This document summarizes in vitro biology and drug discovery services offered by a contract research organization. It discusses computer-aided drug design, structure-based drug design, cheminformatics, virtual screening, and homology modeling services. It also describes medicinal chemistry, ADMET/pharmacokinetic services, and chemistry services including hit identification, lead optimization, and preclinical/clinical development. Resource estimates and funding models for various stages of drug discovery are provided. The document discusses moving projects from in vitro to in vivo testing and considerations for outsourcing various capabilities.

1. In Vitro Biology
Services

2. Computer-Aided Drug Discovery (CADD) Services
Software and Hardware
Structure-Based Drug Design
Cheminformatic clustering
Property calculations
Virtual Screening
Similarity
Pharmacophore Searching
Structure-Based VS
Library Design and Enumeration
Homology Modeling
Medicinal Chemistry Integration

3. ADMET/ PK Services
Selected AMRI in vitro ADMET Assays

4. Chemistry Services
Medicinal Chemistry – Hit-to-Lead & Lead Optimization
• In silico screening, computational chemistry, cheminformatics, structure-
based drug design, homology modeling, QSAR, database integration
• Analogue design & synthesis
• S.A.R. elucidation (primary drug target & drug properties)
• Obtain PK/PD profile consistent with route of drug administration
• Optimize Drug safety margin
• Establish intellectual property position
• Synthetic scale up of advanced compounds (mg to grams)
Chemical Development – Preclinical & Clinical Development
• Scale-up multi-gram to kilogram quantities of API
• Remove API synthesis as bottleneck on critical path
• GLP material for toxicology studies
• cGMP synthesis

5. Hit Generation Stage - Resource Estimates
Fee-For-Service Model**
Drug Discovery Stage Duration** Fixed Fee
#FTE* option available
Hit Generation 3-6 months
CADD 0.25 - 0.50 yes
Medicinal Chemistry 1-2 n/a
In Vitro ADMET 0.25 - 1.0 yes
In Vitro Biology 9 -12 months 1 -2 n/a
* FTE = Full-Time Equivalent **Average estimates
Fixed Fee – well-defined process, experimental details established, leads to a
deliverable, i.e. specific chemical compound, results from bioassay or
computational study that supports a program (risk belongs to CRO)
FTE – research-based unit of work for defined period of time, FF model
impractical and risk is too high for CRO to do under FF agreement
Time & Materials – lies somewhere between FF & FTE (Risk belongs to
customer) no guarantee of a deliverable

6. Iterative Drug Discovery Cycle for Lead
Generation & Lead Optimization

7. Lead Generation
Goal of ‘Hit-to-Lead’ Process
Identify a Lead Chemical Series that meets target product profile:
• Demonstrate a reproducible concentration-response curve in primary assays
(biochemical & cellular)
• Works via desired mechanism of action
• Selectivity over closely related counter targets
• Devoid of undesirable structural features
• Possess drug-like properties
• Biological activity is responsive to structural changes at multiple sites in the molecule
• Tractable SAR for drug target(s) and drug properties
• Strong potential for development of new intellectual property space
• Demonstrates acceptable pharmacokinetics and efficacy in animal model

8. Lead Generation/Optimization Resource Estimates
Fee-For-Service Model**
Drug Discovery Stage Duration** Fixed Fee
#FTE*
option
Hit Generation 3-6 months
CADD 0.25 - 0.50 yes
Medicinal Chemistry 1-2 n/a
In Vitro ADMET 0.25 - 1.0 yes
In Vitro Biology 9 -12 months 1 -2 n/a
Lead Generation 6 - 12 months
Lead Optimization 12 - 18 months
CADD 0.25 - 0.50 n/a
Medicinal Chemistry 4-8 n/a
In Vitro ADMET 0.50 - 1.0 yes
In Vitro Biology 1 -2 n/a
Off-Target Activity Screens n/a yes
In Vivo PK/PD n/a yes

