PRNewswire - Friday, December 18, 1998

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Ziagen has been studied in clinical trials that have included previously untreated patients as well as heavily pre-treated patients -- including a large, well-controlled study in heavily pre-treated children. Studies show that combinations containing Ziagen have proven antiviral activity in patients who have not previously received treatment with antiretroviral drugs. Patients who have had prolonged prior exposure to Retrovir« (zidovudine; AZT) and Epivir« (lamivudine; 3TC) may have a minimal response to combinations containing Ziagen. However, studies have shown some of these patients to have experienced significant antiviral activity as a result of switching to new combinations containing Ziagen.

Ziagen in combination with other antiretroviral agents is indicated for the treatment of HIV-1 infection. This indication is based on analyses of surrogate markers in controlled studies of up to 24 weeks in duration. At present, there are no results from controlled trials evaluating long-term suppression of HIV-RNA or disease progression with Ziagen.

Today's approval of Ziagen is based on results from three phase III studies. In a planned interim analysis at 16 weeks of a study of adults with no previous treatment history, the three drug combination of Ziagen+Epivir+Retrovir was shown to be superior to the combination of Epivir+Retrovir in reducing HIV-1 RNA viral load. In this study, 75 percent of 87 patients on triple combination including Ziagen were at less than 400 copies/mL using the Roche Amplicor HIV MONITOR«Test compared to 35 percent of 86 patients on dual therapy. Through 16 weeks of therapy, the median CD4 changes from baseline were 47 cells/mm3 in the group receiving Ziagen and 112 cells/mm3 in the placebo group. This difference was not statistically significant.

In a planned interim analysis at 24 weeks of a study of children with extensive prior nucleoside treatment, the three drug combination of Ziagen+Epivir+Retrovir was shown to be superior to the combination of Epivir+Retrovir in reducing HIV-1 RNA viral load. In this study, 13 percent of 102 patients on triple combination including Ziagen were at less than 400 copies/mL using the Roche Amplicor HIV MONITOR«Test compared to 2 percent of 103 patients on dual therapy. After 16 weeks of therapy, the median CD4 increases from baseline were 69 cells/mm3 in the group receiving Ziagen and 9 cells/mm3 in the control group.

Preliminary findings from a second controlled study in therapy-naive adults were supportive of the efficacy of Ziagen through 16 weeks of treatment. This study compares Ziagen+Combivir(tm) (lamivudine/zidovudine) with the combination of Crixivan(tm) (indinavir; protease inhibitor; Merck)+Combivir, and is continuing through 48 weeks.

"Ziagen appears to be a highly potent drug that will have potential in a variety of drug combinations because of its ease of dosing and the fact that it has a low likelihood of interactions with other antiretroviral drugs that are metabolized by the cytochrome P450 enzyme system," said Robert Schooley, M.D., professor of medicine at the University of Colorado Health Sciences Center.

Ziagen will be dosed as one 300-mg tablet twice daily with no food or water restrictions or requirements. It is expected that Ziagen will be available in pharmacies in early January.

In clinical trials to date, the most commonly reported adverse events were headache, nausea, vomiting, malaise and diarrhea when Ziagen was taken, primarily with Epivir and Retrovir but also with all marketed and most investigational compounds. Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues alone or in combination, including abacavir and other antiretrovirals.

The most serious adverse event associated with Ziagen is a hypersensitivity reaction that can be life threatening and has been fatal in some cases. The hypersensitivity reaction has been observed in approximately 3 to 5 percent of patients receiving Ziagen in clinical trials and is characterized by fever, skin rash, fatigue, and gastrointestinal symptoms, such as nausea, vomiting, diarrhea, or abdominal pain. The symptoms of this reaction get progressively worse if treatment continues. Patients experiencing these symptoms should stop taking Ziagen and contact a physician immediately. Symptoms of this reaction usually occur within the first six weeks of treatment and generally resolve following permanent discontinuation of Ziagen. Patients experiencing this reaction must not take Ziagen again as restarting the drug after a hypersensitivity reaction has resulted in cases of life-threatening and fatal reactions. Glaxo Wellcome will be issuing to patients a Medication Guide for Ziagen to provide further information on optimizing care with this drug. This may be the first such Medication Guide issued under the FDA's new regulations announced on December 1, 1998.

"Though it only occurs in a small percentage of patients, the potential for a hypersensitivity reaction is something that patients and physicians should be aware of, particularly during the first six weeks of treatment with Ziagen," said Lynn Smiley, M.D., vice president, HIV and Opportunistic Infections Clinical Development at Glaxo Wellcome. "The syndrome is fairly well characterized but much work is being done to better understand the underlying etiology."

The Glaxo Wellcome price to wholesalers for Ziagen will be $9.70/day, or $3,540 annually, though retail prices paid by patients will be different. However, the price to state ADAP programs is 15 percent less, or approximately $3,000 annually. This price is expected to enable ADAPs to quickly add Ziagen to state formularies. The company's pricing decision related to Ziagen included and reflected input from HIV treatment advocates and ADAP administrators who requested a meeting with company representatives prior to a pricing decision in order to share information on the current HIV treatment funding environment. Ziagen was discovered and is being developed by Glaxo Wellcome. The rights to related compounds and technology, including intermediates used in the manufacture of Ziagen, resulting from the research by Dr. Robert Vince, et. al, were licensed to Glaxo Wellcome by the University of Minnesota.

Glaxo Wellcome is the pharmaceutical industry leader in HIV research and therapies. In addition to Ziagen, Glaxo Wellcome also recently submitted a New Drug Application to the FDA for the investigational protease inhibitor AgeneraseÖ (amprenavir). Glaxo Wellcome also manufactures and markets the widely used anti-HIV medicines Epivir, Retrovir and Combivir. The company is currently conducting a unique expanded access program for Agenerase, is engaged in basic research programs designed to investigate new targets to treat HIV, and is continuing to lead the way in pioneering efforts to study the viability of increasing access to HIV therapies in the developing world.

For complete prescribing information for Ziagen, Epivir, Retrovir and/or Combivir, please call 919-483-2311 or 919-483-8580.

SOURCE: Glaxo Wellcome
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