thomas davis, md celldex therapeutics,...

Thomas Davis, MDCelldex Therapeutics, Inc.

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

Broad view and final endpoint is critical◦ Keep next steps and final ambition in mind

Build value with minimal risk◦ Biphasic interest curve Exciting early data or proven technology more viable

Single agent or simple development preferable

Fail early and learn IP and competition are critical Limited ability to talk publicly

Antibodies are no longer “immunotherapy” “Checkpoint inhibitors” have validated generic

immune activation approaches◦ Had a tenuous start

Vaccines are still not accepted readily◦ RR versus OS◦ Manufacturing and Marketing complexity of DC

vaccine has compromised the field Individual vaccine platforms are even harder

to validate◦ Proof of principle important

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 More potent effects are important◦ 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 PHASE 3

Rindopepimut

CDX-011

Rindopepimut

CDX-1135

CDX-1127

CDX-301

CDX-1401

INDICATION

Front-line Glioblastoma

Breast Cancer

Recurrent GBM

Dense Deposit Disease

Lymphoma, Cancer

HSC Transplantation

Multiple Solid Tumors

PHASE 2PHASE 1

EMERGE TrialEMERGE Trial

ReACT TrialReACT Trial

ACT IV Registration TrialACT IV Registration Trial

PilotPilot

Rindopepimut: both PFS and OS improvement against non-study comparators

Surv

ival

Pro

babi

lity

Median (months)

OS at 24

Months

OS at 36 Months

Comparison to Historical

Control

ACT III (n=65) 24.6 52% 31% p = <0.0001ACT II (n=22) 24.4 50% 23% p = 0.0034ACTIVATE (n=18) 24.6 50% 33% p = 0.0003Matched historical control (n=17)

15.2 6% 6%

Vaccinations begin approximately 3 months after diagnosisOS from Diagnosis (Months)

Median duration of follow-up: ACT III: 48.7 monthsACT II: 71.8 monthsACTIVATE: 99.3 months

Enhanced immunity to protein vaccines by antigen delivery to DCs in situ◦ Targeting antigens with mAbs to MR and DEC-205

Enhancing T cell responses with co-stimulation◦ Development of an anti-human CD27 agonist mAb

Expansion of DC subsets◦ Flt3L-back in the clinic

DEC-205CD205MR

CD206

B11Hu IgG1

3G9Hu IgG1

Antibody Specificity APC Binding in human tissues AffinityKD (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

Genetically fused

antigen

Recombinant antibody product

Human mAbto MR orDEC-205

HER2

NY-ESO-1Mesothelin

EGFRvIII

Takemasa Tsuji et al J Immunol. 2011, 186: 1218

IFN-CD8+

DC

Recognition by NY-ESO-1-specific CD8+ T cell clone

0

100

200

300

400

500

600

M

R-C

on

t

M

R-E

SO

D

EC

-Co

nt

D

EC

-ES

O

ES

O p

rote

in

Pep

tid

e (9

4-10

2)

Un

pu

lsedN

umbe

r of

IFN

-sp

ots

/ 2,

000

cells

NY-ESO-1protein

-MR-NY-ESO-1or

-DEC-NY-ESO-1

Targeting improves crossTargeting improves cross--presentation presentation of NYof NY--ESOESO--11

-1401

1-20

11-3

0

21-4

0

31-5

0

41-6

0

51-7

0

61-8

0

71-9

0

81-1

00

91-1

10

101-

120

111-

130

119-

143

131-

150

139-

160

151-

170

161-

180

#1-1

7

Unp

ulse

d

Num

ber o

f IFN

-sp

ots

0

100

200

300

400

500

600

700

peptide pool3G9-NYESO-1

Presensitized with

Peptide 101-109/ HLA-B*4002

Peptide 124-133/ HLA-B*4002

Peptide 157-165/ HLA-A*0201

NY-ESO-1 peptide

Stimulation of NY-ESO-1 CD8+ T cell responses from patient SB

Takemasa Tsuji et al J Immunol. 2011, 186: 1218

2 weeks

CDX‐1401 (i.c.)

Poly ICLC (s.c.)R848 (topical or s.c.)

Repeat ifStable Disease

Treatment schedule

Cohort 10.1 mg CDX-1401 i.c.

500 g topical resiN = 9 / NY-ESO-1+ = 3

Cohort 21 mg CDX-1401 i.c.500 g topical resi

N = 8 / NY-ESO-1+ = 3

Cohort 33 mg CDX-1401 i.c.500 g topical resi

N = 6 / NY-ESO-1+ = 3

Cohort 61 mg CDX-1401 i.c.

