U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES National Institutes of Health National Institute of Neurological Disorders and Stroke Big Discoveries, Small Molecules (…and other aspects of translational research via NINDS) March 4, 2016 Jill Morris PhD

U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES National Institutes of Health National Institute of Neurological Disorders and Stroke 2 Translational Funding Opportunities Anticonvulsant Screening Program (ASP) Biotechnology Products and Biologics - CREATE Bio Small Business Program: SBIR & STTR Small Molecules – Blue Print Neurotherapeutics (BPN) Countermeasures Against Chemical Threats (CounterACT) Devices - CREATE Device Early Translation - IGNITE IGNITE: Innovation Grants to Nurture Initial Translational Efforts CREATE: Cooperative Research to Enable and Advance Translational Enterprises Discovery Preclinical Development Small Clinical Trials

U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES National Institutes of Health National Institute of Neurological Disorders and Stroke “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 3 Discovery Preclinical Development Small Clinical Trials The Office of Translational Research

U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES National Institutes of Health National Institute of Neurological Disorders and Stroke Innovation Grants to Nurture Initial Translational Efforts (IGNITE) –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 )RFA-NS a well-validated Assay (PAR ):PAR Well-characterized early-stage Agents suitable for Optimization (PAR )PAR Amir Tamiz, PhD

U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES National Institutes of Health National Institute of Neurological Disorders and Stroke 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 RFA-NS RFA-NS Development and Validation of Model Systems and/or Pharmacodynamic Markers to Facilitate the Discovery of Neurotherapeutics (R21/R33) 5 Innovation Grants to Nurture Initial Translational Efforts (IGNITE)

U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES National Institutes of Health National Institute of Neurological Disorders and Stroke Two Phases in Each Grant 6 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 Planning/Development Phase  Meet Milestones IGNITE RFA (Models and Markers)

U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES National Institutes of Health National Institute of Neurological Disorders and Stroke –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 7 IGNITE PAR (Assays and Agents) PAR PAR Innovation Grants to Nurture Initial Translational Efforts (IGNITE): Assay Development and Therapeutic Agent Identification and Characterization to Support Therapeutic Discovery (R21/R33)

U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES National Institutes of Health National Institute of Neurological Disorders and Stroke –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 8 IGNITE PAR (Pharmcodynamics, Efficacy) PAR PAR Innovation Grants to Nurture Initial Translational Efforts (IGNITE): Pharmacodynamics and In vivo Efficacy Studies for Small Molecules and Biologics/Biotechnology Products (R21/R33)

U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES National Institutes of Health National Institute of Neurological Disorders and Stroke IGNITE PARs (Assay-Target and Pharmacodynamics) Two Phases in Each Grant 9 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 Planning/Development Phase  Meet Milestones

U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES National Institutes of Health National Institute of Neurological Disorders and Stroke 10 Hao Wang, PhD

U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES National Institutes of Health National Institute of Neurological Disorders and Stroke CREATE PROGRAM COMPARISON Discovery Track U01 (PAR ) Development Track Uh2/UH3 (PAR ) PurposeOptimization of Therapeutic Leads IND-Enabling and Early phase clinical trials End GoalsCharacterize and select a candidate with: stability, bioavailability, in vivo efficacy and/or target engagement An IND application submitted to the FDA. MechanismU01 (4 years)-milestonesUH2/UH3 (5 years)-milestones Funds Available <$500K DC/year<$1M DC/year for 2 years (UH2) <$1.5M DC/year (UH3) 11

U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES National Institutes of Health National Institute of Neurological Disorders and Stroke Optimization in Preparation for Development of Biotechnology Products and Biologics (U01) (PAR )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 12 Discovery Track

U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES National Institutes of Health National Institute of Neurological Disorders and Stroke Preclinical and Early-phase Clinical Development for Biotechnology Products and Biologics (UH2/UH3) (PAR )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) 13 Development Track

U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES National Institutes of Health National Institute of Neurological Disorders and Stroke Neuroscience Blueprint (NIH) Includes: –Office of the Director (OD) –15 Institutes/Centers with a Neuroscience Mission BRAIN Initiative –Cells, Circuits (Imaging, Technology) Grand Challenges –Human Connectome Project Map connections in the Human brain –Pain Consortium –Blueprint Neurotherapeutics Program 14 Blueprint Neurotherapeutics Network

U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES National Institutes of Health National Institute of Neurological Disorders and Stroke 15 Amir Tamiz, PhD Program Director 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” Blueprint Neurotherapeutics Network

U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES National Institutes of Health National Institute of Neurological Disorders and Stroke –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 16 Blueprint Neurotherapeutics Network

U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES National Institutes of Health National Institute of Neurological Disorders and Stroke 17 Blueprint Neurotherapeutics Network (BPN)

U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES National Institutes of Health National Institute of Neurological Disorders and Stroke A Few Final Points –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 dex.htmhttp:// dex.htm 18