Document:

Exhibit 10.6

 

STRICTLY CONFIDENTIAL

 

AMENDMENT N°1 TO PHARMACEUTICAL DEVELOPMENT*
 AGREEMENT

 

BETWEEN

 

BEAUFOUR IPSEN INDUSTRIE S.A.S., a French corporation incorporated under the laws of France, located at rue d’Ethe Virton, 28100, France, duly represented by Jean-Pierre Dubuc, President,

 

hereinafter referred to as “Ipsen”, on the one hand,

 

AND

 

RADIUS HEALTH Inc., a United States corporation incorporated under the laws of the State of Delaware, United States, with its principal office at 300 Technology Square5th Floor, Cambridge, MA, USA and formerly known as Nuvios, Inc., duly represented by Richard Lyttle, Chief Executive Officer,

 

hereinafter referred to as “Radius”, on the other hand.

 

WHEREAS

 

A.                                   Ipsen and Radius are parties to that certain License Agreement dated September 27, 2005 (the “License Agreement”).

 

B.                                     Within the framework of the License Agreement, Ipsen and Radius have entered into a pharmaceutical development agreement to develop a multidose injection for BIM 44058 dated as of January 2, 2006 (the “Pharmaceutical Development Agreement”) pursuant to which Ipsen performs certain research and development tasks and activities in view of developing a new formulation of Licensed Compound and/or Licensed Product.

 

C.                                     Since (i) the work to be performed by Ipsen has taken longer than originally planned in the Work Plan of the Pharmaceutical Development Agreement and (ii) Radius wishes Ipsen to perform additional work to the work initially set out in the Work Plan, Ipsen and Radius have decided to further extend the duration and the scope of the Work Plan and to provide for the consideration relating to such an extension under an amendment to the Pharmaceutical Development Agreement (this “Amendment n°1”).

 

NOW, THEREFORE, in consideration of the premises and the performance of the covenants herein contained, IT IS AGREED AS FOLLOWS:

 

1.                                       In this Amendment n°1, unless otherwise expressly provided herein, the capitalized words and phrases shall have the same meaning as in the Pharmaceutical Development Agreement.

 

* Confidential Treatment Requested by the Registrant. Redacted Portion Filed Separately with the Commission.

 

1

 

2.                                       The December 31, 2006 deadline initially agreed upon for the performance by Ipsen or its subcontractors of all the work set out in the Work Plan as it exists prior to this Amendment (the “Original Work Plan”) and its payment by Radius, is extended to May 31, 2007.

 

For sake of clarity, any reference to the date of December 31, 2006 in Article 10 of the Pharmaceutical Development Agreement which relates to the performance of the Original Work Plan shall be replaced by and extended to May 31, 2007. The budget agreed upon in respect to all the work described in the Original Work Plan shall remain unchanged, except for the over overrun of €[*] approved by Radius in Q4, 2006.

 

3.                                       The Work Plan is amended so as to include the work described in Appendix A to this Amendment n°1 (the “Extended Work Plan”),  some of which is to be performed in 2007 and the rest in 2008. For clarity, all references to the Work Plan in the Pharmaceutical Development Agreement shall be deemed to include all work described in the Extended Work Plan, as well as the work described in the Original Work Plan. Should Radius wish Ipsen to perform any other work in addition to the 2007 and 2008 activities described in the Extended Work Plan, Radius and Ipsen shall enter into a new agreement or amendment.

 

4.                                       Payments:

 

(a) Subject to any modification of the budget included in the Extended Work Plan to be prior agreed in writing by the parties by Mike Dey, Vice-President, Pharmaceutical Development for Ipsen and by Nick Harvey, Chief Financial Officer to Radius or by any other representative designated by the relevant Party, the total amount to be paid by Radius to Ipsen in connection with the research activities and tasks pursuant to the Extended Work Plan and this Amendment n°1 shall be as specified in the here attached Appendix B, that is to say:

 

(i) The total amount to be paid by Radius to Ipsen in connection with the 2007 activities described Appendix A shall be:

 

·                                          [*] euros ([*]€) for the additional activities on Drug Substance;

 

·                                          [*] euros ([*]€) for additional activities on Drug Product;

 

(ii) The total amount to be paid by Radius to Ipsen in connection with the 2008 activities described in Appendix A shall be:

 

·                                          [*] euros ([*]€) for the additional activities on Drug Substance;

 

·                                          [*] euros ([*]€) for additional activities on Drug Product;

 

Such total amount includes all costs in connection with such research activities, including costs of materials, supplies, services, personnel, subcontractors and overhead, regardless of whether such research activities are performed by Ipsen or by a subcontractor or both. The budget included in the Extended Work Plan as described in Appendix B to this Amendment shows the breakdown by calendar quarter of such total amounts in Euros.

