Safety, tolerability, pharmacokinetics (PK), and antiviral activity of the 3rd generation capsid inhibitor AB-836 in healthy subjects (HS) and subjects with chronic hepatitis B (CHB)

Background and aims: EDP-514, a novel class II HBV core inhibitor, demonstrated nanomolar potency in vitro, and a >4-log viral load reduction in an HBV mouse model.Here, we present the safety, pharmacokinetic (PK) and antiviral activity from a phase 1b study of multiple ascending doses (MAD) of EDP-514 in nucleot (s)ide (nuc)suppressed chronic hepatitis B (CHB) patients.Method: This phase 1a/b, randomized, double-blind, placebocontrolled study was conducted in two parts.In Part 1, healthy adult subjects received single or multiple ascending doses of EDP-514 or placebo.In Part 2, noncirrhotic, HBeAg (+) or (-) subjects virologically suppressed on nuc therapy received EDP-514 or placebo in a 3:1 ratio (24 subjects in 3 cohorts: 200 mg, 400 mg, 800 mg) for 28 days.Results: The 24 subjects enrolled were mostly male (63%), Asian (67%), HBeAg (-) (88%), treated with tenofovir (92%), with a mean age of 45 years and a mean BMI of 27 kg/m 2 .All TEAEs (n = 20) were mild except for 1 moderate event (200 mg) of abdominal pain that led to drug discontinuation, and 1 severe allergic reaction to aloe cream (800 mg).There were no other grade 3 TEAEs or any SAEs.No clinicallysignificant laboratory abnormalities, liver function tests elevations or clinically relevant ECG or vital signs changes were observed.EDP-514 exhibited PK supportive of once daily (QD) dosing, with trough concentrations of up to ∼21-fold above the paEC 50 .HBV DNA remained undetectable and no virologic failures or breakthroughs were reported through 28 days of treatment.At Day 28, a maximum HBV RNA reduction of 2.3 log in HBeAg (-) and 2.8 log in HBeAg (+) patients was observed in EDP-514 arms compared to 1.2 log in placebo.There were no discernible changes in HBeAg, HBcrAg, and HBsAg.Conclusion: EDP-514 was safe and well tolerated through 28 days of treatment in CHB nuc-suppressed patients, showed time-linear PK supportive of QD dosing with concentrations of up to ∼21-fold above the paEC 50 , and resulted in a higher log reduction in HBV RNA, up to a maximum of 2.8 log, was observed in HBeAg (+) patients receiving EDP-514.