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Annual Review of Medicine

Volume 69, 2018

New Therapeutic Approaches for Familial Hypercholesterolemia

Abstract

Familial hypercholesterolemia (FH) is a common genetic condition characterized by elevated plasma levels of low-density lipoprotein cholesterol (LDL-C), premature atherosclerotic cardiovascular disease, and considerable unmet medical need with conventional LDL-C-lowering therapies. Between 2012 and 2015, the US Food and Drug Administration approved four novel LDL-C-lowering agents for use in patients with FH based on the pronounced LDL-C-lowering efficacy of these medicines. We review the four novel approved agents, as well as promising LDL-C-lowering agents in clinical development, with a focus on their mechanism of action, efficacy in FH cohorts, and safety.

Keyword(s): LDL, lomitapide, low-density lipoprotein, mipomersen, proprotein convertase subtilisin/kexin 9
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2018-01-29
2025-06-20
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Literature Cited

  1. Goldstein JL, Hobbs HH, Brown MS. 1.  2014. Familial hypercholesterolemia. The Online Metabolic and Molecular Bases of Inherited Disease AL Beaudet, B Vogelstein, KW Kinzler et al. Ch. 120 New York: McGraw-Hill doi: 10.1036/ommbid.149 [Google Scholar]
  2. Perez de Isla L, Alonso R, Watts GF. 2.  et al. 2016. Attainment of LDL-cholesterol treatment goals in patients with familial hypercholesterolemia: 5-year SAFEHEART Registry follow-up. J. Am. Coll. Cardiol. 67:111278–85 [Google Scholar]
  3. Kuiper JG, Sanchez RJ, Houben E. 3.  et al. 2017. Use of lipid-modifying therapy and LDL-C goal attainment in a high-cardiovascular-risk population in the Netherlands. Clin. Ther. 39:4819–827.e1 [Google Scholar]
  4. Raal FJ, Pilcher GJ, Panz VR. 4.  et al. 2011. Reduction in mortality in subjects with homozygous familial hypercholesterolemia associated with advances in lipid-lowering therapy. Circulation 124:202202–7 [Google Scholar]
  5. Hooper AJ, Burnett JR, Watts GF. 5.  2015. Contemporary aspects of the biology and therapeutic regulation of the microsomal triglyceride transfer protein. Circ. Res. 116:1193–205 [Google Scholar]
  6. Wetterau JR, Aggerbeck LP, Bouma ME. 6.  et al. 1992. Absence of microsomal triglyceride transfer protein in individuals with abetalipoproteinemia. Science 258:5084999–1001 [Google Scholar]
  7. Sharp D, Blinderman L, Combs KA. 7.  et al. 1993. Cloning and gene defects in microsomal triglyceride transfer protein associated with abetalipoproteinaemia. Nature 365:644165–69 [Google Scholar]
  8. Cuchel M, Bloedon LT, Szapary PO. 8.  et al. 2007. Inhibition of microsomal triglyceride transfer protein in familial hypercholesterolemia. N. Engl. J. Med. 356:2148–56 [Google Scholar]
  9. Cuchel M, Meagher EA, du Toit Theron H. 9.  et al. 2013. Efficacy and safety of a microsomal triglyceride transfer protein inhibitor in patients with homozygous familial hypercholesterolaemia: a single-arm, open-label, phase 3 study. Lancet 381:986040–46 [Google Scholar]
  10. Blom DJ, Averna MR, Meagher EA. 10.  et al. 2017. Long-term efficacy and safety of the microsomal triglyceride transfer protein inhibitor lomitapide in patients with homozygous familial hypercholesterolemia. Circulation 136332–35 [Google Scholar]
  11. Stefanutti C, Blom DJ, Averna MR. 11.  et al. 2015. The lipid-lowering effects of lomitapide are unaffected by adjunctive apheresis in patients with homozygous familial hypercholesterolaemia—a post-hoc analysis of a Phase 3, single-arm, open-label trial. Atherosclerosis 240:2408–14 [Google Scholar]
