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Monoclonal antibody therapeutics

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Presentation on theme: "Monoclonal antibody therapeutics"— Presentation transcript:

1 Monoclonal antibody therapeutics
3/27/2017 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 Therapeutic category
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 Sequester soluble targets
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
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 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 Non-Hodgkin’s lymphoma Herceptin Breast cancer Mylotarg Acute myeloid leukemia Campath CLL Zevalin NHL Bexxar NHL Erbitux Colorectal cancer Avastin Colorectal cancer Vectibix 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 Transplant rejection Zenapax Transplant rejection Simulect Transplant rejection Remicade Crohn’s disease Humira Rheumatoid arthritis Xolair Allergy-related asthma Raptiva Psoriasis Tysabri Multiple sclerosis Soliris Paroxysmal nocturnal hemoglobinuria

26 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 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) Senior Research Fellow Tufts Center for the Study of Drug Development (617)

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