AMENDMENT NO. 4
 
TO
SPONSORED RESEARCH COLLABORATION AGREEMENT

This Amendment No. 4 to Sponsored Research Collaboration Agreement (“Amendment
No. 4”) is entered into and effective as of October 24, 2011, by and between
University Health Network, an Ontario corporation incorporated under the Toronto
Hospital Act 1997, having a principal research office at 610 University Avenue,
Suite 7-504, Toronto, Ontario, Canada MSG 2M9 (“UHN”), and VistaGen
Therapeutics, Inc., a Nevada corporation having its principal address at 384
Oyster Point Blvd., Suite 8, South San Francisco, California 94080 (“VistaGen”).
 
R E C I T A L S
 
WHEREAS, VistaGen and UHN entered into that certain Sponsored Research
Collaboration Agreement, dated September 18, 2007 (as amended, the “Agreement”),
pursuant to which VistaGen is funding stem cell research and development Project
One (as defined in the Agreement) and has the option to fund additional research
and development projects (as defined in the Agreement, as amended, the
“Options”) involving pluripotent stem cell technologies, with each such research
project principally performed or to be principally performed by or under the
direction of Gordon Keller, Ph.D. (“Dr. Keller”), Director of the McEwen Center
for Regenerative Medicine (the “McEwen Centre”), a stem cell research center
within UHN;
 
WHEREAS, VistaGen and UHN acknowledge and agree that (i) VistaGen has made
substantial sponsored research payments to UHN prior to the effective date of
the Amendment No. 4 and (ii) such prior sponsored research payments have served
to exercise the Options and certain Future Project Options with respect to the
Sponsored Research Projects (as defined below), VistaGen and UHN now desire to
enter into this Amendment No. 4 to further set forth (A) the sponsored research
projects currently being funded, and, for at least the next twelve (12) months,
to continue to be funded, by VistaGen under the Agreement (the “Sponsored
Research Projects”), (B) the budget for each Sponsored Research Project, as
agreed to by the parties, for the twelve (12) month period following the
effective date of this Amendment No. 4 (collectively, the “Sponsored Research
Project Budgets”) and (C) the schedule of  payments to be made by VistaGen to
UHN pursuant to the Agreement with respect to the Sponsored Research Project
Budgets; and
 
WHEREAS, Section 8.7 of the Agreement provides that the Agreement may be amended
only with the written consent of VistaGen and UHN.
 
NOW, THEREFORE, for good and valuable consideration, receipt of which is hereby
acknowledged, VistaGen and UHN hereby agree to amend the Agreement as follows:
 
AM E N D M E N T
 
1. Definitions.  Except as otherwise provided herein, capitalized terms used in
this Amendment shall have the definitions set forth in the Agreement, as
amended.
 
2.           Amendment to Exhibits B-1 to B-5 to Amendment No. 3 to the
Agreement.  Exhibit B-1, Exhibit B-2, Exhibit B-3, Exhibit B-4, and Exhibit B-5
to the Agreement, as amended in Amendment No. 3 thereto, shall be deleted in
their entirety and amended to read in their entirety as Exhibit B-1, Exhibit
B-2, Exhibit B-3, Exhibit B-4 and Exhibit B-5 attached to this Amendment No. 4.
 
3.           Amendment to Exhibit D to Amendment No. 3 to the
Agreement.  Exhibit D to this Amendment No. 4 is the schedule of sponsored
research payments to be made by VistaGen to UHN with respect to the Sponsored
Research Project Budgets during the twelve (12) month period beginning on the
effective date of this Amendment No. 4 and ending on September 15,
2012.  Accordingly, Exhibit D to Amendment No. 3 to the Agreement shall be
deleted in its entirety and amended to read in its entirety as Exhibit D to this
Amendment No. 4.  The parties acknowledge and agree that such sponsored research
funds shall be used solely for research and development activities for the
benefit of VistaGen pursuant to the Agreement and under the direction of Dr.
Keller, unless VistaGen shall agree otherwise in writing.
 

 
 

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4.           Future Sponsored Research Project Budgets.  VistaGen anticipates
providing additional sponsored research funding to UHN during the twelve (12)
month period from October 15, 2012 to September 15, 2013.  The parties hereby
agree to use reasonable efforts to meet, by teleconference and/or in person,
before June 2012 to discuss and determine the specific projects to which
VistaGen’s sponsored research funds for such period shall be applied.  The
parties acknowledge and agree that such sponsored research funds shall be used
solely for research and development activities for the benefit of VistaGen
pursuant to the Agreement and under the direction of Dr. Keller, unless VistaGen
shall agree otherwise in writing.
 
