Dataset Information

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

ABSTRACT:

Background

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.

Methods

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.

Results

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.

Conclusions

Treatment with 120 mg GLS4 was tolerated and had antiviral activity in patients with chronic HBV infection.

Clinical trials registration

Chinese Clinical Trial Registry; CTR20160068. http://www.chinadrugtrials.org.cn.

SUBMITTER: Zhang H

PROVIDER: S-EPMC8516514 | biostudies-literature | 2021 Jul

REPOSITORIES: biostudies-literature

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Publications

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

Zhang Hong H Wang Fengjiao F Zhu Xiaoxue X Chen Yunfu Y Chen Hong H Li Xiaojiao X Wu Min M Li Cuiyun C Liu Jingrui J Zhang Yingjun Y Ding Yanhua Y Niu Junqi J

Clinical infectious diseases : an official publication of the Infectious Diseases Society of America 20210701 2

<h4>Background</h4>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.<h4>Methods</h4>Twenty-four patients with chronic HBV were randomized to receive a 28-day course of GLS4 (120 or 240 mg) and ritonavir (100 mg) com ...[more]

PMID: 32649736

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Project description:ObjectiveWe present the final analysis results of the phase 2 JADE study (ClinicalTrials.gov Identifier: NCT03361956).Design232 patients with chronic hepatitis B (CHB) not currently treated at study start (NCT) at study start or virologically suppressed were randomised to receive 75 mg (part 1) or 250 mg (part 2) JNJ-56136379, a hepatitis B virus (HBV)-capsid assembly modulator, one time per day or placebo with nucleos(t)ide analogue (NA) (tenofovir disoproxil fumarate/entecavir) or JNJ-56136379 alone (NCT-only) for ≥24 and ≤48 weeks.ResultsIn patients who are NCT hepatitis B e-antigen (HBeAg) positive, JNJ-56136379 75 mg+NA and 250 mg+NA showed limited mean (SE) hepatitis B surface antigen (HBsAg) declines (0.14 (0.10) and 0.41 (0.15), respectively) from baseline at Week 24 (primary endpoint; placebo+NA: 0.25 (0.11) log10 international unit (IU)/mL).In patients who are NCT HBeAg positive, mean (SE) HBV DNA declines at Week 24 were 5.53 (0.23) and 5.88 (0.34) for JNJ-56136379 75 mg+NA and 250 mg+NA, respectively, versus 5.21 (0.42) log10 IU/mL for placebo+NA. In NCT patients, mean (SE) HBV RNA declines were 2.96 (0.23) and 3.15 (0.33) versus 1.33 (0.32) log10 copies/mL, respectively.Patients with HBsAg declines had HBeAg and hepatitis B core-related antigen (HBcrAg) declines and some early on-treatment isolated alanine aminotransferase flares. Viral breakthrough occurred with JNJ-56136379 monotherapy with the emerging resistant-variant T33N, but not with JNJ-56136379+NA. JNJ-56136379 treatment beyond Week 24 had a generally small additional effect on viral markers.No study treatment-related serious adverse events or clinically significant changes in laboratory parameters occurred.ConclusionsIn patients with non-cirrhotic CHB, JNJ-56136379+NA showed pronounced reductions in HBV DNA and HBV RNA, limited HBsAg or HBeAg declines in patients who are NCT HBeAg positive, and was well tolerated, but no clear benefit with regards to efficacy of JNJ-56136379 over NA was observed.

Dataset Information

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

Background

Methods

Results

Conclusions

Clinical trials registration

Publications

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

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