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 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.
This therapeutic potential is based on the fact that TNF-alpha is the "master regulator" (as coined by Marc Feldmann, Phd, and Ravinder N. Maini BCh, recipients of the 2003 Lasker Award for their anti-TNF research in rheumatoid arthritis) of the inflammatory response in many organ systems.
In North America, etanercept is co-marketed by Amgen and Wyeth under the trade name Enbrel in two separate formulations, one in powder form, the other as a pre-mixed liquid. Wyeth is the sole marketer of Enbrel outside of North America.
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.
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.
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).
Although these three agents - etanercept, infliximab and adalimumab - are all biologic anti-TNF therapeutics, their methods of administration, dosing, and side effect profiles are somewhat different. These differences may be accounted for by fundamental differences in their biologic structure. Both infliximab and adalimumab fix complement, and have the ability to lyze cells. While potentially contributing to their therapeutic efficacy in disorders such as Crohn's disease (for which both of these monoclonal antibodies are now FDA-approved), these mABs also carry black-box warnings. In addition infliximab has a higher propensity for the development of anaphylaxis, perhaps as a result both of its chimeric structure and its intravenous route of administration.
On May 2, 2008, the FDA placed a black box warning on etanercept due to a number of serious infections associated with the drug.
Alzheimer's disease : A 2006 pilot study showed small but significant improvements in various cognitive rating scales in patients with Alzheimer's disease after treatment with etanercept. A further study, administering to a single AD patient via perispinal infusion, showed rapid and significant improvement in Alzheimer's symptoms. A small number of US physicians offer etanercept treatment for AD at a cost of $10,000 to $40,000 per annum.