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

Cystic fibrosis is a common inherited condition, particularly affecting people from a northern European background.  It's caused by various mutations of the Cystic Fibrosis Transmembrane Conductance Regulator gene, shortened to "CFTR".  A new Cochrane Review from August 2018 examines a class of drug that aims to correct the basic defect for people with CF with a specific mutation, and we asked lead author, Kevin Southern from the University of Liverpool in the UK, to tell us what they found.

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Monaz: Cystic fibrosis is a common inherited condition, particularly affecting people from a northern European background.  It's caused by various mutations of the Cystic Fibrosis Transmembrane Conductance Regulator gene, shortened to "CFTR".  A new Cochrane Review from August 2018 examines a class of drug that aims to correct the basic defect for people with CF with a specific mutation, and we asked lead author, Kevin Southern from the University of Liverpool in the UK, to tell us what they found.

Kevin: There are many mutations of the CFTR gene, which cause CF, but one is particularly common.  This is called F508del or deltaF508, and it's what we refer to as a class 2 mutation. Although a full length of protein is formed in the cells of people with this mutation, the protein is abnormal and is unable to get to the outer cell membrane, where it needs to be in order to fulfil its role in transporting salt.  This is known as a trafficking defect and researchers have been exploring a set of agents known as correctors that might solve the problem and let the deltaF508 protein reach the cell membrane.  We did our review to examine the evidence that would support the use of these correctors as a therapy for people with CF.
We identified 13 trials, enrolling just over 2200 people with CF.  Seven trials, which provide low to moderate quality evidence, randomised the participants to receive a single agent or a placebo. We refer to this as monotherapy and the studies found no clinically important differences between the drug and the placebo for people with two copies of the deltaF508 mutation.
The other six randomised trials examined two agents, lumacaftor and tezacaftor, each of which was combined with another agent, ivacaftor. These are called combination therapies and our overall grading of the quality of the evidence from the six studies came out as moderate to high.
The combination therapies (lumacaftor-ivacaftor and tezacaftor-ivacaftor) resulted in small but significant improvements in clinical outcomes relevant to people with CF with two copies of the deltaF508 mutation.  Both combinations showed similar efficacy, with improvements in patient's quality of life and respiratory function and a reduction in the rate at which they had a pulmonary exacerbation. On the downside, lumacaftor-ivacaftor was associated with an increase in early shortness of breath, although this did not tend to last long, and with longer-term increases in blood pressure. These adverse effects were not observed for tezacaftor-ivacaftor, which has a better initial safety profile, but it's important to note that data were not available for children under 12 years of age. In these younger children, although lumacaftor-ivacaftor had a positive impact on respiratory function with no apparent immediate safety concerns, we need to be cautious when considering the use of this combination in young people with CF because of the transient shortness of breath and increase in blood pressure seen in adults.
This area of research for people with CF is moving quickly, and following on from the closed trials that we were able to include in this first version of our review, other trials are now examining new agents. We will update this review regularly as the new data become available.

Monaz: If you'd like to read more about the review's findings for the monotherapy and combination therapy treatments that have already been tested, and watch for updates of the review as the findings for the new agents become available, just go online to Cochrane Library dot com and search 'correctors and CF'.

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