48-Week Data Demonstrate Ability of Viread to Suppress Viral Load in Patients With Multiple Treatment-Resistant HIV Mutations

BARCELONA, Spain, Jul 11, 2002 (BW HealthWire) --

Results of Genotypic and Phenotypic Analyses from Two Studies Presented at International AIDS Conference in Barcelona

Gilead Sciences, Inc. (Nasdaq:GILD) today announced that its novel treatment for HIV-infected patients, Viread(R) (tenofovir disoproxil fumarate), demonstrates durable and sustained anti-HIV activity through 48 weeks, even in highly treatment-experienced HIV-infected patients with multiple thymidine analogue mutations (TAMs). TAMs include any mutation in HIV reverse transcriptase resulting directly from treatment with the thymidine nucleoside analogues zidovudine (AZT) or stavudine (d4T), two of the most commonly prescribed antiretroviral agents.

These data, which further characterize the resistance profile of Viread, were described in an oral presentation (#1390) by Michael Miller, PhD, Director of Clinical Virology, Gilead Sciences, at the XIV International AIDS Conference in Barcelona. This presentation is one of 16 Viread abstracts to be featured at the conference.

"Resistance to available antiretrovirals is among the most serious treatment challenges facing physicians and their patients," commented Dr. Miller. "We have extensively evaluated the resistance profile of Viread, and will continue to invest in this important research to provide treating physicians with additional information that will help them to construct optimal regimens for their HIV patients."

    HIV Resistance Analysis
Genotypic and phenotypic analyses of HIV sampled from patients enrolled in two placebo-controlled clinical trials (Studies 902 and 907) demonstrated that most patients who received Viread in addition to their existing combination antiretroviral regimen achieved significant HIV RNA reductions relative to placebo, regardless of the number and type of TAMs present. Patients treated with Viread in addition to their stable combination antiretroviral regimen experienced a significant mean HIV RNA reduction at week 24 of 0.59 log10 copies/mL (p less than 0.001 relative to placebo; n=222 Viread-treated, n=110 placebo-treated) that was durable through week 48 (reduction of 0.56 log10 copies/mL). Patients who were switched from placebo to Viread at week 24 (n=103) experienced an average HIV RNA decrease of 0.65 log10 copies/mL by week 48.

Patients with no TAMs who received the Viread-containing regimen experienced a significant reduction in mean HIV RNA level of 0.80 log10 copies/mL at 24 weeks (p less than 0.001; n=68). In patients with one to two TAMs, the mean HIV RNA level was reduced by a level comparable to that of the overall Viread treatment population at 24 weeks (reduction of 0.66 log10 copies/mL, p less than 0.001; n=55). Patients with three or more TAMs not including M41L or L210W experienced a mean reduction in HIV RNA level of 0.67 log10 copies/mL at 24 weeks, consistent with the overall Viread treatment population and significantly superior to placebo (p less than 0.001; n=42). In patients with three or more TAMs that included M41L or L210W, the susceptibility of HIV to Viread combination treatment was less, with a demonstrated mean HIV RNA level reduction of 0.21 log10 copies/mL at 24 weeks. This result was statistically significantly superior to the response in patients receiving placebo in addition to their existing combination therapy (p=0.013; n=57).

           HIV RNA Response at Week 24 by Number and Type of
     Baseline Thymidine Analogue Mutations in Studies 902 and 907
                         (Intent-To-Treat)(1)
Number of baseline               VIREAD                P-value
thymidine analogue         Change in HIV RNA(3)(N)   versus Placebo
mutations(2)
None                            -0.80 (68)           p less than 0.001
1 - 2                           -0.66 (55)           p less than 0.001
greater than or
 equal to 3 without
 M41L or L210W                  -0.67 (42)           p less than 0.001
greater than or
 equal to 3 including
 M41L or L210W                  -0.21 (57)           p=0.013
1.  Genotypic testing performed by Virco Laboratories and Visible
    Genetics TruGene(TM) technology
2.  M41L, D67N, K70R, L210W, T215Y/F or K219Q/E/N in RT
3.  Average HIV RNA change from baseline through week 24 (DAVG24) in
    log10 copies/mL
"The majority of patients with TAMs responded quite well to Viread," said Dr. Miller. "The specific TAMs M41L and L210W, which are always found in conjunction with the T215Y and often other mutations, represent a rather advanced pattern of TAM resistance and are known to result in the strongest cross-resistance to NRTIs. Even among patients with these mutations, there was a significant reduction in viral load with Viread treatment that was not seen in the placebo population and about 20 percent of these patients showed a viral load decrease of greater than 0.5 log10 copies/mL. Although Viread may still work in these patients with advanced TAMs, treatment should really be striving for approaches that do not lead to such extensive TAM development."

