Triple Therapy for Cystic Fibrosis Phe508del-Gating and -Residual Function Genotypes

Abstract

Background: Elexacaftor-tezacaftor-ivacaftor is a small-molecule cystic fibrosis transmembrane conductance regulator (CFTR) modulator regimen shown to be efficacious in patients with at least one Phe508del allele, which indicates that this combination can modulate a single Phe508del allele. In patients whose other CFTR allele contains a gating or residual function mutation that is already effectively treated with previous CFTR modulators (ivacaftor or tezacaftor-ivacaftor), the potential for additional benefit from restoring Phe508del CFTR protein function is unclear.

Methods: We conducted a phase 3, double-blind, randomized, active-controlled trial involving patients 12 years of age or older with cystic fibrosis and Phe508del-gating or Phe508del-residual function genotypes. After a 4-week run-in period with ivacaftor or tezacaftor-ivacaftor, patients were randomly assigned to receive elexacaftor-tezacaftor-ivacaftor or active control for 8 weeks. The primary end point was the absolute change in the percentage of predicted forced expiratory volume in 1 second (FEV₁) from baseline through week 8 in the elexacaftor-tezacaftor-ivacaftor group.

Results: After the run-in period, 132 patients received elexacaftor-tezacaftor-ivacaftor and 126 received active control. Elexacaftor-tezacaftor-ivacaftor resulted in a percentage of predicted FEV₁ that was higher by 3.7 percentage points (95% confidence interval [CI], 2.8 to 4.6) relative to baseline and higher by 3.5 percentage points (95% CI, 2.2 to 4.7) relative to active control and a sweat chloride concentration that was lower by 22.3 mmol per liter (95% CI, 20.2 to 24.5) relative to baseline and lower by 23.1 mmol per liter (95% CI, 20.1 to 26.1) relative to active control (P<0.001 for all comparisons). The change from baseline in the Cystic Fibrosis Questionnaire-Revised respiratory domain score (range, 0 to 100, with higher scores indicating better quality of life) with elexacaftor-tezacaftor-ivacaftor was 10.3 points (95% CI, 8.0 to 12.7) and with active control was 1.6 points (95% CI, -0.8 to 4.1). The incidence of adverse events was similar in the two groups; adverse events led to treatment discontinuation in one patient (elevated aminotransferase level) in the elexacaftor-tezacaftor-ivacaftor group and in two patients (anxiety or depression and pulmonary exacerbation) in the active control group.

Conclusions: Elexacaftor-tezacaftor-ivacaftor was efficacious and safe in patients with Phe508del-gating or Phe508del-residual function genotypes and conferred additional benefit relative to previous CFTR modulators. (Funded by Vertex Pharmaceuticals; VX18-445-104 ClinicalTrials.gov number, NCT04058353.).

Figure 1.. Efficacy End Points.

Panel A shows the absolute change from baseline at each visit in the percentage of predicted forced expiratory volume in 1 second (FEV₁) on the basis of a mixed-effects model for repeated measures. Panel B shows the absolute change from baseline at each visit in the sweat chloride concentration on the basis of a mixed-effects model for repeated measures. Panel C shows the absolute change from baseline at each visit in the score on the respiratory domain of the Cystic Fibrosis Questionnaire–Revised (CFQ-R) on the basis of a mixed-effects model for repeated measures. Respiratory domain scores are normalized to a 100-point range, with higher scores indicating a higher patient-reported quality of life with regard to respiratory symptoms; the minimal clinically important difference (MCID) is 4 points and is indicated in the plot by the straight gray line. In Panels A through C, data are least-squares means, and the I bars indicate standard errors; the dashed line at 0 cor responds to no change from baseline. The sample size shown under each x axis is the number of patients at that time point with data that could be evaluated. ELX–TEZ–IVA denotes elexacaftor–tezacaftor–ivacaftor, IVA ivacaftor, and TEZ–IVA tezacaftor–ivacaftor.