|Year : 2020 | Volume
| Issue : 3 | Page : 226-233
PCSK9 (Proprotein Convertase Subtilisin/Kexin Type 9): A Narrative Review
Pamila Dua, KH Reeta
Department of Pharmacology, AIIMS, New Delhi, India
|Date of Submission||09-Jan-2020|
|Date of Decision||05-Sep-2020|
|Date of Acceptance||10-Sep-2020|
|Date of Web Publication||23-Dec-2020|
Dr. Pamila Dua
BK2/27, Shalimar Bagh, New Delhi - 110 088
Source of Support: None, Conflict of Interest: None
Coronary artery disease (CAD), the most common type of heart disease, is the leading reason for mortality in both developing and developed countries. Increased cholesterol and fatty deposits (called plaques) may cause hardening or narrowing of the arteries which supply blood to heart muscles. Triglycerides, low density lipoproteins (LDL), high density lipoproteins (HDL) are different types of cholesterols found in the blood and LDL is the main target for lipid modifying therapy, with the aim of improving long term CAD prognosis. Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) is one of the candidate genes with expression of PCSK9 protein and PCSK9 inhibitors are coming up as newer lipid lowering therapy. This narrative review highlights the journey of drug development from recognition of PCSK9 gene to the recent approvals of PCSK9 targeting LDL lowering pharmacotherapy. A bibliographic survey was made with titles PCSK9, PCSK9 inhibitors and coronary artery disease in different search engines from year 2000 to 2019 and filtered with review, preclinical and clinical studies. Retrieved articles were revisited and it was observed that PCSK9 is expressed mainly in hepatocytes and to some extent in mesenchymal cells of kidney, intestinal ileum, colon epithelia and in telencephalon neurons of embryonic brain. In hepatocytes, loss-of function mutations of PCSK9 leads to higher levels of LDL receptors. These receptors make LDL receptor-LDL cholesterol complex, which is directed to the lysosome for degradation of LDL in hepatocytes and lowers LDL cholesterol levels, ultimately resulting in protection from CAD. Gain-of-function mutations hamper LDL degradation. PCSK9 research has proposed an exciting new area for cholesterol management and CAD risk reduction. Different PCSK9 inhibitors with different therapeutic targets for CAD are evolving day by day from bench to bedside. This review could be valuable for helping researchers acquire a deeper insight for PCSK9 and its Inhibitors.
Keywords: Hypercholesterolemia, LDL (low density lipoproteins) cholesterol, PCSK9 (proprotein convertase subtilisin/kexin type 9), therapeutic targets
|How to cite this article:|
Dua P, Reeta K H. PCSK9 (Proprotein Convertase Subtilisin/Kexin Type 9): A Narrative Review. J Pract Cardiovasc Sci 2020;6:226-33
|How to cite this URL:|
Dua P, Reeta K H. PCSK9 (Proprotein Convertase Subtilisin/Kexin Type 9): A Narrative Review. J Pract Cardiovasc Sci [serial online] 2020 [cited 2022 Aug 17];6:226-33. Available from: https://www.j-pcs.org/text.asp?2020/6/3/226/304522
| Introduction (Rationale and Objective)|| |
There is a steady increase in the number of patients suffering from coronary artery disease (CAD). In heart diseases, this is the leading reason for mortality. Cholesterol is an important lipid found in the cell membrane. There are different types of cholesterol found in the blood cells such as triglycerides, low-density lipoprotein (LDL), high-density lipoprotein (HDL), very LDL. Increased LDL levels lead to hardening or narrowing of the arteries which supply blood to heart muscles. Hence, LDL is the main target for lipid-modifying therapy, with the aim of improving long-term CAD prognosis. Various hypolipidemic drugs are used in reducing LDL cholesterol (LDL-C), the most commonly used being statins. Certain adverse effects such as musculoskeletal symptoms, higher chances of developing diabetes, and hemorrhagic stroke may occur on long-term therapy of statins. Moreover, they can reduce LDL only to a certain extent. Due to these limitations of statins, there is need for newer therapeutic targets. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors with different therapeutic targets hold promise for reducing this residual cardiovascular (CV) risk. The present narrative review aims to synthesize information regarding PCSK9 gene and protein, its pathophysiology, PCSK9 inhibitors, and development of different therapeutic targets. In this article, an attempt has been made to gather all the scattered knowledge regarding the evolution of PCSK9 inhibitors till date for ready reference of both researchers and clinicians.
