Etanercept

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Etanercept, sold under the brand name Enbrel among others, is a biologic medical product that is used to treat autoimmune diseases by interfering with tumor necrosis factor (TNF), a soluble inflammatory cytokine, by acting as a TNF inhibitor. It has US Food and Drug Administration (FDA) approval to treat rheumatoid arthritis, juvenile idiopathic arthritis and psoriatic arthritis, plaque psoriasis and ankylosing spondylitis. Tumor necrosis factor alpha (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.<ref name="titleTNF defined as a therapeutic target for rheumatoid arthritis and other autoimmune diseases - Nature Medicine">Template:Cite journal</ref>

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.<ref>Template:Cite web</ref>

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.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref>

These investigators also patented the protein,<ref>U.S. Patent number: 5,447,851</ref> selling all rights to its use to Immunex, a Seattle biotechnology company that was acquired by Amgen in 2002.<ref name="DukeMedNews">Template:Cite web</ref>

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">Template:Cite journal</ref> juvenile rheumatoid arthritis, psoriasis, psoriatic arthritis, rheumatoid arthritis, and, potentially, in a variety of other disorders mediated by excess TNFα. Etanercept is a therapeutic alternative on the World Health Organization's List of Essential Medicines.<ref name="WHO24th">Template:Cite book</ref>

Medical uses

In the United States, etanercept is indicated for:

• Moderate to Severe Rheumatoid Arthritis (RA) (Nov 1998)<ref name="Enbrel FDA label" /><ref>Template:Cite letter</ref>
• Moderate to Severe Polyarticular Juvenile Rheumatoid Arthritis (May 1999)<ref name="Enbrel FDA label" /><ref>Template:Cite letter</ref>
• Psoriatic Arthritis (Jan 2002)<ref name="Enbrel FDA label" /><ref>Template:Cite letter</ref>
• Ankylosing Spondylitis (AS) (July 2003)<ref name="Enbrel FDA label" /><ref>Template:Cite letter</ref><ref>Template:Cite journal</ref>
• Moderate to Severe Plaque Psoriasis (April 2004)<ref name="Enbrel FDA label" /><ref>Template:Cite letter</ref>

In the European Union, etanercept is indicated to treat:

• moderate to severe active rheumatoid arthritis<ref name="Enbrel EPAR" />
• severe, active and progressive rheumatoid arthritis<ref name="Enbrel EPAR" />
• juvenile idiopathic arthritis<ref name="Enbrel EPAR" />
• polyarthritis (rheumatoid-factor-positive or -negative) and extended oligoarthritis in children and adolescents<ref name="Enbrel EPAR" />
• active and progressive psoriatic arthritis<ref name="Enbrel EPAR" />
• enthesitis-related arthritis
• axial spondyloarthritis<ref name="Enbrel EPAR" />
• severe active ankylosing spondylitis<ref name="Enbrel EPAR" />
• severe non-radiographic axial spondyloarthritis<ref name="Enbrel EPAR" />
• moderate to severe plaque psoriasis<ref name="Enbrel EPAR" />
• chronic severe plaque psoriasis pediatric plaque psoriasis<ref name="Enbrel EPAR" />

Unrecognized uses

An American physician, Edward Tobinick, has attempted to use etanercept to treat chronic neurological dysfunction after stroke and brain injury<ref>Template:Cite news</ref> and issued U.S.<ref>Template:Cite patent</ref> and foreign patents. Writing for Science-Based Medicine, Steven Novella said that it was "unethical for physicians to practice outside of their area of competence and expertise". Tobinick sued Novella in response, and lost.<ref>Template:Cite web</ref> Of this treatment, the American Academy of Neurology advise "there is insufficient evidence to determine its effectiveness and that the treatment may be associated with adverse outcomes and high cost".<ref name=aan>Template:Cite web</ref>

Adverse effects

On 2 May 2008, the US Food and Drug Administration (FDA) placed a black box warning on etanercept due to a number of serious infections associated with the drug.<ref name="Wyeth and Amgen">Template:Cite web</ref> Serious infections and sepsis, including fatalities, have been reported with the use of etanercept including reactivation of latent tuberculosis and hepatitis B infections.<ref name="Enbrel FDA label" /><ref name="FDAReport">Template:Cite conference</ref>

