Inclisiran

Identification

Summary

Inclisiran is a PCSK9-targeting short interfering RNA (siRNA) that lowers plasma LDL-cholesterol levels.

Brand Names

Leqvio

Generic Name

Inclisiran

DrugBank Accession Number

DB14901

Background

Inclisiran is a long-acting, synthetic small interfering RNA (siRNA) directed against proprotein convertase subtilisin-kexin type 9 (PCSK9), which is a serine protease that regulates plasma low-density lipoprotein cholesterol (LDL-C) levels. By binding to PCSK9 messenger RNA, inclisiran prevents protein translation of PCSK9, leading to decreased concentrations of PCSK9 and plasma concentrations of LDL cholesterol.^1,2 Lowering circulating plasma LDL-C levels offers an additional benefit of reducing the risk of cardiovascular disease (CVD) and improving cardiovascular outcomes, as hypercholesterolemia is a major known risk factor for CVD.^1,2

On December 11, 2020, the European Commission (EC) granted authorization for marketing inclisiran as the first and only approved siRNA for the treatment of adults with primary hypercholesterolemia (heterozygous familial and non-familial) or mixed dyslipidemia, alone or in combination with other lipid-lowering therapies.⁸ Inclisiran was later approved by the FDA on December 22, 2021, for the treatment of heterozygous familial hypercholesterolemia (HeFH) or clinical atherosclerotic cardiovascular disease in adults.¹⁰ It is marketed under the trade name Leqvio.

Type

Biotech

Groups

Approved, Investigational

Biologic Classification

Gene Therapies
Other gene therapies

Synonyms

ALN-PCSsc
Inclisiran

External IDs

ALN-60212
ALN-PCSsc

Pharmacology

Indication

In Europe, inclisiran is indicated for the treatment of primary hypercholesterolemia (heterozygous familial and non-familial) or mixed dyslipidemia in adults, as an adjunct to diet. It can be used in combination with a statin or statin with other lipid-lowering therapies in patients who cannot reach LDL-C goals with the maximum tolerated dose of a statin. In patients who cannot tolerate statins or in whom a statin is contraindicated, inclisiran can be used as monotherapy or in combination with other lipid-lowering therapies.⁹

In the US, inclisiran 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 lowdensity lipoprotein cholesterol (LDL-C).¹¹

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Associated Conditions

Contraindications & Blackbox Warnings

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Pharmacodynamics

Inclisiran is a long-acting small interfering RNA (siRNA) that works to lower plasma LDL-cholesterol (LDL-C) levels. In clinical trials, the reduction of LDL-C levels was observed within 14 days post-dose: mean reductions of LDL-C by 48-51% were observed 30 to 60 days post-dose and reduction of LDL-C levels by 53% persisted after 180 days post-dose.⁹ In healthy volunteers, inclisiran reduced PCSK9 levels by 70-80% and LDL-C levels by 27-60%.¹ In a clinical trial consisting of subjects with atherosclerotic cardiovascular disease with or without diabetes, inclisiran reduced LDL-C levels by 28-52%.⁶

The long-term effect of inclisiran on cardiovascular outcomes has not yet been elucidated,³ although reductions in the levels of LDL-C have been associated with a reduction of cardiovascular risk.¹

Mechanism of action

Low-density lipoprotein (LDL) receptors expressed on hepatocytes are responsible for the removal of circulating LDL-C from plasma via receptor-mediated endocytosis.⁴ Proprotein convertase subtilisin-kexin type 9 (PCSK9) is a serine protease that is mainly produced by hepatocytes. It binds to LDL receptors and targets them for lysosomal degradation, thereby reducing the levels of LDL receptors, attenuating the recycling of LDL receptors, and elevating the levels of circulating plasma LDL-C.¹

Inclisiran is conjugated to triantennary N-acetylgalactosamine carbohydrates, which can bind to asialoglycoprotein receptors expressed in the liver. Binding to asialoglycoprotein receptors facilitates the uptake of inclisiran into the hepatocytes. Once inside the hepatocyte, inclisiran binds to the RNA-induced silencing complex (RISC), which is a ribonucleoprotein complex that serves as a template for recognizing the target complementary mRNA, activate RNAse, and cleave the target mRNA.⁵ Inclisiran incorporated into the RISC allows the drug to cleave PCSK9 mRNA and prevent PCSK9 translation, thus decreasing hepatic production of PCSK9.¹ Less PCSK9 protein available allows more LDL receptors to be recycled to the hepatic membrane for circulating LDL-C uptake.⁷

Target	Actions	Organism
AProprotein convertase subtilisin/kexin type 9	antisense oligonucleotide	Humans