  12. Rader DJ, Kastelein JJP. 12.  2014. Lomitapide and mipomersen: two first-in-class drugs for reducing low-density lipoprotein cholesterol in patients with homozygous familial hypercholesterolemia. Circulation 129:91022–32 [Google Scholar]
  13. D'Erasmo L, Cefalu AB, Noto D. 13.  et al. 2017. Efficacy of lomitapide in the treatment of familial homozygous hypercholesterolemia: results of a real-world clinical experience in Italy. Adv. Ther. 34:51200–10 [Google Scholar]
  14. Kolovou GD, Kolovou V, Papadopoulou A. 14.  et al. 2016. MTP gene variants and response to lomitapide in patients with homozygous familial hypercholesterolemia. J. Atheroscler. Thromb. 23:7878–83 [Google Scholar]
  15. Underberg J, Cannon C, Larrey D. 15.  et al. 2016. Global real-world data on the use of lomitapide in treating homozygous familial hypercholesterolemia: the Lomitapide Observational Worldwide Evaluation Registry (LOWER), two-year data. Circulation 134:Suppl. 1A12117 (Abstr. No. 12117) [Google Scholar]
  16. Samaha FF, McKenney J, Bloedon LT. 16.  et al. 2008. Inhibition of microsomal triglyceride transfer protein alone or with ezetimibe in patients with moderate hypercholesterolemia. Nat. Clin. Prac. Cardiovasc. Med. 5:8497–505 [Google Scholar]
  17. 17. US Food and Drug Administration. 2012. FDA Briefing Document: Lomitapide Mesylate Capsules. http://wayback.archive-it.org/7993/20170405220228/https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM323841.pdf 124–38 [Google Scholar]
  18. Di Filippo M, Moulin P, Roy P. 18.  et al. 2014. Homozygous MTTP and APOB mutations may lead to hepatic steatosis and fibrosis despite metabolic differences in congenital hypocholesterolemia. J. Hepatol. 61:4891–902 [Google Scholar]
  19. Sacks FM, Stanesa M, Hegele RA. 19.  2014. Severe hypertriglyceridemia with pancreatitis: thirteen years’ treatment with lomitapide. JAMA Intern. Med. 174:3443–47 [Google Scholar]
  20. Brown WV, Bramlet DA, Ross JL. 20.  et al. 2016. JCL roundtable: risk evaluation and mitigation strategy. J. Clin. Lipidol. 10:61288–96 [Google Scholar]
  21. Schonfeld G, Lin X, Yue P. 21.  2005. Familial hypobetalipoproteinemia: genetics and metabolism. Cell. Mol. Life Sci. 62:121372–78 [Google Scholar]
  22. Stein EA. 22.  2009. Other therapies for reducing low-density lipoprotein cholesterol: medications in development. Endocrinol. Metab. Clin. North Am. 38:199–119 [Google Scholar]
  23. Raal FJ, Santos RD, Blom DJ. 23.  et al. 2010. 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. Lancet 375:9719998–1006 [Google Scholar]
  24. Raal FJ, Braamskamp MJ, Selvey SL. 24.  et al. 2016. Pediatric experience with mipomersen as adjunctive therapy for homozygous familial hypercholesterolemia. J. Clin. Lipidol. 10:4860–69 [Google Scholar]
  25. Akdim F, Visser ME, Tribble DL. 25.  et al. 2010. Effect of mipomersen, an apolipoprotein B synthesis inhibitor, on low-density lipoprotein cholesterol in patients with familial hypercholesterolemia. Am. J. Cardiol. 105:101413–19 [Google Scholar]
  26. Stein EA, Dufour R, Gagne C. 26.  et al. 2012. 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. Circulation 126:192283–92 [Google Scholar]
  27. Santos RD, Duell PB, East C. 27.  et al. 2015. Long-term efficacy and safety of mipomersen in patients with familial hypercholesterolaemia: 2-year interim results of an open-label extension. Eur. Heart J. 36:9566–75 [Google Scholar]
  28. Raal FJ, Stein EA, Dufour R. 28.  et al. 2015. PCSK9 inhibition with evolocumab (AMG 145) in heterozygous familial hypercholesterolaemia (RUTHERFORD-2): a randomised, double-blind, placebo-controlled trial. Lancet 385:9965331–40 [Google Scholar]
