Evolocumab

{{Short description|Pharmaceutical drug}} {{Use dmy dates|date=June 2024}} {{cs1 config |name-list-style=vanc |display-authors=6}} {{Infobox drug | type = mab | image = | width = | alt = | caption =

| mab_type = mab | source = u | target = PCSK9

| pronounce = e-voe-LOK-ue-mab | tradename = Repatha | Drugs.com = {{drugs.com|monograph|evolocumab}} | MedlinePlus = | DailyMedID = Evolocumab | pregnancy_AU = B1 | pregnancy_AU_comment = | pregnancy_category= | routes_of_administration = Subcutaneous | class = | ATC_prefix = C10 | ATC_suffix = AX13 | ATC_supplemental =

| legal_AU = S4 | legal_AU_comment = <ref>{{cite web | title=Prescription medicines: registration of new chemical entities in Australia, 2015 | website=Therapeutic Goods Administration (TGA) | date=21 June 2022 | url=https://www.tga.gov.au/prescription-medicines-registration-new-chemical-entities-australia-2015 | access-date=10 April 2023}}</ref> | legal_BR =  | legal_BR_comment = | legal_CA = Rx-only | legal_CA_comment = <ref>{{cite web | title=Health Canada New Drug Authorizations: 2015 Highlights | website=Health Canada | date=4 May 2016 | url=https://www.canada.ca/en/health-canada/services/publications/drugs-health-products/health-canada-new-drug-authorizations-2015-highlights.html | access-date=7 April 2024}}</ref> | legal_DE =  | legal_DE_comment = | legal_NZ =  | legal_NZ_comment = | legal_UK =  | legal_UK_comment = | legal_US = Rx-only | legal_US_comment = <ref name="Repatha FDA label">{{cite web | title=Repatha- evolocumab injection, solution Repatha- evolocumab kit | work = DailyMed | publisher = U.S. National Library of Medicine | date=6 May 2020 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=cd61e902-166d-4aa6-9f3c-a18c1008d07e | access-date=20 October 2020}}</ref> | legal_EU = Rx-only | legal_EU_comment = <ref>{{cite web | title=Repatha EPAR | website=European Medicines Agency | date=17 July 2015 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/repatha | access-date=29 June 2024}}</ref> | legal_UN =  | legal_UN_comment = | legal_status = Rx-only

| CAS_number_Ref = | CAS_number = 1256937-27-5 | CAS_supplemental = | PubChem = | IUPHAR_ligand = | DrugBank_Ref = | DrugBank = | ChemSpiderID_Ref = | ChemSpiderID = none | UNII_Ref = {{fdacite|correct|FDA}} | UNII = LKC0U3A8NJ | KEGG_Ref = {{keggcite|correct|kegg}} | KEGG = D10557 | ChEBI_Ref = | ChEBI = | ChEMBL_Ref = | ChEMBL = | NIAID_ChemDB = | PDB_ligand = | synonyms = AMG-145<ref name=sheridan2013>{{cite journal | vauthors = Sheridan C | title = Phase 3 data for PCSK9 inhibitor wows | journal = Nature Biotechnology | volume = 31 | issue = 12 | pages = 1057–1058 | date = December 2013 | pmid = 24316621 | doi = 10.1038/nbt1213-1057 | s2cid = 34214247 }}</ref>

| IUPAC_name = | C=6242 | H=9648 | N=1668 | O=1996 | S=56 | SMILES = | StdInChI = | StdInChI_comment = | StdInChIKey = | density = | density_notes = | melting_point = | melting_high = | melting_notes = | boiling_point = | boiling_notes = | solubility = | sol_units = | specific_rotation = }}

'''Evolocumab''',<ref>{{cite journal | year = 2013 | title = International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 70 | journal = WHO Drug Information | volume = 27 | issue = 3 | hdl = 10665/331167 | hdl-access = free }}</ref> sold under the brand name '''Repatha''', is a monoclonal antibody that is an immunotherapy medication for the treatment of hyperlipidemia.

