A Phase I study to explore the activity and safety of SCH532706,a small molecule chemokine receptor-5 antagonist in HIV type-1-infected patients

Abstract

Background

SCH532706 is a novel small molecule chemokine receptor-5 (CCR5) antagonist with high in vitro potency (mean 90% inhibitory concentration [IC₉₀] 0.15– 7.0 nM) against diverse HIV type-1 (HIV-1) isolates.

Methods

A single arm study was undertaken to examine the safety, antiviral activity and pharmacokinetics (PK) of 10 days of SCH532706 coadministered with ritonavir (RTV). The trial enrolled formerly treated (off therapy >3 months) or untreated HIV-1-infected patients.

Results

The study enrolled 12 males with CD4⁺ T-cell count >100 cells/μl. Median (range) CD4⁺ T-cell count was 327 cells/μl (117–1,008), HIV-1–RNA was 4.6 log₁₀ copies/ml (3.8–5.5) and patients had phenotypically con-firmed R5-tropic HIV-1 only. Mean (95% confidence interval) changes from baseline plasma HIV-1–RNA at days 10 and 15 (4 days off SCH532706) were -1.31 log₁₀ copies/ ml (-1.6– -1.0) and -1.62 log₁₀ copies/ml (-2.0– -1.3), respectively. Day 10 median (range) time to maximum plasma concentration, mean (±sd) effective half-life and mean (±sd) trough concentration were 1.4 h (1.0-4.0), 39.4 h (±14.5) and 178 ng/ml (±34), respectively. All virus isolates remained R5-tropic pre-study, on study and at study end. There were no laboratory or QTc interval changes reportable as adverse events. In total, 11 patients reported ≥1 treatment emergent adverse event, most commonly gastrointestinal upset. One serious adverse event, pericarditis (grade 2), occurred 13 days after drug administration. It was considered to be possibly related to study drug.

Conclusions

Overall, SCH532706 with RTV was safe, generally well tolerated and active against HIV-1 over 10 days of dosing. In this setting, SCH532706 trough concentrations exceed the mean in vitro IC (1.1 ng/ml) by >30-fold (after correction for 80% plasma protein binding) and provide a PK rationale for the observed efficacy.