New analyses from a Phase 2 study of
BMS-986036 (pegylated FGF21) in NASH further support non-invasive
methods for assessing liver fibrosis
New analyses from CheckMate -040
demonstrating efficacy and safety of Opdivo in patients with
HCC, including those infected with chronic HBV or HCV, to be
featured in a Presidential Plenary
Bristol-Myers Squibb Company (NYSE:BMY) today announced that new
data across serious liver diseases, including nonalcoholic
steatohepatitis (NASH) and hepatocellular carcinoma (HCC), will be
presented at The Liver Meeting® 2017 in Washington, DC, October 20
– 24, 2017.
Key data presentations include:
- Two analyses from a Phase 2 study of
BMS-986036 (pegylated FGF21) in NASH, which provide further support
of non-invasive methods, including imaging studies and serum
Pro-C3, for assessing liver fibrosis
- Updated data for Opdivo (nivolumab) in
HCC from CheckMate -040, the trial which was the basis for the
recent FDA approval for the treatment of HCC patients previously
treated with sorafenib, will be presented in a Presidential
Plenary
“The data being presented at The Liver Meeting® demonstrate our
commitment to advancing the science in HCC and NASH, two serious
liver diseases with unmet medical need,” said Tom Lynch, M.D.,
executive vice president and chief scientific officer,
Bristol-Myers Squibb. “We are excited to share new analyses for
Opdivo in HCC from CheckMate -040. In NASH, the breadth of the data
that we and our collaborators are presenting reinforces our focus
on investigating new treatment options for liver fibrosis and
improving diagnostic processes, and these results are shaping the
development program for BMS-986036.”
The Company is engaged in productive discussions with health
authorities to advance the development program for BMS-986036.
Bristol-Myers Squibb exclusively licensed the rights to
research, develop and commercialize BMS-986036 from Ambrx, Inc.
Also at The Liver Meeting®, Nitto Denko will present the results
of a Phase 1b/2 study of HSP47 (ND-L02-s0201), which was licensed
by Bristol-Myers Squibb for investigation in advanced liver
fibrosis. Nordic Bioscience, with which Bristol-Myers Squibb
collaborates to research collagen biomarkers in liver fibrosis,
will share new data on Pro-C3, a biomarker that specifically
detects the formation of type III collagen and can be measured with
a blood test. Validated biomarkers are needed to assess disease
activity and response to interventions in patients with NASH.
Bristol-Myers Squibb will also present study results regarding
the occurrence of Hepatitis B Virus (HBV)-associated and other
clinical and treatment-associated outcome events in patients taking
long-term Baraclude vs. other nucleos(t)ide monotherapy.
Bristol-Myers Squibb research tied to Hepatitis B and C during the
past two decades has played a transformational role in the
treatment of viral hepatitis around the globe.
Bristol-Myers Squibb data presentations at The Liver Meeting®
2017:
Title
Presenting Author/Type
Date/Time (EDT)
Location/Session
Nivolumab in Sorafenib-Naive and -Experienced Patients with
Advanced Hepatocellular Carcinoma: Survival, Hepatic Safety, and
Biomarker Assessments in CheckMate 040 B. Sangro /
Presidential Plenary Oral
Oct. 23, 20178:30 – 8:45 a.m.
Presidential Plenary: Clinical Convention Center Ballroom
Treatment Patterns and Healthcare (HC) Costs by Lines of Therapy
Among Advanced Hepatocellular Carcinoma (aHCC) Patients Treated
with Systemic Cancer Therapy M. Bonafede / Poster
Oct. 22, 201712:30 – 2:00 p.m.
Clinical Liver Cancer
Hall D
Prospective, Randomized Assessment of HBV-associated and other
Clinical Outcome Events During Long-Term Therapy With Entecavir or
Other HBV Nucleos(t)ide Analogues in Patients with Chronic HBV
Infection J. Hou / Oral
Oct. 22, 20178:45 – 9:00 a.m.
Parallel 3: Hepatitis B: Approved Treatments
Room 207
BMS-986036 (pegylated FGF21) in Patients with Non-Alcoholic
Steatohepatitis: A Phase 2 study A. Sanyal / Oral
Oct. 23, 20171:30 – 1:45 p.m.
Parallel 27: NASH: Novel Imaging and Therapeutics
Room 202
Multi-Biomarker Validation of MRI-PDFF- and MRE-Derived Treatment
Response with BMS-986036 (peg-FGF21): A Secondary Analysis of a
Multi-center Clinical Trial in Non-Alcoholic Steatohepatitis
(NASH). R. Loomba / Poster
Oct. 20, 201712:00 – 1:30 p.m.
Imaging and Noninvasive Fibrosis Assessment
Hall D
Baseline Serum Pro-C3 Predicts Response to BMS-986036 (peg-FGF21):
A Secondary Analysis of a Multi-Center Clinical Trial in
Non-Alcoholic Steatohepatitis (NASH) M. Abdelmalek / Poster
Oct. 23, 201712:30 – 2:00 p.m.
Steatosis and Steatohepatitis
Hall D
Bristol-Myers Squibb collaborator presentations include:
Title
Presenting Author/Type
Date/Time (EDT)
Location/Session
Development and Validation of the Collagen Neo-Epitope Biomarker
Pro-C3 “FIB-C3 Score” for Detection and Staging of Advanced
Non-Alcoholic Fatty Liver Disease in a Large International
Multi-Centre Patient Cohort M. Boyle / Oral
Oct. 22, 20173:00 – 3:45 p.m.
