Document:

Exhibit 10.18

 

DEVELOPMENT AND CLINICAL SUPPLIES AGREEMENT*

 

This Development and Clinical Supplies Agreement (the “Agreement”) is entered into as of the 19th day of June 2009 (“Effective Date”) by and among:

 

1.                                      3M COMPANY (“3M”) and 3M INNOVATIVE PROPERTIES COMPANY (“3M IPC”) with its principal address as 3M Center, St. Paul, MN 55144 USA; and

 

2.                                      Radius Health Inc. with its principle address at 300 Technology Square, Cambridge, MA  02139 (“RADIUS”).

 

WHEREAS

 

1.                                      3M, through its Drug Delivery Systems Division, has developed expertise and has rights in technology relating to drug delivery, including a proprietary microstructured transdermal system (“MTS”) for delivering drugs into and through the skin;

 

2.                                      RADIUS has experience and expertise in the research, development and commercialization of pharmaceutical products, including expertise in their proprietary compound BA058 (“Compound”);

 

3.                                      3M and RADIUS have entered a Feasibility Agreement for the development of BA058 coated MTS product (“Product”) on December 5, 2008 (the “Feasibility Agreement”) and are nearing conclusion of work under that agreement;

 

4.                                      3M and RADIUS wish to continue the Product development activities and to have 3M provide clinical and toxicology supplies to RADIUS suitable for preclinical, phase I and phase II studies.  If successful, RADIUS or its sublicensee may wish to further develop and commercialize the Product and 3M may wish to further develop and manufacture such Product for RADIUS or its sublicensee.

 

IT IS AGREED as follows:

 

1.                                      DEFINITIONS

 

1.1                                                                   “Affiliate” shall mean any company, firm or other entity controlling, under common control with or controlled by the relevant entity by 

 

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ownership, direct or indirect, of more than fifty percent (50%) of the shares of outstanding capital stock thereof.  For the purpose of this Agreement, the terms “3M” and “Radius” shall include each Affiliate.

 

1.2                                                                   “Information” shall mean all written information relating to Compound, MTS, components, formulations, Product, Workplan and business plans, including but not limited to data; know-how; technical and non-technical materials; and compound and formulation samples, test results and specifications, which either Party shall deliver to the other pursuant to this Agreement or produced during performance of the work hereunder, stamped “Confidential” and all oral material which each Party declares to be “confidential” and confirms in writing within thirty (30) days of disclosure.

 

1.3                                                                   “Invention” shall mean all discoveries, inventions, ideas, data, know-how whether patentable or not arising during and out of the Program under this Agreement.

 

1.4                                                                “Program” shall mean a development and clinical supplies  program comprised of work conducted pursuant to a Workplan as amended in writing from time to time in accordance with the terms of this Agreement.

 

1.5                                                                “Workplan” (an example is attached hereto as Exhibit A) shall mean a reasonably detailed definition of the scope of work to be performed, timeline and deliverables in connection with the Program.

 

2.                                      SCOPE and CONDUCT OF WORK:

 

2.1                                                            3M and RADIUS shall use reasonable commercial efforts to carry out their obligations in respect of the work described in the Workplan in a timely and effective manner making available those of their respective personnel necessary to perform the Workplan.  The Workplan is staged in a series of go/no go decision points.

 

2.2                                                            3M will carry out agreed development activities relating to the MTS array, coating, and applicator in conjunction with Compound as detailed in the Workplan.  3M will develop formulations as detailed in the Workplan.

 

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2.3                                                            Any material change in the Workplan requiring more than a [*]% increase in the estimated cost to Radius specified in Exhibit C for any phase of the Workplan (having reference to the upper bound of the estimated cost for such phase) shall be agreed between the Parties in writing in the form of a change order, the form of which is attached hereto as Exhibit B (a “Change Order”) via the change order process provided in Section 2.4.

 

2.4                                                            If Radius elects to make changes to the subject matter or scope of any Program, Radius will provide 3M with the information set forth in Exhibit B (“Change Order Form”), and, within 10 business days, the Parties will in good faith negotiate any change to the Workplan including timelines or budget.  Neither Radius nor 3M will have any obligation to implement changes or recognize suggested changes unless and until a revised Change Order Form and amended Workplan is agreed and executed by the Parties.

 

2.5                                                            3M and Radius recognize that there is no certainty as to the outcome of any Workplan, and neither makes any warranties to the other regarding technical success, commercial success, or noninfringement of resulting Product.  Furthermore, neither Radius nor 3M has any obligation under this Agreement to proceed beyond the Workplan.

 

3.                                      MANAGEMENT OF PROGRAM

 

3.1                                                            In order to have appropriate coordination between the parties in the course of the implementation of the Workplan, each party agrees to (i) appoint a technical project leader, (ii) appoint a commercialization manager, (iii) set up a joint technical team for product development management, comprising appropriate membership from 3M and RADIUS.

 

3.2                                                            The commercialization managers shall be in charge of the daily and regular communication between the parties with respect to the implementation of the Workplan. The technical project leaders shall be in charge of overseeing the implementation of the Workplan. The Joint Technical Team shall provide general guidance to the parties with respect to the implementation of the Workplan, manage all issues that may occur in connection with the Workplan, and define timelines and budget .

 

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3.3                                                            The parties will keep each other informed of their progress and provide written minutes following each meeting summarizing the results of work completed.

 

3.4                                                       Radius will supply to 3M such technical, scientific, and other information concerning the Compound and the Program as 3M shall reasonably require from time to time in order to complete the Workplan.

 

3.5                                                            Radius agrees to liaise with 3M during the course of the Program and to deal promptly within 15  business days with any reasonable requests for information or further instructions in connection with the Program.

 

4.                                      SUPPLY OF COMPOUND AND COMPONENTS

 

4.1                                                            Radius shall supply 3M (i) free of charge with sufficient quantities of the Compound to enable 3M to conduct the Program as set forth in the Workplan and (ii) a certificate of analysis for the Compound.  Any Compound unused by 3M for its Workplan activities at the termination of the Program shall be returned upon request to Radius.

 

4.2                                                            Radius shall promptly provide 3M with all information in or coming into its possession concerning the Compound that 3M will reasonably require for the safe handling, storage, testing, use and transport thereof.

 

4.3                                                            3M shall supply excipients, MTS and any other agreed upon materials or components required to complete its activities under the Workplan.

 

5.                                      CLINICAL STUDIES AND TOXICOLOGY STUDIES

 

5.1                                                            RADIUS shall at its own expense be responsible for any clinical studies and/or toxicology studies and all contact with any regulatory authority concerning the Product.

 

5.2                                                            RADIUS understands and acknowledges that it will have sole responsibility for the safe handling, storage, testing, use and transport of Product in preclinical and clinical studies.

 

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5.3                                                            3M will provide a non-confidential data package  with the CMC section of regulatory submissions in support of RADIUS’ regulatory filings.  If needed, 3M will provide for regulatory review by right of reference to Drug Master Files.

 

5.4                                                            At RADIUS’ request and expense, and with reasonable advance notice, 3M will attend and participate in meetings with the FDA or other regulatory authorities regarding Product.

 

5.5                                                            3M will also provide RADIUS any other relevant information required for regulatory filings (e.g. preclinical data, local tolerance of materials, etc.)

 

5.6                                                            3M will manufacture and release preclinical and clinical supplies under the Workplan meeting agreed upon specifications and in compliance with current Good Manufacturing Practices (“cGMPs”) and/or current Good Laboratory Practices (“cGLPs”).

 

6.                                      PAYMENTS

 

6.1                                                            Radius shall pay 3M at a rate of [*] Dollars ($[*]) per hour for work carried out in connection with the Workplan.  The estimated costs for the Workplan are listed on Exhibit C.  Both Parties acknowledge that the costs are estimates and 3M shall make reasonable efforts to stay within the estimates.  If during the program 3M anticipates that the estimated cost of the program will exceed 110% of the costs listed in Exhibit C (i.e., exceed the upper bound of the estimated cost for any phase of the Workplan), the Parties shall meet to determine what if any adjustments in the Workplan and/or estimates should be made.  3M shall have the right to increase the hourly rate once per calendar year in an amount equal to the increase in the Employment Cost Index (“ECI”) over the previous calendar year upon thirty (30) days’ written notice to RADIUS with the first such notice delivered not earlier than January 31, 2010.

 

6.2                                                            RADIUS shall also reimburse 3M for its reasonable, and documented  incidental costs incurred pursuant to the Workplan including but not limited to travel and 3M’s out-of-pocket costs.

 

6.3                                                            Payments by Radius shall be net thirty (30) days from receipt of invoice with interest accruing at 1.0% per month for late payments.

 

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

 

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6.4                                                            RADIUS shall pay the above considerations  by a wire transfer to a bank account designated by 3M.

 

Name of the bank:  JP Morgan Chase

Address:  1 Chase Manhattan Plaza

New York, NY  10081

 

ABA:  021000021

Beneficiary:  777180811

The Name of the Account Holder:  3M Company

Swift Address:  [*]

 

7.                                      INTELLECTUAL PROPERTY

 

7.1                                                            Except as necessary to conduct the work under this Agreement, neither 3M, 3M IPC, nor RADIUS grant any right or license under any patent rights or other intellectual property rights conceived prior to effective date of this Agreement.  It is, however, understood that the licenses previously granted by each party to the other party(ies) under the Feasibility Agreement shall remain in effect with respect to any rights in inventions, patents or data developed pursuant to the Feasibility Agreement in the event and to the extent such inventions, patents or data are necessary or useful to the performance of the activities contemplated by this Agreement (and subject to the provisions of this Section 7) treating such inventions, patents and data as if they were developed during and out of the work performed under this Agreement from and after the Effective Date.

 

7.2                                                            Except as otherwise provided below, any inventions conceived during and out of the work performed under this Agreement, and patents and applications filed thereon (“Program Patents”), shall be owned according to U.S. law as follows: those conceived solely by employees or agents of one party shall be owned by that party; those conceived jointly by an employee or agent of 3M and an employee or agent of Radius shall be owned jointly by 3M and Radius and will be considered Confidential Information of both parties with each joint owner having the right, subject to this Agreement, to practice, license, and transfer its undivided rights in such joint inventions without permission of or accounting to the other(s)) under the conditions provided for in this Agreement; provided that it is 

 

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

 

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expressly understood and agreed that other than to conduct the work contemplated by this Agreement, (a) 3M shall have no right to use jointly owned inventions or jointly owned Program Patents in conjunction with the Compound or any prescription pharmaceutical product that includes, as an active ingredient, any compound, other than the Compound, which is a PTH related protein, analogue or derivative but specifically excluding PTH itself or any analogue or derivative, and (b) RADIUS shall have no right to use jointly owned inventions or jointly owned Program Patents in conjunction with MTS.  Information and data developed during and resulting from the work under this Agreement (“Program Data”), solely by employees or agents of one party shall be owned by that party; those data developed jointly during and resulting from the work under this Agreement by an employee or agent of 3M and an employee or agent of Radius shall be owned jointly by 3M and Radius (and each joint owner shall have the right to practice, license, and transfer its undivided rights in such jointly owned Program Data without permission of or accounting to the other(s)) under the conditions provided for in this Agreement; provided that it is expressly understood and agreed that other than to conduct the work contemplated by this Agreement, (i) 3M shall have no right to use jointly owned Program Data in conjunction with the Compound or any prescription pharmaceutical product that includes, as an active ingredient, any compound, other than the Compound, which is a PTH related protein, analogue or derivative but specifically excluding PTH itself or any analogue or derivative, and (ii) RADIUS shall have no right to use jointly owned Program Data in conjunction with MTS.

 

7.3                                                            Notwithstanding the foregoing provisions of this Section 7, Program Patents and Program Data directly relating to the Compound, an improved Compound, or method of making or using Compound, regardless of inventorship, shall be owned by Radius; and Program Patents and Program Data directly relating to MTS devices (including manufacturing, coating, or uses thereof), regardless of inventorship, shall be owned by 3M.

 

7.4                                                            3M, 3M IPC and RADIUS grant each other a worldwide, perpetual, royalty-free, nonexclusive license under Program Data and Program Patents concerning or covering formulations of Compound solely for purposes of conducting the work contemplated by this Agreement.  It is expressly understood and agreed that other than to conduct the work contemplated by this Agreement, (a) 3M shall have no right to use such Program Data or Program Patents that are licensed to it by Radius under this Section 7.4 in conjunction with the Compound or any prescription 

 

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pharmaceutical product that includes, as an active ingredient, any compound, other than the Compound, which is a PTH related protein, analogue or derivative but specifically excluding PTH itself or any PTH analogue or derivative, and (b) RADIUS shall have no right to use such Program Data or Program Patents that are licensed to it by 3M or 3M IPC under this Section 7.4 in conjunction with MTS.

 

7.5                                                            The above licenses shall be transferable by 3M in connection with the sale of its MTS business or RADIUS in connection with sale of its pharmaceutical business, and sub licensable in relation to products developed, manufactured, or sold by 3M or RADIUS.

 

7.6                                                            Upon the termination of this Agreement, each party will, at its election, return or destroy any tangible materials embodying the technology owned by the other party.

 

7.7                                                            Each party shall promptly disclose to the other party(ies) any inventions to the extent related to the other party’s or parties’ materials or technology conceived during and out of the work under this Agreement, that might, under applicable law, be patentable or otherwise protectable.  Each party may prepare, file, prosecute, maintain, abandon, terminate, enforce, and otherwise handle solely owned patent rights at its sole discretion and expense.  Joint patent applications and patents may be prepared, filed, prosecuted, and maintained primarily by RADIUS at its expense if claiming an invention that is based primarily on the Compound and by 3M IPC at its expense if based primarily on the MTS devices, and if the invention being claimed is not clearly either of the foregoing, the parties will agree in good faith how best to handle the cost, preparation, filing, prosecution, maintenance, abandonment, or termination of such joint applications and patents.  Within forty five (45) days following the date of disclosure regarding the existence of particular jointly owned patents, the parties shall confer and mutually agree as to appropriate protection for such jointly owned patents, including an application, preparation, prosecution and maintenance strategy.  The parties shall use outside counsel reasonably acceptable to each party to execute the agreed upon protection strategy, which counsel shall be responsible to both RADIUS and 3M, and shall use reasonable efforts to solicit both RADIUS’ and 3M’s advice on material application, preparation, prosecution and maintenance matters related thereto.  If, within six (6) months of the date of disclosure regarding the existence of particular jointly owned

 

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patent rights, the Parties have not reached mutual agreement on a protection strategy and outside counsel to execute the protection strategy, either party may initiate dispute resolution under Section 12.5.  All expenses incurred in obtaining and maintaining any patent on jointly owned patents shall be equally shared  (50% each), unless one party declines to share in such expenses, then in that event the other party may assume responsibility for the prosecution and maintenance thereof, at its sole expense, provided that:  (i) title to the patent remains in the names of both parties, and (ii) the non-paying party shall have an automatic, worldwide, royalty-free, nonexclusive license thereto.  If a party that proceeds to pursue patent prosecution or maintenance activities pursuant to the preceding sentence of this Section 7.7 subsequently declines to continue such prosecution and maintenance, then the other party may take over the prosecution and maintenance thereof, at its sole expense and subject to reimbursement of one-half (50%) of the expenses paid by the other party during the period when it was not funding its share of such activities, at which time such other party shall recapture all rights thereto.  It is understood and agreed that subject to compliance with this Section 7.7, the non-filing party shall consent to the disclosure of jointly owned Confidential Information concerning jointly owned Program Patents.

 

8.                                      CONFIDENTIALITY

 

8.1                                                       The Parties agree to use reasonable efforts to maintain Information disclosed by the other in confidence, including at least efforts fully commensurate with those to protect its own confidential information.  Neither Party will use the Information of the other Party except for the performance of the work described in the Program. Each Party will disclose the Information only to its officers and employees directly concerned with the Program to whom it is necessary or useful to disclose such Information, but will neither disclose the Information to any third party nor use the Information for any other purpose; provided that Radius may disclose the Information to third party collaborator(s) as necessary for purposes of establishing Radius’ satisfaction of development milestones with respect to the Compound if such collaborators are subject to a written confidentiality agreement no less restrictive than the terms of this Section 8.  Each Party acknowledges that, except for the rights expressly granted under this Agreement, it will not obtain any rights of any sort in or to the Information of the other Party as a result of such 

 

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disclosure and that any such rights must be the subject of separate written agreement(s).

 

8.2                                                           The disclosing Party may at any time notify the receiving Party in writing that such receiving Party must return to the disclosing Party the disclosing Party’s Information.  Each Party hereby agrees to, within thirty  (30) days of such notification:  (i) return all documents and tangible items it or its employees or agents have received or created pursuant to this Agreement pertaining, referring or relating to the other Party’s Information; and (ii) return or certify (in a writing attested to by a duly authorized officer of such Party) destruction of all copies, summaries, modifications or adaptations that such Party or its employees or agents have made from the materials provided by the disclosing Party; provided, however, that a Party is permitted to retain one copy of such materials in its legal files to be used to verify compliance with its obligations hereunder.

 

8.3                                                           Neither Party will make any public announcement as to the execution of this Agreement or its terms without the prior written authorization of the other Party.  This shall not prevent a Party from such disclosures regarding the existence or terms of this Agreement to the extent required under applicable federal or state securities laws or any rule or regulation of any nationally recognized securities exchange.  In such event, however, the disclosing Party shall use good faith efforts to notify and consult with the other Party prior to such disclosure and, where applicable, shall diligently seek confidential treatment to the extent such treatment is available under applicable securities laws, rules, or regulations.  In addition, each Party may provide a copy of this Agreement or disclose the terms of this Agreement (i) to any finance provider in conjunction with a financing transaction, if such finance provider agrees to keep this Agreement confidential, (ii) to enforce its rights under this Agreement, (iii) to any legal or financial advisor of such Party, or (iv) in response to a subpoena or other validly issued administrative or judicial process requesting disclosure of same; provided, the Party that receives such order or process provides prompt notice to the disclosing Party before making any disclosure (to the extent possible) and permits the disclosing Party to oppose or narrow such request for disclosure and supports any of disclosing Party’s reasonable efforts to oppose such request (at disclosing Party’s expense) and shall disclose the terms of this Agreement only in the event of a final judgment or administrative order requiring such disclosure, and only to the extent necessary to comply with such request.

 

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8.4                                                           The Parties’ obligation of nondisclosure and the limitations upon the right to use the other Party’s Information, samples and test results shall not apply to the extent that a recipient can demonstrate that the applicable Information:  (a)  was in its possession prior to the time of disclosure; or (b)  is or becomes public knowledge through no fault or omission of the receiving Party; or (c)  is obtained by the recipient from a third party under no obligation of confidentiality to the disclosing Party; or (d)  is independently developed by the receiving Party, as evidenced by the receiving Party’s written records, without access to the disclosing Party’s Information.  A receiving Party may also disclose Information if it is required to disclose the Information in response to a subpoena or other validly issued administrative or judicial process requesting disclosure of same, provided that such receiving Party will give the disclosing Party prompt notice of such request before making any disclosure (to the extent possible) and permit the disclosing Party to oppose or narrow such request for disclosure.  The disclosing Party may seek an appropriate protective order or other remedy and/or waive compliance with the provisions of this Agreement.  If such disclosing Party seeks a protective order or other remedy, the receiving Party will cooperate and support any of the disclosing Party’s reasonable efforts to oppose such request (at disclosing Party’s expense).  If such disclosing Party fails to obtain a protective order or waive compliance with the relevant provisions of this Agreement, the receiving Party will disclose only in the event of a final judgment or administrative order requiring such disclosure, and only to the extent necessary to comply with such request.

 

8.5                                                           The obligations with respect to maintaining confidentiality and non-use of Information under Section 8 shall survive the termination of this Agreement for a period of five  (5) years with respect to the Workplan and Radius’ business information, but shall remain in effect for an indefinite period of time with respect to each Party’s technical information which the disclosing Party shall indicate to be a trade secret at the time of disclosure.  In this latter case the recipient Party shall keep this trade secret as confidential unless and until it ceases to be Confidential Information pursuant to items (a), (b), (c) or (d) of Section 8.4.  It is understood and agreed that nothing in this Agreement obligates any Party to disclose or receive any Confidential Information that is of a technical nature but that if a Party refuses to accept such Confidential Information and such Confidential Information is necessary to perform 

 

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the transactions contemplated by this Agreement then the disclosing Party may terminate this Agreement without any obligation to pay the costs set forth above.

 

9.                                      EXCLUSIVE RELATIONSHIP

 

9.1                                                            During the term of this Agreement the parties shall work exclusively with one another for Compound delivery by MTS.

 

9.2                                                            In the event that RADIUS elects to further develop the Product developed by 3M hereunder for commercialization, 3M shall have the exclusive right to further develop and manufacture Product for RADIUS and/or RADIUS licensees at a reasonable, good faith price, consistent with customary drug supply pricing and such other terms and conditions as are reasonable and customary in the commercial supply of pharmaceutical compounds.  Any such development and supply agreements shall be negotiated in good faith between the parties.  3M’s pricing for commercial supply of Product to RADIUS and/or RADIUS licensees will depend, among other things, on such factors as the components used, packaging, formulation, sales volume, and other costs that are not known at this time.  3M shall make its election with respect to further development and commercial manufacture/supply upon request by RADIUS at any time following completion of Phase I clinical testing of Product, and if 3M elects to further develop and manufacture/supply Product, 3M and RADIUS shall promptly negotiate in good faith the terms of a formal “Commercial Supply Agreement” within 6 months of the start of Phase II clinical testing.

 

9.3                                                            Neither RADIUS nor 3M has any obligation under this Agreement to proceed beyond the Workplan.

 

10.                               WARRANTIES, LIMITED REMEDY/LIMITIATION of LIABILITIES, and INDEMNIFICATION

 

10.1                                                     Each party warrants that it (i) has the right to enter into this Agreement; and (ii) it has no obligations to any other person or entity which are in conflict with its obligations under this Agreement.

 

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10.2                                                     RADIUS hereby represents and warrants that all Compound supplies shall at the time of delivery to 3M meet specifications agreed upon in writing by 3M and RADIUS.

 

10.3                                                     3M warrants to RADIUS that 3M will store and handle the Compound supplied by RADIUS as well as the Products in accordance with RADIUS instructions.

 

10.4                                                     3M warrants that it will manufacture any toxicology supplies of the Product in accordance with cGLPs or cGMPs and any clinical supplies of the Product in accordance with cGMPs, and that such Product will at the time of shipment meet any specifications agreed upon in writing by the parties, provided that RADIUS’ sole remedy for supply of defective Product shall be replacement of such Product, and 3M shall have no obligation to replace Product or indemnify RADIUS pursuant to this section for Product that does not meet the specifications because of RADIUS’ failure to supply Compound meeting the agreed specifications.

 

10.5                                                     EXCEPT AS EXPRESSLY SET FORTH IN THIS SECTION 10, NEITHER PARTY GIVES ANY EXPRESS OR IMPLIED WARRANTY RELATED TO THIS AGREEMENT, THE PERFORMANCE OR NON-PERFORMANCE OF THIS AGREEMENT, OR ANY OTHER MATTER OR SUBJECT ARISING OUT OF THIS AGREEMENT, INCLUDING BUT NOT LIMITED TO, THE IMPLIED WARRANTIES OF MERCHANTABILITY AND FITNESS FOR A PARTICULAR PURPOSE, OR NONINFRINGEMENT OF THIRD PARTY PATENT RIGHTS.

 

10.6                                                     3M shall indemnify, defend, and hold RADIUS harmless from and against any and all third party loss or liability for any and all judgments, claims, causes of action, suits, proceedings, losses, damages, demands, fees, expenses, fines, penalties or costs (including without limitation reasonable attorney’s fees, costs and disbursements) arising from any personal injury or alleged personal injury claim against Radius to the extent that such claim results from 3M’s breach of warranty, and, provided that 3M shall be liable only to the extent such breach resulted in the harm or injury for which RADIUS seeks indemnification.

 

10.7                                                     Except for the preceding indemnification provided by 3M for supplying Product that fails to meet specifications, RADIUS shall indemnify, defend, and hold 3M and 3M IPC harmless from and against any and all other third party loss or liability for any and all judgments, claims, causes 

 

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of action, suits, proceedings, damages, demands, fees, expenses, fines, penalties and costs (including without limitation reasonable attorney’s fees, costs and disbursements) arising from RADIUS’ or its agent’s use, testing or clinical studies of Product.

 

10.8                                                     Both RADIUS and 3M are obligated to promptly notify the other party of any claim for which they intend to seek indemnification under the terms of this Agreement.  Failure to give notice shall not constitute a defense, in whole or in part, to any claim by any indemnified entity hereunder except to the extent the rights of the indemnitor are materially prejudiced by such failure to give notice.  If either party accepts the defense of and indemnification for a case without reserving the right to later seek contribution or indemnity from the tendering party, then the tendering party shall have no control over the defense of such case.  If either party accepts the defense of and indemnification for a case, but reserves the right to later seek indemnity or contribution from the tendering party, then the tendering party shall have the right to actively participate in the defense of the case with the non-tendering party and outside counsel, and any settlements shall require the consent of both parties. If a claim arises within the scope of an indemnity, the party seeking indemnity will fully cooperate in the defense of any such claim.

 

10.9                                                     If both parties desire to defend a case together, then the parties shall jointly control the defense of such case. If either party desires to defend a case with separate counsel, then each party shall be entitled to control its own legal defense of any claim; provided, however, that any party seeking indemnification or contribution shall in good faith consult with the other party regarding the defense strategy to be employed throughout the case, but only to the extent such consultation does not reveal matters that may be at issue between the party seeking indemnification and the other party.  A party seeking indemnification or contribution from the other party cannot settle a case without the consent of the other party.

 

10.10                                              EXCEPT FOR THE INDEMNIFICATION OBLIGATIONS SET FORTH ABOVE, AND NOTWITHSTANDING ANYTHING IN THIS AGREEMENT TO THE CONTRARY, NEITHER PARTY SHALL BE LIABLE TO THE OTHER FOR INDIRECT, INCIDENTAL, SPECIAL, PUNITIVE OR CONSEQUENTIAL DAMAGES RELATED TO PRODUCT OR PERFORMANCE OR NON-PERFORMANCE OF THIS AGREEMENT REGARDLESS OF THE LEGAL THEORY ASSERTED INCLUDING, BUT NOT LIMITED TO, CONTRACT, FAULT, NEGLIGENCE OR STRICT LIABILITY.

