Chemistry:Etanercept

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Etanercept
Enbrel.jpg
Clinical data
Trade namesEnbrel, Benepali, Erelzi, others
Other namesetanercept-szzs, etanercept-ykro
AHFS/Drugs.comMonograph
License data
Pregnancy
category
  • AU: B2
  • US: B (No risk in non-human studies)
Routes of
administration		Subcutaneous
ATC code
Legal status
Legal status
  • AU: S4 (Prescription only)
  • UK: POM (Prescription only)
  • US: ℞-only
Pharmacokinetic data
Bioavailability58–76% (SC)
MetabolismReticuloendothelial system (speculative)
Elimination half-life70–132 hours
Identifiers
CAS Number
PubChem SID
DrugBank
ChemSpider
  • none
UNII
KEGG
ChEMBL
Chemical and physical data
FormulaC2224H3475N621O698S36
Molar mass51235.07 g·mol−1

Etanercept, sold under the brand name Enbrel among others, is a biopharmaceutical that treats autoimmune diseases by interfering with tumor necrosis factor (TNF, a soluble inflammatory cytokine) by acting as a TNF inhibitor. It has U.S. F.D.A. approval to treat rheumatoid arthritis, juvenile idiopathic arthritis and psoriatic arthritis, plaque psoriasis and ankylosing spondylitis. TNF-alpha is the "master regulator" of the inflammatory (immune) response in many organ systems. Autoimmune diseases are caused by an overactive immune response. Etanercept has the potential to treat these diseases by inhibiting TNF-alpha.[1]

Etanercept is a fusion protein produced by recombinant DNA. It fuses the TNF receptor to the constant end of the IgG1 antibody. First, the developers isolated the DNA sequence that codes the human gene for soluble TNF receptor 2, which is a receptor that binds to tumor necrosis factor-alpha. Second, they isolated the DNA sequence that codes the human gene for the Fc end of immunoglobulin G1 (IgG1). Third, they linked the DNA for TNF receptor 2 to the DNA for IgG1 Fc. Finally, they expressed the linked DNA to produce a protein that links the protein for TNF receptor 2 to the protein for IgG1 Fc. The prototypic fusion protein was first synthesized and shown to be highly active and unusually stable as a modality for blockade of TNF in vivo in the early 1990s by Bruce A. Beutler, an academic researcher then at the University of Texas Southwestern Medical Center at Dallas, and his colleagues.[2][3]

These investigators also patented the protein,[4] selling all rights to its use to Immunex, a biotechnology company that was acquired by Amgen in 2002.[5]

It is a large molecule, with a molecular weight of 150 kDa, that binds to TNFα and decreases its role in disorders involving excess inflammation in humans and other animals, including autoimmune diseases such as ankylosing spondylitis,[6] juvenile rheumatoid arthritis, psoriasis, psoriatic arthritis, rheumatoid arthritis, and, potentially, in a variety of other disorders mediated by excess TNFα.

Medical uses

In the United States etanercept is indicated for:

  • Moderate to Severe Rheumatoid Arthritis (RA) (Nov 1998)[7]
  • Moderate to Severe Polyarticular Juvenile Rheumatoid Arthritis (May 1999)[8]
  • Psoriatic Arthritis (Jan 2002)[9]
  • Ankylosing Spondylitis (AS) (July 2003)[10][11]
  • Moderate to Severe Plaque Psoriasis (April 2004)[12]

In the European Union etanercept is indicated to treat:

  • moderate to severe active rheumatoid arthritis[13]
  • severe, active and progressive rheumatoid arthritis[13]
  • juvenile idiopathic arthritis[13]
  • polyarthritis (rheumatoid-factor-positive or -negative) and extended oligoarthritis in children and adolescents[13]
  • active and progressive psoriatic arthritis[13]
  • enthesitis-related arthritis
  • axial spondyloarthritis[13]
  • severe active ankylosing spondylitis[13]
  • severe non-radiographic axial spondyloarthritis[13]
  • moderate to severe plaque psoriasis[13]
  • chronic severe plaque psoriasis pediatric plaque psoriasis[13]

Safety

On May 2, 2008, the FDA placed a black box warning on etanercept due to a number of serious infections associated with the drug.[14] Serious infections and sepsis, including fatalities, have been reported with the use of etanercept including reactivation of latent tuberculosis and hepatitis B infections.[15][16]

