AASLD: Protease Inhibitors Open New Front on HCV

SAN FRANCISCO, Nov. 14 - Protease inhibitors may soon do for the hepatitis C virus (HCV) what they've done for HIV -- namely, keep the virus in check.
Action Points
Inform interested patients that the drugs described here appear to be safe and effective against hepatitis C viral infections, but have not been approved for clinical use, and may be about three years away from FDA approval.
These studies were published as abstracts and presented orally at a conference. These data and conclusions should be considered to be preliminary as they have not yet been reviewed and published in a peer-reviewed publication.
That's according to European researchers who presented results of early studies of two new protease inhibitors for HCV at the annual meeting of the American Association for the Study of Liver Diseases here today.
In one study, an investigational oral agent called VX-950 was shown to have potent antiviral activity and to be well tolerated at all dose levels in a 14-day phase IB study, reported Henk Reesink, M.D., of the Academic Medical Center in Amsterdam, The Netherlands.
VX-950 is a highly selective inhibitor of HCV protease NS3-4A, an enzyme important in the viral replication cycle.
Dr. Reesink reported on the final results of the study, which involved 24 healthy volunteers and 36 patients with HCV genotype 1 infection, the form most resistant to conventional therapy with pegylated interferon (PEG-IFN) and ribavirin. Patients and healthy volunteers were divided into three dosing groups on two different schedules.
In the first part of the study, participants received either placebo or VX-950 at one of three dose levels: 450 mg, 750 mg, or 1,250 mg every eight hours for five days. In the second half, patients received VX-950 on the same schedule (except for twice daily instead of three-times daily dosing for those on the 1,250 mg dose) for 14 days.
The primary study endpoints were safety and tolerability, but there was also an efficacy component as a secondary endpoint
The investigators found that the drug was safe and well tolerated at all dose levels in both healthy volunteers and the HCV-positive participants, with no serious adverse events and no discontinuations of therapy because of intolerability. The most commonly reported drug-related adverse events were headache and diarrhea, which occurred equally in the active drug and placebo groups.
In terms of efficacy, every patient had at least a 2-log (100-fold) reduction in viral load, and in the 750 mg group, in which the highest trough plasma concentrations of the protease inhibitor were seen, there was a median reduction in HCV RNA of 4.4 log (over 10,000 fold) at the end of 14 days of dosing.
Among the other dosing groups, in which plasma trough concentrations were lower, there was also a potent antiviral effect, with HCV RNA reductions > 2 log (100-fold) occurring between days three and seven. From days seven to 14, however, investigators saw an increase in viral load, Dr. Reesink said.
In addition, median alanine aminotransferase (ALT) levels normalized during the two-week dosing period in all dose groups, with a median change from base line of 25-30 U/L.
Dr. Reesink noted that the drug produced a rapid viral response, with 26 of 28 patients receiving any dose of VX-950 having more than a 3-log (1000 fold) reduction in plasma HCV RNA within two days.
In the second study, Stephan Zeuzem, M.D., of Saarland University Hospital in Homburg/Saar, Germany and colleagues presented data on a different protease inhibitor, dubbed SCH503034, which has also been shown in preclinical studies (replicon assays) to have potent activity against HCV-1.
In a double-blind dose-escalation trial, the investigators looked at SCH503034 in adults with HCV-1 who had failed therapy with PEG-IFN. The definition of failure used in the study was a 2-log (100-fold) reduction in HCV RNA after 12 weeks.
Patients were randomized to either placebo or oral SCH 503034 in one of four doses: 100 mg b.i.d., 200 mg b.i.d., 400 mg b.i.d. or 400 mg t.i.d. for 14 days
In all, 45 patients received the active drug and 16 received placebo. The authors found that the protease inhibitor was rapidly absorbed following oral administration of capsules with a mean therapeutic effect at one to two hours across doses, as well as dose-related increases in peak concentrations.
The highest plasma trough concentrations occurred in the 400 mg thrice-daily group, Dr. Zeuzem noted. "SCH 503034 exhibited potent dose-related antiviral activity that was first detectable 24 hours post-dose," he said.
Mean viral load reductions correlated positively with exposure to the drug, with patients in the 400 mg t.i.d. dosing group having a mean reduction of 2.06 log10 from baseline (range 1.1 to 2.7 log).
As with VX-950, there was a significant decline in liver enzymes (AST and ALT) corresponding to viral load reductions. This agent also was well tolerated at all dose levels.
Asked whether resistance to protease inhibitors for HCV might be expected to become problematic as it is with similar agents for HIV, Dr. Reesink said that whereas protease inhibitors for HIV must be taken indefinitely, it's expected that patients with HCV will only need to take PIs for as long as it takes to ensure adequate viral suppression or clearance, which could be as little as one year.Primary source: AASLDSource reference: Zeuzem S et al Anti-viral Activity of SCH Monotherapy in Hepatitis Interferon (Peg-IFN). Abstract 94, presented Nov. 14. Additional source: AASLDSource reference: Reesink H W et al. Final Results of a Phase Ib Multiple-Dose Study of VX-950, A Hepatitis C Virus Protease Inhibitor. Abstract 96 presented Nov. 14.