Ironwood, Allergan with positive topline data from LINZESS testing in Adults with Irritable Bowel Syndrome with Constipation (IBS-C)

June 19, 2019 Off By BusinessWire

– Phase IIIb study met all primary and secondary endpoints
with statistical significance and demonstrated that linaclotide improved
the overall abdominal symptoms of bloating, pain and discomfort in
adults with IBS-C –

– Results further support the efficacy and safety of LINZESS for the
millions of adults suffering from multiple frequent and bothersome
symptoms associated with IBS-C –

CAMBRIDGE, Mass.–(BUSINESS WIRE)–Ironwood
Pharmaceuticals, Inc. (NASDAQ: IRWD) and Allergan
plc (NYSE:AGN) today announced positive topline data from a Phase
IIIb clinical trial evaluating LINZESS (linaclotide) 290 mcg on multiple
abdominal symptoms in adult patients with IBS-C. The trial met its
primary multi-component endpoint and demonstrated that linaclotide
improved the overall abdominal symptoms of bloating, pain and discomfort
in adult IBS-C patients compared to placebo. The trial also met both
secondary endpoints. This trial was designed to highlight the impact of
LINZESS on the overall abdominal symptoms of bloating, pain and
discomfort, which are part of patients’ reported real-world experience,
thereby enabling better communication about these symptoms.

LINZESS is marketed by Ironwood and Allergan in the United States and is
indicated for the treatment of adults with IBS-C or chronic idiopathic
constipation (CIC). Research has shown that approximately 95 percent of
adults with IBS-C experience bothersome abdominal bloating, pain, and/or
discomfort, with the majority experiencing these symptoms once a week or
more. There are an estimated 13 million adults in the U.S. with IBS-C.^1,2

“While research clearly suggests that the symptoms of abdominal
bloating, pain, and discomfort have a considerable impact on adults
suffering from IBS-C, in the clinical setting patients often use the
word ‘constipation’ as a general term to represent their abdominal and
bowel symptoms. This can lead to a less precise communication regarding
their symptoms between patient and physician and can impact management,”
said Lin Chang, M.D., Professor of Medicine at the Vatche and Tamar
Manoukian Division of Digestive Diseases at the University of
California, Los Angeles (UCLA). “I believe the data from this LINZESS
Phase IIIb trial will be very important in helping patients and
physicians have a more comprehensive dialogue about the multiple
symptoms associated with IBS-C.”

Topline data from a randomized, double-blind, placebo-controlled Phase
IIIb trial showed that linaclotide 290 mcg administered orally once
daily demonstrated a statistically significant and clinically meaningful
improvement in overall abdominal symptoms compared to placebo across the
primary and both secondary endpoints. In the multi-component primary
endpoint, linaclotide-treated patients showed a 29.7% mean decrease from
baseline in their weekly abdominal score (bloating, pain and discomfort)
through the 12-week treatment period, compared to 18.3% for the
placebo-treated patients (p<0.0001). In the secondary endpoints, 40.5%
of patients treated with linaclotide 290 mcg demonstrated a clinically
meaningful response, as defined by the abdominal symptom score
responder, compared to 23.4% of placebo-treated patients (p<0.0001). An
abdominal symptom score responder was defined as a patient who
experienced an improvement of at least two-points from baseline in their
weekly abdominal score for at least six of 12 weeks of treatment period.
These findings add to the significant body of data supporting the impact
of linaclotide on the overall abdominal symptoms of bloating, pain and
discomfort in adult IBS-C patients.

Linaclotide was well-tolerated in this Phase IIIb study, with the most
commonly reported adverse event being diarrhea. During the treatment
period, diarrhea was reported in 4.6% of patients on linaclotide 290 mcg
as compared to 1.6% of patients on placebo. Study discontinuation
resulting from diarrhea occurred in 1.6% of linaclotide 290 mcg patients
compared to none of the placebo-treated patients.

“These topline results demonstrated that LINZESS can help provide
overall relief of some of the multiple abdominal symptoms that IBS-C
patients identify as among the most bothersome,” said Mike Shetzline,
M.D., Ph.D., chief medical officer, senior vice president and head of
drug development at Ironwood. “As the 10^th Phase III trial of
linaclotide to meet its primary endpoint, this study further contributes
to the robust body of evidence supporting the use of LINZESS in adults
with IBS-C and further strengthens its clinical profile.”

