Meta Analysis Shows Slow Decline of Muscle Function With Ataluren for Nonsense Mutation DMD


A new meta analysis of 3 studies presented at MDA 2024 revealed that ataluren significantly slowed the decline in muscle function for patients with nonsense mutation Duchenne muscular dystrophy.

Christian Werner, MD, executive director of Global Medical Affairs – Global DMD and Gene Therapy Lead at PTC Therapeutics

Christian Werner, MD

Credit: PTC Therapeutics

In a new meta analysis of a large, heterogeneous population from the intention-to-treat (ITT) populations of Study 041 (NCT03179631), Study 007 (NCT00592553), and the ACT DMD study (NCT01826487), findings showed that ataluren (Translarna; PTC Therapeutics) slowed decline in muscle function across multiple clinically meaningful end points compared with placebo for patients with nonsense mutation DMD (nmDMD).1

Among 354 patients treated with ataluren and 347 patients treated with the placebo, investigators observed statistically significant differences in change from baseline to week 48 in 6-minute walk distance (6MWD), timed function tests (TFTs), and the North Star Ambulatory Assessment (NSAA) scores between ataluren- and placebo-treated patients. 

The findings from the meta-analysis were presented at the 2024 Muscular Dystrophy Association (MDA) Clinical & Scientific Conference, held March 3-6, in Orlando, Florida, by lead author Christian Werner, MD, executive director of Global Medical Affairs and the Global DMD and Gene Therapy Lead at PTC Therapeutics, and colleagues. In the meta analysis, investigators used a weighted random-effects model and included ITT populations from Study 041, Study 007, and ACT DMD. The end points included changes from baseline to week 48 in 6MWD, TFTs, and NSAA total and linear scores (Study 041 and ACT DMD only). In addition, researchers assessed the mean 48-week change in 6MWD in a subgroup of patients with a baseline 6MWD score of 300 m to 400 m.

Top Clinical Takeaways

  • Ataluren demonstrated significant benefits in slowing 6-minute walk distance decline, timed function tests, and NSAA scores for patients with nmDMD.
  • The meta-analysis, presented at the 2024 MDA Conference, highlights ataluren's efficacy across diverse clinically meaningful endpoints.
  • Notably, in the 6MWD 300 m to 400 m subgroup, ataluren exhibited a 33.7-m change in decline compared with placebo (P <.0001).

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The differences observed favored ataluren (least-squares mean difference, 6MWD: 15.8m [P = .0032]; 10m walk/run: −1.1s [P = .0026]; climb 4 stairs: −1.3s [P = .0025]; descend 4 stairs: −1.3s [P = .0021]; NSAA total score: 1.1 [P = .0010]; NSAA linear score: 2.6 [P = .0036]). Additionally, in the 6MWD 300 m to 400 m subgroup, authors observed that ataluren significantly slowed 6MWD decline by 33.7 m compared with the placebo group (P <.0001).

Study 041 is an international, phase 3, randomized, double-blind, placebo-controlled 72-week trial of ataluren followed by a 72-week open-label period. Eligible participants with nmDMD were aged at least 5 years and with a 6MWD at least 150 m were randomly assigned 1:1 to receive ataluren or placebo. The ITT population comprised patients who received at least 1 dose of the study treatment.

In an additional dataset from Study 041 presented at MDA 2024, with analysis conducted by Werner and colleagues, results showed that ataluren treatment delayed clinically meaningful milestones of nmDMD progression that are predictive of ambulatory decline at 72 weeks.2 In this analysis, investigators assessed the effects of ataluren on persistent 10% or 5% worsening and 30-m decline in 6MWD in patients with DMD. The predefined subgroups included patients with baseline 6MWD of 300 m to 400 m, and patients with baseline 6MWD of at least 300 m and stand from supine of at least 5 seconds.

In the ITT population (ataluren, n = 183; placebo, n = 176), investigators observed a significant reduction in the risk of persistent 10% and 5% worsening in 6MWD by 31% (P = .0078) and 30% (P= .0082), respectively, and 30-m decline by 31% (P = .0067), compared with placebo. In the 6MWD 300 m to 400 m subgroup, researchers reported ataluren significantly reduced the risk of persistent 10% and 5% worsening in 6MWD by 47% (P = .0011) and 42% (P= .0029), respectively, and 30 m decline by 47% (P = .0009), compared with placebo. Additionally, the authors noted a trend towards reduced risk of 10% persistent worsening in 6MWD for patients treated with ataluren compared with placebo in the primary analysis subgroup, although it did not reach statistical significance (P = .0659).

Ataluren, a protein restoration therapy for patients with nmDMD, was originally approved in Europe under conditional circumstances in 2014.3 The treatment is a small molecule treatment that allows for stop-codon read-through to produce dystrophin in patients with nonsense mutations, which affects up to 15% of DMD diagnoses. Ataluren gained a conditional nod in Europe based on data from Study 007. In the trial, those on ataluren doses of 10 mg/kg and 20 mg/kg (n = 57) showed favorable, but not statistically significant, differences vs placebo on the primary end point of change in 6MWD at week 48. Secondary end points, which included timed function tests, showed meaningful differences between ataluren 10 mg/kg and 20 mg/kg and placebo.4

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1. Werner C, Jong YJ, Karachunski P, et al. Ataluren slows the decline of muscle function in patients with nmDMD: a meta-analysis of three randomized, double-blind, placebo-controlled trials. Presented at: 2024 MDA Clinical and Scientific Conference; March 3-6; Poster M167.
2. Werner C, Wu S, Gulati S, et al. Ataluren delays clinically meaningful milestones of decline in 6MWD in patients with nmDMD from Study 041, a phase 3, placebo-controlled trial. Presented at: 2024 MDA Clinical and Scientific Conference; March 3-6; Poster M166.
3. CHMP issues negative opinion for renewal of conditional marketing authorization for Translarne (ataluren) following re-examination procedure. News release. PTC Therapeutics. January 25, 2024. Accessed March 2, 2024.
4. Bushby K, Finkel R, Wong B, et al. Ataluren treatment of patients with nonsense mutation dystrophinopathy. Muscle & nerve. 2014;50(4):477-487. doi:10.1002/mus.24332
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