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.
Thank You!MEETING SPONSORS
BRONZE SPONSORS
SCIENTIFIC ADVISORY COMMITTEEKurt 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
SCIENTIFIC ADVISORY COMMITTEE
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
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
13th International Conference on Alzheimer’s Drug Discovery
September 10-11, 2012 • Jersey City, NJacross from NYC on the Hudson River
SAVE THE DATE!
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
•WHO estimates neurodegenerative disorders will be the major unmet medical need of the 21st century, •surpassing cancer as the worlds’ second leading cause of death by the year 2040
Neurodegenerative Diseases Affect >22 Million Worldwide
Alzheimer’s disease; 5,000,000
Parkinson’s disease; 1,000,000
ALS; 30,000
Multiple sclerosis; 400,000 Huntington’s, 30,000
Some symptomatic agents, few disease modifying drugs
Developing a Drug is Risky, Takes 12-15 years and Costs Over $1.2B
1 FDAApproved
Drug
HUMAN STUDIES BIOLOGY
AND CHEMISTRY
ANIMALSTUDIES and
PHARMACOLOGY
InnovationProof
of MechanismSafety and
Proof of ConceptProof
of Efficacy
10,000 to>1 millionchemicals
Drug Discovery is a Vital Stage in Drug DevelopmentWhen Innovation is Created
Opportunity and Challenges for Success:A Perspective On The Origin of FDA Approved Drugs
From: T. Bartfai and GV Lees, Drug Discovery from Bedside to Wall Street, 2006;Le Couteur, et al 2011
Most are variants on formulation and delivery
Many anti-microbials
Less than 500 distinct chemical entities
Targeting ~266 human genome derived proteins
~50M compounds in Chem Abstracts;1040-10100 possible small molecules
20,000 human genes100,000 proteins
~10,000 approved drugs
Less than 50 unique chemical scaffolds
• 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)
How a Biologist Thinks About Drug Discovery:Many Targets for Neurodegeneration?
• Target types– GPCR (small ligand)– Enzyme (small ligand)– Ion channel– Nuclear receptor– Protease– Enzyme (large ligand)– GPCR (large ligand)– Cytotoxic (other)– Protein kinase– Protein-protein
High
Success
Low
How a Chemist Thinks About Targets for Drug Discovery:Success Rates of Target Types
Why A Biological Network Approach to Drug Discovery is Needed: Signaling in the Synapse is Complex
How Were New Drugs Discovered? Phenotypic Screening Vs. Target-based
Screening
Swinney, et al, Nature Reviews Drug Discovery, July, 2011
Test for in vivo activity
Focused Medicinal Chemistry
Selection of leads
High throughput screen (500,000 cpds.)
Assay development
Screening approach
Inhibitor Development
Rational design approach
generation ofprotein
CrystalStructure
ComputerModel
MedicinalChemistry
PK
Specificity
Potency
Identification of hits
Case Studies: Routes to Drug Discovery
beta-secretase inhibitors gamma-secretase inhibitors
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
Drug Discovery and Development Requires Multidisciplinary Teams of Scientists
Clinical DevelopmentClinical Trialists
IND enabling studies: ADMET, formulation and scale-up chemistryPharamaceutical Scientists
In vivo Testing and Preclinical Proof of MechanismBiomarker Development
Animal Trialists
High Throughput Screening
Lead Identification and optimization
Structure Based Chemistry
Medicinal Chemistry, Pharmacology
Assay DevelopmentChemical Libraries
Computational Chemistry
Target identification Basic Neurobiology
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
Feeding the Pipeline:The Alzheimer’s Drug Discovery
Foundation
www.AlzDiscovery.org
Drug Discovery: The “Valley of Death”? Or “Welcome to An Amazing Journey”!
Where is drug discovery going?
Christopher A. LipinskiScientific Advisor, Melior Discovery
20DDND 2012 Lipinski keynote
Outline• Academic targets and the translational gap
–is it just a missing resource issue?
• Chemistry & attrition - worse with time–reductionism , genomics, HTS to blame?