 

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11.                               TERM AND TERMINATION

 

11.1                                                     The Agreement shall remain in force for the earlier of (a) two (2) years from the date of execution by the Parties or (b) completion of work and deliverables under the Workplan, after which time the Agreement shall expire.

 

11.2                                                     Either Party may terminate this Agreement in the event of a material breach of the Agreement by the other Party that the breaching Party has failed to cure within thirty (30) days of receipt of written notice from the non-breaching Party.  In the event of termination of this Agreement by 3M pursuant to this provision, Radius shall be obliged to pay 3M within thirty (30) days of termination any unpaid balance of the fees or expenses for work performed prior to termination.

 

11.3                                                     Radius may terminate without cause this Agreement upon sixty (60) days written notice to 3M.  Upon receiving notice of Radius’s intent to terminate, 3M shall make commercially reasonable efforts to stop all activities under any Workplan as soon as practicable.

 

11.4                                                     All charges and expenses owed to 3M prior to the effective date of termination shall become due and payable, and except in the event of termination due to 3M’s breach, Radius shall pay all charges and expenses reasonably incurred by 3M in winding down its activities at a rate of $[*] per hour during the sixty (60) day notice periods referred to above, provided that 3M shall act diligently to minimize all wind down costs, upon receipt of a termination notice. In the event of termination for any reason, the parties shall upon request provide the other party, if not in material breach, with any preliminary data (preclinical or clinical) and any unanalyzed samples available within 30 days of termination.

 

11.5                                                     In the event this Agreement expires or is terminated, the provisions of Sections 7, 8, 10, and paragraphs 12.1, 12.4, 12.5, 12.7 and 12.8 shall survive said expiration or termination in accordance with their terms.

 

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

 

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12.                               MISCELLANEOUS

 

12.1                                                     This Agreement contains the complete and entire agreement between the parties hereto, and supersedes any previous communications, representations, or agreements whether verbal or written relating to the subject matter hereof.

 

12.2                                                     No change, addition, waiver, amendment, or modification of any of the terms or conditions hereof shall be valid or binding on either party unless in writing and signed by authorized representatives of both parties.

 

12.3                                                     Neither Radius nor 3M shall be considered in default or be liable to the other Party for any delay in performance or non-performance caused by circumstances beyond the reasonable control of such Party, including but not limited to acts of God, explosion, fire, flood, earthquake, war whether declared or not, accident, labor strike or labor disturbances, sabotage, transportation strike or interference, order or decrees of any court or action of governmental authority or shortages in or an inability to procure materials; provided, however, that diligent efforts are made to resume performance as quickly as possible.

 

12.4                                                     The Parties consent to and this Agreement shall be construed under Delaware law, notwithstanding any choice of law provision to the contrary.   The failure to enforce any right or provision herein shall not constitute a waiver of that right or provision.  If any provisions herein are found to be unenforceable on the grounds that they are overly broad or in conflict with applicable laws, it is the intent of the Parties that such provisions be replaced, reformed, or narrowed so that their original business purpose can be accomplished to the extent permitted by law, and that the remaining provisions shall not in any way be affected or impaired thereby.  The rights and obligations of Radius and 3M which by intent or meaning have validity beyond such termination or expiration (including, but not limited to, rights with respect to confidentiality, intellectual property, and liability limitations) shall survive the termination or expiration of this Agreement or any Workplan.

 

12.5                                                     Any questions, claims, disputes or litigation arising from or related to the making, performance or alleged breach of this Agreement, or to any available remedies (a “dispute”), shall be governed by the laws of Delaware, without regard to conflicts of law principles, and shall be resolved as follows: (i) upon written notice of dispute (the “notice”), by in-person negotiation between senior business representatives of the

 

16

 

 

parties who have authority to fully resolve the dispute; (ii) if within 60 days of the notice the dispute has not been fully resolved, the parties shall conduct a confidential mediation using a location, mediator, and rules acceptable to both parties (with the costs of mediation shared equally); (iii) if the dispute is not then resolved, and as a last resort only, either party may commence litigation.  Nothing herein shall preclude either party from taking whatever actions it deems necessary to prevent immediate, irreparable harm to its interests.

 

12.6                                                     This Agreement may not be assigned by either Party except by prior written consent of the other Party (not to be unreasonably withheld); provided that this Agreement may be assigned by 3M without the consent of Radius in connection with the sale of substantially all of 3M’s MTS drug delivery business (whether by merger, consolidation or sale of all or substantially all the assets relating to such business (including the grant of an exclusive license covering all or substantially all of the intellectual property rights of such business)); and this Agreement may be assigned by Radius without the consent of 3M in connection with the sale of substantially all of Radius’ business relating to the Compound (whether by merger, consolidation or sale of all or substantially all the assets relating to such business (including the grant of an exclusive license covering all or substantially all of the intellectual property rights of such business).

 

12.7                                                     Radius and 3M shall comply in all material respects with the requirements of all applicable laws, rules, regulations and orders of any government authority in handling or disposing of the Compound and formulations.

 

12.8                                                     Any notice or other communications sent or delivered hereunder shall be in writing and shall be effective if hand delivered or if sent by telex, express delivery service or certified or registered mail, postage prepaid.

 

	
If to Radius:
    	
 
    	
Radius Health, Inc.
    
	
 
    	
 
    	
300 Technology Square
    
	
 
    	
 
    	
Cambridge, MA 02139
    
	
 
    	
 
    	
Attention: Chief Executive   Officer
    
	
 
    	
 
    	
 
    
	
If to 3M:
    	
 
    	
3M Drug Delivery Systems
    
	
 
    	
 
    	
3M Center Building 275-3E-10
    
	
 
    	
 
    	
St. Paul, MN 55144-1000
    

 

17

 

	
 
    	
 
    	
Attention: Division Vice   President
    

 

With a copy to Legal Affairs at the above address

 

 

	
EXECUTED by the parties
    	
 
    	
 
    
	
 
    	
 
    	
 
    
	
 
    	
 
    	
 
    
	
For and on behalf of:
    	
 
    	
 
    
	
 
    	
 
    	
 
    
	
3M COMPANY
    	
 
    	
 
    
	
 
    	
 
    	
 
    
	
 
    	
 
    	
 
    
	
Signed:
    	
/s/ James A. Vaughan
    	
 
    	
Dated:
    	
June 23, 2009
    
	
 
    	
 
    	
 
    	
 
    	
 
    
	
Printed: James A. Vaughan
    	
 
    	
Title: 3M Drug Delivery System 
   Division Vice- President
    
	
 
    	
 
    	
 
    
	
3M INNOVATIVE PROPERTIES COMPANY
    	
 
    	
 
    
	
 
    	
 
    	
 
    
	
 
    	
 
    	
 
    	
 
    
	
Signed:
    	
/s/ Robert W. Sprague
    	
 
    	
Dated:
    	
June 23, 2009
    
	
 
    	
 
    	
 
    	
 
    	
 
    
	
Printed: Robert W. Sprague
    	
 
    	
Title: Secretary
    
	
 
    	
 
    	
 
    
	
 
    	
 
    	
 
    
	
RADIUS HEALTH, INC.
    	
 
    	
 
    
	
 
    	
 
    	
 
    
	
 
    	
 
    	
 
    	
 
    
	
Signed:
    	
/s/ B.N. Harvey
    	
 
    	
Dated:
    	
June 19, 2009
    
	
 
    	
 
    	
 
    
	
Printed: B. Nicholas Harvey
    	
 
    	
Title: Chairman, President, Chief   
   Executive Officer
    

 

18

 

Exhibit A

 

WORK PLAN SUMMARY

 

Objective:

 

The objective of the work plan is to develop two additional BA-058 sMTS patch formulations and processes (150 and 200 μg/array), and to prepare four strengths of product (50, 100, 150, 200 μg/array) plus a placebo to be utilized by Radius to complete preclinical tox evaluations and a Phase I clinical study.

 

Deliverables:

 

·                  Shipment of 4 distinct formulations/strengths of BA-058 sMTS (Ex Works 3M’s site) for preclinical toxicology studies and a Phase I clinical POC study (50, 100, 150, 200 μg/array)

·                  Shipment of a representative placebo sMTS (Ex Works 3M’s site) for preclinical toxicology studies and a Phase I clinical POC study

·                  Data to support the stability of key formulations of the product through the time needed to conduct the Phase I clinical POC study

·                  Data to support the stability of key formulations of the product through the proposed shelf life of the product (up to 2 years)

·                  On-site training support for clinicians for application of the sMTS

·                  3M shall establish and maintain proprietary Drug Master Files (DMFs) including information on the components, coating and manufacturing processes sufficient to support regulatory filings in the U.S. and Canada.  A right of reference to 3M’s DMFs will be granted to Radius to support regulatory filings in the U.S. and Canada.  Outside the U.S., 3M will provide Radius with nonconfidential information from the DMFs necessary to support regulatory filing in said country

·                  Formulation information sufficient to support regulatory filings in the U.S. and Canada

 

Timing:

 

The overall time estimate from start of Stage 3 to shipment of clinical supplies for the Phase I study is estimated to be 4-7 months.

 

This estimate assumes initiation of the Phase I trial as soon as possible following the preclinical tox study.  The estimate does not include timing associated with the in-vivo portion of the preclinical toxicology study.

 

19

 

Assumptions of the work plan:

 

·                  Lot sizes for BA058-sMTS drug product not to exceed [*] GMP-grade units; lot size for placebo unit not to exceed [*] units.

·                  The starting formulation (BA-058 + excipients) will be provided to 3M by Radius, sterile and in a form compatible with aseptic processing unless the formulation is determined to be stable through terminal sterilization.

·                  Radius will be responsible for executing all elements (protocols, regulatory filings, conduct) of the GLP toxicology studies.

·                  Radius will be responsible for executing all elements (protocols, regulatory filings, conduct) of the Phase I trial.

·                  Work plan assumes the use of the POC MTS applicator system and patch design.

·                  Timing required for conducting the GLP toxicology studies is not included in the estimate; timing assumes the Phase I trial will start as soon as possible following the toxicology studies.

·                  If results determine that additional doses of BA058-sMTS arrays are needed, additional costs and time may be incurred.

·                  Quantity of BA-058 required to perform the work plan is to be determined.

·                  sMTS patches for use in the POC clinical study will be bulk labeled by 3M and provided to Radius for further labeling according to the requirements of the clinical protocol.

·                  The clinical trial will be conducted in the United States or Canada under an IND sponsored by Radius.  Stability studies on key formulations will be a maximum of 24 months in length; the stability report will be completed within 2 months of the completion of the stability study.

·                  If results from Stage 2 of the feasibility agreement indicate, the supplies will be terminally sterilized.

 

Stage 3: Formulation development, preparation of toxicology and clinical supplies

 

Summary:  3M will develop 2 additional doses of BA058-sMTS (150 and 200 μg/array), manufacture toxicology supplies and GMP supplies for shipment to Radius for preclinical toxicology testing and for a Phase I clinical study.  3M will write and submit DMF(s) for reference by Radius and contribute documentation needed to support a pre-IND and IND filing.  3M will also run the supporting stability studies with these studies going out to 2 years for key doses.

 

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

 

20

 

3M Tasks

Develop and optimize 2 additional BA058-sMTS products (150 and 200 μg/array)

Complete experiments to demonstrate BA058 release in vivo in selected animal model

Agree with Radius on study design for preclinical toxicology evaluation; consult with Radius on clinical study protocol and with the clinical site for aspects related to sMTS application

Adapt and verify BA-058 patch manufacturing processes, as required 

Finalize specifications and methods for array patch and applicator supplies

Develop and verify low bioburden or terminal sterilization mfg. approach; verify supplies meet low bioburden or sterility criteria, as applicable

Draft and approve protocols for assembly, sterilization, formulation, coating, and bulk packaging of supplies; write methods and specifications to characterize toxicology supplies and Phase I supplies

3M/Radius to finalize specifications for BA-058 s-MTS selected formulations

Complete raw material/component clearances, including API

Provide sterile ready to coat formulation (BA058+excipients).

Mold arrays, manufacture and characterize for toxicology studies and Phase I study

Manufacture and ship toxicology and clinical supplies to Radius (FOB)

Initiate screening stability studies on selected formulations

Provide Certificate of Conformance and Certificate of GMP compliance along with shipment of BA058-sMTS product

Provide chemistry, manufacturing and controls (CMC) information pertaining to BA058-sMTS formulation.  Write and provide documents describing manufacturing process for regulatory submissions. 3M to provide Radius with letters of authorization to reference 3M DMFs describing the device manufacture and coating processes.

Perform stability studies on select doses (6 months for all doses; up to 24 months for 1-2 key doses) 

 

Radius Tasks

Develop regulatory strategy 

3M/Radius to finalize specifications and methods for selected formulations and final products

3M/Radius to agree on stability testing plan

Design and perform GLP toxicology studies

Receive, label and provide final product clearance of Phase I clinical supplies

Author Investigators Brochure, pre-IND and IND submission

Write clinical protocol, define safety and efficacy endpoints 

Execute or oversee the Phase I clinical study

 

21

 

Exhibit B

 

Change Order Form

 

Change order under Agreement dated: [add title and date of agreement]

 

Between:

 

Project Name:

 

 

Change requested by:

Name:

Company:

Date:

 

Description of change: [Include details here of the task changes or additions and any change in timelines and/or fees, with reference to the original tasks, timeline or fees where applicable.  These details may be attached as a schedule to this change order.]

 

In all other respects, the terms and conditions of the Agreement remain in full force and effect.

 

Requested task, dates and costs are approved by:

 

	
RADIUS   HEALTH, INC.:
    	
 
    	
3M COMPANY:
    
	
Name:
    	
 
    	
Name:
    
	
Signature:
    	
 
    	
Signature:
    
	
Position:
    	
 
    	
Position:
    
	
Date (dd/mm/yy):
    	
 
    	
Date (dd/mm/yy):
    

 

22

 

Exhibit C

 

Estimated Costs by Stage

 

	
Stage
    	
 
    	
Timing
    	
 
    	
Program Cost Estimate
    
	
 
    	
 
    	
 
    	
 
    	
 
    
	
Stage 3 — Formulation development, Preparation of Toxicology and   Clinical Supplies
    	
 
    	
4-7 month
    	
 
    	
$750,000 - $1,250,000
    

 

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

 

23

 

DEVELOPMENT AND CLINICAL SUPPLIES AGREEMENT AMENDMENT NO. 1*

 

Radius Health Inc. (“RADIUS”) and 3M COMPANY (“3M”) and 3M INNOVATIVE PROPERTIES COMPANY (“3M IPC”) entered into the certain Development and Clinical Supplies Agreement (the “Agreement”) as of June 19, 2009 (“Effective Date”).

 

Pursuant to Paragraph 9.4 of the Agreement, the parties wish to enter into this Amendment No. 1 to the Agreement (“Amendment No. 1”) effective as of December 31, 2009 (“Amendment Date”).  Capitalized terms used in this Amendment No. 1 and not defined herein are used with the meanings ascribed to them in the Agreement.

 

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

 

1.  Change in Work Plan; Change in Price Structure.  The parties were required to undertake additional work not contemplated by the Work Plan concerning viscosity experiments with respect to the Product.  This additional work increased the costs to perform Stage 3 of the Work Plan above the Program Cost Estimate set forth in the Agreement.  The parties have conferred with respect to these incremental costs as well as the activities and pricing outlined in the Work Plan and have agreed that the costs for these viscosity experiments as well as all other activities outlined in the Work Plan, including but not limited to preclinical and clinical activities relating to the development and manufacturing of the [*] and [*] mcg doses, stability testing, information supporting manufacturing and regulatory filings, as well as on site training support for clinicians shall not exceed $1,325,000 in the aggregate.

 

2.  Ratification.  Except to the extent expressly amended by this Amendment No. 1, all of the terms, provisions and conditions of the Agreement are hereby ratified and confirmed and shall remain 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.

 

3.  General.  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.

 

[remainder of this page intentionally left blank]

 

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

 

1

 

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

 

	
3M COMPANY
    	
 
    	
 
    	
 
    
	
 
    	
 
    	
 
    	
 
    
	
 
    	
 
    	
 
    	
 
    
	
Signed:
    	
/s/ James A. Vaughan
    	
 
    	
Dated:
    	
01/18/2010
    
	
 
    	
 
    	
 
    	
 
    	
 
    
	
Printed: James A. Vaughan
    	
 
    	
Title: 3M Drug Delivery System   Division 
   Vice-President
    
	
 
    	
 
    	
 
    
	
 
    	
 
    	
 
    
	
3M INNOVATIVE PROPERTIES COMPANY
    	
 
    	
 
    
	
 
    	
 
    	
 
    
	
 
    	
 
    	
 
    	
 
    
	
Signed:
    	
/s/ Robert W. Sprague
    	
 
    	
Dated:
    	
January 13, 2010
    
	
 
    	
 
    	
 
    	
 
    	
 
    
	
Printed: Robert W. Sprague
    	
 
    	
Title: Secretary
    
	
 
    	
 
    	
 
    
	
 
    	
 
    	
 
    
	
RADIUS HEALTH INC.
    	
 
    	
 
    
	
 
    	
 
    	
 
    	
 
    
	
Signed:
    	
/s/ B.N. Harvey
    	
 
    	
Dated:
    	
2/24/10
    
	
 
    	
 
    	
 
    	
 
    	
 
    
	
Printed: B. Nicholas Harvey
    	
 
    	
Title: Chief Financial Officer
    

 

2

 

Second Amendment To Development and Clinical Supplies Agreement*

 

This Amendment, dated September 16, 2010 by and between 3M Company, and 3M Innovative Properties Company having a principal office at 3M Center, Building 275-3E-10, St. Paul, MN  55144-1000 (hereinafter “3M”), and Radius Health Inc. having a principal office at 300 Technology Square, Cambridge, MA (hereinafter “Radius”) amends the Development and Clinical Supplies Agreement dated June 19, 2009  (hereinafter “the Agreement”) as follows:

 

RECITALS:

 

A.            Whereas, 3M and Radius have previously entered into a Development and Clinical Supplies Agreement dated June 19, 2009 (“Agreement”) for the development and delivery of clinical supplies up through Phase II for a BA058 coated MTS  product (“Product”);

B.            Whereas,  Radius has conducted preclinical and clinical trials with Product; including a Phase Ia clinical trial with Product which rendered results that did not meet predetermined criteria;

C.            Whereas, Radius is willing to repeat the Phase Ia clinical trial with new Product made by 3M using a different, proprietary array material;

D.            Whereas, 3M is willing to manufacture new clinical supplies of Product at its own expense subject to the terms of this Amendment.

E.             Whereas, Radius also requires additional clinical supplies, including Phase Ib supplies.

F.              Whereas, 3M will have the capability or producing Phase II supplies by August 31, 2011 and will assume the capital expenditures costs for Phase II supplies;

G.            Whereas, all terms of the Agreement not explicitly amended by this Amendment shall remain in full force and effect.  To the extent not modified or defined by this Amendment, all capitalized and defined terms shall have the meaning ascribed to them in the Agreement.

 

NOW, THEREFORE, in consideration of the Recitals (which are incorporated herein) and other good and valuable consideration, the receipt and sufficiency of which is hereby acknowledged, the Parties agree as follows:

 

1.              3M shall manufacture three (3) doses plus Placebo of Phase Ia/b clinical supplies of Product using 3M’s proprietary array material in quantities and for such uses as set forth below.  Phase Ia will be provided at 3M’s expense.  Included in the runs shall be small quantities of 200 mcg and Placebo (50 each) for preclinical studies. Such supplies shall be manufactured in September and October 2010 with a target release of approximately three (3) weeks after each run. The supplies will be manufactured in the following order: 100 mcg, Placebo, 200 mcg and 150 mcg. Production of the 100 mcg dose is targeted September 27, 2010, with the target release date on or before October 31, 2010. The Placebo is targeted to be released within a week or less afterwards. The 200 mcg and 150 mcg doses are targeted 

 

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

 

1

 

to be released one and two weeks after that, respectively. The preclinical supplies, 200 mcg and Placebo, are targeted to be released under quarantine by October 11 and October 18, 2011, respectively.

 

	
 
    	
 
    	
100 mcg dose
    	
 
    	
150 mcg dose
    	
 
    	
200 mcg dose
    	
 
    	
Placebo
    
	
Study   supplies (Phase 1+7-day tox)
    	
 
    	
198
    	
 
    	
215
    	
 
    	
232
    	
 
    	
218
    
	
Extras
    	
 
    	
15
    	
 
    	
15
    	
 
    	
15
    	
 
    	
15
    
	
Retains
    	
 
    	
100
    	
 
    	
100
    	
 
    	
100
    	
 
    	
100
    
	
Release
    	
 
    	
55
    	
 
    	
55
    	
 
    	
55
    	
 
    	
40
    
	
Stability
    	
 
    	
140
    	
 
    	
140
    	
 
    	
140
    	
 
    	
0
    
	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    
	
Needed   Arrays
    	
 
    	
508
    	
 
    	
525
    	
 
    	
542
    	
 
    	
373
    
	
Total   with 25% overage
    	
 
    	
635
    	
 
    	
656
    	
 
    	
678
    	
 
    	
466
    

 

2.                                      3M shall conduct a limited stability protocol on all three doses of the clinical supplies of Product.  The stability protocol shall include two storage conditions: 4C/ambient humidity with four (4) pulls (1,3,6, and 12 months), not including release, and 25C/60%RH with a single (1) pull at 1 month.  3M shall also conduct a limited stability protocol on the ready-to-coat (RTC) solutions for Phase 1a/b supplies.  The stability protocol shall include one storage condition: 4C/ambient humidity with five (5) pulls (1,2,3,4 and 6 months) for each solution. The RTC solution will also be tested prior to each manufacturing run for confirmation of formulation. 3M shall invoice Radius [*] Dollars ($[*]) per pull point for this stability testing at the conclusion of testing of the each pull.

 

3.                                      Upon request by 3M, Radius shall provide 3M with certain requested preclinical and clinical data generated by Radius under any previous Workplans; Radius shall not be required to provide preclinical or clinical data to 3M in the event and to the extent that the relevant data is being used or intended for use to support a patent application unless the parties mutually agree upon a method of disclosure that does not present a risk to the integrity of the applicable patent application.  3M shall have the right to use the preclinical and clinical data provided by Radius pursuant to this Section 3 (as well as any preclinical and clinical data previously provided to 3M by Radius) for purposes of marketing its MTS technology, so long as 3M does not disclose (i) the identity of Radius, (ii) the identity of BA058, or (iii) any information related to BA058 that would allow any third party to ascertain the identity of BA058, the therapeutic areas for which BA058 is useful for, including but not limited to the prevention and/or treatment of osteoporosis.  Before disclosing any Radius preclinical or clinical data provided pursuant to this Section 3 (as well as any preclinical and clinical data previously provided to 3M by Radius), 3M shall provide Radius with a draft of the portions of any proposed disclosure that contain such data no fewer than thirty (30) days prior to the 

 

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

 

2

 

planned disclosure date so that Radius may review the planned disclosure and confirm that it does not disclose any of the information covered by (i)-(iii).  3M shall comply with Radius’ reasonable request to delete references to information covered by (i)-(iii).  If there is a dispute regarding publications, such dispute shall be resolved by the parties and will include an undertaking by each party to propose scientifically meaningful equivalent disclosure that does not disclose the information covered by (i)-(iii).  It is specifically understood that disclosure of preclinical and/or clinical information to 3M under this Section 3 shall not alter its status (if applicable) as Radius Confidential Information.  It is further understood that after a disclosure has been approved by Radius under this Section 3 and approved that disclosure may be reused in the same format without resort to a separate review by Radius.  Radius also agrees to provide 3M with certain requested clinical data generated under any future Workplans upon Radius approval, which shall not be unreasonably withheld, and subject to the limitations set forth above with respect to data generated by Radius under previous Workplans.

 

4.                                      3M shall provide approximately seven hundred (700) Phase Ib supplies (included in the table above in (1)) 3M shall invoice Radius for such supplies on a time and material basis.  The estimated cost for the Phase Ib supplies is $85,000.

5.                                      3M shall provide proof to Radius that a DMF reference letter is on file. 3M shall provide Radius with an updated CMC section and finalized non-redacted copies of preclinical and clinical reports describing safety of the TAZ arrays, as well as any other information necessary for Radius regulatory filings.

6.                                      3M shall provide up to fifty (50) applicators for clinical use.

7.                                      The term of the Agreement shall be extended until June 19, 2013.

 

IN WITNESS WHEREOF, the parties hereto have caused this Amendment to be duly executed in duplicate as of the date and year the last Party signs below.

 

ACCEPTED AND AGREED TO:

 

	
3M   COMPANY
    	
 
    	
Radius   Health, Inc.
    
	
 
    	
 
    	
 
    
	
By
    	
/s/   Jim A. Vaughan
    	
 
    	
By
    	
/s/   B.N. Harvey
    
	
Print   Name
    	
Jim   A. Vaughan
    	
 
    	
Print   Name 
    	
B.N.   Harvey
    
	
Title
    	
Division   VP & GM
    	
 
    	
Title
    	
CFO   and SVP
    
	
Date
    	
Sept.   22, 2010
    	
 
    	
Date
    	
16   Sept, 2010
    

 

 

3M INNOVATIVE PROPERTIES COMPANY

 

	
By
    	
/s/   Robert W. Sprague
    	
 
    

 

3

 

	
Print   Name
    	
Robert   W. Sprague
    	
 
    
	
Title
    	
Secretary
    	
 
    
	
Date
    	
9-20-2010
    	
 
    
	
 
    	
ACR   # 201004140
    	
 
    

 

4

 

EXECUTION COPY

 

Third Amendment To Development and Clinical Supplies Agreement*

 

This Amendment, dated September 29, 2010 by and between 3M Company, and 3M Innovative Properties Company having a principal office at 3M Center, Building 275-3E-10, St. Paul, MN  55144-1000 (hereinafter “3M”), and Radius Health Inc. having a principal office at 300 Technology Square, Cambridge, MA (hereinafter “Radius”) amends the Development and Clinical Supplies Agreement dated June 19, 2009  (hereinafter “the Agreement”) as follows:

 

RECITALS:

 

A.            Whereas, 3M and Radius have previously entered into a Development and Clinical Supplies Agreement dated June 19, 2009 for the development and delivery of clinical supplies up through Phase II for a BA058 coated MTS  product (“Product”) and have entered into a Second Amendment to the Agreement dated September 16, 2010 (the “Agreement”);

B.            Whereas, Radius also requires additional clinical supplies, including chronic dermal toxicology supplies

C.            Whereas, Radius  may require stability testing of any clinical or toxicology  supplies provided by 3M;

D.            Whereas, to meet Radius required timing, 3M must invest in additional facilities and equipment;

E.             Whereas Radius is willing to guaranty repayment of a portion of the planned work to enable 3M to justify its investment in the event that Radius does not expend certain additional sums with 3M under existing and future Workplans by Dec 20, 2011 ;

F.              Whereas, all terms of the Agreement not explicitly amended by this Amendment shall remain in full force and effect.  To the extent not modified or defined by this Amendment, all capitalized and defined terms shall have the meaning ascribed to them in the Agreement.

