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Top-line Results Show Each Trial Met Primary and All Secondary Endpoints
CAMBRIDGE, Mass. & NEW YORK(BUSINESS WIRE)
Ironwood Pharmaceuticals, Inc. and Forest Laboratories, Inc. (NYSE: FRX)
today announced positive top-line results from two Phase 3 clinical
trials assessing the safety and efficacy of once-daily dosing of the
investigational drug linaclotide in patients with chronic constipation
(CC). Analyses of the data indicate that in both multicenter,
randomized, double-blind, placebo-controlled trials, statistical
significance was achieved for the primary endpoint of 12-week complete
spontaneous bowel movement (CSBM) overall responder at the two doses
studied in each trial (133 mcg/day: p-values?0.0012 and 266 mcg/day:
p-values<0.0001). In both trials, statistical significance (p<0.01) was
achieved for all prespecified secondary endpoints, which included
measures of bloating, abdominal discomfort, and average weekly CSBMs.
The results of these two trials confirm the potential for linaclotide
to bring relief to the millions of patients suffering from many of the
symptoms associated with chronic constipation,? said Howard Solomon,
Chairman and Chief Executive Officer of Forest Laboratories. These
outcomes are the result of outstanding collaboration between Ironwood
and Forest, with both companies participating in these clinical trials.
We look forward to further advancing the development of linaclotide, a
novel product in a therapeutic category where patients have very limited
treatment options.?
Peter Hecht, Chief Executive Officer of Ironwood, said, We are very
pleased to observe how well the top-line results of these larger Phase 3
trials replicate the effect of linaclotide observed in our Phase 2b
trial.?
These two trials are part of Ironwood and Forest's larger Phase 3
program investigating the effect of linaclotide treatment on patients
with CC or irritable bowel syndrome with constipation (IBS-C). The
companies are currently enrolling two additional pivotal Phase 3 trials
in North America to assess the safety and efficacy of linaclotide in
patients with IBS-C and expect results in the second half of calendar
year 2010.
Trial 01 Results
Trial 01 was conducted in 633 patients meeting modified Rome II criteria
for CC. The trial included a two-week pretreatment baseline period and a
12-week treatment period. The primary efficacy endpoint was 12-week CSBM
overall responder. A 12-week CSBM overall responder is a patient who had
three or more CSBMs per week and an increase of at least one CSBM per
week over baseline for at least nine of the 12 weeks of the treatment
period. During the baseline period, 72 percent of patients had no CSBMs.
Based on the intent-to-treat population:
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The 12-week CSBM overall responder rate was 16.0 percent in the 133
mcg linaclotide group (p=0.0012) and 21.3 percent in the 266 mcg
linaclotide group (p<0.0001), a numerical increase of 2.6 and 3.5
fold, respectively, as compared to 6.0 percent in the placebo group. A
total of 16.0 percent (p=0.0012) of patients receiving 133 mcg and
21.8 percent (p<0.0001) of patients receiving 266 mcg of linaclotide
experienced ?3 weekly CSBMs in at least nine out of 12 weeks as
compared to 6.0 percent of patients receiving placebo. In addition
31.0 percent (p<0.0001) of patients receiving 133 mcg and 40.1 percent
(p<0.0001) of patients receiving 266 mcg of linaclotide achieved an
increase of ?1 from baseline in weekly CSBMs in at least nine out of
12 weeks as compared to 13.0 percent of patients receiving placebo.
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Linaclotide-treated patients demonstrated a significant increase in
average weekly CSBMs from baseline (0.6 for placebo; 2.0 for 133 mcg,
p<0.0001; 2.7 for 266 mcg, p<0.0001) and a significant increase in
average weekly spontaneous bowel movements (SBMs) from baseline (1.1
for placebo; 3.4 for 133 mcg, p<0.0001; 3.7 for 266 mcg, p<0.0001).
All secondary endpoints measured in Trial 01, which included those
detailed in the previous paragraph as well as bloating, abdominal
discomfort, stool consistency, straining, and constipation severity,
were statistically significant (p<0.001) for linaclotide versus placebo
at both doses.
Trial 303 Results
Trial 303, conducted in 643 patients, was identical to Trial 01 in
design except Trial 303 also included a four-week randomized withdrawal
period. During the baseline period, 68 percent of patients had no CSBMs.
Based on the intent-to-treat population:
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The 12-week CSBM overall responder rate was 21.2 percent in the 133
mcg linaclotide group (p<0.0001) and 19.4 percent in the 266 mcg
linaclotide group (p<0.0001), a numerical increase of 6.3 and 5.8
fold, respectively, as compared to 3.3 percent in the placebo group. A
total of 21.7 percent (p<0.0001) of patients receiving 133 mcg and
19.4 percent (p<0.0001) of patients receiving 266 mcg of linaclotide
experienced ?3 weekly CSBMs in at least nine out of 12 weeks as
compared to 3.8 percent of patients receiving placebo. In addition
39.2 percent (p<0.0001) of patients receiving 133 mcg and 37.0 percent
(p<0.0001) of patients receiving 266 mcg of linaclotide achieved an
increase of ?1 from baseline in weekly CSBMs in at least nine out of
12 weeks as compared to 11.0 percent of patients receiving placebo.
