Tackling Translational Challenges

14th Annual

WORLD PRECLINICAL June 10-12, 2015 CONGRESS Westin Boston Waterfront, Boston, MA Tackling Translational Challenges

June 10-11 June 11-12 Preclinical Models in Oncology Tumor Models for Immunotherapy Imaging in Oncology 3D Cellular Models Targeting GPCRs Targeting Histone Acetylation Predicting Drug Toxicity Functional Genomics Technologies Blood-Brain Barrier

Mastering Medicinal Chemistry Property-Based Drug Design Chemical Biology for Chemical Proteomics for Target Validation Target Validation

EVENT HIGHLIGHTS:

• 13 conferences covering the hottest • 11 short courses offering interactive • Student fellowships bringing together young topics in preclinical research discussions with experts in the field researchers looking to make a difference • 950+ international delegates focusing • Exclusive training seminar on Applying • Expansive exhibit hall showcasing 65+ on preclinical research and the Pharmacology to New Drug Discovery sponsors & exhibitors challenges and opportunities in early • Plenary keynote panel featuring experts • Dedicated poster viewing, roundtables drug discovery and development talking about the breakthrough drugs in and panel discussions for active networking recent years

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Organized by: Cambridge Healthtech Institute WorldPharmaCongress.com Conference-at-a-Glance

Tuesday, June 9 Pre-Conference Short Courses* * Separate registration required.

Translational Chemical Novel Preclinical New Models for Mastering Imaging in Targeting Blood-Brain Biology Models in Predicting Drug Medicinal Cancer Drug GPCRs Barrier for Target Wednesday, Oncology Toxicity Chemistry Development Validation June 10

Plenary Keynote Panel

Applying Thursday, Synergistic Use Property-Based Chemical Tumor Models Targeting Pharmacology June 11 3D Cellular of Functional Drug Design Proteomics for Cancer Histone to New Drug Models Genomics in Medicinal for Target Immunotherapy Acetylation Discovery Technologies Chemistry Validation Training Seminar*

Dinner Short Courses* * Separate registration required.

Applying Synergistic Use Property-Based Chemical Tumor Models Targeting Pharmacology Friday, 3D Cellular of Functional Drug Design Proteomics for Cancer Histone to New Drug June 12 Models Genomics in Medicinal for Target Immunotherapy Acetylation Discovery Technologies Chemistry Validation Training Seminar*

Tackling Translational Plenary Keynote Panel Plenary Keynote Panelists: Challenges Wednesday, June 10 | 5:00 pm Clinical Development of Keytruda David Kaufman, M.D., Ph.D., Director/ The World Preclinical Congress (WPC; formerly the Our Plenary Keynote Panel this year Senior Principal Scientist, Oncology/ th World Pharma Congress), now in its 14 year, is making features senior executives from pharma/ Immunotherapy Clinical Research, Merck a commitment to focus predominantly on preclinical biotech who have played an important Discovery of Ivacaftor, an Orally research and highlight the challenges and opportunities role in bringing to market some of the Bioavailable CFTR Potentiator in early drug discovery and development. World most innovative drugs in recent years. Peter Grootenhuis, Ph.D., Senior Director, Preclinical Congress 2015 brings together some of They are here to share their stories on Chemistry, Vertex Pharmaceuticals the hottest topics being discussed in the pharma/ what transpired behind-the-scenes, how biotech world and provides a unique forum for scientists they could overcome the translational Harvoni Drug Development and clinicians to exchange ideas and collaborate to challenges, and what they see as key Challenges: The Role of Risk in overcome some of the translational challenges. This drivers in making similar breakthroughs Rapid Development coincides with the event moving to Boston, now a going forward. Phillip Pang, M.D., Ph.D., Director, Clinical premier hub for preclinical activity and alliances. Research, Gilead Sciences

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CORPORATE SUPPORT SPONSOR

WorldPharmaCongress.com World Preclincial Congress | 2 SHORT COURSES

Student Fellowship

Full time graduate students and PhD Candidates are encouraged to apply for the World Preclinical Congress Student Fellowship. Applications are due by March 27, 2015.

• Interested students must complete the application • This fellowship is limited to 10 students and is for for the 2015 Student Fellowship the Main Conference Only*, June 10-12, 2015. • Fellows are required to present a scientific poster. • All accepted 2015 Student Fellows will be asked to A poster title and abstract are due at the time of help promote the conference onsite at their college, the application. and throughout their social media networks. • All applications will be reviewed by the scientific • Students not accepted for the 2015 Student review committee and the accepted students will Fellowship, can register at a discounted rate $295*, be notified no later than April 3, 2015 if they were and will not be required to present a poster accepted for the 2015 Student Fellowship • Accepted 2015 Student Fellows will receive a discounted conference rate of $195*, which must be paid in full by April 24, 2015. Credit card information is requested at the time of the application and will be charged upon application approval.

* This discounted rate cannot be combined with any other discounts for this event. Your discounted registration does not grant access to any of the short courses or pre-conference events. It also does not include hotel, travel or meals.

Hotel & Travel Information

Take advantage of the Car Rental Discounts: discounted group rate! Special discount rentals have been established with Hertz for this conference. • Visit www.hertz.com to make your reservation and use Hertz Convention Number (CV) 04KL0006 • Call Hertz directly at 800-654-3131 and reference our Hertz Convention Number 04KL0006 Conference Venue and Host Hotel: Top Reasons to Stay at the Westin Boston Waterfront Hotel Westin Boston Waterfront • Just three miles from Boston’s Logan 425 Summer St. International Airport Boston, MA 02210 • Complimentary wireless internet access in guest rooms T: 617-532-4600 • A short walk, bus, taxi or train ride to Room Rate: $299 s/d Boston’s historic sites and family attractions Reservation Cutoff: May 13, 2015 • Minutes from some of Boston’s finest restaurants Please visit the hotel and travel page of our website to • Pet friendly reserve your sleeping accommodations. You will need to identify yourself as a Cambridge Healthtech Institute We understand that you have many choices when conference attendee to receive the discounted room making your travel arrangements. Please understand rate with the host hotel. Reservations made after the that reserving your room in the CHI room block at the cut-off date or after the group room block has been filled conference hotel allows you to take full advantage (whichever comes first) will be accepted on a space- of the conference sessions, events and networking and-rate-availability basis. Rooms are limited, so please opportunities, and ensures that our staff will be book early. available to help should you have any issues with your accommodations.

WorldPharmaCongress.com World Preclincial Congress | 3 2014 Attendee Demographics

COMPANY TYPE COMPANY TITLE GEOGRAPHIC LOCATION

Commercial (Pharma/Biotech) 58% Scientist/Technologist 42% USA* 72% Academic 24% Executive/Director/Manager 31% Europe 14% Healthcare/Hospital 8% Professor 15% Asia 9% Government 5% Sales/Marketing 12% Other 5% Services/Societies 4% *USA Breakdown:

Press 1% East Coast 75% West Coast 14% Midwest 11%

A focused group with a diversified background. The interaction among the attendees was superb. “ Senior ”Principal Scientist, Chemical R&D, Pfizer

PRESENT A POSTER AND SAVE $50! Cambridge Healthtech Institute encourages attendees to gain further Reasons you should present your research poster at this conference: exposure by sharing their work in the poster sessions. To secure a • Your poster will be seen by our international delegation, representing poster board and inclusion in the conference materials, your abstract leaders from top pharmaceutical, biotech, academic and must be submitted, approved and your registration paid in full by government institutions April 24, 2015. • Receive $50 off your registration Register online, or by phone, fax or mail. Please indicate that you would like to present a poster. Once your registration has been fully • Your poster abstract will be published in our conference materials processed, we will send an email with a unique link and instructions for submitting your abstract using our online abstract submission tool. Please see the website for more details.

WorldPharmaCongress.com World Preclincial Congress | 4 June 9, 2015 | Boston, MA SHORT COURSES*

Afternoon Courses | 2:00 – 5:00 pm Dinner Courses | 6:00 – 9:00 pm

AllostericStudent Modulators of GPCRs, Fellowship (PAMs NAMs) Understanding and Dealing with Drug Disposition in CNS The course will provide an overview on allosteric modulation of class A, B and C Topics to be covered: GPCRs: screening, molecular pharmacology, signal bias, medicinal chemistry and • Enabling faster compound selection in CNS drug discovery by Pharmacokinetics/ development challenges. For each of these areas, we will cover the theory and best pharmacodynamics (PK/PD) modeling and simulation. practices while delving into case studies to highlight key challenges and caveats. • Disposition of Biologics: the absorption, distribution and clearance of bio- Instructors: therapeutics Corey Hopkins, Ph.D., Research Assistant Professor, Vanderbilt Center for • Kinetic relationship between systemic circulation and CNS Neuroscience Drug Discovery • Understanding Factors that affect Brain ISF/CSF production and clearance and Cody J. Wenthur, Pharm. D., Graduate Student, Department of Pharmacology, its implications Vanderbilt University Medical Center Onset of CNS diseases Drug – drug interaction Imaging of Blood-Brain Barrier Function Dosing strategy for drugs that may have CNS implications. Topics to be covered: Instructors: Qin Wang, Ph.D., Principal Scientist, Translational Sciences, Biogen Idec • Review of structure and function of the BBB and delivering therapeutic agents to specific regions of the brain Margareta Hammarlund-Udenaes, Ph.D., Professor, Translational PK/PD, Department of Pharmaceutical Biosciences, Uppsala University • In vitro imaging, both qualitative and quantitative, microscopy and other imaging techniques Sponsored by Navigating the CiPA Landscape • In vivo imaging in animals, both qualitative and quantitative using different imaging modalities, nuclear, ultrasound, MRI and optical This dinner course will provide an important update on the CiPA (Comprehensive in vitro Proarrhythmia Assay) initiative. Present ICH S7A and S7B • In vivo imaging in humans, both qualitative and quantitative guidelines regulate non-clinical testing for cardiovascular safety. The ICH guidelines have Instructors: focused on QT/QTc intervals and potential arrhythmia. Experience has shown, however, King C. Li, M.D., FRCP(C), MBA, Senior Associate Dean for Clinical and Translational that cardiovascular assessment should include more than the hERG assay and evaluation Research; Professor and Chair, Department of Radiology, Wake Forest School of of other ion channels should be considered for a more comprehensive cardiovascular Medicine evaluation. The session will introduce and review these ion channel assays, describe other Lawrence Berliner, Ph.D., Professor of Chemistry and Biochemistry, University of in vitro assays (i.e., stem cells cardiomyocytes), and in vivo and secondary cardiovascular Denver; Emeritus, Ohio State University assays. The current pharmaceutical and regulatory thinking process of cardiovascular evaluation will be discussed, including a proposal of modification/elimination of ICH E14. Drug Metabolism and Its Impact on Decisions in Drug Discovery & Instructors: Development Arthur M. “Buzz” Brown, M.D., Ph.D., Managing Director, ChanTest, a Charles River Company This short course will focus on concepts important for those wanting to understand how drug metabolism is applied to drug discovery and development. Topics Bernard Fermini, Ph.D., Associate Research Fellow, Global Safety Pharmacology, will include how drugs are metabolized, the enzymes involved and the growing Pfizer Global Research & Development importance of transporters in drug disposition and safety. Those scientists involved Gary Gintant, Ph.D., Research Fellow, Integrative Pharmacology, Abbvie in medicinal chemistry, pharmacology and drug metabolism will benefit from this overview. Jeremy N. Ruskin, M.D., Professor of Medicine, Harvard Medical School; Director, Cardiac Arrhythmia Service, Massachusetts General Hospital • Biotransformation and the role of metabolism in drug toxicity • Strategies to identify drug metabolites • Enzymes involved in the metabolism of drugs * Separate registration required. • Metabolism-based drug-drug interactions • Transporters relevant for drug uptake and efflux • Experimental systems to investigate transporters Instructors: David Stresser, Program Manager, Corning Gentest Contract Research Services John Erve, Ph.D., DABT, Jerve Scientific Consulting, Inc. Mingxiang Liao, Ph.D., Senior Scientist I, DMPK, Takeda Pharmaceutical Intl. Company

WorldPharmaCongress.com World Preclincial Congress | 5 June 11, 2015 | Boston, MA SHORT COURSES*

Dinner Courses | 7:00 – 10:00 pm 3D Printing The promise of 3D bioprinting to create human tissues layer by layer is immense. How to BestStudent Utilize Organotypic Fellowship 3D Cell Cultures in Oncology Creating viable 3D screening models can lead to more effective drug development and more accurate drug testing. However, organ and tissue structures vary in The course will provide an overview of the various 3D cell culture models available, complexity, and printing with living cells is complicated. their strengths and weaknesses, and where and how these models are being used, specifically for oncology research. The instructors will share their experiences on Topics to be covered: how they tested and evaluated various cell culture reagents and growth matrices, • 3D Printer Platforms: Inkjet vs. Pressurized Printing what worked and what didn’t and what you need to consider when setting up low • 3D Modeling (CAT Scans, Laser Scans and CAD) and high throughput screening experiments using 3D cell cultures in your lab. The challenges working with 3D cell cultures, from experimental design to data analysis • Scaffold Selection will be discussed. • Cell Source Selection Instructors: • Bioinks • Vascularization Arvind Rao, Ph.D., Assistant Professor, Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center This dinner course is designed for biological researchers who are interested in learning more about 3D bioprinting, applying it to building a living tissue or organ of Geoffrey A. Bartholomeusz, Ph.D., Associate Professor and Director of the siRNA their choice and understanding the potential role in pharmaceutical drug research. Core Facility, Department of Experimental Therapeutics, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center Instructors: Sophie Lelièvre, D.V.M., LLM, Ph.D., Professor, Department of Basic Medical Michael Drues, Ph.D., President, Vascular Sciences Sciences; Associate Director, Collaborative Science, NCI-Designated Purdue Center Richard J. Gilbert, M.D., Research Professor, Department of Chemistry and for Cancer Research, Purdue University Chemical Biology, Northeastern University David Kolesky, Research Scientist, Jennifer Lewis Laboratory, School of Engineering and Applied Sciences and Wyss Institute for Biologically Inspired Engineering, Harvard University

PDX Models Update Topics to be covered: • PDX technology: core principles and latest advances • Major applications including novel ones such as, circulating tumor cell-derived PDX advancements • PDX models to study the immune response of cancer patients to their tumors, and others • Utilizing data to inform clinical decisions Instructors: Richard B. Bankert, V.M.D., Ph.D., Professor, Department of Microbiology and Immunology, State University of New York at Buffalo Neal Goodwin, Ph.D., Vice President Corporate Research Development Champions Oncology, Inc. Additional Instructors to be Announced * Separate registration required.

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WorldPharmaCongress.com World Preclincial Congress | 6 June 11-12, 2015 | Boston, MA Applying Pharmacology to New Drug Discovery The System-Independent Quantification of Molecular Drug Properties for Prediction of Therapeutic Utility

Course Outline Thursday, June 11 | 2:00 - 6:30 pm 1. Assay Formats/Experimental Design a. Binding Friday, June 12 | 8:00 am - 3:30 pm b. Functional Assays c. Null Method Assays

Over the past 6 six years, the primary cause of new drug candidate failures (50%) 2. Agonism has been failure of therapeutic efficacy. Put another way, drug discovery programs a. Agonist Affinity/Efficacy do everything right, get the defined candidate molecule, only to have it fail in b. Black/Leff Operational model therapeutic trials. Among the most prevalent reasons proposed for this shortcoming is the lack of translation of in vitro and recombinant drug activity to therapeutic in 3. Biased Signaling (Agonism) vivo whole systems. Drug activity in complete systems can be characterized with the a. Mechanism of Biased Signaling application of pharmacological principles which translate drug behaviors in various b. Quantifying Biased Agonism organs with molecular scales of affinity and efficacy. c. Therapeutic application(s) Pharmacological techniques are unique in that they can convert descriptive data (what we see, potency, activity in a given system) to predictive data (molecular 4. Orthosteric Antagonism (I) scales of activity that can be used to predict activity in all systems including the a. Competitive therapeutic one, i.e. affinity, efficacy). The predicted outcome of this process is a far b. Non-Competitive/Irreversible lower failure rate as molecules are progressed toward clinical testing. This course will describe pharmacological principles and procedures to quantify 5. Orthosteric Antagonism (II) affinity, efficacy, biased signaling and allostery to better screen for new drugs and a. Partial Agonism characterize drug candidates in lead optimization assays. b. Inverse Agonism

Instructor: Terry Kenakin presently is a Professor of Pharmacology in 6. Allosteric Modulation (I) the Dept of Pharmacology, University of North Carolina School of a. Functional Allosteric Model Medicine. The course is taught from the perspective of industrial drug b. Negative Allosteric Modulators (NAMs) discovery; Dr. Kenakin has worked in drug industry for 32 years (7 at Burroughs-Wellcome, RTP, NC and 25 at GlaxoSmithKline, RTP. NC). 7. Allosteric Modulation (II) He is Editor-in-Chief of the Journal of Receptors and Signal Transduc- a. Positive Allosteric Modulators (PAMs) tion and Co-Editor-in-Chief of Current Opinion in Pharmacology and is b. Allosteric Agonism on numerous journal Editorial Boards. In addition, he has authored over 200 peer reviewed papers and reviews and has written 10 books on Pharmacology. 8. Drug-Receptor Kinetics a. Measuring Target Coverage Allosteric Proof-of-Concept Course Material: Summary sheets, exercises with answers, relevant papers b. Application of Real-Time Kinetics are included as well as a pdf of allslides. The course is based on the book A c. Pharmacology Primer: Techniques for More Effective and Strategic Drug Discovery. 4th Edition, Elsevier/Academic Press, 2014. The table of contents of 9. Drug Screening this book can be viewed here. a. Design of Screening Assays b. Screening for Allosteric Modulators

WorldPharmaCongress.com World Preclincial Congress | 7 June 10-11, 2015 | Boston, MA

4th Annual Novel Preclinical Models in Oncology PDX and Other Models to Inform Clinical Trials and Guide Patient Care

9:35 Next-Generation Genetically Engineered Cancer Models Suggested Event Package: Professor Dieter Saur, M.D., Consultant and Senior Group Leader, Technische Universität München (TUM), School of Medicine June 10-11: Novel Preclinical Models in Oncology Conference We generated an inducible dual-recombinase based PDAC model that permits June 11-12: Tumor Models for Cancer Immunotherapy Conference spatial and temporal control of gene expression. This tool provides unparalleled June 11 Dinner Short Course*: PDX Models Update access to the native biology of cancer cells and their hosting stroma, and rigorous * Separate registration required. genetic validation of candidate therapeutic targets. We performed tumor cell- autonomous and non-autonomous targeting, uncovered hallmarks of human multistep carcinogenesis, validated genetic tumor therapy, and showed that mast Conferences Dedicated to Preclinical Models in Oncology cells in the tumor microenvironment, which had been thought to be key oncogenic at World Preclinical Congress 2015 players, are in fact dispensable for tumor formation. June 10-11 June 11-12 10:05 Coffee Break in the Exhibit Hall with Poster Viewing Preclinical Models in Oncology Tumor Models for Immunotherapy ANALYSING AND LEVERAGING RESULTS Imaging in Oncology 3D Cellular Models 10:45 Chairperson’s Opening Remarks Neal Goodwin, Ph.D., Director, Corporate Research Development, Champions Oncology WEDNESDAY, JUNE 10 10:50 Statistical Analysis of PDX Studies and Preclinical Phase-II-Like 7:00 am Registration and Morning Coffee Trials (PP2T) at EMD Serono Anderson Clark, Ph.D., Director, In vivo Pharmacology, Oncology, EMD Serono MODELING FOR CANCER GENOMIC MEDICINE Research & Development Institute At EMD Serono, we use PDX models in Preclinical Phase 2-Like Trials (PP2T) to 7:55 Chairperson’s Opening Remarks support Phase 2 clinical decisions for which the use of statistics has become

Peter Olson, Ph.D., Senior Principal Scientist, Pfizer Pharmaceuticals paramount. Working closely with clinical biostatisticians, we have developed « statistical approaches to different aspects of the trials which will be discussed, such 8:00 KEYNOTE PRESENTATION: ENGINEERING THE as trial design, relationships between preclinical responses and RECIST criteria, CANCER GENOME responses and how to measure them, and determining treatment differences. Tyler Jacks, Ph.D., Koch Institute for Integrative Cancer Research at MIT 11:20 The Art of the Cocktail: Optimizing Multidrug Combinations in Preclinical Studies 8:30 Session Break Arijit Chakravarty, Ph.D., Director, Modeling & Simulation (DMPK), Takeda 8:35 Preclinical Models Uncover a Novel Notch Mutant Oncogenic Pharmaceutical International Co. Driver Class in Triple Negative Breast Cancer Sensitive to a Gamma The design of optimal combinations relies on maximizing combination efficacy for Secretase Inhibitor a given toxicity budget. This presentation will describe the development of novel mathematical modeling methods (based on tricks used by bartenders to develop Peter Olson, Ph.D., Senior Principal Scientist, Pfizer Pharmaceuticals recreational cocktails), to visualize and design efficient studies for two-drug (and While the Notch pathway is reportedly activated in breast cancer, the molecular higher-order) combinations, and their application in a practical drug development mechanisms leading to hyperactivation are poorly understood. To identify predictive context, showing their impact on actual study design, and validation with in biomarkers for the gamma secretase inhibitor PF-03084014, we sequenced vivo datasets. sensitive PDX models and mined The Cancer Genome Atlas. We uncovered a disparate array of alterations in the extracellular and PEST domains in multiple 11:50 Evaluating Efficacy Coupled with Toxicity in Sponsored by Notch receptors that activated the pathway and were sensitive to drug. These data a Preclinical Model of Head and Neck Cancer define a new oncogenic driver class that may respond to Notch targeted therapies. Benjamin G. Cuiffo, Ph.D., Scientist, Biomodels, LLC 9:05 Patient Derived Xenograft Clinical Trial Program Sponsored by Chemoradiation used for the treatment of HNC results in regimen- related mucosal Neal Goodwin, Ph.D., Director, Corporate Research toxicity (mucositis) which impedes optimum cancer therapy and causes significant Development, Champions Oncology physiologic and resource adversities. We present a new, highly translational animal model which simultaneously assesses both the targeted efficacy of new anti-tumor A PDX clinical program to guide patient treatment has engrafted >750 patient agents and their impact on mucositis. specimens with a 70% patient tumor take rate and a >80% correlative treatment Sponsored by accuracy in completed clinical tests. This program has been expanded to support 12:05 Expanding Pre-Clinical Research predictive clinical trials for breast, sarcoma, and lung cancers in partnership with Possibilities via Animal Study Workflow Software clinical trial centers and cooperative trial groups. Ultimately, this program will Eric Ibsen, Vice President, Studylog Systems, Inc. include matched patient translational studies across numerous patient models for Studylog’s Animal Study Workflow Software® makes research easier by intuitively Phase II trial patient stratification. managing study workflow, not just data. Reducing many labs’ study-related labor by half, users can flexibly design, oversee, schedule, conduct & analyze animal studies in a more standardized, efficient manner. Preserve results in perpetuity & improve quality, searchability and collaboration.

