This is a briefing on the PD-1 and PD-L1 targeted agents. This briefing provides a summary of the agents in clinical development for the treatment of cancer. The briefing specifically focusses on the clinical and commercial development of nivolumab which includes a product profile, clinical development program and timeline, SWOT, potential issues, strategy, etc. More details on the products contained in this briefing can be obtained upon special request.

1. Source:
Depiction
courtesy
of
Genentech
By
Will
Roettger
Principal
Consultant
20/20
Market
Insights,
LLC
November
3,
2013

2. Page
Introduction/Background
5-­‐7
PD-­‐1/PD-­‐L1
Targeted
Agents
8-­‐10
PD-­‐1/PD-­‐L1
Product
Profiles
11-­‐19
Nivolumab
Clinical
Development
20-­‐27
Nivolumab
Commercial
Development
28-­‐32
Conclusions
33-­‐35
(Summary,
PD-­‐L1
Targeted
Tumors,
Comparison
Chart)
(nivolumab,
BMS936559,
lambrolizumab,
MPDL3280A
,
pidilizumab,
nivolumab
vs.
lambrolizumab,
first
to
market
strategy)
(efficacy,
development
program,
phase
III
clinical
trials,
development
timeline)
(SWOT,
Short
&
Long
Term
Planning,
Issues
to
Consider,
Positioning,
2

3. Will
Roettger
is
an
established
career
professional
in
the
pharmaceutical
and
biotech
industry.
Having
worked
for
Novartis,
AstraZeneca,
Merck,
Alexion,
and
Dendreon
he
has
developed
expertise
across
the
therapeutic
areas
of
oncology,
hematology,
and
immunology
for
pipeline
and
launch
products.
He
has
been
instrumental
in
establishing
marketing
intelligence
as
a
core
capability
in
support
of
clinical
and
commercial
new
product
development,
solving
the
many
commercial
challenges
that
high-­‐priced
specialty
products
face
from
a
patient,
provider,
and
investor
perspective.
Additionally
he
has
supported
two
specialty
product
launches,
providing
actionable
insights
and
recommendations
by
integrating
market
research
findings
with
competitive
intelligence.
As
a
principal
for
20/20
Market
Insights,
LLC,
he
is
dedicated
to
providing
clients
with
clear
vision
into
competitor
landscapes,
strategies,
and
product
assessments
that
drive
strategic
business
decisions
in
new
drug
development.
Contact
Information:
Will
Roettger
Principal
Consultant
20/20
Market
Insights,
LLC
908-­‐391-­‐4362
will.roettger@gmail.com
3

4. 4

5. 5

6. Source:
1. Oelke
et
al.
and
Schneck
Trends
in
MolecMed
(2005)
2. Keir,
Annu
Rev
Immunol.
2008
26:677-­‐704
3. Ribas,
N
Engl
J
Med.
366:
2517-­‐2519,
2012
4. Pardol,
Johns
Hopkins,
Nature
Reviews
Cancer
12,
252-­‐264
(April
2012)
5. Weber,
J
Semin
Oncol
2010
Positive
signal:
promotes
activation
&
proliferation
Repressive
signal:
promotes
supression
6

7. 7

8. 8

9. Tumor
Type
Estimated
PD-­‐L1
Prevalence
NSCLC
(SCC)
50%
NSCLC
(adeno)
45%
Colon
45%
Melanoma
40%
RCC
20%
As
one
of
the
highest
prevalent
cancers,
NSCLC
represents
a
significant
opportunity
to
leverage
the
effects
of
PD-­‐1/PD-­‐L1
blocking
agents
9

