Dados do Trabalho

Título

Ataluren slows the decline of muscle function in patients with nmDMD: a meta-analysis of three randomized, double-blind, placebo-controlled trials

Introdução

Study 041 (NCT03179631) is an international, phase 3, randomized, double-blind, placebo-controlled 72-week trial of ataluren in patients with nonsense mutation DMD (nmDMD) followed by a 72-week open-label period.

Objetivo

To assess ataluren muscle function efficacy results from a meta-analysis of the Study 041 placebo-controlled phase and two randomized, double-blind, placebo-controlled, 48-week ataluren trials (Study 007 [phase 2b; NCT00592553] and ACT DMD [phase 3; NCT01826487]).

Método

In all three studies, boys were eligible if they had genetically confirmed nmDMD. The meta-analysis used a weighted random-effects model and included intention-to-treat populations from Study 041, Study 007 and ACT DMD. Endpoints included changes from baseline to week 48 in 6MWD, TFTs and NSAA total and linear scores (Study 041 and ACT DMD only); mean 48-week change in 6MWD was assessed in a subgroup of patients with baseline 6MWD 300–400m.

Resultados

The meta-analysis included 354 ataluren-treated patients and 347 placebo-treated patients. The differences in change from baseline to week 48 in 6MWD, TFTs and the NSAA scores between ataluren- and placebo-treated patients were statistically significant, favoring ataluren (least-squares mean difference; 6MWD: 15.8m, p=0.0032; 10m walk/run: −1.1s, p=0.0026; climb four stairs: −1.3s, p=0.0025; descend four stairs: −1.3s, p=0.0021; NSAA total score: 1.1, p=0.0010; NSAA linear score: 2.6, p=0.0036). In the 6MWD 300–400m subgroup, ataluren significantly slowed 6MWD decline by 33.7m versus placebo (p<0.0001).

Conclusão

In this meta-analysis of a large, heterogeneous population from the intention-to-treat populations of Study 041, Study 007 and ACT DMD, ataluren slowed decline in muscle function across multiple clinically meaningful endpoints versus placebo.

Referências

1.BirnkrantDJet al.Lancet Neurol2018;17:251–67.
2.Van Ruiten HJet al. Arch Dis Child2014;99:1074–7.
3.Bello L, Pegoraro Eet al.Acta Myol2016;35:122–7.
4.PichavantCet al.Mol Ther2011;19:830–40.
5.Roy Bet al.Proc Natl AcadSci USA2016;113:12508–13.
6.PTC Therapeutics International Ltd. Summary of product characteristics, Translarna. European Medicines Agency, 2023. Available from: https://www.ema.europa.eu/en/documents/product-information/translarna-epar-product-information_en.pdf(Accessed August 21, 2023).
7.McDonald CM et al. LSVP 26. NeuromusculDisord2022;32:S154–202.
8.McDonald CM et al. LSVP 37. NeuromusculDisord2022;32:S154–202.
9.BushbyK et al.MuscleNerve2014;50:477–87.
10.McDonaldCM et al. Lancet2017;390:1489–98.
11.ClinicalTrials.gov [Internet].Long-term outcomes of ataluren in Duchenne muscular dystrophy. Available from https://clinicaltrials.gov/study/NCT03179631 (Accessed August 21, 2023).
12.Campbell C et al.J CompEffRes2020;9:973–84.

Palavras Chave

DMD; ataluren; meta-analysis