ADVANCING INNOVATION TOWARDS BREAKTHROUGH CANCER THERAPIES - LISTED EURONEXT Paris NASDAQ Copenhagen - onxeo
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ADVANCING INNOVATION
TOWARDS BREAKTHROUGH
CANCER THERAPIES
LISTED
EURONEXT │ Paris
NASDAQ │ Copenhagen April 2019
EPA: ONXEO
Important Information IMPORTANT: You must read the following before continuing. In accessing this document, you agree to be bound by the following terms and conditions. This document has been prepared by Onxeo SA (together with its subsidiaries, the "Group") and is for information purposes only. The content of this document is provisional and for information purposes only and is not to be construed as providing investment advice. The information, statements and opinions contained in this document (the “Information”) are provided as of the date of this document only and may be subject to significant changes at any time without notice. Neither the Group, nor its advisors, nor any other person is under any obligation to update the Information. Subject to applicable law, none of the Company or its advisors accepts any responsibility whatsoever and makes no representation or warranty, express or implied, as to the fairness, accuracy, completeness or correctness of the Information. The Information has not been subject to independent verification and is qualified in its entirety by the business, financial and other information that the Group is required to publish in accordance with the rules, regulations and practices applicable to companies listed on Euronext Paris, including in particular the risk factors in the Company’s Registration Document filed with the French Financial Markets Authority (Autorité des marchés financiers) under number D.17‐0423 on April 24, 2017, in any other periodic report and in any other press release, which are available free of charge on the websites of the Group (www.onxeo.com) and/or the AMF (www.amf‐france.org). This document contains information on the use of the Group's products and its competitive position. Some of the Information is from third parties. While this third party information has been obtained from sources believed to be reliable, there is no guarantee of the accuracy or completeness of such data. 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Developing disruptive therapies in the field of tumor DNA Damage 3
Response (DDR) to address unmet needs in oncology
DIFFERENTIATED SCIENCE IN DNA DAMAGE STRONG SCIENTIFIC, TRANSLATIONAL
RESPONSE & CLINICAL CAPACITY
AsiDNA™, lead candidate at clinical stage, A highly skilled & experienced team of 35,
first‐in‐class agonist showing unique anti‐ with in‐house capabilities to lead
tumoral properties compounds from preclinical to proof‐of‐
PlatON™, proprietary chemistry platform of concept in man
decoy oligonucleotides, generating
new compounds
A WELL‐DEFINED BUSINESS MODEL NEXT KEY MILESTONES FUNDED
Create value through partnerships & product LISTED Financial resources (€13m at 09/30/2018)
in‐licensing and monetize these assets to EURONEXT │ Paris to support strategic plan, delivering near‐
NASDAQ │ Copenhagen
generate revenues. term clinical inflection points
EPA: ONXEO
An experienced management team and board of directors 4
JOSEPH ZAKRZEWSKI
Chairman of the Board
Former VP Corp. Development, Eli Lilly
& Venture Partner, Orbimed
JUDITH GRECIET (PHARM.D), CEO
(formerly Pharmacia, Wyeth, Eisai) JUDITH GRECIET DANIÈLE GUYOT‐CAPARROS
CEO Senior Advisor Deloitte Consulting
FRANCOISE BONO (PHD), CSO Chairman of Audit committee
(Sanofi, Evotec)
CHRISTINE GARNIER ELVIRA SANZ
OLIVIER DE BEAUMONT (MD), CMO Co‐Founder of AEC Partners Former President Pfizer
(Aventis, Quintiles, Stallergenes Greer) Strategic consulting Spain & Portugal
NICOLAS FELLMAN, CFO NICOLAS TREBOUTA THOMAS HOFSTAETTER
(Pfizer, Ernst & Young) representing Financière Former head of VaxInnate Corp
de la Montagne Chairman of BD committee
PHILIPPE MAITRE, EVP, CBDO
(Aventis, PPD, mAbRx) JEAN‐PIERRE BIZZARI JEAN‐PIERRE KINET
Former EVP Clinical Immunologist,
Oncology Celgene Harvard Medical School
Demonstrated track record in product development
as well as business development
Onxeo: a differentiated financing model, both demanding and 5
rewarding
BIOTECH FINANCING MODEL
Biotech model is different from traditional
services or product industries DISCOVERY/ ACQUISITION
PRECLINICAL ACTIVITIES
ROYALTIES
Investment during the development phase, 1 $$ $$
ROI comes from monetization of assets INVESTMENT Post‐market
through partnerships, licenses, royalties
RE‐INVESTMENT $$ Continued
Key factors of success development to
market
Flawless development design to build a convincing data REVENUE
3 PARTNERSHIP,
package for potential partners
2 INVESTMENT LICENSE
Thoughtful selection of priority indications for early $$ $$ $$ $$
clinical development, such as orphan indications or EARLY‐STAGE
UPFRONT,
acute unmet needs, to accelerate ROI CLINICAL MILESTONES
DEVELOPMENT
Disciplined allocation of cash towards value‐generating
development activities, careful control of overhead
Leading‐edge R&D pipeline with unique mechanisms of action in DDR 6
Programs OPTIMIZATION PRECLINICAL PHASE I PHASE II PHASE III MARKET
platON™ Proprietary Platform GENERATION OF DISRUPTIVE COMPOUNDS TARGETING DNA‐BINDING FUNCTIONS
OX402 in Q1 2019
DNA Damage Response
Decoy Oligoucleotides
AsiDNA™ + radiotherapy
Local (IT) administration. DRIIM study in metastatic melanoma
AsiDNA™
Systemic (IV) administration.
