Lack of Pharmacokinetic Drug-Drug Interactions Between Bepirovirsen and Nucleos(t)ide Analogs.

Abstract

Bepirovirsen is an antisense oligonucleotide currently in Phase 3 development to treat chronic hepatitis B virus (HBV) infection. Given the importance of coadministration of bepirovirsen and standard-of-care nucleos(t)ide analogs (NAs), we evaluated drug-drug interactions (DDIs) between bepirovirsen, entecavir (ETV), and tenofovir (TFV) using in vitro and clinical data obtained through innovative study design and sampling strategy. Static models employing in vitro data indicated that bepirovirsen is not a direct inhibitor or inducer of most drug-metabolizing enzymes or an inhibitor or substrate of drug transporters and poses no clinical DDI risk against NAs. Bepirovirsen plasma pharmacokinetic parameters and concentration-time profiles in patients with chronic HBV in the CS3 study (NCT02981602) were similar with or without ETV or TFV coadministration, indicating no effect of NA coadministration on bepirovirsen pharmacokinetics. In patients with chronic HBV receiving both bepirovirsen and ETV or TFV in the B-Clear study (NCT04449029), NA plasma concentrations and pharmacokinetic parameters were similar to those published without bepirovirsen coadministration, suggesting no effect of bepirovirsen coadministration on NA pharmacokinetics. This analysis demonstrated no DDI potential between bepirovirsen and NAs, suggesting that dedicated clinical DDI studies are not required. Bepirovirsen is currently being evaluated in Phase 3 studies in combination with NA.