10. Nivolumab
(BMS936558)
Lambrolizumab
(MK-­‐3475)
Pidilizumab
(CT-­‐011)
MPDL3280A
Company
BMS
Merck
Genentech/Roche
CureTech
Target/MOA
PD-­‐1
PD-­‐1
PD-­‐L1
PD-­‐1
Human,
IgG4
Humanized,
IgG4
Human,
IgG1
Humanized,
IgG1
Melanoma,
NSCLC,
RCC
Melanoma
Melanoma,
NSCLC,
RCC,
Colon,
Gastric,
HNSCC,
Lymphoma
Melanoma,
pancreatic,
lymphoma,
CRC,
RCC,
MM
Phase
III/(melanoma,
NSCLC,
RCC)
[6-­‐phase
III
trials]
Phase
III/(melanoma)
Phase
II
(NSCLC)
Phase
II
(NSCLC)
Phase
II
(CRC,
lymphoma,
Hep-­‐C
pancreatic,
PCa
Melanoma:
all
cohorts
(ORR=31%)
3mg/kg
Q2W
cohort
(ORR
41%)
NSCLC:
(17%),
RCC
(29%)
Melanoma:
all
cohorts
(ORR>38%)
10mg/kg
Q2W
cohort
(ORR=52%)
NSCLC:
nscc
cohort
ORR=23%),
scc
cohort
(ORR=33%)
Melanoma:
(ORR
29%,
SD
87%
,
PFS
43%),
NSCLC
(24%)
NSCLC:
all
cohorts
(ORR=23%)
RCC:
(ORR=13%)
+50%
increase
in
CD4,
+40%
increase
in
CD8
Melanoma:
3mg/kg
Q2W
cohort
mOS=20.3
mths
NSCLC:
mOS=9.9
mths
Melanoma:
mPFS=>7
mths
NSCLC:
nscc
cohort
mPFS=9.1
wks),
scc
cohort
(mPFS=23.5
wks)
All
Tumors:
39%
vs.
13%
NSCLC:
100%
vs.
15%
1. Squamous
NSCLC
2. RCC
1. Melanoma
1. NSCLC
ADCC/CDC
Toxicity
none
none
none
Pneumonitis
3-­‐4%
3-­‐4%
none
All
Grade
3/4
=
14%
• Fatigue
2%
• Diarrhea
1%
• Pruritus
0.3%
• Nausea
0.3%
• Hb
decrease
0.3%
All
Grades
3/4
=
12.6%
• Fatigue
1.5%
• Rash
2.2%
• Pruritus
0.7%
All
Grade
3/4
=
43%
• Hyperglycemia
5%
• Fatigue
4%
• Increased
ALT
3%
• Dyspnea
3%
• Hypoxia
3%
Antibody
Targeted
Tumors
Latest
Clinical
Phase
Development
Activity/response
rates
Efficacy
Fast
Approval
Strategy
(w/phase
II)
Grade
3/4
Adverse
Events
(blocks
PD-­‐L1/PD-­‐L2
)
(blocks
PD-­‐L1/PD-­‐L2
)
(blocks
PD-­‐L1
)
(effector
T-­‐cell
function)
(effector
T-­‐cell
function)
-­‐
none

11. 11

12. Trademark:
Generic
Name:
nivolumab
Synonyms:
BMS-­‐936558,
MDX-­‐1106,
ONO-­‐4538
MOA:
PD-­‐1
checkpoint
inhibitor,
fully
human
mAb
anti-­‐PD-­‐1
IgG4
receptor
blocker.
Blocks
binding
of
PD-­‐1
to
PD-­‐L1
and
PD-­‐L2
Originating
Company
Ono
Pharmaceuticals,
Ltd./Medarex
Licensing
Company
Bristol-­‐Myers
Squibb
Formulation/Dose
IV
infusion,
3
mg/kg
solution
intravenously
Q2W,
[12
cycles
(48
doses),
4-­‐doses
per
cycle]
1st
Launch/Indication
/Metastatic
NSCLC
2nd
Launch/Indication
/Metastatic
RCC
or
Metastatic
melanoma
Patent
No./Expiration
COM
2027
(US)
Sales
Force
Size
Cost
Not
available
Comments
Pneumonitis
AEs
of
3-­‐4%,
3-­‐deaths
to
date,
1-­‐CRC,
2-­‐nsclc.
No
known
Fc
function
(ADCC,
CDC).
6-­‐phase
III
trials
are
underway
in
NSCLC,
Melanoma,
and
RCC.
12

