Session:Monday September 21, 2015 at 11:45-12:30

Biomarkers to DiagnosticsThe Essential Tool Box for Drug DevelopmentThe Essential Tool Box for Drug Development

Johan LuthmanJohan Luthman, VP Neuroscience Clinical Development

Eisai Neuroscience & General Medicine Product Creation Unit, Wood Cliff Lake NJ USA

Evolution Summit;

Wood Cliff Lake, NJ, USA

;September 20-22, 2015, Red Rock Resort & Spa, Las Vegas, NV

Critical Tools - Animal Models & Biomarkers

Overall Program RiskBeyond target validationy g

EL

strong

MEDIUM LOW

MO

DE MEDIUM LOW

Validated modelNo biomarker

Validated modelValidated biomarker

NIM

AL

MEDIUMHIGHN d l

AN

none

e g

No modelNo biomarker

No modelValidated biomarker

BIOMARKERnone

stro

n

Steps from Biomarker to Diagnostic/Outcome Measure

Regulatory Process

Clinical QualificationDiagnostic

g yApproved DiagnosticAccepted Outcome measure

Diagnostic Outcome measure (surrogate)

Assay ValidationPrototype assay to Assay “lock down” A f t i ( kit)

Clinical Application“Fit for purpose”

Assay manufacturing (e.g. kit)Assay standardization

Exploratory BiomarkerExploration of candidate biomarker

Fit for Purpose AssayCustom developed assay

Biomarker IdentificationHypothesis driven or Un-biasedModality? / Invasive or Non-invasive?

p

Biomarkers in Early Development

Drug Presence & Target Engagement (TE)Drug reaches target organ & interacts with target

1g g g g

• Proof of Distribution / Presence - Reaching target organ• Proof of Target Occupancy - Binding to molecular target (TE)

Proof of Mechanism (PoM)Proof of Mechanism (PoM)Target mechanism = Pharmacodynamic (PD) readout• Proof of Biological Activity (PoBA)• Mechanism of Action (MoA)

2

• Mechanism of Action (MoA)

Proof of Principle (PoP)Mechanism influences pathophysiology

I ti t b t l h lth l t if h i l i t th h i l

3• In patients, but also healthy volunteers if physiology approximates pathophysiology • Also called “PoC Lite”

Proof of Concept (PoC)4 p ( )Mechanism can be used to treat disease• Traditionally Phase IIB study, however strive is to obtain PoC as early as possible in

custom designed small patient studies

4

Target Engagement Determination:PET imaging Key Technology

• Valid PoC requires adequate receptor occupancyC ffi i t b hi t ll t l t d d ?– Can sufficient occupancy be achieve at well tolerated doses ?

– Is it worthwhile testing efficacy?

No occupancy - no efficacy – not surprising New molecule needed

Full occupancy – no efficacy- concept flawed Do something else

• PET helps dose selection for efficacy trialsOpen therapeutic window and limit manufacturing costs– Open therapeutic window and limit manufacturing costs

Borsook, Becerra and Hargreaves (2006) Nature Reviews Drug Discovery 5: 411-425h

Target Engagement – PET OccupancyTranslational biomarker (animal-Ph0-Ph1)

PET set doses for H3 Inverse Agonist PoC Study•PET imaging of H3 receptorB s lin

7.5 mg 50 mg PET imaging of H3 receptor occupancy in humans

•H3 PET tracer allowed dose selection of MK-0249 in PoC study

Baseline 6h post-dose 6h post-dose

•Acceleration of Phase I to IIB94%80%AN04

POC f E i D ti Sl iPOC for Excessive Daytime Sleepiness:

Program termination:Program termination: MK-0249 in POC study had excellent dose –occupancy range, but p y g ,kept humans awake in sleep period

Cerebrospinal fluid (CSF) Aβ peptide Target-Proximal Translational PD biomarker (animal-Ph2)

BACE Inhibitors Potently Reduces Aβ40 Peptide in CSF and Cortex

Reduction of brain and CSF Aβ levels in rat and CSF in monkeys after single

Dose-dependent >90% reduction in CSF Aβ levels in human healthy volunteers after multiple dosing of MK 8931in rat and CSF in monkeys after single

dose administration BACE inhibitormultiple dosing of MK-8931

Data presented at the Alzheimer’s Association International Conference. 2012.

Quantitative & Qualitative Pharma EEGTarget-Distal Partially Translational Biomarker (animal-Ph1-Ph2)

Compound Class- EGG Fingerprint

“Pharmaco EEG”Pharmaco-EEGFingerprinting of pharmacological responseAcross species translatability?