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Linaclotide-treated patients demonstrated a significant increase in
average weekly CSBMs from baseline (0.5 for placebo; 1.9 for 133 mcg,
p<0.0001; 2.0 for 266 mcg, p<0.0001) and a significant increase in
average weekly SBMs from baseline (1.1 for placebo; 3.0 for 133 mcg,
p<0.0001; 3.0 for 266 mcg, p<0.0001).
All secondary endpoints measured in Trial 303, which included those
detailed in the previous paragraph as well as bloating, abdominal
discomfort, stool consistency, straining, and constipation severity,
were statistically significant (p<0.01) for linaclotide versus placebo
at both doses.
Across both trials, the most common adverse events in
linaclotide-treated patients were diarrhea, flatulence, and abdominal
pain. Overall rates of discontinuation due to adverse events were 7.4
percent for linaclotide and 4.2 percent for placebo.
The results of Trial 01 and Trial 303 were consistent with the
previously reported CC Phase 2b trial in which weekly SBM was the
primary endpoint. Once full analyses of the CC Phase 3 data have been
completed, Ironwood and Forest expect to present detailed results at an
appropriate scientific conference.
About Linaclotide Doses
The doses of linaclotide referenced in previous public disclosures
represented the total peptide content; however, moving forward the doses
will be expressed as linaclotide content. The 150 and 300 mcg
linaclotide referenced in prior public disclosures are equivalent to the
133 and 266 mcg linaclotide content referenced in this public disclosure
and all public disclosures going forward.
Glossary of Terms
Spontaneous bowel movement (SBM): An SBM is a bowel movement that
occurs in the absence of laxative, enema, or suppository usage within
the preceding 24 hours.
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.
About Linaclotide
Linaclotide is an orally delivered peptide that acts locally in the gut
with no detectable systemic exposure at therapeutic doses and is
intended for once-daily administration. Linaclotide is an agonist of
guanylate cyclase type-C (GC-C), a receptor found on the lining of the
intestine. Activation of GC-C leads to increases in intracellular and
extracellular cGMP. In preclinical models, extracellular cGMP inhibited
afferent nerve firing and positively affected markers of abdominal pain,
while intracellular cGMP led to activation of anion channels which
stimulated anion and fluid secretion into the intestine, leading to
accelerated intestinal transit. Linaclotide is a first-in-class compound
in Phase 3 clinical development for the treatment of IBS-C and CC.
Linaclotide demonstrated proof of concept in a comprehensive Phase 2b
program, comprised of two clinical studies in over 700 patients with
either IBS-C or CC. In patients with IBS-C, linaclotide significantly
reduced abdominal pain, abdominal discomfort, and bloating and improved
bowel function throughout the 12-week treatment period. In patients with
CC, linaclotide reduced constipation, abdominal discomfort, and bloating
throughout the four-week treatment period. Across both studies, the most
common and only dose-responsive adverse event in the linaclotide-treated
groups was diarrhea, and diarrhea was the most common adverse event
leading to discontinuation. All other adverse events occurred with
similar frequency across the placebo and linaclotide dose groups. An
issued composition of matter patent for linaclotide provides protection
to 2025. In September 2007, Ironwood and Forest entered into a 50/50
collaboration to co-develop and co-promote linaclotide in the United
States. In April 2009, Ironwood licensed to Almirall the European rights
to develop and commercialize linaclotide.
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. Half of
patients are not satisfied with currently available treatments.
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 Ironwood Pharmaceuticals
Ironwood Pharmaceuticals (www.ironwoodpharma.com)
is an entrepreneurial pharmaceutical company dedicated to the art and
science of great drugmaking. Linaclotide, the Company's first-in-class
compound, 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 has raised
$306 million in private equity financing and is located in Cambridge,
Massachusetts.
About Forest Laboratories, Inc.
Forest Laboratories (NYSE: FRX) is a U.S.-based pharmaceutical company
with a long track record of building partnerships and developing and
marketing products that make a positive difference in people's lives. In
addition to its well-established franchises in therapeutic areas of the
central nervous and cardiovascular systems, Forest's current pipeline
includes product candidates in all stages of development and across a
wide range of therapeutic areas. The company is headquartered in New
York, NY. To learn more about Forest Laboratories, visit www.FRX.com.
Except for the historical information contained herein, this release
contains forward-looking statements within the meaning of the Private
Securities Litigation Reform Act of 1995. These statements involve a
number of risks and uncertainties, including the difficulty of
predicting FDA approvals, the acceptance and demand for new
pharmaceutical products, the impact of competitive products and pricing,
the timely development and launch of new products, and the risk factors
listed from time to time in Forest Laboratories Annual Report on Form
10-K, Quarterly Report on Form 10-Q, and any subsequent SEC filings.
Forest Laboratories, Inc.
Frank J. Murdolo, 1-212-224-6714
Vice
President - Investor Relations
Frank.Murdolo@frx.com
or
Ironwood
Pharmaceuticals, Inc.
Susan Brady, 1-617-621-8304
Corporate
Communications
sbrady@ironwoodpharma.com
Source: Forest Laboratories, Inc. and Ironwood Pharmaceuticals, Inc.
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