By Liz Highleyman

Given the limitations of interferon-based therapy for chronic hepatitis C virus (HCV) infection -- especially in patients with hard-to-treat HCV genotype 1 -- investigators have explored several small molecule agents, collectively called "STAT-C," that directly target various steps of the viral lifecycle.

Two posters at the 59th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2008) last week in San Francisco presented data from a study of PF-00868554, a novel non-nucleoside HCV polymerase inhibitor being developed by Pfizer.

Preclinical studies showed that PF-00868554 inhibits genotype 1a and 1b HCV replicons in vitro, and its safety and tolerability were demonstrated in healthy volunteers receiving up to 300 mg 3-times-daily for 14 days (abstract 1898).

In a double-blind study, investigators then evaluated the safety, tolerability, pharmacokinetics, and antiviral activity of PF-00868554 in 32 treatment-naive patients with genotype 1 chronic hepatitis C (abstract LB11). Most participants (84%) were men, almost all (97%) were white, and the mean age was about 45 years.

Four cohorts of 8 patients each were randomly assigned to receive oral PF-00868554 at doses of 100, 300, or 450 mg twice-daily or 300 mg 3-times-daily, or else placebo, for 8 days.

Results

• All 32 randomized participants completed the study.

• The half life of PF-00868554 ranged from 10 to 12 hours for all dose arms.

• All doses resulted in plasma concentrations that exceeded the median protein binding adjusted in vitro 50% effective concentration (EC50) for genotype 1 HCV.

• HCV RNA decreased rapidly during the first 48 hours of PF-00868554 administration.

• Mean maximum reductions in HCV RNA were 0.97 log10 in the PF-00868554 100 mg twice-daily arm, 1.84 log10 in the 300 mg twice-daily arm, 1.73 log10 in the 450 mg twice-daily arm, and 2.13 log10 in the 300 mg 3-times-daily arm, compared with 0.27 log10 in the placebo group.

• 4 of 6 patients (66%) in the 300 mg 3-times-daily group achieved > 2.0 log10 maximum reduction in HCV RNA, compared with 33% in the 450 mg twice-daily arm, 17% in the 300 mg twice-daily arm, and none in the 100 mg twice-daily or placebo arms.

• Following the first phase of viral suppression, most patients experienced a plateau or rebound in HCV RNA.

• However, 1 patient in the 300 mg twice-daily group and 3 in the 300 mg 3-times-daily arm maintained viral suppression through the completion of dosing on day 8.

• Mean reductions in HCV viral load at the end of PF-00868554 treatment on day 8 were 0.68, 1.26, 1.21, and 1.95 log10, respectively, in the 4 dose groups, versus 0.08 in the placebo group.

• One subject in the 450 mg twice-daily cohort experienced < 0.5 log10 reduction in HCV RNA; sequence analysis of the HCV NS5B gene at baseline identified an R422K mutation, which could potentially reduce susceptibility to PF-00868554.

• All doses of PF-00868554 were well-tolerated.

• The most frequently reported adverse events (AEs) -- all mild or moderate in severity -- were headache, flatulence, and fatigue.

• No dose-limiting AEs, serious AEs, grade 3 or 4 laboratory abnormalities, withdrawals due to AEs, or deaths were reported.

"Results from this study indicate that PF-00868554 was safe and well tolerated at all dose levels," the investigators concluded. "PF-00868554 potently inhibited viral replication in HCV-infected, treatment naive subjects, with mean maximum reductions in HCV RNA ranging from -0.97 to -2.13."

"Results from the present study support the further evaluation of PF-00868554," they added, noting that a study investigating PF-00868554 in combination with pegylated interferon alpha-2a (Pegasys) and ribavirin in treatment naive subjects is currently underway.

Infectious Diseases, Pfizer Global Research and Development, New London, CT; Charité Research Organisation, Berlin, Germany; Clinical Pharmacology, Parexel International, Berlin, Germany; Pfizer Clinical Research Unit, Pfizer Global Research and Development, Erasme, Belgium. Pfizer Global Research and Development, New London, CT.

11/11/08

References

JL Hammond, VS Purohit, J Fang, and others. Safety, Tolerability and Pharmacokinetics of the HCV Polymerase Inhibitor PF-00868554 Following Multiple Dose Administration in Healthy Volunteers. 59th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2008). San Francisco. October 31-November 4, 2008. Abstract 1898.

JL Hammond, MC Rosario, F Wagner, and others. Antiviral Activity of the HCV Polymerase Inhibitor PF-00868554 Administered as Monotherapy in HCV Genotype 1 Infected Subjects. 59th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2008). San Francisco. October 31-November 4, 2008. Abstract LB11.