-Phase 2 data showed mean absolute improvements
in ppFEV1 of 9.7 and 12.0 percentage points for VX-152 and VX-440,
respectively, in triple combination with tezacaftor and ivacaftor
in F508del/Min patients; Initial data from Phase 1 study showed
mean absolute improvement in ppFEV1 of 9.6 percentage points with
VX-659 triple combination in F508del/Min patients-
-First data to demonstrate the potential to
treat the underlying cause of CF in people with F508del/Min
mutations, a severe and difficult-to-treat type of the disease-
-Initial Phase 2 data also showed mean absolute
improvements in ppFEV1 of 7.3 and 9.5 percentage points when VX-152
or VX-440 was added in people with two copies of the F508del
mutation (F508del/F508del), who were already receiving tezacaftor
and ivacaftor-
-All 3 triple combination regimens were
generally well tolerated across the studies-
Vertex Pharmaceuticals Incorporated (Nasdaq: VRTX) today
announced positive data from Phase 1 and Phase 2 studies of three
different triple combination regimens in people with cystic
fibrosis (CF) who have one F508del mutation and one minimal
function mutation (F508del/Min). These are the first data to
demonstrate the potential to treat the underlying cause of CF in
these patients, who have a severe and difficult-to-treat type of
the disease. Data from the Phase 2 studies in these patients showed
mean absolute improvements in percent predicted forced expiratory
volume in one second (ppFEV1) of 9.7 and 12.0 percentage points
from baseline for the triple combination regimens with VX-152
(200mg q12h) or VX-440 (600mg q12h), respectively. Initial data
from a Phase 1 study showed a mean absolute improvement in ppFEV1
of 9.6 percentage points from baseline for the triple combination
regimen of VX-659, tezacaftor and ivacaftor in people with one
F508del mutation and one minimal function mutation. The company
also announced today initial data showing improvements in mean
absolute ppFEV1 of 7.3 and 9.5 percentage points when VX-152 or
VX-440 was added in people with two copies of the F508del mutation,
who were already receiving tezacaftor and ivacaftor. Vertex will
host a conference call for investors today, July 18, 2017 at 5:00
p.m. EDT, to discuss these results.
The triple combination regimens were generally well tolerated
across all three studies, and the majority of adverse events were
mild to moderate in severity. Across the studies, the
discontinuation rate due to adverse events was low.
“These safety and efficacy data are clear and compelling,
indicating significant potential benefit for people with CF from
each of these three different triple combination regimens,” said
Jeffrey Chodakewitz, M.D., Executive Vice President and Chief
Medical Officer at Vertex. “We will be collecting and evaluating
additional data from these and other studies and will make a
decision on which regimen(s) to take forward into pivotal
program(s), which we expect to begin in the first half of
2018.”
Vertex has established a Steering Committee of global CF experts
and clinical trial investigators to support the design, conduct and
execution of the triple combination pivotal study program. This
committee is co-chaired by Steven M. Rowe, M.D., M.S.P.H.,
Professor of Medicine, Pediatrics, and Cell, Developmental and
Integrative Biology, Director of the Gregory Fleming James Cystic
Fibrosis Research Center, Nancy and Eugene Gwaltney Endowed Chair
for Medical Research, University of Alabama at Birmingham, and
Jennifer Taylor-Cousar, M.D., Associate Professor, Departments of
Medicine and Pediatrics, Pulmonary Divisions, Medical Director of
Clinical Research Services and Co-Director and Director of the CF
Therapeutics Development Network, Adult CF Program, National Jewish
Health, Colorado.
“Patients with minimal function mutations have been waiting for
a medicine to treat the underlying cause of their disease, which
makes these data showing pronounced improvements in lung function
particularly important,” said Dr. Rowe. “It’s also encouraging to
see that the addition of a next-generation corrector may lead to
substantial additional benefits for patients with two copies of the
F508del mutation, who were already receiving tezacaftor and
ivacaftor.”
Next Steps
Vertex has advanced four next-generation correctors in parallel
with the goal of developing the best triple combination regimen or
regimens for people living with CF.
