-The combination was generally well tolerated
and all patients completed 12 weeks of treatment-
-Mean within-group absolute improvement from
baseline in lung function of 4.4 (p=0.009) and 3.0 (p=0.026)
percentage points at week 4 and through 12 weeks of treatment,
respectively, in patients who received VX-661 (100 mg once daily)
in combination with ivacaftor (150 mg every 12 hours)-
-Data were consistent with prior Phase 2
studies of VX-661 and ivacaftor and support ongoing Phase 3 program
evaluating VX-661 in combination with ivacaftor in people with one
or two copies of the F508del mutation-
Vertex Pharmaceuticals Incorporated (Nasdaq:VRTX) today
announced data from a 12-week Phase 2 study evaluating VX-661 in
combination with ivacaftor in 39 people with CF ages 18 and older
who have two copies of the F508del mutation. The study evaluated
two doses of VX-661 (100 mg once daily or 50 mg every 12 hours) in
combination with ivacaftor (150 mg every 12 hours). The primary
endpoint of the study was safety. The study showed that the
combination regimen was generally well tolerated, and all patients
completed 12 weeks of treatment. The most common adverse events
were pulmonary exacerbation, which occurred in 38 percent of all
patients who received VX-661 and 44 percent of those who received
placebo, and cough, which occurred in 33 percent of all patients
who received VX-661 and 39 percent of those who received
placebo.
Secondary endpoints evaluated the effect of the combination on
lung function (percent predicted forced expiratory volume in one
second; ppFEV1), and the mean within-group absolute improvement
from baseline in ppFEV1 for those who received 100 mg of VX-661 in
combination with ivacaftor (n=15) was 4.4 (p=0.009) and 3.0
(p=0.026) percentage points at week 4 and through 12 weeks of
treatment, respectively. Consistent with prior Phase 2 studies that
evaluated 4 weeks of treatment with VX-661 in combination with
ivacaftor, this study showed a rapid improvement in lung function
within four weeks of treatment, and after patients completed
treatment, lung function returned to baseline.
These safety and efficacy data, together with other data from
multiple previously completed Phase 2 studies of VX-661, support
Vertex’s ongoing Phase 3 program of VX-661 in combination with
ivacaftor. The Phase 3 program is evaluating VX-661 (100 mg once
daily) in combination with ivacaftor (150 mg every 12 hours) and
consists of four Phase 3 studies, including a study in people with
two copies of the F508del mutation that began enrollment in
February. The other three studies will enroll people with CF who
have one copy of the F508del mutation and a second mutation that is
either a gating mutation, residual function mutation or a mutation
that results in minimal CFTR function.
“The safety and efficacy data from this study are consistent
with prior Phase 2 studies of VX-661 in combination with ivacaftor
and provide further support for our ongoing Phase 3 program in
people with one or two copies of the F508del mutation,” said
Jeffrey Chodakewitz, M.D., Executive Vice President and Chief
Medical Officer at Vertex.
Cystic fibrosis is caused by a defective or missing CFTR protein
resulting from mutations in the CFTR gene. In people with two
copies of the most common mutation in the CFTR gene, F508del,
little to no CFTR protein reaches the cell surface. VX-661, known
as a CFTR corrector, is designed to address the processing defect
of F508del-CFTR to enable it to reach the cell surface. Ivacaftor,
known as a CFTR potentiator, keeps cell surface CFTR protein
channels open more often to increase the flow of salt and
water.
About the Study
The Phase 2 randomized, double-blind, placebo-controlled study
treated 39 people with CF ages 18 and older with two copies of the
F508del mutation. Fifteen patients received VX-661 (100 mg once
daily) in combination with ivacaftor (150 mg every 12 hours) and 18
patients received placebo. The study also enrolled six patients in
an arm that evaluated VX-661 (50 mg every 12 hours) in combination
with ivacaftor (150 mg every 12 hours) that was included in the
study prior to selection of the 100 mg VX-661 once daily dose to be
used for further development. The mean ppFEV1 at baseline was 57.2
percentage points and the mean baseline sweat chloride was 106.2
mmol/L. The baseline characteristics were well balanced across
treatment arms. The primary endpoint of the study was safety, and
secondary endpoints evaluated the effect of the combination on
ppFEV1, sweat chloride and other measures.
