Hey, great. We have, now I know it's 1:00 P.M., Kairos Pharma. Ticker is, I don't have the ticker in front of me, so I apologize. KAPA, I see it up there on John's background. And Dr. John Yu is a biotech veteran. He and I actually go way back, well, at least for me, to a vaccine he was developing with a prior company, right, for brain cancer. Yep. Was the ticker back then. Had some really good data, never worked out, but it comes from Cedars-Sinai, and so does this technology that is the foundation of this new group, Kairos Pharma, that he started, so we're really excited to learn more about it, and it's really focused on CD105 and a monoclonal antibody targeting that. They're in prostate cancer, they're in lung cancer, so there's a lot to learn here, so John, welcome back. It's good to see you again. Good to see you, Jason. How are you? Thanks for having me. I think maybe give everybody an introduction to yourself, 'cause you've done a lot of incredible things over the course of your career, and then maybe a kind of a top-down view of Kairos. Sure, yeah. My name's John Yu. I'm the CEO and Chairman of Kairos Pharma, and I'm a neurosurgeon by training. And one of the most difficult things that I have to do is give a patient the diagnosis of a brain cancer. And as difficult that is for patients to take, it pales in comparison to when the cancer comes back despite the chemotherapy that they're on, and that's when you can really see the hope leave their eyes. And what Kairos Pharma is focused on doing is developing therapeutics that reverse cancer drug resistance, and allows the cancer drug to start working again after the tumors come back. So Kairos Pharma is a clinical stage pharmaceutical company that is developing therapeutics to reverse cancer drug resistance, and reverse immune suppression caused by cancer. We're in a phase 2 randomized controlled trial in multiple centers in a phase 2 trial for prostate cancer. We're in a phase 1 trial for EGFR-dependent non-small cell lung cancer with Tagrisso. And the idea is that cancers become resistant to drugs despite them working well for, you know, six months to a year. And we've identified a central mechanism of cancer drug resistance, and that's in the development of CD105, which is a molecule on the cell surface, and we've developed an antibody that targets this protein and reverses the impact that it has on resistance, by reducing the survival signal that it gives to the cell. And so, when that happens, then the cell becomes susceptible to the drug again, and so that's really what the goal of our therapeutic is. And we also develop therapeutics that target really central mechanisms of T cell activation and growth. So, that's what we're all about, and happy to be here to talk about it. CD105, don't hear a lot about it. I wonder if you could discuss it a little bit more. It's upregulated in response to certain treatments. Can you just describe it a little bit more to us? Yeah, sure. So it's a cell surface protein that has two components. It blocks TGF signaling, and it promotes BMP4 signaling. And so by blocking it with an antibody on the cell surface, it just blocks the BMP4 signaling. And as it blocks the BMP4 signaling, it blocks the signal for survival to the cell, and it blocks dedifferentiation of the cell. And so this impacts several mechanisms of resistance in prostate cancer, whether it be through the expression of androgen receptor decoy receptors, through neuroendocrine differentiation of the tumor, or through a dedifferentiation of the tumor. And so impacts each of these mechanisms of resistance, and so appears to be a central one. And it also impacts resistance to Tagrisso as well through a separate mechanism, and that's through a dedifferentiation mechanism in this tumor type. From a theoretical perspective, I guess. So I feel like we've seen, been seeing a bit more of this. We saw it for several companies over the course of this conference, that FDA continues to seem to like these novel therapies that can extend treatment of things they're already familiar with, whether it's chemotherapy, it's a checkpoint inhibitor, we're seeing that with like TuHURA Biosciences is doing that, radiation, some combination of those. What are your thoughts on that? Because that's exactly what ENV105 leans into, right? Yeah. If you could just get them out a little bit long, even in prostate cancer, which we'll talk about... with the anti-androgens, you know, Xtandi or, Erleada or whatever. Yeah. What are your thoughts on FDA's view or maybe clearing paths for novel therapies to extend therapies for things they already know work? Yeah, so I think it's almost like having, you know, synergistic drugs work together. But, you know, clearly our drug is a very different mechanism in that it allows a drug that's failed to work again. And I think in the setting of a very low toxicity profile, where the drug has no grade three or four toxicities in and of itself, when added to the other drugs, I think it's a very attractive scenario. The central mechanism I describe as central because it's really relevant in several different