I think we're going to get started. Welcome, everybody. My name's Daina Graybosch. I'm a senior analyst here at Leerink Partners, covering immuno-oncology companies and a little bit beyond. I'm excited to have the management here from Werewolf Therapeutics, Randi and Dan. I'm going to jump right in, if you don't mind, because we have 30 minutes and we have a lot of content to get through. I think if you polled, and I sort of do this informally, a typical pharma or biotech investor about cytokines, they'd say, "That was played out and failed. What's next?" I want to know why you think, what are these investors missing and why should they still be interested in cytokines and Werewolf? It's a pleasure to be here, Daina. Thanks for the question. Thanks for starting with the very easy question to start things off. I don't think investors are necessarily missing anything in terms of their assessment of past programs or attempts to improve upon cytokine therapy. However, I also don't think it's reasonable to paint the entire cytokine area with a broad brush. There have been a lot of things that we've learned from the past failures, and there's still a lot of merit to developing cytokine therapies that actually can overcome some of the challenges of past attempts. I think what investors should be looking for are approaches and modalities that are different from kind of just another variation of kind of the same theme, not necessarily another recapitulation of a non-alpha approach, for an example. I think the bar for the kind of data sets to show that you're actually improving tolerability, getting the molecules to where they need to be, and actually having the kind of activity, and by that, I mean monotherapy activity, are much more important today than they were maybe five, ten years ago. When we started with Werewolf, we were pretty clear about what we felt was the necessary data sets that we needed to establish. We needed to establish real tolerability, tolerability where every patient with an unmet need could come into the clinic and actually receive the drug. You didn't have to be a super patient or a patient that could be selected and actually tolerate therapy. You also had to achieve tolerable doses that could get to exposures where you could actually see mechanism-based immune activation. That's something that's another critical box to check. Lastly, you need to see actually bona fide monotherapy activity. We had dose escalation data that we came out with last year for our interleukin-2 INDUKINE, WTX-124, and also dose escalation data for WTX-330, which is our IL-12 molecule. In both of those data sets, we actually checked those boxes that we set out to establish very early on in the clinical development of the program. Hopefully, investors will take notice of that. Later this year, we'll be coming out with data sets for WTX-124, which I'm sure we'll get into a discussion on that a little bit later, but expansion data sets where we're going to have more response rate data, durability of response, and then really a path for this program going forward. That is what I would, as an investor, keep my eye on. I think a lot of investors are quite focused on the single-agent activity, so that third arm. The debate is not if you have it, because if you do not, I think it is a no-go for any investor, but how much is just a little bit good enough, and then you can believe in combination and synergy? Do you have to exceed this magic 20% bar at the lower end of your confidence interval, let's say, in an expansion cohort? I wonder how you think about how much single-agent activity is necessary to validate an approach and if we have any analogs to help us set that threshold. You want to take that? Sure. I mean, if you look at the immunotherapy agents that we have that have demonstrated monotherapy activity, the key piece of it, Daina, is really the tail. I mean, you look at high-dose IL-2, Proleukin, approved in the 1990s. Complete response rates, single-digit overall response rates in the teens. Those patients had, at a time when there was nothing else, they had durable responses. If you had a complete response, you basically could be considered cured. You look at ipilimumab, and same kind of thing. It's that tail. I think that's so critical. I think a 20% response rate for a monotherapy is, especially in a relapse refractory population where there's nothing else. You look at something like after a checkpoint inhibitor for cutaneous squamous cell, second line. Even second line for melanoma as a single agent for patients who could not receive a checkpoint inhibitor again because of a prior immune-related adverse event. I think it's reasonable for that response rate. You think about what does it do in combination. I mean, we certainly have seen those kinds of activity with WTX-124, our IL-2. In combination, we certainly have glimmers that the data could be even better in patients who've already received a checkpoint inhibitor. We reported last June about two patients in combination at 12 mg who had both melanoma patients who had partial responses. This morning in our release, we've updated that information. One of those patients has become a complete response. Both of them still continue on studies. Durability, we're now out greater than eight months, and the patients are tolerating treatment and have durable responses. The other thing for us is that we have activity in liver mets. That's something that's very difficult to treat, as you know, in oncology and certainly in melanoma. I think all of these things together, at least for WTX-124, give us enough confidence that this is a drug. This is something we're going to move forward with. One more broad question, sort of a strategy question. You focus on cytokines. You have this validated INDUKINE conditional activation platform. There have been a lot of them out there that have not worked. I think pharmacokinetically, dynamically, and clinically, you have shown it works. Some competitors, when they have something that works, have started to broaden to, let's say, T-cell engagers and other modalities that you want to be conditional. I wonder how you are thinking about that strategically now that you have this