Innovative Strategies to Accelerate Academic Drug Discovery. Vincent Groppi, Ph.D Director Center for the Discovery of New Medicines

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1 Innovative Strategies to Accelerate Academic Drug Discovery Vincent Groppi, Ph.D Director Center for the Discovery of New Medicines

2 9 out of 10 Drugs Fail Hay, Thomas, Craighead, Economides & Rosenthal. Nature Biotechnology 2014 Figure 2 Phase success and LOA from phase 1 by disease for all indications. The bars represent phase 2 and phase 3 success rates and the line represents LOA from phase 1 2

3 CDNM Improves the Odds for Success Why academic drug discovery? The primary focus of academic researchers is basic science. Over years this builds unparalleled expertise, and unique entry points to create novel and needed therapeutics. Why U-M? We are a research powerhouse with $1.3 billion in research expenditures, including $700 million in the biosciences. U-M ranks No. 3 among public universities for National Institutes of Health awards. And we re home to more than 100 top 10-ranked graduate programs. Why CDNM? The Center for the Discovery of New Medicines partners with U-M researchers to accelerate drug discovery by identifying, funding and mentoring the most promising projects from across the university.

Funded by NIH & NSF grants PI driven Characteristics Improves standard of care Societal Impact Broad and

4 Translational Research Builds on a Foundation of Basic Research Basic Research Translational Research Advances scientific knowledge Science Impact Silo; Inch wide and mile deep Exploratory; Novel discoveries Funded by NIH & NSF grants PI driven Characteristics Improves standard of care Societal Impact Broad and cross functional Focused; Milestone-based plan (fail fast) Funded by grants, foundations, alliances Team based 4

5 Sweet Spot for Project Selection There is broad interest in all life science departments at U-M for translating basic science observations into therapeutic based projects. There are a large and growing resources to start and advance projects with potential to generate therapeutic agents Goal: Make U-M a leader in academic drug discovery Commercial Opportunity ~200 projects at U-M Guidance Funding Expertise Unmet Medical Need Scientific Strength Partnering licensing CDNM PROJECT

6 CDNM is the Science Hub of Drug Discovery Grant funding of up to $50,000 to U-M faculty, primarily for use in core labs. Guidance through the labyrinth of the drug discovery process, from concept to clinical trial. Expertise in today s leading drug discovery technologies and strategies. Project support that allows faculty to remain focused on basic science while advancing drug discovery projects. Connections between basic researchers, clinicians and drug discovery experts to give promising projects their best chance of success. Industry alliances work with FFMI and OTT to ensure discoveries can benefit patients as soon as possible. Education and training for faculty students and staff.

NINDS Virtual Pharma Model of Drug Discovery Rubel Hearing Loss Project Case Study Lead Development Team Principal investigator * Industry-seasoned consultants NIH staff (navigator) Bioactivity/

7 NINDS Virtual Pharma Model of Drug Discovery Rubel Hearing Loss Project Case Study Lead Development Team Principal investigator * Industry-seasoned consultants NIH staff (navigator) Bioactivity/ Efficacy Studies Medicinal Chemistry (AMRI) PK/Tox (Southern, SRI) GMP/ Formulation Ph 1 Clinical Trials *10% commitment PI Retains IP NIH Contracts Disclosure: I am a cofounder of Oricula Therapeutics 7

8 Zebrafish Hair Cell Phenotypic Screen 8

BPN-001: Represented an Early Drug-like Lead NH 2 Cl O HN S N BPN-001 was identified from the ChemBridge library of compounds N H O Key Facts Molecular Weight 378.88 Zebrafish ED50: 3.

9 BPN-001: Represented an Early Drug-like Lead NH 2 Cl O HN S N BPN-001 was identified from the ChemBridge library of compounds N H O Key Facts Molecular Weight Zebrafish ED50: 3.0 μm Maximum hair cell protection: 100% No significant CYP inhibition Acceptable aqueous stability No measurable cytotoxicity up to 300 µm Cell permeable Excellent microsomal stability across species No reactive metabolites detected Orally bioavailable and brain penetrant in rat PK t½ in the rat is comparable with AGs 9

10 ED 50 (µm) SAR to Improve Potency and ADME Over 350 compounds synthesized PROTO1 Class A: ED50 <100 nm Cl O N H HN NH 2 O S BPN-001 ED μm N Class B: ED nm Class C: ED50 <100 nm Maximum % Hair Cell Survival Use Patent Granted Composition of Matter Patents Granted Lead compounds active in vivo rat model of hearing loss 10

