James Stodder, (Ph.D., Economics, Yale 1990) Lally School of Management & Technology
Craig M. Crews, Ph.D. Dennis Wright, Ph.D. - Yale University · 2019-12-30 · Yale University....
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Craig M. Crews, Ph.D. Lewis B. Cullman Professor of Molecular, Cellular, and Developmental Biology Chemistry, Pharmacology Center for Molecular Discovery Yale University Dennis Wright, Ph.D. Professor of Medicinal Chemistry NPDD Initiative UCONN School of Pharmacy University of Connecticut
Transcript of Craig M. Crews, Ph.D. Dennis Wright, Ph.D. - Yale University · 2019-12-30 · Yale University....
Craig M. Crews, Ph.D.Lewis B. Cullman Professor of Molecular, Cellular, and Developmental Biology Chemistry, PharmacologyCenter for Molecular DiscoveryYale University
Dennis Wright, Ph.D.Professor of Medicinal ChemistryNPDD InitiativeUCONN School of PharmacyUniversity of Connecticut
PITCH: What?
An Collaboration between Yale and UCONN to Help Academic Projects Cross the Valley of Death
PITCH: What?
PITCH: What?
• Provide a streamlined translational pathway for researchers to convert their discoveries to new therapeutics
PITCH: What?
• Provide a streamlined translational pathway for researchers to convert their discoveries to new therapeutics
• Increase the number of biotech companies in the State by encouraging faculty entrepreneurism
PITCH: What?
• Provide a streamlined translational pathway for researchers to convert their discoveries to new therapeutics
• Increase the number of biotech companies in the State by encouraging faculty entrepreneurism
• Employ the latent pool of pharmaceutical talent statewide
PITCH: What?
• Provide a streamlined translational pathway for researchers to convert their discoveries to new therapeutics
• Increase the number of biotech companies in the State by encouraging faculty entrepreneurism
• Employ the latent pool of pharmaceutical talent statewide
• Establish a new paradigm for robust, synergistic research programs between Yale and UCONN, and ultimately to other institutions in the state
PITCH: What?
• Provide a streamlined translational pathway for researchers to convert their discoveries to new therapeutics
• Increase the number of biotech companies in the State by encouraging faculty entrepreneurism
• Employ the latent pool of pharmaceutical talent statewide
• Establish a new paradigm for robust, synergistic research programs between Yale and UCONN, and ultimately to other institutions in the state
• Recruit additional venture investment to the state
PITCH: What?
• Provide a streamlined translational pathway for researchers to convert their discoveries to new therapeutics
• Increase the number of biotech companies in the State by encouraging faculty entrepreneurism
• Employ the latent pool of pharmaceutical talent statewide
• Establish a new paradigm for robust, synergistic research programs between Yale and UCONN, and ultimately to other institutions in the state
• Recruit additional venture investment to the state
• Put Connecticut on the map for a new paradigm in drug discovery
PITCH: Who?
Craig M. Crews, Ph.D.Lewis B. Cullman Professor of Molecular, Cellular, and Dev. Biol. Chemistry, PharmacologyCenter for Molecular DiscoveryYale University
Dennis Wright, Ph.D.Professor of Medicinal ChemistryNPDD InitiativeUCONN School of PharmacyUniversity of Connecticut
Dennis Wright, Ph.D.Professor of Medicinal ChemistryNPDD InitiativeUCONN School of PharmacyUniversity of Connecticut
PITCH: Who?
BackgroundWest Liberty State BS (Chemistry)Ohio University Ph.D. (Chemistry)Stanford Postdoc TrainingUCONN Joined Faculty in 2006
Experience• New Pathways in Drug Discovery (NPDD)
-Co-Founder
• Promiliad, Inc.-Co-Founder
• Synaptic Dynamics, Inc.-Co-Founder
PITCH: Who?
