Radius Health

RADIUS HEALTH, INC.

FORM 10-K
(Annual Report)

Filed 02/25/16 for the Period Ending 12/31/15

Address

Telephone
CIK

ATTN: CHIEF FINANCIAL OFFICER
950 WINTER STREET
WALTHAM, MA 02451
617-551-4000
0001428522

Symbol RDUS

SIC Code
Industry

2834 - Pharmaceutical Preparations
Biotechnology & Drugs

Sector Healthcare

Fiscal Year

12/31

http://www.edgar-online.com
© Copyright 2016, EDGAR Online, Inc. All Rights Reserved.
Distribution and use of this document restricted under EDGAR Online, Inc. Terms of Use.

  
  
Use
these
links
to
rapidly
review
the
document
TABLE
OF
CONTENTS
INDEX
TO
CONSOLIDATED
FINANCIAL
STATEMENTS
PART
IV
Table
of
ContentsUNITED
STATES
SECURITIES
AND
EXCHANGE
COMMISSION
Washington,
D.C.
20549FORM
10-KCommission
file
number:
001-35726Radius
Health,
Inc.
(Exact
name
of
registrant
as
specified
in
its
charter)Delaware
(State
or
other
jurisdiction
of
incorporation
or
organization)
80-0145732
(I.R.S.
Employer
Identification
No.)950
Winter
Street
Waltham,
Massachusetts
(Address
of
principal
executiveoffices)
02451
(Zip
Code)617-551-4000
(Registrant's
telephone
number,
including
area
code)








Securities
issued
pursuant
to
Section
12(b)
of
the
Act:
Common
Stock








Securities
issued
pursuant
to
Section
12(g)
of
the
Act:
NoneTitle
of
each
class
Name
of
each
exchange
on
which
registeredCommon
Stock,
par
value
$0.0001
per
share
The
NASDAQ
Global
Market








Indicate
by
check
mark
if
the
registrant
is
a
well-known
seasoned
issuer,
as
defined
in
Rule
405
of
the
Securities
Act.
Yes

ý




No

o








Indicate
by
check
mark
if
the
registrant
is
not
required
to
file
reports
pursuant
to
Section
13
or
Section
15(d)
of
the
Act.
Yes

o




No

ý








Indicate
by
check
mark
whether
the
registrant
(1)
has
filed
all
reports
required
to
be
filed
by
Section
13
or
15(d)
of
the
Securities
Exchange
Act
of
1934during
the
preceding
12
months
(or
for
such
shorter
period
that
the
registrant
was
required
to
file
such
reports),
and
(2)
has
been
subject
to
such
filing
requirementsfor
the
past
90
days.
Yes

ý




No

o








Indicate
by
check
mark
whether
the
registrant
has
submitted
electronically
and
posted
on
its
corporate
Web
site,
if
any,
every
Interactive
Data
File
required
tobe
submitted
and
posted
pursuant
to
Rule
405
of
Regulation
S-T
during
the
preceding
12
months
(or
for
such
shorter
period
that
the
registrant
was
required
tosubmit
and
post
such
files).
Yes

ý




No

o(MarkOne)

ý
ANNUAL
REPORT
PURSUANT
TO
SECTION
13
OR
15(d)
OF
THE
SECURITIES
EXCHANGE
ACTOF
1934For
the
fiscal
year
ended
December
31,
2015ORo
TRANSITION
REPORT
PURSUANT
TO
SECTION
13
OR
15(d)
OF
THE
SECURITIES
EXCHANGE
ACTOF
1934For
the
transition
period
from

































to










































Indicate
by
check
mark
if
disclosure
of
delinquent
filers
pursuant
to
Item
405
of
Regulation
S-K
is
not
contained
herein,
and
will
not
be
contained,
to
the
bestof
registrant's
knowledge,
in
definitive
proxy
or
information
statements
incorporated
by
reference
in
Part
III
of
this
Form
10-K
or
any
amendment
to
this
Form
10-K.

o








Indicate
by
check
mark
whether
the
registrant
is
a
large
accelerated
filer,
an
accelerated
filer,
a
non-accelerated
filer,
or
a
smaller
reporting
company.
See
thedefinitions
of
"large
accelerated
filer,"
"accelerated
filer"
and
"smaller
reporting
company"
in
Rule
12b-2
of
the
Exchange
Act.
(Check
one):








Indicate
by
check
mark
whether
the
registrant
is
a
shell
company
(as
defined
in
Rule
12b-2
of
the
Act).
Yes

o




No

ý








The
aggregate
market
value
of
the
registrant's
common
stock,
$0.0001
par
value
per
share
("Common
Stock"),
held
by
non-affiliates
of
the
registrant,
basedon
the
last
sale
price
of
the
Common
Stock
at
the
close
of
business
on
June
30,
2015
was
$2.1
billion.
For
the
purpose
of
the
foregoing
calculation
only,
alldirectors
and
executive
officers
of
the
registrant
are
assumed
to
be
affiliates
of
the
registrant.








Number
of
shares
outstanding
of
the
registrant's
common
stock,
par
value
$0.0001
per
share,
as
of
February
19,
2016:
43,014,243DOCUMENTS
INCORPORATED
BY
REFERENCE








Portions
of
the
registrant's
definitive
proxy
statement
for
its
2016
annual
meeting
of
stockholders
are
incorporated
by
reference
into
Part
III
of
this
Form
10-K.


Large
accelerated
filer

ý
Accelerated
filer

o
Non-accelerated
filer

o
(Do
not
check
if
a
smaller
reporting
company)
Smaller
reporting
company

oTable
of
ContentsRadius
Health,
Inc.
Annual
Report
on
Form
10-K
For
the
Fiscal
Year
Ended
December
31,
2015
INDEX

Special
Note
Regarding
Forward-Looking
Statements

1

Currency
and
Conversions

2
PART
I



ITEM
1:
Business

3
ITEM
1A:
Risk
Factors

35
ITEM
1B:
Unresolved
Staff
Comments

63
ITEM
2:
Properties

63
ITEM
3:
Legal
Proceedings

63
ITEM
4:
Mine
Safety
Disclosures

63
PART
II



ITEM
5:
Market
for
Registrant's
Common
Equity,
Related
Stockholder
Matters
and
Issuer
Purchases
of
EquitySecurities

64
ITEM
6:
Selected
Financial
Data

66
ITEM
7:
Management's
Discussion
and
Analysis
of
Financial
Condition
and
Results
of
Operations

68
ITEM
7A:
Quantitative
and
Qualitative
Disclosures
About
Market
Risk

88
ITEM
8:
Financial
Statements
and
Supplementary
Data

89
ITEM
9:
Changes
in
and
Disagreements
With
Accountants
on
Accounting
and
Financial
Disclosure

120
ITEM
9A:
Controls
and
Procedures

120
ITEM
9B:
Other
Information

122
PART
III



ITEM
10:
Directors,
Executive
Officers
and
Corporate
Governance

123
ITEM
11:
Executive
Compensation

127
ITEM
12:
Security
Ownership
of
Certain
Beneficial
Owners
and
Management
and
Related
Stockholder
Matters

128
ITEM
13:
Certain
Relationships
and
Related
Transactions,
and
Director
Independence

128
ITEM
14:
Principal
Accountant
Fees
and
Services

128
PART
IV



ITEM
15:
Exhibits
and
Financial
Statement
Schedules

129

Signatures

130
Table
of
ContentsSPECIAL
NOTE
REGARDING
FORWARD-LOOKING
STATEMENTS









This report, including in the sections titled "Risk Factors," "Management's Discussion and Analysis of Financial Condition and Results of Operations" and"Business," contains, in addition to historical information, forward-looking statements. We may, in some cases, use words such as "project," "believe,""anticipate," "plan," "expect," "estimate," "intend," "continue," "should," "would," "could," "potentially," "will," "may" or similar words and expressions thatconvey uncertainty of future events or outcomes to identify these forward-looking statements. Forward-looking statements in this Annual Report on Form 10-K mayinclude, among other things, statements about:•the progress of, timing of and amount of expenses associated with our research, development and commercialization activities; •the success of our clinical studies for our investigational product candidates; •our ability to obtain U.S. and foreign regulatory approval for our product candidates and the ability of our investigational product candidates tomeet existing or future regulatory standards; •our expectations regarding federal, state and foreign regulatory requirements; •the therapeutic benefits and effectiveness of our investigational product candidates; •the safety profile and related adverse events of our investigational product candidates; •the timing of and our ability to commercialize abaloparatide following regulatory approval; •our plans with respect to collaborations and licenses related to the development, manufacture or sale of our investigational product candidates; •our expectations as to future financial performance, expense levels and liquidity sources; •our ability to compete with other companies that are or may be developing or selling products that are competitive with our investigational productcandidates; •anticipated trends and challenges in our potential markets; •our ability to attract and motivate key personnel; and •other factors discussed elsewhere in this report.








The outcome of the events described in these forward-looking statements is subject to known and unknown risks, uncertainties and other important factorsthat could cause actual results to differ materially from the results anticipated by these forward-looking statements. These important factors include our financialperformance, our ability to attract and retain customers, our development activities and those other factors we discuss in Item 1A of this Annual Report onForm 10-K under the caption "Risk Factors." You should read these factors and the other cautionary statements made in this report as being applicable to allrelated forward-looking statements wherever they appear in this report. These risk factors are not exhaustive and other sections of this report may includeadditional factors which could adversely impact our business and financial performance.1Table
of
ContentsCURRENCY
AND
CONVERSIONS








In
this
report,
references
to
"dollar"
or
"$"
are
to
the
legal
currency
of
the
United
States,
and
references
to
"euro"
or
"€"
are
to
the
single
currency
introducedon
January
1,
1999
at
the
start
of
the
third
stage
of
European
Economic
and
Monetary
Union,
pursuant
to
the
Treaty
establishing
the
European
Communities,
asamended
by
the
Treaty
on
European
Union
and
the
Treaty
of
Amsterdam.
Unless
otherwise
indicated,
the
financial
information
in
this
report
has
been
expressed
inU.S.
dollars.
Unless
otherwise
stated,
the
U.S.
dollar
equivalent
information
translating
euros
into
U.S.
dollars
has
been
made,
for
convenience
purposes,
on
thebasis
of
the
noon
buying
rate
published
by
the
Board
of
Governors
of
the
Federal
Reserve
as
of
December
31,
2015,
which
was
€1.00
=
$1.0859.
Such
translationsshould
not
be
construed
as
a
representation
that
the
euro
has
been,
could
have
been
or
could
be
converted
into
U.S.
dollars
at
the
rate
indicated,
any
particular
rateor
at
all.







Trademarks
appearing
in
this
report
are
the
property
of
their
respective
holders.2Table
of
ContentsPART
I
ITEM
1.



BUSINESS.









Unless otherwise provided in this report, all references in this report to "we," "us," "our company," "our," or the "Company" refer to Radius Health, Inc.Overview







We
are
a
science-driven
biopharmaceutical
company
that
is
committed
to
developing
innovative
therapeutics
in
the
areas
of
osteoporosis,
oncology
andendocrine
diseases.
Our
lead
product
candidate,
the
investigational
drug
abaloparatide
for
subcutaneous
injection,
has
completed
Phase
3
development
for
potentialuse
in
the
reduction
of
fracture
risk
in
postmenopausal
women
with
osteoporosis
and
is
currently
under
regulatory
review
in
Europe.
Our
clinical
pipeline
alsoincludes
an
investigational
abaloparatide
transdermal
patch
for
potential
use
in
osteoporosis
and
the
investigational
drug
RAD1901
for
potential
use
in
hormone-driven,
or
hormone-resistant,
breast
cancer,
and
vasomotor
symptoms
in
postmenopausal
women.
Our
preclinical
pipeline
includes
RAD140,
a
non-steroidalselective
androgen
receptor
modulator,
or
SARM,
under
investigation
for
potential
applications
in
oncology
and
multiple
conditions
where
androgen
modulationmay
offer
therapeutic
benefit.Our
Investigational
Product
Candidates







The
following
table
identifies
the
investigational
product
candidates
in
our
current
product
portfolio,
their
proposed
indication
and
stage
of
development:*We
submitted
an
MAA
in
the
European
Union
for
abaloparatide-SC
in
November
2015,
which
was
validated
in
December
2015.Abaloparatide







Abaloparatide
is
an
investigational
therapy
for
the
potential
treatment
of
women
with
postmenopausal
osteoporosis
who
are
at
an
increased
risk
for
a
fracture.Abaloparatide
is
a
novel3Table
of
Contentssynthetic
peptide
analog
that
engages
the
parathyroid
hormone
receptor,
or
PTH1
receptor,
and
was
selected
for
clinical
development
based
on
its
favorable
bonebuilding
activity.
Abaloparatide
was
created
to
have
a
unique
mechanism
of
action
with
the
goal
of
stimulating
enhanced
bone
building
activity
including
boneformation,
increasing
bone
mineral
density,
restoring
bone
microarchitecture
and
augmenting
bone
strength.
We
are
developing
two
formulations
of
abaloparatide:•Abaloparatide-SC— Abaloparatide
has
completed
Phase
3
development
for
potential
use
as
a
daily
self-administered
injection,
which
we
refer
to
asabaloparatide-SC.
We
hold
worldwide
commercialization
rights
to
abaloparatide-SC,
except
for
Japan.
In
December
2014,
we
announced
thepositive
18-month
top-line
data
from
our
Phase
3
ACTIVE
clinical
trial,
in
which
abaloparatide-SC
met
the
primary
endpoint
with
a
statisticallysignificant
reduction
in
new
vertebral
fractures
versus
placebo,
and
in
June
2015,
we
announced
the
positive
top-line
data
from
the
first
six
monthsof
the
ACTIVExtend
clinical
trial
and
the
24-month
combined
data
from
ACTIVE
and
ACTIVExtend.
In
November
2015,
we
submitted
amarketing
authorization
application,
or
MAA,
to
the
European
Medicines
Agency,
or
EMA,
which
was
validated
and
is
currently
undergoingregulatory
review
by
the
EMA.
We
intend
to
enter
into
one
or
more
partnerships
or
collaborations
for
the
potential
commercialization
ofabaloparatide-SC
prior
to
a
commercial
launch.
We
plan
to
submit
a
new
drug
application,
or
NDA,
in
the
United
States,
at
the
end
of
the
firstquarter
of
2016.
Subject
to
regulatory
review
and
a
favorable
regulatory
outcome,
we
anticipate
the
first
commercial
sales
of
abaloparatide-SC
willtake
place
in
2016.
•Abaloparatide-TD— We
are
also
developing
abaloparatide-transdermal,
which
we
refer
to
as
abaloparatide-TD,
based
on
3M's
patentedMicrostructured
Transdermal
System
technology
for
potential
use
as
a
short
wear-time
transdermal
patch.
We
hold
worldwide
commercializationrights
to
the
abaloparatide-TD
technology.
During
2014,
we
reported
progress
towards
the
development
of
an
optimized
transdermal
patch
that
maybe
capable
of
demonstrating
comparability
to
abaloparatide-SC.
In
preliminary,
nonhuman
primate
pharmacokinetic
studies,
we
achieved
adesirable
pharmacokinetic
profile,
with
comparable
AUC,
Cmax,
Tmax
and
T1/2
relative
to
abaloparatide-SC.
We
believe
that
these
results
supportcontinued
clinical
development
of
abaloparatide-TD
toward
future
global
regulatory
submissions
as
a
potential
post-approval
line
extension
of
theinvestigational
drug
abaloparatide-SC.
We
commenced
a
human
replicative
clinical
evaluation
of
the
optimized
abaloparatide-TD
patch
inDecember
2015,
with
the
goal
of
achieving
comparability
to
abaloparatide-SC.
We
expect
to
complete
our
clinical
evaluation
of
the
optimizedabaloparatide-TD
patch
during
2016.RAD1901







RAD1901
is
a
selective
estrogen
receptor
down-regulator/degrader,
or
SERD,
that
at
high
doses
has
potential
for
use
as
an
oral
non-steroidal
treatment
forhormone-driven,
or
hormone-resistant,
breast
cancer.
RAD1901
is
currently
being
investigated
in
postmenopausal
women
with
advanced
estrogen
receptorpositive,
or
ER-positive,
HER2-negative
breast
cancer,
the
most
common
form
of
the
disease.
The
compound
has
the
potential
for
use
as
a
single
agent
or
incombination
with
other
therapies
to
overcome
endocrine
resistance
in
breast
cancer.







In
September
2015,
we
announced
results
from
a
Phase
1
maximum
tolerated
dose,
or
MTD,
study
of
RAD1901
in
52
healthy
volunteers.
In
the
study,RAD1901
was
administered
to
healthy
postmenopausal
women
in
doses
ranging
from
200mg
to
1000mg,
and
the
data
showed
that
RAD1901
was
well-toleratedand
the
overall
safety
was
supportive
of
continued
development.
In
addition,
a
subset
of
subjects
that
received
18F
estradiol
positron
emission
tomography,
or
FES-PET,
imaging
demonstrated
suppression
of
the
FES-PET
signal
to
background
levels
after
six
days
of
dosing.







In
December
2014,
we
commenced
a
Phase
1,
multicenter,
open-label,
two-part,
dose-escalation
study
of
RAD1901
in
postmenopausal
women
with
advancedER-positive
and
HER2-negative
breast4Table
of
Contentscancer
in
the
United
States
to
determine
the
recommended
dose
for
a
Phase
2
clinical
trial
and
to
make
a
preliminary
evaluation
of
the
potential
anti-tumor
effect
ofRAD1901.
We
expect
to
complete
this
study
by
the
middle
of
2016.
Dose
escalation
is
currently
ongoing
with
no
dose
limiting
toxicities
to
date
and
we
expect
toinitiate
expansion
cohorts
in
2016.







In
December
2015,
we
commenced
a
Phase
1
FES-PET
study
in
patients
with
metastatic
breast
cancer
in
the
European
Union
which
includes
the
use
of
FES-PET
imaging
to
assess
estrogen
receptor
occupancy
in
tumor
lesions
following
RAD1901
treatment.







In
July
2015,
we
announced
that
early
but
promising
preclinical
data
showed
that
our
investigational
drug
RAD1901,
in
combination
with
Pfizer's
palbociclib,a
cyclin-dependent
kinase,
or
CDK,
4/6
inhibitor,
or
Novartis'
everolimus,
an
mTOR
inhibitor,
was
effective
in
shrinking
tumors.
In
patient-derived
xenograft,
orPDx,
breast
cancer
models
with
either
wild
type
or
mutant
ESR1,
treatment
with
RAD1901
resulted
in
marked
tumor
growth
inhibition,
and
the
combination
ofRAD1901
with
either
agent,
palbociclib
or
everolimus,
showed
anti-tumor
activity
that
was
significantly
greater
than
either
agent
alone.
We
believe
that
thispreclinical
data
suggests
that
RAD1901
has
the
potential
to
overcome
endocrine
resistance,
is
well-tolerated,
and
has
a
profile
that
is
well
suited
for
use
incombination
therapy.







In
January
2016
we
entered
into
a
worldwide
clinical
collaboration
with
Novartis
Pharmaceuticals
to
evaluate
the
safety
and
efficacy
of
combining
RAD1901,with
Novartis'
investigational
agent
LEE011
(ribociclib),
a
CDK
4/6
inhibitor,
and
BYL719
(alpelisib),
an
investigational
phosphoinositide
3-kinase
inhibitor.







RAD1901
is
also
being
evaluated
at
low
doses
as
an
estrogen
receptor
ligand
for
the
potential
relief
of
the
frequency
and
severity
of
moderate
to
severe
hotflashes
in
postmenopausal
women
with
vasomotor
symptoms.
We
commenced
a
Phase
2b
clinical
study
of
RAD1901
for
the
potential
treatment
of
postmenopausalvasomotor
symptoms
in
December
2015.Our
Strategy







Our
goal
is
to
become
a
leading
provider
of
therapeutics
for
osteoporosis,
cancer
and
other
serious
endocrine
diseases.
To
achieve
this
goal
we
plan
to:•Obtain
regulatory
approval
of
abaloparatide-SC
and
establish
sales
and
marketing
capabilities
to
commercialize
abaloparatide-SC
in
theUnited
States.


We
completed
a
Phase
3
clinical
trial
and
the
first
six
months
of
an
extension
trial
of
abaloparatide-SC
for
the
potential
use
in
thereduction
of
fractures
in
postmenopausal
osteoporosis.
We
submitted
an
MAA
in
the
European
Union
for
abaloparatide-SC
in
November
2015,which
was
validated
in
December
2015,
and
plan
to
submit
an
NDA
for
abaloparatide-SC
in
the
United
States
at
the
end
of
the
first
quarter
of
2016.
•Selectively
pursue
partnerships
or
collaborations
to
develop
and/or
commercialize
our
product
candidates.


We
intend
to
enter
into
one
ormore
partnerships
or
collaborations
for
the
development
or
commercialization
of
our
product
candidates.
We
intend
to
establish
one
or
morepartnerships
or
collaborations
for
the
potential
commercialization
of
abaloparatide-SC
prior
to
a
commercial
launch.
•Extend
the
lifecycle
of
abaloparatide
through
the
continued
development
of
abaloparatide-TD
and
additional
clinical
research.


We
aredeveloping
abaloparatide-TD
as
a
short-wear-time
transdermal
patch
and
we
anticipate,
pending
successful
development
and
a
favorable
regulatoryoutcome,
commercial
launch
two
to
three
years
after
the
approval
and
first
commercial
sale
of
abaloparatide-SC.
We
initiated
the
clinical
evaluationof
the
optimized
abaloparatide-TD
patch
in
December
2015,
with
the
goal
of
achieving
pharmacokinetic
equivalence
to
abaloparatide-SC.
Weexpect
to
complete
our
clinical
evaluation
of
the
optimized
abaloparatide-TD
patch
during5Table
of
Contents2016.
We
believe
abaloparatide-TD
may
be
submitted
for
regulatory
approval
based
upon
a
demonstration
of
bioequivalence
to
abaloparatide-SC.Upon
completion
of
clinical
evaluation
of
the
optimized
abaloparatide-TD
patch,
we
will
meet
with
regulatory
agencies
to
discuss
the
regulatorypath
for
the
abaloparatide-TD
program.
If
our
clinical
trials
of
abaloparatide-SC
and
abaloparatide-TD
are
successful,
we
expect
to
seek
marketingapproval
of
abaloparatide-TD
as
a
line
extension
of
abaloparatide-SC.We
are
continuing
to
evaluate
other
underserved
osteoporosis
patient
populations
that
might
benefit
from
abaloparatide
therapy.
We
may
engage
inadditional
clinical
research
to
achieve
additional
labeling
to
treat
these
populations.•Advance
the
development
of
RAD1901
for
the
treatment
of
breast
cancer
and
vasomotor
symptoms.


During
2015,
we
completed
a
Phase
1MTD
study
of
RAD1901
in
healthy
volunteers,
and
commenced
Phase
1
studies
in
patients
with
metastatic
breast
cancer
in
the
United
States
andthe
European
Union.
Preliminary
results
show
that
RAD1901
has
a
favorable
safety
and
tolerability
profile
and
potential
anti-tumor
effect.
Weexpect
to
initiate
expansion
cohorts
in
2016.
In
addition,
we
commenced
a
Phase
2b
study
of
RAD1901
for
the
treatment
of
vasomotor
symptoms
inDecember
2015.
•Continue
to
expand
our
product
portfolio.


We
plan
to
leverage
our
drug
development
expertise
to
discover
and
develop
additionalinvestigational
product
candidates
focused
on
serious
endocrine-related
diseases
and
conditions.
We
may
also
consider
opportunistically
expandingour
product
portfolio
through
in-licensing,
acquisitions
or
partnerships.Our
OpportunityOsteoporosis







Osteoporosis
is
a
disease
characterized
by
low
bone
mass
and
structural
deterioration
of
bone
tissue,
which
leads
to
greater
fragility
and
an
increase
in
fracturerisk.
All
bones
become
more
fragile
and
susceptible
to
fracture
as
the
disease
progresses.
People
tend
to
be
unaware
that
their
bones
are
getting
weaker,
and
aperson
with
osteoporosis
can
fracture
a
bone
from
even
a
minor
fall.
The
debilitating
effects
of
osteoporosis
have
substantial
costs.
Loss
of
mobility,
admission
tonursing
homes
and
dependence
on
caregivers
are
all
common
consequences
of
osteoporosis.
The
prevalence
of
osteoporosis
is
growing
and,
according
to
theNational
Osteoporosis
Foundation,
or
NOF,
is
significantly
under-recognized
and
under-treated
in
the
population.
While
the
aging
of
the
population
is
a
primarydriver
of
an
increase
in
cases,
osteoporosis
is
also
increasing
from
the
use
of
drugs
that
induce
bone
loss,
such
as
chronic
use
of
glucocorticoids
and
aromataseinhibitors
that
are
increasingly
used
for
breast
cancer
and
hormone
therapies
used
for
prostate
cancer.







The
NOF
has
estimated
that
10
million
people
in
the
United
States,
composed
of
eight
million
women
and
two
million
men,
already
have
osteoporosis,
andanother
approximately
44
million
have
low
bone
mass
placing
them
at
increased
risk
for
osteoporosis.
In
addition,
the
NOF
has
estimated
that
osteoporosis
isresponsible
for
more
than
two
million
fractures
in
the
United
States
each
year
resulting
in
an
estimated
$19
billion
in
costs
annually.
The
NOF
expects
that
thenumber
of
fractures
in
the
United
States
due
to
osteoporosis
will
rise
to
three
million
by
2025,
resulting
in
an
estimated
$25.3
billion
in
costs
each
year.
Worldwide,osteoporosis
affects
an
estimated
200
million
women
according
to
the
International
Osteoporosis
Foundation,
or
IOF,
and
causes
more
than
8.9
million
fracturesannually,
which
is
equivalent
to
an
osteoporotic
fracture
occurring
approximately
every
three
seconds.
The
IOF
has
estimated
that
1.6
million
hip
fractures
occurworldwide
each
year,
and
by
2050
this
number
could
reach
between
4.5
million
and
6.3
million.
The
IOF
estimates
that
in
Europe
alone,
the
annual
cost
ofosteoporotic
fractures
could
surpass
€76
billion
by
2050.6Table
of
Contents







In
2015,
total
sales
of
branded
osteoporosis
drugs
approximated
$6.4
billion,
worldwide,
of
which
more
than
$3.0
billion
was
attributable
to
injectabletherapies
(Source:
EvaluatePharma,
February
2016,
Evaluate
Ltd,
www.evaluate.com).
There
are
two
main
types
of
osteoporosis
drugs
currently
available
in
theUnited
States,
anti-resorptive
agents
and
anabolic
agents.
Anti-resorptive
agents
act
to
prevent
further
bone
loss
by
inhibiting
the
breakdown
of
bone,
whereasanabolic
agents
stimulate
bone
formation
to
build
new
bone.
We
believe
there
is
a
large
unmet
need
in
the
market
for
osteoporosis
treatment
because
existingtherapies
have
been
reported
to
have
shortcomings
in
efficacy,
tolerability
and
convenience.
For
example,
one
current
standard
of
care,
bisphosphonates,
which
areanti-resorptive
agents,
has
been
associated
with
infrequent
but
serious
adverse
events,
such
as
osteonecrosis
of
the
jaw
and
atypical
fractures,
especially
of
longbones.
These
side
effects,
although
uncommon,
reportedly
have
created
increasing
concern
with
physicians
and
patients.
Many
physicians
are
seeking
alternativesto
bisphosphonates.
Lilly's
Forteo/Forsteo
and
Amgen's
Prolia
are
the
two
primary
alternatives
to
bisphosphonates
that
are
approved
for
the
treatment
ofosteoporosis.
In
2015,
Forteo/Forsteo
had
reported
worldwide
sales
of
approximately
$1.3
billion,
$0.6
billion
in
the
U.S.
and
$0.7
billion
outside
of
the
U.S.,
andProlia
had
reported
sales
of
approximately
$1.3
billion,
$0.8
billion
in
the
U.S.
and
$0.5
billion
outside
of
the
U.S.
Forteo,
a
34
amino
acid
recombinant
peptide
ofhuman
parathyroid
hormone,
is
the
only
anabolic
drug
approved
in
the
United
States
for
the
treatment
of
osteoporosis.







Today,
the
treatment
of
osteoporosis
has
no
clear
consensus
goals
for
BMD,
bone
turnover
biomarkers
or
fracture
risk.
Patients
suffering
from
osteoporosisare
generally
treated
with
a
bisphosphonate
first,
regardless
of
their
initial
BMD
or
fracture
risk
in
order
to
preserve
bone.
Those
patients
that
have
already
sufferedfrom
a
fracture,
lost
BMD,
or
cannot
tolerate
or
comply
with
bisphosphonate
therapies
may
progress
to
other
therapies
such
as
a
RANK-L
inhibitor
(denosumab)
oranabolic
therapy
(such
as
teriparatide).
Anabolic
bone
building
agents
have
been
reserved
primarily
for
patients
with
the
most
severe
BMD
loss
or
who
fail(i.e.
fracture)
on
prior
anti-resportives.
The
current
anti-resorptive
treatment
paradigm
means
that
the
majority
of
patients
only
maintain
their
bone
mass
withouthaving
a
sustained
benefit
in
terms
of
fracture
reduction.







We
believe
there
is
substantive
effort
underway
to
update
osteoporosis
treatment
guidelines
towards
goal
directed
therapy
that
could
improve
outcomes
forboth
patients
and
payers.
In
this
new
potential
goal
directed
paradigm,
patients
may
be
stratified
by
severity
of
BMD
and
fracture
risk
in
order
to
create
anindividualized
treatment
plan
based
on
achieving
a
target
goal
(either
BMD
or
improved
10
year
fracture
risk
reduction).
Patients
will
then
be
offered
therapies
thatreduce
the
near
term,
higher
risk
of
fracture
and
then
monitored
periodically
to
ensure
they
remain
at
goal
(i.e.
the
lowest
possible
achievable
fracture
risk
score).







We
believe
there
is
a
significant
opportunity
for
anabolic
agents
that
have
the
potential
to
provide
early,
extensive
and
durable
effects
on
both
BMD
andfracture
risk
compared
to
other
approve
therapies,
with
the
potential
added
advantages
of
convenience
and
safety.
With
the
addition
of
new
guidelines,
expandingresearch,
increased
diagnosis
effort,
higher
awareness
of
the
long
term
risk
associated
with
osteoporotic
fracture,
and
new,
more
effective
therapies
we
believeosteoporosis
treatment
will
expand
and
thus
our
potential
commercial
opportunity.Our Investigational Drug—Abaloparatide







Abaloparatide
is
a
novel
synthetic
peptide
analog
that
engages
the
PTH1
receptor
and
was
selected
for
clinical
development
based
on
its
favorable
bonebuilding
activity.
Parathyroid
hormone,
or
PTH,
analogs
(like
Forteo
(teriparatide)
and
parathyroid
hormone-related
protein,
or
PTHrP)
represent
a
family
ofproteins
and
peptides
that
share
regions
of
partial
or
complete
amino
acid
sequence
similarity.
The
first
34
amino
acids
of
PTH
analogs
contain
the
binding
site
forengaging
the
PTH1
receptor.
Abaloparatide
is
a
unique
34
amino
acid
PTH
analog
that
has
41%
homology
(i.e.
amino
acid
similarity)
to
Forteo
(teriparatide)
andhas
76%
homology
to
the
first
34
amino
acids7Table
of
Contentsof
PTHrP.
Abaloparatide
is
manufactured
using
organic
chemistry
techniques
to
create
the
34
amino
acid
peptide.







Abaloparatide
was
created
to
have
a
unique
mechanism
of
action
with
the
goal
of
stimulating
enhanced
bone
building
activity
including
bone
formation,increasing
bone
mineral
density,
restoring
bone
microarchitecture
and
augmenting
bone
strength.
We
believe
that
abaloparatide
is
the
most
advanced
PTH
analogin
clinical
development
for
the
treatment
of
osteoporosis
and
that,
subject
to
regulatory
review
and
approval,
it
could
have
the
potential
to
provide
the
followingadvantages
over
other
current
standard
of
care
treatments
for
osteoporosis:•improved
efficacy—greater
bone
build
at
hip
and
spine
with
lower
vertebral
and
non-vertebral
fracture
risk;
•earlier
onset
of
building
bone;
•shorter
treatment
duration;
•no
refrigeration
of
multi-dose
injection
pen;
and
•less
hypercalcemia.







We
acquired
and
maintain
exclusive
worldwide
rights,
excluding
development
and
commercialization
rights
for
Japan,
to
certain
patents,
data
and
technicalinformation
related
to
abaloparatide
through
a
license
agreement
with
an
affiliate
of
Ipsen
Pharma
SAS,
or
Ipsen.







We
are
developing
two
formulations
of
abaloparatide:
abaloparatide-SC,
an
injectable
subcutaneous
formulation
of
abaloparatide,
and
abaloparatide-TD,
aline
extension
of
abaloparatide-SC
in
the
form
of
a
convenient,
short-wear-time,
transdermal
patch.







We
believe
that
the
results
from
our
Phase
3
ACTIVE
clinical
trial
and
the
first
six
months
of
our
ACTIVExtend
clinical
trial,
have
demonstrated
theimproved
efficacy
of
abaloparatide
relative
to
teriparatide
(Forteo/Forsteo)
in
treating
osteoporosis,
while
still
maintaining
a
well-tolerated
long-term
safety
profile.In
November
2015,
we
submitted
an
MAA
in
Europe,
which
was
validated
in
December
2015,
and
are
on
track
to
submit
an
NDA
in
the
United
States,
at
the
endof
the
first
quarter
of
2016.







During
2014,
we
reported
progress
towards
the
development
of
an
optimized,
short-wear-time
transdermal
patch
that
may
be
capable
of
demonstratingcomparability
to
abaloparatide-SC
injection.
In
preliminary,
nonhuman
primate
pharmacokinetic
studies,
we
observed
a
favorable
pharmacokinetic
profile,
withcomparable
AUC,
Cmax,
Tmax
and
T1/2
relative
to
abaloparatide-SC.
We
believe
that
these
results
support
continued
clinical
development
of
abaloparatide-TDtoward
future
global
regulatory
submissions
as
a
potential
post-approval
line
extension
of
the
investigational
drug
abaloparatide-SC.
We
commenced
the
clinicalevaluation
of
the
optimized
abaloparatide-TD
patch
at
the
end
of
2015,
with
the
goal
of
achieving
comparability
to
abaloparatide-SC.
If
our
clinical
trials
ofabaloparatide-SC
and
abaloparatide-TD
are
successful,
we
expect
to
seek
marketing
approval
of
abaloparatide-TD
as
a
line
extension
of
abaloparatide-SC.
Webelieve
abaloparatide-TD
may
be
submitted
for
regulatory
approval
based
upon
a
demonstration
of
bioequivalence
to
abaloparatide-SC.
Upon
completion
ofclinical
evaluation
of
the
optimized
abaloparatide-TD
patch,
we
will
meet
with
regulatory
agencies
to
discuss
the
regulatory
path
for
the
abaloparatide-TD
program.The
FDA's
approval
of
abaloparatide-TD,
and
the
timing
of
any
such
approval,
is
dependent
upon
the
approval
of
abaloparatide-SC.Abaloparatide-SC Phase 3 Clinical Trial







In
2014,
we
completed
a
multicenter,
multinational,
double-blind,
placebo-controlled
Phase
3
clinical
trial
of
abaloparatide-SC,
or
the
ACTIVE
trial,
in
which2,463
postmenopausal
women
aged
498Table
of
Contentsto
86
received
daily
doses
of
one
of
the
following:
80
µg
of
abaloparatide,
a
matching
placebo,
or
the
approved
dose
of
20
µg
of
Forteo
for
18
months.







On
February
15,
2012,
we
received
a
letter
from
the
FDA
stating
that,
after
internal
consideration,
it
believes
that
a
minimum
of
24-month
fracture
data
arenecessary
for
approval
of
new
products
for
the
treatment
of
postmenopausal
osteoporosis.
We
subsequently
met
with
the
FDA
on
March
21,
2012
to
discusssatisfying
the
24-month
data
request
while
preserving
the
current
18-month
primary
endpoint.
Based
upon
our
discussion
with
the
FDA,
we
believe
that
the
18-month
primary
endpoint
will
be
acceptable,
provided
that
our
NDA
includes
the
24-month
fracture
data
derived
from
a
6-month
extension
of
the
abaloparatide
80µg
and
placebo
groups
in
our
Phase
3
study
during
which
patients
received
an
approved
alendronate
(generic
Fosamax)
therapy
for
osteoporosis
management.Accordingly,
patients
from
the
abaloparatide-SC
and
placebo
groups
from
our
ACTIVE
trial
were
eligible
to
continue
in
an
extension
study,
or
the
ACTIVExtendtrial,
in
which
they
received
70
mg
once
weekly
of
an
approved
alendronate
therapy
for
osteoporosis
management.
We
intend
to
submit
the
NDA
with
the
24-month
fracture
data
at
the
end
of
the
first
quarter
of
2016.







The
ACTIVE
trial
was
designed
to
evaluate
as
the
primary
endpoint
whether
abaloparatide-SC
is
superior
to
placebo
for
prevention
of
vertebral
fracture.
Thetop-line
results
of
the
18-month
ACTIVE
trial
showed
that
abaloparatide-SC
met
the
primary
endpoint
with
a
statistically
significant
86%
reduction
in
newvertebral
fractures
versus
placebo,
and
Forteo
met
the
same
endpoint
with
a
statistically
significant
80%
reduction.
On
the
secondary
endpoints,
as
compared
toplacebo,
abaloparatide
achieved
a
statistically
significant
reduction
of
43%
in
non-vertebral
fracture;
a
statistically
significant
reduction
of
43%
in
the
clinicalfracture;
and
a
significant
difference
in
the
time
to
first
incident
of
non-vertebral
fracture
and
clinical
fracture.







An
exploratory
analysis
of
the
ACTIVE
trial
showed
that,
for
major
osteoporotic
fractures,
there
was
a
statistically
significant
70%
reduction
in
majorosteoporotic
fractures
for
the
abaloparatide
treatment
group
versus
placebo,
and
a
statistically
significant
55%
reduction
in
major
osteoporotic
fractures
for
theabaloparatide-SC
treatment
group
as
compared
to
Forteo
over
the
18-month
period.







The
results
from
the
first
six
months
of
the
ACTIVExtend
study
showed
that
the
group
previously
treated
with
abaloparatide-SC
had
no
new
vertebralfractures
during
the
first
six
months
of
receiving
alendronate.
From
the
start
of
the
ACTIVE
trial,
this
group
showed
a
statistically
significant
87%
reduction
in
newvertebral
fractures,
a
52%
reduction
in
non-vertebral
fractures,
a
45%
reduction
in
clinical
fractures
and
a
58%
reduction
in
major
osteoporotic
fractures
over
the24-month
period,
as
compared
to
placebo.Abaloparatide-SC Phase 2 Clinical Trial







In
2009,
we
completed
a
randomized,
placebo-controlled,
parallel
group
dose-finding
Phase
2
study
in
the
United
States,
Argentina,
India
and
the
UnitedKingdom.
Data
from
our
Phase
2
study
showed
abaloparatide
produced
faster
and
greater
BMD
increases
at
the
spine
and
the
hip
after
six
months
and
12
months
oftreatment
than
did
Forteo,
which
was
a
comparator
in
our
study.
Key
findings
were
that
the
highest
dose
of
abaloparatide
tested
of
80
µg
increased
mean
lumbarspine
BMD
at
six
months
and
12
months
by
6.7%
and
12.9%
compared
to
the
increases
seen
with
Forteo
trial
arms
of
5.5%
and
8.6%,
respectively.
Abaloparatidealso
produced
increases
in
mean
femoral
neck
BMD
at
the
hip
at
six
months
and
12
months
of
3.1%
and
4.1%
compared
to
increases
for
Forteo
of
1.1%
and
2.2%,respectively.
Abaloparatide
was
generally
safe
and
well
tolerated
in
this
study,
with
adverse
events
similar
between
abaloparatide,
placebo
and
Forteo
groups.
Inaddition,
the
occurrence
of
hypercalcemia
as
a
side
effect
for
the
80
µg
dose
of
abaloparatide
was
half
that
seen
with
Forteo.Abaloparatide-SC Phase 1 Clinical Trials







We
have
completed
seven
Phase
1
clinical
trials
of
abaloparatide-SC.
Together
with
our
Phase
2
and
Phase
3
clinical
trials,
over
1,500
patients
have
receivedany
dose/route
of
abaloparatide.
The
results
of
our
Phase
1
clinical
trials
suggest
that
abaloparatide-SC
is
safe
and
well
tolerated
at
doses
of
up
to
240
m
gadministered
once
daily.9Table
of
ContentsAbaloparatide-TD Phase 2 Clinical Trial







In
2013,
we
completed
a
randomized,
double-blind,
placebo-controlled,
Phase
2
clinical
trial
of
abaloparatide
administered
via
a
coated
transdermalmicroarray
delivery
system
in
healthy
postmenopausal
women
with
osteoporosis.
This
study
was
conducted
in
nine
centers
in
the
United
States,
Denmark,
Polandand
Estonia.
The
primary
objective
of
this
study
was
to
determine
the
clinical
safety
and
efficacy
of
abaloparatide-TD
as
assessed
by
changes
in
BMD
whencompared
to
a
transdermal
placebo
and
abaloparatide-SC.
The
results
showed
that
for
each
abaloparatide-TD
dose
there
was
a
statistically
significant
mean
percentincrease
from
baseline
in
BMD
at
the
lumbar
spine,
as
compared
to
placebo.
For
the
100
µg
and
150
µg
abaloparatide-TD
doses,
there
was
also
a
statisticallysignificant
mean
percent
increase
from
baseline
in
BMD
at
the
hip,
as
compared
to
placebo.
The
highest
abaloparatide-TD
dose
of
150
µ
g
produced
increases
inBMD
from
baseline
in
the
lumbar
spine
and
total
hip
of
+2.9%
and
+1.5%,
respectively,
compared
to
changes
in
the
placebo
group
of
+0.04%
and
–0.02%,respectively.
In
addition,
there
was
a
consistent
dose
effect
seen
with
increasing
doses
of
abaloparatide-TD,
with
a
statistically
significant
dosing
trend
seen
forchanges
in
both
spine
and
total
hip
BMD.
Further,
the
overall
tolerability
and
safety
profile
was
acceptable;
there
were
no
clinically
significant
signs
of
anti-abaloparatide
antibodies;
and
patient
ratings
of
patch
adhesion
and
local
skin
response
to
the
transdermal
patch
technology
were
also
acceptable.Abaloparatide-TD Phase 1 Clinical Trials







We
have
completed
three
Phase
1
clinical
trials
that
collectively
evaluated
the
safety,
PK,
time
course
of
delivery
and
dose
ranging
of
abaloparatide-TD.Abaloparatide-TD
was
characterized
by
a
rapid
release
of
abaloparatide
with
a
faster
time
to
reach
peak
concentration
as
well
as
more
rapid
elimination
in
plasmacompared
to
abaloparatide-SC.
Peak
transdermal
drug
levels
were
consistent
with
abaloparatide-SC.
An
optimal
wear
time
of
five
minutes
or
less
was
identified
aswell
as
effective
sites
of
application.
Abaloparatide-TD
showed
an
increase
in
the
bone-formation
marker
P1NP
in
serum
after
seven
days
of
exposure,
consistentwith
bone-building
activity,
and
was
shown
to
be
safe
and
well
tolerated
in
all
doses
studied.Preclinical Pharmacology of Abaloparatide







We
have
completed
several
preclinical
studies
of
abaloparatide,
and
we
observed
the
following:•abaloparatide
was
a
potent
selective
agonist
of
the
human
PTH
type
1
receptor
(PTHR1),
with
binding
selectivity
for
the
RG
vs
R0
receptorconformation
compared
to
PTH(1-34)
and
greater
selectivity
than
PTHrP(1-34);
•in
models
of
calcium
mobilization,
abaloparatide
has
significantly
less
calcium
mobilizing
activity
at
higher
doses
than
PTHrP(1-34),
and
lessactivity
than
PTH(1-34);
•abaloparatide-SC
stimulated
the
formation
of
normal,
well-organized
bone
and
restored
BMD
in
ovariectomized,
or
OVX,
osteopenic
rats
andprimates;
mechanical
testing
of
bones
from
OVX
rats
after
treatment
with
abaloparatide-SC
revealed
a
significant
increase
in
femur
and
vertebralbone
strength;
similar
studies
in
rats
with
abaloparatide-TD
showed
comparable
restoration
of
bone;
•abaloparatide-SC
was
generally
well
tolerated
over
a
wide
range
of
doses
in
two
species,
rats
and
primates,
for
up
to
six
months
and
nine
months,respectively;
and
•safety
pharmacology
studies
showed
no
respiratory,
gastroenterologic,
hematologic,
renal
or
central
nervous
system
effects.







A
two-year
subcutaneous
injection
carcinogenicity
study
of
abaloparatide
in
Fischer
344
albino
rats
was
conducted
to
assess
the
carcinogenic
potential
ofabaloparatide.
The
study
was
conducted
according10Table
of
Contentsto
the
provisions
set
forth
in
Guidance
ICH-S1A,
ICH-S1B
and
ICH-S1C(R2),
and
the
design
was
accepted
under
a
Special
Protocol
Assessment
by
the
FDA
onJuly
15,
2009.
This
study
evaluated
three
abaloparatide
dose
levels.
The
doses
were
selected
based
upon
findings
and
tolerance
in
completed
long-term
rattoxicology
studies
and
the
anticipated
tolerance
over
a
two-year
dosing
period.
Furthermore,
the
doses
represent
an
exposure
multiple
over
maximum
clinicaldoses.
The
study
included
a
cohort
of
rats
being
dosed
with
a
daily
subcutaneous
injection
of
PTH(1-34)
as
a
positive
control,
as
it
was
anticipated
thatosteosarcomas
would
be
observed
with
this
treatment,
as
previously
published
for
both
rhPTH(1-34)
and
rhPTH(1-84)
in
similar
two-year
rat
carcinogenicitystudies.
The
positive
control
served
to
provide
confirmation
of
the
sensitivity
of
the
model.
The
results
of
the
study
revealed
osteosarcomas
in
our
carcinogenicitystudy
in
both
the
abaloparatide
and
PTH(1-34)
treated
groups,
with
similar
frequency
between
abaloparatide
and
PTH(1-34)
when
comparing
comparable
exposuremultiples
to
the
human
therapeutic
dose.







We
have
also
conducted
one
preclinical
bone
quality
study
in
OVX
rats
with
12
months
of
daily
abaloparatide-SC
dosing
and
a
second
preclinical
bone
qualitystudy
in
adult
OVX
monkeys
for
16
months.
The
primary
objective
of
these
studies
was
to
determine
the
long-term
treatment
effects
of
abaloparatide-SC
on
bonequality.
Effects
on
bone
mass,
both
cortical
bone
and
cancellous
bone,
were
assessed
by
BMD
and
peripheral
quantitative
CT,
and
bone
strength
was
determined
bybiomechanical
testing.
The
mechanisms
by
which
abaloparatide
affects
bone
were
assessed
by
evaluation
of
biomarkers
of
bone
turnover
and
histomorphometricindices
of
bone
turnover.
Data
from
the
12-month
rat
study
showed
marked,
dose
dependent
increases
in
BMD
following
abaloparatide
treatment,
increases
in
boneformation
markers,
but
not
bone
resorption,
and
an
increase
in
bone
strength.







Results
from
the
16-month
monkey
OVX
study
have
also
shown
significant
BMD
gains,
together
with
increases
in
bone
strength.Breast Cancer







According
to
the
World
Health
Organization,
breast
cancer
is
the
second
most
common
cancer
in
the
world
and
the
most
prevalent
cancer
in
women,accounting
for
16%
of
all
female
cancers.
The
major
cause
of
death
from
breast
cancer
is
metastases,
most
commonly
to
the
bone,
liver,
lung
and
brain.Approximately
30%
of
early-stage
patients
develop
metastatic
disease,
and
of
those
patients
90%
relapse
between
therapy
levels.
About
5%
of
patients
have
distantmetastases
at
the
time
of
diagnoses,
and
these
patients
have
a
five-year
survival
rate
of
only
25%,
compared
with
a
greater
than
99%
survival
rate
for
patients
withonly
local
disease.
Importantly,
even
patients
without
metastases
at
diagnosis
are
at
risk
for
developing
metastases
over
time.







Approximately
70%
of
breast
cancers
express
the
ER
and
depend
on
estrogen
signaling
for
growth
and
survival.
Patients
with
ER-positive
breast
cancers
aretypically
treated
with
endocrine
therapies.
There
are
three
main
classes
of
therapies
for
ER-positive
tumors
available:
aromatase
inhibitors,
or
AIs;
selectiveestrogen
receptor
modulators,
or
SERMs;
and
selective
estrogen
receptor
degraders,
or
SERDs.
AIs,
which
block
the
generation
of
estrogen,
and
SERMs,
whichselectively
inhibit
an
ER's
ability
to
bind
estrogen,
both
block
ER-dependent
signaling
but
leave
functional
ERs
present
on
breast
cancer
cells.
For
this
reason,although
AIs
and
SERMs
are
effective
treatments
for
some
breast
cancers,
some
patients
often
acquire
resistance
to
them
by
developing
the
ability
to
signalthrough
the
ER
in
a
ligand-independent
manner.
In
contrast,
SERDs
are
a
class
of
endocrine
therapies
that
directly
induce
ER
degradation.
Therefore,
SERDsshould
have
the
potential
to
treat
ER-dependent
tumors
without
allowing
ligand-independent
resistance
to
develop,
and
to
act
on
AI-
and
SERM-resistant
ER-positive
tumors.







Currently
only
one
SERD,
fulvestrant,
is
approved
for
the
treatment
of
ER-positive
metastatic
breast
cancer.
We
believe
a
significant
opportunity
exists
fornew
oral
therapies
that
do
not
allow
ligand-independent
resistance
to
develop
and
can
more
effectively
treat
ER-positive
breast
cancer.11Table
of
ContentsOur Investigational Drug—RAD1901







RAD1901
is
a
SERD
that
at
high
doses
has
potential
for
use
as
an
oral
non-steroidal
treatment
for
hormone-driven,
or
hormone-resistant,
breast
cancer.RAD1901
is
currently
being
investigated
in
postmenopausal
women
with
advanced
ER-positive,
HER2-negative
breast
cancer,
the
most
common
form
of
thedisease.
The
compound
has
the
potential
for
use
as
a
single
agent
or
in
combination
with
other
therapies
to
overcome
endocrine
resistance
in
breast
cancer.RAD1901
selectively
binds
to
and
degrades
the
estrogen
receptor.
In
preclinical
models
of
ER-positive
breast
cancer,
RAD1901
has
shown
potent
anti-tumoractivity
and
complete
degradation
of
the
ER
and
progesterone
receptor,
an
ER-regulated
gene.
RAD1901
has
shown
good
tissue
selectivity
in
preclinical
modelsand
does
not
appear
to
stimulate
the
uterine
endometrium
while
it
appears
to
protect
against
bone
loss
in
an
ovariectomy-induced
osteopenia
rat
model.
WhenRAD1901
was
used
in
combination
with
other
approved
breast
cancer
agents
such
as
everolimus,
an
mTOR
inhibitor,
or
the
inhibitor
palobciclib,
a
CDK
4/6inhibitor,
greater
tumor
shrinkage
in
PDx
animal
models
was
achieved
than
with
the
agents
alone.
In
addition,
RAD1901
has
been
shown
to
effectively
inhibittumor
growth
in
PDx
models
that
harbor
mutations
in
the
ER,
a
potential
mechanism
of
endocrine
therapy
resistance.
In
a
healthy
volunteer
study,
FES-PETimaging
was
used
to
assess
how
much
RAD1901
has
engaged
in
the
ER,
RAD1901
showed
suppression
of
the
FES-PET
signal
to
background
levels
after
six
daysof
dosing.







Studies
with
RAD1901
have
established
the
PK
profile,
including
demonstration
of
good
oral
bioavailability.
We
believe
that,
subject
to
successfuldevelopment,
regulatory
review
and
approval,
RAD1901
could
have
the
potential
to
offer
the
following
advantages
over
other
current
standard
of
care
treatmentsfor
ER-positive
breast
cancer:•ability
to
suppress
estrogen
receptor
turnover;
•favorable
tolerability
profile;
•oral
administration;
and
•treatment
of
hormone-resistant
breast
cancers.







We
exclusively
licensed
the
worldwide
rights
to
RAD1901
from
Eisai
Co.
Ltd.,
or
Eisai.Phase 1 Studies—Breast Cancer







In
September
2015,
we
announced
results
from
a
Phase
1
maximum
tolerated
dose,
or
MTD,
study
of
RAD1901
in
52
healthy
volunteers.
In
the
study,RAD1901
was
administered
to
healthy
postmenopausal
women
in
doses
ranging
from
200mg
to
1000mg,
and
the
data
showed
that
RAD1901
was
well-toleratedand
the
overall
safety
was
supportive
of
continued
development.
In
addition,
a
subset
of
subjects
that
received
18F
estradiol
positron
emission
tomography,
or
FES-PET,
imaging
demonstrated
suppression
of
the
FES-PET
signal
to
background
levels
after
six
days
of
dosing.







In
December
2014,
we
commenced
a
Phase
1,
multicenter,
open-label,
two-part,
dose-escalation
study
of
RAD1901
in
postmenopausal
women
with
advancedER-positive
and
HER2-negative
breast
cancer
in
the
United
States
to
determine
the
recommended
dose
for
Phase
2
studies
and
to
make
a
preliminary
evaluation
ofthe
potential
anti-tumor
effect
of
RAD1901.
We
expect
to
complete
this
study
by
the
middle
of
2016.
Dose
escalation
is
currently
ongoing
with
no
dose
limitingtoxicities
to
date,
and
we
expect
to
initiate
expansion
cohorts
in
2016.







In
December
2015,
we
commenced
a
Phase
1
FES-PET
study
in
patients
with
metastatic
breast
cancer
in
the
European
Union
which
includes
the
use
of
FES-PET
imaging
to
assess
estrogen
receptor
occupancy
in
tumor
lesions
following
RAD1901
treatment.







In
January
2016
we
entered
into
a
worldwide
clinical
collaboration
with
Novartis
Pharmaceuticals
to
evaluate
the
safety
and
efficacy
of
combining
RAD1901,with
investigational
agent
LEE01112Table
of
Contents(ribociclib),
a
CDK
4/6
inhibitor
and
BYL719
(alpelisib),
an
investigational
phosphoinositide
3-kinase
inhibitor.Preclinical Pharmacology of RAD1901







RAD1901
has
been
shown
to
bind
with
good
selectivity
to
the
ER
alpha,
or
ER
a
,
and
to
have
both
estrogen-like
and
estrogen
antagonist
effects
in
differenttissues.
RAD1901
has
also
been
shown
to
have
estrogen-like
behavioral
effects
in
an
animal
model
of
partner
preference
and
to
reduce
vasomotor
signs
in
ananimal
model
of
menopausal
hot
flashes.
In
bone,
RAD1901
protected
against
gonadectomy-induced
bone
loss.
RAD1901
does
not
stimulate
the
endometrium,
asshown
in
short-
and
long-term
animal
models,
where
changes
in
uterine
weight,
uterine
epithelial
thickness,
and
C3
gene
expression
are
measured,
all
of
which
aresensitive
indicators.
In
studies
in
which
an
estrogen
is
used
to
stimulate
the
endometrium,
RAD1901
antagonizes
this
estrogen-mediated
stimulation
of
theendometrium.
In
cell
culture,
RAD1901
does
not
stimulate
replication
of
breast
cancer
cells,
and
antagonizes
the
stimulating
effects
of
estrogen
on
cellproliferation.
Furthermore,
in
breast
cancer
cell
lines
a
dose
dependent
down
regulation
of
ER
a
is
observed,
a
process
we
have
shown
to
involve
proteosomal-mediated
degradation
pathway.
In
a
model
of
breast
cancer,
in
which
human
breast
cancer
cells
are
implanted
in
mice
and
allowed
to
establish
tumors
in
responseto
estrogen
treatment,
we
observed
that
treatment
with
RAD1901
results
in
decreased
tumor
growth.







In
July
2015,
we
announced
that
early
but
promising
preclinical
data
show
that
our
investigational
drug
RAD1901,
in
combination
with
Pfizer's
palbociclib,
aCDK
4/6
inhibitor,
or
Novartis'
everolimus,
an
mTOR
inhibitor,
was
effective
in
shrinking
tumors.
In
PDx
breast
cancer
models
with
either
wild
type
or
mutantESR1,
treatment
with
RAD1901
resulted
in
marked
tumor
growth
inhibition,
and
the
combination
of
RAD1901
with
either
agent,
palbociclib
or
everolimus,showed
anti-tumor
activity
that
was
significantly
greater
than
either
agent
alone.Our Investigational Drug—RAD140







RAD140
is
a
potent,
orally
bioavailable
non-steroidal
SARM
that
resulted
from
an
internal
drug
discovery
program
focused
on
the
androgen
receptorpathway,
which
is
highly
expressed
in
many
ER-positive
and
ER-negative
breast
cancers.
Due
to
its
receptor
and
tissue
selectivity,
potent
oral
activity
and
longduration
half-life,
RAD140
could
have
clinical
potential
in
the
treatment
of
oncology
and
multiple
conditions
where
androgen
modulation
may
offer
therapeuticbenefit.Vasomotor symptoms







Vasomotor
symptoms,
such
as
hot
flashes,
hot
flushes
and
night
sweats,
are
common
during
menopause,
with
up
to
85%
of
women
experiencing
them
duringthe
menopause
transition,
for
a
median
duration
of
four
years.
An
estimated
two
million
women
go
through
menopause
every
year
in
the
United
States,
with
a
totalpopulation
of
45
million
postmenopausal
women.
In
addition,
most
women
receiving
systemic
therapy
for
breast
cancer
suffer
hot
flashes,
often
with
more
severeor
prolonged
symptoms
than
women
experiencing
natural
menopause.
These
symptoms
can
disrupt
sleep
and
interfere
with
quality
of
life.







Historically
hormone
replacement
therapy,
or
HRT,
with
estrogen
and/or
progesterone
has
been
considered
the
most
efficacious
approach
to
relievingmenopausal
symptoms
such
as
hot
flashes.
However,
data
from
the
Women's
Health
Initiative,
or
WHI,
identified
increased
risks
for
malignancy
andcardiovascular
disease
associated
with
estrogen
therapy.
Sales
of
HRT
declined
substantially
after
the
release
of
the
initial
WHI
data,
but
HRT
remains
the
currentstandard
of
care
for
many
women
suffering
from
hot
flashes.
However,
due
to
concerns
about
the
potential
long-term
risks
and
contraindications
associated
withHRT,
we
believe
that
there
is
a
significant
need
for
new
therapeutic
options
to
treat
vasomotor
symptoms.13Table
of
ContentsOur Investigational Drug—RAD1901







RAD1901
is
also
being
evaluated
at
low
doses
as
an
estrogen
receptor
ligand
for
the
potential
relief
of
the
frequency
and
severity
of
moderate
to
severe
hotflashes
in
postmenopausal
women
with
vasomotor
symptoms.
We
believe
that
the
studies
completed
to
date
have
demonstrated
RAD1901's
acceptable
safetyprofile
and
potential
to
reduce
or
prevent
hot
flashes
associated
with
menopause,
while
simultaneously
providing
a
bone-protective
effect,
without
stimulatingbreast
or
uterine
tissues.







We
commenced
a
Phase
2b
clinical
study
of
RAD1901
for
the
potential
treatment
of
postmenopausal
vasomotor
symptoms
in
December
2015.
We
plan
toenroll
300
healthy
postmenopausal
women
between
the
ages
of
40
and
65
years
old
with
moderate
to
severe
hot
flashes
in
approximately
sixty
clinical
sites
acrossthe
United
States.Phase 2 Study—Vasomotor Symptoms







A
Phase
2
proof-of-concept
study
was
conducted
in
100
healthy
perimenopausal
women
using
four
doses
of
RAD1901
(10
mg,
25
mg,
50
mg
and
100
mg)and
placebo.
The
primary
study
outcome
was
reduction
in
the
frequency
and
severity
of
moderate
and
severe
hot
flashes.
While
a
classic
dose-response
effect
wasnot
demonstrated,
efficacy
was
determined
to
occur
at
the
10
mg
dose
level
which
achieved
a
statistically
significant
reduction
in
the
frequency
of
moderate
andsevere
hot
flashes
both
by
linear
trend
test
and
by
comparison
to
placebo
and
in
overall
(mild-moderate-severe)
hot
flashes
at
either
the
two-,
three-
or
four-weektime-points.
A
similar
reduction
in
composite
score
(frequency
×
severity
of
hot
flashes)
was
identified
at
all
time-points,
with
a
statistically
significant
differencefrom
placebo
achieved
at
the
two-,
three-
or
four-week
time-points.
Numerical
reductions
in
mean
severity
and
mean
daily
severity
were
observed,
but
did
notreach
statistical
significance.
We
believe
RAD1901
is
an
attractive
candidate
for
advancement
to
Phase
3
development
as
a
potential
treatment
for
vasomotorsymptoms.







No
serious
adverse
events,
or
SAEs,
were
reported
during
the
course
of
the
study.
Overall,
69%
of
patients
had
an
adverse
event,
generally
mild
or
moderatein
severity,
with
some
evidence
of
dose
dependency,
and
events
were
most
commonly
gastrointestinal
symptoms
and
headaches.
Three
severe
adverse
eventsoccurred,
one
in
a
placebo
patient,
none
of
which
were
considered
treatment
related.
Two
patients
discontinued
treatment
due
to
an
adverse
event,
neither
inrelation
to
the
10
mg
dose.Phase 1 Study—Vasomotor Symptoms







We
have
conducted
Phase
1
safety,
PK
and
bioavailability
studies
of
RAD1901
in
80
healthy
postmenopausal
women
over
a
range
of
doses.
Bioavailabilitywas
determined
to
be
approximately
10%.
Food
effect
was
also
investigated
and
the
presence
of
food
was
determined
to
increase
absorption
and
delay
clearance
ofRAD1901.
RAD1901
was
generally
well
tolerated
at
all
dose
levels
tested.
All
study-related
adverse
events
were
of
mild
intensity,
with
some
increase
in
frequencyat
the
higher
doses
in
the
multiple
dose
group,
most
commonly
gastrointestinal
symptoms
and
headaches.
There
were
no
SAEs
observed.Manufacturing







We
do
not
own
or
operate
manufacturing
facilities
for
the
production
of
any
of
our
investigational
product
candidates,
nor
do
we
have
plans
to
develop
ourown
manufacturing
operations
in
the
foreseeable
future.
The
active
pharmaceutical
ingredient,
or
API,
of
abaloparatide
is
manufactured
on
a
contract
basis
byLonza
Group
Ltd.,
or
Lonza,
using
a
solid
phase
peptide
synthesis
assembly
process,
and
purification
by
high
pressure
liquid
chromatography.
Abaloparatide-SC
issupplied
as
a
liquid
in
a
multi-dose
cartridge
for
use
in
a
pen
delivery
device.
The
pen
delivery
device
is
manufactured
by
Ypsomed
AG.
The
multi-dose
cartridgesand
pen
delivery
device
are
filled,
assembled
and
packaged
by
Vetter
Pharma
Fertigung
GmbH
&
Co.
Abaloparatide-TD
is
manufactured
by
3M
based
on
their14Table
of
Contentspatented
microneedle
technology
to
administer
drugs
through
the
skin,
as
an
alternative
to
subcutaneous
injection.
The
API
of
RAD1901
is
manufactured
for
us
ona
contract
basis
by
Patheon,
Inc.







Manufacturing
is
subject
to
extensive
regulations
that
impose
various
procedural
and
documentation
requirements,
which
govern
record
keeping,manufacturing
processes
and
controls,
personnel,
quality
control
and
quality
assurance,
among
others.
Our
contract
manufacturing
organizations
are
required
tomanufacture
our
investigational
product
candidates
under
current
Good
Manufacturing
Practice,
or
cGMP,
conditions.
cGMP
is
a
regulatory
standard
for
theproduction
of
human
pharmaceuticals
that
imposes
extensive
procedural,
substantive
and
record
keeping
requirements
on
the
manufacturing
process
and
associatedproduction
and
testing
facilities.Intellectual
Property







As
of
December
31,
2015,
we
owned
or
co-owned
11
issued
U.S.
patents,
as
well
as
29
pending
U.S.
patent
applications
and
about
39
pending
foreign
patentapplications
in
Europe
and
15
other
jurisdictions,
and
about
22
granted
foreign
patents.
As
of
December
31,
2015,
we
had
licenses
to
8
U.S.
patents
related
tocompositions
and
related
uses
thereof
as
well
as
numerous
foreign
counterparts
to
many
of
these
patents
and
patent
applications.







We
strive
to
protect
the
proprietary
technology
that
we
believe
is
important
to
our
business,
including
seeking
and
maintaining
patents
intended
to
cover
ourinvestigational
product
candidates
and
compositions,
their
methods
of
use
and
processes
for
their
manufacture
and
any
other
inventions
that
are
commerciallyimportant
to
the
development
of
our
business.
We
also
rely
on
trade
secrets
to
protect
aspects
of
our
business
that
are
not
amenable
to,
or
that
we
do
not
considerappropriate
for,
patent
protection.







Our
success
will
significantly
depend
on
our
ability
to
obtain
and
maintain
patent
and
other
proprietary
protection
for
commercially
important
technology
andinventions
and
know-how
related
to
our
business,
defend
and
enforce
our
patents,
preserve
the
confidentiality
of
our
trade
secrets,
and
operate
without
infringingthe
valid
and
enforceable
patents
and
proprietary
rights
of
third
parties.
We
also
rely
on
know-how
and
continuing
technological
innovation
to
develop
andmaintain
our
proprietary
position.Abaloparatide







We
acquired
and
maintain
exclusive
worldwide
rights,
excluding
development
and
commercialization
rights
for
Japan,
to
certain
patents,
data
and
technicalinformation
related
to
abaloparatide
through
a
license
agreement
with
an
affiliate
of
Ipsen.
Composition
of
matter
of
abaloparatide
is
claimed
in
the
United
States(U.S.
Patent
No.
5,969,095),
Europe,
Australia,
Canada,
China,
Hong
Kong,
South
Korea,
New
Zealand,
Poland,
Russia,
Singapore,
Mexico,
Hungary,
and
Taiwan.These
patents
have
a
statutory
expiration
date
of
2016.
European
Patent
No.
0847278,
which
was
included
in
the
license
from
Ipsen
and
claimed
the
composition
ofmatter
of
abaloparatide,
lapsed
due
to
Ipsen's
failure
to
pay
annuities.
We
are
pursuing
restoration
of
those
patent
rights.
To
date,
the
patent
rights
in
Austria,Belgium,
Denmark,
Finland,
France,
Germany,
Ireland,
Italy,
the
Netherlands,
Portugal,
Spain,
Sweden,
and
the
United
Kingdom
have
been
restored.
We
believethat
the
data
and
market
exclusivity
provided
in
Europe
for
a
new
chemical
entity,
coupled
with
the
need
for
a
potential
competitor
to
conduct
clinical
trials
willlikely
provide
a
longer
barrier
to
entry
than
the
patent
protection
provided
by
the
original
European
patent
term,
which
will
expire
in
2016.
The
Phase
3
clinicaldosage
of
abaloparatide
by
the
subcutaneous
route
for
potential
use
in
treating
osteoporosis
is
covered
by
Patent
No.
7,803,770
until
the
statutory
term
expiresOctober
3,
2027
which
we
expect
will
be
extended
to
March
26,
2028
(statutory
term
extended
with
175
days
of
patent
term
adjustment
due
to
delays
in
patentprosecution
by
the
United
States
Patent
and
Trademark
Office,
or
USPTO)
in
the15Table
of
ContentsUnited
States
(not
including
any
patent
term
extension
under
the
Hatch-Waxman
Act).
The
intended
therapeutic
formulation
for
abaloparatide-SC
is
covered
byPatent
No.
8,148,333
until
2027
in
the
United
States
(not
including
any
patent
term
extension
under
the
Hatch-Waxman
Act).
Related
patents
granted
in
Australia,China,
Israel,
Japan,
South
Korea,
Mexico,
New
Zealand,
Russia,
Singapore,
and
Ukraine,
and
currently
pending
in
Brazil,
Canada,
Europe,
Hong
Kong,
India,South
Korea,
Norway,
and
Singapore,
will
have
a
patent
expiration
date
of
2027,
not
taking
into
account
extension
under
any
applicable
laws.
Patent
applicationswhich
cover
various
aspects
of
abaloparatide
for
microneedle
application
are
pending
in
the
United
States,
Australia,
Brazil,
Canada,
China,
Europe,
Hong
Kong,Israel,
India,
Japan,
South
Korea,
Mexico,
New
Zealand,
Russia,
Singapore,
and
Ukraine.
Any
patents
that
might
issue
from
these
applications
will
have
a
statutoryexpiration
date
in
2032,
not
taking
into
account
extension
under
any
applicable
laws.RAD1901







We
exclusively
licensed
the
worldwide
rights
to
RAD1901
from
Eisai.
US
Patent
No.
7,612,114
(statutory
term
expires
December
25,
2023
which
we
expectwill
be
extended
up
to
August
18,
2026
with
967
days
of
patent
term
adjustment
not
taking
into
account
any
Hatch-Waxman
patent
term
extensions)
coversRAD1901
as
a
composition
of
matter
as
well
as
the
use
of
RAD1901
for
treatment
of
estrogen-dependent
osteoporosis
or
estrogen-dependent
breast
cancer.Corresponding
patents
issued
in
Australia,
Canada
and
Europe
and
pending
in
India
will
have
a
statutory
expiration
date
in
2023,
not
taking
into
account
extensionunder
any
applicable
laws.
Patent
applications
covering
methods
of
using
RAD1901
for
the
treatment
of
vasomotor
symptoms
are
issued
in
the
United
States
(USPatent
No.
8,933,130,
statutory
term
expires
June
22,
2027,
which
we
expect
will
be
extended
up
to
October
19,
2031
with
1,580
days
of
patent
term
adjustmentnot
taking
into
account
any
Hatch-Waxman
patent
term
extensions),
Canada
and
Europe;
any
issued
patents
will
have
a
statutory
expiration
date
in
2027.
Patentapplications
covering
a
dosage
form
have
been
filed
in
the
United
States,
Europe,
Canada
and
Mexico,
and
any
claims
that
might
issue
from
these
applications
willhave
a
statutory
expiration
date
in
2031.RAD140







The
composition
of
matter
of,
and
methods
of
using,
RAD140
are
covered
by
US
Patent
No.
8,067,448
(statutory
term
expires
February
19,
2029,
which
weexpect
will
be
extended
to
September
25,
2029,
with
218
days
of
patent
term
adjustment
due
to
delays
by
the
USPTO,
not
taking
into
account
any
Hatch
Waxmanpatent
term
extensions)
and
U.S.
Patent
No.
8,268,872
(statutory
term
expires
February
19,
2029
which
we
expect
will
be
extended
to
September
25,
2029
withpatent
term
adjustment,
subject
to
a
terminal
disclaimer
of
Patent
Nos.
8,067,448
and
8,455,525).
Related
patents
have
been
granted
in
Australia,
Canada,
Europe,Japan
and
Mexico
and
additional
patent
applications
are
pending
in
Brazil
and
India.
Any
patents
issued
from
these
filings
will
have
a
statutory
expiration
date
in2029.







There
can
be
no
assurance
that
an
issued
patent
will
remain
valid
and
enforceable
in
a
court
of
law
through
the
entire
patent
term.
Should
the
validity
of
apatent
be
challenged,
the
legal
process
associated
with
defending
the
patent
can
be
costly
and
time
consuming.
Issued
patents
can
be
subject
to
oppositions,interferences
and
other
third-party
challenges
that
can
result
in
the
revocation
of
the
patent
or
that
can
limit
patent
claims
such
that
patent
coverage
lacks
sufficientbreadth
to
protect
subject
matter
that
is
commercially
relevant.
Competitors
may
be
able
to
circumvent
our
patents.
Development
and
commercialization
ofpharmaceutical
products
can
be
subject
to
substantial
delays
and
it
is
possible
that
at
the
time
of
commercialization
any
patent
covering
the
product
has
expired
orwill
be
in
force
for
only
a
short
period
of
time
following
commercialization.
We
cannot
predict
with
any
certainty
if
any
third
party
U.S.
or
foreign
patent
rights,
orother
proprietary
rights,
will
be
deemed
infringed
by
the
use
of
our
technology.
Nor
can
we
predict
with
certainty
which,
if
any,
of
these
rights16Table
of
Contentswill
or
may
be
asserted
against
us
by
third-parties.
Should
we
need
to
defend
ourselves
and
our
partners
against
any
such
claims,
substantial
costs
may
be
incurred.Furthermore,
parties
making
such
claims
may
be
able
to
obtain
injunctive
or
other
equitable
relief,
which
could
effectively
block
our
ability
to
develop
orcommercialize
some
or
all
of
our
products
in
the
United
States
and
abroad,
and
could
result
in
the
award
of
substantial
damages.
In
the
event
of
a
claim
ofinfringement,
we
or
our
partners
may
be
required
to
obtain
one
or
more
licenses
from
a
third
party.
There
can
be
no
assurance
that
we
can
obtain
a
license
on
areasonable
basis
should
we
deem
it
necessary
to
obtain
rights
to
an
alternative
technology
that
meets
our
needs.
The
failure
to
obtain
a
license
may
have
a
materialadverse
effect
on
our
business,
results
of
operations
and
financial
condition.







We
also
rely
on
trade
secret
protection
for
our
confidential
and
proprietary
information.
No
assurance
can
be
given
that
we
can
meaningfully
protect
our
tradesecrets
on
a
continuing
basis.
Others
may
independently
develop
substantially
equivalent
confidential
and
proprietary
information
or
otherwise
gain
access
to
ourtrade
secrets.







It
is
our
policy
to
require
our
employees
and
consultants,
outside
scientific
collaborators,
sponsored
researchers
and
other
advisors
who
receive
confidentialinformation
from
us
to
execute
confidentiality
agreements
upon
the
commencement
of
employment
or
consulting
relationships.
These
agreements
provide
that
allconfidential
information
developed
or
made
known
to
these
individuals
during
the
course
of
the
individual's
relationship
with
us
is
to
be
kept
confidential
and
is
notto
be
disclosed
to
third
parties
except
in
specific
circumstances.
The
agreements
provide
that
all
inventions
conceived
by
an
employee
shall
be
our
property.
Therecan
be
no
assurance,
however,
that
these
agreements
will
provide
meaningful
protection
or
adequate
remedies
for
our
trade
secrets
in
the
event
of
unauthorized
useor
disclosure
of
such
information.







Our
success
will
depend
in
part
on
our
ability
to
obtain
and
maintain
patent
protection,
preserve
trade
secrets,
prevent
third
parties
from
infringing
upon
ourproprietary
rights
and
operate
without
infringing
upon
the
proprietary
rights
of
others,
both
in
the
United
States
and
other
territories
worldwide.Competition







The
development
and
commercialization
of
new
products
to
treat
the
targeted
indications
of
our
investigational
product
candidates
is
highly
competitive,
andour
products,
if
approved,
will
face
considerable
competition
from
major
pharmaceutical,
biotechnology
and
specialty
pharmaceutical
companies,
includingAmgen,
UCB
S.A.,
Merck
&
Co,
Novartis,
Lilly,
Pfizer,
Roche,
Asahi
Kasei,
Corium
and
Zosano,
that
currently
market
and/or
are
seeking
to
develop
products
forsimilar
indications.
Many
of
our
competitors
have
substantially
more
resources
than
we
do,
including
financial,
manufacturing,
marketing,
research
and
drugdevelopment
resources.
In
addition,
many
of
these
companies
have
longer
operating
histories
and
more
experience
than
us
in
preclinical
and
clinical
development,manufacturing,
regulatory
and
global
commercialization.Abaloparatide







There
are
two
main
types
of
osteoporosis
drugs
currently
available
in
the
United
States,
anti-resorptive
agents
and
anabolic
agents.
Anti-resorptive
agentsincluding
bisphosphonates,
estrogen,
SERMs
and
Amgen's
Prolia
are
the
most
common
treatments
for
osteoporosis.
Lilly's
Forteo,
is
the
only
anabolic
drugapproved
in
the
United
States
for
the
treatment
of
osteoporosis.
In
addition,
there
are
other
organizations
working
to
develop
new
therapies
to
treat
osteoporosis.
InApril
2012,
UCB
and
Amgen
started
a
Phase
3
clinical
trial
program
for
their
anti-sclerostin
antibody
for
the
treatment
of
osteoporosis.
We
are
also
aware
of
atleast
one
biosimilar
to
Lilly's
Forteo,
which
is
currently
under
review
by
the
EMA.
In
addition,
we
are
aware
that
Corium
and
Zosano
are
developing
a
transdermalform
of
PTH(1-34)
that
would
compete
with
abaloparatide-TD.17Table
of
ContentsRAD1901







RAD1901
for
the
treatment
of
breast
cancer
will
face
competition
from
SERDs,
CNS-penetrant
anti-cancer
agents
and
from
chemotherapy
derivatives.AstraZeneca's
Faslodex
is
the
only
SERD
currently
approved
in
the
United
States
for
the
treatment
of
metastatic
breast
cancer.
In
addition,
there
are
otherorganizations
working
to
develop
new
therapies
to
treat
metastatic
breast
cancer,
including
Roche,
which
is
developing
two
oral
SERD's
which
are
currently
inPhase
1
and
Phase
2
clinical
development.







RAD1901
for
the
treatment
of
vasomotor
systems
will
face
competition
from
recently
launched
products
including
Pfizer's
Duavee
and
Premarin,
and
NovenTherapeutic's
Brisdelle.







We
cannot
assure
you
that
our
current
investigational
product
candidates,
if
successfully
developed
and
approved,
will
be
able
to
compete
effectively
againstthese,
or
any
other
competing
therapeutics
that
may
become
available
on
the
market.Collaborations
and
License
AgreementsNordic Bioscience        Abaloparatide-SC Phase 3 Clinical Trial —We
have
entered
into
agreements
with
Nordic
Bioscience
Clinical
Development
VII
A/S,
or
Nordic,
to
conductthe
ACTIVE
trial.
On
March
29,
2011,
we
entered
into
a
Clinical
Trial
Services
Agreement,
or
the
Clinical
Trial
Services
Agreement.
On
the
same
date,
we
alsoentered
into
Work
Statement
NB-1,
as
amended
on
December
9,
2011,
June
18,
2012,
March
28,
2014,
May
19,
2014,
July
22,
2014,
August
15,
2014
andMarch
12,
2015,
or
Work
Statement
NB-1,
and
the
Stock
Issuance
Agreement,
as
amended
and
restated
on
May
16,
2011,
and
as
further
amended
on
February
21,2013,
March
28,
2014,
and
May
19,
2014,
or
the
Stock
Issuance
Agreement.        Abaloparatide-SC Phase 3 Clinical Extension Study —On
February
21,
2013,
we
entered
into
the
Work
Statement
NB-3,
as
amended
on
February
28,
2014,March
23,
2015,
July
8,
2015
and
October
21,
2015,
or
the
Work
Statement
NB-3.
Pursuant
to
the
Work
Statement
NB-3,
Nordic
performed
the
ACTIVExtend
trialfollowing
the
completion
of
the
ACTIVExtend,
and,
upon
completion
of
the
ACTIVExtend
trial,
an
additional
period
of
18
months
of
standard-of-care
osteoporosismanagement,
or
the
Second
Extension.







In
April
2015,
we
entered
into
an
amendment
to
the
Work
Statement
NB-3,
or
the
NB-3
Amendment.
The
NB-3
Amendment
was
effective
as
of
March
23,2015
and
provides
that
Nordic
will
perform
additional
services,
including
monitoring
of
patients
enrolled
in
the
Second
Extension.
Payments
in
cash
to
be
made
toNordic
under
the
NB-3
Amendment
are
denominated
in
euros
and
total
up
to
approximately
€4.1
million
($4.5
million).







Payments
in
cash
to
be
made
to
Nordic
under
the
Work
Statement
NB-3,
are
denominated
in
both
euros
and
U.S.
dollars
and
total
up
to
€11.9
million($12.9
million)
and
$1.1
million,
respectively.
In
addition,
payments
are
due
to
Nordic
in
connection
with
the
Work
Statement
NB-3
pursuant
to
the
Stock
IssuanceAgreement,
as
discussed
below.        Stock Issuance Agreement —Pursuant
to
the
Stock
Issuance
Agreement,
Nordic
agreed
to
purchase
6,443
shares
of
our
Series
A-5
convertible
preferred
stock,which
provided
them
with
the
right
to
receive
quarterly
stock
dividends,
payable
in
shares
of
our
Series
A-6
convertible
preferred
stock,
for
services
rendered
underWork
Statement
NB-1
and
Work
Statement
NB-3.
The
Stock
Issuance
Agreement
was
later
amended
to
provide
that
in
the
event
an
initial
public
offering
of
ourcommon
stock
occurred
prior
to
June
30,
2014,
any
rights
to
receive
stock
dividends
in
relation
to
Work
Statement
NB-1
and
Work
Statement
NB-3,
for
all
periodsof
time
after
2014,
would
be
changed
from
the
right
to
receive
stock
to
the
right
to
receive
a
total
cash
payment
of
$4.3
million,
payable
in
ten
equal
monthlyinstallments
of
$430,000
beginning
on
March
31,
2015.
The
amendment
also
stipulated18Table
of
Contentsthat
all
consideration
to
be
paid
to
Nordic
pursuant
to
the
Stock
Issuance
Agreement
at
any
time
after
the
consummation
of
an
initial
public
offering
be
payable
incash.
As
we
completed
an
initial
public
offering
on
June
11,
2014,
Nordic
no
longer
has
the
right
to
receive
stock
and
has
been
paid
in
cash
for
all
periods
afterJune
11,
2014.3M







In
June
2009,
we
entered
into
a
Development
and
Clinical
Supplies
Agreement
with
3M
under
which
3M
is
responsible
for
the
development
of
anabaloparatide-TD
product
and
the
manufacture
of
clinical
and
toxicology
supplies
of
the
abaloparatide-TD
product
for
preclinical,
Phase
1
and
Phase
2
studies
onan
exclusive
basis
during
the
term
of
the
Development
and
Clinical
Supplies
Agreement.
In
December
2012,
we
entered
into
an
amendment
to
the
Developmentand
Clinical
Supplies
Agreement
in
which
3M
agreed
to
develop
and
manufacture
clinical
and
toxicology
supplies
for
the
Phase
3
abaloparatide-TD
clinical
study.In
addition,
3M
agreed
that
it
will
not
use
jointly
owned
intellectual
property
developed
during
and
resulting
from
its
work
with
us
on
abaloparatide-TD
in
relationto
any
other
PTH
or
PTHrP
analogue
or
derivative.
We
hold
exclusive
worldwide
rights
to
this
use
of
the
3M
transdermal
technology.







We
pay
3M
for
services
delivered
pursuant
to
the
Development
and
Clinical
Supplies
Agreement
on
a
fee-for-service
or
a
fee-for-deliverable
basis
asspecified
in
the
Development
and
Clinical
Supplies
Agreement.
We
have
paid
3M
approximately
$16.7
million,
in
the
aggregate,
through
December
31,
2015
inrespect
to
services
and
deliverables
delivered
pursuant
to
the
Development
and
Clinical
Supplies
Agreement.







The
Development
and
Clinical
Supplies
Agreement,
as
amended,
provides
for
services
through
December
31,
2017,
unless
it
is
sooner
terminated.
Either
partymay
terminate
the
Development
and
Clinical
Supplies
Agreement
upon
a
material
breach
by
the
other
party
unless
such
other
party
cures
the
alleged
breach
withinthe
notice
period
specified
in
the
Development
and
Clinical
Supplies
Agreement.
The
Development
and
Clinical
Supplies
Agreement
contains
customary
riskallocation
clauses
with
3M
indemnifying
us
in
respect
of
third-party
claims
arising
from
any
personal
injury
to
the
extent
that
such
claim
results
from
3M's
breachof
warranty
with
respect
to
abaloparatide-TD
meeting
applicable
specifications;
and
us
indemnifying
3M
in
respect
of
third-party
claims
arising
from
our
or
ouragent's
use,
testing
or
clinical
studies
of
abaloparatide-TD.
The
Development
and
Clinical
Supplies
Agreement
contains
other
customary
clauses
and
terms
as
arecommon
in
similar
agreements
in
the
industry.Ipsen Pharma







In
September
2005,
we
entered
into
a
license
agreement
with
Ipsen,
as
amended
on
September
12,
2007
and
May
11,
2011,
or
the
License
Agreement,
underwhich
we
exclusively
licensed
certain
Ipsen
compound
technology
and
related
patents
covering
abaloparatide
to
research,
develop,
manufacture
and
commercializecertain
compounds
and
related
products
in
all
countries,
except
Japan
(where
we
do
not
hold
abaloparatide-SC
development
and
commercialization
rights)
andFrance
(where
our
commercialization
rights
are
subject
to
certain
co-marketing
and
co-promotion
rights
exercisable
by
Ipsen,
provided
that
certain
conditionsincluded
in
the
License
Agreement
have
been
met).
Ipsen
also
granted
us
an
exclusive
right
and
license
under
the
Ipsen
compound
technology
and
related
patents
tomake
and
have
made
compounds
or
product
in
Japan.
Ipsen
also
granted
us
an
exclusive
right
and
license
under
certain
Ipsen
formulation
technology
and
relatedpatents
solely
for
purposes
of
enabling
us
to
develop,
manufacture
and
commercialize
compounds
and
products
covered
by
the
compound
technology
license
in
allcountries,
except
Japan
(where
we
do
not
hold
abaloparatide-SC
development
and
commercialization
rights)
and
France
(where
our
commercialization
rights
aresubject
to
certain
co-marketing
and
co-promotion
rights
exercisable
by
Ipsen,
provided
that
certain
conditions
included
in
the
License
Agreement
have
been
met).With
respect
to
France,
if
Ipsen
exercises
its
co-marketing
and19Table
of
Contentsco-promotion
rights,
then
Ipsen
may
elect
to
receive
a
percentage
of
the
net
sales
of
the
product
by
both
parties
in
France
(subject
to
a
mid-double
digit
percentagecap),
and
Ipsen
shall
bear
a
corresponding
percentage
of
the
costs
and
expenses
incurred
by
both
parties
with
respect
to
such
marketing
and
promotion
efforts
inFrance;
Ipsen
shall
also
pay
us
a
mid-single
digit
royalty
on
Ipsen's
allocable
portion
of
net
sales
of
the
product
by
both
parties
in
France.
Specifically,
we
licensedUS
Patent
No.
5,969,095
(statutory
term
expires
March
29,
2016),
entitled
"Analogs
of
Parathyroid
Hormone,"
US
Patent
No.
6,544,949
(statutory
term
endsMarch
29,
2016),
entitled
"Analogs
of
Parathyroid
Hormone,"
and
the
corresponding
foreign
patents
and
continuing
patent
applications.
European
PatentNo.
0847278,
which
was
included
in
the
license
from
Ipsen
and
claimed
the
composition
of
matter
of
abaloparatide,
lapsed
due
to
Ipsen's
failure
to
pay
annuities.We
are
pursuing
restoration
of
those
rights.
To
date,
the
patent
rights
in
Austria,
Belgium,
Denmark,
Finland,
France,
Germany,
Ireland,
Italy,
the
Netherlands,Portugal,
Spain,
Sweden,
and
the
United
Kingdom
have
been
restored.
We
believe
that
the
data
and
market
exclusivity
provided
in
Europe
for
a
new
chemicalentity,
coupled
with
the
need
for
a
potential
competitor
to
conduct
clinical
trials,
will
likely
provide
a
longer
barrier
to
entry
than
the
patent
protection
provided
bythe
original
European
patent
term,
which
will
expire
in
2016.







