Paxalisib is a novel targeted therapy that modulates the PI3K pathway. Kazia licensed paxalisib (as GDC-0084) from Genentech in 2016 and is developing it as a potential treatment for glioblastoma in a Phase II clinical trial. Four additional investigator-led clinical studies are also underway for children with DIPG, for breast cancer which has metastasised to the brain, and also for any form of primary cancer which has metastasised to the brain.

  • Market Need

    Glioblastoma is the most common and most aggressive form of brain cancer. Despite all efforts, there have been few significant advances in treatment over the last decade, and the prognosis remains poor. The five-year survival rate is around 3%, compared with approximately 89% for patients with breast cancer.

    It is estimated that approximately 2 out of every 100,000 people will develop GBM each year, and there are approximately 12,500 new cases per annum in the United States. The disease commonly begins with innocuous symptoms such as headache and nausea, but progresses rapidly if untreated.

    Newly-diagnosed patients typically undergo surgery to remove as much of the tumour as possible, and are then treated with radiotherapy and a drug named temozolomide in order to delay recurrence. However, the vast majority of patients soon experience disease progression and survival, even in optimally-treated patients, averages approximately fifteen months.

    The Science Behind It

    The phosphoinositide-3-kinase (PI3K) signalling pathway is one of the central control mechanisms for cells in the human body. It is disordered in many types of cancer, and for some years researchers have experimented with drugs that inhibit this pathway as an approach to treating cancer. At present, one drug, idelalisib, is approved for use in certain kinds of leukaemia and lymphoma.

    The PI3K pathway is disordered in many types of cancer, and has been well validated in clinical trials as a target for new treatments.

    The PI3K pathway appears to be disordered in more than 85% of cases of glioblastoma, and so this appears to be a high-potential target for new glioblastoma therapies.

    Paxalisib is a potent inhibitor of the PI3K pathway, and has been shown to have an anti-tumour effect in animal models of glioblastoma. Paxalisib is distinguished by its ability to cross the so-called blood-brain barrier, which prevents many drugs from fully affecting brain tissue.

    In a phase I clinical trial conducted by Genentech, paxalisib (as GDC-0084) was shown to have acceptable tolerability in a group of patients with advanced brain tumours, including a majority of patients with glioblastoma. Paxalisib also showed an ability to reduce tumour size in some patients, and demonstrated a reduction in the activity of some tumours using an experimental imaging technology known as FDG-PET. These data were presented at the ASCO Annual Meeting in June 2016.


    Investigator-led studies


    In addition to our in-house clinical program, paxalisib is also involved in four additional clinical trials which are sponsored by and performed at world-leading reserch hospitals, by clinicians who are top experts in their field. These studies are also primarily funded by sources external to Kazia, so our own modest financial investment is amplified many times over by the bigger committments of these partners.

    Each clinical trial is in a different patient group, and any one of them could define a path forward for the drug.


    Timing and Market Implications

    There are a number of upcoming milestones arising from our five clinical trials, with initial data or preliminary read outs anticipated over the coming months:


    • Kazia Therapeutics commenced a clinical study of paxalisib in glioblastoma in early 2018. This study will aim to provide definitive clinical proof-of-concept data for paxalisib, and data is expected from part B of this trial in 1H 2020.
    • Positive interim efficacy data, published in November 2019, showed median progression-free survuval (PFS) of 8.4 months, against an existing standard of care of of 5.3 months (although cross-study comparisons should always be treated with caution). Overall survival (OS) cannot yet be evaluated as 75% of evaluable patients remained alive at the cut-off date for analysis.
    • A Phase I study with St Jude Children's Hospital is examining paxalisib in DIPG.  This study is recruiting well and we anticipate being able to share some initial insights in mid 2020.
    • In October 2018, the Dana-Farber Cancer Institute commenced a Phase II study of paxalisib in breast cancer brain metastases, in combination with Herceptin.  We hope to have some initial news to report in 1H 2020.
    • In May 2019, paxalisib was included in the Alliance study for cancer which has spread to the brain, along with drugs supplied by Eli Lilly and Genentech.
    • Memorial Sloan Kettering Cancer Centre is investigating the potential use of paxalisib in combination with radiotherapy in a Phase I clinical trial for cancer which has spread to the brain.
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    • Interim efficacy data released in November 2019 with promising results
    • the provisional name for GDC-0084 has been selected by WHO, with confirmation anticipated by the end of the year.  The provisional name is "paxalisib"
    • GDC-0084 was selected to join the prestigious Alliance open label trial into brain metastases, whereby patients will be allocated to receive one of three drugs (the other two being supplied by Eli Lily and Genentech) depending on the genetic profile of their tumour
    • Superior safety and tolerability data was announced from the Phase IIA study in newly diagnosed glioblastoma patients.  Seven sites have participated so far in the trial, including Dana Farber Cancer Institute, MD Anderson Cancer Centre in Houston, Texas, John Theurer Cancer Centre in Hackensack, NJ, Massachusetts General Hospital Boston, Stephenson Cancer Centre Oklahoma, University of California Los Angeses and University of Colorado Cancer Centre.  


    November 2018


    • All sites were open to recruitment and the first cohort of patients fully enrolled and undergoing treatment
    • GDC-0084 also involved in two additional studies with St Jude Childrens' Research Hospital in DIPG (a rare and aggressive form of brain cancer in children) and Dana-Farber Cancer Institute in breast cancer brain metastases
    • an additional batch of GDC-0084 capsules commenced manufacture in anticipation of the ongoing clinical trials  
    • the PI3K inhibitor class of drugs has seen some dramatic developments, with FDA approving Copiktra from Verastem, bringing the number of FDA-approved PI3K inhibitors to three
    • Kazia has been undertaking a 13-week toxicology study of GDC-0084 in two animal species - as required by FDA