Collaboratively Enabling Drug Discovery ... Collaboratively Enabling Drug Discovery Robert E. Pacifici,

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