With Sarepta’s gene therapy Elevidys now available to a majority of Duchenne muscular dystrophy patients, experts express cautious optimism while emphasizing the need for further data.
Since the June 2024 full approval and label expansion of Sarepta Therapeutics’ Elevidys, the Duchenne muscular dystrophy community has been clamoring for more information on the gene therapy to effectively treat patients. Earlier this month, Sarepta provided new data on Elevidys, but experts say the company did little to answer the open questions that remain.
First approved through the FDA’s accelerated approval pathway in June 2023, Elevidys missed the primary functional endpoint—change from baseline in North Star Ambulatory Assessment (NSAA) total score at week 52 following treatment—in the Phase III EMBARK trial four months later. The gene therapy did, however, hit key secondary endpoints, such as time to rise, a measurement again emphasized by the company during its presentations at the World Muscle Society meeting, held Oct. 8–12 in Prague.
Specifically, Sarepta presented five-year outcomes data from the first four patients treated with Elevidys compared to natural history projections, while two other studies looked at the gene therapy’s effects on the heart and skeletal muscles. In the five-year outcomes study, Sarepta reported that while there was a “slight increase” in the time it took Elevidys-treated patients to rise from the floor at five years vs. four years, they remained under the “critical 5-second threshold, which is known to predict early loss of ambulation,” according to a company spokesperson.
While Michael Kelly, chief scientific officer at CureDuchenne, said that the timed function tests suggest treatment with Elevidys was associated with a slower disease progression, he told BioSpace via email that the new study was “a small open-label trial, not powered for this analysis.”
Moreover, when it comes to the newly approved patient populations—non-ambulatory and older boys—experts see much bigger data gaps.
Data Wanted for New Patient Populations
Earlier this year, the FDA granted full approval for Elevidys in ambulatory DMD patients 4 years and older and accelerated approval for non-ambulatory patients. The initial label was much narrower, applying only to ambulatory patients 4 to 5 years of age.
But these label expansions were given with limited data, BioCentury’s Lauren Martz wrote in June. “Without published data, the risks and benefits are largely unknown to treating physicians, who are scrambling to find consensus on how to monitor older patients, and how to manage adverse events that may arise,” Martz wrote. Potential risks include liver toxicities associated with higher AAV doses.
Craig McDonald, chair of the Department of Physical Medicine & Rehabilitation at UC Davis Health, agreed that more efficacy data in this population is required. “I think we do still have limited data on the older ambulatory patients that are clearly in the skill-losing phase of the disease,” he told BioSpace. “I think it’ll be important to show that either there’s a significant reduction in the rate of slowing of disease progression or the patient’s actually showing stability and stabilization of their disease over time.”
Additionally, he said, cardiac function declines over time in DMD patients, and “we don’t have a lot of experience dosing patients with more impaired cardiac function.”
And while Sarepta touted the time-to-rise measurement in its Study 101 presentation, Courtney Rice, principal at Acadia Strategy Partners, noted that this measurement does not apply to wheelchair-bound non-ambulatory patients who can’t rise from the ground at all. This patient group is where Rice said the real demand for knowledge lays, and “this World Muscle data does little to fill the void.”
Despite the desire for further data, a recent survey conducted by TD Cowen showed that “although specialists’ views on Elevidys’ efficacy profile were mixed, 50% of them still plan to administer Elevidys to all DMD pts regardless of ambulation status.” However, 40% of surveyed specialists plan to prioritize ambulatory patients younger than 13 years.
Sarepta is currently conducting the confirmatory ENVISION trial in non-ambulatory patients and aims to complete enrollment in 2025. The trial’s primary endpoint is change from baseline in the total score of performance of upper limb at week 72.
Louise Rodino-Klapac, head of R&D and chief scientific officer at Sarepta, told BioSpace in an email that dosing is “well underway” in ENVISION, and the company is continuously monitoring safety. “We have seen a consistent safety profile as we have been dosing more older patients both clinically and commercially,” she said. A Sarepta spokesperson added in an email that the company is “committed to completing the study in 2027, and updates will be provided when they are meaningful.”
Study Limitations and Future Expectations
Kelly noted other limitations with Sarepta’s newly presented studies. One, he said, is that the five-year data came from only four patients in an open-label study “and it’s difficult to compare this small data set with results produced in later trials with [Elevidys].”
The second relates to differences in the manufacturing processes used in this early study compared to later trials, he said. The early process (Process A) used AAV-based purification that allowed near complete removal of empty AAV capsids from the final formulated product while the later process (Process B) used a scaled-up purification method that incorporated chromatography-based methods for separating empty capsids from full ones.
“The Process B purification method resulted in poor separation of empty AAV capsids from full AAV capsids,” Kelly said, affecting purity. “Patients received the same dose of transgene (as the dose was based on vector genomes), but it’s possible that the extra empty capsids in Process B material could interfere with transduction or safety.”
Sarepta also presented results from an MRI imaging study at the World Muscle Society meeting, but Kelly said these data did not indicate a significant functional advantage for DMD patients. More work is needed, he continued, to understand the risk/benefit profile of Elevidys and its long-term effect on muscles.
McDonald is looking for long-term durability data from Elevidys, which he noted is a one-time gene therapy infusion. “The patients develop antibodies to the viral transmission vector, so at this point in time, we can’t do redosing of them,” he said. “So . . . does this treatment stabilize disease for five years, six years, seven years, and potentially even beyond?”
Sarepta maintains that “Elevidys is having a significant and clinically meaningful impact for patients,” Rodino-Klapac said. “The biomarker and functional data repeatedly demonstrate that Elevidys stabilizes or slows the progression of DMD, regardless of age, weight or ambulatory status.”
However, Jeff Chamberlain, president of the American Society for Gene and Cell Therapy and the McCaw Chair in Muscular Dystrophy at the University of Washington School of Medicine, previously told BioSpace he is seeing mixed results with the Elevidys.
“We’re seeing most of the boys are doing better, but they’re not doing as much better as we were hoping they would,” he said. “I think it’s fairly effective in slowing down the progression of the dystrophy, and some of the patients are showing increased strength, but a lot of them are not.”
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