Tricoci Pierluigi, D'Andrea Denise M, Gurbel Paul A, Yao Zhenling, Cuchel Marina, Winston Brion, Schott Robert, Weiss Robert, Blazing Michael A, Cannon Louis, Bailey Alison, Angiolillo Dominick J, Gille Andreas, Shear Charles L, Wright Samuel D, Alexander John H
Duke Clinical Research Institute, Durham, NC (P.T., M.A.B., J.H.A.).
CSL Behring, King of Prussia, PA (D.M.A., Z.Y., C.L.S., S.D.W.).
J Am Heart Assoc. 2015 Aug 25;4(8):e002171. doi: 10.1161/JAHA.115.002171.
CSL112 is a new formulation of human apolipoprotein A-I (apoA-I) being developed to reduce cardiovascular events following acute coronary syndrome. This phase 2a, randomized, double-blind, multicenter, dose-ranging trial represents the first clinical investigation to assess the safety and pharmacokinetics/pharmacodynamics of a CSL112 infusion among patients with stable atherosclerotic disease.
Patients were randomized to single ascending doses of CSL112 (1.7, 3.4, or 6.8 g) or placebo, administered over a 2-hour period. Primary safety assessments consisted of alanine aminotransferase or aspartate aminotransferase elevations >3× upper limits of normal and study drug-related adverse events. Pharmacokinetic/pharmacodynamic assessments included apoA-I plasma concentration and measures of the ability of serum to promote cholesterol efflux from cells ex vivo. Of 45 patients randomized, 7, 12, and 14 received 1.7-, 3.4-, and 6.8-g CSL112, respectively, and 11 received placebo. There were no clinically significant elevations (>3× upper limit of normal) in alanine aminotransferase or aspartate aminotransferase. Adverse events were nonserious and mild and occurred in 5 (71%), 5 (41%), and 6 (43%) patients in the CSL112 1.7-, 3.4-, and 6.8-g groups, respectively, compared with 3 (27%) placebo patients. The imbalance in adverse events was attributable to vessel puncture/infusion-site bruising. CSL112 resulted in rapid (T(max)≈2 hours) and dose-dependent increases in apoA-I (145% increase in the 6.8-g group) and total cholesterol efflux (up to 3.1-fold higher than placebo) (P<0.001).
CSL112 infusion was well tolerated in patients with stable atherosclerotic disease. CSL112 immediately raised apoA-I levels and caused a rapid and marked increase in the capacity of serum to efflux cholesterol. This potential novel approach for the treatment of atherosclerosis warrants further investigation.
URL: http://www.ClinicalTrials.gov. Unique identifier: NCT01499420.
CSL112是一种新型的人载脂蛋白A-I（apoA-I）制剂，正在研发用于降低急性冠脉综合征后的心血管事件。这项2a期随机双盲多中心剂量范围试验是首次评估CSL112输注在稳定型动脉粥样硬化疾病患者中的安全性和药代动力学/药效学的临床研究。
患者被随机分配接受单剂量递增的CSL112（1.7、3.4或6.8克）或安慰剂，在2小时内给药。主要安全性评估包括丙氨酸氨基转移酶或天冬氨酸氨基转移酶升高超过正常上限3倍以及与研究药物相关的不良事件。药代动力学/药效学评估包括apoA-I血浆浓度以及血清促进细胞内胆固醇外流能力的测量。在随机分组的45例患者中，分别有7例、12例和14例接受了1.7克、3.4克和6.8克的CSL112，11例接受了安慰剂。丙氨酸氨基转移酶或天冬氨酸氨基转移酶没有出现临床上显著的升高（超过正常上限3倍）。不良事件不严重且轻微，CSL112 1.7克、3.4克和6.8克组分别有5例（71%）、5例（41%）和6例（43%）患者发生，而安慰剂组有3例（27%）患者发生。不良事件的不平衡归因于血管穿刺/输注部位瘀伤。CSL112导致apoA-I迅速（T(max)≈2小时）且呈剂量依赖性增加（6.8克组增加145%）以及总胆固醇外流增加（比安慰剂高3.1倍）（P<0.001）。
CSL112输注在稳定型动脉粥样硬化疾病患者中耐受性良好。CSL112立即提高了apoA-I水平，并使血清胆固醇外流能力迅速且显著增加。这种潜在的治疗动脉粥样硬化的新方法值得进一步研究。
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