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Collaboratively Enabling Drug Discovery
Robert E. Pacifici, Ph.D.Chief Scientific Officer
Aresty Auditorium
Harlyne J. Norris Research Tower
USC Health Sciences Campus
1450 Biggy Street,
Los Angeles, California
International Regulatory Science Symposium
2014 Summerfest Kickoff
June 19th, 2014
2
The “exhaustive” drill…
~35,000 genes →
~100,000 proteins
…is not physically possible!
All combinations of
atoms <700 mw
Chemical
Diversity Space
You should work on a drug that…
5
Has $1 billion
fifth year
peak sales
Pharmaceutical Companies
Cures my
specific rare
disease
Disease Foundations
Involves my
scientific discovery
(compound or target)
Academic Researchers
Leverages our
technology
Biotech Companies
Safely reverses a
lifetime of unhealthy
behaviors
Aging Population
The Main Sources of “Risk” for any Therapeutic Program
6
Chemistry or Compound Related
• Potency, Solubility, Selectivity, PK & ADME
• CMC: Synthesis, Stability, Formulation
• Intellectual Property
Biology or Target Related
• On-mechanism toxicity & robustness
• Tractability & Pharmacology
• Validation / Disease association
Clinical or Trial Related
• Outcome measures
• Trial design: subjects, timing/stage, length
• Statistics: power, calculations
The Main Sources of “Risk” for any Therapeutic Program
7
Biology or Target Related
• On-mechanism toxicity & robustness
• Tractability & Pharmacology
• Validation / Disease association
“The two major causes of compound failure are lack of efficacy in man, and
unexpected toxicity either in animals or man.”Jackie Hunter, Drug Discovery World, 2014
“It’s the human biology...stupid!”Robert Pacifici, just now
Biological and Chemical Tractability
Biology Driven
Risk:
Never identify
a candidate
Protein Tyrosine Phosphatase – 1B
Target Drugability
Targ
et
Va
lid
ati
on
Chemistry drivenRisk:
Safe, Well tolerated
Phase II failure
Any “orphan” G-protein coupled receptor
Innovate around target tractability / drugability
RNAiVirus
Device Lifestyle
PeptideProteinAntibody
Innovate around target identification / validation
DNAGenome
RNATranscriptome
PROTEINProteome
CELLSIn vitro phenotype
CIRCUITSElectrophysiology
BIOMODULESProtein:Protein Interactions
PATHWAYSSignal Cascades
ORGANSHistopathology
ORGANISMPhenotype
POPULATIONEpidemiology
There is nothing more valuable to a drug hunter than an
observation made in the population you seek to treat!
What is CHDI…exactly?
Page 12
– Motivated by TIME not MONEY
– No COMPETITORS only COLLABORATORS
– Fully integrated research: discovery-translational-
clinical
A not-for-profitdrug discovery organization
Utilizing the “virtual” or outsourced model
– Approximately 70 internal FTEs across
three sites (NY, NJ, & LA) covering all
scientific and G&A competencies
– No internal wet-labs. All experimentation
is done externally via collaborative
partners and contract research
organizations. Circa 600 FTE
– Select the “best-of-the-best”; yet
fungible
Exclusively dedicated to Huntington’s disease
– Removes serendipitous indications discovery
– Unambiguous continuity, focus, passion
– IP, legal, business terms all designed to protect
our primary indication (allows others)
Foundation funded– All funds from private donors (~$80MM/yr)
– Driven by drug candidates
– Not by hype, press releases, or trial initiations
So how do we: Collaborate, Innovate, Globalize
Enable the best academic investigators to contribute
• Centralized repositories
– Harvest existing and de novo generation
– One-click MTA
– Quality control / Standardization
• Provide research funding
– CHDI has provided millions of dollars of support
– Thousands of contracts (not grants) executed
– Business structure tailored to match the scientific needs
• Information exchange
– PLoS Currents HD
– HD Research CrossRoads
– Yearly Therapeutics Conference
Identify & characterize every affected subject on earth
• Huntington’s is a rare disease– Important to have the largest possible catch basin
• Sub populations may have unique features– Genetic modifiers
– Environmental factors
– Large isolated kindred's
• Enroll HD
– A global prospective observational study
– Worldwide registry of patients and physicians
– Integrated global clinical research infrastructure
• Informatics
• Bio-banking
– A platform to facilitate clinical studies in experimental medicine,
observational studies and therapeutic trials
Access the most innovative Biotech approaches
• Survey the landscape for the most applicable
technologies
– Leverage existing platform, people, and intellectual property
– True collaborative partnership: money and know-how
– We share the (new) intellectual property
– De-risk the program to make it attractive for licensing
