PCSK9 Inhibitors: Novel Therapeutic Strategies for Lowering LDLCholesterol

Author(s): Yan Wang, Zhao-Peng Liu*.

Journal Name: Mini-Reviews in Medicinal Chemistry

Volume 19 , Issue 2 , 2019

Become EABM
Become Reviewer

Graphical Abstract:


Statins are currently the major therapeutic strategies to lower low-density lipoprotein cholesterol (LDL-C) levels. However, a number of hypercholesterolemia patients still have a residual cardiovascular disease (CVD) risk despite taking the maximum-tolerated dose of statins. Proprotein convertase subtilisin/kexin type 9 (PCSK9) binds to low-density lipoprotein receptor (LDLR), inducing its degradation in the lysosome and inhibiting LDLR recirculating to the cell membranes. The gain-offunction mutations in PCSK9 elevate the LDL-C levels in plasma. Therefore, PCSK9 inhibitors become novel therapeutic approaches in the treatment of hypercholesterolemia. Several PCSK9 inhibitors have been under investigation, and much progress has been made in clinical trials, especially for monoclonal antibodies (MoAbs). Two MoAbs, evolocumab and alirocumab, are now in clinical use. In this review, we summarize the development of PCSK9 inhibitors, including antisense oligonucleotides (ASOs), small interfering RNA (siRNA), small molecule inhibitor, MoAbs, mimetic peptides and adnectins, and the related safety issues.

Keywords: Proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9), low-density lipoprotein cholesterol (LDL-C), low-density lipoprotein receptor (LDLR), cardiovascular disease (CVD), hypercholesterolemia, alirocmab, evolocumab.

Robinson, J.G. Management of familial hypercholesterolemia: A review of the recommendations from the national lipid association expert panel on familial hypercholesterolemia. J. Manag. Care Pharm., 2013, 19(2), 139-149.
George, M.; Selvarajan, S.; Muthukumar, R.; Elangovan, S. Looking into the crystal ball-upcoming drugs for dyslipidemia. J. Cardiovasc. Pharmacol. Ther., 2015, 20(1), 11-20.
Cohen, J.C.; Boerwinkle, E.; Mosley, Jr, T.H.; Hobbs, H.H. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N. Engl. J. Med., 2006, 354(12), 1264-1272.
Norata, G.D.; Ballantyne, C.M.; Catapano, A.L. New therapeutic principles in dyslipidaemia: focus on LDL and Lp (a) lowering drugs. Eur. Heart J., 2013, 34(24), 1783-1789.
Halcox, J. P.; Tubach, F.; Lopez-Garcia, E.; De Backer, G.; Borghi, C.; Dallongeville, J.; Guallar, E.; Medina, J.; Perk, J.; Sazova, O., Low rates of both lipid-lowering therapy use and achievement of low-density lipoprotein cholesterol targets in individuals at highrisk for cardiovascular disease across Europe. PLoS One,, 2015, 10(2), e0115270. doi: 10.1371/journal.pone.0115270. eCollection 2015.
Cannon, C.P.; Braunwald, E.; McCabe, C.H.; Rader, D.J.; Rouleau, J.L.; Belder, R.; Joyal, S.V.; Hill, K.A.; Pfeffer, M.A.; Skene, A.M. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N. Engl. J. Med., 2004, 350(15), 1495-1504.
Avis, H.J.; Hutten, B.A.; Gagné, C.; Langslet, G.; McCrindle, B.W.; Wiegman, A.; Hsia, J.; Kastelein, J.J.; Stein, E.A. Efficacy and safety of rosuvastatin therapy for children with familial hypercholesterolemia. J. Am. Coll. Cardiol., 2010, 55(11), 1121-1126.
Rodriguez, F.; Olufade, T.; Heithoff, K.; Friedman, H.S.; Navaratnam, P.; Foody, J.M. Frequency of high-risk patients not receiving high-potency statin (from a large managed care database). Am. J. Cardiol., 2015, 115(2), 190-195.
(a) Ray, K.K.; Kastelein, J.J.; Boekholdt, S.M.; Nicholls, S.J.; Khaw, K-T.; Ballantyne, C.M.; Catapano, A.L.; Reiner, Ž.; Lüscher, T.F. The ACC/AHA 2013 guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular disease risk in adults: the good the bad and the uncertain: A comparison with ESC/EAS guidelines for the management of dyslipidaemias 2011. Eur. Heart J., 2014, 35(15), 960-968.
(b) Chi, M.D.; Vansomphone, S.S.; Liu, I.; Cheetham, C.; Green, K.R.; Scott, R.D.; Reynolds, K. Adherence to statins and LDL-cholesterol goal attainment. Am. J. Manag. Care, 2014, 20(4), e105-e112.
Abifadel, M.; Varret, M.; Rabès, J-P.; Allard, D.; Ouguerram, K.; Devillers, M.; Cruaud, C.; Benjannet, S.; Wickham, L.; Erlich, D. Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nat. Genet., 2003, 34(2), 154-156.
(a) Allard, D.; Amsellem, S.; Abifadel, M.; Trillard, M.; Devillers, M.; Luc, G.; Krempf, M.; Reznik, Y.; Girardet, J.P.; Fredenrich, A. Novel mutations of the PCSK9 gene cause variable phenotype of autosomal dominant hypercholesterolemia. Hum. Mutat., 2005, 26(5), 497.
