Download the presentation here: PDF

Game Changing Plays in the
Pain Market
Ginger S. Johnson, PhD
Vice President
Defined Health
1
© Defined
© Defined
Health,
Health,
2009
2009
Pain Insight Briefing

2
© Defined Health, 2009
Pain Insight Briefing

Our Disclaimer
3
The information in this presentation has been obtained from what are
believed to be reliable sources and has been verified whenever possible.
Nevertheless, we cannot guarantee the information contained herein as
to accuracy or completeness.
All expressions of opinion are the responsibility of Defined Health and,
though current as of the date of this report, are subject to change.
The contents of this presentation are not meant to be comprehensive, but
to encourage a spirited dialogue. Feedback, comments and corrections
are welcome.
© Defined Health, 2009
Pain Insight Briefing

What’s Next for Pain?
4
• Continued efforts to improve on current standard of care.
• Increasing use of experimental/translational methodologies for early
clinical PoC (e.g., neuroimaging).
• Big pharma focus on novel mechanisms.
• More biologicals targeting pain mediators.
© Defined Health, 2009
Pain Insight Briefing

Everyone Hurts
“Pain is whatever the experiencing person says it is, existing whenever he/she
says it does". (Margo McCaffery, 1968)
http://www.anes.ucla.edu/pain/FacesScale.jpg
5
© Defined Health, 2009
Pain Insight Briefing

An Estimated 250 M Suffer From Chronic Pain WW
6
Acute pain and chronic pain differ in their etiology, pathophysiology and
treatment.
• Acute pain is self-limiting and serves a protective biological function; however, we still want
it minimized.
• Chronic pain (both nociceptive/inflammatory and neuropathic), on the other hand, is itself a
disease process.
Pfizer Analyst and Investor Meeting Oct. 28, 2008
© Defined Health, 2009
Pain Insight Briefing
For several of these chronic
conditions, such as chronic low
back pain (CLBP), fibromyalgia and
neuropathic pain, prevalence
estimates are likely to be significant
undercalls, as treatment specific for
these pain types is either nonexistent
or nascent.
= untapped market potential.

It’s A Big Market with a Few Dominant Players
7
The pain market is well over $7 billion worldwide.
20%
Purdue
EvaluatePharma
King/Alpharma
Cephalon
18%
Endo
7%
4%
© Defined Health, 2009
Pain Insight Briefing
22%
J&J
30%
Pfizer

And Several Recent “Specialty-Size” Success Stories
$ Millions
8
350
300
250
200
150
100
Sales Ramp Up of Selected Branded Pain Meds Introduced
Since 1998 (WW)
50
0
1998
EvaluatePharma
2000
2002
2004
2006
2008
2010E
2012E
2014E
© Defined Health, 2009
Pain Insight Briefing
Avinza
Opana/Opana
ER
Fentora
Jurnista

$ Millions
But Few “Big Pharma-Size” Successes
9
Sales Ramp Up of Selected Branded Pain Meds Introduced
Since 1998 (WW)
5,000
4,500
4,000
3,500
3,000
2,500
2,000
1,500
1,000
500
0
1998
EvaluatePharma
2000
2002
2004
2006
2008
2010E
© Defined Health, 2009
Pain Insight Briefing
2012E
2014E
Avinza
Lyrica
Opana/Opana
ER
Fentora
Jurnista
VIOXX
Celebrex

Pain Historically: Drug Delivery has “Delivered”
10
Drug Delivery-Based Pain Products Have Greatly Surpassed Expectations
• OXYCONTIN
• MS-CONTIN
• DURAGESIC
• ACTIQ
• ORALET
• AVINZA
• KADIAN
• STADOL
• LIDODERM
© Defined Health, 2009
Pain Insight Briefing
The initial sales forecast for
Oxycontin was $350 M (Wall
Street Journal, May 2002) …
now a billion+ dollar franchise.

Pain Historically: Drug Delivery has “Delivered”
11
Drug Delivery-Based Pain Products Have Greatly Surpassed Expectations
• The epidemiology of pain is uncertain at best
• Off-label use is always greater than anticipated
• Nature of a symptom-driven market welcomes the next new thing
• Healthy price hikes
THE BAR
Development Risk Regulatory Risk
Market Risk
© Defined Health, 2009
Pain Insight Briefing

Pain Historically: Drug Delivery has “Delivered”
12
Drug Delivery-Based Pain Products Have Greatly Surpassed Expectations
• The epidemiology of pain is uncertain at best
• Off-label use is always greater than anticipated
• Nature of a symptom-driven market welcomes the next new thing
• Healthy price hikes
Development Risk
Regulatory Risk
THE BAR
© Defined Health, 2009
Pain Insight Briefing
Market Risk

It’s Getting Tougher
Labopharm LabopharmGets Gets FDA FDA Okay Okay For For Once-Daily Tramadol (Ryzolt) --Finally Finally
December
December
31,
31,
2008:
2008:
12:03
12:03
PM
PM
ET
ET
To
To
say
say
Labopharm
Labopharm
Inc.'s
Inc.'s
(DDSS)
(DDSS)
first
first
U.S.
U.S.
drug
drug
approval
approval
followed
followed
a
a
long
long
and
and
winding
winding
road
road
would
would
be
be
an
an
understatement,
understatement,
but
but
the
the
tramadol
tramadol
saga
saga
with
with
the
the
U.S.
U.S.
FDA
FDA
is
is
finally
finally
over
over
and
and
investors
investors
aren't
aren't
dwelling
dwelling
on
on
the
the
past.
past.
Earlier
Earlier
Wednesday,
Wednesday,
the
the
Canadian
Canadian
specialty-pharma
specialty-pharma
company
company
announced
announced
that
that
the
the
FDA
FDA
approved
approved
its
its
once-daily
once-daily
formulation
formulation
of
of
painkiller
painkiller
tramadol,
tramadol,
named
named
Ryzolt.
Ryzolt.
Labopharm,
Labopharm,
which
which
has
has
been
been
public
public
for
for
12
12
years,
years,
went
went
through
through
hoops
hoops
to
to
get
get
the
the
drug
drug
approved,
approved,
having
having
to
to
redo
redo
trials,
trials,
construct
construct
new
new
statistical
statistical
analyses,
analyses,
and
and
even
even
engage
engage
the
the
U.S.
U.S.
regulator's
regulator's
formal
formal
dispute-resolution
dispute-resolution
process.
process.
It
It
expects
expects
marketing
marketing
partner
partner
Purdue
Purdue
Pharma
Pharma
to
to
launch
launch
the
the
product
product
in
in
the
the
second
second
quarter.
quarter.
"This
"This
is
is
a
a
great
great
milestone
milestone
for
for
the
the
company
company
and
and
fantastic
fantastic
news
news
for
for
investors,
investors,
but
but
this
this
approval
approval
has
has
been
been
a
a
long
long
time
time
coming,"
coming,"
said
said
a
a
biotech
biotech
observer
observer
familiar
familiar
with
with
the
the
company.
company.
"I
"I
can't
can't
help
help
but
but
believe
believe
the
the
opportunity
opportunity
today
today
is
is
much
much
smaller
smaller
than
than
it
it
was
was
a
a
few
few
years
years
ago.
ago.
The
The
results
results
will
will
be
be
apparent
apparent
enough
enough
once
once
the
the
company
company
launches
launches
the
the
drug."
drug."
…
In
In
the
the
U.S.,
U.S.,
Ryzolt
Ryzolt
will
will
face
face
competition
competition
from
from
Biovail
Biovail
Corp.'s
Corp.'s
Ultram
Ultram
ER,
ER,
which
which
has
has
a
a
three-year
three-year
head
head
start
start
and
and
is
is
backed
backed
by
by
marketing
marketing
juggernaut
juggernaut
Johnson
Johnson
&
Johnson.
Johnson.
Despite
Despite
the
the
lead
lead
and
and
having
having
the
the
market
market
to
to
itself,
itself,
the
the
drug's
drug's
sales
sales
have
have
been
been
a
a
disappointment
disappointment
to
to
investors.
investors.
In
In
2007,
2007,
Biovail's
Biovail's
revenue
revenue
from
from
Ultram
Ultram
ER
ER
was
was
$86.7
$86.7
million;
million;
through
through
the
the
third
third
quarter
quarter
of
of
2008,
2008,
revenue
revenue
was
was
$
$
64.1
64.1
million.
million.
13
CNNMoney.com
© Defined Health, 2009
Pain Insight Briefing

