Chan Mark Y, Cohen Mauricio G, Dyke Christopher K, Myles Shelley K, Aberle Laura G, Lin Min, Walder James, Steinhubl Steven R, Gilchrist Ian C, Kleiman Neal S, Vorchheimer David A, Chronos Nicholas, Melloni Chiara, Alexander John H, Harrington Robert A, Tonkens Ross M, Becker Richard C, Rusconi Christopher P
Duke Clinical Research Institute, 2400 Pratt St, Terrace Level Room 0311, Durham, NC 27705, USA.
Circulation. 2008 Jun 3;117(22):2865-74. doi: 10.1161/CIRCULATIONAHA.107.745687. Epub 2008 May 27.
Whether selective factor IXa inhibition produces an appropriate anticoagulant effect when combined with platelet-directed therapy in patients with stable coronary artery disease is unknown. REG1 consists of RB006 (drug), an injectable RNA aptamer that specifically binds and inhibits factor IXa, and RB007 (antidote), the complementary oligonucleotide that neutralizes its anti-IXa activity.
We evaluated the safety, tolerability, and pharmacodynamic profile of REG1 in a randomized, double-blind, placebo-controlled study, assigning 50 subjects with coronary artery disease taking aspirin and/or clopidogrel to 4 dose levels of RB006 (15, 30, 50, and 75 mg) and RB007 (30, 60, 100, and 150 mg). The median age was 61 years (25th and 75th percentiles, 56 and 68 years), and 80% of patients were male. RB006 increased the activated partial thromboplastin time dose dependently; the median activated partial thromboplastin time at 10 minutes after a single intravenous bolus of 15, 30, 50, and 75 mg RB006 was 29.2 seconds (25th and 75th percentiles, 28.1 and 29.8 seconds), 34.6 seconds (25th and 75th percentiles, 30.9 and 40.0 seconds), 46.9 seconds (25th and 75th percentiles, 40.3 and 51.1 seconds), and 52.2 seconds (25th and 75th percentiles, 46.3 and 58.6) (P<0.0001; normal 25th and 75th percentiles, 27 and 40 seconds). RB007 reversed the activated partial thromboplastin time to baseline levels within a median of 1 minute (25th and 75th percentiles, 1 and 2 minutes) with no rebound increase through 7 days. No major bleeding or other serious adverse events occurred.
This is the first experience of an RNA aptamer drug-antidote pair achieving inhibition and active restoration of factor IXa activity in combination with platelet-directed therapy in stable coronary artery disease. The preliminary clinical safety and predictable pharmacodynamic effects form the basis for ongoing studies in patients undergoing elective revascularization procedures.
在稳定型冠状动脉疾病患者中，选择性抑制因子IXa与血小板靶向治疗联合使用时是否能产生适当的抗凝效果尚不清楚。REG1由RB006（药物）和RB007（解毒剂）组成，RB006是一种可注射的RNA适配体，能特异性结合并抑制因子IXa，RB007是能中和其抗IXa活性的互补寡核苷酸。
我们在一项随机、双盲、安慰剂对照研究中评估了REG1的安全性、耐受性和药效学特征，将50名正在服用阿司匹林和/或氯吡格雷的冠状动脉疾病患者分配至4个剂量水平的RB006（15、30、50和75毫克）和RB007（30、60、100和150毫克）组。中位年龄为61岁（第25和第75百分位数分别为56岁和68岁），80%的患者为男性。RB006能剂量依赖性地延长活化部分凝血活酶时间；单次静脉推注15、30、50和75毫克RB006后10分钟时，活化部分凝血活酶时间的中位数分别为29.2秒（第25和第75百分位数分别为28.1秒和29.8秒）、34.6秒（第25和第75百分位数分别为30.9秒和40.0秒）、46.9秒（第25和第75百分位数分别为40.3秒和51.1秒）和52.2秒（第25和第75百分位数分别为46.3秒和58.6秒）（P<0.0001；正常范围第25和第75百分位数分别为27秒和40秒）。RB007能在中位数1分钟（第25和第75百分位数分别为1分钟和2分钟）内将活化部分凝血活酶时间恢复至基线水平，且在7天内无反跳性升高。未发生大出血或其他严重不良事件。结论：这是首次在稳定型冠状动脉疾病患者中使用RNA适配体药物-解毒剂对，结合血小板靶向治疗实现对因子IXa活性的抑制和活性恢复。初步的临床安全性和可预测的药效学效应为正在进行的择期血管重建手术患者的研究奠定了基础。
