Good day, and thank you for standing by. Welcome to the Third Harmonic Bio webcast and teleconference for the THB335 phase I clinical trial results. At this time, all participants are in a listen-only mode. After the speaker's presentation, there will be a question-and-answer session. To ask a question during the session, you will need to press star one one on your telephone. You will then hear an automated message advising your hand is raised. To withdraw your question, please press star one one again. Please be advised that today's conference is being recorded. I would now like to hand the conference over to your speaker today, Chris Murphy, Chief Financial and BU.S.iness Officer. Please go ahead. Thank you, Operator. Good morning, and thank you for joining us to review the phase I clinical trial results for our oral KIT inhibitor, THB335. My name is Chris Murphy, and I am the Chief Financial and Business Officer of Third Harmonic Bio. I am joined today by CEO Natalie Holles and Chief Medical Officer Dr. Ed Conner. Before we begin, I would like to remind you that we will be making forward-looking statements during this call. Because forward-looking statements relate to the future, they are subject to inherent uncertainties and risks that are difficult to predict, and many of which are outside of our control. Important risks and uncertainties are set forth in our most recent public filings with the SEC at sec.gov. We undertake no obligation to update any forward-looking statements, whether as a result of new information, future developments, or otherwise. A webcast of this call will be available on the Investor Relations page at Third Harmonic Bio's website. I would now like to turn the call over to Natalie to give a few opening remarks before turning the call over to Ed to review the THB335 clinical trial results. Thank you, Chris. This morning, we announced the results from our phase I clinical trial of our oral KIT inhibitor, THB335. In addition, we announced our intention to advance 335 toward phase II readiness by the middle of this year and, in parallel, to run a broadly defined strategic review process to identify opportunities to maximize shareholder value across all assets within the company. We also announced an immediate restructuring in which we are halting all non-335-related research and discovery activities and reducing our workforce by approximately 50%. These restructuring actions will strengthen our already robust balance sheet and further streamline our operations, and will leave us well-positioned to evaluate and act upon the best ideas for generating shareholder value. We'll take these topics in turn, including more context on the rationale for this parallel approach to determining the best path forward for the company. First, I will hand it over to Ed to walk through the trial design and the results. Ed? Thank you, Natalie. I'll begin by stating that these study results, while complete, are still undergoing final QC and should be considered preliminary at this time. We plan to present the final data set in a poster session at the American Academy of Allergy, Asthma, and Immunology, or AAAAI, on Sunday, March 2, 2025. Now, to orient you to the trial design, this first inhuman study of THB335 is a single and multiple ascending dose study conducted in healthy volunteers. Dose levels for both the SAD and MAD cohorts are outlined on the left and right of the slide, respectively. We'll focus most of the discussion today on the results of the MAD cohorts, which were conducted at once-daily dose levels of 21, 41, 82, and 164 mg. Key study objectives were to assess safety and tolerability, evaluate the pharmacokinetics and pharmacodynamics of 335 as measured by serum tryptase, a biomarker of mast cell activation. This slide summarizes the baseline demographics of the healthy volunteers enrolled in the study. Generally speaking, baseline characteristics were balanced across cohorts. The one exception is with regard to sex, as this study predominantly enrolled women. As with the phase I study of our first-generation KIT inhibitor, THB001, we excluded non-vasectomized males from the MAD cohorts while we completed our reproductive toxicology studies in parallel with the phase I study. In the 41 mg cohort, there were three male subjects. Other cohorts were exclusively women. We don't believe this imbalance materially impacts the interpretation of the study results. This next slide summarizes the PK results for the study with a focus on the MAD data. While not shown, the SAD PK data demonstrated the expected dose-dependent increases in drug exposure with a half-life of approximately 40 hours, enabling once-daily dosing. We also observed a mild positive food effect and an exposure variability coefficient of 41%. In the MAD cohorts, we also see dose-proportional increases in exposure that exceed the KIT IC90 at doses of 41 mg daily and higher. I will note that at the 164 mg dose level, we are exceeding the KIT IC90 by almost sevenfold. This is a much higher level of KIT inhibition than what we saw with THB001 and may contribute to the on-target safety profile we will discuss later. I will also direct your attention to day 15, where we see exposure levels remaining high after completion of dosing on day 14. This is relevant for the discussion of the single liver enzyme elevation AE that occurred in an active treated subject. Let's move on to the next slide. This