Slide 1: Pro-Pharmaceuticals, Inc. Advancing Drugs Through Glycoscience
P R O P H A R M A C E U T I C A L S , I N C. A D V A N C I N G D R U G S T H R O U G H G L Y C O S C I E N C E Amex: P R W P R O - P H A R M A C E U T I C A L S , I N C . www.Pro-Pharmaceuticals.com Amex: PRW
Slide 2: Forward Looking Statements
Forward Looking Statements Any statements in this presentation about future expectations, plans and prospects for the Company, including statements containing the words "believes," "anticipates," "plans," "expects," and similar expressions, constitute forward looking statements, which are subject to
Slide 3: Agenda
Agenda Highlights DAVANAT Milestones To Date The Commercial Opportunity Clinical Trial Summary DAVANAT/5-FU Side Effects Milestones 2H07-1H08 Product Development Pipeline Intellectual Property Regulatory Strategy Management Team Financial Summary Appendices: Carbohydrate Technology DAVANAT: Pre-Clin
Slide 4: Highlights
Highlights PRW has developed a new class of proprietary carbohydrate compounds, DAVANAT, which Provides a paradigm shift in drug delivery Improves the pharmacokinetics/pharmacodynamics and toxicity profile of current and ‘shelved’ drugs Creates new intellectual property Implements life cycle managem
Slide 5: DAVANAT
DAVANAT Proprietary polysaccharide galactomannan polymer consisting of galactose units attached to a mannan backbone Derived from seeds of the plant Cyamopsis tetragonoloba Affects biology of galectin molecules Changes the efficacy, toxicity, pharmacokinetic and distribution properties of chemothera
Slide 6: Key Milestones To Date
Key Milestones To Date PRW commenced operations in 2001 Raised $36 million to date Built strong team with carbohydrate polymer experience 5 patents issued Completed Phase l/ll cancer trials; 60 patients dosed with DAVANAT/5-FU Stabilized 43% of end stage patients w/ measurable disease: 2-13 months S
Slide 7: DAVANAT/5-FU Commercial Opportunity
DAVANAT/5-FU Commercial Opportunity 7
Slide 8: Clinical Trial Summary
Clinical Trial Summary 60 cancer patients dosed with DAVANAT/5-FU in completed Phase l/ll Stabilized 43% of end stage patients with measurable disease: 2-13 months Stabilized 36% of end stage colorectal cancer patients vs. 19% for Avastin Maximum Tolerated Dose/Dose Limiting Toxicity not reached DAV
Slide 9: DAVANAT/5FU Major Side Effects
DAVANAT/5FU Major Side Effects No Mucositis No Drug Related Diarrhea No Drug Related Abdominal Cramping No Drug Related Leukopenia “For as long as I have been in practice, 5-FU/LV has been the standard of care for patients with localized colon cancer. Side effects included mucositis, frequent diarrh
Slide 10: Upcoming Milestones 2H07-1H08
Upcoming Milestones 2H07 1H08 Submit 505(b)(2) application to FDA with DAVANAT as a functional excipient to 5-FU Submit DAVANAT/5-FU/Leucovorin under 505(b)(2) Submit DAVANAT/5-FU/Leucovorin/Irinotecan under 505(b)(2) Submit DAVANAT/5-FU/Leucovorin/Avastin under 505(b)(2) Report additional results f
Slide 11: Product Development Pipeline: August 2007
Product Development Pipeline: August 2007 PRODUCT INDICATION DEVELOP PRE-CLINICAL PHASE 1 PHASE 2 DAVANAT/ 5-FU DAVANAT/ 5-FU/LV/ AVASTIN DAVANAT/ 5-FU PRO-GR 300 Biliary Cancer Ongoing Colorectal Cancer Ongoing All Solid Tumors Completed Liver Disease Microbial Disease PHASE 3 DAVANAT/ 5-FU Colorec
Slide 12: Strong IP Position in Carbohydrate Polymers
