“West Meets East” Chinese Medicine Could be a Cornerstone for Developing Future Medicine...

“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)


Plant Tissue12

n


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

Biological Response 1


Biological Response






Biological Response






Biological Response






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)

http://www.free-clipart-archive.com/photopost/showphoto.php?photo=1172&password=&sort=7&thecat=2

• CPT-11

• Capecitabine, 5-FU

• CPT-11/5-FU/LV

• VP-16

• L-OddC

• Gemcitabine

• Oxaliplatin

• Colorectal Cancer

• Liver Cancer


• Lung Cancer

• Leukemia, Pancreatic

• Pancreatic 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


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)

http://www.free-clipart-archive.com/photopost/showphoto.php?photo=1172&password=&sort=7&thecat=2

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



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


•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

http://www.tcmedicine.org/

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

http://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

“West Meets East” Chinese Medicine Could be a Cornerstone for Developing Future Medicine...

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