Safety and efficacy of vebicorvir in virologically suppressed patients with chronic hepatitis B virus infection

Abstract

Background & aims: HBV nucleos(t)ide reverse transcriptase inhibitors (NrtIs) do not completely suppress HBV replication. Previous reports indicate persistent viremia during NrtI treatment despite HBV DNA being undetectable. HBV core inhibitors may enhance viral suppression when combined with NrtIs. This phase II trial (NCT03576066) evaluated the efficacy and safety of the investigational core inhibitor, vebicorvir (VBR), in virologically- suppressed patients on NrtIs.

Methods: Non-cirrhotic, NrtI-suppressed patients with chronic HBV were randomised to VBR 300 mg once daily or matching placebo (PBO) for 24 weeks. Treatment was stratified by hepatitis B e antigen (HBeAg) status. The primary endpoint was change from Baseline in serum HBeAg or hepatitis B surface antigen (HBsAg) after 24 weeks.

Results: Of 73 patients enrolled, 47 were HBeAg positive and 26 were HBeAg negative. In HBeAg-positive and -negative patients, there were no differences in the change from Baseline at Week 24 for HBsAg or HBeAg. Using a novel, high-sensitivity assay to detect HBV DNA, a greater proportion of patients with detectable HBV DNA at Baseline achieved undetectable HBV DNA at Week 24 in the VBR+NrtI vs. PBO+NrtI group. In HBeAg-positive patients, a greater change from Baseline in HBV pregenomic (pg)RNA was observed at Week 24 with VBR+NrtI vs. PBO+NrtI. Treatment-emergent adverse events (TEAEs) in VBR+NrtI patients included upper respiratory tract infection, nausea, and pruritus. No serious adverse events, Grade 4 TEAEs, or deaths were reported.

Conclusions: In this 24-week study, VBR+NrtI demonstrated a favourable safety and tolerability profile. While there were no significant changes in viral antigen levels, enhanced viral suppression was demonstrated by greater changes in DNA and pgRNA with the addition of VBR compared to NrtI alone.

Clinical trials number: NCT03576066.

Lay summary: Core inhibitors represent a novel approach for the treatment of chronic hepatitis B virus (HBV) infection, with mechanisms of action distinct from existing treatments. In this study, vebicorvir added to existing therapy reduced HBV replication to a greater extent than existing treatment and was generally safe and well tolerated.

Keywords: HBV; NrtI; antiviral; cccDNA; core inhibitor; hepatitis; pgRNA.