DRIIV study in solid tumors
AsiDNA™ + PARPi Solid tumors
AsiDNA™ + chemotherapy Solid tumors
Epigenetics
Beleodaq®2 2nd line PTCL3 US4
belinostat + platON™ Solid tumors
1 IT: intratumoral – IV: intravenous 4 Commercialized in the US by Spectrum Pharmaceuticals (SPPI) Onxeo’s partner and holder of the conditional
2 Beleodaq®: commercial brand name of belinostat (IV form) in the US in r/r PTCL market authorization from the FDA for the use of Beleodaq® in the treatment of 2nd line PTCL
3 4 PTCL : Peripheral T‐cell lymphoma – a rare form of blood cancer
Sustained interest from pharma companies for very innovative and 7
promising early‐stage projects in oncology
Most deals are signed after Phase I as the product has DNA‐related projects are the new and upcoming field of
proven its safety and before the commitment to a Phase III interest, with the rarity of quality projects generating high
Phase II i.e. ‘proof‐of‐concept’ stage offers the best deal values, on par with immuno‐oncology
risk/reward balance to both pharma and biotech companies 1200 $m total deal value
$m total deal value 1000
1800
1600 Ph1 Ph2 Ph3 AsiDNA™
800
1400 field
3rd quartile 1200 600
1000
800
1st quartile 400
600
400
200
200
Mean upfront payment ($m) 83 121 63
0
0
Nb. of deals in Oncology 1 24 224 3
17
Deals with published
7/ 5 14/ 12 8/8
financials / upfront
Phases I and II drive the highest deal values
Onxeo analysis based on Clarivate Cortellis databse,. Public data with published values only ‐ 2013‐2017 by phase – 2014‐2018 by field
AsiDNA™ is a first‐in‐class product in DNA Damage Response 8
A synthetic cholesterol‐oligonucleotide conjugate forming an intramolecular hairpin
32‐base pair double helix
Active 32 bp DNA duplex
Genomic DNA length optimized to bind and
Cholesterol
IP
activate DNA‐PK and PARP signaling enzymes 3’ 5’ Efficient tumoral and nuclear uptake
of the DNA is mediated via a
Phosphorothioate substitutions at the 5’ and 3’
covalently linked cholesterol
Patent Protection ends to prevent degradation1
molecule2
(Composition of Double‐stranded 32 bp DNA is tethered with a loop
Matter on AsiDNA™ & to prevent disassociation1
related compounds) Sequence not specific, chosen to be non‐
until 2031. homologous and not immunogenic (CpG‐free) 3’
5’
Molecular weight: 22’359.2 daltons Loop
Extendable to 2036
with SPC & PTE.
Robust GMP manufacturing process scaled up to 1.7kg, long shelf stability
No formulation needed to achieve sufficient plasmatic and tumor exposure after
intravenous administration confirmed in vivo as well as in DRIIV‐1 trial
1. Quanz M, et al. PLoS ONE. 2009 4(7), doi: 10.1371/journal.pone.0006298
2. Berthault N, et al. Cancer Gene Therapy (2011), 1‐12, doi: 10.1038/cgt.2011.3
AsiDNA™ is the only decoy agonist in development that disrupts and 9
exhausts the tumor DNA Damage Response
AsiDNA™ mimics DNA breaks in the tumor cell, hyperactivates and then binds the proteins needed for the DDR cascade of
cellular events (sensing, signaling and repairing), diverting the DDR proteins away from the true damage. 1,2,3
AsiDNA™ is not a targeted DDRi (as other DDRi currently in development): it acts upstream of the DDR cascade on multiple
repair pathways, is active regardless of genetic mutations and does not induce resistance in tumor cells
AsiDNA™ is potentially complementary to other anti‐cancer agents, including other DDR targeted therapies
1 AsiDNA™ sends false alarms 3 Actual tumor DNA damage is not
throughout the tumor cell nucleus
repaired and accumulates: cancer cells
(decoy) and then activates and binds
die when dividing with a damaged DNA.
key components of the DNA Damage
Response.