| Methodology|| |
For this comprehensive narrative review, literature search was conducted using four electronic databases such as Medline, PubMed, Scopus, and Google Scholar. Search terms included PCSK9 gene, PCSK9 protein, PCSK9 inhibitors, and CAD, and these were used in different combinations. Articles were read and assessed for the relevance as per the inclusion and exclusion criteria. The inclusion criteria included (i) peer-reviewed academic journals published in English and between 2000 and 2019, (ii) original articles with accessible abstracts and full text, (iii) preclinical and clinical research including trials which focused on the therapeutic targets of PCSK9, (iv) reviews, and (v) different guidelines regarding the use of PCSK9 inhibitors.
Exclusion criteria included (i) non-English and unpublished data, (ii) editorials, (iii) commentaries, (iv) discussion papers, (v) conference abstracts, and (vi) duplicates.
After screening through the articles, 45 relevant articles were included in the review. Each article included was critically evaluated for their key results, limitations, quality of the results obtained, and interpretation of the results. Three major themes were identified:
- Pathophysiology of PCSK9
- Therapeutic targets
- Guidelines and clinical evidence.
Pathophysiology of proprotein convertase subtilisin/kexin type 9
Genome-wide association studies and other genomic studies show a number of variants in many genes which are associated with CAD.
PCSK9 is a candidate gene that is supposed to regulate the lipoprotein retention pathways in the CAD development. The novel proteinase K-like subtilase was characterized as the PCSK9 for the first time by Seidah et al.
PCSK9 gene is also known as FH3, HCHOLA3, and NARC1. This comprises an N-terminal signal peptide followed by three principal domains, a prodomain (residues 31–152) and a catalytic domain (residues 153–451) followed by a C-terminal domain (residues 452–692). The novel proteinase K-like subtilase was characterized as the PCSK9 for the first time by Seidah et al. This is a serine protease encoded 22-kB human PCSK9 gene, located on chromosome 1p32, and contains 12 exons and 11 intron. This gene produces a 3617 base pair mRNA which encodes a 692 amino acid glycoprotein PCSK9 protein, and ultimately, by auto-traversing in the endoplasmic reticulum, it becomes a mature PCSK9 protein. PCSK9 protein is expressed mainly in hepatocytes and to some extent in the kidney mesenchyme cells, intestinal ileum, colon epithelia, and embryonic brain telencephalon neurons.
Role of proprotein convertase subtilisin/kexin type 9 in increasing low-density lipoprotein levels
PCSK9 gene is expressed with “gain-of-function”/over-expression or “loss-of-function” (LOF)/under-expression. LOF mutation (sY142X, C679X, R46L, L108R, and D35Y) may lead to lower plasma LDL-C levels and helps in lowering CV risk in individuals. Gain-of-function mutations (ser127-to-arg, F216, P216L, D374Y, D374Y + N157K), a double mutation C(–161) T and I474V in the PCSK9 gene, are associated with hypercholesterolemia and increased risk of CV events., PCSK9-positive expression is regulated by the transcription factor sterol-responsive element-binding protein 2. It upregulates transcription of 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase and LDL-receptors (LDL-Rs). Low levels of cholesterol upregulate HMG-CoA reductase and LDL-R activity to increase the available cholesterol in the hepatocyte. It is capable of binding with LDL-Rs. However, in circulation, this PCSK9 gets bound to LDL-R at the point of epidermal growth factor-like repeat A (EGF-A) domain. Then, through the process of endocytosis, it undergoes lysosomal degradation. In genetic studies, gain-of-function mutations of PCSK9 were found as the important cause for familial hypercholesterolemia. Individuals with LOF mutations of PCSK9 were linked to lifelong low LDL-C levels and decreased associated comorbidities. These innovations give a way toward the development of PCSK9 inhibitors as a therapy to lower LDL-C. The expression of PCSK9 is mostly in the hepatocytes. Probably, this is the reason that most of the drug development till date with respect to PCSK9 has kept liver as a target organ.
Role of proprotein convertase subtilisin/kexin type 9 in insulin resistance
Studies have revealed that the gene interaction of PCSK9 and APO protein E2 leads toward a common PCSK9R46L LOF mutation, which is featured by increased fasting insulin concentrations, homeostatic model assessment of insulin resistance (HOMA-IR) and increase in the markers of insulin resistance and ultimately diabetes mellitus type-2. Studies also show that PCSK9 levels are normal or increased in obesity and type 2 diabetes.