Craig M. Crews, Ph.D.Lewis B. Cullman Professor of Molecular, Cellular, and Dev. Biol. Chemistry, PharmacologyCenter for Molecular DiscoveryYale University
BackgroundU.Va. BA (Chemistry)Harvard Ph.D. (Biochemistry)Harvard Postdoc TrainingYale Joined Faculty in 1995
Experience• Yale Center for Molecular Discovery (YCMD)
-Founder/Executive Director
• Proteolix, Inc.-Co-Founder
• Arvinas, Inc.-Founder -Chief Scientific Officer
PITCH: Where?
Yale Center for Molecular Discovery (YCMD)Yale West Campus (former Bayer Pharmaceuticals)
PITCH: Where?
•Established in 2003
•Occupies building B27 with ~10,000 sf of laboratory and office space
•9.5 staff: 7 Ph.D., 2 M.S., 1.5 B.S.
•332 Projects in past 5 years with investigators from 25 Yale departments
•Numerous prominent publications
•Providing target identification, small molecule siRNA screening, and medicinal chemistry services
•Multiple corporate interactions and start-ups
Craig M. Crews, Ph.D.MCDB/Chemistry/Pharmacology
Janie Merkel, Ph.D.Director of Biology
Denton Hoyer, Ph.D.Director of Chemistry
• 9.5 Full Time Employees– 5 Biology– 3 Chemistry– 1.5 Administrative
• Experience in Academia & Industry:
PITCH: Where?
Overview of Capabilities
• Biology– Assay Development– High Content Imaging– Screening (siRNA and small molecule)
• Chemistry– Structure-Activity Modeling– Medicinal Chemistry– Compound Synthesis & Analoging
• Assisting with Patent Writing
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PITCH: Where?
YCMD Resources• Liquid Handling & Robotics
– 96-, 384-, 1536-well plate compatibility– Sterile or Non-Sterile Environments
• Multiple Types of Readouts– At molecule level: Protein-protein, Enzymatic assays– Cell-based, Organism-based assays– High Content Screening - Highly subsidized costs
• Medicinal, Computational & Synthetic Chemistry– Synthetic planning & execution/outsourcing– Structure and Ligand-based drug design– Optimization of ligand potency and pharmacokinetics
• Experience with Multiple Therapeutic Areas– Oncology, Neurodegenerative, Infectious Diseases,
Inflammation, Cardiovascular…
PITCH: Where?
Demetrios Braddock, Department of Pathology
R. A
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40.
Assay for Inhibitors of NPP4 Activity
X-Ray Structure of Target
Classical High Throughput Screening
Structure-Based Design
Follow-OnImprovement
Novel Compositionof Matter
Proof of Concept(Repurposing)
PITCH: Where?
Presenter
Presentation Notes
Demetrios Braddock NPP4 Project Initiated: May 2012 Significance: Thrombosis is the leading cause of morbidity and mortality in the Developed World (heart attack, stroke, etc; UPPER LEFT PANEL). Platelet aggregation can be targeted (e.g., Plavix) but there is room for improvement. Specifically, a key feature is to target activated platelets within the thrombotic lesion. Demetrios Braddock recently characterized a novel target, NPP4, which is essential for platelet thrombosis. He has shown that NPP4 plays a key role in disease pathology and also derived an x-ray structure for the enzyme. YCMD Role: Based on Demetrios’ past successes (the Center identified the key molecules for his Autotaxin program), YCMD developed a two-prong strategy to identify selective inhibitors of NPP4-mediated platelet aggregation (UPPER RIGHT PANEL). This particular project and approach emphasizes how different strategies within the Center can complement one another and improve outcomes. The first prong utilized a classic screening approach to identify small molecule inhibitors. To do so, a robust assay of NPP4 activity was developed and applied to high throughput screening. This approach yielded a series of promising molecules, including one FDA-approved drug. The activity of the approved drug was unrelated to NPP4 but can provide an opportunity for rapid clinical translation. In parallel, a structure-based design campaign predicted potential inhibitors and their efficacy was confirmed using the aforementioned assays. These inhibitors are being improved via iterative processes and are anticipated to yield a compound with the potential for greater efficacy and with proprietary advantages for the University. Impact Based on the work at YCMD, a manuscript is being prepared and multiple grants have been submitted. The PI (Dr. Braddock) is interested in exploring clinical trials with the FDA-approved drug and advancing the most promising new chemical entities (NCE) that emerge from ongoing work. NOTE: It could be worth noting the project made considerable progress within a short time period (approximately 7-8 months).
