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Conference Paper: Inhibition of hepatitis B surface antigen by RNA interference therapeutic AB-729 in chronic hepatitis B patients correlates with suppression of all HBsAg isoforms and HBV RNA

TitleInhibition of hepatitis B surface antigen by RNA interference therapeutic AB-729 in chronic hepatitis B patients correlates with suppression of all HBsAg isoforms and HBV RNA
Authors
Issue Date2021
PublisherElsevier BV. The Journal's web site is located at http://www.elsevier.com/locate/jhep
Citation
The International Liver Congress 2021 (ILC 2021): Beating Liver Disease Together, Virtual Conference, 23-26 June 2021. In Journal of Hepatology, 2021, v. 75 n. Suppl. 2, p. S760-S761 How to Cite?
AbstractBackground and aims: Therapeutic strategies to develop a cure for chronic hepatitis B (CHB) must address the high antigenemia that contributes to viral persistence and HBV immune tolerance. AB-729 is an N-Acetylgalactosamine-conjugated short interfering RNA (siRNA) therapeutic, currently in clinical development in combination with other agents for treatment of CHB. AB-729, a single trigger agent, blocks all HBV RNA transcripts including HBx, resulting in suppression of viral replication and all HBV antigens including hepatitis B surface antigen (HBsAg). Here we report the effect of AB-729 on novel HBV markers in nucleos (t)ide suppressed (HBV DNA-) or untreated (HBV DNA+) CHB subjects receiving single or repeat doses of AB-729. Method: Longitudinal plasma samples from CHB subjects receiving a single dose (60–180 mg, n = 22) or undergoing repeat dosing (60 mg every 4 weeks for 6 doses, n = 7 or 60 mg every 8 weeks for 3 doses, n = 7) were assessed for total HBV RNA and pregenomic RNA (pgRNA) by quantitative reverse-transcription polymerase chain reaction, and HBsAg isoforms and HBsAg immune complex by chemiluminescent immunoassays (Abbott Diagnostics). Results: Following AB-729 single or repeat dosing, total HBsAg declines correlated significantly with reductions in total HBV RNA, pgRNA, Large (LHBs) and Middle (MHBs) HBsAg isoforms in HBV DNA- or HBV DNA+ subjects (p < 0.0001, two-tailed Pearson correlation). In HBV DNA- or HBV DNA+ “slow responders” (<0.3 log10 HBsAg decline 4 weeks after AB-729 dose initiation), 0.46 to 1.44 log10 reduction in total HBV RNA or pgRNA was observed in 4/5 subjects which was comparable to subjects with early HBsAg decline (0.02 to 0.99 log10 HBV RNA decrease). Similar suppression of LHBs or MHBs was noted in all subjects undergoing AB-729 single or repeat dosing. No changes in immune complex levels were observed up to 24 weeks after AB-729 dosing initiation. Conclusion: To our knowledge, this is the first assessment of HBsAg isoforms and immune complex in CHB subjects administered single or repeat doses of an HBV-targeting GalNAc-siRNA. Total HBsAg decline correlated with decreases in circulating HBV RNA species and both HBsAg isoforms. Early reduction in HBV RNA was observed in both “slow responders” who showed delayed HBsAg decline as well as in subjects who exhibited early HBsAg inhibition, confirming rapid target engagement by AB-729 in all CHB subjects. The significance of fast vs. slow HBsAg decline is currently being explored.
DescriptionLate breaker posters: Poster presentation: PO-2822
Persistent Identifierhttp://hdl.handle.net/10722/305522
ISSN
2023 Impact Factor: 26.8
2023 SCImago Journal Rankings: 9.857

 

