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

Eitan Kerem; Michael W. Konstan; Kris De Boeck; Frank J. Accurso; Isabelle Sermet-Gaudelus; Michael Wilschanski; J. Stuart Elborn; Paola Melotti; Inez Bronsveld; Isabelle Fajac; Anne Malfroot; Daniel B. Rosenbluth; Patricia A. Walker; Susanna A. McColley; Christiane Knoop; Serena Quattrucci; Ernst Rietschel; Pamela L. Zeitlin; Jay Barth; Gary L. Elfring; Ellen M. Welch; Arthur Branstrom; Robert J. Spiegel; Stuart W. Peltz; Temitayo Ajayi; Steven M. Rowe

doi:10.1016/S2213-2600(14)70100-6

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

Eitan Kerem, Michael W. Konstan, Kris De Boeck, Frank J. Accurso, Isabelle Sermet-Gaudelus, Michael Wilschanski, J. Stuart Elborn, Paola Melotti, Inez Bronsveld, Isabelle Fajac, Anne Malfroot, Daniel B. Rosenbluth, Patricia A. Walker, Susanna A. McColley, Christiane Knoop, Serena Quattrucci, Ernst Rietschel, Pamela L. Zeitlin, Jay Barth, Gary L. ElfringEllen M. Welch, Arthur Branstrom, Robert J. Spiegel, Stuart W. Peltz, Temitayo Ajayi, Steven M. Rowe

Research output: Contribution to journal › Article › peer-review

225 Scopus citations

Abstract

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.

Original language	English (US)
Pages (from-to)	539-547
Number of pages	9
Journal	The Lancet Respiratory Medicine
Volume	2
Issue number	7
DOIs	https://doi.org/10.1016/S2213-2600(14)70100-6
State	Published - Jul 2014
Externally published	Yes

ASJC Scopus subject areas

Pulmonary and Respiratory Medicine

Access to Document

10.1016/S2213-2600(14)70100-6

Cite this

Kerem, E., Konstan, M. W., De Boeck, K., Accurso, F. J., Sermet-Gaudelus, I., Wilschanski, M., Elborn, J. S., Melotti, P., Bronsveld, I., Fajac, I., Malfroot, A., Rosenbluth, D. B., Walker, P. A., McColley, S. A., Knoop, C., Quattrucci, S., Rietschel, E., Zeitlin, P. L., Barth, J., ... Rowe, S. M. (2014). Ataluren for the treatment of nonsense-mutation cystic fibrosis: A randomised, double-blind, placebo-controlled phase 3 trial. The Lancet Respiratory Medicine, 2(7), 539-547. https://doi.org/10.1016/S2213-2600(14)70100-6

Kerem, E, Konstan, MW, De Boeck, K, Accurso, FJ, Sermet-Gaudelus, I, Wilschanski, M, Elborn, JS, Melotti, P, Bronsveld, I, Fajac, I, Malfroot, A, Rosenbluth, DB, Walker, PA, McColley, SA, Knoop, C, Quattrucci, S, Rietschel, E, Zeitlin, PL, Barth, J, Elfring, GL, Welch, EM, Branstrom, A, Spiegel, RJ, Peltz, SW, Ajayi, T & Rowe, SM 2014, 'Ataluren for the treatment of nonsense-mutation cystic fibrosis: A randomised, double-blind, placebo-controlled phase 3 trial', The Lancet Respiratory Medicine, vol. 2, no. 7, pp. 539-547. https://doi.org/10.1016/S2213-2600(14)70100-6

@article{097ecc94cd134407a7cd64fba43cd16f,

title = "Ataluren for the treatment of nonsense-mutation cystic fibrosis: A randomised, double-blind, placebo-controlled phase 3 trial",

abstract = "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.",

author = "Eitan Kerem and Konstan, {Michael W.} and {De Boeck}, Kris and Accurso, {Frank J.} and Isabelle Sermet-Gaudelus and Michael Wilschanski and Elborn, {J. Stuart} and Paola Melotti and Inez Bronsveld and Isabelle Fajac and Anne Malfroot and Rosenbluth, {Daniel B.} and Walker, {Patricia A.} and McColley, {Susanna A.} and Christiane Knoop and Serena Quattrucci and Ernst Rietschel and Zeitlin, {Pamela L.} and Jay Barth and Elfring, {Gary L.} and Welch, {Ellen M.} and Arthur Branstrom and Spiegel, {Robert J.} and Peltz, {Stuart W.} and Temitayo Ajayi and Rowe, {Steven M.}",

