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Abstract
SCH 417690: antiviral activity of a potent new CCR5 receptor antagonist
Schuermann D.1, Pechardscheck C.1, Rouzier R.2, Nougarede R.2, Faetkenheuer G.3, Ochlast I.3, Raffi F.4, Hoffman C.5, Greaves W.6, Sansone A.6
1Charatie Hospital, Berlin, Germany, 2CentreCap, Montpellier, France, 3University of Cologne, Cologne, Germany, 4Biotrial/University Hospital, Nantes and Rennes, France, 5University of Kiel, Kiel, Germany, 6Schering Plough Research Institute, Kenilworth, New Jersey, United States of America
Introduction: This study was designed to evaluate the safety, tolerability, pharmacokinetics, and antiviral activity of SCH 417690 monotherapy administered to HIV-infected subjects.
Methods: Forty eight HIV-infected individuals were enrolled into a sequential rising dose study to evaluate 10 mg, 25 mg and 50 mg BID of SCH 417690 versus placebo for 14 days. Within each of the three cohorts (N = 16), 12 subjects received SCH 417690 and 4 subjects received placebo in a randomized, blinded design. Subjects were either treatment naïve or had had no antiretroviral treatment for a minimum of eight weeks prior to enrollment, had CCR5-tropic virus only, and had CD4+ cell counts ³200/mm3. All subjects were followed for an additional 14 days after completion of dosing.
Results: SCH 417690 was safe and well tolerated. Analysis of the pharmacokinetic profiles in the three dose levels showed dose proportionality with steady-state Cmin values above SCH 417690’s IC90. There was a statistically significant dose-related suppression of HIV RNA across all three dose levels. Mean log10 reductions in HIV RNA were -0.93, -1.49, and -1.62 for the 10 mg BID, 25 mg BID, and 50 mg BID groups, respectively. The 25 and 50 mg BID doses showed a similar maximum antiviral effect that was superior to the 10 mg BID dose. HIV RNA slowly returned toward baseline after completion of dosing. CD4+ counts also improved during treatment.
Conclusions: SCH 417690 demonstrated potent antiviral activity against CCR5-using HIV-1 strains at all doses studied. These findings, along with the marked post-antiviral effect which lasted a number of days after completion of dosing, support further clinical development of SCH 417690.
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