CFTR correctors, a therapy for cystic fibrosis targeted at specific variants (most commonly F508del)

Review question

We looked at drugs (or drug combinations) for correcting the basic defect in the most common cystic fibrosis (CF)-causing gene variant (F508del) and assessed their impact on outcomes important to people with CF (pwCF), e.g. survival, quality of life (QoL), lung function and safety.

Background

The CF gene makes a protein that helps salts move across cells in many parts of the body; over 80% of pwCF have at least one copy of F508del, meaning they make a full length of this protein, but it can not move through the cell correctly. Laboratory experiments suggest that if this protein reaches the cell wall, it may be able to function, restore salt movement and correct the chronic problems that pwCF experience. We examined several agents for correcting F508del. Our original review showed that while single drugs alone were not effective, they were when combined with other drugs. This updated review includes single, dual (corrector plus potentiator) and triple therapies (two different correctors plus one potentiator).

Search date

Evidence is current to: 14 October 2020.

Study characteristics

We included 19 studies (2959 pwCF (children and adults)) lasting between 1 day and 24 weeks (with an extension of two studies up to 96 weeks). Eight studies (344 participants) compared monotherapy: 4PBA, CPX, lumacaftor, cavosonstat and FDL169) to placebo (dummy treatment containing no active medicine), six studies (1840 participants) compared dual therapy (lumacaftor-ivacaftor or tezacaftor-ivacaftor) to placebo. Five studies (775 participants) assessed triple therapy (elexacaftor-tezacaftor-ivacaftor or VX-659-tezacaftor-ivacaftor); only the combination with elexacaftor progressed beyond early studies. In 14 studies participants had two copies of F508del, in two studies participants had one F508del variant and one different variant, while in three studies participants had either two copies of F508del or one copy of F508del and one different variant.

Key results

Monotherapy versus control

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

Dual therapy versus control

Neither the lumacaftor-ivacaftor or tezacaftor-ivacaftor studies in people with two copies of F508del reported any deaths and there were improvements in QoL and lung function. Pulmonary exacerbation (a flare-up of symptoms) rates were also lower. Neither combination therapy was linked to severe side effects, although people starting treatment with lumacaftor-ivacaftor experienced shortness of breath for one to two weeks, this usually stopped without further treatment. More concerningly, in longer studies some people taking lumacaftor-ivacaftor experienced a rise in blood pressure; two people (out of over 500) even stopped lumacaftor-ivacaftor treatment because of high blood pressure. These side effects were not reported for tezacaftor-ivacaftor. Tezacaftor-ivacaftor therapy has not yet been assessed in children with CF under 12 years old.

Triple therapy versus control.

The three studies reported no deaths. Triple therapies improved QoL scores and lung function, with no difference in the number or severity of side effects; there was a longer time until the next pulmonary exacerbation. There is high-quality evidence that elexacaftor-tezacaftor-ivacaftor therapy is clinically effective with few side effects for 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. The side effect profile of elexacaftor-tezacaftor-ivacaftor therapy seems to be similar to tezacaftor-ivacaftor, but we need to collect information over the longer term.

Quality of the evidence

The overall quality of the evidence varied from low to high. There were generally few details about study design, so we could not make clear judgements on potential biases. We had fewer concerns with the larger more recent studies. In 10 studies, some results were not analysed or reported. Some findings were based on studies that were too small to show important effects and for nine studies the results may not be applicable to all pwCF due to the age (i.e. only adults or only children studied) or an unusual design (pwCF received monotherapy and then combination therapy).

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.

Read the full 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 strategy: 

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).

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