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Vertex Announces Initiation of Pivotal Phase 3 Program of VX-809 in Combination with Ivacaftor for the Treatment of People with Cystic Fibrosis Who Have Two Copies of the F508del Mutation
-Global studies to evaluate two different doses of VX-809 in combination with ivacaftor-
- 24-week safety and efficacy data and submission of New Drug Application expected in 2014-
Vertex also plans to conduct a pharmacokinetics and safety study to
evaluate VX-809 in combination with ivacaftor in children with CF ages 6
to 11 who have two copies of the F508del mutation. The company expects
to use the data from this study for subsequent registration in children
ages 6 to 11 in
Vertex will host a conference call for investors and media today,
"This Phase 3 development program is a significant advance in our
efforts to develop new medicines that treat the underlying cause of
cystic fibrosis for people with the most common type of the disease,"
said
Cystic fibrosis is a rare, life-shortening genetic disease for which
there is no cure. Approximately 70,000 people worldwide have CF,
including 30,000 in
About the Phase 3 TRAFFIC and TRANSPORT Studies
Vertex plans to conduct two 24-week, randomized, double-blind,
placebo-controlled Phase 3 studies of VX-809 in combination with
ivacaftor. TRAFFIC and TRANSPORT will each enroll approximately 500
people with CF ages 12 and older who have two copies of the F508del
mutation in the CFTR gene, for a total of 1,000 patients. The
studies have the same design and together will be conducted at
approximately 200 clinical trial sites in
The primary endpoint of each study is relative improvement in lung function (percent predicted FEV1) through 24 weeks of treatment, compared to placebo. Safety and tolerability will also be assessed through 24 weeks. Key secondary endpoints through 24 weeks include absolute improvement in FEV1, change in body mass index (BMI) or weight gain, number of pulmonary exacerbations and improvements in patient-reported outcomes as measured by the CF Questionnaire Revised (CFQ-R), among others.
Each study will include two combination treatment groups and one placebo group. The treatment groups will evaluate two regimens of VX-809 (600mg QD or 400mg q12h) in combination with ivacaftor (250mg q12h). Fixed-dose tablets that contain both VX-809 and ivacaftor, or placebo, will be used in both studies. Vertex plans to follow the initial 24-week treatment period with a separate rollover double-blind extension study where all eligible patients, including those who received placebo, will receive one of the combination regimens for up to an additional 96 weeks. The design of the studies is as follows:
|
|
24-Week Dosing Regimen | ||||
| Group 1 (n=167) | VX-809 (600mg QD) + ivacaftor (250mg q12h) | ||||
| Group 2 (n=167) | VX-809 (400mg q12h) + ivacaftor (250mg q12h) | ||||
| Group 3 (n=167) | Placebo + Placebo |
About the Study in Patients Ages 6 to 11
Vertex also plans to conduct a study of VX-809 in combination with
ivacaftor in children with CF ages 6 to 11 who have two copies of the
F508del mutation. The study will evaluate the pharmacokinetics and
safety of the combination for up to 24 weeks. Vertex expects to use the
data from this study, along with data from TRAFFIC and TRANSPORT, for
registration of the combination in
Phase 2 Data Supporting Phase 3 Trial Design
The Phase 3 studies announced today are supported by data from a Phase 2 study of VX-809 in combination with ivacaftor. The two combination dosing regimens selected for evaluation in Phase 3 were evaluated in Cohorts 2 and 3 of the Phase 2 study.
Cohort 2: As previously reported, the once-daily (QD) 600mg dose of VX-809 in combination with ivacaftor (250mg q12h) was evaluated in 21 patients in the second part (Cohort 2) of the Phase 2 study and resulted in statistically significant improvements in lung function (within group and versus placebo) during the combination dosing period, as noted below:
| Cohort 2 | ||||||||||||
| Mean Absolute and Relative Changes in Percent Predicted FEV1 | Day 0 — 28; VX-809 Alone | Day 28 — 56; VX-809 + ivacaftor | Day 0 - 56 | |||||||||
| VX-809 (600mg QD) + ivacaftor (250mg q12h) |
Absolute Relative |
-2.9 (p=0.07) -3.5 (p=0.13) |
+6.1 (p < 0.001) +9.7 (p < 0.001) |
+3.4 (p=0.03) +5.3 (p=0.02) |
||||||||
|
Versus Placebo Absolute Relative |
-2.0 (p=0.36) -3.9 (p=0.21) |
+8.6 (p < 0.001) +12.8 (p < 0.001) |
+6.7 (p=0.002) +9.2 (p=0.004) |
|||||||||
Cohort 3: Vertex also evaluated a 400mg twice-daily (q12h) dosing regimen of VX-809 in combination with ivacaftor in a third cohort of patients in the Phase 2 study. Cohort 3 evaluated 11 patients who received VX-809 (400mg q12h) for 28 days followed by VX-809 (400mg q12h) in combination with ivacaftor (250mg q12h) for 28 days. This cohort was designed to evaluate safety and pharmacokinetics of the 400mg q12h dose of VX-809 to support inclusion of this dose in the Phase 3 program. Cohort 3 also included the randomization of four patients to placebo to allow for a blinded safety assessment. Three patients completed treatment in the placebo group. A pharmacokinetic model suggested that 400mg dosing every 12 hours (q12h) of VX-809 would provide a higher total exposure (AUC; area under the curve) compared to 600mg QD dosing, and data from Cohort 3 were consistent with this model.
