PSI-7977 (an isomer of PSI-7851)

PSI-7977 is an investigational nucleotide analog currently in Phase 2 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 ability to more easily manufacture PSI-7977, and potentially advantageous in vitro characteristics, PSI-7977 was selected for further clinical development.

Phase 2a Study

During May 2010, we announced efficacy and preliminary safety results from the 28 day phase 2a study with PSI-7977 dosed once daily (QD) in combination with Pegasys(R) (peginterferon alfa-2a) and Copegus(R) (ribavirin), the current standard of care (SOC) in patients with hepatitis C virus (HCV) genotype 1 who were naïve to antiviral therapy.

The primary efficacy endpoint of the trial was the proportion of patients who achieved a rapid virologic response (RVR), defined as HCV RNA below the limit of detection (<15 IU/mL as measured by the TaqMan assay) four weeks after the initiation of treatment. Following 28 days of combination therapy, patients will receive a further 44 weeks of SOC and will be followed through a Sustained Virologic Response (SVR) endpoint.

Potent and consistent antiviral activity was demonstrated in this study following 28 days of treatment with PSI-7977 in combination with SOC. The baseline HCV RNA for all patients enrolled in the study was approximately 6.5 log10 IU/mL, and was similar across all treatment arms. Patients were stratified by IL28B status to ensure balance across cohorts; no patient was excluded based on their status. 63 treatment-naïve patients chronically infected with HCV genotype 1 were enrolled across 7 sites in the US. Initial results demonstrated:

• Following 28 days of treatment with PSI-7977 100mg QD with Pegasys plus Copegus, patients achieved a mean 5.3 log₁₀ IU/mL decrease in HCV RNA and 88% (14 of 16) achieved HCV RNA below the limit of detection (<15 IU/ml), or RVR.
• Following 28 days of treatment with PSI-7977 200mg QD with Pegasys plus Copegus, patients achieved a mean 5.1 log₁₀ IU/mL decrease in HCV RNA and 94% (17 of 18) achieved an RVR
• Following 28 days of treatment with PSI-7977 400mg QD with Pegasys plus Copegus, patients achieved a mean 5.3 log₁₀ IU/mL decrease in HCV RNA and 93% (14 of 16) achieved an RVR
• Following 28 days of treatment with placebo with Pegasys plus Copegus, patients achieved a mean 2.8 log10 IU/mL decrease in HCV RNA and 21% (3 of 14) achieved an RVR

Preliminary Safety Summary

Preliminary safety and tolerability for the 28 day treatment period were similar for PSI-7977 with SOC compared to placebo with SOC. There were no serious adverse events reported during the 28 day treatment period, and no adverse events leading to treatment discontinuation. All adverse events reported were of mild to moderate intensity. A similar proportion of patients in each cohort reported adverse events, with the most common adverse events reported as fatigue, nausea, and arthralgias. The frequency and severity of these adverse events, as well as general body system observations, were similar to clinical experience with the standard of care. There were no dose-related changes in safety laboratory assessments, vital signs or ECGs. A dose-dependent decrease in serum ALT was observed coincident with HCV RNA decline.

Overall, there were no drug-related discontinuations, no serious adverse events, and no dose-related trends in adverse events or laboratory abnormalities as compared to placebo with standard of care.

PSI-7977 is now being advanced in to a Phase 2b trial in combination with SOC.

Phase 1 Study

During March 2009, we initiated a Phase 1 study for PSI-7851, the combination of PSI-7977 and PSI-7976. 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 change from baseline of -0.49 log₁₀ IU/mL, -0.61 log₁₀ IU/mL, -1.01 log₁₀ IU/mL, and -1.95 log₁₀ IU/mL in patients receiving 50mg QD, 100mg QD, 200mg QD and 400mg QD, respectively, after three days.