Primary Endpoint: The combination of VX-661 and ivacaftor
was generally well tolerated, and all patients completed 12 weeks
of treatment. The majority of adverse events were mild to moderate
in severity, and no patients discontinued treatment in the study
due to adverse events. The most common adverse events were
pulmonary exacerbation, which occurred in 38 percent of all
patients who received VX-661 and 44 percent of those who received
placebo, and cough, which occurred in 33 percent of all patients
who received VX-661 and 39 percent of those who received placebo.
Serious adverse events occurred in 24 percent of people who
received the combination regimen and 39 percent of those who
received placebo. The types and frequency of adverse events were
generally similar between the treatment and placebo groups.
Secondary Endpoints: In the patients who received VX-661
(100 mg once daily) in combination with ivacaftor (150 mg every 12
hours), mean within-group absolute improvements from baseline in
ppFEV1 of 4.4 and 3.0 percentage points were observed at week 4 and
through 12 weeks of treatment, respectively. The mean ppFEV1
improvement observed through 12 weeks of treatment for those in the
treatment group returned to baseline during the post-treatment
washout period. The mean within-group absolute change in ppFEV1 for
those who received placebo was -0.4 and 1.0 percentage points at
week 4 and through 12 weeks, respectively. Additional information
on the mean within-group absolute changes from baseline in ppFEV1
is provided below:
Mean Absolute Change from Baseline
in ppFEV1 (percentage points)
VX-661 (100 mg once daily)
+ivacaftor (150 mg every 12 hours)(n=15)
Placebo (n=18)
At Week 4 Within Group 4.4 (p=0.009)
-0.4 (p=0.827)
Through Week 12 Within Group
3.0 (p=0.026) 1.0 (p=0.451)
28 Days Post-Treatment
Within Group 0.5 1.4
In addition, statistically significant mean within-group
absolute decreases in sweat chloride were observed for the group
who received VX-661 (100 mg once daily) in combination with
ivacaftor. These changes were generally modest and consistent with
results from a prior Phase 2 study of this dosing regimen in people
with two copies of the F508del mutation.
In the six patients who received VX-661 (50 mg every 12 hours)
in combination with ivacaftor, the mean within-group absolute
improvements from baseline in ppFEV1 observed at week 4 and through
12 weeks of treatment were 0.9 (p=0.741) and 0.6 (p=0.776)
percentage points. The 28-day post-treatment change from baseline
in ppFEV1for this group was 1.1 percentage points. There was a
statistically significant decrease in sweat chloride for this group
that was generally modest.
Prior Studies of VX-661 and Ivacaftor
in People with the F508del Mutation
Prior to this 12-week study, Vertex completed a 4-week Phase 2
study of VX-661 in combination with ivacaftor in people with two
copies of the F508del mutation. A subsequent study evaluated the
combination regimen in people with both the F508del mutation and
G551D mutation who were already taking KALYDECO. Data from these
studies were reported previously. Across these studies, the safety
profile for the combination treatment regimens was similar. In the
study that enrolled people with two copies of the F508del mutation,
the mean within-group absolute changes from baseline in ppFEV1 for
the two highest doses are noted below:
Mean Absolute Change
fromBaseline in ppFEV1 (percentage
points)
VX-661 (100 mg once daily)+
ivacaftor (150 mg q12h)(n=15)
VX-661 (150 mg oncedaily) +
ivacaftor (150mg q12h) (n=16)
Placebo
(n=23)
At Week 4 Within Group 4.4 (p=0.0019)
4.1 (p=0.0031) -0.4 (p=0.757)
28 Days Post-Treatment
Within Group 0.5 0.7 0.6
In the study that enrolled people with both the F508del mutation
and G551D mutation who were already taking KALYDECO (ivacaftor),
the mean within-group absolute changes from baseline in ppFEV1 were
4.6 percentage points (p=0.012) through week 4 and 1.6 percentage
points 28 days after the end of treatment.
Based on Phase 2 data generated to date, Vertex is currently
conducting a broad Phase 3 development program evaluating the
combination of VX-661 (100 mg once daily) in combination with
ivacaftor (150 mg every 12 hours) in people with one or two copies
of the F508del mutation. The designs of these studies were provided
in January 2015, and a summary of the Phase 3 program is provided
below:
- Two Copies of the F508del
Mutation: Enrollment is ongoing in a Phase 3 study evaluating
the combination of VX-661 and ivacaftor in people ages 12 and older
who have two copies of the F508del mutation. The primary endpoint
of the study is absolute change in ppFEV1 through six months of
treatment versus placebo. The study will enroll approximately 500
patients in North America and Europe.
