Part of the MaRS Best Practices Series - Pre-Clinical development workshop http://www.marsdd.com/bestpractices Speaker: Jack Jiang, VP Medicinal and Analytical Chemistry, Ricerca BioSciences

1. Drug Discovery
the origin of new chemical entity pharmaceuticals
Presented
By
Jack Jiang, Ph.D.
Ricerca Biosciences, LLC
5/23/07
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2. Outline
What is drug discovery?
Current approaches to drug discovery
Issues associated with drug discovery
How to succeed in drug discovery
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3. Drug Composition
Excipient
API
Packaging
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4. Types of New Pharmaceuticals
New Chemical Entity (NCE)
New active pharmaceutical ingredient (API)
New or old formulation
New Formulation
Old API + new formulation
Old API + new delivery system
New Brand
Old API + old formulation
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5. Best of the Best
New Chemical Entity (NCE)
New compounds with new chemical structures
Different interactions with biological targets (MOA)
Better therapeutic response
For patients
Better treatment outcome
Increased efficacy, reduced side effects
May be curative
For drug developers
Better products
Best patent protection
More revenue and profit
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6. What is
Drug Discovery and Development?
Idea
Lock
Biological
Target
Development IND
Lead
Candidate
Candidate
Chemical
Key
Compound
NDA
Phase I Phase II Phase III
To Market
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7. What is Drug Discovery?
Searching for new drugs is like
fishing
Fish are chemical compounds
Bait is the biological assay
Fishing requires patience; so does
drug discovery
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8. What is Drug Discovery?
The best fish
Best chemical compounds provide novel
mechanisms
Novel mechanisms may exhibit superior efficacy with
reduced toxicity
Best chemical compounds are druggable and
developable
The best bait
Biological assays that provide the above
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9. Let’s Go Fishing!
How to catch new fish?
Go to new fish pond with old bait
Go to old fish pond with new bait
Go to new fish pond with new bait
New fish pond
New diverse compound libraries (chemical
diversity)
New bait
New biological assays based on novel biological
targets (molecular biology)
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10. Fish (Compound) Sources
Natural products
Plants
Micro-organisms
Animals
Synthetic compounds
Analogs of existing drugs
Combinatorial synthesis (maximizing analogs)
Rational drug design
Macro molecular structure
Small molecular structure
Molecular interactions
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11. From IP to IND – the preclinical process
Development
Discovery
Chemistry Chemistry
Biological
Target
IND
Development
Lead Candidate
Candidate
Chemical
Discovery
Compound
Development
Biology Biology
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12. From Lead to Development Candidate
Lead optimization
SAR guided by bioassays
Patentability issues
Druggability
Bioavailability in vitro and in vivo
Permeability and metabolic stability
Formulability
Injectable vs. solid dosage form
Solubility, polymorph, excipient compatibility
and stability
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13. !quot;#$%#&'(%)* '(quot;+#,-$%.'/$%-quot;#$+
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14. You Need a Hand
to Guide You from IP to IND to NDA
From IP to IND
Discovery chemistry and biology
Development chemistry and biology
Regulatory compliance
From IND to NDA
Clinical R&D
Development chemistry
Regulatory compliance
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15. The Five Fingers
Discovery
Chemistry
Development
Chemistry
Discovery
Biology
Development
Biology
Regulatory
Consultation
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16. Definitions
Drug Development
Drug Discovery
Development
No development
candidate found candidate identified
Studies non- Studies driven by
protocol driven
protocols
Data not regulated
Data scrutinized by
by FDA
FDA
Timeline flexible
Rigid timeline required
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17. New Mindset Needed for Discovery
Why
The average 10-year R&D timeline per NCE
unacceptable = $1.25 bill per NCE (2004)
Early go-no-go decision saves time and money
First-to-market incentives
Novel targets require new endpoints
How
Address development issues early on
Expand research scope to cover potential
regulatory pitfalls
“Discover” new endpoints
Remove barrier between discovery and
development
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18. Issues in Discovery
Fish pond vs. bait
New assays (new bait) may improve the odds.
New compound libraries (new fish pond) may provide
novel structures.
Novel structures (new fish) offer patentability and
maybe better therapy.
Looking for needles in a haystack
Rational drug design is STILL at its infancy.
The biological system remains a black box.
NCE identification continues to be a numbers game.
The need to improve odds is unchanged.
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19. Issues in Discovery
Target selectivity
Molecular targets are many
Most targets are proteins
Small molecule-protein interaction rarely
specific
Non-selective small molecules produce side-
effects
Models not predictive of clinical outcome
Target relevant assays
Target relevant models
Disease relevant models
Dosing regiment relevant animal models
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20. Issues in Discovery
Therapeutic window
Efficacy vs. toxicity
All chemicals are toxic
Pharmacology is low dose of toxicology
Toxicology is high dose of pharmacology
Bioavailability
Effective drug concentration
Plasma concentration
Tissue concentration
Target concentration
Formulability
What is your ultimate formulation?
Can your compound be formulated?
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21. Issues in Development
Drug Substance (API)
Cost to produce
Scalability
Analytical methods
Stability
Drug Product (Formulated API)
Cost to produce
Scalability
Analytical methods
Stability
Packaging and storage
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22. Issues in Development
Toxicology
Species relevance
Dosing regimen relevance
Drug metabolism relevance
Acute vs. chronic toxicity
Metabolism
Inactive and active metabolites
Toxic metabolites
P450 activity
Drug-drug interaction
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23. New Mindset Needed for Discovery
…additional thoughts…
Efficacy
Selectivity in vitro ! Selectivity in vivo
High potency ! Superior efficacy
Animal ! Human
Toxicity
Structure-toxicity-relationship studies (STR)
Target toxicity ! Drug toxicity
Animal ! Human
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24. Key to Discovery Success
Identify appropriate clinic problems
Unmet medical needs
Underline mechanisms
Select clinically relevant targets
Target specificity
Rescue mechanisms
Establish target relevant assays
Easy
Fast
Non-radioactive
Robust (important to SAR studies)
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25. Key to Discovery Success
Prepare for development issues
CMC
Process
Analytical methods
Toxicology
Anticipate roadblocks
Clinical end points
Side effects
Manufacturing issues
Stability
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26. One Last Reminder……
Non-reg Reg
Biological
Target
IND
Development
Lead Candidate
Candidate
Chemical
Compound
$$$$
$$
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27. Let Us Assist YOU….
!43-Acre site
!3 Bldgs: 260,000 ft2
!Accessible from major airports
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