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DNA FUNCTIONS TOMORROWS NEW HOPE AGAINST RESISTANT CANCER LISTED - - PowerPoint PPT Presentation
TODAYS SCIENCE TARGETING TUMOR DNA FUNCTIONS TOMORROWS NEW HOPE AGAINST RESISTANT CANCER LISTED EURONEXT Paris NASDAQ Copenhagen EPA: ONXEO Important Information IMPORTANT: You must read the following before continuing. In
EURONEXT │ Paris NASDAQ │ Copenhagen EPA: ONXEO
June 2020 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 June 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. 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The Group expressly declines any obligation to update or to confirm projections or estimates made by analysts or to make public any correction to any prospective information in order to reflect an event or circumstance that June occur after the date of this document.
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NEXT KEY MILESTONES FUNDED
Financial visibility to Q1 2022 supports strategic plan to deliver key near-term clinical milestones
STRONG MANAGEMENT & OPERATIONAL TEAM
A highly skilled team of 30, with strong translational & clinical expertise, led by experienced management and board of directors with demonstrated track record in product & business development
DIFFERENTIATED SCIENCE IN DNA DAMAGE RESPONSE
PlatON™, proprietary chemistry platform of decoy
AsiDNA™, lead candidate at clinical stage, a first-in-class decoy agonist showing unique anti-tumoral properties OX401, a newly optimized next-gen PARPi*
A WELL-DEFINED BUSINESS MODEL
Create value by bringing drug candidates from preclinical stage to proof-of concept in man, the best inflection points to monetize these assets and generate revenues.
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* PARP inhibitors (PARPi) are a leading class of targeted therapies, the first approved and marketed in the field of DDR
June 2020
FRANCOISE BONO (PHD) CSO (Sanofi, Evotec) Formerly Executive Vice-President Oncology
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JUDITH GRECIET (PHARM.D) CEO OLIVIER DE BEAUMONT (MD) CMO (Aventis, Quintiles, Stallergenes Greer) Formerly Senior Vice President, Head of Global Clinical Development, Pharmacovigilance and Medical Affairs ofStallergenes Greer PHILIPPE MAITRE EVP of Onxeo US, CBDO (Aventis, PPD, Oscient, mAbRx) Formerly Chief Executive Officer and Co- Founder of mAbRx NICOLAS FELLMANN CFO (Ernst & Young, Pfizer) Formerly Director of Treasury, Tax & Audit of Pfizer France (Pharmacia, Wyeth (Pfizer), Eisai) Formerly President of Eisai France
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Programs
OPTIMIZATION PRECLINICAL PHASE I PHASE Ib PHASE II
platON™ Proprietary Platform of Decoy Oligonucleotides OX401
Next-gen PARPi + STING pathway activation
AsiDNA™ intratumoral AsiDNA™ + chemotherapy Synergistic efficacy AsiDNA™ + PARPi Resistance abrogation AsiDNA™ + other targeted tx Resistance abrogation/ prevention
DRIIV -1b
DRIIV study in solid tumors
GENERATION OF NEW COMPOUNDS TARGETING DNA FUNCTIONS
DNA Damage Response
Ongoing proof-of concept Ongoing proof-of concept
DDR + IO
REVocan
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Source : Quanz M, et al. Clin Cancer Res 2009 15:1308-1316; Quanz M, et al. PLoS ONE. 2009 4(7), doi: 10.1371/ journal.pone. 0006298; Jdey W, et al. Clin Can Res. 2016;22:DOI: 10.1158/ 1078-0432.CCR-16-1193 * PARP inhibitors (PARPi) are a leading class of targeted therapies, the first approved and marketed in the field of DDR
DDR inhibition is clinically-validated in oncology (PARPi*) Decoy-agonist mode of action avoids compensatory mechanisms, blocking the induction of resistance AsiDNA™ acts upstream of the DDR, enabling cytotoxic activity regardless of genetic context Cytotoxic activity is restricted to cancer cells, translating into an outstanding safety profile AsiDNA™ is a decoy agonist oligonucleotide that mimics DNA breaks in the tumor cell (decoy), binds and hyperactivates the proteins (agonist) involved in the DDR cascade (sensing, signaling and repairing) … … diverts them away from the true damage …., … leading to cellular death.
