CONSULTING AGREEMENT
EXHIBIT 10.21
This CONSULTING AGREEMENT (the "Agreement") is made by and between
Pharm-Olam International Ltd., a Texas limited partnership with an address of
000 Xxxxx Xxx Xxxxxxx Xxxx., Xxxxx 000, Xxxxxxx, XX 00000 ("Consultant"), and
Advaxis, Inc., with an address of 000 Xxxxxxxx Xxxxxx, Xxxxx 000, Xxxxxxxxx, Xxx
Xxxxxx 00000 ("Advaxis") and is effective as of January 15, 2005 ("Effective
Date").
RECITALS
A. Consultant, a contract research organization, possesses special expertise
and knowledge in the field of pre-clinical, clinical and regulatory
affairs; and
B. Advaxis, a biotechnology company commercializing novel vaccines, has need
for Consultant's pre-clinical consultant services; and
C. Advaxis and Consultant now desire to enter into this Agreement whereby
Consultant shall perform consulting services for Advaxis on the terms and
conditions set forth below.
AGREEMENT
NOW, THEREFORE, Consultant and Advaxis agree as follows:
1. Description of Services. Subject to the terms and conditions of this
Agreement, Consultant shall perform management of pre-clinical toxicology
studies as defined in Attachment 1 and by cost in Attachment 2. Timelines
for pre-clinical toxicology studies milestone payment schedule are
outlined in Attachment 3
2. Term and Renewal. This Agreement shall be effective as of the Effective
Date and shall remain in effect for a period of Twelve (12) months unless
terminated pursuant to this Agreement. This Agreement may only be renewed
for additional periods on terms mutually agreed upon in writing by the
parties. Neither party shall have any obligation to renew this Agreement.
However, the expiration of this Agreement shall not effect the obligations
of Consultant to complete the services agreed upon in this Agreement.
3. Fees.
a) For return of services as outlined in Attachment 1 and 2, Advaxis
will make milestone payments according to payment chart in
Attachment 3. The cost for project management, animal studies and
DNA assays as outlined in Attachment 2 is $272,163, two hundred
seventy two one hundred sixty three dollars.
b) Advaxis shall also reimburse Consultant for all reasonable and
necessary out-of-scope expenses actually incurred by Consultant in
rendering services under this Agreement. In case of meetings, such
expenses will include reasonable and necessary travel, lodging and
meals. Consultant shall provide Advaxis with a written expense
report, complete with receipts or other reasonable documentation,
for all such expenses requested for reimbursement. Any expense item
greater than $200 shall require Advaxis' prior written or email
approval.
4. Invoices. Milestone payments due hereunder shall be payable upon Advaxis's
receipt ("Due Date") of a written invoice or an expense report and
accompanying supporting documentation therefore. Any amounts which remain
unpaid for thirty (30) days or more after the Due Date shall bear interest
at the rate equal to 8%. Interest shall be computed on the basis of 12
months of 30 days each per year, as the case may be, subject to the
provisions hereof limiting interest to the maximum rate of interest
allowed by applicable law.
5. Confidentiality; Proprietary Information; Intellectual Property.
a) Any and all information which Advaxis or its affiliates may disclose
to Consultant under this Agreement will be considered confidential.
b) Consultant further agrees that all discussions and negotiations with
respect to this Agreement are confidential.
c) Consultant understands that Advaxis possesses and will continue to
possess information that has been created, discovered or developed,
or has otherwise become known to Advaxis or its affiliates and/or in
which property rights have been assigned or otherwise conveyed to
Advaxis or its affiliates, which information has commercial value in
the business in which Advaxis is engaged. All such information,
including the information described in Sections 5 (a) and (b) above,
and including any other information developed by or on behalf of
Consultant pursuant to this Agreement, is hereinafter referred to as
"Proprietary Information." By way of illustration, but not
limitation, Proprietary Information includes trade secrets,
processes, formulae, data and know-how, improvements, inventions,
techniques, marketing plans, strategies, forecasts and customer and
contact lists. Accordingly, Consultant further agrees as follows:
i) All Proprietary Information shall be the sole property
of Advaxis or its affiliates and their assigns, as the
case may be, and such parties shall be the sole owners
of all patents and other rights in connection therewith.
