Targets to Populations to Individuals
Alex Bangs, Co-Founder
SIAM Conference on the Life SciencesJuly 15, 2010
© 2010 Entelos, Inc.
Entelos Overview
• Pioneer in the development of computer-based disease models to predict human response to therapeutic treatment regimens
• Focus on pre-clinical to clinical translation and clinical trial optimization
• Collaborate with pharmaceutical and consumer product companies and other organizations
• American Diabetes Association• FDA• GSK• J&J• Lilly• Novartis
• Organon• Pfizer• Roche• UCB• Unilever• others…
© 2010 Entelos, Inc.
Core Challenge: Bridging the Gap
Target PatientResponse?
© 2010 Entelos, Inc.
T Cells
Chondrocytes & Cartilage Matrix
Macrophages
Fibroblast-like Synoviocytes
Synovial Tissue/ Cartilage Exchange
Synovial Tissue &Bone Erosion
Summary Diagram & Therapies
Cell Contact & Adhesion
Endothelial Cells & Angiogenesis
TNF!
The Complexity of Biology:Can You Predict TNF! Effects in Rheumatoid Arthritis?
©2010Entelos, Inc.
© 2008 Entelos, Inc.
5
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
TNF-alpha TNF-alpha
Anti-B7-1
Anti-B7-1 + Anti-B7-2
Age of NOD mice (weeks)IL-12
Anti-B7-1
STZ
Anti-CD3
Protective
No effect
ExacerbatesAnti-CTLA-4 Anti-CTLA-4 Anti-CTLA-4
Anti-PD1/PDL1 Anti-PD1/PDL1 Anti-PD1/PDL1
mCTLA4Ig
Anti-TNF-alpha
Anti-L-selectin
Anti-alpha4
Anti-TNF-alpha
TNF-alpha
STZ
TNF-alpha
Anti-L-selectin
Anti-alpha4
IFN-alpha
Anti-CD3Anti-CD3Anti-B7-2
hCTLA-4Ig
Anti-B7-2
hCTLA-4Ig
Anti-CD4
Cyclosporin
Oral insulinAnti-CD4 Anti-CD4
(p40)2 (p40)2
Anti-CD8
Anti-Kd
Nicotinamide
NBI-6024 (B:9-23 APL)
Anti-CD43 Anti-CD43
Nicotinamide
Alpha-GalCer Alpha-GalCer
Alpha-GalCer + IL-7
NBI-6024 (B:9-23 APL) pcDNA3, pHSP60, CpG
Anti-LFA-1/ICAM-1
Anti-MAdCAM Anti-MAdCAM
IL-10/FcAnti-LFA-1/ICAM-1 Anti-LFA-1/ICAM-1
Anti-IL-12 Anti-IL-12
Anti-CD3 Anti-CD3
Anti-IFN-gamma
Lip-Cl2MDP
Anti-MAdCAM
Anti-IL-12
Type I Diabetes: Overview of Representative Interventions
© 2010 Entelos, Inc.
Clinical Variability in Type IIa Dyslipidemic Patients
© 2010 Entelos, Inc.
© 2010 Entelos, Inc.
Data
R&DProductivity
&Commercial
Value
© 2010 Entelos, Inc.
Synthesis PredictiveUnderstanding
DecisionMakingData
R&DProductivity
&Commercial
Value
© 2010 Entelos, Inc.
Synthesis PredictiveUnderstanding
DecisionMakingData
R&DProductivity
&Commercial
Value
© 2010 Entelos, Inc.
Reductionism vs.SystemsMolecular Biology vs.
Physiology
Math
Culture Challenges
“You can only Manage what you Measure”
Quality Hypotheses
“Shots on Goal” Mentalityand Associated Incentives
Long Pipeline vs.Short Job Role
Suboptimal Trial Designs,Ambiguous Interpretations,
Indecisive Reactions
Pipeline Assets
BiasedAdvocacy
Synthesis PredictiveUnderstanding
DecisionMakingData
R&DProductivity
&Commercial
Value
Organizational Challenges
SiloedKnowledge
© 2010 Entelos, Inc.
Culture Challenges
Valuable data not leveraged
Synthesis PredictiveUnderstanding
DecisionMakingData
R&DProductivity
&Commercial
Value
Organizational Challenges
Predictions based on simplistic“dominos” mental models
The most valuable alternatives not selected, often not even considered;risk poorly understood and managed
© 2010 Entelos, Inc.
Synthesis PredictiveUnderstanding
DecisionMakingData
R&DProductivity
&Commercial
Value
!
Process
People
TechnologyCulture Challenges
Organizational Challenges
in silico Modeling
© 2010 Entelos, Inc.
in silico Modeling
Burrill & Co., A 20/20 Vision for 2020:
“The majority of drug discovery will be conducted in silico [using
computer simulations]”
BT Pharma Futurology:
“… able to design and test compounds in silico; …99% sure that
they would work, and only testing the surest hits in people”
PWC, Pharma 2020:Virtual R&D:
“…by 2020, virtual cells, organs and animals will be widely employed in
pharmaceutical research”
Synthesis PredictiveUnderstanding
DecisionMakingData
R&DProductivity
&Commercial
Value
© 2010 Entelos, Inc.
