Quality blip halts Sarepta muscular dystrophy gene therapy trial

A phase 1/2a trial Sarepta’s gene therapy for Duchenne muscular dystrophy (DMD) has been placed on clinical hold by the FDA after rogue DNA was found in a test sample.

The regulator sent a letter to Nationwide Children’s Hospital, which is carrying out the trial, saying it had detected a trace fragment of DNA plasmid in one lot of the microdystrophin gene therapy material, according to Sarepta CEO Doug Ingram.

On a conference call to discuss the hold, Ingram said the lot came from research-grade plasmid material supplied by another company for use in the gene therapy, but had not been used in patients. An earlier lot from the same supplier had been used in four patients but seems to have no safety issues as the fragment hasn’t shown up in patient biopsies.

Testing suggests the fragment “does not result in protein expression and is quickly cleared if present,” he continued, adding that the company doesn’t expect a “material delay” in patient dosing in the trial, which is currently expected to conclude by the end of the year.

“We know the source of the problem, we have been given clear guidance on how to address the issue, and we have a plan to allow our clinical development program to remain on track,” Ingram asserted.

The company is working on a corrective action plan, and specifically the use of Good Manufacturing Practice source (GMP-s) grade plasmid material that it says will avoid the issue in future.

According to Ingram, research-grade plasmid material has been routinely used in early-stage clinical trials, particularly those led by academic groups, but changes to FDA guidance means that sponsors are now encouraged to treat even early studies as potentially pivotal—and so use GMP materials.

That presents an opportunity for Sarepta, and the company now says that with the use of GMP-s material on the way, it will request a meeting with the FDA to see whether its phase 1/2a trial of the microdystrophin gene therapy could be upgraded to a registration study.

“It’s possible by the end of this year that we are actually dosing patients in what could be a pivotal trial for our gene therapy program,” said Ingram.

The swift response by Sarepta seems to have settled investors’ nerves that the company might lose ground to rival DMD gene therapy developers such as Solid Bio and Pfizer/Bamboo, and while its share price dipped after hours the sell-off was minimal, falling just over 4% to $125.50.

Last month, shares in the company leaped 50% on the back of preliminary data from three patients in the study, which revealed an increase in microdystrophin—a truncated form of dystrophin—which it said was large enough to indicate that the therapy might stop, or even reverse, DMD progression.