Serious Adverse Event in Study Participant Marks Latest Roadblock for Astellas’ Gene Therapy Trial

In late 2019, Japan’s Astellas bought US gene therapy company Audentes Therapeutics for $3 billion in cash, making it one of the biggest M&A deals of the year. Last December, the company would have heaved a sigh of relief when the FDA lifted the clinical hold placed on Audentes’ Phase 2/3 study following the death of three trial participants. However, early this week, the company announced that it has voluntarily paused the screening and dosing of additional participants in the trial.

The Phase 2/3 ASPIRO trial evaluates AT132, an investigational gene therapy candidate for the treatment of X-linked myotubular myopathy (XLMTM), a rare but life-threatening neuromuscular disease.

Audentes’ decision to pause screening comes after a trial participant suffered a serious adverse event (SAE) as determined by abnormal liver function tests (LFTs) observed in the weeks following dosing. Astellas has now voluntarily paused screening and dosing and is presently discussing this SAE with regulatory agencies.

“We will continue to work with the site investigator and site hepatologist to closely monitor this participant,” said Nathan Bachtell, M.D., Senior Vice President and Head of Gene Therapy, Medical & Development at Astellas. “As we learn more about the case, we will incorporate any new observations into our ongoing investigation in order to have a well-informed discussion with the independent Data Monitoring Committee, our Liver Advisory Panel, and study investigators.”

“Given previous hepatic events within the program, any one SAE needs to be viewed both individually and in the context of the broader program as we move forward. We remain committed to the development of AT132 and the XLMTM patient community. We will provide additional information about our investigation at the appropriate time,” he added.

Gene Therapy Against X-linked Myotubular Myopathy

X-linked myotubular myopathy (XLMTM) is attributed to mutations in the MTM1 gene, leading to a lack or dysfunction of myotubularin for normal development, maturation, and function of skeletal muscle cells. It is characterized by extreme muscle weakness, respiratory failure, and early death, with a mortality rate of around 50% in the first 18 months of life. Patients who survive through infancy have an estimated additional 25% fatality rate by the age of 10.

Most patients need a gastrostomy tube for nutritional intake, and more than 80% of XLMTM patients require ventilator support, which is, unfortunately, the only supportive treatment option.

AT132 is an AAV8 vector containing a functional copy of the MTM1 gene. It 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.

Before the hold in December 2020, a total of 24 patients with XIMTM received AT132 in the study. Seven of them received a 1.3×10⁴ vg/kg dose level and the rest with 3.5×10¹⁴ vg/kg. Three enrollees previously treated at the higher dose experienced progressive cholestatic hepatitis and subsequent decompensated liver failure. These three patients died of either sepsis or gastrointestinal bleeding, all of which were consequences of liver failure. After the hold, one SAE was raised due to abnormal liver function tests.

Author

Judy Ya-Hsuan Lin

Success is the ability to go from one failure to another with no loss of enthusiasm.