Commentary on The potential of PCSK9

Improving the care of high-risk patients: The potential of PCSK9

This month’s commentary highlights the potential of novel agents that target proprotein convertase subtilisin/kexin type 9 (PCSK9). Adding to the monoclonal antibody therapies, the most advanced now in Phase III development, is a proof of concept study for a small interfering RNA (siRNA) that inhibits PCSK9 synthesis. If shown to be safe and effective in the long-term, these agents will play an important role in the management of patients at increased risk of accelerated atherosclerosis and cardiovascular disease, including those with familial hypercholesterolaemia (FH), who are often undertreated. This issue has been highlighted by the European Atherosclerosis Society (EAS) Consensus Statement.1 Recently, the International Atherosclerosis Society recommended that: ‘…the paper should be compulsory reading for all who are committed to reducing the worldwide burden of atherosclerosis and its associated cardiovascular disease.’ 2

Why PCSK9?

PCSK9 plays a critical role in regulating cholesterol homeostasis. It is thought that binding of PCSK9 to the surface of the cell leads to conformational changes, shifting the equilibrium to enhance intracellular degradation of hepatic low-density lipoprotein (LDL) receptors, thereby leading to an increase in plasma LDL cholesterol (LDL-C) levels. Levels of both LDL receptors and PCSK9 are co-regulated by the sterol regulatory element binding protein-2 (SREBP-2), to prevent excessive cholesterol uptake and preserve cholesterol homeostasis. Experimental studies suggest that other pathways, including inflammatory pathways, may also be implicated in mediating the effects of PCSK9 on vascular biology.3,4

Gain of function PCSK9 variants were shown to be associated with lower LDL receptor levels and in turn higher levels of LDL-C, with the severity of hypercholesterolemia dependent on the site of mutation.5,6 However, the identification of loss of function mutations which were associated with very low plasma LDL-C levels and reduction in cardiovascular risk without evidence of adverse effects,7 was the catalyst for investigation of PCSK9 inhibition as a novel therapeutic approach to the management of hypercholesterolaemia.

Although current LDL-C lowering therapies, most notably statins, represent the cornerstone for pharmacotherapeutic management of hypercholesterolaemia, a substantial proportion of high-risk patients fail to achieve guideline-recommended plasma LDL-C goals. In a recent survey involving more than 22,000 patients receiving a statin for either primary or secondary prevention in Europe and Canada, nearly one-half (48.2%) did not attain LDL-C targets as recommended by the Joint European Society of Cardiology (ESC)/EAS guidelines for management of dyslipidaemia.8,9 This issue is especially problematic for patients with FH. In the Netherlands, a country regarded as at the forefront of FH management in Europe, a recent survey reported that only 21% of FH patients attained a LDL-C goal of <2.5 mmol/L (100 mg/dL), even with the use of high-dose statins in combination with other cholesterol lowering therapies.10 Other than inadequate statin dosing, poor adherence with therapy, or adverse effects with high-dose statins are contributory factors to the lack of goal attainment. Thus, new treatment strategies are required. PCSK9-targeted therapy is therefore an interesting proposition that may vastly improve the management of patients at high to very high cardiovascular risk. Furthermore, evidence that statins increase PCSK9 expression, which is counterproductive to their effect on LDL receptor regulation, suggests that inhibiting PCSK9 might also increase the LDL-C lowering efficiency of statin treatment.

Targeting PCSK9: novel approaches

Different therapeutic strategies to inhibit PCSK9 are in development (Table 1), although studies with the monoclonal antibody therapies are currently most advanced.

Table 1.
Investigational approaches targeting PCSK9
• Agents that inhibit binding of PCSK9 to the LDL receptor (e.g. monoclonal antibody therapy)
• Agents that inhibit PCSK9 synthesis (e.g. small interfering RNA, antisense oligonucleotides)
• Potentially, agents that inhibit intracellular processing of PCSK9

Combined data from phase II studies show that treatment with PCSK9 monoclonal antibody therapy achieves clinically meaningful reductions (>60%) in LDL-C plasma levels, on top of statin therapy. These agents are also effective in reducing other atherogenic lipoproteins, including lipoprotein(a) [Lp(a)], and triglyceride-rich lipoproteins (Table 2).11-14 Lowering of Lp(a) is highly relevant, as supported by the EAS Consensus statement for Lp(a) as a cardiovascular risk factor, as well as evidence showing Lp(a) to be an important contributor to residual cardiovascular risk beyond LDL C.15,16 Notably, very few interventions are capable of reducing plasma Lp(a) plasma levels.

Table 2.
Impact of PCSK9 monoclonal antibody therapy on lipoproteins in statin-treated patients11-14
150 mg every 2 weeks
On stable statin therapy-67.3%-28.6%-9.2%
140 mg every 2 weeks
On statin (± ezetimibe)-66.1%-33.7%
420 mg every 4 weeks
On statin (± ezetimibe)-50.3%-19.4%

Data are presented as % change versus placebo
HeFH heterozygous familial hypercholesterolaemia; LDL-C low-density lipoprotein cholesterol;
Lp(a) lipoprotein(a); TG triglycerides

While no adverse signal has so far been identified with these agents, it should be borne in mind that trials to date have been relatively small involving a short duration of treatment (12 weeks) and thus limited exposure.