Injection site reactions such as redness and pain are common, occurring in approximately 11.4% of cases.<ref name="PMID37533141">Template:Cite journal</ref>

Mechanism of action

Etanercept reduces the effect of naturally present TNF, and hence is a TNF inhibitor, functioning as a decoy receptor that binds to TNF.<ref>Template:Cite journal</ref>

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.<ref name="pmid16135466">Template:Cite journal</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.<ref name="pmid1936291">Template:Cite journal</ref> The effect is an artificially engineered dimeric fusion protein.<ref name="pmid1936291" /> Etanercept is a complex molecule containing 6 N-glycans, up to 14 O-glycans and 29 disulfide bridge structures.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref name=":0">Template:Cite journal</ref>

History

The first etanercept-related patent was filed by Immunex in September 1989.<ref>Template:Cite journal</ref> 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.<ref>Template:Cite web</ref> Another patent on such fusion protein technology from Brian Seed at Massachusetts General Hospital was licensed to Immmunex in 1997.<ref>Template:Cite web</ref>

Etanercept was approved for use in the United States in November 1998.<ref name="Enbrel FDA label" /><ref>Template:Cite web</ref>

Etanercept was approved for use in the European Union in February 2000.<ref name="Enbrel EPAR">Template:Cite web Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.</ref>

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.<ref>"What's behind the whopping price tags on the newest generation of drugs: The story behind the production of Enbrel, Amgen's popular rheumatoid arthritis drug, provides insights as to why bioengineered drugs are so expensive." Carol M. Ostrom, Seattle Times, 18 August 2008</ref> By 2011, the cost had exceeded $20,000 per year.<ref name="NYTAmgen2011">Template:Cite news</ref><ref>"Co-pay hike a painful reality; Miracle drug monthly cost jumps from $42 to $600" Template:Webarchive, Margery Eagan, Boston Herald, 3 November 2011</ref> 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.<ref name="IFHP2013">Template:Cite web</ref> 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.<ref name="IFHP2013" />

Etanercept is more expensive in the US than in other countries.<ref name="IFHP2013" /> 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.<ref name="IFHP2013" />

Amgen sells etanercept within the US and Canada, while Pfizer, Inc. sells the drug outside of the US and Canada.<ref name="NYTAmgen2011" /> Sales within the US and Canada were $3.5 billion in 2010.<ref name="NYTAmgen2011" /> Sales of etanercept outside the US and Canada were $3.3 billion in 2010.<ref>Template:Cite web</ref>

In late March 2025, Amgen lost a lawsuit against Colorado over a prescription drug affordability board.<ref>Template:Cite web</ref>

Patents

The patent on etanercept was set to expire in October 2012,<ref>Template:Cite web</ref> but, in the United States, a second patent, granting exclusivity for another 16 years, has been granted.<ref>Template:Cite web</ref>

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) which "requires mandatory clinical testing and periodic review".<ref>Template:Cite web</ref>

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.<ref>Template:Cite web</ref>

Biosimilars

In January 2016, Benepali was approved for use in the European Union.<ref name="Benepali EPAR">Template:Cite web</ref>

In February 2017, Lifmior was approved for use in the European Union.<ref>Template:Cite web</ref> It was withdrawn from the market in February 2020.<ref>Template:Cite web</ref>

In June 2017, Erelzi was approved for use in the European Union.<ref name="Erelzi EPAR">Template:Cite web</ref>

In March 2019, YLB113 (Etanercept biosimilar by YL Biologics) was approved in Japan.<ref>Template:Cite web</ref>

In April 2019, Eticovo received FDA approval.<ref>Template:Cite web</ref><ref>Template:Cite web</ref>

In May 2020, Nepexto was approved for use in the European Union.<ref name="Nepexto EPAR"/>

Rymti and Etera were approved for medical use in Australia in October 2020.<ref name="AusPAR: Etanercept">Template:Cite web</ref><ref>Template:Cite web</ref><ref name="Rymti ARTG">Template:Cite web</ref><ref name="Etera ARTG">Template:Cite web</ref>