Our Polθ inhibitor offers the potential to harness the power of the DDR inhibition to specifically target tumor cells while sparing normal tissue from toxicity. It may allow for effective and widespread use across multiple tumor types including PARP inhibitor resistant cancers, as a combination treatment with other DDR inhibitors, or in combination with ionizing radiation.
ART4215 is an orally dosed inhibitor of Polθ, which we believe is the first specific, rationally designed Polθ inhibitor in clinical development. Polθ represents a highly attractive cancer specific DDR target with a number of vital characteristics that have great potential to confer significant therapeutic advantages over less specific and more ubiquitously expressed DDR targets, such as PARP. Polθ expression in normal tissue is limited in contrast to its over expression in a number of cancer types. Furthermore, dependence on Polθ is induced as certain cancer types adapt and become resistant to several commonly used standard of care therapies.
These features give Polθ the potential to be a highly specific DDR tumor target that offers the prospect of an ability to harness the power of the DDR while sparing normal tissue from toxicity and allowing greater dosing in combination treatments. ART4215 is therefore a potential treatment for a wide range of cancers, including PARP resistant disease, and has substantial promise as a combination treatment. We believe a significant and expanding area of unmet patient need may be fulfilled by combining Polθ with a variety of DNA damaging agents.
DNA damaging agents, such as chemotherapy and IR, represent the most commonly used cancer treatments. However, despite the strong rationale to enhance their efficacy by combining with novel inhibitors that prevent the cancer cell repairing the induced DNA damage, this approach has been largely unsuccessful due primarily to a considerable increase in toxicity. The tumor specificity of Polθ inhibition has the potential to overcome this critical limitation and in turn enhance the efficacy of DNA damaging agents within their current areas of use, as well as potentially expand their therapeutic utility beyond the current treatment indications.
Furthermore, we believe Polθ has significant potential to increase the benefit that may be provided by combining with immuno-oncology medicines and other inhibitors of the DDR, including PARP inhibitors. We submitted an Investigational New Drug, or IND, application for our Polθ inhibitor in June 2021, which was approved by the U.S. Food and Drug Administration, or FDA, in July 2021.