Completion of Phase 3 Clinical testing by Vertex for their investigational drug, Ivacaftor, in cystic fibrosis (CF) patients who have the R117H mutation, has revealed mixed results. Although Ivacaftor is approved to treat patients with cystic fibrosis and the G551D mutation in the CFTR gene, this clinical trial was designed to target the large population of CF patients with the R117H mutation, the most common residual function mutation. In spite of its mixed results, the study was important because “with each study of Ivacaftor, we continue to learn more about [CF] and the effect of Ivacaftor in patients with different CF mutations, ages and severity of disease,” said Robert Kauffman, M.D., Ph.D., Senior Vice President and Chief Medical Officer at Vertex.
Sixty-nine cystic fibrosis patients ages six and older with at least one copy of the R117H mutation were enrolled in the double-blind, placebo controlled, 24-week study. Endpoints were defined by comparing forced expiratory volume in one second (FEV1) after treatment with either Ivacaftor or placebo with FEV1 before treatment. Looking at the entire population, the primary endpoint was not met: neither the absolute nor relative treatment differences in FEV1 were statistically significant (2.1%, p=0.20 and 5.0%, p=0.06, respectively). However, when patients were sectioned according to pre-specified age groups, the subset of patients 18 and older showed statistically significant improvements in FEV1 of patients treated with Ivacaftor (absolute 5.0%, p=0.01 and relative 9.1%, p=0.008). The subset of patients aged six to eleven years showed reverse behavior, with Ivacaftor treatment decreasing FEV1 by 2.8% and placebo increasing FEV1 by 3.5% (absolute treatment difference of -6.3%, p=0.03). The subset of patients aged 12 to 17 contained only two patients, preventing the use of statistical analysis.
Safety of Ivacaftor was consistent with previous trials, with side effects including infective pulmonary exacerbation, cough, and headache, but these symptoms also presented with placebo treatment and were more common (17% of patients treated with placebo vs. 12% with Ivacaftor).
These results will prompt Vertex to file a supplemental New Drug Application (sNDA) with the Food and Drug Administration (FDA) early in 2014. Kauffman says he “looks forward to meeting with the FDA early next year to discuss these data with the goal of bringing Ivacaftor to additional people with CF who may benefit from treatment.”
In addition to this study, Vertex is conducting another Phase 3 study with children ages two to five with gating mutations; the FDA just accepted Vertex’s sNDA for patients six and older with gating mutations. Also, a Phase 2 study with patients 12 and older who have clinical evidence of residual CFTR function is being conducted.
Cystic fibrosis results from a defective or missing CFTR gene. It manifests in abnormally thick, sticky mucus that causes chronic lung infections due to poor flow of salt and water in and out of the lungs. It is a rare disease and affects approximately 75,000 patients in North America, Europe, and Australia.