Parallel 14: Novel Biomarkers for NASH
Room 202
Advanced Machine Learning Techniques To Identify A Panel Of
Biomarkers That Identify Nonalcoholic Steatohepatitis
S. Chernbumroong / Oral
Oct. 22, 20173:00 – 3:15 p.m.
Parallel 14: Novel Biomarkers for NASH
Room 202
Insulin secretion and decreased glucose clearance are associated
with enhanced fibrogenesis and a high risk of disease progression
in non-diabetic patients with Non Alcoholic Fatty Liver Disease.
R. Younes / Poster
Oct. 23, 201712:30 p.m. – 2:00 p.m.
Steatosis and Steatohepatitis
Hall D
The Extracellular Matrix (ECM) Turnover Profile in Cholestatic and
Autoimmune Liver Diseases – an Exploratory Study. M. Nielsen
/ Poster
Oct. 20, 201712:00 – 1:30 p.m.
Autoimmune and Cholestatic Liver Disease
Hall D
Treatment with ND-L02-s0201, a Novel Targeted Lipid Nanoparticle
(LNP) Delivering HSP47 siRNA, Results in Fibrosis Resolution in
Preclinical Rat Models Y. Liu/Poster
Oct. 20, 201712:00 – 1:30 p.m.
Clinical Research and Translational Fibrosis Research
Hall D
Clinical Phase 1b/2 Study Results for Safety, Pharmacokinetics, and
Efficacy of ND-L02-s0201, a Novel Targeted lipid Nanoparticle (LNP)
Delivering HSP47 siRNA for the Treatment of Patients with Advanced
Liver Fibrosis E. Lawitz/Poster
Oct. 20, 201712:00 – 1:30 p.m.
Clinical and Translational Fibrosis Research
Hall D
About Fibrosis and
NASHFibrotic diseases are characterized by chronic
inflammation that leads to excess collagen deposition and scar
formation in an organ or tissue. This scarring response compromises
function and can ultimately lead to organ failure. Nonalcoholic
steatohepatitis (NASH) may progress to cirrhosis, hepatocellular
carcinoma (HCC), the most common type of liver cancer, and liver
failure, and is expected to be the leading cause of liver
transplantation by 2020. The severity of liver fibrosis (scar
tissue in the liver) is measured on a scale of F0 (normal) to F4
(cirrhosis) in a liver biopsy specimen. Approximately 20 million
patients in the U.S. have NASH, and there are currently no approved
pharmacological treatments.
About Fibrosis at Bristol-Myers
SquibbBristol-Myers Squibb is committed to the discovery
and development of medicines for the treatment of fibrosis, the
buildup of scar tissue that impacts organ function. We are
advancing a robust pipeline of investigational compounds to address
areas of high unmet need in patients with fibrotic diseases,
including nonalcoholic steatohepatitis (NASH), a condition with no
approved pharmacological treatment options that may lead to liver
fibrosis and/or cirrhosis; and idiopathic pulmonary fibrosis (IPF),
a progressive lung disease with a high mortality rate. We are
researching multiple mechanisms and approaches to make the biggest
impact on patients.
About Hepatocellular
CarcinomaHepatocellular carcinoma (HCC) is the most
common type of liver cancer and the fastest-growing cause of cancer
death in the U.S. More than 700,000 people around the world,
including about 41,000 people in the U.S., are diagnosed with HCC
each year. The majority of these cases are caused by hepatitis B
virus (HBV) or hepatitis C virus (HCV) infections, making HBV/HCV
the most common risk factors for liver cancer. In the foreseeable
future, the rising prevalence of metabolic syndrome and
nonalcoholic steatohepatitis (NASH) is expected to contribute to
increased rates of HCC.
HCC is often diagnosed in the advanced stage where treatment
options have been limited and outcomes poor, with one-year survival
rates in the advanced setting of approximately 44%. The FDA
recently approved Opdivo for the treatment of HCC following prior
systemic therapy based on tumor response rate and durability of
response, offering an additional treatment option to appropriate
patients.
Bristol-Myers Squibb &
Immuno-Oncology: Advancing Oncology ResearchAt
Bristol-Myers Squibb, patients are at the center of everything we
do. Our vision for the future of cancer care is focused on
researching and developing transformational Immuno-Oncology (I-O)
medicines for hard-to-treat cancers that could potentially improve
outcomes for these patients.
We are leading the scientific understanding of I-O through our
extensive portfolio of investigational compounds and approved
agents. Our differentiated clinical development program is studying
broad patient populations across more than 50 types of cancers with
14 clinical-stage molecules designed to target different immune
system pathways. Our deep expertise and innovative clinical trial
designs position us to advance I-O/I-O, I-O/chemotherapy,
I-O/targeted therapies and I-O/radiation therapies across multiple
tumors and potentially deliver the next wave of therapies with a
sense of urgency. We also continue to pioneer research that will
help facilitate a deeper understanding of the role of immune
biomarkers and how patients’ individual tumor biology can be used
as a guide for treatment decisions throughout their journey.
We understand making the promise of I-O a reality for the many
patients who may benefit from these therapies requires not only
innovation on our part but also close collaboration with leading
experts in the field. Our partnerships with academia, government,
advocacy and biotech companies support our collective goal of
providing new treatment options to advance the standards of
clinical practice.
