In patients with cystic fibrosis (CF) and Phe508del–gating or Phe508del–residual function genotypes, the use of elexacaftor (ELX)-tezacaftor (TEZ)-ivacaftor (IVA) triple therapy has demonstrated safety and efficacy, conferring additional benefits relative to prior cystic fibrosis transmembrane conductance regulator (CFTR) modulators. These were among the results of research recently published in The New England Journal of Medicine.
Researchers conducted a phase 3, double-blind, randomized, active-controlled trial (ClinicalTrials.gov identifier: NCT04058353) to evaluate whether use of triple therapy with ELX-TEZ-IVA can provide additional benefit in patients with CF based on restoration of Phe508d CFTR protein function.
The primary study endpoint was absolute change in the percentage of predicted forced expiratory volume in 1 second (FEV1) from baseline through week 8 in the ELX-TEZ-IVA arm. Key secondary endpoints included absolute change in sweat chloride concentration from baseline through week 8 in the ELX-TEZ-IVA group, absolute change in the percentage of predicted FEV1 from baseline through week 8 with ELX-TEZ-IVA compared with active control (ie, IVA or TEZ-IVA), and absolute change in sweat chloride concentration from baseline through week 8 with ELX-TEZ-IVA vs active control.
Following a 4-week run-in period with IVA or TEZ-IVA, patients were randomly assigned to receive ELX-TEZ-IVA or active control for 8 weeks. After the initial run-in period, a total of 132 patients received the triple therapy and 126 received active control. Treatment with ELX-TEZ-IVA was associated with a percentage of predicted FEV1 that was 3.7 percentage points higher relative to baseline (95% CI, 2.8-4.6) and 3.5 percentage points higher relative to active control (95% CI, 2.2-4.7). Further, patients in the triple therapy arm reported sweat chloride concentrations that were 22.3 mmol per liter lower relative to baseline (95% CI, 20.2-24.5) and 23.1 mmol per liter lower relative to active control (95% CI, 20.1-26.1). All of these comparisons demonstrated statistical significance (P <.001).
Change from baseline in the Cystic Fibrosis Questionnaire–Revised respiratory domain score was 10.3 points in the triple therapy group (95% CI, 8.0-12.7) vs 1.6 points in the active control group (95% CI, –0.8 to 4.1), with higher scores indicating better quality of life. The occurrence of adverse events was similar in both groups.
“This phase 3 trial showed the efficacy of elexacaftor–tezacaftor–ivacaftor therapy in patients with Phe508del–gating and Phe508del–residual function genotypes, with clinical benefit exceeding previous CFTR modulators,” said investigators. “No new safety findings were noted as compared with previous studies involving patients with cystic fibrosis,” they added.
Disclosure: Some of the study authors have declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures.
Barry PJ, Mall MA, Álvarez A, et al; VX18-445-104 Study Group. Triple therapy for cystic fibrosis Phe508del-gating and -residual function genotypes. N Engl J Med. 2021;385(9): 815-825. doi:10.1056/NEJMoa2100665