Proprotein convertase subtilisin/kexin type 9 (PCSK9), first described in 2003, binds to the low-density lipoprotein receptor (LDLR) resulting in its degradation. Inhibition of PCSK9 results in increased LDLR recycling and a reduction in LDL-cholesterol (LDL-C). The clinical development of monoclonal antibodies (mAbs) that bind to circulating PCSK9 has been rapid with large phase II and III trials demonstrating substantial reductions in LDL-C when given to a very broad group of patients including those with familial and non-familial hypercholesterolemia, diabetes, heart disease, and in those intolerant to statins. Despite sub-cutaneous administration these mAbs are well tolerated and have demonstrated good safety. Two agents, alirocumab and evolocumab, received regulatory approval in 2015 in the US and Europe and evolocumab in 2016 in Japan.
PCSK9, low-density lipoprotein (LDL) cholesterol, LDL receptor, cardiovascular disease, familial hypercholesterolemia
Evan A Stein has received consulting fees from Amgen, Regeneron, Sanofi, Genentech, Roche, The Medicines Co, ISIS, Catabasis, AstraZeneca, CymaBay, CVS/ Caremark and BMS related to PCSK9 inhibitors and other lipid lowering drugs. Frederick J Raal has received honoraria and/or consulting fees from AstraZeneca, Pfizer, Merck, Amgen, Sanofi and his institution grants/research support from Amgen and Sanofi. This article is a short opinion piece and has not been submitted to external peer reviewers. No funding was received for the publication of this article.
The authors were solely responsible for the writing and submission of the manuscript.
March 10, 2016 Accepted
April 15, 2016
Evan A Stein, Director Emeritus, Metabolic and Atherosclerosis Research Center, 5355 Medpace Way, Cincinnati, OH, US. E: firstname.lastname@example.org
This article is published under the Creative Commons Attribution Noncommercial License, which permits any noncommercial use, distribution, adaptation, and
reproduction provided the original author(s) and source are given appropriate credit.
Statins, first approved for general use in 1987 based on their low-density lipoprotein cholesterol (LDL-C) lowering ability, took another decade to demonstrate cardiovascular disease (CVD) benefit.1–4 Since 1990 there have been more efficacious statins but only one other modestly effective LDL-C-reducing drug, ezetimibe, has been shown to significantly reduce CVD events compared to statin alone.5–8
There remains an unmet need for patients, many at high CVD risk, who are unable to achieve ‘optimal’ LDL-C targets with statin therapy, or are intolerant to statins. Two new drugs were approved in 2013–2014 both of which inhibit production of LDL, or its precursor very (V)LDL; mipomersen, an apolipoprotein B antisense agent, and lomitapide, an inhibitor of microsomal triglyceride transport protein.9 However their use is strictly limited to the rare orphan population with homozygous familial hypercholesterolemia (HoFH) with prescribing controlled by a Risk Evaluation and Monitoring Strategy in the USA and a ‘named patient’ program in other countries.9 Thus the proprotein convertase subtilisin/ kexin type 9 (PCSK9) monoclonal antibodies (mAbs), alirocumab and evolocumab, approved in late 2015, now provide a new class of drugs which substantially and safely decrease LDL-C.10–13
Proprotein convertase subtilisin/kexin 9 inhibitors
PCSK9 plays a key role in regulating LDL-C clearance by binding to the LDL receptor (LDLR) resulting in its degradation.14 Loss-of-function (LOF) mutations resulting in small lifelong LDL-C reductions are associated with a ~40% reduction in CVD risk.15,16 In 2006, Legace discovered that circulating PCSK9 interacted with the LDLR providing a rationale for development of mAbs to inhibit PCSK9.17 The first two PCSK9 mAbs, alirocumab and evolocumab, entered clinical trials in 2009 and have since demonstrated dramatic, rapid and persistent reductions in LDL-C in patients with a wide variety of lipid pheno- and genotypes, comorbidities and on a variety of background therapies.18–39 This resulted in both compounds receiving US Food and Drug Administration (FDA) and European Medicine’s Agency (EMA) approval in late 2015. evolocumab received approval in Japan in early 2016.10–13,40 A third mAb, bococizumab, is still in phase III clinical development.41
Pharmacokinetic and pharmacodynamics
Following subcutaneous (SC) injection mAbs are rapidly absorbed into the circulation, bind to PCSK9, reducing free PCSK9 and reduce LDL-C within days. At a dose of ~150 mg LDL-C plateaus at roughly 60%, which is maintained for two weeks.18,19 A three-fold increase to 420 mg provides no additional LDL-C reduction but does suppress PCSK9 and LDL-C for four weeks.19
Low-desity lipoprotein cholesterol in nonFH
patients and influence of background therapy As statins cause an increase in synthesis and circulating PCSK9, it was suggested that inhibition of PCSK9 would be synergistic when added to
1. Tobert JA, Lovastatin and Beyond: The History of the HMG CoA Reductase Inhibitors, Nat Rev Drug Discov, 2003;2:517–526.
