Kazia Therapeutics Limited (KZIA) Earnings Call Transcript & Summary

Hello. Thank you for joining us today to discuss Kazia Therapeutics. I'm Soo Romanoff, Head of Healthcare Content here at Edison Group. We look forward to discussing the new data shared at ISPNO earlier this month and how our speakers are working to combat childhood brain cancer. Following this presentation, we'll host a Q&A session. If you would like to submit a question at any point, please do so by using the Q&A box at the bottom of your Zoom application. Before we begin, I'd like to briefly pause here so we can review this forward-looking statement slide. I'd also like to note that today's presentation is being recorded. Joining us today from Kazia, we have Dr. James Garner, Chief Executive Officer; and Dr. John Friend, Chief Medical Officer. James and John will be joined by Associate Professor Matt Dun of Hunter Medical Research Institute. With that being said, I'll hand it over to you, James.

Well, ladies and gentlemen, good morning, and good afternoon, and welcome to this educational webinar. We're grateful to working, to the have the opportunity to talk about a topic which has emerged as one of increasing significance for Kazia in a strategic sense. And well it also, I think, resonates in a very deep and personal way for all of us to work in the company. And that topic is childhood brain cancer. And as you've heard, we're very grateful to be joined today by Associate Professor Matt Dun of Hunter Medical Research Institute, University of Newcastle in Australia, who is going to talk us through that new data that was recently presented at the ISPNO Conference, the International Symposium on Pediatric Neuro-Oncology. And myself and Dr. John Friend, our Chief Medical Officer, will add some commentary on what this really means for Kazia, how we think about this disease area in the company and about some of the other activities that are going on in childhood brain cancer within Kazia. So let me begin by just perhaps making a few contextual remarks here, first of all, and I'd like to begin by just providing an orientation for those who are new to the company or new to the paxalisib program. Paxalisib is a drug that is being developed for brain cancer, primarily for adult brain cancer. Our lead indication, as you can see here is glioblastoma, the most common and the most aggressive primary brain tumor in adults. And the drug is in a Phase III study in glioblastoma. We expect to see final data from that study next year. So the program is well advanced and rapidly approaching potential commercialization in adult brain cancer. Behind that, however, we have a substantial and growing body of work, both in clinical trials and in preclinical research in childhood brain cancer, particularly in 2 forms that you see showing here, DIPG, Diffuse Intrinsic Pontine Glioma; and AT/RT, Atypical Teratoid Rhabdoid Tumors. And both of these have been a subject of recent data readouts, which we'll review today. Behind that, we have other work going on in adult brain cancers primary CNS lymphoma and in brain metastases, and we expect to have more information to share on those in the coming months. And I'd just say that brain cancer is the most common malignancy of childhood. It is a disease that perhaps is often thought about less than diseases like leukemia, which is often sort of perhaps the malignancy that we think of is most common in the pediatric setting. But brain cancer is more common. And not only is it more common, but it is sad to say it's extremely more lethal than hematological malignancies such as leukemia and lymphoma. The number of children passing from brain cancer exceeds that passing from lymphoma by almost twofold. And indeed, many of the fatalities these days in leukemia are due to brain metastases, which as an adult tumor has become very difficult to treat. So this is, sad to say, in the context of pediatric oncology, not a rare disease. This is unfortunately one of the main challenges facing pediatric oncologists. And when we look at our progress in this disease area, it has, sad to say, been exceptionally poor. This chart shows, in the red bar, the survival rates associated with some common childhood tumors first in 1960 and the red bars and then in 2000s in the blue bars. And as you can see for acute lymphoblastic leukemia and myeloid leukemia and non-Hodgkin's lymphoma, all of which are blood cancers, hematological malignancies. We have seen massive improvements in survival associated with better treatment of these diseases. Wilms tumor, a rare tumor of the kidneys that primarily affects children up to the age about 5, similar improvement in survival. But in brainstem gliomas, perhaps one