Gilead Sciences, Inc. (Nasdaq:GILD) today announced that a Phase
II clinical trial of its investigational integrase inhibitor-based,
once-daily, fixed-dose “Quad” regimen of elvitegravir, GS 9350 and
Truvada® (emtricitabine and tenofovir disoproxil fumarate) for the
treatment of HIV-1 infection met its primary objective. The ongoing
study of 71 HIV-infected, antiretroviral treatment-naïve adults
compares the Quad with Atripla® (efavirenz 600 mg/emtricitabine 200
mg/tenofovir disoproxil fumarate 300 mg). Based on 24-week data,
efficacy of the Quad met the statistical criteria of
non-inferiority as compared to Atripla based on the proportion of
subjects with HIV RNA levels (viral load) of less than 50
copies/mL. Discontinuation rates due to adverse events were
comparable in both arms of the study. Full study results will be
submitted for presentation at a scientific meeting in early
2010.
Elvitegravir is Gilead’s investigational HIV integrase
inhibitor. GS 9350 is Gilead’s investigational pharmacoenhancing or
“boosting” agent, being developed to increase blood levels of
certain medicines, including elvitegravir, and allows for
once-daily dosing.
Gilead is also studying GS 9350 as a stand-alone boosting agent
for other antiretrovirals, in particular, protease inhibitors. A
Phase II clinical trial evaluating the safety and efficacy of GS
9350-boosted atazanavir compared to ritonavir-boosted atazanavir,
each in combination with Truvada, is ongoing. The Phase II study
involves 79 HIV-infected, antiretroviral treatment-naïve adults.
The study met its primary objective of achieving HIV RNA levels
(viral load) of less than 50 copies/mL at 24 weeks of treatment. GS
9350-boosted atazanavir and Truvada had similar efficacy to
ritonavir-boosted atazanavir and Truvada. Discontinuation rates due
to adverse events were comparable in both arms of the study.
Ritonavir is currently the only agent used to boost HIV therapy.
Results from this study will also be submitted for presentation at
a scientific meeting in early 2010.
About the Quad Phase II
Study
The Quad Phase II study is a double-blind, multicenter,
randomized, active-controlled 48-week clinical trial evaluating the
safety and efficacy of a fixed-dose regimen containing
elvitegravir, GS 9350 and Truvada versus Atripla, each administered
in HIV-infected treatment-naïve adults with HIV RNA levels (viral
load) greater than or equal to 5,000 copies/mL and CD4 cell counts
greater than 50 cells/mm3 (n=71). Entry criteria required that
patients did not have nucleoside reverse transcriptase inhibitor,
non-nucleoside reverse transcriptase inhibitor or primary protease
inhibitor resistance mutations, as defined by International AIDS
Society-USA guidelines, and no prior use of antiretroviral
treatments.
In the study, trial participants were randomized 2:1 to receive
a once-daily tablet containing elvitegravir 150 mg/GS 9350 150
mg/emtricitabine 200 mg/tenofovir disoproxil fumarate 300 mg (n=48)
or Atripla (efavirenz 600 mg/emtricitabine 200 mg/tenofovir
disoproxil fumarate 300 mg) (n=23).
The study is ongoing. Secondary endpoints will include the
proportion of patients with HIV RNA levels (viral load) less than
50 copies/mL at 48 weeks of treatment, and the safety and
tolerability of the two treatment regimens through 48 weeks of
treatment. After week 48, subjects will continue to take blinded
study drug until treatment assignments have been unblinded, at
which point all subjects will be given the option to participate in
an open-label rollover extension and receive the single-tablet
regimen containing elvitegravir, GS 9350 and Truvada.
Additional information about the study can be found at
www.clinicaltrials.gov.
About the GS 9350 Phase II
Study
The GS 9350 Phase II study is a double-blind, multicenter,
randomized (2:1), active-controlled 48-week clinical trial
evaluating the safety and efficacy of GS 9350-boosted atazanavir
(n=50) compared to ritonavir-boosted atazanavir (n=29), each in
combination with Truvada, in HIV-infected treatment-naïve adults
with HIV RNA levels (viral load) greater than or equal to 5,000
copies/mL and CD4 cell counts greater than 50 cells/mm3. Entry
criteria required that patients did not have nucleoside reverse
transcriptase inhibitor, non-nucleoside reverse transcriptase
inhibitor or primary protease inhibitor resistance mutations, as
defined by International AIDS Society-USA guidelines, and no prior
use of antiretroviral treatments.
The study is ongoing. Secondary endpoints will include the
proportion of patients with HIV RNA levels (viral load) less than
50 copies/mL at 48 weeks of treatment, and the safety and
tolerability of the two treatment regimens through 48 weeks of
treatment. After week 48, subjects will continue to take blinded
study drug until treatment assignments have been unblinded, at
which point all subjects will be given the option to participate in
an open-label rollover extension and receive GS 9350-boosted
atazanavir and Truvada.
