Document:

Exhibit 10.7

 

CONFIDENTIAL— Execution Copy

 

LICENSE AGREEMENT AMENDMENT NO. 1*

 

This Amendment No.°1 (the “Amendment No. 1”) is entered into on September 12, 2007 (the “Amendment Date”) by and between Radius Health Inc., a Delaware Corporation, formerly known as Nuvios, Inc. with its principal office at 300 Technology Square —  5th floor, Cambridge, MA 02139, United States of America, on behalf of itself and its Affiliates (“Radius”), and SCRAS S.A.S., a French corporation, with its principal office at 42 rue du Docteur Blanche, 75016 Paris, France on behalf of itself and its Affiliates (“Ipsen”).

 

RECITALS

 

1.                           Ipsen and Radius (the “Parties”) entered into the certain license agreement as of September 27, 2005 (the “Agreement”).

 

2.                           The Parties wish to enter into this Amendment No. 1 to amend certain provisions of the Agreement in connection with the grant by Radius to Novartis International Pharmaceutical Ltd. (“Novartis”) of certain option rights to take a sublicense from Radius.

 

NOW THEREFORE, in consideration of the mutual covenants and promises contained in this Amendment No. 1, the Parties agree as follows:

 

ARTICLE 1  —  CONDITIONS PRECEDENT

 

This Amendment No. 1 shall enter into force upon the completion of the following cumulative conditions precedent:

 

1.1          Radius and Novartis enter into an option agreement whereby Novartis will have an option to license certain intellectual property rights from Radius under terms and conditions to be agreed (the “Option Agreement”); and

 

1.2          Radius and Novartis agree on the terms of a fully-fledged license agreement which will be attached to the Option Agreement (the “Radius-Novartis Agreement”) as set forth in the Option Agreement; and

 

1.3          Novartis exercises its option under the Option Agreement within [*] ([*]) months after Novartis has received the Study Report (as defined in the Option Agreement) and Radius and Novartis execute the Radius-Novartis Agreement.

 

In the event the condition precedent in paragraph 1.1 is not completed by 31 December 2007, or the condition precedent in paragraph 1.2 is not completed by 31 March 2008 or the condition precedent in paragraph 1.3 is not completed as set forth above, this Amendment No. 1 shall be deemed null and void at the later date relating to the completion of these three conditions precedent as set forth above.

 

ARTICLE 2  —  AMENDMENTS TO CERTAIN PROVISIONS OF THE AGREEMENT

 

2.1          Third Party Payments. Section 4.3 of the Agreement is amended to read in full as follows:

 

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

 

 

“4.3 Adjustments Related to Third Party Payments. If, in connection with any Licensed Compound or Licensed Product, Nuvios is obligated to remit payments to third parties in relation to intellectual property rights owned by such third parties including when Nuvios is obliged to license in formulation technology from third party for use with the Licensed Product and/or as determined pursuant to Article 11.7 of this Agreement Nuvios shall be permitted to offset against payments due to Ipsen under this Agreement up to [*] percent ([*]%) of any payments due to such third parties during any calendar year, provided however that this offset does not result in a reduction of more than [*]% of the royalty payments that would otherwise have been due to Ipsen in any calendar year.

 

If (i) in connection with any Licensed Compound or Licensed Product, Novartis is obligated to remit payment to third parties in relation to intellectual property rights owned by such third parties including when Novartis is obliged to license in formulation technology from third party for use with the Licensed Product and/or as determined pursuant to Article 11.7 of this Agreement (the “NVS Third Party Payments”) and (ii) pursuant to the Radius-Novartis Agreement, Novartis is entitled to deduct part or all of NVS Third Party Payments from the payments due by Novartis to Nuvios (the “Novartis Deduction”), Nuvios shall be permitted to offset against royalty payments due to Ipsen under this Agreement up to [*] percent ([*]%) of the Novartis Deduction during any calendar year, provided however that (a) this offset does not result in a reduction of more than [*]% of the royalty payments that would otherwise have been due to Ipsen in any calendar year and (b) this offset is not superior to [*]% of the NVS Third Party Payments.

