Inclisiran, sold under the brand name Leqvio, is a
medication
A medication (also called medicament, medicine, pharmaceutical drug, medicinal drug or simply drug) is a drug used to diagnose, cure, treat, or prevent disease. Drug therapy (pharmacotherapy) is an important part of the medical field and re ...
for the treatment of people with
atherosclerotic cardiovascular disease
Coronary artery disease (CAD), also called coronary heart disease (CHD), ischemic heart disease (IHD), myocardial ischemia, or simply heart disease, involves the reduction of blood flow to the heart muscle due to build-up of atherosclerotic pla ...
(ASCVD), ASCVD risk-equivalents, and
heterozygous
Zygosity (the noun, zygote, is from the Greek "yoked," from "yoke") () is the degree to which both copies of a chromosome or gene have the same genetic sequence. In other words, it is the degree of similarity of the alleles in an organism.
Mo ...
familial hypercholesterolemia
Familial hypercholesterolemia (FH) is a genetic disorder characterized by high cholesterol levels, specifically very high levels of low-density lipoprotein (LDL cholesterol), in the blood and early cardiovascular disease. The most common mutatio ...
(HeFH).
It is a
small interfering RNA
Small interfering RNA (siRNA), sometimes known as short interfering RNA or silencing RNA, is a class of double-stranded RNA at first non-coding RNA molecules, typically 20-24 (normally 21) base pairs in length, similar to miRNA, and operating wi ...
(siRNA) that acts as an
inhibitor of a proprotein convertase, specifically, inhibiting
translation
Translation is the communication of the Meaning (linguistic), meaning of a #Source and target languages, source-language text by means of an Dynamic and formal equivalence, equivalent #Source and target languages, target-language text. The ...
of the protein
PCSK9
Proprotein convertase subtilisin/kexin type 9 (PCSK9) is an enzyme encoded by the ''PCSK9'' gene in humans on chromosome 1. It is the 9th member of the proprotein convertase family of proteins that activate other proteins. Similar genes (ortholog ...
.
Inclisiran was approved for use in the European Union in December 2020.
[ Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.] In August 2021, it received
NICE
Nice ( , ; Niçard: , classical norm, or , nonstandard, ; it, Nizza ; lij, Nissa; grc, Νίκαια; la, Nicaea) is the prefecture of the Alpes-Maritimes department in France. The Nice agglomeration extends far beyond the administrative c ...
approval for use by the
National Health Service
The National Health Service (NHS) is the umbrella term for the publicly funded healthcare systems of the United Kingdom (UK). Since 1948, they have been funded out of general taxation. There are three systems which are referred to using the " ...
in the UK. In December 2021, it was approved for medical use in the United States.
[ ]
Medical uses
In the European Union, inclisiran is
indicated
In medicine, an indication is a valid reason to use a certain test, medication, procedure, or surgery. There can be multiple indications to use a procedure or medication. An indication can commonly be confused with the term diagnosis. A diagnosis ...
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).
Discovery and mechanism of action
Inclisiran is a
small interfering RNA
Small interfering RNA (siRNA), sometimes known as short interfering RNA or silencing RNA, is a class of double-stranded RNA at first non-coding RNA molecules, typically 20-24 (normally 21) base pairs in length, similar to miRNA, and operating wi ...
that acts as an
inhibitor of a proprotein convertase, specifically, inhibiting
translation
Translation is the communication of the Meaning (linguistic), meaning of a #Source and target languages, source-language text by means of an Dynamic and formal equivalence, equivalent #Source and target languages, target-language text. The ...
of the protein termed proprotein convertase subtilisin/kexin type 9 (
PCSK9
Proprotein convertase subtilisin/kexin type 9 (PCSK9) is an enzyme encoded by the ''PCSK9'' gene in humans on chromosome 1. It is the 9th member of the proprotein convertase family of proteins that activate other proteins. Similar genes (ortholog ...
).
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
Catalysis () is the process of increasing the rate of a chemical reaction by adding a substance known as a catalyst (). Catalysts are not consumed in the reaction and remain unchanged after it. If the reaction is rapid and the catalyst recyc ...
, and thus can cleave multiple copies of the mRNA that it targets; cleaved mRNAs are not
translated into proteins, and thus the 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 receptors results in their increased lysosomal degradation in hepatocytes, a consequence of which is an increase in the level of circulating LDL cholesterol (and inhibition of which, the 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", and 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 were sought and discovered as a means of decreasing PCSK9 levels, and the development of a clinical candidate ensued thereafter.
Clinical study history
In 2019, The Medicines Company announced positive results from pivotal phase III study (all primary and secondary endpoints were met with efficacy consistent with Phase I and II studies). The company anticipated regulatory submissions in the U.S. in the fourth quarter of 2019, and in Europe in the first quarter of 2020. Inclisiran is being developed by The Medicines Company, a subsidiary of
Novartis
Novartis AG is a Swiss-American multinational pharmaceutical corporation based in Basel, Switzerland and
Cambridge, Massachusetts, United States (global research).name="novartis.com">https://www.novartis.com/research-development/research-loc ...
, which licensed the rights to inclisiran from
Alnylam Pharmaceuticals
Alnylam Pharmaceuticals, Inc. is an American biopharmaceutical company focused on the discovery, development and commercialization of RNA interference (RNAi) therapeutics for genetically defined diseases. The company was founded in 2002 and is he ...
.
The effectiveness of inclisiran was studied in three randomized, double-blind, placebo-controlled trials that enrolled 3,457 adults with HeFH or clinical ASCVD.
Enrolled participants were taking maximally tolerated statin therapy but required additional LDL-C lowering based on their risk for cardiovascular events.
In all three studies, the main effectiveness outcome measure was the percent change in LDL-C from the beginning of the trial to day 510 (month 17).
In each trial, participants received under-the-skin injections of either 284 mg inclisiran or a placebo on four separate days: day 1, day 90 (month 3), day 270 (month 9), and day 450 (month 15).
Study 1 enrolled 1,561 adults with ASCVD.
At day 510, the inclisiran group had an average LDL-C decrease of 51% whereas the placebo group had an average LDL-C increase of 1%.
Study 2 enrolled 1,414 adults with ASCVD.
At day 510, the inclisiran group had an average LDL-C decrease of 46% whereas the placebo group had an average LDL-C increase of 4%.
Study 3 enrolled 482 adults with HeFH.
At day 510, the inclisiran group had an average LDL-C decrease of 40% whereas the placebo group had an average LDL-C increase of 8%.
The effect of inclisiran on cardiovascular morbidity (suffering from a disease) and mortality (death) has not been determined.
References
Further reading
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External links
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PCSK9 inhibitors
RNA interference
Novartis brands
Orphan drugs
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