Pharmaceutical Sciences 藥物科學 88% PCSK9 PCSK9 PCSK PCSK9 alirocumab evolocumab FDA 貳 PCSK9 的膽固醇調節作用 PCSK9 692 Signal sequence signal peptide (SP)

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1 PCSK9 摘要 苑裡李綜合醫院藥劑科藥師莊峻毅 大甲李綜合醫院藥劑科藥師林旭志 衛生福利部苗栗醫院藥劑科藥師吳求珍 PCSK9 (Proprotein convertase subilisin/kexin type 9) LDL Receptor (low density lipoprotein receptor; LDL-R) LDL-R (low density lipoprotein cholesterol; LDL-C) PCSK9 FDA monoclonal antibodies (mabs) PCSK9 alirocumab evolocumab PCSK9 alirocumab evolocumab 壹 前言 Nabil Seidah (proprotein convertase) NARC- 1 (neural apoptosis-regulated convertase) Nabil Seidah (familial hypercholesterolemia) NARC-1 PCSK9 (Proprotein convertase subilisin/kexin type 9) PCSK9 gene ("gain of function" mutation) 2.6% PCSK9 gene Y142X C679X variants ("loss of function" mutation) (LDL-C) 28% 32 1 Mar 藥學雜誌 藥物科學新一類降血脂藥 PCSK9 抑制劑

2 Pharmaceutical Sciences 藥物科學 88% PCSK9 PCSK9 PCSK PCSK9 alirocumab evolocumab FDA 貳 PCSK9 的膽固醇調節作用 PCSK9 692 Signal sequence signal peptide (SP), prodomain (PRO), catalytic domain (CAT), hinge region, C-terminal cysteine and histidine rich domain (CHRD) PCSK9 VFAQ 152 SIP prodomain catalytic domain PCSK9 1 ( ) 1 圖一 Zymogen 及 mature PCSK9 結構 PCSK9 LDL-R sterol regulatory element binding protein 2 (SREBP2) 2 SREBP2 gene 22 22q13.2 SREBP2 SREBP2 gene up regulation HMGCoA synthase HMGCoA redutase PCSK9 LDL-R (cholesterol homeostasis) statins HMGCoA reductase SREBP2 PCSK9 LDL-R 3 LDL-R LDL-C PCSK9 LDL-R statins PCSK9 PCSK9 estrogen PCSK9 PCSK9 LDL-C PCSK9 100 ng/ ml LDL-C mmol/l 4 LDL-C LDL-R clathrin coated pits LDL-C lysosome LDL-R LDL-C PCSK9 LDL-R EGF-A domain (epidermal growth factor repeat A) clathrin coated pits lysosome LDL-R ( ) 5 monoclonal antibodies (mabs) PCSK9 LDL-R LDL-R LDL-C ( ) 5 26 THE JOURNAL OF TAIWAN PHARMACY Vol.32 No.1 Mar

3 PCSK9 5 圖二 PCSK9 與 LDL-R 結合 5 圖三 mabs 與 PCSK9 結合 參 PCSK9 抑制劑之臨床研究 一 Alirocumab Alirocumab IgG1 146 kda Alirocumab (heavy chain) (light chain) (variable region) (heterozygous familial hypercholesterolemia, HeFH) (clinical atherosclerotic cardiovascular disease) statin 75 mg 150 mg Phase III ODYSSEY LONG TERM trial 6 (n = 2341) 18 statins statins ( ) ( alirocumab150 mg) ( placebo) 24 LDL-C 24 LDL-C 61.0% 0.8% ( ) 6 78 LDL-C 52.4% 3.6% non-hdl cholesterol apolipoprotein B total cholesterol 1ipoprotein (a) triglycerides ( 81.0% 82.5%) ( 7.2% 5.8%) ( 5.9% 4.2%) ( 5.4% 32 1 Mar 藥學雜誌 藥物科學PCSK9 FDA

4 Pharmaceutical Sciences 藥物科學 2.9%) ( 1.2% 0.5%) ( 2.9%, 1.9%) ( ) ( post hoc analysis) 1.7% 3.3% 圖四 ODYSSEY LONG TERM trial 實驗組及 6 對照組 LDL-C 平均濃度變化 ODYSSEY ALTERNATIVE trial 7 (n = 314) 18 statins placebo ( alirocumab mg placebo) ( placebo ezetimibe 10 mg) ( placebo atorvastatin 20 mg) LDL-C 24 LDL-C 45% (placebo ezetimibe) 14.6% 二 Evolocumab Evolocumab IgG kda Evolocumab (heavy chain) (light chain) (variable region) PCSK9 FDA alirocumab (homozygous familial hypercholesterolemia, HoFH) 140 mg 420 mg HoFH 420 mg OSLER-1 OSLER-2 trial 8 OSLER PROGRAM (n = 4465) parent trial (standard therapy) OSLER-1 56 OSLER ( ) (evolocumab140 mg evolocumab 420 mg standard therapy) (standard therapy) 12 LDL-C 60.9% (Kaplan-Meier estimates 0.95% 2.18% hazard ratio 0.47) ( 69.2% 64.8%) ( 0.9% 28 THE JOURNAL OF TAIWAN PHARMACY Vol.32 No.1 Mar

