Mipomersen

Last updated
Mipomersen
Mipomersen sodium colored.svg
Clinical data
Trade names Kynamro
Other namesISIS 301012
AHFS/Drugs.com Multum Consumer Information
Routes of
administration 		Subcutaneous injection
ATC code
Legal status
Legal status
Pharmacokinetic data
Protein binding ≥90%
Metabolism Nucleases
Elimination half-life 1–2 months
Excretion <4% in urine in 24 hours
Identifiers
  • 2’-O-(2-Methoxyethyl)-P-thioguanylyl-(3’→5’)-2’-O-(2-methoxyethyl)-5-methyl-P-thiocytidylyl-(3’→5’)-2’-O-(2-methoxyethyl)-5-methyl-P-thiocytidylyl-(3’→5’)-2’-O-(2-methoxyethyl)-5-methyl-P-thiouridylyl-(3’→5’)-2’-O-(2-methoxyethyl)-5-methyl-P-thiocytidylyl-(3’→5’)-2’-deoxy-P-thioadenylyl-(3’→5’)-2’-deoxy-P-thioguanylyl-(3’→5’)-P- thiothymidylyl-(3’→5’)-2’-deoxy-5-methyl-P-thiocytidylyl-(3’→5’)-P-thiothymidylyl-(3’→5’)-2’-deoxy-P-thioguanylyl-(3’→5’)-2’-deoxy-5-methyl-P-thiocytidylyl-(3’→5’)-P-thiothymidylyl-(3’→5’)-P-thiothymidylyl-(3’→5’)-2’-deoxy-5-methyl-P-thiocytidylyl-(3’→5’)-2’-O-(2-methoxyethyl)-P-thioguanylyl-(3’→5’)-2’-O-(2-methoxyethyl)-5-methyl-P-thiocytidylyl-(3’→5’)-2’-O-(2-methoxyethyl)-P-thioadenylyl- (3’→5’)-2’-O-(2-methoxyethyl)-5-methyl-P-thiocytidylyl-(3’→5’)-2’-O-(2-methoxyethyl)-5-methylcytidine nonadecasodiumsalt
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
Formula C230H305N67Na19O122P19S19
Molar mass 7594.76 g·mol−1
3D model (JSmol)
    • COCCO[C@@H]1[C@H](OP(=S)(OC[C@H]2O[C@H](C[C@@H]2OP(=S)(OC[C@H]2O[C@H](C[C@@H]2OP(=S)(OC[C@H]2O[C@H](C[C@@H]2OP(=S)(OC[C@H]2O[C@H](C[C@@H]2OP(=S)(OC[C@H]2O[C@H](C[C@@H]2OP(=S)(OC[C@H]2O[C@H](C[C@@H]2OP(=S)(OC[C@H]2O[C@H](C[C@@H]2OP(=S)(OC[C@H]2O[C@H](C[C@@H]2OP(=S)(OC[C@H]2O[C@H](C[C@@H]2OP(=S)(OC[C@H]2O[C@H](C[C@@H]2OP(=S)(OC[C@H]2O[C@H]([C@@H]([C@@H]2OP(=S)(OC[C@H]2O[C@H]([C@@H]([C@@H]2OP(=S)(OC[C@H]2O[C@H]([C@@H]([C@@H]2OP(=S)(OC[C@H]2O[C@H]([C@@H]([C@@H]2OP(=S)(OC[C@H]2O[C@H]([C@@H]([C@@H]2O)OCCOC)n2cc(C)c(nc2=O)N)O)OCCOC)n2cc(C)c(nc2=O)N)O)OCCOC)n2cnc3c2ncnc3N)O)OCCOC)n2cc(C)c(nc2=O)N)O)OCCOC)n2cnc3c2nc(N)[nH]c3=O)O)n2cc(C)c(nc2=O)N)O)n2cc(C)c(=O)[nH]c2=O)O)n2cc(C)c(=O)[nH]c2=O)O)n2cc(C)c(nc2=O)N)O)n2cnc3c2nc(N)[nH]c3=O)O)n2cc(C)c(=O)[nH]c2=O)O)n2cc(C)c(nc2=O)N)O)n2cc(C)c(=O)[nH]c2=O)O)n2cnc3c2nc(N)[nH]c3=O)O)n2cnc3c2ncnc3N)O)[C@H](O[C@H]1n1cc(C)c(nc1=O)N)COP(=S)(O[C@@H]1[C@@H](COP(=S)(O[C@@H]2[C@@H](COP(=S)(O[C@@H]3[C@@H](COP(=S)(O[C@@H]4[C@@H](CO)O[C@H]([C@@H]4OCCOC)n4cnc5c4nc(N)[nH]c5=O)O)O[C@H]([C@@H]3OCCOC)n3cc(C)c(nc3=O)N)O)O[C@H]([C@@H]2OCCOC)n2cc(C)c(nc2=O)N)O)O[C@H]([C@@H]1OCCOC)n1cc(C)c(=O)[nH]c1=O)O
    • 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)/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+,420?,421?,422?,423?,424?,425?,426?,427?,428?,429?,430?,431?,432?,433?,434?,435?,436?,437?,438?/m0/s1
    • Key:XLTMQWVJFPYGMC-QVKFEXRMSA-N

