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Christopher P. Austin. M.D.Di t NIH Ch i l G i C t

The Impact of Genomics on Clinical Research and Drug Development

Director, NIH Chemical Genomics CenterNational Human Genome Research Institute

National Institutes of Health

NIH Introduction to the Principles and Practice of Clinical ResearchFebruary 15, 2011

“Genetic” DiseasesSingle gene variant large contributor to disease

a.k.a., ‘Mendelian’Modifier genes and environment also contributors

e.g., Huntington’s disease,e.g., Huntington s disease, cystic fibrosis, Tay-Sachs6000 rare genetic diseases, but each is individually uncommon (<200,000 U.S. prevalence)As genetic diagnosis improves, lower pentrance alleles being identified incidence increasing

Manolio et al., J. Clin. Invest. 118:1590, 2008

“Genomic” DiseasesVariants in multiple genes changes predisposition to disease

a.k.a., ‘polygenic’, ‘common’, ‘complex’Environmental contributionsEnvironmental contributions generally larger

e.g., hypertension, obesity, Alzheimer’s disease

ApoE (Alzheimer’s disease)Complement Factor H (AMD)

PPARγ (Type 2 diabetes)

(Virtually) all diseases have heritable component

Manolio et al., J. Clin. Invest. 118:1590, 2008

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Stages in Deciphering the Genome

2000: First Draft

2001: Working Draft

April 15, 2003: “Finished” reference sequence

2002-2007: Defining sequence variation in

populations

2007 - 2010: Defining sequence variation in a few individuals

2011 - : “Medical Sequencing”: Defining individual genomes for

clinical care purposes

“Genetic testing” means many things

1. SNPs2. Haplotypes3. Exons4. Insertions-Deletions-Inversions5. Whole genomes6. Gene expression changes7. Epigenetic changes

Haplotypes and Tag SNPs

Manolio et al., J. Clin. Invest. 118:1590, 2008

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Genome-Wide Association Studies (GWAS)

• Method for interrogating all 10 million variable points across the human genome

• Variation inherited in “haplotype blocks” of linkage disequilibrium, so only “tag SNPs” need to be assayedy

• Haplotype blocks are smaller in unrelated individuals

• Technology allows routine testing of 300,000 –500,000 tag SNPs across the genomes of unrelated persons (assumes ~10 kb blocks)

2005

2007

2010

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The First HapMap Success Story:Age-Related Macular Degeneration

Science 2005

NHGRI GWAS catalog now includes >800 publications & >2600 associations>800 publications & >2600 associations

genome.gov/gwastudies

NHGRI GWA Catalogwww.genome.gov/GWAStudies

Published Genome-Wide Associations through 6/2010,904 published GWA at p < 5 x 10-8 for 165 traits

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$100

$1,000

$10,000

Cost per Megabase of Raw DNA Sequence

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$10

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Moore's Law

Cost per Mb

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2000 2010

<1 Human Genome 250-500 Human Genomes

Genome Sequencing as a ‘Commodity’

Celebrity Genomics

Nature (2010)

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Celebrity Genomics: Recent Additions

Celebrity Genomics: Recent Additions

NEJM (2010)

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http://www.genetests.org

Genomic Architecture of Genetic Diseases

Rare, Simple, Monogenic, Mendelian…

Common, Complex, Multigenic, Non-Mendelian…

Mostly Coding Mutations Mostly Non-Coding Mutations

Genome Sequencing: Genetic Diseases

Molecular Basis Unknown (~1800)

Molecular Basis Known (~2900)

Suspected Mendelian Disease/Trait (~2000)

Unknown (~1800)

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NEJM (2010)

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http://projects.tcag.ca/variation

Pharmacogenomics

Use of genetic differences among individual patients to

Improve specificity of diagnosisImprove likelihood of response to aImprove likelihood of response to a drugCustomize drug doseDecrease likelihood of adverse reaction to a drug

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Companies and patients are often ahead of their doctors in use of genetic data

The Genetic Information Nondiscrimination Act of 2008 (GINA)

• A federal law that prohibits health insurers and employers from discriminating based on an individual’s genetic information– Intended to allow Americans to take advantage of

ti t ti ith t f f l i th i h lthgenetic testing without fear of losing their health insurance or their jobs