Additional information about the study can be found at
www.clinicaltrials.gov.
About
Elvitegravir
Elvitegravir is an HIV integrase inhibitor. Unlike other classes
of antiretroviral agents, integrase inhibitors interfere with HIV
replication by blocking the ability of the virus to integrate into
the genetic material of human cells. Elvitegravir, also known as GS
9137 or JTK 303, was licensed by Gilead from Japan Tobacco Inc.
(JT) in March 2005. Under the terms of Gilead’s agreement with JT,
Gilead has exclusive rights to develop and commercialize
elvitegravir in all countries of the world, excluding Japan, where
JT retains rights. Elvitegravir is an investigational compound and
has not yet been determined safe or efficacious in humans.
About GS 9350
GS 9350 is Gilead’s proprietary potent mechanism-based inhibitor
of cytochrome P450 3A (CYP3A), an enzyme that metabolizes drugs in
the body. In addition to studying the agent as part of an
integrase-based fixed-dose regimen, Gilead is also examining GS
9350’s potential stand-alone role in boosting commercially
available HIV protease inhibitors, which are used in many HIV
treatment regimens. GS 9350 is an investigational therapy and has
not yet been determined safe or efficacious in humans.
Important Product Safety
Information About Truvada and Atripla
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 including Viread (tenofovir disoproxil fumarate) a
component of Truvada. Truvada and Atripla are not approved for the
treatment of chronic hepatitis B virus (HBV) infection and their
safety and efficacy have not been established in patients
co-infected with HBV and HIV-1. Severe acute exacerbations of
hepatitis B have been reported in patients co-infected with HIV-1
and HBV who have discontinued Truvada or Atripla. Hepatic
function should be monitored closely with both clinical and
laboratory follow-up for at least several months in patients who
are co-infected with HBV and HIV-1 and discontinue Truvada or
Atripla. If appropriate, initiation of anti-hepatitis B treatment
may be warranted.
It is important for patients to be aware that anti-HIV medicines
including Truvada and Atripla do not cure HIV infection or AIDS and
do not reduce the risk of transmitting HIV to others.
Additional Important
Information About Truvada
Truvada is a fixed-dose combination tablet containing 200 mg of
emtricitabine (Emtriva) and 300 mg of tenofovir disoproxil fumarate
(Viread). 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.
It is not recommended that Truvada be used as a component of a
triple nucleoside regimen. Truvada should not be coadministered
with Atripla, Emtriva, Viread or lamivudine-containing products,
including Combivir® (lamivudine/zidovudine), Epivir® or Epivir-HBV®
(lamivudine), Epzicom® (abacavir sulfate/lamivudine) or Trizivir®
(abacavir sulfate/lamivudine/zidovudine). In treatment-experienced
patients, the use of Truvada should be guided by laboratory testing
and treatment history.
Emtricitabine and tenofovir are principally eliminated by the
kidneys. 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
Viread. It is recommended that creatinine clearance be calculated
in all patients prior to initiating therapy with Truvada and as
clinically appropriate during therapy. Routine monitoring of
calculated creatinine clearance and serum phosphorous should be
performed in patients at risk for renal impairment. Dosing interval
adjustment and close monitoring of renal function are recommended
in all patients with creatinine clearance 30-49 ml/min. Truvada
should be avoided with concurrent or recent use of a nephrotoxic
agent. Truvada should not be co-administered with Hepsera (adefovir
dipivoxil).
Coadministration of Truvada and didanosine should be undertaken
with caution. Patients should be monitored closely for
didanosine-associated adverse events and didanosine should be
discontinued if these occur. Dose reduction of didanosine should be
considered, if warranted. Patients on atazanavir and
lopinavir/ritonavir plus Truvada should be monitored for
Truvada-associated adverse events and Truvada should be
discontinued if these occur. When co-administered with Truvada, it
is recommended that atazanavir be boosted with ritonavir 100 mg.
Atazanavir without ritonavir should not be co-administered with
Truvada.
Decreases in bone mineral density (BMD) at the lumbar spine and
hip have been seen with the use of Viread. The effect on long-term
bone health and future fracture risk is unknown. BMD monitoring
should be considered in patients with a history of pathologic
fractures or who are at risk for osteopenia.
Changes in body fat have been observed in patients taking
anti-HIV medicines. Immune Reconstitution Syndrome has been
reported in patients treated with combination therapy, including
Viread and Emtriva, and may necessitate further evaluation and
treatment.
Most common adverse reactions (incidence ≥10%) are diarrhea,
nausea, fatigue, headache, dizziness, depression, insomnia,
abnormal dreams, and rash.
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. The inventors of Viread have agreed to waive their right
to a royalty on sales of Viread and Truvada in the Gilead Access
Program countries to ensure the product can be offered at a
no-profit price in parts of the world where the epidemic has hit
the hardest.
