No virologic resistance to bulevirtide monotherapy detected in patients through 24 weeks treatment in phase II and III clinical trials for chronic hepatitis delta

Abstract

Bulevirtide (BLV) is a hepatitis D virus (HDV)/hepatitis B virus (HBV) entry inhibitor that has shown virologic response (responder, HDV-RNA undetectable or ≥2 log10 IU/mL decrease from baseline) in >50% of patients after 24-week treatment. However, some patients achieve <1 log10 IU/mL decline in HDV-RNA through 24-week treatment (non-responder). Here we report viral resistance analyses for BLV monotreated participants who were non-responders or experienced virologic breakthrough (VB, 2 consecutive increases in HDV-RNA of ≥1 log10 IU/mL from nadir or 2 consecutive HDV-RNA detectable if previously undetectable) in phase II study MYR202 and phase III study MYR301. Deep-sequencing of BLV-corresponding region in HBV PreS1 and HDV HDAg gene and in vitro phenotypic testing were performed for the participant with VB (n=1) and non-responders (n=20) at baseline (BL) and Week 24 (WK24). No amino acid exchanges within the BLV-corresponding region and HDAg associated with reduced susceptibility to BLV were identified in isolates from any of the 21 participants at BL and WK24. Although variants (HBV n=1; HDV n=13) were detected at BL in some non-responders or the participant with VB, none were associated with reduced sensitivity to BLV in vitro. Furthermore, the same variant was found in virologic responders. A comprehensive phenotypic analysis demonstrated that the BLV EC50 values from 116 BL samples were similar across non-responders, partial responders (HDV RNA decline ≥1 but <2 log10 IU/mL), and responders regardless of the presence of HBV and/or HDV polymorphisms. No amino acid substitutions associated with reduced sensitivity to BLV monotherapy were detected at BL or WK24 in non-responders or the participant with VB after 24-week BLV treatment.