Sarepta Gene Therapy Misses in Phase 3; Prospects Now Rely on FDA Flexibility

Sarepta Gene Therapy Misses in Phase 3; Prospects Now Rely on FDA Flexibility
Sarepta Gene Therapy Misses in Phase 3; Prospects Now Rely on FDA Flexibility


A Duchenne muscular dystrophy gene therapy available under accelerated FDA approval has failed to meet the main goal of a study designed to confirm patient benefit and support expansion of the one-time treatment to a broader age range of patients. But the therapy’s maker, Sarepta Therapeutics, points to success across the study’s secondary goals and it aims to seek a broader FDA approval based on “the totality of evidence.”

Accelerated approval of the gene therapy, Elevidys, covers children ages 4 and 5 who have Duchenne, an inherited muscle-weakening disorder that leads to difficulty sitting up, walking, and eventually breathing. The confirmatory Phase 3 study enrolled children ages 4 to 7. The main goal of the placebo-controlled study was to show, at 52 weeks, a change in score according to a 17-point assessment that measures motor function in Duchenne patients.

According to preliminary results Sarepta released late Monday, patients in the Elevidys group showed an improvement of 2.6 points—not enough to be statistically significant compared to the 1.9 point score change in the placebo arm. Despite that miss, Sarepta noted that the therapy led to statistically significant improvement on all pre-specified secondary endpoints, which included other measures of muscle function such as the time to rise, a 10-meter walk test, and measures of mobility and upper limb function. Speaking on a conference call, Sarepta President and CEO Doug Ingram said the preliminary data from the Phase 3 study have been shared with the FDA.

“On that basis, we are pursuing an application to expand the label of Elevidys and they have confirmed they are open to evaluating an application to expand the label,” he said. “Our goal is to expand the label to cover all amenable Duchenne patients without regard to age or ambulatory status.”

Investors signaled their disappointment with the results. Shares of Cambridge, Massachusetts-based Sarepta opened Tuesday at $57.63 apiece, down more than 46% from Monday’s closing price.

Duchenne, which primarily affects boys, stems from an inherited lack of dystrophin, a protein key to muscle function. Elevidys is an engineered version of the gene that codes for dystrophin. This gene does not code for full-length dystrophin, but rather a truncated version. The accelerated approval was based on test results showing higher levels of this micro-dystrophin in muscle cells. The Phase 3 study was intended to show that these higher dystrophin levels translate to improved muscle function.

In a note sent to investors, William Blair analyst Tim Lugo wrote that the treatment arm performed within management’s expectations, but the placebo group performed better than expected. He added that the achieving the main goal at one year is tough in a disease whose progression occurs over the course of 10 years.

Lugo said the current data support the current label covering 4 and 5 year olds as well as likely expansion to boys ages 6 to 7 after FDA review. But expansion to older boys, especially those who are unable to walk, “is more risky because it is hard to say that current data supports this population—though patient groups will obviously be vocal for full approval and there is precedent for most rare disease approvals for broad labels.”

Leerink Partners analyst Joseph Schwartz called the Elevidys Phase 3 data “extremely disappointing,” adding that the results complicate the regulatory path for the gene therapy. He said in a research note that Elevidys’s future prospects rest on the FDA’s willingness to exercise regulatory flexibility—an approach it has previously embraced with other rare disease drug developers, including Sarepta. In 2016, the FDA approved Sarepta’s first Duchenne drug, Exondys 51, an antisense nucleotide that gets a gene to skip over a missing exon to produce shortened version of the dystrophin protein. That regulatory approval overcame a negative evaluation from FDA reviewers as well as objections from an FDA advisory committee. Sarepta has since won additional approvals for two other exon-skipping therapies.

More recently, regulatory flexibility was shown in amyotrophic lateral sclerosis, where the FDA approved Relyvrio from Amylyx and Qalsody from Biogen. Reata Pharmaceuticals overcame questions about efficacy to win approval for Skyclarys, the first treatment for the ultra-rare neuromuscular disorder Friedreich’s ataxia. Given those affirmative regulatory decisions, Schwartz said it appears the FDA “is willing to work with sponsors and drugs that have less than pristine data packages.”

“Perhaps for any other company, a whiff on the primary endpoint in a Phase 3 would be game over, but [Sarepta] is a special case, especially in a rare neuromuscular disease with a high unmet need like DMD (Duchenne muscular dystrophy),” Schwartz said. “The company has been able to secure accelerated approvals for their three skippers and Elevidys, thus we believe [Sarepta] could also eke out a win here.”

Sarepta said it plans to submit application to the FDA “as soon as possible” seeking an expansion of Elevidys’s label to encompass the treatment of all Duchenne patients. The company also plans to pursue the regulatory steps needed to transition the gene therapy from accelerated approval to traditional approval. Full results from Elevidys’s Phase 3 study will be shared at future medical meetings and published in a medical journal.

Photo by Sarepta Therapeutics



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