# FDA approves Linzess to treat certain cases of irritable bowel syndrome and constipation



## Jeffrey Roberts (Apr 15, 1987)

*FDA NEWS RELEASE*For Immediate Release: Aug. 30, 2012Media Inquiries: Stephanie Yao, 301-796-0394, [email protected] Consumer Inquiries: 888-INFO-FDA*FDA approves Linzess to treat certain cases of irritable bowel syndrome and constipation*The U.S. Food and Drug Administration today approved Linzess (linaclotide) to treat chronic idiopathic constipation and to treat irritable bowel syndrome with constipation (IBS-C) in adults. According to the National Institutes of Health, an estimated 63 million people are affected by chronic constipation. Chronic idiopathic constipation is a diagnosis given to those who experience persistent constipation and do not respond to standard treatment. Additionally, an estimated 15.3 million people are affected by IBS. IBS-C is a subtype characterized mainly by abdominal pain and by hard or lumpy stools at least 25 percent of the time and loose or watery stools less than 25 percent of the time.Linzess is a capsule taken once daily on an empty stomach, at least 30 minutes before the first meal of the day. Linzess helps relieve constipation by helping bowel movements occur more often. In IBS-C, it may also help ease abdominal pain."No one medication works for all patients suffering from these gastrointestinal disorders," said Victoria Kusiak, M.D., deputy director of the Office of Drug Evaluation III in FDA's Center for Drug Evaluation and Research. "With the availability of new therapies, patients and their doctors can select the most appropriate treatment for their condition."The safety and effectiveness of Linzess for the management of IBS-C were established in two, double-blind studies. A total of 1,604 patients were randomly assigned to take 290 micrograms of Linzess or a placebo for at least 12 weeks. Results showed Linzess was more effective in reducing the amount of abdominal pain and increasing the number of complete spontaneous bowel movements compared with placebo.The safety and effectiveness of Linzess for the management of chronic idiopathic constipation also were established in two, double-blind studies. A total of 1,272 patients were randomly assigned to take Linzess at doses of 145 mcg or 290 mcg or a placebo for 12 weeks. Results from these studies showed patients taking Linzess experienced more complete spontaneous bowel movements than those taking the placebo. The 290 mcg dose is not approved for chronic constipation because studies indicated it was no more effective than the 145 mcg dose.Linzess is approved with a Boxed Warning to alert patients and health care professionals that the drug should not be used in patients 17 years of age and younger. The most common side effect reported in during the clinical studies was diarrhea.Linzess is co-marketed by Ironwood Pharmaceuticals Inc., based in Cambridge, Mass., and Forest Pharmaceuticals Inc., based in St. Louis, Mo.For more information:FDA: Questions and AnswersFDA: Drug Innovation NIH: Constipation NIH: Irritable Bowel SyndromeThe FDA, an agency within the U.S. Department of Health and Human Services, protects the public health by assuring the safety, effectiveness, and security of human and veterinary drugs, vaccines and other biological products for human use, and medical devices. The agency also is responsible for the safety and security of our nation's food supply, cosmetics, dietary supplements, products that give off electronic radiation, and for regulating tobacco products.FDA Press Announcement: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm317505.htm


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## Jeffrey Roberts (Apr 15, 1987)

Ironwood Pharmaceuticals Inc. and Forest Laboratories Inc. news release:http://www.ironwoodpharma.com/newsPDF/08.30.12%20LINZESS%20Approval%20FINAL.pdf


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## Jeffrey Roberts (Apr 15, 1987)

