Vertex Selects Triple Combination Regimen of VX-445, Tezacaftor and Ivacaftor to Submit for Global Regulatory Approvals in Cystic Fibrosis
May 30, 2019
-Mean absolute improvement in ppFEV1 of 14.3
percentage points from baseline through week 24 of treatment compared to
placebo (p<0.0001) in patients with one F508del mutation and one minimal
function mutation-
-Statistically significant improvements observed in all key secondary
endpoints in patients with one F508del mutation and one minimal function
mutation, including a 63% reduction in the annualized rate of pulmonary
exacerbations compared to placebo (p<0.0001)-
-Submission of a New Drug Application in the U.S. planned for the
third quarter of 2019 followed by a Marketing Authorization Application
in the EU in the fourth quarter of 2019-
BOSTON–(BUSINESS WIRE)–lt;a href="https://twitter.com/hashtag/cf?src=hash" target="_blank"gt;#cflt;/agt;–Vertex
Pharmaceuticals Incorporated (Nasdaq: VRTX) today announced that it
has selected the triple combination of the next-generation corrector
VX-445 (elexacaftor), tezacaftor and ivacaftor to submit for potential
global regulatory approvals for people ages 12 and older with cystic
fibrosis (CF). Final data announced today from a 24-week Phase 3 study
in people with one F508del mutation and one minimal function
mutation and from a 4-week Phase 3 study in people with two F508del
mutations will form the basis of these submissions. Vertex previously
announced that both of these Phase 3 studies met their primary
endpoints, and the company today announced the final results of these
studies, including results for key secondary endpoints and safety data.
In each study, treatment with the VX-445 triple combination regimen
resulted in statistically significant improvements in all key secondary
endpoints. Data from the 24-week study in people with one F508del
mutation and one minimal function mutation showed a mean absolute
improvement in percent predicted forced expiratory volume in one second
(ppFEV1) of 14.3 percentage points from baseline (p<0.0001)
and a 63% reduction in the annualized rate of pulmonary exacerbations
(p<0.0001) through week 24 in patients who received the VX-445 triple
combination regimen compared to those who received triple placebo. The
VX-445 triple combination regimen was generally well tolerated across
the two Phase 3 studies. In the study in people with one F508del
mutation and one minimal function mutation, 2 and 0 patients,
respectively, who received the VX-445 triple combination or triple
placebo discontinued treatment due to adverse events. There were no
discontinuations for adverse events in either arm of the study in people
with two F508del mutations.
Vertex plans to submit a New Drug Application (NDA) to the U.S. Food and
Drug Administration (FDA) in the third quarter of 2019 and a Marketing
Authorization Application (MAA) to the European Medicines Agency (EMA)
in the fourth quarter of 2019 based on these data in people with CF ages
12 years and older who have one F508del mutation and one minimal
function mutation and in people with two F508del mutations.
“The substantial improvements in lung function and other measures of CF
seen in these Phase 3 studies are unprecedented and represent a defining
moment in the journey to provide medicines that treat the underlying
cause of CF to the vast majority of people with CF,” said Steven M.
Rowe, M.D., M.S.P.H., Director of the Gregory Fleming James Cystic
Fibrosis Research Center, University of Alabama at Birmingham and
co-chair of Vertex’s Triple Combination Steering Committee.
“People with CF who have one F508del mutation and one minimal
function mutation are the largest remaining group of CF patients without
a treatment option for the underlying cause of their disease. The final
Phase 3 data announced today represent a significant step toward
bringing a disease modifying medicine to these patients, as well as
toward providing significantly enhanced benefits to patients with two F508del
mutations,” said Reshma Kewalramani, M.D., Executive Vice President,
Global Medicines Development and Medical Affairs and Chief Medical
Officer at Vertex. “We could not have achieved this important milestone
without the support of the entire CF community, and we are particularly
grateful to those who participated in the triple combination clinical
trials. We now look forward to completing our regulatory submissions
with the aim of bringing the VX-445 triple combination regimen to as
many patients as possible.”