It’s Getting Tougher
Labopharm LabopharmGets Gets FDA FDA Okay Okay For For Once-Daily Tramadol (Ryzolt) --Finally Finally
December December 31, 31, 2008: 2008: 12:03 12:03 PM PM ET ET
To
To
say
say
Labopharm
Labopharm
Inc.'s
Inc.'s
(DDSS)
(DDSS)
first
first
U.S.
U.S.
drug
drug
approval
approval
followed
followed
a
a
long
long
and
and
winding
winding
road road Marketing would would be be an an partner understatement, understatement, Purdue but but Pharma the the tramadol tramadol plans saga saga to with with launch the the U.S. U.S. in FDA FDA Q2 is is 2009. finally finally over over
and
and
investors
investors
aren't
aren't
dwelling
dwelling
on
on
the
the
past.
past.
Earlier
Earlier
Wednesday,
Wednesday,
the
the
Canadian
Canadian
specialty-pharma
specialty-pharma
company
company
announced
announced
that
that
the
the
FDA
FDA
approved approved "This
its its is
once-daily once-daily a great
formulation formulation milestone
of of for
painkiller painkiller the company
tramadol, tramadol, named named and
Ryzolt. Ryzolt. fantastic
Labopharm, Labopharm, news for
which which
has
has
been investors, been
public
public
for
for but 12
12
years, this years, approval went
went
through
through has hoops
hoops been to
to
get
get a the long the
drug
drug time approved,
approved, coming," having
having said to
to
redo
redo a
trials,
trials,
construct
construct
new
new
statistical
statistical
analyses,
analyses,
and
and
even
even
engage
engage
the
the
U.S.
U.S.
regulator's
regulator's
formal
formal
disputedisputeresolutionresolution
biotech process. process. observer familiar with the company. "I can't help but believe
It
It
expects
expects the opportunity marketing
marketing
partner
partner today Purdue
Purdue is much Pharma
Pharma smaller to
to
launch
launch than the
the
product it product was in
in a the
the few second
second years quarter.
quarter. ago.
"This "This is is a a great great milestone milestone for for the the company company and and fantastic fantastic news news for for investors, investors, but but this this approval approval
has
has The
been
been results
a
a
long
long
time
time will
coming,"
coming," be apparent
said
said
a
a
biotech
biotech enough
observer
observer once
familiar
familiar the company
with
with
the
the
company.
company. launches
"I
"I the
can't can't drug." help help but but believe believe the the opportunity opportunity today today is is much much smaller smaller than than it it was was a a few few years years ago. ago.
The
The
results
results
will
will
be
be
apparent
apparent
enough
enough
once
once
the
the
company
company
launches
launches
the
the
drug."
drug."
…
In
In
the
the
U.S.,
U.S.,
Ryzolt
Ryzolt
will
will
face
face
competition
competition
from
from
Biovail
Biovail
Corp.'s
Corp.'s
Ultram
Ultram
ER,
ER,
which
which
has
has
a
a
three-year
three-year
head
head
start
start
and
and
is
is
backed
backed
by
by
marketing
marketing
juggernaut
juggernaut
Johnson
Johnson
&
Johnson.
Johnson.
Despite Despite the the lead lead and and having having the the market market to to itself, itself, the the drug's drug's sales sales have have been been a a disappointment
disappointment
to
to
investors. Ryzolt investors. will In
In
2007, face 2007,
Biovail's
Biovail's competition revenue
revenue from from
Ultram
Ultram Biovail ER
ER
was Corp.'s was
$86.7
$86.7 Ultram million;
million;
through
through ER, which the
the
third
third has
quarter quarter of of 2008, 2008, revenue revenue was was $ $ 64.1 64.1 million. million.
14
To say Labopharm Inc.'s (DDSS) first U.S. drug approval followed a
long and winding road would be an understatement…Ryzolt, a QD
tramadol ER for moderately severe chronic pain, first received an
approvable letter from the FDA in 2006 – not data related. Since
then, Labopharm has filed a formal dispute resolution with the FDA.
a three-year head start and is backed by marketing juggernaut
Johnson & Johnson.
CNNMoney.com
© Defined Health, 2009
Pain Insight Briefing

The Risk : Reward Profile for Novel Pain Agents
15
Development Risk
Regulatory Risk
THE BAR
© Defined Health, 2009
Pain Insight Briefing
Market Risk

The Risk : Reward Profile for Novel Pain Agents
16
Development Risk
Regulatory Risk
THE BAR
© Defined Health, 2009
Pain Insight Briefing
Market Risk
Product Label and/or
Managed Care

Current Standard of Care for Pain…
based on some very old science
poppies and chili peppers
17
• Nociceptive Pain
• Acetaminophen
• NSAIDs
• Opiates
• Local Anesthetics
• Muscle Relaxants
© Defined Health, 2009
Pain Insight Briefing
• Neuropathic Pain
• Anti-depressants
• Anti-epileptics
• Topical Capsaicin
• Topical Lidocaine
• Local Anesthetics

Treatment Largely Guided By Side Effects
& Tolerability
18
Constipation, sedation,
confusion, respiratory
depression, mental
clouding, renal colic,
tolerance to prolonged use
and risk of abuse, misuse,
addiction.
Gastrointestinal
ulcers, stomach
bleeding, tinnitus,
cardiovascular risks.
Gastric erosion, peptic ulcer,
inflammation of the
duodenum and of the colon,
renal toxicity with prolonged
use.
Step 1: Mild Pain (1-3/10)
• Aspirin (ASA)
• Acetaminophen (APAP)
• Nonsteroidal
anti-inflammatory drugs (NSAIDs)
• +/- Adjuvants
World Health Organization
© Defined Health, 2009
Pain Insight Briefing
Step 2: Moderate Pain (4-6/10)
• APAP or ASA +
– Codeine
– Hydrocodone
– Oxycodone
– Dihydrocodeine
– Tramadol (not available
with APAP or ASA)
– +/- Adjuvants
Step 3: Severe Pain (7-10/10)
• Morphine
• Hydromorphone
• Methadone
• Levorphanol
• Fentanyl
• Oxycodone
• +- Nonopiod analgesics
• +/-Adjuvants
•Adjuvant Therapy:
– Anticonvulsants
– Antidepressants
– Corticosteroids
– Dermal analgesics
– Muscle relaxants
– Stimulants

Leaving Plenty of Unmet Need to Be Addressed
19
Relistor (Progenics/Wyeth);
Tapentadol Constipation, (J&J), sedation, DOR
agonists confusion, (Adolor/Pfizer);
respiratory
abuse-deterrent depression, mental opioids clouding,
(King/Alpharma/Acura,
renal colic, tolerance to
prolonged use and risk of
Pain Therapeutics, Acurox)
abuse, misuse, addiction.
Gastrointestinal ulcers,
stomach bleeding,
Celebrex tinnitus (Pfizer)
PN400
(Nexium/naproxen),
AstraZeneca/Pozen
Naproxcinod (NicOx)
Gastric erosion, peptic ulcer,
Topical NSAIDs
inflammation of the duodenum and
of the colon, renal toxicity with
prolonged use
Step 1: Mild Pain (1-3/10)
• Aspirin (ASA)
• Acetaminophen (APAP)
• Nonsteroidal
anti-inflammatory drugs (NSAIDs)
• +/- Adjuvants
World Health Organization
© Defined Health, 2009
Pain Insight Briefing
Step 2: Moderate Pain (4-6/10)
• APAP or ASA +
– Codeine
– Hydrocodone
– Oxycodone
– Dihydrocodeine
– Tramadol (not available
with APAP or ASA)
– +/- Adjuvants
Step 3: Severe Pain (7-10/10)
• Morphine
• Hydromorphone
• Methadone
• Levorphanol
• Fentanyl
• Oxycodone
• +- Nonopiod analgesics
• +/-Adjuvants
•Adjuvant Therapy:
– Anticonvulsants
– Antidepressants
– Corticosteroids
– Dermal analgesics
– Muscle relaxants
– Stimulants

But Here is the Big Problem
20
>50% of Patients Report Suboptimal Relief of Pain
Enter the novel mechanisms…
FAAH inhibitors
TRPV1 antagonists/agonists
NGF inhibitors
CCR2 antagonists
KCC2 modulators
Other biological, mediator-based approaches
Defined Health primary research; Adis R&D Insight
© Defined Health, 2009
Pain Insight Briefing

In the Meantime, Let’s Teach Old Dogs Some
New Tricks
http://www.wxicof.com/Books/training/2460.jpg
21
© Defined Health, 2009
Pain Insight Briefing

A Better NSAID
22
Constipation, sedation,
confusion, respiratory
depression, mental clouding,
renal colic, tolerance to
prolonged use and risk of
abuse, misuse, addiction.
Gastrointestinal ulcers,
stomach bleeding,
Celebrex tinnitus (Pfizer)
PN400 (Nexium/naproxen),
AstraZeneca/Pozen
Naproxcinod (NicOx)
Topical NSAIDs
Gastric erosion, peptic ulcer,
inflammation of the duodenum and
of the colon, renal toxicity with
prolonged use
Step 1: Mild Pain (1-3/10)
• Aspirin (ASA)
• Acetaminophen (APAP)
• Nonsteroidal
anti-inflammatory drugs (NSAIDs)
• +/- Adjuvants
World Health Organization
© Defined Health, 2009
Pain Insight Briefing
Step 2: Moderate Pain (4-6/10)
• APAP or ASA +
– Codeine
– Hydrocodone
– Oxycodone
– Dihydrocodeine
– Tramadol (not available
with APAP or ASA)
– +/- Adjuvants
Step 3: Severe Pain (7-10/10)
• Morphine
• Hydromorphone
• Methadone
• Levorphanol
• Fentanyl
• Oxycodone
• +- Nonopiod analgesics
• +/-Adjuvants
•Adjuvant Therapy:
– Anticonvulsants
– Antidepressants
– Corticosteroids
– Dermal analgesics
– Muscle relaxants
– Stimulants

A Better NSAID: NicOx
• Naproxcinod is a derivative of naproxen with similar anti-inflammatory activity, but less
gastrointestinal side effects. It is the first of a new class of analgesic and antiinflammatory
drugs known as cyclo-oxygenase-(COX)-inhibiting nitric oxide donators
(CINODs).
• The improved gastrointestinal tolerability of naproxcinod appears to be due to its
release of nitric oxide (NO) and the consequent maintenance of tissue perfusion and
integrity. Data to date also suggests that naproxinod may also have a beneficial and
sustained impact on blood pressure.
• Naproxcinod is in Phase III clinical development in Europe, the US and Canada for the
treatment of osteoarthritis. NDA filing is projected for mid-2009.
Adis R&D Insight; NicOx presentation
23
© Defined Health, 2009
Pain Insight Briefing

A Better NSAID: NicOx
24
Company press release
© Defined Health, 2009
Pain Insight Briefing

A Better NSAID: NicOx
25
Company press release
Apparently, the public markets are not impressed.
But then, they are not impressed with much these days.
© Defined Health, 2009
Pain Insight Briefing
Press Release Dec 19