13. Trademark:
Generic
Name:
Not
available
Synonyms:
BMS-­‐936559,
MDX-­‐1105
MOA:
Fully
human
mAb,
PD-­‐L1
IgG4
ligand
blocker.
Blocks
binding
of
PD-­‐L1
to
PD-­‐1
and
B7-­‐1.
Does
not
block
binding
of
PD-­‐L2
to
PD-­‐1
Originating
Company
Ono
Pharmaceuticals,
Ltd./
Licensing
Company
Bristol-­‐Myers
Squibb
Formulation/Dose
IV
infusion/0.1
–
10mg/kg
Q2W
[phase
I,
16
cycles
(48
doses),
3-­‐doses
per
cycle]
1st
Launch/Indication
/Metastatic
Melanoma
2nd
Launch/Indication
/Metastatic
NSCLC
Patent
No./Expiration
Sales
Force
Size
Cost
Not
available
Comments
Development
was
dropped
in
option
to
move
ahead
with
nivolumab
–
a
PD-­‐1
receptor
blocker.
No
reported
pneumonitis
in
BMS-­‐936559.
13

14. Trademark:
Generic
Name:
lambrolizumab
Synonyms:
MK3475,
SCH900475
MOA:
Humanized
mAb
anti-­‐PD-­‐1,
IgG4,
receptor
blocker.
Blocks
binding
of
PD-­‐1
to
PD-­‐L1
and
PD-­‐L2
Originating
Company
Licensing
Company
Merck/Schering
Formulation/Dose
IV
infusion
over
30
minutes,
10
mg/.kg
Q2W
or
10mg/kg
Q3W
or
2mg/kg
Q2W,
[Phase
I,
11-­‐cycles
(34
doses),
3-­‐doses
per
cycle]
1st
Launch/Indication
/Metastatic
Melanoma
2nd
Launch/Indication
/Metastatic
NSCLC
Patent
No./Expiration
US
20130071403
A1
Sales
Force
Size
Cost
Not
available
Comments
Pneumonitis
AEs
of
3-­‐4%,
14

15. Trademark:
Generic
Name:
Not
available
Synonyms:
MPDL3280A,
RG7446
MOA:
A
human
Fc
optimized
anti-­‐PD-­‐L1
mAb,
IgG1,
ligand
blocker
-­‐
binds
to
PD-­‐L1,
blocking
its
binding
to
and
activation
of
its
receptor,
PD-­‐1.
Fc
optimization
does
not
induce
either
antibody-­‐dependent
cytotoxicity
(ADCC)
or
complement-­‐dependent
cytotoxicity
(CDC).
Originating
Company
Licensing
Company
Genentech/Roche
Formulation/Dose
IV
Infusion
of
1200
mg
on
Day
1
of
21-­‐day
cycles
for
a
maximum
of
16
cycles,
Q3W,
1st
Launch/Indication
/Metastatic
NSCLC
2nd
Launch/Indication
/Metastatic
Melanoma
Patent
No./Expiration
Sales
Force
Size
Cost
Not
available
Comments
20%
clinical
benefit
in
PD-­‐L1
negative
tumors
has
been
shown.
The
Fc
portion
of
anti-­‐body
is
engineered
to
prevent
depletion
of
effector
T-­‐cells
by
ADCC
thereby
allowing
PD-­‐1
and
PD-­‐L2
interaction
to
remain
intact
in
pleural
tissues.
As
a
result
no
pneumonitis
has
been
seen.
15