At all times during this Agreement and at all times
after expiration or termination of this Agreement,
Consultant will keep in confidence and trust all
Proprietary Information, and will not use or disclose
any Proprietary Information without the prior written
consent of Advaxis, except as may be necessary in the
ordinary course of performing the duties of Consultant
hereunder. No announcement, oral presentation or
publication of any kind relating to any Proprietary
Information shall be made by Consultant without the
prior written consent of Advaxis; and
ii) All documents, data, records, apparatus, equipment and
other physical property, whether or not pertaining to
Proprietary Information, furnished to Consultant by or
on behalf of Advaxis or developed by or on behalf of
Consultant pursuant to this Agreement, shall be and
remain the sole property of Advaxis and/or its
affiliates and shall be returned promptly as and when
requested by Advaxis. Should Advaxis not so request,
Consultant agrees to return and deliver all such
property upon expiration or termination of this
Agreement for any reason and Consultant shall not retain
or reproduce any such property upon expiration or
termination.
iii) Consultant shall promptly disclose to Advaxis or its
designee all intellectual property (including, but not
limited to any inventions, improvements, formulae,
processes, techniques, know-how, data, patents or
applications for patents, trade secrets, trademarks,
copyrights and confidential information as described in
this Section 5), made or conceived or reduced to
practice or learned by Consultant (collectively,
"Intellectual Property") which (A) result from the tasks
assigned to Consultant hereunder; (B) are funded by or
on behalf of Advaxis or its affiliates; or (C) result
from the use or property or premises owned, leased or
contracted for by or on behalf of Advaxis or its
affiliates.
iv) Consultant agrees to and does hereby sell, assign,
transfer and set over to Advaxis, its affiliates,
successors or assigns, as the case may be, all right,
title and interest in and to all Intellectual Property
developed or conceived individually or in conjunction
with others in performance of this Agreement, to be held
and enjoyed by Advaxis, its affiliates, successor or
assigns, as the case may be, to the full extent of the
term for which any Letters Patent may be granted and as
fully as the Intellectual Property would have been held
by Consultant had this Agreement, sale or assignment not
be made.
v) Consultant shall execute and deliver any and all
instruments and documents and perform any and all acts,
necessary to obtain, maintain or enforce patents,
trademarks, trade secrets and copyrights for such
Intellectual Property, and shall make, execute and
deliver any and all instruments and documents and
perform any and all acts necessary to obtain, maintain
or enforce patents, trademarks, trade secrets and
copyrights for such Intellectual Property as Advaxis may
designate in any and all countries. All costs and
expenses of application and prosecution of such patents,
trademarks, trade secrets and copyrights shall be paid
by Advaxis.
vi) Any copyrightable material prepared by Consultant as a
result of Consultant's activities with Advaxis, in
performance of this Agreement, are prepared as works for
hire for the benefit of Advaxis. Consultant hereby
assigns to Advaxis any copyright to which Consultant is
entitled for any copyrightable material prepared in the
course of the performance of this Agreement for Advaxis.
Advaxis shall have the right to reproduce, modify and
use such material and all results generated as the
result of services rendered under this Agreement for any
propose related to its lawful business.
vii) Upon the written request of Advaxis, Consultant shall
make any assignment provided for in this Section 5
directly to, or for the benefit of, an Advaxis affiliate
or Advaxis's designee, including Consultant's
performance of any related obligations hereunder.
6. Remedies. (a) Consultant acknowledges that Advaxis will have no adequate
remedy at law if Consultant breaches the terms of Section 5 hereof.
Accordingly, in such event, Advaxis shall have the right, in addition to
any other rights it may have at law or equity, to obtain in any tribunal
of competent jurisdiction injunctive relief to restrain any breach or
threatened breach. (b) If, due to reasons within Consultant's reasonable
control, Consultant's products or services fail to meet standards
generally accepted in the applicable industry, or if Consultant fails to
provide agreed-upon products or services in a timely manner Advaxis shall
have the right, in addition to any other remedy it may have at law or
equity, to: (i) terminate this Agreement immediately upon written notice
to Consultant; (ii) require that defective products or services be
replaced or remedied, as the case may be, without charge to Advaxis; and
(iii) correct, or have corrected by a third party, the defective product
or service and withhold from amounts owing to Consultant hereunder all
amounts incurred by Advaxis in taking such corrective measures.
7. Termination. This Agreement may be terminated (a) by Advaxis with or
without cause upon thirty (30) day's prior written notice to Consultant,
or (b) by Consultant in the event of a material breach by Advaxis,
provided that Consultant provides Advaxis with written notice of such
breach and Advaxis fails reasonably to cure such breach within thirty (30)
days of receipt of such notice.
