A raised level of low-density lipoprotein (LDL) cholesterol is one of the most important modifiable risk factors for cardiovascular disease. Despite success in recent decades in lowering LDL cholesterol with statins and other lipid-lowering drugs, a significant proportion of high risk patients fail to achieve LDL cholesterol goal and remain at high risk of cardiovascular events.1-3
How is LDL cholesterol cleared from the plasma?
LDL receptors on the surface of liver cells play a key role in controlling LDL cholesterol levels in the circulation. These receptors are present in clathrin-coated pits on the cell surface, which when bound to LDL, are pinched off to form clathrin-coated vesicles inside the cell. This allows LDL to be bound and internalised in a process known as endocytosis. This process mainly occurs in the liver, which removes approximately 70% of LDL cholesterol from the circulation.
Once the coated vesicle is inside the cell it sheds its clathrin coat and fuses with an acidic endosome. The change in pH causes a change in the receptor so that it releases the bound LDL particle. The receptors are then either destroyed or recycled back to the surface of the cell where the neutral pH will cause the receptor to revert to its native state ready to receive another LDL particle.
See: The PCSK9 Revolution at http://www.pcsk9forum.org/wp-content/uploads/PCSK9-slideset.pdf
Statins, which are currently the most efficacious LDL cholesterol lowering therapy, act mainly by up-regulating this LDL-receptor activity.
Increased understanding of this process has led to the identification of a protein that plays a key role in controlling LDL cholesterol levels: pro-protein convertase subtilisin-like kexin type 9 (PCSK9). PCSK9 promotes the degradation of the LDL-receptor and prevents it recycling to the cell surface. Therefore, inhibition of PCKS9 has been studied as a novel way of reducing hypercholesterolaemia and cardiovascular disease.
The role of PCKS9 in the regulation of LDL receptor expression
See: The PCSK9 Revolution at http://www.pcsk9forum.org/wp-content/uploads/PCSK9-slideset.pdf
What is PCSK9?
PCSK9 is a protein mainly expressed in the liver, but also in other areas of the body including the intestine and kidney. PCSK9 is rapidly removed from the plasma primarily by the LDL- receptor pathway.4
PCSK9 increases the intracellular removal of LDL receptors and thus reduces the number of LDL receptors on the surface of liver cells. This results in a rise in plasma LDL cholesterol levels. However, inhibition of PCSK9 increases the availability of LDL receptors and reduces the levels of circulating LDL cholesterol.5
When was the effect of PCSK9 discovered?
In 2003, three families with autosomal dominant hypercholesterolaemia and premature coronary heart disease were found to have missense mutations in the PCSK9 gene.6
Further studies showed that overexpression of PCSK9 in mice reduced hepatic LDL receptor protein and caused hypercholesterolaemia. In contrast, mice which were genetically deficient in PCSK9 had hypocholesterolaemia.7
Further studies showed that people with a mutation in the PCSK9 gene leading to a loss of its function had reduced LDL cholesterol levels and a reduced risk of cardiovascular disease (risk reduction between 47%-88%), compared with people without these mutations.8
Taken together, these findings provided a rationale for targeting PCSK9 as a valuable novel approach in the treatment of hypercholesterolaemia.
What trial data are available?
A number of monoclonal antibodies targeting PCSK9 are in clinical development. Two of these agents – alirocumab and evolocumab – have been recently approved for clinical use in the USA and Europe. For both of these agents, as well as bococozumab in Phase III development, there are ongoing clinical outcomes studies.
These monoclonal antibodies are injected subcutaneously, twice weekly (alirocumab and bococizumab) or either twice weekly or monthly (evolocumab). Phase III clinical trials have shown that PCSK9 monoclonal antibody treatment was very effective in reducing LDL-C levels, consistently reducing levels by about 55-60%, either as monotherapy or on top of background statin treatment (with or without ezetimibe).9-13
Importantly, LDL cholesterol reduction was similar in patients with familial hypercholesterolaemia (FH) or non-FH, or between patients on background statin therapy or those on diet alone.9-13 There was no difference in the LDL cholesterol lowering response between patients on high-intensity statins (such as atorvastatin or rosuvastatin) or moderate intensity statin treatment.14,15
Evidence to date shows that these PCSK9 inhibitors are well tolerated with minimal injection site reactions and no other adverse signal for side effects.11,12,16,17 Importantly, these treatments do not appear to cause muscle symptoms,11,12,16,17 and have also been shown to be effective and safe in patients with statin intolerance.18.19
Do these novel PCSK9 inhibitors have other lipid effects?
