September 25, 2001
Gilead’s Investigational Antiretroviral Agent Viread™ Reduces Viral Load in HIV Patients with Resistant Virus in Pivotal Phase III Study
Key data scheduled for presentation at now postponed ICAAC
Foster City, CA -- September 25, 2001
Gilead Sciences (Nasdaq: GILD) today released 24-week efficacy and safety results from a pivotal Phase III study of its investigational one tablet, once daily antiretroviral agent Viread™ (tenofovir disoproxil fumarate). The data were to have been presented at the 41st Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) in Chicago, which has been rescheduled as a result of recent events in New York and Washington D.C. Slated for review by the U.S. Food and Drug Administration (FDA) Antiviral Advisory Committee on October 3, 2001, Viread is the only new antiretroviral drug under consideration for marketing approval this year.
Study results demonstrate that patients who received Viread 300 mg in addition to their existing antiretroviral regimen achieved a significant HIV RNA reduction in mean DAVG24 of 0.61 log10 copies/mL (n=368) compared to a reduction of 0.03 log10 copies/mL (n=182) in patients who received placebo (p<0.0001). Patients in this study were highly treatment experienced with a mean of 5.4 years of prior antiretroviral treatment. Consistent with this prior treatment history, at baseline 48 percent of the patients had non-nucleoside reverse transcriptase inhibitor (NNRTI) resistance mutations, 58 percent had protease inhibitor (PI) resistance mutations and 94 percent had nucleoside reverse transcriptase inhibitor (NRTI) resistance mutations. Top-line results from this study previously were announced in a press release on February 20, 2001.
"After an average of more than five years on multi-drug therapy, most of the patients in the study had developed resistance to available treatments, yet they achieved significant reductions in circulating virus when Viread was added to their regimens," said Kathleen Squires, M.D., Associate Professor of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, and investigator on the study. "With this important antiviral effect, a safety profile comparable to placebo over 24 weeks, and convenient once daily dosing, Viread may provide a much-needed new treatment option for physicians and their patients."
About Study 907
The 48-week study, known as Study 907, enrolled 552 treatment-experienced patients in North America, Europe and Australia. Patients had HIV RNA levels of 400 to 10,000 copies/mL (a measure of the amount of HIV in their blood) and had received stable antiretroviral therapy for at least eight weeks prior to entering the study. Upon entry into the study, patients were randomized (2:1) to receive Viread (one tablet dosed once daily) 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.
The results meet the study's primary efficacy endpoint of reduction in viral load. At study entry, patients had a mean HIV RNA level of 3.36 log10 copies/mL and a mean CD4 cell count (a measure of disease-fighting cells in the blood) of 427 cells/mm3. At 24 weeks, patients treated with Viread experienced an HIV RNA reduction in mean DAVG24 of 0.61 log10 copies/mL, compared with a reduction of 0.03 log10 copies/mL in the group receiving placebo (p<0.0001).
In addition, 45 percent (155 of 346) of patients treated with Viread achieved HIV RNA reductions below the level of detection (400 copies/mL) at 24 weeks, compared with 13 percent (23 of 172) in the placebo group (p<0.0001). Reduction in HIV RNA to less than 50 copies/mL was achieved by 22 percent (76 of 346) of patients in the Viread group compared to one percent (2 of 172) in the placebo group (p<0.0001). In the Viread group, the DAVG24 for CD4 cells was an increase of 12.6 cells/mm3 compared with a decrease of 10.6 cells/mm3 in the placebo group (p=0.0008).
Through the first 24 weeks of Study 907, the incidence of serious side effects (defined as grade 3 and 4 laboratory abnormalities and clinical adverse events) was similar between patients receiving Viread and placebo. In addition, the proportion of patients who discontinued treatment at 24 weeks was an identical six percent in both the Viread and placebo arms.
