Companies to develop and commercialize
Opdivo (nivolumab), Yervoy (ipilimumab), and three
early–stage clinical immuno-oncology assets as single agents and
combination regimens
Bristol-Myers Squibb gains access to Opdivo
in Japan, South Korea and Taiwan, broadening company’s leadership
in immuno-oncology
Ono strengthens its immuno-oncology
portfolio with access to additional assets
Collaboration will leverage global clinical
trials by including patients from Japan, South Korea and
Taiwan
Bristol-Myers Squibb Company (NYSE:BMY) and Ono Pharmaceutical
Co., Ltd. (“Ono”) have signed a strategic collaboration agreement
to jointly develop and commercialize multiple immunotherapies as
single agents and combination regimens to help address the unmet
medical needs of patients with cancer in Japan, South Korea and
Taiwan. As part of the agreement, Bristol-Myers Squibb and Ono will
jointly develop and commercialize Opdivo (nivolumab) and Yervoy
(ipilimumab) across a broad range of tumor types.
Opdivo is a PD-1 immune checkpoint inhibitor approved in Japan
for the treatment of patients with unresectable melanoma, making it
the first PD-1 immune checkpoint inhibitor to receive regulatory
approval anywhere in the world, and is being developed in multiple
tumor types in more than 35 clinical trials. Yervoy, a CTLA-4
immune checkpoint inhibitor, is approved in Taiwan for the
treatment of patients with advanced melanoma who have received
prior therapy, and is in late-stage development as a potential
treatment option for melanoma, small cell lung cancer (SCLC) and
non-small cell lung cancer (NSCLC) in Japan. The agreement includes
three additional early-stage clinical immuno-oncology assets from
Bristol-Myers Squibb: lirilumab, an antibody that blocks the KIR
receptor on natural killer cells, urelumab, an agonist of the CD137
co-stimulatory receptor, and BMS-986016, a LAG3 immune checkpoint
inhibitor.
Bristol-Myers Squibb and Ono will jointly pursue development of
monotherapy and combination regimens, with Opdivo as the
foundational therapy in Japan, South Korea and Taiwan, and leverage
global clinical trials by including patients from the three
countries.
“Bristol-Myers Squibb’s collaboration with Ono supports our goal
to maximize the full potential of our immuno-oncology portfolio for
patients worldwide,” said Lamberto Andreotti, chief executive
officer, Bristol-Myers Squibb. “This collaboration combines our
leadership in immuno-oncology with both companies’ experience and
capabilities in Asia, and strengthens our long-standing
relationship with Ono.”
“Our collaboration with Bristol-Myers Squibb strengthens our
ability to further enhance the potential of Opdivo, for which Ono
recently received manufacturing and marketing approval in Japan as
the first PD-1 inhibitor approved anywhere in the world,” said Gyo
Sagara, President, Representative Director and CEO, Ono. “By
pursuing the study of investigational combination regimens of
immunotherapies with Bristol-Myers Squibb, we hope to bring a range
of new therapeutic options to cancer patients.”
Under the terms of the agreement, Bristol-Myers Squibb and Ono
will jointly develop and commercialize all collaboration products
in Japan, South Korea and Taiwan. Development costs and commercial
profits will be shared equally when Opdivo is used in combination
with any Bristol-Myers Squibb compound (Yervoy, lirilumab,
urelumab, BMS-986016). For a Bristol-Myers Squibb compound used as
monotherapy, or two Bristol-Myers Squibb compounds used in a
combination regimen, Bristol-Myers Squibb will fund the substantial
majority of development costs and receive the substantial majority
of commercial profits. When Opdivo is used as a single agent, Ono
will fund the substantial majority of development costs and receive
the substantial majority of commercial profits.
Prior to this announcement, Ono held exclusive rights to develop
and commercialize Opdivo in Japan, South Korea and Taiwan while
Bristol-Myers Squibb held such rights in the rest of the world,
along with sole rights to develop and commercialize Yervoy,
lirilumab, urelumab, and BMS-986016 worldwide. The trade name
Opdivo has been proposed in the U.S. and other countries, but
remains subject to health authority approval.
About Opdivo (nivolumab)
Cancer cells may exploit “regulatory” pathways, such as
checkpoint pathways, to hide from the immune system and shield the
tumor from immune attack. Opdivo is an investigational human PD-1
immune checkpoint inhibitor that binds to the checkpoint receptor
PD-1 (programmed death-1) expressed on activated T-cells. The
companies are investigating whether by blocking this pathway,
Opdivo would enable the immune system to resume its ability to
recognize, attack and destroy cancer cells.
