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The field of monoclonal antibody (mAb) development seems poised to undergo rapid change. The current circumstances recall an extraordinary ten month period between November 1997 and September 1998 when six mAbs, rituximab, trastuzumab, infliximab, daclizumab, basiliximab and palivizumab, were approved by the US Food and Drug Administration (FDA). At the time, these therapeutics represented important advances in the treatment of serious or life-threatening diseases including lymphoma, breast cancer, Crohn disease, prevention of kidney transplant rejection and prevention of respiratory syncytial viral infection. We are in similar circumstances with regard to the numbers, with five mAbs currently undergoing FDA review for anticancer, immunological and antiviral indications, and one under review for treatment of bone disorders. The candidates in review are ofatumumab, tocilizumab, ustekinumab, canakinumab, motavizumab and denosumab. Brief reviews of the clinical development of several of these candidates are included in this issue of mAbs.
However, there are important distinctions between the late 1990s and the current period. First, whereas the mAbs approved in the late 1990s comprised three chimeric and three humanized products, the current batch includes two humanized and four human products. This fact reflects the current trend toward development of human mAbs, which comprise approximately 45% of the candidates that have entered clinical study in the 2000s. Second, a number of the candidates are new and improved versions of the previously approved products-rituxan and ofatumumab are both anti-CD20 mAbs, palivizumab and motavizumab are both anti-respiratory syncytial virus mAbs. The existence of these second-generation molecules is a testament to advances in biological engineering, but also indicates the willingness of companies to compete directly in the previously quite limited mAb market. Third, two of the candidates undergoing FDA review have already been approved in other countries, whereas the US was exclusively the country of first approval for mAbs in the late 1990s. Ustekinumab is approved in the European Union (EU) as well as Canada and tocilizumab is approved in the EU and Japan. This fact illustrates the trend toward globalization of mAb development and dispersal of these therapeutics into global markets.
There are also important differences between the two periods with regard to company pipelines of clinical and preclinical candidates. In the 1990s the focus was still on full-size molecules, whereas interest today is shifting toward development of fragments and alternative, antibody-like scaffolds as therapeutics. Fragments such as Fab and single chain versions (scFv), as well as third generation molecules, are entering clinical study in increasing numbers. Additional diversity in molecular types can be seen in the preclinical pipeline.
Another major change from the 1990s is the imminent entry of biosimilars onto the US market. There are competing legislative acts under consideration in the US House of Representatives. The Promoting Innovation and Access to Life-Saving Medicine Act (HR 1427) proposes five years of market exclusivity for new biologic therapeutics; a similar proposal has been introduced in the Senate. Other bills propose longer periods, e.g., the Pathway for Biosimilars Act proposes a period of 12 years of data protection. The current budget proposal suggests that a compromise of seven years is expected. The provisions within any of the legislative acts need to balance access to less costly therapeutics with incentives to invest in research and development by innovators.
The mAb products are currently buffered from generic competition because most products are still under patent protection, and in general, mAbs are challenging to produce as biosimilars because they are the most complex of the biologically engineered therapeutics. However, mAb developers cannot afford to be complacent. Several antibody therapeutics, abciximab and rituximab are already marketed as biosimilars outside the US and EU. The scientific and development issues, including establishing product specifications and test methods, defining comparability, assessment of immunogenicity, design of clinical trials, substitutability, interchangeability, safety and post-approval surveillance, can be addressed. However, ‘the devil is in the details.’ FDA will need to provide guidance on these issues. The new FDA commissioner's leadership will be critical to defining the path forward for biosimilar therapeutic products.
Previously published online as a mAbs E-publication: www.landesbioscience.com/journals/mabs/article/8590