Thanks so much for everyone joining us. Beautiful conference, not so beautiful weather, but we really do appreciate the attendance. My name is Akash Tewari. I'm a biotech and pharma analyst here at Jefferies. Chris Murphy, Chief Financial Officer of Third Harmonic. Why don't I give it to you, Chris, for some introductory remarks, and then we'll get into one-on-one questions. Absolutely. Well, thanks, Akash. Thanks for having us. Thanks to everybody in the room and also on the webcast. Third Harmonic Bio is focused on developing therapies for mast cell-mediated inflammatory diseases: skin, airway, and gut. We have a first-in-class, potential once-a-day pill in our lead compound, THB335, which is a potent and selective KIT inhibitor. Our lead indication is chronic spontaneous urticaria, or CSU. It's a debilitating disease characterized by red, itchy wheals or hives all over the body. It has a significant impact on patients' lives, including depression, anxiety, and loss of sleep and work. What we hear from patients is that CSU, while it doesn't kill you, it also doesn't let you live. We think that underscores the severity of the disease. We're very pleased with the progress of THB335, our lead candidate. It's currently in an ongoing phase I trial on healthy volunteers. The data is coming soon. It's right around the corner in Q1 2025. And we expect that data to serve as the foundation to move rapidly into a robust phase II trial in CSU and potentially additional mast cell-mediated diseases. And lastly, upfront, Akash, and as CFO, I think very importantly, we have a very strong balance sheet: $296 million in cash as of September 30, which provides us the capital to execute our plan through phase II data and CSU with significant cushion beyond that. Understood. So let's start. And I realize you're a CFO, but it is a biotech, and you have an important readout coming out. Talk to me about what the bar of success is for that first-in-human kind of cut we're getting. I mean, the way I kind of think about it, your first-in program, Okay, you had liver tox, but there were a lot of positives with that study, too, in terms of tryptase reduction and some of the biomarkers that you were seeing. So what are you aiming to show there, and what should investors expect in Q1 of next year? Certainly. So with the phase I data in Q1 2025, we're excited to share that full data package. There's really three key elements of that data package. First, safety and tolerability. Second, we're looking at pharmacokinetics, or PK. And with that, really, the bar is to confirm what we've seen in the preclinical setting is once-a-day treatment. So we're looking to confirm that. And third, we're looking at tryptase, which we believe is a very strong biomarker, a powerful biomarker that's strongly correlated with clinical efficacy in urticaria patients. And so what we're looking for there is a range of tryptase reduction to help us inform dosage levels to take into phase II. Just generally speaking, tryptase reduction probably in line with what you saw with your first-gen molecule. Is that fair to say? Possibly. I mean, with the first gen, we saw about 83% on average. So we're looking for a range, something maybe lower than that and possibly in that range as well. Understood. First-gen program, obviously, there were liver tox that manifested later on. Is this really the de-risking event on liver tox, or are we going to probably need longer N, larger N, in order to really de-risk that program? I know your team's very confident that you've kind of identified the problematic metabolite, but how should we be framing that? Will this Q1 readout significantly de-risk liver tox? Yeah. Well, I'll address that. But first, I'll say we do think the preclinical data that we've generated to date has significantly de-risked THB335. But first of all, I'll take a step back and provide a little bit of background to how we got to where we are today. We started out on this journey with THB001, our first-generation product. This is back in December of 2022. And at that time, unfortunately, two of the first three patients that got to eight weeks of treatment showed high levels of transaminitis, or drug-induced liver injury. On the positive side, based on that, we had to discontinue the trial immediately. We discontinued it at that point where we saw two out of three patients reach transaminitis. However, when we looked at, on the positive side, when we looked at the efficacy data at that time, we had five patients that had been treated through eight weeks of treatment, and four of the five patients had clinical responses. Two of them were partial, and two of them were full responses. So based on that, we knew we had a drug if we could identify what was wrong and fix it. And so next, I'll summarize to get to your question about de-risking some tremendous work, some phenomenal work by the research team at Third Harmonic. So when you see this transaminitis, first thing you do, do we have a biology problem or a chemistry problem? With THB001, as well as THB335, exquisitely selective to KIT. And so we're able to cancel out the biology problem pretty quickly. On the chemistry problem, on the chemistry side, we interrogated greatly THB001 to help better understand what happened. When we looked at THB001 first in an established assay, we were able to see at very high levels of protein adduct formation, which is associated with liver tox. Upon further investigation, it became clear that this was driven by oxidative stress via a metabolic liability on the compound. So we know that with oxidative stress over time, it overwhelms the system and makes liver cells sick. And so with knowing that we had a metabolic liability, we were able to