Ironwood Pharmaceuticals Announces FDA Filing Acceptance and Priority Review of Supplemental New Drug Application for LINZESS® (linaclotide) for Functional Constipation in Children and Adolescents Ages 6-17 Years-Old

Rhea-AI Summary

Ironwood Pharmaceuticals announced that the FDA has granted Priority Review to its supplemental New Drug Application for LINZESS (linaclotide), targeting children aged 6-17 with functional constipation. The FDA set a Prescription Drug User Fee Act (PDUFA) date of June 14, 2023, marking a four-month acceleration from the standard review timeline. If approved, LINZESS will be the first FDA-approved prescription therapy for this condition in the pediatric population, potentially impacting about 6 million children in the U.S. The application is based on a Phase III study involving 330 participants, which showed significant improvements in bowel movement frequency and stool consistency.

Positive

• FDA granted Priority Review for LINZESS, indicating potential for significant treatment improvement.
• PDUFA date set for June 14, 2023, indicating expedited review.
• Study showed statistically significant improvements in bowel movement frequency and stool consistency.
• 6 million children affected, indicating a large potential market.

Negative

• Risk of adverse reactions, with diarrhea being a common side effect (4.3% in treatment group).
• No current FDA-approved therapies for functional constipation in this age group, indicating unmet need.

– FDA assigns 2^nd Quarter 2023 target action date –

– If approved, LINZESS would be the first and only FDA-approved prescription therapy for functional constipation in this patient population –

– Functional constipation affects an estimated 6 million 6-17 year-olds in the U.S.¹ –

BOSTON--(BUSINESS WIRE)-- Ironwood Pharmaceuticals, Inc. (Nasdaq: IRWD), a GI-focused healthcare company, today announced that the U.S. Food and Drug Administration (FDA) has granted Priority Review to the supplemental New Drug Application (sNDA) for LINZESS^® (linaclotide) for the treatment of children and adolescents ages 6-17 years-old with functional constipation (FC). The FDA has assigned the application a Prescription Drug User Fee Act (PDUFA) date of June 14^th, 2023, four months earlier than the standard review cycle.

The FDA grants priority review to therapies that have the potential to provide significant improvements in the treatment, diagnosis, or prevention of serious conditions and to pediatric supplements submitted pursuant to the Best Pharmaceuticals for Children Act.²

“Pediatric functional constipation has a significant impact on young patients and their families, yet there are no FDA-approved prescription therapies available for this population,” said Michael Shetzline, M.D., Ph.D., chief medical officer, senior vice president and head of research and drug development at Ironwood Pharmaceuticals. “We welcome the FDA’s decision to grant priority review, as it brings us even closer to potentially changing the treatment landscape for pediatric patients ages 6-17 years-old with this condition.”

FC in children is defined as a chronic condition with hard, infrequent bowel movements that are often difficult or painful to pass³. The condition affects an estimated 6 million children aged 6-17 years-old in the U.S.¹

“As a company focused on advancing the treatment of GI diseases, we have worked with a sense of urgency to expand the clinical utility of linaclotide to this underserved pediatric population with FC,” said Tom McCourt, chief executive officer of Ironwood Pharmaceuticals. “If approved, we look forward to a commercial launch mid-2023.”

The sNDA filing was based on the results of a large, multicenter, double-blind, Phase III study evaluating linaclotide in patients ages 6-17 years-old with functional constipation. A total of 330 patients were randomized in a 1:1 ratio between linaclotide or placebo. Compared to placebo, linaclotide showed a statistically significant and clinically meaningful improvement from baseline in 12-week spontaneous bowel movement (SBM) frequency rate (SBMs/week), meeting 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). The secondary endpoint of change from baseline to week 12 in stool consistency, assessed by Bristol Stool Form Scale (BSFS) scores, also showed statistically significant improvement with linaclotide compared to placebo. Overall, the Phase III study demonstrated that linaclotide was well-tolerated in the pediatric population. The most common adverse event in the pediatric Phase 3 study was diarrhea, which occurred in 4.3% of linaclotide-treated patients versus 1.8% in the placebo group.

LINZESS is developed and marketed by Ironwood and AbbVie in the United States and is currently 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.

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

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
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 FC; the efficacy and safety of linaclotide in FC in pediatric patients; the potential for linaclotide to change the treatment landscape for pediatric patients ages 6-17 years-old with FC; our expectations regarding the PDUFA date for the sNDA; and, if the sNDA is approved, the anticipation for a commercial launch and the timing thereof. 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 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 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 U.S. FDA Guidance for Industry: Expedited Programs for Serious Conditions – Drugs and Biologics, May 2014.
³ 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/20230213005077/en/

Media:

Beth Calitri, 978-417-2031

bcalitri@ironwoodpharma.com

Investors:

Greg Martini, 617-374-5230

gmartini@ironwoodpharma.com

Matt Roache, 617-621-8395

mroache@ironwoodpharma.com

Source: Ironwood Pharmaceuticals, Inc.

FAQ

What is the significance of the FDA's Priority Review for IRWD's LINZESS?

It indicates that LINZESS may provide significant improvements in treatment for functional constipation in children aged 6-17, with the potential to change the treatment landscape.

When is the PDUFA date for Ironwood Pharmaceuticals' LINZESS?

The PDUFA date for LINZESS is set for June 14, 2023.

How many children in the U.S. are affected by functional constipation?

An estimated 6 million children aged 6-17 in the U.S. suffer from functional constipation.

What were the results of the Phase III study for LINZESS?

The Phase III study with 330 participants showed a significant improvement in bowel movement frequency and stool consistency in patients treated with LINZESS compared to placebo.

What are the common side effects of LINZESS in pediatric patients?

The most common side effect observed was diarrhea, reported in 4.3% of LINZESS-treated patients.