Identification

Name
Mipomersen
Accession Number
DB05528
Type
Small Molecule
Groups
Approved, Investigational
Description

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.

Structure
Thumb
Synonyms
Not Available
External IDs
ISIS 301012 / ISIS-301012
Product Ingredients
IngredientUNIICASInChI Key
Mipomersen sodium18EAY4870E629167-92-6XLTMUFRACYRYJG-UHFFFAOYSA-A
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
KynamroInjection, solution200 mg/1mLSubcutaneousGenzyme Corporation2013-01-292018-10-11Us
KynamroInjection, solution200 mg/1mLSubcutaneousGenzyme Corporation2013-01-292013-01-29Us
KynamroInjection, solution200 mg/1mLSubcutaneousKastle Therapeutics, Llc2016-05-02Not applicableUs
Categories
UNII
9GJ8S4GU0M
CAS number
1000120-98-8
Weight
Average: 7177.11
Monoisotopic: 7172.091682609
Chemical Formula
C230H324N67O122P19S19
InChI Key
XLTMQWVJFPYGMC-UHFFFAOYSA-N
InChI
InChI=1S/C230H324N67O122P19S19/c1-97-55-278(217(309)256-177(97)231)141-45-111(122(381-141)70-362-422(325,441)404-116-50-146(283-66-108(12)196(302)275-228(283)320)387-128(116)76-368-427(330,446)410-120-54-150(294-93-253-154-191(294)266-214(243)270-200(154)306)390-130(120)78-370-428(331,447)408-118-52-148(292-91-250-151-186(240)246-89-248-188(151)292)388-131(118)79-371-430(333,449)412-159-134(394-204(169(159)354-37-27-344-17)286-59-101(5)181(235)260-221(286)313)83-375-435(338,454)417-164-138(398-209(174(164)359-42-32-349-22)291-68-110(14)198(304)277-230(291)322)87-377-434(337,453)415-162-136(396-207(172(162)357-40-30-347-20)289-62-104(8)184(238)263-224(289)316)85-376-433(336,452)414-161-133(393-206(171(161)356-39-29-346-19)288-61-103(7)183(237)262-223(288)315)82-374-432(335,451)411-158-121(69-298)391-211(168(158)353-36-26-343-16)296-95-254-155-192(296)267-215(244)271-201(155)307)401-420(323,439)365-74-127-117(51-147(386-127)284-67-109(13)197(303)276-229(284)321)406-425(328,444)369-77-129-119(53-149(389-129)293-92-252-153-190(293)265-213(242)269-199(153)305)409-426(329,445)367-71-123-112(46-142(382-123)279-56-98(2)178(232)257-218(279)310)402-421(324,440)364-73-125-115(49-145(384-125)282-65-107(11)195(301)274-227(282)319)405-424(327,443)366-75-126-114(48-144(385-126)281-64-106(10)194(300)273-226(281)318)403-423(326,442)363-72-124-113(47-143(383-124)280-57-99(3)179(233)258-219(280)311)407-429