This is a short briefing on the oncology immunotherapy PD-1/PD-L1 targeted agents currently under development. In this briefing we look at the competitive landscape, PD-1/PD-L1 product profiles, positioning, strategy, as well as a development timeline and SWOT on the BMS PD-1 blocker nivolumab. Updates to this briefing will come as newer information is discovered.

1. By
Will
Roettger
Principal
Consultant
20/20
Market
Insights,
LLC
June
12,
2013
CI
Briefing
-­‐
Nivolumab

2. 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
2

3. 3

4. 4

5. 5

6. 6

7. 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
7

8. Nivolumab
(BMS936558)
Company
Bristol-­‐Myers
Squibb
Lambrolizumab
(MK-­‐3475)
Pidilizumab
(CT-­‐011)
MPDL3280A
Merck
Genentech/Roche
CureTech
PD-­‐1
blocker
(blocks
PD-­‐L1/PD-­‐L2
)
PD-­‐L1
(ligand)
blocker
(blocks
PD-­‐L1
)
PD-­‐1
blocker
Humanized,
IgG4
Human,
IgG1
Humanized,
IgG1
(effector
T-­‐cell
function)
(effector
T-­‐cell
function)
Melanoma
Melanoma,
NSCLC,
RCC,
Colon,
Gastric,
HNSCC,
Lymphoma
Melanoma,
pancreatic,
lymphoma,
CRC,
RCC,
MM
Phase
III/(melanoma)
[PIII
Just
initiated]
Phase
II
(NSCLC)
Phase
II
(NSCLC)
Phase
II
(CRC,
lymphoma,
Hep-­‐C
pancreatic,
PCa
Melanoma
(ORR>38%)
Melanoma
(ORR
29%,
SD
87%
,
PFS
43%),
NSCLC
(24%)
+50%
increase
in
CD4,
+40%
increase
in
CD8
Data
pending
39%
vs.
13%
all
tumors
100%
vs.
15%
NSCLC
1. Melanoma
1. NSCLC
ADCC/CDC
Toxicity
none
none
none
Pneumonitis
3-­‐4%
3-­‐4%
none
MOA
PD-­‐1
blocker
(blocks
PD-­‐L1/PD-­‐L2
)
Antibody
Human,
IgG4
Targeted
Tumors
Melanoma,
NSCLC,
RCC
Latest
Clinical
Phase
Phase
III/(melanoma,
Development
NSCLC,
RCC)
[6-­‐phase
III
trials]
Activity/response
rates
Melanoma
(ORR
31%,
RR
67%),
NSCLC
(17%),
RCC
(29%)
Efficacy
Melanoma:
21.1
vs.
12.5
mos
Fast
Approval
Strategy
1. Squamous
NSCLC
(conditional
w/phase
II
data)
2. RCC
-­‐
none

9. Trademark:
Generic
Name:
nivolumab
Synonyms:
BMS-­‐936558,
MDX-­‐1106,
ONO-­‐4538
MOA:
PD-­‐1
checkpoint
inhibitor,
fully
human
mAb
anti-­‐PD-­‐1
IgG1
receptor
blocker.
Blocks
binding
of
PD-­‐1
to
PD-­‐L1
and
PD-­‐L2
Originating
Company
Ono
Pharmaceuticals,
Ltd./
Licensing
Company
Bristol-­‐Myers
Squibb
Formulation/Dose
IV
infusion,
3
mg/kg
solution
intravenously
every
2
weeks
1st
Launch/Indication
/Metastatic
NSCLC
2nd
Launch/Indication
/Metastatic
RCC
or
Metastatic
melanoma
Patent
No./Expiration
Sales
Force
Size
Cost
Comments
Pneumonitis
AEs
of
3-­‐4%,
3-­‐deaths
to
date,
1-­‐CRC,
2-­‐nsclc.
9

10. Trademark:
Generic
Name:
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
1st
Launch/Indication
2nd
Launch/Indication
Patent
No./Expiration
Sales
Force
Size
Cost
Comments
Development
was
dropped
in
option
to
move
ahead
with
nivolumab
–
a
PD-­‐1
receptor
blocker.
No
reported
pneumonitis
in
BMS-­‐936559.
10

11. 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
…
1st
Launch/Indication
/Metastatic
Melanoma
2nd
Launch/Indication
/Metastatic
NSCLC
Patent
No./Expiration
Sales
Force
Size
Cost
Comments
Pneumonitis
AEs
of
3-­‐4%,
11

12. Trademark:
Generic
Name:
Synonyms:
MPDL3280A
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
1st
Launch/Indication
/Metastatic
NSCLC
2nd
Launch/Indication
/Metastatic
Melanoma
Patent
No./Expiration
Sales
Force
Size
Cost
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
12
seen.

13. Trademark:
Generic
Name:
pidilizumab
Synonyms:
CT-­‐011,
MOA:
Humanized
mAb
anti-­‐PD-­‐1,
IgG4,
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
1st
Launch/Indication
2nd
Launch/Indication
Patent
No./Expiration
Sales
Force
Size
Cost
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.
13

14. 14

15. 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
15
3. Nivolumab vs. dacarbazine, 1L
metastatic melanoma,
NCT01721772, n=410,
i=1/2013, f=6/2020

16. 2013
2014
2015
Complete 11/2014
NSCLC
(2nd Line
advanced
metastatic)
2nd
RCC
Line
(advanced
metastatic)
File 4/2015
Non-Squamous Cell
NCT0167387
2017
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)
2016
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

17. 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
+ ipilimumab
NCT01844505
Vs. dacarbazine
NCT01721772
Fast
Track
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)

18. 18

19. Lambrolizumab
Clinical
Trials
NSCLC
Phase II Trials
RCC
Phase II Trials
1. MK3475 vs. Docetaxel, n=920,
T0=Augst 2013, Tf=September
2015, Primary=OS, PFS,
secondary=ORR, RR, US Trial
19
Melanoma
Phase II Trials

20. 20

21. 21

22. Will
Roettger
Principal
Consultant
20/20
Market
Insights,
LLC
908-­‐391-­‐4362
will.roettger@gmail.com
22