All right. Welcome, everyone. I'm Gavin Clark-Gartner from the Evercore ISI Biotech Research Team, and really happy to be here with Chris Murphy, who is the CFO and CBO of Third Harmonic. Thanks for joining us, Chris. Yeah, thanks for having us. Of course. All right, so why don't you just start off giving an overview of Third Harmonic and where things stand today? Sure. So Third Harmonic Bio is a biotech company focused on developing therapies for mast cell-mediated inflammatory diseases of the 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 really a debilitating disease characterized by red, itchy wheals or hives all over the patient's body. It significantly impacts patients' quality of life, including anxiety, depression, loss of sleep, and work. So what we hear from patients is that while CSU doesn't kill you, it also doesn't let you live. So I really think that underscores the severity of the disease that we're looking to treat. But we're very pleased with the progress of THB335. It's currently in an ongoing phase I trial in healthy volunteers, and the data is just around the corner, coming in Q1 2025. We're excited for that data to come. We believe this data will serve as the foundation for us to move rapidly into a phase II trial in CSU and potentially additional mast cell-mediated diseases. Lastly, a very strong balance sheet, $296 million as of September 30th, which provides us the capital to get through phase II data in CSU, and with a significant cushion beyond that. Yeah, great. So obviously many different potential indications here, as you alluded to, focusing kind of first on urticaria, though. Maybe just kind of frame, where do you think oral KITs will fit into the paradigm specifically versus c-KIT antibodies? Absolutely. Yeah, so we see there's really three key differentiators today that we know about and one potential differentiator versus the antibodies. So first, patient preference, patient convenience, and physician preference for potential once-a-day pill versus a painful antibody injection. And second, which we think is the most impactful differentiator, is the risk of anaphylaxis. And so anaphylaxis, as we know, is not monitorable, not something that you can really foresee coming, as well as is potentially fatal. And so we know that's a significant issue, and it's really an antibody-specific risk. And so this is supported by the Xolair experience. And so we know that Xolair's uptake is significantly impacted by the risk of anaphylaxis. They say it's less than 20% of the market. And so we believe the potential introduction of a once-a-day pill can not only significantly increase the number of patients treated, but also the number of treating physicians. And third, with an oral, you have the opportunity for fast on, fast off. And so if a patient would need to get off the medicine at any point in time, they're able to do so pretty quickly. I think additionally, and this is kind of the key question in the KIT space today, is really how much KIT inhibition and tryptase reduction is required to get good efficacy in urticaria patients. And so that's really the key question. So with an oral small molecule like THB335, we have the opportunity to more finely interrogate that therapeutic window and potentially titrate to a sweet spot to find optimal efficacy and find maybe a little more margin on the safety side. There's a little bit of data in this space, some tantalizing data, but nothing that's really wholly addressed this question. For example, in our first-generation compound, THB001, in our phase I trial with 001, we saw tryptase reduction for the 200-mg BID dose in the 50%-60% range. That resulted in an 80% response rate in our phase Ib cold-inducible urticaria trial, or CIndU trial. We think that's interesting. It's obviously small n's, so we don't want to read too far into that. We think it's interesting, and we look forward to really wholly addressing that question in our phase II trial. Yeah, great. And maybe for those people who aren't as familiar with the company or kind of have taken a break and are coming back, maybe just quickly recap what happened with 001 over time and why you've moved over to 335? Sure. So I'll take a step back and provide some background on 001 and how we got to where we are today. So we started on this journey with THB001, which is our first-generation compound. So back in December of 2022, we were in an ongoing phase Ib CIndU trial. And unfortunately, two of the first three patients to reach eight weeks of treatment saw clear signal of liver tox and transaminitis. And so we had to discontinue the trial immediately when we saw that. On the positive side, though, when we looked at the data for the five patients that had been enrolled at that point, as I mentioned, there was an 80% response rate. So four of the five patients that were enrolled had a clinical response. Two of those were complete responses. Two were partial. And so, based on that, we knew we had a drug if we could go and figure out what happened and fix it. And so next, what I'll do is summarize about nine months of phenomenal work by our Third Harmonic Bio research team. And so, the first thing you do when something like this happens, you ask yourself, do I have a biology problem or a chemistry problem? And so, on the biology side, both THB001 as well as THB335, our next-generation compound, are exquisitely selective towards KIT. So, we were able to pretty quickly eliminate that as the problem. On the chemistry side, we deeply interrogated 001 to better understand what happened. To start, we looked at an established assay, which highlighted for us there are significant levels of protein adduct formation with 001, and so that's associated with liver tox. Upon further investigation to understand why that's happening, it became clear to us that that was driven by oxidative stress via metabolic liability on the compound, and so we know that with oxidative