WorldPharmaCongress.com World Preclincial Congress | 8 4th Annual June 10-11, 2015 | Boston, MA Novel Preclinical Models in Oncology

12:20 pm LUNCHEON PRESENTATION: Sponsored by 3:35 Sponsored Presentation (Opportunity Available) 2nd Generation PDX Models Can Help the 4:05 Refreshment Break in the Exhibit Hall with Poster Viewing Progression of Precision Medicine Jean-François Mirjolet, Ph.D., Technology Director, Oncodesign »»5:00 PLENARY KEYNOTE PANEL (see page 2 for details) Panels of PDX models reflecting the genetic diversity of human cancers can 6:00 Welcome Reception in the Exhibit Hall with Poster Viewing increase the predictivity of patients’ tumor response to treatments. But there is still a critical need for better predictive models for novel agents targeting the tumor 7:00 Close of Day microenvironment. In addition to the well characterized syngeneic models used for immuno-oncology drug testing, Oncodesign developed highly refined PDX models in microenvironment-humanized mice, demonstrating usefulness in PDX tumor dissemination and immuno-oncology research. THURSDAY, JUNE 11 1:00 Refreshment Break in the Exhibit Hall with Poster Viewing 7:30 am Interactive Breakout Discussion Groups IMAGING ADVANCES AND END POINTS IN CANCER Each discussion group in this session is led by a moderator/s who ensures focused conversations around key issues. Attendees join a specific group and RESEARCH the small, informal setting facilitates sharing of ideas and active networking. 1:30 Chairperson’s Remarks Topics for discussion will be made available on the conference website. Susanta Sarkar, Ph.D., Adjunct Associate Professor, Radiology, University of Pennsylvania; President, CadenzaMed LLC MODELING CANCER HETEROGENEITY 1:35 Translational Imaging in Oncology 8:35 Chairperson’s Remarks Daniel P. Bradley, Ph.D., Head, Biomedical Imaging, Takeda Boston, Takeda Pharmaceuticals International Co. Jeffrey E. Green, M.D., Chief, Transgenic Oncogenesis and Genomics Section, Laboratory of Cancer Biology and Genetics, National Cancer Institute Daniel will present on a number of programs that he has directly worked on, or working on, that have been developed in translational imaging in oncology. 8:45 Modeling Tumor Cell Dormancy in the Mouse Importantly, this talk will highlight important lessons learned about collaboration, Jeffrey E. Green, M.D., Chief, Transgenic Oncogenesis and Genomics Section, timing, perspectives and science with a hope that other groups in the imaging Laboratory of Cancer Biology and Genetics, National Cancer Institute community can leverage this information for future developments. The Biomedical Although dissemination of tumor cells often occurs at early stages of cancer, Imaging Group balances its portfolio between the use of conventional imaging clinical recurrence as metastatic disease may not become manifest until many biomarkers used in a novel biological and/or pharmacological context to advanced years later following a period of tumor cell dormancy. Modeling the process of imaging techniques. tumor dormancy is critical for understanding mechanisms governing late tumor recurrence and translating this knowledge into potential therapeutic or preventive 2:05 Non-Invasive and Simultaneous Measurement of strategies. Recent advances in studying tumor dormancy and potential translational Pharmacokinetics and Pharmacodynamics in Preclinical Cancer approaches to improve survival will be presented. Models Werner Scheuer, Research Leader, Pharma Research and Early Development, 9:15 Applications of CRISPR-Cas9 for in vivo Genome Editing Discovery Oncology, Roche Diagnostics GmbH Randall Platt, Biological Engineering, MIT, Laboratory of Feng Zhang Non-invasive imaging modalities (optical and micro-computed tomography) in CRISPR-Cas9 is a versatile genome editing technology for studying the function of combination with ex vivo analysis (3D-multispectral fluorescence microscopy, genetic elements. To broadly enable the application of Cas9 in vivo, we established FACS) are an undispensable tool to assess the anti-tumoral efficacy of new a Cre-dependent Cas9 knockin mouse and demonstrated genome editing using compounds. Proliferation of tumor cells, metastasis, angiogenesis, and induction of adeno-associated virus (AAV)-, lentivirus-, or particle-mediated delivery of guide apoptosis as well as phosphorylation of kinases can be monitored in mice carrying RNA in neurons, immune cells and endothelial cells. These genome editing tumor cells s.c. or orthotopically. The quantification of these pharmacodynamics strategies empower a wide range of biological and disease modeling applications. (Pd) read-outs are combined with optical pharmacokinetics (Pk). The simultaneous 9:45 Selected Poster Presentations: 3D Cell Cultures as Tumor measurement of Pd and Pk reduces the number of animals significantly and Models provides a comprehensive evaluation of new drugs. A Multi-Layered, Hyaluronic Acid-Based Hydrogel System for Automated 3D High 2:35 Normalizing Tumor Microvasculature and Microenvironment Throughput Drug Screening of Cancer-Stromal Cell Co-Cultures Dai Fukumura, M.D., Ph.D., Deputy Director, Edwin L. Steele Laboratory; Biologist, Pamela Constantinou, Rice University Department of Radiation Oncology, Massachusetts General Hospital; Associate Modeling Cancer Predisposition: A Patient-Derived lrECM 3D Cell Culture Platform Professor, Harvard Medical School To Study Disease Mechanisms And Drug Response Intravital microscopy techniques and sophisticated animal models have been Amruta Phatak, Indiana University School of Medicine providing unprecedented molecular, cellular, anatomical and functional insights Hetero-cellular Tumor Spheroid Model of Hypoxia, Stem Cell, and Inflammatory in tumor biology. Tumor microvasculature is structurally and functionally abnormal Signalings in Pancreatic Cancer and Evaluation of Nanoparticle-Mediated hindering drug delivery and inducing a hostile microenvironment that causes MicroRNA-34a Delivery ineffectiveness of anti-tumor treatments. Imbalance of pro- and anti-angiogenic Megha Surech, Northeastern University factors is causing these pathophysiological features in the tumor. Hence, restoring the balance of these factors in tumors may “normalize” tumor vasculature, improve 10:15 Mechanisms of resistance to HER2 targeted therapy in HER2+ its function and microenvironment, and enhance the efficacy of cytotoxic therapies. breast cancer Rachel Schiff, Ph.D., Associate Professor, Molecular and Cellular Biology, Lester and 3:05 Imaging based Companion Diagnostics: A New Paradigm in Sue Smith Breast Center, Baylor College of Medicine, Houston Drug Development In spite of the proven efficacy of anti-HER2 combined therapies, resistance still Susanta Sarkar, Ph.D., Adjunct Associate Professor, Radiology, University of remain key challenge, as observed in patients and in preclinical models. Resistance Pennsylvania; President, CadenzaMed LLC is due to either reactivation of the HER pathway via compensatory, redundant, or Development of companion diagnostics will improve the benefit to risk mutated elements of the pathway, or switch to alternative survival pathways that ratio of a given therapy and thus will help reduce drug development costs can bypass HER network inhibition. These escape pathways may be derived from significantly. A molecular imaging approach allows noninvasive assessment of epi/genetic aberrations or compensatory signals and may preexist predominantly in target expression and its interaction with drugs in situ. This presentation will the primary tumor, or enriched under treatment selection. elaborate on these approaches for the successful development of imaging based 10:45 Coffee Break in the Exhibit Hall with Poster Viewing companion diagnostics.

WorldPharmaCongress.com World Preclincial Congress | 9 4th Annual June 10-11, 2015 | Boston, MA Novel Preclinical Models in Oncology

11:30 Preclinical Models for Precision Medicine in Metastatic Colorectal Cancer: Challenges and Opportunities Livio Trusolino, M.D., Ph.D. Associate Professor, Department of Oncological Sciences, University of Torino School of Medicine, Laboratory of Molecular Pharmacology, IRCC, Institute for Cancer Research and Treatment Our objective is to unravel the signaling pathways and genomic makeups that mediate responsiveness to anticancer therapies, with an emphasis on colorectal cancer. To this aim, we use different technological platforms (phosphoproteomics, next-gen DNA/RNA sequencing) and experimental settings (patient-derived tumorgrafts and patient-derived cancer cell lines). Our pipeline involves the integration of large-scale data for discovery, followed by cell-based mechanistic insight and validation in animal models. This knowledge will form a predictive basis for the rational identification of novel tumor targets. 12:00 pm PANEL DISCUSSION: Modeling and Researching Cancer Metastasis Moderator: Bruce R. Zetter, Ph.D., Charles Nowiszewski Professor of Cancer Biology, Department of Surgery, Harvard Medical School Panelists: Arijit Chakravarty, Ph.D., Director, Modeling & Simulation (DMPK), Takeda Pharmaceutical International Co. Jeffrey E. Green, M.D., Chief, Transgenic Oncogenesis and Genomics Section, Laboratory of Cancer Biology and Genetics, National Cancer Institute Jean-François Mirjolet, Ph.D., Technology Director, Oncodesign 12:30 Close of Conference

WorldPharmaCongress.com World Preclincial Congress | 10 June 11-12, 2015 | Boston, MA

2nd Annual Tumor Models for Cancer Immunotherapy Assessing Antitumor Activity and Safety of Immunotherapy Programs

3:35 Studies of Immunotherapy Agents Using Sponsored by Suggested Event Package: Patient-derived Tumor Xenografts in June 10-11: Novel Preclinical Models in Oncology Conference Humanized Mice Walter Ausserer, Ph.D., Business Director, Clinical and June 11-12: Tumor Models for Cancer Immunotherapy Conference In Vivo Services, The Jackson Laboratory June 11 Dinner Short Course*: PDX Models Update We will report on our program to establish in vivo preclinical models of human * Separate registration required. tumor immunotherapy by engrafting immunodeficient mice expressing a partial human immune system with human tumor implants. Humanized NOD-scid IL2Rγ (null) (hu-NSG™) mice initially were generated by transplanting NSG mice with human CD34+ hematopoietic stem and progenitor cells (HSPCs) which support Conferences Dedicated to Preclinical Models in Oncology human hematopoietic and immune system development. Several types of patient- at World Preclinical Congress 2015 derived tumors (non small cell lung cancer, sarcoma, triple negative breast cancer June 10-11 June 11-12 and invasive bladder cancer) were successfully implanted into HLA-mismatched Preclinical Models in Oncology Tumor Models for Immunotherapy hu-NSG mice. Growth rates for all PDX tumors were similar between hu-NSG and non-humanized NSG models. In addition, tumor growth was observed in hu-NSG Imaging in Oncology 3D Cellular Models mice implanted with human ovarian tumor cell line SKOV3-Luc-D3. Treatment with the anti-PD-1 receptor agent pembrolizumab produced significant tumor growth inhibition in both solid tumor and cell line xenografts, suggesting that THURSDAY, JUNE 11 co-engrafted hu-NSG mice may represent an important new model for preclinical immunotherapy research. 12:00 pm Registration 4:05 Refreshment Break in the Exhibit Hall with Poster Viewing TRANSLATIONAL IMMUNO-ONCOLOGY 4:45 Translational Approaches to Preclinical Evaluation of Immune Oncology Agents 2:00 Chairperson’s Opening Remarks Brett Hall, Ph.D., Senior Director & Head, Translational Medicine-Oncology, John Maher, M.D., Ph.D., Senior Lecturer in Immunology, NIHR Biomedical, Research MedImmune Centre at Guy’s and St. Thomas’ NHS Foundation Trust and King’s College London An expanding body of basic and translational research has established a solid 2:05 Preclinical Tumor Models for Evaluating Bispecific Redirected T framework for how the tumor microenvironment (TME) influences cancer biology. Cell Therapeutics The TME influences tumor immune recognition as well as metabolic activity, tumor Chad May, Ph.D., Director, Oncology Research Unit, Pfizer survival, genomic instability, epigenetic state, metastatic progression, tumor Strong evidence exists supporting the important role T-cells play in the immune proliferation and therapeutic resistance. For effective clinical translation of immune response against tumors. Still, the ability to initiate tumor specific immune mediated therapies, it is essential that preclinical models adequately address key responses remains a challenge. We have developed a bispecific protein engineered immuno-modulatory aspects of the human TME. with enhanced pharmacokinetic properties to extend in vivo half-life, and designed to engage and activate endogenous polyclonal T cell populations via the CD3 ENHANCING IMMUNE RESPONSE complex in the presence of tumors expressing target antigens. 5:15 Adoptive Immunotherapy of Cancer Using ex vivo Expanded 2:35 Joint Presentation: Preclinical to Clinical Translation of Anti-PD-1 Vg9Vd2 T Cells Blockade John Maher, M.D., Ph.D., Senior Lecturer in Immunology, NIHR Biomedical, David Kaufman, M.D., Ph.D., Director/Senior Principal Scientist, Oncology/ Research Centre at Guy’s and St. Thomas’ NHS Foundation Trust and King’s College Immunotherapy Clinical Research, Merck London Elaine Pinheiro, Ph.D., Associate Principal Scientist, In vivo Pharmacology – Vg9Vd2 T-cells recognize phosphoantigen intermediates of mevalonate metabolism Oncology, Merck Research Laboratories and thereby play an important role in tumor immunosurveillance. We have Keytruda® (pembrolizumab), a PD-1-specific monoclonal antibody, is approved in developed systems to expand these cells ex-vivo by over 2000-fold in 2 weeks, the U.S. for advanced melanoma, and is being studied in >30 cancers. We have enhancing the feasibility of clinical immunotherapy using this approach. Expanded generated a murine surrogate antibody (muDX400) and determined mechanistic cells exhibit potent anti-tumor activity in xenograft models of ovarian cancer features of PD-1 inhibition in preclinical tumor models. Gene and protein and acute myeloid leukemia in a manner that is potentiated by either free or expression signatures reveal determinants of response and resistance. In addition, liposome-encapsulated aminobisphosphonates. muDX400 has been combined with chemotherapies, targeted therapies, and other immunotherapies, and the systemic and intratumoral immune landscape 5:45 Enhancing Immune Response to DC/Tumor Fusion Cell has been evaluated. These data will facilitate the clinical development of both Vaccination for the Treatment of Hematologic Malignancies pembrolizumab monotherapy and combination therapies. In particular, these data Jacalyn Rosenblatt, M.D., Assistant Professor, Department of Medicine, Harvard will support the development of novel mechanistic biomarkers that will aid in the Medical School customization of immunotherapeutic regimens, elucidation of novel determinants DC/tumor fusion cell vaccination has demonstrated potent immune responses, of response, and identification of early indicators of on-treatment response. In and clinical responses in a subset of patients. Strategies to augment immune turn, data from clinical trials can be used to improve the predictive power of response to vaccination depend on overcoming the immunosuppressive milieu the nonclinical workstream and speed the preclinical development of novel characteristic of patients with malignancy. Combining vaccination with checkpoint immunotherapeutic agents. blockade and immunomodulatory drugs are being evalauted in clinical trials. In pre-

WorldPharmaCongress.com World Preclincial Congress | 11 June 11-12, 2015 | Boston, MA 2nd Annual Tumor Models for Cancer Immunotherapy

clinical models, we have demonstrated that MUC1 plays a critical role in mediating 11:30 A Rapid Establishment of Patient Derived Tumor Xenograft immune tolerance. Strategies to block MUC1 mediated signalling are being Microenvironments that Enable Preclinical Evaluations of Chemo- evaluated as a means of augmenting response to immunotherapy. Immune Therapeutic Strategies 6:15 Close of Day Richard B. Bankert, V.M.D., Ph.D., Professor, Department of Microbiology and Immunology, State University of NY at Buffalo, School of Medicine and Biomedical Sciences We report here a simple and reliable model system in which ovarian tumor cell FRIDAY, JUNE 12 aggregates implanted intraperitoneally into severely immunodeficient NSG mice establish tumor microenvironments within the omentum within one week. The rapid establishment 7:30 am Interactive Breakout Discussion Groups of tumor xenografts within this small anatomically well-defined site enables the recovery, Each discussion group in this session is led by a moderator/s who ensures characterization, and quantification of tumor and tumor-associated T cells. focused conversations around key issues. Attendees join a specific group and 12:00 pm Modulation of Tumor Progression by Sponsored by the small, informal setting facilitates sharing of ideas and active networking. Immune Check Point Inhibitors (anti-PD-1/CTLA-4) in Topics for discussion will be made available on the conference website. Murine Tumor Models Martin R. Graf, Ph.D., Associate Research Director, In Vivo Oncology, Charles River DESIGNING AND ASSESSING COMBINATIONS Laboratories With the increasing success and subsequent interest in tumor immunology, 8:35 Chairperson’s Remarks there is a growing need for well-characterized preclinical models. We evaluated Daniela Cipolletta, Ph.D., Research Investigator, Clinical Translational Oncology, the responsiveness of nine syngeneic tumor models to antibody based, immune TCO, Novartis Oncology checkpoint inhibitor therapeutics, targeting CTLA-4 and PD-1. Our results clearly show a differential response across tumors when these inhibitors were used 8:45 Identification of Novel Immune-Modulatory Combination individually or in combination. This differential allows one to match efficacy with though Transcriptomic and Proteomic-Based Analysis of Tumor model and expands the models available for evaluating combination therapies. Models Daniela Cipolletta, Ph.D., Research Investigator, Clinical Translational Oncology, 12:30 Sponsored Presentation (Opportunity Available) TCO, Novartis Oncology 12:45 LUNCHEON PRESENTATION: Humanized Sponsored by We have used transcriptomic and proteomic approaches to monitor the immune response following perturbation of key onco-pathway and immune-checkpoint Immune System Mice for Immuno-Oncology nodes in preclinical tumor models. This approach has enabled our understanding Applications of tumor induced immune modulation and the identification of novel combinatorial Leon L. Hall, Ph.D., Senior Director, Global Scientific Development strategies in specific cancer settings and Translational Discovery Services, Taconic Biosciences, Inc. Mouse models are widely used in preclinical oncology research but species 9:15 Combining Radiation Therapy and Cancer Immunotherapy: differences can limit efficacy predictions for clinical translation. Taconic Biosciences’ Preclinical Assessment and Translational Approaches Immune system humanization program is being leveraged to accelerate efficacy Maria Angelica Cortez, Ph.D., Postdoctoral Fellow, Experimental Radiation and safety testing of novel immunotherapies. An overview of Taconic’s humanization Oncology, UT MD Anderson Cancer Center program will include data showing the utility of humanized mice in PDX applications The immune-modulating effects of radiation therapy have recently gained for immuno-oncology drug development. Additionally, recent advances utilizing next considerable interest and there have been multiple reports of synergy between generation humanized mice will be presented. radiation and immunotherapy. However, additional pre-clinical studies are needed 1:30 Session Break to demonstrate the antigen-specific nature of radiation induced immune responses and elucidate potential mechanisms of synergy withimmunotherapy. Here we demonstrate the ability of stereotactic radiotherapy to induce endogenous TOOLS AND TECHNOLOGIES antigen-specific immune responses when combined with anti-PD-1 checkpoint 2:00 Chairperson’s Remarks blockade immunotherapy. Gavin Thurston, Ph.D., Vice President, Oncology & Angiogenesis Research, 9:45 Personalized Mouse Model for Preclinical Sponsored by Regeneron Pharmaceuticals Testing of Drugs Targeting Immune Checkpoints 2:05 Genetic Engineering of the Mouse Immune System to Test Keren Paz, Ph.D., CSO, Champions Oncology Novel Cancer Immuno-Therapuetics The blockade of immune checkpoints is a promising therapeutic avenue for cancer Gavin Thurston, Ph.D., Vice President, Oncology & Angiogenesis Research, therapy, with durable objective responses observed in patients with various Regeneron Pharmaceuticals solid tumors. However, current animal models often fail to accurately identify One of the challenges in developing clinical immuno-therapeutics is testing these immunotherapies with the greatest clinical potential and there exists a need for agents in relevant preclinical tumor models. A particular issue has been the lack reliable preclinical tools to test these drugs directly against human cancers. To of cross-reactivity of human-specific therapeutic monoclonal antibodies to murine circumvent this limitation, Champions Oncology has developed the ImmunoGraft, targets. We have used VelociGene® technology to humanize a variety of targets whereby two innovative technologies, the Champions TumorGraft (a type of patient- within the immune system, allowing us to test and compare novel immuno- derived xenograft) and humanized mice (immunodeficient mice reconstituted with therapeutics. Examples will be provided for immune modulatory antibodies and a human immune system), are combined in a single platform. bispecific antibodies. 10:15 Coffee Break in the Exhibit Hall with Poster Viewing 2:35 ImmunoPET Imaging in the Development of Therapeutic Antibodies 11:00 Developing and Deploying Novel Experimental Model Systems Jan Marik, Ph.D., Department of Biomedical Imaging, Genentech, Inc. in Ovarian Cancer for Improved Drug Discovery Positron emission tomography with radiolabeled monoclonal antibodies (ImmunoPET) is becoming a valuable tool in translational development of Ronny I. Drapkin, M.D., Ph.D., Director, Ovarian Cancer Research Center, Perelman therapeutic antibodies. The half-life of positron emitting radionuclide 89Zr (3.3d) School of Medicine, University of Pennsylvania matches well the pharmacokinetics of monoclonal antibodies (mAb) hence good The emergence of the fallopian tube as a dominant site of origin for high-grade quality images can be obtained and inform about the biodistribution of the drug serous ovarian carcinomas has sparked the development of novel model systems, and/or the targeted antigen. Examples of pre-clinical and clinical use of 89Zr-mAbs including PDX and GEM models, that are impacting development of novel drug in the development of targeted cancer therapeutics will be discussed. therapies, methods for early detection and approaches to chemo- and immuno- prevention. Examples of how these models are being integrated to address key clinical issues will be discussed.

WorldPharmaCongress.com World Preclincial Congress | 12 June 11-12, 2015 | Boston, MA 2nd Annual Tumor Models for Cancer Immunotherapy

3:05 Imaging the Immune Response to Cancer Michael Dougan, M.D., Ph.D., Department of Medical Oncology and Cancer Vaccine Center, Dana-Farber Cancer Institute Appropriate surrogate endpoints for monitoring immune therapy to cancer are currently lacking. My talk will cover work we are doing in the lab to use single domain camelid derived antibodies conjugated to radioisotypes to image the response to anti-cancer immune therapy by positron emission tomography. We envision this strategy as potentially providing a novel means for tracking immune therapies for cancer, with the potential to guide therapy as well as assist in the generation of new treatment. 3:35 Close of Conference

WorldPharmaCongress.com World Preclincial Congress | 13 June 10-11, 2015 | Boston, MA

6th Annual Translational Imaging in Cancer Drug Development Novel Imaging Probes and Technologies in Oncology

Treatment of HER2-positive tumors that have innate or acquired resistant to trastuzumab is an important clinical problem. Here we report a two-component delivery Suggested Event Package: system for induced internalization of HER2-targeted nanocarriers with therapeutic June 9 Dinner Short Course*: Imaging in Cancer Research cargo based on click-chemistry in situ reaction between the pretargeting and therapy June 10-11: Translational Imaging in Cancer Drug Development Conference carrier components. This pretargeting strategy provides image guidance for therapeutic June 11-12: Tumor Models for Cancer Immunotherapy Conference applications and has been validated in preclinical models of breast cancer. * Separate registration required. 10:05 Coffee Break in the Exhibit Hall with Poster Viewing ANALYSING AND LEVERAGING RESULTS Conferences Dedicated to Preclinical Models in Oncology 10:45 Chairperson’s Remarks at World Preclinical Congress 2015 Neal Goodwin, Ph.D., Director, Corporate Research Development, Champions June 10-11 June 11-12 Oncology Preclinical Models in Oncology Tumor Models for Immunotherapy 10:50 Statistical Analysis of PDX Studies and Preclinical Phase-II-Like Trials (PP2T) at EMD Serono Imaging in Oncology 3D Cellular Models Anderson Clark, Ph.D., Director, In vivo Pharmacology, Oncology, EMD Serono Research & Development Institute WEDNESDAY, JUNE 10 At EMD Serono, we use PDX models in Preclinical Phase 2-Like Trials (PP2T) to support Phase 2 clinical decisions for which the use of statistics has become 7:00 am Registration and Morning Coffee paramount. Working closely with clinical biostatisticians, we have developed statistical approaches to different aspects of the trials which will be discussed, such as trial design, relationships between preclinical responses and RECIST TRANSLATIONAL IMAGING IN ONCOLOGY criteria, responses and how to measure them, and determining treatment differences. 7:55 Chairperson’s Opening Remarks Paul McCracken, Ph.D., Director of Imaging, Biomarkers and Personalized Medicine 11:20 The Art of the Cocktail: Optimizing Multidrug CFU, Eisai Combinations in Preclinical Studies Arijit Chakravarty, Ph.D., Director, Modeling & Simulation (DMPK), Takeda »»8:00 KEYNOTE PRESENTATION: ENGINEERING THE Pharmaceutical International Co. CANCER GENOME The design of optimal combinations relies on maximizing combination efficacy for Tyler Jacks, Ph.D., Koch Institute for Integrative Cancer Research at MIT a given toxicity budget. This presentation will describe the development of novel mathematical modeling methods (based on tricks used by bartenders to develop recreational cocktails), to visualize and design efficient studies for two-drug (and 8:30 Session Break higher-order) combinations, and their application in a practical drug development 8:35 Improving Decision Making For Drug Discovery and Early context, showing their impact on actual study design, and validation with in vivo Development In Oncology With Imaging datasets. Paul McCracken, Ph.D., Director of Imaging, Biomarkers and Personalized Medicine 11:50 Evaluating Efficacy Coupled with Toxicity in a Sponsored by CFU, Eisai Preclinical Model of Head and Neck Cancer Due to high cost and low probability of success, the pharmaceutical industry Benjamin G. Cuiffo, Ph.D., Scientist, Biomodels, LLC needs to improve the decision making process for compounds entering Phase I, Chemoradiation used for the treatment of HNC results in regimen- related mucosal better using Phase I studies for decision making beyond safety, and improving the toxicity (mucositis) which impedes optimum cancer therapy and causes significant quality of compounds entering clinical trials. Imaging biomarkers can significantly physiologic and resource adversities. We present a new, highly translational animal contribute to the decision making process, such as supporting target engagement, model which simultaneously assesses both the targeted efficacy of new anti-tumor proof of concept, drug safety, patient selection, and dose selection. agents and their impact on mucositis. 9:05 Enabling Translational Cancer Research and Drug Development 12:05 pm Can Animal Study Software Technology Sponsored by Through The Integration Of Preclinical Imaging That Emulates Clinical Trial Methods Improve the Quang-Dé Nguyen, Ph.D., Director of the Lurie Family Imaging Center, Senior Predictability of Clinical Outcome? Scientist, Center for Biomedical Imaging in Oncology, Dana-Farber Cancer Institute Eric Ibsen, Vice President, Studylog Systems, Inc. The Lurie Family Imaging Center (LFIC), the preclinical arm of the Center for Biomedical The 95% failure rate of anticancer therapeutic approvals after positive Phase Imaging in Oncology (CBIO) at the Dana-Farber Cancer Institute, is a state-of-the-art III trials suggests that existing pre-clinical approaches and tools are suboptimal imaging facility that conducts interdisciplinary in vivo translational and experimental predictors of clinical outcome. Recent software innovations enable animal therapeutics studies focused on cancer, with an emphasis on assessment of researchers to mirror multi-arm, multi-site, clinical trials with rolling enrollment and novel cancer therapeutics, multimodality imaging of cancer, molecular imaging of run “piggy-backed” studies under a common protocol. pharmacodynamic efficacy, development of novel probes, and target validation. 9:35 Click-mediated Therapy for HER2-positive Breast Cancer Dmitri Artemov, Ph.D., Associate Professor Departments of Radiology and Oncology , The Johns Hopkins University School of Medicine