validation for cytokines. We have spoken about that in the past a little bit, but maybe this is an opportunity to kind of step back. Werewolf Therapeutics was founded around the idea of developing innovative biologic prodrugs. Not just cytokines, but biologics in general. Our first foray, of course, was the cytokines and the INDUKINE design. We have applied our learnings from the INDUKINEs to other modalities, such as T-cell engagers and other biologics. We are working on those. I think we are in a position also now with clinical data with the INDUKINE programs to apply some of really those key learnings to those modalities and see if we can improve upon some very powerful mechanisms like T-cell engagers as well. Got it. Any of the learnings clinically that are most important in iterating for the next gen? Yeah, I think obviously there's always room for better masking and the way that you mask and the bar there. For example, for T-cell engagers, I think there's a lot of room for improvement there in terms of improving upon the therapeutic index. I think our learnings primarily from our linker designs and the innovation that we spent a lot of time early on in the company's genesis to find novel linkers that can be stable in normal tissues and circulation, but also can be activated across different tumor types and patient populations. We're seeing that now, those early data being recapitulated with our INDUKINEs, and I think we're in a good position to apply some of those learnings to other biologics as well. Got it. Differentiated maybe by the breadth of your linkers. Yeah. I think really it's important to understand that there is kind of a window where a conditionally activated molecule needs to be stable, but also needs to be really active once it's been activated. That's not an easy thing to do. It's not a black-and-white situation where it's completely turned off and then completely turned on. That's almost impossible to achieve. Fine-tuning that and getting that right is incredibly important for conditionally activated biologics. That's something we've worked on a lot. Got it. Okay, let's come back to WTX-124, your IL-2. You foreshadowed this a bit, but could you talk about how it's differentiated from the other programs that are still active? Not alphas, but maybe the ones that are earlier, similar to you guys, next gen, so the bispecifics or the other conditional programs out there. Yeah, that could cover a lot of space. I think with our design and the components in terms of, we'll leave the cytokine and the potency alone and assume there's equal potency and it's not a designer molecule where it's being skewed one way or another. That's an incredibly important part of the overall thinking of our design. The linker technology, as we just touched upon, is incredibly important if it's a conditionally activated molecule. You mentioned bispecifics. That's something we have worked on. It's not something in our own hands that we've been very successful in being able to work as well as the designs that we've been working on. Getting, for example, cytokine exposures to a level that are biologically relevant is not an easy task. The tethering approaches for us have not worked as well as the approaches that we're using currently. Masking approaches can vary considerably. We spent a lot of time on that because, as I mentioned earlier, it's very important to make sure that you're designing the molecules so that they stay turned off in the periphery, but also are well activated once the molecule becomes cleaved and activated in the tumor tissue. Got it. Maybe on the potency side, you use a native IL-2 construct. Can you talk about what's most validating of your approach in that decision so far? I think the monotherapy activity. We set the bar to be able to establish that, and we've seen it consistently. We feel very comfortable with that approach. Some of the other hypotheses where the non-alpha was based, we have not seen any of those kind of issues related to our molecules. I think thus far, it's borne out well in the clinic. What are the issues of non-alpha that you'd say most piloted? There were some hypotheses around maybe toxicity was associated with a high affinity receptor on some immune cell subclasses. That is just not something that we have seen or observed. There is also the Treg hypothesis where there is this idea that patients will not respond to high-dose IL-2 or IL-2 generally because of its binding to the affinity receptor on Tregs. That is also not something that we have observed. Let's talk about what we should expect this year. I think you had an announcement this morning in earnings from the, let's start with the monotherapy expansion. Where are you doing the expansion, how much follow-up, patient numbers, and when will we see that data? We announced that we'll have full enrollment in monotherapy expansion in melanoma, cutaneous melanoma by the end of the first half. We also have, I'm sure, as you know, two other arms in monotherapy expansion where renal cell and cutaneous squamous cell. Those are also enrolling. The expectation for combination expansion is that we will have full enrollment in the cutaneous melanoma. Those are both 20 patients each. That will come by the end of the year. We hope to take our package of data, which also includes dose escalation. We're done with both monotherapy and combination dose escalation. We've chosen 18 mg as the dose to move forward in all the expansion arms at this point. To take that nice package of data to the agency to discuss with them registration pathways, both monotherapy and combination, which may also include an accelerated path and get their buy-in. Are you exploring front-runner paths or single-arm paths? Is it too early to say? We are looking at all possibilities: relapse refractory, second line, up to first line. Yes. First line, obviously, will be in combination. What's your internal efficacy or translational bar that would deepen your conviction, particularly both in the monotherapy and in the combo? I think we're already convinced. I want to make that point that the data that we have has already, I think, met all bars and expectations. If you're looking for sort of