By Daniel Galbraith
2013 was a landmark year for the development of biosimilars. With the global acceptance of biosimilars--also called "follow-on biologics" or just "biologics"--and many new approvals, these drugs are moving to a global supply. This is a real and measurable change for the better, and with the global biosimilars market expected to double by 2017, this could be the single fastest-growing biologics sector in the next 5 years. However, despite many U.S.-based companies producing biosimilars, a clear approval pathway for biosimilars by the FDA is lacking. From that perspective, perhaps this year is not a complete success for these biologic medical products.
Biosimilars continue to be the catalyst for a global revolution in the development of biologics, from a niche market, to encroaching on the small-molecule drugs, to its present status as the largest area of investment in new drugs. All of the big pharmas now have a healthy pipeline of biologics and nearly all have a biosimilars division or partnership. Indeed, partnership seems to be the main vehicle driving the development of biosimilars, and these are still evolving. The main reason for the optimism for biosimilars in Europe and many other countries is simple economics: the need to reduce the overall cost of healthcare. Most forecasts reflect anything from a healthy to a meteoric rise for revenue from biosimilars; one prediction sees a global market for biosimilar monoclonal antibodies of over $19 billion by 2018.
The cost of developing a biologic drug is approximately $800 million. These sums are not for the faint-hearted, but returns can be significant. For example, Enbrel from Pfizer ($PFE) and Amgen ($AMGN) yields annual global sales of over $8 billion. Because of the cost and attendant risk of developing a new biologic drug, until relatively recently many in the pharmaceutical industry saw this as a niche area, buying or licensing successful biologics-based drugs in later stages of development rather than developing their own. Nevertheless, biologics continue to be developed at a rapid pace, as they have the ability to treat conditions that are unresponsive to other drugs. In 2012, 5 of the top 10 best-selling medicines were biologic drugs. Humira, Herceptin and Avastin, for example, have become commonly used in oncology and elsewhere.
The global trend is clear, but in the U.S., it's a different story. It was hoped that in 2013 the FDA would finally issue guidelines for the approval of biosimilars, but unfortunately this has not yet come to pass. Sadly, the FDA's approval pathway places developers of biosimilars at a disadvantage, as they must disclose the dossier used as part of the approval--an unusual step not required by European guidelines. The industry waits with bated breath to see where the FDA will finally settle on this issue.
The near-global introduction of biosimilars has highlighted a number of challenges for the industry. Alongside the need for new production facilities, there is now a considerable analytical requirement for the characterization of biologic molecules, particularly monoclonal antibodies. The innovator product is not usually a single molecular entity but rather a population of molecules in a single batch, and each batch produced will be slightly different. Every vial of product is a mix of molecules, each of a slightly different composition.
Many CROs can provide detailed molecular analysis of the biosimilar in comparison to the innovator. These methods can often pick out subpopulations of molecules with different structures or sugars, or some types of aggregations of molecules, or even degradation of the amino acid backbone. These techniques are extremely useful in assessing the primary comparability of biosimilar to innovator, but these chemistry techniques rarely shed light on the clinical efficacy of these molecules. The biological assessment/comparability of the biosimilar can often be much more illuminating as to the clinical effectiveness. Biological potency assays in vitro mimic some or all of the in vivo biological activities expected from the drug.
One interesting question with respect to differences between innovator molecules and biosimilars relates to impurities, particularly product-related impurities. Frequently, aggregates of the monoclonal antibody are seen in batches of the innovator molecule. This can be seen as an impurity, as it may reduce the amount of available "active" molecules and may also provide a center for immunogenic reactivity. If the biosimilar has less of these aggregates, is this seen as a positive? Or, as these were part of the makeup of the innovator, should these aggregates be maintained at the same level? Such questions will crop up more and more as the field develops.
As we near the end of 2013, the biosimilars story is by no means complete. We in Europe have already seen a number of approvals, with the rate likely to increase over the next few years, but even here it is still very early stages. The next important issue will be the interchangeability of these drugs.
In 2013 the biosimilars industry made significant progress, but a number of hurdles remain globally, not least with the FDA.
Daniel Galbraith, Ph.D., is founder and chief scientific officer of BioOutsource, a contract research company based in Glasgow, Scotland, and with offices in Cambridge, Massachusetts. BioOutsource's main field of technology is the analysis of biologic molecules including biosimilars.