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Autism Spectrum Disorder (ASD) Outcome Measures and Potential Biomarkers
ISCTM Gahan Pandina | February 2016
Senior Director, Venture Leader | Clinical Associate Professor
Janssen Research & Development, LLC | Rutgers Robert Wood Johnson Medical School
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Agenda
Problems and novel solutions for patient selection in clinical trials for the treatment of autism spectrum disorder
Approaches to subtyping in ASD (phenotypic, genetic, biomarker/objective)
Symptomatic and genetic treatments
Challenges with potential of ASD biomarkers, DSM5, and RDOC
Autism … deficits in
• social communication & interaction and
• restricted, repetitive behaviors, interests or activities
Spectrum
1 in 68children diagnosed with ASD*
5xmore likely in boys*
Costs & burden of care over-whelming
$236Bn/yr**
No medicines approved for core symptoms, but novel targets exist…
consider…
Disorder
Examples
Impaired speech, non-verbals(eye contact)
Difficulty w/ social relationships
Repetitive behavior - (hand-flapping)
*Center for Disease Control and Prevention. Autism Spectrum Disorders; Data and Statistics. http://www.cdc.gov/ncbddd/autism/data.html. Accessed April 23, 2014.
*Mandell (2014) JAMA Pediatrics.
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… why not
?invest
rightaway
a tremendous UNMET NEED……and novel molecular targets exist
Current Model is TOO RISKY
There is no "autism doctor;" care is uncoordinated
ASD population is heterogeneous –who do we select for PoC studies?
Research tools are subjective & not sensitive to measuring change
https://gene.sfari.org/autdb/HG_Home.do
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ASD
Social / Communication
Deficits
Repetitive / Restricted Behaviors
Hyper-activity
In-attention
Self Injury
Sleep Deficits
Mood
Anxiety
Tantrums
Aggres-sion
Irritability
Intellectual Disability
GI Problems Seizures
Other Comorbidities
Anxiety
Stim behaviors
OCDGeneralized
Obsession Compulsion
Sensory Hyper/Hypo ReactivitySight, Smell, Taste, Touch,
Hearing
Need for Sameness/ Inflexibility
RRBs, Restricted Interests
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ASD
Social Communication,
Interaction
Restricted Repetitive Behaviors, Interests
Constipation/ Diarrhea
Restricted Diet
Irritability, Anxiety
Mood
SeizuresGrand Mal,
Tonic, Clonic, Absence, Myoclonic
Comorbidities
ADHD
GISleepIntellectual Disability
Psychiatric
Expressive ReceptiveRelation-
shipsNon-verbal
Comm
Reciprocity
Stereotyped Repetitive
Speech Social Behavior
How do we currently diagnose and measure outcome?
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Clinician interview
Screening measures abound– MCHAT
Gold standard measures for research– ADOS
– ADI-R
Diagnosis
Parent and clinician rating scales
Various uses– Broad ASD Symptoms (SRS-2,
SCQ, CARS, ABC…)
– ASD Domains (RBS-R, ABC)
– Comorbid symptoms (CASI)
– Functioning (VABS)
Outcome
Broad ASD phenotype = limited utility at extremes
Designed for alternate purpose
Limited change sensitivity, esp. in short-term (8-12 weeks)
Only a handful used in clinical drug trials
Complexity of ASD symptoms impacts parent measures
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What new approaches are being developed?
Optimization of symptom-based measures
– Validation in ASD clinical population
Development objective measures of “ASD”
– Correlate w/ existing measures, clinical outcomes
Incorporation of technology
– Benefitting from increased computing power, usability, and scalability
Goal is to develop tools that can be used to stratify populations and enhance early outcome detection
= new treatments in development
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Novel, objective measures in research
Adaptive rating scales
Mobile & web phenotyping tools
Neuroimaging & Cognition
#-omics (gene, prote, metabol) microbiome
Other Sensors
Eye-tracking, HR, speech,
video, actigraph, gaming…
DTI, MRI, MRS, fMRI,
fNIRS, MEG, EEG
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Novel, objective measures in research
Useful across a wide population• Age• IQ• Communication level/mode• Functional level• ASD severity (salience)
Function of objective measures considered for several purposes
• Stratify population• Be more sensitive• Measure change early -predict response
• Have face, content validity, reliability• Relate to clinical outcome
• Relate to drug/disease MOA
Adaptive rating scales
Mobile & web phenotyping tools
Neuroimaging & Cognition
#-omics (gene, prote, metabol) microbiome
Other Sensors
Eye-tracking, HR, speech,
video, actigraph, gaming…
DTI, MRI, MRS, fMRI,
fNIRS, MEG, EEG
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Novel, objective measures in research
In the lab… In the wild…vs.
