Transcript
Page 1: Working Group: Behavioral and Psychiatric Symptoms in … · BEHAVIORAL AND PSYCHIATRIC SYMPTOMS IN DEMENTIA 2/21/17, Washington DC Co-chairs Larry Ereshefsky David Miller ... AUTUMN

CONFIDENTIAL © 2014 PAREXEL INTERNATIONAL CORP.

WORKING GROUP:

BEHAVIORAL AND

PSYCHIATRIC SYMPTOMS

IN DEMENTIA

2/21/17, Washington DC

Co-chairs

Larry Ereshefsky

David Miller

Luca Pani

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BPSD WORKING GROUP PROPOSAL ABSTRACT

• Objectives: This working group is being convened to focus on the methodological challenges

facing the development of treatments for the Behavioral and Psychiatric Symptoms of Dementia

(BPSD). This group was in part stimulated by the EMA Alzheimer’s Disease Workshop.

• Convey critical importance of treating BPSD, i.e., Apathy as a means to improve patient QOL,

extend patient’s stay in their home environment; improve overall

• Review of lessons learned from ongoing and prior clinical trials for BPSD.

• Proposing innovative trials designs and regulatory acceptance;

• Managing intrinsic variability of symptoms;

– Evolving AD diagnostic and biomarker approaches

– Staging of illness and impact on symptoms, response, study design;

• Regulatory perspectives

• Workshop Deliverables and Action items/Steps to move the field forward

– Extend collaboration with ISTAART PIA; review activities of PIA and FRS for AAIC;

– Finalize program for 2017 Autumn meeting in Paris

– Consider establishing WG team to:

» look at challenges and lessons learned from past/current clin trials to treat BPSD; create

review article, road map, and/or report for presentation at ISCTM or other meetings

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AGENDA FOR WORKING GROUP ON BPSD

Introductions/Dinner

1. Collaboration between ISTAART, NPS PIA and ISCTM BPSD WG

Co-Chairs – Krista Lanctôt, Joanne Bell PIA

2. Discussion with drug sponsors providing insights Part I:

Agitation/Psychosis/BPSD

3. Discussion with drug sponsors providing insights Part II: Apathy

4. To assess the feasibility/desirability for ISCTM to support a consensus

group.

Identify opportunities and pathways for collaboration with the Biomarkers Consortium even

though the FNIH Endpoints Working Group was not funded

5. Neurocircuitry/Biomarker strategies

6. Action Items/Deliverables:

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RX OF EXISTING SYMPTOMS OR DELAYS/PREVENTION OF LIKELY TO OCCUR SYMPTOMS OF NPS

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AGENDA

• Collaboration between ISTAART, NPS PIA and ISCTM

BPSD WG

• Co-Chairs – Krista Lanctôt, Joanne Bell PIA

• Report on joint NPS PIA and BPSD ISCTM activities including featured

research symposium submitted February 1st to AAIC

• Other activities related to ongoing collaborations, including ISCTM

involvement in the PIA Day and ISTAART involvement in Paris ISCTM

meeting

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AAIC FRS SUBMITTED, LONDON, JULY 16-20, 2017

ADDRESSING THE CHALLENGES IN TREATING APATHY

ASSOCIATED WITH ALZHEIMER'S DISEASE

• Larry Ereshefsky and Krista

Lanctot, co-chairs

• Drug Development and Treatment

of Apathy, David Miller

• Apathy Neurocircuitry, Brain

Imaging Findings and

Implications, David Sultzer

• Examining the Neurocircuitry of

Apathy and Markers of

Neurodegeneration in Early

Alzheimer’s Disease, Gad Marshall

• Pathways Forward in Treating

Apathy: Regulatory Perspectives,

Karl Broich

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• Session 4: Addressing challenges in the drug development of

behavioral and psychological symptoms in dementia

• The constellation of symptoms/syndromes comprising BPSD (NPS) present

a challenge at all levels of health care, from unmet patient and caregiver

needs, to drug discovery, to clinical trials, as well as to regulatory pathways.