 

* Confidential Treatment Requested by the Registrant. Redacted Portion Filed Separately with the Commission.

 

2

 

(b) Ipsen shall invoice Radius no later than [*] days after the end of each calendar quarter for the amount corresponding to actual FTE time spent as per timesheets incurred plus actual external cost bills received and approved by Ipsen during the elapsed quarter, as shall in each case be reported in reasonable detail on the invoice annex. Radius shall make payment of each invoice within [*] days after receipt thereof in Euros.

 

(c) Without the prior written consent of Radius, in no event shall Ipsen invoice Radius for an amount due in respect of any calendar year that is greater than the amount budgeted for such calendar year in the Extended Work Plan plus the [*] percent ([*]%) limit defined in article 4(d) of this Amendment n°1. In addition, and notwithstanding anything expressed or implied in this Agreement to the contrary (including without limitation, the Extended Work Plan), in no event shall Radius have any obligation to make payments to Ipsen pursuant to this Amendment n°1 for any work done by Ipsen at any time after December 31, 2008 unless Radius shall have authorized in writing any such work.

 

Radius shall pay for all work in respect of which Ipsen has entered into legally binding commitments with subcontractors and which occurs before December 31, 2008, that may not be cancelled by Ipsen without incurring penalties, provided that all of such work is within the framework of the Extended Work Plan and the cost of such work is within the budget included in the Extended Work Plan.

 

The remaining samples from stability studies will be made available for Radius to ship to Radius nominated contract laboratory by December 31, 2008. Should Radius request in writing that Ipsen conduct work on Radius behalf, Ipsen will be under no obligation to conduct such work.

 

(d)           Notwithstanding any overruns which have been approved by Radius with respect to work under the Original Work Plan, should external costs incurred by Ipsen in relation to the performance of 2007 or 2008 activities described in the Extended Work Plan be more than as specified in Appendix B hereby attached for such activities, Radius shall reimburse Ipsen such additional costs up to a maximum of [*] percent ([*]%) of the relevant annual amount described in Appendix B for the performance of the specific tasks that resulted in such additional costs. In addition, should internal costs incurred by Ipsen in relation to performance of the Work Plan be more than as specified in Exhibit B due to an increase in the number of FTE’s required (but not the cost per FTE), Radius shall reimburse Ipsen such additional costs up to a maximum of [*] percent ([*]%) of the relevant annual amount described in Appendix B for the performance of the specific tasks that resulted in such additional costs. In either case, any reimbursement of costs in excess of such percentage will have to be prior agreed by Radius and, in the absence of any such prior agreement by Radius, shall be the responsibility of Ipsen. Ipsen shall use all reasonable efforts to avoid any such cost overruns. For clarity, the maximum [*]% adjustment permitted in 2007 will be of [*] ([*]) euros and in 2008 of [*] ([*]) euros. Any reimbursement of costs in excess of such percentage will have to be prior agreed by Radius and, absent any such prior agreement by Radius, shall be the responsibility of Ipsen.

 

* Confidential Treatment Requested by the Registrant. Redacted Portion Filed Separately with the Commission.

 

3

 

5.                                       This Amendment n°1 shall enter into force retroactively upon its signature as of January 1st, 2007 and shall remain in full force and in effect until complete performance of the Extended Work Plan or termination of the Pharmaceutical Development Agreement in accordance with its terms.

 

6.                                       All other terms and conditions of the Pharmaceutical Development Agreement shall remain in full force and effect and shall apply to this Amendment n°1 which is made part of the Pharmaceutical Development Agreement.

 

7.                                       This Amendment n°1 shall be governed by, interpreted and construed in accordance with the laws of the State of New York, U.S.A., without regard to the conflicts of law principles, and shall not be governed by the United Nations Conventions of International Contracts on the Sale of Goods (the Vienna Convention).

 

IN WITNESS WHEREOF, the Parties hereto have caused this Agreement to be duly executed by their respective duly authorized representatives:

 

 

	
Date:   July 16,   2007
    	
 
    	
Date:   29.06.07
    
	
 
    	
 
    	
 
    
	
SIGNED   by B.N. Harvey
    	
 
    	
SIGNED   by Jean-Pierre Dubuc
    
	
 
    	
 
    	
 
    
	
/s/   B.N. Harvey
    	
 
    	
/s/   Jean-Pierre Dubuc
    
	
on   behalf of
    RADIUS HEALTH Inc.
    	