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Decoy Agonist MoA does not induce resistance Differentiated Decoy Agonist MoA in the clinically-validated field
Long IP (up to 2040) Clinical-stage asset
Favorable safety profile incl. in combination Proof of mechanism / signals of efficacy
Collaborations with top-academic centers
(Institut Curie - Gustave Roussy – Oncopole Toulouse…)
REVocan Phase 1b/2 to evaluate the addition of AsiDNA™ on the abrogation resistance to niraparib (to start Q3 2020) Depletes the cells from which resistance to targeted therapies emerge
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20 40 60 2×104 4×104 6×104 8×104 1×105 1×106 2×106 3×106 4×106 5×106 6×106
Nira Nira+Asi continuous Nira+Asi at D34 Days post treatment Cell number
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UWB1.289 (Ovarian Cancer model – BRCA1-/-)
AsiDNA™ leads to niraparib-resistant cells eradication in ovarian cancer model, even if introduced only
REVocan study (REVersion of resistance in Ovarian Cancer with AsiDNA™ and Niraparib) was designed
D17 D24 D31 D40 D17 D24 D31 D40 5 10 15 20 30 60 90 120 150
CA125 (pg/ml)
Introduction at CA125 increase (REVocan study protocol) Start of AsiDNA™ administration
Source: Onxeo, data on file
niraparib Emergence of Resistant cells Cell death Start of AsiDNA™ administration (D34)
June 2020
Results confirmed in in vivo experiments in a triple negative breast cancer model
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MDAMB-436 (TNBC HR deficient - PARPi sensitive)
Source: Onxeo, data on file
June 2020
Non Small Cell Lung Cancer model – anti-EGFR sensitive
AsiDNA™ eradicates cells resistant to anti-EGFR and anti-ALK
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3 5 6 7 10 12 13 14 17 21 24 27 34 38 41 46 49 52
20 40 60 80 100 120
Erlotinib Erlotinib+AsiDNA
Time (days) Surviving cells (%)
No surviving cells Emergence of resistant cells No surviving cells Emergence of resistant cells
PC9-3 (NSCLC EGFRmut) - EGFR T790 mutation is preexisting in PC9 parental cell line. PC9-3 cell line is a sub-clone of PC9 without preexisting T790M.
Non Small Cell Lung Cancer model – anti-ALK sensitive
H3122 (NSCLC EML4-ALK)
Source: Onxeo, data on file
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DRIIV-1 Phase 1 First IV administration in solid tumors
DRIIV-1b Phase 1b (IV) Combo with carboplatin +/- paclitaxel (ongoing)
Cohort 2 (Carboplatin + Paclitaxel) ongoing
REVOCAN Phase 1b/2 (IV) Ovarian cancer in combination w/ PARPi niraparib Proof of Concept: Abrogation of resistance to PARPi FPI expected Q3 2020 Phase 1b/2 (IV) Non small cell lung cancer in combination w/ other targeted therapies (TKI, KRAS,…) Proof of Concept: Prevention/Abrogation of resistance to targeted therapies
SHORT/MID -TERM ONGOING COMPLETED
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Phase I study in I.V.
Open-label, 3+3 dose escalation from 200mg to 1800mg 22 patients; 5 doses Study coordinator: Pr. C. Le Tourneau (Institut Curie) Objectives: to determine the safety and PK/PD profile of AsiDNA™
Primary objective reached: favorable safety outcome
AsiDNA™ 200mg, 400mg, 600mg: No drug-related Serious Adverse Events (SAEs) and no Dose-Limiting Toxicity (DLT) AsiDNA™ 900mg & 1300mg: 3 related SAEs, including 2 DLTs per dose MTD was not reached
DRIIV-1 results were presented at EORTC-NCI-AACR on 10/27/19
181 (89%) 22 (11%) 1
Grade 1/2 Grade 3 Non-related 95%
Non-related 77% Adverse Events
Proof-of-mechanism : Strong activation of γH2AX at cell level, reflecting DNA-PK pathway engagement
Activity, pharmacodynamic biomarkers (on tumor biopsies)
Pre-treatment Post-treatment
γH2AX: Readout of DNA-PK target engagement
Patient 003-001
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AsiDNA™ 600 mg
Cohort 1
carboplatin AsiDNA™ 600 mg carboplatin + paclitaxel
Cohort 2
6 pts
+ +
Patients with ≥ 3 prior lines of treatment, progressing at inclusion Very good tolerance of the combination (no DLT) Disease stabilized (SD) in 2/3 patients for 5.5 mo. (TNBC 6th L) and 10 mo. (NSCLC 3rd L) Disease controlled with AsiDNA™ for significantly longer than with any of the prior treatment lines
3 pts
Topline results expected end 2020 *
* Timelines include Covid-19 impact to date, and may be further reviewed
