Etanercept (trade name Enbrel or Benepali) 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. It has been reported by the Washington Post that etanercept could be active in preventing Alzheimer's disease, based on data from health insurance.[7] In the U.S. the FDA has licensed 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.[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] 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] 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] 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. 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. 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.[24] By 2011, the cost had exceeded $20,000 per year.[25][26] 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.[27] 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.[27] Enbrel is more expensive in the U.S. than in other countries.[27] 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.[27] Amgen sells Enbrel within the U.S. and Canada, while Pfizer, Inc. sells the drug outside of the U.S. and Canada.[25] Sales within the U.S. and Canada were $3.5 billion in 2010.[25] Sales of Enbrel outside the U.S. and Canada were $3.3 billion in 2010.[28] The patent on Enbrel was originally set to expire on October 23, 2012,[29] but, in the United States, a second patent, granting exclusivity for another 16 years, has been granted.[30] 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".[31] 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.[32] 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.[33] 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.[34]