1. Leidos Biomedical Research & National Center for Advancing Translational Sciences (NCATS) Bradley Gillespie 6 May2014 RACD

2. Who am I? PharmD from the University of Illinois 7 years FDA: Clinical Pharmacology Reviewer 14 years Pharma/Biotech: Early Development 2 years PomWonderful: Built clinical development group, filed 2 IND 2-1/2 years at SAIC-F/Leidos: Director of Drug Development. Oversee virtual drug companies- TRND and BrIDGs

3. What is NCATS? Complicated organization with many moving parts- geared towards overcoming barriers, driving partnerships and innovation in drug development One part: Division of Preclinical Innovation (DPI) – Two pieces of DPI are my focus: Therapeutics for Rare and Neglected Disease (TRND) Bridging Interventional Development Gaps (BrIDGs)

4. Probe Devel/NCGC Preclinical Development/TRND RAID/BrIDGs Clinical FDA Collaboration Systems Toxicology (Tox21) RNAi Paradigm/Technology Development Repurposing Lead Optimization Probe/Lead Development Target FDA approval Clinical Trials I II III Project Entry Point Deliverables DPI 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 NCATS Division of Preclinical Innovation: An Integrated Pipeline Target assay Target Validation Preclinical Development

5. Typical NIH Mechanism ApplyReview $ Funding announcement Funding decision ApplyReview Collaborators Receive In-Kind Research in Partnership with NIH Scientists Solicitation at Proposal CENTRAL Select Projects & Form Joint Project Teams with Collaborators TRND/BrIDGs TRND/BrIDGs are Different

6. TRND

7. The Problem of Rare and Neglected Diseases >7,000 diseases affect humankind – but only a small fraction support commercial development of therapeutic agents Two types of neglected diseases: – Low prevalence, i.e., “rare” (<200,000 prevalence in U.S.) There are ~7,000 rare (orphan) diseases Cumulative prevalence in U.S. ~ 25 – 30 million <250 have any pharmacotherapy available – High prevalence but “neglected” Occur chiefly among impoverished and marginalized populations in developing nations (treatment costs prohibitive) Most are infectious

8. Effective Therapies are Needed

9. How Much Does Drug Development Cost? $1 Billion/per drug is the number that I have heard over the past several years Lilly Blog (2/12) states $1,300,000,000/per drug 1 – Unclear on how these were calculated, though I expect that it is actual costs for each approved therapeutic February 2012 Forbes article included development failures (Total R&D $/approvals) 2 : – $4,000,000,000-11,000,000,000 (description of risk) 1 http://lillypad.lilly.com/entry.php?id=1583 2 http://www.forbes.com/sites/matthewherper/2012/02/10/the-truly-staggering- cost-of-inventing-new-drugs

10. Cost of Rare and Neglected vs. Traditional Drug Development – It may be argued that the path to approval is shorter – Some say that the odds of approval are also higher than that of traditional drugs Unclear to me if any of this is true, regardless: – The cost of Orphan Drug Development is extremely costly

11. Drug Development: Risky Most candidates fail: Phase 2 failure rates are at an all time high 3 In one review, only 18% succeeded in Phase 2, of the failures: – 51% of these were due to insufficient efficacy – 29% were due to strategic reasons – 19% were due to safety concerns High Risk + Low Income = Muted Interest 3 Nat Rev Drug Discov, 10;328-9

12. How to pay? Orphans are becoming big business – Established, revenue-generating companies are getting involved Survey Sample: NORD Corporate Council- About 44 Pharma Companies, ranging from 1 employee with no revenue to 126,000 employees with revenue of approximately $65,000,000,000 NORD conclusion: Activity present, but still, not nearly enough commercial interest in most indications

13. What Can Be Done? Cannot increase the number of customers; and Difficult to control global economics; but Reduction of risk will shift the risk benefit analysis – Risk, or lack of, is data-driven Optimize the lead Scale up the process Understand the ADME Characterize the toxicology Conduct a solid Phase 1 study, and obtain human safety and efficacy data IND

14. Model: Collaboration between NIH intramural labs with preclinical drug development expertise and organizations with disease-area/target expertise Projects: – May enter at various stages of development, but prior to IND – Taken to stage needed to attract external organizations to adopt for clinical development (IND filing to Phase 2) Eligible Applicants: – Academic, Non-Profit, Government Lab, Small Business, or Large Biotech / Pharma – Ex-U.S. applicants accepted Therapeutics for Rare and Neglected Diseases (TRND) Program