• Screening diverse compounds–the worst way to discover a drug–novelty drive comes from patents and not science
• Biology and chemistry networks analysis–chemistry due diligence on leads is essential
• What to look for21DDND 2012 Lipinski keynote
Drivers for discovery changes• Chemistry, 65% successful predictivity
• rules and filters, eg. phys chem, structural• ADME predictivity worsens outside of RO5 space
• Safety, 50% successful predictivity• Efficacy, 10% successful predictivity
• Tackle efficacy using academic collaborations• systems biology still too new to save us• target quality is most likely from rich biology
22DDND 2012 Lipinski keynote
Death Valley California
DDND 2012 Lipinski keynote 23
Translational valley of death
DDND 2012 Lipinski keynote 24
"curing disease is a byproduct of the [NIH] system and not a goal," says FasterCures' Simon. Most scientists don't want to and don't have the skills to translate a discovery into a treatment; researchers at a dedicated center would try to do that full-time.
Death valley, politically correct causes?
• Academics lack drug discovery skills• Requires industry / academic collaboration
• eg. medicinal chemists are mostly in industry
• No access to ADMET, drug met, pharm sci etc.• critical disciplines not in academia
• No access to preclinical – clinical interface skills• eg. analytical, process chemistry, formulation
• No access to early development skills• eg. toxicology, biomarkers, project management
25DDND 2012 Lipinski keynote
Death valley, politically incorrect causes?
• Assumption - academic ideas on new targets are of high quality
WRONG• Bayer analysis of validation of academic targets• 50 % of academic targets are wrong• 25% of academic targets are partially flawed• Translational death valley exists (in part) because
of poor quality academic target identification
DDND 2012 Lipinski keynote 26
Why the academic target problem• Culprit is primarily the pressure to publish to
support both grant applications and career development
• A people problem• A government problem• Exacerbated by hypothesis driven research
• The positive: infrastructure collaboration
DDND 2012 Lipinski keynote 27
Bayer observation in NRDD
DDND 2012 Lipinski keynote 28
Has drug discovery gone wrong?
• Prevailing mantra: identify a mechanism and discover a selective ligand for a single target
• Counter responses:• Phenotypic screening• Drug repurposing• Multi targeted drug discovery• In-vivo screening• Non target non mechanism screening
DDND 2012 Lipinski keynote 29
Genomics – Chemistry parallel
• Genome sequence deciphered in 2000• Automated chemistry starts in 1992• Misapplied, both impeded drug discovery
• “The DNA reductionist viewpoint of the molecular genetics community has set drug discovery back by 10-15 years” Craig Venter quote
• “In 1992-1997 if you had stored combinatorial chemistry libraries in giant garbage dumpsters you would have much improved drug discovery productivity” Chris Lipinski quote
DDND 2012 Lipinski keynote 30
Genomics / HTS science madness• Collaborations to mine genomic targets• Massive HTS campaigns to discover ligands• 500 different targets, a million data points • “a wish to screen 100,000 compounds per day
in a drug discovery factory and a wish to make a drug for each target”
Drug discovery and development using chemical genomics. A. Sehgal, Curr Opin in Drug Disc & Dev (2002), 5(4), 526-531.
The drug discovery factory : an inevitable evolutionary consequence of high throughput parallel processing. R. Archer, Nat Biotech (1999), 17(9), 834.
DDND 2012 Lipinski keynote 31
DDND 2012 Lipinski keynote 32
Genomics financial madness
1% success, NPV $34M, Decision Resources March 29, 2004
Target-based drug discovery:
E1 E5
R2R3
R4R5
R6R1
E2
E3 E4 E7
E6
DP 1 DP 2
D1D2
Slide thanks to Andrew Reaume, Melior Discovery
DDND 2012 Lipinski keynote 33
….the real picture
R8
DP 5
E10
E9
E8E1 E5
R2R3
R4R5
R6R1
E2
E3 E4 E7
E6
DP 1 DP 2
R7
R9 R10
R11R12
DP 3DP 4
E7
E8
D1D2
Slide thanks to Andrew Reaume, Melior Discovery
DDND 2012 Lipinski keynote 34
50 years of medicinal chemistry
DDND 2012 Lipinski keynote 35
What Do Medicinal Chemists Actually Make? A 50-Year Retrospective Pat Walters et al. J Med Chem 2011
Attrition rates by phase
The Productivity Crisis in Pharmaceutical R&D, Fabio Pammolli, Laura Magazzini and Massimo Riccaboni, Nature Reviews Drug Discovery 2011 (10) 428-438.
