Abstract
As we enter the new year of 2012, the realm of antibody therapeutics development seems full of possibilities for antibodies to watch. The commercial pipeline of antibody-based therapeutics continues to grow and now totals nearly 350 candidates. The molecular diversity of the candidates, especially those for cancer, is remarkable. Modified antibodies such as antibody-drug conjugates (ADCs), bispecific antibodies, Fc or glyco-engineered antibodies and antibody fragments/domains now comprise more than half of the anticancer antibodies at Phase 1, and ~40% of those at Phase 2 and Phase 3. These types of modified antibodies have not been developed as frequently for other disorders–by comparison, ~90% of antibodies developed for non-cancer indications are unmodified IgG–but development of the new formats for inflammatory and autoimmune disorders is expected to grow. In addition, antibody mixtures and antibodies with indirect mechanisms of action (e.g., agonism of immune activation receptors or antagonism of immune inhibitory receptors) are entering clinical study more frequently.
As we enter the new year of 2012, the realm of antibody therapeutics development seems full of possibilities for antibodies to watch. The commercial pipeline of antibody-based therapeutics continues to grow and now totals nearly 350 candidates. The molecular diversity of the candidates, especially those for cancer, is remarkable. Modified antibodies, such as antibody-drug conjugates (ADCs), bispecific antibodies, Fc or glyco-engineered antibodies and antibody fragments/domains, now comprise more than half of the anticancer antibodies at Phase 1 and ∼40% of those at Phase 2 and Phase 3. These types of modified antibodies have not been developed as frequently for other disorders, by comparison, ∼90% of antibodies developed for non-cancer indications are unmodified IgG, but development of the new formats for inflammatory and autoimmune disorders is expected to grow. In addition, antibody mixtures and antibodies with indirect mechanisms of action (e.g., agonism of immune activation receptors or antagonism of immune inhibitory receptors) are entering clinical study more frequently.
With all of these possibilities, which are the antibodies to watch this year? The approaches I've described are important to track because they are critical to the long-term success of antibody-based therapeutics, but the candidates currently at Phase 3 are always worth watching because they comprise the pool from which new-marketed products will soon emerge. The list of Phase 3 candidates changes frequently as studies are completed and decisions are made regarding the development path of the molecules. With each passing year, some candidates progress to regulatory review, some revert to Phase 2 studies and some are terminated.
As of early November 2011, a total of 25 candidates are on my list of Phase 3 antibody-based therapeutics to watch in 2012. The majority of these are undergoing evaluation as treatments for cancer or immunological diseases; only four (16%) are therapies for other indications. The 12 anticancer Phase 3 candidates include seven canonical IgG1s, as well as two ADCs (inotuzumab ozogamicin, trastuzumab emtansine), a Fab conjugated to staphylococcal enterotoxin A (naptumomab estafenatox), a glyco-engineered mAb (obinutuzumab) and a peptibody composed of a peptide fused with an Fc (AMG 386) (). Compared with the anticancer mAbs, the nine antibodies being evaluated in Phase 3 studies of patients with immunological disorders are limited in their molecular diversity (). All nine are full-length mAbs that are either IgG1 (78%) or IgG4 (22%). Only four antibody-based therapeutics are in Phase 3 studies for indications that are not classified as cancer or immunological diseases (). Two fusion proteins (Factor VIII-Fc, Factor IX-Fc) are in Phase 3 studies of hemophilia patients, and two full-length IgG1s are being evaluated in Phase 3 studies of patients with Alzheimer disease.
Last, but not least, of the antibody-based therapeutics to watch in 2012 are the biosimilars. The area of biosimilar antibody development is positioned for substantial growth as the European Medicines Agency re-evaluates their 2005 guideline on similar biological medicinal products and the US Food and Drug Administration issues their first guidance specifically addressing biosimilar product development. Companies are already evaluating biosimilar versions of rituximab (e.g., from Probiomed and Sandoz), infliximab (e.g., from Celltrion), trastuzumab (e.g., from Celltrion and Shanghai CP Guojian Pharmaceutical Co., Ltd.) and etanercept (e.g., from Hanwha Chemical and EMS) in Phase 3 studies. If the results are suitable, this new year may see the first approval of a biosimilar antibody in the European Union.
Although there are ample hot areas of antibody development to watch in 2012, the year will definitely hold challenges for both large and small companies. The current global economic turmoil has had a chilling effect on investments in drug development because it is a costly, time-consuming and risky business. A goal of new drug development is the production of products that fulfill unmet medical needs, but the development of the new antibody formats poses scientific and regulatory challenges that introduce an additional degree of uncertainty to the process. The biosimilar product development process also includes uncertainty because data requirements for approval are not yet clear. Regardless of whether they are positive or negative, 2012 is sure to include events in antibody-based therapeutics development that I look forward to reporting to you during the year.
Figures and Tables
Table 1 Antibody-based therapeutics in Phase 3 studies as treatments for cancer indications
Table 2 Antibody-based therapeutics in Phase 3 studies as treatments for immunological indications
Table 3 Antibody-based therapeutics in Phase 3 studies as treatments for other indications