Date: 2012-05-29
Type of information: Results
phase: 2
Announcement: results
Company: Vertex Pharmaceuticals (USA - MA)
Product: combination of VX-809 and Kalydeco® (ivacaftor)
Action
mechanism: CFTR potentiator. Ivacaftor is an oral agent that increases ion-function of activated cell-surface CFTR. The CFTR protein is a chloride channel present at the surface of epithelial cells in multiple organs. Ivacaftor facilitates increased chloride transport by potentiating the channel-open probability (or gating) of the G551D-CFTR protein. In vitro, ivacaftor increased CFTR-mediated transepithelial current (IT) in rodent cells expressing G551D-CFTR protein following addition of a cyclic adenosine monophosphate (cAMP) agonist with an EC50 of 100 ± 47 nM; however, ivacaftor did not increase IT in the absence of cAMP agonist. Ivacaftor also increased IT in human bronchial epithelial cells expressing G551D-CFTR protein following addition of a cAMP agonist with an EC50 of 236 nM. Ivacaftor increased the open probability of G551D-CFTR protein in single channel patch clamp experiments using membrane patches from rodent cells expressing G551D-CFTR protein by 10-fold versus untreated cells after addition of PKA and ATP. Kalydeco® was first approved by the FDA in January 2012 for use in people with CF ages 6 and older who have at least one copy of the G551D mutation and in February 2014 for use in people with CF ages 6 and older who have the following additional CFTR mutations: G178R, S549N, S549R, G551S, G1244E, S1251N, S1255P and G1349D. It was approved by the European Medicines Agency in July 2012, by Health Canada in November 2012 and by the Therapeutic Goods Administration in Australia in July 2013 for use in people with CF ages 6 and older who have at least one copy of the G551D mutation in the CFTR gene.
Disease: cystic fibrosis
Therapeutic area: Rare diseases - Genetic diseases
Country:
Trial details:
Latest
news: * On May 29, 2012, Vertex Pharmaceuticals announced a correction to the previously reported responder analysis, as well as additional data from, the recent interim analysis of an ongoing Phase 2 study of VX-809 and Kalydeco® (ivacaftor) that showed significant improvements in lung function (forced expiratory volume in one second, FEV1) among adults with cystic fibrosis who have two copies (homozygous) of the most common mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, F508del. The actual absolute improvements in lung function for these patients are: approximately 35 percent (13/37) experienced an absolute improvement of 5 percentage points or more and approximately 19 percent (7/37) experienced an absolute improvement of 10 percentage points or more from baseline to Day 56. Additional data from the interim analysis are provided for people with two copies of the F508del mutation. A mean absolute improvement in lung function of 8.5 percentage points was observed among those who were treated with VX-809 and Kalydeco® compared to placebo (p=0.002). In addition, the within-group mean absolute improvement from baseline to Day 56 was 4.0 percentage points (p=0.002) for patients treated with the combination. From baseline to Day 56, those treated with placebo experienced a mean absolute decrease in lung function of 4.6 percentage points (p=0.04). These data are from a planned interim analysis that was conducted after approximately half of the patients completed 56 days of treatment. Evaluation of patients with one copy (heterozygous, n=21) of the F508del mutation is ongoing. All patients have now completed dosing. Analyses are ongoing and complete data, including statistical analyses for all patient groups, will be available mid-year. Vertex plans to start a pivotal study of VX-809 and Kalydeco® in people with two copies of the F508del mutation, pending final study results and discussions with regulatory agencies.
As previously announced, there was a statistically significant improvement in lung function (absolute change in percent predicted FEV1) across the combined treatment groups relative to baseline compared to placebo (p=0.002). However the announcement provides a correction to the responder analysis (n=37) for the absolute improvement in lung function compared to baseline and, for the first time, provides the mean absolute improvement in lung function compared to placebo observed among patients who received VX-809 (200mg, 400mg, 600mg; QD) and Kalydeco® (250mg; q12h). The data reported today and earlier this month are based on 37 patients who completed 56 days of treatment with VX-809 and Kalydeco® and 11 patients with one or two copies of the F508del mutation who received placebo. On May 7, 2012 , the company announced that approximately 46 percent (17/37) of patients with two copies of the F508del mutation experienced an improvement in lung function (FEV1) of 5 percentage points or more and approximately 30 percent (11/37) experienced an improvement of 10 percentage points or more from baseline to Day 56 when treated with the combination of VX-809 and KALYDECO. These results were relative improvements, not absolute improvements as originally reported.
As previously announced, none of the patients treated with placebo (0/11) achieved a 5 percentage-point or more mean absolute improvement in lung function from baseline to Day 56.
