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“West Meets East” Chinese Medicine Could be a Cornerstone for Developing
Future Medicine
Yung-Chi ChengHenry Bronson Professor of Pharmacology
Yale School of Medicine
Cancer & Viral Chemotherapy
• Scope of Activity
A.Molecular and Biochemical Pharmacology of Anticancer and Antiviral Compounds
B.Drug Discovery
C.Clinic Protocol Design
• Drug Entity of Current Interest
A.Nucleoside Analogs
B.Natural Products
C.Chinese Medicine
Chemical(s) Indication Clinical Stage
DHPG (Gancyclovir)*
CMV Approved
3TC (Lamivudine)* HBV Approved
L-FTC (Emtricitabine)
HBV Phase III (completed)
L-FMAU (Clevudine)
HBV Approved
L-OddC (Troxacitabine) Solid Tumor Phase I/II
L-Fd4C (Elvucitabine)
HIV
HBV
Phase II
Phase I/II
D-IPdR (Ropidoxuridine)
Radiosensitizer
For solid tumor
Phase I/II
Orphan Drug Status
D-4’Ed4T HIV Preclinical
PHY-906 Cancer Phase II
* Do Not Hold Patent
Chemicals Discovered in this Laboratory (In Collaboration with Others) Under Different Stages of Clinical Development
Nature Product Analogs Under Current Investigation
1. Camptothecin and VP-16 conjugates • Cancer
2. Tylophorine analogs• Cancer and autoimmune diseases
3. Helioxanthin analogs• Hepatitis B Virus
4. Falvanoid analogs• Facilitator of oral uptake of drug
Scope of MedicineScope of Medicine
- For treatment of disease
- For improving use of other medicine
- For prevention of disease
- For enhancement of “quality of life” of patients and “healthy” individuals
The Current Paradigm of Mainstream The Current Paradigm of Mainstream Pharmaceutical DiscoveryPharmaceutical Discovery
• Reductionist approach
• To identify a target associated with disease
• To identify a single compound that can regulate a given target associated with a disease. Such compounds are expected to have potency and selectivity for the treatment of the disease targeted.
Challenges of Current Mainstream Challenges of Current Mainstream Drug Discovery ApproachDrug Discovery Approach
• For a given disease, it can be caused by multiple reasons, it will be difficult to find one chemical with defined target related to diseases
- To treat the majority of patients- To prevent a majority of the population contracting the disease
• For a given treatment, multiple side effects could occur, it will be difficult to find one drug to relieve all the side effects
• For different patients with the same disease caused by the same etiological factor, the response to a given treatment could be different. Host factors need to be taken into consideration
• Many of potent drugs for the treatment or prevention of chronic diseases may require long-term use, delayed toxicity may occur
New Paradigm for Future MedicineNew Paradigm for Future Medicine
• Multiple targets
• Polychemical medicine instead of one chemical medicine with system biology approach in mind
Two Approaches to Two Approaches to Polychemical MedicinePolychemical Medicine
• Conventional “Step by step”• Revisiting history as the basis of reinventing
medicine
Traditional Chinese medicine and other Folk medicine
• Chinese herbal medicine has many chemicals which could target on multiple sites or act on a single site additively or synergistically through direct or indirect interaction.
• Chinese Medicine has multiple medical usage for the treatment of complicated diseases or multiple symptoms as well as disease prevention and improving quality of life.
• Chinese Medicine takes a holistic approach and is an early form of “system biology” and “integrated medicine”.
• Chinese Medicine is prescribed on an individual basis to optimize its usage. It is “individualized medicine”.
Chinese Medicine Could Meet Some of the Current Unmet Medical Needs and Serve as the Basis for Future Medicine”
Botanical Drugs: A new area for Botanical Drugs: A new area for the US FDAthe US FDA
• Guidelines for the Botanical Drug Industry: (June 2004)
• Waive the combination rule• May enter Phase I,II clinical studies with a
documented history of use• Requirements for approval will include:
– Safety– Efficacy– Product Consistency
•“Botanical drug” and drug interaction
•Mechanism(s) of Action(s) & Active Ingredients
How to Make Preparations of Herbal Medicine with Consistency
•Authentication of herb
•Good agricultural practices (GAP)
•Good manufacturing practices (GMP)
Authentication of Herb
1.Micro-morphological analysis
2.Gene sequence analysis
3.Chemical analysis• In vitro (solution state)• In situ (solid state)
Laser
Microscopic Image of Plant Tissue
Chemical Image of Plant Tissue
Digitization(Data Reconstruction)
Mass Spectrum atDifferent Positions of the
Plant Tissue12
nLaserLaser
Microscopic Image of Plant Tissue
Chemical Image of Plant Tissue
Digitization(Data Reconstruction)
Mass Spectrum atDifferent Positions of the
Plant Tissue12
n
Mass Spectrum atDifferent Positions of the
Plant Tissue12
n
12
n
Stem Tissue Coated Stem Tissue
A schematic Diagram Showing the determination a chemical image of herbal tissue by Matrix-Assisted Laser Desorption / Ionization Mass Spectrometry (MALD-MS)
Direct Desorption / Ionization of Morphinane Alkaloids from the Stem Tissue of Sinomenium acutum by MALDI
By: K.M. Ng (HKU) Z. Zhao (BU) et al.