 

NOW, THEREFORE, in consideration of the Recitals (which are incorporated herein) and other good and valuable consideration, the receipt and sufficiency of which is hereby acknowledged, the Parties agree to amend the Agreement as follows:

 

1.                                      3M shall provide approximately seven thousand five hundred (7,800) chronic dermal toxicology supplies (at two doses and Placebo) in amounts shown in the table below.  3M shall invoice Radius for such supplies on a time and material basis.  The estimated cost for the Chronic Dermal Toxicology supplies is $475,000.

 

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

 

1

 

The chronic dermal toxicology supplies will be produced in two runs. The first of each lot is targeted to be manufactured by January 1, 2011. The second of each lot is targeted to be completed by March 1, 2011.

 

	
 
    	
 
    	
100 mcg dose
    	
 
    	
200 mcg dose
    	
 
    	
Placebo
    
	
6 Month Tox
    	
 
    	
2,400
    	
 
    	
2,400
    	
 
    	
2,400
    
	
Extras
    	
 
    	
0
    	
 
    	
0
    	
 
    	
0
    
	
Retains
    	
 
    	
100
    	
 
    	
100
    	
 
    	
100
    
	
Release
    	
 
    	
55
    	
 
    	
55
    	
 
    	
40
    
	
Stability
    	
 
    	
250
    	
 
    	
250
    	
 
    	
0
    
	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    
	
Needed Arrays
    	
 
    	
2,805
    	
 
    	
2,805
    	
 
    	
2,540
    

 

2.                                      3M shall conduct a stability protocol on the two doses of the chronic dermal toxicology supplies. The stability protocol shall include two storage conditions: 5C/ambient humidity with two (2) pulls (6 and 12 months), not including release, and 25C/60%RH with a single pull at one (1) month. 3M shall also conduct a limited stability protocol on the ready-to-coat (RTC) solutions for the chronic dermal toxicology supplies.  The stability protocol shall include one storage condition: 5C/ambient humidity with five (5) pulls (1,2,3,4 and 6 months) for each solution. The RTC solution will also be tested prior to each manufacturing run for confirmation of formulation. 3M shall invoice Radius Three Thousand Six Hundred Dollars ($3,600) per pull point for stability testing at the conclusion of testing of the each pull for any requested stability work.

 

3.                                      Radius understands that for 3M to meet Radius’ requirements under paragraph 1.3M will need to invest in additional facilities and equipment and that the expected revenue from providing these requirements is not sufficient to cover 3M’s investment.  Therefore, Radius agrees that if Radius does not fund at least $1.8 million of work under existing and future Workplans, including the cost of  supplies above and the $85,000 payment made pursuant to the Second Amendment to the Agreement dated September 16, 2010, starting after the effective date of this Amendment and ending by no later than December 20, 2011, or if Radius terminates the Agreement without cause or 3M terminates the Agreement for cause and at the time of such termination or expiration Radius has not expended an aggregate $1.8 million of work during the period from the effective date of this Amendment until the effective date of termination, 3M shall invoice Radius any shortfall from this amount by December 31, 2011 and Radius shall pay 3M unless otherwise agreed by 3M.

 

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

 

2

 

4.                                      Notwithstanding the foregoing, in the event that the results from Radius Phase Ia study from either application sites (the thigh or the abdomen) meet the criterion listed below, Radius shall be obligated to pay for any shortfall under the circumstances set forth in paragraph 3.

Criteria for Phase Ia results:

 

·                  Cmax of low dose OR mid dose will be equal to or exceed 95% of the Cmax associated with the 80 mcg SC dose

·                  Cmax of mid dose OR high dose will be equal to or exceed 125% of the Cmax associated with the 80 mcg SC dose

 

5.                                      Except to the extent expressly amended by this Third Amendment, all of the terms, provisions and conditions of the Agreement are hereby ratified and confirmed and shall remain 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 Third Amendment.

 

6.                                      This Third Amendment 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 to be duly executed in duplicate as of the date and year the last Party signs below.

 

ACCEPTED AND AGREED TO:

 

	
3M COMPANY
    	
 
    	
Radius Health Inc.
    
	
 
    	
 
    	
 
    	
 
    	
 
    
	
 
    	
 
    	
 
    	
 
    	
 
    
	
By
    	
/s/ Jim A. Vaughan
    	
 
    	
By
    	
/s/ B. N. Harvey 
    
	
 
    	
 
    	
 
    	
 
    	
 
    
	
Print Name
    	
Jim A. Vaughan
    	
 
    	
Print Name
    	
B. N. Harvey 
    
	
 
    	
 
    	
 
    	
 
    	
 
    
	
Title
    	
Division VP & GM
    	
 
    	
Title
    	
SVP and CFO
    
	
 
    	
 
    	
 
    	
 
    	
 
    
	
Date
    	
10/7/2010
    	
 
    	
Date
    	
September 29, 2010
    

 

 

3M INNOVATIVE PROPERTIES COMPANY

 

 

	
By
    	
/s/ Robert W. Sprague
    	
 
    
	
 
    	
 
    	
 
    
	
Print Name
    	
Robert W. Sprague
    	
 
    

 

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

 

3

 

	
Title
    	
Secretary
    	
 
    
	
 
    	
 
    	
 
    
	
Date
    	
October 5, 2010
    	
 
    
	
 
    	
 
    	
 
    
	
 
    	
ACR # 201004143
    	
 
    

 

4

 

EXECUTION COPY

 

FOURTH AMENDMENT TO DEVELOPMENT AND CLINICAL SUPPLIES AGREEMENT*

 

This Fourth Amendment (this Amendment”) is entered into as of March 2, 2011 by and between 3M Company, and 3M Innovative Properties Company having a principal office at 3M Center, Building 275-3E-10, St. Paul, MN 55144-1000 (hereinafter “3M”), and Radius Health, Inc. having a principal office at 201 Broadway, 6th Floor, Cambridge, MA (hereinafter “Radius”) and amends the Development and Clinical Supplies Agreement dated June 19, 2009, as amended by the Amendment dated as of December 31, 2009, the Second Amendment dated as of September 16, 2010 and the Third Amendment dated as of September 29, 2010 (hereinafter, the “Agreement”). Capitalized terms used in this Amendment and not defined herein are used with the meanings ascribed to them in the Agreement.

 

RECITALS:

 

WHEREAS, the Parties wish to enter into this Amendment to address certain matters relating to the development and supply of Product to Radius by 3M for use in a Phase II clinical study.

 

NOW, THEREFORE, in consideration of the Recitals (which are incorporated herein) and other good and valuable consideration, the receipt and sufficiency of which is hereby acknowledged, the Parties agree to amend the Agreement as follows:

 

1.                                      3M shall perform the Workplan attached as Attachment 1 to this Amendment with respect to the development and supply of Product for use by Radius in a Phase II clinical study for the Product.  The Workplan may not fully disclose the detailed technical plans and protocols that 3M will follow in the performance of the Workplan, but 3M represents and warrants that it has adopted such plans and protocols and will provide them to Radius upon request. Such requests shall be submitted as Change Orders and shall be provided at Radius’ expense in the event and to the extent that 3M is required to draft such plans and non-proprietary protocols and cannot utilize plans and protocols that exist at the time that Radius makes such request.  If 3M can utilize plans and protocols that are documented at the time Radius makes such request, 3M shall provide such plans and protocols to Radius at no charge.  3M will deliver Product no later than 14 months after the effective date of this Amendment and will use commercially reasonable efforts to accomplish delivery by March 15, 2012.   The costs for development and supply of Product for the Phase II clinical study is estimated to be $5.9 million, based on the assumptions and tasks outlined in Attachment 1.The Parties shall confer regarding the estimated hours set forth in the Workplan attached as Attachment 1 and such hours may be subject to an adjustment in the event that the Parties determine that the hours required to perform the Workplan are different from the estimated hours set forth in Attachment 1.  3M will provide Radius with a list of significant tasks identified in the Workplan and the hours associated with them. 3M and Radius will meet regularly to review the progress and budget.

 

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

 

	
3M Drug Delivery Systems
    	
Confidential
    

 

1

 

2.                                      3M will provide Radius with a copy of documentation as agreed in the Quality Agreement.  3M will also provide a development plan that addresses sterility issues and provides a strategic outline for further development activities until commercialization to Radius.  The plan and any subsequent modifications to the plan will be reviewed with Radius and Radius’ comments will be reasonably considered.   It is understood and agreed that the current plan will be a strategic document that will be subject to revision as the parties move forward.

 

3.                                      Section 2.3 of the Agreement is hereby amended to read in full as follows:

 

“2.3  Either Party may at any time propose a change to the Workplan.  If 3M reasonably believes that a proposed change will increase 3M’s costs or delay completion of the Workplan, the Parties will negotiate in good faith to accommodate such requests.  No such change will be effective unless and until set forth in a written Change Order to the Workplan with an agreed budget and timeline that is approved and signed by authorized representatives of the Parties.  ”

 

4.                                      A new Section 3.6 is hereby added to the Agreement to read in full as follows:

 

“3.6  (a)  A Steering Committee (“Steering Committee”) shall be established with the responsibilities and authority set forth in this Section 3.6.  The Steering Committee shall consist of four (4) members, two (2) members to be appointed by each of Radius and 3M.  The initial Radius members shall be Richard Lyttle and Nick Harvey and the initial 3M members shall be Steve Wick and Ann Meitz.  Each party may, with notice to the other, substitute any of its members serving on the Steering Committee.  The Parties may also, by mutual agreement, increase or decrease the number of members serving on the Steering Committee; provided that the number of members representing each party remains equal.  Radius shall have the right to appoint one of its members to be the chairperson of the Steering Committee.

 

(b)  The general purpose of the Steering Committee is to oversee the performance of the Workplan  concerning the development and supply of Product for the Phase II clinical study.  The Steering Committee shall have the responsibility and authority to: (i) monitor each of Radius’ and 3M’s implementation of their respective responsibilities under the Workplan; (ii) consider, review and approve any proposed amendments to the services or the deliverables set forth in the Workplan; (iii) report regularly to the management of both Parties upon the progress of the Workplan; (iv) provide a forum for exchange of information related to the efforts of each party with respect to the Workplan; (v) resolve disputes (if any) arising among the members of the Joint Technical Team; and (vi) conduct any other functions as Radius and 3M may agree in writing.

 

(c)  The Steering Committee shall hold meetings as mutually agreed by the Parties (but in no event less than quarterly, unless mutually agreed by the Parties).  The first meeting of the Steering Committee shall be held by April 15, 2011 and shall be held in Cambridge, Massachusetts.  After the initial meeting, meetings may be held by telephone or video

 

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

 

2

 

conference, provided  that the Parties shall meet in person at least once per year, and such meetings shall be held in Cambridge, Massachusetts or St. Paul, Minnesota unless the Parties mutually agree to hold such meetings elsewhere.  Minutes of all meetings setting forth decisions of the Steering Committee shall be prepared by the chairperson and circulated to all Parties within thirty (30) days after each meeting, and shall not become official until approved by all Parties in writing; minutes shall be presented for approval as the first order of business at the subsequent Steering Committee meeting, or if it is necessary to approve the minutes prior to such subsequent meeting, then the Parties shall approve the minutes within thirty (30) days of receipt thereof.

 

(d)  The quorum for Steering Committee meetings shall be four (4) members, provided there is at least two (2) members from each of Radius and 3M present.  The Steering Committee will render decisions by unanimous vote.  The members of the Steering Committee shall act in good faith to cooperate with one another and to reach agreement with respect to issues to be decided by the Steering Committee.

 

(e)  Disagreements among the Steering Committee will be resolved via good-faith discussions; provided, that in the event of a disagreement that cannot be resolved within forty five (45) days after the date on which the disagreement arose, then Radius will have the right to make the final decision and such decision shall be final and binding and shall not be subject to Section 12.5; provided that the right of Radius to exercise such final decision under this Section 3.6(e) (i) shall not compel 3M to assume additional costs not agreed to under a Change Order, (ii)  shall not apply to disputes with respect to the interpretation, breach, termination or invalidity of this Agreement, (iii) shall not compel 3M to perform any activities that 3M reasonably considers to be contrary to applicable laws, regulations or ethical principles, and (iv) shall impose a duty on Radius to indemnify and hold 3M harmless from the consequences of any such Radius decision.  Any deadlock not covered by the preceding sentence shall be resolved pursuant to Section 12.5.

 

(f)  The Parties acknowledge and agree that the deliberations and decision-making of the Steering Committee shall be in accordance with the following operating principles:  (i) decisions should be made in a prompt manner; and (ii) the Parties’ mutual objective is to maximize the commercial success of the Product that is the subject of each Workplan, consistent with sound and ethical business and scientific practices.

 

(g)  The Steering Committee will have only such powers as are specifically delegated to it in this Agreement, and will have no power to amend this Agreement or waive a party’s rights or obligations under this Agreement.”

 

5.                                      5.3 will be amended as follows:

 

“5.3  3M will provide a data package to Radius in support of the Drug Product CMC section of regulatory submissions or into 3M’s DMF in support of RADIUS’ regulatory

 

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

 

3

 

filings, such data package to include any data required by applicable regulatory authorities. It is understood and acknowledged that the Phase II clinical study that is the subject of the Workplan may be undertaken in the United States and/or in selected countries outside the United States and, accordingly, 3M will be responsible for providing Radius with all chemistry, manufacturing and control information related to the Product necessary for Radius’ regulatory filings in respect of the Product with any regulatory authority or government agency, such information may be submitted to the government agency in a DMF if this system exists in the country in which the Phase II study is undertaken.  3M shall provide such information by right of reference to a Drug Master File or in support of a Common Technical Document (CTD).  3M acknowledges and agrees that it will also be responsible for maintaining, updating, and providing all supporting chemistry, manufacturing and control information related to the Product necessary to maintain regulatory filings in respect of the product with any regulatory authority or government agency whether through a Drug Master File or in support of a Common Technical Document.”

 

6.                                      A new Section 5.7 is added to the Agreement to read in full as follows:

 

“5.7  (a)  3M shall promptly notify Radius of an impending inspection or audit by any regulatory authority of any facility(ies) where services pursuant to the Workplan are being performed as provided for in Section 5.1 of the Quality Agreement.

 

(b)  3M will notify and inform Radius with respect to the response to any inquiry or observation from any regulatory authority or government agency relating in any way to the Product or the manufacture of the Product at the 3M facility in accordance with the terms and provisions of Section 5.1 of the Quality Agreement.

 

(c)  During an inspection by the FDA or other regulatory authority concerning the services performed pursuant to the Workplan, 3M will not disclose information and materials that are not required to be disclosed to such regulatory authority, without the prior consent of Radius, which shall not unreasonably be withheld.  Such information and materials includes, and is limited to: (i) financial data and pricing data (including, but not limited to, the budget and payment sections of the applicable Workplan); (ii) sales data (other than shipment data); and, (iii) personnel data (other than data as to qualification of technical and professional persons performing functions subject to regulatory requirements).

 

7.                                      Section 6.1 and Section 11.4 of the Agreement are hereby amended to replace the $[*] per hour rate for 3M with the rate of $[*] per hour for work that is not the subject of a Change Order and the rate of $[*] per hour for work that is the subject of a Change Order.

 

8.                                      A new Section 11.3A is hereby added to the Agreement to read in full as follows:

 

“11.3A Radius may terminate within six months of February 28, 2011 with notice to 3M in the event that Radius has determined that the Phase I clinical study for the Product needs to be

 

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

 

4

 

repeated or that additional clinical data is required with respect thereto in order to initiate the Phase II clinical study for the Product.  Radius will provide 3M upon request with certain data concerning the Phase I clinical study upon any termination pursuant to this Section 11.3A in accordance with the provisions of the Agreement concerning the provision of preclinical and clinical data.”

 

9.                                      Except to the extent expressly amended by this Amendment, all of the terms, provisions and conditions of the Agreement are hereby ratified and confirmed and shall remain 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.

 

10.                               This Amendment may be executed in counterparts, each of which will be deemed an original with all such counterparts together constituting one instrument.

 

[remainder of this page intentionally left blank]

 

5

 

IN WITNESS WHEREOF, the parties hereto have caused this Amendment to be duly executed in duplicate as of the date set forth above

 

 

	
3M COMPANY
    	
 
    	
RADIUS HEALTH INC.
    
	
 
    	
 
    	
 
    	
 
    	
 
    
	
By
    	
/s/ Jim A. Vaughan
    	
 
    	
By
    	
/s/ B.N. Harvey
    
	
 
    	
 
    	
 
    	
 
    	
 
    
	
Print Name
    	
Jim A. Vaughan
    	
 
    	
Print Name
    	
B.N. Harvey
    
	
 
    	
 
    	
 
    	
 
    	
 
    
	
Title
    	
Division VP & GM
    	
 
    	
Title
    	
CPO
    
	
 
    	
 
    	
 
    	
 
    	
 
    
	
Date
    	
3-3-2011
    	
 
    	
Date
    	
March 2, 2011
    
	
 
    	
 
    	
 
    	
 
    	
 
    
	
 
    	
 
    	
 
    	
 
    	
 
    
	
3M INNOVATIVE PROPERTIES   COMPANY
    	
 
    	
 
    	
 
    
	
 
    	
 
    	
 
    	
 
    	
 
    
	
By
    	
/s/ Robert W. Sprague
    	
 
    	
 
    	
 
    
	
 
    	
 
    	
 
    	
 
    	
 
    
	
Print Name
    	
Robert W. Sprague
    	
 
    	
 
    	
 
    
	
 
    	
 
    	
 
    	
 
    	
 
    
	
Title
    	
Secretary
    	
 
    	
 
    	
 
    
	
Date
    	
March 3, 2011
    	
 
    	
 
    	
 
    
	
 
    	
# 201104023
    	
 
    	
 
    	
 
    

 

6

 

Attachment 1

 

PROPOSAL TO RADIUS HEALTH INC.

 

FOR DEVELOPMENT OF A BA058-COATED MICROSTRUCTURED 

 

TRANSDERMAL SYSTEM FOR EVALUATION IN A

 

PHASE II CLINICAL STUDY

 

PRESENTED

 

BY

 

o Drug Delivery Systems

 

CONFIDENTIAL

 

7

 

- PROPOSAL -

RADIUS BA058 SMTS PROGRAM

 

EXECUTIVE SUMMARY

 

3M Drug Delivery Systems is pleased to provide Radius Health Inc. (Radius) with this estimate for development and delivery of Phase II clinical supplies for its BA058 product delivered via 3M’s solid Microstructured Transdermal System (sMTS).

 

This estimate supports the attached work plan summary and is based on information exchanged between Radius and 3M regarding the requirements for a BA058 sMTS product.  The scope of work outlined in the summary includes all activities required for formulation development and delivery of clinical supplies to enable Radius to perform a Phase II clinical study in humans. As discussed with Radius, 3M will deliver clinical supplies no later than 14 months after the effective date of this Amendment and will use commercially reasonable efforts to accomplish delivery by March 15, 2012 if Radius approves the Phase II Workplan and initiates work on or before March 2, 2011.  If work does not commence on March 2, 2011, 3 months must be added to the time below to provide sufficient ramp up time to obtain and train resources to re-initiate the project.

 

The estimate for the activities listed in the work plan summary is provided below:

 

	
 
    	
 
    	
PROGRAM
   HOURLY
   ESTIMATE
    	
 
    	
TIMING
    
	
Scale-up Process   Optimization and Preparation of GMP Supplies for Phase II Trial
    	
 
    	
[*] hours
    	
 
    	
(as per indicated in the   above paragraph)
    
	
Direct Costs (Arrays and   Applicators based on quantities defined below arrays for each strength and 300   applicators)
    	
 
    	
$177.3k
    	
 
    	
—
    

 

Deliverables, timing and assumptions are presented in the work plan summary.

 

3M reserves the right to revise this proposal if the intended scope of work deviates from the work outlined.  Any change in this proposal shall be subject to execution of a Change Order.

 

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

 

8

 

WORK PLAN SUMMARY

 

Objective:

 

The objective of the work plan is to optimize manufacturing and analytical activities around the production of BA058-sMTS which will be produced using a new automated process. This work plan will result in the production of BA058-sMTS patches at three different dosage strengths, and a matching placebo patch. This work plan will also support the application for and completion of a Phase 2 clinical study by Radius.

 

Deliverables:

 

·                  Delivery of up to 3 distinct GMP clinical doses of BA058 sMTS product plus 1 placebo dose for a Phase II clinical study and supporting stability work. This includes a maximum of 54,600 patches (detail for quantities is shown below.) and [*] POC applicators. Any additional patches or applicators required to support the clinical trial, stability program and the requirement for clinical retains (as per 3M’s SOP for a non-bioequivalence clinical study) will be provided under a Change Order at Radius request and expense.

 

	
Planned usage
    	
 
    	
Active patches
    	
 
    	
Placebo patches
    
	
clinical study supplies
    	
 
    	
11,250
    	
 
    	
11,250
    
	
Release testing
    	
 
    	
150
    	
 
    	
150
    
	
Retains
    	
 
    	
450
    	
 
    	
600
    
	
Stability
    	
 
    	
2100
    	
 
    	
0
    
	
3M SOP retains
    	
 
    	
250
    	
 
    	
 
    
	
Total quantity
    	
 
    	
14,200
    	
 
    	
12,000
    

 

·                  Crossed over and validated analytical methods to monitor the manufacturing process, the release activities and the stability program

·                  Stability data for each of the three active product lots, as described below.

·                  A stability program for the RTC formulation for up to 6 months as defined in this Workplan

·                  3M shall establish and maintain proprietary Drug Master Files (DMFs) including information on the components, coating and drying manufacturing processes to support regulatory filings in the U.S. and Canada. A right of reference to 3M’s DMFs will be granted to Radius to support regulatory filings in the U.S. and Canada. Outside the U.S., 3M will provide Radius with information necessary to support regulatory filing in all countries where Clinical Development of BA058-sMTS is sited.

 

This estimate does not include the time associated with execution of the Phase II clinical studies nor completion of support stability.

 

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

 

9

 

Milestones for the Workplan:

 

All dates assume Amendment signed by March 2, 2011.  Should the Amendment be signed at a later date, then the target dates for milestones need to be adjusted accordingly.

 

1.              Start preliminary RTC optimization – March 2, 2011

2.              March API requirements delivered by Radius to 3M – March 2, 2011

3.              Methods provided to 3M for crossover – March 4, 2011

4.              April API requirements delivered by Radius to 3M – April 1, 2011

5.              May API requirements delivered by Radius to 3M – May 1, 2011

6.              Initiation of coating optimization – May 1, 2011

7.              RTC optimization concludes – June 30, 2011

8.              July API requirements delivered by Radius to 3M – July 1, 2011

9.              Equipment installation – August 1, 2011

10.       Initiation of final optimization of coating and process verification – November 28, 2011

11.       Completion of coating process verification – December 31, 2011

12.       Release phase II supplies – by March 15, 2012

 

3M assumptions of the work plan:

 

·                  Validated analytical methods exist and can be crossed over to 3M from Radius – if method development is required, a Change Order will be required at Radius expense

·                  No more than 10 analytical methods need to be crossed over

·                  Adequate GMP BA058 starting material will be provided free of charge to 3M for development and clinical supply manufacture by Radius for phase II clinical supplies.

·                  Work plan assumes the use of the POC MTS applicator system and patch design in Phase 2.

·                  Lot size is not to exceed the quantities listed above of GMP-grade BA058 sMTS arrays to best meet the needs of the Phase 2 study and stability program plans.

·                  An additional 300 units per dose will be manufactured for retains in accordance with 3M’s SOPs. Any additional supplies beyond what is shown in the above table can be provided under a Change Order at Radius’ expense.

·                  Phase II product will be manufactured as low bioburden compatible with the process for Phase 3.

·                  sMTS patches and applicators for use in the Phase II clinical study will be bulk labeled by 3M and provided to Radius for further labeling according to the requirements of the clinical protocol.

·                  Radius will be responsible for executing all elements (protocols, regulatory filings, conduct) of the Phase II trial.

·                  The clinical trial will be conducted in countries to be identified by Radius.

·                  Wear time associated with the array is 24 hours or less.

·                  Stability studies on the product in support of Phase II will be performed as indicated; the stability report will be completed within 4 months of the completion of the stability study.

 

10

 

·                  DMFs for BA058-sMTS CCS and Coating and Drying Process will be filed at least 3 month prior to Phase 2 initiation.

 

Radius assumptions of the work plan:

 

·                  The work plan will cover the currently planned activities related to the manufacturing and support of all Phase 2 transdermal clinical trial supplies.  If additional activities are deemed necessary, such activities will be provided under a Change Order with budget and timelines agreed.

·                  This work plan also covers the currently planned CMC/Quality activities required for support of the Phase 2 program for BA058-sMTS, including the 2-year ICH stability program.  If additional activities are deemed necessary, such activities will be provided under a Change Order with budget and timelines agreed.

 

·                  This work plan also covers the currently planned Regulatory activities required for support of the Phase 2 program for BA058-sMTS in the regions and countries selected for the study.  If additional activities are deemed necessary, such activities will be provided under a Change Order with budget and timelines agreed.

 

·                  Patches will be supplied in quantities indicated in the above table to support the clinical trial, clinical retains and the stability program.  Any additional quantities required can be provided on a Change Order.

·                  Phase 2 supplies will be manufactured with a low bioburden and will be compatible with the manufacturing process planned for Phase 3.

