Document:

EXHIBIT 4.9

 

AMENDMENT #2

 

 

THE SYMBOL "[****]" DENOTES
PLACES WHERE PORTIONS OF THIS DOCUMENT HAVE BEEN OMITTED PURSUANT TO A REQUEST FOR CONFIDENTIAL TREATMENT. SUCH MATERIAL HAS BEEN
FILED SEPARATELY WITH THE SECURITIES AND EXCHANGE COMMISSION.

 

AMENDMENT TO THE MASTER SERVICE AGREEMENT
FOR REDHILL 

BIOPHARMA LTD.’S RHB R&D PROGRAM

 

 

 

	BY AND BETWEEN:	RedHill Biopharma Ltd., with principle place of business at 21 Ha’arba’a St. Tel-Aviv 64739, Israel (herein referred to as the “Client”),
	 	 
	AND:	7810962 Canada Inc (doing Business under the name “InSymbiosis”), a body politic and corporate, duly incorporated according to the laws of Canada and with principle place of business at 245 Victoria Ave, Suite 100, Montreal, Quebec, H3Z 2M6, Canada, (herein referred to as the “Provider”),

 

The Client and the Provider are, in this
Agreement, sometimes individually referred to as “Party” and collectively as the “Parties”.

 

WHEREAS on 28
April 2011, the Client and the Provider entered into a Master Service Agreement in relation to the Client’s RHB R&D
Program (the “MSA”);

 

WHEREAS WHEREAS
the MSA was scheduled to terminate on April 28, 2013 and the parties hereby agree to formally extend the term of the MSA until
on April 28, 2015 (the "Extended Period"); and

 

WHEREAS the Parties
have agreed to certain terms and conditions, the whole as is fully set forth below.

 

NOW, THEREFORE, THE PARTIES HERETO AGREE
AS FOLLOWS:

 

		1.	Unless specifically set out otherwise in this agreement (the “AMENDMENT AGREEMENT”),
the terms of the MSA shall continue to apply.

 

		2.	The parties hereby agree to formally extend the term of the MSA until April 28, 2015.

 

		3.	The parties hereby agree that as per Section 7l of the MSA, [****] will replace [****] as clinical
project manager.

 

7810962 Canada Inc

 

    	 

    	 

    

 

		2	 

 

		4.	During the term of the Agreement, PROVIDER will charge CLIENT a monthly project management fee
of $US[****]. This monthly project management fee will be payable each quarter, in advance, upon lawful invoice to be provided by
the PROVIDER to the CLIENT within 21 days of the beginning of the relevant quarter according to the following payment schedule:

 

		·	[****]

 

IN WITNESS WHEREOF,
the parties hereto have executed this Amendment Agreement as of the date first herein above mentioned.

 

REDHILL BIOPHARMA
Ltd.

 

	/s/ Dror Ben-Asher	 	/s/Ori Shilo
	Per:	Dror Ben-Asher	 	Per:	Ori Shilo
	Title:	CEO	 	Title:	VP Finance and Operation
	Date: May 29, 2013	 	Date: May 29, 2013

 

PARTY OF THE FIRST PART

 

7810962 Canada
Inc.

 

	/s/ Alain Guimond	 
	Per:	Alain Guimond	 
	Title:	Senior Director of Research	 
	Date: May 29, 2013	 

 

7810962 Canada Inc

 

    	 

    	 

    

 

		3	 

 

PARTY OF THE SECOND PART

 

7810962 Canada IncEXHIBIT 4.13

 

THE
SYMBOL “[****]”  DENOTES PLACES WHERE PORTIONS
OF THIS DOCUMENT HAVE BEEN OMITTED PURSUANT TO A REQUEST FOR CONFIDENTIAL TREATMENT. SUCH MATERIAL HAS BEEN FILED SEPARATELY WITH
THE SECURITIES AND EXCHANGE COMMISSION.

