A DNA Damage Response inhibitor with a unique mechanism of action
A first-in-class product candidate in the leading field on DNA Damage Response, AsiDNA™ breaks the cycle of tumor DNA repair by acting upstream of the DNA Damage Response, blocking multiple repair pathways, while sparing healthy cells. 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.
DNA damages of cancer cells are caused by cytotoxics (chemo- and radiotherapies) or occur spontaneously in genetically unstable tumors. Cancer cells have robust mechanisms to recognize DNA damage and activate multiple repair pathways and proteins to respond to DNA damage. Approaches to prevent DNA repair mechanisms have been identified as one of the most promising new avenues in cancer treatment.
AsiDNA™ is a short double-stranded DNA molecule (oligonucleotide) that acts as a decoy, mimicking double-strand breaks in the cell’s native DNA. When introduced into a cell, AsiDNA™ molecules trigger false DNA break signals to activate and attract DNA repair proteins, which prevents the recruitment of repair enzymes to the site of actual DNA damage. As a result, the damage of a cell’s native DNA remains 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 death). Healthy cells, on the other hand, will halt cell division until the compound is no longer present and damaged DNA can be repaired.
AsiDNA™ approach is significantly differentiated in the field of tumor DNA Damage Response as it does not inhibit specific enzymes (such as PARP inhibitors) but targets the entire DNA Damage Response cascade of cellular events, acting upstream as an agonist through a decoy strategy.
Preclinical and clinical development
A first-in-man Phase I trial (DRIIM study) performed in combination with radiotherapy in patients with metastatic melanoma demonstrated in 2016 that AsiDNA™ showed good tolerance and safety when administered intratumorally.
Onxeo has initiated since then the development of AsiDNA™ by systemic (intravenous) administration to harvest its broad potential in solid tumors and has achieved significant progress:
The DRIIV-1 study (DNA Repair Inhibitor administered IntraVenously) is an open-label, dose escalation, Phase 1 study evaluating the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of AsiDNA™ via systemic (IV) administration in patients with advanced solid tumors. The study is being conducted at leading oncology centers in France and Belgium.
The primary objective is to determine dose-limiting toxicities and maximum tolerated dose of IV infusion of AsiDNA™. Secondary objectives are to assess the safety profile, PK parameters and target engagement of AsiDNA™ based on the quantification of activity biomarkers in tumor tissue (YH2AX, pHSP90). In addition, proliferation tumor status as measured by KI67 immunostaining, and preliminary efficacy of AsiDNA™, are also being evaluated.
Proof of mechanism through target engagement would trigger the initiation of new phase 1b/2 studies, notably in combination with other treatments. The full data set from DRIIV-1 is expected in H1 2019.View press releases View publications
A versatile and powerful chemistry platform of decoy oligonucleotides
AsiDNA™ is the first compound sourced from platON™, the Company’s patented chemical platform of “decoy” oligonucleotides, introduced in October 2017. Compounds sourced from this platform are designed on the basis of a sequence of double-stranded oligonucleotides, a binding molecule and a molecule favoring intracellular penetration. Each of these three components can be modified to generate various compounds expressing different properties and/or activities, with the common characteristic of acting on tumor intracellular DNA-binding targets through a decoy mechanism.
The Company intends to capitalize on this platform in order to enrich its portfolio with innovative candidate drugs targeting DNA-binding functions. Preclinical evaluation of a new molecule is expected to start in 2019.View press releases
Peripheral T-Cell Lymphoma (PTCL)
Lymphoma is the most common blood cancer*. Hodgkin’s and non-Hodgkin’s lymphoma are the main two forms of lymphoma. The lymphoma survives when the lymphocytes, a type of white blood cell, increase abnormally and accumulate in one or more lymphatic ganglions or in lymphatic tissue. Two types of lymphocytes may develop: B lymphocytes (B cells) and T lymphocytes (T cells). Peripheral T-Cell Lymphoma (PTCL) is a sub-type of non-Hodgkin’s lymphoma which affects T cells. In the United States, PTCL accounts for around 10 to 15% of non-Hodgkin’s lymphoma and its global incidence is estimated at 12,000 cases each year. Currently no 2nd line treatment is available in Europe once the disease has progressed after a 1st line of treatment.
*Lymphoma Research Foundation (www.lymphoma.org)
belinostat is a histone deactylase inhibitor (HDACi). It has been assessed in several clinical trials as a sole treatment (monotherapy) or in combination with other anti-cancer treatments for hematological cancers and solid tumors. Its anti-cancer activity is associated with the inhibition of cell proliferation, the induction of apoptosis (programmed cell death), the inhibition of angiogenesis and the induction of cellular differentiation.
Since 2010, Beleodaq® has been licensed to an American partner, Spectrum Pharmaceuticals, Inc. (SPPI), for the USA and India. Spectrum Pharmaceuticals is responsible for the co-development of Beleodaq® for the United States and for promoting it to oncology and hematology specialists.
Beleodaq® benefits from industrial protection until at least 2026. Its protection (commercial exclusivity) is furthermore strengthened by its status as an orphan drug in Europe and the United States.
Developed to tackle relapsed or refractory peripheral T-cell lymphoma (PTCL), with a positive Phase II, in early July 2014 Beleodaq® obtained New Drug Authorization from the Food and Drug Administration for this indication. This authorization was given within the context of an accelerated registration program which conditionally approves a drug designed for the treatment of a life-threatening disease based on predictive elements of a clinical benefit. The registration is based on the results of the BELIEF clinical trial of 129 patients suffering from peripheral T-cell lymphoma, resistant or in relapse after at least one initial systemic treatment which showed a response level of 25% with a median duration of response of 8.3 months and a good tolerance profile. Beleodaq® has been available to patients since July 2014, promoted by specialist Spectrum Pharmaceuticals oncology sales teams in the United States.
A clinical Phase III trial is planned to assess the efficacy of Beleodaq® in combination with the CHOP treatment, against CHOP in the 1st line of treatment of peripheral T-cell lymphoma (PTCL).
belinostat is could also be considered for development as an oral formulation. This would enable a significant extension of the intellectual property and constitute a real competitive advantage in terms of patient quality of life and compliance. Most importantly, it would be an asset to use belinostat in combination with other anti-cancer agents, which are mostly administered by systemic route.View press releases View publications