Safety and Efficacy of Ataluren in nmDMD Patients from Study 041, a Phase 3, Randomized, Double-Blind, Placebo-Controlled Trial
Craig M. McDonald1, Shiwen Wu2, Sheffali Gulati3, Hirofumi Komaki4, Rosa E. Escobar5, Anna Kostera-Pruszczyk6, Dmitry Vlodavets7, Jong-Hee Chae8, Yuh-Jyh Jong9, Peter Karachunski10, Jeffrey Statland11, Michelle Lorentzos12, Vinay Penematsa13, Connie Chou13, Min Lin13, Christian Werner14, Panayiota Trifillis13, Gregory Gordon13, Karyn Koladicz13, Nicholas Mastrandrea13, Matthew Klein13
1University of California Davis School of Medicine, 2The Third Medical Center of PLA General Hospital, 3All India Institute of Medical Sciences, 4National Center of Neurology and Psychiatry, 5National Institute of Rehabilitation, 6Department of Neurology, Medical University of Warsaw, 7Russian Children Neuromuscular Center, Veltischev Clinical Pediatric Research Institute of Pirogov Russian National Research Medical University, 8Seoul National University Hospital, 9Kaohsiung Medical University Chung-Ho Memorial Hospital, 10University of Minnesota, 11University of Kansas Medical Center, 12The Children’s Hospital at Westmead, 13PTC Therapeutics Inc., 14PTC Therapeutics Germany GmbH
Objective:

To describe the efficacy and safety results from the placebo-controlled phase of Study 041 (NCT03179631).

Background:

Duchenne muscular dystrophy (DMD) is a severe neuromuscular disorder caused by a lack of functional dystrophin. Ataluren promotes readthrough of an in-frame premature stop codon to produce full-length dystrophin and is indicated for the treatment of patients with nonsense mutation (nm) DMD. Study 041 (NCT03179631) is an international, phase 3, randomized, double-blind, placebo-controlled 72-week ataluren trial in patients with nmDMD followed by a 72-week open-label period.

Design/Methods:

Boys with nmDMD aged ≥5 years, on corticosteroids, and with a 6-minute walk distance (6MWD) ≥150m were eligible. The primary objective was to determine ataluren’s effect on ambulatory function, assessed by the 6-minute walk test. Boys were randomized 1:1 to ataluren:placebo. The intention-to-treat (ITT) population comprised randomized boys who received ≥1 dose of study treatment. Predefined subgroups included boys aged ≥7 to ≤16 years with ≥300m 6MWD and ≥5s stand from supine (primary) and boys with 300–400m 6MWD.

Results:

Ataluren and placebo groups in the ITT population and key subgroups were balanced according to enrolment age, baseline 6MWD, corticosteroid use and time to stand from supine. Significant differences in mean 6MWD change from baseline and rate of change favored ataluren in the ITT population (14.4m; 0.20m/week; p=0.0248) and 300–400m 6MWD subgroup (24.2m; 0.34m/week; p=0.0310), representing a 21% and 30% slowing of the decline rate in 6MWD in these groups, respectively. There were significant treatment benefits in time to 10% worsening of 6MWD. The number of ITT patients who lost ambulation receiving placebo was almost double that of those receiving ataluren. Ataluren was well tolerated, had no probable drug-related serious adverse events (AEs), and AE frequency (85.3%) was similar to placebo (84.7%).

Conclusions:

Study 041 confirms ataluren’s favorable risk-benefit as shown in previous clinical and real-world evidence studies.

10.1212/WNL.0000000000202505