conclusions : The preliminary data on 6 months at the low dose and 3 months at the middle dose of HG004 in a total of 6 LCA2 patients showed significant improvement in visual and retinal functions. These two doses (25- to 15-fold lower than the approved AAV2-hRPE65 gene therapy in the Phase 3 trial) in this LIGHT trial showed comparable results, suggesting HG004 may potentially be the best-in-class AAV gene therapy for LCA2. Currently, HG004 is being evaluated in a multi-regional clinical trial (NCT05906953) and has been granted both Orphan Drug Designation and Rare Pediatric Disease Designation by the U.S. FDA.

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