A Better NSAID: Pozen / AstraZeneca
Dec.
Dec.
3,
3,
2008-
2008-
POZEN
POZEN
Announces
Announces
Positive
Positive
Top
Top
Line
Line
Results
Results
for
for
Its
Its
PN
PN
400
400
Phase
Phase
3
3
Trials
Trials
POZEN
POZEN
Inc.
Inc.
(NASDAQ:
(NASDAQ:
POZN),
POZN),
today
today
announced
announced
positive
positive
Phase
Phase
3
3
trial
trial
results
results
for
for
its
its
PN
PN
400
400
product
product
candidate
candidate
(enteric
(enteric
coated
coated
naproxen
naproxen
500
500
mg
mg
and
and
immediate
immediate
release
release
esomeprazole
esomeprazole
20
20
mg)
mg)
conducted
conducted
by
by
POZEN
POZEN
under
under
an
an
agreed
agreed
Special
Special
Protocol
Protocol
Assessment
Assessment
with
with
the
the
FDA.
FDA.
Both
Both
the
the
PN
PN
400-301/302
400-301/302
studies
studies
achieved
achieved
the
the
primary
primary
endpoints.
endpoints.
Subjects
Subjects
taking
taking
PN
PN
400
400
experienced
experienced
statistically
statistically
significantly
significantly
fewer
fewer
endoscopically
endoscopically
confirmed
confirmed
gastric
gastric
ulcers
ulcers
on
on
PN
PN
400
400
compared
compared
to
to
subjects
subjects
receiving
receiving
enteric
enteric
coated
coated
naproxen
naproxen
during
during
the
the
six-month
six-month
period.
period.
In
In
each
each
of
of
the
the
trials,
trials,
approximately
approximately
400
400
subjects
subjects
received
received
either
either
PN
PN
400
400
or
or
enteric
enteric
coated
coated
naproxen
naproxen
500
500
mg,
mg,
twice
twice
daily,
daily,
over
over
a
a
six-month
six-month
treatment
treatment
period.
period.
Subjects
Subjects
underwent
underwent
upper
upper
endoscopies
endoscopies
at
at
baseline
baseline
and
and
at
at
one,
one,
three,
three,
and
and
six
six
months
months
with
with
the
the
primary
primary
endpoint
endpoint
as
as
the
the
cumulative
cumulative
incidence
incidence
of
of
gastric
gastric
ulcers.
ulcers.
The
The
FDA
FDA
has
has
recently
recently
informed
informed
POZEN
POZEN
that
that
the
the
appropriateness
appropriateness
of
of
this
this
endpoint
endpoint
is
is
the
the
subject
subject
of
of
an
an
internal
internal
review
review
and
and
an
an
FDA
FDA
internal
internal
meeting
meeting
is
is
planned
planned
in
in
Q1
Q1
2009
2009
to
to
discuss
discuss
this
this
matter.
matter.
POZEN
POZEN
and
and
AstraZeneca
AstraZeneca
entered
entered
into
into
a
a
co-development
co-development
agreement
agreement
for
for
PN
PN
400
400
in
in
August
August
2006.
2006.
PN
PN
400
400
is
is
an
an
investigational
investigational
product
product
under
under
clinical
clinical
development
development
in
in
patients
patients
who
who
require
require
chronic
chronic
non-steroidal
non-steroidal
anti-inflammation
anti-inflammation
drug
drug
(NSAID)
(NSAID)
treatment
treatment
for
for
arthritis
arthritis
pain,
pain,
such
such
as
as
osteoarthritis
osteoarthritis
and
and
who
who
are
are
at
at
risk
risk
for
for
developing
developing
NSAID-associated
NSAID-associated
gastric
gastric
ulcers.
ulcers.
The
The
NDA
NDA
submission
submission
is
is
planned
planned
for
for
mid-2009.
mid-2009.
26
Company press release
© Defined Health, 2009
Pain Insight Briefing

A Better NSAID: Pozen / AstraZeneca
Dec.
Dec.
3,
3,
2008-
2008-
POZEN
POZEN
Announces
Announces
Positive
Positive
Top
Top
Line
Line
Results
Results
for
for
Its
Its
PN
PN
400
400
Phase
Phase
3
3
Trials
Trials
POZEN
POZEN
Inc.
Inc.
(NASDAQ:
(NASDAQ:
POZN),
POZN),
today
today
announced
announced
positive
positive
Phase
Phase
3
3
trial
trial
results
results
for
for
its
its
PN
PN
400
400
product
product
candidate
candidate
(enteric
(enteric
coated
coated
naproxen
naproxen
500
500
mg
mg
and
and
immediate
immediate
release
release
esomeprazole
esomeprazole
20
20
mg)
mg)
conducted
conducted
by
by
POZEN
POZEN
under
under
an
an
agreed
agreed
Special
Special
Protocol
Protocol
Assessment
Assessment
with
with
the
the
FDA.
FDA.
Both
Both
the
the
PN
PN
400-301/302
400-301/302
studies
studies
achieved
achieved
the
the
primary
primary
endpoints.
endpoints.
Subjects
Subjects
taking
taking
PN
PN
400
400
experienced
experienced
statistically
statistically
significantly
significantly
fewer
fewer
endoscopically
endoscopically
confirmed
confirmed
gastric
gastric
ulcers
ulcers
on
on
PN
PN
400
400
compared
compared
to
to
subjects
subjects
receiving
receiving
enteric
enteric
coated
coated
naproxen
naproxen
during
during
the
the
six-month
six-month
period.
period.
In
In
each
each
of
of
the
the
trials,
trials,
approximately
approximately
400
400
subjects
subjects
received
received
either
either
PN
PN
400
400
or
or
enteric
enteric
coated
coated
naproxen
naproxen
500
500 • 505(b)(2)
mg,
mg,
twice
twice
daily,
daily, Phase
over
over
a
a 3
six-month
six-month trial results
treatment
treatment for
period.
period. PN
Subjects
Subjects 400 product
underwent
underwent
upper
upper
endoscopies
endoscopies
at candidate at
baseline
baseline
and
and (enteric at
at
one,
one,
three,
three, coated and
and
six
six
months naproxen months
with
with
the
the 500 primary
primary mg endpoint
endpoint and as
as
the
the
cumulative
cumulative
incidence
incidence
of
of
gastric
gastric
ulcers.
ulcers.
The
The
FDA
FDA
has
has
recently
recently
informed
informed
POZEN
POZEN
that
that
the
the
appropriateness
appropriateness immediate
of
of
this
this
endpoint
endpoint release
is
is
the
the
subject
subject esomeprazole,
of
of
an
an
internal
internal
review
review Nexium,
and
and
an
an
FDA
FDA 20 mg
internal
internal to
meeting
meeting
is
is
planned
planned
in
in
Q1 provide Q1
2009
2009
to
to
discuss gastroprotection) discuss
this
this
matter.
matter. … statistically significantly
POZEN
POZEN
and
and
AstraZeneca
AstraZeneca
entered
entered
into
into
a
a
co-development
co-development
agreement
agreement
for
for
PN
PN
400
400
in
in
August
August
2006.
2006.
PN
PN
400
400
is
is
an
an 400
investigational
investigational compared
product
product to
under
under subjects
clinical
clinical
development
development receiving
in
in enteric
patients
patients
who
who coated
require
require
chronic
chronic
non-steroidal
non-steroidal
anti-inflammation naproxen anti-inflammation during drug
drug
(NSAID)
(NSAID) the six-month treatment
treatment
for
for period. arthritis
arthritis
pain,
pain,
such
such
as
as
osteoarthritis
osteoarthritis
and
and
who
who
are
are
at
at
risk
risk
for
for
developing
developing
NSAID-associated
NSAID-associated
gastric
gastric
ulcers.
ulcers.
The
The
NDA
NDA
submission
submission
is
is
planned
planned
for
for
mid-2009.
mid-2009.
27
fewer endoscopically confirmed gastric ulcers on PN
• An estimated 25-30% of NSAID prescriptions are
accompanied by a gastroprotective agent.
• 60M people take NSIADs in the US, with serious GI
events in 1-2%.
© Defined Health, 2009
Pain Insight Briefing

A Better NSAID: Topicals
28
The appeal of a topical product lies very clearly in perceived safety advantages
over systemic agents. Topical NSAIDs have enjoyed a long history in Europe,
but are just entering the US market.
On the market in the US:
• Flector patch (1.3% diclofenac; Alpharma – acquired by King)
• Voltaren Gel (1% diclofenac; Endo)
In development:
• Diclofenac patch (Phase II/IIIl; Cerimon)
• Pennsaid Diclofenac in DMSO (Approvable in US, marketed in Canada; Nuvo)
• Ketoprofen cream (Phase III; Transdel)
• Nanoemulsion diclofenac (Phase II; Pharmos)
• Diractin, Ketoprofen in Transferome gel (Phase III; Alpharma)
• Thermoprofen, heat-assisted ketoprofen (Phase III; Zars)
• TPM Diclofenac (Pre-clin; Phosphagenics)
Adis R&D Insight; Company web sites
© Defined Health, 2009
Pain Insight Briefing

The First-to-Market Topical NSAIDs are Off to a
Good Start
And have taken some of the regulatory and market risk out of the
equation … but growth is flattening. How many topical NSAIDs will
the US market support?
29
© Defined Health, 2009
Pain Insight Briefing

But The Benefit May Not Outweigh the Price
• Carries same label warning for cardiovascular and GI risk as oral NSAIDs, language
does make direct comparison between oral versus topical NSAID therapy (topical
administration results in

Even So, Flector is Expected To Be a Major
Growth Driver for the New King Pharma/Alpharma
Combined Entity
31
Cowen and Co. analyst report, Dec 17 2008
© Defined Health, 2009
Pain Insight Briefing

Even So, Flector is Expected To Be a Major
Growth Driver for the New King Pharma/Alpharma
Combined Entity
32
Cowen and Co. analyst report, Dec 17 2008
2008E $128M
2013E $260M
CAGR ~ 15%
© Defined Health, 2009
Pain Insight Briefing

Now We Have a Patch and a Gel
Voltaren Gel (diclofenac), Endo
• In March 2008, Endo announced the acquisition of US marketing rights to
Novartis’ Voltaren Gel, a 1% topical diclofenac (NSAID) gel. Voltaren Gel
was approved by the FDA in October 2007, but was never launched by
Novartis.
• May offer advantages over Flector
– Labeled for use in chronic osteoarthritis pain (Flector carries an acute
use indication)
– Gel formulation allows for use on joints (although 4x/day vs. 1-2)
– Priced at a significant discount (~60%)
SG Cowen Therapeutic Categories Outlook March 2008; Company press release
33
© Defined Health, 2009
Pain Insight Briefing

A Better Opioid
Gastric erosion, peptic ulcer,
inflammation of the duodenum and
of the colon, renal toxicity with
prolonged use
34
Relistor
(Progenics/Wyeth);
Constipation, sedation,
confusion, respiratory
Tapentadol (J&J), DOR
depression, mental clouding,
agonists renal colic, (Adolor/Pfizer);
tolerance to
abuse-deterrent prolonged use and risk opioids of
(King/Alpharma/Acura,
abuse, misuse, addiction.
Pain Therapeutics,
Acurox)
Gastrointestinal ulcers,
stomach bleeding,
tinnitus
Step 1: Mild Pain (1-3/10)
• Aspirin (ASA)
• Acetaminophen (APAP)
• Nonsteroidal
anti-inflammatory drugs (NSAIDs)
• +/- Adjuvants
© Defined Health, 2009
Pain Insight Briefing
Step 2: Moderate Pain (4-6/10)
• APAP or ASA +
– Codeine
– Hydrocodone
– Oxycodone
– Dihydrocodeine
– Tramadol (not available
with APAP or ASA)
– +/- Adjuvants
Step 3: Severe Pain (7-10/10)
• Morphine
• Hydromorphone
• Methadone
• Levorphanol
• Fentanyl
• Oxycodone
• +- Nonopiod analgesics
• +/-Adjuvants
•Adjuvant Therapy:
– Anticonvulsants
– Antidepressants
– Corticosteroids
– Dermal analgesics
– Muscle relaxants
– Stimulants

The Need is Clear
35
© Defined Health, 2009
Pain Insight Briefing

The Need is Clear
36
© Defined Health, 2009
Pain Insight Briefing

Progenics / Wyeth: Making Opioids More Tolerant
• RELISTOR decreases the constipating effects
of opioids in patients with advanced illness who
are receiving palliative care.
• RELISTOR is the first selective peripherally
acting mu–opioid receptor antagonist
displacing opioid binding in tissues such as the
gastrointestinal tract.
• RELISTOR does not diminish the central
analgesic effects of opioids.
• RELISTOR has a unique molecular structure
that restricts it from crossing the blood-brain
barrier.
• In clinical studies, RELISTOR demonstrated:
– No clinically relevant changes in pain
scores from baseline.
– No central opioid withdrawal.
37
www.wyeth.com
© Defined Health, 2009
Pain Insight Briefing
Oral Relistor could enable the
franchise to address a potential
$1B+ market opportunity in the
sizable adult chronic pain
population, but previous
challenges warrant caution.

