The AIDS Clinical Trials Group has reported additional data from a clinical trial of vicriviroc, Schering-Plough’s experimental entry inhibitor currently in the Phase II stage of development. The 48-week results were reported today at the fourth IAS Conference on HIV Pathogenesis, Treatment and Prevention in Sydney.
The primary goal of the study (A5211) was to see how well vicriviroc worked over 14 days in HIV-positive people who had tried other HIV treatments in the past but whose current HIV regimens were failing. Other goals were to study the safety of vicriviroc and to study the effects of vicriviroc on viral load and CD4 cell counts—when used in combination with other HIV medications—over 48 weeks.
After HIV binds to the CD4 protein on T cells, the virus must then latch onto another receptor on the cell's surface, either CCR5 or CXCR4. Vicriviroc, like another entry inhibitor, maraviroc, blocks CCR5, preventing HIV from entering CD4 cells that carry this receptor.
Study participants were randomized to add one of three doses of vicriviroc (5 mg, 10 mg or 15 mg, all once a day) or a placebo to their current HIV drug regimen. After two weeks, participants continued vicriviroc or a placebo, and changed their other HIV drugs to an optimized background treatment (OBT) consisting of approved HIV medications that their virus may be sensitive to.
An independent study monitoring board reviewed the clinical trial for safety from time to time. At its review on October 6, 2005, the committee recommended stopping the 5 mg vicriviroc dose because it wasn't working as well as the other doses. At its review on February 15, 2006, they noted five cancers in participants taking vicriviroc and recommended that all participants be told whether they were taking vicriviroc or not.
The 24-week results, reflecting data collected up until February 15, were reported at the 16th International AIDS Conference last summer in Toronto. The full 48-week data were reported at IAS 2007 by Roy Gulick, MD, MPH, of Weill Cornell Medical College in New York.
A total of 118 patients were enrolled in the study. The average viral load at study entry was 36,380 and the average CD4 count was 146. All patients in A5211 had HIV targeted CCR5 on CD4 cells; individuals with CXCR4-targeting HIV were excluded from the study.
Only five patients assigned to the placebo group remained in the study for the full 48 weeks. Along with the closing of the 5 mg–dosing group, the only noteworthy comparison was between those receiving 10 mg and 15 mg of vicriviroc.
After 48 weeks, participants taking either 10 mg or 15 mg vicriviroc decreased their viral loads by approximately 1.92 log and 1.44 log, respectively. Undetectable viral loads (below 50 copies) were seen in 37 percent of those in the 10 mg group and 27 percent of those in the 15 mg group.
Dr. Gulick also reported changes in CD4 counts after 48 weeks of treatment. In the 10 mg group, counts increased by 130 CD4 cells. In the 15 mg group, counts increased by 96 CD4 cells.
A central concern with entry-inhibitor treatment targeting CCR5 is that it will result in the emergence of HIV using CXCR4, a form of the virus that is believed to be associated with more rapid disease progression. In A5211, CXCR4 virus emerged in four patients in the 10 mg vicriviroc group and three patients in the 15 mg group.
As for side effects, there were no differences between the placebo and vicriviroc groups. The relationship between vicriviroc and the reported malignancies isn’t clear and is still being investigated by researchers.
Schering-Plough is currently conducting a Phase II clinical trial of its own, testing higher doses of vicriviroc in treatment-experienced patients, to see if it can improve on the virologic responses seen in the ACTG study. The study, dubbed VICTOR-E1, is comparing 20 mg and 30 mg doses of the drug to placebo, in combination with an optimized Norvir-boosted, protease inhibitor–containing antiretroviral regimen.
Based on the results of A5211 and VICTOR-E1, the company will select a dose for vicriviroc and move it into Phase III studies.
Source:
Gulick R, Sur Z, Flexner C, et al. ACTG 5211: Phase II study of the safety and efficacy of vicriviroc (VCV) in HIV-infected treatment-experienced subjects: 48-week results [Abstract TUAB102]. Fourth IAS Conference on HIV Pathogenesis, Treatment and Prevention, Sydney, 2007.
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