CAMBRIDGE, Mass. & NEW YORK, Nov 01, 2010 (BUSINESS WIRE) -- Ironwood Pharmaceuticals, Inc. (NASDAQ: IRWD) and Forest Laboratories,
Inc. (NYSE: FRX) today announced positive top-line results from a
26-week Phase 3 clinical trial assessing the efficacy and safety of the
investigational drug linaclotide in patients with irritable bowel
syndrome with constipation (IBS-C). Analyses of the data indicate a
statistically significant improvement (p<0.0001) was achieved for
linaclotide-treated patients compared to placebo-treated patients on all
four primary endpoints, which included two composite responder endpoints
encompassing abdominal pain and complete spontaneous bowel movements
(CSBMs), as well as individual responder endpoints for abdominal pain
and CSBMs. Significant improvement (p<0.001) was also achieved for
linaclotide-treated patients compared to placebo-treated patients on all
pre-specified secondary endpoints, which were measures of abdominal
pain, abdominal discomfort, bloating, and bowel symptoms. Both primary
and secondary endpoints were assessed over the first 12 weeks of the
treatment period, and these results were consistent with the first Phase
3 trial of linaclotide in patients with IBS-C.
Additionally, at each of the 26 weeks in the treatment period, mean
changes from baseline in abdominal pain and CSBMs showed statistically
significant improvements (p<0.0001) for linaclotide-treated patients
compared to placebo-treated patients. The incidence of adverse events
was similar to that observed in the first Phase 3 trial of linaclotide
in patients with IBS-C, with diarrhea being the most common adverse
event in linaclotide-treated patients.
"We are thrilled with the positive results from this trial,
demonstrating a reduction in abdominal pain and an increase in CSBMs
over the 26-week treatment period. Linaclotide's effect on these
symptoms and tolerability profile has been remarkably consistent across
the robust IBS-C and chronic constipation development program," said
Peter Hecht, CEO of Ironwood. "We look forward to the opportunity to
bring this promising treatment to the millions of individuals suffering
from these chronic and highly bothersome gastrointestinal disorders."
"By successfully meeting all the primary and secondary endpoints in this
trial, we now have two positive Phase 3 IBS-C trials and two positive
Phase 3 chronic constipation trials," said Howard Solomon, Chairman and
Chief Executive Officer of Forest Laboratories. "We look forward to
filing the NDA for both indications in 2011."
This trial, MCP-103-302, is part of Ironwood and Forest's Phase 3
program investigating the effect of linaclotide treatment on patients
with IBS-C or chronic constipation (CC). Previously, Ironwood and Forest
reported positive results from the first of two Phase 3 trials in
patients with IBS-C and two Phase 3 trials in patients with CC. The
IBS-C trials were also designed to support regulatory submission in
Europe. Today, in a separate press release, Ironwood and its European
partner, Almirall, announced positive top-line results from this study
for the E.U. endpoints.
Trial MCP-103-302 Results
Trial MCP-103-302 was a multicenter, randomized, double-blind,
placebo-controlled trial conducted in 805 patients meeting modified Rome
II criteria for IBS-C. The trial included a two-week pretreatment
baseline period and a 26-week treatment period with patients receiving a
once-daily dose of linaclotide 266 mcg or placebo. Primary and secondary
endpoints were assessed over the first 12 weeks of treatment. During the
pretreatment baseline period, the mean abdominal pain score was 5.6 (on
a 0 - 10 scale where 0 is no abdominal pain and 10 is very severe
abdominal pain), with 87 percent of patients suffering abdominal pain
every day and 76 percent having no CSBMs. The results for the four
primary endpoints are detailed below.
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Composite responder endpoint 1: abdominal pain and CSBM
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-- A greater proportion of linaclotide-treated patients compared
to placebo-treated patients (12.7 percent vs. 3.0 percent;
p<0.0001) had, in the same week, at least a 30 percent reduction
in abdominal pain, at least three CSBMs, and an increase of one or
more CSBMs. These criteria had to be met for at least nine of the
first 12 weeks of the treatment period for a patient to be
considered a responder for composite responder endpoint 1.
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CSBM responder endpoint
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-- A greater proportion of linaclotide-treated patients compared
to placebo-treated patients (18.0 percent vs. 5.0 percent;
p<0.0001) had, in the same week, at least three CSBMs and an
increase of one or more CSBMs. These criteria had to be met for at
least nine of the first 12 weeks of the treatment period for a
patient to be considered a responder and are components of
composite responder endpoint 1.
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3.