• Identified (htt) gene modulation as an unmet need
– Isis’s 20 years of experience on antisense oligonucleotides
– Sangamo’s novel zinc-finger transcription factors
Access the most innovative Biotech approaches
Leverage the billions of dollars that Pharma has spent
• Large multi-national firms have hundreds of “parked” assets
– Potent, selective, ligands with good “tool-like” properties allow rapid POC
– They bring: IP, knowledge of the mechanism, and the molecule
• Foundations de-risk or lower the barrier to entry into the target
disease
– Disease domain knowledge
– Preclinical testing
• Win – Win scenario
– Pharmacological (in) validation of the target/mechanism
– New indication for “sunk cost” asset
Develop the capabilities to drive campaigns
• Foundations can not rely solely on:
– Repurposing existing compounds
– Reactively minding the “in box”
• If the biology is compelling
– Persevere where others have failed or abandoned
– Initiate de novo efforts if needed
• Orchestrated across a global network of fee-for-
service contract research organizations
– We design and oversee the research
– CHDI owns the intellectual property
Develop the capabilities to drive campaigns
Kynurenine monooxygenase (KMO)
Develop the capabilities to drive campaigns
Develop the capabilities to drive campaigns
A Disease Foundation’s “Wish List”
Pharmaceutical Companies
Disease Foundations Academic Researchers
Biotech Companies
Aging Population
PharmacokineticsWhat dose, route, and
frequency is needed so the drug will reach the needed
tissues at a high enough concentration for a long enough period of time?
Drug never achieved levels above EC50
New compoundNew routeNew dose
Target Engagement
How can we measure that the drug has properly
bound to the its cognate target in situ?
Not bound to receptor ligand domain or enzyme active site.
New compound
New target
Biochemical Engagement
Can we verify that the drug elicited the desired
biochemical effect to the desired extent?
Target is constitutively activated or irreparably
impaired
New target
New mechanism
PK/PD: Don’t go to the Clinic Without It!
You should work on a drug that…
27
Has $1 billion
fifth year
peak sales
• Profit/market driven decisions
• Relatively short attention span
• Organizational constraints
- Outsourced innovation
- Large size
• Strong development and Sales
Pharmaceutical Companies
Cures my
specific rare
disease
• Not-for-profit organizations
• Transgenerational commitment
• Deep domain knowledge
• >7,000 Rare & Neglected diseases
• Major new players in the ecosystem
(>billions of $)
Disease Foundations
Involves my
scientific discovery
(compound or target)
• Driven by publications
• Huge source of innovation
• “Lone-ranger” syndrome
• Bayh-Dole vs precompetitive space
• Quality, robustness, reproducibility
Academic Researchers
Safely reverses a
lifetime of unhealthy
behaviors
• Unrealistic expectations
- 100% safe
- Free
- Drug > lifestyle
- Anytime yesterday
• Power in numbers
• Power in participation
Aging Population
You should work on a drug that…
28
Has $1 billion
fifth year
peak sales
• Profit/market driven decisions
• Relatively short attention span
• Organizational constraints
- Outsourced innovation
- Large size
• Strong development & sales
Pharmaceutical Companies
Cures my
specific rare
disease
• Not-for-profit organizations
• Transgenerational commitment
• Deep domain knowledge
• >7,000 Rare & Neglected diseases
• Major new players in the ecosystem
(>billions of $)
Disease Foundations
Involves my
scientific discovery
(compound or target)
• Driven by publications
• Huge source of innovation
• “Lone-ranger” syndrome
• Bayh-Dole vs precompetitive space
• Quality, robustness, reproducibility
Academic Researchers
Leverages our
technology
• Driven by deals (bio-bucks!)
• Focused innovation
• Limited disease knowledge
• Can be volatile
• Proximal pipe-line expertise
Biotech Companies
You should work on a drug that…
29
Has $1 billion
fifth year
peak sales
Pharmaceutical Companies
Cures my
specific rare
disease
Disease Foundations
Involves my
scientific discovery
(compound or target)
Academic Researchers
Leverages our
technology
Biotech Companies
Safely reverses a
lifetime of unhealthy
behaviors
Aging Population
• Unrealistic expectations
- 100% safe
- Free
- Drug > lifestyle
- Anytime yesterday
• Power in numbers
• Power in participation
The “exhaustive” drill…
Peptide
Protein
Antibody
Small Molecule
~35,000 genes
~100,000 proteins
1,000,000,000,000,000,000,000,000,000,000,000,000,000,000,000,000,00
0,000
000,000,000,000,000,000,000,000,000,000,000,000,000,000,000,000,
000,000,000,000,000,000,000,000,000,000,000,000,000,000,000,000,000,
000,000,000,000,000,000,000,000,000,000,000,000,000,000,000,000,000
…is not physically possible!
