Ironwood Presents New Data Demonstrating Potential of IW-3300 for Visceral Pain at Digestive Disease Week® (DDW) 2022

– Other Studies Highlight Impact of Linaclotide in Adult and Pediatric Populations, Highlight Disease Burden –

BOSTON–(BUSINESS WIRE)–Ironwood Pharmaceuticals, Inc. (Nasdaq: IRWD), a GI-focused healthcare company, presented new findings during the 2022 Digestive Disease Week^® (DDW) meeting that suggest colonic IW-3300 has the potential to help manage abdominopelvic visceral pain in patients with disorders of gut-brain interaction (DGBI) and related visceral pain disorders. The oral presentation, titled Colon-Targeted Delivery Of Guanylate Cyclase-C Agonist IW-3300 Relieves Comorbid Chronic Pelvic And Somatic Pain In A Rat Model Of Early Life Stress-Induced Colonic Hypersensitivity (presentation number 240), provided evidence that delivery of IW-3300 to the colorectal region inhibits overlapping chronic pelvic pain in an established preclinical model of early-life stress induced colonic hypersensitivity.

Ironwood is currently developing IW-3300, a guanylate cyclase-c (GC-C) agonist, for the potential treatment of visceral pain conditions such as interstitial cystitis/bladder pain syndrome (IC/BPS) and endometriosis. The compound is currently in Phase I trials that will lay the foundation to potentially clinically test the cross-talk hypothesis in humans for the first time. Cross-talk is a biological phenomenon where sensations of injury originating in one abdominal or visceral organ can result in altered sensation in a nearby organ because of overlapping nerve pathways.

“Visceral pain is the most common type of pain associated with disease, and yet treating patients with this type of pain remains a significant challenge,” said Beverley Greenwood-Van Meerweld, Ph.D., George Lynn Cross Research Professor Emeritus, President’s Associates Presidential Professor, University of Oklahoma Health Sciences Center. “These results are exciting because they show the potential of IW-3300 to relieve visceral pain via a neuronal cross-talk mechanism mediated by the GC-C pathway. I look forward to future results from clinical trials of the compound.”

Ironwood Pharmaceuticals and its collaborators also presented results from a post-hoc analysis of linaclotide studies focused on further understanding its treatment effect on abdominal symptoms in patients with Irritable Bowel Syndrome with Constipation (IBS-C). Other studies presented highlighted preclinical data on the impact of linaclotide on visceral hypersensitivity, data on the impact of linaclotide on pediatric functional constipation, and studies on the disease burden of IBS-C and chronic idiopathic constipation (CIC).

“As a company, we are focused on understanding the potential of linaclotide for patients who can benefit from its established mechanism treating visceral pain and constipation as well as continually expanding our pipeline to address underserved GI diseases,” said Mike Shetzline, M.D., Ph.D., chief medical officer, senior vice president and head of research and development at Ironwood. “We’re excited to present the wealth of data that we are bringing to the discussion at DDW, and particularly our efforts in pediatric patients with functional constipation as well as our IW-3300 study findings.”

Impact of Linaclotide on IBS-C

• An oral presentation titled Patient-Derived Meaningful Change Thresholds In The Novel Abdominal Score Outcome Measure In Irritable Bowel Syndrome With Constipation (presentation number 179), presented by Jan Tack, M.D., Ph.D., University of Leuven, Leuven, Belgium, summarized data from a post-hoc analysis of two Phase III randomized controlled trials of linaclotide 290 mcg versus placebo in IBS-C. Both trials evaluated meaningful changes from baseline to week 12 in Abdominal Score (AS), a composite of abdominal pain, bloating and discomfort. The post-hoc analysis, which was conducted to understand the relationship between the composite AS and patient reported global relief of abdominal symptoms found that optimal meaningful change thresholds for AS had a graded relationship to levels of perceived relief of abdominal symptoms among patients with IBS-C. An AS improvement of ~2.0 points correlated with any relief and adequate relief, while an AS improvement of ~2.5 points correlated with complete relief. The authors note that these findings may help clinicians set clinical expectations based on clinical trial results.
• A poster titled Race-Related Comparisons Of Irritable Bowel Syndrome With Constipation Symptoms, Treatment Response, And Quality Of Life: Results Of A Pooled Analysis Of Linaclotide Clinical Trials (presentation number Tu1364), presented by Linda Nguyen, M.D., Stanford Health Care, Redwood City, California, detailed findings of a post-hoc analysis of pooled studies of linaclotide in IBS-C. Overall, linaclotide demonstrated efficacy versus placebo within most racial groups based on the combined abdominal pain and constipation (APC+1) responder rate (White and Black: p<0.001; Asian: p<0.05; Other: p=0.5310). In patients treated with linaclotide 290 mcg, higher APC+1 and higher spontaneous bowel movement responder rates were observed in White versus Black patients, and numerically higher IBS severity score responder rates were observed in White versus Asian patients. The authors note that the numbers of patients included in the Asian and Other racial groups were low, limiting the interpretation of these data. They also note that these data highlight the need for greater racial representation in future clinical trials to assess the impact of race on treatment response in IBS-C.

