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Session:
Monday September 21, 2015 at 11:45-12:30
Biomarkers to Diagnostics
The Essential Tool Box for Drug DevelopmentThe...
Critical Tools - Animal Models & Biomarkers
Overall Program Risk
Beyond target validationy g
ELstrong
MEDIUM LOW
MODE
MEDI...
Steps from Biomarker to
Diagnostic/Outcome Measure
Regulatory Process
Clinical Qualification
Diagnostic
g y
Approved Diagn...
Biomarkers in Early Development
Drug Presence & Target Engagement (TE)
Drug reaches target organ & interacts with target
1...
Target Engagement Determination:
PET imaging Key Technology
• Valid PoC requires adequate receptor occupancy
C ffi i t b h...
Target Engagement – PET Occupancy
Translational biomarker (animal-Ph0-Ph1)
PET set doses for H3 Inverse Agonist PoC Study
...
Cerebrospinal fluid (CSF) Aβ peptide
Target-Proximal Translational PD biomarker (animal-Ph2)
BACE Inhibitors Potently Redu...
Quantitative & Qualitative Pharma EEG
Target-Distal Partially Translational Biomarker (animal-Ph1-Ph2)
Compound Class- EGG...
Pharmacodynamic/Efficacy & Safety Biomarker
Target-Distal Partially Translational Complex Biomarker (Ph1-Ph2)
Car driving ...
Notch Signature in Hair Follicles Reveals Side
Effect Liability with γ-Secretase Inhibitors
Identified Notch pathway targe...
Early Development Biomarkers
I t l d i i kiInternal decisions making
Standards & criteria defined internally
Go/No-Go test...
Getting the Efficacious Dose Right
Transitioning Early to Late Development
Dialing in Dose via use of Biomarkers in Adativ...
Steps from Biomarker to
Diagnostic/Outcome Measure
Regulatory Process
Clinical Qualification
Diagnostic
g y
Approved Diagn...
Intended use of Biomarkers in
Late Drug Developmentg p
• Disease Diagnosis
– Supportive in clinical diagnosis, or fine tun...
Role of Diagnostic Biomarkers
• Clinical phenotype – Different diagnostic criteria
• Histopathology gold-standard in bioma...
Regulatory Process Biomarkers to Diagnostics
“Context of Use” Acceptance
Purpose of the measurement (“Clinical Qualificati...
Context of Use
Qualification of Drug Development Tools (DDT)
FDA - Drug Development Tools Qualification Programs
– Allows ...
Biomarker Context of Use Qualification
Critical Path Institute (Tucson, Arizona)
Bridging the Gap between Science & Regula...
Assay Approval
“Fluid” Biomarker Assay Maturity FDA (EMA) Terminology
Research Use Only (RUO)
– Not for diagnostic use
E l...
FDA IVD Classification
Likely Class II
• Information not used for diagnosis
Likely Class III
•Screens for a serious diseas...
USA – Oversight Diagnostics
• Laboratory Developed Test (LDT, “homebrews”)
D l d & d ithi l b– Developed & used within one...
Europe: CE Mark
• Requirements of the In Vitro Diagnostic Directive
98/79/EC
– Manufacturer's declaration that the product...
Stand- Alone Diagnostic
“Independent” diagnostic
–Not associated with specific drug treatmentot assoc ated t spec c d ug t...
Companion Diagnostic Pathway
Drug
Pharmaceutical Drug
Clinical phases RegulatoryDrug
Discovery
Biochemical Biomarker
Precl...
Companion Diagnostic - EMA
• CoDx viewed as low risk - CE markingCoDx viewed as low risk CE marking
• Drug approvals not h...
Alzheimer‘s Disease
Progressive deficits in cognition (memory),
activities of daily living (ADL) & behavior
• Neuropatholo...
“Diagnostic” use of Alzheimer’s Disease
(AD) Biomarkers( )
Pre-Dementia Dementia
Cognitive, Functional & Behavioral defici...
Biomarker & Clinical Change in
Alzheimer’s Disease
Clinical symptom stages - Occurrence
dependent on degree of reserve cap...