types of cancers, as well as several different types of drugs, whether it be in breast cancer, colon cancer, and head and neck cancers to DNA damage and radiation. And so it appears to be impact several mechanisms of resistance in these drugs and in these widespread cancers. And so I think it's particularly given the safety profile it's a attractive means of extending the lives of several of these therapeutics. Does interfering with CD105 change anything immunologically around the tumor and the tumor microenvironment? That's a very good question. Not necessarily, but we've actually seen impact in the lab of resistance to PD-1 antibodies. And so whereas, you know, oftentimes you get resistance to nivolumab or pembrolizumab, ENV105 appears to reverse that mechanism of resistance as well. So does CD105 play a role in PD-L1 expression in the- Yeah, it appears to have an impact on PD-L1 expression on T-cells as well. Okay, so then beyond general resistance to chemo or radiation or some other, I guess, standard of care type of therapy, so you can resensitize to checkpoint inhibition, potentially? Yeah, potentially, and that's what we've seen in vitro. So what type of indication would you go for? We've seen some openness with FDA. TuHURA has got a SPA agreement to go first-line in Merkel cell, just because they're extending checkpoint-failed patients, which is something you don't see that often, getting into phase III these days. So- Mm-hmm ... is that something that you guys are thinking about? Well, we have other targets that are, you know, large markets that we're, you know, targeting, right now. You know, the prostate cancer- Right ... you know, is a very large market, the EGFR-dependent lung cancer. But we're targeting head and neck cancers because that's what we have the most data on, in vivo right now. And you know, and again, breast and colon are targets as well. You know, we're a small company, we can't hit every cancer, but we're hitting them one at a time. Can you talk about the phase II in prostate cancer, and what setting that you're in? Is this post-Xtandi, post Erleada? Yeah. You can't take all of them, right? You can take one, and then you move on to chemotherapy once you progress. Yeah. So no, you can take two or three of them. So all the patients have failed at least two anti-androgen agents. And then this- so, when they fail two agents, and they have a recurrence, a PSA recurrence, then they're put on one of two arms, either with apalutamide alone or apalutamide with ENV105. And the expectation is that apalutamide, despite it being a third-generation anti-androgen agent, is likely to fail in the third line setting, because the mechanism of action is very similar as with the first and second generation anti-androgen agents. And so the likelihood is failure with that, but we add ENV105 to the other arm, and the primary outcome is, endpoint is, progression-free survival. So the trial is looking for approximately 30% increase in progression-free survival from those patients on apalutamide alone. Oh, let me before I get there. So how many patients are... This trial is ongoing, right? How many patients... Yes ... in this study, and kind of how is that study designed? Yeah. So it's designed with a safety lead-in of ten patients. And then patients are randomized to one of the two arms. So the 90 patients will be randomized either with apalutamide or apalutamide plus ENV105. The primary outcome measure is progression-free survival, and there's a crossover component for those on apalutamide alone that fail and have a resistance to that drug alone. And yeah, so we have a safety readout coming in the next month or so. And then we have an interim efficacy readout next year. Okay, and so when you're thinking about prostate cancer or drug resistance to the anti-androgens, I know you have to start in third line where you are now, you get your data. But does it make sense mechanistically that you could use ENV105, I don't know if it's before or concomitant with anti-androgen therapy to actually prevent them? Yeah, that's a good question. From getting resistance. That's a very good question. I think that may be our next trial, but for now, we're looking at when the resistance occurs, which is when they make the most CD105 protein. So it would make sense to treat them after they've developed the resistance. But I think, you know, there's a possibility that if you treat the CD105 as it becomes expressed, then you may make an impact there as well. So is there, when you're screening for patients, are you biopsying tumor and staining for CD105? That's one. And two, like PD-L1, is there a level of expression, a CPS score, like they use for the PD-1 checkpoints, that you might be beholden to see ENV105 work? Yeah, so, both very good questions. What was the anti-androgen question? No, well, it wasn't specific to the anti-androgen. It was more of, what's the level of the 105 expression? Oh, right, right, in biopsies. In biopsies. Yeah, the issue with the prostate cancers at that point is that their prostate have been removed at that point, and they're largely metastatic patients