All right, let's get started. Good afternoon, everyone. Thanks for joining us here at the Leerink Partners Global Healthcare Conference. My name's Tom Smith. I'm one of the senior biotech analysts here at Leerink. It's my pleasure to introduce our next company up on the stage here with me. We have Tourmaline Bio and CEO Sandeep Kulkarni. Sandeep, thanks for joining us. Thank you for having us. Awesome. Big year for the company. Obviously, with your IL-6 pacibekitug, you have multiple ongoing phase II programs. We're going to see data from phase II Tranquility Study and then data later this year from the phase II-B spiriTED Study. Two different indications, but big data year. Maybe for those in the audience who may be a little bit less familiar, Sandeep, if you could just kick us off with some introductory comments and what you guys have been up to at Tourmaline. Yep, yeah, it's my pleasure. Again, thanks, Tom, for hosting us and Leerink for having the conference again here in Miami. It's so nice to look out the window of your one-on-one room and not see a brick wall in Midtown. Thank you. We are Tourmaline Bio. We're based in New York. We're immunology focused. Our company came together in May of 2022 around a program that we licensed from Pfizer, an anti-IL-6 antibody pacibekitug that, even in the early phase I and phase II studies that Pfizer had conducted, already declared itself to have what we think is best-in-class potential there now. The IL-6 field benefits from a lot of understandings about the biology. However, there are new insights that we believe we're in a good position to take advantage of. This reflects the importance of IL-6 biology in any number of indications supported by very strong lines of evidence that span different types. Strong clinical data, strong genetic validation for the target, translational work, epidemiologic work, all kind of pointing to the importance of this pathway across any number of disorders. We are going into two areas right off the bat. Cardiovascular inflammation, as you alluded to, is our first area, which will have data from our Tranquility Trial in Q2 of this year. We'll talk more about the trials for more detail. The second indication we're pursuing is thyroid eye disease, where we're conducting a phase II-B spiriTED Study, which will read out in the second half of this year. These are different indications. However, they are unified in the biology of IL-6 being relevant in both these indications. 2024 for us was an important year of execution. 2025 is the year of data. We are excited for a couple of potentially transformative readouts coming later this year. That's great. Yeah, I want to talk about your expectations for each one of those individually, but maybe we could start just taking a step back and talk about it. It feels like one of the emerging themes within the entire cardiovascular landscape has been this idea of inflammation reduction likely translates to improved clinical benefit. Where does targeting IL-6 kind of fit into all of that? You alluded to the large number of data sets that are emerging across each one of these factors. Just talk about kind of where we are, maybe using a baseball analogy in terms of, I guess, level of conviction that using IL-6 is going to get you there. Right, sure. Yeah, which, I guess, which inning of the game are we in? Right. I mean, I think this is a really exciting time in cardiovascular disease where we have good treatments to reduce occurrence of major adverse cardiovascular events or MACE, meaning heart attack, stroke, cardiovascular death, revascularizations, et cetera. However, patients still continue to experience and die of cardiovascular complications. It really isn't a stretch to say that cardiovascular disease, broadly defined, is the greatest cause of global disease morbidity and mortality. Now, I think the field has rightfully been focused on lipid lowering as a key strategy here to reduce occurrence of heart attack and stroke. However, what's been known for decades is that inflammation is important. I mean, and this is true across any number of types of cardiovascular disease. I mean, when we think of cardiovascular disease, again, it comes in different flavors. Atherosclerosis is certainly a very important component of it. This is that process of plaque formation, plaque progression, plaque rupture that leads to the complications that we all know as being stroke, heart attack, limb amputations, et cetera. That process of atherosclerosis has been very clearly shown to be a chronic inflammatory event. It's really hard to separate out the role of the immune system relative to LDLs. We know that they all work together to kind of cause the events that we're most concerned about. Now, what's newer is not the insight that inflammation is a predictor of cardiovascular disease risk. The part that's newer is how exactly can you