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.

 

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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 €98,000 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:

 

·                                          Seventy three thousand euros (73K€) for the additional activities on Drug Substance;

 

·                                          Two hundred thirty four thousand four hundred euros (234.4K€) 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:

 

·                                          Twenty eight thousand euros (28K€) for the additional activities on Drug Substance;

 

·                                          One hundred and ninety six thousand euros (196K€) 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.

 

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(b) Ipsen shall invoice Radius no later than thirty 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 thirty 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 ten percent (10%) 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 ten percent (10%) 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 ten percent (10%) 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 ten adjustment permitted in 2007 will be of thirty thousand seven hundred (30.7) euros and in 2008 of twenty two thousand four hundred (22.4) 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.

 

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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.
    


 

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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
    	
 
    	
07k   €
    
	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    
	
-   Stability study of batch 01-402:
    	
 
    	
2007
    	
 
    	
[*]FTE
    	
 
    	
55k   €
    
	
 
    	
 
    	
2008
    	
 
    	
[*]FTE
    	
 
    	
28k   €
    
	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    
	
Retest   of reference material
    	
 
    	
2007
    	
 
    	
[*]FTS
    	
 
    	
11k   €
    
	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    
	
TOTAL
    	
 
    	
 
    	
 
    	
73k   € in 2007
    	
 
    	
 
    
	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    
	
 
    	
 
    	
 
    	
 
    	
28k   € in 2008
    	
 
    	
 
    


 




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

 

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.

 

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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 @
   6, 12 and 24 months)
    
	
6   months
    	
 
    	
03/26/07
    	
 
    	
5°C &   25°C/60%RH (including preservative effectiveness at 25°C/60%RH)
    	
 
    	
12 months
    	
 
    	
End Oct. 07
    	
 
    	
[*]+[*] (μbio) 
   + [*]€ (external cost)**
    
	
9   months
    	
 
    	
06/26/07
    	
 
    	
5°C
    	
 
    	
18 months
    	
 
    	
End April 08
    	
 
    	
[*]
    
	
12   months
    	
 
    	
09/26/07
    	
 
    	
5°C   (including preservative effectiveness)
    	
 
    	
24 months
    	
 
    	
End Oct. 08
    	
 
    	
[*]+[*] (μbio)
    
	
18   months
    	
 
    	
March 08
    	
 
    	
5°C
    	
 
    	
24 months
    	
 
    	
End Oct. 08
    	
 
    	
[*]
    
	
24   months
    	
 
    	
Sept.   08
    	
 
    	
5°C   (including preservative effectiveness)
    	
 
    	
24 months
    	
 
    	
End Oct. 08
    	
 
    	
[*]+[*] (μbio) 
   + [*] € (external cost)**
    


 




* Use date = manufacturing date + shelf life

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

 

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
   @ 6, 12 and 24 months)
    
	
6   months
    	
 
    	
02/16/07
    	
 
    	
5°C &   25°C/60%RH (including preservative effectiveness at 25°C/60%RH)
    	
 
    	
12 months
    	
 
    	
End Oct. 07
    	
 
    	
[*]+[*] (μbio)
    
	
9   months
    	
 
    	
05/16/07
    	
 
    	
5°C
    	
 
    	
18 months
    	
 
    	
End 08April
    	
 
    	
[*]
    
	
12   months
    	
 
    	
08/16/07
    	
 
    	
5°C   (including preservative effectiveness)
    	
 
    	
24 months
    	
 
    	
End Oct. 08
    	
 
    	
[*]+[*] (μbio)
    
	
18 months
    	
 
    	
Feb. 08
    	
 
    	
5°C
    	
 
    	
24 months
    	
 
    	
End Oct. 08
    	
 
    	
[*]
    
	
24   months
    	
 
    	
Aug. 08
    	
 
    	
5°C   (including preservative effectiveness)
    	
 
    	
24 months
    	
 
    	
End Oct. 08
    	
 
    	
[*]+[*] (μbio)
    


 




* Use date = manufacturing date + shelf life

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

 

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 6 months until the end of the phase II clinical study

 

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


 




** Subcontracting of sterility test at VETTER

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

 

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 day, during 1 month

 

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


 




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

 

15











 

Drug Product: cost estimation 2007 & 2008

 

	
Year
    	
 
    	
FTE
    	
 
    	
FTE cost *
   (in k€)
    	
 
    	
External cost
   (in k€)
    	
 
    	
Total
   (in k€)
    
	
2007
    	
 
    	
[*]+ [*] (μbio)
    	
 
    	
[*]
    	
 
    	
[*]**
    	
 
    	
234.4
    
	
2008
    	
 
    	
[*]+[*] (μion)
    	
 
    	
[*]
    	
 
    	
[*] **
    	
 
    	
196.0
    


 

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

 




** Subcontracting of sterility test at VETTER + shipment

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

 

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*
    	
 
    	
07k€
    
	
Stability study of batch   01- 402
    	
 
    	
Internal cost — FTE**
   [*]
    	
 
    	
55k€
    
	
Retest of reference   material
    	
 
    	
Internal cost — FTE**
   [*]
    	
 
    	
11k€
    
	
Total
    	
 
    	
 
    	
 
    	
73k€
    


 




* 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)
    	
 
    	
[*]€
    	
 
    	
[*]€
    	
 
    	
234.4€
    


 




* 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
    
	
[*] + [*] (bio)
    	
 
    	
[*]€
    	
 
    	
[*]€
    	
 
    	
[*]€
    


 




* 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.

 

18