A DNA Damage Response inhibitor with a unique mechanism of action
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.
Damages to the DNA 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 alterations 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 tumor cell’s DNA. 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™ 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 Phase I trial (DRIIM study), in which AsiDNA™ administered intratumorally was evaluated in combination with radiotherapy in patients with metastatic melanoma, highlighted in 2016 its good safety profile and showed first signals of efficacy.
Onxeo has since then developed AsiDNA™ by systemic (intravenous) administration to harvest its broad potential in solid tumors and has achieved significant progress:
Other combination studies of AsiDNA™, notably in combination with PARP inhibitors, are expected in 2020.View press releases View publications View AsiDNA™ letters
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. The Company intends to capitalize on this platform in order to enrich its portfolio with innovative drug candidates.
platON™makes it possible to optimize double-stranded oligonucleotide sequences to generate new compounds expressing different properties and / or activities, with the common characteristic of acting on tumor intracellular targets through a decoy mechanism.
Preclinical evaluation of a new molecule, OX401, started in 2019. OX401 aims to be a next-generation PARPi inhibitor that wouldn’t induce resistance but activate the immune response. Preclinical proof-of-concept of OX401, alone and in combination with immunotherapies, is expected before year-end 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 for the USA and India. This partner is responsible for the co-development of Beleodaq® for the United States and for promoting it to oncology and hematology specialists. Beleodaq® has been available to patients in the United states since July 2014.
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.
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