Ataluren Preserves Upper Limb Function in nmDMD Patients from Study 041, a Phase 3 Placebo-Controlled Trial, and the STRIDE Registry
Craig M. McDonald1, Eugenio Mercuri2, Francesco Muntoni3, Heather Gordish-Dressman4, Lauren P. Morgenroth5, Maria Bernadete Dutra de Resende6, Shuizhen Zhou7, Mathukumalli Lakshmi Neeharika8, Kazuhiro Haginoya9, Leigh Ramos-Platt10, Paula Williams11, Vinay Penematsa11, Connie Chou11, Min Lin11, Shelley Johnson11, Karyn Koladicz11, Nicholas Mastrandrea11, Christian Werner12, Panayiota Trifillis11
1University of California Davis School of Medicine, 2Department of Pediatric Neurology, Catholic University, 3UCL Institute of Child Health, 4Center for Genetic Medicine, Children’s National Health System and the George Washington, 5Therapeutic Research in Neuromuscular Disorders Solutions (TRiNDS), 6Faculdade de Medicina, Departamento de Neurologia, Universidade de São Paulo, 7Department of Neurology, Children's Hospital of Fudan University & National Children Medical Center, 8Department of Neurology, Nizam’s Institute of Medical Sciences, 9Miyagi Children'S Hospital, 10Department of Pediatrics, Keck School of Medicine, University of Southern California and Children's Hospital of Los Angeles, 11PTC Therapeutics Inc., 12PTC Therapeutics Germany GmbH
Objective:

To assess performance of upper limb (PUL) function in patients with nonsense mutation Duchenne muscular dystrophy (nmDMD) receiving ataluren plus standard of care (SoC) in Study 041 (NCT03179631) and in the STRIDE Registry (NCT02369731).

Background:

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 nmDMD. Study 041 (NCT03179631) is a phase 3, double-blind, placebo-controlled 72-week trial. The STRIDE Registry (NCT02369731) is an ongoing, long-term, real-world evidence study.

Design/Methods:

In Study 041, boys with nmDMD aged ≥5 years, on a stable corticosteroid regimen, and with a 6-minute walk distance (6MWD) ≥150m were randomized 1:1, ataluren:placebo. The intention-to-treat (ITT) population comprised randomized boys who received at least one dose of study treatment (N=359; mean age 8.1 years); a key subgroup included those with baseline 300–400m 6MWD (n=169). STRIDE patients were propensity-score matched to patients receiving SoC alone in CINRG DNHS (NCT00468832), yielding a comparable population (N=261). Kaplan-Meier analyses estimated age at loss of upper limb function.

Results:

Least-squares mean PUL total score change from baseline to week 72 (by MMRM analysis) numerically favored ataluren versus placebo (0.44, p=0.1059) in the Study 041 ITT population and was significant in the 300–400m 6MWD subgroup (1.02, p=0.0165).

In matched STRIDE versus CINRG patients (mean last assessment age, 13.1 versus 14.6), ataluren preserved hand-to-mouth function by 3.4 years (p=0.0046) as assessed by entry level items of PUL versus Brooke Scale, respectively. Median age at loss of overhead reach numerically favored STRIDE, consistent with the overall trend (15.8 versus 12.6; p=0.2872). Median age at loss of distal hand function was non-estimable for STRIDE patients.  

Conclusions:

These results indicate that ataluren may help preserve upper limb function in patients with advanced nmDMD.

10.1212/WNL.0000000000202507