A review of the ‘lessons learned’ from recent efforts to develop drug

treatments for Agitation or Psychosis in neurodegenerative disorders will be

applied to enable methodological discussions on the development of

treatments for Apathy in Alzheimer’s Disease (AD). We will explore how

Apathy symptoms and potential biomarkers ‘evolve’ across the spectrum

from Mild Brain Impairment (MBI) to Mild Cognitive Impairment (MCI) to AD.

What are accepted diagnostic criteria for Apathy in AD and will disease

progression affect treatment targets and assessment tools? How should

pseudo-specificity be addressed in identifying and assessing apathy?

Differentiation from depression and relationship with changes in cognition

will be discussed. What are the challenges of conducting translational and

proof of concept work in patients with Apathy in MBI/MCI? The application of

neurocircuitry strategies and other biomarker approaches in early drug

development could de-risk POC. Regulatory considerations of approaches

and methodologies to improve the likelihood of meaningful signal detection

and acceptable registration trials will be discussed.

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BEHAVIORAL

AND

PSYCHIATRIC

SYMPTOMS IN

DEMENTIA

(BPSD): A

WAY

FORWARD?

ISCTM

AUTUMN

MEETING, LE

MERIDIEN,

PARIS,

SEPTEMBER

2ND 2017

0830 Background, brief overview of session’s purpose Larry Ereshefsky

Luca Pani

0840 Current drug development for the treatment of Agitation

Address Strengths/weaknesses and trial design considerations of current studies

-- add influence of non drug interventions??

Clive Ballard, King’s College

9:10 Lessons Learned Part II Agitation: Paul Rosenberg,

Johns Hopkins

0940 Discussant, Panel-Audience Discussion: Jill Rasmussen/

Joanne Bell,

1000 Break

1015 Why focus on apathy? David Miller, Bracket

1045 Neuro-circuitry and implications for drug development ; study designs for treatment of

Apathy

Krista Lanctot,

Sunnybrook Health

Sciences Centre,

Toronto

1115 Similarities/differences in the symptoms of apathy in Psychiatry (schizophrenia and

depresson), and in neurodegenerative disorders (Alzheimer’s and Parkinson’s Disease)

Pharma discussant on neurocircuitry strategies: Update on FNIH thinking to address

Apathy/Reward across various diagnostic categories (i.e., assessment tools,

differences in symptom presentation, biological/biomarker implications)

Larry Ereshefsky,

Follow the Molecule

Stephane Pollentier,

Boehringer Ingelheim

(tent)

1200 Regulatory View point(s) EMA confirmed…US view point (necessary?)

Identify a regulatory consultant to provide

Valentina Mantua

and Karl Broich,

EMA

Invite Alzheimer’s

Association, Maria

Carrillo, to comment,

lack funding to

support; would she

be attending ECNP

(to be asked by PIA)

1230-

1 PM

Discussant, Panel-Audience discussionAdjourn

Larry Ereshefsky/

Luca Pani plus

presenters

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STRATEGIES FOR FDA ENGAGEMENT AND

COMMENTARY IN PARIS SYMPOSIUM

• SC/EC suggested a few strategies:

– Pre-recorded comments from a key FDA Regulator on the path forward for Apathy

– Question/Answer interview, also pre-recorded with symposium leader, incorporating

content from the presentations (will require advance input from presenters)

– Less likely, more complex, ‘live’ videoconferencing. Session on Saturday, runs

afternoon to evening EST

– Available by phone to provide comments or Q/A

• Would also ask Valentina, Luca, and/or Karl to highlight in their comments that describe

areas of communication and engagement between EMA and FDA

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Drug development for Behavioral

Symptoms of Dementia:

Methodological Challenges and

Potential Solutions

CEDRIC O’GORMAN MD

THE BPSD WORKING GROUP

WASHINGTON D.C.

21 FEBRUARY 2017

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Background: The Need for BPSD

medicines

No approved treatments for BPSD

Lack of required studies to support efficacy of antipsychotics for BPSD or psychosis of dementia

Many negative and some positive registrational studies – what can we learn?

