Lomitapide and mipomersen: two first-in-class drugs for reducing low-density lipoprotein cholesterol in patients with homozygous familial hypercholesterolemia.

Low-density lipoproteins (LDLs) are a proven causal risk factor for the development of atherosclerotic cardiovascular disease. Plasma levels of LDL cholesterol (LDL-C) and its major protein, apolipoprotein B (apoB), are positively associated with incident cardiovascular events.1 Individuals with genetic conditions of extremely high LDL-C develop premature cardiovascular disease; conversely, those with genetically low LDL-C are protected from cardiovascular disease. Interventions that reduce LDL-C, including statins and bile acid sequestrants, are proven to reduce cardiovascular risk.2 Indeed, therapy to reduce LDL-C is a cornerstone of the treatment and primary prevention of atherosclerotic cardiovascular disease. Despite the commercial availability of 3 major classes of LDL-lowering drugs (statins, bile acid sequestrants, and a cholesterol absorption inhibitor), a substantial unmet need has remained with regard to LDL-lowering treatment. Some patients are intolerant of statins because of myalgias. Others have genetic conditions that substantially elevate their LDL-C and make it challenging to achieve desirable LDL-C levels even with combination therapy. Perhaps the single best example of a genetic condition in which patients frequently fail to achieve acceptable LDL-C levels despite aggressive therapy is familial hypercholesterolemia (FH).3,4 This condition, classically caused by loss-of-function mutations in the LDL receptor,5 is associated with substantially elevated LDL-C and premature atherosclerotic cardiovascular disease. Patients with heterozygous FH typically have untreated LDL-C levels in the range of 200 to 400 mg/dL, and many cannot achieve desirable LDL-C levels on available combination therapy. Patients with 2 mutant LDL receptor alleles have homozygous FH (hoFH) with LDL-C levels usually >400 mg/dL and cannot achieve desirable LDL-C levels on available therapy. There are other causes of autosomal-dominant hypercholesterolemia4 resulting from mutations in the receptor-binding region of apoB (the ligand for the LDL receptor) and gain-of-function mutations in PCSK9 (a protein that targets the LDL receptor for degradation), …

[1]  I. Kamel,et al.  Non-alcoholic fatty liver disease and mortality among US adults: prospective cohort study , 2011, BMJ : British Medical Journal.

[2]  G. Schonfeld,et al.  Familial hypobetalipoproteinemia: genetics and metabolism , 2005, Cellular and Molecular Life Sciences.

[3]  H. Jamil,et al.  An inhibitor of the microsomal triglyceride transfer protein inhibits apoB secretion from HepG2 cells. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[4]  Avnish Patel,et al.  Inhibition of microsomal triglyceride transfer protein improves insulin sensitivity and reduces atherogenic risk in Zucker fatty rats , 2011, Clinical and experimental pharmacology & physiology.

[5]  D. Gaudet,et al.  Efficacy and Safety of Ezetimibe Coadministered With Atorvastatin or Simvastatin in Patients With Homozygous Familial Hypercholesterolemia , 2002, Circulation.

[6]  D. Gaudet,et al.  Apolipoprotein B Synthesis Inhibition With Mipomersen in Heterozygous Familial Hypercholesterolemia: Results of a Randomized, Double-Blind, Placebo-Controlled Trial to Assess Efficacy and Safety as Add-On Therapy in Patients With Coronary Artery Disease , 2012, Circulation.

[7]  J. Mckenney,et al.  Inhibition of microsomal triglyceride transfer protein alone or with ezetimibe in patients with moderate hypercholesterolemia , 2008, Nature Clinical Practice Cardiovascular Medicine.

[8]  F. Akdim,et al.  Efficacy of apolipoprotein B synthesis inhibition in subjects with mild-to-moderate hyperlipidaemia. , 2011, European heart journal.

[9]  R. Davis,et al.  Cell and molecular biology of the assembly and secretion of apolipoprotein B-containing lipoproteins by the liver. , 1999, Biochimica et biophysica acta.

[10]  C. Furberg,et al.  A Meta-Analysis of Low-Density Lipoprotein Cholesterol, Non-High-Density Lipoprotein Cholesterol, and Apolipoprotein B as Markers of Cardiovascular Risk , 2011, Circulation. Cardiovascular quality and outcomes.

[11]  D. Tribble,et al.  Lack of Pharmacokinetic Interaction of Mipomersen Sodium (ISIS 301012), a 2′-—O-Methoxyethyl Modified Antisense Oligonucleotide Targeting Apolipoprotein B-100 Messenger RNA, with Simvastatin and Ezetimibe , 2009, Clinical pharmacokinetics.

