Proprotein convertase subtilisin/kexin type 9, better known as PCSK9, broke dramatically onto the scene of lipid and cholesterol metabolism in 2003, when a collaborative discovery in Paris and Montreal identified families in whom autosomal dominant hypercholesterolaemia and premature CVD was because of rare gain-of-function mutations in this gene . Subsequent studies showed that individuals with loss-of-function mutations or variants in the PCSK9 gene not only displayed lifelong lower plasma levels of LDL-C but also were at lower risk of CVD [11,12,13 ▪ ][11,12,13 ▪ ][11,12,13 ▪ ]. These key findings drove the quest to elucidate PCSK9 biology with the ultimate hope of developing PCSK9-targeted therapeutics.
Intracellular levels of cholesterol in hepatocytes primarily reflect the combination of uptake of cholesterol contained in LDL and other lipoproteins, endogenous cholesterol synthesis, cholesterol conversion to bile acids, excretion of bile acids and biliary cholesterol, and secretion of nascent lipoproteins (principally very low-density lipoprotein). Circulating LDL binds to the LDL receptor on the hepatocyte surface, is endocytosed within clathrin-coated vesicles, trafficked intracellularly in the endosomal pathway, and subsequently degraded by lysosomes. The LDL receptor dissociates from the LDL particle at acid lysosomal pH, and then recycles back to the plasma membrane to bind additional LDL. Ultimate control of circulating LDL-C levels is exerted via two pathways: the sterol regulatory element binding protein-2 (SREBP-2) pathway, which is subject to regulation by intracellular cholesterol concentration and regulates expression of both the LDLR gene and the gene encoding PCSK9, and the inducible degrader of the LDL receptor (IDOL) pathway, which is LDL receptor-specific and under control of the liver X receptor transcription factor [14▪].
PCSK9 is a 692-amino acid serine protease, synthesized as an inactive zymogen (proPCSK9, about 72 kDaltons); it is transformed by autocatalytic cleavage of the prodomain in the endoplasmic reticulum, thereby allowing entry into the secretory pathway. Whereas upregulation of LDLR by SREBP-2 increases LDL receptor availability and plasma clearance of LDL-C, upregulation of PCSK9 by the same transcription factor has the reverse effect, resulting in elevation of plasma LDL-C levels because of attenuated LDL receptor recycling (the reader is referred to recent reviews) [13 ▪ ,15][13 ▪ ,15]. Upregulation of PCSK9 expression by SREBP-2 is equally detrimental for patients with primary hypercholesterolaemia and heterozygous familial hypercholesterolaemia ; importantly, enhanced PCSK9 expression counteracts the beneficial upregulation of LDL receptors by statin to a significant degree [13 ▪ ,15][13 ▪ ,15].
As discussed, familial hypercholesterolaemia is poorly managed even with best available treatment, and thus the likely highest patient priority for PCSK9 inhibitor therapy. Both alirocumab and evolocumab are highly effective in the setting of heterozygous familial hypercholesterolaemia (Table 1) [21 ▪ ,22 ▪ ,23][21 ▪ ,22 ▪ ,23][21 ▪ ,22 ▪ ,23]. In RUTHERFORD-2 (Reduction of LDL-C With PCSK9 Inhibition in Heterozygous Familial Hypercholesterolemia Disorder Study-2) [21▪], treatment with evolocumab (140 mg every 2 weeks or 420 mg monthly) against a background of statin ± ezetimibe resulted in placebo-corrected mean decreases in LDL-C of ∼60–65%, with more than 60% of patients attaining LDL-C goal (<1.8 mmol/l or 70 mg/dl). Importantly, treatment response was similar irrespective of LDLR mutation status. Pooled data from the ODYSSEY familial hypercholesterolaemia I and II studies with alirocumab (75 mg titrating to 150 mg every 2 weeks depending on LDL-C response) showed a similar, sustained LDL-C lowering response [22▪]. Even in severe familial hypercholesterolaemia (LDL-C levels >5 mmol/l or 200 mg/dl on maximally tolerated lipid-lowering therapy), ODYSSEY HIGH familial hypercholesterolaemia showed that 57% of these difficult-to-treat patients attained LDL-C goal (<2.6 mmol/l or 100 mg/dl) on alirocumab .
