Etanercept

Medical uses

In the USA the FDA has licensed Enbrel for :

Safety

On May 2, 2008, the FDA placed a black box warning on etanercept due to a number of serious infections associated with the drug. Serious infections and sepsis, including fatalities, have been reported with the use of Etanercept including reactivation of latent tuberculosis and hepatitis B infections.

There has also been a report of strongyloides hyperinfection after use of Etanercept.

Mechanism of action

It reduces the effect of naturally present TNF, and hence is a TNF inhibitor, functioning as a decoy receptor that binds to TNF.

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 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.

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.

History

Etanercept was developed by researchers at Immunex, and was released for commercial use in late 1998, soon after the release of infliximab (Remicade), which was 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.

Marketing

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.

Sales

The U.S. retail price of Enbrel has risen over time. In 2008, the cost of Enbrel was reported to be $1,500 per month or $18,000 per year. By 2011, the cost had reportedly exceeded $20,000 per year. In 2013, a survey by the International Federation of Health Plans (IFHP) found that the average U.S. cost for Enbrel was $2,225 per month, or $26,700 per year. The IFHP report also found wide variation in prices charged to various U.S. health plans, between $1,946 per month at the 25th percentile and $4,006 per month at the 95th percentile.

Enbrel is more expensive in the U.S. 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 U.S.

Amgen sells Enbrel within the U.S. and Canada, while Pfizer, Inc. sells the drug outside of the U.S. and Canada. Sales within the U.S. and Canada were $3.5 billion in 2010. Sales of Enbrel outside the U.S. and Canada were $3.3 billion in 2010.

Patents

The patent on Enbrel was originally set to expire on October 23, 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. Currently 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 currently have in place a system to approve generic biologics (biosimilars) which "requires mandatory clinical testing and periodic review".

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.

In January 2015, Samsung and Biogen's joint venture "Samsung Bioepis" successfully submitted Benepali, a biosimilar version of the drug, for review to the European Medicines Agency (EMA), and announced that it will seek regulatory approvals in other territories as well. Later the same year, the European Medicines Agency also accepted Sandoz’s application for review of its etanercept product that will be marketed by Novartis.

In the US, Sandoz submitted a biologics license application (BLA) for the proposed etanercept product "GP2015" in July 2016. Upon acceptance of the first application process, the U.S. FDA reviewed data from European clinical trials and bio-analytical investigations, demonstrating the biosimilarity of GP2015 to the US-licensed Enbrel. Sandoz in 2009 tried to invalidate the patents held by Hoffman-La Roche/Immunex and exclusively licensed to Amgen but lost in federal court. Sandoz was then countersued by Amgen for patent infringements related to the methods of treating psoriasis and/or psoriatic arthritis. The case Immunex Corp. et al. vs. Sandoz Inc. et al., 16-cv-01118-CCC-JBC (D.N.J.) is pending.

Research

Etanercept is being studied as treatment for a number of diseases. This includes certain forms of vasculitis (such as granulomatosis with polyangiitis, in which it was not effective).

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