 
    	
as   President of
    BEAUFOUR IPSEN INDUSTRIE S.A.S.
    

 

4

 

APPENDIX A

 

EXTENDED WORK PLAN

 

	
 
    	
BA058:   DEVELOPMENT PLAN
    
	
 
    	
OF   READY TO USE PEN INJECTION
    
	
 
    	
FOR   PHASE II
    
	
 
    	
 
    
	
 
    	
ADDITIONAL   ACTIVITIES - 2007 & 2008
    

 

5

 

 

	
 

APPENDIX A

 

BA058 :   Development plan  
    of Ready to Use Pen  
    Injection for Phase II  

 

Additional   activities - 2007 & 2008
    	

    

 

6

 

Content

 

·                  Drug Substance

 

·                  Drug Product

·                  Proposed IND stability commitment

·                  Stability program

·                  Stability batches

·                  Clinical batches

·                  Stability-in-use

·                  Cost estimation for 2007 & 2008

 

7

 

 

8

 

Activities to support IND submission (API)

 

	
-   Additional test on batch 01-402:
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    
	
(residual solvents , TFA, and optical rotation)
    	
 
    	
2007
    	
 
    	
External   cost
    	
 
    	
[*]   €
    
	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    
	
-   Stability study of batch 01-402:
    	
 
    	
2007
    	
 
    	
[*]FTE
    	
 
    	
[*]   €
    
	
 
    	
 
    	
2008
    	
 
    	
[*]FTE
    	
 
    	
[*]   €
    
	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    
	
Retest   of reference material
    	
 
    	
2007
    	
 
    	
[*]FTS
    	
 
    	
[*]€
    
	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    
	
TOTAL
    	
 
    	
 
    	
 
    	
[*]€ in 2007
    	
 
    	
 
    
	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    
	
 
    	
 
    	
 
    	
 
    	
[*]€ in 2008
    	
 
    	
 
    

 

9

 

 

10

 

 

Proposed IND Stability Commitment

 

Continue the stability study in accelerated (25°C/60%RH) and long-term (5°C) storage conditions in parallel to the clinical study.

 

Monitor periodically clinical batches in a re-assay program at the label claim storage condition (i.e. 5°C).

 

The shelf life period will be extended based on data from accelerated and long-term studies, as well as results from by this re-assay program.

 

11

 

Stability Program: 0.5 & 2 mg/ml

 

	
Time
   Point
    	
 
    	
Pull
   Date
    	
 
    	
Storage Conditions
    	
 
    	
Shelf life
   (extrapolation)
    	
 
    	
Use Date
   of clinical
   supplies *
    	
 
    	
FTE to support analytical
   work (physicochemical and
   microbiological tests - report @
   [*], [*]and [*] months)
    
	
[*] months
    	
 
    	
03/26/07
    	
 
    	
5°C &   25°C/60%RH (including preservative effectiveness at 25°C/60%RH)
    	
 
    	
[*] months
    	
 
    	
End Oct. 07
    	
 
    	
[*]+[*] (μbio) 
   + [*]€ (external cost)**
    
	
[*] months
    	
 
    	
06/26/07
    	
 
    	
5°C
    	
 
    	
[*] months
    	
 
    	
End April 08
    	
 
    	
[*]
    
	
[*] months
    	
 
    	
09/26/07
    	
 
    	
5°C   (including preservative effectiveness)
    	
 
    	
[*] months
    	
 
    	
End Oct. 08
    	
 
    	
[*]+[*] (μbio)
    
	
[*] months
    	
 
    	
March 08
    	
 
    	
5°C
    	
 
    	
[*] months
    	
 
    	
End Oct. 08
    	
 
    	
[*]
    
	
[*] months
    	
 
    	
Sept.   08
    	
 
    	
5°C   (including preservative effectiveness)
    	
 
    	
[*] months
    	
 
    	
End Oct. 08
    	
 
    	
[*]+[*] (μbio) 
   + [*] € (external cost)**
    

 

* Use date = manufacturing date + shelf life

 

12

 

Stability Program: Placebo

 

	
Time
   Point
    	
 
    	
Pull
   Date
    	
 
    	
Storage Conditions
    	
 
    	
Shelf life
   (extrapolation)
    	
 
    	
Use Date
   of clinical
   supplies *
    	
 
    	
FTE to support analytical
   work (physicochemical and
   microbiological tests - report
   @ [*],[*] and [*] months)
    
	
[*] months
    	
 
    	
