PCSK9 inhibitors: Pharmacology, adverse effects, and use
- John JP Kastelein, MD, PhD, FESC
John JP Kastelein, MD, PhD, FESC
- Professor of Medicine
- Academic Medical Center, University of Amsterdam
- Amsterdam, the Netherlands
- Erik SG Stroes, MD, PhD
Erik SG Stroes, MD, PhD
- Professor of Medicine
- Academic Medical Center
- University of Amsterdam
- Lotte CA Stiekema, MD
Lotte CA Stiekema, MD
- Academic Medical Center
Proprotein convertase subtilisin/kexin type 9 inhibitors have been approved by regulatory agencies for the treatment of individuals with inadequately treated levels of low density lipoprotein-cholesterol (LDL-C). They are capable of lowering LDL-C by as much as 60 percent in patients on statin therapy. In addition, they may produce clinical benefits, such as reductions in the rates of cardiac death or myocardial infarction. (See "Lipid lowering with drugs other than statins and fibrates", section on 'PCSK9 inhibitors'.)
MECHANISM OF ACTION
Proprotein convertase subtilisin/kexin type 9 (PCSK9), an enzyme (serine protease) encoded by the PCSK9 gene, is predominantly produced in the liver [1-3]. PCSK9 binds to the low density lipoprotein receptor (LDL-R) on the surface of hepatocytes, leading to the degradation of the LDL-R and higher plasma LDL-cholesterol (LDL-C) levels [4,5]. Blocking antibodies to PCSK9 interfere with its binding of the LDL-R leading to higher hepatic LDL-R expression and lower plasma LDL-C levels .
There are several strategies to lower free plasma PCSK9, including antisense (locked nucleic acid), silencing ribonucleic acid (RNA), and monoclonal antibody strategies. PCSK9-antibodies are the first of these therapies approved for clinical use. These antibodies are specific for PCSK9 and do not bind to other members of the PCSK enzyme family [7,8].
Alirocumab and evolocumab are fully humanized monoclonal antibodies that bind free plasma PCSK9, promoting degradation of this enzyme [9-12]. As a result, less free PCSK9 is available in plasma to bind to LDL-R. This results in a higher fraction of LDL-R recycling towards the hepatocyte surface. As a direct consequence, the liver has the capacity to remove more LDL-C from the circulation, resulting in lower LDL-C plasma levels.
Another potential method of interfering with PCSK9 is to block its synthesis, which is dependent on messenger RNA. A study of a small interfering (siRNA) RNA molecule, which can direct sequence-specific degradation of messenger RNA for PCSK9, is ongoing. In a phase 1 dose-escalation study of healthy adult volunteers with serum LDL-C levels of ≥3 mmol/L (116 mg/dL) who received a single dose of one such siRNA (ALN-PCS), treatment with the highest dose lead to a 70 percent mean reduction in circulating PCSK9 and a mean 40 percent reduction in LDL-C from baseline relative to placebo .
- Maxwell KN, Soccio RE, Duncan EM, et al. Novel putative SREBP and LXR target genes identified by microarray analysis in liver of cholesterol-fed mice. J Lipid Res 2003; 44:2109.
- Seidah NG, Benjannet S, Wickham L, et al. The secretory proprotein convertase neural apoptosis-regulated convertase 1 (NARC-1): liver regeneration and neuronal differentiation. Proc Natl Acad Sci U S A 2003; 100:928.
- Ferri N, Tibolla G, Pirillo A, et al. Proprotein convertase subtilisin kexin type 9 (PCSK9) secreted by cultured smooth muscle cells reduces macrophages LDLR levels. Atherosclerosis 2012; 220:381.
- Zhang DW, Lagace TA, Garuti R, et al. 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; 282:18602.
- Lo Surdo P, Bottomley MJ, Calzetta A, et al. Mechanistic implications for LDL receptor degradation from the PCSK9/LDLR structure at neutral pH. EMBO Rep 2011; 12:1300.