Timeline of development of proprotein convertase subtilisin/kexin type 9 inhibitors
[Table 1] Timeline of development of proprotein convertase subtilisin/kexin type 9 inhibitors:
|Table 1: Timeline of development of proprotein convertase subtilisin/ kexin type 9 inhibitors|
Click here to view
Pharmacological approaches targeting proprotein convertase subtilisin/kexin type 9 synthesis or function
[Table 2] shows the details of therapeutic targets
These are naturally occurring short amino acid monomer chains. These drugs help bind to specific cell surface receptors and activate intracellular pathways. These are like apolipoprotein mimetic peptides which help bind to LDL Receptors, resembling natural binding partners. These mimetics help in recycling of LDL-R to the cell surface and increase LDL uptake by almost 90%. The available peptide mimetics are like suppressor of cytokine signaling, mimetic peptides, incretin mimetics, and annexin-A1 mimetic peptides. Use of these molecules in the CAD treatment is increasing as they provide good opportunities for disease prevention, treatment, and also overcoming the limitations of the current therapies.,,,
Adnectins are similar to monoclonal antibody (mAb) and are less expensive and easier to manufacture. These can be used because of their high target specificity, low toxicity, and low immunogenicity. The adnectin BMS-962476 helps in competitively displacing LDL-R or the EGF-A domain from binding to PCSK9 and ultimately lowering LDL levels.
mAbs inhibit PCSK9 function by specifically binding extracellular PCSK9. The first anti-PCSK9 mAb1 was discovered in 2009. It protects the LDL-R from PCSK9-mediated lysosome degradation and promotes LDL-R recycling. PCSK9 mAbs are to be administered one or two times in a month, are believed to reduce LDL cholesterol levels by 50%–70%, and are safe in patients. There are various drugs in this class such as,, evolocumab,,,, bococizumab,, and alirocumab. However, mAb is cost-prohibitive which is the main reason for their limited usage.
This is a novel genome editing technology which is based on the CRISPR adaptive immune system. The mutagenesis of PCSK9 in the mouse liver cells was achieved in 3–4 days, and more than 50% target was achieved. This approach helps in reducing plasma cholesterol levels by 35%–40%. The edited PCSK9 gene can be a permanent alteration which increases LDL-R. Therefore, it can be a promising gene editing tool for use in humans.
Small molecules (berberine and oleanolic acid)
Small molecules are the compounds that bind target proteins such as DNA or RNA to hamper the target's biological functions. These molecules have advantages over mAbs and small-interfering RNAs (siRNAs) as they can be taken orally and are less costly. These molecules could exert significant lipid-lowering activity and might present multiple nonlipid-lowering actions, including improvement of endothelial dysfunction, arterial stiffness, and anti-inflammatory and antioxidant properties. They could act anywhere along the sequence of PCSK9 and affect autocatalytic processing, secretion, and/or LDL-R interaction. However, it is difficult to develop small-molecule inhibitors as PCSK9 catalytic activity is not involved in LDL-R degradation and the structure of the catalytic triad is similar to many other proteases. Moreover, PCSK9 is difficult to target with small molecules because there is no surface binding pocket that would facilitate specific binding. Hence, small molecule development is somewhat behind. Some nutraceuticals including curcumin and berberine,, are also in the pipeline; these can increase hepatic LDL-R and help decrease plasma LDL-C levels. These cause inhibition of hepatocyte nuclear factor 1a which helps downregulate PCSK9 gene.,
Antisense oligonucleotides are short nucleic acid sequences which inhibit PCSK9 protein expression by specifically binding PCSK9 mRNA, resulting in less extracellular and intracellular PCSK9 levels or LOF or null human PCSK9 mutations. They do not affect HDL cholesterol levels. They are supposed to have the same efficacy as of mAbs, but with a much longer duration of action.,,
This is a new therapeutic approach to inhibit PCSK9 activity. They are recommended for intravenous use. Preclinical studies have reported that siRNA-induced PCSK9 silencing decreased the PCSK9 mRNA levels by 50%–70% and total cholesterol concentrations by 60%. A study in nonhuman primates reduced around 56% of LDL-C levels through siRNA-mediated knockdown of PCSK9. A phase 1 clinical trial showed a 70% reduction in the plasma PCSK9 and a 40% reduction in LDL-C relative to baseline. Phase 2 results were also promising. Inclisiran is an example of RNA-based therapy, which systemically delivered siRNA therapeutic targeting mRNA for PCSK9 inhibition.
