AMENDMENT N°2 TO PHARMACEUTICAL DEVELOPMENT* AGREEMENT
Exhibit 10.8
STRICTLY CONFIDENTIAL
AMENDMENT N°2 TO PHARMACEUTICAL DEVELOPMENT*
AGREEMENT
BETWEEN
BEAUFOUR XXXXX INDUSTRIE S.A.S., a French corporation incorporated under the laws of France, located at rue d’Xxxx Xxxxxx, 00000, Xxxxxx, duly represented by Xxxx-Xxxxxx Xxxxx, 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 000 Xxxxxxxxxx Xxxxxx-0xx Xxxxx, Xxxxxxxxx, XX, XXX and formerly known as Nuvios, Inc., duly represented by Xxxxxxx Xxxxxx, Chief Executive Officer,
hereinafter referred to as “Radius”, on the other hand.
WHEREAS
X. Xxxxx 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.
X. Xxxxx 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 Xxxxxx.
5. Activities related to the manufacture of Phase III clinical batches by Xxxxxx 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 Xxxx Xxxxxx, 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 Xxxx Xxx, Vice-President, Pharmaceutical Development for Ipsen and by Xxxx Xxxxxx, 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.
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.
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:
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Date: January 30, 2009 |
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Date: January 17, 2009 |
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SIGNED by X.X. XXXXXX |
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SIGNED by Xxxx-Xxxxxx Xxxxx |
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CFO |
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/s/ X.X. Xxxxxx |
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/s/ Xxxx-Xxxxxx Xxxxx |
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on behalf of |
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as President of |
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RADIUS HEALTH Inc. |
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BEAUFOUR IPSEN INDUSTRIE S.A.S. |
APPENDIX A
CMC Activities for BA058
Phase III
Radius / Ipsen
1 Stability Batches at Xxxxxx
· Component Supply for [*]ml Cartridge with new crimp cap + current bromobutyl stopper
· Stoppers available as standard stock item in Xxxxxx.
· 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 Xxxxxx in March 2009
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· |
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BA058 placebo |
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· |
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BA058 [*]mg/ml solution |
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[*] cartridges / batch |
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· |
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BA058 [*]mg/ml solution |
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Uses same equipment as used in Ph III |
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Manufacturing starting date |
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March 09 | ||
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Stability studies start |
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April 2009 | ||
· Costs and Timings
Cartridge fill volume will be increased to maximum, to increase assurance of delivering [*] doses from each cartridge
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Filling Stability/Technical batches |
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€ [*] |
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 Xxxxxx 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
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· |
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Costs |
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€ [*] |
· 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
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Activities |
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Duration |
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FTE* |
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FTE cost, |
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External cost |
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Formulation and Process Development |
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New crimp caps Supply |
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[*] weeks |
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— |
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[*] |
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[*] |
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Sterile filtration validation with new API (Millipore) |
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[*] months |
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F: [*] |
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[*] |
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[*] |
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Stability Studies |
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Machinability test & project work |
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[*] month |
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— |
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[*] |
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[*] |
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[*]-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 (Xxxxxx) + µbio validation |
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[*] months (including agreement) Final time point: [*] |
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F: [*] |
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[*] |
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[*] |
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TOTAL |
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[*] |
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[*] |
* F: formulation - A: Analytical - µ: Microbiology
** FTE rates of €[*] per year
4 Testing of Ph III Supplies
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Activities |
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Duration |
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FTE* |
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FTE cost, |
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External cost |
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Clinical Supply |
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Phase III clinical batches manufacturing + release (2 active + 1 placebo) |
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[*] months (including agreement) |
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F: [*] |
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[*] |
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[*] |
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Re-assay program to verify stability |
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[*]months |
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A: [*] |
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[*] |
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[*] |
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IND |
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[*] months |
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F: [*] |
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[*] |
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[*] |
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Project Management |
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— |
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F: [*] |
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[*] |
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[*] |
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TOTAL |
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[*] |
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[*] |
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[*] |
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* 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
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2009 |
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2010 |
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2011 |
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2012 |
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In €000 |
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Q1 |
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Q2 |
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Q3 |
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Q4 |
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Q1 |
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Q2 |
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Q3 |
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Q4 |
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Q1 |
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Q2 |
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Q3 |
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Q4 |
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Q1 |
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Q2 |
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Q3 |
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Q4 |
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Total |
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External costs |
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[*] |
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[*] |
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[*] |
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[*] |
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[*] |
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[*] |
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[*] |
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[*] |
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[*] |
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[*] |
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[*] |
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[*] |
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[*] |
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[*] |
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[*] |
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[*] |
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[*] |
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Internal costs |
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[*] |
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[*] |
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[*] |
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[*] |
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[*] |
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[*] |
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[*] |
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[*] |
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[*] |
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[*] |
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[*] |
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[*] |
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[*] |
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[*] |
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[*] |
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[*] |
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[*] |
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Total costs/Quarter |
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[*] |
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[*] |
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[*] |
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[*] |
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[*] |
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[*] |
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[*] |
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[*] |
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[*] |
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[*] |
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[*] |
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[*] |
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[*] |
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[*] |
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[*] |
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[*] |
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[*] |
* Confidential Treatment Requested by the Registrant. Redacted Portion Filed Separately with the Commission.
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Total cost/year |
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[*] |
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[*] |
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[*] |
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[*] |
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[*] |
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
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Activities |
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Units manufactured |
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API (pure) |
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API batch # |
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Stability studies (ICH Current Formulation with new crimp caps [*]mg/ml & [*]mg/ml |
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[*] cartridges as 1 x [*] ea of [*]mg/ml, [*]mg/ml & placebo |
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[*]g + [*]g = [*]g |
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Lonza API in final cartridge CC and stopper at Xxxxxx at scale for Ph III |
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Optimize/Validate analytical Method |
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/ |
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[*] g |
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M12507 (Ipsen batch) |
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Finalise API methods |
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/ |
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[*]g |
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Lonza API |
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Sterile filtration validation |
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[*]mL |
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[*]g |
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Lonza API to mimic Ph III process |
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Clinical batches for Ph III |
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1 x [*] cart x [*]mg/m1 + 1 x [*]cart x [*]mg/m1+1 x [*]cart x placebo |
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(GMP batch) |
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Two strength to be manufactured at Xxxxxx at Ph III scale |
· Total new API needed for Phase III activities = [*] g (pure peptide)
* Confidential Treatment Requested by the Registrant. Redacted Portion Filed Separately with the Commission.
