Edward Tobinick
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Etanercept, sold under the brand name Enbrel among others, is a
biologic medical product A biopharmaceutical, also known as a biological medical product, or biologic, is any pharmaceutical drug product manufactured in, extracted from, or semisynthesized from biological sources. Different from totally synthesized pharmaceuticals, t ...
that is used to treat
autoimmune disease An autoimmune disease is a condition that results from an anomalous response of the adaptive immune system, wherein it mistakenly targets and attacks healthy, functioning parts of the body as if they were foreign organisms. It is estimated tha ...
s by interfering with
tumor necrosis factor Tumor necrosis factor (TNF), formerly known as TNF-α, is a chemical messenger produced by the immune system that induces inflammation. TNF is produced primarily by activated macrophages, and induces inflammation by binding to its receptors o ...
(TNF), a soluble inflammatory cytokine, by acting as a
TNF inhibitor Tumor necrosis factor (TNF), formerly known as TNF-α, is a chemical messenger produced by the immune system that induces inflammation. TNF is produced primarily by activated macrophages, and induces inflammation by binding to its receptors o ...
. It has US
Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respo ...
(FDA) approval to treat
rheumatoid arthritis Rheumatoid arthritis (RA) is a long-term autoimmune disorder that primarily affects synovial joint, joints. It typically results in warm, swollen, and painful joints. Pain and stiffness often worsen following rest. Most commonly, the wrist and h ...
,
juvenile idiopathic arthritis Juvenile idiopathic arthritis (JIA), formerly known as juvenile rheumatoid arthritis (JRA), is the most common chronic rheumatic disease of childhood, affecting approximately 3.8 to 400 out of 100,000 children. ''Juvenile'', in this context, ref ...
and
psoriatic arthritis Psoriatic arthritis (PsA) is a long-term inflammatory arthritis that may occur in some people affected by the autoimmune disease psoriasis. The classic features of psoriatic arthritis include dactylitis (sausage-like swelling of the fingers ...
,
plaque psoriasis Psoriasis is a long-lasting, noncontagious autoimmune disease characterized by patches of abnormal skin. These areas are red, pink, or purple, dry, itchy, and scaly. Psoriasis varies in severity from small localized patches to complete b ...
and
ankylosing spondylitis Ankylosing spondylitis (AS) is a type of arthritis from the disease spectrum of axial spondyloarthritis. It is characterized by long-term inflammation of the joints of the spine, typically where the spine joins the pelvis. With AS, eye and bow ...
.
Tumor necrosis factor alpha Tumor necrosis factor (TNF), formerly known as TNF-α, is a chemical messenger produced by the immune system that induces inflammation. TNF is produced primarily by activated macrophages, and induces inflammation by binding to its receptors o ...
(TNFα) 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 Fusion proteins or chimeric (kī-ˈmir-ik) proteins (literally, made of parts from different sources) are proteins created through the joining of two or more genes that originally coded for separate proteins. Translation of this '' fusion gene'' ...
produced by
recombinant DNA Recombinant DNA (rDNA) molecules are DNA molecules formed by laboratory methods of genetic recombination (such as molecular cloning) that bring together genetic material from multiple sources, creating sequences that would not otherwise be fo ...
. 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 Immunoglobulin G (IgG) is a type of antibody. Representing approximately 75% of serum antibodies in humans, IgG is the most common type of antibody found in blood circulation. IgG molecules are created and released by plasma B cells. Each IgG ant ...
(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 The University of Texas Southwestern Medical Center (UT Southwestern or UTSW) is a public academic health science center in Dallas, Texas. With approximately 23,000 employees, more than 3,000 full-time faculty, and nearly 4 million outpatient ...
, and his colleagues. These investigators also patented the protein, selling all rights to its use to
Immunex Amgen Inc. (formerly Applied Molecular Genetics Inc.) is an American multinational biopharmaceutical company headquartered in Thousand Oaks, California. As one of the world's largest independent biotechnology companies, Amgen has approximately ...
, a Seattle biotechnology company that was acquired by
Amgen Amgen Inc. (formerly Applied Molecular Genetics Inc.) is an American multinational biopharmaceutical Corporation, company headquartered in Thousand Oaks, California. As one of the world's largest independent biotechnology companies, Amgen has a ...
in 2002. It is a large molecule, with a molecular weight of 150
kDa The dalton or unified atomic mass unit (symbols: Da or u, respectively) is a unit of mass defined as of the mass of an unbound neutral atom of carbon-12 in its nuclear and electronic ground state and at rest. It is a non-SI unit accepted f ...
, that binds to TNFα and decreases its role in disorders involving excess inflammation in humans and other animals, including
autoimmune diseases An autoimmune disease is a condition that results from an anomalous response of the adaptive immune system, wherein it mistakenly targets and attacks healthy, functioning parts of the body as if they were foreign organisms. It is estimated that ...
such as
ankylosing spondylitis Ankylosing spondylitis (AS) is a type of arthritis from the disease spectrum of axial spondyloarthritis. It is characterized by long-term inflammation of the joints of the spine, typically where the spine joins the pelvis. With AS, eye and bow ...
,
juvenile rheumatoid arthritis Juvenile may refer to: In general *Juvenile status, or minor (law), prior to adulthood *Juvenile (organism) Music *Juvenile (rapper) (born 1975), stage name of American rapper Terius Gray *''Juveniles'', a 2020 studio album by the band Kingswoo ...
,
psoriasis Psoriasis is a long-lasting, noncontagious autoimmune disease characterized by patches of abnormal skin. These areas are red, pink, or purple, dry, itchy, and scaly. Psoriasis varies in severity from small localized patches to complete b ...
,
psoriatic arthritis Psoriatic arthritis (PsA) is a long-term inflammatory arthritis that may occur in some people affected by the autoimmune disease psoriasis. The classic features of psoriatic arthritis include dactylitis (sausage-like swelling of the fingers ...
,
rheumatoid arthritis Rheumatoid arthritis (RA) is a long-term autoimmune disorder that primarily affects synovial joint, joints. It typically results in warm, swollen, and painful joints. Pain and stiffness often worsen following rest. Most commonly, the wrist and h ...
, and, potentially, in a variety of other disorders mediated by excess TNFα. It is on the
World Health Organization's List of Essential Medicines The WHO Model List of Essential Medicines (aka Essential Medicines List or EML), published by the World Health Organization (WHO), contains the medications considered to be most effective and safe to meet the most important needs in a health s ...
.


