targets to populations to individuals€¦ · 2020: “the majority of drug discovery will be...

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.