2 This sustained artificial DNA damage
signaling (agonist effect) leads to
AsiDNA™ is not active in healthy cells
exhaustion of the tumor DNA repair
which stop dividing until the false alarm
machinery
disappears.
1. Quanz M, et al. Clin Cancer Res 2009 15:1308‐1316;
2. Quanz M, et al. PLoS ONE. 2009 4(7), doi: 10.1371/ journal.pone.0006298;
3. Jdey W, et al. Oin Can Res. 2016;22:DOI: 10.1158/ 1078‐0432.CCR‐16‐1193
AsiDNA™
Clinical data and
perspectivesAsiDNA™ differentiating features validated in both preclinical and 11
clinical studies*
Preclinical package confirming unique properties of AsiDNA™ alone and in combination*
Repeated treatment with AsiDNA™ leads to sensitization to AsiDNA™ and does not generate resistance
Resistance to PARPi treatment is prevented by co‐treatment with AsiDNA™
Strong synergy of AsiDNA™ in combination with PARPi
Strong synergy of AsiDNA™ in combination with carboplatin
Efficacy and safety demonstrated in man via local administration
Proof‐of‐mechanism and activity in man via IV administration
59% Overall RR in metastatic melanoma (AsiDNA™ + radiotherapy) via IT route
Active doses at 400 and 600 mg via IV
Favorable safety profile
No drug‐related serious adverse events
No MTD
*Data published, submitted for publication or on file at OnxeoDRIIM study: demonstration of an anti‐tumoral efficacy 12
Proof of concept established in completed DRIIM Phase I trial1:
Intratumoral administration + radiotherapy in metastatic melanoma
Overall response rate = 59%3
Complete response = 30%3 (CR from low‐dose radiotherapy alone less than 10%2)
Partial response = 29%3
Durable response (up to 12‐month follow‐up period)
Before treatment 90 days after treatment
IT administration of AsiDNA™: confirmed safety, signal of efficacy, systemic passage suggested
Evaluation of AsiDNA™ via intravenous administration in solid tumors
1. Le Tourneau et al. Br J Cancer. 2016 May 24;114(11):1199‐205 ; 2. Olivier et al., Cancer 2007; Konefal et al., Radiology 1987 ; 3. % of lesionsDRIIV‐1 study: evaluating AsiDNA™ via IV administration
13
DNA Repair Inhibitor administered IntraVenously in patients with advanced solid tumors
(in patients failing previous anticancer therapies)
APRIL 2018 Q4 2018 H1 2019
PHASE I FIRST PATIENT DOSED BIOACTIVITY END OF STUDY
Open‐label, 3+3 dose
escalation 1800 mg
ACTIVE DOSES 1300 mg Dose Level 6
2 European countries: FR, BE 900 mg Dose Level 5
5 centers: Paris(2),Toulouse, 600 mg Dose Level 4
400 mg Dose Level 3 6 patients
Lyon, Brussels
200 mg Dose Level 2 3 patients
Study coordinator: Pr. C. Le Last tested dose
Dose Level 1 4 patients
Tourneau (Institut Curie)
3 patients
DSMB
November 5, 2018
1‐hour IV infusion
TREATMENT SCHEDULE DAY 1 2 3 8 15 21 CYCLE 2 and beyond : once a week
CYCLE 1
OBJECTIVES To determine dose‐limiting toxicities (DLTs) and the maximum tolerated dose (MTD)
To evaluate the pharmacokinetics/pharmacodynamics (PK/PD) effects of AsiDNA™ based on biomarkers of activity in
blood and in tumor tissues
Compelling safety & activity observed as early as dose level 2DRIIV‐1 study: interim results (DL1 to DL3 completed) 14
Safety
AsiDNA™ 200mg (DL1), 400 mg (DL2) & 600 mg (DL3)
(n = 10 patients / infusions = 112)
Drug‐related AE
No drug‐related serious adverse events
No dose‐limiting toxicity Grade 1
Grade 2
No cumulative relevant safety
Only grade 1 & 2 drug‐related adverse events
Maximum tolerated dose not reached
AsiDNA™ favorable safety profile confirms positive regulatory toxicity studies
No genotoxicity
No issue in regulatory toxicity studies, incl. 4‐week study in animal (NOAEL: 100 mg/kg)
Maximum tolerated dose not reached
Favorable safety profile at active doses providing a comfortable therapeutic window
Source: Onxeo, data on fileDRIIV‐1: interim results (DL1 to DL3 completed) 15
Pharmacokinetics
Dose proportionality across the 3 dose levels
