Inclisiran

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Inclisiran
Clinical data
Trade names Leqvio
Other namesALN-PCSsc, ALN-60212
AHFS/Drugs.com Monograph
MedlinePlus a622009
License data
Pregnancy
category
Routes of
administration 		Subcutaneous
Drug class Antilipemic agent
ATC code
Legal status
Legal status
Identifiers
CAS Number
DrugBank
UNII
KEGG
ChEBI
Chemical and physical data
Formula C529H664F12N176O316P43S6
Molar mass 16296.26 g·mol−1

Inclisiran, sold under the brand name Leqvio, is a medication used for the treatment of high low-density lipoprotein (LDL) cholesterol and for the treatment of people with atherosclerotic cardiovascular disease (ASCVD), ASCVD risk-equivalents, and heterozygous familial hypercholesterolemia (HeFH). [5] [7] [6] [9] It is a small interfering RNA (siRNA) that acts as an inhibitor of a proprotein convertase, specifically, inhibiting translation of the protein PCSK9. [10]

Contents

Inclisiran was approved for use in the European Union in December 2020. [7] In August 2021, it received NICE approval for use by the National Health Service in the UK. [11] In December 2021, it was approved for medical use in the United States. [6] [9] [12] The U.S. Food and Drug Administration considers it to be a first-in-class medication. [13] In August 2023, the National Medical Products Administration approved the use of inclisiran in China. [14]

Medical uses

In the European Union, inclisiran is indicated 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. [7]

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). [5] [6] The FDA approved an expansion of its indications to primary hypercholesterolemia patients in July 2023. [15]

In China, inclisiran is indicated in adults with primary hypercholesterolemia (heterozygous familial and non-familial) or mixed dyslipidaemia. [14]

Discovery and mechanism of action

Mechanism of action of inclisiran 11886 2020 1427 Fig1 HTML.webp
Mechanism of action of inclisiran

Inclisiran is a small interfering RNA that acts as an inhibitor of a proprotein convertase, specifically, inhibiting translation of the protein termed proprotein convertase subtilisin/kexin type 9 (PCSK9). [10] [16] [17] [5] 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). [10] The siRNA-RISC complex is catalytic, 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. [10]

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). [10] 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". [10] 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[ clarification needed ] were sought and discovered as a means of decreasing PCSK9 levels, and the development of a clinical candidate ensued thereafter. [10]

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. [18] Inclisiran is being developed by The Medicines Company, a subsidiary of Novartis, which licensed the rights to inclisiran from Alnylam Pharmaceuticals. [19] [20]

The effectiveness of inclisiran was studied in three randomized, double-blind, placebo-controlled trials (trial 1/NCT03397121, trial 2/NCT03399370, and trial 3/NCT03400800) that enrolled 3,457 adults with HeFH or clinical ASCVD. [6] [9] Enrolled participants were taking maximally tolerated statin therapy but required additional LDL-C lowering based on their risk for cardiovascular events. [6] 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). [6] 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). [6]

Study 1 enrolled 1,561 adults with ASCVD. [6] 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%. [6] Study 2 enrolled 1,414 adults with ASCVD. [6] 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%. [6] Study 3 enrolled 482 adults with HeFH. [6] 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%. [6] The trials were conducted in 13 countries: Canada, Czech Republic, Denmark, Germany, Hungary, Netherlands, Poland, South Africa, Spain, Sweden, Ukraine, United Kingdom, and the United States. [9]

The effect of inclisiran on cardiovascular morbidity (suffering from a disease) and mortality (death) has not been determined. [6] [21]

Society and culture

Economics

The wholesale acquisition cost of inclisiran is US$3,250 per injection. [22]

Related Research Articles

<span class="mw-page-title-main">Low-density lipoprotein</span> One of the five major groups of lipoprotein

Low-density lipoprotein (LDL) is one of the five major groups of lipoprotein that transport all fat molecules around the body in extracellular water. These groups, from least dense to most dense, are chylomicrons, very low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), low-density lipoprotein (LDL) and high-density lipoprotein (HDL). LDL delivers fat molecules to cells. LDL is involved in atherosclerosis, a process in which it is oxidized within the walls of arteries.

<span class="mw-page-title-main">Statin</span> Class of drugs used to lower cholesterol levels

Statins are a class of medications that reduce illness and mortality in people who are at high risk of cardiovascular disease. They are the most commonly prescribed cholesterol-lowering drugs.

Lipid-lowering agents, also sometimes referred to as hypolipidemic agents, cholesterol-lowering drugs, or antihyperlipidemic agents are a diverse group of pharmaceuticals that are used to lower the level of lipids and lipoproteins such as cholesterol, in the blood (hyperlipidemia). The American Heart Association recommends the descriptor 'lipid lowering agent' be used for this class of drugs rather than the term 'hypolipidemic'.

<span class="mw-page-title-main">Fibrate</span> Class of chemical compounds

In pharmacology, the fibrates are a class of amphipathic carboxylic acids and esters. They are derivatives of fibric acid. They are used for a range of metabolic disorders, mainly hypercholesterolemia, and are therefore hypolipidemic agents.

