www.hivandhepatitis.com

Gilead Initiates Phase 2 Clinical Trial of Once-daily, Single-tablet, 4-drug Combination Pill Containing Integrase Inhibitor Elvitegravir

Gilead Sciences announced on April 17, 2009 that the company has initiated a Phase 2 clinical trial to assess the safety and efficacy of the new "QUAD" 4-drug combination pill containing elvitegravir, GS 9350, and emtricitabine/tenofovir (the drugs in the Truvada pill) versus the 3-drug efavirenz/tenofivir/emtricitabine (Atripla) combination pill in treatment-naive HIV positive adults.

Elvitegravir is Gilead's experimental HIV integrase inhibitor and GS 9350 is an novel boosting agent that increases blood levels of certain other drugs, including elvitegravir.

Following are edited excerpts from Gilead's announcement of the new trial:

Gilead Initiates Phase II Clinical Trial of Integrase-based, Single-tablet, Once-daily Regimen for the Treatment of HIV

Foster City, CA -- April 17, 2009 -- Gilead Sciences, Inc. today announced that it has begun enrolling patients in a Phase II clinical trial of its investigational integrase-based, single-tablet, once-daily regimen of elvitegravir, GS 9350 and Truvada (emtricitabine 200 mg/tenofovir disoproxil fumarate 300 mg) for the treatment of HIV-1 infection.

GS 9350 is an investigational compound being developed as a pharmaco-enhancing or "boosting" agent to increase blood levels and allow once-daily dosing for certain medicines, including Gilead's investigational HIV integrase inhibitor, elvitegravir.

The Phase II study is designed to evaluate the safety and efficacy of the regimen compared to once-daily Atripla (efavirenz 600 mg/emtricitabine 200 mg/tenofovir disoproxil fumarate 300 mg). The study will enroll 75 HIV-1 infected, antiretroviral treatment-naive adults across approximately 50 investigative sites in the United States.

"The initiation of this Phase II study is an important milestone in the development of our 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. "The single-dose regimen of Atripla has become the standard of care for many patients, particularly those new to therapy. If proven safe and effective, this new single-tablet regimen has the potential to provide an important alternative for them."

Since its approval in 2006, Atripla has remained the only once-daily, single-tablet regimen available for the treatment of HIV. Atripla is jointly marketed in the United States and Europe by Gilead and Bristol-Myers Squibb Company. Gilead is also examining GS 9350 as a stand-alone boosting agent for other antiretrovirals, in particular, protease inhibitors. Later this quarter, Gilead plans to initiate a Phase II clinical trial evaluating the safety and efficacy of GS 9350-boosted atazanavir (Reyataz) compared to ritonavir (Norvir)-boosted atazanavir, each in combination with Truvada. Ritonavir is currently the only boosting agent available for HIV therapy.

About the Phase II Study

The Phase II study is a randomized, double-blind, 48-week clinical trial that will evaluate the safety and efficacy of a single-tablet containing elvitegravir, GS 9350 and Truvada versus Atripla, each administered in HIV-infected treatment-naive 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 require that patients do not have nucleoside reverse transcriptase inhibitor (NRTI), non-nucleoside reverse transcriptase inhibitor (NNRTI) or primary protease inhibitor resistance mutations, as defined by International AIDS Society-USA guidelines, and no prior use of antiretroviral treatments.

Seventy-five trial participants will be 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=50) or Atripla (efavirenz 600 mg/emtricitabine 200 mg/tenofovir disoproxil fumarate 300 mg) (n=25).

The primary endpoint will be the proportion of patients with viral loads less than 50 copies/mL at 24 weeks of treatment. Secondary endpoints will include the proportion of patients with viral loads 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 their 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.

About Elvitegravir

Elvitegravir is an [investigational] 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.

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. 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.

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 coinfected with HBV and HIV-1. Severe acute exacerbations of hepatitis B have been reported in patients coinfected with HIV-1 and HBV who have discontinued Emtriva (emtricitabine) or Viread, which are components of Truvada and Atripla. 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 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.

• 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.

4/21/09

Source

Gilead Sciences. Gilead Initiates Phase II Clinical Trial of Integrase-based, Single-tablet, Once-daily Regimen for the Treatment of HIV. Press Release. April 17, 2009.