Expertise CDNM Drug Discovery Core Labs Located in LSI Led by a full-time Director Open to all investigators Oversight by

11 CDNM Accelerates Drug Discovery at U-M Supported by LSI College of Pharmacy Comprehensive Cancer Center Office of the Provost Department of Internal Medicine Department of Pathology The Endowment for the Basic Sciences Multidisciplinary Expertise CDNM Drug Discovery Core Labs Located in LSI Led by a full-time Director Open to all investigators Oversight by an Executive Committee HTS (CCG) Structure (CSB) Med Chem (VMCC) PK Pharm Sci Pre-clinical Safety (MSU) Clinical CTSA In Progress

Integrating U-M s Drug Discovery and Development Create a coordinated, university-wide base of operations to advance translational therapeutic projects PFD

12 Integrating U-M s Drug Discovery and Development Create a coordinated, university-wide base of operations to advance translational therapeutic projects PFD Cancer Center Forbes Institute LSI Med School Pharmacy LSA Dental Engineering Cores LSI CDNM MCTI Cores CoP FFMI OTT MICHR Ross ISR Clinical Nodes T0 T1 T2 IHPI T3

13 Protein Folding Disease Projects Osawa Chaperones Vesicular Trafficking Weisman Endoplasmic reticulum, Ca Amyloid and metabolism ++ Wang Chapman

14 PFD Pharma Showcase Project Dashboard 14

15 Funding Through NIH Style Request for Application (RFA) CDNM established the criteria for the RFA and selected the members of the review panel for the scientific evaluation of submitted proposals. After funding, each project is tracked and mentored biannually. The impact of the funded projects is evaluated by measuring downstream funding, invention reports, patent applications, licensing, etc. 32 Projects funded since launch in 2012 $852K Granted to faculty to advance drug discovery projects to date $11.9 M Downstream funding of supported projects

CENTER FOR CHEMICAL GENOMICS (CCG) High-throughput screening (HTS)

to utilize sirna, chemical and natural product collections for

for biochemical and cellbased assays 160,000 small molecules and

high-throughput screening Works in close association with med chem,

groups MScreen database reached 13 million data points in 2014 A

institutions Anti-viral 5% Other 14% Metabolic 12% Anti-cancer 31%

16 CENTER FOR CHEMICAL GENOMICS (CCG) High-throughput screening (HTS) expertise with attendant liquid handling and instrumentation needed to utilize sirna, chemical and natural product collections for early-state drug discovery FACILITIES Large collection of instruments for biochemical and cellbased assays 160,000 small molecules and 33,000 natural product extracts RNAi, shrna whole genome high-throughput screening Works in close association with med chem, structure-based design, protein expression groups and pharmacokinetic groups MScreen database reached 13 million data points in 2014 A software-as-a-service agreement makes MScreen available to other institutions Anti-viral 5% Other 14% Metabolic 12% Anti-cancer 31% Anti-bacterial 26% Neuro 9% CV 3% Personnel 6 FTEs with deep experience in all aspect of HTS THERAPEUTIC AREAS

17 NPE Drug Lead Discovery Schematic Sample Collection Natural Product Extracts (NPE) Generation Target Based HTS Assay Developme nt High Throughput Screening Strain Identificatio n and Confirmatio n Natural Product Extracts (NPEs) Generation and High-throughput Screening (HTS) at Center for Chemical Genomics (CCG)

18 CENTER FOR STRUCTURAL BIOLOGY (CSB) High-throughput cloning & protein expression Sequence tailoring Expression testing E. coli, insect & mammalian cells Protein production Scaled-up expression Insect & mammalian cells Protein purification Biophysical characterization Stability, binding Crystallization Protein RNA Structure determination & analysis Crystal characterization & data collection Synchrotron access Crystal structure determination Structure analysis & bioinformatics Electron cryo-microscopy

19 Capabilities of VMCC Follow-up of HTS actives Hit triage Structure-activity relationship (SAR) analysis and expansion Lead selection Analog design and synthesis to improve: Potency/selectivity PK properties (solubility, permeability and metabolic stability) Scale up synthesis for in vivo PK and efficacy studies Collaborative grant preparation Patenting advice and assistance Custom synthesis Computational chemistry Structure-based drug design Ligand- and site-based virtual screening Physical property prediction

