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Press Release Details

May 1, 2014

Addition of VX-661 to KALYDECO® (ivacaftor) Improves Lung Function in People with CF Who Are Heterozygous for the F508del and G551D Mutations in 28-day Phase 2 Proof-of-Concept Study

-Data provide proof-of-concept for use of VX-661 to further enhance CFTR function in people taking KALYDECO who have the F508del mutation and another mutation known to respond to KALYDECO alone-

-Statistically significant improvements in lung function, as well as decreases in sweat chloride, observed through 28 days of treatment with VX-661 and KALYDECO-

BOSTON--(BUSINESS WIRE)-- Vertex Pharmaceuticals Incorporated (Nasdaq: VRTX) today 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 today 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.

"Consistent with observations from in vitro studies, these results provide an important proof-of-concept for the use of VX-661 in combination with KALYDECO to provide the potential for further benefit in people already being treated with KALYDECO alone who have one F508del mutation and another mutation known to respond to KALYDECO alone," said Jeffrey Chodakewitz, M.D., Senior Vice President and Chief Medical Officer at Vertex. "While this study was small and evaluated the combination regimen for only four weeks, it provided important scientific evidence that we continue to make progress toward our goal of helping more people with CF and enhancing the benefit our medicines may provide. We look forward to further evaluation of this regimen to better understand the role that VX-661 and KALYDECO may play in the treatment of people with CF."

About the Study

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.

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:


(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)

Next Steps

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.

About KALYDECO (ivacaftor)

KALYDECO (ivacaftor) is the first medicine to treat the underlying cause of CF in people with specific mutations in the CFTR gene. Known as a CFTR potentiator, KALYDECO is an oral medicine that aims to help the CFTR protein function more normally once it reaches the cell surface, to help hydrate and clear mucus from the airways. KALYDECO (150mg, q12h) was first approved by the U.S. Food and Drug Administration 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.

KALYDECO 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.

Vertex retains worldwide rights to develop and commercialize KALYDECO.


Ivacaftor (150 mg tablets) is indicated for the treatment of cystic fibrosis (CF) in patients age 6 years and older who have a G551D mutation in the CFTR gene.

In the United States only, ivacaftor is also indicated for the treatment of CF in patients age 6 and older who have one of the following mutations in the CFTR gene: G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N or S549R.

Ivacaftor is not effective in patients with CF with 2 copies of the F508del mutation (F508del/F508del) in the CFTR gene. The safety and efficacy of ivacaftor in children with CF younger than 6 years of age have not been established.

Elevated liver enzymes (transaminases; ALT and AST) have been reported in patients receiving ivacaftor. It is recommended that ALT and AST be assessed prior to initiating ivacaftor, every 3 months during the first year of treatment, and annually thereafter. Patients who develop increased transaminase levels should be closely monitored until the abnormalities resolve. Dosing should be interrupted in patients with ALT or AST of greater than 5 times the upper limit of normal. Following resolution of transaminase elevations, consider the benefits and risks of resuming ivacaftor dosing.

Use of ivacaftor with medicines that are strong CYP3A inducers, such as the antibiotics rifampin and rifabutin; seizure medications (phenobarbital, carbamazepine, or phenytoin); and the herbal supplement St. John's Wort, substantially decreases exposure of ivacaftor and may diminish effectiveness. Therefore, co-administration is not recommended.

The dose of ivacaftor must be adjusted when used concomitantly with strong and moderate CYP3A inhibitors or when used in patients with moderate or severe hepatic disease.

Ivacaftor can cause serious adverse reactions including abdominal pain and high liver enzymes in the blood. The most common side effects associated with ivacaftor include headache; upper respiratory tract infection (the common cold), including sore throat, nasal or sinus congestion, and runny nose; stomach (abdominal) pain; diarrhea; rash; and dizziness. These are not all the possible side effects of ivacaftor. A list of the adverse reactions can be found in the product labeling for each country where ivacaftor is approved. Patients should tell their healthcare providers about any side effect that bothers them or does not go away.

Please see KALYDECO U.S. Prescribing InformationEU Summary of Product CharacteristicsCanadian Product MonographAustralian Consumer Medicine Information and Product InformationSwiss Prescribing Information and Patient Information, and the New Zealand Datasheet and Consumer Medicine Information.

About Cystic Fibrosis

Cystic fibrosis is a rare, life-threatening genetic disease affecting approximately 75,000 people in North America, Europe and Australia. Today, the median predicted age of survival for a person with CF is between 34 and 47 years, but the median age of death remains in the mid-20s.

CF is caused by a defective or missing CFTR protein resulting from mutations in the CFTR gene. Children must inherit two defective CFTR genes — one from each parent — to have CF. There are more than 1,900 known mutations in the CFTR gene. Some of these mutations, which can be determined by a genetic, or genotyping test, lead to CF by creating non-working or too few CFTR protein at the cell surface. The defective function or absence of CFTR proteins in people with CF results in poor flow of salt and water into and out of the cell in a number of organs, including the lungs. This leads to the buildup of abnormally thick, sticky mucus that can cause chronic lung infections and progressive lung damage.

Collaborative History with Cystic Fibrosis Foundation Therapeutics, Inc. (CFFT)

Vertex initiated its CF research program in 1998 as part of a collaboration with CFFT, the nonprofit drug discovery and development affiliate of the Cystic Fibrosis Foundation. This collaboration was expanded to support the accelerated discovery and development of Vertex's CFTR modulators.

About Vertex

Vertex is a global biotechnology company that aims to discover, develop and commercialize innovative medicines so people with serious diseases can lead better lives. In addition to our clinical development programs focused on cystic fibrosis, Vertex has more than a dozen ongoing research programs aimed at other serious and life-threatening diseases.

Founded in 1989 in Cambridge, Mass., Vertex today has research and development sites and commercial offices in the United States, Europe, Canada and Australia. For four years in a row, Science magazine has named Vertex one of its Top Employers in the life sciences. For additional information and the latest updates from the company, please visit

Special Note Regarding Forward-looking Statements

This press release contains forward-looking statements as defined in the Private Securities Litigation Reform Act of 1995, including, without limitation, Dr. Chodakewitz's statements in the third paragraph of the press release, and the information provided regarding (i) the potential for a combination of VX-661 and KALYDECO to further enhance CFTR function in people taking KALYDECO who have the F508del mutation and another mutation known to respond to KALYDECO alone; (ii) the requirement of additional studies of longer duration and with additional patients to validate the results from this study; and (iii) plans to discuss with global regulatory authorities the potential approval pathway for VX-661 in combination with KALYDECO. While Vertex believes the forward-looking statements contained in this press release are accurate, these forward-looking statements represent the company's beliefs only as of the date of this press release and there are a number of factors that could cause actual events or results to differ materially from those indicated by such forward-looking statements. Those risks and uncertainties include, among other things, that data from the company's development programs may not support registration or further development of its compounds due to safety, efficacy or other reasons, and other risks listed under Risk Factors in Vertex's annual report and quarterly reports filed with the Securities and Exchange Commission and available through the company's website at Vertex disclaims any obligation to update the information contained in this press release as new information becomes available.


Vertex Pharmaceuticals Incorporated
Michael Partridge, 617-341-6108
Kelly Lewis, 617-961-7530
Zach Barber, 617-341-6992

Source: Vertex Pharmaceuticals Incorporated

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