BOSTON--(BUSINESS WIRE)--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 28, 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).
Detailed data for the primary endpoint in the study are provided below:
| Mean Absolute Change in ppFEV1 (percentage points) |
Placebo
(n=256) |
Tezacaftor + Ivacaftor
(n=248) |
||||||
| Treatment Difference | N/A | +4.0 (p<0.0001) | ||||||
| Within Group | -0.6 (p=0.0601) | +3.4 (p<0.0001) |
Key Secondary Endpoints: Statistically significant improvements were seen in multiple key secondary endpoints, including a 35 percent reduction in the annualized rate of pulmonary exacerbations with the tezacaftor/ivacaftor combination treatment compared to placebo.
Detailed data for key secondary endpoints in the study are provided below:
| Key Secondary Endpoints* |
Placebo
(n=256) |
Tezacaftor + Ivacaftor
(n=248) |
||||||||||
| Mean Relative Change in ppFEV1 (%) Through 24 Weeks | Treatment Difference | N/A | +6.8 (p<0.0001?) | |||||||||
| Within Group | -0.5 (p=0.3823) | +6.3 (p<0.0001) | ||||||||||
| Number of Pulmonary Exacerbations Through Week 24 | Number of Events (rate per 48 weeks) | 122 (0.99) | 78 (0.64) | |||||||||
| Rate Ratio | N/A | 0.65 (p=0.0054?) | ||||||||||
| Change in Body Mass Index at Week 24 | Treatment Difference | N/A | +0.06 (p=0.4127) | |||||||||
| Within Group | +0.12 (p=0.0134) | +0.18 (p=0.0004) | ||||||||||
| Change in CFQ-R Through Week 24 | Treatment Difference | N/A | +5.1 (p<0.0001) | |||||||||
| Within Group | -0.1 (p=0.8889) | +5.0 (p<0.0001) | ||||||||||
|
*A hierarchical testing procedure was performed for the primary
and key secondary endpoints versus placebo, noted strictly in the
order above; p=0.050 required for statistical significance
?Statistical significance was confirmed in the hierarchical testing procedure |
||||||||||||
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.
Selected safety data from the study are provided below:
| Safety Data |
Placebo
(n=258) |
Tezacaftor + Ivacaftor
(n=251) |
||||||
| Number of Patients who Experienced Any Adverse Event | 245 (95.0%) | 227 (90.4%) | ||||||
| Number of Patients who Experienced a Serious Adverse Event | 47 (18.2%) | 31 (12.4%) | ||||||
| Number of Patients who Discontinued Treatment Due To Adverse Events | 8 (3.1%) | 7 (2.8%) | ||||||
| Respiratory Adverse Events* | 41 (15.9%) | 33 (13.1%) | ||||||
| * Respiratory events included dyspnea, respiration abnormal, bronchospasm and other (wheezing, asthma, chest discomfort, and bronchial hyper-reactivity) | ||||||||
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.
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