Cerenis Therapeutics, 265 rue de la Découverte-Bât. A, 31670, Labège, France.
Clin Drug Investig. 2017 May;37(5):483-491. doi: 10.1007/s40261-017-0506-3.
CER-001 comprises recombinant human apolipoprotein A-I complexed with phospholipids that mimics natural, nascent, pre-β high-density lipoprotein (HDL). We present animal model data showing dose-dependent increases in cholesterol efflux with CER-001 and its subsequent elimination by reverse lipid transport, together with inhibition of atherosclerotic plaque progression. We report the first phase I study results with CER-001 in humans, starting at 0.25 mg/kg, which is 1/80th of the safe dose (20 mg/kg) established in 4-week multiple-dose animal studies dosed every second day.
Healthy volunteers, 18-55 years old with a low-density lipoprotein-cholesterol:HDL-cholesterol ratio greater than 3.0, received single intravenous escalating doses of CER-001 (0.25-45.0 mg/kg) and placebo in a double-blind randomised cross-over fashion. Subjects were followed up for 3 weeks post-dose. Assessments included adverse event monitoring, blood sampling, and clinical laboratory measurements.
Thirty-two subjects were enrolled. All CER-001 doses (0.25-45 mg/kg) were safe and well tolerated, with an adverse event profile similar to placebo. Effects on clinical chemistry, haematology and coagulation parameters were comparable to placebo. No adverse effects of CER-001 on electrocardiograms were observed. No antibodies to apolipoprotein A-I were detected following single-dose administration of CER-001. Plasma apolipoprotein A-I levels increased in a dose-related manner and returned to baseline by 24 h post-dose for doses up to 10 mg/kg but remained in circulation for >72 h post-dose for doses >10 mg/kg. CER-001 caused elevations in plasma cholesterol and total and unesterified cholesterol in the HDL fraction. Mobilisation of unesterified cholesterol in the HDL fraction was seen with CER-001 at doses as low as 2 mg/kg.
CER-001 is well tolerated when administered to humans as single doses up to 45 mg/kg and mobilises and eliminates cholesterol via reverse lipid transport.
CER-001 由与人载脂蛋白 A-I 复合的磷脂组成，模拟天然的新生前β高密度脂蛋白（HDL）。我们呈现动物模型数据，表明 CER-001 剂量依赖性增加胆固醇流出，并通过反向脂质转运进行随后的消除，同时抑制动脉粥样硬化斑块进展。我们报告了 CER-001 在人体中的首次 I 期研究结果，起始剂量为 0.25mg/kg，这是在每两天给药的 4 周多剂量动物研究中确定的 20mg/kg 安全剂量的 1/80。
18-55 岁的健康志愿者，其低密度脂蛋白胆固醇：高密度脂蛋白胆固醇比值大于 3.0，以双盲随机交叉方式接受单次递增静脉注射剂量的 CER-001（0.25-45.0mg/kg）和安慰剂。受试者在给药后 3 周内进行随访。评估包括不良事件监测、血液采样和临床实验室测量。
共纳入 32 名受试者。所有 CER-001 剂量（0.25-45mg/kg）均安全且耐受良好，不良事件谱与安慰剂相似。对临床化学、血液学和凝血参数的影响与安慰剂相当。未观察到 CER-001 对心电图有不良影响。单次给予 CER-001 后未检测到针对载脂蛋白 A-I 的抗体。载脂蛋白 A-I 水平呈剂量相关性增加，并在 10mg/kg 及以下剂量给药后 24 小时内恢复基线，但在 10mg/kg 以上剂量给药后超过 72 小时仍在循环中。CER-001 引起 HDL 部分胆固醇、总胆固醇和未酯化胆固醇的升高。在 2mg/kg 及更低剂量时，就观察到 CER-001 引起 HDL 部分未酯化胆固醇的动员。
在人体中单次给药高达 45mg/kg 时，CER-001 耐受良好，并通过反向脂质转运动员和消除胆固醇。
