Since the discovery of the gene responsible for cystic fibrosis, CFTR or cystic fibrosis transmembrane regulator gene, several mutations have been found that lead to the production of abnormal CFTR protein
Since the discovery of the gene responsible for cystic fibrosis, CFTR or cystic fibrosis transmembrane regulator gene, several mutations have been found that lead to the production of abnormal CFTR protein resulting in alterations in chloride and sodium transmembrane transportation in patients with the disease. The protein A kinase activated channel is expressed in the epithelium of several organs, notably the GI tract and the lungs, pancreas and skin. In the lungs, this causes a depletion of the secretion of CFTR-dependent surface fluid, alongside a delay in mucociliary clearance, resulting in a build-up of mucus in the respiratory tract.
The identification of the gene has led to research into drug therapies that might have a direct effect, and one of the results of this effort is Vertex’s CFTR potentiator ivacaftor.1 Initial studies took place in humans because there was no suitable animal model. Subsequently, a randomised, placebo-controlled Phase II trial was carried out in 39 adult cystic fibrosis patients with the G551D-CFTR mutation.2 They were given oral doses of 25, 75 or 150mg or placebo twice a day for 14 days in the first part of the study, and then twice-daily doses of 150mg, 250mg or placebo for 28 days in part two.
A dose-dependent improvement in the activity of CFTR was observed in both parts of the study, with an improvement in CFTR-dependent chloride transport, and also a reduction in sweat chloride. In terms of lung function, a median change in baseline in the predicted forced expiratory volume in 1 sec (FEV-1) was 8.7%. A further randomised, double blind, placebo-controlled study took place in 167 affected subjects with the same genetic defect, aged at least 12.3 They were given 150mg of the drug twice a day for 48 weeks or placebo, with the primary endpoint an improvement in FEV-1.
After 24 weeks, predicted FEV-1 in the treated group was more than 10 percentage points greater than those given placebo, with improvements obvious after two weeks. These subjects were also 55% less likely to experience a pulmonary exacerbation. Adverse event profiles were similar between the two groups.
In another trial in patients with a different mutation, F508del-CFTR, there was a 16 week randomised double blind placebo-controlled period, followed by an open label extension.4 However, the difference in predictive FEV-1 was just 1.7% between the treated and placebo groups, suggesting that it is unlikely to be a useful treatment for patients with this mutation. It has now been approved by the US FDA for the 4–5% of patients who have the G551D mutation.
1. F. Van Goor et al. Process. Natl. Acad. Sci. USA 2009, 106, 18825
2. F.J. Accurso et al. N. Engl. J. Med. 2010, 363, 1991
3. B.W. Ramsey et al. N. Engl. J. Med. 2011, 365, 1663
4. P.A. Flume et al. Chest 2012 Mar 1, epub ahead of print