Absorption

After uptake into the liver, inclisiran has a long duration of action. Following subcutaneous administration of a single dose ranging from 24 mg to 756 mg, systemic exposure to inclisiran increased in a dose-proportional manner. The mean C_max was 509 ng/mL and the T_max was approximately 4 hours after the administration of 284 mg inclisiran. The mean AUC_0-inf was 7980 ng x h/mL. After 48 hours of dosing, drug plasma concentrations were undetectable. Pharmacokinetic findings following a single-dose administration of inclisiran were comparable to inclisiran administered in multiple doses.⁹

Volume of distribution

The apparent volume of distribution was approximately 500 L following subcutaneous administration of a single 284 mg dose of inclisiran in healthy adults. According to non-clinical studies, inclisiran is highly taken up by the liver.⁹

Protein binding

In vitro, inclisiran is 87% protein bound at clinically relevant plasma concentrations.⁹

Metabolism

Inclisiran is metabolized by nucleases to form smaller nucleotides of varying lengths. It is not anticipated to be a substrate for cytochrome P450 enzymes.⁹

Route of elimination

About 16% of the total dose of inclisiran is cleared through the kidney.⁹

Half-life

The terminal elimination half-life of inclisiran is approximately 9 hours.⁹

Clearance

There is limited information on the clearance rate of inclisiran.

Adverse Effects

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Toxicity

There is no information on the LD₅₀ value of inclisiran. There were no clinically relevant adverse reactions in healthy volunteers who received inclisiran at doses up to three times the therapeutic dose. If an overdose is suspected, symptomatic and supportive treatments should be initiated.⁹

Pathways

Not Available

Pharmacogenomic Effects/ADRs

Not Available

Interactions

Drug Interactions: This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
Not Available
Food Interactions: No interactions found.

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Product Ingredients

Ingredient	UNII	CAS	InChI Key
Inclisiran sodium	UPC6BTX7PY	1639324-62-1	Not applicable

International/Other Brands

Leqvio (Novartis)

Brand Name Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End
Leqvio	Injection, solution	284 mg/1.5ml	Subcutaneous	Novartis Europharm Limited	2022-06-06	Not applicable
Leqvio	Solution	284 mg / 1.5 mL	Subcutaneous	Novartis	2022-09-26	Not applicable
Leqvio	Injection, solution	284 mg/1.5ml	Subcutaneous	Novartis Europharm Limited	2021-02-08	Not applicable
Leqvio	Injection, solution	284 mg/1.5mL	Subcutaneous	Novartis Pharmaceuticals Corporation	2021-12-22	Not applicable

Chemical Identifiers

UNII: UOW2C71PG5
CAS number: 1639324-58-5

References

General References

Kosmas CE, Munoz Estrella A, Sourlas A, Silverio D, Hilario E, Montan PD, Guzman E: Inclisiran: A New Promising Agent in the Management of Hypercholesterolemia. Diseases. 2018 Jul 13;6(3). pii: diseases6030063. doi: 10.3390/diseases6030063. [Article]
German CA, Shapiro MD: Small Interfering RNA Therapeutic Inclisiran: A New Approach to Targeting PCSK9. BioDrugs. 2020 Feb;34(1):1-9. doi: 10.1007/s40259-019-00399-6. [Article]
Doggrell SA: Inclisiran, the billion-dollar drug, to lower LDL cholesterol - is it worth it? Expert Opin Pharmacother. 2020 Nov;21(16):1971-1974. doi: 10.1080/14656566.2020.1799978. Epub 2020 Aug 4. [Article]
Goldstein JL, Brown MS: Regulation of low-density lipoprotein receptors: implications for pathogenesis and therapy of hypercholesterolemia and atherosclerosis. Circulation. 1987 Sep;76(3):504-7. doi: 10.1161/01.cir.76.3.504. [Article]
Pratt AJ, MacRae IJ: The RNA-induced silencing complex: a versatile gene-silencing machine. J Biol Chem. 2009 Jul 3;284(27):17897-901. doi: 10.1074/jbc.R900012200. Epub 2009 Apr 1. [Article]
Leiter LA, Teoh H, Kallend D, Wright RS, Landmesser U, Wijngaard PLJ, Kastelein JJP, Ray KK: Inclisiran Lowers LDL-C and PCSK9 Irrespective of Diabetes Status: The ORION-1 Randomized Clinical Trial. Diabetes Care. 2019 Jan;42(1):173-176. doi: 10.2337/dc18-1491. Epub 2018 Nov 28. [Article]
Cupido AJ, Kastelein JJP: Inclisiran for the treatment of hypercholesterolaemia: implications and unanswered questions from the ORION trials. Cardiovasc Res. 2020 Sep 1;116(11):e136-e139. doi: 10.1093/cvr/cvaa212. [Article]
Novartis: Novartis receives EU approval for Leqvio (inclisiran), a first-in-class siRNA to lower cholesterol with two doses a year [Link]
Summary of Product Characteristics: Leqvio (inclisiran), solution for subcutaneous injection [Link]
Novartis News: FDA approves Novartis Leqvio® (inclisiran), first-in-class siRNA to lower cholesterol and keep it low with two doses a year [Link]
FDA Approved Drug Products: LEQVIO (inclisiran) injection, for subcutaneous use [Link]

