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Two Phase 3 Studies of the Tezacaftor/Ivacaftor Combination Treatment Met Primary Endpoints with Statistically Significant Improvements in Lung Function (FEV1) in People with Cystic Fibrosis

BOSTON--(BUSINESS WIRE)-- March 28, 2017 -- Vertex Pharmaceuticals Incorporated (Nasdaq: VRTX) today announced results from two Phase 3 studies of the tezacaftor (VX-661) / ivacaftor combination treatment that showed statistically significant improvements in lung function (percent predicted forced expiratory volume in one second, or ppFEV1) in people with cystic fibrosis (CF) ages 12 and older who have certain mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The 24-week EVOLVE study evaluated the combination treatment in people who have two copies of the F508del mutation. This study met its primary endpoint with a mean absolute improvement in ppFEV1 through 24 weeks of 4.0 percentage points from baseline compared to placebo (p < 0.0001). The second study, EXPAND, was an 8-week crossover study that evaluated the combination treatment in people who have one mutation that results in residual CFTR function and one F508del mutation. This study met the primary endpoints of absolute change in ppFEV1 from baseline to the average of the Week 4 and Week 8 measurements, with the tezacaftor/ivacaftor combination treatment demonstrating a mean absolute improvement of 6.8 percentage points compared to placebo (p < 0.0001) and the ivacaftor monotherapy group demonstrating a mean absolute improvement of 4.7 percentage points compared to placebo (p < 0.0001). Based on these results, Vertex plans to submit a New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) and a Marketing Authorization Application (MAA) to the European Medicines Agency (EMA) in the third quarter of 2017 for the tezacaftor/ivacaftor combination treatment in people with CF ages 12 and older who have two copies of the F508del mutation and in people who have one mutation that results in residual CFTR function and F508del mutation. Vertex will host a conference call for investors tomorrow, March 29, 2017 at 8:00 a.m. EDT, to discuss these results.

Across both studies, the tezacaftor/ivacaftor combination treatment was generally well tolerated. The most common adverse events, regardless of treatment group, were infective pulmonary exacerbation and cough. In both studies, rates of discontinuations due to adverse events were low and similar between placebo and treatment groups (2.1% for placebo vs 1.7% for the tezacaftor/ivacaftor combination). Rates of respiratory adverse events were similar between placebo and treatment groups (15.0% for placebo vs 11.4% for the tezacaftor/ivacaftor combination).

"The tezacaftor/ivacaftor combination treatment demonstrated clinically meaningful benefits, with a favorable safety profile, across multiple patient groups," said Jeffrey Chodakewitz, M.D., Executive Vice President and Chief Medical Officer at Vertex. "This combination treatment may provide a promising new option for treating the underlying cause of CF in the future and brings us increasingly closer to our goal of developing new medicines for all people with the disease."

About the EVOLVE Study

EVOLVE was a global Phase 3, randomized, double-blind, placebo-controlled study designed to evaluate the efficacy and safety of tezacaftor/ivacaftor combination treatment in people with CF ages 12 and older who have two copies of the F508del mutation. The combination group received tezacaftor 100 mg once daily (QD) in combination with ivacaftor 150 mg every 12 hours (q12h). In the study, more than 500 people were treated at more than 90 trial sites in North America and Europe. The primary endpoint was absolute change in ppFEV1 from baseline through Week 24 for those treated with the tezacaftor/ivacaftor combination treatment compared to placebo. The mean ppFEV1 at baseline was approximately 60 percent for each study arm. Of the 477 people who completed the 24-week study, 461 chose to enroll in a rollover study to receive the combination treatment.

Efficacy Results

Primary Endpoint: Through 24 weeks of the study, the mean absolute improvement in ppFEV1 was 4.0 percentage points from baseline for those treated with the tezacaftor/ivacaftor combination compared to placebo (p < 0.0001).

Safety Results

The tezacaftor/ivacaftor combination treatment was generally well tolerated. The majority of adverse events were mild or moderate. The most common adverse events (≥15%), regardless of treatment group, were infective pulmonary exacerbation, cough, headache, nasopharyngitis and sputum increased. The rate of discontinuations due to adverse events was low and similar between the placebo group and the combination treatment group. Rates of adverse events, serious adverse events and respiratory-related adverse events were similar between the placebo and the tezacaftor/ivacaftor combination treatment groups.