Continuous Periodicvs.
• Translational – fit with animal model approaches?
• How combine with / potentiate behavioral therapies?
• Scalable for clinical trials?
Active / cued / task-based
Passive / ‘free range’ / open
vs.
Computer, tablet, phone or environmental challenge tasks
Ecological validity
Adaptive rating scales
Mobile & web phenotyping tools
Neuroimaging & Cognition
#-omics (gene, prote, metabol) microbiome
Other Sensors
Eye-tracking, HR, speech,
video, actigraph, gaming…
DTI, MRI, MRS, fMRI,
fNIRS, MEG, EEG
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What promise may these hold for developing new therapies?
Example – eye-tracking and social deficits
Example - EEG and biological motion
Example –JAKE system and adaptive data collection
Example – genomic data
Janssen IncubatorJanssen Research & Development, LLC Confidential
Activity A
Moving Toy MT
Dyadic Bid DB
Joint Attention JA
Chawarska Videos
Janssen IncubatorJanssen Research & Development, LLC Confidential
Campbell , 2014 Gaze Response to Dyadic bids related to outcomes at 3 years J Autism Dev Disord (2014) 44:431–442Chawarska, 2012 Context modulates attention to social scenes in toddlers with autismJournal of Child Psychology and Psychiatry 53:8 (2012), pp 903–913
• ASD will spend less time looking at faces • ASD will spend more time looking at HAI objects• Attention to the screen during Dyadic Bid will be reduced for ASD compared to TD
Chawarska Videos
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Preference for biological motion (social attention) in TD• Orientation of first gaze to biological motion in TD• Difference in mu waves between biological and non biological more prominent in TD
Shic, 2014 The effects of a novel vasopressin V1A antagonist on orienting to biological motion Poster presentation IMFAR 2014Bernier 2007 EEG Mu Rhythm and Imitation Impairments in Individuals with Autism Spectrum Disorder Brain Cogn 2007, Aug: 64(3): 228-237
Biological Motion
16
… why not
?invest
rightaway
a tremendous UNMET NEED……and novel molecular targets exist
Current Model is TOO RISKY
There is no "autism doctor;" care is uncoordinated
ASD population is heterogeneous –who do we select for PoC studies?
Research tools are subjective & not sensitive to measuring change
What Do We NEED?
A way to organize and access data easily across providers
Smarter data to inform PoCsubpopulation selection
New sensitive, objective endpoints
https://gene.sfari.org/autdb/HG_Home.do
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Continuous
and Periodic (task-based) Biosensors
• Med/development History• Daily tracker• Journal & events• Smart rating scales (ABI)• Adherence tracking• Notifications, reports• Integrate GCO, data mgmt
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1
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Smart research data warehouse & deep data
mining tools
Deep Autism Phenotyping via JAKE™ Portal
Smarter data to inform PoC subpopulation selection
New sensitive, objective endpoints
A way to organize and access data easily across providers123
A System of Tools & Technologies to Optimize Clinical Trials for ASD
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Other large-scale research efforts
• EU-AIMS
• ABC-CT
Objective measurement approach – match with diagnostic approaches?
DSM-V - disorder/syndrome?
RDOCs – tied to systems biology (closer?)
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Animal studies of genes related to ASD phenotypes
Kleijer et al. (2014). Neurobiology of autism gene products: towards pathogenesis and drug targets. Psychoparmacology. Online January 2014, DOI 10.1007/s00213-013-3403-3
ASD gene groups / pathways in the glutamatergic synapse
Protein families
Kleijer et al. (2014). Neurobiology of autism gene products: towards pathogenesis and drug targets. Psychoparmacology. Online January 2014, DOI 10.1007/s00213-013-3403-3
Nlgns, Nrxns, Cntns, Cntnap2
Shanks, PSD95
PTEN, Akt, Tsc1/2, mTor
mGluR, NMDA
FMRP/CYFIP, eIF4-complex
Associated Genes
Cell adhesion molecules
Scaffolding proteins
Signal transduction proteins
Receptors
Translational machinery
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