There has also been a report of strongyloides hyperinfection after use of etanercept.[17]

Mechanism of action

It reduces the effect of naturally present TNF, and hence is a TNF inhibitor, functioning as a decoy receptor that binds to TNF.[18]

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.[19]

Structure

Etanercept is made from the combination of two naturally occurring soluble human 75-kilodalton TNF receptors linked to an Fc portion of an IgG1.[20] The effect is an artificially engineered dimeric fusion protein.[20] Etanercept is a complex molecule containing 6 N-glycans, up to 14 O-glycans and 29 disulfide bridge structures.[21][22][23]

History

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 sold the rights to Immunex.[citation needed] The first etanercept-related patent was filed by Immunex on September 5, 1989.[24]

Etanercept was approved for use in the United States in November 1998.[25]

Etanercept was approved for use in the European Union in February 2000.[13]

Society and culture

Marketing

In North America, etanercept is marketed by Amgen under the trade name Enbrel in two separate formulations, one in powder form, the other as a pre-mixed liquid. Wyeth (now part of Pfizer) was the sole marketer of Enbrel outside North America excluding Japan where Takeda Pharmaceuticals markets the drug.

Sales

The U.S. retail price of Enbrel has risen over time. In 2008, the cost of Enbrel was $1,500 per month or $18,000 per year.[26] By 2011, the cost had exceeded $20,000 per year.[27][28] In 2013, a survey by the International Federation of Health Plans (IFHP) found that the average U.S. cost for Enbrel was $2,225 per month, or $26,700 per year.[29] The IFHP report also found wide variation in prices charged to various U.S. health plans, between $1,946 per month at the 25th percentile and $4,006 per month at the 95th percentile.[29]

Enbrel is more expensive in the U.S. than in other countries.[29] 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 U.S.[29]

Amgen sells Enbrel within the U.S. and Canada, while Pfizer, Inc. sells the drug outside of the U.S. and Canada.[27] Sales within the U.S. and Canada were $3.5 billion in 2010.[27] Sales of Enbrel outside the U.S. and Canada were $3.3 billion in 2010.[30]

Patents

The patent on Enbrel was originally set to expire on October 23, 2012,[31] but, in the United States, a second patent, granting exclusivity for another 16 years, has been granted.[32]

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. Currently many countries do not permit the manufacture of generic biologics. However, the European Union and the United States (Biologics Price Competition and Innovation Act of 2009) do currently have in place a system to approve generic biologics (biosimilars) which "requires mandatory clinical testing and periodic review".[33]

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. The company's April 17, 2013 press release claimed that the biosimilar will cost 30% less as compared to the innovator.[34]

In January 2015, Samsung and Biogen's joint venture "Samsung Bioepis" successfully submitted Benepali, a biosimilar version of the drug, for review to the European Medicines Agency (EMA), and announced that it will seek regulatory approvals in other territories as well. Later the same year, the European Medicines Agency also accepted Sandoz’s application for review of its etanercept biosimilar Erelzi which will be marketed by Novartis.[35]

In the U.S., Sandoz submitted a biologics license application (BLA) for the proposed etanercept product "GP2015" in July 2016. Upon acceptance of the first application process, the U.S. FDA reviewed data from European clinical trials and bio-analytical investigations, demonstrating the biosimilarity of GP2015 to the US-licensed Enbrel. Sandoz in 2009 tried to invalidate the patents held by Hoffman-La Roche/Immunex and exclusively licensed to Amgen but lost in federal court. Sandoz was then countersued by Amgen for patent infringements related to the methods of treating psoriasis and/or psoriatic arthritis. The case Immunex Corp. et al. vs. Sandoz Inc. et al., 16-cv-01118-CCC-JBC (D.N.J.) is pending.[36]

Biosimilars

In January 2016, Benpali was approved for use in the European Union.[37]

In February 2017, Lifmior was approved for use in the European Union.[38] It was withdrawn from the market in February 2020.[39]

In June 2017, Erelzi was approved for use in the European Union.[40]

In May 2020, Nepexto was approved for use in the European Union.[41]