About OpdivoOpdivo is a
programmed death-1 (PD-1) immune checkpoint inhibitor that is
designed to uniquely harness the body’s own immune system to help
restore anti-tumor immune response. By harnessing the body’s own
immune system to fight cancer, Opdivo has become an important
treatment option across multiple cancers.
Opdivo’s leading global development program is based on
Bristol-Myers Squibb’s scientific expertise in the field of
Immuno-Oncology and includes a broad range of clinical trials
across all phases, including Phase 3, in a variety of tumor types.
To date, the Opdivo clinical development program has enrolled more
than 25,000 patients. The Opdivo trials have contributed to gaining
a deeper understanding of the potential role of biomarkers in
patient care, particularly regarding how patients may benefit from
Opdivo across the continuum of PD-L1 expression.
In July 2014, Opdivo was the first PD-1 immune checkpoint
inhibitor to receive regulatory approval anywhere in the world.
Opdivo is currently approved in more than 60 countries, including
the United States, the European Union and Japan. In October 2015,
the company’s Opdivo and Yervoy combination regimen was the first
Immuno-Oncology combination to receive regulatory approval for the
treatment of metastatic melanoma and is currently approved in more
than 50 countries, including the United States and the European
Union.
U.S. FDA-APPROVED INDICATIONS FOR
OPDIVO®
OPDIVO® (nivolumab) as a single agent is indicated for the
treatment of patients with BRAF V600 mutation-positive unresectable
or metastatic melanoma. This indication is approved under
accelerated approval based on progression-free survival. Continued
approval for this indication may be contingent upon verification
and description of clinical benefit in the confirmatory trials.
OPDIVO® (nivolumab) as a single agent is indicated for the
treatment of patients with BRAF V600 wild-type unresectable or
metastatic melanoma.
OPDIVO® (nivolumab), in combination with YERVOY® (ipilimumab),
is indicated for the treatment of patients with unresectable or
metastatic melanoma. This indication is approved under accelerated
approval based on progression-free survival. Continued approval for
this indication may be contingent upon verification and description
of clinical benefit in the confirmatory trials.
OPDIVO® (nivolumab) is indicated for the treatment of patients
with metastatic non-small cell lung cancer (NSCLC) with progression
on or after platinum-based chemotherapy. Patients with EGFR or ALK
genomic tumor aberrations should have disease progression on
FDA-approved therapy for these aberrations prior to receiving
OPDIVO.
OPDIVO® (nivolumab) is indicated for the treatment of patients
with advanced renal cell carcinoma (RCC) who have received prior
anti-angiogenic therapy.
OPDIVO® (nivolumab) is indicated for the treatment of adult
patients with classical Hodgkin lymphoma (cHL) that has relapsed or
progressed after autologous hematopoietic stem cell transplantation
(HSCT) and brentuximab vedotin or after 3 or more lines of systemic
therapy that includes autologous HSCT. This indication is approved
under accelerated approval based on overall response rate.
Continued approval for this indication may be contingent upon
verification and description of clinical benefit in confirmatory
trials.
OPDIVO® (nivolumab) is indicated for the treatment of patients
with recurrent or metastatic squamous cell carcinoma of the head
and neck (SCCHN) with disease progression on or after
platinum-based therapy.
OPDIVO® (nivolumab) is indicated for the treatment of patients
with locally advanced or metastatic urothelial carcinoma who have
disease progression during or following platinum-containing
chemotherapy or have disease progression within 12 months of
neoadjuvant or adjuvant treatment with platinum-containing
chemotherapy. This indication is approved under accelerated
approval based on tumor response rate and duration of response.
Continued approval for this indication may be contingent upon
verification and description of clinical benefit in confirmatory
trials.
OPDIVO® (nivolumab) is indicated for the treatment of adult and
pediatric (12 years and older) patients with microsatellite
instability high (MSI-H) or mismatch repair deficient (dMMR)
metastatic colorectal cancer (CRC) that has progressed following
treatment with a fluoropyrimidine, oxaliplatin, and irinotecan.
This indication is approved under accelerated approval based on
overall response rate and duration of response. Continued approval
for this indication may be contingent upon verification and
description of clinical benefit in confirmatory trials.
OPDIVO® (nivolumab) is indicated for the treatment of patients
with hepatocellular carcinoma (HCC) who have been previously
treated with sorafenib. This indication is approved under
accelerated approval based on tumor response rate and durability of
response. Continued approval for this indication may be contingent
upon verification and description of clinical benefit in the
confirmatory trials.
IMPORTANT SAFETY
INFORMATION
WARNING: IMMUNE-MEDIATED ADVERSE REACTIONS
YERVOY can result in severe and fatal immune-mediated adverse
reactions. 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),
adrenocorticotropic hormone (ACTH) level, and thyroid function
tests at baseline and before each dose.
Permanently discontinue YERVOY and initiate systemic
high-dose corticosteroid therapy for severe immune-mediated
reactions.
