Avalon Pharmaceuticals: The next generation in drug discovery

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Avalon PharmaceuticalsThe next generation in
drug discovery

• December 2005

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Avalon Pharmaceuticals

• 50 employees - Germantown, MD
• Ambitious company that thinks big
• Improving all stages of drug discovery and
  development
• State-of-the-art facility
• Growing list of programs and partnerships

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Avalons Mission and Vision

• Avalon Pharmaceuticals is discovering and
  developing better medicines with an innovative
  chemical genomics engine
• The Company is currently focused in oncology.

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The problem enormous complexity in cellular
signaling pathways
Avalons proprietary engine measures specific
changes in gene-expression providing a unique,
powerful, unifying system for all stages of drug
discovery and development
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From Screen to Lead Beta-catenin
An intractable target pathway unlocked
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Beta-catenin The promise and the challenge

• Pathway is activated by mutation in gt90 of
  colon cancers and many other tumor types.The
  protein has no known enzymatic activity.Classical
  ly un-drugableDisruption of pathway inhibits
  tumor formation.
• Focus of many Big Pharma discovery programs
  but few if any good drug candidates

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HITS Screening The Basics
Measure Target Gene Signature
100,000 Compounds
Cells

• HITS (High-throughput Integrated Transcriptional
  Screening)
• Proprietary cost-effective modifications to
  384-well qPCR
• Customized automation LIMS for data flow
• Typically monitor multiple genes (5-10) per
  compound

Custom fully flexible HTS robotics screening
system
HITS V3 platform 100,000 qPCRs/day
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Baseline Gene Expression Measured by AvalonRx
Gene 1 2 3 4 5 6
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Gene Expression after RNAi or Target Inhibition
Gene 1 2 3 4 5 6
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Screening Signature Developed by AvalonRx
Gene 1 2 3 4 5 6
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Hit Compound Signature Matches Screening
Signature
Gene 1 2 3 4 5 6
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The Beta-catenin Target Gene Signature
Beta catenin RNAi
Change in gene expression
Negative control RNAi
Genes
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The beta-catenin screen identified several
promising hit compounds
Screening Hit compound
Screening Hit compound
RNAi generated profile

Beta catenin RNAi
Desired profile
Negative control compound - TOPO inhibitor
Negative control compound - HDAC inhibitor

• 9 confirmed hit families
• hit multiple points in pathway

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Avalons METS approach A powerful and practical
tool for drug profiling
current drugs
failed drug candidates
New drug candidates
Expression Of 10,000 genes
Compound Classification
METS Database
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METS provides critical predictions of compound
activities both on and off primary mechanism
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AVN-399 compound series has nanomolar potency and
closely mimics Beta-catenin RNAi profile
Optimization Series Drug Candidates
I
II
III
IV
Beta-catenin RNAi profile
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TSAR Optimization using gene expression
Cycle Threshold (CT) value
Concentration uM
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TI50 Chemical genomics driven SAR for better
drugs
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From hits to preclinical candidates Efficacy
testing in animal disease models
RACETraCK (Rapid Assessment of Compound Efficacy,
Transcriptional Change, Kinetics)

• A single RACETraCK experiment provides
  information on
• Tumor exposure
• Predictions of efficacy
• In vivo biomarkers
• Dose/ schedule optimization
• Identify sensitive patients
• Rapid way to evaluate many compounds/analogs in
  animals
• (e.g. 40 compounds can be assessed in vivo for
  efficacy within 6 weeks)

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AVN944

• Best in class, oral small molecule IMPDH
  inhibitor for hematologic and solid tumor cancers
• More potent and selective than prior IMPDH
  inhibitors
• Improved pharmaceutical properties
• Good efficacy in preclinical models
• Phase I human data Good PK, inhibits target at
  safe doses
• Clinicians are very excited about the potential
  for patient benefit

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Denovo DNA synthesis an essential function for
proliferating cells
AVN-944
IMPDH is highly upregulated in most hematologic
cancers
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The Role of IMPDH in Cancer

• IMPDH is required for synthesis of DNA and RNA
• IMPDH is highly upregulated in most hematologic
  cancers, including AML, CLL and multiple myeloma
• First generation IMPDH inhibitors have shown
  efficacy in cancer patients, but also had
  off-target side effects1,2
• Preclinical studies have shown that both
  hematologic and solid tumor cancer cells are
  sensitive to IMPDH inhibition

(1) Takebe, et al. Clin. Cancer Res.,
108301-8308, 2004 (2) Malek, et al. Leukemia
Research, 281125-1136, 2004
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AVN-944 is broadly active in cell lines from many
types of hematologic cancers

• Equipotent in cells with
• Gleevec-resistance
• Melphalan-resistance
• Doxorubicin-resistance
• Dexamethasone-resistance
• Flt3-ITD or point mutated Flt3
• Ph BCR-ABL
• Cytokine-dependence
• Co-cultured with BMSCs
• Pgp or MRP MDR pumps

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AVN-944 Activity in patient samples supports
clinical proof of concept of other IMPDH
inhibitors
Patient number 1 2 3 4 5 6 7 8 Mean Median
AVN-944 0.167 0.149 0.241 0.428 0.181 0.253 0.106
0.216 0.218 ? 0.092 0.199

• IMPDH inhibitor clinical proof of concept
• Tiazofuran is active in cancer patients
• Malek, et. al. Leukemia Research 2004
• Mycophenolic Acid tested by NCI
• Knudtzon and Nissen, Cancer Chemother.
• Res., 1972
• MPA reduces tumor incidence in
• transplant patients (Roche report)

Killing of primary blast cells from AML patients
- denotes Flt3-ITD patients
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Colon tumor cells are sensitive to AVN-944 even
if resistant to standard therapies
?AVN-944 1uM ?FU/LEU 23uM
Primary tumor isolates from 15 patients surgical
samples
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AVN944 Preclinical EfficacySupports Clinical
Rationale

• Kills hematologic cancer cell lines at IC50
  80 nM
• Kills solid tumor cell lines at IC50 30 nM
• Kills primary AML blast cells from patients at
  IC50 218 nM
• In vivo efficacy shown in leukemia mouse model
  (at right)

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AVN944 Phase I Trials Results

• Oral dosing gave good exposure in humans
• Plasma concentrations exceed those needed to kill
  cancer cells
• Sustained IMPDH inhibition at moderate doses
• No adverse effects at highest doses tested
• Provides rationale for starting dose in next
  Phase I

Average IC50 for AML blast cells
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AVN944 Has Potential in Multiple Cancers

• Fastest routes to approval
• CLL in combination with or versus Campath
• AML in combination with or versus Mylotarg
• Multiple Myeloma versus Velcade or Revlimid
• Why poor second line therapy with high unmet
  medical need
• Expect broad activity across hematologic and
  solid tumors
• Strategy expand label post-registration
• AvalonRx allows us to make better clinical
  development decisions based on biomarkers

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AVN944 Program Plan
File IND
Hematologic Cancer
Phase I
Phase II
Phase III
Prepare and File NDA
FDA Review
FDA Approval
Solid Tumors
Phase I
Phase II
Phase III
Prepare and File NDA
FDA Review
FDA Approval
2005
2009
2010
2011
2006
2007
2008
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AvalonRx Is Guiding AVN944 Development
Patient Selection
Drug Combinations
Disease Response
Optimal Indications
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Anticipated Pipeline and AvalonRx Output by 2007
AVN944 Leukemia
AVN944 Myeloma
AVN944 Solid Tumor
Beta-Catenin
Aurora Kinase
Medarex Antibody 1
MedImmune
Sanofi-Aventis
Big Pharma 2005