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Audentes sees FDA hold lifted after 3 trial deaths blighted $3B program

Japanese pharma Astellas and its new biotech buyout Audentes got a Christmas gift from the FDA when the agency lifted a clinical hold on its gene therapy.

It’s been a tough 12 months for Audentes. Soon after the high of one year ago, when Astellas spent $3 billion to snap up the Californian biotech, several patients died in a trial of the company’s leading hope, AT132, a gene therapy for the rare disorder known as X-linked myotubular myopathy (XLMTM).

AT132 uses an AAV8 vector to deliver a working copy of the myotubularin 1 gene. Previous trials showed it could improve neuromuscular function and reduce dependence on ventilators in myotubular myopathy patients, who suffer muscle weakness that can make breathing difficult.

Astellas went all in after these data, with Audentes on the cusp of filing AT132 in 2020. But it was forced to scrap those plans when three trial patients died. The FDA slapped a full clinical hold on the trial, called Aspiro, last summer.

In May, Audentes told patient groups that an XLMTM patient had died after receiving AT132. The patient, one of the three older children who received a higher dose in the trial, died from sepsis. The trial enrolled patients up to 5 years of age, according to Clinicaltrials.gov.

Then in June, Audentes shared details of a second death: The patient was another one of the three older children treated with the trial’s higher dose.

Preliminary reports showed the two children had followed a similar clinical course in the weeks before they died.

 The second patient who died suffered from progressive liver disease in the four to six weeks after AT132 therapy. The liver disease, characterized by excess bilirubin in the blood, didn’t respond to standard treatment. Despite “aggressive medical treatment,” the child died of bacterial infection and sepsis.

That’s when the FDA put the trial on hold. Things then got worse after a third patient died in August, with early data suggesting the “immediate cause of death was gastrointestinal bleeding.” The child was the last of the three older trial participants who received the higher dose.

But now, Audentes has won a reprieve—and a chance to redeem the $3 billion Astellas put up for the biotech. The FDA has lifted the hold, and the Astellas unit is now “working to complete all clinical and regulatory activities necessary to resume dosing and plans to have discussions at a future date with the regulators on the path forward toward global registration filings for AT132,” the company said in a statement.

Audentes did not say why FDA lifted the hold. The reprieve comes amid a tough period for the gene therapy arena, already no stranger to safety issues over the decades. Te FDA has slapped partial and full holds on a host of biotechs including Passage Bio, Solid Bio—later lifted—uniQure/CSL and Voyager.

“We are grateful for the efforts of our team and investigators who have worked tirelessly to answer the FDA’s questions and we now look forward to resuming this study,” CEO Natalie Holles said in the statement.

“We want to again extend our deepest sympathies to patients’ families impacted by the events earlier this year. We are deeply committed to the continued safe development of AT132 for the families and patients living with XLMTM, a disease with no existing treatments.”