DDND 2012 Lipinski keynote 36
Nanomolar is not necessary
DDND 2012 Lipinski keynote 37
Mean po dose is 47 mg Mean pXC50 is 7.3 (IC50 5 x 10-8)Gleeson, M. Paul; Hersey, Anne; Montanari, Dino; Overington, John. Probing the links between in vitro potency, ADMET and physicochemical parameters. Nature Reviews Drug Discovery (2011), 10(3), 197-208.
Phenotypic screening advantageThe majority of small-molecule first-in-class NMEs that were discovered between 1999 and 2008 were first discovered using phenotypic assays (FIG. 2): 28 of the first-in-class NMEs came from phenotypic screening approaches, compared with 17 from target-based approaches.
How were new medicines discovered? David C. Swinney and Jason Anthony Nature Reviews Drug Discovery 2011 (10) 507-519.
DDND 2012 Lipinski keynote 38
Phenotypic screening
• Finally government is paying attention• NIH new institute TRND• 25% of assays are reserved for phenotypic
screening
DDND 2012 Lipinski keynote 39
Chemistry novelty is harmful• Patents direct towards chemistry novelty
• Chemistry novelty correlates with decreased drug discovery success
• “The role of the patent system in promoting pharmaceutical innovation is widely seen as a tremendous success story. This view overlooks a serious shortcoming in the drug patent system: the standards by which drugs are deemed unpatentable under the novelty and non-obviousness requirement bear little relationship to the social value of those drugs or the need for a patent to motivate their development” Benjamin N. Roin, Texas Law Review
40DDND 2012 Lipinski keynote
Screening diverse compounds is the worst way to discover a drug
• Every publication I know of argues that biologically active compounds are not uniformly distributed through chemistry space
DDND 2012 Lipinski keynote 41
Do drug structure networks map on biology networks?
DDND 2012 Lipinski keynote 42
Chemistry drug class network
DDND 2012 Lipinski keynote 43
Network comparison conclusions• “A startling result from our initial work on
pharmacological networks was the observation that networks based on ligand similarities differed greatly from those based on the sequence identities among their targets.”
• “Biological targets may be related by their ligands, leading to connections unanticipated by bioinformatics similarities.”
DDND 2012 Lipinski keynote 44
What is going on?
• Old maxim: Similar biology implies similar chemistry
• If strictly true biology and chemistry networks should coincide
DDND 2012 Lipinski keynote 45
Network comparisons – meaning?• “Structure of the ligand reflects the target”• Evolution selects target structure to perform a
useful biological function• Useful target structure is retained against a
breadth of biology• Conservation in chemistry binding motifs• Conservation in motifs where chemistry
binding is not evolutionarily desired–eg. protein – protein interactions
DDND 2012 Lipinski keynote 46
Hit / lead implications• You have a screening hit. SAR on the historical
chemistry of your hit can be useful even if it comes from a different biology area
• Medicinal chemistry principles outside of your current biology target can be extrapolated to the ligand chemistry (but not biology) of the new target
• Medicinal chemistry due diligence is essential
DDND 2012 Lipinski keynote 47
Changes in drug discovery
• Questioning of reductionist approach• A positive development in CNS drug discovery• Very few CNS agents are found rationally• Experimental observations in the clinic• Multiple Sclerosis as a paradigm• No drugs until disease progression biomarkers• Multiple MS drugs recently available
DDND 2012 Lipinski keynote 48
What to look for
• Disease progression biomarkers–first impact in drug discovery–later impact when therapy arrives
• Orphanization of disease diagnosis–new drugs or fitting patients to current drugs?–challenges to cost structures
• Exploring drug or target combinations
DDND 2012 Lipinski keynote 49