Kazia Therapeutics Annual Report 2021

The final potential advantage for EVT801 is something that would be less obvious from an understanding of its mechanism of action. For reasons that are incompletely understood, drugs targeting angiogenesis and lymphangiogenesis have the effect of changing the balance of white blood cells in and around the tumour. White blood cells are the main actors in the immune system, and this effect has important therapeutic consequences. One of the most significant advances of the last decade has been the ability to use the body’s own immune system to fight cancer. ‘Immuno- oncology’ drugs have rapidly gained a foothold in diseases such as melanoma and lung cancer. However, many tumours do not have many white blood cells in them, or they have the wrong kind of white blood cells, and in these ‘cold’ tumours, immuno- oncology drugs are usually ineffective. If EVT801 is able to turn cold tumours ‘hot’, as it does in the laboratory, then it may be a valuable adjunct to these therapies. TARGETING VEGFR3 – A SELECTIVE APPROACH TO LYMPHANGIOGENESIS Targeting lymphangiogenesis is much more technically challenging. Of the five subtypes of VEGF, VEGF-C and VEGF-D are substantially involved in promoting lymphangiogenesis, but they also promote angiogenesis, so they are not promising as targets for a selective therapy. Fortunately, there are three subtypes of VEGF receptor, and VEGFR3 is specifically involved in lymphangiogenesis. A drug which was able to inhibit VEGFR3 would selectively reduce the formation of new lymphatic vessels but would leave blood vessels untouched. The result should be a reduction in tumour growth, without the problem of hypoxia-induced resistance. That is the principle that led to the invention of EVT801. EVT801 – A NEXT GENERATION ANTI-LYMPHANGIOGENESIS THERAPY EVT801 was originally invented by Sanofi, a French pharmaceutical company, and was licensed to Evotec as part of a transaction between those companies. Evotec took the drug through the complex process of preclinical development, building a formidable body of data that supports its activity. The drug is a selective VEGFR3 inhibitor. This selectivity is very important. Several of the existing anti-angiogenesis drugs do have some activity against VEGFR3. However, they are all relatively non-specific, affecting a wide variety of other targets, and this leads to substantial toxicity. A drug which is selective for VEGFR3 should successfully inhibit lymphangiogenesis without the many toxicities seen in other agents. EVT801 inhibits the growth of tumours in the same way as older anti- angiogenic therapies: by starving the tumour of essential nutrients. However, it also has two other important benefits. First, many tumours spread (metastasise) via the lymphatic system. By restricting the development of lymphatic vessels, EVT801 is likely to reduce the potential metastasis of the tumour. This would be very valuable, because tumours become much more difficult to treat when they spread. EVT801 IS EXPECTED TO HAVE THREE PRIMARY MECHANISMS OF ACTION TUMOR KILLING Direct effect on VEGFR3-expressing tumor cells (typically from endothelial origin, eg. sarcoma) 1 INCREASE IN ANTI-TUMOR IMMUNE ACTIVITY Increased infiltration of effector T-cells, and reduction in immunosupressive myeloid cells 2 INHIBITION OF METASTASIS Stabilsation of tumor vasculature and avoidance of hypoxia decreases potential for metastatic spread 3 Normal tissue Tumor cell Lymphatic vessel Blood vessel Kazia Therapeutics Limited Annual Report 2021 17 2021 AT A GLANCE CHAIRMAN’S LETTER CEO’S REPORT KEY MILESTONES PIPELINE REVIEW PARTNER FOR SUCCESS WORK WITH THE BEST #2 IN THE KAZIA STORY FINANCIAL REPORTS