144-week data from gilead's study 934 comparing viread® and emtriva®to combivir®both in combination with sustiva(r) published in journal of acquired immune deficiency syndrome
Patrick O’Brien, Investors
For Immediate Release
GILEAD ANNOUNCES DATA DEMONSTRATING PHARMACOKINETIC BOOSTING
ACTIVITY OF GS 9350
-- Phase I Data Support Development of a Fixed-Dose Combination Regimen Containing GS 9350,
Elvitegravir and Truvada® for the Treatment of HIV/AIDS --
MONTREAL, CANADA, February 9, 2009
– 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-naïve 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.
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data presented at CROI showed that GS 9350 has no anti-HIV activity at concentrations up to
90μM. 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 30μM and less than 10 percent
inhibition of insulin-stimulated glucose uptake at 10μM. 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
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
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 <30 mL/min or patients requiring
Coadministration of Truvada with drugs that are eliminated by active tubular secretion may increase
concentrations of emtricitabine, tenofovir, and/or the coadministered drug. Drugs that decrease renal
function may increase concentrations of emtricitabine and/or tenofovir.
No drug interaction studies have been conducted using Truvada. The U.S. package insert advises that
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. 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
coadministered with Truvada, it is recommended that atazanavir be given with ritonavir 100 mg.
Atazanavir without ritonavir should not be coadministered 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. Cases of osteomalacia
(associated with proximal renal tubulopathy) have been reported in association with the use of Viread.
Changes in body fat have been observed in patients taking anti-HIV medicines. The mechanism and
long-term health effect of these conditions are unknown. Immune Reconstitution Syndrome has been
reported in patients treated with combination therapy, including Viread and Emtriva.
The most common (incidence ≥10%, any severity) and/or treatment-emergent (Grade 2–4, occurring in
≥5% of patients) adverse reactions occurring in Study 934 through 144 weeks include diarrhea, nausea,
fatigue, sinusitis, upper respiratory tract infections, nasopharyngitis, headache, dizziness, depression,
insomnia, abnormal dreams and rash. Skin discoloration has been reported with higher frequency among
Emtriva-treated patients. Skin discoloration, manifested by hyperpigmentation on the palms and/or soles
was generally mild and asymptomatic. The mechanism and clinical significance are unknown.
For complete prescribing information for Truvada, visit . For full prescribing
information outside of the United States, physicians should consult their local product labeling. 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 risks
related to our ability to initiate a Phase II study of the single tablet fixed-dose regimen containing
elvitegravir, GS 9350 and Truvada as planned, the possibility of unfavorable results from our clinical
trials of GS 9350, the need to modify or delay our clinical trials or to perform additional trials and the risk
of failing to obtain U.S. Food and Drug Administration approval and other regulatory body approvals. As
a result, GS 9350 may never be successfully commercialized either as a stand-alone booster or co-
formulated with other products. Further, we may make a strategic decision to discontinue development of
GS 9350 if, for example, we believe commercialization will be difficult relative to other opportunities in
our 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 Annual Report on
Form 10-K for the year ended December 31, 2007 and its Quarterly Report on Form 10-Q for the first,
second and third quarters of 2008, 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.
Truvada, Emtriva 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, please call the Gilead Public Affairs Department at 1-800-GILEAD-5
(1-800-445-3235) or visit www.gilead.com.
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