Ironwood Pharmaceuticals, Inc. (NASDAQ: IRWD) and Forest
Laboratories, Inc. (NYSE: FRX) announced today that LINZESS™
(linaclotide) was approved by the U.S. Food and Drug Administration
(FDA) as a once-daily treatment for adult men and women suffering
from irritable bowel syndrome with constipation (IBS-C) or chronic
idiopathic constipation (CIC).
IBS-C and CIC are chronic functional gastrointestinal disorders
that affect as many as 13 million1 and 35 million2 adult Americans,
respectively. Symptoms associated with IBS-C include abdominal pain
and constipation; symptoms associated with CIC include constipation
(infrequent stools, hard stools and incomplete evacuation). There
are few treatment options for these conditions, particularly
options that relieve abdominal pain associated with IBS-C.
“The symptoms experienced by patients with IBS-C and chronic
idiopathic constipation can have a significant impact on affected
individuals,” said William D. Chey, M.D., professor of
gastroenterology at the University of Michigan Health System. “The
approval of LINZESS provides physicians with a new, evidence-based,
effective treatment option for their adult patients with IBS-C and
chronic idiopathic constipation.”
Linaclotide, the active ingredient in LINZESS, is a
first-in-class guanylate cyclase-C (GC-C) agonist and acts locally
in the intestine with minimal systemic exposure. In nonclinical
studies, linaclotide has been shown to reduce intestinal pain and
accelerate gastrointestinal transit. Linaclotide-induced intestinal
pain reduction is thought to result from an increase in cyclic
guanosine monophosphate (cGMP), which has been shown to decrease
the activity of pain-sensing nerves.
In placebo-controlled Phase III clinical trials of more than
2,800 adults, LINZESS was shown to significantly reduce abdominal
pain in IBS-C patients and significantly increase bowel movement
frequency in both IBS-C patients and CIC patients. Improvements
were reported in the first week of treatment and maintained
throughout the treatment period. When a subset of LINZESS-treated
patients in the trials were switched to placebo, they reported
their symptoms returned toward pretreatment levels within one week,
while placebo-treated patients switched to LINZESS reported symptom
improvements. LINZESS has not been studied in pediatric patients.
LINZESS is contraindicated in pediatric patients up to 6 years of
age. The use of LINZESS in pediatric patients 6 through 17 years of
age should be avoided.
Ironwood and Forest expect LINZESS to be available in the fourth
quarter of 2012.
“The discovery of LINZESS by Ironwood scientists, and the
development work done together by Ironwood and our partner Forest,
has resulted in a new medicine with the potential to improve the
lives of millions of highly symptomatic IBS-C and CIC patients,”
said Peter Hecht, Chief Executive Officer of Ironwood. “As
Ironwood’s first FDA-approved drug, LINZESS represents significant
progress towards achieving our goals of delivering medicines to
patients and value to shareholders.”
Howard Solomon, Chairman, Chief Executive Officer and President
of Forest Laboratories, said: “The approval of LINZESS validates
Forest and Ironwood’s commitment to bringing forth an effective
treatment in disease categories that previously had limited
treatment options. We look forward to making this treatment
available to the millions of adults with IBS-C and CIC in the
United States. This achievement is the result of our close working
relationship with Ironwood over the past five years in the
development of this exciting product.”
Data Highlights: Irritable Bowel Syndrome with Constipation
(IBS-C)
The safety and efficacy of LINZESS to treat IBS-C were evaluated
in two double-blind, placebo-controlled Phase III clinical trials
in which LINZESS met all four primary endpoints examining changes
in abdominal pain and constipation in each trial. The trials
involved 1,605 patients aged 18 to 87 years old, of which 807 were
treated with LINZESS 290 mcg. The data from these trials is
scheduled for publication in the October 2012 issue of the American
Journal of Gastroenterology.