WorldPharmaCongress.com World Preclincial Congress | 14 June 10-11, 2015 | Boston, MA 6th Annual Translational Imaging in Cancer Drug Development Sponsored by 12:20 LUNCHEON PRESENTATION: 2nd 3:35 Light In and Sound Out: High Resolution Sponsored by Generation PDX Models Can Help the Deep Tissue Imaging Via Multispectral Progression of Precision Medicine Optoacoustic Tomography Imaging Jean-François Mirjolet, Ph.D., Technology Director, Oncodesign Neal C. Burton, Ph.D., Senior Application Specialist, iThera Medical Panels of PDX models reflecting the genetic diversity of human cancers can Multispectral optoacoustic tomography (MSOT) imaging opens up a wide field of increase the predictivity of patients’ tumor response to treatments. But there is research for development of novel tumor markers and therapeutic agents, dynamic still a critical need for better predictive models for novel agents targeting the tumor contrast enhancement, and toxicological assessment of novel pharmaceuticals microenvironment. In addition to the well characterized syngeneic models used for in small animal models. Initial results of MSOT clinical imaging studies are also immuno-oncology drug testing, Oncodesign developed highly refined PDX models showing high potential for clinical translation. in microenvironment-humanized mice, demonstrating usefulness in PDX tumor dissemination and immuno-oncology research. 4:05 Refreshment Break in the Exhibit Hall with Poster Viewing 1:00 Refreshment Break in the Exhibit Hall with Poster Viewing »»5:00 PLENARY KEYNOTE PANEL (see page 2 for details) IMAGING ADVANCES AND END POINTS IN CANCER 6:00 Welcome Reception in the Exhibit Hall with Poster Viewing RESEARCH 7:00 Close of Day 1:30 Chairperson’s Remarks THURSDAY, JUNE 11 Susanta Sarkar, Ph.D., Adjunct Associate Professor, Radiology, University of Pennsylvania; President, CadenzaMed LLC 1:35 Translational Imaging in Oncology 7:30 am Interactive Breakout Discussion Groups Daniel P. Bradley, Ph.D., Head of Biomedical Imaging at Takeda Boston, Takeda Each discussion group in this session is led by a moderator/s who ensures Pharmaceuticals International Co. focused conversations around key issues. Attendees join a specific group and the small, informal setting facilitates sharing of ideas and active networking. Daniel will present on a number of programs that he has directly worked on, Topics for discussion will be made available on the conference website. or working on, that have been developed in translational imaging in oncology. Importantly, this talk will highlight important lessons learned about collaboration, timing, perspectives and science with a hope that other groups in the imaging CASE STUDIES community can leverage this information for future developments. The Biomedical Imaging Group balances its portfolio between the use of conventional imaging 8:30 Chairperson’s Remarks biomarkers used in a novel biological and/or pharmacological context to advanced Jonathan Wall, Ph.D., Professor of Medicine, Human Immunology and Cancer imaging techniques. Program; Director, Amyloid and Preclinical Molecular Imaging Laboratory, University of Tennessee Graduate School of Medicine 2:05 Non-Invasive and Simultaneous Measurement of Pharmacokinetics and Pharmacodynamics in Preclinical Cancer Models 8:35 Preclinical Development of Peptide Radiotracers for Detecting Werner Scheuer, Research Leader, Pharma Research and Early Development, Visceral Amyloid Associated with Multiple Myeloma Discovery Oncology, Roche Diagnostics GmbH Jonathan Wall, Ph.D., Professor of Medicine, Human Immunology and Cancer Non-invasive imaging modalities (optical and micro-computed tomography) in Program; Director, Amyloid and Preclinical Molecular Imaging Laboratory, University combination with ex vivo analysis (3D-multispectral fluorescence microscopy, of Tennessee Graduate School of Medicine FACS) are an undispensable tool to assess the anti-tumoral efficacy of new Multiple myeloma, the second most common hematologic malignancy in the US, compounds. Proliferation of tumor cells, metastasis, angiogenesis, and induction of and related plasma cell dyscrasias, are characterized by the secretion of monoclonal apoptosis as well as phosphorylation of kinases can be monitored in mice carrying immunoglobulin light chains that often deposit as insoluble amyloid fibrils in visceral tumor cells s.c. or orthotopically. The quantification of these pharmacodynamics organs. The abundance of amyloid deposits and their anatomic distribution often (Pd) read-outs are combined with optical pharmacokinetics (Pk). The simultaneous inform prognosis and treatment options. At present there are no clinical methods measurement of Pd and Pk reduces the number of animals significantly and for the non-invasive, quantitative measurement of amyloid. To this end we have provides a comprehensive evaluation of new drugs. generated synthetic, poly-basic peptides that preferentially bind amyloid and, when radiolabeled, can be used for disease detection by molecular imaging. 2:35 Normalizing Tumor Microvasculature and Microenvironment Dai Fukumura, M.D., Ph.D., Deputy Director, Edwin L. Steele Laboratory; Biologist, 9:05 PARP1 Status Annotation in Cancers of the Oral Cavity Department of Radiation Oncology, Massachusetts General Hospital; Associate Thomas Reiner, Ph.D., Assistant Member, Memorial Sloan-Kettering Cancer Professor, Harvard Medical School Center; Assistant Attending Chemist, Radiochemistry & Imaging Sciences Service; Intravital microscopy techniques and sophisticated animal models have been Assistant Professor, Weill Cornell Medical College providing unprecedented molecular, cellular, anatomical and functional insights The enzyme PARP1 has attracted attention for its diagnostic and prognostic value, in tumor biology. Tumor microvasculature is structurally and functionally abnormal and quantification of PARP1 expression could impact the clinical decision-making hindering drug delivery and inducing a hostile microenvironment that causes process directly. A noninvasive imaging tool that can unambiguously quantify the ineffectiveness of anti-tumor treatments. Imbalance of pro- and anti-angiogenic expression of PARP1 in vivo, however, is an unmet clinical goal. Here, we report on factors is causing these pathophysiological features in the tumor. Hence, restoring the use of a PARP1 imaging agent as a probe for the early detection of oral cancer, the balance of these factors in tumors may “normalize” tumor vasculature, improve discuss its pharmacological properties and selectivity in vivo, and illustrate its its function and microenvironment, and enhance the efficacy of cytotoxic therapies. potential impact on future clinical research. 3:05 Imaging based Companion Diagnostics: A New Paradigm in 9:45 Utility of 3D Ultrasound and Photoacoustic Imaging in Subject Drug Development Stratification and Treatment Prediction Susanta Sarkar, Ph.D., Adjunct Associate Professor, Radiology, University of Srivalleesha Mallidi, Ph.D., Research Fellow, Laboratory of Tayyaba Hasan, Harvard-MIT Pennsylvania; President, CadenzaMed LLC Prediction of response and tumor recurrence following a given therapy is necessary Development of companion diagnostics will improve the benefit to risk for effective treatment. In this talk, we demonstrate an approach towards this goal ratio of a given therapy and thus will help reduce drug development costs with an example of photodynamic therapy (PDT) as the treatment modality and significantly. A molecular imaging approach allows noninvasive assessment of photoacoustic imaging (PAI) as a non-invasive, response and disease recurrence target expression and its interaction with drugs in situ. This presentation will monitor in a murine model of glioblastoma (GBM). PDT is a photochemistry-based, elaborate on these approaches for the successful development of imaging based clinically used technique that consumes oxygen to generate cytotoxic species thus companion diagnostics. causing changes in blood oxygen saturation (StO2).

WorldPharmaCongress.com World Preclincial Congress | 15 June 10-11, 2015 | Boston, MA 6th Annual Translational Imaging in Cancer Drug Development

10:15 Proteomic Imaging of Caveolae to Penetrate Solid Tumors Jan E. Schnitzer, M.D., Director, Professor of Cellular & Molecular Biology, PRISM, Proteogenomics Research Institute for Systems Medicine Access inside solid tumors is poor yet critical for imaging and therapeutic agents to be effective. These agents rely on passive movement across endothelial barriers to reach targets inside tumors. Our “proteomic-imaging” efforts discovered a new pathway and class of delivery targets for active transport into tumors. In vivo imaging reveals caveolae-targeted antibodies, drugs, imaging agents, and nanoparticles being pumped across endothelium to achieve >100-fold more tumor delivery and efficacy. 10:45 Coffee Break in the Exhibit Hall with Poster Viewing IMAGE GUIDED INTERVENTIONS 11:30 Drug and Diagnostic Imaging with Mass Spectrometry Nathalie Agar, PhD, Assistant Professor of Neurosurgery, Assistant Professor of

Radiology, Harvard Medical School, Director, Surgical Molecular Imaging 12:00« PM KEYNOTE PRESENTATION: CLINICAL TRANSLATION OF NEAR-INFRARED FLUORESCENCE IMAGING FOR IMAGE- GUIDED SURGERY John V. Frangioni, M.D., Ph.D., Professor, Department of Medicine and Radiology, Harvard Medical School Invisible near-infrared (NIR) light in the 700 nm to 900 nm range penetrates several millimeters into living tissue. In conjunction with target-specific fluorescent contrast agents, NIR light can highlight all desired structures on the surgical field, such as tumors that need to be resected and critical structures that need to be avoided. This talk will introduce the first principles of near-infrared light for surgical guidance and review clinical translation of NIR imaging systems and contrast agents.

12:30 Close of Conference

WorldPharmaCongress.com World Preclincial Congress | 16 June 11-12, 2015 | Boston, MA

Inaugural 3D Cellular Models Revitalizing Phenotypic Screening

tissue stem cell toxicity against any human tissue in a relatively inexpensive cell Suggested Event Package: culture format. June 10-11: New Models for Predicting Drug Toxicity Conference TAKING SCREENING INTO A NEW DIMENSION June 11-12: 3D Cellular Models Conference Sponsored by June 11 Dinner Short Course*: 3D Printing 3:35 NanoCulture Plate (NCP): Scaffold Type * Separate registration required. High-Throughput 3D Cell Culture System M. Mamunur Rahman, Ph.D., PI & Lab Director, 3D Cell Culture, SCIVAX USA, Inc. Conferences Dedicated to Preclinical Models in Oncology NCP is engineered with micro-patterned square or honeycomb structure on the plate surface that supports cells to form cell spheroid. NCP is prime for many at World Preclinical Congress 2015 studies, i.e. signaling, hypoxia, live imaging, anti-cancer drug sensitivity screen, June 10-11 June 11-12 primary cancer cell culture, EMT assay, toxicology or regenerative medicine Preclinical Models in Oncology Tumor Models for Immunotherapy researches, co-culture, and stem cells differentiation. Sponsored by Imaging in Oncology 3D Cellular Models 3:50 Use of Co-Spheroids Systems for the Analysis of the Impact of Stromal Cells on Anti- Cancer Drug Activity THURSDAY, JUNE 11 Jan E. Ehlert, Ph.D., Head, Cellular Drug Discovery, ProQinase GmbH 12:00 pm Registration In cancer treatment, stroma-derived microenvironmental cues are suspected to exert an adversary impact on anti-cancer drug efficacy. For taking such influences into account, we established a spheroid-based co-culture system for the analysis APPLYING 3D MODELS FOR TOXICOLOGY RESEARCH of compound effects on the proliferation of tumor as well as of stromal cells. 2:00 Chairperson’s Opening Remarks This modular HTS-compatible assay system generates information on stroma- Jeffrey Morgan, Ph.D., Professor, Medical Science and Engineering, Department of attenuated drug activity that may prove valuable in early drug development to focus

Molecular Pharmacology, Physiology and Biotechnology, Brown University on compounds that remain active under microenvironmental conditions. « 4:05 Refreshment Break in the Exhibit Hall with Poster Viewing 2:05 FEATURED PRESENTATION: 3D SPHEROIDS FOR INVESTIGATING DRUG 4:45 Challenges & Opportunities toward Enabling Phenotypic UPTAKE, ACCUMULATION AND TRANSPORT Screening of Complex & 3D Cell Models Jeffrey Morgan, Ph.D., Professor, Medical Science and Christophe Antczak, Ph.D., Laboratory Head, CPC Integrated Lead Discovery, Engineering, Department of Molecular Pharmacology, Physiology Novartis Institutes for Biomedical Research and Biotechnology, Brown University More and more complex and three-dimensional cell models derived from primary or iPS In addition to recapitulating normal and disease phenotypes, the cells are described that recapitulate aspects of in vivo tissue organization and function. small 3D microtissues formed by multi-cellular spheroids also mimic the physical/ Challenges toward enabling high-throughput phenotypic assays relying on these biological barriers to drug penetration that are significant contributors to a drug’s emerging models can be overcome by new opportunities in detection technologies. efficacy as well as toxicity. This talk covers the use of micro-mold technology to Progress toward enabling live, minimally invasive readouts is key to being able to take full form long-lived designer spheroids and their use to quantify drug transport. advantage of more physiologically relevant cell models in drug discovery.

2:35 Engineered 3D Microsystems: Recapitulating in vivo Form, 5:15 Developing More Disease-Predictive Assays for Function and Responses Phenotypic Screening Christopher S. Chen, M.D., Ph.D., Professor, Biomedical Engineering, Boston University Fabien Vincent, Ph.D., Associate Research Fellow, Assay Development and Wyss Institute for Biologically Inspired Engineering, Harvard University and Pharmacology, Hit Discovery and Lead Profiling, Pfizer Global Research & Development The 3D organization of cells defines the adhesive, mechanical and soluble microenvironment that ultimately governs cell phenotype. Understanding how Phenotypic screening promises to positively impact the translation of preclinical forces, form and cellular function are related provides a mechanism for engineering discoveries to the clinic. Nonetheless, not all phenotypic screens will offer the same potential in that regard. A critical question then follows: What are the 3D cultures that can more faithfully reproduce in vivo function. This presentation discusses both the underlying fundamental insights and examples of engineered characteristics of the best phenotypic screens? This presentation covers an analysis cultures that have the potential for enhancing discovery, validation and safety studies. of this question conducted by a team of Pfizer scientists as well as proposes three specific criteria to help identify and design the most promising screens. 3:05 When Time Is the Third Dimension: Combining Computer 5:45 3D Skin Equivalents for the Assessment of Skin Health Benefits Simulation and Primary Tissue Cell Culture to Identify Tissue Stem Cell-Toxic Drug Candidates Teresa DiColandrea, Ph.D., Senior Scientist, Life Sciences Innovation Core, Procter & Gamble James L. Sherley, M.D., Ph.D., Director, Asymmetrex, LLC Three-dimensional skin and hair equivalents offer the potential for preclinical Screening out drug candidates that are toxic to tissue stem cells before assessment of technologies for skin health but face challenges in specificity, conventional preclinical testing would accelerate drug development and reduce its robustness, scale and cost for integration into screening methods. Examples of high cost. Human tissue stem cell toxicity may also elude animal testing and lead characterization and application of 3D models for preclinical studies will be discussed. to even more expensive failures due to intolerable toxicity in clinical trials or after marketing. AlphaSTEM is a new computer simulation technology for predicting 6:15 Close of Day

WorldPharmaCongress.com World Preclincial Congress | 17 June 11-12, 2015 | Boston, MA Inaugural 3D Cellular Models

FRIDAY, JUNE 12 11:00 Targeting Biomarker Modulation, Cellular Heterogeneity and EMT in a Microfluidic Model for 3D Tumor Growth 7:30 am Interactive Breakout Discussion Groups Imran Rizvi, Ph.D., Instructor, Medicine and Dermatology, Medicine, Brigham and Women’s Hospital and Harvard Medical School Each discussion group in this session is led by a moderator/s who ensures focused conversations around key issues. Attendees join a specific group and Understanding the role of hydrodynamic stress as a physical modulator of genetic, the small, informal setting facilitates sharing of ideas and active networking. molecular and morphologic heterogeneity in tumor metastases may have important Topics for discussion will be made available on the conference website. implications in treatment resistance and the design of targeted therapies. The impact of flow on tumor morphology and biomarker modulation was investigated in a microfluidic model for 3D ovarian cancer. Flow-induced shear stress caused APPLYING 3D MODELS FOR ONCOLOGY RESEARCH an increase in epithelial-mesenchymal transition and increased expression and activation of molecular markers associated with aggressive disease. 8:30 Chairperson’s Remarks Christophe Antczak, Ph.D., Laboratory Head, CPC Integrated Lead Discovery, 11:30 Modeling Pain and Peripheral Neuropathy Using Fibroblast-

Novartis Institutes for Biomedical Research Derived Nociceptor Neurons « Elizabeth D. Buttermore, Ph.D., Research Fellow, F.M. Kirby Neurobiology Center, 8:35 FEATURED PRESENTATION: 3D Boston Children’s Hospital; Neurobiology Department, Harvard Medical School PRINTING OF IN VITRO CELL/TISSUE MODELS Current model systems for preclinical pain and peripheral neuropathy studies are FOR DRUG TESTING not providing adequate options in the clinic. To address this issue, we developed Wei Sun, Ph.D., Albert Soffa Chair Professor, Mechanical a method for deriving nociceptor neurons in vitro from mouse and human Engineering, College of Engineering, Drexel University; Professor fibroblasts. With these derived neurons, phenotypic screens can be completed and Director, Biomanufacturing Research Center, Mechanical to identify novel therapeutic strategies for ailments ranging from chronic pain Engineering, Tsinghua University to chemotherapy-induced neuropathy, with the goal of increased success rates Rui Yao, Ph.D., Assistant Professor, Biomanufacturing Research moving into the clinic. Center, Mechanical Engineering, Tsinghua University This presentation reports on the application of 3D cell printing 12:00 pm Cancer-on-a-Chip for Target Identification and Drug Screening techniques to construct functional in vitro cell/tissue models for Sophie Lelièvre, D.V.M., LLM, Ph.D., Professor, Department of Basic Medical drug testing. Examples of printing of HeLa cells for 3D cervical Sciences; Associate Director, Collaborative Science, NCI-Designated Purdue Center tumor models in vitro and the printing of micro-organ devices will for Cancer Research, Purdue University be presented. Tissue architecture has been long known as an important feature to reproduce in order to identify pathways that control cancer onset and progression. Here I 9:05 Engineering the Tumor Microenvironment ex vivo for Translation discuss specifically the impact of tissue geometry, notably that of ductal structures, Studies Using Patient-Derived Explants on the architecture and behavior of breast tumors, and the consequences for the Amir Aref, Ph.D., Instructor, Cancer Biology, Dana-Farber Cancer Institute, Harvard development and assessment of therapeutic approaches. Medical School 12:30 Drug Discovery with Patient-Specific 3D Engineered Heart Tissues Personalized cancer medicine is based on an emerging knowledge of the cancer Tetsuro Wakatsuki, CSO, InvivoSciences, Inc. mutation repertoire and the tailored application of drugs that target altered InvivoSciences developed an in vitro disease model that recapitulates individual genes or pathways in individual patients. This work will enhance studies of tumor patient’s cardiomyopathy in 3D engineered heart tissues (EHTs) using the patient- cell biology in a physiologic context, open a new avenue for drug screening derived cells. Automated cell culture and cardiomyocyte-differentiation protocol and biomarker development and accelerate the preclinical evaluation of novel improved the productivity and reproducibility for generating patient-specific disease personalized medicine strategies for patients in real time. models for drug and diagnostics development. Sponsored by 9:35 Epigenetic Screening: Phenotypic Cancer 12:45 Luncheon Presentation (Sponsorship Opportunity Available) or Cell Line Profiling with Long-Term Cell Culture Enjoy Lunch on Your Own + Univariate Genetic Analyses in a Single Platform Euroﬁns Pharma Discovery Services Don Axworthy, Senior Director, In Vivo Pharmacology, Eurofins Pharma Discovery 1:30 Session Break Services Epigenetic target inhibition may exhibit delayed drug responses undetected by ENGINEERING FUNCTIONAL 3D MODELS FROM short-term cell growth assays. The OncoPanel™ profiling assay of 240 genomically characterized cell lines, optimized for subconfluent exponential growth over 10 day ORGANS TO SYSTEMS cultures. Epigenetic selective inhibitors elicit drug responses dependent on assay 2:00 Chairperson’s Remarks duration, mutational status, confirmed by univariate genomic analysis. Jeffrey Borenstein, Ph.D., Laboratory Technical Staff, Biomedical Microsystems,

Draper Laboratory

9:50 Physiologically Relevant Tissue Models in Sponsored by « High Throughput Organ-on-a-Chip Platform 2:05 FEATURED PRESENTATION: ORGANS- Jos Joore, Ph.D., Chief Business Officer, MIMETAS BV ON-CHIPS: ENGINEERING THE CELLULAR Abstract OrganoPlates™ are a novel microfluidic culture platform enabling long- MICROENVIRONMENT TO RECREATE TRUE term, membrane-free 3D co-culture models in a microtiterplate format. We have HUMAN PHYSIOLOGY AND ADVANCE DRUG developed a large variety of tissue- and disease models, applicable for drug testing DISCOVERY and evaluation. The platform is compatible with standard readout equipment, Geraldine A. Hamilton, Ph.D., President and CSO, Emulate; former making the technology suitable for high‐throughput automation. Senior Staff Scientist, Wyss Institute for Biologically Inspired Engineering, Harvard University 10:20 Coffee Break in the Exhibit Hall with Poster Viewing Organs-on-Chips are smart in vitro surrogates of the human body that may accelerate the identification of novel therapeutics, ensure their safety and efficacy, and reduce significant drug development costs. We review our Organs- on-Chips platform, which goes beyond conventional 3D cell culture models by recapitulating tissue-tissue interfaces, spatiotemporal chemical gradients, mechanical microenvironments and physiological function in an organ-specific context. Based on experimental data collected from this platform, it is evident that it stands as a more predictive, human-relevant alternative to traditional drug development methods.

WorldPharmaCongress.com World Preclincial Congress | 18 June 11-12, 2015 | Boston, MA Inaugural 3D Cellular Models

2:35 Lab-on-a-Chip Technologies for Automated High-Throughput Drug Discovery Jeffrey Borenstein, Ph.D., Laboratory Technical Staff, Biomedical Microsystems, Draper Laboratory We have developed a range of technologies capable of automating the screening of compounds in a medium- to high-throughput manner. These technologies have been applied to important problems in cardiovascular diseases, in addition to kidney, liver and lung models. In this presentation we demonstrate the use of

these prototype lab-on-a-chip systems in several applications. « 3:05 KEYNOTE PRESENTATION: INTEGRATING MULTIPLE ORGANS-ON-CHIPS: WHAT MIGHT WE LEARN, WHAT DO WE NEED AND HOW MIGHT WE DO IT? John P. Wikswo, Ph.D., Founding Director, Vanderbilt Institute for Integrative Biosystems Research and Education and Gordon A. Cain University Professor, Vanderbilt University Organs-on-chips (OoCs) are beginning to recapitulate human physiology in compact, two- and three-dimensional tissue models that are more accurate than monolayer monocultures on plastic or matrix, and minimize the dilution of paracrine signals intrinsic to Petri-dish or well-plate culture. Refined OoC microfluidics and analytics are now enabling the study of organ-organ interactions, including physiological regulation and drug toxicity. The next step is to optimize insertion of coupled OoCs into the drug development pipeline.