Critical Role of International Pre-competitive
Consortia in Progressing Alzheimer’s Biomarkers
World Wide Alzheimer’s Dise...
Biomarkers Used to Select Prodromal Subjects or
to Demonstrate Disease Modification
• Prodromal AD patient “diagnosis” in ...
Amyloid PET For Prodromal AD
Diagnosis & Trial Enrichment
Amyloid Negative Example
Amyloid Positive Example:Amyloid Positi...
Challenges with Multi-Site Amyloid PET
Workflow for Multicenter Clinical PET imaging study
CyclotronCyclotron
((1818
F pro...
Cerebrospinal Fluid Biomarkers of AD:
Aβ42 and Tauβ
Tau:
Phospho-Tau:
Plaques
Tangles Aβ42 monomers:
Tau/Aβ42 ratio:
Aβ42 ...
CSF Tau & Aβ42 Predict Progression From
Mild Cognitive Impairment (MCI) to AD
Mild Cognitive Impairment to AD Predicted by...
Example of Receiver Operating Characteristic Curve for
Tau/Aβ42 Assay in Cerebrospinal Fluid
Alzheimer’s Disease (n=84) vs...
Inter-changeable Use of CSF Biomarkers &
Amyloid PET for Enrichment
Florbetapir Amyloid PET & CSF Aβ42 relationship
374 re...
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?
...
Biomarkers in Drug R&D…..?
BiBio-
marker
Bio-
marker
Bio-
marker
Thank you for your attention!
For more information about theFor more information about the 
marcus evans Pharma 
S it iSummits series: 
pharmaseries@mar...
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Biomarkers to Diagnostics – The Essential Tool Box for Drug Development - Johan Luthman, Eisai Pharmaceuticals

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Biomarkers to Diagnostics – The Essential Tool Box for Drug Development - Presentation delivered by Johan Luthman, Vice President, Neuroscience Clinical Development, Eisai Pharmaceuticals at the marcus evans Evolution Summit Fall 2015 in Las Vegas

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Biomarkers to Diagnostics – The Essential Tool Box for Drug Development - Johan Luthman, Eisai Pharmaceuticals

  1. 1. Session: Monday September 21, 2015 at 11:45-12:30 Biomarkers to Diagnostics The 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
  2. 2. Critical Tools - Animal Models & Biomarkers Overall Program Risk Beyond target validationy g ELstrong MEDIUM LOW MODE MEDIUM LOW Validated model No biomarker Validated model Validated biomarker NIMAL MEDIUMHIGH N d l AN none e g No model No biomarker No model Validated biomarker BIOMARKER none stron
  3. 3. Steps from Biomarker to Diagnostic/Outcome Measure Regulatory Process Clinical Qualification Diagnostic g y Approved Diagnostic Accepted Outcome measure Diagnostic Outcome measure (surrogate) Assay Validation Prototype assay to Assay “lock down” A f t i ( kit) Clinical Application “Fit for purpose” Assay manufacturing (e.g. kit) Assay standardization Exploratory Biomarker Exploration of candidate biomarker Fit for Purpose Assay Custom developed assay Biomarker Identification Hypothesis driven or Un-biased Modality? / Invasive or Non-invasive? p
  4. 4. Biomarkers in Early Development Drug Presence & Target Engagement (TE) Drug reaches target organ & interacts with target 1 g 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
  5. 5. Target Engagement Determination: PET imaging Key Technology • Valid PoC requires adequate receptor occupancy C 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 trials Open 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
  6. 6. Target Engagement – PET Occupancy Translational 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 IIB 94%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, butp y g , kept humans awake in sleep period
  7. 7. 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 inhibitor multiple dosing of MK-8931 Data presented at the Alzheimer’s Association International Conference. 2012.
