Mipomersen

Identification

Summary

Mipomersen is an oligonucleotide drug used for the treatment of homozygous familial hypercholesterolemia.

Brand Names
Kynamro
Generic Name
Mipomersen
DrugBank Accession Number
DB05528
Background

Mipomersen sodium, which was known as the investigational drug, isis-301012, is the salt form of a synthetic phosphorothioate oligonucleotide. Mipomersen sodium prevents the formation of apo B-100, resulting in a decrease in the levels of apolipoprotein B (apo B), low density lipoprotein (LDL), and total cholesterol. Mipomersen is indicated in patients with homozygous familial hypercholesterolemia as an adjunct to diet and other lipid-lowering medications. It is marketed under the brand name Kynamro in the United States, and the FDA label includes a black box warning of hepatoxicity. Specifically, elevations in the liver enzymes, i.e. transaminases, and in liver fat (hepatic steatosis) have been reported. Due to this serious risk of liver toxicity, mipomersen sodium is only available to patients under the restricted program called Kynamro Risk Evaluation and Mitigation Strategy program.

Type
Small Molecule
Groups
Approved, Investigational
Structure
Thumb
Weight
Average: 7177.11
Monoisotopic: 7172.091682609
Chemical Formula
C230H324N67O122P19S19
Synonyms
  • Mipomersen
External IDs
  • ISIS 301012
  • ISIS-301012

Pharmacology

Indication

Used in patients with homozygous familial hypercholesterolemia as an adjunct to diet and other lipid-lowering medications.

Pharmacology
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Associated Conditions
Contraindications & Blackbox Warnings
Contraindications
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Pharmacodynamics

Mipomersen sodium decreases the levels of apolipoprotein B (apo B), low density lipoprotein (LDL) non-high density lipoprotein-cholesterol, and total cholesterol.

Mechanism of action

Mipomersen binds to the mRNA that codes for apoB-100. This binding leads to double-stranded RNA, which is degraded by RNase H and prevents translation of the mRNA to form the apo B-100 protein.

TargetActionsOrganism
AmRNA of ApoB-100
binder
Humans
Absorption

The maximum mipomersen concentration is reached in about 3-4 hours after subcutaneous injection. Additionally the bioavailability of mipomersn is dose-dependant and ranges from 54%-78%.

Volume of distribution

The volume of distribution for mipomersen was not quantified.

Protein binding

Plasma protein binding for mipomersen is greater than or equal to 90%.

Metabolism

Mipomersem is metabolized by endonucleases. Once degraded into shorter oligonucleotides, it is metabolized further by exonucleases.

Route of elimination

24 hours after mipomersem administration, less than 4% of mipomersem and/or it's metabolites were excreted in the urine.

Half-life

Mipomersem has a very long half life of 1-2 months.

Clearance

Clearance of mipomersem was not quantified.

Adverse Effects
Adverseeffects
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Toxicity

The FDA label includes a black box warning of mipomersem induced hepatoxicity. Other less serious adverse effects include nausea, headache, fatigue, local injection site reactions, and flu-like symptoms.

Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
DrugInteraction
AcetaminophenAcetaminophen may increase the hepatotoxic activities of Mipomersen.
AmiodaroneAmiodarone may increase the hepatotoxic activities of Mipomersen.
DemeclocyclineDemeclocycline may increase the hepatotoxic activities of Mipomersen.
DoxycyclineDoxycycline may increase the hepatotoxic activities of Mipomersen.
EravacyclineEravacycline may increase the hepatotoxic activities of Mipomersen.
EthanolEthanol may increase the hepatotoxic activities of Mipomersen.
IsotretinoinIsotretinoin may increase the hepatotoxic activities of Mipomersen.
LomitapideLomitapide may increase the hepatotoxic activities of Mipomersen.
LymecyclineLymecycline may increase the hepatotoxic activities of Mipomersen.
MetacyclineMetacycline may increase the hepatotoxic activities of Mipomersen.
Interactions
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Food Interactions
  • Avoid excessive or chronic alcohol consumption. Alcohol may increase the risk of liver injury.