go about drugging inflammation? How can you use an anti-inflammatory to improve cardiovascular outcomes? There really is an overwhelming body of evidence that continues to grow, seems like every week with new publications coming out, implicating inflammation and pointing to different pathways. Now, we think IL-6 is the pathway that has the most validation that comes in any number of types of evidence. The genetic validation for the target, looking at naturally occurring polymorphisms in the IL-6 pathway that are associated with a decreased risk of cardiovascular events, applying a causal relationship. There is very strong epidemiologic data looking at a key marker of IL-6 pathway activation, hs-CRP, high sensitivity C-reactive protein as a predictor of risk. Finally, the clinical trial data all very clearly points at IL-6 as being an important node to be targeting within this inflammatory context here. It is, in some ways, hard to kind of build a model to fully capture the fact that this could be a sea change in thinking about a brand new axis of risk and set of treatments that could modify what we think could be the most important risk factor that patients may have after being on other standard care agents. Yep. When you talk about most important risk factor, I guess I think back to kind of the second half of last year, we saw a late-breaking presentation at European Society of Cardiology, a company with New England Journal publication from Dr. Ridker. I know Dr. Ridker has actually joined your scientific advisory board. Maybe if you could just high-level cover that data set and put that in perspective, because I know we looked at a lot of different markers there. We looked at LDL. We looked at some of these other lipid markers and inflammation, very strong relationship here with outcomes. Right. You're right. Dr. Ridker is on our SAB. We are tremendously fortunate to have someone of his experience helping us think through these important topics. There really is no one who has been a bigger proponent of the field and really kind of shined the light on how to go after inflammation within cardiovascular disease. The publication you were referring to was presented at ESC and published in the New England Journal. It comes from 30 years' worth of data from the Women's Health Study, which looked at 28,000 women who at that point had no evidence of cardiovascular disease and looked at the predictive power of three biomarkers. HS-CRP, again, a marker of IL-6 pathway activation, an important marker of inflammation. Two, LDL levels, what we all know and track and know and track very well. And then three, Lp(a). What you see in the Women's Health Trial as published was HS-CRP, again, a marker of inflammation, was the strongest predictor of occurrence of major adverse cardiovascular events, irrespective of what quartile of risk you were in, all pointing to the central importance of inflammation here as being the orchestrator of what we know to be the adverse kind of complications of cardiovascular disease. That publication was, of course, important. However, it doesn't stand in isolation. There were other publications, including from the CLEAR Outcomes Trial, testing bempedoic acid, looking at CRP vis-à-vis LDL levels in patients who are already on statin treatments or maybe on other means of lowering lipid levels, where CRP continues to be a strong predictor and maybe even a greater predictor of risk compared to LDL levels here. It all kind of works together, just suggesting that this is an axis of cardiovascular disease risk that just has not been well addressed to date. We think we're finally kind of at the point where this field's just about to take off. Right. OK. Yeah, that continues to set the stage for your IL-6 inhibitor and the role pacibekitug could have in the marketplace. I guess if we're looking out across the other IL-6s that have generated data, either in ASCVD or at least looking at reductions in CRP levels, I think most are familiar with Novo's ziltivekimab that they acquired via Abcentra. Also, CSL has an IL-6. How does pacibekitug stack up versus these other IL-6 compounds? Right. Again, we license our antibody from Pfizer. It comes from the Medarex platform. It is a fully human long-acting IL-6 antibody. In phase I and phase II, Pfizer tested the drug looking at a sub-Q formulation given infrequently. In phase II, Pfizer tested every eight-week sub-Q administration, which itself is already a first for the field, where this is the only IL-6 pathway inhibitor that we're aware of that has generated data and reported clinical data with every eight-week administration. All the other regimens that either have been approved or have been in development have tested more frequent administration with the longest interval every four weeks. Already eight weeks is unique relative to the field. In our phase II Tranquility Trial, we're