BET蛋白抑制剂RVX-208对冠状动脉粥样硬化进展的影响：2b期随机双盲多中心ASSURE试验结果
Effect of the BET Protein Inhibitor, RVX-208, on Progression of Coronary Atherosclerosis: Results of the Phase 2b, Randomized, Double-Blind, Multicenter, ASSURE Trial.
作者信息
Nicholls Stephen J, Puri Rishi, Wolski Kathy, Ballantyne Christie M, Barter Philip J, Brewer H Bryan, Kastelein John J P, Hu Bo, Uno Kiyoko, Kataoka Yu, Herrman Jean-Paul R, Merkely Bela, Borgman Marilyn, Nissen Steven E
机构信息
South Australian Health and Medical Research Institute, PO Box 11060, Adelaide, SA, 5001, Australia.
Department of Cardiovascular Medicine and Cleveland Clinic Coordinating Center for Clinical Research, Cleveland Clinic, Cleveland, OH, USA.
出版信息
Am J Cardiovasc Drugs. 2016 Feb;16(1):55-65. doi: 10.1007/s40256-015-0146-z.
BACKGROUND
Bromodomain and extra-terminal (BET) proteins regulate transcription of lipoprotein and inflammatory factors implicated in atherosclerosis. The impact of BET inhibition on atherosclerosis progression is unknown.
METHODS
ASSURE was a double-blind, randomized, multicenter trial in which 323 patients with angiographic coronary disease and low high-density lipoprotein cholesterol (HDL-C) levels were randomized in a 3:1 fashion to treatment with the BET protein inhibitor RVX-208 200 mg or placebo for 26 weeks. Plaque progression was measured with serial intravascular ultrasound imaging. Lipid levels, safety, and tolerability were also assessed.
RESULTS
During treatment, apolipoprotein (apo)A-I increased by 10.6% with placebo (P < 0.001 compared with baseline) and 12.8% with RVX-208 (P < 0.001 compared with baseline), between groups P = 0.18. HDL-C increased by 9.1% with placebo (P < 0.001 compared with baseline) and 11.1% with RVX-208 (P < 0.001 compared with baseline), between groups P = 0.24. Low-density lipoprotein cholesterol (LDL-C) decreased by 17.9% with placebo (P < 0.001 compared with baseline) and 15.8% with RVX-208 (P < 0.001 compared with baseline), between groups P = 0.55. The primary endpoint, the change in percent atheroma volume, decreased 0.30% in placebo-treated patients (P = 0.23 compared with baseline) and 0.40% in the RVX-208 group (P = 0.08 compared with baseline), between groups P = 0.81. Total atheroma volume decreased 3.8 mm(3) in the placebo group (P = 0.01 compared with baseline) and 4.2 mm(3) in the RVX-208 group (P < 0.001 compared with baseline), P = 0.86 between groups. A greater incidence of elevated liver enzymes was observed in RVX-208-treated patients (7.1 vs. 0%, P = 0.009).
CONCLUSION
Administration of the BET protein inhibitor RVX-208 showed no greater increase in apoA-I or HDL-C or incremental regression of atherosclerosis than administration of placebo.
TRIAL REGISTRATION
ClinicalTrials.gov identifier-NCT01067820.
背景
溴结构域和额外末端（BET）蛋白调节与动脉粥样硬化相关的脂蛋白和炎症因子的转录。BET抑制对动脉粥样硬化进展的影响尚不清楚。
方法
ASSURE是一项双盲、随机、多中心试验，323例患有血管造影证实的冠心病且高密度脂蛋白胆固醇（HDL-C）水平低的患者以3:1的比例随机接受BET蛋白抑制剂RVX-208 200 mg治疗或安慰剂治疗26周。通过连续血管内超声成像测量斑块进展。还评估了血脂水平、安全性和耐受性。
结果
治疗期间，安慰剂组载脂蛋白（apo）A-I升高10.6%（与基线相比P<0.001），RVX-208组升高12.8%（与基线相比P<0.001），组间P=0.18。安慰剂组HDL-C升高9.1%（与基线相比P<0.001），RVX-208组升高11.1%（与基线相比P<0.001），组间P=0.24。安慰剂组低密度脂蛋白胆固醇（LDL-C）降低17.9%（与基线相比P<0.001），RVX-208组降低15.8%（与基线相比P<0.001），组间P=0.55。主要终点，动脉粥样硬化体积百分比变化，安慰剂治疗患者降低0.30%（与基线相比P=0.23），RVX-208组降低0.40%（与基线相比P=0.08），组间P=0.81。安慰剂组总动脉粥样硬化体积减少3.8 mm³（与基线相比P=0.01），RVX-208组减少4.2 mm³（与基线相比P<0.001），组间P=0.86。RVX-208治疗患者中观察到肝酶升高的发生率更高（7.1%对0%，P=0.009）。
结论
与给予安慰剂相比，给予BET蛋白抑制剂RVX-208在apoA-I或HDL-C升高或动脉粥样硬化消退方面并无更大效果。
试验注册
ClinicalTrials.gov标识符-NCT01067820。
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