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

Background Cystic fibrosis (CF) is a common life‐shortening genetic condition caused by a variant in the cystic fibrosis transmembrane conductance regulator (CFTR) protein. A class II CFTR variant F508del is the commonest CF‐causing variant (found in up to 90% of people with CF (pwCF)). The F508del variant lacks meaningful CFTR function ‐ faulty protein is degraded before reaching the cell membrane, where it needs to be to effect transepithelial salt transport. Corrective therapy could benefit many pwCF. This review evaluates single correctors (monotherapy) and any combination of correctors (most commonly lumacaftor, tezacaftor, elexacaftor, VX‐659, VX‐440 or VX‐152) and a potentiator (e.g. ivacaftor) (dual and triple therapies). Objectives To evaluate the effects of CFTR correctors (with or without potentiators) on clinically important benefits and harms in pwCF of any age with class II CFTR mutations (most commonly F508del). Search methods We searched the Cochrane CF Trials Register (28 November 2022), reference lists of relevant articles and online trials registries (3 December 2022). Selection criteria Randomised controlled trials (RCTs) (parallel design) comparing CFTR correctors to control in pwCF with class II mutations. Data collection and analysis Two authors independently extracted data, assessed risk of bias and judged evidence certainty (GRADE); we contacted investigators for additional data. Main results We included 34 RCTs (4781 participants), lasting between 1 day and 48 weeks; an extension of two lumacaftor‐ivacaftor studies provided additional 96‐week safety data (1029 participants). We assessed eight monotherapy RCTs (344 participants) (4PBA, CPX, lumacaftor, cavosonstat and FDL169), 16 dual‐therapy RCTs (2627 participants) (lumacaftor‐ivacaftor or tezacaftor‐ivacaftor) and 11 triple‐therapy RCTs (1804 participants) (elexacaftor‐tezacaftor‐ivacaftor/deutivacaftor; VX‐659‐tezacaftor‐ivacaftor/deutivacaftor; VX‐440‐tezacaftor‐ivacaftor; VX‐152‐tezacaftor‐ivacaftor). Participants in 21 RCTs had the genotype F508del/F508del, in seven RCTs they had F508del/minimal function (MF), in one RCT F508del/gating genotypes, in one RCT either F508del/F508del genotypes or F508del/residual function genotypes, in one RCT either F508del/gating or F508del/residual function genotypes, and in three RCTs either F508del/F508del genotypes or F508del/MF genotypes. Risk of bias judgements varied across different comparisons. Results from 16 RCTs may not be applicab