Opdivo was approved in Japan on July 4, 2014 for the treatment
of patients with unresectable melanoma and is being studied in
multiple tumor types in more than 35 trials – as monotherapy or in
combination with other therapies – in which more than 7,000
patients have been enrolled worldwide. Among these are several
potentially registrational trials in NSCLC, melanoma, renal cell
carcinoma (RCC), head and neck cancer, glioblastoma and non-Hodgkin
lymphoma. In 2013, the FDA granted Fast Track designation for
Opdivo in NSCLC, melanoma and RCC. In May 2014, the FDA granted
Opdivo Breakthrough Therapy Designation for the treatment of
patients with Hodgkin lymphoma after failure of autologous stem
cell transplant and brentuximab.
About Yervoy (ipilimumab)
Yervoy, which is a recombinant, human monoclonal antibody,
blocks the cytotoxic T- lymphocyte-associated antigen-4 (CTLA-4).
CTLA-4 is a negative regulator of T-cell activation. Yervoy binds
to CTLA-4 and blocks the interaction of CTLA-4 with its ligands,
CD80/CD86. Blockade of CTLA-4 has been shown to augment T-cell
activation and proliferation. The mechanism of action
of Yervoy’s effect in patients with melanoma is indirect,
possibly through T-cell mediated anti-tumor immune responses. On
March 25, 2011, the FDA approved Yervoy 3 mg/kg
monotherapy for patients with unresectable or metastatic
melanoma. Yervoy is now approved in more than 40
countries, including Taiwan. There is a broad, ongoing development
program in place for Yervoy spanning multiple tumor
types. This includes Phase 3 trials in prostate and lung
cancers.
Yervoy (ipilimumab) INDICATION & IMPORTANT SAFETY
INFORMATION
Yervoy (ipilimumab) is indicated for the treatment of
unresectable or metastatic melanoma.
Important Safety Information
WARNING: IMMUNE-MEDIATED ADVERSE REACTIONS
Yervoy can result in severe and fatal immune-mediated
adverse reactions due to T-cell activation and proliferation. These
immune-mediated reactions may involve any organ system; however,
the most common severe immune-mediated adverse reactions are
enterocolitis, hepatitis, dermatitis (including toxic epidermal
necrolysis), neuropathy, and endocrinopathy. The majority of these
immune-mediated reactions initially manifested during treatment;
however, a minority occurred weeks to months after discontinuation
of Yervoy.
Assess patients for signs and symptoms of enterocolitis,
dermatitis, neuropathy, and endocrinopathy and evaluate clinical
chemistries including liver function tests (LFTs) and thyroid
function tests at baseline and before each dose.
Permanently discontinue Yervoy and initiate systemic
high-dose corticosteroids for sever immune-mediated
reactions.
Recommended Dose Modifications
Withhold dose for any moderate immune-mediated adverse reactions
or for symptomatic endocrinopathy until return to baseline,
improvement to mild severity, or complete resolution, and patient
is receiving <7.5 mg prednisone or equivalent per day.
Permanently discontinue Yervoy for any of the following:
- Persistent moderate adverse reactions
or inability to reduce corticosteroid dose to 7.5 mg prednisone or
equivalent per day
- Failure to complete full treatment
course within 16 weeks from administration of first dose
- Severe or life-threatening adverse
reactions, including any of the following:
- Colitis with abdominal pain, fever,
ileus, or peritoneal signs; increase in stool frequency (≥7 over
baseline), stool incontinence, need for intravenous hydration for
>24 hours, gastrointestinal hemorrhage, and gastrointestinal
perforation
- AST or ALT >5 × the upper limit of
normal (ULN) or total bilirubin >3 × the ULN
- Stevens-Johnson syndrome, toxic
epidermal necrolysis, or rash complicated by full-thickness dermal
ulceration or necrotic, bullous, or hemorrhagic manifestations
- Severe motor or sensory neuropathy,
Guillain-Barré syndrome, or myasthenia gravis
- Severe immune-mediated reactions
involving any organ system
- Immune-mediated ocular disease which is
unresponsive to topical immunosuppressive therapy
Immune-mediated Enterocolitis:
- In the pivotal Phase 3 study in
Yervoy-treated patients, severe, life-threatening, or fatal
(diarrhea of ≥7 stools above baseline, fever, ileus, peritoneal
signs; Grade 3-5) immune-mediated enterocolitis occurred in 34 (7%)
and moderate (diarrhea with up to 6 stools above baseline,
abdominal pain, mucus or blood in stool; Grade 2) enterocolitis
occurred in 28 (5%) patients
- Across all Yervoy-treated patients
(n=511), 5 (1%) developed intestinal perforation, 4 (0.8%) died as
