Recent developments in treatment for cystic fibrosis have targeted the underlying genetic defect and these have been life-changing for some patients. Kevin Southern from Alder Hey Children’s Hospital in the UK is an Editor for the Cochrane Cystic Fibrosis Group and an author of the updated review of these corrective therapies, which was published in November 2023. Here he is to tell us about the review.
Mike: Hello, I'm Mike Clarke, podcast editor for the Cochrane Library. Recent developments in treatment for cystic fibrosis have targeted the underlying genetic defect and these have been life-changing for some patients. Kevin Southern from Alder Hey Children’s Hospital in the UK is an Editor for the Cochrane Cystic Fibrosis Group and an author of the updated review of these corrective therapies, which was published in November 2023. Here he is to tell us about the review.
Kevin: Cystic fibrosis, or CF, is a life-limiting genetic condition, affecting around 90,000 people worldwide. The CF gene makes a protein that helps salts move across cells in many parts of the body. When this gene is faulty, salt movement across cells is affected and sticky mucus builds up in several organs in the body. In the airways, this can lead to recurring chest infections. There are hundreds of gene abnormalities that can cause CF, but one called F508del, is particularly common and affects over 80% of people with CF. People with CF who have the F508del abnormality make the CF protein, but it is misshaped and does not get to the cell wall where it is needed for salt transport. Laboratory experiments suggest that if this protein can get to this part of the cell, it may be able to function, and salt transport can be corrected, which, in turn, might correct the chronic problems that people with CF experience.
Over the last 10 years, several drugs have been tested to see if they can correct the salt transport problem associated with the F508del gene abnormality. Early trials assessed the use of single drugs, and subsequent trials have tested combinations.
For this update, we searched for studies that compared any of the treatments to a control treatment in people with CF and at least one copy of the F508del gene abnormality. We looked at the effects on outcomes important to people with CF such as survival, quality of life and lung function, as well as side effects.
In total, we included 34 studies, with nearly 4800 people with CF. Treatment in the trials lasted from 1 day to 48 weeks and all of the trials compared an active drug to placebo.
Eight studies looked at treatment with a single drug (known as monotherapy). These studies did not report any deaths or clinically relevant improvements in quality-of-life scores. There was not enough evidence to show an effect on lung function and a wide range of side effects were experienced by a small number of participants. Our confidence in the evidence from these monotherapy trials ranges from low to high.
We have high confidence in the evidence from the 16 studies, with just over 2600 participants, that assessed a combination of two drugs (known as dual therapy), which was either tezacaftor plus ivacaftor or lumacaftor plus ivacaftor, for people with CF with two copies of the F508del gene abnormality. One person taking tezacaftor plus ivacaftor sadly died, but this was not considered to be related to the trial drug. Both dual therapies improved quality of life and lung function measurements. Rates of pulmonary exacerbations (a flare-up of symptoms) were also lower. Neither dual therapy was linked to severe side effects, but people starting treatment with lumacaftor plus ivacaftor experienced some shortness of breath for one to two weeks. Of more concern, longer studies of lumacaftor plus ivacaftor found a rise in blood pressure and two people (out of over 500) stopped this treatment because of high blood pressure. These side effects were not reported for tezacaftor plus ivacaftor.
We also have high confidence in the evidence from 11 studies assessing different combinations of three drugs (or triple therapy) for people with CF with one or two copies of the F508del abnormality. The combinations were based on tezacaftor with ivacaftor (or deutivacaftor, which is a similar, but chemically altered version of ivacaftor) and investigators then added either elexacaftor or other agents such as VX-659, VX-440 or VX-152. These triple combinations were compared to either triple placebo, or tezacaftor with ivacaftor and one placebo (for participants already on this dual combination). There were no deaths during the trials and all triple therapies improved quality of life and lung function scores, with no difference in the number or severity of side effects. Fewer people with two copies of F508del taking elexacaftor plus tezacaftor plus ivacaftor experienced a pulmonary exacerbation than those taking the control treatment.
In summary, there is a lack of evidence to support monotherapy, some evidence to support dual therapy for people with CF who have two copies of the F508del gene abnormality, and greater improvements with triple therapy. In addition, fewer side effects were reported for triple therapy than for lumacaftor-ivacaftor dual therapy.
In conclusion, therefore, there is a high level of evidence to support triple therapy, while the evidence base to support dual therapy for people with CF who have two copies of the F508del gene abnormality is less robust. More research is needed to assess triple therapy combinations in children and to monitor for emerging side effects. There continues to be much work in the field, and we will update this review as more data become available.
Mike: Thanks Kevin. If listeners would like to read the full review, it’s available from CochraneLibrary.com with a simple search for ‘CF and F508del’.