1. Partnerships with NIH to Advance New Technologies Cindy K. Fuchs, J.D. Director, Technology Advancement Office, NIDDK Lili M. Portilla, M.P.A. Director, Office of Strategic Alliances, NCATS AIPLA 2012 Annual Meeting

2. NIH Translational Research Resources for Advancing Early Stage Technologies Cindy K. Fuchs, J.D. Director, Technology Advancement Office, NIDDK Disclaimer: The information presented herein is not intended to be and should not be construed as legal advice.

3. Translational Research Process Product Regulatory Approval Clinical Trials Preclinical Development Lead Compound Optimization Screen for Activity (Dr. Gold identified known drugs but no novel compounds) Assay Development Target Validation Identify Molecular Target 1 New Medicine 10,000 Molecules

4. Common Translational Research Needs R&D Plan: unmet need, full commitment, resources and capabilities (HTS, medchem, relevant models, broad team-based expertise) IP Package: convert a basic research discovery into a marketable product with a strong IP portfolio to protect R&D investment Pre-clinical Package: de-risk technology (lead optimization, toxicity, efficacy, etc.) to prove clinical relevance and incentivize commercial investment

5. PROOF OF CLINICAL RELEVANCE REQUIRED Early Discovery Hit to Lead Lead to Pre-clinical Candidate Pre-clinical Development Clinical Trials Drug Discovery Biotech/Pharma Companies Academia Drug Candidate Target Identification Assay Development Validated Hits Target Validation Lead Preclinical and Clinical Development New Medicine Basic Science: Identification of Molecular Pathways Commercial Partnering Interest Has Shifted 1 Early Stage Research Discovery --> Pre-Clinical/Clinical Success ------------------------------------------> 1 Stewart, J., Campbell Alliance Dealmakers’ Intentions Survey 2012; Christini, A., Nat. Biotechnol. 30, 933-936 (2012)

6. PROOF OF STRONG IP REQUIRED After Ariad v. Lilly (2010) -Patents are not awarded for discovering key mechanisms - no matter how groundbreaking -Broad patent claims should be supported by a representative number of working examples in specification -Filing an application too early (with incomplete written description) may reduce incentives for commercial partners

7. Options for Advancing Dr. Gold’s Technology Traditional patent licensing model - a broad mechanism of action claim not likely patentable under Ariad - create R&D plan: design and evaluate novel analogs - create IP package: file on novel analogs - create pre-clinical package: lead optimization, pharm-tox, efficacy, etc. New “drug re-purposing” model -new use of known drugs –> typically limited commercial potential exceptions: orphan drug status, new formulation (combination, delayed release, etc.), off-label use - highlights need for pre-competitive partnerships between academia, non-profits, govt. labs, FDA, industry

8. Current Focus on “Translational Research” K. Pienta, MD, Univ. Mich. Nature Publishing Group

9. NIH Translational Research Addresses Unmet Needs FDA Regulatory Science Anti-Cancer Therapies & Diagnostics HIV Therapies & Diagnostics Vaccines, Drugs, Diagnostics, Enhanced Facilities/Workforce

10. NIH INTRAMURAL RESEARCH (NIH Laboratories) NIH EXTRAMURALRESEARCH (Grantees and Contractors) Supports: Bethesda, MD; Arizona; Montana 27 NIH Institutes & Centers >6,000 scientists & research personnel Basic Translational & Clinical Research 10% of overall NIH budget Supports: >3,000 institutions worldwide >300,000 scientists & research personnel Awards issued in over 100 countries Basic Translational & Clinical Research 90% of overall NIH budget Courtesy of OER/NIH

11. NIH Intramural Translational Resources NIH Intramural Laboratories – 27 Institutes & Centers (ICs) Each IC has a unique mission and is organized by -disease (cancer, diabetes) -organ system (heart lung & blood, eye) -life stage (child health, aging) -scientific discipline (infectious diseases, genomics) ICs employ world-class scientists - potential research collaborations - access to special patient populations - research tools (cell lines, antibodies, mouse models)

