Good afternoon, everyone. I'm Alex Thompson, a biotech analyst here at Stifel. My pleasure to introduce Natalie Holles, CEO of Third Harmonic Bio, for a fireside chat this afternoon. So, Natalie, always a pleasure. Great to be here. Thank you. I'm going to start with a brief overview, and then we'll get into Q&A. Absolutely. So, at Third Harmonic, we are focused on bringing the first new oral medicine for mast cell inflammatory diseases to patients suffering from these conditions in a generation. We're focused on KIT as really the optimal target for diseases of the mast cell. We benefit from a really robust emerging clinical data set, not only from our own work, but from others in our colleague companies in the space. And as I'm sure we'll talk about, we believe for a number of really important reasons beyond just the convenience of a pill versus a painful injection, there are some real benefits to an oral tyrosine kinase inhibitor approach to KIT that we think positions us as potentially best in disease for not only urticaria, but other mast cell-mediated inflammatory diseases. And we've got clinical data coming in the first quarter, which is exciting. Great. Yeah. And I think starting off, you know, why mast cells and why do they represent a unique and interesting target, or even emerging target right now in I&I? Yeah. I think I've said it previously. It feels like mast cells are having a moment. There's been really, and I would say that the KIT programs in particular have been really useful tools for elucidating the role of mast cells in a number of inflammatory conditions. I think urticaria is the best example. Prior to clinical data with KIT inhibitors in the treatment of chronic spontaneous urticaria, chronic inducible urticaria, there was actually an open question of the role of mast cells in the pathophysiology of urticaria. And since we are so clear on the truly central role of KIT in all elements of mast cell function and survival, demonstrating that KIT inhibition was providing really high watermark efficacy in this indication was an inference that it truly is the mast cell that's the key effector in urticaria. We believe that there are data in other inflammatory diseases, asthma, severe asthma is one that we're particularly interested in, where there's similar evidence for a really central role of mast cells, which makes a KIT, and an oral KIT, more specifically a really exciting therapeutic modality to study. Yeah. And you talk about urticaria. Obviously, that's the lead indication here for the KIT inhibitors. Can you talk a little bit about, and maybe set the stage as it relates to the sort of the current commercial landscape and unmet need for the treatment of urticaria today? I feel like, is it urticaria or urticaria? Are you saying it right, and the rest of us are saying it wrong? But OK. I'll call it CSU. OK. So. It's CIndU. So chronic spontaneous urticaria, which is the more prevalent form of urticaria, we can talk about inducible urticarias as well. But the first thing I'll say about CSU is that the severity of this condition, I think, is severely underappreciated, certainly among the investment community, but I would argue even potentially among the treating community. There was a burden of disease study that was published in January of this year that showed on multiple metrics, so patient-reported quality of life, mental health-related outcomes, health resource utilization, that CSU is actually a more severe disease than atopic dermatitis or psoriasis. And so when we talk about the need for new treatments, it is driven not only by this really highly severe condition that, as the late Marcus Maurer used to say, it doesn't kill you, but it doesn't let you live. I think that's one important element of the need here. But the second, to go to your first question about the commercial opportunity, there's only one approved therapy for post-antihistamine patients. So patients who have spent years on what he used to call the antihistamine carousel and are still getting no relief, there's one antibody treatment available. And its utilization is really limited by some of its safety liabilities, as I'm sure we'll talk about. So I think the combination of the disease severity and the broad under-treatment, if you will, of the disease by currently available therapies means that this is a truly important undertaking that we are doing at Third Harmonic Bio, bringing a new oral therapy to market. And then I think you alluded to it in the beginning as well. So there's been very strong validation of KIT as a target in CSU and CIndU and related urticarias. Yeah. And so maybe can you set the stage and sort of talk about the barzolvolimab experience so far, and then we'll get into the initial data for THB-01. Yeah. I don't want to spend too much time talking about my colleague's data, but I think it does serve as, as you said, a really important validating data set for the utility of KIT inhibition in the treatment of urticaria. So I think first what we're seeing is really profound efficacy in terms of complete response rates, on the order of double the complete response rates of any other therapies tested in this disease. So that's a really important place to start. In terms of the safety side of the ledger with KIT inhibitors, we