Ironwood Pharmaceuticals Announces That The American Journal of Gastroenterology Publishes Full Results from Positive LINZESS® (linaclotide) Phase IIIb Trial in Adults with Irritable Bowel Syndrome with Constipation (IBS-C)

– Results demonstrated that linaclotide improved the overall abdominal symptoms of bloating, pain and discomfort in adults with IBS-C –

– LINZESS U.S. prescribing information updated in September 2020 to reflect Phase IIIb data –

Ironwood Pharmaceuticals, Inc. (NASDAQ: IRWD), a GI-focused healthcare company, today announced that The American Journal of Gastroenterology – the official journal of The American College of Gastroenterology – published full results from the company’s Phase IIIb clinical trial evaluating LINZESS® (linaclotide) 290 mcg on multiple abdominal symptoms in adult patients with irritable bowel syndrome with constipation (IBS-C). The results, which can be viewed here, demonstrated that linaclotide 290 mcg administered orally once daily to adult IBS-C patients was associated with a statistically significant and clinically meaningful improvement in overall change in abdominal score compared to placebo. Ironwood reported topline results from this trial in June 2019.

The abdominal score, which comprises symptoms of bloating, pain and discomfort, reflects symptoms that have been identified by IBS-C patients as bothersome and important to treat.¹ The trial was the first Phase III study to evaluate IBS-C treatment efficacy using the Diary for IBS Symptoms-Constipation (DIBSS-C), a patient-reported outcome instrument that assesses the three abdominal symptoms constituting the abdominal score, in addition to other symptoms of IBS-C.^2,3

Following U.S. Food and Drug Administration (FDA) approval of a supplemental New Drug Application (sNDA) based on data from this trial, the LINZESS U.S. prescribing information was updated in September 2020 to reflect the impact of LINZESS on overall abdominal symptoms in adult IBS-C patients.

“During patients’ conversations with their doctors, there is often an unfortunate but avoidable communication gap in which patients only describe their ‘constipation’ without discussing specific symptoms such as abdominal bloating, pain and/or discomfort,” said Lin Chang, M.D., vice chief at the Vatche and Tamar Manoukian Division of Digestive Diseases at the University of California, Los Angeles. “Results from this trial may help physicians and patients have a more comprehensive discussion about these bothersome symptoms and ways to manage them.”

Research has shown that approximately 95% of surveyed adults with IBS-C reported experiencing bothersome abdominal bloating, pain and/or discomfort, with the majority reporting that they experience these symptoms once a week or more.^4,5 There are an estimated 11.5 million adults in the U.S. with IBS-C.²

“The Phase IIIb data expand and strengthen the clinical profile of LINZESS, underscoring its value as a treatment option for adult patients with IBS-C,” said Mike Shetzline, M.D., Ph.D., chief medical officer, senior vice president and head of drug development at Ironwood. “We continue to educate physicians and patients on these data and the clinical benefits of LINZESS on multiple abdominal symptoms associated with IBS-C, with the goal of enabling improved communication between them and thereby meeting patients’ needs more effectively.”

For the multi-component primary endpoint of overall change from baseline in the abdominal score (the average of bloating, discomfort and pain symptoms at their worst), linaclotide demonstrated a significant improvement compared to placebo over the 12 weeks of the trial: -1.9 (29.7% decrease from baseline) with linaclotide vs. -1.2 (18.3% decrease) with placebo (p<0.0001). Significant improvements in abdominal score with linaclotide vs. placebo were observed beginning at week one of the trial and continued throughout. Additionally, 40.5% of linaclotide patients in the trial were abdominal score responders – defined as patients who reported experiencing an improvement of at least two points from baseline in their weekly abdominal score for at least six of the 12-week treatment period – compared to 23.4% of placebo patients (p<0.0001).

Linaclotide was well-tolerated in this Phase IIIb trial, with the most commonly reported adverse event being diarrhea. During the treatment period, diarrhea was reported in 4.6% of patients on linaclotide 290 mcg as compared to 1.6% of patients on placebo. Trial discontinuation resulting from diarrhea occurred in 1.6% of linaclotide 290 mcg patients compared to none of the placebo-treated patients.

