Clinical Trials

Date: 2014-05-01

Type of information: Results

phase: 2

Announcement: results

Company: Vertex Pharmaceuticals (USA - MA)

Product: VX-661 ( tezacaftor) 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:

• Patients in this randomized, double-blind study must have received Kalydeco^® for at least four weeks prior to entering the study. Patients in the study were ages 12 and older and had received Kalydeco^® for an average of approximately one year. Patients received VX-661, or placebo, in combination with their ongoing Kalydeco^® treatment for four weeks. To measure both the on-treatment and off-treatment effect of VX-661 in combination with Kalydeco^®, observations were made at baseline (Day 0), every week during the treatment period (Day 0 - 28) and at multiple timepoints in the four-week period after the completion of treatment (Day 28 - 56). Eighteen patients enrolled in the study, and 14 of these patients received VX-661 (100 mg once daily) in addition to their ongoing treatment with Kalydeco^® (150 mg q12h). The remaining four patients received placebo and Kalydeco^® to ensure the study was blinded. 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; PPFEV₁) was measured as a secondary endpoint.

Latest news:

• • On May 1, 2014, Vertex Pharmaceuticals has announced that treatment with the combination of VX-661 and Kalydeco^® (ivacaftor) in a 28-day Phase 2 study showed statistically significant improvements in lung function (FEV₁) in people with both the F508del mutation and G551D mutation who were already taking Kalydeco^®. VX-661 was added to patients\' ongoing Kalydeco^® treatment for four weeks to evaluate the safety of the combination regimen as well as the effect on lung function, sweat chloride and other measures. In addition to improvements in FEV₁, the addition of VX-661 also resulted in decreases in sweat chloride through the 28-day treatment period. Treatment with a combination of Kalydeco^® and VX-661 for 28 days resulted in a mean within-group absolute improvement in lung function of 4.6 percentage points (p=0.012), a mean within-group relative improvement in lung function of 7.3% (p=0.012) and a mean reduction in sweat chloride of -7.02 mmol/L (p=0.053) through the end of treatment. Following the 28-day treatment period, lung function and sweat chloride levels returned toward baseline. VX-661 was generally well-tolerated when dosed in combination with Kalydeco^®, and all 18 patients completed the 28-day treatment period.
• This is the first proof-of-concept clinical study of a combination of a CFTR corrector (VX-661) and Kalydeco^® in people with CF heterozygous for the F508del mutation and a mutation, such as G551D, known to be responsive to Kalydeco^®. The study was conducted following in vitro observations that showed the addition of VX-661 to Kalydeco^® further enhanced CFTR function in human bronchial epithelial (HBE) cells heterozygous for the F508del and G551D mutations. The clinical results announced demonstrated the potential for a combination of VX-661 and Kalydeco^® to further enhance the benefit of treatment with Kalydeco^® alone in people with the F508del mutation and a mutation known to respond to Kalydeco^®.
• Safety Results: In the study, VX-661 was generally well-tolerated when dosed in combination with Kalydeco^®, and all 18 patients completed the study. The most common adverse events in the treatment group were cough, pulmonary exacerbation, headache and upper respiratory tract infection. One serious adverse event of arthritis occurred in the VX-661 treatment arm and was deemed unrelated to VX-661 or Kalydeco^®.
• Efficacy Results: The baseline lung function and sweat chloride levels for patients who were randomized to receive VX-661 and KALYDECO were 59.1 percent predicted FEV₁ and 52.9 mmol/L, respectively. A summary of the lung function and sweat chloride data for patients who received VX-661 in combination with Kalydeco^® is provided below:

VX-661 + KALYDECO  (Within-Group; n=14)	Day 0 Through Day 28  (End of VX-661 Treatment)	Day 28 to Day 56  (4 Weeks Following  the End of VX-661 Treatment)
Mean Absolute Change  in Lung Function (PPFEV1)	+4.60 percentage points (p=0.012)	-3.44 percentage points (p=0.010)
Mean Relative Change in Lung Function (PPFEV1)	+7.3% (p=0.012)	-5.4% (p=0.008)
Sweat Chloride	-7.02 mmol/L (p=0.053)	+12.26 mmol/L (p=0.001)

• Additional studies of longer duration and with additional patients will be required to further validate these results. Currently, a 12-week study of VX-661 in combination with ivacaftor is ongoing in people with two copies of the F508del mutation. This study is designed to evaluate safety, efficacy and pharmacokinetics to characterize VX-661 for further clinical development. Based on the data announced today, and pending data from the ongoing 12-week study in patients homozygous for the F508del mutation, Vertex plans to discuss with global regulatory authorities the potential approval pathway for VX-661 in combination with Kalydeco^® for people with CF who have the F508del mutation and another mutation known to respond to Kalydeco^® alone.

Is general: Yes