Unlike statin therapy, PCSK9 inhibitors are also able to reduce levels of lipoprotein(a) [Lp(a)], an established cardiovascular risk factor, by 20-30%.20,21
PCSK9 inhibition: a new era in LDL cholesterol lowering?
The first of these novel agents have now been approved for clinical use, by both US and European regulatory agencies. The specific indications approved are summarised below.
Evolocumab (Repatha): European Medicines Agency (21 May 2015); US Food and Drug Administration statement expected by 27 August 2015
Hypercholesterolaemia and mixed dyslipidaemia
Adults with primary hypercholesterolaemia (heterozygous familial and non-familial) or mixed dyslipidaemia, as an adjunct to diet:
– in combination with a statin or statin with other lipid-lowering therapies in patients unable to reach LDL-C goals with the maximum tolerated dose of a statin or,
– alone or in combination with other lipid-lowering therapies in patients who are statin-intolerant, or for whom a statin is contra-indicated.
Homozygous familial hypercholesterolaemia
Repatha is indicated in adults and adolescents aged 12 years and over with homozygous familial hypercholesterolaemia in combination with other lipid-lowering therapies.
US Food and Drug Administration (24 July 2015)
As an adjunct to diet and maximally tolerated statin therapy for the treatment of adults with heterozygous familial hypercholesterolemia or clinical atherosclerotic cardiovascular disease (ASCVD), who require additional lowering of low-density lipoprotein (LDL) cholesterol.
European Medicines Agency (24 July 2015)
Treatment of adult patients with primary hypercholesterolemia (heterozygous familial hypercholesterolemia [HeFH] and non-familial) or mixed dyslipidemia as an adjunct to diet:
- a) in patients unable to reach their low density lipoprotein cholesterol (LDL-C) goals with a maximally-tolerated statin, Praluent would be used in combination with a statin, with or without other lipid-lowering therapies; and
- b) for patients who are statin intolerant, or for whom a statin is contraindicated, Praluent would be used alone or in combination with other lipid-lowering therapies.
Do the PCSK9 inhibitors reduce cardiovascular outcomes?
Researchers are hopeful that PCSK9 inhibition provides the key to reducing the residual cardiovascular risk that persists in high risk patients whose clinical needs are not met with current lipid lowering therapy. This includes:
- Patients with familial hypercholesterolaemia (FH), an inherited hypercholesterolaemia. Only one in five FH patients achieves LDL cholesterol targets with current treatments.22
- High-risk patients (particularly those with established heart disease) not at goal on maximum lipid-lowering therapy or with insufficient response to lipid-lowering therapy
- High cardiovascular risk patients who cannot tolerate statin therapy, and cannot reach LDL cholesterol goals with other lipid-lowering therapy.
There are encouraging signs from exploratory analyses that treatment with either alirocumab or evolocumab may reduce cardiovascular outcomes in high risk patients by 50%.23,24 .However, we need to await the final results of ongoing large scale trials with alirocumab (ODYSSEY OUTCOMES)25, evolocumab (FOURIER)26 and bococizumab (SPIRE-1 and SPIRE-2)27,28 in patients at high cardiovascular risk on statin therapy, for definitive answers to this question.
Approval of the First PCSK9 Inhibitors: A view from leading international experts
Professor M. John Chapman, Co-Editor of PCSK9 Forum, University of Pierre and Marie Curie, and National Institute for Health and Medical Research (INSERM), Pitié-Salpêtrière University Hospital, Paris, France:
‘These agents allow clinicians for the very first time to lower LDL cholesterol levels to those recommended in guidelines for these high risk patients.’
Professor Henry N. Ginsberg, Co-Editor of PCSK9 Forum, Irving Institute for Clinical and Translational Research, College of Physicians and Surgeons, Columbia University, New York, USA:
‘For familial hypercholesterolaemia, these agents will allow us to attain LDL cholesterol goal in most of our patients, almost unheard of previously.’
