September 18, 2000
Gilead Sciences Announces Results from 48-Week Study of Once-Daily Anti-HIV Agent Tenofovir DF
Presentations to be made at 40th ICAAC
Toronto, Ontario -- September 18, 2000
Gilead Sciences, Inc. (Nasdaq: GILD) today announced results from a Phase II dose-ranging clinical trial (Study 902) evaluating the safety and efficacy of once-daily tenofovir disoproxil fumarate (tenofovir DF). In this study, tenofovir DF was used to intensify a stable background antiretroviral regimen in heavily treatment-experienced HIV patients. Confirming earlier efficacy results, tenofovir DF was associated with significant and sustained antiviral activity. Additionally, the company reported that, as of early September, 115 patients remain on study drug beyond the 48-week study period with a median treatment duration of 84 weeks. This comprises the longest safety evaluation of tenofovir DF to date, and there remains no evidence of drug-related toxicities.
The data were presented by Robert Schooley, MD, Professor and Division Head, Department of Infectious Diseases, University of Colorado, on Monday, September 18, 2000, at 9:00 a.m. in an oral presentation at the 40th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) in Toronto, Canada. Preliminary 48-week data from Study 902 were presented in April at the International Conference for Antiviral Research in Baltimore, Maryland.
Study 902 Design
This 48-week double-blind, dose-ranging study enrolled 189 treatment-experienced patients who were on a stable antiretroviral regimen for at least eight weeks prior to entering the study. Prior to enrollment, patients had received a mean of 4.6 years of antiretroviral therapy. Patients were randomized to receive one of three tenofovir DF doses (300 mg, 150 mg or 75 mg) or placebo in addition to their existing treatment regimen. At week 24, all patients receiving placebo were switched in a blinded fashion to treatment with tenofovir DF 300 mg.
At baseline, patients had a mean HIV RNA of 3.7 log10 copies/mL and a mean CD4 cell count of 374 cells/mm3. Baseline genotypic analyses of HIV isolates from 187 of the 189 patients enrolled in the study revealed that 94 percent had evidence of nucleoside reverse transcriptase inhibitor resistance mutations, 57 percent had protease inhibitor resistance mutations and 32 percent had non-nucleoside reverse transcriptase inhibitor resistance mutations. The high prevalence of mutations associated with the three commonly prescribed classes of antiretrovirals is consistent with the extensive treatment experience of this study population.
In Study 902, antiviral activity was observed in all three active treatment arms, with the greatest mean difference from baseline associated with the 300 mg dose of tenofovir DF. Results from Study 902 include intent-to-treat analyses from all patients initially enrolled in the trial. The mean change in HIV RNA from baseline for patients receiving the 300 mg dose for 48 weeks of treatment was –0.62 log10 copies/mL (n=43). Patients in the 150 mg and 75 mg tenofovir DF arms had mean changes in viral load of –0.58 log10 copies/mL (n=35) and –0.40 log10 (n=42), respectively. In addition, patients who had received placebo for the first 24 weeks of the study and switched to the 300 mg dose for the second 24 weeks had a mean change in HIV RNA of –0.56 log10 at 48 weeks (n=19).
“These data demonstrate that tenofovir can have a sustained, clinically significant antiviral effect even in patients with more than four years of previous antiretroviral experience. It is important to note that many patients in Study 902 initiated anti-HIV treatment before the advent of HAART and consequently have developed resistance mutations to all three classes of currently available antiretroviral drugs,” said Dr. Schooley, who served as a principal investigator on Study 902. “The dosing regimen is simple and the safety profile is very encouraging, suggesting that tenofovir may become an important new option for patients whose alternatives are limited by viral resistance.”
Study 902 Safety Results
Through 24 weeks, the placebo-controlled portion of the trial, there was no difference in the rate of grade 3 or 4 laboratory abnormalities or clinical adverse events between the placebo and tenofovir DF arms of the study. At 24 weeks, seven patients (25 percent) in the placebo group had discontinued; after 24 weeks, all placebo patients who remained on study medication rolled over to the 300 mg dose of tenofovir DF. Through 48 weeks, there was no difference in the rate of grade 3 or 4 laboratory abnormalities or clinical adverse events among the three dosage arms of tenofovir DF and the discontinuation rate in the study was similar across all treatment arms – 11 patients (20 percent) in the 300 mg dose group, 12 patients (24 percent) in the 150 mg dose group and 14 patients (26 percent) in the 75 mg dose group.
Tenofovir Resistance Analyses
Additional data describing the emerging resistance profile of tenofovir will be presented on Wednesday, September 20 at 9:30 a.m. in an oral presentation given by Michael Miller, Ph.D., of Gilead Sciences. In this study, phenotypic analyses using the Antivirogram™ assay were performed on 72 out-patient HIV samples to characterize the tenofovir susceptibility of clinical HIV samples expressing either 3TC, high-level AZT, multinucleoside (Q151M or T69S insertions), ddI or abacavir resistance mutations.
Results from this study suggest that HIV with common forms of AZT, 3TC, ddI or abacavir resistance is susceptible to tenofovir. Moreover, tenofovir appears uniquely active against multinucleoside-resistant HIV expressing Q151M. It shows cross-resistance to the rare T69S insertions but this is partially reversed in the presence of the 3TC-associated M184V mutation. In addition, based on earlier clinical data from a virology sub-study of Study 902, it appears that treatment with tenofovir DF does not induce the development of new reverse transcriptase mutations.
“To truly make a difference in today’s HIV treatment landscape, a new drug candidate must stand out from current options in multiple areas – efficacy, safety, tolerability, resistance profile and convenience,” said John C. Martin, Ph.D., President and Chief Executive Officer, Gilead Sciences. “The data seen to date suggest that tenofovir DF has the potential to provide additional benefit in each of these categories. Gilead is working diligently to complete enrollment in Phase III studies of tenofovir DF in treatment-naïve and treatment-experienced patients and to further accelerate the development timeline for this investigational product.”
Ongoing Tenofovir DF Phase III Program
To further evaluate the safety and efficacy of tenofovir DF 300 mg in combination with other antiretroviral agents for the treatment of HIV infection, Gilead initiated Phase III clinical testing with Study 907 in November 1999 and completed enrollment in June 2000 with 552 patients. Underway in the United States, Europe and Australia, Study 907 is an intensification study in patients who are antiretroviral treatment-experienced.
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 up to 600 patients who have not previously received antiretroviral treatment. Study 903 is currently enrolling patients in the United States, Europe and South America.
Patients and physicians who would like more information about enrollment in Study 903 may call the AIDS Clinical Trials Information System (ACTIS) at 1-800-TRIALS-A or Gilead Sciences Medical Information at 1-800-GILEAD-5 (1-800-445-3235) or 1-650-574-3000 from outside the United States.
Gilead Sciences, Inc., headquartered in Foster City, CA, 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, development or manufacturing 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 the risk that the safety, efficacy and resistance data observed in Gilead’s Phase II clinical trials and preclinical testing may not be observed in Gilead’s more reliable Phase III clinical trials and 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, 1999 on file with the U.S. Securities and Exchange Commission.
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