Schering-Plough Initiates Study With Vicriviroc In Treatment-Naive HIV-Infected Patients

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Schering-Plough Corporation has initiated a Phase II clinical study with vicriviroc, its investigational CCR5 antagonist, for use in first-line therapy of adult treatment-naive HIV-infected patients with R5-type virus only. Vicriviroc is a next-generation HIV entry inhibitor designed to prevent the virus from infecting CD4 cells by blocking its predominant entry route, the CCR5 co-receptor. Approximately 80-90 percent of treatment-naive patients have virus that uses the CCR5 co-receptor. Vicriviroc also is being studied in two large Phase III clinical studies in treatment-experienced HIV patients, which are ongoing and currently enrolling patients.

The study in treatment-naive patients evaluates the virologic benefit of vicriviroc, administered once-daily as a single 30 mg tablet, in combination with ritonavir-boosted atazanavir, compared to a control group receiving Truvada (emtricitabine and tenofovir disoproxil fumarate) plus ritonavir- boosted atazanavir, which is a currently recommended option for first-line therapy. Atazanavir is a product in the protease inhibitor (PI) class of HIV medications. Truvada is a combination product in the nucleoside reverse transcriptase inhibitor (NRTI) class.

"A nucleoside-sparing vicriviroc regimen for initial treatment may have the added strategic benefit of preserving most products used to create a highly active antiretroviral therapy "cocktail" for later use in patients, while also avoiding the risk of toxicity known to be associated with the nucleoside class," said Joseph C. Gathe, Jr., M.D., F.A.C.P., clinical instructor, department of internal medicine, Baylor College of Medicine, Houston, and lead investigator for the study. "This treatment strategy could also prove beneficial for the growing number of patients who already have primary resistance to NRTIs prior to any treatment."

In previous studies in treatment-experienced HIV-infected patients, vicriviroc in combination with an optimized ritonavir-boosted PI-containing regimen demonstrated potent and sustained viral suppression through 48 weeks of treatment.

The standard of care for treatment-naive HIV-infected individuals is to combine three drugs from two classes to initiate antiretroviral therapy. The combinations characteristically use two NRTIs with either a non-nucleoside reverse transcriptase inhibitor (NNRTI) or a ritonavir-boosted PI. While these combinations have been demonstrated to be highly effective, long-term tolerance may be limited by the toxicity specifically associated with nucleosides, which can include neuropathy, myopathy, renal toxicity, hepatic steatosis, lactic acidosis, bone marrow suppression, fat atrophy and, with certain agents, increased risk of myocardial infarction.

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"As a next-generation HIV entry inhibitor, vicriviroc has the potential to benefit a broad range of patients by offering potent and sustained viral suppression, and a single once-daily dose for use in combination with other antiretroviral agents," said Robert J. Spiegel, M.D., chief medical officer and senior vice president, Schering-Plough Research Institute. "CCR5 antagonists such as vicriviroc have a novel mechanism of action in fighting HIV, and may play a unique role as physicians seek to construct new regimens to meet the specific needs of their patients, whether they are starting treatment or have been treated with several different combinations over a period of time."

About the Phase II Naive Study

This randomized, controlled, open-label study is projected to enroll approximately 200 treatment-naive HIV-infected adult patients at more than 20 sites in North America, Central America, Europe and South Africa. Patients coinfected with hepatitis B or C may be included in the study.

The primary efficacy endpoint of the study is the mean change from baseline in viral load (log10 HIV RNA) at week 48 of treatment. A key secondary efficacy endpoint is the proportion of patients with plasma HIV RNA less than 50 copies/mL at week 48 of treatment.

The study will be conducted in two stages. In the first stage, 80 patients will be randomized (40 per treatment arm) into the study. When the 80 subjects from the first stage have completed 24 weeks of treatment, a formal interim analysis will be conducted and the results presented to an independent Data Safety Monitoring Board (DSMB) to assure the safety of the study participants. The study will be extended to stage 2 based on the results of the 24-week interim analysis; at which time an additional 120 patients (60 per treatment arm) will be enrolled. The final analysis will be conducted at week 48 of treatment for all patients.

Atazanavir boosted by ritonavir was selected for use in this study because it is recommended as an option for first-line therapy in both the International AIDS Society and Department of Health and Human Services guidelines for antiretroviral therapy. Additionally, it has been shown to have a more favorable lipid profile than other drugs in the PI class.