Immune-Mediated Pneumonitis
OPDIVO can cause immune-mediated pneumonitis. Fatal cases have
been reported. Monitor patients for signs with radiographic imaging
and for symptoms of pneumonitis. Administer corticosteroids for
Grade 2 or more severe pneumonitis. Permanently discontinue for
Grade 3 or 4 and withhold until resolution for Grade 2. In patients
receiving OPDIVO monotherapy, fatal cases of immune-mediated
pneumonitis have occurred. Immune-mediated pneumonitis occurred in
3.1% (61/1994) of patients. In patients receiving OPDIVO with
YERVOY, immune-mediated pneumonitis occurred in 6% (25/407) of
patients.
In Checkmate 205 and 039, pneumonitis, including interstitial
lung disease, occurred in 6.0% (16/266) of patients receiving
OPDIVO. Immune-mediated pneumonitis occurred in 4.9% (13/266) of
patients receiving OPDIVO: Grade 3 (n=1) and Grade 2 (n=12).
Immune-Mediated Colitis
OPDIVO can cause immune-mediated colitis. Monitor patients for
signs and symptoms of colitis. Administer corticosteroids for Grade
2 (of more than 5 days duration), 3, or 4 colitis. Withhold OPDIVO
monotherapy for Grade 2 or 3 and permanently discontinue for Grade
4 or recurrent colitis upon re-initiation of OPDIVO. When
administered with YERVOY, withhold OPDIVO and YERVOY for Grade 2
and permanently discontinue for Grade 3 or 4 or recurrent colitis.
In patients receiving OPDIVO monotherapy, immune-mediated colitis
occurred in 2.9% (58/1994) of patients. In patients receiving
OPDIVO with YERVOY, immune-mediated colitis occurred in 26%
(107/407) of patients including three fatal cases.
In a separate Phase 3 study of YERVOY 3 mg/kg, 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%) patients. Across all
YERVOY-treated patients in that study (n=511), 5 (1%) developed
intestinal perforation, 4 (0.8%) died as a result of complications,
and 26 (5%) were hospitalized for severe enterocolitis.
Immune-Mediated Hepatitis
OPDIVO can cause immune-mediated hepatitis. Monitor patients for
abnormal liver tests prior to and periodically during treatment.
Administer corticosteroids for Grade 2 or greater transaminase
elevations. For patients without HCC, withhold OPDIVO for Grade 2
and permanently discontinue OPDIVO for Grade 3 or 4. For patients
with HCC, withhold OPDIVO and administer corticosteroids if AST/ALT
is within normal limits at baseline and increases to >3 and up
to 5 times the upper limit of normal (ULN), if AST/ALT is >1 and
up to 3 times ULN at baseline and increases to >5 and up to 10
times the ULN, and if AST/ALT is >3 and up to 5 times ULN at
baseline and increases to >8 and up to 10 times the ULN.
Permanently discontinue OPDIVO and administer corticosteroids if
AST or ALT increases to >10 times the ULN or total bilirubin
increases >3 times the ULN. In patients receiving OPDIVO
monotherapy, immune-mediated hepatitis occurred in 1.8% (35/1994)
of patients. In patients receiving OPDIVO with YERVOY,
immune-mediated hepatitis occurred in 13% (51/407) of patients.
In Checkmate 040, immune-mediated hepatitis requiring systemic
corticosteroids occurred in 5% (8/154) of patients receiving
OPDIVO.
In a separate Phase 3 study of YERVOY 3 mg/kg, 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%.
Immune-Mediated Neuropathies
In a separate Phase 3 study of YERVOY 3 mg/kg, 1 case of fatal
Guillain-Barré syndrome and 1 case of severe (Grade 3) peripheral
motor neuropathy were reported.
Immune-Mediated Endocrinopathies
OPDIVO can cause immune-mediated hypophysitis, immune-mediated
adrenal insufficiency, autoimmune thyroid disorders, and Type 1
diabetes mellitus. Monitor patients for signs and symptoms of
hypophysitis, signs and symptoms of adrenal insufficiency, thyroid
function prior to and periodically during treatment, and
hyperglycemia. Administer hormone replacement as clinically
indicated and corticosteroids for Grade 2 or greater hypophysitis.
Withhold for Grade 2 or 3 and permanently discontinue for Grade 4
hypophysitis. Administer corticosteroids for Grade 3 or 4 adrenal
insufficiency. Withhold for Grade 2 and permanently discontinue for
Grade 3 or 4 adrenal insufficiency. Administer hormone-replacement
therapy for hypothyroidism. Initiate medical management for control
of hyperthyroidism. Withhold OPDIVO for Grade 3 and permanently
discontinue for Grade 4 hyperglycemia.
In patients receiving OPDIVO monotherapy, hypophysitis occurred
in 0.6% (12/1994) of patients. In patients receiving OPDIVO with
YERVOY, hypophysitis occurred in 9% (36/407) of patients. In
patients receiving OPDIVO monotherapy, adrenal insufficiency
occurred in 1% (20/1994) of patients. In patients receiving OPDIVO
with YERVOY, adrenal insufficiency occurred in 5% (21/407) of
patients. In patients receiving OPDIVO monotherapy, hypothyroidism
or thyroiditis resulting in hypothyroidism occurred in 9%
(171/1994) of patients. Hyperthyroidism occurred in 2.7% (54/1994)
of patients receiving OPDIVO monotherapy. In patients receiving
OPDIVO with YERVOY, hypothyroidism or thyroiditis resulting in
hypothyroidism occurred in 22% (89/407) of patients.