·                  Phase 2 supplies will be manufactured with residual solvents consistent with USP 467 and its European equivalent, extractables,

·                  Each major work plan task identified below will be associated with a protocol (either existing or to be written under a Change Order) and report, both to be reviewed and agreed with Radius.  Such reports may be redacted to protect 3M proprietary information

·                  All manufacturing activities will be compliant with:

 

ICH Q1A(R2): Stability Testing of New Drug Substances and Products 3M level 2 validation of analytical procedures.  3M will provide data supporting chemistry, manufacturing and control information necessary for regulatory filings with authorities in and outside the United States

 

WORKPLAN SUMMARY OF TASKS:

BA058-sMTS Drug Product Development and

Manufacturing Process Scale-up including Phase 2 Supply Production

 

3M Environmental Health and Safety

 

Update Hazard Review

 

11

 

Update Risk Assessment (internal)

Update Animal Use Protocols

Qualification of Suppliers

 

3M Product Development

 

Terminal sterilization study

RM Receipt and Part Manufacture

RTC Optimization/Characterization

Formulation Optimization/Characterization

Process Optimization (including drying)

Packaging Optimization

[stability program is defined elsewhere]

Supply Production for additional Bridging Tox, if required (additional charge)

 

3M Product Scale-up to Phase 2

 

RM Receipt and Part Manufacture

System Integration

Product Development/Optimization:  RTC Optimization, Process Optimization

Process/Product Verifications

 

3M Support for Execution of Phase 2 Supply Manufacture

 

Validate Analytical Methods required for the manufacturing process, release and stability programs associated with the Phase 2 clinical trial supplies

Development and Verification of Specifications for Phase 2

Development and Verification of Shipping and Storage Requirements

Update Regulatory Documentation:  Provide up-to-date Drug Product CMC data to support updated IND, File Product Specific DMFs (sMTS-BA058 CCS and sMTS-BA058 Coating and Drying Process)

 

3M Phase 2 Supply Manufacture and Stability

 

RM Receipt and Part Manufacture

RM and Component Clearance

RTC Formulation Manufacture and Clearance

Execute Clinical Tickets: Applicator Construction, estimated 300 units; 3 active doses at a maximum as indicated in the table above.

Stability of RTC at 5C/ambient RH – 1,3,6 months

Stability of RTC at 25C/60% RH – 2 days, 1 week

Stability of Phase 2 Supplies:  5C/ambient RH – 1,3,6,9,12 months; 25C/60% RH - 1,3,6,9,12 months; 40C/75% RH – 1,3,6 months; the 18 and 24 months timepoints will be added under a Change Order.

Clear, release and ship Clinical Supplies

 

12

 

Radius Clinical Supplies Manufacturing Tasks

 

Provide GMP-grade, BA058 API, ready for formulating

Receive, label and release Phase II clinical supplies

Author Investigators Brochure and IND submission

Write clinical protocol, define safety and efficacy endpoints 

Execute or oversee the Phase II clinical study

 

13

 

3M DRUG DELIVERY SYSTEMS CONTACT INFORMATION

 

For inquiries related to the proposal, please contact:

 

Mary Mathisen

Product Commercialization Manager

3M Drug Delivery Systems

3M Center, Bldg. 260-4N-12

St. Paul, MN 55144

Tel:  651-733-9125

Fax:  651-5751729

Cell: 651-503 0861

E-Mail: mmathisen@mmm.com

 

Mark Tomai Ph.D.

Head of Vaccine Business

3M Drug Delivery Systems

3M Center, Bldg. 275-3E-10

St. Paul, MN 55144

Tel:  651-733-5375

Cell: 651-403-0455

E-Mail: matomai@mmm.com

 

14

 

	
Confidential   Treatment Requested
    	
 
    	
 
    
	
Under 17 C.F.R.   §§ 200.80(b)(4) and
    	
 
    	
 
    
	
240.24b-2
    	
 
    	
 
    

 

FIFTH AMENDMENT TO DEVELOPMENT AND CLINICAL SUPPLIES AGREEMENT

 

This Fifth Amendment (“Amendment”) is entered into as of November 30, 2012 by and between 3M Company, and 3M Innovative Properties Company having a principal office at 3M Center, Building 275-3E-10, St. Paul, MN  55144-1000 (hereinafter “3M”), and Radius Health, Inc. having a principal office at 300 Technology Square, Cambridge, MA (hereinafter “RADIUS”) and amends the Development and Clinical Supplies Agreement dated June 19, 2009, as amended by the Amendment dated as of December 31, 2009, the Second Amendment dated as of September 16, 2010, the Third Amendment dated as of September 29, 2010 and the Fourth Amendment dated as of March 2, 2011 (hereinafter, the “Agreement”). Capitalized terms used in this Amendment and not defined herein are used with the meanings ascribed to them in the Agreement.

 

RECITALS:

 

WHEREAS, 3M, through its Drug Delivery Systems Division, has developed expertise and has rights in technology relating to active transdermal, intradermal, and microneedle drug delivery, including its proprietary microstructured transdermal system (“MTS”) for delivering drugs into and through the skin;

 

WHEREAS, RADIUS has experience and expertise in the research, development and commercialization of pharmaceutical products, including expertise in its proprietary compound BA058 (“Compound”);

 

WHEREAS, the Parties wish to enter into this Amendment to address certain matters relating to exclusivity and to the development and supply of Product to RADIUS by 3M for use in a Phase III clinical study.

 

NOW, THEREFORE, in consideration of the Recitals (which are incorporated herein) and other good and valuable consideration, the receipt and sufficiency of which is hereby acknowledged, the Parties agree to amend the Agreement as follows:

 

1.              Section 1 shall be amended to include the following:

 

1.6                               “PTH” shall mean synthetic, natural or recombinant parathyroid hormone and/or any of its active fragments, analogues, derivatives and/or other variants.

 

1.7                               “PTH Related Protein” shall mean synthetic, natural or recombinant parathyroid hormone-related protein and/or any of its active fragments, analogues, derivatives and/or other variants.

 

2.                                      Section 9.1 shall be replaced in its entirety as follows:

 

[*] Certain information in this document has been omitted and filed separately with the Securities and Exchange Commission. Confidential treatment has been requested with respect to the omitted portions.

 

 

During the term of this Agreement, with respect to the delivery of Compound, PTH and/or PTH Related Protein via active transdermal, intradermal, or microneedle technology, 3M shall work exclusively with RADIUS and RADIUS shall work exclusively with 3M.

 

3.                                      3M shall perform the Workplan attached as Exhibit A and Exhibit B to this Amendment with respect to the development and supply of Product for use by RADIUS in a Phase III clinical study for the Product.

 

4.                                      Section 6.1 and Section 11.4 of the Agreement are hereby amended to replace the $[*] per hour rate for 3M with the rate of $[*] per hour for work that is not the subject of a Change Order and the rate of $[*] per hour for work that is the subject of a Change Order, with the following exception: for work performed by 3M from the effective date of this Amendment through June 30th, 2013, the rate per hour will be $[*], whether or not the subject of a Change Order.

 

5.                                      3M shall provide phase III supplies as requested by RADIUS.  RADIUS shall pay 3M [*] dollars ($[*]) per unit for coated arrays and [*] ($[*]) per unit for applicators, both to be used in Phase III studies.

 

6.                                      Section 7.2 shall be replaced in its entirety as follows:

 

Except as otherwise provided below, any inventions conceived during and out of the work performed under this Agreement, and patents and applications filed thereon (“Program Patents”), shall be owned according to U.S. law as follows: those conceived solely by employees or agents of one party shall be solely owned by that party; those conceived jointly by an employee or agent of 3M and an employee or agent of RADIUS shall be owned jointly by 3M and RADIUS and will be considered Confidential Information of both parties with each joint owner having the right, subject to this Agreement, to practice, license, and transfer its undivided rights in such joint inventions without permission of or accounting to the other(s)) under the conditions provided for in this Agreement; provided that it is expressly understood and agreed that other than to conduct the work contemplated by this Agreement, during the term of the Agreement and, if applicable, any commercial supply agreement among the Parties related to any product containing the Compound and/or PTH Related Protein, (a) 3M shall have no right to use jointly owned inventions or jointly owned Program Patents in conjunction with the Compound or any pharmaceutical product that includes, as an active ingredient, PTH or PTH Related Protein and (b) RADIUS shall have no right to use jointly owned inventions or jointly owned Program Patents in conjunction with the Compound or any pharmaceutical product that includes, as an active ingredient, PTH or PTH Related Protein with any active transdermal, intradermal, or microneedle delivery technology.  Information and data developed during and resulting from the work under this Agreement (“Program Data”), solely by employees or agents of one party shall be solely owned by that party;

 

[*] Certain information in this document has been omitted and filed separately with the Securities and Exchange Commission. Confidential treatment has been requested with respect to the omitted portions.

 

 

those data developed jointly during and resulting from the work under this Agreement by an employee or agent of 3M and an employee or agent of RADIUS shall be owned jointly by 3M and RADIUS (and each joint owner shall have the right to practice, license, and transfer its undivided rights in such jointly owned Program Data without permission of or accounting to the other(s)) under the conditions provided for in this Agreement; provided that it is expressly understood and agreed that other than to conduct the work contemplated by this Agreement, during the term of the Agreement and, if applicable, any commercial supply agreement among the Parties related to any product containing the Compound and/or PTH Related Protein, (i) 3M shall have no right to use jointly owned Program Data in conjunction with the Compound or any pharmaceutical product that includes, as an active ingredient, PTH or PTH Related Protein and (ii) RADIUS shall have no right to use jointly owned Program Data in conjunction with the Compound or any pharmaceutical product that includes, as an active ingredient, PTH or PTH Related Protein with any active transdermal, intradermal, or microneedle delivery technology.  In the event that the Parties are no longer working together under this Agreement or a commercial supply agreement related to any product that includes, as an active ingredient, the Compound, PTH or PTH Related Protein, then for a period of three years after termination, 3M shall have no right to use jointly owned Program Patents or jointly owned Program Data in conjunction with the Compound or PTH Related Protein, provided that (i) Radius has made commercially reasonable good faith efforts to submit the regulatory filing for the Product in the US by [*] or if not, (ii) Radius has made commercially reasonable good faith efforts to financially and operationally support the Workplan through [*].  In the event that Radius has not complied with (i) above and has not complied with (ii) above, 3M shall have no restriction on the use of jointly owned Program Patents or jointly owned Program Data.  For the avoidance of doubt, 3M may use jointly owned Program Patents and jointly owned Program Data in conjunction with a pharmaceutical product that includes, as an active ingredient, PTH.

 

7.                                      Section 7.3 shall be replaced in its entirety with the following:

 

Notwithstanding the foregoing provisions of this Section 7, Program Patents and Program Data directed towards and claiming (in the case of Program Patents) the Compound, or a method of making or using the Compound, regardless of inventorship, shall be solely owned by RADIUS; and Program Patents and Program Data directed towards active transdermal, intradermal, or microneedle delivery technology, including, without limitation, microneedle devices, components, arrays, applicators, manufacturing, coating and formulations, packaging, or uses thereof, regardless of inventorship, shall be solely owned by 3M.

 

8.                                      Section 7.4 shall be replaced in its entirety with the following:

 

[*] Certain information in this document has been omitted and filed separately with the Securities and Exchange Commission. Confidential treatment has been requested with respect to the omitted portions.

 

 

3M, 3M IPC and RADIUS grant each other a worldwide, royalty-free, license under Program Data and Program Patents owned solely by the other Party, solely for purposes of conducting the work under this Agreement or a commercial supply agreement related to any product containing the Compound and/or PTH Related Protein.  The licenses under this Section 7.4 shall be exclusive with respect to any product containing the Compound and/or PTH Related Protein, but only as long as the Parties are working together under this Agreement or a commercial supply agreement among the Parties related to any product containing the Compound and/or PTH Related Protein.  In the event that the Parties are no longer working together under this Agreement or a commercial supply agreement related to any product containing the Compound and/or PTH Related Protein, the exclusive licenses to any Program Patents under this Section 7.4 are terminated, but the Parties shall continue to have a non-exclusive, worldwide, royalty-free, license under Program Patents and Program Data owned solely by the other Party, provided that 3M shall have no right to such Program Patents and Program Data solely owned by RADIUS in conjunction with the Compound and/or PTH Related Protein, and (ii) RADIUS shall have no right to use such Program Patents and Program Data solely owned by 3M in conjunction with any active transdermal, intradermal, or microneedle delivery technology.

 

For clarity, the licenses under this Section 7.4 are limited to Program Data or Program Patents do not and shall not be construed to give the licensees any right or license, by implication or otherwise, to any of the licensor’s other intellectual property.

 

9.                                      Upon execution of this Fifth Amendment, 3M shall take action to procure capital equipment to enable the manufacture of phase III supplies.  In the event that the Agreement is terminated prior to [*] without RADIUS submitting a regulatory filing for the Product in the US, RADIUS shall reimburse 3M for [*] percent [*]  the cost of any such equipment specifically procured for RADIUS’ phase III supplies, with RADIUS’ share estimated to be approximately [*] Dollars ($[*]) if (i) RADIUS has not made commercially reasonable good faith efforts to financially and operationally support the Workplan through [*] or (b) if terminated by 3M for RADIUS material breach or (c) if terminated by RADIUS for any reason other than 3M material breach,

 

10.                               Except to the extent expressly amended by this Amendment, all of the terms, provisions and conditions of the Agreement are hereby ratified and confirmed and shall remain 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.

 

11.                               This Amendment may be executed in counterparts, each of which will be deemed an original with all such counterparts together constituting one instrument.

 

[remainder of this page intentionally left blank]

 

[*] Certain information in this document has been omitted and filed separately with the Securities and Exchange Commission. Confidential treatment has been requested with respect to the omitted portions.

 

 

IN WITNESS WHEREOF, the parties hereto have caused this Amendment to be duly executed in duplicate as of the date set forth above

 

 

	
3M   COMPANY
    	
 
    	
RADIUS   HEALTH INC.
    
	
 
    	
 
    	
 
    	
 
    	
 
    
	
By
    	
/s/   James D. Ingebrand
    	
 
    	
By
    	
/s/   Michael Wyzga
    
	
 
    	
 
    	
 
    	
 
    	
 
    
	
Print   Name
    	
James   D. Ingebrand
    	
 
    	
Print   Name
    	
Michael   Wyzga
    
	
 
    	
 
    	
 
    	
 
    	
 
    
	
Title
    	
President   and GM
    	
 
    	
Title
    	
President   and CEO
    
	
 
    	
 
    	
 
    	
 
    	
 
    
	
Date
    	
December 14,   2012
    	
 
    	
Date
    	
December 14,   2012
    
	
 
    	
 
    	
 
    	
 
    	
 
    
	
 
    	
 
    	
 
    	
 
    	
 
    
	
3M   INNOVATIVE PROPERTIES COMPANY
    	
 
    	
 
    	
 
    
	
 
    	
 
    	
 
    	
 
    	
 
    
	
By
    	
/s/   Robert W. Sprague
    	
 
    	
 
    	
 
    
	
 
    	
 
    	
 
    	
 
    	
 
    
	
Print   Name
    	
Robert   W. Sprague
    	
 
    	
 
    	
 
    
	
 
    	
 
    	
 
    	
 
    	
 
    
	
Title
    	
Secretary
    	
 
    	
 
    	
 
    
	
 
    	
 
    	
 
    	
 
    	
 
    
	
Date
    	
December 14,   2012
    	
 
    	
 
    	
 
    
									

 

[*] Certain information in this document has been omitted and filed separately with the Securities and Exchange Commission. Confidential treatment has been requested with respect to the omitted portions.

 

 

EXHIBIT A

 

WORK PLAN SUMMARY 07SEPT2012

 

Note:  This workplan summary represents 3M’s estimated hours and tasks as of the September 7, 2012, but does not reflect the rate reduction contemplated in Section 4 of this amendment.  The impact of the rate reduction is summarized in a footnote at the end of Exhibit A.

 

Objective

 

This work plan covers the development of the BA058-sMTS drug product from the current configuration through manufacture of Phase III clinical supplies.  The work includes optimization and characterization of a modified formulation for the drug product as well as generation of preclinical tox and bridging Phase I clinical supplies to verify the suitability of the new dose for inclusion in the Phase III study.

 

The work plan includes 12 months of stability data to be collected prior to submission of the IND for Phase III.  This stability study will be reflective of the final formulation and container closure system (CCS) material configuration for the Phase III product.  Further, the work plan includes the documentation and analysis necessary to support verification of the [*] manufacturing process that will be used to manufacture [*] BA058-sMTS Phase III supplies, [*].

 

The work plan includes the development (as necessary), documentation, and full validation of analytical methods and development of specifications necessary to support clearance and characterization of the drug product, CCS, and raw materials.  These methods include validation of the [*] and a shipping study to verify the suitability of the CCS.

 

The work plan includes the manufacture and clearance of approximately [*] Phase III supplies along with development of CMC/IND documentation needed to support regulatory filings in the US and/or the EU.

 

The work described here (through manufacture of Phase III clinical supplies) is expected to take [*] months from the date of initiation and assumes that a single dose formulation has been identified.

 

Work Plan Assumptions

 

·                  Work plan assumes the development of a sterile (aseptically manufactured), single-dose BA058-sMTS drug product with a minimum of [*] months stability at room temperature that is intended to be administered with a reusable applicator

 

[*] Certain information in this document has been omitted and filed separately with the Securities and Exchange Commission. Confidential treatment has been requested with respect to the omitted portions.

 

 

designed to meet the needs of the target patient population (post-menopausal women with osteoporosis or pre-osteoporosis).

·                  Work plan assumes that work required to optimize the sMTS applicator for the BA058-sMTS product will be started immediately upon initiation of the work plan.  Certain elements of this work plan (e.g. Product Stability to Support Phase III Filing and Bridging Phase I Supply Manufacture) are dependent on the timely execution of tasks within the Applicator Development work plan.

·                  Work plan assumes Radius will provide sufficient quantities of BA058 on time to complete the product and process development work described here.

·                  Work plan assumes that a single dose of BA058-sMTS, plus placebo, will be prepared for GLP preclinical tox studies ([*] units each) and for the bridging Phase I clinical study ([*] units each); these supplies will meet previously established specifications [*].  The quantities listed include supplies sufficient to cover stability and retains.  If additional quantities are required, a change order will be issued.

·                  GLP preclinical tox supplies will utilize the existing POC applicator system.

·                  Phase I clinical supplies will be applied utilizing the new applicator.

·                  Work plan assumes that the stability work initiated to support the pre-Phase III filing will be completed using materials, but not necessarily the dimensions or mechanical configuration, representative of the final CCS.

·                  Work plan assumes that BA058-sMTS Phase III supplies will be manufactured as a [*].

·                  Work plan assumes all supply manufacturing work described will be conducted in 3M’s St. Paul 260 Clinical Supply Area.

·                  Work plan assumes that all sterilization, sterility testing, process simulation testing, microbial testing and endotoxin testing will be done at outside contract facilities.

·                  Any 3M out-of-pocket expenses to be reimbursed by Radius including tooling and testing and will be billed at 3M’s actual cost.

·                  Work plan assumes that [*] supplies (single dose + placebo) will be manufactured for Phase III via lots sizes of approximately [*] units/lot.  The stability of each lot will be characterized.  The quantities listed include supplies sufficient to cover stability and retains assuming the lot size indicated and that [*] units are used for dosing.  If additional quantities are required, a change order will be issued.

·                  Work plan assumes that the GLP preclinical tox study, the Phase I clinical study and the Phase III clinical study will be conducted by Radius.

·                  Work plan assumes that all clinical work will be conducted in the US and/or the EU.

·                  Work plan assumes that some product/process development work described here may not represent the final state and that additional DOE and process characterization work may be necessary prior to commercial launch.

·                  3M will initiate approval procedures for the capital expenditure upon signed agreement of the Amendment.

·                  Radius is responsible for transport of product from St. Paul to tox or clinical facility.

 

[*] Certain information in this document has been omitted and filed separately with the Securities and Exchange Commission. Confidential treatment has been requested with respect to the omitted portions.

 

 

·                  This work plan is developed following the general project plan and technical and regulatory strategy agreed to by the Radius/3M JTT on 01 August 2012.  Assumptions re: project timing depends on both 3M and Radius completing critical path activities on time including, finalization of product specific applicator, dose/formulation selection for GLP preclinical tox work, initiation and completion of bridging Phase I study, dose/formulation selection for Phase III supply manufacture.

 

[*] Certain information in this document has been omitted and filed separately with the Securities and Exchange Commission. Confidential treatment has been requested with respect to the omitted portions.

 

 

Work Plan Tasks and Projected Resource Needs

 

	
Estimated Costs
    	
 
    	
Start
    	
 
    	
Finish
    	
 
    	
Project   Tasks
    	
 
    	
Deliverables
    
	
[*] hours
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
Product   and Process Risk Management

Required   documentation and process analysis for drug product including risk   identification, risk analysis, risk evaluation, risk mitigation,   re-evaluation, risk management report
    	
 
    	
·      Product risk   management report, suitable for regulatory submission, including elements   addressed in adjacent column
    
	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    
	
[*] hours
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
Product   and Process Design Control Documentation

Required   documentation and analysis for drug product and process including update of   the Design Requirements Specification (DRS), Design Specification (DS),   Design Failure Mode and Effects Analysis (DFMEA), Design Reviews, Design   Verification
    	
 
    	
·      Design   Requirements Specification

·      Device   Specification

·      Design Review   Reports (including FMEA)

·      Product   Breakdown Structure
    
	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    
	
[*] hours
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
Product   Design Formulation Development

Forced   degradation study for final formulation and product, GMP process development   for Tox Supply generation at target dose
    	
 
    	
·      Formulation   development report (for submission)

·      Forced   degradation report (for submission)

·      GMP process   for Tox supplies, 1 active dose + 1 placebo
    

 

[*] Certain information in this document has been omitted and filed separately with the Securities and Exchange Commission. Confidential treatment has been requested with respect to the omitted portions.

 

 

	
[*] hours

 

$[*] sterilization facility/bioburden testing
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
Terminal   Sterilization Process for Components

Dose   titration and component characterization (physical and chemical), patient   wear panel re: stick to skin adhesion for final conditions in target   population, terminal sterilization analysis and report
    	
 
    	
·      Aseptic   Process Justification Report

·      Component   characterization, Bioburden and Dose Selection Report

·      Validated   Terminal Sterilization Process and Validation Report
    
	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    
	
[*] hours

 

$[*] tray tooling
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
Primary   Packaging Characterization

[*], array CCS   optimization for shipping and applicator coupling, shipping study, label   creation and validation

 

Note:  This does not include the development of   the primary packaging which will be outsources.
    	
 
    	
·      [*]

·      Validation   Process for Label creation and Validation Report

·      Tooling for   Primary Packing
    
	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    
	
[*] hours
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
Ready   to Coat (RTC) - Process Characterization and Validation

Mixing,   filtering, material compatibility characterization, mixing qualification,   filter qualification, stability
    	
 
    	
·      RTC Mixing   and Filtration Process master batch record

·      Stability   Data and Report on Final RTC Process
    
	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    
	
[*] hours
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
Coating   - Process Characterization and Improvements

Coating   conditions with final formulation
    	
 
    	
·      Coating   Process master batch record

·      Optimized   coating process including development report
    

 

[*] Certain information in this document has been omitted and filed separately with the Securities and Exchange Commission. Confidential treatment has been requested with respect to the omitted portions.

 

 

	
[*] hours
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
Product   Stability to Support Phase III Filing (minimum 12 months stability on 1   formulation)

Full   ICH Stability on select formulation with representative CCS (materials)
    	
 
    	
·      Twelve month   stability study report with CCS materials suitable for supporting Phase III   filing
    
	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    
	
[*] hours
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]   Process Characterization for BA058-sMTS

Required   documentation and analysis for drug product including risk assessment, HAZOP,   HACCP, process definition
    	
 
    	
·      [*] process   risk management plan

·      [*] process   definition
    
	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    
	
[*] hours
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]   Process Simulation for BA058-sMTS

[*] test method,   process simulation design and protocol development, simulation study,  analysis and study report
    	
 
    	
·      Process simulation   protocol

·      [*]   modifications completed, hardware installed, optimized and characterized

·      Process   simulation report
    
	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    
	
[*] hours

 

$[*] for materials for supplies
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
Bridging   GLP Preclinical Tox Supply – new formulation, existing applicator, ([*] doses   active; [*] doses placebo)

RM   characterization, supply manufacture: components, supply manufacture: RTC,   supply manufacture: coated patches, stability of supplies (assumes 12 months   for 1 dose), stability report
    	
 
    	
·      GLP Supplies   for 9M tox study, 1 active dose + 1 placebo

·      12 month   stability data on tox supplies
    

 

[*] Certain information in this document has been omitted and filed separately with the Securities and Exchange Commission. Confidential treatment has been requested with respect to the omitted portions.

 

 

	
[*] hours

 

$[*] for materials for supplies
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
Bridging   Phase I Clinical Supply – new formulation, new applicator ([*] doses active;   [*] doses placebo)

IND/CMC   documentation preparation, RM characterization, supply manufacture:   components, supply manufacture: RTC, supply manufacture: coated patches,   stability of supplies (assumes 12 months for 1 dose), stability report
    	
 
    	
·      Supplies for   Phase I Clinical Study, 1 active dose + 1 placebo

·      Data and   report on 12 M stability study on clinical supplies

·      Updated CMC   documentation, including description and operation instructions for new   applicator
    
	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    
	
[*] hours
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
CCS :   Test Method Development, Method Development Report, Validation Protocol   development, Validation (to Level 3) and Validation Report, Specification   Development and Specification Justification Report

Methods   anticipated: [*]
    	
 
    	
·      Validated   methods and Validation reports for [*]

·      Method   development reports for all methods, as appropriate

·      Validated [*] method for the drug product

·      Validated   performance methods for [*]
    
	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    
	
[*] hours

 

$[*] for lab equipment
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
API-related   : Test Method Development, Method Development Report, Validation (to Level 3)   and Validation Report, Specification Development and Specification   Justification Report

Methods   anticipated: [*]
    	
 
    	
·      Validated   methods and validation reports for drug product and RTC testing (listed in   adjacent column).

·      Method   development reports for methods listed in adjacent column.
    

 

[*] Certain information in this document has been omitted and filed separately with the Securities and Exchange Commission. Confidential treatment has been requested with respect to the omitted portions.

 

 

	
[*] hours
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
Extractables:   Test Method Development, Method Development Report, Validation (to Level 3)   and Validation Report, Specification Development and Specification   Justification Report

Methods   anticipated: Liquid Chromatography (LC) and Size Exclusion Chromatography   (SEC)
    	
 
    	
For   array, filter, and syringe body:

·      Validated   methods and validation reports for characterization of extractables   (anticipate 2-4 methods/matrix)

·      Method   development reports for extractables.

·      Extractables   Study Protocol

·      Extractables   Study Report
    
	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    
	
[*] hours
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
Drug   Product Specification and Supplier Qualification

Characterization,   analysis and specification development for RMs, RTC in-process analysis and   specification development, drug product specification analysis and report,
    	
 
    	
·      Completed   qualifications for all suppliers

·      DP   Specifications and Specification Justification Reports
    

 

[*] Certain information in this document has been omitted and filed separately with the Securities and Exchange Commission. Confidential treatment has been requested with respect to the omitted portions.

