Ataluren shows real-world benefit for nonsense mutation Duchenne muscular dystrophy

AUSTIN, TEX. – Real-world effectiveness of ataluren for the treatment of Duchenne muscular dystrophy (DMD) with nonsense mutation was similar to the benefit seen in the randomized controlled trial that led to its European approval, according to new data.

“Participants in the STRIDE Registry [real-world patients] showed a reduction in functional decline over 48 weeks, compared with patients receiving placebo” in the trial, reported Abdallah Delage of PTC Therapeutics in Zug, Switzerland, and his associates.

Duchenne muscular dystrophy affects an estimated 1 in 3,600-6,000 male births globally, about 10%-15% of whom have nonsense mutation DMD. This mutation causes a truncated, nonfunctional dystrophin protein due to a premature stop codon, the authors explained. Ataluren “promotes ribosomal read-through of the premature stop codon to produce a full-length dystrophin protein,” they explained.

Ataluren is currently approved for ambulatory patients age 2 and older with nonsense mutation DMD in the European Union and several other European countries. Israel, Korea, Chile, and Ukraine have approved it for patients aged 5 and older.

The Strategic Targeting of Registries and International Database of Excellence (STRIDE) Registry contains real-world data from patients using ataluren as part of an ongoing multicenter observational postapproval safety study. The investigators are tracking patients for at least 5 years after enrollment in 14 countries where ataluren is approved or commercially available through early-access programs. Patients take 40 mg/kg daily: 10 mg/kg in the morning, 10 mg/kg midday, and 20 mg/kg in the evening.

The researchers compared outcomes in 216 patients in the STRIDE Registry with participants in a randomized controlled phase 3 study of ataluren involving 228 boys, aged 7-16, who received ataluren (n = 114) or placebo (n = 114) for 48 weeks. Patients were an average 9 years old in STRIDE and in both arms of the randomized controlled trial.

The STRIDE Registry participants, comprising 184 ambulatory and 26 nonambulatory patients at enrollment, had at least 48 weeks between their first and last assessment. All of the patients in the phase 3 study and 88.6% of the STRIDE Registry patients were receiving corticosteroids along with ataluren. The researchers compared the 184 ambulatory STRIDE participants with the participants of the randomized controlled trial for one primary and four secondary endpoints from baseline to 48 weeks.

For the primary endpoint, 6-minute walk distance, average distance was 35 meters shorter than baseline in STRIDE Registry participants (n = 66), 42.2 meters shorter in the patients receiving ataluren in the phase 3 study (n = 109), and 57.6 meters shorter in RCT patients receiving placebo in the phase 3 trial (n = 109).

A secondary endpoint, the time it took patients to walk or run 10 meters, increased 1.6 seconds from baseline to 48 weeks in STRIDE Registry participants (n = 61), 2.3 seconds in participants receiving ataluren in the phase 3 trial (n = 109), and 3.5 seconds in study participants receiving placebo (n = 110).

Another secondary endpoint, the change in time it took for patients to stand from supine position from baseline to 48 weeks, was 2.9 additional seconds for STRIDE participants (n = 55), 3.8 additional seconds in study participants receiving ataluren (n = 101), and 3.9 additional seconds in study participants receiving placebo (n = 96).

Two final secondary endpoints were the changes in time to climb four stairs and to descend four stairs from baseline to 48 weeks. STRIDE participants (n = 47) climbed four stairs 1.2 seconds more slowly at 48 weeks, compared with 2.7 seconds more slowly in the participants who received ataluren in the phase 3 trial (n = 105) and 4.5 seconds more slowly in those who received placebo. Descending four stairs took 0.5 more seconds at 48 weeks in STRIDE participants (n = 40), 2.2 more seconds in participants who received ataluren in the phase 3 trial (n = 106), and 4.0 more seconds in those who received placebo (n = 100).

At least one adverse event occurred in 20.7% of registry participants; seven of these were considered treatment related. Treatment-related side effects included abdominal pain, vomiting, headache, stomach ache, diarrhea, and increased serum lipids.

The study and STRIDE Registry is funded by PTC Therapeutics with TREAT-NMD and the Cooperative International Neuromuscular Research Group. Mr. Delage and five other authors are employees of PTC Therapeutics, and six authors had received speaker or consultancy fees or served on the advisory board of a variety of companies.

SOURCE: Delage A et al. AANEM 2019, Abstract 115.