Thanks. All right, welcome to the Fireside Chat with Xilio. I'm Michael Schmidt, biotech analyst with Guggenheim, and it's my pleasure to welcome René Russo, CEO of Xilio. Welcome, René. Thank you. Thanks for having me. Maybe just quickly for those that are not familiar with the story, could you just provide a brief introduction of your company and also your tumor selective masking platform, and also perhaps talk about how you selected your three programs that are in the clinic now? Sure. Perfect. Yeah, so Xilio exists primarily for two reasons. One, we believe immuno-oncology remains really the mainstay and future of the potential for curative cancer therapy, right? What we know about immunotherapy is the long-term durability of survival, and that's what we're really all chasing, right? Real long-term cures. And so we think IO is still so prominent and so much to be still discovered and moved forward. But we also recognize that because we administer all cancer therapies, but immunotherapy in particular, systemically, we're not activating the immune system in the tumor where we need it, we're activating it throughout the body. And to get really potent immunotherapies comes with really substantial side effects. In fact, we were just speaking with a patient, who's four months post-therapy, that the side effect, he said he can't believe it's called a side effect. It was so life-altering and horrible to go through, and this is with an immunotherapy. So we believe that we can better engineer, as a field, therapeutics that are potent immune stimulants, but are preferentially activated in the tumor, because tumors, solid tumors have different biology. So we, of course, can treat them differently and activate drugs differently there. And if we do that, we can get to unprecedented high doses, keep people on therapy for a long time, and ultimately get to combinations that are untouchable today, right? And this is all about having long-term curative agents. So that's the underlying technology. It's really about tumor-activated immunotherapy that's specifically activating inside the tumor. And then the way we pick targets, because all of this is new, right? And we're pioneering, especially in the cytokine space, tumor-activated cytokines, which hasn't been done before, we wanted to start with targets that have known, biology, clinically validated, to shrink tumors, but also have known therapeutic index challenges, where it's known if you push the dose higher, the outcome is better, but it cannot be done because of toxicity. So CTLA-4, IL-2, IL-12, obvious places to start. So all validated targets. Great. So why don't we just talk about some of the programs, perhaps starting with IL-2 or XTX 202, where you are heading towards some key data inflection points later this year that could provide some additional clinical validation for the program. Could you perhaps remind us why you think IL-2 remains a compelling target? There's been several other attempts historically. Yes. -that have, you know, had a less desirable outcome, I believe. Yes, yes, yes. Yeah, so I think IL-2, you know, one of the hallmarks and why we're all chasing IL-2, is getting back to that long-term durable cures, right? We saw a long time ago with first-line aldesleukin, and first-line, I think, is key, but we saw, you know, 10-year durable response rates in patients who achieved a response, and that is something, you know, we need and we need to have for patients. So I think it's the durability, and also that we know IL-2 is essential for T-cell biology. So it's a component that if we can deliver, it is obviously synergistic with so many other mechanisms. In addition to checkpoints, T-cell engager mechanisms, cell therapies, vaccines, like if we can add in a safe IL-2, it's going to boost all of these agents just based on its T-cell biology. The challenge, of course, has been extreme toxicity, you know, because you're doing this with indiscriminately all over the body with a systemic agent. I think this is a hard one to crack, right? A lot of people have been working on it for a long time. I think worthwhile to crack. We do have an upcoming data readout that we're anticipating by the end of this quarter, which will be our first phase II data readout. It's an initial data readout. We expect to have 20 patients in our phase II at a high dose, 4 milligrams per kilogram, and those patients will be either melanoma or renal cell patients, which historically have had responses with IL-2s, but of course, often in first-line positions from aldesleukin days. Yeah. So I remember you have some very, you know, interesting preclinical or non-human primate data. Maybe, perhaps provide a bit of context to the 4 milligrams per kg that you've sort of selected as your RP2D, and how does that compare to aldesleukin, perhaps? What do we know from the preclinical studies around that dose? Yeah, so when you're doing this for the first time, right, you're learning a lot along the way. So we initially were targeting a similar dose to the aldesleukin approved dose, which for us would have been around a 1 mg/kg dose. And we are