Low-density Lipoprotein-Cholesterol Lowering Strategies for Prevention of Atherosclerotic Cardiovascular Disease: Focus on siRNA Treatment Targeting PCSK9 (Inclisiran)

Abstract

Abstract Purpose of Review The aim of low-density lipoprotein-cholesterol (LDL-C) lowering therapies is to safely achieve a consistent and long-term reduction in exposure of the vasculature to atherogenic lipoproteins in order to reduce the risk of atherosclerotic cardiovascular (CV) disease and the associated CV events, such as myocardial infarctions and ischemic strokes. This review summarizes the concept and clinical development of a novel molecular approach to efficiently lower LDL-C, a synthetic small interfering ribonucleic acid (siRNA)—inclisiran—directed against proprotein convertase subtilisin-kexin type 9 (PCSK9). Recent Findings The understanding of genes regulating atherogenic lipoproteins and their causal role in the development of atherosclerotic CV disease has substantially advanced over the past years. This has opened the possibility for development of molecular therapies targeting these atherogenic lipoproteins, in particular by RNA-targeted treatment approaches. The most advanced clinical development program is the siRNA-treatment targeting PCSK9 (inclisiran), involving more than 4000 patients in clinical studies. Phase 1 and 2 studies have identified the dose of 300 mg inclisiran for efficient LDL-C lowering. Most recently, three phase 3 studies demonstrated that a regimen of inclisiran every 6 months was feasible and reduced LDL-C by approximately 50% in patients at high or very high CV risk or with familial hypercholesterolemia. Adverse events were similar in the inclisiran and the placebo groups, except for more frequent transient injection site reactions with inclisiran than with placebo. Summary siRNA therapy targeting PCSK9 (inclisiran) applied twice a year efficiently reduced LDL-C by approximately 50% and was safe in recent phase 3 studies. The effects of this treatment on CV outcome are currently further assessed in a large ongoing CV outcome trial.