463 New era in hypercholesterolemia treatment, inclisiran: early and sustained LDL-C reduction with a twice per year administration

Inclisiran is a synthetic small-interfering RNA (siRNA) that works with the RNA interference (RNAi) mechanism. SiRNA binds its target mRNA, leading to silencing the protein synthesis by the related mRNA degradation. Inclisiran is designed to bind solely PCSK9 mRNA, decreasing PCSK9 expression, thus leading to lower LDL-C level. Several chemical modifications were added to obtain a stable compound delivering a rapid effect and generally well tolerated [Khvorova A. Oligonucleotide therapeutics—a new class of cholesterol-lowering drugs. N Engl J Med 2017; 376 4–7]. High cholesterol levels and prolonged time of exposure enhance risk of new or recurrent CV events, therefore also timing became crucial for atherosclerotic cardiovascular disease (ASCVD) patients [Ference BA, Graham I, Tokgozoglu L, et al. Impact of lipids on cardiovascular health: JACC health promotion series. J Am Coll Cardiol 2018; 72 1141–1156]. Therefore, an early and effective LDL-C lowering effect is positively correlated with CV risk reduction, together with the life-long LDL-C reduction that will impact definitively on the global CV risk [Cohen JC, Boerwinkle E, Mosley TH Jr, et al. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N Engl J Med 2006; 354 1264–1272]. The siRNA conjugation with a triantennary GalNAC leads to a specific targeted hepatic delivery therefore, the 284 mg inclisiran dose is undetectable in blood stream after 24–48 h from the subcutaneous injection [Wright RS, Collins MG, StoekenbroekRM, et al. Effects of renal impairment on the pharmacokinetics, efficacy, and safety of inclisiran: an analysis of the ORION-7 and ORION-1 studies. Mayo Clin Proc 2020; 95 77–89]. The LDL-C lowering effect starts early upon the hepatic cell entry (24–48 h) and the LDL-C level drop is already significant at 14 days post injection, and by Day 30 the mean reduction is about 50%, as shown in the ORION-1 phase II trial [Ray KK, Landmesser U, Leiter LA, et al. Inclisiran in patients at high cardiovascular risk with elevated LDL cholesterol. N Engl J Med 2017; 376 1430–1440]. Other chemical modifications at the siRNA back-bone level, protect inclisiran from degradation by liver nucleases, which may occur upon the hepatic cell uptake. In the cytoplasm, RNAi mechanism occurs by the siRNA—RISC protein complex coupling. Physiologically, this bond last for long and the inclisiran back-bone modifications further enhance the complex stability [Khvorova A. Oligonucleotide therapeutics—a new class of cholesterol-lowering drugs. N Engl J Med 2017; 376 4–7]. Moreover, one siRNA-RISC complex has an effect on multiple PCSK9 mRNA units, allowing inclisiran administration twice per year (after initial dose at baseline and 3 months), granting an early, sustained and effective LDL-C level reduction that lasts for 6 months. A pooled analysis of the 3 phase III trials (ORION-9/10/11) shows a time averaged (18 months) LDL-C reduction of 50.5% on top of therapy with statins±ezetimibe [Wright RS, Ray KK, Raal FJ, et al. Pooled patient-level analysis of inclisiran trials in patients with familial hypercholesterolemia or atherosclerosis. J Am Coll Cardiol 2021; 77 1182–1193]. Inclisiran provides effective evidence-based results on lowering LDL-C levels in different high CV risk populations (HeFH/established ASCVD/ASCVD-risk equivalent), which is demonstrated to be crucial for the reduction of patients’ CV risk. Furthermore, the twice per year administrations may positively improve adherence, thereby simplifying patient management and control during follow-up. Based on these findings, we are stepping into a new era of biologic therapeutics, where inclisiran represents the new, effective and safe therapeutic candidate for lowering LDL-C levels.