Tourmaline Bio, Inc. (TRML) Earnings Call Transcript & Summary

Good morning, and welcome to today's Investor Day. Thank you for joining us. We'll be recording today's event, which can be accessed later on the Events page of Tourmaline's website at www.tourmalinebio.com. [Operator Instructions] I would now like to introduce Tourmaline's Co-Founder and CEO, Dr. Sandeep Kulkarni. Please go ahead, Doctor.

Good morning, everyone. On behalf of the entire team at Tourmaline, I want to welcome all of you to our first Investor Day. We are very honored to be joined today by Dr. Marc Bonaca, Executive Director of the Colorado Prevention Center Clinical Research and a professor within the Division of Cardiology at the University of Colorado. I'm also joined today by Dr. Emil deGoma, our SVP of Medical Research and a Board-certified Cardiologist and Gerhard Hagn, our SVP, Head of Commercial and Business Development. Today, we will be sharing exciting updates on our progress in 2024 and where we are heading in 2025 when we plan to deliver 2 transformational readouts. We plan to -- before we dive in, I want to quickly address some housekeeping items. As you may know, we'll be discussing our forward-looking statements during this presentation. These statements reflect our current beliefs and expectations, but they are subject to various risks and uncertainties that could cause actual results to differ from those discussed today. I encourage everyone to review our filings with the SEC for more details on those risks. Here is the agenda for today's Investor Day. I will start by reflecting on the important progress we have made thus far and what we expect to come in 2025. After my opening remarks, we will hear from Dr. Bonaca on the significant unmet need in cardiovascular disease and the urgent need to address residual inflammatory risk. Emil will then further elaborate on this next frontier in cardiovascular disease by addressing inflammation through IL-6 inhibition. Next, Gerhard will articulate our conviction in pacibekitug and our approach to differentiation in cardiovascular disease. He will then take you through some exciting market research we have conducted this year, confirming pacibekitug best-in-disease opportunity in thyroid eye disease or TED. Finally, we will conclude with Q&A. Our company has come a long way since we acquired the rights of pacibekitug less than 3 years ago from Pfizer. Our mission remains the same as it was then, to develop transformative medicines that dramatically improve the lives of patients with life-altering immune and inflammatory diseases. We seek to develop medicines that have the potential to establish new standards of care in areas of high unmet medical needs. Since inception, we've cleared 2 IND applications, became a publicly traded company in October of last year, initiated 2 Phase II clinical trials, completed multiple GMP manufacturing runs and built an organization with deep expertise in developing and commercializing monoclonal antibodies, just to name a few accomplishments. And our team has made significant progress leading our 2 clinical trials, TRANQUILITY and spiriTED. We are now transitioning from a year of execution to a year of data. Carrying this momentum into 2025, we plan to deliver 2 potentially transformational readouts next year, TRANQUILITY and spiriTED. We now expect to report TRANQUILITY topline data in the second quarter of 2025, tightening our previous guidance from the first half of 2025, which will be the first data readout for our company. Results from this trial, if positive, are expected to unlock pacibekitug path forward in cardiovascular inflammation, allowing us to be Phase III ready in atherosclerotic cardiovascular disease, or ASCVD. This will be a pivotal step towards our mission of transforming the lives of millions of high-risk CV patients and one that could potentially translate into multibillion-dollar revenue opportunities. Later in 2025, we expect to report topline results from spiriTED, our pivotal Phase IIb trial in thyroid eye disease, or TED. TED is an independent shot on goal to address a rare debilitating disease, persisting unmet need, which has its own blockbuster potential. We are very excited about the announcement we made this morning. The TRANQUILITY trial has surpassed its target enrollment with 143 patients enrolled as compared to 120 patients originally anticipated. We believe this rapid over enrollment in just 7 months underscores the cardiovascular community's enthusiasm to address IL-6 driven inflammation and pacibekitug's potential to deliver meaningful benefit for patients. As a reminder, pacibekitug is a long-acting anti-IL-6 monoclonal antibody with best-in-class potential. Its attributes have been demonstrated in an extensive clinical and preclinical data package. Pacibekitug may provide substantial benefits to patients such as: first, quarterly administration; second, rapid and robust IL-6 inhibition, easily measurable by reductions in high sensitivity C-reactive protein or hs-CRP; third, durable effects with low doses due to limited immunogenicity observed to date. Fourth, a patient-friendly subcutaneous injection given in less than 1 milliliter. And finally, a generally well-tolerated safety profile. In addition to the ongoing TRANQUILITY and spiriTED trials, we are excited to announce very important advancements in our clinical development pipeline for pacibekitug. First, we've initiated early preparations for a Phase III trial in our CV lead indication, ASCVD in close collaboration with our Scientific Advisory Board. Second, we are thrilled to announce our third indication, abdominal aortic aneurysm or AAA, a CV indication currently with no FDA-approved treatment despite very high unmet need, including high mortality. Dr. Bonaca and Dr. deGoma will share more details later on. Lastly, given the very large opportunity we are pursuing in cardiovascular inflammation for pacibekitug, coupled with the goal of being Phase III ready in ASCVD after our Phase II TRANQUILITY trial, we have made a strategic decision to date the initiation of the Phase III TED trial on the results from the Phase IIb spiriTED trial. Positive top line results from spiriTED, which we expect in the second half of 2025, would enable initiation of the Phase III trial in TED, the second of 2 pivotal trials that will be required for a BLA filing. To help us drive forward the development of pacibekitug in this exciting time, we've assembled a world-class cardiovascular Scientific Advisory Board, or SAB. As you saw this morning, we are incredibly pleased to announce the expansion of this SAB with 2 new members, Dr. Deepak Bhatt and Dr. Dipender Gill. Dr. Bhatt joins as Chair of the SAB, he is the Director of the Mount Sinai Fuster Heart Hospital; and the Dr. Valentin Fuster, Professor of Cardiovascular Medicine at the Icahn School of Medicine at Mount Sinai in New York City. Dr. Bhatt was previously Professor of Medicine at Harvard Medical School, Executive Director of Interventional Cardiology Programs at Brigham & Women's Hospital and Senior Investigator in the TIMI Study Group. Dr. Bhatt has served as Principal Investigator for a number of groundbreaking cardiovascular clinical trials, bringing to the CV SAB decades of clinical trial expertise across a wide range of cardiovascular diseases and therapeutic mechanisms. Dr. Gill is the CEO of Sequoia Genetics and a leading expert in leveraging human genetic data to inform drug discovery and development. He holds a medical degree from the University of Oxford and a PhD and Genetic Epidemiology from Imperial College London. Dr. Gill's academic expertise centers on human genetics and Mendelian randomization as applied to studying drug effects and unraveling disease mechanisms with over 250 research papers in this area. We were pleased to host him last month at our Genetic Validation Webinar. He will continue to bring those translational insights, leveraging human genetic evidence to our strategic focus. Now it is my distinct honor to introduce Dr. Marc Bonaca, one of our SAB members and a true pioneer in cardiovascular research. Dr. Bonaca is a cardiologist and vascular medicine specialist. He is the William R Hiatt Endowed Chair in Cardiovascular Research and Professor of Medicine at the University of Colorado Anschutz and the Executive Director of Colorado Prevention Center Clinical Research, an affiliated academic research organization. Dr. Bonaca has extensive experience designing and conducting large multicenter randomized clinical trials. First, as a faculty member and TIMI investigator at Brigham & Women's Hospital and Harvard Medical School and then at CPMC. Among other landmark studies, Dr. Bonaca led VOYAGER PAD, the first drug trial for registration to include major adverse limb events as components of the primary endpoint. Dr. Bonaca's research focuses on ischemic risk in patients with atherosclerotic vascular disease, risk prediction and risk modification using novel therapies. We are so pleased to have him on our SAB and to welcome him today.