Evolocumab is a fully human monoclonal antibody that inhibits proprotein convertase subtilisin/kexin type 9 (PCSK9). PCSK9 is a protein that targets LDL receptors for degradation; its inhibition thereby enhances the liver's ability to remove LDL-C, often colloquially referred to as "bad" cholesterol, from the blood.<ref>{{cite journal | vauthors = Coppinger C, Movahed MR, Azemawah V, Peyton L, Gregory J, Hashemzadeh M | title = A Comprehensive Review of PCSK9 Inhibitors | journal = Journal of Cardiovascular Pharmacology and Therapeutics | volume = 27 | article-number = 10742484221100107 | date = 20 May 2022 | pmid = 35593194 | doi = 10.1177/10742484221100107 | s2cid = 248918656 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Weinreich M, Frishman WH | title = Antihyperlipidemic therapies targeting PCSK9 | journal = Cardiology in Review | volume = 22 | issue = 3 | pages = 140–146 | date = 2014 | pmid = 24407047 | doi = 10.1097/CRD.0000000000000014 | s2cid = 2201087 }}</ref>

In 2023, it was the 188th most commonly prescribed medication in the United States, with more than 2 million prescriptions.<ref name="Top 300">{{cite web | title=Top 300 of 2023 | url=https://clincalc.com/DrugStats/Top300Drugs.aspx | website=ClinCalc | access-date=12 August 2025 | archive-date=12 August 2025 | archive-url=https://web.archive.org/web/20250812130026/https://clincalc.com/DrugStats/Top300Drugs.aspx | url-status=live }}</ref><ref>{{cite web | title = Evolocumab Drug Usage Statistics, United States, 2014 - 2023 | website = ClinCalc | url = https://clincalc.com/DrugStats/Drugs/Evolocumab | access-date = 19 August 2025 }}</ref>

==Mechanism== Evolocumab is designed to bind to PCSK9 and inhibit PCSK9 from binding to LDL receptors on the liver surface. In the absence of PCSK9, there are more LDL receptors on the surface of liver cells to remove LDL-C from the blood.<ref>{{cite web | url = https://spisaniemd.bg/md-magazine/2016/11/pcsk9-inhibitori-nov-klas-medikamenti-za-lechenie-na-dislipidemiya | title = PCSK9 инхибитори – нов клас медикаменти за лечение на дислипидемия | work = Списание МД | trans-title = PCSK9 inhibitors – a new class of drugs for the treatment of dyslipidemia | trans-work = MD Journal | via = spisaniemd.bg | date = November 2016 | access-date = 28 October 2018 | language = Bulgarian | archive-date = 28 October 2018 | archive-url = https://web.archive.org/web/20181028190320/https://spisaniemd.bg/md-magazine/2016/11/pcsk9-inhibitori-nov-klas-medikamenti-za-lechenie-na-dislipidemiya }}</ref> In 2023, Amgen discontinued the monthly 420 mg dosing option for Repatha, retaining only the biweekly 140 mg option.<ref>{{Cite web |title= |url=https://www.repatha.com/~/media/12A733ED009842C68F1DA5F83532C636.ashx}}</ref>

==Adverse effects== Injection site reactions such as redness and pain are common and are reported in approximately 2.1–4.3% of cases.<ref name="PMID32821708">{{cite journal | vauthors = Choi JY, Na JO | title = Pharmacological Strategies beyond Statins: Ezetimibe and PCSK9 Inhibitors | journal = Journal of Lipid and Atherosclerosis | volume = 8 | issue = 2 | pages = 183–191 | date = September 2019 | pmid = 32821708 | doi = 10.12997/jla.2019.8.2.183 | pmc = 7379114 }}</ref><ref name="PMID28304224">{{cite journal | vauthors = Sabatine MS, Giugliano RP, Keech AC, Honarpour N, Wiviott SD, Murphy SA, Kuder JF, Wang H, Liu T, Wasserman SM, Sever PS, Pedersen TR | title = Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease | journal = The New England Journal of Medicine | volume = 376 | issue = 18 | pages = 1713–1722 | date = May 2017 | pmid = 28304224 | doi = 10.1056/NEJMoa1615664 | s2cid = 1972937 | doi-access = free | hdl = 10536/DRO/DU:30157496 | hdl-access = free }}</ref>

