P70 Corrector therapies (with or without potentiators) for people with cystic fibrosis with class II CFTR gene variants (most commonly F508del)

Résumé fourni par la source

Introduction Cystic fibrosis (CF) is caused by abnormal variants of the cystic fibrosis transmembrane conductance regulator (CFTR) gene, of which F508del, is the commonest. The F508del protein is degraded before reaching the cell membrane. Therapy to correct this defect would benefit many people with CF (pwCF). Objectives To evaluate the effects of CFTR correctors on clinically important outcomes in pwCF of any age with class II CFTR variants. Methods We searched the Cochrane Cystic Fibrosis and Genetic Disorders Cystic Fibrosis Trials Register, reference lists of relevant articles and online trials registries. The most recent search was conducted on 31st December 2021. We searched for randomised controlled trials (RCTs) of parallel design comparing CFTR correctors to control in pwCF with class II variants and contacted authors for additional data. Two authors then independently extracted data, assessed risk of bias and evidence quality (GRADE). Results A total of 34 RCTs were included (1754 participants); eight monotherapy RCTs (4PBA, CPX, lumacaftor, cavosonstat and FDL 169), fifteen dual-therapy RCTs (lumacaftor-ivacaftor or tezacaftor-ivacaftor) and eleven triple-therapy RCTs (elexacaftor-tezacaftor-ivacaftor, VX-659- tezacaftor-ivacaftor, VX-440-tezacaftor-ivacaftor and VX-152-tezacaftor-ivacaftor). For monotherapy trials, there were no clinically relevant improvements in quality of life (QoL) or lung function. For the dual therapy data, there were small but significant improvements in QoL and lung function. For lumacaftor-ivacaftor some participants experienced transient dyspnoea and an overall rise in blood pressure was noted. For triple therapy, there were improvements in QoL scores and respiratory function (FEV1). In 175 participants with F508del/F508del elexacaftor-tezacaftor-ivacaftor improved QoL respiratory scores (MD 15.90 (95% CI 11.74 to 20.06)) and absolute change in FEV1 (MD 10.20 (95% CI 8.26 to 12.14)) compared to control through six months. Conclusions There is no evidence to support corrector monotherapy use and limited evidence to support dual therapy. There were significant and clinically relevant differences found across outcomes in the triple therapy studies, with improved safety profile. More research is needed into assessing these therapies in paediatric patients and the longer-term safety profiles of these new therapies, but these early results suggest this will be a transformational intervention for pwCF with class 2 CFTR gene variants.

Ce résumé expose les affirmations des auteurs. BNTIC ne l’interprète pas comme une validation indépendante des résultats.