    About HIV Drug Resistance
Resistance to antiretroviral agents can arise one of two ways: (1) in direct response to antiretroviral therapy, or (2) through the acquisition of drug-resistant HIV. Each drug with anti-HIV activity attacks HIV viral replication in a slightly different way by acting on certain regions of the reverse transcriptase or protease enzymes. Certain mutations that arise during treatment confer resistance only to a specific drug, whereas other mutations confer broad cross-resistance to an entire class of drug. Because of the implications of resistance on treatment outcomes in HIV-infected patients, current expert guidelines recommend resistance testing (genotyping or phenotyping) for all treatment-experienced patients with virologic failure and for all patients with suboptimal suppression of HIV viral load after initiation of therapy. Studies have shown that in patients with failing regimens, changes in therapy guided by resistance testing result in significantly better viral load reductions than when such changes are made without benefit of resistance testing.

    About Study 902
Study 902 was a 48-week Phase II, double-blind, placebo-controlled clinical trial designed to evaluate the safety and efficacy of Viread as a component of combination therapy in 189 heavily treatment-experienced patients. The patients were randomized to receive Viread 75, 150 or 300 mg or placebo in addition to their existing treatment regimens. At week 24, all patients receiving placebo were switched in blinded fashion to the Viread 300 mg treatment arm. The average prior duration of antiretroviral therapy was 4.6 years. Patients had resistance to all three classes of available antiretroviral drugs at baseline, with 94 percent exhibiting NRTI mutations, 57 percent with protease inhibitor (PI) mutations and 32 percent with non-nucleoside reverse transcriptase inhibitor (NNRTI) mutations.

    About Study 907
Study 907 was a 48-week Phase III, double-blind, placebo-controlled clinical trial of Viread 300 mg added to a stable background regimen of antiretroviral agents in 550 treatment-experienced HIV patients in North America, Europe and Australia. To be eligible for the study, patients had to have an HIV RNA level of 400 to 10,000 copies/mL and have received stable antiretroviral therapy for at least eight weeks prior to entering the study. At baseline, patients had a mean HIV RNA level of 3.36 log10 copies/mL, a mean CD4 cell count of 427 cells/mm3 and had received a mean of 5.4 years of prior antiretroviral therapy. Genotypic analysis of resistance mutations at baseline revealed a high prevalence of existing antiretroviral resistance, with 94 percent of patients exhibiting resistance to NRTIs, 58 percent to PIs and 48 percent to NNRTIs.

Upon entry, patients were randomized (2:1) to receive Viread or placebo in addition to their existing antiretroviral therapy. After 24 weeks of blinded, placebo-controlled dosing, all patients were switched to receive open-label Viread for the remainder of the 48-week study period.

Forty-eight week efficacy and safety results from Study 907 were discussed yesterday in an oral presentation (#1266) by Anton Pozniak, MD, Chelsea and Westminster Hospital, London, United Kingdom.

    About Viread
Viread is the first nucleotide analogue reverse transcriptase inhibitor (NtRTI) approved for the treatment of HIV in the United States and Europe. It was approved in the United States in October 2001 and was approved in the European Union in February 2002. In clinical trials and expanded access programs, approximately 10,000 patients have been treated with Viread alone or in combination with other antiretroviral products for periods up to three years. The drug works by blocking reverse transcriptase, an enzyme involved in the replication of HIV. The approved dose of Viread for the treatment of HIV infection is 300 mg once daily taken orally with a meal.