We
also
have
rights
to
joint
intellectual
property
related
to
abaloparatide,
including
rights
to
the
jointly
derived
intellectual
property
contained
in
US
PatentNo.
7,803,770
(statutory
term
expires
October
3,
2027
which
we
expect
will
be
extended
to
March
26,
2028
with
175
days
of
patent
term
adjustment
due
to
delaysin
patent
prosecution
by
the
USPTO),
US
Patent
No.
8,148,333
(statutory
term
expires
October
3,
2027
which
we
expect
will
be
extended
to
November
8,
2027with
36
days
of
patent
term
adjustment
due
to
delays
in
patent
prosecution
by
the
USPTO)
and
related
patents
and
patent
applications
both
in
the
United
States
andworldwide
that
cover
the
method
of
treating
osteoporosis
using
the
ACTIVE
trial
dosage
strength
and
form.
Two
corresponding
European
applications
are
pendingwith
claims
to
the
intended
therapeutic
formulation
for
abaloparatide-SC.
Examination
has
been
requested,
and
substantive
examination
has
commenced
for
oneapplication
and
has
not
yet
commenced
for
the
other
one.
Upon
grant,
these
patents
could
be
validated
in
any
designated
contracting
or
extension
states
andpotentially
could
be
considered
for
a
Supplemental
Protection
Certificate
depending
upon
the
timing
of
its
grant.
Related
cases
granted
in
Australia,
China,
Israel,Japan,
South
Korea,
Mexico,
New
Zealand,
Russia,
Singapore,
and
Ukraine,
and
currently
pending
in
Brazil,
Canada,
Europe,
Hong
Kong,
India,
South
Korea,Norway,
and
Singapore,
will
have
a
patent
expiration
date
of
2027.
Patent
applications
which
cover
various
aspects
of
abaloparatide
for
microneedle
application
arepending
in
the
United
States,
Australia,
Brazil,
Canada,
China,
Europe,
Hong
Kong,
Israel,
India,
Japan,
South
Korea,
Mexico,
New
Zealand,
Russia,
Singapore,and
Ukraine.
Any
patents
that
might
issue
from
these
applications
will
have
a
statutory
expiration
date
in
2032,
not
taking
into
account
extension
under
anyapplicable
laws.







In
consideration
for
the
rights
to
abaloparatide
and
in
recognition
of
certain
milestones
having
been
met
to
date,
we
have
paid
to
Ipsen
an
aggregate
amount
of$1.0
million.
The
license
agreement
further
requires
us
to
make
payments
upon
the
achievement
of
certain
future
clinical
and
regulatory
milestones.
The
range
ofmilestone
payments
that
could
be
paid
under
the
agreement
is
€10.0
million
to
€36.0
million
($10.9
million
to
$39.1
million).
Should
abaloparatide
be
approvedand
subsequently
become
commercialized,
we
or
our
sublicensees
will
be
obligated
to
pay
to
Ipsen
a
fixed
five
percent
royalty
based
on
net
sales
of
the
product
ona
country-by-country
basis
until
the
later
of
the
last
to
expire
of
the
licensed
patents
or
for
a
period
of
10
years
after
the
first
commercial
sale
of
the
licensedproducts
in
such
country.
The
date
of
the
last
to
expire
of
the
abaloparatide
patents
licensed
from
or
co-owned
with
Ipsen,
barring
any
extension
thereof,
isexpected
to
be
March
26,
2028.
In
the
event
that
we
sublicense
abaloparatide
to
a
third
party,
we
are
obligated
to
pay
a
percentage
of
certain
payments
receivedfrom
such
sublicensee
(in
lieu
of
milestone
payments
not
achieved
at
the
time
of
such
sublicense).
The
applicable
percentage
is
in
the
low
double
digit
range.
Inaddition,
if
we
or
our
sublicensees
commercialize
a
product
that
includes
a
compound
discovered
by
us
based
on
or
derived20Table
of
Contentsfrom
confidential
Ipsen
know-how,
we
will
be
obligated
to
pay
to
Ipsen
a
fixed
low
single
digit
royalty
on
net
sales
of
such
product
on
a
country-by-country
basisuntil
the
later
of
the
last
to
expire
of
our
patents
that
cover
such
product
or
for
a
period
of
10
years
after
the
first
commercial
sale
of
such
product
in
such
country.The
license
agreement
contains
other
customary
clauses
and
terms
as
are
common
in
similar
agreements
in
the
industry.







The
License
Agreement
expires
on
a
country-by-country
basis
on
the
later
of
(1)
the
date
the
last
remaining
valid
claim
in
the
licensed
patents
expires
in
thatcountry;
or
(2)
a
period
of
10
years
after
the
first
commercial
sale
of
the
licensed
products
in
such
country,
unless
it
is
sooner
terminated.







The
License
Agreement
may
be
terminated
by
us
with
prior
notice
to
Ipsen.
The
License
Agreement
may
be
terminated
by
Ipsen
upon
notice
to
us
withimmediate
effect,
if
we,
in
any
country
of
the
world,
bring
an
action
or
proceeding
seeking
to
have
any
Ipsen
patent
right
declared
invalid
or
unenforceable.
TheLicense
Agreement
can
also
be
terminated
by
Ipsen
if
we
fail
to
use
reasonable
commercial
efforts
to
develop
the
licensed
product
for
sale
and
commercializationin
those
countries
within
the
territory
where
it
is
commercially
reasonable
to
do
so
as
contemplated
by
the
License
Agreement,
or
fail
to
use
reasonable
commercialefforts
to
perform
our
obligations
under
the
latest
revised
version
of
the
development
plan
approved
by
the
joint
steering
committee,
or
fail
to
use
reasonablecommercial
efforts
to
launch
and
sell
one
licensed
product
in
those
countries
within
the
territory
where
it
is
commercially
reasonable
to
do
so.
Either
party
may
alsoterminate
the
License
Agreement
upon
a
material
breach
by
the
other
party
unless
such
other
party
cures
the
alleged
breach
within
the
notice
period
specified
in
thelicense
agreement.
Ipsen
may
terminate
the
License
Agreement
in
the
event
that
the
License
Agreement
is
assigned
or
sublicensed
or
in
the
event
that
a
third
partyacquires
us
or
in
the
event
that
we
acquire
control
over
a
PTH
or
a
PTHrP
compound
that
is
in
clinical
development
or
is
commercially
available
in
the
territory
andthat,
following
such
assignment,
sublicense,
acquisition,
or
acquisition
of
control
by
us,
such
assignee,
sublicensee,
acquirer
or
we
fail
to
meet
the
timetable
underthe
latest
revised
version
of
the
development
plan
approved
by
the
joint
steering
committee
under
the
License
Agreement.
Any
failure
to
meet
such
timetable
forpurposes
of
such
termination
clause
is
deemed
a
material
breach
by
us.







The
License
Agreement
contains
customary
risk
allocation
clauses
with
each
party
indemnifying
the
other
in
respect
of
third-party
claims
arising
out
of
orresulting
from:
(1)
the
gross
negligence
or
willful
misconduct
of
such
party,
its
affiliates,
licensees,
distributors
or
contractors;
(2)
any
breach
by
such
party
of
itsrepresentations
and
warranties
or
any
other
provision
of
the
License
Agreement
or
any
related
agreement;
(3)
the
manufacture
on
behalf
of
such
party
of
anylicensed
product
or
compound;
(4)
(in
the
case
of
Ipsen)
the
use,
development,
handling
or
commercialization
of
any
licensed
compound,
licensed
product
or
theIpsen
formulation
technology
by
or
on
behalf
of
Ipsen
or
any
of
its
affiliates,
licensees,
distributors
or
contractors;
and
(5)
(in
our
case)
the
making,
use,development,
handling
or
commercialization
of
any
licensed
compound
or
any
licensed
product
by
or
on
our
behalf
or
any
of
our
affiliates,
licensees
or
contractors.The
license
agreement
contains
other
customary
clauses
and
terms
as
are
common
in
similar
agreements
in
the
industry.







Prior
to
executing
the
License
Agreement
for
abaloparatide
with
Radius,
Ipsen
licensed
the
Japanese
rights
for
abaloparatide
to
Teijin
Limited,
or
Teijin,
aJapanese
pharmaceutical
company.
Teijin
has
completed
a
Phase
2
clinical
study
of
abaloparatide
in
Japan
for
the
treatment
of
postmenopausal
osteoporosis.Eisai







In
June
2006,
we
exclusively
licensed
the
worldwide
rights
to
research,
develop,
manufacture
and
commercialize
RAD1901
and
related
products
from
Eisai,or
the
Eisai
Agreement.
Our
license
with
Eisai
did
not
originally
include
rights
for
Japan,
however,
on
March
9,
2015,
we
entered
into
an
amendment
to
the
EisaiAgreement
in
which
Eisai
granted
us
an
exclusive
right
and
license
to
research,21Table
of
Contentsdevelop,
manufacture
and
commercialize
RAD1901
in
Japan,
or
the
Eisai
Amendment.
Specifically,
we
licensed
the
patent
application
that
subsequently
issued
asUS
Patent
No.
7,612,114
(statutory
term
expires
December
25,
2023
which
we
expect
will
be
extended
to
August
18,
2026
with
967
days
of
patent
term
adjustmentdue
to
delays
by
the
USPTO),
entitled
"Selective
Estrogen
Receptor
Modulator,"
the
corresponding
foreign
patent
applications
and
continuing
patent
applications.As
consideration
for
the
rights
to
RAD1901,
we
paid
Eisai
an
initial
license
fee
of
$0.5
million.
We
have
also
agreed
to
pay
Eisai
certain
fees
in
the
range
of$1.0
million
to
$20.0
million
(inclusive
of
the
$0.5
million
initial
license
fee),
payable
upon
the
achievement
of
certain
clinical
and
regulatory
milestones.
Inconsideration
for
the
rights
to
RAD1901
in
Japan,
we
paid
Eisai
an
initial
license
fee
of
$0.4
million
upon
execution
of
the
Eisai
Amendment.
The
EisaiAmendment
also
provides
for
additional
payments,
payable
upon
the
achievement
of
certain
clinical
and
regulatory
milestones
in
Japan.







Under
the
license
with
Eisai,
as
amended
by
the
Eisai
Amendment,
or
the
Eisai
Agreement,
should
a
product
covered
by
the
licensed
technology
becommercialized,
we
will
be
obligated
to
pay
to
Eisai
royalties
in
a
variable
mid-single
digit
range
based
on
net
sales
of
the
product
on
a
country-by-country
basis.The
royalty
rate
will
be
reduced,
on
a
country-by-country
basis,
at
such
time
as
the
last
remaining
valid
claim
in
the
licensed
patents
expires,
lapses
or
isinvalidated
and
the
product
is
not
covered
by
data
protection
clauses.
In
addition,
the
royalty
rate
will
be
reduced,
on
a
country-by-country
basis,
if,
in
addition
tothe
conditions
specified
in
the
previous
sentence,
lawful
generic
versions
of
such
product
account
for
more
than
a
specified
minimum
percentage
of
the
total
salesof
all
products
that
contain
the
licensed
compound
during
a
calendar
quarter.
The
latest
patent
to
expire,
barring
any
extension
thereof,
is
expected
on
August
18,2026.







We
were
also
granted
the
right
to
sublicense
with
prior
written
approval
from
Eisai.
If
we
sublicense
the
licensed
technology
to
a
third
party,
we
will
beobligated
to
pay
Eisai,
in
addition
to
the
milestone
fees
referenced
above,
a
fixed
low
double
digit
percentage
of
certain
fees
we
receive
from
such
sublicensee
androyalties
in
the
low
single
digit
range
based
on
net
sales
of
the
sublicensee.
The
license
agreement
expires
on
a
country-by-country
basis
on
the
later
of
(1)
the
datethe
last
remaining
valid
claim
in
the
licensed
patents
expires,
lapses
or
is
invalidated
in
that
country,
the
product
is
not
covered
by
data
protection
clauses,
and
thesales
of
lawful
generic
version
of
the
product
account
for
more
than
a
specified
percentage
of
the
total
sales
of
all
pharmaceutical
products
containing
the
licensedcompound
in
that
country;
or
(2)
a
period
of
10
years
after
the
first
commercial
sale
of
the
licensed
products
in
such
country,
unless
it
is
sooner
terminated.







The
Eisai
Agreement
may
be
terminated
by
us
with
respect
to
the
entire
territory
with
prior
notice
to
Eisai
if
we
reasonably
determine
that
themedical/scientific,
technical,
regulatory
or
commercial
profile
of
the
licensed
product
does
not
justify
continued
development
or
marketing.
The
license
agreementcan
also
be
terminated
by
Eisai
on
a
country-by-country
basis
at
any
time
prior
to
the
date
on
which
we
have
submitted
for
either
an
NDA
approval
or
EMAmarketing
approval
with
respect
to
a
licensed
product,
upon
prior
written
notice
to
us
if
Eisai
makes
a
good
faith
determination
that
we
have
not
used
commerciallyreasonable
efforts
to
develop
the
licensed
product
in
the
territory
having
reference
to
prevailing
principles
and
time
scales
associated
with
the
development,
clinicaltesting
and
government
approval
of
products
of
a
like
nature
to
such
licensed
product,
unless
such
default
is
cured
within
the
period
specified
in
the
EisaiAgreement
or
if
not
capable
of
being
cured
within
such
period
we
commence
efforts
to
cure
and
make
diligent
efforts
to
do
so.
Either
party
may
also
terminate
theEisai
Agreement
upon
a
material
breach
by
the
other
party
unless
such
other
party
cures
the
alleged
breach
within
the
notice
period
specified
in
the
EisaiAgreement.
Either
party
may
also
terminate
the
Eisai
Agreement
upon
the
bankruptcy
or
insolvency
of
the
other
party.
Eisai
may
also
terminate
the
EisaiAgreement
with
prior
notice
if
we
are
acquired
by,
or
if
we
transfer
all
of
our
pharmaceutical
business
assets
(or
an
essential
part
of
such
assets)
or
more
than
50%of
our
voting
stock
to,
any
third
party
person
or
organization,
or
otherwise
come
under
the
control
of,
such
a
person
or
organization,22Table
of
Contentswhether
resulting
from
merger,
acquisition,
consolidation
or
otherwise
in
the
event
that
Eisai
reasonably
determines
that
the
person
or
organization
assumingcontrol
of
us
is
not
able
to
perform
the
Eisai
Agreement
with
the
same
degree
of
skill
and
diligence
that
we
would
use,
such
determination
being
made
withreference
to
the
following
criteria
with
respect
to
the
person
or
organization
assuming
control
of
us:
(1)
whether
such
person
or
organization
has
the
financialresources
to
assume
our
obligations
with
respect
to
development
and
commercialization
of
products;
(2)
whether
such
person
or
organization
has
personnel
withskill
and
experience
adequate
to
assume
our
obligations
with
respect
to
development
and
commercialization
of
products
at
the
stage
of
development
andcommercialization
as
of
the
date
of
such
change;
and
(3)
whether
such
person
or
organization
expressly
assumes
all
obligations
imposed
on
us
by
the
EisaiAgreement
and
agrees
to
dedicate
personnel
and
financial
resources
to
the
development
and
commercialization
of
the
licensed
product
that
are
at
least
as
great
asthose
provided
by
us.
Eisai
shall
further
have
the
right
to
terminate
if
the
acquiring
person
or
organization:
(a)
has
any
material
and
active
litigations
with
Eisai;
or(b)
is
a
hostile
takeover
bidder
against
us
which
has
not
been
approved
by
our
board
of
directors
as
constituted
immediately
prior
to
such
change
of
control.







The
Eisai
Agreement
contains
customary
risk
allocation.
We
agreed
to
indemnify
Eisai
in
respect
of
third-party
claims
arising
out
of
or
resulting
from:(1)
negligence,
recklessness
or
intentional
acts
or
omissions
by
us,
our
affiliates
and
licensees;
(2)
any
breach
by
us
of
a
representation,
warranty
or
covenant;
and(3)
any
personal
injury
arising
out
of
the
labeling,
packaging,
package
insert,
other
materials
or
promotional
claims
with
respect
to
any
licensed
product
by
us,
ouraffiliates,
licensees
or
distributors
in
the
territory.
Eisai
agreed
to
indemnify
us
for
(1)
negligence,
recklessness
or
intentional
acts
or
omissions
by
Eisai
or
itsaffiliates
and
licensees
and
(2)
any
breach
by
Eisai
of
a
representation,
warranty
or
covenant.
The
license
agreement
contains
other
customary
clauses
and
terms
asare
common
in
similar
agreements
in
the
industry.Lonza







In
October
2007,
we
entered
into
a
Development
and
Manufacturing
Services
Agreement
with
Lonza
as
amended
in
May
2011,
January
2014
and
December2015,
or
the
Development
and
Manufacturing
Service
Agreement.
We
and
Lonza
have
entered
into
a
series
of
Work
Orders
pursuant
to
the
Development
andManufacturing
Services
Agreement
pursuant
to
which
Lonza
has
performed
pharmaceutical
development
and
manufacturing
services
for
our
abaloparatide
product.We
pay
Lonza
for
services
rendered
and
deliverables
delivered
pursuant
to
these
work
orders
on
a
fee
for
service
basis
as
specified
in
the
applicable
workstatement.
The
Development
and
Manufacturing
Services
Agreement
will
expire
on
March
31,
2016
unless
it
is
sooner
terminated,
and
is
subject
to
renewal
by
usfor
successive
multiple-year
terms
with
notice
to
Lonza.







The
Development
and
Manufacturing
Services
Agreement
or
any
Work
Order
may
be
terminated
by
either
party
upon
a
material
breach
by
the
other
partywith
respect
to
the
Development
and
Manufacturing
Services
Agreement
unless
such
other
party
cures
the
alleged
breach
within
the
notice
period
specified
in
theDevelopment
and
Manufacturing
Services
Agreement.
Either
party
may
also
terminate
a
Work
Order
if
force
majeure
conditions
have
prevented
performance
bythe
other
party
for
more
than
a
specified
period
of
time
with
respect
to
such
Work
Order.
Termination
of
any
Work
Order
for
force
majeure
shall
not
result
intermination
of
the
Development
and
Manufacturing
Services
Agreement
or
any
other
Work
Orders,
which
shall
remain
in
force
until
terminated.
Either
party
mayalso
terminate
the
Development
and
Manufacturing
Services
Agreement
upon
the
bankruptcy
or
insolvency
of
the
other
party.
We
may
also
terminate
theDevelopment
and
Manufacturing
Services
Agreement
or
any
Work
Order
with
prior
notice
to
Lonza
for
convenience.
We
may
also
terminate
the
Development
andManufacturing
Services
Agreement
or
any
Work
Order
if
we
reasonably
determine
that
Lonza
is
or
will
be
unable
to
perform
the
applicable
services
in
accordancewith
the
agreed
upon23Table
of
Contentstimeframe
and
budget
set
forth
in
the
applicable
Work
Order,
or
if
Lonza
fails
to
obtain
or
maintain
any
material
governmental
licenses
or
approvals
required
inconnection
with
such
services.







The
Development
and
Manufacturing
Services
Agreement
contains
customary
risk
allocation
clauses
with
each
party
indemnifying
the
other
in
respect
ofthird-party
claims
arising
out
of
or
resulting
from:
(i)
the
negligence
or
willful
misconduct
of
such
party,
its
affiliates
and
their
respective
officers,
directors,employees
and
agents
in
performing
its
obligations
under
the
Developing
and
Manufacturing
Services
Agreement;
and
(ii)
any
breach
by
such
party
of
itsrepresentations
and
warranties
under
the
Development
and
Manufacturing
Services
Agreement.
We
have
agreed
to
indemnify
Lonza
in
respect
of
third-party
claimsarising
from
or
relating
to
the
use
of
our
product.Government
RegulationUnited States—FDA Process







The
research,
development,
testing,
manufacture,
labeling,
promotion,
advertising,
distribution
and
marketing,
among
other
things,
of
our
product
candidatesare
extensively
regulated
by
governmental
authorities
in
the
United
States
and
other
countries.
In
the
United
States,
the
FDA
regulates
drugs
under
the
FederalFood,
Drug,
and
Cosmetic
Act,
or
the
FDCA,
and
its
implementing
regulations.
Failure
to
comply
with
the
applicable
United
States
requirements
may
subject
us
toadministrative
or
judicial
sanctions,
such
as
FDA
refusal
to
approve
pending
NDAs,
warning
letters,
product
recalls,
product
seizures,
total
or
partial
suspension
ofproduction
or
distribution,
injunctions,
and/or
criminal
prosecution.
We
expect
abaloparatide,
RAD1901
and
RAD140
will
each
be
subject
to
review
by
the
FDA
asa
drug
pursuant
to
the
NDA
process,
and
we
currently
only
have
active
IND
applications
in
relation
to
abaloparatide
and
RAD1901
in
the
United
States.        Approval Process —None
of
our
drugs
may
be
marketed
in
the
United
States
until
the
drug
has
received
FDA
approval
of
an
NDA.
The
steps
required
to
becompleted
before
a
drug
may
be
marketed
in
the
United
States
include,
among
others:•preclinical
laboratory
tests,
animal
studies,
and
formulation
studies,
all
performed
in
accordance
with
the
FDA's
Good
Laboratory
Practice,
or
GLP,regulations;
•submission
to
the
FDA
of
an
IND
application
for
human
clinical
testing,
which
must
become
effective
before
human
clinical
trials
may
begin
andmust
be
updated
annually;
•adequate
and
well-controlled
human
clinical
trials
to
establish
the
safety
and
efficacy
of
the
drug
for
each
proposed
indication
to
FDA's
satisfaction;•submission
to
the
FDA
of
an
NDA;
•satisfactory
completion
of
an
FDA
pre-approval
inspection
of
one
or
more
clinical
trial
site(s)
at
which
the
drug
was
studied
in
a
clinical
trial(s)
toassess
compliance
with
Good
Clinical
Practices,
or
GCP,
regulations;
•satisfactory
completion
of
an
FDA
pre-approval
inspection
of
the
manufacturing
facility
or
facilities
at
which
the
drug
is
produced
to
assesscompliance
with
cGMP
regulations;
and
•FDA
review
and
approval
of
the
NDA.







Preclinical
tests
include
laboratory
evaluation
of
product
chemistry,
toxicity,
and
formulation,
as
well
as
animal
studies.
The
conduct
of
the
preclinical
testsand
formulation
of
the
compounds
for
testing
must
comply
with
federal
regulations
and
requirements.
The
results
of
the
preclinical
tests,
together
withmanufacturing
information
and
analytical
data,
are
submitted
to
the
FDA
as
part
of
an
IND
application,
which
must
become
effective
before
human
clinical
trialsmay
begin.
An
IND
application
will
automatically
become
effective
30
days
after
receipt
by
the
FDA,
unless
before
that
time
the
FDA
raises
concerns
or
questionsabout
issues
such
as
the
conduct
of
the
trials
as
outlined
in24Table
of
Contentsthe
IND
application.
In
such
a
case,
the
IND
application
sponsor
and
the
FDA
must
resolve
any
outstanding
FDA
concerns
or
questions
before
clinical
trials
canproceed.
We
cannot
be
sure
that
submission
of
an
IND
application
will
result
in
the
FDA
allowing
clinical
trials
to
begin.







Clinical
trials
involve
the
administration
of
the
investigational
drug
to
human
subjects
under
the
supervision
of
qualified
investigators.
Clinical
trials
areconducted
under
GCP
pursuant
to
protocols
detailing
the
objectives
of
the
study,
the
parameters
to
be
used
in
monitoring
safety,
and
the
effectiveness
criteria
to
beevaluated.
Each
protocol
must
be
submitted
to
the
FDA
as
part
of
the
IND
application.







Clinical
trials
necessary
for
product
approval
are
typically
conducted
in
three
sequential
phases,
but
the
Phases
may
overlap.
The
study
protocol
and
informedconsent
information
for
study
subjects
in
clinical
trials
must
also
be
approved
by
an
Institutional
Review
Board,
or
IRB,
for
each
institution
where
the
trials
will
beconducted,
and
each
IRB
must
monitor
the
study
until
completion.
Study
subjects
must
provide
informed
consent
and
sign
an
informed
consent
form
beforeparticipating
in
a
clinical
trial.
Clinical
testing
also
must
satisfy
the
extensive
GCP
regulations
for
informed
consent
and
privacy
of
individually
identifiableinformation.







Phase
1
usually
involves
the
initial
introduction
of
the
investigational
drug
into
people
to
evaluate
its
short-term
safety,
dosage
tolerance,
metabolism,pharmacokinetics
and
pharmacologic
actions,
and,
if
possible,
to
gain
an
early
indication
of
its
effectiveness.
Phase
1
studies
are
usually
conducted
in
healthyindividuals
and
are
not
intended
to
treat
disease
or
illness.
However,
Phase
1b
studies
are
conducted
in
healthy
volunteers
or
in
patients
diagnosed
with
the
diseaseor
condition
for
which
the
study
drug
is
intended,
who
present
some
biomarker,
surrogate,
or
possibly
clinical
outcome
that
could
be
considered
for
"proof
ofconcept."
Proof
of
concept
in
a
Phase
1b
study
typically
confirms
the
hypothesis
that
the
current
prediction
of
biomarker,
or
outcome
benefit
is
compatible
with
themechanism
of
action.







Phase
2
usually
involves
trials
in
a
limited
patient
population
to:
(1)
evaluate
dosage
tolerance
and
appropriate
dosage;
(2)
identify
possible
adverse
effects
andsafety
risks;
and
(3)
evaluate
preliminarily
the
efficacy
of
the
drug
for
specific
target
indications.
Several
different
doses
of
the
drug
may
be
looked
at
in
Phase
2
tosee
which
dose
has
the
desired
effects.
Patients
are
monitored
for
side
effects
and
for
any
improvement
in
their
illness,
symptoms,
or
both.







Phase
3
trials
usually
further
evaluate
clinical
efficacy
and
test
further
for
safety
by
using
the
drug
in
its
planned
commercial
form
in
an
expanded
patientpopulation.
A
Phase
3
trial
usually
compares
how
well
the
study
drug
works
compared
with
an
inactive
placebo
and/or
another
approved
medication.
One
group
ofpatients
may
receive
the
investigational
new
drug
being
tested,
while
another
group
of
patients
may
receive
the
comparator
drug
(already
approved
drug
for
thedisease
being
studied),
or
placebo.







There
can
be
no
assurance
that
Phase
1,
Phase
2
or
Phase
3
testing
will
be
completed
successfully
within
any
specified
period
of
time,
if
at
all.
Furthermore,we
or
the
FDA
or
an
IRB
(with
respect
to
a
particular
study
site)
may
suspend
clinical
trials
at
any
time
on
various
grounds,
including
a
finding
that
the
subjects
orpatients
are
being
exposed
to
an
unacceptable
health
risk.







Assuming
successful
completion
of
the
required
clinical
testing,
the
results
of
the
preclinical
studies
and
of
the
clinical
studies,
together
with
other
detailedinformation,
including
information
on
the
manufacture
and
composition
of
the
drug,
are
submitted
to
the
FDA
in
the
form
of
an
NDA
requesting
approval
tomarket
the
product
for
one
or
more
proposed
indications.
The
testing
and
approval
process
requires
substantial
time,
effort
and
financial
resources.
The
FDAreviews
the
application
and
may
deem
it
to
be
inadequate,
and
companies
cannot
be
sure
that
any
approval
will
be
granted
on
a
timely
basis,
if
at
all.
The
FDA
mayalso
refer
the
application
to
an
appropriate
advisory
committee,
typically
a
panel
of
clinicians,
for
review,
evaluation
and
a
recommendation
as
to
whether25Table
of
Contentsthe
application
should
be
approved.
The
FDA
is
not
bound
by
the
recommendations
of
the
advisory
committee,
but
the
Agency
historically
has
tended
to
followsuch
recommendations.







The
FDA
has
various
programs,
including
fast
track
designation,
breakthrough
therapy
designation,
priority
review
and
accelerated
approval,
which
areintended
to
expedite
or
simplify
the
process
for
reviewing
drugs
and/or
provide
for
approval
on
the
basis
of
surrogate
endpoints.
Generally,
drugs
that
may
beeligible
for
one
or
more
of
these
programs
are
those
intended
to
treat
serious
or
life-threatening
diseases
or
conditions,
those
with
the
potential
to
address
unmetmedical
needs
for
those
disease
or
conditions,
and
those
that
provide
meaningful
benefit
over
existing
treatments.
For
example,
a
sponsor
may
be
granted
FDAdesignation
of
a
drug
candidate
as
a
"breakthrough
therapy"
if
the
drug
candidate
is
intended,
alone
or
in
combination
with
one
or
more
other
drugs,
to
treat
aserious
or
life-threatening
disease
or
condition
and
preliminary
clinical
evidence
indicates
that
the
drug
may
demonstrate
substantial
improvement
over
existingtherapies
on
one
or
more
clinically
significant
endpoints,
such
as
substantial
treatment
effects
observed
early
in
clinical
development.
If
a
drug
is
designated
asbreakthrough
therapy,
FDA
will
expedite
the
development
and
review
of
such
drug.
From
time
to
time,
we
anticipate
applying
for
such
programs
where
we
believewe
meet
the
applicable
FDA
criteria.
A
company
cannot
be
sure
that
any
of
its
drugs
will
qualify
for
any
of
these
programs,
or
even
if
a
drug
does
qualify,
that
thereview
time
will
be
reduced.







Before
approving
an
NDA,
the
FDA
usually
will
inspect
the
facility
or
the
facilities
at
which
the
drug
is
manufactured
and
will
not
approve
the
product
unlessthe
manufacturing
and
production
and
testing
facilities
are
in
compliance
with
cGMP
regulations.
If
the
NDA
and
the
manufacturing
facilities
are
deemedacceptable
by
the
FDA,
it
may
issue
an
approval
letter,
or
in
some
cases,
a
Complete
Response
Letter.
An
approval
letter
authorizes
commercial
marketing
of
thedrug
with
specific
prescribing
information
for
a
specific
indication(s).
A
Complete
Response
Letter
indicates
that
the
review
cycle
of
the
application
is
completeand
the
application
is
not
ready
for
approval.
A
Complete
Response
Letter
may
require
additional
clinical
data
and/or
an
additional
pivotal
Phase
3
clinical
trial(s),and/or
other
significant,
expensive
and
time-consuming
requirements
related
to
clinical
trials,
preclinical
studies
or
manufacturing.
Even
if
such
additionalinformation
is
submitted,
the
FDA
may
ultimately
decide
that
the
NDA
does
not
satisfy
the
criteria
for
approval.
The
FDA
could
also
require,
as
a
condition
ofNDA
approval,
post-marketing
testing
and
surveillance
to
monitor
the
drug's
safety
or
efficacy,
or
impose
other
conditions.
Approval
may
also
be
contingent
on
aRisk
Evaluation
and
Mitigation
Strategy,
or
REMS,
that
limits
the
labeling,
distribution
or
promotion
of
a
drug
product.
The
FDA
also
may
condition
approval
on,among
other
things,
changes
to
proposed
labeling,
development
of
adequate
controls
and
specifications,
or
a
commitment
to
conduct
one
or
more
post-marketingstudies
or
clinical
trials.
Once
issued,
the
FDA
may
withdraw
product
approval
if
ongoing
regulatory
requirements
are
not
met
or
if
safety
problems
occur
after
theproduct
reaches
the
market.







After
approval,
certain
changes
to
the
approved
product,
such
as
adding
new
indications,
making
certain
manufacturing
changes
or
making
certain
additionallabeling
claims,
are
subject
to
further
FDA
review
and
approval.
Before
a
company
can
market
products
for
additional
indications,
it
must
obtain
additionalapprovals
from
the
FDA.
Obtaining
approval
for
a
new
indication
generally
requires
that
additional
clinical
studies
be
conducted.
A
company
cannot
be
sure
thatany
additional
approval
for
new
indications
for
any
investigational
product
candidate
will
be
approved
on
a
timely
basis,
or
at
all.        Post-Approval Requirements —Often
times,
even
after
a
drug
has
been
approved
by
the
FDA
for
sale,
the
FDA
may
require
that
certain
post-approvalrequirements
be
satisfied,
including
the
conduct
of
additional
clinical
studies.
If
such
post-approval
conditions
are
not
satisfied,
the
FDA
may
withdraw
its
approvalof
the
drug.
In
addition,
holders
of
an
approved
NDA
are
required
to:
(1)
report
certain
adverse
reactions
to
the
FDA,
(2)
comply
with
certain
requirementsconcerning
advertising
and
promotional
labeling
for
their
products,
and
(3)
continue
to
have
quality
control
and
manufacturing
procedures
conform
to
cGMPregulations
after
approval.
The
FDA
periodically
inspects
the
sponsor's26Table
of
Contentsrecords
related
to
safety
reporting
and/or
manufacturing
facilities;
this
latter
effort
includes
assessment
of
ongoing
compliance
with
cGMP
regulations.Accordingly,
manufacturers
must
continue
to
expend
time,
money
and
effort
in
the
area
of
production
and
quality
control
to
maintain
cGMP
compliance.
We
haveused
and
intend
to
continue
to
use
third-party
manufacturers
to
produce
our
products
in
clinical
and
commercial
quantities,
and
future
FDA
inspections
mayidentify
compliance
issues
at
the
facilities
of
our
contract
manufacturers
that
may
disrupt
production
or
distribution,
or
require
substantial
resources
to
correct.
Inaddition,
discovery
of
problems
with
a
product
after
approval
may
result
in
restrictions
on
a
product,
including
recall
or
withdrawal
of
the
product
from
the
market.        Hatch-Waxman Act —Under
the
Drug
Price
Competition
and
Patent
Term
Restoration
Act
of
1984,
also
known
as
the
Hatch-Waxman
Act,
Congress
createdan
abbreviated
FDA
review
process
for
generic
versions
of
pioneer
(brand
name)
drug
products.
In
considering
whether
to
approve
such
a
generic
drug
product,
theFDA
requires
that
an
Abbreviated
New
Drug
Application,
or
ANDA,
applicant
demonstrate,
among
other
things,
that
the
proposed
generic
drug
product's
activeingredient
is
the
same
as
that
of
the
reference
product,
that
any
impurities
in
the
proposed
product
do
not
affect
the
product's
safety
or
effectiveness,
and
that
itsmanufacturing
processes
and
methods
ensure
the
consistent
potency
and
purity
of
its
proposed
product.







The
Hatch-Waxman
Act
provides
five
years
of
data
exclusivity
for
new
chemical
entities,
which
generally
(except
as
discussed
below)
prevents
the
FDA
fromaccepting
ANDAs
and
505(b)(2)
applications
containing
the
protected
active
ingredient
during
the
five-year
period.
We
expect
to
be
eligible
for
five
years
of
dataexclusivity
following
any
FDA
approval
of
abaloparatide-SC.







The
Hatch-Waxman
Act
also
provides
three
years
of
exclusivity
for
applications
containing
the
results
of
new
clinical
investigations
(other
than
bioavailabilitystudies)
essential
to
the
FDA's
approval
of
new
uses
of
approved
products,
such
as
new
indications,
delivery
mechanisms,
dosage
forms,
strengths,
or
conditions
ofuse.
For
example,
if
abaloparatide-SC
is
approved
for
commercialization
and
we
are
successful
in
performing
a
clinical
trial
of
abaloparatide-TD
that
provides
anew
basis
for
approval
(a
different
delivery
mechanism),
it
is
possible
that
we
may
become
eligible
for
a
three
year
period
of
market
exclusivity
which
protectsagainst
the
approval
(but
not
the
filing)
of
ANDAs
and
505(b)(2)
applications
for
the
protected
use
but
will
not
prohibit
the
FDA
from
accepting
or
approvingANDAs
or
505(b)(2)
applications
for
other
products
containing
the
same
active
ingredient.







The
Hatch-Waxman
Act
requires
NDA
applicants
and
NDA
holders
to
provide
certain
information
about
patents
related
to
the
drug
for
listing
in
the
FDA's
listof
Approved
Drug
Products
with
Therapeutic
Equivalence
Evaluations
(commonly
known
as
the
Orange
Book).
ANDA
and
505(b)(2)
applicants
must
then
certifyregarding
each
of
the
patents
listed
with
the
FDA
for
the
reference
product.
A
certification
that
a
listed
patent
is
invalid
and/or
will
not
be
infringed
by
themarketing
of
the
applicant's
product
is
called
a
"Paragraph
IV
certification."
If
the
ANDA
or
505(b)(2)
applicant
provides
such
a
notification
of
patent
invalidity
ornon-infringement,
then
the
FDA
may
accept
the
ANDA
or
505(b)(2)
application
beginning
four
years
after
approval
of
the
NDA.
If
an
ANDA
or
505(b)(2)application
containing
a
Paragraph
IV
certification
is
submitted
to
the
FDA
and
accepted
as
a
reviewable
filing
by
the
Agency,
the
ANDA
or
505(b)(2)
applicantthen
must
provide,
within
20
days,
notice
to
the
NDA
holder
and
patent
owner
stating
that
the
application
has
been
submitted
and
providing
the
factual
and
legalbasis
for
the
applicant's
opinion
that
the
patent
is
invalid
and/or
not
infringed.
The
NDA
holder
or
patent
owner
then
may
file
suit
against
the
ANDA
or
505(b)(2)applicant
for
patent
infringement.
If
this
is
done
within
45
days
of
receiving
notice
of
the
Paragraph
IV
certification,
a
one-time
30-month
stay
of
the
FDA's
abilityto
approve
the
ANDA
or
505(b)(2)
application
is
triggered.
The
30-month
stay
begins
at
the
end
of
the
NDA
holder's
data
exclusivity
period,
or,
if
data
exclusivityhas
expired,
on
the
date
that
the
patent
holder
is
notified
of
the
submission
of
the
ANDA.
The
FDA
may
approve
the
proposed
product
before
the
expiration
of
the30-month
stay
if
a
court
finds
the
patent
invalid
and/or
not
infringed
or
if
the
court
shortens
the
period
because
the
parties
have
failed
to
cooperate
in
expediting
thelitigation.27Table
of
ContentsEuropean Union—EMA Process







In
the
EU,
medicinal
products
are
authorized
following
a
similar
demanding
process
as
that
required
in
the
United
States
and
applications
are
based
on
theICH
Common
Technical
Document.
In
the
European
Economic
Area,
or
EEA
(comprised
of
28
EU
Member
States
plus
Iceland,
Liechtenstein
and
Norway),medicines
can
be
authorized
by
using
either
the
centralized
authorization
procedure
or
national
authorization
procedures.        Centralized procedure —Under
the
centralized
procedure,
following
the
opinion
of
the
EMA's
Committee
for
Medicinal
Products
for
Human
Use
(CHMP),the
European
Commission
issues
a
single
marketing
authorization
valid
across
the
EEA.
The
centralized
procedure
is
compulsory
for
human
medicines
derivedfrom
biotechnology
processes,
advanced
therapy
medicinal
products
(such
as
gene
therapy,
somatic
cell
therapy
and
tissue
engineered
products),
containing
a
newactive
substance
indicated
for
the
treatment
of
certain
diseases,
such
as
HIV/AIDS,
cancer,
or
neurodegenerative
disorders,
diabetes,
autoimmune
diseases
andother
immune
dysfunctions,
viral
diseases,
and
officially
designated
orphan
medicines.
For
medicines
that
do
not
fall
within
these
categories,
an
applicant
has
theoption
of
submitting
an
application
for
a
centralized
marketing
authorization
to
the
EMA,
as
long
as
the
medicine
concerned
contains
a
new
active
substance
notyet
authorized
in
the
EEA,
is
a
significant
therapeutic,
scientific
or
technical
innovation,
or
if
its
authorization
would
be
in
the
interest
of
public
health
in
the
EEA.In
November
2015,
we
submitted
an
MAA
for
abaloparatide-SC
to
the
EMA
under
the
centralized
procedure.
The
MAA
was
validated
in
December
2015
and
iscurrently
undergoing
regulatory
review
by
the
EMA.        National authorization procedures —There
are
also
two
other
possible
routes
to
authorize
medicinal
products
in
several
countries,
which
are
available
forproducts
that
fall
outside
the
scope
of
the
centralized
procedure:•Decentralized procedure. 

Using
the
decentralized
procedure,
an
applicant
may
apply
for
simultaneous
authorization
in
more
than
one
EU
countryof
a
medicinal
product
that
has
not
yet
been
authorized
in
any
EU
country
and
that
does
not
fall
within
the
mandatory
scope
of
the
centralizedprocedure.
•Mutual recognition procedure. 

In
the
mutual
recognition
procedure,
a
medicine
is
first
authorized
in
one
EU
Member
State,
in
accordance
with
thenational
procedures
of
that
country.
Thereafter,
further
marketing
authorizations
can
be
sought
from
other
EU
countries
in
a
procedure
whereby
thecountries
concerned
agree
to
recognize
the
validity
of
the
original,
national
marketing
authorization.







In
light
of
the
fact
that
there
is
no
policy
at
the
EU
level
governing
pricing
and
reimbursement,
the
28
EU
Member
States
each
have
developed
their
own,
oftenvarying,
approaches.
In
many
EU
Member
States,
pricing
negotiations
must
take
place
between
the
holder
of
the
marketing
authorization
and
the
competentnational
authorities
before
the
product
is
sold
in
their
market
with
the
holder
of
the
marketing
authorization
required
to
provide
evidence
demonstrating
thepharmaco-economic
superiority
of
its
product
in
comparison
with
directly
and
indirectly
competing
products.
We
have
reviewed
our
development
program,proposed
Phase
3
study
design,
and
overall
non-clinical
and
clinical
data
package
and
believe
they
support
future
regulatory
approval
of
abaloparatide-SC
in
theEU.        Good manufacturing practices —Like
the
FDA,
the
EMA,
the
competent
authorities
of
the
EU
Member
States
and
other
regulatory
agencies
regulate
andinspect
equipment,
facilities
and
processes
used
in
the
manufacturing
of
pharmaceutical
and
biologic
products
prior
to
approving
a
product.
If,
after
receivingclearance
from
regulatory
agencies,
a
company
makes
a
material
change
in
manufacturing
equipment,
location,
or
process,
additional
regulatory
review
andapproval
may
be
required.
Once
we
or
our
partners
commercialize
products,
we
will
be
required
to
comply
with
cGMP,28Table
of
Contentsand
product-specific
regulations
enforced
by,
the
European
Commission,
the
EMA
and
the
competent
authorities
of
EU
Member
States
following
product
approval.Also
like
the
FDA,
the
EMA,
the
competent
authorities
of
the
EU
Member
States
and
other
regulatory
agencies
also
conduct
regular,
periodic
visits
to
re-inspectequipment,
facilities,
and
processes
following
the
initial
approval
of
a
product.
If,
as
a
result
of
these
inspections,
it
is
determined
that
our
or
our
partners'equipment,
facilities,
or
processes
do
not
comply
with
applicable
regulations
and
conditions
of
product
approval,
regulatory
agencies
may
seek
civil,
criminal
oradministrative
sanctions
and/or
remedies
against
us,
including
the
suspension
of
our
manufacturing
operations
or
the
withdrawal
of
our
product
from
the
market.        Data and Market Exclusivity —Similar
to
the
United
States,
there
is
a
process
for
approval
of
generic
versions
of
innovator
drug
products
in
the
EU.
Abridgedapplications
for
the
authorization
of
generic
versions
of
drugs
authorized
by
EMA
can
be
submitted
to
the
EMA
through
the
centralized
procedure
referencing
theinnovator's
data
and
demonstrating
bioequivalence
to
the
reference
product,
among
other
things.







New
medicinal
products
in
the
EU
can
receive
eight
years
of
data
exclusivity
coupled
with
two
years
of
market
exclusivity,
and
a
potential
one
year
extension,if
the
marketing
authorizations
holder
obtains
an
authorization
for
one
or
more
new
therapeutic
indications
that
demonstrates
"significant
clinical
benefit"
incomparison
with
existing
therapies;
this
system
is
usually
referred
to
as
"8+2+1".
We
expect
to
be
eligible
for
at
least
ten
years
of
exclusivity
(8
years
of
dataexclusivity
+
2
years
of
market
exclusivity)
following
any
approval
of
abaloparatide-SC.
At
this
time
we
do
not
believe
that
there
are
orphan
or
pediatricapplications
for
abaloparatide
that
would
be
likely
to
result
in
a
grant
of
exclusivity
or
supplemental
protection
certificate
in
the
EU.







Abridged
applications
cannot
rely
on
an
innovator's
data
until
after
expiry
of
the
8-year
data
exclusivity
term;
applications
for
a
generic
product
can
besubmitted
after
that
8
th

year,
but
the
product
cannot
be
marketed
until
the
end
of
the
market
exclusivity
term.Other International Markets—Drug approval process







In
some
international
markets
(e.g.,
China
or
Japan),
although
data
generated
in
United
States
or
EU
trials
may
be
submitted
in
support
of
a
marketingauthorization
application,
additional
clinical
trials
conducted
in
the
host
territory,
or
studying
people
of
the
ethnicity
of
the
host
territory,
may
be
required
prior
tothe
filing
or
approval
of
marketing
applications
within
the
country.Pricing and Reimbursement







In
the
United
States
and
internationally,
sales
of
products
that
we
market
in
the
future,
and
our
ability
to
generate
revenues
on
such
sales,
are
dependent,
insignificant
part,
on
the
availability
and
level
of
coverage
and
reimbursement
from
third-party
payors
such
as
state
and
federal
governments,
managed
care
providersand
private
insurance
plans.
Private
insurers,
such
as
health
maintenance
organizations
and
managed
care
providers,
have
implemented
cost-cutting
andreimbursement
initiatives
and
likely
will
continue
to
do
so
in
the
future.
These
include
establishing
formularies
that
govern
the
drugs
and
biologics
that
will
beoffered
and
also
the
out-of-pocket
obligations
of
member
patients
for
such
products.
In
addition,
particularly
in
the
United
States
and
increasingly
in
othercountries,
we
may
be
required
to
provide
discounts
and
pay
rebates
to
state
and
federal
governments
and
agencies
in
connection
with
purchases
of
our
products
thatare
reimbursed
by
such
entities.
It
is
possible
that
future
legislation
in
the
United
States
and
other
jurisdictions
could
be
enacted
which
could
potentially
impact
thereimbursement
rates
for
the
products
we
are
developing
and
may
develop
in
the
future
and
also
could
further
impact
the
levels
of
discounts
and
rebates
paid
tofederal
and
state
government
entities.
Any
legislation
that
impacts
these
areas
could
impact,
in
a
significant
way,
our
ability
to
generate
revenues
from
sales
ofproducts
that,
if
successfully
developed,
we
bring
to
market.29Table
of
Contents







The
Medicare
Prescription
Drug,
Improvement,
and
Modernization
Act
of
2003,
or
MMA,
established
the
Medicare
Part
D
program
to
provide
a
voluntaryprescription
drug
benefit
to
Medicare
beneficiaries.
Under
Part
D,
Medicare
beneficiaries
may
enroll
in
prescription
drug
plans
offered
by
private
entities
toprovide
coverage
of
outpatient
prescription
drugs.
Part
D
plans
include
both
stand-alone
prescription
drug
benefit
plans
and
prescription
drug
coverage
as
asupplement
to
Medicare
Advantage
plans.
Unlike
Medicare
Parts
A
and
B,
Part
D
coverage
is
not
standardized.
Part
D
prescription
drug
plan
sponsors
are
notrequired
to
pay
for
all
covered
Part
D
drugs,
and
each
Part
D
prescription
drug
plan
can
develop
its
own
drug
formulary
that
identifies
which
drugs
it
will
cover
andat
what
tier
or
level.
However,
Part
D
prescription
drug
formularies
must
include
drugs
within
each
therapeutic
category
and
class
of
covered
Part
D
drugs,although
not
necessarily
all
of
the
drugs
within
each
category
or
class.
Any
formulary
used
by
a
Part
D
prescription
drug
plan
must
be
developed
and
reviewed
by
apharmacy
and
therapeutic
committee.
We
anticipate
that
a
significant
proportion
of
patients
eligible
for
abaloparatide-SC
will
be
Medicare
beneficiaries
and
weexpect
that
abaloparatide-SC,
if
approved,
will
be
covered
under
Medicare
Part
D,
although
we
cannot
assure
you
that
Part
D
prescription
drug
plan
sponsors
willcover
abaloparatide-SC,
or,
if
covered,
at
what
tier
or
level.







Government
payment
for
some
of
the
costs
of
prescription
drugs
may
increase
demand
for
any
of
our
products
that
is
successfully
developed
and
approved.However,
any
negotiated
prices
for
our
products
covered
by
a
Part
D
prescription
drug
plan
will
likely
be
lower
than
the
prices
we
might
otherwise
obtain.Moreover,
although
the
MMA
applies
only
to
drug
benefits
for
Medicare
beneficiaries,
private
payers
often
follow
Medicare
coverage
policy
and
paymentlimitations
in
setting
their
own
payment
rates.
Accordingly,
any
reduction
in
payment
under
Medicare
may
result
in
a
similar
reduction
in
payments
from
non-governmental
payers.







We
expect
that
there
will
continue
to
be
a
number
of
federal
and
state
proposals
to
implement
governmental
pricing
controls
and
limit
the
growth
of
healthcarecosts,
including
the
cost
of
prescription
drugs.
Currently,
Medicare
is
prohibited
from
negotiating
directly
with
pharmaceutical
companies
for
drugs.
However,
theU.S.
Congress
may
in
the
future
consider
legislation
that
would
lift
the
ban
on
federal
negotiations.







The
American
Recovery
and
Reinvestment
Act
of
2009
provides
funding
for
the
federal
government
to
compare
the
effectiveness
of
different
treatments
forthe
same
illness.
A
plan
for
the
research
would
be
developed
by
the
Department
of
Health
and
Human
Services,
the
Agency
for
Healthcare
Research
and
Qualityand
the
National
Institutes
of
Health,
and
periodic
reports
on
the
status
of
the
research
and
related
expenditures
would
be
made
to
the
U.S.
Congress.
Although
theresults
of
the
comparative
effectiveness
studies
are
not
intended
to
mandate
coverage
policies
for
public
or
private
payers,
it
is
not
clear
whether
research
wouldhave
any
effect
on
the
sales
of
any
of
our
products
that
is
successfully
developed
and
approved,
if
the
product
or
the
condition
that
it
is
intended
to
treat
becomesthe
subject
of
a
study.
It
is
also
possible
that
comparative
effectiveness
research
demonstrating
benefits
of
a
competitor's
product
could
adversely
affect
the
sales
ofany
of
our
products
that
is
successfully
developed
and
approved.
If
third-party
payers
do
not
consider
our
products
to
be
cost-effective
compared
to
other
availabletherapies,
they
may
not
cover
our
products
after
approval
as
a
benefit
under
their
plans
or,
if
they
do,
the
level
of
payment
may
not
be
sufficient
to
allow
us
to
sellour
products
on
a
profitable
basis.







The
Patient
Protection
and
Affordable
Care
Act,
or
the
ACA,
as
amended
by
the
Health
Care
and
Education
Affordability
Reconciliation
Act
of
2010,
orcollectively
the
ACA,
is
expected
to
have
a
significant
impact
on
the
health
care
industry.
The
ACA
expands
coverage
for
the
uninsured
while
at
the
same
timecontaining
overall
healthcare
costs.
Among
other
things,
the
ACA
expands
and
increases
industry
rebates
for
drugs
covered
under
Medicaid
programs
and
makechanges
to
the
coverage
requirements
under
the
Medicare
Part
D
program.
In
addition,
other
legislative
changes
have
been
proposed
and
adopted
in
the
UnitedStates
since
the
ACA
was
enacted.
On
August
2,
2011,
the
Budget30Table
of
ContentsControl
Act
of
2011,
among
other
things,
created
measures
for
spending
reductions
by
Congress.
A
Joint
Select
Committee
on
Deficit
Reduction,
tasked
withrecommending
a
targeted
deficit
reduction
of
at
least
$1.2
trillion
for
the
years
2013
through
2021,
was
unable
to
reach
required
goals,
thereby
triggering
thelegislation's
automatic
reduction
to
several
government
programs.
This
includes
aggregate
reductions
to
Medicare
payments
to
providers
of
2%
per
fiscal
year,which
went
into
effect
on
April
1,
2013
and,
due
to
subsequent
legislative
amendments
to
the
statute,
will
remain
in
effect
through
2025
unless
additionalCongressional
action
is
taken.
On
January
2,
2013,
President
Obama
signed
into
law
the
American
Taxpayer
Relief
Act
of
2012,
or
the
ATRA,
which
among
otherthings,
further
reduced
Medicare
payments
to
several
providers,
including
hospitals,
imaging
centers
and
cancer
treatment
centers.







There
is
no
legislation
at
the
EU
level
governing
the
pricing
and
reimbursement
of
medicinal
products
in
the
EU.
As
a
result,
the
competent
authorities
of
eachof
the
28
EU
Member
States
have
adopted
individual
strategies
regulating
the
pricing
and
reimbursement
of
medicinal
products
in
their
territory.
These
strategiesoften
vary
widely
in
nature,
scope
and
application.
However,
a
major
element
that
they
have
in
common
is
an
increased
move
towards
reduction
in
thereimbursement
price
of
medicinal
products,
a
reduction
in
the
number
and
type
of
products
selected
for
reimbursement,
and
an
increased
preference
for
genericproducts
over
innovative
products.
These
efforts
have
mostly
been
executed
through
these
countries'
existing
price-control
methodologies,
including
price
cuts,mandatory
rebates,
value-based
pricing,
and
reference
pricing
(i.e.,
referencing
prices
in
other
countries
and
using
those
reference
prices
to
set
a
price).
Thegovernment
of
the
UK
announced
the
phase-out
of
its
established
Pharmaceutical
Pricing
Reimbursement
Scheme
approach
in
January
2014
and
the
adoption
of
anew
value-based
pricing
approach,
at
least
for
new
product
introductions.
Under
this
approach,
in
a
complete
departure
from
established
methodologies,reimbursement
levels
of
each
drug
will
be
explicitly
based
on
an
assessment
of
value,
looking
at
the
benefits
for
the
patient,
unmet
need,
therapeutic
innovation,and
benefit
to
society
as
a
whole.
It
is
increasingly
common
in
many
EU
Member
States
for
Marketing
Authorization
Holders
to
be
required
to
demonstrate
thepharmaco-economic
superiority
of
their
products
as
compared
to
products
already
subject
to
pricing
and
reimbursement
in
specific
countries.
In
order
for
drugs
tobe
evaluated
positively
under
such
criteria,
pharmaceutical
companies
may
need
to
re-examine,
and
consider
altering,
a
number
of
traditional
functions
relating
tothe
selection,
study,
and
management
of
drugs,
whether
currently
marketed,
under
development,
or
being
evaluated
as
candidates
for
research
and/or
development.







Future
legislation,
including
the
current
versions
being
considered
at
the
federal
and
state
level
in
the
United
States
and
at
the
national
level
in
EU
MemberStates,
or
regulatory
actions
implementing
recent
or
future
legislation
may
have
a
significant
effect
on
our
business.
Our
ability
to
successfully
commercializeproducts
depends
in
part
on
the
extent
to
which
coverage
and
reimbursement
for
the
costs
of
our
products
and
related
treatments
will
be
available
in
the
UnitedStates
and
worldwide
from
government
health
administration
authorities,
private
health
insurers
and
other
organizations.
Substantial
uncertainty
exists
as
to
thereimbursement
status
of
newly
approved
healthcare
products
by
third-party
payors.
In
addition,
negotiating
prices
with
government
authorities
under
current
andproposed
legislation
can
delay
the
commercialization
of
our
product
candidates.Sales and Marketing







The
FDA
regulates
all
advertising
and
promotion
activities
for
products
under
its
jurisdiction
both
prior
to
and
after
approval.
A
company
can
make
only
thoseclaims
relating
to
safety
and
efficacy
that
are
approved
by
the
FDA
following
review
and
approval
of
an
NDA.
Physicians
may
prescribe
legally
available
drugs
foruses
that
are
not
described
in
the
drug's
labeling
and
that
differ
from
those
tested
by
us
and
approved
by
the
FDA.
Such
off-label
uses
are
common
across
medicalspecialties,
and
often
reflect
a
physician's
belief
that
the
off-label
use
is
the
best
treatment
for
the
patients.
The
FDA
does
not
regulate
the
behavior
of
physicians
intheir
choice
of
treatments,
but
FDA
regulations
do
impose31Table
of
Contentsstringent
restrictions
on
manufacturers'
communications
regarding
off-label
uses.
Failure
to
comply
with
applicable
FDA
requirements
may
subject
a
company
toadverse
publicity,
enforcement
action
by
the
FDA,
corrective
advertising,
consent
decrees
and
the
full
range
of
civil
and
criminal
penalties
available
to
the
FDA.







We
may
also
be
subject
to
various
federal
and
state
laws
pertaining
to
healthcare
"fraud
and
abuse,"
including
anti-kickback
laws
and
false
claims
laws.
Anti-kickback
laws
make
it
illegal
for
a
prescription
drug
manufacturer
to
solicit,
offer,
receive,
or
pay
any
remuneration
in
exchange
for,
or
to
induce,
the
referral
ofbusiness,
including
the
purchase
or
prescription
of
a
particular
drug.
Due
to
the
breadth
of
the
statutory
provisions
and
the
absence
of
guidance
in
the
form
ofregulations
and
very
few
court
decisions
addressing
industry
practices,
it
is
possible
that
our
practices
might
be
challenged
under
anti-kickback
or
similar
laws.Moreover,
recent
healthcare
reform
legislation
has
strengthened
these
laws.
For
example,
the
ACA,
among
other
things,
amends
the
intent
requirement
of
thefederal
anti-kickback
and
criminal
healthcare
fraud
statutes,
so
that
a
person
or
entity
no
longer
needs
to
have
actual
knowledge
of
this
statute
or
specific
intent
toviolate
it
in
order
to
have
committed
a
violation.
In
addition,
ACA
permits
the
government
to
assert
that
a
claim
that
includes
items
or
services
resulting
from
aviolation
of
the
federal
anti-kickback
statute
constitutes
a
false
or
fraudulent
claim
for
purposes
of
the
false
claims
statutes.
False
claims
laws
prohibit
anyone
fromknowingly
and
willingly
presenting,
or
causing
to
be
presented
for
payment,
to
third-party
payors
(including
Medicare
and
Medicaid)
claims
for
reimbursed
drugsor
services
that
are
false
or
fraudulent,
claims
for
items
or
services
not
provided
as
claimed,
or
claims
for
medically
unnecessary
items
or
services.
Our
activitiesrelating
to
the
sale
and
marketing
of
our
products,
if
approved,
may
be
subject
to
scrutiny
under
these
laws.
Violations
of
fraud
and
abuse
laws
may
be
punishableby
criminal
and
civil
sanctions,
including
fines
and
civil
monetary
penalties,
the
possibility
of
exclusion
from
federal
healthcare
programs
(including
Medicare
andMedicaid)
and
corporate
integrity
agreements,
which
impose,
among
other
things,
rigorous
operational
and
monitoring
requirements
on
companies.
Similarsanctions
and
penalties
also
can
be
imposed
upon
executive
officers
and
employees,
including
criminal
sanctions
against
executive
officers
under
the
so-called"responsible
corporate
officer"
doctrine,
even
in
situations
where
the
executive
officer
did
not
intend
to
violate
the
law
and
was
unaware
of
any
wrongdoing.







Given
the
significant
penalties
and
fines
that
can
be
imposed
on
companies
and
individuals
if
convicted,
allegations
of
such
violations
often
result
insettlements
even
if
the
company
or
individual
being
investigated
admits
no
wrongdoing.
Settlements
often
include
significant
civil
sanctions,
including
fines
andcivil
monetary
penalties,
and
corporate
integrity
agreements.
If
the
government
were
to
allege
or
convict
us
or
our
executive
officers
of
violating
these
laws,
ourbusiness
could
be
harmed.
In
addition,
private
individuals
have
the
ability
to
bring
similar
actions.
The
majority
of
states
also
have
anti-kickback
and
false
claimslaws,
which
establish
similar
prohibitions
and
in
some
cases
may
apply
to
items
or
services
reimbursed
by
any
third-party
payor,
including
commercial
insurers.Our
activities
could
be
subject
to
challenge
for
the
reasons
discussed
above
and
due
to
the
broad
scope
of
these
laws
and
the
increasing
attention
being
given
tothem
by
law
enforcement
authorities.







There
has
also
been
a
recent
trend
of
increased
federal
and
state
regulation
of
payments
made
to
physicians
and
other
healthcare
providers.
The
ACA,
amongother
things,
imposes
new
reporting
requirements
on
drug
manufacturers
for
payments
made
by
them
to
physicians
and
teaching
hospitals,
as
well
as
ownership
andinvestment
interests
held
by
physicians
and
their
immediate
family
members.
Failure
to
submit
required
information
may
result
in
civil
monetary
penalties
of
up
toan
aggregate
of
$150,000
per
year
(or
up
to
an
aggregate
of
$1
million
per
year
for
"knowing
failures"),
for
all
payments,
transfers
of
value
or
ownership
orinvestment
interests
that
are
not
timely,
accurately
and
completely
reported
in
an
annual
submission.
Drug
manufacturers
are
required
to
submit
reports
to
thegovernment
by
the
90th
day
of
each
calendar
year.
Certain
states
also
mandate
implementation
of
compliance
programs,
impose
restrictions
on
drug
manufacturermarketing
practices
and/or
require
the
tracking
and
reporting
of
gifts,
compensation
and
other
remuneration
to
physicians.
Many
of
these
laws32Table
of
Contentscontain
ambiguities
as
to
what
is
required
to
comply
with
the
laws.
Given
the
lack
of
clarity
in
laws
and
their
implementation,
our
actions
could
be
subject
to
thepenalty
provisions
of
the
pertinent
state
authorities.







Similar
rigid
restrictions
are
imposed
on
the
promotion
and
marketing
of
medicinal
products
in
the
EU
and
other
countries.
Laws
(including
those
governingpromotion,
marketing
and
anti-kickback
provisions),
industry
regulations
and
professional
codes
of
conduct
often
are
strictly
enforced.
Even
in
those
countrieswhere
we
are
not
directly
responsible
for
the
promotion
and
marketing
of
our
products,
inappropriate
activity
by
our
international
distribution
partners
can
haveadverse
implications
for
us.Other Laws and Regulatory Processes







We
are
subject
to
a
variety
of
financial
disclosure
and
securities
trading
regulations
as
a
public
company
in
the
United
States,
including
laws
relating
to
theoversight
activities
of
the
SEC
and
the
regulations
of
the
NASDAQ
Global
Market
or
any
national
securities
exchange
on
which
our
capital
stock
may
be
traded.
Inaddition,
the
Financial
Accounting
Standards
Board,
or
FASB,
the
SEC
and
other
bodies
that
have
jurisdiction
over
the
form
and
content
of
our
accounts,
ourconsolidated
financial
statements
and
other
public
disclosure
are
constantly
discussing
and
interpreting
proposals
and
existing
pronouncements
designed
to
ensurethat
companies
best
display
relevant
and
transparent
information
relating
to
their
respective
businesses.







Our
international
operations
are
subject
to
compliance
with
the
Foreign
Corrupt
Practices
Act,
or
the
FCPA,
which
prohibits
corporations
and
individuals
frompaying,
offering
to
pay,
or
authorizing
the
payment
of
anything
of
value
to
any
foreign
government
official,
government
staff
member,
political
party,
or
politicalcandidate
in
an
attempt
to
obtain
or
retain
business
or
to
otherwise
influence
a
person
working
in
an
official
capacity.
We
also
may
be
implicated
under
the
FCPAfor
activities
by
our
partners,
collaborators,
clinical
research
organizations,
vendors
or
other
agents.







Our
present
and
future
business
has
been
and
will
continue
to
be
subject
to
various
other
laws
and
regulations.
Various
laws,
regulations
and
recommendationsrelating
to
safe
working
conditions,
laboratory
practices,
the
experimental
use
of
animals,
and
the
purchase,
storage,
movement,
import
and
export
and
use
anddisposal
of
hazardous
or
potentially
hazardous
substances
used
in
connection
with
our
research
work
are
or
may
be
applicable
to
our
activities.
Certain
agreementsentered
into
by
us
involving
exclusive
license
rights
or
acquisitions
may
be
subject
to
national
or
supranational
antitrust
regulatory
control,
the
effect
of
whichcannot
be
predicted.
The
extent
of
government
regulation,
which
might
result
from
future
legislation
or
administrative
action,
cannot
accurately
be
predicted.Employees







As
of
December
31,
2015,
we
employed
73
full-time
employees
and
2
part-time
employees,
20
of
whom
held
Ph.D.
or
M.D.
degrees.
Forty-eight
of
ouremployees
were
engaged
in
research
and
development
activities
and
27
were
engaged
in
support
administration,
including
business
development
and
finance.
Weintend
to
use
CROs
and
other
third
parties
to
perform
our
clinical
studies
and
manufacturing.Corporate
Information







We
were
incorporated
in
the
state
of
Delaware
on
February
4,
2008
under
the
name
MPM
Acquisition
Corp.
In
May
2011,
we
entered
into
a
reverse
mergertransaction,
or
the
Merger,
with
our
predecessor,
Radius
Health,
Inc.,
a
Delaware
corporation
formed
on
October
3,
2003,
or
the
Former
Operating
Company,pursuant
to
which
the
Former
Operating
Company
became
a
wholly-owned
subsidiary
of
ours.
Immediately
following
the
merger
transaction,
the
Former
OperatingCompany
was
merged
with
and
into
us
and
we
assumed
the
business
of
the
Former
Operating
Company
and
changed
our
name
to
Radius
Health,
Inc.33Table
of
ContentsLegal
Proceedings







We
are
not
currently
involved
in
any
material
legal
proceedings.Investor
Information







Financial
and
other
information
about
us
is
available
on
our
website
at
www.radiuspharm.com.
We
make
available
on
our
website,
free
of
charge,
copies
ofour
Annual
Report
on
Form
10-K,
Quarterly
Reports
on
Form
10-Q,
current
reports
on
Form
8-K
and
amendments
to
those
reports
filed
or
furnished
pursuant
toSection
13(a)
or
15(d)
of
the
Exchange
Act
as
soon
as
reasonably
practicable
after
we
electronically
file
such
material
with,
or
furnish
it
to,
the
SEC.
In
addition,we
have
previously
filed
registration
statements
and
other
documents
with
the
SEC.
Any
document
we
file
may
be
inspected,
without
charge,
at
the
SEC's
publicreference
room
at
100
F
Street
NE,
Washington,
DC
20549,
or
at
the
SEC's
internet
address
at
www.sec.gov.
These
website
addresses
are
not
intended
to
functionas
hyperlinks,
and
the
information
contained
in
our
website
and
in
the
SEC's
website
is
not
intended
to
be
a
part
of
this
filing.
Information
related
to
the
operationof
the
SEC's
public
reference
room
may
be
obtained
by
calling
the
SEC
at
800-SEC-0330.34Table
of
ContentsITEM
1A.



RISK
FACTORS.









Our business faces significant risks and uncertainties. Certain important factors may have a material adverse effect on our business prospects, financialcondition and results of operations, and you should carefully consider them. Accordingly, in evaluating our business, we encourage you to consider the followingdiscussion of risk factors, in its entirety, in addition to other information contained in or incorporated by reference into this Annual Report on Form 10-K and ourother public filings with the SEC.Risks
Related
to
Our
Business
Risks
Related
to
Our
Financial
Position
and
Need
for
CapitalWe are not currently profitable and may never become profitable.







We
had
net
losses
of
$101.5
million,
$62.5
million,
and
$60.7
million
for
the
years
ended
December
31,
2015,
2014,
and
2013,
respectively.
As
ofDecember
31,
2015,
we
had
an
accumulated
deficit
of
$445.8
million.
Until
we
succeed
in
developing
and
commercializing
one
or
more
of
our
product
candidates,we
expect
to
incur
substantial
losses
and
may
never
achieve
or
maintain
profitability.
We
also
expect
to
continue
to
incur
significant
operating
and
capitalexpenditures
and
anticipate
that
our
expenses
will
increase
substantially
as
we:•continue
to
undertake
preclinical
development
and
clinical
trials
for
product
candidates;
•seek
regulatory
approvals
for
product
candidates;
•implement
additional
internal
systems
and
infrastructure;
and
•hire
additional
personnel.







We
also
expect
to
experience
negative
cash
flow
as
we
fund
our
operating
losses
and
capital
expenditures.
As
a
result,
we
will
need
to
generate
significantrevenues
in
order
to
achieve
and
maintain
profitability.
Accordingly,
unless
and
until
we
generate
revenues
and
become
profitable,
we
will
need
to
raise
additionalcapital
to
continue
to
operate
our
business.
Our
failure
to
achieve
or
maintain
profitability
or
to
raise
additional
capital
could
negatively
impact
the
value
of
oursecurities.We currently have no product revenues and we may need to raise additional capital, which may not be available on favorable terms, if at all, in order tocontinue operating our business.







To
date,
we
have
generated
no
product
revenues.
Until,
and
unless,
we
receive
approval
from
the
U.S.
Food
and
Drug
Administration,
or
FDA,
or
foreignregulatory
authorities
for
our
product
candidates,
we
will
not
be
permitted
to
sell
our
drugs
and
will
not
have
product
revenues.
Currently,
our
only
productcandidates
are
abaloparatide-SC,
abaloparatide-TD,
RAD1901
and
RAD140,
and
none
of
these
product
candidates
is
approved
by
the
FDA
or
foreign
regulatoryauthorities
for
sale.
Therefore,
for
the
foreseeable
future,
we
will
have
to
fund
our
operations
and
capital
expenditures
with
our
existing
cash
and
cash
equivalentsand
short
and
long-term
marketable
securities,
or
through
strategic
financing
opportunities,
that
could
include,
but
are
not
limited
to
partnering
or
othercollaboration
agreements,
future
offerings
of
our
equity,
and/or
the
incurrence
of
debt.







Based
upon
our
cash,
cash
equivalents
and
short-term
marketable
securities
balance
at
December
31,
2015,
we
believe
that,
prior
to
the
consideration
ofrevenue
from
the
potential
future
sales
of
any
of
our
investigational
products
that
may
receive
regulatory
approval,
we
have
sufficient
capital
to
fund
ourdevelopment
plans,
U.S.
commercial
scale-up
and
other
operational
activities
into
2018.
We
have
based
this
estimate
on
assumptions
that
may
prove
to
be
wrong,and
we
could
use
up
our
available
capital
resources
sooner
than
we
currently
expect.
If
we
fail
to
obtain
additional
capital,
we
may
be
unable
to
complete
ourplanned
preclinical
and
clinical
trials
and
obtain
approval
of
any
product
candidates
from
the
FDA
and
foreign
regulatory
authorities.
In
addition,
we
could
beforced
to35Table
of
Contentsdiscontinue
product
development,
reduce
or
forego
sales
and
marketing
efforts
for
any
product
candidate
that
is
approved,
forego
attractive
business
opportunitiesor
discontinue
our
operations
entirely.
Any
additional
sources
of
financing
may
not
be
available
or
may
not
be
available
on
favorable
terms
and
will
likely
involvethe
issuance
of
additional
equity
securities,
which
will
have
a
dilutive
effect
on
stockholders.
Our
future
capital
requirements
will
depend
on
many
factors,including
the
scope
and
progress
made
in
our
research
and
development
activities
and
our
clinical
studies.Raising additional capital may cause dilution to our existing stockholders, restrict our operations or require us to relinquish rights to our technologies orproduct candidates.







Until
such
time,
if
ever,
as
we
can
generate
substantial
product
revenues,
we
expect
to
finance
our
cash
needs
through
a
combination
of
collaborations,strategic
alliances,
licensing
arrangements,
other
marketing
and
distribution
arrangements,
equity
offerings,
and
debt
financings.
We
do
not
have
any
committedexternal
source
of
funds.
To
the
extent
that
we
raise
additional
capital
through
the
sale
of
equity
or
convertible
debt
securities,
your
ownership
interest
will
bediluted,
and
the
terms
of
these
securities
may
include
liquidation
or
other
preferences
that
adversely
affect
your
rights
as
a
stockholder.
Debt
financing,
if
available,may
involve
agreements
that
include
covenants
limiting
or
restricting
our
ability
to
take
specific
actions,
such
as
incurring
additional
debt,
making
capitalexpenditures
or
declaring
dividends.
If
we
raise
additional
funds
through
marketing
and
distribution
arrangements
or
other
collaborations,
strategic
alliances
orlicensing
arrangements
with
third
parties,
we
may
have
to
relinquish
valuable
rights
to
our
technologies,
future
revenue
streams,
research
programs
or
productcandidates,
or
we
may
need
to
grant
licenses
on
terms
that
may
not
be
favorable
to
us.
If
we
are
unable
to
raise
additional
funds
through
equity
or
debt
financingswhen
needed,
we
may
be
required
to
delay,
limit,
reduce
or
terminate
our
product
development
or
commercialization
efforts
or
grant
rights
to
develop
and
marketproduct
candidates
that
we
would
otherwise
prefer
to
develop
and
market
ourselves.We are a company with a limited operating history upon which to base an investment decision.







We
are
a
company
with
a
limited
operating
history
and
have
not
demonstrated
an
ability
to
perform
the
functions
necessary
for
the
successfulcommercialization
of
any
product
candidates.
The
successful
commercialization
of
any
product
candidates
will
require
us
to
perform
a
variety
of
functions,including:•continuing
to
undertake
preclinical
development
and
clinical
trials;
•participating
in
regulatory
approval
processes;
•formulating
and
manufacturing
products;
and
•conducting
sales
and
marketing
activities
for
products
if
approved.







Our
operations
have
been
limited
to
organizing
and
staffing
our
company,
acquiring,
developing
and
securing
our
proprietary
technology
and
undertakingpreclinical
and
clinical
trials
of
our
product
candidates.
These
operations
provide
a
limited
basis
for
you
to
assess
our
ability
to
commercialize
our
productcandidates
and
the
advisability
of
investing
further
in
our
securities.Our financial results may fluctuate from quarter to quarter, which makes our results difficult to predict and could cause our results to fall short ofexpectations.







Our
financial
results
may
fluctuate
as
a
result
of
a
number
of
factors,
many
of
which
are
outside
of
our
control.
For
these
reasons,
comparing
our
financialresults
on
a
period-to-period
basis
may
not
be
meaningful,
and
you
should
not
rely
on
our
past
results
as
an
indication
of
our
future
performance.
Our
revenues,
ifany,
may
fluctuate
from
quarter
to
quarter
and
our
future
quarterly
and
annual
expenses
as
a
percentage
of
our
revenues
may
be
significantly
different
from
thosewe
have
recorded
in36Table
of
Contentsthe
past
or
which
we
expect
for
the
future.
Our
financial
results
in
some
quarters
may
fall
below
expectations.
Any
of
these
events
as
well
as
the
various
risk
factorslisted
in
this
"Risk
Factors"
section
could
adversely
affect
our
financial
results
and
cause
our
stock
price
to
fall.Our cash and cash equivalents could be adversely affected if the financial institutions in which we hold our cash and cash equivalents fail.







We
regularly
maintain
cash
balances
at
third-party
financial
institutions
in
excess
of
the
Federal
Deposit
Insurance
Corporation
insurance
limit.
While
wemonitor
daily
the
cash
balances
in
the
operating
accounts
and
adjust
the
balances
as
appropriate,
these
balances
could
be
impacted,
and
there
could
be
a
materialadverse
effect
on
our
business,
if
one
or
more
of
the
financial
institutions
with
which
we
deposit
fails
or
is
subject
to
other
adverse
conditions
in
the
financial
orcredit
markets.
To
date,
we
have
experienced
no
loss
or
lack
of
access
to
our
invested
cash
or
cash
equivalents;
however,
we
can
provide
no
assurance
that
accessto
our
invested
cash
and
cash
equivalents
will
not
be
impacted
by
adverse
conditions
in
the
financial
and
credit
markets.Our investments in marketable securities are subject to market, interest and credit risk that may reduce their value.







The
value
of
our
investments
in
marketable
securities
may
be
adversely
affected
by
changes
in
interest
rates,
downgrades
in
the
creditworthiness
of
any
bondswe
hold,
turmoil
in
the
credit
markets
and
financial
services
industry
and
by
other
factors
which
may
result
in
other
than
temporary
declines
in
the
value
of
ourinvestments.
Decreases
in
the
market
value
of
our
marketable
securities
could
have
an
adverse
impact
on
our
statements
of
financial
position,
results
of
operationsand
cash
flow.Risks
Related
to
the
Discovery,
Development
and
Commercialization
of
Our
Product
CandidatesWe are heavily dependent on the success of our investigational product candidate abaloparatide-SC. We cannot be certain that abaloparatide-SC will receiveregulatory approval or be successfully commercialized even if we receive regulatory approval.







Abaloparatide-SC
is
our
only
product
candidate
in
late-stage
clinical
development,
and
our
business
currently
depends
heavily
on
its
successful
development,regulatory
approval
and
commercialization.
We
have
no
drug
products
for
sale
currently
and
may
never
be
able
to
develop
approved
and
marketable
drug
products.The
research,
testing,
manufacturing,
labeling,
approval,
sale,
marketing
and
distribution
of
drug
products
are
subject
to
extensive
regulation
by
the
FDA
andforeign
regulatory
authorities
in
the
United
States
and
other
countries,
which
regulations
differ
from
country
to
country.
We
are
not
permitted
to
marketabaloparatide-SC
in
the
United
States
unless
and
until
we
receive
approval
of
a
new
drug
application,
or
NDA,
from
the
FDA,
or
in
any
foreign
countries
unlessand
until
we
receive
the
requisite
approval
from
regulatory
authorities
in
those
foreign
countries.
In
addition,
the
approval
of
abaloparatide-TD
as
a
line
extensionto
abaloparatide-SC
is
dependent
on
the
earlier
approval
of
abaloparatide-SC.
Obtaining
approval
of
a
product
candidate
is
an
extensive,
lengthy,
expensive
anduncertain
process,
and
any
approval
of
abaloparatide-SC
may
be
delayed,
limited
or
denied
for
many
reasons,
including:•we
may
not
be
able
to
demonstrate
that
abaloparatide
is
safe
and
effective
as
a
treatment
for
reduction
of
fracture
risk
in
postmenopausal
womenwith
osteoporosis
to
the
satisfaction
of
the
FDA
or
foreign
regulatory
authorities;
•the
results
of
our
clinical
studies
may
not
meet
the
level
of
statistical
or
clinical
significance
required
for
marketing
approval;
•the
FDA
or
foreign
regulatory
authorities
may
disagree
with
the
number,
design,
size,
conduct
or
implementation
of
our
clinical
studies;37Table
of
Contents•any
clinical
research
organizations,
or
CROs,
that
we
have
retained
or
may
in
the
future
retain,
to
conduct
clinical
studies
may
take
actions
outsideof
our
control
that
materially
adversely
impact
our
clinical
studies;
•the
FDA
or
foreign
regulatory
authorities
may
not
find
the
data
from
preclinical
studies
and
clinical
studies
sufficient
to
demonstrate
thatabaloparatide's
clinical
and
other
benefits
outweigh
its
safety
risks;
•the
FDA
or
foreign
regulatory
authorities
may
disagree
with
our
interpretation
of
data
from
our
preclinical
studies
and
clinical
studies
or
mayrequire
that
we
conduct
additional
studies;
•the
FDA
or
foreign
regulatory
authorities
may
not
accept
data
generated
at
our
clinical
study
sites;
•the
FDA
or
foreign
regulatory
authorities
may
not
agree
with
our
proposed
labeling
and
may
require
labeling
that
undermines
or
otherwisesignificantly
impairs
the
commercial
value
of
the
product
if
it
were
to
be
approved
with
such
labeling;
•the
FDA
may
require
development
of
a
Risk
Evaluation
and
Mitigation
Strategy,
or
REMS,
as
a
condition
of
approval;
•if
our
NDA
is
reviewed
by
an
advisory
committee,
the
FDA
may
have
difficulties
scheduling
an
advisory
committee
meeting
in
a
timely
manner
orthe
advisory
committee
may
recommend
against
approval
of
our
application
or
may
recommend
that
the
FDA
require,
as
a
condition
of
approval,additional
preclinical
studies
or
clinical
studies,
limitations
on
approved
labeling
or
distribution
and
use
restrictions;
or
•the
FDA
or
foreign
regulatory
authorities
may
identify
deficiencies
in
the
manufacturing
processes
or
facilities
of
our
third-party
manufacturers.







In
addition,
the
FDA
or
foreign
regulatory
authorities
may
change
its
approval
policies
or
adopt
new
regulations.
For
example,
on
February
15,
2012,
wereceived
a
letter
from
the
FDA
stating
that,
after
internal
consideration,
the
FDA
believes
that
a
minimum
of
24-month
fracture
data
are
necessary
for
approval
ofnew
products
for
the
treatment
of
postmenopausal
osteoporosis.
Our
abaloparatide-SC
pivotal
Phase
3
clinical
trial
is
designed
to
produce
fracture
data
based
on
an18-month
primary
endpoint.
Based
on
our
discussions
with
the
FDA,
we
believe
that
continued
use
of
the
18-month
primary
endpoint
will
be
acceptable,
providedthat
our
NDA
includes
the
24-month
fracture
data
derived
from
the
first
six
months
extension
of
the
abaloparatide
80
µg
and
placebo
groups
in
our
Phase
3
study,which
groups
received
an
approved
alendronate
(generic
Fosamax)
therapy
for
osteoporosis
management.
The
NDA
that
we
plan
to
submit
to
the
FDA
forabaloparatide-SC
as
a
proposed
treatment
for
osteoporosis
will
include
the
24-month
fracture
data.
We
cannot
be
certain
that
the
FDA
will
be
supportive
of
thisplan,
will
not
change
this
approval
policy
again
or
will
not
adopt
other
approval
policies
or
regulations
that
adversely
affect
any
NDA
that
we
may
submit,
theoccurrence
of
any
of
which
may
further
delay
FDA
approval.







We
cannot
assure
you
that
we
will
receive
the
approvals
necessary
to
commercialize
abaloparatide-SC,
or
any
of
our
product
candidates,
including
anyproduct
candidates
we
are
currently
developing
or
may
acquire
or
develop
in
the
future.
In
order
to
obtain
FDA
approval
of
abaloparatide-SC,
or
any
productcandidate,
we
must
submit
to
the
FDA
an
NDA
demonstrating
that
the
product
candidate
is
safe
for
humans
and
effective
for
its
indicated
use.
This
demonstrationrequires
significant
research
and
animal
tests,
which
are
referred
to
as
preclinical
studies,
as
well
as
human
tests,
which
are
referred
to
as
clinical
trials.
Satisfactionof
the
FDA's
regulatory
requirements
typically
takes
many
years,
depends
upon
the
type,
complexity
and
novelty
of
the
product
candidate
and
requires
substantialresources
for
research,
development
and
testing.
We
cannot
predict
whether
our38Table
of
Contentsresearch
and
clinical
approaches
will
result
in
drugs
that
the
FDA
considers
safe
for
humans
and
effective
for
proposed
uses.







In
2007,
we
entered
into
a
global
pharmacovigilance
agreement
with
Teijin
Limited,
or
Teijin,
a
Japanese
pharmaceutical
company,
that
provides
for
theexchange
of
information
related
to
serious
and
non-serious
adverse
reactions
to
abaloparatide
by
patients
enrolled
in
clinical
studies.
The
purpose
of
the
agreementis
to
enable
safety
reporting
to
global
health
agencies.
Teijin
has
completed
a
Phase
2
clinical
study
of
abaloparatide-SC
in
Japan
for
the
treatment
ofpostmenopausal
osteoporosis.
Should
Teijin
advise
us
in
accordance
with
our
agreement
of
a
serious
adverse
event
experienced
by
patients
enrolled
in
their
study,we
would
need
to
report
the
serious
adverse
event
to
the
FDA
and
the
European
Medicines
Agency,
or
EMA,
which
could
adversely
affect
or
delay
our
ability
toobtain
regulatory
approvals
in
the
United
States
and
Europe.







In
addition,
the
FDA
has
substantial
discretion
in
the
drug
approval
process
and
may
require
us
to
conduct
additional
preclinical
and
clinical
testing
or
toperform
post-marketing
studies.
The
approval
process
may
also
be
delayed
by
changes
in
government
regulation,
future
legislation
or
administrative
action
orchanges
in
FDA
policy
that
occur
prior
to
or
during
its
regulatory
review,
such
as
the
request
we
received
from
the
FDA
with
respect
to
providing
a
minimum
of24-month
fracture
data
for
approval
of
abaloparatide-SC.
Delays
in
obtaining
regulatory
approvals
may:•delay
commercialization
of,
and
our
ability
to
derive
product
revenues
from,
our
product
candidates;
•impose
costly
procedures
on
us;
and
•diminish
any
competitive
advantages
that
we
may
otherwise
enjoy.







