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Conference Paper: Safety, tolerability, pharmacokinetics (PK), and antiviral activity of the capsid inhibitor (CI) AB-506 in healthy subjects (HS) and chronic hepatitis B (CHB) subjects

TitleSafety, tolerability, pharmacokinetics (PK), and antiviral activity of the capsid inhibitor (CI) AB-506 in healthy subjects (HS) and chronic hepatitis B (CHB) subjects
Authors
Issue Date2019
PublisherJohn Wiley & Sons, Inc. The Journal's web site is located at http://www.hepatology.org/
Citation
The 70th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD): The Liver Meeting 2019, Boston, MA, USA, 8-12 November 2019. In Hepatology, 2019, v. 70 n. 6, p. 1492A-1493A, abstract no. LP7 How to Cite?
AbstractBackground: AB-506 is an oral, class II, selective HBV CI for the treatment of CHB with activity against genotypes A-H and nucleos(t)ide resistant variants in vitro. The objectives of this ongoing first-in-human study are to evaluate the safety, tolerability, PK, and antiviral activity of AB-506 in HS and HBV-DNA+ CHB subjects. Methods: In Part 1, 2 cohorts of HS were randomized 6:2 to receive single ascending doses of AB-506 from 30mg to 1000mg or placebo (PBO). In Part 2, 1 cohort of 12 HS was randomized 10:2 to receive AB506 400mg or PBO once daily (QD) for 10 days. In Part 3, two cohorts of 12 non-cirrhotic, HBV DNA+ subjects were randomized 10:2 to receive AB-506 or PBO for 28 days at either 160mg or 400mg QD. Safety, tolerability, PK, immune markers, viral sequence and antiviral activity were assessed. Results: No serious adverse events (AEs) were observed in HS; most AEs were mild and considered unrelated to AB-506. No clinically significant abnormalities in laboratory tests, ECGs, or vital signs were noted. CHB subjects were aged 22-59 years and were mostly female, Asian and genotype C or D. HBV DNA and HBV RNA responses by dose and e-antigen status are shown in Table 1. There was no viral breakthrough on treatment. Baseline substitutions at positions Y38, I105, and T109 were noted in 5, 4 and 2 of the 24 subjects respectively; one subject with I105T had no response to treatment. There were no serious AEs; most AEs were mild. 6 subjects across both cohorts had transient, reversible ALT elevations (2 Grade 2, 4 Grade 4), with 2 subjects discontinuing study drug per protocol on Days 23 and 24. Bilirubin, albumin, and INR values remained normal in all subjects; none met drug-induced liver injury (DILI) criteria. All had declining HBV DNA levels of >2 log10 on treatment, and none had unusual AB-506 exposures. One subject has had persistent HBeAg (>2.6 log10) and HBsAg (>1.4 log10) declines from baseline 8 months-post flare and was the only subject with increases from baseline in interferon gamma (IFN-γ) and other T cell activation markers that preceded the ALT flare. The other Grade 4 flare subjects had accompanying increases in IP-10, but no changes in IFN-γ. A novel, longer duration (28 day) study of AB-506 in HS is ongoing. Conclusion: AB-506 was generally safe and well-tolerated and robust antiviral effects were observed in CHB subjects. The ALT flares observed in CHB subjects may be immune-mediated and may lead to beneficial declines in HBV markers.
DescriptionLate‐Breaking Poster Abstract - no. LP7
Persistent Identifierhttp://hdl.handle.net/10722/289899
ISSN
2023 Impact Factor: 12.9
2023 SCImago Journal Rankings: 5.011

 

