rare diseases research at NIH NCATS, TRND and ATAXIA Research

1. John H. Ferguson MD, Medical Consultant, ORDR/NCATS/NIH rare diseases research at NIHNCATS, TRND and ATAXIA Research

2. No relationships to disclose or list Presenter Disclosures

3. Rare Diseases Office of Rare Diseases Research (ORDR) National Center for Advancing Translational Sciences – NCATS Therapeutics for Rare and Neglegted Diseases –TRND Ataxia research with ORDR, NCATS and TRND agenda

4. 18 - 25million people in the US are affected - Exact Prevalences Unknown • Estimated 6%-8% of Population • Prevalence definition: < 200,000 people in the USA • > 7000 Genetic and Acquired Rare Diseases • Need Collaborative Efforts of the Rare Diseases Community • Academic Researchers • Federal Research and Regulatory Programs • > 1100 Patient Advocacy Groups/Philanthropic Foundations • Industry • Congressional Rare Diseases Caucus Established Rare diseases

5. 19 Consortia supported by ORDR, NINDS, NIAMS, NICHD, NHLBI, NIDDK, NIAID, NIDCR and NCI • Required • 3 diseases • longitudinal studies of patients, • Encouraged : Phase I, II and III  trials; • Training of Investigators in clinical research of rare diseases; • Pilot studies/demonstration projects • Collaboration with Patient Advocacy Groups • Data Management Coordinating Center DMCC • > 192 Institutions World-wide, 42 International Sites, > 200 Diseases • 9393 patients enrolled in 68 studies Rare diseases clinical research network

6. Coalition of Patient Advocacy Groups (CPAG) The Data Management and Coordinating Center • Collaborative Clinical Research • Public Resources and Education • Centralized Data Coordination and Technology Development • Training Chronic Graft Versus Host Disease Consortium

7. To catalyze the development 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 Creation of the National Center for Advancing Translational Sciences (NCATS)

8. Development of New Therapeutics Clinic Access Phase iv Stage 4 FDA Review Stage 1 Drug Discovery Stage 2 Pre-clinical Stage 3 Clinical Trials Phase I Phase II Phase III IND Submitted NDA Submitted 6.5 years 6 years 1.5 years

9. Components of Molecular Libraries Program Therapeutics for Rare and Neglected Diseases Office of Rare Diseases Research Bridging Interventional Development Gaps (BrIDGs) Clinical and Translational Science Awards (CTSA) FDA-NIH Regulatory Science Cures Acceleration Network NCATS Research Programs

10. NCATS STRUCTURE National center for advancing translational scineces Office of the Director Tom Insel (Acting Director) Kathy Hudson (Acting Deputy Director) Council CAN Board Executive Office Erin Shannon (Acting) Office of Grants Management & Review Jane Steinberg (Acting) Office of Rare Diseases Research Steve Groft Office of Policy, Communications, & Strategic Alliances Kathy Hudson (Acting) Division of Pre-Clinical Innovation Chris Austin Division of Clinical Innovation Josie Briggs (Acting)

11. Clinical and Translational Science Activities • CTSAs Clinical Translational Science Awards • Rare Diseases Research and Therapeutics • Office of Rare Diseases Research ORDR • Therapeutics for Rare and Neglected Diseases (TRND) • Re-engineering Translational Sciences • NIH Chemical Genomics Center/Molecular Libraries program • Bridging Interventional Development Gaps BrIDGs • Toxicology in the 21st Century Ncats unifies three program areas

12. Academia Government Biopharmaceuticals Patient Advocacy Groups Trnd partners

13. Successful applicants don’t receive grants Form joint project teams with TRND Receive in kind support from TRND scientists, laboratory and contract resources Goal is advancing compounds to FDA IND  clinical trials in humans trnd

14. Niemann- Pick C Hereditary Inclusion Body Myopathy Sickle cell anemia - IND received Chronic Lymphocytic Leukemia  IND received Shistosomiasis Trnd pilot projects, proof of concept

15. Duchenne Muscular Dystrophy Fragile X Cryptococcal Meningitis Core binding factor leukemia TRND – 4 drug development projects approved

16. An inhibitor compound for Rx of fibrodysplasia ossificans • Applicant is academic MD • Compound shows efficacy in mouse model • Novel Rx for creatine transporter deficiency • Applicant is a pharmaceutical Co. • Mouse model show incr. brain metabolism and cognative function • Compount for Rx of neonatal herpes simplex • Applicant is academic pediatrician • Compound can penetrate CNS, NIAID studied Latest TRND projects approved

17. Deuterimum modified compound for shistosomiasis • Applicant is pharmaceutical co. • Enables lower and less frequent dosing • Drug candidate for Duchenne MD • Applicant is pharmaceutical co. • Drug is for a specific subgroup mutation • Rx for autoimmune pulmonary alveolar proteinosis • Applicant is academic MD • Developed as an inhaled Rx Latest trnd projects approved

18. If no effect in animal models Too much toxicity in preclinical testing Poor bioavailability – can’t be absorbed Trnd will follow milestones and terminate projects – for instance

19. Cures Acceleration Network (CAN) • Address challenges that impede translational research • Rescuing and Repurposing Drugs e.g. lithium • Designing a Tissue Chip for Drug Screening • With FDA and the Defense Advanced Research Projects Agency (DARPA) • “organ on a chip” • Identifying and Validating Drug Targets Other ncats programs

20. Many potential drug targets for new compounds heard at AIM 2012 High throughput screening at NCATS of thousands of molecules already being used by ataxia researchers Rescuing and repurposing drugs is NCATS program and many examples given at AIM 2012 Programs at ORDR, NeuroNext, NCATS and TRND should offer HUGE opportunities for ataxia research ncats.nih.gov Ncats, ordr and ataxia research

21. NIH Office of Rare Diseases Research - Staff Steve Groft PharmD Ms. Mary Demory Dr. David Eckstein Ms. Marita Eddy (Angel Flight) Dr. John Ferguson Dr. Rashmi Gopal-Srivastava Mr. Christopher Griffin Ms. Henrietta Hyatt-Knorr Dr. Lata Nerurkar Ms. Susan Orr Lowe Ms. Geraldine Pollen Dr. Yaffa Rubinstein Dr. William Gahl (Clinical Director, NHGRI) Dr. P.J . Brooks (NIAAA)