now at a dose that's about 4 times the full course of an aldesleukin dose, and most patients don't get the full course. That's the 2 full courses. We did not expect to be able to go this high, but what we've learned along the way is that the efficacy range, where we're getting that pharmacodynamic achieved results, both in the tumor and even seeing that peripherally, is, you know, upwards of 2.8 mg/kg. We're starting to see that, and it plateaus somewhere around 4 mg/kg. So between 2.8 and 4 mg per kg, we believe we're getting on, exactly, the therapeutic range we need to activate CD8s and NKs in the tumor, and still maintaining a safety profile that's consistent with an outpatient administration, combination therapy, et cetera. Yeah. And, do you have— So maybe just stepping back again, so, you know, this is a masked IL-2. Just remind us, you know, do we know how much of it is converted to the active form? Mm-hmm. How have you assessed that? Yeah. So this idea, right, that our molecules are masked or turned off when they're circulating in the periphery is sort of the safety side, and I think now across our platform, across all the molecules, we've treated over 100 patients. I think we understand that we are getting good safety profile and minimal activation in the periphery. And with our IL-2 in particular, it's, you know, often below the limit of detection. There's almost none in the periphery. It's about a 50-fold increase in the IL-2 in the tumor versus periphery, although we've only measured it in a single patient, intra-tumorally once so far. However, that 50-fold is a relatively low amount that's getting activated at a single point in time in the tumor, which is about 15%, which is why we're up to the 4 mg per kg dose. It's okay to activate 15% because we can safely get to that 4 mg per kg dose. So we're learning how our masking for that particular molecule is activating in the tumor and the periphery. This is our first cytokine, so we were very conservative, wanted to lock that down. Now, I'll point out a couple of things. When we measure the activation in the tumor and we got 15%, it's a single point in time. We measured this day 2 after a dose. In vitro... In vivo, we see the maximum activation usually at 72 hours, so probably it's a little higher. And this is a continuous process. So we're measuring it at a point in time. Mm-hmm. - but it's a continuous process. Gotcha. Super, super interesting. And so the 20 patients you said at the end of this quarter, you know, how should we think about efficacy benchmarks here, especially since you said those are probably much more heavily pretreated than what we saw for Proleukin historically? Yeah. Yeah. Yeah, I think we're all sort of trying to understand what is the efficacy bar for monotherapy IL-2 in today's late-line populations. I can tell you we're seeing robust pharmacodynamics in the tumor peripherally and good safety. I think what we all want to see is a RECIST PR, a clear anti-tumor activity as a monotherapy that just demonstrates, you know, that we're getting that efficacy before you go into combinations, right? Yeah. As a monotherapy. I think we'll all debate what level. Yeah. I think there's different views when you look at certain PRs, you know, the depth, the durability, the type of tumor, you know, sort of metastatic state, I think all matters in how you look at certain responses. So probably premature to say- Yeah ... but I think we want to see some monotherapy anti-tumor activity. Gotcha. Okay, super interesting. So looking forward, for that later, this quarter. And then maybe switching over actually to XTX101, your CTLA-4 antibody. You know, again, we saw some, monotherapy data, last year. Again, just remind us of, of sort of the findings here. You know, to what degree does it validate the concept behind that, that molecule? And, yeah, what should we expect, going forward from the program? Yeah. Yeah, so it's interesting. The CTLA-4, we designed intentionally a bit differently than our IL-2. We believed we wanted to have more active drug circulating periphery and potentially need some in draining lymph nodes, just mechanistically. So when we look across all of the data today for our CTLA-4, there's about 15% active CTLA-4 in peripheral circulation. So very different than the undetectable IL-2. We've also learned in two patient biopsies that the active drug in the tumor is between 70%-90% active in the tumor. So this is a more readily cleaved molecule by design. And our dose that we selected for our RP2D is 150 mg q 6 weeks. We shared what we thought was very compelling safety data at 150 Q6, differentiated from traditional CTLA-4s, where we saw no colitis at that dose, which is the primary issue with CTLA-4s. That takes patients off therapy. We saw very minimal skin reactions. We had a single case of a dermatitis, and skin reactions are a hallmark of, you know, an early CTLA-4 tox. And we didn't see any endocrine-related toxicity, which is also a CTLA-4 sort of hallmark tox. So we definitely felt that we had achieved this masking and that that 15% active in periphery was allowing us to