etanercept

In the United States, etanercept is indicated for:

• Moderate to Severe Rheumatoid Arthritis (RA) (Nov 1998){{cite letter | vauthors = Siegel YP | recipient = Sally Gould | subject = Approval of Etanercept for treatment of rheumatoid arthritis | date = 2 November 1998 | access-date = 14 April 2015 | url = https://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/TherapeuticBiologicApplications/ucm088659.pdf | archive-url = https://web.archive.org/web/20090712080943/http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/TherapeuticBiologicApplications/ucm088659.pdf | url-status = dead | archive-date = 12 July 2009 | publisher = U.S. Food and Drug Administration (FDA)}}
• Moderate to Severe Polyarticular Juvenile Rheumatoid Arthritis (May 1999){{cite letter | vauthors = Weiss KD | recipient = Sally Gould | subject = Approval of Etanercept for treatment of polyarticular course juvenile rheumatoid arthritis (JRA) | date = 27 May 1999 | access-date = 14 April 2015 | url = https://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/TherapeuticBiologicApplications/ucm088844.pdf | archive-url = https://web.archive.org/web/20090712080814/http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/TherapeuticBiologicApplications/ucm088844.pdf | url-status = dead | archive-date = 12 July 2009 | publisher = U.S. Food and Drug Administration (FDA)}}
• Psoriatic Arthritis (Jan 2002){{cite letter | vauthors = Weiss KD | recipient = Sally Gould | subject = Approval of Etanercept for treatment of psoriatic arthritis | date = 15 January 2002 | access-date = 14 April 2015 | url = http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2002/etanimm011502L.htm | archive-url = https://web.archive.org/web/20120630012600/http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2002/etanimm011502L.htm | url-status = dead | archive-date = 30 June 2012 | publisher = U.S. Food and Drug Administration (FDA)}}
• Ankylosing Spondylitis (AS) (July 2003){{cite letter | vauthors = Keegan P | recipient = Douglas Hunt | subject = Approval of Etanercept for treatment of ankylosing spondylitis | date = 24 July 2003 | access-date = 14 April 2015 | url = http://www.accessdata.fda.gov/drugsatfda_docs/nda/2003/103795-5123_Enbrel_approv.pdf | archive-url = https://web.archive.org/web/20150414204927/http://www.accessdata.fda.gov/drugsatfda_docs/nda/2003/103795-5123_Enbrel_approv.pdf | url-status = dead | archive-date = 14 April 2015 | publisher = U.S. Food and Drug Administration (FDA)}}{{cite journal | vauthors = Maxwell LJ, Zochling J, Boonen A, Singh JA, Veras MM, Tanjong Ghogomu E, Benkhalti Jandu M, Tugwell P, Wells GA | display-authors = 6 | title = TNF-alpha inhibitors for ankylosing spondylitis | journal = The Cochrane Database of Systematic Reviews | volume = 2015 | issue = 4 | pages = CD005468 | date = April 2015 | pmid = 25887212 | doi = 10.1002/14651858.CD005468.pub2 | pmc = 11200207 }}
• Moderate to Severe Plaque Psoriasis (April 2004){{cite letter | vauthors = Walton M | recipient = Douglas Hunt | subject = Approval of Etanercept for treatment of moderate to severe plaque psoriasis | date = 30 April 2004 | access-date = 14 April 2015 | url = http://www.accessdata.fda.gov/drugsatfda_docs/appletter/biologics/2004/103795_5149ltr.pdf | archive-url = https://web.archive.org/web/20150414205243/http://www.accessdata.fda.gov/drugsatfda_docs/appletter/biologics/2004/103795_5149ltr.pdf | url-status = dead | archive-date = 14 April 2015 | publisher = U.S. Food and Drug Administration (FDA)}}

In the European Union, etanercept is indicated to treat:

