The advent of a new class of drugs “biosimilars” has driven a revolution in biologics. Until 2006 biologics were seen as a class of drugs almost exclusively used in high cost Western medicine. These drugs were expensive to develop and expensive to produce, but more importantly were unable to be copied so the generics market seen in the small molecule drug field was not an option. This proposition was blown out of the water by Sandoz who took these preconceptions head on and with diligent scientific effort and close discussions with the regulators the first biosimilar in Europe was approved. Since that time the floodgates have opened with companies trying to develop copies of drugs that have lost their patent protection. It is difficult to find anyone in the pharma industry today who does not have a project or partnership in the biosimilar market, and this phenomenon is not exclusive to the Western market anymore – the expansion is truly global.
With this interest the question arises – why have so many projects been delayed or failed? The reason lies in the issue that we are still not in full control of how these hugely complicated drugs are produced and incredibly small changes to the manufacturing process can have huge impacts on the drugs clinical activity.
For example, the simple sugar fucose is one of the glycan structures that is added onto the antibody after it has been transcribed, part of the post-translational modifications that take place in the production cells. The percentage of antibodies that have the fucose added is dependent on many factors but are in part due to the media we use, the cells genetic makeup and even the temperature we are fermenting the cells at. Antibodies that have fucose as part of the glycan structure are less likely to strongly bind to the CD-16 receptor on natural killer cells; part of the immune response to foreign cells such as tumour cells.
This effect is measurable and can be over 100 fold less potent than those antibodies which do not contain fucose. A manufacturer of a biosimilar will need to match the exact fucose content of the innovator drugs to yield the same biological activity. In the complicated situation of a fermentor with so many parameters to control this can be an extremely difficult task. What also must be kept in perspective is that this is only one of the many different chemical constituents that go to make up an antibody, all inter-related and adding to the overall potency of the drugs. With this in mind it is easy to understand the complexity of biosimilar development.
To prevent costly and more importantly time consuming mistakes analysis needs to be undertaken as early as possible in the development of the drug. The sooner we apply analytics to ensure confirmation of biosimilarity the easier regulatory acceptance becomes.