5 PCSK9 藥物科學 0.3%) LDL-C 30.9% TESLA Part B trial 9 (n = 49) 肆 結論 PCSK9 12 (HoFH) 12 PCSK9 2 1 (33 16 ) (evolocumab 420 mg standard therapy) ( placebo standard therapy) 5 ODYSSEY 12 LDL-C OUTCOMES trial (n = 18,000) FOURIER 12 trial (n = 27,564) PCSK9 Inhibitors - New Classification Antihyperlipidemia Medication Chun-Yi Chuang 1, Hsu-Chih Lin 2, Chiu-Jen Wu 3 Department of Pharmacy, Yuanli Lee s General Hospital, Lee s Medical Corporation 1 Department of Pharmacy, Dajia Lee s General Hospital, Lee s Medical Corporation 2 Department of Pharmacy, Miao-Li General Hospital, Department of Health 3 Abstract PCSK9 (Proprotein convertase subilisin kexin type 9) is a protein produced by liver biosynthesis. It plays a crucial role in cholesterol homeostasis. PCSK9 binding to the specific region of LDL-R to induce intracellular degradation and prevent LDL-R from reaching the hepatocyte surface and further reaction to affect the eliminating cholesterol from serum. It results in great increasing LDL-C of serum level and the risk of cardiovascular diseases (CVD). Theoretically, medication which can inhibit PCSK9 will reduce LDL-C level and CVD risk 藥學雜誌 Mar

6 藥Pharmaceutical Sciences 物科學2015, July and August the U.S. Food and Drug Administration have respectively approved alirocumab and evolocumab which are monoclonal antibodies (mabs) PCSK9 inhibitors firstly approved as new class of cholesterol-lowering agents for treating hyperchlesterolemia and familial hypercholesterolemia. These are alternate choice for patients who suffered from intolerance of other cholesterol-lowering agents. 參考資料 : 1. Steve Poirier, Gaétan Mayer: The biology of PCSK9 from the endoplasmic reticulum to lysosomes: new and emerging therapeutics to control low-density lipoprotein cholesterol. Drug Design, Development and Therapy 2013; 7 : Gwang-woong Goa, Arya Mani: Low-density lipoprotein receptor (LDLR) family orchestrates cholesterol homeostasis. Yale Journal of Biology and Medicine. 2012; 85 : Greg Welder, Issam Zineh, Michael A. Pacanowski, et al: High-dose atorvastatin causes a rapid sustained increase in human serum PCSK9 and disrupts its correlation with LDL cholesterol. J. Lipid Res. 2010; 51: Rainer Schulz, Klaus-Dieter Schlüter, Ulrich Laufs: Molecular and cellular function of the proprotein convertase subtilisin/kexin type 9 (PCSK9). Basic Res Cardiol 2015; 110:4 5. Razvan T. Dadu, Christie M. Ballantyne: Lipid lowering with PCSK9 inhibitors. Nature Reviews Cardiology. 2014; 11: Jennifer G Robinson, Michel Farnier, Michel Farnier, et al: Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. N Engl J Med 2015; 372: Patric M. Moriarty, Terry A. Jacobson, Eric Bruckert, et al: Efficacy and safety of alirocumab, a monoclonal antibody to PCSK9, in statin-intolerant patients: Design and rationale of ODYSSEY ALTERNATIVE, a randomized phase 3 trial. Journal of Clinical Lipidology 2014; 8 : Marc S. Sabatine, Robert P. Giugliano, Stephen D. Wiviott, et al: Efficacy and safety of evolocumab in reducing lipids and cardiovascular events. N Engl J Med 2015; 372: Mohamed Hassan, Magdi Yacoub: GAUSS-2, RUTHER- FORD-2, LAPLACE-2, DESCARTES, and TESLA Part B: PCSK9 inhibitors gain momentum. Global Cardiology Science and Practice 2014; 49: THE JOURNAL OF TAIWAN PHARMACY Vol.32 No.1 Mar