Medical uses

In the United States, etanercept is
indicated In medicine, an indication is a valid reason to use a certain test, medication, procedure, or surgery. There can be multiple indications to use a procedure or medication. An indication can commonly be confused with the term diagnosis. A diagnosis ...
for: * Moderate to Severe
Rheumatoid Arthritis Rheumatoid arthritis (RA) is a long-term autoimmune disorder that primarily affects synovial joint, joints. It typically results in warm, swollen, and painful joints. Pain and stiffness often worsen following rest. Most commonly, the wrist and h ...
(RA) (Nov 1998) * Moderate to Severe Polyarticular
Juvenile Rheumatoid Arthritis Juvenile may refer to: In general *Juvenile status, or minor (law), prior to adulthood *Juvenile (organism) Music *Juvenile (rapper) (born 1975), stage name of American rapper Terius Gray *''Juveniles'', a 2020 studio album by the band Kingswoo ...
(May 1999) *
Psoriatic Arthritis Psoriatic arthritis (PsA) is a long-term inflammatory arthritis that may occur in some people affected by the autoimmune disease psoriasis. The classic features of psoriatic arthritis include dactylitis (sausage-like swelling of the fingers ...
(Jan 2002) *
Ankylosing Spondylitis Ankylosing spondylitis (AS) is a type of arthritis from the disease spectrum of axial spondyloarthritis. It is characterized by long-term inflammation of the joints of the spine, typically where the spine joins the pelvis. With AS, eye and bow ...
(AS) (July 2003) * Moderate to Severe
Plaque Psoriasis Psoriasis is a long-lasting, noncontagious autoimmune disease characterized by patches of abnormal skin. These areas are red, pink, or purple, dry, itchy, and scaly. Psoriasis varies in severity from small localized patches to complete b ...
(April 2004) In the European Union, etanercept is indicated to treat: * moderate to severe active rheumatoid arthritis * severe, active and progressive rheumatoid arthritis * juvenile idiopathic arthritis *
polyarthritis Polyarthritis is any type of arthritis that involves 5 or more joints simultaneously. It can be associated with autoimmune conditions; it may be experienced at any age and is not sex specific. Causes Polyarthritis is often caused by an auto-immun ...
(rheumatoid-factor-positive or -negative) and extended
oligoarthritis Oligoarthritis (from Greek ''oligos'' - 'few') is defined as arthritis Arthritis is a general medical term used to describe a disorder that affects joints. Symptoms generally include joint pain and stiffness. Other symptoms may include red ...
in children and adolescents * active and progressive psoriatic arthritis * enthesitis-related arthritis * axial spondyloarthritis * severe active ankylosing spondylitis * severe non-radiographic axial spondyloarthritis * moderate to severe plaque psoriasis * chronic severe plaque psoriasis pediatric plaque psoriasis


