Third Patient Dies in Audentes’ Gene Therapy Study for Neuromuscular Disease

A third pediatric patient involved in a gene therapy trial for a rare, neuromuscular disease conducted by Audentes Therapeutics has died. The trial remains on clinical hold and continues to indefinitely delay the company’s plans to seek regulatory approval for the treatment.

This morning, Audentes, which was acquired by Astellas Pharma late last year, announced the death of the third patient involved in the company’s ASPIRO clinical trial evaluating AT132 in patients with X-linked Myotubular Myopathy (XLMTM). The disease is a life-threatening neuromuscular disease that almost exclusively impacts males and 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. The disease affects approximately 1 in 40,000 to 50,000 newborn males. X-linked Myotubular Myopathy also disrupts normal bone development and can lead to fragile bones and joint deformities. Those diagnosed with the disease usually only survive into early childhood. Audentes’ gene therapy uses an AAV8 vector to deliver a working copy of the myotubularin 1 gene into the patient to correct the disease.

According to the company, preliminary findings indicate that the immediate cause of death in this patient was gastrointestinal bleeding. In its announcement this morning, Audentes said the patient was one of three study patients previously disclosed to have received AT132 at the dose of 3x10¹⁴ 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 and Audentes noted that more than half of the patient enrolled in the ASPIRO study show evidence of pre-existing hepatobiliary disease. However, the company said that has not been associated with similar progressive liver dysfunction in any of the patients who received AT132 at the 1x10¹⁴ vg/kg dose nor in the other patients who received the 3x10¹⁴ vg/kg dose.

The U.S. Food and Drug Administration placed the ASPIRO study on clinical hold in June after Audentes disclosed two pediatric patients who received the higher doses of the gene therapy developed sepsis and died.

Audentes said it is closely monitoring all patients in the study. To date, 23 patients in the ASPIRO study have received AT132. Six patients received the gene therapy at the 1x10¹⁴ vg/kg dose and 17 patients received AT132 at the 3x10¹⁴ vg/kg dose, the company said. There are no other patients in the study known to be currently experiencing similar liver dysfunction, Audentes said.

“Audentes, together with the ASPIRO investigators and independent Data Monitoring Committee, continue to closely monitor all patients enrolled in the study. Additionally, Audentes’ investigation regarding why these three patients developed progressive liver dysfunction is ongoing,” the company said in its announcement.

The company plans to provide further information on the ASPIRO program based on both ongoing data collection and future regulatory status updates. Last year Audentes presented positive data from ASPIRO at the 24th International Annual Congress of the World Muscle Society. It was this data the company hoped to build upon in order to file a Biologics License Application with the FDA.