Cystic fibrosis is caused by a defective or missing CFTR protein resulting from mutations in the CFTR gene. In people with two copies of the most common mutation in the CFTR gene, F508del, little to no CFTR protein reaches the cell surface. VX-661, known as a CFTR corrector, is believed to help CFTR protein reach the cell surface. Ivacaftor, known as a CFTR potentiator, keeps cell surface CFTR protein channels open longer to increase the flow of salt and water. Worldwide, nearly half of people with CF have two copies of the F508del mutation and an additional one-third have one copy of the F508del mutation.
About the study
The Phase 2 randomised, double-blind, placebo-controlled study treated 128 people with CF ages 18 and older with two copies of the F508del mutation. One group of patients was randomised to receive either VX-661 (10, 30, 100 and 150mg dosed once daily), or placebo, alone for 28 days. A separate group of patients was randomised to receive the combination of VX-661 (10, 30, 100 and 150mg dosed once daily) and ivacaftor (150mg dosed twice daily), or placebo, for 28 days. The primary endpoints of the study were safety, tolerability and change in sweat chloride. Change in lung function (percent predicted forced expiratory volume in one second; FEV1) was measured as a secondary endpoint.
There were statistically significant mean absolute decreases in sweat chloride, both within-group and versus placebo, across the combination and monotherapy groups. These changes were generally modest and were variable across the dose groups.
VX-661 was generally well-tolerated when dosed alone and in combination with ivacaftor. The most common adverse events were pulmonary in nature. Most adverse events were mild to moderate in severity and similar between the treatment and placebo groups, and the types and frequency of adverse events were similar between the treatment and placebo groups. The rate of serious adverse events was also similar between the treatment groups and those who received placebo.
Lung function results for combination dosing
Mean absolute and relative improvements in lung function were observed in all the combination dosing groups (10, 30, 100 and 150mg), both within group and versus placebo. The improvements in lung function were dose dependent, with the greatest improvements observed in the groups that received the highest doses of VX-661 in combination with ivacaftor.
Patients in the two highest combination dose groups (VX-661 100mg or 150mg in combination with ivacaftor 150mg) showed statistically significant mean relative improvements in lung function, versus placebo, of 9.0% (p=0.01) and 7.5% (p=0.02), respectively at Day 28. Improvements in FEV1 were observed early in treatment, and the mean relative FEV1 improvements, versus placebo, for the highest combination group (VX-661 150mg in combination with ivacaftor 150mg) were statistically significant at Days 14, 21 and 28. The mean relative FEV1 across the combination dose groups returned toward baseline during the post-treatment 28-day washout period. Additional lung function results are noted below:
In the dose group that evaluated 100mg of VX-661 in combination with ivacaftor, 66.7% (10/15) of patients had a 5% or greater relative improvement (within subject) in lung function at Day 28. In the dose group that evaluated 150mg of VX-661 in combination with ivacaftor, 56.3% (9/16) of patients had a 5% or greater relative improvement (within subject) in lung function at Day 28. 21.7% (5/23) of patients who received placebo had a 5% or greater relative improvement (within subject) in lung function at Day 28.
Results for VX-661 monotherapy dosing
Mean absolute and relative increases in lung function were observed in all the VX-661 monotherapy dosing groups (10, 30, 100 and 150mg), both within group and versus placebo at Day 28. These increases were variable, not dose-dependent and not statistically significant in any of the monotherapy dosing groups.
Advancing multiple correctors
Vertex has advanced three correctors from research into development – VX-809, VX-661 and VX-983. VX-809 is Vertex’s lead corrector and is currently being evaluated in combination with ivacaftor as part of two ongoing Phase 3 studies expected to enroll a total of approximately 1,000 people ages 12 and older with two copies of the F508del mutation. Vertex expects to obtain 24-week safety and efficacy data from these studies and to submit a New Drug Application (NDA) to the US. Food and Drug Administration (FDA) in 2014, pending study results. VX-661 is Vertex’s second corrector to enter clinical development.
Vertex plans to conduct additional studies of VX-661 to further evaluate its potential for late-stage development, pending regulatory discussions. VX-983 is the third corrector to enter clinical development and is currently being evaluated as part of a Phase 1 multiple-ascending-dose study in healthy volunteers. In the second half of 2013, Vertex plans to begin a 28-day study of VX-983 in combination with ivacaftor in people with two copies of the F508del CFTR mutation.
In addition to Vertex’s development activities focused on combinations of a corrector with ivacaftor, the company has an active research program that has identified next-generation correctors that could be used as part of future combination regimens for people with CF.