Assessing the developing pharmacotherapeutic landscape in hepatitis B treatment: a spotlight on drugs in phase II clinical trials

ABSTRACT

Introduction

Functional cure, defined as sustained HBsAg seroclearance, is associated with favorable outcomes in chronic hepatitis B (CHB). While nucleos(t)ide analogues (NAs) are effective in suppressing HBV replication, NAs are unable to induce functional cure at high rates. A range of novel HBV antivirals, aiming to induce functional cure, are currently under development.

Areas covered

This article covered novel hepatitis B virus (HBV) antivirals that have entered phase II trials. Virus-directing agents covered include entry inhibitors, transcription inhibitors, RNA silencers, core protein allosteric modulators, noncompetitive polymerase inhibitors, and viral protein export inhibitors. Immunomodulators covered include innate immune stimulators, T-cell modulators, therapeutic vaccines, and monoclonal antibodies. Upcoming developmental directions would also be discussed.

Expert opinion

Among novel HBV antivirals, RNA silencers, viral protein export inhibitors (with pegylated interferon), and entry inhibitors (with pegylated interferon) appear to be effective in suppressing HBsAg and may even induce functional cure. The other virus-targeting agents have variable effects on HBV DNA, HBsAg, HBeAg, and HBcrAg. Immunomodulators have modest effects on HBsAg but may have important roles in combination therapy. Upcoming trials will answer important questions on ideal dosing, long-term drug effects, and efficacy of combination regimens.

KEYWORDS:

• HBV
• functional cure
• HBsAg
• RNAi
• CpAM
• NAPs
• entry inhibitor
• polymerase inhibitor
• immunomodulator

Abbreviations

ASOAntisense oligonucleotides

ASPINactive site polymerase inhibitor nucleotide

cccDNA Covalently closed circular DNA

CHBChronic hepatitis B

CpAMCore protein allosteric modulator

FXRFarnesoid X receptor

GalNAcN-acetylgalactosamine

HBcAgHepatitis B core antigen,

HBcrAg Hepatitis B core-related antigen

HBeAg Hepatitis B e-antigen

HBsAgHepatitis B surface antigen

HBVHepatitis B virus

HCCHepatocellular carcinoma

HCV Hepatitis C virus

HDVHepatitis D virus

IAPInhibitors of apoptosis

ImmTAV Immune-mobilizing monoclonal T-cell receptors against virus

mRNA messenger RNA

NANucleos(t)ide analogue

NAPNucleic acid polymer

NOD2Nucleotide-binding oligomerization domain-containing protein 2

NTCPSodium taurocholate co-transporting polypeptide

PAPD Poly(A) RNA polymerase-associated domain containingprotein

PD-1 Programmed Cell Death Protein 1

PD-L1Programmed Death-ligand 1

Peg-IFNαPegylated interferon alpha,

RNAiRNA interference

rcDNARelaxed circular DNA

RIG-IvRetinoic acid-inducible gene I (RIG-I)

RISCRNA-induced silencing complex

siRNAsmall-interfering RNA

STOPSS-antigen Transport-inhibiting Oligonucleotide Polymers

TAFTenofovir alafenamide

TDFTenofovir disoproxil fumarate

TLRToll-like receptor

WHO World Health Organization

Declaration of interest

WK Seto received speaker’s fees from AstraZeneca and Mylan, is an advisory board member of CSL Behring, is an advisory board member and received speaker’s fees from AbbVie, and is an advisory board member, received speaker’s fees and researching funding from Gilead Sciences. MF Yuen is an advisory board member and/or received research funding from AbbVie, Arbutus Biopharma, Assembly Biosciences, Bristol Myer Squibb, Dicerna Pharmaceuticals, GlaxoSmithKline, Gilead Sciences, Janssen, Merck Sharp and Dohme, Clear B Therapeutics, Springbank Pharmaceuticals; and received research funding from Arrowhead Pharmaceuticals, Fujirebio Incorporation, and Sysmex Corporation. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers in this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.