"These data, along with those described in 10 additional presentations originally scheduled to be featured at ICAAC, underscore the potential Viread may have to significantly suppress viral replication - even of highly resistant viral strains - and simplify multi-drug regimens by making them more tolerable and easier to take. Importantly, these effects are durable as shown by patients in the extension phase of one study who have been on Viread treatment for nearly two years without evidence of serious drug-related side effects," said John C. Martin, Ph.D., President and CEO of Gilead Sciences. "With regulatory filings submitted for Viread in the United States, the European Union and Australia, and review by the FDA's Antiviral Advisory Committee scheduled in early October, Gilead is rapidly advancing this novel therapeutic toward commercialization."
Results of a virology substudy of 274 patients randomly selected from Study 907 were also to be featured at ICAAC. At baseline, 94 percent of the 253 evaluable patients in the virology substudy had viral mutations associated with resistance to the class of antiretroviral agents known as NRTIs. Of those, 69 percent had AZT/thymidine analogue mutations (TAMs), 68 percent had the 3TC-associated M184V mutation and 45 percent had both. In comparison to placebo, statistically significant reductions in HIV RNA ranging from 0.47 to 0.97 log10 copies/mL (p<0.0001) were observed for the Viread-treated patients whose HIV contained TAMs, M184V mutations or both.
Genotypic analyses were performed at week 24 in 171 patients. The remaining 103 patients in the virology substudy had insufficient HIV RNA for analysis - 85 of whom received Viread and 18 received placebo. Based on week 24 analysis, Viread treatment was associated with development of the K65R mutation in five patients, or three percent of those receiving Viread. Additionally, Viread treatment significantly reduced the development of mutations associated with the class of antiretroviral agents known as PIs (two percent), compared with the placebo group (eight percent; p=0.02).
Two additional presentations of in vitro data that further define the distinct resistance profile of Viread were to be presented. One study conducted in collaboration with Steven Tuske, Ph.D., Rutgers University, revealed that the unique acyclic chemical structure of tenofovir may contribute to the infrequency of cross-resistance and resistance development. The other study demonstrated that chain-terminator removal by HIV occurs more readily with nucleosides than tenofovir and may contribute to the higher level of resistance associated with nucleosides. The interaction of the acyclic structure of tenofovir combined with its resistance to chain-terminator removal may help explain why resistance to tenofovir is infrequent and slow to occur in vitro.
In another presentation, long-term safety data from the extension phase of Study 902, Gilead's Phase II trial designed to evaluate the safety and efficacy of Viread, demonstrate that treatment with Viread continues to be associated with an adverse event profile similar to that observed in the placebo group during the first 24 weeks and sustained reductions in HIV RNA in treatment-experienced patients after nearly two years of treatment.
More than 900,000 people in the United States and 36 million people worldwide are infected with HIV, the virus that causes AIDS. For patients with access to therapy, treatment with antiretroviral agents offers a crucial way of keeping levels of the dangerous virus under control and delaying the emergence of AIDS-defining events. Over years of treatment, however, multiple factors can lead to the development of viral mutations that render patients' HIV resistant to currently available medications. Of the approximately 342,000 patients currently receiving antiretroviral treatment in the United States, more than 60 percent have moved beyond their first regimen to second, third and subsequent drug combinations.
Viread is dosed as a single 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 Viread to the FDA and a Marketing Authorisation Application to the European Agency for the Evaluation of Medicinal Products. In August, Gilead submitted an application seeking regulatory approval in Australia. As an investigational compound, Viread has not yet been determined safe or efficacious in humans for its ultimate intended use.
Gilead is conducting Study 903 to evaluate Viread as a potential therapy for treatment-naive patients with HIV infection. This 96-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 601 patients, and the 48-week efficacy and safety data will be available in the first half of 2002.
Expanded Access Program
In January, Gilead announced the initiation of an expanded access program to provide Viread to people with advanced HIV infection. Nearly 5000 patients have enrolled in Viread expanded access programs in the United States, Canada, France, Germany, Ireland, Italy, Portugal, Spain and the United Kingdom.
For more information regarding the Viread expanded access program or to request registration materials, physicians in the United States and Canada 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, 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 the risk that the FDA and other regulatory agencies may not approve Viread for marketing or may require additional data to support approval, and the risk that the safety, efficacy and resistance profile of Viread may appear less favorable following longer periods of treatment. 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.