For complete prescribing information for Truvada, visit
www.Truvada.com.
Additional Important
Information About Atripla
In the United States, 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 contains the components Truvada (emtricitabine and
tenofovir disoproxil fumarate) and Sustiva (efavirenz),
co-formulated as a single tablet. As such, the important safety
information appearing in the above Truvada section also applies to
Atripla, in addition to the following important product
information.
As a fixed-dose regimen of Viread (tenofovir disoproxil
fumarate), Emtriva (emtricitabine) and Sustiva (efavirenz), Atripla
should not be coadministered with Viread, Emtriva, Truvada
(emtricitabine and tenofovir disoproxil fumarate) or Sustiva. Due
to similarities between Emtriva and lamivudine, Atripla should not
be coadministered with drugs containing lamivudine, including
Combivir® (lamivudine/zidovudine), Epivir® or Epivir-HBV®
(lamivudine), Epzicom® (abacavir sulfate/lamivudine) or Trizivir®
(abacavir sulfate/lamivudine/zidovudine).
Atripla should not be taken with bepridil, cisapride, midazolam,
pimozide, triazolam, and ergot derivatives due to a
contraindication with efavirenz. Use of Atripla with voriconazole,
St. John's wort (Hypericum perforatum) or St. John's
wort-containing products is not recommended. Use of Atripla with
atazanavir or atazanavir/ritonavir is not recommended.
Atripla should not be given to patients with creatinine
clearance less than 50 ml/min.
Serious psychiatric adverse experiences, including severe
depression (2.4 percent), suicidal ideation (0.7 percent), nonfatal
suicide attempts (0.5 percent), aggressive behavior (0.4 percent),
paranoid reactions (0.4 percent) and manic reactions (0.2 percent)
have been reported in patients treated with efavirenz, a component
of Atripla. 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 death by 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. Patients
should tell their doctor if they have a history of mental illness
or are using drugs or alcohol.
Fifty-three percent of patients in clinical studies have
reported central nervous system symptoms including dizziness (28.1
percent), insomnia (16.3 percent), impaired concentration (8.3
percent), somnolence (7.0 percent), abnormal dreams (6.2 percent)
and hallucinations (1.2 percent) when taking efavirenz compared to
25 percent 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
percent in patients treated with regimens containing efavirenz.
Nervous system symptoms are not predictive of the less frequent
psychiatric symptoms.
Women should not become pregnant or breastfeed while taking
Atripla. Serious birth defects have been seen in children of women
treated with efavirenz during pregnancy. Women must use a reliable
form of barrier contraception, such as a condom, even if they also
use other methods of birth control.
Rash is a common side effect that usually goes away without any
change in treatment. Rash may be a serious problem in some
children.
In patients with known or suspected history of hepatitis B or C
and in patients treated with other medications associated with
liver toxicity, monitoring of liver enzymes is recommended.
Atripla should be used 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.
Invirase® (saquinavir) should not be used as the only protease
inhibitor in combination with Atripla.
The most significant adverse events observed in patients treated
with Sustiva are nervous system symptoms, psychiatric symptoms and
rash. The most common adverse events (at least 5 percent) observed
in clinical studies with Sustiva include fatigue, pain, dizziness,
headache, insomnia, impaired concentration, nausea, vomiting,
diarrhea, depression, rash and pruritus.
For complete prescribing information for Atripla, visit
www.Atripla.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.
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 risks related to Gilead’s ability to submit full
study results of the Phase II clinical trial of the Quad or GS 9350
as a stand-alone boosting agent for presentation at a scientific
meeting in early 2010 as currently contemplated. In addition, there
may be unfavorable results of the ongoing or any further clinical
trials of the Quad or GS 9350, and Gilead may need to modify or
delay such clinical trials. Gilead may ultimately be unable to
obtain the U.S. Food and Drug Administration and other regulatory
body approvals, and as a result, the Quad or GS 9350 may never be
successfully commercialized. Further, Gilead may make a strategic
decision to discontinue development of the Quad or GS 9350 if, for
example, it believes commercialization will be difficult relative
to other opportunities in its pipeline. 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
Gilead’s Quarterly Report on Form 10-Q for the third quarter of
2009, as 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.
U.S. full prescribing information for
Truvada is available at www.Truvada.com.U.S. full prescribing
information for Atripla is available at www.Atripla.com.U.S. full
prescribing information for Viread is available at
www.Viread.com.U.S. full prescribing information for Emtriva is
available at www.GileadHIV.com.U.S. full prescribing information
for Hepsera is available at www.Hepsera.com.
Truvada, Emtriva, Hepsera and Viread
are registered trademarks of Gilead Sciences, Inc.Atripla is a
registered trademark of Bristol-Myers Squibb & Gilead Sciences,
LLC.
For more information on Gilead
Sciences, please visit the company's website at www.gilead.com or
call Gilead Public Affairs at 1-800-GILEAD-5 or 1-650-574-3000.
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