(332,448)373-81-139-166(176(361-44-34-351-24)212(400-139)297-96-255-156-193(297)268-216(245)272-202(156)308)419-438(341,457)379-86-137-163(173(358-41-31-348-21)208(397-137)290-63-105(9)185(239)264-225(290)317)416-436(339,455)380-88-140-165(175(360-43-33-350-23)210(399-140)295-94-251-152-187(241)247-90-249-189(152)295)418-437(340,456)378-84-135-160(170(355-38-28-345-18)205(395-135)287-60-102(6)182(236)261-222(287)314)413-431(334,450)372-80-132-157(299)167(352-35-25-342-15)203(392-132)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,323,439)(H,324,440)(H,325,441)(H,326,442)(H,327,443)(H,328,444)(H,329,445)(H,330,446)(H,331,447)(H,332,448)(H,333,449)(H,334,450)(H,335,451)(H,336,452)(H,337,453)(H,338,454)(H,339,455)(H,340,456)(H,341,457)(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)
IUPAC Name
({2-[({[(2-{[({[2-({[({2-[({[(2-{[({[2-({[({2-[({[(2-{[({[5-(6-amino-9H-purin-9-yl)-2-({[hydroxy({[2-({[hydroxy({[2-({[hydroxy({[2-({[hydroxy({[2-({[hydroxy({[5-(6-hydroxy-2-imino-3,9-dihydro-2H-purin-9-yl)-2-(hydroxymethyl)-4-(2-methoxyethoxy)oxolan-3-yl]oxy})sulfanylidene-λ⁵-phosphanyl]oxy}methyl)-5-(2-hydroxy-4-imino-5-methyl-1,4-dihydropyrimidin-1-yl)-4-(2-methoxyethoxy)oxolan-3-yl]oxy})sulfanylidene-λ⁵-phosphanyl]oxy}methyl)-5-(2-hydroxy-4-imino-5-methyl-1,4-dihydropyrimidin-1-yl)-4-(2-methoxyethoxy)oxolan-3-yl]oxy})sulfanylidene-λ⁵-phosphanyl]oxy}methyl)-5-(4-hydroxy-5-methyl-2-oxo-1,2-dihydropyrimidin-1-yl)-4-(2-methoxyethoxy)oxolan-3-yl]oxy})sulfanylidene-λ⁵-phosphanyl]oxy}methyl)-5-(2-hydroxy-4-imino-5-methyl-1,4-dihydropyrimidin-1-yl)-4-(2-methoxyethoxy)oxolan-3-yl]oxy})sulfanylidene-λ⁵-phosphanyl]oxy}methyl)oxolan-3-yl]oxy}(hydroxy)sulfanylidene-λ⁵-phosphanyl)oxy]methyl}-5-(6-hydroxy-2-imino-3,9-dihydro-2H-purin-9-yl)oxolan-3-yl)oxy](hydroxy)sulfanylidene-λ⁵-phosphanyl}oxy)methyl]-5-(4-hydroxy-5-methyl-2-oxo-1,2-dihydropyrimidin-1-yl)oxolan-3-yl}oxy)(hydroxy)sulfanylidene-λ⁵-phosphanyl]oxy}methyl)-5-(2-hydroxy-4-imino-5-methyl-1,4-dihydropyrimidin-1-yl)oxolan-3-yl]oxy}(hydroxy)sulfanylidene-λ⁵-phosphanyl)oxy]methyl}-5-(4-hydroxy-5-methyl-2-oxo-1,2-dihydropyrimidin-1-yl)oxolan-3-yl)oxy](hydroxy)sulfanylidene-λ⁵-phosphanyl}oxy)methyl]-5-(6-hydroxy-2-imino-3,9-dihydro-2H-purin-9-yl)oxolan-3-yl}oxy)(hydroxy)sulfanylidene-λ⁵-phosphanyl]oxy}methyl)-5-(2-hydroxy-4-imino-5-methyl-1,4-dihydropyrimidin-1-yl)oxolan-3-yl]oxy}(hydroxy)sulfanylidene-λ⁵-phosphanyl)oxy]methyl}-5-(4-hydroxy-5-methyl-2-oxo-1,2-dihydropyrimidin-1-yl)oxolan-3-yl)oxy](hydroxy)sulfanylidene-λ⁵-phosphanyl}oxy)methyl]-5-(4-hydroxy-5-methyl-2-oxo-1,2-dihydropyrimidin-1-yl)oxolan-3-yl}oxy)({[3-({[(3-{[({3-[({[5-(6-amino-9H-purin-9-yl)-3-({hydroxy[(3-{[hydroxy({[3-hydroxy-5-(2-hydroxy-4-imino-5-methyl-1,4-dihydropyrimidin-1-yl)-4-(2-methoxyethoxy)oxolan-2-yl]methoxy})sulfanylidene-λ⁵-phosphanyl]oxy}-5-(2-hydroxy-4-imino-5-methyl-1,4-dihydropyrimidin-1-yl)-4-(2-methoxyethoxy)oxolan-2-yl)methoxy]sulfanylidene-λ⁵-phosphanyl}oxy)-4-(2-methoxyethoxy)oxolan-2-yl]methoxy}(hydroxy)sulfanylidene-λ⁵-phosphanyl)oxy]-5-(2-hydroxy-4-imino-5-methyl-1,4-dihydropyrimidin-1-yl)-4-(2-methoxyethoxy)oxolan-2-yl}methoxy)(hydroxy)sulfanylidene-λ⁵-phosphanyl]oxy}-5-(6-hydroxy-2-imino-3,9-dihydro-2H-purin-9-yl)-4-(2-methoxyethoxy)oxolan-2-yl)methoxy](hydroxy)sulfanylidene-λ⁵-phosphanyl}oxy)-5-(2-hydroxy-4-imino-5-methyl-1,4-dihydropyrimidin-1-yl)oxolan-2-yl]methoxy})sulfanylidenephosphinous acid
SMILES
[H]C1(CC([H])(OP(O)(=S)OCC2([H])OC([H])(CC2([H])OP(O)(=S)OCC2([H])OC([H])(CC2([H])OP(O)(=S)OCC2([H])OC([H])(CC2([H])OP(O)(=S)OCC2([H])OC([H])(CC2([H])OP(O)(=S)OCC2([H])OC([H])(CC2([H])OP(O)(=S)OCC2([H])OC([H])(CC2([H])OP(O)(=S)OCC2([H])OC([H])(CC2([H])OP(O)(=S)OCC2([H])OC([H])(CC2([H])OP(O)(=S)OCC2([H])OC([H])(N3C=NC4=C3NC(=N)N=C4O)C([H])(OCCOC)C2([H])OP(O)(=S)OCC2([H])OC([H])(N3C=C(C)C(=N)N=C3O)C([H])(OCCOC)C2([H])OP(O)(=S)OCC2([H])OC([H])(N3C=NC4=C(N)N=CN=C34)C([H])(OCCOC)C2([H])OP(O)(=S)OCC2([H])OC([H])(N3C=C(C)C(=N)N=C3O)C([H])(OCCOC)C2([H])OP(O)(=S)OCC2([H])OC([H])(N3C=C(C)C(=N)N=C3O)C([H])(OCCOC)C2([H])O)N2C=C(C)C(=N)N=C2O)N2C=C(C)C(O)=NC2=O)N2C=C(C)C(O)=NC2=O)N2C=C(C)C(=N)N=C2O)N2C=NC3=C2NC(=N)N=C3O)N2C=C(C)C(O)=NC2=O)N2C=C(C)C(=N)N=C2O)N2C=C(C)C(O)=NC2=O)C([H])(COP(O)(=S)OC2([H])CC([H])(OC2([H])COP(O)(=S)OC2([H])C([H])(COP(O)(=S)OC3([H])C([H])(COP(O)(=S)OC4([H])C([H])(COP(O)(=S)OC5([H])C([H])(COP(O)(=S)OC6([H])C([H])(CO)OC([H])(N7C=NC8=C7NC(=N)N=C8O)C6([H])OCCOC)OC([H])(N6C=C(C)C(=N)N=C6O)C5([H])OCCOC)OC([H])(N5C=C(C)C(=N)N=C5O)C4([H])OCCOC)OC([H])(N4C=C(C)C(O)=NC4=O)C3([H])OCCOC)OC([H])(N3C=C(C)C(=N)N=C3O)C2([H])OCCOC)N2C=NC3=C(N)N=CN=C23)O1)N1C=NC2=C1NC(=N)N=C2O

