LAPLACE2试验A阶段3双盲随机

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LAPLACE-2试验:一项3期、双盲、随机、安慰剂和依西替米对照、多中心研究

LAPLACE-2试验:一项3期、双盲、随机、安慰剂和依西替米对照、多中心研究to Evaluate Safety, Tolerability an Efficacy of Evolocumab (AMG 145) in Combination With Statin Therapy in Subjects With Primary Hypercholesterolemia and Mixed Dyslipidemia Jennifer G. Robinson, 1 Bettina S. Nedergaard, 2 William J. Rogers, 3 Jonathan Fialkow, 4 Joel M. Neutel, 5 David Ramstad, 6 Ransi Somaratne, 7 Jason C. Legg, 7 Patric Nelson, 7 Robert Scott, 7 Scott M. Wasserman, 7 and Robert Weiss, 8 for the LAPLACE-2 Investigators 1 College of Public Health, University of Iowa, Iowa City, IA, USA; 2 Center for Clinical and Basic Research, Aalborg, Denmark; 3 University of Alabama Medical Center, Birmingham, AL, USA; 4 Herbert Wertheim College of Medicine, Florida International University, Miami, FL, USA; 5 Orange County Research Center, Tustin, CA, USA; 6 Hampton Roads Center for Clinical Research, Suffolk, VA, USA; 7 Amgen Inc. , Thousand Oaks, CA, USA; 8 Maine Research Associates, Auburn, ME, USA March 30, 2014, Late-Breaking Clinical Trials Session 402 American College of Cardiology, Washington DC

背景:他汀类药物是减少动脉粥样硬化性心血管疾病(ASCVD)的一线疗法。Ø

背景:他汀类药物是减少动脉粥样硬化性心血管疾病(ASCVD)的一线疗法。Ø2013 ACC/AHA胆固醇指南1§A高强度他汀类药物(≥ 建议高危患者服用50%低密度脂蛋白胆固醇(LDL-C降低)临床ASCVD;…岁≤ 75 y•LDL-C≥ 190毫克/日。L(4.9 mmol/L)•糖尿病;年龄40-75岁,有≥ 7.5%10-y ASCVD风险??否则建议使用中等强度他汀类药物(LDL-C降低30-<50%)。§对于不能耐受高强度他汀类药物、疗效低于预期或患有遗传性高胆固醇血症的高危患者,建议使用非他汀类药物治疗。1发行量。2013年11月出版前在线。2.

Ø在美国以外,指南建议LDL-C <100 mg/d。L或者

Ø在美国以外,指南建议LDL-C <100 mg/d。L或<70 mg/d。L,取决于风险程度。Ø许多接受中强度或高强度他汀治疗的患者将需要添加另一种LDL-C降低药物。4 -5 Ø Evolocumab (amg145)是一种人抗PCSK 9的单克隆抗体。Ø Evolocumab耐受性良好,在2期试验中显示LDL-C显著降低,包括一项长期的、52周的研究。10 1。Can J Cardiol. 2013;2: 151 -167。2. Atherosclerosis. 2012; 223: 1 -68. 3. J Clin Lipidol 2013; 7: 561 -565. 4. N Engl J Med. 2005; 352: 1425 -1435. 5. JAMA. 2005; 294: 2437 -2445. 6. Lancet. 2012; 380: 1995 -2006. 7. Lancet. 2012; 380: 2007 -2017. 8. JAMA. 2012; 308: 2497 -2506. 9. Circulation. 2012; 126: 2408 -2417. 10. Circulation. Online ahead of print November 2013. 3

pcsk9单克隆检测LDL-C的LAPLACE-2研究L抗体抑制结合

LAPLACE-2研究用PCSK 9单克隆评估LDL-C。L抗体抑制联合他汀类药物Th。Erapy–2(NCT 01763866)设计:一项为期12周、随机、双盲、安慰剂和依齐米对照的III期研究目的:评估高胆固醇血症患者每两周(140 mg)或每月(420 mg)服用伊沃单抗联合他汀类药物的疗效和安全性4

LAPLACE-2:研究设计总N = 1896资格:筛查时LDL-C≥150 mg/d。

LAPLACE-2:研究设计总N = 1896资格:筛查时LDL-C≥150 mg/d。L(4。0 mmol/L):无他汀≥100 mg/d。L(2。6 mmol/L):非强化他汀≥80 mg/d。L(2。1 mmol/L): 1896例患者随机接受至少一剂研究药物。LDL-C,低密度脂蛋白胆固醇;PBO安慰剂;Evo。 Mab, evolocumab; EZE, ezetimibe; PO, oral; Q 2 W, biweekly; QM, monthly; QD, daily; SC, subcutaneous; W, week. Clinical Cardiology. Online ahead of print January 2014. 5

