Welcome to Managing Director and Senior Biotech Analyst Agency Wayne Wright, and I'm joined today by Jim Bianco, the CEO of TuHURA Biosciences. Jim, thank you for joining us today. Appreciate it. So why don't we just dive right in? So for those who may be unfamiliar with TuHURA, could you provide a brief overview of the company and its pipeline? Sure. Before we get started, as is common for presentations of this variety, we'll be making forward-looking statements and referring to our SEC filings for more information about the company. I got it. I can take instructions. You know, work, but I can do it. Okay. So we're a phase three immuno-oncology company and we're focused essentially in three strategic areas. Both have to deal with two most common reasons why cancer immunotherapy fails, which is predominantly overcoming primary resistance to immunotherapies and/or acquired resistance to immunotherapy. And we have a pipeline of three different technologies to do that. So I guess let's start, because earlier this year you did some financing that removed the overhang that was holding back the stock. What steps did you take to remove that overhang? What were the terms of those deals? And what's the current operational runway? Well, good questions. Okay. So let's take the step back. I had previously done a couple of these royalty pharma deals. And so we felt the currency of the company obviously was too low. So into our largest shareholder, who believes in the history of the company, where the company can go, and clearly his $32 million equity investment would be more important to him than loaning us money. So we structured a credit facility, $50 million that's interest-only for five years, 12% simple interest, and importantly, there's no conversion feature. So you can't convert his interest into stock at a discount, et cetera. So it's just literally plain debt. Then there's an IFX royalty associated with that, which I think says a lot about his belief in IFX. I mean, if you think of it, most royalty pharma deals are done when a company has a phase three program that's finished, you have a pending application in front of the FDA, and they typically make you take all the debt down at once, whether you're going to use it or not. And so this is really kind of a pull down when you need it. You're not paying the interest on the full 50. And so I think it's a real vote of confidence from him that gives us adequate runway through next year into the first quarter. So certainly through completion of the enrollment for the phase three study, taking the AML drug Vista through its AML phase one and into its phase two program, and hopefully bringing a novel ADC candidate into first in the human trials. You know, let's focus on your lead asset first, IFX 2.0. Maybe walk us through or remind us what the mechanism of action is for that drug and the clinical data that you've generated to date. Okay. I'm going to pull it up just so we can do it. Mechanistically, we'll jump ahead to that and then we'll come back. So the major obstacle for having checkpoint inhibitors to work is that you need to have an activated tumor-specific response, right? Checkpoints are on T cells, so you want to checkpoint release the T cells so they can go and amplify and seek out the tumor and destroy it. 80% of patients do not have an activated immune response against the tumor. They used to call them cold tumors, but so the holy grail is how do you make a tumor look foreign to your immune system and generate an immune-specific anti-tumor response? You can generate nonspecific immune responses. That's not going to work. We saw that with TLR9. You saw it with CGASTING. Just activating an immune response is not enough, right? And so what IFX does is actually an exquisite way to leverage evolution and to leverage your innate immune system. And what it does is if you inject the tumor with the PDNA, it encodes for a immunogenic bacterial protein. And that protein gets transported to the top of the surface of the tumor cell. Every protein, whether it be every pathogen, be it virus, be it bacteria, be it fungi, have specific molecular patterns. They're called pathogen-associated molecular patterns or PAMPs. And those motifs were conserved through evolution in your innate immune cells. Your immune system grew up with them. And so we have pattern recognition receptors on our innate immune system, which is what you're born with. And they will recognize that motif as being a bacterium. And they will phagocytose what they think is a bacterium. When in fact, they'll engulf and chew up, quote unquote, the tumor cell. And any non-self antigens, including the protein from the bacterial coating, will get presented to newly produced T cells and B cells. Now you have tumor-specific activated T cells that have activation checkpoints like PD-1, et cetera, and even activated tumor-specific B cells that make neutralizing antibodies. And everything we just said translationally, we've shown in our clinical