A patient who developed liver problems after receiving an experimental Astellas Pharma gene therapy for a rare neuromuscular disorder has died. The death is the fourth in the clinical trial and the first since the study was cleared to resume following an inquiry into the three prior deaths.
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The cause of the most recent death has not yet been determined, and Tokyo-based Astellas said that it is gathering information that will be added to the ongoing investigation about the other serious adverse events observed in the clinical trial. But the Sept. 9 death raises questions about whether the gene therapy is safe at any dose. The three deaths reported last year occurred in patients who received the high dose of the gene therapy. The most recent death was a patient given the low dose. The Astellas study has again been placed under clinical hold, a regulatory action the FDA took after the company’s Sept. 1 disclosure of abnormal liver function in the patient.
The Astellas gene therapy, AT132, is an experimental treatment for X-linked myotubular myopathy (XLMTM), a disease caused by a mutation in the MTM1 gene. That gene provides the instructions for making myotubularin, a key protein for the development and function of muscle cells. The rare disease leads to muscle weakness, respiratory failure, and eventually, death. The vast majority of patients who have the disease require ventilators and feeding tubes.
AT132 uses an engineered virus, adeno-associated virus (AAV), to deliver to cells a functioning copy of the MTM1 gene. The AAV used was selected for its ability to target skeletal muscle and increase the expression of myotubularin in those tissues. Astellas added AT132 to its pipeline via a $3 billion acquisition of San Francisco-based Audentes Therapeutics last year.
The open-label study of AT132 initially tested two doses of the gene therapy. In June of last year, Astellas disclosed the deaths of two patients, leading to the first FDA clinical hold. Two months later, the company reported that a third patient in the study had died. The company said the preliminary cause was gastrointestinal bleeding. All of the deaths were in the high-dose group and Astellas said that all three patients had pre-existing signs of hepatobiliary disease, which are disorders affecting the liver and bile ducts. However, liver toxicity is one of the most common adverse events reported in clinical trials testing gene therapies that employ AAV vectors.
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The FDA lifted the clinical hold last December, clearing the Astellas gene therapy to resume testing at the low dose. The fourth patient who died was the only one who received that dose. After the serious adverse events were reported earlier this month, Astellas paused screening and dosing of additional patients. In the most recent death, Astellas said that the patient had a history of intermittent cholestasis, a type of liver disease. But prior to receiving the gene therapy, the company said this patient had a normal liver ultrasound and liver function tests were normal.
Astellas said Tuesday that the FDA’s notification of the clinical hold was given by email and a written letter is expected in the next several weeks. The company added that after receiving the letter, it will review it and discuss with the FDA the path forward for the gene therapy program.
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