Combination therapy with tobevibart and elebsiran potently reduces hepatitis B virus surface antigen levels in preclinical in vivo models

ABSTRACT RNA interference (RNAi) therapeutics targeting hepatitis B virus (HBV) RNAs and monoclonal antibodies (mAbs) targeting HBV surface antigen (HBsAg) represent potential strategies for enabling functional cure in chronic HBV patients. Tobevibart (VIR-3434) is an investigational, Fc-engineered human mAb that targets HBsAg with pan-genotypic neutralizing activity. Elebsiran (VIR-2218) is an investigational small interfering RNA targeting a conserved region of the HBV genome. The in vitro antiviral activity of elebsiran was assessed in HBV-infected primary human hepatocytes and hepatoma cells and showed potent inhibition of viral markers HBeAg (EC 50 of 2.5 nM and 53.7 pM, respectively) and HBsAg (EC 50 of 1.4 nM and 66.5 pM, respectively). Tobevibart and elebsiran activity in vivo was determined using two well-established HBV mouse models: AAV-HBV transduced C57BL/6 mice and human liver-chimeric mice. Mice were treated with a monotherapy or a combination of muHBC34 (the murinized parental mAb of tobevibart) and elebsiran at different doses. In both models, the mouse surrogate of tobevibart or elebsiran monotherapy was effective in reducing blood HBsAg levels. Combined treatment improved suppression of HBsAg (maximum mean reductions of 2.81 log in the AAV-HBV model and 2.51 log in human liver-chimeric mice) and HBV DNA over monotherapy. Tobevibart and elebsiran have been tested in clinical trials for the treatment of chronic hepatitis B and chronic hepatitis Delta.