Message #119 From:
NewsBot Date: December 15, 2006 05:30:00 AM
GILD News 96-Week Data From Gilead's Study 934 Comparing Viread(R) and Emtriva(R) to Combivir(R) Both in Combination With Sustiva(R) Published in Journal of Acquired Immune Deficiency Syndrome
FOSTER CITY, Calif.--(BUSINESS WIRE)--Gilead Sciences, Inc. (Nasdaq:GILD) today announced the publication of
96-week data from an ongoing clinical trial, Study 934, in the Journal
of Acquired Immune Deficiency Syndrome (JAIDS). This study
compares a once-daily regimen of Viread®
(tenofovir disoproxil fumarate), Emtriva®
(emtricitabine) and Sustiva®
(efavirenz) to a twice-daily regimen of Combivir®
(lamivudine/zidovudine) with Sustiva once daily. The study article, “Tenofovir
Disoproxil Fumarate, Emtricitabine, and Efavirenz Versus Fixed-Dose
Zidovudine/Lamivudine and Efavirenz in Antiretroviral-Naïve
Patients,” appears in the December 15 issue
of JAIDS (Vol. 43; issue 5).
“The efficacy, safety and resistance profile
of Viread/Emtriva/Sustiva in this study underscores the importance of
this treatment option for antiretroviral therapy-naïve
patients,” said lead author Anton Pozniak,
MD, of the Chelsea and Westminster Hospital, London. “Sustiva,
Emtriva and Viread were administered as individual agents in this trial,
but a fixed-dose combination of these drugs is now available, offering
more convenient dosing.”
Viread and Emtriva are available as once-daily Truvada®
(emtricitabine and tenofovir disoproxil fumarate), the most commonly
prescribed backbone for HIV combination therapy. Viread, Emtriva and
Sustiva are available in the United States as ATRIPLATM
(efavirenz 600 mg/ emtricitabine 200 mg/ tenofovir disoproxil fumarate
300 mg), the only once-daily single tablet regimen for the treatment of
HIV-1 infection in adults. ATRIPLA was developed through a U.S. joint
venture between Bristol-Myers Squibb and Gilead Sciences. Together with
Merck & Co., Inc., the companies recently submitted a Marketing
Authorisation Application (MAA) for the product to the European
Medicines Agency (EMEA).
Ninety-six week data from this study were originally presented at the
XVI International AIDS Conference in Toronto, Canada in August, 2006.
Data from this analysis have not been reviewed by the U.S. Food & Drug
Administration.
Study 934
Study 934 is a Phase III, open-label, non-inferiority study that
enrolled 517 HIV-infected patients in the United States and Europe. The
study’s primary endpoint was at 48 weeks and
the study is continuing through 144 weeks. The prespecified primary
efficacy population included 487 patients. Twenty-four patients (12 from
each arm) who completed week 48 of the study with HIV RNA less than 400
copies/mL did not consent to participate after week 48 and were excluded
from the analysis. Participants were randomized to receive Viread 300
mg, Emtriva 200 mg and Sustiva 600 mg, all dosed once daily, or Combivir
twice daily and Sustiva 600 mg once daily. At study entry, patients were
treatment-naive and had HIV RNA (viral load) greater than 10,000
copies/mL.
After 96 weeks of treatment (n=463), 75 percent of
Viread/Emtriva/Sustiva patients compared to 62 percent of
Combivir/Sustiva patients achieved and maintained viral load less than
400 copies/mL using the Time to Loss of Virologic Response algorithm
(TLOVR) (p=0.004; 95% CI, +4% to +21%). Sixty-seven percent of patients
in the Viread/Emtriva/Sustiva arm compared to 61 percent of patients in
the Combivir/Sustiva arm achieved and maintained viral load less than 50
copies/mL using TLOVR (p=0.16; 95% CI, -2% to +15%). Patients receiving
Viread/Emtriva/Sustiva experienced a significantly greater increase from
baseline in CD4 cell counts at week 96 compared to those receiving
Combivir/Sustiva (270 vs. 237 cells/mm3;
p=0.036).
There was a significant difference between the two study arms in terms
of virologic rebound at 96 weeks (defined as having a confirmed viral
load of greater than 400 copies/mL after achieving confirmed viral load
of less than 400 copies/mL). Five percent of patients in the
Combivir/Sustiva group experienced rebound compared to less than 1
percent of Viread/Emtriva/Sustiva patients (p=0.007).
Through 96 weeks, 43 patients in the study met criteria for resistance
testing. The K65R mutation, which can be selected by Viread, did not
arise in any patient. There was a significant difference between study
arms in the development of the M184V mutation, which was observed in 2
patients in the Viread/Emtriva/Sustiva group compared with 9 patients in
the Combivir/Sustiva group (p=0.036).
After 96 weeks of treatment, discontinuation of study medications due to
adverse events was significantly higher among Combivir/Sustiva patients
compared to the Viread/Emtriva/Sustiva arm (11 vs. 5 percent,
respectively; p=0.008). The most common cause of discontinuation related
to study drug in at least 2 percent of patients in either arm include
anemia (6 percent in the Combivir/Sustiva group vs. 0 percent in the
Viread/Emtriva/Sustiva group), fatigue (2 percent in the
Combivir/Sustiva group vs. 0 percent in the Viread/Emtriva/Sustiva
group), nausea (2 percent in the Combivir/Sustiva group vs. less than 1
percent in the Viread/Emtriva/Sustiva group), and rash (less than 1
percent in the Combivir/Sustiva group vs. 2 percent in the
Viread/Emtriva/Sustiva group).