Sortilin and Sec 24a
Sortilin and Sec 24a are known to act as PCSK9 inhibitors as they help in reducing LDL-C by facilitating PCSK9 to constitutive secretory vesicles of hepatocytes with concomitant effects on LDL-R. Therefore, they can be good targets for the treatment of hypercholesterolemia. Preclinical studies in sortilin-deficient mice showed reduction in the plasma PCSK9 levels. Moreover, a positive correlation exists between the levels of circulating PCSK9 and sortilin levels in healthy humans. Sec 24a is also known as coat protein complex II adaptor proteins. In a study, it was observed that the absence of Sec 24a inhibited the early transport of PCSK9 from the endoplasmic reticulum to the cis-Golgi, leading to an increase in LDL-R levels and a decrease in LDL-C levels. Further study on SRT3025, a sirtuin1 deacetylase activator, also showed similar results.
Guidelines and clinical evidence
Recommendations regarding the use of monoclonal antibodies or use of proprotein convertase subtilisin/kexin type 9 inhibitors (National Institute for Health and Care Excellence Guidelines)
- Evolocumab for treating primary nonfamilial hypercholesterolemia or mixed dyslipidemia is not recommended without cardio vascular disorders (CVD) and is recommended as an option only if LDL concentrations is persistently above 4.0 mmol/L in patients of CVD even with greater risk of CV disorders and above 3.5 mmol/L in very high risk of even with maximal tolerated lipid-lowering therapy or further titration is limited by intolerance
- In primary heterozygous familial hypercholesterolemia, evolocumab is recommended without CVD only if LDL-C concentration is persistently more than 5.0 mmol/L and with any type of CVD only if LDL-C concentration is persistently above 3.5 mmol/L
- Similarly, alirocumab for treating primary nonfamilial hypercholesterolemia or mixed dyslipidemia is not recommended without CVD and is recommended as an option only if LDL concentration is persistently above 4.0 mmol/L in CVD patients with greater risk and above 3.5 mmol/L in very high risk of CVD despite maximal tolerated lipid-lowering therapy or further titration is limited by intolerance
- In primary heterozygous familial hypercholesterolemia, alirocumab is recommended without CVD only if LDL-C concentration is persistently above 5.0 mmol/L and with any type of CVD only if LDL-C concentration is persistently above 3.5 mmol/L
- High-risk type of CVD includes acute coronary syndrome (ACS) associated with myocardial infarction or unstable angina requiring hospitalization, coronary or other arterial revascularization procedures, coronary heart disease, ischemic stroke, peripheral arterial disease, and very high risk of CVD is defined as recurrent CV events or CV events in more than one vascular bed, i.e., polyvascular disease
- Latest version of 2018 American Heart Association/American College of Cardiology Multi society Guidelines on the Management of Blood Cholesterol recommends a stepwise approach to manage LDL-C, which begins with a first step of adopting lifestyle changes before starting therapeutic therapy. In the second step, guidelines are recommended in the four statin benefit groups, which include patients with atherosclerotic cardiovascular disease (ASCVD), LDL-C >190 mg/dL, or diabetes mellitus, as well as primary prevention patients with an ASCVD risk score of >7.5%. Then, in the third step, if the LDL-C target is not reached, regardless of whether a patient with LDL-C levels ≥190 mg/dL (≥4.9 mmol/L) is found to have a genetic mutation associated with familial hypercholesterolemia (FH), those with very high LDL-C values are most likely to achieve the greatest benefit from evidence-based LDL-C–lowering therapy. Consequently, in the fourth step, patients who have a baseline LDL-C level ≥220 mg/dL (≥5.7 mmol/L) and an on-treatment LDL-C level ≥ 130 mg/dL (≥3.4 mmol/L) despite maximally tolerated statins and ezetimibe therapy may be considered for treatment with a PCSK9 inhibitor. This is to be done after a clinician–patient discussion of the net benefits versus the costs of such therapy.
It was 2012 when PCSK9 mAbs were used in phase 1 studies. In 2015, the United States Food and Drug Administration (USFDA) approved evolocumab and alirocumab. In most of clinical trials, mAbs were used and the latest one in 2019; a trial ORION 9 was conducted in which the effect of inclisiran, in the siRNA class, was assessed.
