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Treatment for hepatitis delta virus with the prenylation inhibitor lonafarnib: It's getting closer

Hepatitis delta virus (HDV) is an incomplete RNA virus that is codependent on hepatitis B virus (HBV). It is currently estimated that approximately 15-20 million people worldwide are chronically infected with the virus. HDV is the most severe form of viral hepatitis. Rapid progression to cirrhosis occurs in the majority of infected individuals, and once cirrhosis has ensued, the risk for hepatocellular carcinoma increases 3-fold and for mortality 2-fold compared to patients with cirrhosis with HBV monoinfection. Over the last three decades, tremendous progress made in HBV and HCV research has led to the development of highly efficacious medications capable of suppressing or eliminating these viruses. Unfortunately, similar advances in the management of HDV have not yet been accomplished. At present, there is no U.S. Food and Drug Administration–approved treatment for HDV. Pegylated interferon-alpha (PegIFN), the only available drug for HDV, shows at best, a 40% response rate following 48 weeks of therapy, but is poorly tolerated and is associated with high relapse rates. Treatment for HDV therefore presents a significant unmet medical need. Development of new drugs for HDV is challenging, as unlike other hepatotrophic viruses, HDV encodes for only one protein and is completely dependent on host RNA polymerases for its replication. As a result there are relatively few HDV-specific targets to pursue for clinical development. At the current state of knowledge, it therefore seems that emergence of novel therapeutics for this disease will largely rely on the ability to intervene in nonreplicative steps of the HDV life cycle, such as viral entry and virion assembly. One such possible strategy would involve disruption of hepatitis D antigen (HDAg) interaction with hepatitis B surface antigen (HBsAg). Prenylation is a posttranslational and site-specific modification of proteins that facilitates protein-protein and protein-membrane interactions. In a landmark report, more than two decades ago, Glenn et al. identified that prenylation of the carboxy terminus of the large HDAg was a necessary step for facilitating HDAg binding to HBsAg (Fig. 1) and subsequent HDV virion assembly. Farnesyltransferase inhibitors, were shown, in the following years, to inhibit HDV-like particles in in vitro cell lines and animal models. Recently, in a proof-ofconcept (POC) clinical trial, Koh et al. demonstrated that the farnesyltransferase inhibitor lonafarnib (LNF) administered at 100 mg BID (twice-daily) and 200 mg BID for 28 days led to statistically significant HDV viral load declines compared to placebo. Of note, nonresponse to LNF was not associated with development of resistant HDV mutations. Several additional and important observations were made during that study. First, a highly linear relationship was demonstrated between LNF serum concentration and HDVRNA log decline, suggesting that using still higher concentrations of the drug may have an even greater antiviral effect. Second, the improved efficacy Abbreviations: ALT, alanine aminotransferase; BID, twice-daily; CYP3A4, cytochrome P450 3A4; GI, gastrointestinal; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; HDAg, hepatitis D antigen; HDV, hepatitis delta virus; LNF, lonafranib; PegIFN, pegylated interferon-alpha; POC, proof-of-concept; RTV, ritonavir.