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Conference Paper: RO7062931 antisense oligonucleotide phase 1 study demonstrates target engagement in patients with chronic hepatitis B on established nucleos(t)ide therapy

TitleRO7062931 antisense oligonucleotide phase 1 study demonstrates target engagement in patients with chronic hepatitis B on established nucleos(t)ide therapy
Authors
Issue Date2020
PublisherElsevier BV. The Journal's web site is located at http://www.elsevier.com/locate/jhep
Citation
Digital International Liver Congress (Digital ILC 2020), 27-29 August 2020. In Journal of Hepatology, 2020, v. 73 n. Suppl. 1, p. S51 How to Cite?
AbstractBackground and Aims: RO7062931 is a N-acetylgalactosamine (GalNAc) conjugated single-stranded oligonucleotide (SSO) with locked nucleic acid (LNA) that results in RNAse H mediated degradation of HBV transcripts. We previously reported (AASLD 2019) results from Part 1 of the Phase 1 study (NCT03505190) where single doses of RO7062931 up to 4 mg/kg were safe and well tolerated in healthy volunteers (HVs). Herein we present the results from Study Part 2 of multiple dose RO7062931 treatment regimens in patients with chronic hepatitis B (CHB). Method: 59 CHB patients on established nucleos(t)ide therapy were randomized 3:1 to RO7062931 (0.5, 1.5, 3, or 4 mg/kg) or placebo across six 4-week treatment regimens. Eligible subjects were BeAgpositive or negative at screening with serum levels of HBsAg ≥1,000 IU/mL, HBV DNA ≤90 IU/mL and ALT ≤1.5× upper limit of normal (ULN). Depending on the dosing frequency (monthly [QM], bi-weekly [Q2W] or weekly [QW]), subjects received between 2–5 subcutaneous RO7062931 doses in total. Subsequently, all subjects entered a 12-week post-treatment follow-up. Results: Majority of subjects were male (88%), Asian (90%), with a mean (range) age of 45 (25 to 65) years. At baseline, 58% were HBeAgnegative, 86% had ALT ≤ULN, and the mean HBsAg level was 5,172 (952 to 27,620) IU/mL. No serious AEs, severe AEs, or withdrawals due to AEs were reported. Injection site reactions were reported for 7 (12%) subjects, of which 5 and 2 were of mild and moderate intensity, respectively. Laboratory safety parameters were unremarkable except for 2 subjects (3 mg/kg QW group) with transient ALT >3× ULN elevations that were associated with declining HBsAg levels. RO7062931 treatment was associated with dose-dependent reductions in HBsAg. At Day 29, mean (SD) change in HBsAg IU/mL levels were −0.03 (0.05) in the placebo group; −0.03 (0.04), −0.15 (0.21) and −0.17 (0.07) in the 0.5, 1.5 and 3 mg/kg QM groups; −0.23 (0.17) and −0.38 (0.25) in the 3 mg/kg Q2W and QW groups; and −0.14 (0.28) in the 4 mg/kg QW group. Nadir HBsAg change from baseline data with mean ± 95CI are shown in below Figure, which were similar regardless of baseline HBeAg status. A rebound in HBsAg levels was typically evident by 2–3 weeks post-treatment, which returned to baseline levels by 12-weeks post-treatment. Pharmacokinetic data in CHB patients was consistent to that previously reported for HVs. Conclusion: RO7062931 administered over 4-weeks, at doses of up to 4 mg/kg, in CHB patients is safe, well tolerated, and demonstrates target engagement by antiviral activity.
DescriptionOral presentation - Session: Hepatitis B and D – Drug Development - no. AS069
Persistent Identifierhttp://hdl.handle.net/10722/290212
ISSN
2020 Impact Factor: 25.083
2015 SCImago Journal Rankings: 4.570

 

