Afternoon, everybody. We are closing out HealthCONx with Werewolf Therapeutics. Thank you, Dan and Randi, for being with me today this afternoon. We'll get into the nitty-gritty, I think, on all your programs in just a moment. But I'd love to start with an intro and background from you guys. We've seen a lot of high-profile recent success with certain masking technologies. Been in the news a lot in the past week or so. But cytokines historically have had some mixed results with masks. What drew you to cytokine space? And maybe what differentiates your technology from other modified cytokines we've seen in the field? Sure. Thanks for inviting us, Jon. It's a pleasure to be here. Yeah, we definitely think the conditional activation approach is starting to come of age, for sure. Just maybe a little background on Werewolf and our technology. We are a clinical stage biopharmaceutical company, and we are developing a novel class of cytokine therapeutics that we refer to as INDUKINE. These are cytokine prodrugs or conditionally activated molecules. And the goal there is really to take these powerful immune-stimulating mechanisms and design them in a way that they can be systemically administered to patients, reduce the off-target normal tissue toxicity that you would have with a normal cytokine, and then deliver them to the appropriate disease tissue and immune cells to then elicit anti-tumor immunity. The company has two lead programs in clinical development: WTX-124, which is our interleukin-2 molecule, which is now in phase I expansion studies. We can talk more about that. We also have our IL-12 INDUKINE molecule, which is WTX-330. We just presented at SITC a few weeks ago, our first in human data for that program, and we're now transitioning into a phase I/II study. What really makes the INDUKINE molecule and the way we conditionally activate our molecules different is we've taken a number of design approaches to the molecule to keep the molecule in a fully potent active state. The cytokine, we don't attenuate it or modify it in any way to eliminate some of the pharmacology. We actually keep it a fully active cytokine in our design. We have a very unique and novel masking approach that we use to keep the molecule turned off but be activated in the tumor tissue appropriately. And what we've seen is now in the clinic, we can really drive the INDUKINE exposure in tumor tissue to high exposures to the extent where we can then activate it through our novel linkers that we have designed into the molecule and release enough IL-2 to show monotherapy activity, which we can talk about, which is very important, but still have a very favorable tolerability profile. And we really believe that our IL-2 molecule is really showing the kind of proof of concept for the INDUKINE design that really kind of substantiates all of the work or validates all of the work that we did in the design and bodes well for some of the future development of a number of our molecules in our portfolio. Excellent. Well, let's dive into that IL-2 since we had recent data at ASCO. Obviously, still in dose escalation and in a heterogeneous set of tumors there, but you do see a couple of responses in the higher dose cohorts, which are all post-checkpoint exposed patients, which is really nice to see for that immune mechanism. But what I struggle with sometimes is thinking of the right comp. And obviously, it's challenging to do direct comps in a dose escalation sense. But for a cytokine in a post-checkpoint setting, how do you view the bars for success? Should we be thinking about IO retreatment bars or other mechanisms are more appropriate? Sure. That's actually an incredibly interesting question. People only say that when they don't have an answer in their back pocket. I know. I do, and I'm trying to think about which angle to go at this first. Yeah. In the relapse refractory setting in the immunotherapy sensitive tumor types, and what I mean by those are tumor types for which checkpoint inhibitors are approved, and now it's 17. The places where you've got responses as well. That's exactly right, and perfect place for the IL-2 mechanism of proliferation and activation. We know this. Of T cells in the existing tissue. There, in the diseases that we're looking at, so we're looking at melanoma, we're looking at renal cell, we're looking at cutaneous squamous cell as the first three. Sure. After you have seen a checkpoint inhibitor or other standard of care in the first line or for renal cell, potentially the second line, there isn't a lot left for those patients, and I think as everyone knows, the majority of patients are not cured with checkpoint inhibitor therapy. What our WTX-124 allows is for investigators, for physicians, oncologists to have an option to take off the shelf and use as monotherapy in these patients and to see responses, and we have presented data on a complete response in a patient, a primary refractory cutaneous squamous cell patient who had extensive disease, and that patient is now, after being off drug for many months, is still in a complete response at over a year. We drove that response very quickly. That's something that is very unique about the molecule, is that you know very quickly if a patient is going to respond. And because of that, if you think about using that in a therapeutic setting, that's very positive. The investigator knows, the patient knows very quickly, yes, you're responding and continues. Or we don't see something in the first two months, so let's move on to something else. So it gives a lot of optionality in these diseases. There is a very important track for monotherapy approval in these diseases. And when you say comp, if you look at IO retreatment, so just checkpoint inhibitor. I think 5%-10%, maybe 15%. It's very low. That's exactly right, and so as a bar for treatment after patients have failed, now is it going to be at the same level as, let's say, perhaps a new modality in any of the indications? Maybe not, but it doesn't