– New data highlight both stoma and
colon-in-continuity (CIC) patients drove the positive primary
endpoint with significant relative change from baseline in weekly
parenteral support (PS) volume reduction at week 24 –
– Additional secondary endpoints show
significant increases in days off PS and clinical responder rates
with apraglutide, including achieving enteral autonomy in both
stoma and CIC patients –
– Data from largest GLP-2 Phase III study to
date adds to body of evidence on safety and efficacy of once-weekly
apraglutide in adults with SBS-IF –
– New details on safety and tolerability to be
presented; showing apraglutide to be well tolerated with a safety
profile consistent with previously reported apraglutide studies in
this patient population –
Ironwood Pharmaceuticals, Inc. (Nasdaq: IRWD), a
GI-focused healthcare company, will present late-breaking data
during the 2024 Digestive Disease Week® (DDW) meeting from its
pivotal Phase III clinical trial, STARS, which evaluated the
efficacy and safety of once-weekly subcutaneous apraglutide in
adult patients with short bowel syndrome with intestinal failure
(SBS-IF). These findings build on the positive topline data that
Ironwood previously announced in February 2024. Based on these
results, the company is working to submit a new drug application
(NDA) to the U.S. Food and Drug Administration (FDA) and marketing
applications to other regulatory agencies for apraglutide for the
treatment of adult patients with SBS who are dependent on
parenteral support (PS).
SBS-IF, a rare chronic debilitating malabsorptive condition in
which patients are dependent on PS, affects an estimated 18,000
adult patients in the U.S., Europe, and Japan. Apraglutide is the
first and only investigational once-weekly GLP-2 analog that has
successfully demonstrated positive results in a Phase III
placebo-controlled study.
The late-breaking data at DDW are from the largest global SBS-IF
clinical trial conducted to date and are being shared during an
oral presentation titled “Efficacy and Safety of Apraglutide
Once-Weekly in Patients with Short Bowel Syndrome and Intestinal
Failure (SBS-IF): Results from the STARS Study - A Global Phase 3
Double-Blind, Randomized, Placebo-Controlled Trial.” Ironwood
previously reported that the STARS clinical trial met its primary
endpoint of relative change from baseline in actual weekly PS
volume at week 24 vs. placebo (-25.5% vs. -12.5%; p=0.001), driven
by both stoma and colon-in-continuity subpopulations. Treatment
effect with relative PS volume reduction was observed from week 8
onward (-8% vs -1.6% placebo, p=0.002).
Findings from the late-breaking presentation include:
- Significantly more apraglutide-patients gained additional days
off from PS per week at week 24 versus placebo (≥2 days: 24.5% vs
11.3%, p=0.021; ≥3 days: 11.8% vs 1.9%, p=0.006)
- Significantly more apraglutide-treated patients in the overall
and the stoma populations were clinical responders and clinical
high responders (defined as ≥20% and ≥40% PS volume reduction,
respectively), at both weeks 20 and 24 versus placebo
- Overall population: Clinical responders 42.7% vs 20.8%,
p=0.003; Clinical high responders 22.7% vs 9.4%, p=0.018
- Stoma subpopulation: clinical responders 40.7% vs 15.4%,
p=0.02; clinical high responders 20.4% vs 0%, p=0.009
- Seven apraglutide-treated patients achieved enteral autonomy
(three in the stoma subpopulation, four in the colon-in-continuity
subpopulation) by week 24 (6.4% apraglutide vs 0% placebo,
p=0.006). Three additional colon-in-continuity patients achieved
enteral autonomy by week 48: 7/56 [12.5%] apraglutide vs 2/27
placebo [7.4%], p=0.387.
“Given the burden that parenteral support places on people
living with SBS-IF, the goal of treatment is to importantly gain
additional days off PS, and ultimately achieve enteral autonomy in
those who can achieve it,” said Kishore R Iyer, MBBS, FRCS (Eng),
FACS, Director of Adult and Pediatric Intestine Rehabilitation
& Transplantation at The Mount Sinai Hospital in New York,
Coordinating Principal Investigator of the trial, paid scientific
advisor to Ironwood and chair of the scientific steering committee
for the STARS clinical trial. “The fact that some CIC and stoma
patients on apraglutide achieved enteral autonomy at week 24 and
sustained that autonomy through 48 weeks is an important outcome
and demonstrates the potential of apraglutide for these
patients.”