studies. Now if you give them a checkpoint inhibitor, you now have the substrate for that checkpoint inhibitor to work on. And that was the whole mechanism. And then obviously we demonstrated that in the phase one study, one B study, and that's what led us and the FDA to move it into the frontline setting. So, you know, when we think about the phase three trial for IFX 2.0, maybe walk us through that trial design and when can we expect to see potential initial data for that trial? Right. So I'm going to take a step back, talk a little bit about Merkel cell. I mean, everyone's familiar with melanoma, probably nobody knows I certainly didn't know what Merkel was. All right. Unlike melanoma, unlike basal cell or squamous, a very aggressive type of skin cancer, the kinetics for this disease are terrible if you don't get it under control. About 3,000 patients each year. Actually, it's about 3,400. About 10% of these patients present with potentially curable disease. If you're familiar with the Moderna story for melanoma, same thing, surgically excisable, potentially curable. You give them adjuvant pembrolizumab and they do very well. About 10% will present with lesions that they didn't know it was Merkel. Deep-seated lesions. And then the other 80% are what's going to be the subject of the phase three study. So these are patients who will respond to frontline checkpoint inhibitor therapy in about half of them. And for the other half of patients, there's no approved therapies. So that's the unmet medical need. That was the population we went to in the phase one B study because again, there are no approver effective therapies. And if you can make pembrolizumab, make Keytruda work better in this disease, that may address an unmet medical need. Therefore, that discussion with the FDA would be one for accelerated approval. Assuming this will move forward. That one, right? All right. One more. Yeah, raise ita little more. Okay. You're bringing it in front instead of putting it in the back. All right. So we did a phase one B study, right? And this was 13 patients with Merkel cell, patients who had checkpoint inhibitor naive. They got checkpoint inhibitor therapy. If they progressed through it, i.e., they had resistance, they came off of the checkpoint inhibitor like pembrolizumab, they then got IFX injected in up to three skin or nodal lesions, weekly times one, two, or three. So we had three cohorts, three patients in each. Wanted to see if giving more of it makes it better in terms of the immune response against it. Then they went back on the same class of checkpoint inhibitor and these were the type of results that we saw. So there were for example, the first three patients, progressed got IFX, went back on, in this case, the first one was on a Velimab, had a CR that lasted 23 months. The bottom line is you have six out of nine patients that had pretty dramatic, very durable responses in the frontline and the second line progressive setting. And so, you know, we went to the FDA and you would think the FDA is going to sit there and tell you, well, all right, you need to do second line, et cetera. And if you look at, you know, look at the CAT scans, I mean, these are large lesions that were expanding while getting pembrolizumab or a Velimab. They get IFX injected into those lesions. They go back on the same PD-1 antagonist. And it shrinks or goes away, right? And in the case of the left-hand panel, that arrow shows a cavitated lesion. That lesion was removed. It was pathologically a CR. And in the other panel, you can see that those large retroperitoneal lesions, the subdermal lesions where the arrows are, were injected. With IFX, after this patient progressed on pembrolizumab, went back on, in this case, a Velimab, and the lesions shrunk by about 80%. And again, they're durable. So what the FDA did, we went to come on. Maybe you can do it manually. There you go. All right. So we went to the oncology center of excellence, which is at an office level. We work with the same division, for example, at Replimune works with the Stellan Gene Therapy Group. And the FDA in 2022 has this project front-runner initiative. And what they told us was, look, if you can take patients who are progressing failing a therapy in the second line setting, it may actually be beneficial to them if you can prevent them from progressing, right? I.e., can they respond to frontline? And so they encouraged us to move it into the first line therapy. Frontline. Standard of care, pembrolizumab. And the treatment arm pembrolizumab plus IFX. And the primary endpoint, they said, even though it's a frontline randomized placebo-controlled trial, we'll still use response rate for accelerated approval. And then the key part that was really unique, it was that they came to us and said, you can show that these responses are durable, right? And so if the control arm has, let's say, 50% response and you have 75%, and this is just illustrative in the treatment arm, and they're both durable, you're