Inclisiran: present and future perspectives of a new effective LDL cholesterol-lowering agent

Abstract

Purpose of review To highlight critical aspects of inclisiran, from preclinical studies to current recommendations in clinical practice and future perspectives. Recent findings Inclisiran use has been recently approved by regulatory agencies. The evidence of its efficacy and safety makes it a promising therapeutical tool for treating dyslipidemias. Summary The link between LDL-cholesterol and atherosclerotic cardiovascular disease (ASCVD) is well established. Inclisiran, a small interfering RNA, has proven its safety and efficacy in reducing LDL-cholesterol, and FDA and EMA have recently approved its use. This review illustrates the development, structure, and mechanism of action of inclisiran and provides information regarding its efficacy, safety, and current recommendation in clinical practice. Moreover, it provides key information on the most recent/ongoing trials that will help us to implement the use of inclisiran in clinical practice.

Hepatocyte-Targeted siTAZ Therapy Lowers Liver Fibrosis in NASH Diet-Fed Chimeric Mice with Hepatocyte-Humanized Livers

“…Advances over the last decade in the area of hepatocyte-targeted siRNA therapy have led to the approval of four drugs for use in humans: patisiran, which targets TTR to treat familial amyloid polyneuropathy (8); givosiran, which targets ALAS1 to treat acute porphyria (9); lumasiran, which targets HAO1 to treat primary hyperoxaluria type 1 (10); and inclisiran, which targets PCSK9 to treat hypercholesterolemia (11). Moreover, several other hepatocyte-targeted siRNAs are in clinical trials for a variety of other diseases.…”

“…In this context, the last two decades have witnessed the development of therapies that can silence genes specifically in hepatocytes using siRNA conjugated with hepatocyte-specific targeting motifs, notably, N-acetylgalactosamine (GalNAc) (7). Most importantly, several hepatocyte-targeted siRNAs have been recently approved by the FDA for specific disease indications (8)(9)(10)(11).…”

Ups and downs in PCSK9 inhibition in the cardiovascular arena: a review

“…Subsequently, the large randomized, placebocontrolled trials, Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk (FOURIER) [3] and Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment with Alirocumab (ODYSSEY Outcomes) [4] showed significant reductions in the primary cardiovascular composite endpoints of 15% in patients with stable ASCVD and in patients post-ACS, respectively. More recently, inclisiran, a first-inclass small interfering RNA inhibitor (siRNA) of PCSK9 was approved for use in both Europe (December 2020) and the United States (December 2021) based upon its ability to lower LDL-C by approximately 50% with subcutaneous injections administered at days 0, 90, and every 180 days thereafter [12,13].…”