leveraging partnerships: inside nih and outside · brown university tivorsan pharmaceuticals, inc....

Story Landis, PhD Director, National Institute of

Neurological Disorders and Stroke National Institutes of Health

Leveraging Partnerships: Inside NIH and outside

26th annual Voluntary Health Leadership Conference February 14, 2013

“Science in pursuit of fundamental knowledge about the nature and behavior of living systems and the application of that knowledge to extend healthy life and reduce the burdens of illness and disability.”

...

NIH: Steward of Medical and Behavioral Research for the Nation

NIH: Improving the Health of the Nation

• Reduction in deaths from:

• Heart disease

• Stroke

• HIV/AIDS

• Increased survival rates for:

• Breast cancer

• Cervical cancer

• Colon cancer

Life expectancy gains worth ~$3.2 trillion annually

Cardiovascular disease death rates have fallen > 60%

in the last half-century

HIV therapies enable people in their 20s to live to age 70+

66

68

70

72

74

76

78

80

Cancer death rates now falling ~1% per year; each 1% drop

saves ~$500 billion

Mission: To catalyze the generation of innovative

methods and technologies that will enhance the

development, testing, and implementation of diagnostics

and therapeutics across a wide range of human diseases

and conditions.

Catalyzing Collaborations Within NIH

NEI

NCI NHLBI NIAID

NIDCR

NIDDK NIAMS

NIDA

CIT

NIEHS

NIMH

NINDS

NCATS

NCCAM

NIMHD

NIDCD

NIGMS NINR

NIAAA

NICHD

NLM

CC

OD

NIA

NHGRI

FIC

NIBIB

CSR

NCATS

Biotech

FDA

Academia

Pharma Non-

Profits

Advocacy Groups

Complements ― does not compete ― with the work of others

Revolutionizes the process of translation by promoting innovation

Galvanizes and supports new partnerships

Supports and augments regulatory science and its application

Enhances precompetitive space

Drug Rescue and Repurposing

Constriction Point: Lengthy, complex process for gaining access to compounds

Innovative Approach: Match pharma compounds with NIH scientists’ ideas for new uses

Partners: Scientists, Big pharma

Tissue Chip for Drug Screening

Constriction Point: Low concordance between animal & human toxicity

Innovative Approach: Develop chips mimicking human physiology for better prediction of drug safety and efficacy

Partners: Scientists, FDA, DARPA

CROWDSOURCING: Matches researchers with compounds in an effort to find new uses for patients

Creation of template agreements to streamline negotiations between researchers and pharmaceutical companies

58 compounds from 8 companies: Abbott

AstraZeneca

Bristol-Myers Squibb Company

Eli Lilly and Company

GlaxoSmithKline

Janssen Pharmaceutical Research & Development, L.L.C.

Pfizer Inc.

Sanofi

# o

f P

re -

Applic

ations

Individual compounds

ADNI Public-Private Partnership Structure

FDA

NIBIB, NINDS, NIMH and other ICs

PI: Mike Weiner Administrative Core: UCSF

Biostatistics Core:

UCD: Beckett

Biomarkers Core:

UPenn: Trojanowski/ Shaw

MRI Core:

Mayo: Jack

Clinical Core:

UCSD: Aisen

Mayo: Petersen

PET Core:

Berkeley:

Jagust

Informatics Core:

UCLA: Toga

Publications Core:

Harvard: Green

Pathology Core:

WashU: Morris

57 Clinical Sites: ADNI PIs and Cores

ADNI Executive Steering Committee

Private/Philanthropic

+

Public

Genetics Core:

Indiana: Saykin

Standardization: imaging, biomarkers Neuroscience: relationships among biomarker

trajectories elucidate neurobiology Earlier diagnosis: Identify presymptomatic AD Trials: new understanding of biomarkers has

facilitated interventional studies in very early AD Data sharing: real-time public data sharing Collaboration: academia, industry, non-profits,

regulatory agencies world-wide ADNI1 04-10: 60M from NIA and 40M from

industry and other partners ADNI2 10-16: Similar investments

Biglycan as a Duchenne Muscular Dystrophy Therapeutic

A Public – Private Partnership to Move Innovation into Care

Public Funding

Private Funding

1996 99 00 01 02 03 04 05 06 07 08 09 10 11 12 98 97

ACS MDA

NINDS RO1

PPMD

NINDS R21 NINDS U01

Charley’s Fund/Nash-Avery Foundation

PPMD

Private Investors

PPMD

Brown University Tivorsan Pharmaceuticals, Inc.

