• 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

BOSTON / May 08, 2023 / Business Wire / 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 14^th, 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).

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.

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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.