Non-approved use of existing antipsychotics (20-50%1) and other sedative medications have serious safety concerns (increased mortality, CVAs, drowsiness, falls, increased morbidity)

Class labelling for atypical antipsychotics (weight, type 2 diabetes, metabolic syndrome and hyperlipidemia)

BPSD are highly prevalent and a leading cause of institutionalization

Clinicians and regulators recognize the need for newer safer and effective treatments for BPSD

1. Feng, Z. et al. (2009) Use of physical restraints and antipsychotic

medications in nursing homes. Int J Geriatr Psychiatry 24: 1110–1118.

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Challenges in the development of

medicines for BPSD

Clinical Trial Design Considerations

Patient Population – Who? What? Where? (At home vs. In assisted-living; nursing homes etc)

Diagnosis

Symptom Eligibility: Duration, Severity and Frequency

Duration of treatment

Patient-reported outcomes

Role of the caregiver

Rating, Raters & Rater Training

Understanding how placebo response may differ in this setting

Trial design (traditional, adaptive, placebo-lead in, SPCD, Enrichment, Learn & Confirm, Arm-dropping)

Clinical Trial Collaborators (adjudication and monitoring)

Trajectory of response versus endpoint analysis

Role of non-pharmacologic intervention

Allowance of concomitant meds?

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Challenges in the development of

medicines for BPSD

Choosing an appropriate outcome measures: Primary & Secondary

A number of reliable and valid measures of agitation/aggression

Sensitivity of outcome measures to change over time

Qualitative versus Quantitative

Pseudo-specificity

Clinical Meaningfulness

Harm vs. Benefit – Composite Endpoint of Safety and Efficacy

The Role of Cognition, Functioning and Quality of Life

Regulatory Path

With no approved medicines for BPSD, the regulatory path is unclear

Special Considerations in an Elderly Population

Reduced burden of assessments on the patient

Concomitant Medications

Safety

Death

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Potential strategies to address

methodological challenges

Despite lack of approved therapies, much clinical data has been generated

How can we best utilize these existing data to inform future clinical design?

Great variability in criteria across studies

Industry Partner Collaboration

Both drug developers and regulators are keen to see drugs approved for BPSD

How can developers and regulators partner in the development of a consensus

statement/guidance document for BPSD clinical development?

Plans for White Paper and Consensus Statement

Participants from Industry, Regulatory authorities, Clinicians, Researchers,

Organizations

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2016 WG PRIOR COMMENTS: HOW DOES STAGE OF ILLNESS INTERACT WITH DRUG DEVELOPMENT STRATEGY AND APPROVAL?• NPSD has fluctuating course over illness• Symptom clusters, are these fixed and useful aggregations?

• i. Study duration• ii . Risk factors and selection of study population• iii. Challenges

• Measurement: Appropriate rating instruments for registration and approval• Influence of patient care environment, culture, and stage of illness on rating

scales validity/reliability• i. Sensitivity of scales

• ii. Use of broad and/or specific scales as primary outcome» Raised as an issue today at EC/SC

» Cohen-Mansfield Agitation acceptable to PMDA? » NPI» BEHAVE- AD

• iii. Assessments and Scales to assess WORSENING of cognition or function, i.e, MMSE, ADCS-ADL mentioned by PMDA; adequate?

• Regulatory questions• Future directions• i. Use of a neurocircuitry based approach modeled on valences and RDOC

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DISCUSSION POINTS: HOW TO MOVE FORWARD?• Does Pharma have interest, assets and resources to pursue novel

Rx’s of Apathy?– What is the state of the field?

– Lack of current ‘pharma’ sponsored studies for Rx of Apathy highlights the challenges facing us

– We believe there are substantial health care and patient outcome gains in Rx Apathy; yet this is a ’negative’ symptom as compared to agitation and psychosis that are ‘positive’ more ‘evident’ symptoms

• Rx of existing symptoms or delays/prevention of likely to occur symptoms

• Methodologies to address ‘pseudospecificity’ concerns

• Rating and evaluations assessment tools limitations

• Publications will be considered as an interim work product and will evolve to mesh with the publication plans of the PIA

• Develop position paper/roadmap that could lead to broadly supported Consensus Conference to meaningfully move drug development in this field further along