02/16/07
    	
 
    	
5°C &   25°C/60%RH (including preservative effectiveness at 25°C/60%RH)
    	
 
    	
[*] months
    	
 
    	
End Oct. 07
    	
 
    	
[*]+[*] (μbio)
    
	
[*] months
    	
 
    	
05/16/07
    	
 
    	
5°C
    	
 
    	
[*] months
    	
 
    	
End 08April
    	
 
    	
[*]
    
	
[*] months
    	
 
    	
08/16/07
    	
 
    	
5°C   (including preservative effectiveness)
    	
 
    	
[*] months
    	
 
    	
End Oct. 08
    	
 
    	
[*]+[*] (μbio)
    
	
[*]months
    	
 
    	
Feb. 08
    	
 
    	
5°C
    	
 
    	
[*] months
    	
 
    	
End Oct. 08
    	
 
    	
[*]
    
	
[*] months
    	
 
    	
Aug. 08
    	
 
    	
5°C   (including preservative effectiveness)
    	
 
    	
[*] months
    	
 
    	
End Oct. 08
    	
 
    	
[*]+[*] (μbio)
    

 

* Use date = manufacturing date + shelf life

 

13

 

Re-assay program: 0.5, 1, 2 mg/ml & Placebo

 

·                  To ensure the quality of the clinical supplies throughout the study :

 

It is proposed to re-test clinical batches stored at the label claim storage condition (i.e. 5°C) every [*] months until the end of the phase II clinical study

 

	
Re-Test Date
    	
 
    	
Re-Test Time Point
    	
 
    	
FTE
    
	
April 07
    	
 
    	
[*] months
    	
 
    	
[*]
    
	
October 07
    	
 
    	
[*] months
    	
 
    	
[*]
    
	
April 08
    	
 
    	
[*]months
    	
 
    	
[*]
    
	
October 08
    	
 
    	
[*] months
    	
 
    	
0.06 + 0.10 (μbio) 
   + [*] € (external cost)**
    

 

** Subcontracting of sterility test at VETTER

 

14

 

Stability program: stability in-use

 

·                  To simulate patient use, as far as possible

·                  Cartridge activated, inside the pen

·                  Storage at room temperature

·                  1 simulation of injection per [*], during [*] month

 

	
Time point
    	
 
    	
Pull date
    	
 
    	
Storage conditions
    	
 
    	
FTE
    
	
1 [*]
    	
 
    	
Feb. 07
    	
 
    	
25°C/60%RH
    	
 
    	
[*]+[*] (μbio)
    
	
[*]
    	
 
    	
Nov. 08
    	
 
    	
25°C/60%RH
    	
 
    	
[*]+ [*] (μbio)
    

 

15

 

Drug Product: cost estimation 2007 & 2008

 

	
Year
    	
 
    	
FTE
    	
 
    	
FTE cost *
   (in k€)
    	
 
    	
External cost
   (in k€)
    	
 
    	
Total
   (in k€)
    
	
2007
    	
 
    	
[*]+ [*] (μbio)
    	
 
    	
[*]
    	
 
    	
[*]**
    	
 
    	
[*]
    
	
2008
    	
 
    	
[*]+[*] (μion)
    	
 
    	
[*]
    	
 
    	
[*] **
    	
 
    	
[*]
    

 

·FTE rates of $[*], converted at $[*]/€ to give €[*] per year

 

** Subcontracting of sterility test at VETTER + shipment

 

16

 

APPENDIX B

 

EXTENDED WORK PLAN

 

I.              2007 BUDGET

 

I.1           DRUG SUBSTANCE

 

	
Additional test on batch   01- 402 
   (residual solvents, TFA and optical rotation)
    	
 
    	
External cost*
    	
 
    	
[*]€
    
	
Stability study of batch   01- 402
    	
 
    	
Internal cost — FTE**
   [*]
    	
 
    	
[*]€
    
	
Retest of reference   material
    	
 
    	
Internal cost — FTE**
   [*]
    	
 
    	
[*]€
    
	
Total
    	
 
    	
 
    	
 
    	
[*]€
    

 

* Subcontracting of Additional test on batch 01- 402 at EXPANSIA + shipment 
 ** FTE rates at [*]€

 

1.2          DRUG PRODUCT

 

	
FTE
    	
 
    	
FTE cost*
    	
 
    	
External cost**
    	
 
    	
Total
    
	
[*] + [*] (μbio)
    	
 
    	
[*]€
    	
 
    	
[*]€
    	
 
    	
[*]€
    

 

* FTE rates at [*]€
 ** Subcontracting of sterility test at VETTER + shipment

 

