Bristol-Myers
Squibb Company (NYSE:BMY) announced today the submission of a new
drug application (NDA) on April 4, 2014 to the U.S. Food and Drug
Administration (FDA) for a fixed-dose combination of atazanavir sulfate,
a protease inhibitor marketed as Reyataz®, and cobicistat, an
investigational pharmacokinetic enhancer, or boosting agent, that can
increase the level of certain HIV-1 medicines in the blood and make them
more effective. Bristol-Myers Squibb is seeking approval of the
fixed-dose combination tablet for use in combination with other
antiretroviral agents for the treatment of HIV-1 infection. If approved,
atazanavir sulfate and cobicistat could offer patients living with HIV-1
a single tablet that eliminates the need to take a boosting agent in a
separate tablet. Cobicistat is being developed by Gilead Sciences, Inc.
Approximately 245,000 patients in the U.S. have been treated with Reyataz
since its launch in 2003, nearly twice that of any other protease
inhibitor launched since that time. Reyataz is currently used in
combination with other antiretroviral agents and is most commonly used
with ritonavir, a pharmacokinetic enhancer. A once-daily therapy, Reyataz
is indicated for the treatment of HIV-1 infection in treatment-naïve and
treatment-experienced adult patients and pediatric patients six years of
age or older.
“Bristol-Myers Squibb is committed to enhancing our existing regimens,
as well as developing new therapies to make HIV treatment simpler for
patients,” said Brian
Daniels, M.D., senior vice president, Global Development and Medical
Affairs, Bristol-Myers Squibb. “The submission of this NDA represents an
important step forward in our efforts to provide patients with new
options for Reyataz treatment.”
Reyataz is the only protease inhibitor that has been evaluated
with cobicistat in a prospective, randomized, Phase III double-blind
clinical trial (Gilead’s Study 114), which compared the efficacy and
safety of cobicistat-boosted Reyataz (atazanavir sulfate) versus
ritonavir-boosted Reyataz in treatment-naïve adult patients for
48 weeks. Study 114 may support the clinical use of atazanavir and
cobicistat together.
“Adhering to HIV treatment regimens can be challenging for some
patients, and if the prescribed medications are not taken properly, it
could result in treatment failure,” said Calvin J. Cohen, M.D., MPH,
director of research, Community Research Initiative of New England and
internist, Harvard Vanguard Medical Associates. “If approved by the FDA,
a once-daily, fixed-dose combination of atazanavir sulfate and
cobicistat would offer patients living with HIV-1 another treatment
option.”
In October 2011, Bristol-Myers Squibb announced a licensing agreement
with Gilead for the development and commercialization of a once-daily,
single tablet fixed-dose combination product of atazanavir sulfate and
Gilead's cobicistat. Under the terms of the agreement, Bristol-Myers
Squibb and its affiliates are responsible for the formulation,
manufacturing, registration, distribution and commercialization of the
atazanavir sulfate and cobicistat fixed-dose combination product
worldwide. Gilead retains sole rights for the manufacture, development
and commercialization of cobicistat as a stand-alone product and for use
in combination with other agents.
About Bristol-Myers Squibb’s HIV Research Portfolio
For more than 20 years, Bristol-Myers Squibb has focused on discovering,
developing and delivering innovative medicines to help meet the needs of
patients living with HIV-1 and continues to pursue advances in
treatment, for both children and adults with HIV-1. Studies are ongoing
for new treatments including an HIV-1 attachment inhibitor (BMS-663068),
an HIV-1 maturation inhibitor (BMS-955176) and an anti-PD-L1
(BMS-936559).
INDICATION and IMPORTANT SAFETY INFORMATION about REYATAZ (atazanavir
sulfate) 200mg/300mg Capsules:
INDICATION:
REYATAZ® (atazanavir sulfate) is indicated in combination with other
antiretroviral agents for treatment of HIV-1 infection. This is based on
analyses of plasma HIV-1 RNA levels and CD4+ cell counts from controlled
studies of 96 weeks (treatment-naive) and 48 weeks
(treatment-experienced) duration in adult and pediatric patients at
least 6 years of age. The following should be considered when initiating
REYATAZ:
-
In Study 045, REYATAZ/ritonavir and lopinavir/ritonavir were similar
for the primary efficacy measure of time-averaged difference in change
from baseline in HIV RNA. This study was not large enough to reach a
definitive conclusion that REYATAZ/ritonavir and lopinavir/ritonavir
are equivalent on the secondary efficacy measure of proportions below
the HIV RNA lower limit of detection.
-
The number of baseline primary protease inhibitor mutations affects
virologic response to REYATAZ/ritonavir.
IMPORTANT SAFETY INFORMATION:
-
Hypersensitivity: REYATAZ is contraindicated in patients with
previously demonstrated clinically significant hypersensitivity (eg,
Stevens-Johnson syndrome, erythema multiforme, or toxic skin
eruptions) to any of the product components.
-
Contraindicated Drugs: Coadministration with drugs highly
dependent on CYP3A or UGT1A1 for clearance and for which elevated
plasma concentrations are associated with serious and/or
life-threatening events is contraindicated. These and other
contraindicated drugs are alfuzosin, rifampin, irinotecan, orally
administered midazolam, triazolam, dihydroergotamine, ergotamine,
ergonovine, methylergonovine, cisapride, St. John’s wort (Hypericum
perforatum)-containing products, lovastatin, simvastatin,
pimozide, sildenafil dosed as Revatio®, or indinavir.
-
Drug Interactions: Coadministration with the following drugs is
not recommended.