Well, thank you for that kind introduction, and it's really an honor to have an opportunity to talk about the unmet need here. As you heard, I spent my career focused on leading large clinical trials and novel therapies to improve outcomes in patients with high-risk vascular disease. But as you'll hear, we have a significant unmet need, particularly for -- particularly for very high-risk populations. And I want to walk you through some of the clinical unmet need and then why we're so excited about the potential for anti-inflammatory therapies in this population. And I want to begin with a sobering observation that while there are a lot of medical issues to focus on out there and a lot of focus on cancer and other things, cardiovascular disease remains the leading cause of death globally. And you can see that on the left side of the slide that ischemic heart disease and stroke as well as complications of vascular disease are the leading causes of mortality and they share a common underlying pathobiology, which is shown on the right side of this slide. This is a cartoon of an artery. And you can see, as you move from left to right, you can see that progression of plaque deposition and then acute coronary syndromes and plaque rupture. And that happens in the context of exposure to risk factors over time, the deposition of lipids and then you can see about halfway through inflammation. And inflammation is actually the primary driver of what turns a plaque in an artery into something that is a ticking time bomb that can rupture and cause the most feared manifestations of atherosclerotic vascular disease, things like heart attack and stroke. Now atherosclerosis is a systemic disease, that's that common shared pathobiology. It is unfortunately frequent and prevalent. Over 500 million suffer from this globally and about 20 million people died in 2021. Where the plaque is determines much of the morbidity that follows. So people that have plaque and progression in the cerebrovasculature in the brain tend to have strokes. Patients who have disease in the coronary arteries have what's called acute coronary syndrome, that's the worst manifestation being a heart attack and those that have plaque in the legs called peripheral artery disease, or PAD, have amputation and limb ischemia. As you heard before, we now have novel pathways for approval for drugs that can improve those limb outcomes. And it's important to recognize that these aren't individual patients, that patients may manifest symptoms in multiple territories. And in fact, that's what we consider the highest risk population. If you liken it to cancer, these are the patients that suffer from metastatic atherosclerosis with symptomatic disease in multiple territories. And I'm going to speak more about that in a few minutes. Now what's important to understand is that risk mitigation in patients of atherosclerotic vascular disease depends on the pathways of risk. And on the left, these are genetic data highlighting specific pathways of risk. On the right side, a simplistic depiction I made showing that these pathways all contribute to atherosclerotic vascular disease. What's important to understand is that these are orthogonal pathways, they're independent. And so that as we look at therapies that have been developed to address these pathways of risk, none of them is the magic bullet. All of them moderate some risk, but not all of it. So when we look at LDL lowering with PCSK9 inhibitors for lipid risk in the FOURIER trial, we saw a 15% reduction, meaning 85% of the risk remained. When we look at semaglutide in patients with diabetes, the SOUL trials reporting their press release of 14% reduction. That means 86% of the risk remains. And the same for thrombosis risk, where we -- even for effective therapy, see 15% to 20% reductions. A lot of risk remains. And as clinicians, we have effective therapies shown on this slide for many of these axes of risks. We have lipid-lowering therapies. We have novel diabetes therapies and antithrombotics. The axis of risk that means completely unaddressed is that for inflammatory risk. And that's why we believe there's a great opportunity for improving outcomes in populations by adding inflammatory risk reduction to the other pillars of therapy you see on the slide. Now as a clinician, we're talking about a huge population here, atherosclerotic vascular disease. For implementation and for translation, we are always thinking in clinical domain about who's at the highest risk, where is the greatest unmet need. And I want to highlight for you several populations that I think are novel and important opportunities for clinical outcomes and for novel therapies. And the first is that population that I previously mentioned, those that have metastatic atherosclerosis, or symptomatic disease in multiple territories. And we've seen in every outcomes trial, a recapitulated reality, which is if you manifest symptoms in more than one territory, you are at much higher risk than those who have a single symptomatic territory. To demonstrate this, I put 2 trials on this slide, One was called the EUCLID trials over 12,000 patients with peripheral artery disease. On the right, PEGASUS-TIMI 54, which is a coronary trial. And you can see that people that had symptomatic disease in the yellow bar in each trial had high risk, very high risk. But if they had metastatic disease or polyvascular disease, meaning symptomatic disease in the legs and the heart in the red bars, they were at 50% to 60% higher risk of having an event over 3 years, dramatically higher risk with event rates approaching 1 in 5. We saw something similar in the FOURIER trial. And in the FOURIER trial, this was a trial that enrolled all high-risk patients. You had to have a stroke, a prior MI or PAD. The first thing you'll notice is that the patients with peripheral artery disease, lower extremity disease actually have the highest risk. So you can see on this slide that patients in the orange, that PAD have a significantly higher risk, 80% higher risk than patients who've had an MI or stroke. And this is risk of having cardiovascular death, MI or stroke. It's counterintuitive that if someone that has plaque in the legs would be higher risk of having a heart attack than someone who's had a heart attack. But the reality is they have so much burden of athero and they're so inflamed, their risk profile is much higher. Now that risk is not uniform. In fact, when you stratify that orange into the red, those are polyvascular disease, meaning PAD and CAD or PAD alone in the yellow, yes, the PAD patients remain at higher risk than those of prior MI or prior stroke. But if you take the patients that have symptomatic disease in 2 territories, they're at about a doubling of the risk of patient with prior MI. And from a clinical perspective, we see these patients all the time. And we know even though they walk into the office and they're not complaining, they say they're doing okay, that they are at extremely high risk because they have a large extent of inflamed plaques. This is an easy clinical criteria to identify a very high-risk population. Second population I want to highlight for you is that with peripheral artery disease. I mentioned this on the first slide. There are over 230 million patients worldwide, not as many as coronary disease, but a significant burden, more than 12 million to 14 million in the United States. And that population is growing. Actually, PAD is underdiagnosed. So that's an underestimate of the true prevalence. Now you might ask, are we just measuring it more? Are we just detecting it more? And actually, that's not the case. There is more PAD and the prevalence is truly increasing both in overall terms, but also in the most severe manifestations. And that's because peripheral artery disease, lower extremity disease is tightly linked to the pandemic of cardiometabolic disease, obesity and diabetes. Diabetes is the strongest risk factor for developing PAD along with age, and we have an aging population with more obesity and type 2 diabetes. And when you think of it in that context, it's not surprising that we're seeing more. But what's really troubling is that while event rates for coronary revascularization and other things are going down, we see the opposite trend for PAD outcomes. So we have more patients showing up at the hospital with severe limb outcomes requiring procedures to try to salvage their legs. And so this is an important unmet need. Now in terms of the PAD population, who's the highest risk. There's been a lot of work here. This is a busy slide, but it's a simple answer. When you look amongst large trials of patients with peripheral artery disease, I'm showing you 3 big trials here in EUCLID, as I mentioned, PEGASUS, which I mentioned, also a big large trial called TRA2P-TIMI 50, all of them had large PAD populations. And when we looked at risk for who is going to have an adverse limb event, all the trials told us exactly the same answer. If you have a patient who's undergone a leg procedure to restore blood flow, so revascularization. That patient remains at a heightened risk of major adverse limb events over the long term. They're never returned to the risk profile of a pre-intervention patient. And that risk is substantial. It's a three- to fourfold risk of major adverse limb events. So I know in the office, when a patient walks in and I see in the chart, they've had a limb procedure ever, even if it was 2 years ago, I know that patient is extremely high risk for adverse limb events. Now importantly, on the left side of the slide, what we've also seen in these trials and these are the data from TRA2P is that risk is not only high, but it's modifiable. Now these are modifiable endpoints. They're modifiable with lipid lowering. They're modifiable with antithrombotic therapy, and we believe this should be modifiable with anti-inflammatory therapy. So this is a population that's very promising in terms of risk and modifiability. The last trial in population I want to talk about are those with acute coronary syndromes, who have additional risk factors. Acute coronary syndrome is essentially a term for heart attack. These are patients who come into the hospital with chest pain, having an occluded artery, we treat them aggressively. But we know that they remain at high risk for recurrent events. But that risk is not uniform amongst all populations. What you can see on this slide, are data from a trial called the IMPROVE-IT trial. This is an 18,000 patient trial with exquisitely well treated lipids. These patients are treated much better than routine practice. And what you can see is outcomes over 7 years in terms of recurrent heart attacks, strokes or cardiovascular death. And you can see a gradient of risk. So in patients that came in without diabetes or having polyvascular disease, the risk was in the green was 17%, which is high. But if you add diabetes or peripheral artery disease in the yellow or blue, that risk increases substantially. And so those are both risk enrichers. Unfortunately, if you combine the 2, meaning they have diabetes and peripheral vascular disease or polyvascular