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FDA Converts Sarepta Therapeutics DMD Gene Therapy to Full Approval, Expands Indication

Sarepta Therapeutics, building exterior

NEW YORK – The US Food and Drug Administration on Thursday said it has expanded the approval of Sarepta Therapeutics' Duchenne muscular dystrophy gene therapy Elevidys (delandistrogene moxeparvovec-rokl), converting its previously awarded accelerated approval to traditional approval and expanding the indication to cover older patients, despite concerns from some agency reviewers.

The FDA also granted the gene therapy accelerated approval in a subpopulation of non-ambulatory patients.

Sarepta's stock price jumped more than 30 percent on the announcement, which was made Thursday evening. Sarepta's stock price opened at $161.97 Friday, up from $123.50 at market close Thursday.

The FDA granted Sarepta accelerated approval for Elevidys in June 2023 after an agency advisory panel narrowly voted in favor of the gene therapy.

However, the FDA at the time limited Elevidys' indication to ambulatory patients between 4 and 5 years old with the rare progressive muscle disease and a confirmed mutation in the DMD gene. Sarepta has been set on expanding the indication to all ages, despite failing to meet the primary endpoint in its Phase III EMBARK clinical trial.

The FDA has now granted traditional approval for the drug in ambulatory patients 4 years of age and older with a confirmed DMD mutation, as well as accelerated approval in non-ambulatory individuals in the same age range.

"The initial approval of Elevidys was a significant milestone, and the expanded indication means clinicians now have a treatment option for the great majority of boys and young men living with Duchenne," Jerry Mendell, co-inventor of Elevidys and senior adviser of medical affairs at Sarepta, said in a statement.

Elevidys delivers a gene that encodes for microdystrophin, an engineered protein developed by Sarepta that it says can carry out the normal functions of dystrophin, the protein deficient or abnormal in DMD patients.

Peter Marks, director of the FDA's Center for Biologics Evaluation and Research, in a statement characterized the regulatory decision as "helping to address the ongoing, urgent treatment need for patients with this devastating and life-threatening disease."

"We remain steadfast in our commitment to help advance safe and effective treatments for patients who desperately need them," he added.

However, memos released by the FDA on Thursday showed that multiple review teams had recommended not approving the gene therapy. Instead, they suggested issuing a complete response letter to Sarepta outlining some concerns, including that the evidence submitted did not verify clinical benefit in the population that already had accelerated approval and that it did not demonstrate a benefit of the gene therapy in older patients or in non-ambulatory patients. FDA officials also suggested that the company conduct additional clinical trials. But Marks — who has repeatedly advocated for getting gene therapies to rare disease patients more quickly — overruled the recommendations.

In the EMBARK study, DMD patients ages 4 to 7 years old who received the gene therapy improved on the North Star Ambulatory Assessment (NSAA) — the clinical trial's primary endpoint — compared to those who received a placebo, but the 0.65-point difference fell short of reaching statistical significance.

Elevidys-treated patients did meet secondary endpoints in the study, including increased levels of microdystrophin expression and other mobility outcomes and upper extremity functions, such as improvements in time to rise from the floor, 10-meter walk/run, time to ascend four steps, and creatine kinase levels. 

The FDA on Thursday said that "based on the totality of the evidence," the company had verified the gene therapy's clinical benefit in those 4 years of age and above, but that there was inadequate safety data available to expand the indication to patients younger than that.

The FDA further granted accelerated approval for non-ambulatory patients based on data from an ongoing randomized-controlled clinical trial and evidence that the mechanism of action for Elevidys is similar in ambulatory and non-ambulatory populations. However, the agency said there was only a modest amount of safety data on the population. A randomized-controlled Phase III clinical trial, known as ENVISION, enrolling non-ambulatory patients and older ambulatory patients is underway, which Sarepta said is intended to serve as the post-marketing confirmatory study.

Elevidys is contraindicated in patients with deletions in exon 8 or exon 9 in the DMD gene.

Elevidys is the first gene therapy for DMD to reach the market in the US, although other companies like Genethon, Regenxbio, and Solid Biosciences are also advancing candidates in clinical trials. Pfizer last month paused dosing in a Phase III clinical trial of its DMD gene therapy candidate and more recently reported that the study failed to meet its primary endpoint.