All right. Good afternoon, everyone. Welcome back. My name is Yatin Suneja, one of the biotech analysts here at Guggenheim. Welcome to our inaugural Healthcare Innovation Conference. It is my pleasure to welcome our next presenting company, Tourmaline. From the company, we have the Chief Executive Officer, Sandeep Kulkarni, here with us. Sandeep, why don't you spend five, seven minutes? Just tell us the story of Tourmaline. What asset do you have? What are the indications you are pursuing? And what are some of the upcoming milestones? And then, you know, we'll dive into the Q&A session after that. Yeah, it's my pleasure, and thank you for hosting us and Guggenheim for having us at the conference again this year. So, in a nutshell, Tourmaline, we are an immunology-focused company based in New York City. In short, our goal is to develop medicines that have the potential to change standards of care, to really go after areas of high unmet need where we think we have something special that can define a new standard of care. We came together in May of 2022 around a program that we licensed from Pfizer, pacibucutog. It is an anti-IL-6 antibody that really does have best-in-class potential and differentiating features. It has a very long half-life, very low immunogenicity. Most of the data Pfizer had generated was with every eight-week sub-Q administration, which we believe we can push out to every quarter administration, which we're looking to do for certain of our indications that we are pursuing. The IL-6 class over the years has achieved a fair degree of commercial and clinical success. However, there's just a lot of new insights about the biology here that we are really excited about, and to pursue areas that pharma and industry has not systematically addressed to date or even studied this mechanism here until now. With the data we have from Pfizer, over 400 patients who've been dosed across phase I and phase, we're starting our development campaign already with a very good handle on how the drug performs, looking for areas where, again, we can either prove how our drug is best or potentially first in those areas. Right out of the gates, we picked two indications to pursue, ASCVD, atherosclerotic cardiovascular disease, as well as TED, thyroid eye disease, both of which are very different in their nature, but are complementary and have very large data sets evidenced to support use in both of those areas. We very much try to follow the breadcrumbs, you know, look for signals of activity, and be able to pursue that in a concerted registration-directed efforts. We're currently running two trials, one in ASCVD, one in TED. 2024 for us has been an execution year, but we'll have data for both studies coming up in 2025. The ASCVD, or Tranquility study, we'll read out in the first half of 2025. That is a PK/PD study looking at a biomarker endpoint, high-sensitivity CRP, which is a very good biomarker for IL-6 pathway activation. We'll read out that study first half 2025, and on the TED side, we're running the SPIRITED study, which is a phase II B trial, which we intend to be one of our two pivotal trials here, looking at two doses of drug versus placebo, and we designed it to be in line with other regulatory precedents here to serve for registration, so those data will come second half of 2025. We are well-capitalized. We've been public for just about a year now. We have over $300 million in cash on the balance sheet, which takes us into 2027. We are well-capitalized to be able to deliver data for both the indications that we are, that we are describing. Got it. Very good. So let's double-click on the CV side. I think you recently hosted an event where you, you know, outlined some of the genetic evidence for targeting IL-6 in CV. So first, could you summarize to us the key main takeaways from that presentation or the event that you hosted? Right. So, we're really excited about the potential to use an anti-inflammatory in cardiovascular disease. Cardiovascular disease is a set of indications. There's not a single niche here, but a lot of different indications which are united by common biology. Now, many of those indications involve atherosclerosis. Mm-hmm. Right. So this is the process of forming plaques in the blood vessels, progressing, then leading to heart attack, stroke, all the complications you might imagine. It has been well, really well understood over the last several decades that atherosclerosis is fundamentally a chronic inflammatory process. Yes. Right. Of course, lipids play an important role, but the immune system is critical for again, plaque formation, plaque progression, plaque rupture. Now, when we look through like why we think IL-6 makes sense here, the evidence really comes in three flavors. First is the genetic validation, looking at Mendelian randomization studies, other means