The DIBBS-C instrument used in the study was developed by the IBS working group of the Critical Path Institute’s Patient-Reported Outcome (PRO) consortium following extensive qualitative research and PRO development work. The Critical Path Institute is a non-profit, public-private partnership with the FDA.⁶ The IBS working group included academic experts in IBS, a patient advocate and representatives from pharmaceutical companies including Ironwood Pharmaceuticals.¹ A psychometric evaluation and validation of the DIBSS-C abdominal score using data from an Ironwood Phase IIb clinical trial in IBS-C was published in 2020 in Value in Health, an international journal that publishes original research and health policy articles.³ Value in Health also published the earlier foundational DIBSS research characterizing how surveyed IBS-C patients experience and speak about their symptoms.¹

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. 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. LINZESS should be taken at least 30 minutes before the first meal of the day.

LINZESS is contraindicated in pediatric patients less than 6 years of age. The safety and effectiveness of LINZESS in pediatric patients less than 18 years of age have not been established. In neonatal mice, linaclotide increased fluid secretion as a consequence of guanylate cyclase-C (GC-C) agonism resulting in mortality within the first 24 hours due to dehydration. Due to increased intestinal expression of GC-C, patients less than 6 years of age may be more likely than patients 6 years of age and older to develop severe diarrhea and its potentially serious consequences. In adults with IBS-C or CIC treated with LINZESS, the most commonly reported adverse event was diarrhea.

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).

IMPORTANT SAFETY INFORMATION

Contraindications

• LINZESS is contraindicated in patients less than 6 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 6 years of age. The safety and effectiveness of LINZESS in patients less than 18 years of age have not been established. In neonatal mice, linaclotide increased fluid secretion as a consequence of GC-C agonism resulting in mortality within the first 24 hours due to dehydration. Due to increased intestinal expression of GC-C, patients less than 6 years of age may be more likely than patients 6 years of age and older to develop severe diarrhea and its potentially serious consequences.
• Use of LINZESS should be avoided in pediatric patients 6 years to less than 18 years of age. Although there were no deaths in older juvenile mice, given the deaths in young juvenile mice and the lack of clinical safety and efficacy data in pediatric patients, use of LINZESS should be avoided in pediatric patients 6 years to less than 18 years of age.

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) 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 adult patients with IBS-C; the potential for linaclotide to offer IBS-C patients relief from overall abdominal symptoms of bloating, pain and discomfort; the efficacy and safety of linaclotide; IBS-C symptoms and the size of the potential patient population; and the potential of the Phase IIIb data to improve physician-patient dialogue. 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 a 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; 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, including due to the impacts of the COVID-19 pandemic; 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 we may never get additional patent protection for linaclotide and other product candidates; 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; outcomes in legal proceedings to protect or enforce the patents relating to our products and product candidates, including abbreviated new drug application litigation; developments in the intellectual property landscape; challenges from and rights of competitors or potential competitors; 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; and the risks listed under the heading "Risk Factors" and elsewhere in Ironwood's Quarterly Report on Form 10-Q for the quarter ended March 31, 2021, and in our subsequent SEC filings. In addition, the COVID-19 pandemic and the associated containment efforts have had a serious adverse impact on the economy, the severity and duration of which are uncertain. Government stabilization efforts will only partially mitigate the consequences. The extent and duration of the impact on our business and operations is highly uncertain. Factors that will influence the impact on our business, operations and financial results include the duration and extent of the pandemic, the extent of imposed or recommended containment and mitigation measures, and the general economic consequences of the pandemic. The pandemic could have a material adverse impact on our business, operations and financial results for an extended period of time.

1. Fehnel SE, Ervin CM, Carson RT, et al. Development of the Diary for Irritable Bowel Syndrome Symptoms to Assess Treatment Benefit in Clinical Trials: Foundational Qualitative Research. Value Health 2017;20:618-626.
2. Qualification of the Diary for Irritable Bowel Syndrome Symptoms- Constipation: A Patient-Reported Outcome Instrument for Measurement of Overall Irritable Bowel Syndrome–Constipation Symptom Severity. FDA.gov. Available at https://www.fda.gov/media/145333/download. Accessed April 29, 2021
3. Coon CD, Hanlon J, Abel JL, et al. Psychometric Analysis of the Abdominal Score From the Diary for Irritable Bowel Syndrome Symptoms-Constipation Using Phase IIb Clinical Trial Data. Value Health 2020;23:362-369.
4. GfK “IBS in America”, 2016.
5. Lieberman GI Patient Landscape Survey, 2010
6. Patient Reported Outcome Consortium. Critical Path Institute. Available at: https://c-path.org/programs/proc/. Accessed April 29, 2021

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