Phase IIIb Comparison of Baraclude (Entecavir) Monotherapy Versus Baraclude Plus Tenofovir Combination Shows No Statistical Difference Between Study Arms
• 96-week study in a population of nucleos(t)ide-naïve patients with chronic hepatitis B (CHB) infection
• Data presented at the American Association for the Study of Liver Diseases congress in San Francisco
(SAN FRANCISCO, November 8, 2011) – Bristol-Myers Squibb
Company (NYSE: BMY) today announced 96-week results from the
BE?LOW™ study, a Phase IIIb clinical trial comparing
BARACLUDE monotherapy (0.5mg once daily) with BARACLUDE (0.5mg once
daily) plus tenofovir (300mg once daily) in treatment-naïve
adult patients with HBeAg-positive and HBeAg-negative chronic
hepatitis B (CHB) with compensated liver disease. In this study, no
statistically significant difference was observed between the two
treatment arms in the primary efficacy endpoint of HBV DNA <50
iu>
([1] HBV DNA carries the genetic blueprint of the hepatitis B
virus. The number of HBV DNA “copies” found in a
person’s blood, or “viral load,” indicates how
rapidly the virus is reproducing in their liver. Low levels of HBV
DNA, recognized as 300 copies per milliliter or less, indicate an
“inactive” hepatitis B infection.)
“In these 96-week data comparing entecavir monotherapy to
combination of entecavir plus tenofovir, we found that combination
therapy did not result in statistically significant difference in
virologic response compared to entecavir monotherapy. The BE-LOW
study data confirmed the results of previous studies showing
limited or no benefit of combination therapy compared to
monotherapy for treatment-naïve patients with chronic
hepatitis B,” said principal investigator Anna Lok, MD, FRCP,
director of clinical hepatology and professor in the department of
internal medicine at the University of Michigan Medical School in
Ann Arbor.
Study Results
In this study, 379 nucleos(t)ide-naïve patients with CHB were
randomized to receive either BARACLUDE (entecavir) 0.5 mg once
daily (n=182) or BARACLUDE 0.5 mg plus tenofovir 300 mg once daily
(n=197). Key findings at week 96 are:
• A comparable proportion of patients in both treatment arms
achieved the primary efficacy endpoint of HBV DNA <50 iu>
• Among HBeAg-positive patients, the proportion achieving HBV
DNA <50 iu>
• Among HBeAg-negative patients, the proportion achieving HBV
DNA <50 iu>
Secondary efficacy endpoints measured in the study included alanine
aminotransferase (ALT) normalization, HBeAg seroconversion, and
HBeAg loss. ALT normalization was observed in 81.9% (149/182) of
patients in this study in the BARACLUDE (entecavir) monotherapy arm
versus 69% (136/197) in the BARACLUDE plus tenofovir arm. HBeAg
seroconversion was observed in 32.5% (41/126) of patients in the
BARACLUDE (entecavir) monotherapy arm versus 21.7% (30/138) in the
BARACLUDE plus tenofovir arm in this study.
Two patients (1.1%) in the BARACLUDE monotherapy arm compared to
five patients (2.5%) in the BARACLUDE plus tenofovir arm
discontinued treatment prior to week 96. Patients who discontinued
therapy prior to week 96 were considered treatment failures.
The overall adverse event profiles were similar across study arms.
A total of three deaths occurred among treated patients, all on the
BARACLUDE plus tenofovir arm: one due to bile duct tumor; one due
to a late-onset exacerbation of hepatitis which was associated with
breakthrough viremia while on continued treatment; and one due to
cardiac arrest. One patient (0.5%) in the BARACLUDE monotherapy arm
and two patients (1.0%) in the BARACLUDE plus tenofovir arm
experienced on treatment ALT flares, defined as >2 x baseline
ALT and >10 x ULN. No patients (0.0%) in either arm experienced
off-treatment ALT flares. Six patients (3.3%) in the BARACLUDE
monotherapy arm and four (2.0%) patients in the BARACLUDE plus
tenofovir arm experienced serum creatinine increase ≥0.3 mg/dL.
A total of five malignancies occurred among patients in the study:
four (2.2%) patients in the BARACLUDE monotherapy arm and one
(0.5%) patient in the BARACLUDE plus tenofovir arm. In the
BARACLUDE monotherapy arm, there were three diagnoses of
hepatocellular carcinoma (two on-treatment and one off-treatment)
and one case of gastric cancer. In the BARACLUDE plus tenofovir arm
there was one case of breast cancer.
