Audentes Puts Hold on AAV Gene Therapy Trial After Two Deaths

Audentes Therapeutics said it placed a hold on the clinical trial evaluating its experimental AAV gene therapy AT132 in patients with X-linked myotubular myopathy after the death of a second patient had been given the highest dose of the therapy.

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.

While the immediate cause of death for both patients, one of whom died in May, was sepsis, they were among a group of three older patients who received a high dose of 3×1014 vg/kg of AT132, and who developed serious adverse events (SAEs) of liver and biliary system disease within four to six weeks of dosing.

In a statement to the XLMTM community that was posted on the Joshua Frase Foundation website, Audentes said the three patients with SAEs were older, heavier in weight, and had exhibited pre-existing liver/biliary system disease. The company noted that among six patients treated at the lower dose of 1×1014 vg/kg, four had a previous history of liver/biliary disease, and none developed liver SAEs, “despite being years out from treatment.”

Audentes, which was acquired by the Japanese pharmaceutical Astellas in December 2019 for $3 billion, had previously recently 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.

Audentes’ gene therapy AT132 is an AAV8 vector containing a functional copy of the MTM1 gene, for the treatment of XLMTM. AAV delivery of gene therapy has gained widespread use but has also been linked to SAEs. Most recently, Solid Biosciences’ AAV gene therapy for Duchenne muscular dystrophy remains on hold after a patient experienced SAEs that Solid continues to try to figure out and prevent from happening again.

Prior to the deaths, Audentes said it had already halted further dosing of patients enrolled in the ASPIRO trial. Following the two deaths and interactions with the U.S. Food and Drug Administration, the ASPIRO trial has been put on formal clinical hold, with Audentes continuing to monitor enrolled patients and assess the impact of the deaths on potential regulatory filing timelines.