stress over time, it overwhelms the system, and liver cells become sick, and so that's what ultimately caused the transaminitis, so we looked at that, and when you know you have a metabolic liability, you look at the metabolic profile of 001, and when we did so, we saw the formation of an end product major metabolite, or a diol, that was generated via a reactive intermediate, and so we looked at that diol, and from that, we were able to back into the structural liability on the compound, so thankfully, at this point in time, we had medicinal chemistry work going on in the background. And from that medicinal chemistry work, we happened to have several compounds in mid-tier screening that had the necessary modifications to divert metabolism elsewhere on the compound. And so from that, THB335 came out of that screen. And so we moved forward with THB335. We deeply interrogated it to gain the confidence that we have today that we've addressed the liver tox. And there's really three key data points that we were able to give us confidence to move forward, and we think it's behind us now. The first one being, we looked across species and test systems and saw no GSH adduct formation, which is associated with liver tox. Number two, we knew it was a metabolic liability with 001. And when we looked at the metabolic profile of 335, it's very distinct, very different than 001. Specifically, we did not see the diol formed. So that gave us additional confidence. But then you ask yourself, okay, what if we're wrong about this hypothesis of the mechanism that's driving it, oxidative stress? So the last thing we did, we looked at an orthogonal phenotypic screen, looking at a range of gene signatures associated with liver tox. And when we did that and we ran a closely related tool compound of 335 through that screen, there was no activity. And when we ran THB001 through that screen, it lit it up like a Christmas tree. So based on all of those data points, we're able to have the confidence we have today that we've moved past it. And the nice thing is these modifications that we made to 335 from 001 qualify as a selection intervention within the prior art. So it resets our composition of matter clock, and now we have coverage through the end of 2043. Awesome. Very comprehensive. All right, so shifting gears to the phase I trial, maybe you could just kind of lay out the design, what you've said on cohort size, dose, dose levels, and also what you haven't said. Yeah. So what we have said is that it's a standard SAD-MAD or single-ascending dose, multiple-ascending dose trial, and each cohort has eight healthy volunteers, six on drug, two placebo. We have not disclosed the number of cohorts nor the dosage levels, but we plan to provide a holistic data package in Q1 of 2025 with all that information. Okay. And any other comments around kind of the target dosing profile that you're aiming for at this point? Sure. So I think to the data we expect in Q1, there's a few key things that we're looking to see out of the data. First, on overall safety, so phase I trial, we're looking at safety. Two, on PK, on pharmacokinetics, looking to confirm once-daily dosing. And so that's what we've modeled from our preclinical work, so we'd like to confirm that. But one differentiation between 001 and 335, 335 is much more soluble. And so if we aren't able to achieve that in our phase I, then we have the ability to formulate our way into that much easier at the starting line versus with 001. So that's on the PK side. On the PD or pharmacodynamic side, looking at tryptase, which is a powerful biomarker, we believe, that's closely correlated with urticaria efficacy in urticaria patients. And so we'll look to that. What we're looking for there is really a range of tryptase reductions really to help inform where we're going to move forward with dosage levels for phase II. To further increase our confidence that we've moved past the liver tox, we plan to look at Met ID, or the metabolic profile of THB335 in the clinical setting, to confirm what we saw in the preclinical setting that is very distinct from 001, and that specifically, we don't see that diol, major metabolite, end product metabolite formed that we saw with 001. All of that will be part of the data package in Q1. Great. Maybe just remind us the greatest amount of tryptase reduction you got with 001. And for 335, what would an optimal target be in this dosing period? And one of the questions that starts to dovetail that I'm assuming you guys have gotten is, do you think an oral KIT can cause full depletion mechanistically, or is there some amount of inhibition also bundled within there? Yeah. So with 001, what we did see with 001 in our phase Ib trial in CIndU, this 200 mg BID dose, which was actually our lowest planned dose, in CIndU patients, we saw an 83% on average tryptase reduction. So we feel like that's significantly impacting and really bottoming out tryptase with what was our planned, lowest planned dose. So that gives us confidence that we're able to hit the target hard enough to bottom out tryptase. But like I said, the question is, do we need to? And that's what we look to. And really, I would say what we're saying on the target tryptase levels, really our target is to look for a range, not really a target percentage, but really a range to help inform our dosage levels to take into phase II. That makes sense. And turning over to the safety side, one of the events where more attention has been focused on recently, given the long-term data from Celldex's barzolvolimab, is the hypopigmentation, which happens with extended duration treatment, but also the hair color changes that happen a little bit earlier. So I guess, big picture, what is your guys' view on the hair color changes with the mechanism? And then a little more granularly, what is the range or the bar to kind of compare to other agents in the class? Sure. So we look at these hair color