Progenics / Wyeth: Making Opioids More Tolerant
• RELISTOR decreases the constipating effects
$700 of opioids in patients with advanced illness who
Source: EvaluatePharma
are receiving palliative care.
$600
• RELISTOR is the first selective peripherally
$500
acting mu–opioid receptor antagonist
$400 displacing opioid binding in tissues such as the
USD, in millions
gastrointestinal tract.
$300
• RELISTOR does not diminish the central
$200 analgesic effects of opioids.
• $100 RELISTOR has a unique molecular structure
that
$0
restricts it from crossing the blood-brain
barrier.
• In clinical studies, RELISTOR demonstrated:
38
2007
– No clinically relevant changes in pain
scores from baseline.
– No central opioid withdrawal.
www.wyeth.com
Annual Relistor Sales Estimates
2008
2009
2010
2011
2012
2013
2014
© Defined Health, 2009
Pain Insight Briefing
Oral Relistor could enable the
franchise to address a potential
$1B+ market opportunity in the
sizable adult chronic pain
population, but previous
challenges warrant caution.

Adolor / Pfizer: Making Opioids More Tolerant
39
Pharmaprojects PharmaprojectsR&D R&D Pipeline Pipeline News News Feed Feed
Adolor Adolorand and Pfizer Pfizer join join forces forces on on novel novel pain pain compounds
compounds
7 Dec Dec 2007 2007
Pfizer Pfizer has has signed signed a deal deal with with Adolor Adolorsecuring securing exclusive exclusive worldwide worldwide rights rights to to two two novel novel
compounds compounds for for pain. pain. The The deal deal grants grants Pfizer Pfizer access access to to Adolor's Adolor'sADL-5859 ADL-5859 and and ADL- ADL-
5747, 5747, both both proprietary proprietary delta delta opioid opioidreceptor receptor agonists agonists with with potential potential application application
in in a wide wide range range of of inflammatory, inflammatory, neuropathic neuropathic and and acute acute pain pain conditions. conditions.
There There are are three three known known opioid opioidreceptors receptors --mu, mu, kappa kappa and and delta. delta. All All current current opioid opioid
analgesics analgesics exert exert their their effect effect mainly mainly on on the the mu mu variant, variant, with with no no presently-approved
presently-approved
compounds compounds targeted targeted specifically specifically at at the the kappa kappa or or delta delta types. types. Preclinical Preclinical work work suggests suggests
that that delta-specific delta-specific agonists agonists may may exhibit exhibit superior superior analgesic analgesic properties properties to to mu mu agonists agonists
whilst whilst avoiding avoiding some some of of their their common common and and undesirable undesirable side-effects.
side-effects.
ADL-5859 ADL-5859 is is the the most most advanced advanced compound, compound, currently currently in in Phase Phase IIa IIatrials trials in in
inflammatory inflammatory pain, pain, with with more more Phase Phase II II trials trials planned planned for for 2008. 2008. An An IND IND for for ADL-5747 ADL-5747 is is
pending pending and and Adolor Adoloris is planning planning to to initiate initiate clinical clinical development development in in the the first first quarter quarter of of
2008. 2008.
© Defined Health, 2009
Pain Insight Briefing

Adolor / Pfizer: Making Opioids More Tolerant
40
Pharmaprojects PharmaprojectsR&D R&D Pipeline Pipeline News News Feed Feed
Adolor Adolorand and Pfizer Pfizer join join forces forces on on novel novel pain pain compounds
compounds
7 Dec Dec 2007 2007
Pfizer Pfizer has has signed signed a deal deal with with Adolor Adolorsecuring securing exclusive exclusive worldwide worldwide rights rights to to two two novel novel
compounds compounds for for pain. pain. The The deal deal grants grants Pfizer Pfizer access access to to Adolor's Adolor'sADL-5859 ADL-5859 and and ADL- ADL-
5747, 5747, both both proprietary proprietary delta delta opioid opioidreceptor receptor agonists agonists with with potential potential application application
in in a wide wide range range of of inflammatory, inflammatory, neuropathic neuropathic and and acute acute pain pain conditions. conditions.
There There are are three three known known opioid opioidreceptors receptors --mu, mu, kappa kappa and and delta. delta. All All current current opioid opioid
analgesics analgesics exert exert their their effect effect mainly mainly on on the the mu mu variant, variant, with with no no presently-approved
presently-approved
compounds compounds ADL-5859 targeted targeted specifically and specifically ADL-5747, at at the the kappa kappa both or or delta delta proprietary types. types. Preclinical Preclinical delta work work suggests opioid suggests
that that delta-specific delta-specific receptor agonists agonists may may exhibit exhibit with superior superior potential analgesic analgesic application properties properties to to mu in mu agonists a agonists wide
whilst whilst avoiding avoiding some some of of their their common common and and undesirable undesirable side-effects.
side-effects.
range of inflammatory, neuropathic and acute pain
ADL-5859 ADL-5859 is is the the most most advanced advanced compound, compound, currently currently in in Phase Phase IIa IIatrials trials in in
inflammatory inflammatory conditions.
pain, pain, with with more more Phase Phase II II trials trials planned planned for for 2008. 2008. An An IND IND for for ADL-5747 ADL-5747 is is
pending pending and and Adolor Adoloris is planning planning to to initiate initiate clinical clinical development development in in the the first first quarter quarter of of
2008. 2008.
© Defined Health, 2009
Pain Insight Briefing

Like All Things CNS, It’s Not So Easy
41
F I N A L T R A N S C R I P T
Dec. 18. 2008 / 8:30AM, ADLR - Adolor Corporation Investor Update Call
Just completed two Phase IIa trials on ADL5859 to explore safety and efficacy in two
distinct models of pain: diabetic peripheral neuropathy as a model of neuropathic
pain; and rheumatoid arthritis as a model of chronic inflammatory pain. Neither
showed statistical significance on efficacy measures, but were safe and well
tolerated. The company is now evaluating the current formulation and considering
an increase in exposure and decrease in variability before initiating additional studies
in patients.
For ADL5747, our second Delta Agonist, we recently have completed enrollment in a
multiple ascending dose Phase I trial in 32 healthy volunteers. To date, we have not
observed any dose-limiting toxicity or clinically significant adverse events. Pfizer and
we intend to initiate a proof of concept trial of 5747 in osteoarthritis during the third
quarter of 2009 and in neuropathic pain in the fourth quarter of 2009.
To close the Delta section of this call, it is our interpretation that the results of
these preliminary Phase IIa trials of ADL5859 were inconclusive as to efficacy.
Pfizer and we continue to believe that Delta Agonists represent an exciting
new class of drugs to treat pain and are in agreement that both ADL5859 and
ADL5747 merit continued clinical development.
© Defined Health, 2009
Pain Insight Briefing

Like All Things CNS, It’s Not So Easy
42
F I N A L T R A N S C R I P T
To close the Delta section of this call, it
is our interpretation that the results of
these preliminary Phase IIa trials of
Dec. 18. 2008 / 8:30AM, ADLR - Adolor Corporation Investor Update Call
Just completed two Phase IIa trials on ADL5859 to explore safety and efficacy in two
distinct models of pain: diabetic ADL5859 peripheral neuropathy were inconclusive as a model of neuropathic as to
pain; and rheumatoid arthritis as a model of chronic inflammatory pain. Neither
showed statistical significance efficacy. on efficacy Pfizer measures, and we but were continue safe and well to
tolerated. The company is now evaluating the current formulation and considering
an increase in exposure and decrease in variability before initiating additional studies
in patients.
believe that Delta Agonists represent an
exciting new class of drugs to treat pain
and are in agreement that both ADL5859
For ADL5747, our second Delta Agonist, we recently have completed enrollment in a
multiple ascending dose Phase and I trial ADL5747 in 32 healthy merit volunteers. continued To date, we clinical have not
observed any dose-limiting toxicity development.
or clinically significant adverse events. Pfizer and
we intend to initiate a proof of concept trial of 5747 in osteoarthritis during the third
quarter of 2009 and in neuropathic pain in the fourth quarter of 2009.
To close the Delta section of this call, it is our interpretation that the results of
these preliminary Phase IIa trials of ADL5859 were inconclusive as to efficacy.
Pfizer and we continue to believe that Delta Agonists represent an exciting
new class of drugs to treat pain and are in agreement that both ADL5859 and
ADL5747 merit continued clinical development.
© Defined Health, 2009
Pain Insight Briefing

A New, and Better Opioid from J&J / Grunenthal
43
Tapentadol IR
dosing non-inferior
to oxycodone IR in
terms of efficacy
with lower incidence
of nausea, vomiting
and constipation.
The Journal of Pain, Volume 9, Issue 4, Supplement 1, April 2008, Page 32
M. Afilalo, C. Oh, A. Okamoto, I. Van Hove, J. Stegmann, D. Upmalis
© Defined Health, 2009
Pain Insight Briefing

