Long-term open-label vebicorvir for chronic HBV infection: Safety and off-treatment responses.

Autor:	Yuen MF; Department of Medicine and State Key Laboratory of Liver Research, School of Clinical Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong., Fung S; Department of Medicine, Division of Gastroenterology and Hepatology, University of Toronto, Toronto, Canada., Ma X; Office of Xiaoli Ma, Philadelphia, PA, USA., Nguyen TT; T Nguyen Research and Education, Inc., San Diego, CA, USA., Hassanein T; Southern California Research Center, Coronado, CA, USA., Hann HW; Department of Medicine, Division of Gastroenterology and Hepatology, Thomas Jefferson University Hospital, Philadelphia, PA, USA., Elkhashab M; Toronto Liver Centre, Toronto, Canada., Nahass RG; ID Care, Hillsborough, NJ, USA., Park JS; Northwell Health, Manhasset, NY, USA., Jacobson IM; NYU Langone Health, New York, NY, USA., Ayoub WS; Cedars-Sinai Medical Center, Los Angeles, CA, USA., Han SH; Pfleger Liver Institute, University of California, Los Angeles, CA, USA., Gane EJ; University of Auckland, Auckland, New Zealand., Zomorodi K; Assembly Biosciences, Inc., South San Francisco, CA, USA., Yan R; Assembly Biosciences, Inc., South San Francisco, CA, USA., Ma J; Assembly Biosciences, Inc., South San Francisco, CA, USA., Knox SJ; Assembly Biosciences, Inc., South San Francisco, CA, USA., Stamm LM; Assembly Biosciences, Inc., South San Francisco, CA, USA., Bonacini M; Quest Clinical Research, San Francisco, CA, USA., Weilert F; Waikato Hospital, Hamilton, New Zealand., Ramji A; GastroIntestinal Research Institute, Vancouver, Canada., Bennett M; Medical Associates Research Group, San Diego, CA, USA., Ravendhran N; Gastrohealth, Catonsville, MD, USA., Chan S; Sing Chan MD, New York, NY, USA., Dieterich DT; Department of Medicine, Division of Liver Diseases, Icahn School of Medicine, Mount Sinai Hospital, New York, NY, USA., Kwo PY; Stanford University Medical Center, Stanford, CA, USA., Schiff ER; Schiff Center for Liver Diseases, University of Miami School of Medicine, Miami, FL, USA., Bae HS; Asian Pacific Liver Center, Los Angeles, CA, USA., Lalezari J; University of Toronto, Toronto, Canada., Agarwal K; Institute of Liver Studies, King's College Hospital, London, UK., Sulkowski MS; Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Jazyk:	angličtina
Zdroj:	JHEP reports : innovation in hepatology [JHEP Rep] 2024 Jan 18; Vol. 6 (4), pp. 100999. Date of Electronic Publication: 2024 Jan 18 (Print Publication: 2024).
DOI:	10.1016/j.jhepr.2023.100999
Abstrakt:	Background & Aims: The investigational first-generation core inhibitor vebicorvir (VBR) demonstrated safety and antiviral activity over 24 weeks in two phase IIa studies in patients with chronic HBV infection. In this long-term extension study, patients received open-label VBR with nucleos(t)ide reverse transcriptase inhibitors (NrtIs). Methods: Patients in this study (NCT03780543) previously received VBR + NrtI or placebo + NrtI in parent studies 201 (NCT03576066) or 202 (NCT03577171). After receiving VBR + NrtI for ≥52 weeks, stopping criteria (based on the treatment history and hepatitis B e antigen status in the parent studies) were applied, and patients either discontinued both VBR + NrtI, discontinued VBR only, or continued both VBR + NrtI. The primary efficacy endpoint was the proportion of patients with HBV DNA <20 IU/ml at 24 weeks off treatment. Results: Ninety-two patients entered the extension study and received VBR + NrtI. Long-term VBR + NrtI treatment led to continued suppression of HBV nucleic acids and, to a lesser extent, HBV antigens. Forty-three patients met criteria to discontinue VBR + NrtI, with no patients achieving the primary endpoint; the majority of virologic rebound occurred ≥4 weeks off treatment. Treatment was generally well tolerated, with few discontinuations due to adverse events (AEs). There were no deaths. Most AEs and laboratory abnormalities were related to elevations in alanine aminotransferase and occurred during the off-treatment or NrtI-restart phases. No drug-drug interactions between VBR + NrtI and no cases of treatment-emergent resistance among patients who adhered to treatment were observed. Conclusions: Long-term VBR + NrtI was safe and resulted in continued reductions in HBV nucleic acids following completion of the 24-week parent studies. Following treatment discontinuation, virologic relapse was observed in all patients. This first-generation core inhibitor administered with NrtI for at least 52 weeks was not sufficient for HBV cure. Clinical Trial Number: NCT03780543. Impact and Implications: Approved treatments for chronic hepatitis B virus infection (cHBV) suppress viral replication, but viral rebound is almost always observed after treatment discontinuation, highlighting an unmet need for improved therapies with finite treatment duration producing greater therapeutic responses that can be sustained off treatment. First-generation core inhibitors, such as vebicorvir, have mechanisms of action orthogonal to standard-of-care therapies that deeply suppress HBV viral replication during treatment; however, to date, durable virologic responses have not been observed after treatment discontinuation. The results reported here will help researchers with the design and interpretation of future studies investigating core inhibitors as possible components of finite treatment regimens for patients with cHBV. It is possible that next-generation core inhibitors with enhanced potency may produce deeper and more durable