(b) Cohen, J.; Pertsemlidis, A.; Kotowski, I.K.; Graham, R.; Garcia, C.K.; Hobbs, H.H. Low LDL cholesterol in individuals of African descent resulting from frequent nonsense mutations in PCSK9. Nat. Genet., 2005, 37(2), 161-165.
Goldstein, J.L.; Brown, M.S. The LDL receptor. Arterioscler. Thromb. Vasc. Biol., 2009, 29(4), 431-438.
Maxwell, K.N.; Soccio, R.E.; Duncan, E.M.; Sehayek, E.; Breslow, J.L. Novel putative SREBP and LXR target genes identified by microarray analysis in liver of cholesterol-fed mice. J. Lipid Res., 2003, 44(11), 2109-2119.
(a) Zhang, D-W.; Lagace, T.A.; Garuti, R.; Zhao, Z.; McDonald, M.; Horton, J.D.; Cohen, J.C.; Hobbs, H.H. Binding of proprotein convertase subtilisin/kexin type 9 to epidermal growth factor-like repeat A of low density lipoprotein receptor decreases receptor recycling and increases degradation. J. Biol. Chem., 2007, 282(25), 18602-18612.
(b) Lagace, T.A.; Curtis, D.E.; Garuti, R.; McNutt, M.C.; Park, S.W.; Prather, H.B.; Anderson, N.N.; Ho, Y.; Hammer, R.E.; Horton, J.D. Secreted PCSK9 decreases the number of LDL receptors in hepatocytes and inlivers of parabiotic mice. J. Clin. Invest., 2006, 116(11), 2995-3005.
(c) Akram, O.N.; Bernier, A.; Petrides, F.; Wong, G.; Lambert, G. Beyond LDL cholesterol, a new role for PCSK9. Arterioscler. Thromb. Vasc. Biol., 2010, 30(7), 1279-1281.
Cariou, B.; Le May, C.; Costet, P. Clinical aspects of PCSK9. Atherosclerosis, 2011, 216(2), 258-265.
Graham, M.J.; Lemonidis, K.M.; Whipple, C.P.; Subramaniam, A.; Monia, B.P.; Crooke, S.T.; Crooke, R.M. Antisense inhibition of proprotein convertase subtilisin/kexin type 9 reduces serum LDL in hyperlipidemic mice. J. Lipid Res., 2007, 48(4), 763-767.
(a) Nielsen, C.B.; Singh, S.K.; Wengel, J.; Jacobsen, J.P. The solution structure of a locked nucleic acid (LNA) hybridized to DNA. J. Biomol. Struct. Dyn., 1999, 17(2), 175-191.
(b) Straarup, E.M.; Fisker, N.; Hedtjärn, M.; Lindholm, M.W.; Rosenbohm, C.; Aarup, V.; Hansen, H.F.; Ørum, H.; Hansen, J.B.R.; Koch, T. Short locked nucleic acid antisense oligonucleotides potently reduce apolipoprotein B mRNA and serum cholesterol in mice and non-human primates. Nucleic Acids Res., 2010, 38(20), 7100-7111.
Gupta, N.; Fisker, N.; Asselin, M-C.; Lindholm, M.; Rosenbohm, C.; Ørum, H.; Elmén, J.; Seidah, N.G.; Straarup, E.M. A locked nucleic acid antisense oligonucleotide (LNA) silences PCSK9 and enhances LDLR expression in vitro and in vivo. PLoS One, 2010, 5(5), e10682.
Lindholm, M.W.; Elmén, J.; Fisker, N.; Hansen, H.F.; Persson, R.; Møller, M.R.; Rosenbohm, C.; Ørum, H.; Straarup, E.M.; Koch, T. PCSK9 LNA antisense oligonucleotides induce sustained reduction of LDL cholesterol in nonhuman primates. Mol. Ther., 2012, 20(2), 376-381.
Multiple ascending dose study of SPC5001 in treatment of healthy subjects and subjects with FH. https://clinicaltrials.gov/ct2/ results?term=NCT01350960&Search=Search (Accessed June 6, 2016).
van Poelgeest, E.P.; Swart, R.M.; Betjes, M.G.; Moerland, M.; Weening, J.J.; Tessier, Y.; Hodges, M.R.; Levin, A.A.; Burggraaf, J. Acute kidney injury during therapy with an antisense oligonucleotide directed against PCSK9. Am. J. Kidney Dis., 2013, 62(4), 796-800.
Albek, N.; Hedtjarn, M.; Lindholm, M.; Nielsen, N.F.; Petri, A.; Ravn, J. Antisense oligomers and conjugates targeting pcsk9. 207232 A1, December 31, 2014.
Jayaraman, M.; Ansell, S.M.; Mui, B.L.; Tam, Y.K.; Chen, J.; Du, X.; Butler, D.; Eltepu, L.; Matsuda, S.; Narayanannair, J.K. Maximizing the potency of siRNA lipid nanoparticles for hepatic gene silencing in vivo. Angew. Chem. Int. Ed., 2012, 51(34), 8529-8533.
Vaishnaw, A.K.; Gollob, J.; Gamba-Vitalo, C.; Hutabarat, R.; Sah, D.; Meyers, R. A status report on RNAi therapeutics. Silence, 2010, 1, 14-26.
Frank-Kamenetsky, M.; Grefhorst, A.; Anderson, N.N.; Racie, T.S.; Bramlage, B.; Akinc, A.; Butler, D.; Charisse, K.; Dorkin, R.; Fan, Y. Therapeutic RNAi targeting PCSK9 acutely lowers plasma cholesterol in rodents and LDL cholesterol in nonhuman primates. P. Natl. Acad. Sci., 2008, 105(33), 11915-11920.