12. Accessing NIH Intramural Translational Resources Managed by IC Technology Development Offices - Facilitate research partnerships, exchange of research materials, data and confidential information - Negotiate transactional agreements: o confidentiality agreements o clinical trial agreements o collaboration agreements, CRADAs - Evaluate new innovations from IC scientists for partnering or patenting - Provide strategic guidance to IC scientists on technology development - Create virtual teams to advance early stage R&D and prove clinical relevance Contact Information - Handout

13. Accessing NIH Extramural Translational Resources Managed by IC Extramural Scientific Program Officers - Financial: grants & contracts - In-Kind (via NIH contracts/grants): - Sample repositories - Screening - Preclinical development - Clinical trial networks Specific Resource Program Information – Handout

14. For More Information… Handouts: NIH Translational Research Resources NIH Intramural Researchers NIH Technology Development Offices Contact Information: cfuchs@mail.nih.gov http://www2.niddk.nih.gov/TechDev/Main-HomePage/

15. Lili M. Portilla, MPA Director of Strategic Alliances, NCATS AIPLA 2012 Annual Meeting

16.  Established on December 23, 2011  Part of Consolidated Appropriations Act 2012 (PL 112-74)

17. “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.”

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

20.  Therapeutics for Rare and Neglected Diseases (TRND)  Toxicology in the 21st Century (Tox21)  Bridging Interventional Development Gaps (BrIDGs)  Molecular Libraries Probe Production Center  RNA interference (RNAi) DPI currently has 300+ collaborations with investigators across the U.S. and around the world.

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

22.  Model: Contract access collaboration between DPI and extramural labs (Formerly NIH-RAID Program)  Projects  Enter with clinical candidate identified  Any disease eligible  Gap analysis followed by data generation using DPI contracts to generate data necessary for IND filing  Exit at or before IND  Milestone driven  Therapeutic modalities: any (small molecules, peptides, oligonucleotides, gene therapy, antibodies, recombinant proteins)  Eligible Applicants  Academic (US and Ex-US), Non-Profit, SBIR eligible businesses Bridging Interventional Development Gaps (BrIDGs) Program

23.  180 applications submitted since 2005  34 approved  19 completed projects (two in FY12)  12/12 submitted INDs approved  5 projects in Phase 1, three in Phase II  5 agents licensed during or after BrIDGs involvement

24. BrIDGs Portfolio September 2012 ApplicantOrganization NameOrg TypeAgentDiseaseFunding Au, JessieOptimum TherapeuticsBiotechSmall MoleculePancreatic CancerCommon Fund Bankiewicz, Krystof University of California San Francisco AcademicGene Vector Aromatic L-amino acid decarboxylase CF/NINDS Bloch, KennethMassachusetts General HospitalAcademicSmall Molecule FOP & Anemia of Inflammation CF/NIAMS/NIDDK Darling, ThomasEdunn BiotechnologyBiotechOligonucleotideAlzheimer's diseaseCF/NIA De Leon, DivaChildren's Hospital of PhiladelphiaAcademicPeptideHyperinsulinismCommon Fund Donn, KarlParion Sciences, inc.BiotechSmall MoleculeChronic dry eyeCommon Fund Dowling, Peter University of Medicine and Dentistry of New Jersey AcademicPeptideMultiple sclerosisCommon Fund Evans, Christopher Beth Israel Deaconess Medical Center Academic*Gene VectorOsteoarthritisCommon Fund Kunos, GeorgeNIH/NIAAAIntramural*Small moleculeMetabolic syndromeCommon Fund Mannstadt, Michael Massachusetts General HospitalAcademic*PeptideHypoparathyroidismCommon Fund Mellon, Synthia University of California San Francisco AcademicSmall MoleculeNiemann-Pick CCF/NINDS Miller, KennethKemmx CorporationBiotechSmall moleculeRheumatoid arthritisCF/NIAMS Rogawski, MichaelUniversity of California, DavisAcademic*Small moleculeEpilepsyCF/NINDS Sutula, ThomasUniversity of Wisconsin MadisonAcademic*Small MoleculeEpilepsyCommon Fund Turner, ScottKinemed, Inc.BiotechPeptideAtherosclerosisCommon Fund * indicates that the investigator is partnered with a company