Dose Cmax AUC (t0‐tlast)
(mg) (µg/mL) (µg.h/mL)
200 41,8 110,9
400 76,9 161,6
600 129,4 247,1
Cmax and AUC are increased proportionally and consistently with dosing
Source: Onxeo, data on fileDRIIV‐1: interim results (DL1 to DL3 completed) 16
Pharmacodynamics ‐ Proof‐of‐Mechanism in man
Analysis of the first 3 dose levels out of 6 planned
Target engagement confirmed by significant increase
10 patients
Activity of activity biomarkers* from dose level 2 and 3
4 biopsies available at baseline and end of cycle 2
= Proof‐of‐Mechanism of AsiDNA™ in man
Activity biomarkers Activity biomarkers
Tumor proliferation Tumor proliferation
DL2 : 400mg H2AX pHSP90 DL3 : 600mg H2AX pHSP90
biomarker biomarker
DL2 : 400mg KI67 DL3 : 600mg KI67 Patient 0106 Patient 0202
Patient 0106 Patient 0202 Patient 0109 Patient 0301
Patient 0109 Patient 0301
Significant increase after treatment with AsiDNA™
Major increase after treatment with AsiDNA™
Decrease or stabilization of tumor proliferation Tumor
rate from dose level 2 and 3 status
Robust target engagement in patients’ tumors demonstrates
AsiDNA™ activity via IV route
Source: Onxeo, data on file
* H2AX and pHSP90 are two established biomarkers of the activation of DNA‐PK, a key DDR enzyme and a major target for AsiDNA™AsiDNA™, a highly differentiated molecule with near‐term clinical 17
milestones
AsiDNA™: a unique Exhaustive and robust Established proof‐of‐
mechanism of action preclinical package mechanism in man, strong
enabling a new approach showing product wide activity, favorable safety,
to cancer treatment potential in combination active doses found
(PARPi, chemos…)
Ready for expanded clinical development in combination
Final data from DRIIV‐1 Phase 1 trial
H1 2019 Initiation of a Phase 1b study in combination
with platinum‐based chemotherapies
H2 2019 Initiation of IND filing in the USAsiDNA™
Robust preclinical &
translational data set supporting
use in combination
as well as in monotherapyAsiDNA™ leads to cancer cell death and does not induce resistance 19
Treatment with AsiDNA™ reduces cancer cells In contrast to targeted therapies (e.g. PARPi),
survival (1‐30µM IC50), while healthy cells are repeated treatment with AsiDNA™ leads to
spared sensitization to AsiDNA™ and does not generate
resistance
Non tumoral cell lines MDAMB231 – TNBC HR proficient BC227 – TNBC HR BRCA1 mutated NCI‐H446 – SCLC
(PARPi are ineffective on this cell line) BC227 NCI-H446
AsiDNA Talazoparib Olaparib
AsiDNA Talazoparib
AsiDNA 120 120
100 100
Survival (%/NT)
Survival (%/NT)
80 80
AsiDNA
60 60
40 40
20 20
0 0 *
1st cycle 2nd cycle 3rd cycle 4th cycle 1st cycle 2nd cycle 3rd cycle 4th cycle
Suggests a compelling opportunity as a maintenance therapy
Source: Onxeo, data on fileAsiDNA™ plus PARPi generates synergies in both HR deficient and 20
proficient cancer cells and prevents resistance to PARPi
AsiDNA™ in combination with PARPi
shows the same efficacy in both HR deficient and proficient cancer cells; combining AsiDNA™ with PARPi may
expand PARPi’s use to HR‐proficient tumors
leads to a rapid and complete inhibition of cancer cell survival, which is not observed with PARPi alone
(synergistic effect)
prevents at low doses the occurrence of resistance in several cancer cell lines
TNBC HR deficient SCLC
Talazoparib AsiDNA+Talazoparib
Olaparib Talazoparib
AsiDNA+Olaparib AsiDNA+Talazoparib
140 100
120
80
Survival (%/NT)
Survival (%/NT)
100
80 60
60 40
40
20
20
0 0
1st cycle 2nd cycle 3rd cycle 4th cycle 1st cycle 2nd cycle 3rd cycle 4th cycle
Olaparib 5 µM ‐ Talazoparib 100nM ‐ AsiDNA™ 1µM Talazoparib 100nM – AsiDNA™ 1µM
Source: Onxeo, data on fileCombination of AsiDNA™ with PARPi demonstrates synergy in HR 21
proficient TNBC
AsiDNA™ in combination with PARPi shows high efficacy in vivo in cancer cells non‐sensitive to PARPi
Opportunity to expand PARPi indications to HR proficient tumors