The
abaloparatide-SC
finished
product
is
a
drug/device
combination
product
candidate
with
both
a
drug
and
device
component
and
with
the
primary
mode
ofaction
being
provided
by
the
investigational
drug
abaloparatide.
Based
on
our
discussions
to
date
with
the
FDA,
we
believe
that
abaloparatide-SC
will
be
regulatedas
a
combination
product
by
the
FDA,
and
both
drug
and
device
components
will
be
required
for
review
as
part
of
our
NDA
submission.
We
expect
that
our
NDAwould
be
submitted
to
the
Center
for
Drug
Evaluation
and
Research
and
be
reviewed
with
support
from
the
FDA
Office
of
Combination
Products
and
the
FDACenter
for
Devices
and
Radiological
Health
for
the
device
aspects
of
the
abaloparatide-SC
product
candidate.
In
addition,
there
are
device-related
manufacturingand
other
regulatory
requirements
(e.g.,
current
good
manufacturing
practices,
or
cGMPs,
and
adverse
event
reporting)
to
which
we
may
be
subject
by
virtue
of
theproduct's
status
as
a
drug/device
combination
product.
As
a
result
of
these
factors,
we
may
experience
delays
in
the
product
development
and
regulatory
review
andapproval
process
in
seeking
a
drug/device
combination
product
approval
under
an
NDA.







Even
if
we
comply
with
all
FDA
requests,
the
FDA
may
ultimately
reject
one
or
more
of
our
NDAs.
We
may
never
obtain
regulatory
approval
forabaloparatide-SC,
or
any
of
our
product
candidates.
Failure
to
obtain
FDA
approval
of
abaloparatide-SC,
or
any
of
our
product
candidates
will
severely
undermineour
business
by
leaving
us
without
a
saleable
product,
and
therefore
without
any
source
of
revenues,
until
another
product
candidate
can
be
developed.
There
is
noguarantee
that
we
will
ever
be
able
to
develop
or
acquire
any
product
candidate.







In
foreign
jurisdictions,
we
must
receive
approval
from
the
appropriate
regulatory
authorities
before
we
can
commercialize
any
drugs.
Foreign
regulatoryapproval
processes
generally
include
all
of
the
risks
associated
with
the
FDA
approval
procedures
described
above.
We
cannot
assure
you
that
we
will
receive
theapprovals
necessary
to
commercialize
abaloparatide-SC,
or
any
of
our
product
candidates
for
sale
outside
the
United
States.39Table
of
ContentsAny collaboration arrangements that we may enter into in the future may not be successful, which could adversely affect our ability to develop andcommercialize abaloparatide-SC, or any of our other product candidates.







Our
product
development
programs
and
the
potential
commercialization
of
our
product
candidates
will
require
substantial
cash
to
fund
expenses.
For
some
ofour
product
candidates,
we
may
decide
to
collaborate
with
pharmaceutical
and
biotechnology
companies
for
the
development
and
potential
commercialization
ofthose
product
candidates.
We
will
face,
to
the
extent
that
we
decide
to
enter
into
collaboration
agreements,
significant
competition
in
seeking
appropriatecollaborators.
Moreover,
collaboration
arrangements
are
complex
and
time
consuming
to
negotiate,
document
and
implement.
We
may
not
be
successful
in
ourefforts
to
establish
and
implement
collaborations
or
other
alternative
arrangements
should
we
so
chose
to
enter
into
such
arrangements.







The
terms
of
any
collaborations
or
other
arrangements
that
we
may
establish
may
not
be
favorable
to
us.
If
that
were
to
occur,
we
may
have
to
curtail
thedevelopment
of
a
particular
product
candidate,
reduce
or
delay
its
development
program
or
one
or
more
of
our
other
development
programs,
delay
its
potentialcommercialization
or
reduce
the
scope
of
our
sales
or
marketing
activities,
or
increase
our
expenditures
and
undertake
development
or
commercialization
activitiesat
our
own
expense.
If
we
elect
to
increase
our
expenditures
to
fund
development
or
commercialization
activities
on
our
own,
we
may
need
to
obtain
additionalcapital,
which
may
not
be
available
to
us
on
acceptable
terms
or
at
all.
If
we
do
not
have
sufficient
funds,
we
will
not
be
able
to
bring
our
product
candidates
tomarket
and
generate
product
revenue.







Any
future
collaborations
that
we
enter
into
may
not
be
successful.
The
success
of
our
collaboration
arrangements
will
depend
heavily
on
the
efforts
andactivities
of
our
future
collaborators.
Collaborators
generally
have
significant
discretion
in
determining
the
efforts
and
resources
that
they
will
apply
to
thesecollaborations.
If
a
collaborator
fails
to
provide
sufficient
effort
and
resources
to
a
development
program,
we
may
not
realize
the
full
potential
or
intended
benefitof
the
collaboration,
and
the
development
program
may
be
delayed
or
curtailed.Clinical trials are very expensive, time-consuming and difficult to design and implement.







Human
clinical
trials
are
very
expensive
and
difficult
to
design
and
implement,
in
part
because
they
are
subject
to
rigorous
regulatory
requirements.
Asubstantial
portion
of
our
abaloparatide
development
costs
is
denominated
in
euros
and
any
adverse
movement
in
the
dollar/euro
exchange
rate
will
result
inincreased
costs
and
require
us
to
raise
additional
capital
to
complete
the
development
of
our
products.
The
clinical
trial
process
is
also
time
consuming.Furthermore,
failure
can
occur
at
any
stage
of
the
trials,
and
we
could
encounter
problems
that
cause
us
to
abandon
or
repeat
clinical
trials.
The
commencement
andcompletion
of
clinical
trials
may
be
delayed
by
several
factors,
including:•changes
in
government
regulation,
administrative
action
or
changes
in
FDA
or
foreign
regulatory
authority
policy
with
respect
to
clinical
trials
thatchange
the
requirements
for
approval;
•unforeseen
safety
issues;
•determination
of
dosing
issues;
•lack
of
effectiveness
during
clinical
trials;
•slower
than
expected
rates
of
patient
recruitment
and
enrollment;
•failure
of
sites
to
comply
with
requirements
for
conducting
clinical
trials;
•inability
to
monitor
patients
adequately
during
or
after
treatment;
and
•inability
or
unwillingness
of
medical
investigators
to
follow
our
clinical
protocols.40Table
of
Contents







In
addition,
we,
the
FDA,
or
other
equivalent
regulatory
authorities
and
ethics
committees
with
jurisdiction
over
our
studies
may
suspend
our
clinical
trials
atany
time
if
it
appears
that
we
are
exposing
participants
to
unacceptable
health
risks
or
if
the
FDA
or
foreign
regulatory
authorities
find
deficiencies
in
ourregulatory
submissions
or
the
conduct
of
these
trials.
Therefore,
we
cannot
predict
with
any
certainty
the
schedule
for
existing
or
future
clinical
trials.
Any
suchunexpected
expenses
or
delays
in
our
clinical
trials
could
increase
our
need
for
additional
capital,
which
may
not
be
available
on
favorable
terms
or
at
all.Most of our investigational product candidates are in early stages of clinical trials.







Except
for
abaloparatide-SC
and
abaloparatide-TD,
each
of
our
other
product
candidates
(i.e.,
RAD1901
and
RAD140)
is
in
the
early
stages
of
developmentand
requires
extensive
preclinical
and
clinical
testing.
We
cannot
predict
with
any
certainty
if
or
when
we
might
submit
an
NDA
or
equivalent
application
toforeign
regulatory
authorities
for
regulatory
approval
for
any
of
our
product
candidates
or
whether
any
such
NDA
or
equivalent
application
would
be
accepted
forfiling
by
the
FDA
or
foreign
regulatory
authorities
or
approved
if
filed.The results of clinical trials may not support our product candidate claims.







Even
if
our
clinical
trials
are
completed
as
planned,
we
cannot
be
certain
that
the
results
will
support
regulatory
approval
of
our
product
candidates.
Success
inpreclinical
testing
and
early
clinical
trials
does
not
ensure
that
later
clinical
trials
will
be
successful,
and
we
cannot
be
sure
that
the
results
of
later
clinical
trials
willreplicate
the
results
of
prior
clinical
trials
and
preclinical
testing.
The
clinical
trial
process
may
fail
to
demonstrate
that
our
product
candidates
are
safe
for
humansand
effective
for
proposed
uses.
This
failure
would
cause
us
to
abandon
a
product
candidate
and
may
delay
development
of
other
product
candidates.
Any
delay
in,or
termination
of,
our
clinical
trials
will
delay
the
submission
of
our
NDAs
to
the
FDA
or
equivalent
application
to
foreign
regulatory
authorities
and,
ultimately,our
ability
to
commercialize
our
product
candidates
and
generate
product
revenues.
In
addition,
our
clinical
trials
to
date
(other
than
the
ACTIVE
Phase
3
ClinicalTrial
for
abaloparatide-SC)
have
involved
small
patient
populations.
Because
of
the
small
sample
sizes,
the
results
of
these
clinical
trials
may
not
be
indicative
offuture
results.







In
addition,
third
parties
could
conduct
clinical
trials
using
the
product
candidates
we
license.
We
would
have
no
control
over
how
these
trials
are
conductedand
the
results
could
potentially
contradict
the
results
we
have
obtained,
or
will
obtain
from
the
clinical
trials
we
conduct.If serious adverse or undesirable side effects are identified during the development of our product candidates, we may need to abandon our development ofsome of our product candidates.







Undesirable
side
effects
caused
by
our
product
candidates
could
cause
us,
regulatory
authorities,
and/or
ethics
committees
to
interrupt,
delay
or
halt
clinicaltrials
and
could
result
in
a
more
restrictive
label
or
cause
the
delay
or
denial
of
regulatory
approval
by
the
FDA
or
other
comparable
foreign
authorities.
It
isimpossible
to
predict
when
or
if
any
of
our
product
candidates
will
prove
effective
or
safe
in
humans
or
will
receive
regulatory
approval,
if
ever.
If
our
productcandidates
result
in
undesirable
side
effects
or
have
characteristics
that
are
unexpected,
we
may
need
to
abandon
their
development.
Drug-related
side
effects
couldaffect
patient
recruitment
or
the
ability
of
enrolled
patients
to
complete
the
trial
or
result
in
potential
product
liability
claims.
Any
of
these
occurrences
may
harmour
business,
financial
condition
and
prospects
significantly.







Additionally
if
one
or
more
of
our
product
candidates
receives
marketing
approval,
and
we
or
others
later
identify
undesirable
side
effects
caused
by
suchproducts,
a
number
of
potentially
significant
negative
consequences
could
result,
including:•regulatory
authorities
may
withdraw
approvals
of
such
product;41Table
of
Contents•regulatory
authorities
may
require
additional
warnings
on
the
label;
•we
may
be
required
to
create
a
medication
guide
outlining
the
risks
of
such
side
effects
for
distribution
to
patients;
•we
could
be
sued
and
held
liable
for
harm
caused
to
patients;
and
•our
reputation
may
suffer.







Any
of
these
events
could
prevent
us
from
achieving
or
maintaining
market
acceptance
of
the
particular
product
candidate,
if
approved,
and
could
significantlyharm
our
business,
results
of
operations
and
prospects.Any product candidate for which we obtain marketing approval could be subject to restrictions or withdrawal from the market and we may be subject topenalties if we fail to comply with regulatory requirements or if we experience unanticipated problems with our products, when and if any of them areapproved.







Any
product
candidate
for
which
we
obtain
marketing
approval,
along
with
the
manufacturing
processes,
post-approval
clinical
data,
labeling,
advertising
andpromotional
activities
for
such
product,
will
be
subject
to
continual
requirements
of
and
review
by
the
FDA
and
foreign
regulatory
authorities.
These
requirementsinclude
submissions
of
safety
and
other
post-marketing
information
and
reports,
registration
and
listing
requirements,
cGMP
requirements
relating
to
qualitycontrol,
quality
assurance
and
corresponding
maintenance
of
records
and
documents,
and
requirements
regarding
the
distribution
of
samples
to
physicians
andrecordkeeping.
Even
if
we
obtain
marketing
approval
of
a
product
candidate,
the
approval
may
be
subject
to
limitations
on
the
indicated
uses
for
which
the
productmay
be
marketed
or
to
the
conditions
of
approval,
or
contain
requirements
for
costly
post-marketing
testing
and
surveillance
to
monitor
the
safety
and/or
efficacy
ofthe
product.
The
FDA
closely
regulates
the
post-approval
marketing
and
promotion
of
drugs
to
ensure
drugs
are
marketed
only
for
the
approved
indications
and
inaccordance
with
the
provisions
of
the
approved
labeling.
The
FDA
imposes
stringent
restrictions
on
manufacturers'
communications
regarding
off-label
use
and,
ifwe
market
our
products
for
other
than
their
approved
indications,
we
may
be
subject
to
enforcement
action
for
off-label
marketing.







In
addition,
later
discovery
of
previously
unknown
problems
with
our
products,
manufacturers
or
manufacturing
processes,
or
failure
to
comply
withregulatory
requirements,
may
yield
various
results,
including:•restrictions
on
such
products,
manufacturers
or
manufacturing
processes;
•restrictions
on
the
labeling
or
marketing
of
a
product;
•restrictions
on
product
distribution
or
use;
•requirements
to
conduct
post-marketing
clinical
trials;
•warning
or
untitled
letters;
•withdrawal
of
the
products
from
the
market;
•refusal
to
approve
pending
applications
or
supplements
to
approved
applications
that
we
submit;
•voluntary
or
mandatory
recall
of
products
and
related
publicity
requirements;
•fines,
restitution
or
disgorgement
of
profits
or
revenue;
•suspension
or
withdrawal
of
marketing
approvals;
•refusal
to
permit
the
import
or
export
of
our
products;
•product
seizure;
or
•injunctions
or
the
imposition
of
civil
or
criminal
penalties.42Table
of
Contents







In
addition,
the
FDA's
policies
may
change
and
additional
government
regulations
may
be
enacted
that
could
prevent,
limit,
or
delay
regulatory
approval
ofour
product
candidates.
We
cannot
predict
the
likelihood,
nature,
or
extent
of
government
regulation
that
may
arise
from
future
legislation
or
administrative
action,either
in
the
United
States
or
abroad.
If
we
are
slow
or
unable
to
adapt
to
changes
in
existing
requirements
or
the
adoption
of
new
requirements
or
policies,
or
if
weare
not
able
to
maintain
regulatory
compliance,
we
may
lose
any
marketing
approval
that
we
may
have
obtained
and
we
may
not
achieve
or
sustain
profitability,which
would
adversely
affect
our
business.The commercial success of any product candidates that we may develop and that may be approved will depend upon the degree of market acceptance byregulators, key opinion leaders, physicians, patients, healthcare payors and others in the medical community.







Even
if
the
FDA
or
foreign
regulatory
authorities
approves
one
or
more
of
our
product
candidates,
physicians
and
patients
may
not
accept
and
use
them.Acceptance
and
use
of
any
of
our
products
will
depend
upon
a
number
of
factors
including:•perceptions
by
members
of
the
healthcare
community,
including
physicians
and
key
opinion
leaders,
about
the
safety
and
effectiveness
of
our
drug;
•cost-effectiveness
of
our
product
relative
to
competing
products;
•availability
of
coverage
and
reimbursement
for
our
product
from
government
or
other
healthcare
payors;
and
•effectiveness
of
marketing
and
distribution
efforts
by
us
and
our
licensees
and
distributors,
if
any.







If
any
of
our
product
candidates
are
commercialized
and
unexpected
adverse
events
are
reported
in
connection
with
the
use
of
any
of
those
products,
physicianand
patient
acceptance
of
the
product
could
deteriorate
and
the
commercial
success
of
such
product
could
be
adversely
affected.
We
are
required
to
report
to
theFDA
or
similar
bodies
in
other
countries
events
associated
with
our
products
relating
to
death
or
serious
injury.
Adverse
events
could
result
in
additional
regulatorycontrols,
such
as
for
the
imposition
of
costly
post-approval
clinical
studies
or
revisions
to
approved
labeling
which
could
limit
the
indications
or
patient
populationfor
a
product
or
could
even
lead
to
the
withdrawal
of
a
product
from
the
market.
Because
we
expect
sales
of
our
current
product
candidates,
if
approved,
to
generatesubstantially
all
of
our
product
revenues
for
the
foreseeable
future,
the
failure
of
these
drugs
to
gain
market
acceptance
or,
once
gained,
a
decrease
in
marketacceptance
would
harm
our
business
and
would
require
us
to
seek
additional
financing.Our ability to successfully commercialize products depends in part on the extent to which coverage and reimbursement for the costs of our products and relatedtreatments will be available in the United States and worldwide from government health administration authorities, private health insurers and otherorganizations.







Our
ability
to
commercialize
our
product
candidates
if
approved,
alone
or
with
collaborators,
will
depend
in
large
part
on
the
extent
to
which
coverage
andreimbursement
will
be
available
post-approval
from:•government
and
health
administration
authorities;
•private
health
maintenance
organizations
and
health
insurers;
and
•other
healthcare
payors.







In
the
United
States
and
internationally,
sales
of
products
that
we
market
in
the
future,
and
our
ability
to
generate
revenues
on
such
sales,
are
dependent,
insignificant
part,
on
the
availability
and
level
of
coverage
and
reimbursement
from
third
party
payors
such
as
state
and
federal
governments,43Table
of
Contentsmanaged
care
providers
and
private
insurance
plans.
Private
insurers,
such
as
health
maintenance
organizations
and
managed
care
providers,
have
implementedcost
cutting
and
reimbursement
initiatives
and
likely
will
continue
to
do
so
in
the
future.
These
include
establishing
formularies
that
govern
the
drugs
and
biologicsthat
will
be
offered
and
also
the
out
of
pocket
obligations
of
member
patients
for
such
products.
In
addition,
particularly
in
the
United
States
and
increasingly
inother
countries,
we
may
be
required
to
provide
discounts
and
pay
rebates
to
state
and
federal
governments
and
agencies
in
connection
with
purchases
of
ourproducts
that
are
reimbursed
by
such
entities.
It
is
possible
that
future
legislation
in
the
United
States
and
other
jurisdictions
could
be
enacted
which
couldpotentially
impact
the
reimbursement
rates
for
the
products
we
are
developing
and
may
develop
in
the
future
and
also
could
further
impact
the
levels
of
discountsand
rebates
paid
to
federal
and
state
government
entities.
Any
legislation
that
impacts
these
areas
could
impact,
in
a
significant
way,
our
ability
to
generaterevenues
from
sales
of
products
that,
if
successfully
developed,
we
bring
to
market.







There
is
no
legislation
at
the
EU
level
governing
the
pricing
and
reimbursement
of
medicinal
products
in
the
EU.
As
a
result,
the
competent
authorities
of
eachof
the
28
EU
Member
States
have
adopted
individual
strategies
regulating
the
pricing
and
reimbursement
of
medicinal
products
in
their
territory.
These
strategiesoften
vary
widely
in
nature,
scope
and
application.
However,
a
major
element
that
they
have
in
common
is
an
increased
move
towards
reduction
in
thereimbursement
price
of
medicinal
products,
a
reduction
in
the
number
and
type
of
products
selected
for
reimbursement,
and
an
increased
preference
for
genericproducts
over
innovative
products.
These
efforts
have
mostly
been
executed
through
these
countries'
existing
price
control
methodologies.
These
efforts
havemostly
been
executed
through
these
countries'
existing
price-control
methodologies,
including
price
cuts,
mandatory
rebates,
value-based
pricing,
and
referencepricing
(i.e.,
referencing
prices
in
other
countries
and
using
those
reference
prices
to
set
a
price).
The
government
of
the
UK
announced
the
phase
out
of
itsestablished
Pharmaceutical
Pricing
Reimbursement
Scheme
approach
in
January
2014
and
the
adoption
of
a
new
value
based
pricing
approach,
at
least
for
newproduct
introductions.
Under
this
approach,
in
a
complete
departure
from
established
methodologies,
reimbursement
levels
of
each
drug
will
be
explicitly
based
onan
assessment
of
value,
looking
at
the
benefits
for
the
patient,
unmet
need,
therapeutic
innovation,
and
benefit
to
society
as
a
whole.
It
is
increasingly
common
inmany
EU
Member
States
for
Marketing
Authorization
Holders
to
be
required
to
demonstrate
the
pharmaco
economic
superiority
of
their
products
as
compared
toproducts
already
subject
to
pricing
and
reimbursement
in
specific
countries.
In
order
for
drugs
to
be
evaluated
positively
under
such
criteria,
pharmaceuticalcompanies
may
need
to
re-examine,
and
consider
altering,
a
number
of
traditional
functions
relating
to
the
selection,
study,
and
management
of
drugs,
whethercurrently
marketed,
under
development,
or
being
evaluated
as
candidates
for
research
and/or
development.







Future
legislation,
including
the
current
versions
being
considered
at
the
federal
and
state
level
in
the
United
States
and
at
the
national
level
in
EU
MemberStates,
or
regulatory
actions
implementing
recent
or
future
legislation
may
have
a
significant
effect
on
our
business.
If
government
and
other
healthcare
payors
donot
provide
adequate
coverage
and
reimbursement
levels
for
our
product
candidates,
once
approved,
market
acceptance
of
our
products
could
be
reduced.
Inaddition,
negotiating
prices
with
government
authorities
under
current
and
proposed
legislation
can
delay
the
commercialization
of
our
product
candidates.We may expend our limited resources to pursue a particular product candidate or indication and fail to capitalize on product candidates or indications that maybe more profitable or for which there is a greater likelihood of success.







Because
we
have
limited
financial
and
managerial
resources,
we
narrowly
focus
on
research
programs
and
product
candidates
that
we
identify
for
specificindications.
As
a
result,
we
may
forego
or
delay
pursuit
of
opportunities
with
other
product
candidates
or
for
other
indications
that
later
prove
to
have
greatercommercial
potential.
Our
resource
allocation
decisions
may
cause
us
to
fail
to
capitalize44Table
of
Contentson
viable
commercial
products
or
profitable
market
opportunities.
Our
spending
on
current
and
future
research
and
development
programs
and
product
candidatesfor
specific
indications
may
not
yield
any
commercially
viable
products.
If
we
do
not
accurately
evaluate
the
commercial
potential
or
target
market
for
a
particularproduct
candidate,
we
may
relinquish
valuable
rights
to
that
product
candidate
through
collaboration,
licensing
or
other
royalty
arrangements
in
cases
in
which
itwould
have
been
more
advantageous
for
us
to
retain
sole
development
and
commercialization
rights
to
such
product
candidate.If we experience delays in the enrollment of patients in our clinical trials, our receipt of necessary regulatory approvals could be delayed or prevented.







We
may
not
be
able
to
initiate
or
continue
clinical
trials
for
some
of
our
product
candidates
if
we
are
unable
to
locate
and
enroll
a
sufficient
number
of
eligiblepatients
to
participate
in
these
trials
as
required
by
the
FDA
or
foreign
regulatory
authorities.
In
addition,
many
of
our
competitors
have
ongoing
clinical
trials
forproduct
candidates
that
could
be
competitive
with
our
product
candidates,
and
patients
who
would
otherwise
be
eligible
for
our
clinical
trials
may
instead
enroll
inclinical
trials
of
our
competitors'
product
candidates.







Enrollment
delays
in
our
clinical
trials
may
result
in
increased
development
costs
for
our
product
candidates,
which
would
cause
the
value
of
the
company
todecline
and
limit
our
ability
to
obtain
additional
financing.
Our
inability
to
enroll
a
sufficient
number
of
patients
for
any
of
our
current
or
future
clinical
trials
wouldresult
in
significant
delays
or
may
require
us
to
abandon
one
or
more
clinical
trials
altogether.Risks
Related
to
Our
Dependence
on
Third
PartiesOur drug development programs depend upon third-party researchers, investigators and collaborators who are outside our control.







We
depend
upon
independent
researchers,
investigators
and
collaborators,
to
conduct
our
preclinical
and
clinical
trials
under
agreements
with
us.
These
thirdparties
are
not
our
employees
and
we
cannot
control
the
amount
or
timing
of
resources
that
they
devote
to
our
programs.
Nevertheless,
we
are
responsible
forensuring
that
each
of
our
studies
is
conducted
in
accordance
with
the
applicable
protocol,
legal,
regulatory
and
scientific
standards
and
requirements,
and
ourreliance
on
third
parties
does
not
relieve
us
of
our
regulatory
responsibilities.
We
and
our
third
party
researchers,
investigators
and
collaborators
are
required
tocomply
with
good
clinical
practice,
or
GCP,
requirements,
which
are
regulations
and
guidelines
enforced
by
the
FDA,
the
Competent
Authorities
of
the
MemberStates
of
the
European
Economic
Area,
or
EEA,
and
comparable
foreign
regulatory
authorities
for
all
of
our
products
in
clinical
development.
Regulatoryauthorities
enforce
these
GCPs
through
periodic
inspections
of
trial
sponsors,
principal
investigators
and
trial
sites.
If
we
or
any
of
our
CROs
fail
to
comply
withapplicable
GCPs,
the
clinical
data
generated
in
our
clinical
trials
may
be
deemed
unreliable
and
the
FDA,
EMA
or
other
comparable
foreign
regulatory
authoritiesmay
require
us
to
perform
additional
clinical
trials
before
approving
our
marketing
applications.
We
cannot
assure
you
that
upon
inspection
by
a
given
regulatoryauthority,
such
regulatory
authority
will
determine
that
any
of
our
clinical
trials
complies
with
GCP
regulations.
In
addition,
our
clinical
trials
must
be
conductedwith
product
produced
under
cGMP
regulations.
Our
failure
to
comply
with
these
regulations
may
require
us
to
repeat
clinical
trials,
which
would
delay
theregulatory
approval
process.
In
addition,
these
third
parties
may
not
assign
as
great
a
priority
to
our
programs
or
pursue
them
as
diligently
as
we
would
if
we
wereundertaking
such
programs
ourselves.
If
outside
collaborators
fail
to
devote
sufficient
time
and
resources
to
our
drug-development
programs,
or
if
theirperformance
is
substandard,
the
approval
of
our
FDA
or
foreign
regulatory
authority
applications,
if
any,
and
our
introduction
of
new
drugs,
if
any,
will
be
delayed.These
collaborators
may
also
have
relationships
with
other
commercial45Table
of
Contentsentities,
some
of
whom
may
compete
with
us.
If
our
collaborators
assist
competitors
at
our
expense,
our
competitive
position
would
be
harmed.If a regulatory or governmental authority determines that a financial interest in the outcome of the Phase 3 study of abaloparatide-SC by any of the entitieswho managed our Phase 3 clinical trial affected the reliability of the data from the Phase 3 clinical trial, our ability to use the data for our planned regulatorysubmissions could be compromised, which could harm our business and the value of our common stock.







The
Phase
3
clinical
trial
and
subsequent
extension
studies
of
abaloparatide-SC
are
being
managed
by
Nordic
Bioscience
Clinical
Development
VII
A/S,
orNordic,
at
certain
clinical
sites
operated
by
the
Center
for
Clinical
and
Basic
Research,
or
CCBR,
a
leading
global
CRO
with
extensive
experience
in
globalosteoporosis
registration
studies.
Nordic
controls,
and
holds
an
ownership
interest
in,
the
local
CCBR
clinical
sites.
The
clinical
trial
investigators
are
employees
ofCCBR
and
may
also
hold
an
equity
interest
in
the
local
CCBR
clinical
trials.







In
consideration
of
Nordic's
management
of
our
Phase
3
clinical
trial
and
subsequent
extension
studies,
we
agreed
to
make
various
cash
payments
to
Nordicdenominated
in
both
euros
and
U.S.
dollars
over
the
course
of
the
Phase
3
ACTIVE
and
ACTIVExtend
clinical
trials,
or
the
ACTIVE
Clinical
Trials,
equal
to
atotal
of
up
to
approximately
€53.0
million
($57.5
million)
and
a
total
of
up
to
approximately
$4.4
million
plus
up
to
an
additional
$5.0
million
in
aggregateperformance
incentive
payments,
payable
in
cash.
We
also
agreed
to
sell
shares
of
capital
stock
to
Nordic
that
were
exchanged
in
May
2011
for
6,443
shares
of
ourseries
A-5
convertible
preferred
stock
for
proceeds
of
approximately
$0.5
million.
These
shares
of
our
series
A-5
convertible
preferred
stock
automaticallyconverted
into
28,258
shares
of
our
common
stock
upon
the
listing
of
our
common
stock
on
the
NASDAQ
Global
Market.
Pursuant
to
the
terms
of
our
agreementswith
Nordic,
we
were
required
to
issue
to
Nordic
shares
of
stock
with
an
aggregate
value
of
up
to
approximately
€44.3
million
($48.1
million)
and
$0.8
million
inconsideration
of
Nordic's
management
of
the
ACTIVE
Clinical
Trials.
These
shares
of
stock
accrued
at
a
quarterly
rate
based
on
the
progress
of
the
ACTIVEClinical
Trials
and
were
issuable
at
a
price
per
share
equal
to
the
greater
of
(1)
the
fair
market
value
of
our
common
stock
as
of
the
applicable
accrual
date
or(2)
$81.42
and
rounding
down
the
resulting
quotient
to
the
nearest
whole
number.
On
each
of
December
31,
2013
and
March
31,
2014,
our
Board
of
Directorsdeclared
a
stock
dividend
to
pay
all
shares
of
stock
that
had
accrued
as
of
such
dates
and
that
were
anticipated
to
accrue
through
December
31,
2014,
representingan
aggregate
of
682,958
shares
of
our
Series
A-6
convertible
preferred
stock
that
automatically
converted
into
2,995,453
shares
of
our
common
stock
upon
thelisting
of
our
common
stock
on
the
NASDAQ
Global
Market.
Following
the
completion
of
our
initial
public
offering
of
shares
of
our
common
stock
on
June
11,2014,
or
our
initial
public
offering,
all
compensation
remaining
payable
to
Nordic
in
consideration
of
their
management
of
the
ACTIVE
Clinical
Trials
becamepayable
in
cash.







The
fair
market
value
of
our
common
stock
may
be
subject
to
wide
fluctuations
in
response
to
various
factors,
many
of
which
are
beyond
our
control.Accordingly,
the
shares
of
stock
that
we
have
issued
to
Nordic
in
consideration
of
Nordic's
management
of
the
ACTIVE
Clinical
Trials
may
be
less
than
the
fullvalue
originally
anticipated
under
our
agreements
with
Nordic,
assuming
Nordic
did
not
expect
the
fair
market
value
of
our
stock
to
fluctuate
widely
over
the
termof
such
agreements.
As
a
result,
the
total
consideration
that
Nordic
received
in
stock
and
will
receive
in
cash
may
be
viewed
to
be
below
the
market
price
paid
byother
companies
for
comparable
clinical
trial
services.







Because
of
the
potential
decrease
in
the
value
of
the
common
stock
issued
to
Nordic
if
there
was
a
negative
outcome
of
the
ACTIVE
Clinical
Trials,
Nordic,CCBR
and
the
clinical
trial
investigators
may
be
viewed
as
having
a
financial
interest
in
the
outcome
of
the
study.
We
have
obtained
written
acknowledgmentsfrom
the
clinical
trial
investigators
certifying
that
they
have
no
financial
interest
in
the
outcome
of
the
ACTIVE
Clinical
Trials.
However,
if
the
FDA,
the
EMA,
orany
other
similar
regulatory
or
governmental
authority
determines
that
Nordic,
CCBR
or
the
clinical
trial
investigators46Table
of
Contentshave
a
financial
interest
that
affected
the
reliability
of
the
data
from
the
ACTIVE
Clinical
Trials,
we
could
be
subject
to
additional
regulatory
scrutiny
and
theutility
of
the
ACTIVE
Clinical
Trials
for
purposes
of
our
planned
regulatory
submissions
could
be
compromised,
which
could
have
a
material
adverse
effect
on
ourbusiness
and
the
value
of
our
common
stock.We will rely exclusively on third parties to formulate and manufacture our product candidates.







We
have
no
experience
in
drug
formulation
or
manufacturing
and
do
not
intend
to
establish
our
own
manufacturing
facilities.
We
lack
the
resources
andexpertise
to
formulate
or
manufacture
our
own
product
candidates.
We
have
entered
into
agreements
with
contract
manufacturers
to
manufacture
our
productcandidates
for
use
in
clinical
trial
activities.
These
contract
manufacturers
are
currently
our
only
source
for
the
production
and
formulation
of
our
productcandidates.
We
may
not
have
sufficient
clinical
supplies
of
our
product
candidates
but
believe
that
our
contract
manufacturers
will
be
able
to
produce
sufficientsupply
of
our
product
candidates
to
complete
all
of
the
planned
clinical
studies.
If
our
contract
manufacturers
are
unable
to
produce,
in
a
timely
manner,
adequateclinical
supplies
to
meet
the
needs
of
our
clinical
studies,
we
would
be
required
to
seek
new
contract
manufacturers
that
may
require
us
to
modify
our
finishedproduct
formulation
and
modify
or
terminate
our
clinical
studies.
Any
modification
of
our
finished
product
or
modification
or
termination
of
our
clinical
studiescould
adversely
affect
our
ability
to
obtain
necessary
regulatory
approvals
and
significantly
delay
or
prevent
the
commercial
launch
of
the
product
if
it
were
to
beapproved,
which
would
materially
harm
our
business
and
impair
our
ability
to
raise
capital.
In
addition,
the
facilities
and
processes
and
controls
used
by
ourcontract
manufacturers
to
manufacture
our
product
candidates
must
be
approved
by
the
EMA,
and
by
the
FDA
pursuant
to
inspections
that
will
be
conducted
afterwe
submit
our
NDA.
We
do
not
control
the
facilities
or
manufacturing
process,
and
are
completely
dependent
on,
our
contract
manufacturing
partners
forcompliance
with
cGMPs
for
manufacture
of
both
active
drug
substances
and
finished
drug
products.
If
our
contract
manufacturers
cannot
successfully
manufacturematerial
that
conforms
to
our
specifications
and
the
strict
regulatory
requirements
of
the
FDA
or
other
regulatory
authorities,
they
will
not
be
able
to
secure
and/ormaintain
regulatory
approval
for
their
manufacturing
facilities.
In
addition,
we
have
no
control
over
the
ability
of
our
contract
manufacturers
to
maintain
adequatequality
control,
quality
assurance
and
qualified
personnel.
If
the
FDA
or
a
comparable
foreign
regulatory
authority
does
not
approve
our
contract
manufacturers
forthe
manufacture
of
our
product
candidates
or
if
they
withdraw
any
such
approval
in
the
future,
we
may
need
to
find
alternative
manufacturing
facilities,
whichwould
significantly
impact
our
ability
to
develop,
obtain
regulatory
approval
for
or
market
our
product
candidates,
if
approved.







We
depend
on
a
number
of
single
source
contract
manufacturers
to
supply
key
components
of
abaloparatide.
For
example,
we
depend
on
Lonza
Group
Ltd.,
orLonza,
which
produces
supplies
of
bulk
drug
product
of
abaloparatide
to
support
the
abaloparatide-SC
and
abaloparatide-TD
clinical
studies
and
any
potentialcommercial
launch.
We
also
depend
on
Vetter
Pharma
Fertigung
GmbH
&
Co,
or
Vetter,
and
Ypsomed
AG,
or
Ypsomed,
for
the
production
of
finished
supplies
ofabaloparatide-SC
and
we
depend
on
3M
Co.
and
3M
Innovative
Properties
Co.,
or,
together
3M,
for
the
production
of
abaloparatide-TD.
Because
of
ourdependence
on
Vetter
for
the
"fill
and
finish"
part
of
the
manufacturing
process
for
abaloparatide-SC,
we
are
subject
to
the
risk
that
Vetter
may
not
have
thecapacity
from
time
to
time
to
produce
sufficient
quantities
of
abaloparatide
to
meet
the
needs
of
our
clinical
studies
or
be
able
to
scale
to
commercial
production
ofabaloparatide.
While
we
are
currently
in
discussions,
to
date,
we
have
not
entered
into
a
long-term
agreement
with
any
of
Lonza,
Vetter
or
Ypsomed,
each
of
whomcurrently
produces
abaloparatide
or
related
components
on
a
purchase
order
basis
for
us.
Accordingly,
Lonza,
Vetter
and
Ypsomed
could
terminate
theirrelationship
with
us
at
any
time
and
for
any
reason.
We
may
not
be
able
to
negotiate
long-term
agreements
on
acceptable
terms,
or
at
all.
If
our
relationship
withany
of
these
contract
manufacturers
is
terminated,
or
if
they
are
unable
to
produce
abaloparatide
or
related
components
in
required
quantities,
on
a
timely
basis
or
atall,
or
if
we
are
forced
to
accept
unfavorable
terms
for
our
future
relationship,
our47Table
of
Contentsbusiness
and
financial
condition
would
be
materially
harmed.
Because
the
manufacturing
process
for
abaloparatide-TD
requires
the
use
of
3M's
proprietarytechnology,
3M
is
our
sole
source
for
finished
clinical
trial
supplies
of
abaloparatide-TD.
To
date,
we
have
not
entered
into
a
commercial
supply
agreement
with3M.
If
we
were
not
able
to
negotiate
commercial
supply
terms
with
3M,
as
we
depend
on
3M
for
production
of
abaloparatide-TD,
we
would
be
unable
tocommercialize
this
product
if
it
were
to
be
approved.
Or,
if
we
are
forced
to
accept
unfavorable
terms
for
our
future
relationship
with
3M,
our
business
andfinancial
condition
would
be
materially
harmed.
If
any
of
our
current
product
candidates
or
any
product
candidates
we
may
develop
or
acquire
in
the
future
receiveFDA
or
foreign
regulatory
authority
approval,
we
will
rely
on
one
or
more
third-party
contractors
to
manufacture
our
drugs
or
related
components.
Our
anticipatedfuture
reliance
on
a
limited
number
of
third-party
manufacturers
exposes
us
to
the
following
risks:•We
may
be
unable
to
identify
manufacturers
on
acceptable
terms,
or
at
all,
because
the
number
of
potential
manufacturers
is
limited
and
the
FDAmust
approve
any
replacement
contractor.
This
approval
would
require
new
testing
and
compliance
inspections.
In
addition,
a
new
manufacturerwould
have
to
be
educated
in,
or
develop
substantially
equivalent
processes
for,
production
of
our
products
after
receipt
of
FDA
approval,
if
any.
•Our
third-party
manufacturers
might
be
unable
to
formulate
and
manufacture
our
drugs
or
related
components
in
the
volume
and
of
the
qualityrequired
to
meet
our
clinical
needs
and
commercial
needs,
if
any.
•Our
contract
manufacturers
may
not
perform
as
agreed
or
may
not
remain
in
the
contract
manufacturing
business
for
the
time
required
to
supply
ourclinical
trials
or
to
successfully
produce,
store
and
distribute
our
products.
•Drug
manufacturers
are
subject
to
ongoing
periodic
unannounced
inspection
by
the
FDA
and
corresponding
state
agencies
to
ensure
strictcompliance
with
cGMP,
and
other
government
regulations
and
corresponding
foreign
standards,
and
failure
to
comply
with
cGMP
or
correspondingforeign
standards
can
result
in
compliance
actions
that
may
limit
a
manufacturer's
production
or
prohibit
a
manufacturer
from
producing
some
or
allproducts
at
a
facility
and/or
importing
it
into
the
United
States
or
a
foreign
country.
We
do
not
have
control
over
third-party
manufacturers'compliance
with
these
regulations
and
standards.
•If
any
third-party
manufacturer
makes
improvements
in
the
manufacturing
process
for
our
products,
any
such
improvement(s)
could
be
subject
toFDA
review
and
prior
approval,
and
we
may
not
own,
or
may
have
to
share,
the
intellectual
property
rights
to
the
innovation.







Each
of
these
risks
could
delay
our
clinical
trials,
the
approval,
if
any,
of
our
product
candidates
by
the
FDA
or
foreign
regulatory
authorities
or
thecommercialization
of
our
product
candidates
or
result
in
higher
costs
or
deprive
us
of
potential
product
revenues.If we fail to establish an effective distribution process utilizing cold chain logistics for abaloparatide-SC, our business may be adversely affected.







We
do
not
currently
have
the
infrastructure
necessary
for
distributing
pharmaceutical
products
to
patients.
We
will
be
contracting
with
a
third-party
logisticscompany
to
warehouse
abaloparatide-SC
and
distribute
it
to
specialty
pharmacies
and
wholesale
distributors
who
will
supply
abaloparatide-SC
to
the
market.
Wewill
require
that
abaloparatide-SC
be
maintained
at
a
controlled
refrigerated
temperature
throughout
the
distribution
chain.
This
distribution
chain
will
requiresignificant
coordination
among
our
manufacturing,
supply-chain
and
finance
teams,
as
well
as
commercial
departments,
including
market
access,
sales,
andmarketing.
In
addition,
failure
to
secure
contracts
with
appropriate
pharmacy
providers
and/or
wholesale
distributors
could
negatively
impact
the
distribution
ofabaloparatide-SC,
and
failure
to
coordinate
financial
systems
could
negatively
impact
our
ability
to
accurately
report48Table
of
Contentsproduct
revenue.
If
we
are
unable
to
effectively
establish
and
manage
the
distribution
process,
the
commercial
launch
and
sales
of
abaloparatide-SC
will
be
delayedor
severely
compromised
and
our
results
of
operations
may
be
harmed.Risks
Related
to
Marketing
and
Sale
of
Our
ProductsWe currently have limited commercial and medical affairs capabilities and have no experience selling, marketing or distributing products. If we are unable tobuild these capabilities on our own or through partnerships or collaborations, we may not be able to successfully commercialize abaloparatide-SC, if approved,or any future product candidates or generate product revenue.







We
currently
have
limited
commercial
and
medical
affairs
capabilities
and
no
sales
capabilities,
and
we
have
no
experience
commercializing
a
pharmaceuticalproduct.
We
intend
to
build
an
internal
sales
force
to
market
and
sell
our
products
to
specialists
within
the
target
indications,
if
approved,
and
also
to
pursuecollaborative
arrangements
to
market
and
sell
our
products
within
the
target
indications
if
approved.
Therefore,
our
future
success
depends,
in
part,
on
our
ability
toenter
into
and
maintain
collaborative
relationships
for
such
capabilities,
the
collaborators'
strategic
interest
in
the
products
under
development
and
suchcollaborators'
ability
to
successfully
market
and
sell
any
such
products.







In
addition,
our
ability
to
build
effective
commercial,
medical
affairs,
marketing,
sales,
market
access,
managerial
and
other
non-technical
capabilities
willdepend
on
a
number
of
factors,
including
our
ability
to:•identify,
recruit,
hire,
train,
incentivize
and
retain
a
significant
number
of
commercial
and
medical
affairs
personnel,
including
a
specialty
salesforce
with
appropriate
technical
expertise;
•train
our
sales
representatives,
who
will
have
no
prior
experience
with
our
company
or
abaloparatide-SC,
to
deliver
clear
and
compelling
messageswithin
the
scope
of
the
approved
labeling
regarding
abaloparatide-SC
and
to
be
credible
and
persuasive
in
educating
physicians
on
the
appropriatesituations
to
consider
prescribing
it
as
set
forth
in
the
approved
labeling;
•ensure
our
commercial
customer-facing
team,
including
sales,
market
access,
and
field
logistics
professionals,
effectively
build
relationships
withtheir
respective
customers;
•manage
a
geographically
dispersed
national
commercial
customer-facing
organization;
and
•manage
our
significant
projected
growth
and
the
integration
of
new
personnel.







Building
our
commercial
and
medical
affairs
capabilities
may
be
more
expensive
and
time
consuming
than
we
anticipate,
requiring
us
to
divert
resources
fromother
intended
purposes
or
preventing
us
from
building
these
capabilities
to
the
desired
levels.
Any
failure
or
delay
in
building
these
capabilities
on
our
own
orthrough
partnerships
or
collaborations
will
adversely
impact
the
successful
commercialization
of
abaloparatide-SC,
or
any
future
product
candidate.
If
we
establisha
partnership
or
collaboration
for
purposes
of
commercializing
abaloparatide-SC,
or
any
future
product
candidate,
the
launch
of
that
product
candidate
would
needto
be
established
in
conjunction
with
our
partner,
which
could
result
in
a
change
in
timing
of
the
commercial
launch.







In
addition,
given
our
lack
of
prior
experience
in
marketing,
selling
and
distributing
pharmaceutical
products,
our
initial
specialty
sales
force
may
bematerially
smaller
than
the
actual
number
of
sales
representatives
required
to
successfully
commercialize
abaloparatide-SC.
As
such,
we
may
be
required
to
hiresubstantially
more
sales
representatives
to
adequately
support
the
commercialization
of
abaloparatide-SC.49Table
of
ContentsIf we cannot compete successfully for market share against other drug companies, we may not achieve sufficient product revenues and our business will suffer.







The
market
for
our
product
candidates
is
characterized
by
intense
competition
and
rapid
technological
advances.
If
any
of
our
product
candidates
receivesFDA
or
foreign
regulatory
authority
approval,
it
will
compete
with
a
number
of
existing
and
future
drugs
and
therapies
developed,
manufactured
and
marketed
byothers.
Existing
or
future
competing
products
may
provide
greater
therapeutic
convenience
or
clinical
or
other
benefits
for
a
specific
indication
than
our
products,or
may
offer
comparable
performance
at
a
lower
cost.
If
our
products
fail
to
capture
and
maintain
market
share,
we
may
not
achieve
sufficient
product
revenues
andour
business
will
suffer.







We
are
seeking
regulatory
approval
of
abaloparatide-SC
for
the
treatment
of
osteoporosis
in
postmenopausal
women.
We
expect
to
compete
against
well-known
treatment
options,
including
Lilly's
Forteo.
In
addition,
there
are
other
organizations
working
to
develop
new
therapies
to
treat
osteoporosis.
In
April
2012,UCB
and
Amgen
started
a
Phase
3
clinical
trial
program
for
their
anti-sclerostin
antibody
for
the
treatment
of
osteoporosis.
In
addition,
there
is
at
least
onebiosimilar
to
Lilly's
Forteo
under
review
by
the
EMA
which,
if
approved,
could
exert
pricing
pressure
on
the
anabolic
class
in
which
abaloparatide-SC
wouldcompete.
In
order
to
compete
successfully
in
this
market,
we
will
have
to
demonstrate
to
physician
and
payors
that
the
treatment
of
osteoporosis
withabaloparatide-SC
is
worthwhile
and
is
a
better
alternative
to
existing
or
new
therapies.







We
face
significant
competition
from
many
fully
integrated
pharmaceutical
companies
and
smaller
companies
that
are
collaborating
with
largerpharmaceutical
companies,
academic
institutions,
government
agencies
and
other
public
and
private
research
organizations.
Many
of
these
competitors
havecompounds
already
approved
or
in
development.
In
addition,
many
of
these
competitors,
either
alone
or
together
with
their
collaborative
partners,
operate
largerresearch
and
development
programs
or
have
substantially
greater
financial
resources
than
we
do,
as
well
as
significantly
greater
experience
in:•developing
drugs;
•undertaking
preclinical
testing
and
human
clinical
trials;
•obtaining
FDA
and
other
regulatory
approvals
of
drugs;
•formulating
and
manufacturing
drugs;
and
•launching,
marketing
and
selling
drugs.Developments by competitors may render our products or technologies obsolete or non-competitive.







The
biotechnology
and
pharmaceutical
industries
are
intensely
competitive
and
subject
to
rapid
and
significant
technological
change.
Some
of
the
drugs
thatwe
are
attempting
to
develop,
such
as
our
investigational
product
candidates
abaloparatide-SC,
abaloparatide-TD,
RAD1901
and
RAD140,
will
have
to
competeagainst
existing
therapies
if
they
are
approved.
In
addition,
a
large
number
of
companies
are
pursuing
the
development
of
pharmaceuticals
that
target
the
samediseases
and
conditions
that
we
are
targeting.
We
face
competition
from
pharmaceutical
and
biotechnology
companies
in
the
United
States
and
abroad.
In
addition,companies
doing
business
in
different
but
related
fields
represent
substantial
competition.
Many
of
these
organizations
competing
with
us
have
substantially
greatercapital
resources,
larger
research
and
development
staffs
and
facilities,
longer
drug
development
history
in
obtaining
regulatory
approvals,
and
greatermanufacturing
and
marketing
capabilities
than
we
do.
These
organizations
also
compete
with
us
to
attract
qualified
personnel
and
parties
for
acquisitions,
jointventures
or
other
collaborations,
and
therefore,
we
may
not
be
able
to
hire
or
retain
qualified
personnel
to
run
all
facets
of
our
business.
These
risks
could
renderour
products
or
technologies
obsolete
or
non-competitive.50Table
of
ContentsWe may incur substantial liabilities and may be required to limit commercialization of our products in response to product liability lawsuits.







The
testing
and
marketing
of
medical
products
entail
an
inherent
risk
of
product
liability.
Even
if
one
of
our
investigational
product
candidates
is
approved
bythe
FDA
or
foreign
regulatory
authorities,
if
we
cannot
successfully
defend
ourselves
against
product
liability
claims,
we
may
incur
substantial
liabilities
or
berequired
to
limit
commercialization
of
our
products.
Our
inability
to
obtain
sufficient
product
liability
insurance
at
an
acceptable
cost
to
protect
against
potentialproduct
liability
claims
could
prevent
or
inhibit
the
commercialization
of
pharmaceutical
products
we
develop,
alone
or
with
collaborators.Risks
Related
to
Our
Intellectual
PropertyIf we fail to comply with our obligations in our intellectual property licenses with third parties, we could lose license rights that are important to our business.







We
are
a
party
to
a
number
of
intellectual
property
license
agreements
with
third
parties
and
expect
to
enter
into
additional
license
agreements
in
the
future.Our
existing
license
agreements
impose,
and
we
expect
that
any
future
license
agreements
will
impose,
various
diligence,
milestone
payment,
royalty,
insuranceand
other
obligations
on
us.
If
we
fail
to
comply
with
these
obligations,
our
licensors
may
have
the
right
to
terminate
these
agreements,
in
which
event
we
mightnot
be
able
to
develop
and
market
any
product
that
is
covered
by
these
agreements.
Termination
of
these
licenses
or
reduction
or
elimination
of
our
licensed
rightsmay
result
in
our
having
to
negotiate
new
or
reinstated
licenses
with
less
favorable
terms.
The
occurrence
of
such
events
could
materially
harm
our
business.If our efforts to protect our intellectual property related to abaloparatide-SC, abaloparatide-TD, RAD1901 and/or RAD140 fail to adequately protect theseassets or if we are unable to secure all necessary intellectual property, we may lose the ability to license or successfully commercialize one or more of thesecandidates.







Our
commercial
success
is
significantly
dependent
on
intellectual
property
related
to
our
portfolio
of
product
candidates.
We
are
either
the
licensee
or
assigneeof
numerous
issued
and
pending
patent
applications
that
cover
various
aspects
of
our
assets,
including
abaloparatide-SC,
abaloparatide-TD,
RAD1901
andRAD140.







Patents
covering
abaloparatide
as
a
composition
of
matter
have
been
issued
in
the
United
States
(US
Patent
No.
5,969,095)
and
several
additional
countries.Because
the
abaloparatide
composition
of
matter
patent
was
filed
in
1996,
it
is
expected
to
have
an
expiration
in
2016
in
the
United
States,
and
additional
countrieswhere
it
has
issued.
European
Patent
No.
0847278,
which
was
included
in
the
license
from
Ipsen
Pharma
SAS,
or
Ipsen,
and
claimed
the
composition
of
matter
ofabaloparatide,
lapsed
due
to
Ipsen's
failure
to
pay
annuities.
We
are
pursuing
restoration
of
those
patent
rights.
To
date,
the
patent
rights
in
Austria,
Belgium,Denmark,
Finland,
France,
Germany,
Ireland,
Italy,
the
Netherlands,
Portugal,
Spain,
Sweden
and
the
United
Kingdom
have
been
restored.
As
a
result
of
the
lapseof
patent
rights,
we
believe
that
some
of
Ipsen's
rights
under
our
license
agreement
with
Ipsen
have
terminated.
We
are
in
discussions
with
Ipsen
regarding
theseIpsen
rights
and
related
terms
of
our
license
agreement.
If
we
fail
to
reach
agreement,
we
or
Ipsen
may
determine
to
pursue
available
remedies,
including
formaldispute
resolution.
We
believe
that
the
data
and
market
exclusivity
provided
in
Europe
for
a
new
chemical
entity,
coupled
with
the
need
for
a
potential
competitorto
conduct
clinical
trials,
will
likely
provide
a
longer
barrier
to
entry
than
the
patent
protection
provided
by
the
original
European
patent
term,
which
will
expire
in2016.







We
and
Ipsen
are
also
co-assignees
to
US
Patent
No.
7,803,770
that
we
believe
provides
exclusivity
until
October
3,
2027
and
may
be
extended
to
March
26,2028
in
the
United
States
(not
including
any
Hatch-Waxman
patent
term
extension)
for
the
method
of
treating
osteoporosis
with
the
intended
therapeutic
dose
forabaloparatide-SC.51Table
of
Contents







We
and
Ipsen
are
also
co-assignees
to
US
Patent
No.
8,148,333
that
we
believe
provides
exclusivity
until
2027
in
the
United
States
(not
including
any
Hatch-Waxman
patent
term
extension)
for
the
intended
therapeutic
formulation
for
abaloparatide-SC.







We
and
3M
are
co-assignees
to
several
foreign
and
corresponding
U.S.
patent
applications
with
the
earliest
priority
date
of
April
22,
2011,
which
covervarious
aspects
of
abaloparatide
for
microneedle
application.
Any
issued
patents
resulting
from
these
applications
will
expire
in
2032.
However,
pending
patentapplications
in
the
United
States
and
elsewhere
may
not
issue
since
the
interpretation
of
the
legal
requirements
of
patentability
in
view
of
claimed
inventions
arenot
always
predictable.
Additional
intellectual
property
covering
abaloparatide-TD
technology
exists
in
the
form
of
proprietary
information
protected
as
tradesecrets.
These
can
be
accidentally
disclosed
to,
independently
derived
by
or
misappropriated
by
competitors,
possibly
reducing
or
eliminating
the
exclusivityadvantages
of
this
form
of
intellectual
property,
thereby
allowing
those
competitors
more
rapid
entry
into
the
marketplace
with
a
competitive
product,
whichreduces
our
advantage
with
abaloparatide-TD.
In
addition,
trade
secrets
may
in
some
instances
become
publicly
available
through
required
disclosures
in
regulatoryfiles.
Alternatively,
competitors
may
sometimes
reverse
engineer
a
product
once
it
becomes
available
on
the
market.
Even
where
a
competitor
does
not
use
anidentical
technology
for
the
delivery
of
abaloparatide,
it
is
possible
that
they
could
achieve
an
equivalent
or
even
superior
result
using
another
technology.
Suchoccurrences
could
lead
to
either
one
or
more
alternative
competitor
products
becoming
available
on
the
market
and/or
one
or
more
generic
competitor
products
onthe
market
gaining
market
share
and
causing
a
corresponding
decrease
in
market
share
and/or
price
for
abaloparatide-TD
even
if
it
were
to
be
successfullydeveloped
and
approved
by
the
FDA.







Patents
covering
RAD1901
as
a
composition
of
matter,
as
well
as
the
use
of
RAD1901
for
the
treatment
of
estrogen-dependent
breast
cancer,
have
been
issuedin
the
United
States,
Canada,
Australia,
Japan
and
Europe,
and
are
pending
in
India.
The
RAD1901
composition
of
matter
patents
in
the
United
States
expire
in2023
and
may
be
extended
to
2026
(not
including
any
Hatch-Waxman
patent
term
extension).
One
patent
has
been
issued
in
the
United
States
(US
PatentNo.
8,933,130)
for
treating
vasomotor
disturbances
or
hot
flashes
on
January
13,
2015
(statutory
term
expires
on
June
22,
2027,
and
may
be
extended
toOctober
19,
2031
with
1,580
days
of
patent
term
adjustment
due
to
delays
in
patent
prosecution
by
the
USPTO).
Additional
patent
applications
relating
to
methodsof
treating
vasomotor
symptoms
and
clinical
dosage
strengths
using
RAD1901
have
been
filed.
Pending
patent
applications
in
the
United
States
and
elsewhere
maynot
issue
since
the
interpretation
of
the
legal
requirements
of
patentability
in
view
of
any
claimed
invention
before
a
patent
office
are
not
always
predictable.
As
aresult,
we
could
encounter
challenges
or
difficulties
in
building,
maintaining
and/or
defending
our
intellectual
property
both
in
the
United
States
and
abroad.







Patent
applications
covering
RAD140
and
other
selective
androgen
receptor
modulator
compounds
have
been
granted
in
the
United
States,
Europe,
Canada,Mexico,
Japan
and
Australia,
and
are
pending
in
Brazil
and
India.
The
RAD140
composition
of
matter
patents
expire
in
2029
in
the
United
States
(not
includingany
Hatch-Waxman
patent
term
extension)
and
additional
countries
if
and
when
they
issue.







Since
patents
are
technical
legal
documents
that
are
frequently
subject
to
intense
litigation
pressure,
there
is
risk
that
even
if
one
or
more
patents
related
to
ourproducts
does
issue
and
is
asserted
that
the
patent(s)
will
be
found
invalid,
unenforceable
and/or
not
infringed
when
subject
to
said
litigation.
Finally,
theintellectual
property
laws
and
practices
can
vary
considerably
from
one
country
to
another
and
also
can
change
with
time.
As
a
result,
we
could
encounterchallenges
or
difficulties
in
building,
maintaining
and
defending
our
intellectual
property
both
in
the
United
States
and
abroad.52Table
of
Contents







We
may
become
party
to,
or
threatened
with,
future
adversarial
proceedings
or
litigation
regarding
intellectual
property
rights
with
respect
to
patents
issued
orlicensed
to
us,
including
interference
proceedings
before
the
USPTO.
Third
parties
also
may
assert
infringement
claims
against
us.
If
we
are
found
to
infringe
athird
party's
intellectual
property
rights,
we
could
be
required
to
obtain
a
license
from
such
third
party
to
continue
developing
and
marketing
our
products
andtechnology.
However,
we
may
not
be
able
to
obtain
any
required
license
on
commercially
reasonable
terms
or
at
all.
Even
if
we
were
able
to
obtain
a
license,
itcould
be
non-exclusive,
thereby
giving
our
competitors
access
to
the
same
technologies
licensed
to
us.
We
could
be
forced,
including
by
court
order,
to
ceasecommercializing
the
infringing
technology
or
product.
In
addition,
we
could
be
found
liable
for
monetary
damages.
A
finding
of
infringement
could
prevent
usfrom
commercializing
our
product
candidates
or
force
us
to
cease
some
of
our
business
operations,
which
could
materially
harm
our
business.
Claims
that
we
havemisappropriated
the
confidential
information
or
trade
secrets
of
third
parties
could
have
a
similar
negative
impact
on
our
business.
For
example,
we
are
aware
of
aprovisional
patent
application
filed
with
the
USPTO
that
could
be
relevant
to
the
use
of
RAD1901
to
treat
indications
for
which
we
are
developing
RAD1901.
If
apatent
issues
from
this
patent
application
with
claims
covering
the
use
of
RAD1901
to
treat
indications
for
which
we
are
developing
RAD1901,
we
may
need
tolicense
the
patent
in
order
to
commercialize
RAD1901
specifically
for
the
treatment
of
such
indications
even
if
RAD1901
were
successfully
developed
andapproved.
We
cannot
assure
you
that
we
will
be
able
to
secure
a
license
on
reasonable
terms,
if
at
all.
If
we
need
a
license
of
such
patent
in
order
to
commercializeRAD1901
and
are
unable
to
secure
one
on
reasonable
terms,
our
business
would
be
materially
harmed.If we are unable to obtain and maintain patent protection for our technology and products, or if our licensors are unable to obtain and maintain patentprotection for the technology or products that we license from them, our competitors could develop and commercialize technology and products similar oridentical to ours, and our ability to successfully commercialize our technology and products may be adversely affected.







Our
success
depends
in
large
part
on
our
and
our
licensors'
ability
to
obtain
and
maintain
patent
protection
in
the
United
States
and
other
countries
with
respectto
our
proprietary
technology
and
products.
In
some
circumstances,
we
may
not
have
the
right
to
control
the
preparation,
filing
and
prosecution
of
patentapplications,
or
to
maintain
the
patents,
covering
technology
or
products
that
we
license
from
third
parties.
Therefore,
we
cannot
be
certain
that
these
patents
andapplications
will
be
prosecuted
and
enforced
in
a
manner
consistent
with
the
best
interests
of
our
business.
In
addition,
if
third
parties
who
license
patents
to
us
failto
maintain
these
patents,
or
lose
rights
to
those
patents,
the
rights
we
have
licensed
may
be
reduced
or
eliminated.







The
patent
position
of
biotechnology
and
pharmaceutical
companies
generally
is
highly
uncertain,
involves
complex
legal
and
factual
questions
and
has
inrecent
years
been
the
subject
of
much
litigation.
As
a
result,
the
issuance,
scope,
validity,
enforceability
and
commercial
value
of
our
and
our
licensors'
patent
rightsare
highly
uncertain.
Our
and
our
licensors'
pending
and
future
patent
applications
may
not
result
in
patents
being
issued
that
protect
our
technology
or
products
orthat
effectively
prevent
others
from
commercializing
competitive
technologies
and
products.
Changes
in
either
the
patent
laws
or
interpretation
of
the
patent
laws
inthe
United
States
and
other
countries
may
diminish
the
value
of
our
patents
or
narrow
the
scope
of
our
patent
protection.
The
laws
of
foreign
countries
may
notprotect
our
rights
to
the
same
extent
as
the
laws
of
the
United
States.
Assuming
the
other
requirements
for
patentability
are
met,
in
the
United
States,
prior
toMarch
16,
2013,
the
first
to
make
the
claimed
invention
was
entitled
to
the
patent,
or
a
"first-to-invent"
system,
while
outside
the
United
States,
the
first
to
file
apatent
application
is
entitled
to
the
patent,
or
a
"first-to-file"
system.
With
the
implementation
of
the
Leahy-Smith
America
Invents
Act,
the
United
States
now
has
afirst-to-file
system
for
patent
applications
filed
on
or
after
March
16,
2013.
We
may
become
involved
in
opposition,
interference
or
derivation
proceedingschallenging
our
patent
rights
or
the
patent
rights
of
others.
Publications
of
discoveries
in
the
scientific
literature
often
lag
behind
the
actual
discoveries,
and
patent53Table
of
Contentsapplications
in
the
United
States
and
other
jurisdictions
are
typically
not
published
until
18
months
after
filing,
or
in
some
cases
not
at
all.
Therefore,
we
cannot
becertain
that
we
or
our
licensors
were
the
first
to
make
the
inventions
claimed
in
our
owned
and
licensed
patents
or
pending
patent
applications,
or
that
we
or
ourlicensors
were
the
first
to
file
for
patent
protection
of
such
inventions.
An
adverse
determination
in
any
such
proceeding
could
reduce
the
scope
of,
or
invalidate
ourpatent
rights,
allow
third
parties
to
commercialize
our
technology
or
products
and
compete
directly
with
us,
without
payment
to
us,
or
result
in
our
inability
tomanufacture
or
commercialize
products
without
infringing
third-party
patent
rights.







Even
if
our
owned
and
licensed
patent
applications
issue
as
patents,
they
may
not
issue
in
a
form
that
will
provide
us
with
any
meaningful
protection,
preventcompetitors
from
competing
with
us
or
otherwise
provide
us
with
any
competitive
advantage.
Our
competitors
may
be
able
to
circumvent
our
owned
or
licensedpatents
by
developing
similar
or
alternative
technologies
or
products
in
a
non-infringing
manner.
The
issuance
of
a
patent
is
not
conclusive
as
to
its
scope,
validityor
enforceability,
and
our
owned
and
licensed
patents
may
be
challenged
in
the
courts
or
patent
offices
in
the
United
States
and
abroad.
Any
challenges
may
resultin
patent
claims
being
narrowed,
invalidated
or
held
unenforceable,
which
could
limit
our
ability
to
stop
or
prevent
us
from
stopping
others
from
using
orcommercializing
similar
or
identical
technology
and
products,
or
limit
the
duration
of
the
patent
protection
of
our
technology
and
products.
Given
the
amount
oftime
required
for
the
development,
testing
and
regulatory
review
of
new
product
candidates,
patents
protecting
such
candidates
might
expire
before
or
shortly
aftersuch
candidates
are
approved
or
commercialized.
As
a
result,
our
owned
and
licensed
patents
may
not
provide
us
with
sufficient
rights
to
exclude
others
fromcommercializing
products
similar
or
identical
to
ours.Payments, fees, submissions and various additional requirements must be met in order for pending patent applications to advance in prosecution and issuedpatents to be maintained. Rigorous compliance with these requirements is essential to procurement and maintenance of patents integral to our productportfolio.







Periodic
maintenance
fees,
renewal
fees,
annuity
fees
and
various
other
governmental
fees
on
patents
and/or
patent
applications
will
come
due
for
paymentperiodically
throughout
the
lifecycle
of
patent
applications
and
issued
patents.
In
order
to
help
ensure
that
we
comply
with
any
required
fee
payment,
documentaryand/or
procedural
requirements
as
they
might
relate
to
any
patents
for
which
we
are
an
assignee
or
co-assignee,
we
employ
competent
legal
help
and
relatedprofessionals
as
needed
to
comply
with
those
requirements.
Our
outside
patent
counsel
uses
Computer
Packages,
Inc.
for
patent
annuity
payments.
We
depend
onEisai
and/or
Ipsen
to
comply
with
any
required
fee
payment,
documentary
and/or
procedural
requirements
as
they
might
relate
to
any
patents
we
have
licensed
fromthem.
Failure
to
meet
a
required
fee
payment,
document
production
or
procedural
requirement
can
result
in
the
abandonment
of
a
pending
patent
application
or
thelapse
of
an
issued
patent.
In
some
instances
the
defect
can
be
cured
through
late
compliance
but
there
are
situations
where
the
failure
to
meet
the
required
eventcannot
be
cured.
Any
failures
could
compromise
the
intellectual
property
protection
around
our
preclinical
or
clinical
candidates
and
possibly
weaken
or
eliminateour
ability
to
protect
our
eventual
market
share
for
that
product.If we are unable to protect the confidentiality of our trade secrets, our business and competitive position would be harmed.







In
addition
to
our
patented
technology
and
products,
we
rely
on
trade
secrets,
including
unpatented
know-how,
technology
and
other
proprietary
information,to
maintain
our
competitive
position.
We
seek
to
protect
these
trade
secrets,
in
part,
by
entering
into
non-disclosure
and
confidentiality
agreements
with
parties
thathave
access
to
our
trade
secrets,
such
as
our
corporate
collaborators,
outside
scientific
collaborators,
sponsored
researchers,
contract
manufacturers,
consultants,advisors
and
other
third
parties.
We
also
enter
into
confidentiality
and
invention
or
patent54Table
of
Contentsassignment
agreements
with
our
employees
and
consultants.
However,
any
of
these
parties
may
breach
the
agreements
and
disclose
our
proprietary
information,and
we
may
not
be
able
to
obtain
adequate
remedies
for
any
breaches.
Enforcing
a
claim
that
a
party
illegally
disclosed
or
misappropriated
a
trade
secret
is
difficult,expensive
and
time-consuming,
and
the
outcome
is
unpredictable.
In
addition,
some
courts
inside
and
outside
the
United
States
are
less
willing
or
unwilling
toprotect
trade
secrets.
If
any
of
our
trade
secrets
were
to
be
lawfully
obtained
or
independently
developed
by
a
competitor,
we
would
have
no
right
to
prevent
themfrom
using
that
technology
or
information
to
compete
with
us.
If
any
of
our
trade
secrets
were
to
be
disclosed
to,
or
independently
developed
by
a
competitor,
ourcompetitive
position
would
be
harmed.If we infringe the rights of third parties, we could be prevented from selling products and could be forced to pay damages and defend against litigation.







If
our
products,
methods,
processes
and
other
technologies
infringe
the
proprietary
rights
of
other
parties,
we
could
incur
substantial
costs
and
may
have
to:•obtain
licenses,
which
may
not
be
available
on
commercially
reasonable
terms,
if
at
all;
•abandon
an
infringing
drug
candidate;
•redesign
our
products
or
processes
to
avoid
infringement;
•stop
using
the
subject
matter
claimed
in
the
patents
held
by
others;
•pay
damages;
or
•defend
litigation
or
administrative
proceedings
which
may
be
costly
whether
we
win
or
lose,
which
could
result
in
a
substantial
diversion
of
ourfinancial
and
management
resources.We may become involved in lawsuits to protect or enforce our patents, which could be expensive, time consuming and unsuccessful.







Competitors
may
infringe
our
patents.
To
counter
infringement
or
unauthorized
use,
we
may
be
required
to
file
infringement
claims,
which
can
be
expensiveand
time
consuming.
In
addition,
in
an
infringement
proceeding,
a
court
may
decide
that
a
patent
of
ours
is
invalid
and/or
unenforceable,
or
may
refuse
to
stop
theother
party
from
using
the
technology
at
issue
on
the
grounds
that
our
patents
do
not
cover
the
technology
in
question.
An
adverse
result
in
any
litigationproceeding
could
put
one
or
more
of
our
patents
at
risk
of
being
invalidated
and/or
interpreted
narrowly.
Furthermore,
because
of
the
substantial
amount
ofdiscovery
required
in
connection
with
intellectual
property
litigation,
there
is
a
risk
that
some
of
our
confidential
information
could
be
compromised
by
disclosureduring
this
type
of
litigation.
In
addition,
our
licensors
may
have
rights
to
file
and
prosecute
these
types
of
claims,
and
we
may
be
reliant
on
them
to
do
so.We may be subject to claims that our employees have wrongfully used or disclosed alleged trade secrets of their former employers.







Some
of
our
employees
were
previously
employed
at
universities
or
other
biotechnology
or
pharmaceutical
companies,
including
our
competitors
or
potentialcompetitors.
Although
we
try
to
ensure
that
our
employees
do
not
use
the
proprietary
information
or
know-how
of
others
in
their
work
for
us,
we
may
be
subject
toclaims
that
we
or
these
employees
have
used
or
disclosed
intellectual
property,
including
trade
secrets
or
other
proprietary
information,
of
any
such
employee'sformer
employer.
Litigation
may
be
necessary
to
defend
against
these
claims.
If
we
fail
in
defending
any
such
claims,
in
addition
to
paying
monetary
damages,
wemay
lose
valuable
intellectual
property
rights
or
personnel.
Even
if
we
are
successful
in
defending
against
such
claims,
litigation
could
result
in
substantial
costsand
be
a
distraction
to
management.55Table
of
ContentsIntellectual property litigation could cause us to spend substantial resources and distract our personnel from their normal responsibilities.







Even
if
resolved
in
our
favor,
litigation
or
other
legal
proceedings
relating
to
intellectual
property
claims
may
cause
us
to
incur
significant
expenses,
and
coulddistract
our
technical
and
management
personnel
from
their
normal
responsibilities,
delaying
the
development
of
our
product
candidates.
In
addition,
there
could
bepublic
announcements
of
the
results
of
hearings,
motions
or
other
interim
proceedings
or
developments,
and
if
securities
analysts
or
investors
perceive
these
resultsto
be
negative,
it
could
have
a
substantial
adverse
effect
on
the
price
of
our
common
stock.
Litigation
or
other
proceedings
could
substantially
increase
ouroperating
losses
and
reduce
our
resources
available
for
development
activities.
We
may
not
have
sufficient
financial
or
other
resources
to
adequately
conduct
anylitigation
or
proceedings.
Some
of
our
competitors
may
be
able
to
sustain
the
costs
of
any
litigation
or
proceedings
more
effectively
than
we
can
because
of
theirsubstantially
greater
financial
resources.
Uncertainties
resulting
from
the
initiation
and
continuation
of
patent
litigation
or
other
proceedings
could
have
a
materialadverse
effect
on
our
ability
to
compete
in
the
marketplace.Risks
Related
to
Legislation
and
Administrative
ActionsHealthcare reform may have a material adverse effect on our industry and our results of operations.







From
time
to
time,
legislation
is
implemented
to
reign
in
rising
healthcare
expenditures.
In
March
2010,
President
Obama
signed
into
law
the
PatientProtection
and
Affordable
Care
Act,
as
amended
by
the
Health
Care
and
Education
Reconciliation
Act,
or
ACA.
ACA
includes
a
number
of
provisions
affecting
thepharmaceutical
industry,
including
annual,
non-deductible
fees
on
any
entity
that
manufactures
or
imports
some
types
of
branded
prescription
drugs
and
biologicsand
increases
in
Medicaid
rebates
owed
by
manufacturers
under
the
Medicaid
Drug
Rebate
Program.
In
addition,
among
other
things,
ACA
also
establishes
a
newPatient-Centered
Outcomes
Research
Institute
to
oversee,
identify
priorities
and
conduct
comparative
clinical
effectiveness
research.
In
addition,
other
legislativechanges
have
been
proposed
and
adopted
since
ACA
was
enacted,
which
also
may
impact
our
business.
On
August
2,
2011,
the
President
signed
into
law
theBudget
Control
Act
of
2011,
or
BCA,
which,
among
other
things,
created
the
Joint
Select
Committee
on
Deficit
Reduction
to
recommend
proposals
in
spendingreductions
to
Congress.
The
Joint
Select
Committee
did
not
achieve
its
targeted
deficit
reduction
of
at
least
$1.2
trillion
for
the
years
2013
through
2021,
triggeringthe
legislation's
automatic
reduction
to
several
government
programs.
These
reductions
include
aggregate
reductions
to
Medicare
payments
to
providers
of
2%
perfiscal
year,
which
went
into
effect
on
April
1,
2013
and,
due
to
subsequent
legislative
amendments,
will
remain
in
effect
through
2025
unless
additionalCongressional
action
is
taken.
On
January
2,
2013,
President
Obama
signed
into
law
the
American
Taxpayer
Relief
Act
of
2012,
or
ATRA,
which
among
otherthings,
further
reduced
Medicare
payments
to
several
providers,
including
hospitals,
imaging
centers
and
cancer
treatment
centers.
The
full
impact
on
our
businessof
these
new
laws
is
uncertain.
We
cannot
predict
whether
other
legislative
changes
will
be
adopted,
if
any,
or
how
such
changes
would
affect
the
pharmaceuticalindustry
generally
or
our
business
in
particular.We are subject to healthcare laws, regulation and enforcement, and our failure to comply with those laws could have a material adverse effect on our results ofoperations and financial conditions.







We
are
subject
to
several
healthcare
regulations
and
enforcement
by
the
federal
government
and
the
states
and
foreign
governments
in
which
we
conduct
ourbusiness.
The
laws
that
may
affect
our
ability
to
operate
include:•the
federal
Health
Insurance
Portability
and
Accountability
Act
of
1996,
as
amended
by
the
Health
Information
Technology
for
Economic
andClinical
Health
Act,
which
governs
the56Table
of
Contentsconduct
of
various
electronic
healthcare
transactions
and
protects
the
security
and
privacy
of
protected
health
information;•the
federal
healthcare
programs'
Anti-Kickback
Statute,
which
prohibits,
among
other
things,
persons
from
knowingly
and
willfully
soliciting,receiving,
offering
or
paying
remuneration,
directly
or
indirectly,
in
exchange
for
or
to
induce
either
the
referral
of
an
individual
for,
or
thepurchase,
order
or
recommendation
of,
any
good
or
service
for
which
payment
may
be
made
under
federal
healthcare
programs
such
as
theMedicare
and
Medicaid
programs.
A
person
or
entity
does
not
need
to
have
actual
knowledge
of
the
federal
Anti-Kickback
Statute
or
specific
intentto
violate
it
to
have
committed
a
violation;
in
addition,
the
government
may
assert
that
a
claim
including
items
or
services
resulting
from
a
violationof
the
federal
Anti-Kickback
Statute
constitutes
a
false
or
fraudulent
claim
for
purposes
of
the
False
Claims
Act;
•federal
false
claims
laws,
which
prohibit,
among
other
things,
individuals
or
entities
from
knowingly
presenting,
or
causing
to
be
presented,
claimsfor
payment
from
Medicare,
Medicaid,
or
other
third-party
payers
that
are
false
or
fraudulent;
•federal
criminal
laws
that
prohibit
executing
a
scheme
to
defraud
any
healthcare
benefit
program
or
making
false
statements
relating
to
healthcarematters.
Similar
to
the
federal
Anti-Kickback
Statute,
a
person
or
entity
does
not
need
to
have
actual
knowledge
of
the
federal
Anti-KickbackStatute
or
specific
intent
to
violate
it
to
have
committed
a
violation;
•the
federal
Physician
Payment
Sunshine
Act,
or
the
Sunshine
Act,
requires
applicable
manufacturers
of
covered
drugs
to
report
payments
and
othertransfers
of
value
to
physicians
and
teaching
hospitals,
and
ownership
and
investment
interests
held
by
physicians
and
their
immediate
familymembers.
Manufacturers
are
required
to
submit
reports
to
the
government
by
the
90th
day
of
each
calendar
year;
and
•state
law
equivalents
of
each
of
the
above
federal
laws,
such
as
anti-kickback
and
false
claims
laws
which
may
apply
to
items
or
servicesreimbursed
by
any
third-party
payer,
including
commercial
insurers;
state
laws
that
require
pharmaceutical
companies
to
comply
with
the
industry'svoluntary
compliance
guidelines
and
the
applicable
compliance
guidance
promulgated
by
the
federal
government
or
otherwise
restrict
payments
thatmay
be
made
to
healthcare
providers
and
other
potential
referral
sources;
state
laws
that
require
drug
manufacturers
to
report
information
related
topayments
and
other
transfers
of
value
to
physicians
and
other
healthcare
providers
or
marketing
expenditures;
and
state
laws
governing
the
privacyand
security
of
health
information
in
certain
circumstances,
many
of
which
differ
from
each
other
in
significant
ways
and
may
not
have
the
sameeffect,
thus
complicating
compliance
efforts.







Our
operations
and
future
commercial
activities
in
connection
with
any
product
candidate
that
is
approved
will
be
subject
to
comprehensive
complianceobligations
under
state
and
federal
fraud
and
abuse,
false
claims,
physician
payment
transparency
laws
and
government
pricing
regulations,
as
described
above.
Ifwe
are
found
to
be
in
violation
of
these
regulations,
we
may
be
subject
to
penalties,
including
civil
and
criminal
penalties,
damages,
fines,
the
curtailment
orrestructuring
of
our
operations,
the
exclusion
from
participation
in
federal
and
state
healthcare
programs
and
imprisonment,
any
of
which
could
adversely
affect
ourability
to
operate
our
business
and
our
financial
results.We may be exposed to liability claims associated with the use of hazardous materials and chemicals.







Our
research
and
development
activities
may
involve
the
controlled
use
of
hazardous
materials
and
chemicals.
Although
we
believe
that
our
safety
proceduresfor
using,
storing,
handling
and
disposing
of
these
materials
comply
with
federal,
state
and
local
laws
and
regulations,
we
cannot
completely
eliminate
the
risk
ofaccidental
injury
or
contamination
from
these
materials.
In
the
event
of
such
an
accident,
we
could
be
held
liable
for
any
resulting
damages
and
any
liability
couldmaterially
adversely57Table
of
Contentsaffect
our
business,
financial
condition
and
results
of
operations.
In
addition,
the
federal,
state
and
local
laws
and
regulations
governing
the
use,
manufacture,storage,
handling
and
disposal
of
hazardous
or
radioactive
materials
and
waste
products
may
require
us
to
incur
substantial
compliance
costs
that
could
materiallyadversely
affect
our
business,
financial
condition
and
results
of
operations.Risks
Related
to
Employee
Matters
and
Managing
GrowthAs we evolve from a company primarily involved in drug discovery and development into one that is also involved in the commercialization of pharmaceuticalproducts, we may have difficulty managing our growth and expanding our operations successfully.







Our
success
will
depend
upon
the
expansion
of
our
operations
and
the
effective
management
of
our
growth,
and
if
we
are
unable
to
manage
this
growtheffectively,
our
business
will
be
harmed.
As
we
advance
our
product
candidates
through
the
development
process,
we
will
need
to
expand
our
development,regulatory,
manufacturing,
quality,
distribution,
sales
and
marketing
capabilities
or
contract
with
other
organizations
to
provide
these
capabilities
for
us.
As
ouroperations
expand,
we
expect
that
we
will
need
to
manage
additional
relationships
with
various
collaborators,
suppliers
and
other
organizations.
Our
ability
tomanage
our
operations
and
growth
requires
us
to
continue
to
improve
our
operational,
financial
and
management
controls,
reporting
systems
and
procedures.
Forexample,
some
jurisdictions,
such
as
the
District
of
Columbia,
have
imposed
licensing
requirements
for
sales
representatives.
In
addition,
the
District
of
Columbiaand
the
Commonwealth
of
Massachusetts,
as
well
as
the
federal
government
by
way
of
the
Sunshine
Act,
have
established
reporting
requirements
that
wouldrequire
public
reporting
of
compensation
and
other
"transfers
of
value"
paid
to
health
care
professionals
and
teaching
hospitals,
as
well
as
ownership
andinvestment
interests
held
by
such
professionals
and
their
immediate
family
members.
Because
the
reporting
requirements
vary
in
each
jurisdiction,
compliance
willbe
complex
and
expensive
and
may
create
barriers
to
entering
the
commercialization
phase.
The
need
to
build
new
systems
as
part
of
our
growth
could
place
astrain
on
our
administrative
and
operational
infrastructure.
We
may
not
be
able
to
make
improvements
to
our
management
information
and
control
systems
in
anefficient
or
timely
manner
and
may
discover
deficiencies
in
existing
systems
and
controls.
Such
requirements
may
also
impact
our
opportunities
to
collaborate
withphysicians
at
academic
research
centers
as
new
restrictions
on
academic-industry
relationships
are
put
in
place.
In
the
past,
collaborations
between
academia
andindustry
have
led
to
important
new
innovations,
but
the
new
laws
may
have
an
effect
on
these
activities.
While
we
cannot
predict
whether
any
legislative
orregulatory
changes
will
have
negative
or
positive
effects,
they
could
have
a
material
adverse
effect
on
our
business,
financial
condition
and
potential
profitability.We may enter into or seek to enter into business combinations and acquisitions which may be difficult to integrate, disrupt our business, divert managementattention or dilute stockholder value.







We
may
enter
into
business
combinations
and
acquisitions.
We
have
limited
experience
in
making
acquisitions,
which
are
typically
accompanied
by
a
numberof
risks,
including:•the
difficulty
of
integrating
the
operations
and
personnel
of
the
acquired
companies;
•the
potential
disruption
of
our
ongoing
business
and
distraction
of
management;
•the
potential
for
unknown
liabilities
and
expenses;
•the
failure
to
achieve
the
expected
benefits
of
the
combination
or
acquisition;
•the
maintenance
of
acceptable
standards,
controls,
procedures
and
policies;
and
•the
impairment
of
relationships
with
employees
as
a
result
of
any
integration
of
new
management
and
other
personnel.58Table
of
Contents







If
we
are
not
successful
in
completing
acquisitions
that
we
may
pursue
in
the
future,
we
would
be
required
to
reevaluate
our
business
strategy
and
we
mayhave
incurred
substantial
expenses
and
devoted
significant
management
time
and
resources
in
seeking
to
complete
the
acquisitions.
In
addition,
we
could
usesubstantial
portions
of
our
available
cash
as
all
or
a
portion
of
the
purchase
price,
or
we
could
issue
additional
securities
as
consideration
for
these
acquisitions,which
could
cause
our
stockholders
to
suffer
significant
dilution.We rely on key executive officers and scientific and medical advisors, and their knowledge of our business and technical expertise would be difficult to replace.







We
are
highly
dependent
on
our
chief
executive
officer
and
our
principal
scientific,
regulatory
and
medical
advisors.
We
do
not
have
"key
person"
lifeinsurance
policies
for
any
of
our
officers.
The
loss
of
the
technical
knowledge
and
management
and
industry
expertise
of
any
of
our
key
personnel
could
result
indelays
in
product
development,
loss
of
customers
and
sales
and
diversion
of
management
resources,
which
could
adversely
affect
our
operating
results.If we are unable to hire additional qualified personnel, our ability to grow our business may be harmed.







We
will
need
to
hire
additional
qualified
personnel
with
expertise
in
preclinical
testing,
clinical
research
and
testing,
government
regulation,
formulation
andmanufacturing
and
sales
and
marketing.
We
compete
for
qualified
individuals
with
numerous
biopharmaceutical
companies,
universities
and
other
researchinstitutions.
Competition
for
such
individuals
is
intense,
and
we
cannot
be
certain
that
our
search
for
such
personnel
will
be
successful.
Attracting
and
retainingqualified
personnel
will
be
critical
to
our
success.Significant disruptions of information technology systems or breaches of data security could adversely affect our business.







Our
business
is
increasingly
dependent
on
critical,
complex
and
interdependent
information
technology
systems
to
support
business
processes
as
well
asinternal
and
external
communications.
Our
computer
systems
are
vulnerable
to
breakdown,
malicious
intrusion
and
computer
viruses.
Any
failure
to
protect
againstbreakdowns,
malicious
intrusions
and
computer
viruses
may
result
in
the
impairment
of
production
and
key
business
processes.
In
addition,
our
systems
arepotentially
vulnerable
to
data
security
breaches,
whether
by
employees
or
others,
which
may
expose
sensitive
data
to
unauthorized
persons.
Such
data
securitybreaches
could
lead
to
the
loss
of
trade
secrets
or
other
intellectual
property,
or
could
lead
to
the
public
exposure
of
personal
information
of
our
employees,
clinicaltrial
patients,
customers,
and
others.
Such
disruptions
and
breaches
of
security
could
expose
us
to
liability
and
have
a
material
adverse
effect
on
the
operatingresults
and
financial
condition
of
our
business.Risks
Relating
to
Our
SecuritiesOur stock price may be volatile, and the value of an investment in our common stock may decline.







The
trading
price
of
our
common
stock
may
be
subject
to
wide
fluctuations
in
response
to
various
factors,
some
of
which
are
beyond
our
control,
including:•results
of
clinical
trials
of
our
product
candidates
or
those
of
our
competitors;
•our
operating
performance
and
the
operating
performance
of
similar
companies;
•the
success
of
competitive
products;
•the
overall
performance
of
the
equity
markets;
•the
number
of
shares
of
our
common
stock
publicly
owned
and
available
for
trading;59Table
of
Contents•threatened
or
actual
litigation;
•changes
in
laws
or
regulations
relating
to
our
products,
including
changes
in
the
structure
of
healthcare
payment
systems;
•any
major
change
in
our
board
of
directors
or
management;
•publication
of
research
reports
about
us
or
our
industry
or
positive
or
negative
recommendations
or
withdrawal
of
research
coverage
by
securitiesanalysts;
•large
volumes
of
sales
of
our
shares
of
common
stock
by
existing
stockholders;
•general
political,
economic
and
market
conditions;
and
•the
other
factors
described
in
this
"Risk
Factors"
section.







