PSI-7977 (Chirally pure isomer of PSI-7851)

PSI-7977 is a prodrug of a nucleotide analog and is currently in development for treatment of chronic HCV infection. PSI-7851 is a mixture of two similar molecules, PSI-7976 and PSI-7977, which exist in PSI-7851 as isomers of each other. Once inside a liver cell, both molecules are rapidly converted to the same active triphosphate. Given the greater improvements in manufacturing and better in vitro potency, PSI-7977 was selected for further clinical development. A superior formulation in the form of a tablet has been developed and has recently been evaluated in a Phase 1 study in healthy volunteers. The 28 day Phase 2a trial using the improved manufacturing process and tablet formulation has now been initiated and interim results from this study are anticipated in the third quarter of 2010.

During March 2009, we initiated a Phase 1 study for PSI-7851. As part of the Phase 1 study, we completed a single ascending dose study that assessed the safety, tolerability and pharmacokinetics of PSI-7851 in healthy subjects at doses ranging from 25mg to 800mg. Preliminary results from this study indicated there were:

• No serious adverse events or discontinuations;
• No dose-related adverse events;
• No grade III/ IV lab abnormalities; and
• No clinically significant changes in vital signs or ECGs.

During June 2009, we initiated a Phase 1 multiple ascending dose study in HCV-infected patients. Subjects were enrolled at two U.S. centers and randomized to PSI-7851 (8 per cohort) or placebo (2 per cohort). The primary objective of this study was to assess the safety, tolerability, and pharmacokinetics of PSI-7851 after once-daily dosing for three days. The secondary objective of this study was to assess antiviral activity by measuring the change in HCV RNA. Three dose cohorts of PSI-7851 (50mg QD, 100mg QD, 200mg QD, and 400mg QD) were evaluated. Final results from this study, presented at AASLD 2009 indicated:

• PSI-7851 was generally safe and well tolerated across all cohorts with no discontinuations, no serious adverse events, and no dose-related trends in adverse events or laboratory abnormalities.
• PSI-7851 demonstrated potent antiviral activity with a mean HCV RNA decrease of -0.49 log IU/mL, -0.61 log IU/mL, -1.01 log IU/mL, and -1.95 log IU/mL in patients receiving 50mg QD, 100mg QD, 200mg QD and 400mg QD, respectively after three days.

During January 2010, we initiated a 28 day Phase 2a trial. The trial is anticipated to enroll about 60 patients with chronic hepatitis C infection who have not been treated previously. The primary goal of the study is to determine the safety and tolerability of PSI-7977 in combination with SOC. The primary efficacy endpoint of the trial will be the proportion of patients who achieve a rapid virologic response (RVR), defined as undetectable levels of HCV (measured by TaqMan assay) four weeks after the initiation of treatment. Patients will continue to be followed through a Sustained Virologic Response (SVR) endpoint. Patients will be randomized to receive one of four treatments:

• PSI-7977 100mg QD in combination with Pegasys and Copegus for four weeks, followed by 44 weeks of Pegasys and Copegus
• PSI-7977 200mg QD in combination with Pegasys and Copegus for four weeks, followed by 44 weeks of Pegasys and Copegus
• PSI-7977 400mg QD in combination with Pegasys and Copegus for four weeks, followed by 44 weeks of Pegasys and Copegus
• Control arm with Pegasys and Copegus

For further information, please refer to the initiation of phase 2a press release