MDA‐MB‐231 (TNBC HR proficient tumor cells) xenograft in mice
NT olaparib AsiDNA™ AsiDNA™ + olaparib
Complete Response = 0/6 Complete Response = 2/8 Complete Response = 4/8 Complete Response = 5/7
0% 25% 50% 71%
Source: Onxeo, data on fileClass‐effect of the combination of AsiDNA™ with PARPi’s supported 22
by extensive preclinical testing
Tumor model
Treatment in combination Observed effect Reference
(cell lines, primary tumors)
TNBC (MDA‐MB‐231 AsiDNA™ + olaparib Complete response more than doubled Data on file
xenograft mice model)
Resistant PDX ovarian model AsiDNA™ + olaparib Synergy delaying tumor growth Data on file
TNBC HR deficient (BC 227) AsiDNA™ + olaparib or + talazoparib Resistance is prevented by co‐treatment Data on file
Ovarian cancer AsiDNA™ + niraparib Resistance is prevented by co‐treatment Data on file
SCLC (NCI‐H446) AsiDNA™ + talazoparib Resistance is prevented by co‐treatment Data on file
TNBC HR deficient (BC 227) AsiDNA™ + talazoparib Rapid and complete inhibition of cancer cell survival Data on file
SCLC (NCI‐H446) AsiDNA™ + talazoparib Rapid and complete inhibition of cancer cell survival Data on file
TNBC HR proficient (MDAMB231) AsiDNA™ + talazoparib Synergistic antitumor effect Data on file
TNBC HR proficient (MDAMB231) AsiDNA™ + niraparib Synergistic antitumor effect Data on file
TNBC HR proficient (MDAMB231) AsiDNA™ + olaparib Synergistic antitumor effect Data on file
Both synergy and abrogation of resistance to treatment occur
with all tested PARPi and regardless of the tumor type,
opening new opportunities for clinical applicationsCombination of AsiDNA™ with carboplatin generates synergies and 23
prevents resistance to carboplatin
AsiDNA™ in combination with carboplatin
shows a synergistic effect in terms of efficacy
prevents the occurrence of resistance to carboplatin
NCI-H446 Carboplatine
- SCLC
120
NT
100 Carboplatin
Carboplatine
Survival (%/NT)
80
carboplatin
AsiDNA+Carboplatine
[AsiDNA™]: 2,5µM [carboplatin]: 2,5µM
60
40
20
0
e
e
e
e
e
cl
cl
cl
cl
yl
cy
cy
cy
cy
tc
d
d
h
h
1s
2n
4t
5t
3r
Source: Onxeo, data on fileCombination of AsiDNA™ with carboplatin shows synergy 24
in resistant TNBC
d - XX graft Endpoint
MDA‐MB‐231 (TNBC HR proficient tumor cells) xenograft in mice 1500 mm3
1000 Week 1 Week 4 Week 7
Group I : vehicle (Nacl 0.9%)
900 Group II : AsiDNA (IP)
Group III : carboplatin (IP)
800
Group IV : AsiDNA (IP)
700 + carboplatin (IP)
Mean volumes (mm3)
600
500 Treatment Median survival
(days)
400 Vehicle NaCl 0,9% 15x IP (n 6) 77
300 Carboplatin 3x 50 mg/kg IP (n 8) 88
AsiDNA 15x 5 mg IP (n 8) 128
200 1/7 complete response
AsiDNA 15x 5mg IP
2/7 stable diseases 175
100 + carboplatin 3x 50mg/kg IP (n 10)
0
0 10 20 30 40 50 60 70 80 90 100
Time after treatment (days)
Source: Onxeo, data on fileData support increased efficacy of the combination of AsiDNA™ with 25
DNA‐damaging agents in multiple in vivo models
Tumor model
Treatment in combination Route of administration Reference
(cell lines, primary tumors)
Breast cancer (BC227, BC173, MDA‐ Intratumoral + Peritumoral Subcutaneous
MB468, MDA‐MB231) AsiDNA™ standalone Intraperitoneal (MDA‐MB231) Data on file
Breast cancer (MDAMB231, BC227) AsiDNA™ + carboplatin Intraperitoneal Data on file
Glioblastoma AsiDNA™ + Radiotherapy Intratumoral Coquery et al, 2012
Subcutaneous / Peritumoral Schlegel et al, 2012
Cutaneous melanoma AsiDNA™ + Radiotherapy Intratumoral + subcutaneous / Peritumoral Biau et al, 2014
Colorectal cancer AsiDNA™ + RFA (hyperthermia) Intratumoral + subcutaneous Devun et al, 2014
Colorectal Liver metastasis (HT29) AsiDNA™ + 5FU + oxaliplatin Intraperitoneal Herath et al, 2016
HCC (HepG2) AsiDNA™ + doxorubicin Intraperitoneal Herath et al, 2016
Head & neck (Hep2) AsiDNA™ + Radiotherapy Intratumoral Quanz et al, 2009
Head & Neck (Hep2) AsiDNA™ + carboplatin Intraperitoneal Data on file