• moderate to severe active rheumatoid arthritis
• severe, active and progressive rheumatoid arthritis
• juvenile idiopathic arthritis
• polyarthritis (rheumatoid-factor-positive or -negative) and extended oligoarthritis in children and adolescents
• active and progressive psoriatic arthritis
• enthesitis-related arthritis
• axial spondyloarthritis
• severe active ankylosing spondylitis
• severe non-radiographic axial spondyloarthritis
• moderate to severe plaque psoriasis
• chronic severe plaque psoriasis pediatric plaque psoriasis

An American physician, Edward Tobinick, has attempted to use etanercept to treat chronic neurological dysfunction after stroke and brain injury{{cite news |publisher=Springer Select |date=31 October 2012 |title=New hope for survivors of stroke and traumatic brain injury | url=https://www.springer.com/about+springer/media/springer+select?SGWID=0-11001-6-1394543-0 |access-date=17 November 2018 }} and issued U.S.{{Cite patent|country=US|number=8900583|title=Methods for treatment of brain injury utilizing biologics|inventor = Tobinick EL |pubdate=2014-12-02}} and foreign patents. Writing for Science-Based Medicine, Steven Novella said that it was "unethical for physicians to practice outside of their area of competence and expertise". Tobinick sued Novella in response, and lost.{{Cite web |date=24 February 2017 |title=Another Free Speech Win In Libel Lawsuit Disguised As A Trademark Complaint |url=https://abovethelaw.com/2017/02/another-free-speech-win-in-libel-lawsuit-disguised-as-a-trademark-complaint/ |access-date=27 June 2022 |website=Above the Law |language=en-US}} Of this treatment, the American Academy of Neurology advise "there is insufficient evidence to determine its effectiveness and that the treatment may be associated with adverse outcomes and high cost".{{cite web |publisher=American Academy of Neurology |title=Practice Advisory: Etanercept for Poststroke Disability |url=https://www.aan.com/Guidelines/home/GetGuidelineContent/747 |date=6 June 2016 |format=pdf}}

On 2 May 2008, the US Food and Drug Administration (FDA) placed a black box warning on etanercept due to a number of serious infections associated with the drug.{{cite web|url=https://money.cnn.com/news/newsfeeds/articles/apwire/21965cf0a650a8b5897142bfcbccb427.htm |title=Wyeth and Amgen heighten warning of life-threatening infections on skin drug Enbrel |access-date=2 May 2008 |archive-url=https://web.archive.org/web/20080505133653/https://money.cnn.com/news/newsfeeds/articles/apwire/21965cf0a650a8b5897142bfcbccb427.htm |archive-date=5 May 2008 |url-status=dead }} Serious infections and sepsis, including fatalities, have been reported with the use of etanercept including reactivation of latent tuberculosis and hepatitis B infections.{{cite conference | url=https://www.fda.gov/ohrms/dockets/ac/01/briefing/3779b2_01_cber_safety%20_revision2.pdf | title=Safety Update on TNF- α Antagonists: Infliximab and Etanercept | publisher=U.S. Food and Drug Administration (FDA) | access-date=20 December 2013 | pages=13–14 | conference= | archive-date=24 September 2015 | archive-url=https://web.archive.org/web/20150924170456/http://www.fda.gov/ohrms/dockets/ac/01/briefing/3779b2_01_cber_safety%20_revision2.pdf | url-status=dead }}

Injection site reactions such as redness and pain are common, occurring in approximately 11.4% of cases.{{cite journal | vauthors = Kim PJ, Lansang RP, Vender R | title = A Systematic Review and Meta-Analysis of Injection Site Reactions in Randomized-Controlled Trials of Biologic Injections | journal = Journal of Cutaneous Medicine and Surgery | volume = 27 | issue = 4 | pages = 358–367 | date = July 2023 | pmid = 37533141 | doi = 10.1177/12034754231188444 | pmc = 10486173 }}

