17 Kazia Theraputics Limited Annual Report 2023 Chairman and CEO’s Letter Key Milestones Introduction to Kazia’s CEO Pipeline Review Environment, Society and Governance Financial Reports Kazia Therapeutics Limited Clinical Pipeline Overview Paxalisib Kazia’s lead program is paxalisib, an investigational brain-penetrant inhibitor of the PI3K / Akt / mTOR pathway, that was specifically designed to treat brain cancer. Brain cancers account for about 15% of paediatric cancers and are the second most common type of cancer in children whereas over 300,000 adults are diagnosed every year with primary brain cancer. It is important to recognize that paxalisib, by design, has the potential to be an integral component to precision medicine. As a targeted therapeutic, we have focused many of the ongoing trials to evaluate paxalisib in patients who have PI3K pathway mutations. Enriching clinical trials with patients who have the potential to have the greatest response and benefits accelerates clinical trial recruitment and time to commercialization. The overall clinical development strategy for paxalisib has been crafted into three core pillars. Within the adult brain cancer pillar, we have four ongoing clinical studies across three different patient populations. There are two actively recruiting clinical studies and one recently completed study in the paediatric brain cancer pillar. Within the brain metastases pillar, there are three ongoing studies. Paxalisib in Adult Brain Cancer Glioblastoma (GBM) is a fast-growing and aggressive brain tumour. Paxalisib is being developed primarily for the ~65% of newly-diagnosed unmethylated GBM patients who generally do not respond to existing chemotherapy with temozolomide. The final data from a phase II study in newly diagnosed GBM patients reported promising signals of clinical activity with paxalisib and was presented at two global conferences in 2023. GBM AGILE Pivotal study GBM AGILE (Glioblastoma Adaptive Global Innovative Learning Environment) evaluates investigational therapies for patients with newly diagnosed and recurrent GBM. The goal is to expedite the approval of new drugs for this disease. Kazia announced on 1 August 2022 that the company had been advised by GCAR that the first stage of the paxalisib arm had completed recruitment. The treatment arm did not meet pre-defined criteria for continuing to a second stage, and patients enrolled in the first stage of the paxalisib arm will therefore continue on treatment as per protocol, and in follow-up, until completion of the final analysis, which we anticipate receiving in 2H CY2023. Depending on the results of the study, Kazia may use such data to support submission of a new drug application for marketing authorisation to the FDA. LUMOS2 phase II study Kazia is supporting the University of Sydney on a molecularly guided phase II clinical study evaluating paxalisib in adult patients with recurrent/progressive isocitrate dehydrogenase (IDH) mutant grade 2 and 3 gliomas (G2/3 gliomas). The LUMOS2 study is sponsored by the University of Sydney with a goal of investigating targeted therapeutics in these patients who have limited options. The study is expected to enrol up to 76 patients with PI3K pathway mutations and will be a multicentre study at several Australian sites, with the potential to expand internationally. We anticipate enrolment to commence in 4Q23. Weill Cornell Medicine The clinical study at Weill Medical College of Cornell University in the United States, is exploring the use of paxalisib in combination with metformin and a ketogenic diet for patients with glioblastoma. A significant and growing body of research has suggested the potential for ketogenic diets to provide benefit in a range of tumour types, including glioblastoma. The study is actively enrolling in two cohorts of GBM patients, and we anticipate providing an update to this study in 4Q CY2023. Dana Farber Cancer Institute (DFCI) In June 2021, Kazia announced that the phase II study of paxalisib in relapsed/refractory patients with primary CNS lymphoma at DFCI had commenced recruitment. As a brain penetrant PI3K inhibitor in mainstream development, paxalisib has unique potential in the form of this disease that occurs within the central nervous system and we anticipate providing a clinical update to this study in 2H23. Paxalisib in Paediatric Brain Cancer Brain cancer is the most common malignancy of childhood and represents about one third of all childhood cancer deaths. The PI3K/AKT/mTOR pathway is frequently upregulated in paediatric cancers and therefore therapeutics that target those pathways could lead to well long-awaited regulatory approvals. Diffuse intrinsic pontine glioma (DIPG) is the most common of a group of childhood brain cancers known as diffuse midline gliomas (DMGs). The disease has no FDA approved drug treatments and average survival from diagnosis is approximately 10 months. Kazia recognizes the critical importance and immense unmet need and is aggressively exploring paxalisib in two common forms of childhood cancer - Diffuse Midline Gliomas (DMG, DIPG) and Advanced Childhood Cancer with PI3K/mTOR mutations. PNOC022 phase II study The PNOC022 study is sponsored by the Pacific Pediatric Neuro-Oncology Consortium (PNOC), an international consortium focused on the development of novel combination therapies. It is an adaptive platform study that is examining paxalisib in combination with ONC201. The study enrolment has been very robust since opening in late 2021 and the study team at PNOC and University of California, San Francisco (UCSF) are preparing data for interim analysis, which is expected in 2H CY2023.
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