Strong IP Position in Carbohydrate Polymers 5 issued patents, 13 pending U.S. applications Composition of matter and field of use patents Subset of key patents U.S. Pat 6,642,205 (11/04/03) Methods and Compositions for Reducing side effects in Chemotherapeutic Treatments U.S. Pat 6,645,946 (11/11/03
Slide 13: Regulatory Strategy
Regulatory Strategy Submit data to allow a 505(b)(2) designation for DAVANAT as a functional excipient to be co-administered w/5-FU for intravenous application to treat cancer Retained Camargo Pharmaceutical to provide regulatory support 24 successful 505(b)(2) programs 150 FDA approvals, NDA, ANDA,
Slide 14: DAVANAT 505(b)(2) Submissions
DAVANAT 505(b)(2) Submissions 5-FU Compound Submission Type Date Treatment Regimen(s) DAVANAT 505(b)(2) 4Q07/1Q08 5-FU Leucovorin 5-FU Irinotecan Leucovorin 2Q08/3Q08 5-FU Avastin Leucovorin 5-FU Oxaliplatin Leucovorin 5-FU Cisplatin Leucovorin Avastin is a registered trademark of Genentech, Inc. 14
Slide 15: Management Team
Management Team David Platt, Ph.D., Chairman & Chief Executive Officer Co-founder, co-developer of Glycoscience technology. Founder: SafeScience; developed anti-angiogenesis drug. U of Michigan, Weizmann Institute, Hebrew U Anatole Klyosov, Ph.D., D.Sc., Chief Scientist Co-founder, co-developer of G
Slide 16: Financial Summary
Financial Summary Founded: July 2000 Capital raised: $36 million (cumulative) Cash: $2.4 million (06/30/07) Burn rate: $1.2 million per quarter Shares outstanding: 40.4 million (06/30/07) Fully diluted: 52.1 million (06/30/07) Debenture converted (except for $280K as of 08/09/07) 16
Slide 17: Appendices
Appendices = PHARMACEUTICALS, INC. ADVANCING DRUGS THROUGH GLYCOSCIENCE®
Slide 18: Carbohydrate Technology
Carbohydrate Technology PRO = PHARMACEUTICALS, INC. ADVANCING DRUGS THROUGH GLYCOSCIENCES
Slide 19: Carbohydrates as Therapeutics
Carbohydrates as Therapeutics A novel class only now beginning to be explored for therapeutic potential Structurally heterogeneous linear and branched, small and large molecules Diverse biological forms as glycoproteins, glycolipids, sugars, and complex carbohydrates in plants, animals, fungi, and b
Slide 20: DAVANAT: Proposed Mechanism of Action
DAVANAT: Proposed Mechanism of Action DAVANAT targets galectins on cancer cells. Galectins affect cell development and angiogenesis DAVANAT “escorts” chemotherapy into cancer cells via galectin receptors in a more efficient manner DAVANAT encapsulates chemotherapy drugs in a CARBOSOMETM formation; i
Slide 21: Hypothesis: CARBOSOME
Hypothesis: CARBOSOME DAVANAT polymer exists as a “3D” structure in solution with lectin targeting units protruding from the mannan backbone 21
Slide 22: Other Technology Platforms: UCLT
Other Technology Platforms: UCLT Enhances delivery to the target by covalently binding a carbohydrate to the inactive side of the molecule 22
Slide 23: DAVANAT: Pre-Clinical and Clinical Studies
DAVANAT: Pre-Clinical and Clinical Studies 23
Slide 24: Pre-Clinical Results: HT-29 Colon Tumor Xenografts
Pre-Clinical Results Response of HT-29, Human Colon Tumor Xenografts to DAVANAT in Combination with 5-FU and Leucovorin Charles River Labs (Dose: I.V., Q4D x 4, of 5-FU: 48 mg/kg; DAVANAT: 120mg/kg; Oral, Leucovorin 25 mg/kg) DAVANAT/5-FU/LV improved tumor inhibition vs. 5-FU/LV (21 to 27 days) 24
Slide 25: Pre-Clinical Results: ZR75-1 Mammary Tumor Xenografts
Pre-Clinical Results Response of SC ZR75-1,Human Mammary Tumor Xenografts, to dose escalation DAVANAT in Combination with Irinotecan Southern Research Institute (Dose I.V., Q4D x 4, of IR 40 mg/kg; DAVANAT: 6, 30 & 120 mg/kg) DAVANAT/Irinotecan improved tumor inhibition by delaying tumor growth vs.