Study to evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of liposomal siRNA in subjects with high cholesterol. https://www.clinicaltrials.gov/ct2/results?term= NCT00927459&Search=Search (Accessed June 6, 2016).
Ason, B.; Tep, S.; Davis, H.R.; Xu, Y.; Tetzloff, G.; Galinski, B.; Soriano, F.; Dubinina, N.; Zhu, L.; Stefanni, A. Improved efficacy for ezetimibe and rosuvastatin by attenuating the induction of PCSK9. J. Lipid Res., 2011, 52(4), 679-687.
Fitzgerald, K.; Frank-Kamenetsky, M.; Shulga-Morskaya, S.; Liebow, A.; Bettencourt, B.R.; Sutherland, J.E.; Hutabarat, R.M.; Clausen, V.A.; Karsten, V.; Cehelsky, J. 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, 2014, 383(9911), 60-68.
Burnett, J.R.; Hooper, A.J. Running interference to lower cholesterol. Lancet, 2014, 383(9911), 10-12.
Benjannet, S.; Hamelin, J.; Chrétien, M.; Seidah, N.G. Loss-and gain-of-function PCSK9 variants cleavage specificity, dominant negative effects, and low density lipoprotein receptor (LDLR) degradation. J. Biol. Chem., 2012, 287(40), 33745-33755.
Pingali, H.; Kalapatapu, V.S.; Makadia, P.; Jain, M.R. Compounds for the treatment of dyslipidemia and related diseases. 051961 A1, May 5, 2011.
Liu, H.; Wang, J.; Zhang, R.; Cairns, N.; Liu, J. Compounds and compositions for reducing lipid levels. 075469 A1, July 1, 2010.
(Accessed June 6, 2016).
(a) Wojcik, J.; Hantschel, O.; Grebien, F.; Kaupe, I.; Bennett, K.L.; Barkinge, J.; Jones, R.B.; Koide, A.; Superti-Furga, G.; Koide, S. A potent and highly specific FN3 monobody inhibitor of the Abl SH2 domain. Nat. Struct. Mol. Biol., 2010, 17(4), 519-527.
(b) Koide, A.; Bailey, C.W.; Huang, X.; Koide, S. The fibronectin type III domain as a scaffold for novel binding proteins. J. Mol. Biol., 1998, 284(4), 1141-1151.
Williams, L.; Sank, M.; Chimalakonda, A.; Ni, Y.; Saewert, M.; DeSilva, B.; Pillutla, R. Development and characterization of a free therapeutic ligand binding assay with assistance from kinetics modeling. J. Immunol. Methods, 2015, 419, 18-24.
Mitchell, T.; Chao, G.; Sitkoff, D.; Lo, F.; Monshizadegan, H.; Meyers, D.; Low, S.; Russo, K.; DiBella, R.; Denhez, F. Pharmacologic profile of the Adnectin BMS-962476, a small protein biologic alternative to PCSK9 antibodies for low-density lipoprotein lowering. J. Pharmacol. Exp. Ther., 2014, 350(2), 412-424.
Stein, E.A.; Kasichayanula, S.; Turner, T.; Kranz, T.; Arumugam, U.; Biernat, L.; Lee, J. LDL cholesterol reduction with BMS-962476, an adnectin inhibitor of PCSK9: results of a single ascending dose study. J. Am. Coll. Cardiol., 2014, 63(12), A1372.
Chan, J.C.; Piper, D.E.; Cao, Q.; Liu, D.; King, C.; Wang, W.; Tang, J.; Liu, Q.; Higbee, J.; Xia, Z. A proprotein convertase subtilisin/kexin type 9 neutralizing antibody reduces serum cholesterol in mice and nonhuman primates. P. Natl. Acad. Sci., 2009, 106(24), 9820-9825.
Dias, C.S.; Shaywitz, A.J.; Wasserman, S.M.; Smith, B.P.; Gao, B.; Stolman, D.S.; Crispino, C.P.; Smirnakis, K.V.; Emery, M.G.; Colbert, A. Effects of AMG 145 on low-density lipoprotein cholesterol levels: results from 2 randomized, double-blind, placebo-controlled, ascending-dose phase 1 studies in healthy volunteers and hypercholesterolemic subjects on statins. J. Am. Coll. Cardiol., 2012, 60(19), 1888-1898.
Koren, M.J.; Scott, R.; Kim, J.B.; Knusel, B.; Liu, T.; Lei, L.; Bolognese, M.; Wasserman, S.M. Efficacy, safety, and tolerability of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 as monotherapy in patients with hypercholesterolaemia (MENDEL): A randomised, double-blind, placebo-controlled, phase 2 study. Lancet, 2012, 380(9858), 1995-2006.
Koren, M.J.; Lundqvist, P.; Bolognese, M.; Neutel, J.M.; Monsalvo, M.L.; Yang, J.; Kim, J.B.; Scott, R.; Wasserman, S.M.; Bays, H. Anti-PCSK9 monotherapy for hypercholesterolemia: the MENDEL-2 randomized, controlled phase III clinical trial of evolocumab. J. Am. Coll. Cardiol., 2014, 63(23), 2531-2540.
(a) Sabatine, M.S.; Giugliano, R.P.; Wiviott, S.D.; Raal, F.J.; Blom, D.J.; Robinson, J.; Ballantyne, C.M.; Somaratne, R.; Legg, J.; Wasserman, S.M. Efficacy and safety of evolocumab in reducing lipids and cardiovascular events. N. Engl. J. Med., 2015, 372(16), 1500-1509.