matter. It's another tool. You're giving something with a known, it's a validated target safely in the outpatient setting to patients and giving them the opportunity of getting a complete response. There's very few things out there in patients who are advanced or metastatic that you can say there's a potential here of a complete response. Maybe I'll switch gears and ask a little bit about dose response for masked cytokine. We saw the waterfalls for just the top two doses at ASCO, but how much concentration effect is there for active drug in the tumor given the mask? So I guess I am wondering where you are in terms of the amount of immune stimulation you can see in the tumor environment? We have both efficacy data, biomarker data, and PK data that basically address that question. And that was part of the ASCO presentation. We did not see activity. We started in our dose escalation at one, actually. And we didn't see activity at one, three, and six, 12 milligrams, or maybe a little bit of biomarker activity at six, where we said a little patient with stable disease that was longer than we expected. Sure. And then all of a sudden at 12 milligrams, we started to see anti-tumor activity. So there certainly is a dose response. And again, 18. And at 18, we saw even further biomarker activity. And that was one of the reasons that we chose 18 as the recommended dose for expansion for both monotherapy and combination. And just to mention that all of our expansion arms are now open for enrollment. I ask that in part because it does seem that although clearly the mask is making this far more tolerable than naked IL-2 ever was, you are running into some inflammatory tox. Looking at the AE charts, I see some things low-grade, very manageable, certainly. But I'm wondering, you pick 18 as the go-forward dose. Are you getting maximal immune stimulation in the tumor? And do you have flexibility in your ability to dose there? So I want to discuss the term you used about inflammatory adverse events because we're not seeing anything that is an inflammatory adverse event. We don't have vascular leak syndrome. We don't have cytokine release syndrome. We don't have infusion-related reactions. Our primary adverse event that we see treatment-related is arthralgias. And the mechanism is really unclear. Pruritus, I typically think of as being immune-mediated. Not necessarily. Myalgia, rash, not. Not necessarily. Not necessarily. Not necessarily, and so I think when you think about the IRAEs, which are clearly immune-related adverse events of CPIs, we don't see those, and we also don't cause those to recur in patients who've had those with prior CPI, so what we're seeing for the adverse event profile is typical of IL-2, so it's typical of what one sees with low-dose IL-2. I would characterize IL-2 tox as inflammatory, no? Not necessarily. Not fair? Not in the way, for example, that IL-12 or maybe other cytokines might be. Sure. Well, I guess it's a similar question on the IL-12 side, right? Because the predominant tox in IL-12, although low grade, is cytokine release. CRS is, and the AE is associated around CRS. Yes. So that to me feels like. But different mechanism. Different mechanism. Very different mechanism. But what it means is that at the doses where you're seeing clinical activity, you do see enough systemic exposure to the cytokine to be able to see the beginnings of. You see, small, so if you look at our PK curves, whether they be from the IL-2 from ASCO or IL-12 from SITC, there is a small amount of free cytokine. And that's enough to drive some of the adverse effects. Some low-grade AEs. Yeah, that's exactly right. Okay. That's exactly right. All right, so the expansion cohorts are ongoing, as you mentioned. Yes. The Pembro combo expansion cohort ongoing, also due next year, I think, highly anticipated. And I'm talking here about 124, about the. The monotherapy. We anticipate next year is going to be a very important year for us. Certainly. In terms of the monotherapy expansion data. Correct. But I wonder. It makes sense to me why you should see initial signs of efficacy in tumors where it's already hot, where we know there's good immune mechanisms for response pre-existing. But I do wonder whether for IL-2 or IL-12, there wouldn't be the opportunity to do the much ballyhooed turning a cold tumor hot sort of a thing where with that immune stimulation mechanism, couldn't you drive a de novo immune response where there wasn't a pre-existing mechanism? So we're seeing that with IL-12. With IL-12. Right. So we have activity in MSS-CRC in patients. And we have beautiful IHC, IF data that we showed at SITC that basically demonstrated where we had cold tumor, and then you see infiltration of immune cells. So not only T effector cells, but NK cells. You see production of gamma interferon, granzyme B. And so in those situations, I think with IL-12, because of its. It's the pleiotropic effect. It's the pleiotropic effect, its effect on antigen-presenting cells. And we see that in NanoString as well. So very different. And I don't know if you were headed toward the idea of combination, but we certainly are too. Excellent. So you mentioned in passing the combination cohort for IL-2 before we leave and talk more about IL-12. Remind us the timelines in more detail. How many patients are you likely to be able to show next year? And again, your bars for success? Okay. So it's monotherapy that we're showing in the first. The first. Right. In the first, hopefully by the end of the first half of 2025. Oh, I thought the Pembro combo was also running for IL-2. It is, but that's not what we've guided to in terms of showing data. That will be likely a quarter to two quarters behind. But the focus for us will be on the homogeneous monotherapy expansion arms because that leads us to the opportunity of an accelerated approval path. Sure, in the post-checkpoint. In the post-checkpoint setting. That's right. Yeah. And so right now, there are 20 patients that we have