Post on 15-Mar-2020
CSF Biomarkers: Perspective
from Industry and Public/Private
Partnerships
William Z Potter, MD, PhD
Co-Chair Emeritus, FNIH BC Neuroscience
Steering Committee & Sr Advisor, OD, NIMH
RASAD, Melbourne, March 28, 2012
Biomarkers: The Essential Link
• Symptom Based Diagnoses of Brain Diseases – A Black Box
– Biomarkers are now accepted as a research tool for staging a disease process
– Quantitative issues come to the fore in multisite studies recruiting over time and using values to select patients (batch issue)
• Testing Hypotheses of Drug Action
– Biomarkers essential to demonstrate action of drug in CNS, the more precise the better
Biomarkers for Hypothesis Testing
• Definition for Drug Development:
– Biomarker = Any Measure of a Drug Action Proximal to a Clinical Effect
• Biochemical (PET, MRS & CSF* for CNS drugs)
• Physiological – EEG, FDG PET, fMRI, ASL, etc
• Behavioural (Responses to Tasks)
• Definition for CNS Disease State
– Biomarker = Quantifiable Measure in Brain Tissue* (including CSF) associated with Severity or Course of Clinical Symptoms
* Plasma and Urine can be Utilized when Established to Reflect CNS
What % of Mechanisms Tested?
Adis R & D Database: Compound Classes
that have at least Entered Phase I
• >75 Potential Antidepressant Targets
• 50 Antipsychotic Targets
• >150 Targets for Alzheimer’s Disease!!
– Only 8 have had associated Biomarker with
6/8 focused on Cognitive Symptoms
Potential & Known Targets for Alzheimer's Disease
• 3-beta hydroxysteroid dehydrogenase inhibitors
• Acetylcholine release stimulants
• Acetylcholinesterase inhibitors
• Adenosine A1 receptor modulators
• Adenosine A2 receptor modulators
• Adenosine triphosphatase stimulants
• Adenosylmethionine decarboxylase inhibitors
• Adenylate cyclase stimulants
• Adrenergic receptor agonists
• Advanced glycosylation end product inhibitors
• Alpha adrenergic receptor antagonists
– Alpha 1 adrenergic receptor antagonists
– Alpha 2 adrenergic receptor antagonists
• AMPA receptor agonists
• Amyloid inhibitors
– Amyloid beta-protein inhibitors
– Amyloid precursor protein secretase inhibitors
• Angiogenesis inhibitors
• Antioxidants
• Hypoxia-inducible factor-1 alpha inhibitors
• Apolipoprotein A I stimulants
• Apoptosis stimulants
• Benzodiazepine receptor inverse agonists
• Beta-secretase inhibitors
• Butyrylcholinesterase inhibitors
• Calcium channel agonists
• Cannabinoid receptor agonists
• Carnitine acetyltransferase stimulants
Source: Adis R&D Insights Database
Alzheimer's Disease (cont.)
• CB1 cannabinoid receptor antagonists
• CCR5 receptor antagonists
• Cdc2 kinase inhibitors
• Cell differentiation stimulants
• Cell membrane permeability enhancers
• Cell-replacements
• Central nervous system stimulants
• Chelating agents
• Chloride channel agonists
• Cholinergic receptor modulators
– Muscarinic receptor agonists
Muscarinic M1 receptor agonists
Muscarinic M4 receptor agonists
– Muscarinic receptor antagonists
Muscarinic M2 receptor antagonists
Muscarinic M3 receptor antagonists
• Cholinergic receptor modulators (cont.)
– Nicotinic receptor modulators
Alpha4-beta2-nicotinic-receptor-modulators
Alpha4 beta2 nicotinic receptor agonist
Alpha7 nicotinic acetylcholine receptor
modulators
Alpha7 nicotinic acetylcholine receptor
agonists
• Corticotropin-releasing hormone stimulants
• Cyclo-oxygenase 2 inhibitors
• Cytokine modulators
– Cytokine inhibitors
– Cytokine synthesis inhibitors
• DNA topoisomerase II inhibitors
• DNA-directed RNA polymerase stimulants
Source: Adis R&D Insights Database
Alzheimer's Disease (cont.)