A New, and Better Opioid from J&J / Grunenthal
44
FDA Approves Tapentadol for Moderate to Severe Acute Pain
November 25, 2008 — The US FDA has announced approval of tapentadol hydrochloride (Johnson &
Johnson/Grunenthal), an immediate-release oral tablet for the relief of moderate to severe acute pain.
The drug acts as both an opioid and nonopioid agent, the FDA release notes. It acts primarily as a
mu-opioid-receptor agonist but also inhibits reuptake of norepinephrine, which may also have
an analgesic effect.
A statement from Johnson & Johnson notes that following this FDA approval, "as per federal
regulation for all controlled substances, tapentadol will be reviewed by the US Drug Enforcement
Administration for scheduling, and it cannot be sold until it receives a scheduling classification."
The approval was based on data from clinical studies involving more than 2100 patients, the Johnson
& Johnson release notes. These phase 3 studies, presented at the 27th Annual Scientific Meeting of
the American Pain Society in May, showed significant relief compared with placebo for patients
undergoing bunionectomy, a common foot surgery; in pain from end-stage joint disease; and with low
back pain or osteoarthritis of the hip or knee. It was generally well tolerated.
The most common adverse effects from tapentadol are nausea, dizziness, vomiting, sleepiness, and
headaches, the FDA release said. "The labeling for tapentadol includes warnings about the risk of
respiratory depression; addictive depressive effects on the central nervous system when taken with
alcohol, other opioids, or illicit drugs; and abuse potential," the FDA release adds.
DEA scheduling review is expected by late Feb 09.
Company press release
© Defined Health, 2009
Pain Insight Briefing

A New, and Better Opioid from J&J / Grunenthal
45
FDA Approves Tapentadol for Moderate to Severe Acute Pain
November 25, 2008 — The US FDA has announced approval of tapentadol hydrochloride (Johnson &
Johnson/Grunenthal), an immediate-release oral tablet for the relief of moderate to severe acute pain.
The drug acts as both an opioid and nonopioid agent, the FDA release notes. It acts primarily as a
mu-opioid-receptor agonist but also inhibits reuptake of norepinephrine, which may also have
an analgesic effect.
A statement from Johnson & Johnson notes that following this FDA approval, "as per federal
regulation for all controlled substances, tapentadol will be reviewed by the US Drug Enforcement
Administration for scheduling, and it cannot be sold until it receives a scheduling classification."
The approval was based on data from clinical studies involving more than 2100 patients, the Johnson
& Johnson release notes. These phase 3 studies, presented at the 27th Annual Scientific Meeting of
the American Pain Society in May, showed significant relief compared with placebo for patients
• Tapentadol acts primarily as a mu-opioid-receptor
undergoing bunionectomy, a common foot surgery; in pain from end-stage joint disease; and with low
back pain or osteoarthritis of the hip or knee. It was generally well tolerated.
agonist but also inhibits reuptake of norepinephrine
• Tapentadol… “cannot be sold until it receives a
The most common adverse effects from tapentadol are nausea, dizziness, vomiting, sleepiness, and
headaches, scheduling the FDA release classification”.
said. "The labeling for tapentadol includes warnings about the risk of
respiratory depression; addictive depressive effects on the central nervous system when taken with
alcohol, other opioids, or illicit drugs; and abuse potential," the FDA release adds.
DEA scheduling review is expected by late Feb 09.
© Defined Health, 2009
Pain Insight Briefing

Tapentadol: Next Generation Ultram
46
• Better Efficacy
• Better Side Effect Profile
• But, Scheduled.
Product label
So why the modest forecast estimates?
© Defined Health, 2009
Pain Insight Briefing

Opioid Abuse Deterrence
47
© Defined Health, 2009
Pain Insight Briefing

King Pharmaceuticals: Making Big Bets on Abuse
Deterrent Opioids
…With Some Help From Acura and Alpharma
48
Cowen & Co. analyst report, Dec 17 2008
© Defined Health, 2009
Pain Insight Briefing

King Pharmaceuticals: Making Big Bets on Abuse
Deterrent Opioids
…With Some Help From Acura and Alpharma
49
USD, in billions
$3.0
$2.5
$2.0
$1.5
$1.0
$0.5
$0.0
Cowen & Co. analyst report, Dec 17 2008
All Other
ALO-03, ALO-04
ALO-02
Embeda
Acurox
Remoxy
2007 2008 2009 2010 2011 2012 2013
© Defined Health, 2009
Pain Insight Briefing

Because There is Significant Market Potential
50
© Defined Health, 2009
Pain Insight Briefing

But Also Significant Hurdles
• Technology not enough, must prove lower abuse – but how?
• FDA labeling may provide false sense of security, resulting in
increased/less scrutinized use.
• Purdue’s patent estate.
51
TheraQuest has an abuse-deterrent extended release Tramadol in Phase I.
© Defined Health, 2009
Pain Insight Briefing

Some Recent Setbacks
• Purdue: Oxy TR
52
• Was front runner, but unsuccessful FDA advisory panel meeting in
May ’08
• Waiting on the 60mg and 80mg strengths
• Pain Therapeutics/King: Remoxy
• Dec ’08: NDA not approvable in present form
• Alpharma: Embeda
• NDA review delayed
Press releases
© Defined Health, 2009
Pain Insight Briefing

The Technologies are Not the Problem …Nor are
the Efficacy or Side Effects
NDA 22-234 Remoxy Advisory Committee Briefing
Alpharma FDA Advisory Committee Briefing Package
Remoxy employs Durect’s Oradur technology in a sustained release
oral gel-cap. Remoxy’s gelatinous formulation allows for the
controlled release of the active pharmaceutical ingredient,
oxycodone, and may deter abuse of the drug.
ALO-01 (Embeda) is comprised of individual pellets of
morphine sulfate with a sequestered naltrexone
hydrochloride inner core. When ALO-01 is taken as
prescribed, morphine is released in an extended-release
profile and naltrexone, an opioid antagonist, remains
sequestered in the core.
However, upon crushing, or complete chewing of the
pellets, both the morphine and naltrexone would be
available and if taken orally, absorbed as an immediaterelease
dosage form.
© Defined Health, 2009
Pain Insight Briefing
53

The Label Challenge
• The FDA wants to differentiate the tamper-resistant opioids to
encourage prescribing over the standard formulations, but does
not want to allow these products to be promoted as abuseresistant
opioids.
• A false sense of security may lead to lax prescribing (and
diversion) problems, particularly with primary care physicians.
Alpharma FDA Advisory Committee Briefing Package
© Defined Health, 2009
Pain Insight Briefing
54

The Real Issue is Risk Management
• Risk management plan negotiations are likely to delay approval of both
Embeda/ALO-01 and Remoxy.
• There is concern over REMS (Risk Evaluation & Mitigation Strategy) plans
to encourage physician education and prevent over-prescribing.
• The FDA will require King and Alpharma to rigorously monitor postmarketing
use of their products in order to gauge abuse levels. This is in
the context of:
• Significant challenges of abuse monitoring,
• Flaws with the tools currently available.
• The likely data focus will be adverse events databases and hospitalization
statistics.
• “Street value” may also be considered as a measure of abusability.
• These data ultimately may lead to stronger tamper-resistance labeling and
perhaps even an abuse-resistance claim, but the prediction was that such
claims are unlikely to be granted for at least 2-3 years post-launch.
Alpharma FDA Advisory Committee Briefing Package
© Defined Health, 2009
Pain Insight Briefing
55

The Future Opioid Marketplace
Assuming these products can jump the regulatory hurdle and make it to
market, will there still be a place for products with no such claim – particularly
as they become generic and cheap?
OxyContin: Branded Generic Branded Generic
SG Cowen Therapeutic Categories Outlook Sept 2008
© Defined Health, 2009
Pain Insight Briefing
56

Fentanyl: Again, REMS is the Big Regulatory Hurdle
• Fentora (Cephalon)
– Follow-on to Actiq – first launched in 1999 for breakthrough cancer pain.
– 80-90% of Actiq use off label in other forms of breakthrough pain.
– Fentora launched in late 2006 (as Actiq went generic).
– Unsuccessful FDA panel meeting in May 2008 to broaden indication; adapting
REMS and will try again in 2010.
• BEMA Fentanyl (BioDelivery Sciences)
• Received complete response letter in Aug, 2008.
• Need to complete a REMS program.
• Approval anticipated in 1H 2009 for breakthrough cancer pain; will be marketed
by MEDA.
• Other fast-acting fentanyls reportedly in development
• Stacatto fentanyl, inhaled (Alexza); licensed to Endo, starting Phase II.
• Taifun fentanyl, inhaled (Akela); finished Phase II.
• Intranasal fentanyl (Nycomed): filed in Europe in 2007.
• Rapinyl (Prostakan - from Endo); Phase III
• Intranasal fentanyl (Archimedes); Phase III
• Oral spray (NovaDel); Pre-clin
Natixis Bleichroeder presentation, Arrowhead Pain Conference 2008
© Defined Health, 2009
57
Pain Insight Briefing

Is There Potential Beyond Cancer Pain: Lessons
from Fentora
58
FDA FDA blocks blocks new new Fentora Fentorauses uses
September September 16, 16, 2008 2008
The The FDA FDA to to Cephalon: Cephalon: Get Get a better better risk-communication risk-communication program. program. That's That's what what
lies lies between between the the drugmaker drugmakerand and new new indications indications for for its its painkiller painkiller Fentora. Fentora. As As you you
know, know, Fentora Fentorais is already already emblazoned emblazoned with with warnings warnings of of potentially potentially life-threatening
life-threatening
risks. risks. Cephalon Cephalonhas has reported reported five five deaths deaths among among Fentora Fentorapatients, patients, from from adverse adverse
reactions reactions or or overdose. overdose.
Already Already approved approved for for breakthrough breakthrough cancer cancer pain, pain, Fentanyl Fentanylwas was up up for for FDA FDA
consideration consideration to to treat treat breakthrough breakthrough pain pain in in patients patients with with chronic chronic lower lower back back and and
nerve nerve pain. pain. But But an an advisory advisory panel panel voted voted 17-3 17-3 against against broadening broadening the the use use of of Fentora, Fentora,
citing citing the the potential potential for for misuse misuse among among even even more more patients. patients.
The The company company said said it it will will continue continue to to educate educate caregivers caregivers and and patients patients to to make make sure sure
the the drug drug is is appropriately appropriately prescribed--but prescribed--but offered offered no no other other word word yet yet on on how how it it plans plans to to
answer answer the the FDA's FDA's concerns. concerns. Though Though the the drug drug was was introduced introduced only only under under strict strict
guidelines guidelines for for use, use, in in its its some some two two years years on on the the market, market, scrips scripshave have grown grown to to
the the point point that that more more than than 80 80 percent percent of of patients patients take take it it off-label. off-label.
http://www.fiercepharma.com/story/fda-blocks-new-fentora-uses/2008-09-16
© Defined Health, 2009
Pain Insight Briefing

