The National Center for Advancing

Translational Sciences

Catalyzing Translational Innovation

CHRISTOPHER P. AUSTIN, M.D.

DIRECTOR, NCATS

INTERNATIONAL CONFERENCE ON ENGINEERING SCIENCE AND TECHNOLOGY

BEIJING, CHINA

JUNE 2, 2014

Take-home messages

• Translation is a team sport

Requires teams of individually expert members

Current operational and incentive structures frequently mitigate

against teams/networks

• Translational failure is 50% scientific, 50% operational

• The problems are systematic, so require systematic solutions

• The current poor efficiency of translation mandates

logarithmic improvement

• NCATS is a catalyst, convener, adaptor, innovator, tragedy-of-

the-commons occupier, NIH venture space, with core values of

Collaboration

Demonstrably useful deliverables

What is Translational Science?

Translational Science is the field of investigation

focused on understanding and addressing the

scientific and organizational challenges underlying

each stage of the translational process.

NCATS studies translation as a

scientific and organizational problem.

The Translational Spectrum

The Best of Times, the Worst of Times

• Poor transition of basic or clinical observations into interventions that tangibly improve human health

• Drug/device/diagnostic development system in crisis

• Clinical trials system in crisis

• Poor adoption of demonstrably useful interventions

Fundamental science unprecedentedly advanced, but:

People unhealthier and funders of biomedical research enterprise (public and private) impatient

NCATS Mission

To catalyze the generation of innovative methods and

technologies that will enhance the development,

testing and implementation of diagnostics and

therapeutics across a wide range of human diseases

and conditions.

Catalyzing Collaboration Within NIH

NEI

NCI NHLBI NIAID

NIDCR

NIDDKNIAMS

NIDA

CIT

NIEHS

NIMH

NINDS

NCATS

NCCAM

NIMHD

NIDCD

NIGMSNINR

NIAAA

NICHD

NLM

CC

OD

NIA

NHGRI

FIC

NIBIB

CSR

NCATS Collaborates Across the

Translational Ecosystem

NCATS

Biotech

FDA

Academia

PharmaNon-

Profits

Advocacy

Groups

Some of the translational problems NCATS

has to solve…• Predictive toxicology

• Predictive efficacy

• Derisking undruggable targets/untreatable diseases

• Data interoperability

• Biomarker qualification process

• Clinical trial networks

• Patient recruitment

• Electronic Health Records for research

• Harmonized IRBs

• Clinical diagnostic criteria

• Clinical outcome criteria (e.g., PROs)

• Adaptive clinical trial designs

• Shortening time of intervention adoption

• Methods to better measure impact on health (or lack of)

Clinical and Translational Science Awards

(CTSA) Program

• A national consortium of medical research institutions

• Work to improve the way clinical and translational research is conducted nationwide

• Provide innovative training for clinical and translation researchers

Clinical and Translational Science Awards (CTSA) Program Sites

Preclinical Development/TRND

BrIDGs

FDA Collaboration

Systems Toxicology (Tox21)

RNAi

Paradigm/Technology Development

Repurposing

Lead

OptimizationPreclinical

DevelopmentProbe/LeadDevelopment

TargetValidation

Target FDA approval

Clinical Trials

I II III

ProjectEntry Point

Deliverables

Repurposing

Unvalidated target

Validated target

Lead compound

Preclinical development

candidate

Genome-wide RNAi systems biology data

Chemical genomics

systems biology data

Small molecule and siRNAresearch probes

More efficient/faster/cheaper translation and therapeutic development

Leads for therapeutic

development

Predictive in vitro toxicology profiles

Approved drugs effective for new

indications

New drugs for untreatable diseases

Novel clinical trial designs

Drugs suitable for adoption for further

development

AssayDev

Assay , Chemistry Technologies

Target assay

DPIProgram

Probe Devel/NCGC

NCATS Division of Preclinical InnovationA Collaborative Pipeline

NCATS Division of Preclinical Innovation

Quantitative High-Throughput Screening (qHTS)Innovation via Engineering-Biology-Informatics Partnership

• Conventional HTS done at single concentration– typically 10 μM

• qHTS assays compounds at multiple concentrations – 7-15 concentrations

– Range = 2 nM – 100 μM

– 1536-well plate format, assay volume ~5 μL, ~1000 cells/well

– Concentration-response curve generated for each compound from primary screen

• Produces robust activity profiles of all compounds– Dramatically reduced FP and FN

– 4-6 months saved compared to conventional HTS

• Informatics pipeline for data processing, curve fitting & classification, extraction of SAR

• Collaborator: Alexander Agoulnik (Florida International University)

• Target: RXFP1, GPCR with multiple physiological effects including anti-fibrotic response;

activation by natural ligand relaxin hormone produced increased survival in human clinical trials

of acute heart failure

• Challenges: Difficult receptor to activate; no small molecules agonists previously reported.

