Abstract
Less than a year after halting its Phase I/II clinical trial of its adeno-associated virus (AAV) gene therapy candidate AT132 in patients with X-linked Myotubular Myopathy, Astellas Gene Therapies (formerly Audentes Therapeutics) acknowledged that a fourth boy has died during the trial.
Unlike the other three boys who all died last year in the Phase I/II ASPIRO trial, the fourth—whose age has not been disclosed—received the lower dose of 1.3×1014 vg/kg. The boy's cause of death “is still pending,” Astellas said.
The three previous patients who died were treated with the trial's higher dose of 3.5×1014 vg/kg before they started to demonstrate signs of liver dysfunction within 3 to 4 weeks after dosing. They developed progressive cholestatic hepatitis and subsequent decompensated liver failure. Two of the three later died of sepsis, while the third succumbed to a gastrointestinal bleed, all of which resulted from the liver failure.
Last year's three deaths led the FDA to impose a clinical hold on the trial. The agency lifted that hold in December 2020, when Astellas eliminated the high dose, and agreed to dose patients at the lower dose.
“Although the dose was lowered from 3.5×1014 vg/kg, it still wasn't a low dose. This new dose of 1.3×1014 vg/kg is still a very high dose, particularly for intravenous infusion, so the serious adverse events will still be the same as we've seen previously with ‘high-dose IV-administered' AAVs,” said Nicole Paulk, assistant professor, University of California, San Francisco.
Astellas acknowledged it had received an email from the FDA placing ASPIRO on a new clinical hold, after the announcement of the fourth death.