Etanercept reduces the effect of naturally present TNF, and hence is a TNF inhibitor, functioning as a decoy receptor that binds to TNF.{{cite journal | vauthors = Zalevsky J, Secher T, Ezhevsky SA, Janot L, Steed PM, O'Brien C, Eivazi A, Kung J, Nguyen DH, Doberstein SK, Erard F, Ryffel B, Szymkowski DE | display-authors = 6 | title = Dominant-negative inhibitors of soluble TNF attenuate experimental arthritis without suppressing innate immunity to infection | journal = Journal of Immunology | volume = 179 | issue = 3 | pages = 1872–1883 | date = August 2007 | pmid = 17641054 | doi = 10.4049/jimmunol.179.3.1872 | doi-access = free }}

Tumor necrosis factor-alpha (TNFα) is a cytokine produced by lymphocytes and macrophages, two types of white blood cells. It mediates the immune response by attracting additional white blood cells to sites of inflammation and through additional molecular mechanisms that initiate and amplify inflammation. Inhibition of its action by etanercept reduces the inflammatory response, which is especially useful for treating autoimmune diseases.

There are two types of TNF receptors: those found embedded in white blood cells that respond to TNF by releasing other cytokines, and soluble TNF receptors that are used to deactivate TNF and blunt the immune response. In addition, TNF receptors are found on the surface of virtually all nucleated cells (red blood cells, which are not nucleated, do not contain TNF receptors on their surface). Etanercept mimics the inhibitory effects of naturally occurring soluble TNF receptors, the difference being that etanercept, because it is a fusion protein rather than a simple TNF receptor, has a greatly extended half-life in the bloodstream, and therefore a more profound and long-lasting biologic effect than a naturally occurring soluble TNF receptor.{{cite journal | vauthors = Madhusudan S, Muthuramalingam SR, Braybrooke JP, Wilner S, Kaur K, Han C, Hoare S, Balkwill F, Ganesan TS | display-authors = 6 | title = Study of etanercept, a tumor necrosis factor-alpha inhibitor, in recurrent ovarian cancer | journal = Journal of Clinical Oncology | volume = 23 | issue = 25 | pages = 5950–5959 | date = September 2005 | pmid = 16135466 | doi = 10.1200/JCO.2005.04.127 }}

Etanercept is made from the combination of two naturally occurring soluble human 75-kilodalton TNF receptors linked to an Fc portion of an IgG1.{{cite journal | vauthors = Smola MG, Soyer HP, Scharnagl E | title = Surgical treatment of dermatofibrosarcoma protuberans. A retrospective study of 20 cases with review of literature | journal = European Journal of Surgical Oncology | volume = 17 | issue = 5 | pages = 447–453 | date = October 1991 | pmid = 1936291 }} The effect is an artificially engineered dimeric fusion protein. Etanercept is a complex molecule containing 6 N-glycans, up to 14 O-glycans and 29 disulfide bridge structures.{{cite journal | vauthors = Houel S, Hilliard M, Yu YQ, McLoughlin N, Martin SM, Rudd PM, Williams JP, Chen W | display-authors = 6 | title = N- and O-glycosylation analysis of etanercept using liquid chromatography and quadrupole time-of-flight mass spectrometry equipped with electron-transfer dissociation functionality | journal = Analytical Chemistry | volume = 86 | issue = 1 | pages = 576–584 | date = January 2014 | pmid = 24308717 | doi = 10.1021/ac402726h }}{{cite journal | vauthors = Mukai Y, Nakamura T, Yoshikawa M, Yoshioka Y, Tsunoda S, Nakagawa S, Yamagata Y, Tsutsumi Y | display-authors = 6 | title = Solution of the structure of the TNF-TNFR2 complex | journal = Science Signaling | volume = 3 | issue = 148 | pages = ra83 | date = November 2010 | pmid = 21081755 | doi = 10.1126/scisignal.2000954 | s2cid = 24226117 }}{{cite journal | vauthors = Lamanna WC, Mayer RE, Rupprechter A, Fuchs M, Higel F, Fritsch C, Vogelsang C, Seidl A, Toll H, Schiestl M, Holzmann J | display-authors = 6 | title = The structure-function relationship of disulfide bonds in etanercept | journal = Scientific Reports | volume = 7 | issue = 1 | pages = 3951 | date = June 2017 | pmid = 28638112 | pmc = 5479810 | doi = 10.1038/s41598-017-04320-5 | bibcode = 2017NatSR...7.3951L }}