“IBS-C is a frustrating and uncomfortable condition, but it can be
treated. We expect that communicating the full clinical profile of
LINZESS on the overall abdominal symptoms of bloating, pain, and
discomfort will broaden physicians’ understanding of the appropriate
patient and may help those who need to find relief,” said David
Nicholson, chief research & development officer at Allergan.

The randomized, double-blind, placebo-controlled, parallel-group study
was designed to evaluate the efficacy and safety of LINZESS 290 mcg on
multiple abdominal symptoms in adult patients with IBS-C. 614 patients
were randomized to placebo or LINZESS 290 mcg once daily for 12 weeks,
followed by a four-week randomized withdrawal period. The primary
efficacy endpoint was change from baseline in abdominal score based on
daily patient assessments of abdominal bloating, pain and discomfort at
their worst, as reported on an 11-point numerical rating scale.
Additional endpoints included change from baseline in spontaneous bowel
movement frequency, complete spontaneous bowel movement frequency, stool
consistency, and straining.

Additional data from this Phase IIIb trial are expected to be shared at
upcoming scientific meetings and via peer-reviewed publications.

About Linaclotide

Linaclotide is a guanylate cyclase-C (GC-C) agonist that is thought to
work in two ways based on nonclinical studies. Linaclotide binds to the
GC-C receptor locally, within the intestinal epithelium. Activation of
GC-C results in increased intestinal fluid secretion and accelerated
transit and a decrease in the activity of pain-sensing nerves in the
intestine. The clinical relevance of the effect on pain fibers, which is
based on nonclinical studies, has not been established. Linaclotide is
marketed by Ironwood and Allergan plc in the United States as LINZESS^® and
is indicated for the treatment of adults with irritable bowel syndrome
with constipation (IBS-C) or chronic idiopathic constipation (CIC).
Linaclotide is marketed by Allergan for the treatment of adults with
moderate to severe IBS-C in Europe under the brand name CONSTELLA^®.
Ironwood is partnered with AstraZeneca for development and
commercialization of linaclotide in China, Hong Kong and Macau. Astellas
has the exclusive rights to develop and commercialize linaclotide in
Japan. Allergan has rights to develop and market in the remaining rest
of world countries.

Important Safety Information

INDICATIONS AND USAGE

LINZESS (linaclotide) is indicated in adults for the treatment of both
irritable bowel syndrome with constipation (IBS-C) and chronic
idiopathic constipation (CIC).

IMPORTANT SAFETY INFORMATION

WARNING: RISK OF SERIOUS DEHYDRATION IN PEDIATRIC PATIENTS

LINZESS is contraindicated in patients less than 6 years of
age. In nonclinical studies in neonatal mice, administration of a
single, clinically relevant adult oral dose of linaclotide caused
deaths due to dehydration. Use of LINZESS should be avoided in
patients 6 years to less than 18 years of age. The safety and
effectiveness of LINZESS have not been established in patients
less than 18 years of age.

Contraindications

LINZESS is contraindicated in patients less than 6 years of age due to
the risk of serious dehydration.
LINZESS is contraindicated in patients with known or suspected
mechanical gastrointestinal obstruction.

Warnings and Precautions
Pediatric Risk

LINZESS is contraindicated in patients less than 6 years of age. The
safety and effectiveness of LINZESS in patients less than 18 years of
age have not been established. In neonatal mice, linaclotide increased
fluid secretion as a consequence of GC-C agonism resulting in
mortality within the first 24 hours due to dehydration. Due to
increased intestinal expression of GC-C, patients less than 6 years of
age may be more likely than patients 6 years of age and older to
develop severe diarrhea and its potentially serious consequences.
Use of LINZESS should be avoided in pediatric patients 6 years to less
than 18 years of age. 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 years to less than 18 years of age.

Diarrhea

Diarrhea was the most common adverse reaction in LINZESS-treated
patients in the pooled IBS-C and CIC double-blind placebo-controlled
trials. The incidence of diarrhea was similar in the IBS-C and CIC
populations. Severe diarrhea was reported in 2% of 145 mcg and 290 mcg
LINZESS-treated patients, and in <1% of 72 mcg LINZESS-treated CIC
patients. If severe diarrhea occurs, dosing should be suspended and
the patient rehydrated.

Common Adverse Reactions (incidence ≥2% and greater than placebo)

In IBS-C clinical trials: 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 trials of a 145 mcg dose: 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%). In a CIC trial of a 72 mcg dose: diarrhea (19%
vs 7% placebo) and abdominal distension (2% vs <1%).