get to this high dose, but with a very different safety profile. This is a molecule that's about tenfold more potent than ipilimumab, both in binding and in vivo, Fc-enhanced, so has the potential to be quite toxic if it was not masked. Yeah, so just remind us again, where are you? It sounds like you selected the RP2D at 150 in the study right now, and yeah, what are the next steps? Yeah. So I think one of the most important findings from the phase I that put us on our path was—First of all, we didn't expect to see monotherapy activity with the CTLA-4 in a phase I, especially early. That's very rare. We did have a number of responses, 1 PR, that met the PR criteria in particular, that was really striking. This was a stage IV non-small cell lung cancer patient, PD-L1 negative, so not anticipated to respond to IO, so a cold tumor type, on our monotherapy, the 150 q6. This patient had over a 50% reduction in lesion size and had a durable PR that lasted 6 months. And their only adverse event was Grade 1 fatigue, so that was really meaningful. So we're getting the masking. We're seeing this really unexpected, meaningful, deep, durable response. But what really was kind of a little, you know, very just surprising and put us on the path to where we are now is this patient presented with innumerable liver metastases at baseline, which are notoriously resistant to IO, even in combination. And we saw clearance of these liver mets after the first cycle of monotherapy, and that continued through 36 weeks. So a little bit unheard of. And that led us on the path to work on colorectal cancer. And even though you're saying there's a response in lung, with liver mets, why colorectal? Well, huge unmet need, third largest cancer type globally. And you probably have been paying—if you probably have seen, right, in many news articles about this big increase in young people under 50 getting diagnosed with late stage, stage 4 colorectal cancer. It's happening at an enormous rate, and we don't really understand why. And the biggest issue is we don't have IO for these patients, right? And they need long-term durable responses. A lot of them are very young. We have chemo, basically radiation, not very many options. And the vast majority, about 70%, get diagnosed with liver metastases, where almost nothing works, right? And so here we are with this agent that we think has the potential to work in colder tumors, right? We have the Fc enhancement for Treg depletion, and we have a monotherapy response in liver mets, and this is where we want to go because huge unmet need. We also think just from a regulatory, and sort of efficiency perspective, this is the type of indication where the PD-L1 or PD-1 contribution is already well documented to be less than 5% efficacy. So the contribution of the CTLA-4 will be very clearly able to demonstrate, you know, efficiently in a relatively small trial as we move forward. So that's how we decided to go first into MSS colorectal in patients with or without liver mets. And then, we're doing that in partnership with Roche. We're using atezolizumab as the PD-L1 combination agent. Great. And so, it sounds like this is at the RP2D of both drugs. Can you just talk a bit more about this study? You know, how many patients will you enroll, and Yes ... you know, will there be any readouts, data readouts? Yeah. So we're starting. We're right now in the dose escalation phase, so we're looking at standard dose atezo, the 1200 Q3. But for us, we are looking at two dose levels. First, a 75 Q6, so a half dose as a starting dose. It is a standard 3 + 3 design. If that looks good, we'll go up to the 150 Q6 with the standard atezo dose. And then from that, open up the phase II, which we anticipate doing in the third quarter, and we expect to read out the first 20 patients from the phase II combo by the end of this year. So both atezo with 101 at the selected RP2D in MSS colorectal patients. Yeah. Just to remind people, what's the efficacy bar in that setting? And sort of what type of efficacy would you view as very, you know, compelling? Yeah. Yeah. So historically, you know, efficacy rates have been under 5%, for IO in this setting. Recently, in patients, importantly, in patients without liver mets, we've seen some new data emerging with and newer engineered CTLA-4s, where that efficacy has been upwards of 20%, a really meaningful difference. We are looking at that as a bar for patients without liver mets. But importantly, we hope with an improved safety profile, particularly with regard to colitis and the types of adverse events that take people off therapy. In patients with liver mets, I think there's a different view of the bar because there really isn't anything, and the efficacy rates are very low. So, I think we're not sure what is the bar there, but we'd like to see any activity in patients with liver mets at this point, I think, would be very meaningful, and almost looked at as a different disease. Right. Right. Okay, great. So looking forward to that. Will we learn anything else from the phase I before the, the colorectal data, or is, is that the main focus