(b) Koren, M.J.; Giugliano, R.; Raal, F.; Sullivan, D.; Bolognese, M.; Langslet, G.; Civeira, F.; Lowy, A.; Somaratne, R.; Liu, T. Two year analysis of the safety and tolerability of evolocumab: the osler-1 study. J. Am. Coll. Cardiol., 2015, 65(10), A1364.
Gitt, A.K.; Drexel, H.; Feely, J.; Ferrières, J.; Gonzalez-Juanatey, J.R.; Thomsen, K.K.; Leiter, L.A.; Lundman, P.; da Silva, P.M.; Pedersen, T. Persistent lipid abnormalities in statin-treated patients and predictors of LDL-cholesterol goal achievement in clinical practice in Europe and Canada. Eur. J. Prev. Cardiol., 2012, 19(2), 221-230.
(a) Giugliano, R.P.; Desai, N.R.; Kohli, P.; Rogers, W.J.; Somaratne, R.; Huang, F.; Liu, T.; Mohanavelu, S.; Hoffman, E.B.; McDonald, S.T. Efficacy, safety, and tolerability of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 in combination with a statin in patients with hypercholesterolaemia (LAPLACE-TIMI 57): A randomised, placebo-controlled, dose-ranging, phase 2 study. Lancet, 2012, 380(9858), 2007-2017.
(b) Hirayama, A.; Honarpour, N.; Yoshida, M.; Yamashita, S.; Huang, F.; Wasserman, S.M.; Teramoto, T. Effects of evolocumab (AMG 145), a monoclonal antibody to PCSK9, in hypercholesterolemic, statin-treated Japanese patients at high cardiovascular risk. Circ. J., 2014, 78(5), 1073-1082.
(c) Robinson, J.G.; Nedergaard, B.S.; Rogers, W.J.; Fialkow, J.; Neutel, J.M.; Ramstad, D.; Somaratne, R.; Legg, J.C.; Nelson, P.; Scott, R. Effect of evolocumab or ezetimibe added to moderate-or high-intensity statin therapy on LDL-C lowering in patients with hypercholesterolemia: The LAPLACE-2 randomized clinical trial. JAMA, 2014, 311(18), 1870-1883.
(d) Kiyosue, A.; Honarpour, N.; Xue, A.; Wasserman, S.; Hirayama, A. Effects of evolocumab (AMG 145) in hypercholesterolemic, statin-treated, Japanese patients at high cardiovascular risk: Results from the phase III yukawa 2 study. J. Am. Coll. Cardiol., 2015, 65(10), A1369.
(e) Blom, D.J.; Hala, T.; Bolognese, M.; Lillestol, M.J.; Toth, P.D.; Burgess, L.; Ceska, R.; Roth, E.; Koren, M.J.; Ballantyne, C.M. A 52-week placebo-controlled trial of evolocumab in hyperlipidemia. N. Engl. J. Med., 2014, 370(19), 1809-1819.
(a) Sullivan, D.; Olsson, A.G.; Scott, R.; Kim, J.B.; Xue, A.; Gebski, V.; Wasserman, S.M.; Stein, E.A. Effect of a monoclonal antibody to PCSK9 on low-density lipoprotein cholesterol levels in statin-intolerant patients: the GAUSS randomized trial. JAMA, 2012, 308(23), 2497-2506.
(b) Stroes, E.; Colquhoun, D.; Sullivan, D.; Civeira, F.; Rosenson, R.S.; Watts, G.F.; Bruckert, E.; Cho, L.; Dent, R.; Knusel, B. 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., 2014, 63(23), 2541-2548.
Scriver, C.R.; Stanbury, J.B.; Wyngaarden, J.B.; Fredrickson, D.S. The metabolic and molecular bases of inherited disease; Metabol. Mol. Bases Inherit. Disease, 2001. (96)80019-7.
(a) Raal, F.; Scott, R.; Somaratne, R.; Bridges, I.; Li, G.; Wasserman, S.M.; Stein, E.A. 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, 2012, 126(20), 2408-2417.
(b) Raal, F.J.; Stein, E.A.; Dufour, R.; Turner, T.; Civeira, F.; Burgess, L.; Langslet, G.; Scott, R.; Olsson, A.G.; Sullivan, D. PCSK9 inhibition with evolocumab (AMG 145) in heterozygous familial hypercholesterolaemia (RUTHERFORD-2): a randomised, double-blind, placebo-controlled trial. Lancet, 2015, 385(9965), 331-340.
Stein, E.A.; Honarpour, N.; Wasserman, S.M.; Xu, F.; Scott, R.; Raal, F.J. Effect of the PCSK9 monoclonal antibody, AMG 145, in homozygous familial hypercholesterolemia. Circulation, 2013, 128(19), 2113-2120.
Raal, F.J.; Honarpour, N.; Blom, D.J.; Hovingh, G.K.; Xu, F.; Scott, R.; Wasserman, S.M.; Stein, E.A.; Investigators, T. Inhibition of PCSK9 with evolocumab in homozygous familial hypercholesterolaemia (TESLA Part B): a randomised, double-blind, placebo-controlled trial. Lancet, 2015, 385(9965), 341-350.
Evaluating PCSK9 binding antibody Influence on cognitive health in high cardiovascular risk subjects. https://clinicaltrials.gov/ ct2/show/study/NCT02207634?term=NCT02207634&rank=1 (Accessed June 6, 2016).