3:45 Close of Conference

WorldPharmaCongress.com World Preclincial Congress | 19 June 10-11, 2015 | Boston, MA

Inaugural Targeting GPCRs Antibody and Small Molecule Approaches for New Drug Leads

if selectively engaging signaling pathways will provide new therapeutics for Suggested Event Package: neurological diseases. Using the Dopamine D2 receptor as example, I will describe our effort generating agonists that exclusively activate D2-Gi/o or D2-Beta-arrestin June 9 Short Course*: Allosteric Modulators of GPCRs, (PAMs NAMs) signaling. Agonists that enabled arrestin engagement, but not Gi/o activation, June 9 Dinner Short Course*: Biased GPCR Ligands: Towards Novel induced prolonged ERK signaling and showed robust antipsychotic activity with Drug Discovery reduced motoric side-effects in rodent models. June 10-11: Targeting GPCRs Conference 10:05 Coffee Break in the Exhibit Hall with Poster Viewing June 11-12 Training Seminar: Applying Pharmacology to New Drug Discovery * Separate registration required. SELECTIVE SIGNALING

10:50 Ligand Bias in the Interaction of Muscarinic M3 Receptor with a Regulator of G Protein Signaling (RGS) Complex, Gβ5-RGS7 WEDNESDAY, JUNE 10 Vladlen Z. Slepak, Ph.D., Professor, Molecular and Cellular Pharmacology, University of Miami 7:00 am Registration and Morning Coffee The G protein β subunit Gβ5 forms obligatory heterodimers with R7 family RGS proteins. Gβ5-RGS7 can directly bind to M3R and has a dual effect: attenuates BIASED SIGNALING the Ca2+ release from stores, while augmenting Ca2+ influx across the plasma membrane. M3R-induced insulin secretion was practically eliminated by Gβ5 8:00 Chairperson’s Opening Remarks knockout, consistent with the idea that Gβ5-RGS7 is necessary for Ca2+ influx

Conrad Cowan, Ph.D., Head, Biology, Trevena in beta cells. Responses to oxotremorine-M were insensitive to Gβ5-RGS7 while « pilocarpine-induced signals were particularly strongly inhibited. 8:05 KEYNOTE SPEAKER: SYSTEMS PHARMACOLOGY LINKS GPCRS WITH RETINAL 11:20 Polypharmacology and Multi-Targeted Directed Ligands DEGENERATIVE DISORDERS (MTDL) for GPCRs Krzysztof Palczewski, Ph.D., Professor and Chair, Department Ronan Bureau, Ph.D., Professor, Molecular Modelling, CERMN, University of Caen, of Pharmacology, School of Medicine, Case Western Reserve France University The design of new type of ligands (MTDL) able to modulate several biological A systems pharmacology approach employs signaling pathways to pathways involved in a specific disease represent a particular challenge. The enhance rational therapeutic strategies for treating complex disorders/diseases. presentation will concern our last results for alzheimer disease implying 5-HT4 and Our proposal for systems pharmacology starts with a quantitative transcriptome H3 receptors. analysis not only of cells, but also of tissues and organs of interest. Next, a reliable animal model that recapitulates the human condition(s) must be 11:50 Structure-Based Computational Approaches Sponsored by available to investigate combinations of drugs that act on one or several network for the Identification and Optimization of pathways to select those most suited for human trials. GPCR Ligands Thijs Beuming, Ph.D., Research Leader, Applications Science, Schrödinger 8:35 Novel Strategies for Biasing GPCR Signaling We present computational strategies for GPCR lead identification and optimization, covering a broad range of applicability. First, we developed a customizable Jeffrey L. Benovic, Ph.D., Professor and Chair, Department of Biochemistry and modeling protocol to optimize homology models, as well as a probabilistic model Molecular Biology, Thomas Jefferson University to boost virtual screening enrichment by considering explicit water molecules in G protein-coupled receptors (GPCRs) interact with three families of proteins in a the GPCR binding site. For optimizing potency, we validated and applied all-atom ligand-dependent manner: heterotrimeric G proteins, GPCR kinases and arrestins. MD-based free energy calculations (FEP) to a variety of GPCR targets. Advanced These interactions play an essential role in regulating GPCR signaling, trafficking hydration site analysis (WaterMap) was used to explain an unintuitive SAR within a and degradation. In this presentation, I will highlight recent strategies used to series of triazolylpurine analogues. bias GPCR signaling with an emphasis on the use of lipidated GPCR peptides (pepducins) to promote GPCR interaction with selective downstream targets. 12:20 pm Luncheon Presentation (Sponsorship Opportunity Available) or Enjoy Lunch on Your Own 9:05 Translating Bias: from the Bench to the Clinic Conrad Cowan, Ph.D., Head of Biology, Trevena 1:00 Refreshment Break in the Exhibit Hall with Poster Viewing Biased ligands targeting GPCRs can selectively stimulate or inhibit distinct downstream signaling pathways, and may provide improved therapeutic efficacy ANTIBODIES FOR GPCRs and/or reduced side effects relative to unbiased ligands. Preclinical and clinical data will be presented on two of our most advanced biased ligand programs, one 1:30 Chairperson’s Remarks a β-arrestin-biased ligand of the Angiotensin type II type 1 receptor for acute heart Jeffrey L. Benovic, Ph.D., Professor and Chair, Department of Biochemistry and failure and the other a G protein-biased ligand of the μ-opioid receptor for pain. Molecular Biology, Thomas Jefferson University 9:35 Biased Agonists for Dopamine D2 Receptors: Novel 1:35 Targeting GPCRs with Monoclonal Antibodies Antipsychotic Drugs? Trevor Wilkinson, Ph.D., Associate Director, Protein Sciences, Antibody Discovery John A. Allen, Ph.D., Principal Scientist, Neuroscience, Pfizer and Protein Engineering, MedImmune We have generated biased ligands for various Dopamine receptors to test G-protein coupled receptors represent a challenging target class for the isolation

WorldPharmaCongress.com World Preclincial Congress | 20 June 10-11, 2015 | Boston, MA Inaugural Targeting GPCRs

and optimization of therapeutic biologics. We have used a combination of BIOSENSORS AND LABEL-FREE ADVANCES immunization and phage display to isolate functional antagonistic antibodies targeting a chemokine receptor and a formyl-peptide receptor which will be 8:35 Chairperson’s Remarks presented as case studies. We also describe how combinatorial mutagenesis Neil Burford, Ph.D., Senior Research Investigator II, Leads Discovery and approaches have been used to make significant improvements to both affinity and Optimization, Bristol- Myers Squibb species cross-reactivity of a lead molecule and demonstrate that the optimised antibodies show significantly increased potency in cellular disease assays. 8:45 Putting a STOP: Structural Visualization of GPCR Desensitization 2:05 Using StaR Proteins as Antigens to Generate Antibodies to GPCRs Arun Shukla, Ph.D., Professor, Department of Biological Sciences and Ali Jazayeri, Ph.D., Head, Engineering, Heptares Bioengineering, Indian Institute of Technology and Wellcome Trust/DBT Indian GPCRs represent excellent antibody targets given their central role in the pathology Alliance Intermediate Fellow of many diseases and cell surface location. However GPCRs make poor antigens The functions of G-protein coupled receptors (GPCRs) are primarily mediated and due to their conformational flexibility, low expression levels, inherent instability and modulated by the heterotrimeric G proteins, the G-protein coupled receptor kinases hydrophobic nature. Using protein engineering approaches we create conformationally (GRKs), and the β-arrestins. Binding of β-arrestins hinders G protein coupling stabilised receptors (StaRs) that can be purified to high purity and homogeneity with and leads to receptor desensitization. I will discuss our efforts to understand the enhanced half-life. StaRs allow generation of high quality antigens that can be used to structural basis of GPCR-β-arrestin interaction and how this interaction mediates raise functional antibodies. desensitization of GPCRs. 2:35 Nanobodies as Tools for Probing GPCR Structure and Function 9:15 Cell-Based Label-Free Dynamic Mass Redistribution Assays for Andrew C. Kruse, Ph.D., Assistant Professor, Department of Biological Chemistry Elucidating GPCR-Mediated Signaling and Molecular Pharmacology, Harvard Medical School Stephanie Hennen, Ph.D., Senior Scientist, Department of Incretin Biology, Global Heavy-chain only camelid antibodies (nanobodies) have emerged as powerful and Research Organization, Novo Nordisk A/S versatile tools in GPCR structural biology. Their use has enabled important insights The majority of techniques currently employed to examine signaling behavior of into the structural basis for GPCR activation and allosteric regulation by small GPCRs requires artificial labels. In contrast to these classical methods, a number of molecule ligands, including active-state structures of adrenergic and muscarinic novel label-free technologies have emerged recently that are competent to resolve receptors. I will discuss the methods used for identifying conformationally selective receptor activity as integrated cellular response. The present talk will introduce nanobodies, and the insights they have offered into the molecular details of GPCR a label-free method based on dynamic mass redistribution and attempt to show activation and allostery. the strengths of holistic label-free detection as compared with classical functional assays but also highlight the challenges. 3:05 Modulating GPCR Signaling using Conformationally Selective Nanobodies 9:45 SPR-based Assays for Ranking and Selecting mAbs Targeting Dean Staus, Ph.D., Robert J. Lefkowitz Lab, Postdoctoral Fellow, Department of GPCRs Medicine, Duke University Medical Center, Howard Hughes Medical Institute Rick Chu, Ph.D., Associate Director, Clinical Assay Development, Genzyme, a The signaling cascades induced by ligand binding to a GPCR are mediated by Sanofi Company stabilization of specific receptor conformations which leads to the coupling and Traditionally, membrane protein binding assays rely on utilizing radioactive labeled activation of G-protein and β-arrestin. A total of 18 conformationally selective single ligands. In order to simplify membrane protein kinetics binding assay, purified domain Camelid antibodies (nanobodies) were tested for their ability to modulate membrane proteins, such as G-protein-coupled receptors (GPCRs), are captured beta-2-adrenergic receptor dependent signaling. When expressed intracellularly on analytical surfaces and further stabilized by limited chemical crosslinking. This (intrabodies), these nanobodies inhibited G protein activation, G protein–coupled limited chemical crosslinking enables high quality label-free kinetics assays of membrane proteins via the same methods that are conventionally used for soluble receptor kinase (GRK)–mediated receptor phosphorylation, β-arrestin recruitment, proteins. and receptor internalization to varying extents. 10:15 A Label-Free, Solution-Based Affinity Assay Sponsored by 3:35 Functional Antibodies for GPCRs for Allosteric GPCR Ligand Binding Using Byeong Doo Song, Ph.D., President, Scripps Korea Antibody Institute Back-Scattering Interferometry GPCRs have not been easy targets to obtain functional antibodies for because Richard J. Isaacs, Ph.D., Applied Research Supervisor, Molecular Sensing, Inc traditional antibody screening requires target preparation. We developed a new Integral membrane proteins such as GPCRs are critical targets for drug discovery method to construct an expandable spatially addressed Fv antibody library from but present a host of challenges to the characterization of their binding affinity for combination of purified proteins, which enables screening of individual antibodies small molecules. Determination of allosteric binding in GPCR targets is especially using cell based assays without target preparation. Direct functional screening valuable and extremely challenging information to obtain by established binding method has lead to discovery of novel antibodies for GPCRs. assay platforms, but can be addressed through a label-free solution-based direct- 4:05 Refreshment Break in the Exhibit Hall with Poster Viewing binding technology, back-scattering interferometry (BSI). »»5:00 PLENARY KEYNOTE PANEL (see page 2 for details) 10:45 Coffee Break in the Exhibit Hall with Poster Viewing 6:00 Welcome Reception in the Exhibit Hall with Poster Viewing ALLOSTERIC MODULATORS 7:00 Close of Day 11:30 Positive Allosteric Modulators of Opioid Receptors Neil Burford, Ph.D., Senior Research Investigator II, Leads Discovery and THURSDAY, JUNE 11 Optimization, Bristol-Myers Squibb Opioid receptors are among the most studied GPCRs and are the targets for opiate ligands including morphine, which are key drugs used in the management 7:30 am Interactive Breakout Discussion Groups of pain. However, these opiate ligands also exhibit serious receptor-mediated Each discussion group in this session is led by a moderator/s who ensures side effects including tolerance and dependence. The recent discovery of opioid focused conversations around key issues. Attendees join a specific group and receptor positive allosteric modulators by our lab offers a novel approach for future the small, informal setting facilitates sharing of ideas and active networking. pain medications because of the potential advantages allosteric ligands have over Topics for discussion will be made available on the conference website. orthosteric ligands.

WorldPharmaCongress.com World Preclincial Congress | 21 June 10-11, 2015 | Boston, MA Inaugural Targeting GPCRs

12:00 pm mGluR3 PAM as a GDNF-inducer Strategy for the Treatment of Neurodegenerative Disorders Stephan Schann, Ph.D., Head of Research, Domain Therapeutics Glial cell line-derived neurotrophic factor (GDNF) is a peptide that previously showed clinical efficacy for the treatment of Parkinson’s disease. mGluR3 constitutes a novel target that could lead to neuroprotection through production of GDNF. This potential was demonstrated with an orthosteric mGluR2/3 agonist and KO mice. Novel small molecules mGluR3 PAMs were recently discovered at Domain. These molecules were characterized in neuroprotection and GDNF production models. Our results show that mGluR3 PAMs shared similar activities with the mGluR3 orthosteric agonist. 12:30 Close of Conference

WorldPharmaCongress.com World Preclincial Congress | 22 June 11-12, 2015 | Boston, MA

Inaugural Targeting Histone Acetylation Innovative Approaches to Modulate HDACs, HATs and Other Epigenetic Targets

4:45 Novel Approaches to the Discovery of Isoform Selective HDAC Suggested Event Package: Inhibitors June 10-11: Chemical Biology for Target Validation Conference Florence Wagner, Ph.D., Senior Group Leader, Medicinal Chemistry, Stanley Center for Psychiatric Research, The Broad Institute of MIT and Harvard June 11-12: Targeting Histone Acetylation Conference While a number of HDAC inhibitors were discovered over the years, the June 11 Dinner Short Course*: Optimizing Physical Properties of Molecules to development of highly potent and isoform selective HDACi is critical not only to Achieve High-Quality Clinical Candidates refine our understanding regarding the relevant isoform(s) for on-target efficacy * Separate registration required. but also to mitigate potential mechanism-based, dose-limiting side effects. I will present design strategies that our group has employed towards the discovery of novel HDACi with tuned kinetic (residence time) and thermodynamic binding THURSDAY, JUNE 11 properties for HDACs 1, 2 and 3. 12:00 pm Registration 5:15 In Search of Structurally and Mechanistically Novel Deacteylase Probes PROBING HDAC INHIBITION Angela Koehler, Ph.D., Professor, Department of Biological Engineering, MIT and Koch Institute for Integrative Cancer Research, MIT and Associate Member, 2:00 Chairperson’s Opening Remarks Broad Institute Simon Jones, Ph.D., Vice President Biology and Preclinical Development, HDACs regulate numerous biological processes and have been implicated in Acetylon Pharmaceuticals various diseases, including cancers, psychiatric disorders, metabolic disorders, 2:05 Isoform Selective Histone Deacetylase Inhibitors (HDACi) in and inflammatory diseases. Despite significant efforts, many of the biological Multiple Myeloma (MM) functions, precise molecular functions, substrates, and binding partners of HDACs Simon Jones, Ph.D., Vice President Biology and Preclinical Development, Acetylon are unknown or poorly understood. Selective chemical probes can aid in studying Pharmaceuticals their relevant functions. Toward this end, our lab has employed unbiased binding We have explored the role of broad acting and selective HDACi in MM preclinically assays in an effort to uncover molecules with novel patterns of selectivity or and in clinical trials, both alone and in combination with novel agents. Broad acting chemical structure. HDACi vorinostat and panobinostat or HDAC 6 selective HDACi ricolinostat have 5:45 Imaging HDAC Density and Drug Inhibition in the Human Brain been combined with bortezomib to block aggresomal and proteasomal protein Jacob Hooker, Ph.D., Associate Professor, Radiology, Harvard Medical School degradation, respectively. Ricolinostat combined with immunomodulatory drugs and Director of Radiochemistry, Martinos Center for Biomedical Imaging, lenalidomide or pomalidomide downregulate cMyc. We will update the rationale Massachusetts General Hospital and use of isoform selective HDACi to both increase response and improve Inhibition of HDACs is being pursued as a therapeutic strategy and yet we do tolerability in MM. not know for most diseases the relationship between HDAC density or function 2:35 HDAC6 as Master Modulator of Immune-related Pathways and disease progression. We have developed an imaging agent, [11C]Martinostat, Alejandro Villagra, Ph.D., Assistant Professor, University of South Florida and to quantify HDAC isoforms non-invasively in humans and are using quantitative Scientist, Department of Immunology, Moffitt Cancer Center imaging to determine the relationships between HDAC and disease in the brain and Histone deacetylases (HDACs), originally described as histone modifiers, have in peripheral organ systems. more recently been demonstrated to target a variety of other proteins unrelated to 6:15 Close of Day the chromatin environment. Particularly, HDAC6 has been identified to deacetylate numerous non-histone proteins, participating in the regulation of cellular processes such as protein trafficking, aggresome formation, and most recently, as a modulator FRIDAY, JUNE 12 of immune-related pathways. This opens new possibilities to use selective HDAC6 inhibitors as potential immunomodulatory agents in cancer. 7:30 am Interactive Breakout Discussion Groups 3:05 Chemogenomic Approaches to Spatiotemporal Regulation of Each discussion group in this session is led by a moderator/s who ensures HDAC Activity focused conversations around key issues. Attendees join a specific group and Ralph Mazitschek, Ph.D., Assistant Professor, Center for Systems Biology, the small, informal setting facilitates sharing of ideas and active networking. Chemical Biology Platform, Massachusetts General Hospital Topics for discussion will be made available on the conference website. HDACs are master regulators of chromatin structure and function. Beyond modulating histones acetylation they are recognized as regulators of non-histone TARGETING SYNERGISTIC PATHWAYS proteins. HDAC inhibitors have been used as tool compounds to study basic biology and recognized as promising therapeutics. However, systemic exposure is 8:35 Chairperson’s Remarks often not well tolerated, or does not provide the required resolution in biological Wayne W. Hancock, M.D., Ph.D., Professor of Pathology and Chief of Transplant model systems. To address these shortcomings we have developed a new Immunology, Children’s Hospital of Philadelphia and University of Pennsylvania approach to control HDAC activity with greater spatial and temporal resolution. 8:45 Novel Systems Therapeutics Approach to Efficiently Modulate 3:35 Sponsored Presentation (Opportunity Available) Histone Acetylation Julen Oyarzabal, Ph.D., Director, Translational Sciences, Center for Applied Medical 4:05 Refreshment Break in the Exhibit Hall with Poster Viewing Research (CIMA), University of Navarra, Spain We have proposed and validated a systems therapeutics approach, based on a

WorldPharmaCongress.com World Preclincial Congress | 23 June 11-12, 2015 | Boston, MA Inaugural Targeting Histone Acetylation

novel mode of action simultaneously targeting two independent but synergistic 12:45 Luncheon Presentation (Sponsorship Opportunity Available) or pathways: phosphodiesterases (PDEs) and HDACs, that significantly induce histone Enjoy Lunch on Your Own acetylation. Thus, potent HDAC inhibitors are not required to achieve a remarkable level of histone acetylation; minimizing any potential toxicity related to HDAC 1:30 Session Break inhibition. To validate this novel approach an in vitro and in vivo proof-of-concept, focused on Alzheimer´s Disease, using two known pharmacological compounds, as UNRAVELING HAT & SIRTUIN BIOLOGY (cont’d) well as novel first-in-class dual inhibitors, will be presented. 2:00 Chairperson’s Remarks 9:15 Immunomodulation and HDAC Inhibitors in Breast Cancer Philip Cole, M.D., Ph.D., Professor and Director, Department of Pharmacology and Pamela Munster, M.D., Professor, Medicine, Program Leader Development Molecular Sciences, Johns Hopkins University Medical School Therapeutics; Director, Early Phase Clinical Trials’ Program, Helen Diller Cancer 2:05 Bioorthogonal Probes to Interrogate Functions of Histone Center, University of California, San Francisco Acetyltransferases In previous trials we have shown that HDAC inhibitors modulate estrogen receptor signaling and reverse hormone therapy resistance. One of the steps of acquired Y. George Zheng, Ph.D., Associate Professor, Department of Pharmaceutical and hormone therapy resistance is believed to involve upregulation of immune Biomedical Sciences, University of Georgia pathways and PD-1 and PD-L1 expression. Several groups have shown a differential Elucidating biological and pathological functions of protein lysine acetyltransferases regulation of cytotoxic and regulatory T-cells by HDAC inhibitors. We are exploring (KATs) greatly depends on the knowledge of the dynamic and spatial localization the role of epigenetic priming to immunotherapy and the differential effects of of their enzymatic targets in the cellular proteome. We report the design and HDAC inhibitors on T-cells in ER+ breast cancer models and a Phase II clinical trial. application of bioorthogonal chemical probes for facile labeling and detection of substrates of the major human KAT enzymes. This study provides powerful 9:45 Selective HDAC Inhibitors in Neurodegenerative Disorders molecular tools for labeling and mapping KAT targets in the context of complex Elizabeth Thomas, Ph.D., Associate Professor, Department of Molecular and biological mixtures at the proteomic level. Cellular Neuroscience, The Scripps Research Institute 2:35 New Insights into Protein Acetylation from Chemoproteomics HDACs have been recognized as potentially useful therapeutic targets for a broad range of neurological disorders. Our findings demonstrate that inhibition Jordan Meier, Ph.D., Investigator, Chemical Biology Laboratory, and Head, of HDAC1 and HDAC3 isotypes can relieve disease phenotypes in Huntington’s Chemical Genomics Section, National Cancer Institute disease model systems. Further studies in our lab have focused on identifying A paradox of modern acetylation biology is that while the number of sites of gene targets of selective HDAC inhibitors. Overall, the knowledge of gene targets acetylation has climbed rapidly, the number of enzymes thought to catalyze this of HDAC inhibitors should help advance these compounds into clinical practice for process has stayed relatively constant. Here we describe the utility of chemical neurodegenerative disorders. proteomic methods to discover and characterize mechanisms of acetylation in endogenous cellular contexts. Our studies highlight an expanded landscape of 10:15 Coffee Break in the Exhibit Hall with Poster Viewing lysine acetyltransferases, as well as new strategies to investigate the metabolic regulation and small molecule inhibition of protein acetylation. UNRAVELING HAT & SIRTUIN BIOLOGY 3:05 Sirtuin Inhibitors as Anti-Cancer Agents 11:00 CBP/p300/PCAF/GCN5 vs. Tip60/Myst1 in Foxp3+ Treg Biology Hening Lin, Ph.D., Professor, Department of Chemistry and Chemical Biology, and Anti-Tumor Immunity Cornell University Wayne W. Hancock, M.D., Ph.D., Professor of Pathology and Chief of Transplant Sirtuins are known as nicotinamide adenine dinucleotide (NAD)-dependent Immunology, Children’s Hospital of Philadelphia and University of Pennsylvania deacetylases. We have discovered several novel enzymatic activities, such Our work aims to identify post-translational modifications regulating Foxp3 and as desuccinylation and defatty-acylation, for several sirtuins with no robust thereby the development and/or function of Foxp3+ T-regulatory (Treg) cells. Using deacetylase activity. This has led to the identification of unknown protein post- genetic and pharmacologic approaches, we show that targeting of CBP or p300, translational modifications and revealed new biology. It has enabled us to develop and GCN5 or PCAF, diminishes Foxp3 acetylation and Treg suppressive function compounds that can inhibit particular sirtuins selectively. Some of the selective and promotes anti-tumor immunity, whereas Tip60 targeting induces lethal sirtuins inhibitors can kill cancer cells in cell culture and inhibit tumor formation in autoimmunity. Our data provide new insights into the roles of HATs in Tregs, and mouse models. how these may be targeted for cancer immunotherapy.

