• Data show approximately 50% reduction of parenteral support (PS) volume 
• 100% of patients were clinical responders 
• 78% of patients achieved one or more days off PS 
• Results support apraglutide as a potentially best-in-class glucagon-like peptide-2 (GLP-2) analog for the spectrum of patients with SBS-IF 

BOSTON / Oct 16, 2023 / Business Wire / Ironwood Pharmaceuticals, Inc. (Nasdaq: IRWD), a global GI-focused healthcare company, presented positive final data from the company’s Phase II STARS Nutrition program during United European Gastroenterology (UEG) Week. This multicenter study of nine patients was designed to evaluate the safety, pharmacokinetics, and efficacy of apraglutide, an investigational next-generation, long-acting synthetic GLP-2 analog, on intestinal absorption in adult patients who have Short Bowel Syndrome with Intestinal Failure (SBS-IF) and Colon-in-Continuity (CIC). Positive interim results from this study were first announced in October 2022.

The data from STARS Nutrition were featured at UEG Week during a late-breaker oral presentation titled “The Long-Acting GLP-2 Analog Apraglutide Provides Clinical Benefit For Patients With Short Bowel Syndrome With Intestinal Failure And Colon In Continuity At 52 Weeks.” The presentation highlighted that apraglutide had an acceptable safety profile, which was the primary study objective, and that apraglutide improved intestinal absorption as indicated by 50% parenteral support (PS) volume and energy content decrease, resulting in one or more days off PS. PS reduction was observed as early as week four and was maintained until the end of the study. Seventy-eight percent (78%) of patients gained one or more days off PS with all patients achieving clinical response.

SBS-IF is a severe organ failure condition due to a reduction in intestinal function below the minimum necessary for nutrient and fluid absorption, leading to dependence on life-long PS to maintain health, growth, and survival. The most severe cases require PS (including parenteral nutrition and/or intravenous fluid) infusions for up to 10 to 15 hours per day. An estimated 17,000 people are thought to suffer from SBS-IF in the U.S. and Europe. Patients with CIC who have a preserved colon with the remnant small intestine, represent over 55% of the SBS-IF population with a large unmet need. STARS Nutrition study is the first-ever study designed to evaluate the clinical benefit of a GLP-2 analog specifically in patients with SBS-IF with CIC.

“In order to secure adequate nutrition and hydration – the fundamental elements of survival – people with SBS-IF-CIC endure a significant impact on quality of life and run the risk of severe complications such as infection,” said Tim Vanuytsel, M.D., Ph.D., gastroenterologist, Co-Chair of the Leuven Intestinal Failure and Transplantation Center and lead investigator. “These data are a strong testament to the durability of the effect of apraglutide on improving intestinal absorption and reducing PS dependency in these patients, and reinforce the interim results announced last year. The STARS Nutrition study with apraglutide represents a significant advance in understanding GLP-2 and how we can help all patients with SBS-IF, including those with colon in continuity. The benefits observed here could have a major impact on clinical care and improving patient's quality of life if confirmed in the ongoing STARS pivotal trial.”

The study showed that PS reduction was observed as early as 4 weeks after PS weaning was allowed with 33% of the patients achieving clinical response. PS volume reduction reached a statistically significant 40% at week 24 and the effect was maintained with a 52% volume reduction at week 52. All patients were clinical responders, defined as those achieving a PS volume reduction of at least 20%. At week 52, seven out of the nine patients (78%) achieved at least one day off PS. At week 52, patients gained an additional 2.1 (0.7 – 3.6) days off per week compared to a mean of 5.2 days per week on PS at baseline, which allowed patients more independence. Apraglutide was well tolerated with an acceptable safety profile.

“These positive data are a crucial advancement that highlight the potential of apraglutide to be a best-in-class GLP-2 analog for the whole spectrum of patients with SBS-IF, including those with CIC,” said Jana Noeldeke, apraglutide life cycle leader and head of Ironwood Pharmaceuticals’ site at Basel, Switzerland. “We welcome these results and are continuing to progress the apraglutide development in the SBS-IF program with a sense of urgency.”

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 CIC. 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 CIC 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 with Intestinal Failure

SBS-IF is a severe organ failure condition due to a reduction in intestinal function below the minimum necessary for nutrient and fluid absorption, leading to dependence on life-long PS to maintain health, growth, and survival. In adults, it is typically caused by irreparable GI damage due to inflammatory bowel disease, ischemia, physical trauma, or surgical resection of large portions of the small intestine. SBS-IF is an anatomically heterogeneous condition in which the type of remnant bowel anatomy, such as CIC or stoma, determines the therapeutic goal, medical needs, clinical response, and the individual patient journey. Patients with the most severe SBS-IF require PS infusions for up to 10 to 15 hours per day. SBS is associated with frequent complications, significant morbidity and mortality, high economic burden and an impaired quality of life. An estimated 17,000 people are thought to suffer from SBS-IF in the U.S. and Europe and require lifelong PS.

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). Apraglutide is owned by VectivBio Holding AG (“VectivBio”), now part of Ironwood.

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), the U.S. branded prescription market leader for adults with irritable bowel syndrome with constipation (IBS-C) or chronic idiopathic constipation (CIC). LINZESS is also approved 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, and has additional operations in Basel, Switzerland.

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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) 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: 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.

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 our ability to develop apraglutide and the expected timing of receiving data from the apraglutide clinical trials; the effect of apraglutide on intestinal absorption in adult patients who have SBS-IF with CIC and the related reduction in PS dependency; the efficacy and safety profile of apraglutide in adult patients who have SBS-IF with CIC; the possibility that trial outcomes could have a major impact on clinical care and improving patient’s quality of life if confirmed in the ongoing STARS pivotal trial; and the size of the population that are thought to suffer from SBS-IF and SBF-IF with CIC in the U.S. and Europe. . 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 efficacy, safety and tolerability of linaclotide, apraglutide and other product candidates; the risk that the therapeutic opportunities for LINZESS, apraglutide or our product candidates are not as we expect; decisions by regulatory and judicial authorities; the risk we may never get additional patent protection for linaclotide, apraglutide and other product candidates, that patents for linaclotide, apraglutide or other products may not provide adequate protection from competition, or that we are not able to successfully protect such patents; outcomes in legal proceedings to protect or enforce the patents relating to our products and product candidates, including abbreviated new drug application litigation; the risk that financial and operating results may differ from our projections; developments in the intellectual property landscape; challenges from and rights of competitors or potential competitors; the risk that we are unable to manage our expenses or cash use, or are unable to commercialize our products as expected; and the risks listed under the heading “Risk Factors” and elsewhere in our Annual Report on Form 10-K for the fiscal year ended December 31, 2022, and in our subsequent SEC filings.