Monoclonal antibody therapeutics

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

Janice Reichert, Ph.D. Senior Research
Fellow Tufts CSDD, Tufts University
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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

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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

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Number of new US approvals/year
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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

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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)

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What can be calculated?

• Clinical development time
• Phase 1, 2, 3 times
• Approval time
• Clinical phase transition probabilities
• Approval success rates

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Important categories

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

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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

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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
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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

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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

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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.

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Antibody structure
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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

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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

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Monoclonal Abs entering clinical study
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Therapeutic proteins entering clinical study per
year
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Mab sequence source over time
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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

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Therapeutic categories under study
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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

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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

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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

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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

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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

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Anti-infective mAb 1st US approval

• Synagis 1998 Prevention of respiratory
  syncytial virus infection

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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

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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

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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

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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

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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

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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
• [phone]
• janice.reichert_at_tufts.edu
• http//csdd.tufts.edu