Global assessment of plaque regression with a PCSK9 antibody as measured by intravascular ultrasound. https://www.clinicaltrials. gov/ct2/show/study/NCT01813422?term=NCT01813422&rank=1 (Accessed June 6, 2016).
Further cardiovascular outcomes research with PCSK9 inhibition in subjects with elevated risk. https://www.clinicaltrials.gov/ ct2/show/study/NCT01764633?term=NCT01764633&rank=1 (Accessed June 6, 2016).
Trial assessing long term use of PCSK9 inhibition in subjects with genetic LDL disorders. https://www.clinicaltrials.gov/ct2/show/ study/NCT01624142?term=NCT01624142&rank=1 (Accessed June 6, 2016).
Stein, E.A.; Mellis, S.; Yancopoulos, G.D.; Stahl, N.; Logan, D.; Smith, W.B.; Lisbon, E.; Gutierrez, M.; Webb, C.; Wu, R. Effect of a monoclonal antibody to PCSK9 on LDL cholesterol. N. Engl. J. Med., 2012, 366(12), 1108-1118.
Lunven, C.; Paehler, T.; Poitiers, F.; Brunet, A.; Rey, J.; Hanotin, C.; Sasiela, W.J. A randomized study of the relative pharmacokinetics, pharmacodynamics, and safety of alirocumab, a fully human monoclonal antibody to PCSK9, after single subcutaneous administration at three different injection sites in healthy subjects. Cardiovasc. Ther., 2014, 32(6), 297-301.
Roth, E.M.; Taskinen, M-R.; Ginsberg, H.N.; Kastelein, J.J.; Colhoun, H.M.; Robinson, J.G.; Merlet, L.; Pordy, R.; Baccara-Dinet, M.T. Monotherapy with the PCSK9 inhibitor alirocumab versus ezetimibe in patients with hypercholesterolemia: Results of a 24week, double-blind, randomized Phase 3 trial. Int. J. Cardiol., 2014, 176(1), 55-61.
Roth, E.M.; McKenney, J.M.; Hanotin, C.; Asset, G.; Stein, E.A. Atorvastatin with or without an antibody to PCSK9 in primary hypercholesterolemia. N. Engl. J. Med., 2012, 367(20), 1891-1900.
McKenney, J.M.; Koren, M.J.; Kereiakes, D.J.; Hanotin, C.; Ferrand, A-C.; Stein, E.A. Safety and efficacy of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 serine protease, SAR236553/REGN727, in patients with primary hypercholesterolemia receiving ongoing stable atorvastatin therapy. J. Am. Coll. Cardiol., 2012, 59(25), 2344-2353.
Latimer, J.; Batty, J.A.; Neely, D.D.; Kunadian, V. Pcsk9 inhibitors in the prevention of cardiovascular disease. J. Thromb. Thrombolys, 2016, 42, 405-419.
(a) Bays, H.; Gaudet, D.; Weiss, R.; Ruiz, J.L.; Watts, G.F.; Gouni-Berthold, I.; Robinson, J.; Zhao, J.; Hanotin, C.; Donahue, S. Alirocumab as add-on to atorvastatin versus other lipid treatment strategies: ODYSSEY OPTIONS I randomized trial. J. Clin. Endocrinol. Metabol., 2015, 100(8), 3140-3148.
(b) Study of alirocumab (REGN727/SAR236553) added-on to rosuvastatin versus other lipid modifying treatments (LMT) (ODYSSEY OPTIONS II). https://www.clinicaltrials.gov/ct2/show/results/NCT01730053?term=NCT01730053&rank=1 (Accessed June 6, 2016).
(c) Kereiakes, D.J.; Robinson, J.G.; Cannon, C.P.; Lorenzato, C.; Pordy, R.; Chaudhari, U.; Colhoun, H.M. Efficacy and safety of the proprotein convertase subtilisin/kexin type 9 inhibitor alirocumab among high cardiovascular risk patients on maximally tolerated statin therapy: The ODYSSEY COMBO I study. Am. Heart J., 2015, 169(6), 906-915.e913.
(d) Cannon, C.P.; Cariou, B.; Blom, D.; McKenney, J.M.; Lorenzato, C.; Pordy, R.; Chaudhari, U.; Colhoun, H.M. Efficacy and safety of alirocumab in high cardiovascular risk patients with inadequately controlled hypercholesterolaemia on maximally tolerated doses of statins: the ODYSSEY COMBO II randomized controlled trial. Eur. Heart J., 2015, 36(19), 1186-1194.
(e) Stroes, E.S.G. ESG, G.J., Farnier M. Efficacy and safety of different dosing regimens of alirocumab (starting doses of 75 mg every two weeks and 150 mg every four weeks) versus placebo in patients with hypercholesterolemia not treated using statins: The ODYSSEY CHOICE I and II studies. American College of Cardiology 64th Annual Scientific Sessions and Expo 2015, San Diego, CA, March 14, 2015.
Stein, E.A.; Gipe, D.; Bergeron, J.; Gaudet, D.; Weiss, R.; Dufour, R.; Wu, R.; Pordy, R. Effect of a monoclonal antibody to PCSK9, REGN727/SAR236553, to reduce low-density lipoprotein cholesterol in patients with heterozygous familial hypercholesterolaemia on stable statin dose with or without ezetimibe therapy: a phase 2 randomised controlled trial. Lancet, 2012, 380(9836), 29-36.
