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Article: Safety, pharmacokinetics, and antiviral activity of the capsid inhibitor AB-506 from Phase 1 studies in healthy subjects and those with hepatitis B

TitleSafety, pharmacokinetics, and antiviral activity of the capsid inhibitor AB-506 from Phase 1 studies in healthy subjects and those with hepatitis B
Authors
Issue Date4-Oct-2022
PublisherLippincott, Williams & Wilkins
Citation
Hepatology Communications, 2022, v. 6, n. 12, p. 3457-3472 How to Cite?
Abstract

AB-506 is a potent, pan-genotypic small molecule capsid inhibitor that inhibits hepatitis B virus (HBV) pregenomic RNA encapsidation. We assessed the safety, pharmacokinetics, and antiviral activity of AB-506 in two randomized, double-blinded Phase 1 studies in healthy subjects (HS) and subjects with chronic HBV infection (CHB). Single ascending and multiple doses of AB-506 or placebo (30-1000 mg or 400 mg daily for 10 days) were assessed in HS. AB-506 or placebo was assessed at either 160 mg or 400 mg daily for 28 days in subjects with CHB. A second follow-up study examined AB-506 or placebo at 400 mg daily for 28 days in 14 Caucasian and 14 East-Asian HS. Twenty-eight days of AB-506 at 160 mg and 400 mg produced mean HBV-DNA declines from baseline of 2.1 log(10) IU/ml and 2.8 log(10) IU/ml, respectively. Four subjects with CHB (all Asian) had Grade 4 alanine aminotransferase (ALT) elevations (2 at each dose) as HBV DNA was declining; three events led to treatment discontinuation. In the second follow-up study, 2 Asian HS had serious transaminitis events leading to treatment and study termination. No subjects had bilirubin elevations or signs of hepatic decompensation. Conclusion: AB-506 demonstrated mean HBV-DNA declines of >2 log(10); however, transient but severe ALT flares were observed in 4 Asian subjects with CHB. In the follow-up study in HS, 2 additional Asian HS had Grade 4 flares, suggesting that AB-506 hepatotoxicity contributed to the ALT elevations. The AB-506 development program was terminated because of these findings.


Persistent Identifierhttp://hdl.handle.net/10722/340811
ISSN
2023 Impact Factor: 5.6
2023 SCImago Journal Rankings: 2.217
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorYuen, MF-
dc.contributor.authorBerliba, E-
dc.contributor.authorSukeepaisarnjaroen, W-
dc.contributor.authorAhn, SH-
dc.contributor.authorTanwandee, T-
dc.contributor.authorLim, YS-
dc.contributor.authorKim, YJ-
dc.contributor.authorPoovorawan, K-
dc.contributor.authorTangkijvanich, P-
dc.contributor.authorSchwabe, C-
dc.contributor.authorEley, T-
dc.contributor.authorBrown, J-
dc.contributor.authorLee, ACH-
dc.contributor.authorThi, EP-
dc.contributor.authorParatala, B-
dc.contributor.authorMani, N-
dc.contributor.authorSofia, MJ-
dc.contributor.authorPicchio, G-
dc.contributor.authorSims, KD-
dc.contributor.authorGane, EJ-
dc.date.accessioned2024-03-11T10:47:27Z-
dc.date.available2024-03-11T10:47:27Z-
dc.date.issued2022-10-04-
dc.identifier.citationHepatology Communications, 2022, v. 6, n. 12, p. 3457-3472-
dc.identifier.issn2471-254X-
dc.identifier.urihttp://hdl.handle.net/10722/340811-
dc.description.abstract<p>AB-506 is a potent, pan-genotypic small molecule capsid inhibitor that inhibits hepatitis B virus (HBV) pregenomic RNA encapsidation. We assessed the safety, pharmacokinetics, and antiviral activity of AB-506 in two randomized, double-blinded Phase 1 studies in healthy subjects (HS) and subjects with chronic HBV infection (CHB). Single ascending and multiple doses of AB-506 or placebo (30-1000 mg or 400 mg daily for 10 days) were assessed in HS. AB-506 or placebo was assessed at either 160 mg or 400 mg daily for 28 days in subjects with CHB. A second follow-up study examined AB-506 or placebo at 400 mg daily for 28 days in 14 Caucasian and 14 East-Asian HS. Twenty-eight days of AB-506 at 160 mg and 400 mg produced mean HBV-DNA declines from baseline of 2.1 log(10) IU/ml and 2.8 log(10) IU/ml, respectively. Four subjects with CHB (all Asian) had Grade 4 alanine aminotransferase (ALT) elevations (2 at each dose) as HBV DNA was declining; three events led to treatment discontinuation. In the second follow-up study, 2 Asian HS had serious transaminitis events leading to treatment and study termination. No subjects had bilirubin elevations or signs of hepatic decompensation. Conclusion: AB-506 demonstrated mean HBV-DNA declines of >2 log(10); however, transient but severe ALT flares were observed in 4 Asian subjects with CHB. In the follow-up study in HS, 2 additional Asian HS had Grade 4 flares, suggesting that AB-506 hepatotoxicity contributed to the ALT elevations. The AB-506 development program was terminated because of these findings.</p>-
dc.languageeng-
dc.publisherLippincott, Williams & Wilkins-
dc.relation.ispartofHepatology Communications-
dc.rightsThis work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.-
dc.titleSafety, pharmacokinetics, and antiviral activity of the capsid inhibitor AB-506 from Phase 1 studies in healthy subjects and those with hepatitis B-
dc.typeArticle-
dc.identifier.doi10.1002/hep4.2095-
dc.identifier.pmid36194181-
dc.identifier.scopuseid_2-s2.0-85139171097-
dc.identifier.volume6-
dc.identifier.issue12-
dc.identifier.spage3457-
dc.identifier.epage3472-
dc.identifier.eissn2471-254X-
dc.identifier.isiWOS:000863690700001-
dc.publisher.placeCHICHESTER-
dc.identifier.issnl2471-254X-

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