Ironwood Announces Publication in The Lancet Gastroenterology & Hepatology of New Linaclotide Phase III Data in Children and Adolescents Aged 6-17 Years with Functional Constipation

– Newly published data highlights additional efficacy endpoints from trial –

– Linaclotide is the first and only FDA-approved prescription therapy for children and adolescents aged 6-17 years with functional constipation –

Ironwood Pharmaceuticals, Inc. (Nasdaq: IRWD), a GI-focused healthcare company, today announced that new data from the Phase III study that evaluated linaclotide in children and adolescents aged 6-17 years with functional constipation were published in The Lancet Gastroenterology & Hepatology. The data highlights additional efficacy endpoints from the company’s pivotal Phase III trial, which formed the basis of the June 2023 U.S. Food and Drug Administration (FDA) approval of linaclotide for the treatment of functional constipation in this population.

Functional constipation in children is defined as a condition with hard, infrequent bowel movements that are often difficult or painful to pass¹. The condition affects an estimated 6 million children aged 6-17 years in the U.S.²

“Functional constipation is among the most common complaints pediatricians and pediatric GIs see in our patients,” said Miguel Saps, Chief of Division of Pediatric Gastroenterology, Hepatology, and Nutrition and the George E. Batchelor Endowed Chair in Pediatrics, University of Miami, University of Miami Health System. “The insights provided by the additional efficacy endpoints in this Phase III clinical trial are an important supplement to clinicians’ knowledge about the available treatment options for this population.”

In this peer-reviewed pivotal study, a total of 328 patients received the study treatment, randomized (1:1) to either linaclotide 72 mcg or placebo. Linaclotide demonstrated a statistically significant and clinically meaningful improvement compared to placebo in 12-week spontaneous bowel movement(s) (SBM) frequency rate (SBMs/week), the primary endpoint. A statistically significant proportion of linaclotide-treated patients achieved 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 week 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). The change from baseline of 12-week complete SBM frequency rate demonstrated a greater increase in the linaclotide group compared with the placebo group (LSM CFB difference=0.96 complete SBMs/week; 95% CI 0.51–1.40; p<0.0001). Additionally, the percentage of patients with at least one SBM within 24 or 48 hours of first dose of study drug was higher in the linaclotide group compared with the placebo group (24 hours: 30.5% vs 20.7%, p=0.043; 48 hours: 56.7% vs 38.4%, p=0.0009).

Overall, linaclotide was well-tolerated in this study. 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%). The most reported treatment-emergent adverse event (TEAE) by patients treated with linaclotide was diarrhea (seven [4%] of 164) and by patients treated with placebo was COVID-19 (five [3%] of 164). The most frequent treatment-related TEAE was diarrhea (linaclotide: six [4%] patients; placebo: two [1%] patients). The safety profile of linaclotide in pediatric patients is consistent with prior linaclotide studies in adults.

The manuscript published in The Lancet Gastroenterology & Hepatology further described that:

• A greater percentage of patients in the linaclotide treatment group were weekly SBM responders (patients who had an increase ≥2 in the SBM weekly rate from baseline for that week) compared with the placebo group at weeks 1, 3, 4, 6, 7, 11, and 12 (p < 0·05).
• Of the patients receiving rescue medicines, significantly fewer patients reported an increase in rescue medication use or use of any other laxative, suppository, or enema in the linaclotide group (25 of 164; 15·2%) compared with the placebo group (43 of 164; 26·2%) [p=0·015].

Linaclotide (marketed as LINZESS®) 72mcg is available in the U.S. for the treatment of functional constipation for pediatric patients aged 6-17 years old.

“We are committed to providing ongoing data about our products to medical professionals and the scientific community,” said Michael Shetzline, M.D., Ph.D., chief medical officer, senior vice president, and head of research and drug development at Ironwood Pharmaceuticals. “The publication of these results in The Lancet Gastroenterology & Hepatology adds to the body of knowledge about linaclotide and helps close the unmet needs gap in pediatric patients ages 6- 17 with FC.”

About Linaclotide

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 in adults 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 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

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.

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). In June 2023, the U.S. Food and Drug Administration also approved LINZESS 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.

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.

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¹ 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.

² 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.

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