All right, we're going to go ahead and get started. Welcome and good morning, everyone, to the second day of the Citizens Life Science Conference. It's my pleasure to introduce the next presenting company, Werewolf Therapeutics. Presenting for the company is Randi Isaacs, the Chief Medical Officer. Welcome, Randi. Thanks for joining us. Oh, Ren, thank you so much for having us. I never know exactly who's in the audience, whether they know anything about Werewolf or not, or anyone listening to the webcast, if they know anything about Werewolf. The first couple of minutes, I'd love for you to just maybe provide an overview of the company and kind of the platform before we dig into some of the details. Sure, I'd love to. Werewolf was started in 2017 with the express purpose of looking at pro-inflammatory mechanisms. And by that, you know, cytokines, we've now, we'll talk a little bit later, we've now sort of branched out a little bit, but it was predominantly cytokines when we started. I think, as everyone knows, cytokines have been approved. IL-2 is an approved cytokine, interferon alpha is approved, but they are associated with toxicity and they really have very poor pharmaceutical properties. The idea was, let's try to make these tolerable for patients. Let's turn them into drugs. We know that they have clinical activity. Let's see whether we can get that clinical activity, that immunoactivity in patients' tumors. What they did was we created a modular approach, and this took a number of years to do, and you can imagine, to protein engineer single polypeptides that incorporate a fully potent wild-type cytokine, which is a little bit different than what some other folks have been doing, where they look to mutate or look to skew to a particular receptor. We use fully potent wild-type cytokines to then block those cytokines in the periphery to prevent binding to any sort of peripheral receptors. That is what gives you the therapeutic index. That is what gives you the safety. To also take something that is a half-life extender, and that was an Anti-HSA or albumin, and then put these together with what we call our secret sauce, which are our linkers. These are protease cleavable linkers. They were discovered in an agnostic fashion. They're not particular for any particular protease class. I think, as everyone knows, in cancer, proteases are dysregulated, and there's a number of them that exist. If you look for a particular substrate, a particular sequence for a particular class, you probably are going to miss the boat on a number of different tumor types. This allowed us to not even have to think when we went into the clinic about which indications to go into, because we were cleaving across all indications. What we looked at was a library of these substrates, of these particular linkers, and there were thousands of them. We screened against hundreds of human tumors associated, and then picked the one that cleaved most across a number of different indications, but didn't cleave in normal tissue. Remember, that's really important because that gives you your specificity. That's the werewolf, that's the molecule. The platform is called a PREDATOR platform. I think you can start seeing, you know, how this werewolf, howl, predator. We call these cytokines that we've created endokines or inducible cytokines. We now have actually branched out beyond oncology and have developed, and we actually reported this morning, we've developed an Interleukin 10 for IBD in the same manner. We've also now have a TCE, T-Cell Engager platform that we are actively pursuing. We've gone beyond, we're still an oncology company, but we've gone beyond the cytokine, the endokine approach. That's a great intro. Thank you for that. Harnessing the power of cytokines. You mentioned, you know, obviously we have some approvals. People have been trying to harness the power of IL-2 now for years, right? Like ever since it's been approved, because of the severe toxicities, the fact that, you know, these patients, if they even got IL-2, would need to be hospitalized or monitored. People have been trying to do this very, very unsuccessfully. If we just take a 10,000-foot kind of view at the space, a lot of interest, pharma had bought out, you know, companies that were working in this space only to have the phase III spare. With very little data, mind you. Yes, with very little data, fair. Just recently, just this year, we had a failure from Mural Oncology, which was also trying to do the same thing. You know, I guess I'd love to kind of get your thoughts of, A, what do you think went wrong, right, with some of these prior, you know, molecules that were advancing through clinical development and ultimately failed? I guess, you know, as part of that, what do you think Werewolf, you know, is doing right? That's a great question. I'm not going, let me spend a couple of minutes just in describing the non-alpha approach that many of these companies took. We now know was probably, I mean, at the time it was thoughtful, but, you know, I think those of us who understood how immunotherapy should work were really a little bit skeptical about whether or not it could be successful. Basically it wasn't. I'll tell you why. IL-2, there's three receptors for IL-2. There's a low affinity, a medium affinity, and a high affinity. If you take a non-alpha molecule, all right, and I think