Twelve-month Findings from Two Phase 1/2 Clinical Studies of Subretinal Gene Therapy Drugs for Achromatopsia

Abstract

Purpose : Achromatopsia (ACHM) is an autosomal recessive retinal disease characterized by absence of cone photoreceptor function. Clinical manifestations include reduced visual acuity, complete loss of color discrimination, and photophobia under daylight conditions. Gene therapy drugs, AGTC-401 and AGTC-402, are being developed to compensate for the mutated genes responsible for over 80% of the ACHM cases, CNGA3 and CNGB3. This is an initial report on the twelve-month safety and efficacy findings from two ongoing, Phase 1/2, open-label, dose-escalation trials using recombinant adeno-associated virus (rAAV) viral vectors.

Methods : A single subretinal injection of either AGTC-401 (rAAV2tYF-PR1.7-hCNGB3) or AGTC-402 (rAAV2tYF-PR1.7-hCNGA3) was administered to participants (n=24), age ≥14, into the macula region of the study eye. Participants were sequentially assigned to one of four dose groups in both studies. The safety and efficacy outcomes were measured by best-corrected visual acuity (BCVA) using ETDRS, light discomfort testing (LDT) by ocular photosensitivity analyzer (OPA), ERG/mfERG, retinal sensitivity by static perimetry and microperimetry, color vision testing by Farnsworth D15 and CAD, and patient-reported outcomes (PROs) using a QoL questionnaire (VLSQ-8).

Results : Both drugs were well-tolerated across all dose ranges. Most AEs were mild-moderate. No SAE was drug-related, and 2 participants had SAEs related to raised IOP due to concomitant steroids. AEs due to ocular inflammation were controlled after modification of the steroid regimen. Immunological response to AAV and genes CNGA3 or CNGB3 were not indicative of a safety concern. Among the 24 treated participants, 4 had a 5-letter improvement on BCVA at month 12. Five participants had a 1-log¹⁰ lux or more improvement for light sensitivity threshold on OPA analysis. PROs showed patient improvement in outdoor light sensitivity, severity of worst light sensitivity, and headache. There were small changes for most assessments at month 12 compared to baseline.

Conclusions : Safety results suggest AGTC-401 and AGTC-402 are safe and well tolerated in ACHM patients. There were no indications of significant immunological responses to the vector or capsid. Data across both studies show encouraging signs of biologic activity. Additional patients will be enrolled in both studies and followed through 5 years.

This is a 2021 ARVO Annual Meeting abstract.