In the event this Agreement is terminated pursuant to this Section prior
to completion of the work to be performed, Consultant shall cease work
upon Advaxis's request, and shall be entitled to receive its fee for work
actually and reasonably performed through the effective date of
termination. In addition, Consultant shall promptly return to Advaxis all
written materials and biological material provided to Consultant by
Advaxis or its partners or affiliates.
The provisions of Sections 5-6 and 9-14, inclusive, shall survive
expiration or termination of this Agreement.
8. Independent Contractor. Consultant shall be an independent contractor and
shall have no authority to enter into contracts on behalf of Advaxis, bind
Advaxis to any third parties or act as an agent on behalf of Advaxis in
any way. Consultant shall account for and report the payment of all
applicable federal and state income taxes, social security taxes, and all
other taxes due on payments received by Consultant hereunder. Consultant
hereby acknowledges than Advaxis will report as compensation all payments
to Consultant hereunder.
9. Consultant's Representation and Warranties. Consultant hereby represents
and warrants to Advaxis that (a) Consultant has the authority to enter
into and perform this Agreement and (b) performance of Consultant's
services as contemplated by this Agreement will not result in the breach
or violation of any contract, arrangement or understanding (including
without limitation any intellectual property rights or any agreement of
confidentiality or non-disclosure, whether written or oral) which
Consultant may have with any third party (including with limitation
current and former employers of Consultant and any other companies or
persons for which Consultant has performed or is performing consulting
services).
10. Compliance Standards. During the term of this Agreement and any renewal
term, Consultant shall comply with all applicable laws, rules and
regulations in the conduct of the services being performed.
11. Severability. If any provision of this Agreement is declared void or
unenforceable, such provision shall be deemed modified to the extent
necessary to allow enforcement, and all other portions of this Agreement
shall remain in full force and effect.
12. Entire Agreement, Amendments. This Agreement contains the entire and
complete agreement between the parties with respect to the subject matter
hereof, and supersedes all prior oral and/or written agreements with
respect to the subject matter hereof, other than any currently effective
confidentiality agreement. Any changes to this Agreement must be in
writing and signed by both parties. The Parties acknowledge that the
confidentiality agreement previously executed beween the parties remain in
full force and effect.
13. Successors. This Agreement shall be binding upon and inure to the benefit
of the successors, assigns and legal representatives of the parties.
14. Governing Law. This Agreement shall be governed by and construed in
accordance with the laws of the State of New Jersey without regard to its
conflicts of laws provisions, and the parties agree to personal
jurisdiction and venue in the state and federal courts of New Jersey, in
any suit or proceeding arising out of the subject matter of this
Agreement.
DATED as of the Effective Date written above, and executed by:
ADVAXIS, INC.:
By: /s/ J. Xxxx Xxxxxx
-------------------------
Name: J. Xxxx Xxxxxx
Title: CEO
PHARM-OLAM INTERNATIONAL LTD.:
By:___________________________
Name:
Title:
ATTACHMENT 1
FOUR WEEK TOXICOLOGY STUDY OF LM-LLO-E7 VECTOR IN MICE
PURPOSE: To examine the toxicity of Advaxis' Lm-LLO-E7 Vector following four
weekly i.v. or s.c. doses to female Balb/C mice.
SCOPE: 10 mice/group
70 FEMALE MICE TOTAL
REGULATORY STATUS: GLP
TEST ARTICLE: Lm-LLO-E7
CONTROL ARTICLES: Control Buffer
ROUTES OF ADMINISTRATION: i.v./s.c.
OVERALL DESIGN:
Wild-Type female Balb/C mice will be administered a single intravenous or
subcutaneous injection of Lm-LLO-E7 Vector or control saline once weekly for
four weeks on Study Days 1, 8, 15 and 22 as described in the table below.