 

In no event shall the provisions of the two (2) above paragraphs be applied cumulatively and in no event shall any offset(s) pursuant to this Section 4.3 result in a reduction of more than [*]% of the royalty payments that would otherwise have been due to Ipsen in any calendar year.”

 

2.2          Royalty Term. Section 1.59 of the Agreement is amended to read in full as follows:

 

“1.59 Royalty Term shall mean for each Licensed Product and each country of the Territory, the later of (a) expiration of the last to expire Licensed Product Claim in such country with respect to such Licensed Product and (b) [*] ([*]) years from the First Commercial Sale in such country of such Licensed Product. Notwithstanding anything express or implied in the foregoing provisions of this definition, if, with respect to any Licensed Product in any country of the Territory, on the date that is [*] ([*]) years from the First Commercial Sale in such country of such Licensed Product, there is no Valid Claim of an issued patent within the Ipsen Patent Rights or the Joint Patent Rights that Covers such Licensed Product in such country, then the Royalty Term for such Licensed Product in such country shall automatically expire and terminate on such date.”

 

2.3          Payment of Share of Sublicense. Section 3.3 is revised to include the following text in the header to the right hand column of the table:

 

“Share payable within [*] ([*]) days following receipt of payments from Novartis under the Radius-Novartis Agreement. Nuvios shall issue the invoice to Novartis promptly upon the occurrence of the event triggering the payments and shall inform Ipsen promptly upon receipt of the corresponding payments from Novartis. In case of a failure of Novartis to pay the due sums to Nuvios within the delay as set forth in the Radius-Novartis Agreement, Nuvios shall pay the

 

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

 

2

 

Share due to Ipsen within [*] ([*]) days upon expiry of the delay granted to Novartis for the payment due to Nuvios as set forth in the Radius-Novartis Agreement.”

 

2.4          Treatment of Sublicensee on Termination. A new Section 15.7 is added to the Agreement to read in full as follows:

 

“15.7 Sublicenses. Notwithstanding any provision of this Agreement to the contrary, in the event this Agreement is terminated by Ipsen pursuant to Section 15.2 and in the event such termination does not result from a material breach of Nuvios’ obligations which results from the performance or the lack of performance by Novartis of its obligations under the Radius-Novartis Agreement, Radius-Novartis Agreement shall be novated from Nuvios to Ipsen and shall become a direct license between Ipsen and Novartis under the following conditions: (i) Novartis agrees to such novation in a writing pursuant to which it acknowledges each of the statements in the following clauses (ii)-(iv), (ii) Ipsen shall have all Nuvios’ rights as provided in the Radius-Novartis Agreement; (iii) Ipsen shall not be bound by obligations towards Novartis in excess of its obligations as set forth in this Agreement including in particular but without limitation Ipsen shall not assume, and shall not be responsible to Novartis for any representations and warranties other than the ones stated in this Agreement, and (iv) Novartis shall remain bound by the terms and conditions of the Radius-Novartis Agreement as if the Radius-Novartis Agreement had been entered into by Ipsen and Novartis.”

 

2.5          Payments and Financial Reporting.

 

(a) Section 1.39 of the Agreement is amended to read in full as follows:

 

