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

Thierry Verbinnen*, Willem Talloen, Harry L.A. Janssen, Fabien Zoulim, Umesh Shukla, Joris J. Vandenbossche, Michael Biermer, Sandra De Meyer, Oliver Lenz

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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.

Original languageEnglish
Article number105660
JournalAntiviral Research
Volume216
DOIs
Publication statusPublished - Aug 2023

Bibliographical note

Funding Information:
The authors acknowledge Edgar Jacoby for his contributions to the structural analyses by HBV genotype. This study was sponsored by Janssen Research & Development , LLC with medical writing support provided by Kim Caldwell, PhD, of Lumanity Communications Inc., and funded by Janssen Global Services, LLC.

Publisher Copyright:
© 2023 Elsevier B.V.

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