Six-month safety and efficacy of ATSN-101 in patients with Leber congenital amaurosis caused by biallelic mutations in GUCY2D (LCA1)

Abstract

Purpose : The goal of this phase 1/2 study was to evaluate the safety, tolerability, and efficacy of ascending doses of ATSN-101, a subretinal gene therapy for Leber congenital amaurosis secondary to mutations in the GUCY2D gene.

Methods : Fifteen patients (median [range] age = 21 [12-76] years; 10 female) received unilateral subretinal injections of ATSN-101. Three adult cohorts (N = 3 each) were treated with three ascending doses: 1.0 x 10¹⁰ vg/eye (low), 3.0 x 10¹⁰ vg/eye (mid), and 1.0 x 10¹¹ vg/eye (high). Subsequently, one adult and one pediatric cohort (N = 3 each) were treated at the high dose. The primary endpoint was the incidence of adverse events, and secondary endpoints included best-corrected visual acuity (BCVA), full-field stimulus testing (FST), and multi-luminance mobility testing (MLMT). Data up to 6 months post-treatment were included in the analysis.

Results : A total of 63 treatment emergent adverse events (TEAE) were observed, 55 of which were related to the surgical procedure. No serious TEAE were related to the study drug. Ocular inflammation observed to date has been infrequent, minimal, and reversible with steroid treatment. Among patients that received the high-dose treatment (N = 9), the mean (SE) change from baseline in retinal sensitivity by dark-adapted FST was significantly greater in treated eyes compared with untreated eyes at all four follow-up visits: day 28 (white stimulus: 15.1 [4.5] vs. 1.0 [1.3] dB, P = 0.04), day 56 (15.6 [4.5] vs. 0.01 [1.2] dB, P = 0.01), day 84 (16.1 [5.3] vs. -1.9 [1.0] dB, P = 0.005), and day 168 (16.7 [5.8] vs. 1.2 [1.7] dB, P = 0.03). Two high-dose patients demonstrated BCVA improvement greater than 0.3 logMAR, and no treated eyes had a decrease in BCVA. Of the five high-dose patients that were tested with MLMT, four tested patients demonstrated either a maximum MLMT score of 6 or a ≥ 2 level improvement, compared to baseline when available or to the untreated fellow eye, at one or more post-treatment visits.

Conclusions : ATSN-101 continues to be well-tolerated 6 months post-treatment, with no serious adverse events related to the drug. Clinically meaningful improvements in FST and MLMT were observed.

This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.