Lessons from Fentora
59
What the FDA expects of Title IX Risk Evaluation and Mitigation
Strategies (REMS).
© Defined Health, 2009
Pain Insight Briefing

For Some Mechanisms, the US Regulatory Risk
May be Too High
60
• Canada:
– 2005 approval for neuropathic pain.
– 2007 as adjunct analgesic in patients with advanced cancer who experience moderate to
severe pain during the highest tolerated dose of strong opioid therapy for persistent
background pain.
• UK: available as prescription on a named patient basis; available on a compassionate access
basis in the Catalonian region of Spain.
• US: investigational drug (Phase II/III) being developed in partnership with Otsuka
Pharmaceutical Co. as an adjunctive analgesic treatment for patients with advanced cancer
whose persistent pain has not been adequately relieved by optimized treatment with strong
opioids. The FDA has not approved Sativex and the product is not available in the US other
than for use in FDA approved clinical trials.
GW Pharmaceuticals presentation, Arrowhead Pain
Therapeutics Summit 2008; Company website
© Defined Health, 2009
Pain Insight Briefing

For Some Mechanisms, the US Regulatory Risk
May be Too High
61
The Controlled Substances Act of 1970, which created the five schedule classification
system for drugs, assigned marijuana a Schedule I designation. This classification
puts marijuana alongside heroin and hallucinogens as a dangerous and addictive drug
with no accepted medical use.
Note: On July 13, 1986, the DEA issued a Final Rule and Statement of Policy
authorizing the "Rescheduling of Synthetic Dronabinol (Synthetic/Extract THC) in
Sesame Oil and Encapsulated in Soft Gelatin Capsules From Schedule I to Schedule
II"(DEA 51 FR 17476-78). This permitted medical use of Marinol (Solvay), albeit with the
severe restrictions associated with Schedule II status. Marinol is now Schedule III.
www.usdoj.gov/dea/pubs/csa.html
© Defined Health, 2009
Pain Insight Briefing

Getting Around The “Cannabis” Issue
Compounds that block MAGL or FAAH enzyme activity (which degrade
endocannabinoids) could lead to treatments with minimal side effects associated
with cannabinoid receptor activation.
Monoacylglycerol lipase
2-arachidonylglycerol
http://www.nature.com/scibx/journal/v1/n17/full/scibx.2008.399.html
© Defined Health, 2009
62
Pain Insight Briefing
Fatty acid amide hydrolase

FAAH Pipeline
63
Compound
SSR 101010
SSR411298
KDS 4103
ORG 231295
OL-135
FAAH Inhibitor
JNJ 2883315
JNJ 1661010
RN-A
RN-B
FAAH Inhibitor
Adis R&D Insight
Developer
sanofi-aventis
sanofi-aventis
Schering-Plough
Schering-Plough
Adolor Corporation
Vernalis
Johnson & Johnson
Johnson & Johnson
Evotec AG
Evotec AG
Infinity/Purdue/Mundipharma
© Defined Health, 2009
Pain Insight Briefing
Phase
I
I
Preclinical
Preclinical
Preclinical
Preclinical
Preclinical
Preclinical
Preclinical
Preclinical
Preclinical
Indications
Anxiety disorders, depression
Anxiety disorders, depression
Anxiety, depression, and pain
Anxiety, depression, and pain
Inflammatory pain
Neuropathic pain
Neuropathic pain
Neuropathic pain
Chronic pain
Chronic pain
Neuropathic pain

FAAH Pipeline
64
FAAH blockers are a very new class
of drugs, as currently there are only
two drugs from this group in the clinic.
Both are owned by sanofi-aventis,
which began clinical testing in March
2006 (SSR411298) and February
2007 (SSR 101010). No data about
either of these trials has been
released to date.
Defined Health analysis
Compound
SSR 101010
SSR411298
KDS 4103
ORG 231295
OL-135
FAAH Inhibitor
JNJ 2883315
JNJ 1661010
RN-A
RN-B
FAAH Inhibitor
Adis R&D Insight
© Defined Health, 2009
Pain Insight Briefing
Developer
sanofi-aventis
sanofi-aventis
Schering-Plough
Schering-Plough
Adolor Corporation
Vernalis
Johnson & Johnson
Johnson & Johnson
Evotec AG
Evotec AG
Infinity/Purdue/Mundipharma
Phase
I
I
Preclinical
Preclinical
Preclinical
Preclinical
Preclinical
Preclinical
Preclinical
Preclinical
Preclinical
Indications
Anxiety disorders, depression
Anxiety disorders, depression
Anxiety, depression, and pain
Anxiety, depression, and pain
Inflammatory pain
Neuropathic pain
Neuropathic pain
Neuropathic pain
Chronic pain
Chronic pain
Neuropathic pain

FAAH Pipeline
KDS-4103, acquired by Schering-
Plough when they purchased
Organon, has shown potent analgesic
activity in models of neuropathic pain
when administered orally and has
proved efficacious following systemic
administration in models of
inflammatory pain and inflammation.
However, high oral doses of this
compound (10–50 mg per kg) are
required to inhibit neuropathic pain,
whereas lower intraperitoneal doses
are not effective against this type of
pain.
65
Nature Reviews Drug Discovery 7, 438-455 (May 2008)
Compound
SSR 101010
SSR411298
KDS 4103
ORG 231295
OL-135
FAAH Inhibitor
JNJ 2883315
JNJ 1661010
RN-A
RN-B
FAAH Inhibitor
Adis R&D Insight
© Defined Health, 2009
Pain Insight Briefing
Developer
sanofi-aventis
sanofi-aventis
Schering-Plough
Schering-Plough
Adolor Corporation
Vernalis
Johnson & Johnson
Johnson & Johnson
Evotec AG
Evotec AG
Infinity/Purdue/Mundipharma
Phase
I
I
Preclinical
Preclinical
Preclinical
Preclinical
Preclinical
Preclinical
Preclinical
Preclinical
Preclinical
Indications
Anxiety disorders, depression
Anxiety disorders, depression
Anxiety, depression, and pain
Anxiety, depression, and pain
Inflammatory pain
Neuropathic pain
Neuropathic pain
Neuropathic pain
Chronic pain
Chronic pain
Neuropathic pain

FAAH Pipeline
JNJ-1661010 attenuates tactile
allodynia in a rat mild thermal
injury model of acute tissue
damage and in the rat spinal
nerve ligation model of
neuropathic pain. JNJ-1661010
also diminishes thermal
hyperalgesia in the inflammatory
rat carrageenan paw model.
However, due to its irreversible
binding to FAAH “These data
suggest that FAAH inhibitors with
modes of action similar to JNJ-
1661010 may be useful clinically
as broad-spectrum analgesics”.
Anesth Analg.2009; 108: 316-329
66
Compound
SSR 101010
SSR411298
KDS 4103
ORG 231295
OL-135
FAAH Inhibitor
JNJ 2883315
JNJ 1661010
RN-A
RN-B
FAAH Inhibitor
Adis R&D Insight
© Defined Health, 2009
Pain Insight Briefing
Developer
sanofi-aventis
sanofi-aventis
Schering-Plough
Schering-Plough
Adolor Corporation
Vernalis
Johnson & Johnson
Johnson & Johnson
Evotec AG
Evotec AG
Infinity/Purdue/Mundipharma
Phase
I
I
Preclinical
Preclinical
Preclinical
Preclinical
Preclinical
Preclinical
Preclinical
Preclinical
Preclinical
Indications
Anxiety disorders, depression
Anxiety disorders, depression
Anxiety, depression, and pain
Anxiety, depression, and pain
Inflammatory pain
Neuropathic pain
Neuropathic pain
Neuropathic pain
Chronic pain
Chronic pain
Neuropathic pain

Addressing the Big Problem
67
>50% of Patients Report Suboptimal Relief of Pain
Enter the novel mechanisms…
FAAH inhibitors
TRPV1 antagonists/agonists
NGF inhibitors
CCR2 antagonists
KCC2 modulators
Other biological, mediator-based approaches
Defined Health primary research; Adis R&D Insight
© Defined Health, 2009
Pain Insight Briefing

New MOA Challenges
68
An increased understanding of the neurobiology of pain has not yet
translated into breakthroughs in pain therapies. Why?
• Development Risk
– Animal models are not disease models, but are useful for
PK/PD.
– Correlations from animals to clinic only exist for precedented
targets.
– Biggest clinical risk is in exposure, limited by safety/tolerability.
– Access to correct compartment (CNS) is next most important
consideration.
NeuroDiscovery/NeuroSolutions presentations, Arrowhead Pain Conference 2008; Stephenson, D.T.
and Arneric, S.P. The Journal of Pain, Vol 9, No 7, 2008: p 567-579
© Defined Health, 2009
Pain Insight Briefing

New MOA Challenges
69
NeuroDiscovery/NeuroSolutions presentations, Arrowhead Pain Conference 2008
© Defined Health, 2009
Pain Insight Briefing

New MOA Challenges
70
NeuroDiscovery/NeuroSolutions presentations, Arrowhead Pain Conference 2008
© Defined Health, 2009
Pain Insight Briefing

New MOA Challenges
71
The identification and validation of imaging biomarkers for chronic pain
have lagged behind areas such as oncology, cardiovascular medicine, and
neurology. The Imaging Consortium for Drug Development (ICD) should
help the field of pain catch up.
https://meitner.mclean.harvard.edu/
The Imaging Consortium for Drug Development (ICD) is a
collaborative research effort between academia and
pharmaceutical companies who are developing novel drugs to
treat central nervous system (CNS) disorders. The ICD uses
functional MRI (fMRI) to elucidate the effects of pain
modulating drugs on neural activity within the brain in humans
and in animal models of CNS disease. This landmark effort
builds on more than a decade of fMRI research into the study
of pain, and realizes the benefits of standardization and costsharing
among consortium members, for pre-competitive
Neuroscience research.
© Defined Health, 2009
Pain Insight Briefing