 

Amendment 2 to Clinical Services
Agreement

 

Sponsor’s study drug RHB-104

 

THIS AMENDMENT #2 (“Amendment”)
to the Clinical Services Agreement signed 15 June 2011 (“Clinical Services Agreement”), is by and among:

 

(1) (1)  RedHill Biopharma
Ltd., having its principle place of business at 21 Ha’arba’a St., Tel Aviv 64739, Israel (hereafter “SPONSOR”);

 

(2) 7810962 Canada Inc., a Canadian
corporation, having its principal office at 245 Victoria Ave, Suite 100, Montreal, Quebec, H3Z 2M6, Canada (hereinafter "MANAGER");

 

Is hereby made effective as of December
11, 2013 (“Effective Date”) and the parties hereby agree as follows:

 

		1.	Amendment 2 to Clinical Services Agreement.

 

This
Change Order constitutes an amendment to the Clinical Services Agreement pursuant to section 3.0 therein. As such, this Change
Order is subject in all respects to the terms and provisions of the Clinical Services Agreement.

 

		2.	Scope of Work

 

In addition to the Services to
be provided in the above-referenced Clinical Services Agreement, Manager will cause inVentiv Health Clinical to perform additional
Services for Sponsor’s study drug RHB-104, in accordance with the Summary of Changes attached hereto and incorporated herein
as Exhibit A. The EU trial is removed from the contract in this amendment to the trial agreement.

 

		3.	Compensation

 

Under this Change Order, inVentiv
Health Clinical’s Professional Fees have decreased by the discounted amount of USD [****], the pass-through costs have increased
by USD [****] and the investigator’s grants costs have Increased by USD [****]. The total cost of the Clinical Services Agreement
have increased to USD [****].

 

    	 

    	 

    

 

Payment due to Manager for the
Services provided under this Change Order shall be made pursuant to the Agreement and the revised unit Payment Schedule attached
hereto and incorporated herein as Exhibit B.

 

		4.	Project Period

 

The term of this Change Order shall commence on the
date of its execution and shall continue until the Services as described in the Clinical Services Agreement are completed, unless
this Change Order or corresponding Clinical Services Agreement are terminated early in accordance with the Clinical Services Agreement.

 

By their signatures below, the parties
hereto agree to the terms of this Change Order and represent that they are authorized to enter into this Change Order on behalf
of their respective companies.

 

ACCEPTED AND AGREED TO:

 

	RedHill Biopharma Ltd.	 	For 7810962 Canada Inc
	 	 	 
	/s/ Dror Ben-Asher	 	/s/ Alain Guimond
	Name: Dror Ben-Asher	 	Name: Alain Guimond
	Title: CEO	 	Title: Sr Director of R&D
	 	 	 
	Date: January 19, 2014	 	Date: January 10, 2014
	 	 	 
	RedHill Biopharma Ltd.	 	 
	 	 	 
	/s/ Ori Shilo	 	 
	Name: Ori Shilo	 	 
	Title: Deputy CEO Finance and Operations	 	 
	 	 	 
	Date: January 19, 2014	 	 

 

    	 

    	 

    

 

Exhibit
A: Summary of Changes

 

 

Study Assumption Changes

 

Changes to the parameters and assumptions
for the study are defined below. Unless otherwise noted, activities will be performed according to the original contract. EU trial
is removed from the study agreement

 

Amendment #2 RedHill Biopharma

 

Overview of major level changes

 

