Document:

Exhibit 4.9

 

CERTAIN PORTIONS OF THIS EXHIBIT HAVE BEEN
OMITTED AND ARE SUBJECT TO A CONFIDENTIAL TREATMENT REQUEST. COPIES OF THIS EXHIBIT CONTAINING THE OMITTED INFORMATION HAVE BEEN
FILED SEPARATELY WITH THE SECURITIES AND EXCHANGE COMMISSION. THE OMITTED PORTIONS OF THIS DOCUMENT ARE MARKED WITH A [***].

 

Development and Manufacturing Services
Agreement 

 

This Development and Manufacturing Services
Agreement (the "Agreement") is made and entered into as of January 26, 2015 (the “Effective
Date”) by and between Perrigo API Ltd., an Israeli company, having its principal offices at 29 Lehi Street, Bnei Brak
51200, Israel (“Perrigo”), Galmed Research and Development Ltd. an Israeli company having its principal offices
at 8, Shaul Ha'Melech Blvd., Tel Aviv 6473307, Israel (“Galmed”).  The parties identified
above are sometimes hereinafter individually referred to as a “Party” and collectively as the “Parties”.

 

WHEREAS, Perrigo is in the business
of development, production and marketing of various active pharmaceutical ingredients and finished dose formulation products and
owns facilities for GMP manufacture of active pharmaceutical ingredients located at Neot Hovav, Israel ("Perrigo's Facility");
and

 

WHEREAS, Galmed is in the process of
developing a novel final dosage pharmaceutical product for the treatment of Non Alcoholic Fatty Liver disorders, including Non-Alcoholic
Steato-Hepatitis, named Aramchol (the "Product"), which is currently in clinical trials Phase IIb; and

 

WHEREAS, the active pharmaceutical ingredient
contained in the Product (the "API") is currently manufactured for Galmed by Cambridge Major Laboratories Netherlands
("CML") in accordance with a manufacturing process that was developed by CML for Galmed and is owned by Galmed
(the "Manufacturing Process") as generally defined in the Route Of Synthesis attached hereto as Annex A
; and

 

WHEREAS, Galmed and Perrigo wish to
set forth the terms with respect to technology transfer, improvement of the Manufacturing Process and scale up to commercial scale
of the API as set forth herein (hereinafter the "Project"); and

 

WHEREAS, the Parties wish to negotiate
a definitive exclusive manufacturing and supply agreement, all as further detailed below;

 

Now Therefore, in consideration for
the mutual covenants set forth herein and other good and valuable consideration, the receipt of which is hereby acknowledged, the
Parties agree as follows.

 

1. Definitions

 

For the purpose of this Agreement, the terms
set forth below will have the meaning given below.

 

“Affiliate” shall mean,
with respect to any party hereto, any person, organization or entity directly or indirectly controlling, controlled by or under
common control with, such party. For purposes of this definition only, “control” of another person, organization or
entity shall mean the ability, directly or indirectly, to direct the activities of the relevant entity, and shall include, without
limitation (i) ownership or direct or indirect control of fifty percent (50%) or more of the outstanding voting stock or other
ownership interest of the other organization or entity, or (ii) possession of, or the power to elect or appoint fifty percent (50%)
or more of the members of the governing body of the organization or other entity.

 

    	 

    	 

    

 

"Batch" means a batch of the
API produced during the same cycle of manufacture.

 

“Batch Record” means the
detailed production instructions for manufacture, production and control of a Batch, including documenting each step in the manufacture,
processing, packing and labeling of the API, produced in accordance with GMP.

 

"Change of Control" means
(i) consolidation or merger of a party or its ultimate parent company with or into any other company, or any other entity or person;
(ii) corporate reorganization in which a party shall not be the continuing or surviving entity of such reorganization; (iii) sale,
license or lease of all or substantially all of a party's assets; (iv) transaction or a series of related transactions
in which a person or entity acquires more than fifty percent (50%) of the issued and outstanding shares, or fifty percent (50%)
or more of the outstanding voting power of a party (treating any convertible preferred shares on an as-converted to ordinary share
basis); (v) transaction or a series of related transactions in which a person or entity or “group,” as such
term is defined and interpreted under Rule 13d-5 of the U.S. Securities Exchange Act of 1934, as amended, acquires the right to
control the appointment or the voting for the election of more than fifty percent (50%) of the directors of a party.

 

“Confidential Information”
means any information and materials disclosed by a Party or an Affiliate of such Party or otherwise on its behalf (the "Discloser")
to the other Party or its Affiliate(s) (the "Recipient"), regarding, without limitation, the technology, intellectual
property, know-how, business, operations facilities and other affairs of the Discloser or affiliates thereof, whether disclosed
in oral, written, electronic, visual or any other form, which information includes, but is not limited to: any information relating
to or concerning the API or the Product, the processes and methods employed in the manufacture of API or the Product; Batch Records,
Specifications; information related to Perrigo's Facilities or the CML facility; information related to manufacturing processes
and/or technologies or to any products produced at Perrigo Facility or the CML facility; API Information; any prices and costs
of the Parties; regulatory filings for the API or the Product; the Parties' business, regulatory plans and strategies, patent disclosures,
patent applications, structures, models, techniques, formulas, processes, compositions, compounds, apparatus, designs sketches,
photographs, plans, drawings, specifications, samples, reports, customer lists, price lists, studies, findings, inventions and
other data and information disclosed or exchanged under this Agreement.

 

“GMP” shall mean all applicable
good manufacturing practices as established by the respective Regulatory Authorities, as applicable for investigational new drugs
in clinical phase III trials, including as established by the USFDA and EU-EMA (Investigational Medicinal Product) and as also
adjusted as and in case required by the Regulatory Authorities in Colombia, Brazil, Peru, Chile and Mexico, as per their applicable
guidelines for investigational new drugs in clinical phase III trials supplied by Galmed prior to the execution of this Agreement.

 

“Intellectual Property”
means all patents and other patent rights, trade secrets, trademarks, service marks, registered designs, applications for any of
the foregoing, trade and business names, unregistered trademarks and service marks, copyrights, rights in designs, inventions,
developments, know-how, discoveries, improvements, methods, processes, techniques, specifications, models, procedures, rights under
licenses, and rights of the same or similar effect or nature, in any part of the world, whether or not registered, published or
unpublished, and registrations and applications for registration thereof, and all rights therein whether provided by international
treaties or conventions or otherwise.

 

    	 

    	 

    

 

“Invention” means any concept,
discovery, development, improvement, formula, process, composition of matter, formulation, method of use or delivery, specification,
computer program or model (whether patentable or not) and any related and/or supporting documentation and data.

 

“API Information” all information
and data relating to the API, including but not limited to formulae, methods of manufacture, product descriptions, test methods,
validation of test methods, specifications, and all other supporting documentation, data and reports provided by Galmed to Perrigo,
or developed or acquired by Perrigo or any of its affiliates during the term of this Agreement in connection with the manufacture
and supply of API, including the information regarding the Process Stabilization the information regarding Scale Up, the Results
and the Reports, as well as all applications, submissions, filings and correspondence of Galmed with or to FDA or any other governmental
or Regulatory Authority with respect to the API.

 

"Specifications" means the
specifications and technical characteristics of the API provided by Galmed as detailed in Annex B, as may
be updated by Galmed from time to time in writing as set forth in Section 7A.1 below.

 

“Regulatory Authority” means
any governmental authority (whether Federal, State, municipal or other), regulating the development, clinical testing , manufacture,
packaging, labeling, storage, import, export, distribution, marketing, sale and/or intended use of the API in the United States
(USFDA), the European Union (EMA) (and each of its respective member states), Colombia, Brazil, Peru, Chile and Mexico and any
other additional country, as will be agreed upon by the Parties in writing.

 

"Qualified Person (QP)"
pursuant to European Union pharmaceutical regulation (Directive 2001/83/EC for Medicinal products for human use), or pursuant to
equivalent regulations by other Regulatory Authorities.

 

2. Scope and Purpose of this Agreement

 

2.1           This
Agreement sets forth the terms upon which Perrigo will provide Galmed with services concerning the Project. For that purpose, the
Parties agree that: (i) Galmed will transfer to Perrigo the documents, information, materials and know-how necessary to provide
the services contemplated under this Agreement and establish the Manufacturing Process at Perrigo's Facility (the "Technology
Transfer"); (ii) Perrigo will perform for Galmed certain laboratory studies for gap closing and stabilization of the current
Manufacturing Process (the "Process Stabilization"), (iii) Perrigo will manufacture and supply 60kg GMP of the
API at Perrigo's Facility (the "Tech Transfer Batches"); (iv) Perrigo will perform for Galmed additional laboratory
studies for further improving and optimizing the Manufacturing Process the "Process Improvement"); and (v) Perrigo
will scale up the Manufacturing Process to commercial scale, and manufacture and supply 900kg GMP of the API at Perrigo's Facility
(the "Scale Up Batches"); all as more fully detailed below. Each of the foregoing shall be deemed a "stage"
of the Project. For the avoidance of doubt, it is clarified that the Tech Transfer Batches and Scale Up Batches shall be, as per
the Route of Synthesis detailed in Annex A, manufactured in Perrigo's Facility in Neot Hovav.

 

2.2           Subject
to each Parties' performance of its obligation hereunder, and except as otherwise specifically agreed in this Agreement, the Parties
agree to negotiate an exclusive commercial contract manufacturing and supply agreement for a minimum term of five years of commercial
supply (the "Supply Agreement"), pursuant to which Perrigo will also provide further services to validate the
Manufacturing Process and compile a DMF and will be assigned as Galmed's exclusive manufacturer and supplier of the API, as further
set forth in Section 9 below. The supply of the API shall be made from Perrigo's Facility in Neot Hovav. Perrigo's Facility in
India may be added as an additional manufacturing site as may be agreed upon in writing by the Parties and subject to a QP audit
on behalf of Galmed, and subject to Galmed's agreement, at its sole discretion, which will not be unreasonably delayed or withheld.
The foregoing undertaking is subject to the parties agreeing on the terms of the Supply Agreement, including, without limitation,
the consideration and terms of supply.

 

    	 

    	 

    

 

2.3 Perrigo undertakes during the term of this
Agreement and the Supply Agreement, not to directly or indirectly develop, manufacture or sell the API, except for Galmed. In addition,
Perrigo shall not, during the term of this Agreement, provide any contract development and manufacturing services to any third
party with respect to any cholic acid derivative investigational new drug.

 

3. Technology Transfer 

 

3.1           To
the extent not already provided to Perrigo at the date of this Agreement, Galmed will transfer to Perrigo (or shall cause CML to
provide to Perrigo, as applicable) the documents, information, materials and know-how necessary to provide the services contemplated
under this Agreement and establish the Manufacturing Process at Perrigo's Facility. The steps to be undertaken and their required
time frames are set forth in a technology transfer protocol attached at Annex C (the "Technology Transfer
Protocol").   

 

3.2           Galmed
acknowledges and agrees that the timely and complete transfer of the Galmed and/or CML deliverables under the Technology Transfer
Protocol are essential for the timely start, performance and completion of the activities contemplated for the Technology Transfer
and the Project. Any delay in the timeframes set forth in the Technology Transfer Protocol caused by Galmed or any third party
on its behalf shall, to the extent reasonably possible and subject to Perrigo's production schedule, push forward the timeframes
of the Project in the least amount of days. To the extent of any such delay, Perrigo undertakes to notify Galmed of such delay
promptly upon its occurrence.

 

3.3           It
is noted that Perrigo has already sent a qualified process engineer to CML's facility in the Netherlands for the purpose of observing
the Manufacturing Process at CML's facility. Galmed will reimburse Perrigo for the travel and accommodation expenses of these two
visits at actual cost, which is NIS 15,950 (Including VAT). In the event that Perrigo determines that an additional visit is required
in order to observe additional critical aspects of the manufacturing cycle, Galmed will bear the additional travel and accommodation
expenses of Perrigo's process engineer for such additional period, provided that these are reasonable and have been approved in
advance by Galmed.

 

4. Process Stabilization

 

4.1           Perrigo
will perform certain laboratory services with respect to the Process Stabilization in the scope defined and set forth in Annex
D (the "Process Stabilization Scope") and, subject to the performance of Galmed's obligations detailed
in Section 4.2 hereunder, in the timeframes set forth therein in Annex D. The Process Stabilization Scope will, subject
to the provisions herein, be completed by April 30, 2015. Perrigo will perform the Process Stabilization Scope in a professional,
timely and diligent manner, in accordance with the specifications set forth in the Process Stabilization Scope and the representations
set forth in Section 12. For removal of doubt, without derogating from Perrigo's undertaking to perform its obligations set forth
in Annex D, it is noted that Perrigo cannot warrant or guarantee the outcome of the Process Stabilization.

 

4.2           For
Perrigo to perform the Process Stabilization, Galmed shall provide Perrigo with the necessary support, as detailed in the Process
Stabilization Scope. Galmed's initial contact person for this shall be Dr. Mizhiritskii Michael, Galmed's CMC consultant,
who may be replaced by Galmed from time to time by a written notice to be sent to Perrigo ("Galmed's Consultant").

 

    	 

    	 

    

 

4.3           Following
the completion of the Process Stabilization, Perrigo will, in consultation with Galmed, prepare Batch Records for the implementation
of the Manufacturing Process at Perrigo's Facility in Neot Hovav based on the existing batch records developed by CML and the outcome
of the Process Stabilization Scope. In the framework of the preparation of the Batch Records as aforesaid, Galmed will request
from CML to send a process engineer to Perrigo's Facility in Neot Hovav to assist with the preparation of the Batch Record, and
Galmed will bear the costs and expenses of such visit, it being clarified that Galmed cannot guaranty that CML will agree to such
visit. Galmed will approve and sign the Batch Records prior to manufacture of the Tech Transfer Batches by Perrigo as contemplated
in Section 5.

 

5. Tech Transfer Batches

 

5.1           Following
the completion of the transfer of the Manufacturing Process to Perrigo in accordance with the Technology Transfer Protocol and
the completion of the Process Stabilization, Galmed shall purchase and Perrigo shall manufacture and deliver the Tech Transfer
Batches to Galmed (60kg of the API) for the consideration set forth in Section 11.1.2, which will be manufactured in accordance
with the Specifications and as further set forth in Section 12. The Tech Transfer Batches shall be used by Galmed only for conducting
clinical trials for the Product and shall not be used otherwise for any commercial purpose or sale of the Product.

 

5.2           The
Tech Transfer Batches shall be delivered by September 30, 2015. Delivery terms of the Tech Transfer Batches shall be according
to Incoterms 2010 EXW (“ex works”) Perrigo's Facility Neot Hovav, Israel.

Any delay in the timeframes of the Technology
Transfer or the Process Stabilization Scope caused by Galmed shall, to the extent reasonably possible and subject to Perrigo's
production schedule, push forward the timeframes of the Project in the least amount of days. To the extent of any such delay, Perrigo
undertakes to notify Galmed of such delay promptly upon its occurrence.

 

As Perrigo intends to commence with the process of manufacturing the Tech Transfer Batches immediately following the execution
of this Agreement, it is agreed that, except in the event of breach of this Agreement by Perrigo, Galmed shall be obliged to purchase
the Tech Transfer Batches.

 

5.3           Galmed's
Consultant shall be reasonably available, during normal business hours, during the production of the Tech Transfer Batches, to
provide support to the critical production stages, either via phone, or to the extent Perrigo, in consultation with Galmed, shall
deem necessary and in coordination with Galmed's Consultant, by being present at Perrigo's Facility (in Israel).

 

5.4 For the purpose of Section 5.3 above, it
is clarified that Galmed cannot guaranty the cooperation of CML in the performance of its obligations under this Agreement, and
any non-compliance and/or non-performance on part of CML under this Agreement shall not constitute a breach of this Agreement by
Galmed. Galmed understands and acknowledges, however, that any such lack of cooperation by CML may cause delays in the timelines
of the Project and any delay or inability to perform any of Perrigo's obligations due to such lack of cooperation shall not constitute
a breach of this Agreement by Perrigo, provided that Perrigo undertakes to notify Galmed of such delay promptly upon its occurrence.

 

    	 

    	 

    

 

6. Process Improvement

 

Following the manufacture of the Tech Transfer
Batches, Perrigo will perform certain laboratory services for the improvement and optimization of the Manufacturing Process in
the scope defined and set forth in Annex E (the "Process Improvement Scope") and in
the timeframes set forth therein. The Process Improvement Scope will be completed by March 31, 2016 (subject to delays caused solely
by Galmed or any third party on its behalf, which will, to the extent reasonably possible and subject to Perrigo's production schedule,
delay the aforementioned date in the least amount of days). Perrigo will perform the Process Improvement Scope in a timely, professional
and diligent manner, however, for removal of doubt, it is noted that Perrigo cannot warrant or guarantee the successful outcome
of the Process Improvement Scope.

During the Process Improvement Scope period,
upon Galmed's request Perrigo shall keep Galmed informed of the progress of the Process Improvement (by way of an update by phone
every two weeks, and monthly report, and a final report), and shall provide Galmed with all information it reasonably requests
from time to time in connection therewith. In the final report with respect to the Process Improvement Scope, Perrigo shall put
into writing all the information regarding the Process Improvement Scope as detailed in Annex E, including a detailed
report on how the manufacturing process was made more efficient, the steps that were taken, a list of the suppliers, a list of
other outsourced contractors, copies of lab reports, lab notebooks and logs, as well as any other information related to the Process
Improvement Scope reasonably requested by Galmed.

 

Within a week following the completion of the
Process Improvement, and prior to the manufacture by Perrigo of the Scale-Up Batches, Perrigo shall provide Galmed with a sample
of the API produced, in order for Galmed to test such samples and confirm that it complies with the Specifications. Galmed shall
test such samples and provide Perrigo with its written input within thirty (30) days from the receipt thereof.

 

7. Scale-Up Batches

 

7.1           Following
the completion of the Process Improvement (whether successful or not), Galmed shall purchase and Perrigo shall manufacture and
deliver the Scale-Up Batches (900 kg GMP of the API) from Perrigo, for the consideration set forth in Section 11.1.4, which will
be manufactured in accordance with the Specifications and with the representations set forth in Section 12. The Scale-Up Batches
shall be used by Galmed only for the purpose of conducting clinical trials for the Product and shall not be used otherwise for
any commercial purpose or sale of the Product.

 

7.2           The
first half of the Scale-Up Batches (450kg GMP) shall be delivered by June 30, 2016. The Second half of the Scale-Up Batches (450kg
GMP) shall be delivered by August 15, 2016 (subject to delays caused solely by Galmed or any third party on its behalf, which,
to the extent reasonably possible and subject to Perrigo's production schedule, will delay the aforementioned date in the least
amount of days).

 

7.3           Delivery
terms of the Scale-Up Batched shall be according to Incoterms 2010 EXW (“ex works”) Perrigo's Facility Neot Hovav,
Israel.

 

7A. Additional Provisions and Regulatory
Matters 

 

With respect to the Tech Transfer Batches,
the Scale-Up Batches and any other API manufactured by Perrigo under this Agreement, the following shall apply:

 

7A.1       The Specifications may be updated
by Galmed from time to time due to regulatory changes or otherwise, by providing Perrigo with written notice and the updated Specifications.
In such event, Perrigo shall notify Galmed within fourteen (14) days the estimated consequences of such changes, and whether or
not such changes result in an increase to the timeframe or costs; in the event that such change results in an increase to the timeframe
or costs, the parties shall discuss such change to timeframes or costs within five (5) days of receipt of Perrigo's reply as aforesaid.
In the event that the Parties agree on a change to the Specifications as aforesaid, then Annex B shall be revised
accordingly.

 

    	 

    	 

    

 

7A.2        During the Project, Perrigo shall
send Galmed monthly written reports detailing the progress of the current stage of the Project, and the achievements to date (the
"Report"). Said Report shall be in a format that is mutually acceptable to the Parties, and may include additional
information reasonably requested by Galmed. Following the completion of each stage of the Project, Perrigo will provide Galmed
with a written final report, setting forth in detail all the information regarding such stage. Without derogating from the above,
to the extent that Galmed shall request to be informed of specific events relating to the progress of the Project, Perrigo shall
provide Galmed with all material information it requests from time to time in connection therewith.

 

7A.3        Perrigo shall be responsible for testing
the APIs in accordance with the protocols and test methods provided by Galmed or developed by Perrigo (and approved in writing
by Galmed) during the Project for testing the API that Perrigo manufactures under this Agreement. Perrigo shall promptly inform
Galmed of any deviations from the Specifications following such test methods and protocols. In addition, Perrigo shall provide
Galmed with the results of such testing promptly upon their occurrence. Perrigo will also be responsible to ensure that each API
Batch is appropriately labeled and traceable.

 

7A.4        Perrigo will deliver to Galmed one
copy of the Batch Records with respect to each Batch of API manufactured and delivered to Galmed pursuant to this Agreement. Perrigo
represents and warrants that all Batch Records and other documentation furnished to Galmed under this Agreement concerning the
manufacture of the API will be accurate and complete. If Galmed requires supplemental documents from Perrigo in order to obtain
or in connection with any Regulatory Authority approvals, Perrigo agrees to cooperate with Galmed and to make available to Galmed
such additional or supplemental documentation in its possession as may reasonably be requested by Galmed. If further work is required
from Perrigo with respect to the above, the Parties shall discuss in good faith the consideration that Perrigo will receive for
performance of such additional work, provided that such consideration will be agreed in advance and in writing. Perrigo will retain
originals of all Batch Records, any and all other records or documentation generated by it in connection with the manufacturing
and testing of API under the terms of this Agreement.

 

7A.5        Regulatory Inspections. Perrigo agrees
to notify Galmed promptly of any inspections by the FDA or other Regulatory Authorities which pertain to the API or the Perrigo
Facility where the API is manufactured, and shall promptly and within seven (7) days of their receipt/sending provide to Galmed
copies of all material reports, observations, notices, findings and replies to such findings and other material pertinent to such
inspections all as may be relevant to the API. Perrigo shall have the right to redact from any such copies only such segments that
do not relate in any manner to API and do not affect Perrigo's performance under this Agreement. Perrigo will allow, and will provide
Galmed with any required authorization to allow, the FDA or any other Regulatory Authority to inspect, audit and review the facilities
at which the APIs are manufactured and all procedures, practices, books, records, and documents to the extent requested by the
FDA and any other Regulatory Authority relating to the API. Perrigo will permit Galmed representatives (subject to signing a confidentiality
and non-use agreement) to be present during such inspections.

 

    	 

    	 

    

 

7A.6        Access to Perrigo's Facility. Galmed
(or any party on Galmed’s behalf) shall have the right, once every 36 months, or upon the occurrence of an event that Galmed
determines requires inspection (such as adverse drug event, product complaint or other event that requires inspection in the course
of Galmed's clinical trials), or as required by the drug manufacturer of the Product to conduct a QP audit (subject to such drug
manufacturer signing of a standard confidentiality and non- use agreement), upon reasonable notice to Perrigo and during normal
business hours, to audit Perrigo's Facilities for the API (to ensure that the APIs are being manufactured, packaged and stored
in compliance with the Specifications, and all applicable laws and regulations, including without limitation, GMP and Galmed's
quality and other standards). During such audits, Perrigo shall permit Galmed to contact and question the appropriate knowledgeable
personnel of Perrigo. Perrigo will cooperate with Galmed with respect to a request to audit any Perrigo third party supplier or
subcontractor involved in the manufacture and/or supply of the API (“Perrigo’s Suppliers”) responsible
for manufacturing, packaging and storing the API. Perrigo shall make available to Galmed and its duly authorized representatives
and agents (subject to the signing of a confidentiality and non-use agreement) all its and, subject to their approval, Perrigo's
Suppliers’ books, records and documents which in any way pertain to the manufacture or quality control, testing and compliance
procedures of the API. It is clarified for the avoidance of doubt, that any audit as aforesaid shall not derogate in any manner
from Perrigo's responsibility hereunder.

 

7A.7        Record Retention. Perrigo will retain
originals of all Batch Records, financial records and all other records or documentation generated by it in connection with the
processing and testing of API under the terms of this Agreement, and all records which are necessary in the event of a product
recall or adverse drug event or product complaint, for not less than seven (7) years after the expiration date of the API to which
the documentation relates and, if longer, such period as is required by applicable law.