DC FieldValueLanguage
dc.contributor.authorThi, EP-
dc.contributor.authorYuen, RMF-
dc.contributor.authorGane, E-
dc.contributor.authorSevinsky, H-
dc.contributor.authorSims, K-
dc.contributor.authorAnderson, M-
dc.contributor.authorLam, AM-
dc.contributor.authorSofia, MJ-
dc.contributor.authorCloherty, G-
dc.contributor.authorPicchio, G-
dc.date.accessioned2021-10-20T10:10:36Z-
dc.date.available2021-10-20T10:10:36Z-
dc.date.issued2021-
dc.identifier.citationThe International Liver Congress 2021 (ILC 2021): Beating Liver Disease Together, Virtual Conference, 23-26 June 2021. In Journal of Hepatology, 2021, v. 75 n. Suppl. 2, p. S760-S761-
dc.identifier.issn0168-8278-
dc.identifier.urihttp://hdl.handle.net/10722/305522-
dc.descriptionLate breaker posters: Poster presentation: PO-2822-
dc.description.abstractBackground and aims: Therapeutic strategies to develop a cure for chronic hepatitis B (CHB) must address the high antigenemia that contributes to viral persistence and HBV immune tolerance. AB-729 is an N-Acetylgalactosamine-conjugated short interfering RNA (siRNA) therapeutic, currently in clinical development in combination with other agents for treatment of CHB. AB-729, a single trigger agent, blocks all HBV RNA transcripts including HBx, resulting in suppression of viral replication and all HBV antigens including hepatitis B surface antigen (HBsAg). Here we report the effect of AB-729 on novel HBV markers in nucleos (t)ide suppressed (HBV DNA-) or untreated (HBV DNA+) CHB subjects receiving single or repeat doses of AB-729. Method: Longitudinal plasma samples from CHB subjects receiving a single dose (60–180 mg, n = 22) or undergoing repeat dosing (60 mg every 4 weeks for 6 doses, n = 7 or 60 mg every 8 weeks for 3 doses, n = 7) were assessed for total HBV RNA and pregenomic RNA (pgRNA) by quantitative reverse-transcription polymerase chain reaction, and HBsAg isoforms and HBsAg immune complex by chemiluminescent immunoassays (Abbott Diagnostics). Results: Following AB-729 single or repeat dosing, total HBsAg declines correlated significantly with reductions in total HBV RNA, pgRNA, Large (LHBs) and Middle (MHBs) HBsAg isoforms in HBV DNA- or HBV DNA+ subjects (p < 0.0001, two-tailed Pearson correlation). In HBV DNA- or HBV DNA+ “slow responders” (<0.3 log10 HBsAg decline 4 weeks after AB-729 dose initiation), 0.46 to 1.44 log10 reduction in total HBV RNA or pgRNA was observed in 4/5 subjects which was comparable to subjects with early HBsAg decline (0.02 to 0.99 log10 HBV RNA decrease). Similar suppression of LHBs or MHBs was noted in all subjects undergoing AB-729 single or repeat dosing. No changes in immune complex levels were observed up to 24 weeks after AB-729 dosing initiation. Conclusion: To our knowledge, this is the first assessment of HBsAg isoforms and immune complex in CHB subjects administered single or repeat doses of an HBV-targeting GalNAc-siRNA. Total HBsAg decline correlated with decreases in circulating HBV RNA species and both HBsAg isoforms. Early reduction in HBV RNA was observed in both “slow responders” who showed delayed HBsAg decline as well as in subjects who exhibited early HBsAg inhibition, confirming rapid target engagement by AB-729 in all CHB subjects. The significance of fast vs. slow HBsAg decline is currently being explored.-
dc.languageeng-
dc.publisherElsevier BV. The Journal's web site is located at http://www.elsevier.com/locate/jhep-
dc.relation.ispartofJournal of Hepatology-
dc.relation.ispartofThe International Liver Congress 2021 (ILC 2021)-
dc.titleInhibition of hepatitis B surface antigen by RNA interference therapeutic AB-729 in chronic hepatitis B patients correlates with suppression of all HBsAg isoforms and HBV RNA-
dc.typeConference_Paper-
dc.identifier.emailYuen, RMF: mfyuen@hku.hk-
dc.identifier.authorityYuen, RMF=rp00479-
dc.description.natureabstract-
dc.identifier.hkuros326619-
dc.identifier.volume75-
dc.identifier.issueSuppl. 2-
dc.identifier.spageS760-
dc.identifier.epageS761-
dc.publisher.placeNetherlands-
dc.identifier.partofdoi10.1016/S0168-8278(21)01843-2-

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