Phase 3 Trial of Ataluren for Nonsense Mutation Cystic Fibrosis

PTC Therapeutics announced the results from a Phase 3 study of ataluren in patients with nonsense mutation cystic fibrosis (nmCF).

The study was a double-blind, placebo-controlled study comparing ataluren (n=116) to placebo (n=116) in nmCF patients. . The 48-week trial enrolled patients aged ≥6 years. Patients were randomly assigned to one of two treatment arms: ataluren (10mg/kg morning, 10mg/kg midday, 20mg/kg evening) or placebo (morning, midday, evening). Patients who completed the study were eligible to receive open-label ataluren in an ongoing extension study. 

The primary endpoint, the relative change from baseline in %-predicted FEV1 at 48 weeks, showed a positive trend favoring ataluren vs. placebo, and a larger effect in the patients not receiving chronic inhaled antibiotics. The effect of inhaled antibiotics was largely attributable to the use of inhaled aminoglycosides. In the intent to treat population, there was a 3% difference in the relative change from baseline in %-predicted FEV1 between the ataluren and placebo groups at Week 48 (-2.5% change on ataluren vs. -5.5% change on placebo; P=0.124). An analysis of the relative change from baseline in %-predicted FEV1 across all post-baseline study visits demonstrated an average difference between ataluren and placebo of 2.5% (-1.8% average change on ataluren vs. -4.3% average change on placebo; P=0.0478).

The study was stratified for age, baseline FEV1, and the use of chronic inhaled antibiotics. A statistically significant effect (P=0.0072) was seen between treatment and use of inhaled antibiotics at baseline, indicating that inhaled antibiotics was a significant confounder of the overall results. A substantial treatment effect was seen in the patients not receiving chronic inhaled antibiotics at baseline; the Week 48 difference between the ataluren and placebo arms in FEV1 was 6.7% (-0.2% change on ataluren vs. -6.9% change on placebo).

The secondary endpoint, the rate of pulmonary exacerbations (ie, the number of pulmonary exacerbations in 48 weeks) also showed a positive trend in favor of ataluren, with the rate in the ataluren group being 23% lower than the placebo group (P=0.0992). In the patients not receiving chronic inhaled antibiotics, the pulmonary exacerbation rate in the ataluren group was 43% lower than the rate in the placebo group.

Ataluren is a protein restoration therapy designed to enable the formation of a functioning protein in patients with genetic disorders caused by a nonsense mutation. A nonsense mutation is an alteration in the genetic code that prematurely halts the synthesis of an essential protein. The resulting disorder is determined by which protein cannot be expressed in its entirety and is no longer functional, such as the cystic fibrosis transmembrane conductance regulator protein (CFTR) in nmCF.

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