Effect of anti-PCSK9 drugs on the association of PCSK9 to LDL

Abstract

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a protein that is known to interact with the LDL receptor, thereby promoting its degradation and blunting the uptake of LDL from the circulation. In this context, anti-PCSK9 monoclonal antibodies (mAbs) and siRNAs have been approved for the treatment of hypercholesterolaemia. Previous studies have shown that a significant proportion of circulating PCSK9 is associated with LDL. The aim of our research is to investigate the effect of mAbs and siRNA on the association of PCSK9 protein with LDL. In this study, 10 statin-intolerant patients received treatment with anti-PCSK9 mAbs or siRNA, in addition to therapy with a low-dose statin and ezetimibe. Their plasma samples were analysed before and after 1, 3, and 6/9 months of treatment. The results showed that both the monoclonal antibodies and inclisiran reduced LDL-C levels by 50% to 60%. LDL-C levels decreased from 92±28 mg/dL to 44±26 mg/dL after siRNA treatment and reached 97±9, 27±10, 32±14, and 23±10 mg/dL after mAbs therapy. The circulating PCSK9 level decreased by 70% after the first siRNA injection, while it increased 10-fold after mAbs therapy. Regardless of treatment, the percentage of PCSK9 bound to LDL did not vary from baseline and remained constant during the treatment period. Whether this is of physiological relevance remains to be addressed.