Kazia Therapeutics Limited (KZIA) Earnings Call Transcript & Summary

Good morning, and welcome to Kazia Therapeutics Corporate Update Call. [Operator Instructions] Please note that today's call is being recorded. Before we begin, I would like to direct your attention to the forward-looking statements disclaimer displayed on the screen. We encourage you to review this information, which applies to the statements made during today's presentation. I would now like to turn the call over to Dr. John Friend, Chief Executive Officer.

All right. Good morning, everybody, and thank you for joining us today. On behalf of Kazia Therapeutics, I appreciate your time to participate in today's investor call. I'm joined today by our Chief Scientific Officer, Professor Sudha Rao. Together, we'll provide a corporate and clinical update following several recent announcements across the paxalisib program, including our emerging data in triple-negative breast cancer, our planned expansion into HR+/HER2- breast cancer and our colorectal cancer program. More importantly, we want to use today's call to connect these developments and provide some perspective on what we believe are emerging clinical and translational data and telling us about pax and how it is shaping our development strategy going forward. With that, let's get started. So today, we're going to provide an update about paxalisib and investment framework. Then we're going to go into the new data with regard to triple-negative breast, our program in HR+, early-stage triple-negative breast, but also pMMR colorectal cancer. We're going to talk a little bit more as far as the clinical trial expansions and then recap and then summary next steps. The next slide. So as you know, pax or paxalisib or paxalisib is our lead-stage asset. This is an oral once-a-day blood brain penetrant small molecule. It is a pan dual PI3K/mTOR inhibitor with epigenetic and immunomodulatory activity. This is a Genentech molecule that we've been in development and working development across glioblastoma, neuro-oncology, pediatric brain cancer, but now especially transitioning and providing a really solid state in the ground in terms of development in breast cancer as well as now colorectal cancer. As discussed the formulation, this is an oral once a day. It is key mechanism in terms of immunotherapy resistance as well as ability to cross the blood-brain barrier, one of a couple of the key sort of differentiating features. We talked about the mechanism of action. This hits all the major isoforms. So it is a traditional dual PI3K/mTOR inhibitor with some additive clinical benefits that we'll be talking to in significant details. IP-wise, you see here. As I mentioned, the initial development strategy for pax was in glioblastoma. We've put several other shots on goal in terms of pediatric brain cancer, but also brain metastasis patients. We've dosed over 550 patients to date. So we have a really solid handle from a safety and tolerability. After several years working with Professor Sudha Rao in terms of understanding how pax could work even outside of brain cancer, but in particular, breast cancer, we launched a Phase Ib trial in Stage IV triple-negative breast last year. The trial schema, you see here on the next slide. This is a Phase Ib multicenter open-label randomized trial evaluating pax in combination with standard of care. So standard of care in Stage IV triple-negative breast consists of checkpoint inhibitor, pembrolizumab plus chemo. So we are adding pax as an add-on therapy to the standard of care. So we are evaluating pax at very low doses, so pax at 15 milligram and pax at 30 milligram in combination with standard of care in Stage IV triple-negative breast frontline setting. You see in terms of total enrollment targets is 36 patients, and we'll be providing some updates as far as the preliminary updates on the first few patients. The primary and secondary endpoints are what you would expect in the Phase I study being safety and tolerability in this new combination, but also importantly, would be secondary endpoints, which are our biomarkers that Sudha will be talking about at some length today, but also the typical response rates, radiographic response rates, progression-free survival and overall survival. The next slide. Today, the data updates that we will be discussing are aligned with our recent press releases over the past few days, and we'll be providing updates on 6 patients dosed with pax or paxalisib in the upfront Stage IV triple-negative breast setting, whereby all 6 patients, we have shown drastic immune restoration. By immune restoration, we mean the ability to see drastic reductions in terminally exhausted CD8 T cells, which we'll talk about more, but also in all 6 patients showing the ability to target these previously untargetable circulating tumor cell clusters, and we'll talk more about those. In addition to radiographic responses where we show 100% clinical benefit response, CBR or clinical benefit response is a characterization of a drug in terms of not all patients having a complete response, partial response or stable disease, and we'll talk more about each of these 6 patients. We're also going to look at one particular patient who had a complete metabolic response and look at her over time, her scans and layer that on with her biomarkers, i.e., her response in terms of reductions in terminally exhausted T cells as well as reductions in these metastatic seeders, these circulating tumor cell clusters. We're super excited to also provide updates as far as our expansion into HR+/HER2- breast cancer, early-stage triple-negative breast as well as MSS/pMMR colorectal cancer, and we'll talk more about that patient population as well. We're not going to focus on the commercial viability and the market potential. We all know that these are huge market potential. We're going to focus on the science as well as the data because we believe that's what we've been focusing on for the past several years, and we believe that will add tremendous value to both our patients but also our shareholders. The next slide, we'll be talking -- and I'll ask Professor Sudha Rao to go through the next few slides, and then we'll jump into additional data as well as the expansion. So Sudha, would you review this slide, please?

