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|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
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.
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.
Data are presented as % change versus placebo
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).
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.