Great need for harmonization & standardizationConsortia efforts

International Pharmaco-EEG Society

Pharmacodynamic/Efficacy & Safety BiomarkerTarget-Distal Partially Translational Complex Biomarker (Ph1-Ph2)

Car driving – On the road or SimulatorEfficacy read-out in e.g. Excessive Daytime Sleepiness patientsEfficacy read out in e.g. Excessive Daytime Sleepiness patients

Safety data on CNS active drugs

Differentiation from Standard of Care (sedative/hypnotics)

Standard Deviation of Lane Position (SDLP) Assesses “weaving”

Differentiation from Standard of Care (sedative/hypnotics)

Verster, 2006

National Advanced Driving Simulator (NADS, U of Iowa) MiniSim

Notch Signature in Hair Follicles Reveals Side Effect Liability with γ-Secretase Inhibitors

Identified Notch pathway target genes signatureMK0752 (γ Secretase Inhibitor) in Ph 1

Notch Signature:ADAM19CCND1DVL1 or

e

MK0752 (γ-Secretase Inhibitor) in Ph-1

DVL1HES4HES5HEY1HEYL h

Sig

natu

re s

co

HEYLNOTCH1NRARP

Ref

ined

Not

ch

Program termination:

Dose (mg):Time (hr):

MK-0752 caused gene signature down-regulation in 10/10 subjects at 1000 mg dose and 5/6 subjects at 350 mg (required dose for Aβ40 lowering)

Early Development Biomarkers

I t l d i i kiInternal decisions makingStandards & criteria defined internally

Go/No-Go tests of molecules & hypothesesTarget interaction, Dose guiding & Safety margin

Development toolsDevelopment tools Rarely commercialization of biomarker itselfOften use of commercialized technology platforms

Getting the Efficacious Dose Right

Transitioning Early to Late Development Dialing in Dose via use of Biomarkers in Adative Designg g

E lExample:Alzheimer’s BACi Ph-2/3

Steps from Biomarker to Diagnostic/Outcome Measure

Regulatory Process

Clinical QualificationDiagnostic

g yApproved DiagnosticAccepted Outcome measure

Diagnostic Outcome measure (surrogate)

Assay ValidationPrototype assay to Assay “lock down” A f t i ( kit)

Clinical Application“Fit for purpose”

Assay manufacturing (e.g. kit)Assay standardization

Exploratory BiomarkerExploration of candidate biomarker

Fit for Purpose AssayCustom developed assay

Biomarker IdentificationHypothesis driven or Un-biasedModality? / Invasive or Non-invasive?

p

Intended use of Biomarkers in Late Drug Developmentg p

• Disease Diagnosis– Supportive in clinical diagnosis, or fine tuning of diagnosis

E l di i t i k di i ( t d t bi k )– Early diagnosis – at risk diagnosis (antecedent biomarkers)

• Prognostic (Predictive) – Disease progression– Diagnosis of disease aggressivenessg gg

• Prognostic (Predictive) – Treatment effect– Outcome measure in trialsOutcome measure in trials– Ultimate goal surrogate outcome measure

Surrogacy qualification time-consuming & costly

• Predictive – Drug safety assessmentPredictive Drug safety assessment

• Stratification– Segmentation into predetermined categoriesg p g

• Enrichment– Inclusion criteria in trials– Companion Diagnostics 14

Role of Diagnostic Biomarkers

• Clinical phenotype – Different diagnostic criteria• Histopathology gold-standard in biomarker qualificationHistopathology gold standard in biomarker qualification

Bridging clinical & histopathology phenotypes (Alzheimer’s disease as example)

Clinical Phenotype Histopathology PhenotypeBiomarker Phenotype

( )

IWG criteria

Clinical Phenotype

Mayocriteria

Histopathology Phenotype

Neuro-fibrillaryAmyloid

plaques

Biomarker Phenotype

CSFAβ42

ApoEisotype2007

IWG-2 criteria

NIA-AA criteria

1999 tangles

Neuro-degen-Inflamm

ation

plaquesAβ42

AmyloidPET

isotype

CSFTaucriteria

2014criteria

2011g

rationation

15

HCVMRI

PET Tau

Regulatory Process Biomarkers to Diagnostics

“Context of Use” AcceptancePurpose of the measurement (“Clinical Qualification”)Purpose of the measurement ( Clinical Qualification )

– Stand Alone or Companion Diagnostic– Outcome Measure - Surrogate Outcome Measure

“Assay” ApprovalTest performing the measurement (“Assay Validation”)

