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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
May 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 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. 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NEXT KEY MILESTONES FUNDED
Financial visibility to Q3 2020 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
May 2020
FRANCOISE BONO (PHD) CSO (Sanofi, Evotec) Formerly Executive Vice-President, Oncology of Evotec
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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 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™ IV AsiDNA™ IV + chemotherapy Synergistic efficacy AsiDNA™ IV + PARPi Resistance abrogation AsiDNA™ IV + TKI Resistance abrogation
DRIIV -1b
DRIIV study in solid tumors
GENERATION OF NEW COMPOUNDS TARGETING DNA FUNCTIONS
DNA Damage Response
IV: intravenous
Ongoing proof-of concept Ongoing proof-of concept
DDR + IO
REVocan
Completed or ongoing
Legend
Planned short-term
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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 H1 2020) Depletes the cells from which resistance to targeted therapy emerges
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A purpose-designed cholesterol-oligonucleotide conjugate
5’ 3’ 3’ 5’ Double-stranded 32 bp DNA is tethered with a loop to prevent disassociation2 Active 32 bp DNA duplex Cholesterol Loop
1 Berthault N, et al. Cancer Gene Therapy (2011), 1-12, doi: 10.1038/cgt.2011.3 2 Quanz M, et al. PLoS ONE. 2009 4(7), doi: 10.1371/journal.pone.0006298
Tumoral and nuclear uptake of the DNA mediated via a covalently linked cholesterol molecule1 Binding and activating DNA-PK and PARP signaling enzymes Phosphorothioate substitutions at the 5’ and 3’ ends to prevent degradation1 Sequence non-homologous and not immunogenic (CpG-free) AsiDNA is not an RNAi therapy, thus avoiding the toxicity issues of this class
Patent Protection
(Composition of Matter on AsiDNA™ & related compounds)
until 2031. Extendable to 2036 with SPC & PTE. Combination patents up to 2040
IP
May 2020
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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 mechanism 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™ 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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No cytotoxic activity in healthy cells Very favorable data in tox. study (monkey)
Autosensitization and no resistance observed
In multiple cell lines Confirmed
Efficacy synergy with PARPi
In multiple PARPi sensitive & resistant cell lines No restriction to specific genetic context AsiDNA™ increases survival & responders
to PARPi Efficacy synergy with chemo
In multiple cell lines
AsiDNA™ increases efficacy & survival Abrogation resistance to PARPi
In multiple cell lines
AsiDNA™ stops resistance to PARPi Abrogation resistance to TKi Ongoing validation with several TKI in multiple cell lines
anti-EGFR, anti-ALK efficacy In vitro data In vivo data
PARP inhibitors (PARPi) and tyrosine kinase inhibitors (TKI) are leading, approved targeted therapies in oncology
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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 AsiDNA admin Emergence of Resistant cells Cell death
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
May 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
May 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
May 2020
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 Q2 2020 Phase 1b/2 (IV) Non small cell lung cancer in combination w/ TKI Proof of Concept: Abrogation of resistance to TKI
SHORT/MID -TERM ONGOING
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COMPLETED
May 2020
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
90% of adverse events were grade 1/ 2, mostly ( 77%) non-related ; no specific type of toxicity 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 Orthostatic hypotension (grade 3/ unlikely related) 2 increase of hepatic enzymes ( grade 3/ unlikely related and grade 4/possibly related) Maximum Tolerated Dose (MTD) was not reached
DRIIV-1 results were presented at EORTC-NCI-AACR on 10/27/19
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181 (89%) 22 (11%) 1 Grade 1/2 Grade 3 Non-related 95% Non-related 77% Adverse Events
May 2020
17 Activity, pharmacodynamic biomarkers (on tumor biopsies) AsiDNA™ 600mg
Pre-treatment Post-treatment γH2AX: Readout of DNA-PK target engagement Patient 003-001
Strong activation of γH2AX at cell level, reflecting DNA-PK pathway engagement
γ
DRIIV-1 study, presented at EORTC-NCI-AACR 27th Oct 2019
May 2020
PHASE 1b
tumors, eligible to the CT regimen
Grand Hôpital de Charleroi
OBJECTIVES
MAY 2019 FIRST PATIENT DOSED
TREATMENT SCHEDULE
H1 2020 END OF STUDY AsiDNA™ DAY 1 22 2 3 8 15 CYCLE 1: 28 days CYCLE 2 and beyond : 21 days Q3 2019 Q42019 29 AsiDNA™ AsiDNA™ AsiDNA™ AsiDNA™ PRELIMINARY EFFICACY OUTCOMES
AsiDNATM 600 mg
Cohort 1 3 pts
carboplatin AsiDNATM 600 mg carboplatin + paclitaxel
Cohort 2 6 pts + +
completed
Carbo Carbo Cohort 1 Pacli Pacli Pacli Pacli Cohort 2 Carbo Carbo
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May 2020
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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 mid-2020 * Full data set H2 2020 *
* Timelines may be affected by Covid-19 pandemic
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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) 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
REVocan REVersion of resistance in Ovarian Cancer with AsiDNA™ and Niraparib FPI expected from H1 2020 => Preliminary data by end 2020 *
PI: Dr. Patricia Pautier (Arcagy Gineco Network)
Clinical collaboration
N = up to 26 pts (6 centers)
* Timelines may be affected by Covid-19 pandemic
May 2020
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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
2024 $6,7B (1) 1st line treatment in a large WW market
1L with anti-EGFR TKI in EGFRm non-small cell lung cancer Target specific population with high risk of progression Address 1st line of treatment
2025 $16,9B (1) REVocan Combo w/ PARPi Combo w/ TKI
* P&R : pricing & reimbursement - (1) GlobalData (8MM)
May 2020
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2nd line treatment : platinum-based chemotherapy (for patients sensitive to platinum) 2nd line maintenance : PARP inhibitors Median PFS 9,3 mo in non-BRCA mutated patients (86%
( vs. 21 mo in patients with BRCA mutation)(2) Development of resistance to PARPi limits duration of response(3) 3rd line with platinum-based CT in sensitive patients, but loss of sensitivity after subsequent relapses leads to lack
> 128,000 new incident cases in 2018(1)
Potential to extend maintenance / PFS, especially in non- BRCA mutated patients Potential to maintain sensitivity to platinum for subsequent lines of treatment
Current
Challenges Population
US 23,000 Japan 10,000 5 EU 31,000 China 64,000
(1) GlobalData (8MM = 5EU + US + JPN + Urban China) (2) NOVA study (3) Mweempwa A, Wilson MK. Mechanisms of resistance to
PARP inhibitors - an evolving challenge in oncology. Cancer Drug Resist2019;2:608-17.
