Chest
Volume 142, Issue 3, September 2012, Pages 718-724
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Original Research
Cystic Fibrosis
Ivacaftor in Subjects With Cystic Fibrosis Who Are Homozygous for the F508del-CFTR Mutation

https://doi.org/10.1378/chest.11-2672Get rights and content

Background

Ivacaftor (VX-770) is a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator that was approved in the United States for the treatment of cystic fibrosis (CF) in patients ≥ 6 years of age who have a G551D mutation; however, the most prevalent disease-causing CFTR mutation, F508del, causes a different functional defect. The objectives of this study were to evaluate the safety of ivacaftor in a larger population and for a longer time period than tested previously and to assess the efficacy of ivacaftor in subjects with CF who are homozygous for F508del-CFTR.

Methods

This was a phase 2 study with a 16-week randomized (4:1), double-blind, placebo-controlled period (part A) and an open-label extension (part B) for subjects who met prespecified criteria.

Results

Part A: The safety profile of ivacaftor was comparable to that of the placebo. The overall adverse event frequency was similar in the ivacaftor (87.5%) and placebo (89.3%) groups through 16 weeks. The difference in the change of FEV1 % predicted from baseline through week 16 (primary end point) between the ivacaftor and placebo groups was 1.7% (P = .15). Sweat chloride, a biomarker of CFTR activity, showed a small reduction in the ivacaftor vs placebo groups of −2.9 mmol/L (P = .04) from baseline through week 16. Part B: No new safety signals were identified. The changes in FEV1 or sweat chloride in part A were not sustained with ivacaftor treatment from week 16 to week 40.

Conclusions

These results expand the safety information for ivacaftor and support its continued evaluation. Lack of a clinical effect suggests that a CFTR potentiator alone is not an effective therapeutic approach for patients who have CF and are homozygous for F508del-CFTR.

Section snippets

Study Design

This was a two-part, phase 2, multicenter, randomized (4:1), placebo-controlled, double-blind study of ivacaftor (Kalydeco, formerly known as VX-770; Vertex Pharmaceuticals Incorporated), 150 mg po administered every 12 h for 16 weeks (part A), followed by an open-label 96-week extension for subjects who met prespecified eligibility criteria (part B). The rationale for selecting subjects for the open-label extension was to determine whether the changes from baseline observed in part A of the

Subjects

The study was conducted between September 2009 and July 2010. Thirty-four study sites in the United States enrolled and randomized 140 subjects (ivacaftor, n = 112; placebo, n = 28). The groups were generally similar at baseline (Table 1).

A total of 104 subjects (92.9%) in the ivacaftor group and 26 (92.9%) in the placebo group completed dosing in part A (Fig 1). The most frequent reason for discontinuation was an adverse event (three subjects [2.7%] in the ivacaftor group and two subjects

Discussion

This randomized, double-blind, placebo-controlled, multicenter study evaluated the safety and efficacy of the CFTR potentiator, ivacaftor, in subjects with CF homozygous for the F508del-CFTR mutation. The safety profile of ivacaftor compared with placebo in this study supports further clinical evaluation in patients with CF. Treatment with ivacaftor was not associated with significant improvements in FEV1 or other clinical end points. There was a small reduction in sweat chloride concentration

Conclusions

This study augments the safety information for ivacaftor and supports the continued evaluation of ivacaftor in subjects with CF. The lack of an observed clinical effect suggests that CFTR potentiation with ivacaftor alone will not benefit patients with CF who are homozygous for the F508del-CFTR mutation. Although a proportion of subjects treated with ivacaftor showed a small change in the sweat chloride biomarker, this was not associated with clinical benefit. Additional studies are needed to

Acknowledgments

Author contributions: Dr Flume served as guarantor of the manuscript.

Dr Flume: contributed to the acquisition of data, analysis and interpretation of data, drafting of the manuscript, critical revision of the manuscript for important intellectual content, and approval of the final version.

Dr Liou: contributed to the acquisition of data and critical revision of the manuscript for important intellectual content and saw and approved the final version.

Dr Borowitz: contributed to the acquisition of

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Funding/Support: The DISCOVER study is sponsored by Vertex Pharmaceuticals Incorporated. This research was supported by the Cystic Fibrosis Foundation to the Women and Children's Hospital of Buffalo [Grant BOROWI03CS0] and to the Medical University of South Carolina [Grant C104-TDC10Y].

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A complete list of study participants is located in e-Appendix 1.

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