Population Pharmacokinetics of Bepirovirsen in Healthy Participants and Participants with Chronic Hepatitis B Virus Infection: Results from Phase 1, 2a, and 2b Studies

Abstract

Introduction: Bepirovirsen is a novel antisense oligonucleotide in development for chronic hepatitis B virus (HBV) infection therapy. Understanding the impact that clinical characteristics may have on bepirovirsen exposure is important for determining efficacious and well-tolerated dosing regimens. This analysis evaluated demographics and clinical characteristics associated with bepirovirsen exposure using a population pharmacokinetic (PK) analysis.

Methods: Population PK analyses were conducted using pooled data from three phase 1/2 clinical studies (NCT03020745/NCT02981602/NCT04449029) to construct a structural PK model for bepirovirsen that adequately described plasma concentration-time profiles and identify covariates that affect systemic exposure. The final population PK model was used to simulate bepirovirsen exposure measures to inform exposures at different dose levels and within different subpopulations.

Results: Bepirovirsen PK data were well-described by a linear, three-compartment model with first-order absorption and absorption delay. Chronic HBV infection status, body weight, and Asian versus non-Asian race were key covariates included in the final model. Visual inspection of correlation scatter plots confirmed general agreement between observed and predicted data from the studies. In simulations, bepirovirsen systemic exposure was dosed proportionally and predicted to be almost completely washed out by 12 weeks following the final 300-mg dose. Differences in body weight, Asian race, or disease status did not result in clinically relevant differences in exposure.

Conclusions: This analysis demonstrated that the linear three-compartmental model accurately described bepirovirsen PK data. The lack of clinically relevant differences seen in exposure indicate that dose adjustments are not recommended for bepirovirsen based on demographics or clinical characteristics.

Keywords: Antisense oligonucleotide; Bepirovirsen; Chronic hepatitis B virus infection; Population pharmacokinetics.

Fig. 1

Schematic of the starting base three-compartment PK model after SC administration. A amount of drug in the compartment, ALAG absorption lag time, CL clearance, CMT compartment, K_a first-order absorption rate constant, PK pharmacokinetic, Q₃ apparent intercompartmental clearance between central and shallow peripheral compartments, Q₄ apparent intercompartmental clearance between central and deep peripheral compartments, SC subcutaneous, V volume of distribution

Fig. 2

Population PK pcVPC by dose cohort and NA treatment status in the phase 2b study B-Clear (panels A and B show on-NA data; panels B and C show not-on-NA data). Observed data: individual (dots), 5th (dashed), median (solid), and 95th (dashed) percentile. Predicted data (shaded): 5th (lower blue), 50th (grey), and 95th (upper blue) prediction intervals and 95% CI around each of the prediction intervals. The probability of < LLOQ: solid line is fraction of observed data that is < LLOQ, and shaded area is 95% CI around predicted proportion. CI confidence interval, LLOQ lower limit of quantification, NA nucleos(t)ide analog, pcVPC prediction-corrected visual predictive check, PK pharmacokinetic

Fig. 3

PK exposure parameters stratified by race in the phase 2b study B-Clear. AUC_tau area under the plasma bepirovirsen concentration–time curve during the dosing interval, C_max maximum plasma bepirovirsen concentration, C_trough trough plasma bepirovirsen concentration, PK pharmacokinetic