Mipomersen, an apolipoprotein B synthesis inhibitor, for lowering of LDL cholesterol concentrations in patients with homozygous familial hypercholesterolaemia: a randomised, double-blind, placebo-controlled trial
Mipomersen, an apolipoprotein B synthesis inhibitor, for lowering of LDL cholesterol concentrations in patients with homozygous familial hypercholesterolaemia: a randomised, double-blind, placebo-controlled trial
复制标题
DOI：
10.1016/s0140-6736(10)60284-x
复制
发表时间：
2010-03-20
期刊：
影响因子：
168.9
通讯作者：
Crooke, Stanley T.
中科院分区：
文献类型：
--
作者：
Raal, Frederick J.;Santos, Raul D.;Crooke, Stanley T.
背景纯合子家族性高胆固醇血症是一种罕见的遗传性疾病，其中两个LDL受体等位基因都有缺陷，导致血浆中LDL胆固醇浓度非常高和早发冠状动脉疾病。本研究探讨是否反义抑制剂的载脂蛋白B合成，米泊美生，是有效和安全的作为一种预防剂，以降低低密度脂蛋白胆固醇浓度的患者与此diseases.Methods这种随机，双盲，安慰剂对照，3期研究进行了9个脂质诊所在7个国家。年龄在12岁及12岁以上，临床诊断或遗传学证实为纯合子家族性高胆固醇血症，且已接受最大耐受剂量的降脂药物的患者，被随机分配至每周皮下注射200 mg米泊美生或安慰剂组，持续26周。随机化由计算机生成，并在集中区组随机化中按体重（≥ 50 kg）分层，采用计算机化交互式语音应答系统实施。所有临床、医疗和药房人员以及患者均对治疗分配设盲。主要终点是LDL胆固醇浓度较基线的百分比变化。该试验在ClinicalTrials.gov注册，编号为NCT 00607373。结果34名患者被分配到米泊美生组，17名患者被分配到安慰剂组;所有患者的数据都进行了分析。45名患者完成了26周的治疗期（28名米泊美生，17名安慰剂）。米泊美生组基线时LDL胆固醇的平均浓度为11.4 mmol/L（SD 3.6），安慰剂组为10.4 mmol/L（3.7）。米泊美生组LDL胆固醇浓度的平均百分比变化（-24.7%，95%CI 31.6 - 17.7）显著大于安慰剂组（-3.3%，12.1 - 5.5; p=0.0003）。最常见的不良事件是注射部位反应（米泊美生组26例[76%]，安慰剂组4例[24%]）。四（12%）患者在米泊美生组，但没有在安慰剂组的丙氨酸氨基转移酶的浓度增加的三倍或更多的上限normal.Interpretation抑制载脂蛋白B合成的米泊美生代表了一种新的，有效的治疗方法，以降低低密度脂蛋白胆固醇浓度的纯合子家族性高胆固醇血症患者已经接受降脂药物，包括高剂量他汀类药物。
Background Homozygous familial hypercholesterolaemia is a rare genetic disorder in which both LDL-receptor alleles are defective, resulting in very high concentrations of LDL cholesterol in plasma and premature coronary artery disease. This study investigated whether an antisense inhibitor of apolipoprotein B synthesis, mipomersen, is effective and safe as an adjunctive agent to lower LDL cholesterol concentrations in patients with this disease.Methods This randomised, double-blind, placebo-controlled, phase 3 study was undertaken in nine lipid clinics in seven countries. Patients aged 12 years and older with clinical diagnosis or genetic confirmation of homozygous familial hypercholesterolaemia, who were already receiving the maximum tolerated dose of a lipid-lowering drug, were randomly assigned to mipomersen 200 mg subcutaneously every week or placebo for 26 weeks. Randomisation was computer generated and stratified by weight (= 50 kg) in a centralised blocked randomisation, implemented with a computerised interactive voice response system. All clinical, medical, and pharmacy personnel, and patients were masked to treatment allocation. The primary endpoint was percentage change in LDL cholesterol concentration from baseline. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00607373.Findings 34 patients were assigned to mipomersen and 17 to placebo; data for all patients were analysed. 45 patients completed the 26-week treatment period (28 mipomersen, 17 placebo). Mean concentrations of LDL cholesterol at baseline were 11.4 mmol/L (SD 3.6) in the mipomersen group and 10.4 mmol/L (3.7) in the placebo group. The mean percentage change in LDL cholesterol concentration was significantly greater with mipomersen (-24.7%, 95% CI 31.6 to 17.7) than with placebo (-3.3%, 12.1 to 5.5; p=0.0003). The most common adverse events were injection-site reactions (26 [76%] patients in mipomersen group vs four [24%] in placebo group). Four (12%) patients in the mipomersen group but none in the placebo group had increases in concentrations of alanine aminotransferase of three times or more the upper limit of normal.Interpretation Inhibition of apolipoprotein B synthesis by mipomersen represents a novel, effective therapy to reduce LDL cholesterol concentrations in patients with homozygous familial hypercholesterolaemia who are already receiving lipid-lowering drugs, including high-dose statins.