== History== Amgen submitted a biologics license application (BLA) for evolocumab to the FDA in August 2014.<ref>{{cite web | url = https://www.amgen.com/newsroom/press-releases/2014/08/amgen-submits-biologics-license-application-for-novel-investigational-ldl-cholesterol-lowering-medication-evolocumab-to-the-fda | title = Amgen Submits Biologics License Application For Novel Investigational LDL Cholesterol-Lowering Medication Evolocumab To The FDA | work = Amgen | date = 28 August 2014 }}</ref> The FDA approved evolocumab injection on 27 August 2015, for some patients who are unable to get their LDL cholesterol under control with current treatment options.<ref name=FDA>{{cite news| work = FDA News Release | publisher = U.S. Food and Drug Administration |title=FDA approves Repatha to treat certain patients with high cholesterol|url=https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm460082.htm|archive-url=https://web.archive.org/web/20150828195438/http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm460082.htm|archive-date=28 August 2015|access-date=30 August 2015|agency=U.S. Food and Drug Administration|date=27 August 2015}}</ref> The European Commission approved it in July 2015.<ref>{{cite web | url = http://investors.amgen.com/phoenix.zhtml?c=61656&p=RssLanding&cat=news&id=2069405 | title = European Commission Approves Amgen's New Cholesterol-Lowering Medication Repatha™ (evolocumab), The First PCSK9 Inhibitor To Be Approved In The World, For Treatment Of High Cholesterol | work = Amgen | date = 21 July 2015 | access-date = 11 January 2020 | archive-date = 22 July 2015 | archive-url = https://archive.today/20150722065627/http://investors.amgen.com/phoenix.zhtml?c=61656&p=RssLanding&cat=news&id=2069405 }}</ref> Evolocumab received approval from Health Canada on 10 September 2015.<ref>{{cite web|title = Regulatory Decision Summary (SBD): REPATHA - 2015 - Health Canada|url = http://www.hc-sc.gc.ca/dhp-mps/prodpharma/rds-sdr/drug-med/rds_sdr_repatha_178234-eng.php|website = www.hc-sc.gc.ca|access-date = 6 October 2015|archive-url = https://web.archive.org/web/20151007082457/http://www.hc-sc.gc.ca/dhp-mps/prodpharma/rds-sdr/drug-med/rds_sdr_repatha_178234-eng.php|archive-date = 7 October 2015}}</ref> Amgen reported approval by Health Canada in a press release on 15 September 2015.<ref>{{cite web|title = Amgen - Media - In The News|url = https://www.amgen.ca/english/media/repatha_press_release.html|website = www.amgen.ca|access-date = 17 September 2015|archive-date = 4 March 2016|archive-url = https://web.archive.org/web/20160304054941/https://www.amgen.ca/english/media/repatha_press_release.html}}</ref>

