- Evotaz is the first and only
protease inhibitor pharmacoenhanced by cobicistat that is supported
by comparative Phase III clinical trial data
- Evotaz is the only protease
inhibitor pharmacoenhanced by cobicistat with virologic failure
rates as low as 6% [HIV-1 RNA ≥50 copies/mL at 48 weeks: 6% Evotaz
arm; 4% Reyataz®(atazanavir)/ritonavir
arm]*
Bristol-Myers Squibb Company (NYSE:BMY) announced today that the
U.S. Food and Drug Administration (FDA) has approved Evotaz
(atazanavir 300 mg and cobicistat 150 mg) tablets in combination
with other antiretroviral agents for the treatment of HIV-1
infection in adults. Evotaz is coformulated to be one pill,
once-daily, combining the protease inhibitor atazanavir, which is
marketed as Reyataz (atazanavir 200 mg/300 mg) capsules, and
cobicistat, a pharmacokinetic enhancer marketed by Gilead Sciences,
Inc. Today’s approval offers patients living with HIV an innovative
treatment option that delivers proven suppression (HIV-1 RNA <50
copies/mL, 85% Evotaz arm; 87% Reyataz/ritonavir arm) through 48
weeks.
The use of Evotaz in patients who have previously received HIV
medication should be guided by their baseline resistance to
protease inhibitors. Evotaz and Reyataz do not cure HIV-1 infection
or AIDS. Evotaz is 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 and in combination with
certain drugs. See Evotaz full contraindications in the Important
Safety Information section below.
As a dedicated partner to the HIV community for more than 20
years, Bristol-Myers Squibb continues to discover and develop
innovative therapies to meet the needs of a broad range of patients
living with HIV. There are approximately 50,000 new cases of HIV
each year, with an estimated 1.1 million people living with the
condition in the U.S. While many are diagnosed and undergoing
treatment, only one quarter are virally suppressed, demonstrating
the continued need for additional treatments to help patients
achieve viral suppression.
“We are pleased to provide physicians and patients with an
important new option to treat HIV; atazanavir with cobicistat
delivers sustained efficacy and safety through 48 weeks, as
demonstrated through its rigorous clinical development plan,
including a head-to-head Phase III trial,” said Murdo Gordon, Head
of Worldwide Markets, Bristol-Myers Squibb. “Evotaz increases the
possibility of providing HIV suppression by combining reduced pill
burden with a low rate of virologic failure (6% Evotaz arm; 4%
Reyataz/ritonavir arm) and zero protease inhibitor mutations.” In
the Evotaz arm, zero patients developed tenofovir-associated
resistance K65R; two patients developed emtricitabine resistance
M184V. In the Reyataz /ritonavir arm, zero resistance was
observed.
Evotaz is the first and only protease inhibitor pharmacoenhanced
by cobicistat that is supported by comparative Phase III trial data
(Gilead Sciences, Inc.’s Study 114). The randomized, double-blind
clinical trial (N=692) evaluated the efficacy and safety 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. Patients had a baseline estimated CrCL >70mL/min, a mean
baseline plasma HIV-1 RNA of 4.8 log10 copies/mL, and a mean
baseline CD4+ cell count of 352 cells/mm. At 48 weeks, 85% of
patients in the Evotaz arm achieved 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% Evotaz
arm; 4% Reyataz/ritonavir arm) were observed at 48 weeks, making
Evotaz the only protease inhibitor pharmacoenhanced with cobicistat
with virologic failure rates as low as 6%.
In the study, zero protease inhibitor resistance was detected
through 48 weeks. No patients developed tenofovir‐associated
resistance, and two patients in the Evotaz arm developed
emtricitabine‐associated resistance. Various degrees of resistance
and cross-resistance have been observed among protease inhibitors;
however, resistance to atazanavir may not preclude the use of other
protease inhibitors.
"Maintaining sufficient drug concentrations inhibits viral
replication and prevents the development of resistance, which are
critical considerations in treating patients with HIV,” said study
investigator Joel Gallant, associate medical director of Specialty
Services at Southwest CARE Center in Santa Fe, New Mexico, and
adjunct professor of medicine in the Division of Infectious
Diseases at the Johns Hopkins University School of Medicine.
“Pharmacokinetic studies and a large clinical trial have
demonstrated that we can expect the same atazanavir drug levels and
clinical efficacy from Evotaz as with ritonavir-boosted Reyataz
with one less pill.”
Evotaz demonstrated a safety profile comparable to
Reyataz/ritonavir. The most common moderate to severe adverse
events in the Evotaz arm and Reyataz/ritonavir arm were: rash (5%,
4%); jaundice (5%, 3%); ocular iterus (3%, 1%); nausea (2%, 2%).
There were similar low rates of discontinuation due to adverse
events (AEs) with Evotaz as compared to Reyataz/ritonavir (7% and
7%, respectively).
Additional research confirmed that Evotaz is bioequivalent to
the co-administration of its components, Reyataz and cobicistat,
when given with a light meal.
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)
Since the approval of Reyataz, a component of Evotaz, in July
2003, more than 7 million prescriptions have been filled in the US*
for once-daily administration, with or without ritonavir as part of
an HIV-1 regimen.
Reyataz is indicated in combination with other antiretroviral
agents for the treatment of HIV-1 infection for patients 3 months
and older weighing at least 10 kg. Reyataz is not recommended for
use in pediatric patients less than 3 months due to the risk of
kernicterus. Use of Reyataz with ritonavir in treatment-experienced
patients should be guided by the number of baseline primary
protease inhibitor resistance substitutions. Reyataz is
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. See Reyataz full contraindications in the Important
Safety Information section below.
For more information, please visit www.reyatazhcp.com.
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).
INDICATIONS for Evotaz (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
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 and may lead to lower exposure and loss of
efficacy of EVOTAZ and REYATAZ
WARNINGS AND PRECAUTIONS
The following Warnings & 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 hepatic impairment
- REYATAZ is not recommended for
patients with severe hepatic impairment
- 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-Barre
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 CrCl. Prior 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
- Risk of Serious Adverse Reactions or
Loss of Virologic Response Due to Drug Interactions:
Coadministration of EVOTAZ with medications that are metabolized by
CYP3A may lead to increased exposures of these medications, which
may increase the risk of clinically significant adverse reactions
(including life-threatening or fatal reactions). Coadministration
of EVOTAZ with CYP3A inducers may lead to lower exposure of
atazanavir and cobicistat and loss of efficacy of atazanavir and
possible resistance. The potential for drug interactions prior to
and during EVOTAZ therapy should be considered, review concomitant
medications and monitor patients for adverse reactions
- 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 resistance
EVOTAZ 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 WARNING AND PRECAUTION
- 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), regardless of
causality:
- 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%),
depression (2%), and fever (2%)
- In pediatric patients taking the
capsule formulation (≥5%): cough (21%), fever (18%),
jaundice/sclera 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: cholchicine
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
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, 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.
*Includes patients who had HIV-1 RNA ≥50 copies/mL in the
Week 48 window; patients who discontinued early due to lack of
efficacy; patients who discontinued for reasons other than an
adverse event, death, or loss of efficacy and at the time of
discontinuation had HIV-1 RNA ≥50 copies/mL
Bristol-Myers SquibbMedia:Chris Clark,
609-252-6269chris.clark@bms.comorInvestors:Ranya Dajani,
609-252-5330ranya.dajani@bms.comorRyan Asay,
609-252-5020ryan.asay@bms.com
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