Market Overview

Vertex Initiates Phase 3 Studies of VX-445, Tezacaftor and Ivacaftor as a Triple Combination Regimen for People with Cystic Fibrosis

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-VX-445 triple combination regimen is the second of two different
triple combination regimens to enter Phase 3 development in 2018-

-Phase 3 study in approximately 360 patients with one F508del
mutation and one minimal function mutation designed to support New Drug
Application based on 4-week primary efficacy endpoint and 12-week safety
data-

-Phase 3 study in approximately 100 patients with two F508del
mutations supported by new Phase 2 data announced today that showed an
incremental mean absolute improvement in ppFEV
1
of 11.0 percentage points when VX-445 was added in patients already
receiving tezacaftor and ivacaftor; triple combination regimen was
generally well tolerated-

-Additional dose-ranging of once-daily potentiator VX-561 to be
conducted to support potential late-stage development of future
once-daily triple combination regimens-

Vertex
Pharmaceuticals Incorporated
(NASDAQ:VRTX) today announced that it
is initiating two Phase 3 studies of VX-445, tezacaftor and ivacaftor as
an investigational triple combination regimen for people with cystic
fibrosis (CF). The first Phase 3 study will evaluate approximately 360
people with CF who have one copy of the F508del mutation and one
minimal function mutation and is designed to support the submission of a
New Drug Application (NDA) in the U.S. using data from the study's
4-week primary efficacy endpoint together with safety data through 12
weeks of treatment. The second Phase 3 study will evaluate approximately
100 people with CF who have two copies of the F508del mutation,
the most common genetic form of the disease, and is designed to support
the submission of an application for approval in patients with two
copies of the F508del mutation in the U.S. using data from the
study's 4-week primary efficacy endpoint together with 24-week safety
data generated from the Phase 3 study in patients with one F508del
mutation and one minimal function mutation. The initiation of the study
in people with two copies of the F508del mutation is supported by
data announced today from a Phase 2 study that showed an incremental
mean absolute improvement in percent predicted forced expiratory volume
in one second (ppFEV1) of 11.0 percentage points from
baseline through week four of treatment when VX-445 (200 mg) was added
in people with CF who have two F508del mutations and were already
receiving tezacaftor in combination with ivacaftor. In the Phase 2
study, the VX-445 triple combination regimen was generally well
tolerated, and the majority of adverse events were mild to moderate in
severity.

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"The initiation of pivotal development for VX-445 marks important
progress toward our goal of advancing two different next-generation
triple combination regimens into pivotal development to allow us to
bring the best regimen to people with CF," said Jeffrey Leiden, M.D.,
Ph.D., Chairman, President and Chief Executive Officer of Vertex. "We
recognize that many people with CF are awaiting the first treatment for
the underlying cause of their disease, and I am pleased that we have
been able to advance both VX-659 and VX-445 into pivotal studies. We
look forward to the rapid progression of these and other studies over
the coming year, including studies in people currently eligible for our
approved medicines where a triple combination regimen may provide
significant benefit."

Vertex also today announced safety and efficacy results for the
once-daily potentiator, VX-561, when dosed as part of a triple
combination regimen with a next-generation corrector (VX-659 or VX-445)
and tezacaftor in Phase 2 studies of people with one F508del
mutation and one minimal function mutation. In these studies, mean
absolute improvements in ppFEV1 of 12.2 and 11.7 and
percentage points from baseline through week four of treatment were
observed for the VX-659 and VX-445 triple combination regimens,
respectively. The once-daily triple combination regimens were generally
well tolerated, and the majority of adverse events were mild to moderate
in severity. Following discussions with the U.S. Food and Drug
Administration (FDA), Vertex plans to conduct additional dose-ranging
for VX-561 to support potential late-stage development of future
once-daily triple combination regimens.