In
addition,
the
stock
market
in
general
has
experienced
extreme
price
and
volume
fluctuations
that
have
often
been
unrelated
or
disproportionate
to
theoperating
performance
of
the
companies
whose
shares
trade
in
the
stock
market.
Securities
class
action
litigation
has
often
been
instituted
against
companiesfollowing
periods
of
volatility
in
the
overall
market
and
in
the
market
price
of
a
company's
securities.
Such
litigation,
if
instituted
against
us,
could
result
in
verysubstantial
costs,
divert
our
management's
attention
and
resources
and
harm
our
business,
operating
results
and
financial
condition.Because we do not anticipate paying any cash dividends on our common stock in the foreseeable future, capital appreciation, if any, will be your sole source ofgain.







We
have
never
declared
or
paid
cash
dividends
on
our
common
stock.
We
currently
intend
to
retain
all
of
our
future
earnings,
if
any,
to
finance
the
growth
anddevelopment
of
our
business.
As
a
result,
capital
appreciation,
if
any,
of
our
common
stock
will
be
your
sole
source
of
gain
for
the
foreseeable
future.We have incurred and will continue to incur increased costs as a result of operating as a public company, and our management is required to devotesubstantial time to compliance initiatives.







As
a
public
company
listed
on
the
NASDAQ
Global
Market,
or
NASDAQ,
we
have
incurred
and
will
continue
to
incur
significant
legal,
accounting
and
otherexpenses.
In
addition,
the
Sarbanes-Oxley
Act
of
2002
and
rules
subsequently
implemented
by
the
Securities
and
Exchange
Commission,
or
the
SEC,
andNASDAQ
have
imposed
various
requirements
on
public
companies,
including
establishment
and
maintenance
of
effective
disclosure
and
financial
controls
andcorporate
governance
practices.
Our
management
and
other
personnel
will
need
to
devote
a
substantial
amount
of
time
to
these
compliance
initiatives.
Moreover,these
rules
and
regulations
have
increased
our
legal
and
financial
compliance
costs
and
are
making
some
activities
more
time-consuming
and
costly.







Pursuant
to
Section
404
of
the
Sarbanes-Oxley
Act
of
2002,
or
Section
404,
we
are
required
to
furnish
a
report
by
our
management
on
our
internal
control
overfinancial
reporting,
and
are
required
to
include
an
attestation
report
on
internal
control
over
financial
reporting
issued
by
our
independent
registered
publicaccounting
firm.
If
we
are
unable
to
maintain
effective
internal
controls,
we
may
not
have
adequate,
accurate
or
timely
financial
information,
and
we
may
be
unableto
meet
our
reporting
obligations
as
a
publicly
traded
company
or
comply
with
the
requirements
of
the
SEC
or
Section
404.
This
could
result
in
a
restatement
of
ourconsolidated
financial
statements,
the
imposition
of
sanctions,
including
the
inability
of
registered
broker
dealers
to
make
a
market
in
our
common
shares,
orinvestigation
by
regulatory
authorities.
Any
such
action
or
other
negative
results
caused
by
our
inability
to
meet
our
reporting
requirements
or
comply
with
legaland
regulatory
requirements
or
by
disclosure
of
an
accounting,
reporting
or
control
issue
could
adversely
affect
the
trading
price
of
our
securities60Table
of
Contentsand
our
business.
Material
weaknesses
in
our
internal
control
over
financial
reporting
could
also
reduce
our
ability
to
obtain
financing
or
could
increase
the
cost
ofany
financing
we
obtain.Our directors and executive officers, together with their affiliates, have substantial influence over us and could delay or prevent a change in corporate control.







Our
directors
and
executive
officers,
together
with
their
affiliates,
beneficially
owned
approximately
7.4
million
shares
of
our
common
stock
as
ofDecember
31,
2015.
These
stockholders,
acting
together,
have
the
ability
to
significantly
influence
the
outcome
of
matters
submitted
to
our
stockholders
forapproval,
including
the
election
of
directors
and
any
merger,
consolidation
or
sale
of
all
or
substantially
all
of
our
assets.
In
addition,
these
stockholders,
actingtogether,
have
the
ability
to
significantly
influence
the
management
and
affairs
of
our
company.
Accordingly,
this
concentration
of
ownership
might
harm
themarket
price
of
our
common
stock
by:•delaying,
deferring
or
preventing
a
change
in
corporate
control;
•impeding
a
merger,
consolidation,
takeover
or
other
business
combination
involving
us;
or
•discouraging
a
potential
acquirer
from
making
a
tender
offer
or
otherwise
attempting
to
obtain
control
of
us.Future sales and issuances of our common stock or rights to purchase common stock, including pursuant to our equity incentive plans, could result inadditional dilution of the percentage ownership of our stockholders and could cause our stock price to fall.







Additional
capital
will
be
needed
in
the
future
to
continue
our
planned
operations.
To
the
extent
we
raise
additional
capital
by
issuing
equity
securities,
ourstockholders
may
experience
substantial
dilution.
We
may
sell
common
stock,
convertible
securities
or
other
equity
securities
in
one
or
more
transactions
at
pricesand
in
a
manner
we
determine
from
time
to
time.
If
we
sell
common
stock,
convertible
securities
or
other
equity
securities
in
more
than
one
transaction,
investorsmay
be
materially
diluted
by
subsequent
sales.
These
sales
may
also
result
in
material
dilution
to
our
existing
stockholders,
and
new
investors
could
gain
rightssuperior
to
our
existing
stockholders.







Pursuant
to
our
equity
incentive
plans,
our
management
is
authorized
to
grant
stock
options
and
other
equity-based
awards
to
our
employees,
directors
andconsultants.
We
have
reserved
6,159,510
shares
of
our
common
stock
for
issuance
under
our
equity
incentive
plans
as
of
December
31,
2015,
which
includes4,408,369
shares
of
common
stock
issuable
upon
the
exercise
of
options
outstanding
as
of
December
31,
2015,
and
25,000
shares
of
common
stock
issuable
uponthe
vesting
of
performance
stock
units,
each
of
which
will
become
eligible
for
sale
in
the
public
market
in
the
future,
subject
to
certain
legal
and
contractuallimitations.
In
addition,
as
of
December
31,
2015,
warrants
to
purchase
631,588
shares
of
our
common
stock
were
outstanding.
Shares
of
our
common
stock
issuedupon
exercise
of
these
warrants
may
be
sold
in
the
public
market,
subject
to
prior
registration
or
under
an
exemption
from
registration.If securities or industry analysts cease to publish research or publish inaccurate or unfavorable research about our business, our stock price and tradingvolume could decline.







The
trading
market
for
our
common
stock
depends
in
part
on
the
research
and
reports
that
securities
or
industry
analysts
publish
about
us
or
our
business.
Ifone
or
more
of
the
analysts
who
cover
us
downgrade
our
stock
or
publish
inaccurate
or
unfavorable
research
about
our
business,
our
stock
price
would
likelydecline.
If
one
or
more
of
these
analysts
cease
coverage
of
our
company
or
fail
to
publish
reports
on
us
regularly,
demand
for
our
stock
could
decrease,
whichmight
cause
our
stock
price
and
trading
volume
to
decline.61Table
of
ContentsWe may be required to pay severance benefits to our employees who are terminated in connection with a change in control, which could harm our financialcondition or results.







Each
of
our
executive
officers
is
party
to
an
employment
agreement,
and
each
of
our
other
employees
is
party
to
an
agreement
or
participates
in
a
plan
thatprovides
change
in
control
severance
benefits
including
cash
payments
for
severance
and
other
benefits
and
acceleration
of
vesting
of
stock
options
and
otherequity
awards
in
the
event
of
a
termination
of
employment
in
connection
with
a
change
in
control
of
us.
The
payment
of
these
severance
benefits
could
harm
ourfinancial
condition
and
results.
The
accelerated
vesting
of
options
and
equity
awards
could
result
in
dilution
to
our
existing
stockholders
and
harm
the
market
priceof
our
common
stock.Anti-takeover provisions contained in our restated certificate of incorporation and amended and restated bylaws, as well as provisions of Delaware law, couldimpair a takeover attempt.







Our
restated
certificate
of
incorporation
and
our
amended
and
restated
bylaws
contain
provisions
that
could
delay
or
prevent
a
change
in
control
of
ourcompany.
These
provisions
could
also
make
it
more
difficult
for
stockholders
to
elect
directors
and
take
other
corporate
actions.
These
provisions
include:•a
staggered
board
of
directors;
•authorizing
the
board
to
issue,
without
stockholder
approval,
preferred
stock
with
rights
senior
to
those
of
our
common
stock;
•authorizing
the
board
to
amend
our
bylaws
and
to
fill
board
vacancies
until
the
next
annual
meeting
of
the
stockholders;
•prohibiting
stockholder
action
by
written
consent;
•limiting
the
liability
of,
and
providing
indemnification
to,
our
directors
and
officers;
•eliminating
the
ability
of
our
stockholders
to
call
special
meetings;
and
•requiring
advance
notification
of
stockholder
nominations
and
proposals.







Section
203
of
the
Delaware
General
Corporation
Law
prohibits,
subject
to
some
exceptions,
"business
combinations"
between
a
Delaware
corporation
and
an"interested
stockholder,"
which
is
generally
defined
as
a
stockholder
who
becomes
a
beneficial
owner
of
15%
or
more
of
a
Delaware
corporation's
voting
stock,
fora
three-year
period
following
the
date
that
the
stockholder
became
an
interested
stockholder.







These
and
other
provisions
in
our
restated
certificate
of
incorporation
and
our
amended
and
restated
bylaws
under
Delaware
law
could
discourage
potentialtakeover
attempts,
reduce
the
price
that
investors
might
be
willing
to
pay
in
the
future
for
shares
of
our
common
stock
and
result
in
the
market
price
of
our
commonstock
being
lower
than
it
would
be
without
these
provisions.Our ability to utilize our net operating loss carryforwards and certain other tax attributes may be limited.







As
of
December
31,
2015,
we
had
$419.5
million
of
federal
and
$323.0
million
of
state
net
operating
loss
carryforwards
available
to
offset
future
taxableincome.
Under
Section
382
of
the
Internal
Revenue
Code
of
1986,
as
amended,
or
the
Code,
if
a
corporation
undergoes
an
"ownership
change"
(generally
definedas
a
greater
than
50%
change
(by
value)
in
its
equity
ownership
over
a
three
year
period),
the
corporation's
ability
to
use
its
pre-change
net
operating
losscarryforwards
and
other
pre-change
tax
attributes
to
offset
its
post-change
income
may
be
limited.
We
are
in
the
process
of
conducting
a
detailed
analysis
todetermine
whether
an
ownership
change
under
Section
382
of
the
Code
has
previously
occurred.
As
a
result,
if
we
earn
net
taxable
income,
our
ability
to
use
ourpre-change
net
operating
loss
carryforwards
to
offset
U.S.
federal
taxable
income
may
become
subject
to
limitations,
which
could
potentially
result
in
increasedfuture
tax
liability
to
us.62Table
of
ContentsITEM
1B.



UNRESOLVED
STAFF
COMMENTS.








None.ITEM
2.



PROPERTIES.








Details
of
each
of
our
principal
properties
as
of
December
31,
2015
are
provided
below:ITEM
3.



LEGAL
PROCEEDINGS.








We
are
not
currently
involved
in
any
material
legal
proceedings.ITEM
4.



MINE
SAFETY
DISCLOSURES.








Not
applicable.63Location
Function
Size
(approximate
square
feet)
Property
InterestWaltham,
MA,
USA
Corporate
Headquarters

24,880
LeasedPasippany,
NJ,
USA
Office
space

10,530
LeasedCambridge,
MA,
USA
Laboratory
and
office
space

4,600
SubleasedTable
of
ContentsPART
II
ITEM
5.



MARKET
FOR
REGISTRANT'S
COMMON
EQUITY,
RELATED
STOCKHOLDER
MATTERS
AND
ISSUER
PURCHASES
OF
EQUITYSECURITIES








Our
common
stock
has
been
traded
on
The
NASDAQ
Global
Market
under
the
symbol
"RDUS"
since
the
initial
public
offering
of
our
common
stock
onJune
6,
2014.
Prior
to
that
time
there
was
no
public
market
for
our
common
stock.
The
following
table
presents
reported
quarterly
high
and
low
per
share
saleprices
of
our
common
stock
on
The
NASDAQ
Global
Market
for
the
periods
presented.









On
February
19,
2016,
the
closing
price
of
our
common
stock
was
$27.00
per
share
as
reported
on
The
NASDAQ
Global
Market.Stock
Performance
Graph








This performance graph is furnished and shall not be deemed "filed" with the SEC or subject to Section 18 of the Exchange Act, nor shall it be deemedincorporated by reference in any filings under the Securities Act of 1933, as amended.







The
graph
set
forth
below
compares
the
cumulative
total
stockholder
return
on
our
common
stock
between
June
6,
2014
(the
date
of
the
initial
public
offeringof
our
common
stock)
and
December
31,
2015,
with
the
cumulative
total
return
of
(a)
the
Nasdaq
Biotechnology
Index
and
(b)
the
Nasdaq
Composite
Index,
overthe
same
period.
This
graph
assumes
the
investment
of
$100
on
June
6,
2014
in
our
common
stock,
the
Nasdaq
Biotechnology
Index
and
the
Nasdaq
CompositeIndex
and
assumes
the
reinvestment
of
dividends,
if
any.
The
graph
assumes
our
closing
sales
price
on
June
6,
2014
of
$8.01
per
share
as
the
initial
value
of
ourcommon
stock
and
not
the
initial
offering
price
to
the
public
of
$8.00
per
share.







The
comparisons
shown
in
the
graph
below
are
based
upon
historical
data.
We
caution
that
the
stock
price
performance
shown
in
the
graph
below
is
notnecessarily
indicative
of,
nor
is
it
intended
to
forecast,
the
potential
future
performance
of
our
common
stock.
Information
used
in
the
graph
was
obtained
from
theNasdaq
Stock
Market
LLC,
a
financial
data
provider
and
a
source
believed
to
be
reliable.
The
Nasdaq
Stock
Market
LLC
is
not
responsible
for
any
errors
oromissions
in
such
information.642015
High
Low
Quarter
Ended
March
31,
2015
$51.22
$35.02
Quarter
Ended
June
30,
2015

69.16

34.76
Quarter
Ended
September
30,
2015

84.64

52.50
Quarter
Ended
December
31,
2015

77.10

45.89
2014
High
Low
Quarter
Ended
June
30,
2014
(beginning
June
6,
2014)
$14.60
$7.46
Quarter
Ended
September
30,
2014

24.28

8.09
Quarter
Ended
December
31,
2014

42.57

16.55
Table
of
Contents*$100
invested
on
June
6,
2014
in
stock
or
indexHolders







As
of
February
19,
2016,
there
were
69
holders
of
record
of
our
common
stock.
The
actual
number
of
stockholders
is
greater
than
this
number
of
recordholders,
and
includes
stockholders
who
are
beneficial
owners,
but
whose
shares
are
held
in
street
name
by
brokers
and
other
nominees.
This
number
of
holders
ofrecord
also
does
not
include
stockholders
whose
shares
may
be
held
in
trust
by
other
entities.Dividends







We
have
not
paid
any
cash
dividends
on
our
common
stock
since
inception
and
do
not
anticipate
paying
cash
dividends
in
the
foreseeable
future.Recent
Sales
of
Unregistered
Securities







We
did
not
make
any
sales
of
unregistered
securities
during
the
fourth
quarter
ended
December
31,
2015.Purchases
of
Equity
Securities
by
the
Issuer
or
Affiliated
Purchasers







There
were
no
repurchases
of
shares
of
common
stock
made
during
the
fourth
quarter
of
the
fiscal
year
ended
December
31,
2015.65Table
of
ContentsITEM
6.



SELECTED
FINANCIAL
DATA.








You
should
read
the
following
selected
financial
data
together
with
our
consolidated
financial
statements
and
the
related
notes
contained
in
Item
8
of
Part
II
ofthis
Annual
Report
on
Form
10-K.
We
have
derived
the
statements
of
operations
data
for
each
of
the
three
years
ended
December
31,
2013,
2014
and
2015
and
thebalance
sheets
data
as
of
December
31,
2014
and
2015
from
the
audited
consolidated
financial
statements
contained
in
Item
8
of
Part
II
of
this
Form
10-K.
Theselected
balance
sheet
data
as
of
December
31,
2011,
2012
and
2013
and
the
statement
of
operations
data
for
the
years
ended
December
31,
2011
and
2012
hasbeen
derived
from
the
audited
financial
statements
for
such
years
not
included
in
this
Form
10-K.







The
financial
information
set
forth
below
for
the
year
ended
December
31,
2011
has
been
recast
to
reflect
the
adoption
of
Accounting
Standards
UpdateNo.
2011-05,
Presentation of Comprehensive Income .







The
historical
financial
information
set
forth
below
may
not
be
indicative
of
our
future
performance
and
should
be
read
together
with
"Management'sDiscussion
and
Analysis
of
Financial
Condition
and
Results
of
Operations"
and
our
historical
consolidated
financial
statements
and
notes
to
those
statementsincluded
in
Item
7
of
Part
II
and
Item
8
of
Part
II,
respectively,
of
this
Annual
Report
on
Form
10-K.66


Year
Ended
December
31,
Statement
of
Operations
and
Comprehensive
Loss
Data
2015
2014
2013
2012
2011



(in
thousands)

Operating
expenses:















Research
and
development
$68,280
$45,719
$60,536
$54,961
$36,179
General
and
administrative

30,797

13,674

6,829

9,469

5,330
Loss
from
operations

(99,077)
(59,393)
(67,365)
(64,430)
(41,509)Other
(expense)
income:















Other
(expense)
income,
net

(1,607)
(713)
9,085

(2,095)
(236)Interest
(expense)
income,
net

(842)
(2,373)
(2,410)
(2,603)
(731)Net
loss

(101,526)
(62,479)
(60,690)
(69,128)
(42,476)Other
comprehensive
loss,
net
of
tax:















Unrealized
gain
(loss)
from
available-for-salesecurities

26

(21)
—

(5)
8
Comprehensive
loss
$(101,500)$(62,500)$(60,690)$(69,133)$(42,468)Net
(loss)
earnings
attributable
to
commonstockholders
$(101,526)$(71,479)$(78,161)$(83,120)$113
Net
(loss)
earnings
per
share
applicable
to
commonstockholders—basic
$(2.56)$(4.04)$(203.91)$(225.71)$0.51
Net
(loss)
earnings
per
share
applicable
to
commonstockholders—diluted
$(2.56)$(4.04)$(203.91)$(225.71)$0.06
Weighted-average
number
of
common
shares
used
innet
(loss)
earnings
per
share
applicable
to
commonstockholders—basic

39,643,099

17,699,487

383,310

368,261

219,254
Weighted-average
number
of
common
shares
used
innet
(loss)
earnings
per
share
applicable
to
commonstockholders—diluted

39,643,099

17,699,487

383,310

368,261

1,774,935
Table
of
Contents67


As
of
December
31,
Balance
Sheet
Data
2015
2014
2013
2012
2011



(in
thousands)

Cash
and
cash
equivalents
$159,678
$28,518
$12,303
$18,653
$25,128
Marketable
securities

313,661

76,758

—

4,000

31,580
Working
capital

459,128

86,774

(22,675)
8,026

56,607
Total
assets

482,465

108,417

12,758

25,300

63,637
Long-term
liabilities

—

24,394

1,945

38,222

19,806
Total
liabilities

21,180

44,953

37,257

55,312

26,589
Total
convertible
preferred
stock
and
redeemable
convertiblepreferred
stock

—

—

252,802

170,649

156,658
Total
liabilities,
convertible
preferred
stock,
redeemableconvertible
preferred
stock
and
stockholders'
equity(deficit)

482,465

108,417

12,758

25,300

63,637
Table
of
ContentsITEM
7.



MANAGEMENT'S
DISCUSSION
AND
ANALYSIS
OF
FINANCIAL
CONDITION
AND
RESULTS
OF
OPERATIONS.









You should read the following discussions in conjunction with our consolidated financial statements and related notes included in this report. This discussionincludes forward-looking statements that involve risk and uncertainties. As a result of many factors, such as those set forth under "Risk Factors," actual resultsmay differ materially from those anticipated in these forward-looking statements.Executive
Overview







We
are
a
science-driven
biopharmaceutical
company
that
is
committed
to
developing
innovative
therapeutics
in
the
areas
of
osteoporosis,
oncology
andendocrine
diseases.
Our
lead
product
candidate,
the
investigational
drug
abaloparatide
for
subcutaneous
injection,
has
completed
Phase
3
development
for
potentialuse
in
the
reduction
of
fracture
risk
in
postmenopausal
women
with
osteoporosis
and
is
currently
under
regulatory
review
in
Europe.
Our
clinical
pipeline
alsoincludes
an
investigational
abaloparatide
transdermal
patch
for
potential
use
in
osteoporosis
and
the
investigational
drug
RAD1901
for
potential
use
in
hormone-driven,
or
hormone-resistant,
breast
cancer,
and
vasomotor
symptoms
in
postmenopausal
women.
Our
preclinical
pipeline
includes
RAD140,
a
non-steroidalselective
androgen
receptor
modulator,
or
SARM,
under
investigation
for
potential
applications
in
oncology
and
multiple
conditions
where
androgen
modulationmay
offer
therapeutic
benefit.Abaloparatide







Abaloparatide
is
an
investigational
therapy
for
the
potential
treatment
of
women
with
postmenopausal
osteoporosis
who
are
at
an
increased
risk
for
a
fracture.Abaloparatide
is
a
novel
synthetic
peptide
analog
that
engages
the
parathyroid
hormone
receptor,
or
PTH1
receptor,
and
was
selected
for
clinical
developmentbased
on
its
favorable
bone
building
activity.
Abaloparatide
was
created
to
have
a
unique
mechanism
of
action
with
the
goal
of
stimulating
enhanced
bone
buildingactivity
including
bone
formation,
increasing
bone
mineral
density,
restoring
bone
microarchitecture
and
augmenting
bone
strength.
We
are
developing
twoformulations
of
abaloparatide:•Abaloparatide-SC —Abaloparatide
has
completed
Phase
3
development
for
potential
use
as
a
daily
self-administered
injection,
which
we
refer
to
asabaloparatide-SC.
We
hold
worldwide
commercialization
rights
to
abaloparatide-SC,
except
for
Japan.
In
December
2014,
we
announced
thepositive
18-month
top-line
data
from
our
Phase
3
ACTIVE
clinical
trial,
in
which
abaloparatide-SC
met
the
primary
endpoint
with
a
statisticallysignificant
reduction
in
new
vertebral
fractures
versus
placebo,
and
in
June
2015,
we
announced
the
positive
top-line
data
from
the
first
six
monthsof
the
ACTIVExtend
clinical
trial
and
the
24-month
combined
data
from
ACTIVE
and
ACTIVExtend.
In
November
2015,
we
submitted
amarketing
authorization
application,
or
MAA,
to
the
European
Medicines
Agency,
or
EMA,
which
was
validated
and
is
currently
undergoingregulatory
review
by
the
EMA.
We
intend
to
enter
into
one
or
more
partnerships
or
collaborations
for
the
potential
commercialization
ofabaloparatide-SC
prior
to
a
commercial
launch.
We
plan
to
submit
a
new
drug
application,
or
NDA,
in
the
United
States,
at
the
end
of
the
firstquarter
of
2016.
Subject
to
regulatory
review
and
a
favorable
regulatory
outcome,
we
anticipate
the
first
commercial
sales
of
abaloparatide-SC
willtake
place
in
2016.
•Abaloparatide-TD —We
are
also
developing
abaloparatide-transdermal,
which
we
refer
to
as
abaloparatide-TD,
based
on
3M's
patentedMicrostructured
Transdermal
System
technology
for
potential
use
as
a
short
wear-time
transdermal
patch.
We
hold
worldwide
commercializationrights
to
the
abaloparatide-TD
technology.
During
2014,
we
reported
progress
towards
the
development
of
an
optimized
transdermal
patch
that
maybe
capable
of
demonstrating
comparability
to
abaloparatide-SC.
In
preliminary,
nonhuman
primate
pharmacokinetic
studies,
we
achieved
adesirable
pharmacokinetic
profile,
with
comparable
AUC,
Cmax,
Tmax
and
T1/268Table
of
Contentsrelative
to
abaloparatide-SC.
We
believe
that
these
results
support
continued
clinical
development
of
abaloparatide-TD
toward
future
globalregulatory
submissions
as
a
potential
post-approval
line
extension
of
the
investigational
drug
abaloparatide-SC.
We
commenced
a
human
replicativeclinical
evaluation
of
the
optimized
abaloparatide-TD
patch
in
December
2015,
with
the
goal
of
achieving
comparability
to
abaloparatide-SC.
Weexpect
to
complete
our
clinical
evaluation
of
the
optimized
abaloparatide-TD
patch
during
2016.RAD1901







RAD1901
is
a
selective
estrogen
receptor
down-regulator/degrader,
or
SERD,
that
at
high
doses
has
a
potential
for
use
as
an
oral
non-steroidal
treatment
forhormone-driven,
or
hormone-resistant,
breast
cancer.
RAD1901
is
currently
being
investigated
in
postmenopausal
women
with
advanced
estrogen
receptorpositive,
or
ER-positive,
HER2-negative
breast
cancer,
the
most
common
form
of
the
disease.
The
compound
has
the
potential
for
use
as
a
single
agent
or
incombination
with
other
therapies
to
overcome
endocrine
resistance
in
breast
cancer.







In
September
2015,
we
announced
results
from
a
Phase
1
maximum
tolerated
dose,
or
MTD,
study
of
RAD1901
in
52
healthy
volunteers.
In
the
study,RAD1901
was
administered
to
healthy
postmenopausal
women
in
doses
ranging
from
200mg
to
1000mg,
and
the
data
showed
that
RAD1901
was
well-toleratedand
the
overall
safety
was
supportive
of
continued
development.
In
addition,
a
subset
of
subjects
that
received
18F
estradiol
positron
emission
tomography,
or
FES-PET,
imaging
demonstrated
suppression
of
the
FES-PET
signal
to
background
levels
after
six
days
of
dosing.







In
December
2014,
we
commenced
a
Phase
1,
multicenter,
open-label,
two-part,
dose-escalation
study
of
RAD1901
in
postmenopausal
women
with
advancedER-positive
and
HER2-negative
breast
cancer
in
the
United
States
to
determine
the
recommended
dose
for
a
Phase
2
clinical
trial
and
to
make
a
preliminaryevaluation
of
the
potential
anti-tumor
effect
of
RAD1901.
We
expect
to
complete
this
study
by
the
middle
of
2016.
Dose
escalation
is
currently
ongoing
with
nodose
limiting
toxicities
to
date
and
we
expect
to
initiate
expansion
cohorts
in
2016.







In
December
2015,
we
commenced
a
Phase
1
FES-PET
study
in
patients
with
metastatic
breast
cancer
in
the
European
Union
which
includes
the
use
of
FES-PET
imaging
to
assess
estrogen
receptor
occupancy
in
tumor
lesions
following
RAD1901
treatment.







In
July
2015,
we
announced
that
early
but
promising
preclinical
data
showed
that
our
investigational
drug
RAD1901,
in
combination
with
Pfizer's
palbociclib,a
cyclin-dependent
kinase,
or
CDK,
4/6
inhibitor,
or
Novartis'
everolimus,
an
mTOR
inhibitor,
was
effective
in
shrinking
tumors.
In
patient-derived
xenograft,
orPDx,
breast
cancer
models
with
either
wild
type
or
mutant
ESR1,
treatment
with
RAD1901
resulted
in
marked
tumor
growth
inhibition,
and
the
combination
ofRAD1901
with
either
agent,
palbociclib
or
everolimus,
showed
anti-tumor
activity
that
was
significantly
greater
than
either
agent
alone.
We
believe
that
thispreclinical
data
suggest
that
RAD1901
has
the
potential
to
overcome
endocrine
resistance,
is
well-tolerated,
and
has
a
profile
that
is
well
suited
for
use
incombination
therapy.







In
January
2016
we
entered
into
a
worldwide
clinical
collaboration
with
Novartis
Pharmaceuticals
to
evaluate
the
safety
and
efficacy
of
combining
RAD1901,with
Novartis'
investigational
agent
LEE011
(ribociclib),
a
CDK
4/6
inhibitor,
and
BYL719
(alpelisib),
an
investigational
phosphoinositide
3-kinase
inhibitor.







RAD1901
is
also
being
evaluated
at
low
doses
as
an
estrogen
receptor
ligand
for
the
potential
relief
of
the
frequency
and
severity
of
moderate
to
severe
hotflashes
in
postmenopausal
women
with
vasomotor
symptoms.
We
commenced
a
Phase
2b
clinical
study
of
RAD1901
for
the
potential
treatment
of
postmenopausalvasomotor
symptoms
in
December
2015.69Table
of
ContentsFinancial
OverviewResearch and Development Expenses







Research
and
development
expenses
consist
primarily
of
clinical
testing
costs,
including
payments
made
to
contract
research
organizations,
or
CROs,
salariesand
related
personnel
costs,
fees
paid
to
consultants
and
outside
service
providers
for
regulatory
and
quality
assurance
support,
licensing
of
drug
compounds
andother
expenses
relating
to
the
manufacture,
development,
testing
and
enhancement
of
our
investigational
product
candidates.
We
expense
our
research
anddevelopment
costs
as
they
are
incurred.







None
of
the
research
and
development
expenses
in
relation
to
our
investigational
product
candidates
are
currently
borne
by
third
parties.
Our
leadinvestigational
product
candidate
is
abaloparatide
and
it
currently
represents
the
largest
portion
of
our
research
and
development
expenses
for
our
investigationalproduct
candidates.
We
began
tracking
program
expenses
for
abaloparatide-SC
in
2005,
and
program
expenses
from
inception
to
December
31,
2015
wereapproximately
$195.9
million.
We
began
tracking
program
expenses
for
abaloparatide-TD
in
2007,
and
program
expenses
from
inception
to
December
31,
2015were
approximately
$33.7
million.
We
began
tracking
program
expenses
for
RAD1901
in
2006,
and
program
expenses
from
inception
to
December
31,
2015
wereapproximately
$27.7
million.
We
began
tracking
program
expenses
for
RAD140
in
2008,
and
program
expenses
from
inception
to
December
31,
2015
wereapproximately
$5.7
million.
These
expenses
relate
primarily
to
external
costs
associated
with
manufacturing,
preclinical
studies
and
clinical
trial
costs.







Costs
related
to
facilities,
depreciation,
stock-based
compensation
and
research
and
development
support
services
are
not
directly
charged
to
programs
as
theybenefit
multiple
research
programs
that
share
resources.







The
following
table
sets
forth
our
research
and
development
expenses
related
to
abaloparatide-SC,
abaloparatide-TD,
RAD1901
and
RAD140
for
the
yearsended
December
31,
2015,
2014
and
2013
(in
thousands):General and Administrative Expenses







General
and
administrative
expenses
consist
primarily
of
salaries
and
related
expenses
for
executive,
finance
and
other
administrative
personnel,
professionalfees,
business
insurance,
rent,
general
legal
activities,
including
the
cost
of
maintaining
our
intellectual
property
portfolio,
and
other
corporate
expenses.







Our
results
also
include
stock-based
compensation
expense
as
a
result
of
the
issuance
of
stock
option
grants
and
performance
unit
grants
to
employees,directors
and
consultants.
The
stock-based
compensation
expense
is
included
in
the
respective
categories
of
expense
in
the
statement
of
operations
(research
anddevelopment
and
general
and
administrative
expenses).
We
expect
to
record
additional
non-cash
compensation
expense
in
the
future,
which
may
be
significant.Interest Income and Interest Expense







Interest
income
reflects
interest
earned
on
our
cash,
cash
equivalents
and
marketable
securities.70


Year
Ended
December
31,



2015
2014
2013
Abaloparatide-SC
$19,870
$32,044
$45,977
Abaloparatide-TD

2,585

1,493

11,459
RAD1901

9,926

2,250

—
RAD140

495

—

—
Table
of
Contents







Interest
expense
reflects
interest
due
under
our
loan
and
security
agreement,
entered
into
on
May
23,
2011
with
General
Electric
Capital
Corporation,
orGECC,
as
agent
and
lender,
and
Oxford
Finance,
as
a
lender,
or
the
Original
Credit
Facility,
and
our
loan
and
security
agreement
entered
into
on
May
30,
2014
withSolar
Capital
Ltd.,
or
Solar,
as
agent
and
lender,
and
Oxford
Finance,
as
lender,
or
the
New
Credit
Facility.
Under
the
Original
Credit
Facility,
we
drew$12.5
million
under
an
initial
and
second
term
loan
during
the
year
ended
December
31,
2011
and
an
additional
$12.5
million
under
a
third
term
loan
during
theyear
ended
December
31,
2012.
Under
the
New
Credit
Facility,
we
drew
$21.0
million
under
an
initial
term
loan
on
May
30,
2014.
On
July
10,
2014,
we
enteredinto
a
first
amendment
to
the
New
Credit
Facility,
or
the
First
Amendment.
Pursuant
to
the
terms
of
the
First
Amendment,
a
second
term
loan
of
$4.0
million
wasdrawn
on
July
10,
2014.







On
May
30,
2014,
we
used
approximately
$9.3
million
of
the
New
Credit
Facility
to
repay
all
the
amounts
owed
under
the
Original
Credit
Facility.







On
August
4,
2015,
we
prepaid
all
amounts
owed
under
the
Credit
Facility
and
the
First
Amendment.
After
consideration
of
relevant
fees
required
under
theCredit
Facility
and
the
First
Amendment,
the
total
payment
amounted
to
$26.5
million.Other Income (Expense)







For
the
years
ended
December
31,
2014
and
2013,
other
income
(expense)
primarily
reflects
changes
in
the
fair
value
of
our
warrant
liability
and
the
series
A-6
convertible
preferred
stock
liability
and
stock
asset
outstanding
prior
to
our
initial
public
offering
from
the
date
of
the
initial
accrual
to
the
reporting
date.Critical
Accounting
Policies
and
Estimates







The
preparation
of
our
consolidated
financial
statements
requires
us
to
make
certain
estimates
and
assumptions
that
affect
the
reported
amounts
of
assets
andliabilities
and
expenses
during
the
reported
periods.
We
believe
the
following
accounting
policies
are
"critical"
because
they
require
us
to
make
judgments
andestimates
about
matters
that
are
uncertain
at
the
time
we
make
the
estimate,
and
different
estimates,
which
would
have
been
reasonable,
could
have
been
used,which
would
have
resulted
in
different
financial
results.Accrued Clinical Expenses







When
preparing
our
consolidated
financial
statements,
we
are
required
to
estimate
our
accrued
clinical
expenses.
This
process
involves
reviewing
opencontracts
and
purchase
orders,
communicating
with
our
personnel
to
identify
services
that
have
been
performed
on
our
behalf
and
estimating
the
level
of
serviceperformed
and
the
associated
cost
incurred
for
the
service
when
we
have
not
yet
been
invoiced
or
otherwise
notified
of
actual
cost.
Payments
under
some
of
thecontracts
we
have
with
parties
depend
on
factors
such
as
successful
enrollment
of
certain
numbers
of
patients,
site
initiation
and
the
completion
of
clinical
trialmilestones.
Examples
of
estimated
accrued
clinical
expenses
include:•fees
paid
to
investigative
sites
and
laboratories
in
connection
with
clinical
studies;
•fees
paid
to
CROs
in
connection
with
clinical
studies,
if
CROs
are
used;
and
•fees
paid
to
contract
manufacturers
in
connection
with
the
production
of
clinical
study
materials.







When
accruing
clinical
expenses,
we
estimate
the
time
period
over
which
services
will
be
performed
and
the
level
of
effort
to
be
expended
in
each
period.
Ifpossible,
we
obtain
information
regarding
unbilled
services
directly
from
our
service
providers.
However,
we
may
be
required
to
estimate
the
cost
of
these
servicesbased
only
on
information
available
to
us.
If
we
underestimate
or
overestimate
the
cost
associated
with
a
trial
or
service
at
a
given
point
in
time,
adjustments
toresearch71Table
of
Contentsand
development
expenses
may
be
necessary
in
future
periods.
Historically,
our
estimated
accrued
clinical
expenses
have
approximated
actual
expense
incurred.Subsequent
changes
in
estimates
may
result
in
a
material
change
in
our
accruals.Research and Development Expenses







We
account
for
research
and
development
costs
by
expensing
such
costs
to
operations
as
incurred.
Research
and
development
costs
primarily
consist
ofpersonnel
costs,
outsourced
research
activities,
pre-commercial
manufacturing
activities,
laboratory
supplies
and
consulting
fees.







Nonrefundable
advance
payments
for
goods
or
services
to
be
received
in
the
future
for
use
in
research
and
development
activities
are
deferred
and
capitalized.The
capitalized
amounts
are
expensed
as
the
related
goods
are
delivered
or
the
services
are
performed.
If
expectations
change
such
that
we
do
not
expect
we
willneed
the
goods
to
be
delivered
or
the
services
to
be
rendered,
capitalized
nonrefundable
advance
payments
would
be
charged
to
expense.Stock-based CompensationOptions







We
measure
stock-based
compensation
cost
at
the
accounting
measurement
date
based
on
the
fair
value
of
the
option,
and
recognize
the
expense
on
a
straight-line
basis
over
the
requisite
service
period
of
the
option,
which
is
typically
the
vesting
period.







We
estimate
the
fair
value
of
each
option
using
the
Black-Scholes
option
pricing
model
that
takes
into
account
the
fair
value
of
our
common
stock,
theexercise
price,
the
expected
life
of
the
option,
the
expected
volatility
of
our
common
stock,
expected
dividends
on
our
common
stock,
and
the
risk-free
interest
rateover
the
expected
life
of
the
option.
Due
to
the
limited
trading
history
of
our
common
stock
since
our
June
2014
initial
public
offering,
we
use
the
simplifiedmethod
described
in
the
SEC's
Staff
Accounting
Bulletin
No.
107,
Share-Based Payment, to
determine
the
expected
life
of
the
option
grants.
The
estimate
ofexpected
volatility
is
based
on
a
review
of
the
historical
volatility
of
similar
publicly
held
companies
in
the
biotechnology
field
over
a
period
commensurate
withthe
option's
expected
term.
We
have
never
declared
or
paid
any
cash
dividends
on
our
common
stock
and
we
do
not
expect
to
do
so
in
the
foreseeable
future.Accordingly,
we
use
an
expected
dividend
yield
of
zero.
The
risk-free
rate
is
based
on
the
U.S.
Treasury
yield
curve
in
effect
at
the
time
of
grant
valuation
for
aperiod
commensurate
with
the
option's
expected
term.
These
assumptions
are
highly
subjective
and
changes
in
them
could
significantly
impact
the
value
of
theoption
and
hence
the
related
compensation
expense.







We
apply
an
estimated
forfeiture
rate
to
current
period
expense
to
recognize
compensation
expense
only
for
those
awards
expected
to
vest.
We
estimateforfeitures
based
upon
historical
data,
adjusted
for
known
trends,
and
will
adjust
the
estimate
of
forfeitures
if
actual
forfeitures
differ
or
are
expected
to
differ
fromsuch
estimates.
Subsequent
changes
in
estimated
forfeitures
are
recognized
through
a
cumulative
adjustment
in
the
period
of
change
and
also
will
impact
theamount
of
stock-based
compensation
expense
in
future
periods.







Stock-based
compensation
expense
recognized
for
options
granted
to
consultants
is
also
based
upon
the
fair
value
of
the
options
issued,
as
determined
by
theBlack-Scholes
option
pricing
model.
However,
the
unvested
portion
of
such
option
grants
is
re-measured
at
each
reporting
period,
until
such
time
as
the
option
isfully
vested.72Table
of
ContentsPerformance Units







We
measure
stock-based
compensation
cost
at
the
accounting
measurement
date
based
on
the
fair
value
of
the
performance
unit
grant,
and
recognize
theexpense
over
the
derived
service
period
of
the
performance
units.







We
estimate
the
fair
value
of
each
grant
using
a
Monte
Carlo
simulation
analysis
that
takes
into
account
the
forecasted
price
of
our
common
stock,
historicalvolatility
of
our
common
stock,
risk-free
rate
as
of
valuation
date,
price
of
our
common
stock
as
of
the
grant
date
and
the
trigger
for
the
performance
condition
tobe
met.







The
derived
service
period
for
each
grant
is
calculated
using
a
Monte
Carlo
simulation
analysis.Fair Value Measurements







We
define
fair
value
as
the
price
that
would
be
received
to
sell
an
asset
or
be
paid
to
transfer
a
liability
in
an
orderly
transaction
between
market
participants
atthe
measurement
date.
We
determine
fair
value
based
on
the
assumptions
market
participants
use
when
pricing
the
asset
or
liability.
We
also
use
the
fair
valuehierarchy
that
prioritizes
the
information
used
to
develop
these
assumptions.







The
fair
value
hierarchy
gives
the
highest
priority
to
unadjusted
quoted
prices
in
active
markets
for
identical
assets
(Level
1)
and
the
lowest
priority
tounobservable
inputs
(Level
3).
Our
financial
assets
and
liabilities
are
classified
within
the
fair
value
hierarchy
based
on
the
lowest
level
of
input
that
is
significantto
the
fair
value
measurement.
The
three
levels
of
the
fair
value
hierarchy,
and
its
applicability
to
our
financial
assets,
are
described
below:Level 1 —Unadjusted
quoted
prices
in
active
markets
that
are
accessible
at
the
measurement
date
of
identical,
unrestricted
assets.Level 2 —Quoted
prices
for
similar
assets,
or
inputs
that
are
observable,
either
directly
or
indirectly,
for
substantially
the
full
term
throughcorroboration
with
observable
market
data.
Level
2
includes
investments
valued
at
quoted
prices
adjusted
for
legal
or
contractual
restrictionsspecific
to
the
security.Level 3 —Pricing
inputs
are
unobservable
for
the
asset,
that
is,
inputs
that
reflect
the
reporting
entity's
own
assumptions
about
the
assumptionsmarket
participants
would
use
in
pricing
the
asset.
Level
3
includes
private
investments
that
are
supported
by
little
or
no
market
activity.







As
of
December
31,
2015
and
2014,
we
held
financial
assets
that
were
measured
using
Level
1
and
Level
2
inputs.
Assets
measured
using
Level
1
inputsinclude
money
market
funds,
which
are
valued
using
quoted
market
prices
with
no
valuation
adjustments
applied.
Assets
measured
using
Level
2
inputs
includemarketable
securities
that
consist
primarily
of
domestic
corporate
debt
securities
(direct
issuance
bonds,
corporate
bonds,
etc.)
and
are
valued
using
third-partypricing
resources,
which
generally
use
interest
rates
and
yield
curves
observable
at
commonly
quoted
intervals
of
similar
assets
as
observable
inputs
for
pricing.







As
of
December
31,
2015
and
2014,
we
held
no
Level
3
assets
or
liabilities.Results
of
Operations







The
following
discussion
summarizes
the
key
factors
our
management
team
believes
are
necessary
for
an
understanding
of
our
consolidated
financialstatements.73Table
of
ContentsYears Ended December 31, 2015 and December 31, 2014        Research and development expenses —For
the
year
ended
December
31,
2015,
research
and
development
expense
was
$68.3
million
compared
to$45.7
million
for
the
year
ended
December
31,
2014,
an
increase
of
$22.6
million,
or
49%.
This
increase
was
primarily
a
result
of
an
increase
in
compensationexpense,
including
an
increase
of
$5.9
million
of
non-cash
stock-based
compensation
expense,
due
to
an
increase
in
headcount
from
16
research
and
developmentemployees
as
of
December
31,
2014
to
48
research
and
development
employees
as
of
December
31,
2015.
This
increase
was
also
driven
by
higher
consulting
costsincurred
to
support
our
MAA
and
planned
NDA
submissions
for
our
investigational
product
candidate
abaloparatide-SC,
and
an
increase
in
contract
service
costsassociated
with
the
development
of
our
investigational
product
candidate
RAD1901
as
a
result
of
the
initiation
of
various
preclinical
and
manufacturing
activities
inlate
2014.
These
amounts
were
partially
offset
by
a
decrease
in
the
total
professional
contract
service
costs
associated
with
the
development
of
abaloparatide-SCresulting
from
the
completion
of
the
Phase
3
18-month
fracture
study
in
October
2014
and
the
first
six
months
of
the
ACTIVExtend
clinical
trial.
We
expect
thatcosts
associated
with
the
development
of
abaloparatide-SC
will
continue
to
decrease
over
the
course
of
the
ACTIVExtend
clinical
trial
as
patients
completetreatment.







We
expect
that
the
costs
associated
with
the
development
of
abaloparatide-TD
will
increase
as
we
begin
to
advance
an
optimized
abaloparatide-TD
product
inadditional
clinical
studies.
We
expect
that
the
costs
associated
with
the
development
of
RAD1901
will
increase
as
we
begin
to
advance
RAD1901
through
variouspreclinical
and
clinical
studies,
including
a
Phase
1
study
in
metastatic
breast
cancer,
which
commenced
in
late
2014,
and
a
Phase
2b
study
in
vasomotor
symptoms,which
commenced
in
December
2015.        General and administrative expenses —For
the
year
ended
December
31,
2015,
general
and
administrative
expense
was
$30.8
million
compared
to$13.7
million
for
the
year
ended
December
31,
2014,
an
increase
of
$17.1
million,
or
125%.
This
increase
was
primarily
the
result
of
an
increase
during
the
yearended
December
31,
2015,
of
approximately
$10.3
million
in
legal
fees
and
professional
support
costs,
including
the
costs
associated
with
growing
Radius'headcount
and
preparing
for
the
potential
commercialization
of
abaloparatide-SC,
subject
to
a
favorable
regulatory
review.
This
increase
was
also
driven
by
anincrease
in
compensation
expense,
including
an
increase
of
$1.8
million
of
non-cash
stock-based
compensation
expense,
due
to
an
increase
in
headcount
from
10general
and
administrative
employees
as
of
December
31,
2014
to
27
general
and
administrative
employees
as
of
December
31,
2015.74


Years
Ended
December
31,
Change



2015
2014
$
%



(in
thousands)

Operating
expenses:












Research
and
development
$68,280
$45,719
$22,561

49%General
and
administrative

30,797

13,674

17,123

125%Loss
from
operations

(99,077)
(59,393)
39,684

67%Other
(expense)
income:












Other
(expense)
income,
net

(35)
(510)
(475)
–93%Loss
on
retirement
of
note
payable

(1,572)
(203)
1,369

674%Interest
(expense)
income,
net

(842)
(2,373)
(1,531)
–65%Net
loss
$(101,526)$(62,479)
39,047

62%Table
of
Contents        Other (expense) income, net —For
the
year
ended
December
31,
2015,
other
expense,
net
of
other
income,
was
$35
thousand,
as
compared
to
$0.5
millionduring
the
year
ended
December
31,
2014.
Other
expense,
net
of
other
income,
for
the
year
ended
December
31,
2015
consisted
primarily
of
state
taxes.
The$0.5
million
of
other
expense,
net
of
income,
for
the
year
ended
December
31,
2014
was
primarily
due
to
an
increase
in
the
fair
value
of
our
warrant
liability
as
aresult
of
an
overall
increase
in
the
fair
value
of
the
underlying
common
stock
from
December
31,
2013
to
June
6,
2014.
Following
our
initial
public
offering
onJune
6,
2014,
the
carrying
value
of
our
warrant
liability
was
reclassified
to
equity.        Loss on retirement of note payable —For
the
year
ended
December
31,
2015,
loss
on
retirement
of
note
payable
was
$1.6
million.
This
loss
was
a
result
of
theprepayment
of
our
New
Credit
Facility
on
August
4,
2015.
For
the
year
ended
December
31,
2014,
loss
on
retirement
of
note
payable
was
$0.2
million.
This
losswas
a
result
of
the
prepayment
of
our
Original
Credit
Facility
on
May
30,
2014.        Interest (expense) income —For
the
year
ended
December
31,
2015,
interest
expense,
net
of
interest
income,
was
$0.8
million,
as
compared
to
$2.4
millionduring
the
year
ended
December
31,
2014,
a
decrease
of
$1.5
million,
or
65%.
This
decrease
was
primarily
a
result
of
the
prepayment
of
all
outstanding
long-termdebt
on
August
4,
2015,
and
an
increase
in
interest
income
as
a
result
of
an
increase
in
our
cash,
cash
equivalents
and
marketable
securities
outstanding
during
theyear
ended
December
31,
2015.Years Ended December 31, 2014 and December 31, 2013        Research and development expenses —For
the
year
ended
December
31,
2014,
research
and
development
expense
was
$45.7
million
compared
to$60.5
million
for
the
year
ended
December
31,
2013,
a
decrease
of
$14.8
million,
or
24%.
This
decrease
is
primarily
a
result
of
a
decrease
in
the
total
professionalcontract
service
costs
associated
with
the
development
of
abaloparatide-SC
and
abaloparatide-TD,
partially
offset
by
an
increase
in
professional
contract
servicescosts
associated
with
the
development
of
RAD1901.
During
the
year
ended
December
31,
2014,
we
incurred
professional
contract
service
costs
associated
with
thedevelopment
of
abaloparatide-SC,
abaloparatide-TD
and
RAD1901
of
$32.0
million,
$1.5
million
and
$2.3
million,
respectively,
compared
to
$46.0
million,$11.5
million
and
zero,
respectively,
for
the
year
ended
December
31,
2013.
The
decrease
in
contract
service
costs
associated
with
the
development
ofabaloparatide-SC
is
primarily
a
result
of
the
completion
of
the
Phase
3
18-month
fracture
study
in
October
2014.
Additionally,
fewer
patients
were
enrolled
in
the6-month
extension
study
as
of
December
31,
2014,
as
compared
to
the
year
ended
December
31,
2013,
as
certain
patients
completed
treatment.
In
addition,
therewill
be
variability
from
quarter
to
quarter
in
the
costs
for
abaloparatide-SC,
driven
primarily
by
the
euro/dollar
exchange
rate,75


Years
Ended
December
31,
Change



2014
2013
$
%



(in
thousands)

Operating
expenses:












Research
and
development
$45,719
$60,536
$(14,817)
–24%General
and
administrative

13,674

6,829

6,845

100%Loss
from
operations

(59,393)
(67,365)
(7,972)
–12%Other
(expense)
income:












Other
(expense)
income,
net

(510)
9,085

9,595

106%Loss
on
retirement
of
note
payable

(203)
—

203

100%Interest
(expense)
income,
net

(2,373)
(2,410)
(37)
–2%Net
loss
$(62,479)$(60,690)
1,789

3%Table
of
Contentswhich
is
more
fully
described
below
under
"Research
and
Development
Agreements."
The
decrease
in
contract
service
costs
associated
with
the
development
ofabaloparatide-TD
is
a
result
of
the
completion
of
the
Phase
2
clinical
trial
(which
began
dosing
patients
in
September
2012)
in
September
2013.
The
increase
incontract
service
costs
associated
with
the
development
of
RAD1901
is
a
result
of
the
initiation
of
various
preclinical,
clinical,
and
manufacturing
activities
in
2014.        General and administrative expenses —For
the
year
ended
December
31,
2014,
general
and
administrative
expense
was
$13.7
million
compared
to$6.8
million
for
the
year
ended
December
31,
2013,
an
increase
of
$6.8
million,
or
100%.
This
increase
was
primarily
due
to
an
increase
in
compensation
costs
of$4.5
million,
including
an
increase
of
$3.9
million
in
non-cash
stock-based
compensation
expense
as
a
result
of
the
issuance
of
new
option
awards
during
2014,
aswell
as
the
acceleration
of
vesting
for
a
portion
of
our
Chief
Executive
Officer's
outstanding
option
awards,
in
accordance
with
his
employment
agreement,
uponcompletion
of
our
initial
public
offering.
This
increase
can
also
be
attributed
to
higher
legal
fees
and
consulting
support
costs
of
approximately
$1.7
million
duringthe
year
ended
December
31,
2014.        Other (expense) income, net —For
the
year
ended
December
31,
2014,
other
expense,
net
of
other
income,
was
$0.5
million,
as
compared
to
other
income,
netof
expense
during
the
year
ended
December
31,
2013
of
$9.1
million.
Other
expense,
net
of
other
income,
primarily
reflects
changes
in
the
fair
value
of
the
stockasset,
stock
liability,
other
liability
and
warrant
liability.
The
$0.5
million
of
other
expense,
net
of
income,
for
the
year
ended
December
31,
2014
was
primarily
dueto
an
increase
in
the
fair
value
of
our
warrant
liability
as
a
result
of
an
overall
increase
in
the
fair
value
of
the
underlying
common
stock
from
December
31,
2013
toJune
6,
2014.
Following
our
initial
public
offering
on
June
6,
2014,
our
warrant
liability
was
reclassified
to
equity.
The
$9.1
million
of
other
income,
net
ofexpense,
as
of
December
31,
2013
was
primarily
due
to
a
decrease
in
the
fair
value
of
our
stock
liability
and
other
liability
as
a
result
of
an
overall
decline
in
thefair
value
of
the
underlying
convertible
preferred
stock
from
December
31,
2012
to
December
31,
2013.        Loss on retirement of note payable —For
the
year
ended
December
31,
2014,
loss
on
retirement
of
note
payable
was
$0.2
million.
This
loss
was
a
result
of
theprepayment
of
our
Original
Credit
Facility
on
May
30,
2014.        Interest (expense) income —For
the
year
ended
December
31,
2014,
interest
expense,
net
of
interest
income,
was
$2.4
million,
consistent
with
$2.4
million
forthe
year
ended
December
31,
2013.Liquidity
and
Capital
Resources







From
inception
to
December
31,
2015,
we
have
incurred
an
accumulated
deficit
of
$445.8
million,
primarily
as
a
result
of
expenses
incurred
through
acombination
of
research
and
development
activities
related
to
our
various
investigational
product
candidates
and
expenses
supporting
those
activities.
Our
totalcash,
cash
equivalents
and
marketable
securities
balance
as
of
December
31,
2015
was
$473.3
million.
We
have
financed
our
operations
since
inception
primarilythrough
the
public
offerings
of
our
common
stock,
private
sale
of
preferred
stock,
borrowing
under
credit
facilities
and
the
receipt
of
$5.0
million
in
fees
associatedwith
an
option
agreement.







Based
upon
our
cash,
cash
equivalents
and
marketable
securities
balance,
we
believe
that,
prior
to
the
consideration
of
revenue
from
the
potential
future
salesof
any
of
our
investigational
products
that
may
receive
regulatory
approval
or
proceeds
from
partnership
activities,
we
have
sufficient
capital
to
fund
ourdevelopment
plans,
U.S.
commercial
scale-up
and
other
operational
activities
into
2018.
We
expect
to
finance
the
future
development
costs
of
our
clinical
productportfolio
with
our
existing
cash,
cash
equivalents
and
marketable
securities,
or
through
strategic
financing
opportunities,
that
could
include,
but
are
not
limited
topartnering
or
other
collaboration
agreements,
future
offerings
of
equity,
or
the
incurrence
of
debt.
However,
there
is
no
guarantee
that
any
of
these
strategicfinancing76Table
of
Contentsopportunities
will
be
available
to
us
on
favorable
terms,
and
some
could
be
dilutive
to
existing
stockholders.
Our
future
capital
requirements
will
depend
on
manyfactors,
including
the
scope
and
progress
made
in
our
research
and
development
and
commercialization
activities,
the
results
of
our
clinical
trials,
and
the
reviewand
potential
approval
of
our
products
by
the
U.S.
Food
and
Drug
Administration,
or
FDA,
and
the
European
Medicines
Agency.
The
successful
development
ofour
investigational
product
candidates
is
subject
to
numerous
risks
and
uncertainties
associated
with
developing
drugs,
which
could
have
a
significant
impact
on
thecost
and
timing
associated
with
the
development
of
our
product
candidates.
If
we
fail
to
obtain
additional
future
capital,
we
may
be
unable
to
complete
our
plannedpreclinical
and
clinical
trials
and
obtain
approval
of
any
investigational
product
candidates
from
the
FDA
and
foreign
regulatory
authorities.







The
following
table
sets
forth
the
major
sources
and
uses
of
cash
for
each
of
the
periods
set
forth
below
(in
thousands):Cash Flows from Operating Activities







Net
cash
used
in
operating
activities
during
the
year
ended
December
31,
2015
was
$87.1
million,
which
was
primarily
the
result
of
a
net
loss
of$101.5
million
and
net
changes
in
working
capital
of
$4.0
million,
partially
offset
by
$18.4
million
of
net
non-cash
adjustments
to
reconcile
net
loss
to
net
cashused
in
operations.
The
$101.5
million
net
loss
was
primarily
due
to
abaloparatide-SC
and
pipeline
program
development
expenses
along
with
employeecompensation
and
consulting
costs
incurred
to
support
future
regulatory
submissions
and
preparation
for
the
potential
commercial
launch
of
abaloparatide-SC.
The$18.4
million
net
non-cash
adjustments
to
reconcile
net
loss
to
net
cash
used
in
operations
included
stock-based
compensation
expense
of
$14.7
million,
loss
onretirement
of
note
payable
of
$1.6
million
and
amortization
of
premiums
(discounts)
on
marketable
securities
of
$1.7
million.







Net
cash
used
in
operating
activities
during
the
year
ended
December
31,
2014
was
$48.3
million,
which
was
primarily
the
result
of
a
net
loss
of
$62.5
million,partially
offset
by
$11.2
million
of
net
non-cash
adjustments
to
reconcile
net
loss
to
net
cash
used
in
operations
and
net
changes
in
working
capital
of
$3.0
million.The
$62.5
million
net
loss
was
primarily
due
to
expenses
incurred
in
connection
with
our
ongoing
Phase
3
clinical
trial
of
abaloparatide-SC.
The
$11.2
million
netnon-cash
adjustments
to
reconcile
net
loss
to
net
cash
used
in
operations
included
stock-based
compensation
expense
of
$7.1
million,
$2.7
million
of
research
anddevelopment
expenses
settled
in
stock,
and
a
$0.5
million
increase
in
the
fair
value
of
our
warrant
liability
and
stock
liability
as
a
result
of
an
increase
in
the
fairvalue
of
the
underlying
convertible
preferred
stock
and
common
stock
from
December
31,
2013
to
June
6,
2014.







Net
cash
used
in
operating
activities
for
the
year
ended
December
31,
2013
was
$45.0
million,
which
was
primarily
the
result
of
a
net
loss
of
$60.7
million,partially
offset
by
net
changes
in
working
capital
of
$9.7
million
and
$6.0
million
net
non-cash
adjustments
to
reconcile
net
loss
to
net
cash
used
in
operations.
The$60.7
million
net
loss
was
primarily
due
to
expenses
incurred
in
connection
with
our
Phase
3
clinical
trial
of
abaloparatide-SC
and
our
Phase
2
clinical
study
ofabaloparatide-TD,
which77


Years
ended
December
31,



2015
2014
2013
Net
cash
(used
in)
provided
by:









Operating
activities
$(87,103)$(48,345)$(45,017)Investing
activities

(239,822)
(78,065)
3,971
Financing
activities

458,085

142,625

34,696
Net
increase
(decrease)
in
cash
and
cash
equivalents
$131,160
$16,215
$(6,350)Table
of
Contentsfinished
dosing
patients
during
the
three
months
ended
September
30,
2013.
The
$6.0
million
net
non-cash
adjustments
to
reconcile
net
loss
to
net
cash
used
inoperations
included
$13.1
million
of
research
and
development
expenses
settled
in
stock
and
stock-based
compensation
expense
of
$1.5
million,
and
was
partiallyoffset
by
a
$9.1
million
reduction
in
the
fair
value
of
our
warrant
liability,
stock
liability
and
other
liability
as
a
result
of
a
decline
in
the
fair
value
of
the
underlyingconvertible
preferred
stock
from
December
31,
2012
to
December
31,
2013.Cash Flows from Investing Activities







Net
cash
used
in
investing
activities
for
the
year
ended
December
31,
2015
was
$239.8
million,
as
compared
to
net
cash
used
in
investing
activities
of$78.1
million
for
the
year
ended
December
31,
2014.







The
net
cash
used
in
investing
activities
during
the
year
ended
December
31,
2015
was
primarily
a
result
of
$579.1
million
in
purchases
of
marketablesecurities
and
$1.2
million
of
purchases
of
property
and
equipment,
partially
offset
by
$340.5
million
of
net
proceeds
received
from
the
sale
or
maturity
ofmarketable
securities.
The
net
cash
used
in
investing
activities
during
the
year
ended
December
31,
2014
was
primarily
a
result
of
$97.7
million
in
purchases
ofmarketable
securities
and
$0.9
million
of
purchases
of
property
and
equipment,
partially
offset
by
$20.5
million
of
net
proceeds
received
from
the
sale
or
maturityof
marketable
securities.
The
net
cash
provided
by
investing
activities
during
the
year
ended
December
31,
2013
was
primarily
a
result
of
$21.0
million
netproceeds
received
from
the
sale
or
maturity
of
marketable
securities,
partially
offset
by
$17.1
million
in
purchases
of
marketable
securities.







Our
investing
cash
flows
will
be
impacted
by
the
timing
of
purchases
and
sales
of
marketable
securities.
All
of
our
marketable
securities
have
contractualmaturities
of
less
than
one
year.
Due
to
the
short-term
nature
of
our
marketable
securities,
we
would
not
expect
our
operational
results
or
cash
flows
to
besignificantly
affected
by
a
change
in
market
interest
rates
due
to
the
short-term
duration
of
our
investments.Cash Flows from Financing Activities







Net
cash
provided
by
financing
activities
for
the
year
ended
December
31,
2015
was
$458.1
million,
as
compared
to
$142.6
million
of
net
cash
provided
byfinancing
activities
for
the
year
ended
December
31,
2014.







Net
cash
provided
by
financing
activities
during
the
year
ended
December
31,
2015
consisted
of
$482.3
million
of
net
proceeds
received
from
public
offeringsof
our
common
stock
in
January
and
July
of
2015,
partially
offset
by
the
repayment
of
our
New
Credit
Facility.







Net
cash
provided
by
financing
activities
during
the
year
ended
December
31,
2014
consisted
of
$50.4
million
of
net
proceeds
from
our
initial
public
offering,$53.4
million
of
net
proceeds
from
our
additional
public
offering
that
closed
October
7,
2014,
$27.4
million
of
net
proceeds
from
the
issuance
of
our
series
B-2convertible
preferred
stock
in
February
and
March
of
2014,
and
$24.6
million
of
net
proceeds
from
our
New
Credit
Facility,
partially
offset
by
payments
under
ourOriginal
Credit
Facility
of
$13.2
million.







Net
cash
provided
by
financing
activities
for
the
year
ended
December
31,
2013
consisted
of
$42.9
million
of
net
proceeds
from
the
issuance
of
our
series
Bconvertible
preferred
stock
in
April
and
May
of
2013,
partially
offset
by
payments
under
our
Credit
Facility
of
$8.2
million.Sales of Common Stock







On
July
28,
2015,
we
completed
a
public
offering
of
4,054,054
shares
of
our
common
stock
at
a
price
of
$74.00
per
share,
for
aggregate
proceeds,
net
ofunderwriting
discounts,
commissions
and78Table
of
Contentsoffering
costs,
of
approximately
$281.5
million.
Also,
on
July
28,
2015,
the
underwriters
purchased
an
additional
608,108
shares
by
exercising
an
option
topurchase
additional
shares
that
was
granted
to
them
in
connection
with
the
offering.
As
a
result
of
the
public
offering
and
subsequent
exercise
of
the
underwriters'option,
we
received
aggregate
proceeds,
net
of
underwriting
discounts,
commissions
and
estimated
offering
costs
of
approximately
$323.8
million.







On
January
28,
2015,
we
completed
a
public
offering
of
4,000,000
shares
of
our
common
stock
at
a
price
of
$36.75
per
share,
for
aggregate
estimatedproceeds,
net
of
underwriting
discounts,
commissions
and
offering
costs,
of
approximately
$137.8
million.
On
January
28,
2015,
the
underwriters
purchased
anadditional
600,000
shares
in
the
aggregate
by
exercising
an
option
to
purchase
additional
shares
that
was
granted
to
them
in
connection
with
the
offering.
As
aresult
of
the
public
offering
and
subsequent
exercise
of
the
underwriters'
option,
we
received
aggregate
proceeds,
net
of
underwriting
discounts,
commissions
andoffering
costs
of
approximately
$158.4
million.







On
October
7,
2014,
we
completed
an
additional
public
offering
whereby
we
sold
2,750,000
shares
of
common
stock
at
a
price
of
$18.25
per
share,
foraggregate
proceeds,
net
of
underwriting
discounts,
commissions
and
offering
costs,
of
approximately
$46.9
million.
On
October
7,
2014,
the
underwriterspurchased
an
additional
378,524
shares
in
the
aggregate
by
exercising
a
portion
of
the
over-allotment
option
granted
to
them
in
connection
with
the
offering.
As
aresult
of
the
public
offering
and
subsequent
exercise
of
the
over-allotment
option,
we
received
aggregate
proceeds,
net
of
underwriting
discounts,
commissions
andoffering
costs
of
approximately
$53.4
million.







On
June
11,
2014,
we
completed
our
initial
public
offering
whereby
we
sold
6,500,000
shares
of
our
common
stock
at
a
price
of
$8.00
per
share.
The
sharesbegan
trading
on
the
NASDAQ
Global
Market
on
June
6,
2014.
In
connection
with
the
completion
of
the
offering,
all
outstanding
shares
of
our
convertiblepreferred
stock
converted
into
19,465,132
shares
of
common
stock,
and
2,862,654
shares
of
common
stock
were
issued
in
satisfaction
of
accumulated
dividendsaccrued
on
the
preferred
stock.
In
addition,
all
outstanding
warrants
to
purchase
shares
of
series
A-1
convertible
preferred
stock
and
warrants
to
purchase
shares
ofseries
B-2
convertible
preferred
stock
were
converted
into
the
right
to
purchase
149,452
shares
of
common
stock
and
our
warrant
liability
was
reclassified
toequity.
On
June
18,
2014
and
June
25,
2014,
the
underwriters
purchased
an
additional
512,744
shares
in
the
aggregate
by
exercising
a
portion
of
the
over-allotmentoption
granted
to
them
in
connection
with
the
initial
public
offering.
As
a
result
of
the
closing
of
the
initial
public
offering
and
subsequent
exercise
of
the
over-allotment
option,
we
received
aggregate
proceeds,
net
of
underwriting
discounts,
commissions
and
offering
costs,
of
approximately
$50.4
million.79Table
of
ContentsSales of Preferred Stock







We
had
no
sales
of
preferred
stock
during
the
year
ended
December
31,
2015.
Through
December
31,
2015,
we
had
received
aggregate
net
cash
proceeds
of$238.2
million
from
the
sale
of
shares
of
our
preferred
stock
as
follows:







On
February
14,
2014,
we
entered
into
a
Series
B-2
Convertible
Preferred
Stock
and
Warrant
Purchase
Agreement,
or
Purchase
Agreement,
pursuant
to
whichwe
were
able
to
raise
up
to
approximately
$40.2
million
through
the
issuance
of
(1)
up
to
655,000
series
B-2
Shares
convertible
preferred
stock,
or
Series
B-2,
parvalue
$.0001
per
share,
and
(2)
warrants
to
acquire
up
to
718,201
shares
of
our
common
stock,
at
an
exercise
price
of
$14.004
per
share.
On
February
14,
2014,February
19,
2014,
February
24,
2014,
March
14,
2014
and
March
28,
2014,
we
consummated
closings
under
the
Series
B-2
Purchase
Agreement,
whereby,
inexchange
for
aggregate
proceeds
to
us
of
approximately
$27.5
million,
we
issued
an
aggregate
of
448,060
Series
B-2
Shares
and
warrants
to
purchase
up
to
a
totalof
491,293
shares
of
our
common
stock.
The
warrants
issuable
pursuant
to
the
Purchase
Agreement
are
exercisable
for
a
period
of
five
years
from
issuance.







On
April
23,
2013,
we
entered
into
a
Series
B
Convertible
Preferred
Stock
and
Warrant
Purchase
Agreement,
or
the
Series
B
Purchase
Agreement,
pursuant
towhich
we
could
raise,
at
any
time
on
or
prior
to
May
10,
2013,
up
to
approximately
$60.0
million
through
the
issuance
of
(1)
up
to
980,000
shares
of
its
Series
Bpreferred
stock
,
or
the
Series
B,
and
(2)
warrants
to
acquire
up
to
approximately
1,075,000
shares
of
its
common
stock
with
an
exercise
price
of
$14.004
per
share.On
April
23,
2013,
we
consummated
a
first
closing
under
the
Series
B
Purchase
Agreement,
whereby
in
exchange
for
aggregate
proceeds
of
approximately$43.0
million,
we
issued
700,098
shares
of
Series
B
and
warrants
to
purchase
up
to
a
total
of
767,651
shares
of
our
common
stock.
On
May
10,
2013,
weconsummated
a
second
closing
under
the
Series
B
Purchase
Agreement,
whereby
in
exchange
for
aggregate
proceeds
of
approximately
$0.1
million,
we
issued1,137
shares
of
Series
B
and
warrants
to
purchase
up
to
a
total
of
1,246
shares
of
our
common
stock.
The
warrants
can
be
exercised
at
any
time
prior
to
the
fifthanniversary
of
their
issuance.







Upon
completion
of
our
initial
public
offering,
all
shares
of
preferred
stock
were
converted
into
shares
of
our
common
stock.80Issue
Year
No.
Shares
Net
Proceeds
(in
thousands)
Series
B
redeemable
convertible
preferred
stock(1)
2003,
2004,
2005

1,599,997
$23,775
Series
C
redeemable
convertible
preferred
stock(1)
2006,
2007,
2008

10,146,629

82,096
Series
A-1
convertible
preferred
stock(1)
2011

9,223,041

61,591
Series
A-5
convertible
preferred
stock(1)
2011

64,430

525
Series
B
convertible
preferred
stock
2013

701,235

42,870
Series
B-2
convertible
preferred
stock
2014

448,060

27,368
Total



22,183,392
$238,225
(1)Share
amounts
stated
in
pre-Merger
shares,
which
converted
into
the
rights
to
one-tenth
of
one
share
pursuant
to
the
Merger.Table
of
ContentsDebt Borrowings







On
May
30,
2014,
we
entered
into
our
New
Credit
Facility
with
Solar
and
Oxford
Finance,
pursuant
to
which
Solar
and
Oxford
agreed
to
make
available
to
us$30.0
million
in
the
aggregate
subject
to
certain
conditions
to
funding.
An
initial
term
loan
was
made
on
May
30,
2014
in
an
aggregate
principal
amount
equal
to$21.0
million,
or
the
Initial
Term
Loan.







The
Initial
Term
Loan
bore
interest
per
annum
at
9.85%
plus
one-month
LIBOR
(customarily
defined).
All
principal
and
accrued
interest
on
the
initial
termloan
had
been
due
on
June
1,
2018.







As
security
for
its
obligations
under
the
New
Credit
Facility,
we
granted
a
security
interest
in
substantially
all
of
our
existing
and
after-acquired
assets
exceptfor
our
intellectual
property
and
certain
other
customary
exclusions.







On
July
10,
2014,
we
entered
into
a
first
amendment
to
the
New
Credit
Facility,
or
the
First
Amendment.
Pursuant
to
the
terms
of
the
First
Amendment,
asecond
term
loan
of
$4.0
million
was
drawn
on
July
10,
2014.







On
August
4,
2015,
the
Company
prepaid
all
amounts
owed
under
the
Credit
Facility
and
the
First
Amendment.
After
consideration
of
relevant
fees
requiredunder
the
Credit
Facility
and
the
First
Amendment,
the
total
payment
amounted
to
$26.5
million.Future Financing Needs







We
expect
to
finance
the
future
development
costs
of
our
clinical
product
portfolio
with
our
existing
cash
and
cash
equivalents
and
marketable
securities,
orthrough
strategic
financing
opportunities,
that
could
include,
but
are
not
limited
to
partnering
or
other
collaboration
agreements,
future
offerings
of
our
equity,
orthe
incurrence
of
debt.
We
anticipate
that
we
will
make
determinations
as
to
which
additional
programs
to
pursue
and
how
much
funding
to
direct
to
each
programon
an
ongoing
basis
in
response
to
the
scientific
and
clinical
data
of
each
investigational
product
candidate,
progress
on
securing
third-party
collaborators,
as
wellas
ongoing
assessments
of
such
investigational
product
candidate's
commercial
potential
and
our
ability
to
fund
this
product
development.







The
successful
development
of
our
investigational
product
candidates
is
subject
to
numerous
risks
and
uncertainties
associated
with
developing
drugs,including,
but
not
limited
to,
the
variables
listed
below.
A
change
in
the
outcome
of
any
of
these
variables
with
respect
to
the
development
of
any
of
ourinvestigational
product
candidates
could
mean
a
significant
change
in
the
cost
and
timing
associated
with
the
development
of
that
investigational
product
candidate.







Abaloparatide-SC
is
our
only
investigational
product
candidate
in
late
stage
development,
and
our
business
currently
depends
heavily
on
its
successfuldevelopment,
regulatory
approval
and
commercialization.
We
submitted
an
MAA
to
the
EMA
in
November
2015
and
plan
to
submit
an
NDA
to
the
FDA
at
the
endof
the
first
quarter
of
2016.
Obtaining
approval
of
an
investigational
product
candidate
is
an
extensive,
lengthy,
expensive
and
uncertain
process,
and
any
approvalof
abaloparatide-SC
may
be
delayed,
limited
or
denied
for
many
reasons,
including:•we
may
not
be
able
to
demonstrate
that
abaloparatide
is
safe
and
effective
as
a
treatment
for
reduction
of
fracture
risk
in
postmenopausal
womenwith
osteoporosis
to
the
satisfaction
of
the
FDA
or
other
foreign
regulatory
authorities;
•the
results
of
our
clinical
studies
may
not
meet
the
level
of
statistical
or
clinical
significance
required
for
marketing
approval;
•the
FDA
or
other
foreign
regulatory
authorities
may
disagree
with
the
number,
design,
size,
conduct
or
implementation
of
our
clinical
studies;81Table
of
Contents•the
CRO
that
we
retain
to
conduct
clinical
studies
may
take
actions
outside
of
our
control
that
materially
adversely
impact
our
clinical
studies;
•the
FDA
or
other
foreign
regulatory
authorities
may
not
find
the
data
from
preclinical
studies
and
clinical
studies
sufficient
to
demonstrate
thatabaloparatide's
clinical
and
other
potential
benefits
outweigh
its
safety
risks;
•the
FDA
or
other
foreign
regulatory
authorities
may
disagree
with
our
interpretation
of
data
from
our
preclinical
studies
and
clinical
studies
or
mayrequire
that
we
conduct
additional
studies;
•the
FDA
or
other
foreign
regulatory
authorities
may
not
agree
with
our
proposed
labeling
and
may
require
labeling
that
undermines
or
otherwisesignificantly
impairs
the
commercial
value
of
the
product
if
it
were
to
be
approved
with
such
labeling;
•the
FDA
or
other
foreign
regulatory
authorities
may
not
accept
data
generated
at
our
clinical
study
sites;
•the
FDA
may
require
development
of
a
Risk
Evaluation
and
Mitigation
Strategy,
or
REMS,
as
a
condition
of
approval;
•if
our
NDA
is
reviewed
by
an
advisory
committee,
the
FDA
may
have
difficulties
scheduling
an
advisory
committee
meeting
in
a
timely
manner
orthe
advisory
committee
may
recommend
against
approval
of
our
application
or
may
recommend
that
the
FDA
require,
as
a
condition
of
approval,additional
preclinical
studies
or
clinical
studies,
limitations
on
approved
labeling
or
distribution
and
use
restrictions;
or
•the
FDA
or
other
foreign
regulatory
authorities
may
identify
deficiencies
in
the
manufacturing
processes
or
facilities
of
our
third-partymanufacturers.







In
addition,
the
FDA
or
other
foreign
regulatory
authorities
may
change
their
approval
policies
or
adopt
new
regulations.Contractual Obligations and Commitments







Contractual
obligations
represent
future
cash
commitments
and
liabilities
under
agreements
with
third
parties,
and
exclude
contingent
liabilities
for
which
wecannot
reasonably
predict
future
payment.
We
enter
into
contracts
in
the
normal
course
of
business
with
CROs
for
preclinical
and
clinical
research
studies,
researchsupplies
and
other
services
and
products
for
operating
purposes.
These
contracts
generally
provide
for
termination
on
notice,
and
therefore
are
cancelable
contractsand
not
included
in
the
table
of
contractual
obligations
and
commitments.
In
addition,
we
have
certain
obligations
to
make
future
payments
to
third
parties
thatbecome
due
and
payable
on
the
achievement
of
certain
development,
regulatory
and
commercial
milestones
(such
as
the
start
of
a
clinical
trial,
filing
of
an
NDA,approval
by
the
FDA
or
product
launch).
The
table
below
excludes
these
potential
payments
we
may
be
required
to
make
under
our
agreements
because
the
timingof
payments
and
actual
amounts
paid
under
those
agreements
may
be
different
depending
on
the
timing
of
receipt
of
goods
or
services
or
changes
to
agreed-uponterms
or
amounts
for
some
obligations,
and
those
agreements
are
cancelable
upon
written
notice
by
us
and
therefore,
not
long-term
liabilities.
Additionally,
theexpected
timing
of
payment
of
the
obligations
presented
below
is
estimated
based
on
current
information.







Our
contractual
obligations
result
from
property
leases
for
office
space.
However,
more
information
regarding
significant
contracts
with
CROs
and
ourobligations
to
make
future
payments
to
third
parties
that
become
due
and
payable
upon
achievement
of
certain
development,
regulatory
and
commercial
milestonescan
be
found
below
under
"Research
and
Development
Agreements"
and
"License
Agreement
Obligations".82Table
of
Contents







The
following
table
summarizes
our
contractual
obligations
at
December
31,
2015:Research and Development Agreements        Abaloparatide-SC Phase 3 Clinical Trial —We
have
entered
into
agreements
with
Nordic
Bioscience
Clinical
Development
VII
A/S,
or
Nordic,
to
conductour
Phase
3
clinical
trial
of
abaloparatide-SC,
or
the
Phase
3
Clinical
Trial.
On
March
29,
2011,
we
entered
into
a
Clinical
Trial
Services
Agreement,
or
the
ClinicalTrial
Services
Agreement.
On
the
same
date,
we
also
entered
into
Work
Statement
NB-1,
as
amended
on
December
9,
2011,
June
18,
2012,
March
28,
2014,May
19,
2014,
July
22,
2014,
August
15,
2014
and
March
12,
2015,
or
Work
Statement
NB-1,
and
the
Stock
Issuance
Agreement,
as
amended
and
restated
onMay
16,
2011,
and
as
further
amended
on
February
21,
2013,
March
28,
2014,
and
May
19,
2014,
or
the
Stock
Issuance
Agreement.







We
recognized
research
and
development
expense
for
the
amounts
due
to
Nordic
under
the
Work
Statement
NB-1
ratably
over
the
estimated
per
patienttreatment
period
beginning
upon
enrollment
in
the
Phase
3
Clinical
Trial,
or
a
twenty-month
period,
except
for
the
amounts
due
under
the
fourth
amendment
to
theWork
Statement
NB-1,
which
we
recognized
on
a
per
patient
basis
when
the
end-of-study
visit
and
all
other
required
procedures
were
completed.
We
recorded
noexpense,
$8.2
million,
and
$31.6
million
of
research
and
development
expense
during
the
years
ended
December
31,
2015,
2014,
and
2013,
respectively
for
perpatient
costs
incurred
for
patients
that
had
enrolled
in
the
Phase
3
Clinical
Study.
As
of
December
31,
2015,
all
obligations
due
to
Nordic
under
Work
StatementNB-1
had
been
paid.        Abaloparatide-SC Phase 3 Clinical Extension Study —On
February
21,
2013,
we
entered
into
the
Work
Statement
NB-3,
as
amended
on
February
28,
2014,March
23,
2015,
July
8,
2015
and
October
21,
2015,
or
the
Work
Statement
NB-3.
Pursuant
to
the
Work
Statement
NB-3,
Nordic
performed
an
extension
study
toevaluate
six
months
of
standard-of-care
osteoporosis
management
following
the
completion
of
the
Phase
3
clinical
trial
of
abaloparatide-SC,
or
the
ExtensionStudy,
and,
upon
completion
of
this
initial
six
months,
an
additional
period
of
18
months
of
standard-of-care
osteoporosis
management,
or
the
Second
Extension.







In
April
2015,
we
entered
into
an
amendment
to
the
Work
Statement
NB-3,
or
the
NB-3
Amendment.
The
NB-3
Amendment
was
effective
as
of
March
23,2015
and
provides
that
Nordic
will
perform
additional
services,
including
monitoring
of
patients
enrolled
in
the
Second
Extension.
Payments
in
cash
to
be
made
toNordic
under
the
NB-3
Amendment
are
denominated
in
euros
and
total
up
to
approximately
€4.1
million
($4.5
million).







Payments
in
cash
to
be
made
to
Nordic
under
the
Work
Statement
NB-3
are
denominated
in
both
euros
and
U.S.
dollars
and
total
up
to
€11.9
million($12.9
million)
and
$1.1
million,
respectively.
In
addition,
payments
are
due
to
Nordic
in
connection
with
the
Work
Statement
NB-3
pursuant
to
the
Stock
IssuanceAgreement,
as
discussed
below.
As
of
December
31,
2015,
services
related
to
the
Second
Extension
are
ongoing
and
all
obligations
due
to
Nordic
in
relation
to
theExtension
Study
have
been
paid.







We
recognize
research
and
development
expense
for
the
amounts
due
to
Nordic
under
the
Extension
Study
and
the
Second
Extension
ratably
over
theestimated
per
patient
treatment
periods
beginning
upon
enrollment
or
over
a
nine-month
and
nineteen-month
period,
respectively.
We
recorded
$5.4
million,$9.6
million,
and
$4.5
million
of
research
and
development
expense
during
the
years
ended
December
31,
2015,
2014,
and
2013,
respectively,
respectively,
for
perpatient
costs
incurred.83


Total
Less
than
1
Year
1
to
3
Years
3
to
5
Years
More
than
5
Years



(in
thousands)

Operating
lease
obligations
$8,273
$1,944
$3,827
$2,502
$—
Table
of
Contents







As
of
December
31,
2015,
we
had
a
liability
of
$2.9
million
reflected
in
accrued
expenses
and
other
current
liabilities
on
the
balance
sheet
resulting
fromservices
provided
by
Nordic
under
the
Second
Extension,
which
are
payable
in
cash.        Stock Issuance Agreement —Pursuant
to
the
Stock
Issuance
Agreement,
Nordic
agreed
to
purchase
6,443
shares
of
our
Series
A-5
convertible
preferred
stock,which
provided
them
with
the
right
to
receive
quarterly
stock
dividends,
payable
in
shares
of
our
Series
A-6
convertible
preferred
stock,
for
services
rendered
underWork
Statement
NB-1
and
Work
Statement
NB-3.
The
Stock
Issuance
Agreement
was
later
amended
to
provide
that
in
the
event
an
initial
public
offering
of
ourcommon
stock
occurred
prior
to
June
30,
2014,
any
rights
to
receive
stock
dividends
in
relation
to
Work
Statement
NB-1
and
Work
Statement
NB-3,
for
all
periodsof
time
after
2014,
would
be
changed
from
the
right
to
receive
stock
to
the
right
to
receive
a
total
cash
payment
of
$4.3
million,
payable
in
ten
equal
monthlyinstallments
of
$430,000
beginning
on
March
31,
2015.
The
amendment
also
stipulated
that
all
consideration
to
be
paid
to
Nordic
pursuant
to
the
Stock
IssuanceAgreement
at
any
time
after
the
consummation
of
an
initial
public
offering
be
payable
in
cash.
As
we
completed
an
initial
public
offering
on
June
11,
2014,
Nordicno
longer
has
the
right
to
receive
stock
and
has
been
paid
in
cash
for
all
periods
after
June
11,
2014.







We
are
also
responsible
for
certain
pass-through
costs
in
connection
with
the
clinical
trials
noted
above.
Pass-through
costs
are
expensed
as
incurred
or
upondelivery.
We
recognized
research
and
development
expense
of
$1.1
million,
$1.3
million,
and
$3.9
million
for
pass
through
costs
during
years
ended
December
31,2015,
2014,
and
2013,
respectively.







We
estimate
that
our
future
cash
obligations
to
Nordic
in
relation
to
Work
Statement
NB-3
will
approximate
the
following
as
of
December
31,
2015
(inthousands):License Agreement ObligationsAbaloparatide







In
September
2005,
we
exclusively
licensed
the
worldwide
rights
(except
for
development
and
commercial
rights
in
Japan)
to
abaloparatide
and
analogs
froman
affiliate
of
Ipsen
Pharma
SAS,
or
Ipsen,
including
US
Patent
No.
5,969,095
(statutory
term
expires
March
29,
2016)
entitled
"Analogs
of
Parathyroid
Hormone"that
claims
abaloparatide
and
US
Patent
No.
6,544,949,
(statutory
term
expires
March
29,
2016)
entitled
"Analogs
of
Parathyroid
Hormone"
that
claimsabaloparatide
and
US
Patent
No.
6,544,949,
(effective
filing
date
March
29,
1996,
statutory
term
expires
March
29,
2016),
entitled
"Analogs
of
ParathyroidHormone"
that
claims
methods
of
treating
osteoporosis
using
abaloparatide
and
pharmaceutical
compositions
comprising
abaloparatide,
and
the
correspondingforeign
patents
and
continuing
patent
applications.
European
Patent
No.
0847278,
which
was
included
in
the
license
from
Ipsen
and
claimed
the
composition
ofmatter
of
abaloparatide,
lapsed
due
to
Ipsen's
failure
to
pay
annuities.
We
are
pursuing
restoration
of
those
rights.
To
date,
the
patent
rights
in
Austria,
Belgium,Denmark,
Finland,
France,
Germany,
Ireland,
Italy,
the
Netherlands,
Portugal,
Spain,
Sweden,
and
United
Kingdom
have
been
restored.
We
believe
that
the
dataand
market
exclusivity
provided
in
Europe
for
a
new
chemical
entity,
coupled
with
the
need
for
a
potential
competitor
to
conduct
clinical84


TOTAL(1)
LESS
THAN
1
YEAR(1)
1
-
3
YEARS(1)



EURO
DENOMINATED
PAYMENTS



EURO
DENOMINATED
PAYMENTS



EURO
DENOMINATED
PAYMENTS






EURO
USD
EQUIVALENT(2)
USD
DENOMINATEDPAYMENTS
EURO
USD
EQUIVALENT(2)
USD
DENOMINATEDPAYMENTS
EURO
USD
EQUIVALENT(2)
USD
DENOMINATEDPAYMENTS
WorkStatementNB-3
€4,748
$5,156
$430
€4,349
$4,723
$430
€399
$433
$—
TotalPayments
€4,748
$5,156
$430
€4,349
$4,723
$430
€399
$433
$—
(1)The
amounts
above
exclude
pass-through
costs
and,
in
accordance
with
work
statement
NB-3,
may
be
adjusted
from
time
to
time
and
at
the
end
of
the
study
to
reflect
actual
studyactivities
completed
by
the
study
subjects.
(2)USD
equivalent
is
based
upon
the
noon
buying
rate
published
by
the
Board
of
Governors
of
the
Federal
Reserve
on
December
31,
2015.Table
of
Contentstrials
will
likely
provide
a
longer
barrier
to
entry
than
the
patent
protection
provided
by
the
original
European
patent
term,
which
will
expire
in
2016.