Results of the FOURIER trial were published in March 2017.<ref>{{cite journal | vauthors = Sabatine MS, Giugliano RP, Keech AC, Honarpour N, Wiviott SD, Murphy SA, Kuder JF, Wang H, Liu T, Wasserman SM, Sever PS, Pedersen TR | title = Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease | language = EN | journal = The New England Journal of Medicine | volume = 376 | issue = 18 | pages = 1713–1722 | date = May 2017 | pmid = 28304224 | doi = 10.1056/nejmoa1615664 | s2cid = 1972937 | doi-access = free | hdl = 10536/DRO/DU:30157496 | hdl-access = free }}</ref> Results from FOURIER-OLE, an open-label follow-up study of 24% of the patients in the treatment arm of FOURIER, were published by Amgen in 2022.<ref>{{cite journal | vauthors = O'Donoghue ML, Giugliano RP, Wiviott SD, Atar D, Keech A, Kuder JF, Im K, Murphy SA, Flores-Arredondo JH, López JA, Elliott-Davey M, Wang B, Monsalvo ML, Abbasi S, Sabatine MS | title = Long-Term Evolocumab in Patients With Established Atherosclerotic Cardiovascular Disease | journal = Circulation | volume = 146 | issue = 15 | pages = 1109–1119 | date = October 2022 | pmid = 36031810 | doi = 10.1161/circulationaha.122.061620 }}</ref> In 2022 a reanalysis of the FOURIER trial based on regulatory data found that cardiac mortality with evolocumab was higher than had been reported in the trial publication, with the authors calling for a full independent trial restoration of FOURIER. Overall cardiovascular mortality, which had been overreported, was found to be higher on evolocumab than on placebo, but the difference was not statistically significant.<ref>{{cite journal | vauthors = Erviti J, Wright J, Bassett K, Ben-Eltriki M, Jauca C, Saiz LC, Leache L, Gutiérrez-Valencia M, Perry TL | title = Restoring mortality data in the FOURIER cardiovascular outcomes trial of evolocumab in patients with cardiovascular disease: a reanalysis based on regulatory data | journal = BMJ Open | volume = 12 | issue = 12 | article-number = e060172 | date = December 2022 | pmid = 36585131 | doi = 10.1136/bmjopen-2021-060172 | doi-access = free| pmc = 9809302 }}</ref>

Regeneron Pharmaceuticals and Amgen each filed for patent protection on their monoclonal antibodies against PCSK9 and the companies ended up in patent litigation in the U.S. In March 2016, a district court found that Regeneron's drug alirocumab infringed Amgen's patents; Amgen then requested an injunction barring Regeneron and Sanofi from marketing alirocumab, which was granted in January 2017. The judge gave Regeneron and Sanofi 30 days to appeal before the injunction went into effect.<ref>{{cite news | vauthors = Feeley J, Bloomfield D, Decker S |title=Amgen Wins Ban on Sanofi's Praluent Cholesterol Drug Sales|url=https://www.bloomberg.com/news/articles/2017-01-05/amgen-wins-ban-on-sanofi-s-sales-of-praluent-cholesterol-drug|work=Bloomberg News|date=5 January 2017}}</ref> After several years of litigation, the patent dispute between Regeneron and Amgen was docketed by the SCOTUS for March-April 2023<ref name = "SCOTUSBlog" /> Numerous legal commentators were surprised by the SCOTUS decision, considering the existing trend not to review patent cases from the United States Court of Appeals for the Federal Circuit, since this court was created in 1982 to assure uniformity in patent law among all federal courts. The question before the US Supreme Court was "Whether enablement is governed by the statutory requirement, that the specification teach those skilled in the art to "make and use" the claimed invention, or whether it must instead enable those skilled in the art "to reach the full scope of claimed embodiments" without undue experimentation—i.e., to cumulatively identify and make all or nearly all embodiments of the invention without substantial "time and effort".<ref name = "SCOTUSBlog">{{cite web | url=https://www.scotusblog.com/case-files/cases/amgen-inc-v-sanofi-2/ | title=Amgen Inc. V. Sanofi | work = SCOTUSblog }}</ref> Other commentators believe that the SCOTUS took the case because of the significance of the legal question, which was deemed comparable to the impact of ''KSR v. Teleflex''.

