PCSK9

For many years, dyslipidaemias failed to receive the attention they deserve, both in Poland and across the world. In many cases, the most common recommendation given to patients suffering from lipid disorders was to change their diet and lifestyle. Despite multiple educational efforts undertaken by medical societies in Poland, including the signatories of the Guidelines, the knowledge of patients about this independent risk factor continues to be very limited even today. As a result, there are nearly 20 million hypercholesterolaemic patients in Poland. Furthermore, there are no medical (lipid) clinics specializing in
the treatment of lipid disorders, and existing outpatient clinics are not usually dedicated specifically to dyslipidaemias, but metabolic disorders
and/or endocrine conditions. Not uncommonly, patients receive treatment in cardiac outpatient clinics. The existing state of affairs stems partly from systemic constraints, which pose a hindrance to the establishment of a network of lipid outpatient clinics – even though a total of 70 lipidologists have already been certified by the Polish Lipid Association (PoLA). This is precisely why the problem of familial hypercholesterolaemia (FH) in Poland was not recognized as significant for many years. Few physicians were able to consider low density lipoprotein cholesterol (LDL-C) concentrations in excess of 190 mg/dl (4.9 mmol/l) or total cholesterol (TC) concentrations of 290 mg/dl (7.5
mmol/l) and more as potentially caused by genetically conditioned disease and, taking the matter further, classify patients presenting with such disorders into high and very high cardiovascular risk groups. This is why the treatment of patients with the most severe lipid disorders with apheresis is practically non-existent in Poland, with only three treatment centres available to patients. In contrast, in neighbouring countries (Germany, Czech Republic), nationwide FH registries have been kept for many years. Germany, in addition, has the largest number of medical centres offering apheresis treatment in Europe. It was first noted about a dozen years ago in the estimation of long-term (20-year) risk or lifetime
risk that dyslipidaemias represented an independent risk factor for cardiovascular (CV) events. It thus follows that optimal effective treatment of lipid disorders is as important as the therapy of diabetes
or arterial hypertension. What is more, even if dyslipidaemia treatment is undertaken, further challenges must be faced such as failure to use/prescribe statins at doses corresponding to the level of CV risk (the situation may affect as much as 80% of all treated patients), discontinuation of therapy, lack of effective combination treatment aimed at reducing residual risk or failure to ensure appropriate management of undesirable treatment-related effects.

In view of the situation outlined above, the PoLA, the College of Family Physicians in Poland (CFPiP) and the Polish Cardiac Society (PCS) have
jointly identified a need to draft the first guidelines regulating the management of dyslipidaemias and addressed to family physicians, as they are usually the first to diagnose lipid disorders and they are largely responsible for the initial therapeutic decisions and for the continuation of lipid-lowering therapy (LLT).

The discovery of PCSK9 in 2003 and its identification as the third protagonist responsible for ADH opened many new avenues of research in the cardiovascular field. Liver PCSK9 binds the LDLR and promotes its degradation in the endosomal/lysosomal pathway. A higher activity of PCSK9 leads to lower liver LDLR levels, resulting in a reduction in LDL-uptake from circulation, and thus in hypercholesterolemia and associated atherosclerosis. Although PCSK9 mutations are rare, their associated phenotypes can be devastating. The most powerful PCSK9 gain-of-function mutation, D374Y, is responsible for LDL cholesterol (LDLc) levels of ~10 mmol/L versus ~3 mmol/L in normal subjects.
The aim of this manuscript is to review the available literature on the identification and pharmacological applications of potent inhibitors of PCSK9 function and/or activity, and to present the latest data on the ongoing clinical trials, mostly related to the use of monoclonal antibodies (mAb) that interfere with PCSK9 function on the LDLR, resulting in a significant drop in circulating LDLc.

The clinical data, so far, are very encouraging with Phase-2 trials from various pharmaceutical companies showing a drop of >60% in LDLc for at least 2 weeks after a single injection of a humanized PCSK9 mAb in the presence or absence of adjunct statin therapy. In view of the absence of overt toxicity associated with this treatment Phase-3 clinical trials have started with >20,000 individuals being tested and anticipated primary outcomes results should be forthcoming by 2016. Other approaches including the use of recombinant adnectins, antisense RNAi or small molecule inhibitors are also undergoing early pre-clinical testing or are already in Phase-1 clinical trials.

Very recent data revealed that absence of PCSK9 can be protective against melanoma invasion in mouse liver, and that this is due to lower circulating LDLc. This opens the door to novel applications of PCSK9 inhibitors/silencers in cancer/metastasis.