Rare Daily Staff

Audentes Therapeutics reported new positive data from ASPIRO, the clinical trial evaluating its gene therapy AT132 in patients with X-linked myotubular myopathy.

X-linked myotubular myopathy (XLMTM) is a serious, life-threatening, rare neuromuscular disease that is characterized by extreme muscle weakness, respiratory failure, and early death. XLMTM is caused by mutations in the MTM1 gene that lead to a lack or dysfunction of myotubularin, a protein that is needed for normal development, maturation, and function of skeletal muscle cells. The disease affects approximately 1 in 40,000 to 50,0000 newborn males. Mortality rates are estimated to be 50 percent in the first 18 months of life, and for those patients who survive past infancy, there is an estimated additional 25 percent mortality by the age of 10. There are no approved therapies for XLMTM.

AT132 is an AAV8 vector containing a functional copy of the MTM1 gene, for the treatment of XLMTM. AT132 may provide patients with significantly improved outcomes based on the ability of AAV8 to target skeletal muscle and increase myotubularin expression in targeted tissues following a single intravenous administration. The preclinical development of AT132 was conducted in collaboration with French biotech Genethon. 

The data, presented at the 24th International Annual Congress of the World Muscle Society, show that among the 12 patients enrolled in the ASPIRO trial, the first seven patients treated with Audentes AT132 gene therapy are now ventilator independent and able to rise to a standing position or walk. All the treated patients also continue to have significant and durable improvements in respiratory function and developmental motor milestones.

“The new ASPIRO data shared today builds upon the encouraging efficacy and safety profile seen to date with AT132,” said James Dowling, Hospital for Sick Children, Toronto, Canada, and presenter at the meeting. “Treated patients across both dose cohorts show significant reductions in ventilator dependence and the progressive attainment of developmental motor milestones, suggesting that AT132 has the potential to deliver transformative benefit to patients and families living with XLMTM.”

The data includes 48 weeks or more of follow-up for seven patients enrolled in two dosing cohorts: Cohort 1, six treated and one untreated control; and 24-48 weeks of follow-up for five patients in Cohort 2, four treated and one untreated control. Key assessments include neuromuscular function as assessed by the achievement of motor milestones and improvement in CHOP INTEND score, and respiratory function as assessed by reduction in ventilator dependence and improvement in maximal inspiratory pressure (MIP). It does not include new muscle biopsy data. AT132 continues to be generally well-tolerated with a manageable safety profile across both dose cohorts. 

The U.S. Food and Drug Administration granted AT132 Regenerative Medicine and Advanced Therapy (RMAT), Rare Pediatric Disease, Fast Track, and Orphan Drug designations. The European Medicines Agency granted AT132 Priority Medicines (PRIME) and Orphan Drug designations.

Next steps in the AT132 development program include the completion of enrollment and follow-up of patients in the ASPIRO pivotal expansion cohort, designed to confirm the safety and efficacy profile of AT132 at a dose of 3×1014 vg/kg, and preparations for filing applications for marketing approval in the United States and European Union.

“We remain focused on our goal of rapidly progressing AT132 toward global regulatory approvals,” said Natalie Holles, president and chief operating officer of Audentes. “Importantly, we have fully enrolled 14 patients into the ASPIRO dose escalation cohorts, and plan to complete enrollment of the ASPIRO pivotal expansion cohort imminently. We remain on track to submit a BLA in the United States in mid-2020 and a MAA in Europe in the second half of 2020.”

Photo: Natalie Holles, president and chief operating officer of Audentes

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