antiviral activity than first-generation agents, including vebicorvir. Competing Interests: M-FY reports being an advisor/consultant for AbbVie, AiCuris, Aligos Therapeutics, Antios Therapeutics, Arbutus Biopharma, Arrowhead Pharmaceuticals, Assembly Biosciences, Clear B Therapeutics, Dicerna Pharmaceuticals, Finch Therapeutics, Fujirebio Incorporation, GlaxoSmithKline, Gilead Sciences, Immunocore, Janssen, Roche, Sysmex Corporation, Tune Therapeutics, Vir Biotechnology, and Visirna Therapeutics and receiving grant/research support from AbbVie, Arrowhead Pharmaceuticals, Assembly Biosciences, Fujirebio Incorporation, Gilead Sciences, Immunocore, Roche, and Sysmex Corporation. SF reports receiving fees for speaking and teaching and/or serving on advisory committees for AbbVie, Assembly Biosciences, Gilead Sciences, Janssen, Lupin, Novo Nordisk, Pfizer, and Springbank Pharma. XM reports being a consultant and being on the speakers' bureau for Gilead Sciences. TTN reports receiving research grant support from Assembly Biosciences and Gilead Sciences. TH 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, Assembly Biosciences, Astra Zeneca, Boehringer Ingelheim, Bristol-Myers Squibb, CARA, Cytodyn, 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. H-WH reports serving on the National Advisory Board and receives research grant support from Gilead Sciences. ME 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. RGN reports having served on advisory boards and as a speaker for Gilead Sciences, Janssen, and Merck and having conducted research for AbbVie, Gilead Sciences, Janssen, and Merck. JSP reports receiving research grants from Assembly Biosciences and GlaxoSmithKline and consulting fees from Gilead Sciences. IMJ reports being a consultant or on advisory boards for AbbVie, Aligos Therapeutics, Arbutus Biopharma, Gilead Sciences, Intercept Pharmaceuticals, Janssen, and Roche; having conducted research (all payments to institution) for Assembly Biosciences, Bristol-Myers Squibb, Cymabay, Eli Lilly, Enanta Pharmaceuticals, Genfit, Gilead Sciences, Intercept, Janssen, Merck, and Novo Nordisk; receiving payment from the Chronic Liver Disease Foundation for manuscript preparation; and participating on a Data Monitoring Committee for Altimmune, Arrowhead Pharmaceuticals, Galmed, GlaxoSmithKline, and Takeda. WSA reports being a member of the speaking bureau for Gilead Sciences and Intercept Pharmaceuticals and has received research grants from Genfit, GlaxoSmithKline, Intercept Pharmaceuticals, Ipsen, Madrigal, Mirum, Pfizer, and Zydus. S-HH reports being a consultant and being on the speakers' bureau for Gilead Sciences. EJG reports serving on advisory boards for AbbVie, Aligos Therapeutics, Assembly Biosciences, Gilead Sciences, GlaxoSmithKline, Intellia, Janssen, Roche, Vir Biotechnology, and Virion and having served as a speaker for Abbott Diagnostics, AbbVie, and Gilead Sciences. KZ, RY, and SJK report being employees of and holding stock interest in Assembly Biosciences. JM and LMS report being former employees of and holding stock interest in Assembly Biosciences. MBo reports being a member of the speaking bureau for AbbVie, Gilead Sciences, and Intercept Pharmaceuticals and has received research support from Assembly Biosciences, Boehringer Ingelheim, Gilead Sciences, Intercept Pharmaceuticals, Inventiva, and Viking Therapeutics. FW reports being a study investigator for AbbVie. AR reports receiving grant support, lecture fees, and advisory board fees from AbbVie, Celgene, Gilead Sciences, Intercept Pharmaceuticals, Merck, and Novartis. MBe reports having no conflicts of interest. NR reports advising, being on the speakers’ bureau for, and receiving grants from AbbVie and Gilead Sciences; being on the speakers’ bureau for Onyx and Salix; and having received grants from Bristol-Myers Squibb and Merck. SC reports receiving clinical trial–related payments from Assembly Biosciences. DTD reports being a consultant for Gilead Sciences and Intercept Pharmaceuticals. PYK reports being an advisor/consultant for AbbVie, Aligos Therapeutics, Antios Therapeutics, Enanta Pharmaceuticals, Gilead Sciences, and Janssen and receives grant/research supports from Altimmune, Arrowhead Pharmaceuticals, Assembly Biosciences, Bristol-Myers Squibb, Eiger Biopharmaceuticals, and Target Registries. ERS reports receiving research and grant support from Assembly Biosciences, Celgene, the University of Florida (TARGET), and Vir Biotechnology and receives royalties from the Schiff Diseases of the Liver, 12th edition. HSB reports having consultancy agreements with and receiving research support from Bristol-Myers Squibb and Gilead Sciences. JL reports having no conflicts of interest. KA reports being on the advisory board, a consultant, and a speaker for AbbVie, Aligos, Arbutus Biopharma, Assembly Biosciences, Bristol-Myers Squibb, Gilead Sciences, Immunocore, Janssen, Merck, Novartis, Roche, Shinogi, Sobi, and Vir Biotechnology and receiving grants from Bristol-Myers Squibb, Gilead Sciences, and Roche. MSS reports receiving grants from AbbVie, Assembly Biosciences, GlaxoSmithKline, Janssen, the National Institutes of Health, and Vir Biotechnology and receiving personal fees from AbbVie, Antios Therapeutics, Arbutus Biopharma, Atea Pharmaceuticals, Gilead Sciences, GlaxoSmithKline, F2G, Immunocore, Precision Biosciences, and Virion Therapeutics. Please refer to the accompanying ICMJE disclosure forms for further details. (© 2024 The Authors.)
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