All right. Good afternoon, everyone. My name is Yatin Suneja. I am one of the biotech analysts here at Guggenheim. It is my pleasure to welcome our next presenting company, Tourmaline, to our SMID Biotech Conference. From the company, we have Sandeep Kulkarni, who is the Chief Executive Officer. Sandeep, why don't you maybe make some opening comments, talk about some of the upcoming milestones that you have, and then we'll go into the Q&A. Yes, my pleasure, Yatin. Thank you for hosting us and to Guggenheim for hosting this event and having us present here. So we are Tourmaline Bio. We're based right here in New York City. We are an immunology-focused company. In a nutshell, we came together in May of 2022 around a program that we licensed from Pfizer. It's an anti-IL-6 antibody that has, we think, really best-in-class potential here. Now, the IL-6 class has achieved a good amount of commercial and clinical success. However, we're taking advantage of new insights about the biology that have really only come to light in the last handful of years that we believe we are well-positioned to take advantage of. We went public via a first merger at the end of 2023 and are currently in the midst of running two phase II studies. Our two therapeutic area focuses are cardiovascular inflammation, which I think we'll talk about a bit, and then thyroid eye disease, where we think there's clear imminent need and a role for an IL-6 inhibitor. 2024 for us was a year of execution. 2025 is a year of data for us. So we're expecting data in our TRANQUILITY trial in Q2 of this year. That is our trial where we're looking at different doses of our drug, pacibekitug, and its ability to reduce a key marker of cardiovascular risk, namely high-sensitivity C-reactive protein. The trial was fully enrolled. In fact, it was over-enrolled as of December, as we announced, and we'll have data from that study in Q2 of this year. On the other side, we are also pursuing thyroid eye disease. As I mentioned, we're in the midst of our phase II-B spiriTED study, which we're guiding to data from that trial in the second half of this year, so two really important readouts that are coming up over the course of 2025. We're well-capitalized over $300 million in cash on the balance sheet, which funds us into 2027, so plenty of resources to execute on our current plan, as well as to add an additional indication, which we nominated recently. That's AAA, abdominal aortic aneurysm, where we're really excited about the potential to be not just first in class, but first in disease in an area with tremendous, tremendous imminent need and no approved medical options. We'll plan to start that study after we get data from TRANQUILITY and pick a dose, so a lot of things brewing this year. Got it. Very good. So maybe starting with the cardiovascular disease program, because that's where I think the key focus has been for our investor, at least. I mean, you have hosted some recent events where you highlighted some of the genetic and epidemiology evidence targeting IL-6 in cardiovascular disease. So could you just talk about what were the main takeaways, why this mechanism and this risk factor is becoming important at this time of development? Yeah, I mean, I think this is a really exciting time in cardiovascular disease where we have better tools to interrogate mechanisms for cardiovascular disease risk, but then also better tools and ways to actually reduce that degree of risk. Now, there have been a number of really big advances within the cardiology field, cardiovascular field over the previous decades. Of course, statins, lipid-lowering treatments are an important part of that. However, I think what's been well understood for literally decades, going back to the kind of first descriptions of atherosclerosis, is that atherosclerosis, that process of artery narrowing due to buildup of plaque, is not just a lipid process. It's been well understood that this is a chronic inflammatory process. We know that immune cells of different types, macrophages, take up lipids, really cause the formation, progression, and rupture of the plaque. But what's becoming more clear is that that risk may be modifiable by using mechanisms that can go after that underlying immune response. And so what we're trying to do is really conceptualize cardiovascular disease in a way that I think makes sense to most academic physicians, but could potentially be a brand new access for treating residual risk in patients who are on statins, have other risk factors well managed, but continue to have risk of having heart attacks and stroke. As you noted, that the evidence here comes in different flavors, which no one piece of evidence is going to yield the answer. The convergence here, we think, is really pretty impressive and consistent, whether it's the genetic validation for the target, which is important in cardiovascular disease, to build your confidence before you commit the resources to running a large outcomes program, to the epidemiologic data, looking at high-sensitivity