NPDD: A Drug Discovery Network
New Pathwaysto
Drug Discovery
ExternalPartners
UCONNHealth
UCONNStorrs The NPDD is a cross-college initiative
dedicated to drug discovery and development with faculty from Pharmaceutical Sciences, Chemistry, MCB and UCH/CICATS
PITCH: Where?
UCONN School of Pharmacy
The SOP provides an exciting, highly interactiveenvironment for experimental therapeutics withscientists from a broad range of backgrounds unitedby an interest in drug discovery and development.We are organized into three disciplines…
Pharmaceutics: expertise in small molecule formulation, formulation of biologics and drug delivery
Medicinal Chemistry: expertise in drug design, drug target structure and mechanism of action
Pharmacology/Toxicology: expertise in liver toxicology, metabolism and stem cell biology
Medicinal Chemistry Capabilities
High-Throughput Screening
Structure-Based Drug Design
Medicinal Chemistry
Drug design/SAR Complex
molecule/parallel synthesis
Stereoselective synthesis
In vitro metabolism Physico-chemical
property determination
Automated handling 150K lead library Pharmacological
Screens (LOPAC) Target and Phenotypic
screens
X-ray crystallography Biomolecular NMR Docking Virtual Screening Rational Design
Drug Target Studies at UCONN Health
Protein Expression Protein Purification Protein Characterization High Field NMR (800 MHz) Other Biophysical Studies
External Advisory Board
EvaluationUCONN
Yale
AssaySubmission
Due: October 1
PITCH: How?
External Advisory Board
EvaluationUCONN
Yale
AssaySubmission
Bill LaRochelle, (Sr.Dir, Roche Sequencing SolutionsBrian Dixon, (CEO, BioRelix)Peter Farina, (SVP, Boehringer Ingelheim)Amy Burd, (Exe. Dir. Res Strategy, Leukemia & Lymphoma Society)Henry Showell (Sr. Res Fellow, Pfizer)
PITCH: How?
Live Presentations to the EAB10am-1:30pm October 30Yale Center for Molecular Discovery (YCMD)West Haven, CT
Originating Lab or CRO
AssayDevelopment
AssaysScreened
Virtual HitExpansion
[in vivo Testing]
BusinessPlan
Pitch
External Advisory Board
Evaluation
SAR/Med Chem
YCMD UCONNPharm
UCONN
Yale
AssaySubmission
New Leaf Ventures
Elm Street Ventures
OrbiMed Ventures
Canaan Partners Ventures
Other VCs/PharmaVenture Funds?
Out-license?
YCMD
UCONNProtein
ProductionCore
PITCH: How?
36 AssaysDeveloped
30 AssaysScreened
24 Virtual HitExpansions
12 SAR/Med Chem
8 BusinessPlans
8 Pitches# AssaysSubmitted?
Three Year Goals
PITCH: When?
Deadlines:
Submission of Slidedeck PITCH Application: October 1
PITCH: When?
Deadlines:
Submission of Slidedeck PITCH Application: October 1
Faculty Presentation to External Advisory Board: October 30th (at the YCMD)
PITCH: When?
Deadlines:
Submission of Slidedeck PITCH Application: October 1
Faculty Presentation to External Advisory Board: October 30th (at the YCMD)
Notification of Awards: Mid November
Project Title
Investigators
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To see TIPS and FAQS for each slide, please look at this template in Notes view.
Presenter
Presentation Notes
The goal of this PowerPoint is to demonstrate that your assay or chemistry approach, depending on entry point, is doable and that there is strong commercial potential to develop a start-up company based on new scientific evidence which demonstrates the link between your target and disease. TIPS Provide a descriptive name for your project List Principal Investigator(s) for the project.
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Two Year Goal Statement
Your two year goal will frame the following assessment.
