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Directed molecular evolution: lifecycle management for biologics Although biologics have an extremely attractive growth rate profile compared to small molecules, the rapid market expansion expected to occur between 2005 and 2010 will not continue at the same rate, due in part to the emergence of biosimilars. Thus, biologics manufacturers need to look at optimizing the lifecycle of their products through directed molecular evolution. In 2005, 83% of pharmaceutical drug sales were from small molecule products. However, the small molecule share of total sales is forecast to fall to 76% by 2010, in part due to the number of challenges the product class faces, not least of which is a very high level of competition from generics players. Biologics (composed of therapeutic proteins and monoclonal antibodies, or mAbs) accounted for just 15% of sales in 2005, but this is expected to grow to 22% by 2010, with a new Datamonitor report forecasting that the value of the biologics market will reach $106 billion by 2010 - a 70% increase on 2005's sales value. Biologics do not face the intense generic pressures of the small molecule class, although biosimilars (or biogenerics) are an emerging threat, particularly for therapeutic proteins. The vaccine product class is also expected to increase its sales performance representation by 2010, from 1.9% in 2005 to 2.8% in 2010, driven by the launches of innovative human papilloma virus (HPV) therapeutic vaccines. However, while biologics have an attractive growth rate profile compared to small molecules, it is clear that both therapeutic protein and mAb sales growth rates will be slowing down by 2010. Although biologics are a very attractive segment of the pharmaceutical market, there are threats to this product class; one of the most significant challenges being the emergence of biosimilars. Biologics facing generic threat for first time The FDA and the European Medicines Agency have recently approved Sandoz' Omnitrope (somatropin), which copies an existing growth hormone used to treat growth deficiencies. While Omnitrope cannot be considered a true biogeneric, as it was approved via a regulatory loophole, the introduction of the first biosimilar marks the first real generic threat to biotechnology drug makers and thus underlines the importance of lifecycle management. In addition to the biosimilar threat, the biotechnology product sector covering both therapeutic proteins and mAbs is suffering from increasing competition and 'target crowding'. There are expected to be 16 new mAbs launched from 2005 to 2010, increasing the number of marketed mAbs from 30 to 46. Therapeutic proteins treatments will also contribute 13 new product launches during this time. In total, there will be 29 new biologic treatments launched from 2005 onwards on the market by 2010, all of which will help contribute to this sales-burgeoning class of treatment. Not only are the number of biologics on the market increasing, there also appear to be a lot of 'me-too' targets that these companies are developing. There is a lot of target crowding with respect to some common, well-known targets - such as CD20, CD22, CD30, TNF and VEGF. Perhaps one of the most crowded fields is the anti-rheumatoid arthritis field, and most specifically the anti-TNF treatments. Currently, Johnson & Johnson/Centocor's Remicade (infliximab), Abbott's Humira and Amgen's Enbrel are the leading treatments in this therapy area. Given the emergence of biosimilars and increasing numbers of competitor products, the commercial need for next-generation biologics with superior product characteristics has been heightened. Directed molecular evolution as a lifecycle management strategy Directed molecular evolution (DME) is a technique that mimics natural evolution to produce optimized protein candidates. In contrast to current techniques for protein optimization, DME is a method that can be applied in the absence of prior structural/functional information. In some ways, DME can be thought of as combinatorial chemistry for biologics - instead of (or in addition to) knowledge-based methods of optimizing biologics. DME can be applied to explore the 'protein sequence space' of a candidate protein product. Given this, DME may be exactly the right technology to usher in a wave of next-generation versions of already marketed biologics, in order to stay one step ahead of biogeneric and competitive threats. DME has significant potential as a method of optimizing protein candidates and can be deployed commercially according to three broad business models. The first is 'hostile optimization,' in which the DME company targets competitors' already marketed biologics and develops optimized versions for its own internal pipeline. Second is 'collaborative optimization,' whereby the DME company develops an optimized next-generation version of a first-generation biologic on behalf of the partner company, usually a big-pharma. The DME company receives alliance revenues and milestones while the partner company gains access to DME technology in order to manage the product lifecycle of its first-generation biologic. The third model is 'development optimization,' in which the DME company does not target an already marketed biologic (as in the former two strategies) and instead applies DME to the optimization of novel protein candidates still in the pipeline. The two leading DME companies, Applied Molecular Evolution (AME) and Maxygen, are both pursuing 'hostile optimization' to populate their internal pipelines. AME reports that it has optimized next-generation versions of Johnson & Johnson's Remicade and Roche/Genentech's Rituxan (rituximab), while Maxygen is targeting G-CSF, a treatment currently dominated by Amgen's Neupogen (filgrastim)/Neulasta (pegfilgrastim) for enhancement. MedImmune set to benefit from DME first AME has also employed the 'collaborative optimization' business strategy, by collaborating with US biotech firm MedImmune for the DME optimization of the anti-respiratory syncytial virus (RSV) monoclonal antibody Synagis (palivizumab). The outcome of this development alliance was the next-generation anti-RSV mAb Numax (motavizumab), which is forecast to launch in 2008. MedImmune's decision to engage AME with the task of DME-optimizing Synagis in 1999 looks set to pay off by the end of this decade. DME has handed MedImmune a next-generation mAb that created the opportunity to reshape its relationship with the Synagis marketing partner - US big pharma company Abbott - ultimately ensuring a greater share of Numax revenues flow to MedImmune then was the case for Synagis. This particular example highlights the power of DME as a broadly applicable method for product lifecycle management of biologics. Related research:
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