Inclisiran

Identification

Summary

Inclisiran is a PCSK9-targeted short interfering RNA 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. It is marketed under the trade name Leqvio 8 and is also currently under review by the FDA.

Type
Biotech
Groups
Approved, Investigational
Biologic Classification
Gene Therapies
Other gene therapies
Synonyms
  • ALN-PCSsc
  • Inclisiran
External IDs
  • ALN-60212
  • ALN-PCSsc

Pharmacology

Indication

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

Pharmacology
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Associated Conditions
Contraindications & Blackbox Warnings
Contraindications
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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

TargetActionsOrganism
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 Cmax was 509 ng/mL and the Tmax was approximately 4 hours after the administration of 284 mg inclisiran. The mean AUC0-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
Adverseeffects
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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.

Products

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International/Other Brands
Leqvio (Novartis)
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
LeqvioInjection, solution284 mgSubcutaneousNovartis Europharm Limited2021-02-08Not applicableEU flag

Categories

Drug Categories
Classification
Not classified
Affected organisms
  • Humans and other mammals

Chemical Identifiers

UNII
UOW2C71PG5
CAS number
1639324-58-5

References

General References
  1. 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]
  2. 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]
  3. 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]
  4. 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]
  5. 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]
  6. 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]
  7. 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]
  8. Novartis: Novartis receives EU approval for Leqvio (inclisiran), a first-in-class siRNA to lower cholesterol with two doses a year [Link]
  9. Summary of Product Characteristics: Leqvio (inclisiran), solution for subcutaneous injection [Link]
Wikipedia
Inclisiran

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
3Active Not RecruitingTreatmentASCVD / Elevations of serum cholesterol / Heterozygous Familial Hypercholesterolemia (HeFH) / Homozygous Familial Hypercholesterolaemia (HoFH)1
3Active Not RecruitingTreatmentHomozygous Familial Hypercholesterolaemia (HoFH)1
3CompletedTreatmentASCVD / Cardiovascular Risk / Elevations of serum cholesterol1
3CompletedTreatmentASCVD / Elevations of serum cholesterol1
3CompletedTreatmentElevations of serum cholesterol / Heterozygous Familial Hypercholesterolemia (HeFH)1
3Not Yet RecruitingTreatmentAtherosclerotic Cardiovascular Diseases1
3Not Yet RecruitingTreatmentAtherosclerotic Ischemic Disease / High Cholesterol1
3RecruitingHealth Services ResearchAtherosclerotic Cardiovascular Disease Risk Equivelents / Atherosclerotic Cardiovascular Diseases / Elevated low density lipoprotein cholesterol1
3RecruitingPreventionAtherosclerotic Cardiovascular Diseases1
3RecruitingTreatmentAcute Coronary Syndrome (ACS)1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
Injection, solutionSubcutaneous284 MG
SolutionSubcutaneous284 mg / 1.5 mL
Prices
Not Available
Patents
Not Available

Properties

State
Not Available
Experimental Properties
Not Available

Targets

Drugtargets2
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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
  1. 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]
  2. 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]
  3. 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 on May 20, 2019 14:33 / Updated on February 21, 2021 18:55