CROI: CCR5 antagonist SCH532706 shows potent activity and good tolerability in small trial

A new experimental CCR5 antagonist, SCH532706, boosted with ritonavir, demonstrated potent anti-HIV activity and was generally well-tolerated in a small ten-day monotherapy study, according to data presented Monday at the Fifteenth Conference on Retroviruses and Opportunistic Infections in Boston.

SCH532706 is a second-generation CCR5 antagonist from Schering-Plough, which also has a first-generation CCR5 antagonist, vicriviroc, in late clinical development (Phase 2 results were presented in the same session).

CCR5 antagonists work by blocking the CCR5 co-receptor, one of the two pathways HIV can use to enter cells. An individual’s virus may be exclusively CCR5-tropic, CXCR4-tropic (using the other co-receptor), or dual- or mixed-tropic (able to use both pathways). CCR5 antagonists only work against CCR5-tropic HIV.

Test tube studies found that SCH532706 had high potency (IC₉₀

Sarah Pett of Australia’s National Centre for HIV Epidemiology at the University of New South Wales reported findings on the antiviral activity, pharmacokinetics, and safety of 60mg twice-daily SCH532706 boosted with 100mg once-daily ritonavir taken for ten days. As with some protease inhibitors, ritonavir boosts the blood level of SCH532706 and makes it last longer in the body. After ten days, there was a 14-day “wash out” period, then participants started standard combination antiretroviral therapy.

The study included twelve individuals with CCR5-tropic HIV. Four were treatment-naive and eight were treatment-experienced but off therapy for at least three months. All were men, more than 90% were white, and the median age was 36 years (range 30 – 52 years). At baseline, the median CD4 count was 327 cells/mm³ and the median viral load was 4.56 log₁₀ copies/ml.

Intensive pharmacokinetic monitoring took place on days 1 and 10. On day 10, the mean C_max was found to be 295 ng/ml. The median time it took to reach this highest blood plasma level was 1.4 hours (range 1 – 4 hours) and the median half-life was 39.4 hours. The median trough (lowest) level, at 186 ng/ml, was more than 30-fold higher than the in vitro IC₉₀ value of 1.1 ng/ml (after correction for plasma protein binding).

At day 10, the mean HIV viral load reduction from baseline was 1.31 log₁₀ copies/ml. Due to the drug’s long half-life, viral load continued to drop after day 10. Consequently, at day 15 (four days after participants stopped the drug), the mean viral load reduction from baseline was 1.62 log₁₀ copies/ml. Even at day 20, viral load was still about 1 log₁₀ copies/ml below the baseline level, though it returned to the initial level by day 25. At day 10, CD4 count had increased by 59 cells/mm³ over the baseline level.

Overall, SCH532707 was well tolerated. There were no abnormal laboratory safety results or unusual electrocardiograph tests in any of the participants. Although eleven of the twelve (92%) reported at least one treatment-emergent adverse event, most commonly gastrointestinal upset, 75% of these were considered to be mild, and 58% were thought to be unlikely to be related to SCH532706.

There was one serious adverse event, moderate pericarditis (inflammation of the sac which surrounds the heart), that was classified as “possibly related” to SCH532706 because the investigators could not identify any other cause, but this occurred thirteen days after the last dose of the study drug.

In all participants, HIV remained CCR5-tropic during the study period, with no switch to CXCR4 tropism.

Based on these findings, the researchers concluded that SCH532706 is safe and well tolerated, and is suitable for once-daily dosing as part of a ritonavir-containing antiretroviral regimen.