of the more common malignant tumors of the brain in children, really no progress at all. And that has been partly a function of no new therapies in this disease. As you can see on the panel on the right-hand side of the slide, we have no FDA-approved drugs to treat any of these common childhood brain cancers. And so this is, as we sometimes say in Kazia, this is very much the definition of our unmet medical need. We have a disease that represents the most common cause of childhood cancer death, but for which we have no drug treatments. And when we talk about childhood brain cancer, it's important to note that we are talking about an extremely diverse spectrum of illness. About 5,000 incident cases a year in the United States and a little over half of those are malignant in nature. A number of non-malignant tumors and angiomas and choroid plexus tumors and so on, which we won't talk about today. But within the malignant category, gliomas are the most common as a disease of the glial cells in the brain, which is the same cell that gets derived to diseases like glioblastoma. And within that group, a subset is a group of cancers called diffuse midline gliomas, tumors essentially at the spinal cord, brainstem and thalamus. And, just a word on terminology here. We talk a lot about DIPG, Diffuse Intrinsic Punting Glioma, a particular form of glioma that occurs in children, DMGs ,Diffuse Midline Glioma, this is a more modern terminology and a slightly broader term than DIPG. For practical purposes, the 2 are somewhat interchangeable these days, but you'll hear us talk about both DMGs and DIPGs. They -- in the way that we use they tend to mean roughly the same thing. There's also a category of embryonal tumors here which comprises again, a range of different cancers, AT/RT is one that we'll speak about today. And I'll just note and pass on medulloblastoma, another form of embryonal childhood brain cancer, which has been an area of interest for the company where we've had some stimulating discussions in recent months and something we may come to look out more closely in the months ahead. And I'd just say that this has historically been perhaps a neglected area for the pharmaceutical industry. Childhood cancer, in general, has not seen a lot of new approvals up until about 5 years ago, and this chart shows FDA approvals of new therapies for childhood cancers over the last decade. As you can see half of the decade, fairly fast. But over the last 5 or 7 years, a real burst of activity with more than a dozen new therapies being approved for childhood cancers. Sad to say, none of these for childhood brain cancer at this stage, but certainly, I think this reflects the growing focus of the industry, growing prioritization of pediatric malignancies. Why is this happening? Well, one reason is that the regulatory environment has really moved in favor of companies trying to develop drugs for these kind of diseases. This slide characterizes some of the key legislation in both the United States and Europe that pertains to the development of diseases -- of drugs with pediatric indications. And I would characterize it by saying that the public policy has really moved from character stick over the last couple of decades. If we look at back at BPCA, one of the initial pieces of legislation right back in 2002, it's really provided some fairly gentle incentives for sponsors to develop drugs for childhood diseases. But if we look at the more recent legislation, the race for Children Act about 5 years ago, this really imposes obligations on pharmaceutical companies to provide pediatric development plans. And so we've really seen a shift in the regulatory framework from incentive due to obligation. And I think that's been one of the drivers behind the increasing interest of industry here. There are, however, still very substantial incentives and one of those is noted at the bottom here, The Creating Hope Act of 2012, which created the opportunity for pediatric priority review vouchers, the ability on submitting a drug for a pediatric indication to receive a priority review voucher, which can be sold to other companies and which have historically commanded significant value in the secondary market. And those who follow the Kazia story are aware we do have rare pediatric disease designation from FDA for DIPG. It is kind of the crucial designation that opens this opportunity for us. So again, as I say, a mixture of commitment and incentive here in terms of the regulatory framework. And so with that very brief overview, I'd like to hand over now to Associate Professor Matt Dun, to talk through some of the data he recently presented at the ISPNO conference in Hamburg, Germany. And Matt, over to you.

