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Research Article
22 August 2025

Confirmatory long-term efficacy and safety results of ataluren in patients with nmDMD from Study 041, an international, randomized, double-blind, placebo-controlled, Phase III trial

Authors: Dmitry Vlodavets https://orcid.org/0000-0003-2635-2752 [email protected], Shiwen Wu, Anna Kostera-Pruszczyk, Jong-Hee Chae, Sheffali Gulati, Jin-Hong Shin, Michelle Lorentzos, … Show All … , Anita Cairns, Yuh-Jyh Jong, Hirofumi Komaki, Jeffrey Statland, Alexandra Prufer de Queiroz Campos Araujo, Juliana Gurgel-Giannetti, Yasuhiro Takeshima, Rosa E Escobar Cedillo, Peter Karachunski, Kazuhiro Haginoya, Vinay Penematsa, Connie Chou, Paula Williams, Christian Werner, and Craig M McDonaldAuthor Info & Affiliations
Volume 14, Number 10
https://doi.org/10.57264/cer-2024-0238
PDFFormats

Abstract

Aim: To report the efficacy and safety of ataluren in patients with nonsense mutation Duchenne muscular dystrophy (nmDMD) from the phase III, 72-week, placebo-controlled period of Study 041. Materials & methods: Inclusion criteria: boys with nmDMD aged ≥5 years, on a stable corticosteroid regimen for ≥12 months, and baseline 6-minute walk distance (6MWD) ≥150 m. Randomization: 1:1, ataluren (40 mg/kg/day):placebo. Primary end point: slope of 6MWD change (average rate of change). Secondary end points: changes in 6MWD, time to 10% persistent worsening in 6MWD, North Star Ambulatory Assessment score, timed function tests and safety. Study populations: intention-to-treat; patients aged ≥7 to ≤16 years with baseline 6MWD ≥300 m and stand from supine ≥5 s; patients with baseline 6MWD 300–400 m. Results: In the intention-to-treat population (n = 359), over 72 weeks, ataluren reduced the rate of 6MWD decline by 21% (p = 0.0248), reduced the average 6MWD change (p = 0.0248), delayed time to 10% persistent worsening in 6MWD (p = 0.0078), and reduced North Star Ambulatory Assessment total score decline (p = 0.0235), change in 10 m walk/run time (p = 0.0422) and change in time to climb four stairs (p = 0.0293) versus placebo. In the 6MWD 300–400 m subgroup (n = 169), ataluren reduced the rate of 6MWD decline by 30% (p = 0.0310) versus placebo. Ataluren treatment benefits were seen in secondary end points in this subgroup, except for change in time to descend four stairs. In the 6MWD ≥300 m and time to stand from supine ≥5s subgroup (n = 185), there was a 9% slower rate of 6MWD decline for ataluren versus placebo over 72 weeks (p = 0.3626). Ataluren reduced change in time to climb four stairs (p = 0.0179) versus placebo in this subgroup; no treatment benefits were seen for other secondary end points. Ataluren was well tolerated (serious adverse events: ataluren, 7.1%; placebo, 6.8%); no deaths occurred. Conclusion: Long-term ataluren treatment has a favorable benefit–risk profile, slowing motor function decline in the largest phase III nmDMD study to date.

Plain language summary: Results from a phase III clinical trial describing the effect of treatment with ataluren on muscle function decline & assessing its safety in patients with nmDMD

What is this article about?

This article describes findings from Study 041. Study 041 was a clinical trial that aimed to confirm if ataluren, a treatment for people with nonsense mutation Duchenne muscular dystrophy (nmDMD), worked compared with placebo (a substance with no therapeutic effect) in a large number of participants with nmDMD over a period of 72 weeks. Ataluren has previously been compared with placebo in 48-week clinical trials. The aim of Study 041 was to confirm if ataluren slows muscle function decline compared with placebo and to assess ataluren safety results over 72 weeks.

What were the results?

In a group of 359 participants, ataluren slowed the decline in the participants’ ability to walk, physical function and ability to perform everyday activities that rely on lower limbs and upper limbs compared with placebo over 72 weeks. There were no safety concerns associated with taking ataluren. Results from this study were similar to those from previous ataluren clinical trials.

What do the results of the study mean?

These results helped to confirm that ataluren slows muscle function decline compared with placebo, without safety concerns, in participants with nmDMD over 72 weeks in the largest phase III study of nmDMD yet.