5.           Terms of Agreement.  Except as expressly modified hereby, all
terms, conditions and provisions of the Agreement shall continue in full force
and effect.
 
6.           Conflicting Terms.  In the event of any inconsistency or conflict
between the Agreement and this Amendment, the terms, conditions and provisions
of this Amendment No. 4 shall govern and control.
 
7.           Entire Agreement.  The Agreement, as amended by Amendment No. 1,
Amendment No. 2, Amendment No. 3 and this Amendment No. 4 (collectively, the
“Amendments”), constitute the entire and exclusive agreement between the parties
with respect to the subject matter hereof.  All previous discussions and
agreements with respect to this subject matter are superseded by the Agreement,
as amended by the Amendments.  This Amendment No. 4 may be executed in one or
more counterparts, each of which shall be an original and all of which taken
together shall constitute one and the same instrument.

[Signature Page Follows]
 

 
 

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IN WITNESS WHEREOF, the parties have executed this Amendment No. 4 as of the
date first above written.
 

UNIVERSITY HEALTH NETWORK

By:                                                                       
       Christopher J. Paige, PhD
        Vice President, Research

VISTAGEN THERAPEUTICS, INC.

By:                                                                       
 Shawn K. Singh, J.D.
 Chief Executive Officer

 
 

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EXHIBIT B-1
 
RESEARCH PROJECT ONE
 
Development of Drug Discovery and Screening Approaches with Pluripotent Stem
Cell-derived Cardiomyocytes.
 
The overall goal of these studies is to establish improved methods for the
production of mature of human pluripotent stem cell (hPSC)-derived
cardiomyocytes suitable for use in cell therapy, drug discovery, drug screening,
drug toxicology assessment and drug rescue. This project builds on recent
advancements from Dr. Keller’s lab relating to new methods for the efficient and
reproducible generation of cardiomyocytes from hPSC. The project will focus on
addressing the following: 1) characterization of the functional and maturational
status of the hPSC-derived cardiomyocytes in vitro; 2) development of methods
for the large scale production of hPSC-derived cardiomyocytes suitable for use
in cell therapy, drug discovery, drug screening and drug rescue; 3) provide
cells and methods for the study of response of cardiomyocytes to select known
drugs and compounds that effect their biology and functional
activity;  4) provide cells and methods for the use and validation of
cardiomyocytes as predictive toxicology screening assays; and 5) preclinical
research and development of iPS Cell-derived cardiomyocytes for potential cell
therapy applications.
 
Sponsored Research Project Budget (October 2011 through September 2012)
 
Technician
$ 70,000

Supplies
$ 40,000

Overhead
$ 33,000

 
Total $ 143,000

 
Initialed: ______________ (UHN)

______________ (VistaGen)

 

 
 

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EXHIBIT B-2
 
RESEARCH PROJECT TWO
 
Human Pluripotent Stem Cell-derived Hepatocytes.
 
The overall goal of these studies is to establish improved methods for the
production of mature of human pluripotent stem cell (hPSC)-derived hepatocytes
suitable for use in cell therapy, drug discovery, drug screening, drug
toxicology assessment, and drug rescue. This project builds on recent
advancements from Dr. Keller’s lab relating to improved methods for the
efficient and reproducible generation of endodermal cells from hPSC. The project
will focus on addressing the following: 1)  characterization of the functional
and maturational status of the hPSC-derived hepatocytes in vitro; 2) development
of methods to produce mature hPSC-derived hepatocytes expressing mature adult
levels of functional P450 enzymes for drug metabolism studies; 3) development of
methods for the large scale production of hPSC-derived hepatocytes suitable for
cell therapy, drug metabolism and toxicity screening; and 3) preclinical
development of iPS Cell-derived hepatocytes for potential cell therapy
applications.
 
Sponsored Research Project Budget (October 2011 through September 2012)
 
Technician
$70,000

Post-doc (50% time)
$30,000

Supplies
$30,000

Overhead
$39,000

 
Total $169,000

 
Initialed: ______________ (UHN)

______________ (VistGen)

 

 
 

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EXHIBIT B-3
 
RESEARCH PROJECT THREE
 
Human Pluripotent Stem Cell-derived Beta-islet Cells.
 