Thanks, James. Good morning and good evening, ladies and gentlemen. Thanks for the opportunity for me to present some of our data that's been focused on working of paxalisib for the treatment of DIPG and DMG over the last 4.5 years. Next slide, please, James. So for those of the uninitiated, Diffuse Intrinsic Pontine Glioma or Diffuse Midline Glioma is a glioma diagnosed within the brainstem of the central nervous system. So the brainstem sits the top of the spinal column, and it's a really critical organ that regulates life-essential functions. And they include the autonomic functions such as cardiac control and respiratory control, but also numerous and critical neurons trap to reverse the brainstem that allow our body to move. So our motor neurons run parallel to the brainstem. So a tumor that's diagnosed and grows rapidly within this organ has devastating consequences. Unfortunately, [indiscernible], as James beautifully articulated, there is no recognized therapies for the DIPG other than radiotherapy and children succumb their disease within 9 to 11 months. So it really highlights the need to identify therapies that may have somewhat circumvent this terrible survival statistic. Next slide, please, James. So DIPG is a heterogeneous disease, which means that there's a lot of changes to the cell's DNA that keeps arise to the disease. But more importantly, I think DIPG is an epigenetic disease. So what does that mean? It means that the regulation of the genes that are responsible for the growth and survival of the tumor are completely unraveled, and they are able to be created and drive the growth of the disease very rapidly. And what I mean by that is that they mostly regulate the way that the cell produces energy. Now there's a number of mutations within DIPG that are seen across all patients. And many of these gene mutations are linked to the targets of paxalisib and these include the PIK3CA, PIK3R1 and the PTEN gene. Now when you have mutations in these genes, it leads to unfettered control of this PI 3-kinase/ AKT Signaling Pathway and the cells are rapidly able to generate new energy from various range of sources, which may be directly from glucose uptake, insulin and also fats. And that means that the cells are almost completely metabolically immortal. So paxalisib makes a good way to target some of these pathways because it hits the PI3-kinase Pathway at the top of the tree. Next slide, please, James. So here, we've been using a number of drugs in combination with paxalisib particularly, I'd like to point out this drug called ONC201. Now ONC201 was discovered in 2012 as a way to kill cancer cells that have loss of function of the most mutated gene in cancer, and that's TP53. This drug, ONC201, is a very small molecule that crosses the blood-brain barrier and gets into the brain. And it's a very safe drug with very few adverse events being recorded on multiple clinical trials that it's tested, its maximum tolerated dose and trials that are now starting to investigate efficacy. We collected the data on 28 DIPG patients that had gained access to ONC201 over a 2.5 or 3-year period. and report here in the panel on the left, immediate in overall survival of approximately 18 months, so a 7- to 8-month improvement on historical controls. But as you can see in the middle, the preclinical testing of the drug shows the DIPG cells, which are mostly harvested from patients that were donated by their families at autopsy. There's a various and hydrogeneous range of responses to the drug, meaning that more than 50% of the cells that we've tested show absolutely no response to the drug. So we wanted to use that as a basis for investigating why the cells respond and why they failed. And when we did so, we investigated numerous of these cell lines that showed no response to the drug and that they all popped up to show they had hyperactivated PI 3-kinase/AKT Signaling here on the right, and that was driving processes that led to immortality such as turning off the cell's intrinsic ability to die, which is called apoptosis, turning the cells into more of a stem cell-like cell, which means that they don't respond to radiotherapy or chemotherapy. And then upregulating pathways that synthesize glucose and insulin to drive their metabolic needs. Next slide, please, James. So once we were armed with that information, we took very poorly sensitive DIPG cells that were taken from a patient at autopsy. And we implanted these into research animals and tested both drugs as a monotherapy and also in combination. And here, you can see from the Kaplan-Meier curve on the left, that both drugs provide a modest survival benefit compared