Gilead Sciences, Inc. (Nasdaq: GILD) today announced preclinical
data and results from two Phase I studies for GS 9350, an
investigational compound being developed as a pharmacoenhancing
agent (�booster�) to increase blood levels and allow once-daily
dosing for certain medicines, including Gilead�s investigational
HIV integrase inhibitor, elvitegravir. These data suggest that GS
9350 has significant and selective pharmacoenhancing ability, no
antiviral activity against HIV and differentiated biological
properties in vitro compared to ritonavir, currently the only drug
used to boost certain HIV treatments, including protease
inhibitors. Study results also show that GS 9350 effectively boosts
elvitegravir, when both drugs are dosed as part of a single tablet
complete fixed-dose regimen with Truvada� (emtricitabine 200 mg and
tenofovir disoproxil fumarate 300 mg). These data were presented
today during an oral session at the 16th Conference on Retroviruses
and Opportunistic Infections (CROI) in Montreal (Abstract#
N-121).
�These data represent the first major step forward in Gilead�s
clinical development of a new integrase-based, single tablet,
once-daily regimen for HIV,� said Norbert Bischofberger, PhD,
Executive Vice President, Research and Development and Chief
Scientific Officer, Gilead Sciences. �Results also indicate that GS
9350 holds promise as a stand-alone alternative to ritonavir for
patients receiving boosted HIV protease inhibitor-based treatment
regimens.�
A boosting agent is used to increase the blood levels of certain
antiretroviral drugs prescribed to treat HIV infection. Gilead is
developing GS 9350 to enable once-daily dosing for elvitegravir,
which is currently being evaluated in combination with
ritonavir-boosted HIV protease inhibitors, in comparison to
twice-daily raltegravir, in a Phase III clinical trial among
treatment-experienced HIV patients. The company plans to initiate a
Phase II study of the complete single tablet fixed-dose regimen
containing elvitegravir, GS 9350 and Truvada in treatment-na�ve
patients in the second quarter of this year. Currently, the only
available single tablet regimen for the treatment of HIV is
Atripla� (efavirenz 600 mg/emtricitabine 200 mg/tenofovir
disoproxil fumarate 300 mg), which is jointly marketed in the
United States by Gilead and Bristol Myers-Squibb Company.
Gilead is also examining GS 9350�s potential to boost HIV
protease inhibitors, which are used in many HIV treatment regimens.
Gilead has initiated a pharmacokinetic study of GS 9350 that will
assess its ability to boost atazanavir, one of the most widely
prescribed HIV protease inhibitors.
Preclinical
Results
In vitro data presented at CROI showed that GS 9350 has no
anti-HIV activity at concentrations up to 90?M. These data also
suggest that GS 9350 is a more specific inhibitor of human
cytochrome P450 3A (a key enzyme that metabolizes drugs in the
body) than ritonavir. Further, GS 9350 exhibited reduced effects on
adipocytes (cells that play a role in the synthesis and storage of
fat) when compared with ritonavir, including no inhibition of lipid
accumulation in adipocytes at 30?M and less than 10 percent
inhibition of insulin-stimulated glucose uptake at 10?M.
Interference with adipocyte function is believed to be involved in
some metabolic disorders associated with antiretroviral therapy,
such as elevated levels of triglycerides (fat) in the blood and
insulin resistance (hyperglycemia).
About the GS 9350 Phase I
Studies
Study GS-216-0101
This Phase I double-blind, double-dummy study evaluated the
safety, tolerability, pharmacokinetics and boosting capacity of GS
9350 compared to ritonavir 100 mg in healthy volunteers over a
14-day period. Single and multiple doses of three dose levels of GS
9350 (50, 100 and 200 mg once daily) were assessed in separate
cohorts each comprising 18 evaluable patients. Within each cohort,
subjects were randomized to receive GS 9350 (n=12), ritonavir 100
mg (n=3) or placebo (n=3). Trial participants also received oral
midazolam, at the beginning of the study and when receiving study
drug, as a standardized test compound to assess boosting
properties.