note = "Funding Information: Neither relative change in percent-predicted FEV 1 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 FEV 1 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 FEV 1 compared with patients in the placebo group, who had a relative decline in FEV 1 of −5·5% (or −3·1% absolute), which emphasises the severity of disease in these patients with nonsense-mutation cystic fibrosis. Class I (eg, nonsense mutations) and class II (eg, Phe508del) CFTR mutations usually result in complete absence of CFTR at the epithelial cell membrane, generally resulting in a severe disease phenotype. By contrast, CFTR class III (eg, Gly551Asp) mutations usually result in full-length CFTR that is appropriately trafficked to the epithelial cell membrane and retains some residual activity. These differences in the underlying CFTR defect might be expected to affect the nature of the clinical efficacy produced by drugs targeting different mutation classes. Similarly, treatment that alleviates signs and symptoms (eg, inhaled antibiotics) addresses a complication of disease (eg, infection), whereas ataluren treatment is disease-modifying, targeting the underlying cause of disease (nonsense mutations), suggesting that the expectations for clinical efficacy might also be different. Although an increase in FEV 1 has generally been expected in interventional studies in cystic fibrosis, preservation of lung function is also a clinically important goal of cystic fibrosis treatment. For example, treatment of chronic P aeruginosa infection with inhaled antibiotics aims to preserve lung function for as long as possible. 29 In this trial, the frequency of pulmonary exacerbation events was lower over 48 weeks in the ataluren group than in the placebo group, although not significantly so (p=0·099). The three prespecified stratification factors (baseline age, use of inhaled antibiotics, and baseline percent-predicted FEV 1 ) balanced patient allocation across treatment groups, and were identified a priori as clinically relevant. Particularly, stratification by use of inhaled antibiotics was intended to allocate evenly patients who were receiving these drugs; this group typically comprises a sicker population of patients who have P aeruginosa infection. 30 The most frequently used inhaled antibiotic, tobramycin, is an aminoglycoside with a bacterial ribosomal binding mechanism of action. 31 Ataluren also acts through modulation of the ribosome to enable readthrough of nonsense mutations. The mode of binding of tobramycin might interfere with ataluren's mechanism of action. In-vitro testing showing the interference of aminoglycoside antibiotics with ataluren activity supports this hypothesis ( appendix ). Results of the post-hoc analysis of patients not receiving chronic inhaled tobramycin showed a significant difference in the mean relative change from baseline in percent-predicted FEV ). 1 at week 48 of 5·7% in favour of ataluren. Similarly, in patients who were not taking chronic inhaled tobramycin, the frequency of pulmonary exacerbation events was significantly lower in the ataluren group than in the placebo group. The disparity in several endpoints between the subgroup of patients who were not prescribed chronic inhaled tobramycin and the subgroup of patients who were supports the hypothesis that inhaled tobramycin might interfere with ataluren's mechanism of action. In a separate post-hoc in-vitro experiment, ataluren did not affect the antibacterial activity of tobramycin ( appendix ). The use of other inhaled antibiotics did not seem to modify the treatment effect of ataluren. These data support the development of a confirmatory trial targeting the subgroup of patients who do not use chronic inhaled aminoglycosides ( panel An unexpected result of this study was the absence of a difference between treatment groups in NPD, particularly in the context of the ataluren effect on NPD shown in the phase 2 programme. 12,14,15 This study was the first to assess NPD in a large, multicentre, long-term, placebo-controlled clinical trial. Notably, a prespecified analysis in this study showed a relatively high NPD response rate (ie, change ≥5·0 mV from baseline) in the placebo group. Of patients who received placebo, 16 (15%) had an NPD response (ie, at least a −5 mV improvement) at week 48. When even larger thresholds for defining NPD response are used (eg, change of at least −8·0 mV from baseline), six (6%) of 100 patients had an NPD response in the ataluren group compared with eight (8%) of 103 in the placebo group, suggesting that a large number of false positives were reported. These results, and the complexity of undertaking NPD at many sites that did not have previous experience, might have contributed to the failure to reproduce previous results with this outcome measure. Sweat chloride concentrations also did not change during this study. Whereas NPD results were positive in the previous phase 2 studies, sweat chloride results were not. Both sweat chloride concentration and NPD have been used as pharmacodynamic endpoints in a number of clinical trials of CFTR restoration therapies, at times with discrepant results. 