1. 6th DRUG DISCOVERY FOR
NEURODEGENERATION
CONFERENCE:
An Intensive Course on Translating Research into Drugs
February 12-14, 2012 - New York City
Howard Fillit, MD
Executive Director, Alzheimer’s Drug Discovery Foundation

2. THANK YOU!
Funding for this conference was made possible in part
by
Cooperative Agreement U13AG031125-05 from the
National Institute on Aging.
The views expressed in written conference materials or publications and by speakers and
moderators do not necessarily reflect the official policies of the Department of Health and Human
Services; nor does mention by trade names, commercial practices, or organizations imply
endorsement by the U.S. Government.

3. Thank You!
MEETING SPONSORS
BRONZE SPONSORS

4. SCIENTIFIC ADVISORY COMMITTEE
SCIENTIFIC ADVISORY COMMITTEE
Kurt R. Brunden, PhD, University of Pennsylvania
Neil S. Buckholtz, PhD, National Institute on Aging
Rebecca Farkas, PhD, National Institute of Neurological Disorders and Stroke
Howard Fillit, MD, Alzheimer’s Drug Discovery Foundation
Brian Fiske, PhD, Michael J. Fox Foundation for Parkinson’s Research
Mark Frasier, PhD, Michael J. Fox Foundation for Parkinson’s Research
Abram Goldfinger, MBA, New York University
Lorenzo Refolo, PhD, National Institute on Aging
Suzana Petanceska, PhD, National Institute on Aging
Diana Shineman, PhD, Alzheimer’s Drug Discovery Foundation
Edward G. Spack, PhD, Fast Forward, LLC
D. Martin Watterson, PhD, Northwestern University

5. ADDF Staff
• Diana Shineman, PhD – Assistant Director, Scientific Affairs
• Rachel Lane, PhD – Scientific Program Manager
• Filomena Machleder – Assistant Director, Institutional Partnerships
• Natalie Romatz – Partnerships Assistant, Institutional Partnerships
• Niyati Thakker – Grants Assistant
• World Events Forum – Conference Secretariat

6. NOTES
Please remember to complete and submit the
meeting survey!
CME Certificates available at the Registration Desk
A webcast of the conference will be available soon on our
website:
www.alzdiscovery.org

7. SAVE THE DATE!
13th International Conference on
Alzheimer’s Drug Discovery
September 10-11, 2012 • Jersey City, NJ
across from NYC on the Hudson River

8. Goals of the Meeting
• Knowledge:
– The principles and practice of drug discovery, with a focus
on the unique aspects for neurodegenerative diseases
• Network:
– >190 attendees from 20 countries, ~40% from industry
– Exchange ideas, foster alliances, partnerships and
collaborations

9. Neurodegenerative Diseases
Affect >22 Million Worldwide
Some symptomatic agents, few disease modifying drugs
Multiple Huntington’s, 30,
sclerosis, 400,00 000
ALS, 30,000 0
• WHO estimates
neurodegenerative disorders will Parkinson’s
be the major unmet disease, 1,000,00
0
medical need of the 21st
century,
• surpassing cancer as the Alzheimer’s
disease, 5,000,00
worlds’ second leading cause of 0
death by the year 2040

10. Drug Discovery is a Vital Stage in Drug Development
When Innovation is Created
Proof Safety and Proof
Innovation
of Mechanism Proof of Concept of Efficacy
ANIMAL
BIOLOGY STUDIES and
AND CHEMISTRY HUMAN STUDIES
PHARMACOLOGY
10,000 to 1 FDA
>1 million Approved
chemicals Drug
Developing a Drug is Risky,
Takes 12-15 years and Costs Over $1.2B

11. Opportunity and Challenges for Success:
A Perspective On The Origin of FDA Approved Drugs
20,000 human genes ~50M compounds in Chem Abstracts;
100,000 proteins 1040-10100 possible small molecules
~10,000 approved drugs
Most are variants on
formulation and delivery
Many anti-microbials
Less than 500 distinct chemical entities
Targeting ~266 human genome derived proteins
Less than 50 unique chemical scaffolds
From: T. Bartfai and GV Lees, Drug Discovery from Bedside to Wall Street, 2006;
Le Couteur, et al 2011

12. How a Biologist Thinks About Drug Discovery:
Many Targets for Neurodegeneration?
• Deposits of Misfolded Protein
– Β-Amyloid, tau, α-synuclein, TDP-43, poly-Q aggregates
• Oxidative stress
• Inflammation
• Mitochondrial dysfunction
• Synaptic and neuronal cell dysfunction
• Vascular ischemia and damage
• Other novel mechanisms (eg. epigenetics)

13. How a Chemist Thinks About Targets for Drug Discovery:
Success Rates of Target Types
• Target types
– GPCR (small ligand) High
– Enzyme (small ligand)
– Ion channel
– Nuclear receptor
– Protease Success
– Enzyme (large ligand)
– GPCR (large ligand)
– Cytotoxic (other)
– Protein kinase
– Protein-protein Low

14. Why A Biological Network Approach to Drug Discovery is
Needed: Signaling in the Synapse is Complex

15. How Were New Drugs Discovered?
Phenotypic Screening Vs. Target-based
Screening
Swinney, et al, Nature Reviews Drug Discovery, July, 2011

16. Case Studies: Routes to Drug Discovery
beta-secretase inhibitors gamma-secretase inhibitors
Inhibitor Development
Rational design
approach Screening approach
Assay development
generation of
protein High throughput screen (500,000 cpds.)
Identification of hits
Crystal Computer
Structure M odel
Selection of leads
Focused Medicinal Chemistry
Potency
M edicinal
Chemistry
Specificity
PK
Test for in vivo activity

17. Improving Success Rates?
Drug Discovery in Academia
• Drug discovery is the interface between basic research
and clinical development
• Requires extensive resources and collaboration between
teams of investigators
• Increasingly requires partnerships between
pharma, biotechs, non-profits, and
government, especially for neurodegenerative diseases

18. Drug Discovery and Development Requires
Multidisciplinary Teams of Scientists
Clinical Trialists Clinical Development
IND enabling studies: ADMET,
Pharamaceutical Scientists
formulation and scale-up chemistry
Animal Trialists
In vivo Testing and
Biomarker Development Preclinical Proof of Mechanism
Medicinal Chemistry, Pharmacology Lead Identification and optimization
Assay Development High Throughput Structure Based
Chemical Libraries Screening Chemistry
Computational Chemistry
Basic Neurobiology Target identification

19. Feeding the Pipeline:
The Alzheimer’s Drug Discovery Foundation
The ADDF has granted over $55 million to >370
Alzheimer’s drug discovery programs in academic centers
and biotechnology companies in 20 countries
ADDF funding has resulted in
>$2 billion in follow-on commitments,
and several novel drugs entering clinical trials
www.AlzDiscovery.org

20. Drug Discovery: The “Valley of Death”?
Or “Welcome to An Amazing Journey”!