9. Intellectual Property
Creation & Protection

10. Lead Optimization
Goal: Identify Preclinical Development candidate with desirable Target Profile
• In vitro potency & selectivity toward primary drug target(s)
• Minimal off-target activity
• Acceptable physicochemical properties
• Acceptable drug properties
• Drug metabolism & pharmacokinetic profile suitable for route of administration
• Acceptable safety margin, no genetic toxicity, acceptable hERG and CYP Inh.
• Efficacy in animal models
• Target Engagement, biomarker or surrogate marker for efficacy
• Acceptable margin of safety at efficacious dose
• Patentable
• Robust chemistry to deliver large quantity of compound for preclinical studies
• Identify final form of drug substance

11. Moving from in vitro to in vivo……….
What are you trying to achieve?
1. Does the in vitro data translate into in vivo actions?
2. Are the in vivo models predictive of the disease?
3. Are the models confirming an action at the target site?
4. Are the in vivo effects due to ‘target engagement’?
5. Can we demonstrate good PK/PD relationship?
6. Translatability to studies in man.

12. Outsourcing in vivo studies
• Many providers offer in vivo efficacy testing. How do you select the right one?
• What is the question you are trying to answer?
• Can the provider do both efficacy and PK?
• Minimize number of providers
• Every time a new provider is involved, new variables are introduced.
• Vehicles, formulation preparation etc.
• When it comes to in vivo efficacy testing, specialist niche providers have a key role.
• Efficacy testing requires therapeutic area expertise
• You don’t want your xenograft measured by a behavioral pharmacologist!
• And you don’t want your behavioral experiment run by an oncology expert!
• Toxicology / Safety testing
• Large GLP accredited Tox / Safety CROs.
• Cost effective outsourcing.
• Have they the experience of running regulatory studies.
• Who carries out the pathology, reads the slides?
• Do they have the board certified pathologists?

13. Filling in the Gaps in your Drug Discovery Capabilities?
I-------------------------------------In Vitro Biology--------------------------I
I------------------Medicinal Chemistry----------------------I
I---------------Computational Chemistry----------------I
I-----------Pharmacology-------------------------------I
I------------DMPK---------------------------------------------I
I-----------------------Analytical Chemistry---------------I
I--------Pharmaceutics------------------I
I-----Drug Safety/Toxicology----------I
I------Chemical Development---------I
I--------------------------Patent Law-------------------------------I

14. $$ Cost of Outsourcing $$
• Cost a significant barrier to direct use of CRO services
• Academic drug discovery centers
• Non-profits, Foundations and Government Agencies, like
the NINDS are making translation of academic innovation
into drug therapies possible by providing the financial
means for the universities, the NINDS and CROs to work
together.

15. CROs and Venture-Based Groups working with Academia
Albany, NY (January 5, 2012) AMRI Announces Preferred Provider Agreement with
BioPontis Alliance LLC
Albany, NY (January 5, 2012)—AMRI (NASDAQ: AMRI), a global contract services
organization, announced today that it has entered into a preferred provider agreement with
BioPontis Alliance LLC. The agreement is aimed at supporting BioPontis’ mission to
bridge the gap between early-stage research and technologies being discovered and
developed in academia and other research entities. AMRI will provide its services in small
molecule discovery, development, and manufacturing in BioPontis’ drug discovery research
programs.

16. Drug Discovery Services - Why Outsource?
• Stay focused on your core strength
• Plug the gaps in your drug discovery capabilities
• Access technology
• Leverage industry drug discovery expertise
• Get to proof of concept more rapidly
• Improve chances of success

17. Thank you!
We would like to learn more about your drug
discovery research needs and discuss ways that
AMRI could help you achieve your goals?
Kelly.Grover@amriglobal.com
Bruce.Molino@amriglobal.com

18. Advancing Preclinical Therapy Development for Alzheimer’s Disease:
Funding Opportunities and Services at the NIA
6th ADDF Drug Discovery for Neurodegeneration Conference
Feb 12-14, 2012
Suzana Petanceska PhD
Division of Neuroscience
National Institute on Aging

19. Alzheimer’s Disease: a Public Health Crisis
 Currently ~5 million people are affected in the US alone; this number
is projected to triple by 2050.
 An additional 5.4 million are estimated to be suffering from MCI.
 Approximately 10% of these will progress to AD each year.
 The therapeutic needs of patients with Alzheimer’s Disease remain unmet.

