Viral sequence analysis of chronic hepatitis B patients treated with the capsid assembly modulator JNJ-56136379 in the JADE phase 2a study
Copyright © 2023 Elsevier B.V. All rights reserved..
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:216 |
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| Enthalten in: |
Antiviral research - 216(2023) vom: 01. Aug., Seite 105660 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Verbinnen, Thierry [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 01.08.2023 Date Revised 01.08.2023 published: Print-Electronic ClinicalTrials.gov: NCT03361956 Citation Status MEDLINE |
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| doi: |
10.1016/j.antiviral.2023.105660 |
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| 245 | 1 | 0 | |a Viral sequence analysis of chronic hepatitis B patients treated with the capsid assembly modulator JNJ-56136379 in the JADE phase 2a study |
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| 500 | |a Date Completed 01.08.2023 | ||
| 500 | |a Date Revised 01.08.2023 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a ClinicalTrials.gov: NCT03361956 | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2023 Elsevier B.V. All rights reserved. | ||
| 520 | |a 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 | ||
| 520 | |a 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) | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 520 | |a CLINICAL TRIAL NUMBER: NCT03361956 | ||
| 650 | 4 | |a Clinical Trial, Phase II | |
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Capsid assembly modulator | |
| 650 | 4 | |a Genome sequencing | |
| 650 | 4 | |a Hepatitis B virus | |
| 650 | 4 | |a JNJ-56136379 | |
| 650 | 4 | |a Polymorphisms | |
| 650 | 4 | |a Viral breakthrough | |
| 650 | 7 | |a JNJ-56136379 |2 NLM | |
| 650 | 7 | |a Antiviral Agents |2 NLM | |
| 650 | 7 | |a DNA, Viral |2 NLM | |
| 650 | 7 | |a Hepatitis B e Antigens |2 NLM | |
| 650 | 7 | |a Capsid Proteins |2 NLM | |
| 700 | 1 | |a Talloen, Willem |e verfasserin |4 aut | |
| 700 | 1 | |a Janssen, Harry L A |e verfasserin |4 aut | |
| 700 | 1 | |a Zoulim, Fabien |e verfasserin |4 aut | |
| 700 | 1 | |a Shukla, Umesh |e verfasserin |4 aut | |
| 700 | 1 | |a Vandenbossche, Joris J |e verfasserin |4 aut | |
| 700 | 1 | |a Biermer, Michael |e verfasserin |4 aut | |
| 700 | 1 | |a De Meyer, Sandra |e verfasserin |4 aut | |
| 700 | 1 | |a Lenz, Oliver |e verfasserin |4 aut | |
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