Kazia Therapeutics Annual Report 2021

CHAPTER TWO IN THE KAZIA STORY (continued) TODAY, A WIDE VARIETY OF MARKETED DRUGS TARGET ANGIOGENESIS Some, like Avastin, work by targeting VEGF. Others target the receptor on blood vessels to which VEGF binds, which is known as the VEGF receptor or VEFGR. Drugs which work this way include Nexavar (sorafenib) and Sutent (sunitinib). In aggregate, drugs modulating angiogenesis account for more than US$ 10 billion in annual sales. Product Company Target(s) Indications Annual Sales (US$) Avastin (bevacizumab) Genentech VEGF-A – Colorectal cancer – Lung cancer – Breast cancer – Other cancers $7 billion Nexavar (sorafenib) Bayer VEGFR PDGFR RAF kinases – Hepatocellular carcinoma – Renal call carcinoma – Thyroid cancer $1 billion Sutent (sunitinib) Pfizer VEGFR PDGFR – Renal cell carcinoma – Gastro-intestinal stromal tumor $750 million Votrient (pazopanib) Novartis VEGFR PDGFR c-Kit FGFR – Renal cell carcinoma – Soft tissue sarcoma $1 billion Inlyta (axitinib) Pfizer VEGFR c-Kit PDGFR – Renal cell carcinoma $400 million As effective as it is, targeting angiogenesis has a very significant problem. Cutting off the blood supply reduces the oxygen levels in the tumour, a situation described as hypoxia in scientific literature. Initially, hypoxia stops the tumour from growing. However, prolonged hypoxia triggers adaptive mechanisms in the tumour which allow it to grow via different means. Because of this, as tumours mutate and develop, they eventually become resistant to anti-angiogenic therapies. Avastin, and therapies like it, are never curative, and will eventually become ineffective in most patients. Thankfully, the human body has two circulations. The blood circulation is the best known and most visible. But the lymphatic circulation runs in parallel and is just as important for the growth of tissues. Cells need access to both systems. One can think of them as similar to the water and electricity supply to a house – both are critical for the house to be habitable. Targeting the lymphatic system may be just as effective in treating cancer. And as a bonus, oxygen is carried almost entirely by the blood, and so cutting off the lymphatic supply to a tumour does not cause the same level of hypoxia. In principle, a drug targeting lymphangiogenesis may have all the advantages of a drug targeting angiogenesis, without the downside of resistance. FROM ANGIOGENESIS TO LYMPHANGIOGENESIS – BUILDING A BETTER CANCER DRUG Kazia Therapeutics Limited 16 Annual Report 2021