By Liz Highleyman

Given the suboptimal efficacy, side effects, and cost of interferon-based therapy for chronic hepatitis C virus (HCV) infection -- especially in hard-to-treat patients such as those with HCV genotype 1 and prior non-responders -- investigators are exploring several new drugs that directly target various steps of the viral lifecycle, an approach referred to as "STAT-C."

Data on several such agents in the development pipeline were reported at the recent 59th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2008) in San Francisco.

Preclinical and early clinical studies of 3 other pipeline STAT-C agents are described below.

MK-7009

E. Lawitz and colleagues presented results from a study of the safety, tolerability, and antiviral activity of Merck's NS3/4A protease inhibitor MK-7009. The agent previously demonstrated potent activity in HCV replicon systems and infected chimpanzees.

In the present study, 33 treatment-naive and treatment-experienced chronic hepatitis C patients (85% men) with HCV genotype 1 (73% 1a) and high baseline viral load were randomly assigned to receive placebo or MK-7009 monotherapy at doses of 125 mg once-daily (qd), 600 mg qd, 25 mg twice-daily (bid), 75 mg bid, 250 mg bid, or 500 mg bid for 8 days. They were then followed for 14 days after the last dose.

After 8 days of therapy, the maximum observed decrease in HCV RNA was about 4 log10 IU/mL, and 70% overall achieved more than a 3 log10 decrease in HCV RNA at least once. The most common AEs overall were diarrhea and nausea. No serious adverse events (AEs) were reported, no pattern of laboratory or ECG abnormalities was observed, and no participants discontinued the study due to clinical or laboratory AEs.

"MK-7009 has potent antiviral activity during 8 days of monotherapy in patients with chronic genotype 1 HCV infection," the investigators concluded. "In these patients, MK-7009 was generally well-tolerated with no serious AEs, discontinuations due to AEs or safety laboratory abnormalities. Further development of this HCV NS3/4A protease inhibitor, including studies in combination with other anti-HCV agents, is warranted."

In a related pharmacokinetics study of MK-7009 in healthy HCV negative volunteers, investigators likewise observed no serious AEs. Taking the drug with a high-fat meal did not have a meaningful effect on plasma levels. Accumulation occurred over the 14-day dosing period in all subjects, and the apparent terminal half-life was about 4.5 hours regardless of dose, which suggests the feasibility of twice-daily dosing.

ANA598

In a late-breaker presentation, researchers from Anadys Pharmaceuticals described the latest data on ANA598, a novel non-nucleoside HCV NS5B polymerase inhibitor. Prior in vitro studies showed that ANA598 exhibits potent antiviral activity in genotype 1a and 1b replicon systems.

The present Phase 1 single-dose escalation trial evaluated the safety, tolerability, and pharmacokinetics of ANA598 capsules in healthy HCV negative volunteers. Participants were randomly allocated to treatment cohorts (n= 6 each) receiving single ascending oral doses of 400, 800, 1400, 2000 mg fasted or 2000 mg fed, while 2 subjects received placebo. An additional cohort received 800 mg bid for 2 doses. Safety and pharmacokinetics were assessed over 7 days following administration.

ANA598 was well tolerated at all doses studied. No serious AEs were observed and there were no study withdrawals. All AEs were classified as mild, with no apparent dose relationship and no pattern of events within any body system. All doses produced plasma drug concentrations predicted to display substantial antiviral activity based on preclinical results. Systemic exposure to the drug increased in participants who ate a high-fat meal. The pharmacokinetic profile demonstrated sustained plasma levels of ANA598 with a half-life of more than 24 hours

The researchers concluded that pharmacokinetic and tolerability profiles support further testing of once- or twice-daily administration. In an upcoming Phase 1b study, scheduled to begin by the end of 2008, treatment-naive patients with HCV genotype 1 will receive ANA598 at dose levels of 200 mg, 400 mg, and 800 mg twice-daily.

IDX375

Finally, researchers from Idenix Pharmaceuticals presented preclinical data on the company's novel specific non-nucleoside HCV polymerase inhibitor, IDX375.

Candidate agents were evaluated in a biochemical NS5B polymerase assay (genotypes 1a, 1b, 2a, and 3a) and in a genotype 1b HCV replicon system. The selectivity of these compounds was determined using a panel of human cellular polymerases and cell-based assays.

IDX375 demonstrated high potency in the HCV replicon model, with EC50 (50% effective concentration) values of 2 to 3 nM. Cellular cytotoxicity testing in Huh-7 cells demonstrated that it was not toxic to cells at tested doses. In biochemical studies, the agent inhibited HCV genotype 1b and 1a polymerases, but did not exhibit strong activity against genotype 2a or 3a polymerases. Furthermore, IDX375 did not inhibit human cellular DNA polymerases, demonstrating selective activity against HCV. In rats, the drug demonstrated good oral bioavailability and it reached 40-fold higher concentrations in the liver compared with plasma.

Based on these results, the researchers stated, IDX375 will be evaluated in human pharmacology and toxicology studies.

11/25/08

References

EJ Lawitz, MS Sulkowski, IM Jacobson, and others. Safety, Tolerability and Antiviral Activity of MK-7009, a Novel Inhibitor of the Hepatitis C Virus NS3/4A Protease, in Patients with Chronic HCV Genotype 1 Infection. 59th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2008). San Francisco. October 31-November 4, 2008. Abstract 211.

D Wright, JL Miller, I Verlinden, and others. Safety, Tolerability, and Pharmacokinetic Data Following Single- and Multiple-Dose Administration of MK-7009, a Hepatitis C Virus Non-structural 3/4a Protease Inhibitor, to Healthy Male Subjects. 59th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2008). San Francisco. October 31-November 4, 2008. Abstract 1910.

MH Rahimy, CA Crowley, JL Freddo, and others. Results of a Phase I Safety, Tolerability and Pharmacokinetic Study of ANA598, a Non-Nucleoside NS5B Polymerase Inhibitor, 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 LB13.

PA Thompson, R Patel, RE Showalter, and others. In Vitro Studies Demonstrate that Combinations of Antiviral Agents that Include HCV Polymerase Inhibitor ANA598 have the Potential to Overcome Viral Resistance. 59th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2008). San Francisco. October 31-November 4, 2008. Abstract 1908.

DN Standring, JP Bilello, CB Dousson, and others. In Vitro Activity and Pharmacological Properties of IDX375, a Novel HCV Non-Nucleoside Inhibitor. 59th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2008). San Francisco. October 31-November 4, 2008. Abstract 1913.

Other Source
Anadys Pharmaceuticals, Inc. Anadys Pharmaceuticals Announces Successful Outcome of ANA598 Healthy Volunteer Study and Finalization of Study Design for Phase Ib Trial in HCV Patients. Press release. September 24, 2008.