 

8. API Acceptance

 

8.1           Galmed
shall have the right to return any shipment to Perrigo, at Perrigo's expense, for visually detectable defects within thirty (30)
days of receiving the API, or if Galmed determines that the API does not conform to the Specifications by testing and inspection
in accordance with industry standards, within the earlier of fourteen (14) days following the completion of testing of the API
by Galmed (or by the QP of Galmed's drug manufacturer) or three (3) months of delivery of the API.

 

8.2           Any disputes between the Parties as
to whether all or any part of a shipment rejected by Galmed conforms to the API Specifications shall be first resolved between
the Parties, which shall cooperate to mutually investigate the route-cause for the discrepancy in the analytical results (for example:
repeating the analytical tests of the original sample, resampling and repeat the analytical tests, replace analytical instrument,
the analyst performing the tests, and any other measures as will be decided between the Parties). If the Parties are unable to
agree as to whether a rejected shipment conforms to the Specifications the dispute shall be finally resolved by a mutually acceptable
third party independent expert (the "Expert"), who, if required according to said expert's discretion,
may engage a third party analytical laboratory, which shall be referred to within fourteen (14) days of the Parties establishing
the dispute. The determination of the said Expert shall be binding on the Parties, and all the expenses related to such testing
and shipment, if required, will be borne by the Party at fault. In the event that the shipment was justifiably rejected, Galmed
shall return the rejected shipment to Perrigo, which shall replace the rejected shipment (either by reprocessing or manufacturing
of additional material). In the event that the Expert shall determine that the rejected shipment was unjustifiably rejected, Galmed
shall [covered in one before previous sentence] pay for such shipment.

 

Galmed
shall have the right to request Perrigo to reprocess/replace the API which is disputed prior to receiving the determination of
the Expert. In that event, Galmed shall return the disputed shipment to Perrigo, and Perrigo will reprocess/replace the API and
the costs of such reprocessed/replaced API shall be borne by the Party at fault according to the determination of the Expert.

 

    	 

    	 

    

 

CERTAIN PORTIONS OF THIS EXHIBIT HAVE BEEN
OMITTED AND ARE SUBJECT TO A CONFIDENTIAL TREATMENT REQUEST. COPIES OF THIS EXHIBIT CONTAINING THE OMITTED INFORMATION HAVE BEEN
FILED SEPARATELY WITH THE SECURITIES AND EXCHANGE COMMISSION. THE OMITTED PORTIONS OF THIS DOCUMENT ARE MARKED WITH A [***].

 

9. Supply Agreement 

 

9.1           
As mentioned above, the Parties wish to negotiate a Supply Agreement, pursuant to which Perrigo will also provide further services
to validate the Manufacturing Process and compile a DMF and will be assigned as Galmed's exclusive manufacturer and supplier of
the API, subject to (i) the successful completion of Clinical Phases II and III of the Project and obtaining a marketing authorization
for the marketing of the Product by a Regulatory Authority and (ii) agreement between the Parties on the terms of the Supply Agreement,
as set forth in Section 9.2 below.

 

9.2           The
fees for these additional services and the commercial terms of said Supply Agreement shall be discussed and agreed between the
Parties in good faith. The contract manufacturing shall also take into account annual volumes of production. The Supply Agreement
shall also include customary provisions and customary representations and warranties by the Parties, as well as the supply terms
as applicable to such agreements, as shall be discussed between the parties in good faith.

 

9.3           
For the avoidance of doubt, it is acknowledged that neither Party shall be under obligation to enter into the Supply Agreement,
including in the event that the Parties do not agree on the terms of the Supply Agreement.

 

Furthermore, it is acknowledged that nothing
in the foregoing shall limit Galmed's right to negotiate other proposals with third party manufacturers.

 

10. Project Management and Communication

 

The Parties will establish a Project management
team, to which each Party will delegate at least one representative. Perrigo and Galmed will keep each other informed about the
progress of the Project and the services contemplated hereunder, periodically discuss the progress and results and, if needed,
jointly agree on adjustments to the annexures hereto.

 

11. Consideration

 

11.1         For
the services contemplated hereunder Galmed shall pay Perrigo the following consideration:

 

 11.1.1     Upon
completion of the Technology Transfer and Process Stabilization Galmed shall pay to Perrigo [***] ([***]US Dollars.

 

 11.1.2     For the manufacture
of the Tech Transfer Batches (60kg of API) as per Section 5 above, Galmed shall pay Perrigo $[***] ([***] US Dollars) per kg of
API, in two installments as follows:

 

(a)          An
advance payment of [***] ([***] US Dollars) shall be paid to Perrigo upon execution of this Agreement. Galmed acknowledges that
the said advance payment will be used by Perrigo to purchase the materials necessary for the manufacture of the Tech Transfer Batches
and is not refundable.

 

    	 

    	 

    

 

CERTAIN PORTIONS OF THIS EXHIBIT HAVE BEEN
OMITTED AND ARE SUBJECT TO A CONFIDENTIAL TREATMENT REQUEST. COPIES OF THIS EXHIBIT CONTAINING THE OMITTED INFORMATION HAVE BEEN
FILED SEPARATELY WITH THE SECURITIES AND EXCHANGE COMMISSION. THE OMITTED PORTIONS OF THIS DOCUMENT ARE MARKED WITH A [***].

 

(b)          The
balance amount shall be invoiced by Perrigo upon delivery of the Tech Transfer Batches ex works in accordance with Section 5.2.

 

11.1.3     Upon completion
of the Manufacturing Process Improvement in accordance with Section 6 (and in accordance with Annex E), Galmed shall
pay Perrigo [***] ([***] US Dollars).

 

11.1.4     For the manufacture
of the Scale Up Batches as per Section 7 above, Galmed shall pay Perrigo [***] ([***] US Dollars) per kg of API, in two installments
as follows:

 

(a)          An
advance payment equal to the costs of the purchase of the required raw materials, estimated at [***] ([***] US Dollars) shall be
paid to Perrigo no later than six months prior to the then expected delivery of the Scale Up batches (the "Advance Payment").
Galmed acknowledges that the said advance payment will be used by Perrigo to purchase the materials necessary for manufacture of
the Scale Up Batches and is not refundable. Alternatively, Galmed may, not later than seven months prior to the expected delivery
of the Scale Up Batches notify Perrigo of its wish to make direct payments to the suppliers of the raw materials required for the
manufacture of the API, in which case, such cost of direct payment to suppliers by Galmed will be reduced from the consideration
due to Perrigo under this Section 11.1.4 of the Agreement.

 

(b)          The
balance amount shall be invoiced by Perrigo upon delivery of the Scale Up Batches ex works in accordance with Section 7.3.

 

Perrigo will make an effort to improve the
quote for the price for the commercial supply under the Supply Agreement such that it will aim to be lower than [***] per kg of
API, subject to the outcome and extent of the cost improvements achieved during the Manufacturing Process Improvement. It is clarified
that the price of [***] per kg of API is not Galmed's target price, and that a competitive price is one of the considerations that
are important to Galmed in deciding whether or not to enter into the Supply Agreement.

 

11.2         All
payments to Perrigo by Galmed for work performed by Perrigo under the Agreement shall be made in New Israeli Shekels equivalent
to the U.S Dollars amount at the official exchange rate applicable on the date of invoice. The above consideration is final and
inclusive of all taxes and/or duties of whatever nature which are imposed or may be imposed with regard to the consideration, other
than value added tax which will be added to all amounts mentioned in this Agreement, at the appropriate rate as required by law.
Payments shall be made by wire transfer, money order or other method of payment approved in writing by Perrigo, within 30 (thirty)
days of Perrigo's invoice for the same. Any payment due to Perrigo by Galmed that is not paid when it is due shall accrue
interest, from the date when the same was due and payable, at the rate of 12 month LIBOR plus [***] (LIBOR as quoted by BBA –
British Bankers' Association - http://www.bba.org.uk), compounded annually, payable on demand.

 

11.3         For
removal of doubt it is noted that the full and timely payment of any part of the consideration hereunder is considered a material
obligation. Without derogating from any of the rights available to Perrigo, it may withhold services until full payment for services/APIs
is settled.

 

    	 

    	 

    

 

11.4         Payments
to Perrigo shall be done without any deduction on account of taxes. Perrigo shall provide Galmed with a current and valid tax exemption
certificate of the Israeli Tax Authority that indicates that no amount due to Perrigo under this Agreement needs to be withheld.

 

11.5         Galmed
acknowledges that Perrigo shall exert a considerable effort in time and resources in providing the services contemplated under
this Agreement and would have not entered into this Agreement unless for the obligation to purchase from it the Scale Up Batches
and negotiate the Supply Agreement in good faith.

 

11.6         Perrigo acknowledges that Galmed is
a clinical-stage company, and as such, time is of the essence, and it is dependent on the timely delivery of the Project and each
of its stages under this Agreement by Perrigo (including timely delivery of the APIs), and would have not entered into this Agreement
unless for Perrigo's foregoing acknowledgement as aforesaid, and its undertaking and obligation, subject to the provisions of this
Agreement and the timely performance of Galmed's (and third parties on its behalf) obligation hereunder, to timely deliver the
Project and each of its stages. The timely performance of Perrigo's obligations as aforesaid is considered a material obligation.

 

12. Warranty; Representations; Undertakings. 

 

12.1 Representations Warranties and Undertakings
of Perrigo. Perrigo represents, warrants and undertakes to Galmed that: (i) it is acknowledged that the Product that includes the
API will be used to undergo clinical trials and accordingly, the API must comply with the GMP ; (ii) it shall obtain and maintain
all necessary permits, registrations and licenses required, if required, to manufacture and supply the API under this Agreement,
including without limitation FDA and any other applicable Regulatory Authority; (iii) it will comply in all material respects with
all laws, rules and regulations applicable to the performance of its obligations under this Agreement, including all GMP of the
Regulatory Authority applicable to its manufacture, labeling, packaging, storage and shipment of the API in effect from time to
time as applicable for investigational new drugs in clinical Phase III trials; (iv) the API supplied pursuant to this Agreement
shall fully conform with the Specifications, free of any defects, will be manufactured in compliance with GMP and other applicable
laws, rules and regulations of the Regulatory Authorities as applicable for investigational new drugs in clinical Phase III trials
and shall be capable of maintaining such until any expiration of shelf life date for the API; (v) Perrigo's Facility was audited
by one or more third party QP audits in the last calendar quarter of 2014, and that there were no adverse findings discovered in
any of the QP processes which have not been cured; (vi) it will perform the Services under this Agreement in a competent and professional
manner, and the API shall be manufactured only by personnel who are highly qualified to provide services of the type of the Services;
(vii) Perrigo has full right and authority to enter into this Agreement without the consent or approval of any third party.

Furthermore, Perrigo represents, warrants and
undertakes towards Galmed that: (a) it has not during the last calendar year been found by the FDA or any other Regulatory Authority
or any state or other authorized government official to have violated any statutes, rules, or regulations; or (b) it has not, during
the last calendar year, received any relevant warning letter, observations, findings or the like from the FDA or other Regulatory
Authority, which have not been cured; and Perrigo further undertakes to promptly notify Galmed in the event that it receives a
warning letter, observations, findings or the like from the FDA or other Regulatory Authority during the term of this Agreement,
to the extent that it relates to the API.

 

    	 

    	 

    

 

Other than the foregoing representations, Perrigo
makes no representation or warranty regarding the Project or the API, including but not limited to warranties with respect to safety
or effectiveness of the API and/or the Product. Galmed acknowledges and agrees that, Perrigo and Perrigo personnel (i) have not
participated in and are not responsible for the invention, development, testing, clinical and/or safety evaluation of the API;
(ii) have not evaluated and will not evaluate and are not responsible for the API's safety or suitability for use in humans or
others; and (iii) have not participated in the development of the Manufacturing Process.

 

12.2 Representations and Warranties of Galmed.
Galmed represents and warrants to Perrigo that, (i) to the best of its knowledge it has the requisite Intellectual Property rights
related to the API and the Manufacturing Process; (ii) the performance of Perrigo's obligations under this Agreement shall not
give rise to a cause of action by a third party against Perrigo for infringement or another violation of Intellectual Property
rights relating to the API; (iii) it will comply in all material respects with all laws, rules and regulations, GMP, and Regulatory
Authority regulations applicable to the API and the Product. Without derogating from the generality of the afore-mentioned, Galmed
shall specifically comply with the U.S. Foreign Corrupt Practices Act (“FCPA”), the UK Anti-Bribery Act 2010 and any
local anti-bribery and anti-corruption laws, a breach of which is considered for the purposes of this Agreement a material breach;
and (iv) that it has full right and authority to enter into this Agreement without the consent or approval of any third party.

 

13. Confidential Information 

 

Each Recipient will hold, and cause their respective
representatives and advisers to hold at all times, any Confidential Information disclosed by the Discloser in strict confidence
from any person (other than its affiliates or their representatives or advisers), and undertakes to maintain the Confidential Information
in strict confidence and not to disclose or transfer it to others and not to make any use of the Confidential Information, for
personal or other needs, without the prior written consent of the Discloser. Recipient shall use the same degree of care to preserve
the secrecy and confidentiality of the Confidential Information and to avoid the unauthorized disclosure of the Confidential Information
to third parties as it uses with respect to its own confidential, proprietary or trade secret information, but in any event no
less than a reasonable degree of care.

 

Notwithstanding the
foregoing, disclosure by the Recipient in the event such Recipient is compelled to disclose the Confidential Information by judicial
or administrative authority and process shall not be deemed a breach of the confidentiality undertaking provided, however, if the
Recipient becomes subject to a demand for discovery or disclosure of the Discloser’s Confidential Information under lawful
process, the Recipient (a) shall, to the extent permitted by law, give immediate notice to the Discloser prior to furnishing the
Confidential Information so that the Discloser may seek an appropriate protective order, (b) shall not (unless expressly required)
provide such disclosure until the Discloser has had the opportunity to obtain such protective order, (c) shall disclose only that
portion of the Confidential Information which falls within the scope of such lawful process, and (d) shall cooperate in seeking
reasonable protective arrangements requested by the Discloser.

 

The foregoing confidentiality undertaking shall
not apply to the extent that:

 

13.1         The
Confidential Information was in the public domain (either prior to or after the furnishing of such documents or information hereunder)
through no fault and by reason other than a breach of this Agreement of such Recipient; or

 

13.2         The
Confidential Information was already in the possession of a party as demonstrated by competent evidence or was later acquired by
the Recipient from another legitimate source if the receiving party is not aware that such source is under an obligation to another
party hereto to keep such documents and information confidential; or

 

    	 

    	 

    

 

13.3         It
can be shown that the Confidential Information was independently developed by the Recipient without reliance on the Confidential
Information disclosed by the Discloser; or

 

13.4 Information set forth
in Section 14.2 below.

 

This Agreement does
not constitute the conveyance of ownership with respect to or a license to any Confidential Information, except as otherwise provided
in this Agreement. Upon the expiration or termination of this Agreement for any reason, each party agrees, except as otherwise
provided in this Agreement, to return to the other party all documentation or other tangible evidence or embodiment of Confidential
Information belonging to the other party and not to use same, unless otherwise agreed later.

 

This Section 13 shall
survive the expiration or termination of this Agreement for a period of fifteen (15) years.

 

14. Public Disclosure

 

14.1         No disclosure
(whether or not in response to an inquiry) of the terms and conditions of this Agreement shall be made by any Party hereto unless
approved by the other Party prior to release. Such approval shall not be unreasonably denied or delayed.

 

14.2         Notwithstanding
the foregoing, either Party may disclose such terms as are required to be disclosed in its publicly-filed financial statements
or other public statements, pursuant to applicable securities laws, regulations and stock exchange rules; provided that, to the
extent practicable, such Party shall provide the other Party with a copy of the proposed text of such statements or disclosure
at least forty eight (48) hours in advance of the scheduled release or publication thereof to afford such other Party a reasonable
opportunity to review and comment upon the proposed text (including redacted versions of this Agreement).

 

15. Intellectual Property Provision

 

15.1         Each
Party acknowledges that all Confidential Information, background information and Intellectual Property rights ("IPR")
owned, obtained or generated before or outside the Project by the other Party will at all times remain in the ownership of the
other Party. 

 

15.2         All
Confidential Information such as raw data, information, test material, reference materials, and other Intellectual Property rights
relating to the API and provided by Galmed to Perrigo pursuant to this Agreement shall remain the property of Galmed. Galmed grants
Perrigo a non-exclusive, nontransferable, royalty free license, during the term of this Agreement, to use the foregoing in connection
with the performance of the Services hereunder.

 

Furthermore, any Inventions specific to the
API discovered by Perrigo in the course of this Agreement or any Inventions specific to the API discovered as a result of performing
the Project or the Services, and the results and deliverables (as defined in Annex D and Annex E;)
(collectively, the "Results") will be owned exclusively by Galmed and vested with Galmed, regardless of the Party
that develops same, with the exception of the Perrigo Inventions (as defined below). Perrigo shall disclose the Results promptly
to Galmed within the Report, and shall cooperate with Galmed in defending or taking steps necessary or as requested by Galmed to
vest title to such Results in Galmed, at Galmed’s expense. Galmed shall promptly reimburse Perrigo for any reasonable costs
made in this respect. Only Galmed is entitled to acquire industrial and/or intellectual property rights anywhere in the world for
its IPR (including, for the avoidance of doubt, the Results). Galmed will at all times have an unrestricted right to use the Results.

 

    	 

    	 

    

 

15.3         Perrigo
will own all IPR and Inventions discovered in the course of this Agreement related to the research development and manufacturing
methodologies which are not specific to the API (the "Perrigo Inventions"). The Perrigo Inventions shall, as far
as generated or developed by Perrigo, become and remain the exclusive property of Perrigo and only Perrigo is entitled to acquire
industrial and/or intellectual property rights anywhere in the world for its IPR. Where necessary, Galmed will co-operate in the
acquisition of Perrigo Inventions by Perrigo, at Perrigo’s expense. Notwithstanding the foregoing, subject to the payment
by Galmed of the consideration for the Tech Transfer, Tech Transfer Batches and the Process Improvement, Perrigo hereby grants
Galmed a non-exclusive, irrevocable, royalty free license, unlimited in time, to make use of the Perrigo Inventions solely for
the purpose of manufacturing the API or the Product, either by Galmed, its Affiliates or any third party on Galmed's behalf (the
"License"). The License shall be transferrable, solely in connection with or as part of an Assignment under Section
20.10 below, in which event the assignee shall receive a License at the same terms stipulated herein.

 

15.4 The Parties further acknowledge and agree
that Galmed is engaging Perrigo as an independent contractor to manufacture and supply the API in accordance with the Specifications
and this Agreement and that all API Information is and shall be the sole property of Galmed.

Galmed will grant Perrigo the right to use
all such API Information and know-how owned or licensed by Galmed which is necessary for, and for the sole purpose of, the manufacture
of the Products for Galmed, on and subject to the terms of and only for the duration of this Agreement.

Upon the termination of this Agreement, or
upon Galmed's written request, Perrigo shall deliver to Galmed all the Batch Records and API Information relating to the manufacture
of the API.

 

16.  Indemnification and Limitation
of Liability.

 

16.1         Galmed
shall indemnify and hold harmless Perrigo and its Affiliates and their respective officers, directors, employees and agents (collectively
"Perrigo Indemnitees") from and against any and all claims, damages, costs and expenses of any kind (including
reasonable attorneys' and experts' fees) (collectively: "Claims") arising out of or resulting from any third party
claims made or suits brought against Perrigo which arise or result from (i) the breach of any of Galmed's representations, warranties,
covenants, obligations or agreements set forth in this Agreement; (ii) Galmed's negligence or willful misconduct in the performance
of this Agreement; (iii) the use of the Product; except in the event of (i), (ii) or (iii) above, to the extent caused by the negligence
or willful misconduct or breach of this Agreement by a Perrigo Indemnitee; or (iii) any third-party Intellectual Property infringement
claims relating to the APIs or the Product.

 

16.2 Perrigo shall indemnify, defend and hold
Galmed and its Affiliates and their respective officers, directors, employees and agents (collectively "Galmed Indemnitees")
harmless from and against any and all Claims arising out of or resulting from any third party claims made or suits brought against
Galmed which arise or result from (i) the breach of any of Perrigo's representations, warranties, covenants or agreements set forth
in this Agreement, or (ii) Perrigo's negligence or willful misconduct in the performance of this Agreement; except in each case,
to the extent caused by any Galmed Indemnitee's negligence or willful misconduct or breach of this Agreement.

 

    	 

    	 

    

 

16.3         In the event that any party seeks
indemnification under the terms of this Section 16 (the "indemnified party"), it shall as soon as reasonably possible
inform the other party (the "indemnifying party") in writing of the Claim, provided, however, that the failure
to give such notification shall not affect the indemnification provided hereunder except to the extent the indemnifying party shall
have been actually prejudiced as a result of such failure. The indemnified party shall permit the indemnifying party to assume
direction and control of the defense of the Claim and shall cooperate as requested (at the expense of the indemnifying party) in
the defense of the Claim. The indemnifying party shall not settle any Claim with the indemnified party's prior written consent,
which consent shall not be unreasonably withheld or delayed.

 

16.4         EACH
PARTY HEREBY AGREES THAT SUBJECT TO APPLICABLELAW, AND EXCEPT IN THE EVENT OF (I) BREACH OF CONFIDENTIALITY OBLIGATION UNDER THIS
AGREEMENT, OR (II) FRAUD OR WILLFUL MISCONDUCT, THE OTHER PARTY'S LIABILITY TO SUCH PARTY FOR ANY AND ALL INJURIES, CLAIMS, LOSSES,
EXPENSES, OR DAMAGES, WHATSOEVER, ARISING OUT OF OR IN ANY WAY RELATED TO THE WORK PERFORMED BY PERRIGO UNDER THE AGREEMENT, FROM
ANY CAUSE OR CAUSES, INCLUDING, BUT NOT LIMITED TO, NEGLIGENCE, ERRORS, OMISSIONS OR STRICT LIABILITY, SHALL NOT EXCEED THE SUM
OF TWO MILLION USD ($2,000,000).  

 

16.5         EXCEPT
IN THE EVENT OF (I) BREACH OF CONFIDENTIALITY OBLIGATION UNDER THIS AGREEMENT, OR (II) FRAUD OR WILLFUL MISCONDUCT IN NO EVENT
SHALL EITHER PARTY BE LIABLE TO THE OTHER OR ANY OF ITS AFFILIATES FOR ANY CONSEQUENTIAL, INCIDENTAL, INDIRECT, SPECIAL, PUNITIVE
OR EXEMPLARY DAMAGES (INCLUDING, WITHOUT LIMITATION, LOST PROFITS, BUSINESS OR GOODWILL) SUFFERED OR INCURRED BY SUCH OTHER PARTY
OR ITS AFFILIATES IN CONNECTION WITH THIS AGREEMENT, EVEN IF ADVISED OF THE POSSIBILITY OF SUCH DAMAGES.

 

17. Security and Safety Procedures. 

 

Galmed and CML personnel authorized to have
access to the Perrigo facility in connection with the work performed by Perrigo under the Agreement shall abide by the security
and safety procedures established by Perrigo.  Galmed shall be liable for any breaches of security and/or safety by Galmed
or CML personnel.  All Galmed personnel shall agree to abide by Perrigo policies and standard operating procedures established
by Perrigo.

 

18. Force Majeur

 

Neither Party will be liable for any failure
to perform or for delay in performance resulting from any cause beyond its reasonable control, strikes, lockouts, labour troubles,
restrictive government or judicial orders, or decrees, riots, insurrection, war, terror, or Acts of God, provided that payment
of sums due shall not be excused due by any such force majeure. A Party seeking to claim Force Majeure must give the other party
prompt notice of the Force Majeure with reasonably full particulars and an estimate of the extent and duration of its delay in
performance, or inability to perform, and use all possible diligence to remove the Force Majeure as quickly as possible. If the
delay continues beyond sixty (60) days after the notice given, the Parties must meet to discuss in good faith a mutually satisfactory
resolution of the problem and if unable to achieve such resolution within a further 14 days, either Party may elect to terminate
this Agreement by fourteen (14) days prior written notice to the other.

 

    	 

    	 

    

 

19. Term and Termination 

 

19.1         This
Agreement is valid from the date of signature by both Parties and shall remain in force and effect for the duration of the provision
of the services contemplated hereunder.

 

19.2         This
Agreement may be terminated by either Party upon thirty (30) days prior written notice in the event of a breach of term of this
Agreement by the other Party, provided that the breach is not cured within such 30 day notice period.

