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Constella® (Linaclotide), The First Approved Prescription Therapy In A New Class Of Treatments For Adults With IBS-C, Is Now Available In Europe

Almirall, S.A. (ALM:MC) and Ironwood Pharmaceuticals, Inc. (NASDAQ: IRWD) announced the launch of Constella® (linaclotide 290mcg capsules once daily), the first approved prescription therapy in a new class of treatments for adults suffering from moderate to severe IBS-C[i], in Europe. Constella® is now available in Germany, the UK and Nordic countries and is expected to be launched in several other European countries in 2013.

Constella is the first and only product approved in the EU for the treatment of IBS-C in adults and has been demonstrated in clinical trials to improve abdominal pain – one of the hallmark symptoms of IBS-C, as well as to improve constipation-related symptoms. IBS is a functional, chronic and relapsing gastrointestinal disorder affecting over 10% of the European population, and it is estimated that one-third of IBS patients suffer from IBS-C[ii] with different degrees of severity. Symptoms associated with IBS-C include abdominal pain and/or discomfort, bloating and constipation.

“The availability of linaclotide is excellent news for the one-third of adult IBS patients that have constipation. The symptoms associated with the condition can negatively impact the lives of patients. A targeted prescription treatment specifically for IBS-C is extremely welcome – for both appropriate patients and physicians alike who can now better manage this unpleasant, chronic condition”, said Professor Eamonn Quigley, Gastroenterologist.

The IBS-C Diagnosis

The diagnosis and management of IBS-C can be frustrating for both patients and clinicians alike[iii]. 30% of gastrointestinal problems reported in general practice consultations are IBS[iv] but only 19% of patients are diagnosed during their first consultation[iv] with 56% of patients requiring up to five consultations before a diagnosis is made.

Adult patients with IBS-C have been shown to not only have a significantly lower level of health-related quality of life compared with healthy individuals, but also similar to patients with asthma, migraine, and other different disease states.[iii], [v], [vi]

Prior to the approval of Constella, IBS-C treatment options consisted mainly of therapies for individual symptoms such as antispasmodics or unlicensed antidepressants for pain and laxatives for constipation[iii].

“Thousands of adult patients are seeking help for IBS-C symptoms such as abdominal discomfort and constipation and, up until now, there was no specific prescription treatment available for their disease. Through the combined efforts of many people, we now have the ability to provide relief to many of these adult patients”, said Luciano Conde, Chief Operating Officer at Almirall. “This condition also causes significant distress and economic cost to patients and poses a considerable economic burden in Europe overall.[vii]”

“Bringing linaclotide to appropriate patients worldwide is an important aspect of Ironwood’s mission,” said Tom McCourt, Chief Commercial Officer at Ironwood. “Building on our strong initial launch of linaclotide in the U.S., we now hope to make a difference in the lives of adult European IBS-C patients suffering from this prevalent and very bothersome condition.”

The SMC Resolution

Also, yesterday, the Scottish Medicines Consortium (SMC) recommended Constella® for adult patients with moderate to severe IBS-C who have not responded adequately to or cannot tolerate other suitable treatment options. The SMC clinical experts highlighted an unmet need in this patient group and accepted the use of Constella® within NHS Scotland. Experts welcome “an additional symptomatic treatment for IBS-C in an area where there is a lack of documented, reliable and licensed treatment options”.

Constella® was approved in November 2012 by the European Commission, and it is under registration for regulatory approval in Switzerland.

About Constella® (linaclotide)[iv]

Linaclotide is a Guanylate Cyclase-C receptor agonist (GCCA) with visceral analgesic and secretory activities. Linaclotide is a 14-amino acid synthetic peptide structurally related to the endogenous guanylin peptide family. Both linaclotide and its active metabolite bind to the Guanylate Cyclase-C (GC-C) receptor, on the luminal surface of the intestinal epithelium. Through its action at GC-C, linaclotide has been shown to reduce visceral pain and increase GI transit in animal models and increase colonic transit in humans. Activation of GC-C results in an increase in concentrations of cyclic guanosine monophosphate (cGMP), both extracellularly and intracellularly. Extracellular cGMP decreases pain-fiber activity, resulting in reduced visceral pain in animal models. Intracellular cGMP causes secretion of chloride and bicarbonate into the intestinal lumen, through activation of the cystic fibrosis transmembrane conductance regulator (CFTR), which results in increased intestinal fluid and accelerated transit.

Linaclotide was discovered by scientists at Ironwood and is marketed in Europe by Almirall through a license agreement between the two companies. Constella® is a trademark owned by Ironwood Pharmaceuticals, Inc.

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 function and with features of disordered defecation[viii]. IBS-C is one of four clinically different subtypes of IBS. One-third of patients with IBS are thought to have IBS-C[ix] and suffer chronically from both abdominal pain and constipation. The Rome III Diagnostic Criteria for Functional Gastrointestinal Disorders includes criterion for the diagnosis of IBS[iii] 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 defecation
- onset associated with a change of frequency of stool
- onset associated with a change in form (or appearance) of stool”

The estimated prevalence of IBS over 10% of the European populationii. 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 there are minimal therapeutic options.[x]

Source

[i] Product information: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002490/WC500135622.pdf

[ii] 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.

[iii] Frank L, Kleinman L, Rentz A et al. Health-related quality of life associated with irritable bowel syndrome: comparison with other chronic diseases. Clin Ther 2002; 24(4):675-689

[iv] Thompson WG et al. Irritable bowel syndrome in general practice: prevalence, characteristics, and referral. Gut 2000;46:78-82

[v] Dibonaventura MD, Prior M, Prieto P et al. Burden of constipation-predominant irritable bowel syndrome (IBS-C) in France, Italy, and the United Kingdom. Clin Exp Gastroenterol 2012; 5:203-212 Jones J et al. British Society of Gastroenterology guidelines for the management of the irritable bowel syndrome. Gut 2000;47(Suppl II):ii1-19

[vi] Gralnek IM, Hays RD, Kilbourne A et al. The impact of irritable bowel syndrome on health-related quality of life. Gastroenterology 2000; 119(3):654-660

[vii] Digestive and Liver Disease 38 (2006) 717–723 – Review Article – Irritable bowel syndrome: The burden and unmet needs in Europe – E.M.M. Quigley et al.

[viii] Longstreth GF, Thompson WG, Chey WD et al. – Functional Bowel Disorders. Gastroenterology 2006; 130: 1480-1491

[ix] 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:S1-35

[x] Camilleri M, Chang L. – Challenges to the therapeutic pipeline for irritable bowel syndrome: end points and regulatory hurdles. Gastroenterology 2008;135:1877–1891

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