他汀+安慰剂(N = 558)阿托伐他汀+ Ezetimibe (N

他汀+安慰剂(N = 558)阿托伐他汀+ Ezetimibe (N= 221) Any Statin + Evolocumab (N = 1117) 60 (10) 61 (9) 60 (10) Female, % 48 49 44 Coronary artery disease, % 22 17 24 Peripheral arterial disease or cerebrovascular disease, % 10 9 11 Diabetes mellitus, Type 2, % 13 20 16 Age (years), mean (SD) Total N = 1896* *1896 patients were randomized and received at least one dose of study drug. Baseline characteristics were collected at randomization to statin. SD, standard deviation. 6

他汀+安慰剂(N = 558)阿托伐他汀+ Ezetimibe (N

LAPLACE-2:基线脂类任意他汀+安慰剂(N = 558)阿托伐他汀+ Ezetimibe (N = 221)任意他汀+ Evolocumab (N = 1117) LDL-C, 1 mg/d。L,平均(SD) 108(40) 109(37) 110(42)载脂蛋白。B, g/L,平均(SD) 88 (25) 90 (27) TG, mg/d。L,平均(SD) 129 (66) 136 (77) 137 (82) HDL-C, mg/d。L,平均(SD) 55 (17) 52 (15) 53 (16) Lp(a), mg/d。L,平均(SD) 86 (100) 92 (104) 91 (113) PCSK 9, ng/m。L,均值(SD) 353(114) 351(112) 355(111)基线特征随机分组收集。a.当计算LDL-C < 40 mg/d时,通过制备超离心法进行自反试验的Friedewald公式确定。L或甘油三酯为> 400 mg/d。L. LDL-C,低密度脂蛋白胆固醇; Apo. B, apolipoprotein B; TG, triglycerides; HDL-C, high-density lipoprotein cholesterol; Lp(a), lipoprotein (a); PCSK 9, proprotein convertase subtilisin/kexin type 9. 7

LAPLACE-2:第10周和第12周的LDL-C反应平均百分比变化

LAPLACE-2:平均第10周和第12周时LDL-C反应与基线相比LDL的平均变化百分比−C Evolocumab Q 2 W&QM:LDL-C与安慰剂依西替米比降低63%至75%:LDL-C与安慰剂阿托伐他汀降低19%至32%80 mg瑞舒伐他汀40 mg阿托伐他汀10 mg与安慰剂和依西替米比相比,所有治疗差异均具有统计学意义(P<0.001)。第10周和第12周的平均值与第12周的平均值无显著差异。低密度脂蛋白胆固醇;Q 2W,每两周一次;QM,每月一次。垂直线代表95%的CI。瑞舒伐他汀5 mg辛伐他汀40 mg 8

LAPLACE-2:筛选、基线检查和治疗期间LDL-Ca LDL-C<70 mg/d。L:中等强度他汀类药物Q

LAPLACE-2:筛选、基线检查和治疗期间LDL-Ca LDL-C<70 mg/d。L:中等强度他汀类药物Q 2 W 88-94%;QM 86至90%LDL-C,mg/d。低密度脂蛋白胆固醇<70毫克/天。L:高强度他汀类药物Q 2 W 94%;QM 93至95%a。第10周和第12周的平均值。第10周和第12周的平均值与第12周的平均值无显著差异。低密度脂蛋白胆固醇;LSP,脂质稳定期;Q 2W,每两周一次;QM,每月一次。9

LAPLACE-2:其他脂类在平均周10/12平均百分比变化基线非hdl - c Q

LAPLACE-2:与安慰剂载脂蛋白相比,非hdl - c Q 2w - 58 - 65%平均周其他脂类变化10/12平均百分比。阿托伐他汀80 mg瑞舒伐他汀10 mg瑞舒伐他汀40 mg 5 mg辛伐他汀40 mg所有治疗与安慰剂和依折麦布的差异均有统计学意义(P<0。05).垂直线代表95%的CIs。10周和12周的平均值与仅12周的平均值之间没有显著差异。非高密度脂蛋白胆固醇;13日。B,载脂蛋白B;Q 2 W,两周;QM,每月。 10

拉普拉斯-2:平均第10周/12周第2周W-21至-

LAPLACE-2:其他脂质是指周10/12问2 W - 21 - 36%和安慰剂意味着变化百分比从基线脂蛋白(a)阿托伐他汀80毫克伐40毫克阿托伐他汀10毫克伐5毫克辛伐他汀治疗40毫克臂所有治疗差异与安慰剂和ezetimibe具有统计学意义(P < 0。05).10周和12周的平均值与仅12周的平均值之间没有显著差异。垂直线代表95%的CIs。Q 2 W,两周;QM,每月。11

