Download Traditional Chinese Medicine

Convergence of Paradigm of Western Medicine and Traditional
Chinese Medicine: Challenges and Strategies to Develop West
facing East (WE) evolved Medicine
A case study of PHY(YIV)906, a traditional Chinese medicine
formula, as adjuvant for cancer patients under treatment
Yung-Chi Cheng
Henry Bronson Professor of Pharmacology
Yale University School of Medicine
World is Changing
• Paradigm Shift of Health Needs
Disease Care
Health Care
• Age-associated diseases and symptoms are a major
health issue around the world. To name a few:
•
•
•
•
•
•
•
Cancer
Cardiovascular disease
Bone and marrow function degeneration
Neuronal degeneration
Immune dysfunction
Metabolic disease
Others
Taipei-November 2, 2015
Scope of Medicine Needed Today
- For treatment of disease (Therapeutic Medicine)
- For prevention of disease (Preventative Medicine)
- For enhancement of “quality of life” of patients
and “healthy” individuals (Functional Medicine)
- For improving use of other medicine (Adjuvant
Medicine)
Taipei-November 2, 2015
New Paradigm is Needed
Current Paradigms for Drug Discovery Not Sufficient
• Reduction approach, in current mainstream drug discovery,
is not sufficient for complicated disease.
• Poly-Chemical and Poly-Target approach should be explored
• Chinese medicine could address current unmet medical needs.
• Has its own concept and could serve as the basis for developing new drugs
4
Convergence
Western Medicine > < Traditional Chinese Medicine
Western Medicine
Moving toward… >>>
Traditional Chinese Medicine
Based on…
System biology oriented
integrative medicine approach
Harmonization of surrounding and individual
elements within the system-holistic approach
(天人合一 )
Precision treatment
Individual treatment (因人施治)
Reemphasizing prevention of disease and
Quality of Life
Adjustment of “sub health” condition and
prevent of aging process (调理，治未病)
Single target –single chemical reductionist to
polychemical approach
Multiple targets-multiple herbs (polychemical)
and herbal interaction approach ( 一药多用，
配方 )
Tissue oriented drug targeting (nanoparticle
or liposom)
One herb to lead other herb to be more
effective (药引 )
5
Cancer and Viral Pharmacology
• Scope of Activity
• Molecular and Biochemical Pharmacology of
Anti-Cancer and Anti-Viral Compounds
• Drug Discovery
• Clinical Protocol Design
• Drug Entities of Interest
• Nucleoside Analogs
• Natural Products
• Chinese Medicine
6
Drugs Discovered in our Laboratory
And in Collaboration
Drug
Indication
Clinical Stage
DHPG (Gancyclovir)*
CMV
First Approved
3TC (Lamivudine)*
HBV
First Approved
L-FTC (Emtricitabine)
HBV
Approved
L-FMAU (Clevudine)
HBV
Approved (Korea, Philippines),
Phase III (Worldwide)
Solid Tumor
Phase I/II
HIV
HBV
Phase II
Phase I/II
Radiosensitizer
For solid tumor
Phase I/II
Orphan Drug Status
D-4’Ed4T
HIV
Phase IIb
PHY-906
Cancer
Phase II
L-OddC (Troxacitabine)
L-Fd4C (Elvucitabine)
D-IPdR (Ropidoxuridine)
* Do Not Hold Patent
7
Target Oriented Cancer Drugs Alone have Their Value
AND Limitations
• Heterogeneity of tumor cells in tumor tissue
• Genetic mutation of tumor cells
• Epigenetic alteration of tumor cells
• Microenvironment:
•
•
•
•
•
Cell and cell interaction
Different types of cells
Chemokines, cytokines and hormones
Nutrition for tumor growth
Hypoxia, Angiogenesis
• Different tumor cells in tumor tissue will not have the same sensitivity
to a target orientated chemical
8
Strategies for Development of Cancer Drugs
• More selective anti-cancer drugs and protocols with less toxicities
• Decrease the toxicity of current cancer treatment modalities without
compromising their anti-cancer activity
9
Toxicity of Anti-Cancer Modalities
• Hematological side-effects
• Non-hematological side-effects
•
•
•
•
Vomiting
Nausea
Diarrhea
Etc…
10
PHY906
Modern Platform Cancer Drug Inspired by Chinese Medicine
• Inspired by 1800 year-old Formula – Huang Qin Tang
• Traditional use (since 300 A.D.) for Diarrhea, vomiting, nausea, intestinal cramping, fever
Scutellaria baicalensis Georgi.
Plant and roots
Glycyrrhiza uralensis Fisch
Plant and roots
Ziziphus jujuba Mill.
