The European Commission approval is based
upon Phase III clinical trial - Reyataz®(atazanavir) and
cobicistat combination demonstrated virologic failure rates as low
as 6% at 48 weeks and 8% at 144 weeks [HIV-1 RNA ≥50 copies/mL: 6%
Reyataz/cobicistat arm and 4% Reyataz/ritonavir arm at 48 weeks; 8%
Reyataz/cobicistat arm and 5% Reyataz/ritonavir arm at 144
weeks]
Reyataz/cobicistat safety was demonstrated
through 144 weeks in clinical trials
Bristol-Myers Squibb Company (NYSE:BMY) announced today that the
European Commission has approved Evotaz (atazanavir 300 mg and
cobicistat 150 mg) tablets in combination with other antiretroviral
agents for the treatment of HIV-1 infected adults without known
mutations associated with resistance to atazanavir. Coformulated to
be one pill, once-daily, Evotaz combines the protease inhibitor
atazanavir, which is marketed as Reyataz (atazanavir) capsules, and
cobicistat, a pharmacokinetic enhancer marketed as Tybost® by
Gilead Sciences, Inc. Today’s approval allows for the marketing of
Evotaz in all 28 Member States of the European Union (EU) and
offers patients living with HIV an innovative treatment option that
delivers proven suppression through 144 weeks. The marketing
authorization follows a positive opinion by the Committee for
Medicinal Products for Human Use (CHMP) in May 2015. The U.S. Food
and Drug Administration (FDA) approved Evotaz in the United States
in January 2015.
Evotaz is contraindicated in patients with previously
demonstrated clinically significant hypersensitivity to the
active substances or to any of the excipients of Evotaz, in
combination with certain drugs, and in patients with moderate to
severe hepatic impairment. Evotaz and Reyataz do not cure HIV-1
infection or AIDS.
There are 2.2 million people living with HIV in the European
region, according to recent estimates from UNAIDS and WHO, and
between 2004 and 2013, more than 300,000 people were newly
infected. Only one-third of diagnosed patients (35%) in the eastern
European region were receiving antiretroviral therapy in 2012, a
number that is significantly below the 80% coverage goal set by WHO
for 2015. Virologic suppression, or the reduction of HIV viral load
to undetectable amounts in the blood, is the goal of antiretroviral
treatment in all patients.
“HIV remains a significant public health concern throughout the
world, and the increase in new infections in recent years in Europe
means that it is more important than ever to continue to deliver
new treatment options to help patients achieve virologic
suppression,” said Murdo Gordon, Head of Worldwide Markets,
Bristol-Myers Squibb. “By combining reduced pill burden with a low
rate of virologic failure and no protease inhibitor mutations,
Evotaz increases the possibility of suppressing HIV, and we are
pleased to bring it to physicians and patients in the EU.”
Study Design
Evotaz is the first and only fixed-dose combination (FDC) of a
protease inhibitor pharmacoenhanced by cobicistat that is supported
by comparative Phase III trial data. The European Commission’s
approval is based on data from Gilead’s Study 114, a randomized,
double-blind clinical trial (N=692) evaluating the safety and
efficacy of Reyataz 300 mg with cobicistat 150 mg (the components
of Evotaz) (n=344) versus Reyataz 300 mg with ritonavir 100 mg
(Reyataz/ritonavir) (n=348), another pharmacokinetic enhancing
agent, in combination with emtricitabine/tenofovir disoproxil
fumarate in treatment-naive adults. At 48 weeks, 85% of patients in
the Reyataz/cobicistat arm achieved virologic success (HIV-1 RNA
levels of <50 copies/mL) compared to 87% of patients in the
Reyataz/ritonavir arm. Low rates of virologic failure (HIV-1 RNA
≥50 copies/mL: 6% Reyataz/cobicistat arm; 4% Reyataz/ritonavir arm)
were also observed at 48 weeks. The long-term data at week 144 also
confirmed these results, with virologic success and failure rates
of 72% and 8%, respectively, in the Reyataz/cobicistat arm, and 74%
and 5%, respectively, in the Reyataz/ritonavir arm. Virologic
failure, which occurs when therapies are unable to completely
suppress HIV, may be caused in part by drug resistance. Limited
data are available on the development of resistance to
Reyataz/cobicistat. However, in the clinical trial, no patients
taking Reyataz/cobicistat who had virologic failure developed
protease inhibitor resistance through 48 weeks. Specifically, zero
patients developed tenofovir-associated resistance K65R, and two
patients developed emtricitabine resistance M184V. In the
Reyataz/ritonavir arm, zero resistance was observed.