a result of complications, and 26 (5%) were hospitalized for severe
enterocolitis
- Infliximab was administered to 5 of 62
(8%) patients with moderate, severe, or life-threatening
immune-mediated enterocolitis following inadequate response to
corticosteroids
- Monitor patients for signs and symptoms
of enterocolitis (such as diarrhea, abdominal pain, mucus or blood
in stool, with or without fever) and of bowel perforation (such as
peritoneal signs and ileus). In symptomatic patients, rule out
infectious etiologies and consider endoscopic evaluation for
persistent or severe symptoms
- Permanently discontinue Yervoy in
patients with severe enterocolitis and initiate systemic
corticosteroids (1-2 mg/kg/day of prednisone or equivalent). Upon
improvement to ≤Grade 1, initiate corticosteroid taper and continue
over at least 1 month. In clinical trials, rapid corticosteroid
tapering resulted in recurrence or worsening symptoms of
enterocolitis in some patients
- Withhold Yervoy for moderate
enterocolitis; administer anti-diarrheal treatment and, if
persistent for >1 week, initiate systemic corticosteroids (0.5
mg/kg/day prednisone or equivalent)
Immune-mediated Hepatitis:
- In the pivotal Phase 3 study in
Yervoy-treated patients, severe, life-threatening, or fatal
hepatotoxicity (AST or ALT elevations >5x the ULN or total
bilirubin elevations >3x the ULN; Grade 3–5) occurred in 8 (2%)
patients, with fatal hepatic failure in 0.2% and hospitalization in
0.4%
- 13 (2.5%) additional Yervoy-treated
patients experienced moderate hepatotoxicity manifested by LFT
abnormalities (AST or ALT elevations >2.5x but ≤5x the ULN or
total bilirubin elevation >1.5x but ≤3x the ULN; Grade 2)
- Monitor LFTs (hepatic transaminase and
bilirubin levels) and assess patients for signs and symptoms of
hepatotoxicity before each dose of Yervoy. In patients with
hepatotoxicity, rule out infectious or malignant causes and
increase frequency of LFT monitoring until resolution
- Permanently discontinue Yervoy in
patients with Grade 3-5 hepatotoxicity and administer systemic
corticosteroids (1-2 mg/kg/day of prednisone or equivalent). When
LFTs show sustained improvement or return to baseline, initiate
corticosteroid tapering and continue over 1 month. Across the
clinical development program for Yervoy, mycophenolate treatment
has been administered in patients with persistent severe hepatitis
despite high-dose corticosteroids
- Withhold Yervoy in patients with Grade
2 hepatotoxicity
- In a dose-finding trial, Grade 3
increases in transaminases with or without concomitant increases in
total bilirubin occurred in 6 of 10 patients who received
concurrent Yervoy (3 mg/kg) and vemurafenib (960 mg BID or 720 mg
BID)
Immune-mediated Dermatitis:
- In the pivotal Phase 3 study in
Yervoy-treated patients, severe, life-threatening, or fatal
immune-mediated dermatitis (e.g., Stevens-Johnson syndrome, toxic
epidermal necrolysis, or rash complicated by full thickness dermal
ulceration, or necrotic, bullous, or hemorrhagic manifestations;
Grade 3–5) occurred in 13 (2.5%) patients
- 1 (0.2%) patient died as a result of
toxic epidermal necrolysis
- 1 additional patient required
hospitalization for severe dermatitis
- There were 63 (12%) Yervoy-treated
patients with moderate (Grade 2) dermatitis
- Monitor patients for signs and symptoms
of dermatitis such as rash and pruritus. Unless an alternate
etiology has been identified, signs or symptoms of dermatitis
should be considered immune-mediated
- Permanently discontinue Yervoy in
patients with severe, life-threatening, or fatal immune-mediated
dermatitis (Grade 3-5). Administer systemic corticosteroids (1-2
mg/kg/day of prednisone or equivalent). When dermatitis is
controlled, corticosteroid tapering should occur over a period of
at least 1 month. Withhold Yervoy in patients with moderate to
severe signs and symptoms
- Treat mild to moderate dermatitis
(e.g., localized rash and pruritus) symptomatically. Administer
topical or systemic corticosteroids if there is no improvement
within 1 week
Immune-mediated Neuropathies:
- In the pivotal Phase 3 study in
Yervoy-treated patients, 1 case of fatal Guillain-Barré syndrome
and 1 case of severe (Grade 3) peripheral motor neuropathy were
reported
- Across the clinical development program
of Yervoy, myasthenia gravis and additional cases of Guillain-Barré
syndrome have been reported
- Monitor for symptoms of motor or
sensory neuropathy such as unilateral or bilateral weakness,
sensory alterations, or paresthesia. Permanently discontinue Yervoy