The first etanercept-related patent was filed by Immunex in September 1989.{{cite journal | vauthors = Norman P | title = Enbrel and etanercept biosimilars: a tale of two patent systems | journal = Pharmaceutical Patent Analyst | volume = 6 | issue = 1 | pages = 5–7 | date = January 2017 | pmid = 28201948 | doi = 10.4155/ppa-2016-0043 }} The fusion protein was developed by Bruce A. Beutler, an academic researcher then at the University of Texas Southwestern Medical Center at Dallas, and colleagues, who patented it and licensed the rights in 1995 to Immunex.{{cite web | title=A three-decade monopoly: How Amgen built a patent thicket around its top-selling drug | date=1 November 2021 | vauthors = Gardner J | url=https://www.biopharmadive.com/news/amgen-enbrel-patent-thicket-monopoly-biosimilar/609042/}} Another patent on such fusion protein technology from Brian Seed at Massachusetts General Hospital was licensed to Immmunex in 1997.{{cite web | vauthors = Kowalczyk L | date = 24 March 2002 | title = Lucrative Licensing Deals With Drug, Biotech Firms Are Raising Ethics Issues For Hospitals | url = https://www.sskrplaw.com/lucrative-licensing-deals-with-drug-biotech-firms-are-raising-et.html | access-date = 27 November 2022 | archive-date = 2 October 2023 | archive-url = https://web.archive.org/web/20231002114824/https://www.sskrplaw.com/lucrative-licensing-deals-with-drug-biotech-firms-are-raising-et.html | url-status = dead }}

Etanercept was approved for use in the United States in November 1998.{{cite web | title=Etanercept Product Approval Information - Licensing Action 12/2/98 | website=U.S. Food and Drug Administration (FDA) | date=1 April 2016 | url=https://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/TherapeuticBiologicApplications/ucm080536.htm | archive-url=https://web.archive.org/web/20170118085127/https://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/TherapeuticBiologicApplications/ucm080536.htm | archive-date=18 January 2017 | url-status=dead | access-date=4 June 2020}}

Etanercept was approved for use in the European Union in February 2000.{{cite web | title=Enbrel EPAR | website=European Medicines Agency (EMA) | date=11 September 2009 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/enbrel | access-date=2 April 2020}} Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.

The US retail price of etanercept has risen over time. In 2008, the cost of etanercept was $1,500 per month or $18,000 per year.[http://seattletimes.com/html/health/2008120449_drugs18m.html "What's behind the whopping price tags on the newest generation of drugs:] The story behind the production of Enbrel, Amgen's popular rheumatoid arthritis drug, provides insights as to why bioengineered drugs are so expensive." Carol M. Ostrom, Seattle Times, 18 August 2008 By 2011, the cost had exceeded $20,000 per year.{{cite news | title=Amgen's New Enbrel Patent May Undercut Health Care Plan | website=The New York Times | date=23 November 2011 | url=https://www.nytimes.com/2011/11/23/business/amgens-new-enbrel-patent-may-undercut-health-care-plan.html | access-date=10 March 2023 | vauthors = Pollock A }}[http://bostonherald.com/news/columnists/view/2011_1103painful_reality "Co-pay hike a painful reality; Miracle drug monthly cost jumps from $42 to $600"] {{Webarchive|url=https://archive.today/20130118110008/http://bostonherald.com/news/columnists/view/2011_1103painful_reality |date=18 January 2013 }}, Margery Eagan, Boston Herald, 3 November 2011 In 2013, a survey by the International Federation of Health Plans (IFHP) found that the average US cost for etanercept was $2,225 per month, or $26,700 per year.{{cite web |url=https://static1.squarespace.com/static/518a3cfee4b0a77d03a62c98/t/534fc9ebe4b05a88e5fbab70/1397737963288/2013+iFHP+FINAL+4+14+14.pdf |title=2013 Comparative Price Report |publisher=International Federation of Health Plans |access-date=24 November 2017 |archive-date=22 October 2017 |archive-url=https://web.archive.org/web/20171022020959/http://static1.squarespace.com/static/518a3cfee4b0a77d03a62c98/t/534fc9ebe4b05a88e5fbab70/1397737963288/2013+iFHP+FINAL+4+14+14.pdf |url-status=dead }} The IFHP report also found wide variation in prices charged to various US health plans, between $1,946 per month at the 25th percentile and $4,006 per month at the 95th percentile.

