Exhibit 10.26


 


EXECUTION VERSION


 


Confidential
Materials omitted and filed separately with the 

Securities and Exchange Commission. 
Asterisks denote omissions.


 


 


AMENDED AND RESTATED


 


LICENSE AND COMMERCIALIZATION AGREEMENT


 


BY AND AMONG


 


IKARIA DEVELOPMENT SUBSIDIARY ONE LLC


 


AND


 


BIOLINERX LTD.


 


AND


 


BIOLINE INNOVATIONS JERUSALEM L.P.


 


 


AUGUST 26, 2009



















 


Table of Contents


 


	
   

  	
   

  	
  Page

  
	
   

  	
   

  	
   

  
	
  Article I Definitions;
  Interpretation

  	
  1

  
	
  Section 1.1

  	
  “Affiliate”

  	
  1

  
	
  Section 1.2

  	
  “BGN License Agreement”

  	
  2

  
	
  Section 1.3

  	
  “BioLineRx Know-How”

  	
  2

  
	
  Section 1.4

  	
  “BioLineRx Patent Rights”

  	
  2

  
	
  Section 1.6

  	
  “Business Day”

  	
  2

  
	
  Section 1.7

  	
  “Commercialization” or “Commercialize”

  	
  2

  
	
  Section 1.8

  	
  “Commercially Reasonable Efforts”

  	
  2

  
	
  Section 1.9

  	
  “Confidential Information”

  	
  2

  
	
  Section 1.10

  	
  “Control”

  	
  3

  
	
  Section 1.11

  	
  “Cover” or “Covered”

  	
  3

  
	
  Section 1.12

  	
  “Development” or “Develop”

  	
  3

  
	
  Section 1.13

  	
  “Development Term”

  	
  3

  
	
  Section 1.14

  	
  “EU”

  	
  3

  
	
  Section 1.15

  	
  “EU Milestone Conditions”

  	
  3

  
	
  Section 1.16

  	
  “Executive Officers”

  	
  4

  
	
  Section 1.17

  	
  “FDA”

  	
  4

  
	
  Section 1.18

  	
  “Field”

  	
  4

  
	
  Section 1.19

  	
  “First Commercial Sale”

  	
  4

  
	
  Section 1.20

  	
  Intentionally Omitted

  	
  4

  
	
  Section 1.21

  	
  Intentionally Omitted

  	
  4

  
	
  Section 1.22

  	
  Intentionally Omitted

  	
  4

  
	
  Section 1.23

  	
  Intentionally Omitted

  	
  4

  
	
  Section 1.24

  	
  Intentionally Omitted

  	
  4

  
	
  Section 1.25

  	
  “Know-How”

  	
  4

  
	
  Section 1.26

  	
  “Knowledge”

  	
  4

  
	
  Section 1.27

  	
  “Licensee”

  	
  4

  
	
  Section 1.28

  	
  “Manufacturing” or “Manufacture”

  	
  4

  
	
  Section 1.29

  	
  “Net Sales”

  	
  5

  
	
  Section 1.30

  	
  “On-Going Phase I/II Trial”

  	
  6

  
	
  Section 1.31

  	
  “Other On-Going Trials”

  	
  6

  
	
  Section 1.32

  	
  “Party”; “Parties”

  	
  6

  
	
  Section 1.33

  	
  “Patent Rights”

  	
  6

  
	
  Section 1.34

  	
  “Person”

  	
  6

  
	
  Section 1.35

  	
  “Pivotal Clinical Trial”

  	
  6

  
	
  Section 1.36

  	
  “Primary Indication”

  	
  6

  
	
  Section 1.37

  	
  “Product”

  	
  6

  
	
  Section 1.38

  	
  “Regulatory Approval”

  	
  6

  
	
  Section 1.39

  	
  “Regulatory Authority”

  	
  7

  
	
  Section 1.40

  	
  “Royalty Term”

  	
  7

  
	
  Section 1.41

  	
  “Sublicensed IP”

  	
  7

  
	
  Section 1.42

  	
  “Successful Completion”

  	
  7

  



 


i

















 


Table of Contents


 


	
   

  	
   

  	
  Page

  
	
   

  	
   

  	
   

  
	
  Section 1.43

  	
  “Territory”

  	
  7

  
	
  Section 1.44

  	
  “Third Party”

  	
  7

  
	
  Section 1.45

  	
  “Valid Claim”

  	
  8

  
	
  Section 1.46

  	
  Additional Definitions

  	
  8

  
	
  Section 1.47

  	
  Interpretation

  	
  9

  
	
   

  	
   

  	
   

  
	
  Article II Grant of Rights

  	
  9

  
	
  Section 2.1

  	
  BioLineRx License Grant to Ikaria; Consent of OCS

  	
  9

  
	
  Section 2.2

  	
  Non-Competition

  	
  10

  
	
  Section 2.3

  	
  Existing Product Agreements

  	
  10

  
	
  Section 2.4

  	
  Intentionally Omitted

  	
  10

  
	
  Section 2.5

  	
  Section 365(n) of the Bankruptcy Code

  	
  10

  
	
  Section 2.6

  	
  Retained Rights

  	
  11

  
	
   

  	
   

  	
   

  
	
  Article III Development;
  Manufacturing; Commercialization

  	
  11

  
	
  Section 3.1

  	
  General

  	
  11

  
	
  Section 3.2

  	
  Joint Development Committee

  	
  11

  
	
  Section 3.3

  	
  On-Going Trials

  	
  12

  
	
  Section 3.4

  	
  Regulatory Matters

  	
  12

  
	
  Section 3.5

  	
  Technology Exchange

  	
  13

  
	
  Section 3.6

  	
  Manufacturing

  	
  13

  
	
  Section 3.7

  	
  Commercialization

  	
  14

  
	
  Section 3.8

  	
  Efforts

  	
  15

  
	
   

  	
   

  	
   

  
	
  Article IV
  Financial Provisions

  	
  15

  
	
  Section 4.1

  	
  Milestone Payments

  	
  15

  
	
  Section 4.2

  	
  Royalties on Net Sales of Products

  	
  16

  
	
  Section 4.3

  	
  Reports and Accounting

  	
  17

  
	
  Section 4.4

  	
  Currency Amounts

  	
  18

  
	
  Section 4.5

  	
  Currency Exchange

  	
  18

  
	
  Section 4.6

  	
  Tax Withholding

  	
  18

  
	
  Section 4.7

  	
  Upfront Payments Received Under Sublicenses

  	
  18

  
	
   

  	
   

  	
   

  
	
  Article V Intellectual
  Property Ownership, Protection and Related Matters

  	
  18

  
	
  Section 5.1

  	
  Ownership of Inventions

  	
  18

  
	
  Section 5.2

  	
  Prosecution and Maintenance of Patent Rights

  	
  19

  
	
  Section 5.3

  	
  Third Party Infringement

  	
  20

  
	
   

  	
   

  	
   

  
	
  Article VI Confidentiality;
  Non-Solicitation; Standstill

  	
  23

  
	
  Section 6.1

  	
  Confidential Information

  	
  23

  
	
  Section 6.2

  	
  Disclosures to Employees, Consultants, Advisors, Etc

  	
  23

  
	
  Section 6.3

  	
  Non-Solicitation

  	
  24

  
	
  Section 6.4

  	
  Standstill

  	
  24

  



 


ii

















 


Table of Contents


 


	
   

  	
  Page

  
	
   

  	
   

  
	
  Section 6.5

  	
  Term

  	
  24

  
	
  Section 6.6

  	
  Publicity

  	
  24

  
	
  Section 6.7

  	
  Publications

  	
  25

  
	
   

  	
   

  	
   

  
	
  Article VII Representations
  and Warranties 

  	
  25 

  
	
  Section 7.1

  	
  Representations of Authority

  	
  25

  
	
  Section 7.2

  	
  Consents

  	
  25

  
	
  Section 7.3

  	
  No Conflict

  	
  26

  
	
  Section 7.4

  	
  Enforceability

  	
  26

  
	
  Section 7.5

  	
  Additional BioLineRx Representations

  	
  26

  
	
  Section 7.6

  	
  BGN License Agreement

  	
  27

  
	
  Section 7.7

  	
  Employee, Consultant and Advisor Legal Obligations

  	
  27

  
	
  Section 7.8

  	
  Accuracy of Representations and Warranties on Effective
  Date

  	
  28

  
	
  Section 7.9

  	
  No Warranties

  	
  28

  
	
   

  	
   

  	
   

  
	
  Article VIII Term and
  Termination

  	
  28

  
	
  Section 8.1

  	
  Term

  	
  28

  
	
  Section 8.2

  	
  Termination for Material Breach

  	
  28

  
	
  Section 8.3

  	
  Development-Related Termination

  	
  28

  
	
  Section 8.4

  	
  Effect of Certain Terminations and Expiration

  	
  28

  
	
  Section 8.5

  	
  Survival

  	
  29

  
	
  Section 8.6

  	
  Termination Prior to Effective Date

  	
  29

  
	
   

  	
   

  	
   

  
	
  Article IX Dispute
  Resolution

  	
  29

  
	
  Section 9.1

  	
  Negotiation

  	
  29

  
	
  Section 9.2

  	
  Escalation

  	
  30

  
	
  Section 9.3

  	
  Mediation

  	
  30

  
	
  Section 9.4

  	
  Litigation

  	
  30

  
	
  Section 9.5

  	
  Equitable Relief

  	
  30

  
	
   

  	
   

  	
   

  
	
  Article X Miscellaneous
  Provisions

  	
  30

  
	
  Section 10.1

  	
  Indemnification

  	
  30

  
	
  Section 10.2

  	
  Governing Law

  	
  31

  
	
  Section 10.3

  	
  Submission to Jurisdiction

  	
  32

  
	
  Section 10.4

  	
  Assignment

  	
  32

  
	
  Section 10.5

  	
  Entire Agreement; Amendments

  	
  32

  
	
  Section 10.6

  	
  Notices.

  	
  32

  
	
  Section 10.7

  	
  Force Majeure

  	
  33

  
	
  Section 10.8

  	
  Independent Contractors

  	
  34

  
	
  Section 10.9

  	
  Limitations of Liability

  	
  34

  
	
  Section 10.10

  	
  No Implied Waivers; Rights Cumulative

  	
  34

  
	
  Section 10.11

  	
  Severability

  	
  34

  
	
  Section 10.12

  	
  Execution in Counterparts; Facsimile Signatures

  	
  34

  



 


iii

















 


Table of Contents


 


	
  Schedules

  	
   

  	
   

  
	
  Schedule 1.30

  	
  Protocol
  for On-Going Phase I/II Trial

  	
   

  
	
  Schedule 1.31

  	
  Descriptions
  of Other On-Going Trials

  	
   

  
	
  Schedule 1.35

  	
  Outline
  of Initial Pivotal Clinical Trial

  	
   

  
	
  Schedule 1.42(a)

  	
  Independent
  Safety Monitoring Board Charter

  	
   

  
	
  Schedule 2.3

  	
  Existing
  Product Agreements

  	
   

  
	
  Schedule 3.1

  	
  Initial
  Development Plan

  	
   

  
	
  Schedule 3.3

  	
  Independent
  Safety Monitoring Board

  	
   

  
	
  Schedule 3.7

  	
  Preliminary
  Commercialization Plan

  	
   

  
	
  Schedule 4.3(a)

  	
  Wire
  Transfer Information

  	
   

  
	
   

  	
   

  	
   

  
	
  Exhibits

  	
   

  	
   

  
	
  Exhibit A

  	
  Technology Exchange Plan

  	
   

  
	
  Exhibit B

  	
  BioLineRx Patent Rights

  	
   

  



 


iv





















 


AMENDED
AND RESTATED

LICENSE AND COMMERCIALIZATION AGREEMENT


 


This Amended and Restated License and
Commercialization Agreement (the “Agreement”) is entered into this 26th day of August, 2009, by and among Ikaria Development Subsidiary One LLC, a Delaware limited
liability company having a principal place of business at 6 State Route 173,
Clinton, NJ 08809, USA (“Ikaria”), BioLineRx Ltd.,
a corporation organized and existing under the laws of the State of Israel and
having a principal place of business at 19 Hartum Street, P.O. Box 45158,
Jerusalem 91450, Israel (“BioLineRx Ltd.”), and BioLine
Innovations Jerusalem L.P., a limited partnership organized and
existing under the laws of the State of Israel and having a principal place of
business at 19 Hartum Street, P.O. Box 45158, Jerusalem 91450, Israel (“BioLine
Innovations”; together with BioLineRx Ltd., “BioLineRx”).


 


INTRODUCTION


 


WHEREAS, BioLineRx owns or
controls certain intellectual property rights covering a liquid polymer
composed of Sodium Alginate and Ca-D-Gluconate (designated by BioLineRx as “BL-1040”);


 


WHEREAS, BioLineRx is
currently developing the Product (as defined below) as a medical device for the
direct treatment of cardiac tissue following acute myocardial infarction;


 


WHEREAS, BioLineRx is
concluding the safety and clinical trials of the Product that were initiated by
BioLineRx prior to the Effective Date (as defined below);


 


WHEREAS, BioLineRx desires
to grant to Ikaria the worldwide exclusive rights to Develop, Manufacture, and
Commercialize Products (as such capitalized terms are defined below); and


 


WHEREAS, Ikaria desires to
obtain such exclusive rights in accordance with the terms and conditions of
this Agreement.


 


NOW, THEREFORE, BioLineRx and Ikaria agree as
follows:


 


Article I

Definitions; Interpretation


 


When used in this Agreement, each of the following
capitalized terms has the meaning set forth in this Article I:


 


Section 1.1            “Affiliate” shall mean, with respect to a Party,
any Person that controls, is controlled by, or is under common control with
such Party.  For purposes of this Section 1.1,
“control” shall refer to (a) in the case of a Person that is a corporate
entity, direct or indirect ownership of more than fifty percent (50%) of the
stock, shares or membership units having the right to vote for the election of
a majority of the directors of such Person, and (b) in the case of a
Person that is an entity, but is not a corporate entity, the possession,
directly or indirectly, of the 


 


1

















 


power to direct, or cause the direction of, the management or policies
of such Person, whether through the ownership of voting securities, by contract
or otherwise.


 


Section 1.2            “BGN License Agreement” shall mean that certain
License Agreement, dated January 10, 2005, as amended, by and among
BioLine Jerusalem L.P. and B.G. Negev Technologies and Applications Ltd. (“BGN”)
on behalf of Ben Gurion University.


 


Section 1.3            “BioLineRx Know-How” shall mean all Know-How that
is (a) necessary or useful for the Development, Manufacture, or
Commercialization of any Product and (b) either (i) is Controlled by
BioLineRx as of the Effective Date or (ii) BioLineRx comes to Control
during the term of this Agreement.


 


Section 1.4            “BioLineRx Patent Rights” shall mean Patent Rights
that claim or disclose BioLineRx Know-How, including the Patent Rights listed
in Exhibit B.


 


Section 1.5            “BioLineRx Intellectual Property” shall mean
BioLineRx Patent Rights (including Patent Rights in the Sublicensed IP), and
BioLineRx Know-How (including Know-How in the Sublicensed IP).


 


Section 1.6            “Business Day” shall mean a day that is not a
Saturday, a Sunday or a day on which banking institutions in New York, New
York, USA are authorized by law to remain closed.


 


Section 1.7            “Commercialization” or “Commercialize”
shall mean any activities directed to marketing, promoting, distributing,
importing, exporting, or selling a product.


 


Section 1.8            “Commercially Reasonable Efforts” shall mean the
efforts, expertise and resources normally used by a Party to Develop,
Manufacture and Commercialize a product owned by it or to which it has rights,
which is of similar market potential at a similar stage in its development or
product life, taking into account issues of safety and efficacy, product
profile, difficulty in developing the product, competitiveness of the
marketplace for the product, the proprietary position of the product, the
regulatory structure involved, the availability and level of reimbursement for
such treatment by Third Party payors or health insurance plans, the potential
total profitability of the applicable product(s) marketed or to be
marketed and other relevant factors affecting the cost, risk and timing of
Development and the total potential reward to be obtained if a product is
Commercialized. The Parties agree that Commercially Reasonable Efforts shall
require a Party to expend efforts, expertise and resources that such Party
would normally expend to Develop, use, Manufacture and Commercialize a product
owned by it or to which it has rights, taking into account the foregoing
factors.


 


Section 1.9            “Confidential Information” shall mean, with
respect to a disclosing Party, all Know-How or other information (whether or
not patentable) regarding such Party’s technology, products, business
information or objectives (whether disclosed before or after the Effective
Date) that is of a confidential and proprietary nature, including reports and
audits under Section 4.3, the Development Plan, the Commercialization
Plan, the terms of this Agreement, and all proprietary tangible materials (and
data and information associated therewith) of such Party.  Notwithstanding the foregoing, Confidential
Information shall not include Know-How or other information that:


 


2

















 


(a)           was
rightfully known or used by the receiving Party or its Affiliates without an
obligation of confidentiality prior to its date of disclosure to the receiving
Party as demonstrated by contemporaneous written records; or


 


(b)           either
before or after the date of the disclosure to the receiving Party is lawfully
disclosed to the receiving Party or its Affiliates by sources other than the
disclosing Party rightfully in possession of such information and not bound by
confidentiality obligations to the disclosing Party; or


 


(c)           either
before or after the date of the disclosure to the receiving Party or its
Affiliates is or becomes published or otherwise is or becomes part of the
public domain through no breach hereof on the part of the receiving Party or
its Affiliates; or


 


(d)           is
independently developed by or for the receiving Party or its Affiliates without
reference to or use of the Confidential Information of the disclosing Party as
demonstrated by contemporaneous written records.


 


Section 1.10           “Control” shall mean the legal authority or right
of a Party or its Affiliates to grant a license or sublicense of intellectual
property rights to the other Party, or to provide tangible material to or
otherwise disclose proprietary or trade secret information to such other Party,
without breaching the terms of any agreement with a Third Party.  For the avoidance of doubt, BioLineRx
Controls the Sublicensed IP.


 


Section 1.11          “Cover” or “Covered” shall mean, with respect
to a Patent Right and a product, that, in the absence of ownership of (with a
retained right to exploit), or a license granted under, a Valid Claim included
in such Patent Right, the Manufacture, Development, Commercialization, use,
sale, import, or offer for sale, as applicable, of such product would infringe
such Valid Claim in the country where such activity occurs.


 


Section 1.12          “Development” or “Develop”
shall mean development activities, including test method development and
stability testing, toxicology, formulation, optimization, quality
assurance/quality control development, statistical analysis, clinical studies,
regulatory affairs, product approval, and registration.


 


Section 1.13          “Development Term” shall mean the term of
development of Products by Ikaria.


 


Section 1.14          “EU” shall mean the European Union and all the
member states thereof, as it may be comprised from time to time.


 


Section 1.15          “EU Milestone Conditions” shall mean (a) satisfaction
of all requirements for [**], (b) [**] set forth therein, and (c) [**].


 


3

















 


Section 1.16          “Executive Officers” shall mean the Chief Executive
Officer of Ikaria (or a senior executive officer of Ikaria designated by
Ikaria) and the Chief Executive Officer of BioLineRx (or a senior executive
officer of BioLineRx designated by BioLineRx).


 


Section 1.17          “FDA” shall mean the United States Food and Drug
Administration or any successor agency thereof.


 


Section 1.18          “Field” shall mean any and all uses described or
claimed in the BioLineRx Patent Rights.


 


Section 1.19          “First Commercial Sale” shall mean, with respect to
a Product in a country, the first commercial sale of such Product by Ikaria,
its Affiliates, distributors, agents or Licensees in such country.  Sales for clinical trial purposes or
compassionate or similar use shall not be considered to constitute a First
Commercial Sale.


 


Section 1.20          Intentionally Omitted


 


Section 1.21          Intentionally Omitted


 


Section 1.22          Intentionally Omitted


 


Section 1.23          Intentionally Omitted.


 


Section 1.24          Intentionally Omitted.”


 


Section 1.25          “Know-How” shall mean any tangible or intangible
know-how, expertise, information, inventions, discoveries, documents and other
works of authorship, copyrights, trade secrets, data, or materials, whether
proprietary or not, including ideas, concepts, formulas, methods, procedures,
designs, technologies, compositions, plans, applications, technical data, data
generated in clinical trials, samples, chemical compounds and biological
materials and all derivatives, modifications and improvements thereof.


 


Section 1.26          “Knowledge” shall mean, with respect to a Party, the
Party’s actual knowledge together with any knowledge of any of the Party’s
officers or director-level employees, that a Person in such party’s position
would be expected to obtain given the exercise of reasonably prudent scientific
and business diligence in accordance with the standards of companies of such
Party’s size in such Party’s industry.


 


Section 1.27          “Licensee” shall mean any Person to whom Ikaria
licenses its rights under this Agreement in the manner provided in Section 2.1,
including any Third Party contractors.


 


Section 1.28          “Manufacturing” or “Manufacture” shall mean
any activities associated with the production, manufacture, supply, processing,
filling, packaging, labeling, shipping, or storage of a product or any components
thereof, including process and formulation development, process validation,
stability testing, manufacturing scale-up, development and commercial
manufacture and analytical development, product characterization, quality
assurance and quality control development, testing, and release.


 


4

















 


Section 1.29          “Net Sales” shall mean, with respect to a Product,
the gross amounts billed by Ikaria, its Affiliates, or Licensees in respect of
sales of such Product by Ikaria and its Affiliates or Licensees to unrelated
Third Parties, in each case less the following deductions:


 


(a)           Trade,
cash, or quantity discounts (including amounts incurred in connection with
government mandated rebate programs) actually allowed and taken with respect to
such sales;


 


(b)           Tariffs,
duties, excises, sales taxes or other taxes imposed upon and paid with respect
to the production, sale, delivery, or use of the Product (excluding national,
state, or local taxes based on income);


 


(c)           Amounts
repaid or credited by reason of billing corrections, rejections, defects,
recalls, or returns (due to spoilage, damage, expiration of useful life or
otherwise) or because of chargebacks, refunds or retroactive price reductions
and allowances for wastage replacement and bad debts;


 


(d)           Portions
of invoices sales amounts included in Net Sales in prior periods that are
actually written off by Ikaria, its Affiliates, or licenses as uncollectible;
and


 


(e)           Postage,
freight, shipping, insurance, and other transportation related charges incurred
in shipping a Product to Third Parties.


 


Such amounts shall be determined from the books and
records of Ikaria, its Affiliates, or Licensees, maintained in accordance with
generally accepted accounting principles, consistently applied.  For the avoidance of doubt, in no event will
fines, penalties or other monetary damages assessed against Ikaria, its
Affiliates or Licensees by any governmental authority for violation of any
applicable law, result in an appropriate deduction to Net Sales.


 


If one or more Products is sold as part of a
Combination Product (as defined below), the Net Sales from the Combination
Product, for the purposes of determining royalty payments, shall be determined
by multiplying the Net Sales (as determined above) of the Combination Product,
during the applicable royalty reporting period, by the fraction, A/(A+B), where
A is the average sale price of the Product(s) when sold separately in
finished form and B is the average sale price of the other components included
in the Combination Product when sold separately in finished form, in each case
in the applicable country during the applicable royalty reporting period or, if
sales of both the Product(s) and the other components did not occur in
such country in such period, then in the most recent royalty reporting period
in which sales of both occurred.  If such
average sale price cannot be determined for both the Product(s) and all
other components included in such Combination Product, Net Sales for the purposes
of determining royalty payments shall be calculated by multiplying the Net
Sales of the Combination Product by the fraction of C/(C+D) where C is the fair
market value of the Product(s) and D is the fair market value of all other
components included in the Combination Product. 
In such event, the Parties shall negotiate in good faith to arrive at a
determination of the respective fair market values of the Product(s) and
all other components included in the Combination Product.  If the Parties are unable to agree on such
determination within sixty (60) days, then such matter shall be resolved as
provided in Article IX.


 


5














 


As used above, the term “Combination Product”
means any therapeutic medical product that includes both (i) one or more
Product(s) and (ii) other component(s).


 


Section 1.30          “On-Going Phase I/II Trial” shall mean that certain
clinical trial of a Product that was initiated by BioLineRx prior to and that
is ongoing as of the Effective Date, the protocol for which is attached hereto
as Schedule 1.30.


 


Section 1.31          “Other On-Going Trials” shall mean those
pre-clinical and CMC trials (other than the On-Going Phase I/II Trial) that
were initiated by BioLineRx prior to, and that are ongoing as of, the Effective
Date, descriptions of which are attached hereto as Schedule 1.31.


 


Section 1.32          “Party” shall mean BioLineRx or Ikaria; “Parties”
shall mean BioLineRx and Ikaria.


 


Section 1.33          “Patent Rights” shall mean United States and foreign
patents and patent applications (including provisional applications) and all
substitutions, divisionals, continuations, continuations-in-part, reissuances,
reexaminations, registrations, renewals, confirmations, supplementary
protection certificates and extensions thereof.


 


Section 1.34          “Person” shall mean any natural person or any
corporation, company, partnership, joint venture, firm, university, other
entity, governmental authority, or subdivision thereof.


 


Section 1.35          “Pivotal Clinical Trial” shall mean a randomized,
controlled clinical trial of a Product designed to demonstrate statistically
significant clinical efficacy and safety in human patients (in conjunction with
performance of a therapeutic procedure) pursuant to a clinical study agreed
with the FDA, which trial the FDA accepts as a pivotal clinical trial necessary
for Regulatory Approval of such Product. 
An outline of the structure of the initial Pivotal Clinical Trial is
attached as Schedule 1.35.


 


Section 1.36          “Primary Indication” shall mean
the diagnosis, prevention, mitigation, or treatment of injury to myocardial
tissue via the administration of a Product to a human patient.


 


Section 1.37          “Product” shall mean a liquid
polymer composed of Sodium Alginate and Ca-D-Gluconate (designated by BioLineRx
as “BL-1040”), or any back-ups or second-generation polymers or polymer
combinations thereof that is Developed under the Development Program.


 


Section 1.38          “Regulatory Approval” shall mean, with respect to a
jurisdiction, the approval of the applicable Regulatory Authority required to
market and sell a Product in such jurisdiction. 
For clarity, Regulatory Approval for a Product shall occur:


 


(a)   in
the United States, on the date when the FDA approves a Premarket Approval (PMA)
application;


 


(b)   in
Europe, on the date when such Product may first be placed on the market as a
medical device (as such terms are defined in Art. 1 Paragraphs 2(a) and (h) of
Directive 93/42/EEC, as amended) bearing the CE marking according to Art. 17 of
Directive 93/42/EEC, as amended, in any member state of the EU; and


 


6

















 


(c)   in
Japan, on the date when the Ministry of Health approves a marketing authorization.


 


Section 1.39          “Regulatory Authority” shall mean any national (e.g., the FDA), supra-national or other regulatory agency or
governmental entity involved in the granting of Regulatory Approval for, or in
the regulation of human clinical studies of, therapeutic medical devices.


 


Section 1.40          “Royalty Term”
shall mean, with respect to a Product in a country of the Territory, the period
of time commencing on the First Commercial Sale of such Product in such country
and ending upon the earlier of (a) the expiration of the last-to-expire
Valid Claim in the BioLineRx Patent Rights that Covers the sale or use of such
Product in the Field in such country, or (b) the date of a judicial
determination from which no appeal can be taken of invalidity of a set of
claims in the BioLineRx Patent Rights that Cover the sale or use of such
Product in the Field in such country and that are asserted through litigation
(whether in an infringement action, a declaratory judgment action, or
otherwise) to exclude a Third Party from selling or using a product in the
Field in such country.


 


Section 1.41          “Sublicensed IP” shall mean that portion of the
BioLineRx Intellectual Property licensed to BioLineRx pursuant to the BGN
License Agreement.


 


Section 1.42          “Successful Completion” shall mean:


 


(a)           with
respect to the On-Going Phase I/II Trial, no treatment-related safety findings
during the treatment period and the six (6) month follow up period, that
were considered by the Independent Safety Monitoring Board for the On-Going
Phase I/II Trial (in accordance with and subject to the Independent Safety
Monitoring Board Charter attached hereto as Schedule 1.42(a)) to be of
sufficient concern to discontinue the On-Going Phase I/II Trial;


 


(b)           with
respect to the Interim Analysis of the Pivotal Clinical Trial/Phase IIb Proof
of Concept, safety and efficacy data from completion of all patients at the [**]
follow up demonstrates more than a [**] probability of meeting pre-specified
endpoints at [**] in the Pivotal Clinical Trial, and no apparent safety signal
in the treatment group for the entire cohort at all times;


 


(c)           with
respect to the Pivotal Clinical Trial for the Primary Indication, safety and
efficacy data from completion of all patients at the [**] follow up meets the
primary endpoint and demonstrates a positive benefit-to-risk ratio to enable
FDA submission; and


 


(d)           with
respect to all other clinical trials of a Product, that the JDC has determined
that the final results of such clinical trial have achieved the success
criteria established by the JDC with respect to such clinical trial.


 


Section 1.43          “Territory” shall mean the entire world.


 


Section 1.44          “Third Party” shall mean any Person other than a
Party or any of its Affiliates or Licensees.


 


7

















 


Section 1.45          “Valid Claim” shall mean a claim of any issued,
unexpired patent that has not been revoked or held unenforceable or invalid by
a decision of a court or governmental agency of competent jurisdiction from
which no appeal can be taken, or with respect to which an appeal is not taken
within the time allowed for appeal, and that has not been disclaimed or
admitted to be invalid or unenforceable through reissue, reexamination,
disclaimer, or otherwise.


 


Section 1.46          Additional Definitions.  Each of the following terms is defined in the
section of this Agreement indicated below:


 


 


	
  Term

  	
   

  	
  Section

  
	
   

  	
   

  	
   

  
	
  “Agreement”

  	
   

  	
  Preamble

  
	
  “Bankruptcy
  Code”

  	
   

  	
  Section 2.5

  
	
  “BGN”

  	
   

  	
  Section 1.2

  
	
  “BioLineRx”

  	
   

  	
  Preamble

  
	
   

  	
   

  	
   

  
	
  “BL-1040”

  	
   

  	
  Section 1.37

  
	
  “Breaching
  Party”

  	
   

  	
  Section 8.2

  
	
  “Combination
  Product”

  	
   

  	
  Section 1.29

  
	
  “Commercialization
  Plan”

  	
   

  	
  Section 3.7

  
	
  “Competitive
  Infringement”

  	
   

  	
  Section 5.3(a)

  
	
  “Effective
  Date”

  	
   

  	
  Section 2.1

  
	
  “Existing
  Product Agreements”

  	
   

  	
  Section 2.3

  
	
  “Ikaria”

  	
   

  	
  Preamble

  
	
   

  	
   

  	
   

  
	
  “Development
  Plan”

  	
   

  	
  Section 3.1

  
	
  “Development
  Program”

  	
   

  	
  Section 3.1

  
	
  “Force
  Majeure Event”

  	
   

  	
  Section 10.7

  
	
  “Indemnified
  Party”

  	
   

  	
  Section 10.1(c)

  
	
  “Indemnifying
  Party”

  	
   

  	
  Section 10.1(c)

  
	
  “Invalidity
  Claim”

  	
   

  	
  Section 5.3(d)

  
	
  “Joint
  Development Committee” or “JDC”

  	
   

  	
  Section 3.2

  
	
   

  	
   

  	
   

  
	
  “Joint
  Manufacturing Committee” or “JMC”

  	
   

  	
  Section 3.6(c)

  
	
  “Lead
  Party”

  	
   

  	
  Section 5.3(e)

  
	
  “Losses”

  	
   

  	
  Section 10.1(a)

  
	
  “New
  Indication”

  	
   

  	
  Section 2.4

  
	
  “New
  Indication Invention”

  	
   

  	
  Section 5.1(a)

  
	
  “Non-Breaching
  Party”

  	
   

  	
  Section 8.2

  
	
  “OCS”

  	
   

  	
  Section 2.1

  
	
  “SEC”

  	
   

  	
  Section 6.1

  
	
  “Severed
  Clause”

  	
   

  	
  Section 10.11

  
	
   

  	
   

  	
   

  
	
  “Technology
  Exchange”

  	
   

  	
  Section 3.5

  
	
  “Technology
  Exchange Plan”

  	
   

  	
  Section 3.5

  
	
  “Third
  Party Payment”

  	
   

  	
  Section 4.2(b)

  



 


8

















 


Section 1.47          Interpretation. 
Whenever the context may require, any pronoun shall include the
corresponding masculine, feminine, and neuter forms.  The words “include”, “includes” and “including”
shall be deemed to be followed by the phrase “without limitation”. The word “will”
shall be construed to have the same meaning and effect as the word “shall”.  The word “or” shall be construed to have the
same meaning and effect as “and/or”. 
This Agreement has been prepared jointly with the assistance of counsel
and shall not be strictly construed against either Party.  The captions or headings of the sections or
other subdivisions hereof are inserted only as a matter of convenience or for
reference and shall have no effect on the meaning of the provisions hereof.  Unless the context requires otherwise, (a) any
definition of or reference to any agreement, instrument, or other document
herein shall be construed as referring to such agreement, instrument, or other
document as from time to time amended, supplemented, or otherwise modified
(subject to any restrictions on such amendments, supplements, or modifications
set forth herein or therein), (b) any reference to any laws herein shall
be construed as referring to any law, statute, rule, regulation, ordinance, or
other pronouncement having the effect of law of any federal, national,
multinational, state, provincial, county, city, or other political subdivision,
domestic or foreign, as they from time to time may be enacted, repealed, or
amended, (c) any reference herein to any Person shall be construed to include
the Person’s successors and assigns, (d) the words “herein”, “hereof”, and
“hereunder”, and words of similar import, shall be construed to refer to this
Agreement in its entirety and not to any particular provision hereof, (e) any
reference herein to the words “mutually agree” or “mutual written agreement”
shall not impose any obligation on either Party to agree to any terms relating
thereto or to engage in discussions relating to such terms except as such Party
may determine in such Party’s sole discretion, and (f) all references
herein to Articles, Sections, Exhibits, or Schedules shall be construed to
refer to Articles, Sections, Exhibits, and Schedules of this Agreement.


 


Article II

Grant of Rights


 


Section 2.1            BioLineRx License Grant to Ikaria; Consent of OCS.  Subject to the terms and conditions of this
Agreement, including the consent of the Office of the Chief Scientist of the
State of Israel (“OCS”), BioLineRx hereby grants to Ikaria the
exclusive, royalty-bearing right and license in the Territory under the
BioLineRx Intellectual Property (including, for clarity, a sublicense under the
Sublicensed IP) to Develop, Manufacture and Commercialize Products for use in
the Field.  Subject to the consent of BioLineRx,
which consent shall not be unreasonably withheld, conditioned or delayed, the
foregoing license includes the right to grant sublicenses under the BioLineRx
Intellectual Property, provided  that, with respect to sublicenses
granted under the Sublicensed IP, Ikaria shall (a) grant such sublicenses
only for consideration and at arm’s-length transactions, and (b) grant
such sublicenses only pursuant to written agreements that contain such terms
and conditions as may be required for Ikaria to comply with this
Agreement.  BioLineRx shall use its best
efforts to obtain the written consent of the OCS to this Agreement within [**]
days after August 26th, 2009, which consent must be in a form that is satisfactory to each
Party.  If the OCS has still not provided
such consent during such [**] days, Ikaria shall have the right to require
BioLineRx to continue to use best efforts to obtain such consent within the
subsequent [**] day period.  In addition,
(i) Ikaria shall have the right to have a representative present at all
interactions between BioLineRx’s representatives and the OCS relating to such
consent, (ii) BioLineRx shall (A) provide Ikaria with a reasonable
opportunity to review and approve the request for consent submitted to the OCS
and (B) keep Ikaria fully 


 


9

















 


informed as to the progress of such request for consent and shall
consult with Ikaria in good faith with respect thereto, (iii) BioLineRx
shall not engage in any activities or discussions with any Third Party relating
to the subject matter of this Agreement, including pursuing any other
transactions relating to the BioLineRx Intellectual Property, without Ikaria’s
consent, and (iv) Ikaria shall have the right, prior to the Effective
Date, to unilaterally modify this Agreement to comply with the specific,
formal, written requests of the OCS, provided  that such
modifications have no detrimental financial impact on BioLineRx under this
Agreement.  Notwithstanding BioLineRx’s
obligation to exercise best efforts to obtain the consent from the OCS as
described above, BioLineRx shall not be required to (y) agree to any
request by the OCS that would require BioLineRx to pay to the OCS an aggregate
amount of more than $[**] or (z) obtain a consent based on the
characterization of this Agreement as a “transfer of know-how outside of Israel”
under Section 19B of the Israeli Law for the Encouragement of Industrial
Research & Development, 1984. 
Notwithstanding anything herein to the contrary, subject to Section 8.6,
the provisions of this Agreement other than this Section 2.1, Section 2.2,
Article VII, Section 8.6 and Article X shall not be effective
until such consent has been obtained and each Party has delivered the
certificate set forth in Section 7.8 (the “Effective Date”).


