Shionogi Announces Licensing of Symproic® (naldemedine) to BioDelivery Sciences International Inc.

OSAKA, Japan & FLORHAM PARK, N.J.–(BUSINESS WIRE)–Shionogi Inc. (hereafter “Shionogi”) announced today that BioDelivery
Sciences International, Inc. (NASDAQ: BDSI), a rapidly growing
commercial-stage specialty pharmaceutical company dedicated to patients
living with chronic pain, has licensed full rights to commercialize
Symproic® (naldemedine) tablets 0.2 mg in the United States. The
transfer of rights is effective immediately.

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.

“The decision to license Symproic is part of our ongoing strategy to
sharpen our commercial focus in specialty therapeutic areas,” said Dr.
Isao Teshirogi, President and CEO of Shionogi & Co., Ltd. “Given
BioDelivery Sciences International’s strong commercial capabilities, we
feel they are the best partner to maximize the value of Symproic as a
treatment option for adult patients suffering from chronic non-cancer
pain and struggling with opioid-induced constipation.

Under the terms of the transaction, Shionogi Inc. will receive an
upfront cash payment of $20 million, an additional $10 million in six
months, as well as quarterly royalty payments.

Shionogi regained full rights to Symproic in June 2018. The exclusive
rights are now granted to BioDelivery Sciences International Inc.

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 U.S. 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 BioDelivery Sciences International Inc.

BioDelivery Sciences International, Inc. (NASDAQ: BDSI) is a rapidly
growing commercial-stage specialty pharmaceutical company dedicated to
patients living with chronic pain. BDSI is utilizing its novel and
proprietary BioErodible MucoAdhesive (BEMA^®) technology and
other drug delivery technologies to develop and commercialize, either on
its own or in partnership with third parties, new applications of proven
therapies aimed at addressing important unmet medical needs. BDSI’s
marketed products and those in development address serious and
debilitating conditions such as chronic pain, breakthrough cancer pain,
and opioid dependence. For more information, please visit us at www.bdsi.com
or follow us on Facebook.com/BioDeliverySI
or Twitter BDSI
@BioDeliverySI.

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
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
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
(https://www.shionogi.com/).
For more information on Shionogi & Co., Ltd., visit www.shionogi.co.jp.en
(http://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.

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.

Contacts

Corporate Communications, Shionogi & Co., Ltd.
Telephone:
+81-6-6209-7885
Fax: +81-6-6229-9596

Shionogi Inc. U.S.
Media
Barbara Kalavik
Telephone: (973) 307-3373