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“ West Meets East” Chinese Medicine Could be a Cornerstone for Developing Future Medicine. Yung-Chi Cheng Henry Bronson Professor of Pharmacology Yale School of Medicine. Cancer & Viral Chemotherapy. Scope of Activity

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slide1

“West Meets East” Chinese Medicine

Could be a Cornerstone for Developing

Future Medicine

Yung-Chi Cheng

Henry Bronson Professor of Pharmacology

Yale School of Medicine

cancer viral chemotherapy

Cancer & Viral Chemotherapy

  • Scope of Activity
    • Molecular and Biochemical Pharmacology of Anticancer and Antiviral Compounds
    • Drug Discovery
    • Clinic Protocol Design
  • Drug Entity of Current Interest
    • Nucleoside Analogs
    • Natural Products
    • Chinese Medicine
slide3

Chemicals Discovered in this Laboratory (In Collaboration with Others)

Under Different Stages of Clinical Development

slide4

Nature Product Analogs Under Current Investigation

  • Camptothecin and VP-16 conjugates
      • Cancer
  • Tylophorine analogs
      • Cancer and autoimmune diseases
  • Helioxanthin analogs
      • Hepatitis B Virus
  • Falvanoid analogs
      • Facilitator of oral uptake of drug
scope of medicine
Scope 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

slide6

The Current Paradigm of Mainstream Pharmaceutical 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 drug discovery approach
Challenges of Current Mainstream Drug 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 medicine
New Paradigm for Future Medicine
  • Multiple targets
  • Polychemical medicine instead of one chemical medicine with system biology approach in mind
two approaches to polychemical medicine
Two Approaches to Polychemical Medicine
  • Conventional “Step by step”
  • Revisiting history as the basis of reinventing medicine

Traditional Chinese medicine and other Folk medicine

slide10

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 the us fda
Botanical Drugs: A new area for the 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
slide12

How to Make Preparations of Herbal Medicine

with Consistency

  • Authentication of herb
  • Good agricultural practices (GAP)
  • Good manufacturing practices (GMP)
slide13

Authentication of Herb

  • Micro-morphological analysis
  • Gene sequence analysis
  • Chemical analysis
    • In vitro (solution state)
    • In situ (solid state)
slide14

StemTissue

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)

slide15

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.

slide16

Spatial distribution of two metabolites from within stem tissue of Sinomenium acutum

collected from different growing areas

◊ 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)

slide17

Botanical Quality Control

Good Agricultural Practicesconsistency 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 Practiceconsistency of drug substance and product

  • PhytomicsQC
    • Chemical Analysis
    • Biological Analysis
    • Informatics / Data mining
quality control for complex mixtures
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 Measures

two tier approach to botanical qc
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
Criteria for PhytomicsQC
  • Information-intensive fingerprints
  • Molecular resolution
  • Quantitative analysis
  • Robust, integrated technologies
  • Centralized informatics
  • Validated platform with SOPs
  • Chemical and biological metrics
phytomicsqc tm
PhytomicsQCTM

BioResponse fingerprint

Chemical fingerprint

DNA

“blueprint”

RNA

“messenger”

Protein

“executioner”

Mr. Mouse / Pharmacology

Provided by PhytoCeutica Inc.

(A Yale University Sponsored Company)

slide22

Chemotherapeutic AgentIndication

  • 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

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

phy906 identification using lc ms data
PHY906: Identification using LC/MS Data

In collaboration with PhytoCeutica Inc.

(A Yale University Sponsored Company)

psi ratio vs intensity
PSI Ratio vs. Intensity

Intensity

PSI

Provided by PhytoCeutica Inc.

(A Yale University Sponsored Company)

psi distribution of 15 sources of same formula
PSI Distribution of 15 Sources of same Formula

Provided by PhytoCeutica Inc.

