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


RESULTS
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.


CONCLUSIONS
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.


BACKGROUND
PTC Therapeutics, Cystic Fibrosis Foundation, US Food and Drug Administration's Office of Orphan Products Development, and the National Institutes of Health.
Center for Cystic Fibrosis, Hadassah Hebrew University Medical Center, Jerusalem, Israel.
Eitan
E
Kerem
Rainbow Babies & Children's Hospital and Case Western Reserve University, Cleveland, OH, USA. Electronic address: michael.konstan@case.edu.
Michael W
MW
Konstan
University Hospitals Leuven/Catholic University of Leuven, Leuven, Belgium.
Kris
K
De Boeck
Children's Hospital Colorado, Aurora, CO, USA.
Frank J
FJ
Accurso
Centre de Ressource et de Competence de la Mucoviscidose, Service de Pediatrie Generale, Service de Pneumologie Pediatrique, Service de Radiologie Pediatrique, Centre d'Investigation Clinique Hôpital Necker-Enfants Malades, Paris, France.
Isabelle
I
Sermet-Gaudelus
Center for Cystic Fibrosis, Hadassah Hebrew University Medical Center, Jerusalem, Israel.
Michael
M
Wilschanski
Centre for Infection and Immunity, Queen's University, Belfast, Northern Ireland, UK.
J Stuart
JS
Elborn
Centro Regionale Veneto di Ricerca, Prevenzione e Cura Fibrosi Cistica, Azienda Ospedaliera di Verona, Verona, Italy.
Paola
P
Melotti
Department of Pulmonology, University Medical Centre Utrecht, Utrecht, Netherlands.
Inez
I
Bronsveld
Université Paris Descartes, Sorbonne Paris Cité, Paris, France; Department of Physiology, Hôpital Cochin, AP-HP, Paris, France.
Isabelle
I
Fajac
Cystic Fibrosis Clinic, Universitair Ziekenhuis Brussel/Vrije Universiteit Brussel, Brussels, Belgium.
Anne
A
Malfroot
Pulmonary and Critical Care Medicine, Washington University School of Medicine, St Louis, MO, USA.
Daniel B
DB
Rosenbluth
Pulmonary Medicine, Mount Sinai Hospital, New York, NY, USA.
Patricia A
PA
Walker
Ann & Robert H Lurie Children's Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
Susanna A
SA
McColley
Department of Chest Medicine, Hôpital Universitaire Erasme, Brussels, Belgium.
Christiane
C
Knoop
Regional Cystic Fibrosis Centre, Paediatrics and Infant Neuropsychiatry Department, 'Sapienza' University of Rome, Rome, Italy.
Serena
S
Quattrucci
Cystic Fibrosis Centre, Children's Hospital University of Cologne, Cologne, Germany.
Ernst
E
Rietschel
Pediatric Pulmonology, Johns Hopkins Pediatric Specialty Clinic, Rubenstein Child Health, Baltimore, MD, USA.
Pamela L
PL
Zeitlin
PTC Therapeutics, South Plainfield, NJ, USA.
Jay
J
Barth
PTC Therapeutics, South Plainfield, NJ, USA.
Gary L
GL
Elfring
PTC Therapeutics, South Plainfield, NJ, USA.
Ellen M
EM
Welch
PTC Therapeutics, South Plainfield, NJ, USA.
Arthur
A
Branstrom
PTC Therapeutics, South Plainfield, NJ, USA.
Robert J
RJ
Spiegel
PTC Therapeutics, South Plainfield, NJ, USA.
Stuart W
SW
Peltz
PTC Therapeutics, South Plainfield, NJ, USA.
Temitayo
T
Ajayi
Translational Research Unit, Pulmonary and Critical Care Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.
Steven M
SM
Rowe
D058186:Acute Kidney Injury / Q000139:chemically induced; D000293:Adolescent; D000328:Adult; D000900:Anti-Bacterial Agents / Q000008:administration & dosage; D002648:Child; D002712:Chlorides / Q000032:analysis; D018389:Codon, Nonsense; D003550:Cystic Fibrosis / Q000188:drug therapy* / Q000235:genetics* / Q000503:physiopathology; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics*; D018450:Disease Progression; D004311:Double-Blind Method; D005260:Female; D005541:Forced Expiratory Volume; D006801:Humans; D008297:Male; D008875:Middle Aged; D010069:Oxadiazoles / Q000009:adverse effects / Q000627:therapeutic use*; D013542:Sweat / Q000737:chemistry; D014031:Tobramycin / Q000008:administration & dosage; D055815:Young Adult
D000900:Anti-Bacterial Agents; C505032:CFTR protein, human; D002712:Chlorides; D018389:Codon, Nonsense; D010069:Oxadiazoles; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; C515878:ataluren; D014031:Tobramycin