32–34 Organ (eg, sweat gland vs lung) effects might vary because of differences in tissue drug availability, CFTR regulation in different cell types, or the responsiveness of mutant CFTR in different tissue compartments. 35 This issue of organ specificity is noted in the 2010 European Medicines Agency guideline on clinical development of medicinal products for the treatment of cystic fibrosis 36 and might be relevant to the effects of ataluren. Ataluren was generally well tolerated during 48 weeks of treatment in this trial. Safety profiles were similar for ataluren and placebo, other than cases of acute kidney injury (ie, increases in creatinine concentrations), the most severe of which were associated with the combination of potentially nephrotoxic antibiotics with ataluren. Thus, the combination of ataluren and aminoglycosides has been prohibited, effectively managing those clinically significant creatinine increases. This study was a well designed, well controlled trial of ataluren in patients with nonsense-mutation cystic fibrosis. The main limitation of the study was the choice of a population of patients that includes those who used chronic inhaled tobramycin, which we postulate might interfere with ataluren at the ribosomal level. Another limitation was the inability to find a biomarker that could be implemented worldwide that can differentiate the effects of ataluren treatment from placebo. Ataluren has been developed as a potential treatment for the underlying cause of cystic fibrosis in patients with nonsense mutations. Overall, ataluren showed no statistically significant difference compared with placebo for relative change in percent-predicted FEV 1 at week 48 and pulmonary exacerbation rate during 48 weeks. Concomitant administration of inhaled tobramycin interfered with readthrough of CFTR nonsense mutations by ataluren in vitro and in the clinic. In patients with nonsense-mutation cystic fibrosis not taking chronic inhaled tobramycin, ataluren produced a notable treatment effect compared with placebo for percent-predicted FEV 1 and pulmonary exacerbation. In view of the subgroup effect on spirometry and pulmonary exacerbation in patients not receiving chronic inhaled tobramycin, and a favourable safety profile, this study supports further testing of ataluren for patients with nonsense-mutation cystic fibrosis not receiving chronic inhaled tobramycin. A confirmatory phase 3 efficacy and safety trial of ataluren in patients not receiving chronic inhaled tobramycin (ACT CF trial) is in progress. Contributors EK, MWK, KDB, FJA, JSE, GLE, JB, RJS, SWP, TA, and SMR contributed to study design, data collection, interpretation of the data, intellectual content of the manuscript, writing of the manuscript, and reviewing of the final version of the manuscript. PM, IB, IF, AM, DBR, PAW, SAM, CK, SQ, ER, and PLZ contributed to study design, data collection, interpretation of the data, and reviewing of the final version of the manuscript. IS-G and MW contributed to data collection, intellectual content of the manuscript, and reviewing of the final version of the manuscript. EMW and AB designed and analysed the in-vitro combination experiments, contributed to the intellectual content of the manuscript, and reviewed the final version of the manuscript. Declaration of interests JB, GLE, EMW, AB, RJS, SWP, and TA are employees of PTC Therapeutics, the funder of this clinical trial, and hold financial interests in the company. MWK and SMR received compensation for consultant services from PTC Therapeutics during this study. EK, KDB, IS-G, and MW received compensation for travel expenses for meetings related to the study. All other authors declare no competing interests. Acknowledgments We thank the patients and families who committed their time and effort to this study. We thank the principal investigators, supporting investigators, clinical coordinators, clinical evaluator trainers, clinical evaluators, and study coordinators, and INC Research for statistical programming support. We also thank the Cystic Fibrosis Foundation Therapeutics–Therapeutics Development Network Coordinating Center and the European Cystic Fibrosis Society Clinical Trials Network for their protocol review; the University of Alabama at Birmingham Center for Clinical and Translational Science for their technical assistance; and the patient advocacy organisations, particularly the Cystic Fibrosis Foundation, for the collaboration and support that made this trial possible. Michael W O'Donnell, a medical writer employed by PTC Therapeutics, assisted in the preparation of this manuscript for publication. ",