The first report for ALN-PCS, a siRNA that directs sequence-specific messenger RNA for PCSK9 thereby inhibiting PCSK9 synthesis, published in The Lancet adds another therapeutic possibility.17 The rationale for this proof of concept study was supported by evidence that a PCSK9-specific siRNA reduced hepatocyte-specific synthesis of PCSK9 in animal models, resulting in increased numbers of LDL receptors on the hepatocyte membrane and substantial reduction of plasma levels of LDL-C.18

This was a randomised, single-blind, placebo-controlled Phase I study in 32 healthy individuals (30 men and 2 women) with LDL-C levels ≤3.0 mmol/L. Individuals were randomly allocated to receive a single intravenous dose of ALN-PCS (dose range 0.015 to 0.40 mg/kg, n=24) or placebo (n=8). The primary endpoint of the study was safety and tolerability.

Overall, ALN-PCS was well tolerated, with a similar proportion of mild to moderate treatment-emergent adverse events in individuals receiving ALN-PCS or placebo (19 [79%] versus 7 [88%]). The most commonly reported event was rash, reported for 50% of patients per treatment group, 12 individuals receiving PCN-ALS versus 4 receiving placebo; all cases were mild and resolved spontaneously. There were no clinically significant changes in liver function tests, troponin or inflammatory markers.

Dosing with ALN-PCS resulted in rapid and dose-dependent reduction in PCSK9, and lowering of plasma levels of LDL C. Compared with placebo, the highest dose (0.4 mg/kg) was associated with a mean 70% reduction from baseline in PCSK9, and a mean 40% reduction in plasma LDL-C concentration.

In summary, the key message from this study is that ALN-PCS, a siRNA that targets PCSK9 synthesis, may be a viable approach to blocking PCSK9 function, thus providing a rationale for future trials to assess the efficacy and safety of ALN-PCS in different patient populations (Box 1).

Box 1.
Key points
• This proof of concept study showed that a single dose of ALN-PCS, a siRNA that inhibits PCSK9 synthesis, was well tolerated and resulted in a 40% reduction in plasma LDL-C levels in healthy individuals with raised cholesterol.

• The efficacy at reducing circulating PCSK9 is lower than that for the monoclonal antibodies, and this may explain the lower decrease in LDL C plasma levels.

• The study provides support for further trials investigating the potential of this agent in different patient populations, including those on statin therapy.

Looking to the future: Unanswered questions

LDL-C is indisputably the priority for management of dyslipidaemia. However, it is clear that a substantial proportion of high to very high risk patients, notably those with FH, do not attain guideline-recommended targets for LDL-C, or even an acceptable decrease in LDL-C levels. Clearly, there is an unmet need for new therapeutic strategies.

Inhibition of PCSK9 is a major focus of investigation. Monoclonal antibodies targeting PCKS9, have been shown to be effective and well tolerated in phase II trials. However, long-term efficacy and safety data are needed to fully evaluate the benefit versus risk of these novel therapies. Finally, this first proof of concept study suggests that a siRNA that inhibits PCSK9 synthesis may offer another viable therapeutic approach. Clearly further study in appropriate patient populations is merited.


  1. 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 Sep 12. [Epub ahead of print].
  2. International Atherosclerosis Society. From the IAS President’s desk. September 2012. Available at Accessed October 3, 2013.
  3. Urban D, Pöss J, Böhm M, Laufs U. Targeting the proprotein convertase subtilisin/kexin type 9 (PCSK9) for the treatment of dyslipidemia and atherosclerosis. J Am Coll Cardiol 2013;[Epub ahead of print].
  4. Norata GD, Ballantyne CM, Catapano AL. New therapeutic principles in dyslipidaemia: focus on LDL and Lp(a) lowering drugs. Eur Heart J 2013;34:1783-9.
  5. Abifadel M, Varret M, Rabès JP et al. Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nat. Genet 2003;34:154-6.
  6. Allard D, Amsellem S, Abifadel M et al. Novel mutations of the PCSK9 gene cause variable phenotype of autosomal dominant hypercholesterolemia. Hum Mutat 2005;265:497.
  7. 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.
  8. Gitt AK, Drexel H, Feely J et al; DYSIS Investigators. Persistent lipid abnormalities in statin-treated patients and predictors of LDL-cholesterol goal achievement in clinical practice in Europe and Canada. Eur J Prev Cardiol 2012;19:221-30.
  9. Catapano AL, Reiner Z, 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). Atherosclerosis 2011;217 Suppl 1:S1-44.
  10. Pijlman AH, Huijgen R, Verhagen SN et al. Evaluation of cholesterol lowering treatment of patients with familial hypercholesterolemia: a large cross-sectional study in The Netherlands. Atherosclerosis 2010;209:189-94.
  11. 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.
  12. 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.
  13. Giugliano RP, Desai NR, Kohli P et al; LAPLACE-TIMI 57 Investigators. 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.
  14. 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.
  15. Nordestgaard BG, Chapman MJ, Ray K et al; European Atherosclerosis Society Consensus Panel. Lipoprotein(a) as a cardiovascular risk factor: current status. Eur Heart J 2010;31:2844-53.
  16. Albers JJ, Slee A, O’Brien KD et al. Relationship of apolipoproteins A-1 and B, and lipoprotein (a) to cardiovascular outcomes in the AIM-HIGH Trial. J Am Coll Cardiol 2013. [Epub ahead of print Aug 21].
  17. Fitzgerald K, Frank-Kamenetsky M, Shulga-Morskaya S et al. Effect of an RNA interference drug on the synthesis of proprotein convertase subtilisin/kexin type 9 (PCSK9) and the concentration of serum LDL cholesterol in healthy volunteers: a randomised, single-blind, placebo-controlled, phase 1 trial. Lancet 2013;Epub ahead of print. October 3, 2013.
  18. Frank-Kamenetsky M, Grefhorst A, Anderson NN, et al. Therapeutic RNAi targeting PCSK9 acutely lowers plasma cholesterol in rodents and LDL cholesterol in nonhuman primates. Proc Natl Acad Sci USA 2008;105:11915–20.