Hyperthyroidism occurred in 8% (34/407) of patients receiving
OPDIVO with YERVOY. In patients receiving OPDIVO monotherapy,
diabetes occurred in 0.9% (17/1994) of patients. In patients
receiving OPDIVO with YERVOY, diabetes occurred in 1.5% (6/407) of
patients.
In a separate Phase 3 study of YERVOY 3 mg/kg, 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.
Immune-Mediated Nephritis and Renal Dysfunction
OPDIVO can cause immune-mediated nephritis. Monitor patients for
elevated serum creatinine prior to and periodically during
treatment. Administer corticosteroids for Grades 2-4 increased
serum creatinine. Withhold OPDIVO for Grade 2 or 3 and permanently
discontinue for Grade 4 increased serum creatinine. In patients
receiving OPDIVO monotherapy, immune-mediated nephritis and renal
dysfunction occurred in 1.2% (23/1994) of patients. In patients
receiving OPDIVO with YERVOY, immune-mediated nephritis and renal
dysfunction occurred in 2.2% (9/407) of patients.
Immune-Mediated Skin Adverse Reactions and Dermatitis
OPDIVO can cause immune-mediated rash, including Stevens-Johnson
syndrome (SJS) and toxic epidermal necrolysis (TEN), some cases
with fatal outcome. Administer corticosteroids for Grade 3 or 4
rash. Withhold for Grade 3 and permanently discontinue for Grade 4
rash. For symptoms or signs of SJS or TEN, withhold OPDIVO and
refer the patient for specialized care for assessment and
treatment; if confirmed, permanently discontinue. In patients
receiving OPDIVO monotherapy, immune-mediated rash occurred in 9%
(171/1994) of patients. In patients receiving OPDIVO with YERVOY,
immune-mediated rash occurred in 22.6% (92/407) of patients.
In a separate Phase 3 study of YERVOY 3 mg/kg, severe,
life-threatening, or fatal immune-mediated dermatitis (eg,
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.
Immune-Mediated Encephalitis
OPDIVO can cause immune-mediated encephalitis. Evaluation of
patients with neurologic symptoms may include, but not be limited
to, consultation with a neurologist, brain MRI, and lumbar
puncture. Withhold OPDIVO in patients with new-onset moderate to
severe neurologic signs or symptoms and evaluate to rule out other
causes. If other etiologies are ruled out, administer
corticosteroids and permanently discontinue OPDIVO for
immune-mediated encephalitis. In patients receiving OPDIVO
monotherapy, encephalitis occurred in 0.2% (3/1994) of patients.
Fatal limbic encephalitis occurred in one patient after 7.2 months
of exposure despite discontinuation of OPDIVO and administration of
corticosteroids. Encephalitis occurred in one patient receiving
OPDIVO with YERVOY (0.2%) after 1.7 months of exposure.
Other Immune-Mediated Adverse Reactions
Based on the severity of the adverse reaction, permanently
discontinue or withhold OPDIVO, administer high-dose
corticosteroids, and, if appropriate, initiate hormone-replacement
therapy. Across clinical trials of OPDIVO monotherapy or in
combination with YERVOY, the following clinically significant
immune-mediated adverse reactions, some with fatal outcome,
occurred in <1.0% of patients receiving OPDIVO: myocarditis,
rhabdomyolysis, myositis, uveitis, iritis, pancreatitis, facial and
abducens nerve paresis, demyelination, polymyalgia rheumatica,
autoimmune neuropathy, Guillain-Barré syndrome, hypopituitarism,
systemic inflammatory response syndrome, gastritis, duodenitis,
sarcoidosis, histiocytic necrotizing lymphadenitis (Kikuchi
lymphadenitis), motor dysfunction, vasculitis, and myasthenic
syndrome.
Infusion Reactions
OPDIVO can cause severe infusion reactions, which have been
reported in <1.0% of patients in clinical trials. Discontinue
OPDIVO in patients with Grade 3 or 4 infusion reactions. Interrupt
or slow the rate of infusion in patients with Grade 1 or 2. In
patients receiving OPDIVO monotherapy, infusion-related reactions
occurred in 6.4% (127/1994) of patients. In patients receiving
OPDIVO with YERVOY, infusion-related reactions occurred in 2.5%
(10/407) of patients.
Complications of Allogeneic HSCT after OPDIVO
Complications, including fatal events, occurred in patients who
received allogeneic HSCT after OPDIVO. Outcomes were evaluated in
17 patients from Checkmate 205 and 039, who underwent allogeneic
HSCT after discontinuing OPDIVO (15 with reduced-intensity
conditioning, 2 with myeloablative conditioning). Thirty-five
percent (6/17) of patients died from complications of allogeneic
HSCT after OPDIVO. Five deaths occurred in the setting of severe or
refractory GVHD. Grade 3 or higher acute GVHD was reported in 29%
(5/17) of patients. Hyperacute GVHD was reported in 20% (n=2) of
patients. A steroid-requiring febrile syndrome, without an
identified infectious cause, was reported in 35% (n=6) of patients.
Two cases of encephalitis were reported: Grade 3 (n=1) lymphocytic
encephalitis without an identified infectious cause, and Grade 3
(n=1) suspected viral encephalitis. Hepatic veno-occlusive disease
(VOD) occurred in one patient, who received reduced-intensity
conditioned allogeneic HSCT and died of GVHD and multi-organ
failure. Other cases of hepatic VOD after reduced-intensity
conditioned allogeneic HSCT have also been reported in patients
with lymphoma who received a PD-1 receptor blocking antibody before
transplantation. Cases of fatal hyperacute GVHD have also been
reported. These complications may occur despite intervening therapy
between PD-1 blockade and allogeneic HSCT.