disease, the event rate is in red. It dramatically increases. These work synergistically in an inflamed high-risk patient to the order that 1 and 2 have a recurrent event over the next 7 years despite having very well-managed lipids. And so this is a substantial unmet need, and these patients are very prevalent. So in summary, patients with atherosclerotic vascular disease are at high risk for heart attack, stroke and limb outcomes, which are now modifiable and improvable outcomes. But there are populations in a lot of these patients around that are at substantially higher risk, where we have even more unmet need. That's the polyvascular patient, those with symptomatic disease in multiple territories, patients with lower extremity artery disease after revascularization procedure and coronary patients, who present with high-risk features, meaning a recent acute coronary syndrome or that combined with other markers like type 2 diabetes or polyvascular disease. Despite a lot of development of novel therapies, including thrombotic risk, lipid risk and other axes of risk, there's substantial residual risk. None of these trials really move the needle in terms of substantial reduction. And that's because we are not addressing a key pillar of risk. That's inflammation. So no matter what we do with lipid lowering, we can move LDLs to 0, and we would have substantial residual risk. And without inflammation, we're never going to really move the needle in this population. And so this is really now a question of target toxicity and matching the treatment to the population. I want to talk to you a little bit about why we're so excited about IL-6 as a target. Now the first thing I want to mention is to show you some evidence that these are independent risk factors. I mentioned that in my first slide that these are orthogonal pathways of risk. These are beautiful data published by Paul Ridker just recently in the New England Journal of Medicine. And what you can see in these 3 panels is the relationship of CRP and risk after you account for other risk factors. So on the left side, LDL cholesterol in the middle, sort of a hot topic right now is lipoprotein(a). And then you can see the combination of LDL and Lp(a). And the take-home message from this slide is quite simple that the curves separate regardless of whether you account for lipid risk, meaning LDL, Lp(a) or both. CRP is an independent marker of risk. And even after you account for very low levels of LDL or Lp(a), that risk remains unmitigated. So it's an independent risk factor. It's not just independent, but it's actually additive. And so for patients that have high inflammatory risk, high Lp(a) risk and high LDL risks, so you can see the sort of curves here, 0, 1, 2 and 3 in terms of the number of risk factors, the more that you add to an individual patient, the higher the risk. And so then this supports the notion that these are additive and that in order to significantly modify risk, you can't just treat LDL or Lp(a), you need to treat inflammation as well. But the question has been how do we treat inflammation. Inflammation is a broad term. These pathways are very complicated, and we've been overly simplistic in general. This is a nice simplified cartoon by Peter Libby. This shows you some of the axes of inflammation and risk. You can see the inflammatory cell at the top and the NLRP3 inflammasome. You can see IL-1 beta and then the key actors here in the vessel wall, which are the endothelial cells. Then you can see the vessel on the right in terms of the target for the inflammation and then the liver, which produces acute phase reactants. There are many potential places you could try to interrupt this pathway. The problem is if you act too high up in this pathway, you get off-target effects. In order to have enough effect on the endothelial cell, you may have other effects and other adverse effects in order to get the desired response. The core of this slide is the center that if you want to interrupt inflammation at its key driver of risk, that is IL-6, and that's why IL-6 inhibition is such a promising target. I'll show you more data to support that. I think the other thing to recognize from this slide is that the direct consequence of IL-6 is hs-CRP. So hs-CRP is tightly linked to IL-6 and a great biomarker of IL-6 activity. It's also easy to measure and clinically available in many settings. And so while we measure hs-CRP to understand what's happening with IL-6, hs-CRP is not a target for therapy because it's downstream. And we need to address the problem at its core driver of risk. How do we know that IL-6 is a problem? Well, there are a number of studies. This is actually a very robust data set, and I don't have time to go through all of them today, but I'll show you some key findings. The first is that we know there are people that are born lucky enough to have variance in their IL-6 receptors to have less sort of IL-6 activation, if you will. And you can see that those patients tend to have lower CRPs because that is the biomarker of risk and that those patients then if you observe them have lower risk of developing atherosclerotic vascular disease as well as CRP. So on the left side of the slide, you can see that by genotype, depending on the potency of the genotype, you have a lower risk of coronary heart disease. On the right side of the slide is what makes this even more exciting, and that's the breadth of vascular complications that are associated with IL-6. You can see on the right, we have aneurysmal disease. We have peripheral artery disease, we have coronary disease. What this tells you is this is a robust finding. This is not just one individual outcome that we're seeing linked to IL-6. It is a constellation or grouping of diseases that we know to be related and all of them align with an elevated IL-6 or there's protection to be specific in this analysis with lower IL-6 activity or the variance with reduced receptor function. So we see from genetic data, a strong association, which is very supportive. We also see in genetic data that the outcomes are quite specific. So on this slide, you can see the IL receptor variants and their association with protection of coronary artery disease in the top panel and peripheral artery disease. And you can see both are protected to a similar extent, and that's very promising. But these are broad bins and they are nonspecific. And so what we really like to see for biologic plausibility is a tighter relationship with more specific events. And when you look at the lower panel, you can see as you go from nonspecific term to claudication, which is a little bit more specific to CLTI and amputation, which are the most specific outcomes that we want to modify the relationship is even stronger. And this really supports biologic plausibility for causality. So beyond genetics, we have measuring IL-6 levels and concentrations in the risk of incident CHD as well as MACE in CKD. So if you look on the left side of the slide, you can't really see all of the types. I know it's very small, but you don't need to. What I'm trying to communicate in this middle panel is that there have been many studies that have looked at IL-6 in the incidence of coronary heart disease, and all of them show consistent relationship. This eye chart tells you consistency amongst many studies. This is not a spurious finding. To take it a level further on the left, you can see that the risk is not just higher, but there is a gradient of risk. The higher your IL-6 level, the higher the risk, meaning this is a dose response type observation that again supports biologic plausibility for causality. We also see consistency in high-risk populations on the right. So in patients with chronic kidney disease, you can see that the relationship for risk is clear. The likes of blue bars are always higher than the dark blue bars, but that the -- in the context of higher or increasing absolute risk amongst patients, who have worsening renal function, there is still higher risk in those elevated IL-6 and the gradient or the difference between the 2 remains with greater absolute risk in the highest risk patients. And you can see that in the cubic spline of the line graph below as well. So strong supportive data from measuring IL-6 levels of epidemiologic studies. What about very specific studies? Well, I mentioned PRA2P-TIMI 50. That was the first trial to show you could modify limb outcomes by using a drug that was directed at thrombin inhibition. And we developed a risk score to predict those limb outcomes and all of the independent predictors are listed in the table here. And while there are things that are clinically intuitive, meaning if you've had a prior revasc, I told you about that, if you have a low ABI that you'd be higher risk. But if one biomarker that was extremely strong and did not correct after any adjustment, meaning it remained independent with CRP, patients who had high sensitivity CRP of 2 to 3 were at significantly higher risk. And you can see the spectrum or the distribution of risk in the bar graph here, and this risk was modified, meaning it is modifiable risk. And so inflammation is one of the core drivers of risk in this population, even in clinical trials. What do we have to address this risk? Well, in the clinical domain, we don't have much. In the research domain, we do have supportive evidence that treating inflammation does, in fact, reduce risk. So CANTOS evaluated a drug called Canakinumab. You can see here in terms of the pharmacodynamics that there was a dose effect in terms of higher doses of Canakinumab in hs-CRP levels. I think what's important to recognize about the data, I'll show you next is that Canakinumab has no effect on LDL or triglycerides, Lp(a) for that matter. It is a very specific anti-inflammatory targeted IL-1 beta. And then the question is, does this improve outcomes in patients with vascular disease? And the answer is yes. This is the primary endpoint shown by Paul Ridker of the CANTOS trial. And you can see when you add Canakinumab to standard background therapy, there's a significant lowering of risk. This is over the course of 4 to 5 years, you can see early separation of the curves, continued separation over time with a 17% reduction in MACE-Plus. So you can clearly see that lowering inflammation and the measure of effectiveness here, and I'll show you this in a moment, is hs-CRP improves outcomes in patients with high-risk vascular disease. And this is the crux. And I think important to understand, there's been mixed results for Colchicine and other things is if you don't lower CRP, you're not arresting inflammation. If you do lower CRP, you are targeting inflammation. And you can see in CANTOS that, in fact, the benefit of the drug was dependent on the ability or the effectiveness of it lowering CRP levels in patients. So you can see in the green boxes here that for cardiovascular mortality, if you took Canakinumab and either for whatever reason, your CRP didn't go down, the hazard ratio was 0.99. There was a little effect, if any. If your CRP did go down to less than 2, you had a very large effect of 31% relative risk reduction in