Inclisiran, sold under the brand name Leqvio, is a medication used for the treatment of high low-density lipoprotein (LDL) cholesterol and for the treatment of people with atherosclerotic cardiovascular disease (ASCVD), ASCVD risk-equivalents, and heterozygous familial hypercholesterolemia (HeFH). It is a small interfering RNA (siRNA) that acts as an inhibitor of a proprotein convertase, specifically, inhibiting translation of the protein PCSK9. Inclisiran was approved for use in the European Union in December 2020. In August 2021, it received NICE approval for use by the National Health Service in the UK. In December 2021, it was approved for medical use in the United States. The U.S. Food and Drug Administration considers it to be a first-in-class medication. In August 2023, the National Medical Products Administration approved the use of inclisiran in China.
Medical uses In the European Union, inclisiran is indicated in adults with primary hypercholesterolemia (heterozygous familial and non-familial) or mixed dyslipidaemia, as an adjunct to diet in combination with a statin or statin with other lipid-lowering therapies in people unable to reach LDL-C goals with the maximum tolerated dose of a statin, or alone or in combination with other lipid-lowering therapies in people who are statin-intolerant, or for whom a statin is contraindicated. In the United States, it is indicated as an adjunct to diet and maximally tolerated statin therapy for the treatment of adults with heterozygous familial hypercholesterolemia (HeFH) or clinical atherosclerotic cardiovascular disease (ASCVD), who require additional lowering of low- density lipoprotein cholesterol (LDL-C). The FDA approved an expansion of its indications to primary hypercholesterolemia patients in July 2023. In China, inclisiran is indicated in adults with primary hypercholesterolemia (heterozygous familial and non-familial) or mixed dyslipidaemia.
Mechanism of action
Inclisiran is a small interfering RNA that acts as an inhibitor of an enzyme that degrades LDL receptors and thereby increases LDL levels in the blood. Since Inclisiran inhibits the degradation of receptors, it results in an increased number of receptors, and therefore LDL is removed from the blood. More specifically, Inclisiran inhibits translation of the protein termed proprotein convertase subtilisin/kexin type 9 (PCSK9). Small interfering RNA molecules (siRNAs) are designed to intervene in the pathway of RNA interference (RNAi), a naturally operating mechanism, wherein they bind to a complex within the cell termed the RNA-induced silencing complex (RISC); after binding, the RISC structure in the siRNA-RISC complex is altered, allowing it to cleave specific messenger RNA molecules (mRNAs). The siRNA-RISC complex is catalytic, and thus can cleave multiple copies of the mRNA that it targets; cleaved mRNAs are not translated into proteins, and thus since less of the target protein is made, the resulting concentration of the protein targeted by the siRNA design is decreased. The proprotein convertase, PCSK9, is a liver-produced and secreted serine protease whose binding and action on LDL receptor protein result in their increased lysosomal degradation in hepatocytes. A consequence of this is an increase in the level of circulating LDL cholesterol in the bloodstream (and conversely, inhibition of which results in a decrease in this level). Studies of PCSK9 genetics supported the conclusion that decreases in circulating LDL cholesterol accomplished in this way would result in "diminished cardiovascular risk... with no apparent negative health consequences". Also, long term administration of antibodies with short in vivo half-lives, 1-2 times a month, reduced circulating PCSK9 and LDL cholesterol levels, with the result of a "lower incidence of cardiovascular events than placebo". Together, these results contributed to the validation of PCSK9-targeting siRNAs for development as a new therapeutic for use in LDL cholesterol–lowering therapy; specifically, small interfering RNA (siRNA) molecules of appropriate sequence and structure targeting mRNA encoding PCSK9 were sought and discovered as a means of decreasing PCSK9 levels, and the development of a clinical candidate ensued thereafter.
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