Xiaojie Wu, Jicheng Yu, Beikang Ge, Jeffrey Wang, Xiaoran Han, Chunye Zhang, Xiaomeng Mao, Hindu Kalluru, Candace Bramson, Steven G Terra, Jing Liu
{"title":"反义寡核苷酸 Vupanorsen 在甘油三酯升高的中国成人中的随机、开放标签、I 期、单剂量研究。","authors":"Xiaojie Wu, Jicheng Yu, Beikang Ge, Jeffrey Wang, Xiaoran Han, Chunye Zhang, Xiaomeng Mao, Hindu Kalluru, Candace Bramson, Steven G Terra, Jing Liu","doi":"10.1007/s40268-024-00467-5","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Vupanorsen is a GalNAc<sub>3</sub>-conjugated antisense oligonucleotide targeting angiopoietin-like 3 (ANGPTL3) mRNA shown to reduce atherogenic lipoproteins in individuals with dyslipidemia.</p><p><strong>Objectives: </strong>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).</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>Absorption of vupanorsen was rapid (median time to maximum concentration [T<sub>max</sub>]: 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<sub>max</sub>]) 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.</p><p><strong>Conclusions: </strong>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.</p><p><strong>Trial registration: </strong>ClinicalTrials.gov identifier: NCT04916795.</p>","PeriodicalId":49258,"journal":{"name":"Drugs in Research & Development","volume":" ","pages":"253-262"},"PeriodicalIF":2.2000,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11315818/pdf/","citationCount":"0","resultStr":"{\"title\":\"A Randomized, Open-Label, Phase I, Single-Dose Study of Antisense Oligonucleotide, Vupanorsen, in Chinese Adults with Elevated Triglycerides.\",\"authors\":\"Xiaojie Wu, Jicheng Yu, Beikang Ge, Jeffrey Wang, Xiaoran Han, Chunye Zhang, Xiaomeng Mao, Hindu Kalluru, Candace Bramson, Steven G Terra, Jing Liu\",\"doi\":\"10.1007/s40268-024-00467-5\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>Vupanorsen is a GalNAc<sub>3</sub>-conjugated antisense oligonucleotide targeting angiopoietin-like 3 (ANGPTL3) mRNA shown to reduce atherogenic lipoproteins in individuals with dyslipidemia.</p><p><strong>Objectives: </strong>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).</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>Absorption of vupanorsen was rapid (median time to maximum concentration [T<sub>max</sub>]: 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<sub>max</sub>]) 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.</p><p><strong>Conclusions: </strong>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. 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A Randomized, Open-Label, Phase I, Single-Dose Study of Antisense Oligonucleotide, Vupanorsen, in Chinese Adults with Elevated Triglycerides.
Background: Vupanorsen is a GalNAc3-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 [Tmax]: 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 [Cmax]) 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.
期刊介绍：
Drugs in R&D is an international, peer reviewed, open access, online only journal, and provides timely information from all phases of drug research and development that will inform clinical practice. Healthcare decision makers are thus provided with knowledge about the developing place of a drug in therapy.
The Journal includes:
Clinical research on new and established drugs;
Preclinical research of direct relevance to clinical drug development;
Short communications and case study reports that meet the above criteria will also be considered;
Reviews may also be considered.
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