• Dopamine receptor agonists
– Dopamine D1 receptor agonists
– Dopamine D2 receptor agonists
• Dopamine D2 receptor antagonists
• Dopamine uptake inhibitors
• Estrogen receptor modulators
– Estrogen receptor agonists
– Estrogen receptor antagonists
• Fibroblast growth factor stimulants
• Free radical scavengers
• Nitric oxide synthase type II inhibitors
• G protein-coupled receptor modulators
• GABA modulators
– GABA A receptor agonists
GABA A alpha 2 receptor agonists
GABA A alpha 3 receptor agonists
– GABA B receptor antagonists
GABA-A receptor antagonists
• Gamma secretase modulators
– Gamma-secretase inhibitors
• Glial cell line-derived neurotrophic factor agonists
• Glucocorticoid receptor antagonists
• Glucose stimulants
• Glutamate agonists
• Glutamate receptor antagonists
• Glutamate release antagonists
• Glycine agonists
• Glycine NMDA-associated agonists
• Glycine reuptake inhibitors
• Glycogen synthase kinase 3 inhibitors
• Gonadotropin releasing hormone agonists
• Gonadotropin releasing hormone antagonists
• Growth hormone releasing factor agonists
• Histamine H3 receptor antagonists
• HMG-CoA reductase inhibitors
Source: Adis R&D Insights Database
Alzheimer's Disease (cont.)
• Immunomodulators
• Immunophilin modulators
• Immunostimulants
• Immunosuppressants
• Insulin-like growth factor I agonists
• Intercellular signalling peptide and protein stimulants
• Interleukin 2 stimulants
• Lipid peroxidation inhibitors
• L-lactate dehydrogenase stimulants
• Melatonin MT1 receptor agonists
• Melatonin MT2 receptor agonists
• Membrane transport protein inhibitors
• Microtubule protein inhibitors
• Microtubule-associated protein modulators
• Mitochondrial protein stimulants
• Mitochondrial-permeability-transition-pore-modulators
• Mitogen-activated protein kinase inhibitors
• Mitosis inhibitors
• Mixed-lineage kinase inhibitors
• Monoamine oxidase inhibitors
– Monoamine oxidase B inhibitors
• Monoamine uptake inhibitors
• Nerve growth factor stimulants
• Neuropeptide stimulants
• Neurotransmitter modulators
– Neurotransmitter stimulants
• NF-kappa B inhibitors
• Nitric oxide donors
• Nitric oxide synthase type II inhibitors
• NMDA receptor agonists
• NMDA receptor antagonists
• Notch signalling pathway inhibitors
• Opioid receptor agonists
• Ornithine decarboxylase inhibitors
Source: Adis R&D Insights Database
Alzheimer's Disease (cont.)
• Oxidoreductase stimulants
• Peptide stimulants
• Peroxisome proliferator-activated receptor agonists
– Peroxisome proliferator-activated receptor gamma
agonists
• Phospholipase A2 inhibitors
• Phosphoric diester hydrolase inhibitors
• Plasminogen activator inhibitor-1 antagonists
• Platelet activating factor inhibitors
• Platelet activating factor stimulants
• Platelet aggregation antagonists
• Potassium channel antagonists
• Progesterone receptor antagonists
• Prolyl endopeptidase inhibitors
• Prostaglandin endoperoxide synthase inhibitors
• Prostaglandin synthase inhibitors
• Protein synthesis stimulants
• Reactive oxygen species stimulants
• RNA synthesis inhibitors
• Selective estrogen receptor modulators
• Serotonin modulators
– Serotonin 1A receptor agonists
– Serotonin receptor antagonists
Serotonin 1A receptor antagonists
Serotonin 2 receptor antagonists
Serotonin 2A receptor antagonists
Serotonin 3 receptor antagonists
Serotonin 4 receptor antagonists
Serotonin 6 receptor antagonists
– Serotonin uptake inhibitors
• Sigma-1 receptor agonists
• Signal transduction pathway inhibitors
• Sodium channel antagonists
• Somatotropin receptor antagonists
• Spermidine/spermine N1-acetyltransferase stimulants
Source: Adis R&D Insights Database
Alzheimer's Disease (cont.)
