Cystic fibrosis is a recessive genetic disease that is characterized by difficulty in breathing, lung infections, sinus infections, poor digestion, decreased growth, diarrhea, and infertility. The disease results from mutations in the gene for a protein termed the cystic fibrosis transmembrane conductance regulator (CFTR), which was discovered in 1989. Mutations in the gene result in abnormal transport of chloride and sodium across mucous epithelium which leads to the production of thick and viscous secretions in the lungs, pancreas, digestive system, and liver. Most therapies have been targeted at symptomatic support and treatment of infections, and lung transplantation has been used to prolong the lifespan of cystic fibrosis patients. These treatments have improved the quality of life and increased the median survival from 11 years to 37 years. Researchers, lead by Dr. Bonnie Ramsey from Seattle Children’s Hospital, have recently reported promising results with the first medication, termed ivacaftor (VX-770), to directly increase and potentiate the activity of the CFTR protein in patients with the G551D mutation. The G551D mutation occurs in about 4-5% of patients with cystic fibrosis. The results of their study were published online in the New England Journal of Medicine. The investigation was conducted as a randomized, double blind, placebo controlled trial using ivacaftor in cystic fibrosis patients with at least one allele mutated for G551D. Study participants were 12 years of age or older and received 150 mg of ivacaftor every 12 hours or placebo for 48 weeks. The primary end point was the change in the percent of predicted forced expiratory volume in 1 second (FEV1) at baseline compared to that at week 24. The investigators found a greater than 10% increase in the FEV1 of the ivacaftor group compared to the placebo group. In addition, study participants in the ivacaftor group were 55% less likely to have a pulmonary exacerbation compared to those study participants in the placebo group. Study participants in the ivacaftor group had gained, on average, 2.7 kg more weight by week 48 than those study participants in the placebo group. The treatment group also had improvement of sweat chloride and improved measurements on the respiratory symptoms domain of the Cystic Fibrosis Questionnaire. The study authors wrote, “Ivacaftor was associated with improvements in lung function at 2 weeks that were sustained through 48 weeks. Substantial improvements were also observed in the risk of pulmonary exacerbations, patient-reported respiratory symptoms, weight, and concentration of sweat chloride”. In an accompanying editorial, Dr. Pamela Davis wrote, “This success of ivacaftor is a triumph resulting from the discovery of the cystic fibrosis gene in 1989, followed by insightful and collaborative basic-science studies conducted by academic and industry investigators that led to clinical trials in an established clinical-research network to produce and validate a novel therapeutic agent for a dread disease… This study is also a great victory in the war against genetic diseases and marks the end of the beginning for the treatment of the cystic fibrosis defect”. A number of important questions still remain. Future research will need to address the safety of ivacaftor in children and infants and whether it has negative effects when taken for prolonged periods of time. In addition, the therapeutic utility of ivacftor for the treatment of the more common delta 508 mututation needs to be addressed.
Listen to the Medpage Today audio report with Dr. Bonnie Ramsey below:
Bonnie W. Ramsey et al. “A CFTR Potentiator in Patients with Cystic Fibrosis and the G551D Mutation” N Engl J Med 2011; 365:1663-1672