 

 

	
[*] hours for mfg   support

 

[*] hours for   stability

 

$[*] Phase III supplies

 

$[*] process simulation testing 
    	
 
    	
[*]
    	
 
    	
[*]

 

(stability continues after this date)
    	
 
    	
Phase   III Clinical Supply ([*] doses active + placebo)

IND/CMC   documentation preparation, RM characterization and clearance, supply   manufacture and clearance: components, supply manufacture and clearance: RTC,   supply manufacture and clearance: coated patches, stability of supplies   (anticipate [*] months for 1 formulation),   analysis and stability report
    	
 
    	
·      Cleared,   Sterile product for Phase 3 clinical trial, 1 dose active + 1 placebo

·                  [*] clinical   doses

·                  Release testing   supplies

·                  Required   retains

·                 Stability   supplies

·      Stability   Study

·                  Full ICH   testing of 1 lot of active and 1 lot of placebo

·                  12M testing   only, on [*] other lots.

·      Final report   on stability study

·      Updated CMC   documentation

·      Process   Simulation Protocol

·      Process   Simulation Final Report
    

 

Summary of Costs (Original)

 

	
[*]
   $[*]
    	
 
    	
Labor   Hours 
   Labor Costs ($[*]/hour)
    
	
$ [*]
    	
 
    	
Tox   and Clinical Supplies (Phase I & Phase III)
    
	
$ [*]
    	
 
    	
Direct   Costs (materials, equipment, sterilization, etc)
    

 

Exibit A Footnotes

[*]

 

[*] Certain information in this document has been omitted and filed separately with the Securities and Exchange Commission. Confidential treatment has been requested with respect to the omitted portions.

 

 

Summary of Costs (Revised 10Dec2012)

 

	
[*]

$[*] ($[*]/$[*])
    	
 
    	
Labor   Hours

Labor   Costs ($[*]/hour/$[*]/hour)
    
	
$ [*]
    	
 
    	
Tox   and Clinical Supplies (Phase I & Phase III)
    
	
$ [*]
    	
 
    	
Direct   Costs (materials, equipment, sterilization, etc)
    

 

[*] Certain information in this document has been omitted and filed separately with the Securities and Exchange Commission. Confidential treatment has been requested with respect to the omitted portions.

 

 

EXHIBIT B

 

WORK PLAN SUMMARY 07SEPT2012

 

Note:  This workplan summary represents 3M’s estimated hours and tasks as of the September 7, 2012, but does not reflect the rate reduction contemplated in Section 4 of this amendment or the change in the mix of work between 3M and its design firm based on an updated quote.  The impact of the rate reduction and change in mix of work is summarized in a footnote at the end of Exhibit B.

 

Objective

 

This work plan covers the optimization of 3M’s existing prototype sMTS applicator for use with the BA058-sMTS drug product, with a primary patient population of post-menopausal women diagnosed with moderate to severe osteoporosis.   3M has made a significant investment in the development of applicator subsystems, general human factors studies, and characterization of critical application and wear performance for use of the sMTS array patches.  This work plan uses this foundation for optimization of the applicator specifically to support the approval of the BA058-sMTS drug product.

 

The work plan includes design refinement work provided by an external medical device design firm.  3M will manage this design firm and will work with Radius to establish critical device specifications and performance verification.  3M will oversee a VOC/Human Factors study with the target population to verify design choices.  3M will also manage suppliers and vendors necessary to manufacture Phase III and commercial supplies of the applicator.  The manufacture of these devices for clinical devices may include sub-contractors.  3M will characterize device performance during optimization and will provide verification of the device performance consistent with Design Control requirements in the US and the EU, including Human Factors studies.  Usability studies for the target patient population will be conducted by 3M with input from Radius input.

 

Although existing methods will be used whenever possible, the work plan includes the development (as necessary), documentation, and full validation of all analytical methods and specifications necessary to support clearance and characterization of the applicator and per the design requirements.  The work plan includes a stability study necessary to support the use of the device in Phase III.   The work described here is expected to take [*] months from the date of initiation.

 

Work Plan Assumptions

 

·                  3M has unrefined designs for each of the major applicator subsystems (i.e. energy source, array loading, counter, indicator, end of life lockout (end of life)) and general form factor data that will be used as a starting point for design of the BA058-sMTS drug product applicator optimization.

 

·                  3M has characterized critical parameters for array application and wear; these parameters will be used as a starting point for BA058-sMTS drug product applicator.

 

[*] Certain information in this document has been omitted and filed separately with the Securities and Exchange Commission. Confidential treatment has been requested with respect to the omitted portions.

 

 

·                  3M has developed and validated certain methods for characterization of device performance (e.g., [*]).  These methods will be used whenever possible to facilitate optimization and characterization of the BA058-sMTS applicator.

·                  The applicator will be designed for use by Radius’ target patient population (post-menopausal women) with 3M’s LCP sMTS arrays and array patches, currently in-use in Radius’ BA058-sMTS Phase II clinical trial.

·                  3M will select and manage the external medical device design firm with input from Radius on areas such as, but not limited to, Design Specifications, User Requirements and Risk Management.

·                  An external medical device design firm will be contracted to refine the applicator subsystems and refine the device human factors to fit the needs of the BA058-sMTS target patient population.  The external medical device design firm will be responsible for applicator design and the production of prototypes sufficient to support patient use and performance characterization studies.

·                  Any 3M out-of-pocket expenses to be reimbursed by Radius including tooling, external medical device firm and human factors facility will be billed at 3M’s actual cost.

·                  Single cavity tooling will be fabricated to support design verification.  Parts molded from this tooling may also be used in a Phase I, Phase II and/or Phase III clinical trials.

·                  3M will have responsibility to select and manage all suppliers and/or vendors needed to manufacture the applicator for Phase III and commercial supply manufacture.

·                  All clinical work utilizing the device will be conducted in the US and/or the EU.

·                  Radius will be responsible for the device design validation (Phase III clinical trial).

 

Work Plan Tasks and Projected Resource Needs

 

	
Original
   Estimated
   Costs
    	
 
    	
Revised
   Estimated
   Costs
   (10Dec2012)
    	
 
    	
Start
    	
 
    	
Finish
    	
 
    	
Project   Tasks
    	
 
    	
Deliverables
    
	
[*] hours
    	
 
    	
[*] hours

 
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
Project   Initiation

Agreement   between 3M and Radius on Project Charter, DRS , User Requirements, etc
    	
 
    	
·      Project   Charter

·      Design   Requirements Specification
    

 

[*] Certain information in this document has been omitted and filed separately with the Securities and Exchange Commission. Confidential treatment has been requested with respect to the omitted portions.

 

 

	
[*] hours

 

$[*] External Design Firm
    	
 
    	
[*] hours

 

$[*] External Design Firm

 

$[*] External Design Firm Capital   Expenses
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
Management   of External Medical Device Design Firm

Management   of external medical device firm; host meetings (frequency to be agreed upon)   between 3M, Radius and external medical device firm to progress   optimization.  Engineering design   consultation related to optimization of existing subsystems, critical device   parameters and performance and design for manufacturability, maintenance of   design control documentation.

 

Added   (10Dec2012):

Patient   Use and Human Factor Studies for Design

Design   and orchestration of patient use studies, 1 in the US and 1 in the EU for the   target patient population (estimated at 2 days each); construction of device   stimulus supplies.  Studies at each   site will include interviews with patients and/or health care providers and   will be conducted under protocol and include a final summary report

 
    	
 
    	
·      Meeting   Minutes

·      Engineering   Drawings suitable for tooling manufacture

·      Summary   reports of prototype testing

·      Design   control documentation via Design History File

·      Engineering   design review (including design for manufacturability) and critical device   parameters input by 3M

 

Added   (10Dec2012):

·      Human Factors   Study Protocols

·      Looks-like   models for usability/HF testing

·      Patient   feedback on design elements

·      Human Factors   Study Final Report and Recommendations

·      Validated   design requirements
    

 

[*] Certain information in this document has been omitted and filed separately with the Securities and Exchange Commission. Confidential treatment has been requested with respect to the omitted portions.

 

 

	
[*] hours 

 

$[*] Human 
   Factors Test
   Facility 

 

$[*] Travel
    	
 
    	
NA

 

NA

 

 

 

NA
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
Patient   Use and Human Factor Studies for Design

Design   and orchestration of patient use studies, 1 in the US and 1 in the EU for the   target patient population (estimated at 2 days each); construction of device   stimulus supplies.  Studies at each   site will include interviews with patients and/or health care providers and   will be conducted under protocol and include a final summary report.

 

This   work will be completed by the External Design Firm per the previous row in   this table.
    	
 
    	
·      Human Factors   Study Protocols

·      Looks-like   models for usability testing

·      Patient   feedback on design elements

·      Human Factors   Study Final Report and Recommendations

·      Validated   design requirements
    
	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    
	
[*] hours
    	
 
    	
[*] hours
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
Device   Characterization Studies, Development

On-going   characterization as the design progresses to gauge success towards key design   requirements, including [*]
    	
 
    	
·      Regular   updates on test results

·      Refined   device specification

·      Summary   reports as appropriate, minimally for specified design requirements
    

 

[*] Certain information in this document has been omitted and filed separately with the Securities and Exchange Commission. Confidential treatment has been requested with respect to the omitted portions.

 

 

	
[*] hours
    	
 
    	
[*] hours
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
Analytical   Method and Validation (Level 3) and Specification Development

As   needed, for example, [*]
    	
 
    	
·      Method   validation protocols (estimated, n=8)

·      Method   validation reports (estimated, n=8)

·      Method   development reports (est. n=8)

·      Method   documents

·      Component   specifications and specification justification reports (number depends on   final design)
    
	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    
	
[*] hours
    	
 
    	
[*] hours
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
Supplier   Approval and Material Qualification

Risk   assessment and analysis and independent testing of the raw materials, as   applicable and dictated by the risk assessment.
    	
 
    	
·      Supplier   Approval documents

·      Supply chain   risk analysis
    

 

[*] Certain information in this document has been omitted and filed separately with the Securities and Exchange Commission. Confidential treatment has been requested with respect to the omitted portions.

 

 

	
[*] hours

 

$[*] Human 
   Factors Test
   Facility

 

$[*] Single 
   Cavity Tooling

 

 

$[*] Devices
    	
 
    	
[*] hours

 

NA

 

 

 

$[*] Single 
   Cavity 
   Tooling

 

$[*] Devices
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
Device   Verification Studies, including Human Factors

Applicators   manufactured with molded parts will be characterized in-vivo in design   verification studies prior to use in Phase III.  Human factors studies, 1 in the US and 1 in   the EU, for the target patient population (estimated at 2 days each) designed   to verify performance endpoints related to the target patient population will   also be conducted.  Studies will be   conducted under protocol and will include a final summary report.
    	
 
    	
·      Looks   like/works like prototypes for Human Factors Study (using needleless, placebo   arrays)

·      Human Factors   study protocol

·      Human Factors   Study Final Report

·      Regular   updates on device verification test results

·      Design Review   summary reports

·      Device ready   for design validation (i.e. Phase 3)
    
	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    
	
[*] hours
    	
 
    	
[*] hours
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
Product   Design Control Documentation

Required   documentation and analysis of device and drug product performance including   update of the Design Requirements Specification (DRS, Design Specification   (DS), Design Failure Mode and Effects Analysis (DFMEA), Design Reviews,   Design Verification, Device Specifications
    	
 
    	
·      Design   Requirements Specification

·      Device   Specification

·      Product   Specification

·      Specification   Justification Report

·      DFMEA report

·      Design review   reports

·      Design   History File

·      DHF Index
    

 

[*] Certain information in this document has been omitted and filed separately with the Securities and Exchange Commission. Confidential treatment has been requested with respect to the omitted portions.

 

 

	
[*] hours
    	
 
    	
[*] hours
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
Device   Stability

Device   stability sufficient to support device use in Phase 3 (six months accelerated   stability with testing at initial and final time points).

 
    	
 
    	
·      Stability   Study Protocol

·      Stability   Final Report

·      Thru-study   updates on testing results
    

 

Summary of Costs (Original)

 

	
[*]  
   $ [*]
    	
 
    	
Labor   Hours 
   Labor Costs ($[*] /hour)
    
	
$ [*]
    	
 
    	
Direct   Costs (external design firm deliverables, materials, facility use, etc)
    

 

[*] Certain information in this document has been omitted and filed separately with the Securities and Exchange Commission. Confidential treatment has been requested with respect to the omitted portions.

 

 

Exhibit B Footnotes

 

[*]

 

[*] Certain information in this document has been omitted and filed separately with the Securities and Exchange Commission. Confidential treatment has been requested with respect to the omitted portions.

 

 

Summary of Costs (Revised 10Dec2012)

 

	
[*]  
   $ [*] ($[*]/$[*])
    	
 
    	
Labor   Hours 
   Labor Costs ($[*] /hour/$[*] /hour)
    
	
$ [*]
    	
 
    	
Direct   Costs (external design firm deliverables, materials, facility use, etc)
    

 

[*] Certain information in this document has been omitted and filed separately with the Securities and Exchange Commission. Confidential treatment has been requested with respect to the omitted portions.

 

 

Change Order Form - Amendment 5*

 

Change order under Agreement dated: Development and Clinical Supply Agreement dated 19 June 2009

 

Between: Radius Health and 3M

 

Project Name: Radius Health proprietary compound BA058 and 3M proprietary microstructured transdermal system

 

Change requested by: Radius

 

Name:  Maria Grunwald

Company:  Radius Health, Inc

Date:   4 February 2011

 

Description of change:  Radius has asked 3M to prepare three Workplans that identify activities that could be initiated in February 2011.  These activities are summarized on the following Workplans:

 

Workplan #1 — Microscopic Evaluation of Clinical Supplies Workplan Summary

Workplan #2 — Residual Drug Analysis of Clinical Supplies Workplan Summary

Workplan #3 — Optimization of Ready-to-Coat Formulation and Process and Method  Development for Product Development Workplan Summary

Workplan #4 — DMF preparation for FDA response

 

In addition to the Workplans listed above, 3M will deliver responses to the FDA Advice/Information letter for the sMTS development received by Radius. These responses incorporate current testing plans (Workplan #1, #2, current manufacturing plan, in process controls, and the depth of penetration) & planned future development plan (i.e., DMFs development and sterile manufacturing process).  For the avoidance of doubt, 3M will provide Radius information on the depth of penetration studies funded by 3M at no charge to Radius.  The current responses to the FDA letter, and any authorized work, and reports conducted under the Workplans #1 and #2 will be completed by 3M and delivered to Radius by the end of February 2011 for Radius’ response submission.

 

Radius authorizes 3M to work up to a maximum of [*] hours at a rate of $[*] per hour in February under this change order.  Radius will prioritize the Workplans #1 and #2, and in the case of Workplan  #3, Radius will advise which tasks that it wishes 3M to commence in

 

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

 

1

 

February to complete the [*] authorized hours.  Radius understands that the deliverables accomplished under Workplan #3 will correlate to the amount of work authorized by Radius.

 

In all other respects, the terms and conditions of the Agreement remain in full force and effect.

 

Requested task, dates and costs are approved by:

 

	
Company: Radius
    	
3M
    
	
Name: Nick Harvey
    	
Name:   Mary Mathisen
    
	
Signature:
    	
/s/   B.N. Harvey
    	
 
    	
Signature:
    	
/s/ Mary   Mathisen
    
	
Position:   CFO
    	
Position: Commercialisation Mgr
    
	
Date (dd/mm/yy): February 4,   2011
    	
Date   (dd/mm/yy):4 February 2011
    
					

 

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

 

2

 

Workplan #1

 

MICROSCOPIC EVALUATION WORK PLAN SUMMARY

 

Objective:

 

The objective of the work plan is to perform microscopic evaluation BA058-sMTS patches and arrays to assess for microneedle fracture, deformation of the needle, residual drug, or biological matter deposits following removal from dosed clinical subjects of Period 2, Protocol BA058-05-006.

 

Scope:

 

Approximately 49 patches (controls and samples) will be evaluated microscopically. Group 2a, Day 4 and Day 5 BA058-sMTS samples of each subject ([*]mcg) removed following dosing will be sent for residual drug analysis. Group 2b, Day 4 and Day 5 BA058-sMTS samples of each subject (Placebo and [*]mcg) removed following dosing will be send for residual drug analysis. Group 2c, Day 4 and Day 5 BA058-sMTS samples of each subject ([*]mcg) removed following dosing will be sent for residual drug analysis. Three BA058-sMTS unused samples from each dose (Placebo, [*]mcg, and [*]mcg) will be used as controls. Each BA058-sMTS will be examined at 100x power by microscope and assessed for microneedle fracture (breaks, cracks, and chips), deformation of the needle (bends and/or blunting), residual drug, or biological matter deposits.

 

Materials:

 

Forceps

Microscope, capable of 100x magnification and equipped with a digital camera

Control and sample patches (Placebo, [*]mcg, and [*]mcg) currently stored at 2-8°C.

 

Procedure:

 

Placebo Controls;

 

1.              Remove samples from 2-8°C and allow the sample to reach room temp. (about 1 hour).

 

2.              Carefully remove one of the BA058-sMTS placebo patches from the collar.

 

PATCHES THAT ARE DISLODGED FROM THE COLLAR DURING SHIPPING WILL NOT BE ASSAYED.

 

3.              Using 100x magnification examine the patch and array for microneedle fracture, deformation of the needle, residual drug, or biological matter deposits.

 

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

 

3

 

4.              Document observations on Attachment 2.

 

5.              Photograph the damaged needles.

 

6.              Repeat 1 through 5 for the other BA058-sMTS placebo controls.

 

Repeat the above for the BA058-sMTS Placebo samples, [*]mcg controls, [*]mcg samples, [*]mcg controls and [*]mcg samples.

 

Projected Hours

 

Visual testing of 49 arrays                 [*] hours

Preparation, review, and release of report      [*] hours

Total Hours          [*]

 

Deliverables

 

A summary report describing the type and frequency of observations.

 

Attachments:

 

Example Photo

Observations

Summary Observations

 

Example Photo

 

 

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

 

4

 

OBSERVATIONS

 

Sample ID:

 

 

Describe appearance of patch:

 

5

 

Enter code for damaged array on to chart.

 

Codes: R — break, C — chip, K — crack, D — bend, L — blunt, B — biological matter, F — partial fill, S - residual drug

 

Add sequence number for digital image.

 

SUMMARY OBSERVATIONS

 

	
Sample
   ID
    	
 
    	
Microneedle fracture
   (breaks, cracks, and
   chips)
    	
 
    	
Deformation of
   the needle (bends
   and/or blunting)
    	
 
    	
Residual
   drug
    	
 
    	
Biological
   matter
   deposits
    	
 
    	
Digital
   Photo
    ()
    
	
 
    	
 
    	
Breaks
    	
 
    	
Cracks
    	
 
    	
Chips
    	
 
    	
Bends
    	
 
    	
Blunting
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    
	
 
    	
 
    	
Breaks
    	
 
    	
Cracks
    	
 
    	
Chips
    	
 
    	
Bends
    	
 
    	
Blunting
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    
	
 
    	
 
    	
Breaks
    	
 
    	
Cracks
    	
 
    	
Chips
    	
 
    	
Bends
    	
 
    	
Blunting
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    
	
 
    	
 
    	
Breaks
    	
 
    	
Cracks
    	
 
    	
Chips
    	
 
    	
Bends
    	
 
    	
Blunting
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    
	
 
    	
 
    	
Breaks
    	
 
    	
Cracks
    	
 
    	
Chips
    	
 
    	
Bends
    	
 
    	
Blunting
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    
	
 
    	
 
    	
Breaks
    	
 
    	
Cracks
    	
 
    	
Chips
    	
 
    	
Bends
    	
 
    	
Blunting
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    
	
 
    	
 
    	
Breaks
    	
 
    	
Cracks
    	
 
    	
Chips
    	
 
    	
Bends
    	
 
    	
Blunting
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    
	
 
    	
 
    	
Breaks
    	
 
    	
Cracks
    	
 
    	
Chips
    	
 
    	
Bends
    	
 
    	
Blunting
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    
	
 
    	
 
    	
Breaks
    	
 
    	
Cracks
    	
 
    	
Chips
    	
 
    	
Bends
    	
 
    	
Blunting
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    
	
 
    	
 
    	
Breaks
    	
 
    	
Cracks
    	
 
    	
Chips
    	
 
    	
Bends
    	
 
    	
Blunting
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    
	
 
    	
 
    	
Breaks
    	
 
    	
Cracks
    	
 
    	
Chips
    	
 
    	
Bends
    	
 
    	
Blunting
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    

 

6

 

	
 
    	
 
    	
Breaks
    	
 
    	
Cracks
    	
 
    	
Chips
    	
 
    	
Bends
    	
 
    	
Blunting
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    
	
 
    	
 
    	
Breaks
    	
 
    	
Cracks
    	
 
    	
Chips
    	
 
    	
Bends
    	
 
    	
Blunting
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    
	
 
    	
 
    	
Breaks
    	
 
    	
Cracks
    	
 
    	
Chips
    	
 
    	
Bends
    	
 
    	
Blunting
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    
	
 
    	
 
    	
Breaks
    	
 
    	
Cracks
    	
 
    	
Chips
    	
 
    	
Bends
    	
 
    	
Blunting
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    

 

7

 

Workplan #2

 

RESIDUAL DRUG ANALYSIS WORK PLAN SUMMARY

 

Objective:

 

The objective of the work plan is to perform residual drug analysis of BA058-sMTS arrays following removal from dosed clinical subjects of Period 2, Protocol BA058-05-006 to assess residual drug remaining on the array.

 

Scope:

 

Approximately 49 arrays (controls and samples) will be evaluated for residual drug. Group 2a, Day 6 and Day 7 BA058-sMTS samples of each subject ([*] mcg) removed following dosing will be sent for residual drug analysis. Group 2b, Day 6 and Day 7 BA058-sMTS samples of each subject (Placebo and [*]mcg) removed following dosing will be send for residual drug analysis. Group 2c, Day 6 and Day 7 BA058-sMTS samples of each subject ([*] mcg) removed following dosing will be sent for residual drug analysis. Three BA058-sMTS unused samples from each dose (Placebo, [*] mcg, and [*] mcg) will be used as controls. Each BA058-sMTS will be analyzed in accordance with Method-07-001836.

 

Materials:

 

Forceps

Snap-cap polypropylene sample vials (5mL, Nalgene Part 6250-0005)

BA058-sMTS Control and sample patches (Placebo, [*] mcg, and [*] mcg) stored at -20°C.

 

Procedure:

 

Prepare the controls and samples as follows;

 

7.              Remove samples from -20°C storage and allow to reach room temp. (approx. 2 hours).

 

8.              Carefully remove one of the BA058-sMTS patches from the collar.

 

PATCHES THAT ARE DISLODGED FROM THE COLLAR DURING SHIPPING WILL NOT BE ASSAYED.

 

9.              Separate the large circular adhesive from the hard plastic disc containing the micro array needles by holding the array patch across the patch diameter with the thumb and finger.

 

DO NOT TOUCH THE MICRO ARRAY.

 

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

 

8

 

10.       Pinch the thumb and finger together to bend the patch away from the array. (Figure A).

 

Figure A.                Use the forceps to grab the array from the bent adhesive patch.

 

 

11.       Use a forceps to grasp the array and to peel the array from the patch (Figure A).

 

12.       Place the disc containing the micro array into a labeled plastic snap cap container (needles-down orientation) and seal.

 

13.       Analyze each in accordance with Method-07-001836.

 

Projected Hours

 

	
HPLC analysis and review of data for 49 patches
    	
 
    	
[*]   hours
    
	
Preparation, review, and release of report
    	
 
    	
[*]   hours
    
	
Total
    	
 
    	
[*]   hours
    

 

Deliverables

 

Summary report describing residual BA058 content of arrays.

 

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

 

9

 

Workplan #3

 

RTC Process Development and Analytical Methods WORK PLAN SUMMARY

 

Objective

 

Determine operating conditions for RTC mixing and filtration that provide a robust process for preparing sterile, homogeneous ready-to-coat (RTC) formulation.  Following these experiments, the process and parameters for preparing RTC should be finalized.

 

Some method development efforts are also addressed below.

 

Background

 

[*]  Consequently, the RTC formulation is prepared by using a [*].  This results in a very inhomogeneous formulation that needs to be thoroughly mixed prior to sterile filtration.  Currently, the RTC is [*] for [*] prior to sampling.   An additional [*] of [*] does not appear to effect the concentration, but limited data is available at this time point[*] after the filtration step appears to substantially improve the consistency of the RTC.

 

Process efficiency is currently about [*].  Variations in filtration media and devices will be investigated to improve this number.

 

Scope

 

Observed response variables for the mixing experiments are average content, variance of the content, and viscosity.  Two mixing methods will be investigated: [*] (the current method) and [*], a [*].  For [*], three times ([*],[*],[*]min) prefiltration and four times ([*],[*],[*],[*] minutes) postfiltration will be tested.  For [*], three times will be investigated prefiltration ([*],[*],[*] minutes) and four times postfiltration ([*],[*] ,[*], and [*] minutes).    To investigate the effect of the RTC concentration, mixing will be performed with [*]% and [*]% bulk drug substance (w/w).  The current manufacturing process uses [*]% w/w.

 

Only one lot of BA058 will be used.  Any variability due to the lot of BA058 should be minimal due to controls on its composition.

 

Materials

 

14 g BA058

Miscellaneous lab supplies

 

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

 

10

 

Procedure

 

For each mixing technique, the prefiltration experiments will be performed.  The best prefiltration mixing time will be used for the postfiltration experiments.  The procedure will be repeated for the two concentrations of BA058.

 

The average and variance of the content will be determined by taking multiple samples from each mixing experiment and assayed using a validated HPLC method (Method-07-001836).   Viscosity of the RTC following each experiment will be tested using a Rheosense m-VROC.

 

Each experiment will use [*]  mL of RTC ([*] g of bulk drug substance).  Smaller volumes would not be indicative of performance at larger scales, and larger amounts result in exessive consumption of BA058.  The 14 g figure is considerably larger than previously quoted.  The previous quote assumed material could be saved by using the RTC from the mixing experiments to begin the coating process experiments.  Of course, unused RTC from this work will be saved for future use.

