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Paper details Astellas gene therapy study that led to patient deaths

A new paper published online in The Lancet Neurology Wednesday provides key new details on a gene therapy study that left four patients dead and posed broader questions about safety for the emerging field.

The article lays out data from the so-called Aspiro trial of Astellas Pharma’s AT132, a therapy designed to treat X-linked myotubular myopathy, a rare neuromuscular condition that almost exclusively affects young boys. The disease leads to death within the first 18 months of life for about half of affected individuals, often robbing children of the ability to sit up, eat or breathe.

Given the rare nature of the disease, the study included 24 boys who received the gene therapy. The treatment had some remarkable results, with researchers finding that a significant portion of patients could begin sitting up without assistance and even stop using a ventilator. But four deaths in the treatment group marred the results, and the trial has been on hold since 2021.

Now, researchers are suggesting a link to pre-existing liver function issues. All four patients who died in the treatment group had serious hepatobiliary issues, compared with five of the 20 surviving patients who received the therapy, Astellas said Wednesday. The propensity of some children with X-linked myotubular myopathy patients to have cholestatic liver disease was previously unknown, researchers said.

“The unprecedented findings of ventilator independence and acquisition of motor milestones in Aspiro should be carefully weighed against the potential for fatal adverse events in the context of a life-threatening disease,” according to the researchers led by Perry B. Shieh, a neurology professor at the University of California, Los Angeles.

The Food and Drug Administration placed the trial on hold in 2020 and researchers attempted to understand what led to the death of three high-dose patients in the treatment group in May, June and August of that year. The FDA allowed the trial to restart with a lower dose in December 2020, but the only patient treated after the restart also died, prompting another hold.

Researchers said in the Lancet Neurology that the toxicity observed among the patients in the Aspiro trial was different from the non-cholestatic liver issues seen in patients on approved gene therapies. That suggests that the issues facing AT132 may be unique to the patient population without more sweeping implications for gene therapy research broadly. 

The paper only includes data through Feb. 28, 2022, but Astellas confirmed in an emailed statement that there have been no subsequent deaths among the 20 surviving patients who received its gene therapy. The company also highlighted the promise of the treatment for patients faced with a bleak prognosis, including the unexpected effect of freeing some patients from a ventilator.

Most of the patients who entered the study were on a ventilator 22 to 23 hours a day and only one in each group — high-dose, low-dose and control — could sit unassisted for 30 seconds. None could stand or walk. Of the 24 patients who received treatment, 17 received a higher dose. Patients who received treatment in the study were between 7 months and 6 years old, while patients in the control group were between 6 months and 3 years old.

None of the control group patients were free of a ventilator or able to walk without help by Feb. 28, 2022. But researchers found that 86% of lower-dose patients and 82% of higher-dose patients had stopped using a ventilator and 71% of lower-dose and 35% of higher-dose patients could walk without help. They also found the therapy helped more patients sit unassisted for 30 seconds and pull themselves up to stand.

Promising early results for the therapy prompted Astellas to buy the original developer of AT132, Audentes Therapeutics, for $3 billion back in early 2020. Astellas said it’s working closely with the FDA to resolve the clinical hold on the therapy, saying it’s had “productive and collaborative dialogue with regulators.”