Meta-analyses of ataluren randomized controlled trials in nonsense mutation Duchenne muscular dystrophy

Abstract

Aim: Assess the totality of efficacy evidence for ataluren in patients with nonsense mutation Duchenne muscular dystrophy (nmDMD). Materials & methods: Data from the two completed randomized controlled trials (ClinicalTrials.gov: NCT00592553; NCT01826487) of ataluren in nmDMD were combined to examine the intent-to-treat (ITT) populations and two patient subgroups (baseline 6-min walk distance [6MWD] ≥300–<400 or <400 m). Meta-analyses examined 6MWD change from baseline to week 48. Results: Statistically significant differences in 6MWD change with ataluren versus placebo were observed across all three meta-analyses. Least-squares mean difference (95% CI): ITT (n = 342), +17.2 (0.2–34.1) m, p = 0.0473; ≥300–<400 m (n = 143), +43.9 (18.2–69.6) m, p = 0.0008; <400 m (n = 216), +27.7 (6.4–49.0) m, p = 0.0109. Conclusion: These meta-analyses support previous evidence for ataluren in slowing disease progression versus placebo in patients with nmDMD over 48 weeks. Treatment benefit was most evident in patients with a baseline 6MWD ≥300–<400 m (the ambulatory transition phase), thereby informing future trial design.

Human iPSC-Based Model Reveals NOX4 as Therapeutic Target in Duchenne Cardiomyopathy

“…We demonstrated re-expression of Dystrophin after PTC124 addition in a fraction of differentiating DMD iPSC-CMs. Recently, a phase 3 randomized placebo-controlled trial, evaluating an improvement in the 6-minute walking test after 48 weeks, has been completed ( 53 ), and a clinical trial to study Dystrophin expression levels in a small cohort of PTC124-treated patients with DMD is currently ongoing. These clinical studies aim at targeting the primary cause of DMD progression.…”

Innovative Therapeutic Approaches for Duchenne Muscular Dystrophy

“…Despite two randomized, placebo-controlled studies (NCT00592553 and NCT01826487) showing a slowing of disease progression provided by ataluren, no significant effect on dystrophin restoration was detected. The reasons can be found in the patients' loss of target tissues and in the relatively short clinical trial's time [64]. The authors tested ataluren efficacy by collecting trial data to explore the intent-to-treat (ITT) populations and two patient baseline 6-min-walk-distance (6MWD) subgroups.…”

Ataluren—Promising Therapeutic Premature Termination Codon Readthrough Frontrunner

“…In case of the <400 m 6MWD subgroup, statistically significant differences were observed in all secondary endpoints: time to walk/run 10 m, climb four stairs, descend four stairs, and time to persistent 10% 6MWD worsening. Almost all the observed treatment effects were improved compared with those of the individual studies [ 19 ].…”

“…In 2018, the indication was extended to include children from 2 to less than 5 years old that are able to walk [ 18 ]. Ataluren is also indicated for the treatment of DMD patients aged 2 years or older in Iceland, Israel, Kazakhstan, Lichtenstein, and Norway and patients aged 5 years or older in Brazil, Chile, Ukraine, and the Republic of Korea [ 19 , 20 ]. In Russia, it was granted marketing approval for DMD in December 2020 [ 21 ], whereas in the US, ataluren is an investigational drug [ 22 ], which means that it has been approved by the US Food and Drug Administration (FDA) for testing in people, and clinical trial results confirming its safety are awaited.…”