Efficacy and safety of the elexacaftor plus tezacaftor plus ivacaftor combination regimen in people with cystic fibrosis homozygous for the F508del mutation: a double-blind, randomised, phase 3 trial

Abstract

Background: Cystic fibrosis transmembrane conductance regulator (CFTR) modulators correct the basic defect caused by CFTR mutations. Improvements in health outcomes have been achieved with the combination of a CFTR corrector and potentiator in people with cystic fibrosis homozygous for the F508del mutation. The addition of elexacaftor (VX-445), a next-generation CFTR corrector, to tezacaftor plus ivacaftor further improved F508del-CFTR function and clinical outcomes in a phase 2 study in people with cystic fibrosis homozygous for the F508del mutation.

Methods: This phase 3, multicentre, randomised, double-blind, active-controlled trial of elexacaftor in combination with tezacaftor plus ivacaftor was done at 44 sites in four countries. Eligible participants were those with cystic fibrosis homozygous for the F508del mutation, aged 12 years or older with stable disease, and with a percentage predicted forced expiratory volume in 1 s (ppFEV₁) of 40-90%, inclusive. After a 4-week tezacaftor plus ivacaftor run-in period, participants were randomly assigned (1:1) to 4 weeks of elexacaftor 200 mg orally once daily plus tezacaftor 100 mg orally once daily plus ivacaftor 150 mg orally every 12 h versus tezacaftor 100 mg orally once daily plus ivacaftor 150 mg orally every 12 h alone. The primary outcome was the absolute change from baseline (measured at the end of the tezacaftor plus ivacaftor run-in) in ppFEV₁ at week 4. Key secondary outcomes were absolute change in sweat chloride and Cystic Fibrosis Questionnaire-Revised respiratory domain (CFQ-R RD) score. This study is registered with ClinicalTrials.gov, NCT03525548.

Findings: Between Aug 3 and Dec 28, 2018, 113 participants were enrolled. Following the run-in, 107 participants were randomly assigned (55 in the elexacaftor plus tezacaftor plus ivacaftor group and 52 in the tezacaftor plus ivacaftor group) and completed the 4-week treatment period. The elexacaftor plus tezacaftor plus ivacaftor group had improvements in the primary outcome of ppFEV₁ (least squares mean [LSM] treatment difference of 10·0 percentage points [95% CI 7·4 to 12·6], p<0·0001) and the key secondary outcomes of sweat chloride concentration (LSM treatment difference -45·1 mmol/L [95% CI -50·1 to -40·1], p<0·0001), and CFQ-R RD score (LSM treatment difference 17·4 points [95% CI 11·8 to 23·0], p<0·0001) compared with the tezacaftor plus ivacaftor group. The triple combination regimen was well tolerated, with no discontinuations. Most adverse events were mild or moderate; serious adverse events occurred in two (4%) participants receiving elexacaftor plus tezacaftor plus ivacaftor and in one (2%) receiving tezacaftor plus ivacaftor.

Interpretation: Elexacaftor plus tezacaftor plus ivacaftor provided clinically robust benefit compared with tezacaftor plus ivacaftor alone, with a favourable safety profile, and shows the potential to lead to transformative improvements in the lives of people with cystic fibrosis who are homozygous for the F508del mutation.

Funding: Vertex Pharmaceuticals.

Figure 1.. Study Design.

Phase 3, randomised, double-blind, active-controlled, parallel-group, multicentre study. Eligible participants received tezacaftor/ivacaftor therapy during a 4-week run-in period. After completing the run-in period participants were randomised (1:1) to receive elexacaftor/tezacaftor/ivacaftor triple combination therapy or tezacaftor/ivacaftor for 4 weeks. Randomisation was stratified by percent predicted FEV₁ (<70 vs ≥70) determined during the run-in period and age (<18 vs ≥18 years) determined at the screening visit. ELX=elexacaftor; FEV₁=forced expiratory volume in 1 second; IVA=ivacaftor; QAM=once daily in the morning; QPM=once daily in the evening; TEZ=tezacaftor. * Baseline was defined as the most recent non-missing measurement (scheduled or unscheduled) collected before the first dose of trial drug in the treatment period (ie, ELX/TEZ/IVA vs TEZ/IVA). † Participants who completed the trial regimen were eligible to enrol in a separate 96-week open-label extension study within 28 days after the last dose of trial drug; a safety follow-up visit was required for all participants unless they completed the week 4 visit and enrolled in the open-label extension study.

Figure 2.. Absolute Change Over Time in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV₁) From Baseline.

Data are least squares means based on a mixed-effects model for repeated measures, and error bars indicate standard errors; the dashed line indicates no change from baseline (measured at the end of the tezacaftor/ivacaftor run-in).

Figure 3.. Absolute Change Over Time in Sweat Chloride Concentration From Baseline.

Panel A shows the absolute change in sweat chloride from baseline (measured at the end of the tezacaftor/ivacaftor run-in period). Panel B shows the mean sweat chloride concentration for each treatment group by visit. Data are least squares means based on a mixed-effects model for repeated measures for panel A and sample means for panel B; error bars indicate standard errors; the dashed line in panel A indicates no change from baseline; the dotted line in panel B indicates the 60 mmol/L diagnostic threshold for sweat chloride concentration.

Figure 3.. Absolute Change Over Time in Sweat Chloride Concentration From Baseline.

Panel A shows the absolute change in sweat chloride from baseline (measured at the end of the tezacaftor/ivacaftor run-in period). Panel B shows the mean sweat chloride concentration for each treatment group by visit. Data are least squares means based on a mixed-effects model for repeated measures for panel A and sample means for panel B; error bars indicate standard errors; the dashed line in panel A indicates no change from baseline; the dotted line in panel B indicates the 60 mmol/L diagnostic threshold for sweat chloride concentration.

Figure 4.. Absolute Change Over Time in Cystic Fibrosis Questionnaire–Revised Respiratory Domain Score From Baseline.

Scores range from 0 to 100, with higher scores indicating a higher participant-reported quality of life with regard to respiratory status. Data are least squares mean based on a mixed-effects model for repeated measures, and error bars indicate standard errors; the dashed line indicates no change from baseline; solid light grey line indicates a change in 4 points, which is the minimal clinically important difference for pwCF with stable disease. CFQ-R=Cystic Fibrosis Questionnaire–Revised.