Since the full approval and label expansion of Sarepta Therapeutics’ Elevidys in June 2024, the Duchenne muscular dystrophy (DMD) community has been seeking more information to effectively treat patients. Recent data presentations by Sarepta have left experts wanting more, particularly regarding the efficacy and safety in newly approved patient populations.
Unmet Data Needs in Expanded Patient Groups
Elevidys initially received accelerated approval for ambulatory DMD patients aged 4 to 5 years, but the FDA later expanded the label to include ambulatory patients 4 years and older and granted accelerated approval for non-ambulatory patients. This expansion occurred despite limited data, raising concerns among physicians about monitoring older patients and managing potential adverse events, such as liver toxicities associated with higher adeno-associated virus (AAV) doses.
Craig McDonald, chair of the Department of Physical Medicine & Rehabilitation at UC Davis Health, noted the need for more efficacy data in older ambulatory patients, especially those in the skill-losing phase of the disease. He emphasized the importance of demonstrating a significant reduction in disease progression or stabilization over time. Additionally, he highlighted the lack of experience in dosing patients with impaired cardiac function, which declines over time in DMD.
Concerns Over Functional Measurements
Sarepta's presentation at the World Muscle Society meeting emphasized the time-to-rise measurement from Study 101. However, Courtney Rice, principal at Acadia Strategy Partners, pointed out that this measurement is irrelevant for non-ambulatory, wheelchair-bound patients. The demand for knowledge is particularly acute in this patient group, and the presented data did little to address it.
Mixed Specialist Views and Future Trials
A recent TD Cowen survey revealed mixed views among specialists regarding Elevidys' efficacy profile. While 50% plan to administer Elevidys to all DMD patients regardless of ambulation status, 40% intend to prioritize ambulatory patients younger than 13 years. Sarepta is currently conducting the confirmatory ENVISION trial in non-ambulatory patients, with enrollment expected to be completed in 2025. The primary endpoint is the 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, stated that dosing is well underway in ENVISION, and the company is continuously monitoring safety, observing a consistent safety profile in older patients. Sarepta anticipates completing the study in 2027.
Study Limitations and Long-Term Expectations
Michael Kelly, chief scientific officer at CureDuchenne, highlighted limitations in Sarepta’s presented studies, including the small sample size (four patients) in the five-year data from an open-label study. He also noted differences in manufacturing processes between early and later trials, with the early process (Process A) allowing near-complete removal of empty AAV capsids, while the later process (Process B) resulted in poorer separation, potentially affecting transduction or safety.
McDonald is looking for long-term durability data, given that Elevidys is a one-time gene therapy infusion. Patients develop antibodies to the viral transmission vector, precluding redosing. The critical question is whether the treatment stabilizes the disease for five, six, seven, or more years.
Jeff Chamberlain, president of the American Society for Gene and Cell Therapy, has observed mixed results with Elevidys, noting that while most boys are doing better, the improvement is not as significant as hoped. He believes the therapy effectively slows down the progression of the dystrophy, but increased strength is not consistently observed.
