Cornerstone Pharmaceuticals

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Cornerstone Pharmaceuticals
More than 10 million Americans living with cancer
More than 1.2 million newly diagnosed cases each
year
Three of four Americans expected to experience
cancer during their lifetime
Need for breakthrough technology considered
urgent for emerging leading cause of death

• Make a Difference

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Can We Do For Cancer What Antibiotics Have Done
for Infectious Disease? If So, How?

• Discover New Drugs With New Molecular Targets
  Unique To Cancer
• Discover New Drugs With Mechanisms Of Action
  Unique To Cancer
• Make Drugs Go Only To Cancer Cells and Not To
  Sensitive Healthy Cells

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Cornerstone Pharmaceuticals, Inc.

• Experienced Management Team, Serial
  Entrepreneurs, Blockbuster Drugs Brought to
  Market
• Incorporated in 2002, Privately Held,
  Approximately 29MM Raised to Date
• Seeking 10MM to Further Support Proof Of
  Concept Clinical Trials Already Initiated
• Technology In-Licensed from SUNY Stony Brook
• Invited Presentations Made at AACR, and Cold
  Spring Harbor.
• Grant Funding Awarded by NYS Center For
  Biotechnology, and Baldwin Breast Cancer Research
  Foundation

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CPI-613Small Molecule Drug
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Proprietary Technology Platform

• Cancer Specific Bioenergetics
• New molecular targets
• New mechanism of action
• Unique for multiple tumors

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CPI-613 Small Molecule Drug

• CPI-613 Lead Candidate Drug From Proprietary
  Technology Platform for Proof of Concept Clinical
  Study
• New Drug Class, New Chemical Entity, First In
  Human
• Broad-spectrum Of Cancer Cell Selectivity
  Observed
• In Vitro Human Tumor Cells In Culture
• Human Tumor Biopsy Testing
• Human Tumor Xenograft Models
• Broad Therapeutic Window In Toxicology Testing

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Status Multisite, Multiple Phase I/II Clinical
Trials. Patients Enrolled and Recruiting

• Proof of Concept As Single Agent
• Phase I PK, MTD, Efficacy in Patients with
  Diverse Solid Tumors
• Phase II Proof Of Concept As Single Agent in
  Selected Indications Safety and Efficacy
• Proof of Concept As Combination With Known
  Therapeutics

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CPI-613 Proof of Concept As Single Agent

• An Open Label, Phase I/II Evaluation,
  Dose-Escalation Study of Safety, Tolerability,
  Maximum Tolerated Dose (MTD), Efficacy, and
  Pharmacokinetics (PKs) of CPI-613 Given Twice
  Weekly for Three Consecutive Weeks in Cancer
  Patients With Diverse Solid Tumors Who Have
  Failed Existing Therapies

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CPI-613 Proof of Concept As Combination

• A Phase I/II Open-Label Dose-Escalation Clinical
  Trial of CPI-613 in Combination with Gemcitabine
  in Newly Diagnosed Patients With Tumors Intended
  to Be Treated With Gemcitabine

