HBV Therapeutic AdvancesDirect antiviral drugs

Dr.Mohammed A. Aboelmagd MDEndemic and Infectious diseases department

Introduction

• Chronic hepatitis B infection remains a major disease burden globally, and leads to high risk of hepatocellular carcinoma development.

• Although effective vaccines have been available for more than three decades, hepatitis B virus (HBV) infection remains a global public health issue. It is estimated around 248 million people are chronically infected by HBV, and most of them are residing in the Asia-Pacific region

Clinical relevance of chronic hepatitis Band the need for therapeutic advances

• About 4 % of the global population, are chronically infected with hepatitis B virus (HBV).

• is the dominant risk factor for development of hepatocellular carcinoma (HCC) in Asia and sub-Saharan Africa

Clinical relevance of chronic hepatitis Band the need for therapeutic advances

• Vaccination coverage remains low in many countries and a low percentage of individuals have no or low development of antibody response upon vaccination

• HBV infection occurs during birth or during adolescence, the likelihood of development into chronic hepatitis B is estimated at 90 % and 20–30 % respectively.

Overview of hepatitis B viral life cycle

• HBV is a DNA virus that belongs to the family of Hepadnaviridae, and has a 3.2 kD double stranded genome surrounded by nucleocapsid and envelope proteins.

• All four of the open reading frames (ORFs) overlap and are present on the minus strand, encoding for the viral polymerase and reverse transcriptase, envelope, precore and X proteins.

Overview of hepatitis B viral life cycle

• HBV is highly hepatotrophic and species-specific, which means that HBV replicates exclusively within human hepatocytes.

• The viral replication cycle can be divided into early and intermediate events (reverse transcriptase-independent) and late events (reverse transcriptase-dependent).

Overview of hepatitis B viral life cycle

• Early events:- Attachment- Penetration- Uncoating• Intermediate events:- Replication ( cccDNA)• Late events:- Assembly- Release

Overview of the immune response to acuteand chronic hepatitis B

• It remains strongly debated whether the lack of innate response within the infected hepatocytes is due to active suppression by HBV or defective immune sensing mechanisms.

• Even though HBV lacks the ability to trigger a strong innate immune response, it remains susceptible to the effects of innate antiviral cytokines.

Overview of the immune response to acute

and chronic hepatitis B• CD4 T cells produce cytokines that

help in the CD8 T cell response, and the CD8 T cell response clears HBV infected hepatocytes through cytolytic and non-cytolytic mechanisms.

• Functional HBV specific CD4 and CD8 T cell responses are required for HBV control in both chimpanzees and humans

Overview of the immune response to acute

and chronic hepatitis B• Importantly, the immunological profiles

between acute and chronic hepatitis B patients are different. During chronic HBV infection, unlike acute HBV infection, the T cell response is characterized by exhaustion, where HBV specific T cells upregulate expression of inhibitory molecules ,and T cells are physically deleted through apoptosis

Overview of the immune response to acute

and chronic hepatitis B• The importance of adaptive immunity

in effective control of HBV infection stems from observations that transplantation of bone marrow from HBV immunized individuals, which contain HBV-specific memory T and B cells, into chronic hepatitis B patients achieves control of chronic HBV infection

Current treatments against chronic hepatitis Band development into HCC

• Current treatments for chronic hepatitis B have developed in two main directions.

1- Nucleot(s)ide analogues that target reverse transcription during the HBV life cycle and prevent infectious virion release.However, because nucleot(s)ide analogues do not directly target cccDNA,the chance of relapse after drug withdrawal is high and lifelong nucleot(s)ide treatment is costly.Resistance.

