The Era of Protease Inhibitors for the Treatment of HCV:  An Overview of SCH 503034

By Marina Nunez, MD

SCH 503034 is a new, orally administered HCV protease inhibitor that has shown potent activity against HCV in earlier laboratory testing.

In a phase 1 study (randomized, single rising dose, double blind), the pharamcokinetics and safety of SCH 503034 oral capsules were evaluated in healthy subjects [1]. SCH 503034 was administered to 36 subjects (50 mg, 100 mg, 200 mg, 400 mg, 600 mg, 800 mg), and placebo to 18 subjects.

The drug was rapidly absorbed, and after attaining Tmax (1-2.25 h), plasma SCH 503034 concentrations declined in a biphasic manner, with a mean terminal phase half-life (T_1/2) of 7.0 to 15 h. Cmax and AUC increased in a dose-related manner. The safety profiles were similar in subjects receiving SCH 503034 and placebo.

In a double-blind placebo-controlled 14-day dosing study  performed in adult patients with HCV-1 infection who had failed pegylated interferon (pegIFN)-a therapy,  SCH 503034 exhibited dose-dependent HCV antiviral activity [2].

In a phase Ib study comparing SCH 503034 alone (200 mg or 400 mg for 7 days) versus pegIFN-a-2b alone (for 14 days) versus SCH 503034 with pegIFN-a-2b (for 14 days), the combined therapy showed greater log reductions of HCV RNA (mean, 2.4 log for 200 mg and 2.9 log for 400 mg) than pegIFN-a-2b monotherapy (1.1 log) [3]. The adverse event profile for combination treatment was similar to PEG-Intron alone, except for a slight increase in the incidence of headache.

In a study applying viral dynamic modeling to analysis of data from the previous clinical trial, results indicated that the decay of HCV RNA under the effect of pegIFN is substantially augmented in the presence of SCH 503034, compared to its value for IFN monotherapy in IFN nonresponders [3,4]. This suggests that SCH 503034 may act to enhance IFN antiviral activity.

The molecular activity of SCH 503034 was examined by Malcolm and colleagues [5]. The drug binds the NS3 protease inhibiting its activity. Viral propagation is interrupted as a consequence, since the cleavage of the HCV polyprotein by the NS3 protease is essential. Given that the NS3-mediated cleavage of host factors involved in IFN response, inhibition of the NS3 protease might also increase the activity of IFN.

The SCH 503034 NS3 binding activity was determined by spectophotometry. Antiviral potency was assayed in replicon cells exposed to increasing amounts of SCH 503034. The effect of SCH 503034 on response to IFN was evaluated by incubating cells with SCH 503034 and IFN.

SCH 503034 exhibited potent antiviral activity both alone and in combination with IFN in the HCV replicon assay. SCH 503034 combined with IFN was more effective than the line of additivity, though the difference was non-significant. Nevertheless, the combination of SCH 503034 with IFN may lead to enhanced clinical efficacy.

With the available data, there is great expectation about the prospects of this new drug. Belonging to a new family of drugs, it is awaited with the hope that it may improve the efficacy of the treatment of HCV infection.

11/23/05

References

1. J Zhang and others. Single dose pharamcokinetics of a novel hepatitis C protease inhibitor, SCH 503034, in an oral capsule formulation. Abstract 862. 56^th annual meeting of the American Association for the Study of Liver Diseases    (56^th AASLD). November 11-15, 2005. San Francisco, CA.
2. S Zeuzem and others. Anti-viral Activity of SCH 503034, a HCV Protease Inhibitor, Administered as Monotherapy in Hepatitis C Genotype-1 (HCV-1) Patients Refractory to Pegylated Interferon (Peg-IFN-a). Abstract 94. 56^th annual meeting of the American Association for the Study of Liver Diseases    (56^th AASLD). November 11-15, 2005. San Francisco, CA.
3. S Zeuzem and others. Combination therapy with the HCV protease inhibitor, SCH 503034, plus Peg-Intron in hepatitis C Genotype-1 Peg-Intron non-responders: phase Ib results. Abstract 201. 56^th annual meeting of the American Association for the Study of Liver Diseases    (56^th AASLD). November 11-15, 2005. San Francisco, CA.
4. B A Malcolm and others. Modeling of HCV dynamics during combination therapy with peginterferon alfa-2b and the NS3 protease inhibitor SCH 503034. Abstract 1266. 56^th annual meeting of the American Association for the Study of Liver Diseases    (56^th AASLD). November 11-15, 2005. San Francisco, CA.
5. SCH 503034, a mechanism-based inhibitor of hepattis C virus (HCV) NS3 suppresses polyprotein maduration and enhances the antiviral activity of interferon-alfa-2b (INF). Abstract 864. 56^th annual meeting of the American Association for the Study of Liver Diseases    (56^th AASLD). November 11-15, 2005. San Francisco, CA.