We
also
have
rights
to
joint
intellectual
property
related
to
abaloparatide,
including
rights
to
the
jointly
derived
intellectual
property
contained
in
US
PatentNo.
7,803,770
(statutory
term
expires
October
3,
2027,
and
may
be
extended
to
March
26,
2028
with
175
days
of
patent
term
adjustment
due
to
delays
in
patentprosecution
by
the
United
States
Patent
and
Trademark
Office,
or
USPTO),
US
Patent
No.
8,148,333
(statutory
term
expires
October
3,
2027
and
may
be
extendedto
November
8,
2027
with
36
days
of
patent
term
adjustment
due
to
delays
in
patent
prosecution
by
the
USPTO)
and
related
patents
and
patent
applications
both
inthe
United
States
and
worldwide
that
cover
the
method
of
treating
osteoporosis
using
the
Phase
3
Clinical
Trial
dosage
strength
and
form.
A
correspondingEuropean
application
is
pending
with
claims
to
the
intended
therapeutic
formulation
for
abaloparatide-SC.
Examination
has
been
requested,
but
substantiveexamination
has
not
yet
commenced.
Upon
grant,
this
patent
could
be
validated
in
any
designated
contracting
or
extension
states
and
potentially
could
beconsidered
for
a
Supplemental
Protection
Certificate
depending
upon
the
timing
of
its
grant.
Related
cases
granted
in
China,
Australia,
Singapore,
Japan,
Israel,Mexico,
New
Zealand,
Russia
and
Ukraine,
and
currently
pending
in
Europe,
Canada,
Brazil,
Singapore,
South
Korea,
India,
Norway,
and
Hong
Kong
will
have
apatent
expiration
date
of
2027.
Patent
applications
which
cover
various
aspects
of
abaloparatide
for
microneedle
application
are
pending
in
the
United
States,Australia,
Brazil,
Canada,
China,
Europe,
Hong
Kong,
Israel,
India,
Japan,
Korea,
Mexico,
New
Zealand,
Russia,
Singapore,
and
Ukraine.
Any
patents
that
mightissue
from
these
applications
will
have
an
expiration
date
in
2032,
not
taking
into
account
extension
under
applicable
laws.







In
consideration
for
the
rights
to
abaloparatide
and
in
recognition
of
certain
milestones
having
been
met
to
date,
we
have
paid
to
Ipsen
an
aggregate
amount
of$1.0
million.
The
license
agreement
further
requires
us
to
make
payments
upon
the
achievement
of
certain
future
regulatory
and
commercial
milestones,
includingupon
acceptance
of
an
NDA
submission
for
review
by
the
FDA.
The
range
of
milestone
payments
that
could
be
paid
under
the
agreement
is
€10.0
million
to€36.0
million
($10.9
million
to
$39.1
million).
Should
abaloparatide
be
approved
and
subsequently
commercialized,
we
will
be
obligated
to
pay
to
Ipsen
a
fixedfive
percent
royalty
based
on
net
sales
of
the
product
by
us
or
our
sublicensees
on
a
country-by-country
basis
until
the
later
of
the
last
to
expire
of
the
licensedpatents
or
for
a
period
of
10
years
after
the
first
commercial
sale
in
such
country.
The
date
of
the
last
to
expire
of
the
abaloparatide
patents
licensed
from
or
co-owned
with
Ipsen,
barring
any
extension
thereof,
is
expected
to
be
March
26,
2028.
In
the
event
that
we
sublicense
abaloparatide
to
a
third
party,
we
are
obligatedto
pay
a
percentage
of
certain
payments
received
from
such
sublicensee
(in
lieu
of
milestone
payments
not
achieved
at
the
time
of
such
sublicense).
The
applicablepercentage
is
in
the
low
double
digit
range.
In
addition,
if
we
or
our
sublicensees
commercialize
a
product
that
includes
a
compound
discovered
by
us
based
on
orderived
from
confidential
Ipsen
know-how,
we
will
be
obligated
to
pay
to
Ipsen
a
fixed
low
single
digit
royalty
on
net
sales
of
such
product
on
a
country-by-country
basis
until
the
later
of
the
last
to
expire
of
licensed
patents
that
cover
such
product
or
for
a
period
of
10
years
after
the
first
commercial
sale
of
such
productin
such
country.
The
license
agreement
contains
other
customary
clauses
and
terms
as
are
common
in
similar
agreements
in
the
industry.







Prior
to
executing
the
license
agreement
for
abaloparatide
with
us,
Ipsen
licensed
the
Japanese
rights
for
abaloparatide
to
Teijin
Limited,
or
Teijin,
a
Japanesepharmaceutical
company.
Teijin
has
completed
a
Phase
2
clinical
study
of
abaloparatide
in
Japan
for
the
treatment
of
postmenopausal
osteoporosis.RAD1901







We
exclusively
licensed
the
worldwide
rights
to
RAD1901
from
Eisai
Co.
Ltd.,
or
Eisai.
Our
license
with
Eisai
did
not
originally
include
rights
for
Japan,however,
on
March
9,
2015,
we
entered85Table
of
Contentsinto
an
amendment
to
the
Eisai
Agreement
in
which
Eisai
granted
us
an
exclusive
right
and
license
to
research,
develop,
manufacture
and
commercialize
RAD1901in
Japan.
In
consideration
for
the
rights
to
RAD1901
in
Japan,
we
paid
Eisai
an
initial
license
fee
of
$0.4
million
upon
execution
of
the
amendment,
which
wasexpensed
during
the
three
months
ended
March
31,
2015.







In
consideration
for
the
rights
to
RAD1901
and
in
recognition
of
certain
milestones
having
been
met
to
date,
we
have
paid
to
Eisai
an
aggregate
amount
of$1.9
million.
The
range
of
milestone
payments
that
could
be
paid
under
the
agreement
is
$1.0
million
to
$20.0
million.
The
license
agreement
further
requires
us
tomake
payments
upon
the
achievement
of
certain
future
clinical
and
regulatory
milestones.
Should
RAD1901
be
approved
and
subsequently
becomecommercialized,
we
will
be
obligated
to
pay
to
Eisai
a
royalty
in
a
variable
mid-single
digit
range
based
on
net
sales
of
the
product
on
a
country-by-country
basisfor
a
period
that
expires
on
the
later
of
(1)
the
date
the
last
remaining
valid
claim
in
the
licensed
patents
expires,
lapses
or
is
invalidated
in
that
country,
the
productis
not
covered
by
data
protection
clauses,
and
the
sales
of
lawful
generic
version
of
the
product
account
for
more
than
a
specified
percentage
of
the
total
sales
of
allpharmaceutical
products
containing
the
licensed
compound
in
that
country;
or
(2)
a
period
of
10
years
after
the
first
commercial
sale
of
the
licensed
products
insuch
country,
unless
it
is
sooner
terminated.
The
latest
valid
claim
is
expected
to
expire,
barring
any
extension
thereof,
on
August
18,
2026.
The
royalty
rate
shallthen
be
subject
to
reduction
and
the
royalty
obligation
will
expire
at
such
time
as
sales
of
lawful
generic
version
of
such
product
account
for
more
than
a
specifiedminimum
percentage
of
the
total
sales
of
all
products
that
contain
the
licensed
compound.
We
were
also
granted
the
right
to
grant
sublicenses
with
prior
writtenapproval
from
Eisai.
If
we
sublicense
RAD1901
to
a
third
party,
we
will
be
obligated
to
pay
Eisai,
in
addition
to
the
milestones
referenced
above,
a
fixed
lowdouble
digit
percentage
of
certain
fees
we
receive
from
such
sublicensee
and
royalties
in
a
variable
mid-single
digit
range
based
on
net
sales
of
the
sublicensee.
Thelicense
agreement
contains
other
customary
clauses
and
terms
as
are
common
in
similar
agreements
in
the
industry.Net Operating Loss Carryforwards







As
of
December
31,
2015,
we
had
federal
and
state
net
operating
loss
carryforwards
of
approximately
$419.5
million
and
$323.0
million,
respectively,
the
useof
which
may
be
limited,
as
described
below.
If
not
utilized,
the
net
operating
loss
carryforwards
will
expire
at
various
dates
through
2035.







Under
Section
382
of
the
Code,
substantial
changes
in
our
ownership
may
limit
the
amount
of
net
operating
loss
carryforwards
that
could
be
used
annually
inthe
future
to
offset
taxable
income.
Specifically,
this
limitation
may
arise
in
the
event
of
a
cumulative
change
in
ownership
of
our
company
of
more
than
50%within
a
three-year
period.
Any
such
annual
limitation
may
significantly
reduce
the
utilization
of
the
net
operating
loss
carryforwards
before
they
expire.
Theprivate
placements
and
other
transactions
that
have
occurred
since
our
inception,
may
have
triggered
an
ownership
change
pursuant
to
Section
382,
which
couldlimit
the
amount
of
net
operating
loss
carryforwards
that
could
be
utilized
annually
in
the
future
to
offset
taxable
income,
if
any.
Any
such
limitation,
whether
asthe
result
of
prior
private
placements,
sales
of
common
stock
by
our
existing
stockholders
or
additional
sales
of
common
stock
by
us,
could
have
a
material
adverseeffect
on
our
results
of
operations
in
future
years.
We
are
in
the
process
of
completing
a
study
to
assess
whether
an
ownership
change
has
occurred,
or
whetherthere
have
been
multiple
ownership
changes
since
our
inception.
In
each
period
since
our
inception,
we
have
recorded
a
valuation
allowance
for
the
full
amount
ofour
deferred
tax
asset,
as
the
realization
of
the
deferred
tax
asset
is
uncertain.
As
a
result,
we
have
not
recorded
any
federal
or
state
income
tax
benefit
in
ourstatement
of
operations.86Table
of
ContentsOff-Balance Sheet Arrangements







We
do
not
have
any
off-balance
sheet
arrangements
or
any
relationships
with
unconsolidated
entities
of
financial
partnerships,
such
as
entities
often
referred
toas
structured
finance
or
special
purpose
entities.Accounting Standards Updates







For
a
discussion
of
recent
accounting
standards
updates,
see
note
2
to
our
consolidated
financial
statements
included
in
this
Annual
Report.87Table
of
ContentsITEM
7A.



QUANTITATIVE
AND
QUALITATIVE
DISCLOSURES
ABOUT
MARKET
RISK.








We
are
exposed
to
market
risk
related
to
changes
in
the
dollar/euro
exchange
rate
because
a
portion
of
our
development
costs
are
denominated
in
euros.
We
donot
hedge
our
foreign
currency
exchange
rate
risk.
However,
an
immediate
10
percent
adverse
change
in
the
dollar/euro
exchange
rate
would
not
have
a
materialeffect
on
financial
results.







We
are
exposed
to
market
risk
related
to
changes
in
interest
rates.
As
of
December
31,
2015,
we
had
cash,
cash
equivalents
and
short-term
marketablesecurities
of
$473.3
million,
consisting
of
cash,
money
market
funds,
domestic
corporate
debt
securities,
domestic
corporate
commercial
paper,
and
asset-backedsecurities.
This
exposure
to
market
risk
is
interest
rate
sensitivity,
which
is
affected
by
changes
in
the
general
level
of
U.S.
interest
rates,
particularly
because
ourinvestments
are
in
marketable
securities.
Due
to
the
short-term
duration
of
our
investment
portfolio
and
the
low
risk
profile
of
our
investments,
an
immediate
10%change
in
interest
rates
would
not
have
a
material
effect
on
the
fair
market
value
of
our
portfolio.
We
generally
have
the
ability
to
hold
our
investments
untilmaturity,
and
therefore
we
would
not
expect
our
operating
results
or
cash
flows
to
be
affected
to
any
significant
degree
by
the
effect
of
a
change
in
market
interestrates
on
our
investments.
We
carry
our
investments
based
on
publicly
available
information.
As
of
December
31,
2015,
we
do
not
have
any
hard
to
valueinvestment
securities
or
securities
for
which
a
market
is
not
readily
available
or
active.







We
are
not
subject
to
significant
credit
risk
as
this
risk
does
not
have
the
potential
to
materially
impact
the
value
of
assets
and
liabilities.88Table
of
ContentsITEM
8.



FINANCIAL
STATEMENTS
AND
SUPPLEMENTARY
DATA.
FINANCIAL
STATEMENTS
Radius
Health,
Inc.
Index
to
Consolidated
Financial
Statements89


PAGE
Report
of
Independent
Registered
Public
Accounting
Firm

90
Consolidated
Balance
Sheets
as
of
December
31,
2015
and
2014

91
Consolidated
Statements
of
Operations
and
Comprehensive
Loss
for
the
years
ended
December
31,
2015,
2014
and2013

92
Consolidated
Statements
of
Convertible
Preferred
Stock,
Redeemable
Convertible
Preferred
Stock
and
Stockholders'Equity
(Deficit)
for
the
years
ended
December
31,
2015,
2014
and
2013

93
Consolidated
Statements
of
Cash
Flows
for
the
years
ended
December
31,
2015,
2014
and
2013

95
Notes
to
Consolidated
Financial
Statements

96
Table
of
ContentsReport
of
Independent
Registered
Public
Accounting
FirmThe
Board
of
Directors
and
Shareholders
of
Radius
Health,
Inc.







We
have
audited
the
accompanying
consolidated
balance
sheets
of
Radius
Health,
Inc.
as
of
December
31,
2015
and
2014,
and
the
related
consolidatedstatements
of
operations
and
comprehensive
loss,
convertible
preferred
stock,
redeemable
convertible
preferred
stock
and
stockholders'
equity
(deficit),
and
cashflows
for
each
of
the
three
years
in
the
period
ended
December
31,
2015.
These
financial
statements
are
the
responsibility
of
the
Company's
management.
Ourresponsibility
is
to
express
an
opinion
on
these
financial
statements
based
on
our
audits.







We
conducted
our
audits
in
accordance
with
the
standards
of
the
Public
Company
Accounting
Oversight
Board
(United
States).
Those
standards
require
thatwe
plan
and
perform
the
audit
to
obtain
reasonable
assurance
about
whether
the
financial
statements
are
free
of
material
misstatement.
An
audit
includesexamining,
on
a
test
basis,
evidence
supporting
the
amounts
and
disclosures
in
the
financial
statements.
An
audit
also
includes
assessing
the
accounting
principlesused
and
significant
estimates
made
by
management,
as
well
as
evaluating
the
overall
financial
statement
presentation.
We
believe
that
our
audits
provide
areasonable
basis
for
our
opinion.







In
our
opinion,
the
financial
statements
referred
to
above
present
fairly,
in
all
material
respects,
the
consolidated
financial
position
of
Radius
Health,
Inc.
atDecember
31,
2015
and
2014,
and
the
consolidated
results
of
its
operations
and
its
cash
flows
for
each
of
the
three
years
in
the
period
ended
December
31,
2015,
inconformity
with
U.S.
generally
accepted
accounting
principles.







We
also
have
audited,
in
accordance
with
the
standards
of
the
Public
Company
Accounting
Oversight
Board
(United
States),
Radius
Health
Inc.'s
internalcontrol
over
financial
reporting
as
of
December
31,
2015,
based
on
criteria
established
in
Internal
Control—Integrated
Framework
issued
by
the
Committee
ofSponsoring
Organizations
of
the
Treadway
Commission
(2013
framework)
and
our
report
dated
February
25,
2016
expressed
an
unqualified
opinion
thereon.Boston,
Massachusetts
February
25,
201690

/s/
Ernst
&
Young
LLPTable
of
ContentsRadius
Health,
Inc.
Consolidated
Balance
Sheets
(In
thousands,
except
share
and
per
share
amounts)



See
accompanying
notes
to
consolidated
financial
statements.91


December
31,
2015
December
31,
2014
ASSETS






Current
assets:






Cash
and
cash
equivalents
$159,678
$28,518
Marketable
securities

313,661

76,758
Prepaid
expenses
and
other
current
assets

6,969

2,057
Total
current
assets

480,308

107,333
Property
and
equipment,
net

1,897

842
Other
assets

260

242
Total
assets
$482,465
$108,417
LIABILITIES
AND
STOCKHOLDERS'
EQUITY






Current
liabilities:






Accounts
payable
$6,228
$2,292
Accrued
expenses
and
other
current
liabilities

14,952

18,267
Total
current
liabilities

21,180

20,559
Note
payable,
net
of
current
portion
and
discount

—

24,394
Total
liabilities
$21,180
$44,953
Commitments
and
contingencies






Stockholders'
equity:






Common
stock,
$.0001
par
value;
200,000,000
shares
authorized,
42,984,243
shares
and32,924,535
shares
issued
and
outstanding
at
December
31,
2015
and
2014,
respectively

4

3
Additional
paid-in-capital

907,040

407,720
Accumulated
other
comprehensive
income
(loss)

5

(21)Accumulated
deficit

(445,764)
(344,238)Total
stockholders'
equity

461,285

63,464
Total
liabilities
and
stockholders'
equity
$482,465
$108,417
Table
of
ContentsRadius
Health,
Inc.
Consolidated
Statements
of
Operations
and
Comprehensive
Loss
(In
thousands,
except
share
and
per
share
amounts)



See
accompanying
notes
to
consolidated
financial
statements.92


December
31,



2015
2014
2013
OPERATING
EXPENSES:









Research
and
development
$68,280
$45,719
$60,536
General
and
administrative

30,797

13,674

6,829
Loss
from
operations

(99,077)
(59,393)
(67,365)OTHER
(EXPENSE)
INCOME:









Other
(expense)
income,
net

(35)
(510)
9,085
Loss
on
retirement
of
note
payable

(1,572)
(203)
—
Interest
income

1,043

94

30
Interest
expense

(1,885)
(2,467)
(2,440)NET
LOSS
$(101,526)$(62,479)$(60,690)OTHER
COMPREHENSIVE
LOSS,
NET
OF
TAX:









Unrealized
gain
(loss)
from
available-for-sale
securities

26

(21)
—
COMPREHENSIVE
LOSS
$(101,500)$(62,500)$(60,690)LOSS
ATTRIBUTABLE
TO
COMMON
STOCKHOLDERS—BASIC
ANDDILUTED
(Note
12)
$(101,526)$(71,479)$(78,161)LOSS
PER
SHARE:









Basic
and
diluted
$(2.56)$(4.04)$(203.91)WEIGHTED
AVERAGE
SHARES:









Basic
and
diluted

39,643,099

17,699,487

383,310
Table
of
ContentsRadius
Health,
Inc.Consolidated
Statements
of
Convertible
Preferred
Stock,
Redeemable
Convertible
Preferred
Stock
and
Stockholders'
Equity
(Deficit)(In
thousands,
except
share
and
per
share
amounts)See
accompanying
notes
to
consolidated
financial
statements.93


Convertible
Preferred
Stock



Series
B-2
Series
B
Series
A-1
Series
A-2
Series
A-3
Series
A-4
Series
A-5
Series
A-6



Shares
Amount
Shares
Amount
Shares
Amount
Shares
Amount
Shares
Amount
Shares
Amount
Shares
Amount
Shares
Amount
Balance
atDecember
31,2012

—

—

—

—

939,612
$71,957

983,208
$86,714

142,227
$11,182

3,998
$271

6,443
$525

—
$—
Net
loss
















































Stock
optionsexercised
















































Issuance
ofpreferred
stock







701,235

41,514































496,111

23,168
Accretion
ofdividends
onpreferred
stock










2,378




6,780




7,263




1,050


















Stock-basedcompensationexpense
















































Balance
atDecember
31,2013

—
$—

701,235
$43,892

939,612
$78,737

983,208
$93,977

142,227
$12,232

3,998
$271

6,443
$525

496,111
$23,168
Net
loss
















































Unrealized
lossfrom
available-for-salesecurities
















































Issuance
ofpreferred
stock

448,060

26,152





































186,847

10,109
Accretion
ofdividends
onpreferred
stock




685




1,515




3,084




3,246




470


















Issuance
ofwarrants
















































Exercise
ofwarrants
















































Stock
optionsexercised
















































Stock-basedcompensationexpense
















































Issuance
ofcommon
stock,net
















































Conversion
ofconvertiblepreferred
stockinto
commonstock

(448,060)
(26,837)
(701,235)$(45,407)
(939,612)
(81,821)
(983,208)
(97,223)
(142,227)
(12,702)
(3,998)
(271)
(6,443)
(525)
(682,958)
(33,277)Reclassificationof
warrantliability
toadditional
paidin
capital
















































Balance
atDecember
31,2014

—
$—

—
$—

—
$—

—
$—

—
$—

—
$—

—
$—

—
$—
Net
loss
















































Unrealized
gainfrom
available-for-salesecurities
















































Exercise
ofwarrants
















































Exercise
ofoptions
















































Stock-basedcompensationexpense
















































Issuance
ofcommon
stock,net
















































Balance
atDecember
31,2015

—
$—

—
$—

—
$—

—
$—

—
$—

—
$—

—
$—

—
$—
Table
of
ContentsRadius
Health,
Inc.
Consolidated
Statements
of
Convertible
Preferred
Stock,
Redeemable
Convertible
Preferred
Stock
and
Stockholders'
Equity
(Deficit)
(Continued)
(In
thousands,
except
share
and
per
share
amounts)



See
accompanying
notes
to
consolidated
financial
statements.94


Stockholders'
Equity
(Deficit)



Common
Stock
Additional
Paid-In-Capital
Accumulated
Other
ComprehensiveIncome
(Loss)
AccumulatedDeficit
TotalStockholders'
(Deficit)
Equity



Shares
Amount
Amount
Amount
Amount
Amount
Balance
at
December
31,
2012

380,328
$—
$—
$—
$(200,661)$(200,661)Net
loss













(60,690)
(60,690)Stock
options
exercised

5,336




13







13
Issuance
of
preferred
stock
















—
Accretion
of
dividends
on
preferred
stock







(1,521)



(15,950)
(17,471)Stock-based
compensation
expense







1,508







1,508
Balance
at
December
31,
2013

385,664
$—
$—
$—
$(277,301)$(277,301)Net
loss













(62,479)
(62,479)Unrealized
loss
from
available-for-sale
securities










(21)



(21)Issuance
of
preferred
stock
















—
Accretion
of
dividends
on
preferred
stock







(4,542)



(4,458)
(9,000)Issuance
of
warrants







41







41
Exercise
of
warrants

20,435













—
Stock
options
exercised

49,382




170







170
Stock-based
compensation
expense







7,070







7,070
Issuance
of
common
stock,
net

10,141,268

1

103,803







103,804
Conversion
of
convertible
preferred
stock
intocommon
stock

22,327,786

2

298,061







298,063
Reclassification
of
warrant
liability
to
additionalpaid
in
capital







3,117







3,117
Balance
at
December
31,
2014

32,924,535
$3
$407,720
$(21)$(344,238)$63,464
Net
loss













(101,526)
(101,526)Unrealized
gain
from
available-for-sale
securities










26




26
Exercise
of
warrants

529,862













—
Exercise
of
options

267,684




2,337







2,337
Stock-based
compensation
expense







14,734







14,734
Issuance
of
common
stock,
net

9,262,162

1

482,249







482,250
Balance
at
December
31,
2015

42,984,243
$4
$907,040
$5
$(445,764)$461,285
Table
of
ContentsRadius
Health,
Inc.
Consolidated
Statements
of
Cash
Flows
(In
thousands)



See
accompanying
notes
to
consolidated
financial
statements.95


Year
Ended
December
31,



2015
2014
2013
CASH
FLOWS
USED
IN
OPERATING
ACTIVITIES:









Net
loss
$(101,526)$(62,479)$(60,690)Adjustments
to
reconcile
net
loss
to
net
cash
used
in
operating
activities:









Depreciation
and
amortization

176

77

27
Amortization
of
premium
(accretion
of
discount)
marketable
securities,
net

1,714

429

27
Stock-based
compensation
expense

14,734

7,070

1,508
Research
and
development
expense
settled
in
stock

—

2,717

13,118
Change
in
fair
value
of
other
current
assets,
warrant
liability
and
other
liability

—

505

(9,087)Non-cash
interest

183

295

387
Loss
on
retirement
of
note
payable

1,572

57

—
Changes
in
operating
assets
and
liabilities:









Prepaid
expenses
and
other
current
assets

(4,914)
(1,639)
1,721
Other
long-term
assets

(108)
(105)
—
Accounts
payable

3,936

1,991

(250)Accrued
expenses
and
other
current
liabilities

(2,870)
2,737

8,222
Net
cash
used
in
operating
activities

(87,103)
(48,345)
(45,017)CASH
FLOWS
(USED
IN)
PROVIDED
BY
INVESTING
ACTIVITIES:









Purchases
of
property
and
equipment

(1,231)
(857)
(2)Purchases
of
marketable
securities

(579,088)
(97,678)
(17,070)Sales
and
maturities
of
marketable
securities

340,497

20,470

21,043
Net
cash
(used
in)
provided
by
investing
activities

(239,822)
(78,065)
3,971
CASH
FLOWS
PROVIDED
BY
FINANCING
ACTIVITIES:









Proceeds
from
exercise
of
stock
options

2,337

170

13
Net
proceeds
from
the
issuance
of
preferred
stock,
net

—

27,368

42,870
Proceeds
from
note
payable,
net

—

24,555

—
Proceeds
from
issuance
of
common
stock,
net

482,250

103,804

—
Deferred
financing
costs

—

(116)
—
Payments
on
note
payable

(25,000)
(13,156)
(8,187)Fee
for
early
prepayment
of
note
payable

(1,502)
—

—
Net
cash
provided
by
financing
activities

458,085

142,625

34,696
NET
INCREASE
(DECREASE)
IN
CASH
AND
CASH
EQUIVALENTS

131,160

16,215

(6,350)CASH
AND
CASH
EQUIVALENTS
AT
BEGINNING
OF
YEAR

28,518

12,303

18,653
CASH
AND
CASH
EQUIVALENTS
AT
END
OF
YEAR
$159,678
$28,518
$12,303
SUPPLEMENTAL
DISCLOSURES:









Cash
paid
for
interest
$1,490
$1,971
$1,796
NON-CASH
FINANCING
ACTIVITIES:









Accretion
of
dividends
on
preferred
stock
$—
$9,000
$17,471
Reclassification
of
preferred
stock
to
common
stock
$—
$298,063
$—
Fair
value
of
series
A-6
convertible
preferred
stock
issued
as
settlement
of
liability
$—
$10,109
$23,168
Fair
value
of
warrants
issued
$—
$1,552
$1,356
Table
of
ContentsRadius
Health,
Inc.
Notes
to
Consolidated
Financial
Statements
1.
Nature
of
Business







Radius
Health,
Inc.
("Radius"
or
the
"Company")
is
a
science-driven
biopharmaceutical
company
that
is
committed
to
developing
innovative
therapeutics
inthe
areas
of
osteoporosis,
oncology
and
endocrine
diseases.
The
Company's
lead
product
candidate,
the
investigational
drug
abaloparatide
for
subcutaneousinjection
("abaloparatide-SC"),
has
completed
Phase
3
development
for
potential
use
in
the
reduction
of
fracture
risk
in
postmenopausal
women
with
osteoporosisand
is
currently
under
regulatory
review
in
Europe.
The
Company's
clinical
pipeline
also
includes
an
investigational
abaloparatide
transdermal
patch("abaloparatide-TD")
for
potential
use
in
osteoporosis
and
the
investigational
drug
RAD1901
for
potential
use
in
hormone-driven,
or
hormone-resistant,
breastcancer,
and
vasomotor
symptoms
in
postmenopausal
women.
The
Company's
preclinical
pipeline
includes
RAD140,
a
non-steroidal
selective
androgen
receptormodulator,
under
investigation
for
potential
applications
in
oncology
and
multiple
conditions
where
androgen
modulation
may
offer
therapeutic
benefit.







The
Company
is
subject
to
the
risks
associated
with
emerging
companies
with
a
limited
operating
history,
including
dependence
on
key
individuals,
adeveloping
business
model,
the
necessity
of
securing
regulatory
approval
to
market
its
investigational
product
candidates,
market
acceptance
of
the
Company'sinvestigational
product
candidates
following
receipt
of
regulatory
approval,
competition
for
its
investigational
product
candidates
following
receipt
of
regulatoryapproval,
and
the
continued
ability
to
obtain
adequate
financing
to
fund
the
Company's
future
operations.
The
Company
has
incurred
losses
and
expects
to
continueto
incur
additional
losses
for
the
foreseeable
future.
As
of
December
31,
2015,
the
Company
had
an
accumulated
deficit
of
$445.8
million,
and
total
cash,
cashequivalents
and
marketable
securities
of
$473.3
million.







Based
upon
its
cash,
cash
equivalents
and
marketable
securities
balance
as
of
December
31,
2015,
the
Company
believes
that,
prior
to
the
consideration
ofrevenue
from
the
potential
future
sales
of
any
of
its
investigational
products
that
may
receive
regulatory
approval
or
proceeds
from
partnership
activities,
it
hassufficient
capital
to
fund
its
development
plans,
U.S.
commercial
scale-up
and
other
operational
activities
into
2018.
The
Company
expects
to
finance
the
futuredevelopment
costs
of
its
clinical
product
portfolio
with
its
existing
cash
and
cash
equivalents
and
marketable
securities,
or
through
strategic
financing
opportunitiesthat
could
include,
but
are
not
limited
to
partnering
or
other
collaboration
agreements,
future
offerings
of
its
equity,
or
the
incurrence
of
debt.
However,
there
is
noguarantee
that
any
of
these
strategic
or
financing
opportunities
will
be
executed
or
executed
on
favorable
terms,
and
some
could
be
dilutive
to
existingstockholders.
If
the
Company
fails
to
obtain
additional
future
capital,
it
may
be
unable
to
complete
its
planned
preclinical
and
clinical
trials
and
obtain
approval
ofcertain
investigational
product
candidates
from
the
U.S.
Food
and
Drug
Administration
or
foreign
regulatory
authorities.2.
Summary
of
Significant
Accounting
Policies        Basis of Presentation —The
consolidated
financial
statements
include
the
accounts
of
the
Company
and
its
wholly-owned
subsidiary,
Radius
Health
SecuritiesCorporation.
All
material
intercompany
balances
and
transactions
have
been
eliminated
in
consolidation.        Reverse Stock Split —On
April
24,
2014,
the
Company
effected
a
reverse
stock
split
of
the
Company's
common
stock.
The
number
of
authorized
shares
of
theCompany's
common
stock
and
the
par
value
did
not
change.
Pursuant
to
the
stock
split,
every
2.28
shares
of
the
Company's
issued
and
outstanding
common
stockwere
automatically
combined
into
one
issued
and
outstanding
share
of
the96Table
of
ContentsRadius
Health,
Inc.Notes
to
Consolidated
Financial
Statements
(Continued)2.
Summary
of
Significant
Accounting
Policies
(Continued)Company's
common
stock.
All
shares
and
per
share
amounts
in
the
financial
statements
and
accompanying
notes
have
been
retroactively
adjusted
to
give
effect
tothe
reverse
stock
split.        Use of Estimates —The
preparation
of
consolidated
financial
statements
in
conformity
with
accounting
principles
generally
accepted
in
the
United
States("GAAP")
requires
the
Company's
management
to
make
estimates
and
assumptions
that
affect
the
amounts
reported
in
the
consolidated
financial
statements
andaccompanying
notes.
Actual
results
could
differ
from
those
estimates.
The
Company
considers
events
or
transactions
that
occur
after
the
balance
sheet
date
butbefore
the
consolidated
financial
statements
are
issued
as
additional
evidence
for
certain
estimates
or
to
identify
matters
that
require
additional
disclosure.Subsequent
events
have
been
evaluated
up
to
the
date
of
issuance
of
these
consolidated
financial
statements.        Cash Equivalents —The
Company
considers
all
highly
liquid
investment
instruments
with
an
original
maturity
when
purchased
of
three
months
or
less
to
becash
equivalents.
Money
market
funds
represents
a
majority
of
the
cash
equivalent
balance
at
December
31,
2015
and
2014.        Marketable Securities —All
investment
instruments
with
an
original
maturity
date,
when
purchased,
in
excess
of
three
months
have
been
classified
as
currentmarketable
securities.
The
Company
classifies
securities
that
are
available
to
fund
current
operations
as
current
assets.
These
marketable
securities
are
classified
asavailable-for-sale
and
are
carried
at
fair
value.
Unrealized
gains
and
losses,
if
any,
are
included
within
other
comprehensive
(loss)
income
within
stockholders'equity
(deficit).
The
amortized
cost
of
debt
securities
in
this
category
is
adjusted
for
amortization
of
premiums
and
accretion
of
discounts
to
maturity.
Suchamortization
is
included
in
interest
income.
Realized
gains
and
losses
on
available-for-sale
securities
are
included
in
interest
income.
The
cost
of
securities
sold
isbased
on
the
specific
identification
method.
The
Company
periodically
reviews
the
portfolio
of
securities
to
determine
whether
an
other-than-temporaryimpairment
has
occurred.
No
such
losses
have
occurred
to
date.
There
were
no
realized
gains
or
losses
on
the
sale
of
securities
for
the
years
ended
December
31,2015
and
2014.        Fair Value Measurements —The
Company
determines
the
fair
market
values
of
its
financial
instruments
based
on
the
fair
value
hierarchy,
which
requires
anentity
to
maximize
the
use
of
observable
inputs
and
minimize
the
use
of
unobservable
inputs
when
measuring
fair
value.
The
following
are
three
levels
of
inputsthat
may
be
used
to
measure
fair
value:        Concentrations of Credit Risk and Off-Balance-Sheet Risk —Financial
instruments
that
potentially
subject
the
Company
to
credit
risk
primarily
consist
of
cashand
cash
equivalents
and
available-for-sale
marketable
securities.
The
Company
mitigates
its
risk
with
respect
to
cash
and
cash
equivalents
and97
Level
1
Quoted
prices
in
active
markets
for
identical
assets
or
liabilities
that
the
Company
has
the
ability
to
access
at
the
measurement
date.
Level
2
Observable
inputs
other
than
Level
1
prices
such
as
quoted
prices
for
similar
assets
or
liabilities;
quoted
prices
in
markets
that
are
not
active;
or
otherinputs
that
are
observable
or
can
be
corroborated
by
observable
market
data
for
substantially
the
full
term
of
the
assets
or
liabilities.
Level
3
Unobservable
inputs
that
are
supported
by
little
or
no
market
activity
and
that
are
significant
to
the
fair
value
of
the
assets
or
liabilities.Table
of
ContentsRadius
Health,
Inc.Notes
to
Consolidated
Financial
Statements
(Continued)2.
Summary
of
Significant
Accounting
Policies
(Continued)marketable
securities
by
maintaining
its
deposits
and
investments
at
high-quality
financial
institutions.
The
Company
invests
any
excess
cash
in
money
marketfunds
and
other
securities,
and
the
management
of
these
investments
is
not
discretionary
on
the
part
of
the
financial
institution.
The
Company
has
no
significantoff-balance-sheet
risks
such
as
foreign
exchange
contracts,
option
contracts,
or
other
hedging
arrangements.        Inventory —The
Company
capitalizes
inventories
produced
in
preparation
for
initiating
sales
of
a
drug
candidate
when
the
related
drug
candidate
is
approvedor
considered
to
have
a
high
likelihood
of
regulatory
approval
and
the
related
costs
are
expected
to
be
recoverable
through
sales
of
the
inventories.
An
assessmentof
inventory
capitalization
begins
either
on
or
after
the
date
a
New
Drug
Application
is
accepted
for
filing
by
the
U.S.
Food
and
Drug
Administration,
or
aninternational
equivalent.
Determining
whether
or
not
to
continue
to
record
the
commercial
supply
costs
related
to
a
product
candidate
as
research
and
developmentexpenses
or
to
capitalize
these
costs
as
inventory
involves
significant
judgment.
There
were
no
capitalized
inventories
as
of
December
31,
2015
and
2014.        Property and Equipment —Property
and
equipment
are
recorded
at
cost
and
depreciated
using
the
straight-line
method
over
the
estimated
useful
lives
of
therespective
assets.        Research and Development Costs —The
Company
accounts
for
research
and
development
costs
by
expensing
such
costs
to
operations
as
incurred.
Researchand
development
costs
primarily
consist
of
clinical
testing
costs,
including
payments
made
to
contract
research
organizations,
personnel
costs,
outsourced
researchactivities,
laboratory
supplies,
and
license
fees.







Nonrefundable
advance
payments
for
goods
or
services
to
be
received
in
the
future
for
use
in
research
and
development
activities
are
deferred
and
capitalized.The
capitalized
amounts
are
expensed
as
the
related
goods
are
delivered
or
the
services
are
performed.        Licensing Agreements —Costs
associated
with
licensing
early
stage
technology
are
expensed
as
incurred,
and
are
included
in
research
and
developmentexpenses.        Impairment of Long-Lived Assets —The
Company
evaluates
long-lived
assets
for
potential
impairment
when
there
is
evidence
that
events
or
changes
incircumstances
have
occurred
that
indicate
that
the
carrying
amount
of
a
long-lived
asset
may
not
be
recovered.
Recoverability
of
these
assets
is
assessed
based
onthe
undiscounted
expected
future
cash
flows
from
the
assets,
considering
a
number
of
factors,
including
past
operating
results,
budgets
and
economic
projections,market
trends,
and
product
development
cycles.
Impairment
in
the
carrying
value
of
each
asset
is
assessed
when
the
undiscounted
expected
future
cash
flowsderived
from
the
asset
are
less
than
its
carrying
value.







An
impairment
loss
would
be
recognized
in
an
amount
equal
to
the
excess
of
the
carrying
amount
over
the
undiscounted
expected
future
cash
flows.
Noimpairment
charges
have
been
recognized
since
the
Company's
inception.        Segment Information —Operating
segments
are
defined
as
components
of
an
enterprise
engaged
in
business
activities
for
which
discrete
financial
informationis
available
and
regularly
reviewed
by
the
chief
decision
maker
in
determining
how
to
allocate
resources
and
in
assessing
performance.
The
Company
views
itsoperations
and
manages
its
business
as
one
operating
segment
and
operates
in
one
geographic
area.98Table
of
ContentsRadius
Health,
Inc.Notes
to
Consolidated
Financial
Statements
(Continued)2.
Summary
of
Significant
Accounting
Policies
(Continued)        Income Taxes —The
Company
recognizes
deferred
tax
assets
and
liabilities
for
the
future
tax
consequences
attributable
to
differences
between
the
financialstatement
carrying
amounts
of
existing
assets
and
liabilities
and
their
respective
tax
basis,
as
well
as
operating
loss
and
tax
credit
carryforwards.
The
Companymeasures
deferred
tax
assets
and
liabilities
using
enacted
tax
rates
expected
to
apply
to
taxable
income
in
the
years
in
which
those
temporary
differences
andcarryforwards
are
expected
to
be
recovered
or
settled.
Deferred
tax
assets
are
reduced
by
a
valuation
allowance
to
reflect
the
uncertainty
associated
with
theirultimate
realization.
The
effect
on
deferred
tax
assets
and
liabilities
as
a
result
of
a
change
in
tax
rates
is
recognized
as
income
in
the
period
that
includes
theenactment
date.







The
Company
uses
judgment
to
determine
the
recognition
threshold
and
measurement
attribute
for
financial
statement
recognition
and
measurement
of
a
taxposition
taken
or
expected
to
be
taken
in
a
tax
return.
Any
material
interest
and
penalties
related
to
unrecognized
tax
benefits
are
recognized
in
income
tax
expense.







Due
to
uncertainty
surrounding
the
realization
of
the
favorable
tax
attributes
in
future
tax
returns
the
Company
has
recorded
a
full
valuation
allowance
againstotherwise
realizable
net
deferred
tax
assets
as
of
December
31,
2015
and
2014.        Financial Instruments Indexed to and Potentially Settled in the Company's Common Stock —The
Company
evaluates
all
financial
instruments
issued
inconnection
with
its
debt
borrowings
and
equity
offerings
when
determining
the
proper
accounting
treatment
for
such
instruments
in
the
Company's
consolidatedfinancial
statements.
The
Company
considers
a
number
of
generally
accepted
accounting
principles
to
determine
such
treatment
and
evaluates
the
features
of
theinstrument
to
determine
the
appropriate
accounting
treatment.
The
Company
utilizes
the
Black-Scholes
method
or
other
appropriate
methods
to
determine
the
fairvalue
of
its
derivative
financial
instruments.
Key
valuation
factors
in
determining
the
fair
value
include,
but
are
not
limited
to,
the
current
stock
price
as
of
the
dateof
measurement,
the
exercise
price,
the
remaining
contractual
life,
expected
volatility
for
the
instrument
and
the
risk-free
interest
rate.
For
financial
instruments
thatare
determined
to
be
classified
as
liabilities
on
the
balance
sheet,
changes
in
fair
value
are
recorded
as
a
gain
or
loss
in
the
Company's
statement
of
operations,
withthe
corresponding
amount
recorded
as
an
adjustment
to
the
liability
on
its
balance
sheet.        Stock-Based Compensation-Options —The
Company
measures
stock-based
compensation
cost
at
the
accounting
measurement
date
based
on
the
fair
value
ofthe
option,
and
recognizes
the
expense
related
to
awards
to
employees
on
a
straight-line
basis
over
the
requisite
service
period
of
the
option,
which
is
typically
thevesting
period.







The
Company
estimates
the
fair
value
of
each
option
using
the
Black-Scholes
option
pricing
model
that
takes
into
account
the
fair
value
of
its
common
stock,the
exercise
price,
the
expected
life
of
the
option,
the
expected
volatility
of
its
common
stock,
expected
dividends
on
its
common
stock,
and
the
risk-free
interestrate
over
the
expected
life
of
the
option.
Due
to
the
limited
trading
history
of
the
Company's
common
stock
since
its
June
2014
initial
public
offering,
the
Companyuses
the
simplified
method
described
in
the
SEC's
Staff
Accounting
Bulletin
No.
107,
Share-Based Payment, to
determine
the
expected
life
of
the
option
grants.The
estimate
of
expected
volatility
is
based
on
a
review
of
the
historical
volatility
of
similar
publicly
held
companies
in
the
biotechnology
field
over
a
periodcommensurate
with
the
option's
expected
term.
The
Company
has
never
declared
or
paid
any
cash
dividends
on
its
common
stock
and
does
not
expect
to
do
so
inthe
foreseeable
future.
Accordingly,
it99Table
of
ContentsRadius
Health,
Inc.Notes
to
Consolidated
Financial
Statements
(Continued)2.
Summary
of
Significant
Accounting
Policies
(Continued)uses
an
expected
dividend
yield
of
zero.
The
risk-free
rate
is
based
on
the
U.S.
Treasury
yield
curve
in
effect
at
the
time
of
grant
valuation
for
a
periodcommensurate
with
the
option's
expected
term.
These
assumptions
are
highly
subjective
and
changes
in
them
could
significantly
impact
the
value
of
the
option
andhence
the
related
compensation
expense.







The
Company
applies
an
estimated
forfeiture
rate
to
current
period
expense
to
recognize
compensation
expense
only
for
those
awards
expected
to
vest.Forfeitures
are
estimated
based
upon
historical
data,
adjusted
for
known
trends,
and
the
Company
will
adjust
the
estimate
of
forfeitures
if
actual
forfeitures
differ
orare
expected
to
differ
from
such
estimates.
Subsequent
changes
in
estimated
forfeitures
are
recognized
through
a
cumulative
adjustment
in
the
period
of
change
andalso
will
impact
the
amount
of
stock-based
compensation
expense
in
future
periods.







Stock-based
compensation
expense
recognized
for
options
granted
to
consultants
is
also
based
upon
the
fair
value
of
the
options
issued,
as
determined
by
theBlack-Scholes
option
pricing
model
and
recognized
on
an
accelerated
basis.
However,
the
unvested
portion
of
such
option
grants
is
re-measured
at
each
reportingperiod,
until
such
time
as
the
option
is
fully
vested.        Stock-Based Compensation-Performance Units —The
Company
measures
stock-based
compensation
cost
at
the
accounting
measurement
date
based
on
thefair
value
of
the
performance
unit
grant,
and
recognizes
the
expense
over
the
derived
service
period
of
the
performance
units.







The
Company
estimates
the
fair
value
of
each
grant
using
a
Monte
Carlo
simulation
analysis
that
takes
into
account
the
forecasted
price
of
its
common
stock,historical
volatility
of
its
common
stock,
risk-free
rate
as
of
valuation
date,
price
of
its
common
stock
as
of
the
grant
date
and
the
trigger
for
the
performancecondition
to
be
met.







The
derived
service
period
for
each
grant
is
calculated
using
a
Monte
Carlo
simulation
analysis.        Net Loss Per Common Share —Net
loss
per
common
share
is
calculated
using
the
two-class
method,
which
is
an
earnings
allocation
formula
that
determinesnet
loss
per
share
for
the
holders
of
the
Company's
common
shares
and
participating
securities.
Prior
to
the
initial
public
offering,
all
of
the
Company's
series
ofpreferred
stock
contained
participation
rights
in
any
dividend
paid
by
the
Company
and
were
deemed
to
be
participating
securities.
Net
income
available
tocommon
shareholders
and
participating
preferred
shares
was
allocated
to
each
share
on
an
as-converted
basis
as
if
all
of
the
earnings
for
the
period
had
beendistributed.
The
participating
securities
do
not
include
a
contractual
obligation
to
share
in
losses
of
the
Company
and
are
not
included
in
the
calculation
of
net
lossper
share
in
the
periods
that
have
a
net
loss.







Diluted
net
income
per
share
is
computed
using
the
more
dilutive
of
(a)
the
two-class
method,
or
(b)
the
if-converted
method.
Prior
to
the
initial
publicoffering,
the
Company
allocated
net
income
first
to
preferred
stockholders
based
on
dividend
rights
and
then
to
common
and
preferred
stockholders
based
onownership
interests.
The
weighted-average
number
of
common
shares
outstanding
gives
effect
to
all
potentially
dilutive
common
equivalent
shares,
includingoutstanding
stock
options,
warrants,
and,
prior
to
the
Company's
initial
public
offering,
potential
issuance
of
stock
upon
the
issuance
of
the
Company's
series
A-6convertible
preferred
stock
("Series
A-6")
as
settlement
of
the
liability
to
Nordic
Bioscience
("Nordic").
Common
equivalent
shares
are
excluded
from
thecomputation
of
diluted
net
income
per
share
if
their
effect
is
anti-dilutive.100Table
of
ContentsRadius
Health,
Inc.Notes
to
Consolidated
Financial
Statements
(Continued)2.
Summary
of
Significant
Accounting
Policies
(Continued)        Comprehensive Income (Loss) —Comprehensive
income
(loss)
refers
to
revenues,
expenses,
gains
and
losses
that
are
excluded
from
net
income
(loss),
asthese
amounts
are
recorded
directly
as
an
adjustment
to
stockholders'
equity
(deficit),
net
of
tax.
The
Company's
other
comprehensive
(loss)
income
is
comprised
ofunrealized
gains
(losses)
on
its
available-for-sale
marketable
securities.        Accounting Standards Updates —In
August
2014,
the
Financial
Accounting
Standards
Board
("FASB")
issued
Accounting
Standards
Update
No.
2014-15,Disclosures of Uncertainties about an Entity's Ability to Continue as a Going Concern ("ASU
2014-15").
ASU
2014-15
provides
guidance
in
GAAP
aboutmanagement's
responsibility
to
evaluate
whether
there
is
substantial
doubt
about
an
entity's
ability
to
continue
as
a
going
concern
and
to
provide
related
footnotedisclosures.
The
amendments
under
ASU
2014-15
are
effective
for
interim
and
annual
fiscal
periods
beginning
after
December
15,
2016,
with
early
adoptionpermitted.
The
Company
does
not
expect
the
adoption
of
ASU
2014-15
to
have
a
material
impact
on
its
results
of
operations,
financial
position
or
cash
flows.







In
January
2015,
the
FASB
issued
Accounting
Standards
Update
No.
2015-01,
Income Statement—Extraordinary and Unusual Items (Subtopics 225-20)("ASU
2015-01").
ASU
2015-01
eliminates
the
concept
of
extraordinary
items
from
GAAP.
The
amendments
under
ASU
2015-01
are
effective
for
interim
andannual
fiscal
periods
beginning
after
December
15,
2015,
with
early
adoption
permitted.
The
Company
does
not
expect
the
adoption
of
ASU
2015-01
to
have
amaterial
impact
on
its
results
of
operations,
financial
position
or
cash
flows.







In
April
2015,
the
FASB
issued
Accounting
Standards
Update
No.
2015-03,
Interest—Imputation of Interest (Subtopic 835-30) ("ASU
2015-03").
ASU
2015-03
requires
that,
instead
of
presentation
as
an
asset,
debt
issuance
costs
be
presented
in
the
balance
sheet
as
a
direct
deduction
from
the
carrying
amount
of
that
debtliability,
consistent
with
debt
discounts.
The
amendments
under
ASU
2015-03
are
effective
for
interim
and
annual
fiscal
periods
beginning
after
December
15,2015,
with
early
adoption
permitted,
and
should
be
applied
on
a
retrospective
basis.
The
Company
does
not
expect
the
adoption
of
ASU
2015-03
to
have
a
materialimpact
on
its
results
of
operations,
financial
position
or
cash
flows.







In
April
2015,
the
FASB
issued
Accounting
Standards
Update
No.
2015-05,
Intangibles-Goodwill and Other-Internal-Use Software (Subtopic 350-40) ("ASU2015-05").
ASU
2015-05
updates
guidance
regarding
accounting
for
cloud
computing
arrangements.
The
amendments
under
ASU
2015-05
are
effective
for
interimand
annual
fiscal
periods
beginning
after
December
15,
2015,
with
early
adoption
permitted.
The
Company
does
not
expect
the
adoption
of
ASU
2015-05
to
have
amaterial
impact
on
its
results
of
operations,
financial
position
or
cash
flows.







In
November
2015,
the
FASB
issued
Accounting
Standards
Update
No.
2015-17,
Income Taxes (Topic 740) ("ASU
2015-17").
ASU
2015-17
requiresdeferred
tax
liabilities
and
assets
to
be
classified
as
noncurrent
in
a
classified
statement
of
financial
position,
instead
of
separating
deferred
income
tax
liabilitiesand
assets
into
current
and
noncurrent
amounts.
The
amendments
under
ASU
2015-17
apply
to
all
entities
that
present
a
classified
statement
of
financial
positionand
are
effective,
for
public
entities,
for
financial
statements
issued
for
annual
periods
beginning
after
December
15,
2016,
and
interim
periods
within
those
annualperiods,
with
early
adoption
permitted
for
all
entities
as
of
the
beginning
of
an
interim
or
annual
reporting
period.
The
Company
elected
to
early
adopt
ASU
2015-17
effective
December
31,
2015
on
a
prospective
basis.
Adoption
of
this
ASU
resulted
in
a
reclassification
of
our
net
current
deferred
tax
asset
to
the
net
non-current
deferred
tax
asset
in
our
Consolidated
Balance
Sheet
as
of
December
31,
2015.
No
prior
periods
were
retrospectively
adjusted.101Table
of
ContentsRadius
Health,
Inc.Notes
to
Consolidated
Financial
Statements
(Continued)2.
Summary
of
Significant
Accounting
Policies
(Continued)







In
January
2016,
the
FASB
issued
Accounting
Standards
Update
No.
2016-01,
Financial Statements—Overall (Subtopics 825-10) ("ASU
2016-01").
ASU2016-01
provides
updated
guidance
on
the
recognition
and
measurement
of
financial
assets
and
financial
liabilities
that
will
supersede
most
current
guidance.
ASU2016-01
primarily
affects
the
accounting
for
equity
investments,
financial
liabilities
under
the
fair
value
option,
and
the
presentation
and
disclosure
requirementsfor
financial
instruments.
The
amendments
in
ASU
2016-01
supersede
the
guidance
to
classify
equity
securities
with
readily
determinable
fair
values
into
differentcategories
and
require
equity
securities
to
be
measured
at
fair
value
with
changes
in
the
fair
value
recognized
through
net
income.
The
amendments
under
ASU2016-01
are
effective,
for
public
business
entities,
for
periods
beginning
after
December
15,
2017,
including
interim
periods
within
those
fiscal
years,
and
withearly
adoption
permitted.
The
Company
does
not
expect
the
adoption
of
ASU
2016-01
to
have
a
material
impact
on
its
results
of
operations,
financial
position
orcash
flows.3.
Marketable
Securities







Available-for-sale
marketable
securities
and
cash
and
cash
equivalents
consist
of
the
following
(in
thousands):102


December
31,
2015



Amortized
Cost
Value
Gross
Unrealized
Gains
Gross
Unrealized
Losses
Fair
Value
Cash
and
cash
equivalents:












Cash
$2,934
$—
$—
$2,934
Money
market

83,257

—

—

83,257
Domestic
corporate
commercial
paper

39,984

—

—

39,984
Government-sponsored
enterprise
debt
securities

15,996

—

—

15,996
Domestic
corporate
debt
securities

10,007

—

—

10,007
Asset-backed
securities

7,500

—

—

7,500
Total
$159,678
$—
$—
$159,678
Marketable
securities:












Domestic
corporate
debt
securities
$173,142
$—
$(107)$173,035
Domestic
corporate
commercial
paper

84,004

154

—

84,158
Asset-backed
securities

56,510

1

(43)
56,468
Total
$313,656
$155
$(150)$313,661
Table
of
ContentsRadius
Health,
Inc.Notes
to
Consolidated
Financial
Statements
(Continued)3.
Marketable
Securities
(Continued)









There
were
no
debt
securities
that
had
been
in
an
unrealized
loss
position
for
more
than
12
months
as
of
December
31,
2015
or
December
31,
2014.
Therewere
57
debt
securities
in
an
unrealized
loss
position
for
less
than
12
months
at
December
31,
2015
and
there
were
34
debt
securities
that
had
been
in
an
unrealizedloss
position
for
less
than
12
months
at
December
31,
2014.
The
aggregate
unrealized
loss
on
these
securities
as
of
December
31,
2015
and
2014
was
less
than$150
thousand
and
$34
thousand,
respectively,
and
the
fair
value
was
$225.7
million
and
$68.9
million,
respectively.
The
Company
considered
the
decline
inmarket
value
for
these
securities
to
be
primarily
attributable
to
current
economic
conditions.
As
it
was
not
more
likely
than
not
that
the
Company
would
be
requiredto
sell
these
securities
before
the
recovery
of
their
amortized
cost
basis,
which
may
be
maturity,
the
Company
did
not
consider
these
investments
to
be
other-than-temporarily
impaired
as
of
December
31,
2015
and
2014.







As
of
December
31,
2015
and
2014,
marketable
securities
consisted
of
investments
that
mature
within
one
year.103


December
31,
2014



Amortized
Cost
Value
Gross
Unrealized
Gains
Gross
Unrealized
Losses
Fair
Value
Cash
and
cash
equivalents:












Cash
$1,519
$—
$—
$1,519
Money
market
funds

23,994

—

—

23,994
Domestic
corporate
debt
securities

3,005

—

—

3,005
Total
$28,518
$—
$—
$28,518
Marketable
securities:












Domestic
corporate
debt
securities

69,542

—

(33)
69,509
Domestic
corporate
commercial
paper

7,237

12

—

7,249
Total
$76,779
$12
$(33)$76,758
Table
of
ContentsRadius
Health,
Inc.Notes
to
Consolidated
Financial
Statements
(Continued)4.
Property
and
Equipment







Property
and
equipment
consists
of
the
following
(in
thousands):







During
the
year
ended
December
31,
2014,
the
Company
retired
$0.7
million
of
property
and
equipment.
The
retirement
was
primarily
due
to
the
disposal
ofleasehold
improvements
and
other
property
as
a
result
of
the
Company's
office
relocation.
All
assets
were
fully
depreciated
prior
to
retirement.5.
Accrued
Expenses
and
Other
Current
Liabilities







Accrued
expenses
consist
of
the
following
(in
thousands):6.
Loan
and
Security
Agreement







On
May
23,
2011,
the
Company
entered
into
a
loan
and
security
agreement
with
Oxford
Finance
LLC
("Oxford")
and
General
Electric
Capital
Corporation("GECC")
pursuant
to
which
Oxford
and
GECC
agreed
to
lend
the
Company
up
to
$25.0
million.
Upon
entering
into
the
loan
and104





December
31,



Estimated
Useful
Life
(In
Years)



2015
2014
Furniture
and
fixtures
5
$314
$167
Computer
equipment
and
software
3

479

230
Manufacturing
equipment
10

1,127

598
Leasehold
improvements
Shorter
of
useful
life
or
remaining
leaseterm

322

16




2,242

1,011
Less
accumulated
depreciation
andamortization



(345)
(169)Property
and
equipment,
net


$1,897
$842



December
31,



2015
2014
Research
costs—Nordic(1)
$2,898
$11,536
Research
costs—other

5,178

3,336
Payroll
and
employee
benefits

3,330

1,659
Professional
fees

3,546

1,304
Accrued
interest
on
notes
payable

—

234
Other

—

198
Total
accrued
expenses
and
other
current
liabilties
$14,952
$18,267
(1)Includes
amounts
accrued
ratably
over
the
estimated
per
patient
treatment
period
under
the
Nordic
Work
Statement
NB-1
andWork
Statement
NB-3.
Amounts
do
not
include
pass-through
costs
which
are
expensed
as
incurred
or
upon
delivery.
See
note
10for
additional
information.Table
of
ContentsRadius
Health,
Inc.Notes
to
Consolidated
Financial
Statements
(Continued)6.
Loan
and
Security
Agreement
(Continued)security
agreement,
the
Company
borrowed
$6.3
million
on
May
23,
2011("Term
Loan
A"),
$6.3
million
on
November
21,
2011
("Term
Loan
B")
and
anadditional
$12.5
million
on
May
29,
2012
("Term
Loan
C").







Interest
on
the
outstanding
Term
Loan
A
was
payable
on
a
monthly
basis
through
and
including
December
1,
2011.
Principal
and
interest
payments
on
TermLoan
A
was
payable
in
36
equal
monthly
installments
beginning
December
1,
2011
through
November
1,
2014,
with
a
final
balloon
payment
of
$0.6
million
dueupon
maturity
on
November
22,
2014.
Interest
was
payable
on
Term
Loan
A
at
an
annual
interest
rate
of
10.16%.
Interest
on
the
outstanding
Term
Loan
B
waspayable
on
a
monthly
basis
through
and
including
June
1,
2012.
Principal
and
interest
payments
on
Term
Loan
B
was
payable
in
30
equal
monthly
installmentsbeginning
June
1,
2012,
through
November
1,
2014,
with
a
final
balloon
payment
of
$0.6
million
due
upon
maturity
on
November
22,
2014.
Interest
was
payableon
Term
Loan
B
at
an
annual
interest
rate
of
10%.
Interest
on
Term
Loan
C
was
payable
on
a
monthly
basis
through,
and
including,
November
1,
2012.
Principaland
interest
payments
on
Term
Loan
C
was
payable
in
24
monthly
installments
beginning
December
1,
2012,
through
November
1,
2014
with
a
final
balloonpayment
of
$1.3
million
upon
maturity
on
November
22,
2014.
Interest
was
payable
on
Term
Loan
C
at
an
annual
interest
rate
of
10%.







On
May
30,
2014,
the
Company
entered
into
a
loan
and
security
agreement
(the
"Credit
Facility),
with
Solar
Capital
Ltd.
("Solar"),
as
collateral
agent
and
alender,
and
Oxford,
as
a
lender
(the
"Lenders"),
pursuant
to
which
Solar
and
Oxford
agreed
to
make
available
to
the
Company
$30.0
million
in
the
aggregatesubject
to
certain
conditions
to
funding.
An
initial
term
loan
was
made
on
May
30,
2014
in
an
aggregate
principal
amount
equal
to
$21.0
million
(the
"Initial
TermLoan").
The
Company
used
approximately
$9.3
million
of
the
Initial
Term
Loan
to
repay
all
amounts
owed
under
its
loan
and
security
agreement
with
GECC
andOxford.







On
July
10,
2014,
the
Company
entered
into
a
first
amendment
to
the
Credit
Facility
(the
"First
Amendment").
The
terms
of
the
First
Amendment,
amongother
things,
provided
the
Company
with,
subject
to
certain
customary
funding
conditions,
additional
term
loans
in
an
aggregate
principal
amount
of
$4.0
millionupon
the
closing
of
the
First
Amendment.
The
Company
borrowed
the
additional
$4.0
million
on
July
10,
2014.







The
Company
had
been
required
to
make
interest-only
payments
through
December
1,
2015,
and
beginning
on
January
1,
2016,
it
would
have
been
required
tomake
payments
of
principal
and
accrued
interest
in
equal
monthly
installments
over
a
term
of
30
months.
The
Initial
Term
Loan
bore
interest
per
annum
at
9.85%plus
one-month
LIBOR
(customarily
defined).
All
principal
and
accrued
interest
on
the
Initial
Term
Loan
had
been
due
on
June
1,
2018.







On
August
4,
2015,
the
Company
prepaid
all
amounts
owed
under
the
Credit
Facility
and
the
First
Amendment.
After
consideration
of
relevant
fees
requiredunder
the
Credit
Facility
and
the
First
Amendment,
the
total
payment
amounted
to
$26.5
million,
which
resulted
in
a
loss
on
retirement
of
$1.6
million
during
thethird
quarter
of
2015.7.
Stockholders'
Equity
and
Convertible
Preferred
StockCommon Stock







On
June
11,
2014,
the
Company
completed
its
initial
public
offering
whereby
the
Company
sold
6,500,000
shares
of
common
stock
at
a
price
of
$8.00
pershare.
The
shares
began
trading
on
the105Table
of
ContentsRadius
Health,
Inc.Notes
to
Consolidated
Financial
Statements
(Continued)7.
Stockholders'
Equity
and
Convertible
Preferred
Stock
(Continued)NASDAQ
Global
Market
on
June
6,
2014.
In
connection
with
the
offering,
all
outstanding
shares
of
our
convertible
preferred
stock
converted
into
19,465,132shares
of
common
stock
and
2,862,654
shares
of
common
stock
were
issued
in
satisfaction
of
accumulated
dividends
accrued
on
the
preferred
stock.
In
addition,
alloutstanding
warrants
to
purchase
shares
of
series
A-1
convertible
preferred
stock
and
warrants
to
purchase
shares
of
series
B-2
convertible
preferred
stock
wereconverted
into
the
right
to
purchase
149,452
shares
of
common
stock
and
the
Company's
warrant
liability
was
reclassified
to
equity.







On
June
18,
2014
and
June
25,
2014,
the
underwriters
purchased
an
additional
512,744
shares
in
the
aggregate
by
exercising
a
portion
of
the
over-allotmentoption
granted
to
them
in
connection
with
the
initial
public
offering.
As
a
result
of
the
closing
of
the
initial
public
offering
and
subsequent
exercise
of
the
over-allotment
option,
the
Company
received
aggregate
proceeds,
net
of
underwriting
discounts,
commissions
and
offering
costs,
of
approximately
$50.4
million.







On
October
7,
2014,
the
Company
completed
an
additional
public
offering
whereby
it
sold
2,750,000
shares
of
common
stock
at
a
price
of
$18.25
per
share,for
aggregate
proceeds,
net
of
underwriting
discounts,
commissions
and
offering
costs,
of
approximately
$46.9
million.
On
October
7,
2014,
the
underwriterspurchased
an
additional
378,524
shares
in
the
aggregate
by
exercising
a
portion
of
the
over-allotment
option
granted
to
them
in
connection
with
the
offering.
As
aresult
of
the
public
offering
and
subsequent
exercise
of
the
over-allotment
option,
the
Company
received
aggregate
proceeds,
net
of
underwriting
discounts,commissions
and
offering
costs
of
approximately
$53.4
million.







On
January
28,
2015,
the
Company
completed
an
additional
public
offering
of
4,000,000
shares
of
its
common
stock
at
a
price
of
$36.75
per
share,
foraggregate
estimated
proceeds,
net
of
underwriting
discounts,
commissions
and
offering
costs,
of
approximately
$137.8
million.
Also,
on
January
28,
2015,
theunderwriters
purchased
an
additional
600,000
shares
in
the
aggregate
by
exercising
an
option
to
purchase
additional
shares
that
was
granted
to
them
in
connectionwith
the
offering.
As
a
result
of
the
public
offering
and
subsequent
exercise
of
the
underwriters'
option,
the
Company
received
aggregate
proceeds,
net
ofunderwriting
discounts,
commissions
and
offering
costs
of
approximately
$158.4
million.







On
July
28,
2015,
the
Company
completed
an
additional
public
offering
of
4,054,054
shares
of
its
common
stock
at
a
price
of
$74.00
per
share,
for
aggregateproceeds,
net
of
underwriting
discounts,
commissions
and
offering
costs,
of
approximately
$281.5
million.
Also,
on
July
28,
2015,
the
underwriters
purchased
anadditional
608,108
shares
by
exercising
an
option
to
purchase
additional
shares
that
was
granted
to
them
in
connection
with
the
offering.
As
a
result
of
the
publicoffering
and
subsequent
exercise
of
the
underwriters'
option,
the
Company
received
aggregate
proceeds,
net
of
underwriting
discounts,
commissions
and
estimatedoffering
costs
of
approximately
$323.8
million.Preferred Stock







On
April
23,
2013,
the
Company
entered
into
a
Series
B
Convertible
Preferred
Stock
and
Warrant
Purchase
Agreement
(the
"Series
B
Purchase
Agreement"),pursuant
to
which
the
Company
could
raise,
at
any
time
on
or
prior
to
May
10,
2013,
up
to
approximately
$60.0
million
through
the
issuance
of
(1)
up
to
980,000shares
of
its
Series
B
preferred
stock
(the
"Series
B")
and
(2)
warrants
to
acquire
up
to
approximately
1,075,000
shares
of
its
common
stock
with
an
exercise
priceof
$14.004
per
share.
On
April
23,
2013,
the
Company
consummated
a
first
closing
under
the
Series
B
Purchase
Agreement,
whereby
in
exchange
for
aggregateproceeds
of
approximately
$43.0
million,
it
issued
700,098
shares
of106Table
of
ContentsRadius
Health,
Inc.Notes
to
Consolidated
Financial
Statements
(Continued)7.
Stockholders'
Equity
and
Convertible
Preferred
Stock
(Continued)Series
B
and
warrants
to
purchase
up
to
a
total
of
767,651
shares
of
its
common
stock.
On
May
10,
2013,
the
Company
consummated
a
second
closing
under
theSeries
B
Purchase
Agreement,
whereby
in
exchange
for
aggregate
proceeds
of
approximately
$0.1
million,
it
issued
1,137
shares
of
Series
B
and
warrants
topurchase
up
to
a
total
of
1,246
shares
of
its
common
stock.
The
warrants
can
be
exercised
at
any
time
prior
to
the
fifth
anniversary
of
their
issuance.







On
February
14,
2014,
the
Company
entered
into
a
Series
B-2
Convertible
Preferred
Stock
and
Warrant
Purchase
Agreement
(the
"Series
B-2
PurchaseAgreement"),
pursuant
to
which
the
Company
was
able
to
raise
up
to
approximately
$40.2
million
through
the
issuance
of
(1)
up
to
655,000
shares
of
its
preferredstock
(the
"Series
B-2")
and
(2)
warrants
to
acquire
up
to
718,201
shares
of
its
common
stock
with
an
exercise
price
of
$14.004
per
share.
In
February
and
March2014,
the
Company
consummated
closings
under
the
Series
B-2
Purchase
Agreement,
whereby,
in
exchange
for
aggregate
gross
proceeds
to
the
Company
ofapproximately
$27.5
million,
the
Company
issued
an
aggregate
of
448,060
shares
of
Series
B-2
and
warrants
to
purchase
up
to
a
total
of
491,293
shares
of
itscommon
stock.
The
warrants
can
be
exercised
at
any
time
prior
to
the
fifth
anniversary
of
their
issuance.8.
Fair
Value
Measurements







The
following
table
summarizes
the
financial
instruments
measured
at
fair
value
on
a
recurring
basis
in
the
accompanying
consolidated
balance
sheets
as
ofDecember
31,
2015
and
December
31,
2014
(in
thousands):107


As
of
December
31,
2015



Level
1
Level
2
Level
3
Total
Assets












Cash
and
cash
equivalents:












Cash
$2,934
$—
$—
$2,934
Money
market
funds(1)

83,257

—

—

83,257
Domestic
corporate
commercial
paper(2)

—

39,984

—

39,984
Government-sponsored
enterprise
debt
securities(2)

—

15,996

—

15,996
Domestic
corporate
debt
securities(2)

—

10,007

—

10,007
Asset-backed
securities(2)

—

7,500

—

7,500
Total
$86,191
$73,487
$—
$159,678
Marketable
Securities












Domestic
corporate
debt
securities(2)
$—
$173,035
$—
$173,035
Domestic
corporate
commercial
paper(2)

—

84,158

—

84,158
Asset-backed
securities(2)

—

56,468

—

56,468
Total
$—
$313,661
$—
$313,661
Table
of
ContentsRadius
Health,
Inc.Notes
to
Consolidated
Financial
Statements
(Continued)8.
Fair
Value
Measurements
(Continued)

9.
License
Agreements







On
September
27,
2005,
the
Company
entered
into
a
license
agreement
(the
"Ipsen
Agreement"),
as
amended,
with
SCRAS
S.A.S,
a
French
corporation
onbehalf
of
itself
and
its
affiliates
(collectively,
"Ipsen").
Under
the
Ipsen
Agreement,
Ipsen
granted
to
the
Company
an
exclusive
right
and
license
under
certain
Ipsencompound
technology
and
related
patents
to
research,
develop,
manufacture
and
commercialize
certain
compounds
and
related
products
in
all
countries,
exceptJapan
(where
the
Company
does
not
hold
development
and
commercialization
rights)
and
France
(where
the
Company's
commercialization
rights
are
subject
tocertain
co-marketing
and
co-promotion
rights
exercisable
by
Ipsen,
provided
that
certain
conditions
included
in
the
Ipsen
Agreement
have
been
met).
With
respectto
France,
if
Ipsen
exercises
its
co-marketing
and
co-promotion
rights,
then
Ipsen
may
elect
to
receive
a
percentage
of
the
net
sales
of
the
products
by
both
partiesin
France
(subject
to
a
mid-double
digit
percentage
cap),
and
Ipsen
shall
bear
a
corresponding
percentage
of
the
costs
and
expenses
incurred
by
both
parties
withrespect
to
such
marketing
and
promotion
efforts
in
France.
Ipsen
shall
also
pay
the
Company
a
mid-single
digit
royalty
on
Ipsen's
allocable
portion
of
net
sales
ofthe
product
by
both
parties
in
France.
Abaloparatide
is
subject
to
the
Ipsen
Agreement.
Ipsen
also
granted
the
Company
an
exclusive
right
and
license
under
theIpsen
compound
technology
and
related
patents
to
make
and
have
made
compounds
or
product
in
Japan.
Ipsen
also
granted
the
Company
an
exclusive
right
andlicense
under
certain
Ipsen
formulation
technology
and
related
patents
solely
for
purposes
of
enabling
the
Company
to
develop,
manufacture
and
commercializecompounds
and
products
covered
by
the
compound
technology
license
in
all
countries,
except
Japan
(where
the
Company
does
not
hold
commercialization
rights)and
France
(where
the
Company's
commercialization
rights
are
subject
to108


As
of
December
31,
2014



Level
1
Level
2
Level
3
Total
Assets












Cash
and
cash
equivalents:












Cash
$1,519
$—
$—
$1,519
Money
market
funds(1)

23,994

—

—

23,994
Domestic
corporate
debt
securities(2)

—

3,005

—

3,005
Total
$25,513
$3,005
$—
$28,518
Marketable
securities:












Domestic
corporate
debt
securities(2)
$—
$69,509
$—
$69,509
Domestic
corporate
commercial
paper(2)

—

7,249

—

7,249
Total
$—
$76,758
$—
$76,758
(1)Fair
value
is
based
upon
quoted
market
prices.
(2)Fair
value
is
based
upon
quoted
prices
for
similar
instruments
in
active
markets,
quoted
prices
for
identical
or
similar
instruments
inmarkets
that
are
not
active
and
model-based
valuation
techniques
for
which
all
significant
assumptions
are
observable
in
the
market
or
canbe
corroborated
by
observable
market
data
for
substantially
the
full
term
of
the
assets.
Inputs
are
obtained
from
various
sources,
includingmarket
participants,
dealers
and
brokers.Table
of
ContentsRadius
Health,
Inc.Notes
to
Consolidated
Financial
Statements
(Continued)9.
License
Agreements
(Continued)certain
co-marketing
and
co-promotion
rights
exercisable
by
Ipsen,
provided
that
certain
conditions
included
in
the
Ipsen
Agreement
have
been
met).







In
consideration
for
these
licenses,
the
Company
made
a
nonrefundable,
non-creditable
payment
of
$0.25
million
to
Ipsen,
which
was
expensed
during
2005.The
Ipsen
Agreement
provides
for
further
payments
upon
the
achievement
of
certain
future
regulatory
and
commercial
milestones,
including
upon
acceptance
of
anew
drug
application
submission
for
review
by
the
U.S.
Food
and
Drug
Administration.
The
range
of
milestone
payments
that
could
be
paid
under
the
agreement
is€10.0
million
to
€36.0
million
($10.9
million
to
$39.1
million).
Should
abaloparatide
be
approved
and
subsequently
commercialized,
the
Company
will
beobligated
to
pay
to
Ipsen
a
fixed
five
percent
royalty
based
on
net
sales
of
the
product
by
the
Company
or
its
sublicensees
on
a
country-by-country
basis
until
thelater
of
the
last
to
expire
of
the
licensed
patents
or
for
a
period
of
10
years
after
the
first
commercial
sale
in
such
country.







If
the
Company
sublicenses
the
rights
licensed
from
Ipsen,
then
the
Company
will
also
be
required
to
pay
Ipsen
a
percentage
of
certain
payments
receivedfrom
such
sublicensee
(in
lieu
of
milestone
payments
not
achieved
at
the
time
of
such
sublicense).
The
applicable
percentage
is
in
the
low
double
digit
range.
Inaddition,
if
the
Company
or
its
sublicensees
commercialize
a
product
that
includes
a
compound
discovered
by
it
based
on
or
derived
from
confidential
Ipsen
know-how,
it
will
be
obligated
to
pay
to
Ipsen
a
fixed
low
single
digit
royalty
on
net
sales
of
such
product
on
a
country-by-country
basis
until
the
later
of
the
last
to
expireof
licensed
patents
that
cover
such
product
or
for
a
period
of
10
years
after
the
first
commercial
sale
of
such
product
in
such
country.







In
June
2006,
the
Company
entered
into
a
license
agreement
(the
"Eisai
Agreement"),
with
Eisai
Co.
Ltd.,
("Eisai").
Under
the
Eisai
Agreement,
Eisai
grantedto
the
Company
an
exclusive
right
and
license
to
research,
develop,
manufacture
and
commercialize
RAD1901
and
related
products
from
Eisai
in
all
countries,except
Japan.
In
consideration
for
the
rights
to
RAD1901,
the
Company
paid
Eisai
an
initial
license
fee
of
$0.5
million,
which
was
expensed
during
2006.
The
EisaiAgreement
provides
for
further
payments
in
the
range
of
$1.0
million
to
$20.0
million
(inclusive
of
the
$0.5
million
initial
license
fee),
payable
upon
theachievement
of
certain
clinical
and
regulatory
milestones.







On
March
9,
2015,
the
Company
entered
into
an
amendment
to
the
Eisai
Agreement
(the
"Eisai
Amendment")
in
which
Eisai
granted
to
the
Company
theexclusive
right
and
license
to
research,
develop,
manufacture
and
commercialize
RAD1901
in
Japan.
In
consideration
for
the
rights
to
RAD1901
in
Japan,
theCompany
paid
Eisai
an
initial
license
fee
of
$0.4
million
upon
execution
of
the
Eisai
Amendment,
which
was
recognized
as
research
and
development
expense
in2015.
The
Eisai
Amendment
also
provides
for
additional
payments,
payable
upon
the
achievement
of
certain
clinical
and
regulatory
milestones
in
Japan.







Under
the
Eisai
Agreement,
as
amended,
should
a
product
covered
by
the
licensed
technology
be
commercialized,
the
Company
will
be
obligated
to
pay
toEisai
royalties
in
a
variable
mid-single
digit
range
based
on
net
sales
of
the
product
on
a
country-by-country
basis.
The
royalty
rate
will
be
reduced,
on
a
country-by-country
basis,
at
such
time
as
the
last
remaining
valid
claim
in
the
licensed
patents
expires,
lapses
or
is
invalidated
and
the
product
is
not
covered
by
dataprotection
clauses.
In
addition,
the
royalty
rate
will
be
reduced,
on
a
country-by-country
basis,
if,
in
addition
to
the
conditions
specified
in
the
previous
sentence,sales
of
lawful
generic
versions
of
such
product
account
for
more
than
a
specified
minimum
percentage
of
the
total
sales
of
all
products
that
contain
the
licensedcompound
during
a
calendar
quarter.
The
latest
valid
claim
to
expire,
barring
any
extension
thereof,
is
expected
on
August
18,
2026.109Table
of
ContentsRadius
Health,
Inc.Notes
to
Consolidated
Financial
Statements
(Continued)9.
License
Agreements
(Continued)







The
Eisai
Agreement,
as
amended,
also
grants
the
Company
the
right
to
grant
sublicenses
with
prior
written
approval
from
Eisai.
If
the
Company
sublicensesthe
licensed
technology
to
a
third
party,
the
Company
will
be
obligated
to
pay
Eisai,
in
addition
to
the
milestones
referenced
above,
a
fixed
low
double
digitpercentage
of
certain
fees
received
from
such
sublicensee
and
royalties
in
the
low
single
digit
range
based
on
net
sales
of
the
sublicensee.
The
license
agreementexpires
on
a
country-by-country
basis
on
the
later
of
(1)
the
date
the
last
remaining
valid
claim
in
the
licensed
patents
expires,
lapses
or
is
invalidated
in
thatcountry,
the
product
is
not
covered
by
data
protection
clauses,
and
the
sales
of
a
lawful
generic
version
of
the
product
account
for
more
than
a
specified
percentageof
the
total
sales
of
all
pharmaceutical
products
containing
the
licensed
compound
in
that
country;
or
(2)
a
period
of
10
years
after
the
first
commercial
sale
of
thelicensed
products
in
such
country,
unless
it
is
sooner
terminated.10.
Research
Agreements        Abaloparatide-SC Phase 3 Clinical Trial —On
March
29,
2011,
the
Company
and
Nordic
entered
into
a
Clinical
Trial
Services
Agreement
(the
"Clinical
TrialServices
Agreement"),
a
Work
Statement
NB-1,
as
amended
on
December
9,
2011,
June
18,
2012,
March
28,
2014,
May
19,
2014,
July
22,
2014,
August
15,
2014and
March
12,
2015
(the
"Work
Statement
NB-1")
and
a
Stock
Issuance
Agreement,
as
amended
and
restated
on
May
16,
2011,
and
as
further
amended
onFebruary
21,
2013,
March
28,
2014,
and
May
19,
2014
(the
"Stock
Issuance
Agreement").
Pursuant
to
the
Work
Statement
NB-1,
Nordic
managed
the
Phase
3clinical
trial
of
abaloparatide-SC
(the
"Phase
3
Clinical
Trial").







The
Company
recognized
research
and
development
expense
for
the
amounts
due
to
Nordic
under
the
Work
Statement
NB-1
ratably
over
the
estimated
perpatient
treatment
period
beginning
upon
enrollment
in
the
Phase
3
Clinical
Trial,
or
a
twenty-month
period.
The
Company
recognized
research
and
developmentexpense
for
the
amounts
due
to
Nordic
under
the
fourth
amendment
to
the
Work
Statement
NB-1,
which
was
recognized
on
a
per
patient
basis
when
the
end-of-study
visit
and
all
other
required
procedures
were
completed.
The
Company
recorded
no
expense,
$8.2
million,
and
$31.6
million
during
the
years
endedDecember
31,
2015,
2014,
and
2013,
respectively,
for
per
patient
costs
incurred
for
patients
that
had
enrolled
in
the
Phase
3
Clinical
Study.
As
of
December
31,2015,
all
obligations
due
to
Nordic
under
Work
Statement
NB-1
had
been
paid.        Abaloparatide-SC Phase 3 Clinical Extension Study —On
February
21,
2013,
the
Company
entered
into
a
Work
Statement
NB-3,
as
amended
on
February
28,2014,
March
23,
2015,
July
8,
2015
and
October
21,
2015
(the
"Work
Statement
NB-3").
Pursuant
to
the
Work
Statement
NB-3,
Nordic
performed
an
extensionstudy
to
evaluate
six
months
of
standard-of-care
osteoporosis
management
following
the
completion
of
the
Phase
3
Clinical
Trial
(the
"Extension
Study"),
and,upon
completion
of
this
initial
six
months,
an
additional
period
of
18
months
of
standard-of-care
osteoporosis
management
(the
"Second
Extension").







In
April
2015,
the
Company
entered
into
an
amendment
to
the
Work
Statement
NB-3
(the
"NB-3
Amendment").
The
NB-3
Amendment
was
effective
as
ofMarch
23,
2015
and
provides
that
Nordic
will
perform
additional
services,
including
additional
monitoring
of
patients
enrolled
in
the
Second
Extension.
Paymentsin
cash
to
be
made
to
Nordic
under
the
NB-3
Amendment
are
denominated
in
euros
and
total
up
to
approximately
€4.1
million
($4.5
million).110Table
of
ContentsRadius
Health,
Inc.Notes
to
Consolidated
Financial
Statements
(Continued)10.
Research
Agreements
(Continued)







Payments
in
cash
to
be
made
to
Nordic
under
the
Work
Statement
NB-3
are
denominated
in
both
euros
and
U.S.
dollars
and
total
up
to
€11.9
million($12.9
million)
and
$1.1
million,
respectively.
In
addition,
payments
are
due
to
Nordic
in
connection
with
the
Work
Statement
NB-3
pursuant
to
the
Stock
IssuanceAgreement,
as
discussed
below.
As
of
December
31,
2015,
services
related
to
the
Second
Extension
are
ongoing
and
all
obligations
due
to
Nordic
in
relation
to
theExtension
Study
have
been
paid.







The
Company
recognizes
research
and
development
expense
for
the
amounts
due
to
Nordic
under
the
Extension
Study
and
the
Second
Extension
ratably
overthe
estimated
per
patient
treatment
periods
beginning
upon
enrollment,
or
over
a
nine-month
and
nineteen-month
period,
respectively.
The
Company
recorded$5.4
million,
$9.6
million,
and
$4.5
million
for
the
years
ended
December
31,
2015,
2014,
and
2013
respectively,
for
per
patient
costs
incurred.







As
of
December
31,
2015,
the
Company
had
a
liability
of
$2.9
million
reflected
in
accrued
expenses
and
other
current
liabilities
on
the
consolidated
balancesheet
resulting
from
services
provided
by
Nordic
under
the
Second
Extension,
which
are
payable
in
cash.        Stock Issuance Agreement —Pursuant
to
the
Stock
Issuance
Agreement,
Nordic
agreed
to
purchase
6,443
shares
of
the
Company's
Series
A-5
convertiblepreferred
stock,
which
provided
Nordic
with
the
right
to
receive
quarterly
stock
dividends,
payable
in
shares
of
the
Company's
Series
A-6
convertible
preferredstock
("Series
A-6")
for
services
rendered
under
Work
Statement
NB-1
and
Work
Statement
NB-3.
The
Stock
Issuance
Agreement
was
later
amended
to
providethat
in
the
event
an
initial
public
offering
of
the
Company's
common
stock
occurred
prior
to
June
30,
2014,
any
rights
to
receive
stock
dividends
in
relation
to
WorkStatement
NB-1
and
Work
Statement
NB-3,
for
all
periods
of
time
after
2014,
would
be
changed
from
the
right
to
receive
stock
to
the
right
to
receive
a
total
cashpayment
from
the
Company
of
$4.3
million,
payable
in
ten
equal
monthly
installments
of
$430,000
beginning
on
March
31,
2015.
The
amendment
also
stipulatedthat
all
consideration
to
be
paid
to
Nordic
pursuant
to
the
Stock
Issuance
Agreement
at
any
time
after
the
consummation
of
an
initial
public
offering
be
payable
incash.
As
the
Company
completed
an
initial
public
offering
on
June
11,
2014,
Nordic
no
longer
has
the
right
to
receive
stock
from
the
Company
and
has
been
paidin
cash
for
all
periods
after
June
11,
2014.







Prior
to
the
issuance
of
shares
of
stock
to
Nordic
in
satisfaction
of
quarterly
dividends
earned
under
Work
Statement
NB-1
and
Work
Statement
NB-3,
theliability
to
issue
shares
of
stock
was
being
accounted
for
as
a
liability
in
the
Company's
balance
sheet,
based
upon
the
fair
value
of
the
Series
A-6.
Changes
in
thefair
value
from
the
date
of
accrual
to
the
date
of
issuance
of
the
Series
A-6
shares
were
recorded
as
a
gain
or
loss
in
other
(expense)
income
in
the
statement
ofoperations.11.
Stock-based
Compensation







The
Company
has
the
following
stock-based
compensation
plans
as
of
December
31,
2015,
under
which
equity
awards
have
been
granted
to
employees,directors
and
consultants:•2003
Long-Term
Incentive
Plan;
and
•2011
Equity
Incentive
Plan.