Combined Responder
In both trials, the proportion of LINZESS-treated patients who
were combined responders was statistically significantly higher
than placebo-treated patients. Two definitions of combined
responder were used. A 9 of 12 week combined responder is a patient
who reported at least a 30% reduction from baseline in abdominal
pain, at least three CSBMS, and an increase of at least one CSBM
from baseline, all in the same week for at least 9 out of 12 weeks.
A 6 out of 12 week responder is a patient who reported at least a
30% reduction from baseline in abdominal pain and an increase of at
least one CSBM from baseline, all in the same week for at least 6
out of 12 weeks. This second definition is consistent with the FDA
guidance document on IBS and was one of the four pre-specified
primary endpoints in the LINZESS Phase III IBS-C trials.
In 9 out of 12 weeks, 12% (Study 1) and 13% (Study 2) of
LINZESS-treated patients were combined responders, versus 5% (Study
1) and 3% (Study 2) of placebo-treated patients. In 6 out of 12
weeks, 34% (Study 1) and 34% (Study 2) of LINZESS-treated patients
were combined responders, versus 21% (Study 1) and 14% (Study 2) of
placebo-treated patients. During a two-week pre-treatment period,
these patients reported a mean abdominal pain score of at least 3
on a 0-to-10-point scale and less than three CSBMs per week.
Abdominal Pain
LINZESS 290 mcg was proven to significantly reduce abdominal
pain; effects were seen within the first week of treatment and
improvements were maintained throughout the treatment period. In
the two trials, 34% (Study 1) and 39% (Study 2) of patients treated
with LINZESS experienced at least a 30% reduction in abdominal pain
from baseline for at least 9 out of 12 weeks versus 27% (Study 1)
and 20% (Study 2) of placebo-treated patients. For at least 6 out
of 12 weeks (a secondary endpoint), 50% (Study 1) and 49% (Study 2)
of LINZESS-treated patients versus 38% (Study 1) and 35% (Study 2)
of placebo-treated patients experienced at least a 30% reduction in
abdominal pain from baseline.
Constipation Symptoms
LINZESS significantly increased the frequency of complete
spontaneous bowel movements (CSBMs), with 20% (Study 1) and 18%
(Study 2) of patients treated with LINZESS experiencing an increase
of at least one CSBM from baseline for at least 9 out of 12 weeks
versus 6% (Study 1) and 5% (Study 2) of placebo-treated patients.
For at least 6 out of 12 weeks (secondary endpoint), 49% (Study 1)
and 48% (Study 2) of LINZESS-treated patients versus 30% (Study 1)
and 23% (Study 2) of placebo-treated patients experienced at least
three CSBMs and an increase of at least one CSBM from baseline. In
each trial, the drug reached maximum effectiveness within the first
week of treatment, and improvements were maintained throughout the
treatment period.
Data Highlights: Chronic Idiopathic Constipation
(CIC)
The efficacy of LINZESS for the management of CIC was
established in two double-blind, placebo-controlled Phase III
clinical trials in which LINZESS met the primary endpoint in both
trials. The primary endpoint in these trials examined changes in
bowel function. The trials involved 1,275 patients aged 18 to 85
years old, of which 430 received LINZESS 145 mcg and 422 received
LINZESS 290 mcg. During a two-week pretreatment period at the
beginning of the trials, these patients reported less than three
CSBMs per week. The data were published in the August 11, 2011
issue of the New England Journal of Medicine4.
Constipation Symptoms
LINZESS significantly increased the frequency of CSBMs in
treated patients. At the 145 mcg dose, 20% (Study 3) and 16% (Study
4) of LINZESS-treated patients experienced at least 3 CSBMs and an
increase of at least one CSBM from baseline in the same week for at
least 9 of the 12 weeks (CSBM responder) versus 3% (Study 3) and 6%
(Study 4) of placebo patients. In each trial, the drug reached
maximum effectiveness within the first week of treatment, and
improvements were maintained throughout the treatment period.
