ELEVIDYS Two-Year Durability Signal Expands Age Range But External-Control Design Caps Evidentiary Weight

ELEVIDYS Shows Functional Benefit in Older Duchenne Patients

Sarepta Therapeutics presented new data at the 2026 World Muscle Society Annual Congress for ELEVIDYS (delandistrogene moxeparvovec) in Duchenne muscular dystrophy. The analysis showed durable and clinically meaningful functional benefits over two years in older ambulatory patients aged 8-12, compared to an external control group, across measures like NSAA and timed function tests. Separately, robust micro-dystrophin expression and transduction efficiency were observed at 12 weeks in children aged 2 to under 3. The safety profile remained consistent across both analyses, with no new signals identified, expanding the evidence base for ELEVIDYS across different age groups of ambulant Duchenne patients.

• In ambulatory Duchenne patients aged 8-12 (n=25 from EMBARK and ENDEAVOR studies), ELEVIDYS treatment demonstrated durable and clinically meaningful functional benefits over two years compared to a well-matched external control group (n=99). Statistically significant differences were observed in NSAA (3.32 points, P=0.0022), Time to rise from floor velocity (0.041 rise/second, P=0.0019), and 10-meter walk run velocity (0.195 meters/second, P=0.0114) at both one and two years post-infusion.
• An analysis of ambulatory patients aged 2 to under 3 from the ENDEAVOR and ENVOL studies showed robust delandistrogene moxeparvovec-dystrophin expression and sarcolemmal localization 12 weeks after infusion. Higher overall mean and minimum micro-dystrophin expression (Western blot: 93.9% control in ENDEAVOR Cohort 6, 72.8% in ENVOL Cohort B) was observed in this younger cohort compared to previous results in older patients.
• The safety profile of delandistrogene moxeparvovec remained manageable and consistent with previously known data across all analyzed patient populations, with nausea and vomiting being the most common treatment-related adverse events. These new data, presented at WMS 2026, reinforce the potential of timely treatment with delandistrogene moxeparvovec to change the disease trajectory across a broader range of ambulatory Duchenne patients.

Durable Functional Benefits of ELEVIDYS in Older Ambulatory Duchenne Patients

Delandistrogene moxeparvovec has demonstrated sustained functional benefit over extended follow-up in ambulatory pediatric patients with DMD. In the open-label phase 1/2a Study 101 (NCT03375164), four patients (mean age 5.1 years) received a single intravenous infusion and were followed for 4 years. Mean North Star Ambulatory Assessment (NSAA) total score increased from 20.5 at baseline to 27.5 at year 4, representing a mean change of +7.0 (SD 2.9). A post hoc analysis against a propensity-score-weighted external control cohort demonstrated a statistically significant and clinically meaningful 9-point difference in NSAA score (least-squares mean [standard error] = 9.4 [3.4]; P = .0125). All 18 treatment-related adverse events occurred within 70 days post-treatment and resolved, supporting a favorable long-term safety profile.

The phase 2 double-blind crossover study SRP-9001-102 (Study 102; NCT03769116) further characterised durability of response up to 2 years post-treatment. SRP-9001 dystrophin expression was achieved in all patients, with mean change from baseline to Week 12 of 23.82% and 39.64% normal in Parts 1 and 2, respectively. In Part 1, the change from baseline to Week 48 in NSAA score was +1.7 (0.6) with treatment versus +0.9 (0.6) for placebo (p = 0.37) for the overall population; however, in 4- to 5-year-olds with matched baseline motor function, the difference was +2.5 points (p = 0.0172). In Part 2, comparison against a propensity-score-weighted external control cohort yielded a statistically significant least-squares mean difference of +2.0 points in NSAA score (p = 0.0009). A systematic review and meta-analysis encompassing 302 participants from 4 studies confirmed that, at 1 year, delandistrogene moxeparvovec significantly improved NSAA scores (MD = 2.48, p = 0.04), time to rise (MD = -0.85, p < 0.01), and muscle dystrophin content (MD = 28.39, p < 0.01).

For exon-skipping therapies, viltolarsen demonstrated stabilisation of time to stand from supine and time to run/walk 10 meters from baseline through Week 109, while a matched historical control group showed decline, with statistically significant differences at multiple timepoints. No treatment-related serious adverse events and no discontinuations were reported over more than 2 years of follow-up. Eteplirsen, targeting exon 51 skipping, showed evidence of durable dystrophin production at combined study Week 180, with Western blot analysis demonstrating an 11.6-fold increase in dystrophin content versus untreated controls (p = 0.007) and a 7.4-fold increase in percent dystrophin-positive fibers (p < 0.001). Across the broader DMD treatment landscape, glucocorticoids administered after loss of ambulation were associated with preserved late-stage functional abilities, respiratory function, and lower frequency of left ventricular ejection fraction <50%, with no significant differences observed between prednisone and deflazacort in these outcomes.

ELEVIDYS Micro-Dystrophin Expression and Early Insights in Young Duchenne Patients

Recent clinical evidence for delandistrogene moxeparvovec (ELEVIDYS) spans early-phase through pivotal trials, collectively characterizing its functional benefit and safety profile in ambulatory pediatric patients with DMD. Across studies, functional improvements measured by the North Star Ambulatory Assessment (NSAA) and timed function tests have been sustained over multiple years, while safety signals — primarily transaminase elevations and immune-mediated events — have remained manageable with appropriate monitoring and immunosuppression.