◊ 0311007 and □ 0311008 are two different samples from Shaanxi province ▲ 0311011 and ●0312032 are from Anhui province and Chongqin city, respectively. K.M. Ng et al. (Unpublished Results)
Spatial distribution of two metabolites from within stem tissue of Sinomenium acutum collected from different growing areas
Good Agricultural Practices consistency of raw ingredients– Botanical authentication
• Macro and micro histology– Agricultural contaminants
• Heavy metals, pesticides, fungicides, herbicides …• Bacterial, plant, fungal contaminants
– Harvest time• “Raw Plant” fingerprints
Good Manufacturing Practice consistency of drug substance and product– PhytomicsQC
• Chemical Analysis• Biological Analysis• Informatics / Data mining
Botanical Quality Control
Quality Control for Complex Mixtures• Regulatory and Scientific Challenge
– What do you measure?– How do you measure it?– How do you compare it?
A NOVEL APPROACH IS REQUIRED!!• What can be done now
• Multiple parameters
• Inclusive
Comprehensive Quality Control MeasuresBiological Response
Chemical Fingerprint 1
Chemical Fingerprint 2
Chemical Fingerprint
Biological Response 1
Biological Response 2
Biological Response
Chemical Fingerprint 1
Chemical Fingerprint 2
Chemical Fingerprint
Biological Response 1
Biological Response 2
Biological Response
Chemical Fingerprint 1
Chemical Fingerprint 2
Chemical Fingerprint
Biological Response 1
Biological Response 2
Biological Response
Chemical Fingerprint 1
Chemical Fingerprint 2
Chemical Fingerprint
Biological Response 1
Biological Response 2
Two Tier Approach to Botanical QC
• Tier One: Individual Analysis– Specific, Absolute Quantitation
• Individual Chemical Marker Compounds• Specific Enzyme/Receptor Target Activities
• Tier Two: Fingerprint Analysis– Global, Relative Quantitation
• Chemical Fingerprint• Bioresponse Fingerprint
Criteria for PhytomicsQC
• Information-intensive fingerprints• Molecular resolution• Quantitative analysis• Robust, integrated technologies• Centralized informatics• Validated platform with SOPs
• Chemical and biological metrics
PhytomicsQCTM
DNA
Protein
“blueprint” RNA“messenger”
“executioner”
BioResponse fingerprintChemical fingerprint
Mr. Mouse / Pharmacology Provided by PhytoCeutica Inc.
(A Yale University Sponsored Company)
• CPT-11
• Capecitabine, 5-FU
• CPT-11/5-FU/LV
• VP-16
• L-OddC
• Gemcitabine
• Oxaliplatin
• Colorectal Cancer
• Liver Cancer
• Colorectal Cancer
• Lung Cancer
• Leukemia, Pancreatic
• Pancreatic Cancer
• Colorectal Cancer
Chemotherapeutic Agent Indication
PHY906 *
•Composition
– Spray dried aqueous extract of four botanicals
•Traditional use (since 300 A.D.)
–Diarrhea, vomiting, nausea, intestinal cramping
•Modern use (2000 A.D.) : An adjuvant for cancer chemotherapy
* U.S. Patent 7,025,993 B2 ; IND: 62,627
Flavanoids
Coumarins
Glycosides
Sapponins
Triterpenoids
Others
Flavanoids
Coumarins
Glycosides
Sapponins
Triterpenoids
Others0
200
400
600
800
1000
1200
1400
0 10 20 30 40 50 60
Retention Time
Mass
Unidentified
Identified
5.00 10.00 15.00 20.00 25.00 30.00 35.00 40.00 45.00 50.00 55.00T im e0
100
%
29 .86
22 .77
21 .54
4 .86 17 .11
24 .23
28 .09
35 .11
33 .83
32 .0638 .94
46 .09 48 .03
PHY906: Identification using LC/MS Data
In collaboration with PhytoCeutica Inc. (A Yale University Sponsored Company)
PSI Ratio vs. Intensity
PHY906-6 PHY906-7 PHY906-8 PHY906-F
PHY906-6 1 0.998 0.993 0.981
PHY906-7 1 0.994 0.981
PHY906-8 1 0.994
PHY906-F 1
Intensity
PSI
Provided by PhytoCeutica Inc. (A Yale University Sponsored Company)
PHY906-6 PHY906-7 PHY906-8 PHY906-F
PHY906-6 1 0.99 0.991 0.729
PHY906-7 1 0.986 0.726
PHY906-8 1 0.722
PHY906-F 1
PSI Distribution of 15 Sources of same Formula
Provided by PhytoCeutica Inc. (A Yale University Sponsored Company)
Biological Response for Quality Control of Herbal Medicine
•Enzyme or Receptor Assays
•Cell-Based AssaysCell growth or behaviorsFunctional genomicsProteomicsPhytomics
•In Vivo Assays
PhytomicsQCTM
DNA
Protein
“blueprint” RNA“messenger”
“executioner”
BioResponse fingerprintChemical fingerprint
Mr. Mouse / Pharmacology Provided by PhytoCeutica Inc.
