|Other names||ISIS 301012|
|Drug class||Antisense oligonucleotide|
|Main uses||Homozygous familial hypercholesterolemia|
|Side effects||Tiredness, nausea, headache, liver problems, fever, high blood pressure, abdominal pain|
|Typical dose||200 mg q wk|
|Elimination half-life||1–2 months|
|Excretion||<4% in urine in 24 hours|
|Chemical and physical data|
|Molar mass||7594.76 g·mol−1|
|3D model (JSmol)|
Mipomersen, sold under the brand name Kynamro, is a medication used to treat homozygous familial hypercholesterolemia. Effects on overall risk of heart disease or death is unclear. Benefits in other types of high cholesterol is unknown. It is given by injection under the skin.
Common side effects include tiredness, nausea, headache, liver problems, fever, high blood pressure, and abdominal pain. Other side effects may include pain at the site of injection and angioedema. It is a short fragment of DNA, known as an antisense oligonucleotide, that blocks the production of apolipoprotein B.
Mipomersen was approved for medical use in the United States in 2013. In Europe it was denied approval in 2013 due to concerns of greater side effects than benefits. In the United States it costs about 407,000 USD per year.
The typical dose is 200 mg per week.
In clinical trials, 18% of subjects taking mipomersen stopped using the drug due to adverse effects; the most common adverse effects leading to discontinuation were injection site reactions, increases of transaminases, flu-like symptoms (fever, chills, abdominal pain, nausea, vomiting), and abnormal liver tests.
Pregnancy and breastfeeding
Mipomersen is pregnancy category B; women who are pregnant or intending to become pregnant should only use this drug if needed. It is unknown if it is secreted in human breast milk, but it was found to be secreted in the breast milk of rats.
Mechanism of action
Mipomersen binds to the messenger RNA coding for apolipoprotein B-100 (ApoB-100), a protein that is the main component of low-density lipoprotein (LDL) and very low-density lipoprotein (VLDL). As a consequence, the RNA is degraded by the enzyme ribonuclease H, and ApoB-100 is not translated.
After subcutaneous injection, mipomersen reaches highest blood levels after 3 to 4 hours. It accumulates in the liver, which is convenient since apolipoprotein B predominantly acts there. Protein binding is over 90%. The molecule is slowly broken up by endonucleases and subsequently by exonucleases. After 24 hours, less than 4% of the degradation products are found in the urine, and overall half-life is 1 to 2 months.
The compound is a 'second-generation' antisense oligonucleotide; the nucleotides are linked with phosphorothioate linkages rather than the phosphodiester linkages of RNA and DNA, and the sugar parts are deoxyribose in the middle part of the molecule and 2’-O-methoxyethyl-modified ribose at the two ends. These modifications make the drug resistant to degradation by nucleases, allowing it to be administered weekly.
The drug was discovered and developed to Phase 2 by Ionis Pharmaceuticals and subsequently licensed to Genzyme Corporation in 2008 by an auction bid. Ionis earned an upfront payment of $325 million, with payments of a further $825 million if milestones are met.
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