look at the metabolic profile of THB001, and we were able to look at that. What we saw when looking at that via MetID, we saw a diol, or a major metabolite, end product metabolite, caused by a reactive intermediate. And so with that, we were able to look deeply at that diol, that intermediate, or actually at the metabolite, and able to, from there, back into the metabolic liability on the parent compound. And so from that, we were able to look at, and thankfully, we were investing in medicinal chemistry in the background. And so at that time, when we were doing this investigation, we had several compounds in mid-tier screening, and that actually happened to have the modifications necessary to divert metabolism to other areas of the parent molecule, including THB335. So that's where we moved forward with 335. We feel very confident we've addressed the liver injury risk with 335 based on the data we've generated to date, including when we look at across test systems and species, we see no GSH adduct formation, which we know is associated with oxidative stress. Second, we looked at the metabolic profile, very distinct metabolic profile for 335 versus 001, and there's no diol that's formed, the major metabolite, that's associated with liver tox. And then third, when we did orthogonal phenotypic screen, looking at a range of gene signatures associated with liver tox, we ran that with a closely related tool compound, 2335, and saw no activity, and then ran that with 001, and it lit it up like a Christmas tree. So there's a lot of activity. So based on all of that, we feel like we've really de-risked THB335 at this point. Additionally, just one thing to note, those modifications that we made, they do qualify, and they're sufficiently differentiated to qualify as a selection invention within the prior art. So now we've been able to reset our composition of matter clock, and now we have coverage through 2043. Understood. How many CFOs can give that detail of an answer? That's incredibly impressive. Now, outside of just liver toxicity, I mean, there are other attributes with 335 that you've tried to tune out, whether it's blood-brain barrier penetration, testicular toxicity. Talk to me about some of those other aspects where maybe this next-gen compound could differentiate. Sure. And so really the key with THB335, what we wanted to do was maintain the positive elements of THB001 while modifying this one metabolic liability. So a lot of the elements are similar. However, one of the differentiators is one thing that we were aiming for was limiting the peripheral distribution. And so first, on reprotox, our THB335 reprotox is ongoing. But what I'll say on THB001's reprotox, when we did that, we did see a histologic effect. But when you look at all doses, we saw no functional fertility effect for rodents, meaning that rodents were able to impregnate their cage mates. So we think that's an important note as well. When it comes to CNS penetration, we abide by the general rule. If you don't need a drug in the brain, then we don't want it there. Yeah. Makes sense. I think I get this question a lot. Like, Okay, Celldex has neutropenia, but will the orals really differentiate there? And that's where I think it kind of comes down to your titration and how you dose patients. When you have a shorter half-life, you might be able to really get an individual patient to the right dose. Talk to me about, A, your confidence on differentiating from a safety perspective when it comes to heme tox. But then, B, let's say you don't have it. Who cares? What does your market research suggest going simply oral provide to patients in urticaria? Yeah. So first, on heme effects. So when we look at the heme effects for what we've seen in the antibody program ahead of us and from our own data, we see it's very mild, and we believe that it's reversible. And also, it's important to note that for those heme effects, even at the lower levels of neutrophils that are seen in clinical trials to date, they're not dropping below levels of where it's increased risk of infection. So I think that's really important. And the other question. What has your market research shown in terms of, let's say you have similar heme tox, fine, but you're an oral compound? Why should investors feel confident you can take a significant share in the market, given you're years behind, but you're oral? Absolutely, and so I think first, what I'll say is very clearly, orals, there's a patient convenience element as well as physician preference. So we think that's very important upfront. And beyond that, we do think that anaphylaxis is a major differentiator when you look at us compared to an antibody approach to KIT inhibition. So we think that's a really important element as well. Understood. Now, I think this is something even our team's trying to understand. You have Enanta, you have Blueprint, you have your compound. There's privates in the space as well that are kind of looking at it from a bispecific approach. Are we overthinking clinical differentiation? Is it really more important about getting onto the market speed, generating the data? And then when you look at your peers, is it maybe too soon to say that you're different from any of these other next-gen oral kits? Yeah. Well, first, what I'll say is for CSU patients, we think it's most important that they have additional options for physicians to be able to treat patients with CSU. We know that with XOLAIR, it's less than 20% of the post-antihistamine patient population. So anything else that gets on the market is a positive for patients and physicians. When we think about ourselves as a KIT inhibitor, we think that based on the data from the antibody program ahead of us, that onset