3:35 Close of Conference « 11:30 KEYNOTE PRESENTATION: CHEMICAL APPROACHES TO UNDERSTANDING HISTONE ACETYLTRANSFERASES Philip Cole, M.D., Ph.D., Professor and Director, Department of Pharmacology and Molecular Sciences, Johns Hopkins University Medical School Lysine acetylation/acylation modifications, first identified on histones, are widespread post-translational modifications (PTMs) on cellular proteins and regulate cell growth and gene expression in normal and disease states. This presentation will discuss chemical methods to interrogate HATs, enzymes responsible for catalyzing protein lysine acetylation, and describe progress toward developing HAT inhibitors as therapeutics. We will also describe novel chemical strategies for developing site-specifically modified acyl-Lys containing proteins to explore the role of particular PTMs in regulating protein function.

12:30 pm Sponsored Presentation (Opportunity Available)

WorldPharmaCongress.com World Preclincial Congress | 24 June 10-11, 2015 | Boston, MA

8th Annual New Models for Predicting Drug Toxicity Effective Use of 3D Cells, Stem Cells, Organotypic Cultures and Humanized Animal Models

9:05 Proteomic Approaches to the Discovery of Preclinical Suggested Event Package: Biomarkers of Toxicity Li-Rong Yu, Ph.D., Associate Co-Director, Biomarkers and Alternative Models June 9 Short Course*: Drug Metabolism and Its Impact on Decisions in Branch, Division of Systems Biology, National Center for Toxicological Research, Drug Discovery & Development U.S. Food and Drug Administration June 9 Dinner Short Course*: Navigating the CiPA Landscape Advances of proteomics and its application to toxicological studies have led to the development of a new discipline, toxicoproteomics. One of the major research June 10-11: New Models for Predicting Drug Toxicity Conference areas of toxicoproteomics is to identify novel biomarkers of toxicity. Mass June 11-12: 3D Cellular Models Conference spectrometry-based quantitative proteomic approaches have been applied to the identification of biomarkers of multiple organ toxicity in preclinical models. June 11 Dinner Short Course*: How to Best Utilize Organotypic 3D Cell Cultures in Oncology 9:35 Predictivity of in vitro Models Including Co-Cultures for the * Separate registration required. Detection of Hepatotoxic Drugs in Humans Franck Atienzar, Ph.D., Associate Director, In Silico, In Vitro Toxicology, Non Clinical Development, UCB BioPharma SPRL WEDNESDAY, JUNE 10 Drug Induced Liver Injury (DILI) is a major cause of attrition during early and late stage drug development. Consequently, there is a need to develop better in vitro 7:00 am Registration and Morning Coffee tools for predicting hepatotoxicity in humans. The presentation will focus on the predictivity of different human in vitro models such as primary hepatocytes, HepG2 HOW USEFUL ARE CURRENT IN VITRO AND IN VIVO and co-culture models. Toxicity and metabolism data will be presented to better MODELS judge the relevance of such in vitro models. 8:00 Chairperson’s Opening Remarks 10:05 Coffee Break in the Exhibit Hall with Poster Viewing Gary Peltz, M.D., Ph.D., Professor of Anesthesiology, Perioperative and Pain Medicine, Stanford University School of Medicine HOW USEFUL ARE CURRENT IN VITRO AND IN VIVO

8:05 Current Use of Stem Cell-Derived Cardiomyocytes to Assess QT MODELS (cont’d) Prolongation and Proarrhythmia 10:50« KEYNOTE PRESENTATION: MICE WITH Bernard Fermini, Ph.D., Associate Research Fellow, Global Safety Pharmacology, ‘HUMANIZED’ LIVERS: FROM SAFER DRUGS TO Pfizer Global Research & Development LIVER REGENERATION An increasing number of published studies support the use of human embryonic Gary Peltz, M.D., Ph.D., Professor of Anesthesiology, Perioperative and iPSC derived cardiomyocytes for the assessment of drug-induced QT and Pain Medicine, Stanford University School of Medicine prolongation. While some of the studies conclude that these cells represent a Drug-induced liver injury (DILI) has become a leading cause of suitable predictive model, others question their value based on reports of mixed acute liver failure, and for regulatory actions after drug approval. phenotype, unforeseen pharmacology, and conflicting ion channel profile. In this Drugs that produced minimal toxicity in animals sometimes caused significant presentation we review some of the more controversial issues and attempt to DILI in humans. The fatalities occurring in 7 of 15 patients treated with fialuridine provide a holistic view of the field. provides a tragic example of this. We have developed chimeric TK-NOG mice, where transplanted human liver cells replace mouse liver. We recently 8:35 How Useful Are In vitro Tools to Predict Hyperbilirubinemia: demonstrated that DILI caused by fialuridine and bosentan were easily detected Utility of UGT1A1, OATP1B1, OATP1B3, MRP2 and BSEP Inhibition in chimeric TK-NOG mice, which indicates that their use in preclinical studies Assays could improve drug safety. Jae Chang, Ph.D., Senior Scientist, DMPK, Genentech, Inc. Hyperbilirubinemia may arise due to inadequate clearance of bilirubin from the 11:35 Irinotecan Toxicity: 11 Novel Organ and Drug-specific Non- body, a multifaceted process consisting of uptake of bilirubin into hepatocytes facilitated by OATP1B1 and OATP1B3. Once in the hepatocytes, it is extensively PK/PD, Non-DNA Repair Genes Detected in Mice Are Predictors of glucuronidated by UGT1A1. This talk would 1) provide justification on the potential Individual Toxic Reactions role of drug transporters in hyperbilirubinemia, 2) show inhibition data against Peter Demant, M.D., Ph.D., Distinguished Member and Professor, Roswell Park UGT1A1, OATP1B1, OATP1B3, MRP2 and BSEP with marketed drugs and 3) Cancer Institute discuss the application of in vitro assays for prediction of hyperbilirubinemia. Irinotecan serves as an important paradigm of pharmacogenetics of host toxicity. Although many homozygotes for UGT1A1 variants deficient in inactivation of irinotecan’s toxic metabolite SN-38 develop severe neutropenia, 75% of all such neutropenias affect UGT1A1 wild-type patients, indicating additional genes. A linkage analysis in mice detected 11 novel Adri (Adverse drug reactions-irinotecan) genes controlling tolerance to irinotecan. They are distinct from known PK/PD and DNA-repair genes and cumulatively determine individual susceptibility to irinotecan toxicity.

WorldPharmaCongress.com World Preclincial Congress | 25 June 10-11, 2015 | Boston, MA 8th Annual New Models for Predicting Drug Toxicity

12:05 Experiences with the Comprehensive Sponsored by 3:35 Utility of an In Vitro Platform to Assess Neuronal Toxicity Using In Vitro Proarrhythmia Assay (CiPA) Human iPSC-Derived Neurons Arthur M. “Buzz” Brown, M.D., Ph.D., Managing Director, Dinah Misner, Ph.D., DABT, Senior Scientist and Group Leader, Investigative ChanTest, a Charles River Company Toxicology, Safety Assessment, Genentech Inc. The regulatory paradigm for nonclinical cardiac risk assessment has shifted from delayed repolarization, hERG block and QT prolongation to involvement of major human 4:05 Refreshment Break in the Exhibit Hall with Poster Viewing cardiac ion channels and proarrhythmic effects on human cardiomyocytes. Please join 5:00 PLENARY KEYNOTE PANEL (see page 2 for details) the discussion to learn more about our experiences with this multi-faceted approach. »» 6:00 Welcome Reception in the Exhibit Hall with Poster Viewing 12:20 LUNCHEON PRESENTATION: Sponsored by E Unum Pluribus: Evolution of iPSC Technologies 7:00 Close of Day from Cell Lines to Functional Tissues Greg Luerman, Ph.D., Head, N.A. Applications, Axiogenesis AG THURSDAY, JUNE 11 iPSC technology is a rapidly evolving, increasingly accessible tool helping to humanize science. Axiogenesis „ready-to-use“ cell types, exhibiting mature electrophysiological and primary tissue-like function, have been adopted into pre-clinical compound 7:30 am Interactive Breakout Discussion Groups screens, safety/tox assessment, and phenotypic assay development. This presentation Each discussion group in this session is led by a moderator/s who ensures will demonstrate how Axiogenesis is tackling the next frontier: engineering functional focused conversations around key issues. Attendees join a specific group and tissues to more accurately reflect in situ drug environments. the small, informal setting facilitates sharing of ideas and active networking. Topics for discussion will be made available on the conference website. 1:00 Refreshment Break in the Exhibit Hall with Poster Viewing

EXPLORING ENGINEERED MODELS PREDICTIVITY OF COMPUTATIONAL TOOLS 1:30 Chairperson’s Remarks 8:35 Chairperson’s Remarks Michael Shuler, Ph.D., Samuel B. Eckert Professor of Chemical Engineering and Yvonne Will, Ph.D., Senior Director, Drug Safety and Head, Science and Technology James and Marsha McCormick Chair of Biomedical Engineering, Cornell University Strategy, Pfizer R&D 1:35 Body-on-a-Chip Devices for Drug Testing: Opportunities and 8:45 eTOX: Assembling Animal Study Data from 6000 Reports From Limitations 13 Pharmaceutical Companies Michael Shuler, Ph.D., Samuel B. Eckert Professor of Chemical Engineering and Philippe Marc, Ph.D., Global Head, Informatics, Preclinical Safety, Novartis James and Marsha McCormick Chair of Biomedical Engineering, Cornell University Institutes for BioMedical Research Human surrogates for drug testing can be created using tissue engineered In 2010, within the Innovative Medicines Initiative, the eTOX project started to constructs, microfabrication, and PBPK (Physiologically Based Pharmacokinetic) extract data from legacy preclinical toxicology reports with the objective of creating models and may be used to make better decisions about which drugs to select for a collaborative preclinical study database. The current version of the database human clinical trials. We will describe our “pumpless” system, results with multi- contains data for 1791 small molecule drugs and drug candidates extracted from organ models, and progress toward a 10+ organ human model. We will discuss the 6105 reports donated by 13 pharmaceutical companies. The database is currently limitations of such technologies and potential solutions. growing by approximately 180 studies per month, and we envisage the creation of the largest preclinical database available. 2:05 Human Contractile Engineered Muscle for Drug and Toxicity Studies Nenad Bursac, Ph.D., Rooney Family Associate Professor, Department of 9:15 Enhanced Prediction of Drug-Induced Liver Injury by the Biomedical Engineering, Duke University Development of Liver Toxicity Knowledge Base Current in vitro models of human muscle do not exhibit contractile behavior. We Minjun Chen, Ph.D., Division of Bioinformatics and Biostatistics, National Center for engineered electrically and chemically responsive, contractile human muscle Toxicological Research, U.S. Food and Drug Administration tissues (“myobundles”) made of primary myogenic cells. These biomimetic Here, we will introduce our efforts to develop the Liver Toxicity Knowledge Base constructs exhibit aligned architecture, multinucleated and striated myofibers, (LTKB), which focuses on collecting drug properties data and aims to develop and a satellite cell pool, and respond to electrical stimuli with twitch and tetanic predictive models for assessing DILI risk in humans. We will discuss some contractions. Use of GCaMP6-reported calcium responses enables long-term simple rules derived from drug physiochemical and toxicological properties and its non-invasive tracking of myobundle function and response to drugs and provides a significant association with DILI risk in humans. After confirmation and validation, platform for predictive drug and toxicology screening. these DILI predictive rules may support decision-making in drug development or 2:35 Towards Organoid Microarrays for Screening Within Neural Tissues regulatory processes to reduce potential DILI liability. Krishanu Saha, Ph.D., Assistant Professor, Biomedical Engineering and Bioethics, 9:45 An In silico Approach to Predict Intrinsic In vitro Cytotoxicity for University of Wisconsin, Madison Compounds in Primary Human Hepatocytes Current human pluripotent stem cell-derived neural models consist of 2D BinQing Wei, Ph.D., Scientist, Discovery Chemistry, Genentech, Inc. disorganized cultures of cell phenotypes representative of only one or a few We present work in progress in the development of a computational model that regions of endogenous tissues. This ignores the vast diversity of cell phenotypes is used to predict the outcome of hepatocyte screening for a set of preclinical and structured 3D niches that exist in vivo and thereby limits their modeling compounds with significant accuracy. We show that this model proved very capacity in regulatory science settings. To overcome these limitations, we used useful in reducing compound attrition for internal projects. Furthermore, the emerging microfabrication methods to generate an array of 3D neural tissues (e.g., physicochemical property space that this work has implicated as being associated organoids) within standard multi-well plates for screening purposes. with toxicity may also provide clues toward understanding the underlying 3:05 The Impact of Assay Technology as Applied to Safety Assessment mechanism(s) of toxicity.

in Reducing Compound Attrition in Drug Discovery

Yvonne Will, Ph.D., Senior Director, Drug Safety, and Head, Science and Technology Strategy, Pfizer R&D

Attrition in the drug industry due to safety findings remains high and requires a shift in the current safety testing paradigm. Many companies are now positioning safety

assessment at each stage of the drug development process, including discovery, where an early perspective on potential safety issues is sought, often at chemical scaffold level, using a variety of emerging technologies.

WorldPharmaCongress.com World Preclincial Congress | 26 June 10-11, 2015 | Boston, MA 8th Annual New Models for Predicting Drug Toxicity

10:15 Tissue Chips for Drug Discovery and Screening Kristin Fabre, Ph.D., Scientific Program Manager, Tissue Chip for Drug Screening Program, National Center for Advancing Translational Sciences (NCATS), NIH The Tissue Chip Program is supporting development of platforms to mimic human physiology that will recapitulate the complex environment for human multi-cellular tissues to be studied. Within five years, major organs systems will be developed and applied to the assessment of biomarkers, bioavailability, efficacy, and toxicity of therapeutic agents prior to clinical trials. It will deliver a valid alternative to standard methodologies and will produce human-physiologically relevant findings, reduce animal experimentation, and improve translational research efficacy. 10:45 Coffee Break in the Exhibit Hall with Poster Viewing NEW PARADIGMS FOR SAFETY TESTING 11:30 Bioinformatic and Cheminformatic Approaches to Assess Cardiac Arrhythmias Siobhan Malany, Ph.D., Chemical Biology Team Leader, Chemical Genomics Center, Sanford Burnham Medical Research Institute The combination of hiPSC-cardiomyocytes and real-time cellular impedance measurements has provided for higher throughput toxicological screening in physiologically-relevant cellular assays. We have monitored dose-dependent changes in beat rhythm of hiPSC-cardiomyocytes induced by pharmaceutical compounds. For compounds that induce atypical beat patterns, we apply bioinformatic approaches, limit cycle analysis and autocorrelation, and present quantitative results to examine irregular beat patterns induced by channel blockers and provide automated solutions to analyze large kinetic datasets for web-based reporting. 12:00 pm Assay Platforms for Toxicity Evaluation in Small Molecules and Nanomaterials Robert Damoiseaux, Ph.D., Scientific Director, Molecular Screening Shared Resource, California Nanosystems Institute, University of California, Los Angeles Small molecule and nano-toxicity can follow quite different paradigms, requiring thoughtful use of adequate assay platforms for toxicity evaluation. In this talk we will have a look at the differences in paradigms and their corresponding assay platforms. We will give examples for each and also present a novel laser scanning cytometry based platform for the direct quantification of genotoxic potential of a substance via quantification of the DNA damage response by quantifying H2AX phosphorylation. 12:30 Close of Conference

WorldPharmaCongress.com World Preclincial Congress | 27 June 11-12, 2015 | Boston, MA

Inaugural Synergistic Use of Functional Genomics Technologies Exploiting RNAi and Gene Editing For Drug Discovery

Large scale loss-of-function genetic screens with complex heterogeneous pools of lentiviral shRNA and sgRNA constructs directly identify genes regulating cellular Suggested Event Package: responses that can then be targeted by novel therapeutics. This presentation will June 10-11: Chemical Biology for Target Validation Conference discuss the development of Cellecta’s flexible platform to generate both RNAi and June 11-12: Synergistic Use of Functional Genomics Technologies Conference CRISPR libraries, and describe lethal interactions identified in recent screens of June 11 Dinner Short Course*: How to Best Utilize Organotypic 3D Cell PDX-derived cell line pairs with our genome-wide sgRNA and shRNA libraries. Cultures in Oncology 4:05 Refreshment Break in the Exhibit Hall with Poster Viewing * Separate registration required. USING GENE EDITING FOR DRUG DISCOVERY THURSDAY, JUNE 11 4:45 Manipulating Cell Phenotype with CRISPR/Cas9-Based Epigenome Editing 12:00 pm Registration Charles Gersbach, Ph.D., Assistant Professor, Department of Biomedical Engineering, Center for Genomic and Computational Biology, Duke University RNAi & CRISPR SCREENS FOR ONCOLOGY New methods for programming cell phenotype have broadly enabled drug screening, disease 2:00 Chairperson’s Opening Remarks modeling, and regenerative medicine. However many of the current protocols are slow, inefficient, and lead to heterogeneous cell populations. We are exploring genome engineering Charles Gersbach, Ph.D., Assistant Professor, Department of Biomedical tools, such as CRISPR/Cas9-based gene regulation and epigenome editing, to more precisely Engineering, Center for Genomic and Computational Biology, Duke University reprogram gene networks and control cellular decision making. We have successfully used 2:05 An RNAi Screen Utilizing a 3D Spheroid Model Suggests these tools to generate cell sources useful for many areas of biotechnology. Destabilizing Tumor Architecture as a Potential Anti-Cancer Therapy 5:15 Use of CRISPR/Cas9 Technology to Study Retinal Development Geoffrey Bartholomeusz, Ph.D., Associate Professor and Director, siRNA Core Facility, Department of Experimental Therapeutics, Division of Cancer Medicine, and Disease The University of Texas M.D. Anderson Cancer Center Donald Zack, M.D., Ph.D., Associate Professor of Ophthalmology and The compact architecture of solid tumors results in hypoxia that contributes Neuroscience, Johns Hopkins University School of Medicine to chemotherapy/radiation resistance. We propose targeting non-neoplastic Advances in human stem cell technology have made possible the differentiation components within the tumor architecture as an effective alternative anti-cancer of retinal eyecups in vitro. We have been using CRISPR/Cas9 technology to therapy. Using a high throughput RNAi screen and a multicellular tumor spheroid generate retinal cell type-specific reporter ES and iPS lines and to introduce retinal model we identified TLR4 as a potential target. Silencing TLR4 inhibited the degeneration-associated mutations. These reporter lines can be used to follow expression of E-cadherin, altered the integrity of the spheroid architecture, reduced retinal neuronal specification during differentiation, they allow the purification of hypoxia, inhibited the hypoxic tolerance response and sensitized MCTS to radiation. specific cell types by sorting and immunopanning, and they also are useful for the development of drug screening assays. 2:35 Modeling Cancer In vivo Using CRISPR/Cas9 Sidi Chen, Ph.D., Postdoctoral Fellow, Laboratory of Dr. Feng Zhang, Broad Institute and 5:45 A Versatile Functional Genetics Platform for Malarial Parasites the Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology Enabled by Efficient CRISPR-Mediated Genome Editing Cancer genomics has revealed hundreds to thousands of mutations associated Jacquin C. Niles, M.D., Ph.D., Associate Professor of Biological Engineering, with human cancer. To test the roles of these mutations, we applied CRISPR/Cas9- Massachusetts Institute of Technology mediated genome editing platform to engineer specific mutations in oncogenes Functional genetics in the human malaria parasite, Plasmodium falciparum, has and tumor suppressor genes. This results in tumorigenesis in several internal previously been frustratingly inefficient and time consuming. This bottleneck has organs in mice. Our method expedites modeling of multigenic cancer with virtually limited the opportunities to validate and prioritize parasite targets to motivate the any combination of mutations. development of new therapeutics. We have now established strategies for robustly achieving controllable gene expression, and have integrated these into an experimental 3:05 Combining RNAi and Genome Editing: New Avenues for framework that facilitates efficient interrogation of virtually any target parasite gene Orthogonal Validation of Functional Genomic Profiles using CRISPR/Cas9 editing. With these technologies, we are querying the essentiality Donald Apanovitch Ph.D., Director, Functional Genomics, Oncology, Pfizer Research of parasite proteins to validate them as potential drug targets and developing RNAi-based functional genomics is a staple of gene pathway and drug target approaches to identify the targets of compounds having antimalarial activity. exploration. While great strides have been made in the reagents and workflows for 6:15 Close of Day shRNA and siRNA screening, there is a need for tools to provide rapid orthogonal validation of gene candidate that emerge from RNAi campaigns. CRISPR, CRISPRi, and CRISPRa are not only developing into primary screening platforms, they are a promising method to compliment RNAi and enhance the quality of functional FRIDAY, JUNE 12 genomic datasets. 3:35 Loss-of-Function Genetic Screens with Sponsored by 7:30 am Interactive Breakout Discussion Groups Pooled CRISPR and sgRNA Libraries Each discussion group in this session is led by a moderator/s who ensures Paul Diehl, Ph.D., Director, Business Development, Cellecta, Inc. focused conversations around key issues. Attendees join a specific group and Both CRISPR/Cas9 knockout and RNA interference (RNAi) have the small, informal setting facilitates sharing of ideas and active networking. proven effective tools for targeted interruption of gene function. Topics for discussion will be made available on the conference website.

WorldPharmaCongress.com World Preclincial Congress | 28 June 11-12, 2015 | Boston, MA Inaugural Synergistic Use of Functional Genomics Technologies

EXPLORING NEW ASSAYS & PLATFORMS 11:00 Massively Parallel Combinatorial Genetics for Developing Combinatorial Therapeutics 8:35 Chairperson’s Remarks Timothy Lu, M.D., Ph.D., Associate Professor, Synthetic Biology Group, Department James Inglese, Ph.D., Head Assay Development & Screening Technologies, of Electrical Engineering and Computer Science and Department of Biological National Center for Advancing Translational Sciences (NCATS) and Adjunct Engineering, Synthetic Biology Center, Massachusetts Institute of Technology

Investigator, National Human Genome Institute (NHGRI) We have developed technologies for the scalable and barcoded assembly of « high-order combinatorial genetic libraries. These strategies enable multiplexed 8:45 KEYNOTE PRESENTATION: GENOME tracking of individual genetic combinations with next-generation sequencing in EDITING-ENABLED HTS ASSAYS FOR pooled screens. We have used these technologies to perform massively parallel CHEMICAL BIOLOGY AND TRANSLATIONAL high-order combinatorial genetics in bacteria and human cells and to modulate RESEARCH phenotypes relevant to important human diseases. Insights derived from massively James Inglese, Ph.D., Head Assay Development & Screening parallel combinatorial genetics can inform the design of effective and novel Technologies, National Center for Advancing Translational Sciences combinatorial therapeutics. (NCATS) and Adjunct Investigator, National Human Genome Institute (NHGRI) 11:30 Building, Using and Maintaining a Functional Genomics In Parkinson’s disease (PD) loss of function mutations in the Parkin gene Arsenal (PARK2) are associated with early-onset forms of PD suggesting a role in Robert Damoiseaux, Ph.D., Scientific Director, Molecular Shared Screening Resource, neuronal survival. We therefore have developed qHTS assays using novel California NanoSystems Institute, University of California, Los Angeles coincidence reporter technology targeting the PARK2 genetic locus to uncover Functional Genomics is one of the most useful modalities for pre- and post-screen pathways and pharmacological agents that can modulate transcription of this target identification and validation. Functional genomics platforms include cDNA, gene. Findings from the qHTS of several thousand drugs and chemical probes siRNA, lentiviral shRNA and CRISPR and each platform has unique advantages and using this novel reporter biocircuit-based assay will be discussed. constraints. Here, we will discuss these properties, talk about how to organize and build a functional genomics arsenal that contains such a comprehensive 9:30 CRISPR-based Genome Editing Tools: New Sponsored by set of tools and cover some of the most common issues encountered during Applications and Streamlined Workflows maintenance and use of these tools. Xiquan Liang, Ph.D., Staff Scientist, Synthetic Biology R&D, Thermo Fisher Scientific 12:00 pm Multiplexed Gene Editing of Human Pluripotent CRISPR-Cas9 is rapidly evolving as the tool of choice for genome editing in Stem Cells mammalian cells. Here we describe novel methods for rapid synthesis of gRNA Krishanu Saha, Ph.D., Assistant Professor, Biomedical Engineering and Bioethics, and delivery of Cas9 protein/gRNA complexes into a variety of cells. University of Wisconsin, Madison Human pluripotent stem cells possess unique ability to mature into any cell type 9:45 High Content RNAi Screening with Persomics: Sponsored by of the body, and therefore are attractive platforms for disease modeling, toxicology Reduction of Scale and Cost with Turnkey Printed and regenerative medicine research. We developed multiplexed CRISPR/Cas9 Libraries gene editing tools to insert reporters, knockout or correct candidate genes in Neil Emans, Ph.D., CEO, Persomics USA, Inc. patient-specific pluripotent stem cells. Our strategies exploit patterned biomaterial RNA interference is routinely used in High Content and Phenotypic screening. substrates with live-imaging to increase throughput and screening for desired However, set-up and operational costs of conventional methods remain beyond phenotypes in edited cell populations. the scope of individual labs or limit screens in facilities. Persomics technology 12:30 Sponsored Presentation (Opportunity Available) miniaturizes, accelerates and de-industrializes RNAi screening. Turnkey, preprinted libraries enable off-the-shelf focused screens and integrate with High Content 12:45 Luncheon Presentation (Sponsorship Opportunity Available) platforms, and existing image analysis strategies. This lowers cost, labor, waste and overall time for any scale of screening; enabling individual labs or facilities to 1:30 Session Break do more. REFINING THE USE OF CRISPR TECHNOLOGY 10:00 Evolution of Target Discovery and Validation Sponsored by – From Large Scale RNAi to Focused CRISPR/Cas9 2:00 Chairperson’s Remarks (Sponsorship Opportunity Available) Jeroen DeGroot, Ph.D., Research Manager, Charles River Nederland BV 2:05 CRISPR Tools for Gene Regulation Applications David F. Fischer, Ph.D., Senior Director, Biology, and Head, Leiden Site, Lei Stanley Qi, Ph.D., Assistant Professor, Department of Bioengineering, and Charles River Nederland BV Department of Chemical and Systems Biology, Stanford University RNAi screening has been the method of choice to discover and validate novel Precise regulation of genes for activation or repression is an important approach for drug targets and recently moved to human primary/patient-derived and stem cell cell engineering and disease modeling. We develop the bacterial CRISPR system models, for instance with our adenoviral (SilenceSelect) library. Target validation as a toolset for sequence-specific gene regulation. The CRISPR tools enable in mouse using CRISPR is also an integrated part of the discovery of new multiplexable, inducible and high-throughput activation or repression of mammalian drug targets. genes, allowing genome wide perturbation for probing gene networks. The CRISPR technology thus provides a powerful screening approach to studying gene function 10:15 Coffee Break in the Exhibit Hall with Poster Viewing and chemical genomics in addition to the RNAi method. 2:35 Small Molecules Modulating CRISPR Editing Sheng Ding, Ph.D., William K. Bowes, Jr. Distinguished Investigator, Gladstone Institute of Cardiovascular Disease; Professor, Department of Pharmaceutical Chemistry, University of California, San Francisco CRISPR-Cas9 system has emerged as an effective tool for genome editing, but challenges remain. To enhance CRISPR-mediated gene editing, we screened chemical libraries and had identified distinct small molecules that can enhance either HDR-based gene knock-in or NHEJ-based knock-out. The use of small molecules provides a simple and effective strategy that enhances precise genome engineering applications and facilitates the study of DNA repair mechanisms in

mammalian cells.

