This document provides an overview of resources and services available for advancing drug discovery. The session discusses academic models of drug discovery utilizing outsourcing to contract research organizations (CROs). An academic perspective is presented on drug discovery centers and utilizing CROs. A CRO perspective is also provided on collaborating with academics. Funding and resources for preclinical therapeutic development in neurological disorders from the National Institute of Neurological Disorders and Stroke are discussed.

1. S E S S IO N V I
R e s o u r c e s a n d S e r v ic e s F o r
A d v a n c in g D r u g D is c o v e r y
C h a ir — S u z a n a P e t a n c e s k a , P h D, Na t io n a l I n s t it u t e o n
A g in g
S e s s io n O v e r v ie w
Suzana Petanceska, PhD, National Institute on Aging
A n A c a d e m ic P e r s p e c t iv e o n D r u g D is c o v e r y
S e r v ic e s : C e n t e r s & C R O s
Marcie Glicksman, PhD, Harvard NeuroDiscovery Center
A D r u g D is c o v e r y S e r v ic e s P e r s p e c t iv e o n A c a d e m ic
C o lla b o r a t io n s
Bruce Molino, PhD, Albany Molecular Research, Inc.
P r e c lin ic a l T h e r a p e u t ic s D e v e lo p m e n t f o r
N e u r o lo g ic a l D is o r d e r s : F u n d in g & R e s o u r c e s
Rebecca Farkas, PhD, National Institute of Neurological Disorders and Stroke

2. Laboratory for Drug Discovery in Neurodegeneration (LDDN)
“Academic Models of Drug Discovery: Services and
Utilizing CROs”
Marcie Glicksman
6th Annual Drug Discovery Course
February 13-14, 2012

3. Outline
> Why outsource?
> Academic Resources
> Contract Research Organizations
Disclaimer: this will in no way be complete!
Harvard NeuroDiscovery Center

4. Why Outsource?
> Lack of internal resources
> Lack of expertise
> Lack of proper equipment
– Chemistry scale up
– Robotics
– Chemical libraries
> Flexibility
– Can accommodate needs when you have them
Harvard NeuroDiscovery Center

5. What resources do you need?
Discovery PreClinical Clinical Approval
•Bioinformatics
•Pharmacokinetics •API supply •NDA filing
•Target ID
•ADME studies •Scale-up •Approval
•Target validation
•Toxicology •Stability trials •Launch
•Assay development
•Pharmacology •Formulation •Manufacturing
•Virtual screening
•Analytical methods •Patient access
•HTS screening
•Route development •Clinical trials (I-IV)
•Reference compounds
•Non-GMP scale-up •Drug product
•Compound libraries
•cGMP scale-up
•Medicinal Chemistry
•Pre-formulation
•secondary assays
•In vivo studies
•Patent writing
Harvard NeuroDiscovery Center

6. What to outsource?
> Outsourcing is a HUGE industry, est. $7-8 billion market.
> Every segment of the drug discovery process can be
outsourced.
> What are your core competencies?
> What resources do you have?
> Gold standards
– HERG channel activity = Chantest
– Preclinical toxicity studies
– GLP studies
– GMP studies
Harvard NeuroDiscovery Center

7. Academic Resources
> More than 72 Screening centers around the world!
– You can find a directory here: http://www.slas.org/screeningFacilities/facilityList.cfm
> Medicinal chemistry centers
– Sometimes paired with screening centers
– New Directory http://www.slas.org/mcFacilities/facilityList.cfm
> In vivo Pharmacology
– Pharmacy schools
> Animal models
– Foundations for specific disease area
• e.g. MJ Fox Foundation, ADDF, Families of SMA
– Psychogenics
– JSW Research
– SRI
– Academic labs
> GMP Synthesis
Harvard NeuroDiscovery Center

8. Internet Resources
> Equipment
– LabAutopedia
• Topics related to automation, tools and technologies
• http://www.labautopedia.com/mw/index.php/Main_Page
– LabMan blog
• http://www.slas.org/blog/index.cfm
> Assay technologies
– Assay Guidance Manual
• http://spotlite.nih.gov/assay/index.php/Table_of_Contents
> Web courses and forums
– Society for Laboratory Automation and Screening (SLAS)
• Webinars, short courses
– AAAS
• webinars
– Discussion groups (LinkedIn, Facebook, YouTube)
> Local State Biotechnology Council
– e.g. MBC sponsors regular programs
Harvard NeuroDiscovery Center

