The rise of 'biosimilars'
Published on 07 January 2014
New biological therapies for inflammatory arthritis continue to flood the market. With patents for the older anti-TNF-therapies, such as infliximab, due to expire in the next couple of years, a new class of cheaper, similar drugs will become available. Catherine Watson looks at the implication of the emergence of these ‘biosimilars’.
In recent years, biological therapies have become increasingly used for the treatment of inflammatory conditions. The most well-known of the biological therapies are probably the TNF-α inhibitors, pioneered at the Arthritis Research UK-funded Kennedy Institute in the 1990s. These antibody-based drugs specifically target TNF-α, a cytokine or ‘messenger’ protein, which has been found to play an important role in inflammation. Essentially, anti-TNF drugs provide a blockade that halts the cycle of inflammation that is a hallmark of rheumatoid arthritis.
Unfortunately, anti-TNF therapy does not work for everyone. Around 40% of patients who are prescribed these drugs either cannot tolerate or do not respond to this type of treatment. It is still unclear why some people respond to anti-TNF and some do not. Doctors are unable to tell before starting treatment whether it will work, so the current method of prescribing is trial and error – when one therapy fails, another is tried.
In order to avoid putting people on expensive medications which may not work, researchers are looking for clues to predict who will or will not benefit. Studies have been conducted investigating a number of genes and proteins, as well as metabolites (products of reactions that take place within the body) present in urine, and even brain activity. This area of research is in the early stages, but some of these have shown real promise and may eventually allow doctors to tailor treatment to the individual patient; so-called ‘personalised medicine’.
As more becomes known about the inflammatory pathways and messengers involved in individual conditions, researchers have been able to use new drugs, targeting different components of the inflammatory process. One such treatment is rituximab (MabThera), which targets a protein called CD20, on the surface of B cells. This drug is currently prescribed as a second-line treatment for rheumatoid arthritis and is undergoing Arthritis Research UK-funded clinical trials for use in the treatment of lupus and a type of vasculitis.
Biological therapies are expensive compared to conventional drugs (such as methotrexate), so the costs of these can mount up quickly. In the UK, biologics are only prescribed to patients with an active moderate to severe condition where conventional therapies have previously been unsuccessful. Cost reduction, with a view to improving access to biological therapies, is therefore an important focus of ongoing research. The ORBIT trial, led by Dr Duncan Porter at the University of Glasgow and jointly funded between Arthritis Research UK and six Scottish NHS trusts, is comparing the effectiveness of rituximab with that of the TNF inhibitors adalimumab (Humira) and etanercept (Enbrel) for the treatment of rheumatoid arthritis. Rituximab may be anywhere between 20-60% cheaper per year than TNF inhibitors, so being able to prescribe this in the first instance could potentially be of enormous benefit to the NHS and ultimately to patients, if access to biologics is improved.
When a new drug is discovered, it is usually patent protected, which gives the patent holding company exclusive marketing rights of that drug for the life of the patent. This helps them to offset the enormous costs incurred during the research and development process. Drug patents usually only cover a period of 20 years, meaning patents on some of the original biological therapies, such as infliximab (Remicade), etanercept and rituximab, are due to expire in coming years. This will allow other drug companies to manufacture ‘biosimilars’. Because these companies will not be privy to the ‘recipe’ for the original compound, small differences in the manufacturing process may result in products which are slightly different form the original.
A biosimilar drug is defined by the World Health Organisation as one that is similar in terms of quality, safety and efficacy to an original, licensed product. Biosimilars are permitted to have small, structural differences from the original but these must not alter the how well the drug works, how safe it is or how the drug reacts with the body’s immune system. For conventional drugs, this is relatively simple but for proteins such as antibodies or receptors, it becomes more challenging. The way a protein works depends heavily on its 3D shape so small differences in the structure of a protein have the potential to bring about huge changes in its function. As such, there have been concerns raised about whether biosimilars of biological therapies will be effective, or even safe.
Biosimilars are regulated in the same way as the original biological therapies, by the European Medicines Agency (EMA), with the added condition that drug companies must prove that the structure of their drug is similar to the original, before clinical trials for equivalence can begin. This requires laboratory testing: using specialist equipment to examine the sequence of parts which make up the antibody. Results of these experiments for the new biosimilar are then compared to those from the original drug. By definition, biosimilars cannot perform markedly better or worse than their respective ‘bio-originals’, as any differences in biological activity or safety would constitute a novel product.
The first monoclonal antibody biosimilars have recently been licensed for use in the UK. Inflectra, marketed by Hospira and Remsima, manufactured by Celltrion, are essentially the same infliximab biosimilar of the original product Remicade, made by Johnson & Johnson. They have been approved by the EMA for the treatment of inflammatory conditions including rheumatoid arthritis, ankylosing spondylitis and psoriatic arthritis. Although Inflectra and Remsima have been approved, a last minute extension of the original patent on Remicade means that they are now unlikely to be available in the UK before February 2015. When they finally hit the shelves, Inflectra and Remsima are predicted to be around 30% cheaper than the original drug. Another infliximab biosimilar, as well as several etanercept and rituximab biosimilars, are also currently in late stage clinical trials.
Biological therapies have come a long way in the last 20 years, and the situation looks even brighter for the future. Research is leading us towards better performing, safer, more specific drugs as well as ways to ensure patients receive the best drug for them. The reduced costs of biosimilars also have huge potential for improving access to biological therapies in years to come.
How do biological therapies work?
Biological therapies act by combatting inflammation. A large number of these biological therapies are based around antibodies. Antibodies are proteins produced by the immune system, in response to a detected ‘threat’ such as a virus or bacteria. Each type of antibody has a unique structure that specifically recognises one particular molecule, like a lock and key. When the antibody and molecule come into contact they become joined to one another so tightly that the threat is rendered inactive, allowing other immune cells to destroy it. Researchers have exploited this mechanism and used the knowledge to design antibodies that can destroy some of the key signalling molecules involved in arthritis.