GS 9350 doses of 100 mg and 200 mg inhibited midazolam clearance
by 92 percent and 95 percent, respectively, compared with 95
percent for the 100 mg dose of ritonavir, thereby providing
clinical proof-of-concept of GS 9350 as a pharmacokinetic booster
in humans.
Both single and multiple doses of GS 9350 were well tolerated.
One drug-related Grade 3 adverse event (discoordination) occurred
in one trial participant during multiple dose administration of GS
9350 100 mg. No trial participants developed drug-related Grade 3
or 4 laboratory abnormalities or Grade 4 adverse events.
Study GS-236-0101
This open-label, partially-randomized, adaptive Phase I study
evaluated the relative bioavailability, pharmacokinetics and safety
of a fixed-dose single tablet regimen containing elvitegravir 150
mg, GS 9350 and Truvada in healthy volunteers (n=44). Two versions
of this fixed-dose combination regimen were assessed � one
containing GS 9350 100 mg and one containing GS 9350 150 mg. The
pharmacokinetic profile of elvitegravir when dosed as part of the
single-tablet regimen was compared to the profile of elvitegravir
boosted with ritonavir 100 mg and the components of Truvada
(emtricitabine 200 mg and tenofovir disoproxil fumarate 300
mg).
In this study, both the 100 mg and 150 mg doses of GS 9350
effectively boosted elvitegravir when administered as part of the
fixed-dose regimen. The 150 mg GS 9350 dose resulted in
elvitegravir pharmacokinetics that were at the targeted levels
based on ritonavir boosting, including maintenance of appropriately
high trough concentrations. Additionally, the study verified
achievement of needed exposures of the agents in Truvada following
administration of the fixed-dose regimen containing elvitegravir,
GS 9350 and Truvada compared to when emtricitabine plus tenofovir
disoproxil fumarate were administered individually.
All observed treatments were well tolerated. A single trial
participant discontinued study with a drug-related Grade 3
laboratory abnormality (elevated liver aspartate aminotransferase)
that was considered an adverse event. There were no other
drug-related Grade 3 or 4 laboratory abnormalities or adverse
events observed.
About GS 9350
GS 9350 is a potent mechanism-based inhibitor of cytochrome P450
3A (CYP3A), an enzyme that metabolizes drugs in the body. Gilead�s
goal is to develop and bring to market a pharmacokinetic enhancer
that does not have HIV activity, can be dosed once daily as a solid
dosage form and is stable at room temperature, such that it can be
co-formulated with elvitegravir and Truvada into a single tablet.
Gilead is also examining GS 9350�s potential 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.
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 therapy and
has not yet been determined safe or efficacious in humans.
Important Information About
Truvada
Truvada, a combination of Emtriva� and Viread�, 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.
Lactic acidosis and severe hepatomegaly with steatosis,
including fatal cases, have been reported with the use of
nucleoside analogs alone or in combination with other
antiretrovirals.
Truvada is not approved for the treatment of chronic
hepatitis B virus (HBV) infection, and the safety and efficacy of
Truvada have not been established in patients coinfected with HBV
and HIV-1. Severe acute exacerbations of hepatitis B have been
reported in patients who are coinfected with HBV and HIV-1 and have
discontinued Emtriva or Viread, the components of Truvada.
Hepatic function should be monitored closely with both clinical
and laboratory follow-up for at least several months in patients
who are coinfected with HIV-1 and HBV and discontinue Truvada. If
appropriate, initiation of anti-hepatitis B therapy may be
warranted.
It is important for patients to be aware that anti-HIV medicines
including Truvada do not cure HIV infection or AIDS and do not
reduce the risk of transmitting HIV to others.
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, a component of Truvada. 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 of 30-49
ml/min. Truvada should not be administered to patients with
CrCl
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