Vertex conducted two Phase 3 programs in parallel that evaluated two
different triple combination regimens with the goal of selecting the
best regimen to submit for global regulatory approvals. One program
evaluated VX-659 in combination with tezacaftor and ivacaftor, and the
other program evaluated VX-445 in combination with tezacaftor and
ivacaftor. Each of the programs consisted of a Phase 3 study in people
with one F508del mutation and one minimal function mutation and a
Phase 3 study in people with two F508del mutations. The Phase 3
studies in both programs met their primary endpoints and showed
statistically significant improvements across all key secondary
endpoints. Additionally, each of the two triple combination regimens was
generally well tolerated, and more than 98% of patients in each of the
two programs completed the Phase 3 study treatment periods and elected
to enroll in the open-label extension study for each regimen.
Both regimens showed highly similar and positive benefit-risk profiles.
Vertex ultimately determined that the VX-445 triple combination regimen
could benefit the greatest number of CF patients. This decision was
based on a detailed assessment of multiple factors, including favorable
profiles for safety, tolerability and drug-drug interactions, the
ability for co-administration with hormonal contraceptives, and the lack
of photosensitivity.
About the Phase 3 Study of VX-445, Tezacaftor
and Ivacaftor in People with One F508del Mutation and One Minimal
Function Mutation
The final 24-week efficacy and safety
data announced today are from a randomized, double-blind,
placebo-controlled Phase 3 study that enrolled people ages 12 and older
with one F508del mutation and one minimal function mutation.
Patients randomized to the triple combination arm received 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.
Patients randomized to the control arm received triple placebo in the
morning and ivacaftor placebo in the evening.
The study randomized and dosed 403 patients, including 200 in the VX-445
triple combination regimen arm and 203 in the placebo arm. 400 patients
completed the 24-week treatment period, including 197 in the VX-445
triple combination regimen arm and 203 in the placebo arm. All 400
patients elected to enroll in the 96-week open-label extension study
where all patients receive the VX-445 triple combination regimen.
Efficacy Results: As previously announced, treatment with
the VX-445 triple combination regimen resulted in a mean absolute
improvement in ppFEV1 of 13.8 percentage points from baseline
at week 4 compared to triple placebo (p<0.0001), which was the primary
endpoint of the study in the U.S. This improvement in ppFEV1 was
maintained through 24 weeks of treatment in the study, as announced
today. In addition, statistically significant improvements in all key
secondary endpoints were observed after treatment with the VX-445 triple
combination. A summary of the Phase 3 efficacy data, including results
announced today for 24-week key secondary endpoints, is provided below:
|
|
Triple Placebo |
VX-445/TEZ/IVA |
Treatment |
|||||
| Primary Endpoint** | ||||||||
| Absolute Change in ppFEV1 from Baseline at Week 4 | -0.2 | 13.6 |
13.8 |
|||||
| 24-Week Key Secondary Endpoints** | ||||||||
| Absolute Change in ppFEV1 from Baseline Through Week 24 | -0.4 | 13.9 |
14.3 |
|||||
| Number of Pulmonary Exacerbations Through Week 24 | Number of Events (rate per 48 weeks) | 113 (0.98) | 41 (0.37) | — | ||||
| Rate Ratio | — | — |
0.37 |
|||||
| Absolute Change in Sweat Chloride from Baseline Through Week 24 | -0.4 | -42.2 |
-41.8 |
|||||
|
Absolute Change in CFQ-R Respiratory Domain from Baseline Through Week 24 |
-2.7 | 17.5 |
20.2 |
|||||
| Absolute Change in BMI from Baseline at Week 24 | 0.09 | 1.13 |
1.04 |
|||||
*Treatment difference provided as the outcome
measure for changes in ppFEV1, sweat chloride,
CFQ-R and BMI; Rate ratio provided as the outcome measure for the number
of pulmonary exacerbations
**The primary
endpoint was evaluated as part of a previously announced interim
analysis; secondary endpoints were evaluated as part of the final
analysis; Absolute change in ppFEV1 from
baseline through week 24 was the primary endpoint of the study in the EU
Safety Results: The VX-445 triple combination was
generally well tolerated in this 24-week study. The majority of adverse
events were mild or moderate. Serious adverse events were observed in
13.9% (n=28) of patients who received the VX-445 triple combination
regimen and in 20.9% (n=42) of patients who received triple placebo. The
most common adverse events that occurred in 15% or more of patients,
regardless of treatment arm, were infective pulmonary exacerbation,
sputum increased, headache and cough. Two patients (1%) who received the
VX-445 triple combination discontinued treatment due to adverse events,
and 0 (0%) patients who received triple placebo discontinued treatment
due to adverse events.