CRP, which is an important biomarker of IL-6 pathway activation. It's also the primary endpoint for our study, which is a strong predictor of risk of future occurrence of major adverse cardiovascular events, and finally, the clinical trial data all kind of converges on this idea that IL-6 and the IL-6 pathway is an important or maybe the important node to target in reducing residual inflammatory risk that patients suffer from, so when we think about, we recognize that this is an area that is, I think, new to most folks on the street. So we've tried to do our part to help raise awareness here and hosted a webinar to go through the genetic validation. We did an Investor Day last month in December, sorry. We'll continue to feature additional presentations by our SAB at conferences to really raise awareness that this is sort of an axis of cardiovascular disease risk that just has been not well addressed to date. Got it, so on the risk factor, if we look at some of the other risk factors, whether it's Lp(a), where is CRP, hsCRP relative to some of these other markers? Yes. So I think this is what's important is that across any number of publications, hsCRP, again, a marker of inflammation and more specifically a marker of IL-6 mediated inflammation, is an important independent predictor of risk. Now, hsCRP is not pathogenic in itself. It doesn't cause cardiovascular disease, doesn't cause plaque formation or progression. It is a marker of inflammation. In IL-6, we believe, is very closely linked to it. There's no mechanism that we're aware of that can lower CRP more than a potent IL-6 inhibitor can. And we see that in the clinical data generated for our drug in Pfizer's hands, along with all the data for the class. So I think there's very strong recognition that this is an important marker and that IL-6 is an important way to modify it. You mentioned Lp(a). There are other risk factors here, which I think all speaks to the fact that cardiovascular disease is multifactorial. We have good treatments to date to go after blood pressure, good treatments to go after diabetes, good treatments to go after lipid levels and atherogenic lipids, including LDL, including Lp(a) that potentially could be coming. But these are all things we think are important. And the way the field's probably going to evolve is that for any given patient, those risk factors, the contribution of those may be different. We think having a targeted anti-inflammatory really could be an important way to modify what could be the biggest risk factor the patients have. There was a publication that came out in the New England Journal recently from Dr. Paul Ridker at the Brigham and Women's Hospital in Boston, who is truly the intellectual leader of this field. We're thankful to have him on our SAB as well. In that publication from late last year, they looked at the Women's Health Study and 30,000 women who had been enrolled in the trial and had 30 years of follow-up. In that trial, patients received a blood test and had three things measured, among other things in the trial, but LDL, Lp(a), and hsCRP. And what we see very clearly is that hsCRP is a very strong predictor of risk and even outperforms Lp(a) and even LDL in terms of predicting risk of MACE. Just further raising the question of, in someone who is already on a statin, what's the incremental benefit of a lipid-lowering treatment versus maybe we should be going after a different axis to really modify risk that has been poorly reduced so far? Got it. Very, very interesting. So with regard to the TRANQUILITY study, could you just walk us through the study design, how it is set up, what are the ultimate goal, what would you like to achieve? And also, I think you are testing them in CKD patients. Is there anything particular about the CKD patient that makes them ideal for proof of concept? Absolutely. I think those are all important questions. So we've been excited about the potential of this mechanism in CV for a while. So we've seen a number of publications, of course, supporting the role of anti-inflammatory approaches. There have been a couple of trials that have been run. And so we essentially started with some of those designs, the RESCUE trial in particular from ziltivekimab, which is in a number of outcomes trials being run by Novo Nordisk as a starting point as we think through what our trial might look like. So our trial has been designed largely similar to the RESCUE study. We did meet with FDA in November of 2023 to talk through our trial design, our plans before starting the study. The goals from the trial are threefold. One is to confirm we can dose every quarter. Pfizer, in their experience, tested every eight-week administration with a sub-Q formulation. We think our modeling supports going out to every quarter, looking at hsCRP levels from the trials and putting that into our model. So confirming we can dose every quarter. Two is to pick a dose that we'd like to advance for subsequent studies in CV. And then finally, from a safety database point of view, have enough