===========================================================================================================
FOUR WEEK TOXICOLOGY STUDY OF LM-LLO-E7 IN FEMALE MICE
-----------------------------------------------------------------------------------------------------------
Group Treatment Dose Level Route Dosing Days Females
============ ======================= ====================== ========== ==================== ===============
1 Saline 0 i.v. 1,8,15, 22 10
------------ ----------------------- ---------------------- ---------- -------------------- ---------------
2 Lm-LLO-E7 Low i.v. 1,8,15, 22 10
------------ ----------------------- ---------------------- ---------- -------------------- ---------------
3 Lm-LLO-E7 Mid i.v. 1,8,15, 22 10
------------ ----------------------- ---------------------- ---------- -------------------- ---------------
4 Lm-LLO-E7 High i.v. 1,8,15, 22 10
============ ======================= ====================== ========== ==================== ===============
5 Lm-LLO-E7 Low s.c. 1,8,15, 22 10
------------ ----------------------- ---------------------- ---------- -------------------- ---------------
6 Lm-LLO-E7 Mid s.c. 1,8,15, 22 10
------------ ----------------------- ---------------------- ---------- -------------------- ---------------
7 Lm-LLO-E7 High s.c. 1,8,15, 22 10
============ ======================= ====================== ========== ==================== ===============
IN-LIFE PROCEDURES:
o CLINICAL OBSERVATIONS: Twice Daily cageside observation for signs of
mortality, moribundity and/or toxicity.
o PHYSICAL EXAMS, BODY WEIGHTS AND FOOD CONSUMPTION: At randomization, prior
to treatment on SD1 and weekly thereafter.
TERMINAL PROCEDURES:
Twenty-four hours following the final dose:
o Blood samples are obtained from all surviving mice for clinical pathology
and hematological analysis. (5 animals for hematology, 5 for clinical
chemistry per group)
o Body weights
o Necropsy:
Full gross necropsy on all main study mice, and will include examination of
external surface of body, all orifices, and cranial, thoracic and abdominal
cavities and their contents. The following tissues will be obtained at necropsy
and preserved in neutral buffered formalin:
---------------------- -------------- ----------- ---------------- --------------- -------------- ---------- ---------------
Adrenals Aorta Bone Brain Cecum Colon Cervix Duodenum
---------------------- -------------- ----------- ---------------- --------------- -------------- ---------- ---------------
epididymides Esophagus Eyes Femur Gallbladder Heart Ileum Jejunum
---------------------- -------------- ----------- ---------------- --------------- -------------- ---------- ---------------
Kidneys Liver Lungs Lymph nodes Salivary gl Mammary Gl Optic Ovaries
nerves
---------------------- -------------- ----------- ---------------- --------------- -------------- ---------- ---------------
Pancreas Pituitary Gross Sciatic Nerve Skin Spinal cord Spleen Stomach
Lesions
---------------------- -------------- ----------- ---------------- --------------- -------------- ---------- ---------------
Administration Site Thymus Thyroid Parathyroid Trachea Skeletal Vagina Uterus
Muscle
---------------------- -------------- ----------- ---------------- --------------- -------------- ---------- ---------------
All Tissues from control and high dose treated animals will be embedded in
paraffin, stained with hematoxylin and eosin, and examined microscopically by a
board certified veterinary pathologist. Tissues from the mid and low dose group
will be retained and evaluated only if findings were noted in corresponding
tissues from high dose treated animals.
TEST ARTICLE DOSAGE VERIFICATION:
INFORMATION TO BE SUPPLIED BY THE SPONSOR. (REQUIRED FOR GLP STUDY)
ACUTE DOSE TOXICITY STUDY OF LM-LLO-E7 IN BALB/C MICE
PURPOSE:
o To determine the Maximum Tolerated Dose (MTD) of Lm-LLO-E7 Vector via both
s.c. and i.v. routes to female Balb/C
o To compare the tolerability of Balb/C mice to Lm-LLO-E7 relative to WT
Listeria
RATIONALE:
o 24 Female mice for Dose Range phase.
o Only females will be used since the indication for Lm-LLO-E7 is Cervical
Cancer
o No difference is anticipated between sexes
o Balb/c mice will be used since they are more sensitive to Listeria than
C57BL/6 Mice.
o LD50 for Lm-LLO-E7 in Balb/c mice is reported to be ~108 pfu via ip route.
o Sensitivity to i.v. route of administration should be greater.
o Dose levels will be adjusted based on results of initial determinations
from groups 3 and 6 below.
