Inclisiran: A First-in-Class siRNA Therapy for Lowering Low-Density Lipoprotein Cholesterol

• Published in: Annals of Pharmacotherapy 2023-03, Vol.57 (3), p.317-324
• Main Authors: Samuel, Essie, Watford, Maya, Egolum, Ugochukwu O., Ombengi, David N., Ling, Hua, Cates, Drew W.
• Format: Article
• Language: English
• Subjects: Anticholesteremic Agents - therapeutic use; Atherosclerosis - drug therapy; Cholesterol, LDL; Humans; PCSK9 Inhibitors; Proprotein Convertase 9 - genetics; Proprotein Convertase 9 - metabolism; RNA, Small Interfering - adverse effects
• ISSN: 1060-0280; 1542-6270
• DOI: 10.1177/10600280221105169

Objective: To review the current pharmacology, pharmacokinetics/pharmacodynamics, safety, and efficacy of inclisiran in lowering lipid levels. Data Sources: A PubMed (from December 1, 2014 to April 15, 2022) and ClinicalTrials.gov search was conducted using ALN-PCSsc, ALN-60212, PCSK9si KJX-839, and inclisiran. Additional articles were identified by hand from references. Study Selection and Data Extraction: We included English-language articles evaluating inclisiran pharmacology, efficacy, or safety in humans for lowering low-density lipoprotein cholesterol (LDL-C). Data Synthesis: Inclisiran is a novel small interfering RNA-based therapy administered as a twice-yearly subcutaneous injection. By binding to the messenger RNA (mRNA) precursor of proprotein convertase subtilisin/kexin type 9 (PCSK9), inclisiran inhibits expression of the PCSK9 gene, resulting in increased recycling and expression of LDL receptors and decreased levels of LDL-C. Like PCSK9 inhibitors, inclisiran was associated with a comparable extent of LDL-C reduction in several phase II/III trials. Compared with placebo, inclisiran was found to have similar adverse events except for injection-site reaction. Relevance to Patient Care and Clinical Practice: Currently, inclisiran lacks data on clinical outcome improvement or long-term safety. However, it may play a role in patients with atherosclerotic cardiovascular disease (ASCVD) or ASCVD risk equivalent if optimal LDL-C cannot be achieved by statins and PCSK9 inhibitors cannot be tolerated. The drug may be used for heterozygous familial hypercholesterolemia. Conclusion: Inclisiran is an effective and safe medication for lowering LDL-C levels. Additional data regarding efficacy on cardiovascular outcomes and long-term safety profile with inclisiran are needed.