Product Developed Through U.S. Joint Venture between Bristol-Myers
Squibb and Gilead Sciences, the First of Its Kind in HIV Treatment
Bristol-Myers Squibb Company (NYSE:BMY) and Gilead Sciences, Inc.
(Nasdaq:GILD) today announced the U.S. Food and Drug Administration
(FDA) has granted approval of ATRIPLA(TM) (efavirenz 600 mg/
emtricitabine 200 mg/ tenofovir disoproxil fumarate 300 mg) for the
treatment of HIV-1 infection in adults. ATRIPLA is the first-ever
once-daily single tablet regimen (STR) for HIV intended as a
stand-alone therapy or in combination with other antiretrovirals. The
product combines SUSTIVA(R) (efavirenz), manufactured by Bristol-Myers
Squibb, and Truvada(R) (emtricitabine and tenofovir disoproxil
fumarate), manufactured by Gilead Sciences. Truvada itself is a
fixed-dose product that contains two of Gilead's anti-HIV medications,
Viread(R) (tenofovir disoproxil fumarate) and Emtriva(R)
(emtricitabine), in a single once-daily tablet for use as part of
combination therapy. ATRIPLA will be available in the United States
within seven business days.
"The availability of ATRIPLA marks the culmination of ten years of
efforts to simplify dosing while helping to achieve and maintain
effective viral suppression for adults infected with HIV-1," said John
G. Bartlett, MD, Johns Hopkins University.
The collaboration between Bristol-Myers Squibb and Gilead is the
first of its kind in the 25-year history of the AIDS epidemic. On
December 20, 2004 the companies established a U.S. joint venture to
develop and commercialize the single tablet regimen.
"We appreciate the recognition by the FDA of this important
therapeutic advance, and with their approval of ATRIPLA in just over
two months, patients will now have rapid access to the first
once-daily single tablet regimen for the treatment of HIV-1 infection
in adults," said John C. Martin, PhD, President and CEO of Gilead
Sciences. "We are proud to have worked closely with Bristol-Myers
Squibb in this precedent-setting collaboration to simplify therapy for
physicians and patients."
"With the approval of ATRIPLA, Bristol-Myers Squibb continues two
decades of progress in the development and commercialization of
medications to treat HIV. Partnering with Gilead, we are able to
address another area of need for adults infected with HIV-1," said
Anthony C. Hooper, President, U.S. Pharmaceuticals, Bristol-Myers
Squibb. "ATRIPLA is an important step forward as we continue our focus
on discovering, developing and providing innovative treatments for
serious diseases."
The once-daily single tablet regimen contains three medicines from
two classes of anti-HIV drugs. ATRIPLA contains 600 mg of efavirenz, a
non-nucleoside reverse transcriptase inhibitor (NNRTI), 200 mg of
emtricitabine and 300 mg of tenofovir disoproxil fumarate, both
nucleoside reverse transcriptase inhibitors (NRTIs). All three active
ingredients work by blocking reverse transcriptase, an enzyme
necessary for HIV replication.
Clinical data support the use of the three-drug regimen contained
in ATRIPLA in HIV treatment-naive patients. An ongoing randomized,
open label, active-controlled, multicenter, non-inferiority study,
Study 934, compares a once-daily regimen of Viread, Emtriva and
SUSTIVA, the components of ATRIPLA, with twice-daily Combivir(R)
(lamivudine and zidovudine) and once-daily SUSTIVA in treatment-naive
patients with HIV. Through 48 weeks, 84% of patients in the
Viread/Emtriva/SUSTIVA group (n=244) compared to 73% of patients in
the Combivir/SUSTIVA group (n=243) achieved and maintained HIV-1 RNA
less than 400 copies/mL. This difference largely results from the
higher number of discontinuations in the Combivir/SUSTIVA group due to
adverse events (9% vs. 4% in the Viread/Emtriva/SUSTIVA group) and
other reasons including lost to follow-up, patient withdrawal,
non-compliance and protocol violation (14% vs. 10% in the
Viread/Emtriva/SUSTIVA group). In addition, 80% and 70% of patients in
the Viread/Emtriva/SUSTIVA group and the Combivir/SUSTIVA group,
respectively, achieved and maintained HIV-1 RNA less than 50
copies/mL. The mean increase from baseline in CD4 cell count was 190
cells/mm3 in the Viread/Emtriva/SUSTIVA group and 158 cells/mm3 in the
Combivir/SUSTIVA group. Selected adverse events observed in greater
than or equal to 5% of patients in the Viread/Emtriva/SUSTIVA group
include dizziness, nausea, diarrhea, fatigue, headache and rash.
