Inclisiran as a siRNA Inhibitor of Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9); Past, Present, and Future.

Reducing low-density lipoprotein cholesterol (LDL-C) levels has been shown to reduce the risk of developing atherosclerotic cardiovascular disease (ASCVD). Statins are the foundation of LDL-C lowering therapy with other non-statin agents used in circumstances where goal LDL-C levels are not reached or owing to intolerance to adverse effects of statins. In 2003, the discovery of the role of the proprotein convertase subtilisin/kexin type 9 (PCSK9) system in promoting elevated LDL-C levels led to new avenues of drug development to achieve target LDL-C. In 2021, inclisiran, a small interfering ribonucleic acid (siRNA) molecule targeting PCSK9 was approved by the Food and Drug Administration (FDA). Inclisiran has demonstrated effective reductions of LDL-C, such as in the large phase-3 ORION-9, ORION-10, and ORION-11 trials in which it achieved LDL-C reductions of 39.7%, 52.3%, and 49.9%, respectively. This review discusses the current clinical evidence and ongoing clinical studies of inclisiran as well as analyzes other areas of PCSK9 inhibition development.
Competing Interests: Declarations. Funding: No funding was used in the preparation of this manuscript. Conflicts of Interest: T.M., B.H.R., K.G., S.S.P., D.A., A.M., M.A.R., S.S.V., V.N., A.M.K.M., and S.K.G.K. declare that they have no potential conflicts of interest that might be relevant to the contents of this manuscript. Author Contributions: T.M. carried out study conceptualization, data curation, investigation, methodology, project administration, supervision, visualization, writing, and reviewing and editing; B.H.R. K.G., S.S.P., D.A., A.M., M.A.R., S.S.V., V.N., and A.M.M.K. carried out reviewing and editing; S.K.G.K. carried out reviewing and editing, visualization, supervision, and conceptualization. Data Availability Statement: Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study. Ethics Approval: Not applicable. Code Availability: Not applicable. Consent to Participate: Not applicable. Consent for Publication: Not applicable.
(© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)