Featured Review: Drugs for correcting the basic defect in the most common cystic fibrosis-causing gene variant

Read this recently published Cochrane review about CFTR correctors, a therapy for cystic fibrosis targeted at specific variants (most commonly F508del)

In this review, the authors 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 Cystic Fibrosis, e.g. survival, quality of life (QoL), lung function and safety.

Professor Kevin Southern, lead author of this review, has been involved in the care of children with CF for over 30 years, and has a deep appreciation of the impact of this condition on the young people and their families. "It has been great to work with the team to produce this comprehensive review, which clearly identifies the positive impact that triple therapy has on the well being of people with CF. The benefits identified in trials will prove to be transformational for young adults with CF like Freya Miao (pictured here with her glass of milk to take this therapy), who can now focus on maintaining good health as they move through adult life."

He continued, "The review concludes that people with CF with one or two F508del gene variants will benefit from this intervention.  In some countries, people with this gene variant are not able to access this important new therapy because of both funding and regulatory issues, and this represents a significant inequality that needs to be addressed.”


The CF gene makes a protein that helps salts move across cells in many parts of the body; over 80% of people with Cystic Fibrosis 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 people with Cystic Fibrosis experience. The authors examined several agents for correcting F508del. Their 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).

Study characteristics

The authors included 19 studies (2959 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

No deaths were reported in the three studies. 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).

Thursday, December 17, 2020