Transcript PPT

Hypothesis-Driven Drug Re-profiling
Based on A Novel Systems Biology Framework
August 19, 2007
Fredric S. Young
Chief Scientist
Pipeline of Cancer Products
Product
Indication
Preclinical
Proof-of-Concept
Pilot Trial
Phase 2
Phase 3
VT-122
Cachexia
VT-211
Mucositis
VT-310
Fatigue
$3 million dollar investment to date
Today
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Pipeline of Cancer Products
Product
Indication
Preclinical
Proof-of-Concept
Pilot Trial
Phase 2
Phase 3
VT-122
Cachexia
VT-211
Mucositis
VT-310
Fatigue
2008
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Overview
The Vicus approach is based on a novel systems
biology framework
Health
Flow balance: positive feedback within range
Disease
Flow imbalance: a vicious circle: a “VICUS”
Therapy
Restore balance: target reaction blocks
Literature
Search, read, extract, assemble, model
Validation/
Focused, well-designed early phase studies
Confirmation and larger confirmatory trials
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Vicus Technology
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A Theory of Self Organization
Equilibrium Thermodynamics
Non-equilibrium Thermodynamics
Self
Organization
X
Heat
Cool
Liquid
Gas
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A Theory of Self Organization
Non-equilibrium Thermodynamics
Self
Organization
Net ATP
Usage
X
ADP/AMP
ATP
Net ATP
Production
Liquid
“Structure” of water not predicted
From equilibrium thermodynamics
Ilya Prigogine, Nobel Prize, Chemistry, 1977
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Theory of Universal Control
What enables self organization to
persist in a changing environment?
“Determination and Stabilization of the Bacterial
Growth Rate”, Fredric S. Young, Ph.D. Thesis, 1977
Hierarchical Network of Universal Control Modules
(“HiNET”)
Modify enzymatic activity and gene expression
Restore energy and particle flux balance
(homeostasis)
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Vicus System Biology Framework
Literature
Observing Man
Sensor
- O2/CO2 levels in blood
Input Flux Pipe
Energy Generating Process
- Blood oxygenation
Buckets
Hi – Low Energy Transition
- Release of oxygen from RBC
to muscle
Disease Model
Universal
Control Module
Spigots
Short Term Feedback
- Increased heart rate
Drugs and
Diagnostics
Maximum Capacity
Tissue remodeling
- Heart/muscle size
Outside Force
Environmental signal
- Signal for muscle
contraction
Output Flux Pipe
Energy Utilizing Process
- Muscle Contraction
The Universal Control Module is the representation of
the underlying paradigm
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Disease Model
Animation demonstrating the basic
concepts of the Universal Control Module
Animation
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Points made by animation
•A positive feedback module sustains flux balance
•HiNET is distributed over a volume
•HiNET maintains homeostasis of organism
•Flux outside an adaptive range initiates a VICUS
•A VICUS causes disease progression
•A drug restores flux balance and stops the VICUS
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Cancer Cachexia
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Cancer Cachexia
Large unmet need, yet challenging to enroll
Cachexia Syndrome
Incidence of Weight Loss
(At Time of Diagnosis, Stage IV Cancers)
•Muscle wasting
20%
Br
ea
st
0%
Pa
nc
re
at
ic
•Reduced life expectancy
`
40%
Pr
os
ta
te
•Intolerance to therapy
60%
Co
lo
n
•Anxiety & depression
80%
NS
CL
C
•Fatigue & immobility
<5% prior six months
100%
Percent of Total
•Loss of appetite
>5%
125K with significant loss, 250K+ with some weight loss
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Conventional Approach
Macrophage & Other
immune cells
Glucose
Protein Association
Lactate
Cancer
Protein
AA
Brain
Release of
TNF-α, IL-1,
IFN-γ, IL-6,
etc
Amino
Acids
30+ targets identified
No drugs approved
Protein
Muscle
Lactate
Glucose
GI tract
AA
Liver
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Building A Disease Model
Weight Loss
X
Nutrition
Severe Stress
Malnutrition
Function
Anorexia
Nutrition
Chronic
Acute
Systemic
Inflammatory
Response (SIRS)
Normal response to
severe injury, trauma
or infection
Diet
Starvation
Neuro-endocrineImmune activation
ANS Dysregulation
Inflammation
Cachexia
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Targets and Therapy
Weight Loss
Severe Stress
Chronic
Systemic
Inflammatory
Response (SIRS)
Neuro-endocrineImmune activation
NSAID
Beta Blocker
ANS Dysregulation
Inflammation
Cachexia
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Diagnostics
Weight Loss
No
Obstruction
Severe Stress
Malnutrition
Chronic
Starvation
Slower
Metabolism
Elevated
CRP
No
Infection
Systemic
Inflammatory
Response (SIRS)
Lower
Heart Rate
Stage IV
disease
Elevated
Heart Rate
Neuro-endocrineImmune activation
ANS Dysregulation
Inflammation
Cachexia
Faster
Metabolism
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Investigator Led Studies
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Investigator Led Pilot Studies
•Enrollment criteria of studies
-End-stage cancer subjects
-Loss of 2.3kg in 2 months
-Heart rate of 80 bpm or greater
-Able to ingest food or food supplements
•Safety and efficacy endpoints of six week study
-Treatment related adverse events
-Total body weight
-Quality of Life Assessments
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Effect of VT-122 On Weight
Weight Stability Post Therapy
(Average 4-6 weeks)
Percent of Subjects
100%
78%
80%
60%
40%
27%
20%
0%
Historic Control (n=46)
Treated (n=9)
Weight Losing Advanced Cancer Patients
3 NSCLC
4 Colorectal
2 Prostate
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Effect of VT-122 Over Time
Total Body Weight (Lbs)
Average Weight Change (n=5)
125
120
Start Treatment
115
110
105
100
-8
-6
-4
-2
0
2
4
6
Weeks Pre- and Post- Treatment
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Effect of VT-122 on QOL
Change In Quality of Life
0=not at all, 4 = very much
Magnitude of Distress
Condensed Memorial Symptom Assessment Scale
(N=5 responders)
4.00
3.60
3.50
3.00
2.80
2.40
2.50
2.00
2.00
1.80
1.60
1.50
1.00
1.08
1.00
0.70
0.60
0.50
0.00
Weight
Energy
Appetite
Prior to Therapy
Nausea
All
Post Therapy
Quality of Life Category
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FDA Phase 2 Trial
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FDA Phase 2 Study
60 Subject Randomized Controlled Study
Added Inclusion Criteria
•Stage IV NSCLC
•Not on chemotherapy
Added Exclusion Criteria
•Compliance established with one week “run-in” period
•Weight loss of > 15%
•Blood pressure less than 100/65.
Primary Objectives:
•Safety and dose tolerability
•Efficacy: Lean Body Mass
Secondary Endpoints
•Grip Strength
•Total Body Weight
•QOL
•Survival
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Summary
•Literature
HiNET + Vicus
Disease Models
•Broad applicability: metabolic, wound healing, CNS
•Reactions blocks for drug targets
•Diagnostics for clinical trial
•Intellectual property
•Encouraging early data
•www.vicustherapeutics.com/publications.htlm
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