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A workshop with potentially far-reaching implications for developers of antibody therapeutics will be held on July 2, 2009 in London. The European Medicines Agency (EMEA) will gather an invited group together to discuss biosimilar monoclonal antibodies (mAbs). Prior to this event, no regulatory agency has addressed key issues associated with the development of these complex products in such an open forum, or appeared to be considering the approval of them through a biosimilar regulatory pathway. The workshop will be chaired by Dr. Christian Schneider and a mAbs representative (yours truly) will be in attendance. A report of the meeting will be included in the September/October 2009 issue of mAbs.
The objective of the workshop is to discuss relevant questions on chemistry, manufacturing and controls (CMC), non-clinical and clinical issues and outcome measures with key stakeholders. Presentations have been invited from both the innovator and generic industries. The perspective of European Union regulators will also be presented. Key questions in CMC include: how well do current methods detect physicochemical differences between mAbs? To what extent do biological and functional assays substitute for a gap in sensitivity? Can quality data substitute for gaps in knowledge in functional assays? How similar does the glycosylation need to be? Does a biosimilar mAb need to have the same distribution of antibody variants compared to the innovator product? What differences should be considered acceptable?
Discussions of non-clinical and clinical issues are likely to be lively. On non-clinical issues, key questions surround what non-clinical studies should be requested, given that the studies often need to be done in monkeys to be relevant, and whether pharmacodynamic measures could be supplementary to quality development. Questions for discussion on clinical issues will include whether efficacy can be extrapolated from one indication to another and to what extent safety can be extrapolated. In the outcomes measures area, questions for discussion will include which endpoints should be used, given that measures of patient benefit might not be sensitive to product differences and, if activity endpoints are used, should these conform to existing guidelines or should new endpoints be developed. A key point for discussion will be the extent to which a risk-based approach to immunogenicity will apply, given that mAbs do not have endogenous counterparts.
The workshop may open up opportunities for some companies, but will serve as a harbinger for others. The only full-size biosimilar mAb currently on the market is Dr. Reddy's version of rituxan (Reditux™), which was launched in India in 2007. However, other top-selling mAbs such as infliximab and trastuzumab, both of which were first approved in the US in 1998, are undoubtedly attractive targets. Defining a regulatory pathway for biosimilar mAbs in the EU is a necessary step in getting (presumably) lower cost versions on the market. The US Food and Drug Administration is well behind the EMEA in defining pathways for biosimilar development of any type of protein therapeutic because legislation addressing legal aspects has not yet been passed by the US Congress.
Despite the potential new competition, innovator companies will undoubtedly continue to do well by exploiting the versatility of mAbs. Advances in technology continue to make the future promising. For example, creative solutions to unmet medical needs might be found in the application of antibody fragments as therapeutics. Fragments have numerous attractive features, including the potential to target masked or hidden epitopes that are not accessible to full-size molecules, and a variety of single-chain variable fragments, dromedary and miniaturized antibody molecules have recently entered clinical study.
Previously published online as a mAbs E-publication: www.landesbioscience.com/journals/mabs/article/9076