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and Hepatitis.com Coverage of the
17th Conference on Retroviruses and
Opportunistic Infections (CROI 2010)
February 16 - 19, San Franciso, California
Vicriviroc Fails to Beat Stiff Competition, Merck Will Not File for Treatment-experienced Approval
Vicriviroc is an entry inhibitor designed to block HIV from using one of the 2 surface co-receptors (CCR5 and CXCR4) the virus uses to enter CD4 T-cells. Maraviroc (Selzentry) is the sole approved drug in this class. Vicriviroc has had a bumpy road through the development process, facing concerns about suboptimal efficacy and adverse events including certain malignancies.
The VICTOR-E3 and VICTOR-E4 studies were identical Phase 3 trials conducted in different geographical regions in North America, Latin America, Europe, and South Africa.
The 2 trials combined enrolled more than 800 treatment-experienced participants with documented resistance to at least 2 antiretroviral drug classes. They were randomly assigned (2:1) to take either 30 mg once-daily vicriviroc or placebo, in combination with an optimized background regimen, for 48 weeks.
Participants were required to have at least 2 active drugs in their background regimen, 1 being a ritonavir-boosted protease inhibitor (the small boosting dose of ritonavir was not counted as a separate drug). A majority of patients (about 60%), however, used a background regimen containing 3 or more active drugs.
Patients were allowed to include newer drugs such as darunavir (Prezista, used by about 40% in both trials) and raltegravir (Isentress, used by about 40% in VICTOR-E3 and just under 30% in VICTOR-E4). Where these agents were widely available, it becomes much easier to construct an active regimen, since they are more likely to still be active in people who have developed resistance to older drugs.
The analysis presented at CROI focused on a modified intent-to-treat (ITT) population of 721 participants (from both trials combined) who had exclusively CCR5-tropic HIV as determined using the original Trofile assay (tropism was confirmed at the end of the study using the new higher-sensitivity Trofile-ES, but those data are still blinded).
70% of study participants were men, a majority were white (about 65%
in VICTOR-E3 and about 55% in VICTOR-E4), and the average age was 43
years. At baseline, the average HIV viral load was about 40,000 copies/mL
and the mean CD4 cell count was approximately 260 cells/mm3.
Based on these findings, the investigators concluded that vicriviroc was well-tolerated in both Phase 3 studies, but "did not meet the primary efficacy endpoint."
However, they added, the optimized background regimen in these trials included more potent antiretroviral drugs than those used in earlier Phase 2 trials of vicriviroc or Phase 3 trials of recently approved drugs.
"For subjects with 2 or fewer available active drugs, vicriviroc provided additional opportunity to achieve full viral suppression," the researchers concluded. "With the success of recently available therapies for treatment-experienced subjects, new agents will require novel study designs to demonstrate efficacy."
In their printed abstract, they wrote, "Future trials designed for advanced patients must account for changes in the therapeutic landscape."
As previously reported, Merck informed investors in January that it does not plan to seek U.S. Food and Drug Administration (FDA) approval of vicriviroc for treatment-experienced patients. The company said it would, however, continue to evaluate vicriviroc as first-line therapy for treatment-naive patients.
"While these results are disappointing, it is becoming increasingly difficult for an additional HIV medicine to demonstrate a significant incremental benefit as the fourth or fifth drug added to optimized background therapy," Merck's director of clinical research Lisa Dunkle said in a company press release. "We will further evaluate these results to better understand these findings and define a potential path forward for vicriviroc."
Therapeutic Concepts PA, Houston, TX; Federal University of Sao Paulo, Brazil; University of Cologne, Germany; Desmond Tutu HIV Foundation, Cape Town, South Africa; Merck Research Labs, Kenilworth, NJ.