STUDY DESCRIPTION:
Test Article: Lm-LLO-E7 Listeria Monocytogenes Bacterial Vector
Control Article: WT Listeria Monocytogenes Vector
ROUTE OF ADMINISTRATION: Intravenous or subcutaneous (as indicated)
A. DOSE RANGE FINDING TOXICITY PHASE:
==========================================================================================================
ACUTE DOSE RANGE FINDING TOXICITY STUDY OF LM-LLO-E7 VECTOR IN BALB/C MICE
------------ ---------------------------- ------------------------ -------------- ------------------------
GROUP TREATMENT DOSE LEVEL ROUTE NUMBER OF FEMALES
(PFU)
------------ ---------------------------- ------------------------ -------------- ------------------------
1 WT Listeria MTD i.v. 3
------------ ---------------------------- ------------------------ -------------- ------------------------
2 WT Listeria MTD s.c. 3
============ ============================ ======================== ============== ========================
3 Lm-LLO-E7 106 i.v. 3
------------ ---------------------------- ------------------------ -------------- ------------------------
4 Lm-LLO-E7 107* i.v. 3
------------ ---------------------------- ------------------------ -------------- ------------------------
5 Lm-LLO-E7 108* i.v. 3
------------ ---------------------------- ------------------------ -------------- ------------------------
6 Lm-LLO-E7 106 s.c. 3
------------ ---------------------------- ------------------------ -------------- ------------------------
7 Lm-LLO-E7 107* s.c. 3
------------ ---------------------------- ------------------------ -------------- ------------------------
8 Lm-LLO-E7 108* s.c. 3
============ ============================ ======================== ============== ========================
*Based on results of dosing groups 3 and 6 mice.
o Groups 1-2 female Balb/c mice will receive a single i.v. or s.c. dose of
WT Listeria on study Day 1 and will be monitored for signs of toxicity.
This dose will be based on published data on the known toxicity of WT
listeria.
o Mice in groups 3-5 will be dosed i.v. with increasing doses of LmLLO-E7
starting at 106 pfu. If this dose is well tolerated, a higher dose will be
administered until a MTD is established.
o Mice in groups of 6-8 will be dosed s.c. with increasing doses of LmLLO-E7
starting at 106 pfu. If this dose is well tolerated, a higher dose will be
administered until a MTD is established.
B. MAIN PHASE ACUTE TOXICITY STUDY
Groups of 5 female mice will be dosed once on Study Day 1 as described in the
table below. Mice will be administered a single i.v. or s.c. injection of the
Lm-LLO-E7 Vector or WT Listeria (Groups 1-2) on Study Day 1.
Mice will be observed for clinical signs and changes in body weight and food
consumption during the next 14 days. Surviving mice will be sacrificed on Study
day 15, and gross necropsies will be performed.
==========================================================================================================
ACUTE DOSE IV AND SC TOXICITY STUDY OF LM-LLO-E7 VECTOR IN BALB/C MICE
----------------------------------------------------------------------------------------------------------
GROUP TREATMENT DOSE LEVEL ROUTE NUMBER OF FEMALES
(PFU)
------------ ---------------------------- ------------------------ -------------- ------------------------
1 WT Listeria MTD (sub LD50) i.v. 5
------------ ---------------------------- ------------------------ -------------- ------------------------
2 WT Listeria MTD (sub LD50) s.c. 5
============ ============================ ======================== ============== ========================
3 Lm-LLO-E7 106 i.v. 5
------------ ---------------------------- ------------------------ -------------- ------------------------
4 Lm-LLO-E7 107* i.v. 5
------------ ---------------------------- ------------------------ -------------- ------------------------
5 Lm-LLO-E7 108* i.v. 5
============ ============================ ======================== ============== ========================
6 Lm-LLO-E7 106 s.c. 5
------------ ---------------------------- ------------------------ -------------- ------------------------
7 Lm-LLO-E7 107* s.c. 5
------------ ---------------------------- ------------------------ -------------- ------------------------
8 Lm-LLO-E7 108* s.c. 5
============ ============================ ======================== ============== ========================
o Mice will be dosed once as described in the table above either i.v. or
s.c., and will be monitored for clinical signs of toxicity.
o Other assessments will include weekly body weights and food consumption.
o Surviving mice will be weighed and sacrificed on SD 15. Gross necropsies
only. Only gross lesions to be retained.
PILOT BIODISTRIBUTION STUDY OF LM-LLO-E7 IN FEMALE MICE
PURPOSE: The purpose of this pilot study is to determine the biodistribution of
Lm-LLO-E7 vector following a single i.v. administration to female Balb/c mice,
and to optimize conditions for PCR detection of Lm-LL0-E7 following i.v.
administration in mice.