I started to speak to this when I was talking about the differentiation of our platform. If you take a non-alpha molecule, and what does that mean? It'll be an IL-2 that's either mutated or skewed or in some way doesn't bind to the high affinity receptor, doesn't bind to the alpha chain, which you need for high affinity. The intermediate receptor is a beta gamma. If it doesn't bind to alpha and doesn't bind to the high affinity receptor, you're not going to get full efficacy. You can't. I mean, the thinking was that the high affinity receptor conferred toxicity, the high affinity receptor conferred the activity on Tregs, which was immunosuppressive. Biology doesn't work that way. You know, it's not cut and dry. It's not black and white. What happens is that in the clinic, many of them did not show monotherapy activity. You must have monotherapy activity with your drug in order to imagine that when you combine it with other agents, you're going to get added, at least additive activity. I think SITC, which is the Society for Immunotherapy, has now come out with guidance that basically said if you're going to have a successful phase three trial, you better have monotherapy activity. These agents didn't have monotherapy activity or very little monotherapy activity. What happens is you have to start to escalate the dose until you get toxicity because the beta gamma receptor also confers toxicity. In order to get any anti-tumor activity in the clinic, they were escalating and escalating until they got to toxic doses with no monotherapy activity. It is not surprising that many of them, you know, despite the fact that some of the data from the early companies look very promising. Now Werewolf, as I think I mentioned when I was talking about our molecule, we use a fully wild type. We don't skew. We want the full potency. What we do is in order to achieve that is we have blocking in the periphery, we have half-life extension, and then we have those linkers in order to be able to have activity across a broad range of oncology indications. Let's jump right into it. Your most advanced product, you know, trying to harness the power of IL-2. This is WTX-124. Can you remind us kind of where we are in the clinic? What's the data so far? And since you've brought up monotherapy activity, what are we, you know, what are we seeing here? I think, you know, most importantly, just to kind of set expectations, you know, is the activity that you're seeing exactly what you were hoping to see, you know, or is there room to be improved? Right. I can tell you that we, you know, as we reported today, we are done with dose escalation. We had both monotherapy in combination with Pembrolizumab. We have a clinical trial service agreement with Merck for provision of Pembrolizumab to the trial. Our dose escalation arms were run in parallel. We landed on a dose of 18 milligrams, flat dose of WTX-124 in order to move into dose expansion arms. We have done so and all of our arms are open now. We have both monotherapy expansion and combination expansion. IL-2 is actually Proleukin, is approved in melanoma and renal cell cancer. We have arms for both of those, for both monotherapy and combination. We also have cutaneous squamous cell carcinoma in the monotherapy arm. We can talk a little bit more about why that is, but we've seen some very dramatic activity. In fact, we have a patient who received our drug after failing standard of care checkpoint inhibitor and went on very quickly to a complete response and actually has been in complete response for over a year. The decision was made, let's open up an arm for monotherapy. There is nothing in second line after checkpoint inhibitors for this advanced disease, cutaneous squamous cell. We have that open. In combination, we have an arm open in non-small cell lung cancer, PD-L1 positive. All of those arms, those six arms, are ongoing and enrolling very, very well. I can tell you that as far back as our first presentation, which was in November 2023 at SITC, we showed things that no one else had shown. We showed not only monotherapy, early monotherapy activity, we showed beautiful dose-dependent biomarker. This was something that a number of the other companies never did. From the get-go, from our first dose, we did biopsies on patients pre and on treatment and looked at a number of different parameters. The ones that we actually landed on that were most revealing to us were nanostring, which I think everyone knows is gene expression analysis. We're looking specifically at T-Cell genes and then IHC-IF looking at the environment. Not only if you do nanostring, you're basically doing bulk RNA, but what you can do with the IHC-IF is you can actually see the cells. What we were able to show in a very, very nice way in our biopsies is that we had a dose-dependent increase not only in T -effector cells, CD8+ cells that you could see on immunofluorescence. All of these things are on our website if people are interested in looking at the slides. We also saw Granzyme B and a number of other different gamma interferon. We knew not only that we were increasing CD8+ cells, but they were pro-inflammatory and they were secreting pro-inflammatory enzymes, right? As we think about this program now, right, whether it's in cutaneous, the expansion cohorts, you know, or the monotherapy, maybe just starting off with the monotherapy, like