New Therapies for Chronic Hepatitis b

Maya Bitton Alaluf; Amir Shlomai

DISCLOSURES 

Liver International. 2016;36(6):775-782. 

 

• Add to Email Alerts

IN THIS ARTICLE

Interference With Viral Life Cycle and Spreading rna Interference (rnAi)

The RNA interference (RNAi) method enables the design of short interfering RNAs (siRNAs) complementary to target mRNAs, resulting in their degradation.^[22] As a result of the overlapping nature of the HBV genome, a single siRNA can knock down the entire repertoire of HBV mRNAs, making HBV an ideal target for RNAi-based therapy.^[23–25]Furthermore, as the excess of secreted HBsAg act as a decoy for the immune system, knocking-down HBsAg using RNAi may lead to a reversal of the immune tolerance normally observed in chronically infected patients. Following encouraging results from experiments performed in chimpanzees,^[26] a phase II randomized double blind placebo-control study of a synthetic poly-conjugated anti-HBV siRNA compound, ARC-520©(Arrowhead research corporation) was performed. This study population was composed of chronically HBeAg negative patients who were on entecavir treatment. A single IV dose of ARC-520 resulted in a significant reduction of up to 50% at the level of HBsAg, which was sustained for up to 43 days post-treatment.^[27] Further studies should clarify whether the observed reduction in HBsAg also translates to restoration of a proper antiviral immune response and a better control of the virus and its cccDNA. In addition, one of the major challenges in clinical implication of RNAi is its in vivoefficient and liver-specific delivery. The development of a delivery system based on a hepatocyte-targeted endosome-releasing agent and a cholesterol-conjugated siRNA (chol-siRNA),^[28] the basis for the ARC-520©compound, is an example for such a technology.

Core/Capsid Inhibitors

The viral capsid and its building block, the core protein, have a major role in viral life cycle as well as in cccDNA amplification and maintenance.^[29] The heteroaryldihydropyrimidines (HAPs) are potent inhibitors of capsid assembly and the prototype compound, BAY 41–4109, has been extensively studied in different HBV models.^[30,31] BAY 41–4109 presumably inhibits encapsidation and decreases the half-life of the core protein.

Another compound, the NVR 3–778, binds to the core protein and promotes the formation of abnormal capsids. This compound has been shown to inhibit HBV replication in HepG2.2.15 cell line and more recently in uPA-SCID humanized mouse model.^[32,33] A phase Ia safety study has confirmed its safety in humans with a single daily dose.^[34] Recently, a high-resolution crystal structure of the capsid inhibitor NVR-010–001-E2 bound to the core protein has been reported.^[35] This important work enables a better understanding of potential natural viral mutants resistant to this class of drugs and provides essential information for future structure-guided design of more efficient anticapsid compounds.