Open-Label Evaluation of Eteplirsen in Patients with Duchenne Muscular Dystrophy Amenable to Exon 51 Skipping: PROMOVI Trial

Abstract

BackgroundEteplirsen received accelerated FDA approval for treatment of Duchenne muscular dystrophy (DMD) with mutations amenable to exon 51 skipping, based on demonstrated dystrophin production.ObjectiveTo report results from PROMOVI, a phase 3, multicenter, open-label study evaluating efficacy and safety of eteplirsen in a larger cohort.MethodsAmbulatory patients aged 7-16 years, with confirmed mutations amenable to exon 51 skipping, received eteplirsen 30 mg/kg/week intravenously for 96 weeks. An untreated cohort with DMD not amenable to exon 51 skipping was also enrolled.Results78/79 eteplirsen-treated patients completed 96 weeks of treatment. 15/30 untreated patients completed the study; this cohort was considered an inappropriate control group because of genotype-driven differences in clinical trajectory. At Week 96, eteplirsen-treated patients showed increased exon skipping (18.7-fold) and dystrophin protein (7-fold) versus baseline. Post-hoc comparisons with patients from eteplirsen phase 2 studies (4658-201/202) and mutation-matched external natural history controls confirmed previous results, suggesting clinically notable attenuation of decline on the 6-minute walk test over 96 weeks (PROMOVI: -68.9 m; phase 2 studies: -67.3 m; external controls: -133.8 m) and significant attenuation of percent predicted forced vital capacity annual decline (PROMOVI: -3.3%, phase 2 studies: -2.2%, external controls: -6.0%; p < 0.001). Adverse events were generally mild to moderate and unrelated to eteplirsen. Most frequent treatment-related adverse events were headache and vomiting; none led to treatment discontinuation.ConclusionsThis large, multicenter study contributes to the growing body of evidence for eteplirsen, confirming a positive treatment effect, favorable safety profile, and slowing of disease progression versus natural history.

Keywords: Muscular dystrophy; clinical trial; duchenne; phase 3; safety; treatment efficacy.

Fig. 1

Participant flow diagram and analysis subsets. Abbreviations: CINRG = Cooperative International Neuromuscular Research Group; DNHS = Duchenne Natural History Study (DNHS); FVC%p = percent predicted forced vital capacity; LOA = loss of ambulation; 6MWT = 6-minute walk test; NSAA = North Star Ambulatory Assessment. ^aEteplirsen studies 201 (NCT01396239) [24] and 202 (NCT01540409) [28]. ^bUntreated patients in the CINRG DNHS exon 51 cohort (age 10–18 years) [11]. ^cItalian DMD Telethon Registry [12, 25, 26] and the Leuven NMRC Registry [27].

Fig. 2

Exon 51 skipping by quantitative ddPCR (A), dystrophin protein quantification by western blot (B), percentage of dystrophin-positive fibers by IHC (C) and dystrophin intensity by IHC (D) from Baseline to Week 96 in eteplirsen-treated patients. Abbreviations: SE = standard error. ^*p < 0.05. ^†p < 0.001. ^aMean of individual patient fold changes. ^bp value is based on one-sample permutation t-test.

Fig. 3

Post-hoc analysis: Mean change from baseline to Week 96 in 6MWT (A), and FVC%p (B) in eteplirsen-treated patients and matched comparisons. Abbreviations: FVC%p = percent predicted forced vital capacity; 6MWT = 6-minute walk test; SE = standard error. ^aAt Weeks 12, 72, and 96 (n = 41). One patient did not have a value at Week 12, but had at later visits. Another patient withdrew after Week 48. ^bEteplirsen studies 201 (NCT01396239) [24] and 202 (NCT01540409) [28]. ^cItalian DMD Telethon Registry [12, 25, 26] and the Leuven NMRC Registry [27]. ^dUntreated patients in the CINRG DNHS exon 51 cohort (age 10–18 years) [11].