16. Trademark:
Generic
Name:
pidilizumab
Synonyms:
CT-­‐011,
MOA:
Humanized
mAb
anti-­‐PD-­‐1,
IgG1,
receptor
blocker.
Blocks
binding
of
PD-­‐1
to
PD-­‐L1
and
PD-­‐L2
resulting
in
the
attenuation
of
apoptotic
processes
in
lymphocytes,
primarily
effector/memory
T
cells,
and
the
augmentation
of
the
anti-­‐tumor
activities
of
NK
cells.
Originating
Company
CureTech
Licensing
Company
Formulation/Dose
IV
infusion,
0.2
to
0.6
mg/kg
(dose
to
be
determined)
1st
Launch/Indication
Diffuse
Large
B
Cell
Lymphoma
(DLBCL)
2nd
Launch/Indication
mCRC
Patent
No./Expiration
US
7332582B2,
EP
1575484A
Sales
Force
Size
None
Cost
Not
available
Comments
As
of
January
2013,
Teva
dropped
their
development
agreement
with
Curetech
on
this
product.
At
this
point
Teva
is
without
a
development
partner
and
continues
ahead
with
phase
II
trials.
16

17. Nivolumab
BMS936558,
ONO4538
PD-­‐1
checkpoint
inhibitor,
fully
human
mAb
anti-­‐
PD-­‐1
IgG4
receptor
blocker.
Blocks
binding
of
PD-­‐1
to
PD-­‐L1
and
PD-­‐L2
Ono
Pharmaceuticals,
Ltd./Medarex
BMS
IV
infusion,
3
mg/kg
solution,
Q2W,
[phase
I,
12
cycles
(48
doses),
4-­‐doses
per
cycle]
Not
yet
approved/NSCLC
Not
yet
approved/Melanoma
COM
2027
(US)
Lambrolizumab
Synonyms
MOA
Originating
Company
Licensing
Company
Formulation/Dose
MK3475,
SCH900475
Humanized
mAb
anti-­‐PD-­‐1,
IgG4,
receptor
blocker.
Blocks
binding
of
PD-­‐1
to
PD-­‐L1
and
PD-­‐L2
Schering
Merck
IV
infusion
over
30
minutes,
10
mg/.kg
Q2W
or
10mg/
kg
Q3W
or
2mg/kg
Q2W,
[Phase
I,
11-­‐cycles
(34
doses),
3-­‐doses
per
cycle]
1st
Approval/Indication
Not
yet
approved/NSCLC
2nd
Approval/Indication
Not
yet
approved/Melanoma
Patent
No./Expiration
Sales
Force
Size
phase
I,
12
cycles
(48
doses)
Duration
of
Therapy
Phase
I,
11-­‐cycles
(34
doses)
Not
available
Pricing
Not
available
Not
available
Cost
of
Treatment
Not
available
17

18. Nivolumab
•
•
•
•
ORR:
31%
(n=107)
ORR:
41%
@
3
mg/kg
Q2W
(n=17)
mPFS:
3.7
months
Yervoy
treated
ORR:
20%
Lambrolizumab
Efficacy:
Melanoma
• ORR:
17%
RECIST
[17.6%
NSCC,
16.7%
SCC]
1-­‐yr
survival=42%,
2-­‐yr
survival=24%,
mOS=9.9
mths
(n=129)
All
Grade
3/4
=
14%
• Fatigue
2%
• Diarrhea
1%
• Pruritus
0.3%
• Nausea
0.3%
• Hb
decrease
0.3%
Efficacy:
NSCLC
ADEs
Pneumonitis:
4%
(any
grade),
1%
(grade
3/4)
Notable
Toxicities
•
•
•
•
•
ORR:
38%
(n=117)
ORR:
52%
@
10
mg/kg
Q2W
(n=52),
CR=10%
mPFS:
>7
months
Yervoy
treated
ORR:
62%
@
10
mg/kg
Q2W
(n=13)
Yervoy
naïve
ORR:
49%
@
10
mg/kg
Q2W
(n=39)
• ORR:
21%
RECIST(n=38)
All
Grades
3/4
=
12.6%
• Fatigue
1.5%
• Rash
2.2%
• Pruritus
0.7%
Pneumonitis:
4.4%
(grade
1/2)
Warnings
Not
available
NCCN
Guideline
Not
available
Manufacturer
Not
available
Sales
18
Not
available