So one of the key highlights or focuses of our clinical trial has been a longitudinal liquid biopsy analysis in our clinical predative facilities where we've been able to monitor for one of the first time both the CTC clusters and the terminally exhausted T cells in the blood in real time and dynamically. And importantly, these are the feeders of metastases that standard of care immunotherapy or chemotherapy cannot target. Now the key take-home message of this slide, and I've been in this field for more than a decade is that this represents one of the first times clinically that we are able to dual target both the CTC clusters and the terminally exhausted T cells. If I can draw you to the slide -- to the Panel 1, in baseline, you see that these are patients with high metastatic burden. The black dots represent the CTC clusters. What is quite exciting here is that in 6 out of our 6 patients, within a few weeks of treatment, we see a dramatic reduction in the CTC clusters. If I can then draw you to Panel 3, what we see simultaneously in the same blood within 1 to 3 weeks of treatment is a reduction in the terminally exhausted T cells. So these are the exhausted T cells that immunotherapy cannot touch. Importantly, the total T cells pool remains the same. We are not killing the T cells. Instead, what we're observing for one of the first times is selective rewiring of these terminally exhausted T cells to distinct phenotypes. Next slide, please. What we are observing here importantly is that we see, firstly, an increase in the effector T cells. These are the killer cells, which are required to attack the tumor. Secondly, what we're observing is an increase in cancer immunity, which means that the cancer cells themselves become visible to the immune system. But thirdly, we see increase in immune memory, suggesting that we're likely to have durable, sustained responses. Next slide, please. This is an example really to show the depth at which we are able to do undertake a multimodal analysis using one of our patients who had complete response as an example. Now the clear take-home message of this slide is that our early efficacy readout with our liquid biopsy analysis indeed is able to predict what we observed in our radiographic or metabolic scans. If I can draw you through the left of the slide, at baseline, the patient has a high metastatic burden. In parallel to that, the patient has a high CTC cluster burden, a high T cell exhaustion burden. With a few drops of blood, we're able to look at the patient's own immune system and the patient's immune system is poor at this stage. Within 2 weeks of our treatment, there's a reduction in CTC clusters, reduction in terminally exhausted T cells and the patient's immune system starts to get restored. Within 4 months, the patient starts to have complete response as far as the metabolic scans are observed. Within subsequent blood analysis, the patient then ultimately has no CTC clusters visible at all and the immune system is completely restored. And as of August, the patient is a complete response. So this is the depth at which we've been able to undertake a multimodal liquid analysis. And importantly, this is giving us a real insight of the mode of action as we move forward into the patient responses.

