UNITED
STATES
SECURITIES
AND EXCHANGE COMMISSION
Washington,
D.C. 20549
_______________
FORM
8-K
_______________
CURRENT
REPORT
Pursuant
to Section 13 or 15(d) of the Securities Exchange Act of
1934
August
10, 2007
Date
of Report (Date of earliest event reported)
_______________
PRO-PHARMACEUTICALS,
INC.
(Exact
Name of Registrant as Specified in Charter)
_______________
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NEVADA
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000-32877
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04-3562325
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(State
or Other Jurisdiction
of
Incorporation)
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(Commission
File Number)
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(IRS
Employer
Identification
No.)
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7
WELLS AVENUE
NEWTON,
MASSACHUSETTS
02459
(Address
of Principal Executive Offices) (Zip Code)
(617)
559-0033
(Registrant’s
telephone number, including area code)
_______________
Check
the
appropriate box below if the Form 8-K filing is intended to simultaneously
satisfy the filing obligation of the registrant under any of the following
provisions (see General Instruction A.2. below):
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¨
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Written
communications pursuant to Rule 425 under the Securities Act (17
CFR
230.425)
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¨
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Soliciting
material pursuant to Rule 14a-12 under the Exchange Act (17 CFR
240.14a-12)
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¨
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Pre-commencement
communications pursuant to Rule 14d-2(b) under the Exchange Act (17
CFR
240.14d-2(b))
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¨
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Pre-commencement
communications pursuant to Rule 13e-4(c) under the Exchange Act (17
CFR
240.13e-4(c))
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Regulation
Fair Disclosure
Item 7.01.
Regulation FD Disclosure.
The
information in this Report, including the slides attached hereto as Exhibit
99.1, is being furnished pursuant to this Item 7.01 and shall not be deemed
“filed” for purposes of Section 18 of the Securities Exchange Act of 1934
(the “Exchange Act”) or otherwise subject to the liabilities of that section,
and it shall not be deemed incorporated by reference in any filing under the
Securities Act of 1933 or under the Exchange Act, whether made before or after
the date hereof, except as expressly set forth by specific reference in such
filing to this Report.
By
filing
this Report and furnishing this information, the Company makes no admission
as
to the materiality of any information in this Report. The information contained
in the slides is summary information that is intended to be considered in the
context of the Company’s filings with the Securities and Exchange Commission
(the “SEC”) and other public announcements that the Company makes, by news
release or otherwise, from time to time. The Company undertakes no duty or
obligation to publicly update or revise the information contained in this
Report, although it may do so from time to time as its management believes
is
appropriate. Any such updating may be made through the filing of other reports
or documents with the SEC, through news releases or through other public
disclosure.
The
Company cautions you that information included in the slides attached hereto
as
Exhibit 99.1 that are not a description of historical facts are forward-looking
statements that involve risks, uncertainties, assumptions and other factors
that, if they do not materialize or prove to be accurate, could cause the
Company’s results to differ materially from historical results or those
expressed or implied by such forward-looking statements. Such forward-looking
statements are made based on management’s current expectations and beliefs and
should not be regarded as a statement or representation by the Company that
any
of its plans, including its anticipated milestones, will be achieved on time
or
at all. The potential risks and uncertainties that could cause actual results
to
differ materially include, but are not limited to: the risk that the Company
will be unable to raise sufficient capital to fund the projects necessary to
meet its anticipated or stated goals and milestones; the potential to attract
a
strategic partner and the terms of any related transaction; the ability to
timely enroll subjects in the Company’s current and anticipated clinical trials;
the potential for DAVANAT® to receive regulatory approval for one or more
indications on a timely basis or at all, and the uncertain process of seeking
regulatory approval; other difficulties or delays in developing, testing,
manufacturing and marketing of and obtaining regulatory approval for DAVANAT®;
the market potential for carbohydrate-based compounds, and the Company’s ability
to compete in those markets; unexpected adverse side effects or inadequate
therapeutic efficacy of DAVANAT® or the Company’s other products that could
delay or prevent regulatory approval or commercialization, or that could result
in recalls or product liability claims; the risk that pre-clinical results
are
not indicative of the success of subsequent clinical trials and that products
will not perform as pre-clinical data suggests or as otherwise anticipated;
the
potential for regulatory authorities to require additional pre-clinical work
or
other clinical requirements to support regulatory filings; the scope and
validity of patent protection for DAVANAT® and the Company’s other product
candidates; and other risks and uncertainties more fully described in the
Company’s news releases and periodic filings with the Securities and Exchange
Commission. The Company’s public filings with the Securities and Exchange
Commission are available at http://www.sec.gov.
