Emerging LDL therapies: Mipomersen¡ªantisense oligonucleotide therapy in the management of?hypercholesterolemia

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• 作者：Peter P. Toth ; MD ; PhD ; FAAFP ; FICA ; FNLA ; FAHA ; FCCP ; FACC ; ^{peter.toth@cghmc.com}
• 关键词：Antisense oligonucleotide ; Apolipoprotein B ; Familial hypercholesterolemia ; Low-density lipoprotein cholesterol ; Mipomersen
• 刊名：Journal of Clinical Lipidology
• 出版年：2013
• 出版时间：May-June, 2013
• 年：2013
• 卷：7
• 期：3_supp_S
• 页码：S6-S10
• 全文大小：259 K

文摘

Familial hypercholesterolemia (FH) is characterized by severe elevations in low-density lipoprotein cholesterol (LDL-C) and poses considerable treatment challenges. Substantive LDL-C reductions are difficult to achieve with standard therapies, and many patients with FH do not tolerate currently available lipid-lowering medications. Mipomersen is an antisense oligonucleotide injectable drug that was recently approved by the Food and Drug Administration for the treatment of homozygous FH. It is complementary in sequence to a segment of the human apolipoprotein (Apo) B-100 messenger RNA and specifically binds to it, blocking translation of the gene product. Reducing the production of?Apo B-100 reduces hepatic production of very low-density lipoprotein, consequently decreasing circulating levels of atherogenic very low-density lipoprotein remnants, intermediate-density lipoproteins, LDL, and lipoprotein(a) particles. Results from a pivotal trial conducted in patients with homozygous FH, and supporting trials in patients with heterozygous FH with coronary artery disease (CAD) (LDL-C ¡Ý100 mg/dL, triglycerides <?200 mg/dL), severe hypercholesterolemia (LDL-C ¡Ý300 mg/dL or ¡Ý200 mg/dL with CAD), and individuals at high risk for CAD (LDL-C ¡Ý100 mg/dL, triglycerides?¡Ü?200 mg/dL), have indicated that mipomersen reduces all Apo B-containing atherogenic lipoproteins. The average LDL-C reduction was >100 mg/dL in homozygous FH and severe hypercholesterolemia populations. The main on-treatment adverse events were mild-to-moderate injection site reactions and flu-like symptoms. Available data regarding the efficacy, safety and tolerability of mipomersen, including results at up to 104 weeks of therapy, support the use of mipomersen for the treatment of FH.