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 accommo ...

; 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 (LDL cholesterol), in the blood and early cardiovascular disease. The most common mutatio ...

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 into the subcutis, the layer of skin directly below the dermis and epidermis, ...

. 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. Signs and symptoms Some of the si ...

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 apply ...

(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 co ...

liver enzymes. Drugs.com: 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 on the package insert for certain prescription drugs, so called because the U.S. Food and Drug Administration specifies that it ...

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, 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 right side of the abdomen. Complicat ...

. 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 ischemia, insufficient blood flow to the Cardiac muscle, heart muscle (myocardium). It is most commonly a symptom of coronary artery disease. Angina is typical ...

and palpitations,

edema Edema, also spelled oedema, and also known as fluid retention, dropsy, hydropsy and swelling, is the build-up of fluid in the body's Tissue (biology), tissue. Most commonly, the legs or arms are affected. Symptoms may include skin which feels t ...

, 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 determining the fate of substances administered ...

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 p ...

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 densit ...

(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, low-density lipo ...

(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 nearl ...

, and ApoB-100 is not

translated Translation is the communication of the meaning of a source-language text by means of an equivalent target-language text. The English language draws a terminological distinction (which does not exist in every language) between ''transla ...

Pharmacokinetics

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

liver The liver is a major Organ (anatomy), organ only found in vertebrates which performs many essential biological functions such as detoxification of the organism, and the Protein biosynthesis, synthesis of proteins and biochemicals necessary for ...

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

endonuclease Endonucleases are enzymes that cleave the phosphodiester bond within a polynucleotide chain. Some, such as deoxyribonuclease I, cut DNA relatively nonspecifically (without regard to sequence), while many, typically called restriction endonucleases ...

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 the ...

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 Oligonucleotides are short DNA or RNA molecules, oligomers, that have a wide range of applications in genetic testing, research, and forensics. Commonly made in the laboratory by solid-phase chemical synthesis, these small bits of nucleic acids ...

; the nucleotides are linked with

phosphorothioate Thiophosphates (or phosphorothioates, PS) are chemical compounds and anions with the general chemical formula (''x'' = 0, 1, 2, or 3) and related derivatives where organic groups are attached to one or more O or S. Thiophosphates feature tetrahedr ...

linkages rather than the

phosphodiester In chemistry, a phosphodiester bond occurs when exactly two of the hydroxyl groups () in phosphoric acid react with hydroxyl groups on other molecules to form two ester bonds. The "bond" involves this linkage . Discussion of phosphodiesters is d ...

linkages of

RNA Ribonucleic acid (RNA) is a polymeric molecule essential in various biological roles in coding, decoding, regulation and expression of genes. RNA and deoxyribonucleic acid ( DNA) are nucleic acids. Along with lipids, proteins, and carbohydra ...

and DNA, 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 A nuclease (also archaically known as nucleodepolymerase or polynucleotidase) is an enzyme capable of cleaving the phosphodiester bonds between nucleotides of nucleic acids. Nucleases variously effect single and double stranded breaks in their t ...

, 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 3 commercially approved medicines: Spinraza (Nusinersen), Tegsedi ( I ...

and subsequently licensed to

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

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 medicinal products. Prior to 2004, it was known as the European Agency for the Evaluation of Medicinal Products or Euro ...

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.Staff (29 January 2013
FDA approves new orphan drug Kynamro to treat inherited cholesterol disorder
U.S. Food and Drug Administration, Retrieved 31 January 2013

References

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