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.

 

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* 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

 

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* 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.

 

14

--------------------------------------------------------------------------------

 

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.

 

15

--------------------------------------------------------------------------------

 

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

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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

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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

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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

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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

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- 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

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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

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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

 

GRAPHIC [g17732lo25i001.jpg]

 

--------------------------------------------------------------------------------

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

 

4

--------------------------------------------------------------------------------

 

OBSERVATIONS

 

Sample ID:

 

[g17732lo25i002.jpg]

 

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.

 

[g17732lo27i001.jpg]

 

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.

 

--------------------------------------------------------------------------------