Supplementary Material

File (supplementary appendix.docx)
File (supplementary figures.pdf)
File (supplementary tables.docx)

References

Papers of special note have been highlighted as: • of interest; •• of considerable interest
1.
Birnkrant DJ, Bushby K, Bann CM et al. Diagnosis and management of Duchenne muscular dystrophy, part 1: diagnosis, and neuromuscular, rehabilitation, endocrine, and gastrointestinal and nutritional management. Lancet Neurol. 17(3), 251–267 (2018).
PubMed
Google Scholar
2.
Bello L, Pegoraro E. Genetic diagnosis as a tool for personalized treatment of Duchenne muscular dystrophy. Acta Myol. 35(3), 121–127 (2016).
PubMed
Google Scholar
3.
Pichavant C, Aartsma-Rus A, Clemens PR et al. Current status of pharmaceutical and genetic therapeutic approaches to treat DMD. Mol. Ther. 19(5), 830–840 (2011).
PubMed
Google Scholar
4.
Welch EM, Barton ER, Zhuo J et al. PTC124 targets genetic disorders caused by nonsense mutations. Nature 447(7140), 87–91 (2007).
PubMed
Google Scholar
•• Describes ataluren's mechanism of action including its oral bioavailability and pharmacological properties.
5.
Haas M, Vlcek V, Balabanov P et al. European Medicines Agency review of ataluren for the treatment of ambulant patients aged 5 years and older with Duchenne muscular dystrophy resulting from a nonsense mutation in the dystrophin gene. Neuromuscul. Disord. 25(1), 5–13 (2015).
PubMed
Google Scholar
6.
Bushby K, Finkel R, Wong B et al. Ataluren treatment of patients with nonsense mutation dystrophinopathy. Muscle Nerve 50(4), 477–487 (2014).
PubMed
Google Scholar
•• Reports findings from a phase IIb, randomized, double-blind, placebo-controlled, multicenter trial of ataluren in patients with nonsense mutation Duchenne muscular dystrophy (nmDMD) aged 5 years or older.
7.
Campbell C, Barohn RJ, Bertini E et al. Meta-analyses of ataluren randomized controlled trials in nonsense mutation Duchenne muscular dystrophy. J. Comp. Eff. Res. 9(14), 973–984 (2020).
PubMed
Google Scholar
•• Reports results from meta-analyses of two randomized, placebo-controlled trials of ataluren in patients with nmDMD (phase IIb and phase III).
8.
McDonald CM, Campbell C, Torricelli RE et al. Ataluren in patients with nonsense mutation Duchenne muscular dystrophy (ACT DMD): a multicentre, randomised, double-blind, placebo-controlled, Phase III trial. Lancet 390(10101), 1489–1498 (2017).
PubMed
Google Scholar
•• Reports findings from a phase III, randomized, double-blind, placebo-controlled, multicenter trial of ataluren in patients with nmDMD aged 7–16 years.
9.
Mercuri E, Muntoni F, Osorio AN et al. Safety and effectiveness of ataluren: comparison of results from the STRIDE Registry and CINRG DMD Natural History Study. J. Comp. Eff. Res. 9(5), 341–360 (2020).
PubMed
Google Scholar
10.
Mercuri E, Osorio AN, Muntoni F et al. Safety and effectiveness of ataluren in patients with nonsense mutation DMD in the STRIDE Registry compared with the CINRG Duchenne Natural History Study (2015–2022): 2022 interim analysis. J. Neurol. 1–18 (2023).
Google Scholar
•• Reports real-world data on the safety and effectiveness of ataluren in patients with nmDMD from the Strategic Targeting of Registries and International Database of Excellence (STRIDE) Registry, from the January 2022 data cut.
11.
Muntoni F, Desguerre I, Guglieri M et al. Ataluren use in patients with nonsense mutation Duchenne muscular dystrophy: patient demographics and characteristics from the STRIDE Registry. J. Comp. Eff. Res. 8(14), 1187–1200 (2019).
PubMed
Google Scholar
12.
Straub V, Mercuri E, Aartsma-Rus A et al. Report on the workshop: meaningful outcome measures for Duchenne muscular dystrophy, London, UK, 30–31 January 2017. Neuromuscul. Disord. 28(8), 690–701 (2018).
PubMed
Google Scholar
13.
Arora H, Willcocks RJ, Lott DJ et al. Longitudinal timed function tests in Duchenne muscular dystrophy: imaging DMD cohort natural history. Muscle Nerve 58(5), 631–638 (2018).
PubMed
Google Scholar
14.
Goemans N, Vanden Hauwe M, Signorovitch J et al. Individualized prediction of changes in 6-minute walk distance for patients with Duchenne muscular dystrophy. PLoS One 11(10), e0164684 (2016).
PubMed
Google Scholar
15.
McDonald CM, Henricson EK, Abresch RT et al. The 6-minute walk test and other endpoints in Duchenne muscular dystrophy: longitudinal natural history observations over 48 weeks from a multicenter study. Muscle Nerve 48(3), 343–356 (2013).
PubMed
Google Scholar
