Bristol-Myers Squibb Receives Positive Decision from National Institute of Health and Clinical Excellence (NICE) for YERVOY®

  Bristol-Myers Squibb Receives Positive Decision from National Institute of
  Health and Clinical Excellence (NICE) for YERVOY® (ipilimumab)

  *Decision will enable patients in England and Wales to routinely access
    YERVOY through National Health Services, supporting UK government’s
    position on importance of access to innovative medicines as driver for
                             better patient outcomes
  *Reimbursement for YERVOY, indicated in the European Union (EU) for
    previously-treated advanced melanoma, now granted for majority of eligible
    patients in EU after NICE outcome and recent positive decision by Spanish
    Health Authorities

Business Wire

PRINCETON, N.J. -- November 02, 2012

Bristol-Myers Squibb Company (NYSE: BMY) is pleased to announce that today the
National Institute of Health and Clinical Excellence (NICE)  has decided to
recommend  YERVOY^® (ipilimumab), which is approved in the European Union for
the treatment of previously-treated metastatic (advanced) melanoma, within the
Final Appraisal Determination (FAD). This important decision will enable
eligible patients in England and Wales to routinely access treatment with
YERVOY through the National Health Services (NHS).

“Today’s decision is very welcome news and marks a major milestone in the
treatment of advanced melanoma,” said Dr. Paul Lorigan, Senior Lecturer in
Medical Oncology, the Christie NHS Foundation Trust. “Ipilimumab’s potential
to provide a long-term survival benefit in some patients makes it an important
treatment option and represents a genuine step change in the management of
this disease.”

Metastatic melanoma is the deadliest form of skin cancer with an average life
expectancy of just six to nine months and a one-year mortality rate of 75%.
YERVOY is the only approved treatment for metastatic melanoma to deliver a
durable long-term survival benefit at two years for 24 percent of patients. In
the pivotal study, which included more than 4.5 years of follow up, median
overall survival was 10 months (95% CI: 8.0-13.8) for YERVOY and 6 months (95%
CI: 5.5-8.7) for the gp100 control arm. Five-year follow up results from three
Phase 2 exploratory studies were recently presented during the European
Society of Medical Oncology congress (September 12 – October 2), adding to the
growing body of long-term survival data for YERVOY in metastatic melanoma.

Overall, the types of adverse events (AEs) attributed to YERVOY are generally
mechanism (immune)- based.YERVOY can result in severe and fatal
immune-related adverse reactions due to T-cell activation and proliferation.
Adverse events associated with YERVOY are managed with protocol-specific
guidelines, including the administration of systemic corticosteroids, dose
interruption/discontinuation and/or other immunosuppressants.

“Bristol-Myers Squibb is committed to leading advances in immuno-oncology, a
field that is focused on harnessing the immune system to fight cancer and one
that is increasingly recognized as a fourth pillar of the cancer-treatment
platform,” said Beatrice Cazala, executive vice president, commercial
operations, Bristol-Myers Squibb. “YERVOY, the first-approved compound from
our immuno-oncology pipeline, exemplifies how this type of medical innovation
can address a significant unmet clinical need. We are pleased that our close
collaboration with NICE on this appraisal over the past year has resulted in
an outcome that is in the best interest of patients. Today’s decision supports
the UK government’s statement that access to innovative medicines is a key
driver for better patient outcomes.”

The NICE approval follows the provision of access to treatment with YERVOY for
previously-treated advanced melanoma patients in an increasing number of
European countries, including Spain, Germany, Austria, Switzerland, Denmark,
Luxembourg, Belgium, Finland, Netherlands, Ireland and Sweden. Bristol-Myers
Squibb is working closely with other European authorities to secure further
access to YERVOY to address the unmet need.

Immuno-Oncology at Bristol-Myers Squibb

Historically, common approaches to cancer treatment have included surgery,
radiation and chemotherapy or systemic therapy. However, recent advances in
the development of immunotherapies have provided further scientific evidence
that these novel agents play a role in mediating cancer regression. This,
coupled with the increasing use of immunotherapies, has resulted in the
recognition of immunotherapy as a fourth pillar of the cancer-treatment
platform.

Immuno-oncology, which focuses on the scientific potential of harnessing the
unique properties of the immune system to fight cancer, is a prioritized area
of research and development at Bristol-Myers Squibb. The Company is committed
to leading advances in this important field of research and is exploring a
variety of innovative compounds and immunotherapeutic approaches to help
address significant unmet medical needs in a broad range of cancers. More
information can be found at www.BMSImmunoOncology.com.

About YERVOY

In March 2011, the FDA approved YERVOY 3 mg/kg monotherapy for patients with
unresectable or metastatic melanoma. It received regulatory approval in the
European Union in July 2011 for previously-treated metastatic (advanced)
melanoma, making it the first medicine to be licensed in the UK for the
treatment of this disease since dacarbazine in 1970. YERVOY is now approved in
41 countries worldwide.

In October, YERVOY received the prestigious Prix Galien USA 2012 Award for
Best Biotechnology Product. The Prix Galien Awards were created to honor
medical research and pharmacology for outstanding efforts to improve the human
condition through approval of innovative treatments and medicines.

YERVOY, which is a recombinant, human monoclonal antibody, is the
first-approved cancer immunotherapy that blocks the cytotoxic T- lymphocyte
antigen-4 (CTLA-4). CTLA-4 is a negative regulator of T-cell activation. ^
Ipilimumab 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 ipilimumab’s effect
in patients with melanoma is indirect, possibly through T-cell mediated
anti-tumor immune responses.

U.S. Indication and 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 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

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 9patients 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, 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, and
    autoimmune thyroiditis
  *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
    3mg/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.

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 about Bristol-Myers Squibb, visit
www.bms.com, or follow us on Twitter at http://twitter.com/bmsnews.

Contact:

Bristol-Myers Squibb Company
Media:
Sarah Koenig, 609-252-4145
sarah.koenig@bms.com
or
Investors:
John Elicker, 609-252-4611
john.elicker@bms.com
 
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