Reporter Shin Chang-min of Biospectator
‘AT132’, a treatment for
Astellas Pharma appears to have found a clue to the possibility of continuing the development of AAV gene therapy, which had its clinical trial halted three years ago when four patients died.
The patient who died in the clinical trial was found to have had an underlying disease related to cholestasis, and as a result, there was a possibility to continue development by excluding patients with cholestasis from recruitment in the future. However, it is still unclear whether clinical development will resume.
On the 15th, Astellas announced that these clinical results were published in the international academic journal ‘The Lancet Neurology’ and disclosed the results of analyzing the cause of patient death following treatment administration.
Astellas was developing a gene therapy drug ‘AT132’ for the indication of X-linked myotubular myopathy (XLMTM), a rare genetic disease, but due to liver/hepatobiliary side effects in phase 1/2 clinical trials in 2020, 3 One patient died, and one additional patient died the following year. As a result, Astellas was placed on clinical hold by the U.S. Food and Drug Administration (FDA).
AT132 is an asset acquired by Astellas when it acquired Audentes Therapeutics for $3 billion in 2020. AT132 is a concept that treats MTM1, the causative gene of X-linked myotubular myopathy (XLMTM), by delivering it using an AAV8 vector.
AT132 was evaluated as a promising treatment by the industry as it showed efficacy in patients’ ventilator independence and sitting without assistance in phase 1/2 clinical trials. However, a total of four patients died in both the high-dose and low-dose treatment groups, darkening the prospects for developing the treatment.
According to this paper published by Astellas, all four patients who died in phase 1/2 clinical trials had underlying diseases such as cholestasis, such as hyperbilirubinaemia and cholestatic hepatitis, before receiving AT132. It was found that there was clinical evidence related to .
In addition, the paper explained that the liver damage-related side effects confirmed in AT132’s clinical trials have different characteristics from the non-cholestatic hepatotoxicity found in currently commercially available AAV-based gene therapy drugs. Hepatotoxicity confirmed in gene therapy for hemophilia and Duchenne muscular dystrophy (DMD) was related to immune response, and symptoms improved as immunosuppression occurred. However, in the case of hepatotoxicity confirmed in clinical trials of AT132, immunosuppression was not effective.
Astellas explained that following the death of a patient due to cholestatic hepatopathy, it is investigating the tendency of cholestasis in XLMTM patients and is identifying the mechanism related to AT132. It is expected that this will reduce the risk of side effects in patients receiving AT132 in the future. Astellas is considering blood bile acid testing to analyze patients’ tendency to cholestasis.
Richard Wilson, Senior Vice President, Genetic Regulation, Astellas, said, “We are working to address the challenges of currently halted trials, and this paper provides a guide to advance promising treatments for XLMTM. “I think we can do it,” he said.