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Patients selection: patients under 2nd line of maintenance with niraparib > 6 months Inclusion at CA 125 increase (CA 125 : well established predictive biomarker of resistance in OC) n= up to 26 patients, platinum-sensitive relapsed ovarian cancer Primary objective: Safety run & CA125 decrease (GCIG criteria) Secondary objective: Efficacy: PFS (RECIST criteria) - OS
REVersion of resistance in Ovarian Cancer with AsiDNA™ and Niraparib Study approved by regulatory authorities late May 2020 FPI expected from H2 2020 => Preliminary data by end 2020/early 2021 *
PI: Dr. Patricia Pautier (Arcagy Gineco Network)
Clinical collaboration
N = up to 26 pts & 6 centers
* Timelines include Covid-19 impact to date, and may be further reviewed
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❶ ❷
“Resistance is the biggest challenge in cancer biology” (Paul Workman – ICR)
Strategic objectives Targeted Indications Opportunity Approval / Full Market Size
Optimal market access (fast, favorable P&R*)
2L with niraparib (PARPi) in ovarian cancer Short endpoint: PFS Expansion of maintenance treatment and delay new course of platinum
2025/26 $6,7B (1) Access large WW markets
E.g. 1L with TKI or other targeted tx in non-small cell lung cancer Target specific population with high risk of progression e.g. $16,9B (1) for 1L NSCLC
REVocan Combo w/ PARPi Combo w/ other targeted therapies
* P&R : pricing & reimbursement - (1) GlobalData (8MM)
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Financière de la Montagne 13% Invus 11% Free float 76%
Cash position of €7.3m at 03/31/2020
shareholder, & Financière de la Montagne, historical shareholder Cash runway to Q1 2022
Shares outstanding
78.3m
Average Daily Volume
555,980 shares
Dual listing Euronext Paris & Nasdaq Copenhagen
ISIN: FR0010095596
At 06/11/2020 YTD at 06/12/2020
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DRIIV-1b cohort 2 Topline data
H2 2019 H1 2020 * H2 2020 *
DRIIV-1b cohort 1
REVOCAN First data set DRIIV-1b cohort 2 Preliminary data
AsiDNA™ +Tx
data to support clinical plan
AsiDNA™ +Tx
Data to support clinical plan Preclinical validation of OX401 profile
Tolerance in combination + first signals of efficacy
DRIIV–1b
AsiDNA™ + carboplatin +/- paclitaxel
REVOCAN phase 1b/2
AsiDNA™ + niraparib
Clinical Research agreement
Reversion of Resistance Prevention of resistance
AsiDNA™ + TKI/KRAS/…
Preclinical proof-of-concept
Next-gen PARPi + activation of immune response
OX401
Preclinical proof of mechanism
* *
* Timelines include Covid-19 impact to date, and may be further reviewed
FPI
*
Reg. approvals
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Broad development and commercial potential in multiple indications with high unmet needs AsiDNA™, innovative product at clinical stage, with confirmed activity in man and favorable safety profile including in combination. 2nd phase 1b/2 study REVocan initiated to demonstrate unique ability to fight tumor acquired resistance to PARPi and to deliver data in the short term platON™ platform to generate promising compounds based on unique decoy agonist mechanism of action AsiDNA™, first-in-class DDR inhibitor, the only decoy agonist in the DDR field, with a robust preclinical package supporting a broad range of potential indications/combinations Profile of next candidate from platON™ to be announced mid 2020, positioning Onxeo at the cross road of DDR (PARP inhibition) and immuno-oncology (STING pathway)
June 2020
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Hyperactivation of DNA-PK by double-strand break mimicking molecules disorganizes DNA damage response. Quanz M et al. PLoS One. 2009, 4:e6298. Histone γH2AX and Poly(ADP-Ribose) as Clinical Pharmacodynamic Biomarkers, Redon CE et al. Clin Cancer Res 2010; 16(18) Comparison of distribution and activity of nanoparticles with short interfering DNA (Dbait) in various living systems. Berthault N. et al. 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. et al. J Biol. Chem. 2012, 287:8803-15. Preclinical study of the DNA repair inhibitor Dbait in combination with chemotherapy in colorectal cancer. Devun F et al. 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 et al. Mol Ther Nucleic Acids. 2012, 1:e33. Distribution and radiosensitizing effect of cholesterol-coupled Dbait molecule in rat model of 5 glioblastoma. Coquery N et al. PLoS One. 2012;7(7):e40567. Resistance to PARP-Inhibitors in Cancer Therapy. Montoni A et al. Front Pharmacol. 