summarizes the PD of THB335 as measured by serum tryptase. Here, we see dose-dependent decreases in serum tryptase across the MAD cohorts, with mean changes from baseline at day 15 ranging from 13%-84%. Peak tryptase reductions occur at day 15 across cohorts, indicating maximal drug effect at one day post-dosing completion. We believe that the tryptase reductions seen at the 41, 82, and 164 mg dose levels sustained over time have the potential to drive meaningful clinical benefit in patients living with CSU. We'll now turn our attention to the safety profile in this phase I study. THB335 was generally safe and well tolerated in the SAD cohorts. Here, we are showing the adverse events occurring in two or more subjects in the MAD cohorts. Starting at the top of the table, we observed adverse events which are consistent with the known effects of on-target KIT inhibition, namely hair color change and decreases in hemoglobin in the 82 and 164 mg cohorts, as well as decreases in neutrophil and white blood cell counts at the 41, 82, and 164 mg dose levels. In addition, there were three AEs of liver enzyme elevations, two in placebo subjects and one in an active subject that we'll discuss shortly. Importantly, all adverse events resolved either during dosing or in the follow-up period. Of note, there was one subject in the 164 mg cohort who discontinued on study day three due to unrelated pre-existing hypertension. There were no discontinuations due to drug-related adverse events in any cohort. Slide 9 provides additional detail on the liver enzyme adverse events. We observed three liver AEs in the MAD cohorts, one in a placebo subject in the 21 mg cohort, and the 164 mg cohort, one in placebo and one in an active subject. Notably, there are published data on the background frequency of LFT elevations in inpatient healthy volunteer phase I studies, so this is not an unprecedented occurrence. The lighter gray line on the plot shows that for the 21 mg cohort placebo subject, liver enzyme values spiked and then returned to normal levels during the dosing period. The darker gray line and the red line show the liver values of the placebo and active subjects, respectively, in the 164 mg cohort. A few things to note. First, the enzyme spikes are largely consistent in time course and magnitude for these two subjects. The peak ALT values for the active treated subject remained well below the consensus threshold of 500 units per liter for drug-induced liver injury, or DILI. Additionally, for the active treated subject, liver values began declining on day 15 when, for the PK and tryptase data we showed earlier, drug exposure and PD effect remained high. This is very different from our experience with THB001, where ALT elevations greatly exceeded the DILI threshold and continued to rise for several days after drug was discontinued. Finally, plasma metabolite identification data from the study are consistent with a non-clinical metabolic profile of 335 and show no evidence for the presence of reactive intermediates. Given our experience with THB001, we interrogated these findings rigorously with multiple experts and agree with their unanimous view that the single occurrence of liver enzyme elevations in the active treated subject is not drug-related. This next slide provides the absolute neutrophil count data. As has been shown previously in our work and others, reductions in neutrophil counts are an on-target effect of KIT inhibition. As such, we see the expected generally dose-dependent reductions in neutrophil counts. Importantly, we did not limit our inclusion criteria for the study with respect to minimum neutrophil counts for enrollment. All subjects with baseline ANC values above the lower limit of normal were enrolled. Notably, the three subjects who experienced neutrophil adverse events were all in the lower range of normal limits with neutrophil counts below 3,000 at baseline. All neutrophil declines resolved in the follow-up period. Despite the nominally higher AE frequency, our overall impression of these data is we do not believe there is a more pronounced effect on neutrophils with 335 versus 001. Based on our limited ability to interpret the neutrophil data disclosed by others in the field, we believe these findings are generally consistent with other KIT inhibitors. Turning then to hemoglobin values on the next slide, we observed a dose-dependent decrease in hemoglobin across the MAD cohorts that resulted in adverse events in the 82 and 164 mg cohorts. We believe this is an on-target effect as KIT inhibition is known to affect hematopoiesis of the erythrocytic lineage. This has been evident in our non-clinical toxicology studies of both 0001 and 335. In interpreting these data, it is important to note that there is a clear phlebotomy effect due to the daily blood draws included in the study protocol, as evidenced by the hemoglobin decreases observed in placebo subjects. In this study, we see a more pronounced phlebotomy effect than was observed in the 0001 phase I study, likely due in part to the greater total blood volume drawn in this protocol. One more point to note in the interpretation of these data, as well as the adverse events table on the following slide, is that the 164 mg cohort baseline hemoglobin values are among the lowest across the cohorts, which may have affected adverse event frequency and severity. Nonetheless, the data trends do show a more pronounced hemoglobin