of building a causal inference that this mechanism is causally related to atherosclerosis and other CV outcomes. The second area is the strength of the epidemiologic data, looking at hsCRP levels as a predictor of cardiovascular events, hsCRP being a strong marker of IL-6 pathway activation. And then finally, the clinical trial data. So as you noted, we did host a webinar a couple of weeks ago to go through that first pillar. I mentioned the genetic validation here, which we think is very important and to de-risk novel mechanisms, especially in CV. We host the webinar in part because I think investors understand a bit more how to understand the epidemiologic data and the clinical trial data. But the genetic validation is, it's an emerging field. And so we want to make sure that we really explain why this is important and how to interpret that evidence here. So in our webinar, our goals were threefold. One is to explain what is genetic validation, what it means, what it doesn't mean. Two is to explain how that's being used to prioritize medicines and targets for in cardiovascular disease, and then finally, to just go through the abundance of data for IL-6. Yeah. From a genetic point of view to validate this as being an important target within cardiovascular disease. When you look across those publications, it's not just one or two publications, but several publications. In fact, we are working on additional ones as well across pretty much every CV indication. You see just this consistency effect suggesting that inflammation matters. And more importantly, IL-6 inflammation does drive that. So what exactly are the genetics saying? Like, what is the evidence? Is there a certain type of polymorphism that is driving? Just, like, explain, like, high level, like, what's driving it? Sure. So, the genetic evidence, this goes beyond just a general association between certain polymorphisms and an outcome of interest. But. Yeah. Using certain techniques, including Mendelian randomization, we can infer a causal relationship. So. I see. The analyses look at polymorphisms in the IL-6 receptor that are not naturally occurring but are associated with a decreased level of signaling through the pathway. Yep. We see that in people who have these variants, they tend to have slightly lower levels of CRP. Mm-hmm. Again, suggesting that this polymorphism is leading to a functional implication in activation through the pathway. Now, these polymorphisms essentially, like, mimic a weak inhibitor of IL-6 signaling. Mm-hmm. Right, where even small decreases in signaling in the pathway can be seen to be associated with decreased risk of cardiovascular events, namely MACE in the context of ischemic heart disease. Yeah. Ischemic stroke, AAA, any number of sub-indications here, which all infers that this pathway is causally related to those outcomes, which that in itself doesn't tell the whole story. It's really that data in the context of the clinical trial data, the epidemiologic data all holds together very tightly. So this convergence of lines of evidence we think is really quite robust. Got it. Also, can you maybe then talk a little bit about the CRP? Because that also is a risk factor, right? I mean, I think there is some recent data that talks about alpha-little A and CRP. Yeah. In fact, higher, better correlation with CRP. So just put that in context, because in the end, blocking IL-6, you're measuring CRP levels. So that gets downregulated, right? So just talk about that whole dynamic. Right. So CRP is a liver-produced protein that is a marker of inflammation and more specifically a marker of IL-6-mediated inflammation. Now, CRP is not a risk factor in that CRP is not directly pathogenic. Mm-hmm. It is a risk marker, okay, again, of inflammation, namely IL-6-mediated inflammation. Now, there's been decades-long research looking at CRP as a predictor of future MACE events. And what we see very clearly across all of these publications is, higher levels of CRP, again, a predictor or a marker of inflammation predicts a higher likelihood of cardiovascular events occurring. There was a recent publication in the New England Journal, which we think did a really nice job of showcasing the importance of inflammation vis-à-vis other risk factors that just have gotten a lot more attention and interest over the last few decades. So in this publication from the New England Journal, the authors looked at three risk factors: LDL, Lp(a), and CRP. This is based on 28,000 women who enrolled in the Women's Health Trial in early 1990s and have been followed now for 30 years. Over that timeframe, we see some very important trends develop. First of all, these three risk factors, Lp(a), CRP, and LDL, each are predictors of cardiovascular risk in otherwise healthy population, which is important to note. The other thing that we think is