New lipid-lowering drugs-targeting PCSK9

Cardiovascular disease (CVD) is one of the leading causes of death in the world. The prevalence of CVD in China is increasing year by year. Strengthening blood lipid management is conducive to controlling cardiovascular risk factors, and is of great significance in reducing the incidence rate, mortality rate and disability rate of cardiovascular diseases.

The preprotein invertase subtilisin / kexin9 (PCSK9) is a receptor involved in the regulation of liver low density lipoprotein (LDLR) a secretory protein in the life cycle. PCSK9 can bind to the extracellular domain of LDLR and enhance the degradation of LDLR in lysosomes, resulting in an increase in the level of circulating LDL-C. PCSK9 inhibitors can interfere with the binding of PCSK9 to LDLR, reduce the degradation of LDLR and reduce the level of plasma LDL-C.

In recent years, the progress of human gene research and biotechnology has promoted the rapid development of PCSK9 targeted therapy. In this paper, the existing PCSK9 inhibitors are summarized, and the future research direction in this field is prospected.

Monoclonal antibody or mimic antibody protein drug

The earliest developed PCSK9 inhibitors were two fully humanized monoclonal antibodies (mAbs), namely alirocumab and eloyumab Evolocumab can block the interaction between circulating PCSK9 protein and LDLR. These two drugs have been approved for clinical use. Large clinical trials have shown that both drugs can reduce the plasma LDL-C level by about 60% in patients who have received the maximum tolerated dose of statins and significantly reduce the incidence of cardiovascular events.

Bococizumab is a humanized monoclonal antibody targeting PCSK9, which can significantly reduce the level of LDL-C and the incidence of cardiovascular events in patients at high risk of cardiovascular events. However, since a considerable number of patients will produce high titers of anti drug antibodies, the effect of bococizumab on reducing LDL-C levels may weaken over time. This finding confirmed that fully humanized monoclonal antibodies were superior to humanized monoclonal antibodies in the treatment of chronic diseases.

Lerodalcibep is a recombinant fusion protein containing PCSK9 binding domain and human serum albumin. It is currently in phase III clinical trial and shows good curative effect. In addition, a series of novel cyclic peptide oral small molecule inhibitors screened based on RNA can also inhibit the interaction between PCSK9 protein and LDLR.

CRISPR single base editing technology is a lipid-lowering therapy in the stage of animal experiment. Studies have shown that in non-human primates, a single infusion of lipid nanoparticles surrounded by PCSK9 messenger RNA can effectively reduce the levels of PCSK9 protein and LDL-C, with only a low level of off target editing.

More alternative therapies (such as zinc finger nuclease and crispr-cas9 nuclease) are under research, and the off target editing level and long-term safety need to be further evaluated. 

The emergence of PCSK9 inhibitors makes clinicians have a new understanding of lipid-lowering therapy. First, it is important for patients to maintain a low level of LDL-C throughout their life, and it is necessary to start lipid-lowering treatment as soon as possible. Second, the benefit of patients is directly related to the absolute reduction of plasma LDL-C level. Patients with higher cardiovascular risk and LDL-C level will benefit more from lipid-lowering treatment. Third, the degree of LDL-C reduction is more important than the mechanism of LDL-C reduction. Fourth, the relationship between LDL-C level and cardiovascular risk is fixed. The more significant the decrease of LDL-C, the lower the incidence of cardiovascular events. Fifthly, all studies on PCSK9 inhibitors recruited patients treated with the maximum tolerated dose of statins, indicating that PCSK9 inhibitors are effective adjuvant therapy in the secondary prevention of cardiovascular diseases, but the effect of PCSK9 inhibitors as primary prevention or monotherapy needs to be further verified by clinical studies. Sixthly, so far, it has not been found that the risk of adverse events (except injection site reactions) of PCSK9 inhibitors (such as monoclonal antibodies and inclisiran) is greater than that of placebo.

The rapid development of PCSK9 inhibitors brings new hope for lipid-lowering therapy. Using the method of human genetics, researchers identified the loss of function mutation and developed the "loss of function" therapy combined with modern biotechnology, which made the progress of PCSK9 targeted drugs reach an unprecedented level. In other promising target areas, including lipoprotein a, lipoprotein C3 and angiopoietin like protein 3 (ANGPTL3), these research methods have also been rapidly put into use.

 

Cindy