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| Clinical data | |
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| Trade names | Kynamro |
| Other names | ISIS 301012 |
| AHFS/Drugs.com | Multum Consumer Information |
| Routes of administration | Subcutaneous injection |
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| Pharmacokinetic data | |
| Protein binding | ≥90% |
| Metabolism | Nucleases |
| Eliminationhalf-life | 1–2 months |
| Excretion | <4% in urine in 24 hours |
| Identifiers | |
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| CAS Number |
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| PubChemCID | |
| DrugBank | |
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| KEGG | |
| ChEMBL | |
| CompTox Dashboard(EPA) | |
| Chemical and physical data | |
| Formula | C230H305N67Na19O122P19S19 |
| Molar mass | 7594.76 g·mol−1 |
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Mipomersen (INN; trade nameKynamro) is a withdrawn drug that was used to treat homozygousfamilial hypercholesterolemia and is administered bysubcutaneous injection. There is a serious risk ofliver damage from this drug and it was only prescribed in the context of a risk management plan.
Kynamro was used to treat homozygousfamilial hypercholesterolemia and was administered by injection.[1][2]
It was not freely prescribed; every person put on mipomersen was enrolled in aRisk Evaluation and Mitigation Strategies (REMS) program approved by the FDA.[1]
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.[1]
The drug is contraindicated in people with moderate to severe liver impairment, active liver diseases, and unexplained high levels oftransaminase liver enzymes.[1][3]
The drug had ablack box warning about the risk ofliver damage; specifically it can cause elevations in the levels oftransaminases and causesfatty liver disease.[1]
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.[1]
Other adverse effects include: heart problems includingangina and palpitations,edema, pain in legs or arms, headache, insomnia, and hypertension.[1]
Other drugs known for causing liver problems might add to mipomersen's risk of liver damage. Nopharmacokinetic interactions have been described.[3]
Mipomersen binds to themessenger RNA coding forapolipoprotein B-100 (ApoB-100), a protein that is the main component oflow-density lipoprotein (LDL) andvery low-density lipoprotein (VLDL). As a consequence, the RNA is degraded by the enzymeribonuclease H, and ApoB-100 is nottranslated.[3]
After subcutaneous injection, mipomersen reaches highest blood levels after 3 to 4 hours. It accumulates in theliver,[citation needed] which is convenient since apolipoprotein B predominantly acts there. Protein binding is over 90%. The molecule is slowly broken up byendonucleases and subsequently byexonucleases. After 24 hours, less than 4% of the degradation products are found in the urine, and overall half-life is 1 to 2 months.[3]
The compound is a "second-generation"antisense oligonucleotide; the nucleotides are linked withphosphorothioate linkages rather than thephosphodiester linkages ofRNA andDNA, and the sugar parts aredeoxyribose in the middle part of the molecule and 2’-O-methoxyethyl-modified ribose at the two ends, making mipomersen agapmer. These modifications make the drug resistant to degradation bynucleases, allowing it to be administered weekly.
The complete sequence is portrayed below:[5][1]: 10
5’—G*—mC*—mC*—mU*—mC*—dA—dG—dT—dmC—dT—dG—dmC—dT—dT—dmC—G*—mC*—A*—mC*—mC*—3’* = 2’-O-(2-methoxyethyl)m = 5-methyld = 2’-deoxyThe drug was discovered and developed to Phase 2 byIonis Pharmaceuticals (then called Isis Pharmaceuticals) and subsequently licensed toGenzyme 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.[6]
Mipomersen was rejected by theEuropean Medicines Agency in 2012[7] and again in 2013 due to concerns about the liver and cardiovascular adverse effects.[8]
In January 2013, the United States Food and Drug Administration approved mipomersen for the treatment ofhomozygous familial hypercholesterolemia.[9][10]
In 2016, Ionis regained the rights to the drug and sold it to Kastle Pharmaceuticals.[11] In 2019, the FDA withdrew approval for the drug.[12][13]