Consistent Safety Profile of ELEVIDYS Across Duchenne Patient Populations

Delandistrogene moxeparvovec has been evaluated across multiple clinical trials and real-world settings in ambulatory male patients with Duchenne muscular dystrophy (DMD), generating a substantial body of safety and tolerability data. Across studies spanning up to 5 years of follow-up, the overall safety profile has been characterized as manageable and consistent, with no treatment-related deaths or study discontinuations due to adverse events reported in the phase 3 EMBARK trial through week 104.

• Hepatotoxicity is the most clinically significant adverse event, ranging from transient liver enzyme elevations to, in rare cases, acute liver failure (ALF). In EMBARK, 7 patients (11.1%) experienced 10 treatment-related serious adverse events. Two fatal cases of ALF have been reported to date, both in nonambulatory patients aged 15 and 16 years, characterized by abrupt aminotransferase elevations approximately 4 weeks post-administration, followed by rising total bilirubin despite intervention. An expert panel concluded that no single biomarker consistently predicted progression from severe acute liver injury (ALI) to ALF, and recommended monitoring based on the rate and magnitude of changes from baseline — including a 2–3× increase in alanine aminotransferase within ≤1 week as a trigger for intervention. Intravenous methylprednisolone was the preferred initial treatment for severe ALI, while a case series of four patients demonstrated that adjunctive oral sirolimus (goal trough: 3–7 ng/ml) normalized gamma-glutamyl transferase and improved transaminases within two to four weeks in steroid-refractory hepatotoxicity.

• Cardiac safety, including myocarditis and troponin-I elevations, has been observed but was generally clinically mild. Across clinical trials 101, 102, ENDEAVOR, and EMBARK (N = 218 patients; follow-up ≤5 years), two cases of myocarditis were reported within 4 days of infusion, both resolving within 3 weeks. Troponin-I fluctuations outside these two cases were asymptomatic. Left ventricular ejection fraction (LVEF) remained >50% in all four patients with 5-year follow-up. A systematic review and meta-analysis (80 studies, 1,939 patients) reported a pooled myocarditis incidence rate of 8.6 per 100 patient-years (95% CI, 5.8–10.7), with myocardial injury peaking in week 1 and myocarditis occurring mostly after week 2; 87% of cases had no relevant clinical impact. In real-world data (n = 11), troponin-I elevations were observed in 3 patients, were asymptomatic, and showed no acute functional changes on echocardiogram.

• Gastrointestinal symptoms — including vomiting, decreased appetite, and nausea — were the most common treatment-related adverse events (TRAEs) in clinical trials, occurring predominantly within the first 90 days post-infusion and resolving in all cases. In real-world data (n = 11), gastrointestinal symptoms were reported in 7 of 11 patients.

• Immune-mediated myositis has been identified as a TRAE of clinical relevance. An interdisciplinary Delphi panel established consensus considerations for its evaluation and management alongside vomiting, acute liver injury, and myocarditis, recommending specialist consultation in all confirmed cases and individualized corticosteroid dosing based on risk-benefit assessment.

• Pre-existing anti-AAVrh74 immunity represents a tolerability consideration for patient selection. Practical guidance from clinical trial experience recommends screening for anti-AAVrh74 total binding antibody titers <1:400 prior to infusion. A nonhuman primate study demonstrated that 2–3 plasmapheresis exchanges reduced circulating anti-AAVrh74 antibodies and were well tolerated, with no abnormal clinical or immunological observations, suggesting a potential strategy for circumventing pre-existing immunity or enabling redosing.

• No new safety signals emerged between week 52 and week 104 in EMBARK, and no clinically significant complement-mediated adverse events were reported across the trial program through 2 years of follow-up, supporting the durability of the manageable safety profile observed in earlier assessments.

ELEVIDYS: Expanding the Horizon for DMD Gene Therapy

The latest data for ELEVIDYS represents a significant step forward in addressing the complex challenges of Duchenne muscular dystrophy (DMD) treatment. By demonstrating durable and clinically meaningful functional benefits over two years in older ambulatory patients aged 8-12, this gene therapy is showing promise beyond its initially approved age group. This expansion of evidence, coupled with robust micro-dystrophin expression observed in very young children (2 to under 3 years), suggests a broader applicability for ELEVIDYS across the ambulant DMD spectrum. Such findings are crucial for patients and clinicians, as they point to the potential for earlier intervention and sustained disease modification, which could significantly alter the natural history of this progressive condition.

From a strategic perspective, these results strengthen the case for potential label expansion, opening up a larger patient pool and reinforcing ELEVIDYS's competitive position in the nascent gene therapy market for DMD. The consistent safety profile, with no new signals identified, further supports its favorable risk-benefit assessment, which is vital for physician adoption and reimbursement discussions.

However, the journey for gene therapies is not without its considerations. While the safety profile remains consistent, immune-mediated adverse events such as myocarditis, acute liver injury, and immune-mediated myositis are known risks associated with adeno-associated virus (AAV) vector-based treatments. These necessitate rigorous patient selection, proactive immunoprophylaxis, and vigilant post-treatment monitoring to ensure patient safety. Furthermore, while two-year and even five-year data show sustained benefits, the ultimate long-term durability of micro-dystrophin expression and functional outcomes beyond these periods will require continued follow-up. The complexities of trial design, particularly managing baseline imbalances, also underscore the importance of robust methodologies like external control comparisons to accurately interpret treatment effects across diverse patient cohorts. As the evidence base continues to grow, optimizing patient selection and refining management protocols will be key to maximizing the therapeutic impact of ELEVIDYS for a wider range of Duchenne patients.