Major Achievements and Impact of VMCC Analog design/synthesis for 29 projects (7 with external collaborators) 7 project resulted in achieving in vivo efficacy Over 60

20 Major Achievements and Impact of VMCC Analog design/synthesis for 29 projects (7 with external collaborators) 7 project resulted in achieving in vivo efficacy Over 60 publications 23 patent applications (7 granted US patents) 64 funded grants $41 M in direct funds to UM (external) $8 M in direct funds to VMCC (internal and external)

Pharmacokinetic Core (PK Core) Metabolite identification In Vivo Animal PK Enzyme Inhibition LC-MS Bioanalysis Preclinical and Clinical Pharmacokinetics PK Modeling and Dose Optimization In human

21 Pharmacokinetic Core (PK Core) Metabolite identification In Vivo Animal PK Enzyme Inhibition LC-MS Bioanalysis Preclinical and Clinical Pharmacokinetics PK Modeling and Dose Optimization In human Microsomal Stability Monitor Drug Concentration in Human Protein Binding B/P ratio Enzyme Induction Enzyme Identification FY 2015 By the Numbers 445 compounds has been screened with different assay 10 publications 33 grant applications supported 45 U-M labs supported 5 external collaborations PK core supports lead candidate selection in drug discovery and dose optimization in clinical trials; PK core offers standard and customized preclinical ADME studies and clinical pharmacokinetics The Last Five Years PK Core has expanded to 13 full time employees and 5 instruments, including 3 LC-MS Completed DMPK studies for more than 2200 compounds Supported 10 clinical trials Contributed to more than 100 grant applications, which resulted in over $43 million in funding to UM Published 30 papers 5 patents issued and 6 pending Participated in three oncology drugs license agreements Consulted more than 70 U-M labs and 20 external labs Future Plans Set up a mass spectrometry imaging system for drug distribution in tissues and biomarker identification in preclinical and clinical tissue samples

CDNM s Approach to Driving Drug Discovery at U-M Milestone-driven project plan based on the technical aspects of the project and the medical need Evaluation of commercial potential is part of the

22 CDNM s Approach to Driving Drug Discovery at U-M Milestone-driven project plan based on the technical aspects of the project and the medical need Evaluation of commercial potential is part of the portfolio management process PIs commit as little as 10% their time for each project Project work done by experts in core labs Allows PIs to continue to devote their time to basic research and education Project management support growing Co-PI can be added if needed (future) Fail fast - Identify and experimentally address risks early Project plan constructed with quantitative go/no go criteria

23 Summary of CDNM s Drug Discovery Portfolio Therapeutic Area Projects Cancer 8 CV/Atherosclerosis/Inflammation 5 Infectious Disease 5 Neuroscience 3 Renal Disease 2

24 Examples from the CDNM pipeline 20 Active Projects Ron Buckanovich (Cancer) ADLH as drug target to treat ovarian and forms of cancer. 140,000 deaths/year high unmet need. Accelerated the project by leveraging chemical matter via a collaboration; Supported by CDNM/Stuart Family Fund Vern Carruthers (Microbiology) Cathepsin is a genetically validated target for treating toxoplasmosis; 60 million Americans are chronically infected with this parasite; High quality screening hits plus structure-based drug design provide the path for the selection of an advanced lead molecule Ray Trievel, Wen Ju (Biochemistry and Nephrology) Precision medicine strategy identified a novel drug target for treating chronic kidney disease and other indications; Current standard of care is dialysis and transplant; Biochemical and screening expertise at U-M accelerated the project timeline

25 Potential at U-M There is broad interest in all life science departments at U-M for translating basic science observations into therapeutic based projects. Initial estimates indicate that there are as many as 200 projects with potential to generate therapeutic agents Multiple targets from Protein Folding Disease Initiative; 5 yr program Multiple targets for treating CKD; Precision Medicine Multiple targets for treating central pain; Precision Medicine Novel growth factor PAM approach for treating small fiber neuropathy; Genetics and small molecule pharmacology Innovative Cancer Projects New approaches for treating infectious diseases ~200 projects at U-M optimized support & guidance 5-10% success rate (licensing, LLC, IND, etc.)

26 Future: Continuous Project Funding Granted at Milestones Similar to The Blavatnik Center for Drug Discovery at Harvard 26

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