In vivo reduction of hepatitis B virus antigenemia and viremia by antisense oligonucleotides

Billioud, Gaëtan; Kruse, Robert L.; Carrillo, Melissa; Whitten-Bauer, Christina; Gao, Dacao; Kim, Aneeza; Chen, Leon; McCaleb, Michael L.; Crosby, Jeff; Hamatake, Robert; Hong, Zhi; Garaigorta, Urtzi; Swayze, Eric E.; Bissig, Karl‐Dimiter; Wieland, Stefan

doi:10.1016/j.jhep.2015.11.032

Cited by 46 publications

(46 citation statements)

References 54 publications

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“…20 Previous attempts to reduce both intracellular and circulating HBsAg have been limited to injectable RNA therapeutics targeting various regions of the intracellular HBV transcripts that in turn leads to the inhibition of viral replication and production of HBsAg. 28,29 In this communication, we report the discovery and characterization of a novel small molecule viral gene expression inhibitor. To the best of our knowledge, RG7834 is the first oral viral expression inhibitor with a high degree of selectivity towards HBV.…”

Section: Discussionmentioning

confidence: 99%

A novel orally available small molecule that inhibits hepatitis B virus expression

Mueller

Wildum

Luangsay

et al. 2018

Journal of Hepatology

121

116

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We discovered a novel small molecule viral expression inhibitor that is highly selective for HBV and unlike current therapy inhibits the expression of viral proteins by specifically reducing HBV mRNAs. RG7834 can therefore potentially provide anti-HBV benefits and increase HBV cure rates, by direct reduction of viral agents needed to complete the viral life cycle, as well as a reduction of viral agents involved in evasion of the host immune responses.

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Section: Discussionmentioning

confidence: 99%

A novel orally available small molecule that inhibits hepatitis B virus expression

Mueller

Wildum

Luangsay

et al. 2018

Journal of Hepatology

121

116

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“…ASOs are small, single‐stranded nucleic acid sequences that bind with high selectivity to their target RNAs, triggering degradation via an RNase H–dependent pathway (Figure ). They have shown potent suppression of HBV replication . GSK3389404 consists of an ASO targeting the HBV mRNA conjugated via a linker to a trimer of N ‐acetylgalactosamine (GalNAc) moieties that targets delivery to hepatocytes through interaction with the predominantly hepatocyte‐expressed asialoglycoprotein receptor .…”

Section: Rationale/scientific Objectivesmentioning

confidence: 99%

“…They have shown potent suppression of HBV replication. 14 GSK3389404 consists of an ASO targeting the HBV mRNA conjugated via a linker to a trimer of N-acetylgalactosamine (GalNAc) moieties that targets delivery to hepatocytes through interaction with the predominantly hepatocyte-expressed asialoglycoprotein receptor. 15 GSK3389404 can be considered a prodrug because its metabolite GSK3228836 (the free ASO without the link and GalNAc) is the active drug ( Figure 1).…”

mentioning

confidence: 99%

A Randomized, Double‐Blind, Placebo‐Controlled, First‐Time‐in‐Human Study to Assess the Safety, Tolerability, and Pharmacokinetics of Single and Multiple Ascending Doses of GSK3389404 in Healthy Subjects

Han

Cremer

Elston

et al. 2019

Clinical Pharm in Drug Dev

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GSK3389404 is a liver‐targeted antisense oligonucleotide that inhibits synthesis of hepatitis B surface antigen and all other hepatitis B virus proteins. This first‐in‐human, randomized, double‐blind, phase 1 study assessed the safety and pharmacokinetics of GSK3389404 administered subcutaneously (SC) in healthy subjects. Four single ascending‐dose cohorts (10 mg, 30 mg, 60 mg, and 120 mg) and 3 multiple ascending‐dose cohorts (30 mg, 60 mg, and 120 mg once weekly for 4 weeks) each comprised 6 subjects randomized to GSK3389404 and 2 subjects randomized to placebo. There were no serious adverse events (AEs) or withdrawals due to AEs. The safety profile did not worsen with repeated dosing. The most frequent treatment‐related AEs were injection site reactions (19.0% [n = 8/42], frequency unrelated to dose levels); all were mild (Grade 1) and resolved without dose modification or discontinuation. GSK3389404 administered subcutaneously was readily absorbed with a time to maximum plasma concentration (Tmax) of 1–4 hours and an elimination half‐life of 3–6 hours in plasma. Plasma area under the concentration‐time curve (AUC) and maximum observed concentration (Cmax) were dose‐proportional. Dose‐normalized plasma AUC from time 0 to infinity averaged 69.9 ng·h/(mL·mg dose) across cohorts, and Cmax 9.5 ng/(mL·mg dose). Pharmacokinetic profiles and parameters were comparable between single and multiple dosing. No accumulation was observed with once‐weekly dosing. The metabolite was undetectable in urine and plasma. In the pooled urine, GSK3389404 was estimated to account for <0.1% of the total dose. In summary, GSK3389404 dosing has been tested up to 120 mg for 4 weeks with an acceptable safety and pharmacokinetic profile, supporting further clinical investigation in patients with chronic hepatitis B.

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“…RNAi can inhibit all steps of HBV replication, and ARC520 has been tested in a phase 2 trial in patients with chronic hepatitis B [95] . In contrast, a single injection of ASO, consisting of livertargeted peptides, into a mouse model of chronic HBV infection was shown to reduce HBVRNA, proteins and HBVDNA for a long time, suggesting that ASO may become a promising treatment in patients with chronic HBV [98] . Furthermore, disubstituted sulfona mide was shown to selectively inhibit the formation of cccDNA [99] .…”

Section: Inhibition Of Hbv Replicationmentioning

confidence: 99%

New horizon for radical cure of chronic hepatitis B virus infection

Tajiri¹,

Shimizu²

2016

WJH

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About 250 to 350 million people worldwide are chronically infected with hepatitis B virus (HBV), and about 700000 patients per year die of HBV-related cirrhosis or hepatocellular carcinoma (HCC). Several anti-viral agents, such as interferon and nucleos(t)ide analogues (NAs), have been used to treat this disease. NAs especially have been shown to strongly suppress HBV replication, slowing the progression to cirrhosis and the development of HCC. However, reactivation of HBV replication often occurs after cessation of treatment, because NAs alone cannot completely remove covalentlyclosed circular DNA (cccDNA), the template of HBV replication, from the nuclei of hepatocytes. Anti-HBV immune responses, in conjunction with interferon-γ and tumor necrosis factor-α, were found to eliminate cccDNA, but complete eradication of cccDNA by immune response alone is difficult, as shown in patients who recover from acute HBV infection but often show long-term persistence of small amounts of HBV-DNA in the blood. Several new drugs interfering with the life cycle of HBV in hepatocytes have been developed, with drugs targeting cccDNA theoretically the most effective for radical cure of chronic HBV infection. However, the safety of these drugs should be extensively examined before application to patients, and combinations of several approaches may be necessary for radical cure of chronic HBV infection.

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In vivo reduction of hepatitis B virus antigenemia and viremia by antisense oligonucleotides

Cited by 46 publications

References 54 publications

A novel orally available small molecule that inhibits hepatitis B virus expression

A novel orally available small molecule that inhibits hepatitis B virus expression

A Randomized, Double‐Blind, Placebo‐Controlled, First‐Time‐in‐Human Study to Assess the Safety, Tolerability, and Pharmacokinetics of Single and Multiple Ascending Doses of GSK3389404 in Healthy Subjects

New horizon for radical cure of chronic hepatitis B virus infection

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