Slide 26: Pre-Clinical Results: COLO 205 Xenografts with 5-FU and Bevacizumab
100 1000 10000 0 10 20 30 40 Time post implanatation (Days) Tumor size (mg) Control IR40/DAV6 IR40/DAV30 IR40/DAV120 Pre-Clinical Results Response of COLO 205, Human Colon Tumor Xenografts, to DAVANAT in Combination with 5-FU & Bevacizumab Southern Research Institute (Dose: I.V., Q4D x 4, of 5-FU 50
Slide 27: Clinical Trial Summary
Clinical Trial Summary 60 cancer patients dosed with DAVANAT/5-FU in completed Phase l/ll Stabilized 43% of end stage patients with measurable disease: 2-13 months Stabilized 36% of end stage colorectal cancer patients vs. 19% for Avastin Maximum Tolerated Dose/Dose Limiting Toxicity not reached DAV
Slide 28: DAVANAT vs. AVASTIN
DAVANAT vs. AVASTIN Response rate stable disease in end-stage colorectal cancer patients Stable disease rate of DAVANAT/5-FU at 36% vs. 19% for Avastin/5-FU/LV in end stage colorectal cancer patients No head-to-head studies conducted. Data obtained from AVASTIN drug insert/ASCO Abstract. Avastin is
Slide 29: Stable Disease Rate Comparison
5-FU/LV (Historical) AVASTIN/5-FU/LV (Genentech/Literature) DAVANAT/5-FU (Pro-Pharmaceuticals) Median progression free survival 5.2 months Stable disease rate 19% 100 Patients Stable disease rate 36% 25 Patients Phase I Clinical Trial All Solid Tumors (End Stage) 29
Slide 30: Phase I Trial Design and Patient Outcomes
Indication: All solid tumors. End stage patients; minimum 12 weeks to live Objectives: Primary Safety Secondary Tumor progression; PK profile of 5-FU Design: Multi-center (4 sites), open label study. Two cycles; six cohorts. Cycle 1 DAVANAT alone Cycle 2- DAVANAT/5-FU Regimen: DAVANAT escalating dos
Slide 31: Phase I Results: White Blood Cell Counts
Phase l Results White Blood Cell Counts Fluctuations vs. Cycle day in 10 Subjects (Cohort 6) Dosed with DAVANAT (280 mg/m2) plus 5-FU (500mg/m2) 31
Slide 32: Phase I Results: Blood Platelet Count
Phase l Results Blood Platelet Count Fluctuations vs. AUCDay 1 in 10 Subjects (Cohort 6) Dosed with DAVANAT (280 mg/m2) plus 5-FU (500mg/m2) 32
Slide 33: Phase I SAEs by Patient, Cycle, and Relationship
Phase I SAEs by Patient, Cycle, and Relationship to Study Drug DAVANAT (mg/m2) Patient No. Cycle SAE (MEDRA preferred Term) Relationship to Study Drug 30 01003 1 Colon cancer metastatic Death Not related Not related 100 02004 3 Rectal hemorrhage Anemia Hemorrhoids Hemorrhoidal hemorrhage Not related
Slide 34: Phase I SAEs by Patient, Cycle, and Relationship (cont.)