effect at the higher doses studied, which is consistent with the high levels of KIT inhibition achieved at the 82- and 164 mg dose levels in particular. Finally, it is important to note that all values normalize in the follow-up period. The final data slide provides a more detailed look at the hematology adverse events observed in the MAD cohorts. Here we are showing hemoglobin, neutrophil, and total white blood cell count AEs by severity grading and dose level. I'll start by focusing attention on the neutrophil events. As stated previously, all three subjects with neutrophil AEs were on the lower end of the normal range of baseline. Low white blood cell counts are generally reflective of neutrophil levels, and we don't believe the slight differences between ANC and WBC event frequency is meaningful. Nonetheless, we are seeing a clear signal on neutrophil counts that we believe is generally consistent with what was observed in the THB001 phase I study. For hemoglobin, there is evidence of a different clinical effect with THB335 versus THB001. There was an increase in frequency and severity of adverse events observed at the two highest doses evaluated in this study, with two moderate hemoglobin adverse events in the 81 mg cohort and five adverse events in the 164 mg cohort, two graded as moderate and three graded as severe. Importantly, the principal investigator at the phase I unit did not consider any of these adverse events to be clinically severe, nor did they require any intervention. In comparing these data to the 0001 clinical experience, we note that the two phase I studies used different adverse event grading scales, which impacts the severity rating of the hemoglobin events. For the 0001 phase I study, which was conducted in Europe, hematology adverse events were graded using the NCI CTC AE criteria, which is footnoted at the bottom of this slide. For the THB335 phase I study, which was conducted in the U.S., AEs were graded using the FDA guidance on preventative vaccine clinical trials, which is also footnoted. The FDA vaccine guidance imposes more stringent criteria on adverse event grading and provides for AEs to be called at the investigator's discretion on either absolute values, as is the case with the CTC AE criteria, or change from baseline, which does not account for the phlebotomy effect from frequent blood draws. In the case of this study, the PI at the phase I unit utilized change from baseline to adjudicate severity rather than absolute values. However, by absolute value measures under the FDA vaccine guidance, all of the AEs in the 81 mg and 164 mg cohorts would be either grade 1 or 2. Likewise, under the CTC AE criteria, which we used in the THB001 phase I study, all hemoglobin adverse events in this study would be considered grade 1. In summary, while the increased frequency of the hemoglobin effect is real, the severity of the decreases differs depending upon the grading scale used. In summary, the phase I study achieved its objectives of characterizing the pharmacokinetics, pharmacodynamics, safety, and tolerability of 335 in a healthy volunteer population. We are pleased with the consistent dose-dependent increases in drug exposure and long half-life that support once-daily dosing and achieve high levels of target coverage, exceeding the KIT IC90 at daily doses of 41 mg and higher. Furthermore, we believe the dose-dependent reductions in serum tryptase seen in the 41, 82, and 164 mg cohorts reach levels which have the potential to drive meaningful clinical benefit for CSU patients. We believe the safety profile is largely consistent with the known on-target effects of KIT inhibition, but we acknowledge that even with the caveats we have outlined today, the more pronounced effects on hemoglobin in particular will likely limit the doses we are able to study moving forward in clinical development. With that being said, we do believe that there is a potential path forward with 335 to evaluate the utility of consistent moderate KIT inhibition, specifically that there is potential for therapeutic index optimization in a larger, longer-term phase II study in CSU. As such, from here, our development team is turning its attention to phase II readiness activities, including completion of subchronic toxicology studies and submission of the appropriate regulatory filings to support a potential phase II study start by the middle of this year. With that, I would now like to turn the call back to Natalie. Thank you, Ed. Before turning the call over to questions, I want to take a moment to provide more context on our decision to proceed towards phase II with 335, as Ed just outlined, while simultaneously restructuring the company and launching the strategic review process. We acknowledge that this is an atypical path forward, but after a lot of thought, data review, strategic analysis, and discussion with our board, we believe this is the right thing to do. In coming to this decision, we had to consider where we are with the 335 program, both from a drug development perspective and through the lens of shareholder value creation. From a drug development perspective, we believe there is a path forward here. As any experienced drug developer knows, and several have said, you don't make go-no-go decisions based on comparative analyses of competitive phase I data sets. A lot can and often does change in mid and late-stage development. Our own history with