Christopher P. Austin, M.D. NCATS Director IQ Symposium December 5, 2012

Transcription

1 Christopher P. Austin, M.D. NCATS Director IQ Symposium December 5, 2012

2 Basic Laboratory Research Clinical Research Improved Public Health Translational Research Population Research

3 Basic Laboratory Research Patient-oriented Clinical Research Improved Public Health Population-based Clinical Research Clinical Trials

4 Established on December 23, 2011 Part of Consolidated Appropriations Act 2012 (PL )

5 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.

6 Launched several major research initiatives Cultivated promising strategic partnerships Established a presence at NIH and in the biomedical research communities Become a hub of innovation for translational sciences Continues to evolve and catalyze translational science within and beyond the NIH by: Complementing not competing with the work of others Revolutionizing the process of translation by promoting innovative research Galvanizing and supporting new collaborations and partnerships Supporting and augmenting regulatory science and its application Expanding the precompetitive space

7 NCI NHLBI NIAID OD NIDCR NEI NIA NLM CC NIDDK NIAMS NIDA FIC CIT NHGRI NICHD NCATS NIEHS NIBIB CSR NIAAA NIDCD NINDS NIMH NCCAM NINR NIGMS NIMHD

8 Biotech Academia NCATS Advocacy Groups Complements does not compete with the work of others Revolutionizes the process of translation by promoting innovative research Pharma Non- Profits Galvanizes and supports new partnerships FDA Supports and augments regulatory science and its application Expands the precompetitive space

9 COUNCIL/ CAN BOARD OFFICE OF THE DIRECTOR Christopher Austin, M.D. (Director) (Deputy Director Vacant) EXECUTIVE OFFICE Erin Shannon, M.B.A. (Acting Executive Officer) OFFICE OF GRANTS MANAGEMENT & SCIENTIFIC REVIEW Sheryl Brining, Ph.D. (Acting Director) OFFICE OF RARE DISEASES RESEARCH Stephen Groft, Pharm.D. (Director) OFFICE OF POLICY, COMMUNICATIONS & STRATEGIC ALLIANCES Lili Portilla, M.B.A. (Acting Director) DIVISION OF PRE- CLINICAL INNOVATION John McKew, Ph.D. (Acting Director) DIVISION OF CLINICAL INNOVATION Josephine Briggs, M.D. (Acting Director)

10 NIH Chemical Genomics Center RNA interference (RNAi) Program Toxicology in the 21st Century (Tox21) program Therapeutics for Rare and Neglected Diseases (TRND) program Bridging Interventional Development Gaps (BrIDGs) program DPI currently has 300+ collaborations with investigators across the U.S. and around the world.

11 DPI is administratively intramural No independent PIs, no tenure system All projects are collaborations, 90% of which are with extramural investigators/foundations/companies Projects are selected via solicitation/review Science is intermediary between mechanistic research and commercialization Adaptor function Each project has tangible deliverable and technology/paradigm development components It is disease agnostic, works across disease spectrum Common mechanisms and principles to make translation better/faster/cheaper for all Focuses on new technologies, enabling tools, dissemination

12 NCATS DPI: A Collaborative Pipeline Project Entry Point Unvalidated target Validated target Target assay Lead compound Preclinical development candidate Clinical development candidate Target DPI Target Validation RNAi Assay Dev Probe Devel/NCGC Probe/Lead Lead Development Optimization Assay, Chemistry Technologies Repurposing Preclinical Development/TRND BrIDGs FDA Collaboration Systems Toxicology (Tox21) Paradigm/Technology Development Preclinical Development Clinical Trials I II III Repurposing FDA approval Deliverables Genome-wide RNAi systems biology data Chemical genomics systems biology data Small molecule and sirna research probes Leads for therapeutic development Predictive in vitro toxicology profiles Approved drugs effective for new indications Drugs suitable for adoption for further development More efficient/faster/cheaper translation and therapeutic development New drugs for untreatable diseases Novel clinical trial designs

13 Informatics Scientific and Admin Management Lab Operations Automation and Cmd Mgt Chemistry Assay Development and Biology

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15 Conventional HTS done at single concentration typically 10 μm qhts assays compounds at multiple concentrations No known bioactivity: 7 concs Known bioactivity: 15 concs Range = 2 nm 100 μm 1536-well plate format, assay volume ~5 μl, ~1000 cells/well Concentration-response curve generated for each compound from primary screen Produces robust activity profiles of all compounds Dramatically reduced FP and FN 4-6 months saved compared to conventional HTS Informatics pipeline for data processing, curve fitting & classification, extraction of SAR

16 NCATS Toxicology Technology Development: The Tox21 Program

17 Tox21: Predicting Toxicity Complex Cellular and HCS HTS Exposure Tissue Dose Biochemical HTS Molecular Targets Molecular Pathways Cell Changes Tissues Cellular Systems Cellular Networks Toxicity Cell-Based HTS Model Organism MTS Virtual Tissues

18 AC50 1 nm Activation Inhibition 1 µm 100 µm Inactive Inconclusive 100 µm 1 µm 1 nm Compounds screened: NTP-1408 and EPA-1462