About the EXPAND Study

EXPAND was a global Phase 3, randomized, double-blind, placebo-controlled, crossover, multicenter study designed to evaluate the efficacy and safety of tezacaftor/ivacaftor combination treatment as well as ivacaftor monotherapy in people with CF ages 12 and older who have one mutation that results in residual CFTR function and one copy of the F508del mutation. Patients were randomized to one of six treatment groups to receive tezacaftor/ivacaftor, ivacaftor monotherapy or placebo for eight weeks, followed by an 8-week washout period. Following the washout period, patients switched to one of the other two treatment regimens for another eight weeks. The combination treatment group evaluated tezacaftor 100 mg once daily (QD) in combination with ivacaftor 150 mg every 12 hours (q12h), and the monotherapy group evaluated ivacaftor 150 mg every 12 hours (q12h). In the study, approximately 250 people were treated at more than 80 trial sites, mainly in North America and Europe. The primary endpoints were absolute change in ppFEV1 from baseline to the average of the Week 4 and Week 8 measurements for each of the treatment groups (tezacaftor/ivacaftor combination treatment and ivacaftor monotherapy) compared to placebo. The mean ppFEV1 at baseline was approximately 62 percent for each study arm. Of the 235 people who completed the study, 227 chose to enroll in a rollover study to receive tezacaftor/ivacaftor combination treatment.

Efficacy Results

Lung Function: The mean absolute improvement in ppFEV1 was 6.8 percentage points from baseline compared to placebo (p < 0.0001) for those receiving the tezacaftor/ivacaftor combination and was 4.7 percentage points compared to placebo (p < 0.0001) for those receiving ivacaftor alone. An additional pre-specified analysis of the combination group compared to the monotherapy group showed that the tezacaftor/ivacaftor combination treatment provided a statistically significant improvement in ppFEV1 over the use of ivacaftor alone (2.1 percentage points, p < 0.0001).

CFQ-R: The key secondary endpoint was absolute change in the Cystic Fibrosis Questionnaire-Revised (CFQ-R) respiratory domain score from baseline to the average of the Week 4 and Week 8 measurements for each of the treatment groups (tezacaftor/ivacaftor combination treatment and ivacaftor monotherapy) compared to placebo.

Safety Results

In the EXPAND study, the safety profile observed for the tezacaftor/ivacaftor combination treatment was favorable and similar to that seen in the EVOLVE study. The tezacaftor/ivacaftor combination treatment as well as ivacaftor monotherapy were both generally well tolerated. The majority of adverse events were mild or moderate. The most common adverse events (≥15%), regardless of treatment group, were cough and infective pulmonary exacerbation. There were no discontinuations due to adverse events in the combination treatment group. Discontinuations due to adverse events were low and similar between the placebo group and the ivacaftor monotherapy group. The incidence of adverse events, serious adverse events and respiratory-related adverse events was similar between the placebo, tezacaftor/ivacaftor combination and ivacaftor monotherapy groups.

About CF

CF is a rare, life-shortening genetic disease affecting approximately 75,000 people in North America, Europe and Australia.

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 approximately 2,000 known mutations in the CFTR gene. Some of these mutations, which can be determined by a genetic test, 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 protein results in poor flow of salt and water into and out of the cell in a number of organs. In the lungs, this leads to the buildup of abnormally thick, sticky mucus that can cause chronic lung infections and progressive lung damage in many patients that eventually leads to death. The median age of death is in the mid-to-late 20s.

In people with the F508del mutation, the CFTR protein is not processed, or folded, normally within the cell and generally does not reach the cell surface. Tezacaftor 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, we believe there are more than 22,000 people ages 12 and older who have two copies of the F508del mutation, and there are more than 1,500 people ages 12 and older who have one mutation that results in residual CFTR function and one copy of the F508del mutation.

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 seven 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 www.vrtx.com.

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

Vertex initiated its CF research program in 2000 as part of a collaboration with CFFT, the nonprofit drug discovery and development affiliate of the Cystic Fibrosis Foundation. KALYDECO® (ivacaftor), ORKAMBI® (lumacaftor/ivacaftor) and tezacaftor were discovered by Vertex as part of this collaboration.

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, and the information provided regarding Vertex's plans to submit regulatory applications for tezacaftor/ivacaftor combination treatment, including a New Drug Application (NDA) in the United States and Marketing Authorization Application (MAA) in Europe, in the third quarter of 2017. 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 Vertex could experience unforeseen delays in submitting regulatory filings, that regulatory authorities may not approve, or approve on a timely basis, tezacaftor/ivacaftor combination treatment 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 www.vrtx.com. Vertex disclaims any obligation to update the information contained in this press release as new information becomes available.

Source: Vertex Pharmaceuticals Incorporated

Posted: March 2017

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