Ironwood and Allergan Report Positive Topline Data from Phase IIIb Trial of LINZESS® (linaclotide) in Adults with Irritable Bowel Syndrome with Constipation (IBS-C)

CAMBRIDGE, Mass.--(BUSINESS WIRE)-- Ironwood Pharmaceuticals, Inc. (NASDAQ: IRWD) and Allergan plc (NYSE:AGN) today announced positive topline data from a Phase IIIb clinical trial evaluating LINZESS (linaclotide) 290 mcg on multiple abdominal symptoms in adult patients with IBS-C. The trial met its primary multi-component endpoint and demonstrated that linaclotide improved the overall abdominal symptoms of bloating, pain and discomfort in adult IBS-C patients compared to placebo. The trial also met both secondary endpoints. This trial was designed to highlight the impact of LINZESS on the overall abdominal symptoms of bloating, pain and discomfort, which are part of patients’ reported real-world experience, thereby enabling better communication about these symptoms.

LINZESS is marketed by Ironwood and Allergan in the United States and is indicated for the treatment of adults with IBS-C or chronic idiopathic constipation (CIC). Research has shown that approximately 95 percent of adults with IBS-C experience bothersome abdominal bloating, pain, and/or discomfort, with the majority experiencing these symptoms once a week or more. There are an estimated 13 million adults in the U.S. with IBS-C.^1,2

“While research clearly suggests that the symptoms of abdominal bloating, pain, and discomfort have a considerable impact on adults suffering from IBS-C, in the clinical setting patients often use the word ‘constipation’ as a general term to represent their abdominal and bowel symptoms. This can lead to a less precise communication regarding their symptoms between patient and physician and can impact management,” said Lin Chang, M.D., Professor of Medicine at the Vatche and Tamar Manoukian Division of Digestive Diseases at the University of California, Los Angeles (UCLA). “I believe the data from this LINZESS Phase IIIb trial will be very important in helping patients and physicians have a more comprehensive dialogue about the multiple symptoms associated with IBS-C.”

Topline data from a randomized, double-blind, placebo-controlled Phase IIIb trial showed that linaclotide 290 mcg administered orally once daily demonstrated a statistically significant and clinically meaningful improvement in overall abdominal symptoms compared to placebo across the primary and both secondary endpoints. In the multi-component primary endpoint, linaclotide-treated patients showed a 29.7% mean decrease from baseline in their weekly abdominal score (bloating, pain and discomfort) through the 12-week treatment period, compared to 18.3% for the placebo-treated patients (p<0.0001). In the secondary endpoints, 40.5% of patients treated with linaclotide 290 mcg demonstrated a clinically meaningful response, as defined by the abdominal symptom score responder, compared to 23.4% of placebo-treated patients (p<0.0001). An abdominal symptom score responder was defined as a patient who experienced an improvement of at least two-points from baseline in their weekly abdominal score for at least six of 12 weeks of treatment period. These findings add to the significant body of data supporting the impact of linaclotide on the overall abdominal symptoms of bloating, pain and discomfort in adult IBS-C patients.

Linaclotide was well-tolerated in this Phase IIIb study, 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. Study discontinuation resulting from diarrhea occurred in 1.6% of linaclotide 290 mcg patients compared to none of the placebo-treated patients.

“These topline results demonstrated that LINZESS can help provide overall relief of some of the multiple abdominal symptoms that IBS-C patients identify as among the most bothersome,” said Mike Shetzline, M.D., Ph.D., chief medical officer, senior vice president and head of drug development at Ironwood. “As the 10^th Phase III trial of linaclotide to meet its primary endpoint, this study further contributes to the robust body of evidence supporting the use of LINZESS in adults with IBS-C and further strengthens its clinical profile.”

“IBS-C is a frustrating and uncomfortable condition, but it can be treated. We expect that communicating the full clinical profile of LINZESS on the overall abdominal symptoms of bloating, pain, and discomfort will broaden physicians’ understanding of the appropriate patient and may help those who need to find relief,” said David Nicholson, chief research & development officer at Allergan.

The randomized, double-blind, placebo-controlled, parallel-group study was designed to evaluate the efficacy and safety of LINZESS 290 mcg on multiple abdominal symptoms in adult patients with IBS-C. 614 patients were randomized to placebo or LINZESS 290 mcg once daily for 12 weeks, followed by a four-week randomized withdrawal period. The primary efficacy endpoint was change from baseline in abdominal score based on daily patient assessments of abdominal bloating, pain and discomfort at their worst, as reported on an 11-point numerical rating scale. Additional endpoints included change from baseline in spontaneous bowel movement frequency, complete spontaneous bowel movement frequency, stool consistency, and straining.

