Bepirovirsen induces innate immune proteins independent of HBV

BACKGROUND: Bepirovirsen, an antisense oligonucleotide that targets all hepatitis B virus (HBV) mRNAs, is in development for the treatment of chronic HBV infection. Clinical studies have demonstrated that bepirovirsen has multiple mechanisms of action, including lowering HBV DNA, reducing viral protein production, and inducing immune activation. Post hoc analysis of biomarker samples from three studies was performed to further characterize changes in soluble protein biomarkers after bepirovirsen dosing. METHODS: Across three studies (CS3 [NCT02981602] in participants with chronic HBV infection; PFS [NCT06058390] and QTc [NCT06422767] in healthy volunteers) participants received bepirovirsen (150 mg, 300 mg, or 450 mg) or placebo. Longitudinal serum samples were taken for exploratory proteomics analysis. Relative expression of soluble proteins, including immune-related biomarkers, was measured, and differential expression was determined across arms. Clustering analysis was performed to identify kinetic patterns. RESULTS: Bepirovirsen induced significant, transient protein differential expression in the hours after dosing, while there were relatively minor changes in placebo. There were many similarities in protein biomarkers induced in CS3 participants with chronic HBV infection and in the two healthy volunteer studies. Additionally, bepirovirsen treatment increased abundance of many proteins to a higher degree with increasing dose. CONCLUSIONS: These findings strengthen the association between bepirovirsen treatment and changes in innate immune-related proteins and indicate that this effect does not require the presence of HBV. The kinetic patterns of protein expression suggest that there are multiple waves of protein induction, which could impact recruitment and activation of innate and adaptive immune cell types. CLINICAL TRIAL NUMBER: NCT02981602, NCT06058390, NCT06422767.