exposure in hand so that we can use this trial and go directly into phase III on the other side of it. So we have good alignment with the FDA on that before starting this trial again, following a clear precedent beforehand. Now, in terms of CKD, this is where we chose a CKD population, folks who have stage 3 or 4, so moderate to severe chronic kidney dysfunction. As a means of running a more efficient study, we enrolled 143 patients in the study in just about seven months compared to a plan of 120. So the brisk enrollment is part due to just the sheer unmet need here, the sheer number of patients. But patients with chronic kidney disease tend to have high inflammatory markers as measured by an hsCRP greater than two. So as we think through the use cases here, it's been well known that patients with chronic kidney disease do have high risk of cardiovascular disease and high degrees of inflammation. Likely, these are all kind of tied together. So there's a high risk group of patients to be able to target. However, we think the potential applicability of a treatment like this could extend beyond chronic kidney disease patients, where irrespective of kidney function, if patients have a high CRP, they likely do have residual inflammatory risk that could be modified with drugs such as ours. So our plan for phase II is to be able to get the data in a CKD-positive population, help pick a dose, inform that relationship of what is the right dose to advance, how much CRP lowering do we see with that. At the same time, we're planning for phase III that does not necessarily need to be limited by whether patients have chronic kidney disease. Got it. Got it. So what would be the expectation? Number one, actually, is that do we know if there is a consensus on a particular percentage reduction in hsCRP that is needed to drive these benefits? One. Two, what would you like to achieve relative to what Novo has shown already? Yeah, certainly. So I mean, I think there's a lot of interesting and important parallels between the CRP lowering field and LDL lowering, where the way we think about LDL treatments isn't how do I get my patients' LDL reduced by 50% or 70%. It's usually a threshold. We're trying to treat to get people below 70 milligrams per deciliter or 55, depending on what the risk factors are. So this is where we think when we think of CRP reduction as well, the way to look at it may not just be as percent reduction, but maybe what percent of patients get below a certain threshold. The emerging view from leaders in the field is two milligrams per liter for hsCRP is the key threshold here, where in completed clinical trials, patients who achieve hsCRPs below that threshold appear to drive the most benefit. So when we look at our data from TRANQUILITY, we will look at CRP a multitude of ways, including the median percent change, but also the percentage of patients who achieve that critical threshold of two and fall below it. Okay. For the basically a responder rate, right, if you are below two, do we know what Novo has shown in? Yeah. Yeah. Right. So looking at the RESCUE trial from ziltivekimab, 82% of patients who were at the go-forward dose of 15 milligrams every month achieved that threshold of two or below. So our goal from the study is essentially to show that we can get comparable levels of CRP reduction measured both those different ways. There's no IL-6 inhibitor that we're aware of that has generated data with every quarter administration. So we will be the first company to show that. So that would be, we think, really important in a cardiovascular disease setting where we know that adherence to treatment can be a challenge. So drugs that involve less patient, caregiver, healthcare system burden with less frequent administration do appear to be preferred. We see that across either the PCSK9 inhibitors, even with the Lp(a) lowering treatments. I think there's a clear recognition that less frequent in a prevention setting really could potentially drive better real-world outcomes. Yeah. So outside of AAA, which I know is your second indication, in your primary indication, how much of a read-through there will be from Novo? Because my understanding is that Novo is running a very big program, three phase III studies, right? Do we need to wait for those data before you sort of finalize the plan? I'm just curious for you to articulate for me how much of a read-through, what you will be looking for, and I don't know if you have any crystal ball on when their data is going to come. Right. I unfortunately do not have a crystal ball, but I can tell you what I do know. Right. So I think when we look at the Novo program, they actually have four outcomes trials ongoing. These span different types of cardiovascular disease, one in an established chronic population. This is the ZEUS trial. Another in an acute MI population, ARTEMIS, so patients who are either 36 or 48 hours after having an acute myocardial infarction, so heart attack. And then the remaining two are in HFpEF patients, so heart failure with preserved