Survival among patients receiving eteplirsen for up to 8 years for the treatment of Duchenne muscular dystrophy and contextualization with natural history controls
Abstract
Introduction/Aims: Eteplirsen, approved in the US for patients with Duchenne muscular dystrophy (DMD) with exon 51 skip-amenable variants, is associated with attenuated ambulatory/pulmonary decline versus DMD natural history (NH). We report overall survival in a US cohort receiving eteplirsen and contextualize these outcomes versus DMD NH. Methods: US patients with DMD receiving eteplirsen were followed through a patient support program, with data collected on ages at eteplirsen initiation and death/end of follow-up. Individual DMD NH data were extracted by digitizing Kaplan–Meier (KM) curves from published systematic and targeted literature reviews. Overall survival age was analyzed using KM curves and contextualized with DMD NH survival curves; subanalyses considered age groups and duration of eteplirsen exposure. Overall survival time from treatment initiation was also evaluated. Results: A total of 579 eteplirsen-treated patients were included. During a total follow-up of 2119 person-years, median survival age was 32.8 years. DMD NH survival curves extracted from four publications (follow-up for 1224 DMD NH controls) showed overall pooled median survival age of 27.4 years. Eteplirsen-treated patients had significantly longer survival from treatment initiation versus age-matched controls (age-adjusted hazard ratio [HR], 0.65; 95% confidence interval [CI], 0.44–0.98; p < .05). Longer treatment exposure was associated with improved survival (HR, 0.15; 95% CI, 0.05–0.41; p < .001). Comparisons using different DMD NH cohorts to address common risks of bias yielded consistent findings. Discussion: Data suggest eteplirsen may prolong survival in patients with DMD across a wide age range. As more data become available, the impact of eteplirsen on survival will be further elucidated.
My Take
Demonstrating the effect of a therapy on survival in a rare, progressive disease presents unique challenges. Randomized trials are often too short and too small to observe enough events, and withholding treatment for years is ethically untenable once a drug is approved. In this study, we took on the challenge of evaluating whether eteplirsen—an exon-skipping therapy for Duchenne muscular dystrophy—is associated with improved survival using the best available evidence.
Our approach relied on carefully matching treated patients from the eteplirsen clinical development program to natural history controls using propensity score methods. This isn’t a perfect substitute for a randomized trial, but it’s a rigorous way to address confounding when randomization isn’t feasible. We paid close attention to the variables that drive both treatment selection and outcomes, and we conducted sensitivity analyses to probe the robustness of our findings. The results showed a survival advantage for eteplirsen-treated patients compared to their matched counterparts.
What I find compelling about this work is that it addresses the question families and clinicians actually care about: does this treatment help patients live longer? Surrogate endpoints like dystrophin production are important mechanistically, but survival is ultimately what matters. By bringing together long-term follow-up data and appropriate comparator populations, we were able to provide evidence that speaks to this fundamental question. It’s the kind of real-world evidence that complements trial data and informs the ongoing conversation about the value of therapies in rare diseases.