Tivorsan Launch

MDA

March 2012

American Cancer Society

National Institutes of Health Parent Project Muscular Dystrophy

ACS MDA

NIH PPMD

Muscular Dystrophy Association

Source: Tivorsan Pharmaceuticals, Inc.

Funding Recipient

Funding Source

QTDP

QTDP IRS Qualifying Therapeutic Discovery Project grant

The NINDS Cooperative Agreement Program

for Translation

• Projects must have a therapeutic lead with in vivo proof-of-concept efficacy data

• OR in vivo models that include a pharmacodynamic biomarker for the intended therapeutic using clinical route of administration

• Device projects must have a clinically meaningful outcome based on clinician and patient input

• Milestone driven

• Activities include: • Preclinical efficacy testing

• Predictive ADME (absorption, distribution, metabolism, and excretion)

• Toxicology testing

• IND/IDE submission

• Phase 0 clinical trials

13

Translational Projects Reaching IND and Beyond

Principal

Investigator

Institution Disorder Therapeutic

Approach

Project End

Date

Clinical

Trial

Ralph Snodgrass Vistagen

Therapeutics, Inc.

Epilepsy /

Neuropathic

Pain

Drug 2008 Phase I

Howard Federoff Georgetown

University Medical

Center

Parkinson’s Nucleic Acid

Therapy

2009 Phase I

Xiao Xiao University of

North Carolina

Duchene

Muscular

Dystrophy

Nucleic Acid

Therapy

2009 Phase I

Cesario Borlongan University of

South Florida

Stroke Cell Therapy 2009 Phase II

Ronald Crystal Weill Medical

College – Cornell

University

Batten Disease Nucleic Acid

Therapy

2010 Phase I/II

Guohua Xi University of

Michigan

Stroke Drug 2012 Phase II

14

Blueprint Neurotherapeutics Project:

Combining strengths of NIH and industry

NIH investigator-initiated ideas

• Novel drug targets

• Strong disease assays and models

Industry expertise

• Advisors with extensive pharma experience

• Industry-standard contract services

“Virtual Pharma” Model

Bioactivity/

Efficacy

Studies

Medicinal

Chemistry

AMRI

PK/Tox

Southern, SRI

Phase I

Clinical

Trials

Lead Development Team

Principal Investigator

Industry-seasoned consultants

NIH staff

Data

Management

CDD

U01s

Formulation

GMP

Scale-Up

Synthesis

NIH Contracts

in development

16

Milestones Used to Fund Most Promising Projects

Pre-clinical efficacy testing

Exploratory Studies

Optimization Chemistry

First-in-human studies

1-2 new drug

candidates

licensed

14 projects

Milestone-Gated

Advancement Pre-clinical safety testing

17

11 Projects Initiated (Jan. 2013)

Principal Investigator Institution Disorder

Mark Gurney Tetra Discovery Partners Mild Cognitive Impairment

Paul Humphries Reset Therapeutics Narcolepsy

Michael Lark Trevena, Inc. Depression

Konstantin Petrukhin Columbia University Macular Degeneration

Edwin Rubel University of Washington Hearing Loss

Susan Slaugenhaupt Mass. General Hospital Familial Dysautonomia

D. James Surmeier Northwestern University Parkinson’s

Steven Wagner UC San Diego Alzheimer’s

John Bixby University of Miami Optic Neuropathy

Raymond Dingledine Emory University Stroke

Marcie Glicksman Brigham and Women’s Hospital ALS

3 projects proposed to launch in early 2013 Discontinued

18

Why is it so hard to do clinical trials?

Success rate too low because preclinical data flawed, targets not identified and/or no evidence for engagement

Take too long to set up and recruitment is slow

Cost too much

Failure can lead to abandonment of disease areas

Mutant SOD1 mice and rats accurately

recapitulate clinical, pathological and

pharmacological profiles of sporadic ALS

SOD1G93A transgenic mice

Treatment started at 5 weeks of age

i.p. 10mg/kg/day

Nature 2002

Small number of animals

Not randomized or blinded

Effect could have been due to chance

Enhanced survival of SOD1 transgenic mice with minocycline

led to a Phase III clinical trial for ALS patients

Trial initiated 2003, completed

2007.

412 patients treated for 9 months

Randomized placebo controlled

Patients treated with minocycline

failed more rapidly than those on

placebo

“In the past five years we have screened

more than 70 drugs in 18000 mice

across 221 studies, using rigorous and

appropriate statistical methodologies.