About the Phase 3 Study of VX-445, Tezacaftor
and Ivacaftor in People with Two F508del Mutations
The
final 4-week data announced today are from a randomized, double-blind,
controlled Phase 3 study that enrolled people ages 12 and older with two F508del
mutations. All patients received tezacaftor in combination with
ivacaftor during a 4-week run-in prior to randomization. Patients
randomized to the active treatment arm received 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. Patients
randomized to the control arm received placebo, tezacaftor (100 mg) and
ivacaftor (150 mg) in the morning followed by ivacaftor (150 mg) in the
evening.
The study randomized and dosed 107 patients, including 55 in the VX-445
triple combination regimen arm and 52 in the control arm. All 107
patients completed the 4-week treatment period and elected to enter the
96-week open-label extension study where all patients receive the VX-445
triple combination regimen.
Efficacy Results: As previously announced, data from this
study showed a mean absolute improvement in ppFEV1 of 10.0
percentage points from baseline at week 4 when VX-445 was added in
patients who were already receiving tezacaftor in combination with
ivacaftor compared to those in whom placebo was added to tezacaftor and
ivacaftor (p<0.0001), which was the primary endpoint of the study. In
addition, statistically significant improvements in both key secondary
endpoints were observed at week 4 of the study. A summary of the Phase 3
efficacy data, including results announced today for key secondary
endpoints, is provided below:
|
Placebo/TEZ/IVA |
VX-445/TEZ/IVA |
Treatment |
||||
| Primary Endpoint* | ||||||
| Absolute Change in ppFEV1 from Baseline at Week 4 | 0.4 | 10.4 |
10.0 |
|||
| Key Secondary Endpoints* | ||||||
| Absolute Change in Sweat Chloride from Baseline at Week 4 | 1.7 | -43.4 |
-45.1 |
|||
| Absolute Change in CFQ-R Respiratory Domain from Baseline at Week 4 | -1.4 | 16.0 |
17.4 |
|||
*Primary and secondary endpoints were evaluated as
part of the final analysis
Safety Results: The VX-445 triple combination was generally well
tolerated in this 4-week study. The majority of adverse events were mild
or moderate. Serious adverse events were observed in 3.6% (n=2) of the
patients who received VX-445, tezacaftor and ivacaftor and in 1.9% (n=1)
of the patients who received placebo, tezacaftor and ivacaftor. There
were no adverse events that occurred in 15% or more of patients in
either arm of the study. There were no discontinuations due to adverse
events in either arm of the study.
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 cells
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, Australia and Latin America. 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 nine 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), SYMDEKOTM/SYMKEVITM
(tezacaftor/ivacaftor and ivacaftor), and VX-445 (elexacaftor)
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. Rowe’s statements in the fourth paragraph, Dr. Kewalramani’s
statements in the fifth paragraph, and the information provided
regarding (i) the plan to seek global regulatory approvals for a triple
combination regimen in both F/MF and F/F populations, and (ii) the
expected timing of the NDA and MAA submissions for the VX-445 triple
combination regimen. 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 the company could
experience unforeseen delays in submitting regulatory filings, that
regulatory authorities may not approve, or approve on a timely basis, a
triple-combination regimen 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)
Contacts
Investors:
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Eric Rojas,
617-961-7205 or
Zach Barber, 617-341-6470
Media:
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