Shionogi Announces Upcoming Presentations from Symproic® (naldemedine) Studies at PAINWeek® 2018 Annual Conference

Symproic is an oral tablet which functions as a peripherally acting mu-opioid receptor antagonist medication indicated in the U.S. for the treatment of opioid-induced constipation (OIC) in adult patients with chronic non-cancer pain, including patients with chronic pain related to prior cancer or its treatment who do not require frequent (e.g., weekly) opioid dosage escalation.

Shionogi will present two clinical posters, which are integrated analyses of the three pivotal Phase 3 studies that further demonstrated the safety and efficacy of Symproic for the treatment of OIC in adult patients with chronic non-cancer pain. Also presented at the conference will be pre-clinical data which demonstrated negligible brain penetration due to Symproic’s limited ability to cross the blood brain barrier. Additionally, there will be pre-clinical data that showed the effect of Symproic on gastrointestinal motility with minimal impact on the analgesic effect of opioids.

Presenters will be available at the PAINWeek Poster Session and Reception Thursday, September 6, at 6:30-8:30 p.m. PDT.

Pre-clinical data

• Poster #102: Mechanisms Contributing to the Low Brain Distribution of Naldemedine, a Peripherally Acting µ-Opioid Receptor Antagonist

Presenter: Ryosuke Watari

• Poster #119: Effects of Naldemedine, a Peripherally-Acting µ-Opioid Receptor Antagonist, in Rat Models of Opioid-Induced Constipation
  Presenter: Eric Krauter

Clinical data

• Poster #34: Effects of Naldemedine on Frequency of Spontaneous Bowel Movements and Associated Symptoms

Presenter: Martin Hale

• Poster #75: Safety of Naldemedine for the Treatment of Opioid-Induced Constipation in Subjects with Chronic Non-Cancer Pain Receiving Opioid Therapy: Results of Three Global Phase 3 Clinical Trials
  Presenter: Lynn Webster

About Opioid-Induced Constipation (OIC)

Constipation is one of the most commonly reported side effects associated with opioid treatment, including among patients with chronic non-cancer pain.¹ OIC is a result of increased fluid absorption and reduced GI motility due to mu opioid receptor binding in the GI tract. OIC is defined as a change in bowel habits that 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.² In patients receiving opioid therapy for chronic non-cancer pain, the prevalence of OIC ranges from approximately 40-50 percent.^3-6

About Symproic

Symproic^® (naldemedine) is indicated for the treatment of OIC in adult patients with chronic non-cancer pain, including patients with chronic pain related to prior cancer or its treatment who do not require frequent (e.g., weekly) opioid dosage escalation. Symproic^® was made available to patients in the US in October 2017.

Please see Important Safety Information, including Warnings & Precautions, and Adverse Reactions below.

IMPORTANT SAFETY INFORMATION

CONTRAINDICATIONS

Patients with known or suspected gastrointestinal (GI) obstruction and patients at increased risk of recurrent obstruction, due to the potential for GI perforation.

Patients with a history of a hypersensitivity reaction to Symproic. Reactions have included bronchospasm and rash.

WARNINGS AND PRECAUTIONS

Cases of GI perforation have been reported with use of another peripherally acting opioid antagonist in patients with conditions that may be associated with localized or diffuse reduction of structural integrity in the wall of the GI tract. Monitor for the development of severe, persistent, or worsening abdominal pain; discontinue if this symptom develops.

Symptoms consistent with opioid withdrawal, including hyperhidrosis, chills, increased lacrimation, hot flush/flushing, pyrexia, sneezing, feeling cold, abdominal pain, diarrhea, nausea, and vomiting have occurred in patients treated with Symproic.

Patients having disruptions to the blood-brain barrier may be at increased risk for opioid withdrawal or reduced analgesia. Take into account the overall risk-benefit profile when using Symproic in such patients. Monitor for symptoms of opioid withdrawal in such patients.

DRUG INTERACTIONS

Avoid use with strong CYP3A inducers (e.g., rifampin) because they may reduce the efficacy of Symproic.

Use with moderate (e.g., fluconazole) and strong (e.g., itraconazole) CYP3A inhibitors and P-glycoprotein inhibitors (e.g., cyclosporine) may increase Symproic concentrations. Monitor for potential adverse reactions.

Avoid use of Symproic with another opioid antagonist due to potential for additive effect and increased risk of opioid withdrawal.

USE IN SPECIFIC POPULATIONS

Symproic crosses the placenta and may precipitate opioid withdrawal in a fetus due to the immature fetal blood-brain barrier. Symproic should be used during pregnancy only if the potential benefit justifies the potential risk. Because of the potential for serious adverse reactions, including opioid withdrawal in breastfed infants, a decision should be made to discontinue breastfeeding or discontinue the drug, taking into account the importance of the drug to the mother.

Avoid use in patients with severe hepatic impairment. No dose adjustment of Symproic is required in patients with mild or moderate hepatic impairment.

ADVERSE REACTIONS

The most common adverse reactions with Symproic as compared to placebo in clinical trials were: abdominal pain (8% vs 2%), diarrhea (7% vs 2%), nausea (4% vs 2%), and gastroenteritis (2% vs 1%).

In pooled Studies 1 and 2, the incidence of adverse reactions of opioid withdrawal was 1% (8/542) for Symproic and 1% (3/546) for placebo. In Study 3 (52-week data), the incidence was 3% (20/621) for Symproic and 1% (9/619) for placebo.

To report suspected Adverse Reactions, contact Shionogi at 1-800-849-9707 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Please see accompanying Full Prescribing Information including Medication Guide for Symproic or visit www.symproic.com/pi.

About Shionogi

Shionogi & Co., Ltd. is a Japanese major research-driven pharmaceutical company dedicated to bringing benefits to patients based on its corporate philosophy of “supplying the best possible medicine to protect the health and wellbeing of the patients we serve.” Shionogi Inc., the US.. 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 anti-infectives, pain, cardiovascular diseases and gastroenterology. Our pipeline is focused on infectious disease, pain, CNS and oncology. For more details on Shionogi Inc., visit www.shionogi.com. For more information on Shionogi & Co., Ltd., visit www.shionogi.co.jp/en.

Forward-Looking Statements

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.

References

1. Sehgal N, Colson J, Smith HS. Chronic pain treatment with opioid analgesics: benefits versus harms of long-term therapy. Expert Rev Neurother. 2013;13:1201-1220.

2. Camilleri M, Drossman DA, Becker G, Webster LR, Davies AN, Mawe GM. Emerging treatments in neurogastroenterology: a multidisciplinary working group consensus statement on opioid-induced constipation. Neurogastroenterol Motil. 2014;26: 1386-1395.

3. Kalso E, Edwards JE, Moore RA, McQuay HJ. Opioids in chronic noncancer pain: systematic review of efficacy and safety. Pain. 2004;112:372–80.

4. Cook SF, Lanza L, Zhou X, et al. Gastrointestinal side effects in chronic opioid users: results from a population based survey.Aliment Pharmacol Ther. 2008;27(12):1224-1232.

5. Brown RT, Zuelsdorff M, Fleming M. Adverse effects and cognitive function among primary care patients taking opioids for chronic nonmalignant pain. J Opioid Manag. 2006;2(3):137–146.

6. Tuteja AK, Biskupiak J, Stoddard GJ, Lipman AG. Opioid induced bowel disorders and narcotic bowel syndrome in patients with chronic non-cancer pain. Neurogastroenterol Motil. 2010;22(4):424-430.

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