	Category	 	Contract	 	
        Change Order 

        – NA Project
	 	Rationale for change
	Study Start- Up period	 	[****]	 	[****]	 	Work on global project began mid-July2011, with kick-off meeting August 10, 2011. Final protocol for NA expected early September, and then delayed until December 2011. [****]. On Mar. 1, 2012, the project was put on hold with an agreed upon charge of $[****]K/month; a contract amendment was put in place. The hold lasted [****] months, at which time inVentiv Health Clinical was instructed to restart start-up activities in full. Start-up activities continue.
	Enrolment period	 	[****]	 	[****]	 	Per client
	Stats Timeline	 	[****]	 	[****]	 	 
	# of countries	 	[****]	 	[****]	 	EU sites are removed from the study agreement. [****].
	# of sites	 	[****]	 	[****]	 	Per client
	# of subjects	 	[****]	 	[****]	 	Per client
	# of CRF pages/book	 	[****]	 	[****]	 	Number of visits in NA study has [****][****]
	# of unique CRF pages	 	[****]	 	[****]	 	CRFs are complete [****].
	# RMVs per site	 	[****]	 	[****]	 	Calculated based on total number of CRF pages. [****] 
	# of PSVs	 	[****]	 	[****]	 	Additional sites, therefore additional PSVs
	# of SIVs	 	[****]	 	[****]	 	Additional sites, therefore additional SIVs
	# of RMVs	 	[****]	 	[****]	 	Additional CRF pages to be monitored (as detailed above), therefore additional RMVs required
	# of COVs	 	[****]	 	[****]	 	Additional sites, therefore additional COVs
	# of internal meetings	 	[****]	 	[****]	 	Dependent upon duration of trial: meetings typically held weekly during start-up and enrolment, then monthly thereafter
	# of client telecons	 	[****]	 	[****]	 	Dependent upon duration of trial: meetings typically held weekly during start-up and enrolment, then monthly thereafter

 

    	3

    	 

    

 

	Category	 	Contract	 	
        Change Order 

        – NA Project
	 	Rationale for change
	Investigator Meeting	 	[****]	 	[****]	 	Per client
	# of vendors	 	[****]	 	[****]	 	[****]
	# of edit checks	 	[****]	 	[****]	 	[****]: have 2 unique databases now, and larger CRF for each
	# of imports	 	[****]	 	[****]	 	[****]: imports occur monthly from FPI to LPO plus one month, plus 1 test and 1 final
	# of SAEs	 	[****]	 	[****]	 	Increased because # of subjects has increased. Assume 5% SAE rate in each study.
	# of SAE Narratives	 	[****]	 	[****]	 	As above. Require 1 narrative for each SAE.
	IVRS	 	[****]	 	[****]	 	Client request to include IVRS for randomization with 1 drug assignment/site, and unblinding capability
	eCRF Changes 	 	[****]	 	[****]	 	Amended protocol required changes to the previously finalized eCRF

 

    	4

    	 

    

 

		1.1	Revised Costs

 

Costs for this study are presented
below in two categories, pass-through costs and professional fees.

 

		1.1.1	Pass-Through Costs

 

Pass-through costs are in US
dollars and include, but are not limited to, those expenses listed below. Manager will invoice Sponsor for actual costs in these
areas. Actual costs will be kept to reasonable levels through adherence to inVentiv Health Clinical’s travel policy and prudent
negotiation with outside providers. Pass-through costs are presented in the table below:

 

	Task	 	Original 
(USD)	 	New NA 
(USD)	 	Assumption 
Changes 
influencing the 
change in the 
budget	 	Additional 
comments
	 	 	 	 	 	 	 	 	 
	Site Visit Travel	 	[****]	 	[****]	 	Original contract has a total of [****] site visits. [****]	 	 
	Investigators' Meeting Organisation	 	[****]	 	[****]	 	WebEx costs included in original budget. Investigator meetings have been changed to F2F.	 	 
	Kick-off Meeting Travel/Attendance	 	[****]	 	[****]	 	Originally assumed [****] cover study globally, as studies and timelines were the same. Now assume [****] for each study, since timelines are vastly different and study teams not identical.	 	 
	Shipping/Photocopying	 	[****]	 	[****]	 	Original contract assumes [****]. New NA budget assumes [****].	 	 
	Translation	 	[****]	 	[****]	 	Original contract [****]. New NA budget [****];	 	Costs for translating patient recruitment materials have been removed as this service is not included in updated budgets.

