Results: Similar baseline HCV (median 7.5 log cp/ml) and hAlb (median 7.2 log mg/ ml) were found among the three groups (p>0.4). The median viral decline from baseline to day 1 and day 2 was 0.5 and 0.4 log cp/ml, respectively, with no difference among the groups (p>0.7). A significantly (p=0.016) higher viral drop at day 3 from baseline was observed in group 1 (median 0.9 log cp/ml) compared to group 2 (median 0.6 log cp/ml) and group 3 (median 0 log cp/ml). The 14 day longitudinal data reveled that while
in group 3 virus rebounded to baseline levels, in group 2 an extremely slow decline or plateau phase was observed (0.03 log cp/ml/day). Only in group 1 was Selleckchem C646 a rapid 2nd phase decline observed (0.11 and 0.21 log cp/ml/day; Fig.1). In all mice hAlb remained at pretreatment levels (Fig. 1). Conclusions: The 2nd phase decline in the 469 mg/kg dosing group in the absence of the adaptive immune response is reminiscent of the high 2nd phase decline slope (0.3 logIU/mL/day), seen
in SIL treated patients and may rule out the importance of any adaptive immunomodulatory effect in vivo. The observation that hAlb remained at baseline levels throughout therapy suggests that the 2nd phase of viral decline is mainly governed by loss of intracellular HCV and not loss of infected cells. Disclosures: Ralf T. Pohl – Employment: Madaus GmbH Alan S. Perelson – Consulting: Achillion Pharmaceuticals, Roche, Santaris Pharma, Gilead; Grant/Research Support: Novartis; Stock Shareholder: Pfizer, Merck, Glaxo Kazuaki Chayama – Advisory Committees or Review Panels: Selleck 3-deazaneplanocin A Eisai, Mitsubishi Tanabe; Consulting: AbbVie, BMS; Grant/Research Support: Ajinomoto, Kyorin, MSD, Eisai, Chugai, Torii, Tsumura, Teijin, Nippon Shinyaku, Toray, selleck Dainippon Sumitomo, Mitsubishi Tanabe, BMS, Takeda, DAIICHI SANKYO, Nippon Sei-yaku, AstraZeneca, Nippon Kayaku, Kowa; Speaking and Teaching: Ajinomoto, MSD, Astellas, AstraZeneca, Bayer, BMS, Chugai, DAIICHI SANKYO, Dainippon Sumitomo, Eisai, GlaxoSmithKline, Janssen, Takeda, Otsuka, Zeria, Meiji Seika, Mitsubishi Tanabe Harel Dahari – Consulting: Abbive; Speaking and Teaching: RottapharmlMadaus The following people have nothing to disclose: Swati DebRoy, Nobuhiko
Hiraga, Michio Imamura, Laetitia Canini, Stefano Persiani, Susan L. Uprichard, Chise Tateno TG-2349 is a novel hepatitis C virus (HCV) NS3/4A protease inhibitor with pan-genotypic activity currently under Phase II development. In a proof-of-concept study against genotype 1 chronic hepatitis C patients a steep and rapid HCV RNA reduction was observed with three-day QD dosing (Tsai et.al., 2013 AASLD LB-18). Over 3.4 log of maximum viral load drop was found in GT-1a subjects. Here we describe the in vitro antiviral profile of TG-2349. The antiviral activity of TG-2349 was evaluated using enzyme- and replicon-based inhibition assays. The IC50 values measured against wild type HCV NS3/4A proteases derived from genotype 1 to 6 were below 4 nM.