1 / 33

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

Monoclonal antibody therapeutics SLA Pharmaceutical & Health Tech. Division April 2008. Janice Reichert, Ph.D. Senior Research Fellow Tufts CSDD, Tufts University. Topics. Brief overview of industry and benchmarking Monoclonal antibody therapeutics Structure and function

brooklyn
Télécharger la présentation

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

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  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

More Related