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.

Autor:	Yang P; Casey Eye Institute, Oregon Health & Science University, Portland, OR, USA. Electronic address: yangp@ohsu.edu., Pardon LP; Atsena Therapeutics, Durham, NC, USA., Ho AC; Wills Eye Hospital, Philadelphia, PA, USA., Lauer AK; Casey Eye Institute, Oregon Health & Science University, Portland, OR, USA., Yoon D; Atsena Therapeutics, Durham, NC, USA., Boye SE; Division of Cellular and Molecular Therapy, Department of Pediatrics, University of Florida, Gainesville, FL, USA., Boye SL; Powell Gene Therapy Center, Department of Pediatrics, University of Florida, Gainesville, FL, USA., Roman AJ; Center for Hereditary Retinal Degenerations, Scheie Eye Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA., Wu V; Center for Hereditary Retinal Degenerations, Scheie Eye Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA., Garafalo AV; Center for Hereditary Retinal Degenerations, Scheie Eye Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA., Sumaroka A; Center for Hereditary Retinal Degenerations, Scheie Eye Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA., Swider M; Center for Hereditary Retinal Degenerations, Scheie Eye Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA., Viarbitskaya I; Center for Hereditary Retinal Degenerations, Scheie Eye Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA., Aleman TS; Center for Hereditary Retinal Degenerations, Scheie Eye Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA., Pennesi ME; Casey Eye Institute, Oregon Health & Science University, Portland, OR, USA; Retina Foundation of the Southwest, Dallas, TX, USA., Kay CN; VitreoRetinal Associates, Gainesville, FL, USA., Fujita KP; Atsena Therapeutics, Durham, NC, USA., Cideciyan AV; Center for Hereditary Retinal Degenerations, Scheie Eye Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Electronic address: cideciya@pennmedicine.upenn.edu.
Jazyk:	angličtina
Zdroj:	Lancet (London, England) [Lancet] 2024 Sep 07; Vol. 404 (10456), pp. 962-970.
DOI:	10.1016/S0140-6736(24)01447-8
Abstrakt:	Background: Leber congenital amaurosis 1 (LCA1), caused by mutations in GUCY2D, is a rare inherited retinal disease that typically causes blindness in early childhood. The aim of this study was to evaluate the safety and preliminary efficacy of ascending doses of ATSN-101, a subretinal AAV5 gene therapy for LCA1. Methods: 15 patients with genetically confirmed biallelic mutations in GUCY2D were included in this phase 1/2 study. All patients received unilateral subretinal injections of ATSN-101. In the dose-escalation phase, three adult cohorts (n=3 each) were treated with three ascending doses: 1·0 × 10 10 vg/eye (low dose), 3·0 × 10 10 vg/eye (middle dose), and 1·0 × 10 11 vg/eye (high dose). In the dose-expansion phase, one adult cohort (n=3) and one paediatric cohort (n=3) were treated at the high dose. The primary endpoint was the incidence of treatment-emergent adverse events (TEAEs), and secondary endpoints included full-field stimulus test (FST) and best-corrected visual acuity (BCVA). A multi-luminance mobility test (MLMT) was also done. Data through the 12-month main study period are reported. Findings: Patients were enrolled between Sept 12, 2019, and May 5, 2022. A total of 68 TEAEs were observed, 56 of which were related to the surgical procedure. No serious TEAE was related to the study drug. Ocular inflammation was mild and reversible with steroid treatment. For patients who received the high dose, mean change in dark-adapted FST was 20·3 decibels (dB; 95% CI 6·6 to 34·0) for treated eyes and 1·1 dB (-3·7 to 5·9) for untreated eyes at month 12 (white stimulus); improvements were first observed at day 28 and persisted over 12 months (p=0·012). Modest improvements in BCVA were also observed (p=0·10). Three of six patients who received the high dose and did the MLMT achieved the maximum score in the treated eye. Interpretation: ATSN-101 is well tolerated 12 months after treatment, with no drug-related serious adverse events. Clinically significant improvements in retinal sensitivity were sustained in patients receiving the high dose. Funding: Atsena Therapeutics. Competing Interests: Declaration of Interests PY has received consulting fees from 4D Molecular Therapeutics, AAVantarde Bio, Adverum, Astellas, BlueRock Therapeutics, Eluminex Biosciences, Nanoscope Therapeutics, and TeamedOn. PY has also received research support from 4D Molecular Therapeutics, Acucela, Atsena Therapeutics, Beacon Therapeutics, Biogen, Editas, Endogena, Foundation Fighting Blindness, Iveric Bio, Ocugen, PYC Therapeutics, Reneuron, Sanofi, and Spark Therapeutics. PY has participated on a data safety monitoring board or advisory board for Foundation Fighting Blindness, Janssen, and MeiraGTx. LPP, DY, and KPF are employees of and have equity or options in Atsena Therapeutics. ACH has received research support from Atsena Therapeutics. AKL has received a grant or contract from Oxford BioMedica and consulting fees from Ascidian, Astellas, Atsena Therapeutics, Beyeonics, Beacon Therapeutics, Blue Rock Therapeutics, Biogen, Iveric Bio, Johnson & Johnson, REGENXBIO, SpliceBio, and Vanotech/Origen. AKL has also participated on a data safety monitoring board or advisory board for Splice Bio, REGENXBIO, and Vanotech/Origen. AKL has served on the American Board of Ophthalmology and the Accreditation Council for Graduate Medical Education. SEB and SLB have received research support, royalties or licences, and consulting fees from Atsena Therapeutics and have equity or options in Atsena Therapeutics. SEB also serves as a member of the Board of Directors for Atsena Therapeutics. TSA has received research support from Atsena Therapeutics. MEP has received consulting fees from 4D Molecular Therapeutics, Acuta, Akous, Aldeyra, Alia Therapeutics, Alpha Insights, Apex Consulting, Aquilo Capital, Arrowhead Pharmaceuticals, Aldebaran, Ascidian, Atsena Therapeutics, Astellas, BlueRock Therapeutics, Clarivate, Clearview, Coave, Codiak, Dedham, Dompe, Editas, EnterX, eyeDNA Therapeutics, FaunaBio, GenKore, Gerson Lehrman Group, GlobalData, Guidepoint, Ingel Therapeutics, Intergalactic Therapeutics, IQVIA, J-Cyte, Janssen, Kala Bio, Kiora, Medacorp, Octant, Ocugen, Ora, PPD-Denali, PTC Therapeutics, Putman, PYC Therapeutics, RestoreVision, Sago, SAI-Med, Slingshot, Sparing Vision, SpliceBio, Spotlight Therapeutics, Thea, Theranexus, Triangle Insights, Vedere, and ZipBio. MEP has also received research support from Foundation Fighting Blindness. MEP has equity in Aldebaran, Atsena Therapeutics, Endogena, EnterX, Kiora, Nacuity Pharmaceuticals, Ocugen, and ZipBio. CNK has received consulting fees from Alkeus, Atsena Therapeutics, Ascidian Therapeutics, Guidepoint, Kiora Pharmaceuticals, and Nanoscrope. CNK also has equity or options in Atsena Therapeutics and Kiora Therapeutics and has received research support from Beacon Therapeutics, Foundation Fighting Blindness, Alkeus, Ascidian Therapeutics, Biogen, 4D Therapeutics, Iveric Bio/Astellas, Janssen, Gyroscope, US National Institutes of Health, REGENXBIO, and Belite Bio. AVC has received research support from Atsena Therapeutics and Sanofi. All other authors declare no competing interests. (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)
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