going to have a 40% relative difference between the two. And that may equate into a clinically beneficial endpoint, not a surrogate like accelerated approval, like PFS. So if you put PFS as a secondary endpoint in the study, you could get accelerated approval. When PFS matures, if it's successful, yes, your confirmatory trial. So it not only allows you to not have to have a confirmatory trial both time and expense and quite frankly, regulatory outcome risk, but you can do a single study and get both applications through, right? And we haven't under an SPA with the FDA, which has been really valuable during a lot of the moving chairs at the FDA. Yeah, I think it may be beneficial for you to actually walk us through what an SPA is because obviously, you know, what we saw with Replimune, there's a whole bunch of hoopla associated with that entire approval process. What is it that the SPA does that prevents you from potentially going down that whole tumultuous process that Replimune actually went through? Yep. Good points. I never thought they'd get three by the apple. And I'm glad they did. From a patient standpoint, absolutely. So SPA is a special protocol assessment agreement, which means the FDA works with you on the protocol design, the endpoints, the stat plan, the charters, the independent radiographic, assessments, everything that you need to have a package that if you do, if you conduct the trial, the program, if you will, per the protocol, and you meet the primary endpoint and/or the secondary endpoints, they're essentially it's a legally binding document that the approval has to go with it. So there will be no ODAC or anything associated with it. There shouldn't be. And I'll tell you one other thing that is probably the best having even though pastors are not there anymore, but the mentality still is correct. That a single-arm study, you don't know what to make of a 30% response rate. You have a randomized placebo-controlled trial. This is a gold standard for the disease. You're either going to win or you're not. It's not going to be equivocal, right? You either hit the p-value and you're done. So we're, you know, we're really pleased from a regulatory risk mitigation perspective that SPA is very important. We're excited that we worked with the office as well as the division because the office always overrules the division if, for example, that was the first CRL that Replimune got. No doubt that that was Rick Bester didn't like it. So we'll see. That trial is enrolling. We're going to have, I think we'll get up to 50 sites by year end and we should complete the enrollment as we said in the second half of next year. Okay, perfect. So potential readout maybe in 2028 then. Correct. Okay. Why don't we shift gears now over to your Vista targeted monoclonal? I note that you intend on developing this MPM1 positive or perhaps refactor AML in combination with amendment inhibitor. You know, when we think about Vista, and the data that has been generated in the past for Vista targeted monoclonal antibodies, you know, some people might be a little wary about why is this different this time? Obviously, there is a lot of underlying biology that is different this time, right? AML is not solid tumor. So maybe provide a little more granularity around that concept. Sure. I mean, every company has their own development strategy. Some like to go into the large market. Some like to go into kind of where some of the biology drives the equation, right? I mean, you know, for us coming out of a center that kind of pioneered the whole leukemia lymphoma side of it at the Fred Hutch, we have guys like Alan List who's a board member who's defined MDS, who's an expert in the space. If you ask anybody what's Vista's role in biology, and it is essentially expressed in the myeloid compartment and it's one of the only checkpoints on quiescent resting T cells. All of the literature that has come out in '22 and '23 and '24 and is a growing body tells you that Vista is probably the most important target in AML. Yeah. So it just makes sense if, and this is patient data. So if you look at the Human Genome Atlas from AML, what's the checkpoint that's upregulated? Vista. If you look at which mutation is the most common in AML, NPM1, FLT3, ITD, I mean, that's 60, 65% of all patients. Highly upregulated with those mutations. And if you look at patients who have AML and their blasts express Vista, their survival is 50% or less than patients whose blasts don't. So human clinical data, pretty comprehensive that maybe this is important. And then if you look at the translational work that's been done, if you gene edit the VSIR, Vista gene, or you block Vista in these NPM1 mutated models, it shows that the mutation drives Vista expression on the leukemic blast, which is keeps T cells from being activated, i.e., immune evasion. But then there's so much literature that has evolved that MDSCs and macrophages express Vista. Yeah. So they create the environment to make sure that the