500 g s.c. resi2 mg Poly ICLC s.c.

N = 6 / NY-ESO-1+ = 6

Cohort 51 mg CDX-1401 i.c.20-500 g s.c. resi

N = 7 / NY-ESO-1+ = 7

Cohort 41 mg CDX-1401 i.c.2 mg Poly ICLC s.c.

N = 5 / NY-ESO-1+ = 3

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- ELISPOT7 day IVS with

NY-ESO-1 peptide pool(control peptides subtracted)

Specimen_001_Tube_003 ESO pep.fcs

APC-A

Paci

fic B

lue-

A

101 102 103 104 105101

102

103

104

10529.14% 0.49%

69.81% 0.56%

Specimen_001_Tube_002 ctr pep.fcs

PE-Cy7-A

Paci

fic B

lue-

A

101 102 103 104 105101

102

103

104

10530.74% 0.05%

69.09% 0.13%

Specimen_001_Tube_003 ESO pep.fcs

PE-Cy7-A

Paci

fic B

lue-

A

101 102 103 104 105101

102

103

104

10529.46% 0.17%

70.11% 0.26%

IFN-

CD

8

Specimen_001_Tube_002 ctr pep.fcs

APC-A

Paci

fic B

lue-

A

101 102 103 104 105101

102

103

104

10530.60% 0.18%

69.01% 0.21%

TNF-

CD

8

NY-ESO-1 peptidesControl peptides

# CDX‐1401

Adjuvant Pre Post

1

0.1 mg

Topical Resi

2 3 4 5 6 7 8 1

1.0 mg

Topical Resi

2 3 4 5 6 7 1

3.0 mg

Topical Resi

2 3 4 1

1.0 mg

Poly ICLC2 3 4 5 1

1.0 mg

S.C. Resi

2 3 4 5 6 1

1.0 mg

S.C. Resi +

Poly ICLC

2 3 4 5 6

On-going

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

Co-stimulatory molecule◦ Role in generation and long-term maintenance of T cell immunity◦ Role in NK cell differentiation/activation

CD27 activation:◦ Signaling through Traf2, Traf5◦ Activation of the NF-κB pathway◦ Cell survival, activation, proliferation

104 syngeneic CT26 cells inoculated s.c. in huCD27Tg mice on day 0Antibody treatment ‐ 600 g i.p. on days 3, 5, 7, 9, 11

1 11 21 31 41 51 61 71

mouse 11mouse 12mouse 13mouse 14mouse 15mouse 16mouse 17mouse 18mouse 19mouse 20

1 11 21 31


Tum

or V

olum

e (c

m3)

Saline CDX‐1127

Days Days

3

2

1

0

3

2

1

00 11 22 33 44 55 66 77


104 CT26 cells s.c. on day 0(day 99 relative to 1st inoculation)

1 11 21 31 41 51 61 71 81

mouse 11mouse 12mouse 13mouse 14mouse 15mouse 16mouse 17mouse 18

Re‐challenge

Days

3

2

1

0

3

2

1

0

Re‐challenge Controls

104 CT26 cells s.c. on day 0

Days

2000

3000

4000

1000Tum

or V

olum

e (m

m3 )

Days post tumor inoculation

No treatment

Control mAb, 0.1 mg/dose

CDX-1127 0.1 mg/doseCDX-1127 0.03 mg/dose

No treatment

Control mAb, 0.1 mg/dose

CDX-1127 0.1 mg/doseCDX-1127 0.03 mg/dose

5000

Treatment

CDX-1127 has direct efficacy on CD27-expressing human lymphoma cells in immuno-compromised (SCID) mice

Similar efficacy with other human B and T cell tumor lines- Daudi, Namalwa, CCRF-CEM

Xenograft model of human B lymphoblastic tumor cell line (Raji) in SCID mice

Flt3L: potent stem cell mobilizer and dendritic cell growth factor

Previous clinical studies (Immunex/Amgen) demonstrated safety and biological activity (>500 subjects dosed)

Program acquired from Amgen in 2009 Multiple clinical opportunities

Niro Anandasabapathy and Ralph Steinman

0102 103 104 1050

102

10310410564 4.8

2011

24 1.3

6510

0.34 33

643.1

0.18 1.3

899.1

CFSE

IFN

CFSE

IFN

D0 D10 D30 D40 D45-52Flt3L

DEC-205-HIVgag(p24)+PolyICLC

boost collect serum and splenocytes

Flt3L p24 PBS p24 Flt3L p17 PBS P17

Anti-p24 IgG

thomas davis, md celldex therapeutics,...

Documents