A second patient has died after receiving Audentes Therapeutics’ gene therapy against a rare genetic neuromuscular disorder. Audentes, which Astellas Pharma acquired for $3 billion, has dropped plans to file for approval imminently and paused a clinical trial while it reviews the situation.
In May, Audentes told patient groups that a person with X-linked myotubular myopathy (XLMTM) had died after receiving AT132, a gene therapy that uses an AAV8 vector to deliver a working copy of the myotubularin 1 gene. The patient, one of three older individuals to receive the higher dose of AT132, died from sepsis.
Now, Audentes has shared details of a second death. The patient was another one of the three older individuals to receive the higher dose of AT132. Preliminary reports show the two patients followed a similar clinical course in the weeks before they died.
The second patient to die suffered from progressive liver disease in the four to six weeks after being dosed with AT132. The liver disease, which was characterized by excess bilirubin in the blood, didn’t respond to standard treatment. Despite receiving “aggressive medical treatment,” the patient died of bacterial infection and sepsis.
Audentes has seen similar serious adverse events (SAEs) in the three older patients who received the higher doses of AT132. The patients were of a “heavier weight.” As AT132 is dosed per kilogram, the heavier people will have received a bigger viral load. Some research suggests systemic administration of high doses of adeno-associated virus (AAV) vectors directly damages liver cells and causes inflammation.
None of the six patients who received the lower dose experienced liver SAEs, despite four of them having a history of hepatobiliary disease. Audentes has years of follow-up on its lower-dose cohort of XLMTM patients.
The SAEs prompted Audentes to halt dosing prior to the deaths. Later, talks with the FDA led to the trial being put on clinical hold.
An investigation into the SAEs is ongoing. The findings will inform the development plan, but some things are already clear. Audentes has abandoned its long-held plans to file for approval around the middle of 2020. It is unclear when Audentes will be in a position to file for approval.
The timing of the filing is relevant to Astellas, which paid $3 billion for Audentes despite the biotech only having AT132, a gene therapy targeting a tiny patient population, in the clinic. Astellas saw value in Audentes’ other assets, too, leading it to put the biotech’s early-stage pipeline and manufacturing capabilities at the heart of a new genetic regulation unit.
Those assets could enable Astellas to make the Audentes acquisition pay even if AT132 fails. Yet, it is also possible the problems faced by AT132 will affect other high-dose AAV gene therapies, potentially denting the prospects of Audentes’ other assets and candidates in development at other companies.