Similar agents

References

  1. ↑ "TNF defined as a therapeutic target for rheumatoid arthritis and other autoimmune diseases". Nature Medicine 9 (10): 1245–50. October 2003. doi:10.1038/nm939. PMID 14520364. 
  2. ↑ "A tumor necrosis factor (TNF) receptor-IgG heavy chain chimeric protein as a bivalent antagonist of TNF activity". The Journal of Experimental Medicine 174 (6): 1483–89. December 1991. doi:10.1084/jem.174.6.1483. PMID 1660525. 
  3. ↑ "Expression of a TNF inhibitor in transgenic mice". Journal of Immunology 151 (10): 5699–703. November 1993. PMID 7693816. 
  4. ↑ U.S. Patent number: 5,447,851
  5. ↑ "Arthritis Drug Effective for Depression in Psoriasis Sufferers". http://www.dukemednews.org/news/article.php?id=9419. Retrieved 2008-01-10. 
  6. ↑ "Improvement in patient-reported outcomes for patients with ankylosing spondylitis treated with etanercept 50 mg once-weekly and 25 mg twice-weekly". Rheumatology 46 (6): 999–1004. June 2007. doi:10.1093/rheumatology/kem069. PMID 17389658. 
  7. ↑ Siegel JP (November 2, 1998). "Approval of Etanercept for treatment of rheumatoid arthritis" (PDF). Letter to Sally Gould. Food and Drug Administration. Retrieved April 14, 2015.
  8. ↑ Weiss, Karen D. (May 27, 1999). "Approval of Etanercept for treatment of polyarticular course juvenile rheumatoid arthritis (JRA)" (PDF). Letter to Sally Gould. Food and Drug Administration. Retrieved April 14, 2015.
  9. ↑ Weiss KD (January 15, 2002). "Approval of Etanercept for treatment of psoriatic arthritis". Letter to Sally Gould. Food and Drug Administration. Retrieved April 14, 2015.
  10. ↑ Keegan P (July 24, 2003). "Approval of Etanercept for treatment of ankylosing spondylitis" (PDF). Letter to Douglas Hunt. Food and Drug Administration. Retrieved April 14, 2015.
  11. ↑ "TNF-alpha inhibitors for ankylosing spondylitis". The Cochrane Database of Systematic Reviews 4 (4): CD005468. April 2015. doi:10.1002/14651858.CD005468.pub2. PMID 25887212. http://ecite.utas.edu.au/120128. 
  12. ↑ Walton M (April 30, 2004). "Approval of Etanercept for treatment of moderate to severe plaque psoriasis" (PDF). Letter to Douglas Hunt. Food and Drug Administration. Retrieved April 14, 2015.
  13. ↑ 13.00 13.01 13.02 13.03 13.04 13.05 13.06 13.07 13.08 13.09 13.10 "Enbrel EPAR". https://www.ema.europa.eu/en/medicines/human/EPAR/enbrel.  Text was copied from this source which is © European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  14. ↑ "Wyeth and Amgen heighten warning of life-threatening infections on skin drug Enbrel". Archived from the original on 2008-05-05. https://web.archive.org/web/20080505133653/http://money.cnn.com/news/newsfeeds/articles/apwire/21965cf0a650a8b5897142bfcbccb427.htm. Retrieved 2008-05-02. 
  15. ↑ "Safety Update on TNF- α Antagonists: Infliximab and Etanercept". Food and Drug Administration. pp. 13–14. https://www.fda.gov/ohrms/dockets/ac/01/briefing/3779b2_01_cber_safety%20_revision2.pdf. Retrieved 20 December 2013. 
  16. ↑ "Prescribing Information – Enbrel". Archived from the original on 2007-10-14. https://web.archive.org/web/20071014032450/http://enbrel.com/prescribing-information.jsp. Retrieved 2008-01-10. 
  17. ↑ "UpToDate". http://www.uptodate.com/contents/strongyloidiasis/abstract/67?utdPopup=true. 
  18. ↑ "Dominant-negative inhibitors of soluble TNF attenuate experimental arthritis without suppressing innate immunity to infection". Journal of Immunology 179 (3): 1872–83. August 2007. doi:10.4049/jimmunol.179.3.1872. PMID 17641054. 
  19. ↑ "Study of etanercept, a tumor necrosis factor-alpha inhibitor, in recurrent ovarian cancer". Journal of Clinical Oncology 23 (25): 5950–59. September 2005. doi:10.1200/JCO.2005.04.127. PMID 16135466. 