DC FieldValueLanguage
dc.contributor.authorYuen, RMF-
dc.contributor.authorBerliba, E-
dc.contributor.authorSukeepaisarnjaroen, W-
dc.contributor.authorAhn, SH-
dc.contributor.authorTanwandee, T-
dc.contributor.authorLim, Y-S-
dc.contributor.authorKim, YJ-
dc.contributor.authorPoovorawan, K-
dc.contributor.authorTangkijvanich, P-
dc.contributor.authorChan, HLY-
dc.contributor.authorEley, T-
dc.contributor.authorBrown, J-
dc.contributor.authorMoore, C-
dc.contributor.authorLee, ACH-
dc.contributor.authorKim, J-
dc.contributor.authorThi, EP-
dc.contributor.authorMani, N-
dc.contributor.authorRijnbrand, R-
dc.contributor.authorCole, A-
dc.contributor.authorSofia, MJ-
dc.contributor.authorPicchio, GR-
dc.contributor.authorSims, K-
dc.contributor.authorGane, EJ-
dc.date.accessioned2020-10-22T08:19:04Z-
dc.date.available2020-10-22T08:19:04Z-
dc.date.issued2019-
dc.identifier.citationThe 70th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD): The Liver Meeting 2019, Boston, MA, USA, 8-12 November 2019. In Hepatology, 2019, v. 70 n. 6, p. 1492A-1493A, abstract no. LP7-
dc.identifier.issn0270-9139-
dc.identifier.urihttp://hdl.handle.net/10722/289899-
dc.descriptionLate‐Breaking Poster Abstract - no. LP7-
dc.description.abstractBackground: AB-506 is an oral, class II, selective HBV CI for the treatment of CHB with activity against genotypes A-H and nucleos(t)ide resistant variants in vitro. The objectives of this ongoing first-in-human study are to evaluate the safety, tolerability, PK, and antiviral activity of AB-506 in HS and HBV-DNA+ CHB subjects. Methods: In Part 1, 2 cohorts of HS were randomized 6:2 to receive single ascending doses of AB-506 from 30mg to 1000mg or placebo (PBO). In Part 2, 1 cohort of 12 HS was randomized 10:2 to receive AB506 400mg or PBO once daily (QD) for 10 days. In Part 3, two cohorts of 12 non-cirrhotic, HBV DNA+ subjects were randomized 10:2 to receive AB-506 or PBO for 28 days at either 160mg or 400mg QD. Safety, tolerability, PK, immune markers, viral sequence and antiviral activity were assessed. Results: No serious adverse events (AEs) were observed in HS; most AEs were mild and considered unrelated to AB-506. No clinically significant abnormalities in laboratory tests, ECGs, or vital signs were noted. CHB subjects were aged 22-59 years and were mostly female, Asian and genotype C or D. HBV DNA and HBV RNA responses by dose and e-antigen status are shown in Table 1. There was no viral breakthrough on treatment. Baseline substitutions at positions Y38, I105, and T109 were noted in 5, 4 and 2 of the 24 subjects respectively; one subject with I105T had no response to treatment. There were no serious AEs; most AEs were mild. 6 subjects across both cohorts had transient, reversible ALT elevations (2 Grade 2, 4 Grade 4), with 2 subjects discontinuing study drug per protocol on Days 23 and 24. Bilirubin, albumin, and INR values remained normal in all subjects; none met drug-induced liver injury (DILI) criteria. All had declining HBV DNA levels of >2 log10 on treatment, and none had unusual AB-506 exposures. One subject has had persistent HBeAg (>2.6 log10) and HBsAg (>1.4 log10) declines from baseline 8 months-post flare and was the only subject with increases from baseline in interferon gamma (IFN-γ) and other T cell activation markers that preceded the ALT flare. The other Grade 4 flare subjects had accompanying increases in IP-10, but no changes in IFN-γ. A novel, longer duration (28 day) study of AB-506 in HS is ongoing. Conclusion: AB-506 was generally safe and well-tolerated and robust antiviral effects were observed in CHB subjects. The ALT flares observed in CHB subjects may be immune-mediated and may lead to beneficial declines in HBV markers.-
dc.languageeng-
dc.publisherJohn Wiley & Sons, Inc. The Journal's web site is located at http://www.hepatology.org/-
dc.relation.ispartofHepatology-
dc.relation.ispartofThe 70th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD): The Liver Meeting 2019-
dc.titleSafety, tolerability, pharmacokinetics (PK), and antiviral activity of the capsid inhibitor (CI) AB-506 in healthy subjects (HS) and chronic hepatitis B (CHB) subjects-
dc.typeConference_Paper-
dc.identifier.emailYuen, RMF: mfyuen@hku.hk-
dc.identifier.authorityYuen, RMF=rp00479-
dc.description.natureabstract-
dc.identifier.hkuros317241-
dc.identifier.volume70-
dc.identifier.issue6-
dc.identifier.spage1492A-
dc.identifier.epage1493A-
dc.publisher.placeUnited States-
dc.identifier.partofdoi10.1002/hep.31033-
dc.identifier.issnl0270-9139-

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