Gene Therapy AT132 Improves Ventilator Dependence in X-linked Myotubular Myopathy in Phase 1/2 ASPIRO Trial


New preliminary data showed that more than 50% of dosed pediatric patients with X-linked myotubular myopathy achieved ventilator independence, with some attaining the ability to walk independently.

Perry B. Shieh, MD, PhD, FAAN, professor of neurology and pediatrics at the University of California, Los Angeles

Perry B. Shieh, MD, PhD, FAAN

Newly published in The Lancet Neurology, preliminary data from the phase 1/2 ASPIRO trial (NCT03199469) assessing Astellas Pharma’s investigational AT132 (resamirigene bilparvovec), an adeno-associated viral vector (AAV) gene replacement therapy, showed significant improvements in ventilator dependence and motor function among most of the pediatric patients with X-linked myotubular myopathy (XLMTM) dosed with the therapy.1 While ASPIRO remains on clinical hold because of safety concerns, these findings suggest the potential of a therapeutic approach for myotubularin replacement using recombinant AAV gene therapy.2

At the time of the analysis (Feb 28, 2022) findings showed that among 24 patients with XLMTM, participants administrated a lower dose (1.3 × 1014 vector genomes [vg]/kg bodyweight) of AT132 had an estimated 77.7% (95% CI, 40.22-115.24) greater reduction in least squares mean hours per day of ventilator support from baseline versus controls (P = .0002) at week 24. Notably, in the same week, the participants administrated the higher dose (3·5 × 1014 vg/kg bodyweight) of AT132 had a 22.8% (6.15-39.37) greater reduction from baseline versus controls (P = .0077).

Clinical Takeaways

  • ASPIRO trial's early data on Astellas Pharma's gene therapy (AT132) suggest significant improvements in patients with XLMTM for ventilator dependence and motor function.
  • Despite an FDA trial hold, the findings emphasize the need for XLMTM treatments and highlight gene therapy's potential benefits, with attention to liver health.
  • ASPIRO trial shows promise in reducing ventilator support for patients with XLMTM, but ongoing investigations into deaths have paused higher-dose dosing.

"There is a real need for treatments for these patients. These preliminary data document for the first time that there is potential for gene therapy to provide clinical improvements in patients with XLMTM, including improvement in ventilator dependence and achievement of major motor milestones. Additionally, important issues related to liver health in participants with XLMTM receiving gene therapy have been identified and will continue to require careful evaluation,“ principal investigator Perry B. Shieh, MD, PhD, FAAN, professor of neurology and pediatrics at the University of California, Los Angeles, said in a statement.2

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ASPIRO is an open-label, dose-escalation trial of boys younger than 5 years with XLMTM who required mechanical ventilator support, spanning 7 academic medical centers in Canada, France, Germany, and the USA. Initially in 2 parts, the first part of the trial planned to assess safety and dose-escalation phase through randomly allocating (2:1) participants and the second part intended to confirm the dose selected in part 1. The patients were administered a single intravenous infusion of either the first dose level of AT132 or delayed treatment. For later participants, a higher dose of AT132 or delayed treatment was given. An untreated control group comprised of boys who participated in the INCEPTUS run-in trial (NCT02704273) or those in the delayed treatment cohort who did not receive any dose. The primary efficacy end point was the change from baseline to week 24 in hours of daily ventilator support.

Thirty participants were screened for eligibility between Aug 3, 2017, and June 1, 2021, and 26 of them were enrolled into the trial with 6 allocated to the lower dose, 13 to the higher dose, and 7 to delayed treatment. Of the delayed treatment group, 4 patients later received the higher dose (higher dose cohort total, n = 17), 1 received the lower dose (lower dose cohort total, n = 7), and 2 received no dose and joined the control group (total including 12 from INCEPTUS, n = 14). The median age 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 at dosing or enrollment. The median 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 for follow-up.

All told, 1 participant from the lower dose cohort and 3 from the higher dose cohort died, and all had cholestatic liver failure following gene therapy at the time of death. The immediate causes of death included sepsis, hepatopathy, severe immune dysfunction, and pseudomonal sepsis; gastrointestinal hemorrhage, and septic shock. Additionally, 3 individuals in the control group died with the cause of death included hemorrhage presumed related to hepatic peliosis, aspiration pneumonia, and cardiopulmonary failure. Following the unexpected deaths, dosing at the higher dose was paused and investigators eliminated Part 2 of the trial. The authors noted that analyses were done on an as-treated basis and are deemed exploratory because of changes to the study design during its implementation. Additionally, the investigators noted that ASPIRO is currently on hold while deaths in the dosed participants are being investigated.

"We are grateful for the opportunity to share this important analysis. We are focused on patients and the potential impact of gene therapy and are driven to deliver transformational benefits for people living with rare genetic diseases. While we continue our efforts to address the ongoing clinical hold for ASPIRO, this publication serves to provide information that may guide efforts aimed at advancing promising therapies for XLMTM,” Richard Wilson, senior vice president, Primary Focus Lead of Genetic Regulation at Astellas, said in a statement.2

1. Shieh PB, Kuntz NL, Dowling JJ, et al. Safety and efficacy of gene replacement therapy for X-linked myotubular myopathy (ASPIRO): a multinational, open-label, dose-escalation trial. Lancet Neurol. 2023;22(12):1125-1139. doi:10.1016/S1474-4422(23)00313-7
2. Astellas Announces Data from ASPIRO Study in X-linked Myotubular Myopathy Published in The Lancet Neurology. News Release. Published November 15, 2023. Accessed December 13, 2023.
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