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Unknown † Evaluation of the Efficacy of Rasagiline in Apathy in Drug-

naïve Patients With Parkinson's Disease by a Multi-center

Study

Drug-naïve Patients With Parkinson's Disease; Apathy

Drug: AZILECT®; Drug: Placebo

Completed Bupropion for the Treatment of Apathy in Alzheimer's

Dementia

Apathy in Dementia

Drug: Elontril; Drug: placebo

Completed Rasagiline and Apathy in Parkinson's Disease

Parkinson's Disease Apathy

Drug: Rasagiline

Completed Apathy Associated With Alzheimer's Disease

Dementia; Alzheimer Disease, Apathy

Drug: Dextroamphetamine; Drug: Methylphenidate

Completed

Has ResultsTreatment of Apathy in Alzheimer's Disease With Modafinil

Apathy; Alzheimer's Disease,

Drug: Modafinil; Drug: Placebo

Active, not recruiting Transcranial Magnetic Stimulation for Apathy in Mild

Cognitive Impairment:Pilot Study

Apathy; Mild Cognitive Impairment

Device: Neurostar repetitive transcranial magnetic stimulator

Recruiting Repetitive Transcranial Magnetic Stimulation for Apathy in

Alzheimer's Dementia

Apathy; Alzheimer's Dementia

Device: Neurostar repetitive transcranial magnetic stimulator

Completed

Has ResultsMethylphenidate for Apathy in Alzheimer's Dementia: A

Controlled Study

Alzheimer's Disease; Apathy; Dementia

Drug: Methylphenidate; Other: Placebo

Recruiting Non Motors Aspects in De Novo Parkinson's Disease

Parkinson Disease; Apathy

Drug: Rotigotine; Drug: Placebo

Has ResultsTrial to Evaluate The Efficacy Of Rotigotine on Parkinson's

Disease-Associated Motor Symptoms And Apathy

Idiopathic Parkinson's Disease, Apathy

Drug: Rotigotine; Other: Placebo

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Completed Study of Rivastigmine to Treat Parkinsonian Apathy Without

Dementia

Parkinson's Disease; Apathy; no Dementia

Drug: rivastigmine; Drug: placebo

Terminated

Has Results

Exploring the Use of Transdermal Methylphenidate to Reduce

Fall Risk in Patients With Dementia.

Dementia; Accidental Falls; Apathy

Drug: Transdermal Methylphenidate

Recruiting Apathy in Dementia Methylphenidate Trial 2

Apathy; Alzheimer's Disease

Drug: Methylphenidate; Drug: Placebo

Unknown † Improving Function, Quality of Life, Glycemia in Diabetics With

Dementia

Diabetes Mellitus; Alzheimer's Disease; Apathy; Dementia

Drug: Methylphenidate; Drug: Placebo

Recruiting Efficacy of RIVAstigmine on Motor, Cognitive and Behavioural

Impairment in Progressive Supranuclear Palsy

Progressive Supranuclear Palsy (PSP), behavioral impair

Drug: Rivastigmine; Drug: Placebo

Unknown † Efficacy of Continuous Apomorphine Infusion on Cognitive and

Neuropsychological Functions in Parkinson's Disease

Parkinsons's Disease NPS

Drug: Continuous Apomorphine infusion; Drug: Usual dopaminergic

per os treatment

Completed Long-Term Effects of Amantadine in Parkinsonian (AMANDYSK)

Parkinson's Disease

Drug: mantadix

Completed D-serine Adjuvant Treatment for Parkinson's Disease

Parkinson's Disease

Drug: D-serine (~2g/day)

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Completed Serotonergic Function and Behavioural and Psychological

Symptoms of Frontotemporal Dementia

Frontotemporal Dementia, NPS

Drug: Citalopram

Completed

Has Results

"Pilot Study of Armodafinil in Patients With Dementia With Lewy

Bodies"

Dementia With Lewy Bodies, Attention deficits

Drug: Armodafinil

Completed Study of Methylphenidate to Treat Gait Disorders And Attention

Deficit In Parkinson's Disease (PARKGAIT-II)