(A Yale University Sponsored Company)
Pathway Distribution
Other
Cell Death
Cell Growth
Cell Cycle
Cancer
Metabolism
Signalling
Coagulation
18%
4%35%
7%
4%2%
26%
4%
Pathway Analysis of Regulated Genes
PHY906-6 in HepG2 cells (regulated genes > 1.2 fold in dChip analysis)
Batch 6 Batch 7 Batch 8 Batch 9 Batch F
Batch 6 1.00 0.99 0.99 0.92 0.32
Batch 7 1.00 0.99 0.93 0.36
Batch 8 1.00 0.95 0.42
Batch 9 1.00 0.45
Batch F 1.00
PSI Calculations (based on 20 genes)
Genomic BioResponse Fingerprint Comparison of PHY906 Batches
Batch 6, 7, 8 : clinical batches (GMP)Batch 9: non-clinical batch (manufactured unde GMP protocol) Batch F: non-clinical batch (non-GMP protocol)
Her
b 1
Her
b 2
G. L
uci
diu
m
PH
Y 9
06
524 “union” gene set in HepG2
Wh
ite
Re
d
Am
eri
ca
n
Ginseng
BioResponse Gene Expression Profiles
• Iso-IC50 drug treatment dose
• Different BioResponse patterns observed for different herbals
• Can distinguish different herbal preparations, herbal variants and herbal species
Conclusion:
Genomic Expression provides a sensitive, global bio-fingerprint as a unique response pattern to the herbal chemical composition
PHY906
G. Lucidium
Ginseng
Herb 1
Herb 2
Issues of TCM Clinical Trial
• Be sure that a consistent preparation of clinical trial material can be made.
• Double blind and Placebo design is preferable. Other alternative designs could be considered.
• A clear clinical endpoint which is acceptable worldwide should be used for efficacy. Toxicity should be closely monitored.
• Statistical consideration is critical in the design.
PHY906 in Advanced Colorectal CancerPHY906 in Advanced Colorectal Cancer Phase I/IIA Randomized, Double-Blind, Placebo-Controlled, Phase I/IIA Randomized, Double-Blind, Placebo-Controlled,
Cross-over Dose EscalationCross-over Dose Escalation
Study Day
= Dosing
-14 1 28 42 70 84
Course 0(Baseline)
Course 2Course 1
Crossover
Randomize
Sequence 1
Sequence 2
CPT-11/FU/LV orCPT-11 alone
PHY906 PHY906
Placebo Placebo
CPT-11/FU/LV or CPT-11 alone
CPT-11/FU/LV or CPT-11 alone
CPT-11/FU/LV or CPT-11 alone
Study Sites•Shivani Kummar, M.D., Oncologist Yale Univ/Veterans Administration CT Cancer Center, West Haven, CT•Scott Wadler, M.D., Oncologist, Weill Cornell Medical Center, New York, NY •Mark O’Rouke, M.D., Oncologist Cancer Centers of the Carolinas, Greenville, SC•Leslie R. Laufman, M.D. Hematology/Oncology Consultants, Inc., Columbus, OH
Study Design
Results:•Safe at two doses (NO SAEs) •Reduced diarrhea/nausea by one grade•No effect on metabolism of CPT-11, 5FU•Out of 17 patients, 15 patients showed either partial response or
stable disease after 2 courses of treatmentProvided by PhytoCeutica Inc. (A Yale University Sponsored Company)
PHY906 in Hepatocellular CarcinomaPhase I/II Open Label, Dose-Escalation, Safety, and Efficacy Study
Clinical Study Sites• Yun Yen, M.D., Ph.D.
City of Hope National Medical Center• Michal Rose, M.D.
Yale University/ Veterans Administration CT Cancer
Center, West Haven, CT• Samuel So, M.D.
