Brain Science Institute

Translating Basic to

Clinical

Neuroscience Jeffrey D. Rothstein MD,

PhD

Director

BSi

BSi Mandate and Objectives

• Initiated in 2007 as a program to bridge Basic and Clinical

Neuroscience

• Solve fundamental questions about brain development and

function and to use these insights to understand the mechanisms

of brain disease

• Translate findings to usable practices and policies, therapies,

interventions and pharmaceutical solutions

• Aide in the translation of these basic science discoveries into small

molecule therapeutics, diagnostics and biomarkers

• Partner with Industry

• Develop interdisciplinary collaborations

Global view of BSi Programs 2013

Faculty-based BSi

The Power of Brain Science:

5 years of Accomplishments

• Collaboration: Initiated new and innovative partnerships

across all JHU

• Working Group Model: Integrated research efforts across

the broad field

• Institution-wide cores provides outstanding tools and

techniques to over 450 research scientists

• Novel interactions with industry for new therapeutic

targets

• Local and National Communications /Education

• BSi NeuroTranslational Program created a seamless

translation from basic neuroscience discoveries to new

therapies

BSi Funding and Metrics

• Every dollar invested to fund novel

research, resulted in > 2-3 fold return

of investment in NIH and foundation

grants

• >150 publications

• Many in the highest profile

neuroscience/science journals

• Fundamental new discoveries in

basic and clinical neuroscience as

well as approaches to patient-

oriented problems/diagnoses

• Held or participated in dozens of

conferences throughout the world

Total external funding as a

result of BSi “primed” research: >$100 mil

Cores

Perception/Cognition

Nerve Regen/Repair

Schizophrenia

Industry

SINImaging

NeuroTranslation

BSi Collaborators and Cores

Total collaborators and

Core Users of BSi

supported programs:

>400

BSi Distribution of Project

Investments:

No Barriers to collaboration

School of Medicine

University-wide

School of Medicine

Arts and Sciences

School of Engineering

School of Educa onSchool of Public Health

KKI

Anesthesiology

Biological ChemistryBiomedical EngineeringCell Biology

IGMMedicine

Molecular Biology

Neurology

NeuroscienceNeurosurgery

OphthalmologyOrthopedic Surgery

Otolaryngology

Pathology

PM&R

Physiology

Psychiatry

Radiology

BSi Accomplishments to Date

• Launched and funded interdisciplinary research programs (each $1.5-6 mil):

• Perception and Cognition

• Regeneration and Repair

• Schizophrenia

• Synapses, Circuits and Cognitive Disorders Program

• Traumatic Brain Injury

• Autism

• The NeuroTranslational Program ($25 mil)

• Brain Education

• Brain Night (monthly)

• Brain Talk radio

• NeuroInvestor

• Incubated successful high risk initiatives across the University:

• Neuro-Education Initiative

• Neuroesthetics

New or Ongoing BSi Working

Groups/Programs 2013

• Clinical/Basic Neuroscience

• Traumatic Brain Injury

• Blood Brain Barrier

• Autism

• Brain Activity Map

• Neuroesthetics-Brain Perception

• Music Cognition

• Music-Sound-Safety

• BSi NeuroInvestor

• Motor relearning- TBI/Stroke

BSi Neuroesthetic program

The Brain: Perception and Patient

Recovery • Multiple environmental factors

influence patient recovery/health in

the hospital

• Environment/room architecture

• Colors

• Smells

• Sound

Evaluating The Hospital Soundscape:

Sound/Noise in the Patient Room and

ICU

• High sound hinders recovery

• Peak noise reaches chainsaw level (80 db)

• ICU typical 67db; surgical wards 42 db

• Noise typically conversations, alarms, pagers, intercoms

• 42% patients woken by noise/sounds

• Leads to 1-2 hours less sleep!

• Noise/sound - can it influence patient safety???

Sound: Safety and Patient

Healing

• Peter Pronovost

• Director, Armstrong Institute of Patient Safety

• Susan Weiss

• Chair, Musicology, Peabody Conservatory

• James West

• Department of Electrical and Computer Engineering

• Inventor of the electret microphone

BSi Brain Education/Communications

• Brain Night Lectures

• teaches grad an undergrads

about careers in neuroscience

• All taped and available by Web

• Faculty/Student attendance:

175/lecture

• Brain Talk - Syndicated Radio

education

• Web based Community

• BSi Drug Discovery Consortium

• Major Symposiums

• Traumatic Brain Injury

• PET Imaging Scan Symposium

• Academic-Industry Collaboration

• Art and the Brain/Neuroesthetics

• Autism (2013)

Sources: 1J. DiMasi and H. Grabowski, "The Cost of Biopharmaceutical R&D: Is Biotech Different?," Managerial and

Decision Economics, 2007; J. DiMasi et al., “The Price of Innovation: New Estimates of Drug Development Costs,” Journal

of Health Economics, 2003.

