tnf superfamily modulators next generation …...tnf receptor super family signaling antagonists...
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June 2015
TNF Superfamily Modulators –Next Generation ImmunotherapyDr. Thomas Hoeger, CEO
Apogenix GmbH
• Founded in 2005 in Heidelberg, Germany, as a spin out from
• Focus on next-generation immunotherapeutic drugs for treatment of cancer
• Approach: Novel antibody-like Fc fusion proteins targeting TNF SF members
Status of Lead Compound APG101
• Proof of concept in recurrent glioblastoma (GB) shown
• Proof of principle and ongoing phase I in myelodysplastic syndromes (MDS)
• Mode of action broad applicability for treatment of solid tumors
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Company Overview
Jefferies Healthcare Conference 2015June 2015
Finance
• € 55.5m in four financing rounds
• € 8.5m public grants
• Upfront payment through partnering
Compound TNF SuperfamilyTarget
Indication Discovery Preclinical Phase I Phase II“PoC”
Phase III
June 2015 Jefferies Healthcare Conference 2015 3
Apogenix´ Pipeline 2015
Solid Tumors
Glioblastoma
MyelodysplasticSyndromes (MDS)
Solid Tumors
Solid Tumors
CD95 LigandAPG101
TRAIL ReceptorsAPG880
CD40 Receptoreg. APG1233
TNF SF Receptor Agonists
Market
TNF SF Inhibitors
Current status 2015 Partnered ProgramPoC: Proof of concept
Apogenix Targets TNF Superfamily Members
June 2015 Jefferies Healthcare Conference 2015 4
B7-1/B7-2
T-cell
APC* / Tumor cell
Checkpoint inhibitors have attractedconsiderable attention (e.g. PD-L1/PD-1)
Apogenix TNF SF modulators target receptor/ligand systems discovered ascheckpoints for cancer immunotherapy
MSD, AstraZeneca, Celgene, Roche, BMS, Merck-Serono, Regeneron, Novartis..
*APC: Antigen presenting cell
TNF Superfamily
TNF receptor super family signaling
AntagonistsReceptor - Fc fusion proteins
(eg. APG101)
Apogenix´ TNF Receptor Superfamily Modulators
June 2015 Jefferies Healthcare Conference 2015 5
• Signaling in the TNF receptor superfamily is stimulated by receptor multimerization after
interaction with the respective trimeric ligand
• Ligand members: TNF, CD95L, TRAIL, CD40L, OX40L, LIGHT etc.
ReceptorMultimerization
Signaling
Receptor
TrimericLigand
Apogenix TNF-SF Modulators
AgonistsHexameric receptor agonists
(eg. APG880)
Mode of Action:
• APG101 restores CD95 ligand-mediated
immune surveillance of solid tumors and
inhibits invasive cancer cell growth
APG101:
• Fully human Fc fusion protein
• Excellent safety profile
• Intravenous administration
(30 min., once weekly)
Clinical development:
• Immunotherapeutic mechanism of action
offers broad applicability in tumor indications
• Initial indication: Glioblastoma (brain tumor)
• Second indication: Myelodysplastic Syndromes
(disease of the bone marrow)
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CD95 Ligand Inhibitor APG101
CD95 ligand signaling
CD95 Ligand Signaling
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• Best described role of CD95L signaling is the regulation of T-cell homeostasis by
“activation-induced cell death”
• Cancer cells use this pathway to stimulate their own growth and migration and to evade
immune surveillance by killing immune cells
ReceptorMultimerisation
Signaling
CD95Receptor
CD95Ligand
APG101 – CD95 ligand inhibitor
CD95Receptor
CD95Ligand
APG101
No Signaling
• Endothelial cells of solid tumors and tumor cells express CD95L
– E.g., breast, colon, renal, bladder, prostate, ovarian cancer, glioblastoma
• APG101 binds to CD95L, thereby blocking its interaction with the CD95 receptor and protecting tumor-infiltrating immune cells from apoptosis (as shown by Motz et al.)