 

19.3         This Agreement may be terminated by
either Party upon thirty (30) days prior written notice to the other Party if the other Party is declared bankrupt, becomes insolvent,
ceases its business activities or has been operating under court appointed receivership.

 

19.4         Galmed shall have the right, at any
time, on thirty (30) days prior written notice to Perrigo, subject to the provisions of this Agreement, to terminate this Agreement,
in the event that due to the failure or inconclusive results in clinical trials that it is conducting or will conduct, or in any
other event that Galmed shall decide at its discretion to finally not proceed with the commercialization of the Product.

 

19.5         
In the event of a substantial delay by either party in the timeline of the Project (of more than three months in total), the parties
shall discuss in good faith a new timeframe for the Project. In the event that the parties cannot agree on such new timeframe,
the other Party may terminate this Agreement with fourteen (14) days prior written notice.

 

19.6         In the event of a Change of Control
of Perrigo, or in the event that Perrigo publically announces that it has entered into an agreement pursuant to which a Change
of Control of Perrigo will occur, Galmed shall have the right, but not the obligation to terminate this Agreement on thirty (30)
days prior written notice to Perrigo. In the event that Galmed chooses not to terminate this Agreement, Perrigo’s rights
and obligations shall be fulfilled by Perrigo’s successors.

 

19.7         In the event of a change of control
of Galmed, including without limitation the license by Galmed of substantially all of Galmed's rights in the Product or IPR related
to the Product, Galmed shall, subject to the payment of a break-up fee of two-hundred and fifty thousand USD ($250,000) and subject
further to the full payment of the consideration for the Tech Transfer Batches, have the right, but not the obligation to terminate
this Agreement on thirty (30) days prior written notice to Perrigo.

 

19.7         Notwithstanding
anything to the contrary in this Agreement, except in the event of termination of the Agreement by Galmed in accordance with Section
19.2 above due to a breach by Perrigo, Galmed shall remain obliged to pay Perrigo for the Tech Transfer and the Tech Transfer Batches
as per and subject to the terms of Sections 5.2, 11.1.1 and 11.1.2 and subject to the terms thereof (including, for the avoidance
of doubt, delivery of the Tech Transfer Batches in accordance with Sections 5.1 and 5.2).

 

19.8         The termination of this Agreement
for any reason shall be without prejudice to, and shall not affect any other rights of either Party and all such rights of both
shall survive any such termination. In addition, any termination of this Agreement shall not release the Parties from liabilities
and obligations accrued until the time of termination. Notwithstanding anything to the contrary that may be contained herein, in
the event of the termination or expiration of this Agreement, Sections 7A.5 (Regulatory Inspections), 7A.6 (Access to Perrigo's
Site), 7A.7 (record retention), 12 (representations and warranties) 13 (confidentiality), 15 (intellectual property), 16 (indemnification
and limitation on liability), 19 (term and termination) and 20 (miscellaneous) shall survive the termination or expiration of this
Agreement and continue in effect. Furthermore, the obligation of Galmed to pay any amounts which are due under the Agreement as
of the date of termination shall survive termination of this Agreement.

 

    	 

    	 

    

 

20. Miscellaneous

 

20.1         Severability:
In the event that any part, article, paragraph, sentence, section or clause of this Agreement shall be held to be invalid or otherwise
unenforceable, the invalid or unenforceable provision shall be deemed deleted, and the remaining part of the Agreement shall continue
in the full force and effect. If any tribunal or court of competent jurisdiction deems any provision hereof unenforceable, such
provision shall be modified only to the extent necessary to render it enforceable and this Agreement shall be valid and enforceable
and the Parties hereto agree to be bound by and perform same as thus modified

 

20.2         Independent
Contractors. Nothing in this Agreement shall create any relationship of agency, joint venture, partnership employer/employee
or similar relationship between the Parties. Each Party is an independent contractor of the other Party.

 

20.3         Amendments.
Any amendment or supplement to this Agreement shall be effective only if made in writing and signed by both Parties

 

20.4         Waiver.
A waiver by either Party of any term or condition of this Agreement in any one instance shall not be deemed or construed to be
a waiver of such terms or conditions for any similar instance in the future or of any subsequent breach hereof

 

20.5         Entire
Agreement. This Agreement sets forth the entire agreement between the Parties regarding the subject matter hereof and supersedes
all prior agreements, whether written or oral, between the Parties with respect to such subject matter.

 

20.6 Further Assurances. The Parties
agree to execute any and all documents reasonably necessary and to cooperate with each other in order to consummate, implement
and give full force and effect to the obligations of the Parties under this Agreement. Perrigo shall transfer all documentation
in Perrigo's possession, as may be reasonably necessary by Galmed from time to time for regulatory purposes; and any documentation
(including the API Information) in its possession reasonably required by Galmed in the event transferring the API Information,
including following the termination of this Agreement. Furthermore, Perrigo undertakes to reasonably cooperate with Galmed following
the termination of this Agreement in the technology transfer of the manufacturing process of the API from Perrigo to a third party,
including transferring the API Information and manufacturing procedure from Perrigo to another facility of a third party, in consideration
for the payment to Perrigo of reasonable fees for any additional work that may be required and time actually spent in connection
therewith (including reimbursement of expenses), to be agreed by the Parties at such time. Additional scope of work (not specifically
described in this Section 20.6 or elsewhere in this Agreement), may be agreed upon by the Parties in writing.

 

20.7         Notices.
Any notice or other communication required or permitted to be delivered to any Party under this Agreement shall be in writing and
shall be deemed properly delivered, given and received when delivered (by hand, by registered mail, by courier or express delivery
service or by facsimile) to the address for such Party first set forth above (or to such other address or facsimile telephone number
as such Party shall have specified in a written notice given to the other Parties hereto). Furthermore, day to day correspondences
may be sent by email with confirmation receipt.

 

20.7 Equitable Remedies. Each of the
Parties acknowledges and agrees that, in the event of a breach or threatened breach of this Agreement by any Party or the failure
of a Party to perform in accordance with the specific terms hereof, the other party hereto maybe irreparably damaged and that monetary
damages may not provide an adequate remedy. Accordingly, it is agreed that, in addition to any and all other rights which may be
available, at law or in equity, the non-breaching party shall be entitled to seek injunctive relief and/or specifically to enforce
the terms and provisions hereof in any court of competent jurisdiction.

 

    	 

    	 

    

 

20.8 Remedies Cumulative. The rights
and remedies given in this Agreement to a non-defaulting party shall be deemed cumulative, and the exercise of one of such remedies
shall not operate to bar the exercise of any other rights and remedies reserved to a non-defaulting party under the provisions
of this Agreement or, subject to the provisions of this Agreement, given to a non-defaulting party at law or in equity.

 

20.9         Governing
Law

 

This Agreement shall be construed in accordance
with, and governed in all respects by, the laws of the State of Israel. The competent courts of Tel Aviv shall have exclusive jurisdiction
over any dispute between the Parties arising hereunder or in connection herewith (including non-contractual claims), which cannot
be promptly resolved on an amicable basis.

 

20.10         Assignment

This Agreement shall be binding upon and inure
to the benefit of the parties hereto and their respective successors and permitted assigns.

Galmed shall be entitled, at any time, to assign
this Agreement to an Affiliate of Galmed, provided Galmed shall remain jointly responsible for any and all financial liabilities
hereunder, or to a successor in case of a merger, acquisition or as part of a transaction transferring all or substantially all
the business or assets of Galmed relating to this Agreement (collectively, an "Assignment").

Subject to Section 19.5 above, Perrigo shall
not assign its rights and obligations under this Agreement without first obtaining the written consent of Galmed.

 

[Signature Page Follows] 

 

    	 

    	 

    

 

IN WITNESS WHEREOF, the Parties have
executed this Agreement on the date first written above.

 

	PERRIGO API LTD.:	 	GALMED RESEARCH AND DEVELOPMENT LTD.:	 
	 	 	 	 	 	 
	By:	/s/ Yoav Grinberg	 	By: 	/s/ Chaim Hurvitz	 
	 	 	 	 	 	 	 
	Name: 	Yoav Grinberg	 	Name: 	Chaim Hurvitz	 
	 	 	 	 	 	 
	Title:	General Manager	 	Title:	Chairman	 
	 	 	 	 	 	 
	Date:	27/1/2015	 	Date:	1/27/15	 
	 	 	 	 	 	 
	 	 	 	By: 	/s/ Allen Baharaff	 
	 	 	 	 	 	 
	 	 	 	Name: 	Allen Baharaff	 
	 	 	 	 	 	 
	 	 	 	Title:	CEO	 
	 	 	 	 	 	 
	 	 	 	Date:	27.1.2015	 

 

    	 

    	 

    

 

Annex A

 

Route of Synthesis

 

 

CERTAIN PORTIONS OF THIS EXHIBIT HAVE BEEN OMITTED AND ARE SUBJECT
TO A CONFIDENTIAL TREATMENT REQUEST. COPIES OF THIS EXHIBIT CONTAINING THE OMITTED INFORMATION HAVE BEEN FILED SEPARATELY WITH
THE SECURITIES AND EXCHANGE COMMISSION. THE OMITTED PORTIONS OF THIS DOCUMENT ARE MARKED WITH A [***].

 

	Aramchol	Galmed
    Pharmaceuticals Ltd.
	IND 79,200	CONFIDENTIAL

 

    TABLE
    OF CONTENTS

 

	3.2.S.2.2 	Description ofManufacturing
    Process and Process Controls	2

 

    LIST
    OF FIGURES 

	Figure 1.	Synthetic Route B	2
	Figure 2.	Flow Chart for Route B Step i	5
	Figure 3.	Flow Chart for Route B Step ii	6
	Figure 4.	Flow Chart for Route B Step iii (Part A, [***])	7
	Figure 5.	Flow Chart for Route B Step iii (Part B, [***]) 	8
	Figure 6.	Flow Chart for Route B Step iv	10
	Figure 7.	Flow Chart for Route B Step v	11

  

    	 

    	 

    

 

	Aramchol	Galmed Pharmaceuticals Ltd.
	IND 79,200	CONFIDENTIAL

 

3.2.S.2.2  Description of Manufacturing
Process and Process Controls

 

Aramchol is a conjugated bile acid formed by the amide coupling
of the carboxylic acid in Arachidic acid (C20:0) to an amine containing derivative of cholic acid. The starting materials are
derived from cholic acid and arachidic acid. To date Aramchol has been manufactured by two similar synthetic routes.

 

The present synthetic route is described by Route B (Figure 1).
In this scheme the starting material is [***]                         
which is purchased from an approved supplier. Aramchol is then synthesized via
a five step process as described below and in the flow charts in Figure
2 to Figure 7. Current processes afford
approximately [***] Kg of Aramchol per reaction / lot. The contents of several lots can be pooled into a final batch which is
then controlled by final release testing.

 

Figure 1. Synthetic
Route B

 

 

[***]

 

3.2.S Drug Substance

CERTAIN PORTIONS
OF THIS EXHIBIT HAVE BEEN OMITTED AND ARE SUBJECT TO A CONFIDENTIAL TREATMENT REQUEST. COPIES OF THIS EXHIBIT CONTAINING THE OMITTED
INFORMATION HAVE BEEN FILED SEPARATELY WITH THE SECURITIES AND EXCHANGE COMMISSION. THE OMITTED PORTIONS OF THIS DOCUMENT ARE
MARKED WITH A [***].

 

    	2

    	 

    

 

	Aramchol	Galmed Pharmaceuticals Ltd.
	IND 79,200	CONFIDENTIAL

 

Step i

 

[***]

 

Step ii

 

An [***]             is
charged with [***]                                                                             [***].
The reactor is rinsed with [***]         and then the reaction is [***]         to
obtain a slight reflux. The reaction is [***].                                        In
process control testing is performed to determine the extent of conversion. [***]                        is
dosed into the reaction whilst maintaining the [***].                                        The
[***]                   of the reaction
is monitored and is stirred. The [***]           by-product is [***] and the
[***] is retained. An [***]                                                   [***]
of the [***]                   is performed.
[***]                     is
charged to the reactor and is concentrated by [***] prior to addition of [***].                           The
contents of the reactor are concentrated again and then [***]                                        which
effects a solvent switch to begin to induce crystallisation. The contents of the reactor are then concentrated once more and then
[***]              is added. The contents of the reactor [***]
          and the resulting crystalline mass is collected by filtration. The
cake is washed with [***]         and then the [***]                      product
is dried on the filter. In process control testing is performed for purity; [***]                     ;
LOD, Karl Fischer analysis and then dry [***] product is discharged.

 

Step iii

 

[***] (product from step ii) and [***] is
charged into an [***].                                        The
suspension [***]         to obtain a solution. [***]                       is
charged to the reactor and the [***] solution is stirred. The reaction is [***] and then [***]            is
charged to the reactor. The reaction is [***]     with stirring. The contents of the reactor are filtered
on a [***]           and the [***] is washed with [***].                 A
phase separation is performed and the lower organic layer is collected and dried with [***].                     The
[***]        is removed by [***]         and the [***]
is charged into a reactor and part of the [***]                    solvent
is removed by [***]. In process testing of the solution of [***]                               is
performed for purity.

 

3.2.S Drug Substance

CERTAIN PORTIONS
OF THIS EXHIBIT HAVE BEEN OMITTED AND ARE SUBJECT TO A CONFIDENTIAL TREATMENT REQUEST. COPIES OF THIS EXHIBIT CONTAINING THE OMITTED
INFORMATION HAVE BEEN FILED SEPARATELY WITH THE SECURITIES AND EXCHANGE COMMISSION. THE OMITTED PORTIONS OF THIS DOCUMENT ARE
MARKED WITH A [***].

 

    	3

    	 

    

 

 

	Aramchol	Galmed Pharmaceuticals Ltd.
	IND 79,200	CONFIDENTIAL

 

[***] is charged to the [***]                              in
the reactor. The lines of the reactor are rinsed with [***].                          A
solution of [***] is
dosed into the reactor. The dosing line is rinsed with [***].                         The
reaction is stirred at [***].                   In-process
testing is performed to determine the extent of conversion. A solution of [***]                          (as
much as is required to complete conversion) is dosed in to the reactor. The dosing line is rinsed with [***].               The
reaction is stirred at [***].                       In-process
testing is performed to determine the extent of conversion to [***]. [***]                                                  is
charged to the reactor and the [***]                      is
stirred. Once the layers have separated the lower organic layer is collected and [***]              is
removed by [***].                              [***]
is charged to the reactor. Further [***]        is removed by [***].              The
contents of the reactor are [***]               and then
[***]        is charged to the reactor. Further [***]          is
removed by [***]                    .
[***] is charged to the reactor and the contents of the reactor are [***]               to
obtain a solution. The solution is [***]                   to
induce crystallisation. If crystallization does not occur then [***] must be added. The solution/slurry is [***]. The crystalline
mass is [***]                          and
is then isolated by [***] and the cake is [***] with [***] and then [***]                                       .
In process testing is performed to determine purity. Crude [***]                              is
discharged from the filter and is then dissolved in [***].                         
The solution is [***]                      to
allow crystallization. The
solution is [***] and is then [***]. The
product is collected by filtration and the cake is washed with [***]. The pure [***]                                               is
dried on the filter. In process testing is performed for LOD and purity. Pure and dry [***]                            [***]
is discharged.

 

Step iv

 

[***], water and [***] is charged into an [***]. [***]

[***]
is charged to the reactor. The dosing lines of the reactor are [***].

 

The reaction is stirred at [***]. In-process
testing is performed to determine the extent of conversion. To the reaction concentrated [***] is added and the [***]. The
reaction is [***] and then the [***]. The [***]                                        are
collected by filtration and the cake is washed with [***]. Crystalline product is dried on the filter. In process control testing
is performed for purity. The crystalline cake is [***] with [***] at [***]                [***].
The product is collected and dried on the filter with [***].                  In-process testing is performed for LOD and purity.

 

Pure [***] is discharged from the reactor.

 

In some instances full release testing then
takes place on [***]            once it has been discharged from the reactor.
However, the [***] active substance can be [***]                       prior
to release testing.

 

Step v

 

[***] are transferred to an [***]                                                                               configured
such that fumes pass through an [***]. The reaction is [***]. [***]       is
dosed into the reaction, keeping the [***].                                                        The
reactor dosing lines are rinsed with [***]. The reaction is stirred and reaction progress monitored. The reaction is [***]                      to
in-process testing is performed to determine the extent of conversion prior to discharge of [***] solution for use in step
[***].

 

3.2.S Drug Substance

CERTAIN PORTIONS
OF THIS EXHIBIT HAVE BEEN OMITTED AND ARE SUBJECT TO A CONFIDENTIAL TREATMENT REQUEST. COPIES OF THIS EXHIBIT CONTAINING THE OMITTED
INFORMATION HAVE BEEN FILED SEPARATELY WITH THE SECURITIES AND EXCHANGE COMMISSION. THE OMITTED PORTIONS OF THIS DOCUMENT ARE
MARKED WITH A [***].

 

    	4

    	 

    

 

	Aramchol	Galmed
    Pharmaceuticals Ltd.
	IND 79,200	CONFIDENTIAL

 

Figure
2. Flow Chart for Route B Step i

 

[***]

 

3.2.S Drug Substance

CERTAIN PORTIONS
OF THIS EXHIBIT HAVE BEEN OMITTED AND ARE SUBJECT TO A CONFIDENTIAL TREATMENT REQUEST. COPIES OF THIS EXHIBIT CONTAINING THE OMITTED
INFORMATION HAVE BEEN FILED SEPARATELY WITH THE SECURITIES AND EXCHANGE COMMISSION. THE OMITTED PORTIONS OF THIS DOCUMENT ARE
MARKED WITH A [***].

 

    	5

    	 

    

 

	Aramchol	Galmed
    Pharmaceuticals Ltd.
	IND 79,200	CONFIDENTIAL

 

Figure
3. Flow Chart for Route B Step ii

 

[***]

 

3.2.S Drug Substance

CERTAIN PORTIONS
OF THIS EXHIBIT HAVE BEEN OMITTED AND ARE SUBJECT TO A CONFIDENTIAL TREATMENT REQUEST. COPIES OF THIS EXHIBIT CONTAINING THE OMITTED
INFORMATION HAVE BEEN FILED SEPARATELY WITH THE SECURITIES AND EXCHANGE COMMISSION. THE OMITTED PORTIONS OF THIS DOCUMENT ARE
MARKED WITH A [***].

 

    	6

    	 

    

 

 

	Aramchol	Galmed
    Pharmaceuticals Ltd.
	IND 79,200	CONFIDENTIAL

 

Figure 4. Flow Chart for Route B Step
iii (Part A, [***])

 

[***]

 

3.2.S Drug Substance

CERTAIN PORTIONS
OF THIS EXHIBIT HAVE BEEN OMITTED AND ARE SUBJECT TO A CONFIDENTIAL TREATMENT REQUEST. COPIES OF THIS EXHIBIT CONTAINING THE OMITTED
INFORMATION HAVE BEEN FILED SEPARATELY WITH THE SECURITIES AND EXCHANGE COMMISSION. THE OMITTED PORTIONS OF THIS DOCUMENT ARE
MARKED WITH A [***].

 

    	7

    	 

    

 

 

	Aramchol	Galmed Pharmaceuticals
    Ltd.
	IND 79,200	CONFIDENTIAL

 

Figure 5. Flow Chart for Route B Step iii
(Part B, [***])

 

[***]

 

3.2.S Drug Substance

CERTAIN PORTIONS
OF THIS EXHIBIT HAVE BEEN OMITTED AND ARE SUBJECT TO A CONFIDENTIAL TREATMENT REQUEST. COPIES OF THIS EXHIBIT CONTAINING THE OMITTED
INFORMATION HAVE BEEN FILED SEPARATELY WITH THE SECURITIES AND EXCHANGE COMMISSION. THE OMITTED PORTIONS OF THIS DOCUMENT ARE
MARKED WITH A [***].

 

    	8

    	 

    

 

 

	Aramchol	Galmed Pharmaceuticals
    Ltd.
	IND 79,200	CONFIDENTIAL

 

[***]

 

3.2.S Drug Substance

CERTAIN PORTIONS
OF THIS EXHIBIT HAVE BEEN OMITTED AND ARE SUBJECT TO A CONFIDENTIAL TREATMENT REQUEST. COPIES OF THIS EXHIBIT CONTAINING THE OMITTED
INFORMATION HAVE BEEN FILED SEPARATELY WITH THE SECURITIES AND EXCHANGE COMMISSION. THE OMITTED PORTIONS OF THIS DOCUMENT ARE
MARKED WITH A [***].

 

    	9

    	 

    

 

 

	Aramchol	Galmed Pharmaceuticals
    Ltd.
	IND 79,200	CONFIDENTIAL

 

Figure
6. Flow Chart for Route B Step iv

 

[***]

 

3.2.S Drug Substance

CERTAIN PORTIONS
OF THIS EXHIBIT HAVE BEEN OMITTED AND ARE SUBJECT TO A CONFIDENTIAL TREATMENT REQUEST. COPIES OF THIS EXHIBIT CONTAINING THE OMITTED
INFORMATION HAVE BEEN FILED SEPARATELY WITH THE SECURITIES AND EXCHANGE COMMISSION. THE OMITTED PORTIONS OF THIS DOCUMENT ARE
MARKED WITH A [***].

 

    	10

    	 

    

 

 

	Aramchol	Galmed Pharmaceuticals
    Ltd.
	IND 79,200	CONFIDENTIAL

 

Figure
7. Flow Chart for Route B Step v

 

[***]

 

3.2.S Drug Substance

CERTAIN PORTIONS
OF THIS EXHIBIT HAVE BEEN OMITTED AND ARE SUBJECT TO A CONFIDENTIAL TREATMENT REQUEST. COPIES OF THIS EXHIBIT CONTAINING THE OMITTED
INFORMATION HAVE BEEN FILED SEPARATELY WITH THE SECURITIES AND EXCHANGE COMMISSION. THE OMITTED PORTIONS OF THIS DOCUMENT ARE
MARKED WITH A [***].

 

    	11

    	 

    

 

Annex B

 

Specifications

 

 

Analytical R&D

 

 

 

Annex B – API Specifications

 

Material name: Aramchol

 

Stage: End Product

 

Identification code: 3ARMCN0 Ed. 01

Project code: ARMC

 

 

 

Superseded Ed.
No.: N/A           from: N/A

 

Changes:

 

This document is Perrigo Company confidential and proprietary information.
Individuals printing a copy of a Perrigo procedural document are responsible for ensuring that it is the most current revision.

 

    	 	3ARMCN0-01	Page 1 of 4

    	 

    

 

Analytical R&D

 

 

Material name: Aramchol

 

Stage: End Product

 

Identification code: 3ARMCN0 Ed. 01

Project code: ARMC

 

 

 

	Approvals	 	Name	 	 Signature	 	 Date
	Issued by Analytical R&D Department	 	 	 	 	 	 
	Approved by Synthetic R&D Manager	 	 	 	 	 	 
	Approved by QC Manager	 	 	 	 	 	 
	Approved by QA Engineer	 	 	 	 	 	 

 

	Test	 	Requirement	 	Method
	Description	 	White to off white powder	 	ARMC-01
	Identification:	 	 	 	 
	a)HPLC	 	Complies with Retention time of RS	 	ARMC-06
	 	 	 	 	 
	b) IR	 	IR absorption spectrum of the test sample complies with the IR spectrum of the RS	 	ARMC-02
	 	 	 	 	 
	c) XRD	 	XRD-gram corresponds to reference	 	ARMC-03
	 	 	 	 	 
	d) Melting point	 	[***]	 	ARMC-04
	Water content	 	Not more than [***]	 	ARMC-05
	Residue on ignition*	 	Not more than [***]	 	ARMC-09
	Assay by HPLC (as is)	 	[***]	 	ARMC-06

 

This document is Perrigo Company confidential and proprietary information.
Individuals printing a copy of a Perrigo procedural document are responsible for ensuring that it is the most current revision.

 

CERTAIN PORTIONS OF THIS EXHIBIT HAVE BEEN
OMITTED AND ARE SUBJECT TO A CONFIDENTIAL TREATMENT REQUEST. COPIES OF THIS EXHIBIT CONTAINING THE OMITTED INFORMATION HAVE BEEN
FILED SEPARATELY WITH THE SECURITIES AND EXCHANGE COMMISSION. THE OMITTED PORTIONS OF THIS DOCUMENT ARE MARKED WITH A [***].