Apraglutide also demonstrated statistical significance on two
key secondary endpoints, with more patients in the combined
population achieving at least one day/week off PS relative to
baseline at week 24 versus placebo (43.0% vs. 27.5%; p=0.040) and
more patients treated with apraglutide versus placebo demonstrating
improvement in relative change from baseline in actual weekly PS
volume at week 24 in the stoma subpopulation (-25.6% vs. -7.8%;
p<0.001). Apraglutide was well-tolerated, with no new safety
signals identified and the safety profile was consistent with
previous apraglutide studies.
“Our data at DDW reflect Ironwood’s key priorities, which focus
on advancing the treatment of GI diseases,” said Michael Shetzline,
M.D., Ph.D., chief medical officer, senior vice president and head
of research and drug development at Ironwood Pharmaceuticals. “The
apraglutide findings showcase the breadth and depth of positive
clinical trial outcomes with this compound to date, with the
strength of the Phase III data enabling a strong submission and a
path to potential FDA and other regulatory approvals. We’re excited
for the opportunity to unlock a new and potentially differentiated
treatment option for adult patients with SBS dependent on
parenteral support.”
In addition to the STARS Phase III oral presentation, Ironwood,
and its collaborators presented data highlighting findings across
the apraglutide development program.
Impact of once weekly apraglutide on intestinal absorption
Three posters were presented by Astrid Verbiest, researcher at
the Translational Research Center for Gastrointestinal Disorders
(TARGID), University of Leuven, Leuven, Flanders, Belgium,
summarizing new findings from STARS Nutrition. STARS Nutrition is a
multicenter open-label Phase II metabolic balance study of nine
patients that was designed to evaluate the safety,
pharmacokinetics, and efficacy of apraglutide on intestinal
absorption in adult patients who have SBS-IF and
Colon-in-Continuity. Positive final data from this study were
announced in October 2023.
- “Changes in Bowel Morphology and Motility Assessed by MRI in
Patients with Short Bowel Syndrome Intestinal Failure (SBS-IF) and
Colon-In-Continuity Treated with Apraglutide” (poster number
Su1946) demonstrated that apraglutide treatment was associated with
small bowel lengthening and increased duodenal wall thickness
suggesting an intestinotrophic (stimulates/regulates growth of
intestinal tissue) effect that may contribute to an increased
surface area for absorption. The authors note that whether bowel
lengthening results from a direct effect of apraglutide vs. changes
in motility with passive elongation is subject of further
investigation.
- “Parenteral Support Weaning, Clinical Benefit and Improved
Patient Reported Outcomes in Short Bowel Syndrome Intestinal
Failure (SBS-IF) Patients with Colon-In-Continuity Treated with The
Long-Acting Glucagon-Like Peptide-2 (GLP-2) Analog Apraglutide”
(poster number Su1947) showed that apraglutide has an acceptable
safety profile and is associated with significant reductions in PS
needs in SBS-IF patients with colon-in continuity, resulting in
days off PS and subjective improvement based on patient reported
outcomes.
- "Apraglutide Treatment in Short Bowel Syndrome with Intestinal
Failure (SBS-IF) and Colon-In-Continuity is Associated with
Increased Oral Intake and Improved Energy and Carbohydrate
Absorption at 48 Weeks" (poster number Su1948) showed that in
patients with SBS-IF and colon-in-continuity, apraglutide treatment
resulted in an early reduced fecal output and improved wet weight
absorption. After 48 weeks, oral intake was increased despite
stable fecal output, leading to increased energy and carbohydrate
absorption.
Impact of apraglutide on gastric emptying
- "The Effect of Apraglutide on Gastric Emptying in Healthy
Individuals: A Phase 1 Randomized, Placebo-Controlled,
Double-Blind, Single-Center Trial" (poster number Su1949) was
presented by Gerard Greig, Ironwood Pharmaceuticals. The data
suggest that apraglutide does not affect gastric emptying of
liquids in healthy individuals, as measured by acetaminophen
pharmacokinetics (PK), and can therefore be used in a broad patient
population.
Irritable Bowel Syndrome with Constipation (IBS-C) and
Functional Constipation
- “Real World Prescribing Patterns for Pediatric Patients with
Functional Constipation and Irritable Bowel Syndrome with
Constipation” (presentation number Su2047) was presented by Julie
Khlevner, M.D., New York Presbyterian Morgan Stanley Children’s
Hospital, New York, NY, showing that, based on a retrospective,
observational study, approximately one-third of children and
adolescents diagnosed with FC or IBS-C were prescribed medication
for constipation during a five year period (January 2018 – June
2023). Polyethylene glycol 3350 was the most frequently prescribed
medication for pediatric FC and IBS-C, followed by lactulose.