 


Section 2.2            Non-Competition. 
During the term of this Agreement, BioLineRx shall not, within the
Territory, directly or indirectly (including through its Affiliates), conduct
research or discovery activities, Develop, Manufacture (except as set forth in Section 3.6),
Commercialize, or grant any rights or options or provide assistance to any
Third Party to conduct research or discovery activities, Develop, Manufacture
(except as set forth in Section 3.6) or Commercialize, (a) the
Product or (b) any compound, substance, polymer, or product (whether
pharmaceutical or device in nature) the method of action or effect of which is
similar to any Product.


 


Section 2.3            Existing Product Agreements.  BioLineRx hereby agrees that, upon the
written request of Ikaria, BioLineRx shall assign to Ikaria each of the
agreements listed in Schedule 2.3 attached hereto (the “Existing
Product Agreements”), and all of its rights, title, and interest
therein.  BioLineRx shall cooperate with
Ikaria, including by executing and recording documents, as may be necessary to
effectuate such assignments and the exercise by Ikaria of its rights under the
Existing Product Agreements.


 


Section 2.4            Intentionally Omitted.


 


Section 2.5            Section 365(n) of the Bankruptcy Code.  All rights and licenses granted under or
pursuant to any Section of this Agreement, including under this Article II
and with respect to any BioLineRx Intellectual Property subject to Technology
Exchange under Section 3.5, are rights to “intellectual property” (as
defined in Section 101(35A) of Title 11 of the United States Code (such
Title, the “Bankruptcy Code”)). 
Each of Ikaria and BioLineRx hereby acknowledges “embodiments” of such
intellectual property for purposes of Section 365(n) of the
Bankruptcy Code shall include (a) copies of research data, (b) laboratory
samples, (c) product samples, (d) formulas, (e) laboratory notes
and notebooks, (f) data and results related to clinical studies, (g) regulatory
filings and approvals, (h) rights of reference in respect of regulatory
filings and approvals, (i) research data and results, and (j) marketing,
advertising, and promotional materials, in each case, that relate to such
intellectual property.  Each Party shall
retain and may fully exercise all of its rights and elections under the
Bankruptcy Code or analogous legislation in any other jurisdiction.  Upon the institution by or against BioLineRx
of any assignment for the 


 


10

















 


benefit of creditors, composition, or any bankruptcy, reorganization,
arrangement, insolvency, or similar proceedings under the laws of any
jurisdiction, Ikaria shall further be entitled to a complete duplicate of, or
complete access to, as appropriate, any such intellectual property (including
embodiments thereof), and such intellectual property and embodiments, if not
already in its possession, shall be promptly delivered to Ikaria, unless
BioLineRx elects to continue, and continues, to perform all of its obligations
under this Agreement.


 


Section 2.6            Retained Rights. 
Except as otherwise specifically provided for in this Agreement, each
Party retains all rights and licenses to exploit its own intellectual property.


 


Article III

Development; Manufacturing; Commercialization


 


Section 3.1            General. 
Ikaria shall be solely responsible for conducting and funding all
Development activities pursuant to the Development Plan, and shall have the
sole right to Develop, Manufacture, and Commercialize Products in the Field in
the Territory.  Subject to its obligations
under Section 3.8, Ikaria shall prepare a non-binding plan (the “Development
Plan”) for the Development of Product(s) (the “Development Program”).  The Development Plan shall include an
estimated budget setting forth Ikaria’s anticipated development costs.  Ikaria shall provide BioLineRx with a copy of
its then-current Development Plan at least [**] per year, but no later than
[**] days following the beginning of each year. 
The initial Development Plan is attached hereto as Schedule 3.1, which
shall be non-binding, including any timelines or milestones that may be
included therein.  In addition, Ikaria
shall, within [**] days after the Effective Date, provide BioLineRx with a
revised draft protocol for the Interim Analysis of the Pivotal Clinical Trial/Phase
IIb Proof of Concept and the Pivotal Clinical Trial, after taking into account
any comments BioLineRx may wish to provide based on the initial draft of the
protocol attached hereto as Schedule 1.35, that would include modifications
designed to maximize the likelihood of obtaining reasonable reimbursement for
one or more Products in any one or more of the following countries [**].  Upon the Successful Completion of the Interim
Analysis of the Pivotal Clinical Trial/Phase IIb Proof of Concept, or, failing
that, upon the Successful Completion of the Pivotal Clinical Trial, Ikaria
shall, within [**] days thereafter, submit a formal written request for a
reimbursement price for one or more Product(s) to the applicable
governmental agency in one or more of the following countries: [**]


 


Section 3.2            Joint Development Committee.


 


(a)           The
Parties shall establish a Joint Development Committee (the “Joint
Development Committee” or “JDC”), comprised of [**] representatives
of Ikaria and [**] representatives of BioLineRx, to oversee the Development of Products.  Each Party shall make its initial designation
of its representatives not later than [**] days after the Effective Date.  Each Party may change any one or more of its
representatives to the Joint Development Committee at any time upon notice to the
other Party.


 


(b)           The
JDC shall meet at least [**] during the Development Term or more or less
frequently as the JDC may agree.  The JDC
may meet in person or by means of a telephone or video conference call.  One meeting of the JDC per year shall be held
in person at Ikaria’s 


 


11

















 


headquarters in Clinton, NJ and one meeting of the JDC per year shall
be held in person at BioLineRx’s headquarters in Israel, provided, that the
Parties’ representatives may participate in person, via telephone, or video
conference in their discretion.  Each
Party shall use reasonable efforts to cause its representatives to attend the
meetings of the JDC.  If a representative
of a Party is unable to attend a meeting, such Party may designate an alternate
to attend such meeting in place of the absent representative.  Each Party shall bear its own costs with
respect to its participation on the JDC. 
Prior to every meeting of the JDC, Ikaria will provide to the JDC
detailed reports describing Ikaria’s current clinical and development
activities and plans.


 


(c)           The
JDC shall be the vehicle by which BioLineRx may offer insight and guidance to
Ikaria with respect to (i) establishing the Development Plan setting forth
the Development Program’s objectives and the activities to be conducted, (ii) reviewing
and updating the Development Plan from time to time, (iii) monitoring the
progress and results of the Development Program, (iv) determining future
Development Program activities, including Development activities relating to
Manufacturing, to be conducted during the Development Term, and (v) establishing
success criteria for the clinical trials (other than those for which success
criteria are set forth in this Agreement), and determining whether the results
of such clinical trials have achieved the applicable success criteria.


 


(d)           The
JDC shall only act unanimously, with each Party given one (1) vote
regardless of the number of representatives. 
If, however, the JDC is unable to reach agreement with respect to any
matter within [**] days, the matter shall be referred to the Parties’
respective Executive Officers for resolution. 
If the Executive Officers are not able to resolve any such matter by
consensus within [**] days following referral, Ikaria’s Executive Officer shall
have the right to decide the matter taking into account Ikaria’s obligation to
use Commercially Reasonable Efforts under Section 3.8.


 


Notwithstanding anything in
this Section 3.2, neither Party shall have a unilateral right to resolve
any dispute involving the breach or alleged breach of this Agreement, to amend
or modify this Agreement or the Parties’ respective rights and obligations
hereunder or, except as expressly provided in this Section 3.2, any
Development Plan or the Parties’ respective rights and obligations thereunder.


 


Section 3.3            On-Going Trials. 
BioLineRx shall retain control of, bear all costs relating to the
On-Going Phase I/II Trial and the Other On-Going Trials, and shall exercise
Commercially Reasonable Efforts to continue and complete the On-Going Phase
I/II Trial and the Other On-Going Trials, which shall be managed by
BioLineRx.  BioLineRx may modify the
On-Going Phase I/II Trial and the Other On-Going Trials, including any changes
to the protocols therefor, only with the prior written consent of Ikaria, which
consent shall not be unreasonably withheld, conditioned or delayed.


 


Section 3.4            Regulatory Matters.  Ikaria shall prepare and submit all filings
with Regulatory Authorities relating to Products, which filings shall be in
Ikaria’s name, provided  that Ikaria shall provide BioLineRx [**]
days prior notice to enable BioLineRx to review and provide any comments on
such submissions.  With respect to
regulatory matters concerning Products, BioLineRx shall cooperate with Ikaria
in the preparation and support of each application for Regulatory Approval and
shall provide Ikaria with such reasonable assistance as Ikaria may 


 


12

















 


request.  For example, upon Ikaria’s
request, BioLineRx shall describe the materials in sufficient and reasonable
detail as requested by Ikaria, the Manufacturing techniques and other
appropriate characteristics of Products (and the components thereof), and
provide Ikaria with such other information related to the Products, including
materials, chemistry, Manufacturing, technical dossier and controls data, batch
records, analytical and quality control, device master files (if applicable),
data from the On-Going Phase I/II Trial or Other On-Going Trials, or other
information as Ikaria may reasonably request.


 


Section 3.5            Technology Exchange.


 


(a)           As
soon as reasonably practicable after Ikaria’s written request, BioLineRx shall
complete the activities assigned to BioLineRx as set forth on the technology
exchange plan attached hereto as Exhibit A (the “Technology
Exchange Plan”), to effect the transfer to Ikaria (or Ikaria’s designee(s))
of all embodiments of and information relating to BioLineRx Intellectual
Property reasonably necessary for the exercise of Ikaria’s rights under the
license granted pursuant to Section 2.1, including the Manufacturing of
Products (“Technology Exchange”). 
BioLineRx shall make available to Ikaria (or Ikaria’s designee(s)) such
number of technical personnel as may be set forth in the Technology Exchange
Plan to answer any questions or provide instruction as reasonably requested by
Ikaria (or Ikaria’s designee(s)) concerning the items delivered pursuant to
this Section 3.5, in connection with the Development,  Manufacture and Commercialization of Products
hereunder.  Each Party shall bear its own
costs with respect to the Technology Exchange.


 


(b)           The
Joint Development Committee shall be responsible for coordinating the
technology exchange activities under the Technology Transfer Plan.  Each Party shall cooperate with the other
Party in such other Party’s conduct of technology exchange activities under the
Technology Exchange Plan.


 


(c)           If
Ikaria desires that BioLineRx provide technology exchange services beyond the
scope of the Technology Exchange Plan, BioLineRx shall provide such services on
terms to be agreed upon in good faith by the Parties.  Notwithstanding the foregoing, BioLineRx
shall provide Ikaria with reasonable access to BioLineRx’s employees and consultants
involved prior to the Effective Date and during the term of this Agreement with
the Development of any Product.


 


Section 3.6            Manufacturing.


 


(a)           Ikaria
shall be solely responsible for the Manufacture of Products for Development or
for Commercialization in the Field in the Territory, which Ikaria may conduct
itself or through Affiliates or Licensees.


 


(b)           BioLineRx
Ltd. shall have the option (either directly or through an Affiliate),
exercisable in its sole discretion no later than [**] months prior to the date
on which Ikaria intends to file for Regulatory Approval in the U.S., to
Manufacture Product pursuant to the terms of a supply agreement to be
negotiated in good faith by the Parties, provided  that (i) BioLineRx
may exercise the foregoing option only to the extent that it has the
demonstrated ability to manufacture the Product, including compliance with cGMP
and all applicable laws and 


 


13

















 


regulations, including those of the FDA and EMEA, (ii) BioLineRx
shall bear all expenses required to establish and qualify the BioLineRx
manufacturing site, including the costs of scale-up batches, process validation
batches and stability batches, (iii) BioLineRx shall not be entitled to
assign such option or to utilize subcontract manufacturing, and (iv) neither
Party shall have any obligation to enter into such agreement unless all of the
terms and conditions thereof are acceptable to both Parties.  If BioLineRx Ltd. exercises such option and
the Parties enter into a supply agreement, (x) Ikaria shall be required to
purchase no less than twenty percent (20%) of its requirements for the Product
from BioLineRx, and (y) the per unit price for the Product shall be the
[**], provided  that the price shall not exceed [**] percent
([**]%) of the Net Sales price per unit of Product; provided, further,
that if BioLineRx at any time shall fail to supply Product on time or
such supply is otherwise disrupted, the minimum purchase requirement set forth
in the preceding clause (x) shall no longer apply.  Any clinical supply provided to Ikaria by
BioLineRx would be provided at cost.


 


(c)           The
Parties will discuss the most efficient structure for the Manufacture and
supply of Product for Development and Commercialization purposes.  If the Parties determine that coordination in
Manufacturing is appropriate, the Parties will establish a Joint Manufacturing
Committee (the “Joint Manufacturing Committee” or “JMC”) to
coordinate Manufacturing efforts.  If
established, the JMC would be comprised of [**] representatives of Ikaria and
[**] representatives of BioLineRx, to oversee the Manufacturing of
Products.  Each Party would make its
initial designation of its representatives not later than [**] days after the
Parties agreed to establish the JMC. 
Each Party shall designate as its representatives individuals who have
the requisite experience and knowledge to discuss the Manufacturing of
Products.  Each Party would be permitted
to change any one or more of its representatives to the JMC at any time upon
notice to the other Party.


 


(d)           The
JMC would meet at least [**] or more or less frequently as the JMC may
agree.  The location of such meetings
shall be as mutually agreed by the Parties. 
The JMC may also meet by means of a telephone or video conference
call.  Each Party shall use reasonable
efforts to cause its representatives to attend the meetings of the JMC.  If a representative of a Party is unable to
attend a meeting, such Party may designate an alternate to attend such meeting
in place of the absent representative. 
Each Party would bear its own costs with respect to its participation on
the JMC.


 


(e)           The
JMC would only act unanimously.  If,
however, the JMC is unable to reach agreement with respect to any matter within
[**] days, the matter shall be referred to the Parties’ respective Executive
Officers for resolution.  If the
Executive Officers are not able to resolve any such matter by consensus within
[**] days following referral, Ikaria’s Executive Officer shall have the right
to decide the matter taking into account Ikaria’s obligation to use
Commercially Reasonable Efforts under Section 3.8.


 


Section 3.7            Commercialization. 
Ikaria shall be solely responsible for conducting, itself or through
Affiliates or Licensees, the Commercialization of Products in the Field in the
Territory, including (a) contracting with customers and booking sales, (b) setting
the price and terms and conditions under which a Product may be sold to
customers, and (c) handling of managed care accounts, and, subject to Section 1.29,
Section 4.2(b), Section 5.2(d), Section 5.3(e) and Section 10.1(b),
as between the Parties, Ikaria shall bear all costs associated therewith.  Ikaria shall 


 


14

















 


produce and update from time to time a comprehensive Commercialization
plan (the “Commercialization Plan”), which shall include plans for
Commercializing Product in each major market in which Ikaria does not then have
a presence.  The Commercialization Plan
shall include a preliminary timeline for the initial Commercialization of
Products, which is intended as a planning and informational tool and shall not
constitute a binding obligation on Ikaria, and shall be subject to adjustment
by Ikaria from time to time, provided, that, Ikaria shall provide
BioLineRx with prior written notice of any material proposed change to a
timeline.  The most recent preliminary
Commercialization Plan is attached hereto as Schedule 3.7.


 


Section 3.8            Efforts. 
Ikaria shall use Commercially Reasonable Efforts, either itself or
through Affiliates or Licensees, (a) to Develop at least one Product in
the Territory and (b) to Commercialize at least one Product in the
Territory.


 


Article IV

Financial Provisions


 


Section 4.1            Milestone Payments.


 


(a)           Development
and Regulatory Milestones.  With
respect to each of the following milestones, Ikaria shall pay BioLineRx the
corresponding payment set forth below within [**] days after the achievement by
Ikaria, its Affiliates or Licensees of such milestone:


 


	
  MILESTONE

  	
   

  	
  PAYMENT

  
	
   

  	
   

  	
   

  
	
  1.

  	
  Effective
  Date

  	
   

  	
  $

  	
  7,000,000

  
	
   

  	
   

  	
   

  	
   

  
	
  2.

  	
  Successful
  Completion of On-Going Phase I/II Trial

  	
   

  	
  $

  	
  10,000,000

  
	
   

  	
   

  	
   

  	
   

  
	
  3.

  	
  [**]

  	
   

  	
  $

  	
  [**]

  
	
   

  	
   

  	
   

  	
   

  
	
   

  	
   

  	
   

  	
  $

  	
  [**]  

  	
   

  	
   

  
	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
   

  	
   

  	
   

  	
  $

  	
  [**]

  	
   

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
  4.

  	
  [**]

  	
   

  	
  $

  	
  [**]

  
	
   

  	
   

  	
   

  	
   

  
	
  5.

  	
  [**]

  	
   

  	
  $

  	
  [**]

  
	
   

  	
   

  	
   

  	
   

  
	
  6.

  	
  [**]

  	
   

  	
  $

  	
  [**]

  
	
   

  	
   

  	
   

  	
   

  
	
  Total Development and
  Regulatory Milestone Payments

  	
   

  	
  132,500,000

  



 


15














 


(b)           Commercialization
Milestones.  Ikaria shall pay each of
the following milestone payments to BioLineRx within [**] days after the
achievement of such milestone:


 


 


	
  MILESTONE

  	
   

  	
  PAYMENT

  	
   

  
	
   

  	
   

  	
   

  	
   

  	
   

  
	
  1.  Annual Net Sales in Territory exceed
  $[**] in a Calendar Year

  	
   

  	
  $

  	
  [**]

  	
   

  
	
   

  	
   

  	
   

  	
   

  	
   

  
	
  2.  Annual Net Sales in Territory exceed
  $[**] in a Calendar Year

  	
   

  	
  $

  	
  [**]

  	
   

  
	
   

  	
   

  	
   

  	
   

  	
   

  
	
  3.  Annual Net Sales in Territory exceed
  $[**] in a Calendar Year

  	
   

  	
  $

  	
  [**]

  	
   

  



 


Each of the milestones set forth in Section 4.1(a) and
Section 4.1(b) shall be paid only once regardless of the number of
Products that achieve such milestone.


 


Section 4.2            Royalties on Net Sales of Products.  During the Royalty Term applicable to each
Product, and subject to adjustment as set forth in Section 4.2(b), Ikaria
shall pay to BioLineRx royalties on a Product-by-Product basis, with the amount
of such royalties calculated as a percentage of Net Sales in a calendar year
for such Product as set forth below:


 


	
   

  	
  Net
  Sales

  	
   

  	
  Royalty

  	
   

  	
   

  
	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
   

  	
  Up to $[**]

  	
   

  	
  [**]

  	
  %

  	
   

  
	
   

  	
  >$[**] to $[**]

  	
   

  	
  [**]

  	
  %

  	
   

  
	
   

  	
  >$[**]

  	
   

  	
  [**]

  	
  %

  	
   

  



 


(a)           Royalties
Payable Only Once.  The obligation to
pay royalties is imposed only once with respect to Net Sales of the same unit
of a Product.


 


(b)           Royalty
Reductions for Third Party Payments. 
Ikaria shall use Commercially Reasonable Efforts to avoid any Third
Party Payments.  Ikaria shall provide
BioLineRx written notice within [**] days of its receipt of any request or
demand that Ikaria, its Affiliates or any Licensee obtain a license or immunity
from suit from any Third Party in order for Ikaria, its Affiliates, or any
Licensee to exercise or use the rights granted to Ikaria herein.  If Ikaria is required to obtain a license or
immunity from suit from any Third Party in order for Ikaria, its Affiliates, or
any Licensee to exercise or use the rights granted to Ikaria herein, and
Ikaria, its Affiliates, or any Licensee pays any Third Party any up-front fee,
milestone, royalty, or other payment (each, a “Third Party Payment”) in
connection with such license or immunity from suit, Ikaria shall have the right
to set off against any amounts payable to BioLineRx under this Article IV
[**] percent ([**]%) of any Third Party Payments provided  that in
no event will the royalty paid to BioLineRx on Net Sales in the applicable
country fall below [**] percent ([**]%). 
If the amount of Third Party Payments that Ikaria is entitled to set off
exceeds the amount otherwise payable to BioLineRx at any given time, or is
limited by the foregoing [**] percent ([**]%), Ikaria shall be entitled to
carry over the excess for set off against amounts payable to BioLineRx in
subsequent periods until Ikaria has been credited for the full amount it is
entitled to set off.  Prior to paying any
Third Party Payment, the Parties shall obtain an analysis from their 


 


16

















 


respective counsel in respect of the validity of the claim of any Third
Party seeking Third Party Payments.  If
the Parties are unable to agree on an assessment of the claim, the Parties shall
jointly engage mutually acceptable independent patent counsel not regularly
employed by either Party to assess such claims. 
Ikaria shall substitute the decision of such independent patent counsel
for that of its own counsel with respect to deciding whether to obtain a
license or immunity from suit from any Third Party in order for Ikaria, its
Affiliates, or any Licensee to exercise or use the rights granted to Ikaria
herein.


 


(c)           Duration
of Payments.  The amounts payable to
BioLineRx under Section 4.2 shall be paid on a Product-by-Product and
country-by-country basis until the expiration of the Royalty Term for such
Product in such country.


 


(d)           Price
Concessions.  Ikaria shall not, and
shall ensure that its Affiliates and Licensees do not, sell or distribute the
Product at a discount (including in the form of government mandated rebates)
(with or without consideration) in return substantially for (i) concessions
or consideration received in transactions involving products or services other
than the Product or (ii) concessions from any government or governmental
authority relating to products or services other than the Product.


 


Section 4.3            Reports and Accounting.


 


(a)           Reports;
Payments.  Ikaria shall deliver to
BioLineRx, within [**] days after the end of each calendar quarter, reasonably
detailed written accountings of Net Sales of Products that are subject to
payment obligations to BioLineRx for such calendar quarter.  Such quarterly reports shall indicate (i) gross
sales and Net Sales on a country-by-country basis, (ii) the calculation of
payment amounts owed to BioLineRx from such gross sales and Net Sales, and (iii) any
amounts set off pursuant to Section 4.2(b) against payments owed to
BioLineRx.  When Ikaria delivers such
accounting to BioLineRx, Ikaria shall also deliver all amounts due under Section 4.2
to BioLineRx for the calendar quarter. 
All payments shall be made by wire transfer to the account specified in Schedule
4.3(a).


 


(b)           Audits
by BioLineRx.  Ikaria shall keep, and
shall require its Affiliates and Licensees to keep, complete and accurate
records of the most recent [**] years relating to gross sales and Net Sales and
all information relevant under Section 4.1 and Section 4.2.  For the sole purpose of verifying amounts
payable to BioLineRx, BioLineRx shall have the right no more than [**] per
calendar year, at BioLineRx’s expense, to engage independent accountants to
review such records in the location(s) where such records are maintained
by Ikaria, its Affiliates, and its Licensees upon reasonable notice and during
regular business hours.  Prior to any
review conducted pursuant to this Section 4.3(b), BioLineRx’s accountants
shall have entered into a written agreement with Ikaria limiting the use of
such records to verification of the accuracy of payments due under this
Agreement and prohibiting the disclosure of any information contained in such
records to a Third Party and to BioLineRx for a purpose other than as set forth
in this Section 4.3(b).  The right
to audit any royalty report or quarterly report or payment shall extend for
[**] years from the end of the calendar year in which such royalty report or
quarterly report was delivered or such payment made.  Results of such review shall be made available
to Ikaria.  If the review reflects an
underpayment to BioLineRx, such underpayment shall be promptly remitted to
BioLineRx.  Likewise, if the review
reflects an overpayment, Ikaria shall be entitled 


 


17

















 


to reduce any subsequent payments by the amount of the
overpayment.  If the underpayment to
BioLineRx is equal to or greater than [**] percent ([**]%) of the amount that
was otherwise due, BioLineRx shall be entitled to have Ikaria reimburse
BioLineRx’s reasonable out-of-pocket costs of such review.


 


Section 4.4            Currency Amounts. 
All dollar ($) amounts specified in this Agreement are United States
Dollar amounts.


 


Section 4.5            Currency Exchange. 
With respect to sales of Products invoiced in U.S. Dollars and other
amounts received or paid by Ikaria, its Affiliates or Licensees in U.S.
Dollars, such amounts and the amounts payable hereunder shall be expressed in
U.S. Dollars.  With respect to sales of
Products invoiced in a currency other than U.S. Dollars and other amounts
received or paid by Ikaria, its Affiliates or Licensees in a currency other
than U.S. Dollars, such amounts and the amounts payable hereunder shall be
expressed in their U.S. Dollar equivalent calculated using the applicable rate
of exchange reported by The Wall Street Journal
(Eastern U.S. edition) on the last Business Day of the calendar quarter  to which the report under Section 4.3(a) relates.  All payments hereunder shall be made in U.S.
Dollars.


 


Section 4.6            Tax Withholding. 
The Parties shall use all reasonable and legal efforts to reduce tax
withholding on payments made to BioLineRx. 
The Parties agree to cooperate in good faith to provide one another with
such documents and certifications as are reasonably necessary to enable Ikaria
to minimize any withholding tax obligations. 
Ikaria shall promptly provide to BioLineRx documentation of the payment
of any withholding taxes that are paid pursuant to this Section 4.6,
including copies of receipts or other evidence reasonably required and
sufficient to allow BioLineRx to document such tax withholdings adequately for
purposes of claiming foreign tax credits and similar benefits.


 


Section 4.7            Upfront Payments Received Under Sublicenses.  If Ikaria receives an upfront payment
consideration under a sublicense granted to a Third Party under this Agreement,
Ikaria shall pay to BioLineRx ten percent (10%) of any such payment within 30
days after actual receipt thereof from the Third Party.


 


Article V

Intellectual Property Ownership, Protection and Related Matters


 


Section 5.1            Ownership of Inventions.


 


(a)           Intentionally
Omitted.


 


(b)           Intentionally
Omitted.


 


(c)           Inventorship.  Questions of inventorship shall be resolved
in accordance with United States patent laws. 
In the event of a dispute regarding inventorship, if the Parties are unable
to resolve the dispute, the Parties shall jointly engage mutually acceptable
independent patent counsel not regularly employed by either Party to resolve
such dispute.  The decision of such
independent patent counsel shall be binding on the Parties with respect to the
issue of inventorship.


 


18

















 


(d)           Further
Actions and Assignments.  Each Party
shall take all further actions and execute all assignments requested by the
other Party and reasonably necessary or desirable to vest in the other Party
the ownership rights set forth in this Section 5.1.


 


Section 5.2            Prosecution and Maintenance of Patent Rights.


 


(a)           Intentionally
Omitted.


 


(b)           BioLineRx
Intellectual Property.  Upon the
Effective Date, Ikaria shall assume responsibility for the management of the
preparation, filing prosecution and maintenance of any and all patent
applications, including any interference proceedings related thereto, included
in the BioLineRx Intellectual Property (including, for clarity, the Sublicensed
IP, BioLineRx Patent Rights and patents and patent applications that claim or
disclose BioLineRx Know-How).


 


(c)           BioLineRx
Step-in Right.  If Ikaria, on a
country-by-country basis, declines to file and prosecute, or elects not to take
actions necessary to avoid abandonment of, any patent applications or maintain
any patent in any country, in each case for which it has responsibility under Section 5.2(a) or
Section 5.2(b), it shall give BioLineRx reasonable notice to this effect
sufficiently in advance to permit BioLineRx to undertake such filing and
prosecution without a loss of rights, and thereafter BioLineRx may, upon
written notice to Ikaria, file and prosecute such patent applications and
maintain such patents in such country. 
If BioLineRx files, prosecutes or maintains any such patent application
or patent in such country and any resulting Valid Claim of BioLineRx Patent
Rights constitutes the only BioLineRx Patent Rights Covering the Product in
such country  (i.e., there are
no other BioLineRx Patent Rights Covering the Product in such country), then [**].


 


If BioLineRx exercises the
foregoing step-in right following the election by Ikaria to abandon all
existing BioLineRx Patent Rights in a given country, Ikaria shall, within [**]
days following BioLineRx’s written request, notify BioLineRx in writing whether
Ikaria intends to Commercialize a Product in the Field in such country.  If Ikaria notifies BioLineRx that Ikaria has
no intent to Commercialize a Product in the Field in such country, BioLineRx
may, upon written notice to Ikaria within [**] days of receipt of Ikaria’s
notice of lack of intent, exercise a right to directly Commercialize a Product
in the Field in such country.  If
BioLineRx provides Ikaria with such notice: [**].


 


(d)           Costs
and Expenses.  Ikaria shall pay the
costs and expenses of preparing, filing, prosecuting, and maintaining the Patent
Rights covered by Section 5.2(a) or Section 5.2(b), [**].


 


19

















 


(e)           Cooperation
Between Parties.  Each Party agrees
to cooperate with the other with respect to the preparation, filing,
prosecution and maintenance of Patent Rights pursuant to this Section 5.2,
including the execution of all such documents and instruments and the performance
of such acts as may be reasonably necessary in order to permit the other Party
to continue any preparation, filing, prosecution or maintenance of such Patent
Rights, including Patent Rights that such Party has elected not to pursue, as
provided for in subsections (a), (b) and (c) above.  In addition, the filing, prosecuting and
maintaining Party in subsections (a), (b) and (c) above shall
promptly forward to the other Party copies of any substantive correspondence
and actions prepared for or received from the U.S. Patent and Trademark Office
or any foreign patent office that may materially affect the Patent Rights being
prosecuted or maintained.  The other
Party’s patent counsel may provide comments to the filing, prosecuting and
maintaining Party.  If any comments by
the other Party’s patent counsel are provided in sufficient time for the
filing, prosecuting and maintaining Party to reflect such comments in its
correspondence or response, and such comments are reasonably directed to
maximizing the coverage of the claims of the Patent Rights being prosecuted or
maintained, the filing, prosecuting and maintaining Party shall reflect such
comments in its correspondence or response, if its patent counsel deems it
prudent to do so.


 


(f)            Coordination
with BioLineRx pursuant to the Sublicensed IP.  With respect to any Sublicensed IP which
Ikaria is responsible for filing, prosecuting, and maintaining, Ikaria shall:


 


(i)            consult
with BioLineRx regarding the preparation, filing, and prosecution of all patent
applications, and the maintenance of all patents, included within such
Sublicensed IP, including the content, timing, and jurisdiction of the filing
of such patent applications and their prosecution, and other details and
overall global strategy pertaining to the procurement and maintenance of Patent
Rights in such Sublicensed IP, and shall file, prosecute, and maintain all such
Patent Rights through a law or patent attorney firm selected by Ikaria and
approved by BioLineRx (and  BioLineRx
shall exercise its rights under the BGN License Agreement as may be necessary
to obtain BGN’s approval); and


 


(ii)           provide
BioLineRx with copies of all patent applications that claim or disclose such
Sublicensed IP, and BioLineRx shall exercise its rights under the BGN License
Agreement to ensure that BGN cooperates in a timely manner with Ikaria’s
efforts to register such Patent Rights, including by causing BGN to execute any
documents as may be required for such purpose.


 


BioLineRx shall take all actions required to remain
in compliance with the BGN License Agreement in connection with the foregoing.


 


Section 5.3            Third Party Infringement.


 


(a)           Notice.  Each Party shall promptly report in writing
to the other Party during the term of this Agreement any (i) known or
suspected infringement of any of the BioLineRx Patent 


 


20

















 


Rights or (ii) unauthorized use of any of the BioLineRx Know-How
of which such Party becomes aware, including, in the case of either clause (i) or
clause (ii) involving, or that may reasonably lead to, the Development,
Manufacture, use or Commercialization of a product or product candidate that is
or may be competitive with a Product in the Field (“Competitive Infringement”),
and shall provide the other Party with all available evidence supporting such
infringement, suspected infringement, unauthorized use or suspected
unauthorized use.


 


(b)           BioLineRx
Intellectual Property; Step-in Rights.


 


(i)            Ikaria
shall have the first right, but not the obligation, to initiate a suit or take
other appropriate action that either Party reasonably believes is required to
protect BioLineRx Intellectual Property from Competitive Infringement .  Ikaria shall give BioLineRx sufficient
advance notice of its intent to file any such suit or take any such action, and
the reasons therefor, and shall provide BioLineRx with an opportunity to make
suggestions and comments regarding such suit or action.  Thereafter, Ikaria shall keep BioLineRx
informed, and shall from time to time consult with BioLineRx regarding the
status of any such suit or action and shall provide BioLineRx with copies of
all material documents (i.e.,
complaints, answers, counterclaims, material motions, orders of the court,
memoranda of law and legal briefs, interrogatory responses, depositions,
material pre-trial filings, expert reports, affidavits filed in court,
transcripts of hearings and trial testimony, trial exhibits and notices of
appeal) filed in, or otherwise relating to, such suit or action.  Any recovery obtained as a result of any
proceeding pursuant to this subsection (b)(i), by settlement or otherwise,
shall be applied in the following order of priority: (A) first, each Party
shall be reimbursed, on a pro rata basis, for all costs incurred by such Party
in connection with such suit; and (B) second, [**].


 


(ii)           If
Ikaria chooses not to initiate a suit or take other appropriate action under
subsection (b)(i) above to protect BioLineRx Intellectual Property from
Competitive Infringement, Ikaria will so notify BioLineRx of its intention, in
which case BioLineRx shall have the right to initiate such suit or take such
other appropriate action.  BioLineRx
shall give Ikaria sufficient advance notice of its intent to file any such suit
or take any such action, and the reasons therefor, and shall provide Ikaria
with an opportunity to make suggestions and comments regarding such suit or
action.  Thereafter, BioLineRx shall keep
Ikaria informed, and shall from time to time consult with Ikaria regarding the
status of any such suit or action and shall provide Ikaria with copies of all
material documents (i.e.,
complaints, answers, counterclaims, material motions, orders of the court,
memoranda of law and legal briefs, interrogatory responses, depositions,
material pre-trial filings, expert reports, affidavits filed in court,
transcripts of hearings and trial testimony, trial exhibits and notices of
appeal) filed in, or otherwise relating to, such suit or action.  Any recovery obtained as a result of any
proceeding pursuant to this subsection (b)(ii), by settlement or otherwise,
shall be applied in the following order of priority: (A) first, each Party
shall be reimbursed, on a pro rata basis, for all costs incurred by such Party
in connection with such suit; and (B) second, any remainder shall be
shared [**]% for BioLineRx and [**]% for Ikaria.


 


(iii)          If
BioLineRx chooses not to initiate a suit or take other appropriate action under
subsection (b)(ii) above to protect Sublicensed IP from Competitive
Infringement and 


 


21

















 


BGN exercises its rights under the BGN License Agreement to prosecute,
prevent, or terminate such Competitive Infringement, any amount received by
BioLineRx in connection therewith, whether by settlement or otherwise, [**].