ejection fraction. These are very distinct clinical entities, which I think highlights how broadly applicable an anti-inflammatory could be, not limited to any one subset of cardiovascular disease, which it's impressive to be able to launch four outcomes trials in parallel without yet having seen the results from any one of those studies yet. But again, I think this reflects the high degree of conviction, the convergence of evidence from the genetics, the clinical trial data, the EPI data, which all suggest that these are, we think, credible, rational, reasonable trial designs to pursue. So in terms of read-through, the ZEUS trial we think will be the first one to read out that should come kind of early 2026. We don't know anything that the public doesn't know already, but we estimate early 2026 is probably the timing on it. I think the read-through is important and clear given that it's a similar mechanism. We think what they're doing in ZEUS makes sense. It kind of builds on earlier studies using anti-inflammatories in cardiovascular disease. So we think this is a really reasonable, high-probability shot on goal to be taking. We, of course, will track that study carefully and see what the results look like. This is an example of where being second in cardiovascular disease, where we're talking about long lead times, big studies, being second presents real clear benefits. We see a number of companies and assets within cardiovascular disease really succeeding in overtaking the lead programs by being second, by being able to use the learnings from that first program to design better, tighter trials, whether it's slight tweaks, the inclusion-exclusion criteria, whether it's new endpoints, additional endpoints, whether it's overall trial sizing. There's ways to learn that we think we could incorporate into our trial design. The other studies will come later after the ZEUS trial begin. These highlight different ranges of indications where we could pursue. You had mentioned AAA. We are excited about AAA. This is yet another example of how we can differentiate with different strategy going into an area that no one has tested an IL-6 inhibitor in so far. So it is uncharted territory from that point of view, but the mechanistic rationale, the support of evidence from the genetics, the EPI, is all very quite clear. So the trial designs that Novo is pursuing, even the ones that we've proposed so far, are by no means exhaustive. This really is like a sea change in thinking about cardiovascular disease, not just a lipid or hemodynamic process, but as an inflammatory one that plays an important role. Got it. So then what is the path forward, right? So you start the phase II study in AAA once you have completed TRANQUILITY, and while you are formulating your thoughts around a MACE study that you're going to run? Right. Yeah, that's generally right. We're doing a few things in parallel here. First of all, we are focused on getting TRANQUILITY, the results out Q2. Things are on track for that. Again, we over-enrolled the study where the study continues on exactly as planned. No major changes to the dosing arms, addition or subtraction of doses. It's all on track. So Q2 is when we plan to have data from that study. In parallel, we are working with our CV SAB, which represents a really broad range of disciplines within cardiovascular disease, including imaging, bioinformatics, heart failure specialists. We have, of course, like Dr. Ridker, folks who are experts on atherosclerosis helping advise us on what a phase III trial would look like in our hands. And then in parallel with that, we are having discussions with potential partners about funding paths here, which doesn't necessarily rely all upon equity financing. As you can imagine, there's a lot of interest in cardiometabolic disease right now. And I think there's recognition certainly from academia and I think pharma as well that this is an aspect of cardiovascular disease that we've not well addressed. And there are very few targeted anti-inflammatories in mid to late-stage development. So we benefit the scarcity value here, we believe. Got it. Right. So our plan after we get TRANQUILITY is to pick a dose, use that same dose to go into a proof of concept trial for AAA at the same time, plan to go to the FDA, talk about our data, talk about our plans for phase III as we finalize what phase III will look like and how we're going to pursue it. Okay. Before I move to TED, one more question I have. So this is more on the safety side. So could you put in perspective the safety for IL-6 as it relates to its applicability in CV? I mean, there are certain IL-6 that have a black box. I don't know it is because whether they are approved in RA or not. But I'm curious for you to, for a broader adoption of a mechanism, how should we think about the safety? Certainly, so we think the safety is something that is on our side and something that we benefit from, just how much experience there is for IL-6 inhibition to date. Over a million patients have been dosed in