The treatment of homozygous familial hypercholesterolaemia, which is characterized by onset of symptomatic atherosclerotic vascular disease as early as the second decade of life, continues to present major challenges [24▪]. In a proof-of-concept study with evolocumab, a wide range in LDL-C reduction was observed in six LDL receptor-defective patients (4–48% with 2-week dosing of 420 mg), whereas no reduction was seen in two LDL receptor-negative patients . These findings were entirely consistent with those in a statin-induced skin fibroblast system in vitro, in which alirocumab upregulated LDLR expression in receptor-defective homozygous familial hypercholesterolaemia fibroblasts, whereas no effect was seen in receptor-negative cells . Subsequently, TESLA (Trial Evaluating PCSK9 Antibody in Subjects With LDL Receptor Abnormalities) Part B in homozygous familial hypercholesterolaemia (n = 49), showed that evolocumab (420 mg every 4 weeks for 12 weeks) lowered LDL-C by 30.9% (placebo-corrected) against a background of maximally tolerated lipid-lowering therapy, but excluding lipoprotein apheresis [27▪▪]. In individuals with two different LDLR defective alleles, mean LDL-C lowering was higher (46.9%) [27▪▪]. Yet even in responders, LDL-C levels remained markedly elevated (mean 7.0 mmol/l or 270 mg/dl), underlining the inherent difficulties in managing these severely affected patients . Most recently, TAUSSIG (Trial Assessing long term USe of PCSK9 Inhibition in Subjects wIth Genetic LDL Disorders) showed sustained LDL-C lowering (by 20–25%) over 48 weeks of treatment with evolocumab in homozygous familial hypercholesterolaemia patients (95% with LDLR mutations). Lipoprotein apheresis slightly reduced the LDL-C lowering response . Clearly, and given the excellent tolerability of PCSK9 inhibitors in these studies, PCSK9 inhibition presents a new therapeutic option in this serious disorder, provided that at least one allele is not LDLR negative.
To prevent the high risk of premature CHD associated with familial hypercholesterolaemia, early identification and initiation of optimal treatment, ideally in children and adolescents, is crucial [30▪▪]. Yet to date, studies of PCSK9 inhibitors have excluded these key groups. HAUSER-RCT (Trial Assessing Efficacy, Safety and Tolerability of PCSK9 Inhibition in Paediatric Subjects With Genetic LDL Disorders), currently enrolling familial hypercholesterolaemia patients aged 10–17 years, is pivotal to assessment of the role of PCSK9 inhibition (evolocumab) in younger patients .
Statin-intolerant patients represent a major high-risk group of concern. Two key studies showed benefit of PCSK9 monoclonal antibody therapy over ezetimibe, currently the primary option for this group [49,50][49,50]. Both studies were similar in the definition of patient population (unable to tolerate at least two statins) but differed in design. ODYSSEY ALTERNATIVE (alirocumab) included both a blinded 4-week placebo run-in period to exclude patients reporting muscle symptoms, and also a rechallenge atorvastatin arm, in addition to ezetimibe. Not surprisingly given the possibility of allocation to statin, myalgia rates were higher compared with those reported in GAUSS-2 (Goal Achievement After Utilizing an Anti-PCSK9 Antibody in Statin Intolerant Subjects -2) with evolocumab, although in long-term follow-up of ODYSSEY ALTERNATIVE, there was virtually no myalgia reported with alirocumab. Irrespective of these differences in protocol design, both studies showed a consistent LDL-C lowering response with the PCSK9 inhibitor as reported in other high-risk groups (55–60%), which was significantly superior to that for ezetimibe.
Elevated levels of lipoprotein a [Lp(a)] constitute a causal factor for accelerated CVD, as well as myocardial infarction, aortic valve stenosis, and ischaemic stroke [52,53 ▪ ][52,53 ▪ ]. Given that Lp(a) is essentially refractory to both lifestyle intervention and statin treatment, we lack efficacious pharmacotherapeutic interventions that specifically target this atherothrombogenic particle. Importantly, PCSK9 inhibitors have been shown to reduce Lp(a) by 25–30% as a function of baseline level [54 ▪ ,55 ▪ ][54 ▪ ,55 ▪ ]. Although the mechanism of Lp(a) catabolism in vivo and the impact of PCSK9 on this process has been contentious, recent in vitro studies have overturned previous thinking that the LDL receptor does not play any role in Lp(a) catabolism. Indeed, under the supraphysiological LDL receptor availability and low circulating LDL-C levels resulting from PCSK9 inhibition, Lp(a) is a ligand of this receptor, and thus may contribute to Lp(a) catabolism and clearance . Definitive proof is, however, awaited from in vivo studies. Finally, it is relevant that markedly low plasma levels of small dense LDL acceptor particles possessing apo B 100 in an optimal conformation for linkage to apo(a) may limit formation of Lp(a), thereby contributing to PCSK9 inhibitor-mediated reduction in Lp(a) levels.