<span class="mw-page-title-main">Hypercholesterolemia</span> High levels of cholesterol in the blood

Hypercholesterolemia, also called high cholesterol, is the presence of high levels of cholesterol in the blood. It is a form of hyperlipidemia, hyperlipoproteinemia, and dyslipidemia.

Dyslipidemia is a metabolic disorder characterized by abnormally high or low amounts of any or all lipids or lipoproteins in the blood. Dyslipidemia is a risk factor for the development of atherosclerotic cardiovascular diseases (ASCVD), which include coronary artery disease, cerebrovascular disease, and peripheral artery disease. Although dyslipidemia is a risk factor for ASCVD, abnormal levels don't mean that lipid lowering agents need to be started. Other factors, such as comorbid conditions and lifestyle in addition to dyslipidemia, is considered in a cardiovascular risk assessment. In developed countries, most dyslipidemias are hyperlipidemias; that is, an elevation of lipids in the blood. This is often due to diet and lifestyle. Prolonged elevation of insulin resistance can also lead to dyslipidemia. Likewise, increased levels of O-GlcNAc transferase (OGT) may cause dyslipidemia.

<span class="mw-page-title-main">Atorvastatin</span> Cholesterol-lowering medication

Atorvastatin is a statin medication used to prevent cardiovascular disease in those at high risk and to treat abnormal lipid levels. For the prevention of cardiovascular disease, statins are a first-line treatment. It is taken by mouth.

<span class="mw-page-title-main">Ezetimibe/simvastatin</span> Drug combination used for the treatment of dyslipidemia

Ezetimibe/simvastatin is a drug combination used for the treatment of dyslipidemia. It is a combination of ezetimibe and the statin drug simvastatin.

<span class="mw-page-title-main">Torcetrapib</span> Chemical compound

Torcetrapib was a drug being developed to treat hypercholesterolemia and prevent cardiovascular disease. Its development was halted in 2006 when phase III studies showed excessive all-cause mortality in the treatment group receiving a combination of atorvastatin (Lipitor) and torcetrapib.

<span class="mw-page-title-main">Pitavastatin</span> Chemical compound

Pitavastatin is a member of the blood cholesterol lowering medication class of statins.

<span class="mw-page-title-main">Familial hypercholesterolemia</span> Genetic disorder characterized by high cholesterol levels

Familial hypercholesterolemia (FH) is a genetic disorder characterized by high cholesterol levels, specifically very high levels of low-density lipoprotein cholesterol, in the blood and early cardiovascular diseases. The most common mutations diminish the number of functional LDL receptors in the liver or produce abnormal LDL receptors that never go to the cell surface to function properly. Since the underlying body biochemistry is slightly different in individuals with FH, their high cholesterol levels are less responsive to the kinds of cholesterol control methods which are usually more effective in people without FH. Nevertheless, treatment is usually effective.

<span class="mw-page-title-main">PCSK9</span> Mammalian protein found in humans

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 (orthologs) are found across many species. As with many proteins, PCSK9 is inactive when first synthesized, because a section of peptide chains blocks their activity; proprotein convertases remove that section to activate the enzyme. The PCSK9 gene also contains one of 27 loci associated with increased risk of coronary artery disease.

<span class="mw-page-title-main">Lomitapide</span> Chemical compound

Lomitapide, sold under the brand name Juxtapid in the US and Lojuxta in the EU, is a medication used as a lipid-lowering agent for the treatment of familial hypercholesterolemia, developed by Aegerion Pharmaceuticals. It has been tested in clinical trials as single treatment and in combinations with atorvastatin, ezetimibe and fenofibrate.

Alirocumab, sold under the brand name Praluent, is a medication used as a second-line treatment for high cholesterol for adults whose cholesterol is not controlled by diet and statin treatment. It is a human monoclonal antibody that belongs to a novel class of anti-cholesterol drugs, known as PCSK9 inhibitors, and it was the first such agent to receive FDA approval. The FDA approval was contingent on the completion of further clinical trials to better determine efficacy and safety.

Evolocumab, sold under the brand name Repatha, is a monoclonal antibody that is an immunotherapy medication for the treatment of hyperlipidemia.

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 headquartered in Cambridge, Massachusetts. In 2016, Forbes included the company on its "100 Most Innovative Growth Companies" list.

Evinacumab, sold under the brand name Evkeeza, is a monoclonal antibody medication for the treatment of homozygous familial hypercholesterolemia (HoFH).

Bempedoic acid, sold under the brand name Nexletol among others, is a medication for the treatment of hypercholesterolemia.

<span class="mw-page-title-main">Ezetimibe/rosuvastatin</span> Cholesterol medication

Ezetimibe/rosuvastatin, sold under the brand name Ridutrin among others, is a combination medication used to treat high cholesterol. In some countries it is sold as a kit or a pack containing two distinct pills.