 


(c)           Claimed
Infringement.  If a Party becomes
aware of any claim that the Development, Manufacture, or Commercialization of
Products for use in the Field in the Territory infringes Patent Rights or any
other intellectual property rights of any Third Party, such Party shall
promptly notify the other Party.  In any
such instance, Ikaria shall have the exclusive right to settle such claim.


 


(d)           Patent
Invalidity Claim.  If a Third Party
at any time asserts a claim that any BioLineRx Patent Rights is invalid or
otherwise unenforceable (an “Invalidity Claim”), whether (i) as a
defense in an infringement action brought by Ikaria or BioLineRx pursuant to
subsection (b) above, or (ii) in an action brought against Ikaria or
BioLineRx referred to in subsection (c) above, or (iii) otherwise,
the Parties shall cooperate with each other in preparing and formulating a
response to such Invalidity Claim. 
Neither Party shall settle or compromise any Invalidity Claim without
the consent of the other Party, which consent shall not be unreasonably
withheld, conditioned or delayed.


 


(e)           Conduct
of Certain Actions; Costs.  Ikaria
shall have the sole and exclusive right to select counsel for any suit
initiated by it referenced in subsection (b)(i) above or against it referenced
in subsection (c) above, and BioLineRx shall have the sole and exclusive
right to select counsel for any suit initiated by it referenced in subsection
(b)(ii) above.  If required under
applicable law in order for a Party (the “Lead Party”) to initiate or
maintain such suit, the other Party shall join as a party to the suit.  Such other Party shall offer reasonable
assistance to the Lead Party in connection therewith at no charge to the Lead
Party except for reimbursement of such other Party’s reasonable out-of-pocket
expenses incurred in rendering such assistance. 
The Lead Party shall assume and pay all of its own out-of-pocket costs
incurred in connection with any litigation or proceedings referenced in the first
sentence of this subsection (e), including the fees and expenses of the counsel
selected by it.  Subject to applicable
law, the other Party shall have the right to participate and be represented in
any such suit by its own counsel at its own expense.


 


(f)            Coordination
with BGN.  With respect to any suit
to protect Sublicensed IP from infringement for which Ikaria is the Lead Party,
notwithstanding anything to the contrary in this Section 5.3:


 


(i)            if
required under applicable law in order for Ikaria to initiate or maintain such
suit, BioLineRx shall (A) exercise its rights under the BGN License
Agreement to cause BGN to join as a party to such suit, (B) exercise its
rights under the BGN License Agreement to obtain BGN’s approval of counsel
selected by Ikaria to represent Ikaria and BGN in such suit, and (C) [**];


 


(ii)              Ikaria shall not compromise or settle such suit without
the prior written consent of BGN, which consent BioLineRx shall exercise its
rights under the BGN License Agreement to obtain; and


 


22

















 


(iii)          any
recovery obtained by Ikaria as a result of such suit, by settlement or
otherwise, shall be applied in the following order of priority: (A) first,
each Party shall be reimbursed, on a pro rata basis, for all costs incurred by
such Party in connection with such suit (for clarity, BioLineRx shall be
reimbursed for any costs of BGN paid by BioLineRx in accordance with clause (i)(C) above);
(B) second, [**] percent ([**]%) of any remainder shall paid to BioLineRx
for remittance to BGN as provided in Section 10.1.2 of the BGN License
Agreement ; and (C) third, the remaining [**] percent ([**]%) shall be
retained by Ikaria; [**].


 


Article VI

Confidentiality; Non-Solicitation; Standstill


 


Section 6.1            Confidential Information.  Each Party agrees that all Confidential
Information disclosed to it or its Affiliates by the other Party (a) shall
not be used by the receiving Party or its Affiliates except to fulfill its
obligations or exercise its rights under this Agreement, (b) shall be
maintained in confidence by the receiving Party and its Affiliates, and (c) shall
not be disclosed by the receiving Party or its Affiliates to any Third Party
who is not a consultant of, or an advisor to, the receiving Party or its
Affiliates without the prior written consent of the disclosing Party, which
consent the disclosing Party may withhold in its sole discretion.  Notwithstanding the foregoing, either Party
may disclose Confidential Information of the other Party if such Party is
required to make such disclosure by applicable law, regulation or legal
process, including by Israeli securities laws, the rules or regulations of
the United States Securities and Exchange Commission (the “SEC”) or any
similar regulatory agency in a country other than the United States or of any
stock exchange, including the Tel Aviv Stock Exchange, in which event such
Party shall provide prior notice of such intended disclosure to such other
Party, if possible under the circumstances, and shall disclose only such
Confidential Information of the other Party as is required to be
disclosed.  If this Agreement shall be
included in any report, statement or other document filed by either Party or an
Affiliate of either Party pursuant to the preceding sentence, such Party shall
use, or shall cause its Affiliate, as the case may be, to use, reasonable
efforts to obtain confidential treatment from the SEC, similar regulatory
agency or stock exchange of any financial information or other information of a
competitive or confidential nature, and shall include in such confidentiality
request such provisions of this Agreement as may be reasonably requested by the
other Party.


 


Section 6.2            Disclosures to Employees, Consultants, Advisors, Etc.  Each Party agrees that it and its Affiliates
shall provide Confidential Information received from the other Party only to
the receiving Party’s respective employees, consultants, advisors, Licensees
and potential Licensees, and to the employees, consultants and advisors of the
receiving Party’s Affiliates, who have a need to know such Confidential
Information to assist the receiving Party in fulfilling its obligations under
this Agreement and only under conditions of confidentiality and non-use at
least as stringent as the conditions imposed by this Agreement, provided
that BioLineRx and Ikaria shall each remain responsible for any failure
by its and its Affiliates’ respective employees, consultants, advisors,
Licensees and potential Licensees to treat such information and materials as
required under Section 6.1.  For clarity,
(a) Ikaria is permitted to disclose Confidential Information to actual or
potential Licensees, acquirors or financing sources; and (b) BioLineRx is
permitted to disclose this Agreement and the Development Plan to BGN, solely to



 


23

















 


the extent required under the BGN License Agreement; provided  that
any such disclosure subjects the receiving Third Party to conditions of
confidentiality and non-use at least as stringent as the conditions imposed by
this Agreement.


 


Section 6.3            Non-Solicitation. 
During the term of this Agreement and continuing for [**] months after
the termination of this Agreement, neither Party shall directly or indirectly,
for its own account or for the account of others, urge, induce, entice, or in
any manner whatsoever solicit any employee directly involved in the activities
conducted pursuant to this Agreement to leave the employment of the other Party
or any of its Affiliates.  For purposes
of the foregoing, “urge”, “induce”, “entice” or “solicit” shall not be deemed
to mean: (a) circumstances where an employee of a Party initiates contact
with the other Party or any of its Affiliates with regard to possible
employment; or (b) general solicitations of employment not specifically
targeted at employees of a Party or any of its Affiliates, including responses
to general advertisements.


 


Section 6.4            Standstill. 
Neither Ikaria nor any of its Affiliates shall directly or indirectly,
for its own account or for the account of others, acquire more than [**] of the
equity or debt securities of BioLineRx, or urge, induce, entice or solicit any
Third Party to acquire the equity or debt securities of BioLineRx, in either
case without the consent of BioLineRx, which may be withheld in its sole discretion.  The obligations of Ikaria under this Section 6.4
shall terminate in the event that (a) any Third Party initiates a tender
or exchange offer, or otherwise publicly proposes or agrees to acquire, a
majority of the equity or debt securities of BioLineRx (provided that the
restrictions set forth in this Section 6.4 shall be reinstated in the
event that such tender or exchange offer, or proposal, is terminated or
withdrawn), (b) it is publicly disclosed that voting securities
representing at least [**] of the total voting power of BioLineRx have been
acquired by any one or more Third Parties, (c) BioLineRx publicly
announces that it intends to seek a Third Party acquirer (provided that the
restrictions set forth in this Section 6.4 shall be reinstated in the
event that BioLineRx publicly announces that it no longer is seeking a Third
Party acquirer and so notifies Ikaria in writing), (d) BioLineRx enters
into any agreement to merge with, or sell or dispose of [**] or more of its
assets or securities, or (e) this Agreement is terminated pursuant to Article VIII.  BioLineRx shall provide Ikaria with prompt
written notice of the occurrence of any of the foregoing events to the extent
permitted under applicable law.  For
clarity, the acquisition by any employee benefit plan of Ikaria or its
Affiliates in any diversified index, mutual or pension fund, which fund in turn
holds BioLineRx securities, shall not be deemed a breach of this Section 6.4.


 


Section 6.5            Term.  All
obligations of confidentiality imposed under this Article VI shall survive
until the date that is [**] years after the expiration or termination of this
Agreement.


 


Section 6.6            Publicity. 
During the term of this Agreement, the content of any press release or
public announcement relating to this Agreement or a Product shall be mutually
approved by the Parties, except that (a) a Party may issue such press
release or public announcement if the contents of such press release or public
announcement have previously been made public other than through a breach of
this Agreement by the issuing Party, (b) a Party may issue such a press
release or public announcement if it is advised by counsel that such press
release or public announcement is required by applicable law, regulation or
legal process, including by Israeli securities laws, the rules or
regulations of the SEC or any similar regulatory agency in a country 


 


24

















 


other than the United States or of any stock exchange, including the
Tel Aviv Stock Exchange, and (c) Ikaria shall remain free to issue press
releases and public announcements regarding the Development, Manufacturing,
Commercialization and use of Products in the Field, provided  that
Ikaria shall provide BioLineRx with advance notice of at least [**] days prior
to public disclosure of such releases and announcements or such shorter period
as required to comply with any applicable law. 
In addition, BioLineRx shall reasonably implement any changes that Ikaria
may recommend with respect to any filing to be made in accordance with the rules or
regulations of the SEC or any similar regulatory agency in a country other than
the United States or of any stock exchange, including the Tel Aviv Stock
Exchange; provided that such Ikaria shall only have the right to comment upon
portions of such filings that directly related to Ikaria or this
Agreement.  Nothing in the foregoing
shall require BioLineRx to implement any change that Ikaria may recommend that
is not consistent with the rules or regulations of the Israel Securities
Authority, Tel Aviv Stock Exchange, the rules or regulations of the SEC,
or any similar regulatory agency in a country other than the United States or
Israel, as advised in writing by BioLineRx’s legal counsel.  BioLineRx’s legal counsel will provide Ikaria
confirmation of such advise.


 


Section 6.7            Publications. 
The results of the Development Program may be published by a Party as
part of a scientific presentation or publication only after scientific review
by and approval of the Joint Development Committee unless the other Party,
acting reasonably, disapproves of the presentation or publication in writing
within [**] days after receipt of the presentation or publication.  Either Party may require that such Party’s
Confidential Information be redacted from such presentation or publication and
may reasonably require that other information also be redacted.  In addition, at the request of either Party,
the date of submission for presentation or publication shall be delayed for a
period of time sufficiently long to permit a Party to seek appropriate patent
protection.  Other than as provided for
herein, BioLineRx shall not make any publication regarding any Product or
containing any Confidential Information of Ikaria without the prior written consent
of Ikaria.  Notwithstanding the
foregoing, to the extent necessary or appropriate as determined in Ikaria’s
discretion, Ikaria may disclose information otherwise covered by this Section 6.7
in documents filed with the SEC.


 


Article VII

Representations and Warranties


 


Section 7.1            Representations of Authority.  BioLineRx and Ikaria each represents and
warrants to the other Party that, except for the consent of the OCS, it has
full corporate right, power and authority to enter into this Agreement and to
perform its respective obligations under this Agreement and that it has the
right to grant to the other Party the rights and licenses granted pursuant to
this Agreement.


 


Section 7.2            Consents. 
BioLineRx and Ikaria each represents and warrants to the other Party
that, except for the consent of the OCS, all necessary consents, approvals and
authorizations of all government authorities and other Persons required to be
obtained by it as of the date hereof in connection with the execution, delivery
and performance of this Agreement have been obtained.


 


25














 


Section 7.3            No Conflict.  BioLineRx and Ikaria each represents and
warrants to the other Party that, notwithstanding anything to the contrary in
this Agreement, except for the consent of the OCS, the execution and delivery
of this Agreement, the performance of such Party’s obligations in the conduct
of the collaboration and the licenses and rights to be granted pursuant to this
Agreement (a) do not conflict with or violate any requirement of
applicable laws or regulations existing as of the date hereof and (b) do
not conflict with, violate, breach or constitute a default under any
contractual obligations of such Party or any of its Affiliates existing as of
the date hereof.


 


Section 7.4            Enforceability.  BioLineRx and Ikaria each represents and
warrants to the other Party that this Agreement is a legal and valid obligation
binding upon it and is enforceable against it in accordance with its terms.


 


Section 7.5            Additional
BioLineRx Representations. 
BioLineRx represents and warrants to Ikaria that:


 


(a)           BioLineRx has
the right to grant the licenses granted to Ikaria on the terms set forth in
this Agreement;


 


(b)           BioLineRx is
not engaged with any Third Party in any Development efforts directed to
Products in the Field in the Territory other than with respect to the On-Going
Phase I/II Trial, the Other On-Going Trials or the Existing Product Agreements;


 


(c)           BioLineRx has
provided Ikaria with true and complete copies of each of the Existing Product
Agreements, each of which is in full force and effect in accordance with its
terms as of the date hereof, and has obtained all consents necessary for the
assignment to Ikaria of each of the Existing Product Agreements hereunder, and,
following such assignment, Ikaria shall have the legal right to exercise all
rights of BioLineRx that existed thereunder immediately prior to such
assignment;


 


(d)           to BioLineRx’s
Knowledge, the BioLineRx Patent Rights listed in Exhibit B are
valid and enforceable and constitute all of the Patent Rights necessary or
useful for Ikaria to fully exercise and enforce its rights hereunder;


 


(e)           to BioLineRx’s
Knowledge, the BioLineRx Patent Rights are not being infringed and the
BioLineRx Know-How is not being misappropriated by any Third Party;


 


(f)            BioLineRx owns
the entire right, title and interest in and to the BioLineRx Intellectual
Property (other than the Sublicensed IP) free and clear of any liens, charges,
claims and encumbrances, and no other Person has any claim of ownership or
right to obtain compensation with respect to such BioLineRx Intellectual
Property;


 


(g)           to BioLineRx’s
Knowledge, the Products developed in the Development Program and the
Development, Manufacture and Commercialization of such Products will not
infringe or misappropriate any intellectual property rights not licensed to
Ikaria hereunder; and


 


(h)           BioLineRx has
not received and has no Knowledge of any claim or demand of any Person
pertaining to, or any proceeding which is pending or threatened that asserts,
the 


 


26

















 


invalidity, misuse or unenforceability of the BioLineRx Patent Rights
or that challenges BioLineRx’s ownership of the BioLineRx Intellectual Property
or that makes any adverse claim with respect thereto, and, to the Knowledge of
BioLineRx, there is no basis for any such claim, demand or proceeding.


 


Section 7.6            BGN License
Agreement.  BioLineRx
represents, warrants and covenants to Ikaria that:


 


(a)           BioLineRx has
provided Ikaria with a true and complete copy of the BGN License Agreement,
which is in full force and effect in accordance with its terms as of the date
hereof;


 


(b)           BioLineRx shall
obtain and provide to Ikaria within ten (10) days of execution of this
Agreement a written statement from BGN certifying that the terms of this
Agreement are consistent with those of the BGN License Agreement, including in
the context of Section 13.4.1(c) thereof;


 


(c)           BioLineRx has (i) achieved
by its designated performance date each Milestone (as that term is defined in
the BGN License Agreement) having a designated performance date on or before
the date hereof, or obtained a waiver in respect thereof, and (ii) neither
(A) committed any material breach of the its obligations under the BGN
License Agreement nor (B) received any notice from BGN of any alleged
material breach thereof by BioLineRx or of any Failure (as that term is defined
therein);


 


(d)           BioLineRx shall
upon receipt by BioLineRx promptly provide Ikaria with a copy of any notice
from BGN described in the foregoing clause (c)(ii)(B);


 


(e)           BioLineRx shall
not terminate, amend, supplement or otherwise modify the BGN License Agreement
without Ikaria’s prior written consent;


 


(f)            the rights and
obligations of BioLine Jerusalem L.P. under the BGN License Agreement have been
assigned and delegated, or otherwise transferred, to BioLineRx;


 


(g)           as between
BioLineRx and Ikaria, BioLineRx shall be responsible for any and all payments
to be made under the BGN License Agreement;


 


(h)           in the event of
any termination of the BGN License Agreement, BioLineRx shall, at Ikaria’s request,
provide all reasonable assistance to Ikaria in Ikaria’s efforts to obtain from
BGN an exclusive license to the Sublicensed IP, including through enforcement
of the provisions of Sections 5.2.3 and 13.4.1(c) of the BGN License
Agreement.


 


Section 7.7            Employee,
Consultant and Advisor Legal Obligations.  BioLineRx and Ikaria each represents and
warrants that each of its and its Affiliates’ employees, consultants and
advisors who is or will be involved in performing any obligations hereunder has
executed or will have executed an agreement or have an existing obligation
under law requiring assignment to such Party of all intellectual property made
during the course of and as the result of his, her or its association with such
Party or such Affiliate, and obligating such employee, consultant or advisor to
maintain the confidentiality of Confidential Information to the extent required
under 


 


27

















 


Article VI.  BioLineRx and
Ikaria each represents and warrants that, to its Knowledge, none of its or its
Affiliates’ employees, consultants or advisors who is or will be involved in
performing any obligations hereunder is, as a result of the nature of such
obligations to be performed by the Parties, in violation of any covenant in any
contract relating to non-disclosure of proprietary information, non-competition
or non-solicitation.


 


Section 7.8            Accuracy of
Representations and Warranties on Effective Date.  The representations and warranties of each of
the Parties set forth in the preceding sections of this Article VII remain
true and accurate on and as of the Effective Date.  Each Party shall promptly following receipt
of acceptable consent from the OCS deliver to the other Party a certificate to
such effect executed by its Chief Executive Officer.


 


Section 7.9            No Warranties.  EXCEPT AS OTHERWISE EXPRESSLY SET FORTH IN
THIS AGREEMENT, THE PARTIES MAKE NO REPRESENTATIONS AND EXTEND NO WARRANTIES OF
ANY KIND, EITHER EXPRESS OR IMPLIED, INCLUDING THAT ANY PRODUCTS WILL BE ECONOMICALLY
OR TECHNICALLY UTILIZABLE, THAT ANY SALES OF ANY PRODUCTS WILL OCCUR, THAT THE
DEVELOPMENT PROGRAM ACTIVITIES WILL BE COMPLETED IN THE EXPECTED TIMEFRAME, OR
THAT ANY PRODUCT WILL BE FREE OF ANY THIRD PARTY RIGHTS.


 


Article VIII

Term and Termination


 


Section 8.1            Term.  The term of this Agreement shall begin on the
Effective Date, may be terminated as set forth in this Article VIII, and
shall expire on a Product-by-Product and country-by-country basis upon the date
of expiration of the Royalty Term for such Product in such country, and shall
expire in its entirety upon the last-to-expire Royalty Term, unless earlier
terminated as set forth in this Article VIII.


 


Section 8.2            Termination for
Material Breach.  Upon any
breach of a material provision of this Agreement by a Party (the “Breaching
Party”), the other Party (the “Non-Breaching Party”) may terminate
this Agreement by providing ninety (90) days written notice to the Breaching
Party specifying the material breach. 
The termination shall become effective at the end of the notice period
unless the Breaching Party cures such breach during such notice period.  Ikaria may terminate this Agreement pursuant
to this Section 8.2 immediately upon any termination of the BGN License
Agreement.


 


Section 8.3            Development-Related
Termination.  Ikaria
shall have the right to terminate this Agreement upon sixty (60) days prior
written notice, if Ikaria at any time determines, in its sole judgment, that
the results of the Development Program do not warrant further Development of
Products.


 


Section 8.4            Effect of
Certain Terminations and Expiration.


 


(a)           If this
Agreement is terminated by Ikaria under Section 8.2:


 


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(i)            The licenses
granted by BioLineRx to Ikaria under Section 2.1 and, notwithstanding any
other provision in this Agreement to the contrary, Ikaria’s obligations under Section 4.2,
shall survive;


 


(ii)           Section 2.2
shall survive until Ikaria is no longer obligated to pay royalties to BioLineRx
under Section 4.2; and


 


(iii)          Section 5.1
and Section 5.3 shall survive.


 


(b)           If this
Agreement is terminated by either BioLineRx under Section 8.2, or by
Ikaria under Section 8.3, the licenses granted under Section 2.1
shall terminate as of the effective date of such termination; provided, however,
that Ikaria, its Affiliates, and its Licensees shall be afforded a commercially
reasonable period of time (but no less than [**] months) to sell off any then
existing or in process stocks of the Products, subject to the terms and
conditions of this Agreement, including the payment of royalties thereon.


 


(c)           Upon any
termination or expiration of this Agreement, each Party shall return to the
other Party any tangible property owned by the other Party, including any books
and records and Confidential Information, in accordance with the reasonable
instructions given by the other Party, with any shipping costs to be borne by
the other Party, provided, however, that a Party may
retain a copy of any regulatory records it is required to maintain in
accordance with applicable law.


 


Section 8.5            Survival.  In the event of any expiration or termination
of this Agreement, (a) all financial obligations under Article IV and
Article V owed as of the effective date of such expiration or termination
shall remain in effect, including such obligations that have accrued, but have
not been invoiced, as of such effective date, and (b) the obligations set
forth in Section 5.1, Article VI, Article IX and Article X,
and all other terms, provisions, representations, rights and obligations
contained in this Agreement that by their express terms survive expiration or
termination of this Agreement (including Section 8.4 and this Section 8.5),
shall survive and all other terms, provisions, representations, rights and
obligations contained in this Agreement shall terminate.


 


Section 8.6            Termination
Prior to Effective Date. 
Notwithstanding anything to the contrary in this Article VIII,
Ikaria may terminate this Agreement prior to the Effective Date, with no liability
to BioLineRx, if the OCS does not consent to the Agreement in a form reasonably
satisfactory to both Parties within forty-five (45) days after the execution of
this Agreement.  The provisions of Article X
(except for Section 10.1(a)) and this Section 8.6 shall survive such
termination, and all other terms, provisions, representations, rights and
obligations contained in this Agreement shall terminate.


 


Article IX

Dispute Resolution


 


Section 9.1            Negotiation.  Any controversy, claim or dispute arising out
of or relating to this Agreement shall be settled, if possible, through good
faith negotiations between the Parties.


 


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Section 9.2            Escalation.  If the Parties are unable to settle any
dispute after good faith negotiations pursuant to Section 9.1 after [**]
days, such dispute (except for any matter that by its express terms shall be
resolved as provided in this Agreement, including any matter arising under Section 3.2
or Section 3.6) shall be referred to the Executive Officers to be resolved
by negotiation in good faith as soon as is practicable but in no event later
than [**] days after referral.


 


Section 9.3            Mediation.  Solely with respect to a dispute as to
whether Ikaria has breached its obligations to use Commercially Reasonable
Efforts as set forth in Section 3.8, if the Executive Officers are unable
to settle such dispute after good faith negotiations pursuant to Section 9.2
within [**] days after referral to the Executive Officers, the Parties shall,
within [**] days thereof, engage a mutually agreeable Third Party mediator on a
non-binding basis to assist the Parties in determining whether such a breach
has occurred.  The Parties agree that
they will participate in good faith in an effort to resolve the dispute in an
informal, inexpensive and expeditious manner and that any mediator selected
shall agree to render any judgments in a timely manner, but no later than [**]
days after the mediator is selected.  All
expenses of the mediator will be shared equally by the Parties.


 


Section 9.4            Litigation.  If the Executive Officers are unable to
settle any dispute after good faith negotiations pursuant to Section 9.2
(other than a dispute as to whether Ikaria has breached its obligations to use
Commercially Reasonable Efforts as set forth in Section 3.8) within [**]
days after referral, or if the Parties continue to dispute whether Ikaria has
breached its obligations to use Commercially Reasonable Efforts as set forth in
Section 3.8 following mediation pursuant to Section 9.3, then either
Party may seek resolution of the dispute (except for any matter that by its
express terms shall be resolved as provided in this Agreement, including any
matter arising under Section 3.2 or Section 3.6) through remedies
available at law or in equity from any court of competent jurisdiction as set
forth in Section 10.3.


 


Section 9.5            Equitable
Relief.  Each Party acknowledges and
agrees that the other Party would be damaged irreparably if any of the
provisions of Article II, Article V and Article VI are not
performed in accordance with their specific terms or otherwise are
breached.  Accordingly, each Party agrees
that the other Party shall be entitled to an injunction or other equitable
relief to prevent breaches of such provisions, to preserve status quo, and to
enforce specifically such provisions in any action instituted in any court
having jurisdiction over the Parties and the matter, in addition to any other
remedy to which it may be entitled, at law or in equity.


 


Article X

Miscellaneous Provisions


 


Section 10.1          Indemnification.


 


(a)           By Ikaria.  Ikaria agrees to defend BioLineRx, its
Affiliates and their respective directors, officers, employees and agents at
Ikaria’s cost and expense, and shall indemnify and hold harmless BioLineRx and
its Affiliates and their respective directors, officers, employees and agents
from and against any liabilities, losses, costs, damages, fees or expenses
(collectively, “Losses”) arising out of any Third Party claim to the
extent relating to (i) any breach by Ikaria of any of its representations,
warranties or obligations pursuant to this Agreement, or (ii) personal 


 


30

















 


injury, property damage, product liability or other damage resulting
from the Development, Manufacture, use or Commercialization of a Product by
Ikaria or its Affiliates or Licensees, excluding any claim for which BioLineRx
indemnifies Ikaria under subsection (b) below.


 


(b)           By BioLineRx.  BioLineRx agrees to defend Ikaria, its Affiliates
and their respective directors, officers, employees and agents at BioLineRx’s
cost and expense, and shall indemnify and hold harmless Ikaria and its
Affiliates and their respective directors, officers, employees and agents from
and against any Losses arising out of any Third Party claim to the extent
relating to (i) any breach by BioLineRx of any of its representations,
warranties or obligations pursuant to this Agreement, (ii) personal
injury, property damage or other damage resulting from the conduct of the
On-Going Phase I/II Trial or the Other On-Going Trials by or on behalf of
BioLineRx or its Affiliates, (iii) the BGN Agreement, or (iv) any
allegation that the practice of the BioLineRx Intellectual Property rights in
the Development Program infringes or misappropriates any Third Party
intellectual property rights, to the extent BioLineRx had Knowledge that such
practice would infringe or misappropriate such Third Party intellectual
property rights on or before the Effective Date.


 


(c)           Claims for
Indemnification.  A Person
entitled to indemnification under this Section 10.1 (an “Indemnified
Party”) shall give prompt written notification to the Party from whom
indemnification is sought (the “Indemnifying Party”) of the commencement
of any action, suit or proceeding relating to a Third Party claim for which
indemnification may be sought or, if earlier, upon the assertion of any such
claim by a Third Party (it being understood and agreed, however, that the
failure by an Indemnified Party to give notice of a Third Party claim as
provided in this Section 10.1(c) shall not relieve the Indemnifying
Party of its indemnification obligation under this Agreement except and only to
the extent that such Indemnifying Party is actually damaged as a result of such
failure to give notice).  Within [**]
days after delivery of such notification, the Indemnifying Party may, upon
written notice thereof to the Indemnified Party, assume control of the defense
of such action, suit, proceeding or claim with counsel reasonably satisfactory
to the Indemnified Party.  If the
Indemnifying Party does not assume control of such defense, the Indemnified
Party shall control such defense.  The
Party not controlling such defense may participate therein at its own
expense.  The Party controlling such
defense shall keep the other Party advised of the status of such action, suit,
proceeding or claim and the defense thereof and shall consider recommendations
made by the other Party with respect thereto. 
The Indemnified Party shall not agree to any settlement of such action,
suit, proceeding or claim without the prior written consent of the Indemnifying
Party, which consent the Indemnifying Party shall not unreasonably withhold,
condition or delay.  The Indemnifying
Party shall not agree, without the prior written consent of the Indemnified
Party, which consent the Indemnified Party shall not unreasonably withhold,
condition or delay, to any settlement of such action, suit, proceeding or claim
or consent to any judgment in respect thereof that does not include a complete
and unconditional release of the Indemnified Party from all liability with
respect thereto or that imposes any liability or obligation on the Indemnified
Party.


 


Section 10.2          Governing Law.  This Agreement shall be construed and the
respective rights of the Parties determined in accordance with the laws of the
State of New York, USA (other than any principle of conflict or choice of laws
that would cause the application of the laws of any other jurisdiction).


 


31

















 


Section 10.3          Submission to
Jurisdiction.  Each Party (a) submits
to the jurisdiction of any state or federal court sitting in the State of New
York, USA in any action or proceeding arising out of or relating to this Agreement,
(b) agrees that all claims in respect of such action or proceeding may be
heard and determined in any such court, (c) waives any claim of
inconvenient forum or other challenge to venue in such court, and (d) agrees
not to bring any action or proceeding arising out of or relating to this
Agreement in any other court, unless the state or federal courts sitting in the
State of New York decline to exercise jurisdiction over any such action or
proceeding or if those courts lack proper jurisdiction, then any action or
proceeding arising out of or relating to this Agreement may be brought in any
other U.S. court of competent jurisdiction. 
Each Party agrees to accept service of any summons, complaint or other
initial pleading made in the manner provided for the giving of notices in Section 10.6,
provided  that nothing in this Section 10.3 shall affect the
right of either Party to serve such summons, complaint or other initial
pleading in any other manner permitted by law.


 


Section 10.4          Assignment.  Ikaria may assign this Agreement or any right
hereunder, or delegate any obligation hereunder, in its sole discretion, to (a) any
Affiliate of Ikaria or (b) any entity acquiring all or substantially all
of the assets of Ikaria Holdings, Inc. and its Affiliates.  All other assignments by Ikaria, including (i) to
any entity acquiring all or substantially all of the assets of Ikaria to which
this Agreement relates or (ii) to any entity with which or into which
Ikaria may consolidate or merge, are subject to BioLineRx’s prior approval,
which approval shall not be unreasonably withheld, conditioned or delayed.  BioLineRx may assign its right to receive
payments hereunder to a Third Party, in its sole discretion, but BioLineRx
shall not otherwise be permitted to assign this Agreement, in whole or in part,
without the prior written consent of Ikaria, which approval shall not be
unreasonably withheld, conditioned or delayed. 
Any assignments in contravention of this Section 10.4 shall be null
and void.


 


Section 10.5          Entire Agreement;
Amendments.  This
Agreement constitutes the entire agreement between the Parties with respect to
the subject matter hereof, and supersedes all previous arrangements between the
Parties with respect to the subject matter hereof, whether written or oral,
except for that certain Mutual Non Disclosure Agreement between the Parties
dated February 25, 2009.  Without
limiting the generality of the foregoing, this Agreement hereby supersedes and
replaces in its entirety the License and Commercialization Agreement by and
among the parties dated as of July 5th, 2009.  To
the extent that any provision of this Agreement conflicts with any provisions
of such Mutual Non Disclosure Agreement, the provision of this Agreement shall
control.  Except as set forth in Section 2.1(iv),
any amendment or modification to this Agreement shall be made in writing signed
by both Parties.


 


Section 10.6          Notices.


 


Notices to Ikaria shall be addressed to:


 


Ikaria
Development Subsidiary One LLC

6 State Route 173

Clinton, NJ 08809, USA

Attention: Chief Executive Officer


 


with
copy to:


 


32

















 


Ikaria
Holdings, Inc.

6 State Route 173

Clinton, NJ 08809, USA

Attention: General Counsel


 


Notices to BioLineRx Ltd. shall be addressed
to:


 


BioLineRx
Ltd.

19 Hartum Street

P.O. Box 45158

Jerusalem 91450, Israel

Attention:  Chief Executive Officer


 


with
copy to:


 


Arent
Fox LLP

1050 Connecticut Avenue

Washington, DC  20036, USA

Attention: John Dwyer, Esq.


 


Notices to BioLine Innovations Jerusalem L.P.
shall be addressed to:


 


BioLine
Innovations Jerusalem L.P.

19 Hartum Street

P.O. Box 45158

Jerusalem 91450, Israel

Attention:  Chief Executive Officer


 


with
copy to:


 


Arent
Fox LLP

1050 Connecticut Avenue

Washington, DC  20036, USA

Attention: John Dwyer, Esq.


 


Any Party may change its address by giving notice to
the other Party in the manner herein provided. 
Any notice required or provided for by the terms of this Agreement shall
be in writing and shall be (a) sent by registered or certified mail,
return receipt requested, postage prepaid, (b) sent via a reputable
international courier service, (c) sent by facsimile transmission, or (d) personally
delivered, in each case properly addressed in accordance with the paragraph
above.  The effective date of notice shall
be the actual date of receipt by the Party receiving the same.


 


Section 10.7          Force Majeure.  No failure or omission by a Party in the
performance of any obligation of this Agreement shall be deemed a breach of
this Agreement or create any liability if the same shall arise from any cause
or causes beyond the control of such Party, including the following: acts of
God; fire; storm; flood; earthquake; accident; war; rebellion; insurrection;
riot; and invasion (each such event, a “Force Majeure Event”) and provided
that such Party cures such 


 


33

















 


failure or omission resulting from one of the above causes as soon as
is practicable after the occurrence of one or more of the above-mentioned
causes.


 


Section 10.8          Independent
Contractors.  It is
understood and agreed that the relationship between the Parties hereunder is
that of independent contractors and that nothing in this Agreement shall be
construed as authorization for either BioLineRx or Ikaria to act as agent for
the other.


 


Section 10.9          Limitations of
Liability.  NEITHER
PARTY SHALL BE LIABLE FOR ANY INDIRECT, INCIDENTAL, CONSEQUENTIAL, SPECIAL,
EXEMPLARY OR PUNITIVE DAMAGES ARISING OUT OF THIS AGREEMENT OR THE EXERCISE OF
ITS RIGHTS HEREUNDER, OR FOR LOST PROFITS ARISING FROM OR RELATING TO ANY
BREACH OF THIS AGREEMENT, REGARDLESS OF ANY NOTICE OF SUCH DAMAGES.  NOTHING IN THIS SECTION 10.9 IS INTENDED
TO LIMIT OR RESTRICT (A) THE INDEMNIFICATION RIGHTS OR OBLIGATIONS OF
EITHER PARTY WITH RESPECT TO THIRD PARTY CLAIMS; (B) ANY LOSSES, INCLUDING
LOST PROFITS, ARISING FROM ANY (I) BREACH OF A PARTY’S OBLIGATIONS WITH
RESPECT TO THE OTHER PARTY’S CONFIDENTIAL INFORMATION, (II) BREACH BY
BIOLINERX OF THE EXCLUSIVE RIGHTS GRANTED IN SECTION 2.1 OR THE COVENANT
CONTAINED IN SECTION 2.2, OR (III) USE OF ANY PATENT RIGHTS OR
KNOW-HOW LICENSED HEREUNDER BEYOND THE SCOPE OF SUCH LICENSE; OR (C) ANY
LOSSES ARISING AS A RESULT OF A PARTY’S FRAUD, GROSS NEGLIGENCE OR WILLFUL
MISCONDUCT.


 


Section 10.10       No Implied
Waivers; Rights Cumulative.  No failure on the part of BioLineRx or Ikaria
to exercise, and no delay in exercising, any right, power, remedy or privilege
under this Agreement, or provided by statute or at law or in equity or
otherwise, shall impair, prejudice or constitute a waiver of any such right,
power, remedy or privilege or be construed as a waiver of any breach of this
Agreement or as an acquiescence thereto, nor shall any single or partial
exercise of any such right, power, remedy or privilege preclude any further or
other exercise thereof or the exercise of any other right, power, remedy or
privilege.


