Inclisiran: A Novel Small Interfering RNA Drug for Low‐Density Lipoprotein Reduction

Inclisiran increases the number of low-density lipoprotein surface receptors expressed on hepatocytes using small interfering RNA directed against proprotein convertase subtilisin/kexin type 9 (PCSK9) mRNA. This novel mechanism can reduce low-density lipoprotein by ≈50%, like reductions achieved with high-intensity statins or PCSK9-inhibiting monoclonal antibodies. Inclisiran is indicated in the treatment of adults with heterozygous familial hypercholesterolemia or clinical atherosclerotic cardiovascular disease, unable to achieve target LDL concentrations with diet and maximally tolerated statin therapy. It is more expensive than PCSK9-inhibiting monoclonal antibodies and still lacks clinical evidence for the expected reduction in atherosclerotic cardiovascular disease events when added to statin therapy. Although some patients experience injection-site reactions of mild or moderate severity, current evidence suggests a strong safety profile with total and serious adverse events approximating that of placebo. The dosing protocol of inclisiran offers its biggest clinical advantage over PCSK9-inhibiting monoclonal antibodies, being administered only every 6 months after initial baseline and 3-month doses rather than every second or fourth week. Unlike PCSK9-inhibiting monoclonal antibodies, inclisiran has not as yet been noted to induce neutralizing antidrug antibodies that can impact drug efficacy. Thus, inclisirin is a novel small interfering RNA molecule that provides further options in the management of hypercholesterolemia refractory to statins alone. However, cost and evidence considerations suggest it should not supplant adjunctive therapy with the PCSK9-inhibiting monoclonal antibodies, despite having an efficacy, safety, tolerability, and drug interaction profile superior to other antihypercholesterolemic options such as lomitapide, niacin, bile acid sequestrants, and bempedoic acid.