Follow patients closely for early evidence of transplant-related
complications such as hyperacute GVHD, severe (Grade 3 to 4) acute
GVHD, steroid-requiring febrile syndrome, hepatic VOD, and other
immune-mediated adverse reactions, and intervene promptly.
Embryo-Fetal Toxicity
Based on their mechanisms of action, OPDIVO and YERVOY can cause
fetal harm when administered to a pregnant woman. Advise pregnant
women of the potential risk to a fetus. Advise females of
reproductive potential to use effective contraception during
treatment with an OPDIVO- or YERVOY- containing regimen and for at
least 5 months after the last dose of OPDIVO.
Lactation
It is not known whether OPDIVO or YERVOY is present in human
milk. Because many drugs, including antibodies, are excreted in
human milk and because of the potential for serious adverse
reactions in nursing infants from an OPDIVO-containing regimen,
advise women to discontinue breastfeeding during treatment. Advise
women to discontinue nursing during treatment with YERVOY and for 3
months following the final dose.
Serious Adverse Reactions
In Checkmate 037, serious adverse reactions occurred in 41% of
patients receiving OPDIVO (n=268). Grade 3 and 4 adverse reactions
occurred in 42% of patients receiving OPDIVO. The most frequent
Grade 3 and 4 adverse drug reactions reported in 2% to <5% of
patients receiving OPDIVO were abdominal pain, hyponatremia,
increased aspartate aminotransferase, and increased lipase. In
Checkmate 066, serious adverse reactions occurred in 36% of
patients receiving OPDIVO (n=206). Grade 3 and 4 adverse reactions
occurred in 41% of patients receiving OPDIVO. The most frequent
Grade 3 and 4 adverse reactions reported in ≥2% of patients
receiving OPDIVO were gamma-glutamyltransferase increase (3.9%) and
diarrhea (3.4%). In Checkmate 067, serious adverse reactions (73%
and 37%), adverse reactions leading to permanent discontinuation
(43% and 14%) or to dosing delays (55% and 28%), and Grade 3 or 4
adverse reactions (72% and 44%) all occurred more frequently in the
OPDIVO plus YERVOY arm (n=313) relative to the OPDIVO arm (n=313).
The most frequent (≥10%) serious adverse reactions in the OPDIVO
plus YERVOY arm and the OPDIVO arm, respectively, were diarrhea
(13% and 2.6%), colitis (10% and 1.6%), and pyrexia (10% and 0.6%).
In Checkmate 017 and 057, serious adverse reactions occurred in 46%
of patients receiving OPDIVO (n=418). The most frequent serious
adverse reactions reported in at least 2% of patients receiving
OPDIVO were pneumonia, pulmonary embolism, dyspnea, pyrexia,
pleural effusion, pneumonitis, and respiratory failure. In
Checkmate 025, serious adverse reactions occurred in 47% of
patients receiving OPDIVO (n=406). The most frequent serious
adverse reactions reported in ≥2% of patients were acute kidney
injury, pleural effusion, pneumonia, diarrhea, and hypercalcemia.
In Checkmate 205 and 039, adverse reactions leading to
discontinuation occurred in 7% and dose delays due to adverse
reactions occurred in 34% of patients (n=266). Serious adverse
reactions occurred in 26% of patients. The most frequent serious
adverse reactions reported in ≥1% of patients were pneumonia,
infusion-related reaction, pyrexia, colitis or diarrhea, pleural
effusion, pneumonitis, and rash. Eleven patients died from causes
other than disease progression: 3 from adverse reactions within 30
days of the last OPDIVO dose, 2 from infection 8 to 9 months after
completing OPDIVO, and 6 from complications of allogeneic HSCT. In
Checkmate 141, serious adverse reactions occurred in 49% of
patients receiving OPDIVO. The most frequent serious adverse
reactions reported in at least 2% of patients receiving OPDIVO were
pneumonia, dyspnea, respiratory failure, respiratory tract
infection, and sepsis. In Checkmate 275, serious adverse reactions
occurred in 54% of patients receiving OPDIVO (n=270). The most
frequent serious adverse reactions reported in at least 2% of
patients receiving OPDIVO were urinary tract infection, sepsis,
diarrhea, small intestine obstruction, and general physical health
deterioration. In Checkmate 040, serious adverse reactions occurred
in 49% of patients (n=154). The most frequent serious adverse
reactions reported in at least 2% of patients were pyrexia,
ascites, back pain, general physical health deterioration,
abdominal pain, and pneumonia.
