Articles
Ataluren for the treatment of nonsense-mutation cystic fibrosis: a randomised, double-blind, placebo-controlled phase 3 trial

https://doi.org/10.1016/S2213-2600(14)70100-6Get rights and content

Summary

Background

Ataluren was developed to restore functional protein production in genetic disorders caused by nonsense mutations, which are the cause of cystic fibrosis in 10% of patients. This trial was designed to assess the efficacy and safety of ataluren in patients with nonsense-mutation cystic fibrosis.

Methods

This randomised, double-blind, placebo-controlled, phase 3 study enrolled patients from 36 sites in 11 countries in North America and Europe. Eligible patients with nonsense-mutation cystic fibrosis (aged ≥6 years; abnormal nasal potential difference; sweat chloride >40 mmol/L; forced expiratory volume in 1 s [FEV1] ≥40% and ≤90%) were randomly assigned by interactive response technology to receive oral ataluren (10 mg/kg in morning, 10 mg/kg midday, and 20 mg/kg in evening) or matching placebo for 48 weeks. Randomisation used a block size of four, stratified by age, chronic inhaled antibiotic use, and percent-predicted FEV1. The primary endpoint was relative change in percent-predicted FEV1 from baseline to week 48, analysed in all patients with a post-baseline spirometry measurement. This study is registered with ClinicalTrials.gov, number NCT00803205.

Findings

Between Sept 8, 2009, and Nov 30, 2010, 238 patients were randomly assigned, of whom 116 in each treatment group had a valid post-baseline spirometry measurement. Relative change from baseline in percent-predicted FEV1 did not differ significantly between ataluren and placebo at week 48 (–2·5% vs −5·5%; difference 3·0% [95% CI −0·8 to 6·3]; p=0·12). The number of pulmonary exacerbations did not differ significantly between treatment groups (rate ratio 0·77 [95% CI 0·57–1·05]; p=0·0992). However, post-hoc analysis of the subgroup of patients not using chronic inhaled tobramycin showed a 5·7% difference (95% CI 1·5–10·1) in relative change from baseline in percent-predicted FEV1 between the ataluren and placebo groups at week 48 (–0·7% [–4·0 to 2·1] vs −6·4% [–9·8 to −3·7]; nominal p=0·0082), and fewer pulmonary exacerbations in the ataluern group (1·42 events [0·9–1·9] vs 2·18 events [1·6–2·7]; rate ratio 0·60 [0·42–0·86]; nominal p=0·0061). Safety profiles were generally similar for ataluren and placebo, except for the occurrence of increased creatinine concentrations (ie, acute kidney injury), which occurred in 18 (15%) of 118 patients in the ataluren group compared with one (<1%) of 120 patients in the placebo group. No life-threatening adverse events or deaths were reported in either group.

Interpretation

Although ataluren did not improve lung function in the overall population of nonsense-mutation cystic fibrosis patients who received this treatment, it might be beneficial for patients not taking chronic inhaled tobramycin.

Funding

PTC Therapeutics, Cystic Fibrosis Foundation, US Food and Drug Administration's Office of Orphan Products Development, and the National Institutes of Health.

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

References (36)

  • EM Welch et al.

    PTC124 targets genetic disorders caused by nonsense mutations

    Nature

    (2007)
  • S Gonzalez-Hilarion et al.

    Rescue of nonsense mutations by amlexanox in human cells

    Orphanet J Rare Dis

    (2012)
  • M Du et al.

    PTC124 is an orally bioavailable compound that promotes suppression of the human CFTR-G542X nonsense allele in a CF mouse model

    Proc Natl Acad Sci USA

    (2008)
  • I Sermet-Gaudelus et al.

    Ataluren (PTC124) induces cystic fibrosis transmembrane conductance regulator protein expression and activity in children with nonsense mutation cystic fibrosis

    Am J Respir Crit Care Med

    (2010)
  • JP Clancy et al.

    A phase 2 study of PTC124 in cystic fibrosis patients harboring premature stop mutations

    Pediatr Pulmonol

    (2006)
  • M Wilschanski et al.

    Chronic ataluren (PTC124) treatment of nonsense mutation cystic fibrosis

    Eur Respir J

    (2011)
  • JL Hankinson et al.

    Spirometric reference values from a sample of the general U.S. population

    Am J Respir Crit Care Med

    (1999)
  • X Wang et al.

    Pulmonary function between 6 and 18 years of age

    Pediatr Pulmonol

    (1993)
  • Cited by (289)

    View all citing articles on Scopus
    *

    Contributed equally

    Members listed in the appendix

    View full text