Vertex Pharmaceuticals Incorporated announced results from two Phase 3 studies of lumacaftor in combination with ivacaftor that showed statistically significant improvements in lung function (percent predicted forced expiratory volume in one second, or ppFEV1) in people ages 12 and older with cystic fibrosis (CF) who have two copies (homozygous) of the F508del mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. All four 24-week combination treatment arms in the studies, known as TRAFFIC and TRANSPORT, met their primary endpoint of mean absolute improvement in ppFEV1 from baseline compared to placebo at the end of treatment. Mean absolute improvements in ppFEV1 of between 2.6 and 4.0 percentage points from baseline compared to placebo were observed across the studies (p=0.0004), with mean relative improvements of 4.3 percent to 6.7 per cent (p=0.0007).

The combination regimens were generally well tolerated. The most common adverse events, regardless of treatment group, were infective pulmonary exacerbation, cough, headache and increased sputum. 4.2 per cent of patients who received the combination regimens discontinued treatment because of adverse events compared to 1.6 percent of those who received placebo. More than 1,000 patients have entered a rollover study to receive a combination regimen.

Data from a pre-specified pooled analysis showed improvements in multiple key secondary endpoints. For patients who received the combination regimens compared to those who received placebo, there were statistically significant reductions in the rates of pulmonary exacerbations and statistically significant improvements in both body mass index and the proportion of patients with at least a 5 percent relative improvement in ppFEV1. Statistically significant changes were not consistently observed for patient-reported respiratory symptoms as reported in the CF questionnaire-revised (CFQ-R).

Based on these data, Vertex plans to submit regulatory applications for approval in multiple countries, including a New Drug Application (NDA) in the United States and Marketing Authorisation Application (MAA) in Europe, in the fourth quarter of 2014 for people with CF ages 12 and older who have two copies of the F508del mutation.

"On average, people with CF who have two copies of the F508del mutation lose nearly two percent of their lung function each year, underscoring the urgent need for new medicines that address the underlying cause of this disease," said Bonnie Ramsey, M.D., Professor of Pediatrics, University of Washington School of Medicine, Director of the Center for Clinical and Translational Research at Seattle Children's Research Institute and a lead Principal Investigator for TRANSPORT. "These data showed consistent evidence of clinical benefit in lung function and other measures of the disease. The significant improvements in pulmonary exacerbations are particularly important given the potential for these events to result in hospitalizations, permanent lung damage and the need for additional treatment with antibiotics and other medicines."

"The combination of lumacaftor and ivacaftor is the first regimen designed to address the underlying cause of CF for people with the most common form of the disease, and based on these data, we plan to move as fast as possible to submit applications for approval of this combination regimen in countries around the world," said Jeffrey Chodakewitz, MD., Senior Vice President and chief medical officer at Vertex. "I would like to thank the more than 1,100 people who took part in these studies worldwide, as well as their families, friends and caregivers."

"These data mark an exciting day for the CF community and validate our more than 30-year commitment to develop medicines that target the underlying basic defect of cystic fibrosis for all people with this devastating disease," said Robert J. Beall, Ph.D., President and CEO, Cystic Fibrosis Foundation. "While we await the FDA's review of these data, we're grateful to the many people with CF, families and volunteers who have committed their time and resources to help accelerate our efforts to bring effective therapies to all people living with the disease."

Cystic fibrosis is a rare genetic disease for which there is no cure. CF is caused by defective or missing CFTR proteins at the cell surface that result from mutations in the CFTR gene. 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. In people with two copies of the F508del mutation, the CFTR protein is not processed, or folded, normally within the cell and generally does not reach the cell surface. Lumacaftor is designed to address the processing defect of F508del-CFTR to enable it to reach the cell surface where ivacaftor can further enhance the protein's function. In North America, Europe and Australia, there are more than 22,000 people ages 12 and older who have two copies of the F508del mutation.

TRAFFIC and TRANSPORT were two global Phase 3, randomized, double-blind, placebo-controlled studies designed to evaluate the efficacy and safety of lumacaftor in combination with ivacaftor in people with CF ages 12 and older who have two copies of the F508del mutation. Each study included two combination treatment groups and one placebo group. The combination treatment groups evaluated lumacaftor dosed at either 600 mg once daily or 400 mg every 12 hours (q12h) in combination with ivacaftor dosed at 250 mg q12h. 1,108 people enrolled and received at least one dose of study drug in the two studies (549 in TRAFFIC; 559 in TRANSPORT) at approximately 200 clinical trial sites throughout North America, Europe and Australia. The primary endpoint of TRAFFIC and TRANSPORT was the mean absolute change from baseline in percent predicted FEV1 at the end of the 24-week treatment period as assessed by the average change in lung function at Week 16 and at Week 24 analysed using a Mixed Model for Repeated Measures (MMRM). Based on the design of the study, which included multiple treatment arms within each study, statistical significance for each arm versus placebo was based on a p-value of less than or equal to 0.0250.

In addition to the primary endpoint analysis for each study, a pre-specified pooled analysis evaluated the two combination treatment groups by dose from each study (two dose arms of lumacaftor 600 mg once daily in combination with ivacaftor 250 mg q12h combined; two dose arms of lumacaftor 400 mg q12h in combination with ivacaftor 250 mg q12h combined; two placebo arms combined).

All four treatment arms within the studies met their primary endpoint. Additionally, statistically significant mean absolute and relative improvements in lung function were observed for all four treatment groups, both within group and versus placebo, at all time points within the study (Weeks 2, 4, 8, 16 and 24). As patients in the study continued to be treated with their standard CF medicines, improvements observed for patients in the combination treatment arms were in addition to any benefits experienced with the use of other CF medicines. The mean baseline lung function of patients was approximately 61 percent predicted FEV1 for patients who received the combination regimen and for patients who received placebo.