商品名：Kynamro 
通用名：Mipomersen sodium 
中文名：米泊美生钠
审批分类：标准审评+孤儿药
适应症：
用于降低纯合子型家族性高胆固醇血症（homozygous familial hypercholesterolemia, FoFH）患者的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（non-HDL-C）。
剂型规格：
本品是澄清、无色或淡黄色注射液，1ml/瓶或支，200mg/ml，200mg/周，仅用于皮下注射。
活性成分：
Mipomersen sodium。Mipomersen sodium是一种合成的硫代磷酸寡核苷酸（phosphorothioate oligonucleotide）钠盐，20个核苷酸长度，其序列为5’-GMeCMeCMeUMeCAGTMeCTGMeCTTMeCGMeCAMeCMeC-3’（下划线表示2’-O-(甲氧乙基)核苷酸，所有残基均为2’-脱氧核苷酸）。
作用机理：
Mipomersen是一种反义寡核苷酸，能够与Apo B-100蛋白mRNA的编码区互补配对，抑制Apo B-100蛋白（LDL和VLDL的主要载脂蛋白）的翻译合成。
黑框警告：
血清转氨酶（ALT (alanine aminotransferase)和/或AST (aspartate aminotransferase)）升高（4% ALT≥3x ULN (upper limit of normal); 3% ALT≥5x ULN）、脂肪肝（hepatic steatosis）。
不良反应：注射部位反应包括红斑（59%）、疼痛（56%）、血肿（32%）、搔痒（29%）、肿胀（18%）、变色（17%）；流感样症状包括发热、寒颤、肌痛、关节疼痛、心神不安、乏力等（30%）；免疫原性（用药6个月后，38%患者检测到抗体）。
药企：Genzyme Corp.

Kynamro是治疗遗传性胆固醇代谢紊乱的新药
纯合子家族性高胆固醇血症(HoFH)是一种罕见的遗传病，影响着百万分之的美国人，当身体不能将血液中一种被称为“坏”胆固醇的低密度脂蛋白胆固醇移除时，会引起血液中低密度脂蛋白胆固醇的水平异常升高。对于那些患有HoFH的患者，在30岁之前通常会出现心脏病及死亡。近日，美国食品药品管理局（FDA）宣布批准注射用胆固醇药物Kynamro（米泊美生钠），该药物可以和其它降脂药物及饮食一起用于治疗HoFH。米泊美生钠的添加使用有助于降低低密度脂蛋白胆固醇(LDL-C)、载脂蛋白B、总胆固醇（TC）以及非高密度脂蛋白胆固醇（非HDL-C）。
Kynamro（米泊美生钠）一周注射一次，与其它降脂药物及饮食用于损坏最终能引起低密度脂蛋白胆固醇升高的脂质粒子产生，它以孤儿药资格批准，意味着该药物开发的目的是治疗不超过20万人的HoFH患者。2012年12月，FDA批准Juxtapid用于降低HoFH患者的低密度脂蛋白胆固醇、总胆固醇、载脂蛋白B及非高密度脂蛋白胆固醇。
根据一项纳入51例HoFH患者参与的临床试验，对Kynamro（米泊美生钠）的安全性和有效性进行了评估。在临床试验头26周，服药患者低密度脂蛋白胆固醇水平平均降低25%。同时Kynamro也有一项严重肝毒性黑框警告，因为随着该药物的长期使用，可导致肝脏疾病的进展。
FDA在批准Kynamro（米泊美生钠）时采用风险评估与减轻策略(REMS)原理以确保该药物能安全使用，内容包括开药者及药房认证，具备安全使用条件的文件，经此要求每一新处方要有一个处方授权书。
Kynamro（米泊美生钠）在临床试验中最常见的副作用是注射部位反应、流感症状、恶心、头疼及肝酶升高（血清转氨酶）。FDA要求对该产品进行四项上市的研究：该药物约束双链DNA的敏感性分析研究；Kynamro服药患者双链DNA抗体存在的评估研究；对HoFH患者进行长期登记以确定Kynamro长期安全性；加强药物警戒以监测Kynamro服药患者恶性肿瘤、免疫介导反应及肝异常的报道。
KYNAMRO Rx
Pharmacological Class:
Oligonucleotide inhibitor of Apo B-100 synthesis.