Common Adverse Reactions
In Checkmate 037, the most common adverse reaction (≥20%)
reported with OPDIVO (n=268) was rash (21%). In Checkmate 066, the
most common adverse reactions (≥20%) reported with OPDIVO (n=206)
vs dacarbazine (n=205) were fatigue (49% vs 39%), musculoskeletal
pain (32% vs 25%), rash (28% vs 12%), and pruritus (23% vs 12%). In
Checkmate 067, the most common (≥20%) adverse reactions in the
OPDIVO plus YERVOY arm (n=313) were fatigue (59%), rash (53%),
diarrhea (52%), nausea (40%), pyrexia (37%), vomiting (28%), and
dyspnea (20%). The most common (≥20%) adverse reactions in the
OPDIVO (n=313) arm were fatigue (53%), rash (40%), diarrhea (31%),
and nausea (28%). In Checkmate 017 and 057, the most common adverse
reactions (≥20%) in patients receiving OPDIVO (n=418) were fatigue,
musculoskeletal pain, cough, dyspnea, and decreased appetite. In
Checkmate 025, the most common adverse reactions (≥20%) reported in
patients receiving OPDIVO (n=406) vs everolimus (n=397) were
asthenic conditions (56% vs 57%), cough (34% vs 38%), nausea (28%
vs 29%), rash (28% vs 36%), dyspnea (27% vs 31%), diarrhea (25% vs
32%), constipation (23% vs 18%), decreased appetite (23% vs 30%),
back pain (21% vs 16%), and arthralgia (20% vs 14%). In Checkmate
205 and 039, the most common adverse reactions (≥20%) reported in
patients receiving OPDIVO (n=266) were upper respiratory tract
infection (44%), fatigue (39%), cough (36%), diarrhea (33%),
pyrexia (29%), musculoskeletal pain (26%), rash (24%), nausea (20%)
and pruritus (20%). In Checkmate 141, the most common adverse
reactions (≥10%) in patients receiving OPDIVO were cough and
dyspnea at a higher incidence than investigator’s choice. In
Checkmate 275, the most common adverse reactions (≥ 20%) reported
in patients receiving OPDIVO (n=270) were fatigue (46%),
musculoskeletal pain (30%), nausea (22%), and decreased appetite
(22%).. In Checkmate 040, the most common adverse reactions (≥20%)
in patients receiving OPDIVO (n=154) were fatigue (38%),
musculoskeletal pain (36%), abdominal pain (34%), pruritus (27%),
diarrhea (27%), rash (26%), cough (23%), and decreased appetite
(22%). The most common adverse reactions (≥20%) in patients who
received OPDIVO as a single agent were fatigue, rash,
musculoskeletal pain, pruritus, diarrhea, nausea, asthenia, cough,
dyspnea, constipation, decreased appetite, back pain, arthralgia,
upper respiratory tract infection, and pyrexia.
In a separate Phase 3 study of YERVOY 3 mg/kg, 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%).
Checkmate Trials and Patient Populations
Checkmate 067 – advanced melanoma alone or in combination
with YERVOY; Checkmate 037 and 066 – advanced melanoma;
Checkmate 017 – squamous non-small cell lung cancer (NSCLC);
Checkmate 057 – non-squamous NSCLC; Checkmate 025 –
renal cell carcinoma; Checkmate 205/039 – classical Hodgkin
lymphoma; Checkmate 141 – squamous cell carcinoma of the
head and neck; Checkmate 275 – urothelial carcinoma;
Checkmate 040 – hepatocellular carcinoma.
Please see U.S. Full Prescribing Information for OPDIVO and
YERVOY, including Boxed WARNING regarding immune-mediated
adverse reactions for YERVOY.
U.S. Indication and Important Safety Information - BARACLUDE®
(entecavir):
INDICATION
BARACLUDE (entecavir) is indicated for the treatment of chronic
hepatitis B virus (HBV) infection in adults and pediatric patients
2 years of age or older with evidence of active viral replication
and either evidence of persistent elevations in serum
aminotransferases (ALT or AST) or histologically active
disease.
The following points should be considered when initiating
therapy with BARACLUDE:
- In adult patients, this indication is
based on clinical trial data in nucleoside-inhibitor
treatment-naïve and lamivudine-resistant subjects with
HBeAg-positive and HBeAgnegative HBV infection and compensated
liver disease and a more limited number of subjects with
decompensated liver disease.
- In pediatric patients 2 years of age
and older, this indication is based on clinical trial data in
nucleoside-inhibitor-treatment-naïve and in a limited number of
lamivudine experienced subjects with HBeAg-positive chronic HBV
infection and compensated liver disease.
IMPORTANT SAFETY INFORMATION
WARNINGS: SEVERE ACUTE EXACERBATIONS OF HEPATITIS B, PATIENTS
CO-INFECTED WITH HIV AND HBV, and LACTIC ACIDOSIS AND
HEPATOMEGALY
- Severe acute exacerbations of
hepatitis B have been reported in patients who have discontinued
anti-hepatitis B therapy, including entecavir. Hepatic function
should be monitored closely with both clinical and laboratory
follow-up for at least several months in patients who discontinue
anti-hepatitis B therapy. If appropriate, initiation of
anti-hepatitis B therapy may be warranted.
- Limited clinical experience suggests
there is a potential for the development of resistance to HIV
(human immunodeficiency virus) nucleoside reverse transcriptase
inhibitors if BARACLUDE is used to treat chronic HBV infection in
patients with HIV infection that is not being treated. Therapy with
BARACLUDE is not recommended for HIV/HBV co-infected patients who
are not also receiving highly active antiretroviral therapy
(HAART).
- Lactic acidosis and severe
hepatomegaly with steatosis, including fatal cases, have been
reported with the use of nucleoside analogues, alone or in
combination with antiretrovirals.
Warnings and Precautions
- Before initiating BARACLUDE therapy,
HIV antibody testing should be offered to all patients. BARACLUDE
has not been studied as a treatment for HIV infection and is not
recommended for this use.