spent a lot of time talking about this. I think one thing I would say is that one of the reasons that we spend so much time talking about the safety considerations around KIT inhibition is just that it's very well understood. This is biology that is very clear. And so we know what to look for from a safety liability perspective. And I think what we're seeing with the antibody approach, with even very high doses of a very potent antibody that is exquisitely selective for KIT, the mechanism-based safety findings in terms of mild decreases in neutrophil, grade 1 hypopigmentation, and hair color change, those are safety signals that in the context of the disease severity and the efficacy profile of the antibody, I think, are completely manageable from a patient experience perspective. The one element of the emerging data set around antibodies directed against KIT, which we know is potentially commercially impactful because it is clinically meaningful, is the risk for paradoxical mast cell activation and anaphylaxis. And this is a really important point of differentiation between a small molecule approach to KIT inhibition and an antibody approach to KIT inhibition. With a small molecule tyrosine kinase inhibitor, to use a little bit of jargon, you mechanistically sidestep this risk altogether, and so as we look at the differences between an oral approach to KIT and an antibody approach to KIT, that is the place to focus. You already have clinical data from your first-generation compounds. Can you walk us through the proof of concept work that you did to really demonstrate that a TKI can achieve comparable efficacy, at least in a proof of concept setting? Yeah. I'm happy to talk about our experience with 01. I will say in fairness, I don't think we can make any definitive conclusions from our inducible urticaria study because we terminated it early, as I'm sure we'll talk about due to liver tox with our first-generation oral KIT inhibitor. What we learned was really important, which was, as I'm sure we'll talk about, there is this open question of how much systemic KIT inhibition is required to really drive optimal efficacy. I think when we started that program three years ago, the only data that we had were the early data sets from the antibody program showing that if you bottomed out tryptase, meaning if you systemically knock out KIT signaling, you got profound efficacy. So the bar back in the day was, can you drive biologic-like decreases in serum tryptase? That was sort of what we needed to do in the early days to demonstrate the potential utility of this approach. And in the phase one study of THB-01, we showed that indeed, at the highest dose tested, we dropped tryptase levels down to the lower limit of quantitation, the lower limit of sensitivity of this particular assay. So that was important. When we moved into the inducible urticaria study, the intended design for the study was a three-tiered dose escalation. And so we were starting with a dose which, in the phase one study, showed about a 50%-60% reduction in serum tryptase. And then we had a middle dose, and then we had a planned high dose that, again, in the phase one study, bottomed out tryptase. What happened in point of fact before we terminated the study is that at that low dose, the 200 mg BID dose, where again, we saw 50%-60% reductions in serum tryptase, we saw an 80% response rate. So that was our first hint in our own hands with our own work that, oh man, we've been sort of focused on hitting it as hard as we can, but maybe we don't need to. And so that was kind of the tantalizing bit of evidence that we needed to think about the other end of the spectrum in terms of degrees of target coverage prior to that program being discontinued. We're now back on our feet with THB-335. Our second generation is clearly an improved molecule. But the question remains, how much tryptase reduction do we need? And I think the honest answer is nobody knows yet. What we want to do is take multiple doses into our planned phase two study in chronic urticaria and answer that question more definitively. Yeah. And before we get to the whole tryptase discussion, can you talk a little bit more about the differences between 335 and 01, both in terms of avoiding this active metabolite that you identified from a structural perspective, but then also drug-like properties? Yeah, certainly. So the first principles in moving from 01 to THB-335, two dual first principles, if I may. So number one was we had identified that the liver injury caused by 01 was the result of a metabolic liability. One of the major metabolic pathways for THB-01 was generating a reactive intermediate, which was causing oxidative stress that ultimately led to the transaminitis that we observed in the clinic. In making structural changes, we were able to divert the metabolism of the parent molecule to different places, essentially knock out that metabolic pathway altogether, and we believe remove the liver injury risk with THB-335. So goal number one was get rid of the liver tox. Goal number two was keep as much of THB-01, what was good about that molecule, as possible. 