Comparative Analysis of Loss of Ambulation in Eteplirsen-Treated Patients With DMD in the EVOLVE Study and Propensity Score–Weighted External Controls

Topic:

Other

Poster Number: P103

Author(s):

Katherine Mathews, MD, University of Iowa, Shannon Grabich, PhD, MS, Sarepta Therapeutics, Inc., Cambridge, MA, USA, Sai Dharmarajan, Sarepta Therapeutics, Inc., Cambridge, MA, USA, Kathryn DeYoung, Sarepta Therapeutics, Inc., Cambridge, MA, USA, Craig Zaidman, MD, Washington University in Saint Louis, Saint Louis, MO, USA, Megan A. Waldrop, MD, Nationwide Children’s Hospital, Columbus, OH, USA, Craig M McDonald, MD, University of California, Davis Health, on behalf of the EVOLVE study group, N/A

Background: The Phase 4 EVOLVE study (NCT06606340) evaluates phosphorodiamidate morpholino oligomers for males with Duchenne muscular dystrophy (DMD) in routine clinical practice. The average age at loss of ambulation (LOA) in patients with exon 51 skip-amenable DMD is ~12 years.

Objectives: To examine the effect of eteplirsen on LOA by comparing patients from EVOLVE to propensity score–weighted external controls (ECs) receiving standard-of-care corticosteroids.

Methods: The study population included male, exon 51 skip-amenable DMD patients ambulant at baseline. Key baseline confounders were balanced in the eteplirsen-treated and EC groups using inverse probability treatment weighting (IPTW), including age (4–7 or 8+ years), corticosteroid use duration (≥1 or <1 year), 10-meter walk/run (10MWR) time velocity, and rise from floor velocity. LOA was defined as the earliest date of patient-/caregiver-reported continuous wheelchair use, verified by attending physician, North Star Ambulatory Assessment walk score of 0 or 10MWR score of ≥30 (if available), or inability to perform 10MWR, and not a temporary event. Results: 33 eteplirsen-treated patients and 75 ECs, derived from 5 EC groups (CINRG-DNHS, FOR-DMD, PRO-DMD-01, Leuven NMRC, Italian DMD Telethon) met inclusion criteria. After IPTW, LOA occurred in 21/33 eteplirsen-treated patients (13.5/100 patient-years [PY]; 4.7-year mean follow-up) and 19/33 weighted ECs (20.8/100 PY; 2.9-year mean follow-up). For those who experienced LOA through the interim analysis, median (95% CI) age at LOA by Kaplan-Meier analysis was 15.3 (11.4–15.8) years in eteplirsen-treated patients vs 11.3 (8.0–12.8) years in ECs. Cox proportional hazard regression analysis suggested eteplirsen reduced LOA risk by 62% (95% CI, 20–82; P=0.011) across the lifespan. We also analyzed patient differences at age 15 for an understanding of eteplirsen treatment impact at a critical point of disease progression. Nonparametric analysis estimated that the probability (95% CI) of remaining ambulant was 0.50 (0.32–0.69) and 0.14 (–0.06 to 0.34) at age 15 for eteplirsen-treated patients and ECs, respectively. Treatment with eteplirsen provided a 36% (95% CI, 9–63) higher likelihood of remaining ambulant by age 15. Conclusions: This interim analysis shows a clinically and statistically significant delay in LOA in eteplirsen-treated patients vs ECs using advanced methods to reduce confounding in a real-world setting.