Astellas Reports Third Patient Death in Audentes Gene Therapy Study

A third patient who received an experimental Audentes gene therapy for a rare neuromuscular disorder has died, a disclosure that comes two months after the deaths of two patients led the FDA to place a clinical hold on the study.

San Francisco-based Audentes, a subsidiary of Japanese pharmaceutical company Astellas Pharma, said Friday that early findings indicate that gastrointestinal bleeding was the cause of the most recent death. That patient received the high dose of the gene therapy, the same dose given to the patients whose deaths were disclosed in June.

The Audentes gene therapy, dubbed AT132, is in development as a treatment for X-linked myotubular myopathy, an inherited disorder that causes extreme muscle weakness, respiratory failure, and early death. It’s caused by a mutation to the MTM1 gene, which codes for an myotubularin, an enzyme that plays a role in the development and maintenance of muscle cells. By providing a functioning version of the gene, the Audentes gene therapy is intended to boost myotubularin levels in muscles.

The open-label clinical trial, which has a target enrollment of 24 patients, has two parts. The first is designed to evaluate a low dose in one group, then a high dose of the gene therapy in a second group. The second part, the pivotal portion of the study, is designed to confirm the safety and efficacy of the gene therapy of the higher dose.

The three patients who have died in the study each received the high dose. According to Audentes, all three had pre-existing signs of hepatobiliary disease, which is an umbrella term for disorders that affect the liver, bile ducts, and gallbladder. The patient who most recently died began showing signs of liver dysfunction within three to four weeks after receiving the gene therapy, Audentes says. The company adds while more than half of the patients enrolled in the clinical trial to date show signs of pre-existing hepatobiliary disease, neither those who received the low dose of AT132 or the other patients who received the gene therapy at the high dose have shown signs of liver problems similar to those experienced by the patients who died.

Before the FDA halted the clinical trial, 23 patients had been dosed with the gene therapy: six at the low dose and 17 at the high dose. Audentes says it knows of no other patients in the study who are currently experiencing the same kind of progressive liver dysfunction that occurred in the patients who died, and that it is monitoring the remaining patients in the study for similar problems. Audentes adds that it is continuing to investigate the cause of the progressive liver problems.

Audentes was acquired by Astellas earlier this year in a $3 billion deal that added gene therapy to the pharmaceutical company’s pipeline. In addition to AT132, Audentes has gene therapies in its pipeline for other neuromuscular diseases. The company’s gene therapies are delivered to cells via an engineered adeno-associated virus (AAV), an approach used by FDA-approved gene therapies, as well as gene therapies still in clinical development.

However, AAV delivery of gene therapy has sparked some safety concerns. In 2018, gene therapy pioneer James Wilson and some colleagues at the University of Pennsylvania published a paper that detailed findings of nerve and liver damage in preclinical gene therapy tests. The paper said that careful monitoring may be needed for other gene therapies that employ a high dose of AAV to deliver the treatment.

The Audentes clinical trial for AT132 is not the only AAV-gene therapy to be placed on hold. In 2018, the FDA halted a Solid Biosciences (NASDAQ: [[ticker:SLDB]]) study evaluating its AAV-based gene therapy for Duchenne muscular dystrophy after complications led to the hospitalization of one patient. The agency later permitted the study to resume with new safeguards, only to halt it again last year after another patient developed similar complications.

The second Solid Bio clincal hold came less than two weeks after a partial hold was placed on studies of Zolgensma, a Novartis (NYSE: [[ticker:NVS]]) gene therapy for spinal muscular atrophy (SMA). Though the FDA approved Zolgensma last year for children younger than 2, Novartis has been conducting additional tests to support use of the AAV-based gene therapy in treating older SMA patients. The partial hold, put in place due to concerns about nerve cell inflammation observed in animal studies, stops new patients from being enrolled in the high-dose group of the study. In its report of financial results for the second quarter of 2020, Novartis said that discussions with the FDA about the partial hold are ongoing.

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