Beyond efficacy, safety and tolerability are key considerations underpinning any novel therapy. Extensive evidence to date with alirocumab and evolocumab attests to a favourable safety profile, with similar low injection site reaction rates (∼5%) [57,58][57,58]. Importantly, data from ODYSSEY LONG TERM showed no increase in the incidence of adverse events in patients attaining very low LDL-C levels (<25 mg/dl or 0.65 mmol/l) ; correspondingly, OSLER (Open Label Study of Long Term Evaluation Against LDL-C Trial) showed no increase in the frequency of adverse events with decreasing LDL-C levels . However, it should be emphasized that long-term exposure data are needed to definitively assess the benefit versus risk profile of these novel agents.
The possibility that PCSK9 inhibitors may induce neurocognitive effects has been queried ever since the US Food and Drug Administration directed their developers to monitor such effects and to consider neurocognitive testing in at least a subset of patients in ongoing trials ; EBBINGHAUS (Evaluating PCSK9 Binding antiBody Influence oN coGnitive HeAlth in high cardiovascUlar risk Subjects), a substudy of FOURIER (Further cardiovascular OUtcomes Research with PCSK9 inhibitors In subjects with Elevated Risk), the evolocumab outcomes study, is addressing this . The justification for this action probably dates from the statin era, although even here there is no definitive prospective evidence of any neurocognitive risks associated with statins . Moreover, it is important to bear in mind that the PCSK9 monoclonal antibodies are large molecules and, therefore, do not normally cross the blood brain barrier.
Another issue involves possible effects on glucose homeostasis, as PCSK9 monoclonal antibody treatment will be coadministered with statins in most high cardiovascular risk patients. Evidence to date suggests a lack of detrimental effects. In the DESIR (Data from an Epidemiological Study on the Insulin Resistance syndrome) study, carriage of the PCSK9 p.R46L loss-of-function variant was not associated with any significant change in markers of glucose homeostasis in nondiabetic patients ; furthermore, these carriers were not at increased risk of new onset type 2 diabetes during a 9 year follow-up period. One year follow-up data from DESCARTES (Durable Effect of PCSK9 Antibody Compared with Placebo Study) showed no increased incidence of new onset type 2 diabetes in patients treated with evolocumab compared with placebo . Clearly, further data both from ongoing trials and from postmarketing surveillance are required.
The key question is whether PCSK9 monoclonal antibody therapy reduces composite endpoints for cardiovascular outcomes in high-risk patients receiving concomitant statin therapy. Indeed, it is pertinent that regulatory approval was given for alirocumab and evolocumab despite the lack of definitive outcomes evidence. There are encouraging findings from exploratory analyses of ODYSSEY LONG TERM (alirocumab, n = 2341) and OSLER (evolocumab, n = 4465), which indicate about 50% reduction in cardiovascular outcomes (using the same definitions as in the ongoing ODYSSEY OUTCOMES and FOURIER trials) over a treatment period of up to 78 weeks [34,42][34,42], although the possibility of positive bias because of failure to exploit the maximal potential of statins has been suggested . Additionally, meta-analysis of 24 trials of PCSK9 monoclonal antibody therapy, including more than 10 000 patients, showed a 55% reduction in all-cause mortality, (odds ratio = 0.45, 95% confidence interval = 0.23–0.86, P = 0.015), as well as 50% reduction in cardiovascular mortality, and 51% reduction in myocardial infarction . These findings are not, however, definitive and we eagerly await completion of the ongoing outcomes studies. Moreover, evidence from genetic studies of lifelong exposure to low LDL-C levels reaffirms the urgent need to start treatment early to optimize CVD benefit. Finally, these studies may also provide insights into the impact of PCSK9 inhibition in cerebrovascular disease and other high cardiovascular risk groups, as defined by guidelines (Fig. 2) , as well as definitive evaluation of the benefit/risk ratio.
The integration of PCSK9 monoclonal antibody therapy into clinical practice will undoubtedly be driven by the severity of cardiovascular risk. For patients with homozygous familial hypercholesterolaemia or severe familial hypercholesterolaemia and established CVD who fail to meet LDL-C targets with current therapy, there is a clear role for PCSK9 therapeutics; patients who are already at LDL-C goal, but remain at high risk because of plaque progression should also be considered. Additionally, there is a potential role for these novel agents in high-risk patients with established CVD who cannot tolerate statin therapy. The extent of clinical risk and the ability to meet cost constraints will no doubt exert major influence on clinical management.
