ACT DMD: Effect of Ataluren on Timed Function Tests (TFTs) in Nonsense Mutation Duchenne Muscular Dystrophy (P3.163)

Objective: Determine the effects of ataluren on motor function in patients with nonsense mutation Duchenne muscular dystrophy (nmDMD) using TFTs.Background: Ataluren is the first drug to treat the underlying cause of nmDMD by promoting readthrough of a premature stop codon to produce full-length functional dystrophin. It is approved in Europe for the treatment of nmDMD in ambulatory patients aged ≥5 years.Design/Methods: ACT DMD (Ataluren Confirmatory Trial in Duchenne Muscular Dystrophy) is a Phase 3, randomized, double-blind, placebo-controlled study. Males 7-16 years of age with nmDMD and a screening six-minute walk distance (6MWD) ≥150m and u003c80[percnt]-predicted were randomized 1:1 to ataluren 40 mg/kg/day or placebo for 48 weeks. A pre-specified subgroup included patients whose baseline 6MWD was 300-400m. Secondary endpoints included TFTs: 10-meter walk/run; 4-stair climb; 4-stair descend. A meta-analysis of the overall ACT DMD population and the ‘ambulatory decline phase’ subgroup of the Phase 2b study (ie, those patients meeting ACT DMD entry criteria) was pre-specified in the ACT DMD statistical plan.Results: In the overall ACT DMD population (N=228), changes in the three TFTs presented below, favored ataluren over placebo: 10-meter walk/run, -1.2s (p=0.117); 4-stair climb, -1.8s (p=0.058); 4-stair descend, -1.8s (p=0.012). In the pre-specified subgroup (n=99), these differences increased to -2.1s, -3.6s, and -4.3s, respectively, and were statistically significant for the 4-stair climb (p=0.003) and 4-stair descend (pu003c0.001), and approached significance for 10-meter walk/run (p=0.066). Results are supported by the meta-analysis (N=291), which demonstrated significant differences in all three TFTs: 10-meter walk/run, -1.4s (p=0.025); 4-stair climb, -1.6s (p=0.018); 4-stair descend, -2.0s (p=0.004).Conclusions: TFT results showed a benefit for ataluren in ACT DMD, and a larger treatment effect in the pre-specified baseline 6MWD 300-400m subgroup as well as the pre-specified meta-analysis of ACT DMD and the Phase 2b study decline subgroup.Supported By: PTC Therapeutics Inc. Disclosure: Dr. Goemans has nothing to disclose. Dr. Campbell has nothing to disclose. Dr. McDonald has nothing to disclose. Dr. Voit has received personal compensation for activities with Prosensa-BioMarin, Tarix Pharmaceuticals, Sarepta, and Fibrogen. Dr. Luo has received personal compensation for activities with PTC Therapeutics as an employee. Dr. Elfring has received personal compensation for activities with PTC Therapeutics as an employee. Dr. Kroger has received personal compensation for activities with PTC Therapeutics, Inc. as an employee. Dr. Riebling has received personal compensation for activities with PTC Therapeutics, Inc. Dr. Ong has received personal compensation for activities with a pharmaceutical company as an employee. Dr. Spiegel has received personal compensation from PTC Therapeutics. Dr. Peltz has nothing to disclose. Dr. Bushby has nothing to disclose.