Rigor Through the Lens of Drug Discovery and Development The game Culture and incentives Our experiences

Drug Discovery Components: It takes a village Biological target (clear link to disease), tractable Predictive in vitro assays that allow decision making Animal models of disease progression and/or symptoms: Often not validated, low volume, inconsistent Tractable chemical matter: SAR, solubility, crystallinity ADME and safety Intellectual property Identification of an accessible clinical population Objective clinical endpoints: dose setting, proof of concept, registration. Drug discovery is difficult, multi-factorial, expensive, and tedious

Why is it difficult for academics to do drug discovery and development? Resources: Money, time, and access to multiple non-academic skill sets Incentives/ Culture

Incentives Feakanomics (Steven Levitt and Stephen Dubner) – “Incentives are the cornerstone of modern life…and understanding them is the key to solving just about any riddle.” – “There are three flavors of incentives: economic, social, and moral. Academic and Industrial cultures/ incentives traditionally differ – Academia: novelty, publication (patent)/ shared results, recognition, shorter time horizon. Objective: new knowledge – Industry: novelty (exclusivity), patent/secrecy (publication), drug’s progress over time (longer time horizon). Objective: clinical compound Challenge: How can you change the incentives and resources for academics to get the desired results: credible and predictable data that leads eventually to clinical trial.

Clinical Trials Target ID Assay Screening Proof of Concept Lead Optimization Candidate Selection Pre-clinical Safety Molecular LibrariesNIH RAID Blueprint Neurotherapeutics Active Small molecule Phase I Clinical Success R01s Blueprint NeuRx Industry Early chemical matter -> Chemical optimization -> Pre-IND -> Phase 1 -> License Blueprint Neurotherapeutics Network: Scope 16 NIH Institutes and Centers Participate (NINDS, NCRR, NEI, NIA, NIAAA, NICHD, NIDA, NIDCD, NIEHS, NIMH, etc)

Blueprint: Virtual Pharma Model Solicit investigator-initiated ideas (U01 RFA)  Novel/ interesting drug targets  Strong disease assays and models Blueprint provides industry expertise  Industry-standard contract services  Industry-seasoned advisors and consultants

BP Learnings : What is important? A clinical path. Target candidate profile and Alice Predictive power and throughput of the primary and secondary assays. Tractable chemical matter: Potency, efficacy, SAR, ADMET, IP Credible and predictive in vivo model Formulation for in vitro and in vivo work Key skills on or accessible to teams: biology, medchem, adme, safety, intellectual property, formulation Clear, measurable and meaningful milestones. Gating and review Jeffersonian triage IP and partnering What is not a factor in approving a project: Market size, past drug development experience

PKD Foundation Experience Disease: chronic, proliferative, inflammatory Clinical outcome: transplant Therapy: chronic, safe, disease modification Strategy: Repurposing Compound choice: candidate, logical target, safe enough, PK Carrot for industry: no upfront cost Tactic: Funded CRO (models: 2 mouse, 1 rat) Why CRO: Consistency (standardization), confidence in result, confidential, cost, choice of compound Outcome first 12 months: one impressive result, pitch to major donors ($)

TRND Portfolio June 2012 CollaboratorOrganization Name(s)Partner Type(s)AgentTherapeutic 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 ProjectNew Zealand Pharmaceuticals, NHGRI Biotech, NIH Intramural Intermediate Replacement Hereditary Inclusion Body Myopathy TRND Pilot ProjectAes-Rx, NHLBI Biotech, NIH Intramural NMESickle Cell Disease TRND Pilot Project Leukemia & Lymphoma Society, Kansas Univ. Cancer Center, NHLBI Disease Foundation, Academic, NIH Intramural Repurposed Approved Drug Chronic Lymphocytic Leukemia Reeves, EricaReveraGen BioPharma BiotechNMEDuchenne Muscular Dystrophy Campbell, DavidAfraxis, Inc. BiotechNMEFragile X Syndrome Garvey, EdwardViamet Pharmaceuticals, Inc. BiotechNMECryptococcal Meningitis Liu, PaulNHGRI NIH IntramuralNMECore Binding Factor Leukemia Kimberlin, DavidUniversity of Alabama Academic Nucleotide Analog Pro-drug Neonatal Herpes Simplex Trapnell, BruceCincinnati Children’s Hospital AcademicBiologic (protein) Autoimmune Pulmonary Alveolar Proteinosis Bloch, KennethMassachusetts General Hospital AcademicNME Fibrodysplasia Ossificans Progressiva Liu, JulieCoNCERT Pharmaceuticals BiotechNMESchistosomiasis Davis, RobertLumos Pharma BiotechNMECreatine Transporter Defect Sazani, PeterAVI BioPharma, Inc. BiotechBiologic (PMO)Duchenne Muscular Dystrophy