From Wikipedia, the free encyclopedia
Jump to: navigation, search
Clinical data
Trade names Enbrel
AHFS/ monograph
  • S4 (Au), POM (UK), ℞-only (U.S.)
Pharmacokinetic data
Bioavailability 58–76% (SC)
Metabolism Reticuloendothelial system (speculative)
Half-life 70–132 hours
PubChem SID10099
DrugBank DB00005
KEGG D00742
Chemical data
Formula C2224H3475N621O698S36
51234.9 g/mol

Etanercept (trade name Enbrel) 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 rheumatoid 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][4] These investigators also patented the protein,[5] selling all rights to its use to Immunex, a biotechnology company that was acquired by Amgen in 2002.[6]

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,[7] juvenile rheumatoid arthritis, psoriasis, psoriatic arthritis, rheumatoid arthritis, and, potentially, in a variety of other disorders mediated by excess TNFα.

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

Etanercept is an example of a protein-based drug created using the tools of biotechnology and conceived through an understanding afforded by modern cell biology.

Medical uses[edit]

In the USA the FDA has licenced Enbrel for :


On May 2, 2008, the FDA placed a black box warning on etanercept due to a number of serious infections associated with the drug.[9] Serious infections and sepsis, including fatalities, have been reported with the use of Etanercept including reactivation of latent tuberculosis and hepatitis B infections.[10][11]

Mechanism of action[edit]

It reduces the effect of naturally present TNF, and hence is a TNF inhibitor, functioning as a decoy receptor that binds to TNF.[12]

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 which 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 which 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.[13]


Etanercept is made from the combination of two naturally occurring soluble human 75-kilodalton TNF receptors linked to an Fc portion of an IgG1. The effect is an artificially engineered dimeric fusion protein.


Etanercept was developed by researchers at Immunex, and was released for commercial use in late 1998, soon after the release of infliximab (Remicade) – the first chimeric monoclonal antibody against TNFα to be marketed for clinical use.

Etanercept is a dimeric molecule,[14] and this dimeric structure is necessary for its proper therapeutic activity. During its development at Immunex Corporation an earlier monomeric version did not have sufficient biologic activity.

Society and culture[edit]


The cost of Enbrel for arthritis is approximately $20,000 a year.[15][16][17] Sales were $3.3 billion in 2010.[18]


The patent on Enbrel was originally set to expire on October 23, 2012,[19] but, in the United States, a second patent, granting exclusivity for another 16 years, has been granted.[20] Even before the extension it was unlikely that a generic would have been available. As a biologic, etanercept is subject to different laws than those applicable to chemical formulations. Currently many countries do not permit the manufacture of generic biologics. However, the European Union and the United States do currently have in place a system to approve generic biologics (biosimilars) which "requires mandatory clinical testing and periodic review".[21]

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.[22]


Etanercept is being studied as treatment for a number of these diseases.[23] This includes certain forms of vasculitis (such as granulomatosis with polyangiitis, in which it was not effective).[24]

Similar agents[edit]


  1. ^ "TNF defined as a therapeutic target for rheumatoid arthritis and other autoimmune diseases - Nature Medicine". Retrieved 2008-01-10. 
  2. ^ Peppel,K. et al. A tumor necrosis factor (TNF) receptor-IgG heavy chain chimeric protein as a bivalent antagonist of TNF activity. J.Exp.Med. 174(6):1483-9, 1991
  3. ^ Peppel,K. et al. Expression of a TNF inhibitor in transgenic mice. J.Immunol. 151(10):5699-703, 1993
  4. ^ Kolls,J. et al. Prolonged and effective blockade of tumor necrosis factor activity through adenovirus-mediated gene transfer. Proc.Natl.Acad.Sci.USA 91(1):215-9, 1994
  5. ^ U.S. Patent number: 5,447,851
  6. ^ "Arthritis Drug Effective for Depression in Psoriasis Sufferers". Retrieved 2008-01-10. 
  7. ^ Braun J, McHugh N, Singh A, Wajdula JS, Sato R (2007). "Improvement in patient-reported outcomes for patients with ankylosing spondylitis treated with etanercept 50 mg once-weekly and 25 mg twice-weekly". Rheumatology (Oxford) 46 (6): 999–1004. doi:10.1093/rheumatology/kem069. PMID 17389658. 
  8. ^ FDA
  9. ^ "Wyeth and Amgen heighten warning of life-threatening infections on skin drug Enbrel". Archived from the original on 2008-05-05. Retrieved 2008-05-02. 
  10. ^ Safety Update on TNF- α Antagonists: Infliximab and Etanercept. Food and Drug Administration. pp. 13–14. Retrieved 20 December 2013. 
  11. ^ "Prescribing Information - ENBREL". Retrieved 2008-01-10. 
  12. ^ Zalevsky J, Secher T, Ezhevsky SA et al. (August 2007). "Dominant-negative inhibitors of soluble TNF attenuate experimental arthritis without suppressing innate immunity to infection". J. Immunol. 179 (3): 1872–83. doi:10.4049/jimmunol.179.3.1872. PMID 17641054. 
  13. ^ Madhusudan S, Muthuramalingam SR, Braybrooke JP et al. (2005). "Study of etanercept, a tumor necrosis factor-alpha inhibitor, in recurrent ovarian cancer". J. Clin. Oncol. 23 (25): 5950–9. doi:10.1200/JCO.2005.04.127. PMID 16135466. 
  14. ^ Smith KJ, Skelton HG (2001). "Rapid onset of cutaneous squamous cell carcinoma in patients with rheumatoid arthritis after starting tumor necrosis factor alpha receptor IgG1-Fc fusion complex therapy". J. Am. Acad. Dermatol. 45 (6): 953–6. doi:10.1067/mjd.2001.117725. PMID 11712048. 
  15. ^ Patent for Amgen Drug May Undercut Health Care Plan, By ANDREW POLLACK, New York Times, November 23, 2011
  16. ^ 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
  17. ^ Co-pay hike a painful reality; Miracle drug monthly cost jumps from $42 to $600, By Margery Eagan, Boston Herald, November 3, 2011
  18. ^ Sales reached $3b in 2010 Pfizer Inc. 2010 Financial Report, Exhibit 24 at
  19. ^
  20. ^
  21. ^
  22. ^
  23. ^ FDA Clinical Trials database
  24. ^ Wegener's Granulomatosis Etanercept Trial (WGET) Research Group (2005). "Etanercept plus standard therapy for Wegener's granulomatosis". N. Engl. J. Med. 352 (4): 351–61. doi:10.1056/NEJMoa041884. PMID 15673801. 

External links[edit]