Two patients (1.0%) in the BARACLUDE monotherapy arm and seven
patients (3.6%) in the BARACLUDE plus tenofovir arm experienced
virologic breakthrough. No recognized genotypic resistance
mutations were observed in either treatment arm.
About The Study
The BE-LOW study is an open-label, multicenter, Phase IIIb study of
379 nucleos(t)ide-naïve patients with CHB. The patients were
randomized 1:1 and treated with either BARACLUDE 0.5 mg once daily
(n=182) or BARACLUDE 0.5 mg plus tenofovir 300 mg once daily
(n=197). Nucleos(t)ide-naïve, HBeAg-negative CHB patient
enrollment was capped at 30%. The primary efficacy endpoint was the
proportion of patients with HBV DNA <50 iu>
About Chronic Hepatitis B
Approximately 350 million people worldwide are chronically infected
with hepatitis B (approximately 5% of the world’s population)
and 75% of these cases occur in the Asia-Pacific region. Most
people with chronic hepatitis B show no signs or symptoms, so many
of those chronically infected are unaware of their status. A blood
test can diagnose chronic hepatitis B. Patients should speak with
their doctor about options available for this condition.
About BARACLUDE (entecavir)
BARACLUDE, a nucleoside analogue discovered at Bristol-Myers
Squibb, was first approved by the U.S. Food and Drug Administration
in March 2005 for use in adult chronic hepatitis B patients with
compensated liver disease. The initial approval was based on
histologic, virologic, biochemical, and serologic responses in
nucleoside-treatment-naïve and lamivudine-resistant adult
subjects with HBeAg-positive or HBeAg-negative CHB infection and
compensated liver disease. BARACLUDE is also indicated for use for
the treatment of chronic hepatitis B in adult patients with
decompensated liver disease based on virologic, biochemical,
serologic, and safety data.
INDICATION and IMPORTANT SAFETY INFORMATION about BARACLUDE (entecavir) Tablets:
INDICATION
BARACLUDE is indicated for the treatment of chronic hepatitis B
virus (HBV) infection in adults 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
BARACLUDE (entecavir):
• This indication is based on histologic, virologic,
biochemical, and serologic responses in
nucleoside-treatment-naïve and lamivudine-resistant adult
subjects with HBeAg-positive or HBeAg-negative chronic HBV
infection and compensated liver disease.
• Virologic, biochemical, serologic, and safety data are
available from a controlled study in adult subjects with chronic
HBV infection and decompensated liver disease.
• Virologic, biochemical, serologic, and safety data are
available for a limited number of adult subjects with HIV/HBV
co-infection who have received prior lamivudine therapy.
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
(entecavir) 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 (entecavir) 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 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 (entecavir) in pregnant women. BARACLUDE should be used
during pregnancy only if clearly needed and after careful
consideration of the risks and benefits.
• 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
• Safety and effectiveness of BARACLUDE in pediatric patients
below the age of 16 years have not been established.
Renal Impairment
• Dosage adjustment of BARACLUDE is recommended for patients
with a creatinine clearance <50 ml>
• The safety and efficacy of BARACLUDE in liver transplant
recipients are unknown. Renal 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.
Dosage and Administration
BARACLUDE should be administered on an empty stomach (at least 2
hours after a meal and at least 2 hours before the next meal).
The recommended dose of BARACLUDE (entecavir):
• in nucleoside-naïve adults and adolescents (16+ yrs)
with compensated liver disease is 0.5 mg once daily
• in adults and adolescents (16+ yrs) with compensated liver
disease, and refractory to lamivudine or with known lamivudine or
telbivudine resistance mutations (rtM204I/V with or without
rtL180M, rtL80I/V, or rtV173L) is 1 mg once daily
• in adults with decompensated liver disease is 1 mg once
daily
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 hepatocellular carcinoma are unknown.
Additional Information
BARACLUDE (entecavir) 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 see accompanying Full Prescribing Information, including Boxed WARNINGS, or click here.
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 http://www.bms.com or follow us on
Twitter at http://twitter.com/bmsnews.
BARACLUDE® (entecavir) is a registered trademark of
Bristol-Myers Squibb.
# # #
Contacts:
Bristol-Myers Squibb
Media: Cristi Barnett, 609-252-6028, cristi.barnett@bms.com
Investors: John Elicker, 609-252-4611, john.elicker@bms.com
Posted: November 2011
