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Monoclonal antibody therapeutics

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Title: Monoclonal antibody therapeutics


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 RD 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
gtUS 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 gt 500 candidates
  • gt200 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
  • gt270 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-Hodgkins 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, Crohns disease,
    allergy/asthma, transplant rejection, etc.
  • Immunological mAb therapeutics
  • gt120 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 Crohns 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), Crohns
    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_at_tufts.edu
  • http//csdd.tufts.edu
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