European Commission Approves Gilead Sciences’ Tybost™, a New Boosting Agent for HIV Therapy

  European Commission Approves Gilead Sciences’ Tybost™, a New Boosting Agent
  for HIV Therapy

 – Tybost Facilitates Once-Daily Dosing of the Protease Inhibitors Atazanavir
                               and Darunavir –

Business Wire

FOSTER CITY, Calif. -- September 25, 2013

Gilead Sciences, Inc. (Nasdaq: GILD) today announced that the European
Commission has granted marketing authorization for once-daily Tybost™
(cobicistat 150 mg tablets), a pharmacokinetic enhancer that boosts blood
levels of certain HIV medicines. Tybost is indicated as a boosting agent for
the HIV protease inhibitors atazanavir 300 mg once daily and darunavir 800 mg
once daily as part of antiretroviral combination therapy in adults with HIV-1
infection. Today’s approval allows for the marketing of Tybost in all 28
countries of the European Union (EU).

“Gilead is pleased to offer HIV patients who rely on protease inhibitors a new
boosting option to help facilitate once-daily dosing – an important factor in
supporting treatment adherence,” said Norbert Bischofberger, PhD, Executive
Vice President, Research and Development and Chief Scientific Officer, Gilead
Sciences.

The EU approval of Tybost is supported by 48-week data from a pivotal Phase 3
study (Study 114), which found that Tybost was non-inferior to ritonavir when
administered with an antiretroviral regimen of atazanavir plus Truvada^®
(emtricitabine 200 mg and tenofovir disoproxil (as fumarate) 245 mg) in
HIV-infected treatment-naïve adults. Approval is also supported by
pharmacokinetic data demonstrating that Tybost boosts blood levels of
atazanavir and darunavir similar to ritonavir. Tybost should only be
co-administered with atazanavir or darunavir.

In Study 114, Tybost was well tolerated and most adverse events were mild to
moderate. The most common adverse reactions (incidence greater than or equal
to 10 percent, all grades) were jaundice, ocular icterus and nausea.

Tybost is a component of Gilead’s Stribild^® (elvitegravir 150 mg/cobicistat
150 mg/emtricitabine 200 mg/tenofovir disoproxil (as fumarate) 245 mg), a
once-daily complete single tablet regimen for the treatment of HIV-1 infection
that was approved in the United States in August 2012 and in the European
Union in May 2013. Gilead submitted a new drug application to the U.S. Food
and Drug Administration (FDA) for Tybost as a single agent in June 2012 and
received a Complete Response Letter in April 2013. Gilead is working on
resubmitting the application to the FDA. Tybost is approved as a single agent
in Canada.

About Tybost

Tybost is a cytochrome P450 3A (CYP3A) inhibitor. It boosts blood levels of
atazanavir and darunavir by suppressing CYP3A, an enzyme that metabolizes
these drugs in the body. Tybost acts only as a pharmacokinetic enhancer and
has no antiviral activity.

Indication and Important Safety Information about Tybost

Tybost is indicated as a pharmacokinetic enhancer of atazanavir 300 mg once
daily or darunavir 800 mg once daily as part of antiretroviral combination
therapy in human immunodeficiency virus-1 (HIV-1) infected adults.

Co-administration with the following medicinal products is contra-indicated
due to the potential for serious and/or life-threatening events or loss of
therapeutic effect:

• alpha 1 adrenoreceptor antagonists: alfuzosin

• antiarrhythmics: amiodarone, quinidine

• anticonvulsants: carbamazepine, phenobarbital, phenytoin

• antimycobacterials: rifampicin

• ergot derivatives: dihydroergotamine, ergometrine, ergotamine

• gastrointestinal motility agents: cisapride

• herbal products: St. John’s wort (Hypericum perforatum)

