1. The National Center for Advancing Translational Sciences Catalyzing Translational Innovation KRISHNA BALAKRISHNAN, PH.D., M.B.A. OFFICE OF STRATEGIC ALLIANCES, NCATS INNOVATION2COMMERCIALIZATION CONFERENCE NOVEMBER 3, 2015

2. The Best of Times, the Worst of Times Poor transition of basic or clinical observations into interventions that tangibly improve human health Drug/device/diagnostic development expensive and failure-prone Clinical trials system inefficient Poor adoption of demonstrably useful interventions Fundamental science unprecedentedly advanced, but: People unhealthier and funders of biomedical research enterprise (public and private) impatient

3. Moore’s Law Source: Wikipedia

4. The number of new drugs approved by the FDA per billion US dollars (inflation-adjusted) spent on research and development (R&D) has halved roughly every 9 years since 1950. Scannell et al., Nature Reviews Drug Discovery 11:191, 2012 Eroom’s Law

5. Disorders with Known Molecular Basis Source: Online Mendelian Inheritance in Man, Morbid Anatomy of the Human Genome ~500 with therapy

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

7. What is Translation? Translation is the process of turning observations in the laboratory, clinic, and community into interventions that improve the health of individuals and the public - from diagnostics and therapeutics to medical procedures and behavioral changes.

8. What is Translational Science? Translational Science is the field of investigation focused on understanding the scientific and operational principles underlying each step of the translational process. NCATS studies translation as a scientific and organizational problem.

9. NCATS Mission 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.

10. Translational Science Spectrum

11. Some of the scientific translational problems on NCATS’ to-do list Predictive toxicology Predictive efficacy Derisking undruggable targets/untreatable diseases Data interoperability Biomarker qualification process Clinical trial networks Patient recruitment Electronic Health Records for research Harmonized IRBs Clinical diagnostic criteria Clinical outcome criteria (e.g., PROs) Adaptive clinical trial designs Shortening time of intervention adoption Adherence Methods to better measure impact on health…

12. Some of the organizational translational problems on NCATS’ to-do list… Data transparency/release IP management Integration of project management Incentives/credit for team science Incentives/credit for health improvements Education/Training (scientific and cultural) Collaborative structures » Public-private partnership models

13. Overcoming Challenges Through Collaboration NCATS Case Studies Drug Rescue and Repurposing program- (Clinical) Crowdsourcing, multiple partners, risk averseness of partners, lack of clear rewards TRND (Pre-Clinical) - Risky programs, lack of incentives Tissue Chip (Re-Engineering) - Massive scale, risk, need for multiple partners, new platform technology development

14. NCATS Scientific Initiatives Clinical Translational Science » Clinical and Translational Science Awards » Rare Disease Clinical Research Network » New Therapeutic Uses program Preclinical Translational Science » NCATS Chemical Genomics Center » Therapeutics for Rare and Neglected Diseases program » Bridging Interventional Development Gaps program Re-engineering Translational Sciences » Toxicology in the 21st Century » Microphysiological Systems (Tissue Chip) program » Office of Rare Diseases Research

15. Division of Clinical Innovation Clinical and Translational Science Awards (CTSA) Program A national consortium of medical research institutions Improves the way clinical and translational research is conducted nationwide Accelerates the research translation process Provides innovative training for clinical and translational researchers

16. Clinical and Translational Science Awards Program CTSA Hubs

17. CTSA Trial Innovation Centers (TICs) Promote innovation to increase the efficiency and quality of clinical trials Provide – Central IRB – Streamlined budgeting and contracting – Other trial coordination functions as needed NCATS will partner with NIH ICs, industry, and other funders to implement trials RFA-TR-15-002

18. CTSA Recruitment Innovation Centers (RICs) RICs will:  Provide data for trial planning, feasibility analysis, site selection, and recruitment implementation  Develop innovative solutions to increase recruitment success RFA-TR-15-004

19. Evolving the CTSA Program to Transform Clinical Translational Science RIC: Recruitment Innovation Centers Feasibility Assessment Recruitment Plan and Implementation TIC: Trial Innovation Centers Central IRB Contracting Budgeting Other support PRN Multi-site Study funded by NIH IC or others CTSA Hubs Clinical Lead Stats/Data Management No need to re-build trial components each time

20.  Problem: 80% of drugs that enter clinic never approved  Opportunity: potential for new treatments via ID of new indications for deprioritized investigational drugs  Program: matches investigational agents from pharma deprioritized for lack of efficacy or business reasons with new indication ideas from academia  NIH provided: template Collaborative Research Agreements (CRAs) and Confidential Disclosure Agreements (CDAs), FOAs, review, funding, oversight  Pharmaceutical partners provided: compounds, biologics, in kind support, pertinent data  Academic researchers provided: deep understanding of disease biology, new concepts to test, access to appropriate patient populations