Parkinson's Disease; Attention deficits, Gait Disorders; Dementia

Drug: methylphenidate; Drug: placebo

Terminated Multicenter Placebo Controlled Study to Assess the Effect of

Rasagiline on Sleep-wake Disturbances in Patients With Parkinson's

Disease

Parkinson's Disease Sleep disturbance

Drug: Rasagiline

Completed Rasagiline in Cognitive-impairment Related Depression: AzileCt in

COgnitive-impairment Related DepressiOn

Depressive Symptoms; Parkinson's Disease

Drug: Rasagiline; Drug: Placebo

Terminated Amantadine for the Treatment of Behavioral Disturbance in

Frontotemporal Dementia (FTD)

Dementia NPS

Drug: amantadine

Completed Efficacy Assessment of Three Non Pharmacological Therapies in

Alzheimer's Disease

Alzheimer's Disease

Behavioral: Standard intervention protocol; Behavioral: Standard

intervention protocol + Cognitive training therapy; Behavioral: Standard

intervention protocol + Reminiscence therapy; Behavioral: Standard

intervention protocol + "Made-to-measure" program

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Completed

Has Results

Aripiprazole in the Treatment of Patients With Psychosis Associated

With Dementia of Alzheimer's Type

Dementia, Alzheimer Type, psychosis

Drug: Aripiprazole (BMS-337039); Drug: Placebo

Completed

Has Results

Rotigotine Versus Placebo to Evaluate the Efficacy on Depressive

Symptoms in Idiopathic Parkinson's Disease Patients

Idiopathic Parkinson's Disease

Drug: Rotigotine; Drug: Placebo

Completed Study of Memantine for Gait Disorders And Attention Deficit In

Parkinson's Disease

Parkinson's Disease; Gait Disorders, Neurologic

Drug: memantine; Drug: placebo

Recruiting INfusion VErsus STimulation in Parkinson's Disease

Parkinson's Disease

Drug: Continuous intrajejunal infusion of levodopa-

carbidopa; Device: deep brain stimulation

Completed

Has Results

Tango for Treatment of Motor and Non-motor Manifestations in

Parkinson's Disease.

Parkinson's Disease

Other: Argentinean Tango classes; Other: Simple pamphlet about the exerci

se in PD

Recruiting Transcranial Direct Current Stimulation for Depression in

Alzheimer's Disease Patient - Preliminary Research

Alzheimer Disease; Depression

Device: Transcranial Direct Current Stimulation; Other: Sham Stimulation

Completed

Has Results

Rasagiline for the Symptomatic Treatment of Fatigue in Parkinson's

Disease

Parkinson's Disease, Fatigue

Drug: Rasagiline; Drug: Placebo

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AGENDA

5. Neurocircuitry/Biomarker strategies

• How do reward and hedonic pathways relate to apathy studies in AD?

• Discussion on role of MBI (mild behavioral impairment) in apathy,

neurocircuitry/biomarker studies, differentiation with depression?

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SUMMARY OF BRAIN FUNCTION AND BEHAVIOUR: ARE THESE

QUANTIFIABLE BY NEUROCIRCUITRY APPROACHES ACROSS

DEMENTIAS?

Ref: Rivard And Puxty BPSD Handbook for Family Physicians 2009

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Behavioral and Psychiatric Symptoms in Dementia WG ISCTM Feb 2017

S. Pollentier*

* = Full time employee of Boehringer Ingelheim

This presentation represents my individual opinion

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• Topics to be covered

– Clinical Endpoints Working group proposal for the

Biomarkers Consortium/FNIH

– ECNP Experimental Medicines Working Group

meeting March 15 Leiden/Netherlands

– IMI-initiative PRISM

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Co-chairs: Jenni Pacheco, PhD, NIMH;

Stephane Pollentier, MD, Boehringer Ingelheim

Clinical Endpoints Working Group: To identify a clinical

outcome measure for “anhedonia, amotivation“ appropriate for

use in late stage drug development (i.e. regulatory acceptable)

• Literature review 2015

• Workshop on behavioral measures around the positive

valence system – February 2016

• Project Concept Proposal November 1, 2016

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• Scale development is cumbersome

• Reluctant industry support

• Concerns of contruct validity

• Acceptance issues across CNS disorders

• Why repeat attempts which have failed?