Plant and fruits
Paeonia lactiflora Pall.
Plant and roots
• Modernized into a New Cancer Drug
• High Quality Sourcing and Selection
• Proprietary Standard Operating Procedure
• Spray dried aqueous extract of four botanicals
• cGMP Final Product
• Mechanism-Based Quality Control
• +90% Batch-to-Batch Consistency over 10 years
11
PHY906 Enhances the Anti-tumor Activity
and Decreases Global Toxicity of Irinotecan
110
Vehicle Control
PHY906
CPT-11
1000
PHY906 /CPT-11
500
P<0.00001
0
0
1
2
3
4
5
6
7
8
9 10 11 12 13 14
Days after CPT-11 Treatment
CPT-11
PHY906
Percentage of Initial B ody Weight
Percentage of Initial Tumor Size
1500
100
Cont rol ( Vehi cl e)
90
CPT- 11
CPT- 11/ PHY906 500 mg/ kg
80
70
1
0
2
13 24
5
3
6
4 7 58 69
10
7 11 8
9
10
Days After CPT-11 Treatment
colon38 xenograft bearing mice
12
Effects of Removing one or three Herbs from the PHY906 Formulation on the Potentiation
of the Antitumor Activity, the Reduction of induced Body Weight Loss, and the
Prevention of Death Caused by CPT-11.
Herbs in Formulation
S
P
G
Z
Potentiation of
Reduction of Body
Prevention of
Antitumor Effect
Weight Loss
Death
+
+
+
+
+++
+++
+++
-
+
+
+
--
--
+
+
-
+
+
+
+++
+++
+
+
-
+
++
--
++
+
+
+
-
+++
--
+
(+++) P ≤ 0.01 very significant effect; (++) P ≤ 0.05 significant effect; (+) P ≥ 0.05 possible effect; (-) no effect.
“Chinese” or “Herbal” medicine and “Western Medicine”
are all “Medicine”
Basic Regulatory Requirements for Modern Drugs
1. High Quality and consistency of preparation
2. Evidence based clinical efficacy
3. Safety
4. Certain Knowledge of its action
•Sites of action(s)
•Active ingredient(s)
•Interactions with other drugs
Taipei-November 2, 2015
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
Chemical Fingerprint 1
Biological Response
Comprehensive Quality Control Measures
Chemical Fingerprint 2
Biological Response 1
Chemical Fingerprint 1
Biological Response
Chemical Fingerprint
Biological Response 2
Chemical Fingerprint 2
(Proposed in 2000)
Biological Response 1
TM
PhytomicsQC
BioResponse fingerprint
100
DNA
“blueprint”
3.0
50
1.5
0.0
“executioner”
Protein
90
0
72
0
M
as
s
54
0
(a
.m 36
0
.u
.)
RNA
“messenger”
(log)
0
Intensity
Absorbance
(%)
Chemical fingerprint
32
28
24
18
0
20
16
ntio
Rete
)
e (min
n Tim
Mr. Mouse / Pharmacology
(Proposed in 2000)
Provided by PhytoCeutica Inc.
(A Yale University Sponsored Company)
Mechanism based Quality Control (MBQC
approach)
• 1. The quality control of herb should depend on its usage
• 2. Methodology used should be relevant to its usage or
mechanism
• 3. Chemical fingerprint has limited utility unless irrelevant
chemicals were eliminated for consideration
• 4. Similarity index is only useful when relevant information is
used
“Phytomics QC
MBQC”
PHY906 Prevents Further Damage, Speeds up Recovery
Synergistic Action Across Multiple Targets
Reduces ‘Bad’ Inflammation in the Intestine
Suppresses pathways and
(-ve IL-6, NF-kB, COX2, iNos)
inhibits inflammation
YIV-906
Promotes progenitor
and stem cell growth
Taipei-November 2, 2015
PHY906 Triggers Tumor Rejection
via M1 Polarization
YIV-906 Enhances ‘Good’ Inflammation
Activates M1 Macrophages, Leading to Tumor Rejection
Irinotecan
Irinotecan+ YIV-906
Tumor
Macrophage
(M1 Activation)
Apoptosis
Macrophage
Apoptosis
Chronic inflammation status
Acute Inflammation
helps trigger tumor rejection
i.e. NF-KB dependent
pro-apoptoic genes
i.e.  INF, IRF5, IL-9, Jak/Stat
innate immune genes
Taipei-November 2, 2015
Correlation analysis for different batches of PHY906 and commercial HQT
A.