- Everett BM, Smith RJ, Hiatt WR. Reducing LDL with PCSK9 Inhibitors--The Clinical Benefit of Lipid Drugs. N Engl J Med 2015; 373:1588.
- McGovern TJ. Tertiary Pharmacology/Toxicology Review REPATHA (evolocumab) U.S. Food and Drug Administration 2015.
- Chung JE. Clinical pharmacology review PRALUENT (Alirocumab). U.S. Food and Drug Administration 2014.
- Stein EA, Swergold GD. Potential of proprotein convertase subtilisin/kexin type 9 based therapeutics. Curr Atheroscler Rep 2013; 15:310.
- Manniello M, Pisano M. Alirocumab (Praluent): First in the New Class of PCSK9 Inhibitors. P T 2016; 41:28.
- Chan JC, Piper DE, Cao Q, et al. A proprotein convertase subtilisin/kexin type 9 neutralizing antibody reduces serum cholesterol in mice and nonhuman primates. Proc Natl Acad Sci U S A 2009; 106:9820.
- Stein EA, Mellis S, Yancopoulos GD, et al. Effect of a monoclonal antibody to PCSK9 on LDL cholesterol. N Engl J Med 2012; 366:1108.
- Fitzgerald K, Frank-Kamenetsky M, Shulga-Morskaya S, et al. 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; 383:60.
- Navarese EP, Kolodziejczak M, Kereiakes DJ, et al. Proprotein Convertase Subtilisin/Kexin Type 9 Monoclonal Antibodies for Acute Coronary Syndrome: A Narrative Review. Ann Intern Med 2016; 164:600.
- Cohen JC, Boerwinkle E, Mosley TH Jr, Hobbs HH. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N Engl J Med 2006; 354:1264.
- Cohen J, Pertsemlidis A, Kotowski IK, et al. Low LDL cholesterol in individuals of African descent resulting from frequent nonsense mutations in PCSK9. Nat Genet 2005; 37:161.
- Benn M, Nordestgaard BG, Grande P, et al. PCSK9 R46L, low-density lipoprotein cholesterol levels, and risk of ischemic heart disease: 3 independent studies and meta-analyses. J Am Coll Cardiol 2010; 55:2833.
- Soutar AK, Naoumova RP. Mechanisms of disease: genetic causes of familial hypercholesterolemia. Nat Clin Pract Cardiovasc Med 2007; 4:214.
- Abifadel M, Varret M, Rabès JP, et al. Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nat Genet 2003; 34:154.
- Leren TP. Mutations in the PCSK9 gene in Norwegian subjects with autosomal dominant hypercholesterolemia. Clin Genet 2004; 65:419.
- Ference BA. Abstract presented at 65th Annual Scientific Session & Expo, American College of Cardiology, April 2016.
- Ference BA. Mendelian randomization studies: using naturally randomized genetic data to fill evidence gaps. Curr Opin Lipidol 2015; 26:566.
- McKenney JM, Koren MJ, Kereiakes DJ, et al. 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; 59:2344.
- Roth EM, McKenney JM, Hanotin C, et al. Atorvastatin with or without an antibody to PCSK9 in primary hypercholesterolemia. N Engl J Med 2012; 367:1891.
- Stein EA, Gipe D, Bergeron J, et al. 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; 380:29.
- Raal F, Scott R, Somaratne R, et al. 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; 126:2408.
- Sullivan D, Olsson AG, Scott R, et al. Effect of a monoclonal antibody to PCSK9 on low-density lipoprotein cholesterol levels in statin-intolerant patients: the GAUSS randomized trial. JAMA 2012; 308:2497.
- Giugliano RP, Desai NR, Kohli P, et al. 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; 380:2007.
- Koren MJ, Scott R, Kim JB, et al. 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; 380:1995.
- Stroes E, Colquhoun D, Sullivan D, et al. 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; 63:2541.
- Koren MJ, Lundqvist P, Bolognese M, et al. Anti-PCSK9 monotherapy for hypercholesterolemia: the MENDEL-2 randomized, controlled phase III clinical trial of evolocumab. J Am Coll Cardiol 2014; 63:2531.