Thanks, Sudha. Great overview. Again, these early signals are super exciting, and we'll be expecting and anticipating this longitudinal biomarker assay across all the future enrolled patients, but also across our expansions into the other indications. So the next slide shows our individual patient responses. So you see here listed all 6 patients, whereby we have 2 patients at 15 milligram and 4 patients that have been dosed at 30 milligram. You see within the 15 milligram, we have 1 patient with a partial response and 1 patient with stable disease. And then within the 30 milligram, we have 3 patients with partial responses and then the 1 patient with a complete metabolic response that Sudha just took you through. As one would expect with a Stage IV triple-negative breast patient population trial that these patients have a number of target lesions, so their radiographic tumor burden as well as, as you saw, their blood burden in terms of circulating tumor cell clusters is pretty extensive, whereby the target lesions can be soft tissue, they can be organs, they can be bone and they can also be CNS or brain target lesions as well. As you can see, patients are showing some nice early preliminary responses to all of these. The time to response also I'll bring you to the far column on the right, we're seeing at the earliest radiographic assessment, so at approximately 3 months, we're showing some radiographic responses, right? So in terms of -- as Sudha walked you through, the circulating tumor cell cluster reductions, but also drastic reductions in terminally exhausted T cells that this could also be playing a part in terms of the radiographic responses that we're seeing here. The next slide, again, we look at all adverse events, Grade 3 or higher are automatically considered serious adverse events. And so this is as of August 1, looking at serious adverse events, and we have no paxalisib-related serious adverse events. Remember, this is in combination with immunotherapy and chemo. So we do have a number of adverse events that, as you see listed here, the ones unrelated to pax are related to chemo or immunotherapy, in particular, pembrolizumab. But importantly is that we've not shown any sort of Grade 3 or Grade 4 stomatitis, mucositis. So we're very, very encouraged with the dose selection. Remember, we're using 15 and 30 milligram once a day in this combination. That's quite a bit different than what we've used in the glioblastoma trials and as well as the weight-based assessments in pediatric brain cancer, whereby that target dose is around 60 milligram once a day. So with this lower dose that's meant the target, the epigenetic as well as our own immune microenvironment that this dose is more effective at the lower at 15 and 30 than we would expect at the 60 milligram. So very exciting from a safety and tolerability perspective. The next slide. This is just a quick summary. From a clinical perspective, we've shown selective reinvigoration, i.e., all patients showing drastic reductions in terminally exhausted T cells with a median at approximately 3 weeks of about half, so about 51% reduction. But also importantly, as Professor Sudha Rao had mentioned that the total number of T cells remains the same. So it isn't like we're selectively reducing the dysfunctional T cells that they're being reprogrammed or required. On top of that, looking at the metastatic seeders, these circulating tumor cell clusters that we know pembro, chemo and others can't touch that they have no effect. They do well with the highly progressing and proliferating cancer cells. But in terms of these fairly dormant cells and clusters, they have no effect. And you can see here, we show a drastic reduction and disruptive effect in these CTC clusters. The next slide. So excitingly, we have not been resting on our laurels. We've obviously been pushing in terms of understanding how pax works in Stage IV triple-negative breast, but also we've been evaluating other potential opportunities for pax because we believe this not just being a PI3K/mTOR inhibitor with kinase inhibition, we are strongly believers that pax add something very unique and different on top of being a kinase PI3K inhibitor. And with that, the 3 that you see here in terms of HR+/HER2-, early-stage triple-negative breast as well as colorectal cancer were top on our list to evaluate. As you'll see as we go through the next couple of slides from an IP perspective, we fully ring-fenced all of these, and we're aggressively moving across the board into these programs. Sudha, the next few slides, would you go into the data -- preclinical data, please?