- One Copy of the F508del Mutation and
a Second Mutation That Results in Residual CFTR Function: In
April, Vertex plans to begin a Phase 3 study to evaluate the
combination of VX-661 and ivacaftor in people ages 12 and older who
have one copy of the F508del mutation and a second mutation that
results in residual CFTR function. This study will also evaluate
ivacaftor dosed without VX-661. The primary endpoint of the study
will be absolute change in ppFEV1 through eight weeks of treatment
as part of a crossover design. The study will enroll approximately
300 patients.
- One Copy of the F508del Mutation and
a Second Mutation that Results in a Gating Defect in the CFTR
Protein: In May, Vertex plans to begin a Phase 3 study to
evaluate the combination of VX-661 and ivacaftor in people ages 12
and older who have one copy of the F508del mutation and a second
mutation that results in a gating defect in the CFTR protein. The
primary endpoint of the study will be absolute change in ppFEV1
through eight weeks of treatment with VX-661 and ivacaftor versus
ivacaftor alone. The study will enroll approximately 200
patients.
- One Copy of the F508del Mutation and
A Second Mutation That Results in Minimal CFTR Function: In
mid-2015, Vertex plans to begin a Phase 3 study to evaluate the
combination of VX-661 and ivacaftor in people ages 12 and older who
have one copy of the F508del mutation and a second mutation that
results in minimal CFTR function. The study will initially enroll
approximately 120 patients, and the primary endpoint will be
absolute change in ppFEV1 through 12 weeks of treatment versus
placebo. Expansion of the study to an additional approximately 150
patients will depend on an interim futility analysis of efficacy
data from the initial approximately 120 patients.
INDICATION AND IMPORTANT SAFETY INFORMATION FOR
KALYDECO® (ivacaftor)
Ivacaftor is a cystic fibrosis transmembrane conductance
regulatory (CFTR) potentiator indicated for the treatment of cystic
fibrosis (CF). In the U.S. (in patients age 2 years and older) and
Europe (in patients age 6 years and older), ivacaftor is indicated
for patients who have one of the following mutations in the CFTR
gene: G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N,
or S549R. In Canada (in patients 6 years and older), ivacaftor is
indicated for patients with these same mutations and also for
patients with the G970R mutation. Additionally, in the U.S. (in
patients age 2 years and older) and Canada (in patients age 18
years and older) ivacaftor is indicated for the treatment of CF in
patients who have an R117H mutation in the CFTR gene.
Ivacaftor is available as 150 mg tablets in countries where it
is approved for patients age 6 years and older, and additionally in
the U.S. as 50 mg and 75 mg oral granules for patients age 2 to
less than 6 years.
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 2 years
of age have not been studied. The use of ivacaftor in children
under the age of 2 years is not recommended.
High liver enzymes (transaminases; ALT and AST) have been
reported in patients with CF receiving ivacaftor. Transaminase
elevations were more common in patients with a history of
transaminase elevations or in patients who had abnormal
transaminases at baseline. 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. For patients with
a history of transaminase elevations, more frequent monitoring of
liver function tests should be considered. 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.
Cases of non-congenital lens opacities/cataracts have been
reported in pediatric patients treated with ivacaftor. Baseline and
follow-up ophthalmological examinations are recommended in
pediatric patients initiating ivacaftor treatment.
Serious adverse reactions that occurred more frequently with
ivacaftor included abdominal pain, increased liver enzymes, and low
blood sugar (hypoglycemia). The most common side effects associated
with ivacaftor include headache; upper respiratory tract infection
(common cold), including sore throat, nasal or sinus congestion,
and runny nose; stomach (abdominal) pain; diarrhea; rash; nausea;
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 (ivacaftor) U.S. Prescribing
Information, EU Summary of Product
Characteristics, Canadian Product Monograph, Australian
Consumer Medicine Information and Product
Information, Swiss 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. In 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
five 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.
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
fourth paragraph of the press release, and the information with
respect to the timing and plans for Phase 3 development of VX-661
in combination with ivacaftor. 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 the
development of VX-661 in combination with ivacaftor 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.
(VRTX-GEN)
Vertex Pharmaceuticals IncorporatedInvestors:Michael Partridge,
617-341-6108orKelly Lewis, 617-961-7530orEric Rojas,
617-961-7205orMedia:Zach Barber, 617-767-9533mediainfo@vrtx.com
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