The Sarepta saga continues, with the FDA slapping a clinical hold across all of the company’s investigational limb-girdle muscular dystrophy (LGMD) trials, while also revoking the biopharma’s gene therapy platform technology designation.
The FDA’s actions follow “three deaths potentially related to these products and new safety concerns that the study participants are or would be exposed to an unreasonable and significant risk of illness or injury,” the regulator said in a release dated July 18.
Two of the deaths occurred in patients receiving the approved Elevidys, a gene therapy designed to treat Duchenne muscular dystrophy (DMD), a severe genetic disease with extremely limited treatment options.
Reports of a third death surfaced last week, this time occurring in a 51-year-old man with LGMD type 2D/R3 participating in a phase 1 trial. The patient had received Sarepta’s investigational gene therapy SRP-9004. As with the previous two deaths in Elevidys patients, the SRP-9004 patient died from acute liver failure.
While the risk-benefit calculus in Elevidys' approved indication differs from that in LGMD given the severity of DMD, the two gene therapies are engineered by Sarepta using the same viral vector.
The LGMD patient’s death occurred in June and was not initially disclosed by Sarepta, but instead by news publication BioCentury. During an investor call last week, Sarepta announced hundreds of layoffs and a pipeline restructuring designed to save $400 million annually but did not mention the LGMD death.
Sarepta said on the call that it would be discontinuing most of its experimental gene therapies against LGMD, excluding one dubbed SRP-9003. When asked at the end of the week why the company didn’t disclose the death related to one of the LGMD assets called SRP-9004, CEO Douglas Ingram said the matter was “neither material nor central to the topics at hand.”
The new hold includes Sarepta’s trials related to candidates SRP-9003, SRP-9004, SRP-6004 and SRP-9005, the last three of which Sarepta had said it would be discontinuing development earlier last week, according to a Securities and Exchange Commission (SEC) filing. On Wednesday, the company said it planned on looking for strategic alternatives, such as partnering, for the deprioritized programs.
In December of last year, Sarepta completed enrollment and dosing in a global phase 3 trial assessing SRP-9003 for LGMD type 2E/R4 in participants aged 4 years and older. At the time, the biopharma said it planned on submitting a biologics license application (BLA) for FDA review in the second half of this year, hopefully via accelerated approval.
Now, Sarepta still plans on discussing a potential accelerated approval pathway with the FDA after the clinical hold is lifted, according to the SEC filing.
As for the recently discontinued SRP-9004, the gene therapy was being studied in an early-stage trial for LGMD type 2D/R3.
Gene therapy SRP-6004 was also being assessed in a phase 1 trial for LGMD type 2B/R2, while SRP-9005 was slated to be tested in another LGMD subtype known as 2C/R5 in an early in-human trial.
"In the studies where patients were dosed, we are working closely with investigators to ensure continuity of care and data integrity to deliver on our regulatory obligations," a Sarepta spokesperson told Fierce Biotech.
As of publication, the FDA has not responded to Fierce Biotech's request for details regarding the clinical holds.
The FDA has also pulled Sarepta’s platform technology designation for its AAVrh74 tech that had been granted on June 2 of this year. The designation can be used to help speed up the FDA review process for new products stemming from the same platform.
“Protecting patient safety is our highest priority, and the FDA will not allow products whose harms are greater than benefits,” Vinay Prasad, M.D., director of the FDA’s Center for Biologics Evaluation and Research, said in the July 18 release. “The FDA will halt any clinical trial of an investigational product if clinical trial participants would be exposed to an unreasonable and significant risk of illness or injury.”
The clinical trial updates come amid a burgeoning dispute between the regulator and the company, with the FDA requesting that Sarepta voluntarily stop all shipments of Elevidys on Friday. Sarepta refused.
Editor's note: This article was updated at 12:15 p.m. ET on July 21 to include a comment from Sarepta.