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Bioenergetics in Healthy and Cancer Cells New
Class of Molecular Targets?
Changes in mitochondrial number, shape, structure
and function, often accompany the transformation
of healthy cells to cancerous
Changes in enzyme structure and function also
occur. Bioenergetics and signal transduction
pathways are linked to cellular regulation
Multiple changes may be and are likely to be
maintained across diverse patient populations and
tumor types
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Bioenergetics Changesfrom Normal to Cancer Cells
Changes in molecular structure of key enzymes
offer new molecular targets
Altered Nutritional Needs And Uptake
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CPI 613 Mechanism of Action
Drug Uptake
Drug Uptake
Drug Concentrates In Mitochondria
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CPI 613 Mechanism of Action
CATASTROPHIC Shutdown of ATP Synthesis
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CPI 613 Mechanism of Action
Membrane Depolarization Death Pathways Activated
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CPI 613 Mechanism of Action
Cell Death
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Mechanism of Action Selective Cancer Cell
Accumulation and Mitochondrial Localization
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Percent Inhibition Of Primary Human Biopsy Tumor
Cell Growth CPI-613 vs. Standard Treatments
Percent inhibition
Same Result For Drug Resistant Patient Biopsy
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CPI-613 H460 NSCLC TGI Xenograft Study
(0.1mg/kg)(n8/group)
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CPI-613 BxPC-3 Pancreatic Xenograft TGI
Study(n10/group)
Last Dose
Dose Administration
P-Value lt 0.02 days 13, 16, 20 and 24 P-Value lt
0.002 days, 31, 34, 37, 41, 45 and 51
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CPI-613 Survival in BxPC-3 Xenograft TGI Study
US FDA orphan drug designation granted
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Emulsiphan Concentrating Drugs in Tumor Cells
withProprietary Composition of Matter Based on
Cancer Cell Metabolic Needs
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Emulsiphan Cancer Cell Internalizing -
Nanoemulsion Delivery Technology Platform

• An lipid-oil-water nanoemulsion with
• No chemical modification of API required
• No phospholipids, proteins (of human or other
  origin)
• Increased cancer cell uptake in diverse tumor
  types in-vitro and vivo
• Significantly increased efficacy in in-vivo
  models
• Well tolerated in-vivo

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Emulsiphan Scientific Approach

• Comprised of a nanoemulsion of neutral
  cholesterol and glycerol analogue excipients
• Excipients appear to improve drug effectiveness
  by becoming more concentrated in cancer cells
• Rationale cancer patients show reduced levels
  of cholesterol, triglycerides and fatty acids
• Tumors selectively take up these molecules
• Link to cachexia (cancer wasting)
• Emulsiphan mimics this uptake mechanism while it
  transports drugs to tumor cells
• Uptake shown in colon, brain, liver, NSC lung,
  breast and other tumors with limited or no uptake
  in healthy cells in culture or in vivo.

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Metabolism and Cancer
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Emulsiphan uptake into glioma cells
Fluorescent
Phase Contrast
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(No Transcript)
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Relative Uptake of Emulsiphan by Diverse Human
Tumor Cells
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Emulsiphan Platform Technology with Multiple
Product Opportunities

• Proof of principal formulations of several FDA
  approved, off-patent or nearly off-patent drugs
  has been achieved, including
• Paclitaxel (TAXOL)
• Docetaxel (TAXOTERE)
• Camptothecin (analogs include Hycamptin and
  Camptosar)
• Etoposide (VEPESID)
• Carmustine (BICNU)

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EmPACAn Emulsiphan Paclitaxel Formulation
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Drug Targets Are Intracellular
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EmPAC Increased relative paclitaxel delivery
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Anti-paclitaxel staining of EmPAC and
Taxol-treated MDA-MB-435 cells
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Comparative Efficacy
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EmPAC Improved Survival Probability
Survival was calculated based on time at which
animals died or were euthanized due to tumor
sizes exceeding regulatory limits.
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EmPAC Safety
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FDA Requirements Pharmacokinetics and
Bioequivalence
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FDA Requirements Pharmacokinetics and
Bioequivalence, Statistical Analysis
Comparative pharmacokinetic analysis

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FDA Requirements Pharmacokinetics and
Bioequivalence Organ and Tissue Distribution
Comparative Biodistribution
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EmPAC Clinical Development Approach

• United States
• Obtain approval based upon Bioequivalence or
  Non-Inferiority/ Superiority (NIS)
• Phase II equivalent studies to enable expanded
  use and further product differentiation within
  the market.
• Under consideration
• Post Approval Combination with other agents (e.g.
  CPI-613)
• Refractory Uterine or Breast Cancer US FDA
  Orphan Drug Designation enabled
• Brain Cancer ODD enabled
• IP administration in Ovarian Cancer
• Improved Safety (reduced neurotoxicity and/or
  hypersensitivity reactions and improved QOL)
• European Union
• NIS Clinical Trial

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