You
are
cautioned not to place undue reliance on these forward-looking statements,
which
speak only as of the date when made. All forward-looking statements are
qualified in their entirety by this cautionary statement and the Company assumes
no obligation to revise or update any forward-looking statement, including
any
information included in the slides attached hereto as Exhibit 99.1, to reflect
events or circumstances arising after the date on which it was made. This
caution is made under the safe harbor provisions of Section 21E of the
Securities Exchange Act of 1934 (the “Exchange Act”) or otherwise subject to the
liabilities of that section, and it shall not be deemed incorporated by
reference in any filing under the Securities Act of 1933 or under the Exchange
Act, whether made before or after the date hereof, except as expressly set
forth
by specific reference in such filing to this Report.
Item 9.01
Financial Statements and Exhibits.
(d)
Exhibits.
The
list
of exhibits called for by this Item is incorporated by reference to the Index
to
Exhibits filed with this report.
SIGNATURES
Pursuant
to the requirements of the Securities Exchange Act of 1934, the registrant
has
duly caused this report to be signed on its behalf by the undersigned hereunto
duly authorized.
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PRO-PHARMACEUTICALS,
INC.
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By:
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/s/
Carl L. Lueders
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Carl
L. Lueders
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Chief
Financial Officer
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Date:
August 10, 2007
EXHIBIT
INDEX
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Exhibit
Number
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Exhibit
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99.1
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Pro-Pharmaceuticals
Presentation Slides - dated August 10,
2007
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Exhibit
99.1
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
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
the
safe harbor for such statements in the Private Securities Litigation Reform
Act
of 1995. Future events could cause actual results to differ materially from
those indicated by such statements. Reference is made to the factors discussed
in the “Management Discussion and Analysis" and "Risk Factors" sections of the
Company's most recent quarterly or annual report filed with the Securities
and
Exchange Commission. The forward-looking statements herein represent the
Company's views as of the date of this presentation and should not be relied
upon to represent the Company's views as of a subsequent date. While the
Company
anticipates that subsequent events may cause the Company's views to change,
the
Company disclaims any obligation to update such forwardlooking statements.
2
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-Clinical and Clinical
Studies Other Pro-Pharmaceuticals’ Compounds Regulatory
Pathway 3
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 management options Focuses
on major unmet medical needs Initial products will increase the
efficacy and reduce toxicity of chemotherapeutics Multi-billion
dollar market opportunity Utilizes the relatively streamlined
505(b)(2) regulatory process to seek FDA approval And, will be
brought to market by PRW working in alliance with strategic partners
4
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 chemotherapeutic drugs in animal & human
models Galactomannans have GRAS (generally recognized as safe) status
5
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 Stabilized 36% of
end stage colorectal cancer patients vs. 19% for Avastin Results from
ongoing Phase ll biliary/colorectal trials promising Hired a major
regulatory consulting firm to advise on regulatory filings Qualified
a manufacturing source with a major biopharmaceutical
partner Completed research agreements with two bio-pharmaceutical
companies Active discussions ongoing with potential commercial
partners 6
DAVANAT/5-FU
Commercial Opportunity 7
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 DAVANAT increased 5-FU exposure with no toxicity
increase Dosing biliary and colorectal cancer patients in Phase ll
front line trials: Biliary (8 patients dosed) 1 PR; 5
stabilized more than 5 cycles Colorectal (8 patients
dosed) 2 PR; 5 stabilized more than 7 cycles 8
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 diarrhea, abdominal cramping and leukopenia” Source: Dr.
George R. Bowers MD/Cooley Dickinson Hospital. CDH Oncology, November 2004,
Volume 8: No 11. 9
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 from ongoing Phase ll biliary and colorectal cancer trials; both
represent potential orphan drug status Scale-up production of
DAVANAT Actively pursue corporate partnerships for
commercialization Continue to complete research agreements with
biopharma companies for drugs with potential 505(b)(2)
submissions Avastin is a registered trademark of Genentech, Inc.
