- 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
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 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, 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 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.
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.
Bristol-Myers Squibb CompanyMedia:Sarah Koenig, 609-252-4145sarah.koenig@bms.comorInvestors:John Elicker, 609-252-4611john.elicker@bms.com