  8. 8. Quantitative & Qualitative Pharma EEG Target-Distal Partially Translational Biomarker (animal-Ph1-Ph2) Compound Class- EGG Fingerprint “Pharmaco EEG”Pharmaco-EEG Fingerprinting of pharmacological response Across species translatability? Great need for harmonization & standardization Consortia efforts International Pharmaco-EEG Society
  9. 9. Pharmacodynamic/Efficacy & Safety Biomarker Target-Distal Partially Translational Complex Biomarker (Ph1-Ph2) Car driving – On the road or Simulator Efficacy 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
  10. 10. Notch Signature in Hair Follicles Reveals Side Effect Liability with γ-Secretase Inhibitors Identified Notch pathway target genes signature MK0752 (γ Secretase Inhibitor) in Ph 1 Notch Signature: ADAM19 CCND1 DVL1 ore MK0752 (γ-Secretase Inhibitor) in Ph-1 DVL1 HES4 HES5 HEY1 HEYL hSignaturesco HEYL NOTCH1 NRARP RefinedNotch 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)
  11. 11. Early Development Biomarkers I t l d i i kiInternal decisions making Standards & criteria defined internally Go/No-Go tests of molecules & hypotheses Target interaction, Dose guiding & Safety margin Development toolsDevelopment tools Rarely commercialization of biomarker itself Often use of commercialized technology platforms
  12. 12. 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
  13. 13. Steps from Biomarker to Diagnostic/Outcome Measure Regulatory Process Clinical Qualification Diagnostic g y Approved Diagnostic Accepted Outcome measure Diagnostic Outcome measure (surrogate) Assay Validation Prototype assay to Assay “lock down” A f t i ( kit) Clinical Application “Fit for purpose” Assay manufacturing (e.g. kit) Assay standardization Exploratory Biomarker Exploration of candidate biomarker Fit for Purpose Assay Custom developed assay Biomarker Identification Hypothesis driven or Un-biased Modality? / Invasive or Non-invasive? p
  14. 14. 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
  15. 15. 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 Mayo criteria Histopathology Phenotype Neuro- fibrillary Amyloid plaques Biomarker Phenotype CSF Aβ42 ApoE isotype 2007 IWG-2 criteria NIA-AA criteria 1999 tangles Neuro- degen- Inflamm ation plaquesAβ42 Amyloid PET isotype CSF Taucriteria 2014 criteria 2011 g ration ation 15 HCV MRI PET Tau
  16. 16. Regulatory Process Biomarkers to Diagnostics “Context of Use” Acceptance Purpose of the measurement (“Clinical Qualification”)Purpose of the measurement ( Clinical Qualification ) – Stand Alone or Companion Diagnostic – Outcome Measure - Surrogate Outcome Measure “Assay” Approval Test 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
  17. 17. 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
  18. 18. 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
  19. 19. 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
  20. 20. 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
  21. 21. 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
  22. 22. 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 Requirements Self-declaration Verified by “Notified Body” (accredited to validate compliance) Permits products’ access to the market CE Marking is not approval by a Health Authority CE 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
  23. 23. 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 diagnostic Post mortem histopathologyPost mortem histopathology
  24. 24. Companion Diagnostic Pathway Drug Pharmaceutical Drug Clinical phases RegulatoryDrug Discovery Biochemical Biomarker Preclinical Phase I Phase II Phase III Regulatory filing Launch PMA/CE Biomarker Discovery Feasibility Verification RUO assay Prototype Regulatory review Commer- cialization IVC IUO assay Clinical Qualification Identifies condition for use of a therapeutic product Ensures the safe & effective use of a therapeutic productEnsures the safe & effective use of a therapeutic product Context of Use established by drug treatment effect No "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)
  25. 25. 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
  26. 26. 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
  27. 27. “Diagnostic” use of Alzheimer’s Disease (AD) Biomarkers( ) Pre-Dementia Dementia Cognitive, Functional & Behavioral deficits Mild Moderate Severe Current diagnosis & treatment Cognitive Impairment MCI / Prodromal AD Symptoms Memory complaints Pre-Symptomatic No apparent symptoms • Risk factors; family • Mild cognitive impairment • AD diagnosis based on clinical Current diagnosis & treatmentSymptomsNo 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 ADy cognitive 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
  28. 28. Biomarker & Clinical Change in Alzheimer’s Disease Clinical symptom stages - Occurrence dependent on degree of reserve capacity Asymptomatic stage - Genetic risk & increasing biomarker signal Max CSF Aβ42 A l id PET dependent on degree of reserve capacityrisk & increasing biomarker signal bnormality Dementia Amyloid PET CSF Tau MRI + FDG PET Cognitive impairment BiomarkerAb MCIDetection Threshold CSF Cerebrospinal fl id B Min Normal Time (years) Cognitive impairment Functional/ Behavioral changes = dementia Jack CR, et al. Lancet Neurol (2013) 12; 207. CSF = Cerebrospinal fluid FDG = Fluorodeoxyglucose MRI = Magnetic resonance imaging PET = Positron emission tomography p g
  29. 29. 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 ADNI Taiwan ADNI Korean ADNI AIBL (Australian ADNI) Argentinian ADNI Source: http://www.alz.org/research/funding/partnerships/ww-adni_overview.asp.
