News Release

Study compares efficacy and adherence to triple nucleoside therapy Ziagen + Combivir with protease inhibitor plus Combivir regimens in therapy-nave

Peer-Reviewed Publication

Public Communications Inc.

Toronto - Sept. 18, 2000 - An interim analysis of an ongoing study comparing efficacy, safety, and patient adherence to the triple nucleoside regimen of Ziagen® (abacavir sulfate) plus Combivir® (lamivudine/zidovudine) with a triple-drug regimen containing a protease inhibitor (PI) as first-line antiretroviral therapy (ART) was presented here today at the 40th annual meeting of the Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC).

Preliminary 24-week data from the open-label randomized trial reported on patient adherence to Ziagen/Combivir compared to the PI-containing regimen. Adherence was assessed by a patient self-reported questionnaire. Preliminary adherence data at week 24 found that 74 percent (108/145) of subjects on Ziagen/Combivir and 45 percent (66/146) on indinavir/Combivir reported they took all antiretroviral doses over the previous four weeks or missed less than one dose per week. Further, 38 percent (55/145) of patients on indinavir/Combivir said their triple regimen was difficult to take, compared to 6 percent (9/146) on Ziagen/Combivir.

The regimen of Ziagen/Combivir consisted of taking one Ziagen® tablet and one Combivir tablet twice a day without dietary restriction. Patients on Combivir plus PI regimen took indinavir tablets every eight hours and one Combivir tablet twice a day. The patients taking indinavir were required to take the tablets 1 hour before or 2 hours after a meal and drink one-and-a-half quarts of water a day in accordance with the approved prescribing information for each product.

"We are pleased to have these additional, preliminary data that assess efficacy, safety and patient adherence to the Ziagen® plus Combivir regimen of two tablets twice a day," said Lynn Smiley, M.D., vice president, HIV and Opportunistic Infections Clinical Development at Glaxo Wellcome.

In this open-label multi-center study (CNAB3014) of 342 antiretroviral therapy-naive patients, patients were randomized to receive Ziagen/Combivir or indinavir/Combivir for 48 weeks. Patients were stratified according to baseline plasma viral load (VL), with 63 percent having a VL greater than 5,000 copies/ml but less than 100,000 copies/ml, and 37 percent having a VL greater than 100,000 copies/ml. The median baseline VL of patients on the Ziagen/Combivir regimen was 59,402 copies/ml and the median baseline CD4+cell count was 323 cells/ml. Patients on indinavir/Combivir had a median baseline VL of 66,386 copies/ml and a median baseline CD4+ cell count of 300 cells/ml. Viral loads were measured using <400 and <50 copies/ml assays (Roche Amplicor MONITOR® assay). The assays were conducted at separate laboratories.

At 24-weeks, in an intent to treat analysis, 68 percent (112/164) of patients on Ziagen/Combivir had VL <400 copies/ml, compared to 57 percent (94/166) on the PI-containing regimen. Of the 245 patients for whom data were available from the <50 copies/ml assay, 79 percent (104/132) on Ziagen/Combivir were below the threshold compared to 73 percent (83/113) on the PI regimen. Among patients whose baseline VL was less than 100,000 copies/ml at the start of treatment, 87 percent (72/83) of the Ziagen/Combivir patients achieved a VL <50 copies/ml, compared to 81 percent (54/67) in the other group. In patients whose baseline VL was above 100,000 copies/ml, 65 percent (32/49) in the Combivir/Ziagen® group achieved VL < 50 copies/ml, compared to 63 percent (29/46) in the other group.

"These early data offer additional information about the triple nucleoside regimen of Ziagen® plus Combivir, and provide additional information on adherence as reported by patients," said Pedro Cahn, M.D., director, Fundacion Huesped, Buenos Aires and principal investigator of the study.

Adverse events were experienced by a total of 127 patients on Ziagen/Combivir, 98 of which were considered drug-related. The following percentages include grades 1-4. The most common included nausea (45 percent), vomiting (22 percent), headache (16 percent), dizziness (10 percent), fatigue (10 percent) and abdominal pain (8 percent). A total of 133 patients experienced adverse events (123 drug-related) in the indinavir/Combivir group. The most common included nausea (58 percent), vomiting (41 percent), headache (11 percent), dizziness (10 percent) and abdominal pain (8 percent).

In the registration clinical trial in therapy-naïve adults (CNA3003), the most commonly reported adverse events observed when Ziagen® was taken in combination with Epivir® (lamivudine) and Retrovir® (zidovudine) were nausea (47 percent), nausea and vomiting (16 percent), diarrhea (12 percent), loss of appetite/anorexia (11 percent) and insomnia and other sleep disorders (7 percent). Only 2 percent of the occurrences of these adverse events were severe (grade 3 and 4) and these were in patients experiencing nausea, and nausea and vomiting. Lactic acidosis and severe hepatomegly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs alone, including abacavir, zidovudine, lamivudine, stavudine, didanosine and zalcitabine, or in combination. Zidovudine in Retrovir and Combivir has been associated with anemia and neutropenia, especially in patients with advanced disease, and with symptomatic myopathy after prolonged use.

The most serious adverse event associated with Ziagen® is a hypersensitivity reaction that can be life threatening and has been fatal in some cases. In more than 25,000 patients who have taken Ziagen® in clinical trials or through the expanded access program, hypersensitivity has been observed in approximately 5 percent of patients. Symptoms of hypersensitivity reaction usually occur in the first six weeks of treatment and get progressively worse, but generally resolve following permanent discontinuation of Ziagen. The reaction is characterized by fever, skin rash, fatigue and gastrointestinal symptoms such as nausea, vomiting, diarrhea or abdominal pain. Respiratory symptoms such as dyspnea, pharyngitis or cough also may occur, and patients should watch for symptoms such as shortness of breath, sore throat or cough. Patients experiencing these symptoms should stop taking Ziagen® and contact their physician immediately. To avoid a delay in diagnosis and minimize the risk of a life-threatening hypersensitivity reaction, Ziagen® should be permanently discontinued if hypersensitivity can not be ruled out, even when other diagnoses are possible (e.g., acute onset respiratory diseases, gastroenteritis, or reactions to other medications). After a diagnosis of hypersensitivity, patients must not take Ziagen® again. Restarting the drug after a hypersensitivity reaction has resulted in cases of life-threatening hypotension and fatal reactions. Severe or fatal hypersensitivity reactions can occur within hours after reintroduction of Ziagen® in patients who have no identified history or unrecognized symptoms of hypersensitivity to abacavir therapy. Patients should be instructed not to reintroduce abacavir without medical consultation and that reintroduction of abacavir should be undertaken only if medical care can be readily accessed by the patient or others.

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.

Combivir in combination with other antiretroviral agents is indicated for the treatment of HIV infection. Ziagen® was discovered and 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.

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Glaxo Wellcome is a pharmaceutical industry leader in HIV research and therapies. In addition to Ziagen® and Combivir, Glaxo Wellcome also manufactures and markets the protease inhibitor Agenerase® (amprenavir). The company is engaged in basic research programs designed to investigate new targets to treat HIV.

Complete prescribing information for Combivir is available at http://www.combivir.com and for Ziagen® at http://www.ziagen.com.

For additional information, please go to http://www.epivir.com, http://www.agenerase.com.



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