- FOURIER trial was aimed to evaluate the effect of evolocumab on total CV events. It was a randomized, double-blind placebo-controlled trial which included 27,564 patients with stable atherosclerotic disease receiving statin therapy with the addition of the PCSK9 inhibitor evolocumab in one group and placebo in the second group. The study continued from May 2017 to February 2019. The primary end point was to assess time of any adverse event such as CV death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization in both groups. In a prespecified analysis, the total CV events were evaluated between both treatment arms. The trial concluded that the addition of the PCSK9 inhibitor evolocumab to statin therapy improved clinical outcomes. The number of events prevented was more than two times with evolocumab versus placebo
- In the ODYSSEY outcomes trial, the safety and efficacy of alirocumab with placebo were assessed. All the participants with a recent ACS and on intensive or maximum-tolerated statin therapy were recruited. Randomized patients were out from an ACS event for about 1–12 months and after a run-in phase of 2–16 weeks of high-intensity statin therapy. Patients (n = 9462) were administered alirocumab every other week subcutaneously or placebo. The drug was titrated between 75 and 150 mg to keep the LDL-C between 25 and 50 mg/dL. The trial concluded that with the use of alirocumab, there was significant reduction in adverse CV events and even in mortality. Based on data from the ODYSSEY outcomes trial in April 2019, the USFDA approved Praluent 1 (alirocumab).
- SPIRE trial initiated in 2013 was conducted to evaluate the efficacy and safety of bococizumab in patients at high CV risk under two broad categories:
- SPIRE lipid-lowering trials (N = 4449) were carried out as six parallel multinational studies involving:
- SPIRE HR (N = 771, with high risk CV event and on maximally tolerated statin)
- SPIRE LDL (N = 2139, with high-risk CV event and on maximally tolerated statin)
- SPIRE FH (N = 370, with familial hypercholesteremia on genetic diagnosis)
- SPIRE SI (N = 184, with statin intolerance)
- SPIRE LL (N = 746, with statin high/very high risk of CV event)
- SPIRE AI (N = 299, with autoinjector hyperlipidemia).
Bococizumab 75 mg subcutaneously every 2 weeks with matching placebo in all groups was given and then followed up prospectively for 6–12 months. The reduction in LDL-C levels was observed over time. The mean percent change among the patients in the bococizumab group was − 41.8% at 52 weeks and −38.3% at 104 weeks. A big variation among lipid-lowering values of the patients was also observed.
SPIRE CV outcome studies (N ~ 28,000), SPIRE-1 and SPIRE-2,, two parallel, placebo-controlled multinational trials including 27,438 participants on bococizumab were done. The drug was used at a dose of 150 mg subcutaneously every 14 days. The primary outcome measure was nonfatal myocardial infarction/stroke, hospitalization requiring urgent revascularization, or CV death. The median follow-up was 10 months. Both the trials were stopped prematurely. There were high rates of antidrug antibodies formation, as seen in data from other studies in the program, but concluded the efficacy of bococizumab involving high-risk patients rather in low-risk patients. The use of PCSK9 inhibitors on top of aggressive statin therapy in selected patients was also recommended. Moreover, genetic analysis for differentiation between those who develop antidrug antibody formation or not was suggested.
OSLER-1 and OSLER-2 were open-label studies for Repatha (evolocumab) followed from October 2011 through June 2014. Both concluded after a prespecified but exploratory analysis that the use of evolocumab as add on as compared to conventional treatment showed significant reduction in LDL-C levels and in the incidence of CV events. More than 1% had joint pain, 4.3% had injection site reactions, and some of patients had headache, limb pain, and fatigue.ORION-9 was a double-blind, placebo-controlled, randomized study trial to assess the safety and efficacy of inclisiran given twice a year and followed up for 18 months (2018–2019) in 482 participants with heterozygous familial hypercholesterolemia. The study showed that inclisiran safely reduced approximately 50% of LDL-C from baseline at 510 day.
| Conclusion|| |
There has been a change in the management of hypercholesterolemia and CV risks with the invention of statins over the past 30 years. However, about 40% of patients still remain at substantial residual risks. The innovations such as ezetimibe, bile acid sequestrants, and PCSK9 inhibitors help in reducing serum LDL-C. Lipoprotein (a) was also reduced in some studies. The PCSK9 inhibitors have different therapeutic targets and thus hold promise for reducing residual CV risks. However, long-term safety and cost of these new drugs are the major limitations. A large number of studies have been done and a number of studies in different phases targeting better results are still going on. Thus, PCSK9 inhibitors are a promising new target in the lipid-lowering therapy.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2]