Long term preliminary safety and efficacy outcomes for x-linked myotubular myopathy with gene replacement therapy

Background: XLMTM is a rare, currently untreated, life-threatening congenital myopathy caused by mutations in the MTM1 gene, with profound muscle weakness and impairment of motor development, congenital respiratory failure, and chronic ventilator dependency.

Objective: We report long-term safety and key efficacy outcomes (up to 42 months) for the first 6 participants dosed in the ASPIRO study.

Methods: ASPIRO (NCT03199469) is a phase 1/2/3 randomized, open-label study investigating the safety and efficacy of AT132 (resamirigene bilparvovec), a single-dose gene replacement therapy for ventilator-dependent XLMTM. Participants were young boys with genetically confirmed XLMTM. The first 6 participants received the lower dose 1.3 x 1014 vg/kg and were compared with 15 untreated controls.

Results: All dosed participants were ventilator dependent at baseline and then achieved ventilator independence, with 5 remaining so. No control participants achieved this milestone. At baseline, 1/6 dosed participant was able to sit independently without support for 30 seconds and 5/6 did not have full head control. Major motor milestones were achieved in all dosed participants; 5/6 remain independently ambulatory without assistive device (Figure 1). In this cohort, 4 (67%) participants had treatment-emergent severe adverse events. Overall, deaths occurred in the higher-dose cohort (3/17) following severe decompensated liver disease, in the lower-dose cohort (1/7) following liver function test abnormalities, and in the control cohort (3/15 from aspiration pneumonia, cardiopulmonary failure, and hepatic hemorrhage with peliosis, respectively).

Conclusions: The substantial improvements observed must be weighed against fatal serious adverse events, for which the ASPIRO program is on clinical hold while investigations continue. Aspiro Study Group: James J. Dowling, (6) Wolfgang Müller-Felber,(7) Astrid Blaschek,(7) Carsten G. Bönnemann,(8) A. Reghan Foley,(8) Dimah N. Saade,(9) Andreea M. Seferian,(10) Laurent Servais, (11) Neema Lakshman, (1) Suyash Prasad, (5) Salvador Rico, (5) (1) Astellas Gene Therapies, San Francisco, CA, USA, (5) Formerly Astellas Gene Therapies, (6) Hospital for Sick Children, Toronto, ON, Canada; (7) Klinikum der Universität München, Munich, Germany; (8) Neuromuscular and Neurogenetic Disorders of Childhood Section, NINDS, NIH, Bethesda, MD, USA; (9) University of Iowa Hospitals and Clinics, Iowa City, IA, USA; (10) I-Motion, Institute of Myology, Paris, France; (11) MDUK Oxford Neuromuscular Centre, Oxford, UK.

No conflict of interest has been declared by the author(s).

Publication History

Article published online:
18 September 2023