Since its initial approval, the industry and patients have eagerly awaited news from a confirmatory trial for Elevidys, the first marketed gene therapy for Duchenne muscular dystrophy (DMD).
Then, in late October, the topline results revealed that Elevidys failed to meet its primary goal in the pivotal phase 3 study called Embark — sending Sarepta Therapeutics' stock into a more than 40% tailspin.
Even so, company officials are undeterred and believe the treatment for the devastating degenerative muscle-wasting disorder caused by a faulty dystrophin gene can still deliver on its promise to help patients.
Sarepta is now working with the FDA to request a label expansion for all age groups. Although the trial fell short of its main goal, patients did show improvement on individual motor function tests, and the study period might not have been long enough to demonstrate the treatment’s full benefit.
“The totality of evidence in Embark supports the conclusion that Elevidys modifies the trajectory of Duchenne, demonstrating a treatment benefit that is clinically meaningful and similar regardless of age; therefore, we believe all patients with Duchenne can benefit from treatment with Elevidys,” said company officials in an email to PharmaVoice.
But will the FDA agree?
A challenging disorder
The stakes are high for Elevidys because there are limited treatment options for DMD and no cure. Sarepta developed three of the four approved exon-skipping drugs, which form a bridge over faulty parts of the dystrophin gene, allowing it to regain some function. But these drugs each target specific mutations, limiting efficacy.
DMD, which primarily affects boys, starves the muscles of the crucial dystrophin protein that keeps them healthy, triggering a slow deterioration. People with the condition often need a wheelchair by the time they reach their teens and can face life-threatening heart and breathing problems in their 30s. Elevidys delivers a gene that codes for a shortened form of dystrophin to muscle cells to improve strength and function.
The FDA signed off on a controversial accelerated approval of Elevidys in June to treat 4- and 5-year-old patients with a confirmed DMD gene mutation. Initially, FDA review teams appeared to be on the verge of rejecting the treatment after weighing the benefits against risks of the treatment, which can cause liver damage, myocarditis and a condition called immune-mediated myositis that damages muscle fibers. But Dr. Peter Marks, who oversees the agency's review of gene therapies, reportedly stepped in to intervene, stating in a memo that he disagreed with the efficacy findings from the review teams. Following an advisory committee vote, the FDA signed off on the approval but narrowed the patient population to 4- and 5-year-olds.
Where Sarepta saw benefit
The phase 3 confirmatory trial results showed that children who received the treatment noteched a 2.6-point increase on the North Star Ambulatory Assessment (NSAA), a standardized motor function test, compared to a 1.9-point increase in the placebo group, which wasn’t statistically significant. On individual motor function tests, such as time to rise and 10-meter walk, some fared better.
“It was clear in the results that the NSAA was not sensitive to meaningful changes that were occurring in the study population and weren’t capturing the full treatment effects that were evident and consistent across multiple key secondary outcomes,” said company officials in the email.
Because the study enrolled a mild patient population, 52 weeks might not have been long enough for the untreated group of patients to show the expected decline in function, affecting the comparison, they said.
“Even though the primary endpoint was not met, we are pleased with the consistency, the magnitude of response and the clinical meaningfulness of the results from Embark and from the body of evidence supporting Elevidys,” said company officials.
Sarepta officials are now working with the FDA to prepare its submission for the label expansion as soon as possible.
“We have shared the Embark topline results with FDA leadership and they have confirmed that, based on the totality of the evidence, they are open to such label expansion if supported by review of the data, and that they intend to proceed rapidly with consideration of the submission,” Sarepta officials stated in the email.