“The clinical efficacy demonstrated by Reyataz/cobicistat – in
one pill rather than two as with ritonavir-boosted Reyataz – is
significant for protecting against drug resistance and helping to
increase the potential for virologic suppression,” said Douglas
Manion, M.D., Head of Specialty Development, Bristol-Myers Squibb.
“Preventing resistance is a paramount consideration for management
of HIV, and a critical success factor in suppressing the
disease.”
Reyataz/cobicistat also demonstrated a safety profile comparable
to Reyataz/ritonavir. The most common moderate to severe adverse
events (AEs) in both treatment arms were jaundice, ocular iterus,
and nausea. There were similar low rates of discontinuation due to
AEs with Reyataz/cobicistat as compared to Reyataz/ritonavir at 48
weeks (6% and 7%, respectively). The Summary of Product
Characteristics will be available at www.ema.europa.eu.
In October 2011, Bristol-Myers Squibb announced a licensing
agreement with Gilead for the development and commercialization of
a once-daily, fixed-dose combination product of atazanavir and
cobicistat, now named Evotaz. Under the terms of the agreement,
Bristol-Myers Squibb and its affiliates are responsible for the
formulation, manufacturing, registration, distribution and
commercialization of the Evotaz 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 Reyataz (atazanavir)
Reyataz, co-administered with low dose ritonavir, is indicated
in the EU for the treatment of HIV-infected adults and pediatric
patients 6 years of age and older in combination with other
antiretroviral medicinal products. Use of Reyataz in
treatment-experienced patients should be based on individual viral
resistance testing and the patient’s treatment history. For more
information, please see the Reyataz Summary of Product
Characteristics at www.ema.europa.eu.
About Bristol-Myers Squibb in HIV
For more than 20 years, Bristol-Myers Squibb has focused on
delivering innovative medicines to help meet the needs of patients
living with HIV-1. Our goal is to help individuals living with HIV
to live longer and healthier lives by achieving and maintaining
viral suppression and addressing the challenges of treatment
resistance. We are investigating new ways to attack the HIV virus,
and studies are ongoing for innovative treatments including an
HIV-1 attachment inhibitor (BMS-663068) and an HIV-1 maturation
inhibitor (BMS-955176).
Important Safety Information (ISI) for Evotaz and Reyataz in
the U.S.
The following ISI is based on information from U.S. Prescribing
Information for Evotaz and Reyataz. Please consult the full
Prescribing Information for all labeled safety information.
INDICATIONS for EvotazTM (atazanavir and
cobicistat) and Reyataz® (atazanavir)
EVOTAZ is a fixed dose combination of atazanavir and cobicistat,
and is indicated for use with other antiretroviral agents for the
treatment of HIV-1 infection in adults.
REYATAZ is indicated in combination with other antiretroviral
agents for the treatment of HIV-1 infection in adults, and for
patients 3 months and older weighing at least 10 kg.
LIMITATIONS OF USE
- Use of EVOTAZ or REYATAZ/ritonavir in
treatment-experienced patients should be guided by the number of
baseline primary protease inhibitor resistance substitutions
- REYATAZ is not recommended for use in
pediatric patients less than 3 months due to the risk of
kernicterus
IMPORTANT SAFETY INFORMATION for EVOTAZ and REYATAZ
CONTRAINDICATIONS
EVOTAZ and REYATAZ are contraindicated:
- In patients with previously
demonstrated clinically significant hypersensitivity (e.g.,
Stevens-Johnson syndrome, erythema multiforme, or toxic skin
eruptions) to any of the product components
- When coadministered with drugs highly
dependent on CYP3A or UGT1A1 for clearance and for which elevated
plasma concentrations of the interacting drugs are associated with
serious and/or life-threatening events. The following are
contraindicated with EVOTAZ and REYATAZ: alfuzosin, rifampin,
irinotecan, triazolam, orally administered midazolam,
dihydroergotamine, ergotamine, methylergonovine, cisapride, St.