 


Section 10.11       Severability.  If, under applicable law or regulation, any
provision of this Agreement is invalid, incomplete or unenforceable, or
otherwise directly or indirectly affects the validity of any other material
provision(s) of this Agreement (such invalid, incomplete or unenforceable
provision, a “Severed Clause”), this Agreement shall endure except for
the Severed Clause.  The Parties shall
consult one another and use reasonable efforts to agree upon a valid, complete
and enforceable provision that is a reasonable substitute for the Severed
Clause in view of the intent of this Agreement.


 


Section 10.12       Execution in
Counterparts; Facsimile Signatures.  This Agreement may be executed in
counterparts, each of which, when so executed and delivered, shall be deemed to
be an original, and all of which, taken together, shall constitute one and the
same instrument even if both Parties have not executed the same counterpart.  Signatures provided by facsimile transmission
shall be deemed to be original signatures.


 


REMAINDER
OF PAGE LEFT EMPTY; NEXT PAGE IS THE SIGNATURE PAGE


 


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IN WITNESS WHEREOF, the Parties have executed this
License and Commercialization Agreement as of the Effective Date.


 


 


	
   

  	
  IKARIA DEVELOPMENT SUBSIDIARY ONE LLC

  
	
   

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
   

  	
  By:

  	
  /s/
  Matthew M. Bennett

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
   

  	
  Name:

  	
  Matthew
  M. Bennett

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
   

  	
  Title:

  	
  Senior
  Vice President

  
	
   

  	
   

  	
   

  
	
   

  	
   

  	
   

  
	
   

  	
  BIOLINERX LTD.

  
	
   

  	
   

  
	
   

  	
   

  	
   

  	
   

  	
   

  
	
   

  	
  By:

  	
  /s/
  Morris Laster M.D.

  	
   

  	
   

  
	
   

  	
   

  	
   

  	
   

  	
   

  
	
   

  	
  Name:
  

  	
  Morris
  Laster M.D.

  	
   

  	
   

  
	
   

  	
   

  	
   

  	
   

  	
   

  
	
   

  	
  Title:

  	
  CEO

  	
   

  	
   

  
	
   

  	
   

  	
   

  	
   

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
   

  	
  BIOLINE INNOVATIONS JERUSALEM L.P.

  by its General Partner, BioLine Innovations Jerusalem, Ltd.

  
	
   

  	
   

  
	
   

  	
   

  	
   

  	
   

  	
   

  
	
   

  	
  By:

  	
  /s/
  Morris Laster M.D.

  	
   

  	
   

  
	
   

  	
   

  	
   

  	
   

  	
   

  
	
   

  	
  Name:

  	
  Morris
  Laster M.D.

  	
   

  	
   

  
	
   

  	
   

  	
   

  	
   

  	
   

  
	
   

  	
  Title:

  	
  Director

  	
   

  	
   

  



 


35

















 


SCHEDULE
1.30


 


PROTOCOL
FOR ON-GOING PHASE I/II TRIAL


 


[PROTOCOL IMMEDIATELY FOLLOWS]


 














 





 


CLINICAL
STUDY


 


Protocol
No. BL-1040.01

Version 5.00 Incorporating Amendments 1, 2, 3 and 4

Safety and Feasibility

Final


 


A
Phase I, multi-center, open label study designed to assess

the safety and feasibility of the injectable BL-1040 implant to

provide scaffolding to infarcted myocardial tissue


 


BioLine
Innovations Jerusalem


 


Confidentiality
Statement


 


This document contains
information that is the property of BioLine Innovations Jerusalem and therefore
is provided to you in confidence for review by you, your staff, an applicable
ethics committee/institutional review board and regulatory authorities. It is
understood that this information will not be disclosed to others without
written approval from BioLine innovations Jerusalem, except to the extent necessary
to obtain informed consent from those persons to whom BL-1040 may be
administered.


 


Annotated Protocol incorporating
Amendment 1, Amendment 2, Amendment 3, and Amendment 4 


01 December 2008


 

















 


	
  

  	
  Protocol
  BL-1040.01, Version 5.00

  Safety and Feasibility study of BL-1040

  Final

  	
  CONFIDENTIAL

  



 


	
  PROTOCOL NUMBER:

  	
  BL-1040.01 Safety and
  Feasibility

  
	
   

  	
   

  
	
  DATE OF PROTOCOL:

  	
  Final, 01 December 2008

  Version 2 incorporating Amendment 1, 07 August 2007

  Version 3 incorporating Amendment 2, 03 December 2007

  Version 4 incorporating Amendment 3, 17 April 2008

  Version 5 incorporating Amendment 4, 27
  November 2008

  
	
   

  	
   

  
	
  PROTOCOL TITLE:

  	
  A Phase I,
  multi-center, open label study designed to assess the safety and feasibility
  of the injectable BL-1040 implant to provide scaffolding to infarcted
  myocardial tissue

  
	
   

  	
   

  
	
  SPONSOR:

  	
  BioLine Innovations
  Jerusalem

  



 


Responsible study personnel:


 


	
  Name:

  	
  Prof. Moshe
  Phillip, MD, Vice-President of Medical Affairs, Sr. Clinical Advisor

  
	
  Address:

  	
  BioLine
  Innovations Jerusalem, 19 Hartum St., POB 45158

  Jerusalem, Israel 91450

  
	
  Phone:

  	
  +972-2-548-9100

  
	
  Fax:

  	
  +972-2-548-9101

  
	
  e-mail:

  	
  moshep@biolinerx.com

  
	
   

  	
   

  
	
  Name:

  	
  Shmuel Tuvia, PhD

  
	
  Address:

  	
  BioLine Innovations
  Jerusalem, 19 Hartum St., POB 45158

  Jerusalem, Israel 91450

  
	
  Phone:

  	
  +972-2-548-9100, ext. 124

  
	
  Fax:

  	
  +972-2-548-9101

  
	
  e-mail:

  	
  shmuelt@biolinerx.com

  
	
   

  	
   

  
	
  Name:

  	
  Moti Gal, Clinical
  Operations Manager

  
	
  Address:

  	
  BioLine Innovations
  Jerusalem, 19 Hartum St., POB 45158

  Jerusalem, Israel 91450

  
	
  Phone:

  	
  +972-2-548-9100, ext.
  147

  
	
  Fax:

  	
  +972-2-548-9101

  
	
  e-mail:

  	
  motig@biolinerx.com

  
	
   

  	
   

  
	
  Name:

  	
  Jonathan Leor, MD,
  Medical Advisor

  
	
  Address:

  	
  Head, Neufeld Cardiac
  Research Institute.

  Tel-Aviv University

  Sheba Medical Center

  Tel-Hashomer, Israel 52621

  
	
  Phone:

  	
  +972-3-534-8685,
  972-3-530-2614

  
	
  Fax:

  	
  +972-3-535-1139

  
	
  e-mail:

  	
  leorj@post.tau.ac.il

  
	
   

  	
   

  
	
  CRO:

  	
  Venn Life Sciences AG

  
	
  Address:

  	
  Elisabethenstrasse
  23/3, CH- 4051 Basel

  
	
  Phone:

  	
  +41 61 201 11 00Fax:     +41
  61 273 42 50

  
	
   

  	
   

  
	
  Authorized
  representative:

  	
  Voisin Consulting

  
	
  Address:

  	
  3, rue des Longs Prés, 92100 Boulogne, France

  
	
  Phone:

  	
  +33-1-41-31-8300

  
	
  Fax:

  	
  +33-1 41-31-8309

  
	
  e-mail:

  	
  voisin@voisinconsulting.com

  
			



 


Page 2 of 52

















 


	
  Medical Monitor, US
  (ISMB support only)

  
	
  Name:

  	
  Sanjay Machado,
  MD

  
	
  Address:

  	
  Venn Life
  Sciences Group

  
	
   

  	
  7355 TransCanada Hwy

  
	
   

  	
  Suite 200

  
	
   

  	
  Saint-Laurent, Quebec, Canada H4T 1T3

  
	
   

  	
   

  
	
  Phone:

  	
  +1 514.315.2992
  ext 117

  
	
  Fax:

  	
  +1 514.315.0995

  
	
  e-mail:

  	
  sanjay.machado@vlsworldwide.com

  
	
   

  	
   

  
	
  Medical Monitor, Europe

  	
   

  
	
  Name:

  	
  Andrea
  Kempf-Mueller, MD

  
	
  Address:

  	
  Venn Life Sciences
  AG

  
	
   

  	
  Elisabethenstrasse
  23/3, 4051 Basel, Switzerland

  
	
  Phone:

  	
  +41 61 201 11 83

  
	
  Fax:

  	
  +41 61 273 42 50

  
	
  e-mail:

  	
  andrea.kempf-mueller@vlsworldwide.com

  



 


Page 3 of 52

















 


Investigator’s
Signature Page


 


INVESTIGATOR:


 


	
  Name:

   

  Address:

  	
   

  
	
   

  Phone:

  Fax:

  e-mail:

  	
   

  



 


I, the undersigned, have
reviewed this Protocol, including Appendices, and I will conduct the clinical
study as described and will adhere to GCP/ICH and all the ethical and
regulatory considerations stated. I have read and understood the contents of
the Investigator Brochure.


 


 


	
  Date/Place

  	
   

  	
   

  	
  Signature

  	
   

  
	
   

  	
   

  	
   

  	
  (Name of Investigator)

  



 


Page 4 of 52

















 


Sponsor
Signature Page


 


	
  Sponsor:

  Address:

  	
  BioLine
  Innovations Jerusalem

  19 Hartum St., POB 45158

  Jerusalem, Israel 91450

  
	
  Phone:

  Fax:

  e-mail:

  	
  +972-2-548-9100

  +972-2-548-9101

  Info@biolineRx.com

  



 


I
have read the protocol and confirm that the protocol follows the current GCP
guidelines.


 


 


	
  Date/Place

  	
  27 Jan 2009

  	
   

  	
  Signature

  	
  /s/ Moshe Phillip

  
	
   

  	
   

  	
   

  	
  (Prof Moshe Phillip, VP of Medical Affairs, Sr. Clinical Advisor)

  
	
   

  	
   

  	
   

  	
   

  
	
  Date/Place

  	
  27 Jan 2009

  	
   

  	
  Signature

  	
  /s/ Shmuel Tuvia

  
	
   

  	
   

  	
   

  	
  (Shmuel Tuvia, PhD, Project Manager)

  
	
   

  	
   

  	
   

  	
   

  
	
  Date/Place

  	
  27 Jan 2009

  	
   

  	
  Signature

  	
  /s/ Moti Gal

  
	
   

  	
   

  	
   

  	
  (Moti Gal, Clinical Operations Manager)

  



 


Page 5 of 52

















 


Medical
Advisor Signature Page


 


	
  Name:

  	
  Prof Jonathan Leor, MD

  
	
  Address:

  	
  Head, Neufeld Cardiac
  Research Institute.

  
	
   

  	
  Tel-Aviv University

  
	
   

  	
  Sheba Medical Center

  
	
   

  	
  Tel-Hashomer 52621

  
	
   

  	
  Israel

  
	
  Phone:

  	
  +972-3-534-8685

  
	
  Fax:

  	
  +972-3-5351139

  



 


I have read the protocol
and confirm that the protocol follows the current GCP guidelines.


 


	
  Date/Place

  	
  28/1/09

  	
   

  	
  Signature

  	
  /s/ Jonathan Leor

  
	
   

  	
   

  	
   

  	
  (Jonathan Leor, MD,
  Medical Advisor)

  



 


Page 6 of 52














 


Synopsis


 


	
  STUDY NUMBER

  	
   

  	
  BL-1040.01

  
	
   

  	
   

  	
   

  
	
  TITLE OF THE STUDY

  	
   

  	
  A Phase I,
  multi-center, open label study designed to assess the safety and feasibility
  of the injectable BL-1040 implant to provide scaffolding to infarcted
  myocardial tissue

  
	
   

  	
   

  	
   

  
	
  STUDY CENTER/COUNTRY

  	
   

  	
  Approximately 10 centers
  in 3 countries: Netherlands, Belgium, Germany, Israel, possibly
  Switzerland

  
	
   

  	
   

  	
   

  
	
  PLANNED STUDY PERIOD +

  CLINICAL PHASE

  	
   

  	
  Q1 2008 to Q1 2010  

   

  Phase I

  
	
   

  	
   

  	
   

  
	
  INDICATION AND
  RATIONALE

  	
   

  	
  Heart failure after
  myocardial infarction (MI) is often precipitated by early and progressive
  extracellular matrix degradation and pathological remodeling of the left
  ventricle (LV). In response to MI, a series of molecular, cellular and
  physiological responses are triggered, which can lead to early infarct
  expansion (infarct thinning), which may result in early ventricular rupture
  or aneurysm formation and the transition to heart failure. Late remodeling
  involves the left ventricle globally and is associated with time-dependent
  dilatation, and the distortion of ventricular shape. The failure to normalize
  increased wall stresses results in progressive dilatation, recruitment of
  border zone myocardium into the infarct, and deterioration in contractile
  function. Current anti-remodeling therapies are clearly limited, as many
  ventricles continue to enlarge and mortality and morbidity remain
  significantly high.

  Based on the mechanism
  of LV remodeling, it has been hypothesized that injection of biomaterials
  into the infarct could thicken the infarct, arrest infarct expansion, prevent
  LV dilatation and reduce wall stress that initiates progressive adverse LV
  remodeling. BL-1040 Myocardial Implant is a non-pharmacologic cross-linked
  alginate solution administered via intracoronary (IC) injection to infarcted
  tissue, forming a flexible, three-dimensional mechanical scaffold.

  BL-1040 Myocardial
  Implant presents a novel, safe and non-surgical therapy that directly
  addresses the stability and structural integrity of myocardial tissue while
  potentially preventing post infarction remodeling, primarily via limiting
  left ventricle dilation.

  
	
   

  	
   

  	
   

  
	
  OBJECTIVES

  	
   

  	
  ·                  To evaluate the safety of the BL-1040 myocardial
  implant in patients after MI at high risk for LV remodeling and CHF. 

  ·                  To provide feasibility data in order to initiate and
  conduct a pivotal clinical study evaluating the safety and efficacy of the
  BL-1040 implant in patients following myocardial infarction.

  
	
   

  	
   

  	
   

  
	
  ENDPOINTS

  	
   

  	
  Primary safety
  endpoints 

  Occurrence of all
  adverse events including but not limited to 

  ·                  All MIs 

  ·                  Cardiovascular hospitalization 

  ·                  Serious ventricular arrhythmias sustained: 

  ·                  VT (symptomatic or sustained VT [duration longer
  than 30 seconds or 100 beats, or associated with hemodynamic collapse]) 

  ·                  VF 

  ·                  symptomatic bradycardia, pauses of longer than 3.0
  seconds, complete atrioventricular block, Mobitz II atrioventricular block 

  ·                  Symptomatic heart failure (NYHA criteria + physical
  examination OR hospitalization due to heart failure) 

  ·                  Renal failure 

  ·                  Stroke 

  ·                  Death

  



 


Page 7 of 52

















 


	
   

  	
   

  	
  Secondary safety
  endpoints

  ·                  Change from baseline in LV dimensions (end-systolic
  volume index, end-diastolic volume index, left ventricular mass)

  ·                  Change from baseline in regional (infarct related)
  and global wall motion score

  ·                  Change from baseline in ejection fraction

  ·                  Cardiac rupture

  ·                  NT-proBNP

  
	
   

  	
   

  	
   

  
	
  DESIGN

  	
   

  	
  Multi-center, open
  label

  	
   

  	
   

  
	
   

  	
   

  	
   

  	
   

  	
   

  
	
  PATIENTS

  	
   

  	
  NUMBER

  	
   

  	
  Maximum 30

  
	
   

  	
   

  	
   

  	
   

  	
   

  
	
   

  	
   

  	
  MAIN INCLUSION CRITERIA

  	
   

  	
  ·                  Signed informed consent

  ·                  18 to 75 years of age, inclusive

  ·                  Male or female

  ·                  Negative pregnancy test for women of child-bearing
  potential, or surgically sterile, or post menopausal

  ·                  Acute MI defined as:

  1.               Typical rise and gradual fall (troponin) or more
  rapid rise and fall (CK-MB) of biochemical markers of myocardial necrosis
  with at least one of the following: a) ischemic symptoms: b) development of
  pathologic Qwaves on the ECG: c) ECG changes indicative of ischemia (ST
  segment elevation or depression)

  2.               First anterior or inferolateral STEMI or Qwave MI
  (QMI Anterior: V1-V3 or V1-V4 or V1-V5 or V1-V6.QMI Inferior: L2, L3, AVF, or
  L2, L3, AVF+ V5, V6 or L2, L3, AVF+ V6-V9 [posterior leads])

  3.               Regional wall motion score index (at least 4 out of
  16 akinetic segments)

  ·                  One or more of the following:

  ·                  LVEF >20% and <45% measured and calculated by
  2-dimensional measurement

  ·                  Biomarkers: peak CK > 2000 IU

  ·                  Infarct size > 25% as measured by MRI

  ·                  Successful revascularization with PCI with 1
  stent only, within 7 days of the index MI (only safe and MRI compatible
  stents)

  ·                  At time of application of study device, patient must
  have patent infarct related artery (IRA) and TIMI flow grade = 3

  
	
   

  	
   

  	
   

  	
   

  	
   

  
	
   

  	
   

  	
  MAIN EXCLUSION CRITERIA

  	
   

  	
  ·                  History of CHF, Class I to Class IV, as
  per NYHA criteria

  ·                  History of prior LV dysfunction

  ·                  At time of application of study device - Killip
  III-IV (pulmonary edema, cardiogenic shock - hypotension [systolic < 90
  mmHg] and evidence of peripheral hypoperfusion [oliguria, cyanosis,
  sweating]) or HR > 100 bpm

  ·                  Patient with pacemaker

  ·                  Prior CABG

  ·                  Prior MI

  ·                  History of stroke

  ·                  Significant valvular disease (moderate or severe)

  ·                  Patient is a candidate for CABG or PCI on non-IRA

  ·                  Patient is being considered for CRT within the next

  



 


Page 8 of 52

















 


	
   

  	
   

  	
   

  	
   

  	
  30 days

  ·                  Renal insufficiency (eGFR < 60)

  ·                  Chronic liver disease (> 3 times upper limit of
  normal)

  ·                  Life expectancy < 12 months

  ·                  Current participant in another clinical trial, or participation
  in another trial within the last 6 months

  ·                  Any contraindication to coronary angiography, MRI or
  PCI procedures

  ·                  Patient taking anti-coagulation medication prior to MI

  ·                  Pregnant or lactating women; pregnancy confirmed by
  urine pregnancy test

  
	
   

  	
   

  	
   

  	
   

  	
   

  
	
  STUDY DEVICE

  	
   

  	
  ROUTE OF APPLICATION

  	
   

  	
  Administered via
  intracoronary (IC) injection, using multiple commercially available devices

  
	
   

  	
   

  	
   

  	
   

  	
   

  
	
   

  	
   

  	
  DURATION AND FREQUENCY

  	
   

  	
  2 mL of BL-1040
  administered for no longer than 30 seconds

  
	
   

  	
   

  	
   

  	
   

  	
   

  
	
   

  	
   

  	
  FORMULATION

  	
   

  	
  Calcium D-Gluconate
  (Gluconic acid hemicalcium salt) PRONOVA UP VLVG (Generic name: Sodium
  Alginate)

  Water for Injection
  USP/EP

  
	
   

  	
   

  	
   

  	
   

  	
   

  
	
  SAFETY EVALUATIONS

  	
   

  	
   

  
	
   

  	
   

  	
   

  
	
  TIMING AND ASSESSMENTS
  PERFORMED

  	
   

  	
  Screening

  ·                  lst Coronary
  angiography, PCI and stent (as part of treatment of MI)

  ·                  Physical
  examination

  ·                  Vital
  signs

  ·                  12-lead
  ECG

  ·                  Blood
  and urine sampling for laboratory safety parameters (biochemistry, hematology
  and urinalysis)

  ·                  Total
  CK/CK MB

  ·                  NT-proBNP

  ·                  Mandatory
  echocardiography; MRI as an additional measurement is encouraged 

   

  Telephone contact, 1
  week post-procedure

  ·                  Phone
  call to confirm status of patient discharged from the hospital 

   

  Day 1 and during
  hospitalization

  ·                  Physical
  examination daily during hospitalization

  ·                  Vital
  signs daily during hospitalization

  ·                  12-lead
  ECG prior to and after administration of BL-1040; daily during
  hospitalization

  ·                  24
  hour Holter monitor (after completion of 12-lead ECG)

  ·                  Blood
  and urine sampling for laboratory safety parameters (biochemistry, hematology
  and urinalysis), on Day 1 (only if not done within the previous 48 hours) and
  on day of discharge (only if not done within the previous 48 hours)

  ·                  Total
  CK/CK MB measured prior to, and 8, 16, 24 and 48 hours after administration
  of BL-1040

  ·                  NT-proBNP
  on Day 1 (only if not done within the previous 48 hours) and on day of
  discharge (only if not done within the previous 48 hours)

  ·                  continuous
  ECG during the procedure

  ·                  2nd
  cardiac catheterization (for implantation of BL-1040)

  ·                  PTT
  or ACT measurements, during procedure only (prior to implantation of BL-1040
  and prior to removal of sheath)

  



 


Page 9 of 52

















 


	
   

  	
   

  	
  Follow-up visits (Days
  30, 90 180 [End of Study]; Months 12, 24, 36, 48 and 60)

  
	
   

  	
   

  	
  ·                  Physical examination

  
	
   

  	
   

  	
  ·                  Vital signs

  
	
   

  	
   

  	
  ·                  12-lead ECG

  
	
   

  	
   

  	
  ·                  24 hour ambulatory Holter monitoring

  
	
   

  	
   

  	
  ·                  Blood and urine sampling for laboratory safety
  parameters (biochemistry, hematology and urinalysis)

  
	
   

  	
   

  	
  ·                  NT-proBNP (through Day 180 only)

  
	
   

  	
   

  	
  ·                  Mandatory echocardiography: MRI as an additional
  measurement is encouraged (MRI through Day 180 only)

  
	
   

  	
   

  	
  ·                  Minnesota Living with Heart Failure® questionnaire

  
	
   

  	
   

  	
   

  
	
   

  	
   

  	
  AEs and SAEs will be
  collected throughout the study

  
	
   

  	
   

  	
   

  
	
  PROCEDURE

  	
   

  	
  Patient is admitted to
  the hospital as a result of an AMI. As part of the inclusion criteria for
  this study, the patient will undergo revascularization with PCI stent
  implantation. Within 7 days of the index MI, the patient will undergo an
  echocardiogram to determine LVEF. Although not mandatory, the patient will be
  encouraged to undergo an MRI as an additional assessment. If the patient
  satisfies inclusion/exclusion criteria, a 2nd cardiac catheterization will be performed to
  administer BL-1040 after revascularization but within 7 days of the index
  AMI. BL-1040 is applied via intracoronary injection through the infarct
  related artery. Patients discharged from the hospital will be contacted by
  phone on Day 8 for a safety follow-up. Follow-up examinations are scheduled
  for Day 30, Day 90 and Day 180 (End of Study) post-procedure. In addition,
  the patient will return to the hospital at Months 12, 24, 36, 48 and 60 for
  yearly follow-up assessments, as part of a long-term safety follow-up.

  
	
   

  	
   

  	
   

  
	
  STATISTICAL METHODS

  	
   

  	
  All data recorded will
  be presented in data listings and summary tables, as appropriate. Missing
  values will not be replaced. No formal hypothesis testing will be performed.

  
	
   

  	
   

  	
  All participants who
  received BL-1040 will be included in the safety analysis.

  
	
   

  	
   

  	
  Any excluded cases will
  be documented together with the reason for exclusion.

  
	
   

  	
   

  	
  All decisions on
  exclusions from the analysis will be finalized prior to database lock.

  
	
   

  	
   

  	
  Continuous variables
  (age, height, weight) will be summarized using mean, median, standard deviation,
  minimum, maximum, and number of available observations. Qualitative variables
  will be summarized by counts and percentages.

  
	
   

  	
   

  	
  An interim safety
  analysis will be performed after 5 patients have completed the Day 30 visit,
  on all data collected up to this timepoint.

  



 


Page 10 of 52















 


Schedule of Events


	
  Visits/Week

  	
   

  	
  Hospitalization

  	
   

  	
  Post
  discharge follow-up

  	
   

  
	
  Study days

  	
   

  	
  Screening

  (Day) (-7) to

  Day (-1)

  	
   

  	
  Day 1

  Day of application(1)

  	
   

  	
  Daily during

  hospitalization(2)

  	
   

  	
  Day of discharge

  	
   

  	
  Telephone

  Contact

  Day 8

  (± 1 day)

  	
   

  	
  Day 30

  (± 5 days)

  	
   

  	
  Day 90

  (± 5 days)

  	
   

  	
  Day 180

  (± 7 days)

  End of Study Visit

  	
   

  	
  Follow-up Safety

  Visits

  (Months 12, 24,

  36, 48 60,

  ± 30 days)

  	
   

  
	
  AMI

  	
   

  	
  X

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
  Hospitalization

  	
   

  	
  X

  	
   

  	
  X

  	
   

  	
  X

  	
   

  	
  X

  	
   

  	
  X

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
  Coronary
  angiography, PCI, stent(1)

  	
   

  	
  X

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
  Informed
  consent

  	
   

  	
  X

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
  Inclusion/exclusion
  criteria

  	
   

  	
  X

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
  Pregnancy
  test

  	
   

  	
  X

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
  Demography;
  medical history; concurrent illnesses

  	
   

  	
  X

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
  Physical
  examination

  	
   

  	
  X

  	
   

  	
  X

  	
   

  	
  X

  	
   

  	
  X

  	
   

  	
   

  	
   

  	
  X

  	
   

  	
  X

  	
   

  	
  X

  	
   

  	
  X

  	
   

  
	
  Vital
  signs (temperature, arterial BP, weight)

  	
   

  	
  X

  	
   

  	
  X

  	
   

  	
  X

  	
   

  	
  X

  	
   

  	
   

  	
   

  	
  X

  	
   

  	
  X

  	
   

  	
  X

  	
   

  	
  X

  	
   

  
	
  12-lead
  ECG

  	
   

  	
  X

  	
   

  	
  X

  	
  (4)

  	
  X

  	
   

  	
  X

  	
   

  	
   

  	
   

  	
  X

  	
   

  	
  X

  	
   

  	
  X

  	
   

  	
  X

  	
   

  
	
  Laboratory
  safety parameters

  	
   

  	
  X

  	
  (5)

  	
  X

  	
  (6)

  	
   

  	
   

  	
  X

  	
  (6)

  	
   

  	
   

  	
  X

  	
   

  	
  X

  	
   

  	
  X

  	
   

  	
  X

  	
   

  
	
  Total
  CK/CK MB

  	
   

  	
  X

  	
   

  	
  X

  	
  (7)

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
  NT-proBNP

  	
   

  	
  X

  	
   

  	
  X

  	
  (6)

  	
   

  	
   

  	
  X

  	
  (6)

  	
   

  	
   

  	
  X

  	
   

  	
  X

  	
   

  	
  X

  	
   

  	
   

  	
   

  
	
  Echocardiography/MRI

  	
   

  	
  X

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
  X

  	
   

  	
  X

  	
   

  	
  X

  	
   

  	
  X

  	
   

  
	
  Continuous
  ECG monitoring

  	
   

  	
   

  	
   

  	
  X

  	
  (9)

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
  Cardiac
  catheterization; application of BL- 1040; coronary angiography

  	
   

  	
   

  	
   

  	
  X

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
  PTT
  or ACT measurements

  	
   

  	
   

  	
   

  	
  X

  	
  (10)

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
  24-hour
  ambulatory Holter monitoring

  	
   

  	
   

  	
   

  	
  X

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
  X

  	
   

  	
  X

  	
   

  	
  X

  	
   

  	
  X

  	
   

  
	
  Safety
  contact for discharged patients

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
  X

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
  Minnesota
  Living with Heart Failure

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
  X

  	
   

  	
  X

  	
   

  	
  X

  	
   

  	
  X

  	
   

  
	
  Serious/Adverse
  events and concomitant medication

  	
   

  	
  X

  	
   

  	
  X

  	
   

  	
  X

  	
   

  	
  X

  	
   

  	
  X

  	
   

  	
  X

  	
   

  	
  X

  	
   

  	
  X

  	
   

  	
  X

  	
   

  



 






(1)                   Device to be administered within 7 days
of AMI


(2)                   Patient must remain hospitalized for at
least 48 hours after procedure.


(3)                   Done as treatment of AMI


(4)                   Prior to and after administration of BL-1040


(5)                   Troponin I or T to be measured at Screening only


(6)                   If not done within previous 48 hours


(7)                   Parameters to be assessed prior to, and 8, 16, 24 and
48 hours after administration of BL-1040


(8)                   Echocardiography to be done at each visit.
MRIs are to be encouraged as an additional assessment through Day  180,
but are contingent upon patient agreement. MRIs are not to be requested as part
of the Follow-up Safety visits.


(9)                   Patient to be connected prior to
implantation of BL-1040, and for the duration of the procedure


(10)             Measured prior to implantation of
BL-1040, and prior to removal of sheath


 


Page 11 of 52














 


Table
of Contents


 


	
  List of Abbreviations

  	
  14

  
	
  1

  	
  Introduction

  	
  15

  
	
  1.1

  	
  Background

  	
  15

  
	
  1.1.1

  	
  Acute Myocardial
  Infarction- Definition

  	
  15

  
	
  1.1.2

  	
  Infarction types and
  pathogenesis

  	
  15

  
	
  1.1.3

  	
  Mechanisms of
  myocardial damage

  	
  15

  
	
  1.1.4

  	
  Treatment of AMI

  	
  15

  
	
  1.2

  	
  Rationale and
  justification

  	
  16

  
	
  2

  	
  Study Objectives

  	
  17

  
	
  3

  	
  Safety Endpoints

  	
  18

  
	
  3.1

  	
  Primary endpoints

  	
  18

  
	
  3.2

  	
  Secondary endpoints

  	
  18

  
	
  4

  	
  Investigational Plan

  	
  19

  
	
  4.1

  	
  Summary of study design

  	
  19

  
	
  4.1.1

  	
  Estimated study
  duration

  	
  19

  
	
  4.1.2

  	
  Number of Patients

  	
  19

  
	
  4.2

  	
  Sequential enrollment

  	
  19

  
	
  4.3

  	
  Responsibilities of the
  Independent Safety Monitoring Board

  	
  19

  
	
  4.3.1

  	
  Stopping Criteria

  	
  19

  
	
  4.4

  	
  Inclusion criteria

  	
  20

  
	
  4.5

  	
  Exclusion criteria

  	
  21

  
	
  4.6

  	
  Withdrawal criteria
  during the study

  	
  22

  
	
  4.7

  	
  Treatment allocation

  	
  22

  
	
  4.8

  	
  Method of blinding and
  unblinding

  	
  22

  
	
  5

  	
  Product Overview

  	
  23

  
	
  5.1

  	
  BL-1040

  	
  23

  
	
  5.2

  	
  Formulation

  	
  23

  
	
  5.3

  	
  Dosage and application

  	
  23

  
	
  5.4

  	
  Labelling/Packaging

  	
  24

  
	
  5.5

  	
  Storage

  	
  24

  
	
  5.6

  	
  Compliance

  	
  24

  
	
  5.7

  	
  BL-1040 accountability

  	
  24

  
	
  5.8

  	
  Concomitant medication

  	
  24

  
	
  6

  	
  Study Procedures

  	
  26

  
	
  6.1

  	
  General study aspects

  	
  26

  
	
  6.2

  	
  Outline of study
  procedures

  	
  26

  
	
  6.2.1

  	
  Detailed description of
  study stages/visits

  	
  28

  
	
  6.2.1.1

  	
  Screening, Day -7 to
  Day -1

  	
  28

  
	
  6.2.1.2
  

  	
  Day 1

  	
  28

  
	
  6.2.1.3
  

  	
  Daily during
  hospitalization

  	
  29

  
	
  6.2.1.4
  

  	
  Telephone Contact, Day
  8, =1

  	
  29

  
	
  6.2.1.5
  

  	
  Day 30, Day 90 and Day
  180 (End of Study)

  	
  29

  
	
  6.2.1.6
  

  	
  Extended safety
  follow-up (Months 12, 24, 36, 48, 60 = 30 days)

  	
  30

  
	
  6.3

  	
  Study evaluations and
  procedures

  	
  30

  
	
  6.3.1

  	
  Safety

  	
  30

  
	
  6.3.1.1
  

  	
  Physical examinations

  	
  30

  
	
  6.3.1.2
  

  	
  Vital signs

  	
  30

  
	
  6.3.1.3
  

  	
  ECGs

  	
  31

  
	
  6.3.1.4
  

  	
  Echocardiograms

  	
  31

  
	
  6.3.1.5
  

  	
  MRIs

  	
  31

  
									



 


Page 12 of 52

















 


	
  6.3.1.6

  	
  Clinical safety
  evaluations

  	
  32

  
	
  6.3.2

  	
  Core laboratories

  	
  33

  
	
  6.4

  	
  Minnesota Living with
  Heart Failure® questionnaire

  	
  33

  
	
  7

  	
  Adverse and Serious Adverse
  Events

  	
  35

  
	
  7.1

  	
  Adverse event
  definition

  	
  35

  
	
  7.2

  	
  Recording adverse
  events

  	
  35

  
	
  7.3

  	
  Pre-device events

  	
  35

  
	
  7.4

  	
  General adverse events

  	
  36

  
	
  7.4.1

  	
  Assessment of severity
  of general adverse events

  	
  36

  
	
  7.4.2

  	
  Assessment of causality
  of adverse events

  	
  36

  
	
  7.4.3

  	
  Follow-up of adverse
  events and assessment of outcome

  	
  36

  
	
  7.5

  	
  Serious Adverse Events

  	
  37

  
	
  7.5.1

  	
  Definition of Serious
  Adverse Event (SAE)

  	
  37

  
	
  7.5.2

  	
  Pre-defined SAEs

  	
  38

  
	
  7.5.3

  	
  Reporting serious
  adverse events

  	
  38

  
	
  7.5.4

  	
  Follow-up of serious
  adverse events

  	
  38

  
	
  7.6

  	
  Treatment of adverse
  events

  	
  39

  
	
  7.7

  	
  Pregnancy

  	
  39

  
	
  8

  	
  Data Evaluation and Statistics

  	
  40

  
	
  8.1

  	
  Endpoints

  	
  40

  
	
  8.2

  	
  Estimated sample size

  	
  40

  
	
  8.3

  	
  Planned methods of
  analysis

  	
  40

  
	
  8.3.1

  	
  Analysis population

  	
  40

  
	
  8.3.2

  	
  Analysis of
  demographics

  	
  40

  
	
  8.3.3

  	
  Analysis of safety

  	
  41

  
	
  8.4

  	
  Interim analysis

  	
  41

  
	
  8.5

  	
  Final and follow-up
  reporting

  	
  41

  
	
  8.6

  	
  Quality assurance

  	
  41

  
	
  9

  	
  Ethics and regulatory
  considerations

  	
  42

  
	
  9.1

  	
  Informed Consent

  	
  42

  
	
  9.2

  	
  Authorities

  	
  42

  
	
  9.3

  	
  Protocol Amendments

  	
  42

  
	
  9.4

  	
  Patient confidentiality

  	
  42

  
	
  9.5

  	
  Insurance

  	
  43

  
	
  9.6

  	
  Duration of the study

  	
  43

  
	
  10

  	
  Data Handling and Record
  Keeping

  	
  44

  
	
  10.1

  	
  Documentation

  	
  44

  
	
  10.2

  	
  Case Report Forms

  	
  44

  
	
  10.3
  

  	
  Monitoring and quality
  control

  	
  44

  
	
  10.4
  

  	
  Publication policy

  	
  44

  
	
  11

  	
  References

  	
  45

  
								



 


Appendix A: Declaration
of Helsinki


 


Appendix B: Minnesota
Living with Heart Failure® questionnaire


 


Page 13 of 52

















 


List of Abbreviations


 


	
  AE(s)

  	
  Adverse event(s)

  
	
  ALT

  	
  Alanine transminase

  
	
  AMI

  	
  Acute myocardial
  infarction

  
	
  AST

  	
  Aspartate transaminase

  
	
  BP

  	
  Blood pressure

  
	
  bpm

  	
  Beats per minutes

  
	
  BUN

  	
  Blood urea nitrogen

  
	
  CABG

  	
  Coronary artery bypass
  graft

  
	
  CHF

  	
  Chronic heart failure

  
	
  CRF

  	
  Case Report Form

  
	
  CRT

  	
  Cardiac
  Resynchronization Therapy

  
	
  CV

  	
  Cardiovascular

  
	
  ECG

  	
  Electrocardiogram

  
	
  EF

  	
  Ejection fraction

  
	
  eGFR

  	
  Estimated glomerular
  filtration rate

  
	
  EOS

  	
  End of study

  
	
  GCP

  	
  Good Clinical Practice

  
	
  GGT

  	
  Gamma glutamyl
  transferase

  
	
  GLP

  	
  Good Laboratory
  Practice

  
	
  GMP

  	
  Good Manufacturing
  Practices

  
	
  HPF

  	
  High power field

  
	
  HR

  	
  Heart rate

  
	
  IC

  	
  Intracoronary

  
	
  ICH

  	
  International
  Conference on Harmonization

  
	
  IRA

  	
  Infarct related artery

  
	
  ISMB

  	
  Independent Safety
  Monitoring Board

  
	
  LDH

  	
  Lactate dehydrogenase

  
	
  LV

  	
  Left ventricle

  
	
  LVEF

  	
  Left ventricular
  ejection fraction

  
	
  MedDRA

  	
  Medical Dictionary for
  Regulatory Activities

  
	
  mg

  	
  Milligram

  
	
  MI

  	
  Myocardial infarction

  
	
  min

  	
  Minute

  
	
  mL

  	
  Milliliter

  
	
  MRI

  	
  Magnetic resonance
  imaging

  
	
  NCE

  	
  New chemical entity

  
	
  NT-proBNP

  	
  N-terminal prohormone
  brain natnuretic peptide

  
	
  NYHA

  	
  New York Heart
  Association

  
	
  °C

  	
  Degrees centigrade

  
	
  OTC

  	
  Over the Counter

  
	
  PCI

  	
  Primary coronary
  intervention

  
	
  QMI

  	
  Qwave myocardial
  infarction

  
	
  SAE(s)

  	
  Serious Adverse
  Event(s)

  
	
  SAS

  	
  Statistical Analysis
  System

  
	
  STEMI

  	
  ST-segment elevation
  myocardial infarction

  
	
  TIMI

  	
  Thrombolysis in
  Myocardial Infarction

  
	
  VF

  	
  Ventricular
  fibrillation

  
	
  VT

  	
  Ventricular tachycardia

  



 


Page 14 of 52

















 


1
        Introduction


 


1.1
     Background


 


1.1.1   Acute
Myocardial Infarction- Definition


 


Acute myocardial
infarction (AMI) is defined as death or necrosis of myocardial cells. It is a
diagnosis at the end of the spectrum of myocardial ischemia or acute coronary
syndromes. AMI occurs when myocardial ischemia exceeds a critical threshold and
overwhelms myocardial cellular repair mechanisms that are designed to maintain
normal cardiac function. Ischemia at this critical threshold level, when
present for an extended time period, results in irreversible myocardial cell
damage and cell death.


