Interim Safety Results in Two Phase 1/2 Open-label, Dose-escalation Clinical Trials of Subretinal Gene Therapy with AGTC-401 (rAAV2tYF-PR1.7-hCNGB3) and AGTC-402 (rAAV2tYF-PR1.7-hCNGA3) in Subjects with Achromatopsia (ACHM)

Abstract

Purpose : To report on safety of AGTC-401 and AGTC-402, two gene therapies designed to compensate for the most often mutated genes, CNGB3 and CNGA3, in ACHM, a form of autosomal recessive congenital severe cone photoreceptor dysfunction.

Methods : A macular subretinal injection (≤300 μL) of AGTC-401 (CNGB3, n=31) or AGTC-402 (CNGA3, n=24) was performed in a study eye of 55 subjects, 5-69 years old (37 adults, 18 children). Subjects were sequentially assigned to 1 of 5 (CNGA3) or 6 (CNGB3) dose groups spanning from 4.0e¹⁰ to 3.2e¹²vg/ml. Safety results were evaluated by reported ocular and non-ocular adverse events (AEs), functional and microanatomical imaging-based outcome measures, and chemistry parameters.

Results : Across both trials, 3 drug-related serious adverse event (SAE) cases were seen in children at the highest dose level [3.2e¹²vg/mL, CNGA3 (N=2) and CNGB3 (N=1)], which was assessed to be a dose-limiting toxicity (DLT) dose level in children. Uveitis and posterior segment changes were seen clinically and by imaging studies in 3 children, one of whom also developed subretinal fluid in the untreated fellow eye. No DLTs were observed at any dose level in adults.

At dose levels below the DLT in adults and children, both drugs had a favorable safety profile and none of the 3 SAEs were deemed drug-related [macular hole related to subretinal surgery (n=1); steroid-induced elevated IOP resolved after glaucoma surgery (n=2)]. Most AEs were Grade 1 or 2 (except one Grade-3 anterior chamber inflammation). All intraocular inflammatory AEs were controlled with oral, intravenous and/or topical steroids. Steroid-related IOP elevations were seen in 24 subjects (47.1%), and were non-serious and controlled with IOP-lowering agents in 22 (91.7%). Immunological T-cell and antibody tests to AAV and genes CNGA3 or CNGB3 were not associated with safety findings.

Conclusions : AGTC-401/AGTC-402 gene therapy to potentially treat ACHM was safe and well-tolerated in children up to and including second highest dose (1.1e¹²vg/mL), and in adults up to and including the highest dose (3.2e¹²vg/mL), which was assessed to be a DLT level in children due to intraocular inflammation that responded to adjusted steroid regimens. Imaging studies were very important in characterizing the SAEs.

This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.