The
2011
Equity
Incentive
Plan
replaced
the
2003
Long-Term
Incentive
Plan
when
the
board
of
directors
approved
the
new
plan
on
November
7,
2011.
As
ofDecember
31,
2015,
an
aggregate
of111Table
of
ContentsRadius
Health,
Inc.Notes
to
Consolidated
Financial
Statements
(Continued)11.
Stock-based
Compensation
(Continued)approximately
6,160,000
shares
have
been
authorized
for
issuance
under
the
Company's
stock-based
compensation
plans,
with
approximately
4,408,000
optionsoutstanding.
The
number
of
common
shares
available
for
granting
of
future
awards
under
these
plans
was
approximately
1,100,000
at
December
31,
2015.        2003 Long-Term Incentive Plan —The
Company's
2003
Long-Term
Incentive
Plan
(the
"Incentive
Plan")
provides
for
the
granting
of
incentive
stock
optionsand
nonqualified
options
to
key
employees,
directors
and
consultants
of
the
Company.
The
exercise
price
of
the
incentive
stock
options,
as
determined
by
the
boardof
directors,
must
be
at
least
100%
(110%
in
the
case
of
incentive
stock
options
granted
to
a
stockholder
owning
in
excess
of
10%
of
the
Company's
common
stock)of
the
common
stock
fair
value
as
of
the
date
of
the
grant.
The
provisions
of
the
Incentive
Plan
limit
the
exercise
of
incentive
stock
options,
but
in
no
case
may
theexercise
period
extend
beyond
ten
years
from
the
date
of
grant
(five
years
in
the
case
of
incentive
stock
options
granted
to
a
stockholder
owning
in
excess
of
10%of
the
Company's
common
stock).
Stock
options
generally
vest
over
a
four-year
period.
Certain
options
contain
explicit
performance
conditions.
The
Companyauthorized
approximately
884,000
shares
of
common
stock
for
issuance
under
the
Incentive
Plan.        2011 Equity Incentive Plan —The
Company's
2011
Equity
Incentive
Plan
(the
"Equity
Plan")
provides
for
the
granting
of
incentive
stock
options
andnonqualified
options
to
key
employees,
directors
and
consultants
of
the
Company.
The
exercise
price
of
the
incentive
stock
options,
as
determined
by
the
board
ofdirectors,
must
be
at
least
100%
(110%
in
the
case
of
incentive
stock
options
granted
to
a
stockholder
owning
in
excess
of
10%
of
the
Company's
common
stock)
ofthe
common
stock
fair
value
as
of
the
date
of
the
grant.
The
provisions
of
the
Equity
Plan
limit
the
exercise
of
incentive
stock
options,
but
in
no
case
may
theexercise
period
extend
beyond
ten
years
from
the
date
of
grant
(five
years
in
the
case
of
incentive
stock
options
granted
to
a
stockholder
owning
in
excess
of
10%of
the
Company's
common
stock).
Stock
options
generally
vest
over
a
four-year
period.
During
2015,
the
Company
also
issued
stock
options
to
certain
members
ofits
board
of
directors
which
vested
immediately.
Certain
options
contain
explicit
performance
conditions.
The
Company
has
authorized
approximately
5,276,000shares
of
common
stock
for
issuance
under
the
Equity
Plan.
In
addition,
the
shares
remaining
available
for
issuance
under
the
Incentive
Plan
were
assumed
asshares
authorized
under
the
Equity
Plan.        Options —The
Company
has
historically
granted
stock
options
at
exercise
prices
no
less
than
the
fair
value
of
its
common
stock
as
determined
by
its
board
ofdirectors,
with
input
from
management.
Prior
to
the
Company's
initial
public
offering,
the
Company's
board
of
directors
has
historically
determined,
with
inputfrom
management,
the
estimated
fair
value
of
the
Company's
common
stock
on
the
date
of
grant
based
on
a
number
of
objective
and
subjective
factors,
including:•the
prices
at
which
the
Company
sold
shares
of
convertible
preferred
stock;
•the
superior
rights
and
preferences
of
securities
senior
to
the
Company's
common
stock
at
the
time
of
each
grant;
•the
likelihood
of
achieving
a
liquidity
event
such
as
a
public
offering
or
sale
of
the
Company;
•the
Company's
historical
operating
and
financial
performance
and
the
status
of
its
research
and
product
development
efforts;
and112Table
of
ContentsRadius
Health,
Inc.Notes
to
Consolidated
Financial
Statements
(Continued)11.
Stock-based
Compensation
(Continued)•achievement
of
enterprise
milestones,
including
entering
into
collaboration
and
license
agreements.







Subsequent
to
the
Company's
initial
public
offering,
exercise
prices
in
the
case
of
non-qualified
and
incentive
stock
options
are
not
less
than
the
fair
value
ofthe
underlying
common
stock
on
the
date
of
grant,
as
determined
under
the
Equity
Plan.







The
Company
uses
the
Black-Scholes
option-pricing
model
to
estimate
the
grant
date
fair
value
of
its
employee
stock
options.
The
weighted-average
grant-date
fair
value
per
share
of
options
granted
during
2015,
2014,
and
2013
was
$30.52,
$8.26,
and
$4.67
respectively.
The
weighted-average
assumptions
used
in
theBlack-Scholes
option-pricing
model
were
as
follows:







A
summary
of
stock
option
activity
for
the
year
ended
December
31,
2015
is
as
follows
(in
thousands,
except
for
per
share
and
weighted-average
contractuallife
amounts):







The
aggregate
intrinsic
value
of
options
exercised
(i.e.,
the
difference
between
the
market
price
at
exercise
and
the
price
paid
by
employees
to
exercise
theoption)
during
the
years
ended
December
31,
2015
and
2014
was
$14.7
million
and
$0.7
million,
respectively.113


Years
Ended
December
31,



2015
2014
2013
Expected
term
(years)

6.08

6.06

6.25
Volatility

55%
59%
62%Expected
dividend
yield

0%
0%
0%Risk-free
interest
rates

1.72%
2.06%
2.45%


Shares
Weighted-Average
Exercise
Price
(in
dollars
per
share)
Weighted-Average
Contractual
Life
(In
Years)
Aggregate
Intrinsic
Value
Options
outstanding
at
December
31,
2014

3,220
$13.58






Granted

1,487

57.75






Exercised

(268)
8.73






Cancelled

(31)
17.31






Expired

—

—






Options
outstanding
at
December
31,
2015

4,408
$28.75

8.24
$151,544
Options
exercisable
at
December
31,
2015

1,738
$12.21

6.96
$85,747
Options
vested
or
expected
to
vest
at
December
31,
2015

4,316
$28.43

8.22
$149,570
Table
of
ContentsRadius
Health,
Inc.Notes
to
Consolidated
Financial
Statements
(Continued)11.
Stock-based
Compensation
(Continued)







The
following
table
summarizes
stock-based
compensation
expense
by
financial
statement
line
(in
thousands):        Performance Units —In
September
2015,
the
Company
awarded
25,000
performance
units
("PUs")
to
an
employee.
Each
PU
which
is
earned
entitles
theholder
to
receive
one
share
of
the
Company's
common
stock
if
and
when
the
PU
vests.
The
PUs
can
be
earned
in
the
three
years
subsequent
to
the
grant
date
if
theCompany's
average
closing
stock
price
over
45
consecutive
trading
days
that
begin
and
end
during
such
three-year
period
reaches
certain
thresholds
that
were
set
atthe
time
of
issuance.
The
vesting
of
any
earned
units
is
subject
to
the
employee's
continued
employment
one
year
from
the
last
day
of
the
measurement
period
forwhich
the
PUs
are
earned.
Compensation
expense
is
recognized
over
the
derived
service
period,
calculated
using
a
Monte
Carlo
simulation
analysis.







The
weighted-average
grant-date
fair
value
per
unit
of
PUs
granted
during
the
year
ended
December
31,
2015
was
$49.59,
which
was
calculated
using
aMonte
Carlo
simulation
analysis.
This
valuation
methodology
utilizes
several
key
assumptions
including
the
forecasted
stock
price,
stock
price
volatility,
risk-freerate
as
of
valuation
date,
stock
price
as
of
grant
date
and
the
trigger
for
the
performance
condition
to
be
met.







As
of
December
31,
2015,
there
was
approximately
$51.3
million
of
total
unrecognized
compensation
expense
related
to
unvested
share-based
compensationarrangements,
which
is
expected
to
be
recognized
over
a
weighted-average
period
of
approximately
3
years.114


Years
Ended
December
31,



2015
2014
2013
Research
and
development
$7,864
$1,953
$302
General
and
administrative

6,870

5,117

1,206
Share-based
compensation
expense
included
in
operating
expenses
$14,734
$7,070
$1,508
Table
of
ContentsRadius
Health,
Inc.Notes
to
Consolidated
Financial
Statements
(Continued)12.
Net
Loss
Per
Share







Basic
and
diluted
net
loss
per
share
is
calculated
as
follows
(in
thousands,
except
share
and
per
share
amounts):







The
following
potentially
dilutive
securities,
prior
to
the
use
of
the
treasury
stock
method,
have
been
excluded
from
the
computation
of
diluted
weighted-average
shares
outstanding,
as
they
would
be
anti-dilutive.
For
the
years
ended
December
31,
2015,
2014,
and
2013
all
of
the
Company's
classes
of
convertiblepreferred
stock,
options
to
purchase
common
stock,
warrants
and
performance
units
outstanding
were
assumed
to
be
anti-dilutive
as
earnings
attributable
tocommon
stockholders
was
in
a
loss
position.13.
Income
Taxes







As
of
December
31,
2015
the
Company
had
federal
and
state
net
operating
loss
("NOL")
carryforwards
of
approximately
$419.5
million
and
$323.0
million,respectively,
which
may
be
used
to
offset
future
taxable
income.
The
Company
also
had
federal
and
state
tax
credits
of
$5.8
million
and
$0.8
million,
respectively,to
offset
future
tax
liabilities.
The
NOL
and
tax
credit
carryforwards
will
expire
at
various
dates
through
2035,
and
are
subject
to
review
and
possible
adjustment
byfederal
and
state
tax
authorities.
The
Internal
Revenue
Code
contains
provision
that
may
limit
the
NOL
and
tax
credit
carryforwards
available
to
be
used
in
anygiven
year
in
the
event
of
certain
changes
in
the
ownership
interests
of
significant
stockholders
under
Section
382
of
the
Internal
Revenue
Code.115


Year
Ended
December
31,



2015
2014
2013
Numerator:









Net
loss
$(101,526)$(62,479)$(60,690)Accretion
of
preferred
stock

—

(9,000)
(17,471)Loss
attributable
to
common
stockholders—basic

(101,526)
(71,479)
(78,161)Effect
of
dilutive
convertible
preferred
stock

—

—

—
Loss
attributable
to
common
stockholders—diluted
$(101,526)$(71,479)$(78,161)Denominator:









Weighted-average
number
of
common
shares
used
in
loss
pershare—diluted

39,643,099

17,699,487

383,310
Loss
per
share—basic
and
diluted
$(2.56)$(4.04)$(203.91)


Year
Ended
December
31



2015
2014
2013
Convertible
preferred
stock

—

3,857,664

6,617,686
Options
to
purchase
common
stock

3,903,051

2,466,492

1,743,890
Warrants

822,726

1,271,520

545,797
Performance
units

—

—

—
Table
of
ContentsRadius
Health,
Inc.Notes
to
Consolidated
Financial
Statements
(Continued)13.
Income
Taxes
(Continued)Approximately
$14.1
million
of
the
federal
and
state
NOL
carryforwards
are
attributable
to
excess
tax
benefits
which
will
be
recorded
as
an
increase
to
additionalpaid-in
capital
when
realized.







A
reconciliation
of
income
taxes
computed
using
the
U.S.
federal
statutory
rate
to
that
reflected
in
operations
follows
(in
thousands):







The
Company
is
subject
to
Massachusetts
net
worth
taxes,
not
based
on
income,
which
is
largely
offset
by
allowable
tax
credits
and
recorded
as
a
componentof
operating
expenses.







The
principal
components
of
the
Company's
deferred
tax
assets
are
as
follows
(in
thousands):







Effective
December
31,
2015,
the
Company
early
adopted
ASU
2015-17
on
a
prospective
basis.
ASU
2015-17
requires
deferred
tax
liabilities
and
assets
to
beclassified
as
noncurrent
in
a
classified116


Year
Ended
December
31,



2015
2014
2013
Income
tax
benefit
using
U.S.
federal
statutory
rate
$(34,391)$(21,243)$(20,635)State
income
taxes,
net
of
federal
benefit

(4,434)
(2,494)
(2,255)Stock-based
compensation

752

149

92
Research
and
development
tax
credits

(1,469)
(499)
(1,277)Change
in
the
valuation
allowance

39,291

23,186

27,194
Permanent
items

26

910

(3,085)Other

225

(9)
(34)
$—
$—
$—



December
31,



2015
2014
Current
assets:






Accrued
expenses
$—
$671
Gross
current
deferred
tax
assets

—

671
Valuation
allowance

—

(671)Net
current
deferred
tax
assets
$—
$—
Non-current
assets:






Net
operating
loss
carryforwards
$154,239
$121,278
Capitalized
research
and
development

263

356
Research
and
development
credits

6,313

4,844
Depreciation
and
amortization

(119)
(47)Accrued
Expenses

1,073

—
Stock-based
compensation

7,753

3,158
Other

29

—
Gross
non-current
deferred
tax
assets

169,551

129,589
Valuation
allowance

(169,551)
(129,589)Net
non-current
deferred
tax
assets
$—
$—
Table
of
ContentsRadius
Health,
Inc.Notes
to
Consolidated
Financial
Statements
(Continued)13.
Income
Taxes
(Continued)statement
of
financial
position,
instead
of
separating
deferred
income
tax
liabilities
and
assets
into
current
and
noncurrent
amounts.
Adoption
of
this
ASU
resultedin
a
reclassification
of
our
net
current
deferred
tax
asset
to
the
net
non-current
deferred
tax
asset
in
our
Consolidated
Balance
Sheet
as
of
December
31,
2015.
Noprior
periods
were
retrospectively
adjusted.







The
Company
has
recorded
a
valuation
allowance
against
its
deferred
tax
assets
in
each
of
the
years
ended
December
31,
2015
and
2014,
because
theCompany's
management
believes
that
it
is
more
likely
than
not
that
these
assets
will
not
be
realized.
The
increase
in
the
valuation
allowance
in
2015
primarilyrelates
to
the
net
loss
incurred
by
the
Company.







As
of
December
31,
2015,
the
Company
has
no
unrecognized
tax
benefits
or
related
interest
and
penalties
accrued.
The
Company
has
not,
as
yet,
conducted
astudy
of
research
and
development
credit
carryforwards.
In
addition,
the
Company
is
in
the
process
of
conducting
an
Internal
Revenue
Code
Section
382
study,which
may
impact
its
ability
to
utilize
available
NOL
and
tax
credit
carryforwards.
These
studies
may
result
in
adjustments
to
the
Company's
research
anddevelopment
credit
carryforwards
and
NOL
carryforwards;
however,
until
a
study
is
completed
and
any
adjustment
is
known,
no
amounts
are
being
presented
as
anuncertain
tax
position.
A
full
valuation
allowance
has
been
provided
against
the
Company's
research
and
development
credits
and
net
operating
loss
carryforwardand,
if
an
adjustment
is
required,
this
adjustment
would
be
offset
by
an
adjustment
to
the
valuation
allowance.
Thus,
there
would
be
no
impact
to
the
consolidatedbalance
sheet
or
consolidated
statement
of
operations
if
an
adjustment
were
required.
The
Company
would
recognize
both
accrued
interest
and
penalties
related
tounrecognized
benefits
in
income
tax
expense.
The
Company
has
not
recorded
any
interest
or
penalties
on
any
unrecognized
benefits
since
inception.







The
statute
of
limitations
for
assessment
by
the
Internal
Revenue
Service
("IRS")
and
state
tax
authorities
remains
open
for
years
2012
through
2015.
TheCompany
files
income
tax
returns
in
the
United
States,
Colorado,
Connecticut,
Florida,
Pennsylvania,
New
Jersey,
New
York,
and
Massachusetts.
There
arecurrently
no
federal
or
state
audits
in
progress.14.
Commitments
and
Contingencies        Litigation —The
Company
may
be
subject
to
legal
proceedings
and
claims
which
arise
in
the
ordinary
course
of
its
business.
In
the
Company's
opinion,
theultimate
resolution
of
these
matters
is
not
expected
to
have
a
material
effect
on
its
consolidated
financial
statements.
The
Company
records
a
liability
in
itsconsolidated
financial
statements
for
these
matters
when
a
loss
is
known
or
considered
probable
and
the
amount
can
be
reasonably
estimated.
The
Companyreviews
these
estimates
each
accounting
period
as
additional
information
is
known
and
adjusts
the
loss
provision
when
appropriate.
If
a
matter
is
both
probable
toresult
in
a
liability
and
the
amounts
of
loss
can
be
reasonably
estimated,
the
Company
estimates
and
discloses
the
possible
loss
or
range
of
loss
to
the
extentnecessary
to
make
the
consolidated
financial
statements
not
misleading.
If
the
loss
is
not
probable
or
cannot
be
reasonably
estimated,
a
liability
is
not
recorded
inits
consolidated
financial
statements.        Commitments —The
Company
leases
certain
office
space
in
Massachusetts
and
New
Jersey
under
non-cancellable
operating
leases
that
expire
over
variousterms
through
2020.117Table
of
ContentsRadius
Health,
Inc.Notes
to
Consolidated
Financial
Statements
(Continued)14.
Commitments
and
Contingencies
(Continued)







The
Company
is
obligated
to
make
monthly
rent
payments
pursuant
to
these
non-cancellable
agreements
as
set
forth
below
(in
thousands):







Rent
expense
for
the
years
ended
December
31,
2015,
2014,
and
2013
was
$0.6
million,
$0.2
million
and
$0.2
million,
respectively.15.
Related
Party
Transactions







On
July
24,
2013,
the
Company
entered
into
a
Consulting
Agreement
with
Morana
Jovan-Embiricos,
Ph.D.
(the
"Consulting
Agreement"),
a
member
of
theCompany's
board
of
directors.
Pursuant
to
the
Consulting
Agreement,
Dr.
Jovan-Embiricos
agreed
to
provide
financial
and
strategic
consulting
services
as
may
berequested
by
the
Company,
and
such
other
consulting
services
as
may
be
reasonably
requested
by
the
Company,
from
time
to
time
from
July
1,
2013
until
June
30,2014.
The
Company
agreed
to
pay
Dr.
Jovan-Embiricos
an
aggregate
consulting
fee
in
cash
of
$160,000,
of
which
$80,000
was
paid
on
July
30,
2013
and
theremaining
$80,000
was
paid
on
October
2,
2013.
As
of
December
31,
2015,
no
amounts
were
due
to
or
from
Dr.
Jovan-Embiricos.







On
January
23,
2014,
the
Company
entered
into
a
consulting
agreement
with
Orbit
Advisors
Limited
(the
"Orbit
Agreement"),
a
Swiss
company
("Orbit"),
andMorana
Jovan-Embiricos,
Ph.D.
and
an
agreement
terminating
the
Consulting
Agreement
dated
July
24,
2013.
The
Orbit
Agreement
was
effective
as
of
January
22,2014
and
would
continue
in
effect
until
December
31,
2014
or
until
the
earlier
termination
thereof
in
accordance
with
its
terms
(the
"Term").
Pursuant
to
the
OrbitAgreement,
Orbit
had
agreed
to
provide
financial
and
strategic
consulting
services
as
may
be
requested
by
the
Company,
and
such
other
consulting
services
as
mayhave
been
reasonably
requested
by
the
Company,
from
time
to
time
during
the
Term.
The
Company
agreed
to
pay
Orbit
an
aggregate
consulting
fee
in
cash
of$400,000
in
four
equal
installments
of
$100,000
on
each
of
January
31,
2014,
June
30,
2014,
September
30,
2014
and
December
31,
2014.
The
Orbit
Agreementcontained
customary
provisions,
applicable
to
both
Orbit
and
Dr.
Jovan-Embiricos,
as
Orbit's
representative
under
the
Orbit
Agreement,
regarding
the
treatment
ofthe
Company's
confidential
information
and
assignment
of
inventions,
as
well
as
an
obligation
of
Orbit
and
Dr.
Jovan-Embiricos
to
not
solicit,
during
the
Term
andfor
a
period
of
one
year
thereafter,
any
person
or
entity
engaged
by
the
Company
as
an
employee,
customer
or
supplier
of,
or
consultant
or
advisor
to,
the
Companyto
terminate
such
party's
relationship
with
the
Company.
On
February
27,
2014,
the
Company
entered
into
a
letter
agreement
terminating
the
Orbit
Agreement.
Asof
December
31,
2015,
no
amounts
were
due
to
or
from
Orbit
Advisors
Limited.118Years
ended
December
31,
Future
Lease
Commitments
2016
$1,944
2017

2,214
2018

1,613
2019

1,327
2020

1,175
Total
minimum
lease
payments
$8,273
Table
of
ContentsRadius
Health,
Inc.Notes
to
Consolidated
Financial
Statements
(Continued)16.
Selected
Quarterly
Financial
Data
(Unaudited)







Selected
quarterly
financial
data
for
the
years
ended
December
31,
2015
and
2014
is
as
follows
(in
thousands,
except
for
share
and
per
share
data):119


Three
Months
Ended



March
31,
June
30,
September
30,
December
31,
2015:












Net
loss
$(17,057)
(22,965)
(28,264)$(33,240)Net
loss
applicable
to
common
stock

(17,057)
(22,965)
(28,264)
(33,240)Net
loss
per
share—basic
and
diluted

(0.47)
(0.61)
(0.68)
(0.77)Weighted-average
common
shares
outstanding—basic
anddiluted

36,268,975

37,895,651

41,331,612

42,924,137
2014:












Net
loss
$(14,488)$(12,609)$(17,420)$(17,962)Net
loss
applicable
to
common
stock

(19,457)
(16,640)
(17,420)
(17,962)Net
loss
per
share—basic
and
diluted

(50.45)
(2.22)
(0.59)
(0.55)Weighted-average
common
shares
outstanding—basic
anddiluted

385,664

7,500,148

29,746,426

32,678,459
Table
of
ContentsITEM
9.



CHANGES
IN
AND
DISAGREEMENTS
WITH
ACCOUNTANTS
ON
ACCOUNTING
AND
FINANCIAL
DISCLOSURE.








None.ITEM
9A.



CONTROLS
AND
PROCEDURES.
Limitations
on
Effectiveness
of
Controls
and
Procedures







In
designing
and
evaluating
our
disclosure
controls
and
procedures
and
internal
control
over
financial
reporting,
management
recognizes
that
any
controls
andprocedures,
no
matter
how
well
designed
and
operated,
can
provide
only
reasonable
assurance
of
achieving
the
desired
control
objectives.
In
addition,
the
design
ofdisclosure
controls
and
procedures
and
internal
control
over
financial
reporting
must
reflect
the
fact
that
there
are
resource
constraints
and
that
management
isrequired
to
apply
judgment
in
evaluating
the
benefits
of
possible
controls
and
procedures
relative
to
their
costs.Evaluation
of
Disclosure
Controls
and
Procedures







Our
management,
with
the
participation
of
our
Chief
Executive
Officer
and
Chief
Financial
Officer,
evaluated
as
of
the
end
of
the
period
covered
by
thisAnnual
Report
on
Form
10-K,
the
effectiveness
of
our
disclosure
controls
and
procedures
(as
defined
in
Rules
13a-15(e)
and
15d-15(e)
under
the
SecuritiesExchange
Act
of
1934,
as
amended,
or
the
Exchange
Act.
Based
on
that
evaluation,
our
Chief
Executive
Officer
and
Chief
Financial
Officer
concluded
that
ourdisclosure
controls
and
procedures
were
effective
at
the
reasonable
assurance
level
as
of
December
31,
2015.Management's
Annual
Report
on
Internal
Control
Over
Financial
Reporting







Our
management
is
responsible
for
establishing
and
maintaining
adequate
internal
control
over
financial
reporting,
as
defined
in
Rules
13a-15(f)
and
15d-15(f)under
the
Exchange
Act.
Our
management,
with
the
participation
of
our
Chief
Executive
Officer
and
Chief
Financial
Officer,
assessed
the
effectiveness
of
ourinternal
control
over
financial
reporting
as
of
December
31,
2015,
based
on
the
criteria
set
forth
in
Internal
Control—Integrated
Framework
issued
by
theCommittee
of
Sponsoring
Organizations
of
the
Treadway
Commission
(2013
framework).
Based
on
that
assessment,
our
management
concluded
that
our
internalcontrol
over
financial
reporting
was
effective
as
of
December
31,
2015.







The
effectiveness
of
our
internal
control
over
financial
reporting
as
of
December
31,
2015
has
been
audited
by
Ernst
&
Young
LLP,
an
independent
registeredpublic
accounting
firm,
as
stated
in
their
report
which
is
contained
in
Item
9A
of
this
Annual
Report
on
Form
10-K.Changes
in
Internal
Control
Over
Financial
Reporting







There
was
no
change
in
our
internal
control
over
financial
reporting
during
the
quarter
ended
December
31,
2015
that
has
materially
affected,
or
is
reasonablylikely
to
materially
affect,
our
internal
control
over
financial
reporting.120Table
of
ContentsReport
of
Independent
Registered
Public
Accounting
Firm
The
Board
of
Directors
and
Shareholders
of
Radius
Health,
Inc.







We
have
audited
Radius
Health,
Inc.'s
internal
control
over
financial
reporting
as
of
December
31,
2015,
based
on
criteria
established
in
Internal
Control—Integrated
Framework
issued
by
the
Committee
of
Sponsoring
Organizations
of
the
Treadway
Commission
(2013
framework)
(the
COSO
criteria).
RadiusHealth,
Inc.'s
management
is
responsible
for
maintaining
effective
internal
control
over
financial
reporting,
and
for
its
assessment
of
the
effectiveness
of
internalcontrol
over
financial
reporting
included
in
the
accompanying
Management's
Annual
Report
on
Internal
Control
over
Financial
Reporting.
Our
responsibility
is
toexpress
an
opinion
on
the
company's
internal
control
over
financial
reporting
based
on
our
audit.







We
conducted
our
audit
in
accordance
with
the
standards
of
the
Public
Company
Accounting
Oversight
Board
(United
States).
Those
standards
require
that
weplan
and
perform
the
audit
to
obtain
reasonable
assurance
about
whether
effective
internal
control
over
financial
reporting
was
maintained
in
all
material
respects.Our
audit
included
obtaining
an
understanding
of
internal
control
over
financial
reporting,
assessing
the
risk
that
a
material
weakness
exists,
testing
and
evaluatingthe
design
and
operating
effectiveness
of
internal
control
based
on
the
assessed
risk,
and
performing
such
other
procedures
as
we
considered
necessary
in
thecircumstances.
We
believe
that
our
audit
provides
a
reasonable
basis
for
our
opinion.







A
company's
internal
control
over
financial
reporting
is
a
process
designed
to
provide
reasonable
assurance
regarding
the
reliability
of
financial
reporting
andthe
preparation
of
consolidated
financial
statements
for
external
purposes
in
accordance
with
generally
accepted
accounting
principles.
A
company's
internalcontrol
over
financial
reporting
includes
those
policies
and
procedures
that
(1)
pertain
to
the
maintenance
of
records
that,
in
reasonable
detail,
accurately
and
fairlyreflect
the
transactions
and
dispositions
of
the
assets
of
the
company;
(2)
provide
reasonable
assurance
that
transactions
are
recorded
as
necessary
to
permitpreparation
of
financial
statements
in
accordance
with
generally
accepted
accounting
principles,
and
that
receipts
and
expenditures
of
the
company
are
being
madeonly
in
accordance
with
authorizations
of
management
and
directors
of
the
company;
and
(3)
provide
reasonable
assurance
regarding
prevention
or
timely
detectionof
unauthorized
acquisition,
use,
or
disposition
of
the
company's
assets
that
could
have
a
material
effect
on
the
financial
statements.







Because
of
its
inherent
limitations,
internal
control
over
financial
reporting
may
not
prevent
or
detect
misstatements.
Also,
projections
of
any
evaluation
ofeffectiveness
to
future
periods
are
subject
to
the
risk
that
controls
may
become
inadequate
because
of
changes
in
conditions,
or
that
the
degree
of
compliance
withthe
policies
or
procedures
may
deteriorate.







In
our
opinion,
Radius
Health,
Inc.
maintained,
in
all
material
respects,
effective
internal
control
over
financial
reporting
as
of
December
31,
2015,
based
onthe
COSO
criteria.







We
also
have
audited,
in
accordance
with
the
standards
of
the
Public
Company
Accounting
Oversight
Board
(United
States),
the
consolidated
balance
sheetsof
Radius
Health,
Inc.
as
of
December
31,
2015
and
2014,
and
the
related
consolidated
statements
of
operations
and
comprehensive
loss,
convertible
preferredstock,
redeemable
convertible
preferred
stock
and
stockholders'
equity
(deficit)
and
cash
flows
for
each
of
the
three
years
in
the
period
ended
December
31,
2015
ofRadius
Health,
Inc.
and
our
report
dated
February
25,
2016
expressed
an
unqualified
opinion
thereon.Boston,
Massachusetts
February
25,
2016121
/s/
Ernst
&
Young
LLPTable
of
ContentsITEM
9B.



OTHER
INFORMATION.








None.122Table
of
ContentsPART
III
ITEM
10.



DIRECTORS,
EXECUTIVE
OFFICERS
AND
CORPORATE
GOVERNANCE.








The
following
table
sets
forth
the
name,
age
and
position
of
each
of
our
executive
officers
and
directors:








Robert
E.
Ward
has
served
as
our
President
and
Chief
Executive
Officer
and
as
a
member
of
our
Board
of
Directors
since
December
2013.
Prior
to
joiningRadius,
Mr.
Ward
was
Vice
President
for
Strategy
and
External
Alliances
for
the
New
Opportunities
iMed
of
AstraZeneca,
a
biopharmaceutical
company,
from2011
to
2013.
In
addition,
he
served
as
Co-Chair
of
the
Joint
Development
Committees
in
Astra
Zeneca's
drug
development
partnerships
with
Alcon
and
Galderma.Prior
to
AstraZeneca,
from
2010
to
2011,
Mr.
Ward
was
the
Managing
Director
of
Harriman
Biopartners,
LLC,
a
biopharmaceutical
company,
and
from
2006
to2010
he
was
the
Vice
President
of
Corporate
Development
for
NPS
Pharmaceuticals,
a
pharmaceutical
company.
Mr.
Ward
received
a
B.A.
in
Biology
and
a
B.S.in
Physiological
Psychology,
both
from
the
University
of
California,
Santa
Barbara;
an
M.S.
in
Management
from
the
New
Jersey
Institute
of
Technology;
and
anM.A.
in
Immunology
from
The
Johns
Hopkins
University
School
of
Medicine.
We
believe
Mr.
Ward
is
qualified
to
serve
as
a
member
of
our
Board
of
Directorsbecause
of
his
role
with
us
and
his
extensive
operational
knowledge
of,
and
executive
level
management
experience
in,
the
global
biopharmaceutical
industry.








Lorraine
Fitzpatrick,
M.D.,
has
served
as
our
Chief
Medical
Officer
since
July
2015.
Prior
to
joining
Radius,
Dr.
Fitzpatrick
was
a
Medicine
DevelopmentLeader
and
Group
Director
at
GlaxoSmithKline,
a
pharmaceutical
company,
from
August
2006
to
July
2015.
Prior
to
GlaxoSmithKline,
she
was
an
ExecutiveDirector
at
Amgen
Inc.,
a
biopharmaceutical
company,
focusing123Name



PositionRobert
E.
Ward
58
President,
Chief
Executive
Officer
and
DirectorLorraine
Fitzpatrick,
M.D.

61
Chief
Medical
OfficerB.
Nicholas
Harvey
55
Senior
Vice
President,
Chief
Financial
Officer,
Treasurerand
SecretaryGary
Hattersley,
Ph.D.

49
Senior
Vice
President,
Chief
Scientific
OfficerBrent
Hatzis-Schoch.

51
Senior
Vice
President,
General
CounselDinesh
Purandare
52
Senior
Vice
President,
Head
of
Global
OncologyDavid
Snow
54
Chief
Commercial
OfficerGregory
Williams,
Ph.D.

56
Chief
Development
OfficerAlan
H.
Auerbach(3)(4)
46
DirectorWillard
H.
Dere,
M.D(1)(2).

62
DirectorCatherine
Friedman(1)(3)
55
DirectorAnsbert
K.
Gadicke,
M.D.(2)(3)
57
DirectorJean-Pierre
Garnier(3)
68
DirectorKurt
C.
Graves(2)(3)(4)
48
Chairman
of
the
BoardOwen
Hughes(1)
41
DirectorAnthony
Rosenberg(4)
62
DirectorDebasish
Roychowdhury(2)
54
Director(1)Member
of
the
audit
committee.
(2)Member
of
the
nominating
and
corporate
governance
committee.
(3)Member
of
the
compensation
committee.
(4)Member
of
the
strategy
committee.Table
of
Contentson
osteoporosis
and
oncology
from
2004
to
2006.
She
has
served
as
Chair
of
the
General
Clinical
Research
Center
study
section
of
the
National
Center
forResearch
Resources,
National
Institute
of
Health,
or
NIH;
on
the
Advocacy
Committee
of
the
American
Society
of
Bone
and
Mineral
Research,
or
ASBMR;
and
asChair
of
the
Public
Communications
Committee
and
the
Media
Relations
Steering
Committee
of
The
Endocrine
Society,
TES.
She
has
also
been
a
member
of
thePublications
Committee
of
the
ASBMR
and
TES
and
on
the
Advisory
Committee
for
the
Office
of
Research
on
Women's
Health
at
the
NIH.
Dr.
Fitzpatrick
hasserved
on
the
National
Committee
for
Quality
Assurance
Technical
Subgroup
on
Osteoporosis,
the
Clinical
Guidelines
Committee
of
TES,
the
Scientific
ProgramCommittees
of
North
American
Menopause
Society
and
the
ASBMR,
and
as
Associate
Editor
for
The
Mayo
Clinic
Proceedings
and
the
American
MedicalAssociation
Scientific
Advisory
Board:
Osteoporosis
Guidelines.
Dr.
Fitzpatrick
received
a
B.S.
in
Molecular
Biology
from
Wellesley
College
and
received
hermedical
degree
from
the
Pritzker
School
of
Medicine
at
the
University
of
Chicago.








B.
Nicholas
Harvey
has
served
as
our
Senior
Vice
President,
Chief
Financial
Officer,
Treasurer
and
Secretary
since
November
2010,
and
served
as
a
memberof
our
Board
of
Directors
from
November
2010
until
the
consummation
of
the
merger
of
our
predecessor
company
with
us
in
May
2011,
or
the
Merger.
Prior
tothat,
Mr.
Harvey
served
as
the
Chief
Financial
Officer
and
Senior
Vice
President
of
our
predecessor
company
from
December
2006
until
the
Merger.
Mr.
Harveyreceived
a
Bachelor
of
Economics
degree
and
a
Bachelor
of
Laws
degree
with
first-class
honors
from
the
Australian
National
University
and
an
M.B.A.
from
theHarvard
Business
School.








Gary
Hattersley,
Ph.D.,
served
as
Chief
Scientific
Officer
since
January
2014.
Prior
to
his
current
role,
Dr.
Hattersly
served
as
our
Senior
Vice
President
ofPreclinical
Development
from
December
2011
to
December
2013,
and
President
of
Biology
from
May
2011
to
December
2011.
From
2003
until
the
Merger,Dr.
Hattersly
served
in
various
roles
in
our
predecessor
company,
including
as
Vice
President
of
Biology,
Senior
Director
of
Research
and
Director
of
DiseaseBiology
&
Pharmacology.
Dr.
Hattersley
received
a
Ph.D.
in
Experimental
Pathology
from
St.
George's
Hospital
Medical
School.








Brent
Hatzis-Schoch
has
served
as
our
Senior
Vice
President,
General
Counsel,
since
April
2015.
Prior
to
joining
Radius,
from
July
2013
to
April
2015.Mr.
Hatzis-Schoch
was
Senior
Vice
President
and
Chief
Legal
Counsel
of
Merz
Pharma
in
Frankfurt,
Germany.
Prior
to
Merz,
Mr.
Hatzis-Schoch
served
for
fiveyears
as
General
Counsel
to
Agennix
AG,
a
publicly-traded
development
stage
biopharmaceutical
company.
He
has
held
senior
legal
positions
in
the
U.S.
andinternationally,
including
as
European
legal
counsel
for
Baxter
International,
Associate
General
Counsel
of
Pharmacia
Corporation,
and
General
Counsel
of
GPCBiotech
AG.
Mr.
Hatzis-Schoch
holds
a
J.D.
from
George
Washington
University
and
a
B.A.
from
the
University
of
Delaware.








Dinesh
Purandare
has
served
as
our
Senior
Vice
President,
Head
of
Global
Oncology
since
March
2015.
Prior
to
joining
Radius,
Mr.
Purandare
spent
fiveyears
at
Sanofi
Oncology,
a
pharmaceutical
company.
He
held
the
role
of
Vice
President
and
Head
of
Marketing
from
March
2010
to
September
2012,
and
VicePresident
and
Project
Head,
from
October
2012
to
March
2015.
He
also
co-chaired
the
Joint
Development
Committee
(Oncology)
of
Sanofi
and
RegeneronPharmaceuticals
and
was
a
member
of
the
Oncology
Management
Team
at
Sanofi.
Prior
to
Sanofi,
he
served
as
Vice
President
and
Head
of
Oncology
Center
ofExcellence
at
GlaxoSmithKline
headquarters
in
the
UK
and
held
other
senior
positions
at
Pharmacia
/Pfizer
and
Farmitalia
Carlo
Erba
(Milan,
Italy).
Mr.
Purandarereceived
degrees
in
Business
Management
and
Organic
Chemistry
from
the
University
of
Bombay.
He
also
received
a
Diploma
in
Advanced
MarketingManagement
from
the
Chartered
Institute
of
Marketing,
U.K.








David
Snow
has
served
as
our
Chief
Commercial
Officer
since
September
2015.
Prior
to
joining
Radius,
Mr.
Snow
was
President
of
the
biopharmaceuticalcompany,
AstraZeneca's
China
business
from
January
2012
to
December
2014.
He
was
also
the
first
global
commercialization
Vice
President
for124Table
of
ContentsAstraZeneca's
prescription
medication
Brilinta
and
head
of
U.S.
Commercial
Operations
from
March
2010
to
December
2011.
Before
joining
AstraZeneca,Mr.
Snow
held
numerous
global
and
US
commercial
leadership
roles
for
Bristol-Myers
Squibb,
Searle
and
Hoechst-Roussel.
He
served
on
the
Research
andDevelopment
based
Pharmaceutical
Association
Committee
industry
association
board
in
China
for
several
years.
Mr.
Snow
received
his
B.S.
in
BusinessAdministration
from
Auburn
University,
and
an
M.B.A
from
New
York
University—Leonard
N.
Stern
School
of
Business.








Gregory
Williams,
Ph.D.,
has
served
as
our
Chief
Development
Officer
since
January
2014.
Prior
to
joining
Radius,
Dr.
Williams
was
Vice
President
ofRegulatory
Affairs,
Global
Product
and
Clinical
Development,
and
Program
Management
with
The
Medicines
Company,
a
biopharmaceutical
company,
from
2006to
2013.
He
was
Vice
President
of
Regulatory
Affairs,
Regulatory
Compliance
and
Program
Management
for
NPS
Pharmaceuticals,
a
pharmaceutical
company,from
2004
to
2006.
Dr.
Williams
has
a
Ph.D.
in
Biopharmaceutics
from
Rutgers
University
and
an
M.B.A.
from
Cornell
University.








Alan
H.
Auerbach
has
served
on
our
Board
of
Directors
since
May
2011
and
served
as
a
member
of
the
Board
of
Directors
our
predecessor
company
fromOctober
2010
until
the
Merger.
Mr.
Auerbach
is
currently
the
Founder,
Chief
Executive
Officer,
President
and
Chairman
of
the
Board
of
Puma
Biotechnology,
Inc.,a
company
dedicated
to
in-licensing
and
developing
drugs
for
the
treatment
of
cancer
and
founded
in
2010.
Previously,
Mr.
Auerbach
founded
CougarBiotechnology,
or
Cougar,
in
May
2003
and
served
as
the
company's
Chief
Executive
Officer,
President
and
as
a
member
of
its
Board
of
Directors
until
July
2009.From
July
2009
until
January
2010,
Mr.
Auerbach
served
as
the
Co-Chairman
of
the
Integration
Steering
Committee
at
Cougar
after
its
acquisition
by
Johnson
&Johnson.
Mr.
Auerbach
received
a
B.S.
in
Biomedical
Engineering
from
Boston
University
and
an
M.S.
in
Biomedical
Engineering
from
the
University
of
SouthernCalifornia.
We
believe
Mr.
Auerbach
is
qualified
to
serve
as
a
member
of
our
Board
of
Directors
because
of
his
business
and
professional
experience,
including
hisleadership
of
Cougar
in
drug
development,
private
and
public
financings
and
a
successful
sale
of
the
business.







Willard
H.
Dere,
M.D.




has
served
on
our
Board
of
Directors
since
November
2014.
Dr.
Dere
has
been
Executive
Director
of
Personalized
Health
at
theUniversity
of
Utah
Health
Sciences
Center,
and
a
Professor
of
Medicine
in
the
School
of
Medicine
since
November
2014.
Prior
to
that,
he
served
at
Amgen
Inc.,
abiopharmaceutical
company,
as
the
Senior
Vice
President,
Global
Development
from
December
2004
to
June
2007,
and
from
April
2014
to
October
2014,
and
asInternational
Chief
Medical
Officer
from
January
2007
to
April
2014.
Before
he
joined
Amgen
in
2003,
Dr.
Dere
served
as
Vice
President
of
Endocrine,
Bone
andGeneral
Medicine
Research
and
Development
at
Eli
Lilly
and
Company,
a
biopharmaceutical
company,
where
he
also
held
various
other
roles
in
clinicalpharmacology,
regulatory
affairs,
and
both
early-stage
translational,
and
late-stage
clinical
research.
Dr.
Dere
received
B.A.
degrees
in
history
and
zoology
and
aM.D.
degree
from
the
University
of
California,
Davis.
We
believe
Mr.
Dere
is
qualified
to
serve
as
a
member
of
our
Board
of
Directors
because
of
his
strongmedical
background
and
extensive
experience
in
the
pharmaceutical
industry.








Jean-Pierre
Garnier
has
served
on
our
Board
of
Directors
since
December
2015.
Mr.
Garnier
is
currently
Chairman
of
the
Board
of
Actelion
Ltd.,
and
waspreviously
Chief
Executive
Officer
of
GlaxoSmithKline
plc
from
2000
to
2008.
In
addition,
Mr.
Garnier
is
also
a
member
of
the
Board
of
Directors
of
UnitedTechnologies
Corporation
and
of
Renault
S.A.,
and
an
Operating
Partner
at
Advent
International,
a
global
private
equity
firm.
Mr.
Garnier
previously
served
asChief
Executive
Officer
of
Pierre
Fabre
S.A.
from
2008
to
2010,
as
Chief
Executive
Officer
and
Executive
Member
of
the
Board
of
Directors
ofGlaxoSmithKline
plc
from
2000
to
2008
and
as
Chief
Executive
Officer
of
SmithKline
Beecham
plc
in
2000
and
as
Chief
Operating
Officer
and
ExecutiveMember
of
the
Board
of
Directors
of
SmithKline
Beecham
plc
from
1996
to
2000.
Mr.
Garnier
was
previously
Chairman
of
Cerenis
from
2010
to
2011,
and
aboard
member
of
the
Stanford
Advisory
Council
on
Interdisciplinary
Biosciences,
Weill
Cornell
Medical
College
and
the
Dubai
International
Capital
AdvisoryBoard.
He
is
also
a
member
of
the
Advisory
Board
of
the
Newman's
Own
Foundation.
We
believe
Dr.
Garnier
is125Table
of
Contentsqualified
to
serve
as
a
member
of
our
Board
of
Directors
because
of
his
significant
business
and
professional
experience,
including
his
extensive
experience
in
thelife
sciences
industry,
membership
on
various
boards
of
directors
and
his
previous
leadership
and
management
roles.








Catherine
Friedman
has
served
on
our
Board
of
Directors
since
August
2015.
Previously,
Ms.
Friedman
held
the
position
of
Managing
Director
at
MorganStanley
from
1997
to
2006
and
head
of
West
Coast
Healthcare
and
co-head
of
the
Biotechnology
Practice
at
Morgan
Stanley
from
1993
to
2006.
Since
2007,Ms.
Friedman
has
been
a
director
of
XenoPort
Inc.,
where
she
serves
on
the
Audit
and
Nominating
and
Governance
Committees,
and
Enteromedics,
where
sheserves
as
Chair
of
the
Audit
Committee;
in
June
2014,
she
joined
the
Board
of
Innoviva
(formerly
known
as
Theravance),
where
she
serves
on
the
Audit
andCompensation
Committees;
and
in
May
2013
she
joined
the
Board
of
GSV
Capital,
a
publicly
traded
investment
fund,
where
she
serves
as
Chair
of
the
AuditCommittee
and
on
the
Valuation
Committee.
Ms.
Friedman
is
a
member
of
the
Board
of
Trustees
for
Sacred
Heart
Schools
in
Atherton.
She
is
a
graduate
ofHarvard
University
and
received
an
MBA
from
the
University
of
Virginia
Darden
School
of
Business,
where
she
is
currently
a
Darden
School
Foundation
Board
ofTrustees
member.
We
believe
Ms.
Friedman
is
qualified
to
serve
as
a
member
of
our
Board
of
Directors
due
to
her
extensive
experience
as
a
member
on
variousboards
of
directors,
her
educational
background
and
her
previous
leadership
and
management
roles.







Ansbert
K.
Gadicke,
M.D.




has
served
on
our
Board
of
Directors
since
May
2011
and
served
as
a
member
of
the
board
of
directors
of
our
predecessorcompany
from
November
2003
until
the
Merger.
Dr.
Gadicke
has
been
the
Co-Founder
and
Managing
Director
of
MPM
Capital,
a
venture
capital
firm,
sinceAugust
1996.
Dr.
Gadicke
received
an
M.D.
from
J.W.
Goethe
University
in
Frankfurt.
Dr.
Gadicke
is
a
director
of
Chiasma,
Inc.,
OSS
Healthcare,
Inc.,
SiderisPharmaceuticals,
Inc.,
RWHD,
Inc.
and
Mitokyne,
Inc.
He
served
on
the
board
of
directors
of
Idenix
Pharmaceuticals,
Inc.
from
1998
to
2005,
BioMarinPharmaceuticals,
Inc.
from
1997
to
2001,
Verastem,
Inc.
from
2010
to
2012,
Pharmasset,
Inc.
from
1999
to
2007
and
PharmAthene,
Inc.
from
2004
to
2007.
Webelieve
Dr.
Gadicke
is
qualified
to
serve
as
a
member
of
our
Board
of
Directors
because
of
his
business
and
professional
experience,
including
his
experience
in
theventure
capital
industry
and
his
years
of
analyzing
development
opportunities
in
the
life
sciences
sector.








Kurt
C.
Graves
has
served
on
our
Board
of
Directors
since
May
2011
and
as
Chairman
of
our
Board
of
Directors
since
November
2011.
Mr.
Graves
hasbeen
the
Chairman,
President
and
Chief
Executive
Officer
of
Intarcia
Therapeutics,
a
biotechnology
company,
since
April
2012.
Mr.
Graves
served
as
ExecutiveChairman
of
Biolex
Therapeutics,
a
biotechnology
company,
from
November
2010
to
March
2012,
and
served
as
Executive
Chairman
of
Intarcia
Therapeuticsfrom
August
2010
to
April
2012.
Previously,
he
served
as
Executive
Vice
President,
Chief
Commercial
Officer
and
Head
of
Strategic
Development
at
VertexPharmaceuticals
Inc.
from
July
2007
to
October
2009.
Prior
to
joining
Vertex,
Mr.
Graves
held
various
leadership
positions
at
Novartis
pharmaceuticals
from
1999to
June
2007.
He
was
also
the
first
Chief
Marketing
Officer
for
the
Pharmaceuticals
division
from
September
2003
to
June
2007.
He
currently
serves
as
a
directorof
Intarcia
Therapeutics,
Pulmatrix
Therapeutics
and
Achillion
Pharmaceuticals.
He
served
on
the
board
of
directors
of
Biolex
Therapeutics
and
SpringleafTherapeutics
from
2010
to
2012.
Mr.
Graves
received
a
B.S.
in
Biology
from
Hillsdale
College.
We
believe
Mr.
Graves
is
qualified
to
serve
as
a
member
of
ourBoard
of
Directors
because
of
his
extensive
experience
in
the
life
sciences
industry,
membership
on
various
boards
of
directors
and
his
leadership
and
managementexperience.








Owen
Hughes
has
served
on
our
Board
of
Directors
since
April
2013.
He
has
served
as
the
Chief
Business
Officer
and
Head
of
Corporate
Development
atIntarcia
Therapeutics,
Inc.,
a
biotechnology
company,
since
February
2013.
Prior
to
Intarcia,
he
served
as
a
Director
at
Brookside
Capital,
a
hedge
fund
under
theBain
Capital
umbrella,
managing
public
and
private
healthcare
investments
from
March
2008
to
January
2013.
Mr.
Hughes
has
served
as
a
Senior
PortfolioManager
at
Pyramis
Global
Advisors
from
2006
to
2008,
co-founder
and
partner
at
Triathlon
Fund
Management
from
2003
to
2006,126Table
of
Contentsan
Investment
Associate
at
Ziff
Brothers
Investments
from
2001
to
2003,
and
an
Assistant
Vice
President
at
Morgan
Stanley/Merrill
Lynch
from
1998
to
2001.Mr.
Hughes
is
a
director
of
Malin
PLC.
He
earned
a
bachelor
of
arts
from
Dartmouth
College.
We
believe
Mr.
Hughes
is
qualified
to
serve
as
a
member
of
ourBoard
of
Directors
because
of
his
extensive
business
and
professional
experience,
including
his
experience
in
the
venture
capital
industry
and
years
of
analyzingdevelopment
opportunities
in
the
life
sciences
sector.








Anthony
Rosenberg
has
served
on
our
Board
of
Directors
since
March
2015.
From
January
2013
to
February
2015,
Mr.
Rosenberg
served
as
Corporate
Headof
M&A
and
Licensing
at
Novartis
International,
a
pharmaceutical
company.
From
March
2005
to
December
2012,
he
served
as
Global
Head
of
BusinessDevelopment
and
Licensing
at
Novartis
Pharmaceuticals.
Prior
to
that,
Mr.
Rosenberg
was
Global
Head
of
the
Transplant
and
Immunology
Business
Unit
atNovartis
Pharmaceuticals
from
2000
to
2005.
Mr.
Rosenberg
initially
joined
Sandoz,
a
predecessor
to
Novartis,
in
1980.
Mr.
Rosenberg
served
as
a
director
ofIdenix
Pharmaceuticals,
Inc.
from
June
2009
to
March
2012
and
from
December
2012
to
March
2013.
Mr.
Rosenberg
holds
a
B.Sc
from
the
University
of
Leicesterand
an
M.Sc
in
physiology
from
the
University
of
London.
We
believe
Mr.
Rosenberg
is
qualified
to
serve
as
a
member
of
our
Board
of
Directors
due
to
hisextensive
experience
in
mergers
and
acquisitions
and
licensing
in
the
pharmaceutical
sector.








Debasish
Roychowdhury
has
served
on
our
Board
of
Directors
since
July
2015.
Dr.
Roychowdhury
has
been
President
of
Nirvan
Consultants,
LLC
sinceDecember
2013,
where
he
advises
biotechnology
companies
and
institutions.
He
was
one
of
the
founding
members
of
Seragon
Pharmaceutical's
Clinical
andScientific
Advisory
Board
and
was
Seragon's
Chief
Medical
Officer,
prior
to
its
acquisition
by
Roche
Pharma,
from
March
2014
to
August
2014.
Prior
to
Seragon,Dr.
Roychowdhury
was
the
Senior
Vice
President
and
Head
of
the
Global
Oncology
Division
at
Sanofi
from
August
2009
to
November
2013.
Prior
to
that,
heserved
as
the
Vice
President
for
Clinical
Development
at
GlaxoSmithKline,
from
2005
to
2009,
and
directed
the
Oncology
Global
Regulatory
group
at
Eli
Lilly
andCompany,
a
pharmaceutical
company,
from
1999
to
2005.
Prior
to
his
role
in
industry,
Dr.
Roychowdhury
served
as
faculty
member
at
the
University
ofCincinnati.
He
received
his
M.D
from
the
All
India
Institute
of
Medical
Sciences.
He
is
a
member
of
the
Board
of
Directors
for
Celvad
S.A.
and
Lytix
BiopharmaAS.
We
believe
Dr.
Roychowdury
is
qualified
to
serve
as
a
member
of
our
Board
of
Directors
because
of
his
strong
medical
background,
specifically
related
tooncology,
and
extensive
experience
in
the
pharmaceutical
industry.Code
of
Business
Conduct
and
Ethics







We
have
adopted
a
code
of
business
conduct
and
ethics
that
applies
to
all
of
our
employees,
officers
and
directors,
including
those
officers
responsible
forfinancial
reporting.
The
code
of
business
conduct
and
ethics
is
available
on
our
website
at
www.radiuspharm.com.
Any
amendments
to
the
code,
or
any
waivers
ofits
requirements,
will
be
disclosed
on
our
website.
Information
contained
on
or
accessible
through
our
website
is
not
incorporated
by
reference
into
this
report,
andyou
should
not
consider
information
contained
on
or
accessible
through
our
website
to
be
part
of
this
report.







The
remainder
of
the
response
to
this
item
is
contained
in
our
definitive
Proxy
Statement
for
our
2016
Annual
Meeting
of
Stockholders
and
is
incorporatedherein
by
reference.ITEM
11.



EXECUTIVE
COMPENSATION.








The
information
required
to
be
disclosed
by
this
item
is
contained
in
our
definitive
Proxy
Statement
for
our
2016
Annual
Meeting
of
Stockholders
and
isincorporated
herein
by
reference.127Table
of
ContentsITEM
12.



SECURITY
OWNERSHIP
OF
CERTAIN
BENEFICIAL
OWNERS
AND
MANAGEMENT
AND
RELATED
STOCKHOLDER
MATTERS.







The
information
required
to
be
disclosed
by
this
item
is
contained
in
our
definitive
Proxy
Statement
for
our
2016
Annual
Meeting
of
Stockholders
and
isincorporated
herein
by
reference.ITEM
13.



CERTAIN
RELATIONSHIPS
AND
RELATED
TRANSACTIONS,
AND
DIRECTOR
INDEPENDENCE.








The
information
required
to
be
disclosed
by
this
item
is
contained
in
our
definitive
Proxy
Statement
for
our
2016
Annual
Meeting
of
Stockholders
and
isincorporated
herein
by
reference.ITEM
14.



PRINCIPAL
ACCOUNTANT
FEES
AND
SERVICES.








The
information
required
to
be
disclosed
by
this
item
is
contained
in
our
definitive
Proxy
Statement
for
our
2016
Annual
Meeting
of
Stockholders
and
isincorporated
herein
by
reference.128Table
of
ContentsPART
IV
ITEM
15.



EXHIBITS
AND
FINANCIAL
STATEMENT
SCHEDULES.
(a)Financial
Statements







The
following
consolidated
financial
statements
and
supplementary
data
are
included
in
Part
II
of
Item
8
filed
of
this
Annual
Report
on
Form
10-K:(b)Financial
Statement
Schedules







All
financial
statement
schedules
have
been
omitted
because
they
are
not
applicable
or
are
not
required,
or
because
the
information
required
to
be
set
forththerein
is
included
in
the
consolidated
financial
statements
or
notes
thereto.(c)Exhibits







The
Exhibit
Index
follows
the
signature
pages
hereof
and
is
incorporated
herein
by
reference.129Report
of
Independent
Registered
Public
Accounting
Firm

90
Consolidated
Balance
Sheets
as
of
December
31,
2015
and
2014

91
Consolidated
Statements
of
Operations
and
Comprehensive
Loss
for
the
years
ended
December
31,
2015,
2014
and
2013

92
Consolidated
Statements
of
Convertible
Preferred
Stock,
Redeemable
Convertible
Preferred
Stock
and
Stockholders'Equity
(Deficit)
for
the
years
ended
December
31,
2015,
2014
and
2013

93
Consolidated
Statements
of
Cash
Flows
for
the
years
ended
December
31,
2015,
2014
and
2013

95
Notes
to
Consolidated
Financial
Statements

96
Table
of
ContentsSIGNATURES








Pursuant
to
the
requirements
of
Section
13
or
15(d)
of
the
Securities
Exchange
Act
of
1934,
the
registrant
has
duly
caused
this
annual
report
to
be
signed
on
itsbehalf
by
the
undersigned,
thereunto
duly
authorized.Date:
February
25,
2016







Pursuant
to
the
requirements
of
the
Securities
Exchange
Act
of
1934,
this
report
has
been
signed
by
the
following
persons
on
behalf
of
the
registrant
and
in
thecapacities
and
on
the
dates
indicated.130

RADIUS
HEALTH,
INC.

By:
/s/
ROBERT
E.
WARD
Robert
E.
Ward
President and Chief Executive OfficerSignature
Title
Date




/s/
ROBERT
E.
WARD
Robert
E.
Ward
Chief
Executive
Officer
and
Director
(PrincipalExecutive
Officer)
February
25,
2016/s/
B.
NICHOLAS
HARVEY
B.
Nicholas
Harvey
Chief
Financial
Officer
(Principal
Accountingand
Financial
Officer)
February
25,
2016/s/
ALAN
H.
AUERBACH
Alan
H.
Auerbach
Director
February
25,
2016/s/
WILLARD
H.
DERE
Willard
H.
Dere
Director
February
25,
2016/s/
CATHERINE
FRIEDMAN
Catherine
Friedman
Director
February
25,
2016/s/
ANSBERT
K.
GADICKE
Ansbert
K.
Gadicke
Director
February
25,
2016/s/
JEAN-PIERRE
GARNIER
Jean-Pierre
Garnier
Director
February
25,
2016Table
of
Contents131Signature
Title
Date




/s/
KURT
C.
GRAVES
Kurt
C.
Graves
Director
February
25,
2016/s/
OWEN
HUGHES
Owen
Hughes
Director
February
25,
2016/s/
ANTHONY
ROSENBERG
Anthony
Rosenberg
Director
February
25,
2016/s/
DEBASISH
ROYCHOWDHURY
Debasish
Roychowdhury
Director
February
25,
2016Table
of
ContentsEXHIBIT
INDEX
132Exhibit
Number
Exhibit
Description
Form
File
No.
Exhibit
Filing
Date
Filed/
Furnished
Herewith
3.1
Restated
Certificate
of
Incorporation,
filed
on
June
11,2014
8-K
001-35726
3.1
6/13/14


3.2
Amended
and
Restated
By-Laws
8-K
001-35726
3.2
6/13/14


4.1
Fifth
Amended
and
Restated
Stockholders'
Agreement,dated
April
24,
2014,
by
and
among
the
Company
andthe
stockholders
party
thereto
S-1/A
333-194150
4.2
4/25/14


10.1
Form
of
Warrant
to
Purchase
Shares
of
Common
Stockin
connection
with
the
Series
B
Convertible
PreferredStock
and
Warrant
Purchase
Agreement,
issued
by
theCompany
to
certain
investors
and
attached
schedule
withdetails
8-K
001-35726
10.2
4/25/13


10.2
Form
of
Warrant
to
Purchase
Shares
of
Common
Stockin
connection
with
the
Series
B-2
Convertible
PreferredStock
and
Warrant
Purchase
Agreement,
issued
by
theCompany
to
certain
investors
and
attached
schedule
withdetails
8-K
001-35726
10.2
2/21/14


10.3
Form
of
Warrant
to
Purchase
Shares
of
Series
A-1Convertible
Preferred
Stock
issued
by
the
Company
toGE
Capital
Equity
Investments
10-K
001-35726
10.5
3/10/15


10.4^Clinical
Trial
Services
Agreement,
dated
March
29,2011,
by
and
between
the
Company,
as
successor
toRadius
Health,
Inc.,
and
Nordic
BioScience
ClinicalDevelopment
VII
A/S
8-K/A
000-53173
10.1
10/24/11

Table
of
Contents133Exhibit
Number
Exhibit
Description
Form
File
No.
Exhibit
Filing
Date
Filed/
Furnished
Herewith
10.5^Work
Statement
NB-1,
dated
March
29,
2011,
by
andbetween
the
Company
and
Nordic
Bioscience
ClinicalDevelopment
VII
A/S,
as
amended
on
December
9,2011,
June
18,
2012,
November
6,
2013,
March
28,2014,
May
19,
2014
and
July
22,
2014
10-K
001-35726
10.11
3/10/15


10.5(a)Amendment
No.
8
to
Work
Statement
NB-1,
effective
asof
August
15,
2014,
by
and
between
the
Company
andNordic
Bioscience
Clinical
Development
VII
A/S








*
10.5(b)Amendment
No.
9
to
Work
Statement
NB-1,
effective
asof
March
12,
2015,
by
and
between
the
Company
andNordic
Bioscience
Clinical
Development
VII
A/S
10-Q
001-35726
10.4
5/6/15


10.6^Work
Statement
NB-2,
dated
February
21,
2013,
by
andbetween
the
Company
and
Nordic
Bioscience
ClinicalDevelopment
VII
A/S,
as
amended
on
November
6,2013
10-K
001-35726
10.12
3/10/15


10.7^Work
Statement
NB-3,
dated
February
21,
2013,
by
andbetween
the
Company
and
Nordic
Bioscience
ClinicalDevelopment
VII
A/S,
as
amended
on
February
28,
2014
10-K
001-35726
10.13
3/10/15


10.7(a)Amendment
No.
2
to
Work
Statement
NB-3,
effective
asof
March
23,
2015,
by
and
between
the
Company
andNordic
Bioscience
Clinical
Development
VII
A/S
10-Q
001-35726
10.5
5/6/15


10.7(b)Amendment
No.
3
to
Work
Statement
NB-1,
effective
asof
July
8,
2015,
by
and
between
the
Company
andNordic
Bioscience
Clinical
Development
VII
A/S
10-Q
001-35726
10.8
8/6/15

Table
of
Contents134Exhibit
Number
Exhibit
Description
Form
File
No.
Exhibit
Filing
Date
Filed/
Furnished
Herewith
10.7(c)Amendment
No.
4
to
Work
Statement
NB-3,
effective
asof
October
21,
2015,
by
and
between
the
Company
andNordic
Bioscience
Clinical
Development
VII
A/S








*
10.7(d)Amendment
No.
5
to
Work
Statement
NB-3,
effective
asof
January
15,
2016,
by
and
between
the
Company
andNordic
Bioscience
Clinical
Development
VII
A/S








*
10.8
Amended
and
Restated
Stock
Issuance
Agreement,
datedMay
16,
2011,
by
and
between
the
Company,
assuccessor
to
Radius
Health,
Inc.,
and
Nordic
BioScienceClinical
Development
VII
A/S,
as
amended
onFebruary
21,
2013,
March
28,
2014
and
May
19,
2014
10-K
001-35726
10.14
3/10/15


10.9^License
Agreement,
dated
September
27,
2005,
by
andbetween
the
Company,
as
successor
to
Nuvios,
Inc.,
andIpsen
Pharma
SAS
(f/k/a
SCRAS
S.A.S.)
on
behalf
ofitself
and
its
affiliates,
as
amended
on
September
12,2007
and
May
11,
2011
10-K
001-35726
10.15
3/10/15


10.10^Pharmaceutical
Development
Agreement,
datedJanuary
2,
2006,
by
and
between
the
Company,
assuccessor
to
Radius
Health,
Inc.,
and
Beaufour
IpsenIndustrie
SAS,
as
amended
on
January
1,
2007,January
1,
2009,
June
16,
2010
and
December
15,
2011
10-K
001-35726
10.16
3/10/15


10.10(a)Amendment
No.
6,
dated
August
14,
2015,
to
thePharmaceutical
Development
Agreement,
datedJanuary
2,
2006,
by
and
between
the
Company
andBeaufour
Ipsen
Industrie
SAS,
as
amended
10-Q
001-35726
10.4
11/5/15

Table
of
Contents135Exhibit
Number
Exhibit
Description
Form
File
No.
Exhibit
Filing
Date
Filed/
Furnished
Herewith
10.11^Development
and
Manufacturing
Services
Agreement,dated
October
16,
2007,
by
and
between
the
Company,as
successor
to
Radius
Health,
Inc.,
and
LONZASales
Ltd.,
as
amended
on
May
19,
2011
and
January
30,2014,
and
Work
Orders
thereunder
through
March
9,2014
10-K
001-35726
10.17
3/10/15


10.11(a)Amendment
No.
3
to
Development
and
ManufacturingServices
Agreement,
dated
December
31,
2015,
by
andbetween
the
Company
and
LONZA
Sales
Ltd.








*
10.11(b)Work
Order
#7,
dated
February
24,
2015,
to
theDevelopment
and
Manufacturing
Agreement,
datedOctober
16,
2007,
by
and
between
the
Company,
assuccessor
to
Radius
Health,
Inc.,
and
LONZA
Sales
Ltd.
10-Q
001-35726
10.7
5/6/15


10.11(c)^Work
Order
#8,
dated
March
27,
2015,
to
theDevelopment
and
Manufacturing
Services
Agreement,dated
October
16,
2007,
by
and
between
the
Company,as
successor
to
Radius
Health,
Inc.,
and
LONZASales
Ltd.,
as
amended
10-Q
001-35726
10.4
8/6/15


10.11(d)^Work
Order
#9,
dated
May
7,
2015,
to
the
Developmentand
Manufacturing
Services
Agreement,
datedOctober
16,
2007,
by
and
between
the
Company,
assuccessor
to
Radius
Health,
Inc.,
and
LONZA
Sales
Ltd.,as
amended
10-Q
001-35726
10.5
8/6/15


10.11(e)^Work
Order
#10,
dated
May
22,
2015,
to
theDevelopment
and
Manufacturing
Services
Agreement,dated
October
16,
2007,
by
and
between
the
Company,as
successor
to
Radius
Health,
Inc.,
and
LONZASales
Ltd.,
as
amended
10-Q
001-35726
10.6
8/6/15

Table
of
Contents136Exhibit
Number
Exhibit
Description
Form
File
No.
Exhibit
Filing
Date
Filed/
Furnished
Herewith
10.11(f)^Work
Order
No.
11,
dated
August
11,
2015,
to
theDevelopment
and
Manufacturing
Services
Agreement,dated
October
16,
2007,
by
and
between
the
Companyand
LONZA
Sales
Ltd.,
as
amended
10-Q
001-35726
10.2
11/5/15


10.11(g)^Work
Order
No.
12,
dated
August
24,
2015,
to
theDevelopment
and
Manufacturing
Services
Agreement,dated
October
16,
2007,
by
and
between
the
Companyand
LONZA
Sales
Ltd.,
as
amended
10-Q
001-35726
10.3
11/5/15


10.11(h)^Work
Order
No.13,
dated
September
28,
2015,
to
theDevelopment
and
Manufacturing
Services
Agreement,dated
October
16,
2007,
by
and
between
the
Companyand
LONZA
Sales
Ltd.,
as
amended
10-Q
001-35726
10.7
11/5/15


10.12^Development
and
Clinical
Supplies
Agreement,
datedJune
19,
2009,
by
and
among
the
Company,
as
successorto
Radius
Health,
Inc.,
and
3M
Co.
and
3M
InnovativeProperties
Co.,
as
amended
on
December
31,
2009,September
16,
2010,
September
29,
2010,
March
2,2011
and
November
30,
2012
and
Change
Order
Formsthereunder
through
March
9,
2014
10-K
001-35726
10.18
3/10/15


10.12(a)Change
Order
Form
#22,
dated
March
2,
2015,
to
theDevelopment
and
Clinical
Supplies
Agreement,
datedJune
19,
2009,
by
and
among
the
Company
and
3M
Co.and
3M
Innovative
Properties
Co.,
as
amended
10-Q
001-35726
10.6
5/6/15

Table
of
Contents137Exhibit
Number
Exhibit
Description
Form
File
No.
Exhibit
Filing
Date
Filed/
Furnished
Herewith
10.12(b)^Change
Order
Form
#23,
dated
August
26,
2015,
to
FifthAmendment
to
Development
and
Clinical
SuppliesAgreement,
effective
as
of
November
30,
2012,
by
andamong
the
Company
and
3M
Co.
and
3M
InnovativeProperties
Co.
10-Q
001-35726
10.5
11/5/15


10.12(b)^Change
Order
Form
#26,
dated
May
13,
2015,
to
FifthAmendment
to
Development
and
Clinical
SuppliesAgreement,
effective
as
of
November
30,
2012,
by
andamong
the
Company
and
3M
Co.
and
3M
InnovativeProperties
Co.
10-Q
001-35726
10.3
8/6/15


10.13^License
Agreement,
dated
June
29,
2006,
by
andbetween
the
Company
and
Eisai
Co.,
Ltd.
8-K/A
000-53173
10.25
10/24/11


10.13(a)^License
Agreement
Amendment
No.
1,
dated
March
9,2015,
by
and
between
the
Company
and
Eisai
Co.
Ltd.
10-Q
001-35726
10.3
5/6/15


10.14†Radius
Health,
Inc.
2003
Long-Term
Incentive
Plan
(asamended)
10-K
001-35726
10.20
3/10/15


10.15†Radius
Health,
Inc.
2003
Long-Term
Incentive
PlanForm
of
Stock
Option
Agreement
8-K
000-53173
10.32
5/23/11


10.16†Radius
Health,
Inc.
2011
Equity
Incentive
Plan
(asamended
and
restated)
8-K
001-35726
10.1
5/11/15


10.17†Form
of
Radius
Health,
Inc.
2011
Equity
Incentive
PlanStock
Option
Agreement
S-1/A
333-175091
10.83
11/7/11


10.18†Radius
Health,
Inc.
Non-Employee
DirectorCompensation
Program
10-K
001-35726
10.24
3/10/15


10.19†Employment
Letter
Agreement,
dated
November
14,2003,
by
and
between
the
Company,
as
successor
toNuvios,
Inc.,
and
Gary
Hattersley
8-K
000-53173
10.49
5/23/11

Table
of
Contents138Exhibit
Number
Exhibit
Description
Form
File
No.
Exhibit
Filing
Date
Filed/
Furnished
Herewith
10.20†Employment
Letter
Agreement,
dated
November
15,2006,
by
and
between
the
Company,
as
successor
toRadius
Health,
Inc.,
and
B.
Nicholas
Harvey
8-K
000-53173
10.51
5/23/11


10.21†Executive
Employment
Agreement,
dated
as
ofDecember
12,
2013,
by
and
between
the
Company
andRobert
Ward
8-K
001-35726
10.1
12/17/13


10.22†Employment
Letter
Agreement,
dated
January
3,
2014,by
and
between
the
Company
and
Greg
Williams
S-1/A
333-194150
10.141
4/3/14


10.23†Form
of
Indemnification
Agreement
by
and
between
theCompany
and
the
individuals
listed
on
Schedule
Athereto
10-K
001-35716
10.30
3/10/15


10.24
Indenture
of
Lease,
dated
May
14,
2014,
by
and
betweenthe
Company
and
BP
Bay
Colony
LLC
8-K
001-35726
10.1
5/20/14


10.24(a)First
Amendment,
dated
September
9,
2015,
to
Lease,dated
May
14,
2014,
by
and
between
the
Company
andBP
Bay
Colony
LLC
10-Q
001-35726
10.6
11/5/15


21.1
Subsidiary
of
the
Company








*
23.1
Consent
of
Ernst
&
Young
LLP,
Independent
RegisteredPublic
Accounting
Firm








*
31.1
Rule
13a-14(a)/15d-14(a)
Certification
of
ChiefExecutive
Officer








*
31.2
Rule
13a-14(a)/15d-14(a)
Certification
of
ChiefFinancial
Officer








*
32.1
Section
1350
Certification
of
Chief
Executive
Officer








**
32.2
Section
1350
Certification
of
Chief
Financial
Officer








**
101.INS
XBRL
Instance
Document








*
101.SCH
XBRL
Taxonomy
Extension
Schema
Document








*Table
of
Contents139Exhibit
Number
Exhibit
Description
Form
File
No.
Exhibit
Filing
Date
Filed/
Furnished
Herewith
101.CAL
XBRL
Taxonomy
Extension
Calculation
LinkbaseDocument








*
101.LAB
XBRL
Taxonomy
Extension
Label
Linkbase
Document








*
101.PRE
XBRL
Taxonomy
Extension
Presentation
LinkbaseDocument








*
101.DEF
XBRL
Taxonomy
Extension
Definition
LinkbaseDocument








*^Confidential
treatment
has
been
granted
with
respect
to
redacted
portions
of
this
exhibit.
Redacted
portions
of
this
exhibit
have
been
filedseparately
with
the
SEC.
†A
management
contract
or
compensatory
plan
or
arrangement
required
to
be
filed
as
an
exhibit
pursuant
to
Item
15(a)(3)
of
Form
10-K.
*Filed
herewith.
**Furnished
herewith.Exhibit 10.5(a)
Execution
copy
CLINICAL TRIAL SERVICES AGREEMENT AMENDMENT NO. 8 TO WORK STATEMENT NB-1
RADIUS
HEALTH,
INC.,
a
Delaware
corporation
(“
Radius
”)
and
NORDIC
BIOSCIENCE
CLINICAL
DEVELOPMENT
VII
A/S,
a
Danish
corporation
(“
NB”)
that
is
a
wholly-owned
subsidiary
of
Nordic
Bioscience
Clinical
Development
A/S
entered
into
the
certain
Clinical
Trial
Services
Agreement
(
“Agreement”
)and
that
certain
Work
Statement
NB-1
under
the
Agreement
as
of
March
29,
2011
(
“Effective
Date”
),
and
entered
into
an
Amendment
No.
1,
Amendment
No.
2,Amendment
No.
3,
Amendment
No.
4,
Amendment
No.
5,
Amendment
No.
6
and
Amendment
No.
7
to
Work
Statement
NB-1
as
of
December
9,
2011,
June
18,2012,
November
6,
2013,
March
28,
2014,
May
19,
2014,
July
22,
2014
and
July
22,
2014
respectively,
(as
amended,
“Work
Statement
NB-1”
).
Pursuant
to
Section
2.3,
2.11
and
11.7
of
the
Agreement,
the
parties
wish
to
enter
into
this
Amendment
No.
8
to
Work
Statement
NB-1
(
“Amendment
No.
8”
)effective
as
of
August
15,
2014
(
“Amendment
Date”
).

Capitalized
terms
used
in
this
Amendment
No.
8
and
not
defined
herein
are
used
with
the
meaningsascribed
to
them
in
the
Agreement
and
Work
Statement
NB-1.
NOW THEREFORE ,
in
consideration
of
the
mutual
covenants
and
promises
contained
in
this
Amendment
No.
8,
the
parties
agree
as
follows:
1. End of Study Readiness Visits for BA058-05-003 :
(a)
At
Radius
request,
NB
will
allocate
resources
as
outlined
below
to
perform
additional
activities
to
assist
selected
study
sites
for
the
end
of
the
BA058-05-003Study
in
order
to
meet
consistency
in
documentation
across
the
sites.
The
purpose
of
this
work
statement
is
to
allow
NB
the
resources
to
visit
selected
sites
andvendors
to
perform
end
of
study
readiness
visits.
Radius
is
responsible
for
selecting
the
sites
targeted
for
these
visits.
(b)
A
new
section
at
the
bottom
Attachment
B
to
Work
Statement
NB-1
(
Budgets, Fees, Pass-through Costs, and Payment Schedule )
is
hereby
amended
toread
in
full
as
follows:
Budget Euro 11
days
for
Readiness
Visits
to
selected
sites,
including
reporting
and
follow
up.
Thesewill
be
performed
by
NB.
€33.000
30
days
allocated
to
accompany
the
Readiness
Visits
to
selected
sites
for
translation
andsupport
purposes.
These
will
be
performed
by
the
local
CRA’s.
€75.000
TOTAL
€108.000

(c)

The
“Payment
Schedule”
set
forth
in
Attachment
B
to
Work
Statement
NB-1
(
Attachment
2
to
the
Agreement)
is
amended
to
add
a
new
Paragraph
(16)
immediately
following
Paragraph
(15)
of
the
Payment
Schedule,
which
shall
read
in
full
as
follows:
“ Payment
for
End
of
Study
Readiness
Visits
will
be
paid
in
4
parts;
40%
upon
signing
of
this
work
statement,
30%
after
data
base
transfer
in
October,
2014,
15%when
the
database
is
soft
locked
and
transferred
to
Radius
in
November
2014,
and
15%
when
the
data
base
is
hard
locked
and
transferred
to
Radius
in
December,2014.
Such
payments
shall
include
all
out-of-pocket
travel
expenses
incurred
by
NB
for
study
readiness
visits
”
2.  Ratification. 

Except
to
the
extent
expressly
amended
by
this
Amendment
No.
8,
all
of
the
terms,
provisions
and
conditions
of
the
Agreement
and
WorkStatement
NB-1
are
hereby
ratified
and
confirmed
and
shall
remain
in
full
force
and
effect.

The
term
“Work
Statement
NB-1”,
as
used
in
the
Agreement,
shallhenceforth
be
deemed
to
be
a
reference
to
Work
Statement
NB-1
as
amended
by
this
Amendment
No.
8.
1
3.  General. 

This
Amendment
No.
8
may
be
executed
in
counterparts,
each
of
which
will
be
deemed
an
original
with
all
such
counterparts
together
constitutingone
instrument.
IN
WITNESS
WHEREOF
the
parties
have
caused
this
Amendment
No.
8
under
Work
Statement
NB-1
to
be
executed
by
their
respective
duly
authorized
officers,and
have
duly
delivered
and
executed
this
Amendment
No.
8
under
seal
as
of
the
Amendment
Date.

RADIUS HEALTH, INC. NORDIC BIOSCIENCE CLINICAL DEVELOPMENT VII A/S





/s/
R.E.
Ward
/s/
Jeppe
Ragnar
AndersenBy:
R.E.
Ward
By:Title:
President
&
CEO
Title:
CEO





Notice Address Notice AddressRadius
Health,
Inc.
Nordic
Bioscience
Clinical
Development
VII
A/S950
Winter
Street
Herlev
Hovedgade
207Waltham,
MA
02451
2730
HerlevUSA
DenmarkAttn:
President
&
CEO
Attn:
CEOPhone:
01.617.551.4000
Phone:
45.4452.5251Fax:
01.617.551.4701
Fax:
45.4452.525
2Exhibit 10.7(c)
CLINICAL TRIAL SERVICES AGREEMENT AMENDMENT NO. 4 TO WORK STATEMENT NB-3
RADIUS
HEALTH,
INC.,
a
Delaware
corporation
(“
Radius
”)
and
NORDIC
BIOSCIENCE
CLINICAL
DEVELOPMENT
VII
A/S,
a
Danish
corporation
(“
NB”)
that
is
a
wholly-owned
subsidiary
of
Nordic
Bioscience
Clinical
Development
A/S
entered
into
a
Clinical
Trial
Services
Agreement
dated
March
29,
2011
(“Agreement”
)
and
Work
Statement
NB-3
under
the
Agreement
(
“Work
Statement
NB-3”
)
as
of
February
21,
2013
(
“Effective
Date”
),
and
entered
into
anAmendment
No.
1,
Amendment
No.
2
and
Amendment
No.
3
to
Work
Statement
NB-3
as
of
February
28,
2014,
March
23,
2015
and
July
8,
2015
(as
amended,“Work
Statement
NB-3”).
Pursuant
to
Section
2.3,
2.11
and
11.7
of
the
Agreement,
the
parties
wish
to
enter
into
this
Amendment
No.
4
to
Work
Statement
NB-3
(
“
Amendment
No.
4”
)effective
as
of
October
21,
2015
(
“Amendment
Date”
).
Capitalized
terms
used
in
this
Amendment
No.
4
and
not
defined
herein
are
used
with
the
meaningsascribed
to
them
in
the
Agreement
and
Work
Statement
NB-3.
The
purpose
of
this
Amendment
no.
4
is
to
include
additional
antibody
procedure
services
and
regulatory
submission
of
Protocol
No
BA058-05-005,
Amendment4,
Version
1,
August
24,
2015.
NOW THEREFORE ,
in
consideration
of
the
mutual
promises
contained
in
the
Agreement
and
for
other
good
and
valuable
consideration
the
receipt
andadequacy
of
which
each
of
the
parties
does
hereby
acknowledge,
the
parties
hereby
agree
to
the
terms
of
this
Amendment
No.
4
to
Work
Statement
NB-3
asfollows:
1.  Additional Antibody Procedure Services:
(a)









At
Radius’
request,
NB
will
perform
additional
antibody
procedure
services
(“Additional
AB
Services”)
at
CCBR
and
non-CCBR
sites
to
monitor
anypatients
with
positive
antibodies
in
Radius’
BA058-05-005
clinical
trial.
(b)









As
part
of
the
Additional
AB
Services,
NB
shall
submit
for
regulatory
approval
Protocol
No
BA058-05-005,
Amendment
4,
Version
1,
August
24,
2015to
the
relevant
regulatory
authorities
and
ethical
committees.
(c)










Radius
will
compensate
NB
for
the
Additional
AB
Services
and
regulatory
submissions
as
set
forth
in
Attachment
1.
This
Amendment
No.
4
to
Work
Statement
NB-3
contains
the
following
Attachments,
each
of
which
is
made
a
part
hereof:
Attachment
1—Budget
Summary
including
pricing,
pass-through
costs
and
PaymentScheduleAttachment
2—Protocol
2.  Payment Schedule Clarification. The
parties
agree
to
clarify
that
the
Final
Payment
(15%)
of
617,433.60
Euro
(as
set
forth
in
Amendment
No.
2
to
WorkStatement
NB-3)
will
be
invoiced
when
the
database
is
locked
and
transferred
to
and
accepted
by
Radius
and
payable
in
accordance
with
the
terms
of
theAgreement.
Monthly
Payments
under
Amendment
No.
2
shall
continue
to
be
invoiced
through
March
2017.
Provided
that
the
trial
master
file
is
delivered
to
andaccepted
by
Radius
before
March
2017,
the
final
remaining
monthly
payment(s)
may
be
invoiced
upon
delivery.
If
the
trial
master
file
is
delivered
to
and
acceptedby
Radius
after
March
2017,
the
final
remaining
monthly
payment
may
not
be
invoiced
until
such
delivery
and
acceptance
has
occurred.
The
trial
master
file
isautomatically
considered
accepted
for
the
purpose
of
invoicing
3
weeks
after
delivery,
if
no
objections
have
been
received.
3.  Ratification. 

Except
to
the
extent
expressly
amended
by
this
Amendment
No.
4,
all
of
the
terms,
provisions
and
conditions
of
the
Agreement
and
WorkStatement
NB-3
are
hereby
ratified
and
confirmed
and
shall
remain
in
full
force
and
effect.
The
term
“Work
Statement
NB-3”
,
as
used
in
the
Agreement,
shallhenceforth
be
deemed
to
be
a
reference
to
Work
Statement
NB-3
as
amended
by
this
Amendment
No.
4.

4.  General. 

This
Amendment
No.
4
may
be
executed
in
counterparts,
each
of
which
will
be
deemed
an
original
with
all
such
counterparts
together
constitutingone
instrument.
IN
WITNESS
WHEREOF
the
parties
have
caused
this
Amendment
No.
4
under
Work
Statement
NB-3
to
be
executed
by
their
respective
duly
authorized
officers,and
have
duly
delivered
and
executed
this
Amendment
No.
4
under
seal
as
of
the
Amendment
Date.
   RADIUS HEALTH, INC. NORDIC BIOSCIENCE CLINICAL
DEVELOPMENT VII A/S





/s/
Greg
Williams

/s/
Jeppe
Ragnar
AndersenBy:Greg
Williams,
PhD,
MBA

By:
Title:Chief
Development
Officer

Title:




Nordic
Bioscience



Clinical
Development



Jeppe
Ragnar
Andersen,
CEO



Herlev
Hovedgade
207



2730
Herlev



Notice Address 
Notice AddressRadius
Health,
Inc.