“Net Sales” means the net sales made by Nuvios, Novartis and any of their Affiliates or sublicensees (the “Selling Party”) of the Licensed Product sold to Third Parties other than sublicensees in bona fide, arm’s-length transactions, as determined in accordance with the Selling Party’s usual and customary accounting methods, which are in accordance with its Accounting Standards as consistently applied by such Selling Party: (a) in the case of any sale or other disposal of a Licensed Product between or among Novartis and its Affiliates or sublicensees, for resale, Net Sales shall be calculated only on [*]; (b) in the case of any sale which is not invoiced or is delivered before invoice, Net Sales shall be calculated [*]; (c) in the case of any sale or other disposal for value, such as barter or counter-trade, of any Licensed Product, or part thereof other than in an arm’s-length transaction exclusively for money, Net Sales shall be calculated on [*] or [*]; and (d) in the event the Licensed Product is sold as a Bundled Licensed Product, the Net Sales of the Licensed Product, for the purposes of determining royalty payments, shall be determined by multiplying the Net Sales of the Bundled Licensed Product by the fraction, A/(A+B) where A is the [*] in a particular country of the Licensed Product when sold separately in finished form and B is the [*] in that country of the other Licensed Product(s) sold separately in finished form. In the event that such [*] cannot be determined for both the Licensed Product and the other Licensed Product(s) in Bundled Licensed Product, Net Sales for purposes of determining royalty payments shall be agreed by the Parties based on the [*] each component, such agreement not to be unreasonably withheld. For the avoidance of doubt, sales between Novartis, its Affiliates, sublicensees and designees shall not be considered Net Sales (unless such Person is the end user of the Licensed Product), which shall be calculated on Net Sales of Novartis, its Affiliates, sublicensees and designees to independent third party customers.”

 

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

 

3

 

(b) Section 5.4 of the Agreement is revised to include the following text at the end of Section 5.4:

 

“Ipsen will pay any and all taxes levied on account of any payments made to it under this Agreement. If any taxes are required to be withheld by Nuvios, Nuvios will: (a) deduct such taxes from the payment made to Ipsen; (b) timely pay the taxes to the proper taxing authority; (c) promptly send proof of payment to Ipsen; and (d) promptly and reasonably assist Ipsen in its efforts to obtain a credit for such tax payment. Each Party agrees to reasonably assist the other Party in lawfully claiming exemptions from and/or minimizing such deductions or withholdings under double taxation laws or similar circumstances.”

 

(c) The first sentence of Section 5.2 of the Agreement is revised to read in full as follows:

 

“5.2 Payments and Reporting. After the First Commercial Sale of Licensed Product in the Territory, Nuvios shall calculate royalties quarterly at the end of each Accounting Period (i.e., March 31, June 30, September 30 and December 31) and shall pay royalties on Net Sales quarterly within [*] ([*]) days after the end of each Accounting Period. Nuvios may delay the payment of royalties on Net Sales until a maximum of [*] ([*]) days after the end of each Accounting Period provided that Nuvios shall pay to Ipsen interest on such late payment between the [*] and the effective date of payment of the royalties, at the rate of EURIBOR 1 month plus [*]% on sales in EURO and LIBOR 1 month USD plus [*]% on sales in USD.”

 

2.6          No other changes. Except to the extent expressly amended by this Amendment No. 1, all of the terms, provisions and conditions of the Agreement remain unchanged and in full force and effect. The term “Agreement”, as used in the Agreement, shall henceforth be deemed to be a reference to the Agreement as amended by this Amendment No. 1.

 

ARTICLE 3  —  MISCELLANEOUS

 

3.1          Duration. This Amendment No.1 shall enter into force as set forth in Article 1 and shall remain in full force and effect until the Agreement is terminated, provided however that Articles 2.4 and 3.3 of this Amendment No. 1 shall survive any expiry or termination of the Agreement.

 

3.2          Definitions. Capitalized terms used in this Amendment No. 1 and not defined herein are used with the meanings ascribed to them in the Agreement.

 

3.3          Execution Copy. This Amendment No. 1 may be executed in counterparts, each of which will be deemed an original with all such counterparts together constituting one instrument.

 

IN WITNESS WHEREOF, the Parties hereto have caused this Amendment No. 1 to be executed by their respective duly authorized officers, and have duly delivered and executed this Amendment No. 1 as of the Amendment Date.

 

	
RADIUS HEALTH INC.
    	
