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Safety and efficacy of vebicorvir administered with entecavir in treatment-naive patients with chronic hepatitis B virus infection. Journal of hepatology Sulkowski, M. S., Agarwal, K., Ma, X., Nguyen, T. T., Schiff, E. R., Hann, H. L., Dieterich, D. T., Nahass, R. G., Park, J. S., Chan, S., Han, S. B., Gane, E. J., Bennett, M., Alves, K., Evanchik, M., Yan, R., Huang, Q., Lopatin, U., Colonno, R., Ma, J., Knox, S. J., Stamm, L. M., Bonacini, M., Jacobson, I. M., Ayoub, W. S., Weilert, F., Ravendhran, N., Ramji, A., Kwo, P. Y., Elkhashab, M., Hassanein, T., Bae, H. S., Lalezari, J. P., Fung, S. K., Yuen, M. 2022

Abstract

BACKGROUND AND AIMS: Nucleos(t)ide reverse transcriptase inhibitors do not completely suppress hepatitis B virus (HBV) DNA in chronic HBV infection (cHBV). Vebicorvir (VBR) is an investigational core inhibitor which interferes with multiple aspects of HBV replication. This phase 2 trial (NCT03577171) evaluated the efficacy and safety of VBR in combination with entecavir (ETV) in treatment-naive patients with cHBV.METHODS: Hepatitis B "e" antigen positive, treatment-naive patients without cirrhosis were randomised 1:1 in a double-blind manner, to once-daily VBR 300 mg+ETV 0.5 mg or placebo (PBO)+ETV for 24 weeks (W). The primary endpoint was change in mean log10 HBV DNA from Baseline to W12 and W24.RESULTS: All patients in both treatment groups (PBO+ETV: 12/12; VBR+ETV: 13/13) completed the study. At W12, VBR+ETV led to a greater mean (SD) reduction from Baseline in log10 IU/mL HBV DNA (-4.45 [1.03]) vs PBO+ETV (-3.30 [1.18]; p=0.0077). At W24, VBR+ETV led to a greater reduction from Baseline in log10 IU/mL HBV DNA (-5.33 [1.59]) vs PBO+ETV (-4.20 [0.98]; p=0.0084). Greater mean reductions in pregenomic RNA were observed at W12 and W24 in patients receiving VBR+ETV vs PBO+ETV (p<0.0001 and p<0.0001). Changes in viral antigens were similar in both groups. No drug interaction between VBR and ETV was observed. Two patients experienced HBV DNA rebound during treatment, with no resistance breakthrough detected. Safety of VBR+ETV was similar to PBO+ETV. All treatment-emergent adverse events and laboratory abnormalities were Grade 1/2. There were no deaths, serious AEs, or evidence of drug-induced liver injury.CONCLUSIONS: In this 24-week study, VBR+ETV provided additive antiviral activity over PBO+ETV in treatment-naive patients with cHBV with a favourable safety and tolerability profile.LAY SUMMARY: Hepatitis B is a long-lasting viral infection of the liver. This study demonstrates that vebicorvir (a core inhibitor) with entecavir is generally safe, well tolerated, and demonstrates greater antiviral activity compared with entecavir alone in treatment-naive patients chronically infected with hepatitis B virus. This study supports continued evaluation of vebicorvir in the treatment of chronic hepatitis B.CLINICAL TRIAL NUMBER: NCT03577171.

View details for DOI 10.1016/j.jhep.2022.05.027

View details for PubMedID 35697332