  29. 29. US Food and Drug Administration 2012. FDA Briefing Document, NDA 203568, Mipomersen Sodium Injection 200 mg/mL; Endocrinologic and Metabolic Drugs Advisory Committee Meeting October 18, 2012 https://wayback.archive-it.org/7993/20170405220137/https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM323927.pdf 82–84129–30 [Google Scholar]
  30. Schonfeld G, Patterson BW, Yablonskiy DA. 30.  et al. 2003. Fatty liver in familial hypobetalipoproteinemia: triglyceride assembly into VLDL particles is affected by the extent of hepatic steatosis. J. Lipid Res. 44:3470–78 [Google Scholar]
  31. Tarugi P, Lonardo A, Ballarini G. 31.  et al. 1996. Fatty liver in heterozygous hypobetalipoproteinemia caused by a novel truncated form of apolipoprotein B. Gastroenterology 111:41125–33 [Google Scholar]
  32. Visser ME, Lammers NM, Nederveen AJ. 32.  et al. 2011. Hepatic steatosis does not cause insulin resistance in people with familial hypobetalipoproteinaemia. Diabetologia 54:82113–21 [Google Scholar]
  33. Hashemi N, Odze RD, McGowan MP. 33.  et al. 2014. Liver histology during mipomersen therapy for severe hypercholesterolemia. J. Clin. Lipidol. 8:6606–11 [Google Scholar]
  34. Duell PB, Santos RD, Kirwan B-A. 34.  et al. 2016. Long-term mipomersen treatment is associated with a reduction in cardiovascular events in patients with familial hypercholesterolemia. J. Clin. Lipidol. 10:41011–21 [Google Scholar]
  35. Abifadel M, Varret M, Rabès J-P. 35.  et al. 2003. Mutations in PCSK9 cause autosomal dominant hyper-cholesterolemia. Nat. Genet. 34:2154–56 [Google Scholar]
  36. Cohen JC, Boerwinkle E, Mosley TH. 36.  et al. 2006. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N. Engl. J. Med. 354:121264–72 [Google Scholar]
  37. Abifadel M, Rabes J-P, Devillers M. 37.  et al. 2009. Mutations and polymorphisms in the proprotein convertase subtilisin kexin 9 (PCSK9) gene in cholesterol metabolism and disease. Hum. Mutat. 30:4520–29 [Google Scholar]
  38. Lagace TA, Curtis DE, Garuti R. 38.  et al. 2006. Secreted PCSK9 decreases the number of LDL receptors in hepatocytes and in livers of parabiotic mice. J. Clin. Investig. 116:112995–3005 [Google Scholar]
  39. Bergeron N, Phan BAP, Ding Y. 39.  et al. 2015. Proprotein convertase subtilisin/kexin type 9 inhibition: a new therapeutic mechanism for reducing cardiovascular disease risk. Circulation 132:171648–66 [Google Scholar]
  40. Urban D, Poss J, Bohm M. 40.  et al. 2013. Targeting the proprotein convertase subtilisin/kexin type 9 for the treatment of dyslipidemia and atherosclerosis. J. Am. Coll. Cardiol. 62:161401–8 [Google Scholar]
  41. Dadu RT, Ballantyne CM. 41.  2014. Lipid lowering with PCSK9 inhibitors. Nat. Rev. Cardiol. 11:10563–75 [Google Scholar]
  42. Brown WV, Moriarty PM, McKenney JM. 42.  2016. JCL roundtable: PCSK9 inhibitors in clinical practice. J. Clin. Lipidol. 10:15–14 [Google Scholar]
  43. Hess C, Low Wang CC, Goldfine A, Hiatt WR. 43.  2018. PCSK9 inhibitors: mechanisms of action, metabolic effects, and clinical outcomes. Annu Rev. Med. 69:In press [Google Scholar]
  44. Kastelein JJP, Ginsberg HN, Langslet G. 44.  et al. 2015. ODYSSEY FH I and FH II: 78 week results with alirocumab treatment in 735 patients with heterozygous familial hypercholesterolaemia. Eur. Heart J. 36:432996–3003 [Google Scholar]
  45. Dufour R, Bergeron J, Gaudet D. 45.  et al. 2017. Open-label therapy with alirocumab in patients with heterozygous familial hypercholesterolemia: results from three years of treatment. Int. J. Cardiol. 228:754–60 [Google Scholar]
  46. Kastelein JJP, Hovingh GK, Langslet G. 46.  et al. 2017. Efficacy and safety of the proprotein convertase subtilisin/kexin type 9 monoclonal antibody alirocumab versus placebo in patients with heterozygous familial hypercholesterolemia. J. Clin. Lipidol. 11:1195–203.e4 [Google Scholar]
