10 PIPELINE REVIEW Fast Track Designation Kazia received Fast Track Designation (FTD) from the FDA in July 2023 for paxalisib for the treatment of solid tumour brain metastases harbouring PI3K pathway mutations, in combination with radiotherapy, based on the promising interim clinical data from the MSKCC phase 1 trial. Introduced under the FDA Modernization Act (1997), FTD may be awarded by FDA to investigational drugs which are intended to treat a serious or life-threatening condition, and which fill an unmet medical need. FTD must be requested by the sponsor company and must be accompanied by a detailed review of both preclinical and clinical data. To be awarded FTD, drugs must generally be able to show some potential advantage over existing therapies, either in terms of safety or efficacy. A key benefit of FTD is enhanced access to the FDA, with regular and more frequent opportunities for consultation and discussion. In addition, drugs with FTD may be eligible for Accelerated Approval, in which a new medicine is approved based on a surrogate endpoint, and for Priority Review, in which the standard 12-month review process may be reduced to eight months. Drugs with FTD may also receive a ‘rolling review’ of their NDA submission, in which sections are submitted for review as they become available, potentially expediting the approval process. Genomically Guided phase II study Sponsored by the Alliance for Clinical Trials in Oncology, paxalisib is one of the targeted therapeutics being investigated in this global, multi-drug study (NCT03994796) in patients with brain metastases. Patients with PI3K pathway mutations will be enrolled in three cohorts, breast cancer, non-small cell lung cancer (NSCLC) and other. The enrolment is ongoing for all cohorts including the expansion stage of the study in breast cancer brain metastases patients. HER2+ Breast cancer brain metastases phase II study A phase II investigator initiated clinical study is ongoing at Dana-Farber Cancer Institute exploring paxalisib in combination with trastuzumab (NCT03765983) in patients with brain metastases originating from HER2+ breast cancer. The enrolment is ongoing and we anticipate providing a study update later in the calendar year. EVT801 Kazia is also developing EVT801, a small molecule targeted VEGFR3 inhibitor. Preclinical data showed EVT801 to be active against a broad range of tumour types and has shown evidence of synergy with immunooncology agents. Over the course of the year, these preclinical data have been presented at a number of global conferences, including conferences held by the American Association for Cancer Research and the European Society for Medical Oncology. We anticipate providing additional EVT801 updates and presentations of interim data at medical conferences in 2H CY2023. R&D PIPELINE Paxalisib in Metastatic Melanoma Data from an ongoing research collaboration with the Huntsman Cancer Institute at the University of Utah in Salt Lake City, UT has shown paxalisib to be active in vitro and in vivo against a range of preclinical models of metastatic melanoma, the most aggressive form of skin cancer. Data suggesting substantial activity for paxalisib as monotherapy in preclinical mouse models was presented at the 19th International Congress of the Society for Melanoma Research, held in Edinburgh, Scotland, in 2022. “This is among the most promising single agent data that we have seen in our research,” commented Professor Sheri Holmen, lead investigator on the project. “Despite the widespread adoption of immunotherapy in recent years, there remains substantial unmet need in melanoma, particularly in those patients who develop brain metastases. We look forward to exploring the potential of paxalisib further in our research, and hopefully seeing the drug transition to a clinical trial in the near future.” Paxalisib in Solid Tumours Kazia’s collaboration with QIMR Berghofer Medical Research Institute, one of Australia’s foremost cancer research centres, is currently exploring novel uses of paxalisib in solid tumours. The collaboration is based on research that identified an entirely separate effect of PI3K inhibition: as a modulator of the immune microenvironment within and around the tumour. Administration of PI3K inhibitors such as paxalisib, at doses and frequencies different to those conventionally used, appears to activate the immune system in the tumour, making it more susceptive to immunotherapy. We believe this approach could therefore open up an important opportunity for paxalisib in combination with drugs such as Keytruda® (pembrolizumab, Merck) and Opdivo® (nivolumab, Bristol Myers Squibb) for the treatment of diseases such as breast cancer and lung cancer. The collaboration is ongoing and will build on initial research that has already led to the filing of a provisional patent last year, including the use of paxalisib as an immune modulator in the treatment of diseases such as breast cancer.
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