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The globalmap of biosimilars in 2014.

In monetary terms biologic drugs have become of prime importance to the pharmaceutical industry in recent years, for example, Humira and Herceptin have combined sales in excess of $60 billion; primarily because they are able to treat conditions that have previously been difficult with small molecules. The pharmaceutical market places a high value on biologics. This is evident in the costs paid by large pharmaceutical companies to acquire biologic companies with approved drugs.

The disadvantages to these drugs are the lengthy time to develop and the high cost of production. In turn, these disadvantages have an important benefit; protection of a manufacturer's market share, as the cost and time to develop an alternative product presents a barrier to competition. Bringing a "copycat" biologic to market, until recently was clouded with regulatory uncertainty, with no clear pathway defined for generic biologics. While small molecule drugs can be turned rapidly into generic versions following patent expiration, biologics present a much more difficult proposition. The difficulty being that the product needs to be approved on both the molecule and the process.

However, by the end of 2008, the market changed; Sandoz established a regulatory pathway in Europe to develop a generic biologic - a biosimilar. By using the innovator molecule and showing on all levels that a comparable product could be made this was now licensed in Europe. This prospect revolutionized biologics and the pharmaceutical world; whoever wanted to take a piece of the market from a blockbuster biologic was no longer presented with an uncertain and painful long term development program - a new pathway was born.

IN THE BEGINNING

The first biosimilars were Human Growth Hormone, Erythropoietin and Granulocyte-Macrophage Colony Stimulating Factor. These were the first for three reasons; (i) large market for these drugs, (ii) no patent in Europe and (iii) simple in structure, and therefore easier to produce and characterize. The biosimilar pathway allowed for a reduced cost ($75-250M) and reduced timelines (50-60%) when compared with developing a new molecule, creating a new market. Sandoz has already guided Omnitrope through regulatory submissions and has started on other molecules. The European model is recognised as being sound scientifically and its precepts were quickly adopted by many other global regulators facilitating the approvals of many molecules. The European regulators had the foresight to see that biosimilar s would not stop with the simpler biologics and were quick to put in place guidelines for the next generation of biosimilars--monoclonals antibodies. The European regulators had a bumper year in 2013 approving a number of new biosimi-lars including Remsima and Inflextra (for Remicade), along with Filgrastim, 011itropin alpha and Somatropin.

South America and Asia are the other geographies which moved enthusiastically into biosimilars. Asia has huge domestic markets for these drugs and the opportunity to move into Western markets has encouraged companies in India and Korea to lead this field. South America has experienced a slower introduction into this field than Asia but is now a powerhouse for development of these drugs.

Celltrion, which received approval for a biosimilar monoclonal antibody in Europe in 2013, is seen as the leading Korean company in this area. In India, Hospira and Dr Reddys who both have a great deal of expertise in small molecule generics, were the early adopters of the biosimilar "fever". Hospira have joined with Celltrion, having been the first to have a monoclonal biosimilar approved in Europe. One of the interesting biosimilar innovations in Asia has been the introduction to biologics of some companies with little or no history of similar production; Meiji the large Japanese conglomerate known for producing chocolate and the Korean electronics company Samsung chose Biosimilar s as their means of entry to the biologics market. Biosimilar s are therefore seen as a relatively safe way of entering a new market and the result is a flood of new investment to this technology. Companies in South America have also increased their efforts to produce biosimilar molecules for both the domestic and International markets. Brazil and Argentina have a number of indigenous companies which are developing a pipeline of biosimilar molecules.

THE REGULATORY PATHWAY

Since the regulatory pathway has been (or is being in the case of the USA) defined in most jurisdictions, the two important issues for Biosimilar s developers are (i) production of the drug and (ii) testing of the product to show comparability and compliance. Blockbuster monoclonal antibody drugs currently reach a production volume of one ton; it is thought any Biosimilar competitor product is likely to start with a minimum of 25kg of product per annum. Even if only a small number of new drugs are produced this is a substantial increase in the amount of global biologic products. Traditional biologic facilities using stainless steel fermenter manufacturing will not be able to cope with this increased production. As a result of this, many Biosimilar developers are actively seeking alternative methods of production. Merck Millipore, along with other suppliers have launched a number of products with the direct aim of reducing cost and time to market for biologic drugs with a keen eye on the Biosimilar s market.

Along with questions of production capacity, the analytic requirement for the characterisation of biologic molecules, particularly monoclonal antibodies has increased exponentially. The level of detail and sensitivity required for the analytical comparability challenges the current technologies. Each monoclonal product has an amino acid backbone that is folded, cross-linked and glycosylated by the cells. Due to the large number of biological processes that undertake this manufacture there is always variability at the molecular level in the end product. This variability may improve or reduce the molecules biological activity or function. Development of an innovator molecule normally requires sufficient analytical development to show the important characteristics of the molecule. A Biosimilar molecule requires comparability analysis with the innovator. The specification (variability) of the innovator with respect to each of the functions and analysis needs to be understood. The more analysis that can be carried out, the more we understand the complexity of the innovator products. The question remains; how similar is similar but how different can these molecules be before we can say they are not biosimilar ? A comprehensive library of innovator molecules is clearly required.

The biological comparability of the biosimilar will be closely related to the clinical effectiveness. Biological potency assays often mimic some of the in vivo biological activities expected from the drug. The biological activity however can be extremely complex, the reason some monoclonal antibodies are successful as drugs is because of the many different pathways these molecules act on to treat disease. A drug such as Remicade (Ritindmab) which is widely used in treating oncology patients has a number of different activities; its likely the most important function of the drug is to link the Fc portion of Remicade to the patients Natural Killer cells and mediate Antibody Dependant Cell Cytotoxicity and Complement Dependant Cytotoxicity these activities are important in killing the cancer cells, Rituximab has also been shown to increases MHC II and adhesion molecules, it elicits shedding of CD23, it down regulates the B cell receptor and it induces apoptosis of CD20+ cells. Within this well recognised list there are many different biological processes that are now able to be assessed using in vitro assays. Some of these activities have not been well researched and it is currently unknown where these fit into the clinical efficacy of the drug but some form the core of the biological comparability studies. The challenge for biosimilar manufacturers is to assess the variability of the innovator molecules in these assays using different batches and then assess their biosimilar version and make the argument that these are "similar". Bio0utsource has developed a number of key assays which are used as "off-the-shelf" analytics to allow customers to compare their molecule against the relevant innovator molecules. Diagram 1 shows the variability of batches of Herceptin using an ADCC assay measurement. What is recognized as the acceptable variability of the innovator and how important is this to the biosimilar?

One interesting question with respect to differences between innovator molecules and biosimilar s is the question over impurities, particularly product related impurities. Aggregates of the monoclonal are commonly seen in batches of the innovator molecule, this is an impurity as it may reduce the amount of available "active" molecule and may drive immunogenic reactivity. If the biosimilar has less aggregates, this may be a positive or as these were part of the make up of the innovator should these aggregates be maintained at the same level? Purification technology today also allows us to reduce such impurities, technology which was not available to the innovators at the time of development should we prohibit the use of these to maintain biosimilarity? Questions such as these shall become more common as this exciting field develops.

DISCLOSURE

The views expressed in this paper are the personal views of the author.

By Dr. Daniel Galbraith, Chief Scientific Officer and Founder of BioOutsource
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Title Annotation:OUTSOURCING
Author:Galbraith, Daniel
Publication:Pharmaceutical Processing
Date:Apr 1, 2014
Words:1491
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