Etanercept is more expensive in the US than in other countries. As of 2013, average monthly costs in surveyed nations ranged from $1,017 in Switzerland to $1,646 in Canada, compared to an average monthly cost of $2,225 per month in the US.

Amgen sells etanercept within the US and Canada, while Pfizer, Inc. sells the drug outside of the US and Canada. Sales within the US and Canada were $3.5 billion in 2010. Sales of etanercept outside the US and Canada were $3.3 billion in 2010.{{cite web|url=https://www.sec.gov/Archives/edgar/data/78003/000119312511048877/dex13.htm |title=Portions of the 2010 Financial Report |publisher=Sec.gov |access-date=5 June 2019}}

In late March 2025, Amgen lost a lawsuit against Colorado over a prescription drug affordability board.{{Cite web |date=2025-03-29 |title=Amgen loses battle with Colorado over prescription drug affordability board |url=https://www.statnews.com/pharmalot/2025/03/28/amgen-colorado-pharma-medicines-enbrel-prescription-constitution-drugs/ |access-date=2025-03-29 |archive-url=https://web.archive.org/web/20250329083149/https://www.statnews.com/pharmalot/2025/03/28/amgen-colorado-pharma-medicines-enbrel-prescription-constitution-drugs/ |archive-date=29 March 2025 }}

The patent on etanercept was set to expire in October 2012,{{cite web | url=http://www.uspto.gov/patents/resources/terms/156.html | title=Patent Terms Extended Under 35 USC §156 | access-date=9 December 2009 | archive-date=24 February 2010 | archive-url=https://web.archive.org/web/20100224023842/http://www.uspto.gov/patents/resources/terms/156.html | url-status=dead }} but, in the United States, a second patent, granting exclusivity for another 16 years, has been granted.{{cite web | url=http://www.gabionline.net/Biosimilars/News/New-Amgen-Enbrel-patent-could-block-biosimilars-until-2028 | title=New Amgen Enbrel patent could block biosimilars until 2028 | date=25 November 2011 | access-date=14 July 2019}}

Before the extension it seemed unlikely that a generic would have been available. As a biologic, etanercept is subject to different laws from those applicable to chemical formulations. Many countries do not permit the manufacture of generic biologics. However, the European Union and the United States ([https://web.archive.org/web/20131026073540/http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/TherapeuticBiologicApplications/Biosimilars/ Biologics Price Competition and Innovation Act of 2009]) do have in place a system to approve generic biologics (biosimilars) which "requires mandatory clinical testing and periodic review".{{cite web|url=https://scholarship.law.duke.edu/cgi/viewcontent.cgi?referer=https://en.wikipedia.org/&httpsredir=1&article=1184&context=dltr |title=The Future of Generic Biologics: Should the United States "Follow-On" the European Pathway? | vauthors = Kaldre I |date=2008 |website=www.law.duke.edu |access-date=5 June 2019}}

