AstraZeneca Pharmaceuticals Co., Ltd. and Ironwood Pharmaceuticals, Inc. announced that top-line data demonstrate linaclotide met all primary and secondary endpoints, covering multiple abdominal and constipation symptoms, in a phase III clinical trial of adults with irritable bowel syndrome with constipation (IBS-C).
The trial was conducted primarily in China and the companies intend to file in early 2016 for China Food and Drug Administration (CFDA) approval to market linaclotide. Linaclotide is currently approved in the United States for the treatment of adults with IBS-C or chronic idiopathic constipation (CIC) and in a number of other countries for adults with IBS-C.
“If approved by the CFDA, linaclotide would be the first prescription treatment in China specifically for both male and female adults with IBS-C, which is estimated to affect at least 13 million men and women in this country,” said Leon Wang, president of AstraZeneca China and Hong Kong. “The successful completion of this phase III clinical trial confirms our belief that linaclotide may be able to help millions of these patients suffering from abdominal pain, bloating and multiple other abdominal and constipation symptoms associated with IBS-C.”
“Linaclotide has now met all primary and secondary endpoints in all six of its phase III/IIIb trials. The efficacy and safety results seen in this phase III trial are consistent with the results of previous linaclotide pivotal studies in adults with IBS-C and with our experience in clinical practice, where nearly 700,000 unique IBS-C and CIC patients in the US have filled more than 2.7 million linaclotide prescriptions since launch,” said Mark Currie, Ph.D., chief scientific officer and president of research and development at Ironwood.
“We are making progress toward our goal of bringing linaclotide to appropriate patients around the world, and we continue to innovate with our development and investigation of additional linaclotide indications and formulations intended to address a broad spectrum of patient needs.”
Top-line data from the phase III trial indicate linaclotide-treated patients showed statistically significant improvement compared to placebo-treated patients for both co-primary endpoints. 60 per cent of linaclotide-treated patients were Abdominal Pain/Discomfort Responders, compared to 48.8 per cent of placebo-treated patients (p=0.001). 31.7 per cent of linaclotide-treated patients were IBS Degree of Relief Responders, compared to 15.4 per cent of placebo-treated patients (p<0.0001). Linaclotide-treated patients reported greater improvements in abdominal pain than placebo-treated patients: these effects were evident in the first week of treatment and continued to improve throughout the treatment period, with the greatest decreases in abdominal pain seen at week 12 of treatment (44 per cent decrease for linaclotide compared to 34 per cent decrease for placebo).
Statistically significant improvements were achieved in all pre-specified secondary endpoints in this trial, including abdominal pain, abdominal discomfort, bloating, straining, frequency of complete spontaneous bowel movements, frequency of spontaneous bowel movements and stool consistency.
The most common adverse event reported in linaclotide-treated patients was diarrhea (9.4 per cent for linaclotide vs. 1.2 per cent for placebo). Overall rates of discontinuation due to adverse events were 1.7 per cent for linaclotide vs. 1.4 per cent for placebo, while discontinuation due to diarrhea was 0.7 per cent for linaclotide vs. 0.2 per cent for placebo.
The randomized, double-blind, placebo-controlled phase III clinical trial randomized 839 adults with IBS-C in China, Australia, Canada, New Zealand and the United States. Patients were randomized 1:1 to receive either 290 mcg of linaclotide, or placebo, for 12 weeks. The co-primary endpoints of the trial were (i) 12-week Abdominal Pain/Discomfort Responder, which is defined as a patient who has at least a 30 per cent improvement in his/her abdominal pain or abdominal discomfort level for at least half of the weeks in the 12-week treatment period, and (ii) 12-Week IBS Degree of Relief Responder, which is defined as a patient who rates their IBS symptoms as being "considerably relieved" or "completely relieved" for at least half of the weeks in the 12-week treatment period. The primary endpoints used in this trial were similar to those previously used to support approval of linaclotide in the European Union. For comparison, results were also significant (33.7 per cent for linaclotide-treated patients versus 17.4 per cent for placebo-treated patients, nominal p<0.0001) analysing the data from this trial according to the endpoint from the FDA guidance on IBS (patients reporting at least a 30 per cent reduction from baseline in abdominal pain and an increase of at least one complete spontaneous bowel movement from baseline, all in the same week for at least 6 out of 12 weeks).
Full results from the trial are expected to be submitted for presentation at an upcoming medical congress.
AstraZeneca and Ironwood are jointly responsible for the development and commercialisation of linaclotide in China, with AstraZeneca primarily responsible for local operational execution. Under the terms of the collaboration, AstraZeneca made an upfront payment of $25 million to Ironwood, and the two companies will share the net profits and losses associated with linaclotide in China, with AstraZeneca carrying 55 per cent of each until a certain specified milestone is achieved, moving to a 50/50 split thereafter. Ironwood is also eligible for $125 million in additional commercial milestone payments from AstraZeneca contingent on the achievement of certain sales targets.
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 Actavis in the United States as Linzess and is indicated for the treatment of adults with IBS-C or chronic idiopathic constipation (CIC), with nearly 700,000 unique patients in the US having filled more than 2.7 million linaclotide prescriptions since launch, according to IMS Health.
Linaclotide is marketed by Almirall, S.A. for the treatment of adults with moderate to severe IBS-C in Europe under the brand name Constella. Ironwood also has partnered with Astellas Pharma Inc. for development and commercialisation of linaclotide in Japan and with AstraZeneca for development and commercialisation in China.
AstraZeneca is a global, innovation-driven biopharmaceutical business that focuses on the discovery, development and commercialisation of prescription medicines, primarily for the treatment of cardiovascular, metabolic, respiratory, inflammation, autoimmune, oncology, infection and neuroscience diseases.
Ironwood Pharmaceuticals is focused on creating medicines that make a difference for patients, building value to earn the continued support of our fellow shareholders, and empowering our team to passionately pursue excellence.