[12]  Richard G. Lee,et al.  Comparison of the pharmacological profiles of murine antisense oligonucleotides targeting apolipoprotein B and microsomal triglyceride transfer protein , 2013, Journal of Lipid Research.

[13]  M. Cappa,et al.  Fatty liver and insulin resistance in children with hypobetalipoproteinemia: the importance of aetiology , 2013, Clinical endocrinology.

[14]  P. Ridker,et al.  C-reactive protein and cholesterol are equally strong predictors of cardiovascular risk and both are important for quality clinical care. , 2013, European heart journal.

[15]  A. J. Mcadams,et al.  Liver ultrastructure in abetalipoproteinemia: Evolution of micronodular cirrhosis. , 1974, Gastroenterology.

[16]  L. Aggerbeck,et al.  The role of the microsomal triglygeride transfer protein in abetalipoproteinemia. , 2000, Annual review of nutrition.

[17]  Marie C. M. Lin,et al.  Ethanol down‐regulates the transcription of microsomal triglyceride transfer protein gene , 1997, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[18]  K. Schechtman,et al.  Dissociation between intrahepatic triglyceride content and insulin resistance in familial hypobetalipoproteinemia. , 2010, Gastroenterology.

[19]  R. Movva,et al.  Pharmacokinetic Interactions of the Microsomal Triglyceride Transfer Protein Inhibitor, Lomitapide, with Drugs Commonly Used in the Management of Hypercholesterolemia , 2014, Pharmacotherapy.

[20]  T. Farag.  Familial hypercholesterolemia. , 1988, Journal of the Royal Society of Medicine.

[21]  Mark J Graham,et al.  Antisense Oligonucleotide Directed to Human Apolipoprotein B-100 Reduces Lipoprotein(a) Levels and Oxidized Phospholipids on Human Apolipoprotein B-100 Particles in Lipoprotein(a) Transgenic Mice , 2008, Circulation.

[22]  F. Akdim,et al.  Effect of mipomersen, an apolipoprotein B synthesis inhibitor, on low-density lipoprotein cholesterol in patients with familial hypercholesterolemia. , 2010, The American journal of cardiology.

[23]  F. Sacks,et al.  Severe hypertriglyceridemia with pancreatitis: thirteen years' treatment with lomitapide. , 2014, JAMA internal medicine.

[24]  D. Illingworth,et al.  Abetalipoproteinemia. Report of two cases and review of therapy. , 1980, Archives of neurology.

[25]  M. Graham,et al.  An apolipoprotein B antisense oligonucleotide lowers LDL cholesterol in hyperlipidemic mice without causing hepatic steatosis Published, JLR Papers in Press, February 16, 2005. DOI 10.1194/jlr.M400492-JLR200 , 2005, Journal of Lipid Research.

[26]  J. Kastelein,et al.  Hepatic and Cardiovascular Consequences of Familial Hypobetalipoproteinemia , 2005, Arteriosclerosis, thrombosis, and vascular biology.

[27]  I. Sternlieb,et al.  Hepatic peroxisomal abnormalities in abetalipoproteinemia. , 1989, Gastroenterology.

[28]  K. Ishak,et al.  Morphologic Features of the Liver in Abetalipoproteinemia , 1984, Hepatology.

[29]  D. Gaudet,et al.  Efficacy and safety of a microsomal triglyceride transfer protein inhibitor in patients with homozygous familial hypercholesterolaemia: a single-arm, open-label, phase 3 study , 2013, The Lancet.

[30]  R. Hegele,et al.  Arrest of neuropathy and myopathy in abetalipoproteinemia with high-dose vitamin E therapy. , 1985, Canadian Medical Association journal.

[31]  Børge G Nordestgaard,et al.  PCSK9 R46L, low-density lipoprotein cholesterol levels, and risk of ischemic heart disease: 3 independent studies and meta-analyses. , 2010, Journal of the American College of Cardiology.

[32]  C. Town,et al.  Reduction in Mortality in Subjects With Homozygous Familial Hypercholesterolemia Associated With Advances in Lipid-Lowering Therapy , 2011, Circulation.

[33]  P. Barter,et al.  Plasma PCSK9 levels and clinical outcomes in the TNT (Treating to New Targets) trial: a nested case-control study. , 2012, Journal of the American College of Cardiology.

[34]  Richard G. Lee,et al.  Antisense oligonucleotide reduction of apoB-ameliorated atherosclerosis in LDL receptor-deficient mice[S] , 2011, Journal of Lipid Research.