CD95 Ligand Inhibitor as Cancer Immunotherapy
June 2015 Jefferies Healthcare Conference 2015 8
CD95L positivetumor endothelia
CD
8 im
mu
ne
cells
Motz et al. 2014. Nat Med. 20: 607
CD95L negativetumor endothelia
CD
8 im
mu
ne
cells
(bro
wn
stai
nin
g)
CD95L negative tumors
CD95L positivetumors
Activated T CellsTumor cell T cell death
Activated T CellsTumor cell T cell survival
June 2015 9
Efficacy of APG101 Depends on the Presence of T cells
Survival of VMDK mice in GB SMA* model
Survival of athymic micein GB SMA model
Vehicle: 24 daysAPG101: 32 days
median OS
Vehicle: 20 days
APG101: 21 days
median OS
Survival proportions: Survival of Data 1
Time
Pe
rce
nt
su
rviv
al
0 20 40 600
50
100 vehicle
APG101
Time
Pe
rce
nt
su
r vi v
al
0 20 40 60
0
50
100
TimeP
erc
en
ts
ur v
i va
l
0 20 40 60
0
50
100
Jefferies Healthcare Conference 2015
Survival proportions: Survival of Data 1
Time
Pe
rce
nt
su
rviv
al
0 20 40 600
50
100 vehicle
APG101
*SMA: Spontaneous murine astrocytoma (cells)
+ APG101
APG101 Inhibits Invasive Growth of Tumor Cells
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Patient derived Tumor cell spheroid
• APG101 blocks invasion and proliferation of tumor cells
June 2015
In vitro migration (Matrigel)
+ APG101
In vivo migration (SMA GB Model)
APG101 in GB
• Orphan drug designation in US and EU
• High unmet medical need
• Positive feedback from regulatory authorities (EMA, FDA)
• Support from global KOLs (EU: e.g., Stupp, Weller, Wick; US: e.g., Reardon, Helman, Metha)
• Sales potential > 750 Mio US$
Aggressive brain tumor: Median overall survival 15 months
Standard first-line therapy: Surgery, radiation, Temodar
No approved drug treatment in EU for second-line therapy
Annual treatment costs, e.g., for Avastin approx. 100,000 US$
Incidence US/EU: 25,000 new cases p.a.; prevalence US/EU: 33,000
APG101 – Indication Glioblastoma
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Ref.: www.trajectoryscifi.com
Recurrence DeathProgression
Second Line Therapy
No established standard therapies
First Line Therapy
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Completed Phase II Study Design in Recurrent GB
Centralized, blinded data analysis(Magnetic resonance imaging, pathology)
Surgery/Temodar/RT
Biomarkeranalysis
Follow-upRandomization
(2:1)
56 patients
28 patients
Radiotherapy (18x 2 Gray)
Radiotherapy (18x 2 Gray)
+ APG101 weekly i.v.; 400mg
No further treatmentTumorTissue
• APG101 provides significantly better results compared to Gliadel and TMZ in
the two clinical trials that led to FDA approval in recurrent GB
Controlled Trials in Recurrent GB – TMZ & Gliadel
June 2015 Jefferies Healthcare Conference 2015 13
100
80
60
40
20
020100
Time (months)
Temozolomide
Procarbazine
p 0.33 n=225
Yung et al. (2000). British Journal of Cancer 83(5): 588
Gliadel Temozolomide (TMZ)
Brem et al. (1995). Lancet 345: 1008FDA Approval Letter, 2003
100
80
60
40
20
0403020100
Time (months)
Gliadel (Carmustine Wafer)
Placebo Wafer
HR 0.83 (95%CI 0.63-1.10); p 0.19, n=222
Surv
ival
(%)
Time (Months)
100
80
60
40
20
03528211470 42
Radiotherapy
Radiotherapy + APG101
HR 0.6 (95%CI 0.36-1.01); p 0.056, n=84
APG101
Wick et al. (2014). Clin. Canc. Res (20): 6304
• Treatment with APG101 significantly improved overall survival in patients carrying the
newly identified CD95L epigenetic biomarker
CD95L Identified as Predictive Biomarker in Glioblastoma
June 2015 Jefferies Healthcare Conference 2015 14
Biomarker APG101/RT (n=36) RT (n=19)
CD95L low methyl. Tumors Median (months) 16.1 7.3
Log rank Test p=0.029
CpG2 methylation Cox regression HR 0.31 (95% CI 0.13 – 0.76); p=0.0104
Survival in high methylated CD95L CpG2 Survival in low methylated CD95L CpG2
RT (n=8)APG101/RT (n=19)APG101/RT (n=17)
RT (n=11)
June 2015 Jefferies Healthcare Conference 2015 15
APG101 for Treatment of Myelodysplastic Syndromes(Low-Intermediate I Risk Disease)
http://nonbloodmedicalmanagement.blogspot.de/
Myelodysplastic Syndromes (MDS) = Disease of blood stem cells characterized by ineffective hematopoiesis, resulting in anemia, fatigue, life-threatening infections
Limited treatment options (best supportive care, e.g., blood transfusions)
Only few approved drugs for low-intermediate I classified patients
