Viral sequence analysis of chronic hepatitis B patients treated with the capsid assembly modulator JNJ-56136379 in the JADE phase 2a study.

Abstract

BACKGROUND & AIMS:

In the monotherapy arms of the phase 2 JADE study (ClinicalTrials.gov Identifier: NCT03361956) evaluating the safety and efficacy of JNJ-56136379 (capsid assembly modulator-class E) with/without nucleos(t)ide analogue (NA), viral breakthroughs (VBT) were observed, leading to JNJ-56136379 monotherapy discontinuation. We present the viral sequencing analysis of JNJ-56136379±NA-treated hepatitis B virus (HBV)-infected patients.

METHODS:

The HBV full genome was sequenced using next generation sequencing. Baseline amino acid (aa) polymorphisms were defined as changes versus the universal HBV reference sequence (sequence read frequency >15%). Emerging mutations were defined as aa changes versus baseline sequence (frequency <1% at baseline and ≥15% post-baseline).

RESULTS:

6/28 JNJ-56136379 75 mg monotherapy arm patients experienced VBT; all 6 had emerging JNJ-56136379-resistant variants T33N (n = 5; fold change [FC] = 85) or F23Y (n = 1; FC = 5.2). 1/32 JNJ-56136379 250 mg arm patients (genotype-E) had <1 log10 IU/mL decline in HBV DNA at Week 4, experienced VBT at Week 8, and carried the I105T baseline polymorphism (FC = 7.9), but had no emerging variants. Eight additional monotherapy-treated patients had shallow second phases of their HBV DNA profile and emerging T33N (n = 7) or F23Y (n = 1) variants. NA initiation (switch [75 mg arm]; add-on [250 mg arm]) in all monotherapy patients with VBT resulted in HBV DNA decline in all patients. No VBT was observed during JNJ-56136379+NA combination therapy.

CONCLUSIONS:

JNJ-56136379 monotherapy resulted in VBT and was associated with the selection of JNJ-56136379-resistant variants. Efficacy of NA treatment (de novo combination or rescue therapy for VBT) was not impacted, confirming the lack of cross-resistance between these drug classes.

CLINICAL TRIAL NUMBER:

NCT03361956.

• Authors: Thierry Verbinnen, Willem Talloen, Harry L A Janssen, Fabien Zoulim, Umesh Shukla, Joris J Vandenbossche, Michael Biermer, Sandra De Meyer, Oliver Lenz
• Journal: Antiviral research (Antiviral Res) Vol. 216 Pg. 105660 (08 2023) ISSN: 1872-9096 [Electronic] Netherlands
• PMID: 37385475 (Publication Type: Clinical Trial, Phase II, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2023 Elsevier B.V. All rights reserved.

Chemical References

• JNJ-56136379
• Antiviral Agents
• DNA, Viral
• Hepatitis B e Antigens
• Capsid Proteins

Topics

• Humans
• Hepatitis B, Chronic
• Antiviral Agents (pharmacology, therapeutic use)
• Capsid (metabolism)
• DNA, Viral (genetics, metabolism)
• Treatment Outcome
• Hepatitis B e Antigens (metabolism)
• Hepatitis B virus (genetics, metabolism)
• Capsid Proteins (metabolism)
• High-Throughput Nucleotide Sequencing
• Drug Resistance, Viral (genetics)