Translational Population‐Pharmacodynamic Modeling of a Novel Long‐Acting siRNA Therapy, Inclisiran, for the Treatment of Hypercholesterolemia

Inclisiran is a novel N‐acetylgalactosamine (GalNAc) conjugated small‐interfering ribonucleic acid (siRNA) therapy designed to specifically target proprotein convertase subtilisin/kexin type 9 (PCSK9) mRNA in the liver for the treatment of hypercholesterolemia. Inclisiran's GalNAc attachment results in a rapid uptake into the liver, and thus a short plasma half‐life, but long duration of effects on PCSK9 inhibition and low‐density lipoprotein cholesterol (LDL‐C) lowering. The effects on PCSK9 inhibition and consequent LDL‐C reduction are sustained for more than 6 months following a single subcutaneous (s.c.) dose, despite inclisiran being detectable in the plasma only for up to 48 hours. A kinetic‐pharmacodynamic (K‐PD) model was developed to characterize inclisiran's dose‐related LDL‐C lowering effects and to evaluate the impact of intrinsic and extrinsic factors on LDL‐C lowering. To accommodate the long duration of action, the K‐PD model incorporated an effect compartment which represents the liver. Inclisiran concentration in the liver leads to decreased production of the PCSK9 protein and allow recycling of more LDL‐C receptors on the hepatocyte cell surface, which results in a reduction of circulating LDL‐C. The analysis of covariates identified PCSK9 and LDL‐C baseline levels as important factors for the effects of LDL‐C lowering. Observations and modeling and simulation results demonstrated that PCSK9 and LDL‐C reductions are achieved rapidly after dosing and sustained when patients are treated with a 300 mg s.c. dose once every 6 months.