10
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 Colorectal Cancer
Completed PRO-NAC 050 11
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) Delivery of a Therapeutic Agent in a Formulation for
Reduced Toxicity U.S. Pat 6,914,055 (07/05/06) Delivery of
a Therapeutic Agent in a Formulation for Reduced Toxicity U.S. Pat
6,982,255 (01/03/06) Delivery of a Therapeutic Agent in a Formulation
for Reduced Toxicity U.S. Pat 7,012,068
(03/14/06) Co-administration of a Polysaccharide with a
Chemotherapeutic agent for the Treatment of Cancer Patents pending
for a variety of non-oncology indications 12
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, 505(b)(1), 505(b)(2) Submit additional
505(b)(2) applications DAVANAT/5-FU/Leucovorin
(LV) DAVANAT/5-FU/LV/Irinotecan DAVANAT/5-FU/LV/Avastin DAVANAT/5-FU/LV/Cisplatin DAVANAT/5-FU/LV/Oxaliplatin
Avastin is a registered trademark of Genentech, Inc. 13
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
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 Glycoscience technology.
National Prize in Science & Technology (Russia); Visiting Biochemistry Prof
at Harvard. Moscow State U Carl Lueders, MBA, CPA, Chief Financial
Officer 20+ years in finance & strategic planning at
Polaroid Maureen Foley, Chief Operating Officer 25+ years
in biotech, high-tech in operations management Eliezer Zomer, Ph.D.,
Exec. V.P., Clinical Development & Mfg Former Research Associate
at Harvard Medical Anthony Squeglia, MBA, V.P., Investor
Relations 20+ years in IR/PR David Donabedian, Ph.D., MBA,
Business Development (Consultant) 12+ years in life sciences
industry; VP, Bus Dev, Surface Logix; Accenture; Dow Chemical Bruce
Silver, M.D., Medical Director (Consultant) 20+ years in oncology
15
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
Appendices
17
Carbohydrate
Technology 18
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
bacteria Diverse biological roles structure, energy,
signaling, adhesion, protection Natural biological
sources Interact with lectins carbohydrate-specific
proteins involved in cell-cell and cell-matrix interactions
19
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; improves pharmacokinetics 20
Hypothesis:
CARBOSOME DAVANAT polymer exists as a “3D” structure in solution with
lectin targeting units protruding from the mannan backbone 21
Other
Technology Platforms: UCLT Enhances delivery to the target by
covalently binding a carbohydrate to the inactive side of the molecule
22
DAVANAT:
Pre-Clinical and Clinical Studies 23
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
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. control
25
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
mg/kg;
DAVANAT: 120 mg/kg; AVASTIN: 20-80 mg/kg) DAVANAT enhances effectiveness
of
AVASTIN & 5-FU 26
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 DAVANAT increased 5-FU exposure with no toxicity
increase Dosing biliary and colorectal cancer patients in Phase ll
front line trials: Biliary (8 patients dosed) 1 PR; 5
stabilized more than 5 cycles Colorectal (8 patients
dosed) 2 PR; 5 stabilized more than 7 cycles 27
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 a registered trademark
of
Genentech, Inc. Data compiled from PRW Phase l and Phase ll
colorectal cancer patients. 28
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
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 dose level (30-280 mg/m2); 5-FU constant at 500 mg/m2; dose for
4
consecutive days, observe for 24 days Patients: 40; 3-10 per cohort Completed:
March 2005 SD Stable Di sease PD Progressive Disease NM Non-Measurable Disease
Cycles Completed Dose, cycle 2 /m2 1+2 3 4 5 6 7 1001 PD 1002 SD 2001
Hepatocellular PD 2002 Hepatocellular SD 3001 PD 3002 SD 3004 PD 3003 PD
5001 SD
2004 SD 3005 PD 4001 PD 4002 Colorectal PD 3006 Prostate NM 2005 Colorectal
SD
5003 Colorectal (appendix) NM 5004 SD 4003 PD 2007 Spindle Cell PD 5005
Pancreatic SD 2008 Colorectal SD 2009 Colorectal SD 5006 Billiary SD 2010
Colorectal (cecal) SD 2014 Breast SD 2016 Hepatic PD 2018 Cholangiocarcinoma
SD
5008 Pancreatic PD 280 mg 150 mg Patient Number Tumor Type Outcome, end of
cycle
2 (RECIST) C Y C L E S Colorectal Colorectal 210 mg 30 mg 60 mg Colorectal