20. NIA’s AD Translational Research Program
(2005-present)
Goal: To seed early drug discovery and preclinical drug development projects in
academia and in the small business community and in doing so increase the
number of drug candidates against a variety of therapeutic targets that can be
clinically developed by industry or through various clinical trial programs at the
NIH.

21. Target Discovery
Basic Research
Alzheimer’s Disease Translational Research Program (2005 – present)
-from Target Identification to Clinical Trials-
SBIR/STTR
Clinical Development
IND-enabling
Toxicology AD Pilot Clinical Trials, PAR -11-100 (R01)
Successful Therapeutic
NIA Contract IND AD Cooperative Study (U01) Intervention for AD
Investigator Initiated Clinical Trials (R01)
Industry

22. Portfolio Summary
 The availability of set-aside funds together with specialized review enabled the relatively
rapid creation (FY 2006-present) of a diverse portfolio of preclinical AD therapeutics for a
variety of therapeutic targets.
-~50 early drug discovery projects
-15 preclinical drug development projects
-13 supplemental awards to existing NIA grants
Amyloid beta
Tau neurogenesis
cdk5
HSP90
neuroinflammation
neurotransmitter receptors
phosphodiesterases
ApoE
hormonal signaling
neurotrophin receptor signaling

23. Current NIA Funding Opportunities and Services for
AD Drug Discovery and Preclinical Drug Development
Contract Services
Proof
Assay Lead Candidate IND-enabling
Target ID
Development
Screening of
Optimization Selection toxicology
IND
Concept
R21: PAS 10-051, PAR 10-002 U01: PAR 12-015
2 years; $275K for the entire project 3-5 years; $300K-$1M per year
R01: PAR 10-001
3-5 years; $250K-$499K per year

24. Current NIA Funding Opportunities and Services for
AD Drug Discovery and Preclinical Drug Development cntd.
 R21s and R01s are reviewed at the Center for Scientific Review by the
Drug Discovery for the Nervous System review panel.
-Scientific Review Officer: Mary Custer, PhD
 U01 applications are reviewed at NIA’s scientific review branch by the Drug Development
review panel.
-Scientific Review Officer: Alexander Parsadanian, PhD
 Requests for access to IND-Enabling Services are reviewed by NIA program staff and two
NIA external advisors.

25. Alzheimer’s Disease Preclinical Drug Development: PAR 12-015 (U01)
Milestone Driven Program
 Supports the pre-clinical development of drugs, biologics, as well as
repurposing of drugs already in use for other conditions. For entry into the program,
projects must have one or more identified therapeutic leads and convincing
proof-of-principle of efficacy in animal model(s) relevant to AD, MCI or age related
cognitive decline against a defined therapeutic target.
 Activities supported: chemical optimization, pre-clinical efficacy testing,
predictive ADMET (absorption, distribution, metabolism, excretion, and toxicology)
testing, good manufacturing practices (GMP) synthesis and formulation, pre-IND meeting
with the FDA, IND-enabling toxicology/safety pharmacology and IND submission.
 Does not support hypothesis driven mechanistic research, or early-stage drug
discovery activities such as high throughput screening.
The research plan must include annual quantitative milestones with specific criteria for
go/no-go decision making. The milestones are subject of a special review criterion and they
are used by NIA program staff to assess progress on the project and to recommend further
funding.

26. Services for IND – Enabling Studies: NIA Contract with
Services Provided:
Analytical Chemistry
Pharmacokinetics and Bioavailability
Preliminary Toxicity Screens
Assistance with preparing for a Pre-IND meeting with the FDA
IND-directed toxicology studies including safety pharmacology (14 days/90 days)
Services not Provided:
GMP synthesis
CMC
Long-term IND-directed toxicology

27. How to Apply for Contract Services:
 Contact the project officer:
-Neil Buckholtz PhD buckholn@nia.nih.gov
 Provide the project officer with supporting material/data
justifying the request for the contract services.

