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
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
Ta
rg
e
t
V
a
li
d
a
ti
o
n
Chemistry driven
Risk:
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
DNA
Genome
RNA
Transcriptome
PROTEIN
Proteome
CELLS
In vitro phenotype
CIRCUITS
Electrophysiology
BIOMODULES
Protein:Protein Interactions
PATHWAYS
Signal Cascades
ORGANS
Histopathology
ORGANISM
Phenotype
POPULATION
Epidemiology
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-profit
drug 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
http://www.google.com/url?sa=i&rct=j&q=sangamo+biosciences&source=images&cd=&cad=rja&docid=N-e1k9YG55Oy4M&tbnid=8pPH1aDuGqSODM:&ved=0CAUQjRw&url=http://2011.igem.org/Team:Harvard/Human_Practices&ei=cLAiUYyREqSi2gXIoYDoDg&bvm=bv.42553238,d.aWM&psig=AFQjCNEgzKfWiPxhoxcPMYJOHfLkiwJVJg&ust=1361314191782705
http://www.google.com/url?sa=i&rct=j&q=sangamo+biosciences&source=images&cd=&cad=rja&docid=N-e1k9YG55Oy4M&tbnid=8pPH1aDuGqSODM:&ved=0CAUQjRw&url=http://2011.igem.org/Team:Harvard/Human_Practices&ei=cLAiUYyREqSi2gXIoYDoDg&bvm=bv.42553238,d.aWM&psig=AFQjCNEgzKfWiPxhoxcPMYJOHfLkiwJVJg&ust=1361314191782705
Access the most innovative Biotech approaches
http://www.google.com/url?sa=i&rct=j&q=sangamo+biosciences&source=images&cd=&cad=rja&docid=N-e1k9YG55Oy4M&tbnid=8pPH1aDuGqSODM:&ved=0CAUQjRw&url=http://2011.igem.org/Team:Harvard/Human_Practices&ei=cLAiUYyREqSi2gXIoYDoDg&bvm=bv.42553238,d.aWM&psig=AFQjCNEgzKfWiPxhoxcPMYJOHfLkiwJVJg&ust=1361314191782705
http://www.google.com/url?sa=i&rct=j&q=sangamo+biosciences&source=images&cd=&cad=rja&docid=N-e1k9YG55Oy4M&tbnid=8pPH1aDuGqSODM:&ved=0CAUQjRw&url=http://2011.igem.org/Team:Harvard/Human_Practices&ei=cLAiUYyREqSi2gXIoYDoDg&bvm=bv.42553238,d.aWM&psig=AFQjCNEgzKfWiPxhoxcPMYJOHfLkiwJVJg&ust=1361314191782705
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
http://www.google.com/url?sa=i&rct=j&q=&esrc=s&frm=1&source=images&cd=&cad=rja&docid=g8MFSQRUrYguVM&tbnid=E4fwzdnOe4BABM:&ved=0CAUQjRw&url=http://www.yellow-canaries.com/book/safety-net&ei=P4WDUt-sAevB4APotIDgDg&bvm=bv.56343320,d.dmg&psig=AFQjCNFqoFxZ9tzgZunXthls1RRzV3kiTg&ust=1384437348323869
http://www.google.com/url?sa=i&rct=j&q=&esrc=s&frm=1&source=images&cd=&cad=rja&docid=g8MFSQRUrYguVM&tbnid=E4fwzdnOe4BABM:&ved=0CAUQjRw&url=http://www.yellow-canaries.com/book/safety-net&ei=P4WDUt-sAevB4APotIDgDg&bvm=bv.56343320,d.dmg&psig=AFQjCNFqoFxZ9tzgZunXthls1RRzV3kiTg&ust=1384437348323869
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 driv