9. LabAutopedia
> Automation
– HTS
– Genomics
> Tools and Technologies
> Data collection and processing
> Conference posters
> Science books
http://www.labautopedia.com/mw/index.php/Portal:Contents
03/26/12 Harvard NeuroDiscovery Center

10. Assay Guidance Manual
> All types of assays
> Details on strengths and weaknesses
> Options for target types
http://spotlite.nih.gov/assay/index.php/Table_of_Contents
03/26/12 Harvard NeuroDiscovery Center

11. Example: Harvard ICCB-Longwood
Institute of Chemistry and Cell Biology
> Core facility for investigator initiated screening
> Mainly for Harvard community
> Small molecules and RNAi libraries
> Collaborators perform their own assay development, perform
their own assays, provide all reagents including plates
> Staff maintain and run robotics
> Recharge costs
> Take your compounds with you
> Simple IP
Harvard NeuroDiscovery Center

12. Model at LDDN:
Collaborative Interactions Drive Discovery
> For general academic community
> Small molecule libraries skewed with properties more “drug-like”
and likely BBB penetrable (size,PSA, LogP, Lipinski guidelines)
> LDDN or post-doc develops assay and LDDN runs automation
> LDDN provides medicinal chemistry
> Joint grant submission
> Joint IP/ownership
> Joint licensing
LDDN Staff Collaborating
(12) Lab
Harvard NeuroDiscovery Center

13. Types of Contract Research Organizations
> Fully integrated CRO vs. specialist
– Big-box (one-stop-shop) vs. boutique
– Covance, Ricerca
– Cyprotex, Absorption Systems, Wolfe Labs, AMRI
> Location US, Europe, India, China
> High, medium, low cost vendors
> The staff – ratio of PhD-to-MS/BS techs, &
years experience
– Most important is that they have experience
relevant to your project
– Take advantage of their experience
Harvard NeuroDiscovery Center

14. Types of CRO Models
> FFS (Fee For Service) – Client drives the science
– Competitive RFQs (request for quote)
– Protocols worked out or easier chemistry
– Intermediates,monomers, templates
– Per compound rate
> FTE (Full Time Equivalent) – Client drives the science
– With trusted partners
– Difficult or speculative chemistry
– Reference compounds
– Large queues at low cost CROs
– Do you have enough work for FTE rate?
> Collaborations – CRO helps drive part or all of the science
– May be FTE based
– May include risk sharing
> Reduced fee
> Equity
> Milestone payments
Harvard NeuroDiscovery Center

15. What LDDN Outsources
> Protein purification (e.g. Blue Sky)
> In vitro ADME (e.g. Cyprotex)
– Microsomal stability
– solubility
> Pharmacokinetics (e.g. Absorption Systems)
> Profiling
– Kinome (e.g. Carna Biosciences, Nanosyn)
– Side effect profiling (e.g. MDS Pharma, Cerep, Caliper)
– mechanism
> Supplemental chemistry (e.g. Aberjona)
> In vivo efficacy models
– Academic labs
Harvard NeuroDiscovery Center

16. Recommendations
> Develop a list of CROs with overlapping capabilities
> Give a small pilot project to a CRO before more commitment.
– Some go as far as sending the same project to more than one CRO.
> Make sure you get updates
> Make sure you get reports that are satisfactory and you have
agreed ahead of time on what these reports will look like.
– Contain supporting documentation
– Contain raw values
> Confidentiality agreements are standard
– Is the CRO covered by US/WTO patent laws?
– Proprietary process and product needs to be defined
> Establish a relationship with CROs
Harvard NeuroDiscovery Center

17. Equipment/Technology Partnerships
> What academics can offer vendors
– As a central facility, many scientists gain exposure to the
instrument and technology
– Act as a “Demo” site
– Novel applications
– Collaborations
– Data sharing (no proprietary targets, no long approval process)
D
– Publications
> What vendors can offer academics
– Price discounts
– Collaborations
– Access to new technology early
03/26/12 Harvard NeuroDiscovery Center

