A child born with cystic fibrosis (CF) as recently as four decades ago couldn’t expect to live much beyond age 10. Now, therapeutic advances have increased that median survival to over 37 years. Current interventions, however –airway clearance, antibiotic prophylaxis, exercise and nutrition among them – are based largely on slowing the inevitable progression of lung disease. While patients now live longer, less encumbered by their illness, there is no cure and transplantation remains the end of the road for many of the 70,000 people living with CF worldwide. Treatments directed at the cellular level have been the hope to shift that landscape and now, researchers report a significant step toward this goal.
In this week’s NEJM, Bonnie Ramsey and colleagues describe a new drug, ivacaftor, which works on the faulty protein in CF to improve lung function in a minority of patients. Since the identification of the CF gene in 1989, researchers have known that CF results from mutations in the gene for the protein cystic fibrosis trans-membrane conductance regulator (CFTR). Without functioning CFTR, which is an epithelial ion channel, patients have flawed regulation of salt and water absorption and secretion in the lung, pancreas, liver, intestine and reproductive tract. The majority of people with CF in the United States have a specific CFTR mutation, but there are over 1,500 mutations that can cause this multi-system disease, by affecting either the quantity or the quality of CFTR. Approximately 4-5% of patients with CF have a missense mutation, G551D, which causes the CFTR protein at the cell surface not to open and close properly.
The question, then: is it possible to change the function of this protein channel itself? This is the premise behind ivacaftor, an oral medication that increases the amount of these channels remain open, thus improving chloride transport. Following a small randomized, controlled study of patients with CF and the G551D mutation that showed improvement in lung function in the treated group, Ramsey and colleagues undertook the first double-blind, randomized, placebo-controlled study of this medication.
The authors enrolled 161 subjects between June 2009 and January 2011 to receive ivacaftor or placebo in addition to current standard of care medical therapies. All were believed to have the G551D mutation ivacaftor targets (one patient was subsequently found to have a different mutation, but was included in the analysis regardless). Subjects were, on average, 25.5 years old, and just over half were women. Mean FEV1 (forced expiratory volume in one second, a measure of lung function which declines in CF) was 63.6 percent of predicted.
After 24 weeks, the patients taking ivacaftor had an FEV1 that was 10.6 percentage points higher than patients taking placebo, a change that was maintained at week 48. This corresponds to a relative change of 17.2% compared to placebo. To put this in perspective, inhaled tobramycin – one of the mainstays of current CF treatment – has shown a 12% improvement in FEV1 at 20 weeks.
Additionally, those taking the study drug had fewer cystic fibrosis exacerbations, with less time in the hospital, more weight gain and self-reported improved respiratory symptoms compared to placebo. The authors also measured sweat chloride, as the drug works on the CFTR channel, and found this too to decrease in those receiving the study drug.
Of note, while those receiving ivacaftor more commonly reported adverse events leading them to interrupt taking the drug – such as headaches, upper respiratory tract infections and rashes – they had a lower rate of “serious” adverse events and were less likely than those in the placebo group to discontinue the drug altogether.
Pamela Davis, a cystic fibrosis researcher, wrote in an accompanying editorial that this marks a major step forward. However, she noted, the advance also raises more questions: Will the drug halt the progression of lung disease for patients with this mutation? And what about the 90% of patients in the United States with a different mutation?
While these questions remain unanswered, Davis described the current study as the start of a new era of CF treatment: “This report is the destination of a long journey from the discovery of the CF gene…through definition of the basic defect, identification of drug candidates by high throughput screening, testing in cell and animal models, to initial human trials, to the present gratifying results.”
If you were a physician caring for a patient with cystic fibrosis who had the G551D mutation, would this new medication affect your treatment plan?