|Pregnancy cat.||B2 (Au), B (U.S.)|
|Legal status||S4 (Au), POM (UK), ℞-only (U.S.)|
|Metabolism||Reticuloendothelial system (speculative)|
|Mol. mass||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, juvenile rheumatoid 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.
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. These investigators also patented the protein, selling all rights to its use to Immunex, a biotechnology company that was acquired by Amgen in 2002.
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, 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 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, 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.
Mechanism of action
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 increasing the transport of 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.
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.
In the USA the FDA has licenced Enbrel for :
- Moderate to Severe Rheumatoid Arthritis (RA) (Nov 1998)
- Moderate to Severe Polyarticular Juvenile Idiopathic Arthritis (JIA) (1999)
- Psoriatic Arthritis (2002)
- Ankylosing Spondylitis (AS) (July 2003)
- Moderate to Severe Plaque Psoriasis (April 2004)
Because patients with arthritis found the reconstitution procedure difficult, it was made available as pre-filled 50 mg/ml syringes in late 2004 and a single-use 50 mg autoinjector "pen" was brought to market in mid-2006.
FDA approved dose is 25 mg BIW (twice weekly) or 50 mg QW (once weekly).
On May 2, 2008, the FDA placed a black box warning on etanercept due to a number of serious infections associated with the drug.
It included required changes to the labeling one of which is "In post-marketing reports, serious infections and sepsis, including fatalities, have been reported with the use of Etanercept. Many of these serious events have occurred in patients with underlying diseases that could predispose them to infections. Rare cases of Tuberculosis (TB) have been observed in patients treated with TNF antagonists, including Etanercept. Patients who develop a new infection while undergoing treatment with Etanercept should be monitored closely. Administration of Etanercept should be discontinued if a patient develops a serious infection or sepsis. Treatment with Etanercept should not be initiated in patients with active infections including chronic or localized infections. Physicians should exercise caution when considering the use of Etanercept in patients with a history of recurring infections or with underlying conditions which may predispose patients to infections, such as advanced or poorly controlled diabetes." The report goes on to state "In post-marketing experience, infections have been observed with various pathogens including viral, bacterial, fungal, and protozoal organisms. Infections have been noted in all organ systems and have been reported in patients receiving Enbrel alone or in combination with immunosuppressive agents."
TNF-alpha inhibitors can have immunosuppressant properties. From the company website: "ENBREL can cause serious side effects including: New infections or worsening of infections you already have; hepatitis B can become active if you already have had it; nervous system problems, such as multiple sclerosis, seizures, or inflammation of the nerves of the eyes; blood problems (some fatal); new or worsening heart failure; new or worsening psoriasis; allergic reactions; autoimmune reactions, including a lupus-like syndrome and autoimmune hepatitis." 
Experimental and off-label uses
Given the central role of TNF-alpha in many diseases, etanercept is being studied as treatment for a number of these disease, including over 150 clinical trials. This includes certain forms of vasculitis (such as Wegener's granulomatosis, in which it was not effective).
Alzheimer's disease: A 2006 pilot study showed small but significant improvements in various cognitive rating scales in patients with Alzheimer's disease (AD) after treatment with etanercept. A further study, administering to a single AD patient via perispinal infusion, showed rapid and significant improvement in AD symptoms. A small number of US physicians offer etanercept treatment for AD at a cost of $10,000 to $40,000 per annum.
The patent on Enbrel was originally set to expire on October 23, 2012, but, in the United States, an extension of the patent, for another 16 years, has been granted. 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". The United States Congress was reviewing a bill to introduce such a process in the United States; however, the bill stalled in the House Judiciary Committee.
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.
- Soluble TNF receptor
- Anti-TNF monoclonal antibodies
|Wikimedia Commons has media related to Etanercept.|
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- Amgen/Wyeth Enbrel site
- A case study on the development of Enbrel until Immunex's acquisition by Amgen