Phase 1b randomized study of antidote-controlled modulation of factor IXa activity in patients with stable coronary artery disease
Phase 1b randomized study of antidote-controlled modulation of factor IXa activity in patients with stable coronary artery disease
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DOI：
10.1161/circulationaha.107.745687
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发表时间：
2008-06-03
期刊：
影响因子：
37.8
通讯作者：
Rusconi, Christopher P.
中科院分区：
文献类型：
--
作者：
Chan, Mark Y.;Cohen, Mauricio G.;Rusconi, Christopher P.
背景-在稳定性冠状动脉疾病患者中，选择性因子IXa抑制与血小板导向治疗联合应用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(药物)是一种可注射的RNA适配子，可以特异性地结合和抑制因子IXa，RB007(解毒剂)是中和其抗IXa活性的互补寡核苷酸。方法和结果-我们通过随机、双盲、安慰剂对照研究评估了REG1的安全性、耐受性和药效学特征，将50名服用阿司匹林和/或氯吡格雷的冠心病患者分配到4个剂量水平的RB006(15、30、50和75 mg)和RB007(30、60、100和150 mg)。中位年龄61岁(第25和75百分位数，56和68岁)，80%的患者是男性。单次静脉滴注15、30、50和75 mg RB006后10min活化部分凝血活酶时间的中位数分别为29.2秒(第25和75百分位，28.1和29.8秒)，34.6秒(第25和75百分位，30.9和40.0秒)，46.9秒(第25和75百分位，40.3和51.1秒)，52.2秒(第25和75百分位，46.3和58.6)(P<；0.0001；正常的第25和第75百分位数，27和40秒)。RB007在中位数1分钟(第25和75百分位数，1和2分钟)内将激活的部分凝血活酶时间逆转至基线水平，7天内没有反弹增加。没有发生重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中使用RNA适配子药物-解毒剂对结合血小板导向治疗实现抑制和主动恢复因子IXa活性的经验。初步的临床安全性和可预测的药效学效应构成了对接受选择性血管重建术的患者进行持续研究的基础。
Background - 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.Methods and Results - 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.Conclusions - 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.