Thomas Davis, MD Celldex Therapeutics, Inc.

Thomas Davis, MD
Celldex Therapeutics, Inc.
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Robust science is always the highest goal
Our intent is to help people
Within our system, effective agents require
commercial marketing to make them
available to patients
The path through the regulatory and
commercial gauntlet is therefore unavoidable
Commercialization ultimately defines success,
encouraging further development
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Broad view and final endpoint is critical
◦ Keep next steps and final ambition in mind
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Build value with minimal risk
◦ Biphasic interest curve
 Exciting early data or proven technology more viable
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Single agent or simple development
preferable
Fail early and learn
IP and competition are critical
Limited ability to talk publicly
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Antibodies are no longer “immunotherapy”
“Checkpoint inhibitors” have validated generic
immune activation approaches
◦ Had a tenuous start
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Vaccines are still not accepted readily
◦ RR versus OS
◦ Manufacturing and Marketing complexity of DC
vaccine has compromised the field
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Individual vaccine platforms are even harder
to validate
◦ Proof of principle important
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Smaller companies more prepared to accept risks
◦ Partnering or Commercialization important
◦ While small companies are loath to halt development,
the standards are still similar to larger companies
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More potent effects are important
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Fail early is still important
Modest OS benefits are very difficult to prove efficiently
Immune response alone may be inadequate
It is hard to justify expensive advanced development
based upon the subtler aspects of the Immune Response
Criteria
Reasonable path to approval
◦ Feasibility is critical
CANDIDATE
INDICATION
Rindopepimut
Front-line Glioblastoma
ACT
ACT IV
IV Registration
Registration Trial
Trial
CDX-011
Breast Cancer
EMERGE
EMERGE Trial
Trial
Rindopepimut
Recurrent GBM
ReACT
ReACT Trial
Trial
CDX-1135
Dense Deposit Disease
CDX-1127
Lymphoma, Cancer
CDX-301
HSC Transplantation
CDX-1401
Multiple Solid Tumors
PHASE 1
Pilot
Pilot
PHASE 2
PHASE 3
Rindopepimut: both PFS and OS improvement
against non-study comparators
Survival Probability
Median
(months)
OS at OS at 36 Comparison
24
Months to Historical
Months
Control
ACT III (n=65)
24.6
52%
31%
p = <0.0001
ACT II (n=22)
24.4
50%
23%
p = 0.0034
ACTIVATE (n=18)
24.6
50%
33%
p = 0.0003
Matched historical
control (n=17)
15.2
6%
6%
OS from Diagnosis (Months)
Vaccinations begin approximately 3 months after diagnosis
Median duration of followup:
ACT III: 48.7 months
ACT II: 71.8 months
ACTIVATE: 99.3 months
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Enhanced immunity to protein vaccines by
antigen delivery to DCs in situ
◦ Targeting antigens with mAbs to MR and DEC-205
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Enhancing T cell responses with co-stimulation
◦ Development of an anti-human CD27 agonist mAb
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Expansion of DC subsets
◦ Flt3L-back in the clinic
MR
CD206
DEC-205
CD205
Antibody
Specificity
APC Binding in human tissues
Affinity
KD (M)
B11
Mannose receptor
Dermal DCs, Interstitial DCs, macrophages in most tissues
~7 x 10‐10
3G9
DEC‐205
DCs in lymph nodes, tissue DCs
~2 x 10‐10
3G9
Hu IgG1
B11
Hu IgG1
Recombinant antibody product
Genetically
fused
antigen
Human mAb
to MR or
DEC-205
EGFRvIII
HER2
NY-ESO-1
Mesothelin
Targeting improves cross-presentation
of NY-ESO-1
Recognition by NY-ESO-1-specific CD8 T cell clone
NY-ESO-1
protein
400
300
200
MR-Cont
MR-ESO
DEC-Cont
0
DEC-ESO
100
ESO protein
DC
IFN-
500
Peptide (94-102)
CD8+
600
Unpulsed
-MR-NY-ESO-1
or
-DEC-NY-ESO-1
Number of IFN- spots / 2,000 cells
+
Takemasa Tsuji et al J Immunol. 2011, 186: 1218
Stimulation of NY-ESO-1 CD8+ T cell responses from patient SB
600
Presensitized with
peptide pool
3G9-NYESO-1
-1401
500
400
300
200
Peptide 101-109/
HLA-B*4002
Peptide 124-133/
HLA-B*4002
Unpulsed
#1-17
161-180
151-170
139-160
131-150
119-143
111 -130
101-120
NY-ESO-1 peptide
91-110
81-100
71-90
61-80
51-70
41-60
31-50
21-40
0
11-30
100
1-20
Number of IFN -  spots
700
Peptide 157-165/
HLA-A*0201
Takemasa Tsuji et al J Immunol. 2011, 186: 1218
2 weeks
Treatment schedule
Repeat if
Stable Disease
CDX‐1401 (i.c.)
R848 (topical or s.c.)
Poly ICLC (s.c.)
Cohort 1
0.1 mg CDX-1401 i.c.
500 g topical resi
N = 9 / NY-ESO-1+ = 3
Cohort 4
1 mg CDX-1401 i.c.
2 mg Poly ICLC s.c.
N = 5 / NY-ESO-1+ = 3
Cohort 2
1 mg CDX-1401 i.c.
500 g topical resi
N = 8 / NY-ESO-1+ = 3
Cohort 5
1 mg CDX-1401 i.c.