year = "2014",

month = jul,

doi = "10.1016/S2213-2600(14)70100-6",

language = "English (US)",

volume = "2",

pages = "539--547",

journal = "The Lancet Respiratory Medicine",

issn = "2213-2600",

publisher = "Elsevier Limited",

number = "7",

}

TY - JOUR

T1 - Ataluren for the treatment of nonsense-mutation cystic fibrosis

T2 - A randomised, double-blind, placebo-controlled phase 3 trial

AU - Kerem, Eitan

AU - Konstan, Michael W.

AU - De Boeck, Kris

AU - Accurso, Frank J.

AU - Sermet-Gaudelus, Isabelle

AU - Wilschanski, Michael

AU - Elborn, J. Stuart

AU - Melotti, Paola

AU - Bronsveld, Inez

AU - Fajac, Isabelle

AU - Malfroot, Anne

AU - Rosenbluth, Daniel B.

AU - Walker, Patricia A.

AU - McColley, Susanna A.

AU - Knoop, Christiane

AU - Quattrucci, Serena

AU - Rietschel, Ernst

AU - Zeitlin, Pamela L.

AU - Barth, Jay

AU - Elfring, Gary L.

AU - Welch, Ellen M.

AU - Branstrom, Arthur

AU - Spiegel, Robert J.

AU - Peltz, Stuart W.

AU - Ajayi, Temitayo

AU - Rowe, Steven M.

N1 - Funding Information: Neither relative change in percent-predicted FEV 1 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 FEV 1 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 FEV 1 compared with patients in the placebo group, who had a relative decline in FEV 1 of −5·5% (or −3·1% absolute), which emphasises the severity of disease in these patients with nonsense-mutation cystic fibrosis. Class I (eg, nonsense mutations) and class II (eg, Phe508del) CFTR mutations usually result in complete absence of CFTR at the epithelial cell membrane, generally resulting in a severe disease phenotype. By contrast, CFTR class III (eg, Gly551Asp) mutations usually result in full-length CFTR that is appropriately trafficked to the epithelial cell membrane and retains some residual activity. These differences in the underlying CFTR defect might be expected to affect the nature of the clinical efficacy produced by drugs targeting different mutation classes. Similarly, treatment that alleviates signs and symptoms (eg, inhaled antibiotics) addresses a complication of disease (eg, infection), whereas ataluren treatment is disease-modifying, targeting the underlying cause of disease (nonsense mutations), suggesting that the expectations for clinical efficacy might also be different. Although an increase in FEV 1 has generally been expected in interventional studies in cystic fibrosis, preservation of lung function is also a clinically important goal of cystic fibrosis treatment. For example, treatment of chronic P aeruginosa infection with inhaled antibiotics aims to preserve lung function for as long as possible. 29 In this trial, the frequency of pulmonary exacerbation events was lower over 48 weeks in the ataluren group than in the placebo group, although not significantly so (p=0·099). The three prespecified stratification factors (baseline age, use of inhaled antibiotics, and baseline percent-predicted FEV 1 ) balanced patient allocation across treatment groups, and were identified a priori as clinically relevant. Particularly, stratification by use of inhaled antibiotics was intended to allocate evenly patients who were receiving these drugs; this group typically comprises a sicker population of patients who have P aeruginosa infection. 30 The most frequently used inhaled antibiotic, tobramycin, is an aminoglycoside with a bacterial ribosomal binding mechanism of action. 31 Ataluren also acts through modulation of the ribosome to enable readthrough of nonsense mutations. The mode of binding of tobramycin might interfere with ataluren's mechanism of action. In-vitro testing showing the interference of aminoglycoside antibiotics with ataluren activity supports this hypothesis ( appendix ). Results of the post-hoc analysis of patients not receiving chronic inhaled tobramycin showed a significant difference in the mean relative change from baseline in percent-predicted FEV ). 1 at week 48 of 5·7% in favour of ataluren. Similarly, in patients who were not taking chronic inhaled tobramycin, the frequency of pulmonary exacerbation events was significantly lower in the ataluren group than in the placebo group. The disparity in several endpoints between the subgroup of patients who were not prescribed chronic inhaled tobramycin and the subgroup of patients who were supports the hypothesis that inhaled tobramycin might interfere with ataluren's mechanism of action. In a separate post-hoc in-vitro experiment, ataluren did not affect the antibacterial activity of tobramycin ( appendix ). The use of other inhaled antibiotics did not seem to modify the treatment effect of ataluren. These data support the development of a confirmatory trial targeting the subgroup of patients who do not use chronic inhaled aminoglycosides ( panel An unexpected result of this study was the absence of a difference between treatment groups in NPD, particularly in the context of the ataluren effect on NPD shown in the phase 2 programme. 12,14,15 This study was the first to assess NPD in a large, multicentre, long-term, placebo-controlled clinical trial. Notably, a prespecified analysis in this study showed a relatively high NPD response rate (ie, change ≥5·0 mV from baseline) in the placebo group. Of patients who received placebo, 16 (15%) had an NPD response (ie, at least a −5 mV improvement) at week 48. When even larger thresholds for defining NPD response are used (eg, change of at least −8·0 mV from baseline), six (6%) of 100 patients had an NPD response in the ataluren group compared with eight (8%) of 103 in the placebo group, suggesting that a large number of false positives were reported. These results, and the complexity of undertaking NPD at many sites that did not have previous experience, might have contributed to the failure to reproduce previous results with this outcome measure. Sweat chloride concentrations also did not change during this study. Whereas NPD results were positive in the previous phase 2 studies, sweat chloride results were not. Both sweat chloride concentration and NPD have been used as pharmacodynamic endpoints in a number of clinical trials of CFTR restoration therapies, at times with discrepant results. 