2. Chief, Division of Allergy, Immunology and Rheumatology
Director, Chinese Medicine Clinical Trial Center
Associate professor, Institute of Medicine, Chung Shan Medical University.
Clinical Trials Experience
2010.Oct. FDA GCP SITE INSPECTION PASSED
2012.Aug. TFDA (Taiwan) GCP SITE INSPECTION PASSED
**World top one enroller in
-Norvatis RHAK study in ankylosing spondylitis.
-Pfizer Etanercept study in non-radiographic axial spondyloarthritis.
*
*Taiwan top one enroller in
-BMS abatacept study in rheumatoid arthritis
-UCB anti-IL6 in rheumatoid arthritis
-MSD Etoricoxib in ankylosing spondylitis
-TWi Biotechnology, Inc. IL-1 receptor antagonist in gouty arthritis
3. Pathogenesis of RA
Traditional therapies
Immune target therapies
Biological agents
Small molecules
Summary & Take home message
4. Pathogenesis of RA
Traditional therapies
Immune target therapies
Biological agents
Small molecules
Summary & Take home message
5. Prevalence: 0.4~1%
A prototype of autoimmune chronic
inflammatory arthritis.
Lifelong, progressive damage to
joints and bone.
Market of Humira & Enbrel are top 1
and 2 in the world.
21. Normal Interaction Neutralization of Cytokines
Inflammatory
Cytokine
Monoclonal
Antibody
Cytokine
Receptor
Soluble
Receptor
Inflammatory
Signal
No Signal
Activation of
Receptor Blockade Anti-inflammatory Pathways
Monoclonal
Antibody
Receptor
Antagonist
Antiinflammatory
Cytokine
Block signaling
No Signal
Choy EHS, Panayi GS. N Engl J Med. 2001;344:907–916.
22. -cept : fusion of a receptor
-mab : a monoclonal antibody (mAb)
-ximab: a chimeric mAb
-zumab : a humanized mAb
-tinib: tyrosine kinase inhibitors
40. B cell development
Antigen-independent phase
Surrogate
light chain
Stem cell
Pro-B cell
Pre-B cell
IgM
Immature
B cell
Antigen-dependent phase
IgM
IgD
Mature
B cell
IgM, IgD,
IgA, or IgE
Activated
B cell
CD19
CD20
Adapted from Sell et al. Immunology, Immunopathology, and Immunity. 6th ed. 2001; Roitt et al. Immunology. 6th ed. 2001;
Tedder et al. J Immunol 1985;135:973.
Secreted
IgG, IgA,
IgE, or IgM
Plasma
cell
41. Rituximab(anti-CD20) in RA
Edwards et al. Engl J Med. 2004 Jun 17;350(25):2572-81.
80
70
60
50
ACR 20
ACR 50
ACR 70
40
30
20
10
0
MTX
control
Ritux
only
Ritux + Ritux +
CTX
MTX
• 1000 mg at Day 1&15,
q6m
• Better response in RF+
or CCP+ pts
• TNF-IR RA
• Combine with MTX
48. Co-stimulatory Pathways
APC
There are several co-stimulatory
and co-inhibitory pathways; signals
through these pathways can either
upregulate or downregulate T-cell
activation
+
–
+
T cell
–
56. Pathogenesis of immune system
Immune target therapies
Biological agents
Small molecules
Take home message
57. The MAPK, Syk kinase, NF-κB and JAK/STAT intracellular signalling pathways
Bonilla-Hernán M G et al. Rheumatology 2011;50:15421550
58. The majority of cytokine receptors use three
JAK combinations
Shown are well-studied cases where JAK usage by each cytokine receptor has been established by
genetic and biochemical studies. Exceptions shown are the G-CSFR (*) where it is currently unclear
whether both JAK1 and JAK2 are required together. Additionally, the IL-12R (†) and IL-23R (†)
require TYK2 but the requirement for JAK2 has not been definitively determined. Receptors that
use JAK2 and JAK3, JAK3 alone, TYK2 alone, or JAK3 and TYK2 have not been described.
61. Xeljanz (tofacitinib)
FDA approved on Nov. 6,
2012
5 mg twice daily
adults with moderately to
severely active rheumatoid
arthritis (RA) who have had
an inadequate response to,
or who are intolerant of,
methotrexate.
Cost: 90% of TNFi biologics
72.
Small Molecules Target therapy
JAK
SYK
PGE4
Tyrosine kinase inhibitor, TKI
Histamin-4
73.
74. Chronic inflammation and immune-related
diseases markets arising.
Immune-target therapies is the trend!
Questions to be answered
What is the most important target?
Personalized medicine
Key to success:
Sustained efficacy
Long-term safety
Availability