Stein, E.A.; Bergeron, J.; Gaudet, D.; Weiss, R.; Dufour, R.; Du, Y.; Yang, F.; Andisik, M.; Torri, A.; Pordy, R. One year open-label treatment with alirocumab 150 mg every two weeks in heterozygous familial hypercholesterolemic patients. J. Am. Coll. Cardiol., 2014, 63(12), A1371.
Kastelein, J.J.P.; Robinson, J.G.; Farnier, M.; Krempf, M.; Langslet, G.; Lorenzato, C.; Gipe, D.A.; Baccara-Dinet, M.T. Efficacy and safety of alirocumab in patients with heterozygous familial hypercholesterolemia not adequately controlled with current lipid-lowering therapy: design and rationale of the ODYSSEY FH studies. Cardiovasc. Drugs Ther., 2014, 28(3), 1-9.
Efficacy and safety evaluation of alirocumab in patients with heterozygous familial hypercholesterolemia or high cardiovascular risk patients with hypercholesterolemia on lipid modifying therapy (ODYSSEY JAPAN). https://www.clinicaltrials.gov/ct2/show/ NCT02107898?term=NCT02107898&rank=1 (Accessed June 6, 2016).
(a) Moriarty, P.M.; Jacobson, T.A.; Bruckert, E.; Thompson, P.D.; Guyton, J.R.; Baccara-Dinet, M.T.; Gipe, D. Efficacy and safety of alirocumab, a monoclonal antibody to PCSK9, in statin-intolerant patients: design and rationale of ODYSSEY ALTERNATIVE, a randomized phase 3 trial. J. Clin. Lipidol., 2014, 8(6), 554-561.
(b) Stroes, E.S.G.; Guyton, J.; Farnier, M.; Lepor, N.; Civeira, F.; Gaudet, D.; Watts, G.; Manvelian, G.; Lecorps, G.; Baccara-Dinet, M. Efficacy and safety of different dosing regimens of alirocumab (starting doses of 75 mg every two weeks and 150 mg every four weeks) versus placebo in patients with hypercholesterolemia not treated using statins: the ODYSSEY CHOICE II study. J. Am. Coll. Cardiol., 2015, 65(10), A1370.
Robinson, J.G.; Farnier, M.; Krempf, M.; Bergeron, J.; Luc, G.; Averna, M.; Stroes, E.S.; Langslet, G.; Raal, F.J.; El Shahawy, M. Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. N. Engl. J. Med., 2015, 372(16), 1489-1499.
Efficacy and safety of ALI versus usual care on top of maximally tolerated statin therapy in patients with type 2 diabetes and mixed dyslipidemia. https://www.clinicaltrials.gov/ct2/show/study/ NCT02642159?term=NCT02642159&rank=1 (Accessed June 6, 2016).
Evaluation of alirocumab in addition to lipid-modifying therapy in patients with high cardiovascular risk and hypercholesterolemia in South Korea and Taiwan. https://www.clinicaltrials.gov/ct2/show/ record/NCT02289963?term=NCT02289963&rank=1 (Accessed June 6, 2016).
Open label study of long term safety evaluation of alirocumab. https://www.clinicaltrials.gov/ct2/show/record/NCT01954394?term=NCT01954394&rank=1 (Accessed June 6, 2016).
Study of alirocumab in patients with HeFH undergoing LDL apheresis therapy. https://www.clinicaltrials.gov/ct2/show/study/ NCT02326220?term=NCT02326220&rank=1 (Accessed June 6, 2016).
Schwartz, G.G.; Bessac, L.; Berdan, L.G.; Bhatt, D.L.; Bittner, V.; Diaz, R.; Goodman, S.G.; Hanotin, C.; Harrington, R.A.; Jukema, J.W. Effect of alirocumab, a monoclonal antibody to PCSK9, on long-term cardiovascular outcomes following acute coronary syndromes: Rationale and design of the ODYSSEY Outcomes trial. Am. Heart J., 2014, 168(5), 682-689.e681.
Efficacy and safety of alirocumab versus placebo on top of maximally tolerated lipid lowering therapy in patients with Hypercholesterolemia who have type 1 or type 2 diabetes and are treated with insulin. https://www.clinicaltrials.gov/ct2/show/results/ NCT02585778?term=NCT02585778&rank=1 (Accessed June 6, 2016).
Safety, tolerability, and effect of alirocumab in high cardiovascular risk patients with severe hypercholesterolemia not adequately controlled with conventional lipid-modifying therapies. https://www.clinicaltrials.gov/ct2/show/results/NCT02476006?term=NCT02476006&rank=1 (Accessed June 6, 2016).
Efficacy and safety of alirocumab in patients with hypercholesterolemia not adequately controlled with non-statin lipid modifying therapy or the lowest strength of statin. https://www.clinicaltrials. gov/ct2/show/results/NCT02584504?term=NCT02584504&rank=1 (Accessed June 6, 2016).
Gumbiner, B.; Udata, C.; Joh, T.; Liang, H.; Wan, H.; Shelton, D.; Forgues, P.; Billotte, S.; Pons, J.; Baum, C.M. The effects of single dose administration of RN316 (PF-04950615), a humanized IgG2a monoclonal antibody binding proprotein convertase subtilisin kexin type 9, in hypercholesterolemic subjects treated with and without atorvastatin. Circulation, 2012, 126(21), A13322.
Vinall, P. Effects of 12 weeks of treatment with RN316 (PF-04950615) in hypercholesterolemic subjects on high and maximal dose statins. Circulation, 2012, 126, A13322.
