April 11, 2000
Gilead Presents Preliminary Clinical Data Describing Activity of Adefovir Dipivoxil Against Lamivudine-Resistant Hepatitis B Virus
Data Presented at the 10th International Symposium on Viral Hepatitis and Liver Disease
Atlanta, GA -- April 11, 2000
Gilead Sciences, Inc. (Nasdaq: GILD) announced today the presentation of clinical data from an open-label study, evaluating its investigational agent adefovir dipivoxil in 23 patients with chronic hepatitis B (HBV) infection who have failed treatment with the antiviral agent lamivudine (3TC) due to viral resistance. The data suggest that treatment with adefovir dipivoxil was associated with suppression of HBV DNA to undetectable levels in 80 percent of patients who had 12 to 15 months of treatment. These results complement previous data characterizing adefovir dipivoxil as a compound that remains active against all clinically relevant strains of HBV tested to date.
“Treatment with adefovir dipivoxil appears to decrease HBV viral load in patients who have exhausted other therapeutic options,” said clinical investigator Marion Peters, MD, Professor of Medicine and Chief of Hepatology Research at the University of California, San Francisco Medical Center. “For immunocompromised patients with chronic HBV infection who have undergone liver transplantation or have advanced liver disease, resistance to lamivudine may be particularly threatening. My colleagues and I are encouraged by the virologic response patients have experienced in this open-label study of adefovir dipivoxil, and the durability of that response for 12 months and longer.”
Data collected from 23 patients who received adefovir dipivoxil on a compassionate basis for life-threatening liver disease and lamivudine-resistant HBV were described by Dr. Peters during an oral presentation on Tuesday, April 11 at the 10th International Symposium on Viral Hepatitis and Liver Disease in Atlanta, Georgia.
"We are pleased to see that the emerging profile of adefovir dipivoxil includes potential antiviral activity against both wild-type and HBV with reduced susceptibility to lamivudine,” said John C. Martin, Ph.D., President and Chief Executive Officer. “Gilead is pursuing the development of adefovir dipivoxil 10 mg as first-line monotherapy for the treatment of chronic HBV and as an important treatment option for patients who are experiencing loss of response to currently approved therapies.”
At baseline, 10 patients had received liver transplants, six had decompensated liver disease and seven had compensated liver disease. These patients exhibited elevated levels of HBV DNA circulating in their bloodstream despite treatment with lamivudine, and resistance to lamivudine was confirmed by genotypic analysis in 16 patients. Additionally, 20 patients had abnormal liver function tests (LFTs), including 15 with evidence of hepatic decompensation during lamivudine treatment. All patients had documented loss of virologic or clinical response to lamivudine therapy.
The patients included in this analysis were treated with a once-daily dose of adefovir dipivoxil for a median time of 15 months with a maximum time on treatment of 21 months. Dosage was based upon each patient’s renal function and liver transplantation status at study entry, with 12 patients initiating treatment with adefovir dipivoxil 10 mg. Eleven patients began treatment with 30 mg and were proactively switched to the 10 mg dose during the study. For patients who experienced changes in renal function due to underlying disease or concomitant medications, the 5 mg dose of adefovir dipivoxil was administered. The majority of patients also continued lamivudine therapy.
Adefovir dipivoxil treatment was associated with suppression of serum HBV DNA to undetectable levels in 12 of 15 evaluable patients (80 percent) who had 12 or more months of treatment. Treatment with adefovir dipivoxil also was associated with improvements in laboratory markers of liver function, including serum hepatic transaminase, bilirubin and albumin levels. Serious drug-related side effects were not observed and no patient discontinued therapy due to drug-related side effects.
“While lamivudine therapy is helping many patients maintain liver function, we still need research to determine optimal long-term treatment strategies for this chronic disease,” said Dr. Peters. “We do know that the ideal antiviral, whether dosed as monotherapy or as part of a combination regimen, must produce a rapid, sustained reduction of serum HBV DNA. As important is the need for these drugs to remain active against mutant strains of the virus.”
First HBV Combination Study of Adefovir Dipivoxil and Lamivudine
To help researchers and physicians better understand the clinical impact of HBV resistance and devise new treatment paradigms, Glaxo Wellcome plc (NYSE: GLX) in collaboration with Gilead Sciences, has commenced a controlled clinical trial. Study NUC 20904 is evaluating the once-daily use of adefovir dipivoxil 10 mg as combination therapy with lamivudine 100 mg (Epivir-HBV®) in chronic HBV patients who have experienced diminished therapeutic response to lamivudine monotherapy.
This 52-week randomized, double-blind, placebo-controlled trial will enroll 130 adult patients with chronic compensated or decompensated liver disease due to HBV infection and evidence of diminished therapeutic response to lamivudine at approximately 24 sites in the United States, Australia, Canada, France, Hong Kong, Singapore, Spain and the United Kingdom. Enrollment in this study began in late March of this year.
Ongoing Adefovir Dipivoxil Phase III Clinical Program
Two pivotal Phase III trials are currently underway to evaluate adefovir dipivoxil monotherapy as a potential treatment for chronic HBV. Initiated in March 1999, Study 437 is a randomized, double-blind, placebo-controlled trial of adefovir dipivoxil 10 and 30 mg being conducted at 90 sites in Australia, Europe, North America and Southeast Asia. The trial has completed enrollment with 515 patients. Study 438, initiated in January 2000, is enrolling 180 patients at 32 sites in Australia, Canada, France, Greece, Israel, Italy and Southeast Asia. This trial is evaluating adefovir dipivoxil 10 mg for the treatment of patients with precore mutant HBV infection, a strain of the virus that has evolved without the hallmark HBV “e” antigen. Gilead anticipates completing enrollment of this trial in early summer.
Ongoing Study for Liver Transplant Recipients
In addition to the studies described above, Gilead also is conducting an open-label clinical trial (Study 435) designed to evaluate the use of adefovir dipivoxil for the treatment of liver transplant patients with chronic HBV infection who no longer adequately respond to currently available treatments and have recurrent HBV. This study is being conducted in North America, Asia, Australia and Europe.
About Glaxo and Gilead
Glaxo Wellcome Inc., based in Research Triangle Park, N.C., is one of the nation’s leading research-based pharmaceutical firms. A subsidiary of London-based Glaxo Wellcome plc, the company is committed to fighting disease by bringing innovative medicines and services to patients and to the healthcare providers who serve them.
Gilead Sciences, 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. For more information about Gilead, please visit www.gilead.com.
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Editor’s Note: Physicians and patients seeking information about the clinical trials described in this press release may call 1-800-GILEAD-5.