• 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 

BOSTON / May 21, 2024 / Business Wire / 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.