Safety, Pharmacokinetics and Antiviral Efficacy of Capsid Assembly Modulator Freethiadine in Healthy Volunteers and Chronic Hepatitis B Patients

ABSTRACT Background and Aims Freethiadine is a novel hepatitis B virus capsid assembly modulator. Herein, we report the safety, tolerability, pharmacokinetics and 28‐day antiviral activities of freethiadine. Methods The study consisted of two parts. Part 1 involved a single‐ascending‐dose, a multiple‐ascending‐dose and a food effect study. Part 2 was a double‐blind, double‐dummy, randomised, entecavir‐controlled, multi‐dose escalation study in chronic hepatitis B (CHB) patients. Results A total of 88 healthy subjects and 40 patients with CHB were enrolled in this study. Freethiadine was well tolerated by both healthy subjects and patients. Among freethiadine‐treated patients with CHB, the most common drug‐related adverse event was alanine aminotransferase elevation (28.1%) (mostly grade 1 or 2). Both HEC160208 and its active metabolite, HEC142106, were rapidly absorbed and eliminated in plasma. Food intake did not significantly influence the exposure of either analyte. Following 28 days of treatment, the mean maximum HBV DNA declines from baseline were −2.76, −3.47, −3.56, −2.89 and −2.55 log10 IU/mL for the 100 mg BID, 200 mg QD, 200 mg BID and 300 mg QD of freethiadine or entecavir control cohorts, respectively; simultaneously, the mean maximum pregenomic RNA (pgRNA) declines from baseline were −1.69, −2.26, −2.07, −1.47 and −0.06 log10 copies/mL, respectively. Conclusions Freethiadine has an acceptable safety profile and favourable antiviral activity in patients with CHB. These results support further investigations of freethiadine for the treatment of chronic HBV infection. Trial Registration www.clinicaltrials.gov identifier NCT05391360; www.chinadrugtrials.org.cn identifier CTR20212114