THB001 is a good example. This is also a disease area of tremendous unmet need. There is room for more than one KIT inhibitor for the treatment of mast cell-mediated inflammatory diseases. If this were only about drug development, we might put our heads down and keep going. However, we have to consider our responsibility to our shareholders and our ability to build value over a reasonable time horizon. Given the recent market dynamics around our stock, we believe that solely relying on the progress of 335 to build value is an inefficient approach, particularly when we have such a strong balance sheet and highly capital-efficient operating model. We decided to launch this process to determine how best to position for value creation utilizing all assets within the company, not only the THB335 program, but also our cash, our public corporate entity, and our team. For the first half of this year, we intend to run these efforts in parallel, advance 335 toward phase II readiness, and run a broadly defined process to evaluate strategic alternatives. On the latter, all deal types and structures will be considered. We are entering this process with a very strong balance sheet, with cash and cash equivalents of $285 million as of the end of 2024. We intend to operate efficiently over these next several months. After accounting for expenses related to 335 phase II readiness activities, continuing operations, and restructuring costs, we estimate that we will have cash and cash equivalents in a range of approximately $262-$267 million on June 30, 2025. In closing, we want to thank all our employees, particularly those who are affected by the reduction in force announcement today, for the time in their careers that they have dedicated to this endeavor of turning our science into medicine and to the culture of this company that we've built together. Operator, we are now ready to take questions. As a reminder, to ask a question, please press star one one on your telephone and wait for your name to be announced. To withdraw your question, please press star one one again. In the interest of time, we ask that you please limit yourself to one question and one follow-up. Please stand by while we compile the Q&A roster. Our first question comes from Sam Slutsky with LifeSci Capital. Your line is open. Hey, thanks for the questions. I guess one and a half for me. Just on the phlebotomy protocol between this phase I and the 001 phase I, could you just kind of discuss those differences in terms of how much blood was drawn that could lead to the more pronounced effects, generally speaking? I guess to your point, the neutrophil data looks consistent between 001 and 335, but obviously a little more effect on hemoglobin. I guess any clear reason that comes to mind as to why that disconnect? Thanks, Sam. On the first question, we banked additional samples, serum samples from the study, to give us the opportunity to look for biomarkers around liver elevations if we saw them. It was the protocol specified higher volumes of blood drawn in the study because we had an extra thing that we wanted to have the ability to look at if we needed to. In terms of the differential effect on hemoglobin versus neutrophils, you're right. We agree that the neutrophils look consistent. The hemoglobin does look more pronounced. Really, we don't have any theories on why that is. We're just looking at the data empirically at this point. I think the phlebotomy effect could have something to do with that, as we talked about. What we're seeing here, these are both on-target effects of KIT inhibition. We've seen both in the data set from 001. Why we're seeing a more pronounced effect here, we don't know. The only answer is to run a longer-term study with a larger sample to interrogate it more thoroughly. Got it. Okay. Thanks. Thank you. Our next question comes from Joseph Thome with TD Cowen. Your line is open. Hi there. Good morning, and thank you for taking my questions. Maybe the first one just on the strategic alternatives. I guess, is there an ideal strategic alternative that you think THB335 and your current cash balance would sort of lend itself to? If you do kind of reach mid-year and maybe nothing had materialized, is starting that phase II yourself still on the table? A follow-up on the data itself. The liver enzyme elevation is interesting. Is there anything about the baseline health of these patients from a liver perspective that was off, or is there anything environmental at the sites that you think could have caused this? Thank you. Great. Thanks, Joe. I'll take the second question first. There were no baseline characteristics of the subjects enrolled in the study that would lead to a higher propensity for liver enzyme elevations. We interrogated that thoroughly. First, they were screened thoroughly at enrollment, but then, as you might imagine, when we saw these results, we went back and looked again, and nothing unremarkable in the records of either or any of these subjects. There were three subjects that had liver enzyme elevations. We also did thorough post-hoc analyses of the conduct in the phase I unit. We looked at toxicology screens from the bank samples from those patients. If we could assign causality, we certainly would have let everybody know. We were not able to assign causality. Again, in going back and talking to experts in drug-induced liver injury and looking at the literature, there is a background