– Additional data presentations further
characterize the efficacy and safety profiles of linaclotide in
this patient population –
– Functional constipation affects an estimated
6 million 6-17 year-olds in the U.S.1; there are currently no
FDA-approved prescription therapies –
Ironwood Pharmaceuticals, Inc. (Nasdaq: IRWD), a GI-focused
healthcare company, presented findings during the 2023 Digestive
Disease Week® (DDW) meeting from a Phase III clinical trial on the
potential of linaclotide for children and adolescents ages 6-17
years-old with functional constipation. Ironwood had previously
announced topline data from this study in September 2022.
The presented data at DDW, which provided a more detailed
description of the trial results, were announced during an oral
presentation titled Efficacy and Safety of Linaclotide in Treating
Functional Constipation in Pediatric Patients Aged 6-17 Years: A
Phase 3, Pivotal, Randomized, Placebo-Controlled Trial
(presentation number 145), which highlighted that linaclotide 72
mcg met primary and secondary endpoints for increased frequency of
spontaneous bowel movements (SBM) and improvement in stool
consistency in this patient population. Linaclotide was generally
well-tolerated and exhibited a safety profile consistent with a
prior pediatric Phase II study in functional constipation.
Functional constipation in children is defined as a condition
with hard, infrequent bowel movements that are often difficult or
painful to pass2. The condition affects an estimated 6 million
children ages 6-17 years-old in the U.S.1
“Functional constipation is one of the most common complaints
patients bring to their pediatricians and pediatric
gastroenterologists, yet we have no approved prescription therapies
to offer to our young patients,” said Jeffrey S. Hyams, M.D., Head,
Division of Digestive Diseases, Hepatology, and Nutrition,
Connecticut Children’s Medical Center, Professor of Pediatrics,
University of Connecticut School of Medicine. “These results are
significant because they show the potential of linaclotide in
addressing bothersome symptoms for patients ages 6-17 years-old
with this condition.”
In this pivotal study, linaclotide showed a statistically
significant and clinically meaningful improvement compared to
placebo in 12-week SBM frequency rate (SBMs/week), the primary
endpoint. Linaclotide-treated patients demonstrated a greater than
two-fold least squares mean change from baseline in SBMs/week
(2.220) compared to placebo (1.050) (p<0.0001). Stool
consistency, as assessed by Bristol Stool Form Scale (BSFS) scores,
which was the secondary endpoint, also showed an improvement at
weeks 12 with linaclotide compared to placebo. The BSFS is a
7-point scale ranging from 1 (separate, hard, difficult-to-pass
lumps) to 7 (liquid stools). Overall, linaclotide was
well-tolerated in this study.
The DDW presentation further showed that efficacy in
prespecified age subgroups (6-11 years old and 12-17 years old) was
similar, which further supported the primary efficacy findings.
Additionally, the presentation at DDW provided more insights on
baseline characteristics and safety data:
- Of the 328 patients, 55% were ages 6-11 years-old and 45% were
12-17 years-old at the time of enrollment.
- Demographics and baseline characteristics were similar across
linaclotide and placebo-treated groups. At baseline, mean (SD) SBM
frequency was similar between study groups (LIN 1.156 (0.828), PBO
1.278 (0.865).
- Both study arms had similar proportions of patients with AEs:
TEAEs (LIN, 17%; PBO, 21%), serious AEs (1.2% for both), and TEAEs
leading to study treatment discontinuation (LIN, 1.2%, PBO, 1.8%).
Treatment-emergent AEs (TEAEs) reported in greater than 2% of
patients were diarrhea (LIN, 4.3%; PBO, 1.8%) and COVID-19 (LIN,
2.4%; PBO, 3.0%). One AE of special interest of diarrhea was
reported in a 17 year-old.
Linaclotide is marketed as LINZESS® by Ironwood and AbbVie in
the United States and is indicated for the treatment of adults with
irritable bowel syndrome with constipation (IBS-C) or chronic
idiopathic constipation (CIC). It is not approved for use in
patients less than 18 years of age. Ironwood announced earlier this
year that the U.S. Food and Drug Administration (FDA) granted
priority review to the supplemental New Drug Application (sNDA),
which seeks approval of a new indication of linaclotide for
functional constipation in pediatric patients aged 6-17 years and
assigned a Prescription Drug User Fee Act (PDUFA) date of June
14th, 2023.
In addition to the primary and secondary efficacy data from the
pivotal Phase III study, Ironwood and its collaborators will
present other data describing the efficacy of linaclotide in
addressing bothersome functional constipation symptoms in pediatric
patients ages 6-17 years-old, as well as aggregate data from three
studies on the safety profile of linaclotide in this patient
population.
