A phase 1 study evaluating the neutralizing, vaccinal monoclonal antibody VIR-3434 in participants with chronic hepatitis B virus infection

Abstract

Background and aims: VIR-3434 is a fully human, monoclonal antibody in development for the treatment of chronic hepatitis B virus (HBV) infection with three distinct modes of action: 1) entry inhibition via neutralization of all 10 HBV genotypes in vitro, 2) reduction of circulating HBsAg-containing particles in vivo, and 3) potential therapeutic vaccination via Fc engineering. In the Phase 1a part of this study, single doses up to 3, 000 mg were well tolerated in healthy participants (see Gupta et al., EASL 2021). We report here the preliminary safety and HBsAg reduction data from a Phase 1b study evaluating VIR-3434 in participants with chronic HBV infection. Method: This is an ongoing randomized, double-blind, placebocontrolled Phase 1 single ascending dose study evaluating VIR-3434 in healthy volunteers (Part A) and participants with chronic HBV infection who are receiving nucleos (t)ide reverse transcriptase inhibitor (NRTI) therapy (Parts B-C). In Part B, non-cirrhotic, virally suppressed, HBeAg-negative participants with HBsAg <1,000 IU/ml are randomized 3:1 to receive a single dose of VIR-3434 or placebo administered subcutaneously. Participants are followed for safety, tolerability, pharmacokinetics, and viral biomarkers. Preliminary blinded safety and HBsAg reduction results through Day 29 for the first cohort evaluating a single dose of 6 mg are presented herein. Dose escalation to 18 mg, 75 mg, and 300 mg single doses is planned and ongoing. Results: In this blinded trial, eight participants were enrolled. Six received a single dose of 6 mg of VIR-3434, and two received placebo on Day 1. Among the six participants who responded, a mean HBsAg reduction of 1.3 log10 IU/ml was observed (Figure). One Grade 1 adverse event was reported. No clinically significant changes in safety laboratory parameters were observed. No participant developed clinical or laboratory evidence of immune complex disease. Conclusion: A single low dose of 6 mg of VIR-3434 resulted in rapid reductions in HBsAg that were maintained through 2 weeks after dosing. Having observed no safety signals with doses up to 3, 000 mg in healthy volunteers, this substantial HBsAg reduction in patients supports the potential for VIR-3434 to have a meaningful role in the functional cure of chronic HBV infection. Additional data from this ongoing study, including the effect of higher doses of VIR-3434, will be presented.