Exhibit 10.19

 

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 [*].  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 #[*], #[*], 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 #[*] and #[*] will be completed by 3M and delivered to
Radius by the end of [*] 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
#[*] and #[*], and in the case of Workplan  #[*], 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 #[*] 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: [*]

Signature:

/s/ B.N. Harvey

 

Signature:

/s/ [*]

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 [*] patches (controls and samples) will be evaluated
microscopically. Group 2a, Day [*] and Day [*] BA058-sMTS samples of each
subject ([*]mcg) removed following dosing will be sent for residual drug
analysis. Group 2b, Day [*] and Day [*] BA058-sMTS samples of each subject
(Placebo and [*]mcg) removed following dosing will be send for residual drug
analysis. Group 2c, Day [*] and Day [*] 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 [*] 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 [*] 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 [g127871kv01i001.jpg]

 

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

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

 

4

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

 

OBSERVATIONS

 

Sample ID:

 

[g127871kv01i002.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 [*] arrays (controls and samples) will be evaluated for residual
drug. Group 2a, Day [*] and Day [*] BA058-sMTS samples of each subject ([*] mcg)
removed following dosing will be sent for residual drug analysis. Group 2b, Day
[*] and Day [*] BA058-sMTS samples of each subject (Placebo and [*]mcg) removed
following dosing will be send for residual drug analysis. Group 2c, Day [*] and
Day [*] 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. [*] 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.

 

[g127871kv03i001.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 [*] 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

 

[*]

 

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 [*] method [*].  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.

 

[*]

 

Materials

 

[*] 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).  [*]. 
The [*] 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:

 

[*]

[*]

3M Drug Delivery Systems

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

St. Paul, MN 55144

Tel:  [*]

Fax:  [*]

Cell: [*]

E-Mail: [*]

 

[*]

[*]

3M Drug Delivery Systems

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

St. Paul, MN 55144

Tel:  [*]

Cell: [*]

E-Mail: [*]

 

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

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

 

14

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