SCRAS   S.A.S
    
	
 
    	
 
    	
 
    	
 
    	
 
    
	
By:
    	
/s/   C. R. Lyttle
    	
 
    	
By:
    	
/s/   Claire Giraut
    
	
Name:
    	
C.   Richard Lyttle
    	
 
    	
Name:
    	
Claire   Giraut
    
	
Title:
    	
President   & CEO
    	
 
    	
Title:
    	
Director   General
    

 

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

 

4Exhibit 10.8

 

STRICTLY CONFIDENTIAL

 

AMENDMENT N°2 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 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 (this “Amendment n°2”).

 

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°2, 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.

 

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

 

 

2.                                      The May 31, 2007 deadline agreed upon for the performance by Ipsen or its subcontractors of all the work set out in the Extended Work Plan further to Amendment n°1 and its payment by Radius, is extended to December 31, 2012.

 

For sake of clarity, any reference to the date of December 31, 2006 in Article 10 of the Pharmaceutical Development Agreement and May 31, 2007 in the Amendment n°1 which relates to the performance of the Original Work Plan and the Extended Work Plan shall be replaced by and extended to December 31, 2012. The budget agreed upon in respect to all the work described in the Original Work Plan and the Extended 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°2 (the “Second 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 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 Second Extended Work Plan, Radius and Ipsen shall enter into a new agreement or amendment.

 

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

 

5.                                      Activities related to the manufacture of Phase III clinical batches by Vetter and tested by Ipsen in the Second Extended Work Plan as identified in paragraphs 2, 4, 5 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.

 

6.                                      Payments:

 

(a)                                  Subject to any modification of the budget included in the Second 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 Second Extended Work Plan and this Amendment n°2 shall be as specified in the here aftached 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 Second Extended Work Plan as described in Appendix A to this Amendment n°2 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

 

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

 

2

 

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 Second Extended Work Plan plus the [*] percent ([*]%) limit defined in article 4(d) of this Amendment n°2. In addition, and notwithstanding anything expressed or implied in this Amendment n°2 to the contrary (including without limitation, the Second Extended Work Plan), in no event shall Radius have any obligation to make payments to Ipsen pursuant to this Amendment n°2 for any work done by Ipsen at any time after December 31, 2012 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, 2012, that may not be cancelled by Ipsen without incurring penalties, provided that all of such work is within the framework of the Second Extended Work Plan and the cost of such work is within the budget included in the Second 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, 2012. 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 Second 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 Second 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 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.

 

7.                                      This Amendment n°2 shall enter into force retroactively upon its signature as of January 1st, 2009 and shall remain in full force and in effect until complete performance of the

 

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

 

3

 

Second Extended Work Plan or termination of the Pharmaceutical Development Agreement in accordance with its terms.

 

8.                                      All other terms and conditions of the Pharmaceutical Development Agreement shall remain in full force and effect and shall apply to this Amendment n°2 which is made part of the Pharmaceutical Development Agreement.

 

9.                                      This Amendment n°2 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:   January 30, 2009
    	
 
    	
Date:   January 17, 2009
    
	
 
    	
 
    	
 
    
	
SIGNED   by B.N. HARVEY
    	
 
    	
SIGNED   by Jean-Pierre Dubuc
    
	
CFO
    	
 
    	
 
    
	
 
    	
 
    	
 
    
	
/s/   B.N. Harvey
    	
 
    	
/s/   Jean-Pierre Dubuc
    
	
on   behalf of
    	
 
    	
as   President of
    
	
RADIUS   HEALTH Inc.
    	
 
    	
BEAUFOUR   IPSEN INDUSTRIE S.A.S.
    

 

4

 

APPENDIX A

 

 

CMC Activities for BA058
 Phase III
 Radius / Ipsen

 

1 Stability Batches at Vetter

 

·                  Component Supply for [*]ml Cartridge with new crimp cap + current bromobutyl stopper

·                  Stoppers available as standard stock item in Vetter.