 


1.1.2   Infarction types and pathogenesis


 


Critical myocardial
ischemia may arise as a result of increased myocardial metabolic requirement
and/or reduction in the delivery of oxygen and nutrients to the myocardium
through the coronary circulation, or both. An interruption in the supply of myocardial
oxygen and nutrients occurs when blood flow to the myocardium is interrupted by
occlusion of a coronary artery. Often, this event is caused by a thrombus
superimposed on an ulcerated or unstable atherosclerotic plaque that left
untreated for as little as a 20-40 minutes, can lead to irreversible cell
damage and cell death. A high-grade (> 75%) permanent coronary artery
stenosis due to atherosclerosis or a dynamic stenosis coupled with coronary
vasospasm can also reduce the supply of oxygen and nutrients and be a factor
involved in AMI. Additional cardiac valvular pathologies and low cardiac output
states associated with a decreased aortic diastolic pressure, which is the
prime component of coronary perfusion pressure, can also precipitate AMI.


 


1.1.3    Mechanisms
of myocardial damage


 


The severity of an AMI is
dependent on three factors: the level of the occlusion in the coronary artery,
the length of time of the occlusion, and the presence or absence of collateral
circulation. In general, the more proximal the coronary occlusion, there is a
greater risk of an increased area of necrosis. The larger the AMI, the chance
of death due to a mechanical complication or pump failure increases. In
addition, the longer the time period of vessel occlusion, there is a greater
chance of irreversible myocardial damage distal to the occlusion.


 


The death of myocardial
cells first occurs in the area of myocardium that is most distal to the
arterial blood supply, the endocardium. As the duration of the occlusion increases,
the area of myocardial cell death enlarges, extending from the endocardium to
the myocardium and ultimately to the epicardium. The area of myocardial cell
death then spreads laterally to areas of watershed or collateral perfusion. The
extent of myocardial cell death defines the magnitude of the AMI. If blood flow
can be restored to at-risk myocardium, more heart muscle can be saved from
irreversible damage or death. The ischemic zone will undergo inflammatory
necrotic changes, and the myocardial tissue will eventually be completely
replaced by fibrous infarct tissue. In the early stages after an AMI, the
damage causes deterioration of cardiac muscle contractility and structural
integrity. This results in thinning of the walls of the heart, which can have
severe consequences including rupture at the site, expansion of the area of
damage, and the formation of blood clots. After some weeks or months, this can
evolve to dilatation of the heart, which further reduces its ability to pump
blood efficiently, resulting in heart failure.


 


1.1.4    Treatment
of AMI


 


The goal of treatment for
AMI is early reperfusion by rapid
revascularization of the occluded culprit coronary artery both by
medical means to dissolve the clot with thrombolytics or by cardiac catheterization
with primary coronary intervention (PCI) and deployment of stents to


 


Page 15 of 52

















 


maintain patency of the
culprit coronary artery. However, while re-opening of the culprit coronary
vessel can prevent the development of a large AMI and prevent further loss of
viable myocardium, it does not affect myocardial tissue that has already
undergone irreversible damage. An undeniable adverse outcome of AMI is
progressive worsening of ventricular function that, if left unattended,
culminates in the syndrome of congestive heart failure. To date, no treatment
has been developed to reliably prevent the deterioration of ventricular
function that follows a large AMI. Treatment options for AMI and for the
resulting heart failure include medical management, heart transplantation.
mechanical circulatory assist devices (left ventricular assist
device, etc.), and surgical ventricular restoration, all of which have
specific limitations.


 


1.2   Rationale
and justification


 


BL-1040 Myocardial
Implant presents a novel, safe and non-surgical therapy that directly addresses
the stability and structural integrity of myocardial tissue in this patient
population. BL-1040 potentially prevents post infarction remodeling primarily via
limiting left ventricle (LV) dilation, while the untreated patient LV will
continue to dilate or enlarge. BL-1040, by creating a scaffold, may stabilize
the AMI and limit post AMI expansion manifested as LV dilation.


 


There are currently no
other available medical and/or surgical interventions that directly address the
stability and structural integrity of myocardial tissue damaged as a result of
AMI. In the setting of an AMI, an inflammatory response triggers the
degradation of the extracellular matrix, thus weakening of the collagen
cross-link structure or structural “backbone” of the myocardium. Degradation of
the extracellular matrix leads to infarct expansion manifested by myocardial
wall thinning and often, aneurysmal dilation with subsequent ventricular
enlargement. This process results in progressive LV remodeling and increased LV
wall stress. The latter can increase myocardial oxygen consumption, a condition
that the infarcted and/or failing LV can ill afford and one that can contribute
to increased long-term mortality and morbidity.


 


LV dilation is the
predominant cause for morbidity and mortality in congestive heart failure [2],
demonstrated that patients with LV end systolic volume smaller than 95 mL
showed a 94 % survival after 5 years while LV patients with LV end systolic
volume greater than 130 mL showed a 52 % survival after 5 years. Both diastolic
and systolic were the main predictors for mortality. Patients with end-stage
ischemic heart failure presenting dilated LV with an akinetic/dyskinetic region
over 35% and with left ventricular end systolic index >60 mL/m2 are offered
LV reconstruction or surgical ventricular restoration (SVR) in order to reduce
LV volume and to restore normal LV shape. Overall, in a large number of studies
performed using SVR, there is strong evidence that SVR is safe and effective,
showing significant reduction in mortality and readmission levels together with
significant improvement in ejection fraction as well as in LV end
systolic/diastolic index.


 


Page 16 of 52

















 


2      Study Objectives


 


The objectives of this
study are:


 


·                  to evaluate the safety of the BL-1040
myocardial implant in patients after MI at high risk for LV remodeling and CHF,
and


·                  to provide feasibility data in order to
initiate and conduct a pivotal clinical study evaluating the safety and
efficacy of the BL-1040 implant in patients following myocardial infarction.


 


Page 17 of 52

















 


3
     Safety Endpoints


 


3.1   Primary
endpoints


 


Primary safety endpoints
include:


 


·      occurrence
of all adverse events including but not limited to


·         all
MLs


·         cardiovascular
hospitalization


·         serious
ventricular arrhythmias sustained


·                  VT (symptomatic or sustained VT [duration
longer than 30 seconds or 100 beats, or associated with hemodynamic collapse])


·                  VF


·                  symptomatic bradycardia, pauses of longer
than 3.0 seconds, complete atrioventricular block, Mobitz II atrioventricular
block


·                            symptomatic heart failure (NYHA criteria
+ physical examination OR hospitalization because of heart failure)


·                            renal failure


·                            stroke


·                            death


 


3.2   Secondary endpoints


 


Secondary safety
endpoints include:


 


·                            change from baseline in LV dimensions
(end-systolic volume index, end-diastolic volume index, left ventricular mass)


·                            change from baseline in regional (infarct
related) and global wall motion score


·                            change from baseline in ejection fraction


·                            cardiac rupture


·                            NT-proBNP


 


Page 18 of 52

















 


4
      Investigational
Plan


 


4.1    Summary of study design


 


This is an open label,
multi-center, sequentially enrolled. Phase I study to assess the safety and
feasibility of the injectable BL-1040 myocardial implant to provide scaffolding
to infarcted myocardial tissue.


 


Patients who experience
an MI will be admitted to the hospital. As part of the treatment for the MI,
patients will undergo PCI and stent implantation. Patients will also undergo an
echocardiography (and if they agree, an MRI) to determine the extent of damage
to the infarct related artery (IRA). Patients who satisfy inclusion/exclusion
criteria will be enrolled into the study. The BL-1040 myocardial implant will
be injected into the IRA, distally to the
implanted stent.


 


The first 2 patients will
be sequentially enrolled. After both patients have completed Day 30
assessments, and after approval by the Independent Safety Monitoring Board
(ISMB), the decision will be made to enroll 3 additional patients. After the
ISMB reviews the Day 30 assessments of these patients, the decision will be
made to enroll a maximum of 25 additional patients. Details are provided in
Sec. 4.2.


 


Both female and male
patients must agree to use effective contraception (as agreed with the
Investigator) for 6 months (180 days) after the procedure.


 


4.1.1  Estimated study duration


 


The study is planned to
last from Q1 2008 to Q1 2010. The
clinical study phase is 180 days for
each patient. A long term safety follow-up will include visits at Months 12,
24, 36, 48, and 60. Patients will be consented for the entire 5 year period.


 


4.1.2  Number of Patients


 


The maximum number
of patients enrolled in this study will be 30.


 


4.2  Sequential enrollment


 


The first 2 patients will
be sequentially enrolled into the study. After the 1st patient has completed Day 30 assessments, the
Independent Safety Monitoring Board (ISMB, Sec. 4.3) will review the patient’s
data through Day 30. The ISMB will then decide whether to give approval to
enroll the 2nd patient. After the 2nd patient has
completed Day 30 assessments, the ISMB will again review the data and provide
approval for enrollment of the next 3 patients. After all 3 patients have
completed Day 30 assessments, the ISMB will review the data from these patients
and provide approval for opening enrollment to the balance of the patients
(maximum of 25).


 


4.3  Responsibilities of the Independent Safety
Monitoring Board


 


An Independent Safety
Monitoring Board (ISMB) will be established prior to the start of the study to
monitor the safety of BL-1040 during the conduct of the protocol. This ISMB
will consist of physicians with expertise in cardiovascular disease,
particularly in the area of coronary artery disease and with experience
monitoring safety of drugs and/or devices for cardiovascular applications, and
will have no participation in the trial in any other capacity.


 


The ISMB will ensure that
this study meets the highest standards of patient safety. During the study the
ISMB will have the following main responsibilities:


 


Page 19 of 52

















 


·                  review 30 day safety data
patients from the first 2 sequentially enrolled patients to determine whether 3
additional patients may be enrolled: after reviewing the 30 day safety data
from these 3 patients, will determine whether the balance of patients may be
enrolled


·                  within 30 days of enrolment
of each successive group of 5 patients receiving the device, will review all
SAEs occurring to date and will recommend continuation, discontinuation, or
modification of the procedure or protocol, based on a determination of whether
the occurrence of serious, unexpected, or device-related adverse events (Sec.
7) might outweigh the potential benefit achievable with the device


·                  review emerging findings in
patients and identify potential safety concerns with BL-1040


·                  will receive information, on
an expedited basis, on all Serious Adverse Events (SAEs), clinically
significant laboratory values/vital signs, ECG abnormalities and data from
patients who decided to prematurely discontinue the study. All SAES that occur
in the cath lab during or after the procedure to administer BL-1040 should be
reviewed promptly by the ISMB. The ISMB will review this information and may
decide to interrupt, alter, or terminate the trial


·                  will adjudicate whether or
not an event is unexpected, based on a pre-specified list of expected SAEs
within the study population.


 


4.3.1       Stopping Criteria


 


Given
the uncontrolled nature of the study, and the small sample size, it is not
practical to provide a quantitative stopping rule.


 


Moreover,
given the severely ill nature of the patients who will be enrolled in the study
(those with large myocardial infarction and substantial LV dysfunction),
adverse cardiac outcomes, including fatal ones, are to be expected in this
population, regardless of participation in the study.


 


The
study will be stopped when any of the following occur:


 


1.     Completion of the study


2.     ISMB and sponsor judge that
the study treatment appears to be unsafe for patients. The ISMB will make this
assessment based not only upon the frequency of observed complications, but
also upon the character and qualitative nature of the events. This
determination will be made in the context of clinical judgement of experienced
cardiologists regarding the expected outcome in this population of patients and
whether observed outcomes differ substantively from the expectation. The
committee reserves the right to stop the study after analysis of outcomes of
sequential procedures. A decision to stop will be considered by the ISMB in the
event of occurrence of severe, unusual or unexpected events.


3.     The ISMB may consider
putting the trial on hold or terminating it and will base it decision on
weighing the balance between potential but hypothetical benefits and possible
risks to the participants in the study.


 


4.4          Inclusion criteria


 


The inclusion criteria for this study are:


 


·                  voluntarily signed the
informed consent form prior to the conduct of any study specific procedures


·                  male or female inpatients
aged 18 to 75, inclusive


 


Page 20 of 52














 


·      negative pregnancy test for all women of
child-bearing potential, or surgically sterilized (i.e. tubal ligation,
hysterectomy) prior to Screening, or post-menopausal for at least 1 year


·      acute MI defined as:


·      typical
rise and gradual fall (troponin) or more rapid rise and fall (CK-MB) of
biochemical markers of myocardial necrosis with at least one of the following:
a) ischemic symptoms; b) development of pathologic Qwaves on the ECG; c) ECG
changes indicative of ischemia (ST segment elevation or depression)


·      first
anterior or inferolateral STEMI or Qwave MI (QMI Anterior: V1-V3 or V1-V4 or
V1-V5 or V1-V6.QMI Inferior: L2, L3, AVF, or L2, L3, AVF+ V5, V6 or L2, L3,
AVF+ V6-V9 [posterior leads])


·      regional
wall motion score index (at least 4 out of 16 akinetic segments)


·      one or more of the following:


·      LVEF >20% and <45% measured and
calculated by 2-dimensional measurement


·      Biomarkers: peak CK > 2000 IU


·      infarct size > 25% as measured by MRI


·      successful revascularization with PCI
within 7 days of the index MI (only safe and MRI compatible stents)


·      at time of application of device patient
must have patent infarct related artery (IRA) and TIMI flow grade = 3


 


4.5          Exclusion criteria


 


Exclusion criteria for
this study are:


 


·      history of CHF, Class I to Class IV, as per
NYHA criteria


·      history of prior LV dysfunction


·      at time of application of study device -
Killip III-IV (pulmonary edema, cardiogenic shock - hypotension (systolic <
90 mmHg) and evidence of peripheral hypoperfusion (oliguria, cyanosis, sweating)
or HR > 100 bpm


·      patient with pacemaker


·      prior CABG


·      prior MI


·      history of stroke


·      significant valvular disease (moderate or
severe)


·      patient is a candidate for CABG or PCI on
non-IRA


·      patient is being considered for CRT
within the next 30 days


·      renal insufficiency (eGFR < 60)


·      chronic liver disease (> 3 times upper
limit of normal)


·      life expectancy < 12 months


·      current participant in another clinical
trial, or participation in another trial within the last 6 months


·      any contraindication to coronary
angiography, MRI or PCI procedures


·      patient taking anti-coagulation
medication prior to MI


·      pregnant or lactating women; pregnancy
confirmed by urine pregnancy test


·      patients with a reasonable likelihood for
non-compliance with the protocol


·      any other reason that, in the
Investigator’s opinion, prohibits the inclusion of the patient into the study


 


 


Page 21 of 52

















 


4.6          Withdrawal criteria during the study


 


Each patient has the
right to withdraw from the trial at any time for any reason.


 


The Investigator must
make at least 3 documented attempts to contact those patients who do not return
for the scheduled follow-up visits. Attempts must be recorded in the patient’s
file.


 


The Sponsor reserves the
right to terminate the study at any time.


 


Upon withdrawal from the
study any time after administration of study device, the patient will undergo
the End of Study assessments (Section 6.2.1.5: Table 6.1).


 


Dropouts that
occur after implantation of BL-1040 will not be replaced.




4.7          Treatment allocation


 


This is an open label
study. All patients will be treated with BL-1040. Patient eligibility will be
established prior to treatment with BL-1040.


 


If a patient
discontinues from the study, the patient number will not be reused.


 


4.8          Method of blinding and unblinding


 


As this is an open label
study, there will be no blinding or unblinding procedure.


 


Page 22 of 52

















 


5             Product Overview


 


5.1          BL-1040


 


BL-1040 myocardial
implant is a non-pharmacologic, non-surgical, cross-linked alginate solution
administered via intracoronary (IC) injection to infarcted tissue. BL-1040
completely disintegrates into its constituent polymers within approximately 90
days after deposition, and is excreted in the urine.


 


5.2          Formulation


 


The formulation of
BL-1040 is shown in Table 5.1. 


 


Table 5.1
Formulation of BL-1040


 


	
  0.3% Calcium
  D-Gluconate (Gluconic acid hemicalcium salt)

  	
   

  	
  Sigma, Dr. Paul Lohmann GmbH KG

  
	
  1% PRONOVA UP VLVG
  Generic name: Sodium Alginate

  	
   

  	
  FMC BioPolymer/
  NovaMatrix

  
	
  Water for Injection
  USP/EP

  	
   

  	
   

  



 


5.3          Dosage and application


 


BL-1040 will be
administered to the coronary vasculature using multiple commercially available
devices. Table 5.2 provides a list of the commercially available components
that will be required in order to delivery the BL-1040 implant.


 


Table 5.2
List of Commercially Available BL-1040 Delivery Devices


 


	
  BL-1040
  Implant Delivery Devices

  
	
   

  	
   

  	
   

  
	
  1

  	
   

  	
  Standard endovascular
  sheath (femoral or radial or brachial)

  
	
  2

  	
   

  	
  Standard coronary
  guiding catheter (example — Launcher, ref LA6AR10SH)

  
	
  3

  	
   

  	
  Guidewire 0.014 inch
  (example - Boston Scientific, ref. 383931-035J)

  
	
  4

  	
   

  	
  Torque device (example
  - Boston Scientific, ref. K903606))

  
	
  5

  	
   

  	
  Guidewire introducer
  (example Input Ref. 87311)

  
	
  6

  	
   

  	
  Microcatheter designed
  for coronary intravascular use such as multipurpose probing endovascular
  microcatheter.

  Example:(Boston
  Scientific Catalog number SCH 50058) or Transit microcatheter, (Cordis
  Endovascular Systems, MiMI Lakes, Fla.) or Renegase Hi-Flo microcatheter
  (Boston Scientific)

  
	
  7.

  	
   

  	
  Disposable syringe,
  Intmed 5 mL sterile CE, ISO9001, ISO13488

  



 


Cardiac catheterization
should be done according to the guidelines of the American College of
Cardiology/Society for Cardiac Angiography and Interventions Clinical Expert
Consensus Document on Cardiac Catheterization Laboratory Standards. All
angiographies will be evaluated by a core laboratory. BL-1040 is delivered
intra-coronary (IC) via a microcatheter that is intended for coronary intravascular
use.


 


The timing of BL-1040
administration is within 7 days after the index MI. Two (2) mL of BL-1040
will be injected IC through the infarct related artery supplying the infarcted
area. BL-1040 may not be mixed with any contrast medium.


 


All patients will be
treated in the same manner.


 


Detailed instructions for
the application of BL-1040 are provided in a separate Instruction Manual.


 


Page 23 of 52

















 


5.4          Labelling/Packaging


 


BL-1040 will be packed in
a sterile cylindrical injection vial, type A glass. Vials are filled with
sterile BL-1040 and sealed with a 20 mm rubber stopper, spun-on aluminum seal
and a flip-off top.


 


All packages will be
labeled according to the GMP guideline Volume 4, Annex 13 Manufacture of
Investigational Medicinal Products (July 2003 Revision 1) [1] and local laws.


 


BL-1040 will be packed in
labeled boxes, with at least the following information: study number, patient
number, route of administration, storage guidelines, batch number, expiry date,
instructions for administration, manufacturer name/code, and “Investigational
use only”.


 


The Sponsor must notify
the Site Investigator, who has the overall responsibility for the study device,
of the anticipated date of arrival.


 


5.5          Storage


 


The Site Investigator is
responsible for ensuring that BL-1040 is stored in a safe refrigerated location
(2-8° C) with controlled access. At this temperature, BL-1040 has a shelf life
of 3 months. The temperature must be monitored once daily, and recorded on a
temperature log.


 


BL-104 must be removed
from the refrigerator and kept at room temperature 30 minutes prior to
administration.


 


5.6          Compliance


 


BL-1040 will be
administered by the Investigator only, and will not be dispensed to the patient
or any other personnel.


 


5.7          BL-1040 accountability


 


Under no circumstances is
it permitted to use study supplies for any purposes other than those specified
in the protocol.


 


The Investigator will be
provided with forms to enable accurate recording of all investigational product
at all times. The Investigator must sign a statement that he/she has received
BL-1040 for the study. At any time the figures of supplied, used and remaining
BL-1040 must match. At the end of the study, it must be possible to reconcile
delivery records with those of used and unused stocks. Account must be given of
any discrepancies.


 


At the end of the study,
all unused BL-1040 supplies and empty containers must be returned to the
Sponsor.


 


5.8          Concomitant medication


 


The following medications
may only be administered as indicated:


 


·      ceftriaxone may not be administered
during the 48 hours immediately prior to the administration of BL-1040, and for
the 48 hours immediately following administration of BL-1040


·      calcium solutions may not be administered
during the first week of the study


 


The introduction of any
medication not allowed by the protocol at any point in the study will require a
discussion between the Investigator and the Sponsor. If, in the opinion of the Investigator,
it becomes necessary to administer any medication during the study, the


 


Page 24 of 52

















 


Investigator will
determine the dose and time of intake, and document the medication(s) in
the patient’s CRF.


 


Patients must be
instructed not to begin any new medication before consulting with the
Investigator (unless required for emergency medical use). The patient must be
instructed that this prohibition applies to over-the-counter products as well
as prescription drugs.


 


All patients will receive
optimal medical therapy according to the relevant, updated guidelines from the
European Society of Cardiology [3,4,5]. Optimal therapy including aspirin,
anticoagulation if indicated, angiotensin-converting-enzyme inhibition,
beta-blockade, aldosterone antagonists, when appropriate, and lipid-lowering
therapy, unless contraindicated. Clopidogrel therapy will be initiated before
PCI and continued for 1 year after myocardial infarction [3].


 


Page 25 of 52

















 


6              Study Procedures


 


6.1          General study aspects


 


This is an open label,
multi-center study to assess the safety and feasibility of the injectable
BL-1040 myocardial implant to provide scaffolding to infarcted myocardium.


 


Patients will be admitted
to the hospital for treatment of an acute myocardial infarction (AMI), to
include angioplasty and implantation of a-stent/s. Within 7 days of successful
revascularization, patients will undergo an echocardiogram for assessment of
the extent of the changes to the heart, and to verify cardiac inclusion/exclusion
criteria. MRIs are to be encouraged as an additional assessment, but are
contingent upon the agreement of the patient. After the echocardiogram/MRI, but
still within 7 days of the index AMI, patients will undergo a 2nd cardiac
catheterization to administer BL-1040. Patients will remain hospitalized for at
least 48 hours after the procedure.


 


The BL-1040 scaffold will
be injected into one infarct related artery (IRA), distally to the implanted
stent/s. Patients will undergo cardiac monitoring before, during and after the
procedure: a 12-lead ECG will be done prior to and after administration of
BL-1040; patients will be connected to a continuous ECG monitor and will have
continuous hemodynamic measurements during the procedure; immediately after the
completion of the 12-lead ECG, a Holter monitor will be placed and will remain
connected for the following 24 hours.


 


Patients will undergo
physical examinations, assessment of vital signs and an ECG daily during
hospitalization; safety blood sampling will be done on the day of discharge.


 


Patients who have been
discharged from the hospital will be contacted by phone on Day 8 to confirm the
administration of any concomitant medications, general status of the patient,
and any doctor visits since hospital discharge.


 


Patients will return for
follow-up visits on Day 30, Day 90 and Day 180 (End of Study). Additional
follow-up safety visits are planned for Months 12, 24, 36, 48 and 60. At each
visit, patients will again undergo a physical examination with measurement of
vital signs, ECG, blood sampling, echocardiography and completion of the
Minnesota Living with Heart Failure questionnaire®. At each follow-up visit, the patients
will be hooked up to a 24-hour ambulatory Holter monitor, which will be
returned the following day. MRIs are to be encouraged through Day 180 as an
additional assessment, but are contingent upon the agreement of the patient.
MRIs are not to be requested as part of the long term safety visits.


 


Echocardiograms, ECGs,
Holters, angiographies and MRIs, will be evaluated in a core laboratory.


 


The first 2 patients will
be sequentially enrolled; if approved by the ISMB; 3 additional patients will
be enrolled. After review and approval of the 30 day safety data from these 3
patients, the balance of patients may be enrolled. Details are provided in Sec.
4.2.


 


Both female and male
patients must agree to use effective contraception (as agreed with the
Investigator) for 6 months (180 days) after the procedure.


 


6.2          Outline of study procedures


 


All study procedures are
outlined in the Schedule of Assessments below (Table 6.1). A more detailed
description of the study procedures performed at each study stage/visit is
given in the following sections.


 


Page 26 of 52















 


Table 6.1        Schedule of Events


 


	
   

  	
   

  	
  Hospitalization

  	
   

  	
  Post discharge follow-up

  	
   

  
	
  Visits/Week

  Study days

  	
   

  	
  Screening

  Day (-7) to

  Day (-1)

  	
   

  	
  Day 1

  Day of application(1)

  	
   

  	
  Daily during

  hospitalization(2)

  	
   

  	
  Day of discharge

  	
   

  	
  Telephone

  Contact

  Day 8

  (+ 1 day)

  	
   

  	
  Day 30

  (+ 5 days)

  	
   

  	
  Day 90

  (+ 5 days)

  	
   

  	
  Day 180

  (+ 7 days)

  End of Study Visit

  	
   

  	
  Follow-up Safety

  Visits

  (Months 12, 24,

  36, 48 60,

  + 30 days)

  	
   

  
	
  AM1

  	
   

  	
  X

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
  Hospitalization

  	
   

  	
   

  	
   

  	
  X

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
  Coronary
  angiography, PCI, stent(1)

  	
   

  	
  X

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
  Informed
  consent

  	
   

  	
  X

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
  Inclusion/exclusion
  criteria

  	
   

  	
  X

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
  Pregnancy
  test

  	
   

  	
  X

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
  Demography
  medical history; concurrent illnesses

  	
   

  	
  X

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
  Physical
  examination

  	
   

  	
  X

  	
   

  	
  X

  	
   

  	
  X

  	
   

  	
  X

  	
   

  	
   

  	
   

  	
  X

  	
   

  	
  X

  	
   

  	
  X

  	
   

  	
  X

  	
   

  
	
  Vital
  signs (temperature, arterial BP. weight)

  	
   

  	
  X

  	
   

  	
  X

  	
   

  	
  X

  	
   

  	
  X

  	
   

  	
   

  	
   

  	
  X

  	
   

  	
  X

  	
   

  	
  X

  	
   

  	
  X

  	
   

  
	
  12-lead
  ECG

  	
   

  	
  X

  	
   

  	
  X

  	
  (4)

  	
  X

  	
   

  	
  X

  	
   

  	
   

  	
   

  	
  X

  	
   

  	
  X

  	
   

  	
  X

  	
   

  	
  X

  	
   

  
	
  Laboratory
  safety parameters

  	
   

  	
  X

  	
  (5)

  	
  X

  	
  (6)

  	
   

  	
   

  	
  X

  	
  (6)

  	
   

  	
   

  	
  X

  	
   

  	
  X

  	
   

  	
  X

  	
   

  	
  X

  	
   

  
	
  Total
  CK/CK MB

  	
   

  	
  X

  	
   

  	
  X

  	
  (7)

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
  NT-proBNP

  	
   

  	
  X

  	
   

  	
  X

  	
  (8)

  	
   

  	
   

  	
  X

  	
  (6)

  	
   

  	
   

  	
  X

  	
   

  	
  X

  	
   

  	
  X

  	
   

  	
   

  	
   

  
	
  Echocardiography/MRI

  	
   

  	
  X

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
  X

  	
   

  	
  X

  	
   

  	
  X

  	
   

  	
  X

  	
   

  
	
  Continuous
  ECG monitoring

  	
   

  	
   

  	
   

  	
  X

  	
  (9)

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
  Cardiac
  catheterization; application of BL- 1040; coronary angiography

  	
   

  	
   

  	
   

  	
  X

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
  PTT
  or ACT measurements

  	
   

  	
   

  	
   

  	
  X

  	
  (10)

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
  24-hour
  ambulatory Holler monitoring

  	
   

  	
   

  	
   

  	
  X

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
  X

  	
   

  	
  X

  	
   

  	
  X

  	
   

  	
  X

  	
   

  
	
  Safety
  contact for discharged patients

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
  X

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
  Minnesota
  Living with Heart Failure®

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
  X

  	
   

  	
  X

  	
   

  	
  X

  	
   

  	
  X

  	
   

  
	
  Serious/Adverse
  events and concomitant medication

  	
   

  	
  X

  	
   

  	
  X

  	
   

  	
  X

  	
   

  	
  X

  	
   

  	
  X

  	
   

  	
  X

  	
   

  	
  X

  	
   

  	
  X

  	
   

  	
  X

  	
   

  



 






	
  (1)

  	
   

  	
  Device to be administered
  within 7 days of AMI

  
	
  (2)

  	
   

  	
  Patient must remain
  hospitalized for at least 48 hours after procedure.

  
	
  (3)

  	
   

  	
  Done as treatment of
  AMI

  
	
  (4)

  	
   

  	
  Prior to and after
  administration of BL-1040

  
	
  (5)

  	
   

  	
  Troponin I or T to be
  measured at Screening only

  
	
  (6)

  	
   

  	
  If not done within
  previous 48 hours

  
	
  (7)

  	
   

  	
  Parameters to be
  assessed prior to. and 8, 16, 24 and 48 hours after administration of BL-1040

  
	
  (8)

  	
   

  	
  Echocardiography to be
  done at each visit. MRIs are to be encouraged as an additional assessment
  through Day 180, but are contingent upon patient agreement. MRIs are net to
  be requested as part of the Follow-up Safety visits.

  
	
  (9)

  	
   

  	
  Patient to be connected
  prior to implantation of BL-1040, and for the duration of the procedure

  
	
  (10)

  	
   

  	
  Measured prior to implantation of BL-1040, and prior
  to removal of sheath

  



 


Page 27 of 52














 


6.2.1       Detailed description of study stages/visits


 


6.2.1.1            Screening,
Day -7 to Day -1


Patients
are admitted to the hospital for treatment of an AMI, prior to enrollment into
the study. The treatment will include PCI with placement of a stent. After
signing of Informed Consent, and prior to initiation of any study-related
procedures, the following activities will be carried out:


 


·                  confirmation of inclusion/exclusion criteria


·                  negative pregnancy test for all women of
child-bearing potential (as defined in Inclusion Criteria)


·                  demographics


·                  medical history


·                  physical examination


·                  vitals signs


·                  12-lead ECG, in supine position


·                  blood and urine sampling for laboratory
safety parameters (biochemistry, hematology and urinalysis)


·                  blood sampling for Total CK/CK MB


·                  blood sampling for NT-proBNP


·                  echocardiography


·                  MRI, if patient agrees


·                  concomitant medication record (all currently
prescribed and over the counter medications must be recorded in the Case Report
Form [CRF], with dose and reason for use)


·                  pre-device serious/adverse events


 


6.2.1.2            Day 1


 


BL-1040
must be implanted within 7 days of the index AMI; the day of implant will be
considered Day 1 of the study. Prior to implantation, the following assessments
will be carried out:


 


·                  physical examination


·                  vital signs


·                  12-lead ECG


·                  blood and urine sampling for laboratory
safety parameters (biochemistry [excluding troponin I or T], hematology, and
urinalysis), if not done within the previous 48 hours


·                  Total CK/CK MB


·                  NT-proBNP, if not done within the previous 48
hours


·                  connection to continuous ECG monitoring


 


BL-1040
will be implanted in the infarcted tissue via the IRA, distally to the stent as
outlined in the separate BL-1040 Instruction Manual. During the procedure the
following assessments will be done:


 


·                  continuous ECG monitoring


·                  continuous hemodynamic measurements (arterial
blood pressure)


·                  blood sampling for PTT or ACT, prior to
implantation of BL-1040 and prior to removal of sheath


 


An
additional coronary angiography will be done 3 minutes after implantation of
the BL-1040, and will include an assessment of TIMI flow and myocardial blush.