28. What Follows?
 The project officer sends the material for review to two external
expert advisors.
 If the request is approved the project officer will put the investigator in touch
with the principal investigator (PI) at SRI International:
-Karen Steinmetz, PhD, DABT karen.steinmetz@sri.com
 The PI at SRI prepares a protocol based on the information provided by the
academic/biotech investigator.
 Once the protocol is approved by the NIH contracting office, SRI will carry
out the agreed upon studies.
 Time between submission of request and approval of protocol for IND-
enabling services: 4-6 months.

29. How to Decide Which Funding Opportunity
is Best for Your Project?
 Send a brief summary (one page) of your prospective project outlining the aims and
deliverables to the appropriate program officer(s).
-Suzana Petanceska PhD, petanceskas@nia.nih.gov
 Program staff will set up a teleconference and discuss the best funding venue(s) at the NIA
or refer you to another Institute (NINDS), a trans-NIH funding opportunity, or a non-federal
funding agency (i.e. ADDF).
 If the project is mature enough to enter the U01 program, program staff will
request preliminary milestones and budget and will work with the investigator to
formulate the quantitative milestones for the application.
-Lorenzo Refolo, refolol@nia.nih.gov
 If the project is at late preclinical development stage and needs only IND-safety
pharmacology and toxicology, program staff will advise you to submit a request for access
to these services.
-Neil Buckholtz PhD, buckholn@nia.nih.gov

30. Things to Remember:
 Read the funding opportunity guidelines.
http://grants.nih.gov/grants/guide/pa-files/PAR-12-015.html
http://grants.nih.gov/grants/guide/pa-files/PAS-10-151.html
http://grants.nih.gov/grants/guide/pa-files/PAR-10-001.html
http://grants.nih.gov/grants/guide/pa-files/PAR-10-002.html
-Key Parts: Submission deadlines, Purpose, Scope and Objectives, Budget
 Consult with program staff well in advance of submission.
(6-8 weeks before R21/ R01submission; 10-12 weeks before U01 submission*)
*Applications with annual budget (direct costs) equal or greater than $500K are subject to
pre-submission administrative review.

31. Working Together to Fill in the Translational Funding Gap
The ADDF is now considering financial assistance for relevant NIA and NINDS grant
applications (beginning with applications reviewed in calendar year 2011) that
were scored but not funded AND fall within the ADDF’s current funding priorities.
http://www.alzdiscovery.org/wp-content/uploads/2011/11/2012-nih_addf-funding-initiative.pdf

32. Educational Components of
NIA’s AD Translational Research Program
 U13 Conference Grant to the ADDF: Short Course on Drug Discovery for
Neurodegeneration (2008-2012); co-sponsorship from NINDS and ORD
 AD Translational Research Investigators’ Meeting

33. National Institute on Aging
Alzheimer’s Disease Translational Research Investigators’ Meeting
(2007, 2009, 2011)
Purpose: To provide guidance to NIA investigators funded by the translational
research initiatives, to foster interactions among the investigators and to provide a
venue for the investigators to interface with drug discovery and clinical experts as
well as FDA representatives.

34. NIA Alzheimer’s Disease Translational Research Program
-Work in Progress-

35. NIA AD Translational Program Contacts:
Suzana Petanceska PhD
petanceskas@nia.nih.gov
Lorenzo Refolo PhD Drug discovery and
refolol@nia.nih.gov preclinical drug development
Neil Buckholtz PhD
buckholn@nia.nih.gov
Laurie Ryan PhD Clinical drug development
ryanl@nia.nih.gov

36. National Institutes of Health
Rebecca Farkas, PhD
Program Director, NINDS

37. Which NIH drug discovery program is best for you?
Proof
Lead Pre-clinical Phase I
Target ID Assay Screening Hit to Lead of
Optimization Safety Trials
Concept
NIH offers support in various forms:
 Funding
 Free access to drug discovery services
 Combination of funding + services

38. Examples of NINDS Funding Opportunity
Announcements
Proof
Lead Pre-clinical Phase I
Target ID Assay Screening Hit to Lead of
Optimization Safety Trials
Concept
Exploratory Translational Grants (R21)
Cooperative Program
Tool Compound (U01, U54, U44)
Discovery (R01)
Tool Compound
Optimization (R01)
David Jett Rebecca Farkas Tom Miller
Contacts: jettd@ninds.nih.gov farkasr@nih.gov tm208y@nih.gov