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, which then leads 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,” he added.

The current analysis included 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]

The intention-to-treat (ITT) population comprised boys who received ≥1 dose of the study treatment. Predefined subgroups included 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).

Boys in the ataluren arm had a 21- and 30-percent slower rate of decline in 6MWD for both ITT and 6MWD 300–400 m cohorts, respectively, compared with the placebo group.

In the primary analysis subgroup, ataluren-treated patients had an improvement in 6MWD at week 72 (-81.8 vs -90.1 m for placebo, 8.3 m difference; p=0.3626), although not statistically significant.

“Overall loss of ambulation was a low-frequency event in this study,” said Statland.

Secondary outcomes

Compared with placebo-treated boys, those on ataluren achieved significant improvements in NSAA* total and linear scores in the ITT population.

The same was true in the 6MWD 300–400 m subgroup. Improved NSAA total score was also observed with ataluren vs placebo but was not statistically significant.

There was also a significant improvement in time taken for a 10-m walk/run with ataluren over placebo in both the ITT population and 6MWD 300–400 m cohorts, so was the time to climb four stairs.

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