 

    	 

    	 

    

 

	Task	 	Original 
(USD)	 	New NA 
(USD)	 	Assumption 
Changes 
influencing the 
change in the 
budget	 	Additional 
comments
	 	 	 	 	 	 	 	 	 
	Regulatory Fees	 	[****]	 	[****]	 	assumed [****].	 	Current costing tool separates out Regulatory Fees and [****] fees, as seen in EU costing.
	[****] (& Regulatory) Fees	 	[****]	 	[****]	 	New NA costing 
assumes [****].	 	 For original costing and new NA costing, these fees remain combined.
	EDC Studies/3G Cards	 	[****]	 	[****]	 	[****]	 	 
	[****]	 	[****]	 	[****]	 	 	 	[****]
	EDC Fees ([****])	 	[****]	 	[****]	 	 	 	EDC Fees were included in Professional Fees in initial bid
	 Pass Through Costs	 	[****]	 	[****]	 	 	 	 

 

 

    	 

    	 

    

 

		1.1.2	Investigator Grants Costs

 

	Investigator 
Grants	 	Original 
(USD)	 	NA 
(USD)	 	Assumption Changes 
influencing the

change in the budget	 	Additional 
Comments
	 	 	[****]	 	[****]	 	Original contract assumed [****] patients. New NA costing assumed [****] patients	 	Estimate only. Will be paid based on actual costs as approved by the Client.

 

		1.1.3	Professional Fees

 

Based on the parameters and
assumptions outlined in the original proposal, inVentiv Health Clinical fees are categorised by major activity in the table below
and in USD:

 

	Task	 	Original 
(US Dollars)	 	New NA 
(US Dollars)	 	Assumption Changes 
influencing the change in 
the budget	 	Additional comments
	Pre-study Activities	 	 	 	 	 	 	 	 
	Case Report Form Preparation/Review	 	[****]	 	[****]	 	[****]	 	Original costs were to prepare one CRF that would be utilized by both studies; with different study designs now we are preparing two different CRFs but are able to take efficiencies on pages that will be the same in both studies. Additionally, number of visits in NA study has [****] since details provided in protocol synopsis in April 2011
	Data Management Plan Preparation/Review	 	[****]	 	[****]	 	[****]	 	Originally cost allocation was to prepare one plan to be utilized by both studies; with different study designs now we are preparing two different DM plans.  We are able to copy some aspects/pages of the DM plan from the NA study to the EU study, and where there are not similarities we have allocated cost for new pages/edit specs.
	Informed Consent Preparation/Review	 	[****]	 	[****]	 	[****]	 	 
	[****]	 	[****]	 	[****]	 	[****]	 	 
	Investigators' Meetings	 	[****]	 	[****]	 	[****]	 	 

 

    	 

    	 

    

 

	Task	 	Original 
(US Dollars)	 	New NA 
(US Dollars)	 	Assumption Changes 
influencing the change in 
the budget	 	Additional comments
	Investigator Site Contract	 	[****]	 	[****]	 	[****]	 	 
	Investigator Recruitment	 	[****]	 	[****]	 	[****]	 	[****]
	Project Plan Preparation/Review	 	[****]	 	[****]	 	[****]	 	[****]Assumed that there are efficiencies in the preparation of the EU plan based on finalization of the plan in NA due to similar process where applicable.  EU IPP plan will be different based on countries included outside NA and Israeli.
	Protocol Preparation/Review	 	[****]	 	[****]	 	[****]	 	Assumes a separate CRA team is reviewing/reading protocol due to countries not being the same.  With the start of the EU study subsequent to the NA, there is also a separate team in many functional areas, i.e., separate DM team, biostats, medical writing, and safety.
	Randomization Schedule Preparation	 	[****]	 	[****]	 	Originally allocated cost for 
[****]and now doing [****]	 	 
	Study-Specific Form Preparation	 	[****]	 	[****]	 	Originally allocated cost for [****]Now [****]	 	Efficiencies will be applied in EU study: assume use NA forms modified to suit EU study
	Training - Project-Specific	 	[****]	 	[****]	 	Originally allocated cost for [****]	 	Training two separate teams w larger EU team.  Assumed NA training would be modified for EU training, but protocol designs are different so training different.
	Translations	 	[****]	 	[****]	 	[****]	 	Fewer languages in NA study than EU
	PROMIS	 	[****]	 	[****]	 	[****]	 	Two separate databases; one for each study.
	Monitoring/Site Management	 	 	 	 	 	 	 	 
	Data Clean-up	 	[****]	 	[****]	 	 	 	Increased number of eCRF pages.
	Investigator Grant Administration	 	[****]	 	[****]	 	[****]	 	[****]
	Laboratory Report Review	 	[****]	 	[****]	 	Decrease in total number of patients	 	Originally allocated cost for [****]
	Serious/Significant Adverse Event Management	 	[****]	 	[****]	 	Decreased number of SAEs due to decreased number of subjects	 	Originally allocated cost for [****]

