Noxopharm White Paper

5 Disclaimer: Veyonda is currently not approved in Australia or any other country (i) Oncotoxic outcomes Blocking all three downstream biochemical pathways by IDX leads to a variety of direct (oncotoxic) anti-cancer effects eg., blocking cell growth and division, through to direct killing of cancer cells. These are all standard chemotherapy effects, marking Veyonda as a potential stand-alone chemotherapy for a wide range of solid cancers. However, Noxopharm sees IDX’s oncotoxic functions making a far greater contribution in combination treatment, rather than as a monotherapy. The ability to block DNA repair mechanisms (topoisomerases 1 and 2, PARP 1) explains the chemo- sensitising function of IDX, rendering a wide range of cancer cells more susceptible to killing by other standard DNA-poisoning chemotoxic drugs (taxanes, platinums, doxorubicin, gemcitabine). The ability to block cell division and DNA repair explains the ability of IDX to radio-sensitise, with mitotic arrest rendering the cancer cell’s DNA prone to maximum damage by radiation, and subsequent repair of that damage blocked. (ii) Immunological outcomes The immunological effects of IDX stem from inhibition of S1P levels. The link between S1P and the immune system comes mainly via the S1PR1 and S1PR4 receptors, predominantly expressed by lymphoid and haematopoietic cells. S1P plays an important role in immune function within a tissue, starting with attracting immune cells into the tissue, and then in ensuring that their function remains balanced and controlled: • The attraction of immune cells into tissues comes from the key role of S1P in the way immune cells aremoved around the body (so-called ‘immune cell trafficking’). Immune cells aremobilized from lymphoid tissue and moved into the bloodstream and from there into tissues through the so-called S1P gradient, a gradient from high to low S1P levels that immune cells travel down. • The balance and control comes from regulating a mix of counter-acting immune cells comprising those charged with initiating an immune response (so-called helper T-cells) and those charged with down-regulating an immune response (so-called suppressor T-cells). Cancer cells exploit both of these mechanisms to their own advantage through generating high levels of S1P inside a tumour: • High intra-tumoral S1P levels reverse the normal S1P gradient. The normal higher S1P levels in blood versus tissues drives the flow of immune cells out of blood into the tissues. The reversal of that gradient drives immune cells from the tumour back into blood. • High intra-tumoral S1P levels suppress the activation of the ‘helper’ immune cells (CD4+ T cells) and cytotoxic CD8+ T-cells and stimulatemacrophage/M2 polarization that leads to the secretion of both anti-inflammatory cytokines that help the tumour evade the immune system as well as proteins that support migration and recruitment of additional suppressing immune cells. By blocking the action of S1P on S1PR1 and S1PR4, IDX: • directly stimulates the innate immune system, specifically the CD56+ natural killer (NK) cell population. • activates CD4+ and CD8+ T-cells. • increases trafficking of activated T cells leading to infiltration into tumours, the so-called COLD to HOT tumour conversion.