really particularly worth you know worth flagging is the fact that CRP appears to outperform these other risk markers in terms of predicting occurrence of major adverse cardiovascular events here. So folks who are in the highest quintile of CRP had a 70% greater risk of major adverse cardiovascular events over the 30 years of this study here. We think the call is quickly going to become to be for not measuring just LDL levels, but measuring LDL, Lp(a), CRP to get a more comprehensive assessment of how much risk someone has. Okay. So this, so is there a, it seems like there is not only a threshold effect but a concentration effect. The higher the level of CRP, you do get, you know, especially in that CANTOS trial, you get higher risk. Okay. Then also, I think CANTOS had some interesting findings, right? Can you put that in perspective? And then we're going to discuss, you know, what Novo is doing, how your program is set up for that, how your Tranquility is set up. Right. It's our pleasure. So the idea that, as I mentioned before, it's been long recognized that atherosclerosis is a chronic inflammatory process. There's been longstanding interest in identifying means of drugging that inflammation to reduce atherosclerosis. Now, there have been a number of mechanisms that have failed here, in fact, in this idea of going after inflammation. However, one of the signals that's come out is mechanism does matter here, and mechanisms that lower CRP have been associated with real benefit. Now, the first real big clear demonstration of that was the CANTOS study, which you alluded to, looking at canakinumab, which is an anti-IL-1 beta antibody. IL-1 beta sits upstream of IL-6 and blocking IL-1 beta is a partial inhibitor of IL-6 signaling. Now, that study is viewed as a, like a watershed moment in the field in that it did show a stat-sig benefit of 15% risk reduction using canakinumab in that trial. Now, that 15% risk reduction, again, was not associated with lipid decreases or blood pressure decreases. So, it was a very clear demonstration that a drug that works via an anti-inflammatory mechanism can lead to real reduction in cardiovascular disease risk. Now, in the CANTOS trial, the authors did try to dissect out what predicted the benefit, who benefited the most from IL-1 beta blockade. In the study, in subsequent analyses, which have been pre-specified that were reported on after the primary endpoint had been met, is that the patients who derived the most benefit from CANTOS were the ones who had the deepest reductions in CRP and IL-6 levels, raising the question or at least offering the hypothesis that blocking IL-6 directly may be more efficacious than blocking IL-1 beta. So it's but those data, again, don't exist in isolation from. Sure. The other pieces that included the genetic validation and all the work that's been done on CRP to date, so it all holds together, all really begging for a definitive study to finally prove this point. Yeah. So if you put all of this together, you know, CRP as a, as a risk marker, right, or as, it becomes a little bit more clear. How was the data in these patients in that CANTOS study that had deepest CRP reduction? Was it also 15% or was higher? It was deeper, so that 15% was at the ITT level. Overall. However, in the patients who achieved the deepest reductions in CRP and IL-6 levels, it was more like a 25%-35% risk reduction. That was for three-point MACE. Sure. Yeah. And looking at cardiovascular death reduction was even more impressive. Okay. Very good. Thank you for putting that in perspective. Now, Novo has an IL-6 program. How is your molecule differentiated relative to Novo? What led Novo to go into these very, very big phase three studies that they're running, like multiple phase three studies that they're running? Yeah. So, as I'll just note again, like, we think this is like a really exciting time within the field where, you know, we've all seen the benefits of lipid-lowering treatments. However, I think what we all see is there may be diminishing marginal returns as we continue to kind of go after the same set of risk factors or risk predictors. So to be able to go after a like a new mechanism in an area this big, we think really could lead to outsized benefits, at least has that opportunity. So, you are right. Novo is pursuing ziltivekimab, an anti-IL-6 antibody in a number of outcome trials, the first of which we think will read out data either late next year or early 2026 based on their public disclosures. We think the trial makes sense. We're excited to see the results from it. But what we note is that they are running multiple outcomes trials in parallel, including in heart failure, in acute MI, where the mechanistic hypotheses are a little bit different. But again, I think this showcases just how broadly applicable this could be to the extent