Last Update: November 2018
PCSK9: A key player in lipid metabolism
Elevated serum low-density lipoprotein cholesterol (LDL-C) is a major risk factor for the development of atherosclerosis and the onset of cardiovascular disease (CVD). Reducing LDL-C levels via diet modifications and lifestyle changes, statin or other lipid-lowering therapy has been the mainstay of cholesterol management and has led to a reduction in the incidence of CVD1.
The majority of circulating cholesterol is synthesised in the liver by 3-hydroxy-3-methyl-glutaryl-CoA (HMG CoA) reductase2. The principal means by which LDL-C is removed from the circulation is by LDL-receptors (LDLR) on the surface of hepatocytes (in the liver)3.
- LDL-C binds to the LDLR and the LDL/LDLR complex is internalised into clathrin-coated vesicles
- LDL-C is separated from its receptor in the endosome
- LDL-C is degraded
- LDLR is recycled for reuse
Identification of the gene and protein for PCSK9 in 2003 led to the discovery of a new pathway and mechanism by which to lower LDL-C.4
The PCSK9 pathway was discovered through genetic studies in humans4. Gain-of-function mutations in the PCSK9 gene are associated with diagnoses of familial hypercholesterolaemia (FH), increased LDL-C levels, and increased risk of coronary heart disease (CHD)4,5. Patients with gain-of-function mutations in PCSK9 have a similar clinical phenotype, including elevated LDL-C, to that of patients with the more traditional mutations (in the LDLR gene) that cause FH4.
Conversely, individuals with PCSK9 loss-of-function mutations have lower levels of LDL-C, and a significantly lower incidence of CHD (myocardial infarction, fatal CHD, or coronary revascularisation) compared to matched controls.6,7
PCSK9 and Lipid metabolism
Figure 1. LDLR degradation by PCSK9
PCSK9 is synthesised in the liver as an inactive enzyme pre-cursor that undergoes autocatalytic intra-molecular processing in the endoplasmic reticulum (ER)7.
PCSK9 is secreted by the liver into the plasma where it binds to the LDLR. Once the PCSK9/LDLR complex is internalised, PCSK9 directs the LDLR towards lysosomal degradation, disrupting the recycling of LDLR to the cell surface and leading to a decreased number of LDLR available on surface of cells (figure 1).3,7,8
Genetic studies have shown that people with loss-of-function mutations in PCSK9 not only have substantial reductions in LDL-C levels but associated reductions in the incidence of coronary heart disease6,7. This genetic variation in humans generated interest in PCSK9 as a possible target for treatment of hypercholesterolaemia and inhibition of PCSK9 became an intense focus of research.
PCSK9 inhibition: A pathway to cholesterol lowering
Statins, the mainstay of cholesterol lowering therapies are HMG CoA reductase inhibitors and reduce the rate of cholesterol biosynthesis to reduce LDL-C. Other lipid lowering therapies such as ezetimibe or bile acid sequestrants act by reducing absorption of cholesterol into the circulation2. PCSK9 represents another pathway to lower lipids (figure 2). As described above, PCSK9 regulates LDL-C by LDLR binding and reducing the number of LDLR available to remove circulating cholesterol. PCSK9 inhibition is therefore a rational therapeutic target. The most studied and clinically advanced approach to PCSK9 inhibition is the use of monoclonal antibodies7.
Figure 2: Mechanisms of cholesterol lowering (Adapted from Grundy, 2015)9
Praluent, on top of maximally tolerated statin therapy with or without other lipid-lowering therapy reduces LDL-C by up to 61% (-1.92mmol/L from baseline with 150 mg Q2W). The usual starting dose for Praluent is 75 mg administered subcutaneously once every 2 weeks. Patients requiring larger LDL-C reduction (>60%) may be started on 150 mg once every 2 weeks, or 300 mg once every 4 weeks (monthly), administered subcutaneously.
PCSK9 monoclonal antibodies
Therapeutic monoclonal antibodies are used for a broad range of diseases from cancer to infectious disease, and, more recently, cardiovascular disease, including hypercholesterolaemia.10
Monoclonal antibodies designed to inhibit PCSK9 (such as Praluent) bind to the protein adjacent to the region that is required for LDLR interaction and prevents the interaction between the LDLR and PCSK9 (figure 3). In 2009 the first PCSK9 mAb (mAb1) was discovered (reviewed in Dahu and Ballantyne, 20147). In-vivo animal studies of mAb1 showed increased expression of hepatic LDLR and lowered LDL-C levels. Two monoclonal antibodies which inhibit PCSK9, Praluent11 and evolocumab (Repatha)12 are now available to treat many patients with uncontrolled hypercholesterolaemia (see SPCs for further details).The effect of Praluent on cardiovascular morbidity and mortality has not yet been determined.
Figure 3: PCSK9 inhibition with Praluent
Praluent is a human IgG1 monoclonal antibody produced in Chinese Hamster Ovary cells by recombinant DNA technology11. Praluent binds with high affinity and specificity to PCSK9 preventing binding to LDLR (Figure 3). Ten phase III clinical studies have demonstrated the efficacy and tolerability profile of Praluent in more than 5,000 patients11 (see clinical section). All studies consistently met the primary efficacy endpoint of LDL-C reduction after 24 weeks compared to placebo or ezetimibe11.
- Perk et al., European Guidelines on cardiovascular disease prevention in clinical practice (version 2012): the Fifth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of nine societies and by invited experts) Eur J. Prevent Cardiol. 2012; 19:585-667.
- PCSK9 forum. Introductory guide to PCSK9 inhibition: New therapies in cardiovascular risk reduction. 2015.
- Farnier M. PCSK9: From discovery to therapeutic applications. Arch Cardiovasc Dis. 2014; 107:58-66.
- Abifadel et.al. Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nature Genetics. 2003 34:154-156.
- Foody, J.M. Familial hypercholesterolemia: an under-recognized but significant concern in cardiology practice. Clin. Cardiol. 2014. 37:119-125
- Cohen, J.C.,et al. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease N Engl J Med. 2006. 354:1264-1272
- Dadu RT and Ballantyne CM, Lipid lowering with PCSK9 inhibitors. Nat Rev Cardiol. 11:563-575
- Seidah NG, et al. PCSK9: a key modulator of cardiovascular health. Circ Res. 2014. 114:1022-36.
- Grundy, SM. Dyslipidaemia in 2015: Advances in treatment of dyslipidaemia. Nat Rev Cardiol 2016; 13:74-5.
- Foltz IN, et al. Evolution and emergence of therapeutic monoclonal antibodies: what cardiologists need to know. Circulation. 2013; 127:2222-30
- Praluent Summary of Product Characteristics. Available at https://www.medicines.org.uk/emc/medicine/30956. Accessed August 2018.
- Repatha Summary of Product Characteristics. Available at https://www.medicines.org.uk/emc/medicine/30628. Accessed August 2018.