Ironwood Pharmaceuticals, Inc., a commercial biotechnology company, announced that its partner, Astellas Pharma Inc., secured marketing approval from the Japanese Ministry of Health, Labor and Welfare for Linzess as the first prescription treatment for adults with irritable bowel syndrome with constipation (IBS-C) in Japan. Ironwood anticipates that Astellas will launch the drug in the first half of 2017.

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

“Today’s regulatory approval of Linzess in Japan by our partner Astellas represents important progress toward Ironwood’s goal of bringing innovative medicines to appropriate patients around the world,” said Mark Currie, Ph.D., chief scientific officer and president of research and development at Ironwood. “In Japan, nearly three percent of adults are estimated to suffer from IBS-C. Today’s news is particularly significant for these patients who, until now, did not have a prescription medicine approved to treat the recurring symptoms associated with IBS-C.”

Data from the phase III trial in Japan indicate that patients treated with 500 mcg of linaclotide showed statistically significant improvement compared to placebo-treated patients for both co-primary endpoints. Regarding the first primary endpoint, 34% of linaclotide-treated patients were Global Assessment of Relief of IBS Symptoms Responders, compared to 18% of placebo-treated patients (p<0.001). Regarding the second primary endpoint, 35% of linaclotide-treated patients were Complete Spontaneous Bowel Movement (CSBM) Overall Responders, compared to 19% 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. Diarrhoea rates in this trial were 9.6% for linaclotide vs. 0.4% for placebo; all cases of diarrhea were characterized as mild or moderate in severity. The discontinuation rate for diarrhea in the linaclotide 500 mcg group was 1.6% vs. 0% for placebo.

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-C 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 included an additional 40-week, open-label follow-on study period.

Ironwood and Astellas entered into a licensing agreement in 2009 to develop and commercialize linaclotide in Japan for the treatment of IBS-C, chronic constipation and other gastrointestinal conditions. Per the agreement, Astellas paid Ironwood a $30 million upfront licensing fee, a $15 million development milestone payment upon enrollment of the first patient in the Phase III IBS-C trial, and a $15 million milestone payment upon the IBS-C new drug application submission. The agreement also includes an additional $15 million milestone payment for Ironwood as a result of today’s approval of linaclotide by the Japanese regulatory authority, and provides for Ironwood to receive royalties, which escalate based on sales volume. Additionally, a Phase III trial of linaclotide in patients with chronic constipation is ongoing in Japan, with top-line data expected in 2017.

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 1 million unique patients in the United States having filled more than 5.5 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, 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.

Ironwood Pharmaceuticals is a commercial biotechnology company focused on creating medicines that make a difference for patients, building value for our fellow shareholders, and empowering our passionate team.