• GINA prohibits health insurers from– Requesting or requiring genetic information from an

individual or their family members– Using genetic information for decisions regarding

coverage, rates, or preexisting conditions

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• GINA prohibits employers from– Using genetic information in decisions regarding

hiring, firing, promotion or any other terms of employment (e.g., benefits)

– Retaliating against employees who file a complaint

The Genetic Information Nondiscrimination Act of 2008 (GINA)

under GINA• GINA does not

– Affect underwriting regarding manifest disease –someone who is already sick is not protected by GINA

– Restrict discriminatory use of genetic information in regard to life, long-term care, or disability insurance

– Extend to members of the military

Developing Drugs from the Genome

NumbersHuman genes ~20,000Human proteins (targets) ~500,000Current drugs target ~500 proteins

G id tifi ti l t t t d t i i f tiGene identification only start to determining function and any therapeutic potential“Validation”

Definition of sequence function, role in diseaseDemonstration of manipulability of gene productTransforms gene product into drug target

Genomics is changing how drugs are developed in the clinic

Genetically defined subpopulations for clinical trialsgreater power with reduced n

Smaller patient populations eligible for treatment upon drug approval

Better efficacy data improves chance of formularyBetter efficacy data improves chance of formulary acceptanceFinancial success of drugs for genetically defined populations suggests more “targeted” drugs will be entering trials

HerceptinGleevec AvastinCerezyme

All diseases may eventually be “rare”

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The best of times, the worst of times

How to translate the genome into biological insights and therapeutics?

The Problem of Rare and Neglected Diseases• ~7,000 diseases affect humankind• Only a very small fraction of diseases support commercial development

of therapeutic agents• Two types of neglected diseases:

– Low prevalence, i.e., “rare”• Prevalence <200,000 in USA

• There are >6000 rare (orphan) diseases

• Cumulative prevalence in U.S. ~ 25 – 30 million

• Most are single gene diseases; e.g., cystic fibrosis, Huntington disease, sickle cell disease, Tay-Sachs, OI

• Approximately 200 have any pharmacotherapy available from the 340 products approved by FDA

– High prevalence but “neglected”• Occur chiefly among impoverished and marginalized populations in developing

nations who are unable to afford treatments

• Most are infectious diseases, e.g., malaria, schistosomiasis, leishmaniasis, trypanosomiasis

Only a small % of diseases and genome-encoded targets are being addressed for drug development

Current drug targets:Well understood proteins

Current diseases:Prevalent diseases that affect developed world

Human Genome

Neglected

Human Diseases

Neglected

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1000

1200

1400

1600

1800

2000

Genes Identified: Monogenic Diseases

Gen

es

Human Genome Project Begins

Molecular Basis Known (~2900)

Molecular Basis

Suspected Mendelian Disease/Trait (~2000)

0

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No.

G

Source: Online Mendelian Inheritance in Man (www.ncbi.nlm.nih.gov/omim)

Project BeginsMolecular Basis Unknown (~1800)

Steps in the drug development process

Identify target

Create testing system (aka,

“assay”

Test >100,000

chemicals for activity on

target

Make modifications

to active chemicals to

make suitable for human

use

Test in animals for

safety, effectiveness

Test in humans for

safety, effectiveness

Economics and risks of drug development

Prob

abili

ty

of s

ucce

sstiv

e C

ost

Cum

ulat

Ph IV-V(Additional indications, Safety monitoring)

Dedicated Chem-Biol

Project Team formed

Compound accepted into

Clinical Development

Target identification

Assay develop-ment Hit-to-

Probe

Screening (HTS or otherwise)

1 yr 1 yr 1 yr ~ 3 yrs 1 yr 2 yrs ~3 yrs

Ph III Ph II Ph ILead Development, Optimization

Indefinite Indefinite1.5 yrs

Regulatory review

Clinical Trials

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FDAPharma

and NIH-

Funded Basic

Conventional roles of public and private sectors in drug development

tive

Cos

tPr

obab

ility

of

suc

cess

BiotechScience

Cum

ulat

Ph IV-V(Additional indications, Safety monitoring)

Dedicated Chem-Biol

Project Team formed

Compound accepted into

Clinical Development

Target identification

Assay develop-ment Hit-to-

Probe

Screening (HTS or otherwise)

1 yr 1 yr 1 yr ~ 3 yrs 1 yr 2 yrs ~3 yrs

Ph III Ph II Ph ILead Development, Optimization

Indefinite Indefinite1.5 yrs

Regulatory review

Clinical Trials

“…To empower the research communityresearch community to use small molecule compounds in their research, whether as tools to perturb genes and pathways, or as starting points to the development of new therapeutics for human disease.”

