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

Man-Fung Yuen, Kosh Agarwal, Xiaoli Ma, Tuan T Nguyen, Eugene R Schiff, Hie-Won L Hann, Douglas T Dieterich, Ronald G Nahass, James S Park, Sing Chan, Steven-Huy B Han, Edward J Gane, Michael Bennett, Katia Alves, Marc Evanchik, Ran Yan, Qi Huang, Uri Lopatin, Richard Colonno, Julie Ma, Steven J Knox, Luisa M Stamm, Maurizio Bonacini, Ira M Jacobson, Walid S Ayoub, Frank Weilert, Natarajan Ravendhran, Alnoor Ramji, Paul Yien Kwo, Magdy Elkhashab, Tarek Hassanein, Ho S Bae, Jacob P Lalezari, Scott K Fung, Mark S Sulkowski

Journal: Journal of hepatology 2022;77(3):642-652

PMID: 35460726

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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.

Address: Department of Medicine and State Key Laboratory of Liver Research, Queen Mary Hospital, The University of Hong Kong, Hong Kong. Electronic address: [email protected].; Institute of Liver Studies, King's College Hospital, London, UK.; Office of Xiaoli Ma, Philadelphia, PA, USA.; T Nguyen Research and Education, Inc., San Diego, CA, USA.; Schiff Center for Liver Diseases, University of Miami School of Medicine, Miami, FL, USA.; Thomas Jefferson University Hospital, Philadelphia, PA, USA.; Department of Medicine, Division of Liver Diseases, Icahn School of Medicine, Mount Sinai Hospital, New York, NY, USA.; ID Care, Hillsborough, NJ, USA.; NYU Langone Health, New York, NY, USA.; Sing Chan MD, New York, NY, USA.; Pfleger Liver Institute, University of California, Los Angeles, CA, USA.; New Zealand Clinical Studies, Auckland, New Zealand.; Medical Associates Research Group, San Diego, CA, USA.; Assembly Biosciences, South San Francisco, CA, USA.; Quest Clinical Research, San Francisco, CA, USA.; Cedars-Sinai Medical Center, Los Angeles, CA, USA.; Waikato Hospital, Hamilton, New Zealand.; Digestive Disease Associates, Catonsville, MD, USA.; GastroIntestinal Research Institute, Vancouver, Canada.; Stanford University Medical Center, Stanford, CA, USA.; Toronto Liver Centre, Toronto, Canada.; Southern California Research Center, Coronado, CA, USA.; Asian Pacific Liver Center, Los Angeles, CA, USA.; University of Toronto, Toronto, Canada.; Johns Hopkins University School of Medicine, Baltimore, MD, USA.

DOI: 10.1016/j.jhep.2022.04.005

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MeSH Terms: Antiviral Agents, DNA, Viral, Hepatitis B Surface Antigens, Hepatitis B e Antigens, Hepatitis B virus, Hepatitis B, Chronic, Humans