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Inclisiran | CAS No: 1639324-58-5 | GMP-certified suppliers
A medication that reduces LDL cholesterol as an adjunct to diet and statins for adults with primary hypercholesterolemia, familial forms, or atherosclerotic cardiovascular disease.
Therapeutic categories
Antisense Elements (Genetics)Compounds used in a research, industrial, or household settingDiagnostic Uses of ChemicalsHypolipidemic AgentsHypolipidemic Agents Indicated for HyperlipidemiaLaboratory Chemicals
Generic name
Inclisiran
Molecule type
biotech
CAS number
1639324-58-5
DrugBank ID
DB14901
Approval status
Approved drug, Investigational drug
ATC code
C10AX16
Primary indications
- 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
Product Snapshot
- Inclisiran is a subcutaneous injection classified as an injectable small interfering RNA (siRNA) therapeutic
- It is primarily indicated for the treatment of hypercholesterolemia and mixed dyslipidemia as an adjunct to diet and statin therapy in adults requiring additional LDL cholesterol lowering
- The product is approved and marketed in key regulatory regions including the EU, US, and Canada
Clinical Overview
Inclisiran (CAS number 1639324-58-5) is a synthetic small interfering RNA (siRNA) therapeutic designed to reduce plasma low-density lipoprotein cholesterol (LDL-C) by targeting proprotein convertase subtilisin-kexin type 9 (PCSK9). PCSK9 is a serine protease predominantly produced by hepatocytes that regulates LDL receptor degradation. By binding selectively to PCSK9 messenger RNA, inclisiran prevents translation of the PCSK9 protein, leading to decreased circulating PCSK9 levels and consequently increased recycling of LDL receptors on hepatocyte surfaces. This mechanism enhances hepatic uptake of LDL-C from plasma, thereby lowering LDL-C concentrations.
Clinically, inclisiran is approved for use in adults with primary hypercholesterolemia, including heterozygous familial and non-familial forms, or mixed dyslipidemia. In the European Union, it is indicated as an adjunct to diet, either alone or alongside statins and other lipid-lowering therapies, particularly in patients who have not achieved LDL-C goals with maximally tolerated statin doses or who cannot tolerate statins. The US Food and Drug Administration has approved inclisiran for adults with heterozygous familial hypercholesterolemia or clinical atherosclerotic cardiovascular disease requiring additional LDL-C reduction as an adjunct to diet and maximally tolerated statin therapy. The product is marketed under the trade name Leqvio.
Pharmacodynamically, inclisiran demonstrates sustained LDL-C reduction, with mean decreases of 48-51% observed 30 to 60 days after dosing, and effects persisting for at least six months. PCSK9 protein levels are reduced by approximately 70-80% post-dosing. Uptake of inclisiran into hepatocytes is facilitated by conjugation to triantennary N-acetylgalactosamine ligands targeting asialoglycoprotein receptors, ensuring liver-specific activity. Upon cellular entry, inclisiran incorporates into the RNA-induced silencing complex (RISC), mediating cleavage of PCSK9 mRNA and preventing protein synthesis.
Safety considerations include monitoring for injection site reactions and potential immune-mediated effects. Long-term safety data and definitive cardiovascular outcome evidence remain under evaluation. Inclisiran offers a novel mechanism distinct from monoclonal antibody PCSK9 inhibitors, characterized by infrequent dosing schedules due to its prolonged activity.
From a sourcing perspective, pharmaceutical suppliers must ensure compliance with stringent quality standards for nucleic acid therapeutics, including purity, potency, and impurity profiles. Robust manufacturing controls are essential for consistent siRNA chemical synthesis and conjugation processes. Analytical validation confirming sequence integrity and conjugate attachment is critical for regulatory acceptance and clinical efficacy.
Clinically, inclisiran is approved for use in adults with primary hypercholesterolemia, including heterozygous familial and non-familial forms, or mixed dyslipidemia. In the European Union, it is indicated as an adjunct to diet, either alone or alongside statins and other lipid-lowering therapies, particularly in patients who have not achieved LDL-C goals with maximally tolerated statin doses or who cannot tolerate statins. The US Food and Drug Administration has approved inclisiran for adults with heterozygous familial hypercholesterolemia or clinical atherosclerotic cardiovascular disease requiring additional LDL-C reduction as an adjunct to diet and maximally tolerated statin therapy. The product is marketed under the trade name Leqvio.
Pharmacodynamically, inclisiran demonstrates sustained LDL-C reduction, with mean decreases of 48-51% observed 30 to 60 days after dosing, and effects persisting for at least six months. PCSK9 protein levels are reduced by approximately 70-80% post-dosing. Uptake of inclisiran into hepatocytes is facilitated by conjugation to triantennary N-acetylgalactosamine ligands targeting asialoglycoprotein receptors, ensuring liver-specific activity. Upon cellular entry, inclisiran incorporates into the RNA-induced silencing complex (RISC), mediating cleavage of PCSK9 mRNA and preventing protein synthesis.
Safety considerations include monitoring for injection site reactions and potential immune-mediated effects. Long-term safety data and definitive cardiovascular outcome evidence remain under evaluation. Inclisiran offers a novel mechanism distinct from monoclonal antibody PCSK9 inhibitors, characterized by infrequent dosing schedules due to its prolonged activity.
From a sourcing perspective, pharmaceutical suppliers must ensure compliance with stringent quality standards for nucleic acid therapeutics, including purity, potency, and impurity profiles. Robust manufacturing controls are essential for consistent siRNA chemical synthesis and conjugation processes. Analytical validation confirming sequence integrity and conjugate attachment is critical for regulatory acceptance and clinical efficacy.
