Paris (France), June 25, 2020 – 7.00 am CEST - Onxeo S.A. (Euronext Paris, NASDAQ Copenhagen: ONXEO), (“Onxeo” or “the Company”), a clinical-stage biotechnology company specializing in the development of innovative drugs targeting tumor DNA Damage response (DDR), in particular against rare or resistant cancers, today announced the confirmation of the preclinical profile of OX401, the second candidate from its platON™ platform. OX401 is a potent PARP[1] agonist and represents a new generation of molecules showing strong anti-tumor activity associated with high immunological activity.

Through its action on PARP and the activation of an antitumor immune response via the cGAS-STING pathway, OX401 has shown in vivo a higher potency of activity than current PARP inhibitors, as evidenced by complete control of tumor growth.

The preclinical program already completed has confirmed the key properties of this new compound. OX401 exhibits potent antitumor activity, demonstrated in an animal model of breast cancer, related to PARP hyperactivation and diversion of its DNA repair function in specific tumor cells. PARP is a major component in the DNA repair mechanism, and the clinical benefit of acting on this protein has already been abundantly demonstrated by PARP inhibitors.

In addition, this activity on PARP induces a strong engagement of the cGAS-STING pathway[2], as shown by the increase in key biomarkers of the tumor immune response. Activation of this pathway is now a very promising new approach in immuno-oncology.

Benefiting from an original mechanism of action of decoy agonist like all candidates sourced from platON™, OX401 does not induce tumor resistance to treatment, which represents a clear differentiation from targeted therapies such as PARP inhibitors. Finally, like AsiDNA™, OX401 has no activity on healthy cells, which should provide a favorable safety profile in the clinic.

Françoise Bono, Chief Scientific Officer of Onxeo, commented: "OX401 is the first representative of the OX400 family from our platON™ platform. Based on our expertise in oligonucleotides and our understanding of the decoy agonist mechanism, we have designed this candidate to be a potent inhibitor of DNA repair via the diversion (decoy effect) and hyperactivation of PARP (agonist effect) which, as a result, activates the cGAS-STING pathway. This is what we have just demonstrated: OX401 has a more potent action, in all areas, than that found with the PARP inhibitors available today, without the emergence of acquired resistance. As OX401 triggers robust local anti-tumor immunity, the next key preclinical step will be to study its association with immune checkpoint inhibitors. For this development, we have benefited from all the expertise accumulated during the development of AsiDNA™ and have thus obtained in the span of a few months an optimized compound, ready to enter the final stages of preclinical validation. These translational studies will allow us to best prepare for entry into the clinic, which could take place within 18 to 24 months”.

Immunotherapy has recently shown the potential to transform the treatment of cancer by triggering anti-tumor T cell responses via immune checkpoint blockade. This approach has led to outstanding clinical responses in previously untreatable tumors, although in limited patient subsets. Stimulator of interferon genes (STING) has been identified as having a key role in the field as a critical mediator of the innate immune-sensing of cancer.

In these in vivo proof of efficacy studies, the therapeutic value of OX401 was further demonstrated, as it has now been shown that OX401 triggers robust local anti-tumor immunity involving both adaptive and innate immune responses, in mice bearing syngenic breast tumors. This activity led to complete control of tumor growth with OX401 treatment. These results suggest that OX401 could also increase the effectiveness of the traditional immune checkpoint blockade by overcoming the local immunosuppressive environments seen in cancer.

[1] PARP is a key protein in the tumor DNA repair process

[2] The cGAS-STING pathway is a component of the innate immune system, which detects cytosolic DNA (involved in particular in carcinogenesis) and induces an immune response accordingly

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