Etanercept 732438 220799587 2008-06-21T17:09:40Z DOI bot 6652755 Citation maintenance. Initiated by [[User:Fconaway|Fconaway]]. You can [[WP:DOI|use this bot]] yourself! Please [[User:DOI_bot/bugs|report any bugs]]. {{drugbox | IUPAC_name = Unable to be assigned | image = ENBREL.jpg | width = 153 | CAS_number = 185243-69-0 | ATC_prefix = L04 | ATC_suffix = AA11 | PubChem = N/A | DrugBank = BTD00052 | C=2224 | H=3475 | N=621 | O=698 | S=36 | molecular_weight = 51234.9 g/mol | bioavailability = 58–76% (SC) | metabolism = [[Reticuloendothelial]] system (speculative) | elimination_half-life = 70–132 hours | excretion = | pregnancy_category = B2 <small>([[Australia|Au]])</small>, B <small>([[United States|U.S.]])</small> | legal_status = S4 <small>(Au)</small>, POM <small>([[United Kingdom|UK]])</small>, ℞-only <small>(U.S.)</small> | routes_of_administration = Subcutaneous }} '''Etanercept''' (Enbrel) is a [[recombinant]]-DNA drug made by combining two proteins (a fusion protein). It links human soluble [[CD120|TNF receptor]] to the Fc component of human [[immunoglobulin G1]] (IgG1). 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]],<ref name="pmid17389658">{{cite journal |author=Braun J, McHugh N, Singh A, Wajdula JS, Sato R |title=Improvement in patient-reported outcomes for patients with ankylosing spondylitis treated with etanercept 50 mg once-weekly and 25 mg twice-weekly |journal=[[Rheumatology (Oxford)]] |volume=46 |issue=6 |pages=999–1004 |year=2007 |pmid=17389658 |doi=10.1093/rheumatology/kem069 |url=http://rheumatology.oxfordjournals.org/cgi/content/full/46/6/999}}</ref> [[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. <ref name="titleTNF defined as a therapeutic target for rheumatoid arthritis and other autoimmune diseases - Nature Medicine">{{cite web |url=http://www.nature.com/nm/journal/v9/n10/full/nm939.html |title=TNF defined as a therapeutic target for rheumatoid arthritis and other autoimmune diseases - Nature Medicine |accessdate=2008-01-10 |format= |work=}}</ref> In the United States and the United Kingdom, 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. ==Development== Etanercept was developed by researchers at biotechnology company [[Immunex]], which was subsequently acquired by [[Amgen]] in 2002.<ref name="title|| DukeMedNews || Arthritis Drug Effective for Depression in Psoriasis Sufferers">{{cite web |url=http://www.dukemednews.org/news/article.php?id=9419 |title=Arthritis Drug Effective for Depression in Psoriasis Sufferers |accessdate=2008-01-10 |format= |work=}}</ref> It 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 [[Dimer|dimeric molecule]],<ref name="pmid11712048">{{cite journal |author=Smith KJ, Skelton HG |title=Rapid onset of cutaneous squamous cell carcinoma in patients with rheumatoid arthritis after starting tumor necrosis factor alpha receptor IgG1-Fc fusion complex therapy |journal=[[J. Am. Acad. Dermatol.]] |volume=45 |issue=6 |pages=953–6 |year=2001 |pmid=11712048 |doi=10.1067/mjd.2001.117725 |url=http://linkinghub.elsevier.com/retrieve/pii/S0190-9622(01)47789-9}}</ref> 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. ==Mode of action== Tumor necrosis factor-alpha (TNFα) is a [[cytokine]] produced by [[monocyte]]s and [[macrophage]]s, two types of [[white blood cell]]s. 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 disease]]s. There are two types of TNF [[receptor (biochemistry)|receptor]]s: 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.<ref name="pmid16135466">{{cite journal |author=Madhusudan S, Muthuramalingam SR, Braybrooke JP, ''et al'' |title=Study of etanercept, a tumor necrosis factor-alpha inhibitor, in recurrent ovarian cancer |journal=J. Clin. Oncol. |volume=23 |issue=25 |pages=5950–9 |year=2005 |pmid=16135466 |doi=10.1200/JCO.2005.04.127 |url=http://jco.ascopubs.org/cgi/content/full/23/25/5950}}</ref> ==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. The effect is an artificially engineered dimeric fusion protein. ==Administration== Enbrel is marketed as a [[freeze drying|lyophylized]] powder in 25 mg vials which must be reconstituted with a [[diluent]] and then [[injection (medicine)|injected subcutaneously]], typically by the patient at home. 