  20. ↑ 20.0 20.1 "Surgical treatment of dermatofibrosarcoma protuberans. A retrospective study of 20 cases with review of literature". European Journal of Surgical Oncology 17 (5): 447–53. October 1991. PMID 1936291. 
  21. ↑ "N- and O-glycosylation analysis of etanercept using liquid chromatography and quadrupole time-of-flight mass spectrometry equipped with electron-transfer dissociation functionality". Analytical Chemistry 86 (1): 576–84. January 2014. doi:10.1021/ac402726h. PMID 24308717. 
  22. ↑ "Solution of the structure of the TNF-TNFR2 complex". Science Signaling 3 (148): ra83. November 2010. doi:10.1126/scisignal.2000954. PMID 21081755. 
  23. ↑ "The structure-function relationship of disulfide bonds in etanercept". Scientific Reports 7 (1): 3951. June 2017. doi:10.1038/s41598-017-04320-5. PMID 28638112. Bibcode: 2017NatSR...7.3951L. 
  24. ↑ Norman, Peter (February 16, 2017). "Enbrel and etanercept biosimilars: a tale of two patent system". Pharmaceutical Patent Analyst 6 (1): 5–7. doi:10.4155/ppa-2016-0043. PMID 28201948. 
  25. ↑ "Etanercept Product Approval Information - Licensing Action 12/2/98". 1 April 2016. https://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/TherapeuticBiologicApplications/ucm080536.htm. 
  26. ↑ "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, August 18, 2008
  27. ↑ 27.0 27.1 27.2 "Patent for Amgen Drug May Undercut Health Care Plan", Andrew Pollock, New York Times, November 23, 2011
  28. ↑ "Co-pay hike a painful reality; Miracle drug monthly cost jumps from $42 to $600", Margery Eagan, Boston Herald, November 3, 2011
  29. ↑ 29.0 29.1 29.2 29.3 "2013 Comparative Price Report". International Federation of Health Plans. https://static1.squarespace.com/static/518a3cfee4b0a77d03a62c98/t/534fc9ebe4b05a88e5fbab70/1397737963288/2013+iFHP+FINAL+4+14+14.pdf. Retrieved 24 November 2017. 
  30. ↑ "Portions of the 2010 Financial Report". Sec.gov. https://www.sec.gov/Archives/edgar/data/78003/000119312511048877/dex13.htm. Retrieved 2019-06-05. 
  31. ↑ "Patent Terms Extended Under 35 USC §156". http://www.uspto.gov/patents/resources/terms/156.html. 
  32. ↑ "New Amgen Enbrel patent could block biosimilars until 2028". 2011-11-25. http://www.gabionline.net/Biosimilars/News/New-Amgen-Enbrel-patent-could-block-biosimilars-until-2028. 
  33. ↑ Kaldre, Ingrid (2008). "The Future of Generic Biologics: Should the United States "Follow-On" the European Pathway?". https://scholarship.law.duke.edu/cgi/viewcontent.cgi?referer=https://en.wikipedia.org/&httpsredir=1&article=1184&context=dltr. 
  34. ↑ "Cipla - Home". Cipla.com. http://www.cipla.com/CiplaSite/Media/PDF/News-Archives/Press-Release-Launch-of-first-biosimilar-of-Etanercept-in-India.pdf?ext=.pdf. Retrieved 2019-06-05. 
  35. ↑ Biosimilar etanercept submitted for approval in EU GaBI Online – Generics and Biosimilars Initiative (Jan 2015). Retrieved 13 July 2016.
  36. ↑ FDA Briefing Document Arthritis Advisory Committee Meeting July 13, 2016. FDA AAC Brief. BLA 761042, GP2015, a proposed biosimilar to Enbrel. Retrieved 13 July 2016.
  37. ↑ "Benpali EPAR". 17 September 2018. https://www.ema.europa.eu/en/medicines/human/EPAR/benepali. 
  38. ↑ "Lifmior EPAR". 17 September 2018. https://www.ema.europa.eu/en/medicines/human/EPAR/lifmior. 
  39. ↑ "Public statement on Lifmior: Withdrawal of the marketing authorisation in the European Union". https://www.ema.europa.eu/documents/public-statement/public-statement-lifmior-withdrawal-marketing-authorisation-european-union_en.pdf. 
  40. ↑ "Erelzi EPAR". 17 September 2018. https://www.ema.europa.eu/en/medicines/human/EPAR/erelzi. 
  41. ↑ "Nepexto EPAR". 24 March 2020. https://www.ema.europa.eu/en/medicines/human/EPAR/nepexto. 

External links



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