So importantly, as John has mentioned, our innovation has been backed up by our new compelling new data, which has really further strengthened our IP position and importantly, has unlocked new avenues for differentiation and biomarker discovery in terms of clinical utility. In terms of the HR+ situation, importantly, we've done head-to-head benchmarking experiments comparing geda with pax with other PI3K/mTOR and PI3K inhibitors. And importantly, what we have found is something very unexpected that this is not a class effect. So just to take you one step back, I did my PhD in this area that to target the entire disease aspect of the PI3K/mTOR pathway, you need to target the canonical, which is the cytoplasmic enzymatic traditional activity, but you also need to importantly target the noncanonical pathway, which is the nuclear epigenetic resistance pathway. It's the nuclear epigenetic resistance pathway, which is critical if you want to target resistance and metastases. And what we found for the first time is that pax is superior at targeting the nuclear epigenetic access. Geda actually enriches for this nuclear epigenetic access. And importantly, we know why pax is unique. The features that pax has to allow it to cross the blood-brain barrier, importantly have been hijacked to allow it to now also be superior at crossing the nuclear pool and disrupt this nuclear epigenetic access. And importantly, what we've done is we've developed a novel biomarker to detect this nuclear epigenetic access. We've developed our own tissue IHC test as well as the blood test. And what's really exciting here is that using hundreds of patients that we've profiled bioinformatically, we show that those patients who are enriched in this nuclear epigenetic switch are the ones who have poor survival in the context of the HR+ situation, which means that we can go ahead into a clinical trial where we're able to enrich the certain patient population. Next slide, please. So this is really our early data to show that when we benchmark geda versus pax, side-by-side comparison in terms of targeting the primary tumor activity, they are identical. Where pax is unique is that it's able to target the seeders of metastases and the metastatic burden. Importantly, our extensive preclinical work has shown that we see no toxicity, no decrease in body weight. We have a blinded pathologist who shown that there is no evidence of any stomatitis or any hyperglycemia in any of our preclinical models. Next slide, please. What is really exciting here is that our trial at the moment is in Stage IV TNBC. What we've shown for the first time is that we believe we can advance now to an early Stage II/IIIb setting. What we've shown for the first time here is that pax is able to significantly inhibit local, regional and distal metastases either in combination with chemotherapy or as a triple with immunotherapy as well for the first time. Importantly, we understand the biomarkers towards this that we believe that we can use for further stratification and liquid biopsy analysis as we move into a Stage II/IIIb setting. Next slide, please. This is pretty exciting here. This shows that for the first time in the pMMR CRC setting, paxalisib is able to work as a monotherapy, suggesting it's not able to work in the same fashion in every disease setting. As you know, pMMR CRC is a major unmet need. There's few therapeutic options globally and immunotherapy doesn't work. And what we show for the first time is that paxalisib in our preclinical models that we have developed works as a monotherapy, but importantly, is further inhibited when you combine it with immunotherapy. Importantly, we've developed our own liquid biopsy analysis here where we can monitor the seeders of metastases in pMMR CRC for the first time, allowing us to advance again with a very precision medicine approach into a clinical trial situation.

