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Inclisiran

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Inclisiran
Clinical data
Trade namesLeqvio
Other namesALN-PCSsc, ALN-60212
AHFS/Drugs.comMonograph
MedlinePlusa622009
License data
Pregnancy
category
Routes of
administration		Subcutaneous
Drug classAntilipemic agent
ATC code
Legal status
Legal status
Identifiers
CAS Number
DrugBank
UNII
KEGG
ChEBI
Chemical and physical data
FormulaC529H664F12N176O316P43S6
Molar mass16296.26 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]

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

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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

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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

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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

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Economics

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

References

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  1. ^ a b "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. ^ a b c d "Leqvio- inclisiran injection, solution". DailyMed. Archived from the original on 28 December 2021. Retrieved 27 December 2021.
  6. ^ a b c d e f g h i j k l m n o "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. Public Domain This article incorporates text from this source, which is in the public domain.
  7. ^ a b c d "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. ^ a b c d "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. Public Domain This article incorporates text from this source, which is in the public domain.
  10. ^ a b c d e f g 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. Public Domain This article incorporates text from this source, which is in the public domain.
  14. ^ a b "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.

Further reading

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  • Clinical trial number NCT03399370 for "Inclisiran for Participants With Atherosclerotic Cardiovascular Disease and Elevated Low-density Lipoprotein Cholesterol (ORION-10)" at ClinicalTrials.gov
  • Clinical trial number NCT03400800 for "Inclisiran for Subjects With ACSVD or ACSVD-Risk Equivalents and Elevated Low-density Lipoprotein Cholesterol (ORION-11)" at ClinicalTrials.gov
  • Clinical trial number NCT03397121 for "Trial to Evaluate the Effect of Inclisiran Treatment on Low Density Lipoprotein Cholesterol (LDL-C) in Subjects With Heterozygous Familial Hypercholesterolemia (HeFH) (ORION-9)" at ClinicalTrials.gov
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