NEW YORK – Sarepta Therapeutics on Monday presented top-line results from the second part of its global, randomized-controlled Phase III EMBARK trial, which company executives said reinforce earlier data showing its gene therapy can slow progression of Duchenne muscular dystrophy.
"We're delighted with this data," Sarepta President and CEO Doug Ingram said during a webcast presentation to investors. "It's extremely satisfying to see the consistency of these results."
The US Food and Drug Administration initially granted accelerated approval to the gene therapy, Elevidys (delandistrogene moxeparvovec), in 2023, but since then the company has hit stumbling blocks in proving that its product provides a clinical benefit.
Elevidys, which is the only gene therapy for Duchenne muscular dystrophy on the market, delivers a gene that encodes microdystrophin, an engineered protein developed by Sarepta that it says can carry out the normal functions of the dystrophin protein. In Duchenne muscular dystrophy, the dystrophin protein is deficient or abnormal.
The FDA granted Elevidys accelerated approval based on data from a Phase II trial that showed patients who received the gene therapy experienced increased microdystrophin expression 12 weeks post-infusion. At the time, the regulator limited the gene therapy's indication to ambulatory patients between 4 and 5 years old with certain mutations in the DMD gene.
Sarepta planned to validate Elevidys' ability to not only increase biomarker expression but also improve physical function and mobility in the Phase III EMBARK trial.
Then, in June 2024, the FDA converted Elevidys' accelerated approval to a traditional approval and expanded the indication to cover patients at least 4 years of age, even though the EMBARK trial had failed to meet its primary endpoint, which was to show that the gene therapy improved patients' physical function and mobility one year after treatment based on the North Star Ambulatory Assessment (NSAA). The FDA also granted the product accelerated approval in non-ambulatory patients. These approvals were doled out despite concerns from some agency reviewers, who were overruled by Peter Marks, director of the FDA's Center for Biologics Evaluation and Research.
Executives from Sarepta believe that the updated data from EMBARK now validate the benefits they had observed in smaller clinical trials. Louise Rodino-Klapac, Sarepta's CSO and head of R&D, described the top-line results presented Monday as "extremely clean, powerful" data. "I was extremely pleased with this data," she said during the presentation. "It adds to the totality of evidence."
In the EMBARK trial, investigators enrolled ambulatory patients with Duchenne muscular dystrophy between 4 and 7 years of age. Initially, half of patients received Elevidys, while the remainder received placebo. In the second part of the study, patients who had received placebo "crossed over" and were treated with Elevidys after one year.
Although patients who received the gene therapy in the first part of the study improved on the NSAA compared to the placebo group after one year, the difference fell short of reaching statistical significance. That's because the placebo group's scores didn't decline as much as expected, the Sarepta executives said.
When presenting that data in 2023, Sarepta noted that the results from the clinical trial did meet statistical significance on secondary endpoints such as time to rise (TTR) and a walk test.
A year was too short a period of time to observe a functional decline among the roughly 60 patients in the placebo group, Ingram and Rodino-Klapac said Monday. Now, Sarepta is measuring improvements after two years for the first set of patients, and the initially treated group as well as the second group of crossover patients who only have one year of posttreatment data are being compared to a larger external control group of several hundred patients.
Two years after treatment and compared with an external control group, investigators have observed sustained benefits in patients who received Elevidys in the first part of the study. For example, these patients tended to improve by 2.88 points on the NSAA in the time frame between one and two years posttreatment compared to a group of matched external controls drawn from five other Duchenne muscular dystrophy studies. That indicates that the disease trajectory for patients treated with the gene therapy continues to diverge and improve, compared to the disease's typical progression over time.
Patients also experienced improvements on function tests, including TTR, with an improvement of 2.06 seconds, and a 10-meter walk/run test (10MWR), with an improvement of 1.36 seconds, compared to the external control group. Biopsies taken 64 weeks after treatment also showed sustained expression of microdystrophin compared to biopsies from 12 weeks posttreatment.
Additionally, MRI results showed minimal disease progression in underlying muscle pathology, indicating that the gene therapy was able to prevent muscle damage. That underscores the importance of early treatment to avoid damage that can't be reversed, Rodino-Klapac said.
All patients remained blinded throughout the first and second part of the EMBARK trial, with patients who originally received Elevidys receiving placebo at the start of the second portion.
The crossover patients who then received Elevidys also experienced functional improvements despite being a year older on average than those who were treated in the first part of the clinical trial.
On average, patients treated in the second part of the study were 7.18 years of age, compared to 5.98 years of age in the first part of the clinical trial. Based on natural history studies, it's "extremely unlikely" for patients at age 7 to be gaining function, as they are typically losing functional ability by this age, Rodino-Klapac said.
The crossover patients tended to improve by 2.34 points on the NSAA by one year after treatment with Elevidys compared to the external control group. These patients also showed consistent improvements on function tests, including TTR and 10MWR.
For Cambridge, Massachusetts-based Sarepta, this evidence is compelling because it confirms benefits seen in earlier studies, but over two years and in a larger patient population, Ingram said. However, he doesn't expect this new data to have an immediate impact on sales of the gene therapy, since there's already been significant demand for it.
During the JP Morgan Healthcare Conference in San Francisco earlier this month, he touted Elevidys as "the most successful gene therapy launch in all of history" based on its early sales and said he expects its uptake to continue to grow. The company estimated, based on unaudited financial results, that Elevidys will net around $821.0 million in 2024 revenue.
As part of a collaboration agreement that Sarepta signed with Roche in 2019, Sarepta is responsible for regulatory approval and commercialization of Elevidys in the US, while Roche is responsible for these activities in other parts of the world. Elevidys has been approved in the United Arab Emirates, Qatar, Kuwait, Bahrain, and Oman, among other countries.
"This is really powerful additional evidence," Ingram said of the top-line results from EMBARK. "But we already have an enormous amount of demand, so I wouldn't see this as dramatically changing the uptake this year."