Amgen's issued patents contained a so-called "functional genus claim," which defines an antibody by its epitope, the specific target against which it binds. Although Amgen did discover the target antigen, the antigen itself cannot be patented, because it is a product of nature (i.e. it was discovered rather than invented). However, Amgen was able to convince the USPTO to issue a patent that broadly claimed yet-unmade antibodies with a high affinity to the discovered antigen. Although there are many potential problems with such "functional genus" claims, the lower courts invalidated Amgen's broad claims based on the patent requirements for sufficiency of disclosure. The purposivism justification for disallowing such broad poorly-enabled claims is to allow other pharmaceutical companies to develop other (and potentially better) drugs that target the same antigen. However, the drawback of such narrow interpretation is the resulting reluctance of the antigen discoverers to share their findings with the world, because such early disclosure would prevent them from reaping the maximum profits from their discovery, which they could obtain by developing multiple medications and keeping them secret for many years.<ref>{{cite journal | url=https://www.liebertpub.com/doi/pdf/10.1089/blr.2022.29293.cmh?download=true | doi=10.1089/blr.2022.29293.cmh | title=Amgen v. Sanofi: The Supreme Court Takes up the Enablement Requirement in the Context of Therapeutic Monoclonal Antibodies | year=2022 | vauthors = Holman CM | journal=Biotechnology Law Report | volume=41 | issue=6 | pages=269–282 | s2cid=254435116 | url-access=subscription }}</ref> Such a dilemma is not unique to biologics or to pharmaceuticals, since the purpose of the patent system is to provide an incentive for earlier disclosure in the gambling game from discovery to market, that does not necessarily reward every participant according to their contribution, but encourages discoverers and inventors to play the gambling game nevertheless.<ref name="pmid36972066">{{cite journal | vauthors = Tu SS, Nagar S, Van de Wiele VL | title = Broad Patent Claims Come Before the Supreme Court in Amgen v Sanofi | journal = JAMA | volume = 329 | issue = 19 | pages = 1641–1642 | date = May 2023 | pmid = 36972066 | doi = 10.1001/jama.2023.5638 | s2cid = 257765649 | doi-access = free }}</ref>

== Society and culture ==

=== Economics === In 2015, evolocumab cost about US$14,100 per year. One article calculated this to be about $400,000 to $500,000 per quality-adjusted life year (QALY), which did not meet "generally accepted" cost-benefit thresholds. The authors calculated that an annual cost of $4,500 would meet an acceptable $100,000 per QALY standard.<ref>{{cite journal | vauthors = Kazi DS, Moran AE, Coxson PG, Penko J, Ollendorf DA, Pearson SD, Tice JA, Guzman D, Bibbins-Domingo K | title = Cost-effectiveness of PCSK9 Inhibitor Therapy in Patients With Heterozygous Familial Hypercholesterolemia or Atherosclerotic Cardiovascular Disease | journal = JAMA | volume = 316 | issue = 7 | pages = 743–753 | date = August 2016 | pmid = 27533159 | doi = 10.1001/jama.2016.11004 | doi-access = free }}</ref> On 26 October 2018, Amgen announced a 60% cut in price, setting the new price at $5,850 per year.<ref>{{cite news|url=https://www.marketwatch.com/story/the-bigger-money-message-behind-amgens-decision-to-slash-the-cost-of-its-repatha-cholesterol-drug-2018-10-26?siteid=yhoof2&yptr=yahoo|title=The bigger message behind Amgen's decision to slash cost of its Repatha cholesterol drug| vauthors = Goldman D |work=MarketWatch|access-date=28 October 2018}}</ref>

In Australia, as of April 2025, evolocumab has been added to the Pharmaceutical Benefits Scheme (PBS) and is subsidized for qualified patients. The cost to the PBS is AUD$339.25 for 2 injectable pens (enough for 4 weeks use = AUD$4420/yr), and the cost to the patient is AUD$31.60 (AUD$416/yr) <ref>{{cite web | url = https://www.pbs.gov.au/medicine/item/10958R-11484K-11977J-11985T | title = Evolocumab | work = Pharmaceutical Benefits Scheme | publisher = Commonwealth of Australia }}</ref>

== References == {{Reflist}}

{{Lipid modifying agents}} {{monoclonals for bone, musculoskeletal, circulatory, and neurologic systems}} {{Portal bar | Medicine}} {{Authority control}}

Category:Drugs developed by Amgen Category:PCSK9 inhibitors Category:Monoclonal antibodies