Nordic
Bioscience
Clinical
Development
VII
A/S201
Broadway,
6

Floor

Herlev
Hovedgade
205-207Cambridge,
MA
02139

2730
HerlevUSA

DenmarkAttn:
President
&
CEO

Attn:
CEO,
Jeppe
Ragnar
AndersenPhone:
01.617.551.4700

Phone:
45.4452.5252Fax:
01.617.551.4701

Fax:
45.4452.521
2
Attachment 1 - Budget
 RADIUS    Antibody - BA058-05-003/005    Cost Proposal 21 October 2015      Sponsor:RADIUS Protocol ID:Antibody - BA058-05-003/005 Development Phase:N/A Disease:Osteoporosis Number of Countries:8 Number of Sites:18    Total BudgetEURO 1. Investigator Fee - Re-consent Informed Consent€150 per ICF re-consent 2. Investigator Fee - Blood sampling, scheduled visit€40 per scheduled visit 3. Investigator Fee - Blood sampling, unscheduled visit€96 per unscheduled visitEstimated 75% unscheduled visits4. Central Lab Fee (Synarc Lab)€26.40 per sampleShipment not included. Shipment to be invoiced as pass through5. Regulatory Submissions166.048Submission of amendment 4 to CA and EC’s6. Project management, coordination and oversight2.457 per month 7. Monitoring Visits, incl. travel cost45.000Includes up to 18 monitoring visits   Pass through CostEURO TranslationIncluded in budget Travel Costs for Monitoring VisitsIncluded in budget Investigator MeetingNot included, will be pass-throughNo investigator meeting plannedLab shipmentsNot included, will be pass-throughEstimated 170.000 EURSubmission to EC and CAIncluded in budget EDC systemNot included, will be pass-throughExtra expense only if period extends beyond 005
Invoicing Schedule
NB
shall
submit
invoices
to
Radius
in
accordance
with
the
following:
Items
1-4
shall
be
invoiced
on
a
monthly
basis
in
accordance
with
work
actually
performed.
Items
5
and
7,
EUR
166,048
for
Regulatory
Submission
and
EUR
45,000
for
Monitoring
Visits,
in
total
EUR
211,048,
shall
be
paid
as
a
non-refundable,
upfrontpayment
which
falls
due
upon
signing
of
this
Amendment
No.
4.
th
Item
6,
Project
Management
Fees
of
EUR
2,457
shall
be
added
to
the
amounts
currently
invoiced
on
a
monthly
basis
until
such
time
as
the
final
lab
sample
hasbeen
processed.
3
Attachment 2 - Protocol
Protocol
No
BA058-05-005,
Amendment
4,
Version
1,
August
24,
2015
to
be
supplied
as
a
PDF.
4CLINICAL STUDY PROTOCOL
An Extension Study to Evaluate 24 Months of Standard-of-Care Osteoporosis Management Following Completion of 18 Months of BA058 or PlaceboTreatment in Protocol BA058-05-003
This
study
will
be
conducted
according
to
the
protocol
and
in
compliance
with
Good
Clinical
Practice,
the
ethical
principles
stated
in
the
Declaration
of
Helsinki,and
other
applicable
regulatory
requirements.
Protocol Number:
Protocol
BA058-05-005Protocol Date (Version):
Original
(23
July
2012)

Amendment
1,
Version
1
(13
February
2013)
Amendment
2,
Version
1
(31
March
2014)
Amendment
3,
Version
1
(3
March
2015)
Amendment
4,
Version
1
(24
August
2015)EudraCT Number
2012-002216-10IND Number:
73,176Study Sponsor:
Radius
Health,
Inc.
950
Winter
Street
Waltham,
MA
02451
Tel:
617.551.4000.
Fax:
617.551.4701Sponsor Medical
Lorraine
A.
Fitzpatrick,
MDMonitor/Study Safety
Chief
Medical
Officer,
Radius
Health,
Inc.Officer:
Tel:
617.551.4007.
Fax:
617.551.4701.
Email:
XXXXXXXXXXXXXXXXXXXXXXXXXXXX


Contract Research
Nordic
Bioscience
A/SOrganization (CRO):
Herlev
Hovedgade
207
2730
Herlev,
Denmark
Tel:
+45
4452
5252.
Fax:
+45
4452
5251
Disclosure
StatementThis
document
contains
information
that
is
confidential
and
proprietary
to
Radius
Health,
Incorporated
(RADIUS).
This
information
is
being
provided
to
you
solelyfor
the
purpose
of
evaluation
and/or
conducting
a
clinical
trial
for
RADIUS.
You
may
disclose
the
contents
of
this
document
only
to
study
personnel
under
yoursupervision
and/or
to
your
institutional
review
board(s)
or
ethics
committee(s)
who
need
to
know
the
contents
for
this
purpose
and
who
have
been
advised
on
theconfidential
nature
of
the
document.



Radius
Health,
Inc.
Confidential
PROTOCOL SYNOPSIS
Title: 





An
Extension
Study
to
Evaluate
24
Months
of
Standard-of-Care
Osteoporosis
Management
Following
Completion
of
18
Months
of
BA058
or
PlaceboTreatment
in
Protocol
BA058-05-003
Protocol Number: 



BA058-05-005
Test Drug: 



Alendronate
Study Objectives:
Please
note
that
the
name
of
BA058
Injection
80
µg
has
been
changed
to
Abaloparatide-SC,
therefore
the
name
has
been
changed
throughout
the
document.
The
primary
objective
of
this
study
is
to
collect
clinical
information
regarding
six
months
of
treatment
with
alendronate,
in
subjects
who
have
previously
received18
months
of
blinded
treatment
with
Abaloparatide-SC
or
Placebo
in
Study
BA058-05-003.
Safety
data
will
be
obtained
via
clinical,
laboratory
and
radiologicassessments.
Following
the
initial
six
months
of
treatment
in
the
study,
subjects
will
then
enter
the
long-term
observational
phase
of
the
study
during
whichsubjects
will
continue
to
receive
alendronate
treatment
for
an
additional
18
months
(for
a
total
of
24
months).
The
specific
objectives
of
this
study
are
to:
·


















Provide
additional
information
on
safety
in
study
subjects
receiving
six
months
of
treatment
with
alendronate
following
18
months
of
treatment
withAbaloparatide-SC/Placebo.
·


















Provide
information
on
the
vertebral
fracture
rate
in
subjects
receiving
six
months
of
treatment
with
alendronate
following
18
months
of
treatment
withAbaloparatide-SC/Placebo.
·


















Provide
additional
information
on
non-vertebral
fractures
and
BMD
change
associated
with
six
months
of
treatment
with
alendronate
following
18months
of
treatment
with
Abaloparatide-SC/Placebo.
·


















Provide
additional
information
on
BMD
change
and
osteoporosis
status
associated
with
24
months
of
treatment
with
alendronate
after
18
months
oftreatment
with
Abaloparatide-SC/Placebo.
The
analysis
performed
at
six
months
of
this
Extension
Study
will
be
used
as
a
follow-up
to
the
18
month
fracture
endpoint
for
Study
BA058-05-003.
Vertebralfractures
based
on
radiologic
assessments
will
also
be
analyzed
at
Month
24.
Additional
analyses
for
other
endpoints
will
be
conducted
cumulatively
at
Months
12,18,
and
24
(i.e.,
Visits
4,
5,
and
6).
Full
details
of
the
statistical
procedures
to
be
used
will
be
provided
in
the
Statistical
Analysis
Plan.
Study Population:
Subjects
with
postmenopausal
osteoporosis
who
completed
the
End-of-Treatment
Visit
(Visit
9)
for
Study
BA058-05-003
and
were
previously
randomized
to
eitherblinded
Abaloparatide-SC
or
blinded
Placebo
are
eligible
for
inclusion
into
this
Extension
Study
provided
that
they
fulfill
the
Inclusion/Exclusion
criteria
describedbelow.
Inclusion/Exclusion Criteria
Otherwise
healthy
ambulatory
postmenopausal
women
who
participated
in,
and
who
completed
18
months
of
treatment
with
either
blinded
Abaloparatide-SC
orblinded
Placebo
in
Study
BA058-05-003,
are
scheduled
to
complete
or
have
completed
the
End-of-Treatment
visit
(Visit
9
in
Study
BA058-05-003),
and
who
haveprovided
a
new
written
informed
consent
for
the
Extension
Study,
are
eligible
for
enrollment
into
this
study.
Participants
must
be
no
more
than
40
days
from
Visit
9in
Study
BA058-05-003
to
be
eligible
for
this
study.
The
physical
examinations
and
clinical
laboratory
Protocol
BA058-05-005
Amendment
4,
Version
1
(24
August
2015)
2
Radius
Health,
Inc.
Confidential
measurements
from
the
End-of-Treatment
visit
from
Protocol
BA058-05-003
(Visit
9)
of
the
BA058-05-003
study
will
provide
baseline
data
for
this
ExtensionStudy.
In
addition,
the
subjects
must,
in
the
opinion
of
the
Investigator,
be
appropriate
candidates
for
treatment
with
alendronate.
Subjects
will
not
be
enrolled
if
they
experienced
a
treatment-related
SAE
as
assessed
by
the
Investigator,
or
if
they
were
withdrawn
from
Study
BA058-05-003
forany
reason.
Specific
inclusion
and
exclusion
criteria
are
described
in
Section
4.1
and
Section
4.2,
respectively.
Study Design and Methodology:
Number of Subjects
All
subjects
who
were
randomized
to
the
Abaloparatide-SC/Placebo
arms
in
Study
BA058-05-003,
and
who
completed
18
months
of
treatment
will
be
offered
theopportunity
to
participate
in
this
study.
There
will,
therefore,
be
a
potential
maximum
of
1,600
subjects
eligible
to
be
enrolled
in
this
study.
Design
This
study
will
be
an
open-label
extension
of
Study
BA058-05-003.
The
purpose
of
the
study
is
to
provide
longer
term
safety
data,
fracture
data
and
BMD
dataafter
treatment
with
alendronate,
in
otherwise
healthy
ambulatory
postmenopausal
women
with
severe
osteoporosis
who
have
previously
received
18
months
ofblinded
treatment
with
Abaloparatide-SC
or
Placebo.
The
analysis
performed
at
six
months
will
be
used
as
a
follow-up
to
the
18
month
fracture
endpoint
for
StudyBA058-05-003.
In
addition,
this
study
will
examine
changes
in
osteoporosis
status
after
12,
18,
and
24
months
of
treatment
with
alendronate
in
otherwise
healthyambulatory
women
with
severe
osteoporosis
who
have
previously
received
18
months
of
blinded
treatment
with
Abaloparatide-SC/Placebo.
Subjects
randomized
to
Abaloparatide-SC/Placebo
in
Study
BA058-05-003
and
who
are
candidates
for
alendronate
treatment,
will
receive
six
months
of
treatmentwith
oral
alendronate
at
a
total
dose
of
70
mg
once
per
week.
Following
the
initial
six
months
of
treatment
in
the
study,
subjects
will
then
enter
the
long-termobservational
phase
of
the
study
during
which
subjects
will
continue
to
receive
alendronate
treatment
for
an
additional
18
months
(for
a
total
of
24
months).
Allsubjects
will
undergo
protocol
specified
procedures
(Section
7.0,
Appendix
14.1
and
14.2)
including
BMD
and
fracture
assessment.
The
study
design
is
presentedin
Figure
1,
below.
Protocol
BA058-05-005
Amendment
4,
Version
1
(24
August
2015)
3
Radius
Health,
Inc.
Confidential
Figure 1: Protocol BA058-05-005 Study Design

In
this
study,
the
Follow-up
Visit
from
the
18
month
study
(Visit
10
from
Study
BA058-05-003)
will
serve
as
the
Day
1
Visit
(Visit
1)
for
this
six
month
ExtensionStudy
(Study
BA058-05-005).
Following
the
initial
six
months
of
treatment,
subjects
will
enter
the
long-term
observational
phase
of
this
study
during
which
the
subjects
will
continue
to
receivealendronate
treatment
for
an
additional
18
months.
During
the
long-term
follow-up
of
this
study,
subjects
will
continue
to
undergo
study
related
procedures
asoutlined
in
Section
14.1
and
Section
14.2.
All
subjects
will
continue
to
take
calcium
and
vitamin
D
supplementation
throughout
the
Extension
Study.
Study Visits
At
the
End-of-Treatment
Visit
(Visit
9)
for
Study
BA058-05-003,
the
possibility
of
participating
in
the
Extension
Study
will
be
discussed
with
subjects
randomizedto
Abaloparatide-SC/Placebo.
This
Extension
Study
will
be
comprised
of
24
months
of
treatment
with
alendronate.
In
the
month
between
Visit
9
and
Visit
10(between
months
18
and
19
of
Study
BA058-05-003),
the
Investigator
will
consider
the
results
of
the
assessments
performed
at
Visit
9,
including
a
local
review
ofBMD,
and
determine
if
alendronate
is
appropriate
for
the
subject,
as
part
of
this
Extension
Study.
At
the
Follow-up
(Visit
10
for
Protocol
BA058-05-003,
Day
1
for
Protocol
BA058-05-005)
subjects;
who
were
randomized
to
Abaloparatide-SC/Placebo,
whofulfill
the
inclusion/exclusion
criteria
(Section
4.1
and
Section
4.2),
and
who
have
agreed
to
participate
in
the
Extension
Study;
will
sign
the
Informed
ConsentForm
and
be
enrolled
in
the
study.
Subjects
who
have
been
determined
by
the
Investigator
to
be
candidates
for
alendronate
therapy
will
receive
open-label
oral
alendronate
treatment
at
a
total
dose
of70
mg
once
per
week
for
24
months.
Subjects
will
be
instructed
to
take
their
first
dose
of
alendronate
for
Study
BA058-05-005
in
the
morning,
within
a
week
oftheir
Day
1
visit.
Following
the
initial
six
months
of
treatment
in
this
study,
subjects
will
enter
the
long-term
observational
phase
of
this
study,
during
whichsubjects
will
continue
to
receive
alendronate
treatment
for
an
additional
18
months.
All
subjects
will
have
clinic
visits
for
study
related
procedures
at
Day
1,
Month
3,
Month
6,
Month
12,
Month
18
and
Month
24.
For
the
purpose
of
this
study
onemonth
is
equal
to
30
days.
Protocol
BA058-05-005
Amendment
4,
Version
1
(24
August
2015)
4
Radius
Health,
Inc.
Confidential
Statistical Considerations:
The
statistical
analyses
will
assess
longer
term
safety,
fracture
incidence
(including
vertebral
and
non-vertebral
fracture),
and
BMD
change
following
treatmentwith
alendronate
for
six
months
after
the
completion
of
a
subject’s
participation
of
18
months
in
study
BA058-05-003.
The
efficacy
and
safety
analyses
performed
at
six
months
will
be
used
as
a
follow-up
to
the
18
month
fracture
endpoint
for
Study
BA058-05-003.
At
this
time-point,
subjects
will
be
analyzed
based
on
the
randomization
assignment
in
the
BA058-05-003
study.
Fractures and BMD Analyses
All
specified
endpoints
will
be
summarized
by
treatment
group
and
study
period
using
standard
descriptive
statistics
(n,
mean,
SD,
median,
minimum,
maximum
orn
and
%,
as
appropriate).
The
fracture
incidence;
either
clinically
or
radiologically
determined,
based
on
clinical
events
or
protocol-directed
vertebral
x-rays
atMonth
6
of
this
Extension
Study;
will
be
analyzed.
In
addition,
BMD
results
from
the
six
months
of
treatment
with
alendronate
will
also
be
analyzed
based
on
thetreatment
arm
they
were
randomized
to
in
the
BA058-05-003
study.
These
analyses
will
be
conducted
on
all
subjects
with
baseline
and
post-baseline
data.
In
addition
to
the
6-month
assessment,
vertebral
fractures
based
on
radiologic
assessments
will
also
be
analyzed
at
Month
24.
Additional
analyses
for
the
otherendpoints
will
be
cumulatively
at
Months
12,
18
and
24
(i.e.,
Visits
4,
5
and
6).
Full
details
of
these
analyses
will
be
provided
in
the
Statistical
Analysis
Plan.
Safety Analysis
Data
will
be
summarized
and
tabulated
based
on
the
enrolled
population
for
this
Extension
Study.
All
subjects
enrolled
in
the
Extension
Study
will
be
included
inthe
safety
analysis
that
will
be
performed
on
the
following
parameters:
·






Incidence
and
severity
of
AEs.
·


















Pathological
changes
in
hematology,
chemistry
and
urinalysis
data
based
on
normal
ranges
supplied
by
the
clinical
laboratory,
if
applicable.
Safety
assessments
for
changes
in
physical
examination,
vital
signs,
ECG,
and
laboratory
tests
will
be
descriptively
summarized
by
treatment
and
study
periods.Concomitant
medication
classes
will
be
categorized
using
World
Health
Organization
(WHO)
drug
dictionary
and
summarized
by
number
and
percent
of
subjectsusing
each
class
by
treatment
group.
All
treatment
emergent
adverse
events
(TEAEs)
will
be
coded
for
system
organ
class
(SOC)
and
preferred
term
(PT)
usingMedDRA
and
the
number
(%)
of
subjects
experiencing
each
AE
(SOC/PT)
will
be
summarized
by
treatment,
relationship
to
treatment,
and
severity.
All
seriousadverse
events
(SAE)
will
be
listed
and
the
number
(%)
of
subjects
with
an
SAE
presented
by
treatment
group.
Similar
safety
analyses
will
be
conducted
cumulatively
at
Months
12,
18,
and
24
(i.e.,
Visits
4,
5,
and
6).
Full
details
of
these
analyses
will
be
provided
in
theStatistical
Analysis
Plan.
Procedures and Assessments
Fractures
and
BMD
The
End-of-Treatment
(Visit
9)
evaluations
for
vertebral
fracture
assessment,
non-vertebral
fracture
assessment
and
BMD
from
Study
BA058-05-003
will
serve
asthe
baseline
evaluations
in
this
study.
The
Day
1
assessment
will
be
concurrent
with
the
Follow-up
Visit
(Visit
10)
for
Study
BA058-05-003.
Subjects
will
return
tothe
clinic
for
assessment
of
BMD
at
spine,
hip
and
wrist
(for
those
subjects
who
had
wrist
DXAs
performed
in
Study
BA058-05-003)
at
Month
6,
Month
12,
Month18,
and
at
Month
24.
Any
patient
who
shows
a
continuing
significant
deterioration
(>7%)
of
BMD
at
Protocol
BA058-05-005
Amendment
4,
Version
1
(24
August
2015)
5
Radius
Health,
Inc.
Confidential
spine
or
hip
from
the
Day
1
assessment
of
Study
BA058-05-005
will
have
the
assessment
repeated
and,
if
confirmed,
will
be
discontinued
from
the
study.
Clinicaland
radiographic
assessments
for
fractures
will
be
performed
at
Month
6
and
Month
24,
and
bone
marker
assessments
of
anabolism
(PINP,
bone-specific
alkalinephosphatase
and
osteocalcin)
and
resorption
(CTX)
will
be
performed
at
Day
1
and
Months
6,
12,
18
and
24.
Safety
Safety
evaluations
performed
will
include
physical
examinations,
vital
signs,
12-lead
ECGs,
clinical
laboratory
tests,
and
monitoring
and
recording
of
adverseevents.
Complete
details
of
the
study
assessments
are
provided
in
Section
7.0,
in
the
Schedule
of
Visits
and
Procedures
(Appendix
14.1)
and
in
the
Suggested
Schedule
ofEvents
and
Procedures
by
Study
Visit
(Appendix
14.2).
Treatments Administered
Alendronate
sodium
(Fosamax®,
Merck
&
Co.,
Inc.,
or
other
approved
generic
manufacturer)
70
mg
tablets
for
oral
administration
contain
91.35
mg
ofalendronate
monosodium
salt
trihydrate
which
is
the
molar
equivalent
of
70
mg
free
acid
and
excipients.
Alendronate
should
be
stored
in
a
well-closed
container
atroom
temperature,
15-30ºC.
The
alendronate
may
be
generic
substitutable
approved
versions
which
contain
different
inactive
ingredients,
but
the
amount
of
activefree
alendronate
must
be
equivalent
to
70
mg.
Alendronate
for
Europe,
Hong
Kong
and
the
US
will
be
sourced
centrally;
alendronate
for
South
America
will
besourced
locally
by
the
medical
center
and
reimbursed
by
the
Sponsor.
However,
alendronate
may
be
locally
sourced
in
all
venues
when
centrally
suppliedalendronate
is
unavailable
due
to
unforeseen
delays.
The
local
source
will
be
documented
in
the
study
drug
logs.
Calcium
(500—1000
mg)
and
vitamin
D
(400—800
IU)
supplements
will
be
sourced
locally
by
the
medical
center
and
provided
to
the
subjects
at
the
expense
ofthe
Sponsor.
Subjects
will
continue
to
take
calcium
and
vitamin
D
as
they
did
in
Study
BA058-05-003.
Duration of Subject Participation:
Participation
in
the
initial
phase
of
this
study
will
be
approximately
six
months
from
enrollment
to
completion
of
the
six
month
study
evaluations.
Participation
forboth
the
initial
and
observational
phases
of
the
study
will
be
approximately
24
months.
In
combination
with
Study
BA058-05-003,
subjects
will
participate
in
thisclinical
postmenopausal
osteoporosis
program
for
43
to
44
months.
The
first
visit
of
Study
BA058-05-005
will
be
concurrent
with
Visit
10
of
Study
BA058-05-003.
Protocol
BA058-05-005
Amendment
4,
Version
1
(24
August
2015)
6
Radius
Health,
Inc.
Confidential
TABLE OF CONTENTS
PROTOCOL SYNOPSIS2
 TABLE OF CONTENTS7
 LIST OF ABBREVIATIONS10   1.0INTRODUCTION12
1.1BACKGROUND
INFORMATION121.2DRUG
UNDER
STUDY121.2.1Efficacy
of
Alendronate121.2.2Safety
of
Alendronate
Sodium131.3STUDY
RATIONALE
AND
SELECTION
OF
DOSES141.3.1Study
Rationale141.3.2Study
Design141.3.3Study
Population151.3.4Selection
of
Endpoints151.3.5Selection
of
Dose15 2.0STUDY OBJECTIVES15   3.0INVESTIGATIONAL PLAN16
3.1OVERALL
DESIGN
AND
STUDY
PLAN163.1.1Treatment
Period17 4.0SELECTION OF STUDY POPULATION18
4.1NUMBER
OF
SUBJECTS184.2INCLUSION
CRITERIA184.3EXCLUSION
CRITERIA194.4WITHDRAWAL
OF
SUBJECTS
FROM
THE
STUDY194.5TEMPORARY
SUSPENSION
OF
TREATMENT194.6REPLACEMENT
OF
SUBJECTS20 5.0STUDY TREATMENTS20
5.1STUDY
MEDICATIONS205.1.1Alendronate205.1
.
1.1Restrictions
on
Alendronate
Use205.1.2Calcium
and
Vitamin
D
Supplements205.2PACKAGING,
LABELING
AND
STORAGE205.2.1Storage215.3TREATMENT
ASSIGNMENT215.4STUDY
MEDICATION
ADMINISTRATION215.4.1Alendronate
Administration215.5TREATMENT
COMPLIANCE215.6UNBLINDING
OF
STUDY
MEDICATION21 6.0CONCOMITANT MEDICATIONS22


6.1CONCOMITANT
MEDICATIONS226.2PROHIBITED
MEDICATIONS22   7.0STUDY ASSESSMENTS22


7.1CLINICAL
PROCEDURES/ASSESSMENTS237.1.1Informed
Consent237.1.2Recent
Health
Status237.1.3Vital
Signs237.1.4Height
and
Weight237.1.5Orthostatic
Blood
Pressure
and
Heart
Rate23
Protocol
BA058-05-005
Amendment
4,
Version
1
(24
August
2015)
7
Radius
Health,
Inc.
Confidential



7.1.6Electrocardiogram237.1.7Clinical
Laboratory
Evaluations247.1.8Clinical
Chemistry
and
Urinalysis
(Dipstick)247.1.9Hematology257.1.10Coagulation257.1.1124-Hour
Urine
Collection257.1.12Bone
Mineral
Density257.1.13Serum
Markers
of
Bone
Metabolism267.1.14Clinical
and
Radiologic
Evaluation
of
Fractures267.1.15Abaloparatide
Antibody
Assessments267.1.16Subject
Diaries277.1.17Activity
and
Diet27 8.0ADVERSE EVENTS AND SAFETY EVALUATION27


8.1DEFINITIONS,
DOCUMENTATION,
AND
REPORTING278.1.1Adverse
Event
Definition278.1.2Serious
Adverse
Event
Definition278.2MONITORING
OF
ADVERSE
EVENTS
AND
PERIOD
OF
OBSERVATION288.3PROCEDURES
FOR
RECORDING
AND
REPORTING
AES
AND
SAES288.4RULES
FOR
SUSPENSION
OF
THE
STUDY30   9.0STATISTICAL PROCEDURES30


9.1SAMPLE
SIZE319.2RANDOMIZATION,
STRATIFICATION
AND
BLINDING319.3POPULATIONS
FOR
ANALYSIS319.3.1ITT
(Safety)
Population319.3.2Modified
Intent-to-Treat
Population319.3.3Per
Protocol
Population319.4PROCEDURES
FOR
HANDLING
MISSING,
UNUSED,
AND
SPURIOUS
DATA319.5STATISTICAL
METHODS319.5.1Statistical
Considerations319.5.2Baseline
Comparisons329.5.3Fractures
and
BMD
Analysis329.5.4Safety
Analysis329.5.5Procedures
for
Reporting
Deviations
to
Original
Statistical
Analysis
Plan329.6DATA
OVERSIGHT339.6.1Central
Review
of
Radiographs
and
DXA
Scans33 10.0ADMINISTRATIVE REQUIREMENTS33


10.1GOOD
CLINICAL
PRACTICE3310.2ETHICAL
CONSIDERATIONS3310.3SUBJECT
INFORMATION
AND
INFORMED
CONSENT3310.4PROTOCOL
COMPLIANCE3410.5CASE
REPORT
FORM
COMPLETION3410.6SOURCE
DOCUMENTS3410.7STUDY
MONITORING3510.8ON-SITE
AUDITS3510.9DRUG
ACCOUNTABILITY3510.10RECORD
RETENTION3510.11STUDY
TERMINATION3610.12LIABILITY
AND
INSURANCE36   11.0USE OF INFORMATION AND PUBLICATION OF STUDY FINDINGS36


11.1USE
OF
INFORMATION3611.2PUBLICATION37
Protocol
BA058-05-005
Amendment
4,
Version
1
(24
August
2015)
8
Radius
Health,
Inc.
Confidential
   12.0INVESTIGATOR AGREEMENT3813.0REFERENCES3914.0APPENDICES4114.1SCHEDULE
OF
VISITS
AND
PROCEDURES4214.2SUGGESTED
SCHEDULE
OF
EVENTS
AND
PROCEDURES
BY
STUDY
VISIT4414.3EASTERN
COOPERATIVE
ONCOLOGY
GROUP
(ECOG)
COMMON
TOXICITY
CRITERIA52
Protocol
BA058-05-005
Amendment
4,
Version
1
(24
August
2015)
9
Radius
Health,
Inc.
Confidential
LIST OF ABBREVIATIONS
Abbreviation Term°C
Degree
Celsius°F
Degree
Fahrenheitµg
Microgramµmol
MicromoleAE
Adverse
eventALT
Alanine
aminotransferaseAST
Aspartate
aminotransferaseBMD
Bone
mineral
densityBMI
Body
mass
indexbpm
Beats
per
minuteBSAP
Bone-specific
alkaline
phosphataseBUN
Blood
urea
nitrogencm
CentimeterCPK
Creatine
phosphokinaseCRF
Case
report
formCRO
Contract
research
organizationCTX
C-telopeptides
of
type
1
collagen
crosslinks
(serum)DXA
Dual
energy
x-ray
absorptiometryECG
ElectrocardiogrameCRF
Electronic
case
report
formFDA
Food
and
Drug
Administrationg
GramGCP
Good
clinical
practiceGGT
Gamma-glutamyltranspeptidaseGLP
Good
laboratory
practiceGMP
Good
manufacturing
practiceICH
International
Conference
on
HarmonizationIEC
Independent
ethics
committeeIRB
Institutional
review
boardITT
Intent-to-treatIU
International
unitIV
IntravenousIVRS
Interactive
voice
response
systemkg
KilogramL
LiterLDH
Lactate
dehydrogenaseMCH
Mean
corpuscular
hemoglobinMCHC
Mean
corpuscular
hemoglobin
concentrationMCV
Mean
corpuscular
volume
Protocol
BA058-05-005
Amendment
4,
Version
1
(24
August
2015)
10
Radius
Health,
Inc.
Confidential
Abbreviation TermMedDRA
Medical
dictionary
for
regulatory
activitiesµL
Microlitermg
MilligrammL
MillilitermmHg
Millimeter
of
mercurymsec
MillisecondNPO
Nothing
by
mouthng
NanogramONJ
Osteonecrosis
of
the
jawPA
Posterior-anteriorPD
Pharmacodynamicpg
PicogramPINP
N-terminal
propeptide
of
type
I
procollagenPK
PharmacokineticPT
Prothrombin
timePTH
Parathyroid
hormonePTHrP
Parathyroid
hormone
related
peptidePTT
Partial
thromboplastin
timePUBs
Upper
gastrointestinal
perforations,
ulcers
and
bleedsQT
Total
depolarization
and
repolarization
timeQTc
Total
depolarization
and
repolarization
time
corrected
with
heart
rateRBC
Red
blood
cellSAE
Serious
adverse
eventSC
SubcutaneousSD
Standard
deviationSERMs
Selective
estrogen
receptor
modulatorsSOC
System
organ
classSOP
Standard
operating
procedureTEAEs
Treatment
emergent
adverse
eventsULN
Upper
Limit
of
NormalWBC
White
blood
cellsWHO
World
Health
Organization
Protocol
BA058-05-005
Amendment
4,
Version
1
(24
August
2015)
11
Radius
Health,
Inc.
Confidential
1.0 









INTRODUCTION
1.1 









Background Information
Osteoporosis
is
a
systemic
skeletal
disease
characterized
by
low
bone
mass
and
microarchitectural
deterioration
of
bone
tissue
which
leads
to
enhanced
fragilityand
increased
risk
of
fractures
(Rizzoli,
2001).
It
is
estimated
that
over
200
million
people
worldwide
have
osteoporosis
(Reginster,
2006)
and
osteoporosis
causesmore
than
8.9
million
fractures
worldwide,
of
which
more
than
4.5
million
occur
in
the
Americas
and
Europe
(WHO
Scientific
Group,
2007).
The
vast
majority
ofosteoporotic
fractures
occur
in
elderly
women
and
incidence
increases
markedly
with
age.
Most
fractures
occur
at
the
spine,
wrist
and
hip.
Of
these,
hip
fracturescarry
the
highest
morbidity
and
mortality.
In
1990,
the
total
number
of
hip
fractures
in
men
and
women
was
estimated
to
be
1.26
million
worldwide,
and
it
isestimated
that
this
number
will
increase
to
3.6
million
by
2025
and
to
4.5
million
by
2050
(Gullberg,
1997).
Subjects
enrolled
in
this
Extension
Study
will
have
completed
18
months
of
treatment
with
Abaloparatide-SC/Placebo.
Abaloparatide
is
a
synthetic
34
amino
acidanalog
of
parathyroid
hormone
related
peptide(PTHrP),
with
molecular
modifications
of
specific
amino
acids,
and
is
under
clinical
development
for
the
preventionof
fractures
in
postmenopausal
women
with
severe
osteoporosis
who
are
at
a
risk
for
fracture.
Abaloparatide
shows
particular
potential
for
reversing
bone
loss
atboth
the
spine
and
the
hip,
the
site
of
the
most
debilitating
osteoporotic
fractures
in
elderly
women.
Abaloparatide
is
a
synthetic
analog
of
PTHrP
(1-34)
designed
togive
a
greater
anabolic
effect
than
human
parathyroid
hormone
(hPTH).
Initial
in
vitro
and
in
vivo
studies
identified
abaloparatide
as
displaying
bone
anabolicproperties
without
a
significant
hypercalcemic
effect.
In
humans,
abaloparatide
has
different
pharmacokinetics
(PK)
and
pharmacodynamics
(PD)
properties
thanhPTH(1-34)
and
has
been
shown
in
a
Phase
2
study
(BA058-05-002)
to
have
similar
or
greater
efficacy
in
restoring
bone
mineral
density
(BMD)
in
individualswith
osteoporosis
than
hPTH(1-34).
Overall,
abaloparatide
has
been
well
tolerated
in
previous
studies.
This
is
an
open-label
extension
of
Study
BA058-05-003.
Enrollment
requires
previous
participation
in,
and
successful
completion
of,
18
months
of
treatment
withAbaloparatide-SC/Placebo
in
Study
BA058-05-003.
The
purpose
of
this
extension
is
to
accumulate
longer-term
safety,
fracture,
and
BMD
data
in
subjects
whoreceive
six
months
of
treatment
with
alendronate,
following
18
months
of
treatment
with
blinded
Abaloparatide-SC/Placebo
treatment.
Following
the
initial
sixmonths
of
treatment
in
this
study,
subjects
will
then
enter
the
long-term
observational
phase
of
this
study
during
which
the
subjects
will
continue
to
receivealendronate
treatment
for
an
additional
18
months.
The
analyses
performed
at
six
months
will
be
used
as
a
follow-up
to
the
18
month
fracture
endpoint
for
StudyBA058-05-003.
Additional
analyses
will
be
cumulatively
at
Months
12,
18,
and
24
(i.e.,
Visits
4,
5,
and
6.
Full
details
of
the
statistical
procedures
to
be
used
willbe
provided
in
the
Statistical
Analysis
Plan.
Alendronate,
a
bisphosphonate,
is
approved
and
marketed
world-wide
for
the
treatment
and
prevention
of
osteoporosisin
postmenopausal
women.
1.2 









Drug Under Study
1.2.1






Efficacy
of
Alendronate
Alendronate
is
a
bisphosphonate
that
acts
as
a
specific
inhibitor
of
osteoclast-mediated
bone
resorption.
Bisphosphonates
are
synthetic
analogs
of
pyrophosphatethat
bind
to
the
Protocol
BA058-05-005
Amendment
4,
Version
1
(24
August
2015)
12
Radius
Health,
Inc.
Confidential
hydroxyapatite
found
in
bone.
At
the
cellular
level,
alendronate
shows
preferential
localization
to
sites
of
bone
resorption,
specifically
under
osteoclasts.
Theosteoclasts
adhere
normally
to
the
bone
surface
but
lack
the
ruffled
border
that
is
indicative
of
active
resorption.
Alendronate
does
not
interfere
with
osteoclastrecruitment
or
attachment,
but
it
does
inhibit
osteoclast
activity.
(Fosamax
Package
Insert)
Bisphosphonates
including
alendronate
are
widely
used
to
treat
osteoporosis.
In
animal
models,
minipigs
treated
with
alendronate
exhibited
a
direct
correlationbetween
cancellous
bone
volume
and
bone
strength
(Lefage
1995).
In
primates,
treatment
with
alendronate
increased
the
strength
of
cancellous
bone
between
44and
100%
(the
effect
was
dose
dependent)
when
compared
to
vehicle,
and
also
increased
bone
mass
(Balena
1993).
In
dogs,
this
increase
in
bone
mass
occurredwithout
causing
abnormalities
in
bone
modeling
of
bone
structure
(Balena,
1996).
In
postmenopausal
women,
alendronate
has
been
demonstrated
to
increase
bone
mineral
density,
decrease
bone
turnover
and
reduce
the
risk
of
fracture
amongwomen
with
osteoporosis
(Tucci,
1996;
Devogelaer,
1996;
Liberman,
1995).
The
therapeutic
effects
on
bone
density,
remodeling
and
fracture
prevention
persistfollowing
daily
treatment
at
an
oral
dose
of
10
mg
for
up
to
10
years
(Bone,
2004).
Studies
have
demonstrated
that
sequential
treatment
of
osteoporosis
with
oneyear
of
treatment
with
PTH
followed
by
one
year
of
treatment
with
alendronate
resulted
in
an
increase
in
vertebral
bone
density
that
was
considerably
greater
thanpreviously
reported
for
alendronate
alone
(Rittmaster,
2000).
In
subjects
receiving
PTH(1-84)
followed
by
alendronate,
there
were
significant
increases
in
BMD,
inparticular
trabecular
spine,
when
compared
to
PTH(1-84)
followed
by
placebo
(31%
vs.
14%,
p<0.001)
(Black,
2005).
1.2.2






Safety
of
Alendronate
Sodium
According
to
the
US
package
insert
for
Fosamax®
(alendronate
sodium),
in
studies
of
up
to
five
years
duration,
adverse
experiences
usually
were
mild
andgenerally
did
not
require
discontinuation
of
therapy.
In
a
three-year,
placebo-controlled,
double
blind
study
in
which
196
subjects
were
treated
with
10
mg/day,discontinuation
due
to
any
adverse
experience
occurred
in
4.1%
of
subjects
treated
with
alendronate,
and
6%
of
397
subjects
treated
with
placebo.
The
mostfrequently
reported
adverse
event
(occurring
in
>
2%
of
subjects
treated
with
alendronate)
in
this
study
were
abdominal
pain,
musculoskeletal
pain,
nausea,dyspepsia,
constipation,
diarrhea,
flatulence,
headache
and
acid
regurgitation.
Alendronate
may
cause
local
irritation
of
the
upper
gastrointestinal
mucosa.
Esophageal
adverse
experiences,
such
as
esophagitis,
esophageal
ulcers
and
esophagealerosions
occasionally
with
bleeding
and
rarely
followed
by
esophageal
stricture
or
perforation
have
been
reported.
Osteonecrosis
of
the
jaw
(ONJ),
which
can
occurspontaneously,
is
generally
associated
with
tooth
extraction
and/or
local
infection
with
delayed
healing,
has
been
reported
in
subjects
taking
alendronate.
Forsubjects
requiring
dental
procedures,
discontinuation
of
alendronate
therapy
may
reduce
the
risk
for
ONJ.
Atypical,
low-energy,
or
low
trauma
fractures
of
the
femoral
shaft
have
been
reported
in
bisphosphonate-treated
patients.
These
fractures
can
occur
anywhere
in
thefemoral
shaft
from
just
below
the
lesser
trochanter
to
above
the
supracondylar
flare
and
are
transverse
or
short
oblique
in
orientation
without
evidence
ofcomminution.
Causality
has
not
been
Protocol
BA058-05-005
Amendment
4,
Version
1
(24
August
2015)
13
Radius
Health,
Inc.
Confidential
established
as
these
fractures
also
occur
in
osteoporotic
patients
who
have
not
been
treated
with
bisphosphonates.
Atypical
femur
fractures
most
commonly
occur
with
minimal
or
no
trauma
to
the
affected
area.
They
may
be
bilateral
and
many
patients
report
prodromal
pain
inthe
affected
area,
usually
presenting
as
dull,
aching
thigh
pain,
weeks
to
months
before
a
complete
fracture
occurs.
A
number
of
reports
note
that
patients
were
alsoreceiving
treatment
with
glucocorticoids
(e.g.
prednisone)
at
the
time
of
fracture.
Any
patient
with
a
history
of
bisphosphonate
exposure
who
presents
with
thigh
or
groin
pain
should
be
suspected
of
having
an
atypical
fracture
and
should
beevaluated
to
rule
out
an
incomplete
femur
fracture.
Patients
presenting
with
an
atypical
fracture
should
also
be
assessed
for
symptoms
and
signs
of
fracture
in
thecontralateral
limb.
Interruption
of
bisphosphonate
therapy
should
be
considered,
pending
a
risk/benefit
assessment,
on
an
individual
basis.
According
to
the
Summary
of
Product
Characteristics
for
alendronate
from
the
EMA,
the
following
adverse
experiences
have
been
reported
in
alendronate
treatedsubject
during
clinical
trials
and/or
post-marketing
use:
Common:
Headache,
abdominal
pain,
dyspepsia,
constipation,
diarrhea,
flatulence,
esophageal
ulcer,
dysphagia,
abdominal
distension,
acid
regurgitation
andmusculoskeletal
pain.
Uncommon:
Nausea,
vomiting,
gastritis,
esophagitis,
esophageal
erosions,
melena,
rash,
pruritus
and
erythema.
Rare:
Hypersensitivity
reactions
including
urticarial
and
angioedema,
symptomatic
hypocalcemia
(often
in
association
with
predisposing
conditions),
uveitis,scleritis,
episcleritis,
esophageal
stricture,
oropharyngeal
ulceration,
upper
gastrointestinal
perforations,
ulcers
and
bleeds
(PUBs),
rash
with
photosensitivity,osteonecrosis
of
the
jaw,
atypical
subtrochanteric
and
diaphyseal
femoral
fractures
and
transient
symptoms
as
in
an
acute-phase
response
(myalgia,
malaise
andrarely,
fever),
typically
associated
with
initiation
of
treatment.
1.3 









Study Rationale and Selection of Doses
1.3.1






Study
Rationale
The
purpose
of
the
study
is
to
provide
longer
term
safety
data,
fracture
data
and
BMD
data
after
six
months
of
treatment
with
alendronate,
in
otherwise
healthyambulatory
postmenopausal
women
with
severe
osteoporosis
who
have
previously
received
18
months
of
blinded
treatment
with
Abaloparatide-SC
or
Placebo.Following
the
initial
six
months
of
treatment
in
this
study,
subjects
will
enter
the
long-term
observational
phase
of
the
study
during
which
the
subjects
will
continueto
receive
alendronate
for
an
additional
18
months.
1.3.2






Study
Design
Subjects
randomized
to
Abaloparatide-SC/Placebo,
who
have
completed
18
months
of
treatment
in
Protocol
BA058-05-003
and,
who
meet
the
Inclusion/Exclusioncriteria
(Sections
4.2
and
4.3)
are
eligible
to
participate
in
this
study.
Subjects
originally
randomized
to
Abaloparatide-SC/Placebo
in
Study
BA058-05-003
andwho
are
candidates
for
ongoing
Protocol
BA058-05-005
Amendment
4,
Version
1
(24
August
2015)
14
Radius
Health,
Inc.
Confidential
osteoporosis
care,
will
receive
24
months
of
weekly
open-label
alendronate
treatment
at
a
dose
of
70
mg/week.
1.3.3






Study
Population
The
study
population
in
this
protocol
is
comprised
of
otherwise
healthy
ambulatory
postmenopausal
women
who:
1.




have
participated
in
Study
BA058-05-003,
2.




were
randomized
to
either
Abaloparatide/Placebo,
3.




have
completed
the
End-of-Treatment
Visit
(Visit
9
in
Study
BA058-05-003),
and
4.




have
provided
a
new
written
informed
consent
for
this
protocol.
Subjects
will
not
be
enrolled
if
they
experienced
treatment-related
SAE
or
were
withdrawn
from
Study
BA058-05-003
for
any
reason.
1.3.4






Selection
of
Endpoints
The
fracture
incidence;
either
clinically
or
radiologically
determined,
based
on
clinical
events
or
protocol-directed
vertebral
x-rays
at
Month
6
of
this
ExtensionStudy;
will
be
analyzed.
In
addition,
BMD
results
from
the
six
months
of
treatment
with
alendronate
will
also
be
analyzed.
Bone
formation
(PINP,
osteocalcin,BSAP)
and
resorption
(CTX)
markers
will
also
be
assessed.
Clinical
incidence
of
any
fracture
and
radiologic
incidence
of
vertebral
fracture
will
also
be
evaluatedat
Month
24.
The
End-of-Treatment
(Visit
9)
evaluations
for
BMD,
vertebral
fracture,
and
non-vertebral
fracture
assessments
from
BA058-05-003
will
serve
as
thebaseline
evaluations
in
this
study.
In
addition
to
the
6-month
assessment,
clinical
and
radiologic
assessment
of
the
spine
for
assessment
of
fractures
will
be
performed
at
Month
24.
At
Months
6,
12,18
and
24,
BMD
by
DXA,
as
well
as
clinical
assessments
of
fractures
will
be
performed.
Bone
formation
and
resorption
markers
will
also
be
assessed
at
Day
1
andMonths
6,
12
18
and
24.
Further
details
of
these
assessments
are
in
Section
7.0,
and
in
Appendix
14.1
and
14.2.
Subjects
will
be
monitored
for
safety
events
and
will
have
safety
assessments
performed
at
each
study
visit.
1.3.5






Selection
of
Dose
The
dose
of
alendronate
(70
mg
per
week,
oral)
selected
for
this
study
is
based
upon
the
recommended
daily
dose
in
the
product’s
prescribing
information.
All
enrolled
subjects
will
also
continue
to
receive
calcium
(500-1000
mg)
and
vitamin
D
(400-800
IU)
supplementation.
2.0 









STUDY OBJECTIVES
The
primary
objective
of
this
study
is
to
evaluate
data
obtained
following
six
months
of
treatment
with
alendronate,
in
subjects
who
have
previously
received
18months
of
blinded
Abaloparatide
-SC/Placebo.
Safety
will
be
evaluated
with
clinical,
laboratory
and
radiologic
assessment.
The
analysis
at
six
months
will
bebased
on
the
treatment
that
subjects
were
randomized
to
in
the
BA058-05-003
study.
Following
the
initial
six
months
of
treatment
in
this
study,
subjects
will
thenenter
the
long-term
observational
phase
of
the
study
during
Protocol
BA058-05-005
Amendment
4,
Version
1
(24
August
2015)
15
Radius
Health,
Inc.
Confidential
which
the
subjects
will
continue
to
receive
alendronate
treatment
for
an
additional
18
months.
The
specific
objectives
of
this
study
are
to:
·


















Provide
additional
information
on
safety
in
study
subjects
receiving
six
months
of
treatment
with
alendronate
following
18
months
of
treatment
withAbaloparatide-SC/Placebo.
·


















Provide
information
on
the
vertebral
fracture
rate
in
subjects
receiving
six
months
of
treatment
with
alendronate
following
18
months
of
treatment
withAbaloparatide-SC/Placebo.
·


















Provide
additional
information
on
non-vertebral
fractures
and
BMD
change
associated
with
six
months
of
treatment
with
alendronate
following
18months
of
treatment
with
Abaloparatide-SC/Placebo.
·


















Provide
additional
information
on
BMD
change
and
osteoporosis
status
associated
with
24
months
of
treatment
with
alendronate
after
18
months
ofAbaloparatide-SC/Placebo.
The
analysis
performed
at
six
months
will
be
used
as
a
follow-up
to
the
18
month
fracture
endpoint
for
Study
BA058-05-003.
Vertebral
fractures
based
onradiologic
assessments
will
also
be
analyzed
at
Month
24.
Additional
analyses
for
other
endpoints
will
be
conducted
cumulatively
at
Months
12,
18,
and
24
(i.e.,Visits
4,
5,
and
6).
Full
details
of
the
statistical
procedures
to
be
used
will
be
provided
in
the
Statistical
Analysis
Plan.
3.0 









INVESTIGATIONAL PLAN
3.1 









Overall Design and Study Plan
This
study
is
an
open-label
extension
of
Study
BA058-05-003.
Subjects
and
Investigators
who
participate
in
Study
BA058-05-005
will
remain
blinded
to
priortreatment
assignment
as
part
of
BA058-05-003.
At
the
End-of-Treatment
visit
(Visit
9)
for
Study
BA058-05-003,
the
possibility
of
participating
in
the
ExtensionStudy
will
be
discussed
with
subjects
randomized
to
Abaloparatide-SC/Placebo.
The
Extension
Study
will
be
comprised
of
an
initial
six
months
of
treatment
withalendronate.
In
the
month
between
Visit
9
and
Visit
10,
the
Investigator
will
review
the
results
of
the
assessments
performed
at
Visit
9,
including
a
localinterpretation
of
BMD,
and
determine
if
alendronate
is
appropriate
for
the
subject.
All
subjects
will
continue
to
receive
vitamin
D
and
calcium
supplementation
asthey
did
in
Study
BA058-05-003.
The
study
design
is
presented
in
Figure
2,
below.
Protocol
BA058-05-005
Amendment
4,
Version
1
(24
August
2015)
16
Radius
Health,
Inc.
Confidential
Figure 2: Protocol BA058-05-005 Study Design

Participation
for
both
the
initial
and
observational
phases
of
the
will
be
approximately
24
months.
There
are
a
total
of
six
clinic
visits
during
the
course
of
the
study.
A
brief
summary
of
the
study
is
provided
below.
For
a
summary
of
the
study
assessments
to
be
performed,
refer
to
Section
7.0
(Study
Assessments)
and
to
theSchedule
of
Visits
and
Procedures
(Appendix
14.1).
A
more
detailed
description
of
the
study
procedures
on
a
by-visit
basis
is
provided
in
Appendix
14.2(Suggested
Schedule
of
Events
and
Procedures
by
Study
Visit).
A
suggested
order
of
procedures
is
also
provided
in
this
schedule.
3.1.1






Treatment
Period
Subjects
will
enter
into
Study
BA058-05-005
on
Day
1,
and
Day
1
will
also
serve
as
Visit
10
(the
Follow-up
Visit)
for
Study
BA058-05-003.
The
InformedConsent
must
be
signed
prior
to
undergoing
any
BA058-05-005
study
related
procedures,
and
may
be
signed
at
either
Visit
9
or
Visit
10
of
Study
BA058-05-003.Subjects
who
received
Abaloparatide-SC/Placebo
in
Study
BA058-05-003
will
receive
six
months
of
open-label
oral
alendronate
treatment
as
part
of
this
study(BA058-05-005).
Following
the
initial
six
months
of
treatment
in
this
study,
subjects
will
then
enter
the
long-term
observational
phase
of
this
study
during
whichthe
subjects
will
continue
to
receive
alendronate
care
for
an
additional
18
months.
If
determined
by
the
Investigator
to
be
appropriate,
treatment
will
be
by
oral
administration
of
alendronate
at
a
total
dose
of
70
mg
once
per
week.
Subjects
will
begiven
a
weekly
diary
card
to
record
missed
doses
of
medication
including
calcium
and
vitamin
D.
A
total
of
six
clinic
visits
are
scheduled
during
the
study
(Day
1,
Month
3,
Month
6,
Month
12,
Month
18
and
Month
24).
Subjects
will
be
instructed
to
take
their
first
dose
of
study
drug
for
Study
BA058-05-005
in
the
morning,
within
a
week
of
their
Day
1
visit
(Day
2
of
this
study).Study
subjects
will
Protocol
BA058-05-005
Amendment
4,
Version
1
(24
August
2015)
17
Radius
Health,
Inc.
Confidential
continue
calcium
and
vitamin
D
supplementation
during
this
study
as
was
administered
during
BA058-05-003
(Section
6.1).
At
Month
3,
subjects
will
return
to
the
clinic
for
medication
resupply,
subject
diary
review
and
questioning
as
to
their
use
of
concomitant
medications
and
theoccurrence
of
adverse
events.
At
the
Month
6
visit
ECG,
and
safety
labs
will
be
performed.
Vertebral
fractures
will
be
determined
clinically
and
via
protocol
directed
x-ray
evaluation;
non-vertebral
fractures
will
be
determined
clinically.
In
addition,
subjects
will
undergo
a
DXA
of
the
hip
and
spine
(and
wrist,
if
the
subject
was
enrolled
in
the
wristDXA
sub-study
in
Study
BA058-05-003),
and
have
samples
drawn
for
bone
markers
and
anti-abaloparatide
antibodies.
Procedures
are
to
be
performed
as
describedin
Section
7.0,
Appendix
14.1
and
Appendix
14.2.
At
Months
12
and
18,
subjects
will
return
to
the
clinic
for
safety
labs,
DXA
of
the
hip
and
spine
(and
wrist,
if
the
subject
was
enrolled
in
the
wrist
DXA
sub-studyin
Study
BA058-05-003),
medication
resupply,
subject
diary
review
and
questioning
as
to
their
use
of
concomitant
medications
and
occurrence
of
adverse
events.Serum
samples
for
bone
markers
will
also
be
drawn.
At
Month
24,
subjects
will
return
to
the
clinic
for
safety
labs,
and
will
undergo
clinical
and
radiologic
fracture
assessments
and
have
DXA
of
the
hip
and
spine
(andwrist,
if
the
subject
was
enrolled
in
the
wrist
DXA
sub-study
in
Study
BA058-05-003).
Serum
samples
for
bone
markers
will
also
be
drawn.
Any
adverse
event
orclinical
laboratory
abnormality
recorded
at
the
Month
24
Visit
will
be
monitored
until
it
has
resolved,
become
chronic
or
stable.
4.0 









SELECTION OF STUDY POPULATION
4.1 









Number of Subjects
Subjects
who
completed
18
months
of
treatment
with
either
Abaloparatide-SC/Placebo
in
Study
BA058-05-003
will
be
given
the
opportunity
to
participate
in
theExtension
Study
at
all
participating
centers.
Based
on
randomization
to
the
Abaloparatide-SC/Placebo
arms
in
Study
BA058-05-003,
up
to
1,600
subjects
may
beentered
into
this
study.
The
specific
inclusion
and
exclusion
criteria
for
enrolling
subjects
in
this
study
are
presented
below
in
Sections
4.2
and
4.3,
respectively.
Exceptions
to
thesecriteria
should
occur
infrequently
and
should
be
discussed
in
advance
and
approved
by
the
Sponsor
Medical
Monitor.
4.2 









Inclusion Criteria
Subjects
must
meet
all
of
the
following
criteria
to
be
eligible
to
participate
in
this
study:
1.














The
subject
was
enrolled,
randomized
to
Abaloparatide-SC/Placebo
and
completed
18-months
of
blinded
treatment
within
Study
BA058-05-003.
2.




The
subject
is
no
more
than
40
days
from
Visit
9
in
Study
BA058-05-003.
3.














The
subject
has
read,
understood,
and
signed
the
written
informed
consent
form
for
the
Extension
Study.
Protocol
BA058-05-005
Amendment
4,
Version
1
(24
August
2015)
18
Radius
Health,
Inc.
Confidential
4.3 






























Exclusion Criteria
Subjects
with
any
of
the
following
characteristics
are
not
eligible
to
participate
in
the
study:
1.














Subjects
who
were
withdrawn
from
Study
BA058-05-003
for
any
reason.
2.














Subjects
who
experienced
a
treatment-related
SAE
during
Study
BA058-05-003.
4.4 






























Withdrawal of Subjects from the Study
Subjects
will
be
informed
that
they
have
the
right
to
withdraw
from
the
study
at
any
time
for
any
reason
without
prejudice
to
their
medical
care.
Consistent
with
the
prior
protocol,
BA058-05-003,
the
Investigator
must
withdraw
subjects
from
the
study
prior
at
any
time
in
the
study
for
the
following
reasons:
·













Continuing
significant
deterioration
from
the
Day
1
assessment
of
Study
BA058-05-005
(>7%)
of
BMD
at
spine
or
hip
(after
confirmation
of
thefinding);
·













Treatment-related
SAEs;
·













Refusal
of
treatment;
·













Refusal
or
inability
to
complete
study
procedures;
·













Lost
to
follow-up.
The
Investigator
should
exercise
his/her
best
judgment
and
also
has
the
right
to
withdraw
subjects
from
the
study
during
the
study
for
any
of
the
following
reasons:
·


















ECOG
Grade
3
or
4
adverse
events
[Refer
to
Appendix14.3];
·


















A
complex
of
adverse
events
which,
in
the
judgment
of
the
Investigator
justifies
treatment
cessation;
·


















Serious
intercurrent
illness;
·


















Non-compliance;
·


















Protocol
violations;
·


















Administrative
reasons.
If
a
subject
is
withdrawn
or
discontinued
from
the
study,
the
reason
for
withdrawal
is
to
be
recorded
in
the
source
documents
and
on
the
case
report
form.
Allsubjects
withdrawn
prior
to
completing
the
study
should
be
encouraged
to
complete
the
Month
6
or
Month
24
Visit
(depending
on
the
length
of
time
on
study)including
any
outstanding
radiologic
assessment
or
BMD
assessment
by
DXA.
4.5 






























Temporary Suspension of Treatment
The
Investigator
has
the
right
to
suspend
treatment
with
alendronate
without
withdrawal
of
the
subject
from
the
study.
Reasons
for
temporary
suspension
oftreatment
may
include
a
medical
reason
unrelated
to
an
adverse
event
(e.g.,
a
planned
procedure),
or
important
social
or
administrative
events.
The
reason
for
thesuspension
of
treatment
is
to
be
documented
in
the
electronic
case
report
form
(eCRF)
and
in
source
documents.
Protocol
BA058-05-005
Amendment
4,
Version
1
(24
August
2015)
19
Radius
Health,
Inc.
Confidential
When
treatment
with
alendronate
is
restarted,
the
subject
should
resume
treatment
with
the
next
scheduled
dose
(as
if
treatment
had
not
been
interrupted).
4.6 






























Replacement of Subjects
Subjects
who
have
been
enrolled
into
the
study
and
subsequently
withdraw
or
drop
out
of
the
study
will
not
be
replaced.
5.0 






























STUDY TREATMENTS
5.1 






























Study Medications
Alendronate
will
be
sourced
locally.
Calcium
and
vitamin
D
will
be
provided
by
the
study
centers,
similar
to
their
provision
in
Study
BA058-05-003.
5.1.1





















Alendronate
Alendronate
will
be
sourced
centrally
for
Europe,
Hong
Kong
and
the
US,
and
will
be
sourced
locally
for
South
America
at
the
expense
of
the
Sponsor.
However,alendronate
may
be
locally
sourced
in
all
venues
when
centrally
supplied
alendronate
is
unavailable
due
to
unforeseen
delays.
The
local
source
will
be
documentedin
the
study
drug
logs.
Subjects
will
receive
oral
alendronate
at
a
dose
of
70
mg
once
per
week
beginning
on
Day
2
for
24
months.
Additional
provisions
for
dosing
of
alendronate
shouldbe
followed
based
on
the
prescribing
information.
Alendronate
provided
will
be
in
the
approved,
marketed
formulation.
The
alendronate
may
be
genericsubstitutable
approved
versions
which
contain
different
inactive
ingredients,
but
the
amount
of
active
free
alendronate
must
be
equivalent
to
70
mg
per
week.
5.1.1.1











Restrictions
on
Alendronate
Use
Subjects
should
not
receive
alendronate
if
they
have
the
following
conditions/limitations:
·










































Abnormalities
of
the
esophagus
and
other
factors
which
delay
esophageal
emptying
such
as
stricture
or
achalasia.
·











































Inability
to
stand
or
sit
upright
for
at
least
30
minutes.
·











































Hypocalcemia.
·










































Known
history
of
hypersensitivity
to
alendronate,
alendronate
excipients,
or
related
compounds.
5.1.2





















Calcium
and
Vitamin
D
Supplements
Calcium
and
vitamin
D
supplements
will
be
sourced
locally
and
provided
by
the
sites
at
the
expense
of
the
Sponsor.
5.2 






























Packaging, Labeling and Storage
Centrally
supplied
alendronate
will
not
be
repackaged
for
the
study,
but
will
be
over-labeled
according
to
local
regulatory
requirements
as
necessary.
Calcium
and
vitamin
D
supplements
will
not
be
relabeled
for
the
study.
Protocol
BA058-05-005
Amendment
4,
Version
1
(24
August
2015)
20
Radius
Health,
Inc.
Confidential
5.2.1





















Storage
Alendronate
must
be
kept
in
a
secure,
limited-access
storage
area
until
dispensed
for
use
to
a
study
subject.
Alendronate
sodium
should
be
stored
in
the
containerprovided
at
room
temperature,
15-30ºC
(59-86ºF).
Calcium
and
vitamin
D
supplements
may
be
stored
at
room
temperature.
5.3 






























Treatment Assignment
All
subjects
who
participate
will
continue
to
be
identified
by
the
same
7-digit
subject
number
that
was
assigned
upon
enrollment
into
Study
BA058-05-003throughout
the
study
and
on
the
eCRF.
5.4 






























Study Medication Administration
5.4.1





















Alendronate
Administration
Alendronate
must
be
taken
with
water
only
(not
mineral
water)
at
least
30
minutes
before
the
first
food,
beverage
or
medicinal
product
(including
antacids,
calciumsupplements
and
vitamins)
of
the
day.
Other
beverages
(including
mineral
water),
food
and
some
medicinal
products
are
likely
to
reduce
the
absorption
ofalendronate.
The
following
instructions
should
be
followed
exactly
in
order
to
minimize
the
risk
of
esophageal
irritation
and
related
adverse
reactions.
·


















Alendronate
should
only
be
swallowed
after
getting
up
for
the
day
with
a
full
glass
of
water
(not
less
than
200
mL
or
7
fl.
oz.).·


















Subjects
should
only
swallow
alendronate
whole.
Subjects
should
not
crush
or
chew
the
tablet
or
allow
the
tablet
to
dissolve
in
their
mouths
because
of
apotential
for
oropharyngeal
ulceration.·


















Subjects
should
not
lie
down
until
after
their
first
food
of
the
day.·


















Subjects
should
not
lie
down
for
at
least
30
minutes
after
taking
alendronate.·


















Alendronate
should
not
be
taken
at
bedtime
or
before
arising
for
the
day.
At
the
Month
3,
Month
6,
Month
12
and
Month
18
visits,
the
unused
alendronate
tablets
are
to
be
returned
to
the
clinic
for
counting
and
the
subject
will
bedispensed
additional
alendronate.
At
the
Month
24
visit,
all
unused
alendronate
tablets
are
to
be
returned
to
the
study
site.
5.5 






























Treatment Compliance
The
study
site
personnel
will
perform
drug
accountability
at
each
clinic
visit
and
review
each
subject
diary
(refer
to
Section
7.1.16).
Accountability
will
bedocumented
on
the
appropriate
forms
and
subjects
will
be
re-trained
on
administration
as
appropriate.
All
doses
of
study
medication
are
to
be
self-administered.
If
a
subject
does
not
administer
or
take
all
study
medication
including
vitamin
D
or
calcium,
the
reason
for
the
missed
dosing
is
to
be
recorded
in
source
documentsand
on
the
eCRF.
Returned,
unused
alendronate
will
be
accounted
for
by
the
study
site
and
destroyed
as
appropriate.
5.6 






























Unblinding of Study Medication
Not
applicable.
Protocol
BA058-05-005
Amendment
4,
Version
1
(24
August
2015)
21
Radius
Health,
Inc.
Confidential
6.0 






























CONCOMITANT MEDICATIONS
6.1 






























Concomitant Medications
Vitamin
D
and
calcium
supplements
are
required
to
be
administered
daily
from
Day
1
(continuing
from
Protocol
BA058-05-003)
until
the
Month
6
Visit.
VitaminD
and
calcium
supplements
will
be
administered
in
the
following
doses:
400-800
IU/day
(Vitamin
D)
and
500-100mg/day
(calcium),
or
at
a
dose
to
be
determinedby
the
Investigator
according
to
the
subjects
need.
The
doses
and
schedule
of
Vitamin
D
and
calcium
supplements,
which
are
part
of
the
study
medication
protocol,should
be
adhered
to
and
not
be
changed
other
than
for
medical
necessity.
The
supplements
should
be
taken
in
the
evening
with
or
without
food
or
as
otherwiseinstructed
by
the
Investigator.
For
any
required
concomitant
medication,
such
as
statins
or
antihypertensives,
the
subject
must
be
on
a
stable
dose
at
study
entry
and
every
effort
should
be
madeto
maintain
a
stable
dose
during
study
participation.
The
occasional
use
of
over-the-counter
medications
at
approved
doses
(e.g.,
ibuprofen
or
acetaminophen)
for
headache
or
minor
discomfort
is
allowed.
Occasionalshort
term
(
<
3
months)
use
of
corticosteroids
for
seasonal
allergies
or
asthma
is
also
allowed.
These
are
to
be
recorded
on
the
appropriate
case
report
form.Subjects
should
not
take
any
other
medications,
including
over-the-counter
medications,
herbal
medications,
or
mega-doses
of
vitamins
during
the
study
withoutprior
approval
of
the
Investigator.
If
it
becomes
necessary
for
a
subject
to
take
any
other
medication
during
the
study,
the
specific
medication(s)
and
indication(s)
must
be
discussed
with
theInvestigator.
All
concomitant
medications
taken
during
the
course
of
the
study
must
be
recorded
in
the
Subject’s
medical
record
or
source
document
andtranscribed
into
the
case
report
form.
6.2 






























Prohibited Medications
Subjects
who
require
treatment
during
the
course
of
the
study
with
either
an
anticonvulsant
(phenobarbital,
phenytoin,
carbamazepin
or
primidone)
or
chronictreatment
with
any
form
of
heparin
will
be
discontinued.
Estrogens
given
as
HRT
are
allowed
at
entry
into
the
study
but
cannot
be
initiated
during
the
study
exceptfor
local
low
dose
vaginal
estrogen.
Drugs
that
may
compromise
renal
function
such
as
non-steroidal
anti-inflammatory
drugs
should
be
used
with
caution.
7.0 






























STUDY ASSESSMENTS
Subjects
randomized
to
Abaloparatide-SC/Placebo
in
Study
BA058-05-003
will
receive
alendronate
at
a
dose
of
70
mg
once
per
week
for
a
total
of
24
months.
The
assessments
performed
at
each
study
visit
are
displayed
in
the
Schedule
of
Visits
and
Procedures
in
Appendix
14.1.
Appendix
14.2
provides
a
more
detailedschedule
of
the
study
procedures
by
study
visit
with
a
suggested
order
of
procedure
conduct.
Exact
procedures
for
centrifuging,
storage,
and
shipping
of
laboratorysamples
will
be
detailed
in
a
separate
document.
The
actual
time
of
each
blood
collection
will
be
recorded
on
the
appropriate
source
documents
and
in
the
eCRF.
Protocol
BA058-05-005
Amendment
4,
Version
1
(24
August
2015)
22
Radius
Health,
Inc.
Confidential
Study-specific
assessments
are
to
be
conducted
only
after
the
subject
has
provided
written
informed
consent
to
participate
in
this
study.
The
study
assessments
aredescribed
in
more
detail
in
Section
7.1
below.
7.1 






























Clinical Procedures/Assessments
7.1.1





















Informed
Consent
At
the
End-of-Treatment
Visit
(Visit
9)
for
Study
BA058-05-003,
the
possibility
of
participating
in
the
Extension
Study
will
be
discussed
with
the
subjectsrandomized
to
Abaloparatide-SC/Placebo.
The
Informed
Consent
must
be
signed
prior
to
undergoing
any
BA058-05-005
study
related
procedures,
and
may
besigned
at
either
Visit
9
or
Visit
10
of
Study
BA058-05-003.
7.1.2





















Recent
Health
Status
The
subject’s
health
status
will
be
updated
from
their
last
visit
in
Study
BA058-05-003,
as
necessary.
Any
changes
in
health
status
should
be
recorded
as
an
adverseevent,
as
appropriate.
The
physical
examination
from
the
End-of-Treatment
visit
(Visit
9)
of
Study
BA058-05-003
will
be
the
baseline
for
this
study
(Day
1).
Interim
or
symptom-directed
physical
examinations
may
be
performed
at
the
discretion
of
the
Investigator,
if
necessary,
to
evaluate
adverse
events
or
clinicallaboratory
abnormalities.
7.1.3





















Vital
Signs
Blood
pressure,
body
temperature
(ºC),
pulse
(bpm)
and
respiration
rate
(breaths
per
minute)
are
to
be
measured
and
recorded
at
each
study
visit
(Day
1,
Month
3and
Month
6,
Month
12,
Month
18
and
Month
24).
Only
the
Day
1
blood
pressure
assessments
need
be
conducted
as
an
orthostatic
measurement
(SeeSection
7.1.5).
7.1.4





















Height
and
Weight
Height
and
weight
are
to
be
measured
at
each
study
visit
(Day
1,
Month
3,
Month
12,
Month
18
and
Month
24).
Height
is
to
be
measured
in
the
standing
positionusing
a
medical
stadiometer.
7.1.5





















Orthostatic
Blood
Pressure
and
Heart
Rate
The
Day
1
orthostatic
blood
pressure
measurement
for
Study
BA058-05-005
will
serve
as
the
Visit
10
orthostatic
blood
pressure
for
Study
BA058-05-003.
Bloodpressure
(mmHg;
measured
in
the
same
arm
at
each
visit)
and
pulse
rate
(bpm)
will
be
measured
after
five
minutes
in
the
supine
position.
Immediately
followingthis
measurement,
blood
pressure
will
be
measured
again
after
three
minutes
in
the
standing
position.
7.1.6





















Electrocardiogram
A
twelve-lead
supine
electrocardiograms
(ECGs)
will
be
performed
and
the
following
ECG
parameters
will
be
recorded:
rhythm,
heart
rate,
PR
interval,
QRSduration
and
QT/QTc.
The
Day
1
ECG
measurement
for
Study
BA058-05-005
will
serve
as
the
Visit
10
ECG
measurement
for
Study
BA058-05-003.
An
ECG
will
also
be
obtained
atMonth
6.
Protocol
BA058-05-005
Amendment
4,
Version
1
(24
August
2015)
23
Radius
Health,
Inc.
Confidential
7.1.7





















Clinical
Laboratory
Evaluations
Clinical
laboratory
evaluations
will
be
performed
by
a
central
laboratory.
Prior
to
starting
the
study,
the
Sponsor
(or
its
designee)
will
provide
each
Investigatorwith
copies
of
the
appropriate
laboratory
certifications
and
normal
ranges
for
all
laboratory
parameters
to
be
performed
by
that
laboratory.
The
blood
and
urinalysis
samples
are
to
be
obtained
under
fasting
conditions
(NPO
for
8
hours;
water
is
acceptable)
in
the
morning
of
each
scheduled
study
visitson
Day
1
and
Months
6,
12,
18,
and
24.
All
clinically
significant
laboratory
abnormities
indicating
an
adverse
event
will
be
followed
up
by
repeat
testing
and
further
investigated
as
necessary,
according
tothe
judgment
of
the
Investigator.
7.1.8





















Clinical
Chemistry
and
Urinalysis
(Dipstick)
Clinical
chemistry
and
dipstick
urinalysis
will
be
performed
on
Day
1
and
at
Months
6,
12,
18,
and
24.
Urinalysis
will
be
performed
using
samples
freshly
voidedduring
the
clinic
visit.
If
there
are
positive
findings
noted
on
the
dipstick,
a
urine
microscopic
examination
will
be
performed.
The
following
tests
will
beperformed:
Serum
Chemistry·Sodium·Potassium·Chloride·Inorganic
phosphorus·Albumin·Total
protein·Glucose·Blood
urea
nitrogen
(BUN)·Creatinine·Uric
acid·Aspartate
aminotransferase
(AST)·Alanine
aminotransferase
(ALT)·Gamma-glutamyltranspeptidase
(GGT)·Creatine
phosphokinase
(CPK)·Alkaline
phosphatase·Total
bilirubin·Lactate
dehydrogenase
(LDH)·Cholesterol·Triglycerides·Total
calciumUrinalysis·pH·Glucose·Protein·Ketones·Bilirubin·Blood·Urobilinogen
Protocol
BA058-05-005
Amendment
4,
Version
1
(24
August
2015)
24
Radius
Health,
Inc.
Confidential
·Specific
gravity·Nitrite·Leukocytes
7.1.9





















Hematology
Hematology
testing
will
be
performed
on
Day
1
and
at
Months
6,
12,
18,
and
24.
The
following
tests
will
be
performed:
Hematology
:·Hemoglobin·Hematocrit·WBC
count
with
differential
in
absolute
counts·RBC
count·Mean
corpuscular
volume
(MCV)·Mean
corpuscular
hemoglobin
concentration
(MCHC)·Mean
corpuscular
hemoglobin
(MCH)·Platelet
count
7.1.10














Coagulation
Coagulation
testing
will
be
performed
on
Day
1
and
at
Months
6
and
24.
The
following
tests
will
be
performed:
·Prothrombin
time
(PT)·Partial
thromboplastin
time
(PTT)
7.1.11














24-Hour
Urine
Collection
The
24-hour
urine
collection
is
to
be
begun
the
day
before
the
Day
1
and
Month
6
visits.
If
a
sample
was
not
able
to
be
collected
on
the
day
prior
to
the
Day
1
visit(i.e.,
if
the
subject
had
not
yet
signed
the
ICF
for
study
participation),
a
24-hour
urine
sample
must
be
collected
on
the
day
prior
to
the
Month
3
visit.
Subjects
are
tobe
instructed
to
begin
the
urine
collection
by
discarding
the
first
morning
void
(~6
a.m.)
the
day
prior
to
the
scheduled
clinic
visit
and
to
then
collect
their
urine
for24
hours.
A
final
void
is
to
be
collected
at
the
end
of
the
24-hour
period
and
the
urine
collection
transported
to
the
clinic
by
the
subject.
The
24-hour
urinalysis
willbe
used
to
measure
urinary
calcium
and
urinary
creatinine.
7.1.12














Bone
Mineral
Density
All
subjects
will
have
bone
mineral
density
measurements
(BMD)
taken
via
DXA
at
Months
6,
12,
18,
and
24.
The
End-of-Treatment
(Visit
9)
bone
mineraldensity
tests
for
Study
BA058-05-003
will
serve
as
the
baseline
BMD
measurements
for
Study
BA058-05-005.
DXAs
will
be
performed
on
the
hip
(femoral
neck)
and
spine
(L1-4).
The
spinal
DXA
is
to
be
taken
in
the
postero-anterior
(PA)
projection
with
any
subsequentspinal
DXA
to
be
taken
in
the
same
projection.
Subjects
who
underwent
wrist
DXAs
in
Study
BA058-05-003
will
also
have
wrist
DXAs
performed
at
Months
6,12,
18,
and
24.
The
same
side
of
the
hip
and
wrist
that
were
used
in
Study
BA058-05-003
must
be
used
for
the
DXA
scan,
and
the
same
scanner
should
be
usedthroughout
the
study,
when
possible.
If
the
independent
radiologist
identifies
any
patient
who
shows
a
continuing
significant
deterioration
from
the
Day
1
assessment
of
Study
BA058-05-005
(>7%)
ofBMD
at
spine
or
hip
during
the
study,
the
study
physician
will
be
notified,
the
assessment
will
be
repeated
Protocol
BA058-05-005
Amendment
4,
Version
1
(24
August
2015)
25
Radius
Health,
Inc.
Confidential
and,
if
confirmed,
the
patient
will
be
discontinued
from
the
study.
The
study
physician
will
make
this
determination
on
the
basis
of
the
centrally
read
DXA
relativeto
the
baseline
measurement
in
consultation
with
the
Sponsor
Medical
Monitor.
7.1.13














Serum
Markers
of
Bone
Metabolism
Blood
samples
to
measure
bone
markers
will
be
taken
on
Day
1
and
at
Months
6,
12,
18
and
24.
The
results
of
the
bone
markers
will
be
reported
in
the
same
subsetof
subjects
reported
on
for
Study
BA058-05-003.
The
following
markers
of
bone
formation
will
be
measured:
·

















Serum
N-terminal
propeptide
of
type
I
procollagen
(PINP);
·

















Serum
bone-specific
alkaline
phosphatase
(BSAP);
·

















Serum
osteocalcin.
The
following
marker
of
bone
resorption
will
be
measured:
·


















Serum
C-telopeptides
of
type
1
collagen
crosslinks
(CTX).
7.1.14














Clinical
and
Radiologic
Evaluation
of
Fractures
Subjects
will
undergo
protocol
directed
antero-posterior
and
lateral
radiographs
of
the
lumbar
and
thoracic
spines
at
Month
6
and
Month
24.
The
End-of-Treatment(Visit
9)
clinical
and
radiological
evaluation
of
fractures
for
Study
BA058-05-003
will
serve
as
the
baseline
assessments
for
Study
BA058-05-005.
Subjects
willalso
be
clinically
evaluated
for
non-vertebral
fractures
(wrist,
hip,
rib,
etc.)
that
occur
de
novo
during
the
Treatment
Period.
Documentation
should
be
obtained
onall
de
novo
fractures
that
occur
during
the
Treatment
Period.
This
documentation
should
be
maintained
in
the
source
documents.
All
radiographs
will
be
viewed
and
assessed
centrally
by
a
blinded,
independent
assessor
(radiologist)
on
the
basis
of
existing
baseline
and
study-acquired
vertebraldeformity.
Fractures
will
be
assessed
according
to
the
severity
scale
of
Genant
(1993).
A
second
blinded
radiologist
will
confirm
the
assessment
of
the
firstreviewer
for
all
subject
radiographs
in
which
an
incident
fracture
has
been
identified.
In
the
case
of
any
disagreement,
a
third
consensus
assessment
will
be
made
toadjudicate
the
incident
fracture.
Fractures
identified
during
the
study
will
not
be
recorded
as
AEs
unless
the
subject
is
hospitalized,
the
fracture
is
complicated,
or
the
Investigator
considers
thefracture
to
be
unrelated
to
the
subject’s
underlying
osteoporosis.
All
fractures
(vertebral
and
non-vertebral)
will
be
identified
and
evaluated
as
part
of
the
diseaseassessment
and
will
be
documented
in
the
fracture
page
of
the
case
report
form
and
source
documents.
7.1.15














Abaloparatide
Antibody
Assessments
The
occurrence
of
anti-drug
antibodies
will
be
assessed
at
the
completion
of
the
initial
six
months
of
the
study.
Serum
samples
will
be
drawn
at
Month
6.
Anysubject
who
tests
positive,
or
has
previously
tested
positive
for
antibodies
will
be
retested
at
six
month
intervals
until
the
antibody
titer
is
negative.
At
thecompletion
of
the
24
months
of
the
study,
if
the
subject
is
still
antibody
positive,
the
subject
will
sign
a
new
consent
form
to
allow
the
antibody
draws
to
continue.Exact
procedures
for
collection,
preparation,
storage,
and
shipping
of
these
samples
will
be
detailed
in
a
separate
document.
During
the
24
months
of
the
study,
theactual
time
and
date
of
each
blood
collection
will
be
recorded
on
the
Protocol
BA058-05-005
Amendment
4,
Version
1
(24
August
2015)
26
Radius
Health,
Inc.
Confidential
appropriate
source
document
and
in
the
eCRF.
Information
on
antibodies
collected
subsequent
to
the
24
months
of
the
present
study
will
be
collected
in
a
paper
orelectronic
CRF.
7.1.16














Subject
Diaries
A
weekly
diary
will
be
completed
by
the
subject
beginning
on
the
Day
1
visit
and
continuing
until
the
last
day
of
Month
24.
This
diary
will
capture
missed
doses
ofvitamin
D,
calcium
and
alendronate.
The
weekly
diary
will
be
reviewed
at
each
study
visit.
7.1.17














Activity
and
Diet
Subjects
who
qualify
for
enrollment
in
the
study
will
have
no
restrictions
placed
on
their
usual
level
of
activity
or
on
their
usual
diet,
unless
directed
by
the
treatingphysician
for
medically
justified
reasons.
8.0 






























ADVERSE EVENTS AND SAFETY EVALUATION
Timely,
accurate,
and
complete
reporting
and
analysis
of
safety
information
from
clinical
studies
are
crucial
for
the
protection
of
subjects,
Investigators
and
theSponsor,
and
is
mandated
by
Regulatory
Agencies
worldwide.
All
clinical
trials
sponsored
by
RADIUS
will
be
conducted
in
accordance
with
Standard
OperatingProcedures
(SOPs)
that
have
been
established
to
conform
to
regulatory
requirements
worldwide
to
ensure
appropriate
reporting
of
safety
information.
8.1 






























Definitions, Documentation, and Reporting
8.1.1





















Adverse
Event
Definition
An
adverse
event
(AE)
is
any
untoward
medical
occurrence
in
a
subject
administered
a
pharmaceutical
product,
which
does
not
necessarily
have
a
causalrelationship
with
the
treatment.
An
AE
can
be
any
unfavorable
and
unintended
sign
(including
an
abnormal
laboratory
finding),
symptom,
or
disease
temporallyassociated
with
the
use
of
the
study
drug,
whether
or
not
it
is
considered
to
be
study
drug
related.
This
includes
any
newly
occurring
event
or
previous
conditionthat
has
increased
in
severity
or
frequency
since
the
administration
of
study
drug.
8.1.2





















Serious
Adverse
Event
Definition
A
serious
adverse
event
(SAE)
is
any
adverse
event,
occurring
at
any
dose
and
regardless
of
causality
that:
·


















Results
in
death.
·


















Is
life-threatening.
Life-threatening
means
that
the
subject
was
at
immediate
risk
of
death
from
the
reaction
as
it
occurred,
i.e.,
it
does
not
include
areaction
which
hypothetically
might
have
caused
death
had
it
occurred
in
a
more
severe
form.
·


















Requires
in-patient
hospitalization
or
prolongation
of
existing
hospitalization.
Hospitalization
admissions
and/or
surgical
operations
scheduled
tooccur
during
the
study
period,
but
planned
prior
to
study
entry
are
not
considered
AEs
if
the
illness
or
disease
existed
before
the
subject
was
enrolledin
the
trial.
Provided
that
the
illness/disease
did
not
deteriorate
in
an
unexpected
manner
during
the
trial
(e.g.,
surgery
performed
earlier
thanplanned).
Protocol
BA058-05-005
Amendment
4,
Version
1
(24
August
2015)
27
Radius
Health,
Inc.
Confidential
·


















Results
in
persistent
or
significant
disability/incapacity.
Disability
is
defined
as
a
substantial
disruption
of
a
person’s
ability
to
conduct
normal
lifefunctions.
·


















Is
a
congenital
anomaly/birth
defect.
This
includes
any
anomaly
detected
at
or
after
birth,
or
any
anomaly
that
results
in
fetal
loss.
·


















Is
an
important
medical
event.
An
important
medical
event
is
an
event
that
may
not
result
in
death,
be
life-threatening,
or
require
hospitalization,
butmay
be
considered
an
SAE
when,
based
upon
appropriate
medical
judgment,
it
may
jeopardize
the
subject
and
may
require
medical
or
surgicalintervention
to
prevent
one
of
the
outcomes
listed
in
the
definitions
for
SAEs.
Examples
of
such
medical
events
include
allergic
bronchospasmrequiring
intensive
treatment
in
an
emergency
room
or
at
home,
blood
dyscrasias
or
convulsions
that
do
not
result
in
in-patient
hospitalization,
or
thedevelopment
of
drug
dependency
or
drug
abuse.
Clarification
should
be
made
between
the
terms
“serious”
and
“severe”
since
they
are
not
synonymous.
The
term
“severe”
is
often
used
to
describe
the
intensity(synonym:
severity)
of
a
specific
event
(as
in
mild,
moderate,
or
severe
myocardial
infarction);
the
event
itself,
however,
may
be
of
relatively
minor
medicalsignificance
(such
as
a
severe
headache).
This
is
not
the
same
as
“serious,”
which
is
based
on
subject/event
outcome
or
action
criteria
described
above
and
areusually
associated
with
events
that
pose
a
threat
to
a
subject’s
life
or
functioning.
A
severe
adverse
event
does
not
necessarily
need
to
be
considered
serious.
Forexample,
persistent
nausea
of
several
hours
duration
may
be
considered
severe
nausea
but
not
an
SAE.
On
the
other
hand,
a
stroke
resulting
in
only
a
minor
degreeof
disability
may
be
considered
mild,
but
would
be
defined
as
an
SAE
based
on
the
above
noted
criteria.
Seriousness
(not
severity)
serves
as
a
guide
for
definingregulatory
reporting
obligations.
8.2 






























Monitoring of Adverse Events and Period of Observation
All
AEs
will
be
monitored
until
they
are
resolved
or
have
become
chronic
or
stable.
AEs
and
SAEs
will
be
recorded
on
the
case
report
forms
starting
from
the
timeof
subject
entry
from
Day
1
of
the
study
until
the
final
study
visit
(Month
24).
Any
SAEs
that
occur
at
any
time
after
completion
of
the
study,
which
theInvestigator
considers
to
be
related
to
study
drug,
must
be
reported
to
the
Sponsor
or
its
designee.
8.3 






























Procedures for Recording and Reporting AEs and SAEs
All
adverse
events
spontaneously
reported
by
the
subject
and/or
in
response
to
an
open
question
from
study
personnel
or
revealed
by
observation,
physicalexamination
or
other
diagnostic
procedures
must
be
recorded
in
the
source
document
and
on
the
appropriate
page
of
the
case
report
form.
Any
clinically
relevantdeterioration
in
laboratory
assessments
or
other
clinical
findings
is
considered
an
adverse
event
and
must
be
recorded
on
the
appropriate
pages
of
the
case
reportform.
When
possible,
signs
and
symptoms
indicating
a
common
underlying
pathology
should
be
noted
as
one
comprehensive
event.
All
SAEs
that
occur
during
the
course
of
the
study,
as
defined
by
the
protocol,
must
be
reported
by
the
Investigator
to
the
Study
Safety
Officer
by
completing
andtransmitting
the
SAE
Form
within
one
working
day
from
the
point
in
time
when
the
Investigator
becomes
aware
of
the
SAE.
In
addition,
all
SAEs
including
alldeaths,
which
occur
up
to
and
including
30
days
after
administration
of
the
last
dose
of
study
drug,
must
be
reported
to
the
Study
Safety
Officer
within
one
workingday.
All
SAEs
and
deaths
must
be
reported
Protocol
BA058-05-005
Amendment
4,
Version
1
(24
August
2015)
28
Radius
Health,
Inc.
Confidential
whether
or
not
considered
causally
related
to
the
study
drug.
SAE
forms
will
be
provided
to
the
study
site.
The
information
collected
will
include
a
minimum
of
thefollowing:
Subject
number,
a
narrative
description
of
the
event,
and
an
assessment
by
the
Investigator
as
to
the
intensity
of
the
event,
and
relatedness
to
study
drug.Follow-up
information
on
the
SAE
may
be
requested
by
the
CRO,
the
Study
Safety
Officer
or
the
Sponsor
Medical
Monitor.
Contact
information
for
reportingSAEs
to
the
Study
Safety
Officer
is
provided
on
the
SAE
form.
It
is
the
responsibility
of
the
Investigator
to
promptly
notify
the
Institutional
Review
Board
(IRB)/Independent
Ethics
Committee
(IEC)
of
all
serious
adverse
drugreactions
involving
risk
to
human
subjects
in
accordance
with
the
requirements
of
the
IRB/IEC.
An
unexpected
event
is
one
that
is
not
reported
in
the
Investigator’sBrochure.
Planned
hospital
admissions
or
surgical
procedures
for
an
illness
or
disease
that
existed
before
the
subject
was
enrolled
in
the
trial
or
before
study
drug
was
givenare
not
to
be
considered
AEs
unless
they
occur
at
a
time
other
than
the
planned
date.
Fractures
identified
during
the
study
are
not
to
be
recorded
as
AEs
unless
the
subject
is
hospitalized,
the
fracture
is
complicated,
or
the
Investigator
considers
thefracture
to
be
unrelated
to
the
subject’s
underlying
osteoporosis.
All
fractures
will
be
identified
and
evaluated
as
part
of
the
disease
assessment
and
will
bedocumented
in
the
case
report
forms
and
source
documents.
For
both
serious
and
non-serious
adverse
events,
the
Investigator
must
determine
the
intensity
of
the
event
and
the
relationship
of
the
event
to
study
drugadministration.
Intensity
for
each
AE
will
be
defined
according
to
the
following
criteria:
Intensity Definition


Mild
Awareness
of
sign
or
symptom,
but
easily
tolerated.


Moderate
Discomfort
enough
to
cause
interference
with
normal
daily
activities.


Severe
Inability
to
perform
normal
daily
activities
If
the
intensity
of
an
adverse
event
changes
within
a
day,
the
maximum
intensity
should
be
recorded.
If
the
intensity
changes
over
a
longer
period
of
time,
thechanges
should
be
recorded
as
separate
events
(having
separate
onset
and
stop
dates
for
each
intensity).
Relationship
to
study
drug
administration
will
be
determined
by
the
Investigator
according
to
the
following
criteria:
Relationship Definition


None
No
relationship
between
the
event
and
the
administration
of
study
drug.
The
event
is
related
to
other
etiologies,such
as
concomitant
medications
or
subject’s
clinical
state.


