10/26/2015

1

Producing

Neurological

Therapies:

How we are

DoingWalter J. Koroshetz, M.D.

Director, National Institute of Neurological

Disorders and Stroke, NIH

July 20, 2015

1

The National Institute of Neurological

Disorders and Stroke (NINDS)

The mission of NINDS is to seek fundamental knowledge

about the brain and nervous system and to use that knowledge

to reduce the burden of neurological disease.

Strategies:• Invest across the full spectrum of basic, translational, and clinical

research

• Establish a data-driven process to identify unmet scientific opportunitiesand public health needs within and across neurological diseases

• Support research resources and technical advances that catalyze new discoveries

• Communicate and collaborate with the public and with others involved in biomedical research

• Train a robust and diverse neuroscience research workforce

• Adopt a culture of evaluation and continuous improvement across all NINDS programs

http://www.ninds.nih.gov/about_ninds/plans/NINDS_strategic_plan.htm

10/26/2015

2

Some Big Leaps Forward in Treating

Neurological Disorders

• Annual risk of stroke has dropped 70% since 1960’s and still going down each year.

• Multiple disease-modifying therapies for multiple sclerosis now available, even an oral medication.

• Reperfusion therapy for acute stroke transformed the country’s care of stroke patients.

• Wide variety of anti-seizure medications now available.

• Deep brain stimulation for Parkinson’s disease when medications no longer consistently beneficial.

• Abortive treatment for migraine.

• Gene replacement for some rare childhood disorders.

• Brain and spinal cord neuroimaging has revolutionized neurology and neurosurgery.

NIH Supported Medical Advances:

2014 Lasker-DeBakey Research Award

Alim Louis Benabid

Mahlon R. DeLong

– DeLong fellow at NIH IRP

– DeLong models basal ganglia movement circuits, (NIH IRP and extramural support)

– NIH IRP develops MPTP primate model

– DeLong targets STN to improve akinesia, rigidity, tremor in MPTP primate (NINDS, others)

– Benabid demonstrates DBS of thalamus reduces tremors in human patients

– As a result of DeLong’s paper, Benabid switches to DBS of STN with similar, dramatic results

– FDA approves DBS for PD (Neuroprosthesis Program data contributes)

NINDS/VA trial shows DBS superior to best medical therapy

1960s

1980s

1990s

2000s

1970s

Since 1974 DeLong has received > $25M from

NIH + Intramural support

Subthalamic Nucleus (STN)

Deep Brain Stimulation (DBS)

10/26/2015

3

Revolutionary Advance in Acute Stroke Therapy:

Intra-Arterial Revascularization

1993 NINDS tPA trial

2015 Endovascular trials

• NINDS IMS pilot trials

• NINDS IMS3 shows no

benefit of IA treatment

after IV tPA

• CTA + Perfusion imaging

• To select patients treated

with tPA, Solitaire stent

retrieval device shows

major benefit in five RCTs.

• NNT as low as 3 patients

Swift Prime, NEJM

The Challenge for the 21st Century

Brain disorders – both neurodevelopmental and

neurodegenerative – will be the most disabling

and most costly of the chronic diseases—they will

be in the 21st century what infectious diseases

were in the 20th century.

We do NOT know enough about how brain circuits function and how they dysfunction

to cause disability for persons with neuro/mental/substance abuse disorders.

10/26/2015

4

Total NINDS Extramural Grants Budget

0

0.2

0.4

0.6

0.8

1

1.2

1.4

1.6

19

95

19

96

19

97

19

98

19

99

20

00

20

01

20

02

20

03

20

04

20

05

20

06

20

07

20

08

20

09

20

10

20

11

20

12

20

13

20

14

NIN

DS

Ext

ram

ura

l Gra

nt

Do

llars

(in

Bill

ion

s)NINDS Extramural

adjusted to 1995

dollars

with ARRA

with ARRA--

adjusted to 1995

dollars

RCDC Reporting for Neuroscience & Cancer($$$ in millions)

$4.9

$5.6$5.5

$5.4

$0.0

$1.0

$2.0

$3.0

$4.0

$5.0

$6.0

$7.0

$8.0

$9.0

$10.0

2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014

Neurosciences

Cancer

RCDC Reporting beginning 2008

(Do

llars

in

Bill

ion

s)