testing every quarter administration supported by the strength of the PK/PD modeling. The antibody is a fully native human construct. There's been no FC engineering. The half-life is naturally occurring as a long half-life. We have seen a very low rate of ADAs to date. When we look at any attribute, really, this antibody does appear to have the cleanest profile with the least frequent dosing that we have seen to date. In the context of cardiovascular diseases, we know that adherence can be a challenge when it comes to preventing disease, not just treating disease. There is a clear belief in the cardiovascular disease community that less frequent administration can drive better adherence, and by virtue of that, can drive better or the potential for better real-world outcomes. We see that with either the PCSK9 antibodies, Lp(a) lowering treatments, where a longer dosing interval is believed to help drive better adoption eventually. With every quarterly given drug four times per year, we think that presents a very clear advantage over some of the other treatments here. Taking a step back, I mean, this is a massive set of indications. ASCVD itself is not just a single disorder, but it is really a collection of 20 or 30 different indications when we think about either vascular territory affected, comorbidities, time since onset of disease. Any number of ways to kind of slice and dice it, where we're talking about tens upon tens of millions of patients globally that could benefit from a treatment like this here. You pointed out the Novo Nordisk ziltivekimab program is one we track very closely. They're currently testing their antibody in four separate outcomes trials, not limited to patients with atherosclerosis, but also looking at heart failure with preserved ejection fraction. Again, I think showcasing just the breadth of applicability of an anti-inflammatory, not limited to atherosclerosis, but also applying in other areas of high unmet need. We think they've designed good studies. We, of course, track it very carefully. However, what they're doing is not exhaustive here. We are working with RSAB to think through how we might do certain things differently, either look at endpoints a little bit differently, go after different patient populations. In a field like CV, being second actually poses certain benefits and important benefits by having a chance to see the first programs, be able to learn the lessons from those, and apply those to our program. We've seen this play out for other programs in the CV field here. Overall, we're really excited by the opportunity here and working on how we might do things a little bit differently than how Novo is doing it. Yeah. It seems like quite a bit of white space in the overall landscape. That is exciting. A few questions on Tranquility. You talked about top-line data in Q2, so within just a matter of months here. Maybe you can start talking just about trial design, the patients that have been enrolled into this study relative to some of the other IL-6 ASCVD studies. You actually over-enrolled this study. What do you attribute the over-enrollment to? Yeah. We launched the Tranquility Trial in 2020. We dosed the first patient in May. The design of the study is largely based on the design for the ziltivekimab, the Novo Nordisk phase II program called the RESCUE study. We initially set out to enroll 120 patients in the trial. We ended up over-enrolling the trial, 143 patients in just about seven months, so a brisk enrollment there. We are restricting the trial to patients who have chronic kidney disease, stage III or stage IV, as well as those who have an elevated inflammatory marker of hs-CRP greater than 2. The patients will then be randomized to one of four arms, placebo versus one of three dosing arms, two of which test quarterly administration, one testing every month administration here. The primary endpoint is change from baseline in hs-CRP, again, a marker of IL-6 pathway activation at day 90. We'll look at CRP a number of different ways, including not just in terms of the median percent reduction, but also in terms of a responder analysis, folks who fall below a key threshold of 2 mg/l for hs-CRP. Looking at responder rates is, in many ways, already standard practice for any number of cardiovascular disease risk factors, whether it's A1C, whether it's blood pressure levels, where we think about less is what was the percent change and much more about did I get my patient to the target threshold here or not. Look at those different ways. We'll track other biomarkers, things like Lp(a), fibrinogen, things that are well established to go down when using IL-6 pathway blockers. Safety will be tracking for that as well. Data coming in Q2. Yep. That's great. Just on Tranquility, we don't have visibility into patient baseline characteristics, but relative to the patient population you