Phase I SAEs by Patient, Cycle, and Relationship to Study Drug (cont.) DAVANAT (mg/m2) Patient No. Cycle SAE (MEDRA preferred Term) Relationship to Study Drug 280 02006 1 Pulmonary embolism Hypoglycemia Syncope Not related Not related Not related 02007 1 Hepatic hemorrhage Not related 02010 2 Dyspne
Slide 35: Phase I Clinical (End Stage) Trial Summary
Phase I Clinical (End Stage) Trial Summary DAVANAT was well tolerated in end-stage patients Maximum Tolerated Dose and Dose Limiting Toxicity of DAVANAT not reached DAVANAT 280 mg/m2 recommended for Phase II dose Pharmacokinetics Half life of 5-FU alone is 6-22 minutes Half life of 5-FU with DAVANAT
Slide 36: Phase II Colorectal Cancer Trial (End Stage)
Phase II Colorectal Cancer Trial (End Stage) Indication: Colorectal cancer; End stage patients. Objectives: Complete/ partial tumor response (RECIST); stable disease. Design: Multi-center (6 sites), open label study. Evaluate at least two cycles (up to six) or to disease progression. Regimen: DAVANA
Slide 37: Phase II Colorectal (End Stage) Trial Summary
Phase II Colorectal (End Stage) Trial Summary DAVANAT was well tolerated in end-stage, refractory patients Anti-tumor activity was seen with DAVANAT /5-FU 1 patient experienced Partial Response 6 of 20 patients stabilized for 2-8 months No increase in 5-FU toxicity with increased exposure 37
Slide 38: Phase II Colorectal Trial First Line (Ongoing)
Phase II Colorectal Trial First Line (Ongoing) Indication: First line treatment of patients with metastatic, unresectable colorectal cancer who are unable to tolerate irinotecan or oxaliplatin. Objectives: Complete/partial tumor response (RECIST); 14 of 41 responders (34%). Progression Free Survival
Slide 39: Phase II Biliary Trial First Line (Ongoing)
Phase II Biliary Trial First Line (Ongoing) Indication: First line treatment of patients with biliary cancer. Objectives: Complete/ partial tumor response (RECIST); 7 of 35 responders (20%). Progression free survival. Design: Multi-center, open-label study. Regimen: DAVANATwith 5-FU. Evaluate for 2
Slide 40: Other Plans for DAVANAT
Other Plans for DAVANAT Pre-clinical Stability & compatibility studies of DAVANAT & chemotherapeutics in solution Investigate dose-toxicity response curve Investigate covalent linkers of therapeutics to DAVANAT Animal toxicity studies in combination therapies Clinical Escalating doses of 5-FU: Ident
Slide 41: Other Pro-Pharmaceuticals Compounds
Other Pro-Pharmaceuticals Compounds 41
Slide 42: Other Pro-Pharmaceuticals Compounds: Fibrosis
Other Pro-Pharmaceuticals Compounds Fibrosis No available treatment for fibrosis Fibrosis (scarring) is the reason patients develop liver failure & may need a transplant 25 million Americans have liver/biliary disease More than 4 million Americans with Hepatitis C virus; many will develop severe fib
Slide 43: Regulatory Pathway: 505(b)(2)
Regulatory Pathway: 505(b)(2) 43
Slide 44: 505(b)(2) Regulatory Pathway
505(b)(2) Regulatory Pathway 505(b)(1): “Typical” way most new drugs are approved; all investigations from sponsor 505(b)(2): Used for new formulations of existing drugs; applicant may rely on investigations to which it does not own or have the right of reference (e.g., information in the published
Slide 45: FDA Position Regarding 505(b)(2)
FDA Position Regarding 505(b)(2) “FDA’s longstanding interpretation of section 505(b)(2) … the Agency’s approach is to use the 505(b)(2) drug approval pathway to avoid requiring drug sponsors to conduct and submit studies that are not scientifically necessary.” “The conduct and review of duplicative
Slide 46: 505(b)(2) Avoids Significant Delays in Drug Approval
505(b)(2) Avoids Significant Delays in Drug Approval “FDA has approved more than 80 section 505(b)(2) applications for drugs for indications ranging from cancer pain to attention deficit disorder. …many of these drugs would never have reached the market, or would have been significantly delayed, wit
Slide 47: DAVANAT/5-FU Formulations: Historical Background
DAVANAT/5-FU Formulations: Historical Background 5-Fluorouracil, one of the most widely used cytotoxic agents Less than desirable PK and side effect profile Tiredness, fatigue, nausea, diarrhea, bone marrow depression (may lead to anemia), increased tendency to bruise, mouth sores, altered skin pigm
Slide 48: Benefits of Not Having Efficacy Trial
Benefits of Not Having Efficacy Trial Preservation of resources for other research Immediate availability of a less toxic 5-FU alternative Have more time to develop a strong marketing strategy, resulting in a brand consumers recognize and may prefer Exclusivity beyond 180 days when compared to ANDA
Slide 49: Rationale for No Efficacy Trial
Rationale for No Efficacy Trial Based upon the data, there is no scientific basis to hypothesize that DAVANAT /5-FU will be less effective as adjuvant therapy than 5-FU alone Safely delivers a higher dose of 5-FU than already proven to be effective in adjuvant setting In clinical trials, DAVANAT has