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Parsing Anhedonia - Reward Processing(Der-Avakian, Trends in Neurosci, 2012)

Reward Deficits Animals Humans Circuits

ConsummatorySucrose intake/

preference

CPAS/CSAS

SHAPS

FCPCS

• NAc, ventral pallidum, OFC

AnticipatoryPositive/negative

contrastTEPS

• ACC, OFC, mPFC, basal

ganglia, thalamus,

hypothalamus

Motivational

Effort-based tasks (e.g.,

progressive ratio,

concurrent choice, ICSS)

EEfRT

• VTA to NAc

• Amygdala

• vmPFC to NAc

• ACC

• Lateral hypothalamus

Learning

Response Bias

Probabilistic Reward

Task

• Dorsal basal ganglia

(caudate)

• ACC

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RDoC - Positive Valence domainConstructs & Sub-constructs & Tasks

1. Reward Responsiveness

1.1. Initial Response to Reward Simple Guessing Task

1.2. Reward Anticipation Monetary Incentive Delay Task

1.3. Reward Satiation Fixed-ratio Satiation Schedule

2. Reward Learning

2.1. Habit Devaluation Task ; Habit Task

Habit Learning Task

2.2. Probabilistic & Reinforcement

Learning

Probabilistic Reward Task

Pavlovian Conditioning

Drifting double bandit

Probabilistic Stimulus Selection Task

2.3. Reward Prediction Error Rutledge Passive Lottery Task

Drifting double bandit

3. Reward Valuation

3.1. Reward (probability) Probability Choice Task

Willingness To Pay Task

3.2. Delay Delayed Discounting Task

3.3. Effort Effort Expenditure for Reward TaskNational Advisory Mental Health Council Workgroup on Tasks and Measures for RDoC , April 5-6, 2016

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Immediate wins of a pilot study proposal

• Establish standardization of manuals and methodology (task

parameters)

• Evaluate performance in multi-site setting

• Confirm use of measures across spectrum of CNS disorders

• Generate traction for inclusion in industry sponsored drug

development studies

• Lay foundation for further qualification process steps and

additional tools – and a next project aimed at validation

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Concept Proposal for a Pilot Study

• Indications / Target populations:

• indications that have an anhedonia component as a deficiency such as stable schizophrenia; early Parkinson‘s disease ; abstinent cocaine users ; …)

• N= 80 to 100 subjects

• Pragmatic selection of tests :

– Response Bias Probabilistic Reward Task

– Effort Expenditure for Rewards Task

• Multi-site setting: > 3 sites

• Estimated Budget= 0.5 Million tbc

Decision: proposal not considered in line with BC objectives (too close to „clinical endpoint“)

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ECNP Experimental Medicine Network Validation of Reward Processing tasks15th March 2017

Location: Leiden University Medical School.LUMC Building 2 (Research building), Einthovenweg 20NL-2333 ZC LEIDEN

(Approx 20 mins direct train journey from Schiphol, Amsterdam).

Information if interested: [email protected] Dawson ([email protected])

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10.30 1. Introduction and welcome

a. Overview of objectives for the meeting Gerry

Dawson

10.45 2. Review of reward processing

a. Overview of available tasks

b. Clinical experience with the PRT

c. An academic perspective on task validation

Diego

Pizzagalli

11.45 3. Why do we need validated reward processing task

for drug discovery

a. The need to validating tasks for use in clinical trials

b. Potential routes to validation?

c. Summary of US biomarker consortium discussions

Stephane

Pollentier

ECNP Experimental Medicine Network

Validation of Reward Processing tasks 15th March 2017

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ECNP Experimental Medicine Network

Validation of Reward Processing tasks 15th March 2017

1.00 4. Methodologies

a. IoP experience with reward

processing

b. Uni. of Manchester experience with

reward processing

c. Reward Processing and EEG

Mitul Mehta

Bill Deakin

Valerie Bertaina-Anglade

2.30 5. Perspectives from:

Roche

Lundbeck

Janssen

Heptares

TDB

Søren Rahn Christensen

Peter de Boer

Pradeep Nathan

3.30 6. Discussion & Next Steps

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http://prism-project.eu/en/prism-study/

