PCSK9 Inhibition: Learning from Nature

PCSK9 inhibition is a very good example how clinical pharmacology can learn from nature. PCSK9 is an enzyme that promotes metabolization of the LDL receptor, therefore reduces LDL receptors at cell surfaces and internalization of LDL from plasma and ultimately leads to hypercholesterolaemia. Only very few years ago, it was detected that loss-of-function and gain-of-function mutations exist for PCSK9. Gain-of function leads to hypercholesterolaemia due to elevated LDL particles, whereas loss-of-function leads to low LDL levels. Mendelian randomization studies showed that gain-of-function mutations are highly associated with cardiovascular disease. Therefore drugs were developed to lower PCSK9 in plasma. The most important ones at the moment are monoclonal fully human antibodies, evolocumab and alirocumab have been approved for the treatment of hypercholesterolaemia. In March 2017 the FOURIER-study showed a positive outcome for patients treated with evolocumab in addition to statins. Other approaches like antisense oligonucleotides to lower PCSK9 production are tested now. In conclusion PCSK9 is a natural modulator of LDL receptors and therefore of LDL plasma levels. Pharmacological inhibition of the molecule is useful in clinical practice.