Triple Therapy for Cystic Fibrosis Phe508del-Gating and -Residual Function Genotypes
Abstract
Background: Elexacaftor-tezacaftor-ivacaftor is a combination of small-molecule cystic fibrosis transmembrane conductance regulator (CFTR) modulators proven effective in patients who have at least one Phe508del allele. This suggests that the combination can target and modulate the Phe508del allele. However, for patients whose other CFTR allele contains a gating or residual function mutation that is already well-treated by previous CFTR modulators (ivacaftor or tezacaftor-ivacaftor), the added benefit of restoring Phe508del CFTR protein function remains unclear.
Methods: In this phase 3, double-blind, randomized, active-controlled trial, we studied patients aged 12 years or older with cystic fibrosis and Phe508del-gating or Phe508del-residual function genotypes. After a 4-week run-in with ivacaftor or tezacaftor-ivacaftor, patients were randomly assigned to receive either elexacaftor-tezacaftor-ivacaftor or an active control for 8 weeks. The primary endpoint was the absolute change in the percentage of predicted forced expiratory volume in 1 second (FEV1) from baseline to week 8 for the elexacaftor-tezacaftor-ivacaftor group.
Results: Following the run-in period, 132 patients received elexacaftor-tezacaftor-ivacaftor, and 126 received active control. Elexacaftor-tezacaftor-ivacaftor led to a 3.7 percentage point increase in predicted FEV1 (95% CI, 2.8 to 4.6) compared to baseline, and a 3.5 percentage point increase (95% CI, 2.2 to 4.7) compared to the active control. It also resulted in a 22.3 mmol/L reduction in sweat chloride concentration (95% CI, 20.2 to 24.5) compared to baseline, and a 23.1 mmol/L reduction (95% CI, 20.1 to 26.1) compared to active control (P<0.001 for all comparisons). The change in the Cystic Fibrosis Questionnaire-Revised respiratory domain score (which ranges from 0 to 100, with higher scores indicating better quality of life) was 10.3 points (95% CI, 8.0 to 12.7) for elexacaftor-tezacaftor-ivacaftor and 1.6 points (95% CI, -0.8 to 4.1) for the active control. Adverse events occurred at similar rates in both groups, with treatment discontinuation due to adverse events in one patient (elevated aminotransferase VX-661 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 both effective and safe for patients with Phe508del-gating or Phe508del-residual function genotypes, offering additional benefits over previous CFTR modulators. (Funded by Vertex Pharmaceuticals; VX18-445-104 ClinicalTrials.gov number, NCT04058353.)