 

To determine the optimal approach to sterile filtration, a solution of BSA will be prepared with a viscosity similar to that of the current RTC.  This solution will be used to test filtration setups for easy of use and efficiency.  Once a suitable configuration is found, it will be tested by sterile filtering RTC and checking for changes in viscosity, purity, and content.

 

Projected Hours

 

Mixing Process Development

 

	
Perform   mixing and take samples
    	
 
    	
[*]   hours
    
	
HPLC   analysis
    	
 
    	
[*]   hours
    
	
Viscosity   measurements
    	
 
    	
[*]   hours
    
	
Prepare   report
    	
 
    	
[*]   hours
    
	
Mixing   Process Total
    	
 
    	
[*]   hours
    

 

Filtration Process Development

 

	
Trial   filtration runs
    	
 
    	
[*]   hours
    
	
Confirm   filtration parameters
    	
 
    	
[*]   hours
    
	
Prepare   reports
    	
 
    	
[*]   hours
    
	
Filtration   Process Total
    	
 
    	
[*]   hours
    
	
RTC   Process Development Total
    	
 
    	
[*]   hours
    

 

Deliverables

 

1.              Summary report describing mixing experiments

2.              Summary report describing filtration experiments

3.              Master Batch Record for the ready to coat

4.              Updated specifications for the ready to coat

 

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

 

11

 

Analytical Method Development

 

The following analytical method development activities are proposed. Method development covers laboratory activities intended to define the method. Authoring of method development reports and validation activities are separate and not included in the estimates given here.

 

	
Identification   method
    	
 
    	
Uses   current HPLC method, mix 1:1 sample with reference material, show that only   one peak elutes from HPLC. Update method document.
    	
 
    	
[*] hours
    
	
Aggregation   method
    	
 
    	
Develop   size exclusion chromatography method to characterize any formation of   aggregates in drug product
    	
 
    	
[*] hours
    
	
Release   Method
    	
 
    	
Explore   and develop method for release testing of microneedle patches.
    	
 
    	
[*] hours
    
	
Pouch   Integrity
    	
 
    	
Adapt   ASTM method to microneedle patches
    	
 
    	
[*] hours
    
	
Patch   Adhesion
    	
 
    	
Adapt   ASTM method to microneedle patches
    	
 
    	
[*] hours
    

 

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

 

12

 

Workplan #4

 

FDA RESPONSE WORK PLAN SUMMARY

 

Objective:

 

Respond to FDA’s questions regarding 3M’s manufacturing process and controls.

 

Scope:

 

A DMF will be prepared with information about 3M’s sMTS manufacturing process and controls.

 

Materials:

 

Not Applicable

 

Procedure:

 

Not Applicable

 

Projected Hours

 

	
Prepare,   review, and submit DMF
    	
 
    	
[*]   hours
    

 

Deliverables

 

1)             DMF will be filed with FDA.

2)             Radius will be provided with the DMF number and a letter of access.

 

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

 

13

 

3M DRUG DELIVERY SYSTEMS CONTACT INFORMATION

 

For inquiries related to the proposal, please contact:

 

Mary Mathisen

Product Commercialization Manager

3M Drug Delivery Systems

3M Center, Bldg. 260-4N-12

St. Paul, MN 55144

Tel:  651-733-9125

Fax:  651-575-1729

Cell: 617-503-0861

E-Mail: mmathisen@mmm.com

 

Mark Tomai Ph.D.

Head of Vaccine Business

3M Drug Delivery Systems

3M Center, Bldg. 275-3E-10

St. Paul, MN 55144

Tel:  617-733-5375

Cell: 651-403-0455

E-Mail: matomai@mmm.com

 

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

 

14

 

Change Order Form # 6

 

Change order under Agreement dated:  Third Amendment to Development and Clinical Supplies Agreement dated 29 September 2010

 

Between:  Radius Health, Inc and 3M

 

Project Name:  For the development of Radius’s BA-058 compound delivered via 3M’s Microstructured Transdermal Delivery System

 

Change requested by:  Radius

 

Name:  Gary Hattersley

Company:  Radius

Date:  1 June 2011

 

Description of change:

 

3M has been requested to add 5oC

8-month stability pull for CM-10-00503

3-month stability pull for TM-10-00569

3-month stability pull for TM-10-00570

4-month stability pull for TM-10-00584

@ [*] each pull.*

 

 

 

 

 

 

In all other respects, the terms and conditions of the Agreement remain in full force and effect.

Requested task, dates and costs are approved by:

 

	
Company:   Radius Health, Inc
    	
 
    	
Company:   3M
    
	
Name:   Nick Harvey
    	
 
    	
Name:   Mary Mathisen
    
	
Signature:   /s/ Nick Harvey
    	
 
    	
Signature:   /s/ Mary Mathisen
    
	
Position:   CFO
    	
 
    	
Position:   Commercialization Mgr
    
	
Date   (dd/mm/yy): 6/16/11
    	
 
    	
Date   (dd/mm/yy): 6/20/2011
    

 

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

 

1

 

Change Order Form # 7

 

Change order under Agreement dated:  the Development and Clinical Supplies Agreement dated June 19, 2009, as amended by the Amendment dated as of December 31, 2009, the Second Amendment dated as of September 16, 2010, the Third Amendment dated as of September 29, 2010 and the Fourth Amendment dated March 2, 2011 (the “Agreement”).

 

Between:  Radius Health, Inc and 3M

 

Project Name:  For the development of Radius’s BA-058 compound delivered via 3M’s Microstructured Transdermal Delivery System

 

Change requested by:  3M

Name:  Tom Fenn

Company:  3M

Date:  8 June 2011

Description of change:

 

3M is requesting complete an analytical characterization of the impurities observed in the drug product.

 

BACKGROUND

Impurities are forming in the BA058-sMTS drug product.  These impurities elute [*]in the reverse phase HPLC chromatogram.  These impurities form much more quickly in the lots of [*] produced [*] than in the lots of [*] produced in the [*].  The cause for this has not been identified.  To solve this issue, more information about the identity of these impurities is needed.

 

PURPOSE

Identify the BA058-sMTS impurities at a level of detail sufficient to allow action to be taken to block their formation.

 

PROCEDURE

The work described below will be conducted by 3M’s Corporate Analytical Laboratory.  Be aware that this lab does not operate under GxP regulations.  As much as possible, HPLC conditions will match those used in previous impurities investigations conducted by Radius.

 

Degradation of BA-058

Exposure of BA-058 to [*]C and [*]% humidity produces about [*]% aggregation of the peptide after one week.  The retention times and peak areas of the impurities in samples aged in this fashion matches the results found in the aged drug product.

 

NMR

BA-058 drug substance and degraded BA-058 drug substance will be dissolved in D20 and characterized via two-dimensional NMR experiments to identify any new chemical

 

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

 

 

functionalities present in the aged sample.  Any differences observed will be analyzed to determine possible chemical reactions responsible for the formation of the impurities.

 

We estimate this work will require [*] hours and 100 mg of BA-058.

 

MADI-TOF

Aged BA-058 drug substance will be fractionated by HPLC.  Accurate mass determinations of the impurities will be attempted by analysis of the mass spectra of BA-058 drug substance, degraded BA-058 drug substance, and the HPLC fractions.  The instrument that will be used is a Bruker Daltonics Ultraflex II MALDI-TOF/TOF.

 

We estimate this work will require [*]  hours and 100  mg of BA-058.

 

LC/MS Accurate mass

Analysis of BA-058 peptide samples (BA-058 drug substance and aged drug substance) will be analyzed on an Agilent 6540 Q-TOF LC-MS/MS equipped with an electrospray ionization interface.  Accurate masses will be determined and peptide sequence information may be obtained by fragmentation.

 

We estimate this work will require [*] hours and 200 mg of BA-058

 

	
Summary
    	
 
    	
 
    	
 
    	
 
    
	
Task
    	
 
    	
Hours
    	
 
    	
BA-058   needed
    
	
NMR
    	
 
    	
[*]
    	
 
    	
100   mg
    
	
MALDI- TOF
    	
 
    	
[*]
    	
 
    	
100   mg
    
	
LC/LM Accurate mass
    	
 
    	
[*]
    	
 
    	
200   mg
    
	
Total
    	
 
    	
72   hours
    	
 
    	
400   mg
    

 

Except to the extent expressly amended by this Change Order, the terms and conditions of the Agreement remain 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 Change Order.

 

Requested task, dates and costs are approved by:

 

	
Company:   Radius Health, Inc
    	
 
    	
Company:   3M
    
	
Name:   Nick Harvey
    	
 
    	
Name:   Mary Mathisen
    
	
Signature:
    	
/s/   Nick Harvey
    	
 
    	
Signature:
    	
/s/   Mary Mathisen
    
	
Position:   CFO
    	
 
    	
Position:   Commercialization Mgr
    
	
Date   (dd/mm/yy): 7/29/11
    	
 
    	
Date   (dd/mm/yy): 2 August 2011
    
					

 

2

 

Change Order Form # 8

 

Change order under Agreement dated:  the Development and Clinical Supplies Agreement dated June 19, 2009, as amended by the Amendment dated as of December 31, 2009, the Second Amendment dated as of September 16, 2010, the Third Amendment dated as of September 29, 2010 and the Fourth Amendment dated March 2, 2011 (the “Agreement”).

 

Between:  Radius Health, Inc and 3M

 

Project Name:  For the development of Radius’s BA-058 compound delivered via 3M’s Microstructured Transdermal Delivery System

 

Change requested by:  Radius

Name:  Maria Grunwald and Gary Hattersley

Company:  3M

Date:  20 July 2011

Description of change:

 

Radius is requesting 3M manufacture 420 patches for an additional clinical study Radius wishes to conduct.  The product strength is [*]mcg/array.  3M will continue with development work in accordance with the Agreement.  The additional requirement of these supplies affects the process group ability to meet the timelines in the Work Plan attached to the Fourth Amendment.  The net effect is a delay in the delivery of Phase II supplies by 4 weeks.

 

	
Planned Usage
    	
 
    	
Number of Patches
    
	
Clinical   study supplies
    	
 
    	
[*]
    
	
Release   testing
    	
 
    	
[*]
    
	
Retains
    	
 
    	
[*]
    
	
Stability
    	
 
    	
[*]
    
	
Customer   retains
    	
 
    	
0
    
	
Total   Quantity
    	
 
    	
420
    

 

We estimate this work will require 375 hours and 1.3 grams of BA-058.  Delivery of the clinical supplies is estimated to be the week of September 26.

 

Estimate of additional out of pocket expenses

	
Gamma treatment
    	
 
    	
$
    	
1000
    	
 
    
	
Decontamination of isolator and testing
    	
 
    	
$
    	
1500
    	
 
    
	
Rodac plates
    	
 
    	
$
    	
500
    	
 
    
	
Endotoxin testing
    	
 
    	
$
    	
600
    	
 
    
	
Shipping costs
    	
 
    	
$
    	
500
    	
 
    

 

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

 

1

 

Stability pulls — $[*]per pull point

Limited stability plan:  1, 3, 6, 12 months at 5°C and 1, 3, 6 at 25°C.  An intermediate time point to cover use period may be added at a later date.

 

Except to the extent expressly amended by this Change Order, the terms and conditions of the Agreement remain 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 Change Order.

 

Requested task, dates and costs are approved by:

 

	
Company:   Radius Health, Inc
    	
Company:   3M
    
	
Name:   Nick Harvey
    	
Name:   Mary Mathisen
    
	
Signature:
    	
v/s/   Nick Harvey
    	
 
    	
Signature:
    	
/s/   Mary Mathisen
    
	
Position:   CFO
    	
Position:   Commercialization Mgr
    
	
Date   (dd/mm/yy): 7/27/11
    	
Date   (dd/mm/yy): 7/28/11
    
					

 

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

 

2

 

- AMENDED AND RESTATED PROPOSAL -
 RADIUS BA058 sMTS PROGRAM

 

EXECUTIVE SUMMARY

 

3M Drug Delivery Systems is pleased to provide Radius Health Inc. (Radius) with this estimate for development and delivery of Phase II clinical supplies for its BA058 product delivered via 3M’s solid Microstructured Transdermal System (sMTS).

 

This estimate supports the attached work plan summary and is based on information exchanged between Radius and 3M regarding the requirements for a BA058 sMTS product.  The scope of work outlined in the summary includes all activities required for formulation development and delivery of clinical supplies to enable Radius to perform a Phase II clinical study in humans.  As discussed with Radius, 3M will deliver clinical supplies no later than 14 months after the effective date of this Amendment and will use commercially reasonable efforts to accomplish delivery by March 15, 2012 if Radius approves the Phase II Workplan and initiates work on or before March 1, 2011.  If work does not commence on March lst 2011, 3 months must be added to the time below to provide sufficient ramp up time to obtain and train resources to re-initiate the project.  Effective July 20, 2011, Radius requested 3M manufacture additional Phase I clinical supplies in August 2011.  This will delay delivery of the Phase II clinical supplies four weeks later than previously stated in the Work Plan attached to the Agreement and the Milestone dates set forth below have been revised accordingly.

 

The estimate for the activities listed in the work plan summary is provided below:

 

	
 
    	
 
    	
PROGRAM HOURLY
   ESTIMATE
    	
 
    	
TIMING
    
	
Scale-up   Process Optimization and Preparation of GMP Supplies for Phase II Trial
    	
 
    	
[*]hours
    	
 
    	
(as per indicated in the above paragraph)
    
	
Direct   Costs (Arrays and Applicators based on quantities defined below arrays for   each strength and 300 applicators)
    	
 
    	
$[*] K
    	
 
    	
 
    

 

Deliverables, timing and assumptions are presented in the work plan summary.

 

3M reserves the right to revise this proposal if the intended scope of work deviates from the work outlined.  Any change in this proposal shall be subject to execution of a Change Order.

 

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

 

	
3M   Drug Delivery System
    	
 
    	
 
    	
 
    	
Confidential
    

 

1

 

WORIC PLAN SUMMARY

 

Objective:

The objective of the work plan is to optimize manufacturing and analytical activities around the production of BA058-sMTS which will be produced using a new automated process.  This work plan will result in the production of BA058-sMTS patches at three different dosage strengths, and a matching placebo patch.  This work plan will also support the application for and completion of a Phase 2 clinical study by Radius.

 

Deliverables:

·              Delivery of up to 3 distinct GMP clinical doses of BA058 sMTS product plus 1 placebo dose for a Phase II clinical study and supporting stability work.  This includes a maximum of 54,600 patches (detail for quantities is shown below.) and 300 POC applicators.  Any additional patches or applicators required to support the clinical trial, stability program and the requirement for clinical retains (as per 3M’s SOP for a non-bioequivalence clinical study) will be provided under a Change Order at Radius request and expense.

 

	
Planned usage
    	
 
    	
Active patches
    	
 
    	
Placebo patches
    
	
clinical   study supplies
    	
 
    	
[*]
    	
 
    	
[*]
    
	
Release   testing
    	
 
    	
[*]
    	
 
    	
[*]
    
	
Retains
    	
 
    	
[*]
    	
 
    	
[*]
    
	
Stability
    	
 
    	
[*]
    	
 
    	
0
    
	
3M   SOP retains
    	
 
    	
[*]
    	
 
    	
 
    
	
Total   quantity
    	
 
    	
14,200
    	
 
    	
12,000
    

 

·              Crossed over and validated analytical methods to monitor the manufacturing process, the release activities and the stability program

·              Stability data for each of the three active product lots through 2 years, as described below.

·              A stability program for the RTC formulation for up to 6 months as defined in this Workplan

·              3M shall establish and maintain proprietary Drug Master Files (DMFs) including information on the components, coating and drying manufacturing processes to support regulatory filings in the U.S. and Canada.  A right of reference to 3M’s DMFs will be granted to Radius to support regulatory filings in the U.S. and Canada.  Outside the U.S., 3M will provide Radius with information necessary to support regulatory filing in all countries where Clinical Development of BA058-sMTS is sited.

 

This estimate does not include the time associated with execution of the Phase II clinical studies nor completion of support stability.

 

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

 

2

 

Milestones for the Workplan:

All dates assume Amendment signed by March 2, 2011.  Should the Amendment be signed at a later date, then the target dates for milestones need to be adjusted accordingly.

 

1.             Start preliminary RTC optimization — March 2, 2011

2.             March API requirements delivered by Radius to 3M — March 2, 2011

3.             Methods provided to 3M for crossover — March 4, 2011

4.             April API requirements delivered by Radius to 3M — April 1, 2011

5.             May API requirements delivered by Radius to 3M — May 1, 2011

6.             Initiation of coating optimization — May 1, 2011

7.             RTC optimization concludes — June 30, 2011

8.             July API requirements delivered by Radius to 3M — July 1, 2011

9.             Manufacture additional Phase I clinical supplies (150mcg/array) — by October 1, 2011

10.          Equipment installation — September 1, 2011

11.          Initiation of final optimization of coating and process verification — December 29, 2011

12.          Completion of coating process verification — January 31, 2012

13.          Release phase II supplies — by April 15, 2012

 

3M assumptions of the work plan:

·              Validated analytical methods exist and can be crossed over to 3M from Radius — if method development is required, a Change Order will be required at Radius expense

·              No more than 10 analytical methods need to be crossed over

·              Adequate GMP BA058 starting material will be provided free of charge to 3M for development and clinical supply manufacture by Radius for phase II clinical supplies.

·              Work plan assumes the use of the POC MTS applicator system and patch design in Phase 2.

·              Lot size is not to exceed the quantities listed above of GMP-grade BA058 sMTS arrays to best meet the needs of the Phase 2 study and stability program plans.

·              An additional three hundred units per dose will be manufactured for retains in accordance with 3M’s SOPs.  Any additional supplies beyond what is shown in the above table can be provided under a Change Order at Radius’ expense.

·              Phase II product will be manufactured as low bioburden compatible with the process for Phase 3.

·              sMTS patches and applicators for use in the Phase II clinical study will be bulk labeled by 3M and provided to Radius for further labeling according to the requirements of the clinical protocol.

·              Radius will be responsible for executing all elements (protocols, regulatory filings, conduct) of the Phase II trial.

·              The clinical trial will be conducted in countries to be identified by Radius.

·              Wear time associated with the array is 24 hours or less.

·              Stability studies on the product in support of Phase II will be a maximum of 2 years in length; the stability report will be completed within 4 months of the completion of the stability study.

 

3

 

·                                          DMFs for BA058-sMTS CCS and Coating and Drying Process will be filed at least 3 month prior to Phase 2 initiation.

 

Radius assumptions of the work plan:

·                                          The work plan will cover the currently planned activities related to the manufacturing and support of all Phase 2 transdermal clinical trial supplies.  If additional activities are deemed necessary, such activities will be provided under a Change Order with budget and timelines agreed.

·                                          This work plan also covers the currently planned CMC/Quality activities required for support of the Phase 2 program for BA058-sMTS, including the 2-year ICH stability program.  If additional activities are deemed necessary, such activities will be provided under a Change Order with budget and timelines agreed.

·                                          This work plan also covers the currently planned Regulatory activities required for support of the Phase 2 program for BA058-sMTS in the regions and countries selected for the study.  If additional activities are deemed necessary, such activities will be provided under a Change Order with budget and timelines agreed.

·                                          Patches will be supplied in quantities indicated in the above table to support the clinical trial, clinical retains and the stability program.  Any additional quantities required can be provided on a Change Order.

·                                          Phase 2 supplies will be manufactured with a low bioburden and will be compatible with the manufacturing process planned for Phase 3.

·                                          Phase 2 supplies will be manufactured with residual solvents consistent with USP 467 and its European equivalent, extractables,

·                                          Each major work plan task identified below will be associated with a protocol (either existing or to be written under a Change Order) and report, both to be reviewed and agreed with Radius.  Such reports may be redacted to protect 3M proprietary information

·                                          All manufacturing activities will be compliant with:

ICH Q1A(R2):  Stability Testing of New Drug Substances and Products 3M level 2 validation of analytical procedures.  3M will provide data supporting chemistry, manufacturing and control information necessary for regulatory filings with authorities in and outside the United States

 

WORKMAN SUMMARY OF TASKS:
 BA058-sMTS Drug Product Development and
 Manufacturing Process Scale-up including Phase 2 Supply Production

 

3M Environmental Health and Safety

Update Hazard Review

Update Risk Assessment (internal)

Update Animal Use Protocols

Qualification of Suppliers

 

4

 

3M Product Development

Terminal sterilization study

RM Receipt and Part Manufacture

RTC Optimization/Characterization

Formulation Optimization/Characterization

Process Optimization (including drying)

Packaging Optimization

[stability program is defined elsewhere]

Supply Production for additional Bridging Tox, if required (additional charge)

 

3M Product Scale-up to Phase 2

RM Receipt and Part Manufacture

System Integration

Product Development/Optimization:  RTC Optimization, Process Optimization

Process/Product Verifications

 

3M Support for Execution of Phase 2 Supply Manufacture

Validate Analytical Methods required for the manufacturing process, release and stability programs associated with the Phase 2 clinical trial supplies

Development and Verification of Specifications for Phase 2

Development and Verification of Shipping and Storage Requirements

Update Regulatory Documentation:  Provide up-to-date Drug Product CMC data to support updated IND, File Product Specific DMFs (sMTS-BA058 CCS and sMTS-BA058 Coating and Drying Process)

 

3M Phase 2 Supply Manufacture and Stability

RM Receipt and Part Manufacture

RM and Component Clearance

RTC Formulation Manufacture and Clearance

Execute Clinical Tickets:  Applicator Construction, estimated 300 units; three active doses at a maximum as indicated in the table above.

Stability of RTC at 5C/ambient RH — 1, 3, 6 months

Stability of RTC at 25C/60% RH — 2 days, 1 week

Stability of Phase 2 Supplies:  5C/ambient RH — 1, 3, 6, 9, 12, months; 25C/60% RH - 1, 3, 6, 9, 12, months; 40C/75% RH — 1, 3, 6 months

Clear, release and ship Clinical Supplies

 

Radius Clinical Supplies Manufacturing Tasks

Provide GMP-grade, BA058 API, ready for formulating

Receive, label and release Phase II clinical supplies

Author Investigators Brochure and IND submission

Write clinical protocol, define safety and efficacy endpoints

 

5

 

Execute or oversee the Phase II clinical study

 

6

 

3M DRUG DELIVERY SYSTEMS CONTACT INFORMATION

 

For inquiries related to the proposal, please contact:

 

Mary Mathisen
 Product Commercialization Manager
 3M Drug Delivery Systems
 3M Center, Bldg. 260-4N-12
 St. Paul, MN 55144
 Tel:  651-733-9125
 Fax:  651-5751729
 Cell:  651-503 0861
 E-Mail:

 

Mark Tomai Ph.D.
 Head of Vaccine Business
 3M Drug Delivery Systems
 3M Center, Bldg. 275-3E-10
 St. Paul, MN 55144
 Tel:  651-733-5375
 Cell:  651-403-0455
 E-Mail:

 

7

 

 

Addendum to Change Order Form # 8

 

Change order under Agreement dated:  the Development and Clinical Supplies Agreement dated June 19, 2009, as amended by the Amendment dated as of December 31, 2009, the Second Amendment dated as of September 16, 2010, the Third Amendment dated as of September 29, 2010 and the Fourth Amendment dated March 2, 2011 (the “Agreement”).

 

Between:  Radius Health, Inc and 3M

 

Project Name:  For the development of Radius’s BA-058 compound delivered via 3M’s Microstructured Transdermal Delivery System

 

Change requested by:  Radius

Name:  Maria Grunwald and Gary Hattersley

Company:  3M

Date:  20 July 2011, Addendum 12 August 2011

Description of change:

 

As per Change Order #8, Radius has requested 3M manufacture 420 patches for an additional clinical study Radius wishes to conduct. An additional 12 patches are required per the addendum for visual inspection at time of release.  The product strength is [*]mcg/array.

 

	
Planned Usage
    	
 
    	
Number of Patches
    
	
Clinical   study supplies
    	
 
    	
[*]
    
	
Release   testing
    	
 
    	
[*]   + 12 (visual inspection)
    
	
Retains
    	
 
    	
[*]
    
	
Stability
    	
 
    	
[*]
    
	
Customer   retains
    	
 
    	
0
    
	
Total   Quantity
    	
 
    	
420 +   12 = 432
    

 

The addendum to change order 8 is estimated to add 58 additional hours including, but not limited to visual examination of returned arrays and residual drug content analysis on [*] arrays.

 

Except to the extent expressly amended by this Change Order, the terms and conditions of the Agreement remain 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 Change Order.

 

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

 

1

 

Requested task, dates and costs are approved by:

 

	
Company:   Radius Health, Inc
    	
 
    	
Company:   3M
    
	
Name:   Nick Harvey
    	
 
    	
Name:   Mary Mathisen
    
	
Signature:
    	
/s/Nick   Harvey
    	
 
    	
Signature:
    	
/   Mary Mathisen
    
	
Position:   CFO
    	
 
    	
Position:   Commercialization Mgr
    
	
Date   (dd/mm/yy): August 12, 2011
    	
 
    	
Date   (dd/mm/yy): 16 August 2011
    
					

 

2

 

 

Change Order Form # 9

 

Change order under Agreement dated:  The Development and Clinical Supplies Agreement dated June 19, 2009, as amended by the Amendment dated as of December 31, 2009, the Second Amendment dated as of September 16, 2010, the Third Amendment dated as of September 29, 2010 and the Fourth Amendment dated March 2, 2011 (the “Agreement”).

 

Between:  Radius Health, Inc and 3M

 

Project Name:  For the development of Radius’s BA-058 compound delivered via 3M’s Microstructured Transdermal Delivery System

 

Change requested by:  3M

 

Name:  Tom Fenn

Company:  3M

Date:  22 July 2011

Description of change:  Change Order to conduct initial manufacturing experiments for new strength, [*]mcg/array.

 

Radius is requesting 3M manufacture a new lower strength [*] mcg/array.  3M has not coated this strength before and proposes the following series of experiments:

 

Exp #1 - First screening of formulations and well depths on ATS in existing wells - total of 6.5 days

Exp #2 - Second screening of formulations and well depths on ATS in existing wells - total of 6.5 days

Exp #3 - Verification of well depth and wt% BA058 - total of 6.25 days

 

Efforts include drafting and approval of protocols, preparation of RTC and arrays, GMP experimentation, HPLC analysis and visual examination of coated arrays.

 

We estimate this work will be conducted over a 4 week period and require approximately 300 hours.

 

Except to the extent expressly amended by this Change Order, the terms and conditions of the Agreement remain 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 Change Order.

