CFTR modulator monotherapy for people with cystic fibrosis with class II CFTR gene variants (most commonly F508del)

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 gene variant, F508del, is the commonest CF-causing variant (found in up to 90% of people with CF (pwCF) in some populations). The F508del variant lacks meaningful CFTR function: the faulty protein is degraded before reaching the cell membrane, where it would normally transport salt across the epithelial membrane. Corrective therapy with CFTR modulators could benefit many pwCF. This review evaluates treatment with single modulators (monotherapy).

To evaluate the clinically important benefits and harms of CFTR modulator monotherapy in people of any age with cystic fibrosis with class II CFTR gene variants (most commonly F508del).

We last searched the Cochrane CF Trials Register and online trials registries on 27 June 2025. We also checked the reference lists of relevant articles for additional studies.

We included parallel-group randomised controlled trials (RCTs) comparing any single CFTR modulator to placebo or any other single CFTR modulator in pwCF of any age or disease severity with class II variants.

Our critical outcomes were survival, quality of life (total score and respiratory domain), and forced expiratory volume in one second (FEV₁ % predicted; relative and absolute change from baseline). Our important outcomes included adverse effects and time to first pulmonary exacerbation. We planned to assess outcomes in the immediate term, short term, and longer term.

We assessed risk of bias using the original Cochrane tool (RoB 1).

We analysed available data with RevMan using a fixed-effect model. We reported odds ratios (ORs) for dichotomous outcomes and mean differences (MDs) for continuous outcomes. For adverse events, we reported 99% confidence intervals (CIs); for all other outcomes, we reported 95% CIs. Where we were unable to analyse data, we reported the results narratively. We used GRADE to assess the certainty of the evidence.

We included 10 early-phase placebo-controlled RCTs (424 participants) assessing eight different drugs (4PBA, CPX, N6022, cavosonstat, lumacaftor, FDL169, GLPG2222, and riociguat) in adults; one 4PBA study additionally included adolescents (age ≥ 14 years). All participants were homozygous for F508del. The longest study lasted just 29 days, so we could only assess immediate-term outcomes. Only two studies received no funding from pharmaceutical companies. Our main results are for lumacaftor and cavosonstat, which were the only drugs selected for further investigation in subsequent studies.

Investigators reported no deaths, but also no clinically relevant improvements in quality of life. There was insufficient evidence to determine effects on any measure of lung function. No studies demonstrated differences in the risk of mild, moderate, or severe adverse effects, including pulmonary exacerbations, between CFTR modulator monotherapy and placebo. The clinical relevance of adverse effects is difficult to assess, because each occurred in only a few participants per trial. We assessed the certainty of the evidence for two comparisons (lumacaftor versus placebo and cavosonstat versus placebo), rating the certainty of the evidence to be very low.

There is a lack of evidence to support monotherapy with a CFTR modulator for pwCF who have two F508del variants (F508del/F508del).

This review was completed under a programme of work that is part of the CF Foundation grant funding for Cochrane CF.

The protocol was registered on PROSPERO (https://www.crd.york.ac.uk/PROSPERO/view/CRD420251090914).