Unrecognized uses

An American physician, Edward Tobinick, has attempted to use etanercept to treat chronic neurological dysfunction after
stroke Stroke is a medical condition in which poor cerebral circulation, blood flow to a part of the brain causes cell death. There are two main types of stroke: brain ischemia, ischemic, due to lack of blood flow, and intracranial hemorrhage, hemor ...
and
brain injury Brain injury (BI) is the destruction or degeneration of brain cells. Brain injuries occur due to a wide range of internal and external factors. In general, brain damage refers to significant, undiscriminating trauma-induced damage. A common ...
and issued U.S. and foreign patents. Writing for
Science-Based Medicine ''Science-Based Medicine'' is a website and blog with articles covering issues in science and medicine, especially medical scams and practices. Founded in 2008, it is owned and operated by the New England Skeptical Society, and run by Steve ...
,
Steven Novella Steven Paul Novella (born July 29, 1964) is an American neurology, clinical neurologist and Professors in the United States#Associate Professor, associate professor at Yale University School of Medicine. Novella is best known for his involvement ...
said that it was "unethical for physicians to practice outside of their area of competence and expertise". Tobinick sued Novella in response, and lost. Of this treatment, the
American Academy of Neurology The American Academy of Neurology (AAN) is a professional society representing over 40,000 neurologists and neuroscientists. As a medical specialty society it was established in 1948 by A.B. Baker of the University of Minnesota to advance the a ...
advise "there is insufficient evidence to determine its effectiveness and that the treatment may be associated with adverse outcomes and high cost".


Adverse effects

On 2 May 2008, the US
Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respo ...
(FDA) placed a
black box warning In the United States, a boxed warning (sometimes "black box warning", colloquially) is a type of warning that appears near the beginning of the package insert for certain prescription drugs, so called because the U.S. Food and Drug Administratio ...
on etanercept due to a number of serious infections associated with the drug. Serious infections and
sepsis Sepsis is a potentially life-threatening condition that arises when the body's response to infection causes injury to its own tissues and organs. This initial stage of sepsis is followed by suppression of the immune system. Common signs and s ...
, including fatalities, have been reported with the use of etanercept including reactivation of
latent tuberculosis Latent tuberculosis (LTB), also called latent tuberculosis infection (LTBI), is when a person is infected with ''Mycobacterium tuberculosis'', but does not have active tuberculosis (TB). Active tuberculosis can be contagious while latent tubercul ...
and
hepatitis B Hepatitis B is an infectious disease caused by the '' hepatitis B virus'' (HBV) that affects the liver; it is a type of viral hepatitis. It can cause both acute and chronic infection. Many people have no symptoms during an initial infection. ...
infections.
Injection site reaction Injection site reactions (ISRs) are reactions that occur at the site of injection of a drug. They may be mild or severe and may or may not require medical intervention. Some reactions may appear immediately after injection, and some may be delayed ...
s such as redness and pain are common, occurring in approximately 11.4% of cases.


Mechanism of action

Etanercept reduces the effect of naturally present TNF, and hence is a
TNF inhibitor Tumor necrosis factor (TNF), formerly known as TNF-α, is a chemical messenger produced by the immune system that induces inflammation. TNF is produced primarily by activated macrophages, and induces inflammation by binding to its receptors o ...
, functioning as a
decoy receptor A decoy receptor is a receptor that is able to recognize and bind specific growth factors or cytokines efficiently, but is not structurally able to signal or activate the intended receptor complex. It acts as an inhibitor, binding a ligand and keepi ...
that binds to TNF. Tumor necrosis factor-alpha (TNFα) is a
cytokine Cytokines () are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are produced by a broad range of cells, including immune cells like macrophages, B cell, B lymphocytes, T cell, T lymphocytes ...
produced by
lymphocyte A lymphocyte is a type of white blood cell (leukocyte) in the immune system of most vertebrates. Lymphocytes include T cells (for cell-mediated and cytotoxic adaptive immunity), B cells (for humoral, antibody-driven adaptive immunity), an ...
s and
macrophage Macrophages (; abbreviated MPhi, φ, MΦ or MP) are a type of white blood cell of the innate immune system that engulf and digest pathogens, such as cancer cells, microbes, cellular debris and foreign substances, which do not have proteins that ...
s, two types of
white blood cell White blood cells (scientific name leukocytes), also called immune cells or immunocytes, are cells of the immune system that are involved in protecting the body against both infectious disease and foreign entities. White blood cells are genera ...
s. It mediates the immune response by attracting additional white blood cells to sites of
inflammation Inflammation (from ) is part of the biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. The five cardinal signs are heat, pain, redness, swelling, and loss of function (Latin ''calor'', '' ...
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 disease An autoimmune disease is a condition that results from an anomalous response of the adaptive immune system, wherein it mistakenly targets and attacks healthy, functioning parts of the body as if they were foreign organisms. It is estimated tha ...
s. There are two types of TNF
receptor Receptor may refer to: * Sensory receptor, in physiology, any neurite structure that, on receiving environmental stimuli, produces an informative nerve impulse *Receptor (biochemistry), in biochemistry, a protein molecule that receives and respond ...
s: those found embedded in white blood cells that respond to TNF by releasing other
cytokine Cytokines () are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are produced by a broad range of cells, including immune cells like macrophages, B cell, B lymphocytes, T cell, T lymphocytes ...
s, 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.