Public Sector

Science

Prob

abili

ty

of s

ucce

sstiv

e C

ost

Molecular Libraries program takes first steps in drug development

Science with MLIC

umul

at

Ph IV-V(Additional indications, Safety monitoring)

Dedicated Chem-Biol

Project Team formed

Compound accepted into

Clinical Development

Target identification

Assay develop-ment Hit-to-

Probe

Screening (HTS or otherwise)

1 yr 1 yr 1 yr ~ 3 yrs 1 yr 2 yrs ~3 yrs

Ph III (Efficacy and safety in large populations)

Ph II (Dose finding, initial efficacy

in patient pop.)

Ph I (Safety)

Lead Development, Optimization

Indefinite Indefinite1.5 yrs

Regulatory review

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Case Study: Probe Development for Gaucher’s DiseaseNCGC Collaboration with Ellen Sidransky, NHGRI

• Gaucher’s Disease– Rare disease caused by mutations in

enzyme glucocerebrosidase (GCS)

– Current treatment: enzyme replacement

glucosylceramide

• Limited efficacy, no BBB penetration, expensive

• Many mutations are missense, leading to trafficking defect– Pharmacological chaperones a

therapeutic possibility

Resorufin β-D-glucopyranoside

Cerebrosidase +Resorufin

GlucoseEx 570 nm / Em 590 nm

Fluorogenic substrate assay:

Two approaches to therapeutics for rare and neglected diseases

>400,000 compounds, 15 yrs

1-2 years?

ClinicalTrialsLead

LeadOptimization

PreclinicalDevelopmentHitScreenTarget FDA

approval

3500 drugs

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NCGC Pharmaceutical CollectionStatus April 2010

Drug Source Current Remaining Total

US FDA 1635 187 1822

UK/EU/Canada/Japan 756 174 930

INN 928 3932 4860

Total Approved 2391 361 2752

Total 3319 4293 7612

• Informatics sources for NPC– US FDA: Orange Book, OTC, NDC, Green Book, Drugs at FDA– Britain NHS– EMEA– Health Canada– Japan NHI

• Physical sources for NPC– Procurement from >20 suppliers worldwide– In-house purification of APIs from marketed forms– Synthesis

Case Study: Niemann-Pick Disease Type CCollaboration with Denny Porter (NICHD), Bill Pavan (NHGRI),

Dan Ory (Wash U), Steve Walkley (Einstein)

• NPC – Autosomal recessive disease– Prevalence: 1:150,000

Clinical manifestations: progressive– Clinical manifestations: progressive neurodegeneration, hepatosplenomegaly, death by teens

– Characterized by a lysosomal accumulation of unesterified cholesterol and other lipids.

– Mutated genes: NPC1 (95%) and NPC2 (5%)

• Purpose of project: utilize patient cells and approved drug collection to repurpose an existing drug for NPC

Characterization of NPC Patient Cells

GM005659 (WT) GM003123

NPC28NPC18

GM))5659 (WT) GM003123

NPC18 NPC28

Filipin (Green) Cell Mask (Red)

Lysotracker (Red) Hoechst (Blue)

NPC9

NPC17 NPC32

NPC27

NPC17

NPC9 NPC27

NPC32

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50 uM 25 uM 12.5 uM 6.25 uM DMSO

Filipin (Blue)Cell Mask (Red)

Lysotracker (Red)Hoescht (Blue)

NPC “Corrector” identified from screening of pharmaceutical collection

Reduction in Free Cholesterol Accumulation and Lysosome Size

125.0 62

.531

.315

.6 7.8 3.9

DMSO0

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[Compound], μM

Nor

mal

ized

ATP

Lev

el

Norm

alizedC

holesterol Level

125.0 62

.531

.315

.6 7.8 3.9DMSO

0

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[Compound], μM

Nor

mal

ized

ATP

Lev

el

Norm

alizedC

holesterol Level

Hoescht (Blue)