Conflict of interest statement

Conflict of interest Man-Fung Yuen reports being an advisor/consultant for and/or having received grant/research support from AbbVie, Aligos Therapeutics, Antios Therapeutics, Arbutus Biopharma, Arrowhead Pharmaceuticals, Assembly Biosciences, Bristol-Myers Squibb, Clear B Therapeutics, Dicerna Pharmaceuticals, Finch Therapeutics, Fujirebio Incorporation, GlaxoSmithKline, Gilead Sciences, Immunocore, Janssen, Merck Sharp and Dohme, Roche, Springbank Pharmaceuticals, Silverback Therapeutics, Sysmex Corporation, and Vir Biotechnology. Kosh Agarwal reports being on the advisory board, a consultant, and a speaker for AbbVie, Assembly Biosciences, Aligos, Arbutus, Bristol-Myers Squibb, Gilead Sciences, Immunocore, Janssen, Merck, Novartis, Roche, Sobi, Shinoigi, and Vir; and receiving grants from Bristol-Myers Squibb, Gilead Sciences, and Roche. Xiaoli Ma reports being a consultant and being on the speakers bureau for Gilead Sciences. Tuan T. Nguyen reports receiving research grant support from Gilead Sciences and Assembly Biosciences. Eugene R. Schiff reports receiving research and grant support from Assembly Biosciences, Celgene, and the University of Florida (TARGET) and receives royalties from the Schiff Diseases of the Liver, 12th edition. Hie-Won L. Hann reports serving on the National Advisory Board and receives research grant support from Gilead Sciences. Douglas T. Dieterich reports being a consultant for Gilead Sciences and Intercept Pharmaceuticals. Ronald G. Nahass reports having served on advisory boards and as a speaker for Gilead Sciences, Merck, and Janssen; and having conducted research for Gilead Sciences, Merck, Janssen, and AbbVie. James S. Park reports receiving research grants from Assembly Biosciences and GlaxoSmithKline and consulting fees from Gilead Sciences. Sing Chan reports receiving clinical trial-related payments from Assembly Biosciences. Steven-Huy Han reports being a consultant and being on the speakers bureau for Gilead Sciences. Edward J. Gane reports serving on advisory boards for AbbVie, Aligos Therapeutics, Arbutus Biopharma, Arrowhead Pharmaceuticals, Assembly Biosciences, Avilia Therapeutics, Clear B Therapeutics, Dicerna, Enanta Pharmaceuticals, Finch Therapeutics, Gilead Sciences, GlaxoSmithKline, Immunocore, Janssen, Roche, Silverback, and Vir Bio. and having served as a speaker for Gilead Sciences, AbbVie, and Roche. Michael Bennett reports having no conflicts of interest. Katia Alves reports being a former employee of and holding stock interest in Assembly Biosciences. Marc Evanchik reports having been an employee of and holding stock interest in Assembly Biosciences and is currently an employee of Edgewise Therapeutics. Ran Yan reports being an employee of and holding stock interest in Assembly Biosciences. Qi Huang reports being an employee of and holding stock interest in Assembly Biosciences. Uri Lopatin reports being a former employee and holding stock interest in Assembly Biosciences. Richard Colonno reports being an employee of and holding stock interest in Assembly Biosciences. Julie Ma reports being an employee of and holding stock interest in Assembly Biosciences. Steven J. Knox reports being an employee of and holding stock interest in Assembly Biosciences. Luisa M. Stamm reports being an employee of and holding stock interest in Assembly Biosciences. Maurizio Bonacini reports being a member of the speaking bureau for Intercept Pharmaceuticals, Gilead Sciences, and AbbVie and has received research support from Assembly Biosciences, Intercept Pharmaceuticals, Viking Therapeutics, and Boehringer Ingelheim. Ira M. Jacobson reports being a consultant or on advisory boards for AbbVie, Aligos Therapeutics, Arbutus Biopharma, Gilead Sciences, Janssen, Madrigal and Virion; having conducted research (all payments to institution) for Assembly Biosciences, Bristol-Myers Squib, Eli Lilly, Enanta Pharmaceuticals, Gilead Sciences, Janssen, Merck, and Novo Nordisk; receiving payment from the Chronic Liver Disease Foundation for manuscript preparation; and reports participation on a Data Safety Monitoring Board for GSK, Redhill, Galmed, NeuroBo, and Arrowhead Pharmaceuticals. Walid S. Ayoub reports being a member of the speaking bureau for both Gilead Sciences and Intercept Pharmaceuticals and has conducted research for Assembly Biosciences, Intercept Pharmaceuticals, Enanta Pharmaceuticals, and Gilead Sciences. Frank Weilert reports being a study investigator for AbbVie. Natarajan Ravendhran reports advising, being on the speakers’ bureau for, and receiving grants from Gilead Sciences and AbbVie; being on the speakers' bureau for Salix and Onyx; and having received grants from Bristol-Myers Squibb and Merck. Alnoor Ramji reports receiving grant support, lecture fees, and advisory board fees from AbbVie, Celgene, Gilead Sciences, Intercept Pharmaceuticals, Novartis, and Merck. Paul Yien Kwo reports being an advisor/consultant for AbbVie, Aligos Therapeutics, Antios Therapeutics, Enanta Pharmaceuticals, Gilead Sciences, Janssen, and receives grant/research support from Assembly Biosciences, Arrowhead Pharmaceuticals, Eiger Biopharmaceuticals, Bristol Myer Squibb, Altimmune, and Target Registries. Magdy Elkhashab reports receiving grants from AbbVie, Bristol-Myers Squibb, Eisai, Gilead Sciences, and Roche; and serving on advisory boards for AbbVie, Bristol-Myers Squibb, Gilead Sciences, and Merck. Tarek Hassanein reports being on the advisory committee, review panel, or consulting for AbbVie, Bristol-Myers Squibb, Gilead Sciences, Mallinckrodt Pharmaceuticals, Merck, and Organovo and receiving research support from AbbVie, Allergan, Cytodyn, Assembly Biosciences, Astra Zeneca, Boehringer Ingelheim, Bristol-Myers Squibb, CARA, DURECT Corporation, Enanta Pharmaceuticals, Galectin Therapeutics, Gilead Sciences, Grifols, Intercept Pharmaceuticals, Janssen, Merck, Mirum, Novartis, Novo Nordisk, Nucorion Pharmaceuticals, Pfizer, Salix Pharmaceuticals, Sonic Incytes, Terns Pharmaceuticals, and Valeant. Ho S. Bae reports having consultancy agreements with and receiving research support from Bristol-Myers-Squibb and Gilead Sciences. Jacob P. Lalezari reports having no conflicts of interest. Scott K. Fung reports receiving fees for speaking & teaching and/or serving on advisory committees for AbbVie, Assembly Biosciences, Gilead Sciences, Janssen, and Springbank Pharma. Mark S. Sulkowski reports receiving grants from AbbVie, Assembly Biosciences, Gilead Sciences, Janssen, and the National Institutes of Health; and receiving personal fees from AbbVie, Antios Therapeutics, Arbutus Biopharma, Atea Pharmaceuticals, Gilead Sciences, FH360, and Immunocore. Please refer to the accompanying ICMJE disclosure forms for further details.

Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.