Ballantyne, C.M.; Neutel, J.; Cropp, A.; Duggan, W.; Wang, E.Q.; Plowchalk, D.; Sweeney, K.; Kaila, N.; Vincent, J.; Bays, H. Results of bococizumab, a monoclonal antibody against proprotein convertase subtilisin/kexin type 9, from a randomized, placebo-controlled, dose-ranging study in statin-treated subjects with hypercholesterolemia. Am. J. Cardiol., 2015, 115(9), 1212-1221.
Wang, E.; Plowchalk, D.; Gibiansky, L.; Sweeney, K.; Kaila, N. Population pharmacokinetic and pharmacodynamic modeling of bococizumab (RN316/PF-04950615) in hypercholesterolemic subjects. Atherosclerosis, 2014, 235(2), e262.
A 52 week study to assess the use of bococizumab (PF-04950615; RN316) in subjects with heterozygous familial hypercholesterolemia (SPIRE-FH). https://clinicaltrials.gov/ct2/show/ NCT01968980 (Accessed June 6, 2016).
Randomized clinical trial of bococizumab (PF-04950615; RN316) in subjects with hyperlipidemia or mixed dyslipidemia at risk of cardiovascular events (SPIRE-HR). https://clinicaltrials.gov/ct2/ show/NCT01968954 (Accessed June 6, 2016).
Randomized clinical trial of bococizumab (PF-04950615; RN316) in subjects with hyperlipidemia or mixed dyslipidemia at risk of cardiovascular events (SPIRE-LDL). https://clinicaltrials.gov/ ct2/show/NCT01968967 (Accessed June 6, 2016).
The evaluation of bococizumab (PF-04950615;RN316) in reducing the occurrence of major cardiovascular events in high risk subjects (SPIRE-1). https://clinicaltrials.gov/ct2/show/NCT01975376 (Accessed June 6, 2016).
The evaluation of bococizumab (PF-04950615; RN316) in reducing the occurrence of major cardiovascular events in high risk subjects (SPIRE-2). https://clinicaltrials.gov/ct2/show/NCT01975389 (Accessed June 6, 2016).
Peng, K.; Xu, K.; Liu, L.; Hendricks, R.; Delarosa, R.; Erickson, R.; Budha, N.; Leabman, M.; Song, A.; Kaur, S. Critical role of bioanalytical strategies in investigation of clinical PK observations, a Phase I case study. MAbs, 2014, 6(6), 1500-1508.
(a) Baruch, A.; Peng, K.; Leabman, M.; Budha, N.; Luca, D.; Cowan, K.J.; Davis, J.D.; Tingley, W. Effect of RG7652, a mAb against PCSK9, on apolipoprotein B, oxidized LDL, lipoprotein(a) and lipoprotein-associated phospholipase A2 in healthy individuals with elevated LDL-C. Circulation, 2013, 22, A12009.
(b) Tingley, W.; Luca, D.; Leabman, M.; Budha, N.; Kahn, R.; Baruch, A.; Cowan, K.; Davis, J.C. Effects of RG7652, a fully human mAb against proprotein convertase subtilisin/kexin type 9, on LDL-c: a Phase I, randomised, double-blind, placebo-controlled, single- and multiple-dose study. Heart, 2013, 99(Suppl. 3), A153.
Gelzleichter, T.R.; Wendy, H.; Roy, E.; Amos, B.; Maya, L.; Forrest, A.S.; Satterwhite, C.M.; Kun, P.; Jennifer, C.; Dale, S. Combined administration of RG7652, a recombinant human monoclonal antibody against PCSK9, and atorvastatin does not result in reduction of immune function. Toxicol. Sci., 2014, 140(2), 427-432.
Tingley, W. Effects of RG7652, a monoclonal antibody against proprotein convertase Subtilisin/Kexin type 9, on LDL cholesterol in patients with coronary heart disease or high risk: Results from the EQUATOR study. Eur. Heart J. Suppl., 2014, 2105.
Safety, tolerability, PK and PD of LGT209 in healthy volunteers and patients with hypercholesterolemia. https://www.clinicaltrials. gov/ct2/show/results/NCT01979601?term=LGT209&rank=1 (Accessed June 6, 2016).
Eacho, P.; Schroeder, K.; Beyer, T.; Hansen, R.; Wroblewski, V.; Han, B.; Pickard, R.; Kowala, M. Novel mechanisim for the sustained durability of proprotein convertase subtilisin-kexin type 9 monoclonal antibody LY3015014. J. Am. Coll. Cardiol., 2015, 65(10), A1577.
Kastelein, J.; Nissen, S.; Rader, D.; Krueger, K.; Wang, M-D. Safety and efficacy of LY3015014, a new monoclonal antibody to proprotein convertase subtilisin/kexin type 9 (PCSK9) with an inherently longer duration of action, in patients with primary hypercholesterolemia: A randomized, placebo-controlled, dose-ranging, phase 2 study. J. Am. Coll. Cardiol., 2015, 65(10S)
(a) Li, C.; Lin, L.; Zhang, W.; Zhou, L.; Wang, H.; Luo, X.; Luo, H.; Cai, Y.; Zeng, C. Efficiency and safety of proprotein convertase subtilisin/kexin 9 monoclonal antibody on hypercholesterolemia: A meta-analysis of 20 randomized controlled trials. J. Am. Heart Assoc., 2015, 4(6)
(b) Zhang, X-L.; Zhu, Q-Q.; Zhu, L.; Chen, J-Z.; Chen, Q-H.; Li, G-N.; Xie, J.; Kang, L-N.; Xu, B. Safety and efficacy of anti-PCSK9 antibodies: a meta-analysis of 25 randomized, controlled trials. BMC Med., 2015, 13(1), 1.
