The Body Covers: The 3rd International AIDS Society Conference on HIV Pathogenesis and Treatment
Vicriviroc (SCH 417690, SCH-D), a CCR5 Antagonist, Generally Well Tolerated and Effective in 14-Day Monotherapy Study
July 26, 2005
Reference Abstract: SCH 417690: antiviral activity of a potent new CCR5 receptor antagonist (Oral TuOa0205)
IAS 2005 featured a bevy of oral presentations on CCR5 antagonists, a new class of HIV medications in development that seeks to prevent HIV from binding to the CCR5 cellular co-receptor, which facilitates HIV's entry into the host cell.
This study reported on the continuing clinical development of a Schering-Plough CCR5 antagonist termed SCH 417690, which was previously known as SCH-D and is now called vicriviroc. Several other companies are also developing antagonists of the CCR5 co-receptor for clinical use, including GlaxoSmithKline (which presented data on GSK873140 at this conference) and Pfizer, Inc. (which presented data on UK-427,857, a.k.a. maraviroc) among others. All these compounds are currently at a similar stage of development.
The current report represents a dose-finding study to establish the ability of vicriviroc to achieve antiviral effect in HIV-infected individuals. The study is similar in many ways to efforts by Pfizer and GlaxoSmithKline to better understand the antiviral profiles, pharmacokinetics and safety characteristics of their CCR5-inhibiting compounds.
This randomized, blinded study by D. Schuermann, of Charatie Hospital in Berlin, Germany, et al evaluated 48 HIV-infected individuals who were treated for 14 days with placebo or 1 of 3 twice-daily doses of vicriviroc monotherapy: 10 mg, 25 mg or 50 mg. The patients were divided into 3 cohorts, each consisting of 16 patients. In each cohort, 4 patients received placebo while 12 received one of the doses of vicriviroc.
Among the criteria for entry were that participants should only have detectable CCR5-tropic virus (i.e., no CXCR4-tropic virus), as monitored by the PhenoSense co-receptor assay developed by ViroLogic. Patients also needed to have a CD4+ cell count greater than 200 cells/mm3 and were either treatment naive or had previously received treatment but not for at least 8 weeks prior to enrollment in the current study.
Patients' mean baseline HIV RNA was 4.6 log10 copies/mL, and the mean baseline CD4+ cell count was 478 cells/mm3. Eighty-two percent of the study patients were male.
The results showed that vicriviroc was well tolerated, in doses up to 100 mg daily for 14 days, although 1 or 2 cases of seizures were reported transiently in several of the patients who received the drug. This situation will clearly need to be monitored over longer follow-up in more advanced clinical trials.
Most importantly, vicriviroc resulted in maintenance of steady-state Cmin values that were above the IC90 value for this compound as studied in tissue culture. Consistently, vicriviroc mediated a dose-related suppression of HIV RNA at all 3 doses that were studied, with a mean reduction in viral load of 1.62 log10 copies/mL after 14 days of treatment. Following this period, viral rebound to baseline slowly occurred over 2 weeks in the absence of treatment. An increase in CD4+ cell count was also observed during the period of study.
Clearly, these findings create an important rationale for the further clinical development of vicriviroc. A phase 2 study of vicriviroc is now recruiting treatment-experienced patients at sites throughout the United States; click here for more clinical trial information.
One final note: In this study, the compound was also shown to be effective against viral isolates of multiple subtypes -- not just subtype B -- which raises interesting questions as to the drug's potential usefulness in developing nations, where non-B-subtypes are prevalent. As resistance to existing antiretrovirals continues to increase in places such as Africa, Asia and South America, the availability of new drugs in new classes could become a critical issue.
Authored by: D Schuermann, C Pechardscheck, R Rouzier, R Nougarede, G Faetkenheuer, I Ochlast, F Raffi, C Hoffman, W Greaves, A Sansone
Affiliations: Charatie Hospital, Berlin, Germany; CentreCap, Montpellier, France; University of Cologne, Cologne, Germany; Biotrial/University Hospital, Nantes and Rennes, France; University of Kiel, Kiel, Germany; Schering Plough Research Institute, Kenilworth, New Jersey, United States of America
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