10/26/2015

5

Neuroscience is attracting the best and brightest

http://report.nih.gov/NIHDatabook/Charts/Default.aspx?showm=Y&chartId=267&catId=21

NINDS Funding Trends

10/26/2015

6

History and Purpose

• Launched in 2004 to accelerate discoveries in

neuroscience

• Collaborative of 15 NIH Institutes, Centers and

Offices that support research on the nervous

system

• Pooled resources and expertise

• Cross-cutting research

• Confronts challenges too large for 1 Institute

• MOU under which it operates expires Sept

2016

Blueprint Grand Challenges

1) The Human Connectome Project

• Brain imaging + genetic + behavioral

data on 1,200 adults

2) Grand Challenge on Chronic

Neuropathic Pain

• Multi-investigator projects partnering

researchers in pain and neuroplasticity.

3) Blueprint Neurotherapeutics Network

• Provides research funding + access to

services and expertise to assist in

every step of the drug development

process

10/26/2015

7

NINDS Is Investing Across the Research Spectrum

FDA

Re-

view

Ph. IIIPh. II Ph. IBasic

Research

Disease-

focused

research

Target

ID

Assay

Dev.

High

Thru-

put

Screen

Pre-

Clinical

FDA

IND

NINDS Office of Translational Research (OTR)

Launches New Programs• Goal – advance promising therapies to hand off

to biotech/pharma companies– Innovation Grants to Nurture Initial Translational

Efforts (IGNITE)• Early-stage therapy development • Four separate opportunities from assay development to platform

technology development

– Blueprint Neurotherapeutics Network (BPN) for small molecules

• Development of small molecules• Provides investigators with access to consultants and contracts that

provide discovery, preclinical development, and clinical trial support

– Cooperative Research to Enable and Advance Translational Enterprises (CREATE) Bio and Devices

• Development of biologics (including proteins, peptides, nucleic acids, gene and cell therapies)

• Development of devices (including implants, stents, and prosthetics)

• These programs:– Are milestone driven

– Offer multiple entry points and seamless path of support across the therapy development pipeline

10/26/2015

8

StrokeNet:

Decreasing the Burden of Stroke

• Increase trial efficiency Decreases time to finish studies

• Balanced, prioritized set of early phase and phase 3 trials in prevention, treatment and recovery.

• Improved research man/woman power in stroke research.Provides stable funding for research effort, fellowship training

• Improved data sharing.Single data center with uniform governance for data access

• Stable infrastructure t

Enables improved team research among different subspecialties.

• Improved ability to work in public-private partnerships with non-profits, industry and international partners.

NeuroNEXT : Network for Excellence in

Neuroscience Clinical Trials

The NeuroNEXT program aims to:

• Provide a robust, standardized, and accessible infrastructure to conduct studies of treatments for neurological diseases

• Create and leverage partnerships with academia, private foundations, and industry

• Increase the efficiency of clinical trials

• Support scientifically sound, possibly biomarker-informed, exploratory clinical trials that provide data for clear go/no-go decisions

• Expand the pool of experienced clinical investigators and research staff

10/26/2015

9

The BRAIN InitiativeSM:

A Focus on Circuits and NetworksThe disability that patients with neuro/mental/substance

abuse disorders suffer is a direct result of disordered brain

circuits.

We need to be able to see the circuits in action to:• Determine how to therapeutically modulate brain activity

• Understand how the brain forms memories and how this changes in Alzheimer’s Disease

• Improve motor control in Parkinson’s Disease

• Target rehabilitation therapy to improve recovery after brain injury

Goal: do this with the precision of individual circuits and at

the speed of thought.

“The Next Great American Project”

“So there is this enormous mystery waiting to be unlocked, and

the BRAIN Initiative will change that by giving scientists the tools

they need to get a dynamic picture of the brain in action and

better understand how we think and how we learn and how we

remember. And that knowledge could be – will be –

transformative.”

~President Obama, April 2, 2013

10/26/2015

10

“New directions in science are launched by new tools

much more often than by new concepts. The effect of a

concept-driven revolution is to explain old things in new

ways. The effect of a tool-driven revolution is to discover

new things that have to be explained.”

Freeman Dyson (1997) Imagined Worlds

Harvard University Press, Cambridge, MA

Where Does Scientific Progress Come From?

Original axial CT image form Siretom

CT scanner circa 1975. Physicians

were fascinated by the ability to see

the brain and ventricles for the first

time.