STAR
(Signaling
Transduction
Activity
Response)
B.
qPCR
PHY906-6
PHY906-7
PHY906-8
PHY906-10
PHY906-11
F
CSZ
HQT-38
HQT-39
HQT-40
PHY906-6 PHY906-7 PHY906-8 PHY906-10 PHY906-11
0.956
0.961
0.958
0.937
0.956
0.963
0.959
0.933
0.961
0.963
0.953
0.901
0.958
0.959
0.953
0.959
0.937
0.933
0.901
0.959
0.744
0.788
0.833
0.818
0.736
0.896
0.892
0.841
0.911
0.950
0.734
0.803
0.827
0.844
0.764
0.792
0.846
0.857
0.846
0.778
0.619
0.712
0.727
0.782
0.708
PHY906-6
PHY906-7
PHY906-8
PHY906-10
PHY906-11
F
CSZ
HQT-38
HQT-39
HQT-40
PHY906-6 PHY906-7 PHY906-8 PHY906-10 PHY906-11
0.913
0.895
0.934
0.978
0.913
0.982
0.959
0.939
0.895
0.982
0.971
0.933
0.934
0.959
0.971
0.982
0.978
0.939
0.933
0.982
0.628
0.796
0.835
0.855
0.768
0.990
0.915
0.897
0.947
0.987
0.497
0.684
0.719
0.752
0.657
0.713
0.822
0.844
0.891
0.830
0.883
0.880
0.893
0.957
0.950
F
0.744
0.788
0.833
0.818
0.736
0.771
0.878
0.834
0.766
F
0.628
0.796
0.835
0.855
0.768
0.685
0.968
0.960
0.859
CSZ
0.896
0.892
0.841
0.911
0.950
0.771
HQT-38
0.734
0.803
0.827
0.844
0.764
0.878
0.746
0.746
0.749
0.663
CSZ
0.990
0.915
0.897
0.947
0.987
0.685
0.927
0.898
HQT-38
0.497
0.684
0.719
0.752
0.657
0.968
0.562
0.562
0.759
0.912
Without normalized to mean of each pathways of all batches
0.952
0.810
HQT-39
0.792
0.846
0.857
0.846
0.778
0.834
0.749
0.927
HQT-40
0.619
0.712
0.727
0.782
0.708
0.766
0.663
0.898
0.766
0.766
HQT-39
0.713
0.822
0.844
0.891
0.830
0.960
0.759
0.952
0.932
HQT-40
0.883
0.880
0.893
0.957
0.950
0.859
0.912
0.810
0.932
Signal Transduction Activity response (STAR) of Chinese Herb
stimulation
inhibition
EC50(µg/ml)
IC50(µg/ml)
0
0
COX2
(4mg/ml)
stimulation
inhibition
(%)
(%)
4
4
10
10
100
100
20
20
90
90
30
30
80
80
40
40
70
70
50
50
60
60
60
60
50
50
70
70
40
40
80
80
30
30
90
90
20
20
100
100
10
10
200
200
300
300
0
0
500
500
＝ or -
Blank
No Impact
Not Done
Expansion of Drug Discovery Platform
Based on Botanicals and their Chemicals
Quality
Control
New Usages
STAR
Platform
New
Formulas
New Active
Compounds
22
Phase I/II Advanced Colorectal Cancer Study
• Phase I / IIa Double Blind, Randomized Study of PHY906
+ IFL
23
PHY906 Significantly Reduced Dose-Limiting Toxicities
Phase I/II Advanced Colorectal Cancer
Non-Hematological
Toxicities (Grade 3 / 4)
CPT-11 / FU / LV
+ Placebo
CPT-11 / FU / LV
+ PHY906
Diarrhea
31%
0%
Vomiting
15%
0%
Nausea
13%
7%
Fatigue
30%
0%
Clinical Colorectal Cancer. 2011;10(2):85-96
24
PHY906
MODERN USE (2000 A.D.) : AN ADJUVANT FOR CANCER CHEMOTHERAPY, RADIATION THERAPY
AND IMMUNO CHECK POINT THERAPY
- Decrease of non-hematological side effects
- Enhancement of antitumor activity of chemotherapeutic agents
Chemotherapeutic Agent
Indication
• CPT-11
• Colorectal Cancer
•Capecitabine (5-FU Prodrug)
• Colorectal and Liver Cancer
• CPT-11/5-FU/LV
• Colorectal Cancer
• VP-16
• Lung Cancer
• L-OddC
• Leukemia, Pancreatic Cancer
• Gemcitabine
• Pancreatic Cancer
• Oxaliplatin
• Colorectal Cancer
• Sorafenib
• Renal and Liver Cancer
• Taxol
•Sunitinib
Radiation therapy
Anti Immuno check point therapy
LPD-1, PDL-1 and CTLA-4
• Lung, Breast and
OvarianCancer
• Renal and Liver Cancer
Rectal and prostate cancer
Melanoma, non small cell lung
carcinoma, renal cancer etc.
