VX-950: A TIGHT-BINDING HCV PROTEASE INHIBITOR WITH A SUPERIOR SUSTAINED INHIBITORY RESPONSE IN HCV REPLICON CELLS.

Monday, Oct 27, 2003, 4:00 PM - 4:15 PM

JO4 HCV: Treatment

Kai Lin, Cynthia A. Gates, Yu-Ping Luong, Robert B. Perni, Ann D. Kwong, Vertex Pharmaceuticals Inc, Cambridge, MA.

We have been developing HCV NS3•4A protease inhibitors using a structure-based, rational drug design process. In these studies, we compared our clinical candidate, VX-950, to BILN-2061, another HCV protease inhibitor in clinical development (2002 AASLD Mtg). VX-950 and BILN-2061 exhibit inhibition mechanisms that appear kinetically distinct from each another. Additional studies were designed to investigate the effects of these different mechanisms of protease inhibition on replication in a replicon system. HCV replicon cells were incubated with concentrations of VX-950 or BILN-2061 that were fixed multiples (x10 and x50) of their respective IC50’s in the absence of G418. Two days after the addition of compound, the rate of inhibition of HCV replicon RNA was similar for both drugs. In contrast, at late times (12-15 days) after the addition of drug, VX-950 suppressed HCV replicon RNA to dramatically lower levels than BILN-2061 (typically 1-2 log10). When the same experiment was performed in the presence of G418, more colonies of resistant cells grew in the cultures containing BILN-2061 than VX-950. These results indicate that VX-950 has a more potent and sustainable antiviral response in HCV replicon cells than BILN-2061. These findings will be discussed, in the context of the different chemical structures and enzyme inhibition mechanisms of these two inhibitors.