Astellas, Ironwood Japanese phase III trial of linaclotide to treat chronic constipation meets primary endpoint

Linaclotide is approved in Japan as the first prescription treatment for adults with irritable bowel syndrome with constipation (IBS-C). Linaclotide is currently approved in the United States for the treatment of adults with IBS-C or chronic idiopathic constipation (CIC). It is also approved for adults with IBS-C or CIC in more than 30 other countries. Patients in the phase III CC trial in Japan continue to receive open-label linaclotide for an additional 52 weeks; the blinded efficacy data coupled with these open-label safety data are expected to form the basis for regulatory review and potential approval for this indication in Japan.

“I am really pleased to receive the positive top-line results from the phase III chronic constipation trial. If approved, Astellas expects linaclotide to provide a new therapeutic option for patients suffering from this condition, in addition to IBS-C, for which linaclotide has already obtained marketing approval in Japan,” said Bernhardt G. Zeiher, M.D., President, Development at Astellas Group.

“Today’s positive phase III results for linaclotide in chronic constipation mark the ninth phase III/IIIb clinical trial in which linaclotide has met its primary endpoints, once again demonstrating consistent results in clinical trials across two indications, evaluating multiple doses and conducted in multiple countries,” said Mark Currie, chief scientific officer and president of R&D at Ironwood. “We look forward to working with Astellas to support the launch of linaclotide in Japan for adults with IBS-C and to advance it for CC.”

The double-blind, placebo-controlled phase III clinical trial randomized 186 adults with CC in Japan to receive either 500 mcg of linaclotide or placebo for 4 weeks (1:1 ratio). The top-line trial results indicate that linaclotide-treated patients showed statistically significant improvement compared to placebo-treated patients for the primary endpoint, change from baseline in mean spontaneous bowel movement frequency at Week 1. The most common adverse event reported in this trial was diarrhoea. All cases of diarrhoea were characterized as mild or moderate in severity.

Further detailed results from the phase III trial are expected to be presented at an upcoming scientific meeting.

Linaclotide is a guanylate cyclase-C (GC-C) agonist that is structurally related to the naturally occurring peptides, guanylin and uroguanylin. Linaclotide 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 plc 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), with nearly 1.5 million unique patients in the United States having filled nearly 7 million linaclotide prescriptions since launch, according to IMS Health. Linaclotide is marketed by Allergan for the treatment of adults with moderate to severe IBS-C in Europe under the brand name Constella, and Ironwood’s partner Astellas received approval of linaclotide in Japan under the brand name Linzess for the treatment of adults with IBS-C. Ironwood also has partnered with AstraZeneca for development and commercialization of linaclotide in China, Hong Kong and Macau.

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