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Abdominal pain responder endpoint
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-- A greater proportion of linaclotide-treated patients compared
to placebo-treated patients (38.9 percent vs. 19.6 percent;
p<0.0001) had at least a 30 percent reduction in abdominal pain.
This criterion had to be met for at least nine of the first 12
weeks of the treatment period for a patient to be considered a
responder and is a component of composite responder endpoint 1.
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Composite responder endpoint 2: abdominal pain and CSBM
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-- A greater proportion of linaclotide-treated patients compared
to placebo-treated patients (33.7 percent vs. 13.9 percent,
p<0.0001) had, in the same week, at least a 30 percent reduction
in abdominal pain and an increase of one or more CSBMs. These
criteria had to be met for at least six of the first 12 weeks of
the treatment period for a patient to be considered a responder
for composite responder endpoint 2. This primary endpoint reflects
the Food and Drug Administration (FDA) draft guidance published in
March 2010 for evaluating the efficacy of IBS therapies.
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All secondary endpoints demonstrated statistically significant (p<0.001)
improvements for linaclotide-treated patients compared to
placebo-treated patients. These endpoints include change from baseline
measures of abdominal pain, abdominal discomfort, bloating, percent
pain-free days, CSBM frequency, SBM frequency, stool consistency, and
straining, as well as the individual components of composite responder
endpoint 2 (abdominal pain responder and CSBM responder) as described
below.
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For the abdominal pain component of composite responder endpoint 2, a
greater proportion of linaclotide-treated patients compared to
placebo-treated patients (48.9 percent vs. 34.5 percent, p<0.0001) had
at least a 30 percent or greater reduction in pain for at least six of
the first 12 weeks of the treatment period.
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For the CSBM component of composite responder endpoint 2, a greater
proportion of linaclotide-treated patients compared to placebo-treated
patients (47.6 percent vs. 22.6 percent, p<0.0001) had an increase of
one or more CSBMs for at least six of the first 12 weeks of the
treatment period.
The most common adverse events that occurred more frequently in
linaclotide-treated patients compared to placebo-treated patients
throughout the 26-week treatment period were diarrhea (19.7 percent vs.
2.5 percent), abdominal pain (4.5 percent vs. 4.0 percent), flatulence
(3.7 percent vs. 2.2 percent), viral gastroenteritis (3.7 percent vs.
2.2 percent), and headache (3.2 percent vs. 2.7 percent). Overall rates
of discontinuation due to adverse events were 10.2 percent for the
linaclotide-treated patients and 2.5 percent for the placebo-treated
patients; 4.5 percent of linaclotide-treated patients discontinued due
to diarrhea compared with 0.2 percent of placebo-treated patients.
The companies expect to present detailed results at appropriate
scientific conferences.
New Drug Application (NDA) Timing
The companies expect to submit an NDA to the FDA for both the IBS-C and
CC indications in the third quarter of calendar year 2011. The projected
timeline is driven by commitments to exceed International Conference on
Harmonisation (ICH) guidelines for the number of IBS-C and CC patients
in long-term safety studies, conduct pre-NDA meetings with the FDA, and
complete drug product stability studies to support a room temperature
product for patients.
Glossary of Terms
Spontaneous bowel movement (SBM): An SBM is a bowel movement that
occurs in the absence of laxative, enema, or suppository usage during
the current or preceding day.
Complete spontaneous bowel movement (CSBM): A CSBM is an SBM that
is accompanied by the patient self-reporting a feeling of complete
emptying of the bowel.
ROME II Criteria: A patient who reports abdominal discomfort or
pain for two or more of the following three features for at least 12
weeks, which need not be consecutive, in the 12 months before the
screening visit, or before starting chronic treatment with tegaserod or
lubiprostone: (1) relieved with defecation; (2) onset associated with a
change in frequency of stool; (3) onset associated with a change in form
(appearance) of stool.
About Linaclotide
Linaclotide, an investigational drug, is an agonist of the guanylate
cyclase type-C (GC-C) receptor located on the luminal surface of the
intestine. In preclinical models, linaclotide has been shown to reduce
visceral pain, increase fluid secretion, and accelerate intestinal
transit. The effects on secretion and transit are mediated through
cyclic guanosine monophosphate (cGMP), which is also believed to
modulate the activity of local nerves to reduce pain. Linaclotide is an
orally delivered peptide that acts locally in the gut with no measurable
systemic exposure at therapeutic doses and is intended for once-daily
administration. Linaclotide is in Phase 3 clinical development for the
treatment of irritable bowel syndrome with constipation (IBS-C) and
chronic constipation. An issued composition of matter patent for
linaclotide provides protection to 2025. Ironwood and Forest are
co-developing and will co-promote linaclotide in the United States.