Lung cancer (TC‐1) AsiDNA™ + carboplatin or cisplatin Intraperitoneal Data on file
HCC (VX2 rabbit) AsiDNA™ + TACE (Doxorubicin) Transarterial Herath et al, 2016Confirmed predictive biomarkers available for patient stratification 26
AsiDNA™ sensitivity signature
(bioinformatics analysis from transcriptomic
experiments1) displays a down regulation of
the expression of most DNA repair genes
In vitro validation of this sensitivity signature on 20 cells lines predicted to be more or less sensitive to AsiDNA™2
**
120
Survival to AsiDNA (%/NT)
100
80
60 Confirmation by qPCR analysis3 of the
40 down regulation of 6 genes in cancer cells
highly sensitive to AsiDNA™
20
0
Predicted resistant Predicted sensitive
Confirmed predictive biomarkers of sensitivity to AsiDNA™ open the way
to personalized medicine applications, in monotherapy as well as in combination
Source: 1 Jdey W et al., Clinical Cancer Research 2017 ‐ 2 from Cancer Cell Line Encyclopaedia CCLE sorted by AsiDNA™ ‐ 3 Onxeo, data on fileAll studies of AsiDNA™ to date support its potential in broad 27
indications and combinations
with PARP inhibitors with DNA‐damaging chemotherapies
• Synergistic efficacy observed in vivo
• Synergistic efficacy observed in vivo, including in • 10 to 20% of all cancer patients are treated with
HR proficient tumors platinum‐based chemotherapies
• Indications: OC (ODD), HER2‐ BC • Indications: OC (ODD), SCLC (ODD), NSCLC , HNC
• Strong rationale for use as maintenance therapy (ODD), TNBC.
≈ 550,000 patients1 ≈ 1.3 Million patients2
(incident population in 8MM)* (incident population in 8MM)*
as a monotherapy with radiotherapy
• Selection of the best responding patients with • 50‐60% of cancer patients treated with radiation
stratification biomarkers therapy during the course of their disease
• DRIIM phase 1 study clinical signals of efficacy
To be determined ≈ 3.8 Million patients3
(incident population in 8MM)*
Unique mechanism of action positions AsiDNA™ at the heart of DDR strategies in oncology
HR: Homologous recombination ‐ OC: Ovarian cancer ‐ (TN)BC: (Triple negative) Breast cancer ‐ (N)SCLC: (Non) Small cell lung cancer ‐ HNC: Head & neck cancer ‐ ODD:
Orphan Drug Designation ‐ 1: OC + HER2 Neg BC (both BRCA wild‐type) 2: OC + (N)SCLC + TNBC + HNC 3: All cancers (55% of incidence) *: Company’s estimates in 8
Major Markets (8MM) after GlobalData reports and Globocan 2018 dataPLATON™
CHEMISTRY PLATFORM
OF DECOY OLIGONUCLEOTIDES
Leverage proprietary decoy
oligonucleotides technology to
generate new breakthrough
compounds in oncologyplatON™: proprietary chemistry platform of decoy 29
OligoNucleotides
All three components of the platform can be acted upon to obtain new compounds with different
properties and/or activities
1 3
Oligonucleotide* Vector
2
Linker
Active component Prevention of Spontaneous uptake by cells,
of the molecule strand dissociation no need for a transfection vector
A powerful and versatile platform to generate disruptive compounds
acting on intracellular DNA‐binding targets
* oligonucleotide: ADN fragmentplatON™: broad potential beyond AsiDNA™ with the opportunity to 30
feed the pipeline with differentiated new drug candidates
Objectives for upcoming products from platON™
Regulation of tumor DNA functions through a decoy
mechanism
Decoy oligonucleotides able to induce cancer cell death and
trigger immune response within the tumor, without any effect
on healthy cells 1 3
Oligonucleotide Vector
Clinical positioning clearly differentiated from the one of
AsiDNA™
2
Evaluation of several compounds ongoing Linker
Next candidate to enter regulatory preclinical studies
mid‐S1 2019
In‐vivo proof of concept expected mid yearFINANCIALS & OUTLOOK
Financials and share structure 32
Cash position of €11.3m at 12/31/2018
Dual listing Euronext Paris & Nasdaq Copenhagen
Misc.