“Our data paint a comprehensive picture of the efficacy and
safety profile of linaclotide for pediatric patients ages 6-17 with
functional constipation,” said Michael Shetzline, M.D., Ph.D.,
chief medical officer, senior vice president and head of research
and drug development at Ironwood Pharmaceuticals. “We are excited
to be sharing our robust pediatric data with the DDW community.
Ironwood’s focus on understanding the efficacy and safety of
linaclotide in additional patient groups illustrates how we
continue to advance our pipeline with the goal to address the
significant unmet needs of patients living with GI disorders.”
Impact of Linaclotide on Bothersome Functional Constipation
Symptoms in a Pediatric Population
Two posters will present additional data from the Phase III,
randomized, double-blind, placebo-controlled study in patients ages
6-17 years-old with functional constipation.
- A poster titled Efficacy of Linaclotide in Treating Symptoms of
Incomplete Evacuation and Straining in Pediatric Patients with
Functional Constipation (presentation number Mo2007), will be
presented by Julie Khlevner, M.D., New York Presbyterian Morgan
Stanley Children’s Hospital, New York, NY, showing that
linaclotide-treated patients demonstrated significant improvement
from baseline over 12 weeks in two bothersome functional
constipation symptoms: complete spontaneous bowel movement
frequency and straining with BMs, with improvement seen as early as
the first week after the initial dose. Abdominal bloating also
showed a statistically significant improvement from baseline over
12 weeks compared to placebo.
- Another poster titled Time to Response of Linaclotide in
Treating Functional Constipation in Pediatric Patients Aged 6-17
Years: Data From a Phase 3, Randomized, Placebo-Controlled Trial
(presentation number Mo2008), will be presented by Samuel Nurko,
M.D., Boston Children’s Hospital, Boston, MA, showing that more
than one-half of patients had a SBM within 48 hours of the first
linaclotide dose. Patients with one or more SBM within 48 hours of
the first dose had lower use of rescue medications throughout the
12-week treatment period than other patients in the linaclotide
group.
Aggregate Safety Data in Patients with Functional
Constipation Ages 6-17 Years-Old
A poster titled Long-Term Safety of Linaclotide in Treating
Functional Constipation in Pediatric Patients Aged 6-17 Years:
Interim Analysis of an Open-Label, Phase 3, Extension Trial
(presentation number Mo2016), will be presented by Miguel Saps,
M.D., University of Miami, Miami, FL, further characterizing the
long-term safety profile in pediatric patients ages 6-17 years-old
with functional constipation. Most AEs were mild. There were no
treatment-emergent SAEs and few AEs led to discontinuation of
linaclotide. Most cases of diarrhea were mild and self-resolved.
The safety profile of the 72 mcg and 145 mcg doses looked
similar.
In another poster titled Safety of Linaclotide in Pediatric
Patients with Functional Constipation: A Pooled Analysis of
Placebo-Controlled, Randomized-Controlled Trials (presentation
number Mo2015), will be presented by Jeffrey Samuel Hyams, MD,
Connecticut Children’s Medical Center, Hartford, CT, a pooled
analysis of randomized trials, showing that among children and
adolescents with functional constipation, linaclotide 72 mcg was
well-tolerated. Diarrhea was the most frequent AE related to study
drug, it was typically mild and resolved without sequelae.
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. In the United
States, Ironwood and AbbVie co-develop and co-commercialize
LINZESS® for the treatment of adults with IBS-C or CIC. In Europe,
AbbVie markets linaclotide under the brand name CONSTELLA® for the
treatment of adults with moderate to severe IBS-C. In Japan,
Ironwood's partner Astellas markets linaclotide under the brand
name LINZESS for the treatment of adults with IBS-C or chronic
constipation. In China, (including Hong Kong and Macau) Ironwood’s
partner Astra Zeneca markets linaclotide under the brand name
LINZESS for the treatment of adults with IBS-C. Ironwood is also
partnered with AbbVie for development and commercialization of
linaclotide in all other territories worldwide. 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.
LINZESS 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 LESS THAN 2 YEARS OF AGE
LINZESS is contraindicated in patients
less than 2 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.
