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.