Patients receiving Viread/Emtriva/Sustiva had a significantly greater
median increase in weight from baseline compared to patients receiving
Combivir/Sustiva (2.7 kg vs. 0.5 kg, respectively; p<0.001).
Patients receiving Viread/Emtriva/Sustiva had significantly greater
median limb fat at week 96 compared to patients receiving
Combivir/Sustiva (7.7 kg, n=144 vs. 5.5 kg, n=136, respectively; p<0.001).
In addition, in a subset of patients with 48- and 96-week data,
significant differences in median limb fat were observed (decrease of
0.7 kg in the Combivir/Sustiva arm; n=44; p=0.001; increase of 0.3 kg in
the Viread/Emtriva/Sustiva arm; n=49; p=0.01).
Renal adverse events were uncommon at 96 weeks, which is consistent with
study data at 48 weeks and results from other randomized clinical trials
involving Viread in treatment-naïve and
treatment-experienced patients. Renal safety was similar and renal
function remained stable in the two arms of the study. No patient
discontinued study medication due to renal events.
Important Product Safety Information
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, 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 Viread or Emtriva (components of
ATRIPLA). Hepatic function should be monitored closely with both
clinical and laboratory follow-up for at least several months in
patients who discontinue ATRIPLA, Viread or Emtriva and are co-infected
with HIV and HBV. If appropriate, initiation of anti-hepatitis B therapy
may be warranted.
It is important for patients to be aware that anti-HIV medicines
including ATRIPLA, Viread and Emtriva do not cure HIV infection or AIDS,
nor have they been shown to reduce the risk of transmission of HIV to
others.
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.
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
(emtricitabine/tenofovir disoproxil fumarate). Due to similarities
between emtricitabine and lamivudine, ATRIPLA should not be
coadministered with drugs containing lamivudine, including Combivir
(lamivudine/zidovudine), Epivir®(lamivudine), Epivir-HBV®,
EpzicomTM (abacavir/lamivudine), or Trizivir®(abacavir/lamivudine/zidovudine).
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 (BMD) 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 a 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.
Saquinavir should not be used as the only protease inhibitor in
combination with 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 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.
About Viread
In the United States, Viread is indicated in combination with other
antiretroviral agents for the treatment of HIV-1 infection. Viread
should not be used in combination with Truvada. Truvada should not be
used in combination with its component drugs, Viread or Emtriva.
Drug interactions have been observed when didanosine, atazanavir or
lopinavir/ritonavir is co-administered with Viread 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 and lopinavir/ritonavir plus Viread should be monitored for
Viread-associated adverse events, which may require discontinuation.
When co-administered with Viread, it is recommended that atazanavir 300
mg be given with ritonavir 100 mg. Atazanavir without ritonavir should
not be co-administered with Viread.
Renal impairment, including cases of acute renal failure and Fanconi
syndrome (renal tubular injury with severe hypophosphatemia), has been
reported among patients taking Viread. 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. The effects of Viread-associated changes in BMD and
biochemical markers on long-term bone health and future fracture risk
are unknown. 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 Viread.
The most common adverse events among patients receiving Viread with
other antiretroviral agents in clinical trials were mild to moderate
gastrointestinal events and dizziness. Moderate to severe adverse events
occurring in more than 5 percent of patients receiving Viread included
rash (rash, pruritis, maculopapular rash, urticaria, vesiculobullous
rash and pustular rash), headache, pain, diarrhea, depression, back
pain, fever, nausea, abdominal pain, asthenia and anxiety (Study 903).
Less than 1 percent of patients discontinued participation because of
gastrointestinal events (Study 907).
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 Emtriva
In the United States, Emtriva is indicated in combination with other
antiretroviral agents for the treatment of HIV-1 infection in patients
over three months of age. This indication is based on analyses of plasma
HIV-1 RNA levels and CD4 cell counts from controlled studies of 48 weeks
duration in antiretroviral-naive patients and
antiretroviral-treatment-experienced patients who were virologically
suppressed on an HIV treatment regimen. In
antiretroviral-treatment-experienced patients, the use of Emtriva may be
considered for adults with HIV strains that are expected to be
susceptible to Emtriva as assessed by genotypic or phenotypic testing.
Adverse events that occurred in more than 5 percent of patients
receiving Emtriva with other antiretroviral agents in clinical trials
include abdominal pain, asthenia (weakness), headache, diarrhea, nausea,
vomiting, dizziness and rash (rash, pruritis, maculopapular rash,
urticaria, vesiculobullous rash, pustular rash and allergic reaction).
Approximately 1 percent of patients discontinued participation because
of these events. All adverse events were reported with similar frequency
in Emtriva and control treatment groups with the exception of skin
discoloration, which was reported with higher frequency in the
Emtriva-treated group. Skin discoloration, manifested by
hyperpigmentation on the palms and/or soles, was generally mild and
asymptomatic. The mechanism and clinical significance are unknown.
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 Emtriva. For pediatric patients over
three months of age, the adverse event profile observed during clinical
trials was similar to that of adult patients, with the exception of
anemia and a higher frequency of hyperpigmentation.
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.
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 may not see advantages of ATRIPLA, Viread and
Emtriva over other antiretrovirals and may therefore be reluctant to
prescribe these products. 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 Viread, Emtriva and Truvada is
available at www.gileadHIV.com.
ATRIPLA is a trademark of Bristol-Myers Squibb & Gilead Sciences, LLC.
Viread, Emtriva and Truvada are registered trademarks of Gilead
Sciences, Inc.
