Kazia Therapeutics to collaborate with Cornell University for new paxalisib phase II clinical trial

Kazia Therapeutics Ltd (ASX:KZA) (NASDAQ:KZIA) has teamed up with a medical college from Cornell University to launch a phase two clinical study investigating Kazia’s investigational new drug paxalisib in combination with ketogenesis. Specifically, the study will evaluate Kazia’s paxalisib candidate, in combination with ketogenesis, for treating an aggressive form of cancer known as glioblastoma. Cornell’s Joan & Sanford I Weill Medical College will work with Kazia on the clinical study, which is expected to start recruiting patients towards the end of 2021. Ultimately, data from the study has the potential to significantly enhance the activity of paxalisib in glioblastoma and to minimize certain side effects, including hyperglycemia (generally known as high blood sugar). Shares have jumped as much as 13% higher intra-day to A$1.48 while KZA's market cap at the opening was approximately $173.6 million. “Immensely challenging disease” The principal investigator for the study, Dr Howard Fine, said: “Glioblastoma remains an immensely challenging disease, and we need the most potent array of tools at our disposal in order to treat it. “My lab has extensive experience of translational research in this area, and I am excited to explore the potential for a brain-penetrant PI3K inhibitor in combination with ketogenesis.” Ketogenesis and glioblastoma The upcoming study will investigate the effect of an alternative biochemical pathway known as ketogenesis, in combination with Kazia’s drug candidate, on glioblastoma. Ketogenesis occurs when cells metabolise fats and proteins to provide energy, breaking them down to an intermediate form known as ketones. This process occurs when glucose - generally the primary energy source for cells - isn’t readily available, so fats and proteins can provide an alternative energy source. But, unlike healthy cells, most tumour cells are poorly able to metabolise ketones, and so depend on glucose for their energy needs. Consequently, many researchers have experimented with ‘ketogenic diets’ as a potential treatment for cancer. PI3K signalling Additionally, high levels of glucose in the body have been known to produce insulin, a hormone that has the potential to counteract the anti-tumour effects of PI3K inhibitors. Essentially, studies indicate these inhibitors can combat signalling to cancer cells, which limits their progression and growth. As a result, research by Professor Lew Cantley, who discovered the PI3K pathway, suggests that ketogenesis may enhance the activity of PI3K inhibitors in glioblastoma, with impressive preclinical data previously published in clinical oncology journal Nature. Professor Cantley, who is a scientific advisor to the study, said: “The interplay between the PI3K pathway, insulin signalling and tumour growth has been a focus of scientific interest for some time now. “Our research clearly shows the synergistic benefits of PI3K inhibition and ketosis in animal models of glioblastoma. This is an important project, designed to verify these laboratory findings in the human setting.” More broadly, a 2019 study published in the Molecular Cancer journal found that treatments that inhibit PI3K signalling are effective in treating several types of cancer. Study details Kazia and the Weill Cornell Medicine school’s upcoming study will recruit patients in two cohorts, with approximately 16 candidates initially accepted in each arm. The first cohort will contain patients with newly diagnosed glioblastoma who are essentially resistant to temozolomide, the existing standard-of-care therapy. The second arm will contain patients with recurrent disease, who have progressed after taking standard-of-care therapy. During the study, patients will be administered paxalisib and glycemic control drug metformin in combination with a ketogenic diet. If there are signals of activity in a given cohort, that arm will be expanded to approximately 30 patients. The primary endpoint for the clinical study will be progression-free survival at six months. The initiation of this trial in glioblastoma brings the number of ongoing clinical studies of paxalisib in brain cancer to nine. Current studies evaluating paxalisib in brain cancer.