Vertex has accelerated the development programs for VX-445 and
VX-659. A VX-445 Phase 2 study is underway and a VX-659 Phase 2
study will begin in early August. VX-445 and VX-659 will be
evaluated in triple combination with tezacaftor and ivacaftor in
people with one F508del mutation and one minimal function mutation
and will be evaluated in people with two copies of the F508del
mutation who are already receiving tezacaftor and ivacaftor. Data
from both of these Phase 2 studies are expected in early 2018.
Pending additional data from these Phase 2 studies and the
ongoing studies of VX-152 and VX-440 and discussions with
regulatory agencies and the Steering Committee, Vertex plans to
initiate pivotal development of one or more triple combination
regimens in the first half of 2018.
About the VX-440 Phase 2 Study
This randomized, double-blind Phase 2 study is evaluating VX-440
(200mg and 600mg q12h) in combination with tezacaftor and ivacaftor
in two different groups of people with CF ages 18 and older – those
who have one F508del mutation and one minimal function mutation,
and in those who have two copies of the F508del mutation. Minimal
function mutations are those that result in little-to-no
functioning CFTR protein and are not responsive to ivacaftor,
tezacaftor or the combination of ivacaftor and tezacaftor. The
primary objectives for the study are safety, tolerability and
efficacy as assessed by mean absolute change in ppFEV1 from
baseline. Secondary endpoints include change in sweat chloride and
Cystic Fibrosis Questionnaire-Revised (CFQ-R).
Overall Safety Data: In the study, the triple combination
regimen was generally well tolerated. The majority of adverse
events were mild or moderate. The most common adverse events
(>10%), regardless of treatment group, were infective pulmonary
exacerbation, cough, sputum increased and diarrhea. There was one
discontinuation due to an adverse event in the triple combination
treatment groups (elevated liver enzymes >5x upper limit of
normal in the VX-440 600mg group) and one in the control groups
(respiration abnormal and sputum increased). One additional patient
treated with the triple combination had elevated liver enzymes
(>8x upper limit of normal in the VX-440 600mg group), which
were observed on the final day of dosing. In both patients, the
elevated liver enzymes returned to normal after treatment
discontinuation or completion.
4-Week Efficacy Data in F508del/Min Patients: Part 1 of
the study evaluated the triple combination for four weeks in 47
patients who have one F508del mutation and one minimal function
mutation (11 in placebo, 18 in VX-440 200mg and 18 in VX-440
600mg). A summary of the within-group lung function and sweat
chloride data is provided below:
VX-440 in F508del/Min Patients Mean Absolute
Within-Group Change From Baseline Through Day 29*
Mean Absolute Within-Group Change in
ppFEV1 (percentage points)
Mean Absolute Within-Group Change in
Sweat Chloride (mmol/L)
Triple placebo +1.4
(p=0.4908)
+1.6
(p=0.6800)
VX-440 (200mg q12h) + tezacaftor (50mg q12h or 100mg QD) +
ivacaftor (150mg q12h) +10.0
(p<0.0001)
-20.7
(p<0.0001)
VX-440 (600mg q12h) + tezacaftor (50mg q12h) + ivacaftor (300mg
q12h) +12.0
(p<0.0001)
-33.1
(p<0.0001)
* all p-values are within group p-values
based on mixed effect models; values expressed as ‘Through Day 29’
are the average of Day 15 and Day 29 measures
A secondary endpoint in the study measured mean absolute change
in the respiratory domain of CFQ-R, a validated patient-reported
outcome tool, at Day 29. In this study, the mean absolute
improvements for patients with a minimal function mutation who
received the triple combination were 18.3 points (VX-440 200mg) and
20.7 points (VX-440 600mg). The improvement for those who received
placebo was 2.2 points.