what do you hope to get out of this expansion now at 18 mg? What do you hope to confirm? Ultimately, where does a monotherapy therapy fit within the landscape? Yeah, those are great questions because I think so many people are sort of, you know, focused on combinations and certainly in oncology, you know, as you move into earlier lines of therapy for advanced disease, you're talking about combinations. We are looking at things in parallel. There are places for both monotherapy and combination. We have seen exactly what we were hoping to see with monotherapy in terms of activity in patients who have failed checkpoint inhibitor therapy. In combination, we have these more homogeneous populations in expansion where we can look at overall response rate, durability. In a, remember in dose escalation, we were dealing with a whole array of immunotherapy sensitive tumor types and at various doses and patients who were heavily pretreated. Now that we're in expansion, we have those homogeneous populations. This is a very important year for Werewolf. We are accumulating data. We've guided to having complete enrollment in the melanoma monotherapy expansion arm by the end of this quarter and the combination expansion arm by the end of the year. What we're planning on doing is taking our data to the FDA in order to look at various registration opportunities, including accelerated approval with monotherapy. At the end of the year, take our bolus of data both from escalation, but also from our expansion arms in whatever indications we have data and present that to the community. Excellent. Big year for you guys. With the, you know, as you kind of, I mean, you can't speak for the FDA necessarily right now, especially with things that are happening, but if you had your way by the end of the year, what do you think would be maybe the ideal path forward? That's question number one. Question number two would be, you know, as you think about these different indications, you've clearly picked indications for which, you know, they're already kind of checkpoint sensitive, if you will, right? That's exactly right. They've already shown some sort of. Because IL-2 needs that. IL-2 needs an environment that's already, and we've shown that, already somewhat T-Cell infiltrated. I was going to think that maybe with IL-2, you could go after cold tumors and maybe. That's IL-12. That's our second program. Okay. We'll come to that with that. IL-2 is really, we have shown data that suggests that patients at, when you look at the biopsies of patients pretreatment, those who have already a T-Cell rich environment are those that seem to respond best. Okay. Going back to the first question then, let's just assume that the data across, you know, doesn't matter if it's combination, mono, various indications, they all turn out to be like, hey, we could move forward in any of these. If you had your pick, what? I would do them all. You know, it's expensive. We're a tiny company. I would do as many of them as we possibly could. You know, that's why we're actually, you know, looking for partners. We're looking for other ways of being able to do this. We have, we're focusing on melanoma. The vast majority of our data are in melanoma. We have lots of ideas for where we would place this both from a standpoint of combination, but also monotherapy. I mean, once patients have failed a checkpoint inhibitor or a population, and this is something that most people don't think about, there are patients who've received checkpoint inhibitor therapy who've had immune-related adverse events and either they don't want to receive a checkpoint inhibitor again or their physician doesn't feel that it's appropriate. There's a population for that's an unmet medical need for monotherapy. Monotherapy gives you the best chance of an accelerated approval. I don't know how that's going to play out now, you know, with the new FDA, but there's that opportunity. There's also randomized control trials that we would like to do in combination with Pembro, either in a second line setting. Cutaneous squamous cell monotherapy, nothing in second line. That would be a dream for us to be able, you know, to accelerate that and do that study. About how many patients' worth of data from each of these expansions should we be expecting to see by the end of the year? I'm not going to, I can tell you for melanoma, we have 20 patients in monotherapy and 20 patients in combination. The same is true for renal. Same is true for non-small cell in combination and then 10 patients for cutaneous squamous. It'll be some fraction of that total amount. Got it. Okay. Let's switch gears real quick in the time that we have remaining to WTX-330. Kind of wanted to get your thoughts on that, you know, we've seen some data from that molecule as well. Wanted to get your thoughts on that data and how, you know, you're seeing the development of this product going forward. Sure. IL-12, I don't know if people are as familiar with it as IL-2. IL-12 was developed or started to be developed in the 1990s by a company called Genetics Institute. Unfortunately, it was, the program was stopped because of very severe toxicity. Exactly the kind of molecule that Werewolf approach, you know, was meant to tackle, it's a pleiotropic cytokine. It is the one where you can actually take a cold tumor and I don't, you know, I don't like using that