• STAT transcription factor inhibitors
• Survivin protein inhibitors
• Synuclein inhibitors
• Tau protein inhibitors
• Tubulin polymerisation promoters
• Testosterone congener stimulants
• Thromboxane A2 synthase inhibitors
• Thyrotropin releasing hormone agonists
• Transcription factor inhibitors
– Transcription factor AP-1 inhibitors
• Tubulin inhibitors
• Tumour necrosis factor inhibitors
• Tumour necrosis factor production inhibitors
• Type 4 cyclic nucleotide phosphodiesterase inhibitors
• Vesicular monoamine transporter 2 inhibitors
• Virus replication inhibitors
Source: Adis R&D Insights Database
Lumbar Puncture
• Excellent Safety Record
• Acceptance for Alz Studies;
Required for ADNI 2
Collaborative
• Critical to Evaluate Drugs
Targeted to Abeta and Tau
• Go/No Go Decisions
possible in Volunteers for
Gamma Secretase and
BACE Inhibitors
Time (hr)
-24 -12 0 12 24 36 48 60 72
A40 (
pM
)
0
300
600
900
1200
Vehicle, n=8
L'988 0.3 mpk, n=6
L'988 1.0 mpk, n=6
L'988 3.0 mpk, n=6
L'988 10.0 mpk, n=4
Baseline samples taken at -20, -1 & 0 hr predosecrossover design** p<0.05 vs. Vehicle, 0.3 mpk & 1 mpk* p<0.05 vs. Vehicle & 0.3 mpkstatistics shown for 24 hr only
Validation of Conscious CMP Rhesus Monkey Model
-Secretase Inhibitor, L-000897988, Dose Response
PO Dose
**
**
*
GSI: CSF Sampling from Cisterna Magna Ported (CMP)
Conscious Rhesus Monkeys – 3 mg/kg = red plot
Time (hr)
-24 -12 0 12 24 36 48 60 72
A40 (
pM
)
0
300
600
900
1200
Vehicle, n=8
L'988 0.3 mpk, n=6
L'988 1.0 mpk, n=6
L'988 3.0 mpk, n=6
L'988 10.0 mpk, n=4
Baseline samples taken at -20, -1 & 0 hr predosecrossover design** p<0.05 vs. Vehicle, 0.3 mpk & 1 mpk* p<0.05 vs. Vehicle & 0.3 mpkstatistics shown for 24 hr only
Validation of Conscious CMP Rhesus Monkey Model
-Secretase Inhibitor, L-000897988, Dose Response
PO Dose
**
**
*
GSI: CSF Sampling from Cisterna Magna Ported (CMP)
Conscious Rhesus Monkeys & Limited Effects in HVs* at MFD*
Maximum Effect in HVs at MFD*
*HVs = Healthy Volunteers; MFD = Max Feasible Dose
No Go
Lessons Learned with CSF Abeta?
• The Lilly Secretase Inhibitor produced
<10% decrease in Abeta – might have
argued against taking it forward into patients
• Field now looking for safe BACE Inhibitors
that produce 75% Decreases –e.g. Merck
• Little evidence of clear effects with antibody
approaches – to be seen whether useful
clinical effects achieved without taking into
account whether relevant analytes in CSF
are consistently affected
Biomarkers of Disease State
• Industry Perspective on Issues Facing AD
Drug Development when Focus on
Slowing or Preventing
• Role of Private Partner Scientific Board
(PPSB), formerly Industry Scientific
Advisory Board (ISAB)
15
Original Industry Strategic
Advisory Board Goals: ADNI PROTEOMICS SUBTEAM
Taken from Holly D. Soares
March 30, 2009
Neuroscience Steering Committee Meeting
Proteomics
Metabonomics
AD Biomarkers Drug Development
• No Validated Biomarkers that Correlate with Cognitive
Decline (e.g. Disease Progression Markers).
