ArticlesAtaluren for the treatment of nonsense-mutation cystic fibrosis: a randomised, double-blind, placebo-controlled phase 3 trial
Introduction
Cystic fibrosis is a disabling and life-threatening autosomal recessive disorder resulting from mutations that cause dysfunction in the cystic fibrosis transmembrane conductance regulator (CFTR). About 10% of patients have cystic fibrosis that is caused by a class I nonsense mutation in at least one allele of the CFTR gene.1 Available therapies for treatment of lung manifestations of cystic fibrosis, such as inhaled antibiotics and dornase alfa do not address the underlying defect. Ivacaftor, a recently approved potentiator for the class III Gly551Asp CFTR mutation, does not target the defect associated with cystic fibrosis caused by nonsense mutations,2 which are associated with severe cystic fibrosis lung disease.3, 4, 5, 6, 7
Ataluren (3-[5-(2-fluorophenyl)-[1,2,4]oxadiazol-3-yl]-benzoic acid) is an orally bioavailable, investigational agent that promotes ribosomal readthrough of premature termination codons8, 9, 10, 11 and production of full-length, functional CFTR,11, 12 and is being developed as a disease-modifying treatment for diseases caused by nonsense mutations, including cystic fibrosis.
Phase 2 studies in 77 patients (aged 6–57 years) with nonsense-mutation cystic fibrosis receiving oral ataluren for 14 days to 12 weeks showed that ataluren is well tolerated12, 13, 14, 15 and can generate production of full-length CFTR protein, localised in the apical nasal epithelium.12 Nasal potential difference (NPD) assessments exhibited a pattern of improved total chloride transport with ataluren from baseline to end of treatment followed by a return to baseline values in the post-treatment period in three of the four phase 2 studies.13, 14, 15 These open-label studies had short-term treatment durations and were done at a small number of investigative sites with experience in assessment of NPD. Although no significant changes in percent-predicted forced expiratory volume in 1 s (FEV1) were reported in the short 14-day studies,12, 14, 16 other small, non-significant, positive effects were reported in a 12-week study, suggesting a time-dependent effect.15 This phase 3 clinical trial was designed to assess the efficacy and safety of ataluren for 48 weeks in a large population of patients with nonsense-mutation cystic fibrosis.
Section snippets
Study design and participants
This randomised, double-blind, placebo-controlled, phase 3 trial recruited patients from 36 sites in 11 countries in North America and Europe. Inclusion criteria included: age 6 years or older; abnormal NPD (defined as a less electrically negative value than 5 mV for total chloride conductance [ie, the change in NPD after addition of chloride-free solution and isoprenaline]); sweat chloride of greater than 40 mmol/L; documentation of the presence of a nonsense mutation in at least one allele of
Results
Between Sept 8, 2009, and Nov 30, 2010, 238 patients were randomly assigned to ataluren (n=120) or placebo (n=118; figure 1). Six patients did not have a valid post-baseline spirometry measurement, therefore the ITT population consisted of 232 patients, 116 in each treatment group (figure 1). Types of nonsense mutation were generally well balanced between treatment groups, and the most frequent mutations present in one or both alleles of the CFTR gene were Trp1282X (40 [33%] of 120 patients in
Discussion
Neither relative change in percent-predicted FEV1 at week 48 nor frequency of pulmonary exacerbation events during those 48 weeks were statistically different between ataluren and placebo groups in this trial. However, the average change in percent-predicted FEV1 across all post-baseline visits during the 48 weeks did significantly differ between groups by 2·5%, in favour of ataluren. Ataluren treatment resulted in a smaller decrease in FEV1 compared with patients in the placebo group, who had
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