WorldPharmaCongress.com World Preclinical Congress | 29 June 11-12, 2015 | Boston, MA Inaugural Synergistic Use of Functional Genomics Technologies

3:05 Application of Genome Editing to Generate Animal Models for Drug Discovery Myung Shin, Ph.D., Principal Scientist, Biology-Discovery, Genetics and Pharmacogenomics, Merck Research Laboratories Recent advances in genome editing have greatly accelerated and expanded the ability to generate animal models. These tools allow generating mouse models in condensed timeline compared to that of conventional gene-targeting knock-out/ knock-in strategies in ES cells. Moreover, genome editing methods have expanded the ability to generate animal models beyond mice. In this talk, we will discuss the application of ZFNs and CRISPRs to generate various animal models for drug discovery programs. 3:35 Close of Conference

WorldPharmaCongress.com World Preclincial Congress | 30 June 10-11, 2015 | Boston, MA

Inaugural Blood-Brain Barrier New Understanding, Strategies and Tools for Delivering Therapy to the Brain

The BBB does not always impede therapy for the brain. Migratory cells, including Suggested Event Package: immune effector cells, can enter, and their activity can be modulated before they enter. Some agents work from outside the brain: systemic antibody can prevent June 9 Short Course*: Imaging of Blood-Brain Barrier Function entry of drugs or pathogens, or even draw material out of the brain. Differences June 9 Dinner Short Course*: Understanding and Dealing with Drug between the BBB at sites of pathology vs. normal brain can help to concentrate Disposition in CNS therapy at target sites. June 10-11: Blood-Brain Barrier Conference 10:05 Coffee Break in the Exhibit Hall with Poster Viewing * Separate registration required. UNDERSTANDING & PREDICTION OF BRAIN WEDNESDAY, JUNE 10 PENETRATION: PRECLINICAL MODELS, TOOLS & 7:00 am Registration and Morning Coffee UNMET CHALLENGES 10:50 Human Pluripotent Stem Cell Modeling of the Blood-Brain THE BLOOD-BRAIN BARRIER AT SITES OF Barrier PATHOLOGY Eric V. Shusta, Ph.D., Professor, Chemical and Biological Engineering, University of Wisconsin, Madison 8:00 Chairperson’s Opening Remarks A renewable source of human BBB endothelium could prove enabling for brain Margareta Hammarlund-Udenaes, Ph.D., Professor, Translational PK/PD, research and pharmaceutical development. We demonstrate that endothelial cells

Department of Pharmaceutical Biosciences, Uppsala University generated from human pluripotent stem cells (hPSCs) can be specified to possess « many BBB attributes, including well-organized tight junctions, polarized efflux 8:05 KEYNOTE PRESENTATION: REGULATION transport, and nutrient transporter expression. Importantly, hPSC-derived BBB OF THE BLOOD-BRAIN BARRIER IN HEALTH AND endothelial cells also respond to cues provided by other cells of the neurovascular DISEASE unit such as human pericytes, astrocytes and neurons to generate very tight Richard Daneman, Ph.D., Assistant Professor, University of barrier properties. California, San Francisco The blood-brain barrier (BBB) is crucial to ensure proper neuronal 11:20 FEATURED PRESENTATION: DELIVERY OF function and protect the CNS from injury and disease. We have SMALL AND LARGER DRUGS ACROSS THE BBB used genomic, genetic and molecular approach to elucidate the cellular and – TO MEASURE IS TO KNOW molecular mechanisms that regulate the formation of the BBB as well as the Margareta Hammarlund-Udenaes, Ph.D., Professor, Translational mechanisms that lead to its dysfunction during disease. PK/PD, Department of Pharmaceutical Biosciences, Uppsala University 8:35 Targeting Vascular Dysfunction to Improve CNS Health Methods for measuring delivery of drugs across the BBB are Robert D. Bell, Ph.D., Principal Scientist, Neurovascular Biology Lab Head, Pfizer, now available to accommodate the unbound, active moiety, thereby providing Inc. important information on success rate of compounds for CNS action. The talk The vascular system plays an integral role in maintaining central nervous system will include discussions on the factors needed to be taken into consideration and (CNS) health. Both systemic circulatory changes and alterations directly within methods of choice, as well as new information on regional differences in BBB the BBB have been suggested to contribute to both the onset and progression transport and brain distribution. Quantitative results on nanocarrier delivery will of several neurological conditions. In addition, emerging evidence suggests that also be discussed. vascular risk factors including hypertension, diabetes, obesity, atherosclerosis, metabolic syndrome, and stroke can negatively impact BBB function. The 11:50 Imaging and Detection of Nitric Oxide in the Brain by EPR and relationship between systemic vasculature and BBB in health and disease will NMR be reviewed. Lawrence Berliner, Ph.D., Professor of Chemistry and Biochemistry, Chemistry and 9:05 Cancer-Derived Extracellular Vesicles Promote Brain Metastasis Biochemistry, University of Denver; Emeritus, Ohio State University Naoomi Tominaga, Ph.D., Resercher, Divison of Molecular and Cellular Medicine, In a septic rat, NO complexes with the lipophilic Fe(II)-chelate spin trap, N,N-diethyl- National Cancer Center, Japan dithiocarbamate (DETC), in the brain. The in-vivo L-band EPR spectrum confirms Brain metastasis is an important cause of mortality in breast cancer patients. A [(DETC)2 – Fe(II)-NO]. The radical distribution was ‘visualized’ by MR images key event during brain metastasis is the migration of cancer cells through the displaying significantly enhanced contrast where the NO was generated (called blood-brain barrier (BBB), which consists of the endothelium and surrounding cells. the MRI ‘spin-trapping’).The NO complex was more stable in vivo and a more Transfer of extracellular vesicles (EVs) derived from the cancer cells represents a effective MRI contrast agent than other stable nitrogen containing radicals, such as novel mechanism of communication between cancer cells and normal cells. Here, aminoxyl radicals. we show that breast cancer–derived EVs promote brain metastasis by destruction 12:20 pm Luncheon Presentation (Sponsorship Opportunity Available) of BBB. or Enjoy Lunch on Your Own 9:35 Do We Always Need to Cross the Blood-Brain Barrier? 1:00 Refreshment Break in the Exhibit Hall with Poster Viewing Lois A. Lampson, Ph.D., Associate Professor of Neurosurgery, Brigham & Women’s Hospital / Harvard Medical School

WorldPharmaCongress.com World Preclincial Congress | 31 June 10-11, 2015 | Boston, MA Inaugural Blood-Brain Barrier

UNDERSTANDING & PREDICTION OF BRAIN THURSDAY, JUNE 11 PENETRATION: PRECLINICAL MODELS, TOOLS & UNMET CHALLENGES 7:30 am Interactive Breakout Discussion Groups Each discussion group in this session is led by a moderator/s who ensures 1:30 Chairperson’s Remarks focused conversations around key issues. Attendees join a specific group and Richard Daneman, Ph.D., Assistant Professor, University of California, San Francisco the small, informal setting facilitates sharing of ideas and active networking. Topics for discussion will be made available on the conference website. 1:35 MRI-Guided Focused Ultrasound Activated Stem Cell Facilitated Blood-Brain Barrier Opening King C. Li, M.D., FRCP(C), MBA, Senior Associate Dean for Clinical and Translational DELIVERING THERAPIES ACROSS BBB: CASE Research, Professor and Chair, Department of Radiology, Wake Forest School of Medicine STUDIES & UPDATES FROM THE INDUSTRY The objective of this project is to create a remote-controllable stem cell-based strategy to allow us to open up the blood-brain barrier at the time and place of 8:35 Chairperson’s Remarks our choosing. Drugs and therapeutic agents up to at least 300 nm in size can be Lois A. Lampson, Ph.D., Associate Professor of Neurosurgery, Brigham & Women’s delivered through the blood-brain barrier using this technology. This novel paradigm Hospital / Harvard Medical School utilizing image-guided focused ultrasound and stem cells can potentially be applied 8:45 BBB Disruption and Drug Delivery in Neurodegenerative Disease to all diseases that affect the central nervous system. Nga Bien-Ly, Ph.D., Postdoctoral Fellow, Dept. of Neuroscience, Genentech, Inc. 2:05 New Blood-Brain Barrier Shuttles: Phenotypic Screens and It is generally believed that the BBB is disrupted in many neurodegenerative Targeted Proteomics diseases thus suggesting that drug delivery is enhanced as a consequence of BBB Danica Stanimirovic, Ph.D., Director, Translational Bioscience, Human Health leakage. We set out to determine the extent of BBB disruption in mouse models of Therapeutics Portfolio, National Research Council of Canada neurodegeneration, focusing on antibody permeability and Alzheimer’s disease, by The blood-brain barrier (BBB) expresses a myriad of receptors and transporters assessing the differences in brain uptake of control and transferrin receptor (TfR) at its luminal surface, yet only a handful of targets have been used to develop bispecific antibodies. These results will aid in determining the necessity of developing molecular Trojan horses for brain delivery of large molecules. We have identified improved drug delivery methods for the treatment of neurodegenerative diseases. novel receptor-ligand pairs as brain delivery platforms using workflows that 9:15 Engineering Lysosomal Enzyme Therapeutics for the Brain as combine `function-first` screening of antibody display libraries and targeted IgG Fusion Proteins that Penetrate the Blood-Brain Barrier proteomics to understand their trafficking mechanisms across the BBB. Ruben Boado, Ph.D., Vice President, Research & Development, ArmaGen 2:35 Paracellular Portal to the CNS: Are Macromolecules Permitted? Technologies, Inc. Pankaj Karande, Ph.D., Assistant Professor, Department of Chemical & Biological BBB-penetration of enzyme therapeutics is enabled by re-engineering recombinant Engineering, Center for Biotechnology and Interdisciplinary Studies, Rensselaer enzyme as IgG fusion proteins, wherein the IgG transport domain targets a specific Polytechnic Institute endogenous receptor-mediated transporter within BBB, such as the human Delivery of macromolecules into the central nervous system (CNS) is a formidable insulin receptor (HIR). The therapeutic domain of the IgG fusion protein exerts the challenge. The paracellular route has long been considered an exclusive pathway pharmacological effect in brain once across BBB. Several bi-functional IgG-fusion proteins for entry of small water soluble molecules and ions but it can serve as an attractive have been engineered using a genetically engineered monoclonal antibody directed to the portal for delivery of proteins, polypeptides, and enzymes. We will discuss our BBB HIR as the transport domain. First in human trials are planned for 2015. recent discovery of short peptide vectors, PEPDARTs, that specifically target the 9:45 FEATURED PRESENTATION: OPEN THE paracellular pathway into the CNS for delivery of macromolecular cargo. BLOOD BRAIN BARRIER GATE FOR BIOLOGICS 3:05 CNS Uptake of Large Molecules and Peptides: PK Profile and Per-Ola Freskgard, Ph.D., Vice Director and Senior Leader, Applications to Drug Discovery & Development Neuroscience, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd. Sara Belli, Ph.D., DMPK Project Leader, Pharmaceutical Sciences/p-RED, Roche Although biotherapeutics have vast potential for treating brain Innovation Center Basel Large molecules have great potential as CNS therapeutics since they are able to disorders, their use has been limited due to low exposure mimick function of endogenous neuropeptides, reducing expression of disease- across the blood-brain barrier (BBB). This talk will describe a Brain Shuttle related genes or clearing pathological protein aggregates. Developing novel, technology, which can be engineered into a standard therapeutic antibody or effective, and safe drugs for CNS diseases is hindered by blood–brain barrier other modalities for successful BBB transport. These findings will have major reducing distribution of large molecules candidates to brain. Herein, an overview implications for the development of biologics-based treatment of brain disorders. on current knowledge with examples of brain targeting approaches will be given 10:15 Selected Poster Presentation I: Canonical Wnt Pathway focusing on PK and PKPD profiling. Modulation Impacts Brain Endothelial Cell Response to Hypoxic 3:35 Understanding Antibody Penetration through Blood-Brain Stress Barrier Using Cell Fractionation and Quantitative Proteomics Shyanne Page, Graduate Student, Texas Tech University Health Sciences Center, Arsalan Haqqani, Ph.D., Research Officer, Human Health Therapeutics Portfolio, Dept. of Pharmaceutical Sciences, School of Pharmacy National Research Council Stroke is a leading cause of death and morbidity, yet we suffer from lack of stroke Better understanding of mechanism(s) of antibody penetration through BBB is neuroprotective drugs. We speculate that identifying novel drug candidates capable needed to deliver therapies into the CNS. We describe a multiplexed quantitative of protecting the blood-brain barrier function may help improve stroke outcome in method, involving endosome fractionation and label-free targeted mass patients. Using the human induced pluripotent stem cell (iPSC) model developed spectrometry, to track and quantify BBB-crossing antibodies in various intracellular by Shusta and colleagues, we assessed the ability of these cells to respond compartments of brain endothelial cells. The results show that the method has to hypoxia/ischemia and evaluated the ability of Wnt/b-catenin activation as a a potential to quantitatively compare the trafficking of multiple BBB-crossing vasculoprotective pathway. antibodies, providing an insight into mechanism and antibody characteristics that favor their BBB transcytosis. 10:30 Selected Poster Presentation II: Leukocyte-Endothelial Interactions at the Blood-Brain Barrier Studied in Fully-Human Flow- 4:05 Refreshment Break in the Exhibit Hall with Poster Viewing Based In Vitro Models Incorporating Microfluidics Birgit Obermeier, Ph.D., Postdoctoral Scientist, Neuroimmunology Research, »»5:00 PLENARY KEYNOTE PANEL (see page 2 for details) Biogen Idec. 6:00 Welcome Reception in the Exhibit Hall with Poster Viewing 10:45 Coffee Break in the Exhibit Hall with Poster Viewing 7:00 Close of Day

WorldPharmaCongress.com World Preclincial Congress | 32 June 10-11, 2015 | Boston, MA Inaugural Blood-Brain Barrier

11:30 Use of a Camelid VHH to Engineer Blood-Brain Barrier Crossing Bispecific Graham K. Farrington, Ph.D., Director, Chemical & Molecular Therapeutics, Biological Drug Discovery, Biogen Idec. We have engineered a llama single domain VHH antibody FC5 into mono- and bi-valent proteins fused to a huFc. Upon IV injection in rats up to a 30-fold higher brain exposure was observed compared to control. Upon IV dosing in a Hargreaves model of inflammatory pain up to a 60-fold increase in pharmacological potency was observed. The study demonstrates that modular incorporation of FC5 as the BBB-carrier arm in bi-specific antibodies or antibody-drug conjugates offers an avenue to develop pharmacologically active biotherapeutics for CNS indications. 12:00 pm Blood-Brain Barrier (BBB) Penetrating Dual Specific Binding Proteins for Treating Brain and Neurological Diseases Denise Karaoglu Hanzatian, Ph.D., Principal Research Scientist, Biologics Discovery, AbbVie Bioresearch Center, AbbVie 12:30 Close of Conference

WorldPharmaCongress.com World Preclincial Congress | 33 June 10-11, 2015 | Boston, MA Twelfth Annual Case Studies, MASTERING Hot Topics & Med Chem MEDICINAL Strategy CHEMISTRY

9:05 The Application of Extended Hückel Theory for Sponsored by Suggested Event Package: Pharmacophore Modeling Michael Drummond, Ph.D., Applications Scientist, Chemical June 9 Short Course*: Allosteric Modulators of GPCRs, (PAMs NAMs) Computing Group June 10-11: Mastering Medicinal Chemistry Conference Pharmacophore models play an essential role in drug discovery. Generating June 11-12: Property-Based Drug Design in Medicinal Chemistry Conference pharmacophore models which encode accurate molecular recognition features are June 11 Dinner Short Course*: Optimizing Physical Properties of Molecules to highly dependent on properly defined annotation points. Here we have developed Achieve High-Quality Clinical Candidates a new approach for pharmacophore modeling which is based on a semi-empirical method using Extended Hückel Theory (EHT). The pharmacophore features * Separate registration required. generated through the EHT annotation scheme take into account ligand resonance and electron withdrawing effects and are sensitive to non-standard interactions, WEDNESDAY, JUNE 10 such as C-H and halogen bond interactions, during pharmacophore screening.

7:00 am Registration and Morning Coffee 9:35 Small Molecules in Cancer Immunotherapy Jerry L. Adams, Ph. D., Director, Medicinal Chemistry, EXECUTIVE PANEL: FUTURE ROLE OF MEDICINAL Immuno-Oncology & Combinations DPU, GlaxoSmithKline Pharmaceuticals Modulating the immune system through a small molecule approach offers several CHEMISTRY – SCIENCE, TECHNOLOGY & STRATEGY advantages which are complimentary and potentially synergistic to biologic modalities. Importantly, the successes of checkpoint inhibition provide direction for further advances 8:00 Chairperson’s Opening Remarks in the field of immune-oncology, including what roles small molecule drugs might play. This Stewart L. Fisher, Ph.D., Principal, SL Fisher Consulting, LLC talk will provide an overview of the strategy for and targets druggable by small molecules. 8:05 Target Validation and Reproducibility - A Chemistry Perspective 10:05 Coffee Break in the Exhibit Hall with Poster Viewing Mark Bunnage, Ph.D., Vice President, Worldwide Medicinal Chemistry, Pfizer Reproducibility of the scientific literature is a topic of significant current interest. This discussion will focus on irreproducibility issues in target validation and what it EVOLVING THE KINOME IN DRUG DISCOVERY means for medicinal chemistry. 10:50 Kinase Drug Discovery Past, Present, and Future 8:12 So You Want to Improve Your Medicinal Chemistry? Mark Bunnage, Ph.D., Vice President, Worldwide Medicinal Chemistry, Pfizer Jeremy J. Edmunds, Ph.D., Director, Immunology Medicinal Chemistry, Abbvie Over recent years there has been remarkable progress in the medicinal chemistry When one considers the considerable expense that is associated with developing design of selective protein kinase inhibitors. There are now over 20 kinase a drug, it is clearly the responsibility of the chemist to ensure that they are inhibitor drugs on the market and, with the recent approval of the JAK kinase preparing the most optimal compound. To achieve this we have focused our efforts inhibitor Xeljanz® (tofacitinib citrate), we are now seeing kinase drugs emerge for within Abbvie medicinal chemistry toward excellence in design and excellence in indications beyond Oncology. This presentation will discuss current approaches to synthesis. Here we will describe the trials and tribulations of this approach. kinase inhibitor drug discovery and share a perspective on future directions. 8:19 Outsourcing of Medicinal Chemistry 11:20 Secreted Protein Kinases as Novel Regulators of the David Bauer, Principal Scientist, Head of Medicinal Chemistry Outsourcing, Amgen Extracellular Environment The presentation will give an overview of how leveraging external partnerships is Malcolm Whitman, Ph.D., Professor, Department of Developmental Biology, Harvard being used at Amgen to support our Medicinal Chemistry organization. The key School of Dental Medicine; Department of Cell Biology, Harvard Medical School components of our outsourcing strategy will be discussed. Secreted protein kinases, targeting serine, threonine and tyrosine, have recently been identified and shown to act in the secretory pathway and outside the cell. These novel 8:26 Pre-Competitive Collaboration – How AstraZeneca’s Open kinases are divergent from intracellular kinases and represent a new class of drug Innovation Program is Changing the Way We Deliver Medicine to Patients targets for the modulation of secreted protein and extracellular matrix function. Pamela Hill, Open Innovation Program Manager, Emerging Innovations, AstraZeneca, R&D Boston 11:50 Sponsored Presentation (Opportunity Available) The AstraZeneca Open Innovation platform has been created to help us identify 12:20 pm Luncheon Presentation (Sponsorship Opportunity Available) and establish mutually beneficial collaborations that will lead to the discovery and or Enjoy Lunch on Your Own development of new medicines. We provide collaborators with access to late- stage compounds, our compound collection as well as our cheminformatics and 1:00 Refreshment Break in the Exhibit Hall with Poster Viewing screening technologies to validate and publish novel science. 8:33 Talk Title to be Announced Brian Jones, Head, Discovery Chemistry, Novartis Institute of Biomedical Research 8:40 Panel Q&A with Session Speakers

WorldPharmaCongress.com World Preclincial Congress | 34 June 10-11, 2015 | Boston, MA Twelfth Annual Mastering Medicinal Chemistry