Presenter
Presentation Notes
FAQS What is an example two year goal? The two year goal of this project is to identify <selective> small molecule inhibitors of phosphodiesterase X, involved in solid tumors, demonstrating activity in cell-based assays These initial inhibitors will serve as a Proof-of-Concept that follow on VC funding to develop novel compounds with a favorable therapeutic profile. How much data will be needed to be competitive for early-stage funding? The requirements for funding will depend on your target type, therapeutic area and competitors. Input from the External Advisory Board will be helpful and practical. The goal is to provide a lean dataset for early-stage funding and not a more comprehensive dataset for larger amounts of funding.
• Brief background for team members and their roles on this project.
• Include relevant past experience, if any.• Identify unfilled roles needed.
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Project Team
Presenter
Presentation Notes
FAQS How much detail should be provided for each team member? Give name, title, departmental affiliation, and role on the project. 2. What are example backgrounds and roles? Principal Investigator – Project champion Clinical consultant – clinician with insight into patient population and current treatments Investigator – point person for screening team with knowledge about reagents and resources Technician – will conduct cell culture to support secondary cell-based assays Business Lead – identify market of therapeutic indication, competing products and opportunity 3. How much past experience should be included? Include only relevant experience, such as, “Jim has generated a novel immune therapy that was licensed to a large biotechnology company.” All team members may not have relevant experience yet still be valuable team members. 4. Will my proposal receive a lower score if there are unfilled roles? No. We don’t anticipate that most applicants will have identified the strongest business or clinical partners possible for their project. Partners with relevant and complementary skills can be identified later in the project.
Briefly, introduce background science.
What is the problem worth solving?
What is your solution? Why is it novel?33
Scientific Background and Opportunity
Presenter
Presentation Notes
FAQS What if my approach isn’t novel? Your approach may not be novel technologically, but may be novel for the problem presented. Novelty is an opportunity, yet too much novelty will be viewed as high risk to even early-stage investors. The strongest candidates for follow-on funding have sufficient novelty to represent an opportunity, yet most other aspects of the program have solid precedents. 2. What if I’m not sure of the best problem to solve among several choices? A Clinicians perspective may be helpful here if not already engaged. The External Advisory Board may have experience, or contacts with experience, to help identify the most fruitful problem to focus on.
Describe additional research data needed but which is outside the scope and capability of the investigator’s laboratory.
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Research Plan
Presenter
Presentation Notes
FAQS How much information should I provide? Keep the information at a high level. The additional research data required may be out of your area of expertise and could be provided by YCMD, UConn research support, for example. 2. What are some example plans? Example 1: Identification of a small molecule that inhibits phosphodiesterase X in biochemical and cell-based assays which will require assay optimization for a biochemical and cell-based assay, small molecule screening to identify an inhibitor and medicinal chemistry to optimize small molecule screen hits to develop lead chemical series for validation of the role of target in disease. Example 2: Activity in an animal model of disease, requiring optimization of screen hits by medicinal chemistry for in vivo activity.
1. Describe your target and biological pathway
2. Does biochemical assay exist?
3. Does a cell-based readout exist?
4. What are assay readouts for all assays (e.g. luminescence, fluorescence intensity, image-based, others)?
5. What is your level of experience with the assays?
6. Are all critical reagents for the assays currently available?35
Assay Feasibility Assessment
Presenter
Presentation Notes
FAQS �4) What equipment is available? Please see http://ycmd.yale.edu/resources. YCMD has instrumentation compatible with most plate reader and imaging readout types, but there are some system limitations. Consult with YCMD to determine assay compatibility with instrumentation prior to submission. 5) Do applicants need to have experience performing biochemical or cell-based assays for their project? No. Literature precedent is sufficient to claim feasibility. Discussion with YCMD will help you understand if the resources exist for the assay types presented.
1. Target location(s): extracellular, intracellular, CNS, etc. and tissue type.
2. Can the protein be reliably expressed and purified? How?
3. Does crystal structure of target exist, resolution and RCSB code. If no, what are the closest homologs with crystal structure coordinates?
