LCA1 Gene Therapy ATSN-101 Shows Phase 1/2 Promise at Highest Dose Assessed

ATSN-101 (previously known as SAR439483) has been shown to be tolerated at its highest dose, with signs of efficacy, in patients with Leber congenital amaurosis caused by biallelic mutations in GUCY2D (LCA1), according to an interim data readout from the phase 1/2 clinical trial (NCT03920007) of the investigational adeno-associated virus (AAV) vector-based gene therapy.¹

The data were presented at the 46th Annual Macula Society Meeting, held February 15-18, 2023, in Miami, Florida. The presentation was delivered by investigator Christine N. Kay, MD, a vitreoretinal surgeon and director of Electrophysiology, Retinal Genetics, and Clinical Trials at Vitreoretinal Associates in Gainesville, Florida, and an affiliate assistant professor at the University of South Florida, who also serves as a clinical ophthalmology advisor for Atsena.

When the company announced the presentation, Kenji Fujita, MD, chief medical officer of Atsena Therapeutics, noted in a statement that, “subretinal delivery of ATSN-101 was well tolerated and demonstrated clinically meaningful improvements in vision in patients treated with the highest dose. With no approved treatments available for patients with LCA1, we are honored to be at the forefront of research for this inherited retinal disease and look forward to reporting additional data from our phase 1/2 trial at medical meetings later this year.”²

READ MORE: HuidaGene’s LCA2 Gene Therapy Gets Orphan Drug Designation

The trial includes a total of 15 patients across 5 cohorts assessing varying doses of the therapy, 3 in the dose-escalation portion of the study and 2 in the expansion portion. In the dose-escalation phase, Cohort 1 used the low dose of 1.0x1010 vg/eye (n = 3), Cohort 2 used the mid-level dose of 3.0x1010 vg/eye (n = 3), and Cohort 3 used the high-level dose of 1.0x1011 vg/eye (n = 3). In the expansion phase, Cohort 4 (n = 3) and Cohort 5 (n = 3) both used the high-level dose of 1.0x1011 vg/eye. At baseline, the overall study median best corrected visual acuity (BCVA) logMAR score was 1.32 (20/420; range, 0.72-4.0).

Previously, Kay presented these data on ATSN-101 in a late-breaking presentation at the American Academy of Ophthalmology 2022 Annual Meeting, which showed promising trends in safety and efficacy in the phase 1/2 clinical trial.³ All told, the high dose was deemed more efficacious than the low- or mid-level doses.^1,3

Additionally, there were no treatment-related serious adverse events (AEs) reported, with ocular inflammation occurring minimally and infrequently, and cases reversed with steroid treatment. In total, 3 serious AEs occurred in 2 patients—a macular hole and endophthalmitis/retinal detachment—but all were deemed related to surgical procedure. Of the 56 treatment-emergent AEs reported, 52 were related to surgical procedure. No patients have discontinued from the study because of AEs.

As for efficacy, the BVCA response was variable—2 patients with hand motion level vision (3.0 logMAR) showed improvements of at least 0.3 logMAR (0.7 logMAR in Cohort 3 and 1.4 logMAR in Cohort 4), but other patients did not show this improvement. Significant results were shown in full-field stimulus testing (FST) across all 3 colors tested (white, blue, and red) with dark adapted FST at the 28-, 56-, and 84-days post treatment (white: P <.05 at all 3 time points; blue: P <.05 at 28 and 84 days, P <.01 at 56 days; red: P <.05 at 28 days, P <.01 at 56 days and 84 days).

Similarly, multiluminance mobility test (MLMT) results showed clinically meaningful improvement in the high-dose cohorts. All 4 patients dosed demonstrated an improvement of at least 2 levels on the MLMT compared with baseline or untreated fellow eye. Notably, though, individual patient response was limited by a ceiling effect—3 of 4 patients achieved the maximum score of 6 levels.

Although there are no therapies approved for LCA1—which accounts for an estimated 20% of LCA cases—nor for many of the at least 20 types of LCA that have been described, there are 2 gene therapies approved for LCA caused by 2 RPE65 mutations (LCA2), which accounts for about 6% of LCA cases.⁴

In recent months, the pipeline has bustled with progress, including a recent announcement from HuidaGene in LCA2, noting that the company’s gene therapy HG004 had been granted an orphan drug designation by the FDA.⁵ Just a few days prior, the FDA approved the enrollment of pediatric patients with retinitis pigmentosa (RP) linked to LCA associated with CEP290 gene mutations (LCA10) in a phase 1/2 clinical trial (NCT05203939) of its investigational therapy OCU400.⁶ Additionally, in January 2023, Frontera Therapeutics announced that it had dosed the first patient with LCA2 in its phase 1/2 clinical trial of FT-001 in China.⁷

REFERENCES
1. Kay CN. Safety and Efficacy of ATSN-101 in Patients with Leber Congenital Amaurosis Caused by Biallelic Mutations in GUCY2D (LCA1). Presented at: Annual Macula Society Meeting; February 15-18, 2023; Miami, FL.
2. Atsena Therapeutics to Present Positive Interim Encore Data from the Phase I/II Clinical Trial of ATSN-101 for the Treatment of GUCY2D-associated Leber Congenital Amaurosis (LCA1) at the 46th Annual Macula Society Meeting. News release. Atsena Therapeutics. February 8, 2023. Accessed April 4, 2023. https://atsenatx.com/press-release/atsena-therapeutics-to-present-positive-interim-encore-data-from-the-phase-i-ii-clinical-trial-of-atsn-101-for-the-treatment-of-gucy2d-associated-leber-congenital-amaurosis-lca1-at-the-46th-annual-m/
3. Kay CN, Yang P, Cideciyan A, et al. Safety and Efficacy of SAR439483 in Patients with Leber Congenital Amaurosis Caused by Biallelic Mutations in GUCY2D (LCA1). Presented at: AAO Annual Meeting; September 30-October 1, 2022; Chicago, IL. https://atsenatx.com/wp-content/uploads/2022/10/Atsena-AAO-Final.pdf
4. Leber congenital amaurosis. National Library of Medicine: Medline Plus. Updated 2010. Accessed April 4, 2023. https://medlineplus.gov/genetics/condition/leber-congenital-amaurosis/
5. HuidaGene Receives Orphan Drug Designation for Gene Therapy of Blindness. News release. HuidaGene. April 3, 2023. Accessed April 4, 2023. https://finance.yahoo.com/news/huidagene-receives-orphan-drug-designation-123000357.html
6. Ocugen announces FDA approval for enrollment of pediatric patients in ongoing OCU400 phase 1/2 clinical trial for the treatment of retinitis pigmentosa (RP) and Leber Congenital Amaurosis (LCA). March 27, 2023. Accessed April 4, 2023. https://www.globenewswire.com/news-release/2023/03/27/2634720/0/en/Ocugen-Announces-FDA-Approval-for-Enrollment-of-Pediatric-Patients-in-Ongoing-OCU400-Phase-1-2-Clinical-Trial-for-the-Treatment-of-Retinitis-Pigmentosa-RP-and-Leber-Congenital-Amau.html
7. Frontera Therapeutics doses first patient in phase 1 clinical trial for gene therapy FT-001 for the treatment of leber congenital amaurosis-2. News release. Frontera Therapeutics. January 6, 2023. Accessed April 4, 2023. https://www.fronteratherapeutics.com/frontera-therapeutics-doses-first-patient-in-phase-1-clinical-trial-for-gene-therapy-ft-001-for-the-treatment-of-leber-congenital-amaurosis-2/