 

Requested task, dates and costs are approved by:

	
Company:   Radius Health, Inc
    	
Company:   3M
    
	
Name:   Nick Harvey
    	
Name:   Mary Mathisen
    
	
Signature:
    	
/s/   Nick Harvey
    	
 
    	
Signature:
    	
/s/   Mary Mathisen
    
	
Position:   CFO
    	
Position:   Commercialization Mgr
    
					

 

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

 

 

	
Date   (dd/mm/yy): August 10, 2011
    	
Date   (dd/mm/yy): 12 August 2011
    

 

 

Change Order Form # 10

 

Change order under Agreement dated:  The Development and Clinical Supplies Agreement dated June 19, 2009, as amended by the Amendment dated as of December 31, 2009, the Second Amendment dated as of September 16, 2010, the Third Amendment dated as of September 29, 2010 and the Fourth Amendment dated March 2, 2011 (the “Agreement”).  Fourth Amendment to Development and Clinical Supplies Agreement dated March 2, 2011

 

Between:  Radius Health, Inc and 3M

 

Project Name:  For the development of Radius’s BA-058 compound delivered via 3M’s Microstructured Transdermal Delivery System

 

Change requested by:  Radius

Name:  Gary Hattersley

Company:  3M is providing this proposal for a formal stability bracketing study

Date:  28 September 2011

Description of change:  Change Order to conduct a formal stability study bracketing study on approximately [*]% peptide by weight coated on [*] mcg/array and [*] mcg/array in Phase II packaging with/without desiccant.

 

Radius is requesting 3M manufacture [*]mcg and [*]mcg/array strengths and place on formal stability.  The [*] and [*]mcg/array strength will be packaged with desiccant; in a 3rd arm of the study, [*]mcg/array samples will be packaged without desiccant.  Attached is proposed stability study.

 

Drug Product Testing

 

	
Condition
    	
 
    	
Tests
    	
 
    	
Time points
    
	
NA
    	
 
    	
Content, Purity, Total Moisture, Depth of Coating, in vivo release
    	
 
    	
Initial
    
	
 
    	
 
    	
 
    	
 
    	
 
    
	
25C
    	
 
    	
Content, Purity, Aggregation
    	
 
    	
1,2,3,6 months
    
	
25C
    	
 
    	
Total Moisture
    	
 
    	
3, 6 months
    
	
5C
    	
 
    	
Content, Purity, Aggregation
    	
 
    	
1, 3, 6, 9, 12 months
    
	
5C
    	
 
    	
Total Moisture
    	
 
    	
3, 6, 12 months
    

 

Ready-to-Coat Testing

 

	
Condition
    	
 
    	
Tests
    	
 
    	
Time points
    
	
NA
    	
 
    	
Content, Purity, Viscosity
    	
 
    	
Initial
    
	
25C
    	
 
    	
Content, Purity
    	
 
    	
12 hours, 24 hours, 2 days, 3 days
    
	
25C
    	
 
    	
Viscosity
    	
 
    	
12 hours, 2 days
    
	
5C
    	
 
    	
Content, Purity, Viscosity
    	
 
    	
1 month, 2 months, 3 months
    

 

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

 

 

3M estimates this work will be conducted over a 2-3 week period and require approximately 270 hours.  The stability costs for the RTC will be $[*]per pull point.  The stability costs for the arrays will be $[*]per pull point.  7.1 grams of BA-058 will be needed.

 

Except to the extent expressly amended by this Change Order, the terms and conditions of the Agreement remain 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 Change Order.

 

Requested task, dates and costs are approved by:

 

	
Company:   Radius Health, Inc
    	
Company:   3M
    
	
Name:   Nick Harvey
    	
Name:   Mary Mathisen
    
	
Signature:
    	
/s/   Nick Harvey
    	
 
    	
Signature:
    	
/s/   Mary Mathisen
    
	
Position:   CFO
    	
Position:   Commercialization Mgr
    
	
Date   (dd/mm/yy): 29/9/11
    	
Date   (dd/mm/yy): 3 October 2011
    
					

 

 

STRICTLY CONFIDENTIAL

 

Confidential Treatment Requested  Under 17 C.F.R. §§ 200.80(b)(4) and 240.24b-2

 

Change Order Form # 12

 

Change order under Agreement dated: Fourth Amendment to Development and Clinical Supplies Agreement dated March 2, 2011

 

Between:  Radius Health, Inc and 3M

 

Project Name: For the development of Radius’s BA-058 compound delivered via 3M’s Microstructured Transdermal Delivery System

 

Change requested by: Radius

Name: Mark Tomai

Company:  3M

Date:  03 Feb 2012

Description of change:

 

Radius has requested further development of a ready-to-coat formulation for preparation of sMTS supplies with increased stability compared to the current formulation.

 

OBJECTIVE

 

Optimize a new formulation for sMTS-BA058 to target a scalable formulation with a final configuration that provides 2 years stability under refrigerated conditions and 3 month stability at [*]C.

 

BACKGROUND

 

Initial experiments in using excipients to stabilize the sMTS-BA058 drug product show that certain excipients can dramatically increase the stability of the drug product.  These changes need to be investigated and evaluated with container-closure system (CCS) options.

 

PROCEDURE

 

1.              A composition and coatability study designed as a factorial experiment examining the effect of API concentration and different excipients.

 

2.              A drying study to determine the effect of a drying step on the performance of the trial formulations will be completed.  The study will be started concurrently with Step 1, as coated arrays are prepared.

 

3.              A study evaluating the potential for terminal sterilization of trial formulations will be completed.  Generally, the FDA requires proof that terminal sterilization is not feasible prior to giving approval of a product prepared by aseptic techniques.

 

[*] Certain information in this document has been omitted and filed separately with the Securities and Exchange Commission. Confidential treatment has been requested with respect to the omitted portions.

 

1

 

Therefore, this study needs to be completed to support strategic planning for development of the commercial product.

 

DELIVERABLES

 

·                  Formulations designed for improved stability.

 

·                  Development report describing viability of terminal sterilization for sMTS-BA058.

 

TIMING

 

The required effort in hours, duration of the study in months, and expected end dates (assuming a 01 Mar 2012 start date) for the major tasks covered by this work plan are summarized in the table below.

 

	
Task
    	
 
    	
Estimated
   Effort
   (hours)
    	
 
    	
Estimated
    Duration
   (months)
    	
 
    	
End Date
    
	
Composition and   Coatability
    	
 
    	
[*]
    	
 
    	
3
    	
 
    	
20 May 2012
    
	
Terminal Sterilization   Evaluation
    	
 
    	
[*]
    	
 
    	
2
    	
 
    	
27 May 2012
    
	
Drying Study
    	
 
    	
[*]
    	
 
    	
4
    	
 
    	
20 Jul 2012
    

 

Total elapsed time estimated: 4 months

Total hours estimated: [*] hours

Total direct costs: ~ $40,000

 

In all other respects, the terms and conditions of the Agreement remain in full force and effect.

 

Requested task, dates and costs are approved by:

 

	
Company: Radius   Health, Inc
    	
 
    	
Company: 3M
    
	
Name: B. N. Harvey
    	
 
    	
Name: Mark Tomai
    
	
 
    	
 
    	
 
    
	
Signature: 
    	
/s/ B.N. Harvey
    	
 
    	
Signature: 
    	
/s/ Mark Tomai
    
	
Position: CFO
    	
 
    	
Position: Head of MTS   Business Development
    
	
 
    	
 
    	
 
    
	
Date (dd/mm/yy): 23/02/12
    	
 
    	
Date (dd/mm/yy): 23/02/12
    
					

 

[*] Certain information in this document has been omitted and filed separately with the Securities and Exchange Commission. Confidential treatment has been requested with respect to the omitted portions.

 

2

 

STRICTLY CONFIDENTIAL

 

	
Confidential   Treatment Requested
    	
 
    
	
Under 17 C.F.R.   §§ 200.80(b)(4) and
    	
 
    
	
240.24b-2
    	
 
    

 

Change Order Form # 13

 

Change order under Agreement dated: Fourth Amendment to Development and Clinical Supplies Agreement dated March 2, 2011

 

Between:  Radius Health, Inc and 3M

 

Project Name: For the development of Radius’s BA-058 compound delivered via 3M’s Microstructured Transdermal Delivery System

 

Change requested by: Radius

Name: Mark Tomai

Company:  3M

Date:  12Apr2012

Description of change:

 

Radius has requested further development of a ready-to-coat formulation for preparation of sMTS supplies with increased stability.

 

OBJECTIVE

Test stability of new formulations for sMTS-BA058 to target a scalable formulation with a final configuration that provides long-term stability under refrigerated conditions and supports short-term exposure at [*]C.  Prepare associated documentation to support clinical use of the new formulation.

 

BACKGROUND

A composition and coatability study is described in Change Order 12.  This Change Order describes the work needed to assess the stability of the formulation options developed in Change Order 12, and the effect of container-closure system (CCS) options.

 

PROCEDURE

1.              A stability study examining the effect of packaging.  The study uses the arrays coated under Change Order 12, and will be started concurrently with Change Order 12 as coated arrays are prepared.

 

[*] Certain information in this document has been omitted and filed separately with the Securities and Exchange Commission. Confidential treatment has been requested with respect to the omitted portions.

 

1

 

DELIVERABLES

 

·                  Stability Testing:

·                  [*]°C/ambient

·                  [*], [*], and [*] months for up to [*] formulations

·                  [*], [*], [*], [*], and [*] months for up to [*] formulations

·                  [*]°C/[*]%RH

·                  [*], [*], and [*] months for up to [*] formulations

·                  [*], [*], [*], [*], and [*] months for up to [*] formulations

·                  Formulation Screening Testing:

·                  [*]°C/[*]%RH at [*], [*], and [*] months for up to [*] formulations

 

·                  Tests to include:

·                  Content and purity at all time points

·                  Moisture and either dissolution or in-vivo release at initial time point and at [*] months, only

 

·                  Development report on effect of packaging options and final drying process, if any.

 

·                  Development report supporting performance and characterization of selected formulation.

 

TIMING

 

The required effort in hours, duration of the study in months, and expected end dates for the study covered by this work plan are summarized in the table below.

 

	
Task
    	
 
    	
Estimated
   Effort
   (hours)
    	
 
    	
Estimated
   Duration
   (months)
    	
 
    	
End Date
    	
 
    
	
Stability Study
    	
 
    	
[*]
    	
 
    	
24
    	
 
    	
May 2014
    	
 
    

 

Total elapsed time estimated: 2 years

Total hours estimated: [*] hours

Total direct costs: ~ $3,000

 

[*] Certain information in this document has been omitted and filed separately with the Securities and Exchange Commission. Confidential treatment has been requested with respect to the omitted portions.

 

2

 

In all other respects, the terms and conditions of the Agreement remain in full force and effect.

 

Requested task, dates and costs are approved by:

 

	
Company:   Radius Health, Inc
    	
 
    	
Company:   3M
    
	
Name:  Nick Harvey
    	
 
    	
Name:   Mark Tomai
    
	
Signature:
    	
/s/   Nick Harvey
    	
 
    	
Signature:
    	
/s/   Mark Tomai
    
	
Position:   CFO
    	
 
    	
Position:   Head of MTS Business Development
    
	
Date (dd/mm/yy): 30/04/12
    	
 
    	
Date   (dd/mm/yy): 01/05/12
    
					

 

3

 

	
Confidential   Treatment Requested

Under 17 C.F.R.   §§ 200.80(b)(4) and 230.406
    	
 
    

 

Change Order Form # 14

 

Change order under Agreement dated: Fourth Amendment to Development and Clinical Supplies Agreement dated March 2, 2011

 

Between:  Radius Health, Inc and 3M

 

Project Name: For the development of Radius’s BA-058 compound delivered via 3M’s Microstructured Transdermal Delivery System

 

Change requested by: Radius Health, Inc.

Name: Michele Gehrt

Company:  3M

Date:  20Jul2012

Description of change: Radius has requested the addition of work to perform residual drug analysis and microscopic evaluation of BA058-sMTS patches and arrays (placebo, 50, 100, and 150 mcg/array) following use in the Phase II Clinical Study.

 

SCOPE:

[*] patches will be returned to 3M for residual drug analysis and microscopic evaluation.  The 11 clinical sites will collect the patches and ship them to 3M on a monthly basis.  The patches will be labeled with patient number, sample date, visit number and kit number.  The patches will be stored (at the clinical sites, 3M and PACE) and shipped at [*]°C.  Upon receipt at 3M, the samples will be segregated according to visit number. Patches that are dislodged from the collar during shipping will not be tested.  The analyses will be done at the end of the clinical study at which time Radius will instruct 3M to select certain patches by patient number.

 

Residual drug analysis will be done using 3M Method-07-001836.

 

Microscopic analysis will be done using a [*]x magnification and looking for microneedle fracture, breakage, chipping, deformation, or other damage.  Results for each array will be recorded on the attached observations sheet (Attachment 1) and observation summary sheet (Attachment 2).  Digital photos will be recorded.  An example image is included as Attachment 3.

 

[*] Certain information in this document has been omitted and filed separately with the Securities and Exchange Commission. Confidential treatment has been requested with respect to the omitted portions.

 

 

The following table summarizes the patches to be analyzed.

 

	
Description
    	
 
    	
Number   of Patches
    	
 
    
	
Used   patches for Microscopic Analysis

·      [*] patches per dose

·      4 doses:  placebo, 50   mcg, 100 mcg, 150 mcg

·      Patches collected at Day [*]
    	
 
    	
 

 

[*]
    	
 
    
	
Un-used   patches for Microscopic Analysis

·      [*] patches per dose

·      2 doses:  placebo, 150   mcg

·      Patches collected at end of study (Day 180)
    	
 
    	
 

 

[*]
    	
 
    
	
Used   patches for Residual Drug Analysis

·      [*] patches per dose per timepoint

·      4 doses:  placebo, 50   mcg, 100 mcg, 150 mcg

·      Patches collected at Day [*], Day [*], Day [*]
    	
 
    	
 

 

[*]
    	
 
    

 

DELIVERABLES:

·                  Summary report describing residual BA058 content of arrays

·                  Summary report describing the type and frequency of visual observations.

 

TIMING:

 

The estimated effort in hours is summarized in the table below.

 

	
Task
    	
 
    	
Estimated Effort (hours)
    
	
Preparation, review and approval of testing protocols and reports
    	
 
    	
[*]
    
	
Collection and organization of samples
    	
 
    	
[*]
    
	
Residual drug analysis and microscopic analysis
    	
 
    	
[*]
    
	
Total additional hours
    	
 
    	
[*]
    

 

Total estimated hours:  [*]

Estimated completion date:  August 2013 (60 days after end of clinical study)

Total estimated direct costs:  $5,000 (analytical supplies and storage costs at PACE)

 

In all other respects, the terms and conditions of the Agreement remain in full force and effect.

 

Requested task, dates and costs are approved by:

 

	
Company: Radius   Health, Inc 
    	
 
    	
Company:   3M
    
	
Name: Nick Harvey
    	
 
    	
Name:   Michele Gehrt
    
	
Signature:
    	
/s/ Nick Harvey 
    	
 
    	
Signature:
    	
/s/   Michele Gehrt
    
	
Position: CFO 
    	
 
    	
Position:   Commercialization Mgr
    
	
Date (dd/mm/yy): 15/08/2012
    	
 
    	
Date   (dd/mm/yy):15/08/2012
    
					

 

[*] Certain information in this document has been omitted and filed separately with the Securities and Exchange Commission. Confidential treatment has been requested with respect to the omitted portions.

 

 

ATTACHMENT 1 — OBSERVATIONS

 

Sample ID:

 

	
 

 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    
	
 

 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    
	
 

 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    
	
 

 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    
	
 

 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    
	
 

 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    
	
 

 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    
	
 

 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    
	
 

 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    
	
 

 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    
	
 

 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    
	
 

 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    
	
 

 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    
	
 

 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    
	
 

 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    
	
 

 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    
	
 

 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    
	
 

 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    
	
 

 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    
	
 

 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    

 

Describe appearance of patch:

 

Enter code for damaged array on to chart.

 

Codes: R — break, C — chip, K — crack, D — bend, L — blunt, F — partial fill

 

Add sequence number for digital image.

 

[*] Certain information in this document has been omitted and filed separately with the Securities and Exchange Commission. Confidential treatment has been requested with respect to the omitted portions.

 

 

ATTACHMENT 2 — SUMMARY OBSERVATIONS

 

	
Sample   ID
    	
 
    	
Microneedle   fracture
   (breaks, cracks, and
   chips)
    	
 
    	
Deformation   of
   the needle
   (bends and/or
   blunting)
    	
 
    	
Comments
    
	
 
    	
 
    	
Breaks
    	
 
    	
Cracks
    	
 
    	
Chips
    	
 
    	
Bends
    	
 
    	
Blunting
    	
 
    	
 
    
	
 
    	
 
    	
Breaks
    	
 
    	
Cracks
    	
 
    	
Chips
    	
 
    	
Bends
    	
 
    	
Blunting
    	
 
    	
 
    
	
 
    	
 
    	
Breaks
    	
 
    	
Cracks
    	
 
    	
Chips
    	
 
    	
Bends
    	
 
    	
Blunting
    	
 
    	
 
    
	
 
    	
 
    	
Breaks
    	
 
    	
Cracks
    	
 
    	
Chips
    	
 
    	
Bends
    	
 
    	
Blunting
    	
 
    	
 
    
	
 
    	
 
    	
Breaks
    	
 
    	
Cracks
    	
 
    	
Chips
    	
 
    	
Bends
    	
 
    	
Blunting
    	
 
    	
 
    
	
 
    	
 
    	
Breaks
    	
 
    	
Cracks
    	
 
    	
Chips
    	
 
    	
Bends
    	
 
    	
Blunting
    	
 
    	
 
    
	
 
    	
 
    	
Breaks
    	
 
    	
Cracks
    	
 
    	
Chips
    	
 
    	
Bends
    	
 
    	
Blunting
    	
 
    	
 
    
	
 
    	
 
    	
Breaks
    	
 
    	
Cracks
    	
 
    	
Chips
    	
 
    	
Bends
    	
 
    	
Blunting
    	
 
    	
 
    
	
 
    	
 
    	
Breaks
    	
 
    	
Cracks
    	
 
    	
Chips
    	
 
    	
Bends
    	
 
    	
Blunting
    	
 
    	
 
    
	
 
    	
 
    	
Breaks
    	
 
    	
Cracks
    	
 
    	
Chips
    	
 
    	
Bends
    	
 
    	
Blunting
    	
 
    	
 
    
	
 
    	
 
    	
Breaks
    	
 
    	
Cracks
    	
 
    	
Chips
    	
 
    	
Bends
    	
 
    	
Blunting
    	
 
    	
 
    
	
 
    	
 
    	
Breaks
    	
 
    	
Cracks
    	
 
    	
Chips
    	
 
    	
Bends
    	
 
    	
Blunting
    	
 
    	
 
    
	
 
    	
 
    	
Breaks
    	
 
    	
Cracks
    	
 
    	
Chips
    	
 
    	
Bends
    	
 
    	
Blunting
    	
 
    	
 
    
	
 
    	
 
    	
Breaks
    	
 
    	
Cracks
    	
 
    	
Chips
    	
 
    	
Bends
    	
 
    	
Blunting
    	
 
    	
 
    
	
 
    	
 
    	
Breaks
    	
 
    	
Cracks
    	
 
    	
Chips
    	
 
    	
Bends
    	
 
    	
Blunting
    	
 
    	
 
    

 

[*] Certain information in this document has been omitted and filed separately with the Securities and Exchange Commission. Confidential treatment has been requested with respect to the omitted portions.

 

 

	
 
    	
 
    	
Breaks
    	
 
    	
Cracks
    	
 
    	
Chips
    	
 
    	
Bends
    	
 
    	
Blunting
    	
 
    	
 
    

 

ATTACHMENT 3 — EXAMPLE IMAGE

 

[*]

 

[*] Certain information in this document has been omitted and filed separately with the Securities and Exchange Commission. Confidential treatment has been requested with respect to the omitted portions.

 

 

	
Confidential   Treatment Requested
    	
 
    
	
Under 17 C.F.R.   §§ 200.80(b)(4) and 230.406
    	
 
    

 

Change Order Form # 15

 

Change order under Agreement dated: Fourth Amendment to Development and Clinical Supplies Agreement dated March 2, 2011

 

Between:  Radius Health, Inc and 3M

 

Project Name: For the development of Radius’s BA-058 compound delivered via 3M’s Microstructured Transdermal Delivery System

 

Change requested by: Radius Health, Inc.

Name: Michele Gehrt

Company:  3M

Date:  16July2012

Description of change: Radius has requested the addition of work to perform qualification testing of (3) lots of Phosphate Buffer Solution (from Amresco) per the findings of the QP audit.

 

SCOPE:

Three (3) different lots of Phosphate Buffer Solution (PBS) are to be sourced from Amresco and qualification testing to be performed.  The testing will include appearance (color, clarity, odor), pH and sterility and will be performed by Nelson Labs. Two (2) lots are available immediately and the testing of these two lots will be initiated upon receipt at Nelson labs.  The third lot will not be available for approximately 6-8 weeks dependent upon the depletion of inventory at the supplier.  This lot will be tested as soon as available.

 

DELIVERABLES:

·                  Test results for appearance, pH and sterility

 

TIMING:

The estimated effort in hours and costs are summarized in the table below.

 

	
Task
    	
 
    	
Estimated Effort
   (hours)
    	
 
    	
Estimated Cost
   (dollars)
    	
 
    
	
3M Coordination of testing (ordering, shipping, reporting)
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    
	
PBS
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    
	
Nelson Labs: appearance, pH and sterility analysis
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    
	
Total additional hours/cost
    	
 
    	
[*]
    	
 
    	
$
    	
2,150
    	
 
    
							

 

[*] Certain information in this document has been omitted and filed separately with the Securities and Exchange Commission. Confidential treatment has been requested with respect to the omitted portions.

 

 

Estimated completion date (4 weeks after receipt of PBS):  August 2012 for two (2) lots; October 2012 for the third lot (depending on availability from Amresco).

 

In all other respects, the terms and conditions of the Agreement remain in full force and effect.

 

Requested task, dates and costs are approved by:

 

	
Company:   Radius Health, Inc
    	
 
    	
Company:   3M
    
	
Name:   Nick Harvey
    	
 
    	
Name:   Michele Gehrt
    
	
Signature:
    	
/s/   Nick Harvey
    	
 
    	
Signature:
    	
/s/   Michele Gehrt
    
	
Position:   CFO
    	
 
    	
Position:   Commercialization Mgr
    
	
Date   (dd/mm/yy): 16/07/2012
    	
 
    	
Date   (dd/mm/yy): 16/07/2012
    
					

 

[*] Certain information in this document has been omitted and filed separately with the Securities and Exchange Commission. Confidential treatment has been requested with respect to the omitted portions.

 

 

Change Order Form # 19

 

Change order under Agreement dated: Fourth Amendment to Development and Clinical Supplies Agreement dated March 2, 2011. Change Order #10 dated 03Oct2011.

 

Between:  Radius Health, Inc and 3M

 

Project Name: For the development of Radius’s BA-058 compound delivered via 3M’s Microstructured Transdermal Delivery System

 

Change requested by: Radius

Name: Michele Gehrt

Company:  3M

Date:  03Oct2012

 

Description of change: Radius has requested additional testing for the bracketing stability study beyond that described in Change Order #10.   The bracketing stability study includes drug product containing 50 and 150 mcg BA058 per array.  The drug product was packaged with and without desiccant.

 

There are sufficient supplies in the stability chambers to allow six additional stability time points.  Attached is a proposed extension to the bracketing stability study.  Testing will only be performed on the supplies packaged in desiccant.

 

Drug Product Testing

 

	
Condition
    	
 
    	
Tests
    	
 
    	
Time points
    
	
5C
    	
 
    	
Content and Purity
    	
 
    	
11, 13, 14, 15, 18, 24 months
    

 

3M estimates this work (each pull point) will be conducted over a 2-3 week period.  The stability costs for the arrays will be $[*] per pull point per lot.

 

Except to the extent expressly amended by this Change Order, the terms and conditions of the Agreement remain 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 Change Order.

 

Requested task, dates and costs are approved by:

 

	
Company:   Radius Health, Inc
    	
 
    	
Company:   3M
    
	
Name:   Nick Harvey
    	
 
    	
Name:   Michele Gehrt
    
	
Signature:
    	
/s/   Nick Harvey
    	
 
    	
Signature:
    	
/s/   Michele Gehrt
    
	
Position:   CFO
    	
 
    	
Position:   Commercialization Mgr
    
	
Date   (dd/mm/yy): 07/12/2012
    	
 
    	
Date   (dd/mm/yy):10/12/2012
    
					

 

[*] Certain information in this document has been omitted and filed separately with the Securities and Exchange Commission. Confidential treatment has been requested with respect to the omitted portions.

 

 

Confidential Treatment Requested Under 17 C.F.R. §§ 200.80(b)(4) and 240-24b-2

 

Change Order Form # 21

 

Change order under Agreement dated: Fifth Amendment to Development and Clinical Supplies Agreement dated December 14, 2012

 

Between:  Radius Health, Inc and 3M

 

Project Name: For the development of Radius’s Abaloparatide compound delivered via 3M’s Microstructured Transdermal Delivery System

 

Change requested by: Radius

Name: Michele Gehrt

Company:  3M

Date:  26Feb2014

 

Description of change:

 

Radius has requested that 3M redevelop the Abaloparatide sMTS product to achieve a PK profile comparable to Abaloparatide-SC, as evaluated in [*].

 

OBJECTIVE

 

Redevelop the Abaloparatide product to achieve a PK profile comparable to SC injection. Redevelopment may include changes in [*], [*] or [*].  Prepare iterations of the optimized product for evaluation in [*] studies.

 

BACKGROUND

 

Results of the Phase II study showed lower than expected efficacy of the sMTS product when compared with the SC product.  Radius would like to determine if improved efficacy can be achieved with the sMTS product by changing the product to more closely match the PK profile of Abaloparatide achieved with SC injection.

 

PROCEDURE

 

3M anticipates working through several product iterations in an effort to achieve a more efficacious PK profile for Abaloparatide sMTS.  Planned iterations may include an evaluation of various [*] or [*], [*] and/or [*], and [*], all targeting [*] (relative to Phase II) [*] of BA058 over a [*] period of time.  In developing product iterations, 3M would expect to evaluate potential product configurations via [*],

 

[*] Certain information in this document has been omitted and filed separately with the Securities and Exchange Commission. Confidential treatment has been requested with respect to the omitted portions.