– Could provide additional evidence supporting drug efficacy.
– Disease progression markers that change in response to treatment are
tools to monitor treatment response and compliance.
• No VALIDATED diagnostic test for AD
• Goal: Ideally Blood but CSF if Necessary
– Fluid biomarker performance to be compared to brain imaging
– Go beyond Pre-Specified ADNI Analytes (e.g. Abeta)
PPSB Summary of Biochemical Results
Alzheimer’s & Dementia 6 (2010) 230–238
Update on the biomarker core of the Alzheimer’s
Disease Neuroimaging Initiative subjects
John Q. Trojanowski,*, Hugo Vandeerstichele, Magdalena Korecka,
Christopher M. Clark, Paul S. Aisen, Ronald C. Petersen, Kaj
Blennow, Holly Soares, Adam Simon, Piotr Lewczuk, Robert
Dean, Eric Siemers, William Z. Potter, Michael W. Weiner,
Clifford R. Jack, Jr.,William Jagust, Arthur W. Toga, Virginia M.-Y.
Lee, Leslie M. Shaw; and the Alzheimer’sDisease Neuroimaging
Initiative
18
PPSB CSF A1-42 concentration distribution in
ADNI MCI subjects at BASELINE visit
40 60 80 100 120 140 160 180 200 220 240 260 280 3000
20
40
60
A1-42 concentration (pg/mL)
nu
mb
er
192 pg/mL*
*cutoff concentration from earlier patient with post-mortem confirmation study
Proteomics
Metabonomics
Plasma and CSF Studies
• Plasma: Targeted Multiplex Proteomic Strategies to Identify Biomarkers in Alzheimer’s Disease To qualify a multiplex immunoassay panel as a tool to diagnose and
monitor disease progression in the ADNI one-year plasma samples. - Approved Budget $430,500.00
• CSF: Targeted Multiplex Proteomic Strategies to Identify CSF-Based Biomarkrees in Alzheimer’s disease Specific Aim 1: To qualify a 151 analyte multiplex immunoassay panel
as a tool to diagnose and monitor disease progression in the ADNI cohort using baseline and one year cerebral spinal fluid (CSF).
Specific Aim 2: To examine BACE levels and enzymatic activity in CSF in the ADNI baseline and one year CSF samples.
Specific Aim 3: To qualify a 30 analyte mass spectroscopy MRM panel as a tool to diagnose and monitor disease progression in the ADNI cohort using baseline and one year CSF samples.
RBM CSF Peptide Findings
• Elevated FABP, PPP, Nt-BNP & VEGF in
AD vs HC - replicates previous reports
• Novel : Cancer 19-9 & CD40 Antigens
• Plasma/CSF Correlation Surprises: – 5 values from 0.89-0.64 - leptin, C-Reactive Protein,
apolipoprotein(a), immunoglobulin A, chemokine CC-4
and pancreatic polypeptide(PPP)
– Adjusted for age, gender and APOE status all of which
had large impact on many peptide values in CSF and
plasma
0.5 1 1.5
plasma value
1.5
2
2.5
csf
valu
e
0 1 2
plasma value
-1.5
-1
-0.5
csf
valu
e
-1.6 -1.4 -1.2
plasma value
-0.6
-0.4
-0.2
0
csf
valu
e
2 3
plasma value
1
1.5
2
csf
valu
e
Association Between Plasma and CSF Measurements
ADNI data from RBM
Interleukin-8 (IL-8) (pg/mL)Interleukin-8 (IL-8) (pg/mL) Leptin (ng/mL)Leptin (ng/mL)
Macrophage Colony-Stimulating Factor 1 ( (ng/mL)Macrophage Colony-Stimulating Factor 1 ( (ng/mL) Macrophage Inflammatory Protein-1 beta ( (pg/mL)Macrophage Inflammatory Protein-1 beta ( (pg/mL)
Analyte (unit)
Baseline Diagnosis:
AD
Control
MCI
Issues Emerging from RBM Data
• Core CSF analytes Informative but:
– Are values batch assay dependent even with
“standardized” kits?
