Biotech

Kazia Therapeutics recruits first keto patient to phase II paxalisib study for treatment of glioblastoma

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By Imelda Cotton - 
Kazia Therapeutics ASX KZA KZIA NASDAQ paxalisib metformin ketogenic diet glioblastoma

Kazia的研究将探索paxalisib、二甲双胍和生酮之间的关系。

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Oncology-focused drug development company Kazia Therapeutics (ASX: KZA) has recruited its first patient into a phase II study of investigational new drug paxalisib for the treatment of newly-diagnosed and recurrent glioblastoma.

The two-year study has been initiated at Weill Cornell Medical Centre in New York and will investigate the efficacy of paxalisib in combination with diabetic medication metformin and a ketogenic diet across two arms with an initial cohort of 16 patients each.

The first arm will comprise patients with newly-diagnosed glioblastoma who have unmethylated MGMT promoter status and have responded poorly in the past to current standard of care drug temozolomide.

The second will comprise patients with recurrent disease (regardless of the methylation status of their MGMT promoter) who have progressed after taking standard-of-care therapy.

In each arm, the combination of paxalisib with metformin and a ketogenic diet will be supervised by clinical dieticians to ensure it is scientifically appropriate and that patients are compliant.

If there are signals of activity in a given arm, Kazia said that arm will be expanded to approximately 30 patients.

In addition to efficacy and safety, the study will examine a range of metabolic, pharmacodynamic, and novel radiographic imaging biomarkers to inform future research and clinical practice.

Low insulin state

Research by Professor Lew Cantley, who discovered the PI3K pathway (one of the most important intracellular pathways in the human body which can be considered as a master regulator for cancer), suggests that a low-insulin state may enhance the activity of PI3K inhibitors such as paxalisib.

Inducing a ketogenic state – in which the body is fuelled by fats and proteins rather than by glucose – is reported to be an effective way of reducing insulin levels.

Unlike healthy cells, most tumour cells are poorly able to metabolise ketones and depend on glucose for their energy needs.

Many researchers have experimented with ‘ketogenic diets’ as a potential treatment for cancer.

Adding in a treatment with metformin is intended to further reduce insulin levels on patients in the Kazia study.

Exploring the relationship

Principal study investigator and founding director of the Brain Tumour Centre at Weill Cornell Dr Howard Fine said the study would explore the relationship between paxalisib, metformin and ketogenics.

“My colleagues and I believe that administering paxalisib to patients in a ketogenic state may significantly enhance its efficacy we have extensive and very convincing preclinical data to support this approach,” he said.

“It offers the potential to make a very significant difference in the treatment of glioblastoma, which remains one of the most challenging cancers in modern medicine.”

Dr Fine’s lab has shown that insulin can reverse the anti-tumour effects of PI3K inhibitors specifically in glioblastoma cells.

“For these reasons, there is a sound rationale to explore a combination of metformin, ketogenic diet and paxalisib in glioblastoma,” he said.