Thanks, Sudha. Next slide. As you can imagine, as we said on the slide, all of this has been provisional patents across all 3 of these indications and a number of other provisional patents that we're expecting to file here over the next 6 or 9 months on top of that, just to fully ring-fence how we believe pax is working across these indications. But these sorts of preclinical programs, both in vitro, in vivo and ex vivo blood samples coming from a number of these patient population and indications are great unless you can -- they're not fantastic unless you can create that and move into clinical trials. And that's what you see here on this slide. So we are imminently expanding our ongoing pax-ABC clinical trial in Stage IV triple-negative breast to incorporate the far left, looking at pax in combination with fulvestrant plus palbociclib or CDK4/6 in pretreated HR+/HER2-. We'll be evaluating pax, as you see in those doses of 15 and 30 milligram once a day on top of standard of care for these patients, which is fulvestrant plus CDK4/6. And we're also going to be including an in-study comparator, so looking at fulvestrant as your in-study comparator. So we're very, very excited and be moving forward, and we'll talk about next steps and when to anticipate patients in full enrollment in the next couple of slides. On top of that, also evaluating pax in the adjuvant setting, right, in earlier stage triple-negative breast. So this is additive, as Sudha mentioned, on top of the Stage IV evaluation. So this is adding pax to standard of care, which is pembrolizumab plus capecitabine and other chemotherapy in high-risk residual disease Stage IIb, Stage III. So very, very excited. And again, same dosing evaluating pax at these lower 15- and 30-milligram doses. Lastly, but not less importantly, would be evaluating pax in MSS/pMMR colorectal cancer. And as Sudha had mentioned, this is a huge unmet need. The majority of advanced metastatic colorectal patients are not responsive to immunotherapy, have not been shown to be responsive to immunotherapy. And as you've seen, pax works a little bit differently as one would expect, but we're really understanding and moving it forward from a science, but understanding how we can be beneficial for these patients. And so we'll be evaluating pax both as monotherapy as well as additive with pax plus pembrolizumab, as you saw with the previous slides. On top of that, this will be -- also have an in-study comparator with standard of care. The pMMR colorectal is actually going to be a stand-alone Phase II trial that we are initiating and expect to have first patient in, in the first quarter of next year. Next slide. Recap. So we are extremely excited within the Stage IV triple-negative breast patient population where we've shown the bench to bedside translation of the extensive preclinical program that we've developed here over the last few years, whereby pax has been able to show with the additive to standard of care ability to drastically reduce terminally exhausted CD8 T cells, right? Those cytotoxic cells that are out there searching and killing cancer as well as the ability of all patients showing drastic reductions in circulating tumor cell clusters. The metastatic seeders that we know have not been effectively targeted with immunotherapy and other targeted therapies, but also chemo. And then on top of that, some preliminary radiographic responses across all patients with 1 complete response, 4 partial responses and 1 stable disease. We're very excited now with the financing also to be moving forward in terms of the trials you saw on the last slide. The next slide, please. So again, as we bring the presentation portion of today's call to a close, I want to leave you with a few takeaways. So first, pax is a molecule with a substantial clinical foundation. Again, as we mentioned, more than 550 adult and pediatric patients have now been treated across a multiple of clinical programs, giving us a significant body of experience with its safety, tolerability and pharmacology. What has changed and what I think is particularly important is our understanding of what this molecule may be capable of doing. The emerging clinical and translational data that we've talked about today suggests paxalisib's activity may extend beyond conventional PI3K/mTOR pathway inhibition. We're now seeing evidence across several dimensions of cancer biology, including tumor control, treatment resistance, immune exhaustion and metastatic dissemination. That evolving understanding is directly driving the expansion of our development strategy. In triple-negative breast, we will continue to build on the clinical and translational findings we've discussed today. We're expanding into HR+/HER2- breast cancer where treatment-resistant represents a significant unmet need. And in pMMR colorectal cancer, we're taking this biology into a setting where the overwhelming majority of patients historically derive little to no benefit from immunotherapy. At the same time, we continue to advance our CNS programs, including our discussions regarding glioblastoma, other pediatric brain cancers, but other neuroscience programs on top of this. So when you look at this slide, I think it's an important point to not simply the number of programs. It is that each of these programs gives us an opportunity to test a different dimension of the biology we are seeing with pax, and potentially translate the biology into meaningful clinical benefit for patients. And with the capital from our recent financing, we now have the resources to execute on that strategy. With that, I believe we can open up to questions.

[Operator Instructions] Our first question comes from the line of Kambiz Yazdi with BTIG.

Congratulations on the TNBC data and pax development expansion. Three questions for me this morning on the different indications. First, paxalisib's therapeutic effect may extend beyond the cytoplasmic PI3K/mTOR inhibition. Can you help us understand the mechanistic basis for that hypothesis? What specifically about pax's biology enabled the CTC cluster disruption and the T cells exhaustion reversal you're observing in TNBC? Second question is -- sorry, I'll let you answer, and then I'll ask the 2 follow-ups.

Yes. Let's do that, Kambiz. Yes, thank you for that question. Sudha, would you mind? Let's take each one and then go from there.