• Determines the natural history of clinical measures of disease progression in ambulatory patients with Duchenne muscular dystrophy (DMD), estimates the probability and predictors of clinically meaningful disease progression (defined as persistent 10% worsening in 6-minute walk distance [6MWD]), and assesses the relationship between 6MWD and loss of ambulation from a phase IIb trial.
16.
Mayhew A, Cano S, Scott E et al. North Star Clinical Network for Neuromuscular Disease. Detecting meaningful change using the North Star Ambulatory Assessment in Duchenne muscular dystrophy. Dev. Med. Child Neurol. 55(11), 1046–1052 (2013).
PubMed
Google Scholar
17.
Mayhew A, Cano S, Scott E et al. Moving towards meaningful measurement: Rasch analysis of the North Star Ambulatory Assessment in Duchenne muscular dystrophy. Dev. Med. Child Neurol. 53(6), 535–542 (2011).
PubMed
Google Scholar
18.
McDonald C, Duong T, Henricson E et al. P. 2.11 CINRG Duchenne Natural History Study: relationship of longitudinal measures of ambulatory timed function tests and loss of clinical milestones. Neuromuscul. Disord. 23(9), 752 (2013).
Google Scholar
19.
McDonald CM, Henricson EK, Abresch RT et al. The 6-minute walk test and other clinical endpoints in Duchenne muscular dystrophy: reliability, concurrent validity, and minimal clinically important differences from a multicenter study. Muscle Nerve 48(3), 357–368 (2013).
PubMed
Google Scholar
20.
Bohannon RW, Crouch R. Minimal clinically important difference for change in 6-minute walk test distance of adults with pathology: a systematic review. J. Eval. Clin. Pract. 23(2), 377–381 (2017).
PubMed
Google Scholar
21.
Mazzone E, Martinelli D, Berardinelli A et al. North Star Ambulatory Assessment, 6-minute walk test and timed items in ambulant boys with Duchenne muscular dystrophy. Neuromuscul. Disord. 20(11), 712–716 (2010).
PubMed
Google Scholar
22.
Ayyar Gupta V, Pitchforth JM, Domingos J et al. Determining minimal clinically important differences in the North Star Ambulatory Assessment (NSAA) for patients with Duchenne muscular dystrophy. PLoS One 18(4), e0283669 (2023).
PubMed
Google Scholar
23.
Dang UJ, Damsker JM, Guglieri M et al. Efficacy and safety of vamorolone over 48 weeks in boys with Duchenne muscular dystrophy: a randomized controlled trial. Neurology 102(5), e208112 (2024).
PubMed
Google Scholar
24.
McDonald CM. Timed function tests have withstood the test of time as clinically meaningful and responsive endpoints in Duchenne muscular dystrophy. Muscle Nerve 58(5), 614–617 (2018).
PubMed
Google Scholar
25.
Rothwell PM. Treating individuals 2. Subgroup analysis in randomised controlled trials: importance, indications, and interpretation. Lancet 365(9454), 176–186; 17709-5 (2005).
Google Scholar
26.
McDonald CM, Marden JR, Shieh PB et al. Disease progression rates in ambulatory Duchenne muscular dystrophy by steroid type, patient age and functional status. J. Comp. Eff. Res. 12(4), e220190 (2023).
PubMed
Google Scholar
27.
McDonald CM, Muntoni F, Penematsa V et al. Ataluren delays loss of ambulation and respiratory decline in nonsense mutation Duchenne muscular dystrophy patients. J. Comp. Eff. Res. 11(3), 139–155 (2021).
PubMed
Google Scholar
28.
Zambon AA, Ayyar Gupta V, Ridout D et al. Peak functional ability and age at loss of ambulation in Duchenne muscular dystrophy. Dev. Med. Child Neurol. 64(8), 979–988 (2022).
PubMed
Google Scholar
• Investigates the relationship between functional abilities and age at loss of ambulation in patients with DMD.
29.
Ebrahimi-Fakhari D, Dillmann U, Flotats-Bastardas M et al. Off-label use of ataluren in four non-ambulatory patients with Duchenne muscular dystrophy: effects on cardiac and pulmonary function and muscle strength. Front. Pediatr. 6316 (2018).
Google Scholar
30.
Roy B, Friesen WJ, Tomizawa Y et al. Ataluren stimulates ribosomal selection of near-cognate tRNAs to promote nonsense suppression. Proc. Natl Acad. Sci. U.S.A. 113(44), 12508–12513 (2016).
PubMed
Google Scholar
31.
Bettica P, Petrini S, D'Oria V et al. Histological effects of givinostat in boys with Duchenne muscular dystrophy. Neuromuscul. Disord. 26(10), 643–649 (2016).
PubMed
Google Scholar
32.
Anjum AF, Anjum MB, ur Rehman R. Unleashing the potential of givinostat: a novel therapy for Duchenne muscular dystrophy. Curr. Ther. Res., 102100787 (2025).
Google Scholar
33.
Fang Y, McDonald CM, Clemens PR et al. Modeling early heterogeneous rates of progression in boys with Duchenne muscular dystrophy. J. Neuromuscul. Dis. 10(3), 349–364 (2023).
PubMed
Google Scholar
34.
McDonald CM, Henricson EK, Abresch RT et al. Long-term effects of glucocorticoids on function, quality of life, and survival in patients with Duchenne muscular dystrophy: a prospective cohort study. Lancet 391(10119), 451–461 (2018).
PubMed
Google Scholar
|