Lumacaftor-ivacaftor in patients with cystic fibrosis homozygous for phe508del CFTR

Wainwright, C. E., Elborn, J. S., Ramsey, B. W., Marigowda, G., Huang, X., Cipolli, M., Colombo, C., Davies, J. C., De Boeck, K., Flume, P. A., Konstan, M. W., McColley, S. A., McCoy, K., McKone, E. F., Munck, A., Ratjen, F., Rowe, S. M., Waltz, D., Boyle, M. P. and Traffic and Transport Study Group (2015) Lumacaftor-ivacaftor in patients with cystic fibrosis homozygous for phe508del CFTR. New England Journal of Medicine, 373 3: 220-231. doi:10.1056/NEJMoa1409547

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Author Wainwright, C. E.
Elborn, J. S.
Ramsey, B. W.
Marigowda, G.
Huang, X.
Cipolli, M.
Colombo, C.
Davies, J. C.
De Boeck, K.
Flume, P. A.
Konstan, M. W.
McColley, S. A.
McCoy, K.
McKone, E. F.
Munck, A.
Ratjen, F.
Rowe, S. M.
Waltz, D.
Boyle, M. P.
Traffic and Transport Study Group
Title Lumacaftor-ivacaftor in patients with cystic fibrosis homozygous for phe508del CFTR
Journal name New England Journal of Medicine   Check publisher's open access policy
ISSN 1533-4406
0028-4793
Publication date 2015-07-16
Year available 2015
Sub-type Article (original research)
DOI 10.1056/NEJMoa1409547
Open Access Status File (Publisher version)
Volume 373
Issue 3
Start page 220
End page 231
Total pages 12
Place of publication Waltham, MA, United States
Publisher Massachussetts Medical Society
Language eng
Abstract BACKGROUND Cystic fibrosis is a life-limiting disease that is caused by defective or deficient cystic fibrosis transmembrane conductance regulator (CFTR) protein activity. Phe508del is the most common CFTR mutation.
Formatted abstract
Background:  Cystic fibrosis is a life-limiting disease that is caused by defective or deficient cystic fibrosis transmembrane conductance regulator (CFTR) protein activity. Phe508del is the most common CFTR mutation.

Methods:  We conducted two phase 3, randomized, double-blind, placebo-controlled studies that were designed to assess the effects of lumacaftor (VX-809), a CFTR corrector, in combination with ivacaftor (VX-770), a CFTR potentiator, in patients 12 years of age or older who had cystic fibrosis and were homozygous for the Phe508del CFTR mutation. In both studies, patients were randomly assigned to receive either lumacaftor (600 mg once daily or 400 mg every 12 hours) in combination with ivacaftor (250 mg every 12 hours) or matched placebo for 24 weeks. The primary end point was the absolute change from baseline in the percentage of predicted forced expiratory volume in 1 second (FEV1) at week 24.

Results:  A total of 1108 patients underwent randomization and received study drug. The mean baseline FEV1 was 61% of the predicted value. In both studies, there were significant improvements in the primary end point in both lumacaftor–ivacaftor dose groups; the difference between active treatment and placebo with respect to the mean absolute improvement in the percentage of predicted FEV1 ranged from 2.6 to 4.0 percentage points (P<0.001), which corresponded to a mean relative treatment difference of 4.3 to 6.7% (P<0.001). Pooled analyses showed that the rate of pulmonary exacerbations was 30 to 39% lower in the lumacaftor–ivacaftor groups than in the placebo group; the rate of events leading to hospitalization or the use of intravenous antibiotics was lower in the lumacaftor–ivacaftor groups as well. The incidence of adverse events was generally similar in the lumacaftor–ivacaftor and placebo groups. The rate of discontinuation due to an adverse event was 4.2% among patients who received lumacaftor–ivacaftor versus 1.6% among those who received placebo.

Conclusions:  These data show that lumacaftor in combination with ivacaftor provided a benefit for patients with cystic fibrosis homozygous for the Phe508del CFTR mutation. (Funded by Vertex Pharmaceuticals and others; TRAFFIC and TRANSPORT ClinicalTrials.gov numbers, NCT01807923 and NCT01807949.)
Keyword Cystic fibrosis
Lumacaftor–Ivacaftor
Q-Index Code C1
Q-Index Status Confirmed Code
Grant ID UL1TR000423
P30DK089507
UL1TR000062
UL1TR000439
DK027651
UL1RR025741
MCCOLL14YO
UL1TR000165
DK072482
UL1TR001079
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2016 Collection
Child Health Research Centre Publications
 
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