01 was beautifully potent, exquisitely selective, nice long half-life. We could improve upon it if we wanted to. But for the time lost in going from 01 to 335, I can clearly say that 335 is a better molecule. So we have altered the metabolism to, we believe, abrogate the hepatotoxicity risk. We have maintained the potency, if anything, slightly more potent than 01. We have maintained the exquisite selectivity in moving to 335. But in addition, we have improved the PK profile. We believe that this will be a once-daily dosing drug. That's being tested currently in the phase one study. It's peripherally restricted. We don't see any brain exposure. Generally speaking, if you don't need a drug in the brain, it's better not to have it there. We've improved the lipophilicity. We've improved the solubility, which makes it an easier drug to work with from a drug product formulation perspective. So if we're wrong, and human dose projection models can be wrong, if we're wrong and this is a BID dosing drug as it exists currently in an unformulated basis, we're in a much better position to formulate our way into once dosing. And then finally, we've reset the composition of matter patent clock. So we now have base IP protection out through the end of 2043. Yep. So moving on to phase one, I mean, you alluded to this, the question of tryptase as a biomarker. So in 01's phase one, that 200 mg BID dose at 14 days, you had about a 50% or so reduction. 50%-60%. 50%-60%. Wide error bars. There's some variation. Yeah. In the chronic inducible urticaria proof of concepts, clearly a lot of variation as well. It seems like the tryptase reduction did deepen over time, potentially. I wouldn't say it deepened over time. I think the first comment I would make about the tryptase data in the chronic inducible urticaria study is that this is very much a case of the tyranny of small n's. It was five subjects' worth of data, a single time point at week one. It measured at a mean of 83% reduction in serum tryptase. Bigger numerically than what we saw in the phase one, six subjects' worth of data. I would say, and Conner, our Chief Medical Officer, constantly reminds me, that's within the error bars. I don't think that we can categorically say that there was more tryptase reduction in these five subjects than there was in the phase one. But what we can say categorically is that we saw clinical response. Yep. Two complete responses, two partial responses who, to our eye, looked very much like they were on their way to complete responses if we had continued dosing. So I think the takeaway from that is that, again, we were probably overshooting in looking to bottom out tryptase. But coming out of this phase one study, the hope is that we have doses that provide a range of tryptase reduction so that we can run a bigger study to completion and answer that question definitively. Yeah, so let's then talk about the phase one in terms of that range. I guess on the high end, maybe I'll ask it like this in the sense of, would you be disappointed if your high dose didn't achieve a 60% reduction in tryptase? Would I be disappointed? Gosh, well, disappointment is so contextual. I would like to see, let me answer it this way. What I would be disappointed with is if I did not see some separation of curves such that I could make dose selections going into phase two with some degree of conviction, but yes, we would like to see tryptase reductions, well, let me take a step back even from pharmacodynamics. Pharmacokinetics is the first thing that you look at. So how much exposure am I getting? How much target coverage am I getting? Am I getting into the range that we believe we need to be in in order to see efficacy? So I'm going to look at PK before I look at tryptase, and I want PK and PD to sort of run together too. All right. Then going on to the PK point of this, based on what you saw in 01 study, you have a sense of what sort of target coverage you're looking to achieve at this point? Or is that still TBD given the PD, or I guess the clinical effects that you saw? I think it's still TBD. I think it's something that we will answer in arrears once we have clinical data. Okay. So then in the context of the other end of the spectrum, how wide of a range are we thinking about in the context of the low end of both target coverage and/or Tryptase PD effects? Are we talking 10%? Is the imatinib experience of around 40% a good benchmark to think to on the low end? Or what are we thinking about there? Let me clarify the question. Are you meaning what I hope to see in my phase one or what I believe will be efficacious? In phase one. Yeah. I mean, I think you want to also establish a floor, ideally, a dose at which you're sort of barely seeing activity. It's really the intent, other than providing updates and showing progress in the program to the world, is also just getting the PK and PD data that we need to confidently choose doses for phase 2. Because one of the modifications to our development plan that we made in moving from THB-01 to THB-335 is that we are eliminating the proof of concept study. We're not doing a 1b CSU or 2a and then a 2b. We are doing one definitive phase 2 study in CSU that will allow us to select doses and move directly into phase 3. So the dose selection is important for phase 2 because I get one shot at this. So that's why I'm so focused on really being able to discern my PK/PD relationship with as much