Targeted Enzyme Therapy of Cancers in Humans

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Targeted Enzyme Therapy of Cancers in Humans

• Phoenix Pharmacologics, Inc.
• Frederick Holtsberg, Ph.D.

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Mission

• Rapid transition from basic research to cancer
  therapeutics
• Submitted 2 INDs to FDA
• Human Clinical Trials ongoing for
• ADI-PEG 20
• Uricase-PEG 20
• Cost efficient cGMP capabilities
• Well protected by IP

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Introduction to Pipeline
ADI-PEG 20 Uricase-PEG 20 Angiolysin Glianox
RD Animal Tox Human Phase 1 Human Phase 2
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Management Team

• Mike A. Clark, Ph.D. - President
• SmithKline and Schering Plough
• Vice President of Research, Enzon
• Discovered 4 drugs with combined sales now in
  excess of 2.4 billion
• John Bomalaski, M.D. - Vice President
• Charles Mark Ensor, Ph.D. - Director
• Frederick Holtsberg, Ph.D. - Director

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Collaborations

• Clinical trials ongoing at
• MD Anderson Cancer Center
• Indiana University Cancer Pavilion
• Miami University
• New York University
• Mass General, Boston
• Pascale National Cancer Institute, Italy

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Suite of Compounds

• ADI-PEG 20
• Hepatocellular carcinoma (HCC) and melanoma
• Diagnostic Assay Predicts sensitivity of other
  cancers to ADI-PEG 20 treatment
• Uricase-PEG 20
• Hyperuricemia is a by-product of effective
  treatment with ADI-PEG 20.
• Uricase-PEG 20 can be used to control
  hyperuricemia

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Hepatocellular carcinoma (HCC)

• Arginine
• A non-essential amino acid for normal tissue
• Required for HCC tumor growth
• ADI-PEG 20
• ADI - Arginine deiminase, an arginine degrading
  enzyme
• PEG - Poly(ethylene) glycol
• ADI-PEG 20 selectively kills tumors by
  eliminating extracellular arginine.

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Prevalence of HCC

• US 1 of all cancers
• Most common solid tumor in world with 500,000
  dying annually Asia - up to 50 of all cancers
• Chronic carriers of hepatitis B and hepatitis C
  are at higher risk for HCC
• Only 2 5 of patients diagnosed with HCC are
  candidates for surgery
• Radio Frequency Ablation often times cannot be
  used due to presence of associated disorders such
  as cirrhosis of the liver

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Results First HCC Patient to Complete
Full Dose Schedule

• The University of Texas M.D. Anderson Cancer
  Center
• Dr. Steven Curley

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Results CT Analysis

• Tumor Size
• 3 months pre treatment 5.5 cm x 6.0 cm
• pre treatment 6.7 cm x 6.4 cm
• Post
• 20 IU/m2 6.7 cm x 6.4 cm
• 40 IU/m2 6.2 cm x 6.0 cm
• 80 IU/m2 5.5 cm x 6.0 cm cycle 1 160
  IU/m2 5.0 cm x 5.0 cm cycle 2 160 IU/m2 4.0 cm
  x 4.0 cm cycle 3 160 IU/m2 3.8 cm x 4.0 cm

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Results

• In May 2002 patient was considered to have
  operable disease after three months at optimal
  dose.
• Resection on remaining tumor was performed May
  11, 2002
• All remaining tumor appears to have been removed
• Patient currently working full time and living
  normal life style with no apparent disease

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Results Phase II Clinical Study for HCC

• Pascale National Cancer Institute, Naples, Italy
• Dr. Francesco Izzo

July 1, 2002 to February 3, 2003
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Results Pascale National Cancer Institute,
Naples, Italy

• No observed toxicity (Grade 2 or higher NCI
  criteria)
• 2 complete responses (no observable tumor)
• 4 partial responses (greater than 50 reduction
  in tumor), and
• 9 stable disease
• Preliminary data suggest 79 response rate

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CT scan from Phase II Clinical Study for HCC
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CT scan from Phase II Clinical Study for HCC
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Life Expectancy Phase II Human Clinical Study
Historical Survival Data Cirrhotic patients
mean Simonetti 1997 45 days Nzeako 1996 42 days
All patients El-Serag 2002 102 days

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Phase II Human Clinical Study
Patient Days from diagnosis Cause of
Death Comment 1 62 Heart
Attack Pre-existing heart disease 2
74 Progressive disease Patient had
severe cirrhosis 3 109
Rupture of varices Complication due to cirrhosis
4 125 Rupture of varices
Complication due to cirrhosis
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Additional Studies

• M.D. Anderson Cancer Center
• Study is ongoing
• No toxicity observed
• Patient recruitment continues
• Fast Track Status for ADI-PEG 20 is being sought
  in 2003

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Treatment for Melanoma

• Surgery is standard therapy
• 75 develop metastasis
• Chemotherapy
• Most are unresponsive
• IFN-alpha / IL 2 Therapy
• Not well tolerated and toxic
• ADI-PEG 20 is being tested

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Patients and Dosage Phase I Study - US

• University of Indiana Ted Logan, PI
• University of Miami Lynn Feun, PI
• Phase I studies with melanoma are near completion
• Patients receive 3 injections of ADI-PEG 20 over
  4 weeks
• No toxicity has been observed in any patients
  (N15)

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Diagnostic Assay ADI-PEG 20

• HCC, melanoma, and other tumors

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Diagnostic assay

• Diagnostic assay developed for predicting
  sensitivity of tumors to arginine deprivation
• Approximately 10 tumors, other than melanoma and
  HCC have been found to be sensitive to ADI-PEG 20
  therapy

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Diagnostic assay
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Uricase-PEG 20

• Treatment of hyperuricemia resulting from
• Tumor Lysis Syndrome (TLS)
• Organ Transplantation
• Uncontrolled gout

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Uricase-PEG 20

• A uric acid degrading enzyme, urate oxidase,
  covalently attached to poly(ethylene) glycol
• Novel formulation to minimize hypersensivity
• By removing uric acid, hyperuricemia can be
  eliminated in TLS, organ transplant and gout
  patients

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Patients and Dosage

• Phase I human data on 7 patients
• Clinical centers involved
• New York University
• Mass General
• No toxicity to Uricase-PEG 20 observed
• High degree of efficacy observed

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Suite of Compounds

• ADI-PEG 20
• Diagnostic assay
• Uricase-PEG 20

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Market size for ADI-PEG 20
A typical therapeutic cycle of 24 weekly
treatments with ADI-PEG 20
Based on the number of deaths in 2002
published by American Cancer Society
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Expanded Market for ADI-PEG 20
Based on cancers, some of which are arginine
requiring
Based on the number of deaths in 2002
published by American Cancer Society
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Estimated market size for Uricase-PEG 20
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Major Assets of Phoenix Pharmacologics, Inc.

• Two drugs in clinical studies demonstrating
  safety and efficacy
• Diagnostic assay for increasing market potential
  for ADI-PEG 20
• Validated and robust cGMP manufacturing
  technologies
• Excellent IP portfolio
• Rapid introduction into the marketplace

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Contact Information
Frederick Holtsberg Phone [phone] Email
fholtsberg_at_phoenixpharm.org Networking room M5