2. Pedersen TR, Kjekshus J, Berg K, et al., Scandinavian Simvastatin Survival Study Group. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S), Lancet, 1994;344:1383–1389.
3. Shepherd J, Cobbe SM, Ford I, et al., for the West of Scotland Coronary Prevention Study Group. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia, N Engl J Med, 1995;333:1301–1307.
4. Sacks FM, Pfeffer MA, Moye LA, et al., for the Cholesterol and Recurrent Events Trial Investigators. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels, N Engl J Med, 1996;335:1001–1009.
5. Heinonen T, Stein EA, Weiss S, et al., The Lipid-Lowering Effects of Atorvastatin, a New HMG-CoA Reductase Inhibitor: Results of a Randomized, Double-Masked Study, Clinical Therapeutics, 1996;18:853–863.
6. Jones PH, Davidson MH, Stein EA, et al., Comparison of the Efficacy and Safety of Rosuvastatin Versus Atorvastatin, Simvastatin, and Pravastatin Across Doses (Stellar* Trial), Am J Cardiol, 2003;92:152–160.
7. Stein EA, Results of Phase I/II Clincial Trials with Ezetimibe, a Novel Selective cholesterol Absorption Inhibitor, Euro Heart Journal, 2001;3E;11–16.
8. Cannon CP, Blazing MA, Giugliano RP, et al., Ezetimibe Added to Statin Therapy after Acute Coronary Syndromes, N Engl J Med, 2015; 372:2387–97.
9. Rader DJ, Kastelein JJ, Lomitapide and mipomersen: two firstin- class drugs for reducing low-density lipoprotein cholesterol in patients with homozygous familial hypercholesterolemia, Circulation, 2014; 129: 1022–32.
10. FDA approves Praluent to treat certain patients with high cholesterol. Available at: http://www.fda.gov/NewsEvents/ Newsroom/PressAnnouncements/ucm455883.htm. (accessed February 28, 2016).
11. FDA approves Repatha to treat certain patients with high cholesterol. Available at: http://www.fda.gov/NewsEvents/ Newsroom/PressAnnouncements/ucm460082.htm. (accessed February 28, 2016).
12. Repatha/evolocumab. Available at: http://www.ema.europa.eu/ docs/en_GB/document_library/Summary_of_opinion_-_Initial_ authorisation/human/003766/WC500187093.pdf. (accessed February 28, 2016).
13. Praluent recommended for approval to lower cholesterol. Available at: http://www.ema.europa.eu/docs/en_GB/ document_library/Press_release/2015/07/WC500190458.pdf. (accessed February 28, 2016).
14. Turner T, Raal FJ, Stein EA, Evolving Targets of Therapy: Proprotein Convertase Subtilisin/Kexin 9 Inhibition. In: Ballantyne C, ed. Clinical Lipidology: A Companion to Braunwald’s Heart Disease. 2nd ed: Elsevier; 2014:346–57.
15. 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;354:1264–72.
16. Kathiresan S and the Myocardial Infarction Genetics Consortium, A PCSK9 Missense Variant Associated with a Reduced Risk of Early-Onset Myocardial Infarction, N Engl J Med, 2008;358:2299–2300.
17. Lagace TA, Curtis DE, Garuti R, et al., Secreted PCSK9 decreases the number of LDL receptors in hepatocytes and in livers of parabiotic mice, J Clin Invest, 2006;116:2995–3005.
18. Stein EA, Mellis S, Yancopoulos GD, et al., Effect of a Monoclonal Antibody to PCSK9 on LDL Cholesterol, N Engl J Med, 2012;366:1108–18.
19. 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;60:1888–98.
20. Roth EM, McKenney JM, Hanotin C, et al., Atorvastatin with or without an antibody to PCSK9 in primary hypercholesterolemia, N Engl J Med, 2012;367:1891–900.
21. 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;380:29–36.
22. 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;59:2344–53.
