FDA lifts clinical hold on Astellas’ Pompe gene therapy
The FDA has lifted a clinical hold on Astellas Pharma’s Pompe disease gene therapy trial, the Japanese company announced Friday morning. The FDA put the hold in place last June after investigators flagged a serious case of sensory nerve damage in a patient.
Astellas says it is making strides toward resuming dosing in the Phase I/II clinical trial for adult patients with late-onset Pompe disease, in which they lack an enzyme called GAA that breaks down complex sugars in the body, causing said sugars to build up and damage the muscles. Astellas’ head of regulatory affairs David Smethurst declined to comment on when the trial would resume dosing.
The gene therapy, dubbed AT845, was designed to deliver a copy of the GAA gene via an AAV8 vector to muscle tissues. It would provide a one-time alternative to enzyme replacement therapies Lumizyme/Myozyme and Nexviazyme, all developed by Sanofi and the latter approved in 2021.
Last June, the FDA paused Astellas’ Pompe trial, saying it didn’t have enough information to assess the risk to patients following the safety signal. The adverse event was classified as Grade 1 (meaning it was mild), but was deemed serious due to medical significance. Smethurst said in an email it was “not possible to say with certainty what caused the peripheral sensory neuropathy.”
Smethurst noted in his email a number of changes to the Pompe gene therapy trial design. “The main changes to the protocol include the exclusion of participants with history of risk factors for neuropathy, as well as additional neurological assessments and monitoring throughout the study. We are also proposing to increase the duration between dosing the next two patients in FORTIS and the remainder of the dose cohort, to permit additional safety monitoring,” he wrote.
The safety signal and trial pause were part of a growing number of similar examples facing gene therapies that are delivered via viral vectors called AAVs. Astellas itself presided over one of the most serious cases. The company’s gene therapy unit is built around a 2019 buyout of Audentes Therapeutics, but it stopped its lead program from that purchase after three patients died — and then later a fourth after Astellas restarted the program with a lower dose and more safety measures — after receiving a gene therapy for X-linked myotubular myopathy, or XLMTM, a rare muscle weakness disease.
Researchers and regulators alike are grappling with how to safely deliver these therapies, as AAVs remain one of the primary ways to package and deliver genes to the right organs. Some biotechs are trying to develop new versions of AAVs, while others are eschewing the viral vectors entirely, searching for non-viral delivery methods (and some are working somewhere in between).
This story was updated with comment from David Smethurst.