20-500 g s.c. resi
N = 7 / NY-ESO-1+ = 7
Cohort 3
3 mg CDX-1401 i.c.
500 g topical resi
N = 6 / NY-ESO-1+ = 3
Cohort 6
1 mg CDX-1401 i.c.
500 g s.c. resi
2 mg Poly ICLC s.c.
N = 6 / NY-ESO-1+ = 6
 Advanced melanoma and other cancers  45 patients enrolled, no SAEs
 Of 38 pts analyzed, 12 pts with SD (up 13 Mo)  3 with documented tumor shrinkage
# IFN- ELISPOT
5
10
7 day IVS with
NY-ESO-1 peptide pool
(control peptides subtracted)
NY-ESO-1
peptides
Specimen_001_Tube_003 ESO
pep.fcs
Specimen_001_Tube_002
ctr pep.fcs
Control peptides
5
30.60%
10
0.18%
Pacific Blue-A
Pacific Blue-A
3
CD8
3
10
2
2
10
10
69.01%
69.81%
0.21%
2
10
3
4
10
10
APC-A
Specimen_001_Tube_002 ctr pep.fcs
5
10
10
1
10
2
3
10
10
APC-A
4
5
10
10
Specimen_001_Tube_003 ESO pep.fcs
5
5
30.74%
10
0.05%
4
29.46%
0.17%
4
10
Pacific Blue-A
10
Pacific Blue-A
0.56%
1
1
10
1
10
3
10
2
3
10
2
10
CD8
0.49%
10
10
10
29.14%
4
4
10
TNF-
1 2 3 4 5 6 7 8 1 2 3 4 5 6 7 1 2 3 4 1 2 3 4 5 1 2 3 4 5 6 1 2 3 4 5 6 10
69.09%
0.13%
70.11%
1
10
1
10
0.26%
1
2
10
3
10
PE-Cy7-A
4
10
5
10
10
1
10
2
10
3
10
PE-Cy7-A
4
10
5
10
IFN-
CDX‐
1401 Adjuvant
0.1 mg Topical Resi 1.0 mg Topical Resi 3.0 mg Topical Resi 1.0 mg Poly ICLC
1.0 mg S.C. Resi 1.0 mg S.C. Resi + Poly ICLC
Pre
Post On-going
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Member of the TNF-receptor superfamily (CD40, 4-1BB,OX-40)
◦ Single ligand is CD70 (tightly regulated)
◦ Constitutively expressed on most T cells and a subset of B and NK cells
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Co-stimulatory molecule
◦ Role in generation and long-term maintenance of T cell immunity
◦ Role in NK cell differentiation/activation
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CD27 activation:
◦ Signaling through Traf2, Traf5
◦ Activation of the NF-κB pathway
◦ Cell survival, activation, proliferation
Saline
3
Tumor Volume (cm3)
3
2
2
mouse 1
mouse 2
mouse 11
mouse 3
mouse 12
mouse 4
mouse 13
mouse 5
mouse 14
mouse 6
mouse 15
mouse 7
mouse 16
mouse 8
mouse 17
mouse 18
mouse 9
mouse 10
Re‐challenge
CDX‐1127
3
Re‐challenge Controls
mouse 11
mouse
21
mouse 12
mouse
22
mouse 13
mouse 14
mouse
23
mouse 15
mouse
24
mouse 16
mouse 25
mouse 17
mouse 26
mouse 18
mouse
27
mouse 19
mouse
28
mouse 20
3
2
2
mouse 29
1
1
0 0
1
mouse 30
1
0 0
41 51 61
1 1 111121 31 21
31 71 81 1
0
11
22
33
44
55
66
11 21 31 41Days51 61 71
Days Days
Days
4
4
4
10 CT26 cells s.c. on day 0
10 CT26 cells s.c. on day 0
10 syngeneic
CT26 cells inoculated s.c. in huCD27Tg mice on day 0
st
inoculation)
(day 99 relative to 1
Antibody treatment ‐
600 g i.p. on days 3, 5, 7, 9, 11
77
CDX-1127 model
has direct
efficacyB on
CD27-expressing
human
Xenograft
of human
lymphoblastic
tumor
cell
(SCID) mice
lymphoma cells
in (Raji)
immuno-compromised
line
in SCID mice
Tumor Volume (mm3)
5000
No treatment
4000
3000
Control mAb, 0.1 mg/dose
CDX-1127 0.1 mg/dose
CDX-1127 0.03 mg/dose
2000
1000
Days post tumor inoculation
Treatment
Similar efficacy with other human B and T cell tumor
lines- Daudi, Namalwa, CCRF-CEM
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Flt3L: potent stem cell mobilizer and
dendritic cell growth factor
Previous clinical studies (Immunex/Amgen)
demonstrated safety and biological activity
(>500 subjects dosed)
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Program acquired from Amgen in 2009
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Multiple clinical opportunities
Flt3L
D0
5 64
10
D10
D30
DEC-205-HIVgag(p24)
+PolyICLC
Flt3L p24
4.8 24
PBS p24
Flt3L p17
1.3 0.34
D40
D45-52
boost
PBS P17
33 0.18
collect serum and
splenocytes
1.3
IFN
IFN
4
10
CFSE
3
10
2 11
10
20 10
0
2 10
3 10
4 10
5
010
CFSE
65
3.1
64
9.1
89
Anti-p24 IgG
Niro Anandasabapathy and Ralph Steinman