Antiviral Activity and Pharmacokinetics of the Hepatitis B Virus (HBV) Capsid Assembly Modulator GLS4 in Patients With Chronic HBV Infection.

Abstract

GLS4 is a first-in-class hepatitis B virus (HBV) capsid assembly modulator (class I) that can inhibit HBV replication by interfering with the assembly and disassembly of HBV nucleocapsid. Here, we evaluated its antiviral activity, pharmacokinetics, and tolerability in a double-blind, randomized, parallel, entecavir-controlled study. Twenty-four patients with chronic HBV were randomized to receive a 28-day course of GLS4 (120 or 240 mg) and ritonavir (100 mg) combination (cohorts A and B, respectively) or entecavir treatment (cohort C) at a 1:1:1 ratio. Patients were followed up for 40 days in a phase 1b study. The GLS4/ritonavir combination was a tolerated combination for the treatment of chronic HBV infection. A total of 2, 3, and 3 subjects presented with alanine aminotransferase flare in cohorts A, B, and C, respectively. This contributed to the withdrawal of 1, 2, and 1 patient from cohorts A, B, and C, respectively. The mean Ctrough of GLS4 was 205-218 ng/mL, which was approximately 3.7-3.9 times the 90% effective concentration (55.8 ng/mL), with a lower accumulation (accumulation rate, 1.1-2.0). In cohorts A, B, and C, the mean declines in HBV DNA after 28 days of treatment were -1.42, -2.13, and -3.5 log10 IU/mL; in hepatitis B surface antigen were -0.06, -0.14, and -0.33 log10 IU/mL; in pregenomic RNA were -0.75, -1.78, and -0.96 log10 copies/mL; and in hepatitis B core antigen were -0.23, -0.5, and -0.44 log10 U/mL, respectively. Treatment with 120 mg GLS4 was tolerated and had antiviral activity in patients with chronic HBV infection. Chinese Clinical Trial Registry; CTR20160068. http://www.chinadrugtrials.org.cn.