Current treatments against chronic hepatitis Band development into HCC

2- conventional or pegylated IFNa, whichstimulates the antiviral immune response in patients.(finite therapy,loss of HbsAg for long duration, side effects,contraindicated in advanced cirrohosis)

New waves of HBV therapies

Direct-acting antivirals

A.New investigational agents now in clinical trials1. Prodrugs of HBV polymerase inhibitors:chemical or molecular precursors of active drugs Typically, a prodrug is designed to improve the performance of the active drug substance, usually by decreasing toxicity, improving solubility, enhancing tissue absorption and/or increasing the half-life, so that the agent can be dosed no more frequently than once daily.Prodrugs of tenofovir are in the most advanced stages of developmentTenofovir disproxil fumarate,,tenofovir alafenamide

Direct-acting antivirals

• AGX1009 and TAF. AGX1009 (Agenix) and TAF (Gilead), are prodrugs of tenofovir in Phase 3 clinical trials.

2- small interfering RNA :In principle, siRNA-acting drugs, which target HBV transcripts,should be able to shut down all HBV gene product production. This approach has had great promise, but has been frustrated by the inefficiency in delivery of the nucleic acid oligomers to human hepatocytes, despite extremely compelling results in experimental animal (ARC-520 Inhibit HBsAg, HBeAg and HBV DNA levels).

Direct-acting antivirals

3- HBsAg-reducing agents:RepA9, from Replicor, is a nucleic acid-based polymer(NAP) ,comprised of phosphorothioated nucleic acids The mechanism of action is unclear, but the sponsor reports it acts on HBsAg. As stated, compounds that act on HBsAg are particularly interesting because they also have the potential for direct activity against hepatitis delta virus (HDV)

Direct-acting antivirals

4- Inhibitors of capsid formation:Capsid formation is an essential viral process that does not occur in the uninfected cell, and thus would be expected to provide a virus-selective target. Moreover,capsid proteins are readily detected in the nucleus of infected cells, far from the site of nucleocapsid formation in the cytoplasm. This is consistent with evidence that capsid proteins play a role in regulating HBV cccDNA expression and stability. Three capsid inhibitors have reached clinical phase development: BAY4109 (AiCuris), NV1221 (Novira) and GLS 4 (Sunshine).

Direct-acting antivirals

B-New investigational agents now in clinical trials1-Inhibitors of capsid morphogenesis:All these capsid inhibitors are small molecules that interfere with HBV capsid morphogenesis, but not necessarily at the same step. CpAMs are HBV core protein allosteric modulators that accelerate a dysfunctional capsid protein dimerization.DVRs prevent the association of HBV pregenomic RNA with the capsid

Direct-acting antivirals

2- Inhibitors of HBsAg secretion:is a small molecule that has been shown to prevent the secretion of HBsAg and viral DNA in vitro,possibly by interfering with the ability of HBsAg to associate with the LDL secretion machinery .

Direct-acting antivirals

3-RNase H inhibitorsUnlike other DNA viruses HBV replication depends upon the RNAseH activity of HBV polymerase to degrade pregenomic RNA. RNAseH enzymatic activity should, in principle, be a viable antiviral target as is the reverse transcriptase/DNA polymerase activity of HBV polymerase.

Direct-acting antivirals

4-CRISPR/Cas9 system:The bacterial clustered regularly interspaced short palindromic repeats associated systems (CRISP/Cas9) loci encode RNA guidedendonucleases, derived from bacterial immune response against foreign genetic elements such as bacteriophages. they can be used to targetdestruction of specific DNA sequences, and thus hold a great potential for specific degradation of HBV cccDNA.

Host-targeting antivirals

A-Products in clinical development:1-Viral entry inhibitors(Myrcludex B)2- Immune enhancers3- Therapeutic vaccines4-Birinapant (small molecule that is believed to mimic second mitochondrial activator of caspases (SMAC). SMAC normally binds to IAP (inhibitor of apoptosis), pushing the cell towards apoptosis

5-Zadaxin:natural polypeptide from the thymus

Host-targeting antivirals

B-HTAs in the preclinical stage:1- Immune checkpoint inhibitors2-Epigenetic modifiers3- interferon gene stimulator4- Cyclophilin inhibitors