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

Abstract

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.

Proprotein Convertase Subtilisin/Kexin Type 9 Inhibition: The Big Step Forward in Lipid Control

“…27,28 Small Interfering RNA Inclisiran is a small interfering RNA (siRNA) therapy consisting of a synthetic nucleotide sense strand, as well as an antisense strand, which are conjugated to the N-acetylgalactosamine (GalNAc) ligand. [29][30][31][32] GalNAc binds to the asialoglycoprotein receptor, exclusively expressed on the sinusoidal surface of the liver. 29,30,32 Thus, conjugation of the nucleotide strands to GalNAc effectively targets inclisiran to the liver, minimising offtarget effects and lowering the dose that needs to be administered.…”

“…[29][30][31][32] GalNAc binds to the asialoglycoprotein receptor, exclusively expressed on the sinusoidal surface of the liver. 29,30,32 Thus, conjugation of the nucleotide strands to GalNAc effectively targets inclisiran to the liver, minimising offtarget effects and lowering the dose that needs to be administered. 32,33 Once inside the cell cytoplasm, the antisense strand is loaded into an RNA-induced silencing complex.…”

Emerging Therapies for the Treatment of Atherosclerotic Cardiovascular Disease: From Bench to Bedside

“…Inclisiran, a first-in-class small interfering RNA (siRNA) molecule that inhibits the hepatic synthesis of PCSK9 by RNA interference, first drew attention during the ORION-1 trial [56,57]. The primary benefit of such an approach is the fact that it offers a notably long duration of action and could thus be administered in 6-month periods, effectively solving the adherence problem, one of the main impediments in the clinical application of lipid-lowering therapy [58]. The aforementioned ORION-1 trial randomized 501 patients who suffer from ASCVD along with elevated LDL-C levels to receive either inclisiran or placebo.…”

Progress of potential drugs targeted in lipid metabolism research

“…Currently, there are three drugs marketed worldwide that target the PCSK9 target, of which two are marketed as evolocumab monoclonal antibody and alirocumab monoclonal antibody, which target the binding of PCSK9 to LDL-R (Rifai and Ballantyne, 2021). The other is Inclisiran, a long-acting therapeutic agent developed by Novartis to inhibit PCSK9 expression by means of RNA interference (RNAi) (Samuel et al, 2022). These three PCSK9 inhibitors have the advantages of high specificity and clear mechanism of action, providing a new therapeutic option for cholesterol lowering.…”