cardiovascular mortality. And you can see that on the right side from the side by CRP at median. The take-home message from this is even for an effective therapy, you have to achieve CRP lowering to demonstrate that you've arrested IL-6 activity and inflammation in order to demonstrate a robust benefit. Well, where are we now in the clinical domain? We don't have much to be totally honest. There's is Colchicine that's an old drug that's been around. There were some early trials that suggested there's a benefit. And so the Class II in the guidelines, but the latest largest trial showed absolutely no benefit. It's poorly tolerated. We don't really understand how it works. And there were signals for increased mortality in some of the pivotal trials. And because of that, it's not widely utilized and it will probably be utilized even less given the latest trial. Canakinumab sadly is not available, that is in a different sort of pathway of development. But I think beyond that, IL-6, as we've learned, is the core central bad actor, we think, in the inflammatory pathway. It's the most proximal to its effect on the endothelium. And therefore, a targeted therapy, IL-6 actually holds the most promise to achieving low inflammation, low CRP with an optimal tolerability profile. And because of that, there are programs ongoing in ASCVD with chronic kidney disease, heart failure with preserved ejection fraction and an acute MI. So in summary, atherosclerotic vascular disease remains the #1 killer. It's a systemic disease, and it acts broadly through plaque rupture and inflammation. All the patients with vascular disease are at risk, but there are certain populations, which the ongoing programs and others can not address. And as a clinician, I can tell you, the biggest problem we have in the clinic, and those are with polyvascular disease. Those patients have symptomatic disease in multiple territories, high-risk peripheral artery disease, particularly after intervention and high-risk coronary disease, those with polyvascular disease or diabetes and their event rates are a range between 7% to 10% per year. And so there's a high unmet need. It's great that we have novel therapies for lipids, thrombosis and diabetes, but they are significant residual risk, and we're not going to be able to address that unless we address the remaining pillar or risk driver of inflammation. Of all of the data addressing inflammation, IL-6 has come out as the most specific and important target supported by extensive genetic and observational data and novel therapies targeting IL-6 really hold great promise and broadly in vascular disease and particularly in high-risk patients. Now, I want to transition to another less known entity in vascular disease that is a tremendous unmet need. This is abdominal aortic aneurysm. I see patients with this all the time. It's not talked about as much as heart attack or stroke. But it is really a terrible entity. It's what many patients think about having a ticking time bomb in their abdomen. It's something you sort of watch and wait and you hope it doesn't rupture. I'll tell you a little bit about current treatments. I think the important thing to understand is that there are no medical therapies that are available to prevent the progression of disease and so this is a really important unmet need. It is prevalent. There are around 200 million individuals in the United States that have abdominal aortic aneurysms, a true incidence is probably higher than the true prevalence because there's an underutilization of screening. We define it as a widening of the aorta, the main artery that comes out of the heart and supplies the body, and it should be around 2 centimeters. And as it increases to 50% increase in diameter, so 3 centimeters or greater, it's called an aneurysm. These tend to form over time, just like atherosclerosis in the context of age, hypertension, hypercholesterolemia, but it is a inflammatory disease, and I'll show you a figure about this. What happens and in the context of all these risk factors, people develop inflammation in the wall of the aorta, which makes it weaken and then grow or balloon over time. Unfortunately, it's usually asymptomatic and most -- many patients unfortunately die of it without knowing they ever had it. It can be detected by screening. But when you screen, there's very little you can do about it other than watch until it progresses and requires intervention. So what do we do in the clinic? Well, we treat risk factors like smoking cessation, we lower blood pressure, we treat cholesterol, and that's because a lot of these patients also have the atherosclerosis I just talked about because they're shared risk factors, but we're unable to really modify the progressive nature of disease because we're not treating the inflammation. So inevitably, patients progress to requiring repair. And what does that look like? Well, traditionally, repair look like the left side of this slide, which is a surgical procedure. You have to open up the abdomen and you have to replace that part of the aorta with a graft. This is a highly morbid procedure. There's a lot of upfront risk. And that has been supplanted largely by what are called endovascular or minimally invasive techniques on the right. So you can go in through the groin, you can see that in the picture with a small incision, and you can put this graft within the aneurysm and sort of prevent communication of the blood flow with the aneurysm so the sac can't extend the rupture. The problem is that both of these are associated with a lot of risk. And so the upfront risk of surgery has really shifted us to the right side of the slide. But I'll tell you on the right side of the slide, we've learned there's just no panacea. These patients still after repair have a risk of rupture of about 2% to 5% over 4 years. And the risk of requiring the reintervention because they leak or they have problems or there's continued inflammation in the sac is around 9% to 10% over 4 years. So the requirement after an intervention is that you're not out of woods, but you actually have to have very intensive annual screening and surveillance. And then many times, you need to have intervention in order to replace or improve the graft despite that a significant proportion of rupture. Now AAA is one of the few entities we have in medicine, where there's a Class I indication, multiple guidelines and the U.S. Preventive Services Task Force to screen or supposed to screen. But we have no medical therapy. And so this is a really unusual paradigm, where we have the infrastructure in place to detect it, but we can't do anything about it, and that's why it's such a great unmet need. Despite that, screening remains underutilized. And part of that is because we don't have great interventions to treat these patients or prevent progression. If we do screen and we do intervention, there's around a 40% reduction in mortality. It's not 100% reduction in mortality, and that's because of what I told you the complications afterwards due to residual inflammation. And the adherence to screening is overall underutilized, but part of that again is the absence of an effective medical therapy to target the problem. So how could we do it? Well, this pathobiology has actually been very well described. So if you look at the cross-section of the aortic wall here, this is not atherosclerosis. Many of these patients have atherosclerosis, but this is really purely inflammation. So when you take sections of these aortic aneurysms, you can see a very rich inflamed milieu in the middle of the wall that leads to breakdown of the matrix, the sort of netting or the infrastructure of the wall itself and death of the vascular smooth muscle cells. And as that happens progressively in the context of inflammation, the wall weakens and it dilates and as it dilates, once it reaches a diameter of around 5.5 to 6 centimeters, risk of rupture becomes extremely high. And we need to intervene with the procedure at that point to try to prevent mortality. Why do we think IL-6 is the specific key to inflammation? Well, I showed you the left side of this slide before. And right up there in terms of the statistical significance are aortic aneurysm and abdominal aortic aneurysm. These aortic aneurysms can happen in the thorax as well, but it's truly the abdominal aortic aneurysms under the most inflamed. And you can see that's actually at the top of this figure. When you look on the right side of the slide, at the association between IL-6 and myocardial infarction, which is significant, we all know that. But an aortic aneurysm is actually a much stronger association. You can see the consistency amongst the variants. So a genetic data is very supportive for atherosclerotic vascular disease. It's even more supported as a causal role in aortic aneurysms. So is it just developing an aneurysm? Is it high IL-6, does it mean you're going to develop an aneurysm? Or does that mean more progression? Well, when you look at hs-CRP, it actually means both. You can see here that on this slide, there's a linear relationship between your CRP levels. Again, that's the most sensitive marker, IL-6 activity and the size of your AAA. There are data to support higher risk of developing AAA, or aortic aneurysm. And then on the right side of the slide, what I think is very important is that the rate of change is associated with your inflammation, meaning if you could move someone from right to left on this slide, you could change the rate potentially of progression or rest progression altogether. But the reality is in this disease, if we do show an effective therapy, the benefit is not just in preventing or delaying the procedure. Many patients may require a procedure, but if you look at the slide, this is the totality of the potential for this agent. In the patient that you see who has an aneurysm that hasn't yet progressed for progression, you see they grow at about 2 to 3 millimeters per year in the high rupture rates. So the therapy here could delay the time or even prevent the need for repair. If somebody did go for repair, again, we see very high rates of post-repair rupture and recurrent repair needed. And that's because there's continued inflammation in the aortic sac and adverse remodeling. And so there's the potential to improve post-procedural outcomes by continuing to inhibit the inflammatory pathway. So benefits before and after repair. You also have to think about the broader context, the majority of these patients also have the atherosclerotic vascular disease I talked about. So on top of the risk of their aneurysm, they have a risk of MI, stroke or CV death of about 5% to 10% per year, which remains unmitigated, and there'd be the additional benefit of targeting inflammation to reduce their atherosclerotic vascular disease. So this is really, I think, a novel population, where there's a high unmet need, both in terms of their aneurysm and their vascular disease that could be mitigated potentially with an effective anti-inflammatory therapy. Well, thank you very much for the opportunity to contribute. I'm going to now turn over the presentation to Dr. deGoma.