 


Page 28 of 52

















 


The
following assessments will be done after the procedure:


 


·                  urinalysis


·                  blood sampling at 8 hours, 16 hours and 24
hours after the procedure, for assessment of Total CK/CK MB


·                  12-lead ECG


·                  connection to 24 hour Holtter monitor


 


Adverse
events and concomitant medications will be monitored continuously during the
procedure and recorded on the patient’s CRF.


 


6.2.1.3            Daily
during hospitalization


 


The
patient must remain hospitalized for at least 48 hours after the procedure. The
following assessments and procedures will be carried out during each day of
hospitalization, including day of discharge:


 


·                  physical examination


·                  vital signs


·                  12-lead ECG


·                  blood and urine sampling for laboratory
safety parameters (biochemistry [excluding troponin I or T], hematology and
urinalysis) on day of discharge and only if not done within the previous 48
hours


·                  NT-proBNP on day of discharge and only if not
done within the previous 48 hours


·                  serious/adverse events


·                  concomitant medication


 


6.2.1.4            Telephone
Contact, Day 8, ±1


 


Patients
who have been discharged from the hospital will be contacted by phone 7 days
after application of BL-1040. The patient should be asked the following
questions:


 


1.              How have you been feeling
since your discharge? Have you had any chest pain or experienced any shortness
of breath?


2.              Did you call your doctor for
any reason? If so, when, and for what reason? Did you go to the emergency room
for any reason? If so, when and for what reason?


3.              Are you taking any
medications? If so, which ones?


 


The
information collected from this phone call is to be recorded in the patient’s
CRF.


 


6.2.1.5            Day 30,
Day 90 and Day 180 (End of Study)


 


The
patient will return to the hospital for the following assessments and
procedures on Day 30, Day 90 and Day 180. The visit on Day 180 will be
considered the End of Study visit. If a patient is discontinued prior to Day
180 for any reason, the following assessments should be done at the time of
discontinuation.


 


Assessments
to be carried out include:


 


·                  physical examination:


·                  vital signs


·                  12-lead ECG


 


Page 29 of 52

















 


·                  connection to 24-hour Holter monitor; to be
returned on Day 31/Day 91/Day 181


·                  blood and urine sampling for laboratory
safety parameters (biochemistry [excluding troponin I or T], hematology and
urinalysis)


·                  NT-proBNP


·                  echocardiography


·                  MRI, if patient agrees


·                  completion of the Minnesota Living with Heart
Failure® questionnaire


·                  serious/adverse events


·                  concomitant medication


 


6.2.1.6            Extended
safety follow-up (Months 12, 24, 36, 48, 60 ±30 days)


 


Patients
will return to the hospital yearly for completion of follow-up assessments.


 


Assessments
are to include::


 


·                  physical examination


·                  vital signs


·                  12-lead ECG


·                  connection to 24-hour Holter monitor; the
patient is to be connected at the time of the follow-up visit, and the monitor
is to be returned the following day


·                  blood and urine sampling for laboratory
safety parameters (biochemistry [excluding troponin I or T], hematology and
urinalysis)


·                  echocardiography


·                  completion of the Minnesota Living with Heart
Failure® questionnaire


·                  completion of the following questions:


·                  How have you been feeling since your last
check up?


·                  Have you been hospitalized for any reason? If
so, when, and for what reason?


·                  serious/adverse events


·                  concomitant medication


 


6.3          Study
evaluations and procedures


 


Safety
will be evaluated by analyzing the results of physical examinations, laboratory
examinations and cardiac assessments, as well as AEs (Section 7) and vital
signs. Assessments will be carried out at the time points specified in Section 6.2,
and as shown in Table 6.1.


 


All
safety related investigations are to be performed by the Principal Investigator
or a medically qualified designee, who is responsible for the overall treatment
of the patient.


 


6.3.1       Safety


 


6.3.1.1            Physical
examinations


 


Physical
examinations will include height (Screening only), weight, and a general
assessment of overall body systems (cardiovascular, respiratory).


 


6.3.1.2            Vital signs


 


The
following vital signs will be assessed:


 


·      pulse rate


 


Page 30 of 52

















 


·      blood pressure
(supine, systolic and diastolic)


·      body
temperature


 


The
actual blood pressure and pulse rate should be recorded in the patient’s CRF.
Rounding of values is not allowed.


 


The
following ranges will be used to define acceptable blood pressure:


 


·      supine systolic
blood pressure: 100 - 160 mmHg


·      supine
diastolic blood pressure: 60 - 95 mmHg


·      supine pulse
<100 bpm


 


Body
temperature should be measured using the same methodology at each assessment,
and should be measured in decimals.


 


6.3.1.3            ECGs


 


A
standard supine 12-lead ECG shall be recorded. ECG morphology and ECG intervals
(PR, RR, QRS, QT, and QTc) will be determined: QTc will be calculated using
Bazett’s formula.


 


Patients
will be connected to a 24-hour ambulatory Holter monitor at each follow-up
visit (Day 30, Day 90, Day 180).


 


Printouts/copies
must be placed in the patient’s chart, clearly labeled with the patient number,
time, date, visit, and study number, and signed by the Investigator. A core
laboratory will evaluate the results of both the ECG and Holter.


 


6.3.1.4            Echocardiograms


 


Echocardiograms
will be performed and recorded according to specific criteria established for
this study, and provided in a separate Echocardiogram Reference Manual. The
same parameters will be measured at each assessment, throughout the study.


 


A
core laboratory will evaluate echocardiograms.


 


The
Principal Investigator, the Sponsor or the ISMB may review echocardiograms at
any time if any safety concerns arise. Echocardiograms will be performed at the
times indicated on the Schedule of Events and in Sec. 6.2 of the protocol.


 


6.3.1.5            MRIs


 


While
the MRI is an optional procedure for cardiac assessment at Screening and all
follow-up visits (Day 30, Day 90, Day 180/End of Study), patients should be
encouraged to undergo the procedure at each relevant visit. Performance of the
procedure is always contingent upon patient agreement.


 


MRIs
will be performed according to specific criteria established for this study,
and provided in a separate MRI Reference Manual. A core laboratory will
evaluate MRIs.


 


The
Principal Investigator, the Sponsor or the ISMB may review MRIs at any time if
any safety concerns arise.


 


Page 31 of 52

















 


6.3.1.6            Clinical
safety evaluations


 


Safety
blood sampling


 


All
laboratory samples will be processed at the local laboratory, except for
NT-proBNP, which will be assessed at a core lab.


 


The
Investigator must review the laboratory assessments (initialed and dated)
within 24 hours after the receipt of those results. Out of range values will be
interpreted by the Investigator with a comment of “not clinically significant”
(NCS) or “clinically significant” (CS). Clinically significant abnormal
laboratory values must be repeated on the appropriate clinical follow-up
arranged by the Investigator and documented on the lab report until the lab value
has stabilized or has returned to a clinically acceptable range (regardless of
relationship to BL-1040). Any laboratory value that remains abnormal at the End
of Study visit and is judged to be clinically significant will be followed
according to accepted medical standards for up to 30 days or until resolution
of the abnormality.


 


Approximately
15 mL safety blood samples will be collected at the time points indicated in
Sec 6.2 and shown in Table 6.1. Analyses will include:


 


·      biochemistry


·                  total protein


·                  albumin


·                  total bilirubin


·                  ALT


·                  AST


·                  GGT


·                  LDH


·                  alk phosphate


·                  glucose


·                  sodium


·                  potassium


·                  calcium


·                  phosphate


·                  urea/BUN


·                  creatinine


·                  PTT or ACT


·                  troponin I or T (Screening only)


 


·      hematology


·                  red blood cell count


·                  hemoglobin


·                  hematocrit


·                  mean cell hemoglobin


·                  mean cell hemoglobin concentration


·                  mean cell volume


·                  white blood cell count and differential


·                  platelet count


 


·      cardiac biomarkers


·                  Total CK/CK MB


·                  NT-proBNP


 


·                  urinalysis


 


Page 32 of 52

















 


·                  urine protein


·                  urine glucose


·                  urine blood


·                  leukocytes


·                  nitrites


·                  urobilinogen


·                  bilirubin


·                  pH


·                  specific gravity


·                  ketones


 


If
dipstick analysis reveals any pathological results, a full urine analysis will
be conducted and the following should be checked:


 


1.     Color


2.     Appearance


3.     Leukocytes + erythrocytes
per HPF (High Power Field)


4.     Squamos epithelial cells


5.     Non squamos epithelial cells


6.     Yeast in urine


7.     Amorphous cells


8.     Mucous in urine


9.     Casts


10.  Crystals


 


6.3.2       Core laboratories


 


Results
of echocardiograms, ECGs, Holters, angiographies, and MRIs will be evaluated at
Biomedical Systems:


 


Biomedical
Systems

1945 Ch. de Wavre

B-1160 Brussels-Belgium

phone: +32 2 661 20 70

fax: +32 2 661 20 71

email: sjacobs@biomedsys.com


 


NT-proBNP
samples will be assessed at the central laboratory at the University of
Heidelberg:


 


Universitatsklinikum Heidelberg

Zentrallabor

Im Neuenheimer Feld 671

69120 Heidelberg, Germany

Tel.: 06221-56-8803

Fax: 06221-56-5205


 


6.4          Minnesota Living with Heart
Failure® questionnaire


 


The
Minnesota Living with Heart Failure® questionnaire (MLHQ) is a standardized and
validated questionnaire designed to measure the effects of heart failure and
treatments for heart failure on an individual’s quality of life (ref. 6-8). The
questionnaire measures the effects of symptoms, functional limitations, and
psychological distress on the individual’s life. These items are measured using
a 6 point Likert scale (0-5) to indicate how much each of 21 items has affected
their quality of life.


 


Page 33 of 52

















 


The
scales will be administered by the Investigator or trained/designated
personnel, in the local language.


 


Page 34 of 52














 


7                                         Adverse and Serious Adverse
Events


 


7.1                               Adverse event definition


 


An adverse event (AE) is
any untoward medical occurrence in a clinical trial patient who was
administered a medicinal product and/or medical device and which does not
necessarily have a causal relationship with this treatment. This includes any
noxious, pathological or unintended change in anatomical, physiological or
metabolic functions as indicated by physical signs, symptoms and/or laboratory
detected changes occurring in any phase of the clinical study whether
associated with the study drug/device and whether or not considered related to
study intervention. This includes an exacerbation of pre-existing conditions or
events, intercurrent illnesses, or drug/device interaction. Anticipated
day-to-day fluctuations of pre-existing conditions that do not represent a
clinically significant exacerbation need not be considered AEs. Discrete
episodes of chronic conditions occurring during a study period should be
reported as AEs in order to assess changes in frequency or severity.


 


AEs should be documented
in terms of signs and symptoms observed by the Investigator or reported by the
patient at each study visit. A medical diagnosis should be added.


 


Pre-existing conditions
or signs and/or symptoms (including any which are not recognized at study entry
but are recognized during the study period) present in a patient prior to the
start of the study should be recorded in the Medical History form within the
patient’s CRF.


 


7.2                               Recording adverse events


 


All non-serious AEs
(serious or non-serious) will be recorded from the time of implantation of
BL-1040 on Day 1 until the end of the active study period (Day 180); all
serious AEs will be recorded from the time of implantation of BL-1040 until the
end of the long term follow-up (Month 60). AEs are to be recorded on the
appropriate AE pages in the patient’s CRF: if the AE is serious, the
appropriate box on the AE page of the CRF should also be ticked. Where
possible, a diagnosis rather than a list of symptoms should be recorded. If a
diagnosis has not been made then each symptom should be listed individually.
The nature, time of onset and cessation, and any treatment provided shall be
recorded.


 


According to “Medical
Devices: Post Market Surveillance: Global Guidance for Adverse Event Reporting
for Medical Devices — GHTF/SG2/N54R8: 2006, Study Group 2 Final Document’’,
typical adverse events for medical devices include but are not limited to:


 


·                  a malfunction or deterioration in the
characteristics or performance


·                  an incorrect or out of specification test
result


·                  an inaccuracy in the labeling,
instructions for use and/or promotional materials. Inaccuracies include
omissions and deficiencies. Omissions do not include the absence of information
that should generally be known by the intended users.


·                  use error


 


All AEs (serious and
non-serious) shall be reported as specified in this section of the Protocol and
the expanded Medical Device Reporting Guidelines, which will be provided to all
investigators prior to the start of the study.


 


7.3                               Pre-device events


 


The Investigator will
report any pre-device event directly observed or mentioned by the patient from
the time of signing Informed Consent until the implantation of BL-1040 on Day
1. Pre-device events are reported in the CRF with at least the nature, the
start date and the treatment (if applicable).


 


Page 35 of 52

















 


7.4                               General adverse events


 


Information on any AE
must be recorded when volunteered by the patient, observed by study personnel,
or elicited by a non-leading question, such as “How are you feeling?”.


 


7.4.1                     Assessment of severity of general
adverse events 


 


General events should be
assessed according to the following scale:


 


	
  ·

  	
   

  	
  mild

  	
  the event is easily
  tolerated and does not interfere with usual activity; disappears without
  residual effects

  
	
  ·

  	
   

  	
  moderate

  	
  the event interferes
  with daily activity, but the patient is still able to function

  
	
  ·

  	
   

  	
  severe

  	
  the event is
  incapacitating and the patient is unable to work or complete usual activity;
  considered as unacceptable by the Investigator

  



 


7.4.2                     Assessment of causality of
adverse events


 


Every effort should be
made by the Investigator to explain each AE, both serious and non-serious, and
assess its causal relationship, if any, to implantation of BL-1040.


 


The relationship of
BL-1040 to the event will be determined by how well the event can be understood
in terms of one or more of the following


 


	
  related

  	
  there is suspicion of a
  relationship between BL-1040 and AE (without determining the extent of
  probability); there are no other more likely causes and administration of
  BL-1040 is suspected to have contributed to the AE

  
	
   

  	
   

  
	
  possible

  	
  AE occurs within a
  reasonable time after the implantation of BL-1040 but can also be reasonably
  explained by other factors (as mentioned below)

  
	
   

  	
   

  
	
  unrelated

  	
  there is no suspicion
  that there is a relationship between BL-1040 and AE, there are other more
  likely causes and implantation of BL-1040 is not suspected to have
  contributed to the AE

  



 


Non-serious and serious
AEs will be evaluated as two distinct types of events given their different
medical nature. The Investigator will examine all events assessed as “serious”
(Sec. 7.5.1) in order to determine, as far as possible, ALL contributing
factors applicable to each serious AE.


 


Other possible
contributors include:


 


·                  underlying disease


·                  Other medication


·                  protocol required procedure


·                  other (specify)


 


7.4.3                     Follow-up of adverse events and
assessment of outcome


 


All AEs will be followed
to resolution (patient’s health has returned to baseline status or all
variables have returned to normal); until an outcome has been reached; stabilization
(Investigator does not expect any further improvement of worsening of the
event); or the event is otherwise explained, regardless of whether the patient
is still participating in the study. Where


 


Page 36 of 52

















 


Page appropriate, medical
tests and examinations will be performed to document resolution of the event.
All follow-up information will be recorded in the patient’s CRF until Day 180.


 


7.5                               Serious Adverse Events


 


7.5.1                     Definition of Serious Adverse
Event (SAE)


 


A serious adverse event
(SAE) is any untoward medical occurrence or effect that led to one of the
following outcomes:


 


·                  death of a patient, user or other person


·                  serious injury of a patient, user or
other person


Serious injury (also
known as serious deterioration in state of health) is either:


·                  a life threatening illness or injury *


·                  permanent impairment of a body function or permanent damage to a body
structure†


·                  a condition necessitating medical or surgical intervention to prevent
permanent impairment of a body function or permanent damage to a body structure



The term “permanent”
means irreversible impairment or damage to a body structure or function,
excluding minor impairment or damage


Medical intervention is
not in itself a serious injury. It is the reason that motivated the medical
intervention that should be used to assess the reportability of an event. 


·                  in-patient hospitalization‡ or prolongation of existing hospitalization


·                  an event that might lead to death or serious injury of a patient, user
or other person if the event recurs (sometimes called a ‘‘near incident’’)


 






*Life threatening: An AE
is life threatening if the patient was at risk of death at the time of the
event; it does not refer to an event which hypothetically might have caused
death if it were more severe.


 


†Disabling/incapacitating:
An AE is incapacitating or disabling if the event results in a substantial
disruption of the patient’s ability to carry out normal life functions. This
definition is not intended to include experiences of relatively minor medical
significance such as headache, nausea, vomiting, diarrhea, influenza, or
accidental trauma (e.g. sprained ankle).


 


‡Hospitalization: In general,
hospitalization signifies that the patient has been detained (usually involving
at least an overnight stay) at the hospital or emergency ward for treatment
that would not have been appropriate in the physician’s office or out-patient
setting.


 


Hospitalization for
either elective surgery related to a pre-existing condition which did not
increase in severity or frequency following initiation of the study or for
routine clinical procedures¶ (including hospitalization for “social” reasons)
that are not the result of an AE need not be considered as AEs and are
therefore not SAEs. When in doubt as to whether ‘hospitalization’ occurred or
was necessary, the AE should be considered serious.


 






¶Routine Clinical
Procedure: procedure which may take place during the study period and should
not interfere with the implantation of BL-1040 or any of the ongoing protocol
specific procedures. If anything untoward is reported during an elective
procedure, that occurrence must be reported as an AE, either ‘serious’ or non-serious
according to the usual criteria.


 


For medical devices,
typical serious adverse events include but are not limited to:


 


·                  use error (e.g. untrained user, incorrect
route of administration) related to medical devices, which did result in
death or serious injury


·                  damage to tissue or tissue function
following administration of study device


 


Page 37 of 52

















 


·                  impairment of an organ or organ function
following administration of study device


·                  interaction with concomitant treatment
(other devices or drugs) that might lead to death or serious injury


·                  interaction with materials (e.g.
catheters, stent), substances or gases entering into contact with the device
during normal use that might lead to death or serious injury


·                  non-biocompatibility leading to serious
irritation/allergy that results in in-patient hospitalization or prolongation
of existing hospitalization


 


7.5.2                     Pre-defined SAEs


 


For the purposes of this
study, the following events will be defined as serious:


 


·                  re-infarction


·                  stroke or transient ischemic attack (TIA)


·                  acute heart failure (decompensation)


 


The occurrence of any of
these events after implantation of BL-1040 will be considered an SAE; they are
to be reported and followed up as specified in Sections 7.5.3 and 7.5.4.


 


7.5.3                     Reporting serious adverse events


 


All Serious Adverse
Events (SAEs) must be reported immediately by the Investigator without
filtration, whether considered to be associated with BL-1040 and whether or not
considered related to BL-1040. The Investigator must report SAEs within one
calendar day of becoming aware of the event by telephone, fax or e-mail to the
Study Contact for Reporting Serious Adverse Events as indicated below. This
initial notification should include minimal, but sufficient information to
permit identification of the reporter, the patient, study device, any
medications administered, AEs, causality assessment and date of onset. The
Investigator should not wait for additional information to fully document the
event before providing notification. An acknowledgement letter will confirm the
first notification. The report is then to be followed by submission of a
completed SAE Report Form provided by Venn Life Sciences AG as soon as
possible but at latest within 3 calendar days of the initial telephone/fax or
e-mail report detailing relevant aspects of the AEs in question. All actions
taken by the Investigator and the outcome of the event must also be reported
immediately. For documentation of the  SAE, any actions taken, outcome
and follow-up reports, the SAE Report Forms are to be used. Where applicable,
hospital case records and autopsy reports should be obtained.


 


Investigators must report
SAEs to the appropriate ethics committee if requested by the committee and/or
according to local legal requirements.


 


	
   

  	
   

  	
  Study Contact
  for Reporting Serious Adverse Events.

  
	
   

  	
   

  	
   

  
	
   

  	
   

  	
  Venn Life
  Sciences AG, Elisabethenstrasse 23/3, CH-4051 Basel

  
	
   

  	
   

  	
   

  
	
  Fax:

  	
   

  	
  00800 201 11 011

  
	
  e-mail:

  	
   

  	
  SAE@vlsworldwide.com

  
	
  Tel:

  	
   

  	
  +41 61 201 11 83

  
	
   

  	
   

  	
   

  
	
   

  	
   

  	
  24/24 hour and
  7/7 day availability

  



 


7.5.4                     Follow-up of serious adverse
events


 


All SAEs must be
collected and documented until the end of the long term follow-up (Month 60), and
followed up until the event either resolved, subsided, stabilized, disappeared
or is otherwise


 


Page 38 of 52

















 


explained or the study
patient is lost to follow-up. All follow-up activities must be reported, if
necessary on one or more consecutive SAE report forms, in a timely manner. All
fields with additional or changed information must be completed and the report
form should be forwarded to the Study Contact for Reporting Serious Adverse
Events as soon as possible but latest within 7 calendar days after receipt of
the new information. Clinically significant laboratory abnormalities will be
followed up until they have returned to normal, or a satisfactory explanation
has been provided. Reports relative to the subsequent course of an AE noted for
any patient must be submitted to Venn Life Sciences AG.


 


7.6                               Treatment of adverse events


 


Treatment of any AE is at
the sole discretion of the Investigator and according to current available best
treatment. The applied measures should be recorded in the CRF of the patient.


 


7.7                               Pregnancy


 


The Sponsor must be
notified immediately of any pregnancy that occurs during the study. The SAE
report form should be used to report the pregnancy, even though the pregnancy
is not considered an SAE. Women who become pregnant during the study will be
followed up until birth of the child. The health status of the newborn will be
reported in the patient’s CRF.


 


Page 39 of 52

















 


8                                         Data Evaluation and Statistics


 


In all analyses where a
change from baseline is performed, baseline is defined as the last available
value before device implantation.


 


8.1                               Endpoints


 


The primary
endpoints are occurrence of all adverse events including but not limited to:


 


·                  all MIs


·                  cardiovascular hospitalization


·                  serious ventricular arrhythmias sustained


·              VT (symptomatic or sustained VT [duration
longer than 30 seconds or 100 beats, or associated with hemodynamic collapse]


·              VF


·              symptomatic bradycardia, pauses of longer
than 3.0 seconds, complete atrioventricular block, Mobitz II atrioventricular
block


·                  symptomatic heart failure (NYHA criteria
+ physical examination OR hospitalization due to heart failure)


·                  renal failure


·                  stroke


·                  death


 


Secondary Endpoints
include the parameters:


 


·                  change from baseline in LV dimensions
(end-systolic volume index, end-diastolic volume index, left ventricular mass)


·                  change from baseline in regional (infarct
related) and global wall motion score


·                  change from baseline in ejection fraction


·                  cardiac rupture


·                  NT-proBNP


 


8.2                               Estimated sample size


 


No formal sample size
calculation was performed. Twenty patients followed up to Day 180 were deemed
necessary to meet the objectives of this Phase I study. Taking into account
drop-outs after the device implantation, thirty patients will be enrolled.


 


8.3                               Planned methods of analysis


 


All data recorded will be
presented in data listings and summary tables, as appropriate. Missing values
will not be replaced. No formal hypothesis testing will be performed.


 


8.3.1                   Analysis population


 


All participants who
received the BL-1040 myocardial implant will be included in the safety
analysis. Any excluded cases will be documented together with the reason for
exclusion. All decisions on exclusions from the analysis will be finalized
prior database lock.


 


8.3.2                   Analysis of demographics


 


Continuous demographic
variables (age, height, weight) will be summarized using mean, median, standard
deviation, minimum, maximum, and number of available observations.


 


Page 40 of 52

















 


Qualitative demographic
characteristics will be summarized by counts and percentages. Other patient
characteristics (medical history, clinical findings, prior medications,
inclusion/exclusion criteria) will only be listed.


 


8.3.3                     Analysis of safety


 


AEs will be described in
individual listings and frequency tables by system organ class and preferred
terms (MedDRA version 10.0 or higher), regardless of relationship as well as
for related AEs. The severity of AEs will also be tabulated.


 


Vital signs will be
listed and changes from baseline and raw results will be summarized by means
and standard deviations.


 


Laboratory test values
will be presented by individual listings with flagging of values outside the
normal ranges. Raw laboratory results and changes from baseline will be
summarized by means and standard deviations.


 


12 lead ECG findings will
be presented by listings and frequency tables, as appropriate. Continuous ECG
data will be summarized using standard descriptive statistics.


 


The change from baseline
in cardiac parameter (LV dimensions, wall motion score, ejection fraction) as
well as the NT-proBNP data will be summarized using standard descriptive
statistics.


 


8.4                               Interim analysis


 


An interim safety
analysis will be performed after 5 patients have completed the Day 30 visit, on
all data collected up to this timepoint.


 


8.5                               Final and follow-up reporting


 


The final clinical study
report will be prepared based on data from Day 180, or End of Study, from the
final patient. Thereafter, an annual safety report will be prepared after each
yearly safety follow-up visit (Months 12, 24, 36, 48, 60).


 


8.6                               Quality assurance


 


All data collected in the
CRF will be double entered into a validated computerized clinical data
management system (Clintrial). Laboratory values from the local lab will be
entered into the CRF. Analysis of the data will only be performed after all
queries have been resolved using an appropriate software for analysis (SAS
8.1).


 


Page 41 of 52

















 


9                                         Ethics and regulatory
considerations


 


The study will be
conducted according to Good Clinical Practice, the Declaration of Helsinki 2000
(Appendix A), and the rules and regulations of the European Union and
Israel.


 


9.1                               Informed Consent


 


The nature, purpose and
potential risk of the study as well as the action of the BL-1040 myocardial
implant will be explained to all patients both verbally and in writing. They
will be given adequate time to consider the study before signing the consent
form. Their questions will be actively encouraged. They will be informed that
they may withdraw from the study at any time. This information is documented in
the protocol and participants in the study will sign a consent form confirming
that they have read and understood it; no study activities will take place
until the consent form has been signed. They will also be given a Patient
Information Sheet and copy of the consent form.


 


9.2                               Authorities


 


The procedures laid out
by the local regulatory authorities must be followed and all documents must be
submitted to all concerned authorities, and where needed, approved before a
clinical study may commence.


 


9.3                               Protocol Amendments


 


There will be no
alteration to the protocol without the express written approval of the Sponsor.


 


The local authorities or
ethics committees must approve all major protocol amendments prior to
implementation.


 


No protocol amendments
should be adopted without prior written approval from the ethics committee
except in the following cases:


 


·              in order to eliminate immediate hazard to
the patients,


·              changes involving only logistical or
administrative aspects of the trial. Then notification to the relevant
authorities should be submitted.


 


In these cases, the
implemented deviation or change should be submitted as soon as possible to the
relevant authorities for review and approval.


 


No protocol deviations
are anticipated. However, should any protocol deviations occur, the Principal
Investigator must report the matter to the Sponsor as soon as reasonably
practical. Details of the deviation and, if possible, the reason for its
occurrence must be included in the study report.


 


Major modifications will
need further approval, and will be submitted to the local authorities or ethics
committees, according to local regulations, in the form of an Amendment. Minor
administrative changes require only that the Chairman of the Ethics Committee
be informed in writing without delay.


 


9.4                               Patient confidentiality


 


Individual patient data
obtained as a result of this study is considered confidential. A patient
identification number will identify any patient data collected throughout the
study only.


 


Page 42 of 52

















 


Data generated as a
result of this study are to be available for inspection on request by all
authorized Sponsor personnel, Venn Life Sciences AG personnel, audit personnel
and regulatory authorities. The Informed Consent must clearly reflect this
access.


 


9.5                               Insurance


 


The compensation of the
patient in the event of study related injuries will comply with the applicable
obligatory requirements. Details will be included in the informed Consent.


 


9.6                               Duration of the study


 


The active study phase
for each patient is 180 days. Enrolment is expected to begin in Q1 2008; the
study is expected to end Q1 2010.


 


Page 43 of 52

















 


10                                  Data Handling and Record Keeping


 


10.1                        Documentation


 


Records
must be retained for 15 years after study completion


 


10.2                        Case Report Forms


 


The
Investigator is responsible for maintaining adequate and accurate medical
records from which accurate information will be transferred into the study
database. Case Report Forms (CRFs) should be completed by the Investigator or
delegated personnel.


 


CRFs
will be provided for each patient. All data will be entered in black ink.
Data/corrections entered will be signed or initialed by the study personnel
undertaking that procedure. Overwriting data or use of liquid correcting fluid
is not allowed. Detailed instructions are provided with the CRF.


 


10.3                        Monitoring and quality
control


 


To
ensure compliance with relevant regulations, data generated by this study must
be available for inspection upon request by representatives of BioLine
Innovations Jerusalem, Venn Life Sciences AG(CRO), auditing personnel and
relevant local regulatory authorities.


 


Regular
on-site visits for monitoring of study activities and data recording will be
scheduled. Formal reports of these visits will be generated and copies provided
to relevant Sponsor and study personnel.


 


10.4                        Publication policy


 


The
results of the study are the property of the Sponsor. All manuscripts,
abstracts or other modes of presentation arising from the results of the study
must be reviewed and approved in writing by the Sponsor, in advance of
submission. Co-authorship with any Sponsor personnel will be discussed and
mutually agreed upon before submission of a manuscript to a publisher.


 


Page 44 of 52














 


11                                  References


 


1.         GMP guideline Volume 4, Annex 13
Manufacture of Investigational Medicinal Products (July 2003 Revision 1)


2.         Marcus ML, Wilson RF and White CW.
Methods of measurement of myocardial blood flow in patients: a critical review,
Circulation 1987, 76; 245-253


3.         Bassand et al., Guidelines for the
diagnosis and treatment of patients with non-ST-segment elevation acute
coronary syndromes. European Heart Journal 2007,
27; 1598-1660


4.         Silber S et al. ESC Guidelines:
Guidelines for percutaneous coronary interventions. European Heart Journal 2005, 26; 804-847


5.         Van de Werf et at., Management of acute
myocardial infarction in patients presenting with ST-segment elevation. European Heart Journal 2003, 24; 28-66.


6.         Rector TS, Francis GS, Cohn JN. Patients’
self-assessment of their congestive heart failure. Part 1 Patient
perceived dysfunction and its poor correlation with maximal exercise tests.
Heart Failure 1987, Oct/Nov; 192-196.


7.         Rector TS, Kubo SH, Cohn JN: patients’
self-assessment of their congestive heart failure Part 2: Content,
reliability and validity of a new measure, the Minnesota Living with Heart
Failure questionnaire. Heart Failure. 1987, Oct/Nov; 198-209.


8.         Rector TS. A conceptual model of the
quality of life in relation to heart failure. J
Cardiac Failure 2006.


 


Page 45 of 52

















 


Appendix
A: Declaration of Helsinki


 


Initiated: 1964 17.C                                                           Original:
English


 


WORLD
MEDICAL ASSOCIATION DECLARATION OF HELSINKI


Ethical
Principles


for


 


Medical
Research Involving Human Subjects


 


Adopted by the
18th WMA General Assembly


Helsinki, Finland,
June 1964


and amended by the


29th WMA General
Assembly, Tokyo, Japan, October 1975


35th WMA General
Assembly, Venice, Italy, October 1983


41st  WMA General Assembly, Hong Kong, September 1989


48th WMA General
Assembly, Somerset West, Republic of South Africa, October 1996


and the


52nd WMA General
Assembly, Edinburgh, Scotland, October 2000


 


Note of Clarification
on Paragraph 29 added by the WMA General Assembly, Washington 2002


Note of
Clarification on Paragraph 30 added by the  WMA General Assembly, Tokyo 2004


 


A.
INTRODUCTION


 


1.              The World Medical Association has
developed the Declaration of Helsinki as a statement of ethical principles to
provide guidance to physicians and other participants in medical research
involving human subjects. Medical research involving human subjects includes
research on identifiable human material or identifiable data.


 


2.              It is the duty of the physician to
promote and safeguard the health of the people. The physician’s knowledge and
conscience are dedicated to the fulfillment of this duty.


 


3.              The Declaration of Geneva of the World
Medical Association binds the physician with the words, “The health of my
patient will be my first consideration,” and the International Code of Medical
Ethics declares that, “A physician shall act only in the patient’s interest
when providing medical care which might have the effect of weakening the physical
and mental condition of the patient.”


 


4.              Medical progress is based on research
which ultimately must rest in part on experimentation involving human subjects.


 


5.              In medical research on human subjects,
considerations related to the well-being of the human subject should take
precedence over the interests of science and society.


 


6.              The primary purpose of medical research
involving human subjects is to improve prophylactic, diagnostic and therapeutic
procedures and the understanding of the aetiology and pathogenesis of disease.
Even the best proven prophylactic, diagnostic, and


 


Page 46 of 52

















 


therapeutic methods must
continuously be challenged through research for their effectiveness,
efficiency, accessibility and quality.


 


7.              In current medical practice and in
medical research, most prophylactic, diagnostic and therapeutic procedures
involve risks and burdens.


 


8.              Medical research is subject to ethical
standards that promote respect for all human beings and protect their health
and rights. Some research populations are vulnerable and need special
protection. The particular needs of the economically and medically
disadvantaged must be recognised. Special attention is also required for those
who cannot give or refuse consent for themselves, for those who may be subject
to giving consent under duress, for those who will not benefit personally from
the research and for those for whom the research is combined with care.


 


9.              Research Investigators should be aware of
the ethical, legal and regulatory requirements for research on human subjects
in their own countries as well as applicable international requirements. No
national ethical, legal or regulatory requirement should be allowed to reduce
or eliminate any of the protections for human subjects set forth in this
Declaration.


 


B. BASIC PRINCIPLES FOR ALL
MEDICAL RESEARCH


 


10.       It is the duty of the physician in
medical research to protect the life, health, privacy, and dignity of the human
subject.


 


11.       Medical research involving human subjects
must conform to generally accepted scientific principles, be based on a
thorough knowledge of the scientific literature, other relevant sources of
information, and on adequate laboratory and, where appropriate, animal experimentation.


 


12.       Appropriate caution must be exercised in
the conduct of research which may affect the environment, and the welfare of
animals used for research must be respected.


 


13.       The design and performance of each
experimental procedure involving human subjects should be clearly formulated in
an experimental protocol. This protocol should be submitted for consideration,
comment, guidance, and where appropriate, approval to a specially appointed
ethical review committee, which must be independent of the Investigator, the
sponsor or any other kind of undue influence. This independent committee should
be in conformity with the laws and regulations of the country in which the
research experiment is performed. The committee has the right to monitor ongoing
trials. The researcher has the obligation to provide monitoring information to
the committee, especially any serious adverse events. The researcher should
also submit to the committee, for review, information regarding funding,
sponsors, institutional affiliations, other potential conflicts of interest and
incentives for subjects.


 


14.       The research protocol should always
contain a statement of the ethical considerations involved and should indicate
that there is compliance with the principles enunciated in this Declaration.


 


15.       Medical research involving human subjects
should be conducted only by scientifically qualified persons and under the
supervision of a clinically competent medical person. The responsibility for
the human subject must always rest with a medically qualified person and never
rest on the subject of the research, even though the subject has given consent.


 


16.       Every medical research project involving
human subjects should be preceded by careful assessment of predictable risks
and burdens in comparison with foreseeable benefits to the subject or to
others. This does not preclude the participation of healthy volunteers in
medical research. The design of all studies should be publicly available.


 


Page 47 of 52

















 


17.       Physicians should abstain from engaging
in research projects involving human subjects unless they are confident that
the risks involved have been adequately assessed and can be satisfactorily
managed. Physicians should cease any investigation if the risks are found to
outweigh the potential benefits or if there is conclusive proof of positive and
beneficial results.


 


18.       Medical research involving human subjects
should only be conducted if the importance of the objective outweighs the inherent
risks and burdens to the subject. This is especially important when the human
subjects are healthy volunteers.


 


19.       Medical research is only justified if
there is a reasonable likelihood that the populations in which the research is
carried out stand to benefit from the results of the research.