 

    	 

    	 

    

 

	Task	 	Original 
(US Dollars)	 	New NA 
(US Dollars)	 	Assumption Changes 
influencing the change in 
the budget	 	Additional comments
	Site Management	 	[****]	 	[****]	 	Decreased number of sites and  increased months	 	Originally allocated cost for the management  [****]
	Site Visits - Pre-study Visits	 	[****]	 	[****]	 	Decreased number of sites	 	Originally cost allocation was for [****]
	Site Visits - Initiation Visits	 	[****]	 	[****]	 	Decreased number of sites	 	Originally cost allocation was for [****]
	Site Visits - Routine Visits	 	[****]	 	[****]	 	Increased number of visits due to increased number of CRF pages to monitor	 	Originally cost allocation was for [****]
	Site Visits - Close-out Visits	 	[****]	 	[****]	 	Decreased number of sites	 	Originally cost allocation was for [****]
	Study Master File/Project File Set-up and Maintenance	 	[****]	 	[****]	 	Decreased number of sites and  increased months	 	Originally allocated cost for the management  [****]
	Patient/Site Recruitment	 	[****]	 	[****]	 	 	 	 
	Regulatory	 	 	 	 	 	 	 	 
	Regulatory Documentation Preparation/Review	 	[****]	 	[****]	 	Decreased number of sites	 	Originally cost allocation was  [****]
	Project Management/Project Tracking	 	 	 	 	 	 	 	 
	Financial Project Management	 	[****]	 	[****]	 	Increased study durations; 2 separate studies vs. 1	 	Originally cost allocation was  [****]
	Project Management	 	[****]	 	[****]	 	Increased study durations; 2 separate studies vs. 1	 	Originally cost allocation was  [****]
	Project Tracking/Communications	 	[****]	 	[****]	 	Increased study durations; 2 separate studies vs. 1	 	Originally cost allocation was  [****]
	Vendor Management	 	[****]	 	[****]	 	Added [****] contract payment management	 	[****]
	Data Management	 	 	 	 	 	 	 	 
	Database Archiving	 	[****]	 	[****]	 	 	 	 
	Data Cleanup (DM)	 	[****]	 	[****]	 	[****].	 	 
	Data Management: Database Quality Control Inspection	 	[****]	 	[****]	 	[****]	 	 
	Database Design	 	[****]	 	[****]	 	[****]	 	Assume NA DB designed first with efficiencies taken for similar eCRF pages/edit specs in both studies.  We will reconsider upon receipt of synopsis with final assumptions. Assumed one data base originally and now two
	Dictionary Coding	 	[****]	 	[****]	 	Increased number of subjects, therefore increased number of terms overall	 	 

 

    	 

    	 

    

 