ISIN: FR0010095596 5%
Financière
de la
Montagne
16%
Shares outstanding 54,1m Retail
Fully diluted* 59,6m 60%
Average Daily Volume 333,390 Other
(18 months) shares institutions
19%
*at 01/31/19 at 01/31/19Multiple near to mid‐term value‐creating R&D milestones 33
AsiDNA™ New compound from platON™
Q4 18 DRIIV Phase 1 study: proof‐of‐mechanism in man & active doses found
Today
Confirmation of predictive biomarkers for patient stratification for studies in New compound from platON™ enters
monotherapy / combination regulatory preclinical evaluation and CMC
Scientific presentation at DDR international conference end January (Boston)
and presence at other key international conferences (AACR, …)
DRIIV‐1 full data set (tolerance, PK/PD, biomarkers…)
First patient dosed in a combination phase 1b study
In‐vivo proof‐of‐concept
June 2019
Results of the first combination study with chemotherapies
IND filing in the US
December 2019
« First‐in‐man » in phase 1 study
Other studies in combination
June 2020APPENDICES
AsiDNA™ Publications (1/2) 35 Small‐molecule drugs mimicking DNA damage: a new strategy for sensitizing tumors to radiotherapy. Quanz M, Berthault N, Roulin C, Roy M, Herbette A, Agrario C, Alberti C, Josserand V, Coll JL, Sastre‐Garau X, Cosset JM, Larue L, Sun JS, Dutreix M. Clin Cancer Res. 2009, 15:1308‐16. Hyperactivation of DNA‐PK by double‐strand break mimicking molecules disorganizes DNA damage response. Quanz M, Chassoux D, Berthault N, Agrario C, Sun JS, Dutreix M. PLoS One. 2009, 4:e6298. Comparison of distribution and activity of nanoparticles with short interfering DNA (Dbait) in various living systems. Berthault N, Maury B, Agrario C, Herbette A, Sun JS, Peyrieras N, Dutreix M. Cancer Gene Ther. 2011, 18:695‐706. Heat shock protein 90 (Hsp90) is phosphorylated in response to DNA damage and accumulates in repair foci. Quanz M, Herbette A, Sayarath M, de Koning L, Dubois T, Sun JS, Dutreix M. J Biol. Chem. 2012, 287:8803‐15. Preclinical study of the DNA repair inhibitor Dbait in combination with chemotherapy in colorectal cancer. Devun F, Bousquet G, Biau J, Herbette A, Roulin C, Berger F, Sun JS, Robine S, Dutreix M. J Gastroenterol. 2012, 47:266‐75. Pharmacokinetics and toxicity in rats and monkeys of coDbait: a therapeutic double‐stranded DNA oligonucleotide conjugated to cholesterol. Schlegel A, Buhler C, Devun F, Agrario C, Urien S, Lokiec F, Sun JS, Dutreix M. Mol Ther Nucleic Acids. 2012, 1:e33. Distribution and radiosensitizing effect of cholesterol‐coupled Dbait molecule in rat model of 5 glioblastoma. Coquery N, Pannetier N, Farion R, Herbette A, Azurmendi C, Clarencon D, Bauge S, Josserande V, Rome C, Coll JL, Sun JS, Barbier EL, Dutreix M, Remy CC. PLoS One, 2012, e40567. Therapeutic approach of human peritoneal carcinomatosis with Dbait in combination with capnoperitoneum: proof of concept. Solass W, Herbette A, Schwarz T, Hetzel A, Sun JS, Dutreix M, Reymond MA. Surg Endosc. 2012, 26:847‐52. Kinesin KIFC1 actively transports bare double‐stranded DNA. Farina F, Pierobon P, Delevoye C, Monnet J, Dingli F, Loew D, Quanz M, Dutreix M, Cappello G. Nucleic Acids Res. 2013, 41:4926‐37. Inhibition of DNA damage repair by artificial activation of PARP with siDNA. Croset A, Cordelières FP, Berthault N, Buhler C, Sun JS, Quanz M, Dutreix M. Nucleic Acids Res. 2013, 41:7344‐55. DNA‐PK target identification reveals novel links between DNA repair signaling and cytoskeletal Regulation Kotula E, FaigleW, Berthault N, Dingli F, Loew D, Sun JS, DutreixM and Quanz M PLoS One, 2013, 8:e80313. Colorectal cancer metastasis: the DNA repair inhibitor Dbait increases sensitivity to hyperthermia and improves efficacy of radiofrequency ablation. Devun F, Biau J, Huerre M, Croset A, Sun JS, Denys A, Dutreix M. Radiology. 2014, 270:736‐46.