change, hypopigmentation as really tolerability effects. And I think the first thing to reinforce and make sure it's really important that when you look at these in the trials, they're grade one, mild, fully reversible. So we think that's really important. And we also think it's really important, especially talking to these patients, given the severity of the disease, we think that it's a manageable profile on the tolerability side. It shows up; it's very mild in areas where there's shaving, so like the underarm. And so we think that given the severity of the disease and what we know about how it's a mild effect, then we believe it's a manageable profile. When it comes to the bar, I think we have to see, and that's where I think the really kind of tantalizing question with the oral is, is there a potential to titrate to a lower level of KIT inhibition and tryptase reduction to get good efficacy, but have a little more margin on the safety side? Are you planning to show any longer-term follow-up data, like hypothetically a week or two off a drug to kind of get at that reversibility effect a little bit? Sure. So the MAD portion, the multiple-ascending dose, is 14 days of treatment, so two weeks. And then we have follow-up through day 29. So we'll share all of that data as part of the package in Q1 2025. That makes sense. What should we expect to see on the cell count side? Are you guys planning to show neutrophil graphs, reticulocytes, et cetera? What's the level of disclosure there? Yeah. I think what we've established at Third Harmonic to date, and we plan to going forward, is to be very transparent. So we plan to share a significant level of data, including on cell counts. And again, on particularly neutrophils, we feel like what's important to note, especially with the long-term antibody data, it's primarily mild. And even for those patients that have dropped to lower levels due to being a lower flyer at baseline, it's not dropping to the levels of infection risk, which we think is really important. Yeah. That makes sense. All right, let's shift gears. Let's go a little bit towards the future development path side of things. And maybe even just to say commercially, thinking about the mechanism, where do you see this fitting in relative to Xolair? Can you drive pre, or I should say omalizumab, but are you able to drive pre-omalizumab use? What do you need to show from a clinical profile, and what's the commercial strategy that enables that? Yeah. So we're in phase I today, so I think it's really early to talk in detail about positioning. And we look forward to hopefully the privilege of talking about market share and line treatments. What we do feel like is given KIT inhibition is really the high watermark for efficacy today, based on the long-term efficacy shown by the antibody out in front of us. And so we believe that a similar profile to that, to what we've seen, particularly in the absence of the risk of anaphylaxis, we really think that's a major impediment today and a major differentiator for us. And so we think that would really help us out when it comes to product positioning in the future. That makes sense. Thinking about other indications, I know historically you've alluded to asthma. There's a whole long list. How do you think about indication selection at the moment? And I guess also, after this initial phase I data comes out, how many studies can you get moving at the same time? Yeah. So obviously, CSU is number one. That's our focus, and we're going to move as fast as we can on CSU. We have talked about asthma. We think severe asthma is a really interesting additional indication for us. Particularly, there's biological as well as clinical validation today, and for patients, they haven't had a new oral approved since the 1990s with the anti-leukotrienes. And so we think there's definitely an opportunity there. On that side, to be able to get the signal that we want to see in a phase II trial in severe asthma, we'd want to have 26 weeks of treatment, which we would need to have our chronic tox work done prior to doing that. And so that work will be done concurrent with our phase II trial in CSU, so that's something we would pursue after that. Beyond that, one of the nice things we have is our colleagues in the space that are running a number of trials in additional indications, including PN, EoE, atopic dermatitis. So we look to monitoring those data closely and could potentially fast follow beyond that. But even beyond that, what we're doing, our work and our focus this year has been where is there not only commercial white space, but also clinical white space. And we plan to talk about that more at an appropriate time. Yeah. That makes sense. In just bigger picture, given the whole broad range of potential applications, potential indications to pursue across many different areas, would you consider looking at some type of partnership, whether that's in different areas, different geographies, et cetera? How do you think about that? Yeah. Right now, our plan is to now partner and retain global rights for particularly 335 and anything that comes behind it. That makes sense. Awesome. Any closing remarks you want to provide as we head into exciting data first half of 2025? Yeah. It's exciting. I joined the company in January, and we were a preclinical company and ramping up for phase II, so really exciting year next year, but there's really three key takeaways. I think the first one is very strong balance sheet, so we have the cash we need to get through phase II data in CSU and with significant cushion beyond that. Second, we're excited to pursue phase II trial in CSU, a robust dose ranging trial in CSU, and potentially additional mast cell mediated diseases, and lastly, the data are coming soon, coming right around the corner in Q1 2025, so we look forward to sharing that full package in Q1. Awesome. Thanks so much, Chris. Really appreciate you joining. Thank you.