– Medical Device• In Vivo Ex Vivo or In Vitro application• In Vivo, Ex Vivo or In Vitro application• Do not work via chemical action in the body

– IND / IMP• In Vivo application• Work via chemical action in the body, e.g. PET ligand

Context of Use Qualification of Drug Development Tools (DDT)

FDA - Drug Development Tools Qualification Programs– Allows use in the qualified Context of Use during drug developmentAllows use in the qualified Context of Use during drug development

• Office of Translational Sciences evaluation• No need CDER reconfirming DDT suitability for the qualified context of use

EMA - Qualification of Novel Methodologies for Drug Development

– Voluntary pathway to CHMP opinion (public) or a Scientific Advice– Voluntary pathway to CHMP opinion (public) or a Scientific Advice (confidential) on novel methodologies or methods & drug development tools

• Qualification of biomarkers for a specific intended useQualification of biomarkers for a specific intended use

Biomarkers qualification requires a reliable measurement method of the biomarker, but is conceptually independent of the specificof the biomarker, but is conceptually independent of the specific test performing the measurement• Qualification does not mean approval of a specific test device

Biomarker Context of Use Qualification

Critical Path Institute (Tucson, Arizona) Bridging the Gap between Science & Regulatory acceptance

RegulatoryE l t

Bridging the Gap between Science & Regulatory acceptance

Regulatory Application of

Biomarkers

Exploratory Biomarkers Bmx Qual

• Independent, non-profit organization “Executive” spin-out based on the Critical Path Initiative (FDA)

• Bringing FDA, industry & academia together to improve path forBringing FDA, industry & academia together to improve path for innovative new drugs & diagnostics

• Several projects for DDT qualification with FDA & EMA

Assay Approval “Fluid” Biomarker Assay Maturity FDA (EMA) Terminology

Research Use Only (RUO)– Not for diagnostic use

E l t d i & f– Evaluate design & performance– Developing knowledge related to human disease

Investigational Use Only (IUO)Investigational Use Only (IUO)– Undergoing performance evaluation– Used for diagnosis or treatment decisions or used as part of a drug trial to

determine which arm of the trial subjects will be placed inj p– Meet criteria for Investigational Device Exemption (IDE)

• Pre-IDE consultations and IDE submission is a useful pathway when evaluating the clinical utility of a diagnostic product

In Vitro Diagnostic (IVD) Medical Device (kit)– For diagnosis - to cure, mitigate, treat, or prevent disease – FDA - CDRH (Center for Devices & Radiologic Health)– FDA - CDRH (Center for Devices & Radiologic Health)

• Pre-market and post-market controls• Commercialized to CLIA certified labs

– EMA: IVD Devices have to meet the requirements for Self-Declaration

FDA IVD Classification

Likely Class II• Information not used for diagnosis

Likely Class III•Screens for a serious disease or

diti• Predicate device is available

• Likelihood of misuse is small or i ld t t i

condition

•Test information is diagnostic -patient has a disease or not

misuse would not create a serious situation

• 510(k)s - a predicate device

•Likelihood or harm of misuse is significant / serious

clearance

• de novo 510(k)s - no predicate device clearance

•Information tells physician which drug to use, not use, or how much to use

•Pre-Market Approval (PMA)

•Performance of device against a gold standard or other establishedgold standard or other established end point

USA – Oversight Diagnostics

• Laboratory Developed Test (LDT, “homebrews”)D l d & d ithi l b– Developed & used within one lab

• Not available to other labs• Clinical Laboratory Improvement Amendments (CLIA) standard• FDA has a “risk-based” oversight of LDTs

• “Complementary” Diagnostics– FDA developing frame work for new regulatory category

• Provide additional information on drug use• Provide additional information on drug use– Distinct from “companion diagnostics,” (essential for drug use)– Example - gene “signature” pattern linked to a certain disease.

• No test yet labeled as complementary diagnostics

Europe: CE Mark

• Requirements of the In Vitro Diagnostic Directive 98/79/EC– Manufacturer's declaration that the product conforms

with “Essential Requirements”with Essential RequirementsSelf-declarationVerified by “Notified Body” (accredited to validate compliance)Permits products’ access to the market

CE Marking is not approval by a Health AuthorityCE M ki i t lid ti f li i l tilit• CE Marking is not validation of clinical utility

• CE Marking is not intended for consumer assurance

Stand- Alone Diagnostic

“Independent” diagnostic –Not associated with specific drug treatmentot assoc ated t spec c d ug t eat e t–“Gold standard" against which to judge performanceperformance

