Therapeutic PCSK9 targeting: Inside versus outside the hepatocyte?

As a major regulator of LDL receptor (LDLR) activity and thus of LDL-cholesterol (LDL-C) levels, proprotein convertase subtilisin/kexin type 9 (PCSK9) represents an obvious therapeutic target for lipid lowering. The PCSK9 inhibitors, alirocumab and evolocumab, are human monoclonal antibodies (mAbs) that act outside the cell by complexing circulating PCSK9 and thus preventing its binding to the LDLR. In contrast, inclisiran, a small interfering RNA (siRNA), inhibits hepatic synthesis of PCSK9, thereby resulting in reduced amounts of the protein inside and outside the cell. Both approaches result in decreased plasma LDL-C concentrations and improved cardiovascular outcomes. Marginally superior LDL-C reduction (≈ 60 %) is achieved with mAbs as compared to the siRNA (≈ 50 %); head-to-head comparisons are required to confirm between-class differences in efficacy. Both drug classes have shown variability in LDL-C lowering response between individuals in waterfall analyses. Whereas mAb-mediated inhibition leads to a compensatory increase in plasma PCSK9 levels, siRNA treatment reduces them. These agents differ in their pharmacokinetic and pharmacodynamic features, which may translate into distinct clinical opportunities under acute (e.g. acute coronary syndromes) as compared to chronic conditions. Both drug classes provide additional reduction in LDL-C levels (up to 50 %) beyond those achieved with statin therapy, facilitating attainment of guideline-recommended LDL-C goals in high and very high-risk patients. Additional PCSK9 inhibitors, including an oral macrocyclic peptide, a small PCSK9 binding protein and a novel small molecule, plus hepatic gene editing of PCSK9, are under development. This review critically appraises pharmacological strategies to target PCSK9 either inside or outside the cell.