Monoclonal antibody therapeutics SLA Pharmaceutical & Health Tech. Division April 2008

1. Monoclonal antibody therapeutics SLA Pharmaceutical & Health Tech. Division April 2008 Janice Reichert, Ph.D. Senior Research Fellow Tufts CSDD, Tufts University

2. Topics • Brief overview of industry and benchmarking • Monoclonal antibody therapeutics • Structure and function • Global commercial development since 1980 • Therapeutic categories • Anti-cancer mAbs • Immunological mAbs • Anti-infective mAbs • Future trends

3. Challenges facing the industry • Competitive markets • Industry globalization • Mergers, acquisitions, strategic alliances • Scientific and technological advances • Dynamic regulatory environment • High R&D costs • Long clinical development and approval times • Low approval success rates

4. Number of new US approvals/year

5. Benchmark metrics • Objective is to compare performance against a relative or absolute standard • Important to compare ‘like’ therapeutics • Allows assessment of efficiency and cost-effectiveness • Important for strategic planning • Tufts CSDD focus is on clinical development and approval

6. Input data • IND filing date • First administration to humans date • Phase start dates (Phase 1, 2, 3) • NDA or BLA submission date • FDA approval date • Status at discontinuation (Phase 1, 2, 3)

7. What can be calculated? • Clinical development time • Phase 1, 2, 3 times • Approval time • Clinical phase transition probabilities • Approval success rates

8. Important categories • Composition of matter • Small molecule • Biopharmaceutical (rDNA, mAb, etc.) • Therapeutic category • FDA designations • Orphan • Priority or standard review • Accelerated approval • Fast track

9. Global focus on mAb therapeutics • Acquisitions by major pharmaceutical firms • Merck acquisition of Abmaxis, GlycoFi • GSK acquisition of Domantis • Eisai acquisition of Morphotek • AstraZeneca acquisition of CAT, MedImmune • Development in Asia • First marketing approvals in China • “Generic” mAbs in India and S. Korea

10. >US$ 1billion global markets* • Remicade $4.4 billion • Rituxan $3.9 billion • Herceptin $3.1 billion • Avastin $2.4 billion • Humira $2.0 billion • Erbitux $1.1 billion • Synagis $1.1 billion *2006 sales, as reported in Med Ad News, July 2007

11. MAb therapeutics come of age • Established pathways to demonstrate safety, efficacy and quality • Innovative design of proteins • New technology addressing issues • Immunogenicity • Stability • Affinity • Specificity • Production

12. Antibodies • Five classes based on type of heavy chain • IgA • IgD • IgE • IgG – derived from B-cells, most abundant Ig • IgM • IgG has two primary functions • Bind foreign antigens • Eliminate or inactivate antigen

13. Structural features of IgG • IgG are Y-shaped molecules • Composed of a total of 4 protein chains • 2 heavy chains with 1 variable and 3 constant domains • 2 light chains with 1 variable and 1 constant domain • Stem (Fc) of Y = 2x2 heavy chain constant domains • Each arm (Fab) of Y = 1 variable and 1 constant domain from heavy chain and 1 entire light chain.

14. Antibody structure

15. Functions of IgG • Cell-based target • Target toxin or radiolabel to specific location • Block targeted receptor • Induce apoptosis • Antibody dependent cell cytotoxicity (Fc dependent) • Complement dependent cytotoxicity (Fc dependent) • Sequester soluble targets • Ligand binding

16. New mAb therapeutics, 1980-2007 • World-wide clinical development of protein therapeutics by commercial sponsors • Total > 500 candidates • >200 in clinical studies • Number approved • 21 approved in US and other countries • 3 approved outside US

17. Monoclonal Abs entering clinical study

18. Therapeutic proteins entering clinical study per year

19. Mab sequence source over time

20. Success rates for humanized mAbs • Humanized mAbs, 1988-2006 • N = 131 • US approval success rate = 17% (three in review) • % completion = 49% • Humanized mAbs, 1988-1997 • N = 46 • US approval success rate = 27% • % completion = 80%

21. Therapeutic categories under study

22. Oncology mAb therapeutics • Number of oncology mAb therapeutics • >270 as of March 2008 • 121 (44%) currently in clinical development • Number of oncology mAb approvals to date • 9 approved in US • 3 additional oncology mAbs approved in China

23. Oncology mAbs: first US approvals • Rituxan 1997 Non-Hodgkin’s lymphoma • Herceptin 1998 Breast cancer • Mylotarg 2000 Acute myeloid leukemia • Campath 2001 CLL • Zevalin 2002 NHL • Bexxar 2003 NHL • Erbitux 2004 Colorectal cancer • Avastin 2004 Colorectal cancer • Vectibix 2006 Colorectal cancer

24. Immunological mAb therapeutics • ‘Immunological’ indications include rheumatoid arthritis, psoriasis, Crohn’s disease, allergy/asthma, transplant rejection, etc. • Immunological mAb therapeutics • >120 as of March 2008 • 56 (46%) currently in clinical development • Number of immunological mAb approvals to date • 9 approved in US • 3 in FDA review

25. Immuno. mAbs: 1st US approvals • Orthoclone 1986 Transplant rejection • Zenapax 1997 Transplant rejection • Simulect 1998 Transplant rejection • Remicade 1998 Crohn’s disease • Humira 2002 Rheumatoid arthritis • Xolair 2003 Allergy-related asthma • Raptiva 2003 Psoriasis • Tysabri 2004 Multiple sclerosis • Soliris 2007 Paroxysmal nocturnal hemoglobinuria

26. Anti-infective mAb therapeutics • Anti-infective mAb therapeutics • 50 as of March 2008 • 18 (36%) currently in clinical development • Number of anti-infective mAb approvals to date • 1 approved in US • 1 in FDA review

27. Anti-infective mAb: 1st US approval • Synagis 1998 Prevention of respiratory syncytial virus infection

28. Four mAbs in FDA review • Certolizumab pegol In review (3/07), Crohn’s disease • Tocilizumab In review (11/07), rheumatoid arthritis • Ustekinumab In review (12/07), psoriasis • Motavizumab In review (01/08), prevention of respiratory syncytial virus infection

29. Human mAb therapeutics • Humira and Vectibix are human mAbs • Fewer issues associated with immunogenicity • Multiple methods for candidate selection • Transgenic mouse • Phage display • Commercial production from CHO cells

30. Next generation mAbs • Fragments, e.g. Fab, single chains • Smaller, easier/less costly to manufacture • But, shorter circulating half-life, no effector functions • Approved Fabs: Reopro (1994) and Lucentis (2006) • Modified versions • Enhance ADCC/CDC functions • Modify pharmacokinetic properties – pegylation • Modify affinity and specificity – glycosylation, Fc region engineering

31. Future trends • Opportunities in major therapeutic categories • Anticancer therapeutics • Immunological agents • Anti-infective agents • Increase in marketing approvals if success rates are consistent with previous rates • Human mAbs • Designed protein scaffolds/domains

32. Attraction of mAbs • Expansion of therapeutics pipeline • High(er) approval success rates • Established development and approval pathways • Established production methods • Competitive research and development times • Potentially large markets

33. Questions? Comments? Janice Reichert, Ph.D. Editor-in-Chief, MAbs (Landes Bioscience, launch in January 2009) http://www.landesbioscience.com/journals/mabs Senior Research Fellow Tufts Center for the Study of Drug Development (617) 636-2182 janice.reichert@tufts.edu http://csdd.tufts.edu