About the VX-445 Phase 3 Study in People with One F508del
Mutation and One Minimal Function Mutation

The randomized,
double-blind, placebo-controlled Phase 3 study will evaluate VX-445 in
combination with tezacaftor and ivacaftor, or triple placebo, in
approximately 360 patients ages 12 and older who have one F508del mutation
and one minimal function mutation. A list of the minimal function
mutations currently included in this study can be found here.
The primary endpoint of the study is the mean absolute change in lung
function (ppFEV1) from baseline at week four of triple
combination treatment compared to triple placebo.

The study is designed to support the submission of an NDA to the U.S.
FDA based on data from the 4-week primary efficacy analysis and on
safety data through 12 weeks of treatment. The study will evaluate
VX-445 in combination with tezacaftor and ivacaftor for a total of 24
weeks of treatment to generate additional safety data and data for key
secondary endpoints, including the number of pulmonary exacerbations,
change in body mass index, change in sweat chloride, and change in
patient-reported outcomes as measured by the respiratory domain score of
the Cystic Fibrosis Questionnaire-Revised (CFQ-R), among others. Data
from this study will also be used to support planned regulatory
submissions in Europe and other regions.

The study will evaluate a fixed-dose combination of VX-445 (200 mg),
tezacaftor (100 mg) and ivacaftor (150 mg) in the morning followed by
ivacaftor (150 mg) in the evening. An open-label extension study will be
conducted where all eligible patients, including those who received
triple placebo, will receive the VX-445 triple combination regimen for
up to an additional 96 weeks.

About the VX-445 Phase 3 Study in People with Two F508del
Mutations

The randomized, double-blind, controlled Phase 3
study will evaluate four weeks of treatment with VX-445 or placebo in
combination with tezacaftor and ivacaftor in approximately 100 patients
ages 12 years or older who have two F508del mutations. All
patients will receive tezacaftor in combination with ivacaftor during a
4-week run-in prior to the start of the triple combination treatment
period. The primary endpoint of the study is the mean absolute change in
lung function (ppFEV1) from baseline (end of the 4-week
tezacaftor/ivacaftor run-in) at week four of treatment with VX-445 in
combination with tezacaftor and ivacaftor compared to those who received
placebo, tezacaftor and ivacaftor. Key secondary endpoints will also be
measured at week four and include change in sweat chloride and change in
patient-reported outcomes as measured by the CFQ-R respiratory domain
score.

The study is designed to support an application for U.S. FDA approval of
the VX-445 triple combination regimen in patients with two copies of the F508del
mutation based on data from the 4-week primary efficacy analysis and
secondary safety analysis and on 24-week safety data from the Phase 3
study in patients with one F508del mutation and one minimal
function mutation. Vertex plans to use the study in patients with two F508del
mutations to broaden the potential label for the VX-445 triple
combination regimen and does not anticipate that the study will impact
its initial planned submission of an NDA to the U.S. FDA for patients
with one F508del mutation and one minimal function mutation. Data
from the study in patients with two F508del mutations will also
be used to support planned regulatory submissions in Europe and other
regions.

The study will evaluate a fixed-dose combination of VX-445 (200 mg) with
tezacaftor (100 mg) and ivacaftor (150 mg) in the morning followed by
ivacaftor (150 mg) in the evening, which is the same dosing regimen
being evaluated in the Phase 3 study of patients with one F508del
mutation and one minimal function mutation. An open-label extension
study will be conducted where all eligible patients, including those who
received placebo, tezacaftor and ivacaftor, will receive the VX-445
triple combination regimen for up to an additional 96 weeks.

Phase 2 Data for VX-445 Triple Combination in People with Two F508del
Mutations

The initiation of the Phase 3 study in people with
two F508del mutations is supported by data announced today from a
randomized, double-blind, controlled Phase 2 study where the primary
objectives were safety, tolerability and efficacy as assessed by mean
absolute change in ppFEV1 from baseline (end of the 4-week
tezacaftor/ivacaftor run-in period) through week four of treatment.
Secondary endpoints included absolute change in sweat chloride and
change in the CFQ-R respiratory domain score.