Almirall, S.A. (ALM:MC) and Ironwood Pharmaceuticals, Inc. (NASDAQ: IRWD) announced today that the European Committee for Medicinal Products for Human Use (CHMP) has issued a positive opinion recommending the marketing approval for Constella® (linaclotide 290 micrograms), for the symptomatic treatment of moderate to severe irritable bowel syndrome with constipation (IBS-C) in adults.The CHMP positive opinion is a recommendation to the European Commission (EC) and one of the final steps in the review of a marketing authorization application. The EC usually follows the recommendations of the CHMP. Once approved, it will be marketed under the brand name Constella®.“Patients with IBS-C suffer from several very uncomfortable gastrointestinal symptoms for which there are currently very few available therapies”, said Bertil Lindmark, Chief Scientific Officer at Almirall. “With linaclotide physicians will have one of the first specifically designed therapies with proven efficacy and tolerability over time. Therefore, we are very pleased at Almirall with this first IBS-C treatment recommended for approval by CHMP and are confident in linaclotide’s benefits”.This positive recommendation is based on the efficacy and safety of linaclotide evaluated in two double-blind, placebo-controlled Phase III clinical studies. The clinical trials involved approximately 1,600 adult patients, of which more than 800 were treated with linaclotide 290 mcg. In both trials, treatment with linaclotide resulted in statistically significant improvements in both abdominal pain/discomfort and degree of relief of IBS-C symptoms (co-primary endpoints), as well as complete spontaneous bowel movement frequency, stool consistency and severity of straining and bloating (secondary endpoints). These improvements were maintained over the entire treatment period (12 and 26 weeks). The incidence of adverse events was similar in both studies, with diarrhoea being the most common adverse event in linaclotide-treated patientsi, ii.“This positive opinion is a significant step toward helping these highly symptomatic adult patients; many of whom are searching for new treatment options,” said Mark Currie, PhD, Senior Vice President, R&D and Chief Scientific Officer of Ironwood. “The discovery of linaclotide by Ironwood scientists and the work we have done to reach patients in Europe with our partner, Almirall, has been a collaborative effort with the goal of helping this underserved patient population.”Almirall holds exclusive marketing rights for linaclotide in Europe.About linaclotide (Constella®)Linaclotide is a guanylate cyclase-C agonist (GCCA) that is provided as an oral capsule intended for once-daily administration for the treatment of irritable bowel syndrome with constipation.It binds to guanylate cyclase C locally in the intestine, with no measurable blood plasma concentrations, resulting in an increase in both intracellular and extracellular concentrations of cyclic guanosine monophosphate (cGMP). Elevations in intracellular cGMP are believed to stimulate secretion of intestinal fluid and accelerate gastrointestinal transit resulting in increased frequency of bowel movements. Elevations in extracellular cGMP are believed to decrease activity of pain-sensing nerves, which is thought to be responsible for a reduction in intestinal pain, according to nonclinical models.Constella® is a trademark owned by Ironwood Pharmaceuticals, Inc. and its use in Europe is pending marketing approval from the European Commission.About Irritable Bowel Syndrome with Constipation (IBS-C)IBS is defined as a functional bowel disorder in which abdominal pain or discomfort is associated with defecation or a change in bowel habit and with features of disordered defecation.iii IBS-C is one of four clinically different subtypes of IBS. One-third of patients with IBS are thought to have IBS-Civ and suffer chronically from both abdominal pain and constipation.The Rome III Diagnostic Criteria for Functional Gastrointestinal Disorders includes criterion for the diagnosis of IBSiii as:Recurrent abdominal pain or discomfort at least three days/month, in the last three months with symptom onset at least 6 months prior to diagnosis, associated with two or more of the following:improvement with defecationonset associated with a change of frequency of stoolonset associated with a change in form (or appearance) of stoolThe estimated prevalence of IBS at 10-15% of the European population puts it in line with conditions such as migraine (12%) and asthma (11%).v IBS can have a negative impact on daily living with considerable socio-economic and psychological consequences, and represents a major proportion of gastrointestinal workload in both primary and secondary care. Due to the complex, multimodal nature of the condition there is no cure for IBS and minimal therapeutic options.viAbout AlmirallAlmirall is an international pharmaceutical company based on innovation and committed to health. Headquartered in Barcelona, it researches, develops, manufactures and commercialises its own R&D and licensed drugs with the aim of improving people’s health and wellbeing. Almirall focuses its research resources on respiratory, gastrointestinal, dermatology and pain. Almirall’s products are currently present in over 70 countries in the five continents. With the opening of the Canadian affiliate, Almirall has now direct presence in Europe, Mexico and Canada through 13 affiliates. For further information please visit: www.almirall.comAbout Ironwood PharmaceuticalsIronwood Pharmaceuticals (NASDAQ: IRWD) is an entrepreneurial pharmaceutical company dedicated to the art and science of great drugmaking. Ironwood is located in Cambridge, Mass. To learn more, visit www.ironwoodpharma.com.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, the anticipated approval for marketing authorization by the European Medicines Agency (EMA), the potential indication and patient population for linaclotide and the anticipated brand name 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 the risks that the EMA does not grant marketing authorization for linaclotide, the EMA does not approve the brand name Constella®, serious adverse events arise in patients that are deemed to be definitely or probably related to linaclotide treatment, and the incidence or severity of diarrhea in patients treated with linaclotide is higher than expected, as well as risks related to the difficulty of predicting regulatory approvals. Applicable risks also include those that are listed in Ironwood Pharmaceuticals’ Quarterly Report on Form 10‐Q for the quarter ended June 30, 2012, in addition to the risk factors that are listed from time to time in Ironwood Pharmaceuticals’ Annual Reports on Form 10‐K, Quarterly Reports on Form 10‐Q and any subsequent SEC filings. We undertake no obligation to update these forward‐looking statements to reflect events or circumstances occurring after this press release. 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.Referencesi E.M. Quigley, A.J. Lembo, C. Diaz, et al. Significant improvements in abdominal pain and bowel symptoms in a phase 3 trial of linaclotide in patients with irritable bowel syndrome with constipation (IBS-c): A european perspective. Gut 2011; 60 (Suppl 3) A80.ii A.J. Lembo, J. Fortea, C. Diaz, et al. 26-Week Efficacy and safety of once-daily oral linaclotide in patients with irritable bowel syndrome with constipation: a european perspective. Gut 2011; 60 (Suppl 3) A41.iii Longstreth GF, Thompson WG, Chey WD et al. - Functional Bowel Disorders. Gastroenterology 2006; 130: 1480-1491iv American College of Gastroenterology Task Force on Irritable Bowel Syndrome. An evidence-based position statement on the management of irritable bowel syndrome. Am J Gastroenterol 2009; 104 Suppl 1:S1-35v P. S. Hungin et al - The prevalence, patterns and impact of irritable bowel syndrome: an international survey of 40,000 subjects - Aliment Pharmacol Ther 2003; 17: 643–650.vi Camilleri M, Chang L. - Challenges to the therapeutic pipeline for irritable bowel syndrome: end points and regulatory hurdles. Gastroenterology 2008;135:1877–1891Contacts: Almirall, S.A.Media enquiries:Bianca Daneshfar-Nia , +44 20 7611 [email protected] Molina, +34 93 [email protected] Pharmaceuticals, Inc.Media Relations:Lisa Buffington, [email protected] Relations:Meredith Kaya, [email protected]


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