  30. 30. Biomarkers Used to Select Prodromal Subjects or to Demonstrate Disease Modification • Prodromal AD patient “diagnosis” in MCI 1 B i l id PET i i1. Brain amyloid PET imaging 2. Cerebrospinal fluid (CSF) tau protein / Aβ peptide 3 volumetric MRI – hippocampal volume3. volumetric MRI – hippocampal volume • Outcome measures Biomarkers as secondary & exploratory endpoints to support Disease Modification claimsDisease Modification claims 1. Hippocampal atrophy - volumetric MRI 2. Cerebrospinal fluid total-tau or P-tau 3. Brain amyloid PET imaging (treatment effect)
  31. 31. 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 2014 31
  32. 32. Challenges with Multi-Site Amyloid PET Workflow for Multicenter Clinical PET imaging study CyclotronCyclotron ((1818 F production)F production) Tracer SynthesisTracer Synthesis GMP FacilityGMP Facility SterileSterile ReadyReady--toto--injectinject Distribution to Medical ImagingDistribution to Medical Imaging Center (~ 4Center (~ 4 h from synthesis site)- ReadyReadytoto injectinject tracertracer Selection of Imaging centerSelection of Imaging center -- Camera QualificationCamera Qualification Data 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
  33. 33. Cerebrospinal Fluid Biomarkers of AD: Aβ42 and Tauβ Tau: Phospho-Tau: Plaques Tangles Aβ42 monomers: Tau/Aβ42 ratio: Aβ42 Tau1200 1000 1600 1400 1200 800 600 400 1000 800 600 400 pg/mL 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)
  34. 34. CSF Tau & Aβ42 Predict Progression From Mild Cognitive Impairment (MCI) to AD Mild Cognitive Impairment to AD Predicted by Tau/Aβ42 1 1.0 0.8 AD Normal CSF Pathological CSF 0.6 ressionto Pathological CSF Cut-off values for pathological CSF: T-tau > 350 ng/L Aβ42 < 530 ng/L P-tau181 > 60 ng/L 0.4 0.2 Noprog P tau181 > 60 ng/L Aβ42/P-tau181 ratio < 6.5 0 0 10 20 30 40 50 60 CSF = Cerebrospinal fluid 1. Hansson O et al. Lancet Neurol. (2006) 5(3); 228. Time (months)
  35. 35. Example of Receiver Operating Characteristic Curve for Tau/Aβ42 Assay in Cerebrospinal Fluid Alzheimer’s Disease (n=84) vs. Healthy Elderly (n=108) ivitySensiti 1‐ Specificity
  36. 36. 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
  37. 37. C-Path Institute - CAMD Project Pipeline
  38. 38. FDA Issues Letters of Support to AD Biomarkers 38
  39. 39. FDA Evidentiary Standards Initiative 39
  40. 40. 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
  41. 41. Biomarkers in Drug R&D…..? BiBio- marker Bio- marker Bio- marker Thank you for your attention!
  42. 42. For more information about theFor more information about the  marcus evans Pharma  S it iSummits series:  pharmaseries@marcusevanscy.com

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