with bone metastases. So it's difficult to get biopsies on most of these patients, unless they have some top soft tissue metastases. And so we're really looking at most patients not being able to get biopsies. We do get circulating tumor DNA from these patients, and that's how we determine the three-panel bioassay to determine whether they respond to the ENV105 or not. But as you ask, there are no biopsies to be had in these patients. Okay. With regard to the level of PD1 expression, that's a very good question, and we haven't looked specifically at that. Also becomes challenging, right, without a tumor to take samples from, right? So you can't do the CPS score. Yeah. Right, if they're that metastatic and no prostate organ. Right. Right. But it's considered in general that everybody at this line of therapy is expressing CD105-ish. Yeah, it appears to be. Okay. So how would you pursue a larger trial in prostate cancer, assuming that this goes well in third line plus? Is that where you're gonna start? I mean, that's where the, like, the Xtandi and Zytiga started, too, and they kinda... We used to call it that therapeutic pyramid, kinda worked their way into earlier lines of therapy. Yeah, so you know, we have the same endpoint as a large phase 3 trial would have in terms of progression-free survival, so you know, I guess we'll see what we find in terms of this trial. I mean, based on you know, the data, we would think that we would see a difference in the patients with the number of patients that we have on the trial, but that remains to be seen, and then we would you know, figure out our phase 3 trial based on that, or you know, other opportunities of doing smaller trials at that point, too, if you know, the data seem to be definitive. Can you give us some background on the lung cancer program and the EGFR-driven disease? And I think from the aspect of lines of therapy or what percentage of lung cancer, non-small cell, is EGFR-driven? Yeah, so EGFR-dependent non-small cell lung cancer comprises about 20% of non-small cell lung cancer, and so there are approximately 45,000 patients per year with EGFR-dependent lung cancer largely being treated with Tagrisso, and so you know, Tagrisso is a fantastic drug. I've seen patients with 50 brain tumors, you know, melted away with a great blood-brain barrier profile as well, and so these will keep patients really tumor-free for extended periods of time, you know, six months to a couple of years, but almost all of them do fail it after a time, and so based on animal data that we're about to publish over the next month or so, we went into a large phase 1 trial. This is a trial with 50 patients with a safety lead-in as well, and then 20 patients are those that have recurrences on Tagrisso, and so those patients are treated at that point. The other half of the patients are in an arm where they're incompletely treated with Tagrisso and have circulating tumor DNA from the lung cancer, and so they're being treated with that to determine whether we can make them tumor-free in that setting, so I think both outcomes will be pretty interesting, and it's a pretty large phase 1 trial, so we should have a good signal in both groups. The time to progression once you become resistant to Tagrisso is how long? Approximately six months to a couple of years. So you're looking to extend that time, or- Right ... or re-sensitize to Tagrisso and- Yeah, so after the recurrence, we're looking towards re-sensitizing them to see the responses, and also to see if we can completely get rid of their tumors, you know, with small pockets on Tagrisso, with circulating tumor DNA. Are they metastatic, or are they what stage are they? Yeah, oftentimes they're metastatic. Okay. And you expect... So, it's an early stage study, right? So you're kind of trying to establish your recommended phase 2 dose, hit an MTD, whatever you're trying to do. Exactly. Um- And safety, and also identify biomarker genes for this population of patients as well. What biomarkers? So in our prostate cancer study, we identified a three-gene panel that differentiates those patients that respond to ENV105 versus those that don't, and that's with a P value of 0.0058. So you know, this will lend itself well. We received a $3.2 million grant from the NIH to study this biomarker in the randomized phase two trial. So we're not using the biomarker as a criteria for entry, but we're testing all the patients, and I think this will be important in a potential phase three trial, in decreasing the numbers of the phase three trial by potentially 40%. And also based on having a biomarker, it increases the likelihood of success of any drug from 55% to 76%. So I think having a biomarker is important for any drug in terms of pushing it towards the finish line. Back to that prostate study, do you need to see radiographic response on Mets, or do you need to see changes in PSA? I'm assuming maybe greater than 50% or so to know that you're having an impact. Yeah, so we showed in a previous small phase 2 trial about a 62% clinical benefit rate, meaning that they had either both PSA decreases and tumor