- Robinson JG, Nedergaard BS, Rogers WJ, et al. 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; 311:1870.
- Raal FJ, Stein EA, Dufour R, et al. PCSK9 inhibition with evolocumab (AMG 145) in heterozygous familial hypercholesterolaemia (RUTHERFORD-2): a randomised, double-blind, placebo-controlled trial. Lancet 2015; 385:331.
- Navarese EP, Kolodziejczak M, Schulze V, et al. Effects of Proprotein Convertase Subtilisin/Kexin Type 9 Antibodies in Adults With Hypercholesterolemia: A Systematic Review and Meta-analysis. Ann Intern Med 2015; 163:40.
- Sabatine MS, Giugliano RP, Wiviott SD, et al. Efficacy and safety of evolocumab in reducing lipids and cardiovascular events. N Engl J Med 2015; 372:1500.
- Robinson JG, Farnier M, Krempf M, et al. Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. N Engl J Med 2015; 372:1489.
- Suryanarayana Sista JE. Clinical phramacology review REPATHA (Evolocumab). U.S. Food and Drug Administration 2014.
- Pardridge WM. The blood-brain barrier: bottleneck in brain drug development. NeuroRx 2005; 2:3.
- Zhao Z, Tuakli-Wosornu Y, Lagace TA, et al. Molecular characterization of loss-of-function mutations in PCSK9 and identification of a compound heterozygote. Am J Hum Genet 2006; 79:514.
- Benn M. Abstract 19109: Low PCSK9 and LDL Cholesterol and Risk of Dementia, Parkinson’s Disease, and Epilepsy - A Mendelian Randomization Study. Circulation 2015; 132(Suppl 3):A19109.
- Nissen SE, Stroes E, Dent-Acosta RE, et al. Efficacy and Tolerability of Evolocumab vs Ezetimibe in Patients With Muscle-Related Statin Intolerance: The GAUSS-3 Randomized Clinical Trial. JAMA 2016; 315:1580.
- Zeisel MB, Fofana I, Fafi-Kremer S, Baumert TF. Hepatitis C virus entry into hepatocytes: molecular mechanisms and targets for antiviral therapies. J Hepatol 2011; 54:566.
- Diedrich G. How does hepatitis C virus enter cells? FEBS J 2006; 273:3871.
- Labonté P, Begley S, Guévin C, et al. PCSK9 impedes hepatitis C virus infection in vitro and modulates liver CD81 expression. Hepatology 2009; 50:17.
- Javitt NB. Bile acid synthesis from cholesterol: regulatory and auxiliary pathways. FASEB J 1994; 8:1308.
- Debruyne PR, Bruyneel EA, Li X, et al. The role of bile acids in carcinogenesis. Mutat Res 2001; 480-481:359.
- Reddy BS. Role of bile metabolites in colon carcinogenesis. Animal models. Cancer 1975; 36:2401.
- Sakaguchi M, Minoura T, Hiramatsu Y, et al. Effects of dietary saturated and unsaturated fatty acids on fecal bile acids and colon carcinogenesis induced by azoxymethane in rats. Cancer Res 1986; 46:61.
- Golden MR. Clinical review PRALUENT (Alirocumab) U.S. Food and Drug Administration 2015.
- Craig E. Clinical review REPATHA (Evolocumab). U.S. Food and Drug Administration 2014.
- Rajpathak SN, Kumbhani DJ, Crandall J, et al. Statin therapy and risk of developing type 2 diabetes: a meta-analysis. Diabetes Care 2009; 32:1924.
- Mbikay M, Sirois F, Mayne J, et al. PCSK9-deficient mice exhibit impaired glucose tolerance and pancreatic islet abnormalities. FEBS Lett 2010; 584:701.
- Colhoun HM, Ginsberg HN, Robinson JG, et al. No effect of PCSK9 inhibitor alirocumab on the incidence of diabetes in a pooled analysis from 10 ODYSSEY Phase 3 studies. Eur Heart J 2016.