Professor Eric Bruckert, Pitié-Salpêtrière Hospital, Paris, France:
‘In our day to day practice, we have FH patients in urgent need of additional treatment either because of severe FH or because they cannot tolerate a statin. We need these new options.’
Professor Frederick Raal, University of the Witwatersrand, South Africa:
‘The PCSK9-inhibitors will fulfil an important unmet need. They will allow us to get the vast majority of our heterozygous FH patients to LDL cholesterol target. Evolocumab is also of value in reducing LDL cholesterol levels in the majority of homozygous FH patients who have some residual LDL receptor activity.’
For more information, contact:
PCSK9 Education and Research Forum
Tel: +44 (0)1789 766098; firstname.lastname@example.org
- Reiner Ž, De Bacquer D, Kotseva K et al; EUROASPIRE III Study Group. Treatment potential for dyslipidaemia management in patients with coronary heart disease across Europe: findings from the EUROASPIRE III survey. Atherosclerosis 2013;231:300-7. http://www.ncbi.nlm.nih.gov/pubmed/24267243
- Béliard S, Carreau V, Carrié A, Giral P, Duchêne E, Farnier M, Ferrières J, Fredenrich A, Krempf M, Luc G, Moulin P, Bruckert E. Improvement in LDL-cholesterol levels of patients with familial hypercholesterolemia: can we do better? Analysis of results obtained during the past two decades in 1669 French subjects. Atherosclerosis 2014;234:136-41. http://www.ncbi.nlm.nih.gov/pubmed/24637413
- Chowdhury R, Khan H, Heydon E, Shroufi A, Fahimi S, Moore C, Stricker B, Mendis S, Hofman A, Mant J, Franco OH. Adherence to cardiovascular therapy: a meta-analysis of prevalence and clinical consequences. Eur Heart J 2013;34:2940-8. http://www.ncbi.nlm.nih.gov/pubmed/23907142
- Horton JD, Cohen D, Hobbs H. Molecular biology of PCSK9: its role in LDL metabolism. Trends Biochem Sci 2007;32: 71-7. http://www.ncbi.nlm.nih.gov/pubmed/12730697
- Hedrick JA. Targeting PCSK9 for the treatment of hypercholesterolaemia. Curr Opin Investig Drugs 2009, 10: 938–46. http://www.ncbi.nlm.nih.gov/pubmed/19705336
- Abifadel M, Varret M, Rabes JP et al. Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nat Genet 2003;34:154 http://www.ncbi.nlm.nih.gov/pubmed/12730697
- Horton J, Cohen J, Hobbs H. PCSK9: a convertase that coordinates LDL catabolism. J Lipid Res 2009;50(Suppl): S172-7. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2674748/
- Cohen JC, Boerwinkle E, Mosley TH, Hobbs HH. Sequence variations in PCSK9, low LDL and protection against coronary heart disease. N Engl J Med 2006;354;1264-72. http://www.ncbi.nlm.nih.gov/pubmed/16554528
- Stein EA, Raal F. Reduction of low-density lipoprotein cholesterol by monoclonal antibody inhibition of PCSK9. Annu Rev Med 2014;65:417-31. http://www.ncbi.nlm.nih.gov/pubmed/24422577
- Farnier M. PCSK9: from discovery to therapeutic applications. Arch Cardiovasc Dis 2014;107:58-66. http://www.ncbi.nlm.nih.gov/pubmed/24373748
- Stein EA, Giugliano RP, Koren MJ, Raal FJ, Roth EM, Weiss R, Sullivan D, Wasserman SM, Somaratne R, Kim JB, Yang J, Liu T, Albizem M, Scott R, Sabatine MS; PROFICIO Investigators. 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. http://www.ncbi.nlm.nih.gov/pubmed/24598985
- Zhang XL, Zhu QQ, Zhu L et al. Safety and efficacy of anti-PCSK9 antibodies: a meta-analysis of 25 randomized, controlled trials. BMC Med 2015;13:123. http://www.ncbi.nlm.nih.gov/pubmed/26099511
- Ballantyne CM, Neutel J, Cropp A et al. 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;115:1212-21. http://www.ncbi.nlm.nih.gov/pubmed/25784512
- Robinson JG, Nedergaard BS, Rogers WJ et al, LAPLACE-2 Investigators. 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;311:1870-82. http://www.ncbi.nlm.nih.gov/pubmed/24825642
- Krempf M, Bergeron J, Elassal J, Minini P, Miller K, Kastelein JJP. Efficacy of alirocumab according to background statin intensity and other lipid-lowering therapy in heterozygous familial hypercholesterolemia or high CV risk populations: Phase 3 subgroup analyses. EAS Congress Glasgow, 22-25 March, 2015. Abstract EAS-0493 45.
