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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

  • 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

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