• HMG-CoA reductase inhibitors: lovastatin, simvastatin

• neuroleptics: pimozide

• PDE-5 inhibitors: sildenafil for treatment of pulmonary arterial
hypertension

• sedatives/hypnotics: orally administered midazolam, triazolam

Cobicistat is a strong mechanism-based CYP3A inhibitor and is a CYP3A
substrate. Increased plasma concentrations of medicinal products that are
metabolised by CYP3A (including atazanavir and darunavir) are observed on
co-administration with cobicistat. Higher plasma concentrations of
co-administered medicinal products can result in increased or prolonged
therapeutic effects or adverse reactions. For medicinal products metabolised
by CYP3A these higher plasma concentrations may potentially lead to severe,
life-threatening or fatal events. Co-administration of Tybost and atazanavir
or darunavir with products that induce CYP3A is not recommended because the
resulting levels of cobicistat could be insufficient to achieve adequate
pharmacoenhancement of atazanavir or darunavir. Co-administration of Tybost
with medicinal products that inhibit CYP3A may decrease the clearance of
cobicistat, resulting in increased cobicistat plasma concentrations.
Cobicistat is a weak CYP2D6 inhibitor and is metabolised to a minor extent by
CYP2D6. Co-administration with cobicistat can increase plasma concentrations
of medicinal products that are metabolised by CYP2D6. Cobicistat inhibits the
transporters p-glycoprotein (P-gp), BCRP, MATE1, OATP1B1 and OATP1B3.
Co-administration of Tybost in patients receiving medicinal products that are
substrates of these transporters may result in increased plasma concentrations
of the co-administered medicinal products. Unlike ritonavir, cobicistat is not
an inducer of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19 or UGT1A1. If switching
pharmacoenhancers from ritonavir to cobicistat, caution is required during the
first two weeks of treatment with Tybost, particularly if doses of any
concomitantly administered medicinal products have been titrated or adjusted
during use of ritonavir as a pharmacoenhancer.

No dosing recommendations can be made regarding the use of Tybost with oral
contraceptives. Alternative forms of contraception should be considered.

Tybost must be co-administered with either atazanavir 300 mg once daily or
with darunavir 800 mg once daily. Safety and efficacy have not been
established for use of Tybost with either atazanavir or darunavir when used in
any other dosing regimen. Antiviral efficacy data from randomized controlled
studies is available for cobicistat-boosted atazanavir, but not for
cobicistat-boosted darunavir.

Tybost must not be used as a pharmacokinetic enhancer of any other HIV-1
protease inhibitor or any other antiretroviral medicinal product that requires
boosting since dosing recommendations for such co-administration have not been
established and may result in insufficient plasma level of the antiretroviral
medicinal product(s) leading to loss of therapeutic effect and development of
resistance.

Tybost co-administered with atazanavir or darunavir should not be used in
combination with another antiretroviral agent that requires
pharmacoenhancement by means of co-administration with an inhibitor of CYP3A4
to reach the desired therapeutic plasma concentrations (i.e., another protease
inhibitor or elvitegravir). Dosing recommendations for such combinations have
not been established and co-administration may result in decreased plasma
concentrations of atazanavir, darunavir and/or the other antiretroviral agents
that require pharmacoenhancement leading to loss of antiviral activity and
development of resistance. Tybost should not be used concurrently with
ritonavir due to similar effects of cobicistat and ritonavir on CYP3A. Tybost
should not be used in combination with other medicinal products containing
cobicistat (such as the fixed dose combination tablet elvitegravir/cobicistat/
emtricitabine/tenofovir disoproxil (as fumarate)).

Cobicistat has been shown to decrease estimated creatinine clearance due to
inhibition of tubular secretion of creatinine. This effect on serum
creatinine, leading to a decrease in the estimated creatinine clearance,
should be taken into consideration when Tybost is administered to patients in
whom the estimated creatinine clearance is used to guide aspects of their
clinical management, including adjusting doses of co-administered medicinal
products. Tybost should not be initiated in patients with creatinine clearance
less than 70 ml/min if one or more co-administered agent requires dose
adjustment based on creatinine clearance (e.g. emtricitabine, lamivudine,
tenofovir disoproxil (as fumarate) or adefovir). There are currently
inadequate data to determine whether co-administration of tenofovir disoproxil
(as fumarate) and cobicistat is associated with a greater risk of renal
adverse reactions compared with regimens that include tenofovir disoproxil (as
fumarate) without cobicistat.

Cobicistat has not been studied in patients with severe hepatic impairment
(Child Pugh Class C). Therefore, the use of Tybost is not recommended in these
patients.

Tybost contains the azo colouring agent sunset yellow FCF (E110), which may
cause allergic reactions.

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 Asia Pacific.

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 may
not see advantages of Tybost over ritonavir and may therefore be reluctant to
prescribe the product. In addition, pending marketing applications for Tybost
in the United States and other regions may not be approved or approval may be
delayed, and marketing approvals, if granted, may have significant limitations
on their use. 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 quarter ended June 30, 2013, 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.

  EU Summary of Product Characteristics for Tybost, Stribild and Truvada are
                    available at http://www.ema.europa.eu.

Tybost, Stribild and Truvada are trademarks or registered trademarks of Gilead
                                Sciences, Inc.

For more information on Gilead Sciences, please visit the company’s website at
  www.gilead.com, follow Gilead on Twitter (@GileadSciences) or call Gilead
             Public Affairs at 1-800-GILEAD-5 or 1-650-574-3000.

Contact:

Gilead Sciences, Inc.
Patrick O’Brien, 650-522-1936, Investors
Cara Miller, 650-522-1616, Media (US)
Stephen Head, +44 (208) 587-2359, Media (EU)