19 Aims to develop tissue chips that mimic human physiology to screen for safe, effective drugs using best ideas in engineering, biology, toxicology NIH Investment (NCATS + Common Fund) = $70M/5 years DARPA Investment = $75M/5 years FDA Investment = Regulatory and toxicology expertise NCATS and DARPA independently manage and fund separate but highly coordinated programs

20 November 2011: Funding announcements issued RFA RM : Integrated Microphysiological Systems for Drug Efficacy and Toxicity Testing in Human Health and Disease (UH2/UH3) RFA RM : Stem/Progenitor Cell-Derived Human Microorgans and -tissues (U18) July 2012: 17 awards issued plus two additional awards funded by other NIH Institutes/Centers

21 1-2 years? >400,000 compounds, 15 yrs Target Screen Hit Lead Lead Optimization Preclinical Development Clinical Trials FDA approval 3500 drugs

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23 Drug Repurposing Case Study: Niemann-Pick Type C (NPC) Disease Prevalence: 1:150,000 Progressive neurodegeneration, death by teens NCATS, university investigators, and patient groups are collaborating to repurpose an existing drug for NPC treatment Drug identified in screen of drug collection is entering clinical testing this summer

24 TRND NPC Project Drug: ICV Cyclodextrin Collaborators NIH (Denny Porter, NICHD - Clinical Bill Pavan, NHGRI - Genetics) Washington University (Dan Ory - Biochemistry) Albert Einstein and UPenn (Steve Walkley and Charles Vite - Animal models) Johnson & Johnson Pharmaceuticals NPC disease foundations involved and facilitating Candidate Small Molecules TRND project milestones Proof-of-concept in animals Biomarker development Bio-analytical method development Pharmacokinetics/ pharmacodynamics, toxicology studies IND filing Proof-of-concept clinical trial Biomarkers PK/ PD/Tox Bio-analytical Assay Clinical Trial

25 TRND Portfolio September 2012 Collaborator Organization Name(s) Partner Type(s) Agent Therapeutic Area / Disease TRND Pilot Project NPC-SOAR, Washington Univ., Einstein College of Medicine, UPenn, J&J Pharmaceuticals, NICHD, NHGRI Disease Foundation, Academic, Pharma, NIH Intramural Repurposed Approved Drug Niemann-Pick Type C TRND Pilot Project New Zealand Pharmaceuticals, NHGRI Biotech, NIH Intramural Intermediate Replacement Hereditary Inclusion Body Myopathy TRND Pilot Project TRND Pilot Project Aes-Rx, NHLBI Leukemia & Lymphoma Society, University of Kansas, NHLBI Biotech, NIH Intramural Disease Foundation, Academic, NIH Intramural NME Repurposed Approved Drug Sickle Cell Disease Chronic Lymphocytic Leukemia Reeves, Erica ReveraGen BioPharma Biotech NME Duchenne Muscular Dystrophy Campbell, David Afraxis, Inc. Biotech NME Fragile X Syndrome Garvey, Edward Viamet Pharmaceuticals, Inc. Biotech NME Cryptococcal Meningitis Liu, Paul NHGRI NIH Intramural NME Core Binding Factor Leukemia Kimberlin, David University of Alabama Academic Nucleotide Analog Pro-drug Neonatal Herpes Simplex Trapnell, Bruce Cincinnati Children s Hospital Academic Biologic Bloch, Kenneth Massachusetts General Hospital Academic NME Autoimmune Pulmonary Alveolar Proteinosis Fibrodysplasia Ossificans Progressiva Liu, Julie CoNCERT Pharmaceuticals Biotech NME Schistosomiasis Davis, Robert Lumos Pharma Biotech NME Creatine Transporter Defect Sazani, Peter AVI BioPharma, Inc. Biotech Oligo (PMO) Duchenne Muscular Dystrophy

26 Clinical and Translational Science Awards (CTSAs) Small Business Innovation Research and Small Business Technology Transfer (SBIR/STTR) Programs

27 A consortium-based infrastructure that facilitates a more effective implementation of clinical studies, particularly multisite studies An enriched pipeline of novel therapeutics and diagnostics, moving from basic laboratories (particularly NIH-supported laboratories) into clinical testing Innovation in translational research methods, including novel strategies to promote community and patient engagement in the research process National leadership engaged in protecting human subjects to improve oversight and minimize burden and delays in clinical trials National leadership in developing informatics standards to promote intra-operability of data resources and research tools

28 Rare Diseases Clinical Research Network (RDCRN) Scientific Conferences Program NIH Clinical Center Bedside-to-Bench Program Genetic and Rare Disease Information Center (GARD)

29 Pilot program matching NIH researchers with compounds deprioritized by pharma for efficacy/business reasons Creation of template agreements to streamline negotiations between researchers and pharmaceutical companies 58 compounds from eight companies Abbott AstraZeneca Bristol-Myers Squibb Company Eli Lilly and Company GlaxoSmithKline Janssen Pharmaceutical Research & Development, L.L.C. Pfizer Inc. Sanofi

30 June 2012: Funding announcement issued August 2012: X02 pre-applications received December 2012: Full applications due June 2013: Awards to be issued Program will be evaluated for success: Does the use of template agreements speed negotiation time? Does the pilot advance disease understanding? Does the pilot result in promising new therapeutics?

31 Address significant bottlenecks in the process of translation Highly collaborative across NIH, other government agencies, and with the private sector Quick to respond to needs of biomedical researchers

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