Synthesis PredictiveUnderstanding
DecisionMakingData
R&DProductivity
&Commercial
Value
Data
PhysioLabPlatforms
VirtualPatients
VirtualPopulations
Decision AnalyticModels
© 2010 Entelos, Inc.
EpidemiologicalStudies
Clinical Trialsfor Current
Standard of Care
Synthesis PredictiveUnderstanding
DecisionMakingData
R&DProductivity
&Commercial
Value
Data
© 2010 Entelos, Inc.
Standardof Care
DesiredEfficacy
Efficacy
EpidemiologicalStudies
Clinical Trialsfor Current
Standard of Care
Synthesis PredictiveUnderstanding
DecisionMakingData
R&DProductivity
&Commercial
Value
© 2010 Entelos, Inc.
Standardof Care
DesiredEfficacy
Efficacy
EpidemiologicalStudies
Clinical Trialsfor Current
Standard of Care
Synthesis PredictiveUnderstanding
DecisionMakingData
R&DProductivity
&Commercial
Value
• Circulating Biomarkers• Genetic Markers• Longitudinal Patterns• Imaging
© 2010 Entelos, Inc.
EpidemiologicalStudies
Clinical Trialsfor Current
Standard of Care
Synthesis PredictiveUnderstanding
DecisionMakingData
R&DProductivity
&Commercial
Value
© 2010 Entelos, Inc.
Synthesis PredictiveUnderstanding
DecisionMakingData
R&DProductivity
&Commercial
Value
© 2010 Entelos, Inc.
Synthesis PredictiveUnderstanding
DecisionMakingData
R&DProductivity
&Commercial
Value
© 2010 Entelos, Inc.
Clinical TrialData
EpidemiologicalData
Synthesis PredictiveUnderstanding
DecisionMakingData
R&DProductivity
&Commercial
Value
© 2010 Entelos, Inc.
Clinical TrialData
EpidemiologicalData
Synthesis PredictiveUnderstanding
DecisionMakingData
R&DProductivity
&Commercial
Value
Data
PhysioLabModel
© 2010 Entelos, Inc.
VirtualPopulation
PhysioLabModel
Clinical TrialData
EpidemiologicalData
HypothesisSpace
Phenomena
Mechanism
Synthesis PredictiveUnderstanding
DecisionMakingData
R&DProductivity
&Commercial
Value
Data
© 2010 Entelos, Inc.
VirtualPopulation
PhysioLabModel
Clinical TrialData
EpidemiologicalData
Synthesis PredictiveUnderstanding
DecisionMakingData
R&DProductivity
&Commercial
Value
© 2010 Entelos, Inc.
Clinical TrialData
EpidemiologicalData
VirtualPopulation
PhysioLabModel
Synthesis PredictiveUnderstanding
DecisionMakingData
R&DProductivity
&Commercial
Value
© 2010 Entelos, Inc.
Clinical TrialData
EpidemiologicalData
VirtualPopulation
PhysioLabModel
Synthesis PredictiveUnderstanding
DecisionMakingData
R&DProductivity
&Commercial
Value
© 2010 Entelos, Inc.
Clinical TrialData
EpidemiologicalData
VirtualPopulation
PhysioLabModel
Synthesis PredictiveUnderstanding
DecisionMakingData
R&DProductivity
&Commercial
Value
© 2010 Entelos, Inc.
Clinical TrialData
EpidemiologicalData
VirtualPopulation
PhysioLabModel
NovelCombinations
NovelTherapies
• Additional subpopulations
• Additional measurements
• Additional time points
• Novel protocols
Data mine for:• Responder/non-responder subpopulations
• Biomarker patterns (efficacy and safety)
• Trial optimization
• Risk management
Synthesis PredictiveUnderstanding
DecisionMakingData
R&DProductivity
&Commercial
Value
© 2010 Entelos, Inc.
Clinical TrialData
EpidemiologicalData
VirtualPopulation
PhysioLabModel
NovelCombinations
NovelTherapies
• Additional subpopulations
• Additional measurements
• Additional time points
• Novel protocols
Synthesis PredictiveUnderstanding
DecisionMakingData
R&DProductivity
&Commercial
Value
© 2010 Entelos, Inc.
Synthesis PredictiveUnderstanding
DecisionMakingData
R&DProductivity
&Commercial
Value
Data
PhysioLabPlatforms
VirtualPatients
VirtualPopulations
Decision AnalyticModels
© 2010 Entelos, Inc.
Translational Medicine Case Study: Assessment of a lead compound for clinical development
Background • Preclinical animal data suggests competitive improvement in primary clinical endpoint
• First in class compound positioned for entry into clinical development
Issues • No human precedent, including genetic mutations, to confirm potential efficacy
• Optimal timing and frequency of dosing unknown
Questions • Is the target and compound efficacious in human patients?