·                  Standard RTS crimp caps require 12-14 weeks delivery; as already ordered, estimated delivery date week commencing 26th Jan 2009

·                  Machinability test (cartridges fill with new crimp caps and maximum filling volume and dimensional limits) Project work = [*]€

 

 

·                  Stability Batches Scheduled at Vetter in March 2009

	
·
    	
 
    	
BA058   placebo
    	
 
    	
 
    
	
·
    	
 
    	
BA058   [*]mg/ml solution
    	
 
    	
[*]   cartridges / batch
    
	
·
    	
 
    	
BA058   [*]mg/ml solution
    	
 
    	
 
    
	
 
    	
 
    	
 
    	
 
    	
 
    
	
Uses   same equipment as used in Ph III
    	
 
    	
 
    
	
Manufacturing   starting date
    	
 
    	
March 09
    
	
Stability   studies start
    	
 
    	
April 2009
    

 

·                  Costs and Timings

 

Cartridge fill volume will be increased to maximum, to increase assurance of delivering [*] doses from each cartridge

 

	
Filling Stability/Technical batches
    	
 
    	
€ [*]
    

From €[*] for placebo & [*]€ for stability batches [*]&[*]mg/ml, + [*]€ project management, microbiological validation [*]€, Closure container integrity test [*]€.

 

2 Clinical Batches [*] ml Cartridges

 

·                  Manufacturing of 3 Clinical Batches by Vetter and Tested by lpsen

·                  BA058 placebo

·                  BA058 [*]mg/ml solution [*] cartridges / batch

·                  BA058 [*]mg/ml solution

 

·                  Planned in May 2009 :

·                  Clinical studies start in July 2009

 

	
·
    	
 
    	
Costs
    	
 
    	
€ [*]
    

·                  From [*] per lot + [*]€ project management costs

 

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

 

 

3 Stability Testing of Phase III Preparation Lots

 

	
Activities
    	
 
    	
Duration
    	
 
    	
FTE*
    	
 
    	
FTE cost,
   (k€)**
    	
 
    	
External cost
   (k€)
    
	
Formulation   and Process Development
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    
	
New   crimp caps Supply
    	
 
    	
[*] weeks
    	
 
    	
—
    	
 
    	
[*]
    	
 
    	
[*]
    
	
Sterile   filtration validation with new API (Millipore)
    	
 
    	
[*] months
    	
 
    	
F: [*]
   A: [*]
    	
 
    	
[*]
    	
 
    	
[*]
    
	
Stability   Studies
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    
	
Machinability   test & project work
    	
 
    	
[*] month
    	
 
    	
—
    	
 
    	
[*]
    	
 
    	
[*]
    
	
[*]-month   ICH stability study (2 active + 1 placebo): manufacturing + stab study at 5°C   for [*]months & 25°C for [*] months & stab-in-use + Mixing   study, filtration trials (Vetter) + μbio validation
    	
 
    	
[*] months (including agreement) Final time point: [*]
    	
 
    	
F: [*]
   A: [*]
   μ: [*]
    	
 
    	
[*]
    	
 
    	
[*]
    
	
 
    	
 
    	
TOTAL
    	
 
    	
 
    	
 
    	
[*]
    	
 
    	
[*]
    

 

* F: formulation - A: Analytical - μ: Microbiology

** FTE rates of €[*] per year

 

4 Testing of Ph III Supplies

 

	
Activities
    	
 
    	
Duration
    	
 
    	
FTE*
    	
 
    	
FTE cost,
   (k€)**
    	
 
    	
External cost
   (k€)
    
	
Clinical   Supply
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    
	
Phase   III clinical batches manufacturing + release (2 active + 1 placebo)
    	
 
    	
[*] months (including agreement)
    	
 
    	
F: [*]
   A: [*]
   μ: [*]
    	
 
    	
[*]
    	
 
    	
[*]
    
	
Re-assay   program to verify stability
    	
 
    	
[*]months
    	
 
    	
A: [*]
   μ: [*]
    	
 
    	
[*]
    	
 
    	
