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Potent antiretroviral activity of the once-daily CCR5 antagonist INCB009471 over 14 days of monotherapy

Cohen C.1, DeJesus E.2, Mills A.3, Pierone, Jr. G.4, Kumar P.5, Ruane P.6, Elion R.7, Fusco G.8, Levy R.8, Solomon K.8, Erickson-Viitanen S.8

Introduction: This study was designed to evaluate the safety, tolerability, pharmacokinetics, and antiviral activity of once daily INCB009471 monotherapy administered to HIV-infected subjects harboring R5-tropic virus.
Methods: HIV-infected individuals were enrolled into a study to evaluate 200 mg QD INCB009471 versus placebo for 14 days in a randomized, blinded design. Subjects were either treatment naïve or had no antiretroviral treatment for a minimum of three months.
Results: Twenty-one subjects were enrolled in the study, with 18 receiving INCB009471 and 3 receiving placebo. The mean CD4+ cell count at baseline was 565 ± 68 cells/mm3 and mean VL was 4.7 ± 0.1 log10. INCB009471 was safe and well tolerated. Analysis of the pharmacokinetic profile on Day 14 to Day 16 of the study revealed a mean Cmin of ~500 nM, which is 10-20 fold higher than the protein binding adjusted 90% inhibitory concentration measured in PBMCs in vitro. Subjects receiving INCB009471 showed rapid viral load declines, achieving 0.44 log and 1.14 log reductions on Day 4 and Day 7, respectively. Nadir of mean viral load decline occurred on Day 16, -1.82 logs, N=18. Consistent with the long plasma half life of INCB009471 (approximately 60 hours), viral load continued to be suppressed on Day 20 (-1.72 log), 6 days after the last dose of INCB009471. Two weeks following the last dose of INCB009471, VL was still suppressed > 0.8 log relative to baseline. 17/18 (94%), 15/18 (83%) and 8/18 (44%) of treated subjects achieved viral load declines of > 1.0 log10, > 1.5 log10, and > 2.0 log10, at nadir, respectively. CD4+ cell counts were stable or slightly increased over the 14-day course of therapy in individual subjects.
Conclusions: INCB009471 demonstrated potent and prolonged antiviral activity against R5-tropic HIV-1 when given once daily for 14 days. These findings support further clinical development of INCB009471.

4th IAS Conference on HIV Pathogenesis, Treatment and Prevention
Abstract no. TUAB106

Suggested Citation
"CohenC., et al. Potent antiretroviral activity of the once-daily CCR5 antagonist INCB009471 over 14 days of monotherapy. Oral abstract session: 4th IAS Conference on HIV Pathogenesis, Treatment and Prevention: Abstract no. TUAB106"