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IMI-Project PRISM

Measured by Smart Phone App

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Effort-Expenditure for Reward Task

Plos One 2009;4(8)

Measure of Reward

Valuation

Choose hard or easy taskProbability of win: 12 – 50 – 88%

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Response Bias Probabilistic Reward Task

Measure of Reward Learning

40 of 100 trials inform on RewardBias toward Rich rewarded (30:10)

Discriminate 11.5 vs 13 mm

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NEUROCIRCUITRY/ BIOMARKER STRATEGIES

( S L I D E S N OT P R E S E N T E D D U E TO T I M E C O N S T R A I N T S )

Krista L. Lanctôt, PhDSenior Scientist, Sunnybrook Research Institute;Head, Neuropsychopharmacology;Professor of Psychiatry and Pharmacology, University of Toronto

ISCTM Workgroup Meeting, Washington, Feb 2017

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NEUROCIRCUITRY/ BIOMARKER STRATEGIES

How do reward and hedonic pathways relate to apathy studies in AD?

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QUESTIONS

Are the reward/anhedonia/social/apathy related evaluations discussed in many ways looking to the subdivisions of RDOC domains suitable for apathy in AD (and other neurodegenerative disorders)?

Neurocircuitry/Biomarker strategies

How do reward and hedonic pathways relate to apathy studies in AD?

Discussion on role of MBI (mild behavioural impairment) in apathy, neurocircuitry/biomarker studies, differentiation with depression

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APATHY IN AD IS LINKED TO SPECIFIC NEUROBIOLOGICAL FACTORS

Regional Cortical Atrophy

anterior cingulate, orbitofrontal

+/- Dorsolateral PFC, medial frontal, basal ganglia

White Matter Lesions

Frontal or diffuse white matter hyperintensities

Regional Hypometabolism

anterior cingulate, medial OF, (medial thalamus)

Regional Hypoperfusion

Anterior cingulate, mid OF, (DLPFC, Basal ganglia)

Cortical Receptors

Low DA transporter in putamen

Low ACh binding in L frontal cortex

Apathy Workgroup. NPS PIA. Lanctot et al

Alzheimer’s Dement 2017

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OPTIMIZING TREATMENT OF APATHY IN ALZHEIMER’S DISEASE

1. Neuroimaging

• SPECT shows patients with

apathy have alterations in

rCBF in crucial areas of the

brain reward system

Lanctôt et al 2007

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SPECT—SHOWS NONDEPRESSED AD PATIENTS WITH APATHY HAVE DIFFERENCES IN RCBF IN AREAS CRUCIAL TO DA BRAIN REWARD SYSTEM

0.000.100.200.300.400.500.600.700.800.901.00

rCBF R

atio

Apathetic n=23

Non-Apathetic n=28

Lanctôt et al 2007

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OPTIMIZING TREATMENT OF APATHY IN ALZHEIMER’S DISEASE

200

450

Baseline 60 min 120 min 180 min 240 min

AR

CI P

os

itiv

e E

ffe

cts

Co

mp

os

ite

Apathetic (n=13)

Non-Apathetic (n=7)

2. Pharmacologic challenge—

• In AD patients (n=20) apathetic

patients experience fewer

positive effects following D-

AMPH challenge Repeated

Measures ANOVA F1,17

=4.93,

p=0.04

• Suggests differences in the

DAergic systemLanctôt et al 2008

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OPTIMIZING TREATMENT OF APATHY IN ALZHEIMER’S DISEASE

3. Clinical trial

• Pilot data show apathy decreases

following methlyphenidate

• D-Amph challenge predicts response

Herrmann et al 2008

-20

-15

-10

-5

0

5

AES Total NPI Total MMSE

Methylphenidate Placebo

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APATHY IN DEMENTIA METHYLPHENIDATE TRIAL (ADMET)

Double blind, placebo-controlled, 6-week, 3-centre* RCT in 60 patients with AD

efficacy and safety of methylphenidate (20 mg/d) for clinically significant apathy in AD