were targeting, how does that compare to RESCUE? Yes. We have been really careful to enroll a patient population that reflects who we would look to go after in future studies. Now, we are enrolling CKD stage III/IV patients. However, for a subsequent phase III trial, we would not necessarily be restricted to that group of patients. We have met with FDA before starting our study and have good alignment on that. The truth is, irrespective of CKD status, if you have a high CRP, you likely have residual inflammatory risk that could be addressed with an IL-6 pathway blocker. For the purposes of doing a phase II, we did enroll a CKD stage III/IV population for efficiency of design. CKD patients tend to have high CRP levels. That is one of the reasons why we were able to enroll the trial as quickly as we did, in fact, over-enroll the study. In terms of first to RESCUE, again, we looked at their trial as a blueprint for how to start. There are a couple of notable differences that are worth pointing out. In the RESCUE trial, they mainly enrolled stage III/IV patients. However, there were a single-digit% of patients who had stage V chronic kidney disease. They may not have been on dialysis, but had an eGFR kidney function that qualified as being stage V here. We restricted ours to a population who have stage III or IV chronic kidney disease. By and large, it's a similar patient population, but again, slight differences there that we don't expect to have a meaningful impact on the overall study. That's great. Yeah, how should we think about expectations on the top-line readout relative to what we saw in RESCUE? I think they saw around an 80% CRP reduction. You have three different dose arms, two quarterly, one monthly. Maybe just your expectations in terms of dose response, what you're looking for there. On a sort of absolute basis, what's a good number for you on hs-CRP reduction? Sure. IL-6, the cytokine, not the receptor, the cytokine is expressed at very low levels. This means that small doses of drug given infrequently can adequately cover the target for the entire dosing interval. We benefit from how much data Pfizer generated with this antibody across phase I and phase II studies, looking at a range of different clinical settings, healthy volunteers, patients with RA, patients with lupus, patients with Crohn's, who span a range of baseline hs-CRP levels. What we see across all of those trials is rapid and deep reductions in CRP, well sustained for the dosing interval here. Now, we've taken all that data, plugged it into a PK/PD model, and then essentially simulated what our drug would do with the frequencies we're testing, with the doses we're testing, and what the impact on CRP is in a more CV-style population, folks who have CRPs that are not indicative of a high-grade autoimmune disease, but more indicative of a low-grade chronic simmering inflammation, more like CRPs between 2 and 10. Whether looking at percent reduction in CRP or the responder rate, we would expect, based on modeling, to be very much in the ballpark of where Novo and CSL were with their program. Call it 80% plus reduction in CRP, 80% of patients who achieve that key threshold of 2 or less in that range. Now, I'll point out that for both the Novo program as well as the CSL program, they, in fact, picked the middle dose to advance into phase III relative to what they tested in phase II, all highlighting the importance of this not just being about how to reduce CRP by 90% or 95%, whatever it is. Atherosclerosis, heart disease, these are chronic diseases and likely require lifetime exposure or long-term exposure to a treatment to really modify that important risk factor here. When we look through our Tranquility data, it really is we'll be looking at CRP any number of ways, other biomarkers, and safety, of course, to make sure we pick a dose that is appropriate for long-term administration, again, to manage what likely would be a chronic long-term risk factor. Yep. That makes sense. I mean, it's going to be the balance and 80/80 like that. Safety tolerability also needs to check out. That has come through very clearly in our KOL checks as well. Yeah, it has to be a clear and positive trade-off. Just in terms of, I guess, how you might be thinking about next steps, kind of post Tranquility readout, I mean, you've named a third indication, what we call AAA. Yep. I guess, what would be the timing of moving this into a next step cardiovascular study? Then we'll talk a little bit about the thyroid eye disease opportunity. Yeah, certainly. On the CV side, we have three workstreams ongoing in parallel. First and foremost is getting Tranquility read out on schedule in Q2. Things are well on track. The trial is completed. Enrollment did in Q2. We're confident in time. We're excited about getting those data out. In parallel with the Tranquility work, we're working with our