Meeting report: 30th International Conference on Antiviral Research, in Atlanta, GA, USA

Vere Hodge, R Anthony

The HCV NS5B polymerase is an attractive drug target. It is highly conserved across all HCV genotypes -enhancing the chance of discovering a pan-genotype drug. Also, the highly active, critical nature of the polymerase active site means that any mutations resistant to nucleoside/tide drugs are likely to reduce polymerase efficiency and hence the fitness of the mutated virus and hence reduce the probability of generating highly resistant virus. When Mike joined Pharmasset, the standard-of-care HCV therapy was IFN together with ribavirin (RBV) which could not be used without IFN. The cost was high, in terms of dollars, time (one year) and in severe restrictions on patient lifestyle. Also, the outcome was uncertain, the cure rate being around 40%. But Pharmasset had an early lead compound, PSI-6130 ( Figure 2 ). PSI-6130 was highly selective for HCV versus other viruses, it was active in vitro against HCV polymerases from genotypes (GT) 1, 2, 3 and 4, was a non-obligate chain terminator of viral RNA and it had at least additive activity with other anti-HCV drugs. After passaging in cell culture for six months, a resistant mutant (S282T) was obtained but it was of low viral fitness and with no known pre-existing prevalence in the clinic. In rats and monkeys, the oral bioavailability was $ 20%. Of concern, there was deamination to give the uridine metabolite which was inactive against HCV. In monkeys, there was 40-70% conversion to the uridine metabolite.