LaRosa, J.C.; Pedersen, T.R.; Somaratne, R.; Wasserman, S.M. Safety and effect of very low levels of low-density lipoprotein cholesterol on cardiovascular events. Am. J. Cardiol., 2013, 111(8), 1221-1229.
(a) Shepherd, J.; Blauw, G.J.; Murphy, M.B.; Bollen, E.L.; Buckley, B.M.; Cobbe, S.M.; Ford, I.; Gaw, A.; Hyland, M.; Jukema, J.W. Pravastatin in elderly individuals at risk of vascular disease (PROSPER): A randomised controlled trial. Lancet, 2002, 360(9346), 1623-1630.
(b) Karam, J.G.; Loney-Hutchinson, L.; McFarlane, S.I. High‐dose atorvastatin after stroke or transient ischemic attack: the stroke prevention by aggressive reduction in cholesterol levels (SPARCL) investigators. J. Cardiometab. Syndr., 2008, 3(1), 68-69.
(c) Hsia, J.; MacFadyen, J.G.; Monyak, J.; Ridker, P.M. Cardiovascular event reduction and adverse events among subjects attaining low-density lipoprotein cholesterol < 50 mg/dL with rosuvastatin: the JUPITER trial (justification for the use of statins in prevention: an intervention trial evaluating rosuvastatin). J. Am. Coll. Cardiol., 2011, 57(16), 1666-1675.
(a) Heikkilä, P.; Kahri, A.I.; Ehnholm, C.; Kovanen, P.T. The effect of low-and high-density lipoprotein cholesterol on steroid hormone production and ACTH-induced differentiation of rat adrenocortical cells in primary culture. Cell Tissue Res., 1989, 256(3), 487-494.
(b) Heikkilä, P.; Kahri, A.I.; Kovanen, P.T.; Ehnholm, C. Effects of mevinolin, an inhibitor of cholesterol synthesis, on the morphology and function of differentiating and differentiated rat adrenocortical cells in primary culture. Cell Tissue Res., 1990, 261(1), 125-132.
Blom, D.J.; Djedjos, C.S.; Monsalvo, M.L.; Bridges, I.; Wasserman, S.M.; Scott, R.; Roth, E. Effects of evolocumab on vitamin E and steroid hormone levels results from the 52-week, phase 3, double-blind, randomized, placebo-controlled DESCARTES study. Circ. Res., 2015, 117(8), 731-741.
(a) Martin, S.S.; Blaha, M.J.; Elshazly, M.B.; Brinton, E.A.; Toth, P.P.; McEvoy, J.W.; Joshi, P.H.; Kulkarni, K.R.; Mize, P.D.; Kwiterovich, P.O. Friedewald-estimated versus directly measured low-density lipoprotein cholesterol and treatment implications. J. Am. Coll. Cardiol., 2013, 62(8), 732-739.
(b) Sibal, L.; Neely, R.; Jones, A.; Home, P. Friedewald equation underestimates low-density lipoprotein cholesterol at low concentrations in young people with and without Type 1 diabetes. Diabet. Med., 2010, 27(1), 37-45.
Verbeek, R.; Stoekenbroek, R.M.; Hovingh, G.K. Pcsk9 inhibitors: novel therapeutic agents for the treatment of hypercholesterolemia. Eur. J. Pharmacol., 2015, 763, 38-47.
(a) Roubtsova, A.; Munkonda, M.N.; Awan, Z.; Marcinkiewicz, J.; Chamberland, A.; Lazure, C.; Cianflone, K.; Seidah, N.G.; Prat, A. Circulating proprotein convertase subtilisin/kexin 9 (PCSK9) regulates VLDLR protein and triglyceride accumulation in visceral adipose tissue. Arterioscler. Thromb. Vasc. Biol., 2011, 31(4), 785-791.
(b) Mbikay, M.; Sirois, F.; Mayne, J.; Wang, G-S.; Chen, A.; Dewpura, T.; Prat, A.; Seidah, N.G.; Chretien, M.; Scott, F.W. PCSK9-deficient mice exhibit impaired glucose tolerance and pancreatic islet abnormalities. FEBS Lett., 2010, 584(4), 701-706.
(c) Labonté, P.; Begley, S.; Guévin, C.; Asselin, M.C.; Nassoury, N.; Mayer, G.; Prat, A.; Seidah, N.G. PCSK9 impedes hepatitis C virus infection in vitro and modulates liver CD81 expression. Hepatology, 2009, 50(1), 17-24.
(d) Ranheim, T.; Mattingsdal, M.; Lindvall, J.M.; Holla, Ø.L.; Berge, K.E.; Kulseth, M.A.; Leren, T.P. Genome-wide expression analysis of cells expressing gain of function mutant D374Y-PCSK9. J. Cell. Physiol., 2008, 217(2), 459-467.
(e) Lan, H.; Pang, L.; Smith, M.M.; Levitan, D.; Ding, W.; Liu, L.; Shan, L.; Shah, V.V.; Laverty, M.; Arreaza, G. Proprotein convertase subtilisin/kexin type 9 (PCSK9) affects gene expression pathways beyond cholesterol metabolism in liver cells. J. Cell. Physiol., 2010, 224(1), 273-281.

Rights & PermissionsPrintExport Cite as

Article Details

Year: 2019
Page: [165 - 176]
Pages: 12
DOI: 10.2174/1389557518666180423111442
Price: $65

Article Metrics

PDF: 56
HTML: 12
PRC: 1