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      Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Alirocumab in Healthy Chinese Subjects: A Randomized, Double-Blind, Placebo-Controlled, Ascending Single-Dose Study

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          Abstract

          Background

          The addition of alirocumab (a fully human monoclonal antibody to proprotein convertase subtilisin/kexin type 9 [PCSK9]) to background statin therapy provides significant incremental low-density lipoprotein cholesterol (LDL-C) lowering and cardiovascular event risk reduction.

          Objectives

          Our objectives were to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of single ascending doses of alirocumab in healthy Chinese subjects.

          Methods

          In this double-blind, placebo-controlled, phase I study, 35 Chinese subjects (aged 21–45 years) with baseline LDL-C > 100 mg/dL (2.59 mmol/L) were randomized to receive a single 1 mL subcutaneous injection of alirocumab 75, 150, or 300 mg, or placebo, and followed up for ~ 12 weeks.

          Results

          Treatment-emergent adverse events, most frequently nasal congestion and dry throat, were reported in three of seven or eight subjects in each alirocumab dose group (two of seven in the placebo group). One patient receiving alirocumab 300 mg had a mild local injection-site reaction. No alirocumab recipients demonstrated antidrug antibodies. Maximum alirocumab serum concentrations (6–34 mg/dL) occurred at a median of 3–7 days across the dose groups. Maximum mean LDL-C reductions from baseline were observed on days 8, 15, and 22 with alirocumab 75 (55.3%), 150 (63.7%), and 300 mg (73.7%), respectively. Mean free PCSK9 levels were reduced to below the lower limit of quantification within 4 h of dosing. Total cholesterol, non-high-density lipoprotein cholesterol, and apolipoprotein B were reduced with alirocumab.

          Conclusions

          In Chinese subjects, alirocumab 75, 150, and 300 mg was safe and well-tolerated. Pharmacokinetic/pharmacodynamic parameters, including clinically meaningful reductions in LDL-C and other lipids/lipoproteins, were consistent with data from Japanese and Western populations.

          Clinicaltrials.gov identifier: NCT02979015.

          Electronic supplementary material

          The online version of this article (10.1007/s40256-020-00394-1) contains supplementary material, which is available to authorized users.

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          Most cited references31

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          Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge.

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            Alirocumab and Cardiovascular Outcomes after Acute Coronary Syndrome

            Patients who have had an acute coronary syndrome are at high risk for recurrent ischemic cardiovascular events. We sought to determine whether alirocumab, a human monoclonal antibody to proprotein convertase subtilisin-kexin type 9 (PCSK9), would improve cardiovascular outcomes after an acute coronary syndrome in patients receiving high-intensity statin therapy.
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              2016 ESC/EAS Guidelines for the Management of Dyslipidaemias.

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                Author and article information

                Contributors
                haiyanli1027@hotmail.com
                Journal
                Am J Cardiovasc Drugs
                Am J Cardiovasc Drugs
                American Journal of Cardiovascular Drugs
                Springer International Publishing (Cham )
                1175-3277
                1179-187X
                21 February 2020
                21 February 2020
                2020
                : 20
                : 5
                : 489-503
                Affiliations
                [1 ]GRID grid.411642.4, ISNI 0000 0004 0605 3760, Department of Cardiology, NHC Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, , Peking University Third Hospital, ; 49 North Garden Road, Haidian Distrct, Beijing, 100191 China
                [2 ]GRID grid.411642.4, ISNI 0000 0004 0605 3760, Drug Clinical Trial Center, , Peking University Third Hospital, ; 49 North Garden Road, Haidian Distrct, Beijing, 100191 China
                [3 ]GRID grid.476734.5, ISNI 0000 0004 0485 8549, Sanofi, ; Beijing, China
                [4 ]GRID grid.417924.d, Clinical Development R&D, , Sanofi, ; Montpellier, France
                [5 ]GRID grid.418961.3, ISNI 0000 0004 0472 2713, Regeneron Pharmaceuticals, Inc., ; Tarrytown, NY USA
                [6 ]Sanofi R&D, Shanghai, China
                Article
                394
                10.1007/s40256-020-00394-1
                7548281
                32080823
                e3de66fd-0876-4d99-a8d2-3a48f0d61ac8
                © The Author(s) 2020

                Open AccessThis article is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License, which permits any non-commercial use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc/4.0/.

                History
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/100004339, Sanofi;
                Funded by: FundRef http://dx.doi.org/10.13039/100009857, Regeneron Pharmaceuticals;
                Categories
                Original Research Article
                Custom metadata
                © Springer Nature Switzerland AG 2020

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