Challenges for Brain Science: Cost of developing a new drug has greatly increased

Cost to Develop One New Drug1

Bil

lio

ns

(C

on

sta

nt

Do

lla

rs, Y

ea

r 2

00

0)

Source: 1Tufts Center for the Study of Drug Development, “New drugs entering clinical testing in top 10 firms jumped 52%

in 2003-05,” Impact Report, 2006.

Likelihood of Success for Brain/Spinal cord Investigational Drugs Is Terribly Small

Less than 15% of self-originated new neurological drugs that enter clinical testing will be approved1

Clinical Approval Success Rates by Therapeutic Class1

Failure of CNS drugs during clinical trial development

IDEAL ACTUAL

Trial Stage (Phase)

Musculoskeletal CNS Anti Infective

I2 30% 42% 46%

23 65% 69% 41%

3NDA 14% 50% 16%

Tufts CSDD Impact Report 11(4) July/Aug 2009

Pharma increasingly reluctant to invest in

early stage research, especially in risky areas

such as CNS

Biotech sector is struggling with limited

capitalization

Academia has tried to conduct Translational

Research themselves but has suffered from: • Lack of integrated staff and facilities dedicated to

drug discovery

• Lack of a drug discovery expertise

• Lack of team focus- departmentally divided

traditional academic structure challenges the

integrated, collaborative and synergistic demands of

drug discovery

Nature Clinical Practice Neurology (2006) 2, 59

CNS Drugs

Valley of Death

“Lost In Translation”- the need for academics to engage pharma in drug discovery

In 2010, BSi Initiated NeuroTranslation Drug

Discovery Program

Integrated staff of >25

with industry-experience: • Medicinal Chemistry

• Assay Development

• Animal Pharmacology/Tox

• Drug Metabolism /

Pharmacokinetics

• Academic appointments (not a

Hopkins biotech!)

Working collaboratively with

faculty to translate basic

science discoveries into

small molecule therapeutics

Partner with PHARMA or

spin-out new ventures

Assay

Development

Lead

Optimization

Candidate

SelectionScreening

Clinical

Development

Basic

Sciences

Translational

Research

Preclinical

Testing

Translational Gap

Drugs to

Patients

5-10 years3-6 yearsVariable

Drug Discovery and Development ProcessHistorically NIH

Funded but declining

Pharma

Investment

Drug

Repurposing

$500K $500K $1,000K $500K$500K

Prototype

Molecules

Faculty

Expertise

Faculty

Expertise

NeuroTranslational Drug Discovery Capabilities

Medicinal Chemistry Design, synthesis, purification, characterization, and scale-up of small molecules

HPLC, Mass Spec, NMR

Biochemistry / Assay Development High throughput screening assay development

Receptor pharmacology, Enzyme kinetics and mechanisms, Cell culture

Drug Metabolism and Pharmacokinetics Bioananalysis

Microsomal stability, Protein binding, Caco2, CYP screening, Rodent and primate PK

Animal Pharmacology/Toxicology Rodent non GLP toxicology

Models of peripheral neuropathy, pain, schizophrenia, multiple sclerosis, cognition

Business Development and Licensing Alliance management with PHARMA/Biotech

Liaison between Research Administration, Technology Transfer, and General Counsel

The Science + Technology Park at Hopkins

21

All drug discovery disciplines under one roof in new >15,000 sq ft facilities

Medicinal Chemistry

Biochemistry Assay Develop

Bioanalysis /ADME lab

Built Awareness of JHU’s Druggable Targets

Held individual meetings with >150 faculty interested

in brain sciences Anesthesiology, Biochemistry, Biology, Comparative Medicine, Immunology,

Medicine, Mind Brain Institute, Neurology, Neurosurgery, Neuroscience,

Neurosurgical Oncology, Ocular Molecular Biology, Oncology, Ophthalmology,

Pharmacology & Molecular Sciences, Psychiatry, Physiology, Radiology

Identified novel targets, models, disease expertise,

technologies

Built program for drugs discovery, disease

biomarkers, Imaging tools

Started 5 Integrated Drug Discovery Projects

• Schizophrenia o D-Amino Acid Oxidase (DAAO) Inhibitors

• (Psychiatry)

• Neurodegeneration o Glutaminase Inhibitors

• (Neurosurgery and Immunology)

• Pain o MrgX1 Agonists

• (Neuroscience)

• Peripheral Neuropathy /cognition o GCPII inhibitors

• (Neurology and Psychiatry)

• VALIDATED

• NOVEL

• SCREENING

PARADIGM

Additional Follow-up programs

• Glioblastoma o System XC transporter

• Macular Degeneration o Kinase inhibitor

• Demyelination/Neurodegeneration o MCT1 oligodendroglial transporter (activation)

• Lymphoma/Inflammation o MCT1 transporter (inhibition)

• Biomarker-Imaging: PET ligands o Synaptic density: EAAT2 (astroglial glutamate transporter)

• iPS program: ALS

BSi Individualized Brain Therapeutics

Platform:

Focussed strengths leading to targeted

interventions

Problems in CNS therapy development-

Need to optimize and individualize

• Neurological and psychiatric patients

are not all alike

• Sporadic- may be multiple

different gene mutations (e.g.

