ATSN-101 Gene Therapy Reports Positive Data in Phase 1/2 Trial

ATSN-101 subretinal gene therapy demonstrated a robust safety profile and preliminary evidence of improvements in visual function among patients with Leber congenital amaurosis 1 (LCA1) caused by biallelic mutations in GUCY2D, according to new Phase 1/2 trial data.¹

On average, patients treated with high-dose ATSN-101 experienced an approximate 20 decibels (dB) improvement in dark-adapted full-field stimulus test (FST), representing a 100-fold improvement. Two patients showed significant improvements by more than 40 dB (10,000-fold).

“Even though we previously predicted a large vision improvement potential in LCA1, we did not know how receptive patients’ photoreceptors would be to treatment after decades of blindness,” said Artur Cideciyan, PhD, a research professor of ophthalmology and co-director of the Center for Hereditary Retinal Degeneration at the University of Pennsylvania Perelman School of Medicine.² “It is very satisfying to see a successful multi-center trial that shows gene therapy can be dramatically efficacious.”

LCA is a group of inherited retinal diseases that typically lead to severely reduced vision, and ultimately blindness, from infancy.³ GUCY2D was the first gene linked to LCA and is the cause of up to 20% of cases. Among those with the severe LCA1 form, best-corrected visual acuity (BCVA) can typically range from 20/80 to no light perception, despite photoreceptor structure on optical coherence tomography (OCT) appearing well-preserved.⁴

Without historically available treatments, gene therapy is an emerging field across the spectrum of inherited retinal diseases (IRDs), with approval won in 2017 for LCA caused by mutations in RPE65.⁵ With ATSN-101 the only gene therapy targeting LCA1, Cideciyan and colleagues reported all safety and efficacy data from the Phase 1/2 trial through 12 months of treatment.¹

The trial enrolled 15 participants with genetically confirmed biallelic mutations in GUCY2D, with a study eye BCVA of 20/80 or worse, between September 2019 and May 2022. Each patient received unilateral subretinal injections of ATSN-101 at two sites in the United States.

A dose-escalation phase (Part A) and a dose-expansion phase (Part B) separated the trial. In the dose-escalation phase, 3 adult cohorts (n = 3 each) were treated with ATSN-101 ascending doses: 1.0 x 1010 vg/eye (low dose), 3.0 x 1010 vg/eye (middle dose), and 1.0 x 1011 vg/eye (high dose). The dose-expansion phase consisted of one adult cohort (n = 3) and one pediatric cohort (n = 3) treated with the high dose.

Treatment-emergent adverse events (TEAEs) after ATSN-101 treatment served as the primary endpoint, with FST and BCVA used as secondary endpoints, over the 12-month treatment period. At the study cutoff date, no patient had withdrawn from the study.

Upon analysis, 68 TEAEs were identified, with 56 deemed related to the surgical procedure. All patients experienced ≥1 TEAE and none were greater than moderate severity—the most common were conjunctival hemorrhage and ocular discomfort.

A total of 3 adverse events met the criteria for a serious adverse event, including an intraoperative macular home, endophthalmitis, and retinal detachment. Each event was determined to be related to the surgical procedure and unrelated to ATSN-101.

Among individuals who received high-dose ATSN-101, improvements were identified on Day 28 and persisted to Month 12 (change in dark-adapted FST, 20.3 db; 95% CI, 6.6–34.0; P = .012). Six of 9 patients who received the high dose achieved an improvement of ≥10 dB, with improvements up to 46.5 dB.

Untreated eyes only improved by 1.1 dB (95% CI, –3.7 to 5.9; white stimulus) in the same period. Modest improvements in best-corrected visual acuity (BCVA) were also identified 12 months after treatment with the high dose of ATSN-101 (–0.16 logMar; P = .10).

“That 10,000-fold improvement is the same as a patient being able to see their surroundings on a moonlit night outdoors as opposed to requiring bright indoor lighting before treatment,” Cideciyan said.² “One patient reported for the first time being able to navigate at midnight outdoors only with the light of a bonfire.”

References

1. _{Yang P, Pardon LP, Ho AC, et al. Safety and efficacy of ATSN-101 in patients with Leber congenital amaurosis caused by biallelic mutations in GUCY2D: a phase 1/2, multicentre, open-label, unilateral dose escalation study. Lancet. 2024;404(10456):962-970. doi:10.1016/S0140-6736(24)01447-8}
2. _{PennMedNews. 100x improvement in sight seen after gene therapy trial. EurekAlert! September 5, 2024. Accessed September 9, 2024. https://www.eurekalert.org/news-releases/1056835.}
3. _{Kumaran N, Moore AT, Weleber RG, Michaelides M. Leber congenital amaurosis/early-onset severe retinal dystrophy: clinical features, molecular genetics and therapeutic interventions [published correction appears in Br J Ophthalmol. 2019 Jun;103(6):862. doi: 10.1136/bjophthalmol-2016-309975corr1]. Br J Ophthalmol. 2017;101(9):1147-1154. doi:10.1136/bjophthalmol-2016-309975}
4. _{Jacobson SG, Cideciyan AV, Peshenko IV, et al. Determining consequences of retinal membrane guanylyl cyclase (RetGC1) deficiency in human Leber congenital amaurosis en route to therapy: residual cone-photoreceptor vision correlates with biochemical properties of the mutants. Hum Mol Genet. 2013;22(1):168-183. doi:10.1093/hmg/dds421}
5. _{Russell S, Bennett J, Wellman JA, et al. Efficacy and safety of voretigene neparvovec (AAV2-hRPE65v2) in patients with RPE65-mediated inherited retinal dystrophy: a randomised, controlled, open-label, phase 3 trial [published correction appears in Lancet. 2017 Aug 26;390(10097):848. doi: 10.1016/S0140-6736(17)32235-3]. Lancet. 2017;390(10097):849-860. doi:10.1016/S0140-6736(17)31868-8}