[35]  S. Young,et al.  Genetic analysis of a kindred with familial hypobetalipoproteinemia. Evidence for two separate gene defects: one associated with an abnormal apolipoprotein B species, apolipoprotein B-37; and a second associated with low plasma concentrations of apolipoprotein B-100. , 1987, The Journal of clinical investigation.

[36]  C. Gieger,et al.  Lifelong Reduction of LDL-Cholesterol Related to a Common Variant in the LDL-Receptor Gene Decreases the Risk of Coronary Artery Disease—A Mendelian Randomisation Study , 2008, PloS one.

[37]  G. Mentha,et al.  Persistence of the intestinal defect in abetalipoproteinaemia after liver transplantation , 1998, European Journal of Pediatrics.

[38]  S. Crooke.  Antisense Drug Technology : Principles, Strategies, and Applications, Second Edition , 2007 .

[39]  H. Jamil,et al.  An MTP inhibitor that normalizes atherogenic lipoprotein levels in WHHL rabbits. , 1998, Science.

[40]  M. Hussain,et al.  Multiple functions of microsomal triglyceride transfer protein , 2012, Nutrition & Metabolism.

[41]  Eric Boerwinkle,et al.  Sequence Variations in PCSK 9 , Low LDL , and Protection against Coronary Heart Disease , 2006 .

[42]  F. Sacks,et al.  Antisense inhibition of apoB synthesis with mipomersen reduces plasma apoC-III and apoC-III-containing lipoproteins , 2012, Journal of Lipid Research.

[43]  M. van der Graaf,et al.  Hepatic steatosis does not cause insulin resistance in people with familial hypobetalipoproteinaemia , 2011, Diabetologia.

[44]  M. Hussain,et al.  Decreased secretion of ApoB follows inhibition of ApoB-MTP binding by a novel antagonist. , 2000, Biochemistry.

[45]  R. Crooke,et al.  Cardiovascular Therapeutic Applications , 2007 .

[46]  J. Tardif,et al.  Randomized, Placebo-Controlled Trial of Mipomersen in Patients with Severe Hypercholesterolemia Receiving Maximally Tolerated Lipid-Lowering Therapy , 2012, PloS one.

[47]  W. V. Brown,et al.  Familial homozygous hypobetalipoproteinemia. , 1974, Metabolism: clinical and experimental.

[48]  J. Schölmerich,et al.  Preserved direct hepatic insulin action in rats with diet-induced hepatic steatosis. , 2004, American journal of physiology. Endocrinology and metabolism.

[49]  F. Raal,et al.  Effect of the Proprotein Convertase Subtilisin/Kexin 9 Monoclonal Antibody, AMG 145, in Homozygous Familial Hypercholesterolemia , 2013, Circulation.

[50]  Satoshi Hirayama,et al.  [Familial hypobetalipoproteinemia]. , 2007, Nihon rinsho. Japanese journal of clinical medicine.

[51]  M. Shiomi,et al.  MTP inhibitor decreases plasma cholesterol levels in LDL receptor-deficient WHHL rabbits by lowering the VLDL secretion. , 2001, European journal of pharmacology.

[52]  R. Geary.  Antisense oligonucleotide pharmacokinetics and metabolism. , 2009, Expert opinion on drug metabolism & toxicology.

[53]  D. Blom,et al.  Homozygous Familial Hypercholesterolemia and Its Management , 2004, Seminars in vascular medicine.

[54]  D. Gaudet,et al.  Mipomersen, an apolipoprotein B synthesis inhibitor, for lowering of LDL cholesterol concentrations in patients with homozygous familial hypercholesterolaemia: a randomised, double-blind, placebo-controlled trial , 2010, The Lancet.

[55]  E. Stein,et al.  Other therapies for reducing low-density lipoprotein cholesterol: medications in development. , 2009, Endocrinology and metabolism clinics of North America.

[56]  D. Tribble,et al.  Cross-species comparison of in vivo PK/PD relationships for second-generation antisense oligonucleotides targeting apolipoprotein B-100. , 2009, Biochemical pharmacology.

[57]  I. Kushner,et al.  Acute-phase proteins and other systemic responses to inflammation. , 1999, The New England journal of medicine.

[58]  D. Rader,et al.  Cloning and gene defects in microsomal triglyceride transfer protein associated with abetalipoproteinaemia , 1993, Nature.

[59]  J. Stockman.  Inhibition of Microsomal Triglyceride Transfer Protein in Familial Hypercholesterolemia , 2008 .

[60]  R. Yu,et al.  Cross-Species Pharmacokinetic Comparison from Mouse to Man of a Second-Generation Antisense Oligonucleotide, ISIS 301012, Targeting Human Apolipoprotein B-100 , 2007, Drug Metabolism and Disposition.

