Drugs in Development for Hepatitis B

Abstract

With high morbidity and mortality worldwide, there is great interest in effective therapies for chronic hepatitis B (CHB) virus. There are currently several dozen investigational agents being developed for treatment of CHB. They can be broadly divided into two categories: (1) direct-acting antivirals (DAAs) that interfere with a specific step in viral replication; and (2) host-targeting agents that inhibit viral replication by modifying host cell function, with the latter group further divided into the subcategories of immune modulators and agents that target other host functions. Included among the DAAs being developed are RNA interference therapies, covalently closed circular DNA (cccDNA) formation and transcription inhibitors, core/capsid inhibitors, reverse transcriptase inhibitors, hepatitis B surface antigen (HBsAg) release inhibitors, antisense oligonucleotides, and helioxanthin analogues. Included among the host-targeting agents are entry inhibitors, cyclophilin inhibitors, and multiple immunomodulatory agents, including Toll-like receptor agonists, immune checkpoint inhibitors, therapeutic vaccines, engineered T cells, and several cytokine agents, including recombinant human interleukin-7 (CYT107) and SB 9200, a novel therapy that is believed to both have direct antiviral properties and to induce endogenous interferon. In this review we discuss agents that are currently in the clinical stage of development for CHB treatment as well as strategies and agents currently at the evaluation and discovery phase and potential future targets. Effective approaches to CHB may require suppression of viral replication combined with one or more host-targeting agents. Some of the recent research advances have led to the hope that with such a combined approach we may have a functional cure for CHB in the not distant future.

Interaction between Hepatitis B Virus and Toll-Like Receptors: Current Status and Potential Therapeutic Use for Chronic Hepatitis B

“…Thus, new therapeutic strategies are urgently needed, and there are already trials in preclinical or clinical phases. These novel antiviral therapies can be divided into two categories: (1) direct-acting antivirals (DAAs), which target specific steps in viral replication; and (2) host-targeting agents which suppress viral replication by modifying host cell functions [ 75 ]. Drugs targeting the TLR signaling pathway may represent the latter class.…”

Drug Delivery Strategies for Antivirals against Hepatitis B Virus

“…Data in a study undertaken by Zoulim [ 26 ] assessed the antiviral impact of IFN-α2a or IFN-α2b with attached PEG demonstrating close to 30% HbeAg seroconversion and 3–5% HbsAg seroconversion rates, respectively, with HBsAg seen in around 7% of patients after a six-month follow-up. A combination of NUC therapy (entecavir or tenofovir) with recombinant human IL-7 (CYT107) or with both CYT107 and HBV vaccine (GenHevac B ® , Pasteur, Merieux, Lyon, France) is now being studied [ 27 ].…”

A dendritic cell receptor-targeted chimeric immunotherapeutic protein (C-HBV) for the treatment of chronic hepatitis B

“…16 Immunotherapeutic approaches which aim to induce/restore effective cellular and humoral responses against HBV antigens have been of considerable interest in recent years 17,18 but have not been shown to be able to elicit clinically relevant responses to date. 19,20 An ideal immunotherapy would "break" the immune tolerance status in chronic HBVinfected hosts to restore specific antiviral immunity and eliminate persistent infection by activating T cell responses which appear to be critical in achieving a functional cure.…”