- Koren MJ, Giugliano RP, Raal FJ et al; OSLER Investigators. Efficacy and safety of longer-term administration of evolocumab (AMG 145) in patients with hypercholesterolemia: 52-week results from the Open-Label Study of Long-Term Evaluation Against LDL-C (OSLER) randomized trial. Circulation 2014;129:234-43. http://www.ncbi.nlm.nih.gov/pubmed/24255061
- Koren MJ, Roth EM, McKenney JM et al. Safety and efficacy of alirocumab 150 mg every 2 weeks, a fully human proprotein convertase subtilisin/kexin type 9 monoclonal antibody: A Phase II pooled analysis. Postgrad Med 2015;127:125-32. http://www.ncbi.nlm.nih.gov/pubmed/25609019
- Stroes E, Colquhoun D, Sullivan D et al; GAUSS-2 Investigators. 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. http://www.ncbi.nlm.nih.gov/pubmed/24694531
- Moriarty PM, Thompson PD., Guyton JR et al. ODYSSEY ALTERNATIVE: Efficacy And Safety of the Proprotein Convertase Subtilisin/kexin Type 9 Monoclonal Antibody, Alirocumab, versus Ezetimibe, in Patients With Statin Intolerance as Defined by a Placebo Run-in and Statin Rechallenge Arm. https://my.americanheart.org/idc/groups/ahamah-public/@wcm/@sop/@scon/documents/downloadable/ucm_469597.pdf
- Raal FJ, Giugliano RP, Sabatine MS et al. 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 2014;63:1278-88. http://www.ncbi.nlm.nih.gov/pubmed/24509273
- Gaudet D, Kereiakes DJ, McKenney JM, Roth EM, Hanotin C, Gipe D, Du Y, Ferrand AC, Ginsberg HN, Stein EA. Effect of alirocumab, a monoclonal proprotein convertase subtilisin/kexin 9 antibody, on lipoprotein(a) concentrations (a pooled analysis of 150 mg every two weeks dosing from phase 2 trials). Am J Cardiol 2014;114:711-5. http://www.ncbi.nlm.nih.gov/pubmed/25060413
- Pijlman AH, Huijgen R, Verhagen S, et al. Evaluation of cholesterol lowering treatment of patients with familial hypercholesterolaemia: a large cross-sectional study in the Netherlands. Atherosclerosis 2010;209:189-94 http://www.ncbi.nlm.nih.gov/pubmed/19818960
- Robinson JG, Farnier M, Krempf M et al; ODYSSEY LONG TERM Investigators. Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. N Engl J Med 2015;372:1489-99. http://www.ncbi.nlm.nih.gov/pubmed/25773378
- Sabatine MS, Giugliano RP, Wiviott SD et al; Open-Label Study of Long-Term Evaluation against LDL Cholesterol (OSLER) Investigators. Efficacy and safety of evolocumab in reducing lipids and cardiovascular events. N Engl J Med 2015;372:1500-9. http://www.ncbi.nlm.nih.gov/pubmed/25773607
- ODYSSEY OUTCOMES. Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab SAR236553 (REGN727). ClinicalTrials.gov Identifier: NCT01663402. https://clinicaltrials.gov/ct2/show/NCT01663402
- FOURIER. Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk. ClinicalTrials.gov Identifier: NCT01764633. https://clinicaltrials.gov/ct2/show/NCT01764633
- SPIRE-1. The Evaluation of Bococizumab (PF-04950615;RN316) in Reducing the Occurrence of Major Cardiovascular Events in High Risk Subjects. ClinicalTrials.gov Identifier: NCT01975376. https://clinicaltrials.gov/ct2/show/NCT01975376
- SPIRE-2. The Evaluation of Bococizumab (PF-04950615; RN316) in Reducing the Occurrence of Major Cardiovascular Events in High Risk Subjects. ClinicalTrials.gov Identifier: NCT01975389. https://clinicaltrials.gov/ct2/show/NCT01975389