Ataluren improves ambulation in nonsense mutation DMD

Treatment with ataluren improves ambulatory function, as assessed by the 6-minute walk distance (6MWD) test, among boys with nonsense mutation Duchenne muscular dystrophy (nmDMD), according to the subgroup analysis of Study 041 trial presented at AAN 2023.

“DMD is one of the most prevalent muscular dystrophies affecting about 1 in 3,500 to 1 in 5,000 male live births,” said Dr Jeffrey Statland from the University of Kansas Medical Center in Kansas City, Kansas, US, who presented the study. “It is due to loss of function mutations in the DMD gene leading to a loss of dystrophin, … leading to progressive weakness, loss of ambulation, and loss of upper extremity function.”

“Ataluren was one of our first molecularly targeted therapies designed to increase dystrophin, and there has been a number of clinical trials previously, including a phase IIB study and a prior phase III study,” he added.

The current second phase III, international, double-blind, placebo-controlled trial analysed 360 boys aged ≥5 years with nmDMD who were on a stable corticosteroid regimen for ≥12 months and had a 6MWD of ≥150 metres (m) at baseline. Participants were randomized in a 1:1 ratio to receive either ataluren or placebo for 72 weeks, followed by a 72-week open-label treatment. [AAN 2023, abstract PL5.001]

Participants were divided into three groups, which comprised boys who received ≥1 dose of the study treatment (ITT cohort) and predefined subgroups of boys with 6MWD of 300–400 m at screening (6MWD 300–400 m subgroup) and those aged ≥7 to ≤16 years with a baseline 6MWD of ≥300 m and a baseline supine-to-stand time of ≥5 seconds (primary analysis subgroup).

Treatment benefit
At week 72, patients treated with ataluren achieved statistically significant improvements in 6MWD from baseline compared with placebo in both the ITT population (-53.0 vs -67.4 m, 14.4 m difference; p=0.0248) and the 6MWD 300–400 m subgroup (-55.8 vs -80.0 m, 24.2 m difference; p=0.0310).

In addition, those in the ataluren arm had a 21- and 30-percent slower rate of decline in 6MWD than the placebo arm for both ITT and 6MWD 300–400 m cohorts, respectively.

In the primary analysis subgroup, although not statistically significant, ataluren-treated patients showed improvement in 6MWD at week 72 than the placebo-treated patients (-81.8 vs -90.1 m, 8.3 m difference; p=0.3626), with a 9-percent slowing of the decline in 6MWD.

In all subgroups of patients, fewer ataluren recipients reported loss of ambulation than placebo recipients at week 72 (6.6 percent vs 11.4 percent [ITT], 5.8 percent vs 12.0 percent [6MWD 300–400], and 5.4 percent vs 9.7 percent [primary analysis]). Of note, “overall loss of ambulation was a low-frequency event in this study,” said Statland.

Secondary outcomes
Ataluren-treated patients achieved significant improvements in NSAA* total and linear scores than the placebo-treated patients in the ITT population (difference, 0.9; p=0.0235 and 2.3; p=0.0246, respectively).

Significantly improved NSAA linear score was also observed among patients in the ataluren arm vs the placebo arm in the 6MWD 300–400 m subgroup (difference, 3.3; p=0.0419). Improved NSAA total score was also observed with ataluren vs placebo (difference, 1.1; p=0.0837), but the difference between groups was not statistically significant.

In terms of the timed function tests, a significant improvement in time taken for a 10-m walk/run was observed with ataluren over placebo in both the ITT population and 6MWD 300–400 m cohorts (difference, -0.8 seconds; p=0.0422 and -1.3 seconds; p=0.0429, respectively).

Significant improvements in the time to climb four stairs with ataluren vs placebo were seen across all groups (-1.1 seconds; p=0.0293 [ITT], -2.3 seconds; p=0.0050 [6MWD], and -1.7 seconds; p=0.0179 [primary analysis]).

“Overall, ataluren treatment resulted in significant benefit across several ambulatory endpoints in the ITT population … and a subgroup of patients with a baseline performance of 300–400 m in the 6MWD test,” said Statland.

“Study 041 confirms ataluren’s favourable risk-benefit as shown in previous clinical and real-world evidence studies,” they added.

Adverse events
The incidence of treatment-emergent adverse events (AEs) was comparable between groups, with 85 percent of patients in both groups reporting ≥1 AE.

The most commonly reported AEs with ataluren were vomiting (30 percent) and upper respiratory tract infection and nasopharyngitis (27 percent each), but all were considered mild or moderate.

“Ataluren was well tolerated without any drug-related serious AEs,” noted Statland.

*NSAA: North Star Ambulatory Assessment