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).12
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Indication Type Indication Combined Product Details Approval Level Age Group Patient Characteristics Dose Form Used as adjunct in combination to manage Atherosclerotic cardiovascular diseases •••••••••••• ••••• ••••••••• Adjunct therapy in management of Dyslipidemia (fredrickson type Ⅱa) •••••••••••• ••••• •••••• ••••••••••• ••••••••• Used as adjunct in combination to manage Dyslipidemia (fredrickson type Ⅱa) •••••••••••• ••••• ••••••••• Used as adjunct in combination to manage Dyslipidemia (fredrickson type Ⅱa) •••••••••••• ••••• •••••• ••••• ••••• ••••• •••• ••• ••••••• ••••••••• •••• •• • •••••• ••••••••• Used as adjunct in combination to manage Dyslipidemia (fredrickson type Ⅱa) •••••••••••• ••••• •••••• ••••••••••• ••••••••• - Contraindications & Blackbox Warnings
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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 oligonucleotideHumans - 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
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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
Drug product information from 10+ global regionsOur datasets provide approved product information including:dosage, form, labeller, route of administration, and marketing period.Access drug product information from over 10 global regions.- 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 Region Image Leqvio Injection, solution 284 mg/1.5ml Subcutaneous Novartis Europharm Limited 2022-06-06 Not applicable EU 
Leqvio Solution 284 mg / 1.5 mL Subcutaneous Novartis 2022-09-26 Not applicable Canada 
Leqvio Injection, solution 284 mg/1.5ml Subcutaneous Novartis Europharm Limited 2021-02-08 Not applicable EU Leqvio Injection, solution 284 mg/1.5mL Subcutaneous Novartis Pharmaceuticals Corporation 2021-12-22 Not applicable US 
Categories
- ATC Codes
- C10AX16 — Inclisiran
- Drug Categories
- Antisense Elements (Genetics)
- Compounds used in a research, industrial, or household setting
- Diagnostic Uses of Chemicals
- Hypolipidemic Agents
- Hypolipidemic Agents Indicated for Hyperlipidemia
- Laboratory Chemicals
- Lipid Modifying Agents
- Lipid Modifying Agents, Plain
- Lipid Regulating Agents
- Molecular Probes
- Non-statin Hypolipidemic Agents Indicated for Hyperlipidemia
- Nucleic Acid Probes
- Nucleic Acids
- Nucleic Acids, Nucleotides, and Nucleosides
- PCSK9 Inhibitor
- Proprotein Convertase Subtilisin Kexin Type 9 (PCSK9) Inhibitors
- RNA, Antisense
- RNA, Small Untranslated
- RNA, Untranslated
- Classification
- Not classified
- Affected organisms
- Humans and other mammals
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]
- FDA Approved Drug Products: LEQVIO (inclisiran) injection, for subcutaneous use (July 2023) [Link]
- External Links
- 2588243
- Wikipedia
- Inclisiran
Clinical Trials
- Clinical Trials
Phase Status Purpose Conditions Count 4 Active Not Recruiting Treatment High Cholesterol 1 4 Not Yet Recruiting Treatment Atherosclerotic Cardiovascular Diseases 1 4 Not Yet Recruiting Treatment Coronary Artery Disease (CAD) 1 4 Recruiting Other Atherosclerotic Cardiovascular Diseases (ASCVD) / Cerebrovascular Diseases / Coronary Heart Disease (CHD) / Peripheral Arterial Disease (PAD) 1 4 Recruiting Treatment Coronary Artery Atherosclerosis / Coronary Artery Disease (CAD) 1
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
Form Route Strength Injection, solution Subcutaneous 284 mg/1.5mL Solution Subcutaneous 284 mg / 1.5 mL Injection, solution Subcutaneous 284 mg Solution Subcutaneous 284 mg/1.5ml - Prices
- Not Available
- Patents
Patent Number Pediatric Extension Approved Expires (estimated) Region US10131907 No 2018-11-20 2028-08-24 US US8106022 No 2012-01-31 2029-12-12 US US8546143 No 2013-10-01 2022-01-09 US US8828956 No 2014-09-09 2028-12-04 US US9708610 No 2017-07-18 2024-01-01 US US10273477 No 2019-04-30 2024-03-08 US US9708615 No 2017-07-18 2024-03-08 US US11078485 No 2021-08-03 2023-11-04 US US10590418 No 2020-03-17 2022-07-19 US US10266825 No 2019-04-23 2023-11-04 US US10125369 No 2018-11-13 2034-08-18 US US9370582 No 2016-06-21 2028-12-04 US US9074213 No 2015-07-07 2022-03-09 US US8809292 No 2014-08-19 2027-05-10 US US8222222 No 2012-07-17 2027-12-29 US US10851377 No 2020-12-01 2036-08-25 US US8232383 No 2012-07-31 2023-02-20 US US10806791 No 2020-10-20 2028-12-04 US US10669544 No 2020-06-02 2024-03-08 US US11530408 No 2004-05-18 2024-05-18 US
Properties
- State
- Not Available
- Experimental Properties
- Not Available
Targets
- 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 July 18, 2023 22:57