Other established diagnosticPost mortem histopathologyPost mortem histopathology

Companion Diagnostic Pathway

Drug

Pharmaceutical DrugClinical phases RegulatoryDrug

Discovery

Biochemical Biomarker

PreclinicalPhase I Phase II Phase III

Regulatory filing Launch

PMA/CE

BiomarkerDiscovery

Feasibility Verification

RUO assay Prototype

Regulatory review Commer-

cializationIVC

IUO assay

ClinicalQualification

Identifies condition for use of a therapeutic productEnsures the safe & effective use of a therapeutic productEnsures the safe & effective use of a therapeutic product

Context of Use established by drug treatment effectNo "gold standard" requirement to judge performance

• Collaboration between Center for Drug Evaluation and Research (CDER) and CDRH (Center for Devices & Radiologic Health)

•Commonly a Class III device (Requiring Pre-Market Approval)

Companion Diagnostic - EMA

• CoDx viewed as low risk - CE markingCoDx viewed as low risk CE marking• Drug approvals not held up for kit to be CE marked

• Not yet requiring intended uses of diagnostic products toNot yet requiring intended uses of diagnostic products to change when companion diagnostic associated

• Emerging new EMA regulation: • CoDx will be viewed as class C (high risk)( g )

• Increased Notified Body & Competent authority involvement

Alzheimer‘s Disease

Progressive deficits in cognition (memory), activities of daily living (ADL) & behavior

• Neuropathology:–Extracellular amyloid plaques • Decreased brain

activities of daily living (ADL) & behavior

–Extracellular amyloid plaques– Intracellular neurofibrillary tangles–Neuro-degeneration

Decreased brain metabolism

• Brain atrophy–Neuroinflammation

“Diagnostic” use of Alzheimer’s Disease (AD) Biomarkers( )

Pre-Dementia Dementia

Cognitive, Functional & Behavioral deficitsMild Moderate Severe

Current diagnosis & treatment

Cognitive Impairment MCI / Prodromal ADSymptoms

Memory complaintsPre-SymptomaticNo apparent symptoms

• Risk factors; family • Mild cognitive impairment • AD diagnosis based on clinical

Current diagnosis & treatmentSymptoms No apparent symptoms

• Risk factors; family history, old age, ApoE4 genotype, TBI, mutations

• No symptoms, or subtle

• Mild cognitive impairment (MCI)

• Amnestic Mild Cognitive Impairment (aMCI) - episodic

• AD diagnosis based on clinical symptoms; cognitive deficits & dementia of the AD type

• Biomarker evidence of AD ycognitive deficits (memory complaints)

• Emerging biomarker e idence of AD

( )memory deficits

• aMCI combined with biomarker evidence of AD patholog Prodromal AD

pathology may increase specificity of diagnosis

evidence of AD pathology

pathology = Prodromal AD

Biomarker & Clinical Change in Alzheimer’s Disease

Clinical symptom stages - Occurrencedependent on degree of reserve capacity

Asymptomatic stage - Genetic risk & increasing biomarker signal

Max CSF Aβ42A l id PET

dependent on degree of reserve capacity risk & increasing biomarker signal

bnor

mal

ity

Dementia

Amyloid PETCSF Tau MRI + FDG PET Cognitive impairment

Bio

mar

ker A

b

MCIDetection Threshold

CSF Cerebrospinal fl id

B

MinNormal

Time (years)Cognitiveimpairment

Functional/ Behavioral changes = dementia

Jack CR, et al. Lancet Neurol (2013) 12; 207.

CSF = Cerebrospinal fluidFDG = Fluorodeoxyglucose MRI = Magnetic resonance imagingPET = Positron emission tomography

p g

Critical Role of International Pre-competitive Consortia in Progressing Alzheimer’s Biomarkers

World Wide Alzheimer’s Disease Neuroimaging Initiative (WW-ADNI) Collaborative effort of scientists from around the world

N th A i ADNI (NA ADNI)

PharmaCog (European ADNI)

North American ADNI (NA-ADNI)

Chinese ADNI

Japanese ADNITaiwan ADNIKorean ADNI

AIBL (Australian ADNI)Argentinian ADNI

Source: http://www.alz.org/research/funding/partnerships/ww-adni_overview.asp.