Additional data from this Phase IIIb trial are expected to be shared at upcoming scientific meetings and via peer-reviewed publications.

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. Linaclotide is marketed by Ironwood and Allergan plc in the United States as LINZESS^® and is indicated for the treatment of adults with irritable bowel syndrome with constipation (IBS-C) or chronic idiopathic constipation (CIC). Linaclotide is marketed by Allergan for the treatment of adults with moderate to severe IBS-C in Europe under the brand name CONSTELLA^®. Ironwood is partnered with AstraZeneca for development and commercialization of linaclotide in China, Hong Kong and Macau. Astellas has the exclusive rights to develop and commercialize linaclotide in Japan. Allergan has rights to develop and market in the remaining rest of world countries.

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).

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

About Allergan plc

Allergan plc (NYSE: AGN), headquartered in Dublin, Ireland, is a global pharmaceutical leader focused on developing, manufacturing and commercializing branded pharmaceutical, device, biologic, surgical and regenerative medicine products for patients around the world. Allergan markets a portfolio of leading brands and best-in-class products primarily focused on four key therapeutic areas including medical aesthetics, eye care, central nervous system and gastroenterology. As part of its approach to delivering innovation for better patient care, Allergan has built one of the broadest pharmaceutical and device research and development pipelines in the industry.

With colleagues and commercial operations in approximately 100 countries, Allergan is committed to working with physicians, healthcare providers and patients to deliver innovative and meaningful treatments that help people around the world live longer, healthier lives every day.

For more information, visit Allergan’s website at www.Allergan.com.

About Ironwood Pharmaceuticals

Ironwood Pharmaceuticals (Nasdaq: IRWD) is a GI-focused healthcare company dedicated to creating medicines that make a difference for patients living with GI diseases. We discovered, developed and are commercializing linaclotide, the U.S. branded prescription market leader for adults with irritable bowel syndrome with constipation (IBS-C) or chronic idiopathic constipation (CIC). We are currently advancing a Phase IIIb trial evaluating the efficacy and safety of linaclotide on multiple abdominal symptoms, including bloating, pain, and discomfort, in adult patients with IBS-C.

We are also advancing two late-stage, first-in-category GI product candidates: IW-3718 is a gastric retentive formulation of a bile acid sequestrant being developed for the potential treatment of persistent gastroesophageal reflux disease, and MD-7246 is a delayed-release formulation of linaclotide that is being evaluated as an oral, intestinal, non-opioid, pain-relieving agent for patients suffering from abdominal pain associated with IBS with diarrhea.

Ironwood was founded in 1998 and is headquartered in Cambridge, Mass. For more information, please visit our website at www.ironwoodpharma.com or www.twitter.com/ironwoodpharma; information that may be important to investors will be routinely posted in both these locations.

IRONWOOD®, the three-leaf logo, 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.

Forward-Looking Statements

This press release contains forward-looking statements. Investors are cautioned not to place undue reliance on these forward-looking statements, including, but not limited to, statements about the potential for linaclotide to offer IBS-C patients relief from bothersome symptoms including abdominal bloating, pain and discomfort; the efficacy and safety of linaclotide; IBS-C symptoms and the size of the potential patient population; the size, scope and design of the Phase IIIb study of linaclotide in adults with IBS-C; the potential of the Phase IIIb data to improve physician-patient dialogue; the strength of linaclotide’s clinical profile; the potential of the Phase IIIb data to increase requests for linaclotide; and the development and regulatory plans for linaclotide. 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 preclinical and clinical development, manufacturing and formulation development; the risk that future clinical studies need to be discontinued for any reason, including safety, tolerability, enrollment, manufacturing or economic reasons; the risk that findings from our completed nonclinical and clinical studies may not be replicated in later studies; efficacy, safety and tolerability of our products and product candidates; the risk that the therapeutic opportunities for linaclotide are not as we expect; decisions by regulatory and judicial authorities; the risk that we are unable to successfully commercialize linaclotide; the risk that we may never get sufficient patent protection for our products and our product candidates or that we are not able to successfully protect such patents; the outcomes in legal proceedings to protect or enforce the patents relating to our products and product candidates, including ANDA 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, products or product candidates; the risk that we are unable to manage our operating expenses or cash use for operations, or are unable to commercialize our products, within the guided ranges or otherwise 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, 2019, Allergan’s Quarterly Report on Form 10-Q for the quarter ended March 31, 2019 and in the subsequent SEC filings of each company. These forward-looking statements (except as otherwise noted) speak only as of the date of this press release, and Ironwood and Allergan undertake no obligation to update these forward-looking statements.

¹ GfK “IBS in America”, 2016.
² Lieberman GI Patient Landscape Survey, 2010

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