    Mipomersen (INN; trade name Kynamro) is a drug used to treat homozygous familial hypercholesterolemia and is administered by subcutaneous injection. There is a serious risk of liver damage from this drug and it can only be prescribed in the context of a risk management plan.

    Contents

    Indications

    Kynamro is used to treat homozygous familial hypercholesterolemia and is administered by injection. [1] [2]

    It cannot be freely prescribed; instead every person put on mipomersen is enrolled in a Risk Evaluation and Mitigation Strategies (REMS) program approved by the FDA. [1]

    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. [1]

    Contraindications

    The drug is contraindicated in people with moderate to severe liver impairment, active liver diseases, and unexplained high levels of transaminase liver enzymes. [1] [3]

    Adverse effects

    The drug has a black box warning about the risk of liver damage; specifically it can cause elevations in the levels of transaminases and causes fatty 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 including angina and palpitations, edema, pain in legs or arms, headache, insomnia, and hypertension. [1]

    Interactions

    Other drugs known for causing liver problems might add to mipomersen's risk of liver damage. No pharmacokinetic interactions have been described. [3]

    Pharmacology

    Mechanism of action

    Mipomersen binds to the messenger RNA coding for apolipoprotein B-100 (ApoB-100), a protein that is the main component of low-density lipoprotein (LDL) and very low-density lipoprotein (VLDL). As a consequence, the RNA is degraded by the enzyme ribonuclease H, and ApoB-100 is not translated. [3]

    Pharmacokinetics

    After subcutaneous injection, mipomersen reaches highest blood levels after 3 to 4 hours. It accumulates in the liver,[ citation needed ] which is convenient since apolipoprotein B predominantly acts there. Protein binding is over 90%. The molecule is slowly broken up by endonucleases and subsequently by exonucleases. 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]

    Chemistry

    Chemical structure Mipomersen.svg
    Chemical structure
    Complete skeletal formula Mipomersen sodium.svg
    Complete skeletal formula

    The compound is a 'second-generation' antisense oligonucleotide; the nucleotides are linked with phosphorothioate linkages rather than the phosphodiester linkages of RNA and DNA, and the sugar parts are deoxyribose 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, 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-methyl
    d = 2’-deoxy

    History

    The drug was discovered and developed to Phase 2 by Ionis Pharmaceuticals and subsequently licensed to Genzyme 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 the European 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 of homozygous familial hypercholesterolemia. [9] [10]

    Related Research Articles

    Hypolipidemic agents, cholesterol-lowering drugs or antihyperlipidemic agents, are a diverse group of pharmaceuticals that are used in the treatment of high levels of fats (lipids), such as cholesterol, in the blood (hyperlipidemia). They are called lipid-lowering drugs. These are drugs which lower the level of lipids and lipoproteins in blood.

    Dyslipidemia is an abnormal amount of lipids in the blood. Dyslipidemia is a risk factor for the development of atherosclerotic cardiovascular disease (ASCVD). ASCVD includes coronary artery disease, cerbrovascular disease, and peripheral artery disease. Although dyslipidemia is a risk factor for ASCVD, abnormal levels doesn't mean that lipid lowering agents need to be started. Other factors, such as comorbid conditions and lifestyle in addition to dyslipidemia, is considered in a cardiovascular risk assessment. In developed countries, most dyslipidemias are hyperlipidemias; that is, an elevation of lipids in the blood. This is often due to diet and lifestyle. Prolonged elevation of insulin resistance can also lead to dyslipidemia. Likewise, increased levels of O-GlcNAc transferase (OGT) may cause dyslipidemia.

