Ataluren: An Overview of Clinical Trial Results in Nonsense Mutation Duchenne Muscular Dystrophy (P3.162)

Objective: Provide an overview of ataluren clinical trial results in patients with nonsense mutation Duchenne muscular dystrophy (nmDMD).Background: Ataluren is the first drug to treat the underlying cause of nmDMD. It enables ribosomal readthrough of a premature stop codon to produce full-length functional dystrophin, without affecting normal stop codons.Design/Methods: Phase 2 and 3 trials of ataluren in nmDMD were reviewed, with efficacy and safety/tolerability findings summarized.Results: Clinical trials of ataluren in nmDMD include: a Phase 2a proof-of-concept study (N=38) whose primary endpoint was muscle dystrophin expression following 28 days of treatment; a Phase 2b randomized controlled trial (RCT) (N=174), whose primary endpoint was change in six-minute walk distance (6MWD) over 48 weeks; an ongoing US-based open-label extension (N=108) evaluating long-term safety; an ongoing non-US-based open-label extension (N=94) evaluating long-term safety and efficacy; and a Phase 3 RCT, ACT DMD (N=228), whose primary endpoint was change in 6MWD over 48 weeks. The proof-of-concept study demonstrated increased dystrophin production in post-treatment muscle biopsies from ataluren-treated patients with nmDMD. The Phase 2b results demonstrated an ataluren treatment effect in 6MWD, timed function tests, and other measures of physical functioning, with larger treatment effects observed in patients at higher risk of ambulatory decline. This study was the basis for ataluren’s approval in the European Union. The Phase 3 ACT DMD results demonstrated an ataluren treatment effect in patients with nmDMD in both primary and secondary endpoints, particularly in those with a baseline 6MWD of 300-400m. Ataluren was consistently well-tolerated in all three trials, as well as in the ongoing extension studies. Trial findings will be presented in detail.Conclusions: The totality of the results demonstrates that ataluren enables nonsense mutation readthrough in the dystrophin mRNA, producing functional dystrophin and slowing disease progression in patients with nmDMD.Supported By: PTC Therapeutics Inc. Disclosure: Dr. McDonald has nothing to disclose. Dr. Bushby has nothing to disclose. Dr. Tulinius has nothing to disclose. Dr. Finkel has received personal compensation for activities with Isis Pharmaceuticals and Voyager Therapeutics as a consultant and/or speaker. Dr. Topaloglu has nothing to disclose. Dr. Day has received personal compensation for activities with Sarepta Therapeutics and PTC Therapeutics as a consultant. Dr. Flanigan has received personal compensation for activities with Sarepta Therapeutics; Biomarin; Alexion; Audentes; PTC Therapeutics. Site investigator or co-investigator for clinical trials funded by Biomarin; Akashi Therapeutics; PTC Therapeutics as Dr. Lowes has received personal compensation for activities with Sarepta Pharmaceuticals, Eli Lilly, and Pfizer as a consultant. Dr. Eagle has nothing to disclose. 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. Kirschner has received research support from ISIS Pharmaceuticals, Biogen, PTC Therapeutics, Eli Lilly and Company, BioMarin, and Novartis.