RARE Daily

Third Patient Dies in Audentes’ X-Linked Myotubular Myopathy Gene Therapy Trial

August 21, 2020

Rare Daily Staff

Audentes Therapeutics reported that a third study patient has passed away in 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.

Preliminary findings indicate that the immediate cause of death was gastrointestinal bleeding. The patient was one of three study patients previously disclosed to have received AT132 at the dose of 3×1014 vg/kg who began to demonstrate signs of liver dysfunction within three to four weeks after dosing. All three patients demonstrated evidence of pre-existing hepatobiliary disease. The other two patients passed away at the end of June and the trial was put on hold.

Audentes said that more than 50 percent of patients enrolled in the ASPIRO trial to date show evidence of pre-existing hepatobiliary disease, but it has not been associated with similar progressive liver dysfunction in any of the patients who received AT132 at the lower dose of 1×1014 vg/kg dose, nor in the other patients who received the higher 3×1014 vg/kg dose.

To date, 23 ASPIRO patients have received AT132: six at the 1×1014 vg/kg dose and 17 at the 3×1014 vg/kg dose. Although the ASPIRO study is currently on clinical hold, there are no other patients in the study known to be currently experiencing similar liver dysfunction.

Audentes, which was acquired by the Japanese pharmaceutical Astellas in December 2019 for $3 billion, had previously 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 halted further dosing of patients enrolled in the ASPIRO trial. Following the first two deaths and interactions with the U.S. Food and Drug Administration, the ASPIRO trial was put on formal clinical hold, with Audentes continuing to monitor enrolled patients and assess the impact of the deaths on potential regulatory filing timelines.

Audentes says it is investing why these three patients developed progressive liver dysfunction is ongoing. The company says it remains committed to the AT132 development program and the XLMTM patient community and plans to provide further information on the ASPIRO program based on both ongoing data collection and future regulatory status updates.

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