Ironwood Reports Positive Top-Line Data From Phase II Trial Of Linaclotide In Adult Patients With Opioid-Induced Constipation

CAMBRIDGE, Mass.--(BUSINESS WIRE)--Ironwood Pharmaceuticals, Inc. (NASDAQ: IRWD) announced today that the Phase II clinical trial of linaclotide conducted in adults with opioid-induced constipation (OIC) met its primary endpoint. The OIC clinical trial was conducted jointly by Ironwood and a subsidiary of Allergan plc, Ironwood’s co-development and co-commercialization partner for linaclotide in the United States.

“As a pioneer and a recognized leader in GC-C agonists, we are committed to continued innovation with linaclotide, and we are very pleased with the results of this OIC trial.”

“These top-line data demonstrate the positive effect of the guanylate cyclase-C (GC-C) agonist, linaclotide, on bowel movement frequency and other key endpoints in patients with OIC,” said Dr. Michael Hall, senior vice president, clinical development of Ironwood. “As a pioneer and a recognized leader in GC-C agonists, we are committed to continued innovation with linaclotide, and we are very pleased with the results of this OIC trial.”

Top-line data from the Phase II trial indicate that linaclotide-treated patients showed statistically significant improvement for the pre-specified primary endpoint: change from baseline in the 8-week Spontaneous Bowel Movement (SBM) frequency rate (SBMs/week), during the treatment period, for both doses tested, 145 mcg and 290 mcg, compared to placebo-treated patients. Consistent with previous Phase III trials of linaclotide in irritable bowel syndrome with constipation (IBS-C) and chronic idiopathic constipation (CIC), the most common adverse event reported in linaclotide-treated patients was diarrhea, with the majority being characterized as mild in severity.

This randomized, double-blind, placebo-controlled, multi-site Phase II clinical trial enrolled 254 adult patients with chronic, non-cancer pain who had been receiving a stable dose of an opioid analgesic and suffered from constipation, defined as fewer than three spontaneous bowel movements (SBMs) per week. Patients were randomized to receive 145 mcg of linaclotide, 290 mcg of linaclotide, or placebo for eight weeks.

Ironwood and Allergan will make a decision regarding advancement of the OIC program following a review of results from the linaclotide colonic release Phase IIb trial in adults with IBS-C and continued analysis of the full commercial opportunity. The companies expect data from the linaclotide colonic release Phase IIb trial in the second half of 2016.

Linaclotide is currently approved in the United States for the treatment of adults with IBS-C or CIC. It is also approved for adults with IBS-C or CIC in a number of other countries. Linaclotide is not currently approved for the treatment of OIC.

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 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 also has partnered with Astellas Pharma Inc. for development and commercialization of linaclotide in Japan and with AstraZeneca for development and commercialization in China.

LINZESS and CONSTELLA are trademarks owned by 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

WARNING: PEDIATRIC RISK

LINZESS is contraindicated in pediatric patients under 6 years of age. In nonclinical studies, administration of a single, clinically relevant adult oral dose of linaclotide caused deaths due to dehydration in young juvenile mice. Use of LINZESS should be avoided in pediatric patients 6 through 17 years of age. The safety and efficacy of LINZESS has not been established in pediatric patients under 18 years of age.

Contraindications

• LINZESS is contraindicated in pediatric patients under 6 years of age.
• LINZESS is contraindicated in patients with known or suspected mechanical gastrointestinal obstruction.

Warnings and Precautions
Pediatric Risk

• LINZESS is contraindicated in children under 6 years of age. The safety and effectiveness of LINZESS in pediatric patients under 18 years of age have not been established. In neonatal mice, increased fluid secretion as a consequence of GC-C agonism resulted in mortality within the first 24 hours due to dehydration. Due to increased intestinal expression of GC-C, children under 6 years of age may be more likely than older children and adults to develop significant diarrhea and its potentially serious consequences.
• Use of LINZESS should be avoided in pediatric patients 6 through 17 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 through 17 years of age.