- Careskey HE, Davis RA, Alborn WE, et al. Atorvastatin increases human serum levels of proprotein convertase subtilisin/kexin type 9. J Lipid Res 2008; 49:394.
- Dubuc G, Chamberland A, Wassef H, et al. Statins upregulate PCSK9, the gene encoding the proprotein convertase neural apoptosis-regulated convertase-1 implicated in familial hypercholesterolemia. Arterioscler Thromb Vasc Biol 2004; 24:1454.
- Mayne J, Dewpura T, Raymond A, et al. Plasma PCSK9 levels are significantly modified by statins and fibrates in humans. Lipids Health Dis 2008; 7:22.
- Raal F, Panz V, Immelman A, Pilcher G. Elevated PCSK9 levels in untreated patients with heterozygous or homozygous familial hypercholesterolemia and the response to high-dose statin therapy. J Am Heart Assoc 2013; 2:e000028.
- Farnier M, Jones P, Severance R, et al. Efficacy and safety of adding alirocumab to rosuvastatin versus adding ezetimibe or doubling the rosuvastatin dose in high cardiovascular-risk patients: The ODYSSEY OPTIONS II randomized trial. Atherosclerosis 2016; 244:138.
- Dias CS, Shaywitz AJ, Wasserman SM, et al. 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; 60:1888.
- Raal FJ, Honarpour N, Blom DJ, et al. Inhibition of PCSK9 with evolocumab in homozygous familial hypercholesterolaemia (TESLA Part B): a randomised, double-blind, placebo-controlled trial. Lancet 2015; 385:341.
- Markham A. Alirocumab: First Global Approval. Drugs 2015; 75:1699.
- Markham A. Evolocumab: First Global Approval. Drugs 2015; 75:1567.
- Stroes ES, Thompson PD, Corsini A, et al. Statin-associated muscle symptoms: impact on statin therapy-European Atherosclerosis Society Consensus Panel Statement on Assessment, Aetiology and Management. Eur Heart J 2015; 36:1012.
- Zhang Y, Eigenbrot C, Zhou L, et al. Identification of a small peptide that inhibits PCSK9 protein binding to the low density lipoprotein receptor. J Biol Chem 2014; 289:942.
- Galabova G, Brunner S, Winsauer G, et al. Peptide-based anti-PCSK9 vaccines - an approach for long-term LDLc management. PLoS One 2014; 9:e114469.
- Visser ME, Witztum JL, Stroes ES, Kastelein JJ. Antisense oligonucleotides for the treatment of dyslipidaemia. Eur Heart J 2012; 33:1451.
- Gupta N, Fisker N, Asselin MC, et al. A locked nucleic acid antisense oligonucleotide (LNA) silences PCSK9 and enhances LDLR expression in vitro and in vivo. PLoS One 2010; 5:e10682.
- Frank-Kamenetsky M, Grefhorst A, Anderson NN, et al. Therapeutic RNAi targeting PCSK9 acutely lowers plasma cholesterol in rodents and LDL cholesterol in nonhuman primates. Proc Natl Acad Sci U S A 2008; 105:11915.
- Schroeder CI, Swedberg JE, Withka JM, et al. Design and synthesis of truncated EGF-A peptides that restore LDL-R recycling in the presence of PCSK9 in vitro. Chem Biol 2014; 21:284.
- Dadu RT, Ballantyne CM. Lipid lowering with PCSK9 inhibitors. Nat Rev Cardiol 2014; 11:563.
- MECHANISM OF ACTION
- CLINICAL EFFECT
- Neurocognitive toxicity
- Muscle toxicity
- Hepatitis C virus (HCV) infectivity
- Colon tumors
- Insulin resistance and diabetes
- Drug interactions
- ADVERSE EFFECTS
- Renal and hepatic impairment
- APPROVED INDICATIONS
- CURRENT INVESTIGATION