Biomarkers Used to Select Prodromal Subjects or to Demonstrate Disease Modification

• Prodromal AD patient “diagnosis” in MCI1 B i l id PET i i1. Brain amyloid PET imaging2. Cerebrospinal fluid (CSF) tau protein / Aβ peptide3 volumetric MRI – hippocampal volume3. volumetric MRI – hippocampal volume

• Outcome measuresBiomarkers as secondary & exploratory endpoints to support Disease Modification claimsDisease Modification claims

1. Hippocampal atrophy - volumetric MRI2. Cerebrospinal fluid total-tau or P-tau 3. Brain amyloid PET imaging (treatment effect)

Amyloid PET For Prodromal AD Diagnosis & Trial Enrichment

Amyloid Negative Example

Amyloid Positive Example:Amyloid Positive Example:Diffuse

Amyloid Positive Example: Diffuse + Focal

Sevigny AAN 201431

Challenges with Multi-Site Amyloid PET

Workflow for Multicenter Clinical PET imaging studyCyclotronCyclotron

((1818F production)F production) Tracer SynthesisTracer SynthesisGMP FacilityGMP Facility

SterileSterileReadyReady--toto--injectinject

Distribution to Medical Imaging Distribution to Medical Imaging Center (~ 4Center (~ 4 h from synthesis site)-

ReadyReadytoto injectinjecttracertracer

Selection of Imaging centerSelection of Imaging center

-- Camera QualificationCamera QualificationData acq isitionData acquisition

Multiple referring clinical sites

Transfer of subject to imaging center

-- Selection of Imaging centerSelection of Imaging center-- Qualification of siteQualification of site

-- Data acquisitionData acquisition-- AnnonymizationAnnonymizationof dataof data-- Data transfer to imagingData transfer to imaging lab

Transfer of subject to imaging center

Cerebrospinal Fluid Biomarkers of AD: Aβ42 and Tauβ

Tau:Phospho-Tau:

Plaques

Tangles Aβ42 monomers:Tau/Aβ42 ratio:

Aβ42 Tau1200

1000

1600

1400

1200800

600

400

1000

800

600

400

pg/m

L

200

0

400

200

0

Controls Alzheimer Disease Controls Alzheimer Disease

Sunderland T et al. JAMA. (2003) 289 (16); 2094.

Controls(n = 72)

Alzheimer Disease(n = 131)

Controls(n = 72)

Alzheimer Disease(n = 131)

CSF Tau & Aβ42 Predict Progression From Mild Cognitive Impairment (MCI) to AD

Mild Cognitive Impairment to AD Predicted by Tau/Aβ421

1.0

0.8

AD

Normal CSF

Pathological CSF0.6

ress

ion

to Pathological CSF

Cut-off values for pathological CSF: T-tau > 350 ng/LAβ42 < 530 ng/L

P-tau181 > 60 ng/L

0.4

0.2No

prog

P tau181 > 60 ng/L

Aβ42/P-tau181 ratio < 6.50

0 10 20 30 40 50 60

CSF = Cerebrospinal fluid1. Hansson O et al. Lancet Neurol. (2006) 5(3); 228.

Time (months)

Example of Receiver Operating Characteristic Curve for Tau/Aβ42 Assay in Cerebrospinal Fluid

Alzheimer’s Disease (n=84) vs. Healthy Elderly (n=108)ivity

Sensiti

1‐ Specificity

Inter-changeable Use of CSF Biomarkers & Amyloid PET for Enrichment

Florbetapir Amyloid PET & CSF Aβ42 relationship 374 recently-recruited ADNI-GO/2 subjects

Concordance CSF/PET has consistently been shown to be >85%Key comparison Visual Read on Amyloid PET & CSF assay cut point

36

C-Path Institute - CAMD Project Pipeline

FDA Issues Letters of Support to AD Biomarkers

38

FDA Evidentiary Standards Initiative

39

Are Biomarker Strategies Fully Implemented?

• Are only programs with TE or PD biomarkers progressing in Clinical studies?

Monoclonal antibodies against Aβ progressing without any TE/PD biomarkers

AD symptomatic drugs progressing with TE PET done after Phase 2

• Are Early Development Biomarkers used for clear Stop/Go d i i ?decisions?

γ-Secretase Inhibitors semagacestat and avagacestat progressed with very small PD effects and no safety biomarkers

A bi k d h ibl f d fi i d t i f• Are biomarkers used as much as possible for defining and staging of diseases?

Several AD programs against amyloid progressed without amyloid stratification

“• Are “right” biomarkers being used when there are other possibilities?

Amyloid PET instead of CSF markers for stratification

• Are the “right” validation (Assays) and qualification efforts being done (Context of Use)?

40

Biomarkers in Drug R&D…..?

BiBio-marker

Bio-marker

Bio-marker

Thank you for your attention!

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