in patients with severe neuropathy (interfering with daily
activities) such as Guillain-Barré–like syndromes
- Institute medical intervention as
appropriate for management of severe neuropathy. Consider
initiation of systemic corticosteroids (1-2 mg/kg/day of prednisone
or equivalent) for severe neuropathies. Withhold Yervoy in patients
with moderate neuropathy (not interfering with daily
activities)
Immune-mediated Endocrinopathies:
- In the pivotal Phase 3 study in Yervoy-
treated patients, severe to life-threatening immune-mediated
endocrinopathies (requiring hospitalization, urgent medical
intervention, or interfering with activities of daily living; Grade
3-4) occurred in 9 (1.8%) patients
- All 9 patients had
hypopituitarism, and some had additional concomitant
endocrinopathies such as adrenal insufficiency, hypogonadism, and
hypothyroidism
- 6 of the 9 patients were hospitalized
for severe endocrinopathies
- Moderate endocrinopathy (requiring
hormone replacement or medical intervention; Grade 2) occurred in
12 (2.3%) Yervoy-treated patients and consisted of hypothyroidism,
adrenal insufficiency, hypopituitarism, and 1 case each of
hyperthyroidism and Cushing’s syndrome
- Median time to onset of moderate to
severe immune-mediated endocrinopathy was 11 weeks and ranged up to
19.3 weeks after the initiation of Yervoy
- Monitor patients for clinical signs and
symptoms of hypophysitis, adrenal insufficiency (including adrenal
crisis), and hyper- or hypothyroidism
- Patients may present with fatigue,
headache, mental status changes, abdominal pain, unusual bowel
habits, and hypotension, or nonspecific symptoms which may resemble
other causes such as brain metastasis or underlying disease. Unless
an alternate etiology has been identified, signs or symptoms should
be considered immune-mediated
- Monitor thyroid function tests and
clinical chemistries at the start of treatment, before each dose,
and as clinically indicated based on symptoms. In a limited number
of patients, hypophysitis was diagnosed by imaging studies through
enlargement of the pituitary gland
- Withhold Yervoy in symptomatic
patients. Initiate systemic corticosteroids (1-2 mg/kg/day of
prednisone or equivalent) and initiate appropriate hormone
replacement therapy. Long-term hormone replacement therapy may be
necessary
Other Immune-mediated Adverse Reactions, Including Ocular
Manifestations:
- In the pivotal Phase 3 study in
Yervoy-treated patients, clinically significant immune-mediated
adverse reactions seen in <1% were: nephritis, pneumonitis,
meningitis, pericarditis, uveitis, iritis, and hemolytic
anemia
- Across the clinical development program
for Yervoy, likely immune-mediated adverse reactions also reported
with <1% incidence were: myocarditis, angiopathy, temporal
arteritis, vasculitis, polymyalgia rheumatica, conjunctivitis,
blepharitis, episcleritis, scleritis, leukocytoclastic vasculitis,
erythema multiforme, psoriasis, pancreatitis, arthritis, autoimmune
thyroiditis, sarcoidosis, neurosensory hypoacusis, autoimmune
central neuropathy (encephalitis), myositis, polymyositis, and
ocular myositis
- Permanently discontinue Yervoy for
clinically significant or severe immune-mediated adverse reactions.
Initiate systemic corticosteroids (1-2 mg/kg/day of prednisone or
equivalent) for severe immune-mediated adverse reactions
- Administer corticosteroid eye drops for
uveitis, iritis, or episcleritis. Permanently discontinue Yervoy
for immune-mediated ocular disease unresponsive to local
immunosuppressive therapy
Pregnancy & Nursing:
- Yervoy is classified as pregnancy
category C. There are no adequate and well-controlled studies of
YERVOY in pregnant women. Use Yervoy during pregnancy only if the
potential benefit justifies the potential risk to the fetus
- Human IgG1 is known to cross the
placental barrier and Yervoy is an IgG1; therefore, Yervoy has the
potential to be transmitted from the mother to the developing
fetus
- It is not known whether Yervoy is
secreted in human milk. Because many drugs are secreted in human
milk and because of the potential for serious adverse reactions in
nursing infants from Yervoy, a decision should be made whether to
discontinue nursing or to discontinue Yervoy
Common Adverse Reactions:
- The most common adverse reactions (≥5%)
in patients who received Yervoy at 3 mg/kg were fatigue (41%),
diarrhea (32%), pruritus (31%), rash (29%), and colitis (8%)
Please see Full Prescribing Information, including Boxed
WARNING regarding immune-mediated adverse reactions, available
at www.bms.com.