    Fluvastatin

    Fluvastatin is a member of the statin drug class, used to treat hypercholesterolemia and to prevent cardiovascular disease.

    Ezetimibe Medication used to treat high cholesterol

    Ezetimibe is a medication used to treat high blood cholesterol and certain other lipid abnormalities. Generally it is used together with dietary changes and a statin. Alone, it is less preferred than a statin. It is taken orally. It is also available in the fixed combinations ezetimibe/simvastatin, ezetimibe/atorvastatin, and ezetimibe/rosuvastatin.

    Antisense therapy is a form of treatment that uses antisense oligonucleotides (ASOs) to target messenger RNA (mRNA). ASOs are capable of altering mRNA expression through a variety of mechanisms, including ribonuclease H mediated decay of the pre-mRNA, direct steric blockage, and exon content modulation through splicing site binding on pre-mRNA. Several ASOs have been approved in the United States, the European Union, and elsewhere.

    Antisense RNA

    Antisense RNA (asRNA), also referred to as antisense transcript, natural antisense transcript (NAT) or antisense oligonucleotide, is a single stranded RNA that is complementary to a protein coding messenger RNA (mRNA) with which it hybridizes, and thereby blocks its translation into protein. asRNAs have been found in both prokaryotes and eukaryotes, and can be classified into short and long non-coding RNAs (ncRNAs). The primary function of asRNA is regulating gene expression. asRNAs may also be produced synthetically and have found wide spread use as research tools for gene knockdown. They may also have therapeutic applications.

    Hyperlipidemia is abnormally elevated levels of any or all lipids or lipoproteins in the blood. The term hyperlipidemia refers to the laboratory finding itself and is also used as an umbrella term covering any of various acquired or genetic disorders that result in that finding. Hyperlipidemia represents a subset of dyslipidemia and a superset of hypercholesterolemia. Hyperlipidemia is usually chronic and requires ongoing medication to control blood lipid levels.

    Fenofibrate

    Fenofibrate, is an oral medication of the fibrate class used to treat abnormal blood lipid levels. It is less preferred to statin medications as it does not appear to reduce the risk of heart disease or death. Its use is recommended together with dietary changes.

    Tangier disease or hypoalphalipoproteinemia is an extremely rare inherited disorder characterized by a severe reduction in the amount of high density lipoprotein (HDL), often referred to as "good cholesterol", in the bloodstream. Worldwide, approximately 100 cases have even been identified.

    Familial hypercholesterolemia Genetic disorder characterized by high cholesterol levels

    Familial hypercholesterolemia (FH) is a genetic disorder characterized by high cholesterol levels, specifically very high levels of low-density lipoprotein, in the blood and early cardiovascular disease.The most common mutations diminish the number of functional LDL receptors in the liver. Since the underlying body biochemistry is slightly different in individuals with FH, their high cholesterol levels are less responsive to the kinds of cholesterol control methods which are usually more effective in people without FH. Nevertheless, treatment is usually effective.

    Blood lipids are lipids in the blood, either free or bound to other molecules. They are mostly transported in a protein capsule, and the density of the lipids and type of protein determines the fate of the particle and its influence on metabolism. The concentration of blood lipids depends on intake and excretion from the intestine, and uptake and secretion from cells. Hyperlipidemia is the presence of elevated or abnormal levels of lipids and/or lipoproteins in the blood, and is a major risk factor for cardiovascular disease.

    PCSK9 Mammalian protein found in humans

    Proprotein convertase subtilisin/kexin type 9 (PCSK9) is an enzyme encoded by the PCSK9 gene in humans on chromosome 1. It is the 9th member of the proprotein convertase family of proteins that activate other proteins. Similar genes (orthologs) are found across many species. As with many proteins, PCSK9 is inactive when first synthesized, because a section of peptide chains blocks their activity; proprotein convertases remove that section to activate the enzyme. The PCSK9 gene also contains one of 27 loci associated with increased risk of coronary artery disease.

    Lomitapide

    Lomitapide, sold under the brand name Juxtapid in the US and as Lojuxta in the EU) is a medication used as a lipid-lowering agent for the treatment of familial hypercholesterolemia, developed by Aegerion Pharmaceuticals. It has been tested in clinical trials as single treatment and in combinations with atorvastatin, ezetimibe and fenofibrate.

