Mipomersen (

INN Inns are generally establishments or buildings where travelers can seek lodging, and usually, food and drink. Inns are typically located in the country or along a highway. Before the advent of motorized transportation, they also provided accomm ...

; trade name Kynamro) is a drug used to treat homozygous

familial hypercholesterolemia Familial hypercholesterolemia (FH) is a genetic disorder characterized by high cholesterol levels, specifically very high levels of low-density lipoprotein cholesterol (LDL cholesterol), in the blood and early cardiovascular diseases. The mos ...

and is administered by

subcutaneous injection Subcutaneous administration is the insertion of medications beneath the skin either by injection or infusion. A subcutaneous injection is administered as a bolus (medicine), bolus into the subcutis, the layer of skin directly below the dermis and ...

. There is a serious risk of

liver damage Liver disease, or hepatic disease, is any of many diseases of the liver. If long-lasting it is termed chronic liver disease. Although the diseases differ in detail, liver diseases often have features in common. Liver diseases File:Ground glas ...

from this drug and it can only be prescribed in the context of a risk management plan.

Indications

Kynamro is used to treat homozygous

and is administered by injection. It cannot be freely prescribed; instead every person put on mipomersen is enrolled in a

Risk Evaluation and Mitigation Strategies Risk Evaluation and Mitigation Strategies (REMS) is a program of the US Food and Drug Administration for the monitoring of medications with a high potential for serious adverse effects. REMS applies only to specific prescription drugs, but can app ...

(REMS) program approved by the FDA.

Pregnancy and lactation

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.

Contraindications

The drug is contraindicated in people with moderate to severe liver impairment, active liver diseases, and unexplained high levels of

transaminase Transaminases or aminotransferases are enzymes that catalyze a transamination reaction between an amino acid and an α-keto acid. They are important in the synthesis of amino acids, which form proteins. Function and mechanism An amino acid con ...

liver enzymes.

Drugs.com Drugs.com is an online pharmaceutical encyclopedia that provides drug information for consumers and healthcare professionals, primarily in the United States. It self-describes its information as "accurate and independent" yet limited to being " ...

: Mipomersen .

Adverse effects

The drug has a

black box warning In the United States, a boxed warning (sometimes "black box warning", colloquially) is a type of warning that appears near the beginning of the package insert for certain prescription drugs, so called because the U.S. Food and Drug Administratio ...

about the risk of

; specifically it can cause elevations in the levels of

s and causes

fatty liver disease Fatty liver disease (FLD), also known as hepatic steatosis and steatotic liver disease (SLD), is a condition where excess fat builds up in the liver. Often there are no or few symptoms. Occasionally there may be tiredness or pain in the upper r ...

. 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. Other adverse effects include: heart problems including

angina Angina, also known as angina pectoris, is chest pain or pressure, usually caused by insufficient blood flow to the heart muscle (myocardium). It is most commonly a symptom of coronary artery disease. Angina is typically the result of parti ...

and palpitations,

edema Edema (American English), also spelled oedema (British English), and also known as fluid retention, swelling, dropsy and hydropsy, is the build-up of fluid in the body's tissue (biology), tissue. Most commonly, the legs or arms are affected. S ...

, pain in legs or arms, headache, insomnia, and hypertension.

Interactions

Other drugs known for causing liver problems might add to mipomersen's risk of liver damage. No

pharmacokinetic Pharmacokinetics (from Ancient Greek ''pharmakon'' "drug" and ''kinetikos'' "moving, putting in motion"; see chemical kinetics), sometimes abbreviated as PK, is a branch of pharmacology dedicated to describing how the body affects a specific subs ...

interactions have been described.

Pharmacology

Mechanism of action

Mipomersen binds to the

messenger RNA In molecular biology, messenger ribonucleic acid (mRNA) is a single-stranded molecule of RNA that corresponds to the genetic sequence of a gene, and is read by a ribosome in the process of synthesizing a protein. mRNA is created during the ...

coding for apolipoprotein B-100 (ApoB-100), a protein that is the main component of

low-density lipoprotein Low-density lipoprotein (LDL) is one of the five major groups of lipoprotein that transport all fat molecules around the body in extracellular water. These groups, from least dense to most dense, are chylomicrons (aka ULDL by the overall density ...

