FDA Lifts Hold on Audentes’ Gene Therapy Trial for the Treatment of X-Linked Myotubular Myopathy

Rare Daily Staff

Audentes Therapeutics, a division of Japanese biopharma Astellas, said the U.S. Food and Drug Administration has lifted the clinical hold for the ASPIRO clinical trial evaluating its AAV gene therapy AT132 in patients with the rare disease 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 one 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.

Audentes’ gene therapy AT132 is an AAV8 vector containing a functional copy of the MTM1 gene, for the treatment of XLMTM. Before Astellas acquired it in December 2019 for $3 billion, Audentes had reported positive results in the ASPIRO study of 10 infants treated with the gene therapy, all were able to sit, stand, and walk, and saw a reduction in breathing support after treatment. At the time of the deal, the company believed AT132 could be submitted for approval by mid-2020.

But although AAV delivery of gene therapy has gained widespread use, it has also been linked to serious adverse events. Audentes had already halted further dosing of patients enrolled in the ASPIRO trial when it reported at the end of June that two patients enrolled in the study had died. The ASPIRO trial was put on formal clinical hold with Audentes continuing to monitor enrolled patients and assessing the impact of the deaths on potential regulatory filing timelines. A third patient died in August and it was found that all three patients demonstrated evidence of pre-existing hepatobiliary disease.

The company is now working to complete all clinical and regulatory activities necessary to resume dosing and plans to have discussions at a future date with the regulators on the path forward toward global registration filings for AT132.

AT132 has been granted Regenerative Medicine and Advanced Therapy, Rare Pediatric Disease, Fast Track, and Orphan Drug designations by the FDA, and Priority Medicines (PRIME) and Orphan Drug designations by the European Medicines Agency.