Emerging data suggest future potential for PCSK9 inhibition in other clinical settings, most notably sepsis , given that pathogen lipids, such as lipopolysaccharide, are cleared in part by LDL receptor-mediated hepatic uptake. In support of this hypothesis is evidence that PCSK9 loss-of-function genetic variants are associated with improved survival in septic shock patients, as well as decreased inflammatory cytokine response in both septic shock patients and in healthy volunteers after lipopolysaccharide administration. The opposite effects were observed in septic shock patients with PCSK9 gain-of-function variants . Evaluation of the clinical efficacy of PCSK9 inhibition in the setting of sepsis, therefore, appears warranted.
PCSK9 inhibitors undoubtedly represent an effective strategy to address the unmet clinical needs of high cardiovascular risk patients. These agents efficaciously lower LDL cholesterol, but equally Lp(a); moreover, potential effects on triglyceride-rich lipoproteins, atherogenic remnants and even HDL particles cannot be excluded at this time . There is a clear case for the use of PCSK9 inhibitors in severe familial hypercholesterolaemia, given obvious practical advantages over lipoprotein apheresis, although homozygous familial hypercholesterolaemia patients will continue to need the armamentarium of LDL-C lowering treatments. Definitive answers relating to impact on cardiovascular events, safety and tolerability await the conclusion of ongoing outcomes studies and postmarketing surveillance. Findings of these studies will be needed to inform health economics modelling, as ultimately, accessibility to such treatments will depend on budgetary constraints.
Finally, emerging evidence suggests potential for PCSK9 inhibition in other clinical settings such as infectious disease. The unique PCSK9 story looks set to continue for some time yet.
Papers of particular interest, published within the annual period of review, have been highlighted as:
3▪▪. Goldstein JL, Brown MS. A century of cholesterol and coronaries: from plaques to genes to statins. Cell 2015; 161:161–172.
This review provides fascinating insights into the science of the LDL receptor and its regulation.
4▪▪. Ference BA, Majeed F, Penumetcha R, et al. Effect of naturally random allocation to lower low-density lipoprotein cholesterol
on the risk of coronary heart disease mediated by polymorphisms in NPC1L1, HMGCR, or both: a 2 × 2 factorial Mendelian randomization study. J Am Coll Cardiol 2015; 65:1552–1561.
The outstanding study provides unique insights into facets of genetically determined CHD risk using a Mendelian randomization approach.
5. Reiner Z, Catapano AL, De Backer G, et al. ESC/EAS Guidelines for the management of dyslipidaemias: the task force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS). Eur Heart J 2011; 32:1769–1818.
6▪. Nordestgaard BG, Chapman MJ, Humphries SE, et al. Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: guidance for clinicians to prevent coronary heart disease: consensus statement of the European Atherosclerosis Society. Eur Heart J 2013; 34:3478–3490a.
This important paper is a call to action for improved diagnosis and treatment of familial hypercholesterolaemia and the impetus for the numerous ongoing familial hypercholesterolaemia initiatives.
7. Béliard S, Carreau V, Carrié A, et al. 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; 234:136–141.
8▪. Mundal L, Sarancic M, Ose L, et al. Mortality among patients with familial hypercholesterolemia: a registry-based study in Norway, 1992–2010. J Am Heart Assoc 2014; 3:e001236.
A report from a large familial hypercholesterolaemia registry in the statin era.
9. Postmus I, Trompet S, Deshmukh HA, et al. Pharmacogenetic meta-analysis of genome-wide association studies of LDL cholesterol response to statins. Nat Commun 2014; 5:5068.
10▪. Stroes ES, Thompson PD, Corsini A, et al. Statin-associated muscle symptoms: impact on statin therapy. European Atherosclerosis Society Consensus Panel statement on assessment, aetiology and management. Eur Heart J 2015; 36:1012–1022.
This consensus paper provides a current review of the pathophysiology underlying statin intolerance as well as a pragmatic approach to its clinical management.
11. Abifadel M, Elbitar S, El Khoury P, et al. Living the PCSK9 adventure: from the identification of a new gene in familial hypercholesterolemia towards a potential new class of anticholesterol drugs. Curr Atheroscler Rep 2014; 16:439.
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13▪. Seidah NG, Awan Z, Chrétien M, Mbikay M. PCSK9: a key modulator of cardiovascular health. Circ Res 2014; 114:1022–1036.
Comprehensive overview of the PCSK9 story from one of the key groups involved in its discovery.
14▪. Scotti E, Calamai M, Goulbourne CN, et al. IDOL stimulates clathrin-independent endocytosis and multivesicular body-mediated lysosomal degradation of the low-density lipoprotein receptor. Mol Cell Biol 2013; 33:1503–1514.
Elegant mechanistic overview of the inducible degrader of the LDL receptor pathway.