Rosenberg, Lanctôt, et al 2013

Supported by the National Institute for Aging R01 AG033032-01

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PRIMARY OUTCOMES

0%

5%

10%

15%

20%

25%

methylphenidate placebo

% moderate or marked improvement on CGIC

o Odds ratio (95% CI) for improvement in CGI-C was 3.7 (1.3, 10.8) (p=0.02)

Rosenberg, Lanctôt et al J Clin Psychiatry 2013

Supported by the National Institute for Aging R01 AG033032-01

Mean (SD) 6-week change in AES scores was -1.9 (1.5) for methylphenidate and 0.6 (1.4) for placebo (p=0.23)

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SECONDARY OUTCOMES• NPI Apathy score

improvement 1.8 points (95% CI 0.3, 3.4) greater in methylphenidate vs. placebo (p=0.02)

-10

-5

0

5

10

15

baseline week 6 change

Mean (SE) NPI apathy score

methylphenidate placebo

• MMSE showed trend favouringmethylphenidate: estimated difference of 1.5 (95% C.I. -0.1, 3.1) (p=0.06)

-5

0

5

10

15

20

25

baseline week 6 change

Mean (SE) MMSE score

methylphenidate placebo

Rosenberg, Lanctôt et al J Clin Psychiatry 2013

Supported by the National Institute for Aging R01 AG033032-01

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MBI

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MBI-MILD BEHAVIOURAL IMPAIRMENT

MBI criteria, proposed by the International Society to Advance Alzheimer's Research and Treatment (ISTAART) (Ismail et al., 2016) changes in behavior or personality observed by the patient, informant, or

clinician starting in later life (age ≥50 years)

persisting at least intermittently for a minimum of 6 months (Ismail et al., 2016).

change from the person’s usual behavior or personality as evidenced by at least one of the following five domains: decreased motivation (i.e. apathy),

affective dysregulation,

impulse control,

social inappropriateness

abnormal perception or thought content

impairments in social, occupational, or interpersonal function must be attributable to NPS, and not to cognitive decline in MBI.

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APATHY AND MBI

39.2% of elderly subjects with MBI had apathy from a community based sample (Barcelos-Ferreira et al., 2015).

Taragano et al. demonstrated an apathy prevalence of 29.4% among geriatric outpatients (Taragano et al., 2009).

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MCI AND APATHY

neuroimaging studies reveal consistent abnormalities within regions responsible for motivation such as the anterior cingulate and frontal regions (Grambaite et al., 2011)

Apathy in MCI has also been associated with reduced fronto-parietal control network connectivity (Munro et al 2015)

lower inferior temporal cortical thickness (Guercio et al., 2015b)

significantly decreased metabolism in the posterior cingulate cortex (Delrieu et al., 2014)

greater amyloid burden (Marshall et al 2013)

Abnormalities in frontal regions (associated with impairments in planning and decision making) and anterior cingulate (related to emotional blunting and loss of motivation) consistently associated with apathy in AD and MCI. (Stella 2014)

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DIAGNOSTIC CRITERIA

core feature of apathy, diminished motivation, present x ≥4 weeks

2/3 dimensions of apathy (reduced goal-directed behaviour, goal-directed cognitive activity, and emotions) present

identifiable functional impairments attributable to apathy

exclusion criteria are specified to exclude symptoms and states that mimic apathy

Inter-rater reliability high (kappa 0.93, p=.0001)

Robert et al 2009, Mulin et al 2011

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54

AGENDA

6. Workshop Deliverables and Action items/Steps to move the

field forward

– Establish sub-groups that:

» Focus on lessons learned in seeking approval for Rx’s of Agitation and

Psychosis; develop a methodologies paper summarizing challenges and

strategies to address

» Work to develop a road-map (or white paper, publication) that forms the

basis of our efforts to further treatment of Apathy in dementia

– Extend collaboration with ISTAART PIA; review activities of PIA and FRS

for AAIC;

– Finalize program for 2017 Autumn meeting in Paris

– Consider establishing WG team to:

» look at challenges and lessons learned from past/current clin trials to

treat BPSD; create review article, white paper, and/or report for

presentation at ISCTM or other meetings

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Luca [email protected]

Italian Medicines Agency

European Medicines Agency

Comments

ISCTM Working GroupFebruary 2017, Washington DC


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