治疗血脂异常的小分子干扰RNA药物inclisiran
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摘要
inclisiran是第一个用于调血脂的小分子干扰RNA药物,给药方式为皮下注射,能特异性抑制肝细胞内的前蛋白转化酶枯草菌素9的合成,从而导致低密度脂蛋白-胆固醇水平显著下降,有良好的安全性和耐受性,适用于家族性高胆固醇血症患者和他汀类药物治疗效果不佳的患者,目前正在进行Ⅲ期临床试验,预计2019年获批上市。本文综述了inclisiran的临床前和临床试验的结果,展示它良好的临床应用前景。
Inclisiran, the first si RNA drug to regulate blood lipids, is administered subcutaneously and causes marked reductions in serum levels of proprotein convertase subtilisin/kexin type 9 and low density lipoprotein cholesterol. Inclisiran had well safety and tolerability, which was applied to patients with hypercholesterolemia and who receive poor effect after statin therapy. Inclisiran is undergoing phase Ⅲ clinical trial currently and is expected to be approved in 2019. This review described the results of preclinical and clinical trials of inclisiran, showing the good application prospect in the clinic.
Inclisiran, the first si RNA drug to regulate blood lipids, is administered subcutaneously and causes marked reductions in serum levels of proprotein convertase subtilisin/kexin type 9 and low density lipoprotein cholesterol. Inclisiran had well safety and tolerability, which was applied to patients with hypercholesterolemia and who receive poor effect after statin therapy. Inclisiran is undergoing phase Ⅲ clinical trial currently and is expected to be approved in 2019. This review described the results of preclinical and clinical trials of inclisiran, showing the good application prospect in the clinic.
引文
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[4]FITCHETT DH,HEGELE RA,VERMA S.Cardiology patient page.Statin intolerance[J].Circulation,2015,131(13):e389-e391.
[5]GRUNDY SM.Can statins cause chronic low-grade myopathy?[J].Ann Intern Med,2002,137(7):617-618.
[6]MANSI I.Statin adverse events in primary prevention:between randomized trials and observational studies[J].Am J Med Sci,2015,350(4):330-337.
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[9]PAGE MM,WATTS GF.PCSK9 in context:A contemporary review of an important biological target for the prevention and treatment of atherosclerotic cardiovascular disease[J].Diabetes Obes Metab,2018,20(2):270-282.
[10]URBAN D,POSS J,BOHM M,et al.Targeting the proprotein convertase subtilisin/kexin type 9 for the treatment of dyslipidemia and atherosclerosis[J].J Am Coll Cardiol,2013,62(16):1401-1408.
[11]HOOPER AJ,BURNETT JR.Anti-PCSK9 therapies for the treatment of hypercholesterolemia[J].Expert Opin Biol Ther,2013,13(3):429-435.
[12]王艳,刘兆鹏.一种调血脂的新型单抗药物evolocumab[J].中国新药与临床杂志,2017,36(4):190-195.
[13]NAIR JK,WILLOUGHVY JL,CHAN A,et al.Multivalent N-acetylgalactosamine conjugated si RNA localizes in hepatocytes and elicits robust RNAi mediated gene silencing[J].J Am Chem Soc,2014,136(49):16958-16961.
[14]KHVOROVA A.Oligonucleotide therapeutics-a new class of cholesterol-lowering drugs[J].N Engl J Med,2017,376(1):4-7.
[15]FRANK-KAMENETSKY M,GREFHORST A,ANDERSON NN,et al.Therapeutic RNAi targeting PCSK9 acutely lowers plasma cholesterol in rodents and LDL cholesterol in nonhuman primates[J].Proc Natl Acad Sci USA,2008,105(33):11915-11920.
[16]FITZGERALD K,FRANK-KAMENETSKY M,SHULGA-MORSKAYA S,et al.Effect of an RNA interference drug on the synthesis of proprotein convertase subtilisin/kexin type 9(PCSK9)and the concentration of serum LDL cholesterol in healthy volunteers:a randomised,single-blind,placebocontrolled,phase 1 trial[J].Lancet,2014,383(3911):60-68.
[17]FITZGERALD K,WHITE S,BORODOVSKY A,et al.A highly durable RNAi therapeutic inhibitor of PCSK9[J].N Engl J Med,2017,376(1):41-51.