stability or responses. So that was the idea of doing this larger phase 2 trial. Now, the phase 2 trial is looking at progression-free survival. So after whatever response that they have to the ENV105, we're looking at the time period in which they don't progress- Mm ... from that, and so, yeah, that that's the final measure, and that's the relevant primary endpoint for a phase 3 trial as well. You guys have an immunotherapy side to the company. Do you wanna share- Yeah ... a little bit about that? Different checkpoints than we're typically used to hearing. Everyone's PD-1, CTLA-4, LAG-3, but- Yeah, so- Something different. Yeah, I think this is, you know, we're very, very excited about this, this molecule. It was developed by Ram Murali, who had two PNAS papers that looked at the X-ray crystallography of GITR ligand. And so he really understands the structure of the GITR ligand really well, and the GITR receptor is a TNF-like receptor, and TNF-like receptors all work by trimerization, and so GITR is the same as that. And so this molecule actually stabilizes the trimerization, or the three parts of the GITR ligand, allowing it to physiologically signal the GITR receptor, and the receptor oligomerizes. And so you get this exponential signaling of the T cell to expand. And so not only do you get positive signaling of the T effector cells, but you get negative signaling of T regs. So you see T-effector cells go up, you see T-regs go down, and so this is a lever for a checkpoint for T-cell proliferation. And so what we've seen is dramatic expansion of T-cells in response to tumors. Not only does it actually expand the number of T-cells, T-effector cells, and decreases T-regs, which, as you know, is a significant problem in CAR-T cell therapies or any type of T-cell therapy, but it also makes the T-cells kill the cancers better. So we see a significant increase in cytotoxicity of these T-cells against the cancer. What Ram also did was developed a small molecule that prevents the trimerization of the GITR ligand, and by doing that, he increases T-reg cells and decreases the T effector cells, and we think this is going to be a paradigm shift in autoimmune diseases like Crohn's, multiple sclerosis, rheumatoid arthritis, and organ rejection as well after transplantation. So we're trying to develop these agents. They're at the pre-IND stage right now, but we're very excited about getting those into the clinic over the next year or so. ... Okay, and I don't know if I missed it on the lung cancer side. Sorry to go backwards. What are the next steps or the events in that program? Yeah, so, we have a safety readout over the next couple of months. Okay. And then as we enroll into the two arms, you know, we're looking for efficacy signals in that. Really, it's a dose-finding study, as well as a safety study, but clearly, you know, the efficacy will be something that we're very interested in, in looking at during the study. Great. And just generally, 'cause we're coming up on time, if you could review with everybody what are the next events overall, prostate, lung, biomarkers, and the immune therapy side? Yeah. So, over the next couple of months is the safety readout from both the phase 2 prostate randomized trial, as well as in the lung trial. I think that will have some efficacy data baked in, because those patients have been followed for some time. And then, in 2025, we anticipate our interim efficacy data from our phase 2 trial. And then thereafter, several months later, should be the final readout in the prostate cancer trial, as well as in the lung cancer trial. Great. It's always good to see you, John. It's been so long, right? So, Yeah. It's great to see you, Jason. Thank you for coming on, and we're gonna catch up again after this conference, and you know, talk more about Kairos in detail. Great. Thank you very much for having me. Appreciate it. Have a great day! Okay, you too. All right, welcome back, everybody. We have Alterity Therapeutics, A-T-H. Dr. David Stamler is joining us, CEO of the company. David has quite an extensive background in biotech, particularly on the movement disorder side, neuro side, going all the way—at least for me, going back to Auspex. And that's what jogged my memory when I first met these guys recently. That company was acquired by Teva. We actually hosted them for a movement disorder conference that we had at Maxim in the Chrysler Building, like, 10 years ago. So tremendously successful. Now, fast-forward here to Alterity, and they're working with a new drug. I forgot the acronym, ATH, and it's got a number after it, but David will help us with that. That's an iron transporter. It's not an iron chelator, and they're doing it for multiple system atrophy, which is a Parkinsonian-like disease. Could probably be applied for Parkinson's disease as well. But that difference, David, between chelator and kind of transporter redistribution, we'll get into that. It's very important for people to understand. But exciting things happening at Alterity, so maybe a brief introduction about yourself, better than I did, and some background on the company.