4-Week Efficacy Data in F508del/F508del Patients: Part 2
of the study is ongoing to evaluate the addition of VX-440 for four
weeks in 26 patients who have two copies of the F508del mutation,
who were already receiving the combination of tezacaftor and
ivacaftor (6 in placebo and 20 in VX-440 600mg). In this part of
the study, all participants received four weeks of treatment with
tezacaftor and ivacaftor and were then randomized to the addition
of VX-440 or placebo for four additional weeks. A summary of the
within-group lung function and sweat chloride data for the triple
combination treatment period, from baseline (end of the 4-week
tezacaftor/ivacaftor run-in period), is provided below:
VX-440 in F508del/F508del Patients Mean Absolute
Within-Group Change From Baseline Through Day 29*
Mean Absolute Within-Group Change in ppFEV1
(percentage points) Mean Absolute Within-Group
Change in Sweat Chloride (mmol/L) Placebo + tezacaftor (100mg
QD) + ivacaftor (150mg q12h) -2.5
(p=0.2755)
+2.1
(p=0.7385)
VX-440 (600mg q12h) + tezacaftor (50mg q12h) + ivacaftor (300mg
q12h) +9.5
(p<0.0001)
-31.3
(p<0.0001)
* all p-values are within group p-values
based on mixed effect models; values expressed as ‘Through Day 29’
are the average of Day 15 and Day 29 measures
The safety follow-up portion of the study in patients with two
copies of the F508del mutation is ongoing.
About the VX-152 Phase 2 Study
This ongoing Phase 2 randomized, double-blind study is
evaluating VX-152 (100mg, 200mg and 300mg q12h) in combination with
tezacaftor and ivacaftor in people with CF ages 18 and older who
have one F508del mutation and one minimal function mutation and in
people who have two copies of the F508del mutation. The primary
objective is safety and tolerability. Secondary endpoints include
mean absolute change in ppFEV1 and change in sweat chloride. Data
reported today are from the 100mg and 200mg arms of the study in
people who have one F508del mutation and one minimal function
mutation and from the 200mg arm in people who have two copies of
the F508del mutation.
Overall Safety Data: In the study, the triple combination
regimen was generally well tolerated. The majority of adverse
events were mild or moderate. The most common adverse events
(>10%), regardless of treatment group, were cough, sputum
increased, infective pulmonary exacerbation, productive cough,
diarrhea and fatigue. There was one discontinuation due to an
adverse event in the triple combination treatment groups (pneumonia
in the VX-152 200mg group) and none in the control groups.
2-Week Initial Efficacy Data in F508del/Min Patients: In
Part 1 of the study, the triple combination was evaluated for two
weeks in 21 patients ages 18 and older who have one F508del
mutation and one minimal function mutation (5 in combined placebo,
6 in VX-152 100mg and 10 in VX-152 200mg). A summary of the initial
within-group lung function and sweat chloride data (secondary
endpoints) from the VX-152 100mg and 200mg dose groups is provided
below:
VX-152 in F508del/Min Patients Observed Mean
Absolute Within-Group Change from Baseline at Day 15*
Observed Mean Absolute Within-Group Change in ppFEV1
(percentage points) Observed Mean Absolute
Within-Group Change in Sweat Chloride (mmol/L) Triple placebo
-0.9
(p=0.6245)
+1.0
(p=0.5659)
VX-152 (100mg q12h) + tezacaftor (100mg QD) + ivacaftor (150mg
q12h) +5.6
(p=0.0135)
-19.6
(p=0.0004)
VX-152 (200mg q12h) + tezacaftor (100mg QD) + ivacaftor (150mg
q12h) +9.7
(p=0.0017)
-14.1
(p=0.0219)
* p-values presented are within-group p-values based on 1 sample
t-test; an efficacy analysis using mixed effect models will be
conducted following completion of an additional cohort of patients
currently being treated in the study
This part of the study is ongoing to evaluate the triple
combination of VX-152 (300mg q12h), tezacaftor and ivacaftor in
patients with one F508del mutation and one minimal function
mutation. These data are expected later in 2017.
2-Week Initial Efficacy Data in F508del/F508del Patients:
Part 2 of the study is ongoing to evaluate the addition of VX-152
for two weeks in 14 patients ages 18 and older who have two copies
of the F508del mutation, who were already receiving the combination
of tezacaftor and ivacaftor (4 in placebo and 10 in VX-152 200mg).