15. Drug project-specific activities – New indications for clinical stage drugs and repurposing approved drugs – Medicinal chemistry – Rare disease bioassay development – Efficacy, pharmacology, ADME, toxicology, PK/PD – Compound scale-up, formulation – Clinical and regulatory development strategy, natural history study assessments – First in human clinical trials, and beyond, as needed (Almost) whatever it takes to de-risk agent and make it appealing for full partnering! TRND Features: R&D Capabilities

16. TRND Application Sources Round 1 Round 2

17. TRND Application Disease Areas Infectious Disease Cancer CNS All Other Cardiovasc. Pulmonary Muscular Metabolic Blood Skin Infectious Disease Cancer CNS Round 2 Cardiovascular Pulmonary Muscular Metabolic Blood Skin All Other Infectious Disease Cancer CNS Top Scoring Muscular Cardiovasc. Skin Infectious Disease Round 1 All Muscular Cardiovasc. Skin Blood Metabolic Renal Addictive All Other

18. TRND Portfolio Therapeutic Area / DiseaseCollaborator(s)AgentStatus Sickle Cell Disease Aes-Rx, NHLBI a NME – Small MoleculeClinical Chronic Lymphocytic Leukemia Leukemia & Lymphoma Society, University of Kansas Repurposed Drug – Small Molecule Clinical Hereditary Inclusion Body Myopathy New Zealand Pharmaceuticals, NHGRI b NME – Small MoleculeClinical Niemann-Pick Type C1 Johnson & Johnson, Albert Einstein College of Medicine, Univ. of Pennsylvania, Washington Univ., NICHD c, NINDS d, NHGRI Repurposed Drug - Small Molecule Preclinical Duchenne Muscular Dystrophy ReveraGen BioPharma NME – Small MoleculePreclinical Fragile X Syndrome Afraxis, Inc. NME - Small MoleculePreclinical Cryptococcal Meningitis Viamet Pharmaceuticals, Inc. NME - Small MoleculePreclinical Core Binding Factor Leukemia NHGRI Repurposed Drug - Small Molecule Preclinical Neonatal Herpes Simplex University of Alabama, NIAID e NME – Small MoleculePreclinical Autoimmune Pulmonary Alveolar Proteinosis Cincinnati Children’s Hospital Repurposed Drug - BiologicPreclinical Fibrodysplasia Ossificans Progressiva Massachusetts General Hospital NME - Small MoleculePreclinical Schistosomiasis CoNCERT Pharmaceuticals NME – Small MoleculePreclinical Creatine Transporter Defect Lumos Pharma NME - Small MoleculePreclinical Duchenne Muscular Dystrophy Sarepta Therapeutics NME – BiologicPreclinical a National Heart, Lung, and Blood Institute; b National Human Genome Research Institute; c Eunice Kennedy Shriver National Institute of Child Health and Human Development; d National Institute of Neurological Disorders and Stroke; e National Institute of Allergy and Infectious Diseases

19. 15 projects through pilot phase & 2 public solicitations since 2009 Mix of small molecules and biologics 4 investigational drugs taken into humans CLL: IND filed, safe to proceed Aug 5 th 2011 →Phase 1 trial commenced September 2011 SCD: IND filed, safe to proceed Nov 10 th 2011 →Phase 1 trial commenced December 2011 →Phase 2, patient trials in 2012 and 2013 ManNAc: IND filed, safe to proceed August 24, 2012 → Phase I trial commenced October 2012 NPC: IND filed, safe to proceed December 23, 2012 →Phase 1 trial commenced January 2013 Initiated two natural history studies →Niemann-Pick type C Disease (NPC) →Hereditary Inclusion Body Myopathy (HIBM) TRND Highlights

20. TRND: Sickle Cell Disease (SCD) AesRx, LLC Aes-103 5-hydroxymethyl-2-furfural (5-HMF)

21. SCD Rare and Neglected Primary market: -US: 75,000 (Orphan Drug) -EU: 40,000 Secondary market: -Middle East: 100,000 -India: 1,000,000 Tertiary market: -Sub-Saharan Africa: 12,000,000 o Nigeria: 2% births = 100,000 annually Total: > 13,000,000

22. Aes-103 (5-hydroxymethyl-2-furfural) Discovered at Virginia Commonwealth University (patents) AesRx: exclusive world-wide licensee Small molecule: 126 Da Increases the affinity of HbS for oxygen Orally bioavailable Safe in animal studies when given in large doses NIH SCDRL (NIH Sickle Cell Disease Reference Laboratory): screened 700 compounds, Aes-103 is one of the most potent anti-sickling compounds AesRx hoped to commence Phase 1 clinical trials by 2010, but lacked funding to conduct pre-clinical or clinical studies