frequency of these sort of liver enzyme elevations that occur in phase I units. It can be attributed to changes in diet when they're living in the phase I unit, but in this case, we don't have any specific causality that we can point to. We're really just empirically looking at the data on those two subjects in the 164 mg cohort in particular, where, as Ed said, we see the time course and the magnitude of these liver enzyme elevations is basically right on top of each other. Going back and looking at the PK samples just to double-triple-check, no drug exposure in the placebo subject, as you would expect. Just looking at the data, talking with the liver enzyme experts, one of them said to us, "Those two subjects are definitely reacting to something, but it can't possibly be your drug." On the first question regarding strategic alternatives, I wouldn't say that there's an ideal structure that we have in mind. We are entering this process intentionally keeping it broadly defined. Our view, as we said in the prepared comments, is that we believe that there's a path forward for 335 and that there's room for more than one oral KIT inhibitor in this space. I think ideally, 335 would be positioned in a broader portfolio so that it could be advanced without sort of carrying the sole burden of being the driver of shareholder value over the next year and a half or two years. That being said, we will look at all options and make decisions in conjunction with our board that really optimize for shareholder value across the assets in the company: the program, the cash, the public ticker, the team. Great. Thank you very much. Thanks. Thank you. Our next question comes from Alex Thompson with Stifel. Your line is open. Hey, great. Thanks for taking our questions. I guess on the SAD data, could you just comment on whether you saw consistent PKPD relationships in the SAD as well? In terms of timelines for speaking with regulators, can you talk about the additional chronic tox work and otherwise that you need to complete before talking to the FDA and whether you would talk about that publicly? Thanks. Sure. T he SAD data, we saw what we would expect in terms of consistent dose-dependent increases in drug exposure and commensurate decreases in serum tryptase. Everything that we saw in the SAD cohorts was predictive of what we saw in the MAD cohorts when we advanced to that portion of the study. In terms of what's next for the program, we are nearly complete with the subchronic tox studies. Those are 13-week studies in rats and dogs. We're really just waiting for the studies to read out, get the full audited draft reports before we can submit to the regulators. We would expect our regulatory submissions to go in in the second quarter. I think holistically, we'll provide an update on where we are with the program and the process in due course later in the year. Thank you. Our next question comes from Akash Tawari with Jefferies. Your line is open. Hey, this is Amy on for Akash. Thanks so much for taking our questions. There seems to be a decoupling between 335 PK and PD effect. We've seen that hitting IC90 generally correlates to tryptase reductions of 80%. Why do you think that we're only seeing 50% with the 41 mg dose? Also, can you talk about the selectivity for 335 compared to 001? Could that potentially impact some of the heme parameters that we're seeing? Great. Thanks, Amy. In terms of the PKPD relationship, you're right. In looking at the 001 PKPD relationship versus the 335 PKPD relationship, as we reported in these respective phase I data sets, they do look different. That being said, these are small ends. Tryptase has a fair degree of variability to it. Whether this is a real difference or this is a tyranny of small n's phenomenology from these two phase I studies, we really don't know. By way of example, I'll remind folks that in the 001 phase I study, the 200 mg BID dose drove about a 50% reduction in serum tryptase. That was a six-subject active cohort design as we have here. In the Sindhu study that we subsequently ran with 001, in the five subjects that were enrolled in that study prior to it being discontinued, serum tryptase at the same dose was dropped 83%. I think trying to make definitive conclusions about differences in PKPD between these two programs is not necessarily—I don't think you can necessarily rely completely on these data. As I said earlier about the differences between what we're seeing on hemoglobin and what we're seeing in terms of neutrophils, the answer is you run a bigger, longer-term study in a larger patient population to really understand what the true effect is. In terms of the selectivity of 335, we've shared those data previously. 