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 eva luated 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

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。