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Clinical Trial
. 2015 Jul 16;373(3):220-31.
doi: 10.1056/NEJMoa1409547. Epub 2015 May 17.

Lumacaftor-Ivacaftor in Patients with Cystic Fibrosis Homozygous for Phe508del CFTR

Claire E Wainwright  1 , J Stuart Elborn, Bonnie W Ramsey, Gautham Marigowda, Xiaohong Huang, Marco Cipolli, Carla Colombo, Jane C Davies, Kris De Boeck, Patrick A Flume, Michael W Konstan, Susanna A McColley, Karen McCoy, Edward F McKone, Anne Munck, Felix Ratjen, Steven M Rowe, David Waltz, Michael P Boyle; TRAFFIC Study Group; TRANSPORT Study Group
Collaborators, Affiliations
Clinical Trial

Lumacaftor-Ivacaftor in Patients with Cystic Fibrosis Homozygous for Phe508del CFTR

Claire E Wainwright et al. N Engl J Med. .

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.).

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Figures

Figure 1
Figure 1. Absolute Changes from Baseline in the Percent-age of Predicted Forced Expiratory Volume in 1 Second (FEV1) According to Study Group
The LUM (600 mg/day)–IVA group received 600 mg of lumacaftor (LUM) once daily in combination with 250 mg of ivacaftor (IVA) every 12 hours; the LUM (400 mg every 12 hr)–IVA group received 400 mg of lumacaftor every 12 hours in combination with 250 mg of ivacaftor every 12 hours. Panel A shows the mean absolute change in the percentage of predicted FEV1 over time in each study group; the difference between each active-treatment group and the placebo group at each time point was significant (P<0.025). Panel B shows subgroup analyses of the differences between the active treatment and placebo in the absolute change from baseline in the percentage of predicted FEV1 at week 24. Data in both panels are least-squares means; I bars indicate 95% confidence intervals. The results represent pooled data from the TRAFFIC and TRANSPORT studies.
Figure 2
Figure 2. Pulmonary Exacerbations
The time to first pulmonary exacerbation and number of pulmonary exacerbations leading to hospitalization or treatment with intravenous antibiotics are shown. In Panel B, the number of pulmonary exacerbations observed through week 24 is expressed as a rate over 48 weeks. The results represent pooled data from the TRAFFIC and TRANSPORT studies.
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References

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