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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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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 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


West meets east chinese medicine could be a cornerstone for developing future medicine

Chemicals Discovered in this Laboratory (In Collaboration with Others)

Under Different Stages of Clinical Development


West meets east chinese medicine could be a cornerstone for developing future medicine

  • 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


    West meets east chinese medicine could be a cornerstone for developing future medicine

    • 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


    West meets east chinese medicine could be a cornerstone for developing future 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 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


    West meets east chinese medicine could be a cornerstone for developing future medicine

    How to Make Preparations of Herbal Medicine

    with Consistency

    • Authentication of herb

    • Good agricultural practices (GAP)

    • Good manufacturing practices (GMP)


    West meets east chinese medicine could be a cornerstone for developing future medicine

    Authentication of Herb

    • Micro-morphological analysis

    • Gene sequence analysis

    • Chemical analysis

      • In vitro (solution state)

      • In situ (solid state)


    West meets east chinese medicine could be a cornerstone for developing future medicine

    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)


    West meets east chinese medicine could be a cornerstone for developing future medicine

    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.


    West meets east chinese medicine could be a cornerstone for developing future medicine

    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)


    West meets east chinese medicine could be a cornerstone for developing future medicine

    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)


    West meets east chinese medicine could be a cornerstone for developing future medicine

    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)


    West meets east chinese medicine could be a cornerstone for developing future medicine

    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)


    West meets east chinese medicine could be a cornerstone for developing future medicine

    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)


    West meets east chinese medicine could be a cornerstone for developing future medicine

    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)


    West meets east chinese medicine could be a cornerstone for developing future medicine

    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.


    West meets east chinese medicine could be a cornerstone for developing future medicine

    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)


    West meets east chinese medicine could be a cornerstone for developing future medicine

    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


    West meets east chinese medicine could be a cornerstone for developing future medicine

    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


    West meets east chinese medicine could be a cornerstone for developing future medicine

    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.


    West meets east chinese medicine could be a cornerstone for developing future medicine

    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


    West meets east chinese medicine could be a cornerstone for developing future medicine

    • 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.


    West meets east chinese medicine could be a cornerstone for developing future medicine

    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


    West meets east chinese medicine could be a cornerstone for developing future medicine

    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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