Advancing the pipeline of cystic fibrosis clinical trials: a new roadmap with a global trial network perspective

Cystic fibrosis is caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) protein, and nearly 90% of patients have at least one copy of the Phe508del CFTR mutation. In a phase 2 trial involving patients who were heterozygous for the Phe508del CFTR mutation and a minimal-function mutation (Phe508del-minimal function genotype), the next-generation CFTR corrector elexacaftor, in combination with tezacaftor and ivacaftor, improved Phe508del CFTR function and clinical outcomes.

Cystic fibrosis transmembrane conductance regulator (CFTR) modulators correct the basic defect caused by CFTR mutations. Improvements in health outcomes have been achieved using the combination of a CFTR corrector and potentiator in people with CF (pwCF) homozygous for F508del . The addition of elexacaftor (ELX; VX-445), a next-generation CFTR corrector, to tezacaftor/ivacaftor (TEZ/IVA) further improved F508del-CFTR function and clinical outcomes in a phase 2 study in pwCF homozygous for F508del . A phase 3, multi-centre, randomised, double-blind, active-controlled trial of ELX in triple combination with TEZ/IVA (ELX/TEZ/IVA) in pwCF homozygous for F508del was conducted. Eligible participants were aged ≥12 years with stable disease and percent predicted forced expiratory volume in 1 second (ppFEV 1 ) of 40 to 90, inclusive. After a four-week TEZ/IVA run-in, participants were randomised 1:1 to four weeks of ELX/TEZ/IVA versus TEZ/IVA alone. The primary endpoint was absolute change from baseline (measured at the end of the TEZ/IVA run-in) in ppFEV 1 at week 4. Key secondary endpoints were absolute change in sweat chloride and CF Questionnaire–Revised respiratory domain (CFQ-R RD) score. ClinicalTrials.gov , number NCT03525548 . Between August and December 2018, 113 participants were enrolled. Following the run-in, 107 participants were randomised and completed the 4-week treatment period. The ELX/TEZ/IVA group had improvements in ppFEV 1 (10·0 percentage points, 95% CI 7·4 to 12·6, p<0·0001), sweat chloride concentration (−45·1 mmol/L, 95% CI −50·1 to −40·1, p<0·0001), and CFQ-R RD score (17·4 points, 95% CI 11·8 to 23·0, p<0·0001) compared with the TEZ/IVA group. ELX/TEZ/IVA was well tolerated, with no discontinuations. Most adverse events were mild or moderate; serious adverse events occurred in 4% (n=2) of participants receiving ELX/TEZ/IVA and 2% (n=1) receiving TEZ/IVA. ELX/TEZ/IVA provided clinically robust benefit vs TEZ/IVA alone with a favourable safety profile and demonstrates the potential to lead to transformative improvements in the lives of pwCF homozygous for F508del .

Increasing the activity of defective cystic fibrosis transmembrane conductance regulator (CFTR) protein is a potential treatment for cystic fibrosis. We conducted a randomized, double-blind, placebo-controlled trial to evaluate ivacaftor (VX-770), a CFTR potentiator, in subjects 12 years of age or older with cystic fibrosis and at least one G551D-CFTR mutation. Subjects were randomly assigned to receive 150 mg of ivacaftor every 12 hours (84 subjects, of whom 83 received at least one dose) or placebo (83, of whom 78 received at least one dose) for 48 weeks. The primary end point was the estimated mean change from baseline through week 24 in the percent of predicted forced expiratory volume in 1 second (FEV(1)). The change from baseline through week 24 in the percent of predicted FEV(1) was greater by 10.6 percentage points in the ivacaftor group than in the placebo group (P<0.001). Effects on pulmonary function were noted by 2 weeks, and a significant treatment effect was maintained through week 48. Subjects receiving ivacaftor were 55% less likely to have a pulmonary exacerbation than were patients receiving placebo, through week 48 (P<0.001). In addition, through week 48, subjects in the ivacaftor group scored 8.6 points higher than did subjects in the placebo group on the respiratory-symptoms domain of the Cystic Fibrosis Questionnaire-revised instrument (a 100-point scale, with higher numbers indicating a lower effect of symptoms on the patient's quality of life) (P<0.001). By 48 weeks, patients treated with ivacaftor had gained, on average, 2.7 kg more weight than had patients receiving placebo (P<0.001). The change from baseline through week 48 in the concentration of sweat chloride, a measure of CFTR activity, with ivacaftor as compared with placebo was -48.1 mmol per liter (P<0.001). The incidence of adverse events was similar with ivacaftor and placebo, with a lower proportion of serious adverse events with ivacaftor than with placebo (24% vs. 42%). Ivacaftor was associated with improvements in lung function at 2 weeks that were sustained through 48 weeks. Substantial improvements were also observed in the risk of pulmonary exacerbations, patient-reported respiratory symptoms, weight, and concentration of sweat chloride. (Funded by Vertex Pharmaceuticals and others; VX08-770-102 ClinicalTrials.gov number, NCT00909532.).