In April 2013, the Indian pharma major Cipla made an announcement about launching the first biosimilar of Etanercept in India under the brand name Etacept for the treatment of rheumatic disorders.{{cite web |url=http://www.cipla.com/CiplaSite/Media/PDF/News-Archives/Press-Release-Launch-of-first-biosimilar-of-Etanercept-in-India.pdf?ext=.pdf |title=Cipla - Home |publisher=Cipla.com |access-date=5 June 2019 |archive-date=1 May 2013 |archive-url=https://web.archive.org/web/20130501202841/http://www.cipla.com/CiplaSite/Media/PDF/News-Archives/Press-Release-Launch-of-first-biosimilar-of-Etanercept-in-India.pdf?ext=.pdf |url-status=dead }}

{{see also|Biosimilars}}

In January 2016, Benepali was approved for use in the European Union.{{cite web | title=Benepali EPAR | website=European Medicines Agency (EMA) | date=28 January 2016 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/benepali | access-date=2 April 2020}}

In February 2017, Lifmior was approved for use in the European Union.{{cite web | title=Lifmior EPAR | website=European Medicines Agency (EMA) | date=13 March 2017 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/lifmior | access-date=2 April 2020}} It was withdrawn from the market in February 2020.{{cite web | title=Public statement on Lifmior: Withdrawal of the marketing authorisation in the European Union | url=https://www.ema.europa.eu/documents/public-statement/public-statement-lifmior-withdrawal-marketing-authorisation-european-union_en.pdf | access-date=2 April 2020}}

In June 2017, Erelzi was approved for use in the European Union.{{cite web | title=Erelzi EPAR | website=European Medicines Agency (EMA) | date=29 June 2017 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/erelzi | access-date=2 April 2020}}

In March 2019, YLB113 (Etanercept biosimilar by YL Biologics) was approved in Japan.{{Cite web|title=Japanese approval for Lupin's etanercept biosimilar|url=https://www.gabionline.net/biosimilars/news/Japanese-approval-for-Lupin-s-etanercept-biosimilar}}

In April 2019, Eticovo received FDA approval.{{cite web | title=Drug Approval Package: Eticovo | website=U.S. Food and Drug Administration (FDA) | date=18 June 2019 | url=https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/761066Orig1s000TOC.cfm | archive-url=https://web.archive.org/web/20191218044939/https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/761066Orig1s000TOC.cfm | url-status=dead | archive-date=18 December 2019 | access-date=26 September 2024}}{{Cite web |title=FDA approves etanercept biosimilar Eticovo |url=https://www.gabionline.net/biosimilars/news/FDA-approves-etanercept-biosimilar-Eticovo |access-date=16 July 2024 |website=www.gabionline.net }}

In May 2020, Nepexto was approved for use in the European Union.

Rymti and Etera were approved for medical use in Australia in October 2020.{{cite web | title=Australian Public Assessment Report for Etanercept | date= Feb 2021 | url=https://www.tga.gov.au/sites/default/files/auspar-etanercept-210224.pdf }}{{cite web | title=AusPAR: Etanercept | website=Therapeutic Goods Administration (TGA) | date=25 February 2021 | url=https://www.tga.gov.au/auspar/auspar-etanercept-3 | access-date=12 June 2021}}{{cite web | title=Rymti ARTG | website=Therapeutic Goods Administration (TGA) | url=https://tga-search.clients.funnelback.com/s/search.html?collection=tga-artg&profile=record&meta_i=309830 | access-date=12 June 2021 | archive-date=13 June 2021 | archive-url=https://web.archive.org/web/20210613063803/https://tga-search.clients.funnelback.com/s/search.html?collection=tga-artg&profile=record&meta_i=309830 | url-status=dead }}{{cite web | title=Etera ARTG | website=Therapeutic Goods Administration (TGA) | url=https://tga-search.clients.funnelback.com/s/search.html?collection=tga-artg&profile=record&meta_i=309829 | access-date=12 June 2021 | archive-date=13 June 2021 | archive-url=https://web.archive.org/web/20210613063806/https://tga-search.clients.funnelback.com/s/search.html?collection=tga-artg&profile=record&meta_i=309829 | url-status=dead }}

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