INFO: The Future of Hepatitis C Therapy: What's on the Horizon?

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From Medscape Gastroenterology Hepatitis C Expert Column Posted 03/06/2007 Reau, MD; F. Fred Poordad, MD The Future of Hepatitis C Therapy: What's on the Horizon? The overall response rates with pegylated interferon and ribavirin are in the 50% range, hence the need

for improved therapies. An improved understanding of molecular virology has led to the development of new antiviral strategies, including agents aimed at HCV-specific targets. Pegylated interferon and ribavirin-based regimens are associated with a number of well-established side effects, several of which interfere with adherence to therapy.[11,12] Two drugs in development specifically address these issues. A novel recombinant protein consisting of interferon alfa genetically fused to human albumin is a long-acting interferon with an anticipated dosing interval of every other week, decreasing the frequency of injections by 50%. Registration studies are currently under way to confirm whether this strategy leads to comparable SVRs. Viramidine, a prodrug of ribavirin, induces less hemolytic anemia than ribavirin, and is undergoing further testing to optimize the dosing to achieve similar efficacy.[27-29] STAT-C therapy targets viral enzymes required for viral replication; 2 classes of agents at the forefront of development are protease inhibitors and polymerase inhibitors. During HCV replication, a long polyprotein is generated that contains all of the proteins needed for replication. This polyprotein is then cleaved by various serine proteases. Serine protease inhibition truncates viral replication and assembly, leading to profound viral decline in a short period of time. VX-950, an oral HCV protease inhibitor, currently in phase 2 trials, demonstrated a rapid decline in HCV RNA; 93% of subjects experienced greater than a 3-log drop in viral load in 3 days.[30] A synergistic effect with interferon has also been suggested.[31,32] Viral resistance was documented in some subjects, but was suppressed when the agent was used in combination with pegylated interferon and ribavirin.[32]

Studies in the nonresponder/relapser populations are ongoing. Another compound in this class, SCH 503034, also in phase 2 testing, achieved up to a 2.5-log reduction after 7 days in patients who had previously failed to respond to pegylated interferon plus ribavirin[33]; it also had greater efficacy when combined with pegylated interferon.[34] Viral RNA-dependent RNA polymerase is responsible for synthesis and elongation of viral RNA. Inhibition of this polymerase also appears to be a potent and effective therapeutic strategy. In a phase 1/2 trial of previous nonresponders to interferon-based therapy, treatment with NM283 (a ribonucleoside analog that targets the viral RNA polymerase) combined with pegylated interferon resulted in more than a 2-log reduction in viral load by PCR at 12 weeks, without the development of resistance.[35] Another compound, R1626, a

nucleoside analog oral polymerase inhibitor, in dose-ranging studies demonstrated viral suppression of nearly 4 logs after 15 days at the highest dose investigated.[36] The side-effect profile of these compounds is still not fully appreciated. The current phase 2 studies should yield critical information about both adverse events as well as resistance profiles. http://www.medscape.com/viewarticle/552614_6