 


20.       The subjects must be volunteers and
informed participants in the research project.


 


21.       The right of research subjects to
safeguard their integrity must always be respected. Every precaution should be
taken to respect the privacy of the subject, the confidentiality of the patient’s
information and to minimise the impact of the study on the subject’s physical
and mental integrity and on the personality of the subject.


 


22.       In any research on human beings, each
potential subject must be adequately informed of the aims, methods, sources of
funding, any possible conflicts of interest, institutional affiliations of the
researcher, the anticipated benefits and potential risks of the study and the
discomfort it may entail. The subject should be informed of the right to
abstain from participation in the study or to withdraw consent to participate
at any time without reprisal. After ensuring that the subject has understood
the information, the physician should then obtain the subject’s freely given
informed consent, preferably in writing. If the consent cannot be obtained in
writing, the non-written consent must be formally documented and witnessed.


 


23.       When obtaining informed consent for the
research project the physician should be particularly cautious if the subject
is in a dependent relationship with the physician or may consent under duress.
In that case the informed consent should be obtained by a well-informed
physician who is not engaged in the investigation and who is completely
independent of this relationship.


 


24.       For a research subject who is legally
incompetent, physically or mentally incapable of giving consent or is a legally
incompetent minor, the Investigator must obtain informed consent from the legally
authorised representative in accordance with applicable law. These groups
should not be included in research unless the research is necessary to promote
the health of the population represented and this research cannot instead be
performed on legally competent persons.


 


25.       When a subject deemed legally
incompetent, such as a minor child, is able to give assent to decisions about
participation in research, the Investigator must obtain that assent in addition
to the consent of the legally authorised representative.


 


26.       Research on individuals from whom it is
not possible to obtain consent, including proxy or advance consent, should be
done only if the physical/mental condition that prevents obtaining informed
consent is a necessary characteristic of the research population. The specific
reasons for involving research subjects with a condition that renders them
unable to give informed consent should be stated in the experimental protocol
for consideration and approval of the review committee. The protocol should
state that consent to remain in the research should be obtained as soon as
possible from the individual or a legally authorised surrogate.


 


27.       Both authors and publishers have ethical
obligations. In publication of the results of research, the Investigators are
obliged to preserve the accuracy of the results. Negative as well as positive
results should be published or otherwise publicly available. Sources of
funding, institutional affiliations and any possible conflicts of interest
should be declared in


 


Page 48 of 52

















 


the publication. Reports
of experimentation not in accordance with the principles laid down in this
Declaration should not be accepted for publication.


 


C. ADDITIONAL PRINCIPLES FOR MEDICAL
RESEARCH COMBINED WITH MEDICAL CARE


 


28.       The physician may combine medical
research with medical care, only to the extent that the research is justified
by its potential prophylactic, diagnostic or therapeutic value. When medical
research is combined with medical care, additional standards apply to protect
the patients who are research subjects.


 


29.       The benefits, risks, burdens and
effectiveness of a new method should be tested against those of the best
current prophylactic, diagnostic, and therapeutic methods. This does not
exclude the use of placebo, or no treatment, in studies where no proven
prophylactic, diagnostic or therapeutic method exists.


 


30.       At the conclusion of the study, every
patient entered into the study should be assured of access to the best proven
prophylactic, diagnostic and therapeutic methods identified by the study.


 


31.       The physician should fully inform the
patient which aspects of the care are related to the research. The refusal of a
patient to participate in a study must never interfere with the
patient-physician relationship.


 


32.       In the treatment of a patient, where
proven prophylactic, diagnostic and therapeutic methods do not exist or have
been ineffective, the physician, with informed consent from the patient, must
be free to use unproven or new prophylactic, diagnostic and therapeutic
measures, if in the physician’s judgement it offers hope of saving life,
re-establishing health or alleviating suffering. Where possible, these measures
should be made the object of research, designed to evaluate their safety and
efficacy. In all cases, new information should be recorded and, where
appropriate, published. The other relevant guidelines of this Declaration
should be followed.


 


§  §  §


 


Page 49 of 52

















 


Appendix
B: Minnesota Living with Heart Failure® questionnaire


 


Page 50 of 52

















 


LIVING WITH HEART
FAILURE QUESTIONNAIRE


 


Instructions for Use


 


1.                                      Patients should respond to the
questionnaire prior to other assessments and interactions that may bias
responses. You may tell the patient that you would like to get his or her
opinion before doing other medical assessments.


 


2                                         Ample, uninterrupted time should be
provided for the patient to complete the questionnaire.


 


3.                                      The following instructions should be
given to the patient each time the questionnaire is completed.


 


a.                                 Read the introductory paragraph at the
top of the questionnaire to the patient.


 


b.                                 Read the first question to the patient - “Did
your heart failure prevent you from living as you wanted during the past month
by causing swelling in your ankles or legs”? Tell the patient. “If you did not
have any ankle or leg swelling during the past month you should circle the zero
after this question to indicate that swelling was not a problem during the past
month”. Explain to the patient that if he or she did have swelling that was
caused by a sprained ankle or some other cause that was definitely not related
to heart failure he or she should also circle the zero. Tell the patient, “If
you are not sure why you had the swelling or think it was related to your heart
condition, then rate how much the swelling prevented you from doing things you
wanted to do and from feeling the way you would like to feel”. In other words,
how bothersome was the swelling? Show the patient how to use the 1 to 5 scale
to indicate how much the swelling affected his or her life during the past
month - from very little to very much.


 


4.                                      Let the patient read and respond to the
other questions. The entire questionnaire may be read directly to the patient
if one is careful not to influence responses by verbal or physical cues.


 


5.                                      Check to make sure the patient has
responded to each question and that there is only one answer clearly marked for
each question. If a patient elects not to answer a specific question(s) indicate
so on the questionnaire.


 


6.                                      Score the questionnaire by summating the
responses to all 21 questions. In addition, physical (items 2, 3, 4, 5, 6, 7,
12 and 13) and emotional (items 17, 18, 19, 20, and 21) dimensions of the
questionnaire have been identified by factor analysis, and may be examined to
further characterize the effect of heart failure on a patient’s life.


 


Page 51 of 52

















 


LIVING WITH HEART
FAILURE QUESTIONNAIRE


 


These questions concern how your heart failure (heart condition) has
prevented you from living as you wanted during the last month. The items listed
below describe different ways some people are affected. If you are sure an item
does not apply to you or is not related to your heart failure then circle 0
(No) and go on to the next item. If an item does apply to you, then circle the
number rating how much it prevented you from living as you wanted.


 


Did your
heart failure prevent you from living as you wanted during the last  month
by:


 


	
   

  	
   

  	
   

  	
  No

  	
   

  	
  Very

  little

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
  Very

  much

  
	
  1.

  	
  Causing swelling in
  your ankles, legs. etc.?

  	
   

  	
  0

  	
   

  	
  1

  	
   

  	
  2

  	
   

  	
  3

  	
   

  	
  4

  	
   

  	
  5

  
	
  2.

  	
  Making you sit or lie
  down to rest during the day?

  	
   

  	
  0

  	
   

  	
  1

  	
   

  	
  2

  	
   

  	
  3

  	
   

  	
  4

  	
   

  	
  5

  
	
  3.

  	
  Making your walking
  about or climbing stairs difficult?

  	
   

  	
  0

  	
   

  	
  1

  	
   

  	
  2

  	
   

  	
  3

  	
   

  	
  4

  	
   

  	
  5

  
	
  4.

  	
  Making your working
  around the house or yard difficult?

  	
   

  	
  0

  	
   

  	
  1

  	
   

  	
  2

  	
   

  	
  3

  	
   

  	
  4

  	
   

  	
  5

  
	
  5.

  	
  Making your going
  places away from home difficult?

  	
   

  	
  0

  	
   

  	
  1

  	
   

  	
  2

  	
   

  	
  3

  	
   

  	
  4

  	
   

  	
  5

  
	
  6.

  	
  Making your sleeping
  well at night difficult?

  	
   

  	
  0

  	
   

  	
  1

  	
   

  	
  2

  	
   

  	
  3

  	
   

  	
  4

  	
   

  	
  5

  
	
  7.

  	
  Making your relating to
  or doing things with your friends or family difficult?

  	
   

  	
  0

  	
   

  	
  1

  	
   

  	
  2

  	
   

  	
  3

  	
   

  	
  4

  	
   

  	
  5

  
	
  8.

  	
  Making your working to
  earn a living difficult?

  	
   

  	
  0

  	
   

  	
  1

  	
   

  	
  2

  	
   

  	
  3

  	
   

  	
  4

  	
   

  	
  5

  
	
  9.

  	
  Making your
  recreational pastimes, sports or hobbies difficult?

  	
   

  	
  0

  	
   

  	
  1

  	
   

  	
  2

  	
   

  	
  3

  	
   

  	
  4

  	
   

  	
  5

  
	
  10.

  	
  Making your sexual
  activities difficult?

  	
   

  	
  0

  	
   

  	
  1

  	
   

  	
  2

  	
   

  	
  3

  	
   

  	
  4

  	
   

  	
  5

  
	
  11.

  	
  Making you eat less of
  the foods you like?

  	
   

  	
  0

  	
   

  	
  1

  	
   

  	
  2

  	
   

  	
  3

  	
   

  	
  4

  	
   

  	
  5

  
	
  12.

  	
  Making you short of
  breath?

  	
   

  	
  0

  	
   

  	
  1

  	
   

  	
  2

  	
   

  	
  3

  	
   

  	
  4

  	
   

  	
  5

  
	
  13.

  	
  Making you tired, fatigued,
  or low on energy?

  	
   

  	
  0

  	
   

  	
  1

  	
   

  	
  2

  	
   

  	
  3

  	
   

  	
  4

  	
   

  	
  5

  
	
  14.

  	
  Making you stay in a
  hospital?

  	
   

  	
  0

  	
   

  	
  1

  	
   

  	
  2

  	
   

  	
  3

  	
   

  	
  4

  	
   

  	
  5

  
	
  15.

  	
  Costing you money for
  medical care?

  	
   

  	
  0

  	
   

  	
  1

  	
   

  	
  2

  	
   

  	
  3

  	
   

  	
  4

  	
   

  	
  5

  
	
  16.

  	
  Giving you side effects
  from medications?

  	
   

  	
  0

  	
   

  	
  1

  	
   

  	
  2

  	
   

  	
  3

  	
   

  	
  4

  	
   

  	
  5

  
	
  17.

  	
  Making you feel you are
  a burden to your family or friends?

  	
   

  	
  0

  	
   

  	
  1

  	
   

  	
  2

  	
   

  	
  3

  	
   

  	
  4

  	
   

  	
  5

  
	
  18.

  	
  Making you feel a loss
  of self-control in your life?

  	
   

  	
  0

  	
   

  	
  1

  	
   

  	
  2

  	
   

  	
  3

  	
   

  	
  4

  	
   

  	
  5

  
	
  19.

  	
  Making you worry?

  	
   

  	
  0

  	
   

  	
  1

  	
   

  	
  2

  	
   

  	
  3

  	
   

  	
  4

  	
   

  	
  5

  
	
  20.

  	
  Making it difficult for
  you to concentrate or remember things?

  	
   

  	
  0

  	
   

  	
  1

  	
   

  	
  2

  	
   

  	
  3

  	
   

  	
  4

  	
   

  	
  5

  
	
  21.

  	
  Making you feel
  depressed’?

  	
   

  	
  0

  	
   

  	
  1

  	
   

  	
  2

  	
   

  	
  3

  	
   

  	
  4

  	
   

  	
  5

  



 


Copyright University of Minnesota 1986


 


Page 52 of 52














 


SCHEDULE 1.31


 


DESCRIPTIONS OF OTHER
ON-GOING TRIALS


 


	
  Name
  of Study

  	
   

  	
  Estimated Duration

  	
   

  	
  Estimated End Date

  
	
  [**]

  	
   

  	
  [**]

  	
   

  	
  [**]

  
	
  [**]

  	
   

  	
  [**]

  	
   

  	
  [**]

  
	
  [**]

  	
   

  	
  [**]

  	
   

  	
  [**]

  



 

















 


SCHEDULE 1.35


 


OUTLINE OF STRUCTURE FOR
PIVOTAL CLINICAL TRIAL FOR PRIMARY INDICATION


 


(see Schedule 3.1)


 

















 


SCHEDULE 1.42(a)


 


INDEPENDENT SAFETY
MONITORING BOARD CHARTER


 


Independent Safety Monitoring Board


 


Charter


 


For


 


Bioline Innovations Jerusalem


 


Protocol No. BL-1040


 


A Phase I, multi-center, open label study designed to
assess the safety and feasibility of the injectable BL-1040 implant to provide
scaffolding to infarcted myocardial tissue


 


APPROVING
OFFICIALS


 


	
  Name

  	
   

  	
  Title

  	
   

  	
  Signature

  	
   

  	
  Date

  
	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
  Lincoff,
  A. Michael, M.D

  	
   

  	
  Chairman
  ISMB

  	
   

  	
   

  	
   

  	
   

  
	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
  Moti
  Gal

  	
   

  	
  Sponsor
  Contact Person

  	
   

  	
   

  	
   

  	
   

  
	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
  Andrea
  Kempf-Müller, M.D

  	
   

  	
  Drug Safety Officer

  	
   

  	
   

  	
   

  	
   

  



 














 


Contact
details ISMB members


 


	
  Lincoff,
  A. Michael, M.D.

  	
   

  	
  ISMB
  Chairman

  
	
  The
  Cleveland Clinic Foundation

  	
   

  	
   

  
	
  9500
  Euclid Avenue - F25

  	
   

  	
   

  
	
  Cleveland,
  OH  44195

  	
   

  	
   

  
	
  Phone:  216.444.2367

  	
   

  	
   

  
	
  FAX:  216.636.0609

  	
   

  	
   

  
	
  lincofa@ccf.org

  	
   

  	
   

  
	
   

  	
   

  	
   

  
	
  Philippe Gabriel Steg, M.D., F.A.C.C

  	
   

  	
   

  
	
  Hopital Bichat-Claude BernadService de
  Cardiologie

  	
   

  	
   

  
	
  46 Rue Henri Huchard

  	
   

  	
   

  
	
  75018 Paris

  	
   

  	
   

  
	
  FRANCE

  	
   

  	
   

  
	
  gabriel.steg@bch.aphp.fr

  	
   

  	
   

  
	
   

  	
   

  	
   

  
	
  Michael Marber BSc, MB.BS, PhD, FRCP

  	
   

  	
   

  
	
  Professor
  of Cardiology

  	
   

  	
   

  
	
  King’s
  College London

  	
   

  	
   

  
	
  Honorary
  Consultant Cardiologist

  	
   

  	
   

  
	
  Guy’s &
  St Thomas’ Hospitals

  	
   

  	
   

  
	
  The
  Rayne Institute, St Thomas’ Hospital

  	
   

  	
   

  
	
  Lambeth
  Palace Rd, London SE1 7EH

  	
   

  	
   

  
	
  mike.marber@kcl.ac.uk

  	
   

  	
   

  
	
   

  	
   

  	
   

  
	
  Kerry Lee, Ph.D.

  	
   

  	
   

  
	
  Duke
  Clinical Research Institute

  	
   

  	
   

  
	
  2400
  Pratt Street

  	
   

  	
   

  
	
  Room 0311
  Terrace Level

  	
   

  	
   

  
	
  Durham,
  NC  27705

  	
   

  	
   

  
	
  Ph:
  919-668-8725

  	
   

  	
   

  
	
  Fx:
  919-668-7055

  	
   

  	
   

  
	
  kerry.lee@duke.edu

  	
   

  	
   

  



 

















 


Contact
details BioLine and Averion


 


	
  Project Manager

  	
   

  	
  Address: 2268 chemin de Sourdaine

  
	
  Averion:

  	
   

  	
  F-84140 Montfavet

  
	
  Frederic Liegeois, Msc

  	
   

  	
  Phone: +33 (0)490140997

  
	
   

  	
   

  	
  Mobile: +33 (0)681607626

  
	
   

  	
   

  	
  Email:
  frederic.liegeois@averionintl.com

  
	
   

  	
   

  	
   

  
	
  Senior Drug Development Manager

  Bioline:

  Tuvia Shmuel, PhD

   

  	
   

  	
  Address:
  BioLine Innovations Jerusalem, 

  19
  Hartum St., POB 45158 Jerusalem, 

  Israel
  91450

  Phone:
  +972-2-548-9100, ext. 124

  Fax:
  +972-2-548-9101

  e-mail:
  shmuelt@biolinerx.com

  
	
   

  	
   

  	
   

  
	
  ISMB Sponsor Representative

  Bioline:

  Adina Porat

  	
   

  	
  Address:
  BioLine Innovations Jerusalem, 

  19
  Hartum St., POB 45158

  Phone: +972-2-548-9100 ex. 135

  Mobile: +972-54-5594613

  Fax: +972-2-548-9101

  E-Mail: adinap@biolinerx.com

  
	
   

  	
   

  	
   

  
	
  Clinical Operations Manager

  Bioline:

  Moti Gal

  	
   

  	
  Address:
  BioLine Innovations Jerusalem, 

  19
  Hartum St., POB 45158

  Telephone:
  +972-2-548-9100 ex. 147

  Mobile:
  +972-54-5933127

  Fax:
  +972-2-548-9101

  E-Mail:
  motig@biolinerx.com

  
	
   

  	
   

  	
   

  
	
  ISMB Coordinator

  Venn Life Sciences AG

   

  	
   

  	
  Medical
  Monitor, Europe

  Andrea
  Kempf-Müller, MD

  Venn
  Life Sciences AG

  Elisabethenstrasse
  23/3

  4051
  Basel, Switzerland

   Tel: +41 61 201 11 83

  Mobile: + 41 79 348 54 59

  Fax: +41 61 273 42 50

  Email: andrea.kempf-

  mueller@vlsworldwide.com

   

  Medical
  Monitor, US (only for ISMB contact)

   Sanjay Machado, MD

  Venn Life Sciences

  7355 Trans-Canada Suite 200

  



 

















 


	
   

  	
   

  	
  St-Laurent, QC, Canada

  H4T-1T3

  Tel: (541) 315-2992 117

  Mobile: (514) 946-7678

  Fax: (514) 315-0995

  Email: sanjaym@vlscanada.com

  



 

















 


1.                        PROTOCOL
BL-1040


 


A
Phase I, multi-center, open label study designed to assess the safety and
feasibility of the injectable BL-1040 implant to provide scaffolding to
infarcted myocardial tissue.


 


Venn
Life Sciences AG has been contracted by Bioline Innovations Jerusalem to
provide services as the Contract Research Organization (CRO) for the trial.


 


2.                        SCOPE
OF THE ISMB CHARTER


 


The
International Independent Safety Monitoring Board (ISMB) was formed to monitor
the safety of patients participating in this trial on an ongoing basis.


 


The
ISMB will evaluate quality, accuracy and timeliness of data flow and assure
confidentiality of data.


 


The
ISMB will develop stopping rules for the termination of the study prior to
the initiation.


 


Bioline
Innovations Jerusalem will forward the charter to Regulatory Authorities,
and/or Ethics Committees as necessary.


 


The
objective of the ISMB Charter is to outline the specific purposes and functions
of the ISMB. In addition, it describes the procedures for data abstraction and
data delivery conventions to and from the ISMB members for review purposes.


 


3.                        COMPOSITION
OF THE ISMB


 


The
ISMB is composed of three members, three voting members including the Chairman.
In addition a bio-statistician will consult the ISMB however will not attend as
a voting member. The members are independent physicians in the field of
cardiology and a bio-statistician experienced in evaluating safety data from
cardiology clinical studies. Prof. Lincoff will serve as Chairman of the ISMB.
All ISMB members have been approved by the sponsor, Bioline Innovations
Jerusalem.


 


By
signing the ISMB Charter, voting ISMB members verify that they do not have a
vested interest in the outcome of the study, nor do they have a financial
conflict of interest. ISMB members are not employees of Bioline Innovations
Jerusalem have outside employment and will not be involved in patient
recruitment or as investigators in the study.


 

















 


The
ISMB members are expected to serve until the study is completed. Should a
member resign, the reason and effective date of resignation must be submitted
in writing to Bioline Innovations Jerusalem and the ISMB Chairman. A
replacement member will be sought by Bioline Innovations Jerusalem in
consultation with the ISMB Chairman.


 


Except
for the initial meeting of the ISMB where the background data on BL-1040 and
the study design will be discussed by Bioline Innovations Jerusalem’s’
representatives, Bioline Innovations Jerusalem will not participate in the ISMB
meetings unless requested by the ISMB.


 


ISMB Administration


 


From Venn Life Sciences AG, the ISMB Coordinator will arrange for the
provision of the data and narratives required by the ISMB. Bioline Innovations
Jerusalem will provide administrative, logistical and coordinating services to
the ISMB.


 


ISMB Contacts & Consultants


 


The Chairman will be the representative of the ISMB who will be
responsible for timely official communications between the ISMB and Bioline
Innovations Jerusalem. The Chairman will provide leadership and oversee that
the direction of ISMB meeting operations are in accordance with the ISMB
charter.


 


From the sponsor, Bioline Innovations Jerusalem, an identified
representative will serve as the primary contact person for the ISMB. The
sponsor primary contact is named on the ISMB charter. This individual is not
considered to be a member of the ISMB and will only attend open and final
sessions of ISMB Data Review Meetings.


 


From
Venn Life Sciences AG, the ISMB Coordinator will serve as the primary contact
person for any questions the ISMB members have regarding the contents of the
ISMB Data Reports. This individual is not considered to be a member of the ISMB
and will 


 

















 


only
attend open and final sessions of ISMB Data Review Meetings. Additional individuals
may also be invited to attend the open and final sessions of the ISMB Data
Review meetings, as deemed appropriate.


 


The
ISMB Chairman will ensure that ISMB contacts are not exposed
to the ISMB review of the data until the ISMB has arrived at a conclusion. ISMB
contacts may not  be
present during closed sessions, when the ISMB Data Report is reviewed, ISMB
deliberations are made, ISMB recommendations are discussed and/or ISMB
voting procedures are conducted.


 


4.                        ISMB
ROLE & RESPONSIBILITIES


 


The
ISMB is an independent expert advisory group commissioned and charged with the
responsibility of evaluating accumulating data at regular intervals and
ensuring the safety of the subjects enrolled in the study by monitoring
cumulative safety data collected in the clinical program and providing
recommendations to Bioline Innovations Jerusalem based on review of this data.
The ISMB will contribute to efficient conduct of the trial by providing a fast
review of emerging findings from the study. This ISMB will consist of
physicians with expertise in cardiovascular disease, particularly in the area
of coronary artery disease and with experience monitoring safety of drugs
and/or devices for cardiovascular applications, and will have no participation
in the trial in any other capacity.


 


These
reviews in subsets of patients will have the objective of searching for signals
of clinically important adverse safety findings that may be indicative of risk
to currently enrolled patients as well as increased risk for future patients.
In these reviews, the ISMB will assume a conservative approach in assessing
safety.


 


The
Chairman will be directly responsible for reporting the outcome of all ISMB
meetings and be the primary contact for any emergency meetings, as
appropriately convened. He will be a voting member of the ISMB. The Chairman
will also be responsible for the preparation of the report and/or
recommendations to Bioline Innovations Jerusalem.


 


The
three voting members of the ISMB (along with the Chairman) will be responsible
for evaluating the safety data and making recommendations on the continuation
of the study as set out in the protocol. They may also make other pertinent
safety recommendations for the conduct of the study. They will be guided by the
ISMB Biostatistician’s evaluation of the data, as required.


 

















 


The
bio-statistician will be involved in conducting any analysis that the ISMB
recommends. The Bio-statistician will be responsible for designing and
maintaining the safety database that the ISMB will use for its analysis. This
database may differ from the database by Venn Life Sciences AG and, as such, is
meant only for the use of the ISMB. The database will be created in such a way
that it is reproducible and can be audited, if necessary. If the ISMB is considering
a recommendation of premature termination of the study, the bio-statistician
can contact Venn Life Sciences AG for additional data and/or for the
performance of confirmatory analysis. The Bio-statistician can also arrange for
the necessary ISMB communications to be documented and stored and only to be
released after study completion.


 


The
ISMB will ensure that this study meets the highest standards of patient safety.
In their analysis of the data from the patients, the ISMB will be focused on
determining if there is a signal of clinically significant pattern of change in
safety parameters that may lead to termination of study. This may require the
ISMB to perform/request additional data/analyses prior to making a decision.


 


The
operating procedures of the ISMB are based on and are in compliance with
guidance and definitions of the International Conference on Harmonization and
the Food and Drug Administration. The ISMB will conduct all of its operations
under the ICH Good Clinical Practices (GCP).


 


Specifically,
the ISMB is authorized and charged to perform the following functions:


 


·                  review 30 day
safety data patients from the first 2 sequentially enrolled patients to
determine whether 3 additional patients may be enrolled; after reviewing the 30
day safety data from these 3 additional patients, will determine whether the
rest of patients may be enrolled


·                  within 30 days
of enrolment of each successive group of 5 patients receiving the device, will
review all Serious and Severe Adverse Events occurring to date
and will recommend continuation, discontinuation, or modification of the
procedure or protocol, based on a determination of whether the occurrence of
serious, unexpected, or device-related adverse events (Sec. 7 in protocol)
might outweigh the potential benefit achievable with the device


·                  review emerging
findings in patients and identify potential safety concerns with BL-1040


·                  will receive
information, on an expedited basis, on all Serious and
Severe Adverse Events, clinically significant laboratory values (as
defined in the study safety plan), ECG abnormalities and vital signs that are
associated with Serious and Severe Adverse Events, and data from
patients who decided to withdraw from the study due to Serious and Severe Adverse Events. All Serious and
Severe Adverse Events that occur in the catheter lab during the
administration of BL-1040 or the hospitalization period after the procedure
should be reviewed 


 

















 


 


promptly by the ISMB. The ISMB will review this information and may
decide to interrupt, alter, or terminate the trial.


·                  will adjudicate
whether or not an event is unexpected, based on a pre-specified list of
expected Serious and Severe Adverse Events  as well as clinical judgment within the study
population.


 


All
ISMB members will review the safety data provided by the CRO. The members will
reach their own individual decision on the relatedness and the potential hazard
posed by the event. The ISMB will then collectively discuss the cases. In the
event the majority opinion of the Board is that the events do not pose any
significant risk then the ISMB will recommend continuing the trial as designed.
However, if the Board decides that undue risk could accrue from continuation of
the study as designed, the ISMB has the freedom to recommend appropriate
changes to the study selection criteria, safety evaluations, etc. In
addition, the CRO will provide datasets and listings capturing disposition,
AEs, clinically significant Echocardiography, MRI, angiography, Holter, ECG
vital signs/laboratory changes, once all patients complete study.


 


5.                        VENN
LIFE SCIENCES AG ROLE & RESPONSIBILITIES


 


Venn
Life Sciences AG will provide coordinating services for the study. The ISMB
Coordinator will provide information, on an expedited basis, on all Serious and Severe Adverse Events, clinically significant
laboratory values (as defined in the study safety plan, ECG abnormalities and
vital signs that are associated with Serious and
Severe Adverse Events as required, to the ISMB members. Venn Life
Sciences AG will be charged with the following responsibilities:


 


·             To identify a specific
individual to interface with the ISMB.


·             To provide all required
information in advance of the meeting in a mutually agreeable format approved
at the initial meeting of the ISMB.


·             To provide a standard safety
narrative for all patients who withdraw from the study due to Serious or Severe Adverse Events.


·             To provide specific meeting
issues in advance of the meeting.


·             To keep the ISMB Chairman
informed of any serious safety issues as the study progresses


·             To inform each principal
investigator of the ISMB recommendations, as required.


·             To notify Bioline
Innovations Jerusalem of any issues related to the ISMB which might negatively
influence the study.


 


6.                        BIOLINE
INNOVATIONS JERUSALEM’S RESPONSIBILITIES


 


Bioline
Innovations Jerusalem will be responsible for the following:


 

















 


·             To make any necessary
changes to the protocol recommended by the ISMB and approved by Bioline
Innovations Jerusalem.


·             To ensure that the ISMB is
operating as needed for the purpose of the study.


 


7.                        ONGOING
COMMUNICATIONS & NOTIFICATIONS


 


The
ISMB Chairman will receive relevant information regarding serious adverse
events and Early Terminations on an ongoing basis. The ISMB Chairman will
determine whether further distribution of this material to the remaining voting
ISMB members is necessary.


 


8.                        DATA
REVIEW MEETINGS


 


ISMB Data Review meetings will be held in person or through
teleconferences based on the volume of data to be reviewed. The ISMB
Coordinator will establish the agenda for each ISMB Data Review meeting, with
input from Bioline Innovations Jerusalem and the ISMB Chairman.


 


It
is expected that there will be one initiation and at least three scheduled ISMB
Data Review meetings. The initiation meeting will be held via face-to-face
format, while the Data Review Meetings may be held via teleconference.


 


The first 2 patients will be sequentially enrolled into the
study. After the 1st patient has completed Day 30 assessments, the Independent
Safety Monitoring Board (ISMB, Sec. 4.3) will review the patient’s data through
Day 30 (first ISMB meeting). The ISMB will then decide whether to give approval
to enroll the 2nd patient. After the 2nd patient has completed Day 30
assessments, the ISMB will again review the data and provide approval for
enrollment of the next 3 patients (2nd ISMB meeting). After all 3 patients have
completed Day 30 assessments, the ISMB will review the data from these patients
and provide approval for opening enrollment to the rest of the patients (3rd
meeting)


 


The
ISMB may also elect to hold ad hoc meetings outside of the scheduled dates, if
deemed necessary. For instance, as the ISMB Chairman will receive information
regarding reported serious adverse events on a regular basis, ad-hoc ISMB meetings
may also be held on a triggered basis (e.g. in response to a high number of
safety events).


 

















 


Voting


 


Input
must be obtained from all three ISMB members, for voting purposes. The ISMB
will strive for a consensus opinion regarding the data reviewed. If ISMB
consensus is not possible, a majority vote will be required, to determine the
final ISMB recommendation. If the ISMB vote does not result in a clear
majority, the ISMB Chairman will assemble and present majority and dissenting
opinions for all recommendations considered.


 


Meeting
Minutes


 


ISMB
Data Review meeting minutes will be divided by session and will reflect the
attendance of voting ISMB members, the ISMB Coordinator, ISMB contacts and
consultants and other individuals, as well as whether each individual attended
in person or via teleconference.


 


Since
all details of ISMB deliberations must be kept strictly confidential among
members of the ISMB, portions of the ISMB Data Review meeting minutes must
remain confidential until the completion of the final study analysis.


 


The
ISMB Chairman will file all minutes from all sessions, centrally. Once the
final study analysis is complete, the ISMB Chairman will forward the central
file of all ISMB minutes for all sessions to Bioline Innovations Jerusalem for
appropriate filing.


 


9.                        RECORDS RETENTION


 


The
ISMB Chairman should maintain a record of all ISMB minutes until the
investigation of the study device is discontinued. After this period, the ISMB
Chairman will forward to the sponsor all records to the sponsor to determine if
further retention and/or archiving is necessary.


 


Data
Source and Content


 


10.                 ISMB
COMMUNICATION OF FINAL CONCLUSIONS


 


The
ISMB Chairman will contact Bioline Innovations Jerusalem within two working
days after an ISMB meeting (via facsimile or telephone) to notify them of
recommendations forthcoming from that meeting. Bioline Innovations Jerusalem
will act upon these recommendations as appropriate, i.e., the final decision
will rest with Bioline Innovations Jerusalem. Bioline Innovations Jerusalem’s
VP of Medical Affairs or designee will notify the project team and the CRO of
the ISMB recommendations.


 


Bioline
Innovations Jerusalem’s VP of Medical Affairs will also write a memo to the
files documenting the recommendations of the ISMB and convey to all
investigators the decision to continue/discontinue the study.


 

















 


11.                 IMPLEMENTATION
OF THE ISMB RECOMMENDATIONS


 


The decision to implement the recommendations of the ISMB will be made
by Bioline Innovations Jerusalem. Bioline Innovations Jerusalem will notify the
ISMB of the actual action taken, in response to all recommendations.


 


If
the ISMB recommends early study termination or protocol modification and such
action is not accepted or implemented, Bioline Innovations Jerusalem will address
this decision with the ISMB in writing.


 


12.                 CONFIDENTIALITY


 


The
ISMB will maintain a strictly confidential relationship to the study data. The
ISMB will only reveal specific details and information associated with ISMB
data review to appropriate parties, as specified by this ISMB Charter.


 






 










 


SCHEDULE 2.3


 


EXISTING PRODUCT AGREEMENTS


 


[**]


 

















 


SCHEDULE 3.1


 


INITIAL DEVELOPMENT PLAN


 


Project Boston Clinical Development Plan


 


Objective


 


This
product is a unique concept, and will require a unique and sophisticated
development plan to satisfy all stakeholders.


 


This
product has been given a regulatory designation as a device (rather than drug).
The objective of this development plan is to leverage that designation for a
rapid and efficient regulatory approval, while providing adequate evidence for safety
within the intended patient population.


 


Strategy


 


The
strategy is to complete a minimal additional amount of preclinical safety in
parallel with the clinical development program. 
[**].


 


The
filing will be based on a [**]. We note that the current phase 2 study has no
control group, and can give only general information about safety and
tolerability, and no real information on efficacy in humans. For this reason
the [**] will be designed with a ‘vanguard’ cohort of approximately [**]
patients. Once the vanguard has completed 6 months of follow up, and interim
analysis will be performed, assessing the study for 1) safety, 2) efficacy or
futility and 3) performance of the endpoint. Specific, detailed and
comprehensive criteria will be established to allow for stopping or
continuation, or adjustments in sample size or inclusion criteria. The rules for
the interim analysis will be agreed with regulatory authorities in advance of
any unblinding, and appropriate adjustments will be made for type 1 error.


 


Following
the interim analysis the number of participating centers will be increased to
speed enrollment, and the study will continue to completion.


 


Endpoint
and sample size


 


We
will define [**] and then power the study to show at least a [**] with BL-1040
compared to placebo. This difference is clinically meaningful.


 


To
give maximum power we want to define an endpoint that has a [**] after
treatment, which would be reduced to [**]. We will design a [**] that ensures
an event rate that is [**] in the control arm.


 


[**]
Any one of these events and the patient is [**]; none of these events and the
patient is considered [**]. It is possible that other clinically relevant
events may be added to the composite.


 

















 


Next
we will estimate how often each of these events will happen.  [**].


 


	
  Control Group

  Event Rate

  	
   

  	
  Treatment Group

  Event Rate

  	
   

  	
  Sample size per arm

  90% power and type

  1 error < 5%

  	
   

  	
  Total

  
	
  [**]

  	
   

  	
  [**]

  	
   

  	
  [**]

  	
   

  	
  [**]

  
	
  [**]

  	
   

  	
  [**]

  	
   

  	
  [**]

  	
   

  	
  [**]

  
	
  [**]

  	
   

  	
  [**]

  	
   

  	
  [**]

  	
   

  	
  [**]

  



 


Although
not required under device approval regulations, approximately [**] patients
would be desirable for a safety database. If we assume that the placebo event
rate will be approximately  [**], we would estimate the sample size of the pivotal study to be
approximately [**] patients, including the [**] patients in the vanguard
cohort.


