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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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Drug Composition

API

Excipient

Packaging

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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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