19. 19

20. 20

21. Nivolumab
Efficacy
in
Phase
I
Trial
(NCT00730639)
Tumor
No.
Patients
NSCLC
(1-­‐10)
127
MEL
(0.1-­‐10)
RCC
(1
or
10)
(dose,
mg/kg)
Duration
of
Response
Median
PFS
Median
OS
(mths)
(1-­‐yr)
(2-­‐yr)
16%
17.0
2.3
9.6
43%
32%
107
31%
24.0
3.7
16.8
61%
44%
34
29%
12.9
7.3
>22
70%
52%
(n)
ORR
(mths)
21
(mths)
OS
OS

22. Nivolumab
NSCLC
Efficacy
in
Phase
I
Trial
(NCT00730639)
Stable
Disease
Rate
Median
OS
All
doses
16.7%
14.8%
9.2
0%
26.7%
8.0
22.2%
5.6%
9.5
10
NSCC
ORR
3
SCC
Dose
1
Histology
23.8%
14.3%
10.5
All
doses
17.6%
6.8%
10.1
1
5.6%
5.6
9.9
3
26.3%
10.5%
18.2
10
18.9
5.4%
7.4
(mg/kg)
%
(≥24
weeks
)
22
(months)

23. Combined
Regimen
(Nivoilumab
+
Yervoy)
Nivolumab
Yervoy
(mg/
(mg/kg)
kg)
3
0.3
3
1
1
3
3
3
All
doses
Evaluable
patients
14
17
15
6
52
CR
(n)
PR
(n)
ORR
1
3
1
0
5
2
6
5
3
16
21%
53%
40%
60%
40%
23
≥80%
Tumor
reduction
at
8
wks
4
(28%)
7
(41%)
5
(33%)
0
16
(31%)

24. Nivolumab
Clinical
Trials
NSCLC
RCC
Melanoma
Phase II Trials
Phase II Trials
Phase II Trials
1. Nivolumab in advanced or
metastatic squamous cell
NSCLC, NCT01721759,
n=100, i=11/2012, f=2/2014
1. Nivolumab in clear cell
advanced RCC,
NCT01354431, n=150,
i=5/2011, f=5/2013
1. Nivlumab w/ipilimumab in
advanced or metastatic
melanoma, NCT01783938,
n=80, i=4/2013, f=8/2014
Phase III Trials
Phase III Trials
Phase III Trials
1. Nivolumab vs. docetaxel 2L
advanced or metastatic
squamous cell NSCLC,
NCT01642004, n=264,
i=10/2012, f=8/2015
1. Nivolumab vs. everolimus 2L
advanced or metastatic clear
cell RCC, NCT01668784,
n=822, i=10/2012, f=2/2016
1. Nivolumab + ipilimumab – 1L
Advanced Melanoma,
NCT01844505, n=915,
i=6/2013, f=1/2017
2. Nivolumab vs. dacarbazine or
carbo/paclitaxel in advanced
melanoma following anti
CTLA-4, NCT01721746,
n=390, i=12/2012, f=5/2015
2. Nivolumab vs. docetaxel 2L
advanced or metastatic nonsquamous NSCLC,
NCT01673867,n=574,
i=11/2012, f=11/2014
24
3. Nivolumab vs. dacarbazine, 1L
metastatic melanoma,
NCT01721772, n=410,
i=1/2013, f=6/2020