• What results in healthy subjects suggest efficacy in patients?
• What is the optimal trial design to demonstrate efficacy?
© 2010 Entelos, Inc.
Virtual Patients Were Selected to Represent 7 Clinically Observed Phenotypes
Patient Population
7 Clinical Phenotypes
35 VPs addressing key knowledge gap relevant to target
VirtualPatients
© 2010 Entelos, Inc.
Translational Medicine: Identification of Mechanisms that Determine Efficacy and Explain Species Differences
Virtual patients constrained to observed phenotypes
• No virtual patients, showed an efficacious response to simulated therapy
System pushed to limits of observed human behavior
• Constrained to the edges of normal clinical response
• Numerous validation protocols no longer reproducible
• Unlikely, but testable
Implement Rodent Behavior• Pathway flux and regulation altered
– Inconsistent with human data
• Lifestyle/environmental factors– Not representative of humans
Rodent Response to Therapy• Results suggest novel therapy would be
an effective treatment
% d
ecre
ase
in c
linic
al r
esponse
0.0
-0.25
0.5
1.0
Rodent-Like Human
Observed Phenotypes
RodentData
“But it works in rodents…”
Constrained by Human Data
© 2009 Entelos, Inc.
35PhysioLab Target Prioritization Results:30 Molecular Targets Ranked in Order of Predicted Efficacy
© 2010 Entelos, Inc.
54
Case study: Predicting Cardiovascular Risk for a Combination Therapy of Statin + CETP Inhibitor
Biologically Diverse Virtual Patients Exhibit Variability in:
• Adipose TG Storage level• ApoB-100 Lipoprotein particle metabolism• Arterial wall inflammation level• HDL lipoprotein particle metabolism• Hepatic function & regulation
40
60
80
100
120
140
160
60 80 100 120 140 160 180 200 240
200
Untreated
LDL-C (mg/dl)
HD
L-C
(mg/
dl)
40
60
80
100
120
140
160
60 80 100 120 140 160 180 200 240
200
LDL-C (mg/dl)
HD
L-C
(mg/
dl)
Statin only
HD
L-C
(mg/
dl)
LDL-C (mg/dl)
Statin + CETP inhibitor
40
60
80
100
120
140
160
60 80 100 120 140 160 180 200 240
200
2 years on therapy
© 2010 Entelos, Inc.
CONFIDENTIAL © 2009 Entelos, Inc.
56 56
Population Variability Can Result in Mixed Levels of Cardiovascular Risk
Cha
nge
in p
erce
nt a
ther
oma
volu
me
(sta
tin +
CE
TP in
hibi
tor)
Change in percent atheroma volume (statin alone)
reduced CV risk compared to
statin monotherapy
increased CV risk compared to
statin monotherapy
CV risk increased
CV risk reduced
CV risk unchanged
© 2010 Entelos, Inc.
CONFIDENTIAL © 2009 Entelos, Inc.
57
Baseline Lipids Do Not Correlate With Response To CETP-Inhibitor Treatment
HD
L-C
(mg/
dl)
LDL-C (mg/dl)
© 2010 Entelos, Inc.
CONFIDENTIAL © 2009 Entelos, Inc.
58
A Novel Pre-Tx Biomarker was Identified to Screen Patients with Increased Cardiovascular Risk
Novel Pre-Tx Candidate Multivariate Biomarker Combination of <10 circulating analytes
Cha
nge
in p
rimar
y cl
inic
al e
ndpo
int
(sta
tin +
CE
TP in
hibi
tor)
False negative
True negative
True positive
False positive
CV risk increased
CV risk reduced
CV risk unchanged
© 2010 Entelos, Inc.
Personalized Medicine: Growing wealth of opportunities to get data – what is the value?
© 2010 Entelos, Inc.
Personalized Medicine: Turning data into action
Current risk-assessment tools provide “islands” of prediction
Assessments not extendable to “what if” questions for
interventions or further testing
Tailored action is not takenWhatShould I
do?
© 2010 Entelos, Inc.
Personal Health Simulation:Personal simulation based on “virtual people like me”
Profile for anindividual,
based on their data Virtual population based on multiple studies
© 2010 Entelos, Inc.
Simulation Results – MI risk over time
Years
Cum
ula
tive
pro
bab
ility
of M
I ov
er t
ime
© 2010 Entelos, Inc.
Simulation Results – weight gain, 1 lb per year
Years
Cum
ula
tive
pro
bab
ility
of M
I ov
er t
ime
© 2010 Entelos, Inc.
Simulation Results – weight gain + statin
Years
Cum
ula
tive
pro
bab
ility
of M
I ov
er t
ime
© 2010 Entelos, Inc.
Personalized biomarker analysis – what data is valuable for me?
© 2010 Entelos, Inc.