EVOLVING THE KINOME IN DRUG DISCOVERY THURSDAY, JUNE 11 CONTINUED 1:30 Chairperson’s Remarks Renato Skerlj, Ph.D., Vice President, Drug Discovery and Preclinical Development, Lysosomal Therapeutics, Inc. COVALENT AND IRREVERSIBLE INHIBITORS 1:35 Akt and RNA Metabolism 8:35 Chairperson’s Remarks Philip N. Tsichlis, M.D., Jane F. Desforges Professor of Medicine, Tufts University Byron DeLaBarre, Ph.D., President & Chief Scientist, The Consulting Biochemist LLC School of Medicine 8:45 Covalent Inhibitors as an Approach for Challenging Targets A phosphoproteomics screen of isogenic cell lines expressing different Akt Atli Thorarensen, Ph.D., Research Fellow, BioTx Medicinal Chemistry, Pfizer isoforms identified RNA metabolism as an Akt target. The phosphorylation of one of the Covalent inhibitors provide potential solutions to this difficult target space, but bring regulators of RNA metabolism (IWS1) was shown to epigenetically regulate alternative additional challenge in medicinal chemistry design due to inhibitors intrinsic chemical RNA splicing. The role of other Akt targets in RNA processing is under investigation. reactivity. This talk will provide an overview of selective covalent drug discovery efforts and what key insights are required for successful covalent drug design. 2:05 Using Ovality to Predict Nonmutagenic, Orally Efficacious Pyridazine Amides as Cell-Specific Spleen Tyrosine Kinase 9:05 Discovery of Covalent Inhibitors of Nedd4-1 Ubiquitin Inhibitors Ligase: First-in-Class Covalent Inhibitor of HECT E3s Matt Lucas, Ph.D., Director, Medicinal Chemistry, Discovery Chemistry and Alexander Statsyuk, Ph.D., Assistant Professor, Chemistry Department, Pharmaceutical Research, Cubist Pharmaceuticals Northwestern University Tyrosine Kinase Inhibitors’ inhibition of spleen tyrosine kinase (SYK) has attracted much attention We developed a novel fragment-based drug discovery technology: irreversible as a mechanism for the treatment of cancers and autoimmune diseases. The structure-guided tethering. We used this to discover a covalent small molecule inhibitor of Nedd4-1 optimization of pyridazine amide SYK inhibitors will be presented, along with an approach that led ubiquitin ligase. We will discuss the mechanism of action of Nedd4-1 inhibitor, such as to the successful identification of non-mutagenic examples with reduced cardiovascular liabilities. switching Nedd4-1 mediated polyubiquitin chain growth from processive to distributive. EMERGING GENE FAMILIES & CHALLENGING TARGETS HIT GENERATION & DISCOVERY TECHNOLOGIES: 2:35 Solute Carrier Proteins as a Potential Source of New Drug DNA-ENCODED LIBRARIES, PHENOTYPIC Targets SCREENS & BEYOND David Hepworth, Ph.D., Senior Director, Biotherapeutics Chemistry, Worldwide Medicinal Chemistry, Pfizer 9:25 Direct and Synergistic Inhibition of the HCV NS5A Solute carriers (SLCs) are biologically important proteins that control movement of Replication Complex small molecules and ions across membranes. While the SLC family appears to be Makonen Belema, Ph.D., Senior Principal Scientist, Discovery Chemistry, Bristol Myers generally small molecule druggable and is similar in size to the Class A GPCRs, the Squibb Co. number of drug targets is currently around 10x fewer. The presentation explores this The NS5A protein plays multifunctional roles in the hepatitis C virus replication paradox and provides an overview of the current status of SLC drug discovery. cycle, and its inhibitors are integral components of a promising combination of HCV therapies that secured regulatory approvals recently. Key aspects of the 2:55 Targeting IAP and BCL Protein-Protein Interactions with Small medicinal chemistry effort that optimized a phenotype screen hit to the first-in- Molecules: Lessons Learned class NS5A inhibitor daclatasvir and highlights of mode-of-action studies that Brian Aquila, Ph.D., Associate Director, Medicinal Chemistry Oncology Research, revealed considerable synergistic interaction between two distinct classes of AstraZeneca NS5A-interacting molecules will be discussed. 3:15 Targeting the Arginine Methyltransferases 9:55 Hit Generation Technologies – From DNA-Encoded Libraries & Kenneth W. Duncan, Ph.D., Associate Director, Molecular Discovery, Epizyme, Inc. Phenotypic Screens, to New Chemical Space 3:35 Modern Drug Research Informatics Sponsored by Jörg Holenz, Ph.D., Director, Discovery and Preclinical Sciences, Project Leader, Applications to CNS, Infectious, Neglected, Rare, AstraZeneca Pharmaceuticals LP and Commercial Diseases Lead Generation is defining the quality of chemical assets and - given this importance - has undergone significant changes. New hit generation techniques Barry Bunin, Ph.D., CEO, Collaborative Drug Discovery (CDD) have been added to the pool, and only by cleverly combining these, the challenge A modern approach to drug discovery informatics in 5 collaborative case studies to drug novel demanding targets will be met. This lecture will present learnings showcasing the CDD Vault will be explored. The CDD Vault manages biological and from successful lead generation case histories. chemical private data securely with external data. 10:15 Accounting for Water Energetics in Sponsored by 3:50 Sponsored Presentation (Opportunity Available) Drug Design 4:05 Refreshment Break in the Exhibit Hall with Poster Viewing Michelle Lynn Hall, Ph.D., Senior Applications Scientist, Schrödinger Water plays a ubiquitous role in biology and is critical in understanding molecular recognition. 6:00 Welcome Reception in the Exhibit Hall with Poster Viewing While the importance of water is greatly appreciated, a detailed understanding of how to 7:00 Close of Day incorporate water into the drug design process has been elusive. For example, crystallography provides the location of a subset of water molecules but cannot place waters throughout the entire binding site. We present strategies for deciding whether it is better to displace, avoid, or bridge a given water molecule once insight into hydration site energetics are in hand.

10:45 Coffee Break in the Exhibit Hall with Poster Viewing

WorldPharmaCongress.com World Preclincial Congress | 35 June 10-11, 2015 | Boston, MA Twelfth Annual Mastering Medicinal Chemistry

11:30 Triage of High-Throughput Screening Hits: A PAIN in the Assay Jonathan B. Baell, Ph.D., Director, Australian Translational Medicinal Chemistry Laboratory and Professor, Medicinal Chemistry, Faculty of Pharmacy and Pharmaceutical Science, Monash Institute of Pharmaceutical Sciences Mathematically, a standard hit rate of say 0.7% necessarily furnishes more false positives from a high-throughput screen than the few (if any) real ligands for that target that may lurk within the set of hits identified. This talk will outline some personal experiences and reflections along with advice on how to efficiently identify problematic screening hits. WATER IN DRUG DISCOVERY: COMPUTATIONAL & NEXT GENERATION DESIGN 11:50 Time-Average Solvation Distributions in Drug Design: A Holistic Approach to Drug Discovery, from Binding Kinetics to Dynamic Modeling Robert Pearlstein, Ph.D., Senior Investigator, Global Discovery Chemistry, Computer-Aided Drug Discovery, Novartis Institutes for BioMedical Research, Inc. Our lab has developed a theory from first principles that links solvation to binding kinetics at a molecular level. We use a comprehensive approach to design chemical matter with optimized pharmaco(binding)kinetics, redefining the role of computational medicinal chemistry in drug discovery. 12:10 pm Designing Water-Soluble Molecules in Drug Discovery Michael A. Walker, Ph.D., Principal Scientist, Medicinal Chemistry, Bristol-Myers Squibb Pharmaceutical Research and Development A number of strategies have been applied by medicinal chemists in order to rationally design molecules which exhibit appropriate solubility. A majority of these approaches are focused on reducing the hydrophobicity of the molecule. This talk will provide examples where solubility was increased in unexpected ways. 12:30 Close of Conference

WorldPharmaCongress.com World Preclincial Congress | 36 June 11-12, 2015 | Boston, MA Fourth Annual property-based

DRUGin medicinal DESIGN chemistry Driving Drug Discovery Success by Designing Right Physicochemical and Biophysical Properties

3:35 SA Delicate Balancing Act: Applying Property Sponsored by Suggested Event Package: Filtering to Fragment Replacement in BROOD June 9 Short Course*: Drug Metabolism and Its Impact on Decisions in Drug Gregory L. Warren, Ph.D., Senior Applications Scientist, Discovery & Development OpenEye Scientific Software, Inc. Lead optimization is not a simple one-dimensional optimization of affinity and June 9 Dinner Short Course*: Understanding and Dealing with Drug effective computational tools should allow of optimization of other molecular Disposition in CNS properties. We will present BROOD v 2.1 a fragment-based R-group and template June 10-11: Mastering Medicinal Chemistry Conference replacement lead optimization application that can suggest replacement groups that June 11-12: Property-Based Drug Design in Medicinal Chemistry Conference are simultaneously optimized for many different properties at once. Several examples June 11 Dinner Short Course*: Optimizing Physical Properties of Molecules to to demonstrate this unique ability will be presented. Achieve High-quality Clinical Candidates 3:50 Sponsored Presentation (Opportunity Available) * Separate registration required. 4:05 Refreshment Break in the Exhibit Hall with Poster Viewing THURSDAY, JUNE 11 DESIGNING MOLECULES WITH BETTER 12:00 pm Registration DELIVERABILITY AND TARGETING 4:45 Optimizing Brain Exposure in CNS Drug Discovery PROPERTY-BASED STRUCTURE DESIGN Ruben Alvarez Sanchez, Ph.D., Head, Pharmaceutical Profiling, Drug Disposition CONSIDERATION FOR NEW & NON-TRADITIONAL and Safety, F. Hoffmann-La Roche MOLECULES For drugs actively transported across the blood-brain barrier, unbound plasma and unbound brain concentrations differ to an extent that is commonly unknown. We 2:00 Chairperson’s Opening Remarks report on approaches to assess and predict unbound brain concentration for P-gp

Gregory L. Warren, Ph.D., Senior Applications Scientist, OpenEye Scientific Software, Inc. substrates and how they can be utilized in early CNS drug discovery to enhance « the understanding of PK/PD relationships and support a clinically meaningful 2:05 KEYNOTE PRESENTATION: EXPLORING compound optimization. MACROCYCLES FOR DRUG DISCOVERY: NOVEL LEAD SERIES FOR CHALLENGING PROTEIN- 5:15 Inhalation by Design: Approaches towards Designing Drug PROTEIN INTERACTIONS Candidates for Lung Diseases Nick Terrett, Ph.D., CSO, Ensemble Therapeutics Corp. Peter Jones, Ph.D., Senior Principal Scientist, Medicinal Chemistry-Inflammation Macrocycles are found widely in nature and several are marketed and Remodelling, Pfizer, Inc. as drugs with good drug-like properties. This presentation will Designing compounds with suitable properties for inhalation present unique illustrate how Ensemble can rapidly generate millions of synthetic macrocycles challenges to the medicinal chemist. This talk will discuss a number of programs using DNA-programmed chemistry, and how they are efficiently screened from within Pfizer that have addressed this issue, across numerous target classes, against protein-protein interaction targets to identify hit compounds and SAR. to produce inhaled candidate drug molecules for the treatment of various lung The novel approach will be illustrated with successful examples of lead discovery diseases – Inhibition of GPCRs, PDEs and Kinases have been targeted successfully programs, including the discovery of novel XIAP and IL17A antagonists. via this approach. 2:35 Property- and Fragment-Based Design Considerations for 5:45 Discovery of Asunaprevir (BMS-650032): An Approved NS3 Protein-Protein Interaction Targets, a Case Study Protease Inhibitor for the Treatment of Hepatitis C Christopher N. Johnson, Ph.D., CChem FRSC, Director, Medicinal Chemistry, Astex Paul Scola, Ph.D., Research Fellow & Group Leader, Department of Virology Chemistry, Pharmaceuticals Bristol-Myers Squibb Research Co. Astex has successfully applied fragment-based drug design to protein-protein Hepatitis C Virus (HCV) infection is an insidious liver disease that affects more than interaction targets. Key factors in this success have been (i) detailed structural 170 million people worldwide. The HCV NS3/4A protease is an essential enzyme understanding of binding interactions between fragment and target protein via x-ray for viral replication and, as such, has been validated as a target for anti-HCV therapy crystallography and (ii) rigorous control of physicochemical properties. The approach in clinical trials. In this presentation, the discovery of BMS-650032, a potent and is exemplified by Astex’s Inhibitor of Apoptosis Protein (IAP) project, where potent selective inhibitor of the NS3/4A enzyme, recently approved for treatment of dual antagonists of XIAP and cIAP1 were identified, havingin vivo anti-tumor activity. HCV, will be described. Highlights of this discovery process include the design of the acylsulfonamide chemotype, as well as optimization of ADME and toxicology 3:05 Computational Design for Improving ADME Properties of properties within this chemical series. Peptidic Macrocycles Alan M. Mathiowetz, Ph.D., Director, Worldwide Medicinal Chemistry, Pfizer, Inc. 6:15 Close of Day A great deal of progress has been made in recent years in elucidating design principles for achieving favorable ADME properties in Beyond Rule-of-5 macrocycles. Many of the important principles, such as minimization of exposed polar surface area to improve permeability, are dependent upon the overall 3D structure, which can be computationally predicted and confirmed experimentally. Here we present computational approaches and property/ADME trends seen in a variety of interesting macrocyclic chemotypes.

WorldPharmaCongress.com World Preclinical Congress | 37 June 11-12, 2015 | Boston, MA Fourth Annual Property-Based Drug Design

FRIDAY, JUNE 12 The Drug Efficiency Index (DEI) (potency plus drug efficiency) has been shown to be proportional to receptor occupancy. Simultaneous optimization of potency and drug efficiency can help guide candidate selection toward compounds of increased 7:30 am Interactive Breakout Discussion Groups quality and with reduced chance of later stage failures. Each discussion group in this session is led by a moderator/s who ensures focused conversations around key issues. Attendees join a specific group and 12:00 pm Hepatobiliary Drug Transport: Predicting and Optimizing the small, informal setting facilitates sharing of ideas and active networking. Pharmacokinetics Topics for discussion will be made available on the conference website. Manthena Varma, Ph.D., Senior Principal Scientist, Pharmacokinetics Dynamics & Metabolism, Pfizer, Inc. PREDICTION AND EVALUATION OF DRUG Hepatobiliary transport is a major disposition pathway, and estimating its contribution to the total systemic clearance is extremely valuable for predicting clinical PROPERTIES pharmacokinetics and understanding the possible mechanisms of hepato-biliary toxicity 8:35 Chairperson’s Remarks and potential drug-drug interactions. Furthermore, the clinical importance of hepatic drug transporters has attracted potential design strategies to support liver targeting

Terry Richard Stouch, Ph.D., President, Science for Solutions, LLC – a key approach to maximizing the potential therapeutic index of a compound. Early « assessment of drug exposure (PK) is challenging in this space given the limited 8:45 FEATURED PRESENTATION: PROPERTY- information regarding the specific transporter expression levels, lack of established BASED MOLECULAR DESIGN: WHERE NEXT? IVIVE and lack of sizable datasets. This presentation provide insight into the hepato- Peter Kenny, Ph.D., Visiting Scientist, NEQUIMED-IQSC, biliary transport with relevance to exposure optimization and the current understanding University of São of the physicochemical and structural drivers in order to facilitate rational drug design. I will draw the distinction between hypothesis-driven and 12:30 Sponsored Presentation (Opportunity Available) prediction-driven molecular design before questioning some of the assumptions commonly made in drug discovery. Alternatives 12:45 Luncheon Presentation (Sponsorship Opportunity Available) to the octanol/water partitioning system will be discussed and relationships or Enjoy Lunch on Your Own between structures will be outlined as a framework for analyzing biological activity and physicochemical properties. 1:30 Session Break 9:15 Oral Druggable Space beyond the Rule of 5: Insights from Drugs DESIGNING PROPERTIES TO OVERCOME and Clinical Candidates Jan Kihlberg, Ph.D., Professor, Department of Chemistry, BMC, Uppsala University, CHALLENGES IN DISCOVERY, DEVELOPMENT & Sweden CLINIC Analysis of drugs and clinical candidates having MW >500 Da demonstrate 2:00 Chairperson’s Remarks significant opportunities for discovery of cell permeable and orally bioavailable drugs in physicochemical space far beyond the rule of 5 (bRo5). As compared to Ro5 Robert S. Foti, M.S., Senior Scientist, Pharmacokinetics & Drug Metabolism, compliant drugs, those bRo5 may modulate different kinds of targets, in particular Amgen, Inc. ones having flat and groove shaped binding sites. Interestingly, macrocycles appear 2:05 A Systems Pharmacokinetics Approach to the Optimization to have features that provide special opportunities in bRo5 drug space. of Drug Properties to Help Maximize Therapeutic Index: On the 9:45 Phosphatidylcholine Affinity Chromatography and Link to Quantitative Prediction of Unbound Tissue Distribution and its Compound Promiscuity, Non-Specific Binding and Phospholipidosis Implication for Drug Design Assessment Avijit Ghosh, Ph.D., Director, Mechanism Based Drug Disposition Pharmacodynamics and Metabolism, Janssen R&D John Reilly, Ph.D., Senior Research Investigator, Global Discovery Chemistry, In this work, we leverage a mathematical model of the underlying physiochemical Novartis Institute of Biomedical Research properties of tissues and physicochemical properties of molecules to support the In this work, a high throughput chromatographic phosphatidylcholine (PC) affinity development of hepatoselective glucokinase activators. A case study using this assay has been demonstrated to offer an insight into the prediction of compound approach in the development of hepatoselective glucokinase activators via organic promiscuity, non-specific binding and phospholipidosis-inducing potential (PLIP) of anion-transporting polypeptide–mediated hepatic uptake and impaired passive pharmaceuticals. Results will include >1000 compound study comparing PC affinity distribution to the pancreas is described. to generic compound promiscuity “Target Hit Rate” assay and the benefit of this approach over cLogP. Results will also be presented on how his assay has been a 2:35 Utilizing Physiologically Based Pharmacokinetic Modeling to useful tool to predict for non-specific binding for PET ligand tracers and PLIP.. Inform Formulation and Clinical Development Robert S. Foti, M.S., Senior Scientist, Pharmacokinetics & Drug Metabolism, 10:15 Coffee Break in the Exhibit Hall with Poster Viewing Amgen, Inc. 11:00 Known Unknowns in Drug Discovery Data Physicochemical properties and early ADMET assays guide chemotype evaluation and rational scaffold alteration. This presentation will focus on the integration of Terry Richard Stouch, Ph.D., President, Science for Solutions, LLC these approaches with physiologically based pharmacokinetic modeling (PBPK) to Data drives Drug Discovery research at all levels and determine the outcome of enable the prediction of clinical outcomes and to optimize selection of formulation. many thousands of decisions that govern the progress, success, or failure of any one project. Yet, even the ‘experimental’ error of this data is often unknown, under- 3:05 The Discovery and Development of an HIV-1 Attachment utilized, or unconfirmed and the actual error has been shown to be even larger that Inhibitor Clinical Candidate that. This includes physical property data as well as that from assays, biomolecular Kap-Sun Yeung, Ph.D., Principal Scientist, Discovery Chemistry, Pharmaceutical structure determination, and computational modeling. These errors, their magnitude R&D, Bristol-Myers Squibb Co. and genesis will be discussed with a eye toward informed decision making. The inhibition of the attachment of the HIV-1 viral glycoprotein gp-120 to the 11:30 Physicochemical and Biomimetic Properties to Guide Lead host cell receptor CD4 during the first step of the viral entry represents a novel antiretroviral approach. This talk will discuss the modifications made by medicinal Optimization chemists based on clinical feedback from multiple compounds, discuss a Klara Valko, Ph.D., DSc, FRSC, Senior Scientific Investigator, UK Analytical successful prodrug approach, and describe formulation development leading to a Chemistry, RD Platform Technology & Science, GSK clinical candidate that is currently progressing to Phase III studies. Measurements of physicochemical and biomimetic properties in early drug discovery are used for the estimation of in vivo distribution and drug efficiency. 3:35 Close of Conference

WorldPharmaCongress.com World Preclincial Congress | 38 June 10-11, 2015 | Boston, MA Second Annual

which selectively kill a subset of cancer cells. Using multiple profiling tools Suggested Event Package: and techniques, we identified the mechanism of selectivity to be activation of the compounds by high cellular expression of a phase II metabolic enzyme. June 9 Short Course*: Allosteric Modulators of GPCRs, (PAMs NAMs) Additionally, we show that the compounds covalently modify cellular proteins as June 9 Dinner Short Course*: Imaging in Cancer Research: Key Applications, part of their efficacy mechanism yet are efficiently cleared from animal models. Modalities and Strategies June 10-11: Chemical Biology for Target Validation Conference 9:05 Sulfonyl Fluoride Chemistry for Target Validation, Identification and Other Applications in Chemical Biology June 11-12: Chemical Proteomics for Target Validation Conference Lyn Jones, Ph.D., Head, Chemistry, Chemical Biology & Rare Diseases, Pfizer June 11 Dinner Short Course*: How to Best Utilize Organotypic 3D Cell I will describe the first rational design and synthesis of sulfonyl fluoride covalent Cultures in Oncology probes that specifically target reactive tyrosine residues in a protein binding site. * Separate registration required. Subsequent development of a clickable covalent inhibitor of the mRNA/miRNA metabolizing enzyme DcpS enabled the measurement of target engagement in human primary cells for the first time. This technology validated DcpS as a bona WEDNESDAY, JUNE 10 fide target protein of a series of diaminoquinazoline derivatives and the broader utility of sulfonyl fluoride chemical probes in chemical biology will be described. 7:00 am Registration and Morning Coffee 9:35 Correlating Intracellular Drug Affinity and Sponsored by PHENOTYPIC SCREENING, TARGET IDENTIFICATION Residence Time with Phenotypic Outcomes Using Bioluminescence Resonance Energy Transfer (BRET) AND MOA OF NOVEL BIOACTIVE PROBES Matt Robers, MSc, Senior Research Scientist 2, Research & Development, Integrated 8:00 Chairperson’s Opening Remarks Biology, Promega Corporation To elucidate the process of target engagement as it occurs in cells, we Iván Cornella-Taracido, Ph.D., Senior Principal Scientist, Discovery Chemistry, Merck demonstrate that bioluminescence energy transfer (BRET) can provide a 8:05: Advances and Hurdles in Target Discovery with Small Molecule quantitative biophysical assessment of compound engagement and residence time Probes for chosen intracellular targets. BRET reporter complexes are generated in cells by the binding of cell-permeable fluorescent probes to a selected target protein Iván Cornella-Taracido, Ph.D., Senior Principal Scientist, Discovery Chemistry, Merck fused to a small luciferase (NanoLuc). Compound binding to the target results Chemical Biology and Proteomics approaches have become an integral part of the in competitive disruption of the BRET complex, which can be monitored in real identification and validation of novel therapeutic targets, particularly enabling small time within intact cells. As the specificity of the BRET signal is dictated by the molecule mechanism of action studies. Yet, in spite of the published successes placement of the luciferase on the chosen target, broad-coverage probes enable and high expectations over the last decade, the rate of discovery of new druggable a method to profile the isozyme-specific affinity and binding kinetics over entire targets with clinical translational success has been, so far, apparently disappointing. enzyme classes. The approach has been successfully applied to a variety of target As a general introduction to the symposium, and to highlight the contributions of classes including kinases, integral membrane proteins, and chromatin modifying invited speakers and the topics of the 2015 edition, in these opening remarks we enzymes. The technique has enabled an in-depth analysis of intracellular selectivity, will introduce some potential contributing factors to these shortcomings to seed affinity, and residence time for various classes of histone deacetylase (HDAC) discussions and brainstorm during the “Interactive Breakout Discussion Groups” inhibitors in HeLa cells. An analysis of drug affinity revealed a strong correlation sessions of the event. between isozyme affinity and antiproliferative potency for certain HDACs, while collateral HDAC isozymes were not similarly aligned with antiproliferation. 8:15 Identification of HIV Reactivation Agents through Phenotypic Moreover, non-equilibrium analysis of target engagement revealed a key Screening: Synergy, Mechanism, and Education mechanism of action for a panel of HDAC prodrug inhibitors involving slow binding David Tellers, Ph.D., Principal Scientist, Discovery Chemistry, Merck Research and slow dissociation. This novel application of BRET should allow correlation Laboratories of phenotypic outcomes with target engagement and drug residence time in a common cellular context. Only a limited number of mechanisms have been identified which induce latent HIV expression in vitro in latently infected cell lines, primary cell models and ex vivo 9:50 Sponsored Presentation (Opportunity Available) cells from suppressed HIV infected subjects. To identify novel mechanisms with the potential for use in combination therapy to induce latent HIV, we conducted an 10:05 Coffee Break in the Exhibit Hall with Poster Viewing ultra-high throughput screen using a T-cell HIV latency model system. Results from this screen identified known mechanisms of action and a larger subset of unknown CHEMICAL TOOLS MODULATING GENE pathways. Our progress in elucidating these mechanisms will be detailed. EXPRESSION AND PROTEIN HOMEOSTASIS 8:35: A Trigger Based Selectivity Mechanism of Cell Death Identified 10:50 Featured Presentation: Targeted Protein Degradation of through Chemical Genetics Pathological Proteins Deborah Rothman, Ph.D., Investigator III, Chemical Genetics, Novartis Institutes of Andy Crew, Ph.D., Vice President, Chemistry, Arvinas Biomedical Research Based on an ‘event-driven’ paradigm, targeted protein degradation offers a Phenotypic drug discovery has gained momentum as a complementary approach novel and broad mechanism to irreversibly inhibit protein function, namely, the to target based drug discovery in the last decade. Though a phenotypic drug intracellular destruction of target proteins. This is achieved via small molecule discovery approach, we have identified the N-BICs series of small molecules, mediated recruitment of the target proteins in question to the E3 ligase

