Inclisiran is a novel drug that inhibits PCSK9 synthesis specifically in the liver, harnessing the natural mechanism of RNAi. Phase I and II data show that inclisiran lowers low-density lipoprotein cholesterol levels on average by >50% with a duration of effect that enables twice-yearly dosing. Phases I, II and emerging Phase III data support inclisiran's safety, tolerability and risk-benefit profile. The ongoing ORION program includes Phase III trials that will provide robust evidence of inclisiran's safety and efficacy in individuals at high risk of atherosclerotic cardiovascular disease (ASCVD), including established ASCVD and familial hypercholesterolemia. In addition, the ORION-4 trial will assess the impact of inclisiran on cardiovascular outcomes in approximately 15,000 ASCVD subjects.