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. Etanercept is a complex molecule containing 6 N-glycans, up to 14 O-glycans and 29 disulfide bridge structures.


History

The first etanercept-related patent was filed by
Immunex Amgen Inc. (formerly Applied Molecular Genetics Inc.) is an American multinational biopharmaceutical company headquartered in Thousand Oaks, California. As one of the world's largest independent biotechnology companies, Amgen has approximately ...
in September 1989. 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 licensed the rights in 1995 to Immunex. Another patent on such fusion protein technology from Brian Seed at
Massachusetts General Hospital Massachusetts General Hospital (Mass General or MGH) is a teaching hospital located in the West End neighborhood of Boston, Massachusetts. It is the original and largest clinical education and research facility of Harvard Medical School/Harvar ...
was licensed to Immmunex in 1997. Etanercept was approved for use in the United States in November 1998. Etanercept was approved for use in the European Union in February 2000. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.


Society and culture


Economics

The US retail price of etanercept has risen over time. In 2008, the cost of etanercept was $1,500 per month or $18,000 per year. By 2011, the cost had exceeded $20,000 per year. In 2013, a survey by the International Federation of Health Plans (IFHP) found that the average US cost for etanercept was $2,225 per month, or $26,700 per year. The IFHP report also found wide variation in prices charged to various US health plans, between $1,946 per month at the 25th percentile and $4,006 per month at the 95th percentile. Etanercept is more expensive in the US than in other countries. 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 US. Amgen sells etanercept within the US and Canada, while
Pfizer Pfizer Inc. ( ) is an American Multinational corporation, multinational Pharmaceutical industry, pharmaceutical and biotechnology corporation headquartered at The Spiral (New York City), The Spiral in Manhattan, New York City. Founded in 184 ...
, Inc. sells the drug outside of the US and Canada. Sales within the US and Canada were $3.5 billion in 2010. Sales of etanercept outside the US and Canada were $3.3 billion in 2010. In late March 2025, Amgen lost a lawsuit against Colorado over a prescription drug affordability board.


Patents

The patent on etanercept was set to expire in October 2012, but, in the United States, a second patent, granting exclusivity for another 16 years, has been granted. 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. 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 have in place a system to approve generic biologics (
biosimilars A biosimilar (also known as follow-on biologic or subsequent entry biologic) is a biologic medical product that is almost an identical copy of an original product that is manufactured by a different company. Biosimilars are officially approved v ...
) which "requires mandatory clinical testing and periodic review". In April 2013, the Indian pharma major
Cipla Cipla Limited is an Indian multinational pharmaceutical company headquartered in Mumbai. Cipla primarily focuses on developing medication to treat respiratory disease, cardiovascular disease, arthritis, diabetes, depression, paediatric and var ...
made an announcement about launching the first biosimilar of Etanercept in India under the brand name Etacept for the treatment of rheumatic disorders.


Biosimilars

In January 2016, Benepali was approved for use in the European Union. In February 2017, Lifmior was approved for use in the European Union. It was withdrawn from the market in February 2020. In June 2017, Erelzi was approved for use in the European Union. In March 2019, YLB113 (Etanercept biosimilar by YL Biologics) was approved in Japan. In April 2019, Eticovo received FDA approval. In May 2020, Nepexto was approved for use in the European Union. Rymti and Etera were approved for medical use in Australia in October 2020.


References

{{Authority control TNF inhibitors Amgen Recombinant proteins Immunosuppressants Drugs developed by Wyeth Drugs developed by Pfizer Drugs developed by Novartis World Health Organization essential medicines Disease-modifying antirheumatic drugs