 

    	 	3ARMCN0-01	Page 2 of 4

    	 

    

 

Analytical R&D

 

 

	Test	 	Requirement	 	Method
	Related substances:	 	 	 	 
	RRT [***]	 	Not more than [***]	 	 
	RRT [***]	 	Not more than [***]	 	 
	RRT [***]	 	Not more than [***]	 	ARMC-07
	RRT [***]	 	Not more than [***]	 	 
	RRT [***]	 	Not more than [***]	 	 
	RRT [***]	 	Not more than [***]	 	 
	RRT [***]	 	Not more than [***]	 	 
	RRT [***]	 	Not more than [***]	 	 
	RRT [***]	 	Not more than [***]	 	 
	RRT [***]	 	Not more than [***]	 	 
	 	 	 	 	 
	Any other unknown	 	Not more than [***]	 	 
	Total	 	Not more than [***]	 	 
	Residual solvents:*	 	 	 	 
	 [***]	 	Not more than [***]	 	 
	 	 	Not more than [***]	 	 
	 	 	Not more than [***]	 	ARMC-08
	 	 	Not more than [***]	 	 
	 	 	Not more than [***]	 	 
	 	 	Not more than [***]	 	 
	Heavy Metals:*	 	 	 	 
	 [***]	 	Not more than [***]	 	 
	 	 	Not more than [***]	 	ARMC-10
	 	 	Not more than [***]	 	 
	 	 	Not more than [***]	 	 
	[***]Content	 	Not more than [***]	 	ARMC-11
	[***]	 	Not more than [***]	 	ARMC-12
	PSD*	 	Report value	 	ARMC-13
	 	 	 [***]	 	 

* Not to be performed for stability studies.

 

This document is Perrigo Company confidential and proprietary information.
Individuals printing a copy of a Perrigo procedural document are responsible for ensuring that it is the most current revision.

 

CERTAIN PORTIONS OF THIS EXHIBIT HAVE BEEN
OMITTED AND ARE SUBJECT TO A CONFIDENTIAL TREATMENT REQUEST. COPIES OF THIS EXHIBIT CONTAINING THE OMITTED INFORMATION HAVE BEEN
FILED SEPARATELY WITH THE SECURITIES AND EXCHANGE COMMISSION. THE OMITTED PORTIONS OF THIS DOCUMENT ARE MARKED WITH A [***].

 

    	 	3ARMCN0-01	Page 3 of 4

    	 

    

 

Analytical R&D

 

 

Legend of impurities:

 

	Perrigo Name	 	Chemical Formula	 	Chemical Name
	 	 	 	 	 
	 	 	 	 	 
	 	 	 	 	 
	 	 	 	 	 

 

This document is Perrigo Company confidential and proprietary information.
Individuals printing a copy of a Perrigo procedural document are responsible for ensuring that it is the most current revision.

 

    	 	3ARMCN0-01	Page 4 of 4

    	 

    

 

Annex C

 

Technology Transfer Protocol

 

 

	Document No.: 

         

        Ed. 1
	TECHNOLOGY
    TRANSFER 

PROTOCOL	
	Effective Date	Page 1 of
    19

 

	Name of the API	 	Aramchol
	Technology Provider	 	CML, Netherlands for Galmed Ltd.

 

	Prepared by	Anat Shatkin	 
	 	Process Engineer	 
	 	Perrigo API	Sign / Date
	Reviewed by	Raya Abu	 
	 	Process department	 
	 	Perrigo API	Sign / Date
	 	Silvina Guernik	 
	 	Quality control manager	 
	 	Perrigo API	Sign / Date
	 	Revital ben Daniel	 
	 	R&D manager	 
	 	Perrigo API	Sign / Date
	 	Shira Webshat	 
	 	Facility manager	 
	 	Perrigo API	Sign / Date
	 	Alex Rutman	 
	 	Quality control	 
	 	Perrigo API	Sign / Date
	Approved by	Name	 
	 	Galmed	Sign / Date
	Issued by	Anat Shatkin	 
	 	Process Engineer	 
	 	Perrigo API	Sign / Date

 

    	 

    	 

    

 

	Document No.: 

         

        Ed. 1
	TECHNOLOGY
    TRANSFER

 PROTOCOL	
	Effective Date	Page 2 of 19

 

INDEX

 

	Sr. No.	 	Contents	 	Page No.
	 	 	 	 	 
	1.	 	Objective / Purpose	 	3
	 	 	 	 	 
	2.	 	Scope	 	3
	 	 	 	 	 
	3.	 	Distribution	 	3
	 	 	 	 	 
	4.	 	Responsibilities	 	4
	 	 	 	 	 
	5.	 	Receiving team's Responsibilities	 	6
	 	 	 	 	 
	6.	 	List of current process documents to be received from CML 	 	8
	 	 	 	 	 
	7.	 	List of materials to be received from CML	 	11
	 	 	 	 	 
	8.	 	Transfer plan	 	12
	 	 	 	 	 
	9.	 	Production plan	 	13
	 	 	 	 	 
	10.	 	Critical and Important Process Parameters	 	14
	 	 	 	 	 
	11.	 	Comparison of the process equipment, analytical laboratory instruments & risk analysis	 	15
	 	 	 	 	 
	12.	 	Acceptance criteria for the success of transfer	 	19
	 	 	 	 	 
	13.	 	Annexure A- Standards requirements	 	20
	 	 	 	 	 
	14.	 	Annexure B- Representative samples requirements	 	20
	 	 	 	 	 
	15.	 	Annexure C- Method transfer requirements	 	21
	 	 	 	 	 
	16.	 	Annexure D- Raw materials requirements	 	21
	 	 	 	 	 
	17.	 	Annexure E- In process requirements	 	22
	 	 	 	 	 
	18.	 	Annexure F- Bill of materials	 	24

 

    	 

    	 

    

 

	Document No.: 

         

        Ed. 1
	TECHNOLOGY
    TRANSFER

 PROTOCOL	
	Effective Date	Page 3 of 19

 

		1.	Objective / Purpose: 

 

The Objectives / Purpose of this protocol are:

 

		·	To establish
                                         and provide guidelines for technology transfer of the Aramchol process from CML
                                         to Perrigo API (PAPI).

 

		·	To provide
                                         the plan for the various activities to be completed during the technology transfer.

 

		·	To provide
                                         acceptance criteria for the success of the technology transfer.
	 

     
	 	 

		2.	Scope: 

 

Aramchol was developed by Galmed LTD and is currently
produced in CML, Netherlands.

 

This plan covers the technology transfer of Aramchol
from CML, Netherland to Perrigo API, Neot Hovav (PAPI).

[***]

 

		3.	Distribution:

 

		·	QA
                                         (Perrigo API)- Original

 

		·	Process
                                         Manager (Perrigo API)- Copy

 

		·	QC
                                         (Perrigo API)- Copy

 

		·	R&D
                                         (Perrigo API)- Copy

 

		·	Production
                                         Manager at each site- Copy

 

		·	Business
                                         Development (Perrigo API)- Copy

 

		·	Core team members
                                         at each site- Copy

 

		4.	Responsibilities:

 

The members of technology transfer and receiving teams
and the responsibilities for various activities are given below:

 

CERTAIN PORTIONS OF THIS EXHIBIT HAVE BEEN
OMITTED AND ARE SUBJECT TO A CONFIDENTIAL TREATMENT REQUEST. COPIES OF THIS EXHIBIT CONTAINING THE OMITTED INFORMATION HAVE BEEN
FILED SEPARATELY WITH THE SECURITIES AND EXCHANGE COMMISSION. THE OMITTED PORTIONS OF THIS DOCUMENT ARE MARKED WITH A [***].

 

    	 

    	 

    

 

 

	Document No.: 

         

        Ed. 1
	TECHNOLOGY
    TRANSFER

 PROTOCOL	
	Effective Date	Page 4 of 19

 

		4.1.	Team from the Receiving Site- PAPI: 

 

The team from the receiving site shall drive the total
technology transfer activity.

 

	Team Leader: 	Yael Gafni – R&D Project Manager
	 	 
	 	[***]

 

	Core Team	 	Responsible
    for	 	Phone	 	Email
	Anat Shatkin	 	Process	 	[***]	 	[***]
	Shiran Yehoshua Magal	 	Manufacturing	 	[***]	 	[***]
	Shira Webshat	 	Manufacturing	 	[***]	 	[***]
	Silvina Guernik	 	QC	 	[***]	 	[***]
	Roza Marcu	 	QC	 	[***]	 	[***]
	Alex Rutman	 	QA	 	[***]	 	[***]
	Yakir Geron	 	QA	 	[***]	 	[***]
	Mali Lahav	 	Raw materials & Procurement	 	[***]	 	[***]
	Yulia Rudinski	 	Ecology	 	[***]	 	[***]
	Yair Markowitz	 	Safety	 	[***]	 	[***]
	Revital Ben-Daniel	 	Analytical & Synthetic R&D	 	[***]	 	[***]

 

CERTAIN PORTIONS OF THIS EXHIBIT HAVE BEEN
OMITTED AND ARE SUBJECT TO A CONFIDENTIAL TREATMENT REQUEST. COPIES OF THIS EXHIBIT CONTAINING THE OMITTED INFORMATION HAVE BEEN
FILED SEPARATELY WITH THE SECURITIES AND EXCHANGE COMMISSION. THE OMITTED PORTIONS OF THIS DOCUMENT ARE MARKED WITH A [***].

 

    	 

    	 

    

 

	Document No.: 

         

        Ed. 1
	TECHNOLOGY
    TRANSFER

 PROTOCOL	
	Effective Date	Page 5 of 19

 

		4.2.	Team from Transferring Site- CML:

 

The team from the transferring site shall provide all
the documents & information related to the product for the successful technology transfer.

 

Team Leader: Production manager, Remy Litjens

 

(Phone:____________ , E-mail:
[***])

 

(Please add the team members' names, phone and email)

 

	Core Team	 	Responsible
    for	 	Phone	 	Email
	 	 	Process	 	 	 	 
	 	 	Manufacturing	 	 	 	 
	 	 	QC	 	 	 	 
	 	 	QA	 	 	 	 
	 	 	Raw materials & Procurement	 	 	 	 
	 	 	Ecology	 	 	 	 
	 	 	Safety	 	 	 	 
	 	 	Analytical Development	 	 	 	 
	 	 	.....	 	 	 	 

 

CERTAIN PORTIONS OF THIS EXHIBIT HAVE BEEN
OMITTED AND ARE SUBJECT TO A CONFIDENTIAL TREATMENT REQUEST. COPIES OF THIS EXHIBIT CONTAINING THE OMITTED INFORMATION HAVE BEEN
FILED SEPARATELY WITH THE SECURITIES AND EXCHANGE COMMISSION. THE OMITTED PORTIONS OF THIS DOCUMENT ARE MARKED WITH A [***].

 

    	 

    	 

    

 

 

	Document No.: 

         

        Ed. 1
	TECHNOLOGY
    TRANSFER

 PROTOCOL	
	Effective Date	Page 6 of 19

 

		5.	Receiving Team's Responsibilities- PAPI:

 

		5.1.	For the transfer of process:

 

	Name	 	Department	 	Responsible for 
	Raya Abu	 	Manufacturing	 	[***]
	Anat Shatkin	 	 	 	 
	Shira Webshat	 	 	 	 
	Shiran Yehoshua- Magal	 	 	 	 
	 	 	R&D	 	 
	Yulia Rudinski	 	Ecology	 	[***]
	Yair Markovitz	 	Safety	 	[***]

 

		5.2.	For the transfer of analytical methods:

 

	Name	 	Department	 	Responsible for
	Silvina Guernik	 	QC	 	[***]
	Roza Marcu	 	 	 	 
	 	 	R&D	 	 

 

CERTAIN PORTIONS OF THIS EXHIBIT HAVE BEEN
OMITTED AND ARE SUBJECT TO A CONFIDENTIAL TREATMENT REQUEST. COPIES OF THIS EXHIBIT CONTAINING THE OMITTED INFORMATION HAVE BEEN
FILED SEPARATELY WITH THE SECURITIES AND EXCHANGE COMMISSION. THE OMITTED PORTIONS OF THIS DOCUMENT ARE MARKED WITH A [***].

 

    	 

    	 

    

 

	Document No.: 

         

        Ed. 1
	TECHNOLOGY
    TRANSFER 

PROTOCOL	
	Effective Date	Page 7 of 19

 

		5.3.	For the Transfer of QA & Regulatory documents:

 

	Name	 	Department	 	Responsible for
	Alex Rutan	 	QA	 	[***]
	 	 	 	 	 
	Yakir Geron	 	QA	 	[***]

 

CERTAIN PORTIONS OF THIS EXHIBIT HAVE BEEN
OMITTED AND ARE SUBJECT TO A CONFIDENTIAL TREATMENT REQUEST. COPIES OF THIS EXHIBIT CONTAINING THE OMITTED INFORMATION HAVE BEEN
FILED SEPARATELY WITH THE SECURITIES AND EXCHANGE COMMISSION. THE OMITTED PORTIONS OF THIS DOCUMENT ARE MARKED WITH A [***].

 

    	 

    	 

    

 

	Document No.: 

         

        Ed. 1
	TECHNOLOGY
    TRANSFER 

PROTOCOL	
	Effective Date	Page 8 of 19

 

		6.	List of Current Process documents to be received from
                                         CML: 

 

	Sr. 

    No.	 	Description	 	Target date	 	Responsibility	 	Status
	1.	 	[***]	 	[***]	 	[***]	 	[***]
	2.	 	[***]	 	[***]	 	[***]	 	[***]
	3.	 	[***]	 	[***]	 	[***]	 	[***]
	4.	 	[***]	 	[***]	 	[***]	 	[***]
	5.	 	[***]	 	[***]	 	[***]	 	[***]
	6.	 	[***]	 	[***]	 	[***]	 	[***]
	7.	 	[***]	 	[***]	 	[***]	 	[***]
	8.	 	[***]	 	[***]	 	[***]	 	[***]
	9.	 	[***]	 	[***]	 	[***]	 	[***]
	10.	 	[***]	 	[***]	 	[***]	 	[***]
	11.	 	[***]	 	[***]	 	[***]	 	[***]
	12.	 	[***]	 	[***]	 	[***]	 	[***]
	13.	 	[***]	 	[***]	 	[***]	 	[***]
	14.	 	[***]	 	[***]	 	[***]	 	[***]
	15.	 	[***]	 	[***]	 	[***]	 	[***]
	16.	 	[***]	 	[***]	 	[***]	 	[***]
	17.	 	[***]	 	[***]	 	[***]	 	[***]
	18.	 	[***]	 	[***]	 	[***]	 	[***]
	19.	 	[***]	 	[***]	 	[***]	 	[***]
	20.	 	[***]	 	[***]	 	[***]	 	[***]
	21.	 	[***]	 	[***]	 	[***]	 	[***]
	22.	 	[***]	 	[***]	 	[***]	 	[***]

 

CERTAIN PORTIONS OF THIS EXHIBIT HAVE BEEN
OMITTED AND ARE SUBJECT TO A CONFIDENTIAL TREATMENT REQUEST. COPIES OF THIS EXHIBIT CONTAINING THE OMITTED INFORMATION HAVE BEEN
FILED SEPARATELY WITH THE SECURITIES AND EXCHANGE COMMISSION. THE OMITTED PORTIONS OF THIS DOCUMENT ARE MARKED WITH A [***].

 

    	 

    	 

    

 

	Document No.: 

         

        Ed. 1
	TECHNOLOGY
    TRANSFER 

PROTOCOL	
	Effective Date	Page 9 of 19

 

	Sr. 

    No.	 	Description	 	Target date	 	Responsibility	 	Status
	23.	 	[***]	 	[***]	 	[***]	 	[***]
	24.	 	[***]	 	[***]	 	[***]	 	[***]
	25.	 	[***]	 	[***]	 	[***]	 	[***]
	26.	 	[***]	 	[***]	 	[***]	 	[***]
	27.	 	[***]	 	[***]	 	[***]	 	[***]
	28.	 	[***]	 	[***]	 	[***]	 	[***]
	29.	 	[***]	 	[***]	 	[***]	 	[***]
	30.	 	[***]	 	[***]	 	[***]	 	[***]
	31.	 	[***]	 	[***]	 	[***]	 	[***]
	32.	 	[***]	 	[***]	 	[***]	 	[***]
	33.	 	[***]	 	[***]	 	[***]	 	[***]
	34.	 	[***]	 	[***]	 	[***]	 	[***]
	35.	 	[***]	 	[***]	 	[***]	 	[***]
	36.	 	[***]	 	[***]	 	[***]	 	[***]
	37.	 	[***]	 	[***]	 	[***]	 	[***]
	38.	 	[***]	 	[***]	 	[***]	 	[***]
	39.	 	[***]	 	[***]	 	[***]	 	[***]
	40.	 	[***]	 	[***]	 	[***]	 	[***]

 

CERTAIN PORTIONS OF THIS EXHIBIT HAVE BEEN
OMITTED AND ARE SUBJECT TO A CONFIDENTIAL TREATMENT REQUEST. COPIES OF THIS EXHIBIT CONTAINING THE OMITTED INFORMATION HAVE BEEN
FILED SEPARATELY WITH THE SECURITIES AND EXCHANGE COMMISSION. THE OMITTED PORTIONS OF THIS DOCUMENT ARE MARKED WITH A [***].

 

    	 

    	 

    

 

	Document No.: 

         

        Ed. 1
	TECHNOLOGY
    TRANSFER

 PROTOCOL	
	Effective Date	Page 10 of 19

 

		7.	List of materials to be received from CML for QC:

 

	Sr. 

No.	 	Description	 	Required 

quantity	 	Target date	 	Responsibility
	From R&D/ QC/ Production
	1.	 	[***]	 	[***]	 	[***]	 	[***]
	2.	 	[***]	 	[***]	 	[***]	 	[***]

 

CERTAIN PORTIONS OF THIS EXHIBIT HAVE BEEN
OMITTED AND ARE SUBJECT TO A CONFIDENTIAL TREATMENT REQUEST. COPIES OF THIS EXHIBIT CONTAINING THE OMITTED INFORMATION HAVE BEEN
FILED SEPARATELY WITH THE SECURITIES AND EXCHANGE COMMISSION. THE OMITTED PORTIONS OF THIS DOCUMENT ARE MARKED WITH A [***].

 

    	 

    	 

    

 

	Document No.: 

         

        Ed. 1
	TECHNOLOGY
    TRANSFER

 PROTOCOL	
	Effective Date	Page 11 of 19

 

		8.	Transfer plan:

 

	Sr. 

No.	 	Parameter	 	Responsibility	 	Target date
	1.	 	[***]	 	[***]	 	[***]
	2.	 	[***]	 	[***]	 	[***]
	3.	 	[***]	 	[***]	 	[***]
	4.	 	[***]	 	[***]	 	[***]
	5.	 	[***]	 	[***]	 	[***]
	6.	 	[***]	 	[***]	 	[***]
	7.	 	[***]	 	[***]	 	[***]
	8.	 	[***]	 	[***]	 	[***]
	9.	 	[***]	 	[***]	 	[***]
	10.	 	[***]	 	[***]	 	[***]
	 	 	 	 	 	 	 
	 	 	[***]	 	 	 	[***]
	 	 	[***]	 	 	 	[***]
	11.	 	[***]	 	[***]	 	[***]
	 	 	 	 	 	 	 
	 	 	[***]	 	 	 	[***]
	 	 	[***]	 	 	 	[***]
	12.	 	[***]	 	[***]	 	[***]
	13.	 	[***]	 	[***]	 	[***]
	14.	 	[***]	 	[***]	 	[***]

 

CERTAIN PORTIONS OF THIS EXHIBIT HAVE BEEN
OMITTED AND ARE SUBJECT TO A CONFIDENTIAL TREATMENT REQUEST. COPIES OF THIS EXHIBIT CONTAINING THE OMITTED INFORMATION HAVE BEEN
FILED SEPARATELY WITH THE SECURITIES AND EXCHANGE COMMISSION. THE OMITTED PORTIONS OF THIS DOCUMENT ARE MARKED WITH A [***].

 

    	 

    	 

    

 

	Document No.: 

         

        Ed. 1
	TECHNOLOGY
    TRANSFER

 PROTOCOL	
	Effective Date	Page 12 of 19

 

	Sr.

     No.	 	Parameter	 	Responsibility	 	Target date
	15.	 	[***]	 	[***]	 	[***]
	16.	 	[***]	 	[***]	 	[***]

 

		9.	Production plan: 

 

	Type	 	Batch size

    (RM Input)	 	Batch size 

    (output)	 	Number of

    batches
	[***]	 	[***]	 	[***]	 	[***]

 

CERTAIN PORTIONS OF THIS EXHIBIT HAVE BEEN
OMITTED AND ARE SUBJECT TO A CONFIDENTIAL TREATMENT REQUEST. COPIES OF THIS EXHIBIT CONTAINING THE OMITTED INFORMATION HAVE BEEN
FILED SEPARATELY WITH THE SECURITIES AND EXCHANGE COMMISSION. THE OMITTED PORTIONS OF THIS DOCUMENT ARE MARKED WITH A [***].

 

    	 

    	 

    

 

	Document No.: 

         

        Ed. 1
	TECHNOLOGY
    TRANSFER 

PROTOCOL	
	Effective Date	Page 13 of 19

 

10. Critical and important
Process Parameters:

 

[***]

 

11. Comparison of process equipment,
analytical laboratory instruments & risk analysis:

 

During the assessment of risks due to change in Process
equipments and Instruments & controls (given below), we shall ensure that the changes do not affect the critical process parameters
(given above).

 

		11.1.	Comparison of Process Equipment: (please enter
                                         here the equipment used along the process for each step in the CML column; please include
                                         details such as the volume of the vessels, material of construction, filtration area,
                                         etc.)- prepared in a separate file during the visit to CML

 

	Process step	 	Equipment

    (CML)	 	Equipment

    (PAPI)	 	Comments, Risk assessment, actions 

    required
	[***]	 	 	 	 	 	 
	[***]	 	 	 	 	 	 
	[***]	 	 	 	 	 	 
	[***]	 	 	 	 	 	 
	[***]	 	 	 	 	 	 
	[***]	 	 	 	 	 	 
	[***]	 	 	 	 	 	 
	[***]	 	 	 	 	 	 
	[***]	 	 	 	 	 	 

 

CERTAIN PORTIONS OF THIS EXHIBIT HAVE BEEN
OMITTED AND ARE SUBJECT TO A CONFIDENTIAL TREATMENT REQUEST. COPIES OF THIS EXHIBIT CONTAINING THE OMITTED INFORMATION HAVE BEEN
FILED SEPARATELY WITH THE SECURITIES AND EXCHANGE COMMISSION. THE OMITTED PORTIONS OF THIS DOCUMENT ARE MARKED WITH A [***].

 

    	 

    	 

    

 

	Document No.: 

         

        Ed. 1
	TECHNOLOGY
    TRANSFER 

PROTOCOL	
	Effective Date	Page 14 of 19

 

		11.2.	Comparison of Instrumentation & control system:
                                         (please enter here the equipment used along the process in the CML column. Add rows if
                                         needed)

 

	Critical process 

    automation	 	Related Equipment

    (CML)	 	Related Equipment

    (PAPI)	 	Comments, Risk assessment, actions 

    required
	[***]	 	 	 	 	 	 
	[***]	 	 	 	 	 	 
	[***]	 	 	 	 	 	 
	[***]	 	 	 	 	 	 
	[***]	 	 	 	 	 	 
	[***]	 	 	 	 	 	 
	[***]	 	 	 	 	 	 
	[***]	 	 	 	 	 	 
	[***]	 	 	 	 	 	 

 

CERTAIN PORTIONS OF THIS EXHIBIT HAVE BEEN
OMITTED AND ARE SUBJECT TO A CONFIDENTIAL TREATMENT REQUEST. COPIES OF THIS EXHIBIT CONTAINING THE OMITTED INFORMATION HAVE BEEN
FILED SEPARATELY WITH THE SECURITIES AND EXCHANGE COMMISSION. THE OMITTED PORTIONS OF THIS DOCUMENT ARE MARKED WITH A [***].