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. <ref name="titleEnbrel and Humira Now Have Automated Delivery System">{{cite web |url=http://www.hopkins-arthritis.org/arthritis-news/2006/automated_delivery.html |title=Enbrel and Humira Now Have Automated Delivery System |accessdate=2008-01-10 |format= |work=}}</ref> It cannot be administered [[route of administration|orally]], because the [[digestive system]] would destroy the drug. FDA approved dose is 25 mg BIW (twice weekly) or 50 mg QW (once weekly). == Safety == All TNF inhibitors are [[immunosuppressant]]s. After a number of studies and reports of adverse reactions in patients receiving anti-TNF alpha therapy (including serious and sometimes fatal blood disorders, [[infection]]s, rare reports of [[lymphoma]] and solid tissue cancers, rare reports of serious liver injury, and rare reports of [[demyelinating]] [[central nervous system]] disorders), rare reports of [[congestive heart failure]], the U.S. [[Food and Drug Administration]] issued a warning to doctors appearing in the respective product labeling of these drugs instructing them to screen and monitor potential patients more carefully. <ref name="titlePrescribing Information - ENBREL">{{cite web |url=http://www.enbrel.com/prescribing-information.jsp |title=Prescribing Information - ENBREL |accessdate=2008-01-10 |format= |work=}}</ref> Although these three agents 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 system|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 [[Food and Drug Administration|FDA]]-approved), these mABs also carry [[black-box warning]]s which are not shared by etanercept. 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. <ref name="Wyeth and Amgen"> {{cite web |url=http://money.cnn.com/news/newsfeeds/articles/apwire/21965cf0a650a8b5897142bfcbccb427.htm |title=Wyeth and Amgen heighten warning of life-threatening infections on skin drug Enbrel |accessdate=2008-05-02}}</ref> ==Sales== Enbrel is the most widely used anti-TNF biologic drug in the field of [[rheumatology]] with more patients taking this drug for that indication than either Remicade ([[infliximab]]) or Humira ([[adalimumab]]){{Fact|date=June 2007}}. Infliximab is the most widely used anti-TNF biologic drug when all FDA approved indications (uses) of the drugs are considered, including [[Crohn's disease]] and [[ulcerative colitis]], two autoimmune diseases for which etanercept does not have an FDA approved indication. In addition to their labeled indications, there are multiple published, peer-reviewed scientific studies suggesting potential uses for off-label indications, for which the FDA has not verified either safety or efficacy. ==Experimental/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.<ref>[http://clinicaltrials.gov FDA Clinical Trials database]</ref> This includes certain forms of [[vasculitis]] (such as [[Wegener's granulomatosis]], in which it was not effective).<ref>{{cite journal |author= |title=Etanercept plus standard therapy for Wegener's granulomatosis |journal=N. Engl. J. Med. |volume=352 |issue=4 |pages=351–61 |year=2005 |pmid=15673801 |doi=10.1056/NEJMoa041884|url=http://content.nejm.org/cgi/content/full/352/4/351}}</ref> A 2006 pilot study showed small but significant improvements in various cognitive rating scales in patients with [[Alzheimer's disease]] after treatment with etanercept.<ref name="pmid16926764">{{cite journal |author=Tobinick Edward L., Gross H, Weinberger A, Cohen H |title=TNF-alpha modulation for treatment of Alzheimer's disease: a 6-month pilot study |journal=[[MedGenMed]] |volume=8 |issue=2 |pages=25 |year=2006 |pmid=16926764 |doi= |url=http://www.medscape.com/viewarticle/529176}}</ref> A further study, administering to a single AD patient via perispinal infusion, showed rapid and significant improvement in Alzheimer's symptoms.<ref name=tobinick2008>{{cite journal |author=Tobinick Edward L., Gross H. |title=Rapid cognitive improvement in Alzheimer's disease following perispinal etanercept administration |journal=J. Neuroinflammation |volume=5 |issue=2 |pages=2|year=2008 |pmid=18184433 |doi=10.1186/1742-2094-5-2 |url=http://www.jneuroinflammation.com/content/5/1/2}}</ref> ==Similar agents== * [[Infliximab]] * [[Adalimumab]] * [[Certolizumab pegol]] ==References== {{reflist|2}} ==External links== * [http://www.enbrel.com/ Official site] * [http://www.123wise.net/enbrel.pdf A case study on the development of Enbrel until Immunex's acquisition by Amgen] {{Immunosuppressants}} [[Category:TNF-alpha inhibitors]] [[Category:Amgen]] [[Category:Immunosuppressive agents]] [[Category:Recombinant proteins]] [[de:Etanercept]] [[fr:Étanercept]] [[nl:Etanercept]] [[pl:Etanercept]] [[pt:Etanercepte]] [[sv:Enbrel]]