Novel drug combo shown to improve function of cystic fibrosis protein

A novel two-drug combination has the potential to target and restore a defective protein underlying cystic fibrosis (CF), according to two phase III clinical trials conducted at 187 medical centers around the world, including Johns Hopkins, according to two studies reported in a recent issue of the New England Journal of Medicine.

CF is a chronic, progressive, and frequently fatal genetic (inherited) disease of the body’s mucus glands. CF primarily affects the respiratory and digestive systems in children and young adults. Cystic fibrosis is a life-limiting disease that is caused by defective or deficient cystic fibrosis transmembrane conductance regulator (CFTR) protein activity. Phe508del is the most common CFTR mutation. On the average, individuals with CF have a lifespan of approximately 30 years.

According to study author Professor Stuart Elborn, from the School of Medicine, Dentistry and Biomedical Sciences at Queen’s University in Belfast, UK, "Lumacaftor and ivacaftor were developed by Vertex Pharmaceuticals through high throughput screening. This used cell-based assay for chloride transport to identify the compounds."

Study authors conducted two phase 3, randomized, double-blind, placebo-controlled studies that were designed to assess the effects of lumacaftor (VX-809), a CFTR corrector, in combination with ivacaftor (VX-770), a CFTR potentiator, in patients 12 years of age or older who had CF and were homozygous for the Phe508del CFTR mutation. In both studies, patients were randomly assigned to receive either lumacaftor (600 mg once daily or 400 mg every 12 hours) in combination with ivacaftor (250 mg every 12 hours) or matched placebo for 24 weeks. The primary end point of the trials were the absolute change from baseline in the percentage of predicted forced expiratory volume in 1 second (FEV1) at week 24.

"The study showed significant improvement of around 3% in a measure of lung function (forced expiratory volume in one second) and a significant reduction in pulmonary exacerbations which often require an admission to hospital," Prof. Elborn explained.

The study included 1,108 patients who underwent randomization and received the study combination. The mean baseline FEV1 was 61% of the predicted value. In both studies, there were significant improvements in the primary end point in both lumacaftor–ivacaftor dose groups; the difference between active treatment and placebo with respect to the mean absolute improvement in the percentage of predicted FEV1 ranged from 2.6% to 4.0% (P<0.001), which corresponded to a mean relative treatment difference of 4.3% to 6.7% (P<0.001). Pooled analyses showed that the rate of pulmonary exacerbations was 30% to 39% lower in the lumacaftor–ivacaftor combination groups than in the placebo group; the rate of events leading to hospitalization or the use of intravenous antibiotics was lower in the lumacaftor–ivacaftor groups as well.

"The side effects were modest with some chest tightness described in the first few weeks of treatment," noted Prof. Elborn. He also pinted out that "the drug has had a positive vote by the FDA and may be available in the clinic in the US later this year. It has also been submitted by the FDA."

Study coauthors were from 16 institutions in America, Europe and Australia: the University of Queensland in Australia; Queens University of Belfast in the U.K.; Seattle Children’s Hospital; University of Washington School of Medicine; Azienda Ospedaliera Universitaria Integrata in Italy; University of Milan in Italy; Royal Brompton and Harefield NHS Foundation Trust and Imperial College London in the U.K.; University Hospital Gasthuisberg in Belgium; Medical University of South Carolina; Case Western Reserve University; Rainbow Babies and Children’s Hospital; Northwestern University Feinberg School of Medicine; Nationwide Children’s Hospital; The Ohio State University; St. Vincent’s University Hospital in Ireland; University College Dublin School of Medicine in Ireland; Hôpital Robert Debré, Université Paris; The Hospital for Sick Children, University of Toronto; University of Alabama at Birmingham; and Vertex Pharmaceuticals Inc.