 

    	 

    	 

    

 

	Document No.: 

         

        Ed. 1
	TECHNOLOGY
    TRANSFER 

PROTOCOL	
	Effective Date	Page 15 of 19

 

11.3.  Comparison of analytical
laboratory instruments: (please enter here the equipment used along the process in the CML column)

 

	Test	 	Instrument

    (CML)	 	Instrument

    (PAPI)	 	Comments, Risk 

    assessment, actions 

    required
	[***]	 	 	 	 	 	 
	[***]	 	 	 	[***]	 	 
	[***]	 	 	 	[***]	 	 
	[***]	 	 	 	[***]	 	 
	[***]	 	 	 	[***]	 	 
	[***]	 	 	 	[***]	 	 
	[***]	 	 	 	[***]	 	 
	[***]	 	 	 	[***]	 	 
	[***]	 	 	 	[***]	 	 
	[***]	 	 	 	[***]	 	 
	[***]	 	 	 	[***]	 	 
	[***]	 	 	 	[***]	 	 
	[***]	 	 	 	[***]	 	 
	[***]	 	 	 	[***]	 	 
	[***]	 	 	 	[***]	 	 
	[***]	 	[***]	 	[***]	 	[***]
	[***]	 	 	 	[***]	 	 
	[***]	 	 	 	 	 	 
	[***]	 	 	 	 	 	 
	[***]	 	 	 	 	 	 
	[***]	 	 	 	 	 	 
	[***]	 	 	 	[***]	 	 

 

CERTAIN PORTIONS OF THIS EXHIBIT HAVE BEEN
OMITTED AND ARE SUBJECT TO A CONFIDENTIAL TREATMENT REQUEST. COPIES OF THIS EXHIBIT CONTAINING THE OMITTED INFORMATION HAVE BEEN
FILED SEPARATELY WITH THE SECURITIES AND EXCHANGE COMMISSION. THE OMITTED PORTIONS OF THIS DOCUMENT ARE MARKED WITH A [***].

 

    	 

    	 

    

 

	Document No.: 

         

        Ed. 1
	TECHNOLOGY
    TRANSFER 

PROTOCOL	
	Effective Date	Page 16 of 19

 

12. Acceptance criteria for
the success of transfer:

 

[***]

 

CERTAIN PORTIONS OF THIS EXHIBIT HAVE BEEN
OMITTED AND ARE SUBJECT TO A CONFIDENTIAL TREATMENT REQUEST. COPIES OF THIS EXHIBIT CONTAINING THE OMITTED INFORMATION HAVE BEEN
FILED SEPARATELY WITH THE SECURITIES AND EXCHANGE COMMISSION. THE OMITTED PORTIONS OF THIS DOCUMENT ARE MARKED WITH A [***].

 

    	 

    	 

    

 

	Document No.: 

         

        Ed. 1
	TECHNOLOGY
    TRANSFER 

PROTOCOL	
	Effective Date	Page 17 of 19

 

13. Annexures: 

 

Annexure A

 

ARAMCHOL – Standards Requirements

 

	Sr. No.	 	Name	 	CML Code	 	Qty (gr)
	1	 	[***]	 	[***]	 	[***]
	2	 	[***]	 	[***]	 	[***]
	3	 	[***]	 	[***]	 	[***]
	4	 	[***]	 	[***]	 	[***]
	5	 	[***]	 	[***]	 	[***]
	6	 	[***]	 	[***]	 	[***]
	7	 	[***]	 	[***]	 	[***]
	8	 	[***]	 	[***]	 	[***]

 

Annexure B

 

ARAMCHOL – Representative Samples
Requirements

 

	Sr. No.	 	Name	 	CML Code	 	Qty (gr)
	1	 	[***]	 	[***]	 	[***]
	2	 	[***]	 	[***]	 	[***]
	3	 	[***]	 	[***]	 	[***]
	4	 	[***]	 	[***]	 	[***]
	5	 	[***]	 	[***]	 	[***]
	6	 	[***]	 	[***]	 	[***]
	7	 	[***]	 	[***]	 	[***]
	8	 	[***]	 	[***]	 	[***]
	9	 	[***]	 	[***]	 	[***]

 

Annexure C

 

ARAMCHOL – Method Transfer Requirements

 

	Sr. No.	 	Name	 	CML Code	 	Qty (gr)
	1	 	[***]	 	[***]	 	 
	2	 	[***]	 	[***]	 	 

 

CERTAIN PORTIONS OF THIS EXHIBIT HAVE BEEN
OMITTED AND ARE SUBJECT TO A CONFIDENTIAL TREATMENT REQUEST. COPIES OF THIS EXHIBIT CONTAINING THE OMITTED INFORMATION HAVE BEEN
FILED SEPARATELY WITH THE SECURITIES AND EXCHANGE COMMISSION. THE OMITTED PORTIONS OF THIS DOCUMENT ARE MARKED WITH A [***].

 

    	 

    	 

    

 

	Document No.: 

         

        Ed. 1
	TECHNOLOGY
    TRANSFER

 PROTOCOL	
	Effective Date	Page 18 of 19

 

Annexure D

 

ARAMCHOL – Raw Materials Requirements

 

	Sr.

 No.	 	Name	 	Requirement from CML	 	Remarks
	1	 	[***]	 	[***]	 	[***]
	2	 	[***]	 	[***]	 	[***]
	3	 	[***]	 	 	 	[***]
	4	 	[***]	 	[***]	 	 
	5	 	[***]	 	[***]	 	 
	6	 	[***]	 	[***]	 	[***]
	7	 	[***]	 	[***]	 	[***]
	8	 	[***]	 	 	 	[***]

 

Annexure E

 

ARAMCHOL – In-Process Requirements

 

	Sr. 

No.	 	Name	 	Requirement from CML	 	Remarks
	1	 	[***]	 	[***]	 	[***]
	2	 	[***]	 	[***]	 	[***]
	3	 	[***]	 	[***]	 	[***]
	4	 	[***]	 	[***]	 	[***]
	5	 	[***]	 	[***]	 	[***]
	6	 	[***]	 	[***]	 	 
	7	 	[***]	 	[***]	 	[***]
	8	 	[***]	 	[***]	 	[***]
	9	 	[***]	 	[***]	 	[***]
	10	 	[***]	 	[***]	 	[***]
	11	 	[***]	 	[***]	 	[***]

 

CERTAIN PORTIONS OF THIS EXHIBIT HAVE BEEN
OMITTED AND ARE SUBJECT TO A CONFIDENTIAL TREATMENT REQUEST. COPIES OF THIS EXHIBIT CONTAINING THE OMITTED INFORMATION HAVE BEEN
FILED SEPARATELY WITH THE SECURITIES AND EXCHANGE COMMISSION. THE OMITTED PORTIONS OF THIS DOCUMENT ARE MARKED WITH A [***].

 

    	 

    	 

    

 

	Document No.: 

         

        Ed. 1
	TECHNOLOGY
    TRANSFER 

PROTOCOL	
	Effective Date	Page 19 of 19

 

Annexure F- Bill of materials

 

[***]

 

CERTAIN PORTIONS OF THIS EXHIBIT HAVE BEEN
OMITTED AND ARE SUBJECT TO A CONFIDENTIAL TREATMENT REQUEST. COPIES OF THIS EXHIBIT CONTAINING THE OMITTED INFORMATION HAVE BEEN
FILED SEPARATELY WITH THE SECURITIES AND EXCHANGE COMMISSION. THE OMITTED PORTIONS OF THIS DOCUMENT ARE MARKED WITH A [***].

 

    	 

    	 

    

 

Annex D

 

Process Stabilization Scope

 

 

Aramchol

 

Process Stabilization
Scope of Work

 

Stage 1 of production – [***]

 

[***]

 

Stage 2 of production – [***]

 

[***]

 

Stage 3 of production – [***]

 

[***]

 

Stage 4 of production – [***]

 

[***]

 

Analytical Development Scope 

 

[***]

 

General

 

		·	The
                                         studies described above will be carried out over a period of [***]. Additional
                                         1 month lead time for ordering advanced intermediates / starting materials is required.

 

		·	[***]
                                         will be ordered from Glamed's current source [***]

 

		·	[***]
                                         will be ordered from [***] (Galmed's current source) [***].

 

		·	3
                                         final lab samples of about 30gr will be produced 

 

		·	Once
                                         completed, an evaluation will be carried out to decide whether process can be transferred
                                         directly to [***] or pilot scale up [***] is recommended first. Such pilot
                                         scale up will require [***] of additional work. 

 

Other Working Assumptions

 

		·	All
                                         analytical standards will be supplied by Galmed / CML.

 

		·	Galmed
                                         will provide API sample that was used for passing the TOX study. This sample will serve
                                         as a standard to set the API specifications.

 

CERTAIN PORTIONS OF THIS EXHIBIT HAVE BEEN
OMITTED AND ARE SUBJECT TO A CONFIDENTIAL TREATMENT REQUEST. COPIES OF THIS EXHIBIT CONTAINING THE OMITTED INFORMATION HAVE BEEN
FILED SEPARATELY WITH THE SECURITIES AND EXCHANGE COMMISSION. THE OMITTED PORTIONS OF THIS DOCUMENT ARE MARKED WITH A [***].

 

    	Page 1 of 2

    	 

    

 

		o	Any method that will be developed
                                         by Perrigo API will be applied on this standard.

 

		o	The API specifications will be set
                                         in accordance with the impurity profile of this sample.

 

		·	Any
                                         new impurity that will be discovered throughout Perrigo API campaign that was not observed
                                         in the batch that was used for TOX study is not quoted in the suggested quotation and
                                         will be re-quoted.

 

		·	[***].
                                         Galmed would define the scope of Solid State study if required. 

 

CERTAIN PORTIONS OF THIS EXHIBIT HAVE BEEN
OMITTED AND ARE SUBJECT TO A CONFIDENTIAL TREATMENT REQUEST. COPIES OF THIS EXHIBIT CONTAINING THE OMITTED INFORMATION HAVE BEEN
FILED SEPARATELY WITH THE SECURITIES AND EXCHANGE COMMISSION. THE OMITTED PORTIONS OF THIS DOCUMENT ARE MARKED WITH A [***].

 

    	Page 2 of 2

    	 

    

  

Annex E

 

Process Improvement Scope

 

Aramchol

 

Process Improvement Scope of Work

 

Stage 1 of production – [***]

 

[***]

 

Stage 2 of production – [***]

 

[***]

 

Stage 3 of production – [***]

 

[***]

 

Stage 4 of production – [***]

 

[***]

 

General (All Production Stages):

 

[***]

 

CERTAIN PORTIONS OF THIS EXHIBIT HAVE BEEN
OMITTED AND ARE SUBJECT TO A CONFIDENTIAL TREATMENT REQUEST. COPIES OF THIS EXHIBIT CONTAINING THE OMITTED INFORMATION HAVE BEEN
FILED SEPARATELY WITH THE SECURITIES AND EXCHANGE COMMISSION. THE OMITTED PORTIONS OF THIS DOCUMENT ARE MARKED WITH A [***].

 

    	Page 1 of 1Exhibit
4.10

 

CERTAIN
PORTIONS OF THIS EXHIBIT HAVE BEEN OMITTED AND ARE SUBJECT TO A CONFIDENTIAL TREATMENT REQUEST. COPIES OF THIS EXHIBIT CONTAINING
THE OMITTED INFORMATION HAVE BEEN FILED SEPARATELY WITH THE SECURITIES AND EXCHANGE COMMISSION. THE OMITTED PORTIONS OF THIS DOCUMENT
ARE MARKED WITH A [***].

 

Investigator-Initiated
Clinical Trial Agreement

 

This
Clinical Trial Agreement (“Agreement”) is made and entered into effective as of the full execution hereof (“Effective
Date”), by and between The Regents of the University of California, a California constitutional corporation, on behalf of
its San Diego campus, located at 9500 Gilman Drive, La Jolla, CA 92093, California (“Institution”), and Galmed Research
and Development Ltd., a private company having its principal place of business at 8, Shaul Hamelech Blvd., Tel Aviv, 6473307, Israel
(“Company”), (each may be individually referred to as a “Party” and collectively, as “the Parties”).

 

Whereas,
Dr. Rohit Loomba, M.D., an employee of Institution (“Principal Investigator”), desires to conduct a clinical study (“Study”)
under a protocol entitled “Aramchol Versus Placebo for the Treatment of HIV-associated NAFLD” UCSD#20150180 (“Protocol”),
a copy of which is attached hereto as Exhibit A;

 

Whereas,
Principal Investigator has authored the Protocol and Institution and Principal Investigator have the expertise and facilities to
conduct the Study;

 

Whereas,
Company is providing financial support in accordance with the budget attached hereto as Exhibit C for use in the
Study;

 

Whereas,
the Study is intended to advance scientific and medical knowledge and Institution considers the Study to be research done in the
public interest;

 

Now,
therefore, in consideration of the mutual promises set forth in this Agreement, the Parties hereby agree as follows:

 

		1.	Scope
                                         of Work.

 

		1.1	Principal
Investigator. The Institution shall conduct the Study under the direction of the Principal Investigator. Principal Investigator
may appoint such other appropriate and qualified institution employees to provide services on behalf of Institution to conduct
such Study (“Study Staff”). If Principal Investigator becomes unable or unwilling to continue to conduct the Study, and
a mutually acceptable substitute Principal Investigator (“Substitute Investigator”) is not identified by the parties,
then either Party shall have the option to terminate the Study upon thirty (30) days prior written notice and pursuant to Section
8.4 below. Upon the approval of such Substitute Investigator by the Parties as aforesaid, although not a party, the Substitute
Investigator shall execute this Agreement as having read and understood Principal Investigator obligations under the agreement,
and shall be considered as the “Principal Investigator” for any purpose under this Agreement.

 

		1.2	Institution
as Study Sponsor. If applicable, Institution and Principal Investigator shall act as “Sponsor” of the Study, as such
term is defined by the U.S. Food and Drug Administration (“FDA”) Federal Code of Regulations.

 

    	1

    	 

    

 

		1.3	Study Staff.
Institution, through Principal Investigator, shall supervise Study Staff in their performance of the Study and ensure that all
Study Staff are qualified to perform the duties assigned to such person. Institution shall take reasonable steps to inform Study
Staff of their obligations under this Agreement.

 

		1.4	Conduct of
the Study. Institution shall, and shall cause the Principal Investigator and Study Staff (collectively, “Study Team”)
to, conduct the Study in accordance with this Agreement, the Protocol, and all applicable federal and state laws and regulations
(“Applicable Law”); provided, however, that Institution may deviate from the Protocol and such instructions to the extent
that the safety of Study subjects so requires. For clinical Studies, such conduct includes compliance with International Conference
on Harmonization Good Clinical Practice (ICH GCP), but only to the extent that the ICH GCP guidelines comport with FDA regulations,
the Helsinki Declaration, rules and regulations for protecting the rights, safety and welfare of human subjects and for the control
of new drugs under investigation, including relevant data protection laws, the International Conference on Harmonization of Technical
Requirements for Registration of Pharmaceuticals for Human Use, as well as all applicable laws and regulations pertaining to the
protection of the personal data of subjects (“Rules and Regulations”).

 

		1.5	Manner of
Conduct. Institution represents that it and the Principal Investigator have the requisite skills, knowledge, experience and
human resources to undertake and conduct the Study in accordance with the provisions of this Agreement. Principal Investigator
and Institution represent and warrant, that they, and the Study Staff have all training, information, licenses, approvals or certifications
necessary for safely, adequately and lawfully performing the Study, and all such training, licenses, approvals or certifications
shall be properly maintained throughout the course of the Study.

 

		1.6	Investigational
New Drug Application (“IND”)/lnvestigational Device Exemption (“IDE”). To the extent required to do so
by Applicable Law, Institution will obtain and maintain an IND/IDE pursuant to FDA regulations.

 

		1.7	IRB Approval.
Institution shall obtain approval of the Study, the Protocol, and an informed consent from the appropriate institutional review
board (“IRB”) and shall seek any other approvals required for the Study from applicable safety or review boards or other
authorities.

 

		1.8	Informed Consent.
Prior to a Study subject’s participation in Study, Institution shall obtain from each Study subject participating in the Study
or such Study subject’s legal representative an informed consent, which includes a waiver of medical confidentiality, signed by
the Study subject or his or her legal representative, unless such signature is waived by the IRB. Institution shall ensure that
such informed consent shall be granted only under circumstances that provide the prospective Study Subject (or his or her legal
representative) with reasonable and sufficient opportunity to consider whether or not to participate in the Study and that minimize
the possibility of coercion or undue influence. Such written informed consent shall be obtained in compliance with all Applicable
Law, standards and guidelines. Institution shall further ensure that each Study subject shall execute an authorization form intended
to give the Study subject’s permission to use his or her personal data as necessary to accomplish the goals of the Study.

 

    	2

    	 

    

 

		1.9   	Protocol Ownership
and Changes to the Protocol. Company acknowledges that Investigator is the author of the Study Protocol and research design
of the Study. The Protocol and research design of the Study is the property of the Institution. Institution shall inform Company
of any changes to the Protocol. Protocol changes shall be in writing and will not take effect until approved by the IRB.

 

		1.10 	Multi-Center
Study. In the event of a multi-center Study, Institution agrees that each site involved in the Study (each a “Study Site”
and collectively “Study Sites”) shall enter into a written agreement with Institution regarding its participation in
the Study. Institution and Investigator shall be solely responsible for the conduct of the Study at all Study Sites, and shall
ensure that the Study Sites comply with the terms and conditions of this Agreement and all Applicable Laws. Upon request by Company,
Institution and Investigator shall provide a list of participating sites and any updates thereto. Institution shall prepare the
form of the agreement to be used with the Study Sites, which shall afford Company all rights as set forth in this Agreement.

 

		1.11 	Provision
of Study Drug and Study Supplies. Company shall provide to Institution, without cost, a certain quantity agreed by the parties
of Company’s study drug called Aramchol, to conduct the Study pursuant to the Protocol (“Study Drug”), as well as any
other compounds, comparator drugs, and/or equipment (collectively, “Study Supplies”) which is agreed by the Company and
specified in the Protocol. Company shall also provide Institution with written instructions and prescriptions governing the administration
of the Study Drug, and Institution shall maintain proper and complete records concerning the administration of the Study Drug as
well as maintain an inventory log regarding the current inventories of the Study Drug and shall verify that such log is completed
and updated on an ongoing basis. Institution and the Principal Investigator shall not modify or reverse engineer the Study Drug
and will maintain, safeguard and store the Study Drug in a safe and secure manner consistent with ICH GCP and in strict compliance
with the Protocol, Applicable Law and the Rules and Regulations, and keep or cause to be kept records of all Study Drug received,
used, dispensed, disposed of and/or returned to Company. All Study Supplies, including the Study Drug, provided for the purpose
of carrying out the Study may not be used for any other purpose whatsoever. Principal Investigator and Institution are responsible
for the security and accountability of all such Study Supplies. Where Company requests, Institution shall store the Study Drug
in Institution’s pharmacy (the “Pharmacy”). In such case, the Study Drug shall be stored according to the instructions
of Company, in compliance with the Pharmacy’s practice and policy regarding storage of drugs.

 

    	3

    	 

    

 

		2	Access
                                         and Auditing.

 

		2.1	Access to
Study Data. Upon prior written request to Institution, at mutually agreeable times during Institution’s regular business hours,
and subject to the terms of this Agreement and Applicable Law, Company or its agents may access Institution’s Study data in the
form in which it is available, except that direct identifiers of any Study subject, including, but not limited to. Study subject’s
name, birth date, street address, telephone, social security or health plan beneficiary numbers (“Direct Identifiers”)
shall not be made available to Company. In the event Study data contains Direct Identifiers, such Direct Identifiers shall be redacted.
Company shall be responsible for all costs to Institution for making such Study data available, including any costs associated
with redaction.

 

		2.2	Compliance
with HIPAA and CMIA. The Parties shall comply with all Applicable Laws governing patient privacy and confidentiality of health
information, including without limitation the federal Health Insurance Portability and Accountability Act of 1996 (“HIPAA”)
and its implementing regulations, and the State of California Confidentiality of Medical Information Act (“CMIA”). The
Parties shall take all actions necessary to comply with such laws and regulations, including agreeing to amend this Agreement as
necessary for compliance.

 

Adverse
Event Reporting. Institution is solely responsible for reporting adverse events in the course of a Study in accordance with
Applicable Law and the Protocol to the FDA or other regulatory authorities. Institution shall provide Company with a copy of any
adverse event reports as they are submitted to the FDA or other authority. In the event of a Serious Adverse Event, Institution
and the Study Staff will immediately take all measures at their disposal to evaluate the risk to the other Study subjects and will
agree on which measures to take in order to mitigate that risk.

 

		2.3	Debarment.
Institution certifies that it will not knowingly use the services of any Study Staff to perform services in connection with the
Study who is (i) debarred, disqualified or banned from conducting clinical studies under the Generic Drug Enforcement Act of 1992,
as amended, or (ii) excluded, debarred or suspended from participation in, or is otherwise ineligible to participate in, any federal
health care program or federal procurement or non-procurement program. Institution further certifies that neither it, or the Principal
Investigator nor any person or entity it utilizes to perform services pursuant to this Agreement, has been convicted of a criminal
offense that falls within the ambit of 42 U.S.C. § 1320a-7(a) or is otherwise related to the provision of healthcare items
or services. Institution agrees to inform Company as soon as practicable in writing of any change to this certification.

 

    	4

    	 

    

 

		2.4	Information
and Regulatory Authority Audits. Each of Institution and Company shall notify and provide the other with copies of any inquiries,
correspondence or communications to or from any governmental or regulatory authority related to the Study at Institution as soon
as practicable after their receipt. In addition, if any governmental or regulatory authority: (i) contacts Institution or the Principal
Investigator with respect to the Study; (ii) conducts, or gives notice of its intent to conduct, an inspection at Institution;
or (iii) takes, or gives notice of its intent to take, any other regulatory action with respect to any activity of Institution
or Principal Investigator which could reasonably be expected to impact any data or clinical activity under the Study; the Principal
Investigator must promptly notify the Company of the contact or notice. The Principal Investigator shall provide the Company with
copies of all information and documentation applicable to the Study issued by any governmental or regulatory authority and any
proposed response. The Company will have the right to review and comment in advance on any responses, which pertain to the Study
Drug. Furthermore, Institution and Principal Investigator shall provide the Company within two weeks following the inspection a
written report of the inspection, noting with specificity each Study-related record or document provided to or reviewed by the
regulatory authority. The Parties shall use reasonable efforts to properly address and will cure any and all non-compliance issues.
Institution and the Principal Investigator will consult with and inform the Company of the actions taken and the responses provided
to any report or correspondence issued by any governmental authority which could reasonably be expected to impact the Study Drug.

 

		3.	Compensation

 

Company
shall make payments to Institution in accordance with the payment schedule attached hereto as Exhibit B (“the
Payment Schedule”) and the budget attached hereto as Exhibit C (“Budget”). All payments
shall be provided to Institution within 30 days of the end of the calendar month during which Institution’s invoice is
received by Company. Company shall also make payments to Institution in accordance with Section 7 of this Agreement. The
Parties agree that all such payments made by Company to Institution reflect fair market value for the research performed
hereunder.

 

		4.	Ownership
                                         of Data and Intellectual Property

 

		4.1	Study Data.
All rights, title and interest in Study data shall be the sole and exclusive property of the Institution. Company shall have the
right to use in its sole discretion, for any legal purpose consistent with the informed consents, including publication and regulatory
filings, any Study data provided to Company, at Company’s request. Company shall own the completed Case Report Forms (CRFs) and
the data therein that is provided to Company by Institution, Institutions shall maintain the original CRFs for regulatory compliance
and any other Institution required purpose consistent with Institution policies.

 

		4.2	Final Report.
Within 60 days following completion of the Study, Institution shall provide Company with a final report of the research results
of the Study. Company shall have the unlimited right to use, copy and disseminate the final report for any legal purpose. The Principal
Investigator shall prepare and maintain, both during and following the performance of the Study, current, complete and accurate
written records, accounts, notes, reports and data of the Study, including CRFs, in accordance with the Protocol. Such materials
and data shall be maintained in accordance with Section 5 below.

 

    	5

    	 

    

 

		4.3	Study Inventions.
Institution shall own all patentable inventions and discoveries conceived and reduced to practice in the direct performance of
the Study (“Study Inventions”). Institution shall promptly disclose such Study Inventions to Company.