Thank you, Dr. Bonaca, for reviewing the significant unmet needs in the role of inflammation and IL-6 in atherosclerotic cardiovascular disease and abdominal aortic aneurysm. At Tourmaline, our vision is to lower cardiovascular-related morbidity and mortality in patients with high inflammatory risk through IL-6 inhibition. As noted by Dr. Bonaca, cardiovascular disease continues to be the leading cause of death globally. To achieve this vision, our plan is to, number one, bring pacibekitug to high-risk ASCVD patients as a targeted anti-inflammatory therapy to lower cardiovascular-related morbidity and mortality. Number two, to expand beyond populations currently studied in clinical trials, selecting indications where robust data supports the potential for large and meaningful benefits from IL-6 inhibition. Number three, to support efforts to increase awareness and testing of hs-CRP, the key biomarker of inflammatory risk, leveraging the activities of others in a targeted manner. Number four, leverage the quarterly administration of subcutaneous pacibekitug, if confirmed in the ongoing Phase II study to improve adherence and real-world effectiveness in cardiovascular disease prevention. And number five, to innovate cardiovascular trial design and ultimately patient care by engaging with our experts, including our CV Scientific Advisory Board. Together, we at Tourmaline aspire to lower cardiovascular-related morbidity and mortality so that millions of cardiovascular patients live healthier and longer lives. We believe targeted anti-inflammatory therapies represent the next frontier in the treatment of cardiovascular disease. While numerous existing and emerging drugs affect mediators of risk, including from left to right, thrombotic factors, blood pressure, atherogenic lipoproteins, diabetes and obesity, the therapeutic armamentarium specifically targeting inflammation remains limited. As of today, the only anti-inflammatory therapy currently approved for ASCVD is Colchicine. However, clinical use of Colchicine is very limited for the reasons noted by Dr. Bonaca, including limited effect on hs-CRP, toxicity concerns, contraindications, drug-drug interactions and uncertainty about the mechanism of action. But now we may be on the cusp of change. There's a convergence from multiple lines of evidence that now supports the pivotal role of inflammation in driving cardiovascular disease. Accumulating data from numerous epidemiological studies are complemented by mechanistic experiments and a series of human genetic studies have established a causal role of anti-inflammatory pathways such as IL-6 in cardiovascular disease. Earlier this year, the strong association between hs-CRP and major adverse cardiovascular events was once again shown this time in the 30-year follow-up of the women's health study highlighted in the figure. In the study of almost 28,000 initially healthy women, hs-CRP outperformed both LDL-cholesterol and lipoprotein(a) in term of risk prediction. Women in the highest quintile of hs-CRP had a 70% increased risk of major adverse cardiovascular events compared to those in the lowest quintile. In addition to epidemiological studies, several cardiovascular outcome trials of therapies with direct or indirect anti-inflammatory effects have shown a clinical benefit in ASCVD and heart failure. Importantly, we are approaching the expected completion dates of multiple ongoing studies in ASCVD and heart failure in the next 2 years, in particular, trials of Ziltivekimab, an anti-IL-6 monoclonal antibody. The first expected readout in late 2025, early 2026 is the Phase III ZEUS trial in patients with ASCVD and chronic kidney disease. Among the different targets in cardiovascular disease, we believe that IL-6 inhibition, in particular, is supported by multiple compelling lines of evidence. Human genetic studies have consistently shown an association between genetic variants of downregulated IL-6 signaling and a lower risk of ASCVD across the spectrum of disease in coronary artery disease, in atherosclerotic ischemic large vessel cerebrovascular disease and in peripheral artery disease. A causal relationship was recently identified in Japanese individuals, further extending these findings across ancestries. We are collaborating with experts to review and expand these analyses, which we expect to share when completed. Many large epidemiological studies have demonstrated a robust association between levels of hs-CRP, the key downstream biomarker of IL-6 pathway activity and major adverse cardiovascular events, including cardiovascular death. In recent studies led by Dr. Paul Ridker in both secondary and primary prevention populations, hs-CRP has even outpredicted LDL cholesterol. In addition to the epidemiological evidence supporting hs-CRP as a predictor of risk, directly measured IL-6 levels as well have shown consistent associations with MACE. These data were recently summarized in a review article we participated in for current atherosclerosis reports, which is available on our website. Finally, detailed analyses of CANTOS, the Phase III randomized placebo-controlled trial of Canakinumab highlight the importance of IL-6 pathway inhibition as presented by Dr. Bonaca earlier. Canakinumab is an inhibitor of IL-1 beta, which lies upstream of IL-6, therefore, partially inhibiting IL-6, among other cytokines. In CANTOS, it was a subgroup of patients who achieved robust IL-6 pathway inhibition that showed the largest benefit. The subgroup with on-treatment IL-6 below the median had an over 30% reduction in MACE, as shown here. Similarly, the subgroup who achieved lowering of hs-CRP below 2 milligrams per liter had a large reduction in MACE. Those who did not achieve robust inhibition of the IL-6 pathway did not have a lower risk of MACE. It was these findings that led to the increased interest in targeting IL-6 directly with IL-6 inhibitors such as pacibekitug. Human genetic evidence, results from clinical trials and epidemiological studies, mechanistic data and animal experiments all support IL-6 is a key target to lower ASCVD risk. It is uncommon and exciting to have this degree of concordance among different types of data supporting a drug target in cardiovascular disease. The key biomarker of inflammatory cardiovascular risk remains hs-CRP. The hs-CRP testing is widely available, standardized and inexpensive, and levels of hs-CRP have shown a consistent association with cardiovascular risk, leading to its incorporation into clinical guidelines. Among mechanisms with known or hypothesized anti-inflammatory effects studied in cardiovascular populations to date, IL-6 inhibition has achieved the most rapid and most robust reductions in hs-CRP in clinical trials. Based on available data in cardiovascular populations in cross-study comparisons, reductions in hs-CRP have been rapid and approximately twofold greater with direct IL-6 inhibitors than for Colchicine or GLP-1 receptor agonist. With IL-6 inhibitors, reduction in hs-CRP of 80% or more were achieved within 2 weeks, whereas with GLP-1 receptor agonist, an hs-CRP reduction of approximately 40% was observed at 52 weeks. Similarly, in cross-trial comparisons, with IL-6 inhibitors, about twice as many patients achieved hs-CRP reduction below 2 milligrams per liter, the commonly used threshold for residual inflammatory risk compared to other anti-inflammatory therapies. Approximately 8 out of 10 patients were able to achieve hs-CRP below 2 milligrams per liter when treated with direct IL-6 inhibitors. These results were observed despite higher baseline hs-CRP levels in the studies of IL-6 inhibitors. Notably, pacibekitug has already demonstrated robust hs-CRP suppression in previously completed studies of patients with high-grade inflammatory autoimmune diseases, such as rheumatoid arthritis, Crohn's disease and lupus. Rapid, robust and durable dose-dependent reductions in hs-CRP were observed across approximately 450 subjects previously dosed in 6 Phase I and Phase II studies. In addition to the compelling evidence supporting the potential for efficacy of IL-6 inhibition in CVD, it is important to note that the safety profile of IL-6 inhibition has been well characterized. The safety profile of IL-6 pathway inhibitors has already been tested through substantial clinical experience in patients with high-grade inflammatory diseases. Over 1 million patients have been dosed worldwide with anti-IL-6 and anti-IL-6 receptor monoclonal antibodies across an expanding number of indications since initial approval of tocilizumab for rheumatoid arthritis in 2010. Specifically in patients with or at high risk for cardiovascular disease, the emerging safety profile of IL-6 inhibition has been encouraging to date. For example, in Phase II studies of Ziltivekimab in patients with chronic kidney disease and not autoimmune disorders, there was no signal of clinically meaningful thrombocytopenia, neutropenia or lipid abnormalities, and no increased risk of serious infection was observed. These observations suggest the potential for a more benign profile in patients with cardiovascular disease compared with patients with autoimmune disorders. In addition to date, there have been no reports of major safety-related amendments to the ongoing Ziltivekimab program, which includes 4 global cardiovascular outcome trials expected to enroll over 22,000 patients in total with over 11,000 patients on active drug. Turning to pacibekitug, we are reassured by the safety data observed to date in approximately 450 subjects previously dosed with pacibekitug in 6 completed Phase I and Phase II studies in patients with autoimmune diseases, including highly inflammatory conditions such as Crohn's disease as well as in healthy volunteers. These data were reviewed by FDA and supported the initiation of our 2 ongoing clinical programs in cardiovascular disease and thyroid eye disease, which continue to evaluate the safety of pacibekitug. Importantly, progress in clinical trial monitoring and execution may mitigate safety risks as well. With regard to infections, in the CANTOS trial of the IL-1 beta inhibitor, Canakinumab, an initial increased risk of fatal sepsis was reduced following efforts to improve prompt recognition of infection and initiation of antibiotics. These learnings are being applied to Novo Nordisk's ongoing Phase III studies. Our lead cardiovascular indication is atherosclerotic cardiovascular disease due to the tremendous unmet need and compelling clinical evidence supporting the therapeutic potential of IL-6 inhibition as reviewed by Dr. Bonaca in his presentation. ASCVD continues to be the world's biggest killer as described by the World Health Organization. And despite available and emerging therapies, we believe there is significant unmet need for targeted anti-inflammatory therapies. Dr. Bonaca noted the high rates of cardiovascular death, heart attack and stroke in patients with polyvascular disease, also known as metastatic atherosclerosis. He summarized the high morbidity and mortality in patients with peripheral artery disease, who suffer not only from cardiovascular death, heart attack and stroke, but also major adverse limb events such as limb ischemia requiring urgent procedures such as revascularization or amputation. These are examples of patient populations with inflammation-driven disease where targeted anti-inflammatory therapy has the potential to show substantial benefit. To advance the development of pacibekitub in ASCVD and other cardiovascular diseases, we are conducting the Phase II TRANQUILITY trial. The study has completed enrollment after an over enrolling a total of 143 subjects with elevated hsCRP and chronic kidney disease. Enrollment of chronic kidney disease patients has been used to enrich for study participants with elevated hsCRP. Subjects have been randomized to subcutaneously administered pacibekitub 50 milligrams quarterly, 25 milligrams quaterly,15 milligrams monthly or placebo and will be treated for 6 months and followed for an additional 6 months. The primary endpoint is changed from baseline in hsCRP at 90 days and we are on track for reporting topline data through day 90 in the second quarter of 2025. We will comprehensively characterize changes in hsCRP, including the percent of patients who achieve an hsCRP of less than 2 milligrams per liter, the standard threshold of residual inflammatory risk. We also plan to report safety, tolerability, PK and additional biomarkers such as lipoprotein (a). As a reminder, pacibekitub was previously dosed in approximately 450 subjects with autoimmune disorders and healthy volunteers across 6 completed Phase I and Phase II studies. Based on these prior clinical data, coupled with simulations from a pharmacokinetic, pharmacodynamic model, we aim to demonstrate in TRANQUILITY rapid and robust hsCRP reduction, confirmed quarterly dosing and support a safety profile to proceed directly into Phase III studies. These results would allow us to be Phase III ready in ASCVD as previously aligned with FDA. We are excited to announce today our second cardiovascular indication for pacibekitub, abdominal aortic aneurysm or AAA. Abdominal aortic aneurysm is a common, severe vascular disease associated with significant morbidity and mortality, affecting approximately 2 million people in the U.S. AAA provides a strong strategic fit with our primary cardiovascular indication, ASCVD due to overlapping health care providers and shared patient demographics and comorbidities. The natural history of abdominal aortic aneurysm is one of progressive expansion and an associated increased risk of rupture. The rupture of AAA is a catastrophic and usually fatal event. Studies have shown that most medium-sized abdominal aortic aneurysms grow to the threshold for surgical repair within 5 years. To prevent rupture, surgery is recommended for large abdominal aortic aneurysms. However, surgical repair, whether done via endovascular techniques or open surgery is associated with near-term and long-term complications and is not a simple cure. No treatment has proven effective to slow AAA growth and addressing this treatment gap has been identified as a high priority among vascular specialists and researchers. The totality of data provide compelling evidence to support the therapeutic potential of IL-6 inhibition to slow the growth of abdominal aortic aneurysms. First, let's turn to the human genetic evidence. Naturally occurring human genetic variants that mimic low-dose IL-6 pathway inhibition have been associated with statistically significant reductions in the risk of developing abdominal aortic aneurysm. Shown here are the results of our recent collaboration with Dr. Burgess, Dr. Gill and team at Sequoia Genetics. In this study, the reduction in the risk of abdominal aortic aneurysm was highly statistically significant and consistent across the cohorts examined. The magnitude of risk reduction was notably even larger than the well-established reduction in the risk of coronary artery disease and on par or even larger than the reduction in the risk of autoimmune disorders for which IL-6 pathway inhibitors have been approved, such as rheumatoid arthritis and polymyalgia rheumatica. Also notable is the specificity of the findings for AAA rather than aneurysm in general, which is consistent with the known differences in the underlying biology of these aneurysms. This patient -- this paper has been published in the AHA Journal arteriosclerosis, thrombosis and vascular biology and is available on our website. Epidemiological evidence is supportive as well. Higher circulating levels of IL-6 and higher aortic tissue levels of IL-6 has been associated with the presence of AAA. In addition, levels of hsCRP have been associated with the size of abdominal aortic aneurysm. Finally, experimental evidence has been supportive of the positive impact of IL-6 inhibition on AAA. In mouse models of abdominal aortic aneurysm, genetic and pharmacological inhibition of the IL-6 pathway signaling have been associated with decreased aneurysm expansion. We are planning to initiate a Phase II proof-of-concept study to evaluate the ability of pacibekitub to inhibit the growth of abdominal aortic aneurysms. Serial imaging lies at the foundation of clinical care for patients with abdominal aortic aneurysm, embedded firmly within clinical guidelines. And for our Phase II study, we expect to leverage multimodality imaging to efficiently characterize pacibekitub. Dosing will be informed by TRANQUILITY top line data, which we expect to report in the second quarter of 2025. We plan to discuss with the FDA the Phase II proof-of-concept design and share details of the forthcoming trial prior to study initiation. In summary, we are excited to advance and expand pacibekitub's cardiovascular development plans and look forward to sharing key updates with you all next year. I'll now hand it over to Gerhard.

