1. Funding Opportunities for Inborn Errors of Metabolism March 31, 2016
Jill Morris PhD
Program Director

2. Today's Goals Introduction to NIH Funding at NINDS
NINDS Translational Research Program
Clinical Trial Readiness for Rare Neurological and Neuromuscular Diseases
2016 NINDS Nonprofit Forum
Questions

3. National Institutes of Health
NIH’s mission is to seek fundamental knowledge about the nature and behavior of living systems and the application of that knowledge to enhance health, lengthen life, and reduce the burdens of illness and disability.

4. Comments on the NIH Budget
NIH is part of a much larger federal government agency (DHHS).
Congress “oversees” all federal agencies. (And sets their budgets!)
NIH is NOT immune to political pressures.
NIH employees (and other federal employees) are forbidden from lobbying congress for any given area of research.
NIH Budget: in Fiscal Year 2016 is around billion

5. NIH is a BIG “place” NIH has 27 Institutes & Centers with:
Different missions & priorities
3-5 letter abbreviations; NINDS, NCI, NIDDK
Different budgets
Different ways of doing things (e.g. deciding which grants to fund).
Total NIH budget was more than $20 B in FY01
There were approximately 40K applications
IC’s are thematically organized around disorders (e.g. cancer, diabetes, stroke); organ system (heart/lung/blood, eye, musculoskeletal); or service function (NCRR, CSR, CIT)
Different Strategic Plans
Different Subcultures

6. NIH Office of the Director
National Institutes of Neurological Disorders and Stroke
25 other Institutes and Centers
Center for Scientific Review

7. National Institutes of Neurological Disorders and Stroke
Extramural Research
Intramural Research
Training
Etc.

8. Intramural Vs. Extramural
NIH is divided into INTRAMURAL and EXTRAMURAL components
Intramural:
comparable to an academic medical center and Research Institution
Does its “own” research, has investigators testing hypotheses, laboratories, clinical trials (at the clinical center)
Extramural:
Where I work
Manages grants and contracts
“Administration” of grants across the country/globally which are funded by NIH

9. Who’s who- Extramural NIH Staff?
Program Staff (PD) - PhD or MD
assist applicants, develop initiatives, review progress reports, approve funding
Review Staff (SRO) – PhD or MD
organizes review of applications (study sections), write summary statements
Grants management (GMB) –
accounting, administrative
send out the checks
Assures compliance with regulations of grants, receipt of documents
Contracts Branch
Works with Program to Manage Contracts

11. NIH Funding Mechanisms
Investigator Initiated Awards
NINDS Program Project Awards
Exploratory/Developmental Awards
Training Awards
NINDS Clinical Trial Mechanisms
NINDS Translational Program Awards
Small Business Awards
Basic Science and Early Translation Mechanisms
Translational Research Mechanisms
Clinical Research Mechanisms
Developmental and HyperActive Ras Tumor (DHART) SPORE

12. NINDS Translational Programs
Clinical Trials

13. Translational Funding Opportunities
Discovery
Preclinical Development
Small Clinical Trials
Anticonvulsant Screening Program (ASP)
Early Translation - IGNITE
Biotechnology Products and Biologics - CREATE Bio
Devices - CREATE Device
Small Business Program: SBIR & STTR
Small Molecules – Blue Print Neurotherapeutics (BPN)
Countermeasures Against Chemical Threats (CounterACT)
IGNITE: Innovation Grants to Nurture Initial Translational Efforts
CREATE: Cooperative Research to Enable and Advance Translational Enterprises 13

14. Preclinical Development
The Office of Translational Research
Discovery
Preclinical Development
Small Clinical Trials
“Discovery”
Assay development
Proof of concept in vitro and/or in vivo
Lead optimization and candidate selection
Pre-clinical Development
Toxicology studies
Scalable process development (gram to kg)
Good Manufacturing Practice (GMP) drug manufacture
“Small” Trial
Only as part of certain programs with associated pre-clinical components

15. Innovation Grants to Nurture Initial Translational Efforts (IGNITE)
Allows Investigative Teams to meet the entry criteria for the CREATE or Blue Print Neurotherapeutics (BPN) Program
Upon completion of IGNITE the Investigative Team will have:
appropriate Pharmacodynamic markers/models (RFA-NS )
a well-validated Assay (PAR ):
Well-characterized early-stage Agents suitable for Optimization (PAR )
Early phase requires many parts to be built and fixed…
Mechanism to allow science evaluation “Translational readiness”
IGNITE Website: 15