25.  Model: Comprehensive drug development collaboration between DPI and extramural labs with disease-area / target expertise  Projects  May enter at various stages of preclinical development  Disease must meet FDA orphan or WHO neglected tropical disease criteria  Taken to stage needed to attract external organization to adopt to complete clinical development/registration, max 2a  Milestone driven  Therapeutic modalities: small molecules, proteins  Serve to develop new generally applicable platform technologies and paradigms  Eligible Applicants  Academic, Non-Profit, Government Lab, Biotech / Pharma  Ex-U.S. applicants accepted Therapeutics for Rare and Neglected Diseases (TRND) Program

26. 14 projects through pilot phase & 2 public solicitations since 2009 Mix of small molecules and biologics Two innovative platform technologies 3 investigational drugs taken into humans CLL: IND filed with US FDA 7/12/11, approved 8/5/11 Phase I trial commenced 9/11 SCD: IND filed 10/14/11, approved 11/10/11 Phase I trial commenced 12/11 HIBM: Complete response filed 7/27/12, approved 8/24/12 Phase 1 trial in patients commenced 9/13/12 Initiated first natural history study HIBM: NIH Clinical Center, 1 st patient enrolled September 2011 Every project is a unique Public-Private partnership Many include foundation and patient advocacy input TRND Highlights

27. Active TRND Projects CollaboratorOrganization Name(s)Partner Type(s)AgentTherapeutic Area / Disease TRND Pilot Project NPC-SOAR, Washington Univ., Einstein College of Medicine, NICHD, NHGRI Disease Foundation, Academic, DIR Repurposed Approved Drug Niemann-Pick C TRND Pilot ProjectNew Zealand Pharmaceuticals, NHGRI Biotech, DIR Intermediate Replacement Hereditary Inclusion Body Myopathy TRND Pilot ProjectAes-Rx, NHLBI Biotech, DIRNMESickle Cell Disease TRND Pilot Project Leukemia & Lymphoma Society, Kansas Univ. Cancer Center Disease Foundation, Academic Repurposed Approved Drug Chronic Lymphocytic Leukemia Reeves, EricaReveraGen BioPharma Small BusinessNMEDuchenne Muscular Dystrophy Campbell, DavidAfraxis, Inc. Small BusinessNMEFragile X Syndrome Garvey, EdwardViamet Pharmaceuticals, Inc. Small BusinessNMECryptococcal Meningitis Liu, PaulNHGRI DIR Repurposed Approved Drug Core Binding Factor Leukemia Kimberlin, DavidUniversity of Alabama Academic Nucleotide Analog Pro-drug Neonatal Herpes Simplex Trapnell, BruceCincinnati Children’s Hospital AcademicBiologic Autoimmune Pulmonary Alveolar Proteinosis Bloch, KennethMassachusetts General Hospital AcademicNME Fibrodysplasia Ossificans Progressiva Liu, JulieCoNCERT Pharmaceuticals Small BusinessNMESchistosomiasis Davis, RobertLumos Pharma Small BusinessNMECreatine Transporter Defect Sazani, PeterSarepta Therapeutics Small BusinessOligo (PMO)Duchenne Muscular Dystrophy TRND Portfolio

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29. Partnerships with NIH to Advance New Technologies If you wish to receive an electronic version of this presentation and/or referenced resources, please send your request to: MTA@niddk.nih.govMTA@niddk.nih.gov AIPLA 2012 Annual Meeting