Stanford University Medical Center, Stanford, CA
Phase II Objectives•Primary: Overall survival time (OS)•Secondary
– Time to disease progression (TTP)– Quality of patient life – Safety and tolerability
Phase I Objectives •Primary
– Tolerability of PHY906 plus capecitabine
– Safety of 2 consecutive courses – Evaluation of PHY906 toxicity
and adverse effects
Provided by PhytoCeutica Inc. (A Yale University Sponsored Company)
•Results and above–No grade 3 drug related toxicity
Are All Four Botanicals Necessary?
Botanical A B C D
Protection of body weight loss
(Toxicity)
Enhancement of antitumor effect
(Efficacy)
+ + + + ++ ++ - + + + - - + - + + ++ - + + - + - + + + + - - ++
PHY906:BDF-1 Mice Bearing Colon 38 Tumor CPT-11 Treatment
Principles of Combined Usage of Principles of Combined Usage of Herbs in TCM FormulaHerbs in TCM Formula
• Imperial Herb ( 君 )
The chief herb (main ingredient) of a formula; toxic and nontoxic
• Ministerial Herb ( 臣 )
Ancillary to the imperial herb, augments and promotes the action of the main ingredient
• Assistant Herb ( 左 )
Reduces side effects of the chief herb
• Servant Herb ( 使 )
Harmonizes or coordinates the actions of the other herbs
Mechanisms of Herb Interaction of PHY906 for Absorption of
Phytochemicals into Blood Stream
Inhibition of multiple drug resistant protein which could decrease the uptake of certain chemicals in the GI tract, leading to the increase of oral uptake of certain chemicals.
Inhibition of CYP3A4, a predominant drug metabolic enzyme in the intestine, leading to the increase of oral uptake of certain chemicals.
Inhibition of microfloral β-glucuronidase & glucosidase
Stabilization and/or improvement of modification of solubility of certain chemicals.
INTERACTIONS OF INDIVIDIUAL HERBSInteraction of different ingredients of Chinese formula (described by Tao Hongjing 451-526)
Chinese English translation Explanation
1 相使 Help or reinforce each other
Additive or synergistic enhancement of pharmacologic action by two or more substances with similar properties.
2 相須 Need each other Potentiation or synergism; enhancement of therapeutic action by substances with different properties.
3 相畏 Mutual respect or restraint
Inhibition or reduction of pharmacologic effects by two or more substances with properties in common.
4 相惡 Mutual dislike Inhibition or reduction of an effect of one drug by another with an opposing action.
5 相殺 Kill each other The specific nullification of the effect of one compound by another agent through competitive antagonism, such as between agonist and antagonist compounds.
6 相反 Oppose each other Incompatibility, not suitable for combination due to severe adverse effects.
Botanical Data Mining: The Botanical Data Mining: The Next StepNext Step
• WHY?
– Identification of active phytocompounds– Defining a biologically relevant chemical fingerprint– Development of second generation drugs
• HOW?– Correlation of biological response and chemical fingerprint
What will it take to globalize Chinese medicine?
• Experience-based claims → Evidence-based claims
• Subjective quality control → Objective quality control
• User unfriendly → User friendlyPreparation and Prescription
• Complex formula →Simplified formula• Clarification of dosage and toxicity
Short term vs long term• Clarification of interaction with current medicine• Mechanism(s) of its action(s) and active compounds
involved.• New usage of traditional Chinese medicine or its
Derivatives.
INDUSTRY
ACADEMIC INSTITUTE
GOVERNMENT
-INTRA-REGIONAL COLLABORATION-INTER-REGIONAL COLLABORATION
To globalize Chinese medicine, close collaboration among academia, industry and Government is needed. Given the limitation of resource (human, technology and financial) international collaboration is critical for the advancement.
“Collaboration is Critical”
Consortium for Globalization of Chinese Medicine (CGCM)
• Global• Non-profit• Non-discriminatory• Non-political
www.tcmedicine.org
In pursuit of advancing the field of Chinese herbal medicine to benefitHuman kind through joint efforts of the academic institutions, industriesAnd regulatory agencies around the world.
MISSION OF CONSORTIUM
Working GroupsWorking Groups
• Quality Control
• Chinese Medicine Database
• Herbal Resource
• Clinical Trials
Currently we have 61 members and 7 affiliate industrial members7 Regional Consortiums: Australia, Beijing, Canada, Guangdong, Hong Kong, Shanghai, and Taiwan.
www.tcmedicine.org
Traditional Chinese Medicine (TCM)
Modern Chinese Medicine (MCM)
(China, Japan, Korea, etc)
Globalized Chinese Medicine (GCM)
Future New Medicine (NM) Other Folk Medicine (FM)
(Tibet, India, Europe, etc)
Current Mainstream Medicine (CMM)
Western Medicine (WM)
The Evolution of MedicineThe Evolution of Medicine