Contraindications
- LINZESS is contraindicated in patients less than 2 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 2 years of
age. In neonatal mice, linaclotide increased fluid secretion as a
consequence of age-dependent elevated GC-C agonism resulting in
mortality within the first 24 hours due to dehydration. There was
no age-dependent trend in GC-C intestinal expression in a clinical
study of children 2 to less than 18 years of age; however, there
are insufficient data available on GC-C intestinal expression in
children less than 2 years of age to assess the risk of developing
diarrhea and its potentially serious consequences in these
patients. The safety and effectiveness of LINZESS in patients less
than 18 years of age have not been established.
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
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.
About Ironwood Pharmaceuticals
Ironwood Pharmaceuticals (Nasdaq: IRWD), an S&P SmallCap
600® company, is a leading gastrointestinal (GI) healthcare company
on a mission to advance the treatment of GI diseases and redefine
the standard of care for GI patients. We are pioneers in the
development of LINZESS® (linaclotide), the U.S. branded
prescription market leader for adults with irritable bowel syndrome
with constipation (IBS-C) or chronic idiopathic constipation (CIC).
Under the guidance of our seasoned industry leaders, we continue to
build upon our history of GI innovation and challenge what has been
done before to shape what the future holds. We keep patients at the
heart of our R&D and commercialization efforts to reduce the
burden of GI diseases and address significant unmet needs.
Founded in 1998, Ironwood Pharmaceuticals is headquartered in
Boston, Massachusetts.
We routinely post information that may be important to investors
on our website at www.ironwoodpharma.com. In addition, follow us on
Twitter and on LinkedIn.
Forward-Looking Statements
This press release contains forward-looking statements.
Investors are cautioned not to place undue reliance on these
forward-looking statements, including statements about the clinical
utility of LINZESS as a treatment option for pediatric patients
aged 6-17 with functional constipation; the potential of
linaclotide in addressing bothersome symptoms for patients ages
6-17 years-old with functional constipation; the size of the
pediatric population affected by functional constipation; the
efficacy and safety of linaclotide in functional constipation in
pediatric patients; our expectations regarding the PDUFA date for
the sNDA. These forward-looking statements speak only as of the
date of this press release, and Ironwood undertakes no obligation
to update these forward-looking statements. 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 the effectiveness of development and commercialization
efforts by us and our partners; preclinical and clinical
development, manufacturing and formulation development of
linaclotide and our product candidates; the risk that clinical
programs and studies may not progress or develop as anticipated,
including that studies are delayed or discontinued for any reason,
such as safety, tolerability, enrollment, manufacturing, economic
or other reasons; the risk that findings from our completed
nonclinical and clinical studies may not be replicated in later
studies; the risk that we or our partners are unable to obtain,
maintain or manufacture sufficient LINZESS or our product
candidates, or otherwise experience difficulties with respect to
supply or manufacturing; the efficacy, safety and tolerability of
linaclotide and our product candidates; the risk that the
therapeutic opportunities for LINZESS or our product candidates are
not as we expect; decisions by regulatory and judicial authorities,
including not approving our sNDA submission; the risk that we may
never get sufficient patent protection for linaclotide and other
product candidates, that patents for linaclotide or other products
may not provide adequate protection from competition, or that we
are not able to successfully protect such patents; developments in
the intellectual property landscape; challenges from and rights of
competitors or potential competitors; the risk that the development
of either our clinical pediatric programs in IBS-C and functional
constipation is not successful or that any of our product
candidates is not successfully commercialized; and the risks listed
under the heading "Risk Factors" and elsewhere in Ironwood's Annual
Report on Form 10-K for the year ended December 31, 2022, and in
our subsequent SEC filings.
___________________________________ 1 U.S. Census, 2017 National
Population Projection Tables; Robin, Samantha G. et al, Prevalence
of Pediatric Functional Gastrointestinal Disorders Utilizing the
Rome IV Criteria, The Journal of Pediatrics, December 2017; Koppen,
I. J. N. et al., Prevalence of Functional Defecation Disorders in
Children: A Systemic Review and Meta-Analysis. J Pediatr. 2018.
2 Di Lorenzo C, Hyams JS, Saps M, et al. Chapter 16: Childhood
Functional Gastrointestinal Disorders: Child/Adolescent. In:
Drossman DA, Chang L, Chey WD, et al. Rome IV: Functional
Gastrointestinal Disorders: Disorders of Gut-Brain Interaction.
Raleigh, NC: Rome Foundation; 2016.
View source
version on businesswire.com: https://www.businesswire.com/news/home/20230508005202/en/
Media: Beth Calitri, 978-417-2031
bcalitri@ironwoodpharma.com Investors: Greg Martini,
617-374-5230 gmartini@ironwoodpharma.com Matt Roache, 617-621-8395
mroache@ironwoodpharma.com
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