to vehicle control. But when we combine the PI 3-kinase/AKT inhibitor paxalisib with ONC201, we saw a significant increase in survival. Now taking tumors out of the mice that have been treated with the drug and investigating whether we had on-target effects. This is a really nice way to determine whether, one, the drugs are getting into the brain; and two, whether the drugs are doing what they're meant to do. And as you can see on the left, these are called [ western blot ]. So this is a protein array where we've taken protein out of the primary tumor that was growing in the mouse and investigated whether the targets of the drugs were indeed being down regulated as a consequence of treatment. And here you can see the 2 best markers of paxalisib efficacy, the AKT proteins on the top right, are completely abolished with treatment either used as a monotherapy or in combination with ONC201. And as you can see in the middle column ONC201 indeed drives further activation of the PI 3-kinase/AKT Signaling Pathway, which really highlights why the combination works so well. Next slide, please, James. Now Phase Ib clinical trials for both drugs as monotherapies that have shown very acceptable toxicity profiles, and we've determined maximum tolerated dose thanks to these 2 early-stage clinical trials. And as a consequence, the lead clinicians involved in these studies, we're encouraged to test the combination firstly, in a patient that was on the ONC201 clinical trial as a monotherapy here on the left. And this patient had a stable disease for about 12 months whilst receiving ONC201 alone, and that was started immediately post radiotherapy. The patient experienced quite significant disease progression marked here in C and then elected to have re-irradiation. And whilst you had re-irradiation, she continued on ONC201 and the day after re-irradiation was completed, commenced paxalisib. And she experienced a dramatic regression of the primary tumor, so much so the tumor had reduced back to stable disease settings. And the reduction in the size of the tumor was not seen after primary and diagnostic radiotherapy identifying that we indeed -- we're seeing a therapeutic benefit from paxalisib. The patient experienced almost complete disease clinical symptom regression and she returned to school. But unfortunately, she passed of an unrelated pneumonia and at autopsy we were able to conclude that the tumor hadn't grown, and the tumor looked quite necrotic. And when we performed sequencing on the tumor at autopsy, we indeed identified that she had a PI 3-kinase mutation. The second patient continues on therapy. She commenced on ONC201 and paxalisib post diagnostic and reradiation, where she had a good response to re-irradiation as you can see here in C. The disease stabilized in the 7 weeks prior to the start of the combination. And then she started the combination, and she experienced continual disease progression. And it's now 17 months past diagnosis, and the patient continues to do really well. This patient also harbors a PI3-kinase mutation and other hallmark DIPG-specific mutations and with very few adverse events, some PI3-kinase related side effects, including mucositis, which is now quite well managed using dexamethasone mouthwash. I think that's it for me, James. We'll talk about the Phase II clinical trial. So these data have underpinned our work in the Phase II setting, and that's to combine paxalisib and ONC201 in various disease settings. So firstly, patients at diagnosis will receive paxalisib or ONC201 as a monotherapy combined with diagnostic radiotherapy and then continue on the maintenance therapy of ONC201 plus paxalisib. Because this trial is a patient-centered trial, we really designed it so that patients can almost come at all stages. So patients are able to enroll up to 14 weeks post radiation and diagnosis or at disease progression. And at disease progression, it's encouraged for re-irradiation to again be performed in combination with either the drugs as a monotherapy and then as a consolidation of maintenance therapy, paxalisib and ONC201 continued. We've got various disease markets, and it's a quite detailed study in terms of mechanism of action, pharmacokinetics and pharmacodynamics to ensure that we're really getting across any potential adverse events, toxicities and efficacies. And it's rolling out in 32 pediatric centers around the world, including 26 in America and 8 in Australia. The trial has been opened now since October, recruiting extremely well. And I think we now have over 30 patients that are enrolled on the clinical trials. So things are going well. Next slide, please, James. Thanks.

