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Vertex Announces Positive Phase 1 & Phase 2 Data from Three Different Triple Combination Regimens in People with Cystic Fibrosis Who Have One F508del Mutation and One Minimal Function Mutation (F508del/Min)

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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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