Recombinant hormone must be continuously administrated IV for several days due to T½ ≈10 min

• Accomplishments

Developed first selective and potent RXFP1 agonist (ML290)

Efficacy similar to natural ligand

Excellent PK profile and heart distribution

Binding homology model developed based on mutagenesis studies

Published in Nature Communications

• Current Status: CRADA signed with a major pharmaceutical company

for joint development

Collaboration to Drug the Relaxin Receptor

Needed: 1) a high-value library of small molecules

2) an effective plating process

3) an automated data analysis method

Step 1: Generate single

agent results.

Step 2: Generate 6X6

matrix data to uncover

potential synergies.

Step 3: Expand good combinations

to 10X10 blocks to confirm

synergistic combinations and

perform self-crosses to provide

context for activities.

Creating a technology platform for the discovery of

novel drug combinations

Proof of Concept: Combination Screening Program

• NCATS-NCI collaboration

• Unbiased small-molecule combination (matrix)

screening identified potential drugs to combine

with ibrutinib for activated B-cell like subtype

(ABC) of diffuse large B-Cell lymphoma (DLBCL)• PI3K pathway inhibitors

• BCL family antagonists, navitoclax and ABT-199

• Cytotoxic Chemotherapeutic Agents, including

several components of R-CHOP and EPOCH-R

regimens currently used to treat DLBCL

De-Risking Rare and Neglected Disease

TherapeuticsThe TRND Program

Disease: Sickle cell disease

Collaborator: AesRx, LLC

Compound: Aes-103

– Binds to sickle hemoglobin, increases O2 affinity

TRND partnered with AesRx and accomplished

– Project initiation to IND in <12 mos

– Phase Ia, Ib, IIa studies

Recently licensed to a large pharma for completion of

clinical development, marketing

Partnership: NCATS drug development + investigator disease/target expertise

Projects enter at lead-op, taken to stage needed to attract external adoption for

completion of clinical development

Develop new generally applicable platform technologies and paradigms

19

ToxicityCellChanges

Molecular

Targets

Tissues

CellularNetworks

Cellular Systems

TissueDose

Molecular

Pathways

Innovation to Predict Toxicity

Biochemical

HTS

Cell-Based

HTS

Complex

Cellular and

HCS HTS

Model

Organism

MTS

Virtual Tissues

Exposure

Enabling Predictive ToxicologyThe Tox21 Program

Tox21 Goals

• Identify patterns of

compound-induced biological

response in order to:

characterize toxicity/disease

pathways

facilitate cross-species

extrapolation

model low-dose extrapolation

• Prioritize compounds for more

extensive toxicological

evaluation

• Develop predictive models for

biological response in humans

Microphysiological Systems (MPS) Program(aka, Tissue Chip, Organs-on-Chips)

• Goal Develop organoids on chips to screen for compound toxicity,

efficacy Liver, heart, lung, other cell types

Integrate platform systems

Designed for multiple different readouts

• NIH, DARPA contributing ~$70M each over 5 years NCATS and DARPA independently manage, fund separately

but highly coordinated program

FDA provides regulatory science guidance

• Awards announced in 2012 Supporting the best ideas in engineering, biology, and

toxicology

Engineered Cardiac Muscular Thin Films

Film lengthAutomatic projection tracking

Science 2007;317:1366 Biomaterials 2010;31:3613

Lab Chip 2011;11:4165 J Pharm Tox Methods 2012;65:126 Data provided by Dr. Kit Parker, Wyss Institute

The Future: Body-on-a-Chip

•Human biology• Tissue/organ structure•Cell histology•Cell viability•Mechanical properties• Electrical properties• Signaling pathways•Cell metabolism•Protein synthesis•Gene expression• Enzyme activities• Ion channel properties

•Absorption•Distribution•Metabolism• Excretion• Conc(t)• Effect(t)• Toxicity(t)• Rare toxicities

Read outs

In vivo Correlation

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