Thank you very much indeed. That's a fantastic overview of an enormous body of work. And I'm going to pass now to Kazia's Chief Medical Officer, Dr. John Friend, just to talk about -- briefly about a second -- a more recent area of activity, AT/RT and that's very interesting data that's been emerging there. So John, over to you.

Thanks, James. And we can just jump to the next slide. So Atypical Teratoid/Rhabdoid Tumors are very aggressive pediatric cancers that occur in essential nervous system or generally form in the cerebellum and/or brainstem affecting boys and girls equally. Most children present with symptoms and are diagnosed between 6 months and 3 years of age. Problems with coordination, walking, facial ticks and the constitution of other nonspecific symptoms usually prompt a more in-depth workup, including CT and MRI scans. So without going into too much detail, AT/RT are typically associated with an abnormality of specific gene called SMARCB1 or SMARCB1. This helps prevent tumor growth in the body. Researchers at Johns Hopkins University have demonstrated that the activation of PI3K/AKT/mTOR pathway that you've heard Professor Dun talked about is also commonly observed in AT/RT. There are currently no standard or FDA-approved treatments for children with AT/RT. Multi-modality treatment consisting of surgery, chemotherapy and/or radiation is under evaluation now. So even with this intensive multi-modality treatment, the 4-year event-free survival rate is 37%, and the 4-year overall survival rate in AT/RT is a dismal 43%. Kazia was approached by the Pediatric Neuro-Oncology group at Johns Hopkins, who've been researching and treating rare pediatric brain cancers for decades. Professor Jeffrey Rubens studies how unique interactions between proto-oncogenes, metabolomics and epigenomics drive pediatric brain tumor growth and survival. He looks for vulnerabilities in these regulatory pathways that can be inhibited to selectively target aggressive pediatric brain tumors and improve survival while reducing treatment-related morbidities. Dr. Rubens proposed a stepwise evaluation of paxalisib as monotherapy and in various combinations for the treatment of AT/RT. After establishing monotherapy efficacy via in vitro followed by in vivo models, various potentially synergistic combinations will be evaluated by in vitro and in vivo models in the same process. The ultimate goal really of any preclinical program is translating these findings into a clinical study to evaluate the true clinical relevance and significance. Some of the data that's been generated as a result of this collaboration was presented this year at 2 international scientific congresses, the 2022 AACR meeting in New Orleans, Louisiana; and the 20th International Society of Pediatric Neuro-Oncology or ISPNO meeting in Hamburg, Germany. Thanks, James. So really, after demonstrating positive monotherapy response by in vitro models, paxalisib was evaluated in 2 highly specific AT/RT orthotopic xenograft mouse models vis-a-vis CHLA06 and BT12. The 2 figures on the slide are overall survival curves, comparing paxalisib to control or placebo. In both models, you can clearly see an early separation survival curves with paxalisib-treated mice outliving the control mice. With the first objective of the collaboration completed, the evaluation of various paxalisib combinations was really next on the list. Next, James. Johns Hopkins labs have previously identified, again, a strong activation of the PI3K/AKT/mTOR and MAPK Signaling Pathway in AT/RT. These pathways are frequently activated in other aggressive cancers and really come to the rapid growth and survival in PARP by reprogramming cancer cell metabolism that you may have heard Dr. Dun mentioned earlier. DAY101, also known as tovorafenib. It's an investigational brain-penetrant type II pan-RAF kinase inhibitor, sorry, a little bit of mouthful, that targets a key enzyme in the MAPK signaling pathway. The company day 1, announced earlier this month, some positive data from an ongoing clinical study in pediatric low-grade glioma with nearly 2/3 of the patients having a partial response to DAY101. Therefore, Dr. Rubens proposed to further enhance the benefit already provided by paxalisib by combining with DAY101, the results of which are shown in these top 2 figures. So utilizing a highly specific in vitro cell model, CHLA05, the Hopkins researchers evaluated cancer cell viability after 5 days and 24-hour apoptosis for killing of the cancer cell. In the vehicle represented by the black bar, very low doses of paxalisib. So we're talking doses right here, 600 nanomolar, which is equivalent to 0.6 micromolar, in red; DAY101 is monotherapy in blue; and then the combination of the low-dose paxalisib with DAY101 in green. So as you can see, clearly, in both assays, in both studies, paxalisib is superior to the vehicle and that the addition of DAY101 further enhances that response and the statistical significance. Again, with the goal of identifying other synergistic combinations to paxalisib, histone deacetylase or HDAC inhibitors were considered due to a complementary activation of the FOXO, F-O-X-O, signaling pathways. As such, Dr. Rubens hypothesized that RG2833, just a brain-penetrant HDAC specific or 1/3 specific inhibitor, may be additive or potentially even synergistic to paxalisib. Again using 2 other in vitro cell lines specific to AT/RT, CDK1, and LIN28A. The 2 figures on the bottom of the slide again demonstrate that low doses of paxalisib with the 300-nanomolar range in combination with an HDAC inhibitor are complementary and result in cancer cell cycle disruption. So the team at Johns Hopkins is continuing to work further to validate as well as enhance what they've discovered to date. And then next slide. Great. So then the next -- I have one more slide and then we can get into more of a question and answers, but this kind of gives an overview of Kazia and our program and just enhances a little bit more and provide a little bit more detail on top of what James had mentioned. So today, we've heard Professor Dun eloquently present just a small portion of the work he and his lab published to date on Diffuse Midline Glioma and DIPG. And I would previously like to thank Dr. Dun for truly moving the needle in terms of the science of pediatric brain cancers as well as just an overall increase in awareness and the need for novel therapeutics in the space. The preliminary findings in DIPG patients from the paxalisib Phase I study at St. Jude Hospital were presented a couple of years ago. And the overall study is nearing completion now. The data from this study was truly the foundation for the inclusion of paxalisib in the PNOC022 study that you heard Professor Dun mention. And it's currently in the U.S. and actively recruiting and doing quite well since it was initiated in November of 2021. From a regulatory perspective, you heard that FDA has granted paxalisib both orphan drug designation and rare pediatric disease designation approximately 1.5 years ago. ODD and RPDD are extremely important designations from a corporate perspective, obviously, because of providing additional market exclusivity as well as potentially qualifying for which -- you heard James mentioned that pediatric voucher, that can be further monetized. Just to give you an example, in February of this year, BioMarin sold their pediatric voucher to an undisclosed buyer for USD 110 million. I briefly touched on the Johns Hopkins and Kazia collaboration in AT/RT. They continue to work for the goal of that final objective of this collaboration to creating enough data to justify a clinical trial in AT/RT. We're thrilled to announce last Friday that the FDA did grant paxalisib with Orphan Drug Designation for the treatment of AT/RT. The final column, my call, it's more of a [ catch all ] for now. I believe that in the near term and as data comes to light, we may build out additional columns dedicated to specific other pediatric CNS-related tumors, such as you heard medulloblastoma, high grade glioma, even low grade glioma, just to name a few. At this point, I'll turn it back to Dr. Garner for any closing remarks, and then we can jump into some Q&A.