- “Efficacy, Safety, and Time to Response of Linaclotide in
Patients ≥ 65 with Irritable Bowel Syndrome with Constipation”
(presentation number Tu1653) will be presented by Lin Chang, M.D.,
David Geffen School of Medicine at UCLA, Los Angeles, CA. The data
were based on a post hoc analysis of >2,000 adults with IBS-C.
Treatment-emergent adverse events were similar in both age groups
and were consistent with the known safety profile of linaclotide in
patients with IBS-C.
- “Assessing US Healthcare Disparities in IBS Diagnosis: A
National Survey Analysis” (presentation number Tu1027) will be
presented by Christopher V Almario, M.D., MSHPM, Cedars Sinai
Medical Center, Los Angeles, CA, summarizing survey data from
nearly 90,000 adults in the US. The study analyzed
healthcare-seeking behavior, including the likelihood of seeing a
healthcare provider (HCP) and the type of HCP seen. Respondents who
identified as Black or African American were less likely to be
diagnosed with IBS than those who identified as White, even after
controlling for potential confounding variables, such as
socioeconomic status and symptom severity.
About STARS
The STARS (STudy of ApRaglutide in SBS) pivotal Phase III trial
represents the largest Phase III trial in SBS-IF to date.
This global, multicenter, double-blind, randomized,
placebo-controlled trial evaluated the efficacy and safety of
weekly subcutaneous injections of apraglutide in adult patients
with SBS-IF. STARS randomized 164 patients 2:1 and 163 were dosed
to receive either once-weekly apraglutide or placebo. Patients were
stratified approximately 50/50 by remnant bowel anatomy (stoma vs.
colon-in continuity) and evaluated over 24 weeks (stoma and
colon-in-continuity subpopulations) and 48 weeks
(colon-in-continuity subpopulation only). The primary endpoint was
relative change from baseline in actual weekly PS volume at week
24. Key secondary endpoints included patients who achieved a
reduction from baseline of at least 1 day/week off PS at week 24
(overall population); relative change from baseline in actual
weekly PS volume at week 24 (stoma subpopulation); patients who
achieved a reduction from baseline of at least 1 day/week off PS at
week 48 (colon-in-continuity subpopulation); and patients reaching
enteral autonomy at week 48 (colon-in-continuity
subpopulation).
The study was conducted in 18 countries with enrollment from 68
study sites.
About STARS Nutrition
STARS Nutrition is the first-ever study to prospectively
evaluate the clinical benefit of a GLP-2 analog specifically in
patients with colon-in-continuity. This multicenter, open-label
Phase II metabolic balance study was designed to evaluate the
effect of once-weekly apraglutide 5-mg subcutaneous injection on
intestinal absorption in SBS-IF patients with colon-in-continuity
at 52 weeks. Safety and parameters indicative of clinical efficacy,
including PS volume and energy content reduction, were assessed.
The study enrolled nine adult patients with a mean age of 46.8
years.
About Short Bowel Syndrome
SBS is a serious and chronic condition where there is diminished
absorptive capacity for fluids and/or nutrients, sometimes
requiring dependence on parenteral support to maintain health.
Short bowel syndrome typically occurs because of extensive
intestinal resection, and patients with SBS who are chronically
dependent on parenteral support, also referred to as SBS with
intestinal failure (SBS-IF), often experience significant quality
of life impact and are at risk of severe complications such as
infection. An estimated 18,000 adult patients suffer from SBS-IF in
the U.S., Europe and Japan, and have chronic dependence on PS,
which significantly impacts quality of life and carries the risk of
severe complications such as infection. Those with the most severe
SBS-IF require PS infusions for up to 10 to 15 hours per day.
SBS-IF is associated with frequent complications, significant
morbidity and mortality, high economic burden and an impaired
quality of life.
About Apraglutide
Apraglutide is an investigational, next-generation, long-acting
synthetic GLP-2 analog being developed for a range of rare
gastrointestinal diseases where GLP-2 can play a central role in
addressing disease pathophysiology, including short bowel syndrome
with intestinal failure (SBS-IF) and Acute Graft-Versus-Host
Disease (aGVHD).
About LINZESS
LINZESS® is the #1 prescribed brand in the U.S. for the
treatment of adult patients with irritable bowel syndrome with
constipation (“IBS-C”) or chronic idiopathic constipation (“CIC”),
based on IQVIA data. LINZESS is a once-daily capsule that helps
relieve the abdominal pain, constipation, and overall abdominal
symptoms of bloating, discomfort and pain associated with IBS-C, as
well as the constipation, infrequent stools, hard stools,
straining, and incomplete evacuation associated with CIC. LINZESS
relieves constipation in children and adolescents aged 6 to 17
years with functional constipation. The recommended dose is 290 mcg
for IBS-C patients and 145 mcg for CIC patients, with a 72 mcg dose
approved for use in CIC depending on individual patient
presentation or tolerability. In children with functional
constipation aged 6 to 17 years, the recommended dose is 72
mcg.