All patients received a 4-week run-in of tezacaftor in combination with
ivacaftor. Patients were then randomized to add either once-daily VX-445
(200 mg) or placebo to tezacaftor and ivacaftor for four weeks. After
the 4-week triple combination dosing period, all patients received four
weeks of tezacaftor and ivacaftor, followed by a 4-week safety follow-up
period.

Safety Data: The triple combination regimen was generally well
tolerated, and the safety profile was similar to that observed in
previously reported parts of this study. The majority of adverse events
were mild or moderate. No serious adverse events were reported in the
triple combination group and one serious adverse event (pulmonary
exacerbation) was reported in the group that received placebo added to
tezacaftor and ivacaftor. The most common adverse events occurring in at
least two patients in any treatment group were sputum increased, cough,
infective pulmonary exacerbation, fatigue, pyrexia, AST increased, CPK
increased, chills, hemoptysis, ALT increased, respiration abnormal and
sputum discolored. There was one discontinuation in the triple
combination group due to chest pain, and one patient interrupted then
discontinued treatment in the group that received placebo added to
tezacaftor and ivacaftor due to increased bilirubin without associated
elevations in transaminases. Following treatment discontinuation, the
chest pain resolved and the increased bilirubin returned to baseline.
One patient in the triple combination group interrupted treatment in the
tezacaftor/ivacaftor treatment period that followed triple combination
dosing due to myopathy and increased CPK, ALT and AST. The events
resolved following interruption of treatment, and the patient
subsequently restarted and completed treatment in the
tezacaftor/ivacaftor period without any further incidence.

Efficacy Data: A summary of the within-group lung function and
sweat chloride data is provided below:

VX-445 Added to Ongoing Treatment with Tezacaftor and Ivacaftor
in Patients with Two F508del Mutations

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 (100 mg QD) +
ivacaftor (150 mg q12h)
(n=7)

   

+0.4
(p=0.8869)

 

   

+0.8
(p=0.8712)

 

VX-445 (200 mg QD) + tezacaftor (100
mg QD) + ivacaftor (150
mg q12h)
(n=21)

   

+11.0
(p<0.0001)

 

   

-39.6
(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; baseline reflects the end of the 4-week
tezacaftor/ivacaftor run-in period

A secondary endpoint in the study measured mean absolute within-group
change in the respiratory domain score of the CFQ-R1, a
validated patient-reported outcome measure, at Day 29. The mean absolute
improvement for patients who received VX-445 in addition to tezacaftor
and ivacaftor was 20.7 points. The improvement for those who received
placebo in addition to tezacaftor and ivacaftor was 5.2 points.

Once-daily Triple Combination Regimens
Vertex today
announced the first safety and efficacy results for once-daily triple
combination regimens that included a next-generation corrector (VX-659
or VX-445), tezacaftor and VX-561, a once-daily potentiator, in patients
with one F508del mutation and one minimal function mutation.
These once-daily regimens were evaluated as separate parts within the
Phase 2 studies for VX-659 and VX-445, and safety and efficacy data from
previously completed parts of these studies in patients with one F508del
mutation and one minimal function mutation were reported earlier in
2018. The primary objectives of the studies were safety, tolerability
and efficacy as assessed by mean absolute change in ppFEV1
from baseline through week four of treatment. Secondary endpoints
included change in sweat chloride and change in the CFQ-R respiratory
domain score.

VX-659 Once-daily Regimen
Safety Data: In this study,
the once-daily triple combination regimen of VX-659, tezacaftor and
VX-561 was generally well tolerated, and the safety profile was similar
to that observed in previously reported parts of this study that
evaluated VX-659, tezacaftor and ivacaftor. The majority of adverse
events were mild or moderate. Serious adverse events were reported in
three patients in the placebo group (infective pulmonary exacerbations)
and two in the triple combination group (1 with pyrexia, dyspnea and
pleuritic pain, and 1 with infective pulmonary exacerbation and
pneumonia). None of these serious adverse events were considered related
to treatment and none resulted in treatment discontinuation. The most
common adverse events occurring in at least two patients in any
treatment group were cough, infective pulmonary exacerbation, nausea,
oropharyngeal (throat) pain, pyrexia, rales and rash. One patient in the
triple combination group interrupted treatment for rash and subsequently
restarted then discontinued treatment for drug hypersensitivity, which
resolved after treatment discontinuation. A second patient in the triple
combination treatment group interrupted treatment for rash. The rash
resolved, and the patient restarted and completed triple combination
treatment without any further incidence.