New MOA Challenges
• Animal models are insufficiently representative of the multidimensional
aspects of clinical pain.
• Humans, however, are the species of relevance and volunteers are able to
verbally communicate their experience of pain and pain relief in a way that
is impossible with animals.
• Patients can also be
stratified into subgroups,
to help
develop more specific
treatment strategies.
For example, human
studies are revealing
gender differences in
pain processing, and
showing that
painkillers appear to
work differently in men
and women.
Neuroimage. 2008 Aug 15;42(2):467-73. Epub 2008 May 29.
72
© Defined Health, 2009
Pain Insight Briefing

TRPV1
• The transient receptor potential cation
channel, subfamily V, member 1 also known
as TRPV1 is a ligand-gated nonselective
cation channel that may be activated by a
wide variety of exogenous and endogenous
physical and chemical stimuli, including heat
greater than 43°C, low pH (acidic
conditions), the endocannabinoid
anandamide, N-arachidonoyl-dopamine, and
capsaicin.
• TRPV1 receptors are found in the central
nervous system and the peripheral nervous
system and are involved in the transmission
and modulation of pain, as well as the
integration of diverse painful stimuli.
• TRPV1 blockade in vivo elicits hyperthermia
in multiple species, from rodents to humans,
suggesting that TRPV1 is involved in body
temperature maintenance.
73
Nature Reviews Drug Discovery Vol.6 May 2007
© Defined Health, 2009
Pain Insight Briefing
Homology model of the TRPV1 ion channel
tetramer (where the monomers are individually
colored cyan, green, blue, and magenta
respective) imbedded in a cartoon representation
of a lipid bilayer. PIP2 signaling ligands are
represented by space-filling models (carbon =
white, oxygen = red, phosphorous = orange).

TRPV1: Potential to Address Multiple Types of Pain
74
TRPV1 antagonists may also be useful in treating disorders other than pain.
Chronic
Nociceptive/Inflammatory
Pain
Neuropathic Pain
Nature Reviews Drug Discovery Vol.6 May 2007
Migraine
Chronic Cough
© Defined Health, 2009
Pain Insight Briefing
Irritable Bowel Syndrome
Urinary Incontinence

TRPV1: Target for Novel Analgesics
75
TRPV1 Antagonists:
– TRPV1 knock-out mice show reduced nociception.
– TRPV1 expression is up-regulated during pain state.
– TRPV1 antagonists reverse pain behavior in animal pain models.
– Many pharma companies have TRPV1 antagonist programs. Several
compounds are in clinical development.
TRPV1 Agonists:
• Capsaicin used clinically as analgesic agent but side effects including “burning”
phase limit its utility.
• Different forms of capsaicin are being studied in the clinic.
• Efforts to develop orally-active TRPV1 agonists that lack the burning effect
(P&G, Sandoz, Novartis) faced problems due to systemic side effects and slow
onset of action.
Amgen presentation, Arrowhead Pain Conference 2008
© Defined Health, 2009
Pain Insight Briefing

TRPV1 Antagonists: Hot … Too Hot
Amgen presentation, Arrowhead Pain Conference 2008
76
© Defined Health, 2009
Pain Insight Briefing

TRPV1 Antagonists: Hot … Too Hot
Hypothesized that the thermoregulation is CNS-modulated, but peripheral restriction
of action still caused heat.
Amgen presentation, Arrowhead Pain Conference 2008
77
© Defined Health, 2009
Pain Insight Briefing

TRPV1: Not Dead Yet
78
Potential Opportunities:
• Development by different routes of administration (e.g., topical).
• Development of short half-life antagonists.
• Development of antipyretic + TRPV1 antagonist combination.
• Development of TRPV1 antagonists in primary indications (e.g., OA).
• One compound previously in development (GSK’s SB-705498) did
not induce hyperthermia in patients treated with 400mg of the drug.
Amgen presentation, Arrowhead Pain Conference 2008
© Defined Health, 2009
Pain Insight Briefing

TRPV1 Antagonist Pipeline
Compound
AZD 1386
MK 2295
JTS 653
Vanilloid receptor antagonists
Ion channel modulators
Small molecule therapeutics
Transient receptor potential vanilloid 1
cation channel antagonists
TRPV antagonists
TRPV cation channel inhibitors
TRPV1 antagonists
TRPV1 antagonists
TRPV1 cation channel inhibitors
TRPV1 receptor antagonists
Vanilloid 1 receptor antagonists
Vanilloid receptor antagonists
Vanilloid receptor antagonists
Vanilloid receptor antagonists
TRPV1 cation channel inhibitors
GRC 6211
SB 705498
AMG 517
TRPV1 cation channel antagonists
79
Adis R&D Insight
Developer
AstraZeneca
Merck/Neurogen
Japan Tobacco
Renovis/Pfizer
Hydra Biosciences
Amphora
Abbott
Sanofi-Aventis
Purdue Pharma
Diver Drugs
Eli Lilly
J & J
Traxion
AmorePacific/Schwarz
Neurogen/Merck
Novartis
Pharmeste
Mochida//Wyeth
Glenmark/Eli Lilly
Amgen
Amgen
Phase
Phase-II
Phase-II
Phase-I
Phase-I
Preclinical
Preclinical
Preclinical
Preclinical
Preclinical
Preclinical
Preclinical
Preclinical
Preclinical
Preclinical
Preclinical
Preclinical
Preclinical
Research
Discontinued-II
Discontinued-II
Discontinued-I
Discontinued-
Preclinical
© Defined Health, 2009
Pain Insight Briefing
Indications
Gastro-oesophageal reflux, Pain
Pain
Overactive bladder, Pain
Pain, Urinary incontinence
Asthma, HTN, Inflammation, Kidney disorders, Lung disorders,
Osteoporosis, OAB, Pain
CNS disorders, Metabolic disorders, Pain
Pain
Inflammation, Neuropathic pain
Pain
Inflammation, Pain
Inflammation, Pain, Urinary incontinence
Cough, Pain
Pain
Pain
Pain
Neuropathic pain
Neuropathic pain, Urinary incontinence
Pain
Cystitis, Dental pain, Neuropathic pain, Urinary incontinence

TRPV1 Antagonist Pipeline
80
Compound
AZD 1386
MK 2295
JTS 653
Vanilloid receptor antagonists
Ion channel modulators
Small molecule therapeutics
Transient receptor potential vanilloid 1 cation
channel antagonists
TRPV antagonists
TRPV cation channel inhibitors
TRPV1 antagonists
TRPV1 antagonists
TRPV1 cation channel inhibitors
TRPV1 receptor antagonists
Vanilloid 1 receptor antagonists
Vanilloid receptor antagonists
Vanilloid receptor antagonists
Vanilloid receptor antagonists
TRPV1 cation channel inhibitors
GRC 6211
SB 705498
AMG 517
TRPV1 cation channel antagonists
Developer
AstraZeneca
Merck/Neurogen
Japan Tobacco
Renovis/Pfizer
Hydra Biosciences
Amphora
Abbott Laboratories
Sanofi-Aventis
Purdue Pharma
DiverDrugs
Preclinical Inflammation, Pain
Eli Lilly
Preclinical Inflammation, Pain, Urinary incontinence
with the antagonist.
Johnson & Johnson Preclinical Cough, Pain
Traxion Therapeutics
AmorePacific/Schwarz
Neurogen/Merck
Novartis
Pharmeste
Mochida Pharma/Wyeth
Glenmark/Eli Lilly
Amgen
Amgen
Phase
Phase-II
Gastro-oesophageal reflux, Pain
JNJ has used high throughput
Phase-II
Pain
Phase-I
Pain, Urinary incontinence
cancer Asthma, Hypertension, Inflammation, Kidney disorders, Lung disorders,
Preclinicalpain,
systemic administration of
Osteoporosis, Overactive bladder, Pain
Preclinical
Preclinical
Preclinical
Preclinical
Preclinical
Research
Discontinued-II
Discontinued-II
Discontinued-I
Discontinued-
Preclinical
Adis R&D Insight; Nature Reviews Drug Discovery 6, 357-372 (May 2007)
© Defined Health, 2009
Pain Insight Briefing
Indications
screening Phase-I to Overactive generate bladder, Pain a series of TRPV1
antagonists. In a mouse model of
the Preclinical TRPV1 antagonist CNS disorders, Metabolic disorders, JNJ-17203212
Pain
results in efficacy according to several
Preclinical Pain
behavioral measures of pain. TRPV1-/-
Preclinical Inflammation, Neuropathic pain
mice Preclinical show a Painsimilar
extent of efficacy as
TRPV1+/+ controls that were treated
Pain
Pain
Pain
Neuropathic pain
Neuropathic pain, Urinary incontinence
Pain
Cystitis, Dental pain, Neuropathic pain, Urinary incontinence

TRPV1 Antagonist Pipeline
81
Compound
AZD 1386
MK 2295
Merck/Neurogen
Phase-II
Pain
JTS 653
Japan Tobacco
Phase-I
Overactive bladder, Pain
• Amgen stopped development of AMG-517 when patients
Vanilloid receptor antagonists
Renovis/Pfizer
Phase-I
Pain, Urinary incontinence
experienced long-lasting hyperthermia when treated with AMG-
Asthma, Hypertension, Inflammation, Kidney disorders, Lung disorders,
Ion channel modulators
Hydra Biosciences Preclinical
517 following molar extraction; some patients Osteoporosis, Overactive body bladder, temperature
Pain
Small molecule therapeutics
Amphora
Preclinical CNS disorders, Metabolic disorders, Pain
surpassed 40°C. It is possible that this problem i s due to off-
Transient receptor potential vanilloid 1 cation
Abbott Laboratories Preclinical Pain
channel target antagonistseffects,
as TRPV1 -/- mice do not exhibit hyperthermia.
TRPV • antagonists GSK’s SB-705498 Sanofi-Aventis showed promising Preclinical results Inflammation, Neuropathic in a study pain designed
TRPV cation channel inhibitors
Purdue Pharma
Preclinical Pain
to measure its ability to inhibit heat-evoked pain (capsaicin) and
TRPV1 antagonists
DiverDrugs
Preclinical Inflammation, Pain
skin sensitization (UV B irradiation). In addition, treatment with
TRPV1 antagonists
Eli Lilly
Preclinical Inflammation, Pain, Urinary incontinence
TRPV1 cation channel inhibitors
Johnson & Johnson Preclinical Cough, Pain
TRPV1 abandoned receptor antagonists development Traxion Therapeutics of the Preclinical drug, with Pain no explanation as to
Vanilloid 1 receptor antagonists
Vanilloid receptor antagonists
Neurogen/Merck
Preclinical Pain
• In October 2008 Eli Lilly chose to suspend their trial for GRC-
Vanilloid receptor antagonists
Novartis
Preclinical Neuropathic pain
Vanilloid receptor antagonists
TRPV1 cation channel inhibitors
GRC 6211
SB 705498
AMG 517
TRPV1 cation channel antagonists
Developer
AmorePacific/Schwarz
Amgen
Amgen
Phase
Preclinical
Discontinued-II
Discontinued-I
Discontinued-
Preclinical
© Defined Health, 2009
Pain Insight Briefing
Indications
Three TRPV1 antagonists AstraZeneca which Phase-II had entered Gastro-oesophageal the reflux, clinic Pain have been
discontinued:
400 mg of SB-705498 did not induce hyperthermia. GSK has since
why.
6211, which they were developing in collaboration with Glenmark,
Pharmeste
Preclinical Neuropathic pain, Urinary incontinence
in OA. The companies Mochida Pharma/Wyeth have yet Research to publicly Pain disclose the reason
the trial was ended Glenmark/Eli early. Lilly Discontinued-II Cystitis, Dental pain, Neuropathic pain, Urinary incontinence
Adis R&D Insight; Nature Reviews Drug Discovery 8, 55-68 (January 2009)
Pain