[61]  D. Noto,et al.  Molecular diagnosis of hypobetalipoproteinemia: an ENID review. , 2007, Atherosclerosis.

[62]  S. Young,et al.  Low plasma cholesterol levels caused by a short deletion in the apolipoprotein B gene. , 1988, Science.

[63]  K. Ueshima,et al.  Implitapide, a microsomal triglyceride transfer protein inhibitor, reduces progression of atherosclerosis in apolipoprotein E knockout mice fed a Western-type diet: involvement of the inhibition of postprandial triglyceride elevation. , 2005, Biological & pharmaceutical bulletin.

[64]  M. Lambert,et al.  Mutations of low-density-lipoprotein-receptor gene, variation in plasma cholesterol, and expression of coronary heart disease in homozygous familial hypercholesterolaemia , 1993, The Lancet.

[65]  N. Davidson,et al.  Intestinal and hepatic apolipoprotein B gene expression in abetalipoproteinemia. , 1991, Gastroenterology.

[66]  D. Steinberg,et al.  Metabolic studies in an unusual case of asymptomatic familial hypobetalipoproteinemia with hypolphalipoproteinemia and fasting chylomicronemia. , 1979, The Journal of clinical investigation.

[67]  W. Howard.  Potent Reduction of Apolipoprotein B and Low-Density Lipoprotein Cholesterol by Short-Term Administration of an Antisense Inhibitor of Apolipoprotein B , 2007 .

[68]  Roger A. Davis,et al.  Blocking microsomal triglyceride transfer protein interferes with apoB secretion without causing retention or stress in the ER Published, JLR Papers in Press, February 16, 2003. DOI 10.1194/jlr.M300020-JLR200 , 2003, Journal of Lipid Research.

[69]  Jonathan C. Cohen,et al.  Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. , 2006, The New England journal of medicine.

[70]  W. Cromwell,et al.  Mipomersen, an apolipoprotein B synthesis inhibitor, reduces atherogenic lipoproteins in patients with severe hypercholesterolemia at high cardiovascular risk: a randomized, double-blind, placebo-controlled trial. , 2013, Journal of the American College of Cardiology.

[71]  S. Crooke,et al.  Determination of the Role of the Human RNase H1 in the Pharmacology of DNA-like Antisense Drugs* , 2004, Journal of Biological Chemistry.

[72]  P. Barter,et al.  Plasma PCSK9 levels and clinical outcomes in the TNT (Treating to New Targets) trial: a nested case-control study. , 2012, Journal of the American College of Cardiology.

[73]  Jonathan D. Cohen,et al.  Monogenic hypercholesterolemia: new insights in pathogenesis and treatment. , 2003, The Journal of clinical investigation.

[74]  R. Geary.  Antisense oligonucleotide pharmacokinetics and metabolism , 2009 .

[75]  R. Collins,et al.  Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170 000 participants in 26 randomised trials , 2010, The Lancet.

[76]  C. Bennett,et al.  RNA targeting therapeutics: molecular mechanisms of antisense oligonucleotides as a therapeutic platform. , 2010, Annual review of pharmacology and toxicology.

[77]  D. Rader,et al.  Longitudinal evaluation and assessment of cardiovascular disease in patients with homozygous familial hypercholesterolemia. , 2008, The American journal of cardiology.

[78]  A. Lonardo,et al.  Hepatic steatosis and insulin resistance: does etiology make a difference? , 2006, Journal of hepatology.

[79]  K. Isselbacher,et al.  METABOLIC EFFECTS OF ALCOHOL ON THE LIVER. , 1974, The New England journal of medicine.

[80]  Y. Marcel,et al.  Epitopes of apolipoprotein B-100 and B-48 in both liver and intestine. Expression and evidence for local synthesis in recessive abetalipoproteinemia. , 1986, The Journal of clinical investigation.

[81]  J. Kastelein,et al.  Mipomersen, an apolipoprotein B synthesis inhibitor, lowers low-density lipoprotein cholesterol in high-risk statin-intolerant patients: a randomized, double-blind, placebo-controlled trial , 2012, European heart journal.

[82]  G. Chang,et al.  CP-346086: an MTP inhibitor that lowers plasma cholesterol and triglycerides in experimental animals and in humans. , 2003, Journal of lipid research.

[83]  J. Jukema,et al.  Efficacy and safety of mipomersen, an antisense inhibitor of apolipoprotein B, in hypercholesterolemic subjects receiving stable statin therapy. , 2010, Journal of the American College of Cardiology.

[84]  D. Rader,et al.  Absence of microsomal triglyceride transfer protein in individuals with abetalipoproteinemia. , 1992, Science.