Efficacy Data: A summary of the within-group lung function and
sweat chloride data is provided below:

Once-daily VX-659, tezacaftor and VX-561 in Patients with one F508del
Mutation and One Minimal Function Mutation

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 (n=6)    

-5.0
(p=0.1561)

 

   

-1.3
(p=0.8077)

 

VX-659 (400 mg QD) + tezacaftor
(100 mg QD) + VX-561 (200 mg
QD)
(n=19)

   

+12.2
(p<0.0001)

 

   

-38.1
(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 within-group
change in the respiratory domain score of the CFQ-R1 at Day
29. The mean absolute improvement for patients who received the triple
combination was 14.7 points. The change for those who received placebo
was -4.1 points.

VX-445 Once-daily Regimen
Safety Data: In this study,
the once-daily triple combination regimen of VX-445, tezacaftor and
VX-561 was generally well tolerated, and the safety profile was similar
to that observed in previously reported parts of this study that
evaluated VX-445, tezacaftor and ivacaftor. The majority of adverse
events were mild or moderate. A serious adverse event was reported in
one patient in the placebo group (infective pulmonary exacerbation), and
there were no serious adverse events in the triple combination group.
The most common adverse events occurring in at least two patients in any
treatment group were cough, nausea, oropharyngeal (throat) pain,
infective pulmonary exacerbation, nasal congestion, productive cough,
sputum increased, chest pain, paranasal sinus discomfort, upper
respiratory tract infection and vomiting. There was one discontinuation
in the triple combination group due to rash. Following treatment
discontinuation, the rash resolved.

Efficacy Data: A summary of the within-group lung function and
sweat chloride data is provided below:

Once-daily VX-445, tezacaftor and VX-561 in Patients with One F508del
Mutation and One Minimal Function Mutation

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 (n=8)    

+1.2
(p=0.6407)

 

   

+1.0
(p=0.8359)

 

VX-445 (200 mg QD) + tezacaftor
(100 mg QD) + VX-561 (150 mg
QD)
(n=21)

   

+11.7
(p<0.0001)

 

   

-33.6
(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 within-group
change in the respiratory domain score of the CFQ-R1 at Day
29. The mean absolute improvement for patients who received the triple
combination was 20.2 points. The improvement for those who received
placebo was 20.2 points.

Following discussions with the U.S. FDA, Vertex plans to conduct
additional dose-ranging with VX-561 to support potential late-stage
development of future once-daily triple combination regimens.

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
invests in scientific innovation to create transformative medicines for
people with serious and life-threatening diseases. In addition to
clinical development programs in CF, Vertex has more than a dozen
ongoing research programs focused on the underlying mechanisms of other
serious diseases.

Founded in 1989 in Cambridge, Mass., Vertex's headquarters is now
located in Boston's Innovation District. Today, the company has research
and development sites and commercial offices in the United States,
Europe, Canada and Australia. Vertex is consistently recognized as one
of the industry's top places to work, including being named to Science
magazine's Top Employers in the life sciences ranking for eight years in
a row. 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), SYMDEKO
(tezacaftor/ivacaftor and ivacaftor), 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. Leiden's statements in the second paragraph and the information
provided regarding (i) the timing and design of the Phase 3 studies of
VX-445 in combination with tezacaftor and ivacaftor, (ii) the potential
to submit approval applications to the FDA based on data from these
Phase 3 studies, (iii) potential to support planned regulatory
submissions in Europe and other regions with data from these Phase 3
studies and (iv) plans with respect to further development of VX-561.
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 that data from the
Phase 3 development programs may not support continued development or
approval of the company's triple-combination regimens 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)

1 CFQ-R results reported are based on a mixed effect model
not adjusted for baseline CFQ-R

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