Thank you, John. And I hope the last 25, 30 minutes has really given us a sense of the breadth of the work that's going on here. We also have a debt, I think, some extraordinary science that has been applied to this most challenging form of brain tumor. And we welcome the opportunity to discuss this further now and some Q&A. So I'm going to hand back to Soo and the Edison team to steer us through some questions.

Great. Let's kick this off here. We have a full house. We have quite a few questions. Let's -- maybe the first one goes to James. Pharmaceutical companies have traditionally been reluctant to develop drugs for pediatric cancers for various different reasons. Could you walk us through some of those challenges and perhaps how they may have started to change?

I think that's a fair comment. I think this hasn't historically been seen as an area of focus for most companies. I think partly, there's been a perception of relatively small numbers of patients. And partly, there's been a perception that developing drugs for children and not just for children [indiscernible] with cancer but for children generally is difficult and challenging and risky. The side effect profile can be different. The behavior of the drug can be very different. And running clinical trials can be very different in a pediatric population. I think both of those concerns are rapidly disappearing. I think we have seen as certainly in the field of cancer is, we've seen really the focus move increasingly to very, very precise, often genetically defined subsets of particular tumors. They've started to approximate and size some of these pediatric malignancies. And so for example, we don't really develop drugs for lung cancer anymore, which is the most common cancer. We develop drugs for ALK-positive lung cancer. We develop drugs for third-line EGFR-positive lung cancer. And those patient populations are smaller, and I think proportionally, that's worked in favor of childhood cancers. So I think for those reasons, and some of the regulatory considerations that we touched on earlier, I think this is growing area. And I think companies like Genzyme like Day One Biopharmaceuticals and some private companies like [indiscernible] have really demonstrated this. There's a very valid commercial business case here as well as a huge unmet medical need.

Matt, how about -- a couple here combined. It seems like it's challenging to see therapies for childhood brain cancer. What's motivated you to focus on this disease area? And then maybe you can kind of highlight some key impediments and other things that you think would help improve the outcomes of diseases such as DIPG?

Thanks, Soo. Yes, so I've been a pediatric cancer researcher for 11 years now and about 7 years into my postdoctoral studies, my daughter was diagnosed with Diffuse Intrinsic Pontine Glioma. And of course, in Australia, we're fortunate to be supported by revolutionary clinical trial programs, that used biopsy material to try and get on top of what kind of mutations and changes are causing the tumor. And when we found -- when we did this in my daughter Chelsea's tumor, we found that she had multiple disruptions to the PI3-Kinase/Akt Signaling Pathways which then caused me to search the world for a brain-penetrant PI3-kinase inhibitor, and I came across paxalisib, then GDC-0084 and contacted James, about testing it preclinically in my lab. And of course, Kazia were very accommodating. They came up to my lab. They visited our facilities. We met many times and we started our paxalisib research program. And of course, we used it directly in comparison to glioblastoma cells for which it was in early-stage clinical trials. And we found that at the [indiscernible] alone, regardless of whether they had PI3-kinase mutations we're sensitive to the drug and almost twofold more sensitive than GBM cells. So it really encouraged us to continue to work with the drug and to really work out how we use it appropriately, dosing, timing. And what we combine it with, which is the most important thing. When you have such a heterogeneous and aggressive cancer like DIPG and hybrid glioma, single monotherapies regardless of what they are, are not going to resolve the tumor. So a biological understanding of what contributes to the growth of these tumors, what kind of metabolic programs are being instructed by the changes in the genome. And then what potential therapeutic vulnerabilities may be unlocked by the use of the therapies is really what my group tries to do and we're really pushing forward with understanding how these drugs work within the tumor cells and then what we can exploit to make them work even better. I mean of course, there's many challenges with treating children with brain cancer. The blood-brain barrier is a huge obstacle to any kind of positive benefit from a systemic therapy. But one of the things about paxalisib is its brain penetration and its potential across the CNS and show activity within the brain. And its relatively safe toxicity profile. There are PI3-kinase related side effects, which we're starting to manage. And in some cases, I think some of those side effects are indicative of how well the drug is working. And what I mean by that is, I think the drug plays a role not only in inhibiting the growth of the tumor, but may also encourage some of the body's own defense systems to up-regulate and help the drug to have an effect. And was there anything else in the question? Sorry, there was a few things there, Soo.

Yes. That's awesome. Maybe one for John here. The PNOC022 study is essentially an investor-initiated study and Kazia has a number of partnerships in place. Could you elaborate on this approach?

That's a great question. The PNOC022 is an investigator-initiated trial. I think we call it more of a cooperative group trial, which is a great collaboration from our standpoint because we are talking about a rare pediatric tumor. Most of these patients are seen within a couple of handful of academic centers across the U.S., but also North America, Australia and even Europe. So really, you need those academic centers with that level of expertise to really recruit and enroll both DIPG or DMG, but also potentially even some of the other tumor types such as AT/RT. It makes sense from a cost perspective because these cooperative group studies really offer up some synergies and also in terms of getting studies up and running as time is money, especially when it comes to research. So they can get studies up and running much, much faster than an industry-sponsored trial. And they execute because they're behind the program 100%. They're not getting involved. They're not agreeing to participate in the study unless they believe in what they're doing. They believe in the study, they believe in the arms within the study and the potential benefit for their patients.

Okay. Maybe a follow-up to that question. Is it possible for PNOC [ O2020 ] study to provide a basis for registration in DIPG? Or do you anticipate additional studies will be required?

