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.
Evidence is current to: 24 February 2018.
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.
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.