Kazia Therapeutics — Deep dive into childhood brain cancer

Having established a foothold in adult brain cancer drug development, Kazia’s management is well positioned to extend its platform into child brain cancer. To date, the only options for child brain cancer are intensive radiation and chemotherapy and, in cases where possible, surgery. Despite significant advances in these treatment approaches, the possibility of long-term, debilitating side effects highlights a pressing unmet medical need. The challenges of conducting complex clinical trials for adults are compounded in the smaller children population, including recruitment. Having established a strong recruitment and key opinion leader (KOL) network in brain cancer, the company management is able to collaborate with institutions and organizations such as St. Jude Children’s Research Hospital. We expect that the current lack of treatment options and the company’s progress to date should allow the company to progress in seeking novel solutions to address child brain cancer.

Kazia Therapeutics is investigating the use of paxalisib, a dual inhibitor of mTOR and PI3K, in diffuse intrinsic pontine glioma (DIPG), which is primarily a childhood cancer. Based on preclinical data to date, paxalisib has an uncommon ability to effectively cross the blood-brain barrier (BBB), making it well suited for central nervous system (CNS) indications. PI3K and mTOR amplification/overexpression is estimated to be a driver of tumor progression in up to 80% of DIPG tumors, highlighting this as a potential target for chemotherapy in DIPG. Significant activation of the PI3K/mTOR pathway has also been observed in atypical teratoid rhabdoid tumor (ATRT), a highly aggressive form of CNS cancer primarily diagnosed in early childhood (described further below).

Paxalisib has been shown to inhibit tumor growth in a Phase I trial (NCT01547546), demonstrating stable disease in 19 patients (40%) with progressive or recurrent high-grade gliomas (HGGs) with minimal dose-limiting toxicities. Furthermore, the first patient in a Phase II investigator-led study (NCT05009992) for the treatment of DIPG and other diffuse midline gliomas (DMGs) with paxalisib, was dosed in November 2021. This study utilizes an adaptive platform design to study paxalisib in combination with ONC201 (dopamine D2 receptor inhibitor) with or without radiotherapy in the treatment of DMGs. An adaptive platform trial allows multiple interventions to be evaluated simultaneously in a randomized study. Outcomes can be assessed on accrued data rather than a specified sample size and can inform the trial design as initial questions are answered, making the trial open-ended. This design could potentially overcome problems associated with small patient populations in DIPG. Kazia is completing a further Phase I trial, in collaboration with St. Jude Children’s Research Hospital, investigating the safety and efficacy of paxalisib in pediatric patients with newly diagnosed DIPG or DMGs after radiation therapy.

Preclinical data from Dr Raabe and Dr Barnett (physician scientists at Johns Hopkins University), presented at the AACR Annual Meeting 2022, has identified strong synergism using a combination of RG2833 (an HDAC1/3 inhibitor) and paxalisib to treat DIPG. Evaluation of this combination is ongoing; however, these finding suggest a new possible combination for paxalisib in treating DIPG.

Kazia recently presented results at the AACR Annual Meeting 2022, highlighting the effect of certain paxalisib combinations in preclinical ATRT models. The company reported that Paxalisib slowed tumor growth in orthotopic xenograft models of ATRT and extended median survival from 40 to 54 days. Furthermore, paxalisib combined synergistically with clinical asset TAK580 (DAY101, a pan-RAF kinase inhibitor from Day One Biopharmaceuticals, being studied in NCT03429803, NCT04775485) to reduce ATRT cell growth and viability. Additionally, Kazia reported preclinical findings showing that Paxalisib in combination with RG2833 decreased ATRT cell growth and increased apoptosis. Both combinations were confirmed to be more effective than paxalisib alone in mouse ATRT xenograft pilot studies. We anticipate these findings will form the basis of new clinical trials for the investigation of paxalisib in ATRT as a monotherapy and/or in combination.

Despite the continued innovation of targeted and immunotherapy drugs in adult oncology, there are no meaningful options to address child brain cancer. Using adult glioblastoma (GMB) as a proxy (as childhood cancers are very rare and hence licensing deals in these indications are even more rare), we have summarized comparisons of potential licensing deals for paxalisib in Exhibit 1. From this, licensing deals for kinase inhibitors in GBM appear to range from US$70m to nearly US$400m.

Recent decades have seen the significant innovation of targeted and immunotherapy drugs in the adult oncology space, accompanied by increased survival and quality of life for many patients. Despite this, the field of pediatric oncology is still an area of large unmet medical needs. Childhood cancers of all types are rare: an estimated 10,470 children in the United States under the age of 15 will be diagnosed with cancer in 2022, compared to 1.9 million adults. Exhibit 2 highlights average UK case numbers for the 10 most common pediatric cancers. For biotech and pharmaceutical companies looking to address indications in this field, there are considerable obstacles to overcome. Low patient numbers can result in difficulties filling clinical trials, particularly in less prevalent cancers. Furthermore, many childhood cancers are not observed in the adult population, as they tend to be driven by different factors, hence limiting the read-across from approved chemotherapy agents.

