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

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Presentation on theme: "Monoclonal antibody therapeutics SLA Pharmaceutical & Health Tech. Division April 2008 Janice Reichert, Ph.D. Senior Research Fellow Tufts CSDD, Tufts."— 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, 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, N = 131 US approval success rate = 17% (three in review) % completion = 49% Humanized mAbs, 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 (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 Rituxan1997 Non-Hodgkins lymphoma Herceptin1998Breast cancer Mylotarg2000Acute myeloid leukemia Campath2001CLL Zevalin2002NHL Bexxar2003NHL Erbitux2004Colorectal cancer Avastin2004Colorectal cancer Vectibix2006Colorectal cancer

24 Immunological mAb therapeutics Immunological indications include rheumatoid arthritis, psoriasis, Crohns disease, allergy/asthma, transplant rejection, etc. Immunological mAb therapeutics >120 as of March (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 Orthoclone1986 Transplant rejection Zenapax1997Transplant rejection Simulect1998Transplant rejection Remicade1998Crohns disease Humira2002Rheumatoid arthritis Xolair2003Allergy-related asthma Raptiva2003Psoriasis Tysabri2004Multiple sclerosis Soliris2007Paroxysmal nocturnal hemoglobinuria

26 Anti-infective mAb therapeutics 50 as of March (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 Synagis1998 Prevention of respiratory syncytial virus infection

28 Four mAbs in FDA review Certolizumab pegolIn review (3/07), Crohns disease TocilizumabIn review (11/07), rheumatoid arthritis UstekinumabIn review (12/07), psoriasis MotavizumabIn 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) Senior Research Fellow Tufts Center for the Study of Drug Development (617)


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