an N of 20 in the renal cell, in melanoma, and then N of 10 in cutaneous squamous. And the hope is that there will be some subset, preliminary subset of those patients with data on response rate and durability. In a cohort of 20 patients, post-checkpoint in melanoma, for instance, you would think ORR would be sufficient for approval? No, I think it's just a start. And then the plan would be to go to the health authority and say, "Here are the data. What do you think about expanding?" And it's likely to be something along the lines of 80-100 total patients. In a single arm. In a single arm. If you look at some of the agents that have recently got approval with a single arm. Seems very reasonable. Okay, so let's talk a little bit about IL-12. We mentioned the pleiotropic effect and maybe some of the effects on DC cells already. That's a sort of redundant ATM machine. But most of the patients in the data from SITC are still in those familiar hot tumors already. No, actually, most of them are not. The majority of our patients are MSS-CRC patients in that trial. So there's a whole array of patients enrolled, obviously melanoma as well. And we've seen a partial response. And lung and. And we have a number of different patients who've had a number of different therapies. I think the biggest takeaway for us from the 330 data set as of this time is the amount of IL-12 that we can get safely into patients. And it is 22-fold more than was ever delivered systemically previously. And I'm thinking about the recombinant human IL-12 experience, which was stopped. Highly toxic. Highly toxic, and we are able, 22-fold more at the Cmax, to deliver without that toxicity being given systemically every two weeks and see both clinical activity and biomarker effects. That's the masked parent. That's the mask. That's the masked parent. Yeah, that's right. So what's the relevant concentration of the naked cytokine in the tumor post-mask at peak, for instance, during the dosing interval? So we don't have the data in the tumor because that would require us taking the entire tumor from the patient in order to be able, it's easy to do in animals. It's not so easy to do in people. But we see enough. If you look at our PK curves, we see enough driving that exposure into the tumor at those doses to get the anti-tumor activity that we see, to get the biomarker activity that we see. How do you measure? Obviously, phenomenologically, you can see the immune stimulation. You see the downstream measure. But you don't have direct access to the cleavage. You wouldn't have activity if you didn't cleave. Sure. But I'm thinking about some other masking technologies where the technologies are set up so that the cleavage process can be monitored in PD directly. I can tell you that we have a bespoke assay that has been implemented in both programs. The assay actually takes a portion of the patient's tumor, you dissociate it, and then ex vivo, you look to see whether the tumor cleaves the INDUKINE. Sure. It's the same assay that was used actually in picking the linker, our agnostic linker that's used in both of our clinical. Because when I was looking at the SITC poster, I can see PK on the parent molecule. Yes. But tough to assess efficiency of cleavage in the tumor microenvironment except ex vivo, I guess. Yes. Yes. Do you want to speak to that? It's not an easy measurement. No, certainly. I don't know anyone who monitors cleavage. In situ? In situ. I'm. Oh, well, I'm thinking specifically of Janux, who can monitor in peripheral blood the appearance of the cleavage products. That's the breakdown product. But you don't know where those are generated. No, you don't know where they're generated, although you make a reasonable assumption. I mean, if you think about it, what we see in the free material, because remember in our graphs, we have prodrug and then we have free, the free material, we don't know exactly where that's coming from. We assume it's TME, and I'd be willing to. Not necessarily. It could be some cleavage in the periphery because remember, once you cleave in the Tumor microenvironment. You want to say very low half-life. The cytokine goes back to a very short half-life because you're cleaving off both domains, both the blocking domain and the half-life extension domain. Insofar as you're observing any cytokine, free cytokine in the periphery, it may likely be generated. Probably not. The part that comes from the tumor is probably. We should assume it's much higher in the tumor than it is. It's much higher. And that comes from our knowledge about the preclinical data that we have. That makes sense. All right. Now, we are out of time. But I would love to ask also about the autoimmune programs that are getting started. Where do you expect to see most benefit in IL-10, and what's the most efficient path of value for that program while oncology is still at the bottom? Yeah. Our resources are obviously focused on our two lead clinical programs, and that's the company's expertise. We did discover that protease activity is dysregulated in inflammatory diseases, which we could take advantage of through our INDUKINE design. We have made an IL-10 INDUKINE that works beautifully in preclinical IBD models. It was quite remarkable in terms of being able to deliver the cytokine that a lot of people have been interested in for decades, but it's been very difficult to really deliver the cytokine in the appropriate way to diseased tissue, similar to what you see with cytokines in cancer. So this is a molecule that is purely a molecule that we're having business development discussions around. That's, I think, for the time being where we'll focus our efforts in trying to develop that molecule through a partnership while maintaining the capital and resources within the company around the WTX-124 and WTX-330 programs. Makes sense. All right. Well, thank you guys so much for joining me this afternoon. I really appreciate it. Thank you, Jon. Thank you Jon. Thank you for inviting us.