that inflammation matters on blood vessels, matters on the vasculature. This really could apply pretty broadly across any number of cardiovascular and other vascular disorders. Their testing and their studies in every month delivered drug, our drug from the get-go is that we think we already have data in hand that shows we can dose every eight weeks from the Pfizer experience of previous phase one, phase II trials. Mm-hmm. In our Tranquility trial in CV, we are looking to every quarter administration here, and so I point this out because less frequently administered drugs in cardiovascular disease, we think, are a particularly important. Right. Advantage we have where we're talking about disease prevention, not treatment. Adherence can always be a challenge, so a drug that can be given four times per year in high-risk patients, we think, presents a very clear advantage over them. Now, I'll also add that this is a massive area. There's a lot of different indications to go into, and so we're not resting just on having a long-acting antibody alone to differentiate. Yeah. We think there's any number of ways within our clinical trial designs, our clinical strategy to be able to differentiate the drug within the areas Novo's pursuing. But there's a ton of white space, new indications where no one to date has tested an IL-6 antibody where we think we could be first. So Novo jumped into these big studies, but they never ran a study in patients, right? So what was the hypothesis? Is it the same hypothesis that you are relying on all these data that gets generated? There is a link to higher CRP level? Yeah. The ziltivekimab program was in a phase two trial, the RESCUE. Mm-hmm. Study, which was read out in 2020. Now that trial was essentially the basis for our Tranquility study looking at. Right. Patients with CKD, chronic kidney disease stage three or four and who have an elevated CRP of two or greater. Their study also was a PK/PD trial looking at reductions in CRP. It was on the back of those data that Novo acquired the company, picked a dose, and then moved into the outcomes studies here. So at this point, we benefit from there being a well-established or established regulatory path where a modest size phase two trial can allow us to achieve three things: confirm we can dose every quarter, pick a dose to move forward into later stage trials, and then three, be in a position to be phase three ready right at the time that there are these really important readouts starting to come out from others. Got it. So for your Tranquility study, what is this study? Like how many patients? Yep. I know you're doing quarterly. There is a monthly. What exactly you would want to show if you can sort of just help us frame the expectation and also compare and contrast to what, Novo, not Novartis, Novo showed in the RESCUE study? Sure, so we met with FDA in November of last year to talk through our Tranquility trial design. The goals of the study are threefold, as I mentioned. One is to confirm we can dose every quarter. Quarterly. To pick a dose. And then three, be phase III ready from a safety exposure point of view. We have good alignment with the agency on those three goals, of course, pending success of the trial. It is four arms, three active arms versus placebo where we're testing two arms looking at quarterly administration, one arm looking at monthly administration, and then against placebo. The primary endpoint here is change from baseline in hsCRP at day 90. However, we are looking at other lab-based endpoints as well, including Lp(a), fibrinogen, all the safety labs as well. We'll be studying that, following that as well. So, data from the study were expected in the first half of 2025. It's 120 patients in total, 30 patients per arm here. So we'll plan to report that first half next year. What is the level of CRP for these patients if we have to sort of think about just baseline? Right. These are CKD patients, right? Correct. Yes. So CKD has been well established that patients with CKD tend to have inflammation. In fact, inflammation may drive a lot of the adverse outcomes they see, including the cardiovascular events that CKD patients are at high risk of suffering from. The inclusion criteria for our study is patients with CRP between two and 15. Now we've capped it on the high end to exclude out any unwanted effect from patients who don't necessarily have the chronic low-grade inflammation we're trying to target with the drug like this in this context. But those we're trying to exclude out patients who may have background immune autoimmune disease happening. So, though, I mean, frankly, I think an IL-6 antibody would work and benefit patients who have frank autoimmune disease as it has for RA, for giant cell arteritis, any number of other conditions as well. However, the group of patients that we're