of action, as well as onset of action, as well as being a high watermark for efficacy, is going to be a differentiator against possible other approaches to treating CSU, and when it comes to other oral small molecule KIT inhibitors, we think it's too early to really compare based on the data that's generated to date. Understood. Makes sense. Now, I think what a lot of people don't appreciate is there's a long clinical development path after you just generate that kind of proof of concept data. Talk to me about once you show that data in Q1 2025, what are the next catalysts on 335 that we should be paying attention to and the clinical development path for urticaria going forward? Absolutely, so first, we talked about coming out of the phase I data, we'll be able to finalize the design for our phase II trial in CSU and move into a robust dose-ranging trial in CSU with THB335, so it'll be initiation of that trial and moving forward. One thing that we're also looking at is potential additional mast cell-mediated diseases, other indications we may go in, so I think that'll be another catalyst that we'll talk about at the appropriate time. I'll ask now because it is interesting. I mean, I feel like I cover CellRen. There are companies that have been working in the KIT space and then just mast cell-mediated diseases. And no one's really been able to find that next kind of urticaria-like indication. It does seem like, though, with asthma, COPD, some of these RESP indications, you're going to see a transformative effect with DUPIXENT and biologics kind of entering that market. Preview it for us, maybe for the team. What are the indications out of urticaria where you feel confident that there's the biological hypothesis and particularly an oral program could really differentiate for clinical purposes? Absolutely, so beyond CSU, what we have talked about for the last few years is an interest in severe asthma, and so we think there's a clear biological and some clinical validation in asthma as well, and what we know is that there's been several biologics that have been approved in severe asthma over the last several years. There's been no orals that have been approved for severe asthma since the 1990s in the anti-leukotrienes, so we think there's a huge opportunity there, so that's something we're definitely interested in. Beyond that, we have the benefit of our colleagues in the KIT space that are running a range of trials in additional indications, and so what we're doing is monitoring those closely, including EoE, PN, atopic dermatitis, as well as asthma, and monitoring those closely to help inform should we move forward into those indications or not. Understood. And in terms of de-risking that, I don't think people appreciate it. You don't necessarily have to run huge studies to show kind of a proof of concept there. It might be too early to really ask, but how quickly do you think? It sounds like in urticaria, you have tryptase reduction. You'll know what IC level you're hitting. You're going to have that biological proof of concept. Should we think about asthma and some of these other indications in that same way where maybe earlier than expected, maybe 2025, 2026, we know that there's a path forward in some of these other indications? Yeah. And so potentially, so first on asthma, one thing with asthma, we believe we're going to have to run a trial for six months of treatment. So to be able to run that trial, we have to have chronic tox studies done in advance of that. Chronic tox will be run in parallel with phase II in CSU. So I think after we were able to run the chronic tox studies, we'll be able to talk more about asthma. On the other studies, potentially, most of those trials, some of those potential indications have 12-week endpoints. And so that's something that's potentially on the table. Okay. Understood. Now, maybe just talk about, because you are the CFO after all, you have about $300 million in cash. How do you think about capital allocation priorities and the kind of level of run rate that you want to maintain for Third Harmonic in order to kind of invest as aggressively as you need with 335? Yeah, absolutely. And so obviously, our priority is THB335, and so that's our primary investment. And the way we manage in the business right now is to make sure we have enough capital to get through phase II data in CSU with significant cushion. I think beyond that, we're also making investments in ongoing medicinal chemistry work. So we do see KIT as a pipeline and a target opportunity. So we're developing a franchise of KIT inhibitors that are tailored more to specific profiles of specific mast cell-mediated diseases. So we're also looking at that in the background. Right now, we do have the first-in-class oral KIT inhibitor, but if there's the best in class, we want to make sure that we have that. And so we'll share more on that at an appropriate time, but we're also investing in that as well. Okay. And in terms of your backup compounds, where are you going to try to maybe tweak the profile you already have for 335? Because it seems like, Okay, maybe it'll be maybe 200 mgs or whatever, but you're going to get the target tryptase reduction. You're going to get the target IC coverage. How do you improve with a backup program from that profile? I think, I mean, with any small molecule, you can have a more potent, more selective compound. So that's something we're always looking at. Beyond that, we'll share more information at an appropriate time. Okay. Understood. I'm kind of just thinking out loud. Gleevec obviously has been used in PH historically. There was a company, Aerovate, that tried to do an inhalable one. The human data from Gleevec, obviously, there were side