Noxopharm White Paper

NOXOPHARM L IMITED White Paper 6 Veyonda® – anti-inflammatory effects Inflammationplaysaroleincancer.Cancer ismoreprone to arise in tissues subjected to chronic inflammation, but cancers also co-opt inflammatory processes to assist their growth. Those inflammatoryprocesses involve factors suchasangiogenesis (thedevelopment of new blood vessels) to support vigorous tumour growth, through to manipulation of the local immune system to augment tumour-promoting immune function at the expense of tumour-suppressing immune function. Sphingosine-1-phosphate (S1P) plays a key regulatory role in all of these inflammatory processes. Hence, the S1P-inhibiting effect of Veyonda deprives the cancer cells of those S1P-driven inflammatory processes. In this way, the anti-inflammatory functions of Veyonda are part of a continuum that comprises oncotoxic, immunological and anti-inflammatory functions, all interconnected via the original inhibition of ENOX2. Within that continuum, however, a particular anti-inflammatory action of Veyonda has emerged that points to a potential role for the drug well beyond cancer. That action is a potent inhibitory effect on the key pro-inflammatory signaling pathway, STING (Stimulator of Interferon Genes). • Uncoordinated activation of STING is incriminated in chronic inflammatory diseases and autoimmune diseases including motor neurone disease. • Excessive activation of STING is incriminated in the cytokine release syndrome associated with septic shock, including with disability and death in COVID-19 disease. STING signaling The cyclic GMP-AMP synthase (cGAS)/STING pathway is a primitive surveillance mechanism responsible for sensing the presence of DNA in a cell’s cytoplasm. This DNA can come from infectious pathogens(viruses, bacteria) or from cellular DNA leaking from the nucleus (as in cancer) or from the mitochondria (as seen in acute kidney injury or following radiation). Activation of the cGAS/STING pathway leads to the rapid stimulation of a potent immune/ inflammatory response characterised by strong induction of type I interferons (IFN- β ) and pro inflammatory cytokines such as inerleukin-6 (IL-6) and tumor necrosis factor- α (TNF- α ). The interferon response ensures activation of an immune response, particularly important where infectious organisms are involved. The pro-inflammatory cytokine response ensures repair of the damaged tissues.