  47. Ginsberg HN, Rader DJ, Raal FJ. 47.  et al. 2016. Efficacy and safety of alirocumab in patients with heterozygous familial hypercholesterolemia and LDL-C of 160 mg/dl or higher. Cardiovasc. Drugs Ther. 30:5473–83 [Google Scholar]
  48. Raal F, Scott R, Somaratne R. 48.  et al. 2012. Low-density lipoprotein cholesterol-lowering effects of AMG 145, a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 serine protease in patients with heterozygous familial hypercholesterolemia: the Reduction of LDL-C with PCSK9 Inhibition in Heterozygous Familial Hypercholesterolemia Disorder (RUTHERFORD) randomized trial. Circulation 126:202408–17 [Google Scholar]
  49. Gaudet D, Watts GF, Robinson JG. 49.  et al. 2017. Effect of alirocumab on lipoprotein(a) over ≥1.5 years (from the phase 3 ODYSSEY program). Am. J. Cardiol. 119:140–46 [Google Scholar]
  50. Raal FJ, Giugliano RP, Sabatine MS. 50.  et al. 2014. Reduction in lipoprotein(a) with PCSK9 monoclonal antibody evolocumab (AMG 145): a pooled analysis of more than 1,300 patients in 4 phase II trials. J. Am. Coll. Cardiol. 63:131278–88 [Google Scholar]
  51. Lambert G, Thedrez A, Croyal M. 51.  et al. 2017. The complexity of lipoprotein (a) lowering by PCSK9 monoclonal antibodies. Clin. Sci. 131:4261–68 [Google Scholar]
  52. Koren MJ, Sabatine MS, Giugliano RP. 52.  et al. 2017. Long-term low-density lipoprotein cholesterol-lowering efficacy, persistence, and safety of evolocumab in treatment of hypercholesterolemia: results up to 4 years from the open-label OSLER-1 extension study. JAMA Cardiol 2:6598–607 [Google Scholar]
  53. Stein EA, Honarpour N, Wasserman SM. 53.  et al. 2013. Effect of the proprotein convertase subtilisin/kexin 9 monoclonal antibody, AMG 145, in homozygous familial hypercholesterolemia. Circulation 128:192113–20 [Google Scholar]
  54. Raal FJ, Hovingh GK, Blom D. 54.  et al. 2017. Long-term treatment with evolocumab added to conventional drug therapy, with or without apheresis, in patients with homozygous familial hypercholesterolaemia: an interim subset analysis of the open-label TAUSSIG study. Lancet Diabetes Endocrinol 5:4280–90 [Google Scholar]
  55. Raal FJ, Honarpour N, Blom DJ. 55.  et al. 2015. Inhibition of PCSK9 with evolocumab in homozygous familial hypercholesterolaemia (TESLA Part B): a randomised, double-blind, placebo-controlled trial. Lancet 385:9965341–50 [Google Scholar]
  56. Sabatine MS, Giugliano RP, Keech AC. 56.  et al. 2017. Evolocumab and clinical outcomes in patients with cardiovascular disease. N. Engl. J. Med. 376:181713–22 [Google Scholar]
  57. Robinson JG, Farnier M, Krempf M. 57.  et al. 2015. Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. N. Engl. J. Med. 372:161489–99 [Google Scholar]
  58. Sabatine MS, Giugliano RP, Wiviott SD. 58.  et al. 2015. Efficacy and safety of evolocumab in reducing lipids and cardiovascular events. N. Engl. J. Med. 372:161500–9 [Google Scholar]
  59. Versmissen J, Oosterveer DM, Yazdanpanah M. 59.  et al. 2008. Efficacy of statins in familial hypercholesterolaemia: a long term cohort study. BMJ 337:a2423 [Google Scholar]
  60. Neil A, Cooper J, Betteridge J. 60.  et al. 2008. Reductions in all-cause, cancer, and coronary mortality in statin-treated patients with heterozygous familial hypercholesterolaemia: a prospective registry study. Eur. Heart J. 29:2625–33 [Google Scholar]
  61. Besseling J, Hovingh GK, Huijgen R. 61.  et al. 2016. Statins in familial hypercholesterolemia: consequences for coronary artery disease and all-cause mortality. J. Am. Coll. Cardiol. 68:3252–60 [Google Scholar]
  62. 62. Cholesterol Treatment Trialists’ (CTT) Collaborators. 2012. The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomised trials. Lancet 380:9841581–90 [Google Scholar]