 

		4.4	Grant of License
and Option to License. To the extent legally able, Institution agrees to grant to Company a non-exclusive, worldwide, royalty-free,
fully paid up, transferrable and sublicensable (including through multiple chains) license to use, import, export, have made, make,
commercialize or sell Institution’s interest in all Study Inventions and Institution’s Confidential Information as required to
exploit the Study Inventions. Also, to the extent legally able, Institution shall grant Company a time-limited first right to negotiate
an exclusive, worldwide license to Institution’s rights in any Study Invention on commercially reasonable terms and conditions
agreed between the Parties in advance and in good faith. Company will advise Institution in writing within ninety (90) days of
Institution’s written notification to the Company of a disclosure of Study Invention whether or not it wishes to secure an exclusive
commercial license (“Election Period”). Company shall have one hundred and eighty (180) days from the date of election
to enter into a license agreement with Institution (“Negotiation Period”). In the event it is necessary in the opinion
of the Institution to file a patent application to protect a Study Invention during the Negotiation Period in geographies agreed
between the parties, Company will reimburse Institution for reasonable incurred patent costs during such period.

 

		4.5	No Rights
to Other Proprietary Interests. Nothing contained in this Agreement shall be deemed to grant either directly or by implication,
estoppel, or otherwise, any rights under any patents, patent applications or other proprietary interests, whether dominant or subordinate,
or any other invention, discovery or improvement of either party, other than the specific rights covering Study Inventions under
this Agreement.

 

		5.	Confidentiality

 

		5.1	Institution Confidential
Information. Institution shall only disclose confidential information necessary for Company’s support of the Study. “Institution
Confidential Information” shall mean and include all data and other information which are disclosed by the Institution to
Company, for the purposes of conducting Study which is marked as “Confidential” at the time of disclosure, or (i) in
the case of oral disclosures, identified at the time of such oral disclosure as confidential and reduced to writing and marked
as “Confidential” within thirty (30) days of oral disclosure; (ii) if not marked, regarded as confidential if a reasonable
person in the relevant field would consider such information to be the Institution’s confidential information given its content
and the circumstances of the disclosure. Institution Confidential Information shall not include information to the extent that
it: (i) is, or later becomes publicly known other than through a breach of this Agreement by the Company, its employees, or its
agents; (ii) is lawfully made available to the Company, its employees or its agents, by a third party that Company reasonably
believes owes no obligation of confidentiality to the Institution; or (iii) was already known to or is independently developed
by the Company, its employees, or its agents. During the term of this Agreement and for a period of five (5) years after its expiration
or earlier termination, the Company shall maintain the confidentiality of the institution Confidential Information and may not
transfer or disclose Institution Confidential Information to any third party without the Institution’s prior written consent other
than as required by Applicable Law or as permitted pursuant to the terms of this Agreement.

 

    	6

    	 

    

 

		5.2	Company
                                                             Confidential Information. Company shall only disclose confidential information necessary for Institution’s performance of
                                                             the Study. “Company Confidential Information” shall mean and include all data and other information which are
                                                             disclosed by the Company to Institution for the purposes of conducting Study or related to the Study Drug which is marked as
                                                             “Confidential” at the time of disclosure, or (i) in the case of oral disclosures, identified at the time of such
                                                             oral disclosure as confidential and reduced to writing and marked as “Confidential” within thirty (30) days of oral
                                                             disclosure; (ii) if not marked, regarded as confidential if a reasonable person in the relevant field would consider such
                                                             information to be the Company’s confidential information given its content and the circumstances of the disclosure. Company
                                                             Confidential Information shall not include information to the extent that it: (i) is, or later becomes publicly known other
                                                             than through a breach of this Agreement by the Institution, its employees, or its agents, including the Principal
                                                             Investigator; (ii) is lawfully made available to the Institution, its employees or its agents, including Principal
                                                             Investigator, by a third party that Institution reasonably believes owes no obligation of confidentiality to the Company; or
                                                             (iii) was already known to or is independently developed by the Institution, its employees, or its agents,
                                                             including Principal Investigator without reference to or use of the Company Confidential Information. During the term of this
                                                             Agreement and for a period of five (5) years after its expiration or earlier termination, the Institution shall maintain the
                                                             confidentiality of the Company Confidential Information and may not transfer or disclose Company Confidential Information to
                                                             any third party without the Company’s prior written consent other than as required by Applicable Law or as permitted pursuant
                                                             to the terms of this Agreement.

 

		5.3	Permitted
Uses and Disclosures of a Disclosing Party’s Confidential Information. “Disclosing Party” as used herein means, with
respect to Institution Confidential Information or Company Confidential Information, the Party who owns or otherwise controls such
confidential information, and has disclosed such confidential information under this Agreement. A Disclosing Party’s confidential
information may be used by the Party receiving such confidential information (“Receiving Party”) to the extent that it:
(i) is disclosed for the purpose of performing the Study or exercising such Party’s rights under this Agreement, provided that
the Receiving Party has obligated its employees and agents to hold such Institution Confidential Information or Company Confidential
Information in confidence at least to the same degree of care as the Receiving Party uses to protect its own confidential information
hereunder; or (ii) is disclosed to medical professionals in order to provide reasonable and necessary medical care to a Study subject,
provided that the Receiving Party advises such medical care provider(s) of the need to maintain the confidentiality of such Institution
Confidential Information or Company Confidential Information.

 

    	7

    	 

    

 

		5.4	Required Disclosures
of Institution Confidential Information and Company Confidential Information. Notwithstanding any provisions of this
Agreement, the Receiving Party may disclose Institution Confidential Information or Company Confidential Information which it is
required by governmental order, subpoena or Applicable Law to disclose. The Receiving Party agrees to cooperate with any reasonable
effort of the Disclosing Party to challenge a court-ordered, open records, or similar required disclosure; provided, however,
that, with respect to an open records disclosure, the Receiving Party independently has determined that the information the Disclosing
Party seeks to protect is exempted from disclosure under Applicable Law.

 

		5.5	Return of
Confidential Information. At any time and upon the Disclosing Party’s advance written request, the Receiving Party shall return
to the Disclosing Party promptly, or destroy, any and all Institution Confidential Information or Company Confidential Information
and all copies thereof, furnished to the Receiving Party under this Agreement; provided, however, that the Receiving Party may
retain one copy in a secure location for purposes of compliance with this Agreement and Applicable Law, subject to continuing confidentiality
obligations. The Receiving Party shall not be required to delete or destroy any electronic back-up tapes or other electronic back-up
files that have been created solely by the automatic or routine archiving and back-up procedures of the Receiving Party, to the
extent created and retained in a manner consistent with its or their standard archiving and back-up procedures.

 

		5.6	Accessibility
of Institution Records. Institution, as an instrumentality of the State of California, is subject to certain state regulations
and resolutions regarding access to Institution’s records, including the requirement that Institution make available the terms
and conditions of contracts. The actual contract agreement must be released upon request, although portions of the document may
be withheld when redaction meets one of the legal exemptions under the California Public Records Act. As such, the general terms
and conditions of this Agreement will be released to the public upon request. To the extent disclosure of other records, including
the Protocol, terms of compensation and related documents, is requested, Institution will notify Company and work with Company
to redact material which can be withheld from disclosure, to the extent permitted by law and at Company’s request and expense.
Furthermore, for the avoidance of doubt, Institution maintains a publicly accessible listing of all proposals and awards. The listing
includes the name of the campus, sponsor, award amount, begin and end dates, principal investigator and co-investigator’s name,
project type, award instrument, indirect cost rate, account and fund number, department and academic discipline.

 

		5.7	Use of Name.
Neither party shall use the name, logo, mark or image of the other party in any publicity or advertising without the other party’s
written approval. California Education Code Section 92000 prohibits use of Institution’s names to suggest that Institution endorses
a product or service.

 

    	8

    	 

    

 

		6.	Publication

 

		6.1	Right of Publication.
Institution may freely publish and disseminate the results of the Study, or otherwise publish or submit for publication an article,
manuscript, abstract, report, poster, presentation, or other material containing or dealing with results of the Study (“Publication”),
only after coordinating the Publication in advance with the Company in writing, and provided that to the extent appropriate Institution
shall include a credit to the Company, its research and investors.

 

		6.2	Review Period
of Publications. Institution shall send Company a copy of any proposed Publication sixty (60) days prior to submission for
Publication (“Review Period”). Company may comment upon, but may not make any editorial changes to the proposed Publication,
and any such comments shall be considered in good faith by the Institution. Upon Company’s timely written request prior to submission
to Publication, Institution shall delete any Company Confidential Information in the proposed Publication. At the Company’s request,
Institution shall delay Publication for an additional sixty (60) days in order to protect the potential patentability of an invention
described therein.

 

		6.3	Company’s
Right of Publication. For avoidance of doubt, it is clarified that Company may freely publish and disseminate the data generated
in the performance of, and results of, the Study, or otherwise publish or submit for publication an article, manuscript, abstract,
report, poster, presentation, or other material containing or dealing with results of the Study and will, as appropriate, seek
Institution review of any publication or dissemination under this paragraph if Institution generated the data or results being
published. Additionally, Institution will be provided credit, consistent with scientific custom, for its contributions.

 

		6.4	Registration
of Study. Institution shall register and report the results of the Study in accordance with the International Committee of
Medical Journal Editors (ICMJE) clinical trial requirements for publication and as required under Applicable Law.

 

		7.	Indemnification,
                                         Subject Injury and Insurance

 

		7.1	Institution
Indemnification. To the extent permitted by law, Institution shall defend, indemnify and hold harmless Company, its directors,
officers, agents and employees (“Company Indemnitees”) from and against any and all claims, liabilities, expenses (including
reasonable attorneys’ fees), actions or demands that may be made or instituted against any of them by reason of injury (including
death) to any person, or damage to property, arising out of or in connection with the Study (“Claims”) except to the
extent caused solely by the gross negligence or willful misconduct of Company. Company shall promptly notify Institution in writing
after receipt by Company of any Claim subject to this Section.

 

		7.2	Management
of Indemnification. Institution shall have the right to manage the defense and settlement of any Claim, provided however, that
the Institution shall not admit any liability or wrongdoing on the part of the Company or indemnitees, or settle any Claim which
would involve such an admission, without the prior written consent of the Company, which consent will not be unreasonably withheld.
The Company shall reasonably cooperate with the Institution regarding any such Claims, at the Institution’s expense. Subject to
the foregoing, Company may participate in any such Claims at its/his/her own cost and expense.

 

    	9

    	 

    

 

		7.3	Subject Injury
and Reimbursement for Subject Injury. Institution shall provide medical treatment to subjects injured as a result of their
participation in the Study. Subjects will be advised in the informed consent that if they are injured as a direct result of participation
in the Study, the University of California will provide any medical care they need to treat those injuries. The Company shall not
be required to make any reimbursement in any event.

 

		7.4	Insurance.
The Institution shall have sufficient liability, professional indemnity and clinical trial insurance and other adequate forms of
protection to satisfy all the obligations set forth in this Agreement, including without limitation with respect to Study subjects
and any injury thereto. Institution shall secure and maintain in full force and effect through the performance of the Study (and
following termination of the Study to cover any claims arising from the Study) self - insurance coverage for: (i) medical professional
and/or medical malpractice liability; (ii) general liability; and (iii) workmen’s compensation, each such insurance coverage in
amounts appropriate to the conduct of Institution’s and Principal Investigator’s business activities and the services contemplated
by the Study. The amount of such insurance coverage shall not be construed as creating a limit on any obligations assumed herein.
The insurance policy shall include the Company as additional named insured. The insurance will be regarded as primary insurance
and not contributory. Institution shall present the Company with appropriate insurance confirmation prior to the commencement of
the Study.

 

		7.5	No party hereto
shall be responsible or liable with respect to any subject matter of this Agreement under any contract, negligence, strict liability
or other theory for any indirect, incidental, special or consequential damages including but not limited to loss of revenues and
loss of profits.

 

		8.	Term
                                         and Termination

 

		8.1	Term.
This Agreement shall take effect on the Effective Date and shall continue until the earlier of: (i) completion of the Study and
submission to the Company of a final report summarizing the results of the Study pursuant to this Agreement; or (ii) until Study
is sooner terminated or suspended as provided for in this Agreement and pursuant to the Protocol.

 

		8.2	Termination.
Either Party may terminate this Agreement: (i) upon thirty (30) days prior written notice to the other Party, in its sole discretion;
or (ii) upon written notice to the other Party, if the terminating Party determines that termination of the Study is necessary
for the safety of the Study subjects.

 

    	10

    	 

    

 

		8.3	Termination
                                         for Material Breach. Either Party may terminate this Agreement upon written notice
                                         to the other Party if the other Party materially breaches this Agreement and the breaching
                                         Party fails to cure the breach within thirty (30) days after receipt of written notice
                                         of the breach from the other Party.

 

		8.4	Early Termination
Procedures. If this Agreement is terminated before completion of the Study, the Parties shall negotiate in good faith on the
phase-out for Study subjects and subsequent treatment of Study subjects. In the event such early termination occurs, which is not
due to a breach of this Agreement by Institution and/or Principal Investigator or their bankruptcy/insolvency, and/or is not terminated
by Institution for convenience, Company shall reimburse the Institution for (i) obligations incurred in accordance with the Study
budget that cannot be cancelled or mitigated by Institution using reasonable efforts; (ii) reasonable costs incurred in connection
with the safe withdrawal of Study subjects; and (iii) any other post-termination expenses mutually agreed to by the Parties.

 

		8.5	Return of
Property. Within thirty (30) days following the expiration or earlier termination of this Agreement: (a) the Institution shall
return to the Company, at Company’s sole and reasonable expense (i) any remaining Study Supplies (except as required by Applicable
Law); (ii) any equipment on loan or lease from the Company; and (iii) subject to the terms of Section 5 of this Agreement, any
copies of Company Confidential Information provided by the Company that are in the possession of or are under the control of the
Institution; (b) the Company shall return to the Institution, at Institution’s sole and reasonable expense, subject to the terms
of Section 5 of this Agreement, any copies of Institution Confidential Information provided by Institution that are in the possession
of or are under the control of the Company.

 

		8.6	Survival.
The following provisions shall survive expiration or termination of this Agreement: Sections 1.2,1.3,1.4, 2.1, 3, 4, 5, 6, 7, 8.4,
8.5, 8.6 and 9.

 

8A. Warranties

 

It
is understood that the Study Drug and any other materials provided are investigational in nature. COMPANY MAKES NO WARRANTIES,
EXPRESS OR IMPLIED, INCLUDING AND WITHOUT LIMITATION ANY OF THE IMPLIED WARRANTIES OF MERCHANTABILITY, FITNESS FOR A PARTICULAR
PURPOSE AND NON-INFRINGEMENT, REGARDING THE STUDY DRUG. ADDITIONALLY, COMPANY MAKES NO REPRESENTATION OF ANY KIND, EXPRESS OR IMPLIED,
REGARDING THE SAFETY OR EFFICACY OF THE STUDY DRUG.

 

		9.	Miscellaneous

 

		9.1	Independent Contractor.
All research performed by Institution, Principal Investigator and any Study Staff pursuant to this Agreement shall be performed
as an independent contractor. The relationship between the Parties does not constitute a partnership, joint venture, or agency.
Neither Party shall have the authority to bind the other Party without that other Party’s express and written consent.

 

    	11

    	 

    

 

		9.2	Remedies and
Waiver. The remedies provided in this Agreement are not exclusive and the Party suffering from breach or default of this Agreement
may pursue all other remedies, both legal and equitable. No express or implied waiver by a Party of any breach or default will
be construed as a waiver of a future or subsequent breach or default. The failure or delay of any Party in exercising any of its
rights under this Agreement will not constitute a waiver of any such right, and any single or partial exercise of any particular
right by any Party will not exhaust the same or constitute a waiver of any other right provided in this Agreement.

 

		9.3	Assignment.
Neither Party may assign any of its rights or delegate any of its duties under this Agreement without the prior written consent
of the other Party, except that Company may assign this Agreement to a third party in connection with a merger or sale of all or
substantially all of its assets relating to the Study Drug, and Company may delegate its obligations or assign its rights under
this Agreement to a contractor, provided that Company remains liable for the performance of all delegated obligations and written
notice is provided to Institution. Any unauthorized attempted assignment shall be null and void and of no force or effect.

 

		9.4	Governing
Law. This Agreement is governed by the laws of the State of California without regard to its conflict of law provisions.

 

		9.5	No Implied
Right or License. No implied right or license is granted under this Agreement by either Party except those specifically set
forth herein. Nothing contained in this Agreement shall impose an obligation of exclusivity on one Party to the other Party.

 

		9.6	Severability.
If any provision of this Agreement is held to be unenforceable for any reason, that unenforceability shall not affect the enforceability
of any other provision of this Agreement. The Parties shall negotiate in good faith to substitute an enforceable provision with
similar terms.

 

		9.7	Entire Agreement.
This Agreement, and any Exhibits thereto, constitutes the entire agreement between the Parties and supersedes all prior agreements
and understandings relating to its subject matter. This Agreement, and any Exhibits thereto, may not be altered, modified or waived
in whole or part except in writing signed by duly authorized representatives of both Parties. In the event of a conflict between
the provisions of this Agreement and Exhibit A or other Study document, the provisions of this Agreement will govern.

 

		9.8	Counterparts.
This Agreement may be executed in counterparts, via facsimile or .pdf file and each of which shall be deemed to be an original,
but all of which constitute one instrument.

 

		9.9	Force Maieure.
If either Party’s performance of this Agreement or Study is prevented, restricted or delayed, either totally or in part, for reasons
beyond the affected Party’s reasonable control and is not due to the action or inaction of such Party, the affected Party will,
upon giving notice to the other Party, be excused from such performance to the extent of such prevention, restriction or delay;
provided, that the affected Party will use reasonable efforts to avoid or remove such causes of non-performance and will continue
its performance whenever such causes are removed. For purposes of this Section, a lack of funds shall not be considered a cause
beyond the reasonable control of the Parties.

 

    	12

    	 

    

 

		9.10 	Order of Precedence.
The terms of this Agreement and the Protocol shall take precedence over other documentation, including but not limited to the Informed
Consent in the interpretation and resolution of disputes concerning this Study. In the event that there is a conflict between the
terms of the Protocol and the terms of this Agreement, the terms of this Agreement will govern with respect to legal contract terms,
but the Protocol will govern with respect to the scientific/clinical conduct of the Study.

 

		9.11 	Notices.
All notices required or permitted hereunder must be in writing, and will be deemed to be effective only when delivered personally
or transmitted by email or facsimile, or sent by certified or registered mail, postage prepaid, return receipt requested, and addressed
to the address set out above, with the following additional information:

 

To
the Institution:

 

UCSD
OCGA 

 

Attn:
Contract Officer 

 

Torrey
Pines Center North 

 

9500
Gilman Drive #0934 

 

La
Jolla, CA 92093-0934

 

With
a codv to the Principal Investigator:

 

	Contact person:	Dr. Rohit Loomba
	 	 
	 	Associate Professor of Clinical Medicine
	 	 
	Fax number:	(858) 534-0280
	 	 
	E-mail:	roloomba@ucsd.edu

 

To
the Company:

 

	Contact person:	Allen Baharaff, CEO
	 	 
	Fax number:	+972-3-693-8447
	 	 
	E-mail:	ab@galmedpharma.com

 

or
at such other address, facsimile number or e-mail as a Party shall have given a written notice of pursuant hereto. Notices shall
be deemed properly and effectively served two (or five if sent by airmail) working days after posting and on the first business
day (at the receiving end) following transmission, if transmitted by hand, email or facsimile.

 

    	13

    	 

    

 

In
witness whereof, the Parties have caused this Agreement to be executed by their duly authorized representatives.

 

	COMPANY	 	 	 	 
	 	 	 	 	 
	By:	/s/
    Allen Baharaff	 	By:	 /s/ Maya Halpern
	 	 	 	 	 
	Print
    Name: 	Allen
    Baharaff	 	Print
    Name:	    Maya Halpern
	 	 	 	 	 
	Title:	CEO	 	Title:	CMO
	 	 	 	 	 
	Date:
    	2/8/2015	 	Date:	2/8/2015

 

	THE REGENTS OF THE UNIVERSITY OF CALIFORNIA
	 	 	 
	By:	/s/ Rachel sievert		 
	 	 	 
	Print
    Name: 	Rachel
    Sievert	 
	 	 	 
	Title:
    	Contract
    Officer 	 
	 	 	 
	Date:
    	2/5/2015
    	 

 

WHILE NOT A PARTY TO THIS AGREEMENT I HAVE READ THE AGREEMENT
AND ACKNOWLEDGE MY RESPONSIBILITIES AS THE PRINCIPAL INVESTIGATOR:

 

	/s/ Rohit Loomba	
	 
	Name: Dr. Rohit Loomba 
	 
	Title: Principal Investigator	 
	 	 	 
	Enclosures: 	Exhibit A: Protocol	 
	 	 	 
	 	Exhibit B: Payment Schedule 	 
	 	 	 
	 	Exhibit C: Budget	 

 

    	14

    	 

    

 

Exhibit
A 

 

[Protocol]

 

    	15

    	 

    

 

CLINICAL RESEARCH PROTOCOL

UNIVERSITY OF CALIFORNIA SAN DIEGO

DEPARMENT OF MEDICINE

DIVISION OF GASTROENTEROLOGY

 

	DATE:
    February 4, 2015	CLINICAL
    PROTOCOL NO:
	 	IND
    NO:

 

TITLE:
Aramchol versus placebo in the treatment of HIV-associated nonalcoholic fatty liver disease and lipodystrophy: A randomized,
double-blinded, allocation-concealed, placebo-controlled clinical trial

 

ABBREVIATED TITLE: Aramchol for HIV-associated nonalcoholic
fatty liver disease and lipodystrophy

 

IDENTIFYING WORDS: Aramchol, HIV, Lipodystrophy, Nonalcoholic
fatty liver disease, Obesity, Fatty Liver, Cirrhosis

 

PRINCIPAL INVESTIGATOR:

Rohit Loomba, MD, MHSc

 

ASSOCIATE INVESTIGATORS:

Ahilan Arulanandan, MD

Irine Vodkin, MD

Lisa Richards, NP

Claude Sirlin, MD

 

ESTIMATED DURATION OF STUDY: 16 WEEKS

 

NUMBER AND TYPE OF PATIENTS: Up to 50 patients with HIV,
ages above 18 years, both male and female who have NAFLD.

 

	SUBJECTS
    OF STUDY:	Number	Sex	Age
    Range
	 	 	 	 
	Patients	50	Male
    & Female	Above
    18 years
	Volunteers	None	 	 

 

    	 

    	 

    

 

PROJECT
USES IONIZING RADIATION: No 

PROJECT
USES “DURABLE POWER OF ATTORNEY”: No 

OFF-SITE
PROJECT: No 

MULTI-INSTITUTIONAL
PROJECT: No

 

    	 

    	 

    

 

Abstract

 

One
in every three adult Americans is afflicted by nonalcoholic fatty liver disease (NAFLD). NAFLD represents a spectrum of diseases
ranging from simple steatosis to nonalcoholic steatohepatitis (NASH), the progressive form of liver disease that can lead to cirrhosis
and liver-related mortality in persons who drink little or no alcohol. NASH represents the more severe end of this spectrum and
is characterized by steatosis, ballooning degeneration and lobular inflammation with or without fibrosis. NASH can progress to
hepatocellular carcinoma and liver-related death. The etiology of NASH is not completely understood, but it is often associated
with obesity, type 2 diabetes, hyperlipidemia and insulin resistance. Lipotoxicity, insulin resistance and oxidative stress
appear to be central to the pathogenesis of NASH. Currently, there is no FDA approved treatment for NAFLD or NASH, although weight
loss and exercise have demonstrated some benefit.

 

Among
patients with human immunodeficiency virus (HIV) infection, liver disease is among the leading causes of death. Progression of
liver disease in HIV is linked to metabolic derangements associated with hepatic steatosis. Till date there are no therapies for
the treatment of HIV-associated NAFLD and this area remains understudied with paucity of clinical trials. Recent studies have shown
that Aramchol, a fatty acid-bile acid conjugate, may improve serum alanine (ALT) and aspartate (AST) aminotransferase levels and
liver fat content on magnetic resonance spectroscopy (MRS) in Israeli patients with primary NAFLD. Aramchol inhibits stearoyl coenzyme
A desaturase 1 (SCD1) activity, a key enzyme in fatty acid synthesis. This inhibition may lead to increase in fatty acid oxidation
and reduce hepatic steatosis. In addition, it activates cholesterol efflux by stimulating adenosine triphosphate-binding cassette
transporter Al, a pan-cellular cholesterol export pump, and thereby, reducing hepatic steatosis and reducing atherosclerosis.