16. Innovation Grants to Nurture Initial Translational Efforts (IGNITE)
RFA-NS Development and Validation of Model Systems and/or Pharmacodynamic Markers to Facilitate the Discovery of Neurotherapeutics (R21/R33)
Entry Criteria:
Translational rationale for the proposed model system/or pharmacodynamics marker and evidence of value for drug development
End Goal:
Improved animal models, human tissue ex vivo systems, or endpoints for translational efforts
Mary Ann Pelleymounter

17. Two Phases in Each Grant
IGNITE RFA
(Models and Markers)
Two Phases in Each Grant
Planning/Development Phase
R21
 Meet Milestones
Execution Phase
R33
R21
R33
Budget per year
< $0.25M DC/year
Duration
No more than 2 years (three total)
Budget total (R21/R33)
0.75M for Entire 3 Year Period

18. Entry Criteria: R21 phase R33 phase End Goal: IGNITE PAR-15-070
(Assays and Agents)
PAR Innovation Grants to Nurture Initial Translational Efforts (IGNITE): Assay Development and Therapeutic Agent Identification and Characterization to Support Therapeutic Discovery (R21/R33)
Entry Criteria:
Rationally selected assay(s) and therapeutic agents
R21 phase
Initial development, refinement, and validation of assays
R33 phase
Iterative screening of potential therapeutic agents, further preparation and characterization
Characterization of promising therapeutic agents from the screen
End Goal:
Testing funnel to triage candidates, a battery of assays and starting agents that are well profiled
Examples of activities for R21
Development of assay(s) to support a succinct testing funnel, to measure specificity, potency, stability to protease and/or other metabolic enzymes, and cellular uptake.
A combination of assays may be developed to demonstrate relevant biological activity when a single assay may not provide adequate measurement of overall potency due to a complex mechanism Development of in vitro or ex vivo potency/efficacy assay designed to indicate the specific ability of an agent to achieve a desired biological effect, for example: structural changes that may impact product quality, stability, and efficacy.
Development of assays to evaluate cellular uptake, engagement, infection, aggregation, downstream functional measures in vitro or ex vivo, purity, and specificity. Assays to measure DNA, RNA, and protein levels of either endogenous genes or delivered products, downstream in vitro or ex vivo functional read-outs, viral titer, viral particle load stability and specificity.
Development of assays to evaluate purity and identity of the therapeutic by surface markers or specific proteins, morphological measures, differentiation, purity, functional measures vitro or ex vivo, stability, and immunogenicity 18

19. (Pharmcodynamics, Efficacy)
IGNITE PAR
(Pharmcodynamics, Efficacy)
PAR Innovation Grants to Nurture Initial Translational Efforts (IGNITE): Pharmacodynamics and In vivo Efficacy Studies for Small Molecules and Biologics/Biotechnology Products (R21/R33)
Entry Criteria:
A validated/characterized animal model and pharmacodynamic measure(s)
A testing protocol and Therapeutic agent(s) to test
R21 Phase:
Preparation, characterization of tx agent, dosage forms
Confirm that target is reached
R33 Phase:
Execution of the PD and/or in vivo efficacy studies
Target Engagement
End Goal:
Well-characterized early-stage agents suitable for optimization
Overall Goal: to conduct pharmacodynamics, pharmacokinetics, and in vivo efficacy studies to provide evidence of biological activity of a proposed therapeutic agent(s) 19

20. IGNITE PARs (Assay-Target and Pharmacodynamics) Two Phases in Each Grant
Planning/Development Phase
R21
 Meet Milestones
Execution Phase
R33
R21
R33
Budget per year
< $0.25M/per year
< $0.25M/year
Duration
No more than 2 years (three total)
Budget total (R21/R33)
<0.75M for Entire 3 Year Period

21. Hao Wang, PhD

22. CREATE PROGRAM COMPARISON
Discovery Track U01
(PAR )
Development Track Uh2/UH3
(PAR )
Purpose
Optimization of Therapeutic Leads
IND-Enabling and Early phase clinical trials
End Goals
Characterize and select a candidate with: stability, bioavailability, in vivo efficacy and/or target engagement
An IND application submitted to the FDA.
Mechanism
U01 (4 years)-milestones
UH2/UH3 (5 years)-milestones
Funds Available
<$500K DC/year
<$1M DC/year for 2 years (UH2)
<$1.5M DC/year (UH3)

