Ironwood Pharmaceuticals Announces FDA Approval of New Indication for LINZESS® (linaclotide) for the Treatment of Functional Constipation in Pediatric Patients Ages 6-17 Years-Old

– LINZESS is the first and only FDA-approved prescription therapy for functional constipation in this patient population –

– Approval brings a much-needed option to an estimated 6 million 6-17-year-olds in the U.S.¹ affected by this chronic, prevalent condition –

Ironwood Pharmaceuticals, Inc. (Nasdaq: IRWD), a GI-focused healthcare company, today announced that the U.S. Food and Drug Administration (FDA) has approved LINZESS® (linaclotide) as a once-daily treatment for pediatric patients ages 6-17 years-old with functional constipation. LINZESS is the first and only FDA-approved prescription therapy for functional constipation in this patient population. Earlier this year, the FDA granted a 6-month priority review to our supplemental New Drug Application (sNDA), 4 months earlier than the standard review timeline. LINZESS is developed and marketed by AbbVie and Ironwood Pharmaceuticals in the United States.

Functional constipation in children is a chronic condition characterized by 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

“When you have a child with functional constipation, it is extremely hard to watch them suffer – spending hours in the bathroom and away from their friends – while there is little you can do as a parent to help them,” said Ceciel T. Rooker, President, International Foundation for Gastrointestinal Disorders. “There has long been a critical need for a new therapeutic option due to lack of approved prescription treatment options, so I’m thrilled that we now have a new prescription option for children that can effectively help address symptoms.”

The FDA approval was based on the results of a large, multicenter, double-blind, Phase III study evaluating LINZESS in patients ages 6-17 years-old with functional constipation. A total of 328 patients received the study treatment, randomized in a 1:1 ratio between LINZESS 72 mcg or placebo. In this pivotal study, linaclotide showed a statistically significant and clinically meaningful improvement compared to placebo in 12-week spontaneous bowel movement (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 (2.6) compared to placebo (1.3) (p<0.0001). The most common adverse event in the pediatric Phase 3 study was diarrhea, which occurred in 4% of LINZESS-treated patients versus 2% in the placebo group.

“Pediatric functional constipation is an all-too-common issue that physicians see every day, yet despite the tremendous distress it causes to our patients’ and their families, we haven’t had an FDA-approved prescription treatment to offer until now,” 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. “The approval of LINZESS for the treatment of functional constipation in pediatric patients ages 6-17 years-old is a meaningful advancement for these young patients.”

LINZESS is developed and marketed by Ironwood and AbbVie in the United States and has been available since 2012 for the treatment of adults with irritable bowel syndrome with constipation (IBS-C) or chronic idiopathic constipation (CIC). Linaclotide, the active ingredient in LINZESS, is a first-in-class guanylate cyclase-C (GC-C) agonist and acts locally in the intestine with minimal systemic exposure. Since its launch, it has been used to treat more than 4.5 million unique adult patients with IBS-C and CIC.

“Today, Ironwood has broken new ground again in the history of LINZESS, extending the clinical utility of our blockbuster treatment to 6-17-year-olds seeking relief for functional constipation, a debilitating condition,” said Tom McCourt, chief executive officer of Ironwood. “This approval is a momentous step forward in progressing our mission to advance the treatment of GI diseases and redefine the standard of care for GI patients and in ushering in a new era of growth for our company.”

Based on this FDA approval, LINZESS 72mcg is now available for the treatment of functional constipation for pediatric patients ages 6-17 years old, with immediate accessibility for most patients building on the class-leading formulary coverage already in place for the brand.

About LINZESS (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 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

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 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 IBSC 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

http://www.allergan.com/assets/pdf/linzess_pi

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. 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 Ironwood’s mission, the size of the pediatric 6-17 years-old population in the U.S. affected by functional constipation and the therapeutic benefit to patients suffering from functional constipation. 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; 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 are not successful or that any of our product candidates is not successfully commercialized; the risk that our planned investments do not have the anticipated effect on our company revenues; the risk that we are unable to manage our expenses or cash use, or are unable to commercialize our products as expected; the impact of the COVID-19 pandemic; 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.

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.

View source version on businesswire.com: https://www.businesswire.com/news/home/20230612173180/en/