AsiDNA™ opportunity
May 2020
24 Anti-EGFR TKIs now used in 1st line as well as in 2nd line treatment of EGFR-mutant NSCLC EGFRm NSCLC patients treated with anti-EGFR TKIs will inevitably develop acquired resistance to their treatment(2) Anti-EGFR TKIs now used as 1st line treatment, which limits further treatment options once resistance emerges Increasing progression free survival (PFS) and efficacy of 1st line treatment becomes critical NSCLC = 85% of all lung cancers 920,000 new incident cases in 2020(1) High occurrence of EGFR mutations in NSCLC (≈20%
a critical population in lung cancer(1)
Potential to prevent resistance to anti-EGFR TKIs in 1st line Potential to increase PFS / efficacy of 1st line treatment
Current
Challenges
AsiDNA™ opportunity
Population
US 188,000 Japan 121,000 5 EU 184,000 China 427,000
(1) GlobalData (8MM = 5EU + US + JPN + Urban China).(2) Gao, J., Li, H., Jin, C. et al. Strategies to overcome acquired resistance
to EGFR TKI in the treatment of non-small cell lung cancer. Clin Transl Oncol 21, 1287–1301 (2019).
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Strategic objectives and steps Targeted Indications (for approval) Estimated Approval Optimal market access - fast, favorable P&R
2L maintenance with niraparib (PARPi) in platinum sensitive ovarian cancer after CA125 increase
2024
Establish presence in a large WW market
1L treatment of EGFRm NSCLC with TKI / EGFRi
2025
Expand combos with PARPi and TKI
1L maintenance ovarian cancer with PARPi 2L treatment of HER2 negative metastatic breast cancer 1L treatment of ALKm NSCLC with anti-ALK TKI
2028
Address growth opportunities in combos with DNA breakers
Neoadjuvant TNBC with carboplatin + paclitaxel 2L treatment ovarian cancer with carboplatin + paclitaxel 1L treatment ovarian cancer with carboplatin + paclitaxel
2029
* P& R : pricing & reimbursement
May 2020
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FPI
DRIIV-1b cohort 2 Topline data
H2 2019 H1 2020 * H2 2020 *
DRIIV-1b cohort 1
* Timelines include first estimation of Covid-19 impacts,
which may be further reviewed depending on Covid-19 pandemic evolution
REVOCAN First data set DRIIV-1b cohort 2 Preliminary data
AsiDNA™ +TKI
data to support clinical plan
AsiDNA™ +TKI
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
Preclinical proof-of-concept
Next-gen PARPi + activation of immune response
OX401
Preclinical proof of mechanism
* *
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May 2020
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Financière de la Montagne 12% Other institutions 9% Retail 74% Misc. 5%
Shares outstanding
65.8m
Average Daily Volume (18 months)
142,036
shares Dual listing Euronext Paris & Nasdaq Copenhagen
ISIN: FR0010095596
At 03/31/2020 At 03/31/2020
May 2020
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A promising opportunity available for licensing Significantly de-risked pipeline asset Potential to play a cornerstone role in an oncology portfolio through multiple combinations Sizeable market potential through indications with large unmet needs Broad development and commercial potential in multiple indications with high unmet needs Product at clinical stage, with confirmed activity in man and very favorable safety profile in IV including in combination. Phase 1b/2 key readouts expected in 2020 to validate potential in combos and ability to abrogate resistance to targeted therapies First-in-class DDR, the only decoy agonist in clinical development in this field Solid preclinical package supporting a broad range of potential indications
May 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 May 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 May 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
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Transaction closed on April 06, 2020 Full and worldwide rights to all territories ( ex. US and India, already licensed to Acrotech), IP and know- how on all belinostat forms . License with Pint Pharma for Latin America and contracts with Clinigen and iQone for the named patient program in Europe assigned to Acrotech All future potential revenues from the belinostat franchise to revert to Acrotech Reflects Onxeo ability in terms of BD, alliance management and NPP around the world $6.6M paid by US partner Acrotech Biopharma LLC against the exclusive WW rights to belinostat Financial visibility extended into Q2 2021, beyond key clinical milestones* for AsiDNA™
* Timelines may be affected by Covid-19 pandemic