Advantages and Disadvantages of Inclisiran: A Small Interfering Ribonucleic Acid Molecule Targeting PCSK9—A Narrative Review

Abstract

As dyslipidemias remain one of the main risk factors for developing cardiovascular disease, the question of maintaining optimal lipid levels with pharmacotherapy remains a subject of interest worldwide. In contrast to conventional pharmacotherapy, human monoclonal antibodies directed against proprotein convertase subtilisin/kexin type 9 (PSCK9) and small interfering RNA- (siRNA-) based drug targeting PCSK9 represent a new strategy for managing lipid disorders and reducing cardiovascular risk. Inclisiran is a long-acting, synthetic siRNA that targets hepatic production of PCSK9 and consequently causes a reduction in LDL-C concentrations by approximately 50% compared to placebo. The structural modification of inclisiran has led to better stability and prolonged biological activity of the drug. The main advantage over conventional pharmacotherapy and anti-PCSK9 monoclonal antibodies is its favorable administration regimen (0–90–180 days), which should lead to much better compliance. Clinical trials conducted so far have confirmed the tolerability and efficacy of inclisiran in long-term PCSK9 and LDL-C level reductions. Moreover, a short-term follow-up on the safety of inclisiran showed a relatively good safety profile of the drug. However, it is still of great importance for ongoing and forthcoming clinical trials to be continued on a larger group of patients in order to assess long-term tolerability, efficacy, and safety of inclisiran.

New Therapeutic Approaches in Treatment of Dyslipidaemia—A Narrative Review

“…Inclisiran, an siRNA, interferes with the translation of PCSK9 by cleaving messenger RNA, thereby decreasing PCSK9 production. The absence of PCSK9 results in the upregulation of LDL receptors and, consequently, lowers the circulating level of LDL cholesterol [ 19 , 42 ]. The biggest advantage of inclisiran is its administration scheme.…”

“…Inclisiran is administered subcutaneously on days 1, day 90, day 180, and afterwards once every six months. The usual dosage is 284 mg in a single administration [ 19 ]. Efficacy of inclisiran was observed in ORION trials.…”

“…These trials showed that LDL cholesterol levels were reduced by approximately 50% compared to placebo groups [ 31 ]. Although these results indicate slightly lower efficacy than that of monoclonal PCSK9 inhibitors, patient compliance with inclisiran therapy is believed to be better because of the infrequent administration scheme [ 19 ]. In addition, the ORION studies provided information about the safety profile of inclisiran.…”

“…Since then, new lipid-lowering therapeutics have been evaluated. Among the newly developed drugs is inclisiran, a small interfering RNA targeting hepatic PCSK9 synthesis led to increased LDL receptor recycling and potent LDL cholesterol reduction by 51% when used together with other lipid-lowering agents [ 18 , 19 ]. Another potentially promising molecule is evinacumab, a monoclonal antibody that inhibits ANGPTL3, causing LDL cholesterol reduction regardless of LDL receptor function [ 20 ].…”

Antisense Oligonucleotides and Small Interfering RNA for the Treatment of Dyslipidemias

“…Inclisiran, a siRNA directed against PCSK9, is giving very promising results [97]. Preliminary data have described the advantages of using inclisiran, but longer follow-ups are necessary to assess its long-term tolerability, efficacy, and safety [98]. Unlike antibodies that bind the extracellular protein, subtracting it from the interaction with the LDL receptor, inclisiran penetrates hepatocytes blocking PCSK9 mRNA translation; in this way, a single molecule of siRNA is sufficient to reduce the production of several PCSK9 proteins.…”