Author information
1Department of Medicine and State Key Laboratory of Liver Research, School of Clinical Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong.
2Department of Medicine, Division of Gastroenterology and Hepatology, University of Toronto, Toronto, Canada.
3Office of Xiaoli Ma, Philadelphia, PA, USA.
4T Nguyen Research and Education, Inc., San Diego, CA, USA.
5Southern California Research Center, Coronado, CA, USA.
6Department of Medicine, Division of Gastroenterology and Hepatology, Thomas Jefferson University Hospital, Philadelphia, PA, USA.
7Toronto Liver Centre, Toronto, Canada.
8ID Care, Hillsborough, NJ, USA.
9Northwell Health, Manhasset, NY, USA.
10NYU Langone Health, New York, NY, USA.
11Cedars-Sinai Medical Center, Los Angeles, CA, USA.
12Pfleger Liver Institute, University of California, Los Angeles, CA, USA.
13University of Auckland, Auckland, New Zealand.
14Assembly Biosciences, Inc., South San Francisco, CA, USA.
15Quest Clinical Research, San Francisco, CA, USA.
16Waikato Hospital, Hamilton, New Zealand.
17GastroIntestinal Research Institute, Vancouver, Canada.
18Medical Associates Research Group, San Diego, CA, USA.
19Gastrohealth, Catonsville, MD, USA.
20Sing Chan MD, New York, NY, USA.
21Department of Medicine, Division of Liver Diseases, Icahn School of Medicine, Mount Sinai Hospital, New York, NY, USA.
22Stanford University Medical Center, Stanford, CA, USA.
23Schiff Center for Liver Diseases, University of Miami School of Medicine, Miami, FL, USA.
24Asian Pacific Liver Center, Los Angeles, CA, USA.
25University of Toronto, Toronto, Canada.
26Institute of Liver Studies, King's College Hospital, London, UK.
27Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Abstract
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.