  63. Cohen JC, Boerwinkle E, Mosley TH. 63.  et al. 2006. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N. Engl. J. Med. 354:121264–72 [Google Scholar]
  64. Silverman MG, Ference BA, Im K. 64.  et al. 2016. Association between lowering LDL-C and cardiovascular risk reduction among different therapeutic interventions: a systematic review and meta-analysis. JAMA 316:121289–97 [Google Scholar]
  65. Blom DJ, Hala T, Bolognese M. 65.  et al. 2014. A 52-week placebo-controlled trial of evolocumab in hyperlipidemia. N. Engl. J. Med. 370:191809–19 [Google Scholar]
  66. Moriarty PM, Thompson PD, Cannon CP. 66.  et al. 2015. Efficacy and safety of alirocumab versus ezetimibe in statin-intolerant patients, with a statin rechallenge arm: the ODYSSEY ALTERNATIVE randomized trial. J. Clin. Lipidol. 9:6758–69 [Google Scholar]
  67. Stroes E, Colquhoun D, Sullivan D. 67.  et al. 2014. Anti-PCSK9 antibody effectively lowers cholesterol in patients with statin intolerance: the GAUSS-2 randomized, placebo-controlled phase 3 clinical trial of evolocumab. J. Am. Coll. Cardiol. 63:232541–48 [Google Scholar]
  68. Robinson JG, Rosenson RS, Farnier M. 68.  et al. 2017. Safety of very low low-density lipoprotein cholesterol levels with alirocumab: pooled data from randomized trials. J. Am. Coll. Cardiol. 69:5471–82 [Google Scholar]
  69. Fitzgerald K, White S, Borodovsky A. 69.  et al. 2017. A highly durable RNAi therapeutic inhibitor of PCSK9. N. Engl. J. Med. 376:141–51 [Google Scholar]
  70. 70.  Deleted in proof
  71. Ray KK, Landmesser U, Leiter LA. 71.  et al. 2017. Inclisiran in patients at high cardiovascular risk with elevated LDL cholesterol. N. Engl. J. Med. 376:151430–40 [Google Scholar]
  72. Fitzgerald K, Frank-Kamenetsky M, Shulga-Morskaya S. 72.  et al. 2014. Effect of an RNA interference drug on the synthesis of proprotein convertase subtilisin/kexin type 9 (PCSK9) and the concentration of serum LDL cholesterol in healthy volunteers: a randomised, single-blind, placebo-controlled, phase 1 trial. Lancet 383:991160–68 [Google Scholar]
  73. Pinkosky SL, Newton RS, Day EA. 73.  et al. 2016. Liver-specific ATP-citrate lyase inhibition by bempedoic acid decreases LDL-C and attenuates atherosclerosis. Nat. Commun. 7:13457 [Google Scholar]
  74. Ballantyne CM, Davidson MH, Macdougall DE. 74.  et al. 2013. Efficacy and safety of a novel dual modulator of adenosine triphosphate-citrate lyase and adenosine monophosphate-activated protein kinase in patients with hypercholesterolemia: results of a multicenter, randomized, double-blind, placebo-controlled, parallel-group trial. J. Am. Coll. Cardiol. 62:131154–62 [Google Scholar]
  75. Ballantyne CM, McKenney JM, MacDougall DE. 75.  et al. 2016. Effect of ETC-1002 on serum low-density lipoprotein cholesterol in hypercholesterolemic patients receiving statin therapy. Am. J. Cardiol. 117:121928–33 [Google Scholar]
  76. 76.  Deleted in proof
  77. Lincoff AM, Nicholls SJ, Riesmeyer JS. 77.  et al. 2017. Evacetrapib and cardiovascular outcomes in high-risk vascular disease. N. Engl. J. Med. 376:201933–42 [Google Scholar]
  78. Bowman L, Hopewell JC, Chen F. 78.  et al. 2017. Effects of anacetrapib in patients with atherosclerotic vascular disease. N. Engl. J. Med. 377:1217–27 [Google Scholar]
  79. Tall AR, Rader DJ. 79.  2017. The trials and tribulations of CETP inhibitors. Circ. Res. In press [Google Scholar]
  80. Tardif JC, Rhéaume E, Lemieux Perreault LP. 80.  2015. Pharmacogenomic determinants of the cardiovascular effects of dalcetrapib. Circ. Cardiovasc. Genet. 8:2372–82 [Google Scholar]
  81. Tikka A, Jauhiainen M. 81.  2016. The role of ANGPTL3 in controlling lipoprotein metabolism. Endocrine 52:2187–93 [Google Scholar]
