Kazia Therapeutics Annual Report 2021

22 Kazia Therapeutics Limited 2 Annual Report 2021 study is expected to recruit around 25 patients, and to run for approximately two years. The Principal Investigator is Professor Lakshmi Nayak, a highly experienced clinical researcher in brain cancer, with a specialist interest in PCNSL. In December 2020, the company entered into a letter of intent with the Pacific Pediatric Neuro-Oncology Consortium (PNOC) to execute an investigator-initiated phase II adaptive study of paxalisib in patients with DIPG and other DMGs, a group which collectively constitutes one of the most aggressive childhood cancers. The study will explore paxalisib in combination with ONC-201, a small-molecule investigational new drug which targets dopamine receptor D2 (DRD2), and which is manufactured by Oncoceutics, Inc, a wholly-owned subsidiary of Chimerix, Inc. The St Jude phase I study in DIPG has already provided invaluable information regarding dosing and safety of paxalisib in a paediatric population, but it has always been assumed that combination therapy would be required to achieve meaningful efficacy in such an aggressive tumour. Research by Professor Matt Dun at the Hunter Medical Research Institute in Newcastle, Australia, has shown compelling evidence of combinatorial synergy between paxalisib and ONC-201, and so the PNOC study will investigate this combination, among others, in patients. In June 2021, the company entered into an agreement with the Joan & Sanford I Weill Medical College of Cornell University in New York, NY, known generally as Weill Cornell Medicine, for an investigator-initiated phase II clinical trial combining paxalisib with ketogenesis in patients with newly-diagnosed and recurrent glioblastoma. In addition to the general interest in ketogenic diets as a potential adjunct to treatment for various forms of cancer, research by Professor Lew Cantley and colleagues has demonstrated the potential for insulin to antagonise PI3K inhibition. Administering a PI3K inhibitor in the context of minimal insulin secretion should allow the drug to achieve its full potential, and a combination of ketogenic diet and metformin will be used in this study to achieve a hypoinsulinaemic state. Professor Cantley serves as a scientific advisor to the study, and Dr Howard Fine, a highly experienced neuro-oncologist, will serve as Principal Investigator. The study is expected to commence recruitment during 2H CY2021. The company’s second development candidate is EVT801, a small-molecule selective inhibitor of vascular endothelial growth factor receptor 3 (VEGFR3). EVT801 was originally discovered by Sanofi SA and was licensed to Evotec SE as part of a broader transaction. Evotec conducted an extensive program of preclinical development, which showed compelling evidence of activity in a broad range of animal models. The drug was licensed to Kazia in April 2021. For several decades, it has been clear that growing tumours require an extensive network of newly formed blood vessels and lymphatic vessels to satisfy their substantial nutrient requirements. Drugs which inhibit the formation of new blood vessels (angiogenesis inhibitors) have proven effective in a wide range of solid tumours, with Avastin (bevacizumab) being the best-known example of the class. However, the use of such drugs is limited by hypoxia-induced resistance mechanisms and, in the case of many small-molecule inhibitors, by toxicity. EVT801 has been designed to respond to these challenges by selectively targeting lymphangiogenesis, the formation of new lymphatic vessels. Doing so, and with a high degree of selectivity, is expected to provide many of the same benefits as inhibition of angiogenesis, but without the attendant problems of resistance and toxicity. In addition, drugs which target VEGF receptors have shown the potential to alter the population of immune cells within the tumour micro-environment, thereby potentially making ‘cold’ tumours more susceptible to immuno-oncology agents such as checkpoint inhibitors. A wealth of preclinical evidence supports this hypothesis with EVT801 and provides a second and almost entirely distinct mechanism of action through which the drug may provide benefit to cancer patients. EVT801 is protected by granted or pending composition-of-matter patents in all key territories, with exclusivity generally through to the early 2030s. Kazia has initiated work on a phase I clinical trial of EVT801, which will seek to explore both of these mechanisms, as well as provide critical information regarding the safety, tolerability, and pharmacokinetics of the drug. The planned phase I study will be initiated at two trial sites in France and will aim to recruit up to 96 patients with advanced cancer. Multiple stages of the study will evaluate EVT801 both as monotherapy and in combination with one or more immuno-oncology agents. The study is expected to commence recruitment by the end of CY2021. Subsequent events There were no significant events subsequent to the reporting date. SIGNIFICANT CHANGES IN THE STATE OF AFFAIRS There were no significant changes in the state of affairs of the consolidated entity during the financial year. LIKELY DEVELOPMENTS AND EXPECTED RESULTS OF OPERATIONS The consolidated entity has a reasonable expectation that over the course of the coming 12 months: • Final results will be reported from the phase II clinical trial of paxalisib in glioblastoma; • Interim results will be reported from the phase II clinical trial of paxalisib in combination with trastuzumab in breast cancer metastases; • Interim results will be reported from the phase II genomically-guided study of paxalisib in brain metastases; • Interim results will be reported from the phase I study of paxalisib in combination with radiotherapy in brain metastases; • Final data will be reported from the phase I study of paxalisib in children with diffuse intrinsic pontine glioma (DIPG); • The phase II study of paxalisib in combination with a ketogenic diet in glioblastoma will commence recruitment; • The phase II study of paxalisib in combination with ONC-201 in DIPG and DMGs will commence recruitment; and • The phase I study of EVT801 in patients with advanced solid tumours will commence recruitment. ENVIRONMENTAL REGULATION The consolidated entity is not subject to any significant environmental regulation under Australian Commonwealth or State law.