Astellas Pharma Inc. and Ironwood Pharmaceuticals, Inc. announced that the phase III clinical trial of linaclotide conducted in Japan in adults with irritable bowel syndrome with constipation (IBS-C) met its primary endpoints. Astellas expects to submit a new drug application to the Ministry of Health, Labor and Welfare in Japan in 2016.

Linaclotide is a guanylate cyclase-C (GC-C) agonist currently approved in the United States for the treatment of adults with IBS-C and chronic idiopathic constipation (CIC). It is also approved for adults with IBS-C or CIC in more than 30 other countries.

“I am really pleased to receive the positive top-line data from the phase III IBS-C trial. Astellas expects linaclotide to provide a new therapeutic option for patients suffering from IBS-C,” said Bernhardt G. Zeiher, M.D., president, development at Astellas Group.

“Linaclotide has now met all primary endpoints in all eight of its Phase III/IIIb clinical trials, spanning two indications, three doses and multiple countries,” said Mark Currie, Ph.D., chief scientific officer and president of research and development at Ironwood.

“Our recent positive phase III data in China and now in Japan represent important achievements by Ironwood and our global partners toward bringing linaclotide to appropriate patients around the world, and we continue to innovate with linaclotide as part of our mission to address a broad spectrum of patient needs.”

Top-line data from the phase III trial in Japan indicate linaclotide-treated patients showed statistically significant improvement compared to placebo-treated patients for both of the two co-primary endpoints. Regarding the first primary endpoint, 34 per cent of linaclotide-treated patients were Global Assessment of Relief of IBS Symptoms Responders, compared to 18 per cent of placebo-treated patients (p<0.001). Regarding the second primary endpoint, 35 per cent of linaclotide-treated patients were Complete Spontaneous Bowel Movement (CSBM) Overall Responders, compared to 19 per cent of placebo-treated patients (p<0.001). Additionally, improvements were achieved in pre-specified secondary endpoints in this trial covering abdominal and constipation symptoms, including bloating and abdominal pain/discomfort. Diarrhea rates in this trial were 9.6 per cent for linaclotide vs. 0.4 per cent for placebo; all cases were characterized as mild or moderate in severity.

The double-blind, placebo-controlled phase III clinical trial randomized 500 adults with IBS-C in Japan. Patients were randomized 1:1 to receive either 500 mcg of linaclotide or placebo for 12 weeks. The co-primary endpoints of the trial were (i) Global Assessment of Relief of IBS Symptoms Responder Rate, in which patients rated their improvement in IBS symptoms over each week compared to the baseline period and achieved significant or moderate relief for at least six out of 12 weeks, and (ii) CSBM Overall Responder Rate, in which patients reported experiencing at least three CSBMs per week and an increase of at least one CSBM from baseline in the same week, and achieved both of these measures for at least six out of 12 weeks. The trial also includes an additional 40-week, open-label follow-on study period, which is ongoing.

It is estimated that 2.9 per cent of adults in Japan suffer from IBS-C, and there are no prescription products currently approved in Japan for the treatment of this condition. Ironwood and Astellas entered into a licensing agreement in 2009 to develop and commercialise linaclotide in Japan.

Linaclotide is a guanylate cyclase-C (GC-C) agonist that 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 more than 825,000 unique patients in the U.S. having filled more than 3.5 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. Ironwood also has partnered with Astellas for development and commercialisation of linaclotide in Japan and with AstraZeneca for development and commercialisation in China.