=============================================================================================================
PILOT BIODISTRIBUTION OF LM-LLO-E7 VECTOR IN FEMALE MICE
-------------------------------------------------------------------------------------------------------------
GROUP TREATMENT DOSE LEVEL ROUTE OF FEMALES SCHEDULED SACRIFICES
ADMINISTRATION (3 PER TIMEPOINT)
============ ===================== ============== ===================== ============== ======================
1 Buffer Control 0 Intravenous 4 SD2
------------ --------------------- -------------- --------------------- -------------- ----------------------
2 Lm-LLO-E7 Vector 108 CFU or Xxxxxxxxxxx 00 XX 0, 00, 00
XXX
============ ===================== ============== ===================== ============== ======================
CLINICAL OBSERVATIONS: Twice daily cageside observation for signs of mortality,
moribundity and/or toxicity
PHYSICAL EXAMS: At randomization, prior to treatment on SD1 and weekly
thereafter.
BODY WEIGHTS: At randomization, prior to treatment on SD1 and weekly thereafter.
TERMINAL PROCEDURES: On study day 2, three mice from groups 1 and 2 will be
weighed, bled, and sacrificed by CO2 asphyxiation. Blood samples and tissue
samples will be obtained and will be analyzed for presence of exogenous Test
article DNA using PCR with primers specific for the vector and/or targeted gene.
On study days 10 and 30 respectively, three mice per day from group 2 will be
weighed, bled and sacrificed and blood and tissue samples obtained and analyzed
for exogenous Test article DNA.
o Gross necropsies will be performed only to obtain Tissues for PCR
analysis.
o A portion of the following tissues will be collected using clean sterile
instruments (clean sterile set for each individual animal) and placed in
vials and frozen at -80(Degree)C:
Injection Site Spleen Small Intestine
Ovaries Lymph node (1) Lung
Heart Brain Bone Marrow
Kidney Liver Blood
PCR ANALYSIS: PCR analysis will be performed on the tissues using primers
specific for genetic sequences of the Listeria monocytogenes vector.
TEST ARTICLE DOSAGE VERIFICATION: Information to be supplied by the sponsor.
BIODISTRIBUTION OF LM-LLO-E7 VECTOR IN MICE
PURPOSE: To examine the biodistribution of Lm-LLO-E7 Vector following a single
intravenous or s.c. injection to female Balb/C mice.
SCOPE: 96 Female Mice
REGULATORY STATUS: GLP
TEST ARTICLE: Lm-LLO-E7
CONTROL ARTICLES: Control Buffer
ROUTES OF ADMINISTRATION: Intravenous and Subcutaneous
PURPOSE: To compare overall biodistribution following either i.v. or s.c.
administration of Lm-LLO-E7.
OVERALL DESIGN: Wild-Type female Balb/c mice will be administered a single
intravenous or s.c. injection of Lm-LLO-E7 Vector or control saline on Study Day
1 (SD 1) as described in the table below. Six mice per timepoint will be dosed,
but only five per timepoint will be sacrificed for PCR analysis.
=============================================================================================================
BIODISTRIBUTION OF LM-LLO-E7 LISTERIA VECTOR IN FEMALE MICE
-------------------------------------------------------------------------------------------------------------
Group Treatment Dose Level Route Dose Volume Females
(mL/kg)
============ =================== ================= =================== ================ =====================
1 Saline 0 i.v. 10 24
------------ ------------------- ----------------- ------------------- ---------------- ---------------------
2 Lm-LLO-E7 Low i.v. 10 24
Vector
------------ ------------------- ----------------- ------------------- ---------------- ---------------------
3 Lm-LLO-E7 High i.v. 10 24
Vector
------------ ------------------- ----------------- ------------------- ---------------- ---------------------
4 Lm-LLO-E7 High S.C. 10 24
Vector
============ =================== ================= =================== ================ =====================
CLINICAL OBSERVATIONS: Twice Daily cageside observation for signs of mortality,
moribundity and/or toxicity
PHYSICAL EXAMS: At randomization, prior to treatment on SD1 and weekly
thereafter.
BODY WEIGHTS: At randomization, prior to treatment on SD1 and weekly thereafter.
TERMINAL PROCEDURES: On study days 2, 10 and 30 and 90, five mice per group will
be weighed, bled, and sacrificed by CO2 asphyxiation.
Blood samples will be analyzed for presence of exogenous Test article DNA using
PCR with primers specific for the vector and target gene.
Gross necropsies will be performed only to obtain Tissues for PCR analysis.
