Drug Discovery - The Origin of New Chemical Entity Pharmaceuticals
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Transcript of Drug Discovery - The Origin of New Chemical Entity Pharmaceuticals
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Drug Discoverythe origin of new chemical entity pharmaceuticals
Presented
By
Jack Jiang, Ph.D.
Ricerca Biosciences, LLC
5/23/07
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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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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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Best of the Best
New Chemical Entity (NCE)New compounds with new chemical structures
Different interactions with biological targets (MOA)
Better therapeutic response
For patientsBetter treatment outcome
Increased efficacy, reduced side effects
May be curative
For drug developersBetter products
Best patent protection
More revenue and profit
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What is
Drug Discovery and Development?
BiologicalTarget
ChemicalCompound
Lead
Idea
DevelopmentCandidate
IND
Candidate
Phase I Phase II Phase III NDA
Lock
Key
To Market
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What is Drug Discovery?
Searching for new drugs is likefishing
Fish are chemical compounds
Bait is the biological assay
Fishing requires patience; so doesdrug discovery
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What is Drug Discovery?
The best fish
Best chemical compounds provide novelmechanisms
Novel mechanisms may exhibit superior efficacy withreduced toxicity
Best chemical compounds are druggable anddevelopable
The best bait
Biological assays that provide the above
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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 (chemicaldiversity)
New bait
New biological assays based on novel biologicaltargets (molecular biology)
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Fish (Compound) Sources
Natural productsPlants
Micro-organisms
Animals
Synthetic compoundsAnalogs of existing drugs
Combinatorial synthesis (maximizing analogs)
Rational drug designMacro molecular structure
Small molecular structure
Molecular interactions
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From IP to IND – the preclinical process
LeadDevelopmentCandidate
IND
Candidate
ChemicalCompound
BiologicalTarget
DiscoveryChemistry
DiscoveryBiology
DevelopmentChemistry
DevelopmentBiology
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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 compatibilityand stability
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You Need a Handto 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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The Five Fingers
DiscoveryChemistry
DevelopmentChemistry
DiscoveryBiology
DevelopmentBiology
RegulatoryConsultation
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Definitions
Drug DiscoveryNo developmentcandidate foundStudies non-protocol drivenData not regulatedby FDATimeline flexible
Drug Development
Developmentcandidate identified
Studies driven byprotocols
Data scrutinized byFDA
Rigid timeline required
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New Mindset Needed for Discovery
WhyThe average 10-year R&D timeline per NCEunacceptable = $1.25 bill per NCE (2004)Early go-no-go decision saves time and moneyFirst-to-market incentivesNovel targets require new endpoints
HowAddress development issues early onExpand research scope to cover potentialregulatory pitfalls“Discover” new endpointsRemove barrier between discovery anddevelopment
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Issues in Discovery
Fish pond vs. bait
New assays (new bait) may improve the odds.
New compound libraries (new fish pond) may providenovel structures.
Novel structures (new fish) offer patentability andmaybe 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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Issues in Discovery
Target selectivityMolecular targets are many
Most targets are proteins
Small molecule-protein interaction rarelyspecific
Non-selective small molecules produce side-effects
Models not predictive of clinical outcomeTarget relevant assays
Target relevant models
Disease relevant models
Dosing regiment relevant animal models
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Issues in Discovery
Therapeutic windowEfficacy vs. toxicity
All chemicals are toxic
Pharmacology is low dose of toxicology
Toxicology is high dose of pharmacology
BioavailabilityEffective drug concentration
Plasma concentration
Tissue concentration
Target concentration
FormulabilityWhat is your ultimate formulation?
Can your compound be formulated?
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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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Issues in Development
ToxicologySpecies relevance
Dosing regimen relevance
Drug metabolism relevance
Acute vs. chronic toxicity
MetabolismInactive and active metabolites
Toxic metabolites
P450 activity
Drug-drug interaction
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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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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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Key to Discovery Success
Prepare for development issuesCMC
Process
Analytical methods
Toxicology
Anticipate roadblocksClinical end points
Side effects
Manufacturing issues
Stability
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One Last Reminder……
LeadDevelopmentCandidate
IND
Candidate
ChemicalCompound
BiologicalTarget
Non-reg Reg
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