In the United States, Viread is indicated for use in combination with other antiretroviral agents for the treatment of HIV-1 infection. This indication is based on analyses of plasma HIV-1 RNA levels and CD4 cell counts in a controlled study of Viread of 24 weeks duration and in a controlled, dose-ranging study of Viread of 48 weeks duration. Both studies were conducted in treatment-experienced adults with evidence of HIV-1 viral replication despite ongoing antiretroviral therapy. Studies in antiretroviral-naive patients are ongoing; consequently, the risk-benefit ratio for this population has yet to be determined.

Viread is approved in Europe for use in combination with other antiretroviral agents for the treatment of HIV infection in patients who are experiencing early virological failure.

    Resistance Profile
Resistance to Viread developed in approximately three percent of patients and is slow to develop. Viread selects for the K65R mutation in HIV reverse transcriptase in vitro, and viruses expressing this mutation show a 3- to 4-fold reduced susceptibility to the drug. Zalcitabine, didanosine and abacavir can also select for this mutation. In clinical trials, three percent of patients developed the K65R mutation, which did not always result in treatment failure. The clinical significance of the K65R mutation for patients treated with Viread or other antiretroviral agents is not fully known at this time.

    Safety Profile
Assessment of adverse reactions is based on two studies (902 and 907) in which 653 treatment-experienced patients received treatment with Viread 300 mg (n=443) or placebo (n=210) for 24 weeks followed by extended treatment with the drug. Adverse event rates in the Viread group were similar to those in the placebo-treated patients.

The most common adverse events in patients receiving Viread were mild to moderate gastrointestinal events, such as nausea, diarrhea, vomiting and flatulence. Laboratory abnormalities observed in clinical studies occurred with similar frequency in the Viread and placebo-treated groups. 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.

    Ongoing Clinical Studies
Gilead is conducting Study 903 to further evaluate Viread in treatment-naive patients with HIV infection. This 144-week trial is designed to compare a treatment regimen of Viread, lamivudine (3TC) and efavirenz to a treatment regimen of stavudine (d4T), lamivudine (3TC) and efavirenz in a blinded fashion in patients in the United States, Europe and South America who have not previously received antiretroviral treatment. Enrollment in Study 903 was completed in January 2001 with 600 patients. Preliminary results from Study 903 are also being presented during the XIV International AIDS Conference (presentation #LbOr17) on Friday, July 12 during the late-breaker session between 8:30 a.m. and 10:00 a.m. In addition, Gilead has initiated a program to evaluate Viread in treatment-experienced pediatric patients.

    About HIV/AIDS
More than 920,000 Americans and 560,000 Europeans are infected with HIV, the virus that causes acquired immunodeficiency syndrome (AIDS). Each year, approximately 560,000 U.S. and European patients receive anti-HIV treatment regimens. Globally, it is estimated that 40 million individuals are living with HIV. Treatment with antiretroviral agents is crucial to control viral load and delay the emergence of the debilitating AIDS-defining events.

    About Gilead Sciences
Gilead Sciences is a biopharmaceutical company that discovers, develops and commercializes therapeutics to advance the care of patients suffering from life-threatening diseases worldwide. The company has five marketed products and focuses its research and clinical programs on anti-infectives, including antivirals, antifungals and antibacterials. Headquartered in Foster City, CA, Gilead has operations in the United States, 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 that could cause actual results to differ materially from those referred to in the forward-looking statements. Such risks and uncertainties include the risk that these data will not be observed through longer treatment periods. The reader is cautioned not to rely on these forward-looking statements. These and other risks are described in detail in the Gilead Annual Report on Form 10-K for the year ended December 31, 2001 and in Gilead's Quarterly Reports on Form 10-Q, all of which are on file 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.

    For complete prescribing information, please visit www.viread.com.
Note to Editors: Viread is a registered trademark of Gilead Sciences, Inc.

For more information on Gilead Sciences, please visit the company's web site at www.gilead.com or call the Gilead Corporate Communications Department at 1-800-GILEAD-5 or 1-650-574-3000.

CONTACT:          Gilead Sciences, Inc.                        
                  Susan Hubbard, 650/522-5715 (Investors)      
                  Amy Flood, 44-7715-809-567 (Media)           

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