  82. Wang Y, Gusarova V, Banfi S. 82.  et al. 2015. Inactivation of ANGPTL3 reduces hepatic VLDL-triglyceride secretion. J. Lipid Res. 56:71296–307 [Google Scholar]
  83. Dewey FE, Gusarova V, Dunbar RL. 83.  et al. 2017. Genetic and pharmacologic inactivation of ANGPTL3 and cardiovascular disease. N. Engl. J. Med. 377:3211–21 [Google Scholar]
  84. Gaudet D, Gipe DA, Pordy R. 84.  et al. 2017. ANGPTL3 inhibition in homozygous familial hypercholesterolemia. N. Engl. J. Med. 377:3296–97 [Google Scholar]
  85. Graham MJ, Lee RG, Brandt TA. 85.  et al. 2017. Cardiovascular and metabolic effects of ANGPTL3 antisense oligonucleotides. N. Engl. J. Med. 377:3222–32 [Google Scholar]
  86. Bisgaier CL, Essenburg AD, Barnett BC. 86.  et al. 1998. A novel compound that elevates high density lipoprotein and activates the peroxisome proliferator activated receptor. J. Lipid Res. 39:117–30 [Google Scholar]
  87. Bisgaier CL, Auerbach BJ. 87.  2015. Abstract 17824: Gemcabene and atorvastatin alone and combined markedly reduce LDL-C in LDL receptor-deficient mice, a model of homozygous familial hypercholesterolemia. Circulation 132:Suppl. 3A17824 LP–A17824 [Google Scholar]
  88. 88. Gemphire Therapeutics. 2017. Gemphire announces interim LDL-C lowering data from COBALT-1 phase 2b clinical trial. News release. https://globenewswire.com/news-release/2017/01/30/911895/0/en/Gemphire-Announces-Interim-LDL-C-Lowering-Data-from-COBALT-1-Phase-2b-Clinical-Trial.html
  89. Ajufo E, Cuchel M. 89.  2016. Recent developments in gene therapy for homozygous familial hypercholesterolemia. Curr. Atheroscler. Rep. 18:522 [Google Scholar]
  90. Van Craeyveld E, Jacobs F, Gordts SC. 90.  et al. 2011. Gene therapy for familial hypercholesterolemia. Curr. Pharm. Des. 17:242575–91 [Google Scholar]
  91. Nathwani AC, Reiss UM, Tuddenham EGD. 91.  et al. 2014. Long-term safety and efficacy of Factor IX gene therapy in hemophilia B. N. Engl. J. Med. 371:211994–2004 [Google Scholar]
  92. Lebherz C, Gao G, Louboutin J-P. 92.  et al. 2004. Gene therapy with novel adeno-associated virus vectors substantially diminishes atherosclerosis in a murine model of familial hypercholesterolemia. J. Gene Med. 6:6663–72 [Google Scholar]
  93. Kassim SH, Li H, Vandenberghe LH. 93.  et al. 2010. Gene therapy in a humanized mouse model of familial hypercholesterolemia leads to marked regression of atherosclerosis. PLOS ONE 5:10e13424 [Google Scholar]
  94. Kassim SH, Li H, Bell P. 94.  et al. 2013. Adeno-associated virus serotype 8 gene therapy leads to significant lowering of plasma cholesterol levels in humanized mouse models of homozygous and heterozygous familial hypercholesterolemia. Hum. Gene Ther. 24:119–26 [Google Scholar]
  95. Knowles JW, Howard WB, Karayan L. 95.  et al. 2017. Access to nonstatin lipid-lowering therapies in patients at high risk of atherosclerotic cardiovascular disease. Circulation 135:222204 LP–2206 [Google Scholar]
  96. Stein E, Bays H, Koren M. 96.  et al. 2016. Efficacy and safety of gemcabene as add-on to stable statin therapy in hypercholesterolemic patients. J. Clin. Lipidol. 10:51212–22 [Google Scholar]
  97. Hovingh GK, Kastelein JJ, van Deventer SJ. 97.  et al. 2015. Cholesterol ester transfer protein inhibition by TA-8995 in patients with mild dyslipidaemia (TULIP): a randomised, double-blind, placebo-controlled phase 2 trial. Lancet 386:9992452–60 [Google Scholar]
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New Therapeutic Approaches for Familial Hypercholesterolemia
Annual Review of Medicine 69, 113 (2018); https://doi.org/10.1146/annurev-med-051215-030943
/content/journals/10.1146/annurev-med-051215-030943
/content/journals/10.1146/annurev-med-051215-030943
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