25. Tumor
N
Trial
ID
Melanoma
915
NCT01844505
Global
recruiting
6/2013
1/2017
1st
line,
untreated
advanced
unresectable
or
metastatic
Nivolumab
vs.
10:
OS/PFS,
ORR
Melanoma
390
NCT01721746
Global
recruiting
12/2012
5/2015
Post
CTLA-­‐4,
unresectable
or
metastatic
Nivolumab
vs.
dacarbazine
or
carbo
tax
10:
OS,ORR
20:
PFS,
HRQoL
Melanoma
410
NCT01721772
Ex-­‐US
recruiting
1/2013
6/2020
1st
line,
unresectable
or
metastatic
Nivolumab
vs.
dacarbazine
10:
OS
20:
PFS,
ORR
NSCLC
(NSCC)
264
NCT01642004
Global
recruiting
10/2012
8/2015
2nd
line,
post
platinum
failure,
advanced
metastatic
Nivolumab
vs.
docetaxel
10:
OS,ORR
20:PFS
NSCLC
574
NCT01673867
Global
recruiting
11/2012
11/2014
2nd
line,
post
platinum
failure,
advanced
metastatic
Nivolumab
vs.
docetaxel
10:
OS
20:ORR,
PFS
RCC
822
NCT01668784
Global
recruiting
10/2012
2/2016
4th
line,
pre-­‐treated
advanced
or
metastatic
clear
cell
RCC
Nivolumab
vs.
affinitor
(everlimus)
10:OS
(SCC)
Scope
Status
T0
Tf
25
Segment
Treatment
Endpoint

26. 2013
2014
2015
Complete 11/2014
NSCLC
(2nd Line
advanced
metastatic)
2nd
RCC
Line
(advanced
metastatic)
2016
File 4/2015
Non-Squamous Cell
NCT0167387
Estimated approval
10/2015 (PDUFA V, 6-mth
priority review)
Complete 8/2015
File 1/2016
Estimated approval
7/2016 (PDUFA V, 6-mth
priority review)
Squamous Cell
NCT0167387
Complete 2/2016
File 7/2016
Estimated approval
1/2017 (PDUFA V, 6-mth
priority review)
clear cell
NCT01668784
Complete 11/2014
Melanoma
(1st Line
advanced
metastatic)
2017
File 5/2015
Vs. dacarbazine,or c/p
NCT01721746
Complete 8/2015
+ ipilimumab
NCT01844505
Estimated approval
12/2015 (PDUFA V, 6-mth
priority review)
File 1/2016
Estimated approval
7/2016 (PDUFA V, 6-mth
priority review)
Estimated approval
3/2021 (PDUFA V, 6-mth
priority review)
Vs. dacarbazine
NCT01721772
26

27. 2013
2014
2015
Complete 11/2014
NSCLC
(2nd Line
advanced
metastatic)
2nd
RCC
Line
(advanced
metastatic)
2016
File 4/2015
Non-Squamous Cell
NCT0167387
Phase II Study
Complete 2/2014
Fast
Track
Estimated approval
10/2015 (PDUFA V, 6-mth
priority review)
Complete 8/2015
File 1/2016
Estimated approval
7/2016 (PDUFA V, 6-mth
priority review)
Squamous Cell
NCT0167387
Phase II Study
Complete 5/2013
Fast
Track
Complete 2/2016
File 7/2016
Estimated approval
1/2017 (PDUFA V, 6-mth
priority review)
clear cell
NCT01668784
Complete 11/2014
Melanoma
(1st Line
advanced
metastatic)
2017
File 5/2015
Vs. dacarbazine,or c/p
NCT01721746
Phase II Study
Complete 8/2014
Fast
Track
+ ipilimumab
NCT01844505
Vs. dacarbazine
NCT01721772
Complete 8/2015
Estimated approval
12/2015 (PDUFA V, 6-mth
priority review)
File 1/2016
Estimated approval
7/2016 (PDUFA V, 6-mth
priority review)
Estimated approval
3/2021 (PDUFA V, 6-mth
priority review)
27

28. 28

29. 29

30. 30

31. 31

32. 32

33. 33

34. 34

35. 35

36. Will
Roettger
Principal
Consultant
20/20
Market
Insights,
LLC
908-­‐391-­‐4362
will.roettger@gmail.com
36