https://orcid.org/0000-0002-2266-3935
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ABSTRACT
Introduction
Chronic hepatitis B infection is a major global health issue associated with significant liver-related morbidity and mortality. While existing treatments can suppress the virus effectively, they are incapable of inducing functional cure, as defined by hepatitis B surface antigen (HBsAg) seroclearance. Currently, numerous novel compounds are being developed, including bepirovirsen, an antisense oligonucleotide (ASO).
Areas covered
This review summarizes the mechanism of action, pharmacokinetics, clinical efficacy and safety data collected from phase I and II studies of bepirovirsen. The data were extracted from publications relevant to the pivotal trials of bepirovirsen, in either full manuscript or conference abstracts.
Expertopinion
Bepirovirsen, a 20-mer ASO, has already entered phase III clinical evaluation using the optimal dosing regimen of 300 mg subcutaneous injection weekly for 24 weeks in nucleoside analogue-treated HBeAg-negative non-cirrhotic patients with low (<3000 IU/mL) baseline HBsAg. The durability and long-term clinical outcomes among Bepirovirsen responders will need to be evaluated. The stop-to-cure approach in those reaching HBsAg < 100 IU/mL should also be explored. In the long run, Bepirovirsen has the potential to facilitate viral hepatitis elimination.
Article highlights
Bepirovirsen (GSK3228836), a compound being developed for patients with chronic hepatitis B infection (CHB), is an unconjugated antisense oligonucleotide which suppresses viral protein production by gene silencing.
Phase I study of bepirovirsen has confirmed favorable pharmacokinetic properties with lack of plasma accumulation and minimal renal excretion.
Phase II studies of bepirovirsen were able to demonstrate the efficacy of inducing HBsAg reduction and HBV DNA suppression among CHB patients (overall 6%), with lower baseline hepatitis B surface antigen levels being the most important predictor of response.
Bepirovirsen is in general safe and well tolerated. Most common side effects are injection-related and are mild in severity.
Subcutaneous injection of bepirovirsen 300 mg weekly for 24 weeks followed by nucleoside analogue (NUC) monotherapy with potential NUC cessation is being evaluated in a phase III study.
Combination strategies of bepirovirsen with pegylated interferon or therapeutic vaccines will be evaluated in phase II studies.
List of abbreviations
| CHB | = | chronic hepatitis B infection |
| WHO | = | World Health Organization |
| NUC | = | nucleos(t)ide analogues |
| PEG-IFN | = | pegylated interferon |
| ALT | = | alanine aminotransferase |
| HBeAg | = | hepatitis B e antigen |
| ULN | = | upper limit of normal |
| HBsAg | = | hepatitis B surface antigen |
| TLR | = | toll-like receptor |
| ASO | = | antisense oligonucleotide |
| mRNA | = | messenger RNA |
| GaINAc | = | N-acetylgalactosamine |
| 2’-MOE: | = | 2’-O-(2-methoxyethyl)-modified |
| cccDNA | = | covalently closed circular DNA |
| tmax | = | time to maximum plasma concentration |
| Cmax | = | plasma maximum plasma concentration |
| AUC | = | area under the plasma concentration-time curve |
| Cmin | = | minimum plasma concentration |
| OAT | = | organic anion transporter |
| OCT | = | organic cation transporter |
| AEs | = | adverse events |
| Anti-HBs | = | antibody to HBsAg |
| LLOD | = | lower limit of detection |
| LLOQ | = | lower limit of quantification |
| EOT | = | end of treatment |
| SAE | = | serious adverse event |
| SIRS | = | systemic inflammatory response syndrome |
| siRNA: | = | small interfering RNA |
Declaration of interest
LY Mak is an advisory board member for Gilead Sciences. WK Seto received speaker’s fees from AstraZeneca, is an advisory board member and received speaker’s fees of Abbott, received research funding from Alexion Pharmaceuticals, Boehringer Ingelheim, Pfizer and Ribo Life Science, and is an advisory board member, received speaker’s fees, and researching funding from Gilead Sciences. MF Yuen serves as advisor/consultant for AbbVie, Assembly Biosciences, Aligos Therapeutics, Arbutus Biopharma, Bristol Myer Squibb, Clear B Therapeutics, Dicerna Pharmaceuticals, Finch Therapeutics, GlaxoSmithKline, Gilead Sciences, Immunocore, Janssen, Merck Sharp and Dohme, Hoffmann-La Roche and Springbank Pharmaceuticals, Vir Biotechnology and receives grant/research support from Assembly Biosciences, Aligos Therapeutics, Arrowhead Pharmaceuticals, Bristol Myer Squibb, Fujirebio Incorporation, Gilead Sciences, Immunocore, Merck Sharp and Dohme, Hoffmann-La Roche, Springbank Pharmaceuticals 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
A reviewer on this manuscript has disclosed that they are a co-investigator and coauthor publication of the bepirovirsen phase 2B study and are currently a PI for many bepirovirsen trials. They are a speaker and Advisory Board member for GSK. Other COI: Speaker Bureau: Gilead, Janssen, Roche, Sysmex, GSK Advisory Board: Gilead, Abbott, Roche, GSK, Janssen, Sysmex, Arbutus, Assembly, Grifols, Research Support: Gilead, Abbott, Sysmex, Fibronostics.Another reviewer has disclosed they are an employee and shareholder of Replicor Inc. Replicor is developing nucleic acid polymers for the treatment of hepatitis and hepatitis D infection.
Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.