-
nevirapine, salmeterol
-
when REYATAZ is given with ritonavir: nevirapine, boceprevir,
other HIV protease inhibitors, fluticasone propionate.
Voriconazole should not be administered, unless assessment of
benefit/risk justifies its use. Patients should be carefully
monitored for adverse events and loss of efficacy.
-
when REYATAZ (atazanavir sulfate) is given without ritonavir:
buprenorphine, bosentan, carbamazepine, phenytoin, phenobarbital.
-
in treatment-experienced patients: proton-pump inhibitors or
efavirenz
-
in patients with renal or hepatic impairment: colchicine
See Section 7 (including Table 13), of the Full Prescribing
Information for additional established and other potentially significant
drug interactions, and related dose modification recommendations.
-
Cardiac Conduction Abnormalities: PR interval prolongation may
occur in some patients. Atrioventricular (AV) conduction abnormalities
were asymptomatic and generally limited to first-degree AV block.
There have been rare reports of second-degree AV block and other
conduction abnormalities. Use REYATAZ with caution in patients with
preexisting conduction system disease or when administered with other
drugs that may prolong the PR interval (including beta-blockers other
than atenolol, diltiazem, verapamil, and digoxin), especially drugs
metabolized by CYP3A. When used with REYATAZ, a 50% dose reduction of
diltiazem should be considered, and ECG monitoring is recommended.
-
Rash (all grades, generally mild-to-moderate maculopapular skin
eruptions, regardless of causality) occurred in approximately 20% of
patients treated with REYATAZ in controlled clinical trials. Cases of
Stevens-Johnson syndrome, erythema multiforme, and toxic skin
eruptions, including drug rash, eosinophilia and systemic symptoms
(DRESS) syndrome, have been reported. Discontinue REYATAZ if severe
rash develops.
-
Hyperbilirubinemia: Reversible, asymptomatic elevations in
indirect (unconjugated) bilirubin occurred in most patients treated
with REYATAZ. There are no long-term safety data for patients with
persistent elevations in total bilirubin >5 times upper limit of
normal. Alternative antiretroviral therapy may be considered if
jaundice or scleral icterus present cosmetic concerns.
-
Hepatotoxicity: Use REYATAZ (atazanavir sulfate) with caution
in patients with hepatic impairment because atazanavir concentrations
may be increased. Patients with hepatitis B or C infection or marked
elevations in transaminases are at risk of further transaminase
elevations or hepatic decompensation. In these patients, hepatic
laboratory testing should be performed before and during REYATAZ
therapy.
-
Nephrolithiasis and cholelithiasis have been reported during
postmarketing surveillance in HIV-infected patients receiving REYATAZ.
Some patients required hospitalization and some had complications. If
signs or symptoms of nephrolithiasis and/or cholelithiasis occur,
consider temporary interruption or discontinuation of therapy.
-
New onset or exacerbation of diabetes mellitus and hyperglycemia have
been reported in patients treated with protease inhibitor therapy. A
causal relationship has not been established.
-
Immune reconstitution syndrome has been reported in patients
treated with combination antiretroviral therapy, including REYATAZ.
Autoimmune disorders (such as Graves’ disease, polymyositis, and
Guillain-Barré syndrome) have also been reported to occur in the
setting of immune reconstitution; however, the time to onset is more
variable, and can occur many months after initiation of treatment.
-
Redistribution and/or accumulation of body fat have been seen
in patients receiving antiretroviral therapy. A causal relationship
has not been established.
-
Increased bleeding has been reported in patients with
hemophilia type A and B treated with protease inhibitors.
-
Various degrees of cross-resistance among protease inhibitors
have been observed.
-
The most common moderate or severe adverse reactions were as
follows, regardless of causality:
-
In treatment-naive adult patients (≥2%): nausea
(4-14%), jaundice/scleral icterus (5-7%), rash (3-7%), headache
(1-6%), abdominal pain (4%), vomiting (3-4%), peripheral
neurologic symptoms (<1-4%), diarrhea (1-3%), insomnia (<1-3%),
and dizziness (<1-2%).
-
In treatment-experienced adult patients (≥2%):
jaundice/scleral icterus (9%), myalgia (4%), diarrhea (3%), nausea
(3%), depression (2%), and fever (2%).
-
In pediatric patients (≥5%): cough (21%), fever
(18%), jaundice/scleral icterus (15%), rash (14%), vomiting (12%),
diarrhea (9%), headache (8%), peripheral edema (7%), extremity
pain (6%), nasal congestion (6%), oropharyngeal pain (6%),
wheezing (6%), and rhinorrhea (6%).
-
REYATAZ (atazanavir sulfate) should be used with caution in patients
with mild to moderate hepatic impairment. REYATAZ should not be used
in patients with severe hepatic impairment (Child-Pugh Class
C). REYATAZ/ritonavir has not been studied in patients with hepatic
impairment and is not recommended.
-
REYATAZ should not be used in treatment-experienced patients with end-stage
renal disease managed with hemodialysis.
Please see accompanying Full Prescribing Information 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.
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 the combination
therapy mentioned will receive regulatory approval or, if approved, that
it will become a commercially successful product. Forward-looking
statements in this press release should be evaluated together with the
many uncertainties that affect Bristol-Myers Squibb's business,
particularly those identified in the cautionary factors discussion in
Bristol-Myers Squibb's Annual Report on Form 10-K for the year ended
December 31, 2013 in our Quarterly Reports on Form 10-Q and our Current
Reports on Form 8-K. Bristol-Myers Squibb undertakes no obligation to
publicly update any forward-looking statement, whether as a result of
new information, future events or otherwise.
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