percentage, monotherapy, anything 20% or higher would be a very nice response rate for monotherapy. Durability, if you look at how long responses last after first-line therapy in some of these diseases, four months is probably a reasonable median. In combination, you're looking at something a little bit better. Four months in terms of PFS or duration of response? No, not PFS because it's duration of response, durability of response. PFS is not a good metric for a single arm, as you know. I agree. That's, and then for combination, as I said, something a little bit better would, and these are all patients, at least in second line and beyond, who have already received a checkpoint inhibitor. Durability on the order of six months and probably higher than 20%, more on the order of 30%. Got it. Are you going to have patients in any of these that received adjuvant PD-1 and then relapsed? Yes. What's the split and how should we think about those patients versus ones progressing? Yeah, we don't have a real split. I mean, if you look at the criteria that have been outlined for resistance, if a patient has had adjuvant, neoadjuvant, adjuvant IO, a checkpoint inhibitor, and progresses while on that adjuvant therapy or within a certain period of time, that is still considered, it's still considered a line of therapy and would be very similar to a patient who received it, let's say, in the second line and progressed as well. You look at those patients pretty similarly in terms of their resistance profile. You can't have responded to melanoma, gone three years, and then be metastatic. That patient couldn't enroll in the study. That is correct. That's correct. The patient would then have to receive, because that's not considered a resistance, right? They would have to receive something else at least in, so that patient might be eligible if we were to do a first-line trial, first-line metastatic trial. For a relapse resistant trial, that would not meet the definition. Yeah, I got it. That's helpful to know. Can you talk about sort of your enthusiasm for those three indications? Why melanoma, RCC, and CSCC? It sounds like you enrolled melanoma first. Is that? I mean, they're all enrolling. Are you still behind? Yeah, they're all enrolling. It really has to do with, and our investigators are very motivated and very excited. We have new sites coming on board that are specific for indications. The reason for the initial, and I've been saying this since the inception of the phase I trial, renal and melanoma are benchmark indications. That's where high-dose IL-2, which is rarely used now, is approved. To use that as a way to demonstrate that we have a better mouse trap, a better IL-2. The cutaneous squamous cell was for a couple of reasons. One is that patient from dose escalation, and we presented this patient very early on at SITC in November of 2023. The patient was primary resistant refractory to cemiplimab, had received both a cetuximab and then a cemiplimab-based therapy and had progressed through both of them, came in our study, and within two doses, we knew the patient was responding and went on to have a complete response. We updated on that patient this morning, was out a year off therapy, still in a complete response. Why is the patient off therapy? Because as a conditionally activated molecule, if you do not have a tumor microenvironment and you do not have any disease, there is no reason to continue the drug. The drug was actually discontinued at 22 weeks, and the patient has maintained a complete response for a year from that discontinuation. That is very exciting. Because of that, we made a decision, there is nothing in second line, cutaneous squamous cell. Even though it's a small indication, it's one that does not have a therapy for second line. It's a nice path to an accelerated registration as a monotherapy. That's the reason to have included that. That arm only has 10 patients, unlike all the others that have 20. You know, it's an interesting indication because it seems highly immune sensitive, but Replimune in the end didn't work there. I wonder how you interpret that going forward. Replimune is a, I don't know how to interpret that. Yeah. Maybe I was too hard to say it didn't work. It didn't meet a specific. It didn't meet, right. As an intratumoral injection, I think there are some negatives to the therapy. And so I don't know exactly why it failed in that indication. Actually, it brings up a question of the CR that I've often had of a conditional approach in a monotherapy. When you get down to very few tumor cells and you're getting maybe less and less activation, is it harder to eradicate those last tumor cells because you're getting less activation, or is that just way too theoretical? It's more, my hypothesis would be that actually you've got very rare clones that can recognize tumor and you need that amplification event that IL-2 can provide to really get the population ramped up enough to actually mitigate the disease. The disease in that patient was pretty large and extensive. For other patients, I would assume that's also a similar situation. For checkpoint therapy, you kind of already need to have a good enough population of those clones present in order to have a clinical benefit. That's kind of more the way I would look at it. Right. So you've stimulated a secondary effect, which is the T cells, and those are much more durable dynamically than your drugs. They're going to keep working. That's right. We've shown data that basically shows that our responders have a baseline, have an inflamed tumor microenvironment. It's almost like you're just throwing a little bit of gasoline on the fire. That's been something we've seen. Unfortunately, our biomarker data for our on-treatment biopsies doesn't include our responders because there was no tumor to biopsy. Sort of a plus and a minus on that. It's hard to really understand what worked, right? I mean, we know it does. And the data that we have on the patients who had less than a partial response or had stable disease certainly shows us a dose responsiveness, both in terms of this is by NanoString, both in terms of T-cell increased proliferation, but also activation. Let's talk about IL-12. It has been