Lumacaftor–Ivacaftor in Patients with Cystic Fibrosis Homozygous for Phe508delCFTR

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.)

Efficient, non-toxic anion transport by synthetic carriers in cells and epithelia

“…While symptomatic therapy remains the bedrock of patient care, rational treatments which target the root cause of the disease are beginning to appear. Approaches include gene therapy, which has recently achieved modest success in a clinical trial 41 ; the CFTR potentiator Ivacaftor 42 , which has proved very effective for a small subset of patients with specific CFTR mutations; the CFTR corrector Lumacaftor 43 , which has been used with Ivacaftor for the largest subset of patients (though only with moderate results); and bypass therapy, which aims to provide alternative pathways for anion transport.…”

Disease-modifying drug therapy in cystic fibrosis

“…Lumacaftor (VX-809), the first of these drugs to reach the clinical trial stage, restored CFTR function to around 15% of wild type CFTR levels in vitro, but did not lead to significant clinical changes in Phe508del patients (13) so a combination approach was taken. The phase 3 TRAFFIC and TRANSPORT trials showed significant improvements in FEV1, although this was of a lower magnitude (3-4%) than seen in class III patients with ivacaftor (14) and there was a substantial decrease in the number of pulmonary exacerbations, in particular those leading to the requirement of IV antibiotics. Another corrector, VX-661 is currently undergoing large, phase III clinical trial testing in combination with ivacaftor in patients with a range of mutations (NCT02565914, NCT02392234, NCT02516410), and there are several 'next generation' molecules in development which will be tested as a triple combination.…”

A Review of Recent Advances in Translational Bioinformatics: Bridges from Biology to Medicine

“…Alongside these, the economic cost and impact of delivering precision medicine in an effective and affordable ways also need to be considered. 9 http://www.elixir-europe.org/…”

“…The successful development of the drug ivacaftor in 2012, a potentiator of CFTR function, was the first targeted therapy for patients with cystic fibrosis caused by specific genotypes [6]. In 2015, the approval of the combination therapy of a potentiator and a corrector (ivacaftor and lumacaftor) offered tailored treatments to people with cystic fibrosis caused by the most common CFTR mutation, Phe508del [9]. This treatment is a powerful example of precision medicine.…”