15. McKenney JM. Understanding PCSK9 and anti-PCSK9 therapies. J Clin Lipidol 2015; 9:170–186.
16. Lambert G, Petrides F, Chatelais M, et al. Elevated plasma PCSK9 level is equally detrimental for patients with nonfamilial hypercholesterolemia and heterozygous familial hypercholesterolemia, irrespective of low-density lipoprotein receptor defects. J Am Coll Cardiol 2014; 63:2365–2373.
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19. Fitzgerald K, Kallend D, White S, et al. A phase 1, randomized, placebo-controlled, single ascending and multiple dose study of subcutaneously administered ALN-PCSSC in subjects with elevated low density lipoprotein cholesterol. Eur Heart J 2015; 36 (Abstract Supplement):309.
20. van Poelgeest EP, Hodges MR, Moerland M, et al. Antisense-mediated reduction of proprotein convertase subtilisin/kexin type 9 (PCSK9): a first-in-human randomized, placebo-controlled trial. Br J Clin Pharmacol 2015; [Epub ahead of print].
21▪. Raal FJ, Stein EA, Dufour R, et al. PCSK9 inhibition with evolocumab
(AMG 145) in heterozygous familial hypercholesterolaemia (RUTHERFORD-2): a randomised, double-blind, placebo-controlled trial. Lancet 2015; 385:331–340.
Key study showing the benefit of PCSK9 inhibition in the management of heterozygous familial hypercholesterolaemia.
22▪. Kastelein JJ, 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; [Epub ahead of print].
The largest analysis to date of heterozygous familial hypercholesterolaemia patients treated for up to 78 weeks with alirocumab, showing the durability of LDL lowering response.
23. Ginsberg HN, Rader DJ, Raal FJ, et al. ODYSSEY HIGH FH: efficacy and safety of alirocumab
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24▪. Cuchel M, Bruckert E, Ginsberg HN, et al. Homozygous familial hypercholesterolaemia: new insights and guidance for clinicians to improve detection and clinical management. A position paper from the Consensus Panel on Familial Hypercholesterolaemia of the European Atherosclerosis Society. Eur Heart J 2014; 35:2146–2157.
This is a comprehensive review of homozygous familial hypercholesterolaemia in the pre-PCSK9 inhibitor era.
25. 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.
26. Lambert G, Chatelais M, Petrides F, et al. Normalization of low-density lipoprotein receptor expression in receptor defective homozygous familial hypercholesterolemia by inhibition of PCSK9 with alirocumab
. J Am Coll Cardiol 2014; 64:2299–2300.
27▪▪. Raal FJ, Honarpour N, Blom DJ, et al. Inhibition of PCSK9 with evolocumab
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Key study showing the benefit of PCSK9 inhibition in the management of homozygous familial hypercholesterolaemia, provided patients have at least one LDLR defective allele.
28. Santos RD, Watts GF. Familial hypercholesterolaemia: PCSK9 inhibitors are coming. Lancet 2015; 385:307–310.
29. Raal FJ, Hovingh GK, Blom D, et al.. A. Long-term treatment with evolocumab
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30▪▪. Wiegman A, Gidding SS, Watts GF, et al. Familial hypercholesterolaemia in children and adolescents: gaining decades of life by optimizing detection and treatment. Eur Heart J 2015; 36:2425–2437.
Call to action for the early identification and treatment of familial hypercholesterolaemia in children and adolescents.
31. Trial Assessing Efficacy, Safety and Tolerability of PCSK9 Inhibition in Paediatric Subjects With Genetic LDL Disorders (HAUSER-RCT). Clinical Trials Identifier NCT02392559. https://clinicaltrials.gov/ct2/show/
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36. Kereiakes DJ, Robinson JG, Cannon CP, et al. Efficacy and safety of the proprotein convertase subtilisin/kexin type 9 inhibitor alirocumab
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38. Bays H, Gaudet D, Weiss R, et al. Alirocumab
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42. Robinson JG, Farnier M, Krempf M, et al. Efficacy and safety of alirocumab
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44. 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.
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Important study showing the association of elevated Lp(a) with aortic valve calcification and valve stenosis.
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Pooled analysis confirming the efficacy of PCSK9 inhibition in lowering Lp(a).
55▪. Gaudet D, Kereiakes DJ, McKenney JM, et al. Effect of alirocumab
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Pooled analysis confirming the efficacy of PCSK9 inhibition in lowering Lp(a).
56. Romagnuolo R, Scipione C, Boffa MB, et al. Lipoprotein(a) catabolism is regulated by proprotein convertase subtilisin/kexin type 9 through the low density lipoprotein receptor. J Biol Chem 2015; 290:11649–11662.
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