Clinical Trials

Date: 2017-07-08

Type of information: Publication of results in a medical journal

phase: 3

Announcement: publication of results in The Lancet

Company: PTC Therapeutics (USA - NJ)

Product: Translarna™ (ataluren)

Action mechanism:

• protein restauration therapy/inducer of ribosomal readthrough on nonsense mutation mRNA stop codons. Ataluren (3-[5-(2-fluoro-phenyl)-[1,2,4]oxadiazole-3-yl]-benzoic acid) is an investigational new drug designed to enable the production of functional dystrophin protein in the muscle cells of patients with genetic disorders due to a nonsense mutation. Ataluren is designed to allow the ribosome to ignore the premature stop signal and continue translation of the mRNA, resulting in formation of a functioning protein. Ataluren does not cause the ribosome to read through the normal stop signal.

Disease: nonsense mutation Duchenne Muscular Dystrophy (nmDMD)

Therapeutic area: Rare diseases - Neuromuscular diseases

Country: Australia, Brazil, Bulgaria, Canada, Chile, Czech Republic, France, Germany, Israel, Italy, Korea, Republic of Korea, Poland, Spain, Sweden, Switzerland, Turkey, UK, USA

Trial details:

• ACT DMD is a 48-week clinical trial designed to confirm the effect of Translarna™ on ambulation in patients with nmDMD. The primary endpoint is the change in walking distance as measured by the six-minute walk test. The trial has involved 228 patients in 53 sites across 18 countries. Patients between the ages of 7 and 16 with nmDMD were randomized to receive either Translarna™ 40mg/kg per day (n=114) or placebo (n=114) over 48 weeks. The primary endpoint was change from baseline in the 6MWT. Analyses of data from pre-specified subgroups, including the pre-specified subgroup of patients with baseline 6-minute walk distance (6MWD) of 300 - 400 meters, were also completed. Key secondary outcome measures were timed-function tests, including time to run or walk 10 meters and the time to ascend or descend four stairs. Tertiary endpoints included the North Star Ambulatory Assessment test, a functional scale designed for ambulant boys affected by DMD, and the Pediatric Outcomes Data Collection Instrument (PODCI), a validated tool for measuring quality of life in pediatric patients with orthopedic conditions. Supportive analyses of ambulation were conducted, including the proportion of patients with at least 10% worsening in 6MWD. A pre-specified meta-analysis of combined data from the ACT DMD and Phase 2b (ambulatory decline phase) studies was also performed. (NCT01826487)

Latest news:

• • On July 18, 2017, PTC Therapeutics announced the publication of the results of the ACT DMD trial study ataluren in The Lancet. The primary endpoint was change from baseline in the six-minute walk test. Treatment effects are more likely to be observed in patients in the transition stage of disease (baseline six-minute walk distance of 300-400 meters). Analyses of data from pre-specified subgroups, including the pre-specified subgroup of patients with baseline six-minute walk distance of 300 - 400 meters, were also completed. Key secondary outcome measures were timed-function tests, including time to run or walk 10 meters and the time to ascend or descend four stairs. Exploratory efficacy endpoints were change in physical function as assessed by change in the North Star Ambulatory Assessment, parent-reported health related quality of life, and activities of daily living.
• • On October 15, 2015, PTC Therapeutics  announced results from the Phase 3, double-blind, placebo-controlled, 48-week ACT DMD trial of Translarna™ (ataluren), an oral, first-in-class, protein restoration therapy for the treatment of nonsense mutation Duchenne muscular dystrophy (nmDMD). The trial results showed clinically meaningful benefits for Translarna™-treated patients. In the overall intent-to-treat study population, the primary endpoint of change from baseline in the 6-minute walk test (6MWT) demonstrated a 15 meter benefit (p=0.213), which was not statistically significant. A highly significant benefit of 47 meters (p=0.007) was demonstrated in the pre-specified patient population of 300-400 meters at baseline as measured by the 6MWT, which is in line with the Company's prior experience in its Phase 2b trial and consistent with the evolving understanding of the 6MWT. Importantly, no patients in this group lost ambulation (0/47) versus four patients in the placebo group (4/52). Translarna™ showed a benefit over placebo across key secondary and tertiary endpoints, including timed function tests (10 meter Run/Walk, 4 Stair Climb, 4 Stair Descend) and the North Star Ambulatory Assessment test. In addition, a pre-specified meta-analysis of the combined placebo-controlled ACT DMD and Phase 2b trials demonstrated a statistically significant benefit of Translarna across the primary (p=0.015) and key secondary endpoints. After the completion of ACT DMD, both placebo and treated patients were given the opportunity to continue on Translarna™ in an open-label extension study. Ninety-seven percent of the patients who completed ACT DMD enrolled in the extension study.
• The ACT DMD study confirmed the favorable safety profile of Translarna™, which was generally well-tolerated, consistent with results from previous studies. More than 500 nmDMD patients have now received Translarna, the largest population to be treated with a disease-modifying agent in DMD. Translarna® received marketing authorization from the European Medicines Agency (EMA) in 2014 for use in ambulatory nmDMD patients who are five years of age and older. PTC intends to submit the results from the ACT DMD study to the EMA and to complete its rolling submission for a New Drug Application (NDA) to the FDA by the end of 2015.
• • On September 9, 2014, PTC Therapeutics announced that it has completed enrollment of ACT DMD, the Phase 3 confirmatory trial of Translarna™ (ataluren) for patients with nonsense mutation Duchenne muscular dystrophy (nmDMD). Top-line data from the trial is expected in the second half of 2015 and will support further approvals globally, following European approval received earlier this year.

 

Is general: Yes