Thank you, Emil. Let's now dive into pacibekitub's potential to change clinical practice in cardiovascular disease. Unlike other new and emerging mechanisms of action or MOAs in the cardiometabolic fields, such as GLP, NLRP3 or LP(a) therapies, there is important scarcity value in the IL-6 class. While we see 7 to 11 companies developing assets within the other MOA categories here on the slide, in the IL-6 class, there's only Novo Nordisk with their monthly IL-6 inhibitor, ziltivekimab and our quarterly PACIFIC effect in cardiovascular information development. We would note that clazakizumab is included here for completeness. However, its route of administration is intravenous and CSL's current publicly stated strategy is focused on nephrology as opposed to cardiology. There is strong rationale to develop IL-6 inhibitors in multiple CV diseases with residual inflammatory risk totaling an estimated population of over 20 million patients in the U.S. alone, certainly a very large market opportunity for the only 2 IL-6 inhibitors currently in clinical development. Atherosclerotic cardiovascular disease, or ASCVD, is the largest market with an estimated total addressable market, or TAM, of 14 million patients in the U.S. based on the number of patients with hsCRP levels greater than 2 milligrams per liter. While Novo Nordisk is running 4 cardiovascular outcomes trials, 2 in ASCVD and 2 in heart failure. It's important to note that there is significant white space left for us to assess and to target a broader label than monthly ziltivekimab is currently going after. For example, chronic ASCVD, which is comprised of high-risk factors other than Stage 3 to 4 chronic kidney disease, or CKD, represents approximately 3/4 of the total addressable market of 14 million patients in the U.S. Moreover, and as announced by Sandeep earlier, we're planning a Phase II proof-of-concept trial of pacibekitub in AAA, where we see high unmet medical need and very limited competition. We are taking differentiation very seriously, and our approach is 3-pronged. First and foremost, we believe that pacibekitub's potential for quarterly dosing as opposed to ziltivekimab's monthly dosing has the opportunity to be a real game changer, one that could cement pacibekitub's best-in-class potential. Second, and as I alluded to on the previous slide, we will further differentiate through our development strategy. There are a number of high-risk patient populations within our lead indication ASCVD that we are currently assessing for pacibekitub and where Novo Nordisk is not presently conducting clinical trials. Some potential patient populations were mentioned by Dr. Bonaca in his earlier presentation. Moreover, AAA is a very high-risk patient population where pacibekitub could even be first in disease. Finally, being second to market would offer us tremendous opportunities to learn fast, generate critical insights and act upon them. We are eagerly awaiting Novo Nordisk's first outcomes trial to read out in ASCVD patients with stage III to IV CKD, the ZEUS trial. Learnings from this trial and others may guide us to additional points of differentiation in addition to development strategy and as we're evaluating in our ongoing TRANQUILITY trial quarterly dosing. Quarterly dosing has the potential to drive greater adherence in CV patients, and therefore, could profoundly improve outcomes. It is well established that nonadherence in CV patients is a big problem. Notably, there is substantial evidence demonstrating that greater adherence positively impacts cardiac outcomes and mortality. It is also well characterized that greater adherence leads to fewer hospitalizations and significant economic savings. One way to improve adherence is through the root of administration. Across disease states, long-acting subcutaneous injectables tend to demonstrate greater adherence than orals. And even more importantly, there is compelling evidence demonstrating that less frequent subcutaneous dosing leads to significant improvements in adherence, as shown by the 2 relevant examples depicted on the bottom of this slide. Our second prong and our 3-pronged approach to clear differentiation is development strategy. This illustration depicts how we strategically assess first-in-class as well as first-in-disease opportunities in CV for pacibekitub. As we evaluate target patient populations within ASCVD, we are prioritizing those where we believe pacibekitub can make a real difference for patients and where Novo Nordisk is currently not conducting trials. Dr. Bonaca outlined a few examples of high-risk patient populations earlier. We intend to explore these potential patient populations in addition to the ASCVD patients with Stage 3 to 4 CKD with a view to establishing a broader label than ziltivekimab. AAA is an exciting opportunity for pacibekitub. This is an indication with high mortality risk, strong rationale for IL-6 inhibition and no FDA-approved treatments currently available. We aim to establish proof of concept of pacibekitub here as a first-in-disease medicine. We approach strategic development decisions with 3 criteria in mind, as shown on the right-hand side of this slide. First, we start with the patient populations where the genetic epidemiological and clinical evidence is compelling. Second, we overlay this with high unmet medical need as shown by high and persistent risk of severe related morbidity and mortality. Last, we prioritize overlapping prescriber bases where we will test and demonstrate high motivation to initiate treatment with pacibekitub. If development and approval processes are successful for IL-6 inhibition in cardiovascular inflammation, it is likely that pacibekitub would follow ziltivekimab into the CV market. It is critical for us to learn from successful cardiometabolic brands that have not been first to market yet have gained significant advantage over their first-to-market class competitors. Outlined here are 3 well-known blockbuster brands that have accomplished exactly that, each in large part by successfully wielding 1 of the 3 prongs of our differentiation approach. No analog is perfect, and every launch is different. However, we can learn from Eli Lilly and how they successfully focused on their 1 point of differentiation for Trulicity, dosing and administration despite limited clinical differentiation versus Victoza. Their strategy included evidence generation demonstrating and promoting the benefits of weekly dosing versus daily dosing in their improved injection device. Jardiance is a very good example of a brand that differentiated through choosing the right target patient population and deploying a superior development strategy by generating first-in-class CV outcomes and hence, meaningfully opening the cardiology prescriber base for SGLT2s. And lastly, depicted on the third row on this slide, a very good fast learner example is that of Eliquis overtaking Xarelto after BMS and Pfizer learned from Xarelto's Phase III trial. They saw the opportunity to adjust their own pivotal trial by increasing the sample sites, which enabled them to achieve superiority versus warfarin. Clinical superior data from their Phase III resulted in promotable claims to U.S. cardiologists in addition to safety benefits. Efficacy claims that Xarelto could not make. In each of these examples, we see a brand achieving success over a first-to-market class competitor with just 1 of these strategies. Tourmaline has the opportunity to potentially deploy all 3 strategies, with multiple shots to drive further differentiation versus Novo Nordisk's IL-6 inhibitor. We expect to report TRANQUILITY top line data in the second quarter of 2025. And if positive, we expect those results to unleash multiple attractive paths for pacibekitub in cardiovascular inflammation. First, we aim to demonstrate rapid and robust hsCRP reduction, as we have already demonstrated in highly inflammatory autoimmune diseases. Second, we are evaluating the quarterly dosing that our robust PK/PD modeling predicts. And third, we plan to characterize the safety profile in high-risk cardiovascular disease patients. Results from the TRANQUILITY trial will inform dosing protocols for any Phase III trials we conduct at which point we intend to meet with the FDA and achieve Phase III readiness for ASCVD and possibly other trials. In AAA, we will begin preparation for a Phase II proof-of-concept trial. We believe that this will then put us in a superior position to assess multiple options for 2026, either through financing or partnering. Switching gears now to pacibekitub's best in disease potential in thyroid eye disease. TED is an independent shot on goal for our company. One that comes with its own blockbuster potential. The disease biology is different from cardiovascular inflammation. TED is an autoimmune disease with heterogeneous symptoms and importantly, inflammation at its core. 2024 has been a critical year for us, focusing on clinical trial execution, market research and many key panel leaders or KOL interactions. As Sandeep mentioned earlier, we expect top line data from the Phase IIb SPIRITED trial in the second half of 2025. We have ramped up our KOL engagement and conference attendances through medical affairs significantly this year. Our learnings from these interactions have confirmed a significant unmet needs in TED, starting with Tepezza's durability as a growing concern. In addition Tepezza's adverse event profile including hearing loss, menstrual reproductive issues, hyperglycemia and muscle spasms remains a challenge for TED treaters and its overall complexity represents a major barrier to prescriptions, especially from general ophthalmologists and endocrinologists. It was very encouraging for us to increasingly hear about the desire of endocrinologists to get more involved in the management of TED, a desire that is currently dampened by the the complexity of the available treatments. Notably, we continued to hear loud and clear from physicians about the need for new mechanisms of action in TED, not just new routes of administration for existing treatments. Consequently it is our strong conviction that returning to TED market to meaningful growth will require new therapeutic tools and innovation, the kind that IL-6 inhibition and pacibekitug can potentially offer. Our market research in the U.S. further confirms the significant unmet need in TED. From this research, the 3 most commonly stated issues with the only current FDA-approved treatment were, again, lack of durability, the management of Tepezza's AE profile and Tepezza's high level of administrative burden and complexity. Notably, and as depicted on the right-hand side of the slide, 140 TED treaters in the U.S. reported in quantitative market research that only 1 out of the 2 moderate-to-severe TED patients present with proptosis, which means that the other 50% of patients present with inflammation, diplopia and/or pain, but not proptosis. TED is certainly a heterogeneous disease with inflammation at its core, one for which TED treaters and patients alike desire a medicine that treats the disease holistically. Overall, we have seen very consistent results and feedback through a variety of different channels. We consider the wealth of published tocilizumab data in TED as indicative of our proof-of-concept. Tocilizumab, a first-generation IL-6 receptor inhibitor, has shown promising proptosis and clinical activity score or CAS response rates as well as autoantibody reductions in over 350 mostly steroid-experienced TED patients. Our market research revealed that many HCPs already routinely use IL-6 inhibition in their practice. Based on the previous slides data as well as our existing data package, we developed and tested pacibekitug's target product profile or TPP, one that we believe is possible. I'm pleased to share with you that pacibekitub's TPP offers us multiple differentiation levers as shown on the right-hand side of the slide. Differentiation from either other MOAs or from satralizumab, the second IL-6 inhibitor currently in development for treatment of thyroid eye disease. Pacibekitub targets inflammation, which is at the core of TED and with that has the potential to impact many quality of life impacting symptoms. Pacibekitub has demonstrated a long natural half-life and the safety profile has the potential to be well tolerated. Finally, we are evaluating what would be the most patient-friendly subcutaneous dosing in the TED market. In a mask survey of future TED market basket of potential products, we ran the TPP from the previous page by the same 140 TED treaters in the U.S., 60 general ophthalmologists, 40 oculoplastic surgeons and 40 endocrinologists. In this survey, not only did the IL-6 class capture the highest market share among all MOA classes, pacibekitub also captured the highest market share within the IL-6 class. This was true across all 3 HCP specialties. We also uncovered an important shift in the TED market. The right-hand side depicts a significant increase in the willingness to prescribe from endocrinologists and general ophthalmologists if subcutaneous therapies become available to treat TED in the future. Given the leading market share in this market research, we believe that pacibekitub could capitalize on the shift and therefore, contribute to reaching many more patients in the future than are currently reached by Tepezza, driven significantly -- by significantly more prescriptions from endocrinologists and general ophthalmologists. SPIRITED is our ongoing Phase IIb trial in the first-line TED setting. It is the first of 2 pivotal trials as previously aligned with the FDA. We aim to enroll 81 patients across 3 arms: pacibekitub 50 milligram, a lower dose of pacibekitub with 20-milligram and placebo. The first period of the study includes 3 injections, 1 every 8 weeks in each dosing group. The primary endpoint of the SPIRITED trial is proptosis response rate at week 20. Important secondary endpoints such as CAS and the diplopia responses are included. As mentioned by Sandeep earlier in the presentation, in light of our increased focus on cardiovascular inflammation, initiation of a Phase III trial in TED will now be dependent upon results from the SPIRITED trial. As we look forward into 2025 and beyond, we are incredibly excited about the potential for pacibekitub. To summarize. We expect to report top line data from our Phase II TRANQUILITY trial in quarter 2 2025 and top line data from our Phase IIb SPIRITED trial in the second half of 2025. We also plan to initiate a Phase II proof-of-concept trial in AAA if we report positive data from TRANQUILITY. And with that, we'd like to open the floor now to your questions. Operator?