Ironwood has out-licensed linaclotide to Almirall for European
development and commercialization, and to Astellas Pharma Inc. for
development and commercialization in Japan, Indonesia, Korea, the
Philippines, Taiwan, and Thailand.
About Irritable Bowel Syndrome with Constipation (IBS-C)
IBS-C is a chronic functional gastrointestinal disorder characterized by
abdominal pain, discomfort, and bloating associated with altered bowel
habits, and as many as 11 million people in the U.S. suffer from it.
There are currently few available therapies to treat this disorder and
there is a high rate of dissatisfaction with available therapies.
Patients suffering from IBS-C can be affected physically,
psychologically, socially, and economically.
About Chronic Constipation (CC)
As many as 34 million Americans suffer from symptoms associated with CC
and 8.5 million patients have sought treatment. Patients with CC often
experience hard and lumpy stools, straining during defecation, a
sensation of incomplete evacuation, and fewer than three bowel movements
per week, as well as discomfort and bloating. This condition
significantly affects patients' quality of life by impairing their
ability to work and participate in typical daily activities. There is a
high rate of dissatisfaction with currently available treatments.
About Ironwood Pharmaceuticals
Ironwood Pharmaceuticals (NASDAQ: IRWD) is an entrepreneurial
pharmaceutical company dedicated to the art and science of great
drugmaking. Linaclotide, Ironwood's GC-C agonist, is being evaluated in
a confirmatory Phase 3 program for the treatment of irritable bowel
syndrome with constipation (IBS-C) and chronic constipation. Ironwood
also has a growing pipeline of additional drug candidates in earlier
stages of development. Ironwood is located in Cambridge, Mass. To learn
more about Ironwood Pharmaceuticals, visit www.ironwoodpharma.com.
About Forest Laboratories, Inc.
Forest Laboratories' (NYSE: FRX) longstanding global partnerships and
track record developing and marketing pharmaceutical products in the
United States have yielded its well-established central nervous system
and cardiovascular franchises and innovations in anti-infective
medicine. The Company's pipeline, the most robust in its history,
includes product candidates in all stages of development across a wide
range of therapeutic areas. The Company is headquartered in New York,
NY. To learn more, visit www.FRX.com.
This press release contains forward looking statements relating to
the joint development efforts being undertaken by Forest and Ironwood
with respect to the development of the pharmaceutical product
linaclotide. Investors are cautioned not to place undue reliance on
these forward- looking statements, including, but not limited to, our
top-line assessment of our Phase 3 IBS-C clinical trial data and its
implications for the future development of linaclotide, linaclotide's
potential as a treatment for IBS-C, the successful completion of our
long-term safety studies, our ability to produce an adequate commercial
supply of linaclotide, the timing of our filing of a New Drug
Application with the FDA for linaclotide, and the potential size of
linaclotide's target patient population. Each forward-looking statement
is subject to risks and uncertainties that could cause actual results to
differ materially from those expressed or implied in such statement.
Applicable risks and uncertainties include the risks that our other
joint linaclotide development activities do not progress as expected,
serious adverse events arise in patients that are deemed to be
definitely or probably related to linaclotide treatment, the incidence
or severity of diarrhea in patients treated with linaclotide is higher
than expected, and we are unable to produce an adequate commercial
supply of linaclotide, as well as risks related to the difficulty of
predicting FDA approvals, the acceptance of and demand for new
pharmaceutical products, the impact of competitive products and pricing,
and whether linaclotide will ever be commercialized successfully. In
addition, both Forest and Ironwood (and their respective contributions
to the development of linaclotide) may be affected by the risks that are
listed in each of their Quarterly Reports on Form 10-Q for the quarter
ended June 30, 2010, in addition to those that are listed from time to
time in their Annual Reports on Form 10-K, Quarterly Reports on Form
10-Q, and other SEC filings. Neither Forest nor Ironwood undertakes any
obligation to update these forward-looking statements to reflect events
or circumstances occurring after this press release. These
forward-looking statements speak only as of the date of this press
release. All forward-looking statements are qualified in their entirety
by this cautionary statement.
SOURCE: Forest Laboratories, Inc. & Ironwood Pharmaceuticals, Inc.
Forest Laboratories, Inc.
Frank J. Murdolo, 212-224-6714
Vice President - Investor Relations
[email protected]
or
Ironwood Pharmaceuticals, Inc.
Susan Brady, 617-621-8304
Corporate Communications
[email protected]
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