reliability as possible from phase one. So then I'm setting myself up for success in phase two. Okay. And then in terms of just data disclosure in phase one, what level of granularity do you expect to share in terms of doses, PD markers, PK, target coverage, et cetera? I think we've established ourselves at Third Harmonic as very disclosive and transparent in terms of our data across our programs and our studies, so our expectation is that it is a full data set from our SAD/MAD, so all cohorts of the single ascending dose, all cohorts of the 14-day multiple ascending dose, safety, PK, tryptase from the 14-day MAD. Tryptase from a single dose isn't particularly interpretable, and then the other important piece of data that we'll be collecting and sharing in the first quarter is we will be looking at clinical metabolite ID. We will look at the metabolic profile from our clinical samples, and that allows us to, we expect, confirm that clinical metabolism of THB-335 matches the profile that we showed non-clinically to not be associated with hepatotoxicity if you follow that. It's a meaningful de-risker with respect to the liver injury that we experienced with the first generation program. Yep. And you mentioned you're studying QD doses across the spectrum or QD and BID at this point? That will all be part of the disclosure in phase 1. When you start a phase 1 study, the only thing that you have at the beginning of the study is your starting dose for your single ascending dose, which is set by your tox margins, and then you dose escalate from there. So then phase two, obviously you're not going to disclose the design until you have the phase one data and et cetera. But broad strokes, how are you thinking about a high dose and a low dose sort of testing this therapeutic index? How should we think maybe more philosophically about what you're trying to solve here? That's a good existential question, Alex. I respect that. What are we trying to solve? I think ultimately what you're trying to solve on your way to hopefully an approved important new medicine for people living with urticaria is that you find the sweet spot in terms of target coverage that gives you the best efficacy with sort of the most safe and tolerable side effect profile. So that's the North Star, if you will. The way that you get there in phase two is you study ideally three, if not three, then two doses. That gives you the ability to reliably delineate between dose levels. If the doses are too close, you're not really going to be able to discern what's better. Or if you've got sort of interdependencies in terms of dose frequency and dose level, it becomes really complicated to suss out what the sweet spot is. I think that that's one of the things that's been challenging as a field is as some of the other programs have evolved, the sort of differences between the dose levels aren't always easy to delineate. That's fair. So that's what we're shooting for. I guess to your point there, given the uncertainty here around where we're aiming, do you think two doses is enough potentially? Or why not do four? A couple of reasons that are very pragmatic. The scientific, what your clinical pharmacologist would tell you is that if your doses are too close and you have completely overlapping confidence intervals around exposures and tryptase, then you're not actually discerning a dose response. You've got to have sufficient separation of your doses to be able to reliably discern differences. That's probably the most sort of scientifically meaningful way. The other is patients are waiting. We know a lot about the biology here. The PK/PD relationship is the open question. We're very clear on what's going on in terms of how KIT works on mast cells, how mast cells work on disease, and then importantly, what the endpoints are. We have the opportunity to be efficient, particularly with a second generation program, particularly being arguably third in class at this point. We are absolutely taking advantage of that. Yep. And I guess we're talking about the KIT class and on-target tox, neutropenia, hair color changes, hypopigmentation. I guess at this point, do you still believe it's possible to disentangle those from clinical efficacy? My starting point is that I do not believe that I have to. I think given, again, at the risk of repeating myself, the severity of the disease, the degree of the unmet need, and the profound efficacy that we're seeing, I mean, you really only have to go and talk to people that are living with severe urticaria and maybe spend 10 minutes understanding what life looks like, and I guarantee you you will walk away saying, "Who cares about a little bit of underarm hair color change?", and then likewise, on the neutrophil decline, it is on target. We expect to see it, but what we are seeing, grade 1 neutropenia, that is a lab value abnormality. It is not a clinically meaningful safety risk to patients, so I don't believe that I need to broaden the therapeutic index. If we can, we're going to test that theory. And if we can, that's upside. But if I have a daily oral therapy that delivers efficacy above and beyond what's currently available and doesn't carry the risk of anaphylaxis that an antibody approach to the target does, I think that is a really promising