CV SAB on thinking through what a phase III trial in atherosclerotic cardiovascular disease would look like. There are a few different flavors here. Again, Novo is pursuing a particular path. There's an earlier study, the CANTOS study from Novartis, that also is a reasonable high-probability design that we could pursue. We're working with our SAB on how to do things a little bit differently than how Novo is doing it so far. As I mentioned before, ASCVD is a big set of indications. Coming up with nuanced trial designs is something that we're excited about, and we're working with our team on that. Third is that we're planning for a proof of concept study in AAA, so abdominal aortic aneurysm, that we're excited about because of the different lines of evidence that do support using an anti-inflammatory and specifically an IL-6 blocker in AAA. The genetic evidence, the epidemiologic data, the translational mouse experiments all suggesting an important role for IL-6 here that presents for us not just a first-in-class opportunity, but a first-in-disease opportunity. This is an area of just tremendous unmet need, given that there is no medical treatment that's been shown to stop the growth of AAA. The options are really watch and wait, keep imaging, and then eventually, when it gets big enough to intervene with surgery and prevent what otherwise would be a fatal catastrophic outcome. Those are three things that we're pushing forward in parallel. Our plan is, once we get data from the Tranquility trial, we'll work with our team, our experts, on picking what dose is appropriate for future development of cardiovascular disease. It would likely be the case that the dose that we would advance in ASCVD would be the same thing that we would advance in AAA. We would be able to move that quickly into our proof of concept trial for AAA. We'll plan to meet with FDA in the back half of this year to talk through our phase II data, as well as our phase III plans for ASCVD while we do more of the work about how to actually operationalize it. We recognize that cardiovascular disease and ASCVD in particular requires long trials. They're big. They're expensive. We have a number of really good options here that do not involve only relying on equity capital to be able to do it. As you might imagine, the cardiovascular disease space has gotten a lot of interest from pharma of late. I think the GLPs, semaglutide, tirzepatide as examples, MariTide, have really gotten people excited about going after large indications with real unmet need that could be addressed here. The data for the GLPs does suggest that they work partially via an anti-inflammatory mechanism, which then raises the question of how can we do better, how can we go after different patients, et cetera. We are having a number of conversations with potential BD parties. I would say the engagement's been quite good, and we're excited to get our data out and then be able to accelerate those conversations and be able to make sure we pick the right path here to get the medicine to as many patients as possible, as quickly as possible. Yeah, that makes a lot of sense. Across these parallel workstreams, we also have the Novo study, the large cardiovascular outcomes programs that they have in place. I think it's more than 24,000 patients that are enrolling across the totality of their ziltivekimab cardio program. We could get data potentially as early as 2026, I think, is the current thinking around timeline. Obviously, they're outcomes-driven studies. What do you guys think of as, I guess, clinically meaningful risk reduction that would therefore give you the confidence? I guess, where do the Novo results factor into your next steps in cardiovascular disease? Right. Taking a step back, when we think about the clinical trial data, I mean, this is what we think is really exciting, where it is rare to go into a first-in-class readout for a new mechanism in CV with this degree of conviction that it should work. We can look at the CANTOS trial, which tested canakinumab, an IL-1 beta antibody, IL-1 beta being upstream of IL-6, and a partial inhibitor of IL-6, signaling that was tested in an ASCVD population, secondary prevention, showing a 15% risk reduction on three-point MACE. Now, 15% risk reduction compares favorably with other novel mechanisms, including PCSK9 inhibitors and the FOURIER or ODYSSEY trials as an example here. Now, all of the data for CANTOS suggested that the determinant of benefit was those patients who achieved the deepest reduction in IL-6 and CRP levels, where that 15% risk reduction at the ITT level was more like 25%, 30%, 35% reduction when they're looking at those who achieved the deepest reductions in IL-6 pathway activation as measured by CRP or IL-6 directly here. Overall, we have a lot of conviction that this is the right node to be going after for atherosclerotic cardiovascular