Evolocumab – antibody against PCSK9 with a profound lipid-lowering effect

Czech version

Authors: M. Vráblík
Authors‘ workplace: Centrum preventivní kardiologie, III. interní klinika 1. LF UK a VFN v Praze
Published in: Kardiol Rev Int Med 2015, 17(4): 362-366
Category: Cardiology Review

Overview

About 10 years ago a new protein – proprotein subtilisin kexin convertase 9 (PCSK9) – was discovered as another mechanism determining plasma LDL‑cholesterol levels. Therapeutic targeting of the protein using monoclonal antibodies has followed shortly after its discovery. Inhibition of PCSK9 results in a marked increase of recirculating LDL‑receptor protein expression on the surface of hepatocytes with a consequent decrease of LDL‑cholesterol (and other atherogenic lipids) in the plasma. Evolocumab is a fully human monoclonal antibody against PCSK9. Its lipid lowering effect is significant and reaches 50– 70% additional LDL‑c lowering when added to standard therapies. Evolocumab is being tested in a large research programme PROFICIO. This new therapeutic option represents a new hope for difficult‑ to‑ treat patients with familial hypercholesterolemia or with statin intolerance. In the near future we may anticipate its use also in patients with high and very high cardiovascular risk and inadequately controlled LDL‑cholesterol levels.

Keywords:
cardiovascular risk – LDL‑cholesterol – evolocumab – PCKS9 – monoclonal antibodies

Sources

1. Catapano AL, Papadopoulos N. The safety of therapeutic monoclonal antibodies: Implications for cardiovascular disease and targeting the PCSK9 pathway. Atherosclerosis 2013; 228: 18– 28. doi: 10.1016/ j.atherosclerosis.2013.01.044.

2. Tamhane UU, Gurm HS. The chimeric monoclonal antibody abciximab: a systematic review of its safety in contemporary practice. Expert Opin Drug Saf 2008; 7: 809– 819. doi: 10.1517/ 14740330802500353.

3. Seidah NG. PCSK9 as a therapeutic target of dyslipidemia. Expert Opin Ther Targets 2009; 13: 19– 28. doi: 10.1517/ 14728220802600715.

4. Abifadel M, Varret M, Rabes JP et al. Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nat Genet 2003; 34: 154– 156.

5. 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– 523.

6. Cohen JC, Boerwinkle E, Mosley Jr TH et al. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N Engl J Med 2006; 354: 1264– 1272.

7. Cicero AFG, Colletti A, Borghi C. Profile of evolocumab and its potential in the treatment of hyperlipidemia. Drug Des Devel Ther 2015; 9: 3073– 3082. doi: 10.2147/ DDDT.S67498.

8. Stein EA, Wasserman SM, Dias C et al. AMG‑ 145, Evolocumab. Drugs Fut 2013; 38: 451– 459.

9. 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– 1898.

10. Cicero AF, Tartagni E, Ertek S. Efficacy and safety profile of evolocumab (AMG145), an injectable inhibitor of the proprotein convertase subtilisin/ kexin type 9: the available clinical evidence. Expert Opin Biol Ther 2014; 14: 863– 868. doi: 10.1517/ 14712598.2014.902929.

11. Koren MJ, Scott R, Kim JB et al. Effects of AMG145 on low‑ 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– 2006.

12. Kohli P, Desai NR, Giugliano RP et al. Design and rationale of the LAPLACE‑ TIMI 57 trial: a phase II, double‑blind, placebo‑ controlled study of the efficacy and tolerability of a monoclonal antibody inhibitor of PCSK9 in subjects with hypercholesterolemia on background statin therapy. Clin Cardiol 2012; 35: 385– 391. doi: 10.1002/ clc.22014.

13. 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– 2417. doi: 10.1161/ CIRCULATIONAHA.112.144055.

14. Raal FJ, Honarpour N, Blom DJ et al. The TESLA Investigators. Inhibition of PCSK9 with evolocumab in homozygous familial hypercholesterolemia (TESLA Part B): a randomised, double‑blind, placebo‑ controlled trial. Lancet 2015; 385: 341– 350. doi: 10.1016/ S0140‑ 6736(14)61374‑ X.

15. Bruckert E, Bláha V, Stein E et al. Trial assessing long‑term use of PCSK9 inhibition in patients with genetic LDL disorders (TAUSsIG). Efficacy and safety in patients with familial hypercholesterolemia receiving lipid apheresis. Poster sessions, AHA Scientific Sessions, Chicago 2014.