Diarrhea

• Diarrhea was the most common adverse reaction of LINZESS-treated patients in the pooled IBS-C and CIC double-blind placebo-controlled trials. Severe diarrhea was reported in 2% of LINZESS-treated patients. The incidence of diarrhea was similar in the IBS-C and CIC populations.
• Patients should be instructed to stop LINZESS if severe diarrhea occurs and to contact their healthcare provider. The healthcare provider should consider dose suspension and rehydration.

Adverse Reactions

• In IBS-C clinical trials, the most common adverse reactions in LINZESS-treated patients (incidence =2% and greater than placebo) were 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 clinical trials, the most common adverse reactions in LINZESS-treated patients (incidence =2% and greater than placebo) were 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%).

Please see full Prescribing Information including Boxed Warning: http://www.frx.com/pi/linzess_pi.pdf.

About Opioid-Induced Constipation

Opioids are a commonly prescribed class of pain medications that may reduce fluids and movement within the intestine, resulting in constipation. It is estimated that more than 8 million people in the United States suffer from opioid-induced constipation (OIC). Symptoms of OIC may include reduced bowel movement frequency, straining, incomplete evacuation and a sensation of bowel obstruction.

About Ironwood Pharmaceuticals

Ironwood Pharmaceuticals (NASDAQ: IRWD) is focused on creating medicines that make a difference for patients, building value to earn the continued support of our fellow shareholders, and empowering our team to passionately pursue excellence. We discovered, developed and are commercializing linaclotide, which is approved in the United States and a number of other countries. Our pipeline priorities include exploring further opportunities for linaclotide, as well as leveraging our therapeutic expertise in gastrointestinal disorders and our pharmacologic expertise in guanylate cyclases to address patient needs across the upper and lower gastrointestinal tract. Ironwood was founded in 1998 and is headquartered in Cambridge, Mass. Connect with us at www.ironwoodpharma.com or on Twitter at www.twitter.com/ironwoodpharma; information that may be important to investors will be routinely posted in both these locations.

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 top-line data from the Phase II clinical trial of linaclotide in adults with OIC and the plans for further analysis; the design of the Phase II trial and its impact on the results thereof; the development plans for linaclotide in OIC, including decisions regarding advancement and the drivers and timing thereof; Ironwood’s plans for continued innovation with linaclotide, including the linaclotide colonic release Phase IIb trial in IBS-C and the timing of data from such trial; and OIC symptoms and the causes of such symptoms, as well as prevalence and unmet need. 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, but are not limited to, the risk that Ironwood and Allergan are unable to effectively or timely execute on a development plan for linaclotide in OIC; the risk that unfavorable findings may arise from new clinical data or additional analyses of existing clinical data; the risks related to the development of our pipeline of GC-C agonists, including efficacy, safety and tolerability; the risk that we are unable to complete the Phase IIb clinical trial for linaclotide colonic release in IBS-C on the same timeline as we currently anticipate or that the data from such clinical trial are not available when we currently anticipate them or do not demonstrate the results we expect; the risk that the OIC patient population is not as presently estimated or that there is insufficient commercial opportunity; and those risks related to competition and future business decisions made by Ironwood, Allergan and their competitors or potential competitors. Applicable risks also include those that are listed under the heading "Risk Factors" and elsewhere in Ironwood's Quarterly Report on Form 10-Q for the quarter ended September 30, 2015, in addition to the risk factors that are listed from time to time in Ironwood's Annual Reports on Form 10-K, Quarterly Reports on Form 10-Q and any other subsequent SEC filings. Ironwood undertakes no obligation to update these forward-looking statements to reflect events or circumstances occurring after this press release. Except as otherwise noted, these forward-looking statements speak only as of the date of this press release. All forward-looking statements are qualified in their entirety by this cautionary statement.