disease. In terms of degree of benefit, I would look at a couple of different ways. Historically, 15% has been, on a relative basis, considered kind of the bogey for clinical meaningfulness. However, relative risk reduction in isolation is a little hard to interpret. This is where absolute risk reduction, I think we think, also matters. Now, in the ZEUS trial, as you noted, should read out sometime in the next 12 months, the background rate of MACE in that study was powered around kind of expectation of 6% plus per year risk of having a three-point MACE event, so like heart attack, stroke, cardiovascular death, which is really quite high. Over the course of three years, that's more like 18%-20% risk of having MACE. Even a 15% risk reduction on a relative basis still translates to a very impressive absolute risk reduction. More importantly, in terms of numbers, needed to treat very efficient numbers here. Anything that's north of 15%-20% risk reduction in this high-risk group of patients, we think, would be very quickly standard of care changing. If it works in ZEUS, this is where it gets really exciting. Again, CKD is an important predictor of cardiovascular disease risk, but it's by no means the only predictor of cardiovascular disease risk, where looking at things like multivessel disease, multiple vascular territories being affected, those patients who have diabetes, who have recurrent events, any number of ways to really select for patients who have increased risk, especially when you look at those who have high CRP levels as well. Yep. OK, great. Just in the couple of minutes that we have remaining, we have all these parallel workstreams ongoing in CVD. We also have the phase II-B study in thyroid eye disease. Just remind us kind of how we've designed that study and the population that we've enrolled there, and then what you consider clinical bar for success. Sure. Yeah, we're running the phase II-B spiriTED Study data second half of this year. We've designed it to be the first of two pivotal trials. We met with FDA before starting the study, and got in alignment that this could count as one of our two pivotal studies, of course, pending successful completion of the trial. It's been largely designed after the OPTIC trial, which was the phase III trial for teprotumumab, supporting its approval in thyroid eye disease. When we look at the TED indication, we think there's a world of opportunity here, given the degree of unmet need that we know is out there from teprotumumab launching well initially. However, the class that Tepra is in, I think, has some clear limitations that have impacted and limited the actual real-world uptake of the drug, including concerns about side effect profile, concerns about durability of effect here. When we speak with docs and we do our market research, what is clear to us is that to really get this class back to growth, you need a different mechanism here, just being more of the same, blocking the same pathway that teprotumumab does. Probably is not going to be able to convince any doc or patient who otherwise to use the drug when they haven't adopted it so far, five years into their launch when it's been the only game in town here. Now, what we're doing here, we think, recognizes that thyroid eye disease is an inflammatory autoimmune disease. To use an anti-inflammatory like an IL-6, we think, makes very good sense from a theoretical point of view. There's also a wealth of data using IL-6 inhibitors, mainly off-label and other retrospective and some prospective experiments as well, looking at IL-6 pathway blockers in the context of difficult-to-treat TED patients, where there's, we think, undeniable evidence of activity despite the fact that this mechanism has never been formally tested in a registration-directed study to date, which is what we are looking to do. When we think about what the bar for success here, the goal is not how to out-proptosis Tepra. Proptosis is the primary endpoint for the study. It's what the FDA wants. Tepra is good on reducing the endpoint. This is where we think a drug like ours could bring benefit, not just on proptosis, but more holistically on the other things that cause real functional impairments, things like diplopia, pain, the clinical activity scale, the signs and symptoms of inflammation itself. Here, the goal is to really be that first treatment option that a patient and physician says, I want to try this first, get the disease under control, and keep the other mechanisms in their back pocket for those who become refractory to a treatment like ours. Right, right. Low-volume subq, infrequently dosed, capable of alleviating the symptoms. Yeah, that makes a lot of sense to me. All right, Sandeep, unfortunately, we're up against time. Great. Thank you for joining us and for sharing the insights. We will stay tuned to the Tourmaline story. Great. Thank you.