2013; 4: 18. Kinesin KIFC1 actively transports bare double-stranded DNA. Farina F et al. Nucleic Acids Res. 2013, 41:4926-37. Inhibition of DNA damage repair by artificial activation of PARP with siDNA. Croset A et al. Nucleic Acids Res. 2013, 41:7344-55. DNA-PK target identification reveals novel links between DNA repair signaling and cytoskeletal regulation. Kotula E et al. PLoS One, 2013: 8(11):e80313. Colorectal cancer metastasis: the DNA repair inhibitor Dbait increases sensitivity to hyperthermia and improves efficacy of radiofrequency ablation. Devun F et al. Radiology. 2014, 270:736-46. A preclinical study combining the DNA repair inhibitor Dbait with radiotherapy for the treatment of melanoma. Biau J et al. Neoplasia. 2014, 16:835-44. An update on PARP inhibitors for the treatment of cancer. Benefif S et al. Dbait: An innovative concept to inhibit DNA repair and treat cancer. Biau J et al. Bull Cancer 2016; 103: 227–235 The DNA Repair Inhibitor DT01 as a Novel Therapeutic Strategy for Chemosensitization of Colorectal Liver Metastasis. Herath NI et al. Mol Cancer Ther. 2016 Jan;15(1):15-22. Targeting DNA Repair in Cancer: Beyond PARP Inhibitors, Brown JS et al. Cancer Discov December 21 2016 DOI: 10.1158/2159-8290.CD-16-0860 Targeting DNA repair by coDbait enhances melanoma targeted radionuclide therapy. Viallard C et al. Oncotarget 2016 Mar 15;7(11): 12927-36. First-in-human phase I study of the DNA repair inhibitor DT01 in combination with radiotherapy in patients in with skin metastases from melanoma. Le Tourneau C et al. Br J Cancer. 2016 June 24;114(11):1199-205. Potentiation of Doxurubicin efficacy in hepatocellular carcinoma by the DNA repair inhibitor DT01 in preclinical models. Herath NI et al. Eur Radiol. 2017 Oct, 27(10):4435-4444. Drug Driven Synthetic Lethality: bypassing tumor cell genetics with a combination of AsiDNA and PARP inhibitors. Jdey W et al. Clin Cancer Res. 2017 Feb 15;23(4):1001-1011 Micronuclei Frequency in Tumors Is a Predictive Biomarker for Genetic Instability and Sensitivity to the DNA Repair Inhibitor AsiDNA. Jdey W et al. Cancer Res. 2017 Aug 15;77(16):4207-4216.
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The DNA Repair Inhibitor Dbait Is Specific for Malignant Hematologic Cells in Blood. Thierry S et al. Mol Cancer Ther. 2017 Dec;16(12):2817–27. Combining the DNA Repair Inhibitor Dbait With Radiotherapy for the Treatment of High Grade Glioma: Efficacy and Protein Biomarkers of Resistance in Preclinical Models. Biau J et al. Front
Moving From Poly (ADP-Ribose) Polymerase Inhibition to Targeting DNA Repair and DNA Damage Response in Cancer Therapy. Gourley C et al. J Clin Oncol. 2019 June 3 AsiDNA™ treatment induces cumulative antitumor efficacy with a low probability of acquired resistance. Jdey W et al. Neoplasia (2019)21, 863–871 Preclinical studies comparing efficacy and toxicity of DNA repair inhibitors, olaparib and AsiDNA, in treatment of carboplatin resistant tumors. Jdey W et al. Front. Oncol., 12 November 2019 | https://doi.org/10.3389/fonc.2019.01097
Posters
AACR 2013 Preclinical study of Dbait, an inhibitor of three DNA repair pathways, in breast cancer treatment ASCO 2015 First-in-human phase I study of the DNA repair inhibitor DT01 in combination with radiotherapy in patients with skin metastases from melanoma AACR 2017 AsiDNA™ induces tumor sensitivity to PARP inhibitors in homologous recombination proficient breast cancer AACR 2018 AsiDNA™ and HDAC inhibitors: A cross-potentiation team work to kill tumor cells Evolution of tumor cells under Dbait (AsiDNA) treatment results in “autosensitization” AACR 2019 AsiDNA™ abrogates acquired resistance to PARP inhibitors Development of a Biomarker-driven patient selection strategy for AsiDNA™ treatment Molecular analysis of the mechanism of action of AsiDNA™ brings new clues on DNA damage response regulation AsiDNA™, a novel DNA repair inhibitor to radio-sensitize aggressive medulloblastoma subtypes EORTC-NCI-AACR 2019 Phase I dose escalation study evaluating the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of AsiDNA™, a first-in-class DNA Repair Inhibitor, administered intravenously (IV) in patients with advanced solid tumors AACR 2020 Virtual Meeting (Poster and audio online June 22-24, 2020) Acquired resistance to PARP inhibitors evolves from drug-tolerant persister cells vulnerable to AsiDNA™