Ironwood Pharmaceuticals and its U.S. partner, Forest Laboratories, and European partner, Almirall, separately reported positive top-line results from the first of two pivotal trials evaluating linaclotide in patients with irritable bowel syndrome with constipation (IBS-C). Initial data from a second Phase III trial in IBS-C patients is expected during the fourth quarter of 2010, and submission of an NDA to FDA is planned for mid-2011. Ironwood and Almirall say a European filing date will be determined once data from the second Phase III IBS-C trial is available. Positive data from two Phase III trials of linaclotide in chronic constipation patients has previously been reported.
The placebo-controlled LIN-MD-31 trial included 803 patients in the U.S. who met clinical criteria for IBS-C. The results reported by Ironwood and Forest showed that compared with placebo, linaclotide treatment more than doubled the proportion of patients who had a 30% reduction in abdominal pain and at least three complete spontaneous bowel movements per week, for at least 9 of the 12 weeks of study. There were also statistically significantly improvements in all secondary endpoints. The trial results from the study conducted by Ironwood and Forest will also be used to support regulatory submission in the U.S.
The LIN-MD-31 study data reported by Almirall confirmed that the two co-primary endpoints required by the European Medicines Agency were met, demonstrating that linaclotide therapy led to statistically significant and clinically relevant improvements in terms of abdominal pain/abdominal discomfort and degree of IBS. Significant improvements were also achieved for all prespecified main secondary endpoints (stool frequency, stool consistency, straining, and bloating), Almirall adds.
Linaclotide is Ironwood's lead compound; it acts as an agonist of the guanylate cyclase type-C (GC-C) receptor found on the intestinal lining. The firm claims activation of GC-C increases intracellular and extracellular cGMP, which preclinical models have shown leads to inhibition of afferent nerve firing and reduced abdominal pain, along with activation of anion channels to stimulate anion/fluid movement into the intestine and accelerate intestinal transit.
Ironwood and Forest have a 50/50 partnership to co-develop and co-market linaclotide in the U.S. Ironwood separately out-licensed the drug to Almirall for European development and commercialization, and to Astellas Pharma for development and commercialization in Japan and other Asian countries. Ironwood retains exclusive rights to linaclotide in other territories.