Safety results from the 400mg (q12h) dose group were similar to that of the 600mg (QD) dose group. In both dose groups, VX-809 was generally well-tolerated alone and in combination with ivacaftor. The most common adverse events in both groups were respiratory in nature. In Cohort 3, one patient in the treatment group discontinued treatment because of a pulmonary adverse event.
Together, these pharmacokinetic and safety data support inclusion of VX-809 400mg (q12h) in combination with ivacaftor 250mg (q12h) in the Phase 3 program to evaluate the effect that higher exposures of VX-809 have on efficacy and safety.
The pattern of lung function response observed in Cohort 3 was similar to that observed in the 600mg QD dose group in Cohort 2, with a decline in FEV1 during the VX-809 monotherapy dosing period followed by a statistically significant increase in FEV1 during the VX-809 and ivacaftor combination dosing period. The within-group mean absolute improvement in FEV1 observed during the combination-dosing period in Cohort 3 was 6.6 percentage points, compared to 6.1 percentage points for the 600mg QD dose group in Cohort 2.
Additional lung function results for Cohort 3 are provided below:
| Cohort 3 | ||||||||||||
| Mean Absolute and Relative Changes in Percent Predicted FEV1 | Day 0 — 28; VX-809 Alone | Day 28 — 56; VX-809 + ivacaftor | Day 0 - 56 | |||||||||
| VX-809 (400mg q12h) + ivacaftor (250mg q12h) |
Absolute Relative |
-4.3 (p=0.04) -6.3 (p=0.08) |
+6.6 (p=0.01) +8.8 (p=0.01) |
+1.9 (p=0.57) +2.5 (p=0.67) |
||||||||
Study in People with One Copy of the F508del Mutation
In addition to the Phase 3 studies in people with two copies of the F508del mutation, Vertex plans to conduct an 8-week exploratory Phase 2 study of VX-809 in combination with ivacaftor in people 12 and older with one copy (heterozygous) of the F508del mutation on one allele and a second mutation that is not expected to respond to either ivacaftor or VX-809 alone. This study is designed to provide additional safety and lung function data on the combination in heterozygous patients, and will evaluate the twice daily (q12h) combination of VX-809 (400mg) and ivacaftor (250mg).
VX-809 and ivacaftor were discovered as part of a collaboration with
About Cystic Fibrosis and the Combination of VX-809 and Ivacaftor
Cystic fibrosis is a rare, life-shortening genetic disease affecting
approximately 70,000 people worldwide, including 30,000 people in
CF is caused by a defective or missing CFTR protein resulting from mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Children must inherit two defective CFTR genes — one from each parent — to have CF. There are more than 1,800 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 absence of working CFTR protein 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 the most common mutation in the CFTR gene, F508del, little-to-no CFTR protein reaches the cell surface. As a result, thick, sticky mucus builds up and blocks the passages in many organs, leading to a variety of symptoms. In particular, mucus builds up and clogs the airways in the lungs, causing chronic lung infections and progressive lung damage. VX-809, known as a CFTR corrector, is believed to help CFTR protein reach the cell surface. Ivacaftor, known as a CFTR potentiator, keeps the CFTR protein channels on the cell surface open longer to increase the flow of salt and water into and out of the cell. Globally, nearly half of people with CF have two copies of the F508del mutation and an additional one-third have one copy of the F508del mutation.
As announced in
Collaborative History with
Vertex initiated its CF research program in 1998 as part of a
collaboration with CFFT, the non-profit drug discovery and development
affiliate of the
About Vertex
Vertex creates new possibilities in medicine. Our team discovers, develops and commercializes innovative therapies so people with serious diseases can lead better lives.
Vertex scientists and our collaborators are working on new medicines to cure or significantly advance the treatment of hepatitis C, cystic fibrosis, rheumatoid arthritis and other life-threatening diseases.
Founded more than 20 years ago in
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. Kauffman's statements in the fourth paragraph of this
press release and statements regarding (i) the clinical studies the
company plans to conduct to evaluate VX-809 in combination with
ivacaftor, (ii) the design of these studies, including the primary and
secondary endpoints and the anticipated number of patients to be
enrolled, (iii) the company's expectations regarding when data will be
available from these clinical trials, (iv) the potential submission of
the NDA and MAA for the combination therapy and (v) the expectation that
the data from the study in children 6 to 11 will be used for subsequent
registration in
Conference Call Information
Vertex will host a conference call and webcast today,
To listen to the live call on the telephone, dial 1-866-501-1537 (
The conference ID number for the live call and replay is 15208263.
The call will be available for replay via telephone commencing
Following the live webcast, an archived version will be available on
Vertex's website until
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