CFTR correctors, a therapy for cystic fibrosis targeted at specific mutations

Review question

We looked at drugs (or combination of drugs) that aim to correct the basic defect for the commonest mutation (F508del) that causes cystic fibrosis (CF). We assessed the impact on clinical outcomes that are important to people with CF (e.g., survival, quality of life, lung function and safety).


The CF gene makes a protein that has important function in many parts of the body by helping the movement of salts across cells. People with CF are either not able to make this protein or make a protein that is defective. A common mutation of the CF gene is F508del and over 80% of people with CF have at least one copy of this gene variant. When the CF gene is affected by F508del, a full length of protein is made but it is not able to move through the cell correctly. Laboratory experiments suggest that if this protein can be transported to the cell wall then it may be able to function, restore salt movement and correct the chronic problems experienced by people with CF. We examined a number of agents that might correct the F508del mutation.

Search date

Evidence is current to: 24 February 2018.

Study characteristics

We included 13 studies (2215 children and adults with CF) which lasted between 1 day and 24 weeks (with an extension study of two studies up to 96 weeks). Seven studies (317 participants) looked at single agents (monotherapy: 4PBA (also known as Buphenyl), CPX, lumacaftor and cavosonstat) versus placebo (a dummy treatment containing no active medicine) and six recent studies (1898 participants) assessed combination therapy (lumacaftor-ivacaftor or tezacaftor-ivacaftor) versus placebo. In 12 studies participants had two copies of the F508del mutation and in one study they had one F508del mutation and a second different mutation.

Key results

Monotherapy versus placebo

These studies did not report any deaths or any clinically relevant improvements in quality of life scores. There was not enough evidence to show an effect on lung function. Side effects were reported in all studies, but it is difficult to assess their relevance due to the range of effects and the small number of participants in the studies.

Combination therapy versus placebo

No deaths were reported in either the lumacaftor-ivacaftor or tezacaftor-ivacaftor studies in people with two copies of the F508del mutation and there were improvements in quality of life and lung function. Rates of pulmonary exacerbations (a flare up of symptoms) were also lower. Neither combination therapy was associated with severe side effects, although people on lumacaftor-ivacaftor regularly experienced shortness of breath for one to two weeks at the start of treatment, which usually resolved without further intervention. Of more concern was that in longer studies some people receiving lumacaftor-ivacaftor experienced a rise in blood pressure; of these, two people (out of more than 500 who received the combination in these studies) discontinued lumacaftor-ivacaftor treatment because of high blood pressure. These side effects were not reported for the tezacaftor-ivacaftor combination. Tezacaftor-ivacaftor therapy has not yet been assessed in children with CF younger than 12 years of age.

Quality of the evidence

We judged the overall quality of the evidence for the outcomes measured to vary from low to high. Study design was generally poorly reported, which did not allow us to make clear judgements on any potential bias, but we had fewer concerns with the six larger and more recent studies. We did find that some results were omitted from the analysis or not reported in seven studies. Some findings were based on single studies that were too small to show important effects and for five studies the results may not be applicable to all individuals with CF due to the ages of people recruited into the studies (i.e. adults only, children only) or an unusual design used in which people receive monotherapy and then combination therapy.

Authors' conclusions: 

There is insufficient evidence that monotherapy with correctors has clinically important effects in people with CF who have two copies of the F508del mutation.

Combination therapies (lumacaftor-ivacaftor and tezacaftor-ivacaftor) each result in similarly small improvements in clinical outcomes in people with CF; specifically improvements quality of life (moderate-quality evidence), in respiratory function (high-quality evidence) and lower pulmonary exacerbation rates (moderate-quality evidence). Lumacaftor-ivacaftor is associated with an increase in early transient shortness of breath and longer-term increases in blood pressure (high-quality evidence). These adverse effects were not observed for tezacaftor-ivacaftor. Tezacaftor-ivacaftor has a better safety profile, although data are not available for children younger than 12 years. In this age group, lumacaftor-ivacaftor had an important impact on respiratory function with no apparent immediate safety concerns, but this should be balanced against the increase in blood pressure and shortness of breath seen in longer-term data in adults when considering this combination for use in young people with CF.

Read the full abstract...

