Pictured: Sarepta logo on a building/courtesy of Sarepta Therapeutics
Those in the Duchenne muscular dystrophy and gene therapy spaces hoping for a milestone decision by May 29 will have to wait approximately three more weeks as the FDA set a new action date of June 22 for Sarepta’s gene therapy for the neuromuscular disease.
The FDA told the company Wednesday “it requires modest additional time to complete the review, including final label negotiations and postmarketing commitment discussions,” according to Sarepta’s announcement.
The company went on to say that the FDA indicated it is “working toward potentially granting an accelerated approval for SRP-9001” for DMD patients aged 4-5 years.
If approved, SRP-900 would be the first FDA-authorized gene therapy for DMD.
Sarepta’s shares were down 14% in pre-market trading Wednesday.
Update published May 13:
Sarepta’s Duchenne Therapy Recommended for Accelerated Approval
An FDA advisory committee voted 8-6 on Friday in favor of Sarepta Therapeutics’ gene therapy for Duchenne muscular dystrophy.
The decision came after an all-day meeting with presentations from Sarepta and the FDA.
The meeting started off on a positive note, with Sarepta providing evidence to support its viral vectored gene therapy. This included a video of a 6-year-old patient who’d been successfully treated running, climbing and playing as if he didn’t have Duchenne muscular dystrophy (DMD).
“You cannot detect appreciable differences in this child from another kid on the playground,” University of California, Davis, physician Craig McDonald, presenting on behalf of Sarepta, said during the meeting, STAT reported. The patient’s activities are “something I have never observed in my more than three decades following patients with DMD,” he added.
After the company’s presentation, panelists asked some questions, but none “raised serious objections or concerns about Sarepta’s data,” STAT reported.
After a break for lunch, the panel reconvened to hear patients and their families speak during the open comment portion of the meeting. Parents of treated and untreated patients shared videos of their children, apparently highlighting the drug’s effectiveness.
Two people, however, did voice their dissent.
Michael Abrams of the advocacy group Public Citizen and Diana Zuckerman of the National Center for Health Research noted that Sarepta’s randomized trial of the therapy failed to meet its primary endpoint, a statistically significant increase in the North Star Ambulatory Assessment total score. Zuckerman encouraged using an expanded access program instead of accelerated approval.
Abrams and Zuckerman also said the company still needed to complete confirmatory trials for three other therapies that were previously granted accelerated approval. Earlier in the day, several Sarepta representatives said the ongoing confirmatory study for the therapy currently under discussion would not be affected by approval.
These concerns turned out to be a preview of the FDA’s review, presented in the afternoon. The agency’s speakers questioned the therapy’s efficacy, among numerous other issues, from its structure to its manufacturing.
“The uncertainties make it difficult to consider Sarepta’s microdystrophin a surrogate endpoint ‘reasonably likely to predict clinical benefit’ in support of accelerated approval,” said FDA Clinical Reviewer Mike Singer, STAT reported.
The meeting concluded with a lengthy panel discussion, with members voicing both concerns and support for the experimental gene therapy. In the end, the proponents won out by a narrow margin.
As always, the FDA is not bound by the advisory committee’s recommendation, though it often heeds it. The regulatory agency is expected to provide its decision on accelerated approval of Sarepta’s therapy by May 29.
Original story published May 10:
FDA Briefing Documents Question Safety, Efficacy of Sarepta’s DMD Gene Therapy
Ahead of Friday’s advisory committee meeting for Sarepta Therapeutics’ gene therapy for Duchenne muscular dystrophy, the FDA released briefing documents that raise concerns about its ability to safely and effectively treat patients.
Sarepta is seeking approval of SRP-9001 (delandistrogene moxeparvovec) based on a biomarker—the expression of its proprietary micro-dystrophin after 12 weeks of therapy—as a surrogate endpoint “reasonably likely to predict clinical benefit.” But the FDA appears unconvinced, stating in the briefing documents that “measurement of levels of Sarepta’s micro-dystrophin in muscle tissue only provides information about expression of the transgene product in cells transduced by SRP-9001, rather than insight into a pharmacologic effect on a biomarker in the pathway of the disease.”
Duchenne muscular dystrophy (DMD) is a rare neuromuscular disorder caused by mutations in the dystrophin gene, leading to muscle weakness and developmental delays. SRP-9001 works by delivering to muscle tissues a functional copy of the dystrophin gene, which encodes the novel protein micro-dystrophin. If approved, it would be the first gene therapy for DMD.
Sarepta submitted data from three clinical studies, including one randomized, double-blinded, placebo-controlled trial in its NDA. Despite hitting the primary biological endpoint of micro-dystrophin protein expression, the randomized study missed the primary functional endpoint, failing to show a statistically significant increase in the North Star Ambulatory Assessment (NSAA) total score. The NSAA is used to measure functional motor abilities in ambulant children with DMD.
Overall, the FDA said in the briefing documents that the trials “do not provide unambiguous evidence” of SRP-900’s likely benefit for these patients.
The regulator also wrote that it “has safety concerns related to the possibility of administering an ineffective gene therapy.” The FDA pointed to a clinical hold placed on Sarepta’s IND application in August 2021 after a 9-year-old subject was hospitalized and required respiratory support due to muscle weakness following treatment with SRP-9001.
The FDA’s concerns do not come as a complete surprise, as the agency initially decided it would not hold an adcomm meeting for the therapy—news that the company reported in its full-year 2022 report. In March, however, the regulator changed course, announcing it would convene its Cellular, Tissue and Gene Therapies Advisory Committee on May 12.
Biomarkers on Trial
Sarepta is not the first company to seek accelerated approval based on a biomarker this spring. In March, the FDA’s Peripheral and Central Nervous System Drugs Advisory Committee met to discuss the relative merits of Biogen and Ionis’ tofersen in superoxide dismutase 1 (SOD1)-ALS. Like SRP-9001, tofersen failed to meet the primary functional endpoint in the Phase III trial but led to significant reductions in levels of the SOD1 protein and neurofilament light chain (NfL).
The briefing documents for tofersen were decidedly more optimistic, however, and advisers voted 9-0 that tofersen’s effect on NfL could be a reasonable predictor of clinical benefit. Tofersen (now Qalsody) won accelerated approval on April 25.
The FDA is expected to make a decision on SRP-9001 on May 29.
Heather McKenzie is a senior editor at BioSpace, focusing on neuroscience, oncology and gene therapy. You can reach her at heather.mckenzie@biospace.com. Follow her on LinkedIn and Twitter.