going forward? Yes, I think that, that colorectal readout is the main focus. You know, I think that, that will be the most meaningful near-term readout. Okay, great. So then maybe switching gears and to XTX-301, your IL-12 product candidate, which is in a way, somewhat similar to the IL-2 program, but obviously having a different mechanism. You know, and the drug has been very toxic if given, or IL-12 has been very toxic if given, you know, in its- Yes ... natural form. Just perhaps, you know, step back for a second and talk about, you know, how the sort of experience so far with IL-12 has informed the design of your drug, and where do you see sort of the opportunity for that? Yep. So yeah, IL-12, I think, you know, some people refer to as like the holy grail of IO because potentially, mechanistically, you could start with a very cold tumor, right? With other agents, you need some active CD8s in the tumor. You need something to start with. But I think with IL-12, potentially, you don't, right? And so this is really meaningful if we can bring IO to more cold tumor types and use this in combination, would be very differentiated. The toxicity is even greater, though, than it was with IL-2. In terms of history, you know, we've seen high rates of mortality with IL-12, so it's been really untouchable. So we have been leading on all of the masking data we have for IL-2, so we have over 90 patients on treatment with the IL-2. We feel very confident in the translational data and the engineering and how we're thinking about the activation. And so we are now in the third dose level, which is a 45 microgram per kilogram dose. This is about 100-fold higher than the maximum tolerated dose of historical recombinant human IL-12, so we're at a very large dose. We are in dose escalation. We started out with a Q3-week dosing. We're looking at early PK data, suggests that we can extend that interval, which I think will be good for patients. And very slowly, cautiously building out that data set before we dose escalate further. But unlike our IL-2, where we went to dose level 7-... I feel like this molecule, you know, we are in the active dose range now, even at dose level three, based on our preclinical data. Okay. Do you have a sense of what percentage of the drug is activated in the tumor relative to IL-2? So we don't have that yet, and it's you know, very difficult to get these on-tumor biopsies. They're optional in phase I. I would say, you know, based on our predictions, we expect it to be somewhere between our IL-2 and our CTLA-4, right? It's, but it's hard to say exactly yet. I don't wanna make a prediction at least- Right ... based on our animal data, but we expect it to be, you know, greater than the IL-2- Right based on its protease profile. Gotcha. And, you know, thinking ahead, just, you know, bigger picture, what tumor types do you think might be most- Mm-hmm ... sensitive to IL-12, perhaps compared to IL-2 and CTLA-4, and how does that, you know, affect your development strategy? Yeah, yeah. So we have a very different development strategy on IL-12, I think, because of the potential in cold tumors. So, you know, we're looking at a potential Simon two-stage across many tumor types and look for early signs of activity, you know, in somewhere around 10 patients per tumor type and then move forward. Maybe 3-ish of those would be warmer tumors, where you would expect IO to work, and, you know, about 3 more that are quite cold, where IO has not worked. So quite a large range of tumor types that we're really wanting to expand, enrich, and really understand. I think. It's a little more wide open with IL-12. Okay, great. And so will we learn anything else from the phase I this year? What are your plans for some data disclosures? Yeah. So we've targeted second half of the year or Q4 for our phase I readout, because it's always hard to predict how many dose levels you'll go to. Right. But once we complete the final dose level, we'll be sharing PK/PD safety, hopefully tumor PD and PK. And then, of course, you know, if there is any anti-tumor activity, you know, in the phase I, we would report that as well- Right ... by the end of the year. Is IL-12 expected to be active in all comers, or do you think biomarker selection might be helpful in this context? Yeah. Yeah, I think it's a good question. I would say we don't know enough yet, but that's why we're thinking about a broader. Right ... approach with expansions in up to six different tumor types, so that we can hone that strategy a little bit, and look across both, warm and cold tumors. Great. I can tell you, preclinically, one of the combinations we've been very excited and surprised by is the combination of our IL-12 with our CTLA-4- Mm ... was exceptional in preclinically, and we've looked at many, many combinations, so that's something that is on our mind, down the road for cold tumors. Makes sense. Great. Super. So looking forward to near-term updates on IL-2, CTLA-4, and IL-12 by the end of the year. So super exciting year for you guys, and with that, I think we can conclude. Thank you. Thank you. Appreciate it, Michael.