Safety and efficacy of gene replacement therapy for X-linked myotubular myopathy (ASPIRO): a multinational, open-label, dose-escalation trial.

Background: X-linked myotubular myopathy is a rare, life-threatening, congenital muscle disease observed mostly in males, which is caused by mutations in MTM1. No therapies are approved for this disease. We aimed to assess the safety and efficacy of resamirigene bilparvovec, which is an adeno-associated viral vector serotype 8 delivering human MTM1.
Methods: ASPIRO is an open-label, dose-escalation trial at seven academic medical centres in Canada, France, Germany, and the USA. We included boys younger than 5 years with X-linked myotubular myopathy who required mechanical ventilator support. The trial was initially in two parts. Part 1 was planned as a safety and dose-escalation phase in which participants were randomly allocated (2:1) to either the first dose level (1·3 × 10 ¹⁴ vector genomes [vg]/kg bodyweight) of resamirigene bilparvovec or delayed treatment, then, for later participants, to either a higher dose (3·5 × 10 ¹⁴ vg/kg bodyweight) of resamirigene bilparvovec or delayed treatment. Part 2 was intended to confirm the dose selected in part 1. Resamirigene bilparvovec was administered as a single intravenous infusion. An untreated control group comprised boys who participated in a run-in study (INCEPTUS; NCT02704273) or those in the delayed treatment cohort who did not receive any dose. The primary efficacy outcome was the change from baseline to week 24 in hours of daily ventilator support. After three unexpected deaths, dosing at the higher dose was stopped and the two-part feature of the study design was eliminated. Because of changes to the study design during its implementation, analyses were done on an as-treated basis and are deemed exploratory. All treated and control participants were included in the safety analysis. The trial is registered with ClinicalTrials.gov, NCT03199469. Outcomes are reported as of Feb 28, 2022. ASPIRO is currently paused while deaths in dosed participants are investigated.
Findings: Between Aug 3, 2017 and June 1, 2021, 30 participants were screened for eligibility, of whom 26 were enrolled; six were allocated to the lower dose, 13 to the higher dose, and seven to delayed treatment. Of the seven children whose treatment was delayed, four later received the higher dose (n=17 total in the higher dose cohort), one received the lower dose (n=7 total in the lower dose cohort), and two received no dose and joined the control group (n=14 total, including 12 children from INCEPTUS). Median age at dosing or enrolment was 12·1 months (IQR 10·0-30·9; range 9·5-49·7) in the lower dose cohort, 31·1 months (16·0-64·7; 6·8-72·7) in the higher dose cohort, and 18·7 months (10·1-31·5; 5·9-39·3) in the control cohort. Median follow-up was 46·1 months (IQR 41·0-49·5; range 2·1-54·7) for lower dose participants, 27·6 months (24·6-29·1; 3·4-41·0) for higher dose participants, and 28·3 months (9·7-46·9; 5·7-32·7) for control participants. At week 24, lower dose participants had an estimated 77·7 percentage point (95% CI 40·22 to 115·24) greater reduction in least squares mean hours per day of ventilator support from baseline versus controls (p=0·0002), and higher dose participants had a 22·8 percentage point (6·15 to 39·37) greater reduction from baseline versus controls (p=0·0077). One participant in the lower dose cohort and three in the higher dose cohort died; at the time of death, all children had cholestatic liver failure following gene therapy (immediate causes of death were sepsis; hepatopathy, severe immune dysfunction, and pseudomonal sepsis; gastrointestinal haemorrhage; and septic shock). Three individuals in the control group died (haemorrhage presumed related to hepatic peliosis; aspiration pneumonia; and cardiopulmonary failure).
Interpretation: Most children with X-linked myotubular myopathy who received MTM1 gene replacement therapy had important improvements in ventilator dependence and motor function, with more than half of dosed participants achieving ventilator independence and some attaining the ability to walk independently. Investigations into the risk for underlying hepatobiliary disease in X-linked myotubular myopathy, and the need for monitoring of liver function before gene replacement therapy, are ongoing.
Funding: Astellas Gene Therapies.