- Lactic acidosis with BARACLUDE use has
been reported, often in association with hepatic decompensation,
other serious medical conditions, or drug exposures. Patients with
decompensated liver disease may be at higher risk for lactic
acidosis. BARACLUDE should be suspended in any patient who develops
clinical or laboratory findings suggestive of lactic acidosis or
pronounced hepatotoxicity.
Adverse Reactions
- In clinical trials in patients with
compensated liver disease, the most common (≥3%) adverse reactions
of any severity with at least a possible relation to study drug for
BARACLUDE-treated subjects were headache, fatigue, dizziness, and
nausea. In these trials, the most common adverse reactions of
moderate to severe intensity (grades 2-4) were diarrhea, dyspepsia,
nausea, vomiting, fatigue, headache, dizziness, somnolence, and
insomnia.
- In the decompensated liver disease
trial, the most common adverse reactions of any severity among
patients treated with BARACLUDE, regardless of causality, included:
peripheral edema (16%), ascites (15%), pyrexia (14%), hepatic
encephalopathy (10%), and upper respiratory infection (10%). In
this trial, 18% (18/102) of BARACLUDE patients and 20% (18/89) of
adefovir patients died during the first 48 weeks of therapy. The
majority of those deaths were due to liver related causes.
Drug Interactions
- BARACLUDE (entecavir) is primarily
eliminated by the kidneys; therefore coadministration of BARACLUDE
with drugs that reduce renal function or compete for active tubular
secretion may increase serum concentrations of either entecavir or
the coadministered drug. Patients should be monitored closely when
receiving BARACLUDE with other renally-eliminated drugs.
Pregnancy and Nursing Mothers
- There are no adequate and
well-controlled studies of BARACLUDE in pregnant women. BARACLUDE
should be used during pregnancy only if the potential benefit
justifies the potential risk to the fetus.
- There are no studies on the effect of
BARACLUDE on transmission of HBV from mother to infant. Therefore,
appropriate interventions should be used to prevent neonatal
acquisition of HBV.
- It is not known whether BARACLUDE is
excreted into human milk; however, many drugs are excreted into
breast milk. Due to the potential for serious adverse reactions in
nursing infants from BARACLUDE, risks and benefits should be
considered when deciding whether to discontinue breast-feeding or
discontinue BARACLUDE in nursing women.
Pediatric Use
- The adverse reactions observed in
pediatric patients who received treatment with BARACLUDE were
consistent with those observed in clinical trials of BARACLUDE in
adults. Adverse drug reactions reported in greater than 1% of
pediatric patients included abdominal pain, rash events, poor
palatability (“product taste abnormal”), nausea, diarrhea, and
vomiting.
- Due to limited data, in
lamivudine-experienced pediatric patients, Baraclude should be used
only if the potential benefit justifies the potential risk to the
child. Consideration should be given to the impact of BARACLUDE on
future treatment options.
Renal Impairment
- Dosage adjustment of BARACLUDE is
recommended for patients with a creatinine clearance <50 mL/min,
including those on hemodialysis or continuous ambulatory peritoneal
dialysis. There is insufficient data to recommend specific dosage
adjustments of BARACLUDE in pediatric patients with renal
impairment, however dosage adjustments similar to those for adults
should be considered.
Liver Transplant RecipientsRenal function must be
carefully monitored both before and during treatment with BARACLUDE
in a liver transplant recipient who has received or is receiving an
immunosuppressant that may affect renal function, such as
cyclosporine or tacrolimus.
Duration of Therapy
- The optimal duration of treatment with
BARACLUDE for patients with chronic HBV infection and the
relationship between treatment and long-term outcomes such as
cirrhosis and hepatocellularcarcinoma are unknown.
Additional InformationBARACLUDE is not a cure for HBV.
Patients should be advised that treatment with BARACLUDE has not
been shown to reduce the risk of transmission of HBV to others
through sexual contact or blood contamination.
Please click here for the BARACLUDE full
prescribing information, including Boxed WARNINGS.
About the Bristol-Myers Squibb and Ono
Pharmaceutical Co., Ltd. CollaborationIn 2011, through a
collaboration agreement with Ono Pharmaceutical Co., Ltd. (Ono),
Bristol-Myers Squibb expanded its territorial rights to develop and
commercialize Opdivo globally except in Japan, South Korea and
Taiwan, where Ono had retained all rights to the compound at the
time. On July 23, 2014, Bristol-Myers Squibb and Ono further
expanded the companies’ strategic collaboration agreement to
jointly develop and commercialize multiple immunotherapies – as
single agents and combination regimens – for patients with cancer
in Japan, South Korea and Taiwan.
About Bristol-Myers
SquibbBristol-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 us
at BMS.com or follow us on LinkedIn, Twitter, YouTube and
Facebook.
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 or products mentioned in this release
will receive regulatory approval for any of the indications
described herein. 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,
2016 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.
View source
version on businesswire.com: http://www.businesswire.com/news/home/20171020005178/en/
Bristol-Myers SquibbMedia:Chrissy Trank,
609-252-5609Christina.trank@bms.comorAudrey Abernathy,
919-605-4521audrey.abernathy@bms.comorInvestors:Tim Power,
609-252-7509timothy.power@bms.comorBill Szablewski,
609-252-5894william.szablewski@bms.com
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