 

 

Confidential Treatment Requested Under 17 C.F.R. §§ 200.80(b)(4) and 240-24b-2

 

[*] and [*]([*]).  3M would anticipate producing and packaging supplies to support approximately [*] rounds of in-vivo [*] studies (to be executed by Radius at a CRO). After the first [*] study, the use of [*] as an animal model would be reevaluated for its applicability.  If no correlation is seen between the [*] and [*] studies then this change order would be updated to reduce the use of the [*] model in subsequent iterations. These studies may be supported by minimal stability valuations to verify the integrity of the study. Upon agreement by the JTT, each round of [*] studies may contain up to ([*]) [*] product configurations.  Supplies for [*] studies would be produced as for past preclinical studies ([*], [*]) and shipped to the facility of Radius’ designation.  Stability for promising configurations would be characterized only grossly.  More complete stability characterization is anticipated in the next stage of work, once a promising product configuration has been identified via this evaluation.

 

3M anticipates detailed technical discussions of product development efforts with Radius throughout development and informed by the [*] PK studies carried out during this development period.  These PK data will be used along with data collected by 3M to help determine favorable product development plans.

 

DELIVERABLES

 

·                  Several product iterations characterized by 3M as described above, targeting the necessary PK profile identified by Radius as likely to enhance efficacy.

·                  Samples (approx [*] patch assemblies) for promising configurations agreed to by the JTT for further evaluation by Radius in [*].  It is estimated that [*] studies may be needed during this evaluation period.

·                  Gross stability evaluations for promising patch assembly configurations.

 

TIMING

 

The required effort in hours, duration of the study in months, and expected end dates for the study covered by this work plan are summarized in the table below.

 

	
Task
    	
 
    	
Estimated
   Effort
   (hours)
    	
 
    	
Estimated
   Duration
   (months)
    	
 
    	
Estimated
   Direct Costs
   ($)
    	
 
    	
Estimated End
   Date*
    	
 
    
	
Reformulation Tasks; Assessment of Release in [*]; Preparation of   Samples for PK Evaluation in [*]
    	
 
    	
2626
    	
 
    	
4
    	
 
    	
$
    	
3,657
    	
 
    	
31Jul2014
    	
 
    
											

 

*timing depends on duration of [*] studies

 

Total Estimated Costs:  $568,247

 

In all other respects, the terms and conditions of the Agreement remain in full force and effect.

 

[*] Certain information in this document has been omitted and filed separately with the Securities and Exchange Commission. Confidential treatment has been requested with respect to the omitted portions.

 

 

Confidential Treatment Requested Under 17 C.F.R. §§ 200.80(b)(4) and 240-24b-2

 

Requested task, dates and costs are approved by:

 

	
Company:   Radius Health, Inc
    	
 
    	
Company:   3M
    
	
Name:   Robert Ward
    	
 
    	
Name:   Michele Gehrt
    
	
Signature:
    	
/s/   Robert Ward
    	
 
    	
Signature:
    	
/s/   Michele Gehrt
    
	
Position:   CEO
    	
 
    	
Position:   Commercialization Mgr
    
	
Date   (dd/mm/yy): 18/03/14
    	
 
    	
Date   (dd/mm/yy): 19/03/2014
    
					

 

[*] Certain information in this document has been omitted and filed separately with the Securities and Exchange Commission. Confidential treatment has been requested with respect to the omitted portions.

 

 

Confidential Treatment Requested Under 17 C.F.R. §§ 200.80(b)(4) and 240-24b-2

 

Change Order Form # 22

 

Change order under Agreement dated: Fifth Amendment to Development and Clinical Supplies Agreement dated December 14, 2012

 

Between:  Radius Health, Inc and 3M

 

Project Name: For the development of Radius’ Abaloparatide compound delivered via 3M’s Microstructured Transdermal Delivery System

 

Change requested by: Radius

Name: Michele Gehrt

Company:  3M

Date:  21Jan2015

 

Description of change:

 

Radius has requested that 3M continue to progress the redevelopment of the Abaloparatide sMTS product to achieve a PK profile comparable to Abaloparatide-SC, as evaluated in non-human [*].  This change order will progress the work completed in Change Order #21.

 

Scope:

 

3M to continue to redevelop the Abaloparatide product to achieve a PK profile comparable to SC injection. Redevelopment may include changes in [*], [*] or [*].  3M to prepare up to [*] product configurations for evaluation in non-human [*] studies.

 

Assumptions:

 

·                  3M will progress several product configurations that will build on the knowledge from previous work.

·                  3M will evaluate potential product configurations via [*], [*] and  [*] ([*])

·                  The JTT will meet to review and agree upon the product configurations to be taken into each [*] study.

·                  Supplies for [*] studies would be produced as for past preclinical studies ([*], [*]) and shipped to the facility of Radius’ designation.

·                  Stability for promising configurations would be characterized only grossly

 

[*] Certain information in this document has been omitted and filed separately with the Securities and Exchange Commission. Confidential treatment has been requested with respect to the omitted portions.

 

 

Confidential Treatment Requested Under 17 C.F.R. §§ 200.80(b)(4) and 240-24b-2

 

DELIVERABLES

 

·                  Samples (approx [*] patch assemblies) for promising configurations agreed to by the JTT for further evaluation by Radius in [*].  It is estimated that up to [*] product configurations would be provided for [*] studies during this evaluation period.

·                  Gross stability evaluations for promising patch assembly configurations (limited testing at up to [*] time points for [*] storage condition).

 

TIMING

 

The required effort in hours, duration of the study in months, and expected end dates for the study covered by this work plan are summarized in the table below.

 

	
Task
    	
 
    	
Estimated
   Effort
   (hours)
    	
 
    	
Estimated
   Duration
   (months)
    	
 
    	
Estimated
   Direct Costs
   ($)
    	
 
    	
Estimated End
   Date*
    	
 
    
	
Reformulation Tasks; Assessment of Release in [*]; Preparation of   Samples for PK Evaluation in [*]
    	
 
    	
910
    	
 
    	
2
    	
 
    	
$
    	
2,500
    	
 
    	
31Mar2015
    	
 
    
											

 

*timing depends on duration and scheduling of [*] studies

 

Total Estimated Costs:  $ 198,150

 

In all other respects, the terms and conditions of the Agreement remain in full force and effect.

 

Requested task, dates and costs are approved by:

 

	
Company:   Radius Health, Inc
    	
 
    	
Company:   3M
    
	
Name:   B.N. Harvey
    	
 
    	
Name:   Michele Gehrt
    
	
Signature:
    	
/s/   B.N. Harvey
    	
 
    	
Signature:
    	
/s/   Michele Gehrt
    
	
Position:   CFO
    	
 
    	
Position:   Commercialization Mgr
    
	
Date   (dd/mm/yy): 3/2/15
    	
 
    	
Date   (dd/mm/yy): 03/02/15
    
					

 

[*] Certain information in this document has been omitted and filed separately with the Securities and Exchange Commission. Confidential treatment has been requested with respect to the omitted portions.Exhibit 10.20

 

NUVIOS, INC.

2003 LONG-TERM INCENTIVE PLAN

(As Amended)

 

1.             Definitions. In this Plan, except where the context otherwise indicates, the following definitions shall apply:

 

1.1.         “Affiliate” means a corporation, partnership, business trust, limited liability company or other form of business organization at least a majority of the total combined voting power of all classes of stock or other equity interests of which is owned by the Company, either directly or indirectly, and any other entity designated by the Committee in which the Company has a significant interest.

 

1.2.         “Agreement” means a written agreement or other document evidencing an Award that shall be in such form as maybe specified by the Committee and that may, but need not, be signed by a Participant, as determined by the Committee in its discretion.

 

1.3.         “Award” means a grant of an Option, Right, Restricted Stock, Incentive Shares or Performance Award.

 

1.4.         “Board” means the Board of Directors of the Company.

 

1.5.         “Code” means the Internal Revenue Code of 1986, as amended.

 

1.6.         “Committee” means the Compensation Committee of the Board or such other committee(s), subcommittee(s) or person(s) appointed by the Board to administer this Plan or to make and/or administer specific Awards hereunder. If no such appointment is in effect at any time, “Committee” shall mean the Board.

 

1.7.         “Common Stock” means the common stock, par value $0.01 per share, of the Company.

 

1.8.         “Company” means NuVios, Inc., a Delaware corporation, and any successor thereto.

 

1.9.         “Date of Exercise” means the date on which the Company receives notice of the exercise of an Option or Right in accordance with the terms of Section 8.1 hereof.

 

1.10.        “Date of Grant” means the date on which an Award is granted under this Plan.

 

1.11.       “Eligible Person” means any person who is (a) an Employee (b) hired to be an Employee, (c) a Non-Employee Director, or (d) a consultant or independent contractor to the Company or an Affiliate.

 

 

1.12.        “Employee” means any person determined by the Committee to be an employee of the Company or an Affiliate.

 

1.13.        “Exercise Price” means the price per Share at which an Option may be exercised.

 

1.14.        “Fair Market Value” means, (i) if the Common Stock is traded on a securities exchange or automated dealer quotation system, at the Committee’s election, either (A) the last sale price for a share, as of the relevant date, on such securities exchange or automated dealer quotation system as reported by such source as the Committee may select, or (B) the average of the closing prices of the Common Stock on such exchange or quotation system for the ten (10) trading days immediately preceding the relevant date, or (ii) if the Common Stock is not traded on a securities exchange or automated dealer quotation system, an amount equal to the then fair market value of a Share as determined by the Committee pursuant to a reasonable method adopted in good faith for such purpose.

 

1.15.        “Incentive Shares” means an award providing for the contingent grant of Shares pursuant to the provisions of Section 10 hereof.

 

1.16.        “Incentive Stock Option” means an Option granted under this Plan that the Company designates as an incentive stock option under Section 422 of the Code.

 

1.17.        “Non-Employee Director” means any member of the Company’s or an Affiliate’s Board of Directors who is not an Employee.

 

1.18.        “Nonstatutory Stock Option” means an Option granted under this Plan that is not an Incentive Stock Option.

 

1.19.        “Option” means an option to purchase Shares granted under this Plan in accordance with the terms of Section 6 hereof.

 

1.20.        “Option Period” means the period during which an Option may be exercised.

 

1.21.        “Participant” means an Eligible Person who has been granted an Award hereunder.

 

1.22.        “Performance Award” means a performance award granted under the Plan in accordance with the terms of Section Ii hereof.

 

1.23.        “Plan” means the NuVios, Inc. 2003 Long-Term Incentive Plan, as amended from time to time.

 

1.24.        “Related Option” means an Option in connection with which, or by amendment to which, a Right is granted.

 

 

1.25.        “Related Right” means a Right granted in connection with, or by amendment to, an Option.

 

1.26.        “Restricted Stock” means Shares granted under the Plan pursuant to the provisions of Section 9 hereof.

 

1.27.        “Right” means a stock appreciation right granted under the Plan in accordance with the terms of Section 7 hereof.

 

1.28.        “Right Period” means the period during which a Right may be exercised.

 

1.29.        “Section 422 Employee” means an Employee who is employed by the Company or a “parent corporation” or “subsidiary corporation” (both as defined in Sections 424(e) and (1) of the Code) with respect to the Comp any.

 

1.30.        “Share” means a share of Common Stock.

 

1.31.        “Ten-Percent Stockholder” means a Section 422 Employee who (applying the rules of Section 424(d) of the Code) owns stock possessing more than ten percent (10%) of the total combined voting power of all classes of stock of the Company or a “parent corporation” or “subsidiary corporation” (both as defined in Sections 424(e) and (1) of the Code) with respect to the Company.

 

2.             Purpose. This Plan is intended to assist the Company and its Affiliates in attracting and retaining Eligible Persons of outstanding ability and to promote the identification of their interests with those of the stockholders of the Company and its Affiliates.

 

3.             Administration. The Committee shall administer this Plan and shall have plenary authority, in its discretion, to grant Awards to Eligible Persons, subject to the provisions of this Plan. The Committee shall have plenary authority and discretion, subject to the provisions of this Plan, to determine the Eligible Persons to whom Awards shall be granted, the terms (which terms need not be identical) of all Awards, including without limitation the Exercise Price of Options, the time or times at which Awards are granted, the number of Shares covered by Awards, whether an Option shall be an Incentive Stock Option or a Nonstatutory Stock Option, any exceptions to nontransferability, any provisions relating to vesting, and the period during which Options and Rights may be exercised and Restricted Stock shall be subject to restrictions. In making these determinations, the Committee may take into account the nature of the services rendered or to be rendered by Award recipients, their present and potential contributions to the success of the Company and its Affiliates, and such other factors as the Committee in its discretion shall deem relevant. Subject to the provisions of the Plan, the Committee shall have plenary authority to interpret the Plan and Agreements, prescribe, amend and rescind rules and regulations relating to them, and make all other determinations deemed necessary or advisable for the administration of this Plan and

 

 

Awards granted hereunder. The determinations of the Committee on the matters referred to in this Section 3 hereof shall be binding and final.

 

4.             Eligibility. Awards may be granted only to Eligible Persons.

 

5.             Stock Subject to Plan.

 

5.1.          Subject to adjustment as provided in Section 13 hereof, (a) the maximum number of Shares that may be issued under this Plan is 30,235,000 Shares.

 

5.2.          If an Option or Right expires or terminates for any reason (other than termination by virtue of the exercise of a Related Option or Related Right, as the case may be) without having been fully exercised, if shares of Restricted Stock are forfeited, or if Shares covered by an Incentive Share Award or Performance Award are not issued or are forfeited, the unissued or forfeited Shares that had been subject to the Award shall be available for the grant of additional Awards.

 

5.3.          Upon exercise of a Right (regardless of whether the Right is settled in cash or Shares), the number of Shares with respect to which the Right is exercised shall be charged against the number of Shares issuable under the Plan and shall not become available for the grant of other Awards.

 

6.             Options.

 

6.1.          Options granted under this Plan to Eligible Persons shall be either Incentive Stock Options or Nonstatutory Stock Options, as designated by the Committee; provided, however, that Incentive Stock Options may only be granted to Eligible Persons who are Section 422 Employees on the Date of Grant. Each Option granted under this Plan shall be identified either as a Nonstatutory Stock Option or an Incentive Stock Option and shall be evidenced by an Agreement that specifies the terms and conditions of the Option. Options shall be subject to the terms and conditions set forth in this Section 6 hereof and such other terms and conditions not inconsistent with this Plan as the Committee may specify.

 

6.2.          The Exercise Price of an Incentive Stock Option granted under this Plan shall not be less than one hundred percent (100%) of the Fair Market Value of the Common Stock on the Date of Grant. Notwithstanding the foregoing, in the case of an Incentive Stock Option granted to an Employee who, on the Date of Grant is a Ten-Percent Shareholder, the Exercise Price shall not be less than one hundred and ten percent (110%) of the Fair Market Value of a share on the Date of Grant.

 

6.3.          The Option Period shall be determined by the Committee and specifically set forth in the Agreement; provided, however, that an Option shall not be exercisable after ten (10) years (five (5) years in the case of an Incentive Stock Option granted to a Ten-Percent Stockholder) from its Date of Grant.

 

 

7.             Rights.

 

7.1.          Rights granted under the Plan shall be evidenced by an Agreement specifying the terms and conditions of the Award.

 

7.2.          A Right may be granted under the Plan:

 

(a)    in connection with, and at the same time as, the grant of an Option under the Plan;

 

(b)    by amendment of an outstanding Option granted under the Plan; or

 

(c)    independently of any Option granted under the Plan.

 

A Right described in clause (a) or (b) of the preceding sentence is a Related Right. A Related Right may, in the Committee’s discretion, apply to all or any portion of the Shares subject to the Related Option.

 

7.3.          A Right may be exercised as a whole or in part as provided in the applicable Agreement, and, subject to the terms of the Agreement, entitles a Participant to receive, without payment to the Company (but subject to required tax withholding), either cash or that number of Shares (equal to the highest whole number of Shares), or a combination thereof, in an amount or having an aggregate Fair Market Value as of the Date of Exercise not to exceed the number of Shares subject to the portion of the Right exercised multiplied by an amount equal to the excess of (a) the Fair Market Value on the Date of Exercise of the Right over (b) either (i) the Fair Market Value on the Date of Grant (or such amount in excess of such Fair Market Value as may be specified by the Committee) of the Right if it is not a Related Right, or (ii) the Exercise Price as provided in the Related Option if the Right is a Related Right.

 

7.4.          The Right Period shall be determined by the Committee and specifically set forth in the Agreement; provided, however, that (a) a Right will expire no later than the earlier of(i) ten (10) years from the Date of Grant, or (ii) in the case of a Related Right, the expiration of the Related Option; and (b) a Right that is a Related Right to an Incentive Stock Option may be exercised only when and to the extent the Related Option is exercisable.

 

7.5.          The exercise, as a whole or in part, of a Related Right shall cause a reduction in the number of Shares subject to the Related Option equal to the number of Shares with respect to which the Related Right is exercised. The exercise, as a whole or in part, of a Related Option shall cause a reduction in the number of Shares subject to the Related Right equal to the number of Shares with respect to which the Related Option is exercised.

 

8.             Exercise of Options and Rights.

 

8.1.          An Option or Right may, subject to the terms of the applicable Agreement evidencing the Award, be exercised as a whole or in part by the delivery to the Company of a notice of the exercise, in such form as the Committee may prescribe, accompanied, in the case of an Option, by (a) a full payment for the Shares with respect to which

 

 

the Option is exercised or (b) irrevocable instructions to a broker to deliver promptly to the Company cash equal to the exercise price of the Option. To the extent provided in the applicable Agreement, payment may be made by (i) delivery (including constructive delivery) of Shares (provided that such Shares, if acquired pursuant to an option or other award granted hereunder or under any other compensation plan maintained by the Company or any Affiliate, have been held by the Participant for at least six (6) months) valued at Fair Market Value on the Date of Exercise or (ii) delivery of a promissory note as provided in Section 8.2 hereof.

 

8.2.          To the extent provided in an Agreement and permitted by applicable law, the Committee may accept as payment of all or a portion of the Exercise Price a promissory note executed by the Participant evidencing his or her obligation to make future cash payment thereof. Promissory notes made pursuant to this Section 8.2 shall (a) be secured by a pledge of the Shares received upon exercise of the Option, (b) bear interest at a rate fixed by the Committee, and (c) contain such other terms and conditions as the Committee may determine in its discretion.

 

9.             Restricted Stock Awards. Each grant of Restricted Stock under this Plan shall be subject to an Agreement specifying the terms and conditions of the Award. Restricted Stock granted under this Plan shall consist of Shares that are restricted as to transfer, subject to forfeiture, and subject to such other terms and conditions as may be determined by the Committee.

 

10.           Incentive Share Awards. Each grant of Incentive Shares under this Plan shall be evidenced by an Agreement that: (a) provides for the issuance of Shares to a Participant at such times and (b) contains such other terms and conditions, as determined by the Committee.

 

11.           Performance Awards. Each Performance Award granted under this Plan shall be evidenced by an Agreement that: (a) provides for the payment of cash and/or issuance of Shares to a Participant and (b) contains such other terms and conditions as may be determined by the Committee. For purposes of Section 5.2 hereof, a Performance Award shall be deemed to cover a number of Shares equal to the sum of (a) the maximum number of Shares that may be issued upon payment of the Award and (b) to the extent the Award is not payable in Shares, a number of Shares equal to the quotient obtained by dividing the maximum dollar amount of the Award that is not payable in Shares by the Fair Market Value of a Share as of the Date of Grant of the Award, rounded to the next highest whole number.

 

12.           Dividends and Dividend Equivalents. The terms of an Award may, subject to such terms and conditions as the Committee may specify, provide a Participant with the right to receive dividend payments or dividend equivalent payments with respect to Shares covered by the Award, which payments may be either made currently or credited to an account established for the Participant, and may be settled in cash or Shares, as determined by the Committee.

 

13.           Capital Adjustments. In the event of any change in the outstanding Common Stock by reason of any stock dividend, split-up, recapitalization, reclassification, combination or exchange of shares, merger, consolidation, liquidation or the like, the Committee may, in its discretion, provide for a substitution for or adjustment in (a) the number and class of shares

 

 

subject to outstanding Awards, (b) the Exercise Price of Options and the base price upon which payments under Rights that are not Related Rights are determined, and (c) the aggregate number and class of Shares for which Awards thereafter may be granted under this Plan.

 

14.           Termination or Amendment. The Board may amend or terminate this Plan in any respect at any time; provided, however, that after this Plan has been approved by the stockholders of the Company, no amendment or termination of this Plan shall be made by the Board without approval of(a) the Company’s stockholders to the extent stockholder approval of the amendment is required by applicable law or regulations or the requirements of the principal exchange or interdealer quotation system on which the Common Stock is listed or quoted, if any, and (b) each Participant whose rights or obligations under any Award granted prior to the date of such amendment or termination would be adversely affected by such amendment or termination.

 

15.           Modification, Substitution of Awards.

 

15.1.        Subject to the terms and conditions of this Plan, the Committee may modify the terms of any outstanding Awards; provided, however, that no modification of an Award shall, without the consent of the Participant, adversely affect any of the Participant’s rights or obligations under such Award.

 

15.2.        Notwithstanding anything contained herein to the contrary, Awards may, at the discretion of the Committee, be granted under this Plan in substitution for stock options and other awards relating to capital stock of another corporation that is merged into, consolidated with, or all or a substantial portion of the property or stock of which is acquired by, the Company or one of its Affiliates. The terms and conditions of the substitute Awards so granted may vary from the terms and conditions set forth in this Plan to such extent as the Committee may deem appropriate in order to conform, as a whole or in part, to the provisions of the awards in substitution for which they are granted.

 

16.           Foreign Employees. Without amendment of this Plan, the Committee may grant Awards to Eligible Persons who are subject to the laws of foreign countries or jurisdictions on such terms and conditions different from those specified in this Plan as may in the judgment of the Committee be necessary or desirable to foster and promote achievement of the purposes of this Plan. The Committee may make such modifications, amendments, procedures, sub-plans and the like as may be necessary or advisable to comply with provisions of laws of other countries or jurisdictions in which the Company or any of its Affiliates operate or have employees.

 

17.           Stockholder Approval. This Plan, and any amendments hereto requiring stockholder approval pursuant to Section 14 hereof, are subject to approval by vote of the stockholders of the Company at the next annual or special meeting of stockholders following adoption by the Board.

 

18.           Withholding. The Company’s obligation to issue or deliver Shares or pay any amount pursuant to the terms of any Award granted hereunder shall be subject to satisfaction of applicable federal, state and local tax withholding requirements. To the extent provided in the applicable Agreement and in accordance with rules prescribed by the Committee, a Participant

 

 

may satisfy any such withholding tax obligation by any of the following means or by a combination of such means: (a) tendering a cash payment, (b) authorizing the Company to withhold Shares otherwise issuable to the Participant, or (c) delivering to the Company already-owned and unencumbered Shares. In addition, if there is a public market for Shares at the time any such tax withholding obligations are to be satisfied, then except with respect to Incentive Stock Options, a Participant may satisfy such tax withholding obligations by (i) delivery (including telephonically to the extent permitted by the Corporation) of an irrevocable and unconditional undertaking by a broker acceptable to the Corporation to deliver promptly to the Corporation sufficient funds to satisfy the tax withholding obligations, or (ii) delivery by the Participant to the Corporation of a copy of irrevocable and unconditional instructions to a broker acceptable to the Corporation to deliver promptly to the Corporation cash or a check sufficient to satisfy the tax withholding obligations; provided that such amount is paid to the Corporation at such time as may be required by the Committee.

 

19.           Term of Plan. Unless sooner terminated by the Board pursuant to Section 14, this Plan shall terminate on the date that is ten (10) years after the earlier of that date that the Plan is adopted by the Board or approved by the Company’s stockholders, and no Awards may be granted or awarded after such date. The termination of this Plan shall not affect the validity of any Award outstanding on the date of termination.

 

20.           Indemnification of Committee. In addition to such other rights of indemnification as they may have as members of the Board or Committee, members of the Committee shall be indemnified by the Company against all reasonable expenses, including attorneys’ fees, actually and reasonably incurred in connection with the defense of any action, suit or proceeding, or in connection with any appeal therein, to which they or any of them may be a party by reason of any action taken or failure to act under or in connection with this Plan or any Award granted hereunder, and against all amounts reasonably paid by them in settlement thereof or paid by them in satisfaction of a judgment in any such action, suit or proceeding, if such members acted in good faith and in a manner which they believed to be in, and not opposed to, the best interests of the Company.

 

21.           General Provisions.

 

21.1.        The establishment of this Plan shall not confer upon any Eligible Person any legal or equitable right against the Company, any Affiliate or the Committee, except as expressly provided in this Plan. Participation in this Plan shall not give an Eligible Person any right to be retained in the service of the Company or any Affiliate.

 

21.2.        Neither the adoption of this Plan nor its submission to the Company’s stockholders shall be taken to impose any limitations on the powers of the Company or its Affiliates to issue, grant, or assume options, warrants, rights, or restricted stock, or other awards otherwise than under this Plan, or to adopt other stock option, restricted stock, or other plans, or to impose any requirement of stockholder approval upon the same.

 

 

21.3.        The interests of any Eligible Person under this Plan are not subject to the claims of creditors and may not, in any way, be assigned, alienated or encumbered except to the extent provided in an Agreement.

 

21.4.        This Plan shall be governed, construed and administered in accordance with the laws of the State of Delaware.

 

21.5.        The Committee may require each person acquiring Shares pursuant to Awards granted hereunder to represent to and agree with the Company in writing that such person is acquiring the Shares without a view to distribution thereof. The certificates for such Shares may include any legend that the Committee deems appropriate to reflect any restrictions on transfer. All certificates for Shares issued pursuant to this Plan shall be subject to such stock transfer orders and other restrictions as the Committee may deem advisable under the rules, regulations and other requirements of the Securities and Exchange Commission, any stock exchange upon which the Common Stock is then listed or interdealer quotation system upon which the Common Stock is then quoted, and any applicable federal or state securities laws. The Committee may place a legend or legends on any such certificates to make appropriate reference to such restrictions.

 

21.6.        The Company shall not be required to issue any certificate or certificates for Shares with respect to Awards granted under this Plan, or record any person as a holder of record of such Shares, without obtaining, to the complete satisfaction of the Committee, the approval of all regulatory bodies deemed necessary by the Committee, and without complying to the Board’s or Committee’s complete satisfaction, with all rules and regulations, under federal, state or local law deemed applicable by the Committee.

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