18. Summary
> Lots of resources out there!
> Use resources that are outside of your expertise
> Talk with others for recommendations
> Try a pilot project with a new outsourcing partner
> Establish a relationship
> Make sure you discuss what your expectations are
Harvard NeuroDiscovery Center

19. Thank YOU, for your attention!

20. A Drug Discovery Services
Perspective on Academic
Collaborations
6th Drug Discovery For Neurodegeneration
Conference: An Intensive Course on Translating
Research into Drugs
February 12-14, 2012
Bruce Molino, Ph.D.
Senior Director, AMRI Medicinal Chemistry

21. AMRI Global Integrated Drug Discovery, Development &
Manufacturing Services
As a global leader in drug discovery, AMRI provides valuable contract discovery,
development, and manufacturing services to advance our clients’ goals.
AMRI advantages include:
• Comprehensive in vitro biology, in vitro ADMET and chemistry capability from lead
generation to advanced development to manufacturing
• Substantial capacity located at multiple facilities throughout the world
• Integrated services providing a seamless product to the client
• Cost effective outsourcing solutions with flexible business models

22. Overview
•What are the R&D outsourcing needs of Academic
laboratories?
•What Drug Discovery Services are available from CROs?
•How do you identify the best CRO to meet your needs?
•Outsourcing cost?

23. Role of US Academia in Drug Discovery
• “Academic institutions and their investigators traditionally play a key role in identifying
novel potential targets but do not participate in later stages of the drug discovery
process”
• Survey of ~80 academic drug discovery centers indicated that on average 49% of
targets being investigated are based on unique discoveries that had little validation in
the literature
• “Drug companies cannot afford the risk of investing on a novel approach without
strong validation that the new approach is viable”
• Need to do a better job of translation of these early innovations to the proof of
concept and into human clinical trials
P. Jeffrey Conn, “Translation of Research Across Disciplines to Impact Patient Care” Vanderbilt Center for
Neuroscience Drug Discovery, http://www.vcndd.com/presentations/
S. Frye, M. Crosby, T. Edwards, R. Juliano Nature Rev Drug Discov. 10, 409, 2011

24. CROs work with Non-Profits & Government
Agencies to ‘Bridge the Gap’
Albany, NY (August 18, 2011) – AMRI (NASDAQ: AMRI) today announced it
received a federal contract award from the National Institutes of Health (NIH) /
National Institute of Neurological Disorders and Stroke (NINDS) to provide
chemistry and other drug discovery technologies in support of NINDS Medicinal
Chemistry for Neurotherapeutics Program (MCNP), part of the NIH Blueprint
Neurotherapeutics Network. AMRI has been collaborating with NINDS since 2005
on novel treatments for spinal muscular atrophy, a degenerative neuromuscular
disease.

25. Areas that AD can Benefit from Outsourcing
Many academic programs are in early stages of Drug Discovery,
Hit Generation
• Validated ‘Hits’ identified from biological screening
Lead Generation
• Progress through ‘Hit-to-Lead’ stage to Lead Compound Series
Lead Optimization
• Progress Lead Series to Pre-Clinical Development Candidate
and seek to translate innovative approaches to useful therapies.

26. Hit Generation/Exploratory
Prerequisites
•Target-based or phenotypic-based screen
•Validated screening assay
•Screening strategy – assay format/compounds for testing
Output/Goal of this stage:
•Hit finding
•Hit validation
•Hit selection
•Determine which screening hits have the best chance of
becoming a Lead Chemical Series

27. Hit Validation – Important Considerations
Pay attention to the basics in hit validation
•Confirm bioassay results
•Low cytotoxicity
•Confirm integrity of test compounds, purity, chemical structure
•CADD – similarity searches, cheminformatic clustering, virtual screening,
SBDD docking studies/pharmacophore model/virtual screen
•Apply relevant filters – MW, clogP, tPSA, HBD, HBA, solubility
•Identify frequent hitters, compounds with reactive functionality
Hit Selection
•Emerging S.A.R. from structurally similar analogues
•Cellular proof-of-concept – functional activity
•Freedom to operate in chemical space
•Synthetic feasibility
•DMPK properties

28. What can be outsourced?
Artwork

29. In Vitro Biology
Services