32–34 Organ (eg, sweat gland vs lung) effects might vary because of differences in tissue drug availability, CFTR regulation in different cell types, or the responsiveness of mutant CFTR in different tissue compartments. 35 This issue of organ specificity is noted in the 2010 European Medicines Agency guideline on clinical development of medicinal products for the treatment of cystic fibrosis 36 and might be relevant to the effects of ataluren. Ataluren was generally well tolerated during 48 weeks of treatment in this trial. Safety profiles were similar for ataluren and placebo, other than cases of acute kidney injury (ie, increases in creatinine concentrations), the most severe of which were associated with the combination of potentially nephrotoxic antibiotics with ataluren. Thus, the combination of ataluren and aminoglycosides has been prohibited, effectively managing those clinically significant creatinine increases. This study was a well designed, well controlled trial of ataluren in patients with nonsense-mutation cystic fibrosis. The main limitation of the study was the choice of a population of patients that includes those who used chronic inhaled tobramycin, which we postulate might interfere with ataluren at the ribosomal level. Another limitation was the inability to find a biomarker that could be implemented worldwide that can differentiate the effects of ataluren treatment from placebo. Ataluren has been developed as a potential treatment for the underlying cause of cystic fibrosis in patients with nonsense mutations. Overall, ataluren showed no statistically significant difference compared with placebo for relative change in percent-predicted FEV 1 at week 48 and pulmonary exacerbation rate during 48 weeks. Concomitant administration of inhaled tobramycin interfered with readthrough of CFTR nonsense mutations by ataluren in vitro and in the clinic. In patients with nonsense-mutation cystic fibrosis not taking chronic inhaled tobramycin, ataluren produced a notable treatment effect compared with placebo for percent-predicted FEV 1 and pulmonary exacerbation. In view of the subgroup effect on spirometry and pulmonary exacerbation in patients not receiving chronic inhaled tobramycin, and a favourable safety profile, this study supports further testing of ataluren for patients with nonsense-mutation cystic fibrosis not receiving chronic inhaled tobramycin. A confirmatory phase 3 efficacy and safety trial of ataluren in patients not receiving chronic inhaled tobramycin (ACT CF trial) is in progress. Contributors EK, MWK, KDB, FJA, JSE, GLE, JB, RJS, SWP, TA, and SMR contributed to study design, data collection, interpretation of the data, intellectual content of the manuscript, writing of the manuscript, and reviewing of the final version of the manuscript. PM, IB, IF, AM, DBR, PAW, SAM, CK, SQ, ER, and PLZ contributed to study design, data collection, interpretation of the data, and reviewing of the final version of the manuscript. IS-G and MW contributed to data collection, intellectual content of the manuscript, and reviewing of the final version of the manuscript. EMW and AB designed and analysed the in-vitro combination experiments, contributed to the intellectual content of the manuscript, and reviewed the final version of the manuscript. Declaration of interests JB, GLE, EMW, AB, RJS, SWP, and TA are employees of PTC Therapeutics, the funder of this clinical trial, and hold financial interests in the company. MWK and SMR received compensation for consultant services from PTC Therapeutics during this study. EK, KDB, IS-G, and MW received compensation for travel expenses for meetings related to the study. All other authors declare no competing interests. Acknowledgments We thank the patients and families who committed their time and effort to this study. We thank the principal investigators, supporting investigators, clinical coordinators, clinical evaluator trainers, clinical evaluators, and study coordinators, and INC Research for statistical programming support. We also thank the Cystic Fibrosis Foundation Therapeutics–Therapeutics Development Network Coordinating Center and the European Cystic Fibrosis Society Clinical Trials Network for their protocol review; the University of Alabama at Birmingham Center for Clinical and Translational Science for their technical assistance; and the patient advocacy organisations, particularly the Cystic Fibrosis Foundation, for the collaboration and support that made this trial possible. Michael W O'Donnell, a medical writer employed by PTC Therapeutics, assisted in the preparation of this manuscript for publication.

PY - 2014/7

Y1 - 2014/7

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84904016376&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84904016376&partnerID=8YFLogxK

U2 - 10.1016/S2213-2600(14)70100-6

DO - 10.1016/S2213-2600(14)70100-6

M3 - Article

C2 - 24836205

AN - SCOPUS:84904016376

SN - 2213-2600

VL - 2

SP - 539

EP - 547

JO - The Lancet Respiratory Medicine

JF - The Lancet Respiratory Medicine

IS - 7

ER -

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

Abstract

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this