[Operator Instructions] As a reminder, today's event is being recorded, and this recording can be accessed later on the event page of Tourmaline's website at www.tourmalinebio.com. Once again, this conference is being recorded and can be accessed later on the event page of Tourmaline's website, www.tourmalinebio.com. [Operator Instructions] Our first question today is coming from Yasmeen Rahimi from Piper Sandler.

Two questions. Maybe the first one is on a, I think it was very clear, strong mechanistic rationale, very high unmet need and a large market opportunity. But could you maybe talk about what the regulatory path would be? What would a potential POC study look like? And also, if you could talk about what a registrational study would look like? Just broad strokes. That's sort of question one, in question 1 and 2. And then the last question is, what led to the decision to wait to see the SPIRITED data before kicking off the Phase III? What -- was there a data -- like is it just a competitive field? Is it the cash position? Or what -- I guess, what led to say, let's see the data and then come back to commit to TED. I appreciate your thoughts on it, and I'll jump back into the queue.

Great. Thanks Yasmeen, both good questions. Emil, do you want to take the first one?

Sure. Thanks. Thanks for your question. So we are very excited about AAA, as you noted, just given the prevalence, unmet need, no approved therapies to slow progression and the compelling evidence from multiple lines, suggesting the IL-6 inhibition in particular, maybe a target therapy to slow progression. Now this is an exciting area which where development is unprecedented. So I think that we will require a number of conversations with regulatory authorities in order to clarify next steps and the approach to development. In the context of the Phase II, the high-level aspects of design are more clear in the sense that we'll be looking at imaging parameters to look at progression of size, such as looking at diameter using CT scans. And again, we're thinking through this very carefully with our SAB members in order to refine the design of the Phase II proof-of-concept study. Now for Phase III, this is something again that we'll have to engage the regulators in order to refine what the approach will be. But right now, the base case would be that this may -- would require a clinical composite endpoint, looking at AAA related events. As Dr. Bonaca had mentioned, this is a very high-risk population. So even in the context of a cardiovascular outcome trial, we would anticipate quite an efficient study. Of course, more discussions to be had here as far as the approach.

Great. And in terms of your second question, I mean just to be super clear, like we remain completely masked to all the data from the SPIRITED study. So this decision today is not based on anything specific to the trial. I think what's become clear and in our conversations because I think you recognize this as well is that there's just real enthusiasm for IL-6 inhibition in cardiovascular disease and really massive potential opportunities within CV inflammation. And so we made decision to help prioritize the research so that we put ourselves in the best position possible to take advantage of these potential -- very large opportunities ahead of us. We continue to believe that the TED market opportunity is very -- very exciting the unmet need here still persists and Gerhard pointed out, we do think that returning this class to growth is going to take a different mechanism of action, not just a new route of administration and so we are -- we're committed to running the SPIRITED study as quickly as possible, getting data from it, taking a look at that before committing to next steps within TED.

And then Sandeep, I'm so sorry, I want to squeeze one last question, if I may, which is for a phenomenal speakers and experts. If they could talk about the translation of the TRANQUILITY study and how that population could derisk the development in AAA. I would appreciate that. And I'll jump -- now I will jump into the queue back.

Great. Dr. Bonaca?

So if I understand the question, these are great questions about the TRANQUILITY data and how that might derisk development in AAA space. I think the TRANQUILITY data are going to give us a lot of information that will be supportive in trial design. I think the most important is sort of what happens to inflammatory markers and the CRP in terms of what we understand about the biology of AAA and what we know from observation cohorts of patients with AAA. And so if we think we can achieve or we observed in TRANQUILITY that we've achieved, adequate CRP reduction, I think that gives us a lot of confidence in terms of under -- modifying the underlying biology of AAA. And then in terms of the development programs that's something that then can be tied into a Phase IIb or Phase II type program for potentially an outcomes trial. I think the one thing I'll note is that this is a totally unmet need. There are no medical therapies. And I think there are potentially ways to be created in the development program to accelerate potentially approvals looking at different outcomes. Usually, this is a combination of progression and part outcomes, but depending on what we observe in TRANQUILITY and the potency of the effect, one can even imagine more accelerated pathways. So I think the mechanism of the drug is going to real proof of concept or way of derisking it. And then I think AAA remains a very exciting opportunity.

Next question today is coming from Josh Schimmer from Cantor.

I have 3 quick ones, if that's okay. I guess, first, you've chosen to add a CV indication in lieu of more of an I&I inflammatory or autoimmune indication, does that imply you're kind of increasingly tipping towards cardiovascular as a strategy? Or might we expect additional indications to be added on the I&I side?

Josh, I'll take that. I appreciate the question. Right. So when we set out less than 3 years ago, we were open to which indications made the most sense. We were going to follow the clinical data, the biology here. Like I think the interest in CV, from our point of view, has been clear from day 1. I think the interest has increased organically over the last year and looking through pass it back to talk where the opportunities are. We see a lot within CV inflammation here. So we'll continue to evaluate additional indications as we have over the last few years and think about adding new indications in the future agnostic to are they in CV or not. But I think it's clear that CV inflammation is our focus right now, and we are excited about what we see ahead of us.

