A first-in-class product candidate in the leading field of DNA Damage Response (DDR), AsiDNA™ disrupts and exhausts the ability of tumor cells to repair their DNA by acting upstream of multiple repair pathways. AsiDNA™ and its technology originate from three major French academic centers: Curie Institute, CNRS, and the Museum of Natural History. It aims to offer new treatment options for patients suffering from various types of cancer.
A DIFFERENTIATED MECHANISM OF ACTION IN DNA DAMAGE RESPONSE
AsiDNA™ is a short double-stranded DNA fragment (oligonucleotide) that acts as a decoy, mimicking double-strand breaks in the DNA of the tumor cell. AsiDNA™ molecules trigger false DNA break signals to activate and attract DNA repair proteins, which prevents their recruitment to the site of actual DNA damage. As a result, damages to tumor cells’ DNA remain unrepaired. As cancer cells have lost the ability to regulate cell division, they will continue dividing with damaged DNA, ultimately leading to cancer cell death (mitotic catastrophe). Healthy cells, on the other hand, will halt cell division until the compound is no longer present and damaged DNA can be repaired.
AsiDNA™ mechanism is significantly differentiated in the field of DNA Damage Response as it does not inhibit specific enzymes (such as PARP inhibitors) but targets the entire DNA repair process, acting upstream of multiple DDR pathways as an agonist through a decoy mechanism.
AsiDNA™ mimics DNA breaks in the tumor cell, sends false alarms (decoy mechanism) then binds and activates key proteins of the DNA Damage Response
This sustained artificial DNA damage signaling (agonist effect) leads to exhaustion of the tumor DNA repair mechanisms
The actual tumor DNA breaks are not repaired and accumulate: the cancer cells die when they replicate with damaged DNA.
AsiDNA™ is a multi-target decoy agonist, the only agonist in the field of DDR
Unlike targeted therapies, AsiDNA™ acts on many proteins, particularly PARP and DNA-PK which are involved very early in the damage response, from the detection and signaling stages.
AsiDNA™ does not induce any resistance and reverses resistance to other treatments
AsiDNA™ acts on all repair pathways: the tumor cell cannot use another protein or repair pathway to resist its action, which is the case with targeted therapies.
The more AsiDNA™ is used as a treatment, the more effective it becomes
AsiDNA™ does not oppose, but on the contrary encourages, hyper-activates and hijacks a natural biological process so essential for its survival that the tumor cell cannot stop it. Thus, AsiDNA™ is increasingly effective as the tumor cell exhausts its ability to respond to DNA damage.
Thanks to these distinctive properties and a favorable safety profile, AsiDNA™ is ideally suited for development in combination with other anti-cancer therapies.
An extensive and robust preclinical package has been built highlighting the differentiated properties of AsiDNA™, notably the absence of resistance after repeated treatment, the prevention and reversion of resistance to PARP inhibitors and a strong synergy with other anti-cancer agents such as PARP inhibitors or platinum-based chemotherapies.
AsiDNA ™ has already demonstrated a good safety profile in two phase 1 studies, via intratumoral and via intravenous administration, and is currently being evaluated in combination with chemotherapy (carboplatin and paclitaxel) in solid tumors in the DRIIV- 1b study.
- A first Phase 1 trial (DRIIM study), in which AsiDNA™ administered intratumorally was evaluated in combination with radiotherapy in patients with skin metastases from melanoma, highlighted in 2016 its good safety profile and showed first signals of efficacy.
First-in-human phase I study of the DNA repair inhibitor DT01 in combination with radiotherapy in patients with skin metastases from melanoma.
LeTourneau C et al. Br J Cancer. 2016 May 24;114(11):1199-205.
- In 2018, the DRIIV-1 (DNA Repair Inhibitor administered IntraVenously) phase 1 study has evaluated AsiDNA™ standalone by systemic administration (IV) in metastatic solid tumors and confirmed active doses as well as a favorable safety profile in 22 patients. In this study, AsiDNA™ has achieved proof-of mechanism through the strong engagement of its biological targets. The active dose of 600 mg was determined as optimal for the ongoing clinical development of AsiDNA™ in various combinations.
Access the protocol on ClinicalTrials.gov: Identifier NCT03579628
Access the results in the poster presented at the EORTC-AACR-NCI Conference (October 2019)
Access the results in the article published in the British Journal of Cancer (August 2020)
- Initiated in 2019, the DRIIV-1b study is currently evaluating AsiDNA™ in combination with carboplatin, and carboplatin plus paclitaxel in patients with advanced metastatic tumors. Preliminary results from the first cohort with carboplatin alone have shown good tolerance, stabilized disease and increased durations of treatment vs. previous treatment lines. Favorable preliminary results obtained in 2020 showed promising efficacy signals. A randomized phase 2 trial of this combination in a selected high unmet need indication is scheduled to start in 2021.
- The phase 1b/2 study REVOCAN, sponsored by Gustave Roussy, was designed to assess the abrogation of resistance to PARP inhibitor niraparib by AsiDNA™ in relapsed ovarian cancer and started in late 2020. Preliminary results are expected in 2021.
- AsiDNA™ Children, sponsored by Institut Curie, is a phase 1b/2 study designed to assess the effect of AsiDNA™ with combination with radiotherapy to treat children affected with recurrent high grade glioma. It is expected to start in 2021.
AsiDNA™ is protected internationally by several patent families covering the chemical composition of the product, its method of use or of administration as well as some combinations with other anti-cancer products. These patent families give AsiDNA™ a very wide field of protection.
The main patent protects AsiDNA™ until mid-2031 and may be extended until 2036 via the different supplemental protection systems prevailing in the United States and in Europe. The latest patents on methods of use or combinations - such as with PARP inhibitors - will be valid until 2036, before extension period.
- 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. Onco Targets Ther. 2015; 8: 519–528.
- 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 Wet al. Cancer Res. 2017 Aug 15;77(16):4207-4216.
- 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 Oncol. 2019 Jun 19;9:549.
- 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
- A Phase 1 dose-escalation study to evaluate safety, pharmacokinetics and pharmacodynamics of AsiDNA, a first-in-class DNA repair inhibitor, administered intravenously in patients with advanced solid tumours
Le Tourneau et al. British Journal of Cancer https://doi.org/10.1038/s41416-020-01028-8
AACR VIRTUAL MEETING 2021
- A new generation of PARP interfering drug candidates for cancer treatment
- Acquired resistance to KRASG12C inhibitors evolves from drug tolerant cells vulnerable to AsiDNA™
AACR VIRTUAL MEETING 2020
- Acquired resistance to PARP inhibitors evolves from drug-tolerant persister cells vulnerable to AsiDNA™ (abstract)
- Access the e-poster
- Access the audio commentary
PARP & DDR INHIBITORS SUMMIT 2020
TIDES EUROPE 2019
- AsiDNA™, a first-in-class, clinical stage “Decoy Agonist” targeting DNA repair pathways through a unique MoA enabled by the oligonucleotide modality
- 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
- 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
- AsiDNA™ abrogates acquired resistance to PARP inhibitors
- Development of a Biomarker-driven patient selection strategy for AsiDNA™ treatment
- AsiDNA™ and HDAC inhibitors: A cross-potentiation team work to kill tumor cells
- Evolution of tumor cells under Dbait (AsiDNA) treatment results in “autosensitization”
- AsiDNA™ induces tumor sensitivity to PARP inhibitors in homologous recombination proficient breast cancer
- First-in-human phase I study of the DNA repair inhibitor DT01 in combination with radiotherapy in patients with skin metastases from melanoma