June 05, 2001
Gilead Sciences Presents Data Characterizing Resistance Profile of Tenofovir DF, Investigational Agent for the Treatment of HIV
Data Presented at 5th International Workshop on HIV Drug Resistance and Treatment Strategies
Scottsdale, AZ -- June 5, 2001
Gilead Sciences, Inc. (Nasdaq: GILD) today presented in vitro data further characterizing the resistance profile of tenofovir disoproxil fumarate (tenofovir DF), the company's investigational agent in development for the potential treatment of HIV infection. The resistance profile of tenofovir was studied using phenotypic analyses of nearly 5,000 clinically-derived HIV samples from predominantly treatment-experienced patients, which were provided and analyzed by Tibotec-Virco. The results of the in vitro analyses indicate that reduced susceptibility to tenofovir is infrequent and is not closely correlated with cross-resistance to commercially-available drugs from the nucleoside reverse transcriptase inhibitor (NRTI) or non-nucleoside reverse transcriptase inhibitor (NNRTI) classes.
Scientists at Gilead and Tibotec-Virco, a biotechnology company that markets genotypic, phenotypic and VirtualPhenotype™ resistance testing services, collaborated on this study. The data will be described today in an oral presentation by Michael Miller, Ph.D., Director, Clinical Virology, Gilead Sciences at the 5th International Workshop on HIV Drug Resistance and Treatment Strategies in Scottsdale, Arizona.
Results of this study indicate that over 88 percent of the samples were fully susceptible to tenofovir and were within the normal three-fold range. Decreases in tenofovir susceptibility were infrequent, with seven percent of samples having between a three- and five-fold decrease, four percent of samples having greater than a five-fold decrease and only one percent having greater than a ten-fold decrease. In contrast, 40 percent, 17 percent and 49 percent of these samples had greater than ten-fold reduced susceptibility (resistance) to 3TC, AZT or at least one NNRTI, respectively.
In order to determine the normal range of tenofovir susceptibility (or the biological cut-off), researchers first screened 1,000 samples from HIV treatment-naive patients using the Virco Antivirogram™ assay. More than 97.5 percent of the samples (those falling within two standard deviations) had tenofovir susceptibility less than three-fold above the wild-type control. Therefore, a biological cut-off for tenofovir was set at three-fold for the Antivirogram.
Following the determination of the biological cut-off for tenofovir, Tibotec-Virco screened nearly 5,000 HIV samples derived from predominantly treatment-experienced outpatients to determine the cross-resistance profile of tenofovir and a panel of commercially available HIV drugs. Tibotec-Virco services are utilized by physicians to assist them in selecting HIV treatment regimens for patients who are failing, changing or initiating therapy. Reflecting the treatment-experienced nature of this patient population, the panel of samples showed a broad range of resistance to the commercially available HIV drugs. Specifically, 69 percent had a greater than ten-fold decrease in susceptibility to drugs from at least one antiretroviral drug class, 43 percent to drugs from two classes and 16 percent to drugs from all three classes. In contrast, only one percent of samples had a ten-fold or greater decrease in susceptibility to tenofovir. The three classes of approved HIV antiretroviral agents are nucleoside reverse transcriptase inhibitors (NRTI), non-nucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors (PIs).
"It is becoming increasingly important to fully understand the potential patterns of cross-resistance between the classes of commercially available drugs and those in development," said John C. Martin, Ph.D., President and CEO, Gilead Sciences. "These in vitro data are encouraging in that reduced susceptibility to tenofovir was infrequent. As we have recently completed our regulatory filings for tenofovir DF in both the U.S. and Europe, Gilead is making significant progress towards providing a novel treatment option to treatment-naïve patients and to the growing number of patients who are infected with resistant HIV virus."
Additional Resistance Data
In two additional presentations at the 5th International Workshop on HIV Drug Resistance and Treatment Strategies, Gilead researchers presented data describing the unique structural and enzymological features of tenofovir that may help to explain the compound's favorable resistance profile. One study, which analyzed the crystal structure of HIV-1 reverse transcriptase bound to tenofovir, revealed that the unique acyclic chemical structure of tenofovir might contribute to the infrequency of cross-resitance and resistance development. The other study compared the removal of nucleosides (zidovudine, stavudine, zalcitabine, didanosine and lamivudine) versus nucleotides (tenofovir) using the ATP-dependent chain-terminator removal mechanism. The results demonstrate that chain-terminator removal occurs more readily with nucleosides than nucleotides and may contribute to the higher-level of resistance associated with nucleosides. The interaction of the acyclic structure of tenofovir combined with a unique resistance to chain-terminator removal may help explain why resistance to tenofovir is infrequent and slow to occur in vitro.
About Tenofovir DF
Tenofovir DF is dosed as a single 300 mg tablet taken once daily and works by blocking reverse transcriptase, an enzyme crucial to the replication of HIV. In May 2001, Gilead submitted a New Drug Application for tenofovir DF to the U.S. Food and Drug Administration and a Marketing Authorisation Application to the European Agency for the Evaluation of Medicinal Products. As an investigational compound, tenofovir DF has not yet been determined safe or efficacious in humans for its ultimate intended use.
Tenofovir DF Phase III Program
Gilead currently is evaluating tenofovir DF in two Phase III clinical trials. The first of these, Study 907, is an intensification of therapy study of tenofovir DF in 552 antiretroviral treatment-experience patients and is ongoing at sites in the United States, Europe and Australia. Twenty-four week data from this 48-week study were announced in February 2001, and Gilead expects to present these data at a scientific conference later this year.
Gilead initiated a second Phase III trial, Study 903, to evaluate tenofovir DF as a potential therapy for treatment-naive patients with HIV infection. This 48-week trial is designed to compare a treatment regimen of tenofovir DF, lamivudine (3TC) and efavirenz to a treatment regimen of stavudine (d4T), lamivudine 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 at 601 patients.
Expanded Access Program Initiated
In January, Gilead announced the initiation of an expanded access program to provide tenofovir DF to people with advanced HIV infection. Programs are open for registration in the United States, France, Spain and the United Kingdom. Gilead expects to initiate expanded access programs in Germany, Italy, Canada and other countries as local regulatory approvals are obtained.
For more information regarding the tenofovir DF early access program or to request registration materials, physicians in the United States may call 1-800-GILEAD-5 and those within Europe may call 33-1-44-90-34-46.
Gilead Sciences, Inc., headquartered in Foster City, CA, USA, is an independent biopharmaceutical company that seeks to provide accelerated solutions for patients and the people who care for them. Gilead discovers, develops, manufactures and commercializes proprietary therapeutics for challenging infectious diseases (viral, fungal and bacterial infections) and cancer. Gilead maintains research facilities in Foster City, CA; Boulder, CO; San Dimas, CA; Cambridge, UK; and Dublin, Ireland; and sales and marketing organizations 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 risks related to regulatory approval of tenofovir DF. 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, 2000 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.
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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 (1-800-445-3235).