23. Moriarty PM, Jacobson TA, Bruckert E, et al., 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;8:554–61.
24. Kastelein JJP, Ginsberg HN, Langslet G, et al. ODYSSEY FH I and FH II: 78 week results with alirocumab treatment in 735 patients with heterozygous familial hypercholesterolaemia, Eur Heart J, 2015;36:2996–3003.
25. Cannon CP, Cariou P, Blom D, et al., 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; 36:1186-94
26. Bays H, Gaudet D, Weiss R, et al., Alirocumab as Add-On to Atorvastatin Versus Other Lipid Treatment Strategies: ODYSSEY OPTIONS I Randomized Trial, J Clin Endocrinol Metab, 2015;100:3140–8.
27. 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 cardiovascularrisk patients: The ODYSSEY OPTIONS II randomized trial, Atherosclerosis, 2016;244:138–46.
28. Robinson JG, Farnier M, Krempf M, et al., Efficacy and Safety of Alirocumab in Reducing Lipids and Cardiovascular Events, N Engl J Med, 2015; 372:1489–1499.
29. Stein EA, Giugliano RP, Koren MJ, et al., Efficacy and safety of evolocumab (AMG 145), a fully human monoclonal antibody to PCSK9, in hyperlipidaemic patients on various background lipid therapies: pooled analysis of 1359 patients in four phase 2 trials, Eur Heart J, 2014;35:2249–59.
30. 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;126:2408–17.
31. 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;308:2497–506.
32. 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;380:2007–17.
33. 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;380:1995–2006.
34. 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;63:2541–8.
35. Blom DJ, Hala T, Bolognese M, et al., A 52-Week Placebo- Controlled Trial of Evolocumab in Hyperlipidemia, N Engl J Med, 2014;370:1809–19.
36. Raal FJ, Stein EA, Dufour R, et al, for the RUTHERFORD-2 Investigators. PCSK9 inhibition with evolocumab (AMG 145) in heterozygous familial hypercholesterolaemia (RUTHERFORD-2): a randomised, double-blind, placebo-controlled trial, Lancet, 2015;385:331–340.
37. Stein EA, Honarpour N, Wasserman SM, et al., Effect of the Proprotein Convertase Subtilisin/Kexin 9 Monoclonal Antibody, AMG 145, in Homozygous Familial Hypercholesterolemia, Circulation, 2013;128:2113–2120.
38. 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;385:341–50.
39. Sabatine MS, Giugliano RP, Wiviott SD, et al., on behalf of the OSLER Investigators. Efficacy and Safety of Evolocumab in Reducing Lipids and Cardiovascular Events, New Engl J Med, 2015;372:1500–9.
40. Amgen’s Repatha® (Evolocumab) Approved In Japan. Available at: http://www.prnewswire.com/news-releases/amgensrepatha- evolocumab-approved-as-first-pcsk9-inhibitor-injapan- for-the-treatment-of-high-cholesterol-300208360.html. (accessed February 28, 2016).
41. Ballantyne CM, Neutel J, Cropp A, et al., Results of bococizumab, a monoclonal antibody against proprotein convertase subtilisin/kexin type 9, from a randomized, placebocontrolled, dose-ranging study in statin-treated subjects with hypercholesterolemia, Am J Cardiol, 2015;115:1212–21.
42. Stein EA, Raal FJ, Reduction of Low Density Lipoprotein Cholesterol by Monoclonal Antibody Inhibition of PCSK9, Ann Rev Medicine, 2014;65:417–31.
43. Alirocumab Briefing Document: Endocrine & Metabolic Advisory Committee Meeting, June 9, 2015. Available at: http://www.fda.gov/downloads/ AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/ EndocrinologicandMetabolicDrugsAdvisoryCommittee/ UCM449865.pdf. (accessed February 28, 2016).
44. Evolocumab (Repatha) – Another PCSK9 Inhibitor to Lower LDLCholesterol, Med Lett Drugs Ther, 2015; 57(1479):140.
45. Alirocumab (Praluent) to lower LDL-cholesterol, Med Lett Drugs Ther, 2015; 57:113.
46. Husten L, CardioBrief, First PCSK9 Drug Outcomes Trial Due in 2016 – FOURIER set to finish ahead of schedule, Medpage Today Dec. 22, 2015. Available at: http://www.medpagetoday.com/ Cardiology/CardioBrief/55379. (accessed December 30, 2016).
47. Schwartz GG, Bessac L, Berdan LG, et al., 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;168:682–689.
PCSK9, low-density lipoprotein (LDL) cholesterol, LDL receptor, cardiovascular disease, familial hypercholesterolemia