AsiDNA™ Publications (2/2) 36 A preclinical study combining the DNA repair inhibitor Dbait with radiotherapy for the treatment of melanoma. Biau J, Devun F, Jdey W, Kotula E, Quanz M, Chautard E, Sayarath M, Sun JS, Dutreix M. Neoplasia. 2014, 16:835‐44. Science to practice: why debate the role of Dbait for improving tumor ablation? Goldberg SN. Radiology. 2014 Mar; 270(3):635‐7. Pressurized intraluminal aerosol chemotherapy with Dbait in the distal esophagus of swine. Khalili‐Harbi N, Herath N, Solass W, Giger‐Pabst U, Dutreix M, Reymond MA. Endoscopy 2015; 47:1‐4. Dbait : un concept innovant pour inhiber la réparation de l’ADN et contribuer aux traitements des cancers. J Biau, F Devun, P Verrelle, M Dutreix, Bull Cancer 2016; 103: 227–235 The DNA Repair Inhibitor DT01 as a Novel Therapeutic Strategy for Chemosensitization of Colorectal Liver Metastasis. Herath NI, Devun F, Lienafa MC, Herbette A, Denys A, Sun JS, Dutreix M. Mol Cancer Ther. 2016 Jan;15(1):15‐22. In Vivo feasibility of Electrostatic Precipitation as an Adjunct to Pressurized Intraperitoneal Aerosol Chemotherapy (ePIPAC). Kakchekeeva T, Demtroder C, Herath NI, Griffiths D, Torkington J, Solass W, Dutreix M, Reymond MA. Ann Surg Oncol. 2016 Dec; 23(Supp5):592‐598. Targeting DNA repair by coDbait enhances melanoma targeted radionuclide therapy. Viallard C, Chezel JM, Mishellany F, Ranchon‐Cloe I, Pereira B, Herbette A, Besse S, Boudhraa Z, Jacqemot N, Cayre A, Miot‐Noirault E, Sun JS, Dutreix M, Degoul F. Oncotarget 2016 Mar 15;7(11): 12927‐36. Potentiation of Doxurubicin efficacy in hepatocellular carcinoma by the DNA repair inhibitor DT01 in preclinical models. Herath NI, Devun F, Herbette A, Linafa MC, Chouteau P, Sun JS, Dutreix M, Denys A. Eur Radiol. 2017 Oct, 27(10):4435‐4444. ASCO 2015 annual meeting. Abstract #143029. First‐in‐human phase I study of the DNA repair inhibitor DT01 in combination with radiotherapy in patients in transit melanoma. Le Tourneau C, Dreno B, Kirova Y, Grob JJ, Jouary T, Dutriaux C, Thomas L, Lebbé C, Mortier L, Saiag P, Avril MF, Maubec E, Joly P, Bey P, Cosset JM, Sun JS, Asselain B, Devun F, Marty ME, Dutreix M. Br J Cancer. 2016 May 24;114(11):1199‐205. Drug Driven Synthetic Lethality: bypassing tumor cell genetics with a combination of AsiDNA and PARP inhibitors. Jdey W, Thierry S, Russo C, Devun F, Al Abo M, Noguiez‐Hellin P, Sun JS, Barillot E, Zinovyev A, Kuperstein I, Pommier Y, Dutreix M. Clin Cancer Res. 2017 Feb 15;23(4):1001‐1011. doi: 10.1158/1078‐0432.CCR‐16‐1193. Epub 2016 Aug 24. Micronuclei Frequency in Tumors Is a Predictive Biomarker for Genetic Instability and Sensitivity to the DNA Repair Inhibitor AsiDNA. Jdey W, Thierry S, Popova T, Stern MH, Dutreix M. Cancer Res. 2017 Aug 15;77(16):4207‐4216. doi: 10.1158/0008‐5472.CAN‐16‐2693. Epub 2017 Jun 6. The DNA Repair Inhibitor Dbait Is Specific for Malignant Hematologic Cells in Blood. Thierry S, Jdey W, Alculumbre S, Soumelis V, Noguiez‐Hellin P, Dutreix M. Mol Cancer Ther. 2017 Dec;16(12):2817–27.
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