Impact of Linaclotide on Functional Constipation in a Pediatric Population

A poster titled Safety and Efficacy of Linaclotide in Children Aged 2-5 years With Functional Constipation; Results From a Randomized, Double-blind, Placebo-controlled, Multidose Study (presentation number Tu1390), presented by Carlo Di Lorenzo, M.D., Nationwide Children’s Hospital, Columbus, OH, showed that linaclotide 9 mcg, 18 mcg, 36 mcg and 72 mcg were well tolerated in children aged 2–5 years with functional constipation. The findings were consistent with safety profiles from a previous pediatric linaclotide study in children with FC aged 6–17 years. In this small population, numerically better efficacy results were observed in the LIN 72 mcg dose groups vs. placebo for three of the four key efficacy endpoints, with stool consistency showing a dose-response trend. The authors note that the efficacy and safety of LIN need to be further characterized in a larger study of longer duration.

Impact of Linaclotide on Visceral Hypersensitivity

Two ePosters presented by Andrea Harrington, Ph.D., Flinders University, Adelaide, South Australia, focused on the impact of linaclotide on visceral hypersensitivity in preclinical studies.

• An ePoster titled Colorectal Nociceptive Processing In Ascending Pain Relaying Caudal Ventrolateral Medulla And The Lateral Parabrachial Nuclei Is Increased In A Mouse Model Of Chronic Visceral Hypersensitivity And Is Reversed By Chronic Linaclotide Treatment (presentation number EP1238), suggested that after colitis, colonic nociceptive (relating to pain) signaling is enhanced in ascending pathways relaying into specific medullary nuclei and pontine parabrachial nuclei. The study also demonstrated that enhanced activation in these nuclei is effectively reduced by targeting peripheral hypersensitivity with chronic linaclotide treatment.
• Another ePoster titled Descending Pain Modulation Of Colorectal Nociceptive Processing In The Spinal Cord Is Imbalanced In A Mouse Model Of Post-Colitis Chronic Visceral Hypersensitivity And Is Reduced By Chronic Oral Linaclotide Treatment (presentation number EP1239), indicated that in a preclinical model of chronic visceral hypersensitivity, descending pain modulation mechanisms influencing spinal processing of colorectal nociceptive signaling are imbalanced, with both pro-and anti-nociceptive mechanisms enhanced. Such imbalances were not observed after chronic linaclotide treatment.

IBS-C and CIC Disease Burden

Two posters presented by Brian E. Lacy, M.D., Ph.D., The Mayo Clinic, Jacksonville, FL, summarized findings from a cross-sectional, online health survey of U.S. adults from Aug 2020 – Aug 2021.

• A poster titled Chronic Idiopathic Constipation Sufferers And Treatment Satisfaction: Prescription Vs. Over-The-Counter Medication (presentation number Tu1339), concluded that there remains a considerable disease burden and unmet need for CIC patients, many of whom are not satisfied with the control of their symptoms. CIC patients currently taking a prescription medication with or without concomitant use of over-the-counter (OTC) medication were more satisfied with the control of their symptoms than CIC patients currently taking an OTC only. The authors note there may be an opportunity for clinicians to improve CIC patient education and care.
• Another poster, titled Undiagnosed Irritable Bowel Syndrome with Constipation (IBS-C) and Chronic Idiopathic Constipation (CIC): More Common than we Thought? (presentation number Mo1084), found that of the undiagnosed participants who met Rome IV criteria for IBS-C or CIC, 33.5% did not have a physician diagnosis (PD), despite frequent bothersome symptoms. Many undiagnosed participants noted a reluctance to discuss their symptoms with their HCP. The authors note that proactive, directed questioning of patients about abdominal pain and bowel habits may identify symptomatic undiagnosed patients, leading to education and discussion about treatment options and likely symptom improvement.

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

About IW-3300

Ironwood is currently advancing IW-3300, a guanylate cyclase-C agonist being developed for the potential treatment of visceral pain conditions, such as interstitial cystitis / bladder pain syndrome (IC/BPS) and endometriosis. IC/BPS affects an estimated 4 to 12 million Americans, according to the Interstitial Cystitis Association. An estimated 4 million reproductive-age women in the U.S. have been diagnosed with endometriosis, according to a study published in Gynecologic and Obstetric Investigation. Both diseases have a limited number of treatment options available. Ironwood initiated a clinical study for its IW-3300 program in the first quarter of 2022 to evaluate the safety and tolerability of IW-3300 in healthy volunteers.

About Ironwood Pharmaceuticals

Ironwood Pharmaceuticals (Nasdaq: IRWD) 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 potential of IW-3300 to help manage abdominopelvic visceral pain in patients with DGBI and related visceral pain disorders, to relieve visceral pain via a neuronal cross-talk mechanism mediated by the GC-C pathway, and to treat visceral pain conditions such as IC/BPS and endometriosis; the size of the IC/BPS and endometriosis populations; the potential to clinically test the cross-talk hypothesis in humans for the first time; the potential indications for, and benefits of, linaclotide, including for the treatment of visceral pain and constipation; the impact of linaclotide on visceral hypersensitivity and functional constipation in a pediatric population; and the development and commercial potential of 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.

Contacts

Media:
Beth Calitri, 978-417-2031

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Investors:
Greg Martini, 617-374-5230

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Matt Roache, 617-621-8395

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