Kynamro获准用于治疗纯合子型家族性高胆固醇血症

圣路易斯(MD Consult)——2013年1月29日，美国食品药品管理局(FDA)和健赞公司共同宣布，已批准将Kynamro(mipomersen sodium)用于纯合子型家族性高胆固醇血症(HoFH)患者，作为降脂药物和饮食的辅助药物，以降低低密度脂蛋白胆固醇(LDL-C)、载脂蛋白B (Apo B)、总胆固醇(TC)和非高密度脂蛋白胆固醇(非HDL-C)。Mipomersen是Kynamro的活性成分，是一种以人类apo B-100信使核糖核酸为靶点的反义寡核苷酸，而apo B-100是LDL及其代谢前体极低密度脂蛋白的主要载脂蛋白。

Kynamro的代谢不影响常用处方药物代谢所涉及的细胞色素P450通路，因此发生药物相互作用的可能性很小。当Kynamro与华法林、Kynamro与辛伐他汀或依折麦布同时使用时，未报告任何有临床意义的药代动力学相互作用。

FDA对Kynamro的批准得到了迄今在HoFH患者人群中进行的最大规模临床试验的支持。这项随机、双盲、安慰剂对照的多中心试验中共纳入51例年龄12~53岁的患者，包括7例年龄12~16岁的患者，这些患者正在接受最大可耐受剂量的降脂药物维持治疗。Kynamro治疗使LDL-C l水平从经治疗的基础水平439 mg/dl进一步平均降低113 mg/dl或 25%，并进一步降低所有测定的致动脉粥样硬化颗粒终点。2010年3月，这些数据发表于《柳叶刀》(The Lancet)杂志。

经过对4项3期、随机、双盲、安慰剂对照试验结果的汇总分析，FDA确定了Kynamro的安全性。这些试验共纳入390例患者，其中261例患者接受每周皮下注射Kynamro 200 mg 治疗，129例患者接受安慰剂，中位治疗持续时间为25周。18%接受Kynamro治疗的患者和2%接受安慰剂的患者因不良事件而中断治疗。在Kynamro治疗患者中，导致中断治疗且发生率高于安慰剂组的最常见不良反应为注射部位反应、丙氨酸氨基转移酶和天冬氨酸氨基转移酶水平升高、流感样症状和肝功能检查结果异常。Kynamro标签中包含关于肝脏毒性的加框警告。

Kynamro的用法为200 mg皮下注射，每周1次。

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ST LOUIS (MD Consult) - On January 29, 2013, the US Food and Drug Administration (FDA) and Genzyme announced the approval of Kynamro (mipomersen sodium) as an adjunct to lipid-lowering medications and diet to reduce low density lipoprotein-cholesterol (LDL-C), apolipoprotein B (Apo B), total cholesterol (TC), and non-high density lipoprotein-cholesterol (non HDL-C) in patients with homozygous familial hypercholesterolemia (HoFH). Mipomersen, the active agent in Kynamro, is an antisense oligonucleotide targeted to human messenger ribonucleic acid for apo B-100, the principal apolipoprotein of LDL and its metabolic precursor, very-low-density lipoprotein.

Kynamro is metabolized without affecting the cytochrome P450 pathways used in the metabolism of commonly prescribed drugs, and thus has the potential for limiting drug-drug interactions. No clinically relevant pharmacokinetic interactions were reported between Kynamro and warfarin, or between Kynamro and simvastatin or ezetimibe.

The FDA approval of Kynamro was supported by the largest clinical trial conducted to-date in the HoFH patient population. The randomized, double-blind, placebo-controlled, multicenter trial included 51 patients aged 12 to 53 years, including 7 patients aged 12 to 16 years, who were maintaining a regimen of maximally-tolerated lipid lowering medications. Treatment with Kynamro further reduced LDL-C levels by an average of 113 mg/dL, or 25%, from a treated baseline of 439 mg/dL, and further reduced all measured end points for atherogenic particles. In March 2010, these data were published in The Lancet.

The safety of Kynamro was determined on the basis of pooled results from 4 phase 3, randomized, double-blind, placebo-controlled trials that included a total of 390 patients of whom 261 patients received weekly subcutaneous injections of 200 mg of Kynamro and 129 patients received placebo for a median treatment duration of 25 weeks. Eighteen percent of patients who received Kynamro and 2% of patients who received placebo discontinued treatment as a result of adverse reactions. The most common adverse reactions in patients treated with Kynamro that led to treatment discontinuation and occurred at a rate greater than placebo were injection-site reactions, alanine aminotransferase and aspartate aminotransferase level elevations, flu-like symptoms, and abnormal liver function test results. The label for Kynamro carries a Boxed Warning regarding hepatotoxicity.

Kynamro is administered as a 200-mg weekly subcutaneous injection.