Pharmacology

Indication

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

Associated Conditions
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
Human
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.

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.

Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
AcetaminophenAcetaminophen may increase the hepatotoxic activities of Mipomersen.
AmiodaroneAmiodarone may increase the hepatotoxic activities of Mipomersen.
ClomocyclineClomocycline may increase the hepatotoxic activities of Mipomersen.
DemeclocyclineDemeclocycline may increase the hepatotoxic activities of Mipomersen.
DoxycyclineDoxycycline 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.
MeclocyclineMeclocycline may increase the hepatotoxic activities of Mipomersen.
Food Interactions
  • Limit alcohol to a daily maximum of 1 drink (or equivalent) while using mipomersen sodium.

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. [PubMed:17030687]
  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. [PubMed:23564617]
External Links
KEGG Drug
D08946
PubChem Compound
131704297
PubChem Substance
347827735
ChEMBL
CHEMBL502097
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Mipomersen
ATC Codes
C10AX11 — Mipomersen
FDA label
Download (923 KB)
MSDS
Download (567 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedNot AvailableHealthy Volunteers1
1CompletedTreatmentHealthy Volunteers3
2CompletedTreatmentCongenital Abnormalities / Dyslipidemias / Genetic Diseases, Inborn / High Cholesterol / Hypercholesterolemia, Autosomal Dominant / Hyperlipidemias / Hyperlipoproteinemia Type II / Hyperlipoproteinemias / Infant, Newborn, Diseases / Lipid Metabolism Disorders / Lipid Metabolism, Inborn Errors / Metabolic Diseases / Metabolic Disorders / Metabolism, Inborn Errors1
2CompletedTreatmentCongenital Abnormalities / Dyslipidemias / Genetic Diseases, Inborn / High Cholesterol / Hyperlipidemias / Hypobetalipoproteinemias / Infant, Newborn, Diseases / Lipid Metabolism Disorders / Lipid Metabolism, Inborn Errors / Lipoprotein deficiency / Metabolic Diseases / Metabolic Disorders / Metabolism, Inborn Errors1
2CompletedTreatmentDyslipidemia (Fredrickson Type Ⅱa)2
2CompletedTreatmentDyslipidemias / High Cholesterol / Hyperlipidemias / Lipid Metabolism Disorders / Metabolic Diseases / Metabolic Disorders1
2CompletedTreatmentHigh Cholesterol2
3CompletedTreatmentAtherosclerosis / LDL-hypercholesterolemia1
3CompletedTreatmentCongenital Abnormalities / Dyslipidemias / Genetic Diseases, Inborn / High Cholesterol / Hypercholesterolemia, Autosomal Dominant / Hyperlipidemias / Hyperlipoproteinemia Type II / Hyperlipoproteinemias / Infant, Newborn, Diseases / Lipid Metabolism Disorders / Lipid Metabolism, Inborn Errors / Metabolic Diseases / Metabolic Disorders / Metabolism, Inborn Errors2
3CompletedTreatmentCoronary Artery Disease / Heterozygous Familial Hypercholesterolemia1
3CompletedTreatmentCoronary Heart Disease (CHD) / High Cholesterol2
3CompletedTreatmentHeterozygous Familial / High Cholesterol1

Pharmacoeconomics

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

Properties

State
Liquid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
logP13.27ChemAxon
pKa (Strongest Acidic)1.06ChemAxon
Physiological Charge-13ChemAxon
Hydrogen Acceptor Count140ChemAxon
Hydrogen Donor Count58ChemAxon
Polar Surface Area2430.79 Å2ChemAxon
Rotatable Bond Count156ChemAxon
Refractivity1775.7 m3·mol-1ChemAxon
Polarizability672.05 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

Taxonomy

Description
This compound belongs to the class of organic compounds known as phosphorothioate polynucleotides. These are polynucleotides in which one of the non-bridging oxygens in each phosphodiester linkage has been replaced by sulfur.
Kingdom
Organic compounds
Super Class
Organic Polymers
Class
Phosphorothioate polynucleotides
Sub Class
Not Available
Direct Parent
Phosphorothioate polynucleotides
Alternative Parents
Polysaccharides / Pyrimidine nucleosides / Glycosylamines / 6-aminopurines / Thiophosphate diesters / Hydroxypyrimidines / Pyrimidones / Aminopyrimidines and derivatives / Hydropyrimidines / Imidolactams
show 12 more
Substituents
Phosphorothioate polynucleotide / Polysaccharide / Pyrimidine nucleoside / Glycosyl compound / N-glycosyl compound / 6-aminopurine / Imidazopyrimidine / Purine / Aminopyrimidine / Hydroxypyrimidine
show 30 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
Not Available

Targets

1. mRNA of ApoB-100
Kind
Nucleotide
Organism
Human
Pharmacological action
Yes
Actions
Binder
References
  1. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed:11752352]

Drug created on November 18, 2007 11:25 / Updated on November 02, 2018 08:32