Bempedoic acid/ezetimibe, sold under the brand name Nexlizet among others, is a fixed-dose combination medication used for the treatment of high cholesterol. It is a combination of bempedoic acid and ezetimibe.

References

  1. 1 2 "Leqvio". Therapeutic Goods Administration (TGA). 22 September 2021. Archived from the original on 30 September 2021. Retrieved 30 September 2021.
  2. ↑ "Updates to the Prescribing Medicines in Pregnancy database". Therapeutic Goods Administration (TGA). 12 May 2022. Archived from the original on 3 April 2022. Retrieved 13 May 2022.
  3. ↑ "Summary Basis of Decision (SBD) for Leqvio". Health Canada. 23 October 2014. Archived from the original on 29 May 2022. Retrieved 29 May 2022.
  4. ↑ "Health product highlights 2021: Annexes of products approved in 2021". Health Canada . 3 August 2022. Retrieved 25 March 2024.
  5. 1 2 3 4 "Leqvio- inclisiran injection, solution". DailyMed. Archived from the original on 28 December 2021. Retrieved 27 December 2021.
  6. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 "FDA approves add-on therapy to lower cholesterol among certain high-risk adults". U.S. Food and Drug Administration (FDA). 22 December 2021. Archived from the original on 24 December 2021. Retrieved 24 December 2021.PD-icon.svg This article incorporates text from this source, which is in the public domain .
  7. 1 2 3 4 "Leqvio EPAR". European Medicines Agency . 13 October 2020. Archived from the original on 8 January 2021. Retrieved 6 January 2021. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  8. ↑ "Leqvio Product information". Union Register of medicinal products. Archived from the original on 5 March 2023. Retrieved 3 March 2023.
  9. 1 2 3 4 "Drug Trials Snapshots: Leqvio". U.S. Food and Drug Administration (FDA). 22 December 2021. Archived from the original on 28 July 2023. Retrieved 28 July 2023.PD-icon.svg This article incorporates text from this source, which is in the public domain .
  10. 1 2 3 4 5 6 7 Fitzgerald K, White S, Borodovsky A, Bettencourt BR, Strahs A, Clausen V, et al. (January 2017). "A Highly Durable RNAi Therapeutic Inhibitor of PCSK9". The New England Journal of Medicine. 376 (1): 41–51. doi:10.1056/NEJMoa1609243. PMC   5778873 . PMID   27959715.
  11. ↑ "Novartis signs deal with Britain's NHS for new cholesterol drug Leqvio". Reuters. 1 September 2021. Archived from the original on 1 September 2021. Retrieved 1 September 2021.
  12. ↑ "FDA approves Novartis Leqvio (inclisiran), first-in-class siRNA to lower cholesterol and keep it low with two doses a year". Novartis (Press release). 22 December 2021. Retrieved 24 December 2021.
  13. ↑ Advancing Health Through Innovation: New Drug Therapy Approvals 2021 (PDF). U.S. Food and Drug Administration (FDA) (Report). 13 May 2022. Archived from the original on 6 December 2022. Retrieved 22 January 2023.PD-icon.svg This article incorporates text from this source, which is in the public domain .
  14. 1 2 "Novartis Gains China Approval for Pioneering Cholesterol Drug". www.yicaiglobal.com. Archived from the original on 24 August 2023. Retrieved 24 August 2023.
  15. ↑ "FDA expands inclisiran indication to primary prevention patients". www.healio.com. Archived from the original on 24 August 2023. Retrieved 24 August 2023.
  16. ↑ Spreitzer H (11 September 2017). "Neue Wirkstoffe: Inclisiran". Österreichische Apotheker-Zeitung (in German) (19/2017).
  17. ↑ "Proposed INN: List 114" (PDF). WHO Drug Information. 29 (4). WHO: 531f. 2015. Archived (PDF) from the original on 1 September 2021. Retrieved 5 October 2020.
  18. ↑ "The Medicines Company Announces Positive Topline Results from First Pivotal Phase 3 Trial of Inclisiran". The Medicines Company. Archived from the original on 29 August 2019. Retrieved 29 August 2019.
  19. ↑ Taylor NP (26 August 2019). "Medicines Company's PCSK9 drug hits phase 3 efficacy goals". FierceBiotech. Archived from the original on 1 September 2021. Retrieved 29 August 2019.
  20. ↑ "Novartis successfully completes acquisition of The Medicines Company, adding a potentially first-in-class, investigational cholesterol-lowering therapy inclisiran". Novartis (Press release). 6 January 2020. Retrieved 24 December 2021.
  21. ↑ Santulli G, Jankauskas SS, Gambardella J (May 2021). "Inclisiran: a new milestone on the PCSK9 road to tackle cardiovascular risk". Eur Heart J Cardiovasc Pharmacother. 7 (3): e11–e12. doi: 10.1093/ehjcvp/pvab014 . PMID   33655296.
  22. ↑ "Pricey Inclisiran Is Rolling Out: a 'Buy-and-Bill' Model May Smooth Its Path". TCTMD. 17 January 2022. Archived from the original on 19 June 2023. Retrieved 28 July 2023.

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