term, but a tumor that's less heavily infiltrated. We showed this preclinically and have anti-tumor activity with this molecule. You needed to find a way to deliver it systemically that avoided the severe toxicities. We presented our phase one trial, first in human trial at SITC this past November. For people in the know, I mean, they really understood that we had done something that no one else has been able to do with IL-12. Other folks have either, they're either using extremely low doses, they're not masked, or they're using, people have been using an intratumoral approach, which we know is not, you know, is very difficult to develop an intratumoral drug. This was the most IL-12 that has ever been delivered to a patient, two patients. This was delivered as an outpatient. All of our drugs are delivered every, this is delivered every two weeks. 124 is delivered every two weeks. Outpatient delivery, very nice for patients and for the sites. We showed not only that the drug was tolerable or generally tolerable, we had biomarker activity, we had anti-tumor activity. All of the different features that were really important to understand about IL-12, we've now taken this into a study that we have already dosed a patient in, looking at the best regimen in order to then bring this forward into combination and into particular indications. When would we see data from this program? This next study, I would imagine, you know, we are at this point doing the regimen finding and we have not guided to exactly when, but you know, again, this is open label and as the data emerge, we will evaluate it and maybe have something by, you know, end of year, early next year. Okay. You guys, you know, you guys reported results today. You mentioned in your prepared remarks, IBD, so autoimmune, the other side, the other, you know, the other side of the coin, right? Of the cytokine kind of landscape. Would love to kind of get your, you know, just your initial thoughts. How does this work, you know, with, in autoimmune? And then of course, I think this is the first time we're hearing that you're now in. T-Cell Engagers. T-Cell Engagers, yeah. I'm not an expert by any means in inflammatory bowel disease, but, and there was no reason to think that you couldn't take a cytokine. And remember, most of the treatments for inflammatory bowel disease now are cytokines, that you couldn't take a cytokine that is really not tolerable for patients and do the same kind of masking and, you know, TAF-like extension. We set about doing that. The preclinical results are beautiful. We just presented this past week. I was very jealous. We sent one of our scientists to Hawaii to present at the, I guess it's AIA, the inflammatory disease meetings and showed remarkable activity. What's interesting is that we use the same linkers right now for oncology, but we couldn't use those linkers for inflammatory bowel disease or inflammation in general. That actually was very reassuring to us for some, because we always get the question, if you have inflammation in the body, how do you know that you're not cleaving your oncology, your cancer drug linkers and having, you know, what we know from PK that we're not, but it was a very good question. The fact was that the linkers, that the molecules for IBD did not cleave. In the models, we could not get cleavage for inflammation. We had to do a whole linker discovery effort where the IBD molecule, which is an IL-10, has a different linker, has different linkers than the oncology molecules. It is very interesting. As for the TCEs, there is an enormous amount of work going on in the lab, looking at targets, you know, looking at different ways of masking both the CD3 end and the antigen. The expectation is that there will be a development candidate by the end of this quarter. Development candidate by the end of this quarter, likely an IND filing, let's call it in 2026, right? That would be wonderful. Right. But for AID, what's the, you know. For IBD? Yeah, sorry, IBD. Inflammatory. It's all sort of colitis. We're not in the business of, you know, of inflammatory, you know, but we really are looking for a partner, actively, actively looking for a partner for that, for that program. Just, you know, for the audience to know, this would not be necessarily something new for you. You've already secured a partnership, right, with Jazz Pharmaceuticals. That continues to move forward as well, right? Correct. Early on, Jazz was very, very interested in our interferon alpha molecule. We partnered with them. We brought the molecule to IND filing, and then they've taken it over. They're doing all of the development. You know, we're waiting to see the results. You know, they'll be the ones to share results going forward. Got it. In the last sort of five seconds that are left. Yes. Can you just remind us what's the cash position that, you know, you've reported and how long does this cash last you? Does it take you through, you know, a lot of these, you know, pretty important events that are coming up? Yeah. We're very frugal. We're extremely frugal. At the reporting as of the end of March, we had $92 million on the books. It takes us into the fourth quarter of 2026. It's a year beyond when we expect to really show a large bolus of data, plus our discussions with the FDA and the second half of the year. Excellent. Randi, thank you very much. Thank you.