23. Initial Development Plan Beginning status: pre-IND API (active pharmaceutical ingredient) available via a RAID (now BrIDGs) grant 3-year plan – IND enabling pre-clinical – First in Human Trial – Proof of Concept in patients – End of Phase 2 meeting But, no money and no partners

24. First TRND Partnership IND-enabling pre-clinical – Pharmacology, ADME, toxicology GMP API synthesis Formulation Regulatory Affairs Clinical Trials – FIH – Two phase 2 trials AesRx actively seeking a full development partner

25. Bridging Interventional Development Gaps (BrIDGs) Program Model: In-kind, government contract-based services provided to overcome obstacles in later-stage preclinical development Projects: – May address any disease or disorder, regardless of prevalence or incidence – May require only one or two key development steps Eligible Applicants: – Academic, Non-Profit, or SBIR Eligible Small Business – Ex-U.S. applicants accepted, but businesses must satisfy SBIR criteria

26. Bridging Interventional Development Gaps (BrIDGs) Program NIH-wide contract-access program that assists public or private entities with steps needed to transition from identified clinical candidate to IND ● Supported by the NIH Common Fund ● Provides access to contract services for: ● Production/bulk supply ● GMP manufacturing ● Formulation ● Pharmacokinetic testing ● Animal toxicology ● Manufacture of clinical trial supplies ● Product development planning and advice in IND preparation Involvement terminates at time of IND Filing

27. 180 applications submitted between 2005 – 2011 34 approved projects since 2006 27 different diseases 10 rare or neglected disease projects 11 NIH ICs have co-funded projects 18 completed projects have contributed to 12 INDs 8 projects are in the clinic 3 are in Phase II testing 5 agents were licensed during / after BrIDGs involvement BrIDGs Portfolio

28. Active BrIDGs Projects ApplicantOrganization NameOrg TypeAgentDis TypeFunding Au, JessieOptimum Therapeutics Small business Small 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 Biotechnology Small business OligonucleotideAlzheimer's diseaseCF/NIA De Leon, DivaChildren's Hospital of PhiladelphiaAcademicPeptideHyperinsulinismCommon Fund Donn, KarlParion Sciences, inc. Small business Small 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 syndromeCF/NIAAA Ma, Jian-xing University of Oklahoma Health Sciences Center Academic*Small MoleculeDiabetic retinopathyCommon Fund Mannstadt, Michael Massachusetts General HospitalAcademic*PeptideHypoparathyroidismCommon Fund Mellon, Synthia University of California San Francisco AcademicSmall MoleculeNiemann-pick CCF/NINDS Miller, KennethKemmx Corporation Small business Small moleculeRheumatoid arthritisCF/NIAMS Rogawski, MichaelUniversity of California, DavisAcademic*Small moleculeEpilepsyCF/NINDS Sutula, ThomasUniversity of Wisconsin MadisonAcademic*Small MoleculeEpilepsyCommon Fund Turner, ScottKinemed, Inc. Small business PeptideAtherosclerosisCommon Fund * Investigator is partnered with a company

29. BrIDGs: PF614 Abuse Resistant Opioid Prodrug Program

30. Description of the Problem Prescription opioid abuse and addiction are major burdens to patients and society, resulting in significant costs, illnesses, and deaths. The intertwined issues of – i) the widespread and increasing abuse of prescription opioids; and – ii) reluctance of prescribers to write prescriptions for opioid analgesics: Has resulted in the under-treatment of patients with moderate-to severe pain.

31. PF614: novel delivery technology PF614 is an oxycodone-derived molecular delivery system Designed to resist both oral and non-oral modes of abuse – unaffected by simple physical manipulations (e.g. extraction and/or chewing of the dose form provided to patients – manufactured in a pro-drug, inactive form that becomes effective only when ingested and exposed to trypsin – Inactive in blood, and does not cross the BBB

32. PF614 BrIDGS Support Synthesis of drug material for preclinical and phase 1 clinical studies; Packaging of clinical trial supply; stability studies on drug substance and drug supply Toxicology, genotoxicity and safety pharmacology studies ADME studies Everything needed to file an IND

33. BrIDGsTRND Contract ResourceTeam-based Collaboration PI must have a lead agentPI may start with lead optimization No clinical trial support providedSome clinical trial support provided IP retained by ownerNIH may generate IP Universal disease scopeRare and neglected diseases only Investigator prepares INDRegulatory affairs assistance provided Which Program Is A Fit?