Comparison of Patient Characteristics, Outcome and Selected Grade 3 or 4 Drug-Related Side Effects
Between Sorafenib and PHY906 + Capecitabine Studies
Patient Characteristics, outcome
and side effects
Sorafenib Phase
III
Sorafenib
Phase III
PHY906
(600/800 mg) +
Capecitabine(1)
PHY906
(600/800 mg) +
Capecitabine(2)
# of Patients
299
150
27
20
% of Child-Pugh A
95
97
74
100
% of HBV
19
71
37
50
% of HCV
29
11
26
20
Study Sites
(%)
EU/US
(88/9)
Asia
(100)
US
(100)
US
(100)
Response %
(PR/MR/SD)
2.3 /0/ 71
3/ 0 / 54
0/ 14.8/ 51.9
0 / 0 /65
Median TTP (months)
5.5
2.8
3.4
2.8
Median OS (Months)
10.7(3)
6.5(4)
9.2
10.9
12 Month Survival Rate (%)
44
28
41
50
Grade 3/ 4 drug-related Toxicities (%)
Hand-Foot Skin Reaction
Diarrhea
Fatigue
hypertension
Abdominal pain
Hypophosphatemia
Thrombocytopenia
8
8
4
2
2
11
4
11
6
3
2
NA
NA
NA
3.7
0
0
0
0
0
0
0
0
0
0
0
0
0
1. Phase II patients treated with either 600 mg or 800 mg of PHY906 together with capecitabine (750 mg/m2)
2. Subset of (1). All the patients in this group were classified as Child-Pugh A.
3. Median OS for the placebo group in the US/EU trial was 7.9 months. N Engl J Med. 359:4, 378-390 (2008).
4. Median OS for the placebo group in the Asia trial was 4.2 months. J Clin Oncol 26: 2008 (May 20 suppl; abstr 4509)
5. Yen, Y et al. Anticancer 29:4083-4092 (2009).
26
Kaplan-Meier Survival Curve of Asian vs non-Asian Patients with Child-Pugh A
Treated with PHY906 (600+800 mg) +Capecitabine(N=20)
Percent survival
100
80
median survival (month)
60
CPA (N=20)
10.93
40
CPA & Asian
(N=10)
16.54
20
CPA & non-Asian
(N=10)
6.71
0
0
10
20
30
40
Time (month)
Medium OS for placebo group in US/EU was 7.9 months and in Asia it was 4.2 months (historically)
Taipei-November 2, 2015
Phase I Study of PHY 906 and Sorafenib
in Advanced HCC
Pt
1
2
Age
62
62
Gender
M
M
3
75
M
4
65
M
Background
Etiology
Caucasian
HepC
cirrhosis
HepB
Chinese
Bone
metastasis
Alcoholic
Caucasian
Liver
disease
Cirrhosis
Hispanic Unknown
etiology
Therapeutic
cycle**
AE
1
Gr 4 N/V from underlying disease
Gr 3 hyponatremia, off protocol after
1st cycle.
31 S.D.
Gr 3 HTN in first cycle
*Gr 4 hypertriglyceridemia
1
1
Gr 2 hand foot syndrome
Gr 3 LFT DLT, off protocol after 1st
cycle.
disenroll for non-compliance
Confusion upon start cycle 1, due to
ammonia and underlying disease.
*Delay TX on cycle 6 due to Gr4 hypertriglyceridemia, then dose reduction to PHY906 600mg bid.
**Dose: PHY906 800mg bid 4 days on 3 day off po, sorafenib 400mg bid po.
Pt#2 has been treated with Sorafenib in Hx and no good response. Start TX in July 2014, the 26 cycle was
gave in 8/2016. Hypertriglyceridemia improved with dose hold and reduction of PHY906 to 600mg bid.
Hypertension in history and worse on cycle #1. After dose reduceing Sorafenib, the Hypertension has
improved.