125.0 62

.531

.315

.6 7.8 3.9DMSO

0

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80

100

120

0

20

40

60

80

100

120

[Compound], μM

Nor

mal

ized

ATP

Lev

el

Norm

alizedC

holesterol Level

WT (5659)NPC25GM3123

Cholesterol (6 d)Cholesterol (4 d)Cholesterol (2 d)ATP (6 d)ATP (4 d)ATP (2 d)

Reduction in Cholesterol Accumulation (cholesterol oxidase assay)

Drug now in mouse model; clinic Fall 2011

Pharmas, BiotechsNIH Clinical Center,Academic Clinical

FDA

Bas

ic R

esea

rch

NCGC,Molecular Libraries Initiative

The long pathway to drug development

“Valley of Death”

CentersNIH RAID

B

IND

3 yrs 1 yr 2 yrs ~3 yrs

Ph III Ph II Ph I

Indefinite

Patient Use

1 yr

Review

4 yrs

Identify Target

Identify chemical starting point for drug

Make many chemical modifications to give drug beneficial effect without side effects

Pharmas, BiotechsNIH Clinical Center,Academic Clinical

FDA

Bas

ic R

esea

rch

NCGC,Molecular Libraries Initiative

The long pathway to drug development

TRND

CentersB

3 yrs 1 yr 2 yrs ~3 yrs

Ph III Ph II Ph I

Indefinite

Patient Use

1 yr

Review

4 yrs

Identify Target

Identify chemical starting point for drug

Make many chemical modifications to give drug beneficial effect without side effects

NIH RAID

IND

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NIH Therapeutics for Rare and Neglected Diseases (TRND) ProgramCreating a Drug Development Pipeline at NIH

Congressionally-mandated effort to speed development of new drugs for rare and neglected diseasesAdministration and governance at NIH– Governance/oversight by Office of Rare Diseases Researchg y– Administered by NHGRI

Operations: collaboration between intramural and extramural labs with appropriate expertiseProjects will:– Enter TRND at a variety of stages of development– Be taken to phase needed for external organization to adopt

for clinical development

TRND ScienceIn-house laboratories with expertise in preclinical drug development will collaborate with external laboratories with expertise in disease/target

Distinguishing features– Disease agnostic, take advantage of cross-cutting mechanisms

• “Diseaseome” approach

– Science of preclinical drug development

• Reasons for successes and failures will be investigated and published• Reasons for successes and failures will be investigated and published

– Technology/paradigm development

• 20% of effort, toward improving success rates

– Large-scale systematic repurposing

Project-specific activities– Medicinal chemistry

– Efficacy, pharmacology, ADME, toxicology, PK/PD

– Compound scale-up, formulation

– First in human clinical trials as needed for project

TRND Pilot ProjectsChosen to establish processes in advance of solicitation, with diversity of project stage, type of disease and collaborators

Disease Type Pathology Collaborators Compound type Stage

Schistosomiasis, Hookworm Neglected Infectious

parasite Extramural NME Lead optimization

CNS Disease Fnd, RepurposedNiemann Pick C Rare CNS,

liver/spleen

Disease Fnd, Extramural, Intramural

Repurposed approved

drugPreclinical

Hereditary Inclusion Body

MyopathyRare Muscle Biotech,

IntramuralIntermediate replacement

IND-enabling studies

Sickle Cell Disease Rare Blood Biotech,

Intramural NME

IND-enabling studies &

clinical trials design

Chronic Lymphocytic

LeukemiaRare Cancer Disease Fnd,

Extramural

Repurposed approved

drugPre-IND

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TRND Pilot Project on Sickle Cell DiseasePrincipal Collaborator: AesRx, Inc.Compound: 5-hydroxymethyl-2-furfural (Aes-103)

– binds to sickle hemoglobin and increases oxygen affinity

Stage of project: late pre-clinicalTRND collaborating with AesRx on

– Animal toxicology– CMC (Chemistry, Manufacturing, and Quality Control) studies– Regulatory: interactions with FDA, IND filing– Proof-of-concept clinical trials

Other NIH resources collaborating to get drug to clinic– API (Aes-103) manufactured via NIH-RAID program– NIH Clinical Center Pharmacy collaborating on formulation– NIH Clinical Center Investigator will perform POC clinical trials

• Greg Kato, NHLBI

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Further Information

austinc@mail.nih.gov

http://ncgc.nih.gov

http://trnd.nih.gov