Cystic fibrosis (CF) is a common life-shortening condition caused by mutation in the gene that codes for that codes for the cystic fibrosis transmembrane conductance regulator (CFTR) protein, which functions as a salt transporter. F508del, the most common CFTR mutation that causes CF, is found in up to 80% to 90% of people with CF. In people with this mutation, a full length of protein is transcribed, but recognised as misfolded by the cell and degraded before reaching the cell membrane, where it needs to be positioned to effect transepithelial salt transport. This severe mutation is associated with no meaningful CFTR function. A corrective therapy for this mutation could positively impact on an important proportion of the CF population.


To evaluate the effects of CFTR correctors on clinically important outcomes, both benefits and harms, in children and adults with CF and class II CFTR mutations (most commonly F508del).

Search strategy: 

We searched the Cochrane Cystic Fibrosis and Genetic Disorders Cystic Fibrosis Trials Register. We also searched reference lists of relevant articles and online trials registries. Most recent search: 24 February 2018.

Selection criteria: 

Randomised controlled trials (RCTs) (parallel design) comparing CFTR correctors to placebo in people with CF with class II mutations. We also included RCTs comparing CFTR correctors combined with CFTR potentiators to placebo.

Data collection and analysis: 

Two authors independently extracted data, assessed risk of bias and quality of the evidence using the GRADE criteria. Study authors were contacted for additional data.

Main results: 

We included 13 RCTs (2215 participants), lasting between 1 day and 24 weeks. Additional safety data from an extension study of two lumacaftor-ivacaftor studies were available at 96 weeks (1029 participants). We assessed monotherapy in seven RCTs (317 participants) (4PBA (also known as Buphenyl), CPX, lumacaftor or cavosonstat) and combination therapy in six RCTs (1898 participants) (lumacaftor-ivacaftor or tezacaftor-ivacaftor) compared to placebo. Twelve RCTs recruited individuals homozygous for F508del, one RCT recruited participants with one F508del mutation and a second mutation with residual function.

Risk of bias varied in its impact on the confidence we have in our results across different comparisons. Some findings were based on single RCTs that were too small to show important effects. For five RCTs, results may not be applicable to all individuals with CF due to age limits of recruited populations (i.e. adults only, children only) or non-standard design of converting from monotherapy to combination therapy.

Monotherapy versus placebo

No deaths were reported and there were no clinically relevant improvements in quality of life in any RCT. There was insufficient evidence available from individual studies to determine the effect of any of the correctors examined on lung function outcomes.

No placebo-controlled study of monotherapy demonstrated a difference in mild, moderate or severe adverse effects; however, it is difficult to assess the clinical relevance of these events with the variety of events and the small number of participants.

Combination therapy versus placebo

No deaths were reported during any RCT (moderate- to high-quality evidence). The quality of life scores (respiratory domain) favoured combination therapy (both lumacaftor-ivacaftor and tezacaftor-ivacaftor) compared to placebo at all time points. At six months lumacaftor (600 mg once daily or 400 mg once daily) plus ivacaftor improved Cystic Fibrosis Questionnaire (CFQ) scores by a small amount 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 size was observed for twice-daily lumacaftor (200 mg) plus ivacaftor (250 mg) although the quality of evidence was low (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). Lung function measured by relative change in forced expiratory volume in one second (FEV1) % predicted improved with both combination therapies compared to placebo at six months, by 5.21% with once daily lumacaftor-ivacaftor (95% CI 3.61% to 6.80%; 504 participants; high-quality evidence) and by 2.40% with twice-daily lumacaftor-ivacaftor (95% CI 0.40% to 4.40%; 204 participants; low-quality evidence). One study reported an increase in FEV1 with tezacaftor-ivacaftor of 6.80% (95% CI 5.30 to 8.30%; 520 participants; moderate-quality evidence).

More participants receiving the lumacaftor-ivacaftor combination reported early transient breathlessness, odds ratio 2.05 (99% CI 1.10 to 3.83; 739 participants; high-quality evidence). In addition, participants allocated to the 400 mg twice-daily dose of lumacaftor-ivacaftor experienced a rise in blood pressure over the 120-week period of the initial studies and the follow-up study of 5.1 mmHg (systolic blood pressure) and 4.1 mmHg (diastolic blood pressure) (80 participants; high-quality evidence). These adverse effects were not reported in the tezacaftor-ivacaftor studies.

The rate of pulmonary exacerbations decreased for participants receiving and 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).