100
mg Colorectal Phase l Patient Summary: Stabilized 70% at Highest Dose Level
30
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
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
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
Not
related Not related Not related 05002 1 Perirectal abscess Not related 150
03006
1 Prostate cancer metastatic Death Not related Not related 210 03007 1 Ovarian
epithelial cancer stage IV Death Not related Not related 04003 2 Atrial flutter
Not related 33
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 Dyspnea Possibly related
02012 1 Dehydration Acute renal Failure Possibly related Not related 02013
1
Abdominal Pain Not related 02014 2 Pneumonia Arthritis Not related Not related
02015 1 Asthenia Not related 02017 1 Nausea Vomiting Diarrhea Not related
Not
related Not related 03008 1 Leukocytosis (grade 4) Thrombocytopenia (grade
3)
Abdominal Pain Oedema peripheral Probably related Probably related Not related
Not related 05007 1 Hyperbilirubinemia (grade 3) Not related
34
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 is 28-137
minutes No increase in 5-FU toxicity w/ increased
exposure Stable disease in 14 of 26 evaluable patients 7
of 10 patients stabilized at the highest DAVANAT dose level
35
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: DAVANAT 280 mg/m2; 5-FU 500
mg/m2; dose for 4 consecutive days, observe for 24 days. Patients: Began
dosing
in May 2005. Six sites. Study finalized in August 2006. Results (un-audited):
20
patients: 1 Partial Response (RECIST) 6 Stable Disease. 36
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
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 at
6 and
12 months. Design: Multi-center, open label study. Evaluate for six months
or to
disease progression or toxicity. Regimen: Leucovorin, DAVANAT /5-FU, AVASTIN.
IV
Dose for 3 consecutive days. Repeat cycles disease progression or unacceptable
toxicity. Patients: Up to 50. 8 patients dosed: 2 partial response; 5
stabilized. 38
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
cycles
or to disease progression. Repeat cycles until disease progression. Patients:
Up
to 42. 8 patients dosed: 1 partial response; 5 stabilized. 39
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: Identify Max
Tolerated Dose Test other chemotherapeutics in Phase I trials with
DAVANAT 40
Other
Pro-Pharmaceuticals Compounds 41
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 fibrosis and liver
failure PRO-GR 300, first in class, carbohydrate compound in
combination with other drugs to treat fibrosis Research collaboration
w Dr. Scott Freidman, Division Director of Liver Diseases of Mt. Sinai School
of
Medicine to evaluate the antifibrotic effects of carbohydrate
compounds Pre-clinical studies currently underway results
August 2007 42
Regulatory
Pathway: 505(b)(2) 43
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
literature or in approved NDAs for the RLD) 505(j): For generic drugs
that are the same as the established drug (the “Reference Listed Drug” [RLD])
44
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
studies would… slow the process for drug approval with no corresponding benefit
to the public health.” 45
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,
without
the 505(b)(2) pathway.” 46
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
pigmentation In 2000, Pro-Pharmaceuticals embarked on developing a
more effective, less toxic 5-FU by combining it with
DAVANAT Pre-clinical studies subsequently demonstrated that DAVANAT
significantly improved the pharmacodynamic impact of 5-FU Less
toxicity due to “targeted delivery” Higher intra-tumoral 5-FU
concentration Higher efficacy in multiple tumor types
47
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 approval 48
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 been shown
to be
safe and non-toxic In clinical trials, there is no increase in 5-FU toxicity
w/
increased exposure of 5-FU w/ DAVANAT In preclinical studies, DAVANAT/5-FU
has
greater anti-tumor activity than 5-FU alone Galactomannans already approved
by
FDA (GRAS) NDA DAVANAT will be marketed as a ‘stand-alone’ vial- not as a
combination product 49