Oral resiquimod in chronic HCV infection: Safety and efficacy in 2 placebo-controlled, double-blind phase IIa studies

Background/Aims: To explore safety, pharmacokinetics, and pharmacodynamics of oral administration of resiquimod, a Toll-like receptor 7 and 8 agonist that induces endogenous interferon-alpha, in subjects with chronic hepatitis C virus infection. Methods: Two randomized, double-blind phase Ha studies of resiquimod administered two times per week for 4 weeks. Multicenter study (U.S.): 12 subjects received resiquimod 0.01 mg/kg and 4 received placebo. Single center study (France): 6 subjects received 0.01 mglkg, 11 received 0.02 mg/kg and 6 received placebo. Results: Resiquimod 0.01 mg/kg was tolerated; two 0.2 mg/kg subjects discontinued treatment. More subjects reported severe grade adverse events at 0.02 mg/kg; events were consistent with systemic cytokine induction, including fever, headache, shivering, and lymphopenia. Mean maximum serum resiquimod concentrations were 3.82 +/- 1.47 and 7.55 +/- 4.17 ng/ mL for 0.01 mg/kg and 0.02 mg/kg, respectively. At 0.02 mg/kg, two, three and one subjects had maximal reductions in viral levels of at least 1-, 2- and 3-logs, respectively; reductions were generally transient. Interferon-alpha levels appeared correlated with decreases in viral titer and lymphocyte counts, as well as increase in neutrophil counts.