 

Aramchol
has not been studied in HIV-associated NAFLD. In this study, we propose to treat 50 patients with HIV and NAFLD with either Aramchol
or placebo for 16 weeks. After an initial evaluation for magnetic resonance imaging (MRI) liver fat distribution and dual energy
x-ray absorptiometry (DEXA) whole body fat, patients will receive either 600 mg/day of Aramchol or placebo. Patients will be monitored
at regular intervals for symptoms of liver disease, side effects of Aramchol and serum biochemical and metabolic indices. After
16 weeks, patients will have a repeat medical evaluation, liver MRI, and DEXA scan. Pre and post treatment MRI-derived liver fat
content and total body fat via DEXA will be compared. The primary end point of successful therapy will be improvement in hepatic
steatosis measured by MRI. Secondary end points will be improvement in total body fat, metabolic profile, and liver biochemistry.

 

    	 

    	 

    

 

Background

 

Nonalcoholic
fatty liver disease is the most common cause of chronic liver disease in the United States and it affects almost 30% of adults
in Western countries.1-3 With climbing obesity rates and more sedentary patient populations, the prevalence of NAFLD
is increasing worldwide and is becoming the predominant cause of chronic liver disease in parts of the world.4 NAFLD
represents a spectrum of diseases ranging from simple steatosis to nonalcoholic steatohepatitis (NASH), the progressive form of
fatty liver disease that can lead to cirrhosis and liver-related mortality in persons who drink little or no alcohol. NASH represents
the more severe end of this spectrum and is characterized by steatosis, ballooning degeneration and lobular inflammation with or
without fibrosis.5 Long-term risks of NASH include cirrhosis, hepatocellular carcinoma and end stage liver disease requiring
liver transplantation.6, 7

 

The
majority of patients with NAFLD are asymptomatic. Clinical history, laboratory and radiological investigations are useful in excluding
other causes of liver disease but do not permit an accurate diagnosis of NAFLD8. The diagnosis is usually suspected
in a patient with elevated serum alanine aminotransferase (ALT) who drinks no or minimal amounts of alcohol, who has evidence
of increased fat in the liver by ultrasound, CT scan or MRI, and who tests negative for the common causes of chronic liver disease.
Liver biopsy is the gold standard for the accurate diagnosis of NAFLD, but inherent risks of biopsy such as pain, bleeding, and
bacteremia make interval biopsies impractical in the management of this disease.

 

Recently,
innovative imaging tools have demonstrated potential to change how we study and monitor liver disease.9, 10 An advanced
magnetic resonance imaging based biomarker, the proton-density fat fraction (MRI-PDFF), has been validated as a precise and accurate
method of quantifying liver fat in NAFLD.11-15 This provides a unique opportunity to research the progression
and treatment of NAFLD without invasive procedures.

 

A
subset of patients with NAFLD that have not been extensively studied are those infected with human immunodeficiency virus (HIV).
Among patients with HIV infection, liver disease is one of the leading causes of death.16 Progression of liver disease
in HIV is linked to metabolic derangements associated with hepatic steatosis. Till date there are no therapies for the treatment
of HIV-associated NAFLD and this area remains understudied with paucity of clinical trials.

 

    	 

    	 

    

 

Medical Therapy for NAFLD in HIV patients:

 

Currently,
there is no FDA approved treatment for NAFLD or NASH. Additionally, there have been no significant clinical trials for HIV patients
with NAFLD and there are no approved treatment options. Current treatments for NAFLD are limited to weight loss and exercise, but
this is often difficult to adhere to for many patients. Therapeutic agents are being investigated but the trials thus far including
ursodeoxycholic acid, metformin, clofibrate, betaine, N-acetylcystine, atorvastatin, and orlistat have demonstrated very limited
benefit. Pioglitazone has been shown to be somewhat beneficial reducing liver fat but weight gain due to increased adiposity is
harmful in the long run. Additionally, none of these trials were for HIV-infected patients. Further therapies for NAFLD and NASH
are still under investigation.

 

Aramchol:

 

Aramchol,
also known as arachidyl amido cholanoic acid, is a fatty acid bile acid conjugate (FABAC) that was created by conjugating 2 natural
components, cholic acid and arachidic acid, through a stable amide bond. Aramchol inhibits stearoyl coenzyme A desaturase 1 (SCD1),
a key enzyme in fatty acid synthesis. SCD1 is an endoplasmic reticulum enzyme that catalyzes the rate-limiting step in the biosynthesis
of monounsaturated fatty acids from saturated fatty acids. Inhibiting SCD1 decreases synthesis and increases beta-oxidation of
fatty acids, causing decreased storage of fatty acids. SCD1 has been demonstrated to be tightly associated with control of lipid
homeostasis and body weight regulation. Within in vitro models, Aramchol has demonstrated significant (70% to 83%) inhibition of
the SCD1 activity.17 Additionally, Aramchol increases cholesterol efflux by stimulating the adenosine triphosphate-binding
cassette transporter A1. This has demonstrated an anti-atherogenic effect in animal models with increased fecal sterol output and
decreased plasma cholesterol levels in mice.18

 

    	 

    	 

    

 

 

Aramchol and the liver:

 

The
three proposed mechanisms of Aramchol’s effects on liver fat are 1) reducing de novo fatty acid synthesis, 2) reducing SCD1
activity, and 3) increasing beta-oxidation of fatty acids.19 In a 2003 study by Gilat,20 Aramchol significantly
reduced hepatic fat content in animals (rats, hamsters, and mice) with a high-fat diet model. These animals gained total weight
although they had less fat deposition in their liver, measured histologically, which suggests a redistribution of fat deposition
in the body. The authors hypothesized that redistribution of liver fat to adipose tissue was the most likely explanation, but the
mechanism was unknown.

 

However,
additional animal studies demonstrated that FABACs have specific metabolic effects as they increase cholesterol efflux from fibroblasts
and may not affect the import of dietary fat.21 In addition, preliminary data indicate that Aramchol may increase fatty
acid catabolism in the liver by acting as a peroxisome proliferator-activated receptor agonist.22, 23
These studies have proposed possible mechanisms of FABACs but further study of fatty acid and triglyceride synthesis vs.
degradation in the liver are needed to identify the in vivo mechanisms of Aramchol.

 

Effect of Aramchol on NAFLD and total body fat:

 

A
recent study by Safadi24 demonstrated that Aramchol significantly reduced liver fat content, measured by magnetic resonance
sprectroscopy (MRS), in 60 Israeli NAFLD patients after 12 weeks of 300mg Aramchol per day. Their trial gave patients either 100mg
or 300mg of Aramchol or placebo (3 groups; n = 20/group) once daily for 12 weeks. Their primary finding was that liver fat content
decreased by 12.57% (+/- 22.14% standard deviation) in the high dose Aramchol group. There were no serious or drug-related adverse
events in the study and the authors proposed that Aramchol might be used for the treatment of fatty liver disease. Aramchol has
not yet been studied in HIV-associated NAFLD.

 

Side effects of Aramchol:

 

Patient
trials with Aramchol are limited to the Safadi study,24 but the clinical trial demonstrated no significant adverse events
in the 12-week treatment period for 58 patients that underwent the trial. The few adverse events were mild (abdominal pain, back
pain, constipation) and did not cause anyone
to drop out of the trial. There were no severe adverse effects. The previous studies on Aramchol were done in animal models.

 

    	 

    	 

    

 

Hypothesis

 

It
is well known that MRI is superior to CT in qualitative and quantitative assessment of liver fat and may be a more robust measure
of changes during therapy25. Using MRI to detect changes in liver fat content, we plan to test the following hypotheses
via this randomized-controlled trial.

 

Hypothesis
1: Aramchol at 600 mg orally daily for 16 weeks is superior to placebo in improving liver fat content assessed by MRI in patients
with HIV-associated NAFLD.

 

Hypothesis
2: Aramchol at 600 mg orally daily for 16 weeks is superior to placebo in improving total body fat content assessed by DEXA in
patients with HIV-associated NAFLD.

 

Specific Aims

 

We
plan to conduct a randomized, double-blinded, placebo-controlled clinical trial to examine the efficacy of Aramchol at 600 mg orally
daily versus identical placebo given over 16 weeks to improve HIV-associated hepatic steatosis as measured by a validated and accurate
magnetic resonance imaging (MRI)-based technique.

 

In
this study, we propose to randomize up to 50 patients with HIV-associated NAFLD to either Aramchol or placebo for 16 weeks. We
plan to enroll a total of 55 patients, expecting some drop outs prior to randomization. After an initial evaluation for insulin
sensitivity, liver fat measurement by MRI, and total body fat content by DEXA, patients will be randomized to receive either Aramchol
600 mg or placebo orally for 16 weeks. Patients will be monitored at regular intervals for symptoms of liver disease, side effects
of medication, and serum biochemical and metabolic indices. At the end of 16 weeks, patients will have a repeat medical evaluation,
liver fat measurement, and total body fat content measurement.

 

    	 

    	 

    

 

Pre
and post treatment liver fat by MRI, ALT/AST, HbAlc, CRP, insulin sensitivity, and DEXA for whole body fat will be compared. The
primary end point of successful therapy will be improvement
in liver fat by MRI. Secondary end points will be improvement in insulin sensitivity and liver biochemistry. As this is a pilot
study, we would also like to look at changes in liver histology if funds permit, which would guide the design of future studies
with Aramchol to examine histologic improvement in patients with NAFLD.

 

Primary objectives:

 

		1.	To
examine the efficacy of aramchol 600 mg orally daily versus placebo in improving hepatic steatosis assessed by magnetic resonance
imaging in patients with HIV-associated NAFLD

 

Secondary objectives:

 

		1.	To examine the efficacy
of aramchol 600 mg orally daily versus placebo in improving total body fat content assessed by DEXA in patients with HIV-associated
NAFLD

 

		2.	To examine the efficacy
of aramchol 600 mg orally daily versus placebo in improving serum alanine aminotransferase (ALT) and aspartate aminotransferase
(AST) levels in patients with HIV-associated NAFLD

 

Exploratory objectives:

 

		1.	To
examine the efficacy of aramchol in improving imaging-based biomarkers associated with changes in NAFLD

 

Protocol

 

This
is a randomized, double-blinded, placebo-controlled clinical trial to examine the efficacy of Aramchol at 600 mg orally daily versus
identical placebo given over 16 weeks to improve HIV-associated hepatic steatosis as measured by a validated and accurate magnetic
resonance imaging (MRI)-based technique. 50 subjects will be randomized, monitored at regular intervals for the 16 weeks, and will
be invited to continue participating in the study for an additional 5 years of annual monitoring.

 

    	 

    	 

    

 

Inclusion criteria

 

		1.	Age at entry at least
18 years.

 

		2.	Serum alanine (ALT)
or aspartate (AST) aminotransferase activities that are above the upper limits of normal. 19 or more in women and 30 or more in
men.

 

		1.	An
                                         MRI-determined fat fraction classification threshold (>5%) will be used to
                                         confirm subjects. MR examinations will include four research sequences (three imaging
                                         sequences and one single-voxel spectroscopy sequence) that have been developed and refined
                                         by Dr. Sirlin, allowing for the measurement of liver fat fraction and newer candidate
                                         MR biomarkers for future NAFLD studies. MR examinations will last 20-30 minutes and will
                                         be performed without contrast agents. Subjects will be scanned at 1.5T. To assess
                                         sequence repeatability, two sequences per subject, block randomized, will be run three
                                         times. For MR elastography, MR imaging will be done which will include placing a vibrating
                                         paddle over the abdomen while images are obtained. A comprehensive screening questionnaire
                                         will be utilized prior to subjects having an MRI. Experienced research MR technologists
                                         will perform MR examinations under the supervision of Dr. Sirlin.

 

		3.	History
                                         of HIV documented by a previously positive HIV Elisa or PCR.

 

		4.	Written
                                         informed consent.

 

Exclusion criteria

 

		1.	Evidence
                                         of another form of liver disease.

 

		a.	Hepatitis
B as defined as presence of hepatitis B surface antigen (HBsAg).

 

		b.	Hepatitis
C as defined by presence of hepatitis C virus (HCV) RNA in serum.

 

		c.	Autoimmune
                                                                                                                                           hepatitis as defined by anti-nuclear antibody (ANA) of 1:160 or greater and liver histology consistent with autoimmune
                                                                                                                                           hepatitis or previous response to immunosuppressive therapy.

 

		d.	Autoimmune
cholestatic liver disorders as defined by elevation of alkaline phosphatase and anti-mitochondrial antibody of greater than 1:80
or liver histology consistent with primary
biliary cirrhosis or elevation of alkaline phosphatase and liver histology consistent with sclerosing cholangitis.

 

    	 

    	 

    

 

		e.	Wilson
disease as defined by ceruloplasmin below the limits of normal and liver histology consistent with Wilson disease.

 

		f.	Alpha-1-antitrypsin
deficiency as defined by alpha-1-antitrypsin level less than normal and liver histology consistent with alpha-1-antitrypsin deficiency.

 

		g.	Hemochromatosis
as defined by presence of 3+ or 4+ stainable iron on liver biopsy and homozygosity for C282Y or compound heterozygosity for C282Y/H63D.

 

		h.	Drug-induced
liver disease as defined on the basis of typical exposure and history.

 

		i.	Bile
duct obstruction as shown by imaging studies.

 

		2.	History
of excess alcohol ingestion, averaging more than 30 gm/day (3 drinks per day) in the previous 10 years, or history of alcohol
intake averaging greater than 10 gm/day (1 drink per day or 7 drinks per week) in the previous one year.

 

		3.	Contraindications
to MRI:

 

		a.	The subject has any
                                                                              contraindication to MR imaging, such as patients with pacemakers, metallic cardiac valves, magnetic material such as surgical
                                                                              clips, implanted electronic infusion pumps or other conditions that would preclude proximity to a strong magnetic
                                                                              field.

 

		b.	The
subject has a history of extreme claustrophobia

 

		c.	The
subject cannot fit inside the MR scanner cavity

 

		4.	Decompensated
liver disease, Child-Pugh score greater than or equal to 7 points

 

		5.	History of
                                                                             gastrointestinal bypass surgery or ingestion of drugs known to produce hepatic steatosis including corticosteroids,
                                                                             high-dose estrogens, methotrexate, tetracycline or amiodarone in the previous 6 months.

 

		6.	Recent
use (within the last 90 days) of medications to treat hepatic steatosis such as pioglotazone (or medications in the same class)
or vitamin E.

 

		7.	Use
of Aramchol or agents in the same class.

 

		8.	Recent
use (within the last 90 days) of insulin as an outpatient for management of diabetes.

 

		9.	HbAlc
> 9 or uncontrolled diabetes.

 

    	 

    	 

    

 

		10.	Significant
systemic or major illnesses other than liver disease, including congestive heart failure, coronary artery disease, cerebrovascular
disease, pulmonary disease with hypoxia, renal
failure, organ transplantation, serious psychiatric disease, malignancy that, in the opinion of the investigator would preclude
treatment with Aramchol and adequate follow up.

 

		11.	Active
substance abuse, such as alcohol, inhaled or injection drugs within the previous one year.

 

		12.	Pregnancy
or inability to practice adequate contraception in women of childbearing potential.

 

		13.	Evidence
of hepatocellular carcinoma: alpha-fetoprotein levels greater than 200 ng/ml and/or liver mass on imaging study that is suggestive
of liver cancer.

 

		14.	Advanced
HIV defined as CD4 count of less than 100, and/or life expectancy of less than 2 years.

 

		15.	Any
other condition, which, in the opinion of the investigators would impede competence or compliance or possibility hinder completion
of the study.

 

Initial Evaluation

 

Patients
will be initially screened in the UCSD NAFLD research center clinic with history, physical examination, review of outside medical
records (including HIV status) and routine blood tests. Alcohol history will be assessed in the medical interview, and the lifetime
alcohol consumption will be estimated by standardized questionnaires. All patients will be asked to stop any medication being used
for their liver disease, including herbal medications and vitamins. Only those meeting all inclusion criteria and avoiding all
exclusion criteria will be invited to participate in the study. After the initial visit, those who meet all eligibility criteria
and have no exclusion criteria will undergo more thorough evaluation with liver MRI and DEXA scan for total body fat. Patients
with MRI-PDFF > 5% will be invited to participate in the study.

 

Following
an information session during which the primary consent document, a genetic sampling consent document and the UCSD HIPPA forms
are reviewed, discussed and signed the following tests and procedures will be done shortly before starting therapy at the UCSD
Medical Center, Hillcrest. If they have already been completed elsewhere as part of the patient’s original diagnostic evaluation
at the referring clinic they do not need to be repeated.

 

    	 

    	 

    

 

The following
evaluation will be done shortly before starting therapy.

 

		1.	History
and physical examination.

 

		2.	Blood tests.
                                                                                                                                          These include complete blood count (CBC with differential and platelet count), prothrombin time, alanine
                                                                                                                                          aminotransferase (ALT), aspartate aminotransferase (AST), direct and total serum bilirubin, alkaline phosphatase, albumin,
                                                                                                                                          total protein, fasting plasma glucose, hemoglobin Alc, , creatinine phosphokinase (CPK), sodium, chloride, potassium,
                                                                                                                                          bicarbonate, blood urea nitrogen, creatinine, uric acid, calcium, phosphorus, ferritin, antinuclear antibody, thyroid
                                                                                                                                          stimulating hormone (TSH), HBsAg, anti HBs, anti HAV, anti HCV, ceruloplasmin, alpha-1-antitrypsin, fasting insulin,
                                                                                                                                          C-reactive protein, Elisa HIV test, CD4 count, CK-18 level.

 

		3.	Routine
urinalysis.

 

		4.	Chest
x-ray and electrocardiogram will be done if they have not been done in the previous year.

 

		5.	Detailed
metabolic characterization

 

		a.	Oral
glucose tolerance test (OGTT): after an overnight fast, subjects will be given 75 grams oral glucose solution. Plasma glucose,
insulin levels, and free fatty acids will be obtained from blood samples drawn at 0 and 120 minutes after the oral glucose load
26.

 

		b.	Lipid
profiles. Levels of fasting triglyceride, total cholesterol, LDL cholesterol, HDL cholesterol, free fatty acid will be obtained
after an overnight fast.

 

		6.	Estimation
of body fat and fat distribution

 

		a.	Body
Mass Index (BMI): For each patient, weight (kg) and height (m) will be recorded with empty bowel and bladder. BMI is calculated
by the formula: BMI = weight (kg)/height (m)2.

 

		b.	A
trained investigator will measure waist/hip ratio at the same time as other measures are taken.

 

		c.	DEXA
scan for whole body fat

 

		d.	Magnetic
resonance imaging (MRI) of the liver: MRI is done to evaluate liver size and estimate liver fat content.

 

		e.	MR
Elastography (MRE) of the liver: MRE will be done to evaluate changes in liver stiffness before and after therapy if additional
funding is available.

 

    	 

    	 

    

 

Treatment

 

After
the initial evaluation, patients who continue to fulfill all inclusion criteria will be randomized to receive either Aramchol 600
mg/day (1 tablet) or placebo (1 tablet) orally for a total of 16 weeks. Medication diaries and a count of residual tablets will
monitor patient compliance at scheduled visits. Patients will be interviewed and examined by an investigator and have blood draw
at weeks 0, 4, 8, and 16 of treatment. In addition, an ARFI ultrasound imaging examination of the abdomen will be performed. At
each visit particular attention will be paid to symptoms associated with the possible side effects of Aramchol and patients will
complete a standardized symptom scale.

 

Labs
to be checked during the treatment phase include:

 

		i.	Urinalysis
will be done with extended blood tests.

 

		ii.	Routine
                                         blood tests (Fasting specimens): CD4 counts, Complete metabolic panel (CMP) and protime/INR.
                                         In addition, research blood will be taken for cytokine levels and changes in lipid biomarkers.

 

		iii.	Extended
                                         blood tests (Fasting specimens): Insulin, plasma glucose, lipid profile (cholesterol,
                                         triglyceride, LDL and HDL), free fatty acids (FFA), and creatinephosphokinase (CPK),
                                         and glycosylated hemoglobin (HbAlc). In addition, research blood will be taken for cytokine
                                         levels and changes in lipid biomarkers.

 

		iv.	Stool
and urine sample will be collected for analysis of changes related to the study drug.

 

Post-Treatment
Phase:

 

At
the end of the study, patients will undergo the same evaluation as listed under the initial evaluation as above, following which
treatment will be stopped. Repeat MRI of the liver and full body DEXA scan will also be performed at study conclusion. It is not
possible to predict the outcome of this study, but if Aramchol appears to have a significant effect on liver fat by MRI and/or
total body fat by DEXA, we will likely develop a follow-up protocol to assess long-term therapy with Aramchol in a large multicenter
study to examine the efficacy in improving liver histology.

 

    	 

    	 

    

 

Annual
follow up visits:

 

Patients
will be offered annual follow up visits if they choose to attend. At the annual follow up visit, subjects will undergo a detailed
history and physical examination. Standardized questionnaires Skinner Lifetime Drinking History in addition to the Alcohol Use
Disorders Identification Tests (AUDIT) will be used. A urine pregnancy test will be performed for all women of childbearing age.
Women who have had hysterectomies are excluded from pregnancy testing. If the pregnancy test is positive, the patient will not
be enrolled in the study. The patient will undergo full body DEXA scan, magnetic resonance elastography, and a magnetic resonance
imaging for liver stiffness calculation and hepatic fat fraction, respectively.

 

	Table I. Study design
	Week	0	4	8	16
	Routine blood tests	X	X	X	X
	Serum/plasma	X	X	X	X
	Extended blood tests	X	 	X	X
	StooI/urine/DNA	X	 	X	X
	Physical	X	 	X	X
	DEXA	X	 	 	X
	OGTT	X	 	 	X
	MRI-PDFF	X	 	 	X
	MRE*	X	 	 	X
	Aramchol VS placebo	600mg/d	600mg/d	600mg/d	Stop

*additional funding permitting

 

    	 

    	 

    

 

Assessment of Response and Statistical Analyses

 

The
primary outcome of this study will be improvement in hepatic steatosis by liver MRI. Statistical analyses will compare liver fat
improvement between the treatments versus placebo- arms. It is not possible to predict what the spontaneous or therapeutic response
rate will be. Thus, we predict that the spontaneous
improvement rate would be zero to less than 1%. The sample size is chosen to avoid exposure of a large number of patients to 16
weeks of therapy and extensive evaluation if the study medication has no effect, but also to avoid missing a reasonably significant
beneficial effect. We will require a sample size of 22 patients in each arm to have a power 90% (or higher) with a p of 0.05. We
expect that Aramchol therapy group would have at least 6% reduction in liver fat compared to baseline as compared to 1% or less
improvement in the placebo group. These estimates are also based upon our recent trial using MRJ-PDFF as an accurate and reproducible
marker of hepatic steatosis.12 We expect to enroll up to 55 patients in this study and randomize at least 50 of them
to either treatment or placebo arm for a full 16 weeks with follow up evaluations. Clinical trials of experimental medications
have had variable dropout rates. Our pilot studies of metformin had less than 9% dropouts, and all remaining patients underwent
follow up evaluation and liver biopsy. In the randomized-controlled trial of colesevelam versus placebo, we had a 10% drop rate.
Therefore, we expect less than a 10% drop out. Dropouts would be considered non-responders based upon intention to treat analysis.
A modified intention to treat analysis will be done in which we will exclude the patients who dropped out before getting the week
16 exit evaluation.

 

Secondary
outcomes will be assessed comparing pre-treatment to 16-weeks outcomes on therapy using parametric or non-parametric tests as indicated.
The major secondary outcomes to be evaluated are:

 

		1.	Total
body fat via DEXA scan

 

		2.	Serum
ALT and AST values.

 

		3.	Lipid
profiles.

 

We will compare
the changes in the mean difference in the MRI-PDFF determined fat fraction between the treatment arm and the placebo arm at the
co-localized region of interest. A two-tailed t-test would be utilized to compare the differences between the two groups. A two-tailed
p- value of less than 0.05 is considered statistically significant. We will also conduct segment-to-segment changes in liver fat
before and after treatment. We may perform internal validation by comparing MRI-PDFF with magnetic resonance spectroscopy between
the two treatment arms in selected cases.

