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Article: JNJ-73763989 pharmacokinetics and safety: Liver-targeted siRNAs against hepatitis B virus, in Japanese and non-Japanese healthy adults, and combined with JNJ-56136379 and a nucleos(t)ide analogue in patients with chronic hepatitis B

TitleJNJ-73763989 pharmacokinetics and safety: Liver-targeted siRNAs against hepatitis B virus, in Japanese and non-Japanese healthy adults, and combined with JNJ-56136379 and a nucleos(t)ide analogue in patients with chronic hepatitis B
Authors
Issue Date1-Apr-2022
PublisherSAGE Publications
Citation
Antiviral Therapy, 2022, v. 27, n. 3 How to Cite?
Abstract

Background JNJ-73763989 comprises two hepatitis B virus (HBV)-specific, liver-targeted N-galactosamine-conjugated short interfering RNA triggers, JNJ-73763976 and JNJ-73763924. JNJ-73763989 pharmacokinetics, safety and tolerability were assessed in two phase 1 studies: Japanese (NCT04002752), and non-Japanese healthy participants and chronic hepatitis B (CHB) patients also receiving the HBV capsid assembly modulator JNJ-56136379 and a nucleos(t)ide analogue (NA) (NCT03365947).

Methods Healthy participant cohorts were double-blind and randomized to receive a single subcutaneous JNJ-73763989 dose (non-Japanese participants, 35, 100, 200, 300 or 400 mg; Japanese participants, 25, 100 or 200 mg) or placebo. JNJ-73763976 and JNJ-73763924 plasma concentrations were assessed over 48 h. CHB patients received JNJ-73763989 200 mg every 4 weeks plus daily oral JNJ-56136379 250 mg and NA in an open-label fashion. Safety and tolerability were assessed through Day 28 (healthy participants) or Day 112 (patients).

Results Thirty non-Japanese (n = 4/dose; placebo, n = 10) and 24 Japanese healthy participants (n = 6/dose; placebo, n = 6) were randomized. JNJ-73763976 and JNJ-73763924 exposure generally increased in a dose-proportional manner. Mean plasma half-life was 4-9 h. No differences between pharmacokinetic parameters were apparent between non-Japanese and Japanese healthy participants. In the 12 CHB patients, mean JNJ-73763976, JNJ-73763924 and JNJ-56136379 plasma concentrations 2 h post-dose on Day 29 were 663, 269 and 14,718 ng/mL, respectively. In both studies, all adverse events were mild/moderate.

Conclusion JNJ-73763976 and JNJ-73763924 had short plasma half-lives and exposure generally increased in a dose-proportional manner; there were no pharmacokinetic differences between Japanese and non-Japanese healthy adults. JNJ-73763989 with or without JNJ-56136379 and NA was generally safe and well tolerated.


Persistent Identifierhttp://hdl.handle.net/10722/340810
ISSN
2023 Impact Factor: 1.3
2023 SCImago Journal Rankings: 0.447
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorGane, E-
dc.contributor.authorYuen, MF-
dc.contributor.authorKakuda, TN-
dc.contributor.authorOgawa, T-
dc.contributor.authorTakahashi, Y-
dc.contributor.authorGoeyvaerts, N-
dc.contributor.authorLonjon-Domanec, I-
dc.contributor.authorVaughan, T-
dc.contributor.authorSchluep, T-
dc.contributor.authorHamilton, J-
dc.contributor.authorEdiage, EN-
dc.contributor.authorHillewaert, V-
dc.contributor.authorSnoeys, J-
dc.contributor.authorLenz, O-
dc.contributor.authorTalloen, W-
dc.contributor.authorBiermer, M-
dc.date.accessioned2024-03-11T10:47:26Z-
dc.date.available2024-03-11T10:47:26Z-
dc.date.issued2022-04-01-
dc.identifier.citationAntiviral Therapy, 2022, v. 27, n. 3-
dc.identifier.issn1359-6535-
dc.identifier.urihttp://hdl.handle.net/10722/340810-
dc.description.abstract<p>Background JNJ-73763989 comprises two hepatitis B virus (HBV)-specific, liver-targeted N-galactosamine-conjugated short interfering RNA triggers, JNJ-73763976 and JNJ-73763924. JNJ-73763989 pharmacokinetics, safety and tolerability were assessed in two phase 1 studies: Japanese (NCT04002752), and non-Japanese healthy participants and chronic hepatitis B (CHB) patients also receiving the HBV capsid assembly modulator JNJ-56136379 and a nucleos(t)ide analogue (NA) (NCT03365947). <br></p><p>Methods Healthy participant cohorts were double-blind and randomized to receive a single subcutaneous JNJ-73763989 dose (non-Japanese participants, 35, 100, 200, 300 or 400 mg; Japanese participants, 25, 100 or 200 mg) or placebo. JNJ-73763976 and JNJ-73763924 plasma concentrations were assessed over 48 h. CHB patients received JNJ-73763989 200 mg every 4 weeks plus daily oral JNJ-56136379 250 mg and NA in an open-label fashion. Safety and tolerability were assessed through Day 28 (healthy participants) or Day 112 (patients). <br></p><p>Results Thirty non-Japanese (n = 4/dose; placebo, n = 10) and 24 Japanese healthy participants (n = 6/dose; placebo, n = 6) were randomized. JNJ-73763976 and JNJ-73763924 exposure generally increased in a dose-proportional manner. Mean plasma half-life was 4-9 h. No differences between pharmacokinetic parameters were apparent between non-Japanese and Japanese healthy participants. In the 12 CHB patients, mean JNJ-73763976, JNJ-73763924 and JNJ-56136379 plasma concentrations 2 h post-dose on Day 29 were 663, 269 and 14,718 ng/mL, respectively. In both studies, all adverse events were mild/moderate. <br></p><p>Conclusion JNJ-73763976 and JNJ-73763924 had short plasma half-lives and exposure generally increased in a dose-proportional manner; there were no pharmacokinetic differences between Japanese and non-Japanese healthy adults. JNJ-73763989 with or without JNJ-56136379 and NA was generally safe and well tolerated.</p>-
dc.languageeng-
dc.publisherSAGE Publications-
dc.relation.ispartofAntiviral Therapy-
dc.rightsThis work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.-
dc.titleJNJ-73763989 pharmacokinetics and safety: Liver-targeted siRNAs against hepatitis B virus, in Japanese and non-Japanese healthy adults, and combined with JNJ-56136379 and a nucleos(t)ide analogue in patients with chronic hepatitis B-
dc.typeArticle-
dc.identifier.doi10.1177/13596535221093856-
dc.identifier.pmid35695169-
dc.identifier.scopuseid_2-s2.0-85131814421-
dc.identifier.volume27-
dc.identifier.issue3-
dc.identifier.eissn2040-2058-
dc.identifier.isiWOS:000805019300001-
dc.publisher.placeLONDON-
dc.identifier.issnl1359-6535-

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