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)