[*]
    
	
IND
    	
 
    	
[*] months
    	
 
    	
F: [*]
    	
 
    	
[*]
    	
 
    	
[*]
    
	
Project   Management
    	
 
    	
—
    	
 
    	
F: [*]
    	
 
    	
[*]
    	
 
    	
[*]
    
	
 
    	
 
    	
 
    	
 
    	
TOTAL
    	
 
    	
[*]
    	
 
    	
[*]
    
	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
[*]
    	
 
    	
 
    

 

* F: formulation - A: Analytical - μ: Microbiology

** FTE rates of €[*] per year

 

5 Phasing of Costs for Ph III Program

 

BA058 Phase III Quarterly breakdown for work plan activities

 

Drug Substance & Drug Product Program

 

	
 
    	
 
    	
2009
    	
 
    	
2010
    	
 
    	
2011
    	
 
    	
2012
    	
 
    	
 
    
	
In   €000
    	
 
    	
Q1
    	
 
    	
Q2
    	
 
    	
Q3
    	
 
    	
Q4
    	
 
    	
Q1
    	
 
    	
Q2
    	
 
    	
Q3
    	
 
    	
Q4
    	
 
    	
Q1
    	
 
    	
Q2
    	
 
    	
Q3
    	
 
    	
Q4
    	
 
    	
Q1
    	
 
    	
Q2
    	
 
    	
Q3
    	
 
    	
Q4
    	
 
    	
Total
    
	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    
	
External   costs
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]
    
	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    
	
Internal   costs
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
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[*]
    	
 
    	
[*]
    
	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    
	
Total   costs/Quarter
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
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[*]
    	
 
    	
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[*]
    	
 
    	
[*]
    	
 
    	
[*]
    

 

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

 

 

	
Total   cost/year
    	
 
    	
[*]
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
[*]
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
[*]
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
[*]
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
[*]
    

 

API costs not included; API is supplied by Radius

 

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

 

 

6 API needed for Drug Product development activities

 

·                  Estimation based on available BA058 API available in stock on September, 2008

 

	
Activities
    	
 
    	
Units manufactured
    	
 
    	
API (pure)
   needed
    	
 
    	
API batch #
    
	
Stability   studies (ICH Current Formulation with new crimp caps [*]mg/ml &   [*]mg/ml
    	
 
    	
[*]   cartridges as 1 x [*] ea of [*]mg/ml, [*]mg/ml & placebo
    	
 
    	
[*]g   + [*]g = [*]g
    	
 
    	
Lonza   API in final cartridge CC and stopper at Vetter at scale for Ph III
    
	
Optimize/Validate   analytical Method
    	
 
    	
/
    	
 
    	
[*]   g
    	
 
    	
M12507   (Ipsen batch)
    
	
Finalise   API methods
    	
 
    	
/
    	
 
    	
[*]g
    	
 
    	
Lonza   API
    
	
Sterile   filtration validation
    	
 
    	
[*]mL
    	
 
    	
[*]g
    	
 
    	
Lonza   API to mimic Ph III process
    
	
Clinical batches for Ph III  
    Made to a suitable Validation protocol & to provide   stability lots for long-term storage
    	
 
    	
1   x [*] cart x [*]mg/m1 + 1 x [*]cart x [*]mg/m1+1 x [*]cart x placebo
    	
 
    	
(GMP   batch)
   [*]g + [*]g
   [*]g + [*]g
   [*]g + [*]g
    	
 
    	
Two   strength to be manufactured at Vetter at Ph III scale
   1st lots mid 2009
   2nd lots end 2009
   3rd lots early 2010
    

 

· Total new API needed for Phase III activities = [*] g (pure peptide)

 

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

Source: [{"source": "alea-institute/alea-institute/kl3m-data-edgar-agreements/train-00190-of-00352.parquet"}, [{"source": "alea-institute/alea-institute/kl3m-data-edgar-agreements/train-00190-of-00352.parquet"}]]