Patients taking LINZESS experienced significant improvement in
stool frequency and hardness of stool compared to placebo.
Safety
The most common adverse reactions in IBS-C or CIC patients were
diarrhea, abdominal pain, flatulence and abdominal distension.
Post Approval Pediatric Requirements
As part of the post approval requirements for LINZESS, Ironwood
and Forest have agreed to a pediatric development program which
will initially consist of additional nonclinical studies to
characterize deaths previously observed in neonatal and young
juvenile mice during nonclinical toxicology studies. Linaclotide
did not cause deaths in older juvenile mice (approximately
equivalent to humans age 12 to 17 years). In nonclinical toxicology
studies with adult models, LINZESS was safely dosed up to 5,000
mcg/kg/day (the maximum recommended dose for an average adult
person is 5 mcg/kg/day). To date, there have been no studies of
LINZESS in pediatric patients, and until such nonclinical results
are available and pediatric studies are conducted, children should
not be exposed to LINZESS. A boxed warning in the labeling informs
physicians and patients that LINZESS is contraindicated in
pediatric patients up to 6 years of age and use of LINZESS should
be avoided in pediatric patients 6 through 17 years of age.
About LINZESS
LINZESS is the first and only guanylate cyclase-C (GC-C) agonist
approved by the FDA for the treatment of both irritable bowel
syndrome with constipation (IBS-C) and chronic idiopathic
constipation (CIC) in adults. LINZESS is a once-daily capsule that
helps relieve the chronic abdominal pain and constipation
associated with IBS-C and constipation and hard stools associated
with CIC. The recommended dose is 290 mcg for IBS-C patients and
145 mcg for CIC patients.
LINZESS binds to the GC-C receptor locally in the intestine,
with no measurable blood plasma concentrations, resulting in an
increase in both intracellular and extracellular concentrations of
cyclic guanosine monophosphate (cGMP). Elevations in intracellular
cGMP are believed to stimulate secretion of intestinal fluid and
accelerate gastrointestinal transit resulting in increased
frequency of bowel movements. Elevations in extracellular cGMP are
believed to decrease activity of pain-sensing nerves, which is
thought to be responsible for a reduction in intestinal pain,
according to nonclinical models.
An issued composition of matter patent for linaclotide provides
protection to 2025 in the United States. Ironwood and Forest will
co-promote LINZESS in the United States. Ironwood has out-licensed
linaclotide to Almirall, S.A. 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
Irritable bowel syndrome with constipation (IBS-C) is a chronic
functional gastrointestinal disorder that affects as many as 13
million people in the United States. IBS-C can have a negative
impact on daily living; patients often experience recurring
abdominal pain or discomfort, constipation, and bowel symptoms
including hard or lumpy stools in more than 25% of bowel movements,
and soft or watery stools in less than 25% of bowel movements.
There are currently few available therapies to treat this
disorder.
About Chronic Idiopathic Constipation
Chronic idiopathic constipation (CIC) is a functional
gastrointestinal disorder in which individuals experience
infrequent bowel movements (less than three times per week) for at
least three months. Patients who suffer from CIC may also
experience a sensation of incomplete evacuation and hard stools. As
many as 35 million Americans may suffer from symptoms associated
with CIC.
Important Safety Information
WARNING: PEDIATRIC RISK
LINZESS is contraindicated in pediatric
patients up to 6 years of age. Use should be avoided in pediatric
patients 6 through 17 years of age. In nonclinical studies,
administration of a single, clinically relevant adult oral dose of
linaclotide caused deaths in young juvenile mice.
Contraindications
- LINZESS is contraindicated in pediatric
patients up to 6 years of age.
- LINZESS is contraindicated in patients
with known or suspected mechanical gastrointestinal
obstruction.