Owing to the difficulties associated with developing drugs for pediatric oncology, and the absence of targeted therapies in many cases, treatment of childhood cancers often focuses on radiotherapy and the intensification of chemotherapeutic regimens. Optimization of such multimodal treatments commonly succeeds (80% of pediatric oncology patients survive for at least five years after diagnosis), however the surviving children often experience chronic health effects. This is highlighted in a 2006 study that calculated the cumulative incidence of chronic health conditions in childhood cancer survivors as 73.4% by age 30. Serious chronic conditions reported include cardiomyopathy and secondary cancers. Thus, there is a clear unmet medical need for targeted therapies that can avoid the use of intensive chemo- and radiotherapy in pediatric oncology patients.

To address the problems associated with drug development in pediatric oncology, governments and regulators have implemented a selection of initiatives to incentivize development. For example, in 2012 US Congress expanded the priority review voucher (PRV) program to include drug development in rare pediatric diseases. A drug targeting a qualifying indication that has demonstrated significant improvements in safety and/or efficacy versus standards of care can provide the sponsor with a PRV that can be used for subsequent regulatory applications for other drugs in any indication. Possession of a PRV offers the owner an expedited FDA NDA review process of up to six months (as opposed to a standard NDA review that usually lasts up to 10 months). Importantly, PRVs are transferable and can be sold to other drug developers. As seen in Exhibit 3, this is often for a considerable price, making PRVs a valuable asset to companies they are awarded to. DIPG or other pediatric brain cancer programs studied by Kazia are likely to result in Kazia receiving a PRV if the product eventually gains approval.

The FDA Orphan Drug Designation (ODD) initiative provides another major incentive for the development of pediatric oncology drugs. Qualifying drugs intend to treat, prevent or diagnose rare conditions or diseases that affect fewer than 200,000 people in the United States. Owing to the rarity of childhood cancers, almost all drugs developed to treat a pediatric oncology indication will qualify for this initiative. An ODD qualifies the recipient for benefits including potential market exclusivity of seven years after approval and tax credits for clinical trials.

According to the NCI SEER program, brain cancer is the second most common cancer in children, representing ~16% of all new cancer diagnoses in that age group.

A particularly aggressive and invasive high-grade (Grade IV) glioma that mostly affects young children is DIPG (previously known as diffuse midline glioma, DMG). Tumors of this kind are found in an area of the brain known as the pons, a crucial brainstem structure involved in a range of basic human functions such as breathing, hearing, taste, eye movement and balance. DIPG is predominantly diagnosed in children aged five to 10 and rarely occurs in the adult population. While the incidence of DIPG is low (one to two per 100,000 in US, ~300 new pediatric cases per year), most patients will survive less than one year after diagnosis (median overall survival rate 9–11 months). This stark prognosis is due to the highly invasive and aggressive nature of DIPG often making surgical resection impossible, the heterogeneity of DIPG tumors and the lack of FDA approved targeted treatments. Current standard of care for DIPG patients is palliative radiotherapy and despite modern advances in radiology, outcomes for survival have not changed over the past 20 years.

Up to 90% of DIPGs possess a lysine-27 to methionine point mutation in histone 3 (H3K27M), which is strongly correlated with poor prognosis in such patients. Importantly, the H3K27M mutation cooccurs with changes in signaling genes, including receptor tyrosine kinases, transcriptional regulators, cyclin-dependent kinases, intracellular kinases and tumor suppressors. These mutations may offer attractive targets for new targeted therapy development. A selection of drugs in development for the treatment of DIPG is summarized in Exhibit 4.

Atypical teratoid rhabdoid tumor (ATRT) is another highly aggressive (always diagnosed as Grade IV) form of CNS cancer primarily diagnosed in early childhood. Tumors of this type represent the most common malignant CNS cancer in children below one year of age and over 90% of diagnoses are made in children younger than three years. ATRT diagnosis is incredibly rare, with an estimated 596 people living with the cancer in the United States, or ~60 cases reported each year, and only 50 cases ever reported in adults. The primary treatment for ATRT is multimodal and involves maximum safe surgical resection followed by adjuvant chemo- and radiotherapy, which are accompanied by often severe side-effects. Despite this aggressive line of treatment, many patients will become refractory to therapy and the prognosis for ATRT is generally poor, reflected in a relative five-year survival rate of 32.2%.

Most ATRTs are characterized by the loss of function mutations of SMARCB1, a gene important for normal cell differentiation, the loss of which is associated with uncontrolled cell proliferation and tumor growth. There are currently no approved targeted therapies for the treatment of ATRT, however various attractive targets have presented themselves and several drugs have entered clinical trials. Examples include vorinostat (a histone deacetylase inhibitor), alisertib (an aurora kinase A inhibitor), ribociclib (a cyclin-dependent kinase 4/6 inhibitor) and dasatinib (a multi-tyrosine kinase inhibitor).