Two Naldemedine Phase III Studies Show Consistent Improvement Of Opioid-Induced Constipation

OSAKA, Japan and FLORHAM PARK, N.J., May 23, 2016 /PRNewswire/ -- Shionogi today announced positive results from two identically-designed 12 week phase III studies (COMPOSE I and II) demonstrating consistent efficacy and safety of naldemedine in treating opioid-induced constipation (OIC) in patients with chronic non-cancer pain. The data being presented today during the American Gastroenterological Association Presidential Plenary Session at the 2016 Digestive Disease Week (DDW) in San Diego, CA, also showed that naldemedine had a low incidence of gastrointestinal side effects, and did not impact the analgesic effect of opioids.

Naldemedine is an investigational, once-daily, oral, peripherally-acting mu-opioid receptor antagonist (PAMORA) being studied for the treatment of OIC in adult patients with chronic non-cancer pain. COMPOSE I and COMPOSE II found that, for the primary endpoint*, 47.6 percent and 52.5 percent of patients taking 0.2 mg tablet of naldemedine experienced improvements in the frequency of spontaneous bowel movements (SBMs) for at least nine out of the 12 weeks, compared with 34.6 percent and 33.6 percent of patients on placebo, respectively. Additionally, naldemedine significantly improved all secondary endpoints in both studies, which included a significant increase in the frequency of complete SBMs per week and SBMs without straining per week from baseline to the last two weeks of the study, as compared to placebo.

"This research is good news for patients with OIC, given the significant impact this condition often has, and the difficulty many of them have in finding a safe and effective treatment," said study investigator Martin Hale, M.D., an orthopedic surgeon and pain management specialist who presented the research at DDW. "Many patients start and then stop OIC treatments in reaction to the side effects they experience, so it's particularly encouraging that naldemedine showed a low discontinuation rate among patients in these two studies."  

* The primary endpoint is based on a responder rate defined as nine positive response weeks or more out of the 12- week treatment period and three positive response weeks out of the last four weeks of the 12-week treatment period. A positive response week is defined as ≥ three SBMs/ week and an increase of ≥ one SBM/week from baseline within the same week.   

Abdominal pain and diarrhea were the only treatment-emergent adverse events reported in greater than five percent of patients in the naldemedine group compared to the placebo group. In COMPOSE I, 6.3 percent of patients on naldemedine reported abdominal pain vs. 1.8 percent on placebo; in COMPOSE II, it was 5.2 vs. 1.1 percent, respectively. Diarrhea was reported in 6.6 percent of patients on naldemedine vs. 2.9 percent on placebo in COMPOSE I; the rate was 8.9 vs. 1.8, respectively, in COMPOSE II.  

"The results of these two studies are very encouraging and increase potential treatment options for patients with OIC, an often debilitating condition," said Juan Camilo Arjona Ferreira, M.D., Senior Vice President Clinical Development at Shionogi Inc. "We're especially excited that naldemedine offers patients relief from OIC while showing a low incidence rate of gastrointestinal side effects."

About COMPOSE
The COMPOSE program is a global comprehensive development program comprised of seven clinical studies being conducted in patients with OIC and cancer or chronic non-cancer pain.  

COMPOSE I and II were 12-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group studies. Both studies were designed to evaluate the efficacy and safety of naldemedine therapy versus placebo in patients on opioid therapy for at least three months and on a stable dose of opioids for at least four weeks, and who experience chronic non-cancer pain accompanied by OIC. The sample population for COMPOSE I and II included 547 and 553 patients, respectively.

Shionogi previously announced that naldemedine met its primary and key secondary endpoints in COMPOSE I, II and IV.  COMPOSE IV was conducted in Japan.

In the studies, a bowel movement occurring within 24 hours after rescue laxative therapy was not considered an SBM.

About Opioid-Induced Constipation (OIC)
Opioid-induced constipation (OIC) is characterized by any of the following after initiating opioid therapy: reduced bowel movement frequency, development or worsening of straining to pass bowel movements, a sense of incomplete rectal evacuation, or harder stool consistency.¹ Approximately half of all chronic non-cancer pain patients who have OIC are dissatisfied with laxatives.² Managing OIC and its clinical consequences places a significant burden on the healthcare system and the patient.

About Shionogi
Shionogi & Co., Ltd., is a Japanese pharmaceutical company with a 138-year history discovering and developing innovative therapies. Shionogi Inc., the U.S. based subsidiary of Shionogi & Co., Ltd., continues this focus on the development and commercialization of high quality medicines that protect the health and well-being of the patients we serve. The company currently markets products in several therapeutic areas including women's health, anti-infectives, pain and cardiovascular diseases. Our pipeline is focused on infectious disease, pain, CNS, and oncology. For more details, visit www.shionogi.com. For more information on Shionogi & Co., Ltd., visit www.shionogi.co.jp/en

Forward Looking Statement
This announcement contains forward-looking statements. These statements are based on expectations in light of the information currently available, assumptions that are subject to risks and uncertainties which could cause actual results to differ materially from these statements. Risks and uncertainties include general domestic and international economic conditions such as general industry and market conditions, and changes of interest rate and currency exchange rate. These risks and uncertainties particularly apply with respect to product-related forward-looking statements. Product risks and uncertainties include, but are not limited to, completion and discontinuation of clinical trials; obtaining regulatory approvals; claims and concerns about product safety and efficacy; technological advances; adverse outcome of important litigation; domestic and foreign healthcare reforms and changes of laws and regulations. Also for existing products, there are manufacturing and marketing risks, which include, but are not limited to, inability to build production capacity to meet demand, unavailability of raw materials and entry of competitive products. The company disclaims any intention or obligation to update or revise any forward-looking statements whether as a result of new information, future events or otherwise.

¹ Camilleri. M, Drossman D.A., Becker G.,Webster L.R., Davies A.N., Mawe G.M. Emerging treatments in neurogastroenterology: a multidisciplinary working group consensus statement on opioid-induced constipation. Neurogastroenterology Motil. 2014. 26, 1386-1395.

² Pappagallo M. Incidence, Prevalence, and Management of Opioid Bowel Dysfunction. The American Journal of Surgery. 182 (Suppl to November 2001) 11s-18s.

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