Products

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Product Ingredients
IngredientUNIICASInChI Key
Mipomersen sodium18EAY4870E629167-92-6OSGPYAHSKOGBFY-KMHHXCEHSA-A
International/Other Brands
Kynamro
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
KynamroInjection, solution200 mg/1mLSubcutaneousGenzyme Corporation2013-01-292013-01-29US flag
KynamroInjection, solution200 mg/1mLSubcutaneousKastle Therapeutics, Llc2016-05-02Not applicableUS flag
KynamroInjection, solution200 mg/1mLSubcutaneousGenzyme Corporation2013-01-292017-10-31US flag

Categories

ATC Codes
C10AX11 — Mipomersen
Drug Categories
Classification
Not classified
Affected organisms
  • Humans and other mammals

Chemical Identifiers

UNII
9GJ8S4GU0M
CAS number
1000120-98-8
InChI Key
TZRFSLHOCZEXCC-HIVFKXHNSA-N
InChI
InChI=1S/C230H324N67O122P19S19/c1-97-55-278(217(309)256-177(97)231)141-45-131(112(400-141)70-381-422(327,328)442-136-50-146(283-66-108(12)196(302)275-228(283)320)406-118(136)76-387-427(337,338)448-140-54-150(294-93-253-154-191(294)266-214(243)270-200(154)306)409-120(140)78-389-428(339,340)446-138-52-148(292-91-250-151-186(240)246-89-248-188(151)292)407-121(138)79-390-430(343,344)450-169-124(413-204(160(169)373-37-27-363-17)286-59-101(5)181(235)260-221(286)313)83-394-435(353,354)455-174-128(417-209(165(174)378-42-32-368-22)291-68-110(14)198(304)277-230(291)322)87-396-434(351,352)453-172-126(415-207(163(172)376-40-30-366-20)289-62-104(8)184(238)263-224(289)316)85-395-433(349,350)452-171-123(412-206(162(171)375-39-29-365-19)288-61-103(7)183(237)262-223(288)315)82-393-432(347,348)449-168-111(69-298)410-211(159(168)372-36-26-362-16)296-95-254-155-192(296)267-215(244)271-201(155)307)439-420(323,324)384-74-117-137(51-147(405-117)284-67-109(13)197(303)276-229(284)321)444-425(333,334)388-77-119-139(53-149(408-119)293-92-252-153-190(293)265-213(242)269-199(153)305)447-426(335,336)386-71-113-132(46-142(401-113)279-56-98(2)178(232)257-218(279)310)440-421(325,326)383-73-115-135(49-145(403-115)282-65-107(11)195(301)274-227(282)319)443-424(331,332)385-75-116-134(48-144(404-116)281-64-106(10)194(300)273-226(281)318)441-423(329,330)382-72-114-133(47-143(402-114)280-57-99(3)179(233)258-219(280)311)445-429(341,342)392-81-129-176(167(380-44-34-370-24)212(419-129)297-96-255-156-193(297)268-216(245)272-202(156)308)457-438(359,360)398-86-127-173(164(377-41-31-367-21)208(416-127)290-63-105(9)185(239)264-225(290)317)454-436(355,356)399-88-130-175(166(379-43-33-369-23)210(418-130)295-94-251-152-187