Standard of care: Transfusions; annual treatment costs at least 70,000 US$
Incidence US/EU: 35,000 new cases p.a.; prevalence US/EU >100,000
APG101 in MDS
• APG101 binds to CD95L in bone marrow of MDS patients, thereby protecting blood cell precursor cells from CD95 receptor mediated apoptosis (a.k.a. programmed cell death)
• Orphan drug designation in US
• High unmet medical need
• Peak sales potential > 800 Mio US$
• Myelodysplastic syndromes (MDS) are hematologic malignancies that are characterized by ineffective hematopoiesis, resulting in low red blood cell counts
• CD95 ligand has a key role in mediating hematopoietic commitment and homeostasis
CD95 Ligand in MDS
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No
rmal
H
em
ato
po
iesi
sH
em
ato
po
iesi
sin
MD
S P
atie
nts
Hematopoietic stem cell BFU-E*
Erythrocyte
BFU-E*: „Burst forming unit erythrocyte
CD95 ligand inhibits differentiation and development of erythrocytes in MDS patients
• APG101_CD_003: Phase I, Pharmacodynamic / MoA study; two dose levels; 19 patients
• Study patients were treated with APG101 for a period of 12 weeks; after cessation of therapy the patients were followed for 6 months
• Bone marrow biopsies were taken before start of treatment and then every 12 weeksuntil week 37
Clinical Phase I: APG101 in Low-Int1 MDS Patients
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APG101 Treatment (12 weeks) Observation period 24 weeks
BM Biopsy„Start of Study“
*EoT: End of treatment**EoS: End of Study***BM: Bone marrow
MDS patients
StudyEntry
BM Biopsy„End of Treatment“
Week 13
BM Biopsy„3 months after EoT“
BM Biopsy„End of Study“
Week 25 Week 37Week 1
„EoT*“ „EoS**“
Study Design
• The study CD_003 was designed to test the hypothesis that blocking the CD95 system in vivo using APG101 can improve erythropoiesis in low–int-1 risk MDS patients
APG101 Reduces Frequency of Transfusions in MDS Patients
June 2015 Jefferies Healthcare Conference 2015 18
Start of Study
Nu
mb
ero
ftR
BC
tran
sfu
sio
ns/
8 w
eeks
0
2,5
5
7,5
10
End of Study
Changes in transfusion frequencyduring the course of the study
*RBC-red blood cell
• Short term treatment with APG101 of transfusion dependent MDS patients who are unresponsive to EPO resulted in a remarkably reduced frequency of RBC* transfusions
• Interim data were presented at ASH 2014
• Novel Fc fusion proteins engineered on the basis of a
proprietary technology platform overcome limitations of
agonistic antibodies targeting the TNF-Receptor SF
(Tumor necrosis factor receptor superfamily)
• Conventional antibodies have two binding sites
• Apogenix´ compounds have six binding sites
• Binding of Apogenix´ compounds to receptors induces a
spatially well defined receptor assembly (clustering), thereby
triggering a strong intracellular signal leading to, e.g.,
apoptosis (programmed cell death)
Apogenix´ TNF Superfamily Hexavalent Receptor Agonists
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Signaling
Defined receptor clustering leads to higher efficacy compared to antibodies
June 2015 Jefferies Healthcare Conference 2015 20
Showcase: TRAIL Receptor Agonist APG880 (Partnered with AbbVie)
• Technology platform validated by comprehensive licensing agreement for TRAIL receptor
agonist APG880 with
• Apogenix retains rights to apply its technology for other TNF-SF family members, e.g.,
CD40, OX40, LIGHT, …
TRAIL Receptors
CellMembrane
APG880Antibody
Binding of APG880 to receptors induces a well defined receptor clustering, thereby triggering a strong intracellular signal leading to, e.g., apoptosis
Low clusteringcapacity
High clustering capacity
Compound TNF SuperfamilyTarget
Indication Discovery Preclinical Phase I Phase II“PoC”
Phase III
June 2015 Jefferies Healthcare Conference 2015 21
Development Plan until 2019
Solid Tumors
Glioblastoma
MyelodysplasticSyndromes (MDS)
Solid Tumors
Solid Tumors
Solid Tumors
CD95 LigandAPG101
TRAIL-ReceptorsAPG880
CD40 Receptoreg. APG1233
undisclosedCandidate B
TNF SF Receptor Agonists
Market
TNF SF Inhibitors
Current status 2015 Planned until 2019
PartneredPoC: Proof of concept
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Contact Information
Apogenix GmbHIm Neuenheimer Feld 584D-69120 HeidelbergGermany
Telephone +49 (0)6221 586080Fax +49 (0)6221 5860810
www.apogenix.com