Identification & chemistry
| Generic name | Inclisiran |
|---|---|
| Molecule type | Biotech |
| CAS | 1639324-58-5 |
| UNII | UOW2C71PG5 |
| DrugBank ID | DB14901 |
Pharmacology
| Summary | Inclisiran is a small interfering RNA (siRNA) therapeutic that targets hepatic PCSK9 mRNA, reducing PCSK9 protein synthesis. By decreasing PCSK9 levels, inclisiran promotes increased recycling of LDL receptors on hepatocytes, enhancing clearance of circulating LDL cholesterol (LDL-C). This mechanism results in sustained reduction of plasma LDL-C levels in patients with hypercholesterolemia or mixed dyslipidemia. |
|---|---|
| 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. 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. 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. Inclisiran incorporated into the RISC allows the drug to cleave PCSK9 mRNA and prevent PCSK9 translation, thus decreasing hepatic production of PCSK9. Less PCSK9 protein available allows more LDL receptors to be recycled to the hepatic membrane for circulating LDL-C uptake. |
| 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. In healthy volunteers, inclisiran reduced PCSK9 levels by 70-80% and LDL-C levels by 27-60%. In a clinical trial consisting of subjects with atherosclerotic cardiovascular disease with or without diabetes, inclisiran reduced LDL-C levels by 28-52%. The long-term effect of inclisiran on cardiovascular outcomes has not yet been elucidated, although reductions in the levels of LDL-C have been associated with a reduction of cardiovascular risk. |
Targets
| Target | Organism | Actions |
|---|---|---|
| Proprotein convertase subtilisin/kexin type 9 | Humans | antisense oligonucleotide |
ADME / PK
| 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<sub>max</sub> was 509 ng/mL and the T<sub>max</sub> was approximately 4 hours after the administration of 284 mg inclisiran. The mean AUC<sub>0-inf</sub> 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. |
|---|---|
| Half-life | The terminal elimination half-life of inclisiran is approximately 9 hours. |
| Protein binding | _In vitro_, inclisiran is 87% protein bound at clinically relevant plasma concentrations. |
| 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. |
| Route of elimination | About 16% of the total dose of inclisiran is cleared through the kidney. |
| 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. |
| Clearance | There is limited information on the clearance rate of inclisiran. |
Formulation & handling
- Inclisiran is a biotech injectable administered via subcutaneous injection, requiring appropriate handling of biologic solutions.
- Formulation must ensure stability of the peptide-like molecule in solution to maintain potency and prevent degradation.
- No oral formulations are available, and food sensitivity is not applicable due to subcutaneous route of administration.
Regulatory status
| Lifecycle | The API is currently marketed in the EU, US, and Canada, with primary patent protections in the US expiring between 2024 and 2029. As key patents lapse through 2029, the market is expected to transition toward greater generic competition. |
|---|
| Markets | EU, US, Canada |
|---|
Supply Chain
| Supply chain summary | Inclisiran is primarily marketed under the brand name Leqvio across multiple regions including the US, EU, and Canada, indicating a global presence of branded products. Multiple patents protect the molecule in the United States, with expiry dates ranging from early 2022 to late 2029, suggesting that while some patents have expired, others remain active, potentially limiting the current availability of generic competition but indicating the possibility of future market entry as key patents expire. The originator role appears concentrated among a limited number of companies managing branded supply. |
|---|
Safety
| Toxicity | There is no information on the LD<sub>50</sub> 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. |
|---|
High Level Warnings:
- No definitive LD50 toxicity data available for inclisiran
- Clinical evaluations up to threefold therapeutic doses showed no clinically relevant adverse reactions in healthy subjects
- In cases of suspected overdose, initiate symptomatic and supportive treatment measures
Inclisiran is a type of Lipid-lowering agents
Lipid-lowering agents are a category of pharmaceutical active ingredients (APIs) that are widely used in the treatment of hyperlipidemia, a condition characterized by elevated levels of lipids (such as cholesterol and triglycerides) in the blood. These agents play a crucial role in managing lipid abnormalities and reducing the risk of cardiovascular diseases.
One of the most commonly prescribed lipid-lowering agents is statins. Statins work by inhibiting an enzyme called HMG-CoA reductase, which is responsible for the production of cholesterol in the liver. By blocking this enzyme, statins effectively lower cholesterol levels in the bloodstream.
Another class of lipid-lowering agents is fibric acid derivatives, which primarily target triglyceride levels. These agents activate a nuclear receptor known as PPAR-alpha, which regulates lipid metabolism. By activating PPAR-alpha, fibric acid derivatives enhance the breakdown of triglycerides and increase the elimination of fatty acids from the bloodstream.
Additionally, bile acid sequestrants are often used as lipid-lowering agents. These agents bind to bile acids in the intestine, preventing their reabsorption. As a result, the liver utilizes more cholesterol to produce new bile acids, leading to a decrease in circulating cholesterol levels.
Lipid-lowering agents are available in various formulations, including tablets, capsules, and suspensions, allowing for convenient administration. They are usually prescribed alongside lifestyle modifications, such as dietary changes and regular exercise, to optimize the management of hyperlipidemia.
It is important to note that the use of lipid-lowering agents should be under the supervision of a healthcare professional, as they may have potential side effects and interactions with other medications. Proper monitoring of lipid levels and regular follow-up visits are essential for ensuring the effectiveness and safety of these pharmaceutical agents.