commercial usage and clinical trials with this class, so we're confident that we're not going to get surprised with something that's never been seen before. Now, our drug in Pfizer's hands has been in nearly 450 patients already, and the safety here looks consistent with the IL-6 class. Those phase II publications from Pfizer are in the public domain, and the safety for doses of 50 milligrams and below, 50 being the highest dose that we're testing, we think looks compelling and appropriate for a CV population. Taking a step back, however, I would just point out that the benefit of any drug always needs to be weighed against the risk of that drug. We think there's potential here by going after a risk factor that's been poorly addressed to date. There's potential for an outsized benefit. In the CANTOS trial, we didn't talk much about, but with a related mechanism, reductions in IL-6 did track with reductions in major adverse cardiovascular events to the tune of 25%, 30%, 35%, which is really remarkable and astounding compared to any number of recent contemporary outcomes studies here. I'd also note that with other mechanisms, whether factor Xa inhibitors, these are drugs that do have black box warnings, yet it doesn't prevent their usage. It really does just mean physicians need to be a little bit more vigilant and understand what the risks are. But they do it because there's benefit. They know that. In the case of IL-6 inhibition specifically, of course, infection is the one thing that we all think about for any immunomodulator. Infection risk is always front and center on your minds. From previous trials, CANTOS being an example, there was a signal in terms of infection with IL-1 beta inhibition, IL-1 beta being upstream of IL-6. And so having a different kind of contribution of what pathways it blocks, where it's only a partial inhibitor of IL-6 signaling where there was a small increase in infection that was seen. However, the PI for the trial has commented that a lot of that risk appeared to be related to how the infection may present and that early institution of antibiotics was able to kind of mitigate that risk. So in the later part of the trial, that risk essentially went away. We take some comfort from knowing about the Novo program that we're not aware of any major amendments to the study, any changes in the dosing profile in the ZEUS trial. And of course, there was a subsequent decision to launch the other outcomes trials as well. So we're not trying to be cavalier on safety. It certainly is really important. But so far, we think overall the risk benefit profile has been in favor of the class. Very good. Very helpful. Maybe then a couple of minutes on the TED program. Where are we on the spiriTED study? Where is the enrollment? We're going to have data later this year. What should be our expectation there? Yep, certainly. So the spiriTED study continues on. We're getting to data second half of this year. We haven't given play-by-play guidance in terms of where we are specifically with enrollment. We do recognize there are a number of other competitive agents in the field. However, we continue to be very convinced that there's a role for an anti-inflammatory in what is clearly an inflammatory autoimmune disease. So we've been very careful to enroll patients who we think do have inflammatory active disease and could benefit from a drug such as ours. We benefit from how much class experience there is with IL-6 inhibition, mainly from off-label usage that suggests a profile that is well tolerated, that could be effective, and has appeared to have good durability from the previous reports here, which we think contrasts with some of the other mechanisms that we compete against that may address a part of the disease but may not go after the underlying basis of the disease. The history of autoimmune disease, inflammatory ones in particular, is to get control of the inflammation quickly, which is what we seek to do. Got it. Is there a particular bar there on proptosis or diplopia that you have to sort of meet? Yeah. I mean, I think when we look at the other agents that have reported phase III trials, it kind of ranges. If we're in that same ballpark, call it 60%-70% proptosis response rate, we think that would be an absolute home run. But when we speak with physicians who treat patients, what we hear from them very clearly is that proptosis response is not always present, and even when it is, it may not be the chief complaint that the patients have. And so, as we think through our TPPs, we presented on at our Investor Day in December. What we hear from physicians is a desire to treat the disease more holistically and have a treatment that they can use with confidence that it will control the disease, could have good durability of effect, and is well tolerated to be that first treatment option they want to try and keep the other mechanisms in their back pocket for refractory cases. Got it. Sandeep, that's all we have for you. Thank you so much. Great. Thank you for hosting again. Thank you.