External Links

RxNav: 2588243
Wikipedia: Inclisiran

Clinical Trials

Clinical Trials

Phase	Status	Purpose	Conditions	Count
4	Recruiting	Treatment	High Cholesterol	1
3	Active Not Recruiting	Treatment	Heterozygous Familial Hypercholesterolemia (HeFH)	1
3	Active Not Recruiting	Treatment	High Cholesterol	1
3	Active Not Recruiting	Treatment	Homozygous Familial Hypercholesterolaemia (HoFH)	1
3	Completed	Health Services Research	Atherosclerotic Cardiovascular Disease Risk Equivelents / Atherosclerotic Cardiovascular Diseases / Elevated low density lipoprotein cholesterol	1
3	Completed	Treatment	ASCVD / Cardiovascular Risk / Elevations of serum cholesterol	1
3	Completed	Treatment	ASCVD / Elevations of serum cholesterol	1
3	Completed	Treatment	ASCVD / Elevations of serum cholesterol / Heterozygous Familial Hypercholesterolemia (HeFH) / Homozygous Familial Hypercholesterolaemia (HoFH)	1
3	Completed	Treatment	Elevations of serum cholesterol / Heterozygous Familial Hypercholesterolemia (HeFH)	1
3	Completed	Treatment	Homozygous Familial Hypercholesterolaemia (HoFH)	1

Pharmacoeconomics

Manufacturers

Not Available

Packagers

Not Available

Dosage Forms

Form	Route	Strength
Injection, solution	Subcutaneous	284 mg/1.5mL
Injection, solution	Subcutaneous	284 MG
Solution	Subcutaneous	284 mg / 1.5 mL
Solution	Subcutaneous	284 mg/1.5ml

Prices

Not Available

Patents

Patent Number	Pediatric Extension	Approved	Expires (estimated)
US10131907	No	2018-11-20	2028-08-24
US8106022	No	2012-01-31	2029-12-12
US8546143	No	2013-10-01	2022-01-09
US8828956	No	2014-09-09	2028-12-04
US9708610	No	2017-07-18	2024-01-01
US10273477	No	2019-04-30	2024-03-08
US9708615	No	2017-07-18	2024-03-08
US11078485	No	2021-08-03	2023-11-04
US10590418	No	2020-03-17	2022-07-19
US10266825	No	2019-04-23	2023-11-04
US10125369	No	2018-11-13	2034-08-18
US9370582	No	2016-06-21	2028-12-04
US9074213	No	2015-07-07	2022-03-09
US8809292	No	2014-08-19	2027-05-10
US8222222	No	2012-07-17	2027-12-29
US10851377	No	2020-12-01	2036-08-25
US8232383	No	2012-07-31	2023-02-20
US10806791	No	2020-10-20	2028-12-04
US10669544	No	2020-06-02	2024-03-08
US11530408	No	2004-05-18	2024-05-18

Properties

State: Not Available
Experimental Properties: Not Available

Targets

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Details1. Proprotein convertase subtilisin/kexin type 9

Kind: Protein
Organism: Humans
Pharmacological action: Yes
Actions: Antisense oligonucleotide
Curator comments: Inclisiran-RISC binds and cleaves the PCSK9 mRNA.

General Function: Very-low-density lipoprotein particle receptor binding
Specific Function: Crucial player in the regulation of plasma cholesterol homeostasis. Binds to low-density lipid receptor family members: low density lipoprotein receptor (LDLR), very low density lipoprotein recepto...
Gene Name: PCSK9
Uniprot ID: Q8NBP7
Uniprot Name: Proprotein convertase subtilisin/kexin type 9
Molecular Weight: 74285.545 Da

References

Kosmas CE, Munoz Estrella A, Sourlas A, Silverio D, Hilario E, Montan PD, Guzman E: Inclisiran: A New Promising Agent in the Management of Hypercholesterolemia. Diseases. 2018 Jul 13;6(3). pii: diseases6030063. doi: 10.3390/diseases6030063. [Article]
German CA, Shapiro MD: Small Interfering RNA Therapeutic Inclisiran: A New Approach to Targeting PCSK9. BioDrugs. 2020 Feb;34(1):1-9. doi: 10.1007/s40259-019-00399-6. [Article]
Cupido AJ, Kastelein JJP: Inclisiran for the treatment of hypercholesterolaemia: implications and unanswered questions from the ORION trials. Cardiovasc Res. 2020 Sep 1;116(11):e136-e139. doi: 10.1093/cvr/cvaa212. [Article]

Drug created at May 20, 2019 14:33 / Updated at February 03, 2022 19:50

Inclisiran

Identification

Pharmacology

Interactions

Products

Categories

Chemical Identifiers

References

Clinical Trials

Pharmacoeconomics

Properties

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References