335 is—we consider it basically equally selective to 001. If anything, it's slightly more selective for CSF1R in cell-based assays. In point of fact, we view them as comparably selective. In the tox studies that we've completed, we haven't seen clear evidence of off-target toxicity with either program. I think going to the question of, is this hemoglobin effect more pronounced due to some sort of off-target effect that we're getting with 335, seems improbable, both based on the selectivity data that we've shared previously and the fact that the impact on hemoglobin is a known effect of KIT inhibition. The probability of having an off-target effect that has the exact same clinical phenotype as an on-target effect of KIT, again, seems pretty improbable. Got it. Thank you so much. Thank you. Our next question comes from Laura Prendergast with Raymond James. Your line is open. Hey, guys. Thanks for taking the questions. I'm curious around the selection of CSU to move forward with if you guys do proceed with future development of 335. Have you considered a path forward in any indications besides CSU or skin indications? I believe you guys have previously noted that some research suggests that mast cells in the skin might require more intense inhibition of KIT, making it possible that other indications such as airway or GI tract diseases, you could use a lower dose that would be more maybe appropriate for the profile of this drug. Any commentary on how you're thinking about this would be helpful? Yeah. That is a really interesting question and something that we've actually talked a lot about. I think the reason to move into CSU as the first phase II indication is that the biology is so well understood. It is very clearly a mast cell-driven disease. There is tremendous unmet need, as we all know. That has been the defined path because it is a really good place to establish mechanism-based proof of concept, but it also has the potential to be a really important medicine given the unmet need and the size of the population. That being said, could you look at other disease or tissue targets where, as you said, there are lower levels of KIT inhibition could be sufficient? Absolutely. I think in a pedal-down operating scenario, we would be aggressively going after additional indications, potentially even directly in parallel with CSU. From a drug development perspective, that is a really interesting avenue of inquiry. Again, we have to pull back and look at not only where we are from a drug development perspective, but where we are from a company-building shareholder value perspective. Where we are is in a hole with respect to the stock price with a very strong cash balance sheet. Really, regardless of the indication that we went after next, you're still looking at a really pretty prolonged path to getting back into a position where we can be creating value for shareholders with 335 as being the sole asset, sole means of driving value for shareholders within the company. That puts us back exactly where we are, which is looking at strategic alternatives to figure out, is there a way that we can position all of the assets in the company for more efficient value creation for shareholders? Thank you. Thank you. Our final question comes from Mike Ols with Morgan Stanley. Your line is open. Hi, good morning. It's Avi Novak on the line for Mike. Thank you for taking our questions. I guess just to start, can you share with us the scientific rationale that leads you to believe that certain patient populations could be better served with moderate KIT inhibition, whether it be a certain phenotype of CSU or perhaps other indications? As a follow-up, given the phlebotomy effect as well as the number of patients with neutrophil levels on the lower end of normal, I guess, are there any protocol adjustments you could have made to avoid these issues? Are there any learnings that you may be able to apply to a phase II study protocol? Thank you. Sure. On the first question, to clarify, I do not think our contention is that there are certain subsections of the patient population that would be more amenable to moderate KIT inhibition. I think we've just looked at the data writ large generated by ourselves and others where you see, in albeit small data sets, the potential for really pretty profound efficacy with moderate levels of KIT inhibition. Since across the KIT space, really what we worry about for the most part is the on-target effects of KIT inhibition. The whole supposition has been, can you get by with sustained moderate KIT inhibition, achieve the same level of efficacy, and then dial down some of the on-target effects that we are also familiar with at this point? We still, for clarity, believe that that is an important hypothesis that should be tested. It would not be necessarily in a subpopulation of CSU. It would, again, be in a larger-end, longer-term study to really tease out whether that hypothesis actually bears out. That is point one. Point two, in terms of modifications that we could have made to this study, the study was blinded throughout. There were no, as Ed said, there were no discontinuations due to drug-related adverse events in the study. The study proceeded without issue. It was only upon unblinding that you start getting a look at the actual safety profile of the drug versus the placebo subjects. What you could do going forward, you could potentially raise the sort of lower thresholds for enrollment in your studies, either with respect to neutrophils, as others have done in the KIT space, and potentially even on hemoglobin. Those are all things that we would consider, could be considered in the context of the study designed for a phase II. All right. Great. Thank you for taking our questions. You're welcome. Thank you. Okay. I think that's it. Oh, yeah. This concludes the question and answer session. Now I'd like to turn it back to Natalie Holles for closing remarks. Okay. Thank you very much for dialing in. We will provide updates as we have them, both on the program and the process. Thanks, everyone. This concludes today's conference call. Thank you for participating. You may now disconnect.