Guidelines issued by the U.S. Department of Health and Human
Services (DHHS) list efavirenz, emtricitabine and tenofovir disoproxil
fumarate among the preferred agents for use in an NNRTI-based
treatment regimen in appropriate patients who have never taken
anti-HIV medicines. Efavirenz should not be used during the first
trimester of pregnancy due to the potential harm to the fetus.
Pregnancy should be avoided by women receiving efavirenz.
About HIV/AIDS
2006 marks the 25th anniversary of the start of the AIDS epidemic.
The first cases of HIV/AIDS were reported by the U.S. Centers for
Disease Control and Prevention (CDC) in the June 5, 1981 issue of the
Morbidity and Mortality Weekly Report (MMWR). Today, the CDC estimates
that more than one million Americans are infected with HIV, the virus
that causes AIDS. Of these, approximately 25% are unaware of their
infection. Although HIV treatment options have expanded rapidly in
recent years, the CDC estimates that 216,000 Americans who are HIV
positive and eligible for antiretroviral treatment are currently not
receiving it.
Important Safety Information About ATRIPLA, Truvada, Viread and
Emtriva
Lactic acidosis and severe hepatomegaly with steatosis, including
fatal cases, have been reported with the use of nucleoside analogues
alone or in combination with other antiretrovirals. ATRIPLA, Truvada,
Viread and Emtriva are not indicated for the treatment of chronic
hepatitis B virus (HBV) infection and the safety and efficacy of these
drugs have not been established in patients co-infected with HBV and
HIV. Severe acute exacerbations of hepatitis B have been reported in
patients who have discontinued Emtriva or Viread (components of
ATRIPLA and Truvada). Hepatic function should be monitored closely
with both clinical and laboratory follow-up for at least several
months in patients who discontinue ATRIPLA, Truvada, Emtriva or Viread
and are co-infected with HIV and HBV. If appropriate, initiation of
anti-hepatitis B therapy may be warranted.
Additional Important Information About ATRIPLA
ATRIPLA is indicated for use alone as a complete regimen or in
combination with other antiretroviral agents for the treatment of
HIV-1 infection in adults.
It is important for patients to be aware that ATRIPLA does not
cure HIV infection or AIDS. ATRIPLA has not been shown to reduce the
risk of transmission of HIV to others through sexual contact or blood
contamination.
ATRIPLA is contraindicated for use with astemizole, cisapride,
midazolam, triazolam, ergot derivatives, or voriconazole. Concomitant
use of ATRIPLA and St. John's wort (Hypericum perforatum) or St.
John's wort-containing products is not recommended. Since ATRIPLA
contains efavirenz, emtricitabine and tenofovir disoproxil fumarate,
it should not be coadministered with SUSTIVA, Emtriva, Viread, or
Truvada. Due to similarities between emtricitabine and lamivudine,
ATRIPLA should not be coadministered with drugs containing lamivudine,
including Combivir, Epivir(R), Epivir-HBV(R), Epzicom(TM), or
Trizivir(R).
Serious psychiatric adverse experiences, including severe
depression (2.4%), suicidal ideation (0.7%), nonfatal suicide attempts
(0.5%), aggressive behavior (0.4%), paranoid reactions (0.4%) and
manic reactions (0.2%) have been reported in patients treated with
efavirenz. In addition to efavirenz, factors identified in a clinical
study that were associated with an increase in psychiatric symptoms
included a history of injection drug use, psychiatric history and use
of psychiatric medication. There have been occasional reports of
suicide, delusions, and psychosis-like behavior, but it could not be
determined if efavirenz was the cause. Patients with serious
psychiatric adverse experiences should be evaluated immediately to
determine whether the risks of continued therapy outweigh the
benefits. Fifty-three percent of patients reported central nervous
system symptoms including dizziness (28.1%), insomnia (16.3%),
impaired concentration (8.3%), somnolence (7.0%), abnormal dreams
(6.2%) and hallucinations (1.2%) when taking efavirenz compared to 25%
of patients receiving control regimens. These symptoms usually begin
during the first or second day of therapy and generally resolve after
the first two to four weeks of therapy. After four weeks of therapy,
the prevalence of central nervous system symptoms of at least moderate
severity ranged from 5% to 9% in patients treated with regimens
containing efavirenz. Nervous system symptoms are not predictive of
the less frequent psychiatric symptoms.
