True Biosimilars Do Not Offer A Compelling Business Case

Aug 01, 2010

The full version of this biosimilars feature can be read in the August issue of our digital magazine:

David E. Szymkowski
When faced with patent expiries and the risk of competition from biosimilars, innovator companies generally prefer to look forward by developing new and better drugs rather than looking back at biogeneric competition. That at least is the idealised business strategy. In reality, these companies take a more pragmatic approach to risk; this is where a biosuperior strategy can be advantageous.

How are the innovators dealing with the threat?

The innovators' primary defence against a true biosimilar is to develop a better molecule that can be launched in the time it takes for the true biosimilars to reach the market (which can be nearly as long as the development of a novel biologic). In other words, innovators (by definition) seek to develop drugs to new targets with new mechanisms. However, it is not always possible to identify and exploit such new targets — that's where the "biobetter" or "biosuperior" strategy arises.

Pharma companies, though also innovators, are generally more conservative than smaller biopharmas and biotechs. In my opinion, pharmas are more willing to look sideways at the competition to identify their next blockbuster (the classic "me-too" strategy), and this holds true for biologics as well as small molecules. For examples, simply look at the large number of anti-CD20 antibodies in development following the success of rituximab and the five anti-TNF biologics on the market, with still more in development.

Also, keep in mind that the "threat" of competition is currently just that: an unquantifiable (possibly modest) threat. The general consensus is that the consequences of imminent patent cliffs are not expected to be nearly as dire as for small molecules, where market share can be devastated very quickly. In contrast, in a widely quoted analysis by the US Federal Trade Commission, it was estimated that innovator biologics would maintain the majority of market share (~70–90%) even well after patent expiry.1 There are many reasons for this, including the current lack of an abbreviated regulatory pathway (precluding significant cost or time savings for biosimilars), the potential new safety risks (e.g., due to differences in immunogenicity) and the unique supply chain for biologics (which are frequently handled by speciality and hospital pharmacies).

In summary, from my observation of innovators' response to the perceived threat, they have largely dismissed biogenerics as a viable strategy for themselves, while seeing them as an unavoidable yet modest external threat. Innovators are concerned about erosion of their market share by biogenerics, but are confident that this erosion will be much less severe and more delayed compared with small molecules. On the other hand, innovators are heavily investing in biosuperiors. Even the innovators are looking hard at biobetter strategies to fill their pipelines and provide a lifecycle management strategy for their blockbusters.

Biosimilars vs. biosuperiors

The differences between biogenerics, biosuperiors and next-generation innovative drugs are not clearly defined. I prefer "biosimilars" and "biosuperiors" as the most accurate descriptors. For example, is a humanised version of a chimeric antibody a biosuperior or next-generation molecule? It is clearly not a biogeneric, but on the other hand it is not really an innovative new drug, either. If a biologic has a superior formulation that allows subcutaneous administration of a formerly in vitro infusion, is this still a biogeneric? If a biologic is made using the original 1990s technology, can the biosimilar be manufactured in a state-of-the-art cell expression system?

What a biosimilar is not defines it more than what it is. There is a consensus that biosimilars (also known as followon biologics) must replicate as closely as possible the innovator biologic, as with small molecule generics. The critical point is that all characteristics of the innovator drug must be replicated, including mechanism of action, potency, immunogenicity (or lack thereof), identical pharmacokinetics, etc. By definition, a biogeneric cannot be better in any aspect than the innovator drug. This raises some interesting possibilities. For example, discovering that your biosimilar has a superior halflife in humans would be a damaging result. Ironically, although improved halflife would be an advantage, the result could kill your drug because it would demonstrate that it was not a true biogeneric. As another example, if the purity of the innovator biologic is less than ideal, should the biogeneric intentionally be manufactured to the lower specifications of the innovator drug? Since changes to biologics may result in unpredictable consequences, by definition, the biogeneric must be as good (or as bad) as the innovator drug in all respects. These types of issues are currently under debate and help illustrate why the biogenerics pathway to market is so much more complicated than that of small-molecule generics.

These biosimilar issues are much more transparent when the intent is to create a biobetter (also known as a biosuperior). In marked contrast with biosimilar development, developers are free, and in fact compelled, to improve on the original to generate clinical and market advantages over the innovator. Once the decision is made to improve rather than make a "me-too", there are many routes to generate the biosuperior. However, there is still a line that must not be crossed. For example, a biobetter cannot improve too much upon the original biologic, or it becomes a nextgeneration innovative drug. This certainly has greater rewards but also carries greater risks.