translational considerations in drug development · translational considerations in drug...

11
Translational Considerations in Drug Development Sarah Hollingsworth “Holly” Lisanby, MD Director, Translational Research Division, National Institute of Mental Health Director, Noninvasive Neuromodulation Unit, Experimental Therapeutics and Pathophysiology Branch, NIMH NIH BRAIN Initiative Team B: Neural Recording and Modulation Technologies

Upload: others

Post on 18-Oct-2020

8 views

Category:

Documents


0 download

TRANSCRIPT

Page 1: Translational Considerations in Drug Development · Translational Considerations in Drug Development Sarah Hollingsworth “Holly” Lisanby, MD Director, Translational Research Division,

Translational Considerations in

Drug Development

Sarah Hollingsworth “Holly” Lisanby, MDDirector, Translational Research Division, National Institute of Mental Health

Director, Noninvasive Neuromodulation Unit, Experimental Therapeutics and

Pathophysiology Branch, NIMH

NIH BRAIN Initiative Team B: Neural Recording and Modulation Technologies

Page 2: Translational Considerations in Drug Development · Translational Considerations in Drug Development Sarah Hollingsworth “Holly” Lisanby, MD Director, Translational Research Division,

• The views expressed are my own and do not necessarily

reflect the views of the NIH, DHHS, or the US Federal

Government

• Patent on TMS technology, not licensed, no royalties

• Equipment loan from Magstim Company

• Past (>4 yrs ago) grant support from St Jude/Abbott,

Neuronetics, Neosync, Cyberonics, Brainsway

Disclosures

Page 3: Translational Considerations in Drug Development · Translational Considerations in Drug Development Sarah Hollingsworth “Holly” Lisanby, MD Director, Translational Research Division,

Challenges in Drug Development

• Heterogeneity

– Within diagnoses

– Comorbidities across diagnoses

• Need ways to select and stratify patients going into trials

Page 4: Translational Considerations in Drug Development · Translational Considerations in Drug Development Sarah Hollingsworth “Holly” Lisanby, MD Director, Translational Research Division,

Vision for Precision Psychiatry

Genetic risk, physiology, behavior

Integrated data Data-driven clusters

Source: Zhi-De Deng, modified from Insel and Cuthbert. Science. 2015; 348: 499

Page 5: Translational Considerations in Drug Development · Translational Considerations in Drug Development Sarah Hollingsworth “Holly” Lisanby, MD Director, Translational Research Division,

Objectively quantifiable domains of

function, studied across levels of analysis

from genes to behaviors

Research Domain Criteria (RDoC)

Trans-Diagnostic Research

Framework

Key Deliverables

• Biotypes to characterize

heterogeneity & stratify

samples

• Mechanisms across units

of analysis

• Putative therapeutic

targets

• Quantify target

engagement

Example:• Targeting Anhedonia

transdiagnostically via

FAST-FAIL

Vision for Precision Psychiatry

Page 6: Translational Considerations in Drug Development · Translational Considerations in Drug Development Sarah Hollingsworth “Holly” Lisanby, MD Director, Translational Research Division,

FAST-FAIL Approach

Develop biomarker reflecting activity of drug at the

neurobiological target

YES

Proceed to study with

clinical endpoint

NO

Fail the drug (in an

informative way)

Use biomarker to select dose that engages target

Phase IIa proof of mechanism study with change in

brain activity as primary outcome

Does engaging the target achieve predicted

effect on brain activity?

Page 7: Translational Considerations in Drug Development · Translational Considerations in Drug Development Sarah Hollingsworth “Holly” Lisanby, MD Director, Translational Research Division,

Phase IIa proof of mechanism study with change in

brain activity as primary outcomePhase IIa POM study: inc ventral striatum activation

during reward anticipation primary outcome

FAST-FAIL Approach

Nature Reviews: Drug

Discovery 2019; 18:82

Develop biomarker reflecting activity of drug at the

neurobiological target

YES

Proceed to study with

clinical endpoint

NO

Fail the drug (in an

informative way)

Use biomarker to select dose that engages target

• Transdiagnostic sample (mood or

anxiety disorder) and Snaith score≥20)

Does engaging the target achieve predicted

effect on brain activity?

Biomarker: Kappa opioid receptor – PET ligand

Selected dose with robust KOR antagonism

Page 8: Translational Considerations in Drug Development · Translational Considerations in Drug Development Sarah Hollingsworth “Holly” Lisanby, MD Director, Translational Research Division,

FAST-FAIL Results

Develop biomarker reflecting activity of drug at the

neurobiological target

YES

Proceed to study with

clinical endpoint

NO

Fail the drug (in an

informative way)

Use biomarker to select dose that engages target

Phase IIa POM study: inc ventral striatum activation

during reward anticipation primary outcome

• Met go-criterion on primary outcome:

inc fMRI ventral striatum activation

during reward anticipation

Does engaging the target achieve predicted

effect on brain activity?

Biomarker: Kappa opioid receptor – PET ligand

Selected dose with robust KOR antagonism

Nature Medicine, In Press

Page 9: Translational Considerations in Drug Development · Translational Considerations in Drug Development Sarah Hollingsworth “Holly” Lisanby, MD Director, Translational Research Division,

FAST-FAIL Results

Develop biomarker reflecting activity of drug at the

neurobiological target

YES

Proceed to study with

clinical endpoint

NO

Fail the drug (in an

informative way)

Use biomarker to select dose that engages target

Phase IIa POM study: inc ventral striatum activation

during reward anticipation primary outcome

• Met go-criterion on primary outcome:

inc fMRI ventral striatum activation

during reward anticipation

• Proof of mechanism – engaging target

impacted brain circuitry implicated in

hedonic response in expected

direction

• Supports proceeding with assessment

of clinical impact of target

engagement

Does engaging the target achieve predicted

effect on brain activity?

Biomarker: Kappa opioid receptor – PET ligand

Selected dose with robust KOR antagonism

Nature Medicine, In Press

Page 10: Translational Considerations in Drug Development · Translational Considerations in Drug Development Sarah Hollingsworth “Holly” Lisanby, MD Director, Translational Research Division,

First in Human

Exploratory experimental therapeutics

Confirmatory Efficacy Effectiveness

NIMH Clinical Trials Pipeline

First in human & early stage

clinical trials of novel

drugs/devices U01

Early stage testing of

drug/device R61/33

Development of

psychosocial &

preventative

intervention R61/33

Confirmatory

efficacy trials of non-

drug intervention

R01

Pilot effectiveness of treatment,

prevention, & services

interventions R34

Clinical trials testing effectiveness

of treatment, prevention & services

interventions R01

Page 11: Translational Considerations in Drug Development · Translational Considerations in Drug Development Sarah Hollingsworth “Holly” Lisanby, MD Director, Translational Research Division,