(241)247-90-249-189(152)295)456-437(357,358)397-84-125-170(161(374-38-28-364-18)205(414-125)287-60-102(6)182(236)261-222(287)314)451-431(345,346)391-80-122-157(299)158(371-35-25-361-15)203(411-122)285-58-100(4)180(234)259-220(285)312/h55-68,89-96,111-150,157-176,203-212,298-299H,25-54,69-88H2,1-24H3,(H,323,324)(H,325,326)(H,327,328)(H,329,330)(H,331,332)(H,333,334)(H,335,336)(H,337,338)(H,339,340)(H,341,342)(H,343,344)(H,345,346)(H,347,348)(H,349,350)(H,351,352)(H,353,354)(H,355,356)(H,357,358)(H,359,360)(H2,231,256,309)(H2,232,257,310)(H2,233,258,311)(H2,234,259,312)(H2,235,260,313)(H2,236,261,314)(H2,237,262,315)(H2,238,263,316)(H2,239,264,317)(H2,240,246,248)(H2,241,247,249)(H,273,300,318)(H,274,301,319)(H,275,302,320)(H,276,303,321)(H,277,304,322)(H3,242,265,269,305)(H3,243,266,270,306)(H3,244,267,271,307)(H3,245,268,272,308)/t111-,112-,113-,114-,115-,116-,117-,118-,119-,120-,121-,122+,123-,124-,125+,126-,127+,128-,129-,130+,131+,132+,133+,134+,135+,136+,137+,138+,139+,140+,141-,142-,143-,144-,145-,146-,147-,148-,149-,150-,157+,158+,159-,160-,161+,162-,163-,164+,165-,166+,167-,168-,169-,170+,171-,172-,173+,174-,175+,176-,203+,204-,205+,206-,207-,208+,209-,210+,211-,212-/m1/s1
IUPAC Name
{[(2S,3S,4R,5S)-5-(4-amino-5-methyl-2-oxo-1,2-dihydropyrimidin-1-yl)-2-{[({[(2S,3S,4R,5S)-2-{[({[(2S,3S,4R,5S)-5-(4-amino-5-methyl-2-oxo-1,2-dihydropyrimidin-1-yl)-2-{[({[(2R,3R,4S,5R)-2-{[({[(2R,3S,5R)-5-(4-amino-5-methyl-2-oxo-1,2-dihydropyrimidin-1-yl)-2-{[({[(2R,3S,5R)-2-{[({[(2R,3S,5R)-2-{[({[(2R,3S,5R)-5-(4-amino-5-methyl-2-oxo-1,2-dihydropyrimidin-1-yl)-2-{[({[(2R,3S,5R)-2-{[({[(2R,3S,5R)-2-{[({[(2R,3S,5R)-5-(4-amino-5-methyl-2-oxo-1,2-dihydropyrimidin-1-yl)-2-{[({[(2R,3S,5R)-2-{[({[(2R,3S,5R)-2-{[({[(2R,3S,5R)-2-{[({[(2R,3R,4S,5R)-5-(4-amino-5-methyl-2-oxo-1,2-dihydropyrimidin-1-yl)-2-{[({[(2R,3R,4S,5R)-2-{[({[(2R,3R,4S,5R)-5-(4-amino-5-methyl-2-oxo-1,2-dihydropyrimidin-1-yl)-2-{[({[(2R,3R,4S,5R)-5-(4-amino-5-methyl-2-oxo-1,2-dihydropyrimidin-1-yl)-2-{[({[(2R,3R,4S,5R)-5-(2-amino-6-oxo-6,9-dihydro-1H-purin-9-yl)-2-(hydroxymethyl)-4-(2-methoxyethoxy)oxolan-3-yl]sulfanyl}(hydroxy)phosphoryl)oxy]methyl}-4-(2-methoxyethoxy)oxolan-3-yl]sulfanyl}(hydroxy)phosphoryl)oxy]methyl}-4-(2-methoxyethoxy)oxolan-3-yl]sulfanyl}(hydroxy)phosphoryl)oxy]methyl}-4-(2-methoxyethoxy)-5-(5-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-yl)oxolan-3-yl]sulfanyl}(hydroxy)phosphoryl)oxy]methyl}-4-(2-methoxyethoxy)oxolan-3-yl]sulfanyl}(hydroxy)phosphoryl)oxy]methyl}-5-(6-amino-9H-purin-9