PSI-938 / PSI-661

PSI-938 and PSI-661 are guanine nucleotide analog polymerase inhibitors for the treatment of chronic HCV infection. The drug candidates use different prodrug strategies, but are metabolized to the same active purine triphosphate in human hepatocytes. Our plan is to select one of these product candidates for later-stage clinical development based upon a review of the early human clinical trial results of both PSI-938 and PSI-661.

PSI-938

PSI-938 has demonstrated in vitro anti-HCV activity with EC90 values of 1.43 +/- 0.67 µM. This compound has demonstrated equivalent potency against the S282T mutant which has reduced sensitivity to several other nucleoside analogs including RG7128, PSI-7977, NM283, and IDX184, and is metabolized to the active triphosphate form through a different phosphorylation pathway than our pyrimidine product candidates, RG7128 and PSI-7977, supporting a scientific rationale for a low likelihood of antagonism with the combination. The in vitro half-life of the triphosphate in primary human hepatocytes is approximately 12 hours, which supports the exploration of once-daily dosing in early development.

Phase 1 Studies (ongoing)

We filed an IND with the FDA during February 2010 and on April 7, 2010, dosing started in a Phase 1, single ascending dose (“SAD”) study in healthy subjects. This SAD study is a double-blind (subject and investigator), randomized, parallel, placebo-controlled, first-time-in-human study of PSI-938. The primary objective is to investigate the safety, tolerability, and pharmacokinetics of PSI-938 following single oral administration in healthy subjects. We intend to report preliminary data from this SAD study along with antiviral data from a multiple-ascending dose (“MAD”) study in HCV-infected patients during the third calendar quarter of 2010.

PSI-661

PSI-661 has demonstrated in vitro anti-HCV activity with EC90 values of 0.01 +/- 0.005 µM. PSI-661 uses a different prodrug strategy than PSI-938, but is metabolized to the same active purine triphosphate as PSI-938, and retains activity against HCV with an S282T mutation. Our current plan for PSI-661 is to submit an IND application, or its foreign equivalent, during the fourth calendar quarter of 2010.