28
Current Hypothesis of Synergistic Action of PHY906 and Anti-Cancer
Modalities Against Tumors
MICROENVIRONMENT
TUMOR CELLS
Anti-cancer drugs,
immuno checkpoint, or
radiation
PHY906
Local Inflammation
Process
Dead Cellular
Antigen
Anti-Tumor Response
29
Cancer immune cycle
neoantigen
APC
tumor
APC
MHC CD80/86
T
CD28
tumor
Perforin
GrB
T
CD80/86
CTLA4
Inactive
T IFNg
expansion
MHC
CD28
CTLA4
killing
tumor
T
Effector T
Inactive
MHC
Treg
activity
PDL1 PD1 Treg/Macro
PDL1
T PD1
MHC
antiCTLA4
antiPD1
or antiPDL1
30
PHY906 Triggers Tumor Rejection
via M1 Polarization
YIV-906 Enhances ‘Good’ Inflammation
Activates M1 Macrophages, Leading to Tumor Rejection
Irinotecan
Irinotecan+ YIV-906
Tumor
Macrophage
(M1 Activation)
Apoptosis
Macrophage
Apoptosis
Chronic inflammation status
Acute Inflammation
helps trigger tumor rejection
i.e. NF-KB dependent
pro-apoptoic genes
i.e.  INF, IRF5, IL-9, Jak/Stat
innate immune genes
Taipei-November 2, 2015
Effect of PHY906 and Anti-PD-1 Antibody on Mice Hepa1-6 Hepatic Adenocarcinoma
First Experiment: Initial Tumor size 178.9 mm3
PHY906
0.5g/kg
Placebo
% of Initial Tumor Size
1500
PHY906+
Anti-PD-1
Anti-PD-1
200ug
% of Initial Tumor Size
2000
1500
1000
Placebo
PHY906 0.5g/kg bid
Anti-PD-1 200 ug
PHY906 + Anti-PD-1
1000
500
0
0
500
2
4
6
8 10 12 14 16 18 20
PHY906
Anti-PD-1
Days
0
4
7
10
14
17
20
0
4
7
10
14
17
20
7
10
14
0
4
7
10
14
0
4
0
Second Experiment: Initial Tumor size 279.8 mm3
PHY906
0.5 g/kg
Placebo
Anti-PD-1
70 ug
Anti-PD-1 PHY906 .5g PHY906 .5g
200 ug + PD-1 70ug PD-1 200ug
1500
% of Initial Tumor Size
2000
1500
Placebo
PHY906 0.5g/kg bid
Ant-PD-1 200 ug
PHY906 0.5g/kg + Ant-PD-1200u
1000
500
0
0
2
4
6
8
PHY906
Anti-PD-1
1000
Days
500
21
14
7
0
21
14
7
0
21
14
7
0
21
14
7
0
21
14
7
0
7
9
0
0
2
4
% of Initial Tumor Size
2500
10
12
14
YIV-906 is a Platform adjuvant for Cancer Treatment
YIV-906 + Broad Spectrum of Treatments > Improved Patient Outcomes
YIV-906
ImmunoOncology
Chemotherapy
Potentiates Anti-Tumor Activity
Improves Quality of Life
Radiation
Inadequate Efficacy
Serious GI Side-Effects
Chemotherapy (CPT-11, Capecitabine, CPT-11/5-FU/LV, VP-16, L-OddC, Gemcitabine, Oxaliplatin, Sorafenib, Taxol, Sunitinib),
Radiation therapy, Anti Immuno check point therapy (LPD-1, PDL-1 and CTLA-4)
Colorectal, Melanoma, Liver, Lung, Non Small Cell Lung Carcinoma, Pancreatic, Renal Cancer
33
Consortium for Globalization of
Chinese Medicine (CGCM)
Global
Non-profit
Non-discriminatory
Non-political
Founded on December 15, 2003
•155 Institutional Members
•20 Industrial Affiliate Members
www.tcmedicine.org
Taipei-November 2, 2015
The Evolution of Medicine
Traditional Chinese Medicine (TCM)

Modern Chinese Medicine (MCM)
(China, Japan, Korea, Vietnam, etc)

Globalized Chinese Medicine (GCM)

Future Medicine  WE Medicine  Other Folk Medicine (FM)
(Tibet, India, Europe, Africa, etc)

Current Mainstream Medicine (CMM)

Taipei-November 2, 2015
Western Medicine
(WM)
The inventor of
Becherbitter was Josef
Vitus Becher (1769–1840).
Plum Brandy known as slivovice is also offered as a
folk remedy for everything from sore throat and viral
infection to muscle aches
Becherovka is a herbal bitters,
often drunk as a digestive aid
Taipei-November 2, 2015
Conflict of Interest
• Inventor of the usage of YIV(PHY906), as adjuvant for cancer
treatment as well as the methodology of mechanism based
quality control of herbal product.
•
Co-founder and scientific advisor of Phytoceutical and Yiviva
Pharmaceutical.