(A Yale University Sponsored Company)

slide26

Biological Response for Quality Control of

Herbal Medicine

  • Enzyme or Receptor Assays
  • Cell-Based Assays
  • Cell growth or behaviors
  • Functional genomics
  • Proteomics
  • Phytomics
  • In Vivo Assays
phytomicsqc tm1
PhytomicsQCTM

BioResponse fingerprint

Chemical fingerprint

DNA

“blueprint”

RNA

“messenger”

Protein

“executioner”

Mr. Mouse / Pharmacology

Provided by PhytoCeutica Inc.

(A Yale University Sponsored Company)

slide28

4%

18%

4%

35%

7%

4%

2%

26%

Pathway Analysis of Regulated Genes

PHY906-6 in HepG2 cells (regulated genes > 1.2 fold in dChip analysis)

slide29

Genomic BioResponse Fingerprint Comparison

of PHY906 Batches

PSI Calculations (based on 20 genes)

Batch 6, 7, 8 : clinical batches (GMP)

Batch 9: non-clinical batch (manufactured unde GMP protocol)

Batch F: non-clinical batch (non-GMP protocol)

slide30

BioResponse Gene Expression Profiles

Ginseng

PHY906

G.Lucidium

  • 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

Herb 2

Herb 1

American

White

Red

Herb 2

PHY906

Ginseng

Herb 1

G. Lucidium

524 “union” gene set in HepG2

issues of tcm clinical trial
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.
slide32

PHY906 in Advanced Colorectal Cancer

Phase I/IIA Randomized, Double-Blind, Placebo-Controlled,

Cross-over Dose Escalation

Study Design

  • 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
  • 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 treatment

Provided by PhytoCeutica Inc.

(A Yale University Sponsored Company)

slide33

PHY906 in Hepatocellular Carcinoma

Phase I/II Open Label, Dose-Escalation, Safety, and Efficacy Study

  • Phase I Objectives
  • Primary
    • Tolerability of PHY906 plus capecitabine
    • Safety of 2 consecutive courses
    • Evaluation of PHY906 toxicity and adverse effects
  • Phase II Objectives
  • Primary: Overall survival time (OS)
  • Secondary
    • Time to disease progression (TTP)
    • Quality of patient life
    • Safety and tolerability
  • Results and above
    • No grade 3 drug related toxicity
  • 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

Provided by PhytoCeutica Inc.

(A Yale University Sponsored Company)

are all four botanicals necessary
Are All Four Botanicals Necessary?

PHY906:BDF-1 Mice Bearing Colon 38 Tumor CPT-11 Treatment

slide35

Principles of Combined Usage of Herbs 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
slide36

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.

slide37

INTERACTIONS OF INDIVIDIUAL HERBS

Interaction of different ingredients of Chinese formula (described by Tao Hongjing 451-526)

botanical data mining the next step
Botanical Data Mining: The Next 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
slide41

What will it take to globalize Chinese medicine?

  • Experience-based claims → Evidence-based claims
  • Subjective quality control → Objective quality control
  • User unfriendly → User friendly
  • Preparation 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.
slide42

INDUSTRY

ACADEMIC INSTITUTE

GOVERNMENT

  • INTRA-REGIONAL COLLABORATION
  • INTER-REGIONAL COLLABORATION

“Collaboration is Critical”

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.

c onsortium for g lobalization of c hinese m edicine cgcm
Consortium for Globalization of Chinese Medicine (CGCM)

MISSION OF CONSORTIUM

  • Global
  • Non-profit
  • Non-discriminatory
  • Non-political

www.tcmedicine.org

In pursuit of advancing the field of Chinese herbal medicine to benefit

Human kind through joint efforts of the academic institutions, industries

And regulatory agencies around the world.

working groups
Working Groups
  • Quality Control
  • Chinese Medicine Database
  • Herbal Resource
  • Clinical Trials

Currently we have 61 members and 7 affiliate industrial members

7 Regional Consortiums: Australia, Beijing, Canada, Guangdong,

Hong Kong, Shanghai, and Taiwan.

www.tcmedicine.org

slide45

The Evolution of Medicine

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)

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