looking for tends to have like CRPs more like in the two to 10 range. Okay. Two to 10 range. So I think there are two things, maybe investors are looking at. So one is a percentage change in CRP and then the responder rate, right? Yeah. How many are below two? So I think Novo data is somewhere around 88% at the dose that they're using in the 50, in the phase III. Right. So what exactly is the bar, like about 85%-ish reduction in CRP, that you have to show? Yeah. So, I look at it a couple different ways. I mean, the change, the primary endpoint is the same as what's been used by others. Right. Percent change in median CRP. So we will look at that. You are right that the CRP was 88% for the Novo trial at the dose that they're advancing, that have advanced into phase three here. So that is like one benchmark. The other thing I think is important to look at is the responder analysis looking at percent of patients who achieve a CRP of two or less. Two is emerging as the kind of consensus view on like where most of the risk is mitigated if you can get to that level. We think the responder analysis actually is more clinically relevant and easier for a physician to understand, for patient to understand, you know, do I achieve my threshold or do I not? In the same way with LDL, we don't think about, you know, what is the percent change for someone who gets on a statin. We think about it more as who achieves the guideline. Threshold of 70 or 100, yeah. Threshold 70, 100, depending on who the patient is. So we think both ways are important to look here. We don't think, when we think about athero, it is a chronic process. So patients will likely need to be on a drug for years to benefit. We see that in the Women's Health Trial that you see the effect of inflammation compounds over the course of, you know, decades, 30 years in that experience. So picking a dose that is safe, that's tolerable, probably matters more than trying to eke out every single percentage point of CRP reductions. But it is a PK/PD study. We'll get the data, be able to look at that with our team, with our external advisors. Of course, we'll take that to the agency as well and make sure we pick a dose that makes sense for subsequent study. So somewhere in this ballpark is where, you know, 80, whatever the number is for. Yes. If we can achieve that with every quarter. Quarterly. Quarterly administered product, I think that would be a great outcome. You have enough follow-up on these patients to fit a line for to show that it's a 90-day half-life? Not, not a half-life, that you can dose on a quarterly basis. Yeah, so we, first of all, even before the study, we benefit from how much data Pfizer had generated over 400 patients. Mm-hmm. In phase I and phase II, including one of their trials in Crohn's disease where they did dose out to week 48, so we do already have longer-term dosing data in hand. From our Tranquility trial, we will dose patients for six months. Six. and then follow them for six months afterwards for safety. This readout will be at what time point? The primary endpoint is at day 90. 90. So roughly, after three months. So that's what you're gonna show. Okay. Very good. So these data are coming in the first half. Have you said anything about the enrollment? How is that going? I know you reiterated that it's coming in first half, but how is the enrollment? Right. So we've started the trial earlier this year. We dosed the first patient in May. It's roughly a year-long trial to get from first patient in to data. So, all we've said is that we're on track with enrollment. All right. Very good. I think maybe just maybe a couple minutes on the TED program. Where are you on the, on the TED side? You know, I think you've said that the data are gonna come in the second half, but there is another study that you're supposed to start. When is that starting? Just, Right. Bring us up to speed. Yeah. Absolutely. So, TED, we are conducting the Spirited trial again, a phase II B study. We've guided for data from that study in second half of 2025. We're really excited about TED as well. It's testing a different hypothesis relative to what we're doing in CV, but part of the beauty here is that we think we can present two indications with very different underlying biology, but all is unified by IL-6 being relevant in both, supported by strong data sets in both. So data from Spirited, second half of 2025. We've guided to starting a phase III trial, which will be our second pivotal study in TED by end of this year. We are all capitalized to be able to run that trial. So we are on track to start by end of year. By end of year. 2025 is gonna be a big year for you guys. Tranquility and then TED both. That's right. All right. I think that's all I have for you, Sandeep. Thank you so much. Great. Thank you. Thanks for hosting. Thank you. Thank you.