Comparison of Pharmacokinetics of the GalNAc-Conjugated Antisense Oligonucleotide GSK3389404 in Participants with Chronic Hepatitis B Infection across the Asia-Pacific Region

Han, Kelong; Ito, Hiroshi; Elston, Robert C.; Cremer, Jennifer; Hood, Steve R.; Paff, Melanie; Theodore, Dickens

doi:10.1128/aac.00900-22

Cited by 2 publications

(2 citation statements)

References 20 publications

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“…By contrast, 46.7% (7/15) of the clinical trials targeted the liver, and among the total 15, 20% of liver studies (3/15) were designated Randomized Control Trials (RCT), as compared to only one RCT study (6.7%) among all other organ systems. Among the RCT studies targeting the liver, GalNAc (N-Acetyl galactosamine) ASO conjugation was used in patients with chronic hepatitis B [ 11 ]. This modification involves attaching GalNAc molecules to the oligonucleotide, typically via a linker, which then facilitates specific binding to cell surface receptors known as asialoglycoprotein receptors (ASGPRs) primarily located on hepatocytes in the liver [ 122 ].…”

Section: Asos In Recent Clinical Studiesmentioning

confidence: 99%

“…In one mouse study, the targeted delivery of ASOs to hepatocytes using Gal-Nac structures improved the potency of targeting human apolipoprotein C-III and human transthyretin (TTR) 10-fold in mice [ 123 ]. The authors showed that plasma pharmacokinetics, their primary endpoint analysis, was not significantly altered in their Asia-Pacific population after using GSK3389404, a GalNac-conjugated ASO [ 11 ]. Two additional clinical trials were undertaken utilizing GalNAc3-conjugated 2′-O-methoxyethyl (2′MOE) ASOs in hepatic applications, demonstrating the well-tolerated nature of ASOs with no discernible class effect observed across all doses administered when compared to placebo [ 16 , 17 ].…”

Section: Asos In Recent Clinical Studiesmentioning

confidence: 99%

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The Coming Age of Antisense Oligos for the Treatment of Hepatic Ischemia/Reperfusion (IRI) and Other Liver Disorders: Role of Oxidative Stress and Potential Antioxidant Effect

Yao,

Kasargod,

Chiu

et al. 2024

Antioxidants

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Imbalances in the redox state of the liver arise during metabolic processes, inflammatory injuries, and proliferative liver disorders. Acute exposure to intracellular reactive oxygen species (ROS) results from high levels of oxidative stress (OxS) that occur in response to hepatic ischemia/reperfusion injury (IRI) and metabolic diseases of the liver. Antisense oligonucleotides (ASOs) are an emerging class of gene expression modulators that target RNA molecules by Watson–Crick binding specificity, leading to RNA degradation, splicing modulation, and/or translation interference. Here, we review ASO inhibitor/activator strategies to modulate transcription and translation that control the expression of enzymes, transcription factors, and intracellular sensors of DNA damage. Several small-interfering RNA (siRNA) drugs with N-acetyl galactosamine moieties for the liver have recently been approved. Preclinical studies using short-activating RNAs (saRNAs), phosphorodiamidate morpholino oligomers (PMOs), and locked nucleic acids (LNAs) are at the forefront of proof-in-concept therapeutics. Future research targeting intracellular OxS-related pathways in the liver may help realize the promise of precision medicine, revolutionizing the customary approach to caring for and treating individuals afflicted with liver-specific conditions.

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Section: Asos In Recent Clinical Studiesmentioning

confidence: 99%

Section: Asos In Recent Clinical Studiesmentioning

confidence: 99%

The Coming Age of Antisense Oligos for the Treatment of Hepatic Ischemia/Reperfusion (IRI) and Other Liver Disorders: Role of Oxidative Stress and Potential Antioxidant Effect

Yao,

Kasargod,

Chiu

et al. 2024

Antioxidants

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A Randomized, Open-Label, Phase I, Single-Dose Study of Antisense Oligonucleotide, Vupanorsen, in Chinese Adults with Elevated Triglycerides

Wu,

Yu,

et al. 2024

Drugs R D

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Background Vupanorsen is a GalNAc 3 -conjugated antisense oligonucleotide targeting angiopoietin-like 3 (ANGPTL3) mRNA shown to reduce atherogenic lipoproteins in individuals with dyslipidemia. Objectives The aim of this study was to satisfy Chinese regulatory requirements and support ethnic sensitivity assessment by evaluating pharmacokinetics (PK), pharmacodynamics (PD), and safety of vupanorsen in healthy Chinese adults with elevated triglycerides (TG). Methods In this phase I, parallel-cohort, open-label study, 18 Chinese adults with elevated fasting TG (≥ 90 mg/dL) were randomized 1:1 to receive a single subcutaneous dose of vupanorsen 80 mg or 160 mg. PK parameters, PD markers (including ANGPTL3, TG, non–high-density lipoprotein cholesterol [non–HDL-C]), and safety were assessed. Results Absorption of vupanorsen was rapid (median time to maximum concentration [ T max ]: 2.0 h for both doses), followed by a multiphasic decline (mean terminal half-life 475.9 [80 mg] and 465.2 h [160 mg]). Exposure (area under curve [AUC] and maximum plasma concentration [ C max ]) generally increased in a greater than dose-proportional manner from 80 mg to 160 mg. Time-dependent reductions in ANGPTL3 and lipid parameters were observed. Mean percentage change from baseline for the 80-mg and 160-mg doses, respectively, were – 59.7% and – 69.5% for ANGPTL3, – 41.9% and – 52.5% for TG, and – 23.2% and – 25.4% for non–HDL-C. No serious or severe adverse events (AEs), deaths, or discontinuations due to AEs were reported. Three participants experienced treatment-related AEs; all were mild and resolved by end of study. Conclusions This study provided the first clinical vupanorsen data in China. In Chinese participants with elevated TG, PK and PD parameters were consistent with those reported previously in non-Chinese participants, including in Japanese individuals. No safety concerns were noted. Trial Registration ClinicalTrials.gov identifier: NCT04916795. Supplementary Information The online version contains supplementary material available at 10.1007/s40268-024-00467-5.

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Comparison of Pharmacokinetics of the GalNAc-Conjugated Antisense Oligonucleotide GSK3389404 in Participants with Chronic Hepatitis B Infection across the Asia-Pacific Region

Abstract: GSK3389404, an N-acetyl galactosamine-conjugated antisense oligonucleotide (ASO), was in clinical development for chronic hepatitis B (CHB) treatment. Few studies have examined ASOs in Asian participants.

Cited by 2 publications

References 20 publications

The Coming Age of Antisense Oligos for the Treatment of Hepatic Ischemia/Reperfusion (IRI) and Other Liver Disorders: Role of Oxidative Stress and Potential Antioxidant Effect

The Coming Age of Antisense Oligos for the Treatment of Hepatic Ischemia/Reperfusion (IRI) and Other Liver Disorders: Role of Oxidative Stress and Potential Antioxidant Effect

A Randomized, Open-Label, Phase I, Single-Dose Study of Antisense Oligonucleotide, Vupanorsen, in Chinese Adults with Elevated Triglycerides

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