Ironwood Pharmaceuticals, Inc. announced that its European partner Almirall, SA submitted a Marketing Authorization Application (MAA) to the European Medicines Agency (EMA) for linaclotide, a guanylate cyclase type-C (GC-C) agonist, for the treatment of irritable bowel syndrome with constipation (IBS-C).

The submission includes efficacy and safety data from a phase III programme comprising two double-blind placebo-controlled trials measured against the endpoints required by the EMA and two open-label long term safety studies. A total of more than 1,600 patients with IBS-C received a once-daily dose of either linaclotide or placebo across the two phase III clinical trials. In these trials, statistically significant improvements in abdominal and bowel symptoms were achieved for linaclotide-treated patients versus placebo-treated patients for the co-primary and secondary endpoints.

Safety data collected across the two phase III IBS-C clinical trials demonstrated that diarrhoea was the most commonly reported adverse event and led to study discontinuation in 5 per cent of linaclotide treated patients compared to fewer than 1 percent of patients receiving placebo. Additionally, over 3,200 patients have enrolled in ongoing open-label safety studies and more than 2,000 of those patients have received linaclotide for at least 12 months.

The trials were designed to support regulatory submissions for linaclotide in both Europe and the US. In August 2011, Ironwood and its U.S. partner Forest Laboratories, Inc. submitted a New Drug Application (NDA) for linaclotide to the US Food and Drug Administration (US FDA).

Linaclotide, an investigational drug, is an agonist of the guanylate cyclase type-C (GC-C) receptor located on the luminal surface of the intestine. In preclinical models, linaclotide reduced visceral hypersensitivity, increased fluid secretion, and accelerated intestinal transit. The effects on secretion and transit are mediated through cyclic guanosine monophosphate (cGMP), which is also believed to modulate the activity of local nerves to reduce pain.

Linaclotide is an orally delivered peptide that acts locally in the gut with no measurable systemic exposure at therapeutic doses and is intended for once-daily administration. An issued composition of matter patent for linaclotide provides protection in Europe to 2024. Ironwood and Forest plan to co-promote linaclotide in the United States. Ironwood has out-licensed linaclotide to Almirall, S.A. for European development and commercialization, and to Astellas Pharma Inc. for development and commercialization in Japan, Indonesia, Korea, the Philippines, Taiwan, and Thailand.

IBS-C is a chronic functional gastrointestinal disorder characterized by abdominal pain, abdominal discomfort, and bloating associated with altered bowel habits, and as much as 4 percent of the European population suffers from it. IBS-C can have an impact on daily living. There are currently few available therapies to treat this disorder.

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