Ataluren Confirms Benefit in Nonsense Mutation DMD With Significant Results in Subgroup Analysis


In a subgroup of patients with 300 m to 400 m 6MWD scores in the phase 3 Study 041, ataluren (Translarna; PTC Therapeutics) showed particular improvements from baseline.

Jeffrey Statland, MD, a professor of neurology at the University of Kansas Medical Center in Kansas City, Kansas

Jeffrey Statland, MD

Findings from the phase 3 Study 041 (NCT03179631) of ataluren (Translarna; PTC Therapeutics) confirm the therapy’s positive risk-benefit profile over a 72-week period in patients with Duchenne muscular dystrophy (DMD) and a nonsense mutation. The data align with the treatment’s established profile in prior clinical and real-world evidence studies.

Notably, compared with placebo, there were significant differences in mean 6-minute walk distance (6MWD) in both the intent-to-treat (ITT) population (ataluren, n = 183; placebo, n = 176) and the subgroup of boys with 300 m to 400 m 6MWD (ataluren, n = 86; placebo, n = 83).The change from baseline and rate of change favored ataluren in the ITT population (14.4 m; 0.20 m per week; P = .0248) and 300 m to 400 m 6MWD subgroup (24.2 m; 0.34 m per week; P = .0310). These findings, the authors noted, represented a 21% and 30% slowing of the decline rate in 6MWD in these groups, respectively.

In the primary analysis subgroup (ataluren, n = 92; placebo, n = 93) the change from baseline in 6MWD was –81.8 m and –90.1 m in the ataluren and placebo groups, respectively, for a difference of 8.3 m (P = .3626). This represented a 9% slowing of rate of decline.

The results were presented by Jeffrey Statland, MD, a professor of neurology at the University of Kansas Medical Center in Kansas City, Kansas, at the 2023 American Academy of Neurology (AAN) Annual Meeting, April 22-27, in Boston, Massachusetts. In Study 041, Statland and colleagues aimed to assess ataluren’s effect on ambulation specifically in this patient population. “Approximately 10% to 15% of patients with DMD have a nonsense mutation in the DMD gene, preventing the formulation of functional dystrophin protein. Ataluren promotes readthrough of the in-frame premature stop codon, enabling the production of full-length dystrophin,” they wrote.

In the ITT population, treatment with ataluren “resulted in significant benefits in time to 10% persistent worsening of 6MWD,” Statland and colleagues noted. This analysis included 95 patients (51.9%) in the ataluren group and 67 patients (38.1%) in the placebo group. The median time to 10% persistent worsening was 74.3 weeks (95% CI, 59.1-NA) for the ataluren group compared with 48.0 weeks (95% CI, 36.0-60.9) for the placebo group (log-rank P = .0078), for an HR of 0.7 (95% CI, 0.5-0.9).

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“The number of ITT patients who lost ambulation receiving placebo was almost double that of those receiving ataluren,” the authors wrote. Overall, loss of ambulation occurred in 12 patients (6.6%) in the ITT ataluren group and 20 patients (11.4%) in the ITT placebo group, with similar findings of 5 patients (5.8%) and 10 patients (12.0%) in the 300 m to 400 m 6MWD subgroup, respectively. In the primary analysis subgroup, 5 patients (5.8%) on ataluren and 9 patients (9.7%) on placebo reported loss of ambulation.

Of note, the 300 m to 400 m 6MWD subgroup experienced significant benefits on North Star Ambulatory Assessment (NSAA) scores and timed function test (TFT) scores. Specifically, Statland et al reported that the NSAA liner score between-group difference was 3.3 points (ataluren, –10; placebo, –13.3; P = .0419), while total score between-group difference was 1.1 points (ataluren, –4.4; placebo, –5.5; P = .0837).

Of the 3 components of TFT score, 2 were significant between groups. The 10 m run/walk score between-group difference was –1.3 points (ataluren, 2.99; placebo, 4.28; P = .0429); the 4-stair climb between-group difference was –2.3 points (ataluren, 5.26; placebo, 7.55; P = .0050); and the 4-stair descent between-group difference was –1.0 points (ataluren, 4.62; placebo, 5.59; P = .2714).

At baseline, in the ITT population randomly assigned to ataluren, 6MWD was less than 300 m for 21 individuals (11.5%), between 300 m and 350 m for 40 individuals (21.9%), between 350 m and 399 m for 46 individuals (25.1%), and 400 m or great for 76 individuals (41.5%). In the placebo group, those respective breakdowns included similar numbers, at 21 (11.9%), 37 (21%), 46 (26.1%), and 72 individuals (40.9%). The baseline time to stand from supine was less than 5 seconds for 62 patients (33.9%) and 55 patients (31.3%) in the ataluren and placebo ITT groups, respectively. Both ataluren and placebo groups had 121 patients (ataluren, 66.1%; placebo, 68.8%) with a baseline time to stand from supine of 5 seconds or greater. The number of individuals with a sub-5 second time to stand from supine for the 300 m to 400 m subgroup was 16 (18.6%) for those given ataluren and 15 (18.1%) for those on placebo, with 70 and 68 (81.9% for both groups) patients having baseline times of 5 seconds or greater, respectively.

As for safety, “ataluren was well tolerated, with AE [adverse event] frequency shown to be similar between patients receiving ataluren vs placebo,” Statland et al wrote. There were no probable drug-related serious AEs, with AE frequency being 85.3% with ataluren and 84.7% with placebo. The most commonly occurring AEs with ataluren were vomiting, upper respiratory tract infection, and nasopharyngitis.

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1. McDonald CM, Wu S, Gulati S, et al. Safety and Efficacy of Ataluren in nmDMD Patients from Study 041, a Phase 3, Randomized, Double-Blind, Placebo-Controlled Trial. Presented at: AAN Annual Meeting; April 22-27, 2023; Boston, MA and Virtual. Neurology. doi:10.1212/WNL.00000000002025052
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