4. Predicted binding pocket affinity of target (YCMD determined); i.e., is the target druggable?
5. Are small molecule inhibitors known?
6. Synthetic accessibility (conducted after HTS analysis)36
Med. Chem. Feasibility Assessment
Presenter
Presentation Notes
TIPS 2) Describe protein expression system (E. coli, in vitro transcription/translation, other) and estimated yield. Are constructs available? 2 & 3) Indicate construct (length and domains) of target used in assay and those of any available high resolution structures. 3) If providing the RCSB code of the closest homolog. Please include percent amino acid identity between target and homolog. 4) YCMD can run predictive algorithms on a high resolution structure to suggest the number and quality of potential binding sites. Ideally, these are defined pockets of solvent-accessible surface area that may be available for small molecule binding. 5) Are small molecules reported in the literature, in pharmaceutical company pipelines, or otherwise known by word-of-mouth by experts in the field?
1. Is the biology (i.e. pathway) well characterized?
2. Has modulation of the pathway been shown to correlate with changes in disease burden (e.g. phenotype of KO mice, relevant animal studies, GWAS)
3. Is there precedent for the MOA for similar disease targets?
4. Is there a reliable and predictive animal model that has a history in translating compounds to the clinic?
5. Does a clinically relevant biomarker exist?
6. Competition: Examine approved claims (efficacy and safety) of competitors. Examine the competitive environment for compounds currently in development.37
Clinical Correlation Assessment
Presenter
Presentation Notes
Add a key reference where applicable.
1-2 slides addressing
Scope of unmet medical need• Number people affected by disease (target population)• Current standard of care and market size (commercial
potential)• Unique needs of the target population• Phase II proof of mechanism and patient stratification
strategy
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Clinical Need/Potential Market
Presenter
Presentation Notes
TIP/FAQ What is meant by Phase II Proof of Mechanism and patient stratification strategy? If known biomarker or imaging results can predict treatment efficacy in Phase II clinical trials, include them here. Phase II clinical trials work towards identifying the treatment dose, route of administration, dosing schedule and efficacy metrics. These trials are well beyond the scope of the PITCH program, but are helpful to judge the therapeutic potential of the program.
• 1 slide describing the desired characteristics of the proposed therapeutic for the intended indication
• What is the specific value of your drug/approach to patients? What advantages does it offer over existing or competing approaches? How your product meets the needs of your global market based upon performance features, costs, robustness, etc.
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Targeted Product Attributes
Presenter
Presentation Notes
1. The Targeted Product is a description of attributes that will evolve as information becomes available during the project. Many of these descriptors will be compound- and therapeutic area-dependent. This slide may be more relevant to projects entering PITCH at later stages. Attributes may include: chemical class, mode of action, target class, potency, drug combination potential, single agent potential, formulation, therapeutic window, clinical indication(s), patient population, usage, efficacy, animal model(s) of disease, safety/toxicity profile. This “Product Profile” is important as it defines what is acceptable to physicians dosing the medication. For example, is an iv drug acceptable or can only an oral medication insure patient compliance. What other factors are important to consider the commercial of therapeutic viability of the treatment? 2. What are examples of how the drug may provide specific value to patients? Proposed treatment may include a different route or frequency of administration, lower cost to manufacture or dispense, shorter clinical or regulatory path, higher metabolic and safety profile.
1 slide addressing OCR/T2 disclosure and patentability status
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Intellectual Property Position
Presenter
Presentation Notes
1. Has the invention been disclosed to Yale’s OCR or UCONN’s T2 group? 2. What is meant by patentability status? An invention must be “novel and non-obvious” to be patentable. It cannot be patented in the United States if public disclosure, public use or offer for sale to public have been made more than one year before the filing date. For most other countries, patenting cannot happen after any kind of public disclosure. A thorough search of patents will uncover if the proposed product is novel and non-obvious. You will want to include investigator and institutional names of high impact scientific articles in your searches. Searches should include global sources.
Contact Craig Crews (Yale) or Dennis Wright (UCONN)
Craig [email protected](203) 432-9364
Dennis [email protected](860) 486-9451
Questions about the Program?
Thank You
