Sarepta planning to seek expanded Elevidys approval after EMBARK

Data from Phase 3 trial show improvements for DMD boys on gene therapy

Marisa Wexler, MS avatar

by Marisa Wexler, MS |

A pair of hands, a stethoscope and a handful of pills surround a graph showing measured improvements in a clinical trial.

While a Phase 3 clinical trial of Elevidys (delandistrogene moxeparvovec-rokl) has failed to meet its main goal, the results nonetheless showed that, compared with a placebo, the approved gene therapy led to notable improvements across numerous measures of physical function in boys with Duchenne muscular dystrophy (DMD).

Top-line findings from that trial (NCT05096221), called EMBARK, were announced by the therapy’s developer Sarepta Therapeutics.

“The results of EMBARK, our double-blind, placebo-controlled trial, support the conclusion that Elevidys modifies the trajectory of Duchenne and benefits patients across age groups living with this ferociously degenerative disease,” Doug Ingram, president and CEO of Sarepta, said in a company press release.

“The results favored Elevidys across all endpoints in the study, including achieving statistical significance on all pre-specified key secondary endpoints and in each age subgroup of the key secondary endpoints,” Ingram added.

In a letter to the Duchenne community on the company’s website, Sarepta said it will get the new trial data to the U.S. Food and Drug Administration (FDA) as quickly as is possible. The company said it believes these results are sufficient to support an expansion of the approval of Elevidys — now authorized in the U.S. only for young children able to walk.

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Sarepta said in the release that it will work quickly on its submission, “recognizing the community’s urgency.”

“Importantly,” Ingram said, “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.”

“Based on the EMBARK results, we intend to move swiftly to request an update to expand the labeled indication to treat all patients,” Ingram said.

Importantly, 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.

DMD is caused by mutations that disrupt the production of dystrophin, a protein that normally helps to cushion muscle cells against damage. Elevidys (previously called SRP-9001) is designed to deliver to muscle cells a gene that encodes for a shortened but functional version of the dystrophin protein called micro-dystrophin.

A few months ago, the FDA granted accelerated approval to Elevidys for children with DMD, ages 4 to 5, who are able to walk.

The FDA gives accelerated approval to therapies that have early clinical data showing they’re likely to be effective. Elevidys specifically was approved based on evidence it can induce production of so-called Elevidys micro-dystrophin in patients’ muscles as designed.

As a condition of an accelerated approval, a therapy’s developer is mandated to conduct further testing to confirm a clinical benefit.

The EMBARK trial was expected to serve as a confirmatory study. It enrolled 126 boys with DMD, ages 4 to 7. The participants were given either Elevidys or a placebo, then followed for a year.

The primary endpoint of EMBARK — that is, the study’s main goal — was to evaluate how gene therapy affects scores on the North Star Ambulatory Assessment (NSAA), a standardized measure of motor function in children with DMD who are able to walk.

The results showed that NSAA scores improved by an average of 2.6 points among patients given Elevidys, compared with 1.9 points in patients given the placebo. While scores favored Elevidys, the difference was not statistically significant — meaning that, mathematically, it’s plausible this difference could be due to random chance rather than a true effect of the treatment.

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Several important secondary measures, however, did show a statistically significant benefit with the therapy.

Specifically, the time it took patients to walk 10 meters (about 33 feet) was on average 0.42 seconds faster among patients given the gene therapy. Participants given Elevidys also were able to rise from a lying position to standing significantly faster, by 0.64 second on average, than boys on the placebo.

“Passing 5 seconds on time to rise is the strongest predictor of early loss of ambulation and in EMBARK, Elevidys reduced those odds over 52 weeks by greater than 90 percent,” Ingram said.

The importance of this measure also was highlighted by Craig McDonald, MD, an investigator on the EMBARK study at the University of California, Davis.

“The strong prognostic power of time to rise, and the particular importance of the 5 second milestone in predicting functional decline and future loss of ambulation, is clearly demonstrated in natural history,” said McDonald, chair of UC Davis Health’s department of physical medicine and rehabilitation.

“In EMBARK, the reduction in patients progressing past this milestone when treated with Elevidys is highly clinically relevant,” McDonald added.

In all the patients collectively, the endpoints showed a statistically significant difference favoring Elevidys. Such differences also were seen in subgroups of younger patients, ages 4 to 5, and older boys, ages 6 to 7.

“The consistency of the positive effect across all timed function tests and age groups provides evidence of a meaningful treatment effect,” McDonald said.

Other measures of motor function, such as the time it took patients to climb a set of steps and measures of step speed, also showed “consistent treatment benefit in favor of Elevidys,” according to Sarepta. The company noted that detailed results will be presented at future medical conferences.

Safety data from EMBARK did not reveal any unexpected findings. About 1 in 10 patients experienced a serious side effect related to treatment, but all were within the known range of safety issues with Elevidys gene therapy. The most common treatment-related side effects were fever and digestive issues like vomiting, nausea, and decreased appetite.

In addition to EMBARK, Sarepta is also running another Phase 3 trial called ENVISION (NCT05881408), which is testing Elevidys in older ambulatory boys with DMD, as well as people with DMD of all ages who are unable to walk. That study, started earlier this year, is still recruiting patients at sites in the U.S.