21. 58 Agents made available for this pilot program by 8 pharmaceutical company partners AbbVie (formerly Abbott) AstraZeneca Bristol-Myers Squibb Company Eli Lilly and Company GlaxoSmithKline Janssen (J&J) Pfizer Sanofi NIH MOU Grant CRA Industry Partner Researcher Patients

22. NCATS Scientific Initiatives Clinical Translational Science  Clinical and Translational Science Awards  Rare Disease Clinical Research Network  New Therapeutic Uses program Preclinical Translational Science  NCATS Chemical Genomics Center  Therapeutics for Rare and Neglected Diseases program  Bridging Interventional Development Gaps program Re-engineering Translational Sciences  Toxicology in the 21st Century  Microphysiological Systems (Tissue Chip) program  Office of Rare Diseases Research

23. Steps in the drug development process Identify target Create testing system (aka, “assay” Test >100,000 chemicals for activity on target Make modifications to active chemicals to make suitable for human use Test in animals for safety, effectiveness Test in humans for safety, effectiveness Assay Development HTS Medicinal Chemistry Preclinical Development Clinical Development $50-100K $500K-1M $5-10M$50-100M (Per project cost) Basic research Discovery Preclinical and early clinical Late clinical

24. NCATS DPI Staff

25. Target-to-Lead Development Innovation NCATS Chemical Genomics Center Founded 2004 as part of Molecular Libraries Program Currently > 200 collaborations with investigators worldwide Assay development, HTS, chemical informatics, medicinal chemistry: “target to lead” Focus is unprecedented targets, rare/neglected diseases Mission  Chemical and siRNA probes/leads  New technologies/paradigms to improve efficiency and success rates of target-to-lead stage of drug development  Chemical genomics: general principles of siRNA action, small molecule-target interactions

26. Why Repurposing? Clinical Trials Lead Optimization Preclinical Development Hit Screen Target FDA approval >500,000 compounds, 15 yrs 3000 drugs 1-2 years?

27. NCATS Comprehensive Repurposing Program “Systematizing Serendipity”

28. Drug Repurposing for HCV Infection Collaborator  Jake Liang, NIDDK intramural Background  HCV infection accelerates development of liver diseases (cirrhosis, liver failure, and hepatocellular carcinoma)  New HCV treatments such as Sovaldi (Gilead)  Effective but expensive  Work via viral RNA polymerase inhibition, so genotype specific Project  Identified chlorocyclizine (CCZ), a first generation (generic) antihistamine in NPC screen for anti-HCV agents  CCZ interacts with host target and prevents infection  Combination treatment might reduce costs  Rapid initiation of NIDDK-supported clinical trial of CCZ in HCV at NIH Clinical Center

29. Therapeutics for Rare and Neglected Diseases (TRND) Usual Mechanism Apply, Grants.gov Review, CSR $ Funding announcement Funding decision Apply, Proposal CENTRAL Review, External Panel & NIH IC Input In-Kind Support, Milestone-Driven Collaboration with NCATS Solicitation Select Collaborators, Form Project Teams TRND Grant to Recipient

30. TRND Accomplishment Highlights 15 projects adopted since 2009  Mix of small molecules and biologics  Two innovative platform technologies 4 investigational drugs taken into humans  Chronic Lymphocytic Leukemia: Phase I trial, 9/2011  Hereditary Inclusion Body Myopathy: Phase 1 trial in patients, 9/2012  Niemann-Pick Type C Disease: Phase 1 trial in patients, 1/2013  Sickle Cell Disease: Phase 2 trial, 9/2013 Initiated first natural history study  HIBM: NIH Clinical Center, 1st patient enrolled in 9/2011 Every project is a unique public-private partnership  Many include foundation and patient advocacy input

31. TRND Collaboration on Sickle Cell Disease  Collaborator: AesRx, LLC  Compound: Aes-103 (5-hydroxymethyl-2-furfural) – Binds to sickle hemoglobin, increases O 2 affinity  TRND partnered with AesRx to de-risk – Project initiation to patients in <12 mos – Animal toxicology studies – CMC (Chemistry, Manufacturing, and Quality Controls) – Regulatory: interactions with FDA, IND filing – Ph Ia, Ib, IIa trials  Project acquired by Baxter for completion of clinical development

32. TRND Development of Cyclodextrin for the Treatment of Niemann-Pick Type C1 Disease Collaborators: Multi-party collaboration involving NIH, academia, patient advocacy groups, and Vtesse Inc. of Gaithersburg, MD Objective: Develop HP-  -CD as a therapy for Niemann-Pick Disease, type C (NPC), an LSD where defects in NPC1 or NPC2 proteins cause cholesterol accumulation in lysosomes and pre-clinical development of NCATS owned technology to treat NPC Scope: A comprehensive pre-clinical program to support a Phase I trial for HP-  -CD in NPC, and development of NCATS technology licensed by Vtesse, Inc. Winner of 2015 Federal Laboratory Consortium Mid-Atlantic Regional Award for Excellence in Technology Transfer. Multi-party collaboration NPC WT NPC + HPBCD