I think we all would love to see it as a registration study. I think that's really a discussion that needs to happen with the regulatory bodies. So when you look at a rare pediatric indications such as DMG or DIPG, you look at what is out there? Are there any approved therapies currently? Is this truly an unmet need? Is it a highly aggressive tumor where -- even with non-approved agents, are these patients still progressing very, very quickly. So I think the answer, as you heard Professor Dun and James mention earlier, the answers are clearly a yes. And then it's a matter of, well, how many patients are being enrolled, how many patients are being able to demonstrate both the benefit and the risk to this patient population. And actually, the study is very well designed. It's a very unique design, one of kind of -- more of an adaptive design that the FDA has bought off on multiple other approvals over the last decade or so. And so -- and we mentioned total numbers. We're -- this is the largest -- as far as I know, Matt, but correct me if I'm wrong, but this is by far the largest undertaking in Diffuse Midline Glioma of any trial ever executed. So we're talking several hundred DMG patients is the ultimate goal. It could be a little less and it could be a little bit more.

James, how about this question for you. This data and the design of the PNOC 2020 study links Kazia in some respects to Chimerix, a company developing ONC201. Is this a collaboration or a loose strategic alignment of sorts?

We certainly don't have any formal relationship with Chimerix. But at the same time, we absolutely have some shared interests. So I think there's a lot of cultural similarity between the companies. We're in regular contact with them, we're huge admirers of the work they've done with ONC201. And so I think as the PNOC022 study progresses, as we see more of the state of that increasingly identifies these 2 drugs, ONC201 and paxalisib as a potential new standard of care in this disease. Obviously, those are discussions that are going to get deeper and more frequent. So I think we're in contact, and we're looking forward to seeing where those discussions go.

Great. A follow-up, Matt, what are the advantages and disadvantages of PI3K inhibitor in childhood brain cancer, such as DIPG? What makes the class of medicines interesting to a researcher?

Thanks, Soo. So it appears that all these tumors rely on some kind of glucose homeostasis for their proliferation and metabolomic needs. And so blocking the adaptive protein that links to all of these cell surface receptors directly downstream with them is an attractive therapeutic option. So as you can imagine, these cells are very highly complex, targeting pathways right down the bottom of dysregulation leads to rapid forms of resistance, so it can block the signaling pathways right at the top where the ligand or the substrate's acquired, means that you get a suppression of signaling pathways downstream. Of course, there's always a consequence with targeting such an important protein and an important pathway. But it appears that these tumors rely more specifically on direct glucose uptake than normal cells, for example. And as a consequence, you get a lower amount of drug required to kill the tumor cells compared to normal neurons or normal hematological cells such as bone marrow stem cells, for example. So it's an attractive approach in terms of specificity for the cancer cells. But also, again, what we're kind of doing here is we are shepherding the cells to grow in a particular way by blocking one of the pathways that it needs to -- for survival. And the work that we're really doing is to figure out, okay, we now -- that we've locked that pathway, what's being turned on in compensation because these are aggressive tumor cells. They are preprogrammed to survive, they're meant to be immortal. So they are always going to up-regulate other pathways to drive their growth and survival. And so now all the work that we've done is identifying what pathways they are and whether we can then combine therapies. It's a challenge in kids, of course, because one, as James and John have beautifully articulated, it's a rare disease indication. So getting enough readout about toxicities and benefits and failures is difficult and slow. I suppose a nice thing about PNOC022 is that it's opening at so many centers. And all of the groups that are there are invested in the program. We are getting efficacy readouts in real time. We are getting toxicity readouts, if there are any, in real time. And for example, the weak adverse events in terms of the mucositis is now almost completely been ameliorated with dexamethasone mouthwash. That kind of information is getting across all of the centers in real time. And we meet multiple times a month to discuss clinical outcomes and also preclinical discoveries so that we can design the trial to add additional therapies. Are there therapies that can stop side effects, are there therapies that can make the drugs work better? Are they dietary interventions that might be able to make the drugs work better. And so of course, it's a challenge, but by putting together such a large consortium of researchers and also, of course, of dedicated [ pharmas ] or biotech companies means that we're all working together to try and move the needle in the right direction as quickly as we can.

That's wonderful. John, how about this one for you? Are there lessons from Kazia's work in adult brain cancer that can be translated into this research here?

