Ironwood Pharmaceuticals Reports Positive Topline Data from Phase III Trial of LINZESS® (linaclotide) in Pediatric Patients Aged 6-17 with Functional Constipation

BOSTON, Mass.--(BUSINESS WIRE)-- Ironwood Pharmaceuticals, Inc. (Nasdaq: IRWD), today announced positive topline data from a Phase III clinical trial evaluating LINZESS (linaclotide) 72 mcg in pediatric patients aged 6-17 with functional constipation (FC). The trial met its primary and secondary endpoints, demonstrating that linaclotide (72 mcg) improved frequency of spontaneous bowl movements (SBM) and stool consistency. Linaclotide was generally well-tolerated, and the safety profile is consistent with previously reported studies with linaclotide in FC and irritable bowel syndrome (IBS) in pediatric patients.

“Functional constipation is one of the most common gastrointestinal complaints in pediatric patients, one that significantly impacts young patients’ lives. Despite its high prevalence, FC remains challenging to treat because there are no FDA approved prescription treatments for children,” said Jeffrey S. Hyams, MD, Head, Division of Digestive Diseases, Hepatology, and Nutrition, Connecticut Children’s Medical Center, Professor of Pediatrics, University of Connecticut School of Medicine. “These strong data further our understanding of the safety profile of linaclotide in pediatric patients aged 6-17 with FC and demonstrate evidence of its potential to provide therapeutic benefit to these patients suffering from FC.”

In this study, a total of 330 patients were randomized in a 1:1 ratio between linaclotide or placebo. Topline data indicate that 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 least squares mean change from baseline at week 12 was 1.108 and 0.685 points, respectively (p=0.0001). The BSFS is a 7-point scale ranging from 1 (separate hard, difficult-to-pass lumps) to 7 (liquid stools).

Overall, linaclotide (72 mcg) was well tolerated. The most frequently reported treatment-emergent adverse event was diarrhea, which occurred in 4.3% of linaclotide-treated participants versus 1.8% in the placebo group.

“We are excited by the results of this Phase III trial and are focused on identifying an expeditious regulatory path forward, with our partner AbbVie, to support delivering this potential first functional constipation therapeutic to pediatric patients ages 6-17 in need,” said Mike Shetzline, M.D., Ph.D., chief medical officer, senior vice president and head of research and drug development at Ironwood Pharmaceuticals.

“Our vision for LINZESS has always been simple but powerful – keep patients at the center of everything we do,” said Tom McCourt, chief executive officer at Ironwood Pharmaceuticals. “We have seen the positive impacts that LINZESS has had with more than 4 million unique patients with IBS-C or chronic idiopathic constipation (CIC) treated since launch in 2012, and our team now looks forward to potentially expanding its clinical utility to the treatment of functional constipation in an underserved population.”

These data are from the FC cohort of the Phase III, multicenter, randomized, double-blind, parallel-group, safety, and efficacy study of linaclotide vs. placebo in children ages 6-17 years with FC. Participants in the FC cohort must have fulfilled modified Rome III Criteria for child/adolescent FC.

Ironwood expects to share these Phase III trial data at upcoming scientific meetings and via peer-reviewed publications.

LINZESS is developed and marketed by Ironwood and AbbVie in the United States and is indicated for the treatment of adults with IBS-C or CIC. It is not approved for use in patients less than 18 years of age.

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).

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
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

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 FC; the efficacy and safety of linaclotide in FC and IBS in pediatric patients; the potential for linaclotide to provide therapeutic benefit to patients suffering from FC; and the potential for an sNDA submission for linaclotide. 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 and/or IW-3300 is 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, 2021, and in our subsequent SEC filings.

¹ Robin, Samantha G. et al., Prevalence of Pediatric Functional Gastrointestinal Disorders Utilizing the Rome IV Criteria, The Journal of Pediatrics, December 2017

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