WorldPharmaCongress.com World Preclincial Congress | 39 Second Annual June 10-11, 2015 | Boston, MA Chemical Biology for Target Validation

component of the UPS cellular quality control machinery. The application of the be used as therapeutic agents, but their target binding affinities often precludes Arvinas degradation platform to identification of potent degraders of TBK1 will their use in a clinical setting. Using a phage display strategy and libraries of be described. variant proteins designed based on crystal structure information, we can evolve high affinity variants that show increased binding affinity and improved activity 11:20 Targeting the Stress Chaperome in Disease, Diagnosis and compared to the wild type proteins. Treatment Gabriela Chiosis, Ph.D., Associate Member and Lab Head, Molecular Pharmacology 3:35 Modeling Peptide Therapeutics/A Case Study Sponsored by and Chemistry, Sloan Kettering Institute; Associate Attending, Department of Oscar Villacañas, Ph.D., Head, Computational Chemistry, Medicine, Memorial Sloan Kettering Cancer Center Intelligent Pharma Normal cellular physiology is maintained by the coordinated action of the The identification of small molecules which can mimic peptides has great chaperome, a network of molecular chaperones as well as co-chaperones and potential in overcoming difficulties associated with synthesis, or unfavorable folding enzymes. By using innovative methods, we develop small molecule physical properties. Through a case study we applied our ligand-based virtual chemical tools specifically targeted to the stress chaperome; these act as screening to determine the similarity of a peptide to a set of small molecules “sensors” of the chronic stress, and in turn, of the chronic stress-associated that were experimentally validated. proteome. I will discuss how by the use of these unique tools we aim to 3:50 Sponsored Presentation (Opportunity Available) understand, diagnose and treat cellular processes associated with chronic stress. 4:05 Refreshment Break in the Exhibit Hall with Poster Viewing 11:50 Chemical Modulation of Chromatin Structure Jun Qi, Ph.D., Senior Research Scientist, Bradner Lab, Department of Medical »»5:00 PLENARY KEYNOTE PANEL (see page 2 for details) Oncology, Dana-Farber Cancer Institute 6:00 Welcome Reception in the Exhibit Hall with Poster Viewing 12:20 pm Luncheon Presentation (Sponsorship Opportunity Available) or Enjoy Lunch on Your Own 7:00 Close of Day 1:00 Refreshment Break in the Exhibit Hall with Poster Viewing THURSDAY, JUNE 11 NOVEL SYNTHETIC METHODS FOR MODULATION OF BIOLOGICAL PROCESSES 7:30 am Interactive Breakout Discussion Groups Each discussion group in this session is led by a moderator/s who ensures 1:30 Chairperson’s Remarks focused conversations around key issues. Attendees join a specific group and Alexander Statsyuk, Ph.D., Assistant Professor, Department of Chemistry, the small, informal setting facilitates sharing of ideas and active networking. Northwestern University Topics for discussion will be made available on the conference website. 1:35 Small Molecules to Engineer and Explore Human Immunity David A. Spiegel, Ph.D., M.D., Professor, Department of Chemistry, Yale University KEYNOTE SESSION: TECHNOLOGICAL Research in the Spiegel Laboratory utilizes techniques and insights from organic chemistry to modulate and/or create immunological function, an area termed INNOVATIONS “Synthetic Immunology.” This talk will discuss our recent work toward novel 8:35 Chairperson’s Remarks paradigms for immunotherapy by developing and characterizing synthetic constructs Laura Benitez, Ph.D., Sales and Business Development Manager, Intelligent that harness immune responses. Specific topics to be discussed will include the Pharma rational design and biological characterization of immunomodulatory small molecules, as well as applications in areas ranging from cancer to infectious disease. 8:45 From Yeast to Human Neurons and Back Again: Powerful Platforms for Chemical Biology and Target 2:05 Spliceosome Modulation for the Treatment of Mutant SF3B1 Cancers Validation Gregg F. Keaney, Ph.D., Senior Scientific Investigator, Medicinal Chemistry, H3 Susan Lindquist, Ph.D., Professor, Biology, MIT; Investigator, Biomedicine Howard Hughes Medical Institute This presentation will describe how the pladienolide natural products were Taking advantage of the highly conserved biology of protein folding and originally identified to interact with the spliceosome through target identification trafficking in eukaryotic cells, we have created yeast models of human cross-linking experiments, and how recently-discovered SF3B1 mutations in neurodegenerative diseases that recapitulate the basic pathological processes chronic lymphocytic leukemia (CLL) and myelodysplastic syndrome (MDS) disrupting protein homeostasis. Significantly, each yeast model exhibits represent a novel biological target for therapeutic intervention. The total synthesis cellular toxicity through a different mechanism. The unique advantage of these of 6-deoxypladienolide D, a structurally-complex macrocyclic natural product, along models is the ability to perform ultra-highthroughput screening of chemical with its biological activity in a suite of mutant SF3B1 assays will be described. compound libraries. Hits from these yeast screens rescue patient-derived neurons. With this validation, we return to yeast and use the power of yeast 2:35 Discovering and Validating Drug Targets Using Synthetic Binding genetics to identify targets. This lecture will discuss recent successes and the Shohei Koide, Ph.D., Professor, Department of Biochemistry and Molecular Biology, future promise of these yeast-to-neurons-to-yeast platforms. The University of Chicago We have developed “Monobodies,” synthetic binding proteins that can be 9:30 FITGE-Based Target Identification for the introduced into cells as genetically encoded protein. Remarkably, Monobodies to Connection of Rational Drug Discovery with diverse target proteins are almost always inhibitors of their functions. Like small- Phenotypic Screening molecule drugs, Monobodies modulate endogenous targets by binding them. Seung Bum Park, Ph.D., Professor, Chemistry, Seoul National University Therefore, investigation of cellular effects of Monobodies and of the structural basis We developed a new target identification platform, FITGE, which aims of Monobody-target interactions accelerates target validation and the discovery to preserve protein-small molecule interactions under the intact cellular of potentially druggable sites. I will discuss our approach as applied to signal environment. I will report a phenotype-based discovery of initial hits that transduction and epigenetics. enhance the cellular glucose uptake in myotubes and adipocytes Identification and rational optimization of initial hits can generate lead compounds with 3:05 High-Throughput Generation of Synthetic Peptides Modulating high potency for PPARg transactivation and cellular glucose uptake. I will also Enzyme Function present our current efforts on the development of novel neuroinflammatory Sachdev Sidhu, Ph.D., Professor, Donnelly Centre for Cellular & Biomolecular agents from phenotypic screening and target ID. Research, Department of Molecular Genetics, University of Toronto Peptide ligands are promising small-molecule therapeutic candidates for devastating diseases such as cancer. In principle, some natural proteins could 10:15 Sponsored Presentation (Opportunity Available)

WorldPharmaCongress.com World Preclincial Congress | 40 Second Annual June 10-11, 2015 | Boston, MA Chemical Biology for Target Validation

10:45 Coffee Break in the Exhibit Hall with Poster Viewing CASE STUDIES IN CHEMICAL BIOLOGY TARGETING PPIs AND ALLOSTERY 11:30 Novel Probes for E3 Ligases: pH Cleavable Photocrosslinkers to Map E2/E3 Ligase PPI Interface and UbiFlu Novel Fluorescent Probes Alexander Statsyuk, Ph.D., Assistant Professor, Department of Chemistry, Northwestern University We will present our work toward the development of chemical probes to study the biochemistry and pharmacology of E3 ubiquitin ligases. First we have developed a novel class of pH-cleavable, minimalist photocrosslinkers that can be installed anywhere on the surface of the E2 enzyme using cysteine chemistry. The second part of this talk will outline the invention of a novel class of fluorescent activity based probes for E3 ligases called UbiFlu. 12:00 pm Not All mGluR PAMs Are Created Equal: Designing the Right Allosteric Ligand for Your Clinical Indication Dario Doller, Ph.D., Director, Discovery Chemistry & DMPK, Global Head of Chemical Biology, Lundbeck Research USA Allosteric modulation of glutamate-sensing metabotropic receptors (mGluRs) has the potential to provide new therapies for the most debilitating CNS diseases (AD, PD, MS). Advances in our understanding of the chemical biology of these receptors has enabled the characterization of ligands with distinct phenotype. We will disclose new results in the area of mGlu4 positive allosteric modulation, including careful characterization of different tool compounds. 12:30 Close of Conference

WorldPharmaCongress.com World Preclincial Congress | 41 June 11-12, 2015 | Boston, MA Inaugural

5:15 Tracking Cancer Drugs in Living Cells by Thermal Profiling of the Suggested Event Package: Proteome June 9 Short Course*: Allosteric Modulators of GPCRs, (PAMs NAMs) Marcus Bantscheff, Ph.D., Head, Technology, Cellzome GmbH, Molecular Discovery Research, GlaxoSmithKline June 9 Dinner Short Course*: Imaging in Cancer Research: Key Applications, Modalities and Strategies 5:45 Proteomics-Based Methods for In-Depth Analysis of Key June 10-11: Chemical Biology for Target Validation Conference Molecular Events in Tumorogenesis June 11-12: Chemical Proteomics for Target Validation Conference Jarrod Marto, Ph.D., Department of Biological Chemistry and Molecular Pharmacology, Dana-Farber JuneOPENING 11 Dinner Short KEYNOTE Course*: How SESSION: to Best Utilize TECHNOLOGICAL Organotypic 3D Cell Proteomics-based methods provide a highly parallel readout of multiple biologically Cultures in Oncology INNOVATIONS relevant events in a single experiment. Collectively these data provide a detailed * Separate registration required. 2:00 Chairperson’s Opening Remarks view of key molecular mechanisms in cancer initiation and progression and can also facilitate drug target discovery and improved characterization of small Markus Schirle, Ph.D., Senior Investigator, Developmental and Molecular molecule-based therapeutics. Pathways/Chemogenetics, Novartis Institutes for BioMedical Research THURSDAY, JUNE 11 6:15 Close of Day 2:05: BioPlex 1.0: An Orfeome-Based, Mass 12:00 pm RegistrationSpectrometry-Driven, Human Protein Interaction Network FRIDAY, JUNE 12 Steven P. Gygi, Ph.D., Professor, Cell Biology, Harvard Medical School We report a scalable affinity-purification mass spectrometry (AP-MS) platform 7:30 am Interactive Breakout Discussion Groups and identify interacting partners for 2,594 proteins in HEK293T cells. The Each discussion group in this session is led by a moderator/s who ensures resulting network (BioPlex 1.0) contains 23,744 interactions, 86% previously focused conversations around key issues. Attendees join a specific group and unknown, among 7,668 proteins. This lecture will highlight network’s the small, informal setting facilitates sharing of ideas and active networking. construction and its insights into human disease. Within two years, the Topics for discussion will be made available on the conference website. platform described here will be used to determine interacting partners from a complete pass through the Orfeome collection (~13,000 human genes). CHEMOPROTEOMIC STRATEGIES FOR INHIBITOR 2:50 Mass Spectrometry-based Proteomics in DEVELOPEMENT Preclinical Drug Discovery Bernhard Kuster, Ph.D., Professor, Co-Founder and Chair, 8:35 Chairperson’s Remarks Proteomics and Bioanalytics, Technische Universität München, Alexander Statsyuk, Ph.D., Assistant Professor, Chemistry, Northwestern University OmicScouts GmbH 8:45 Chemical Proteomic Strategies to Investigate Reactive Preclinical stages in the drug discovery process require a multitude of biochemical and genetic assays in order to characterize the effects of drug Cysteines candidates on cellular systems and model organisms. Dramatic technological Eranthie Weerapana, Ph.D., Assistant Professor, Chemistry, Boston College improvements in mass spectrometry-based proteomic and chemical We have applied chemical proteomics to identify and characterize functional proteomic strategies substantially facilitate decision-making throughout cysteines in the human proteome. By combining small-molecule probe synthesis the drug discovery process. Here, we highlight proteomic approaches with mass spectrometry-based proteomics, we have identified reactive and suitable for preclinical drug discovery and illustrate the potential of exciting functional cysteines that can be targeted for covalent inhibitor development. recent developments. Our small-molecule probes act as pharmacological modulators of diverse protein activities. 9:15 Serendipitous Discovery of the Selective Inhibitor of the 3:35 Sponsored Presentation (Opportunity Available) Ubiquitin System Using Chemoproteomic Approaches 4:05 Refreshment Break in the Exhibit Hall with Poster Viewing Alexander Statsyuk, Ph.D., Assistant Professor, Chemistry, Northwestern University While designing chemoproteomic probes for UBL proteins based on covalent PROTEOMICS-ENABLED DISCOVERY Nedd8 E1 enzyme inhibitor MLN4924, we discovered a molecule ABP3 that potently and covalently labeled ubiquitin and Nedd8 proteins inside A549 cells. 4:45 Proteomics as a Contributing Technology in Drug Discovery The key to this discovery was the use of click chemistry that allowed us to Kieran Geoghegan, Ph.D., Research Fellow, Pfizer, Inc. visualize and identify protein targets of ABP3, due to the presence of an alkyne The relationship of proteomics to drug discovery continues to be explored and tag in the molecule. Subsequent follow up experiments showed that ABP3 is a developed. Among the trends driving interest in such approaches are the targeting potent inhibitor of Nedd8 ubiquitin conjugation in cells, but not SUMO, ISG15, and of proteins with deep controlling effects on cell metabolism, a revived interest in Ufm1 conjugation. drugs that form covalent bonds with their targets, and the need to deconvolute the action of potent compounds for which no molecular target is known. All aspects 9:45 Sponsored Presentation (Opportunity Available) of the continuum existing between classical proteomics and chemical biology offer 10:15 Coffee Break in the Exhibit Hall with Poster Viewing potential to elucidate highly valued new information about drug action.

WorldPharmaCongress.com World Preclinical Congress | 42 Inaugural June 11-12, 2015 | Boston, MA Chemical Proteomics for Target Validation

ADVANCES IN TARGET DECONVOLUTION BIOORTHOGONAL TECHNIQUES FOR LABELLING 11:00 Towards Comprehensive Coverage of Drug Target Space in AND IMAGING Chemical Proteomics 2:00 Chairperson’s Remarks Markus Schirle, Ph.D., Senior Investigator, Developmental and Molecular Pathways/ Doug Johnson, Ph.D., Associate Research Fellow, Neuroscience, Medicinal Chemogenetics, Novartis Institutes for BioMedical Research Chemistry, Pfizer Non-covalent approaches have been highly successful for certain target classes. However, they have a significantly lower success rate for important target classes 2:05 Tandem Photoaffinity Labeling - Bioorthogonal Conjugation in that require intact cellular environments. In these cases, covalent strategies such Medicinal Chemistry as photocrosslinking-based experiments using live cell treatment have proven David Lapinsky, Ph.D., Associate Professor, Medicinal Chemistry, Division of to be successful but require careful experimental design and optimization. Our Pharmaceutical Sciences, Duquesne University efforts towards a comprehensive chemical proteomics strategy for de novo This lecture willhighlight recent applications of tandem photoaffinity labeling– target deconvolution that includes covalent and non-covalent approaches will bioorthogonal conjugation as a powerful and versatile chemical approach. In be presented. particular, recent applications of this strategy towards affinity-based protein profiling (AfBPP), drug target identification, binding ensemble profiling, studying 11:30 Case Strudies in Target Identification and Mechanism of Action endogenous biological molecules, and imaging applications will be presented. in Drug Discovery Additionally, recent advances in the development of ‘all-in-one’ compact moieties Monica Schenone, Ph.D., Technical and Scientific Leader, Biochemical Target ID, possessing a photoreactive group and clickable handle will be presented. Proteomics Platform, Broad Institute 2:35 A Modular and Traceless Chemical Method to Locate and Track 12:00 pm Small Molecule Profiling by Protein Stability-Based Endogenous Protein Targets in Live Cells Interaction Proteomics (ProSIP) James Chambers, Ph.D., Assistant Professor, Chemistry, University of Kilian Huber, Ph.D., Senior Fellow, Giulio Superti-Furga Laboratory, CeMM Research Massachusetts, Amherst Center for Molecular Medicine of the Austrian Academy of Sciences I will describe out rationale for designing a traceless, chemistry-based probe We report an unbiased systems-level approach to monitor small-molecule target that allows for tagging endogenous receptors on neurons. The probe combines engagement in live cells based on protein thermal stability and quantitative elements of medicinal chemistry, bio-conjugation, chemical biology, and mass spectrometry. The procedure does not require chemical modification neurobiology. I will provide a detailed discussion of our design and implementation of the compound of interest and in combination with tailored bioinformatic for our first probe that was targeted to glutamate-gated AMPA receptors. I will then analysis constitutes a powerful means to assess target binding in a physiological discuss our present efforts to modularize the system. context. Protein Stability-based Interaction Proteomics (ProSIP) should allow for the systematic mapping of chemical agents, including metabolites, to their 3:05 Chemoproteomics with Clickable Photoaffinity Probes for natural partners. Neuroscience Target ID and Validation Doug Johnson, Ph.D., Associate Research Fellow, Neuroscience, Medicinal 12:30 Utilizing Chemogenomics to Chemoproteomics to Identify and Chemistry, Pfizer Validate New Targets in Drug Discovery This talk will describe how we used clickable photoaffinity probes for (off-)target Erik Hett, Ph.D., Principal Scientist, Chemical Biology, Medicinal Chemistry, Pfizer identification/validation and to measure target engagement in live cells for three During this presentation I will share case studies illustrating the the ultization of neuroscience projects at Pfizer. In the first example, we used clickable γ-secretase gene-family biased small molecule sets in phenotypic screens to identify druggable modulator (GSM) photoaffinity probes to determine the target of GSMs within the targets and to enable target identification, as well as ultilzating activity-based γ-secretase complex. protein profiling to deconvolute phenotypic hits. 3:35 Close of Conference 1:00 Luncheon Presentation (Sponsorship Opportunity Available) or Enjoy Lunch on Your Own 1:30 Session Break

WorldPharmaCongress.com World Preclincial Congress | 43 Sponsorship & Exhibit Opportunities

CHI offers comprehensive sponsorship packages which include presentation Looking for additional ways to opportunities, exhibit space, branding and networking with specific prospects. drive leads to your sales team? Sponsorship allows you to achieve your objectives before, during, and long CHI’s Lead Generation Programs will help you after the event. Any sponsorship can be customized to meet your company’s obtain more targeted, quality leads throughout needs and budget. Signing on early will allow you to maximize exposure to the year. We will mine our database of 800,000+ life science professionals to your qualified decision-makers. specific needs. We guarantee a minimum of 100 leads per program! Opportunities include: Podium Presentations— Available Invitation-Only VIP • Whitepapers within Main Agenda! Dinner/Hospitality Suite • Webinars Showcase your solutions to a guaranteed, targeted Sponsors will select their top prospects from the • Custom Market Research Surveys audience. Package includes a 15- or 30-minute conference pre-registration list for an evening of • Podcasts podium presentation within the scientific agenda, networking at the hotel or at a choice local venue. exhibit space, on-site branding, access to CHI will extend invitations and deliver prospects, cooperative marketing efforts by CHI, and more. helping you to make the most out of this invaluable opportunity. Evening will be customized Breakfast & Luncheon according to sponsor’s objectives i.e.: Podium Presentations • Purely social • Focus group Opportunity includes a 30-minute podium • Reception style presentation. Boxed lunches are delivered into the • Plated dinner with specific conversation focus main session room, which guarantees audience attendance and participation. A limited number of Exhibit presentations are available for sponsorship and Exhibitors will enjoy facilitated networking they will sell out quickly. Sign on early to secure opportunities with qualified delegates. Speak your talk! face-to-face with prospective clients and showcase your latest product, service, or solution. 2015 Exhibitors & Sponsors (As of February 12, 2015) Abcam Halocarbon Products ProQinase AMRI Hybrigenics Reaction Biology Corporation AntiCancer, Inc. Intelligent Pharma Schrödinger Axiogenesis International Institute for the SCIVAX Life Sciences, Inc. Stay Connected Biomodels, LLC Advancement of Medicine Simulations Plus, Inc. Biopta Ltd InvivoSciences, Inc. Solid Form Solutions Ltd #CHIWPC15 Bruker Corporation KIYATEC Inc. Studylog Systems, Inc. Cellular Dynamics International Molecular Sensing, Inc. Sygnature Discovery Champions Oncology Oncodesign Synthonix Charles River Optibrium Taconic Biosciences The Intro-Net offers Chemical Computing Group Persomics USA, Inc. The Jackson Laboratory you the opportunity to PharmAgra Labs, Inc. VisualSonics Collaborative Drug Discovery (CDD) set up meetings with selected attendees Additional branding and sponsorship opportunities available! before, during and after this conference, allowing you to connect to the key people that you want to For sponsorship and exhibit information, please contact: meet. This online system was designed with your Joseph Vacca privacy in mind and is only available to registered Associate Director, Business Development session attendees of this event. 781-972-5431 | [email protected]

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T1A: Novel Preclinical Models in Oncology T1B: Tumor Models for Cancer Immunotherapy A series of diverse reports designed to T2A: Translational Imaging in Cancer Drug Development T2B: 3D Cellular Models keep life science professionals informed T3A: Targeting GPCRs T3B: Targeting Histone Acetylation of the salient trends in pharmaceutical technology, business, clinical development, T4A: New Models for Predicting Drug Toxicity T4B: Synergistic Use of Functional Genomic Technologies and therapeutic disease markets. T5A: Blood-Brain Barrier TSB: Training Seminar: Applying Pharmacology to New Drug Discovery For a detailed list of reports, visit InsightPharmaReports.com, or contact T6A: Mastering Medicinal Chemistry T6B: Property-Based Drug Design in Medicinal Chemistry Rose LaRaia, [email protected], +1-781-972-5444. T7A: Chemical Biology for Target Validation T7B: Chemical Proteomics for Target Validation

SHORT COURSE Single Short Course $699 $399 Barnett is a recognized leader in clinical Two Short Courses $999 $699 education, training, and reference guides Three Short Courses $1,199 $899 for life science professionals involved in the drug development process. For more Please select the short courses you are most likely to attend. information, visit barnettinternational.com. Tuesday, June 9 | 2:00 – 5:00 pm Thursday, June 11 | 7:00 – 10:00 pm (Dinner provided) SC8: Optimizing Physical Properties of Molecules to Achieve High-Quality SC1: Allosteric Modulators of GPCRs, (PAMs NAMs) ADDITIONAL REGISTRATION DETAILS Clinical Candidates Each registration includes all conference SC2: Imaging of Blood-Brain Barrier Function SC9: How to Best Utilize Organotypic 3D Cell Cultures in Oncology sessions, posters and exhibits, food SC3: Drug Metabolism and Its Impact on Decisions in Drug Discovery SC10: 3D Printing functions, and access to the conference Development proceedings link. Tuesday, June 9 | 6:00 – 9:00 pm (Dinner provided) SC11: PDX Models Update Handicapped Equal Access: In accordance with the ADA, Cambridge Healthtech SC4: Biased GPCR Ligands: Towards Novel Drug Discovery Institute is pleased to arrange special SC5: Understanding and Dealing with Drug Disposition in CNS accommodations for attendees with special needs. All requests for such SC6: Navigating the CiPA Landscape assistance must be submitted in writing SC7: Imaging in Cancer Research: Modalities, Agents and Strategies to CHI at least 30 days prior to the start of the meeting. CONFERENCE DISCOUNTS To view our Substitutions/ Cancellations Policy, go to Alumni Discount 20% Off http://www.healthtech.com/regdetails Drug Safety Executive Council (DSEC) Members 25% Off Video and or audio recording of any kind Poster Discount $50 Off is prohibited onsite at all CHI events. POSTER DISCOUNT ($50 Off) Poster abstracts are due by April 24, 2015 Once your registration has been fully processed, we will send an email containing a unique link allowing you to submit your poster abstract. If you do not receive your link within 5 business days, please contact [email protected]. * CHI reserves the right to publish your poster title and abstract in various marketing materials and products. REGISTER 3 - 4th IS FREE: Individuals must register for the same conference or conference combination and submit completed registration form together for discount to apply. ALUMNI DISCOUNT: Cambridge Healthtech Institute (CHI) appreciates your past participation at World Pharma Congress. As a result of the great loyalty you have shown us, we are pleased to extend to you the exclusive opportunity to save an additional 20% off the registration rate. Please note: Our records must indicate you were an attendee of World Pharma Congress in the past in order to qualify. Group Discounts are Available! Special rates are available for multiple attendees from the same organization. For more information on group discounts contact David Cunningham at 781-972-5472 *Alumni, DSEC Membership, Twitter, LinkedIN, Facebook or any other promotional discounts cannot be combined. Discounts not applicable on Event Short Courses. If you are unable to attend but would like to purchase the World Preclinical Congress 2015 CD for $750 (plus shipping), please visit WorldPharmaCongress.com. Massachusetts delivery will include sales tax.

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