ATRIPLA should not be given to patients with creatinine clearance
below 50 mL/min. Renal impairment, including cases of acute renal
failure and Fanconi syndrome (renal tubular injury with severe
hypophosphatemia), has been reported in association with the use of
tenofovir disoproxil fumarate, most often in patients with underlying
systemic or renal disease, or in patients taking concomitant
nephrotoxic agents. Some cases have occurred in patients with no
identified risk factors. ATRIPLA should be avoided with concurrent or
recent use of a nephrotoxic agent.
ATRIPLA may cause fetal harm when administered during the first
trimester to a pregnant woman. Women should not become pregnant or
breastfeed while taking ATRIPLA. Barrier contraception must always be
used in combination with other methods of contraception such as oral
or other hormonal contraceptives. If the patient becomes pregnant
while taking ATRIPLA, she should be apprised of the potential harm to
the fetus.
Mild to moderate rash is a common side effect of efavirenz. In
controlled clinical trials, 26% of patients treated with efavirenz
experienced new-onset skin rash compared with 17% of patients treated
in control groups. Skin discoloration, associated with emtricitabine,
may also occur. ATRIPLA should be discontinued in patients developing
severe rash associated with blistering, desquamation, mucosal
involvement, or fever. Liver enzymes should be monitored in patients
with known or suspected hepatitis B or C and when ATRIPLA is
administered with ritonavir or other medications associated with liver
toxicity. Decreases in bone mineral density have been seen with
tenofovir disoproxil fumarate. Use ATRIPLA with caution in patients
with a history of seizures. Convulsions have been observed in patients
receiving efavirenz, generally in the presence of known medical
history of seizures. Redistribution and/or accumulation of body fat
have been observed in patients receiving antiretroviral therapy.
Immune reconstitution syndrome has been reported in patients treated
with combination antiretroviral therapy, including the components of
ATRIPLA.
Coadministration of ATRIPLA and atazanavir is not recommended due
to concerns regarding decreased atazanavir concentrations. Patients on
lopinavir/ritonavir plus ATRIPLA should be monitored for
tenofovir-associated adverse events. ATRIPLA should be discontinued in
patients who develop tenofovir-associated adverse events.
Coadministration of ATRIPLA and didanosine should be undertaken with
caution. Patients receiving this combination should be monitored
closely for didanosine-associated adverse events. See full prescribing
information for complete list of drug-drug interactions.
In a large controlled clinical trial (Study 934), adverse events
observed in greater than or equal to 5% of patients in the
Viread/Emtriva/SUSTIVA group include dizziness, nausea, diarrhea,
fatigue, headache, and rash.
The dose of ATRIPLA is one tablet once daily taken orally on an
empty stomach. Dosing at bedtime may improve the tolerability of
nervous system symptoms.
Important Information About SUSTIVA
SUSTIVA (efavirenz) in combination with other antiretroviral
agents is indicated for the treatment of HIV-1 infection. This
indication is based on two clinical trials of at least one year
duration that demonstrated prolonged suppression of HIV RNA.
Coadministration with astemizole, cisapride, midazolam, triazolam,
ergot derivatives, or voriconazole is contraindicated. Concomitant use
of SUSTIVA and St. John's wort (Hypericum perforatum) or St. John's
wort-containing products is not recommended. This list of medications
is not complete.