23. Blueprint Neurotherapeutics Network
Combines; NIH, Academic, Industry Expertise
Modality: Small Molecule
Discovery: Hit-to-lead and lead optimization
Development: Formulation, scale up and manufacture, IND-enabling studies, and first-in-man clinical trials
End Goals
Discovery:
Characterize and select a preclinical candidate
Development:
Complete IND-enabling studies
file an IND
Complete first-in-human trial
Advance projects for “hand-off”
Website:
Amir Tamiz, PhD
Program Director 23

24. Blueprint Neurotherapeutics Network
Funding for work in Your Lab-assays, models
Access to NIH-funded contract research organizations (CROs)
Access to consultants-drug discovery and development
Your institution gets assignment of the intellectual property rights to compounds discovered and developed within the program

25. Blueprint Neurotherapeutics Network (BPN)

26. A Few Final Points http://www.ninds.nih.gov/otr
Start with your end goal in mind, and “work backwards”
Team approach is essential
Contact Program Directors “early”
Use Multiple approaches in order to accomplish goals
“Parent” R01, OTR mechanisms, advocacy, industry
Check out the “Decision Tree”; it will walk you through to find which program may be the best fit
x.htm

27. PAR-16-020: Clinical Trial Readiness for Rare Neurological and Neuromuscular Diseases
Validated biomarkers and clinical outcome measures, knowledge of disease course, effective recruitment strategies
Clinical Research Infrastructure
Supported through NeuroNEXT or other networks
Goals of this new initiative:
To acquire knowledge and refine tools that facilitate design of upcoming trials
To develop accurate, sensitive and reliable biomarkers and outcome measures that enable future trials to be well-powered and shorter in duration
To characterize clinical cohorts and test recruitment strategies that will increase the likelihood of successful trials
Candidate Therapeutics
Supported through OTR and other sources
Clinical Trials

28. Description of the Initiative
Types of studies that would be supported through this initiative:
Rare neurological or neuromuscular diseases (<200,000 pts in US)
Needed to facilitate one or more upcoming trials
Aims may include:
Biomarker or clinical outcome measure validation/qualification
Patient cohort characterization
Testing of recruitment strategies through above studies
Newly recruited participants or ancillary to an ongoing clinical trial
Types of studies that would be outside the scope of this initiative:
Natural history studies without direct relevance to upcoming trials
Biomarker discovery, pathophysiology or GWAS studies
Support for establishing clinical research infrastructure or patient registries

29. Description of the Initiative (continued)
Specialized peer review administered by NINDS:
Attention to significance for that rare disease, unmet need and urgency in relation to ongoing therapy development efforts
Reviewer expertise on rare neurological diseases, biomarker/outcome measure validation, multi-site clinical data management and biostatistics
Milestones for enrollment targets and biomarker/outcome measure performance evaluated by reviewers and throughout life of the grant by program
Success in this initiative would lead to increased success in future clinical trials for rare neurological and neuromuscular diseases.

30. 2016 NINDS Nonprofit Forum September 13-14th
Provides an opportunity for nonprofit leaders to network with colleagues and to engage in discussions with NINDS staff
Videocast Available

31. 2016 NINDS Nonprofit Forum 2015 Agenda
Lessons Learned and Case Studies in Patient Registries
NIH 101: Priority Setting, Decision making, NIH basics and Discussion
An Overview of the NIH Strategic Plan and Discussion
Strategies for Stimulating a Basic Research Portfolio
Working with Government and Industry Partners on Translational Research
Partnering Effectively with Industry in Clinical Trials

32. Thank you!
Questions?

33. Discovery Track
Optimization in Preparation for Development of Biotechnology Products and Biologics (U01) (PAR )
Entry
Lead(s) show in vivo efficacy and/or target engagement
Lead(s) have been sufficiently characterized
Well characterized in vitro and in vivo assays exist
Required end goals-completion of:
Optimization:
structure, selectivity, stability, manufacturability, etc.(quantitative)
Candidate characterization:
dose, time and duration of treatment
pharmacokinetics/bioavailability at the relevant site of action
pharmacodynamics
Feasibility for production and reproducible production of the candidate

34. Development Track Entry (same as end goals of “Discovery Track”)
Preclinical and Early-phase Clinical Development for Biotechnology Products and Biologics (UH2/UH3) (PAR )
Entry (same as end goals of “Discovery Track”)
Optimization: structure, selectivity, stability, manufacturability, etc.
Candidate characterization: dose, time and duration of treatment
pharmacokinetics/bioavailability at the relevant site of action, and pharmacokinetics
pharmacodynamics
Feasibility for production and reproducible production of the candidate
End Goal
IND
(Small clinical trial-optional)