C9orf72 ALS vs dementia)

• Different familial forms

• Lessons from cancer therapy

• Target drugs to molecular subset

• Much greater likelihood of success

• Many (smart) Pharma have come to

realize this may be the best way to

make headway into therapies

Tools to optimize Drug Development/Biomarkers: PET- Based Synaptic reporters for neuronal function

• Dendritic simplification: – common pathology in

neurodegeneration

• Wide rang of neurological and

psychiatric disorders – Dementia (AD, FTD), spinocerebellar

ataxia, ALS, Huntington’s, Parkinsons, schizophrenia, autism

• Biomarkers for synapses/glia

– monitor synaptic density/glial biology

– reflecting improvement in neuronal biology following therapy

– Subtype section of patients

Dramatic Purkinje cell simplification in SCA5 Gao et al., J. Neurosci, 2011

PET Biomarkers: Astroglial/synaptic

biology imaging thru EAAT transporter

probe

•Loss of EAAT2 occurs in

~40% SALS

•Transporter changes occur at

disease onset (mice/rats)

•Increased CSF glutamate

~40% SALS (>400 pts)

•Transporter density may

reflect altered excitatory

transmission- in multiple

disorders (ALS, HD, AD,

epilepsy, glioma)

Contro

l

ALS

Tools for pathophysiology and drug discovery: Human iPS Stems Cells from ALS Skin

Oligodendrocytes

Neurons

Astrocytes

Patient specific iP stem cells

Astrocytes

• 40 ALS iPS lines: familial mutations

(C9orf72, SOD1, Ang, TDP43)

• 100 fibroblast lines (sALS)

• Others: Schizophrenia, Parkinsons,

SCA

BSi Training Programs in Drug/Translational Discovery

Graduate Student Courses /Post Doc Workshops Basics of Drug Discovery / Case Studies in Drug Discovery

Drug Discovery & Development / Pharma R&D

Local and International Conference World Health Summit with Carey Business School; Drug Discovery in Academia

Drug Discovery Training Program 15 post docs, undergrad, HS students

Entreprenuer’s “Boot Camp” / PHARMA Seminar Series Instructs faculty on biotech start-ups and industry partnerships

NIH R25 to teach NeuroTherapeutics

Development to academic Scientists UC Davis, Johns Hopkins, Harvard and NorthWestern

Academic-Pharma Partnerships

• Commercialization- a means to bring discoveries to patients

• Collaboration, Training, disease models: o Johnson & Johnson: Translational Post

Docs

o Biogen – Master agreements (MS, AD, ALS)

o Janssen

o Helsin

• Executed Licenses: o Pfizer, Merck, GSK, Genentech,

Galderma, Phospho Solutions, Sanofi Aventis

• Hosted companies for possible Bsi partnering: o Merck, Eli Lilly, Johnson & Johnson,

Biogen, Abbott, Millipore, Lundbeck, Glaxo, Pfizer, AstraZeneca, Sanofi, Novartis, Roche, Genzyme

• Drug Screening-Pharma Partnerships o JHU brings new target and assay

to Eisai

o Eisai screens their internal library on JHU target

o Hit compounds given to JHU for optimization

o Eisai first rights to JHU compounds

o True “WIN-WIN”

• Spun out new company Cerecor for schizophrenia target o raised $23M

National Academic Drug Discovery Consortium

• Establish a network of academic drug discovery scientists and programs from around U.S.

• Exchange know how and expertise - drug discovery programs, technologies, faculty engagement, industry partnerships, contractual arrangements

• Provide education and training for students and for universities interested in establishing centers

• Advocate/Advisory to NIH

• and other funding agencies

• Establish annual meeting

*Approx. 6 centers; Based upon Academic Drug Discovery Consortium (ADDC) Membership

Academic Drug Discovery Centers in 1990

Academic Drug Discovery Centers in 2002

*Approx. 17 centers; Based upon Academic Drug Discovery Consortium (ADDC) Membership

*Approx. 100 centers; Based upon Academic Drug Discovery Consortium (ADDC) Membership,

Molecular Libraries Program, and CTSA catalog

Academic Drug Discovery Centers in 2012

Now Live: ADDConsortium.org

Educational Materials Pharma Partnerships

Drug Discovery Jobs Drug Discovery Services

Drug Discovery Center Profiles

Your Genes, Your Neurons, Your Brain

Designing

Healthy solutions

for your brain

BSi

39

Developing Biomarkers: Integration with Drug Pipeline Development

Discovery Development Ready

Program Biomarker Plan

Biomarker Progress Review

Discovery Lead

Optimization

Preclinical programs

Phase 1 Phase 2 Phase 3

Drug Candidate

Discovery Development Ready

Validation Ready

Biomarker Progress Review

Biomarker Progress Review

Biomarker Progress Review Biomarker needed

in ….

Phase 1

Phase 2

Phase 3

Packard Center for ALS

Research:

Coupling Basic and Clinical

Research to Drive Therapy

for ALS