very challenging. I dare say more challenging than IL-2? Yeah, I think you can historically. Historically, yes. It was never approved. It was actually stopped for toxicity, right? The original program. Yeah, can you just talk about how WTX-330 is different or similar to the past attempts at the high level? Yeah. There, you're talking about a very different mechanism of action in terms of immune activation. It's a pleiotropic cytokine. The real interest in the cytokine over the years has been that it can turn both in immunosensitive diseases as well as diseases that are not necessarily immunosensitive. You can convert them to immunosensitivity through its ability to enhance antigen presentation and neo antigen to the immune system. We've seen that preclinically, actually seen very nice changes in the T cell repertoire in preclinical models with IL-12 treatment with our INDUKINE. The hope there is that you'll see in refractory patients an immune stimulation that's quite different from IL-2. We've actually seen that now in patient samples in the biopsies. We've seen a different profile than what we see with IL-2, with genes representing dendritic cells and antigen-presenting cells being upregulated. That has translated to the clinic. Yeah, that's completely different. We presented that in November at SITC. Yeah. It does seem, though, to have a more narrow therapeutic window than WTX-124. Is that fair? Okay, then tell me why I'm wrong. No, I don't think that's accurate. I think part of that may be that the profile is very different. The AE profile of IL-2 versus IL-12 is quite different. Some of the AEs that you can get with IL-12 treatment can be much more difficult to manage. I think what you saw in our SITC data is that we actually can achieve a therapeutic dose that is manageable. It looks different in the AE profile than 124 for the reasons I just mentioned and the mechanisms. We can get drug to tumor and show the changes that Randi just mentioned in patient samples, and we can establish monotherapy activity for the drug. I think we've achieved a therapeutic index there. I'm not sure we actually have enough data to measure exactly what that is. I'm not sure you could actually compare between the two programs. I mean, if you look at the amount of prodrug we're delivering versus what was delivered with IL-12 in the early studies, it's just dramatically, dramatically more. The masking is working. We have tolerability, and we have both biomarker and anti-tumor activity. I think those were important things to establish in that first-in-human trial. You did see some tachyphylaxis. How are you thinking about that and dose optimizing this going forward? It seems more complex of a challenge. I'm not sure it's going to be that challenging. Okay. The tachyphylaxis is something that's been observed over decades with IL-12. If you give a loading dose, you will not see classic first-dose effects that we saw. Subsequent doses, the tolerability is very, very well managed. We are doing this year a study to look at the merits of a starting dose versus the dosing regimen that we established last year. We had a very deliberate approach with our phase I study to not do a loading dose. The reason for that is because we really wanted to study the masking, the clinical pharmacology, the ability to show immune activation in patient tumors, and to assess whether we could get to doses where we could see monotherapy activity. This year, we'll be looking at, at least early on in the first half of the year, whether there's any merit to looking at a starting dose to mitigate some of those first-dose effects. We're already in a situation where that's pretty well- managed. What we're trying to do as well with that loading dose is to sort of separate what's happening in the periphery. Remember, this is all gamma interferon-driven. To separate what's happening from a safety standpoint and allow for a dose increase with the second dose to maximize and optimize what's happening in the tumor microenvironment. Sort of to separate those two for the first couple of doses because we know that very quickly there's this, and I don't like the word tachyphylaxis, because that's not really what's happening. It's really a negative feedback. And it's meant to control the effects of IL-12, which are so, so potent. That's the rationale for looking at this and to see whether or not how much more we can get into the tumor microenvironment and improve both biomarkers and anti-tumor activity. Is the idea that you have a different therapeutic window to sensitize in the periphery versus the tumor? That is the hypothesis. That's the hypothesis. It gives you negative feedback because there's all these other negative signals in the periphery, not enough in the tumor, and then you come on. Or at least to separate for at least a couple of doses. That's exactly right. We now have the data to be able to actually look at that very carefully. When will we see that data? I meant our data that we showed last year. Now we have the non-loading dose data, and we'll be able to compare that to a loading dose and see whether there's any additional merit there. As I mentioned earlier, I think the bigger challenge for this program is to actually explore where the molecule can be active because there's just not a lot of historical precedents there. Because of the challenges with the therapeutic index, there's not a lot of areas where, I mean, we have our hypotheses on where to go, but we're going to have to establish those ourselves. That study is actually going to open in the first quarter, and there's only a few weeks left in the first quarter. Got it. Just the last question. When will we see some more data from the loading dose? Right now, it's a little difficult to say. I think later this year, we'll be able to say more about what kind of data we were able to generate and also a better idea of where we're going to be going with the program in terms of those exploration of specific indications. Obviously, there's also some clinical development along combination lines that we want to do. Got it. Okay. Thank you very much. I appreciate the time. Thanks, everybody, for the attention. Thank you. Thanks, Daina. Thank you.