1.3          QUARTERLY BREAKDOWN FOR EXTENDED WORK PLAN ACTIVITIES  PERFORMED IN 2007

 

	
 
    	
 
    	
2007
    	
 
    	
2007
    	
 
    
	
In K€
    	
 
    	
Q1
    	
 
    	
Q2
    	
 
    	
Q3
    	
 
    	
Q4
    	
 
    	
Total
    	
 
    
	
External Costs
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    
	
 
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    
	
Internal Costs
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    
	
 
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    
	
FTEs
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    
	
Total Costs 
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    

 

* Confidential Treatment Requested by the Registrant. Redacted Portion Filed Separately with the Commission.

 

17

 

II.            2008 BUDGET

 

II. 1.        DRUG SUBSTANCE

 

	
Stability   study of batch 01- 402
    	
 
    	
Internal cost — FTE**
   [*]
    	
 
    	
[*]€
    
	
Total
    	
 
    	
 
    	
 
    	
[*]€
    

 

** FTE rates at [*]€

 

11.2        DRUG PRODUCT

 

	
FTE
    	
 
    	
FTE cost *
    	
 
    	
External cost**
    	
 
    	
Total
    
	
[*] + [*] (μbio)
    	
 
    	
[*]€
    	
 
    	
[*]€
    	
 
    	
[*]€
    

 

* FTE rates at [*]€

** Subcontracting of sterility test at VETTER + shipment

 

11.3        QUARTERLY BREAKDOWN FOR EXTENDED WORK PLAN ACTIVITIES PERFORMED IN 2008

 

	
 
    	
 
    	
2008
    	
 
    	
2008
    	
 
    
	
 
    	
 
    	
Q1
    	
 
    	
Q2
    	
 
    	
Q3
    	
 
    	
Q4
    	
 
    	
Total
    	
 
    
	
External costs
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    
	
Internal costs (Drug Substance)
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    
	
Internal costs (Drug Product)
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    
	
FTEs
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    
	
Total costs
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    

 

* Confidential Treatment Requested by the Registrant. Redacted Portion Filed Separately with the Commission.

 

18Exhibit 10.9

 

STRICTLY CONFIDENTIAL

 

AMENDMENT N°3 TO PHARMACEUTICAL DEVELOPMENT AGREEMENT*

 

BETWEEN

 

BEAUFOUR IPSEN INDUSTRIE S.A.S., a French corporation incorporated under the laws of France, located at rue d’Ethe Virton, 28100, France, duly represented by Jean-Pierre Dubuc, President,

 

hereinafter referred to as “Ipsen”, on the one hand,

 

AND

 

RADIUS HEALTH Inc., a United-States corporation incorporated under the laws of the State of Delaware, United Sates, with its principal office at 300 Technology Square-5th Floor, Cambridge, MA, USA and formerly known as Nuvios, Inc., duly represented by Richard Lyttle, Chief Executive Officer,

 

hereinafter referred to as “Radius”, on the other hand.

 

WHEREAS

 

A.                                   Ipsen and Radius are parties to that certain License Agreement dated September 27, 2005 (the “License Agreement”).

 

B.                                     Within the framework of the License Agreement, Ipsen and Radius have entered into a pharmaceutical development agreement to develop a multidose injection for BIM 44058 dated as of January 2, 2006 (the “Pharmaceutical Development Agreement”) pursuant to which Ipsen performs certain research and development tasks and activities in view of developing a new formulation of Licensed Compound and/or Licensed Product.

 

C.                                     Ipsen and Radius have decided to further extend the duration and the scope of the Work Plan and to provide for the consideration relating to such an extension under an amendment to the Pharmaceutical Development Agreement ( “Amendment n°1”).

 

D.                                    Radius has requested, and Ipsen had agreed to manufacture some further stability batches and therefore to further extend the duration and the scope of the Work Plan under a second amendment to the Pharmaceutical Development Agreement (“Amendment n°2”).

 

E.                                      The manufacture of Phase III clinical batches under the Second Extended Work Plan as identified in paragraphs 2, 4, 5 of Appendix A of Amendment n°2 was not commenced by Ipsen with authorization in writing by a Radius representative prior to the effective date of this Amendment n°3. However, the stability batches and related stability testing activities (the “Reduced Second

 

* Confidential Treatment Requested by the Registrant. Redacted Portion Filed Separately with the Commission.

