Phase IIa, randomised, double-blind study of GSK3389404 in patients with chronic hepatitis B on stable nucleos(t)ide therapy
- PMID: 35714812
- DOI: 10.1016/j.jhep.2022.05.031
Phase IIa, randomised, double-blind study of GSK3389404 in patients with chronic hepatitis B on stable nucleos(t)ide therapy
Abstract
Background & aims: Bepirovirsen, an antisense oligonucleotide targeting pregenomic and mRNA transcripts of HBV, has been conjugated to N-acetyl galactosamine (GSK3389404) to enhance hepatocyte delivery. This dose-finding study was the first to assess GSK3389404 for chronic HBV infection.
Methods: This phase IIa, randomised, double-blind, placebo-controlled, 2-part study was conducted in 22 centres in Asia (NCT03020745). Pharmacokinetic findings from Part 1 informed Part 2 dosing. In Part 2, patients with chronic hepatitis B on nucleos(t)ide analogue therapy were randomised 11:2 to GSK3389404 (30, 60, 120 mg weekly or 120 mg bi-weekly) or placebo until Day 85. Coprimary endpoints included HBsAg response (≥1.5 log10 IU/ml reduction from baseline) rate, safety and pharmacokinetics.
Results: Parts 1 and 2 included 12 (9 GSK3389404, 3 placebo) and 66 patients (56 GSK3389404, 10 placebo), respectively. In Part 2, one patient each in the 60 mg weekly, 120 mg weekly and 120 mg bi-weekly arms achieved a HBsAg response. HBsAg reductions were dose-dependent (Day 85: mean 0.34 [60 mg weekly] to 0.75 log10 IU/ml [120 mg weekly]) and occurred in hepatitis B e antigen-positive and -negative patients. No patient achieved HBsAg seroclearance. 43/56 (77%) GSK3389404- and 9/10 (90%) placebo-treated patients reported adverse events. No deaths were reported. Alanine aminotransferase flares (>2x upper limit of normal) occurred in 2 GSK3389404-treated patients (120 mg weekly, 120 mg bi-weekly); both were associated with decreased HBsAg, but neither was considered a responder. GSK3389404 plasma concentrations peaked 2-4 hours post dose; mean plasma half-life was 3-5 hours.
Conclusions: GSK3389404 showed an acceptable safety profile and target engagement, with dose-dependent reductions in HBsAg. However, no efficacious dosing regimen was identified.
Clinical trial number: NCT03020745.
Lay summary: Hepatitis B virus (HBV) can result in chronic HBV infection, which may ultimately lead to chronic liver disease, primary liver cancer and death; HBV proteins may prevent the immune system from successfully controlling the virus. GSK3389404 is an investigational agent that targets HBV RNA, resulting in reduced viral protein production. This study assessed the safety of GSK3389404 and its ability to reduce the viral proteins in patients with chronic HBV infection. GSK3389404 showed dose-dependent reduction in hepatitis B surface antigen, with an acceptable safety profile. While no clear optimal dose was identified, the findings from this study may help in the development of improved treatment options for patients with chronic HBV infections.
Keywords: GSK3389404; HBeAg; HBsAg; antisense oligonucleotide; chronic hepatitis B; pharmacokinetics; safety; virological response.
Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.
Conflict of interest statement
Conflict of interest MFY has been an advisor for and received consulting fees from AbbVie, Arbutus, Bristol-Myers Squibb (BMS), Dicerna, GSK, Gilead, Janssen, Merck Sharp & Dohme (MSD), Clear B Therapeutics, Springbank and Roche; and received grants from Assembly biosciences, Arrowhead, BMS, Fujirebio, Gilead, MSD, Springbank and Sysmex. JHeo, YS, QX, JJ, YK, JLT, WX, ZD, S-JP, RK, Y-OK and HJY report no conflicts of interest. HK has received teaching fees from MSD, Gilead, AbbVie, Eisei and Dainippon Sumitomo. FS has received teaching fees from AbbVie and Gilead. JLHou has received consulting fees from Aligos, Assembly, Gilead Sciences, Johnson & Johnson, Roche; lecturer fees from Gilead, Johnson & Johnson, Roche and grants from BMS. KC has received grants from AbbVie and Dainippon Sumitomo; and has received teaching fees from MSD, BMS and Gilead. MI received grants and teaching fees from BMS. S-GL has been an advisor for and received grants from Abbott Diagnostics, Gilead, Roche and MSD; and has been an advisor for Kaleido Bioscience, Arbutus, Assembly Grifols, Janssen, Fibronostics and GSK. YTanaka received grants from Gilead, Janssen and Chugai; and teaching fees from Gilead and Fujirebio, Inc. J-HY received grants from GSK, Dicerna Pharmaceuticals, Roche, AstraZeneca, Daewoong and Hanmi. MK was an advisor for Gilead and GSK; and received speaking fees from Gilead, AbbVie, MSD, Eisai, Chugai and Bayer. MEL has been an advisor for and received speaking fees for Abbott Diagnostics, Hi-Eisai, Menarini, Mylan and Roche. YTao, JC, RE, MD, SB-B, KH, FMC, MP and DT are employees of GSK and hold GSK stocks/options. Please refer to the accompanying ICMJE disclosure forms for further details.
Comment in
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Bepirovirsen/GSK3389404: Antisense or TLR9 agonists?J Hepatol. 2023 Mar;78(3):e107-e108. doi: 10.1016/j.jhep.2022.09.002. Epub 2022 Sep 15. J Hepatol. 2023. PMID: 36116715 No abstract available.
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Antisense oligonucleotides (ASOs) in chronic hepatitis B infection: Opportunities and challenging the orthodoxy.J Hepatol. 2022 Oct;77(4):906-908. doi: 10.1016/j.jhep.2022.08.020. J Hepatol. 2022. PMID: 36116828 No abstract available.
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Reply to: "Bepirovirsen/GSK3389404: Antisense or TLR9 agonists?".J Hepatol. 2023 Mar;78(3):e108-e110. doi: 10.1016/j.jhep.2022.11.023. Epub 2022 Nov 29. J Hepatol. 2023. PMID: 36460165 No abstract available.
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