Serious psychiatric adverse experiences, including severe
depression (2.4%), suicidal ideation (0.7%), nonfatal suicide attempts
(0.5%), aggressive behavior (0.4%), paranoid reactions (0.4%) and
manic reactions (0.2%) have been reported in patients treated with
SUSTIVA. In addition to SUSTIVA, factors identified in a clinical
study that were associated with an increase in psychiatric symptoms
included history of injection drug use, psychiatric history, and use
of psychiatric medication. There have been occasional reports of
suicide, delusions, and psychosis-like behavior, but it could not be
determined if SUSTIVA was the cause. Patients with serious psychiatric
adverse experiences should be evaluated immediately to determine
whether the risks of continued therapy outweigh the benefits.
Fifty-three percent of patients reported central nervous system
symptoms including dizziness (28.1%), insomnia (16.3%), impaired
concentration (8.3%), somnolence (7.0%), abnormal dreams (6.2%) and
hallucinations (1.2%) when taking SUSTIVA compared to 25% of patients
receiving control regimens. These symptoms usually begin during Days
1-2 of therapy and generally resolve after the first 2-4 weeks of
therapy. After four weeks of therapy, the prevalence of central
nervous system symptoms of at least moderate severity ranged from 5%
to 9% in patients treated with regimens containing SUSTIVA. Nervous
system symptoms are not predictive of the less frequent serious
psychiatric symptoms.
SUSTIVA may cause fetal harm when administered during the first
trimester to a pregnant woman. Women should not become pregnant or
breastfeed while taking SUSTIVA. Barrier contraception must always be
used in combination with other methods of contraception (e.g. oral or
other hormonal contraceptives). If the patient becomes pregnant while
taking SUSTIVA, she should be apprised of the potential harm to the
fetus.
Mild to moderate rash is a common side effect of SUSTIVA. In
controlled clinical trials, 26% of patients treated with SUSTIVA
experienced new-onset skin rash compared with 17% of patients treated
in control groups. SUSTIVA should be discontinued in patients
developing severe rash associated with blistering, desquamation,
mucosal involvement, or fever. Rash is more common and often more
severe in pediatric patients.
Liver enzymes should be monitored in patients with known or
suspected hepatitis B or C, in patients treated with other medications
associated with liver toxicity, and when SUSTIVA is administered with
ritonavir. Use SUSTIVA with caution in patients with a history of
seizures. Convulsions have been observed in patients receiving
efavirenz, generally in the presence of known medical history of
seizures. Redistribution and/or accumulation of body fat have been
seen in patients receiving antiretroviral therapy. A causal
relationship has not been established. Immune reconstitution syndrome
has been reported in patients treated with combination antiretroviral
therapy, including SUSTIVA.
It is recommended that SUSTIVA be taken on an empty stomach,
preferably at bedtime. The increased concentrations following
administration of SUSTIVA with food may lead to an increase in
frequency of adverse events. Dosing at bedtime may improve the
tolerability of nervous system symptoms.
Additional Important Information About Truvada
Truvada is a fixed-dose combination product that combines 200 mg
of Emtriva(R) (emtricitabine) and 300 mg of Viread(R) (tenofovir
disoproxil fumarate) in one tablet, taken once a day. In the United
States, Truvada is indicated in combination with other antiretroviral
agents (such as non-nucleoside reverse transcriptase inhibitors or
protease inhibitors) for the treatment of HIV-1 infection in adults.
Truvada should not be coadministered with Emtriva, Viread or
lamivudine-containing products and it is not recommended that Truvada
be used as a component of a triple nucleoside regimen. In
treatment-experienced patients, the use of Truvada should be guided by
laboratory testing and treatment history.
Clinical Study 934 supports the use of Truvada tablets for the
treatment of HIV-1 infection. Additional data in support of the use of
Truvada are derived from Study 903, in which Viread and lamivudine
were used in combination in treatment-naive adults, and clinical Study
303, in which Emtriva and lamivudine demonstrated comparable efficacy,
safety and resistance patterns as part of multidrug regimens.
No drug interaction studies have been conducted using Truvada.
Drug interactions have been observed when didanosine, atazanavir, or
lopinavir/ritonavir are co-administered with Viread, a component of
Truvada, and dose adjustments may be necessary. Data are not available
to recommend a dose adjustment of didanosine for patients weighing
less than 60 kg. Patients on atazanavir or lopinavir/ritonavir plus
Truvada should be monitored for Truvada-associated adverse events that
may require discontinuation. When co-administered with Truvada, it is
recommended that atazanavir 300 mg be given with ritonavir 100 mg.