 

 

Extended Work Plan”) as identified in paragraphs 1 and 3 of Appendix A of Amendment n°2 were completed or are ongoing pursuant to the terms of Amendment n°2. Accordingly, Amendment n°2 shall remain in full force and in effect until complete performance of the Reduced Second Extended Work Plan or termination of the Pharmaceutical Development Agreement in accordance with its terms.

 

F.                                      Radius has requested, and Ipsen had agreed to manufacture Phase III batches and to upgrade analytical methods to NDA filing levels for purity/impurities testing to meet full ICH requirements and therefore to further extend the duration and the scope of the Work Plan under a third amendment to the Pharmaceutical Development Agreement (this “Amendment n°3”).

 

NOW, THEREFORE, in consideration of the premises and the performance of the covenants herein contained, IT IS AGREED AS FOLLOWS:

 

1.              In this Amendment n°3, unless otherwise expressly provided herein, the capitalized words and phrases shall have the same meaning as in the Pharmaceutical Development Agreement and in Amendment n°1 and Amendment n°2 .

 

2.              The Work Plan is amended so as to include the work described in Appendix A to this Amendment n°3 (the “Third Extended Work Plan”). For clarity, all references to the Work Plan in the Pharmaceutical Development Agreement shall be deemed to include all work described in the Extended Work Plan, the Reduced Second Extended Work Plan as well as the work described in the Original Work Plan. Should Radius wish Ipsen to perform any other work in addition to the activities described in the Third Extended Work Plan, Radius and Ipsen shall enter into a new agreement or amendment.

 

3.              Timelines described in Appendix A are subject to the execution by Ipsen of an amendment to its existing agreement with Vetter.

 

4.              Activities related to the manufacture of additional Phase III clinical batches by Vetter and tested by Ipsen in [*] or [*] and any batch Scale Up Plans in the Third Extended Work Plan as identified in paragraphs 2 and 4 of Appendix A shall not be commenced by Ipsen unless authorized in writing by Nick Harvey, Chief Financial Officer of Radius or other representative designated in writing by Radius.

 

5.              Payments:

 

(a)          Subject to any modification of the budget included in the Third Extended Work Plan to be prior agreed in writing by the parties by Mike Dey, Vice-President, Pharmaceutical Development for Ipsen and by Nick Harvey, Chief Financial

 

* Confidential Treatment Requested by the Registrant. Redacted Portion Filed Separately with the Commission.

 

2

 

Officer to Radius or by any other representative designated by the relevant Party, the total amount to be paid by Radius to Ipsen in connection with the research activities and tasks pursuant to the Third Extended Work Plan and this Amendment n°3 shall be as specified in the here attached Appendix A.  Such total amount includes all costs in connection with such research activities, including costs of materials, supplies, services, personnel, subcontractors and overhead, regardless of whether such research activities are performed by Ipsen or by a subcontractor or both. The budget included in the Third Extended Work Plan as described in Appendix A to this Amendment n°3 shows the breakdown by calendar quarter of such total amounts in Euros.

 

(b)         Ipsen shall invoice Radius no later than [*] ([*]) days after the end of each calendar quarter for the amount corresponding to actual FTE time spent as per timesheets incurred plus actual external cost bills received and approved by Ipsen during the elapsed quarter, as shall in each case be reported in reasonable detail on the invoice annex. Radius shall make payment of each invoice within [*] ([*]) days after receipt thereof in Euros.

 

(c)          Without the prior written consent of Radius, in no event shall Ipsen invoice Radius for an amount due in respect of any calendar year that is greater than the amount budgeted for such calendar year in the Third Extended Work Plan plus the [*] percent ([*]%) limit defined in article 4(d) of this Amendment n°3. In addition, and notwithstanding anything expressed or implied in this Amendment n°3 to the contrary (including without limitation, the Third Extended Work Plan), in no event shall Radius have any obligation to make payments to Ipsen pursuant to this Amendment n°3 for any work done by Ipsen at any time after [*] unless Radius shall have authorized in writing any such work.

 

Radius shall pay for all work in respect of which Ipsen has entered into legally binding commitments with subcontractors and which occurs before [*], that may not be cancelled by Ipsen without incurring penalties, provided that all of such work is within the framework of the Third Extended Work Plan and the cost of such work is within the budget included in the Third Extended Work Plan.

 

The remaining samples from stability studies will be made available for Radius to ship to Radius nominated contract laboratory by [*]. Should Radius request in writing that Ipsen conduct work on Radius behalf, Ipsen will be under no obligation to conduct such work.