Active Ingredient(s):
Mipomersen sodium 200mg/mL; soln for SC inj; preservative-free.

Company
Genzyme Corporation
Indication(s):
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).

Pharmacology:
Mipomersen is an antisense oligonucleotide targeted to human messenger ribonucleic acid (mRNA) for Apo B-100, the principal apolipoprotein of LDL and its metabolic precursors, VLDL. The hybridization of mipomersen to the cognate mRNA results in RNase H-mediated degradation of the cognate mRNA thus inhibiting translation of the Apo B-100 protein.

Clinical Trials:
The safety and efficacy of mipomersen were evaluated in a multinational, randomized, placebo-controlled, 26-week trial in 51 patients with HoFH. Patients were randomized to mipomersen 200mg SC injection once weekly (n=34) or placebo (n=17). In total, 44 of the 50 patients were on maximum-dose statin therapy with/without other lipid-lowering drugs. Thirty-eight of the 50 patients were also taking at least one other lipid-lowering drug, most commonly ezetimibe in 37 of 50 patients; patients were not on LDL apheresis.

The primary efficacy endpoint was percent change in LDL-C from baseline to Week 28. At Week 28, the mean and median percent changes in LDL-C from baseline were -25% (P<0.001) and -19%, respectively, for the mipomersen treatment group. The mean and median treatment difference from placebo were -21% (95% CI: -33, -10) and -19%, respectively. Overall, the LDL-C percent changes from baseline with mipomersen were variable among patients with HoFH ranging from a 2% increase to an 82% reduction. The LDL-C percent changes from baseline in the placebo group range from a 43% increase to a 33% reduction.

Legal Classification:
Rx

Adults:
Give on the same day every week. Administer 1st inj under supervision of qualified health care provider. 200mg SC inj once weekly into the abdomen, thigh region, or outer area of the upper arm. Monitor lipids at least every 3 months for the first year; assess LDL-C after 6 months to determine if reduction achieved warrants potential hepatotoxicity. Adjustments and monitoring in elevated transaminases: see full labeling.

Children:
Not established.

Contraindication(s):
Moderate or severe hepatic impairment (Child-Pugh B or C). Active liver disease (including unexplained persistent elevations of serum transaminases).

Warnings/Precautions:
Adjunct to LDL apheresis: not recommended. Risk of hepatotoxicity. Measure ALT, AST, alkaline phosphatase, and total bilirubin before initiating then regularly thereafter. Withhold if ALT or AST are ≥3x ULN; discontinue if persistent or clinically significant elevations, liver injury, bilirubin ≥2x ULN, or active liver disease occurs. Severe renal impairment, significant proteinuria, or on dialysis: not recommended. Do not inject into areas of active skin disease, injury (eg, sunburns, rashes, inflammation, skin infections, active psoriasis areas), tattooed skin, or scarring. Females of reproductive potential should use effective contraception during therapy. Pregnancy (Cat.B). Nursing mothers: not recommended.

Interaction(s)
Caution with concomitant isotretinoin, amiodarone, acetaminophen (>4g/day for ≥3 days/week), methotrexate, tetracyclines, tamoxifen: increased risk for hepatotoxicity. Concomitant other LDL-lowering agents that can increase steatosis: not recommended. Limit one alcoholic drink per day.

Adverse Reaction(s)
Inj site reactions, flu-like symptoms, nausea, headache, elevated serum transaminases (specifically ALT); hepatic steatosis.

Notes:
Available only through the Kynamro REMS program. Under the Kynamro REMS, only certified health care providers and pharmacies may prescribe and distribute Kynamro. Further information is available at www.KynamroREMS.com or call (877) KYNAMRO.

How Supplied:
Single-use vial—1, 4
Single-use prefilled syringe—1, 4

LAST UPDATED:
5/17/2013