 

    	 

    	 

    

 

Hazards and Discomforts

 

1.     The risks and discomforts of frequent phlebotomy. To
document changes in levels of biochemical markers of liver disease and to monitor the metabolic effects and toxicities of Aramchol,
frequent blood sampling will be required. Patients will have between 15 to 20 venipunctures during the period of evaluation, therapy
and follow up. Each venipuncture will remove 15 to 70 ml of blood. However, no more than 6 ml/kg will be drawn from any one person
during a four-week period. Blood collection by venipuncture is associated with mild discomfort, and the possibility of localized
bruising, phlebitis, or extravasation. The risk of infection or fainting is extremely small.

 

2.     The risks and discomforts of HIV testing. Patients
will sign a standard consent for HIV testing for this study.

 

3.     The
risks and discomforts of other tests.

 

		a)	MRI
of abdomen and liver. Patients will undergo two MRI examinations of the liver during this study. Each session will be completed
within 30 minutes. While serial MRI scanning is thought to be safe, the procedure may cause anxiety in some patients since current
equipment used at the Clinical Center uses a closed tube. Patients will be offered sedatives such as Valium if they express worry
about being in a closed space.

 

		b)	MRE
of abdomen and liver. MRE is a type of MR imaging where the images indicate tissue stiffness. MRE imaging involves placing a vibrating
paddle over the abdomen while images are being obtained. This is an FDA-approved procedure when used clinically, but is considered
to be investigational in this study. These vibrations are generally well tolerated by patients, but the vibrating paddle could
be uncomfortable to some subjects. If so, subjects will be instructed to tell the MR technologist if the vibrations become uncomfortable
and the MRE part of the examination will be discontinued.

 

    	 

    	 

    

 

		c)	Oral
glucose tolerance test (OGTT). There will be two OGTT’s during this protocol, one at the beginning and one after 16 weeks
of treatment with Aramchol. The purpose of this test is to assess insulin sensitivity, insulin secretion as well as free fatty
acid metabolism. The patients will have an intravenous catheter placed in the arm and be given 75mg of glucose as an oral solution.
Subjects occasionally complain of nausea and rarely may vomit and there is a small risk of rebound hypoglycemia. Repeat blood
draw will be done at 2 hours. Total amount of blood that will be drawn for glucose and insulin measurements during this test will
be 100 to 120 ml. No more than 6 ml/kg of blood will be drawn from any one person during a four-week period.

 

5. Risks and
hazards of Aramchol:

 

Patient
trials with Aramchol are limited to the Safadi study24, but the clinical trial demonstrated no significant adverse events
in the 12-week treatment period for 58 patients that underwent the trial. The few adverse events were mild (abdominal pain, back
pain, constipation) and did not cause anyone to drop out of the trial. There were no severe adverse effects. The previous studies
were done in animal models. Due to the paucity of clinical trials to evaluate side effects of Aramchol, we will encourage patients
to notify staff of any adverse reactions and we will monitor patients via physical exams and laboratory testing at regular intervals
to ensure patient safety.

 

Dosage modification
and discontinuation of Aramchol:

 

Patients
will be monitored for side effects and the toxicity will be ranked as Grades 1 to 4. We will use the common toxicity criteria
(CTC), version 4.0, for scoring adverse events during therapy. Specific scoring of toxicity for the major safety parameters to
be followed in this study is shown in Table II.
The criteria for grading leukocytes, platelets, prothrombin time, partial thromboplastin time, bilirubin, ALT, and AST are modified
slightly from the CTC version 4.0 because these factors are likely to be abnormal before therapy in patients with chronic liver
disease. An adverse event is defined as any adverse change from the patient’s baseline (pre-treatment)
condition. These include current illness during the course of the study, regardless of the illness being considered unrelated
to treatment.

 

    	 

    	 

    

 

Dose
modification of Aramchol: If any grade 2 adverse events (anemia,
elevated serum CPK, hypoglycemia, decrease in serum bicarbonate, elevation in liver transaminases, elevation in bilirubin, anorexia,
nausea, diarrhea) occur and persist on repeat testing for one week, Aramchol will be reduced from 600 mg daily to 300 mg daily
and the patient will be closely monitored. If the adverse event resolves and in retrospect is not believed to be due to Aramchol,
the drug will be restarted at the dose of 600 mg daily. If the adverse event recurs or persists for 2 weeks despite this dose
reduction, Aramchol will be stopped.

 

Discontinuation
of Aramchol: In this study, discontinuation of Aramchol will
be based upon the scoring of adverse events as shown in the table below. Factors that will lead to discontinuation of Aramchol
include pregnancy, any one of the grade 3 or 4 adverse events or any adverse event, which, in the opinion of the investigator,
places the patient at increased risk. Aramchol will not be restarted unless another cause for the abnormality or symptom is found.

 

Table II. Scoring of toxicity for dose modification

 

	Adverse events	1	2	3	4	5
	
        Allergic

        reaction
	
        Transient
        flushing or rash, drug fever <38 degrees C (<100.4 degrees

        F):

        intervention
        not indicated
	
        Intervention
        or

        infusion

        interruption

        indicated:

        responds

        promptly to

        symptomatic

        treatment
        (e.g.,

        antihistamines,

        NSAIDS,

        narcotics):

        prophylactic

        medications

        indicated
        for

        <=24 hrs
	
        Prolonged
        (e.g., not rapidly responsive to symptomatic medication and/or brief

        interruption
        of infusion); recurrence of symptoms following initial improvement; hospitalization indicated for clinical sequelae (e.g.. renal
        impairment, pulmonary infiltrates)
	
        Life threatening

        consequences:

        urgent

        intervention

        indicate
	Death
	Anaphylaxis	 	 	Symptomatic	Life-threatening	Death

 

    	 

    	 

    

 

	 	 	 	
        bronchospasm,

        with or without

        urticaria;

        parenteral

        intervention

        indicated;
        allergy-

        related

        edema/angioedema;

        hypoten
	
        consequences;

        urgent

        intervention

        indicated
	 
	Anorexia	Loss of appetite without alteration in eating habits	Oral intake altered without significant weight loss or malnutrition; oral nutritional supplements indicated	
        Associated
        with significant weight loss or malnutrition (e.g., inadequate oral caloric and/or fluid intake); tube

        feeding or
        TPN indicated
	
        Life-threatening

        consequences;

        urgent

        intervention

        indicated
	Death
	Nausea	Loss of appetite without alteration in eating habits	
        Oral
        intake

        decreased

        without

        significant

        weight
        loss,

        dehydration
        or

        malnutrition
	Inadequate oral caloric or fluid intake; tube feeding, TPN, or hospitalization indicated	-	-
	Diarrhea	Increase of <4 stools per day over baseline; mild increase in ostomy output compared to baseline	Increase of 4 - 6 stools per day over baseline; moderate increase in ostomy output compared to baseline	
        Increase
        of >=7 stools per day over baseline; incontinence; hospitalization indicated; severe increase in ostomy

        output compared
        to baseline; limiting self care ADL
	
        Life-threatening

        consequences;

        urgent

        intervention

        indicated
	Death
	Fatigue	Fatigue relieved by rest	Fatigue not relieved by rest; limiting instrumental ADL	Fatigue not relieved by rest, limiting self care ADL	-	-
	Anemia	
        Hemoglobin
        (Hgb) <LLN - 10.0 g/dL: <LLN - 6.2 mmol/L;

        <LLN -
        100 g/L
	Hgb
    <10.0 - 8.0 g/dL: <6.2 - 4.9 mmol/L; <100-80g/	
        Hgb <8.0
        - 6.5 g/dL; <4.9 - 4.0 mmol/L; <80 - 65 g/L;

        transfusion

        indicated
	
        Life-threatening

        consequences;

        urgent

        intervention

        indicated
	Death
	
        Leukocytes

        (cell/mm3)
	3300 to 9600	2500 to 3300	2000 to 2500	1000-2000	<1000
	Platelet
    count per mm3	
         154,000
        to

        345,000
	
        70,000 to

        150.000
	50,000 to 70,000	
        10,000 to

        50.000
	<10,000
	
        Prothrombin

        time
	11.8 to 14.7	14.8 to 16	16.1 to 18	>18	-

 

    	 

    	 

    

 

	
        Activated

        partial

        thromboplastin
        time prolonged
	23.4 to 34.5	35.6 to 42	42 to 50	>50	-
	
        Alkaline

        phosphatase

        (U/L)
	37-116	117-250	401 - 400	401-600	>600
	
        ALT

        (U/L)
	Baseline-<1.5 times baseline	>200 and > 1.5 X baseline	300-400 and > 2 x baseline	401-800 and > 3x baseline	>800
	AST

        (U/L)
	Baseline-<1.5 times baseline	>200 and >1.5 X baseline	300-400 and > 2 x baseline	401-800 and > 3x baseline	>800
	Total
    Bilirubin (mg/dL)	0.1 to 1	1.1 to 1.5 and direct bilirubin >0.5	1.5 to 5 and direct bilirubin > 1	5.1 to 10	>10
	
        Albumin

        (g/dL)
	<LLN - 3 g/dL;

 <LLN - 30 g/L	<3 - 2 g/dL; <30

 -20 g/L	<2 g/dL; <20 g/L	
        Life-threatening

        consequences;

        urgent

        intervention

        indicated
	Death
	CPK
    increased (U/L)	>ULN - 2.5 x ULN	>2.5 x ULN - 5 x ULN	>5 x ULN - 10 x ULN	>10 x ULN	-
	
        Glucose

        (mg/dL)
	<LLN - 55 mg/dL; <LLN - 3.0 mmol/L	<55 - 40 mg/dL; <3.0 - 2.2 mmol/L	<40 - 30 mg/dL; <2.2 -1.7 mmol/L	<30 mg/dL; <1.7 mmol/L; life threatening consequences; seizures	Death
	
        Creatinine

        (mg/dL)
	
        Creatinine
        level increase of >0.3 mg/dL;

        creatinine
        1.5 - 2.0 x above baseline
	Creatinine 2-3 x above baseline	Creatinine >3 x baseline or >4.0 mg/dL; hospitalization indicated	
        Life-threatening

        consequences;

        dialysis

        indicate
	Death

 

Table II.
Scoring of toxicity for dose modification. Scoring of toxicity from the CTC Version 4.0,
with modifications for leukocytes, platelets, prothrombin time, partial thromboplastin time, ALT, AST and bilirubin. Normal ranges
for values at UCSD center are used.

  

Radiation
Safety

 

There
are no radiation studies in this protocol.

 

    	 

    	 

    

 

Data and Safety
Monitoring

 

The
principal and research coordinator of this protocol will monitor data and safety regularly at weekly meetings. These meetings
are separate from regular clinical rounds and consist of review of all
study patients including flow sheets of major safety and efficacy measurements. The rationale for not using an outside data and
safety monitoring committee is that this is a small, single center study using a medication that has been associated with few
severe side effects. All measurements and tests are well established in clinical medicine. Yearly reports are made to the UCSD
IRB regarding safety and efficacy.

 

Adverse Event Reporting

 

All
serious adverse events will be reported to the UCSD IRB and Galmed Pharmaceuticals within 7 days. Unexpected and related fatal
or life-threatening events will be reported within 48 hours and reports will be sent to the FDA, MEDWATCH program (telephone
1-800-FDA-1088; or via the Internet at www.fda.gov/medwatch/index.html
and Galmed Pharmaceuticals.

 

Informed Consents

 

All
consents will be stored in well-marked binders in locked file cabinets located in private offices at UCSD Medical center. Databases
with identifying information will be secure as they will be password protected and encrypted. Staff will be trained in HIPPA guidelines
and confidentiality issues.

 

Patient Privacy

 

All
data and study forms will be in secured locations (locked room or cabinet) and access is limited to study personnel. Subject names
are not used; instead a name code is assigned upon enrollment. Release of data to persons or organizations outside study personnel
will require written consent of the subject.

 

    	 

    	 

    

 

MRI
Findings:

 

Liver
MRI (Fat fraction) sequence does not provide detailed information regarding other organs within the abdomen cavity and is mainly
dedicated to the liver. However, if there are any unexpected findings on the liver MRI, we would utilize following protocol to
safeguard patient interest. A trained radiologist will read all MRI images. All abnormal findings will be communicated to the PI
by the radiologist. Dr. Loomba (PI) is a gastroenterologist and a transplant hepatologist at UCSD who routinely provides consultation
and management recommendations to other services regarding abnormal imaging findings. He would clinically correlate the significance
of any unexpected MRI findings. These findings will be discussed with the patient by the study investigator and a follow-up plan
will be established and documented. If the patient desires, this information will be released to the referring physician or any
provider or entity that the patient would like us to send the information. The PI would be available to discuss the findings with
the patient or their health care providers and assist in providing adequate follow-up. These abnormal findings would be systematically
recorded and reported at yearly renewals and in the final manuscript.

 

References

 

		1.	Browning
JD, Szczepaniak LS, Dobbins R, et al. Prevalence of hepatic steatosis in an urban population in the United States: impact of ethnicity.
Hepatology 2004;40:1387-95.

		2.	Zelber-Sagi
S, Nitzan-Kaluski D, Halpern Z, et al. Prevalence of primary non-alcoholic fatty liver disease in a population-based study and
its association with biochemical and anthropometric measures. Liver Int 2006;26:856-63.

		3.	Lazo
M, Clark JM. The epidemiology of nonalcoholic fatty liver disease: a global perspective. Semin Liver Dis 2008;28:339-50.

		4.	Loomba
R, Sanyal AJ. The global NAFLD epidemic. Nat Rev Gastroenterol Hepatol 2013;10:686- 90.

		5.	Loomba
R, Abraham M, Unalp A, et al. Association between diabetes, family history of diabetes, and risk of nonalcoholic steatohepatitis
and fibrosis. Hepatology 2012;56:943-51.

		6.	Saadeh
S, Younossi ZM, Remer EM, et al. The utility of radiological imaging in nonalcoholic fatty liver disease. Gastroenterology 2002;123:745-50.

		7.	Kleiner
DE, Brunt EM, Van Natta M, et al. Design and validation of a histological scoring system for nonalcoholic fatty liver disease.
Hepatology 2005;41:1313-21.

		8.	el-Hassan
AY, Ibrahim EM, al-Mulhim FA, et al. Fatty infiltration of the liver: analysis of prevalence, radiological and clinical features
and influence on patient management. Br J Radiol 1992;65:774-8.

		9.	Venkatesh
SK, Yin M, Ehman RL. Magnetic resonance elastography of liver: clinical applications. J Comput Assist Tomogr 2013;37:887-96.

		10.	Kim
D, Kim WR, Talwalkar JA, et al. Advanced fibrosis in nonalcoholic fatty liver disease: noninvasive assessment with MR elastography.
Radiology 2013;268:411-9.

 

    	 

    	 

    

 

		11.	Tang
A, Tan J, Sun M, et al. Nonalcoholic fatty liver disease: MR imaging of liver proton density fat fraction to assess hepatic steatosis.
Radiology 2013;267:422-31.

		12.	Noureddin
M, Lam J, Peterson MR, et al. Utility of magnetic resonance imaging versus histology for quantifying changes in liver fat in nonalcoholic
fatty liver disease trials. Hepatology 2013;58:1930-40.

		13.	Johnson BL,
                                                                               Schroeder ME, Wolfson T, et al. Effect of flip angle on the accuracy and repeatability of hepatic proton density fat
                                                                               fraction estimation by complex data-based, Tl-independent, T2*- corrected, spectrum-modeled MRI. J Magn Reson Imaging
                                                                               2014;39:440-7.

		14.	Hines
CD, Frydrychowicz A, Hamilton G, et al. T(l) independent, T(2) (*) corrected chemical shift based fat-water separation with multi-peak
fat spectral modeling is an accurate and precise measure of hepatic steatosis. J Magn Reson Imaging 2011;33:873-81.

		15.	Meisamy
S, Hines CD, Hamilton G, et al. Quantification of hepatic steatosis with Tl-independent, T2-corrected MR imaging with spectral
modeling of fat: blinded comparison with MR spectroscopy. Radiology 2011;258:767-75.

		16.	Weber
R, Sabin CA, Friis-Møller N, et al. Liver-related deaths in persons infected with the human immunodeficiency virus: the D:A:D
study. Arch Intern Med 2006;166:1632-41.

		17.	Dobrzyn
A, Ntambi JM. Stearoyl-CoA desaturase as a new drug target for obesity treatment. Obes Rev 2005;6:169-74.

		18.	Leikin-Frenkel
A, Gonen A, Shaish A, et al. Fatty acid bile acid conjugate inhibits hepatic stearoyl coenzyme A desaturase and is non-atherogenic.
Arch Med Res 2010;41:397-404.

		19.	Gilat T,
                                                                               Somjen GJ, Mazur Y, et al. Fatty acid bile acid conjugates (FABACs)—new molecules for the prevention of cholesterol
                                                                               crystallisation in bile. Gut 2001;48:75-9.

		20.	Konikoff
FM, Leikin-Frenkel A, Goldiner I, et al. Biliary and systemic effects of fatty acid bile acid conjugates. Eur J Gastroenterol
Hepatol 2003;15:649-55.

		21.	Goldiner
I, van der Velde AE, Vandenberghe KE, et al. ABCAl-dependent but apoA-l- independent cholesterol efflux mediated by fatty acid-bile
acid conjugates (FABACs). Biochem J 2006;396:529-36.

		22.	Leikin-Frenkel
A, Parini P, Konikoff FM, et al. Hypocholesterolemic effects of fatty acid bile acid conjugates (FABACs) in mice. Arch Biochem
Biophys 2008;471:63-71.

		23.	Gonen
A, Shaish A, Leikin-Frenkel A, et al. Fatty acid bile acid conjugates inhibit atherosclerosis in the C57BL/6 mouse model. Pathobiology
2002;70:215-8.

		24.	Safadi
R, Konikoff FM, Mahamid M, et al. The Fatty Acid-Bile Acid Conjugate Aramchol Reduces Liver Fat Content in Patients With Nonalcoholic
Fatty Liver Disease. Clin Gastroenterol Hepatol 2014.

		25.	Reeder
SB, Cruite I, Hamilton G, et al. Quantitative assessment of liver fat with magnetic resonance imaging and spectroscopy. J Magn
Reson Imaging 2011;34:729-49.

		26.	World
Health Organization: Diabetes Mellitus: Report of a WHO study Group, Geneva, World Health Organization, 1985.

 

    	 

    	 

    

 

Exhibit
B 

 

Payment
Schedule

 

The
Parties agree that this Payment Schedule includes all Study-related costs, as referenced in the Protocol. Institution’s sole payee
for all services under this Agreement is The Regents of the University of California.

 

	Protocol Title:	Aramchol Versus Placebo for the Treatment of HIV-associated NAFLD
	Principal Investigator:	Dr. Rohit Loomba

 

Payee
Information:

 

Checks
shall be made payable to “The Regents of the University of California” and sent to the following address:

 

The
Regents of the University of California 

University
of California-San Diego 

Cashier’s
Office, Mail Code 0009 

9500
Gilman Drive 

La
Jolla, CA 92093-0009

 

Payment
Terms:

 

		•	Initial
Payment. Company will make a non-refundable start-up fee payment of US $170,343 within seven (7) days from the date of contract
execution.

 

		•	Milestones.
Company will pay Institution in accordance with the following milestones:

 

20%
due when first patient randomized

20%
due when 50% of patients randomized

20%
due when all patients randomized

10%
due when the last patient finishes treatment

10%
due when the final report is submitted to Galmed

 

If
a Study subject discontinues from the Study for any reason, Company will pay for all payment-eligible Study visits completed by
Study subject in accordance with Exhibit C.

 

		•	Tax. Should Institution be liable to pay value added tax (or any similar tax) with respect to any amount payable to it by Company
hereunder, Company shall pay Institution the sum of the value added tax imposed on the amount together with the payment thereof,
provided that Institution supplies Company with appropriate documentation supporting such payment obligation. Company shall be
entitled to withhold any amount due as tax or other compulsory payments that applies or that shall apply to any payment due hereunder,
if and to the extent required to do so by law, unless Institution provides Company with the required tax certificates indicating
either exemption from such tax withholding or the percent of tax to be withheld.

 

    	16

    	 

    

 

		•	Final
Payment. Final payment will be based on all work completed in accordance with the Protocol, non-cancelable obligations, if
any, and any mutually agreeable costs associated with the phase-out of Study subjects, if any, including any withheld amounts
earned for Study subject visits. In the event that the scheduled payments made by Company exceed the amount due hereunder, Institution
will promptly refund any such excess to Company.

 

		•	Payment
Upon Termination: In the event this Agreement or Study is terminated prior to Institution’s completion of the Study, which
is not due to a breach of this Agreement by Institution and/or Principal Investigator or their bankruptcy/insolvency, and/or is
not terminated by Institution for convenience, Company shall pay Institution for actual costs incurred in the performance of the
Study up to the date of termination.

 

		•	Screen
Failures. Company will pay Institution for screening potential Study subjects who are not enrolled in the Study at the rate
designated in the Budget, per screened and non-enrolled subject. Institution agrees to use reasonable efforts to select appropriate
potential Study subjects to screen.

 

		•	Unscheduled
Visits. In accordance with the Protocol for those Study subjects who require a visit outside of the scheduled visits, Institution
will be reimbursed at the rate designated in the Budget.

 

		•	Full
Remuneration. Neither Institution, nor the Principal Investigator, shall be entitled to any additional compensation and/or
remuneration other than as explicitly set forth in this Agreement, including any expenses incurred by any of them in the performance
of their tasks pursuant to this Agreement.

 

    	17

    	 

    

 

Exhibit
C

 

[Budget]

 

    	18

    	 

    

 

CERTAIN PORTIONS
OF THIS EXHIBIT HAVE BEEN OMITTED AND ARE SUBJECT TO A CONFIDENTIAL TREATMENT REQUEST. COPIES OF THIS EXHIBIT CONTAINING THE OMITTED
INFORMATION HAVE BEEN FILED SEPARATELY WITH THE SECURITIES AND EXCHANGE COMMISSION. THE OMITTED PORTIONS OF THIS DOCUMENT ARE MARKED
WITH A [***].

 

UCSD
PROPOSAL BUDGET FORM

 

University
of California - San Diego 

 

Cumulative
Budget

 

	Cumulative
    Budget Period:	From	9/1/14	Through	8/31/19	 

 

	 	 	UCSD#	TBD

 

	 	 	Year
    1	 	 	Year
    2	 	 	Year
    3	 	 	Year
    4	 	 	Year
    5	 	 	Cumulative	 
	Salaries	 	 	[***]	 	 	 	[***]	 	 	 	[***]	 	 	 	[***]	 	 	 	[***]	 	 	 	[***]	 
	Fringe
    Benefits	 	 	34,418	 	 	 	36,101	 	 	 	26,632	 	 	 	1,361	 	 	 	1,455	 	 	 	99,967	 
	Tuition
    Remission	 	 	-	 	 	 	-	 	 	 	-	 	 	 	-	 	 	 	-	 	 	 	-	 
	Consultant(s)	 	 	-	 	 	 	-	 	 	 	-	 	 	 	-	 	 	 	-	 	 	 	-	 
	Patient
    Costs	 	 	98,000	 	 	 	98,000	 	 	 	49,000	 	 	 	-	 	 	 	-	 	 	 	245,000	 
	Supplies
    and Materials	 	 	3,000	 	 	 	3,000	 	 	 	3,000	 	 	 	-	 	 	 	-	 	 	 	9,000	 
	Travel	 	 	3,000	 	 	 	6,000	 	 	 	6,000	 	 	 	3,000	 	 	 	-	 	 	 	18,000	 
	Subaward(s)	 	 	-	 	 	 	-	 	 	 	-	 	 	 	-	 	 	 	-	 	 	 	-	 
	Other
    Expenses	 	 	23,007	 	 	 	19,055	 	 	 	19,629	 	 	 	6,512	 	 	 	2,513	 	 	 	70,716	 
	Total
    Direct Costs	 	$	[***]	 	 	$	[***]	 	 	$	[***]	 	 	$	[***]	 	 	$	[***]	 	 	$	[***]	 
	 
	Total
    Indirect Costs	 	$	63,061	 	 	$	63,883	 	 	$	43,079	 	 	$	3,748	 	 	$	1,980	 	 	$	175,750	 
	 
	Total
    Costs Requested	 	$	[***]	 	 	$	[***]	 	 	$	[***]	 	 	$	[***]	 	 	$	[***]	 	 	$	[***]	 

 

Office of Contract and Grant Administration –
11/2018

Source: [{"source": "alea-institute/alea-institute/kl3m-data-edgar-agreements/train-00242-of-00352.parquet"}, [{"source": "alea-institute/alea-institute/kl3m-data-edgar-agreements/train-00242-of-00352.parquet"}]]