	Task	 	Original 
(US Dollars)	 	New NA 
(US Dollars)	 	Assumption Changes 
influencing the change in 
the budget	 	Additional comments
	Edit Check Programming	 	[****]	 	[****]	 	Increased number of edit checks due to increased CRF size	 	Assume NA DB designed first with efficiencies taken for similar eCRF pages/edit specs in both studies.  We will reconsider upon receipt of synopsis with final assumptions.
	Electronic Data Import	 	[****]	 	[****]	 	 	 	[****]
	Case Report Form Data/Document Transfers	 	[****]	 	[****]	 	 	 	[****]
	EDC Fees	 	[****]	 	[****]	 	 	 	[****]
	Statistical Analysis and Table Generation	 	 	 	 	 	 	 	 
	Electronic Data Transfer	 	[****]	 	[****]	 	[****]	 	 
	Interim Analysis/Report Preparation and Review	 	[****]	 	[****]	 	[****]	 	 
	Statistical Analysis Plan Preparation/Review	 	[****]	 	[****]	 	[****]	 	Originally cost allocation was to [****]
	Table Generation	 	[****]	 	[****]	 	[****]	 	Originally preparing [****]
	Table/Listings Review	 	[****]	 	[****]	 	[****]	 	Reviewing [****]separate sets of T&Ls.
	Clinical Study Report	 	 	 	 	 	 	 	 
	Clinical Study Report Preparation/Review	 	[****]	 	[****]	 	 	 	Assumes [****]separate study reports, originally assumed one.
	Team Meetings	 	 	 	 	 	 	 	 
	Project Team Meetings - Internal Meetings	 	[****]	 	[****]	 	[****]	 	 
	Project Team Meetings - Client Teleconferences	 	[****]	 	[****]	 	[****]	 	 
	Project Team Meetings - Kick-off Meeting	 	[****]	 	[****]	 	[****]	 	 
	Total Direct Costs	 	[****]	 	[****]	 	 	 	 

 

Total Costs

 

[****]

 

    	 

    	 

    

 

Exhibit
B Payment Schedule

	 
	 
	Milestone
    Payment Schedule
	7810962
    Canada Inc (11ISB001)

 

[****]

 

Pass Through Costs:

 

		(a)	[****] percent ([****]%) of the average estimated pass through costs equaling $[****] (exclusive of funds
for investigator grants); will be due and payable upon execution of this Agreement. These funds will be drawn down as necessary
to pay incurred pass through costs and will be replenished to the full [****]% once the amounts held are [****]% depleted. This
process to continue until the end of the study.

 

		(b)	The pass-through costs above will be as provided in the expenses estimate and any additional costs
will be pre-approved by the Company. The pass-through costs will be billed as incurred by inVentiv Health Clinical.

 

		(c)	Any unused funds held for pass through costs will be returned within ninety (90) days from the
date of the final reconciliation.

 

		3.	Investigator Grants:

 

		(a)	[****] percent ([****]%) of the estimated grant payments for the study, equaling $[****], will be invoiced
upon commencement of services. These funds will be drawn down as the Investigator Grants are paid and the full [****]% will be
replenished once the amounts held are [****]% depleted). This process to continue until the end of the study.

 

		(b)	inVentiv Health Clinical will submit invoices for the amounts paid to investigators during the
previous month. Any amount exceeding the estimate investigator grant payments will be pre-approved by the Company.

 

		(c)	inVentiv Health Clinical will not make payments to investigators without having sufficient funds
available in advance.

 

		(d)	Any unused funds will be returned within ninety (90) days from the date of the final reconciliation

 

		4.	Payment Conditions:

 

		(a)	For all Services, pass through expenses and investigator grants invoiced, payments are due net
thirty (30) days from invoice date as set forth in Terms, Item 2 of the Agreement. In the event of a dispute, all undisputed portions
of the invoice(s) are due within the above stated terms

 

		(b)	Payments shall be made in the currency identified above and shall be made free of any applicable
local withholding taxes, charges or remittance fees. Invoices will be inclusive of applicable taxes as determined by local laws
and regulations

 

		(c)	InVentiv Health Clinical reserves the right to charge interest against any unpaid overdue balance at the
rate of [****] percent ([****]%) per month

 

		(d)	All services and pass-through payments should be sent via wire or ACH

 

    	Page 11 of 11

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