(A-103) Comparative efficacy and safety of CFTR modulators for people with cystic fibrosis with phe508del mutation: a systematic review and bayesian network meta-analysis

Background: The development of CFTR modulators (correctors and potentiators) emerged as a promising approach, to restore CFTR protein function. A lack of head-to-head trials comparing CFTR modulators leaves uncertainty about the optimal treatment.

Objectives: We aimed to evaluate the comparative efficacy and safety of CFTR modulators for people with cystic fibrosis who have a phe508del mutation.

Methods: We conducted an extensive literature search for both published and unpublished RCTs in databases such as PubMed, EMBASE, Scopus, Ovid, Cochrane Central Register of Controlled Trials, and international trial registers from inception until July 25, 2024. We included studies that used any CFTR modulators 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 (NMA) for each outcome using the gemtc and BUGSnet package in R. The confidence in the NMA (CINeMA) framework was utilized to determine the certainty of evidence.

Results: A total of 32 studies involving 6642 patients examining 36 treatment combinations were included in the analysis. Among the adults treated over 4 to 8 weeks, vanzacaftor 10mg-tezacaftor 100mg-deutivacaftor 150mg combination therapy was superior over placebo in improving ppFEV1 (MD, 15·9; 95% CrI: 7·9 to 23·9) with a SUCRA of 91·3% suggesting the highest probability of effectiveness. Moreover, the bamocaftor 400mg-tezacaftor 100mg-ivacaftor 150mg combination resulted in a significant reduction in sweat chloride levels (MD, -52·0 mmol/L; 95% CrI: -65·4 to -38·7) and vanzacaftor 20mg-tezacaftor 100mg-deutivacaftor 150mg significantly improved CFQ-R respiratory domain score (MD:27·8; 95% CrI: 16·1 to 39·8). We also found that the triple combination therapy of elexacaftor 200mg-tezacaftor 100mg-ivacaftor 150mg significantly improvement in ppFEV1, CFQ-R score, and reduction of sweat chloride concentration in children. Confidence in the estimates ranged from high to low, and safety analyses were limited by the low serious adverse event rates.

Conclusions: We recommend that policymakers and clinicians prioritize the elexacaftor-tezacaftor-ivacaftor and vanzacaftor-tezacaftor-deutivacaftor triple combinations when considering treatment options for patients with cystic fibrosis carrying the phe508del mutation. However, these results should be interpreted cautiously due to limited data and the low quality of existing evidence.