The overall goal of these studies is to establish improved methods for the
production of mature of human pluripotent stem cell (hPSC)-derived -islet cells
suitable for use in cell therapy, drug discovery, drug screening, and drug
rescue. This project builds on recent advancements from Dr. Keller’s lab
relating to improved methods for the efficient and reproducible generation of
endodermal cells from hPSC. The project will focus on addressing the following:
1) characterization of the functional and maturational status of the
hPSC-derived -islet cells in vitro; 2) development of methods to produce mature
glucose-responsive hPSC-derived -islet cells expressing adult levels of
insulin; 3) development of methods for the large scale production of
hPSC-derived -islet cells potentially suitable for in vivo transplantation
studies; and 4) preclinical development of iPS Cell-derived -islet cells for
potential cell therapy applications.
 
Sponsored Research Project Budget (October 2011 through September 2012)
 
Post-doc (50% time)
$60,000

Supplies
$39,780

Overhead
$29,934

 
Total $129,714

 
 
 
Initialed: ______________ (UHN)

______________ (VistaGen)

 
 

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EXHIBIT B-4
 
RESEARCH PROJECT FOUR
 
Human iPS Cell-derived Chondrocytes.
 
The overall goal of these studies is to establish preclinical proof of concept
regarding the use of iPS Cell-derived articular chondrocytes for cell therapy
applications, namely autologous cartilage repair and regeneration. This project
builds on recent advancements from Dr. Keller’s lab relating to differentiation
conditions that produce chondrocytic precursors in murine pluripotent stem
cells.  The project will focus on addressing the following: 1) determination of
whether newly identified murine ES Cell-derived cells are growth plate or
articular chondrocyte precursors (i.e., do they produce bone or cartilage in in
vivo animal studies); 2) development of culture conditions that support the
differentiation and expansion of similar articular chondrocyte precursors from
human iPS Cells; and 3) validation of the functional properties of the human iPS
Cell-derived articular chondrocyte precursors in in vivo animal models.
 
Sponsored Research Project Budget (October 2011 through September 2012)
 
Supplies
$54,286

Overhead
NA

 
Total $54,286

 
 
Initialed: ______________ (UHN)

______________ (VistaGen)

 
 

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EXHIBIT B-5
 
RESEARCH PROJECT FIVE
 
Human iPS Cell-derived Hematopoietic Stem Cells.
 
The overall goal of these studies is to establish preclinical proof of concept
relating to the ability of certain novel iPS Cell-derived precursors to produce
lymphocytes, granulocytic cells, red cells and platelets of the blood.  This
project builds on recent advancements from Dr. Keller’s lab relating to novel
differentiation of a “2nd wave” of blood cell precursors.  The project will
focus on addressing the following: 1) evaluation of the ability of newly
identified murine ES Cell-derived “2nd wave” hematopoietic precursor to survive
in the bone marrow and produce multiple types of blood cells for extended
periods in animal models; 2) identification of culture conditions for producing
the equivalent “2nd wave” hematopoietic precursor from human iPS Cells with
similar properties; and 3) validation of the ability of this precursor to
repopulate the bone marrow, and most if not all of the blood cells, in
immunocompromised mice in long-term repopulation assays.
 
Sponsored Research Project Budget (October 2011 through September 2012)
 
Research Associate (50%)
$ 50,000

Supplies
$ 30,000

Overhead
$ 24,000

 
Total $ 104,000

 
 
Initialed: ______________ (UHN)

______________ (VistaGen)

 

 
 

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EXHIBIT D
 
PAYMENT SCHEDULE FOR SPONSORED RESEARCH PROJECT BUDGETS
 

 
       Payment Date
 
Amount
 
  1.  October 21, 2011
  $ 50,000  
  2.  November 15, 2011
  $ 50,000  
  3.  December 15, 2011
  $ 50,000  
  4.  January 15, 2012
  $ 50,000  
  5.  February 15, 2012
  $ 50,000  
  6.  March 15, 2012
  $ 50,000  
  7.  April 15, 2012
  $ 50,000  
  8.  May 15, 2012
  $ 50,000  
  9.  June 15, 2012
  $ 50,000  
10.  July 15, 2012
  $ 50,000  
11.  August 15, 2012
  $ 50,000  
12.  September 15, 2012
  $ 50,000  
TOTAL
  $ 600,000