blast has the ideal place to essentially survive any potential immune response. And if you're familiar with AML, there is no immunologic response against AML. Unless you have a haplo or an allotransplant. So, you know, one of the things that you guys recently announced was that the FDA prior doc provided IND clearance here. For your phase one B trial. And I'm curious to get your thoughts as to, you know, given that the patients have failed amendment inhibitor, which for which there's no approved alternatives, you know, what are the benchmarks you're looking for when this data set eventually reads out, essentially what's going to be your go-no-go signal for advancing this program into later phase development? Great question. So I'm going to take a step back. I'm going to give the FDA a lot of kudos on this one. Okay. Because they are really gun-shy about checkpoint inhibitors and AML, right? This is a solid tumor. These aren't people who go home and have their normal performance status. These are sick patients, right? Especially in the relapse refractory setting. And so a lot of the checkpoint inhibitors that have been studied in AML had marginal benefit, mostly toxicity. And so they worked really close. When I say really closely, I mean, they could have like said send it in and we'll tell you our comments. Yeah. As opposed to here's our comments before you send it in. And so we had a really good collegial interaction with them. Good. And importantly, they now understand, we think, that this isn't your typical activated checkpoint, right? This is essentially the science is really strong behind it. And we were able to take the data from the solid tumor study for safety and utilize that to essentially truncate a few of the dose levels, right? You can use that PK in safety to justify starting dose here, which, as you can see, you know, we started 100. There are six total dose levels. We'll go up to 1,000. It's a Bayesian design. And again, they were very interactive with us. In fact, if you look, this is the first time that there is an IND to study a Vista inhibiting antibody, right, in a molecularly defined subset of AML. And they were also clear that, you know, if you take patients who fail amendment, which is 80% of the patients, right? And we're going to do it in the NPM1 mutated group. Why? Because if you have the mutation, you have the target. Right? And again, not a criticism, but if you look at all the solid tumor data, you may have had the expression at the beginning. You have no clue what's going on after four or five different treatment failures, right? Here, the relationship is very causal and molecularly there. And so we think that's the right study population. We think, unfortunately, there's enough of those patients to get through the phase one data relatively quickly. Obviously, you have a 28-day period between each dose level, but you can get three patients in the third dose level. It's going to be three, three, three, and six. Right? So total of maybe 17 patients. Once you finish the dose escalation, you do a dose optimization. We'd present that data like we discussed with the FDA, look at the safety data, and then decide what a one or two doses would be appropriate to take into a dose optimization in the same population and they also made it really clear, right? Unmet medical need population, if these patients are failing amendment inhibitors, they have no alternative therapy. And the question is, what would you consider to be a response? Right? With amendment, it was third line. These patients still had other investigational options in front of them. It was CR, CRH, and that setting. They'd go all the way down to MLFS. Which is a morphologic leukemia free state, which is below an incomplete CR, below a hematologic CR, below a CR. Yeah. So I think they recognize that if you can get a signal in this group that could be encouraging, right? Yeah. And certainly if we see that in the dose optimization stage, we'd probably have that discussion very much the way Syndax and CURE are the others did, right? They were doing their phase one. They started their phase two. They had a good signal. They went to the FDA and they essentially did a single-arm study just to expand the size of the study. And I think we're getting that, I don't want to say guidance, but we're getting that same direction from the FDA. Yeah. You know, I remember the data that Kinetha generated in solid tumors. And it seemed like, because they dosed up to 1,000 milligrams. And it was relatively safe. Now, in the AML context here, where do you think you're going to start seeing initial dose? Where do you think you're going to start seeing efficacy, right? So solid tumors, obviously very different for a number of reasons. Very different context. Right? The microenvironment's a barrier. Antibodies getting into the microenvironment's a barrier. And then whether or not tumors express the target is also the issue, right? Getting to cells like MDSCs, that was part of. Part