-yl)oxolan-3-yl]sulfanyl}(hydroxy)phosphoryl)oxy]methyl}-5-(2-amino-6-oxo-6,9-dihydro-1H-purin-9-yl)oxolan-3-yl]sulfanyl}(hydroxy)phosphoryl)oxy]methyl}-5-(5-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-yl)oxolan-3-yl]sulfanyl}(hydroxy)phosphoryl)oxy]methyl}oxolan-3-yl]sulfanyl}(hydroxy)phosphoryl)oxy]methyl}-5-(5-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-yl)oxolan-3-yl]sulfanyl}(hydroxy)phosphoryl)oxy]methyl}-5-(2-amino-6-oxo-6,9-dihydro-1H-purin-9-yl)oxolan-3-yl]sulfanyl}(hydroxy)phosphoryl)oxy]methyl}oxolan-3-yl]sulfanyl}(hydroxy)phosphoryl)oxy]methyl}-5-(5-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-yl)oxolan-3-yl]sulfanyl}(hydroxy)phosphoryl)oxy]methyl}-5-(5-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-yl)oxolan-3-yl]sulfanyl}(hydroxy)phosphoryl)oxy]methyl}oxolan-3-yl]sulfanyl}(hydroxy)phosphoryl)oxy]methyl}-5-(2-amino-6-oxo-6,9-dihydro-1H-purin-9-yl)-4-(2-methoxyethoxy)oxolan-3-yl]sulfanyl}(hydroxy)phosphoryl)oxy]methyl}-4-(2-methoxyethoxy)oxolan-3-yl]sulfanyl}(hydroxy)phosphoryl)oxy]methyl}-5-(6-amino-9H-purin-9-yl)-4-(2-methoxyethoxy)oxolan-3-yl]sulfanyl}(hydroxy)phosphoryl)oxy]methyl}-4-(2-methoxyethoxy)oxolan-3-yl]sulfanyl}({[(2S,3S,4S,5S)-5-(4-amino-5-methyl-2-oxo-1,2-dihydropyrimidin-1-yl)-3-hydroxy-4-(2-methoxyethoxy)oxolan-2-yl]methoxy})phosphinic acid
SMILES
COCCO[C@H]1[C@@H](O)[C@H](COP(O)(=O)S[C@H]2[C@H](COP(O)(=O)S[C@H]3[C@H](COP(O)(=O)S[C@H]4[C@H](COP(O)(=O)S[C@@H]5[C@@H](COP(O)(=O)S[C@H]6C[C@@H](O[C@@H]6COP(O)(=O)S[C@H]6C[C@@H](O[C@@H]6COP(O)(=O)S[C@H]6C[C@@H](O[C@@H]6COP(O)(=O)S[C@H]6C[C@@H](O[C@@H]6COP(O)(=O)S[C@H]6C[C@@H](O[C@@H]6COP(O)(=O)S[C@H]6C[C@@H](O[C@@H]6COP(O)(=O)S[C@H]6C[C@@H](O[C@@H]6COP(O)(=O)S[C@H]6C[C@@H](O[C@@H]6COP(O)(=O)S[C@H]6C[C@@H](O[C@@H]6COP(O)(=O)S[C@H]6C[C@@H](O[C@@H]6COP(O)(=O)S[C@@H]6[C@@H](COP(O)(=O)S[C@@H]7[C@@H](COP(O)(=O)S[C@@H]8[C@@H](COP(O)(=O)S[C@@H]9[C@@H](COP(O)(=O)S[C@@H]%10[C@@H](CO)O[C@H]([C@@H]%10OCCOC)N%10C=NC%11=C%10N=C(N)NC%11=O)O[C@H]([C@@H]9OCCOC)N9C=C(C)C(N)=NC9=O)O[C@H]([C@@H]8OCCOC)N8C=C(C)C(N)=NC8=O)O[C@H]([C@@H]7OCCOC)N7C=C(C)C(=O)NC7=O)O[C@H]([C@@H]6OCCOC)N6C=C(C)C(N)=NC6=O)N6C=NC7=C6N=CN=C7N)N6C=NC7=C6N=C(N)NC7=O)N6C=C(C)C(=O)NC6=O)N6C=C(C)C(N)=NC6=O)N6C=C(C)C(=O)NC6=O)N6C=NC7=C6N=C(N)NC7=O)N6C=C(C)C(N)=NC6=O)N6C=C(C)C(=O)NC6=O)N6C=C(C)C(=O)NC6=O)N6C=C(C)C(N)=NC6=O)O[C@H]([C@@H]5OCCOC)N5C=NC6=C5N=C(N)NC6=O)O[C@@H]([C@H]4OCCOC)N4C=C(C)C(N)=NC4=O)O[C@@H]([C@H]3OCCOC)N3C=NC4=C3N=CN=C4N)O[C@@H]([C@H]2OCCOC)N2C=C(C)C(N)=NC2=O)O[C@@H]1N1C=C(C)C(N)=NC1=O

