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


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


• 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)


CD95 Ligand Inhibitor APG101

CD95 ligand signaling

CD95 Ligand Signaling


• 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


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

10Jefferies Healthcare Conference 2015

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

June 2015 11Jefferies Healthcare Conference 2015

Ref.: www.trajectoryscifi.com

Recurrence DeathProgression

Second Line Therapy

No established standard therapies

First Line Therapy


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


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


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)


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


No

rmal

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po

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sH

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ato

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sin

MD

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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


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


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


Signaling

Defined receptor clustering leads to higher efficacy compared to antibodies


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


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

22Jefferies Healthcare Conference 2015June 2015

Contact Information

Apogenix GmbHIm Neuenheimer Feld 584D-69120 HeidelbergGermany

Telephone +49 (0)6221 586080Fax +49 (0)6221 5860810

www.apogenix.com

tnf superfamily modulators next generation …...tnf receptor super family signaling antagonists...

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