 

(d)         Should external costs incurred by Ipsen in relation to the performance of  the activities described in the Third Extended Work Plan be more than as specified in Appendix A hereby attached for such activities, Radius shall reimburse Ipsen such additional costs up to a maximum of [*] percent ([*]%) of the relevant annual amount described in Appendix A for the performance of the specific tasks that resulted in such additional costs. In addition, should internal costs incurred by Ipsen in relation to performance of the Third Extended Work Plan be more than as specified in Appendix A due to an increase in the number of  FTE’s required (but not the cost per FTE), Radius shall reimburse Ipsen such additional costs up to a

 

* Confidential Treatment Requested by the Registrant. Redacted Portion Filed Separately with the Commission.

 

3

 

maximum of [*] percent ([*]%) of the relevant annual amount described in Appendix A for the performance of the specific tasks that resulted in such additional costs.  In either case, any reimbursement of costs in excess of such percentage will have to be prior agreed by Radius and, in the absence of any such prior agreement by Radius, shall be the responsibility of Ipsen. Ipsen shall use all reasonable efforts to avoid any such cost overruns.

 

6.              This Amendment n°3 shall enter into force retroactively upon its signature and shall remain in full force and in effect until complete performance of the Third Extended Work Plan or termination of the Pharmaceutical Development Agreement in accordance with its terms.

 

7.              All other terms and conditions of the Pharmaceutical Development Agreement shall remain in full force and effect and shall apply to this Amendment n°3 which is made part of the Pharmaceutical Development Agreement.

 

8.              This Amendment n°3 shall be governed by, interpreted and construed in accordance with the laws of the State of New York, U.S.A., without regard to the conflicts of law principles, and shall not be governed by the United Nations Conventions of International Contracts on the Sale of Goods (the Vienna Convention).

 

IN WITNESS WHEREOF, the Parties hereto have caused this Amendment n°2 to be duly executed by their respective duly authorized representatives:

 

 

	
Date:  June 13, 2010
    	
 
    	
Date:  June 16, 2010
    
	
 
    	
 
    	
 
    
	
SIGNED by  B.N. Harvey
    	
 
    	
SIGNED by Jean-Pierre Dubuc  
    
	
/s/ B.N. Harvey
    	
 
    	
/s/ Jean-Pierre Dubuc
    
	
 
    	
 
    	
 
    
	
on behalf of  
    	
 
    	
as President of  
    
	
RADIUS HEALTH Inc.
    	
 
    	
BEAUFOUR IPSEN INDUSTRIE S.A.S.
    

 

* Confidential Treatment Requested by the Registrant. Redacted Portion Filed Separately with the Commission.

 

4

 

APPENDIX  A

 

5

 

Updated CMC Activities for BA058

Phase III Supply

28th May 2010

 

1 Manufacture of Clinical Batches [*] ml Cartridges

 

·                  Manufacturing of [*] Clinical Batches by Vetter and Tested by Ipsen

·                  Gives nominally [*] each, placebo and [*]mg/ml cartridges

·                  from [*] x  approximately [*] cartridge lots of placebo

·                  from [*] x approximately [*] cartridge lots BA 058 [*] mg/ml

·                  based on removal of required

·                  QC and retention ([*] units) from each lot

·                  full ICH stability samples ([*] units) on one lot

 

·                  to provide at least [*] cartridges for clinical use,

·                  from [*] x [*]  cartridges per lot post filling and inspection

·                  less [*] x [*] for QC + [*] for stability = [*] cartridges

·                  Manufacturing dates agreed with Vetter for active/placebo batches made in three campaigns in [*], weeks [*]-[*], [*]-[*] and [*]-[*].

·                  Cartridges despatch to Radius nominated CRO  is planned :

·                  [*] batch active and placebo despatched by end [*]

·                  [*] batch active and placebo despatched by end [*]

·                  [*] batch active and placebo despatched by end [*]

 

[*]

·                  Requiring re-supply in [*], for [*] patients recruited at [*]-[*] per month, over [*] to [*].  Slower recruitment e.g. over [*] months would mean re-supply in [*].

 

·                  Assumes

·                  Purchase Order for €[*] k for [*] lots approved by end [*]

·                  API received by Vetter with C of A by end [*], with full release for use in Ph III documented by Radius

·                  Crimp Caps delivered to Vetter with C of A by mid [*]

·                  [*] weeks post manufacture release by Vetter QA department

 

·                  Costs for Manufacture of [*] lots by Vetter   € [*] k

·                  From € [*] /lot, € [*] project management and € [*] microbiological validation costs

 

2 Testing, Release and Stability Testing of Phase III Lots

 

Supply assumptions above include [*] cartridges (active and placebo] from which samples are assumed to be removed for full ICH stability on one lot.