Yes. Yes. Thanks for the question. So what we know is that with a PI3K/mTOR pathway that there's 2 aspects to target the entire pathway. So we've known this for a long time. One is the cytoplasmic enzymatic pathway. And the second is there's an independent nuclear PI3K/mTOR pathway, which we call the noncanonical pathway, which mediates the epigenetic mechanism. So what we found is that initially, which we didn't expect is that paxalisib was superior at targeting this nuclear epigenetic act as the nucleus complex. So we went and did extensive structural analysis, computational analysis, you name it, we did experiments around it. And what we found was that paxalisib is the size of the paxalisib allows it to penetrate the nuclear pool. But importantly, all of the features, its structural features that allow it to cross the blood-brain barrier that seem to be -- have been utilized to allow it to also cross the nuclear pool, which is pretty exciting. And so by doing so, it is able to then disrupt the nuclear complex and then prevent the resistance access. So it's an extensive analysis with in patient-derived samples in cell lines, and it's evolving. We're actually going to present this work at the San Antonio Breast as well because it's a very, very novel area that is opening up in terms of this PI3K/mTOR axis that we wouldn't have anticipated. And we've also ring-fenced this in terms of IP, but also allows us to develop our own biomarker as we move into any clinical trials as well, which is pretty exciting.

And following up on that, which is my second question, Sudha, you mentioned you've identified a biomarker for this nuclear genetic access and that applies to HR+/HER2- patients. Maybe Sudha or John, will you be looking to enrich for these patients in the 3-arm expansion?

I'll jump in, Sudha, and then you also talk, obviously, from an IP perspective, I think it's important that we obviously have fully ring-fenced that. Yes, I believe that, that opportunity for us to enrich the ongoing -- well, the soon-to-be ongoing clinical trial and expansion into HR+ will be extremely important. As I mentioned, we'll be enrolling a number of patients across all of those, so a minimum of 18 per arm across all 3 of those arms. So we will have extensive data, right? This will be the first time evaluating pax in combination with fulvestrant plus CDK4/6. And then the potential of utilizing this novel biomarker to potentially show responders or super responders or very deep durable responders will then enrich accordingly with the next trial. But yes, I don't know, Sudha, if you have any other comments?

I mean, just to say that in that, we actually have a standard tissue IHC test, so we can stratify patients, but also we have a liquid biopsy test that we can monitor as we go as well to understand the efficacy. And we know already that 40% of patients in terms of a large number of bioinformatics analysis that we've done, the ones that have this switch are the ones which are associated for survival in HR+. There's a large percentage that we'll be capturing, enriching for that population, which is very important in this space.

Great. And my last question, what gives the team conviction to advance to Phase II in colorectal cancer specifically? What is it about pax's mechanism that you believe is reprogramming immune visibility in these tumors?

Great question. Sudha, take that, please.

So this is incredible actually. We wouldn't have anticipated it. So what we're finding, we've actually developed our own preclinical pMMR CRC model. And also, we have access to importantly patient-derived samples as well. And what we're finding is that within the pMMR situation that pax is able to rewire these cancer cells, a unique subset of cancer cells. I can't say too much because we're actually find -- we're ring-fencing this in terms of IP as well. But we've identified a unique metastatic cancer cells that become immune visible by pax. And that immune visibility then allows then the immunotherapy to work more effectively. It's a brand-new mechanism that we've identified who are actually in the process of ring-fencing the IP in this space.

That's a great question, Kambiz. I'll just add to what Sudha mentioned in terms of our conviction. So as we mentioned, we've shown extensive both in vitro, in vivo, ex vivo and now clinical data showing pax in combination with pembro, at least in Stage IV triple-negative breast as, A, safe and tolerated, but also showing clinical activity across both biomarkers and radiographically from that perspective. We have extensive safety and tolerability with pax as monotherapy across a wide range of indications. So in terms of moving forward with the proposed schema that we put a few slides ago, we feel very, very comfortable and highly encouraged that we'll be able to, A, enroll these third-line patients, which is a huge, huge unmet need. Although we've had some movement in terms of recently approved agents over the past couple of years in the third-line setting, really nothing is moving the needle in terms of the resistance, but also the progression of these patients. So in terms of moving into Phase II, we feel highly, highly confident from a safety and tolerability, but also hopefully and potentially some clinical benefits across the board.