33. Wall Street Journal: Trials

34. TRND Support of Pulmonary Alveolar Proteinosis Collaborators  Bruce Trapnell (Cincinnati Children’s Hospital) and Genzyme Clinical Manifestation  Ultra-rare; 7 per million  Accumulation of surfactant fluid in lungs; can lead to respiratory failure Current Treatment  Whole lung lavage under general anesthesia  Technically challenging, invasive, pediatric safety concerns Alternative: Leukine (GM-CSF)  Possibly generate alveolar macrophages to scavenge surfactants and clear liquid  Currently approved in IV form for Myeloid reconstitution after bone marrow transplant Path Forward/Gaps  Need toxicology data on inhaled form of drug  TRND funded GLP toxicology study with Genzyme donated drug PAP infiltration 4 days post lavage Eur J Radiol 2011, May 26; http://dx.doi.org/10.1016/j.ejrad.2011.05.005 Whole Lung Lavage Fluid N Engl J Med 2007; 357:e21

35. NCATS Scientific Initiatives Clinical Translational Science  Clinical and Translational Science Awards  Rare Disease Clinical Research Network  New Therapeutic Uses program Preclinical Translational Science  NCATS Chemical Genomics Center  Therapeutics for Rare and Neglected Diseases program  Bridging Interventional Development Gaps program Re-engineering Translational Sciences  Toxicology in the 21st Century  Microphysiological Systems (Tissue Chip) program  Office of Rare Diseases Research

36. Toxicity is a common reason for drug development failure Kola and Landis, Nature Reviews Drug Discovery 3, 711-716, 2004. Preclinical (21%) + Clinical (12%) Tox = 33% of all failures

37. All ten human physiological systems will be functionally represented by human tissue constructs: Circulatory Endocrine Gastrointestinal Immune Integumentary Physiologically relevant, genetically diverse, and pathologically meaningful. Modular, reconfigurable platform. Tissue viability for at least 4 weeks. Community-wide access. Microphysiological Systems/Tissue Chip Program GOAL: Develop an in vitro platform that uses human tissues to evaluate the efficacy, safety and toxicity of promising therapies. Musculoskeletal Nervous Reproductive Respiratory Urinary

38. Microphysiological Systems from Common Building Blocks Scaffold - purified ECM - synthetic polymers - composites Perfusion - embedded channels - vascularization Bioreactors - optimized culture conditions - biomechanical properties - blood mimetics Spatial/Temporal Patterning - cytokine gradients - controlled release Innervation - signal propagation - coordinated response Host Response - generalized inflammation - specific immunity Cells - stem/progenitor - differentiated - mixed cell types Structure - porosity - topography - stiffness Computational Design - systems integration - multi-scale modeling - simulation - feedback Functional Readout -real-time, label-free, non-destructive sensing - imaging

39. DARPA BAA-11-73 Microphysiological Systems $75 M over 5 years NIH NCATS RFA-RM-11-022 Integrated Microphysiological Systems for Drug Efficacy and Toxicity Testing in Human Health and Disease (UH2/UH3) RFA-RM-12-001 Stem/Progenitor Cell-Derived Human Micro-organs and -tissues (U18) $70 M over 5 years FDA Regulatory advice and toxicology expertise The Tissue-Chip Partnership Develop tissue chips that mimic human physiology to screen for safe, effective drugs using best ideas in engineering, biology, toxicology

40. Flow FITC-inulin DRUG A Lung-on-a-Chip: Predicting Drug Efficacy DRUG A DRUG A @ 100nM Common side effect of IL-2 chemotherapy is vascular leak syndrome or edema Data provided by Dr. Don Ingber, Wyss Institute

41. Engineered Cardiac Muscular Thin Films Film length Automatic projection tracking Science 2007;317:1366Biomaterials 2010;31:3613 Lab Chip 2011;11:4165J Pharm Tox Methods 2012;65:126 Data provided by Dr. Kit Parker, Wyss Institute

42. Overcoming Challenges Through Collaboration Therapeutics Discovery- Crowdsourcing, Multiple partners, R isk averseness of partners, L ack of clear rewards TRND- Program risk, Lack of incentives Tissue Chip- Massive scale, Risk, Multiple partners, New platform technology development

43. Take-home messages The opportunities (and needs) in translational science are huge and require collaboration among multiple partners The scale of the challenges requires transformational change to deliver logarithmic improvements  21 st century needs cannot be solved with 20 th century tools or organizational structures Translation involves both scientific AND organizational challenges Challenges will be addressed more effectively by focusing on the patient Health scientists can learn a lot from engineers!

44. Learn More About NCATS Website: www.ncats.nih.govwww.ncats.nih.gov Facebook: facebook.com/ncats.nih.gov Twitter: twitter.com/ncats_nih_gov YouTube: youtube.com/user/ncatsmedia E-Newsletter: ncats.nih.gov/news-and- events/e-news/e-news.html Email us! info@ncats.nih.govinfo@ncats.nih.gov