1974 2012

7 Tesla MRI brain scan (NINDS)

The BRAIN InitiativeSM:

Imaging the Brain, What ‘s Next?

10/26/2015

11

• “Chemogenetics” - allows modulation of firing rates of specific neuronal groups induced to express an engineered receptor that is activated only by administering a drug (systemically).

• Used to improved social behavior in animal model of autism by increasing firing rate of oxytocin-producing neurons in hypothalamus

Courtesy of Brian Roth, UNC

The BRAIN InitiativeSM DREADD: Designer Receptors

Exclusively Activated by Designer Drugs

Next-Generation Invasive Devices for Recording and

Modulation in the Human Central Nervous System

• Pre-clinical and clinical testing of new devices for

invasive neuromodulation

• UH2/UH3 phased awards (separate UH3

announcement to allow direct-to-clinical projects)

• Necessary first studies that precede follow-on

investment from Industry/Venture Capital for final

system

10/26/2015

12

To map the circuits of the brain, measure the

fluctuating patterns of electrical and chemical

activity flowing within those circuits, and

understand how their interplay creates our

unique cognitive and behavioral capabilities.

The BRAIN InitiativeSM:

A Focus on Circuits and Networks

NOT-OD-15-103: Enhancing Reproducibility

through Rigor and Transparency

Four areas of clarification:

• Scientific premise

• Rigorous experimental

design

• Consideration of

relevant biological

variables, such as sex

• Authentication of Key

Biological and/or

Chemical Resources

10/26/2015

13

NINDS Bridging the Gaps

PhD

MD

Resident/

Fellow

Junior

Staff

Independent

Investigator

PhD and

MD/PhD

Fellowships

R25 and Stroke Net Training

K08/K 23

K02

RO1

Loan

Repaymen

t

NINDS R25:

Research support for residents and fellowsNeurology, Neurosurgery, Neuroradiology Neuropathology,

Neuroanasthesia and Emergency Medicine

● Institutional award started in 2009

● 25 institutional programs now funded

● Supports research by residents; these

residents can continue to receive support

into fellowship

● Over 81 residents supported so far

● 32 supported for 2 years

10/26/2015

14

NINDS K to R01 transition

For K’s terminating 2003-2011 (N =189 K08s, 110 K23s)

42% of all K08s got R01s

53% of all K08s that applied got R01s

40% of all K23s got R01s58% of all K23s that applied got R01s

For both K08s and K23s, ~75% have post-K independent funding

K08 and K23

• 5 years, 75% protected time (salary/fringe)

• $50,000 research costs

• Invited to 2 NINDS/ANA workshops over 5 years

• Goal is independent research career

• Can apply for R01 at any time

• Applicant success rate = ~55%

• Must be US citizen or permanent resident

• NINDS does not have a payline for K awards

10/26/2015

15

NINDS Clinician K-to-R Transition

Data Source: K awards terminating 2003-11

Number of Unique K23

Applications

Number of Unique K08

Applications

Are NINDS K Awardees Still Doing Research?

For K awards terminating 2003-2008

(N = 114 K08s, 65 K23s)

Currently in Academic Position

K08s: 86% K23s: 88%

Published between 2010-May 2012

K08s: 88% K23s: 85%

In Academic Position and Published

K08s: 95% K23s: 96%

10/26/2015

16

ESI/NI Benefit at NINDS

%tile funded

Established NI/ESI

2007 9 >25

2008 10 >25

2009 11 20 / 30

2010 13 20 / 30

2011 14 20 / 30

2012 15 Up to 25

2013 - 2015 14Up to 20-

25

10/26/2015

17

Underlying Issues• Poor training

• Poor evaluation

• Perverse reward incentives

Principles for Addressing these Issues

1. Raise community awareness

2. Enhance formal training

3. Improve the evaluation of applications

4. Protect the integrity of science by adoption of more systematic review processes

5. Increase stability for investigators

Enhancing Reproducibility and Transparency of Research Findings

Questions?

Walter J. Koroshetz, M.D.

Acting Director

National Institute of Neurological Disorders and Stroke

Email: koroshetzw@ninds.nih.gov

Website: http://www.ninds.nih.gov/

34

Follow me @NINDSdirector

Thank You!

10/26/2015

18

NINDS K Applications

# unique K08

Applications#

Ap

plic

atio

ns

# A

pp

lica

tio

ns

# unique K23

Applications