(LDL) and

very low-density lipoprotein Very-low-density lipoprotein (VLDL), density relative to extracellular water, is a type of lipoprotein made by the liver. VLDL is one of the five major groups of lipoproteins (chylomicrons, VLDL, intermediate-density lipoprotein, LDL, low-density ...

(VLDL). As a consequence, the RNA is degraded by the enzyme

ribonuclease H Ribonuclease H (abbreviated RNase H or RNH) is a family of non-sequence-specific endonuclease enzymes that catalyze the cleavage of RNA in an RNA/DNA substrate via a hydrolytic mechanism. Members of the RNase H family can be found in nearly al ...

, and ApoB-100 is not translated.

Pharmacokinetics

After subcutaneous injection, mipomersen reaches highest blood levels after 3 to 4 hours. It accumulates in the

liver The liver is a major metabolic organ (anatomy), organ exclusively found in vertebrates, which performs many essential biological Function (biology), functions such as detoxification of the organism, and the Protein biosynthesis, synthesis of var ...

, which is convenient since apolipoprotein B predominantly acts there. Protein binding is over 90%. The molecule is slowly broken up by

endonuclease In molecular biology, endonucleases are enzymes that cleave the phosphodiester bond within a polynucleotide chain (namely DNA or RNA). Some, such as deoxyribonuclease I, cut DNA relatively nonspecifically (with regard to sequence), while man ...

s and subsequently by

exonuclease Exonucleases are enzymes that work by cleaving nucleotides one at a time from the end (exo) of a polynucleotide chain. A hydrolyzing reaction that breaks phosphodiester bonds at either the 3′ or the 5′ end occurs. Its close relative is th ...

s. After 24 hours, less than 4% of the degradation products are found in the urine, and overall half-life is 1 to 2 months.

Chemistry

The compound is a 'second-generation' antisense oligonucleotide; the nucleotides are linked with phosphorothioate linkages rather than the phosphodiester linkages of

RNA Ribonucleic acid (RNA) is a polymeric molecule that is essential for most biological functions, either by performing the function itself (non-coding RNA) or by forming a template for the production of proteins (messenger RNA). RNA and deoxyrib ...

and

DNA Deoxyribonucleic acid (; DNA) is a polymer composed of two polynucleotide chains that coil around each other to form a double helix. The polymer carries genetic instructions for the development, functioning, growth and reproduction of al ...

, and the sugar parts are

deoxyribose Deoxyribose, or more precisely 2-deoxyribose, is a monosaccharide with idealized formula H−(C=O)−(CH2)−(CHOH)3−H. Its name indicates that it is a deoxy sugar, meaning that it is derived from the sugar ribose by loss of a hydroxy group. D ...

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 In biochemistry, a nuclease (also archaically known as nucleodepolymerase or polynucleotidase) is an enzyme capable of cleaving the phosphodiester bonds that link nucleotides together to form nucleic acids. Nucleases variously affect single and ...

, allowing it to be administered weekly. The complete sequence is portrayed below: :

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-methyl :d = 2’-deoxy

History

The drug was discovered and developed to Phase 2 by

Ionis Pharmaceuticals Ionis Pharmaceuticals, Inc. is a biotechnology company based in Carlsbad, California, that specializes in discovering and developing RNA-targeted therapeutics. The company has three commercially approved medicines: Spinraza ( Nusinersen), Tegse ...

and subsequently licensed to

Genzyme Corporation Genzyme (also known as Genzyme Transgenics Corp or GTC Biotherapeutics) was an American biotechnology company based in Cambridge, Massachusetts. From its acquisition in 2011 to 2022 Genzyme operated as a fully owned subsidiary of Sanofi. In 2010, ...

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. Mipomersen was rejected by the

European Medicines Agency The European Medicines Agency (EMA) is an agency of the European Union (EU) in charge of the evaluation and supervision of pharmaceutical products. Prior to 2004, it was known as the European Agency for the Evaluation of Medicinal Products ...

in 2012 and again in 2013 due to concerns about the liver and cardiovascular adverse effects. In January 2013, The United States Food and Drug Administration approved mipomersen for the treatment of homozygous familial hypercholesterolemia.

References

{{Lipid modifying agents Antisense RNA Hypolipidemic agents Therapeutic gene modulation Sanofi