Abstract

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 (found in up to 90% of people with CF (pwCF)) is the commonest CF‐causing variant. The faulty protein is degraded before reaching the cell membrane, where it needs to be to effect transepithelial salt transport. The F508del variant lacks meaningful CFTR function and corrective therapy could benefit many pwCF. Therapies in this review include single correctors and any combination of correctors and potentiators.

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 Cystic Fibrosis and Genetic Disorders Cystic Fibrosis Trials Register, reference lists of relevant articles and online trials registries. Most recent search: 14 October 2020.

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 evidence quality (GRADE); we contacted investigators for additional data.

Main results

We included 19 RCTs (2959 participants), lasting between 1 day and 24 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), six dual‐therapy RCTs (1840 participants) (lumacaftor‐ivacaftor or tezacaftor‐ivacaftor) and five triple‐therapy RCTs (775 participants) (elexacaftor‐tezacaftor‐ivacaftor or VX‐659‐tezacaftor‐ivacaftor); below we report only the data from elexacaftor‐tezacaftor‐ivacaftor combination which proceeded to Phase 3 trials. In 14 RCTs participants had F508del/F508del genotypes, in three RCTs F508del/minimal function (MF) genotypes and in two RCTs both genotypes.

Risk of bias judgements varied across different comparisons. Results from 11 RCTs may not be applicable to all pwCF due to age limits (e.g. adults only) or non‐standard design (converting from monotherapy to combination therapy).

Monotherapy

Investigators reported no deaths or clinically‐relevant improvements in quality of life (QoL). There was insufficient evidence to determine any important effects on lung function.

No placebo‐controlled monotherapy RCT demonstrated differences in mild, moderate or severe adverse effects (AEs); the clinical relevance of these events is difficult to assess with their variety and small number of participants (all F508del/F508del).

Dual therapy

Investigators reported no deaths (moderate‐ to high‐quality evidence). QoL scores (respiratory domain) favoured both lumacaftor‐ivacaftor and tezacaftor‐ivacaftor therapy compared to placebo at all time points. At six months lumacaftor 600 mg or 400 mg (both once daily) plus ivacaftor improved Cystic Fibrosis Questionnaire (CFQ) scores slightly compared with placebo (mean difference (MD) 2.62 points (95% confidence interval (CI) 0.64 to 4.59); 1061 participants; high‐quality evidence). A similar effect was observed for twice‐daily lumacaftor (200 mg) plus ivacaftor (250 mg), but with low‐quality evidence (MD 2.50 points (95% CI 0.10 to 5.10)). The mean increase in CFQ scores with twice‐daily tezacaftor (100 mg) and ivacaftor (150 mg) was approximately five points (95% CI 3.20 to 7.00; 504 participants; moderate‐quality evidence). At six months, the relative change in forced expiratory volume in one second (FEV1) % predicted improved with combination therapies compared to placebo by: 5.21% with once‐daily lumacaftor‐ivacaftor (95% CI 3.61% to 6.80%; 504 participants; high‐quality evidence); 2.40% with twice‐daily lumacaftor‐ivacaftor (95% CI 0.40% to 4.40%; 204 participants; low‐quality evidence); and 6.80% with tezacaftor‐ivacaftor (95% CI 5.30 to 8.30%; 520 participants; moderate‐quality evidence).

More pwCF reported early transient breathlessness with lumacaftor‐ivacaftor, odds ratio 2.05 (99% CI 1.10 to 3.83; 739 participants; high‐quality evidence). Over 120 weeks (initial study period and follow‐up) systolic blood pressure rose by 5.1 mmHg and diastolic blood pressure by 4.1 mmHg with twice‐daily 400 mg lumacaftor‐ivacaftor (80 participants; high‐quality evidence). The tezacaftor‐ivacaftor RCTs did not report these adverse effects.

Pulmonary exacerbation rates decreased in pwCF receiving additional therapies to ivacaftor compared to placebo: lumacaftor 600 mg hazard ratio (HR) 0.70 (95% CI 0.57 to 0.87; 739 participants); lumacaftor 400 mg, HR 0.61 (95% CI 0.49 to 0.76; 740 participants); and tezacaftor, HR 0.64 (95% CI, 0.46 to 0.89; 506 participants) (moderate‐quality evidence).

Triple therapy

Three RCTs of elexacaftor to tezacaftor‐ivacaftor in pwCF (aged 12 years and older with either one or two F508del variants) reported no deaths (high‐quality evidence). All other evidence was graded as moderate quality. In 403 participants with F508del/minimal function (MF) elexacaftor‐tezacaftor‐ivacaftor improved QoL respiratory scores (MD 20.2 points (95% CI 16.2 to 24.2)) and absolute change in FEV1 (MD 14.3% predicted (95% CI 12.7 to 15.8)) compared to placebo at 24 weeks. At four weeks in 107 F508del/F508del participants, elexacaftor‐tezacaftor‐ivacaftor improved QoL respiratory scores (17.4 points (95% CI 11.9 to 22.9)) and absolute change in FEV1 (MD 10.0% predicted (95% CI 7.5 to 12.5)) compared to tezacaftor‐ivacaftor. There was probably little or no difference in the number or severity of AEs between elexacaftor‐tezacaftor‐ivacaftor and placebo or control (moderate‐quality evidence). In 403 F508del/F508del participants, there was a longer time to protocol‐defined pulmonary exacerbation with elexacaftor‐tezacaftor‐ivacaftor over 24 weeks (moderate‐quality evidence).

Authors' conclusions

There is insufficient evidence that corrector monotherapy has clinically important effects in pwCF with F508del/F508del.

Both dual therapies (lumacaftor‐ivacaftor, tezacaftor‐ivacaftor) result in similar improvements in QoL and respiratory function with lower pulmonary exacerbation rates. Lumacaftor‐ivacaftor was associated with an increase in early transient shortness of breath and longer‐term increases in blood pressure (not observed for tezacaftor‐ivacaftor). Tezacaftor‐ivacaftor has a better safety profile, although data are lacking in children under 12 years. In this population, lumacaftor‐ivacaftor had an important impact on respiratory function with no apparent immediate safety concerns; but this should be balanced against the blood pressure increase and shortness of breath seen in longer‐term adult data when considering lumacaftor‐ivacaftor.

There is high‐quality evidence of clinical efficacy with probably little or no difference in AEs for triple (elexacaftor‐tezacaftor‐ivacaftor) therapy in pwCF with one or two F508del variants aged 12 years or older. Further RCTs are required in children (under 12 years) and those with more severe respiratory function.