– How much variation around cut-off points if
new batch run every day, week, month?
– Impact on any multivariate combos and
apparent association with disease state
• Are plasma/CSF correlations reproducible?
– Contribution of batch effect to correlations
Evolution of Translational Omics:
Lessons Learned and the Path Forward*
• “…Due to the increased risk of overfitting large data sets
in the development of the computational model, the need
for rigor, validation, and accountability is even higher
than for other single biomarker-based tests.”
• Premature applications included “the series of genomics-
based predictive tests used in clinical trials at Duke
University; the commercial tests OncotypeDx,
MammaPrint, Ova1, AlloMap Testing, CorusCAD and
the Tissue of Origin Test…”
• Formal recommendations have emerged
*Christine M. Micheel, Sharly J. Nass, and Gilbert S. Omenn, Editors; Committee on the
Review of Omics-Based Tests for Predicting Patient Outcomes in Clinical Trials; Board
on Health Care Services; Board on Health Sciences Policy; Institute of Medicine
25
Gaps and What’s Next?
• Scientific:
– Lack of biomarkers correlating with disease progression in AD
– Lack of robust biomarker distinctions between likely subtypes of AD
– Lack of knowledge on when any difference first detectable in ultimate
AD subject vs healthy control
• Methodologic:
– Robust standardized measures of single CSF analytes
– Role of multiplex approaches: what is reasonable number of analytes to
include in an assay to achieve same level of performance as with single
targeted measure?
– Will very specific peptide forms, only identifiable with mass spect,
prove crucially informative?
• What are Most Important Next Investments for CSF?
Integration of Efforts?
IRMM, IFCC, JPND, EMEA,
AIBL, J-ADNI…
Discovery & IVD
Companies
US ADNI, FNIH, FDA, CPI/CAMD
AA?
4/23/2012 Confidential Soares Draft 27
Members of Proteomic Work Groups
Holly Soares, - BMS
Peter Alfinito - BMS
Sophie Allauzen – Novartis
Neil Buckholtz - NIA
Patricia Cole – Eisai
Bob Dean - Lilly
Ashok Dongre – BMS
Mats Ferm – AstraZeneca
Dan Holder – Merck
Fred Immerman – Pfizer
David Shera – Merck Statistics
Walter Koroshetz – NINDS/NIH
Brad Navia – J&J
Max Kuhn – Pfizer Statistics
Eve Pickering – Pfizer Statistics
James McNulty – Nat. alliance Mental Illness
Susanne Ostrowitski – Roche
William Potter – FNIH
Jeff Seeburger – Merck
Les Shaw – UPenn
Eric Siemers – Lilly
John Trojanowski – UPenn
Marc Walton – FDA
Hong Wan - Wyeth
Tony Wyss-Coray – Stanford
Alison Drone – FNIH
Judy Siuciak – FNIH
Adam Simon – Independent Contributor
Panos Zagouras – Pfizer Systems Bio
Biomarkers in Brain Disease:
Challenges and Opportunities 3-5 February 2013 The Møller Centre, Cambridge, UK
Scientific organisers
Giovanni Frisoni IRCCS Fatebenefratelli, Italy
Andreas Jeromin Banyan Biomarkers, USA
Andy Lockhart GlaxoSmithKline, UK
William Potter formerly Merck, USA
Full details at: www.wellcome.ac.uk/conferences
Scientific Conferences