John’s wort (Hypericum perforatum), lovastatin, simvastatin,
pimozide, sildenafil when used for pulmonary arterial hypertension,
indinavir, nevirapine. Additionally, EVOTAZ is contraindicated
with: dronedarone, ranolazine, lurasidone, colchicine in
patients with renal and/or hepatic impairment. Additionally,
REYATAZ is contraindicated with ergonovine
- When coadministered with drugs that
strongly induce CYP3A [e.g., rifampin, St. John’s wort (Hypericum
perforatum), nevirapine] and may lead to lower exposure and loss of
efficacy of EVOTAZ and REYATAZ
WARNINGS AND PRECAUTIONS
The following Warnings and Precautions are associated with
EVOTAZ (atazanavir and cobicistat) and REYATAZ
(atazanavir):
- 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 reports of second-degree AV block and other conduction
abnormalities. There is limited clinical experience in patients
with preexisting conduction system disease such as marked first
degree AV block or second or third degree AV block. Consider ECG
monitoring in these patients
- Rash: Cases of Stevens-Johnson
syndrome, erythema multiforme, and toxic skin eruptions, including
drug rash, eosinophilia, and systemic symptoms (DRESS) syndrome,
have been reported in patients receiving atazanavir. Discontinue if
severe rash develops. Mild-to-moderate maculopapular skin eruptions
have also been reported, and generally did not require
discontinuation of treatment
- Nephrolithiasis and
cholelithiasis have been reported during postmarketing
surveillance in HIV-infected patients receiving atazanavir. 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
- Hepatotoxicity: Patients with
hepatitis B or C viral infections 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 therapy
- EVOTAZ is not recommended in
patients with hepatic impairment
- REYATAZ/ritonavir is not
recommended in patients with any degree of hepatic
impairment
- REYATAZ is not recommended for
patients with severe hepatic impairment
- Risk of Serious Adverse Reactions or
Loss of Virologic Response Due to Drug Interactions: In
patients initiating or already receiving EVOTAZ or REYATAZ with
ritonavir, receiving medications metabolized by CYP3A or initiation
of medications metabolized by CYP3A, may increase plasma
concentrations of medications metabolized by CYP3A. In addition,
initiation of medications that inhibit or induce CYP3A may increase
or decrease concentrations of EVOTAZ or REYATAZ with ritonavir,
respectively. These interactions may lead to clinically significant
adverse reactions, potentially leading to severe, life threatening,
or fatal events from greater exposures of concomitant medications,
clinically significant adverse reactions from greater exposures of
EVOTAZ or REYATAZ with ritonavir, or loss of therapeutic effect of
EVOTAZ or REYATAZ with ritonavir and possible development of
resistance
- Hyperbilirubinemia: Reversible,
asymptomatic elevations in indirect (unconjugated) bilirubin
occurred in most patients treated with atazanavir. 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
- Immune reconstitution syndrome
has been reported in patients treated with combination
antiretroviral therapy, including atazanavir. 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
- Diabetes mellitus/hyperglycemia:
New onset of diabetes, exacerbation of preexisting diabetes, and
hyperglycemia have been reported in postmarketing surveillance in
HIV-infected patients treated with protease inhibitor therapy. A
causal relationship has not been established
- Fat Redistribution or
accumulation of body fat including central obesity, dorsocervical
fat enlargement (buffalo hump), peripheral wasting, breast
enlargement, and “cushingoid appearance” have been seen in patients
receiving antiretroviral therapy. A causal relationship has not
been established
- Hemophilia: Increased bleeding
has been reported in patients with hemophilia type A and B treated
with protease inhibitors. A causal relationship has not been
established
EVOTAZ (atazanavir and cobicistat): ADDITIONAL WARNINGS AND
PRECAUTIONS
- Effects on Serum Creatinine:
Cobicistat decreases estimated creatinine clearance (CrCl) by
inhibiting the tubular secretion of creatinine without affecting
actual renal glomerular function. This effect should be considered
when interpreting changes in estimated CrCl in patients initiating
EVOTAZ, particularly in patients with medical conditions or
receiving drugs needing monitoring with estimated CrClPrior to
initiating therapy with EVOTAZ, assess estimated CrCl. Dosage
recommendations are not available for drugs that require dosage
adjustment in cobicistat-treated patients with renal impairment.