 


Budget


 


	
   

  	
   

  	
  2009

  	
   

  	
  2010

  	
   

  	
  2011

  	
   

  	
  2012

  	
   

  	
  2013

  	
   

  	
  2014

  	
   

  	
  2015

  	
   

  	
  2016

  	
   

  	
  TOTAL

  
	
  [**]

  	
   

  	
  [**]

  	
   

  	
  [**]

  	
   

  	
  [**]

  	
   

  	
  [**]

  	
   

  	
  [**]

  	
   

  	
  [**]

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
  [**]

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
  [**]

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
  [**]

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
  [**]

  	
   

  	
   

  	
   

  	
   

  
	
  [**]

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
  [**]

  	
   

  	
  [**]

  	
   

  	
   

  
	
  [**]

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
  [**]

  	
   

  	
   

  
	
  TOTAL

  	
   

  	
  [**]

  	
   

  	
  [**]

  	
   

  	
  [**]

  	
   

  	
  [**]

  	
   

  	
  [**]

  	
   

  	
  [**]

  	
   

  	
  [**]

  	
   

  	
  [**]

  	
   

  	
  [**]

  



 


Phase
III Study


 


Budget
will assume [**] of [**] patients, with a primary endpoint at [**] major
adverse cardiac outcomes at [**], and a safety follow up annually for [**].


 


	
  Clinical:

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
  Monitoring:

  	
   

  	
   

  	
   

  	
  [**]

  	
   

  
	
  Per Patient total:

  	
   

  	
  [**]

  	
   

  	
  [**]

  	
   

  
	
  Pre
  Clinical

  	
   

  	
  [**]

  	
   

  	
  [**]

  	
   

  
	
  Total

  	
   

  	
   

  	
   

  	
  [**]

  	
   

  



 


Given
that 15-20% of the total clinical costs are committed before the first patient
is enrolled, we estimate that cost to decision point is approximately [**]. It
may be possible to reduce cost to the 


 

















 


decision
point by [**], trading off for time-to-launch. This alternative scenario has
not been modeled.


 


Cost by
Year ($M)


 


	
  [**]

  	
   

  	
  [**]

  	
   

  	
  [**]

  	
   

  	
  [**]

  	
   

  	
  [**]

  	
   

  	
  [**]

  
	
  [**]

  	
   

  	
  [**]

  	
   

  	
  [**]

  	
   

  	
  [**]

  	
   

  	
  [**]

  	
   

  	
  [**]

  



 


[**]
Study


 


Budget
will assume a [**] (including ethnicity) of [**]  patients. 
Study will start in [**] and end [**]


 


Cost by Year ($M)


 


	
  [**]

  	
   

  	
  [**]

  	
   

  	
  [**]

  	
   

  	
  [**]

  	
   

  	
  [**]

  	
   

  	
  [**]

  	
   

  	
  [**]

  
	
  [**]

  	
   

  	
  [**]

  	
   

  	
  [**]

  	
   

  	
  [**]

  	
   

  	
  [**]

  	
   

  	
  [**]

  	
   

  	
  [**]

  



 


Timeline


 


Phase
III Study


 


	
  Enrollment

  w/ [**] per site per month

  	
   

  	
  Part 1

  	
   

  	
  Part 2

  
	
  Total Enrollment

  	
   

  	
  [**]

  	
   

  	
  [**]

  
	
  Active Sites

  	
   

  	
  [**]

  	
   

  	
  [**]

  
	
  Enrollment/Site/Month (on average)

  	
   

  	
  [**]

  	
   

  	
  [**]

  
	
  Monthly Study Enrollment

  	
   

  	
  [**]

  	
   

  	
  [**]

  
	
  Time to Enroll Patient per Part (months)

  	
   

  	
  [**]

  	
   

  	
  [**]

  
	
  TOTAL ENROLLMENT TIME (months)

  	
   

  	
  [**]

  



 


	
  Trial Task

  	
   

  	
  End Date

  
	
  Initiate
  Project

  	
   

  	
  [**]

  
	
  FPI

  	
   

  	
  [**]

  
	
  [**]

  	
   

  	
  [**]

  
	
  LPI

  	
   

  	
  [**]

  
	
  DB
  Lock

  	
   

  	
  [**]

  
	
  CSR

  	
   

  	
  [**]

  
	
  Submit
  PMA

  	
   

  	
  [**]

  



 

















 


Probability
of success


 


Based
on the available preclinical data it is not possible to come to a firm estimate
of POS at this time. However, there is evidence of efficacy in preclinical
models, and a consensus among experts that the mechanism is plausible. Given
the existing data on the prior use of this class of compounds in humans, the
likelihood of adequate safety and tolerability seems higher than would
otherwise be possible at this stage, and given the device designation, the
probability of clinical and regulatory success is likewise higher than it might
otherwise be. Assuming the likelihood of adequate safety at [**] and the
likelihood of adequate efficacy at [**], the overall POS to filing is in the
range of [**].


 

















 


SCHEDULE 3.7


 


PRELIMINARY
COMMERCIALIZATION PLAN


 






 










 


Preface:


 


This document is prepared for the management of BioLineRx as a basis
for discussion only, and is intended to be indicative of Ikaria’s current
intent with respect to global commercialization of BL-1040.  Actual launch plans will continue to evolve
over time, in accordance with the evolution of market dynamics, the global
environment for cardiovascular drugs and devices, and the emerging product
profile of BL-1040.


 


I.                                        Situation
Analysis


 


a.              Unmet
Medical Need


 


Each year cardiovascular
disease (CVD) causes over 4.3 million deaths in Europe.  CVD is estimated to cost the European Union
(EU) economy €192 billion a year. The main forms of CVD are coronary heart
disease (CHD) and stroke. Just under half of all deaths from CVD are from
CHD.  CV is also a large problem in
Japan, and is emerging as a public health issue even in the developing
countries.


 


Each year smoking kills over
1.2 million people in Europe (450,000 from CVD)). Dietary patterns across
Europe are playing an increasing role in CVD. Levels of physical inactivity are
high in many European countries and levels of obesity are increasing across
Europe in both adults and children.  Over
48 million adults in Europe have diabetes and the prevalence is increasing.


 


Estimates for population and
cardiovascular statistics are presented in Table 1


 


Table 1


 


	
   

  	
   

  	
   

  	
   

  	
  Est.

  Annual

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
   

  	
   

  	
   

  	
   

  	
  non-fatal

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
  Country

  	
   

  	
  Population

  (000,000)

  	
   

  	
  MI

  (000)

  	
   

  	
  Interventional

  Cardiologist

  	
   

  	
  Annual PCI

  Procedures

  	
   

  
	
  [**]

  	
   

  	
  10.4

  	
   

  	
  34.7

  	
   

  	
  230

  	
   

  	
  28

  	
   

  
	
  [**]

  	
   

  	
  5.5

  	
   

  	
  18.3

  	
   

  	
  85

  	
   

  	
  15

  	
   

  
	
  [**]

  	
   

  	
  5.3

  	
   

  	
  17.7

  	
   

  	
  80

  	
   

  	
  14

  	
   

  
	
  [**]

  	
   

  	
  64.4

  	
   

  	
  214.7

  	
   

  	
  1,772

  	
   

  	
  172

  	
   

  
	
  [**]

  	
   

  	
  82.3

  	
   

  	
  274.3

  	
   

  	
  1,500

  	
   

  	
  219

  	
   

  
	
  [**]

  	
   

  	
  16.7

  	
   

  	
  55.7

  	
   

  	
  266

  	
   

  	
  45

  	
   

  
	
  [**]

  	
   

  	
  0.3

  	
   

  	
  1.0

  	
   

  	
  14

  	
   

  	
  1

  	
   

  
	
  [**]

  	
   

  	
  58.1

  	
   

  	
  193.7

  	
   

  	
  1,879

  	
   

  	
  155

  	
   

  
	
  [**]

  	
   

  	
  40.5

  	
   

  	
  135.0

  	
   

  	
  730

  	
   

  	
  108

  	
   

  
	
  [**]

  	
   

  	
  7.6

  	
   

  	
  25.3

  	
   

  	
  124

  	
   

  	
  20

  	
   

  
	
  [**]

  	
   

  	
  61.1

  	
   

  	
  203.7

  	
   

  	
  1,000

  	
   

  	
  163

  	
   

  
	
  Total Europe

  	
   

  	
  352.2

  	
   

  	
  1,174.0

  	
   

  	
  7,682

  	
   

  	
  939

  	
   

  
	
  [**]

  	
   

  	
  127.0

  	
   

  	
  423.3

  	
   

  	
  2,500

  	
   

  	
  339

  	
   

  
	
  [**]

  	
   

  	
  21

  	
   

  	
  70

  	
   

  	
  373

  	
   

  	
  56

  	
   

  
	
  Grand Total

  	
   

  	
  479.2

  	
   

  	
  1,597.3

  	
   

  	
  10,182

  	
   

  	
  1,278

  	
   

  



 

















 


b.              Product


 


BL-1040,
a novel, injectable, biodegradable polymer designed to be used in conjunction
with Percutaneous coronary intervention (PCI) to provide mechanical
scaffolding  and reduce the risk of
structural remodeling and heart failure in post-myocardial infarction (post-MI)
patients, is currently in development and could be on the market as early as
[**].  If successful, BL-1040 could be a
breakthrough in the management of patients with cardiovascular disease and
could represent a large commercial opportunity for Ikaria and BioLineRx.


 


c.               Assessment
of current level of CV practice


 


There
is significant variability around the medical management of CHD across Europe.
Theses groupings give a high level overview of the most common interventions:


 


Hospital admissions


 


Rates
of admission for CVD vary considerably across Europe. In general, higher
admission rates are found in Eastern European and Scandinavian countries.
Similar geographical trends are seen for CHD.


 


Coronary revascularization and other procedures for
CVD


 


While
rates of revascularization vary widely across Europe, all countries have seen
rates increase significantly since the 1990s. For example, since 1990 rates of
PCI have increased fifteen-fold in Italy and twelve-fold in Finland.  We expect that advances in medical technique
and continued development of medical infrastructure around the world will drive
continued growth in the coronary revascularization market.


 


Drugs


 


The
use of drugs for secondary prevention in CHD patients varies considerably
across populations, except in the case of anti-platelet drugs. Over 80% of
patients took this form of drug (mostly aspirin). The use of beta blockers,
lipid-lowering drugs and ACE inhibitors varies throughout the EU.


 


d.              Pricing  and reimbursement environment


 


The
global market for cardiovascular drugs and devices is highly variable in terms
of pricing and reimbursement climates.


 


Pricing


 


Pricing
in the developed markets of western Europe tends to be similar to U.S. pricing,
although prices can vary significantly by market, with Northern European
markets having higher prices than southern European markets.  By contrast, pricing in less developed
markets (Eastern Europe, Latin America and the Far East) is highly variable,
and will require careful study to ensure an appropriate price is selected in
order to maximize penetration and profitability.  A clear target product profile will be
critical to assessment of pricing strategy in all markets.


 


Reference
pricing is common practice in Europe, so timing of local launches must be
carefully coordinated to ensure optimized pricing across the territory.


 


[**]


 

















 


Reimbursement


 


With
the exception of regulatory approval, reimbursement will be the single most
important driver of commercial success.


 


The
process by which products gain reimbursement can vary greatly from country to
country, and may take a considerable amount of time.  A recent study by IMS suggested that it was
common for newly approved drugs to take between one and three years to gain
widespread reimbursement coverage in the top 16 EU markets.  Because most European countries operate
centralized, government-financed health systems, it is not typical for patients
to pay for treatments privately.  In many
countries where there is virtually no habit of citizens paying for their own
healthcare, initiating selling activity without reimbursement would be virtually
impossible, while inhabitants of some other countries may have no problem
paying for healthcare out of their own disposable income.


 


Expected
timing of reimbursement will, therefore, be a major driver of the timetable for
building out sales infrastructure, and commencing selling activities.  Ikaria will conduct extensive research
between deal closing and launch to ensure that reimbursement conditions are
clearly understood and that plans are in place to ensure broad and favorable
access to major commercial markets.


 


II.                                   Commercialization
Plan


 


Product Positioning Strategy


 


Given
the current expectations of the product profile, we aspire to — and expect that
— BL-1040 will be positioned as the de facto standard for prevention of post-MI
remodeling.


 


While
this depends on the specific results of the clinical trials, the market
conditions, including competitive scenario, and prevailing clinical practice
standards, the goal will be to make BL-1040 use prevalent across a range of
patient sub-groups that are at risk for remodeling. Specifically, the following
patient groups will be addressed in the marketing plan:


 


·                  High-risk STEMI (includes
patients with large myocardial Infarctions (MIs), anterior wall MIs and long
lead time to PCI): [**]


 


·                  Other STEMI (includes all
STEMI patients not considered of the highest risk):  [**]


 


·                  NSTEMI (all patients
who have an NSTEMI): [**]


 


In
addition to the market development efforts listed above, the focus of marketing
strategy will be on creating broad awareness of the significant long-term
effects of remodeling as well as discussing the risks of myocardial damage and
resulting negative consequences for all patients with MIs.   In Europe, this will also require resetting
of the current paradigm of treating non-primary PCI patients with medical
therapy alone, and illustrating the benefits of treatment with a mechanical
scaffolding device such as BL-1040.


 

















 


Organization Size and Structure


 


As
an experienced critical care company, Ikaria is committed to providing
doctors and other medical professionals with a high level of customer
service.  Operating in a highly
specialized, life-or-death environment Ikaria strives to match our customers
own urgency and commitment to patient care.


 


To
be successful in the area of post-MI care we anticipate creating an
organization capable of delivering both the commercial and medical support
desired by our target customer base. 
Ikaria intends to establish itself as the leader in critical care
globally, and will use BL-1040 as the platform on which to establish its
international presence.  As such, we
intend to build a robust but flexible organization with all the competencies
necessary to achieve leadership of the field. 
Although BL-1040 will likely be Ikaria’s first global product, we
anticipate that our own internal pipeline candidates IK-1001 and Covox will not
be far behind.  The infrastructure
envisioned by Ikaria and described in this document will therefore be
sufficient to successfully commercialize all of Ikaria’s present and future pipeline
compounds.


 


Ikaria
proposed to use a “hub and spoke” approach to commercializing BL-1040 in
Europe—the “hub” being a European headquarters and the “spokes” representing
local operating companies (LOCs) in major markets.  The headquarters will provide overall
strategic leadership and will spearhead European product development and
commercial strategy, while local operating companies will be responsible for
selling activity and local tactic implementation.


 


In
addition to strategic marketing and leadership support, the European
headquarters will be responsible for financial management and reporting of
regional results, management of European regulatory affairs functions,
development of a European clinical development program, development of
effective key opinion leadership, development of compelling health economic
data and development of HR strategies to maintain a strong and vibrant European
organization.


 


The
primary role of LOCs is to provide the necessary local sales and marketing
efforts necessary to achieve financial objectives for BL-1040.  In addition to the necessary commercial
infrastructure, the local operating companies would also be staffed with the  support functions essential
to commercial success.  This would
include a small local finance team, medical affairs, regulatory affairs and
human resource functions.  The role of
the local support staff is to implement strategic initiatives conceived at
headquarters level, and support local initiatives as necessary. The medical
affairs staff will be particularly important in supporting marketing in
disseminating the full medical information on BL-1040 and the clinical
specialists will also lead the training of physicians in using this product
appropriately.


 


The
LOC staffing level will be determined as a function of country population,
disease prevalence and target doctor population.  Sales Representatives will be recruited from
companies with a depth of experience in cardiovascular drug and device sales to
ensure we gain rapid access to the necessary prescriber base.  Representatives will be compensated through a
blend of base salary and sales incentive bonus, according to Ikaria’s existing
sales force incentive plan. (See Table 2)


 

















 


Table 2


 


	
   

  	
   

  	
   

  	
   

  	
  Est.

  Annual

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
   

  	
   

  	
   

  	
   

  	
  non-fatal

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
  Country

  	
   

  	
  Population

  (000,000)

  	
   

  	
  MI

  (000)

  	
   

  	
  Interventional

  Cardiologist

  	
   

  	
  Annual PCI

  Procedures (000)

  	
   

  	
  Sales

  Reps

  	
   

  
	
  [**]

  	
   

  	
  10.4

  	
   

  	
  34.7

  	
   

  	
  230

  	
   

  	
  28

  	
   

  	
  [**]

  	
   

  
	
  [**]

  	
   

  	
  5.5

  	
   

  	
  18.3

  	
   

  	
  85

  	
   

  	
  15

  	
   

  	
  [**]

  	
   

  
	
  [**]

  	
   

  	
  5.3

  	
   

  	
  17.7

  	
   

  	
  80

  	
   

  	
  14

  	
   

  	
  [**]

  	
   

  
	
  [**]

  	
   

  	
  64.4

  	
   

  	
  214.7

  	
   

  	
  1,772

  	
   

  	
  172

  	
   

  	
  [**]

  	
   

  
	
  [**]

  	
   

  	
  82.3

  	
   

  	
  274.3

  	
   

  	
  1,500

  	
   

  	
  219

  	
   

  	
  [**]

  	
   

  
	
  [**]

  	
   

  	
  16.7

  	
   

  	
  55.7

  	
   

  	
  266

  	
   

  	
  45

  	
   

  	
  [**]

  	
   

  
	
  [**]

  	
   

  	
  0.3

  	
   

  	
  1.0

  	
   

  	
  14

  	
   

  	
  1

  	
   

  	
  [**]

  	
   

  
	
  [**]

  	
   

  	
  58.1

  	
   

  	
  193.7

  	
   

  	
  1,879

  	
   

  	
  155

  	
   

  	
  [**]

  	
   

  
	
  [**]

  	
   

  	
  40.5

  	
   

  	
  135.0

  	
   

  	
  730

  	
   

  	
  108

  	
   

  	
  [**]

  	
   

  
	
  [**]

  	
   

  	
  7.6

  	
   

  	
  25.3

  	
   

  	
  124

  	
   

  	
  20

  	
   

  	
  [**]

  	
   

  
	
  [**]

  	
   

  	
  61.1

  	
   

  	
  203.7

  	
   

  	
  1,000

  	
   

  	
  163

  	
   

  	
  [**]

  	
   

  
	
  Total Europe

  	
   

  	
  352.2

  	
   

  	
  1,174.0

  	
   

  	
  7,682

  	
   

  	
  939

  	
   

  	
  [**]

  	
   

  
	
  [**]

  	
   

  	
  127.0

  	
   

  	
  423.3

  	
   

  	
  2,500

  	
   

  	
  339

  	
   

  	
  [**]

  	
   

  
	
  [**]

  	
   

  	
  21.0

  	
   

  	
  70.0

  	
   

  	
  373

  	
   

  	
  56

  	
   

  	
  [**]

  	
   

  
	
  Grand Total

  	
   

  	
  479.2

  	
   

  	
  1,597.3

  	
   

  	
  10,182

  	
   

  	
  1,278

  	
   

  	
  [**]

  	
   

  



 


NB:  The number of sales reps anticipated to be
needed in each market has been estimated as a function of [**]


 

















 


Launch
Timelines


 


To
maximize the value of BL-1040 Ikaria intends to be ready to launch at the
earliest possible opportunity.  As
described above, a key driver of launch readiness in any given market will be
the ability to access reimbursement for BL-1040.  Without appropriate reimbursement in place,
attempting to launch BL-1040 would be at best un-productive, and at worst,
damaging to the long-term perception of the product.


 


Ikaria
proposes to immediately undertake a battery of research and analysis to
understand the market-specific reimbursement environments across major target
markets.  Results of this research would
guide future launch plans, and help inform the timing of key investments in
people and infrastructure.


 


Development
of Ikaria’s ex-US presence will occur differently throughout the world:


 


1)             Ikaria already has
management structures in place in Canada, Japan and Australia.  These budding organizations would be expanded
in the near term to allow essential market preparation activities to begin as
soon as possible.  As the product profile
of BL-1040 becomes clearer, and the expectations for launch timing crystallize,
this existing in-country leadership infrastructure will be expanded to include
all the local sales and medical affairs capability necessary to a successful
launch.


 


2)             Establishment of a European
Headquarters function would be a high priority. 
We anticipate filling key leadership positions as early as [**], so that
high-level reimbursement, medical affairs and commercial strategic planning can
commence.  As a clearer view of the
likely launch timeline for BL-1040 emerges, remaining HQ infrastructure will be
built out to ensure a fully operational European headquarters well in advance
of launch. In the event that a positive result emerges from the interim
analysis and a decision is made to move up the commercial launch of the
product, the development of the launch plans — including execution of
reimbursement strategy and creation of marketing materials — will occur in
parallel to the ramp up of the LOCs.


 


3)             Additional, 2nd-tier markets will be
evaluated in parallel with [**] commercial infrastructure development.  Ikaria believes that there will be great
potential for BL-1040 in markets such as [**], but will need more time to evaluate
the optimal way to maximize sales in those territories.


 


[**]


 

















 


Proposed
European Structure


 


Headquarters


 





 


Human
Resources


 


Human
Resources will oversee European benefits programs, ensure compliance with local
employment law, promote employee development and succession planning, and all
functions necessary to building a world-class critical care business in
Europe.  The European HQ team will work
closely with LOC country managers to ensure local employee needs are met and
compliance with local laws is maintained. 
Local in-country contractors may be employed to deliver HR services at
the local level.


 


Anticipated
headcount:     2


 


Government
Affairs


 


Appropriate
reimbursement will be critical to the success of BL-1040.  As described above, reimbursement can be
highly variable across Europe. 
Development of a skilled government affairs capability within Ikaria
Europe will be critical to our success, for BL-1040 as well as future Ikaria
pipeline products.


 


Anticipated
headcount:     1


 


Commercial
Development


 


The
European Commercial Development team is responsible for commercial strategy
formulation across the European area, including both product and sales force
strategy.  The HQ marketing team will
work closely with the Clinton, NJ-based marketing team to develop a cohesive
global strategy suitable for implementation in European markets.  The European team will have responsibility to
ensure that brand strategies are implemented consistently across the area, and
will perform market research to monitor performance and adjust strategy as
appropriate.  The team will also work in
concert with country GMs and local marketing management to implement
large-scale promotional and educations programs.


 


The
European HQ team will also develop and implement European sales force
strategies including development and maintenance of a customer relationship
management system, sales skills training programs, and sales leadership
development.  The HQ team will work
closely with LOC commercial management to ensure a top-class sales effort in
each country.


 


Anticipated
headcount:     5


 


Medical
Affairs


 


Development
of a strong base of key opinion leaders will be critical to the success of
BL-1040.  Cardiology is a fast moving,
highly technical field, and for Ikaria to be a credible player we will need to
make a significant commitment to supporting the medical community through
education, research support, etc.  


 

















 


The
European Medical Affairs team will take the lead in formulating strategy for
the engagement of key opinion leaders in the formulation of brand development
strategy, the development of brand champions and building high-level
relationships between Ikaria and the medical community.  The HQ Medical Affairs team will work closely
with LOC Medical Affairs teams to align strategy across Europe and ensure a
consistent medical approach.


 


The
HQ Medical Affairs team will also be responsible for development of health
outcome data to support cost-effectiveness arguments.  The HQ team will work closely with LOC
commercial teams to package health outcome data for effective presentation to
in-country prescribers and reimbursement decision makers.


 


The
HQ Medical Affairs team will also take responsibility for developing responses
to requests for medical information about Ikaria products.  The team will work with LOC Commercial and
Medical Affairs teams to ensure a high level of customer support and
satisfaction.


 


Anticipated
headcount:     3


 


Regulatory
Affairs


 


The
European Regulatory Affairs (RA) team will lead all regulatory efforts on
behalf of Ikaria’s European operations. 
The HQ RA team will work closely with the Medical Affairs team to ensure
development programs have maximal likelihood of success and that regulatory
compliance is maintained at all times. 
The RA team will work in concert with in-country RA teams to execute on
regulatory strategies and maintain product registrations with local
authorities.


 


Anticipated
headcount:     2


 


Finance


 


The
European Finance team will support all local operating companies with financial
reporting and planning functions as well as accounts payable and accounts
receivable activities.  The HQ team will
consolidate European results and maintain a full European operating
P&L.  The HQ team will perform most
of the finance functions on behalf of the European Area, with LOCs having
minimal local requirement for finance headcount.


 


Anticipated
headcount:     9


 


Information
Technology


 


Ikaria’s
European IT requirements will be delivered by the European HQ team, with local
support from 3rd-party contract
services.  The HQ team will liaise with
Ikaria’s corporate headquarters IT function in Clinton, NJ to ensure reliable
systems functionality and robust customer support.


 


Anticipated
headcount:     3


 

















 


Local
Operating Country (LOC) Structure


 





 


Human
Resources


 


Human
Resources support will be provided from HQ as described above.  Specific local needs will be coordinated with
HQ HR and delivered by local 3rd party
providers


 


Anticipated
headcount:     None


 


Commercial
Development


 


The
LOC Commercial Development team is responsible for implementation of commercial
strategy at the local level.  The
marketing team is responsible for implementation of European product strategy
and for directing local tactical marketing in support of BL-1040.  The LOC commercial director is also responsible
for the development of a skilled critical care sales organization, including
recruitment, training and management of reps and managers.


 


The
number of sales reps required to promote BL-1040 will vary from country to
country according to the market opportunity, the number of prescribing doctors,
and the incidence of PCI procedures. (See Appendix A)


 


Anticipated
headcount:     Various


 


Medical
Affairs


 


Maintenance
of a strong relationships and robust medical affairs response capability will
be essential for success at the local level. 
The LOC medical director will take responsibility for development of
strong local relationships, coordination of company response to medical
information requests. Clinical Specialists in each LOC will be responsible for
training of physicians on use of product and for customer service.


 


Anticipated
headcount:     1-2


 


Regulatory
Affairs (RA)


 


The
LOC RA team will work together with HQ RA teams to execute on regulatory
strategies and maintain product registrations with local authorities.


 


Anticipated
headcount:     1-2


 

















 


Finance


 


The
HQ team will perform most of the finance functions on behalf of the European
Area, with LOCs having minimal local requirement for finance headcount.


 


Anticipated
headcount:     None


 


Information
Technology


 


Ikaria’s
European IT requirements will be delivered by the European HQ team, with local
support from 3rd-party contract
services.


 


Anticipated
headcount:     None


 






 










 


SCHEDULE 4.3(a)


 


BIOLINERX WIRE TRANSFER
INFORMATION


 


	
  Bank
  Name:

  	
  [**]

  
	
   

  	
   

  
	
  Bank
  Address:

  	
  [**]

  
	
   

  	
   

  
	
   

  	
   

  
	
  SWIFT
  Number:

  	
  [**]

  
	
   

  	
   

  
	
  IBAN
  Number:

  	
  [**]

  
	
   

  	
   

  
	
  Account
  Number:

  	
  [**]

  
	
   

  	
   

  
	
  Account Name:

  	
  [**]

  



 

















 


EXHIBIT A


 


TECHNOLOGY EXCHANGE PLAN


 


Upon Ikaria’s request, the following will be
provided by BioLineRx to Ikaria or its designee:


 


7.                                      All materials
(original or copies as appropriate) in BioLineRx’s possession and Control
relating to Product, including documentation relating to Development and all
regulatory filings, clinical information, and data and other documents relating
to the On-Going Phase I/II Trial and the Other On-Going Trials.


 


8.                                      Copies of all
documents and available information in BioLineRx’s possession and Control
necessary for Manufacturing of Product at the time of technology exchange.
These documents will include information necessary to assist Ikaria or its
designee in setting up Manufacturing operations for such things as:


 


·                  raw material test methods, specifications,
qualification and justification for use


·                  raw material vendor lists with part numbers


·                  analytical methods stated purpose,
development, qualification and validation reports


·                  process development reports, laboratory
notebooks and associated electronically stored data


·                  Manufacturing summary including


·                  detailed process description with process
schematics, operating parameters and target ranges, flow charts outlining
critical process controls and steps, cartoons, verbal description including
abbreviations, process scale, yield, and standard process instructions


·                  in-process controls/tests and acceptance
criteria including stated purpose of in-process tests


·                  master batch record(s)


·                  filling/packaging process


·                  aseptic and process development and
validation documents


·                  facility and equipment requirements and
design documents


·                  descriptions of process equipment, including
suppliers, part numbers, and historic invoices


·                  product test methods, specifications and
justification of specifications


·                  product stability, test methods and
qualification/validation reports, stability reports, shelf life recommendations


 


As
available and agreed upon by the JDC at the time of a technology exchange,
BioLineRx will provide requested technical manufacturing or engineering advice
to Ikaria or its designee. Ikaria will ensure designee has necessary expertise
in place to exchange the documentation and expertise in an orderly fashion.


 

















 


EXHIBIT B


 


BIOLINERX PATENT RIGHTS


 


Family 1


 


INJECTABLE
CROSS-LINKED POLYMER PREPARATIONS AND USES THEREOF


 


	
  Country

  	
   

  	
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Family 2


 


A METHOD
OF TREATING MUSCLE TISSUES


 


	
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PAYMENT DATE EXTENSION AMENDMENT


 


Ikaria
Development Subsidiary One LLC, a Delaware limited liability company having a
principal place of business at 6 State Route 173, Clinton, NJ 08809, USA (“Ikaria”),
BioLineRx Ltd., a corporation organized and existing under the laws of the
State of Israel and having a principal place of business at 19 Hartum Street, P.O. Box
45158, Jerusalem 91450, Israel (“BioLineRx Ltd.”), and BioLine
Innovations Jerusalem L.P., a limited partnership organized and existing under
the laws of the State of Israel and having a principal place of business at 19
Hartum Street, P.O. Box 45158, Jerusalem 91450, Israel (“BioLine
Innovations”; together with BioLineRx Ltd., “BioLineRx”) are party to an
Amended and Restated License and Commercialization Agreement dated as of the
26th day of August, 2009 (the “Agreement”).  Any defined terms used herein shall have them
meaning ascribed thereto in the Agreement.


 


Pursuant
to Section 4.1(a) the Agreement, Ikaria is required to make a
milestone payment to BioLineRx of USD $10,000,000 upon the Successful
Completion of the On-Going Phase I/II Trial (the “Second Milestone Payment”)
on or before [**].  BioLine and Ikaria
are currently in discussions to determine whether Ikaria is required to
withhold United States federal income taxes from the Second Milestone
Payment.  In order to enable the parties
to complete those discussions, Ikaria and BioLine hereby agree that the due
date for the Second Milestone Payment is hereby extended to [**].


 


Sections
10.2 (“Governing Law”) and 10.3 (“Submission to Jurisdiction”) of the Agreement are hereby
incorporated herein by reference.


 


Acknowledged,
Agreed, and Confirmed


 


 


	
  /s/
  Daniel Tassé

  	
   

  	
  /s/
  Kinneret Savitsky

  
	
  Daniel
  Tassé

  	
   

  	
  Kinneret
  Savitsky,

  
	
  Chief
  Executive Officer

  	
   

  	
  Chief
  Executive Officer

  
	
  Ikaria
  Development Subsidiary One LLC

  	
   

  	
  On behalf of, and as authorized representative of, both BioLineRx
  Ltd. and BioLine Innovations Jerusalem L.P.

  



 

















 


AMENDMENT TO THE AMENDED AND RESTATED LICENSE AND COMMERCIALIZATION
AGREEMENT


 


This
Amendment (this “Amendment”) is entered into this 21st day of April 2010 (the “Amendment
Effective Date”) by and between Ikaria Development
Subsidiary One LLC, a Delaware limited liability company with a
place of business at 6 Route 173, Clinton, NJ, 08809 USA (“Ikaria”), and
BiolineRx Ltd., a corporation organized
and existing under the laws of the State of Israel and having a principal place
of business at 19 Hartum Street, P.O. Box 45158, Jerusalem 91450, Israel (“BioLineRx
Ltd.”), and BioLine Innovations Jerusalem L.P.,
a limited partnership organized and existing under the laws of the State of
Israel and having a principal place of business at 19 Hartum Street, P.O. Box
45158 Jerusalem 91450, Israel (“BioLine Innovations”; together with
BioLineRx Ltd., “BioLine Rx”) . 
This Amendment amends the Amended and Restated License and
Commercialization Agreement entered into by and between Ikaria and BioLineRx
dated as of the 26th day of August 2009 (the “Agreement”).  Any defined term used in this Amendment not
expressly defined herein shall have the meaning ascribed thereto in the
Agreement.


 


1.             Modification of Payee. All payments to be made
under the Agreement shall be made to BiolineRx Ltd. or any Third Party assignee
of BioLineRx Ltd. permitted under Section 10.4 of the Agreement.


 


2.             Modification of Assignment.
The last two sentences of Section 10.4 of the Agreement are hereby
amended and restated as follows:


 


“BioLineRx
Ltd. may assign its right to receive payments hereunder to a Third Party, in its
sole discretion, provided that BioLineRx Ltd. provides Ikaria with prior
written notice of the assignment and the name and address of the assignee.  Any such Third Party assignee may not further
assign the right to receive payments hereunder without providing Ikaria with
prior written notice of the assignment and the name and address of the
assignee. Ikaria shall maintain a written record of any such assignments. The
parties intend that this Agreement shall be considered to be in “registered
form” as defined in United States Treasury Regulations Section 5f.103-1(c).  BiolineRx shall not otherwise be permitted to
assign this Agreement, in whole or in part, without the prior written consent
of Ikaria, which approval shall not be unreasonably withheld, conditioned, or
delayed.  Any assignment in contravention
of this Section 10.4 shall be null and void.”


 


3.             Ratification of Agreement.  Except as set forth in this Amendment, all of
the other terms and conditions of the Agreement are hereby ratified and
confirmed to be of full force and effect, and shall continue in full force and
effect.  This Amendment is hereby
integrated into and made a part of the Agreement.


 


4.             Counterparts. 
This Amendment may be executed in two or more counterparts, each of
which shall be effective as of the Amendment Effective Date, and all of which
shall constitute one and the same instrument. 
Each such counterpart shall be deemed an original, and it shall not be
necessary in making proof of this Amendment to produce or account for more than
one such counterpart.


 


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5.             Execution and Delivery.  This Amendment shall be deemed executed by
the parties when any one or more counterparts hereof, individually or taken
together, bears the signatures of each of the parties hereto.


 


 


Acknowledged
and Agreed to:


 


	
  BIOLINERX
  LTD.

  	
   

  	
  IKARIA
  DEVELOPMENT SUBSIDIARY ONE LLC

  
	
   

  	
   

  	
   

  
	
  By:
  /s/  Kinneret L. Savitsky /s/ Philip Serlin

  	
   

  	
  By:
  /s/ Matthew M. Bennett

  
	
  Signature

  	
   

  	
  Signature

  
	
   

  	
   

  	
   

  
	
  Kinneret
  L. Savitsky                 Philip
  Serlin

  	
   

  	
  Matthew
  M. Bennett

  
	
  Printed Name

  	
   

  	
  Printed Name

  
	
   

  	
   

  	
   

  
	
  CEO                                          CFO

  	
   

  	
  Vice
  President and Secretary

  
	
  Title

  	
   

  	
  Title

  
	
   

  	
   

  	
   

  
	
  April 21,
  2010

  	
   

  	
  April 21,
  2010

  
	
   

  	
   

  	
   

  
	
   

  	
   

  	
   

  
	
  BIOLINE
  INNOVATIONS JERUSALEM L.P., BY ITS GENERAL PARTNER BIOLINE INNOVATIONS
  JERUSALEM, LTD.

  	
   

  	
   

  
	
   

  	
   

  	
   

  
	
  By:
  /s/  Kinneret L. Savitsky /s/ Philip Serlin

  	
   

  	
   

  
	
  Signature

  	
   

  	
   

  
	
   

  	
   

  	
   

  
	
  Kinneret
  L. Savitsky                 Philip
  Serlin

  	
   

  	
   

  
	
  Printed Name

  	
   

  	
   

  
	
   

  	
   

  	
   

  
	
  CEO                                          CFO

  	
   

  	
   

  
	
  Title

  	
   

  	
   

  
	
   

  	
   

  	
   

  
	
  April 21,
  2010

  	
   

  	
   

  



 


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