DC FieldValueLanguage
dc.contributor.authorYuen, RMF-
dc.contributor.authorGane, E-
dc.contributor.authorKim, DJ-
dc.contributor.authorChan, H-
dc.contributor.authorSurujbally, B-
dc.contributor.authorPavlovic, V-
dc.contributor.authorTriyatni, M-
dc.contributor.authorGrippo, J-
dc.contributor.authorKim, HJ-
dc.contributor.authorLeerapun, A-
dc.contributor.authorLim, TH-
dc.contributor.authorLim, YS-
dc.contributor.authorTanwandee, T-
dc.contributor.authorKim, W-
dc.contributor.authorCheng, W-
dc.contributor.authorHu, TH-
dc.contributor.authorWat, C-
dc.date.accessioned2020-10-22T08:23:36Z-
dc.date.available2020-10-22T08:23:36Z-
dc.date.issued2020-
dc.identifier.citationDigital International Liver Congress (Digital ILC 2020), 27-29 August 2020. In Journal of Hepatology, 2020, v. 73 n. Suppl. 1, p. S51-
dc.identifier.issn0168-8278-
dc.identifier.urihttp://hdl.handle.net/10722/290212-
dc.descriptionOral presentation - Session: Hepatitis B and D – Drug Development - no. AS069-
dc.description.abstractBackground and Aims: RO7062931 is a N-acetylgalactosamine (GalNAc) conjugated single-stranded oligonucleotide (SSO) with locked nucleic acid (LNA) that results in RNAse H mediated degradation of HBV transcripts. We previously reported (AASLD 2019) results from Part 1 of the Phase 1 study (NCT03505190) where single doses of RO7062931 up to 4 mg/kg were safe and well tolerated in healthy volunteers (HVs). Herein we present the results from Study Part 2 of multiple dose RO7062931 treatment regimens in patients with chronic hepatitis B (CHB). Method: 59 CHB patients on established nucleos(t)ide therapy were randomized 3:1 to RO7062931 (0.5, 1.5, 3, or 4 mg/kg) or placebo across six 4-week treatment regimens. Eligible subjects were BeAgpositive or negative at screening with serum levels of HBsAg ≥1,000 IU/mL, HBV DNA ≤90 IU/mL and ALT ≤1.5× upper limit of normal (ULN). Depending on the dosing frequency (monthly [QM], bi-weekly [Q2W] or weekly [QW]), subjects received between 2–5 subcutaneous RO7062931 doses in total. Subsequently, all subjects entered a 12-week post-treatment follow-up. Results: Majority of subjects were male (88%), Asian (90%), with a mean (range) age of 45 (25 to 65) years. At baseline, 58% were HBeAgnegative, 86% had ALT ≤ULN, and the mean HBsAg level was 5,172 (952 to 27,620) IU/mL. No serious AEs, severe AEs, or withdrawals due to AEs were reported. Injection site reactions were reported for 7 (12%) subjects, of which 5 and 2 were of mild and moderate intensity, respectively. Laboratory safety parameters were unremarkable except for 2 subjects (3 mg/kg QW group) with transient ALT >3× ULN elevations that were associated with declining HBsAg levels. RO7062931 treatment was associated with dose-dependent reductions in HBsAg. At Day 29, mean (SD) change in HBsAg IU/mL levels were −0.03 (0.05) in the placebo group; −0.03 (0.04), −0.15 (0.21) and −0.17 (0.07) in the 0.5, 1.5 and 3 mg/kg QM groups; −0.23 (0.17) and −0.38 (0.25) in the 3 mg/kg Q2W and QW groups; and −0.14 (0.28) in the 4 mg/kg QW group. Nadir HBsAg change from baseline data with mean ± 95CI are shown in below Figure, which were similar regardless of baseline HBeAg status. A rebound in HBsAg levels was typically evident by 2–3 weeks post-treatment, which returned to baseline levels by 12-weeks post-treatment. Pharmacokinetic data in CHB patients was consistent to that previously reported for HVs. Conclusion: RO7062931 administered over 4-weeks, at doses of up to 4 mg/kg, in CHB patients is safe, well tolerated, and demonstrates target engagement by antiviral activity.-
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.ispartofDigital International Liver Congress (Digital ILC 2020)-
dc.titleRO7062931 antisense oligonucleotide phase 1 study demonstrates target engagement in patients with chronic hepatitis B on established nucleos(t)ide therapy-
dc.typeConference_Paper-
dc.identifier.emailYuen, RMF: mfyuen@hku.hk-
dc.identifier.authorityYuen, RMF=rp00479-
dc.description.natureabstract-
dc.identifier.doi10.1016/S0168-8278(20)30648-6-
dc.identifier.hkuros315868-
dc.identifier.volume73-
dc.identifier.issueSuppl. 1-
dc.identifier.spageS51-
dc.identifier.epageS51-
dc.publisher.placeNetherlands-
dc.identifier.issnl0168-8278-

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