TRPV3: Hopeful, But Too Early to Tell
82
Glenmark website
© Defined Health, 2009
Pain Insight Briefing

TRPV3: Hopeful, But Too Early to Tell
83
Glenmark website
© Defined Health, 2009
Pain Insight Briefing

TRPV Agonists: NeurogesX Capsaicin Patch
NGX-4010: 8% w/w capsaicin (capsaicin
640 mcg/cm2) patch optimized for rapid
cutaneous delivery.
84
Treatment procedure (in office,
physician supervised):
• Identify painful area
• Apply topical anesthetic
• Cut NGX-4010 to conform to painful
area
• Apply NGX-4010 for 30 to 60 minutes
• Remove NGX-4010, clean area with
Cleansing Gel
Company website
© Defined Health, 2009
Pain Insight Briefing

Good Phase III Data, An Accepted NDA … But No
Commercial Partner
December 19, 2008: NeurogesX Announces FDA Acceptance to Review New
Drug Application for NGX-4010 to Treat Post-Herpetic Neuralgia
Backonja M, et al. Presented at the American Academy of Neurology
60th Annual Meeting, Chicago; April 2008
85
© Defined Health, 2009
Pain Insight Briefing
Primary endpoint (% reduction
from baseline during Weeks 2-8)
•NGX-4010 −32% vs. Control −24%
(p=0.011)
•Consistent results over 3 months
•32% average pain reduction during
Weeks 2-12 (p=0.0172)
•Responders (≥ 30% reduction) 46%
responders (p=0.0196)

Tanezumab/RN 624 (Rinat/Pfizer): Summary
Goldman Sachs Healthcare Conference, June 2008;
Pfizer Analyst and Investor Meeting Oct. 28, 2008
Lee
.
S. Simon, MD, Division Director Analgesic, Anti-inflammatory and
Ophthalmology Drug Products ODEV, CDER, FDA
86
© Defined Health, 2009
Pain Insight Briefing

Pfizer Pursuing Multiple Chronic Pain Types
for Tanezumab
In hopes of a broad chronic moderate-to-severe pain label?
87
Inflammatory Pain
• OA (knee and hip)
• Chronic Low Back Pain
Neuropathic Pain
• Post-herpetic Neuralgia
Adis R&D Insight; Pfizer Analyst Day Presentation, March 5, 2008;
www.clinicaltrials.gov;http://www.docguide.com/news/content.nsf/news/852571020057CCF6852574B0004DF76F
© Defined Health, 2009
Pain Insight Briefing
Visceral Pain
• Interstitial Cystitis
• Endometriosis Pain
Cancer Pain
• Metastatic Bone Pain
Potential beyond pain … Arthritis, Prostatitis, Chronic Headache…

Incredible POC Data for OA of the Knee
• At week 12, 70+% of patients
reported a 30% reduction in pain at
all doses, with more than 50%
having a 50% reduction in pain and
10-30% having a 90% reduction in
pain.
• Compared to an NSAID with 30-50%
of patients reporting a 30%
reduction in pain, dropping to 20-
40% having a 50% reduction and
less than 20% having a 90%
reduction in pain.
Pfizer Analyst and Investor Meeting Oct. 28, 2008
88
© Defined Health, 2009
Pain Insight Briefing

Concerning, but Transient Adverse Events
• Headache, upper respiratory tract infection, paresthesias, hypoesthesias, and
arthralgia or joint pain, were the most frequently reported adverse events for patients
treated with tanezumab.
• In terms of withdrawals due to adverse events, only arthralgia or worsening diabetes
led to the withdrawal in more than one patient across the treatment arms.
• Seven patients experienced a
serious adverse event in this
study.
– Chest pain (placebo)
– Cellulitis, appendicitis
(10µg/kg)
– Breast cancer, bacterial
arthritis (50µg/kg)
– Syncope, lumbar spine
stenosis (200µg/kg)
Pfizer Analyst and Investor Meeting Oct. 28, 2008
89
© Defined Health, 2009
Pain Insight Briefing

NGF Antagonists: A Growing Pipeline
• Including tanezumab, at least 10 compounds (monoclonal antibodies and small
molecules) have been generated to inhibit NGF signaling. Currently only two drugs are
reportedly in clinical trials, Pfizer’s tanezumab and OrthoMcNeil/Janssen
Pharmaceuticals’ AMG 403 (although the status is unknown). Other pharma companies
likely have early stage programs.
Drug
Tanezumab
AMG 403
PG110
PPC-1807
VMD-902
BXL1H5
Anti-NGF
ALE 0540
ReN 1820
ReN 1826
???
90
Company
Pfizer
Amgen/OMJP/Takeda
PainCeptor
VM Discovery
BioXell
Yonsei University College
of Medicine
NPS Pharmaceuticals
ReNeuron
ReNeuron
Big Pharma A,B & C
Adis R&D Insight; IDdb3; Company websites
Lay Line
Genomics/PanGenetics
Class
mAB - NGF
mAB/peptibody - NGF
mAB - NGF
Small molecule
Small molecule
mAB – TrkA
mAB - NGF
Small molecule
Soluble TrkA
Modified ReN 1820
mAB - NGF
© Defined Health, 2009
Pain Insight Briefing
Status
Phase II - Pain
Phase I - Pain
PC - Pain
PC - Pain
PC - Pain
PC - Pain
No development
reported(PC)
Discontinued (PC) -
Neuropathic pain
Discontinued (PC) -
Inflammation
Discontinued (PC) - cancer
???

Will NGF for Pain Be Like TNF is for RA?
Products/
Indication
Clinical Data
Economics/
Providers
91
Enbrel, 1 st
Biologic
Rheumatoid
Arthritis, selfinjectedsubcutaneous
Defined Health analysis
1998 1999 2002 2003 2005-06 2007
Remicade, 1 st
Biologic Crohn’s
Disease, IV-
Infusion
Medicare
Part B covers
Remicade but
not Enbrel
Enbrel
approved for
Juvenile RA
Remicade
approved
for RA
ATTRACT Trial
supports launch of
Remicade into RA
Out-patient infusion
becomes available
© Defined Health, 2009
Pain Insight Briefing
Amgen acquires
Immunex (Enbrel)
Enbrel
approved for
Psoriatic
Arthritis and
Psoriasis
Humira
Launched for
RA, selfinjectedsubcutaneous
Orencia
approved
for RA
Remicade
approved for
Psoriatic
Arthritis and
Psoriasis
ASPIRE Trial shows
positive results of
Remicade for early RA
Rituxan
approved
for RA
Medicare
Part D covers
Enbrel & Humira
Remicade continues
coverage under
Medicare Part B
2008
Humira
launched for
Crohn’s
Disease
Cimzia (SC
injection)
launched for
Crohn’s

TNF Inhibitors: A $13+ Billion Market & Growing
92
SG Cowen Therapeutic Categories Outlook Sept 2008
Note: Arcoxia and Prexige received “non-approvable” letters in the US.
© Defined Health, 2009
Pain Insight Briefing

Repurposed anti-TNF Antibodies for Pain?
• When tissue injury and skin
inflammation ensue, chronic
inflammatory signals are released
from surrounding cells at the
peripheral nerve terminal and lead to
the sensitization of the nociceptors.
• Such factors include, but are not
limited to, adenosine and its related
mono- or polyphosphorylated
compounds (AMP, ADP and ATP),
bradykinin, glutamate, histamine,
interleukin 1, interleukin 6, nerve
growth factor, platelet-activating
factor, prostaglandin E2, substance
P and tumor-necrosis factor-α.
93
Nature Reviews Neuroscience, Vol 10, Jan 2009
Inflammation
© Defined Health, 2009
Pain Insight Briefing
TNF
IL-1
NGF TRPV-1
Potential to repurpose TNF
inhibitors for the treatment
and/or modulation of pain?

Other Repurposed Biological Cytokine Mediators?
• When tissue injury and skin
inflammation ensue, chronic
inflammatory signals are released
from surrounding cells at the
peripheral nerve terminal and lead to
the sensitization of the nociceptors.
• Such factors include, but are not
limited to, adenosine and its related
mono- or polyphosphorylated
compounds (AMP, ADP and ATP),
bradykinin, glutamate, histamine,
interleukin 1, interleukin 6, nerve
growth factor, platelet-activating
factor, prostaglandin E2, substance
P and tumor-necrosis factor-α.
94
Nature Reviews Neuroscience, Vol 10, Jan 2009
Inflammation
© Defined Health, 2009
Pain Insight Briefing
TNF
IL-1
NGF TRPV-1
Potential to repurpose cytokine
mediators inhibitors for the
treatment and/or modulation of
pain?

What’s Next for Pain?
• Continued efforts to improve on current standard of care.
• Increasing use of experimental/translational methodologies for early
clinical PoC (e.g., neuroimaging).
• Big pharma focus on novel mechanisms.
• More biologicals targeting pain mediators.
95
© Defined Health, 2009
Pain Insight Briefing

96
© Defined Health, 2009
Pain Insight Briefing