Atazanavir without ritonavir should not be co-administered with
Truvada.
Four-hundred and forty-seven HIV-1 infected patients have received
combination therapy with Emtriva and Viread with either a
non-nucleoside reverse transcriptase inhibitor (Study 934) or protease
inhibitor for 48 weeks in clinical studies. Adverse events observed in
Study 934 were generally consistent with those seen in other studies
in treatment-experienced or treatment-naive patients receiving Viread
and/or Emtriva. Adverse events observed in more than 5% of patients in
the Viread/Emtriva group in Study 934 include diarrhea, nausea,
fatigue, headache, dizziness and rash.
Renal impairment, including cases of acute renal failure and
Fanconi syndrome (renal tubular injury with severe hypophosphatemia),
has been reported among patients taking Viread, a component of Truvada
(emtricitabine and tenofovir disoproxil fumarate). Renal impairment
occurred most often in patients with underlying systemic or renal
disease or in patients taking concomitant nephrotoxic agents, though
some cases have appeared in patients without identified risk factors.
Decreases in bone mineral density (BMD) at the lumbar spine and hip
have been seen with the use of Viread. Redistribution and/or
accumulation of body fat have been observed in patients receiving
antiretroviral therapy. Immune reconstitution syndrome has been
reported in patients treated with combination antiretroviral therapy
including Truvada, Viread and Emtriva.
The effects of Viread-associated changes in BMD and biochemical
markers on long-term bone health and future fracture risk are unknown.
Skin discoloration, manifested by hyperpigmentation on the palms
and/or soles, has been reported with the use of Emtriva, a component
of Truvada. Skin discoloration was generally mild and asymptomatic and
its mechanism and clinical significance are unknown.
The parent compound of Viread was discovered through a
collaborative research effort between Dr. Antonin Holy, Institute for
Organic Chemistry and Biochemistry, Academy of Sciences of the Czech
Republic (IOCB) in Prague and Dr. Erik DeClercq, Rega Institute for
Medical Research, Katholic University in Leuven, Belgium.
About Bristol-Myers Squibb
Bristol-Myers Squibb is a global pharmaceutical and related
healthcare products company. Visit Bristol-Myers Squibb on the World
Wide Web at www.bms.com.
About Gilead Sciences
Gilead Sciences is a biopharmaceutical company that discovers,
develops and commercializes innovative therapeutics in areas of unmet
medical need. The company's mission is to advance the care of patients
suffering from life-threatening diseases worldwide. Headquartered in
Foster City, California, Gilead has operations in North America,
Europe and Australia. Visit Gilead on the World Wide Web at
www.gilead.com.
Forward-Looking Statements
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 product development. 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 product will be commercially successful. 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, 2005 and in our Quarterly Reports on Form 10-Q.
Bristol-Myers Squibb undertakes no obligation to publicly update any
forward-looking statement, whether as a result of new information,
future events or otherwise.
Gilead Forward-Looking Statement
This press release includes forward-looking statements, within the
meaning of the Private Securities Litigation Reform Act of 1995, that
are subject to risks, uncertainties and other factors, including the
risk that physicians and regulatory agencies may not see advantages of
ATRIPLA over other antiretrovirals and may therefore be reluctant to
prescribe the product. These risks, uncertainties and other factors
could cause actual results to differ materially from those referred to
in the forward-looking statements. The reader is cautioned not to rely
on these forward-looking statements. These and other risks are
described in detail in the Gilead Annual Report on Form 10-K for the
year ended December 31, 2005, filed with the U.S. Securities and
Exchange Commission. All forward-looking statements are based on
information currently available to Gilead and Gilead assumes no
obligation to update any such forward-looking statements.
Full prescribing information for ATRIPLA is available at
www.atripla.com.
Full prescribing information for SUSTIVA is available at
www.bms.com.
Full prescribing information for Truvada, Viread and Emtriva is
available at www.gilead.com
ATRIPLA is a trademark of Bristol-Myers Squibb & Gilead Sciences,
LLC.
SUSTIVA is a registered trademark of Bristol-Myers Squibb Pharma
Company.
Truvada, Viread and Emtriva are registered trademarks of Gilead
Sciences, Inc.