Immuno-Oncology at Bristol-Myers Squibb
Surgery, radiation, cytotoxic or targeted therapies have
represented the mainstay of cancer treatment over the last several
decades, but long-term survival and a positive quality of life have
remained elusive for many patients with advanced disease.
To address this unmet medical need, Bristol-Myers Squibb is
leading advances in the innovative field of immuno-oncology, which
involves agents whose primary mechanism is to work directly with
the body’s immune system to fight cancer. The company is exploring
a variety of compounds and immunotherapeutic approaches for
patients with different types of cancer, including researching the
potential of combining immuno-oncology agents that target different
and complementary pathways in the treatment of cancer.
Bristol-Myers Squibb is committed to advancing the science of
immuno-oncology, with the goal of changing survival
expectations and the way patients live with cancer.
About the Bristol-Myers Squibb and Ono Collaboration
Bristol-Myers Squibb, through its wholly owned subsidiary
Medarex, Inc., and Ono have a long-standing relationship since 2005
to develop and commercialize PD-1 antibodies, including
Opdivo. Bristol-Myers Squibb obtained rights to develop and
commercialize Opdivo in North America in 2009 as part of the
Medarex, Inc. acquisition. Through a collaboration agreement
entered into in September 2011, Ono granted Bristol-Myers Squibb
exclusive rights to develop and commercialize Opdivo in the rest of
the world, except in Japan, South Korea and Taiwan where Ono
retained such rights.
On July 23, 2014, Bristol-Myers Squibb and Ono signed a new
collaboration agreement in which the companies agreed to jointly
develop and commercialize Opdivo, Yervoy and three early-stage
immunotherapies in Japan, South Korea and Taiwan.
About Bristol-Myers Squibb
Bristol-Myers Squibb is a global biopharmaceutical company whose
mission is to discover, develop and deliver innovative medicines
that help patients prevail over serious diseases. For more
information, please visit www.bms.com or follow us on Twitter at
http://twitter.com/bmsnews.
About Ono Pharmaceutical Co., Ltd.
Ono Pharmaceutical Co., Ltd., headquartered in Osaka, Japan, is
an R&D-oriented pharmaceutical company committed to creating
innovative medicines in specific areas. It focuses especially on
the diabetes and oncology areas. For more information, please visit
the company’s website at http://www.ono.co.jp/eng/index.html.
Bristol-Myers Squibb Forward-Looking Statement
This press release contains "forward-looking statements" as that
term is defined in the Private Securities Litigation Reform Act of
1995 regarding the research, development and commercialization of
pharmaceutical products. Such forward-looking statements are based
on current expectations and involve inherent risks and
uncertainties, including factors that could delay, divert or change
any of them, and could cause actual outcomes and results to differ
materially from current expectations. No forward-looking statement
can be guaranteed. Among other risks, there can be no guarantee
that any of the compounds mentioned in this release will receive
regulatory approval in Japan, South Korea or Taiwan, either as
single agents (other than Yervoy in Taiwan and Opdivo in Japan) or
in combination regimens, or, if approved, that they will become
commercially successful products. Forward-looking statements in
this press release should be evaluated together with the many
uncertainties that affect Bristol-Myers Squibb's business,
particularly those identified in the cautionary factors discussion
in Bristol-Myers Squibb's Annual Report on Form 10-K for the year
ended December 31, 2013 in our Quarterly Reports on Form 10-Q and
our Current Reports on Form 8-K. Bristol-Myers Squibb undertakes no
obligation to publicly update any forward-looking statement,
whether as a result of new information, future events or
otherwise.
Bristol-Myers SquibbMedia:Laura Hortas,
609-252-4587laura.hortas@bms.comorKen Dominski,
609-252-5251ken.dominski@bms.comorInvestors:Ranya Dajani,
609-252-5330ranya.dajani@bms.comorRyan Asay,
609-252-5020ryan.asay@bms.comorOno PharmaceuticalCorporate
Communicationspublic_relations@ono.co.jpYukio Tani,
y.tani@ono.co.jpKazuhiko Muraoka, muraoka@ono.co.jp
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