A portion of the following tissues will be collected using clean sterile
instruments (clean sterile set for each individual animal) and placed in small
microcentrifuge vials and frozen at -80(Degree)C:
Injection Site Spleen Blood
Ovaries Mesentary lymph node Lung
Heart Brain Bone Marrow
Kidney Liver Small Intestine
PCR ANALYSIS: Quantitative PCR will be performed on DNA extracted from above
tissue samples and the presence of the vector sequence will be assessed.
TEST ARTICLE DOSAGE VERIFICATION: INFORMATION TO BE SUPPLIED BY THE SPONSOR.
(REQUIRED FOR GLP STUDY)
ATTACHMENT 2
PRE-CLINICAL TOXICOLOGY STUDIES LM-LLO-E7
---------------------------------------------------------------------------------------- --------------------
TASK COST
---------------------------------------------------------------------------------------- --------------------
Acute Dose Toxicity and Main Phase
Includes dose range finding to find MTD (24 mice) and main phase acute toxicity (40
mice), assessments of weekly body weights and food consumption, and gross pathology
with necropsy at 15 days, final clinical and GLP reports. $10,632
---------------------------------------------------------------------------------------- --------------------
FOUR WEEK TOXICITY STUDY
Includes four weekly vaccinations given to 70 mice, sacrifice at 28 days, chemistry
and hematology labs. on 50% of mice, gross pathology, final clinical and GLP reports. $31,500
Histology and pathology of 40 tissues per mouse in control and high dose groups (30
mice) by certified veterinary pathologist with histo-pathology report ($25.00 per $30,000
tissue)
---------------------------------------------------------------------------------------- --------------------
PILOT BIODISTRIBUTION STUDY
Includes 16 mice dosed with 12 serial sacrificed out to 30 days, blood and 11 tissues
per mouse collected for PCR analysis of vector and targeted gene, clinical and GLP $13,000
reports.
---------------------------------------------------------------------------------------- --------------------
BIODISTRIBUTION STUDY
Includes 96 mice dosed with 80 serial sacrificed out to 90 days, daily clinical
observations, weekly physical exams and body weights, blood and 11 tissues taken
for $31,700 PCR analysis of vector and targeted gene, clinical and GLP reports.
---------------------------------------------------------------------------------------- --------------------
PCR ANALYSIS
Lark will analyze 11 tissues and one blood from 3 groups of mice (12, 60 and 20)
using a targeted assay. Lark will also perform spiking experiments on all
samples and extraction efficiency tests. The reactions will be thermal cycled,
recorded and analyzed using the ABI PRISM 7700 Sequence Detection System. All
work will be $135,831 conducted under Good Laboratory Practices.
---------------------------------------------------------------------------------------- --------------------
PROJECT MANAGEMENT
Pharm-Olam will management all the studies to assure conducted to Good Laboratory
Practices and compliant with the protocol, monitor studies at critical points, weekly
sponsor updates, oversee development of all protocols and clinical reports and $19,500
maintain study timelines. (130 hours @ $150/hr)
---------------------------------------------------------------------------------------- --------------------
TOTAL $272,163
---------------------------------------------------------------------------------------- --------------------
If the histo-pathology is needed for the medium and low dose (40 mice) in the 4
week study, the cost will be another $40,000.
ATTACHMENT 3
TIMELINES FOR PRE-CLINICAL TOXICOLOGY STUDIES
February 1 - initiate acute dose toxicity study
March 1 - initiate main phase acute dose toxicity study
March 1 - initiate pilot bio-distribution study
April 1 - initiate 4 week multi-dose study
May 1 - initiate 90 day bio-distribution study
September 1- Final reports completed for all studies
MILESTONE PAYMENT CHART
--------------------------------------------------------------------------------
Milestones Percent Cost
--------------------------------------------------------------------------------
Signing of agreement 10% $27,216.30
--------------------------------------------------------------------------------
Initiation of pilot acute toxicity 10% $27,216.30
--------------------------------------------------------------------------------
Initiation of pilot-distribution & 4 main phase studies 20% $54,432.60
--------------------------------------------------------------------------------
Initiation of 4 week multi-dose study 20% $54,432.60
--------------------------------------------------------------------------------
Initiation of 90 day bio-distribution study 20% $54,432.60
--------------------------------------------------------------------------------
Final reports completed for all studies 20% $54,432.60
--------------------------------------------------------------------------------
Total $272,163
--------------------------------------------------------------------------------