LINZESS is not a laxative; it is the first medicine approved by
the FDA in a class called GC-C agonists. LINZESS contains a peptide
called linaclotide that activates the GC-C receptor in the
intestine. Activation of GC-C is thought to result 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 CIC. Ironwood also has partnered with AstraZeneca for
development and commercialization of LINZESS in China, and with
AbbVie for development and commercialization of linaclotide in all
other territories worldwide.
LINZESS Important Safety Information
INDICATIONS AND USAGE
LINZESS® (linaclotide) is indicated for the treatment of both
irritable bowel syndrome with constipation (IBS-C) and chronic
idiopathic constipation (CIC) in adults and functional constipation
(FC) in children and adolescents 6 to 17 years of age. It is not
known if LINZESS is safe and effective in children with FC less
than 6 years of age or in children with IBS-C less than 18 years of
age.
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
- 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 guanylate cyclase (GC-C)
agonism, which was associated with increased 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.
Diarrhea
- In adults, 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.
- In children and adolescents 6 to 17 years of age, diarrhea was
the most common adverse reaction in 72 mcg LINZESS-treated patients
in the FC double-blind placebo-controlled trial. Severe diarrhea
was reported in <1% of 72 mcg LINZESS treated 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 or CIC adult patients: diarrhea, abdominal pain,
flatulence, and abdominal distension.
- In FC pediatric patients: diarrhea.
Please see full Prescribing Information including Boxed Warning:
https://www.rxabbvie.com/pdf/linzess_pi.pdf
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 global 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), which is the U.S.
branded prescription market leader for adults with irritable bowel
syndrome with constipation (IBS-C) or chronic idiopathic
constipation (CIC) and is also indicated for the treatment of
functional constipation in pediatric patients ages 6-17 years old.
Ironwood is also advancing apraglutide, a next-generation,
long-acting synthetic GLP-2 analog being developed for rare
gastrointestinal diseases, including short bowel syndrome with
intestinal failure (SBS-IF), as well as several earlier stage
assets. Building upon our history of GI innovation, 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, with a site in Basel, Switzerland.
We routinely post information that may be important to investors
on our website at www.ironwoodpharma.com. In addition, follow us on
X and on LinkedIn.
Forward-Looking Statements
This press release contains forward-looking statements within
the meaning of the Private Securities Litigation Reform Act of
1995. Investors are cautioned not to place undue reliance on these
forward-looking statements, including statements about the
assessment of the data from the Phase III STARS clinical trial of
apraglutide; the efficacy, safety and tolerability of apraglutide;
Ironwood’s plan to submit an NDA and marketing applications to
other regulatory filings for apraglutide; the estimated adult
population who suffer from SBS-IF in the U.S., Europe and Japan;
that the findings and the strength of the Phase III data enable a
strong submission and a path to potential FDA and other regulatory
approvals; and the potential opportunity to unlock a new and
differentiated treatment option for adult patients with SBS
dependent on PS. 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 apraglutide; 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 completed nonclinical and clinical
studies may not be replicated in later studies; the risk that the
FDA may not approve our NDA submission; the risk of competition or
that new products may emerge that provide different or better
alternatives for treatment of the conditions that our products are
approved to treat; the risk that healthcare reform and other
governmental and private payor initiatives may have an adverse
effect upon or prevent our products’ or product candidates’
commercial success; the efficacy, safety and tolerability of our
product candidates; the risk that the commercial and therapeutic
opportunities for our product candidates are not as we expect; the
risk that we are unable to successfully partner with other
companies to develop and commercialize products or product
candidates; decisions by regulatory and judicial authorities; the
risk we may never get additional patent protection for our product
candidates, that patents for our products may not provide adequate
protection from competition, or that we are not able to
successfully protect such patents; the risk that the development of
apraglutide is not successful or that any of our product candidates
does not receive regulatory approval or is not successfully
commercialized; outcomes in legal proceedings to protect or enforce
the patents relating to our products and product candidates,
including abbreviated new drug application litigation; challenges
from and rights of competitors or potential competitors; and the
risks listed under the heading “Risk Factors” and elsewhere in our
Annual Report on Form 10-K for the year ended December 31, 2023,
and in our subsequent Securities and Exchange Commission
filings.
View source
version on businesswire.com: https://www.businesswire.com/news/home/20240521515089/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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