Comparative efficacy and safety of CFTR modulators for people with cystic fibrosis with phe508del mutation: a systematic review and bayesian network meta-analysis.

Abstract

The development of cystic fibrosis transmembrane conductance regulator (CFTR) modulators (correctors and potentiators) emerged as a promising approach, aiming to restore CFTR protein function. A lack of head-to-head trials comparing CFTR modulators leaves uncertainty about the optimal treatment. We aimed to evaluate the comparative efficacy and safety of CFTR modulators for people with cystic fibrosis who have a phe508del mutation. We conducted an extensive literature search for both published and unpublished randomized controlled trials in databases such as PubMed, EMBASE, Scopus, Ovid, Cochrane Central Register of Controlled Trials, and international trial registers from inception until May 21, 2025. We included studies that used any CFTR modulators (monotherapy or combination) for the treatment of children and adults with a confirmed diagnosis of cystic fibrosis with phe508del CFTR mutation. Two reviewers independently and in duplicate performed study selection, data extraction, and quality assessment. Our primary outcomes were efficacy (change in percent predicted forced expiratory volume (ppFEV₁), sweat chloride) and safety (frequency of serious adverse events). We performed a random effect bayesian network meta-analysis for each outcome using the gemtc and BUGSnet package in R. The confidence in the network meta-analysis framework was utilized to determine the certainty of evidence. The study protocol was registered with Prospective Register of Systematic Reviews (CRD42024505081). Of the 3473 studies identified through our literature search, 29 studies involving 6450 patients examining 34 treatment combinations were included. For adults treated over 4-8 weeks, vanzacaftor 10 mg-tezacaftor 100 mg-deutivacaftor 150 mg combination therapy had a significant improvement over placebo in improving ppFEV₁ (MD: 15.9; 95% CrI: 7.2-24.2 [high certainty]) with a SUCRA of 92% suggesting the highest probability of effectiveness. Moreover, the vanzacaftor 20 mg-tezacaftor 100 mg-deutivacaftor 150 mg showed a significant reduction in sweat chloride levels (MD: -49.3 mmol/L; 95% CrI: -67.2 to -31.7 [high certainty]) and improved the CFQ-R scores (MD: 39; 95% CrI: 21.2-56.9; [high certainty]) when compared to placebo after 4-8 weeks of treatment. Our findings also highlighted that the triple combination therapies of vanzacaftor 20 mg-tezacaftor 100 mg-deutivacaftor 250 mg and elexacaftor 200 mg-tezacaftor 100 mg-ivacaftor 150 mg provided clinically meaningful improvements across all measured outcomes in adults treated for more than 8 weeks. Confidence in the estimates ranged from high to low, and safety analyses were limited by the low serious adverse event rates. Our findings indicate that vanzacaftor-tezacaftor-deutivacaftor and elexacaftor-tezacaftor-deutivacaftor emerged as the most effective treatment options in adults. However, these results should be interpreted cautiously due to limited data and the low quality of existing evidence. None.