LAPLACE-2:安全性和耐受性n(%)治疗紧急不良事件最常见的AEsa背痛关节痛

LAPLACE-2:安全性和耐受性n(%)治疗紧急不良事件最常见的AEsa背痛关节痛Headache Muscle spasms Pain in extremity Serious AEs leading to study drug discontinuation Deaths CK > 5 x ULN ALT or AST > 3 x ULN Potential injection site reactionsc Neurocognitive AEs Cognitive deterioration Disorientation Post-baseline binding antibodies a Top Any Statin + Placebo (N = 558) Atorvastatin + Ezetimibe (N = 221) Any Statin + Evolocumab (N = 1117) 219 (39) 89 (40) 406 (36) 14 (3) 9 (2) 15 (3) 6 (1) 7 (3) 4 (2) 5 (2) 6 (3) 3 (1) 20 (2) 19 (2) 17 (2) 13 (2) 12 (2) 1 (0. 2) 2 (0. 4) 6 (1) 8 (1) 2 (1) 4 (2) 0 (0)b 0 (0) 3 (1) 23 (2) 21 (2) 0 (0) 1 (0. 1) 4 (0. 4) 15 (1) 0 (0) 1 (0. 5) 0 (0) NA NA 1 (0. 1)d 5 in evolocumab treatment group. b One subject died after the end of study. c Reported using high-level term groupings which included injection site (IS) rash, IS inflammation, IS pruritus, IS reaction, and IS urticaria. d Binding antibody was present at baseline and at the end of study. No neutralizing antibodies were detected. 12 AE, adverse event; ALT, alanine aminotransferase; AST, aspartate aminotransferase; ULN, upper limit of normal.

LAPLACE-2:结论Ø Evolocumab在平均10/12周显著降低LDL-C

LAPLACE-2:结论Ø Evolocumab显著降低了背景他汀治疗的高胆固醇血症患者10/12周的平均LDL-C水平。§中强度和高强度背景他汀治疗在降低百分比方面没有显著差异。Ø Evolocumab 140 mg两周和420 mg一个月的给药方案在临床上是等同的。Ø联合阿托伐他汀时,使用evolocumab的患者LDL-C降低显著高于使用ezetimibe的患者(63 -75%)。Ø LDL-C < 70 mg/d。evolocumab在大多数患者中均达到L。§86 -94%(中强度他汀)§93 -95%(高强度他汀)Ø在evolocumab-、安慰剂-和ezetimibe治疗的患者中,安全性和耐受性没有显著差异。13

Evolocumab Q 2w或正在进行ASCVD结局试验

§Evolocumab Q 2w或QM添加到中强度或高强度他汀治疗中§患者为临床ASCVD (N = 22,500)§该试验正在评估动脉粥样硬化心血管疾病(ASCVD)事件减少和安全性,进一步研究pcsk9抑制在风险升高的受试者中的心血管结局(傅里叶)。可在:http: //临床试验。gov / ct 2 /显示/ NCT 01764633。14

Jennifer G. Robinson,医学博士,公共卫生硕士:研究拨款给机构:Amarin, Amgen, Astra。捷利康,

Jennifer G. Robinson,医学博士,公共卫生硕士:研究拨款给机构:Amarin, Amgen, Astra。捷利康、第一三共、Esperion、Genentech/Hoffman La Roche、葛兰素史克、默克、Regeneron/赛诺菲、仙粉黛/武田。顾问:安进(Amgen), Hoffman La。罗氏公司、辉瑞、赛诺菲。Robert Weiss(医学博士):担任安进、赛诺菲和辉瑞的首席研究员,并在去年获得了以下相关领域的研究资助:安进、赛诺菲、Regeneron、辉瑞、Genentech、Hoffman-Laroche、礼来和默克。Jonathan Fialkow医学博士:担任Amgen赞助的研究项目的首席技术官。辉瑞,百时美施贵宝和阿玛林制药的发言人局。Bettina S. Nedergaard: Amgen赞助的研究项目PI。Joel M. Neutel,医学博士:用于多项临床试验。多家公司的发言人机构。 David Ramstad, MD, MPH: PI for studies sponsored by Amgen, Pfizer, Bristol Myers Squibb, Novartis, Glaxo. Smith. Kline, Takeda, Daiichi-Sankyo, Arete Therapeutics, Akros, Forest Research Institute, Lilly, Shire-Novartis, Hoffman-La. Roche, Aventis, and Novo. Nordisk. William J. Rogers, MD: PI for studies sponsored by Amgen and Sanofi. Ransi Somaratne, MD, MBA; Jason C. Legg, Ph. D; Patric Nelson, MPH, MBA; Robert Scott, MD; and Scott M. Wasserman, MD: employees of Amgen, Inc. and own Amgen stock/stock options. Amgen, Inc. provided editorial support for the production of this presentation. 15

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