Immunomodulation by bepirovirsen may induce killing of infected hepatocytes (B-Together study)

Bepirovirsen is an investigational drug; its multimodal mechanism of action (MoA) is under evaluation. Observations in treated participants show transient alanine aminotransferase (ALT) increases, alongside hepatitis B surface antigen (HBsAg) declines. We investigated bepirovirsen's MoA in relation to virological response, hepatocyte death, and ALT increases.

In B-Together (NCT04676724), 108 participants on stable nucleos(t)ide analogs received bepirovirsen for 24 (Arm 1) or 12 (Arm 2) Weeks, then up to 24 Weeks of pegylated interferon-α-2a. This post hoc peripheral longitudinal biomarker exploratory analysis examined serum proteomics and whole blood transcriptomics from peripheral blood mononuclear cell samples from 82 participants. Relative expressions of immune- and disease-related biomarkers were measured, and differential expression determined across arms and response subgroups.

Increases from baseline in mean expression of serum proteins with immune effector and apoptotic functions (Week 3) and transcripts associated with immune cell proliferation and activation (Week 5) were observed regardless of arm or response subgroup. By Week 8, serum liver and apoptosis-specific proteins were increased; this was more pronounced in responders than non-responders, with the difference more marked in Arm 1 versus Arm 2. Increased abundance of these proteins was highly correlated with ALT levels, which were often associated with transient hepatitis B virus (HBV) DNA elevations and HBsAg decreases.

These findings provide evidence that bepirovirsen may modulate the immune system to facilitate infected hepatocyte killing in chronic HBV infection in addition to its direct antiviral effects; therefore, ALT increases could reflect a therapeutic response to bepirovirsen.

NCT04676724 and NCT04449029.