Unlikely
The
current
state
of
knowledge
indicates
that
a
relationship
to
study
drug
is
unlikely
or
the
temporal
relationshipis
such
that
study
drug
would
not
have
had
any
reasonable
association
with
the
observed
event.


Possible
A
reaction
that
follows
a
plausible
temporal
sequence
from
administration
of
the
study
drug
and
follows
a
knownresponse
pattern
to
the
suspected
study
drug.
The
reaction
might
have
Protocol
BA058-05-005
Amendment
4,
Version
1
(24
August
2015)
29
Radius
Health,
Inc.
Confidential

been
produced
by
the
subject’s
clinical
state
or
other
modes
of
therapy
administered
to
the
subject.


Probable
A
reaction
that
follows
a
plausible
temporal
sequence
from
administration
of
the
study
drug
and
follows
a
knownresponse
pattern
to
the
suspected
study
drug.
The
reaction
cannot
be
reasonably
explained
by
the
knowncharacteristics
of
the
subject’s
clinical
state
or
other
modes
of
therapy
administered
to
the
subject.
For
the
purpose
of
safety
analyses,
all
AEs
that
are
classified
with
a
relationship
to
study
medication
administration
of
possible
or
probable
will
be
consideredtreatment-related
events.
8.4 






























Rules for Suspension of the Study
As
this
is
an
extension
study
using
approved
alendronate
products
it
is
not
anticipated
that
the
study
will
need
to
be
suspended,
and
therefore,
suspension
rules
arenot
assigned.
In
the
event
that
the
prior
study
(Study
BA058-05-003)
is
suspended,
the
circumstances
of
the
Study
BA058-05-003
suspension
will
be
considered
todetermine
if
this
study,
Study
BA058-05-005,
should
be
suspended
as
well.
9.0 






























STATISTICAL PROCEDURES
The
primary
objective
of
this
study
is
to
evaluate
data
obtained
following
six
months
of
treatment
with
alendronate,
in
subjects
who
have
previously
received
18months
of
blinded
treatment
with
Abaloparatide-SC/Placebo.
Safety
data
will
be
obtained
with
clinical,
laboratory
and
radiologic
assessment.
Following
the
initialsix
months
of
treatment
in
this
study,
subjects
will
then
enter
the
long-term
observational
phase
of
this
study
during
which
the
subjects
will
continue
to
receivealendronate
treatment
for
an
additional
18
months.
The
specific
objectives
of
this
study
are
to:
·


















Provide
additional
information
on
safety
in
study
subjects
receiving
six
months
of
treatment
with
alendronate
following
18
months
of
treatment
withAbaloparatide-SC/Placebo.
·


















Provide
information
on
the
vertebral
fracture
rate
of
subjects
receiving
six
months
of
treatment
with
alendronate
following
18
months
of
treatment
withAbaloparatide-SC/Placebo.
·


















Provide
additional
information
on
non-vertebral
fractures
and
BMD
change
associated
with
six
months
of
treatment
with
alendronate
following
18months
of
treatment
with
Abaloparatide-SC/Placebo.
·


















Provide
additional
information
on
BMD
change
and
osteoporosis
status
associated
with
24
months
of
treatment
with
alendronate
after
18
months
oftreatment
with
Abaloparatide-SC/Placebo.
The
analysis
performed
at
six
months
will
be
used
as
a
follow-up
to
the
18
month
fracture
endpoint
for
Study
BA058-05-003.
Analyses
will
also
be
performedcumulatively
at
Month
12,
18,
and
24
(i.e.,
Visits
4,
5,
and
6).
Full
details
of
the
statistical
procedures
to
be
used
will
be
provided
in
the
Statistical
Analysis
Plan.
Protocol
BA058-05-005
Amendment
4,
Version
1
(24
August
2015)
30
Radius
Health,
Inc.
Confidential
9.1 

























Sample Size
As
this
is
an
extension
study,
no
formal
sample
size
analysis
was
performed
for
this
study.
Study
data
will
be
tabulated
and
summarized.
9.2 

























Randomization, Stratification and Blinding
Osteoporosis
treatment
will
be
open
label
and
no
randomization
is
required.
9.3 

























Populations for Analysis
All
analyses
and
data
summaries
will
be
presented
for
the
Intent-to-Treat
(ITT)
or
Safety
Population.
In
addition
key
selected
endpoints
will
also
be
analyzed
forthe
mITT
and
Per
Protocol
Populations.
9.3.1





















ITT
(Safety)
Population
The
Safety
Population
is
comprised
of
all
patients
who
receive
one
or
more
doses
of
study
medication.
9.3.2





















Modified
Intent-to-Treat
Population
The
Modified
ITT
Population
includes
all
patients
with
Pretreatment
and
at
least
one
post-baseline
evaluable
radiologic
assessments.
9.3.3





















Per
Protocol
Population
The
Per-Protocol
(PP)
population
includes
subjects
in
the
mITT
population
who
complied
with
treatment
and
did
not
have
any
protocol
violations.
A
protocol
violation
is
defined
as
a
deviation
from
basic
requirements
of
the
study
protocol,
including
inclusion
and
exclusion
criteria,
concomitantmedication
restrictions,
or
any
other
protocol
requirements
that
result
in
a
significant
added
risk
to
the
study
subject
or
has
an
impact
on
the
quality
of
thedata
collected
or
the
outcome
of
the
study.
A
protocol
deviation
is
defined
as
a
deviation
from
the
protocol
that
does
not
impose
added
risk
to
the
study
design
or
the
study
subject.
The
criteria
forthe
determination
of
the
evaluability
of
subjects
will
be
defined
in
the
Statistical
Analysis
Plan.
9.4 

























Procedures for Handling Missing, Unused, and Spurious Data
All
available
data
will
be
included
in
the
data
listings
and
tabulations.
Where
appropriate,
imputations
of
values
for
missing
data
for
primary
and
secondaryefficacy
analyses
will
be
performed
as
specified
in
the
Statistical
Analysis
Plan.
All
data
recorded
on
the
CRF
will
be
included
in
the
data
listings
that
willaccompany
the
clinical
study
report.
9.5 

























Statistical Methods
9.5.1





















Statistical
Considerations
Statistical
analysis
will
focus
on
safety,
fracture
incidence,
including
vertebral
fracture
and
BMD
change
following
six
months
of
alendronate
treatment
in
subjectswho
have
previously
received
18
months
of
blinded
treatment
with
Abaloparatide-SC/Placebo.
Additional
Protocol
BA058-05-005
Amendment
4,
Version
1
(24
August
2015)
31
Radius
Health,
Inc.
Confidential
analyses
will
also
be
cumulatively
at
Month
12,
18,
and
24
(i.e.,
Visit
4,
5,
and
6).
Full
details
of
these
analyses
will
be
provided
in
the
Statistical
Analysis
Plan.
The
efficacy
and
safety
analyses
performed
at
six
months
will
be
used
as
a
follow-up
to
the
18
month
fracture
endpoint
for
Study
BA058-05-003.
Subjects
will
beanalyzed
based
upon
the
randomization
assignment
in
the
BA058-05-003
study.
9.5.2





















Baseline
Comparisons
Baseline
characteristics,
medical
history,
physical
examination,
vital
signs
and
ECG,
will
be
summarized
using
standard
descriptive
statistics.
9.5.3





















Fractures
and
BMD
Analysis
All
specified
endpoints
will
be
summarized
by
treatment
group
and
study
period
using
standard
descriptive
statistics
(n,
mean,
SD,
median,
minimum,
maximum,or
n
and
%,
as
appropriate).
The
fracture
incidence
and
BMD
results
from
the
additional
six
months
of
treatment
with
alendronate
will
be
analyzed
based
on
thetreatment
arm
they
were
randomized
to
in
the
BA058-05-003
study.
These
analyses
will
be
conducted
on
all
subjects
with
baseline
and
post-baseline
data.
Theanalysis
performed
at
six
months
will
be
used
a
follow-up
to
the
18
month
fracture
endpoint
for
Study
BA058-05-003.
Vertebral
fractures
based
on
radiologic
assessments
will
also
be
analyzed
at
Month
24.
Additional
analyses
for
the
other
endpoints
will
also
be
performedcumulatively
at
Month
12,
18,
and
24
(i.e.,
Visits
4,
5,
and
6).
Full
details
of
these
analyses
will
be
provided
in
the
Statistical
Analysis
Plan.
9.5.4





















Safety
Analysis
Data
will
be
summarized
and
tabulated
based
on
the
enrolled
population
for
this
Extension
Study.
All
subjects
enrolled
in
the
Extension
Study
will
be
included
inthe
safety
analysis
that
will
be
performed
on
the
following
parameters:
·


















Incidence
and
severity
of
AEs;
·


















Pathological
changes
in
hematology,
chemistry
and
urinalysis
data
based
on
normal
ranges
supplied
by
the
clinical
laboratory,
if
applicable;
Safety
assessments
for
changes
in
physical
examination,
vital
signs,
ECG,
and
laboratory
tests
will
be
descriptively
summarized
by
treatment
and
study
periods.The
results
of
anti-BA058
testing
will
be
summarized.
Concomitant
medication
classes
will
be
categorized
using
World
Health
Organization
(WHO)
drugdictionary
and
summarized
by
number
and
percent
of
subjects
using
each
class
by
treatment
group.
All
treatment
emergent
adverse
events
(TEAEs)
will
be
codedfor
system
organ
class
(SOC)
and
preferred
term
(PT)
using
MedDRA
and
the
number
(%)
of
subjects
experiencing
each
AE
(SOC/PT)
will
be
summarized
bytreatment,
relationship
to
treatment,
and
severity.
All
serious
adverse
events
(SAE)
will
be
listed
and
the
number
(%)
of
subjects
with
an
SAE
presented
bytreatment
group.
Similar
safety
analyses
will
be
conducted
cumulatively
at
Months
12,
18,
and
24
(i.e.,
Visits
4,
5,
and
6).
Full
details
of
these
analyses
will
be
provided
in
theStatistical
Analysis
Plan.
9.5.5





















Procedures
for
Reporting
Deviations
to
Original
Statistical
Analysis
Plan
All
deviations
from
the
original
statistical
analysis
plan
will
be
provided
in
the
final
clinical
Protocol
BA058-05-005
Amendment
4,
Version
1
(24
August
2015)
32
Radius
Health,
Inc.
Confidential
study
report.
9.6 

























Data Oversight
9.6.1





















Central
Review
of
Radiographs
and
DXA
Scans
All
radiographs
will
be
viewed
and
assessed
by
a
blinded,
independent
assessor
(radiologist)
on
the
basis
of
existing
baseline
and
study-acquired
vertebraldeformity,
and
fractures
will
be
assessed
according
to
the
method
of
Genant.
A
second
blinded
radiologist
will
review
the
assessment
of
the
first
reviewer
for
allsubject
radiographs
in
which
an
incident
fracture
has
been
identified.
In
the
case
of
any
disagreement,
a
third
consensus
assessment
will
be
made
to
adjudicate
theincident
fracture.
All
study
DXA
scans
will
also
be
evaluated
centrally
by
a
blinded
independent
reviewer.
The
primary
objective
of
the
independent
review
is
toprovide
objective
data
to
determine
the
treatment
benefit
as
demonstrated
on
the
pertinent
radiologic
and
clinical
data
associated
with
this
study.
10.0 


















ADMINISTRATIVE REQUIREMENTS
10.1 


















Good Clinical Practice
This
study
will
be
conducted
in
accordance
with
the
International
Conference
on
Harmonization
(ICH)
for
Good
Clinical
Practice
(GCP)
and
the
appropriateregulatory
requirements.
The
Investigator
will
be
thoroughly
familiar
with
the
appropriate
use
of
the
study
medication
as
described
in
the
protocol
and
theInvestigator’s
Brochure.
Essential
clinical
documents
will
be
maintained
to
demonstrate
the
validity
of
the
study
and
the
integrity
of
the
data
collected.
TheInvestigator/institution
should
establish
master
files
at
the
beginning
of
the
study
which
will
be
maintained
and
updated
during
the
study
and
retained
thereafteraccording
to
the
appropriate
regulations.
10.2 


















Ethical Considerations
The
study
will
be
conducted
in
accordance
with
ethical
principles
founded
in
the
Declaration
of
Helsinki.
The
Institutional
Review
Board
(IRB)/Independent
EthicsCommittee
(IEC)
will
review
all
appropriate
study
documentation
in
order
to
safeguard
the
rights,
safety
and
well-being
of
the
subjects.
The
study
can
only
beconducted
at
study
sites
where
IRB/IEC
approval
has
been
obtained.
The
protocol,
informed
consent
form,
Investigator’s
Brochure,
advertisements
(if
applicable),and
all
other
forms
of
information
given
to
subjects
will
be
provided
to
the
IRB/IEC
by
the
Investigator.
In
addition,
reports
on
the
progress
of
the
study
will
besubmitted
to
the
IRB/IEC
by
the
Investigator
at
the
appropriate
intervals.
10.3 


















Subject Information and Informed Consent
Each
subject
(or
a
legally
authorized
representative)
must
give
written
informed
consent
prior
to
any
new
study-specific
procedures
being
conducted.
It
is
theresponsibility
of
the
Investigator
to
ensure
written
informed
consent
is
obtained
from
each
subject
participating
in
this
study
after
an
explanation
of
the
objectives,methods,
discomforts
and
potential
risks
of
the
study
has
been
provided.
The
Investigator
(or
study
personnel)
must
also
explain
to
each
subject
that
he/she
is
freeto
refuse
participation
in
the
study
or
to
withdraw
from
it
at
any
time.
Each
subject
will
also
be
told
that
his/her
records
may
be
examined
by
competent
authoritiesand
authorized
persons
but
that
personal
information
will
be
treated
as
strictly
confidential
and
will
not
be
publicly
available.
Protocol
BA058-05-005
Amendment
4,
Version
1
(24
August
2015)
33
Radius
Health,
Inc.
Confidential
The
informed
consent
form
must
be
in
accordance
with
the
Declaration
of
Helsinki,
ICH
and
GCP
guidelines,
and
be
approved
by
the
Sponsor
and
the
IRB/IEC.State
or
local
laws
may
require
additional
information.
Each
subject
(or
his/her
legally
authorized
representative)
must
sign
and
be
given
a
copy
of
the
informedconsent
form.
Each
subject’s
signed
informed
consent
form
must
be
maintained
by
the
Investigator
and
be
readily
available
for
review
by
the
Sponsor
(or
itsdesignee)
or
the
Regulatory
Authorities.
10.4 


















Protocol Compliance
The
Investigator
will
conduct
this
study
in
compliance
with
the
protocol
provided
by
the
Sponsor
and
given
approval/favorable
opinion
by
the
IRB/IEC
and
theappropriate
Regulatory
Authority(ies).
Changes
to
the
protocol
will
not
be
made
without
agreement
of
the
Sponsor
Medical
Monitor.
All
changes
to
the
protocolwill
require
IRB/IEC
approval
prior
to
implementation,
except
when
necessary
to
eliminate
an
immediate
hazard
to
study
subjects
or
when
the
change
involvesonly
logistical
or
administrative
aspects
of
the
study
(e.g.,
change
in
Sponsor
Medical
Monitor
or
telephone
number).
The
IRB/IEC
may
provide,
if
applicableregulations
permit,
expedited
review
and
approval/favorable
opinion
for
minor
changes
in
ongoing
studies.
The
Sponsor
will
submit
all
protocol
changes
to
theappropriate
Regulatory
Authority
in
accordance
with
the
governing
regulations.
In
situations
requiring
a
departure
from
the
protocol,
the
Investigator
or
other
physician
in
attendance
will
contact
the
Sponsor
Medical
Monitor
by
telephone,
e-mail
or
fax.
If
possible,
this
contact
will
be
made
before
implementing
any
departure
from
the
protocol.
In
all
cases,
contact
with
the
Sponsor
Medical
Monitormust
be
made
as
soon
as
possible
in
order
to
review
the
situation
and
agree
on
an
appropriate
course
of
action.
The
case
report
form
and
source
document
willdescribe
any
departure
from
the
protocol
and
the
circumstances
requiring
it.
10.5 


















Case Report Form Completion
eCRFs
will
be
developed
to
collect
information
obtained
during
this
study.
It
is
the
Investigator’s
responsibility
to
ensure
that
the
e-CRFs
are
completed
for
eachsubject
enrolled
in
this
study
and
for
the
accuracy,
completeness,
legibility
and
timeliness
of
the
data
reported
in
each
e-CRF.
Data
for
subjects
who
are
screenedbut
not
enrolled
into
the
study
because
they
do
not
meet
study
criteria
or
do
not
complete
all
screening
procedures,
should
be
recorded
in
the
e-CRF.
eCRFs
will
be
completed
and
any
corrections
of
data
will
be
made
according
to
procedures
provided
by
the
Sponsor
(or
designee).
10.6 


















Source Documents
Source
documents
are
defined
as
original
documents,
data
and
records.
This
may
include
hospital
records,
clinical
and
office
charts,
laboratory
data/information,work
sheets,
subjects’
diaries
or
evaluation
checklists,
pharmacy
dispensing
and
other
records,
recorded
data
from
automated
instruments,
microfiches,photographic
negatives,
microfilm
or
magnetic
media,
ECG
printouts,
and/or
x-rays.
The
Investigator(s)/institution(s)
will
permit
trial-related
monitoring,
audits,
IRB/IEC
review,
and
regulatory
inspection(s),
providing
direct
access
to
source
datadocuments.
Protocol
BA058-05-005
Amendment
4,
Version
1
(24
August
2015)
34
Radius
Health,
Inc.
Confidential
10.7 


















Study Monitoring
The
Sponsor
(or
its
designee)
will
ensure
that
the
study
is
monitored
in
accordance
with
ICH-GCP
Guidelines.
Monitoring
is
the
act
of
overseeing
the
progress
of
aclinical
trial
and
of
ensuring
that
it
is
conducted,
recorded,
and
reported
in
accordance
with
the
protocol,
standard
operating
procedures,
Good
Clinical
Practice,
andthe
applicable
regulatory
requirements
and
that
the
study
data
are
accurate,
complete
and
verifiable
from
source
data.
All
study
documentation
and
other
sourcedata
will
be
made
available
to
the
Sponsor
(or
its
designee),
the
IRB
and
to
Regulatory
Authorities
for
inspection
upon
request.
10.8 


















On-Site Audits
Representatives
of
the
IRB
or
the
Sponsor
(or
designee)
may
visit
the
study
site
to
carry
out
an
audit
of
the
study
in
compliance
with
regulatory
guidelines
andcompany
policy.
Such
audits
will
require
access
to
all
study
records
including
source
documents,
CRFs,
and
other
study
documents.
Direct
access
to
these
studyrecords
must
be
guaranteed
by
the
Investigator,
who
must
provide
support
for
these
activities
at
all
times.
Similar
auditing
procedures
may
also
be
conducted
by
agents
of
any
Regulatory
Authority
reviewing
the
results
of
this
study.
The
Investigator/institution
shouldimmediately
notify
the
Sponsor
if
they
have
been
contacted
by
a
Regulatory
Authority
concerning
an
upcoming
inspection.
10.9 


















Drug Accountability
Accountability
for
the
study
medication
at
the
study
site
is
the
responsibility
of
the
Investigator.
Drug
accountability
will
be
performed
only
on
alendronate,calcium
and
vitamin
D.
The
Investigator
will
ensure
that
the
study
medication
is
used
only
in
accordance
with
this
protocol.
Where
allowed,
the
Investigator
maychoose
to
assign
some
of
the
study
medication
accountability
responsibilities
to
qualified
study
personnel.
Study
medication
accountability
records
indicating
the
delivery
date
to
the
study
site,
inventory
at
the
study
site
and
dispensing/use
will
be
maintained.
Theserecords
will
adequately
document
that
the
study
medications
were
dispensed
and
returned
as
specified
in
the
protocol.
Accountability
records
will
include
dates,quantities,
and
subject
numbers.
The
Sponsor
(or
its
designee)
will
review
study
medication
accountability
records
at
the
study
site
on
an
ongoing
basis
during
thestudy.
All
used
and
unused
study
medication
must
be
inventoried,
accounted
for,
and
approved
by
the
Sponsor
(or
its
designee)
prior
to
destruction.
If
the
site
is
notcapable
of
study
drug
disposal/destruction,
the
Sponsor
will
arrange
for
an
alternative
method.
Records
of
disposal
must
be
maintained
with
the
study
records.
10.10 











Record Retention
The
Investigator
will
maintain
all
study
records
according
to
ICH/GCP
and
applicable
regulatory
requirements.
Essential
documents
must
be
retained
for
two
yearsafter
the
final
marketing
approval
in
an
ICH
region
or
at
least
two
years
have
elapsed
since
the
discontinuation
of
clinical
development
of
the
study
medication.
It
isthe
responsibility
of
the
Sponsor
to
inform
the
Investigator
of
when
these
documents
can
be
destroyed.
In
addition,
all
subject
medical
records
and
other
sourcedocumentation
will
be
kept
for
the
maximum
time
permitted
by
the
hospital,
institution
or
medical
practice.
Protocol
BA058-05-005
Amendment
4,
Version
1
(24
August
2015)
35
Radius
Health,
Inc.
Confidential
The
Investigator/institution
will
take
measures
to
prevent
accidental
or
premature
destruction
of
these
documents.
If
the
responsible
Investigator
retires,
relocates,or
for
other
reasons
withdraws
from
the
responsibility
of
keeping
the
study
records,
custody
must
be
transferred
to
a
person
who
will
accept
the
responsibility.
TheSponsor
must
be
notified
in
writing
of
the
name
and
address
of
the
new
custodian.
10.11 











Study Termination
This
study
may
be
terminated
at
any
time
by
the
Sponsor
if
there
is
sufficient
reasonable
cause.
Circumstances
that
may
warrant
termination
include,
but
are
notlimited
to:
·


















Determination
of
unexpected,
significant,
or
unacceptable
risk
to
subjects.
·


















Failure
of
enrollment
·


















Administrative
reasons
·


















Plans
to
modify,
suspend
or
discontinue
the
development
of
the
study
drug.
In
addition,
individual
study
sites
may
be
terminated
from
study
participation
for
reasons
including,
but
not
limited
to
the
following:
·


















Failure
to
enter
subjects
at
an
acceptable
rate.
·


















Insufficient
adherence
to
protocol
requirements.
·


















Incomplete
and/or
non-evaluable
data.
In
all
cases,
the
terminating
parties
will
provide
written
notification
documenting
the
reason
for
study
termination
to
all
the
relevant
parties.
Should
the
study
or
an
individual
site
be
prematurely
closed,
all
study
materials
(completed,
partially
completed,
and
blank
CRFs,
study
drug,
etc.)
must
bereturned
to
the
Sponsor
(or
its
designee).
10.12 











Liability and Insurance
The
Sponsor
has
subscribed
to
an
insurance
policy
covering,
in
its
terms
and
provisions,
its
legal
liability
for
injuries
caused
to
participating
persons
and
arising
outof
this
research
performed
strictly
in
accordance
with
the
scientific
protocol
as
well
as
with
applicable
law
and
professional
standards.
11.0 


















USE OF INFORMATION AND PUBLICATION OF STUDY FINDINGS
11.1 


















Use of Information
All
information
regarding
BA058
supplied
by
the
Sponsor
(or
its
designee)
to
the
Investigator
is
privileged
and
confidential
information.
The
Investigator
agrees
touse
this
information
to
accomplish
the
study
and
will
not
use
it
for
other
purposes
without
prior
consent
from
the
Sponsor.
The
information
developed
during
the
conduct
of
this
clinical
study
is
also
considered
confidential
and
will
be
used
by
the
Sponsor
in
connection
with
thedevelopment
of
BA058.
This
information
may
be
disclosed
as
deemed
necessary
by
the
Sponsor
to
other
clinical
Investigators,
other
pharmaceutical
companies,and
to
Regulatory
Authorities.
To
allow
for
the
use
of
the
information
derived
from
this
study
and
to
ensure
complete
and
thorough
Protocol
BA058-05-005
Amendment
4,
Version
1
(24
August
2015)
36
Radius
Health,
Inc.
Confidential
analysis,
the
Investigator
is
obligated
to
provide
the
Sponsor
(or
its
designee)
with
complete
study
results
and
all
data
developed
in
this
study
and
to
allow
directaccess
to
source
data/documents
for
study-related
monitoring,
audits,
IRB/IEC
review,
and
regulatory
inspection.
11.2 


















Publication
Results
of
this
study
may
not
be
published
prior
to
the
completion
of
this
study
and
completion
of
the
formal
clinical
study
report
and
other
required
regulatoryreports
and
documents.
It
is
anticipated
that
the
results
of
this
study
will
be
presented
at
scientific
meetings
and/or
published
in
a
peer
reviewed
scientific
or
medical
journal.
APublications
Committee
composed
of
Investigators
participating
in
the
study
and
representatives
from
the
Sponsor
as
appropriate
will
be
formed
to
oversee
thepublication
of
the
study
results,
which
will
reflect
the
experience
of
all
participating
study
centers.
Subsequently,
individual
Investigators
may
publish
results
from
the
study
in
compliance
with
their
agreement
with
the
Sponsor.
A
pre-publication
manuscript
mustbe
provided
to
the
Sponsor
at
least
30
days
prior
to
the
submission
of
the
manuscript
to
a
publisher.
Similarly,
the
Sponsor
will
provide
any
company
preparedmanuscript
to
the
Investigators
for
review
at
least
30
days
prior
to
submission
to
a
publisher.
The
Investigator
shall
comply
with
the
policy
of
the
Sponsor
regarding
confidential
or
proprietary
information
in
any
such
paper
and
agrees
to
withhold
publicationof
same
for
an
additional
60
days
in
order
to
permit
the
Sponsor
to
obtain
patent
or
other
proprietary
rights
protection,
if
the
Sponsor
deems
it
necessary.
Protocol
BA058-05-005
Amendment
4,
Version
1
(24
August
2015)
37
Radius
Health,
Inc.
Confidential
12.0 























INVESTIGATOR AGREEMENT
To
be
completed
by
the
Investigator
I
have
read
Protocol
BA058-05-005:
“An
Extension
Study
to
Evaluate
24
Months
of
Standard-of-Care
Osteoporosis
Management
Following
Completion
of
18Months
of
BA058
or
Placebo
Treatment
in
Protocol
BA058-05-003”.
I
agree
to
conduct
the
study
as
detailed
herein
and
in
compliance
with
ICH
Guidelines
for
Good
Clinical
Practice
and
applicable
regulatory
requirements
and
toinform
all
who
assist
me
in
the
conduct
of
this
study
of
their
responsibilities
and
obligations.
The
signature
below
constitutes
my
agreement
to
the
contents
of
this
protocol.



Signature
of
Principal
Investigator
Date





Principal
Investigator
(print)


Signature
of
Sponsor’s
Medical
Officer
(where
applicable)

/s/
Lorraine
Fitzpatrick
24
Aug
15Lorraine
Fitzpatrick,
MD
Date
Protocol
BA058-05-005
Amendment
4,
Version
1
(24
August
2015)
38
Radius
Health,
Inc.
Confidential
13.0 


















REFERENCES
Balena
R,
Toolan
BC,
Shea
M,
Markatos
A,
Myers
ER,
Lee
SC,
Opas
EE,
Seedor
JG,
Klein
H,
Frankenfield
D,
Quartuccio
H,
Fiovanti
C,
Clair
J,
Brown
E,
HayesWC,
Rodan
GA.
The
effects
of
2-year
treatment
with
the
aminobisphosphonate
alendronate
on
bone
metabolism,
bone
histomorphometry,
and
bone
strength
inovariectomized
nonhuman
primates.
J
Clin
Invest
1993;
92:2577-2586.
Balena
R,
Markatos
A,
Seedor
JG,
Gentile
M,
Stark
C,
Peter
CP,
Rodan
GA.
Long-term
safety
of
the
aminobisphosphonate
alendronate
in
adult
dogs.
IIHistomorphometric
analysis
of
the
L5
vertebrae.
J
Pharmacol
Exp
Ther
1996;
276(1):277-83.
Black
DM,
Bilezikian
JP,
Ensrud
KE,
Greenspan
SL,
Palermo
L,
Hue
T,
Lang
TF,
McGowan
JA,
Rosen
CJ.
One
year
of
alendronate
after
one
year
of
parathyroidhormone
(1-84)
for
osteoporosis.
N
Engl
J
Med
2005;
353(6):555-565.
Bone
HG,
Hosking
D,
Devogelaer
JP,
Tucci
JR,
Emkey
RD,
Tonito
RP,
Rodriguez-Portales
JA,
Downs
RW,
Grupta
J,
Santora
AC,
Liberman
UA,
AlendronatePhase
III
Osteoporosis
Treatment
Study
Group.
Ten
years’
experience
with
alendronate
for
osteoporosis
in
postmenopausal
women.
N
Eng
J
Med
2004
;350(12):1189-99.
Devogelaer
JP,
Broll
H,
Correa-Rotter
R,
Coming
DC,
De
Deuxchaisnes
CN,
Geusens
P,
Hosking
D,
Jaeger
P,
Kaufman
JM,
Leite
M,
Leon
J,
Liberman
U,Menkes
CJ,
Meunier
PJ,
Reid
I,
Rodriguez
J,
Romanowicz
A,
Seeman
E,
Vermeulen
A,
Hirsch
LJ,
Lombardi
A,
Plezia
K,
Santora
AC,
Yates
AJ,
Yuan
W.
Oralalendronate
induces
progressive
increases
in
bone
mass
of
the
spine,
hip
and
total
body
over
3
years
in
postmenopausal
women
with
osteoporosis.
Bone
1996;18(2):141-50.
EMEA.
Guideline
on
the
evaluation
of
medicinal
products
in
the
treatment
of
primary
osteoporosis.
2007.
FDA.
Guidelines
for
preclinical
and
clinical
evaluation
of
agents
used
in
the
prevention
or
treatment
of
postmenopausal
osteoporosis.
1994.
FDA.
Draft
guidance:
Development
of
parathyroid
hormone
for
the
prevention
and
treatment
of
osteoporosis.
2000.
Fosamax®
Prescribing
Information.
Whitehouse
Station,
NJ:
Merck
Sharp
&
Dohme
Corp.;
2012.
Genant
HK,
Wu
CY,
van
KC,
and
Nevitt
MC.
Vertebral
fracture
assessment
using
a
semiquantitative
technique.
J
Bone
Miner
Res
1993;
8:1137-1148.
Guidance
for
Industry.
E6
Good
Clinical
Practice:
Consolidated
Guidance.
U.S.Department
of
Health
and
Human
Services,
Food
and
Drug
Administration.April
1996.
Protocol
BA058-05-005
Amendment
4,
Version
1
(24
August
2015)
39
Radius
Health,
Inc.
Confidential Gullberg
B,
Johnell
O,
Kanis
JA.
World-wide
projections
for
hip
fracture.
Osteoporos
Int
1997;
7:407-413.
Lefage
M-H,
Balena
R,
Battle
MA,
Shea
M,
Seedor
JG,
Klein
H,
Hayes
WC,
Rodan
GA.
Comparison
of
alendronate
and
sodium
fluoride
effects
on
cencellous
andcortical
bone
in
minipigs.
J
Clin
Invest
1995;
95:2127-2133.
Liberman
UA,
Weiss
SR,
Broll
J,
Minne
HW,
Quan
H,
Bell
NH,
Rodriguez-Portales
J,
Downs
Jr.
RW,
Dequeker
J,
Favus
M,
Seeman
E,
Recker
RR,
Capizzi
T,Santora
AC,
Lombardi
A,
Shah
RV,
Hirsch
LJ,
Karpe
DB.
Effect
of
oral
alendronate
on
bone
mineral
density
and
the
incidence
of
fractures
in
postmenopausalosteoporosis.
N
Engl
J
Med
1995;
333(22):1437-43.
Reginster
JY,
Burlet
N.
Osteoporosis:
still
increasing
prevalence.
Bone
2006;
38(Suppl
1):S4-9.
Rittmaster
RS,
Bolognese
M,
Ettinger
MP,
Hanley
DA,
Hodsman
AB,
Kendler
DL,
Rosen
CJ.
Enhancement
of
bone
mass
in
osteoporotic
women
with
parathyroidhormone
followed
by
alendronate.
J
Clin
Endocrinol
Metab
2000;
85(6):2129-34.
Rizzoli
R,
Bonjour
JP,
and
Ferrari
SL.
Osteoporosis,
genetics
and
hormones.
J
Mol
Endocrinol
2001;
26:79-94.
Tucci
JR,
Tonino
RP,
Emkey
RD,
Peverly
CA,
Kher
U,
Santora
AC
2
.
Effect
of
three
years
of
oral
alendroneate
treatment
in
postmenopausal
women
withosteoporosis.
Am
J
Med
1996;
101(5):488-501.
WHO
Scientific
Group
on
the
assessment
of
osteoporosis
at
primary
health
care
level.
World
Health
Organization
Summary
Meeting
Report
2007.
World
Medical
Association
Declaration
of
Helsinki.
The
World
Medical
Association,
Inc.
2008.
Protocol
BA058-05-005
Amendment
4,
Version
1
(24
August
2015)
40nd

Radius
Health,
Inc.
Confidential
14.0        APPENDICES
Protocol
BA058-05-005
Amendment
4,
Version
1
(24
August
2015)
41
Radius
Health,
Inc.
Confidential
14.1 





Schedule of Visits and Procedures
 1           Visit Visit 10 003/ 2 3 4 5 6 Study Day/Month: Visit 1(1) 005 Month 3 Month 6 Month 12 Month 18 Month 24 Day 1 90 180 360 540 720 Visit Window (Days) N/A ± 5 ± 14 ± 14 ± 14 ± 14 Procedure












Informed
consent
X










Review
of
entrance
criteria
X










Recent
health
status
X
X
X
X
X
X
Vital
signs,
weight
and
height
measurements(2)
X
X
X
X
X
X
Electrocardiogram
X


X






Urinalysis
(dipstick)
(3)
X


X
X
X
X
Chemistry
blood
collection(4)
X


X
X
X
X
Hematology
blood
collection(5)
X


X
X
X
X
Coagulation
blood
collection(5)
X


X




X
PTH(1-84)




X






25-hydroxy
vitamin
D
level




X






1,25-dihydroxy
vitamin
D
level




X






Serum
markers
of
bone
metabolism(5)
X


X
X
X
X
BA058
antibody
levels(6)




X






24-hour
urine
collection
(for
calcium:
creatinine
and
creatinineclearance)(7)
X
X(8)X






Clinical
and
radiologic
(spine,
lumbar
and
thoracic
vertebrae)fracture
assessments




X




X
Clinical
assessment
of
de
novo
fractures(9)






X
X


Bone
mineral
density
of
hip
and
spine
by
DXA(10)




X
X
X
X
Bone
mineral
density
of
wrist
by
DXA(11)




X
X
X
X
Calcium
and
vitamin
D
supplements


Daily
Alendronate
administration
(if
applicable)


Dosing
as
per
prescribing
information
Study
medication
resupply
(if
applicable)


X
X
X
X


Subject
diary
review(12)


X
X
X
X
X
Document
adverse
events
and
concomitant
medications


Daily

Protocol
BA058-05-005
Amendment
4,
Version
1
(24
August
2015)
42
Radius
Health,
Inc.
Confidential
(1)
The
procedures
for
the
Follow-up
visit
(Visit
10)
for
Study
BA058-05-003
will
serve
as
the
procedures
performed
at
Day
1
(for
Study
BA058-05-005).
Theconsent
form
will
need
to
be
signed
if
it
was
not
signed
during
the
End-of-Treatment
Visit
(Visit
9)
of
Study
BA058-05-003.(2)
Vital
signs
(blood
pressure,
pulse
rate,
body
temperature,
and
respiration
rate)
are
to
be
recorded
at
each
study
visit.
Only
the
blood
pressure
assessment
on
Day1
(Visit
10)
needs
to
be
orthostatic.
Height
is
to
be
measured
at
each
visit
in
the
standing
position
using
a
medical
stadiometer.
Weight
is
to
be
measured
at
eachvisit.
Orthostatic
blood
pressure
is
to
be
measured
initially
after
5
minutes
in
the
supine
position
and
then
again
after
standing
for
three
minutes.(3)
All
routine
urinalysis
will
be
performed
on
a
sample
freshly
voided
during
the
clinic
visit.(4)
These
blood
samples
are
to
be
obtained
under
fasting
conditions
(N.P.O.
for
8
hours;
water
is
acceptable)
in
the
morning
of
each
scheduled
study
visit.(5)
Includes
blood
samples
for
PINP,
bone-specific
alkaline
phosphatase,
serum
osteocalcin
and
CTX.(6)
Subjects
who
remain
positive
at
the
6
month
antibody
draw
will
have
samples
drawn
for
antibodies
every
six
months
until
the
antibody
titer
is
negative.(7)
Twenty-four
hour
urine
collection
will
be
used
for
urinary
calcium
and
urinary
creatinine
measurements.
Subjects
will
discard
the
1

void
and
begin
a
24-hoururine
collection
the
day
prior
to
the
clinic
visit.(8)
A
24-hour
urine
collection
will
be
collected
at
Month
3
only
if
a
sample
was
not
collected
for
the
Day
1
(Visit
10).(9)
Documentation
should
be
obtained
on
all
de
novo
fractures
that
occur
during
the
Treatment
Period.
This
documentation
should
be
maintained
in
the
sourcedocuments.(10)
Each
DXA
for
a
given
subject
should
be
performed
on
the
same
machine,
and
if
available,
preferably
by
the
same
technician(11)
Each
DXA
for
a
given
subject
should
be
performed
on
the
same
machine,
and
if
available,
preferably
by
the
same
technician.
Only
subjects
who
had
wristst
DXA
assessments
in
Study
BA058-05-003
will
have
wrist
DXAs
performed.(12)
The
subjects
will
maintain
a
diary
throughout
the
study
to
record
missed
doses
of
medication
(including
supplements)
on
a
weekly
basis;
the
diaries
are
to
bereviewed
with
the
subject
at
each
study
visit.
Protocol
BA058-05-005
Amendment
4,
Version
1
(24
August
2015)
43
Radius
Health,
Inc.
Confidential
14.2 


















Suggested Schedule of Events and Procedures by Study Visit
The
purpose
of
this
guide
is
to
provide
more
detailed
instructions
for
the
study
procedures
listed
in
Appendix
14.1.
This
guide
presents
the
procedures
in
asuggested
sequence
of
performance
at
each
study
visit.
Further
information
may
be
found
within
the
protocol
and
in
other
study
reference
manuals
(e.g.,
ECG,clinical
laboratory
sample
processing).
Of
note:
·


















Blood
and
urinalysis
samples
are
to
be
obtained
under
fasting
conditions
(NPO.
for
8
hours;
water
is
acceptable)
in
the
morning
of
Day
1
and
Months
6,12,
18,
and
24.
·


















DXA
Scans:
Always
use
the
same
study-validated
machine;
preferably
the
same
technician.
·


















The
24-hour
urine
collection
will
be
started
at
home
the
day
before
the
clinic
visit
where
the
collection
is
required.
Subjects
will
be
instructed
to
discardthe
first
morning
void
and
begin
the
collection
at
least
24
hours
before
their
clinic
visit
the
following
day.
They
will
collect
all
urine
for
24
hours
with
afinal
void
before
coming
to
the
clinic.
Routine
urinalyses
are
to
be
performed
using
samples
freshly
voided
during
the
clinic
visit.
Subjects
should
receivea
reminder
to
initiate
their
24-hour
urine
2
days
before
their
scheduled
visit.
·


















Alendronate
for
Europe,
Hong
Kong
and
the
US
will
be
sourced
centrally;
alendronate
for
South
America
will
be
sourced
locally
by
the
medical
centerand
reimbursed
by
the
Sponsor.
·


















Subjects
will
be
instructed
to
take
the
calcium
and
vitamin
D
supplements
daily
(in
the
evening
with
or
without
food
or
as
otherwise
instructed
by
theInvestigator)
until
discharge
from
the
study.
This
is
required
until
the
end
of
Month
24.
Protocol
BA058-05-005
Amendment
4,
Version
1
(24
August
2015)
44
Radius
Health,
Inc.
Confidential
Definitions of Common Procedures:
The terms used in the by-visit schedule that follows are further defined below.
Recent
health
status
(document
any
changes
from
last
visit)·


















Question
subject
regarding
any
new
health
issues·


















Question
subject
regarding
any
new
adverse
events·


















Question
subject
regarding
any
new
concomitant
medications·


















Question
subject
regarding
any
new
issues
related
to
ability
to
continue
with
studyPulse,
respiration
and
temperature:·


















Pulse rate (beats/minute)
taken
after
approximately
five
minutes
in
the
supine
position.·


















Respiration rate (breaths/minute).·


















Body temperature (°C).Weight
and
height
measurements:·


















Weight (kg).·


















Height (cm)
standing
measurements
are
to
be
performed
using
the
same
medical
stadiometer
and
standardized
procedures
each
time.Orthostatic
blood
pressure:·


















Orthostatic blood pressure (mmHg)
(measured
in
same
arm
each
time/each
visit)
is
measured
after
five
minutes
in
the
supine
position
followed
by
ameasurement
taken
after
3
minutes
in
the
standing
position.
Only
the
blood
pressure
assessment
on
Day
1
(Visit
10)
needs
to
be
orthostatic.ECG·


















Twelve-lead
supine
electrocardiogram·


















Print
hard
copy
for
reading
by
qualified
study
personnel·


















More
than
one
ECG
may
be
performed
per
time-point.24
hour
urine
collection·


















Subject
to
discard
first
morning
void
(suggest
6
a.m.)
on
day
before
clinic
visit·


















Subject
to
collect
urine
for
approximately
24
hours·


















Subject
to
collect
final
void
at
end
of
collection
and
bring
collection
to
clinic.·


















Process
for
calcium
and
creatinineUrinalysis·


















Obtain
under
fasting
conditions
(NPO.
except
water
for
8
hours)·


















Routine
urinalysis
is
to
be
performed
using
a
sample
freshly
voided
during
the
clinic
visit
(microscopic
examination
if
positive
dipstick).Review
study
medication
administration
procedures
with
subject·


















Alendronate
should
be
taken
daily,
preferably
at
the
same
time
each
morning/day
of
the
weekScheduling
and
instructions
for
next
clinic
visit·


















Schedule
visit·


















Remind
subject
of
any
fasting
requirements·


















Provide
urine
collection
instructions
and
materials
as
necessary·


















Remind
subjects
to
complete
the
diaries
until
the
end
of
the
studyVitamin
D
and
calcium
supplements·


















Vitamin
D
and
calcium
supplements
are
required
throughout
the
study.
Only
those
supplements
supplied
as
part
of
study
medication
may
be
used
and
areto
be
used
at
the
daily
recommended
dose
(see
Section
5.1.2)
.·


















Supplements
should
be
taken
in
the
evening,
with
or
without
food
as
instructed
by
the
Investigator.·


















At
each
study
visit,
assess
the
subject’s
supply
and
resupply
as
necessary.·


















Drug
usage
reconciliation
is
to
be
performed
when
a
new
supply
is
provided.
Protocol
BA058-05-005
Amendment
4,
Version
1
(24
August
2015)
45
Radius
Health,
Inc.
Confidential
Visit 10 for Study BA058-05-003Day 1 Visit for Study BA058-05-005Day 1
VISIT ACTIVITIESDay 1 Day 1 Visit for Study BA058- 05-005 Visit 10 for Study BA058- 05-003
Written
informed
consent
must
be
obtainedRecent
health
status·


















Document
any
changes
since
End-of-Treatment
visit
(Visit
9)
from
Study
BA058-
05-003
Study
staff
will
receive
your
prior
days
24-hour
urine
sample
(if
a
24-hour
urine
sample
was
not
collected
prior
to
Day
1,
the
subjectmust
begin
a
24-hour
urine
sample
on
the
day
prior
to
the
Month
3
visitSubject
diary
review·


















Review
study
medication
diary
(calcium
and
vitamin
D)/dispense
new
diary
if
necessary·


















Record
deviations
in
dosing
or
any
AEs
in
source
documents
and
CRFs·


















Collect
diaries
and
enter
data
into
CRF
Vital
signs,
weight
and
height
measurementOrthostatic
blood
pressureECGBlood
collection:
fasting
conditions
(NPO
except
water
for
8
hours)·


















Chemistry·


















Hematology·


















Coagulation
(PT
and
PTT)·


















Serum
markers
of
bone
metabolism,
where
applicable·


















PINP·


















bone-specific
alkaline
phosphatase·


















serum
osteocalcin·


















serum
CTX·


















Urinalysis
(Dipstick)
Study
medication·


















Dispense
three
month
supply
of
alendronate·


















Assess
subject’s
supply
of
calcium
and
vitamin
D
supplements;
resupply
as
necessary·


















Instruct
subject
to
take
daily
until
they
are
discharged
from
the
study
Scheduling
and
instructions
for
next
clinic
visit·


















Remind
subject
to
take
study
medication
as
instructed·


















24-hour
urine
collection:
If
subjects
did
not
provide
a
24-hour
urine
sample
for
Visit
1,
dispense
urine
collection
container
andinstruct
subjects
to
perform
24-
hour
urine
collection
beginning
the
morning
24
hours
prior
to
their
next
scheduled
visit
(Month3)·


















Remind
subject
to
record
study
medication
use
Protocol
BA058-05-005
Amendment
4,
Version
1
(24
August
2015)
46
Radius
Health,
Inc.
Confidential
Month 3 Visit for Study BA058-05-005Day 90 (±5 days)
VISIT
ActivitiesMonth 3
Recent
health
status·


















Document
any
changes
since
previous
visit
Study
staff
will
receive
the
prior
days
24
hour
urine
sample,
if
applicableVital
signs,
height
and
weight
measurementSubject
diary
review·


















Review
study
medication
diary/dispense
new
diary
if
necessary·


















Record
deviations
in
dosing
or
any
AEs
in
source
documents
and
CRFs.·


















Collect
diaries
and
enter
data
into
CRF
Study
medication·


















Dispense
three
month
supply
of
alendronate·


















Assess
subject’s
supply
of
calcium
and
vitamin
D
supplements;
resupply
as
necessary,
instruct
subject
to
take
daily
until
theyare
discharged
from
the
study
Scheduling
and
instructions
for
next
clinic
visit·


















24-hour
urine
collection:
Dispense
urine
collection
container
and
instruct
subjects
to
perform
24-hour
urine
collectionbeginning
the
morning
24
hours
prior
to
their
next
scheduled
visit
(Month
6)·


















Remind
subject
to
take
study
medication
as
instructed·


















Remind
subject
to
record
study
medication
use
Protocol
BA058-05-005
Amendment
4,
Version
1
(24
August
2015)
47
Radius
Health,
Inc.
Confidential
Month 6 Visit for Study BA058-05-005Day 180 (±14 Days)
VISIT ActivitiesMonth 6
Physical
ExaminationRecent
Health
Status·


















Document
any
changes
from
last
visitCollect
24
hour
urine
sample
from
subjectStudy
staff
will
receive
your
prior
days
24-hour
urine
sample·


















Review
diary
of
study
medication·


















Collect
diary
and
enter
data
into
CRF,
record
dosing
deviations
or
any
AEs
in
source
documents
and
CRFsVital
signs,
weight
and
height
measurementECGBlood
collection:
fasting
conditions
(NPO
except
water
for
8
hours)·


















Chemistry·


















Hematology·


















Coagulation
(PT
and
PTT)·


















Serum
markers
of
bone
metabolism,
where
applicable·


















PINP·


















bone-specific
alkaline
phosphatase·


















serum
osteocalcin·


















serum
CTX·


















BA058
antibody
levels·


















Urinalysis
(Dipstick)Clinical
and
radiologic
fracture
evaluations·


















Obtain
antero-posterior
and
lateral
radiographs
of
the
lumbar
and
thoracic
vertebrae·


















Document
any
non-vertebral
fracturesBone
mineral
density·


















Perform
DXA
of
spine
(L1-L4),
hip
(femoral
neck),
and
wrist
(distal
1/3
radius),
where
applicable.Study
Medication·


















Dispense
six
month
supply
of
alendronate·


















Assess
subject’s
supply
of
calcium
and
vitamin
D
supplements,
resupply
as
necessary
Scheduling
and
instructions
for
next
clinic
visit·


















Remind
subject
to
take
study
medication
as
instructed·


















Remind
subject
to
record
study
medication
use
Protocol
BA058-05-005
Amendment
4,
Version
1
(24
August
2015)
48
Radius
Health,
Inc.
Confidential
Month 12 Visit for Study BA058-05-005Day 360 (±5 days)
VISIT ActivitiesMonth 12
Recent
health
status·


















Document
any
changes
since
previous
visit
Vital
signs,
height
and
weight
measurementBlood
collection:
fasting
conditions
(NPO
except
water
for
8
hours)·


















Chemistry·


















Hematology·


















Serum
markers
of
bone
metabolism,
where
applicable·


















PINP·


















bone-specific
alkaline
phosphatase·


















serum
osteocalcin·


















serum
CTX·


















Urinalysis
(Dipstick)Bone
mineral
density·


















Perform
DXA
of
spine
(L1-L4),
hip
(femoral
neck),
and
wrist
(distal
1/3
radius),
where
applicable.
Clinical
fracture
assessment:
Subject
diary
review·


















Review
study
medication
diary/dispense
new
diary
if
necessary·


















Record
deviations
in
dosing
or
any
AEs
in
source
documents
and
CRFs.·


















Collect
diaries
and
enter
data
into
CRF
Study
medication·


















Dispense
six
month
supply
of
alendronate·


















Assess
subject’s
supply
of
calcium
and
vitamin
D
supplements;
resupply
as
necessary,
instruct
subject
to
take
daily
until
theyare
discharged
from
the
study
Scheduling
and
instructions
for
next
clinic
visit·


















Remind
subject
to
take
study
medication
as
instructed·


















Remind
subject
to
record
study
medication
use
Protocol
BA058-05-005
Amendment
4,
Version
1
(24
August
2015)
49
Radius
Health,
Inc.
Confidential
Month 18 Visit for Study BA058-05-005Day 540 (±5 days)
VISIT ActivitiesMonth 18
Recent
health
status·


















Document
any
changes
since
previous
visit
Vital
signs,
height
and
weight
measurementBlood
collection:
fasting
conditions
(NPO
except
water
for
8
hours)·


















Chemistry·


















Hematology·


















Serum
markers
of
bone
metabolism,
where
applicable·


















PINP·


















bone-specific
alkaline
phosphatase·


















serum
osteocalcin·


















serum
CTX·


















Urinalysis
(Dipstick)Bone
mineral
density·


















Perform
DXA
of
spine
(L1-L4),
hip
(femoral
neck),
and
wrist
(distal
1/3
radius),
where
applicable.
Clinical
fracture
assessment:
Subject
diary
review·


















Review
study
medication
diary/dispense
new
diary
if
necessary·


















Record
deviations
in
dosing
or
any
AEs
in
source
documents
and
CRFs.·


















Collect
diaries
and
enter
data
into
CRF
Study
medication·


















Dispense
six
month
supply
of
alendronate·


















Assess
subject’s
supply
of
calcium
and
vitamin
D
supplements;
resupply
as
necessary,
instruct
subject
to
take
daily
until
theyare
discharged
from
the
study
Scheduling
and
instructions
for
next
clinic
visit·


















Remind
subject
to
take
study
medication
as
instructed·


















Remind
subject
to
record
study
medication
use
Protocol
BA058-05-005
Amendment
4,
Version
1
(24
August
2015)
50
Radius
Health,
Inc.
Confidential
Month 24 Visit for Study BA058-05-005Day 720 (±5 days)
VISIT ActivitiesMonth 24
Recent
health
status·


















Document
any
changes
since
previous
visit
Vital
signs,
height
and
weight
measurementSubject
diary
review·


















Review
study
medication
diary·


















Record
deviations
in
dosing
or
any
AEs
in
source
documents
and
CRFs.·


















Collect
diaries
and
enter
data
into
CRFBlood
collection:
fasting
conditions
(NPO
except
water
for
8
hours)·


















Chemistry·


















Hematology·


















Coagulation
(PT
and
PTT)·


















Serum
markers
of
bone
metabolism,
where
applicable·


















PINP·


















bone-specific
alkaline
phosphatase·


















serum
osteocalcin·


















serum
CTX·


















Urinalysis
(Dipstick)
Clinical
and
radiologic
fracture
evaluations·


















Obtain
antero-posterior
and
lateral
radiographs
of
the
lumbar
and
thoracic
vertebrae·


















Document
any
non-vertebral
fractures
Bone
mineral
density·


















Perform
DXA
of
spine
(L1-L4),
hip
(femoral
neck),
and
wrist
(distal
1/3
radius),
where
applicable.
Study
medication·


















Collect
unused
study
medication
Discharge
subject
from
study·


















Subject
is
terminated
from
the
study
unless
adverse
events
require
further
follow
through
Discuss
continuing
treatment
options·


















Subjects
will
receive
standard-of-care
management
according
to
their
physician
Protocol
BA058-05-005
Amendment
4,
Version
1
(24
August
2015)
51
Radius
Health,
Inc.
Confidential
14.3 





Eastern Cooperative Oncology Group (ECOG) Common Toxicity Criteria
Category Toxicity (units) Grade 0 Grade 1 Grade 2 Grade 3 Grade 4Haematology









WBC
(x10
/L)
4
3.0
-
3.9
2.0
-
2.9
1.0
-
1.9
<
1.0Platelets
(x10
/L)
WNL
75.0
-
normal
50.0
-
74.9
25.0
-
49.9
<
25.0Haemoglobin
(g/L);
(mmol/L)
WNL
100.0
–
normal;
6.2
-
normal
80.0
-
99.0;

5.0
–
6.1
65.0
-
79.0
4.0
–
4.9
<
65.0
<
4.0Granulocytes/
Bands
(x10
/L)
2
1.5
-
1.9
1.0
-
1.4
0.5
-
0.9
<
0.5Lymphocytes
(x10
/L)
2
1.5
-
1.9
1.0
-
1.4
0.5
-
0.9
<
0.5Haemorrhage
none
mild,
no
transfusion
gross,1
-
2
unitstransfusion
per
episode
gross,
3
-
4
unitstransfusion
perepisode
massive,
>
4
unitstransfusion
perepisodeCoagulation









Fibrinogen
WNL
0.99
-
0.75
x
N
0.74
-
0.50
x
N
0.49
-
0.25
x
N
<
0.25
x
NProthrombin
time(quick)
WNL
1.01
-
1.25
x
N
1.26
-
1.50
x
N
1.51
-
2.00
x
N
>
2.00
x
NPartial
thromboplastin
time
WNL
1.01
-
1.66
x
N
1.67
-
2.33
x
N
2.34
-
3.00
x
N
>
3.00
x
NMetabolic









9
9
9
9
Hyperglycaemia
(mmol/L)
<
6.4
6.4
–
8.9
9.0
–
13.9
14.0
–
27.8
>
27.8
orketoacidosisHypoglycaemia
(mmol/L)
>
3.6
3.6
–
3.1
3.0
–
2.3
2.2
–
1.7
<
1.7Amylase
WNL
<
1.5
x
N
1.5
-
2.0
x
N
2.1
-
5.0
N
>
5.0
x
NHypercalcaemia
(mmol/L)
<
2.65
2.65
-
2.88
2.89
-
3.13
3.14
-
3.36
>
3.37Hypocalcaemia
(mmol/L)
>
2.10
2.10
-
1.94
1.93
-
1.74
1.73
-
1.52
<
1.51Hypomagnesaemia
(mmol/L)
>
0.58
0.58
-
0.48
0.47
-
0.36
0.35
-
0.24
<
0.23Gastrointestinal









Nausea
none
able
to
eat
reasonableintake
intake
significantlydecreased
but
can
eat
no
significantintake
—Vomiting
none
1
episode
in
24
hrs
2
-
5
episodes
in
24
hrs
6
-
10
episodes
in24
hrs
>
10
episodes
in
24hrs
or
requiringparenteral
supportDiarrhoea
none
increase
of
2
-
3stools/day
over
pre-Rx
increase
of
4
–
6stools/day,
or
nocturnalstools,
or
moderatecramping
increase
of
7
-
9stools/day,
orincontinence,
orsevere
cramping
increase
of
>
10stools/day
orgrossly
bloodydiarrhoea,
or
needfor
parenteralsupportStomatitis
none
painless
ulcers,erythema,
or
mildsoreness
painful
erythema,oedema,
or
ulcers
butcan
eat
solids
painful
erythema,oedema,
or
ulcersand
cannot
eatsolids
requires
parenteralor
enteral
supportfor
alimentationLiver









Bilirubin
(N
=
17
µmol/L)
WNL
—
<
1.5
x
N
1.5
-
3.0
x
N
>
3.0
x
N
Protocol
BA058-05-005
Amendment
4,
Version
1
(24
August
2015)
52
Radius
Health,
Inc.
Confidential
Category Toxicity (units) Grade 0 Grade 1 Grade 2 Grade 3 Grade 4Transaminase
(SGOT,
SGPT)
WNL
2.5
x
N
2.6
-
5.0
x
N
5.1
-
20.0
x
N
>
20.0
x
NAlkaline
phosphatase
or
5-nucleotidase
WNL
<
2.5
x
N
2.6
-
5.0
x
N
5.1
-
20.0
x
N
>
20.0
x
NLiver-
clinical
No
change
frombaseline
—
—
precoma
hepatic
comaKidney, bladder









Creatinine
WNL
<
1.5
x
N
1.5
-
3.0
x
N
3.1
-
6.0
x
N
>
6.0
x
NProteinuria
No
change
1
(+)
or
<
0.3
g%
or
3g/L
2
-
3
(+)
or
0.3-1.0
g%or
3-10
g/L
4
(+)
or
>
1.0
g%or
>
10g/L
nephroticsyndromeHaematuria
Negative
microscopic
only
gross,
no
clots
no
Rxneeded
gross
and
clotsbladder
irrigation
requirestransfusion
orcystectomyWeight
gain/
loss
<
5.0%
5.0
-
9.9%
10.0
-
19.9%
20.00%
—Pulmonary









Pulmonary
none
or
nochange
asymptomatic,
withabnormality
in
PFTs
dyspnoea
on
significantexertion
dyspnoea
atnormal
level
ofactivity
dyspnoea
at
restCardiac









Cardiac
arrhythmias
none
asymptomatic,
transient,requiring
no
therapy
recurrent
or
persistent,no
therapy
required
requirestreatment
requiresmonitoring;
orhypotension,
orventriculartachycardia
orfibrillationCardiac
function
none
asymptomatic,
declineof
resting
ejectionfraction
by
less
than
20%
of
baseline
value
asymptomatic,
declineof
resting
ejectionfraction
by
more
than20%
of
baseline
value
mild
CHF,responsive
totherapy
severe
orrefractory
CHFCardiac
ischaemia
none
non-specific
T-
waveflattening
asymptomatic,
ST
and
Twave
changessuggesting
ischaemia
angina
withoutevidence
ofinfraction
acute
myocardialinfarctionCardiac-
pericardial
none
asymptomatic
effusion,no
intervention
required
pericarditis
(rub,
chestpain,
ECG
changes)
symptomaticeffusion;drainage
required
tamponade;drainage
urgentlyrequiredHypertension
none
or
nochange
asymptomatic,
transientincrease
by
greater
than20
mmHg
(D)
or
to
>150/100
if
previouslyWNL.
No
treatmentrequired.
recurrent
or
persistentincrease
by
greater
than20
mmHG
(D)
or
to
>150/100
if
previouslyWNL.
No
treatmentrequired.
requires
therapy
hypertensivecrisisHypotension
none
or
nochange
changes
requiring
notherapy
(includingtransient
orthostatichypotension)
requires
fluidreplacement
or
othertherapy
but
nothospitalisation
requires
therapyandhospitalisation;resolves
within48
hrs
ofstopping
theagent
requires
therapyandhospitalisationfor
>
48
hrs
afterstopping
theagent
Protocol
BA058-05-005
Amendment
4,
Version
1
(24
August
2015)
53
Radius
Health,
Inc.
Confidential
Category          Toxicity (units) Grade 0 Grade 1 Grade 2 Grade 3 Grade 4Neurologic









Neuro:
sensory
none
or
no
change
mild
paraesthesias;
lossof
deep
tendon
reflexes
mild
or
moderateobjective
sensory
lossmoderate
paraesthesias
severe
objectivesensory
loss
orparaesthesias
thatinterfere
with
function
—Neuro:
motor
none
or
no
change
subjective
weakness;no
objective
findings
mild
objectiveweakness
withoutsignificant
impairmentof
function
objective
weaknesswith
impairment
offunction
paralysisNeuro:
cortical
none
mild
somnolence
oragitation
moderate
somnolenceor
agitation
severe
somnolence,(>50
%
waking
hours),agitation,
confusion,disorientation
orhallucinations
coma,
seizures,
toxicpsychosisNeuro:
cerebellar
none
slight
incoordination,dysdiadochokinesia
intention
tremor,dysmetria,
slurredspeech,
nystagmus
locomotor
ataxia
cerebellar
necrosisNeuro:
mood
no
change
mild
anxiety
ordepression
moderate
anxiety
ordepression
severe
anxiety
ordepression
suicidal
ideationNeuro:
headache
none
mild
moderate
or
severe
buttransient
unrelenting
and
severe
—Neuro:
constipation
none
or
no
change
mild
moderate
severe
ileus
>
96
hrsNeuro:
hearing
none
or
no
change
asymptomatic,
hearingloss
on
audiometryonly
tinnitus
hearing
loss
interferingwith
function
butcorrectable
withhearing
aid
deafness
notcorrectableNeuro:
vision
none
or
no
change
—
—
symptomatic
subtotalloss
of
vision
blindnessPain









Pain
none
mild
moderate
severe
reg.
narcoticsSkin









Skin
none
or
no
change
scattered
macular
orpapular
eruption
orerythema
that
isasymptomatic
scattered
macular
orpapular
eruption
orerythema
with
pruritusor
other
associatedsymptoms
generalisedsymptomatic
macular,papular
or
vesiculareruption
exfoliative
dermatitisor
ulcerating
dermatitisAlopecia









Alopecia
no
loss
mild
hair
loss
pronounced
or
totalhair
loss
—
—
Protocol
BA058-05-005
Amendment
4,
Version
1
(24
August
2015)
54
Radius
Health,
Inc.
Confidential
Category          Toxicity (units) Grade 0 Grade 1 Grade 2 Grade 3 Grade 4Allergy









Allergy
none
transient
rash,
drugfever<
38
C
(<100.4
F)
urticaria,
drug
fever
38C
(100.4
F),
mildbronchospasm
serum
sickness,bronchospasmrequiring
parenteralmedication
anaphylaxisLocal









Local
none
pain
pain
and
swelling
withinflammation
orphlebitis
ulceration
plastic
surgeryindicatedFever of unknownorigin









Fever
of
unknownorigin
none
37.1
-
38.0
C
98.7
-100.4
F
38.1
-
40.0
C
100.5
-104
F
>
40.0
C
(>
104
F)for
less
than
24hrs
>
40.0
C
(>
104
F)for
more
than
24
hrs
oraccompanied
byhypotensionInfection









Infection
none
mild
moderate
severe
life-threateningAdditional events









Asthenia
analogous
toKarnofsky
index(WHO
grading)







Chills
analogous
to
fever







Peripheral
oedema
analogous
to
weightgain







Anorexia
analogous
to
weightloss








Protocol
BA058-05-005
Amendment
4,
Version
1
(24
August
2015)
55o
o
o
o
o
o
o
o
o
o
o
o
o
Exhibit 10.7(d)
CLINICAL TRIAL SERVICES AGREEMENT AMENDMENT NO. 5 TO WORK STATEMENT NB-3
RADIUS
HEALTH,
INC.,
a
Delaware
corporation
(“
Radius
”)
and
NORDIC
BIOSCIENCE
CLINICAL
DEVELOPMENT
VII
A/S,
a
Danish
corporation
(“
NB”)
that
is
a
wholly-owned
subsidiary
of
Nordic
Bioscience
Clinical
Development
A/S
entered
into
a
Clinical
Trial
Services
Agreement
dated
March
29,
2011
(“Agreement”
)
and
Work
Statement
NB-3
under
the
Agreement
(
“Work
Statement
NB-3”
)
as
of
February
21,
2013
(
“Effective
Date”
),
and
entered
into
anAmendment
No.
1,
Amendment
No.
2,
Amendment
No.
3
and
Amendment
No.
4
to
Work
Statement
NB-3
as
of
February
28,
2014,
March
23,
2015,
July
8,
2015and
October
21,
2015
(as
amended,
“Work
Statement
NB-3”).
Pursuant
to
Section
2.3,
2.11
and
11.7
of
the
Agreement,
the
parties
wish
to
enter
into
this
Amendment
No.
5
to
Work
Statement
NB-3
(
“
Amendment
No.
5”
)effective
as
of
January
15,
2016
(
“Amendment
Date”
).
Capitalized
terms
used
in
this
Amendment
No.
5
and
not
defined
herein
are
used
with
the
meaningsascribed
to
them
in
the
Agreement
and
Work
Statement
NB-3.
The
purpose
of
this
Amendment
no.
5
is
to
collect
individual
patient
drug
accountability
log
for
patients
in
Radius’
BA058-05-003
clinical
trial.
NOW THEREFORE ,
in
consideration
of
the
mutual
promises
contained
in
the
Agreement
and
for
other
good
and
valuable
consideration
the
receipt
andadequacy
of
which
each
of
the
parties
does
hereby
acknowledge,
the
parties
hereby
agree
to
the
terms
of
this
Amendment
No.
5
to
Work
Statement
NB-3
asfollows:
1. Additional Monitoring Services:
(a)









At
Radius’
request,
NB
will
perform
additional
Monitoring
Visits
at
the
sites
listed
in
section
1(b)
to
collect
patient
specific
drug
logs
in
Radius’
BA058-05-003
clinical
trial.
(b)









NB
shall
collect
drug
logs
at
sites:
102,
103,
111,
121,
123,
124,
131,
132,
133,
141,
145,
151,
161
and
181.
It
is
estimated
that
45
monitoring
days
areneeded
to
collect
the
drug
logs
at
the
aforementioned
sites.
Other
sites
may
be
added
to
the
list
if
the
sites
are
not
willing
to
make
copies
themselves.
(c)










NB
shall
coordinate
drug
log
collection
at
all
sites
except
US
sites
and
site
101,
including
sites
not
mentioned
in
1(b).
This
is
done
remotely
by
asking
forthe
site’s
assistance
in
copying
the
drug
logs
and
sending
the
documents
to
the
appropriate
individual.
(d)









Radius
will
compensate
NB
for
the
Monitoring
Services
as
set
forth
in
Attachment
1.

All
documents
should
be
collected
and
sent
to
Radius
by
29February
2016,
if
at
all
possible.
This
Amendment
No.
5
to
Work
Statement
NB-3
contains
the
following
Attachments,
each
of
which
is
made
a
part
hereof:
Attachment
1




–




Budget
Summary
including
Payment
Schedule
2. Ratification. 

Except
to
the
extent
expressly
amended
by
this
Amendment
No.
5,
all
of
the
terms,
provisions
and
conditions
of
the
Agreement
and
WorkStatement
NB-3
are
hereby
ratified
and
confirmed
and
shall
remain
in
full
force
and
effect.
The
term
“Work
Statement
NB-3”
,
as
used
in
the
Agreement,
shallhenceforth
be
deemed
to
be
a
reference
to
Work
Statement
NB-3
as
amended
by
this
Amendment
No.
5.
/s/GW

3.  General. 

This
Amendment
No.
5
may
be
executed
in
counterparts,
each
of
which
will
be
deemed
an
original
with
all
such
counterparts
together
constitutingone
instrument.
IN
WITNESS
WHEREOF
the
parties
have
caused
this
Amendment
No.
5
under
Work
Statement
NB-3
to
be
executed
by
their
respective
duly
authorized
officers,and
have
duly
delivered
and
executed
this
Amendment
No.
5
under
seal
as
of
the
Amendment
Date.

RADIUS HEALTH, INC. NORDIC BIOSCIENCE CLINICAL DEVELOPMENT VII A/S





/s/
Gregory
C.
Williams
/s/
Jeppe
Ragnar
AndersenBy:
Gregory
C.
Williams
By:Title:
Chief
Development
Officer
Title:
CEO22
Jan
2016







Notice Address Notice AddressRadius
Health,
Inc.
Nordic
Bioscience
Clinical
Development
VII
A/S201
Broadway,
6

Floor
Herlev
Hovedgade
205-207Cambridge,
MA
02139
2730
HerlevUSA
DenmarkAttn:
President
&
CEO
Attn:
CEO,
Jeppe
Ragnar
AndersenPhone:
01.617.551.4700
Phone:
45.4452.5252Fax:
01.617.551.4701
Fax:
45.4452.521
2th

Attachment 1 - Budget
Budget and Invoicing Schedule
NB
shall
submit
monthly
invoices
to
Radius
in
accordance
with
the
following
on
a
work
performed
basis:
·


















EUR
2,500
per
monitoring
day
as
per
section
1(b)
(not
to
exceed
EUR
112,500)
·


















EUR
150
per
site
not
listed
in
section
1(b)
for
which
NB
coordinates
collection
of
drug
logs
through
the
site
staff.
Details
of
the
cost
will
itemized
on
theinvoice.

It
is
anticipated
that
this
will
not
exceed
8
sites
(or
EUR
1,200)
·


















Any
costs
outside
this
agreement
(i.e.
additional
fees
required
by
sites
for
time
and
materials
above
the
EUR
150)
will
be
managed
on
a
case-by-casebasis
and
must
be
approved
by
Radius.
Pass-through
includes
shipping
and
office
supplies.
Shipping
will
wherever
possible
be
done
on
Radius’s
UPS
account.
/s/GW
3Exhibit 10.11(a)
AMENDMENT NO. 3TODEVELOPMENT AND MANUFACTURING SERVICES AGREEMENT
This
Amendment
No.
3
(the
“Amendment”)
to
the
DEVELOPMENT
AND
MANUFACTURING
SERVICES
AGREEMENT
is
entered
into
onDecember
31,
2015
by
and
between
Radius
Health
Inc.,
a
Delaware
corporation,
with
its
principal
office
at
950
Winter
Street,
Waltham,
MA
02451,
United
Statesof
America
(“RADIUS”)
and
LONZA
Sales
Ltd,
a
Swiss
company
having
an
address
at
Muenchensteinerstrasse
38,
CH-4002
Basel,
Switzerland
(together
with
itsAffiliates,
“Manufacturer”)
and
upon
execution
will
be
incorporated
into
the
Development
and
Manufacturing
Services
Agreement
between
RADIUS
andManufacturer
dated
October
16,
2007
(the
“Original
Agreement”),
as
amended
to
date.
Capitalized
terms
used
in
this
Amendment
will
have
the
same
meaning
asset
forth
in
the
Agreement
as
amended
to
date.
WHEREAS ,
RADIUS
and
Manufacturer
are
parties
to
the
Agreement;
and
WHEREAS ,
RADIUS
and
Manufacturer
are
parties
to
Amendment
No.
1,
entered
into
on
May
19,
2011,
and
Amendment
No.
2,
entered
into
onJanuary
30,
2014,
to
the
Agreement
(such
Amendment
No.
1
and
Amendment
No.
2
together
with
the
Original
Agreement,
the
“Agreement”);
WHEREAS ,
the
Parties
are
in
the
process
of
negotiating
a
commercial
manufacturing
services
agreement
(the
“Commercial
Agreement”);
and
WHEREAS ,
the
Parties
desire
to
further
amend
the
Agreement
as
set
forth
herein.
NOW THEREFORE ,
in
consideration
of
the
above
premises
and
the
mutual
covenants
herein
set
forth,
and
for
other
good
and
valuable
consideration,the
receipt
and
sufficiency
of
which
are
hereby
acknowledged,
the
Parties
hereto
agree
as
follows:
1.














Amendment
to
Section
14.1
.
The
Parties
hereby
agree
to
extend
the
term
of
the
Agreement
to
the
earlier
of
a)
the
date
on
which
the
CommercialAgreement
becomes
effective,
or
b)
March
31,
2016,
unless
earlier
terminated
pursuant
to
Section
14
of
the
Agreement.
Any
further
extensions
of
theterm
shall
be
mutually
agreed
by
the
Parties.
2.














Pending
Work
Orders
.
Any
and
all
Work
Orders
entered
into,
or
Purchase
Orders
issued,
under
and
during
the
term
of
the
Agreement
which
are
stillpending
at
the
time
the
Commercial
Agreement
becomes
effective
shall
immediately
become
governed
by,
and
incorporated
in
and
made
a
part
of,
suchCommercial
Agreement.
3.














Ratification
.
All
lawful
actions
taken
by
RADIUS
and
Manufacturer
which
are
consistent
with
the
terms
of
the
Agreement
are
hereby
authorized,approved
and
ratified,
regardless
of
whether
any
such
actions
were
taken
prior
to
the
date
of
this
Amendment.
4.














Remainder
of
Agreement
.
Except
as
modified
by
this
Amendment,
all
other
terms
and
provisions
of
the
Agreement
shall
remain
in
full
force
and
effectin
accordance
with
their
terms.
5.














Entire
Agreement
.
This
Amendment
and
the
Agreement
supersede
all
other
prior
agreements,
understandings,
representations
and
warranties,
oral
orwritten
between
the
parties
hereto
in
respect
of
the
subject
matter
hereof.

6.














Governing
Law;
Jurisdiction
.
This
Amendment
shall
be
construed,
interpreted
and
enforeced
in
accordance
with
the
internal
substantive
laws
of
the
Stateof
New
York,
without
reference
to
the
choice
of
law
doctrine
of
such
state.
7.














Counterparts;
Delivery
.
This
Amendment
may
be
executed
in
any
number
of
counterparts,
each
of
which
shall
for
all
purposes
be
deemed
an
original
andall
of
which
shall
constitute
the
same
instrument.
Delivery
of
an
executed
signature
page
of
this
Amendment
by
facsimile
or
other
electronic
transmissionsshall
be
as
effective
as
delivery
of
an
original
executed
counterpart
of
this
Amendment.
[Remainder
of
Page
Intentionally
Left
Blank]
2
IN
WITNESS
WHEREOF,
the
Parties
hereto
have
caused
this
Amendment
to
be
executed
by
their
respective
authorized
representatives
effective
as
of
thedate
first
above
written.
LONZA
SALES
LTD.
RADIUS
HEALTH,
INC.


By:/s/
Michael
Maskus
By:/s/
David
C.
HanleyName:Michael
Maskus
Name:David
C.
HanleyTitle:Associate
Director
Title:Executive
Director,
Technical
Operations
Commercial
Development







By:/s/
Cordula
Altekrüger
Reviewed
ByName:Cordula
Altekrüger
CATitle:Senior
Legal
Counsel
Legal
Dept.
3Exhibit 21.1
SUBSIDIARY OF RADIUS HEALTH, INC.
Legal Name of Subsidiary Jurisdiction of OrganizationRadius
Health
Securities
Corporation
Massachusetts
QuickLinks
--
Click
here
to
rapidly
navigate
through
this
documentExhibit
23.1
Consent
of
Independent
Registered
Public
Accounting
Firm








We
consent
to
the
incorporation
by
reference
in
the
Registration
Statement
on
Form
S-3
(No.
333-201610)
and
Form
S-8
(Nos.
333-177800
and
333-195521)of
Radius
Health,
Inc.
and
in
the
related
Prospectus
of
our
reports
dated
February
25,
2016,
with
respect
to
the
consolidated
financial
statements
of
RadiusHealth,
Inc.
and
the
effectiveness
of
internal
control
over
financial
reporting
of
Radius
Health,
Inc.
included
in
this
Annual
Report
on
Form
10-K
for
the
year
endedDecember
31,
2015.Boston,
Massachusetts
February
25,
2016
/s/
Ernst
&
Young
LLPQuickLinks
Exhibit
23.1
Consent
of
Independent
Registered
Public
Accounting
Firm
QuickLinks
--
Click
here
to
rapidly
navigate
through
this
documentExhibit
31.1
Certifications
I,
Robert
E.
Ward,
certify
that:1.I
have
reviewed
this
annual
report
on
Form
10-K
of
Radius
Health,
Inc.;
2.Based
on
my
knowledge,
this
report
does
not
contain
any
untrue
statement
of
a
material
fact
or
omit
to
state
a
material
fact
necessary
to
make
thestatements
made,
in
light
of
the
circumstances
under
which
such
statements
were
made,
not
misleading
with
respect
to
the
period
covered
by
this
report;
3.Based
on
my
knowledge,
the
financial
statements,
and
other
financial
information
included
in
this
report,
fairly
present
in
all
material
respects
the
financialcondition,
results
of
operations
and
cash
flows
of
the
registrant
as
of,
and
for,
the
periods
presented
in
this
report;
4.The
registrant's
other
certifying
officer
and
I
are
responsible
for
establishing
and
maintaining
disclosure
controls
and
procedures
(as
defined
in
ExchangeAct
Rules
13a-15(e)
and
15d-15(e))
and
internal
control
over
financial
reporting
(as
defined
in
Exchange
Act
Rules
13a-15(f)
and
15d-15(f))
for
theregistrant
and
have:
(a)Designed
such
disclosure
controls
and
procedures,
or
caused
such
disclosure
controls
and
procedures
to
be
designed
under
our
supervision,
toensure
that
material
information
relating
to
the
registrant,
including
its
consolidated
subsidiaries,
is
made
known
to
us
by
others
within
thoseentities,
particularly
during
the
period
in
which
this
report
is
being
prepared;
(b)Designed
such
internal
control
over
financial
reporting,
or
caused
such
internal
control
over
financial
reporting
to
be
designed
under
oursupervision,
to
provide
reasonable
assurance
regarding
the
reliability
of
financial
reporting
and
the
preparation
of
financial
statements
for
externalpurposes
in
accordance
with
generally
accepted
accounting
principles;
(c)Evaluated
the
effectiveness
of
the
registrant's
disclosure
controls
and
procedures
and
presented
in
this
report
our
conclusions
about
the
effectivenessof
the
disclosure
controls
and
procedures,
as
of
the
end
of
the
period
covered
by
this
report
based
on
such
evaluation;
and
(d)Disclosed
in
this
report
any
change
in
registrant's
internal
control
over
financial
reporting
that
occurred
during
the
registrant's
most
recent
fiscalquarter
(the
registrant's
fourth
fiscal
quarter
in
the
case
of
an
annual
report)
that
has
materially
affected,
or
is
reasonably
likely
to
materially
affect,the
registrant's
internal
control
over
financial
reporting;
and
5.The
registrant's
other
certifying
officer
and
I
have
disclosed,
based
on
our
most
recent
evaluation
of
internal
control
over
financial
reporting,
to
theregistrant's
auditors
and
the
audit
committee
of
registrant's
board
of
directors
(or
persons
performing
the
equivalent
functions):
(a)All
significant
deficiencies
and
material
weaknesses
in
the
design
or
operation
of
internal
control
over
financial
reporting
which
are
reasonablylikely
to
adversely
affect
the
registrant's
ability
to
record,
process,
summarize
and
report
financial
information;
and
(b)Any
fraud,
whether
or
not
material,
that
involves
management
or
other
employees
who
have
a
significant
role
in
the
registrant's
internal
control
overfinancial
reporting.Date:
February
26,
2016
/s/
ROBERT
E.
WARD
Robert
E.
Ward
President and Chief Executive OfficerQuickLinks
Exhibit
31.1
Certifications
QuickLinks
--
Click
here
to
rapidly
navigate
through
this
documentExhibit
31.2
Certifications
I,
B.
Nicholas
Harvey,
certify
that:1.I
have
reviewed
this
annual
report
on
Form
10-K
of
Radius
Health,
Inc.;
2.Based
on
my
knowledge,
this
report
does
not
contain
any
untrue
statement
of
a
material
fact
or
omit
to
state
a
material
fact
necessary
to
make
thestatements
made,
in
light
of
the
circumstances
under
which
such
statements
were
made,
not
misleading
with
respect
to
the
period
covered
by
this
report;
3.Based
on
my
knowledge,
the
financial
statements,
and
other
financial
information
included
in
this
report,
fairly
present
in
all
material
respects
the
financialcondition,
results
of
operations
and
cash
flows
of
the
registrant
as
of,
and
for,
the
periods
presented
in
this
report;
4.The
registrant's
other
certifying
officer
and
I
are
responsible
for
establishing
and
maintaining
disclosure
controls
and
procedures
(as
defined
in
ExchangeAct
Rules
13a-15(e)
and
15d-15(e))
and
internal
control
over
financial
reporting
(as
defined
in
Exchange
Act
Rules
13a-15(f)
and
15d-15(f))
for
theregistrant
and
have:
(a)Designed
such
disclosure
controls
and
procedures,
or
caused
such
disclosure
controls
and
procedures
to
be
designed
under
our
supervision,
toensure
that
material
information
relating
to
the
registrant,
including
its
consolidated
subsidiaries,
is
made
known
to
us
by
others
within
thoseentities,
particularly
during
the
period
in
which
this
report
is
being
prepared;
(b)Designed
such
internal
control
over
financial
reporting,
or
caused
such
internal
control
over
financial
reporting
to
be
designed
under
oursupervision,
to
provide
reasonable
assurance
regarding
the
reliability
of
financial
reporting
and
the
preparation
of
financial
statements
for
externalpurposes
in
accordance
with
generally
accepted
accounting
principles;
(c)Evaluated
the
effectiveness
of
the
registrant's
disclosure
controls
and
procedures
and
presented
in
this
report
our
conclusions
about
the
effectivenessof
the
disclosure
controls
and
procedures,
as
of
the
end
of
the
period
covered
by
this
report
based
on
such
evaluation;
and
(d)Disclosed
in
this
report
any
change
in
registrant's
internal
control
over
financial
reporting
that
occurred
during
the
registrant's
most
recent
fiscalquarter
(the
registrant's
fourth
fiscal
quarter
in
the
case
of
an
annual
report)
that
has
materially
affected,
or
is
reasonably
likely
to
materially
affect,the
registrant's
internal
control
over
financial
reporting;
and
5.The
registrant's
other
certifying
officer
and
I
have
disclosed,
based
on
our
most
recent
evaluation
of
internal
control
over
financial
reporting,
to
theregistrant's
auditors
and
the
audit
committee
of
registrant's
board
of
directors
(or
persons
performing
the
equivalent
functions):
(a)All
significant
deficiencies
and
material
weaknesses
in
the
design
or
operation
of
internal
control
over
financial
reporting
which
are
reasonablylikely
to
adversely
affect
the
registrant's
ability
to
record,
process,
summarize
and
report
financial
information;
and
(b)Any
fraud,
whether
or
not
material,
that
involves
management
or
other
employees
who
have
a
significant
role
in
the
registrant's
internal
control
overfinancial
reporting.Date:
February
25,
2016
/s/
B.
NICHOLAS
HARVEY
B.
Nicholas
Harvey
Senior Vice President, Chief Financial Officer, Treasurer andSecretaryQuickLinks
Exhibit
31.2
Certifications
QuickLinks
--
Click
here
to
rapidly
navigate
through
this
documentExhibit
32.1
CERTIFICATION
PURSUANT
TO
18
U.S.C.
SECTION
1350,
AS
ADOPTED
PURSUANT
TO
SECTION
906
OF
THE
SARBANES-OXLEY
ACT
OF
2002








In
connection
with
the
Annual
Report
of
Radius
Health,
Inc.
(the
"Company")
on
Form
10-K
for
the
fiscal
year
ended
December
31,
2015
as
filed
with
theSecurities
and
Exchange
Commission
on
the
date
hereof
(the
"Report"),
I,
Robert
E.
Ward,
certify,
pursuant
to
18
U.S.C.
§
1350,
as
adopted
pursuant
to
§
906
ofthe
Sarbanes-Oxley
Act
of
2002,
that
to
my
knowledge:(1)The
Report
fully
complies
with
the
requirements
of
section
13(a)
or
15(d)
of
the
Securities
Exchange
Act
of
1934;
and
(2)The
information
contained
in
the
Report
fairly
presents,
in
all
material
respects,
the
financial
condition
and
results
of
operations
of
the
Company.







A
signed
original
of
this
written
statement
required
by
Section
906
has
been
provided
to
the
Company
and
will
be
retained
by
the
Company
and
furnished
tothe
Securities
and
Exchange
Commission
or
its
staff
upon
request.February
25,
2016
/s/
ROBERT
E.
WARD
Robert
E.
Ward
President and Chief Executive OfficerQuickLinks
Exhibit
32.1
CERTIFICATION
PURSUANT
TO
18
U.S.C.
SECTION
1350,
AS
ADOPTED
PURSUANT
TO
SECTION
906
OF
THE
SARBANES-OXLEY
ACT
OF
2002
QuickLinks
--
Click
here
to
rapidly
navigate
through
this
documentExhibit
32.2
CERTIFICATION
PURSUANT
TO
18
U.S.C.
SECTION
1350,
AS
ADOPTED
PURSUANT
TO
SECTION
906
OF
THE
SARBANES-OXLEY
ACT
OF
2002








In
connection
with
the
Annual
Report
of
Radius
Health,
Inc.
(the
"Company")
on
Form
10-K
for
the
fiscal
year
ended
December
31,
2015
as
filed
with
theSecurities
and
Exchange
Commission
on
the
date
hereof
(the
"Report"),
I,
B.
Nicholas
Harvey,
certify,
pursuant
to
18
U.S.C.
§
1350,
as
adopted
pursuant
to
§
906of
the
Sarbanes-Oxley
Act
of
2002,
that
to
my
knowledge:(1)The
Report
fully
complies
with
the
requirements
of
section
13(a)
or
15(d)
of
the
Securities
Exchange
Act
of
1934;
and
(2)The
information
contained
in
the
Report
fairly
presents,
in
all
material
respects,
the
financial
condition
and
results
of
operations
of
the
Company.







A
signed
original
of
this
written
statement
required
by
Section
906
has
been
provided
to
the
Company
and
will
be
retained
by
the
Company
and
furnished
tothe
Securities
and
Exchange
Commission
or
its
staff
upon
request.February
25,
2015
/s/
B.
NICHOLAS
HARVEY
B.
Nicholas
Harvey
Senior Vice President, Chief Financial Officer, Treasurer and SecretaryQuickLinks
Exhibit
32.2
CERTIFICATION
PURSUANT
TO
18
U.S.C.
SECTION
1350,
AS
ADOPTED
PURSUANT
TO
SECTION
906
OF
THE
SARBANES-OXLEY
ACT
OF
2002