Consider alternative medications that do not require dosage
adjustments in patients with renal impairment. Patients who
experience a confirmed increase in serum creatinine of greater than
0.4 mg/dL from baseline should be closely monitored for renal
safety
- New onset or worsening renal
impairment when used with tenofovir disoproxil fumarate: Renal
impairment, including cases of acute renal failure and Fanconi
syndrome, has been reported when cobicistat was used with tenofovir
disoproxil fumarate (tenofovir DF)
- Coadministration of EVOTAZ and
tenofovir DF is not recommended in patients who have an estimated
creatinine clearance below 70 mL/min
- When EVOTAZ is used with tenofovir DF,
evaluate baseline and perform routine monitoring of estimated CrCl,
urine glucose, and urine protein. Measure serum phosphorus in
patients at risk for renal impairment
- Coadministration of EVOTAZ and
tenofovir DF in combination with concomitant or recent use of a
nephrotoxic agent is not recommended
- Antiretrovirals that are Not
Recommended: EVOTAZ is not recommended in combination with
other antiretroviral drugs that require CYP3A inhibition to achieve
adequate exposures (e.g., other HIV protease inhibitors or
elvitegravir) because dosing for such combinations has not been
established; coadministration may lead to loss of therapeutic
effect and development of resistanceEVOTAZ is not recommended in
combination with products containing the individual components of
EVOTAZ (atazanavir or cobicistat) or in combination with ritonavir
containing products
REYATAZ: ADDITIONAL WARNINGS AND PRECAUTIONS
- Patients with Phenylketonuria:
Phenylalanine can be harmful to patients with phenylketonuria
(PKU). REYATAZ oral powder contains phenylalanine (a component of
aspartame). REYATAZ capsules do not contain phenylalanine
- Resistance/cross resistance in
various degrees have been observed among protease inhibitors
MOST COMMON MODERATE OR SEVERE ADVERSE REACTIONS
EVOTAZ (atazanavir and cobicistat):
- In treatment-naive adults (≥2%):
nausea (2%), ocular icterus (3%), jaundice (5%), rash (5%)
REYATAZ (atazanavir), regardless of causality:
- In treatment-naive adults (≥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 adults
(≥2%): jaundice/scleral icterus (9%), myalgia (4%), diarrhea (3%),
nausea (3%), depression (2%), and fever (2%)
- In pediatric patients taking the
capsule formulation (≥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%)
- In pediatric patients taking the
oral powder formulation: The adverse reactions were generally
similar to that observed in clinical studies of REYATAZ in
pediatric patients taking the capsule formulation
DRUG INTERACTIONS
EVOTAZ: Coadministration of EVOTAZ and the following drugs is
not recommended
- efavirenz, etravirine, ritonavir,
boceprevir, telaprevir, simeprevir, apixaban, rivaroxaban,
dabigatran etexilate (in specific renal impairment groups),
voriconazole, salmeterol, avanafil, inhaled or nasal
corticosteroids that are metabolized by CYP3A
- when EVOTAZ is coadministered with
tenofovir DF and an H2-receptor antagonist in treatment-experienced
patients
- proton pump inhibitors in
treatment-experienced patients
REYATAZ: Coadministration of REYATAZ and the following drugs
is not recommended
- salmeterol
- when REYATAZ is coadministered with
ritonavir: boceprevir, other HIV protease inhibitors,
voriconazole
- when REYATAZ is coadministered without
ritonavir: carbamazepine, phenytoin, phenobarbital, bosentan,
buprenorphine
- in treatment-experienced patients:
proton pump inhibitors or efavirenz
- in patients with renal or hepatic
impairment: colchicine
See Table 5 of the EVOTAZ Full Prescribing Information, and
Table 16 of the REYATAZ Full Prescribing Information for additional
established and potentially significant Drug Interactions, and
related dose modification recommendations.
EVOTAZ and REYATAZ: Use in Renal Impairment
- EVOTAZ and REYATAZ should not be used
in treatment-experienced patients with end-stage renal disease
managed with hemodialysis
Please click here for the EVOTAZ full
prescribing information
Please click here for the REYATAZ full
prescribing information
*From U.S. Prescribing Information. EU SmPC may
differ.
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 Evotaz 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, 2014 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.
Tybost® is a registered trademark of Gilead Sciences, Inc.
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Bristol-Myers SquibbMedia:Rob Perry, 609-419-5278Cell:
407-492-4616rob.perry@bms.comorInvestors:Ranya
Dajani, 609-252-5330ranya.dajani@bms.com
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