Astellas Halts AT132 Gene Therapy Trial for XLMTM Due to Liver-Related Safety Concerns

Compiled and Translated by | Tom Li

Recently, Astellas Pharma announced that it has paused the clinical trial of gene therapy AT132 for patients with X-linked myotubular myopathy (XLMTM) following a serious adverse event in a trial participant.

Previously, Astellas' gene therapy development has repeatedly encountered challenges related to potential adverse effects. AT132 is a gene therapy acquired by the company through its 2019 acquisition of Audentes Therapeutics. In August 2020, Astellas announced that the MTM1 gene therapy AT132 had resulted in the death of a third patient. All three deceased patients received high-dose treatment and had a history of hepatobiliary disease. Due to safety concerns, the clinical trial was placed on hold by regulatory authorities. However, in December 2020, the U.S. Food and Drug Administration (FDA) lifted the clinical hold on the ASPIRO trial evaluating AT132 for patients with X-linked myotubular myopathy.

Regarding the voluntary suspension of the ASPIRO trial, Astellas stated that earlier this year, liver function abnormalities were observed in trial participants several weeks after receiving low-dose AT132 treatment. Astellas noted that the patients had a history of intermittent cholestasis, which affects bile flow in the gallbladder. However, the company indicated that the trial participants had normal liver ultrasounds and normal bilirubin levels prior to dosing. Astellas has also reported this adverse event to regulatory authorities, and both parties are currently discussing the safety concerns associated with this gene therapy.

Nathan Bachtell, Senior Vice President and Head of Gene Therapy, Medicine & Development at Astellas, stated that the company will collaborate with site investigators and hepatologists to monitor the subjects. Despite previous recurrent liver-related adverse events associated with AT132, Bachtell expressed Astellas' confidence in the potential of AT132 as a treatment for XLMTM. In a statement, Bachtell said, "As our understanding of the cases deepens, Astellas will incorporate any new findings into the ongoing investigation to facilitate comprehensive discussions with the Independent Data Monitoring Committee, the Hepatology Advisory Panel, and the study investigators."

XLMTM is an X-linked genetic disorder that primarily affects males. The disease is primarily caused by mutations in the MTM1 gene, which encodes a phosphatase known as myotubularin. Loss of function of this gene leads to abnormalities in muscle cells. Fifty percent of patients die before the age of two, with an average life expectancy of 29 months. AT132 consists of an AAV8 vector containing a functional copy of the MTM1 gene. Astellas believes that this therapy can specifically target skeletal muscle and, following a single administration, increase myotubularin expression in these tissues. In 2018, the FDA granted AT132 Regenerative Medicine Advanced Therapy (RMAT) designation for the treatment of XLMTM. Additionally, the therapy has been granted Orphan Drug designation and Fast Track designation.

After more than half a century of development, gene therapy is progressively establishing itself as a pivotal focus in future medicine. However, with research and development progress falling significantly short of expectations, gene therapies from multiple institutions have frequently been associated with safety risks and patient fatalities. In December 2020, the FDA suspended the Phase III clinical trial of uniQure’s hemophilia B gene therapy, AMT-061, after a patient receiving the treatment developed liver cancer.

Around the same time, the FDA also suspended the Phase II clinical trial RESTORE-1 for VY-AADC (NBib-1817), a gene therapy for advanced Parkinson’s disease jointly developed by Voyager and Neurocrine, due to safety concerns. In August this year, the trial of bluebird bio’s (bluebird) gene therapy elivaldogene autotemcel was also terminated by the FDA due to suspected cases of myelodysplastic syndrome (MDS).

Source: Astellas Pauses Dosing of Gene Therapy After Liver-Linked Concerns