    Alirocumab, sold under the brand name Praluent, is a medication used as a second-line treatment for high cholesterol for adults whose cholesterol is not controlled by diet and statin treatment. It is a human monoclonal antibody that belongs to a novel class of anti-cholesterol drugs, known as PCSK9 inhibitors, and it was the first such agent to receive FDA approval. The FDA approval was contingent on the completion of further clinical trials to better determine efficacy and safety.

    Ezetimibe/atorvastatin is a cholesterol lowering combination drug. In the United States, it was approved in May 2013, by the Food and Drug Administration for the treatment of elevated low-density lipoprotein (LDL) in patients with primary or mixed hyperlipidemia as adjunctive therapy to diet. It has also been approved to reduce elevated total cholesterol and elevated LDL in patients diagnosed with homozygous familial hypercholesterolemia as an adjunctive treatment to other hyperlipidemia treatments.

    Evinacumab, sold under the brand name Evkeeza, is a monoclonal antibody medication for the treatment of homozygous familial hypercholesterolemia (HoFH).

    Ionis Pharmaceuticals Biotechnology company

    Ionis Pharmaceuticals 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 (Inotersen), and Waylivra (Volanesorsen) and has 4 drugs in pivotal studies: tominersen for Huntington’s disease, tofersen for SOD1-ALS, AKCEA-APO(a)-LRx for cardiovascular disease, and AKCEA-TTR-LRx for all forms of TTR amyloidosis.

    Nusinersen Medication used for spinal muscular atrophy

    Nusinersen, marketed as Spinraza, is a medication used in treating spinal muscular atrophy (SMA), a rare neuromuscular disorder. In December 2016, it became the first approved drug used in treating this disorder.

    Volanesorsen, sold under the brand name Waylivra, is a triglyceride-reducing drug. It is a second-generation 2'-O-methoxyethyl (2'-MOE) chimeric antisense therapeutic oligonucleotide (ASO) that targets the messenger RNA for apolipoprotein C3 (apo-CIII).

    Gapmers are short DNA antisense oligonucleotide structures with RNA-like segments on both sides of the sequence. These linear pieces of genetic information are designed to hybridize to a target piece of RNA and silence the gene through the induction of RNase H cleavage. Binding of the gapmer to the target has a higher affinity due to the modified RNA flanking regions, as well as resistance to degradation by nucleases. Gapmers are currently being developed as therapeutics for a variety of cancers, viruses, and other chronic genetic disorders.

    References

    1. 1 2 3 4 5 6 7 8 9 "Kynamro (mipomersen sodium) Injection, Solution for Subcutaneous Injection. Full Prescribing Information" (PDF). Kastle Therapeutics, Chicago, IL.
    2. ↑ Feingold, KR; Grunfeld, C (August 10, 2016). "Cholesterol Lowering Drugs". In De Groot, LJ; et al. (eds.). Endotext [Internet]. South Dartmouth (MA): MDText.com, Inc. PMID   27809434.
    3. 1 2 3 4 Drugs.com: Mipomersen Professional Drug Facts .
    4. ↑ "International Nonproprietary Names for Pharmaceutical Substances (INN). Recommended International Nonproprietary Names: List 61" (PDF). World Health Organization. 2009.
    5. ↑ Geary RS, Baker BF, Crooke ST (February 2015). "Clinical and preclinical pharmacokinetics and pharmacodynamics of mipomersen (kynamro(®)): a second-generation antisense oligonucleotide inhibitor of apolipoprotein B". Clinical Pharmacokinetics. 54 (2): 133–146. doi:10.1007/s40262-014-0224-4. PMC   4305106 . PMID   25559341.
    6. ↑ "Genzyme and Isis Complete Licensing of Mipomersen". 24 June 2008. Archived from the original on 29 September 2011.
    7. ↑ "EMA committee shoots down Sanofi's cholesterol drug mipomersen". FierceBiotech. December 14, 2012.
    8. ↑ "Refusal of the marketing authorisation for Kynamro (mipomersen)" (PDF). EMA. March 21, 2013.
    9. ↑ Pollack, Andrew (29 January 2013) F.D.A. Approves Genetic Drug to Treat Rare Disease The New York Times, Retrieved 31 January 2013
    10. ↑ 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
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