A summary of the initial within-group lung function and sweat
chloride data (secondary endpoints) for the triple combination
treatment period, from baseline (end of the 4-week
tezacaftor/ivacaftor run-in period), is provided below:
VX-152 in F508del/F508del Patients Observed Mean
Absolute Within-Group Change from Baseline at Day 15*
Observed Mean Absolute Within-Group Change in ppFEV1
(percentage points) Observed Mean Absolute
Within-Group Change in Sweat Chloride (mmol/L) Placebo +
tezacaftor (100mg QD) + ivacaftor (150mg q12h) -1.4
(p=0.2773)
+3.4
(p=0.1212)
VX-152 (200mg q12h) + tezacaftor (100mg QD) + ivacaftor (150mg
q12h) +7.3
(p=0.0354)
-20.9
(p=0.0010)
* p-values presented are within-group p-values based on 1 sample
t-test; an efficacy analysis using mixed effect models will be
conducted following completion of an additional cohort of patients
currently being treated in the study
This part of the study is ongoing to evaluate the addition of
VX-152 (300mg q12h) for four weeks in patients with two F508del
mutations, who are already receiving the combination of tezacaftor
and ivacaftor. These data are expected in early 2018.
About the VX-659 Phase 1 Study
This Phase 1 randomized, double-blind, placebo-controlled study
evaluated the safety and tolerability of single and multiple
ascending doses of VX-659 alone and in triple combination with
tezacaftor and ivacaftor in healthy volunteers. It also evaluated
the safety and tolerability of VX-659 as part of a triple
combination for two weeks in 12 people with CF ages 18 and older
who have one F508del mutation and one minimal function mutation (3
in placebo and 9 in VX-659 120mg). In this part of the study, sweat
chloride was evaluated as an additional endpoint, and the absolute
change in ppFEV1 was evaluated as part of the safety analysis.
In CF patients, VX-659 was generally well tolerated in triple
combination with tezacaftor and ivacaftor. The majority of adverse
events were mild or moderate. The most common adverse events
(>10%), regardless of treatment group, were cough, infective
pulmonary exacerbation and productive cough. There were no
discontinuations due to adverse events in either group.
At Day 15, there was a mean absolute improvement in ppFEV1 of
+9.6 percentage points from baseline in those receiving the triple
combination regimen of VX-659 (120mg q12h), tezacaftor and
ivacaftor and a mean decrease in sweat chloride of -41.6 mmol/L.
For those receiving placebo, there was a mean absolute decrease in
ppFEV1 of -0.4 percentage points and a mean decrease in sweat
chloride of -11.0 mmol/L.
Preclinical Toxicology Data
In the Phase 2 study of VX-440, women of childbearing potential
were required to use pre-specified, non-hormonal methods of
contraception based on results from previous preclinical
reproductive toxicology studies. Preclinical reproductive
toxicology studies of VX-152, VX-659 and VX-445 are complete with
no adverse findings of note.
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 proteins
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.
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), tezacaftor, VX-440,
VX-152, VX-659 and VX-445 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 initiate pivotal development of one or more triple
combination regimens in the first half of 2018. 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, (i) that Vertex could experience unforeseen
delays in conducting its development programs relating to triple
combination treatments and in submitting related regulatory
filings, (ii) that the initial results set forth in this press
release may differ from the final results from these ongoing
studies, (iii) that regulatory authorities may not approve, or
approve on a timely basis, triple combination treatments due to
safety, efficacy or other reasons, and (iv) 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)
Conference Call and
Webcast
The company will host a conference call and webcast today at
5:00 p.m. EDT to discuss these results. To access the call, please
dial (866) 501-1537 (U.S.) or +1 (720) 545-0001 (International).
The conference call will be webcast live, and a link to the webcast
may be accessed through Vertex's website at www.vrtx.com in
the "Investors" section under "Events and Presentations." To ensure
a timely connection, it is recommended that users register at least
10 minutes prior to the scheduled webcast. An archived webcast will
be available on the company's website.
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Vertex Pharmaceuticals
IncorporatedInvestors:Michael Partridge, +1
617-341-6108orEric Rojas, +1 617-961-7205orZach Barber, +1
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& Australia: +44 20 3204 5275
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