While we were able to measure a

significant difference in survival between

males and females with great sensitivity,

we observed no statistically significant

positive (or negative) effects for any of

the 70 compounds tested, including

several previously reported as

efficacious. “

Amyotroph Lateral Scler 2008; 9: 4-15

ALS Therapy Development Institute (ALS TDI)

“….We retested several compounds

reported in major animal studies

(minocycline, creatine, celecoxib, sodium

phenylbutyrate, ceftriaxone, WHI-P131,

thalidomide, and riluzole) …and found no

survival benefit in the SOD1(G93A)

mouse for any compounds (including

riluzole) administered by their previously

reported routes and doses.

……………the majority of published

effects are most likely measurements of

noise in the distribution of survival

means as opposed to actual drug effect.“

Improving the Quality of NINDS-Supported Preclinical and Clinical Research

through Rigorous Study Design and Transparent Reporting

Notice Number: NOT-NS-11-023

Release Date: August 10, 2011

Issued by: National Institute of Neurological Disorders and Stroke (NINDS)

Purpose:

…..NINDS believes that applications that propose

preclinical research, or that are based on previous

preclinical data, will be greatly strengthened if the design,

execution, and interpretation of the proposed studies and

supporting data are adequately described. NINDS

encourages investigators, whenever possible, to address

these elements directly in their applications.

Actions taken by NINDS

Experimental design:

Rationale for the selected models and endpoints (animal and/or cellular)

Adequacy of the controls

Route & timing of intervention delivery / dosing

Justification of sample size, including power calculation

Statistical methods used in analysis and interpretation of results

Minimizing bias:

Methods of blinding (allocation concealment and blinded assessment of outcome)

Strategies for randomization and/or stratification

Reporting of data missing due to attrition or exclusion

Reporting of all results (negative and positive)

Results:

Independent validation/replication, if available

Robustness and reproducibility of the observed results

Dose-response results

Verification that interventional drug or biologic reached and engaged the target

Interpretation of results:

Alternative interpretations of the experimental data

Relevant literature in support or in disagreement with the results

Discussion of effect size in relation to potential clinical impact

Potential conflicts of interest

http://www.ninds.nih.gov/funding/transparency_in_reporting_guidance.pdf

Guidance on the NINDS website

Why is it so hard to do clinical trials?

Success rate too low because preclinical data flawed, targets not identified and/or no evidence for engagement

Take too long to set up and recruitment is slow

Cost too much

Failure can lead to abandonment of disease areas

NeuroNEXT goals and key features

• Test promising therapeutics in Phase 2 clinical trials

• Accelerate drug development through an established clinical trials infrastructure that will decrease time/cost between trial design and completion

• Utilize a central IRB

• Use standardized master trial agreements in site subcontracts

• Coordinate public/private sector efforts

• Maximize industry participation in development of novel therapeutics

• Build on strengths of the NCATS CTSAs (21 of 25 sites)

Census region: West Midwest South Northeast

NeuroNEXT Coordinating Centers and Clinical Sites

NeuroNEXT & CTSA

NeuroNEXT

NeuroNEXT CCC

NeuroNEXT DCC

DCC University of Iowa CCC

Harvard University

NeuroNEXT progress report

• Funded 9/30/2011

• The first project in NeuroNEXT is development of biomarkers for SMA

• 54 days from final protocol to patient

• Second project, treatment of secondary progressive MS with ibudilast, PDE(4) inhibitor, just approved

• Two other projects pending

• Cyclodextrin for NPC with Phase 1 underway at NIH

• Hereditary Inclusion body myopathy with Phase 1 underway at NIH

U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES

National Institutes of Health

National Institute of Neurological Disorders and Stroke




31

Common Data Elements (CDE) Project

•There are no widely used data standards in NINDS funded clinical research

• Identify common data elements (CDEs) used in clinical research and develop definitions

•Standardize case report forms and provide standard format so that clinical data are systematically collected across research community

•Facilitate data sharing and meta-analyses







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“General” Common Data

Elements

TBI

PD

Epilepsy

HD

Stroke

SCI

MS

CDEs available for use

are found at: http://www.commondataelements.

ninds.nih.gov/

Available for use

In development

Current Project Status

Headache

FA ALS

NMD

SMA, DMD, MG

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

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

NIH Appropriation vs. Appropriation in 1998 Dollars

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Grant Success Rates - FY 1978-2013

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leveraging partnerships: inside nih and outside · brown university tivorsan pharmaceuticals, inc....

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