 

* Confidential Treatment Requested by the Registrant. Redacted Portion Filed Separately with the Commission.

 

6

 

	
·      Upgrade analytical methods for assay/purity to meet ICH   requirements, for testing of Ph III supplies:
    	
 
    	
FTE   Costs
    	
 
    	
€   [*] k
    
	
 
    	
 
    	
External
    	
 
    	
€   [*] k
    
	
 
    	
 
    	
 
    	
 
    	
 
    
	
·      Testing of [*] phase III   batches in [*]:
    	
 
    	
 
    	
 
    	
€   [*] k
    
	
 
    	
 
    	
 
    	
 
    	
 
    
	
·      Full ICH stability study ([*]-months) on one [*] mg/mL lot with upgraded methods:
    	
 
    	
FTE   cost
    	
 
    	
€   [*] k
    
	
 
    	
 
    	
External
    	
 
    	
€   [*] k
    
	
 
    	
 
    	
 
    	
 
    	
 
    
	
·      Project management activities at Ipsen:
    	
 
    	
 
    	
 
    	
€   [*] k
    
	
 
    	
 
    	
 
    	
 
    	
 
    
	
·      IND update :
    	
 
    	
 
    	
 
    	
€   [*] k
    

 

Phasing of costs is shown below.

 

	
Costs €000s
    	
 
    	
FTE Cost
    	
 
    	
External
    	
 
    	
FTE Cost
    	
 
    	
External
    	
 
    	
FTE Cost
    	
 
    	
External
    	
 
    	
FTE Cost
    	
 
    	
External
    	
 
    	
FTE Cost
    	
 
    	
External
    	
 
    	
FTE Cost
    	
 
    	
External
    
	
Make and test Ph III Lots 3 x2mg/ml and 3 x Placebo
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]
    
	
Full ICH Stability on one 2010 Lot
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]
    
	
Analytical Methods Upgrade
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]
    
	
IND Update
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]
    
	
Project Management activities
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]
    
	
Make and test Ph III Lots 1 x 2mg/ml and 1 x Placebo 2011
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
 
    	
 
    	
 
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    
	
Full ICH Stability on one 2011 Lot
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
 
    	
 
    	
 
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]
    
	
Make and test Ph III Lots 1 x 2mg/ml and 1 x Placebo 2012
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    
	
Full ICH Stability on one 2011 Lot
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]
    
	
SUBTOTAL
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]
    
	
GRAND TOTAL
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]
    

 

Costs based on € [*]k per FTE

 

[*]  API needed for Manufacture and Stability Testing

 

Based on [*] x [*] cartridge lots, each requiring [*]g API, gives [*]g pure peptide weight, for manufacture of lots in [*].  Method upgrades would require [*]g peptide.

 

Reference Standard from Lonza sourced API will be required to QC test and stability test product.  Depending on how supplied, the quantities would vary from [*]g bulk or e.g. [*] vials of [*]mg.

 

* Confidential Treatment Requested by the Registrant. Redacted Portion Filed Separately with the Commission.

 

7

 

4. Scale Up Plans

 

The process currently proven has a maximum batch size of ~[*] cartridges.  To scale-up process, dedicated compounding vessel/equipment will be required.  Two facilities/filling scales are available for future development with approximately [*]-[*] maximum and [*] cartridges.

 

Based on initial annual requirements of [*] rising over [*]-[*] years to [*] cartridges per year, a batch size of [*] to ~ [*] would allow a step in scale of within [*]-[*]x, and [*]-[*] lots per year.  Batch size of [*] cartridges requires [*]g peptide, so increasing to [*] or [*] would require either ~[*]g or ~ [*]g of pure peptide.

 

Once Radius estimated volumes and preferences were confirmed (assumed by end [*]), Vetter plan for scale-up would be developed for Radius agreement (assumed [*]) for implementation in [*], or later.

 

This option would allow [*] scaled up lot made in [*] to re-supply the entire remaining Ph III program in [*], with an assumed [*]m expiry.  As stability data confirms good stability of the product, this expiry date could also be extended.  This option would also provide for one additional full ICH stability study to be conducted.

 

As [*] lots would be required, a [*] lot would need to be manufactured.  The plan assumes this in [*], which would then provide less  storage time data.  Alternatively, by making [*] lots in [*], and stability studies on [*], longer term data on all [*] lots would be provided, with additional spend in [*] of ~ €[*]k.

 

* Confidential Treatment Requested by the Registrant. Redacted Portion Filed Separately with the Commission.

 

8

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