Inclisiran: A Review in Hypercholesterolemia

Abstract

Inclisiran (Leqvio^®) is a first-in-class, subcutaneously administered, small interfering RNA (siRNA) that prevents hepatic synthesis of proprotein convertase subtilisin/kexin type 9 (PCSK9), thereby decreasing circulating low-density lipoprotein cholesterol (LDL-C). In the EU, inclisiran is indicated in adults with primary hypercholesterolemia or mixed dyslipidemia, as an adjunct to diet. It is intended for use in patients unable to reach LDL-C goals on maximally tolerated statin therapy, with or without other lipid-lowering therapies (LLTs). In patients who are statin intolerant or for whom a statin is contraindicated, it can be used with or without other LLTs. In clinical trials, twice-yearly injections of inclisiran (after initial doses at days 1 and 90) approximately halved LDL-C levels in patients with, or at high risk of developing, atherosclerotic cardiovascular disease (ASCVD) who had hypercholesterolemia, irrespective of whether or not their existing treatment included a statin. The safety and tolerability profile of the drug was similar to placebo, although mild to moderate, transient injection-site adverse reactions were more frequent with inclisiran. Pending confirmation of the expected reduction in cardiovascular (CV) events with inclisiran, it is a valuable additional/alternative antihyperlipidemic agent to a statin, as its infrequent maintenance dosing regimen confers a convenience advantage over other non-statin LLTs.

Plain Language Summary

Atherosclerotic cardiovascular disease (ASCVD) is a leading cause of death and disability. ‘Statins’ are the drugs of choice for reducing elevated levels of low-density lipoprotein cholesterol (LDL-C) in patients with, or at risk of developing, ASCVD. However, due to multiple factors, including adverse events and/or poor adherence, many patients don’t achieve their guideline target LDL-C level on conventional (statin-based) therapy and novel, non-statin lipid-lowering therapies (LLTs) are needed. Inclisiran (Leqvio^®) is a small interfering RNA (siRNA) drug that works as an LLT by stopping the liver from making an enzyme [proprotein convertase subtilisin/kexin type 9 (PCSK9)] that otherwise reduces its ability to remove LDL-C from the blood. Subcutaneously injecting inclisiran every 6 months (after initial doses at days 1 and 90) was generally well tolerated and approximately halved LDL-C levels in patients with, or at high risk of developing, ASCVD who had hypercholesterolemia, regardless of whether or not their conventional therapy included a statin. Inclisiran is a potentially valuable additional/alternative antihyperlipidemic agent to a statin because of its infrequent, and therefore more convenient, dosing schedule versus other non-statin LLTs, including anti-PCSK9 monoclonal antibodies.