Competing Interests: Declaration of interests PBS has received funding and provision of study materials from Astellas Gene Therapies (formerly Audentes Therapeutics) to support clinical trial investigations relating to the present manuscript; has received research grants or contracts from Biogen, Novartis Gene Therapies, Pfizer, PTC Therapeutics, Reveragen, Sanofi, Sarepta, and Solid Biosciences; has received consulting fees for advisory board participation from Alexion, Argenx, Biogen, Genentech, Novartis Gene Therapies, UCB, Sanofi, and Sarepta; and has received honoraria for lectures or presentations from Alexion, Argenx, Biogen, Catalyst, CSL Behring, Genentech, and Grifols. NLK has received research funding from Astellas Gene Therapies to her institute as a study site for the ASPIRO clinical trial; has received support from Astellas Gene Therapies for registration fees to attend and present at the International Congress on Neuromuscular Diseases 2022 (travel costs paid personally); has received research grants from Argenx, Biohaven, Biogen, Novartis, Sarepta, and Scholar Rock, consulting fees for participation on medical advisory boards for Argenx, BioMarin, Capacity Bio, and Sarepta, and honoraria for gene therapy lectures for Sarepta; and is on a data safety monitoring board for Sarepta. JJD has received research grants or contracts from Astellas Gene Therapies to his institute as a study site for the ASPIRO clinical trial and for preclinical studies; and has received an honorarium for a sponsored symposium and support for travel to an international meeting to present data from Astellas Gene Therapies. WM-F has received support for study materials and study personnel relating to the present manuscript from Astellas Gene Therapies; consulting fees from Sarepta, PTC Therapeutics, Novartis, and Roche; personal compensation from Novartis and Biogen and institutional funding from Roche, for lectures; and has served on scientific advisory boards for Deutsche Gesellschaft für Muskelkranke and Glykogenosis. CGB has received research grants, contracts, or travel support for various invited lectures at academic meetings from Noelia Foundation, Muscular Dystrophy UK, and Cure CMD; holds a patent for COL6A1 intron 11 pseudoexon skipping technologies unrelated to the present manuscript; has participated (without fees) in advisory boards for Solid Biosciences (IGNITE trial), Rocket Pharma, and Nationwide Children's Hospital; and is Chair of the Scientific Advisory Board of the MDUK Oxford Neuromuscular Centre. LS has received consulting fees and honoraria for lectures from Astellas Gene Therapies; and is coordinating investigator of the European NatHis-CNM study, funded by Dynacure. BKS has received institutional research grants or contracts for her institution to serve as an INCEPTUS and ASPIRO study site from Astellas Gene Therapies. AB reports institutional grants or contracts from PTC Therapeutics; has received payments or honoraria from Roche, Biogen, and Pfizer; and has participated in advisory boards at Roche and Pfizer. ARF has been a member of an independent data monitoring committee for a different clinical trial for MTM1-related myopathy and DNM2-related myopathy (the trial was terminated early). LNA has received grants or contracts from Astellas Gene Therapies via her institution to provide training and quality control services supporting the ASPIRO clinical trial programme. AHB reports research grants or contracts from the NIH, MDA (USA), AFM Telethon, Alexion Pharmaceuticals, Astellas Gene Therapies, Dynacure SAS, Pfizer, Kate Therapeutics, Chan Zuckerberg Initiative, and Avidity; has received consulting fees from Astellas Gene Therapies, Kate Therapeutics, and Roche Pharmaceuticals; has received honoraria for lectures or presentations from GLG and Guidepoint Global; has received support for travel and meeting attendance at the Muscular Dystrophy Association and World Muscle Society; is an executive board member at the World Muscle Society; is an inventor on and has received royalties for a patent for adeno-associated virus gene therapy for X-linked myotubular myopathy; and holds stocks in Kate Therapeutics and Kinea Bio. AB-B has received consulting fees from Astellas Gene Therapies and research funding from the Myotubular Trust for preclinical work related to the present manuscript; and holds a patent on systemic gene replacement therapy for treatment of X-linked myotubular myopathy. MKC has received consulting fees and institutional research funding supporting preclinical experiments for a US investigational new drug application relating to the gene therapy in the present manuscript; holds a patent for a systemic gene replacement therapy for treatment of X-linked myotubular myopathy; and has received option payments from Wake Forest University for the patent. TD has received consulting fees from Astellas Gene Therapies for study training on CHOP INTEND measurement in ASPIRO. RJG reports limited consulting fees from Astellas Gene Therapies for work on the ASPIRO study design and clinical outcome measures. JC is an employee of Astellas Gene Therapies. VMacB has received study funding relating to the present manuscript, in the form of a research grant and consulting fees from Astellas Gene Therapies paid both directly to her and her institution. ESJ was a former employee of Astellas Gene Therapies and formerly held stock in Astellas Gene Therapies. JL, FMa, WM, and FV were formerly employees of Astellas Gene Therapies. MM has received study funding relating to the present publication from Astellas Gene Therapies, formerly held stock in Astellas Gene Therapies, and was formerly employed by Astellas Gene Therepies. CH is an employee of Astellas Pharma Global Development. MN was formerly employed by Astellas Gene Therepies. MWL has received research funding from Astellas Gene Therapies to his academic institution (Medical College of Wisconsin) and to his company (Diverge Translational Science Laboratory) for work related to the present manuscript; has received research grants or contracts to his academic institution from Solid Biosciences, Kate Therapeutics, Taysha Therapeutics, Ultragenyx, and Prothelia; has received consulting fees from Astellas Gene Therapies, Encoded Therapeutics, Modis Therapeutics, Lacerta Therapeutics, AGADA Biosciences, Dynacure, Affinia, Voyager, BioMarin, Locanabio, and Vertex Pharmaceuticals; has received speaker fees and reimbursement for travel related to sponsored research from Astellas Gene Therapies; has received personal fees for scientific advisory board participation for Astellas Gene Therapies and Solid Biosciences; and his institution has received payment from Taysha Therapeutics for his advisory board participation. MWL is currently Chief Executive Officer, founder, and owner of Diverge Translational Science Laboratory, which continues to work under contracts from many gene therapy companies including Astellas Gene Therapies, Solid Biosciences, Rocket Pharma, Kate Therapeutics, Carbon Biosciences, Dynacure, Nationwide Children's Hospital, Taysha Gene Therapies, and Ultragenyx. SP was an employee at Astellas Gene Therapies from February, 2014, to June, 2019, and was the senior physician overseeing the study relating to the present manuscript. SR reports holding stock in Astellas Gene Therapies and was formerly employed by Astellas Gene Therapies. All other authors declare no competing interests.
(Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.)