Please see full Prescribing Information including Boxed Warning: http://www.allergan.com/assets/pdf/linzess_pi

About Allergan plc

Allergan plc (NYSE: AGN), headquartered in Dublin, Ireland, is a global
pharmaceutical leader focused on developing, manufacturing and
commercializing branded pharmaceutical, device, biologic, surgical and
regenerative medicine products for patients around the world. Allergan
markets a portfolio of leading brands and best-in-class products
primarily focused on four key therapeutic areas including medical
aesthetics, eye care, central nervous system and gastroenterology. As
part of its approach to delivering innovation for better patient care,
Allergan has built one of the broadest pharmaceutical and device
research and development pipelines in the industry.

With colleagues and commercial operations in approximately 100
countries, Allergan is committed to working with physicians, healthcare
providers and patients to deliver innovative and meaningful treatments
that help people around the world live longer, healthier lives every day.

For more information, visit Allergan’s website at www.Allergan.com.

About Ironwood Pharmaceuticals

Ironwood Pharmaceuticals (Nasdaq: IRWD) is a GI-focused healthcare
company dedicated to creating medicines that make a difference for
patients living with GI diseases. We discovered, developed and are
commercializing linaclotide, the U.S. branded prescription market leader
for adults with irritable bowel syndrome with constipation (IBS-C) or
chronic idiopathic constipation (CIC). We are currently advancing a
Phase IIIb trial evaluating the efficacy and safety of linaclotide on
multiple abdominal symptoms, including bloating, pain, and discomfort,
in adult patients with IBS-C.

We are also advancing two late-stage, first-in-category GI product
candidates: IW-3718 is a gastric retentive formulation of a bile acid
sequestrant being developed for the potential treatment of persistent
gastroesophageal reflux disease, and MD-7246 is a delayed-release
formulation of linaclotide that is being evaluated as an oral,
intestinal, non-opioid, pain-relieving agent for patients suffering from
abdominal pain associated with IBS with diarrhea.

Ironwood was founded in 1998 and is headquartered in Cambridge, Mass.
For more information, please visit our website at www.ironwoodpharma.com
or www.twitter.com/ironwoodpharma;
information that may be important to investors will be routinely posted
in both these locations.

IRONWOOD®, the three-leaf logo, LINZESS® and CONSTELLA® are registered
trademarks of Ironwood Pharmaceuticals, Inc. Any other trademarks
referred to in this press release are the property of their respective
owners. All rights reserved.

Forward-Looking Statements

This press release contains forward-looking statements. Investors are
cautioned not to place undue reliance on these forward-looking
statements, including, but not limited to, statements about the
potential for linaclotide to offer IBS-C patients relief from bothersome
symptoms including abdominal bloating, pain and discomfort; the efficacy
and safety of linaclotide; IBS-C symptoms and the size of the potential
patient population; the size, scope and design of the Phase IIIb study
of linaclotide in adults with IBS-C; the potential of the Phase IIIb
data to improve physician-patient dialogue; the strength of
linaclotide’s clinical profile; the potential of the Phase IIIb data to
increase requests for linaclotide; and the development and regulatory
plans for linaclotide. 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 those related to preclinical and
clinical development, manufacturing and formulation development; the
risk that future clinical studies need to be discontinued for any
reason, including safety, tolerability, enrollment, manufacturing or
economic reasons; the risk that findings from our completed nonclinical
and clinical studies may not be replicated in later studies; efficacy,
safety and tolerability of our products and product candidates; the risk
that the therapeutic opportunities for linaclotide are not as we expect;
decisions by regulatory and judicial authorities; the risk that we are
unable to successfully commercialize linaclotide; the risk that we may
never get sufficient patent protection for our products and our product
candidates or that we are not able to successfully protect such patents;
the outcomes in legal proceedings to protect or enforce the patents
relating to our products and product candidates, including ANDA
litigation; developments in the intellectual property landscape;
challenges from and rights of competitors or potential competitors; the
risk that our planned investments do not have the anticipated effect on
our company revenues, products or product candidates; the risk that we
are unable to manage our operating expenses or cash use for operations,
or are unable to commercialize our products, within the guided ranges or
otherwise as expected; and the risks listed under the heading “Risk
Factors” and elsewhere in Ironwood’s Quarterly Report on Form 10-Q for
the quarter ended March 31, 2019, Allergan’s Quarterly Report on Form
10-Q for the quarter ended March 31, 2019 and in the subsequent SEC
filings of each company. These forward-looking statements (except as
otherwise noted) speak only as of the date of this press release, and
Ironwood and Allergan undertake no obligation to update these
forward-looking statements.