[18]RAY KK,LANDMESSER U,LEITER LA,et al.Inclisiran in patients at high cardiovascular risk with elevated LDL cholesterol[J].N Engl J Med,2017,376(15):1430-1440.
[19]SEIDAH NG,BENJANNET S,WICKHAM L,et al.The secretory proprotein convertase neural apoptosis-regulated convertase 1(NARC-1):liver regeneration and neuronal differentiation[J].Proc Natl Acad Sci USA,2003,100(3):928-933.
[2]FERENCE BA,GINSBERG HN,GRAHAM I,et al.Lowdensity lipoproteins cause atherosclerotic cardiovascular disease.1.Evidence from genetic,epidemiologic,and clinical studies.Aconsensus statement from the European Atherosclerosis Society Consensus Panel[J].Eur Heart J,2017,38(32):2459-2472.
[3]BAYS H.Statin safety:an overview and assessment of the data-2005[J].Am J Cardiol,2006,97(8):S6-S26.
[4]FITCHETT DH,HEGELE RA,VERMA S.Cardiology patient page.Statin intolerance[J].Circulation,2015,131(13):e389-e391.
[5]GRUNDY SM.Can statins cause chronic low-grade myopathy?[J].Ann Intern Med,2002,137(7):617-618.
[6]MANSI I.Statin adverse events in primary prevention:between randomized trials and observational studies[J].Am J Med Sci,2015,350(4):330-337.
[7]黄震华.9型前蛋白转化酶枯草杆菌蛋白酶/kexin抑制药在调脂治疗中的应用进展[J].中国新药与临床杂志,2016,35(4):237-242.
[8]LEREN TP.Sorting an LDL receptor with bound PCSK9 to intracellular degradation[J].Atherosclerosis,2014,237(1):76-81.
[9]PAGE MM,WATTS GF.PCSK9 in context:A contemporary review of an important biological target for the prevention and treatment of atherosclerotic cardiovascular disease[J].Diabetes Obes Metab,2018,20(2):270-282.
[10]URBAN D,POSS J,BOHM M,et al.Targeting the proprotein convertase subtilisin/kexin type 9 for the treatment of dyslipidemia and atherosclerosis[J].J Am Coll Cardiol,2013,62(16):1401-1408.
[11]HOOPER AJ,BURNETT JR.Anti-PCSK9 therapies for the treatment of hypercholesterolemia[J].Expert Opin Biol Ther,2013,13(3):429-435.
[12]王艳,刘兆鹏.一种调血脂的新型单抗药物evolocumab[J].中国新药与临床杂志,2017,36(4):190-195.
[13]NAIR JK,WILLOUGHVY JL,CHAN A,et al.Multivalent N-acetylgalactosamine conjugated si RNA localizes in hepatocytes and elicits robust RNAi mediated gene silencing[J].J Am Chem Soc,2014,136(49):16958-16961.
[14]KHVOROVA A.Oligonucleotide therapeutics-a new class of cholesterol-lowering drugs[J].N Engl J Med,2017,376(1):4-7.
[15]FRANK-KAMENETSKY M,GREFHORST A,ANDERSON NN,et al.Therapeutic RNAi targeting PCSK9 acutely lowers plasma cholesterol in rodents and LDL cholesterol in nonhuman primates[J].Proc Natl Acad Sci USA,2008,105(33):11915-11920.
[16]FITZGERALD K,FRANK-KAMENETSKY M,SHULGA-MORSKAYA S,et al.Effect of an RNA interference drug on the synthesis of proprotein convertase subtilisin/kexin type 9(PCSK9)and the concentration of serum LDL cholesterol in healthy volunteers:a randomised,single-blind,placebocontrolled,phase 1 trial[J].Lancet,2014,383(3911):60-68.
[17]FITZGERALD K,WHITE S,BORODOVSKY A,et al.A highly durable RNAi therapeutic inhibitor of PCSK9[J].N Engl J Med,2017,376(1):41-51.
[18]RAY KK,LANDMESSER U,LEITER LA,et al.Inclisiran in patients at high cardiovascular risk with elevated LDL cholesterol[J].N Engl J Med,2017,376(15):1430-1440.
[19]SEIDAH NG,BENJANNET S,WICKHAM L,et al.The secretory proprotein convertase neural apoptosis-regulated convertase 1(NARC-1):liver regeneration and neuronal differentiation[J].Proc Natl Acad Sci USA,2003,100(3):928-933.