effects associated with it, but you had a pretty profound benefit. I haven't heard a lot of the companies in the oral KIT space or even Celldex talk about PH, but there are companies that have just kind of become public that are looking at that option. Is PH on that list of priorities for your team, and do you think there could be an interesting clinical development path there? Potentially. Yeah. Okay. Understood. Now, stepping back and thinking about what's the right level of inhibition for tryptase and your IC50 coverage, one of the things I think your team's trying to explore is maybe we don't need to hit our IC90. Maybe we can hit something lower. What are the data points that you've seen that kind of give you confidence that you don't necessarily need to hit the KIT target as hard as the mAbs are, but you can still kind of retain that clinical profile? Yeah. I think that's the key existential question in the KIT space today is do you really need to systematically ablate mast cells and KIT inhibition across the body to get optimal efficacy? And the reality is the answer is we don't know. We don't know right now. But we really look forward to addressing that in our phase II trial in CSU. I think there are data points out there that point to possibly you don't need to systemically ablate KIT signaling to drive optimal efficacy. But the beauty and the opportunity we have with a small molecule approach is that we're able to really interrogate that therapeutic window, and we're able to look at potentially titrating to find a sweet spot of optimal efficacy as well as a little more margin on the safety side. Yeah. I think that titration is so critical because so just for the Q1 2025 read, I probably we're not going to explore titration too much. But can you give us a sense of how many patients you're enrolling, what's the N in each arm, and then kind of what is the range of doses that you're going to be exploring there in terms of, hey, I'm hitting my IC50, IC60 versus I'm going to hit the target as hard as the mAbs are? I mean, how wide-ranging is this data readout? Yeah. We'll show that when we have the full data package. What I can say and what we have talked about is that each cohort has six active patients and two placebo patients. The number of cohorts are driven by really, it's kind of as we go, it's on a rolling basis we're able to identify how many cohorts are running. So we'll share all of that as part of our full package in Q1. Understood. Maybe lastly, I think we're reaching the end of time. Okay, we have some time. In terms of where oral KITs can kind of fit, and I think the question has always been, all right, XOLAIR has been; it's had this issue with the black box warning. You've never been able to really, I guess, penetrate the market for urticaria as much as you'd want to. DUPIXENT's obviously going to get used earlier stage. An oral KIT, let's say, that has a similar heme tox profile but is oral is more convenient option. What gives your team confidence that maybe that goes beyond just that late line setting, but it could actually move up lines of care? Yeah. So I mean, we talked about the patient convenience, the physician preference as well, which provides us more opportunity to broader physician base, including dermatologists, which today are reluctant to prescribe the antibodies with anaphylaxis risk. And so we see that as a big driver. But beyond the patient convenience, physician preference, we really do see anaphylaxis risk as the primary differentiator between us and antibody approaches. So if we could have efficacy in the range of what we're seeing with the antibody program in the absence of anaphylaxis risk, then I think that provides the opportunity to potentially move up in the line of therapy. Understood, and is it fair to say I know I think I don't know if Celldex has gotten their label yet, so it might be a little too soon, but I would say maybe there's been two or three cases of anaphylaxis. I don't want to speak out of turn, but to your understanding, it sounds like your base case assumption is there is going to be a warning for the mAb approaches on anaphylaxis. There's been even if it's modest, there's been enough of a signal to lead to that. Is that kind of the base case assumption for the Third Harmonic team? Or are you expecting doctors are going to see the anaphylaxis signal whether it's on the label or not? Yeah. We're not going to speculate on our own potential label as well as any other company. So I think that's to be seen. Okay. Understood. Maybe just lastly, as we go into targets for KIT that you can use in combination and really exploring the biology of mast cell-mediated diseases and also BD, right? Are there any potential partnerships or targets that you think could work really synergistically with this mechanism of action that maybe investors aren't paying attention to? And then from a BD perspective, whether it's combining this drug and partnering with other assets or doing something externally, where does your team stand on that right now? Yeah. Right now, we're doing a lot of work on that on the research side. Really, number one, we're focused on KIT. We believe that it's really the leader to address mast cells. So we're really focused on that. But in the background, we're always looking at potential opportunities. On the BD side, primarily looking at chemical diversity behind THB335 in the KIT space. And also, depending on how the work comes out from looking at broader targets, then we could talk more about that at an appropriate time. OK. Understood. I think with that, I think we're out of time. We'll wrap it up. But Chris, I really do appreciate it. It was a wonderful conversation. Thank you. Thanks, Akash. Thanks.