therapeutic profile for this disease. Yep. So you've talked about efficiency with this next generation molecule. What needs to happen after the phase 1 to start the phase 2? I mean, you're not going to say when you're going to start the phase 2, obviously, but what do you need to do to get there? So much. Actually, I don't physically need to, personally need to do much, but the team's working really hard. That's not true. I do a lot. So the main thing is that in parallel with the phase one clinical trial, we are completing our subchronic toxicology studies, our reproductive toxicology studies, and we're making material. We're making clinical material. So all three of those work streams are sort of fighting for each other on critical path to go to not only the FDA, but because we plan for this to be an international study, go to ex-US health authorities with our dossier to get approval to initiate the phase two study with the design, the duration, the doses that we want to study. So that's sort of the big milestone will be regulatory feedback on the package. In addition, we've already selected our CRO. We're looking for sites. We're hiring everything that we can do to make sure that we are operationally poised to start that study as soon as we get the green light. We are doing. How competitive is the development, I guess, clinical trial site landscape right now in urticaria? I saw what she did there. You're going to call it urticaria. I wouldn't call it competitive. I think it is getting a much-needed boost in terms of investigator engagement, so I think that historically, the universe of urticariologists, to use the term that I believe Marcus Maurer coined, was really small, and by having all of these clinical development programs going on in parallel, what we're doing is we're actually increasing the universe of physicians who are starting to participate in these clinical trials, which is a net benefit because it drives diagnosis, it drives treatment, it drives comfort in treating these patients that I think will ultimately translate into the much-needed increase in treatment, awareness treatment, and hopefully therapeutic benefit for patients living with this disease, so I'm actually all for it. It is a rising tide floats all boats moment. Yep. So then next indication you've talked about is asthma. Can you talk a little bit about the biologic rationale there? Yeah. I'm happy to. So like in CSU, although to a lesser degree, but I think still convincingly, there is a reasonable body of clinical evidence that's been published on the utility of a KIT inhibitor for the treatment of severe asthma. There was a 2017 New England Journal publication, an academic study in which imatinib was used as a KIT inhibitor for the treatment of an all-comers severe asthma patient population, so non-endotype restricted, and in only 60 subjects in six months demonstrated an improvement in FEV1 and airway hyperreactivity, which was a pretty profound result, which I believe is why it ended up in the New England Journal. So that's one body of evidence that we've talked about a lot. There's also another program out of Europe using a less selective KIT inhibitor, but one of, I would say, reasonably selective against KIT, where two phase three exacerbation studies were actually run. And they showed P values and improvements in exacerbation rates with that TKI. So I think those two clinical data sets are really encouraging to us. We also have the benefit of a number of well-established preclinical models of asthma where we're doing a lot of work right now with our own compounds and generating really interesting data that we're using to drive our strategy here. So I think that, again, as the field is evolving, there is an increase in the appreciation of really the central role of mast cells in severe asthma. And again, since KIT is sort of the perfect instrument with which to smack down mast cells, it really suggests that a KIT inhibitor has the potential to be a really important therapeutic advancement, particularly in oral. We know that there have been a number of biologics approved for severe asthma in the last decade or so. No new oral therapies since the anti-leukotrienes were introduced in the 1990s. So we see a real opportunity here. We had a physician in talking with our team last week, and she was saying, "Oh, an oral would be a game changer." So we're excited about that as another indication. But beyond asthma, there are a number of other inflammatory diseases where mast cells are believed to play a role. And we really see the opportunity for a pipeline and a target, as we say, as we continue our work in this field. Yeah. And multiple readouts in the next year or so as well. Yeah. And then final question, I guess, cash runway currently and what those assumptions are. Sure. So as of the last quarter, we have $296 million on the balance sheet. So we're very well capitalized. We expect that to provide guidance at least through 2026. The way that we're running the business is that we really view beyond this phase one data in the first quarter. The next really meaningful readout for us will be the phase two CSU data. We want to be well capitalized through that readout and beyond. Sounds good. Natalie, always a pleasure. Thank you. Likewise. Thanks. Thanks.