References

General References
  1. Kastelein JJ, Wedel MK, Baker BF, Su J, Bradley JD, Yu RZ, Chuang E, Graham MJ, Crooke RM: Potent reduction of apolipoprotein B and low-density lipoprotein cholesterol by short-term administration of an antisense inhibitor of apolipoprotein B. Circulation. 2006 Oct 17;114(16):1729-35. Epub 2006 Oct 9. [Article]
  2. Hair P, Cameron F, McKeage K: Mipomersen sodium: first global approval. Drugs. 2013 Apr;73(5):487-93. doi: 10.1007/s40265-013-0042-2. [Article]
KEGG Drug
D08946
PubChem Compound
131704297
PubChem Substance
347827735
ChemSpider
58134079
RxNav
1367839
ChEMBL
CHEMBL2219536
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Mipomersen
FDA label
Download (923 KB)
MSDS
Download (567 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
3CompletedTreatmentAtherosclerosis / LDL-hypercholesterolemia1
3CompletedTreatmentCongenital Abnormalities / Dyslipidemia / Genetic Diseases, Inborn / High Cholesterol / Hypercholesterolemia, Autosomal Dominant / Hyperlipidemias / Hyperlipoproteinemia Type II / Hyperlipoproteinemias / Lipid Metabolism, Inborn Errors / Metabolic Diseases / Metabolic Disorders / Metabolism Disorder, Lipid / Metabolism, Inborn Errors / Newborn, Infant, Disease2
3CompletedTreatmentCoronary Artery Disease (CAD) / Heterozygous Familial Hypercholesterolemia (HeFH)1
3CompletedTreatmentCoronary Heart Disease (CHD) / High Cholesterol2
3CompletedTreatmentHeterozygous Familial / High Cholesterol1
2CompletedTreatmentCongenital Abnormalities / Dyslipidemia / Genetic Diseases, Inborn / High Cholesterol / Hypercholesterolemia, Autosomal Dominant / Hyperlipidemias / Hyperlipoproteinemia Type II / Hyperlipoproteinemias / Lipid Metabolism, Inborn Errors / Metabolic Diseases / Metabolic Disorders / Metabolism Disorder, Lipid / Metabolism, Inborn Errors / Newborn, Infant, Disease1
2CompletedTreatmentCongenital Abnormalities / Dyslipidemia / Genetic Diseases, Inborn / High Cholesterol / Hyperlipidemias / Hypobetalipoproteinemias / Lipid Metabolism, Inborn Errors / Lipoprotein deficiency / Metabolic Diseases / Metabolic Disorders / Metabolism Disorder, Lipid / Metabolism, Inborn Errors / Newborn, Infant, Disease1
2CompletedTreatmentDyslipidemia / High Cholesterol / Hyperlipidemias / Metabolic Diseases / Metabolic Disorders / Metabolism Disorder, Lipid1
2CompletedTreatmentHigh Cholesterol1
2CompletedTreatmentPrimary Hypercholesterolemia1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
Injection, solutionSubcutaneous200 mg/1mL
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US7407943No2008-08-052021-08-01US flag
US7015315No2006-03-212023-03-21US flag
US7511131No2009-03-312025-12-13US flag
US6451991No2002-09-172017-02-11US flag
US6166197No2000-12-262017-12-26US flag
US7101993No2006-09-052023-09-05US flag

Properties

State
Liquid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
logP-9.4ChemAxon
pKa (Strongest Acidic)1.28ChemAxon
Physiological Charge-5ChemAxon
Hydrogen Acceptor Count141ChemAxon
Hydrogen Donor Count45ChemAxon
Polar Surface Area2549.43 Å2ChemAxon
Rotatable Bond Count156ChemAxon
Refractivity1599.37 m3·mol-1ChemAxon
Polarizability675.96 Å3ChemAxon
Number of Rings46ChemAxon
Bioavailability0ChemAxon
Rule of FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
Predicted ADMET Features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
Not Available

Targets

Drugtargets2
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Kind
Nucleotide
Organism
Humans
Pharmacological action
Yes
Actions
Binder
This gene product is the main apolipoprotein of chylomicrons and low density lipoproteins. It occurs in plasma as two main isoforms, apoB-48 and apoB-100: the former is synthesized exclusively in the gut and the latter in the liver. The intestinal and the hepatic forms of apoB are encoded by a single gene from a single, very long mRNA. The two isoforms share a common N-terminal sequence. The shorter apoB-48 protein is produced after RNA editing of the apoB-100 transcript at residue 2180 (CAA->UAA), resulting in the creation of a stop codon, and early translation termination. Mutations in this gene or its regulatory region cause hypobetalipoproteinemia, normotriglyceridemic hypobetalipoproteinemia, and hypercholesterolemia due to ligand-defective apoB, diseases affecting plasma cholesterol and apoB levels.
References
  1. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [Article]

Drug created on November 18, 2007 18:25 / Updated on September 25, 2021 23:56