I think it's a similar rate. So as you know, or maybe some of the folks that are on the call, as James had mentioned, we are in a kind of a comparable sort of cooperative group adaptive trial platform, design trial with another cooperative group called GCAR in glioblastoma. And so we've definitely had some lessons learned from that in terms of execution, but also ensuring sort of our own oversight in management of the trial. And really, it goes along the same line that Matt was mentioning. It's the sites, the sites make it -- the proper sites that are really seeing these particular patients and these rare diseases and they buy into the study. They buy into the study design as well as the efficacy that they may be hearing from other collaborators both in other studies, but also in potentially expanded access or compassionate use. They're buying off onto it and seeing those sorts of patients and enrolling those patients. So we've definitely seen that partnering is really key, and we've been very successful both -- on both ends, the adult trials but also in our pediatric program.

Okay. James, positive data from Day One Biopharmaceuticals' tovorafenib program in low-grade glioma has been a noble catalyst for their share price. Does this have any implications for paxalisib? And do you view them as your competition?

Well, it's a different drug in a different disease and very, very different environment altogether. So I don't think there's any direct sense in which paxalisib and Day One are in any meaningful competition here. I think we certainly take a lot of encouragement from what they've done, however. Their focus has been on pediatric brain cancer in their case, pediatric low-grade glioma as sort of almost a counterpart to the sort of diseases that Professor Dun was speaking about. And I think it's shown that the investment community can embrace companies that are focused on what would traditionally be seen as rare or less common cancers. Day One is a $1 billion company today, and they're really focused very, very specifically on this area. So I think it shows that there is a viable business, and there is an argument from corporate strategy to focus on these kind of diseases as well as, of course, an argument for medical need.

Maybe we can squeeze 2 more in here. John, commercially, what do you view as the prospects for DIPG therapy with such small populations? Do you anticipate this to be a profitable business?

I'll jump in. I'm not sure we want the medical guy talking about commercial, but I'll jump in, to give my opinion and then James is the CEO, he may be able to put on his commercial hat and expand. I think James had mentioned that there are a lot of companies out there looking at much more rare diseases than DIPG, DMG and even AT/RT for that matter and have commercially been very, very successful. It's more from my standpoint, what's the medical need and where is the medical need and where [indiscernible] truly can add value. And whether that's from the standpoint of a label indication or in terms of a peer-review journal publication such that researchers and physicians can utilize paxalisib and other potential indications as long as it's been shown and published that it's safe and effective. I don't know, James, if you wanted to talk -- we didn't really talk too much about epidemiology. But as I mentioned, there are a lot of more rare diseases out there and companies that have done quite well.

John, I couldn't agree more. And I think, in some ways, the -- in my view, the question about the commercial viability of these rare predominantly pediatric indications was asked and answered by Genzyme. That company focused primarily on metabolic diseases, but disease is particularly affected child with lysosomal storage diseases, things of that sort. Some of those illnesses have 30 or 40 incident cases worldwide per annum. They are exceptionally rare. And that company was bought by Sanofi for $20 billion. So I think it certainly gives a sense that there is a value here. And although these are smaller patient populations, they're very, very focused in generally academic centers and very science led in terms of the behavior of physicians. So it's just a very different business model for companies, but absolutely a viable one.

Great. Matt, maybe one here -- last one here for you. As someone who's been working in this space for a long time, how excited are you by the progress you've made so far? And are we at a pivotal point here?

When you are so closely linked to the disease and when you speak to families every day, one must always show a cautious optimism. This is horrendous, devastating disease. It needs treatment. I always remain optimistic. If I didn't have any optimism for the -- I mean the work that we were doing, to be honest, I would probably have left the field, and I'd probably be having weekends and enjoying life with my family. But to be honest, we -- I do see some potential in the work that we're doing. And I do hold on hope that the patients will benefit from it. We've seen a couple of cases where some families have experienced a benefit. And of course, unfortunately, for some of those families, it's only been temporary. So there's still a lot of work to do. We really need to understand why some patients respond and why some don't. And what makes them become resistant quickly. So there is a lot of work to do. But again, in any indication where there's absolutely no recognized therapy, we need to first move that needle in the right direction. Then like the case of, for example, acute lymphoblastic leukemia, where patients will receive up to 3 or 4 different cytotoxic and metabolite during their course of therapies, we need to start to move that needle in the right direction to kids with DIPG and DMG and if paxalisib and ONC201 are the starting point, great. Do I think that's the endpoint? Absolutely not. That's really just at the beginning. That's the beginning of how we figure about what kind of drugs and what kind of regimens we designed for these children. And then hopefully, together, we start to see the 2-, 5-, 10-year survivals that they're coming up.

Wow. Thank you for that, and thank you for all your work. I think that this is really all we have time for today. I mean we have a lot more questions, but maybe you can kind of direct those to us at the contact that we have on the Kazia press release. Thank you for joining in this call and really have a great day. Thank you, everyone.

Thank you all.

Thanks very much.