New data presented at the 2025 Muscular Dystrophy Association (MDA) Clinical & Scientific Conference in Dallas, Texas, reveals that eteplirsen (Exondys 51) significantly slows cardiac function decline and delays loss of ambulation in patients with Duchenne muscular dystrophy (DMD) amenable to exon 51 skipping.
The retrospective study marks the first demonstration of significant cardiac function preservation with a therapy designed to increase dystrophin expression, potentially changing the trajectory of cardiac complications in DMD patients.
Cardiac Benefits Demonstrated in Comprehensive Analysis
The analysis examined 122 eteplirsen-treated patients compared to 122 propensity-matched natural history controls with DMD amenable to exon 51 skipping. Researchers evaluated the risk of reaching left ventricular ejection fraction (LVEF) thresholds indicative of cardiac function decline.
Results showed striking differences between the treatment groups:
- No eteplirsen-treated patients reached an LVEF below 50%, compared with 22.1% of control patients
- Only 3.3% of treated patients reached LVEF below 55%, versus 27.1% of controls
- Just 10.7% of treated patients reached LVEF below 60%, compared to 49.2% of controls
The hazard ratio for time to first LVEF below 55% was 0.22 (95% CI, 0.07-0.66; P < .01), representing a 78% risk reduction for eteplirsen-treated patients. Similarly, the hazard ratio for LVEF below 60% was 0.40 (95% CI, 0.22-0.76; P < .01), indicating a 60% risk reduction.
"This study is the first to demonstrate significant change in measured cardiac function with an innovative therapy that aims to increase dystrophin expression, suggesting clinically meaningful multi-year delays in reaching cardiomyopathy milestones for treated patients," the study authors noted.
The annual rate of LVEF decline was also significantly slower among eteplirsen-treated patients (-0.66 percentage points per year) compared to controls (-1.38 percentage points per year).
Preservation of Mobility: EVOLVE Study Results
Complementing the cardiac findings, data from the phase 4 EVOLVE study presented at the same conference demonstrated eteplirsen's ability to delay loss of ambulation (LOA) in patients with DMD.
The study included 33 eteplirsen-treated patients and 75 external controls from five major studies. After adjusting for baseline differences through inverse probability treatment weighting, researchers found:
- 62% reduction in risk of LOA for eteplirsen-treated patients (hazard ratio 0.38, 95% CI, 0.18–0.82; P = .011)
- Median age at LOA was significantly higher for treated patients (15.3 years) compared to external controls (11.3 years)
- By age 15, treated patients had a 36% higher likelihood of remaining ambulant compared to controls
- The probability of remaining ambulant was 0.50 for eteplirsen-treated patients, versus just 0.14 for external controls
LOA was determined by patient-reported wheelchair use, North Star Ambulatory Assessment scores, and 10-meter walk/run scores, validated by attending physicians.
Study Methodology and Limitations
The cardiac analysis drew data from multiple clinical trials, including Study 201 (NCT01396239), Study 202 (NCT01540409), Study 203 (NCT02420379), Study 204 (NCT02286947), and Study 301 (NCT02255552). Natural history control data came from the Cooperative International Neuromuscular Research Group DMD Natural History Study, a Prospective Natural History Study of Progression of Subjects with DMD, and the French DMD Heart Registry.
The mean follow-up durations were 26.5 months for the DMD group and 69.3 months for the control group. Researchers acknowledged the potential limitations of using varied data sources but conducted validation analyses for potential sources of bias, including restricted mean survival time analysis and sensitivity analysis using alternate propensity score matching, which showed consistent results.
"All results consistently indicated a positive association between eteplirsen and significantly lower risk of LVEF decline for patients with DMD, including the post-matching time-to-event and trajectory analysis with adjustment for key cardiac prognostic factors," the authors concluded.
Clinical Implications
Eteplirsen was the first drug approved to treat patients with DMD based on data showing an increase in skeletal muscle dystrophin expression in patients with confirmed mutation of the dystrophin gene amenable to exon 51 skipping. However, until now, data on its impact on cardiac function had been lacking.
These findings suggest that eteplirsen may offer dual benefits by both preserving cardiac function and maintaining mobility longer than standard care alone. This comprehensive approach to addressing both cardiac and skeletal muscle manifestations of DMD could significantly impact disease management strategies and patient outcomes.
As evidence continues to accumulate, eteplirsen's impact on multiple aspects of DMD reinforces its potential as a cornerstone therapy in DMD management, potentially offering patients improved quality of life and extended functional independence.
Joel Iff, PharmD, PhD, executive director of global access, value and evidence at Sarepta Therapeutics, presented the cardiac findings at the conference, highlighting the significance of these results for the DMD community.