Warnings and Precautions
Pediatric Risk
- LINZESS is contraindicated in pediatric
patients up to 6 years of age. In nonclinical studies, deaths
occurred within 24 hours in young juvenile mice (1 to 3 week-old
mice; approximately equivalent to human pediatric patients less
than 2 years of age) following administration of one or two daily
oral doses of linaclotide.
- Use of LINZESS should be avoided in
pediatric patients 6 through 17 years of age. Linaclotide did not
cause deaths in older juvenile mice (approximately equivalent to
humans age 12 to 17 years). Although there were no deaths in older
juvenile mice, given the deaths in young juvenile mice and the lack
of clinical safety and efficacy data in pediatric patients, use of
LINZESS should be avoided in pediatric patients 6 through 17 years
of age.
Diarrhea
- Diarrhea was the most common adverse
reaction of LINZESS-treated patients in the pooled IBS-C and CIC
double-blind placebo-controlled trials. Severe diarrhea was
reported in 2% of LINZESS-treated patients. The incidence of
diarrhea was similar in the IBS-C and CIC populations.
- Patients should be instructed to stop
LINZESS if severe diarrhea occurs and to contact their healthcare
provider, who should consider dose suspension.
Adverse Reactions
- In IBS-C clinical trials, the most
common adverse reactions in LINZESS-treated patients (incidence ≥2%
and greater than placebo) were diarrhea (20% vs 3% placebo),
abdominal pain (7% vs 5%), flatulence (4% vs 2%), headache (4% vs
3%), viral gastroenteritis (3% vs 1%) and abdominal distension (2%
vs 1%).
- In CIC clinical trials, the most common
adverse reactions in LINZESS-treated patients (incidence ≥2% and
greater than placebo) were diarrhea (16% vs 5% placebo), abdominal
pain (7% vs 6%), flatulence (6% vs 5%), upper respiratory tract
infection (5% vs 4%), sinusitis (3% vs 2%) and abdominal distension
(3% vs 2%).
Drug Interactions
No drug-drug interaction studies have been conducted with
LINZESS. Linaclotide and its active metabolite are not measurable
in plasma following administration of the recommended clinical
doses; hence, no systemic drug-drug interactions or drug
interactions mediated by plasma protein binding of linaclotide or
its metabolite are anticipated.
Linaclotide does not interact with the cytochrome P450 enzyme
system based on the results of in vitro studies. In addition,
linaclotide is neither a substrate nor an inhibitor of the efflux
transporter P-glycoprotein (P-gp).
About Ironwood Pharmaceuticals
Ironwood Pharmaceuticals (NASDAQ: IRWD) is an entrepreneurial
pharmaceutical company dedicated to the art and science of great
drugmaking. LINZESS (linaclotide), Ironwood’s guanylate cyclase-C
(GC-C) agonist, is an FDA-approved drug for the treatment of adults
with irritable bowel syndrome with constipation (IBS-C) or chronic
idiopathic constipation (CIC). Ironwood also has a growing pipeline
of additional drug candidates in earlier stages of development.
Ironwood is located in Cambridge, Mass. To learn more, 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 and respiratory,
gastrointestinal, and pain management 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.
References
1. Source: Chey, W. et al “Frequency and Bothersomeness of
Symptoms, Health Care Seeking Behavior and Satisfaction with
Therapy in IBS-C Patients Meeting ROME II Criteria: Results of a
Population Based Survey”. Poster presented at UEGW 2010.
http://uegw10.uegf.org/ (poster # P1275)
2. Brandt LJ, Prather CM, Quigley EMM, Schiller LR, Schoenfeld
P, Talley NJ. Systematic review on the management of chronic
constipation in North America. Am J Gastroenterol.
2005;100(100):S1-S21.
3. Lembo, A., et al. N Engl J Med 2011; 365:527-536.
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 anticipated availability of LINZESS in the retail channels, the
target patient populations in the United States for LINZESS, the
post approval development strategy for LINZESS, 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 each of
Forest’s and Ironwood’s 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.
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