Okay. And then for patients who have AAA, what are the indications for repair? Is it all based on size? Is it a threshold? Or are there other criteria?

Great. Dr. Bonaca?

So thank you, Sandeep. Yes, the indications for repair are most commonly the absolute dimension. So it reaches a certain size when we know if it continues to grow the rupture risk is quite high. We do see some patients that are accelerating rapidly and so the rate of change might identify patient where you perceived even earlier. So it's the rather than 2 to 3 millimeters per year, you see 0.5 centimeter or more over a short time period you can intervene. And in the third place where we tend to intervene sooner as symptoms. And I mentioned this is asymptomatic disease, but there are patients who come in with even more inflamed aneurysms and they develop abdominal pain and discomfort and you know that the aneurysm is going to progress rapidly or is it at risk of imminent rupture and we proceed sooner. So the indications would be absolute size, rate of change or development of symptoms indicating rapid progression.

Got it. And then last question. How sensitive are the imaging techniques, like what could you be realistically able to discern in a Phase II study over, say, 6 to 12 months?

I can start maybe and Dr. Bonaca, feel free to add. So I think this is one of the reasons why we're quite excited about conducting an imaging-based trial at this point in time, our advances in imaging techniques. Historically, trials of AAA and diagnosis of AAA relied on ultrasound scans where the precision of measurements is not great. However, what we are considering using or planning on using is relying on CT scans with the emergence of good CT scanners, talking about the precision compared to ultrasound, it's over -- an older magnitude a better. And so we think that in the context of 1- or 2-year study, 1-year study that we would be able to see with reasonable sample sizes differences between pacibekitub and control in natural history.

Your next question is coming from Thomas Smith from Leerink.

Now that you finished enrollment, any sense for how the patient population here in TRANQUILITY compares to the Phase II RESCUE study of ziltivekimab? And I guess anything you would call out we think about expectations for the top line data in Q2?

Emil can you take that?

No, thanks for the question. Great question. So we have been monitoring the data closely. We won't share at this time yet the characteristics of the patients. I'll just say that they're as would be expected in the similar patient population of patients with chronic kidney disease who are at risk for atherosclerotic cardiovascular disease. So these are patients enrolled who have CKD and elevated CRP.

Understood. Okay. And then with respect to TED, So. wondering if you could just comment on how enrollment into the Phase II SPIRITED trials going and your level of confidence in getting data there in the second half of next year? And I guess a follow-on to that. Now that you're going to wait for the SPIRITED results to start the Phase III. Can you just talk about how quickly you might be able to get that trial off the ground pending the Phase II results and what that might do to your potential registrational time line?

Sure, I'm happy to take that. So we continue to enroll SPIRITED study as quickly as we kind of recognize the competitive landscape here for trials in TED. As we've talked about before, we've been planning to add additional ex U.S. geographies. So that all continues as planned. So where we sit today, we are confident in having data second half of next year. One thing we've said, which I'll reiterate is the need here to make sure we enroll patients who have active inflammatory disease. Gerhard pointed this out, and I think this is completely true. It's just that TED is inflammatory as core. We need to enroll patients who are likely to benefit through IL-6 inhibition. So we're adamant by not relaxing our inclusion/exclusion criteria, just from sake speed, if that comes with a price of potential risk in the study. Now in terms of how quickly we will start the Phase III study. We are -- we have met with the FDA. We have a good alignment on what the overall size of the trial needs to look like, what the endpoints are [indiscernible] fairly well defined at this point. So we built to start the study relatively quickly after getting top line. So I just want to reiterate, we are very excited about what we're seeing in CV or TRANQUILITY trial over enrolled, right on schedule. We've -- we'll have data in the second quarter of next year. There are a lot of different paths to pursue within CV. And so we are excited about being able to keep our optionality open and preserve our balance sheet so that we're able to on make the right decision for the program.

Next question is coming from Roger Song from Jefferies.

Maybe 2 from us. One is related to the CV ASCVD to AAA indication expansion. Maybe correct me if I'm wrong, to me, AAA seems more local disease versus ASCVD more systemic disease. The implication for that is, how should we think about the drug exposure locally for AAA and then how much read-through we can have from the ASCVD data readout and dosing to the AAA dosing? That's the number 1 question. Number 2 is related to the TED understanding you want to wait for the Phase IIb data to start Phase III and then you do have some powering assumption for the Phase IIb. Just curious anything changed in terms of your expectation for the Phase IIb before you start Phase III? And maybe just simplify that is if you hit that the assumption, would you be able to start Phase III?

Thanks, Roger. Maybe Dr. Bonaca, can you take the first question?

Thank you. One great question about the role of inflammation in ASCVD is sort of systemic through the vasculature because you have plaque in different places where AAA is quite localized. And so the answer to that is both. Patients with AAA, it is true that the aneurysm itself is localized. And that's because the abdominal aorta is particularly vulnerable to inflammation in a way that we don't see in the branch arteries. It's also because of where it's located and the effects of other things like that. And so then you tend to see the manifestations in the AAA, but the patients are actually systemically inflamed, and you can see this from CRP levels. This happens in the context of all the risk factors I described in cardiometabolic disease, smoking. So they are systemically inflamed. And what's interesting is that many of the patients with AAA also have plaque atherosclerotic slack in the legs, in the heart and in the brain. And so these are not mutually exclusive diseases. There's actually an overlap there. And therefore, I think systemic therapy is critical. In fact, the localized therapy of exclusion, if you will, and others have said, well, can we just treat inflammation in the order itself. The problem with that is that there's actually broader inflammation in the order, and you'll get -- we're not going to get optimal outcomes even after repair, if you don't treat the systemic inflammation more broadly, but it's also that these patients then have heart attacks and strokes and other things that are driven by systemic inflammation even once you repair to the AAA. So it's a really, really thoughtful question, but I think systemic inflammation is the problem for both, even though you're absolutely right that the abdominal aorta is the most vulnerable to the aneurysmal findings.

Great. And then on your second question regarding TED, I just want to restate that. We have not seen any data from the ongoing trial. We remain completely blinded to the study results at this point. And so the decision today was not driven by anything we've seen in the data, just to be really clear on that point. And so in terms of what this looks like going forward, I think this is being more of a traditional drug development path where we run a Phase IIb study, look at results and then use that to help further refine it for the Phase III design now. We've designed the Phase IIb trial powered around assumption of what we see as a clinically meaningful difference versus placebo on the primary endpoint here. And assuming we hit that, we would expect the size of the Phase III trial would be something that is in line with what we have already agreed upon with the FDA, of course, of -- once we see the data, we'll be able to make any further changes to the protocol at that point, but those will likely be relatively modest.

Our next question today is coming from Yatin Suneja from Guggenheim Partners.

I just wanted to go back on the question that Tom asked earlier, about the baseline. Could you maybe help us understand, is there a reason for us to believe that the baseline of TRANQUILITY patient would be different than the RESCUE study that Novo conducted in terms of the reduction in CRP level, should we basically use that study as a benchmark? I think it was in the 80-plus percent range on percentage reduction and then also on the responder just love your articulation on exactly what we should be expecting.

Thank you for the question. Emil, can you take that?

Yes. No, happy to take that. And just to describe our expectations for the Phase II TRANQUILITY study. Just to take a step back, the dosing that is used in the ongoing TRANQUILITY study was informed by the prior clinical experience. So again, approximately 450 subjects dosed across 6 completed Phase I and Phase II studies in both healthy volunteers and patients with high-grade autoimmune disorders. And that informed a PK/PD model from which we selected the doses and the dose -- dosing regimens, 50 milligrams quarterly, 25 milligrams subcutaneous quarterly, 15 milligrams subcutaneously monthly, they were selected in order to at least achieve a CRP reduction at day 90, our primary endpoint as was observed by ziltivekimab in the RESCUE study. So those were the data and those were the decisions that informed the dosing. So what we would anticipate from TRANQUILITY and we're going to characterize hsCRP robustly and completely. And in particular, 2 key ways or percentage reduction, which I've mentioned and the other key way, which we think may be even more important as a proportion of percentage of patients who achieve an hsCRP less than 2 milligrams per liter. And for both of those endpoints, we would project or expect to get results on par with ziltivekimab and with was accomplished in the RESCUE study. Again, that 2 milligrams per liter has emerged as a critical threshold for defining residual inflammatory risk. And if you look at CANTOS that was the subgroup, the subgroup of patients who achieved a CRP less than 2. That was a subgroup to achieve reductions in major adverse cardiovascular events of 30% and had a significant reduction in cardiovascular death. And so we believe that based on the PK/PD modeling that these doses will achieve similar outcomes in CRP is what was observed in the ziltivekimab Phase II RESCUE study.

Maybe one more. Like in terms of the baseline or the patient population, what generally is the CRP level for this type of population in general?

Yes, so for baseline CRP levels, the information that we have is based on epidemiologic studies and Phase II studies like RESCUE and CANTOS. So in the context of RESCUE, the baseline CRP level was a bit over 5 and in the CANTOS study a bit over 4. And so in the context of patients with CKD and high CRP levels, we would anticipate ranges around those levels seen in trials and other epidemiological studies of patients with chronic kidney disease. So in general, just to review, patients with high-risk cardiovascular disease, residual inflammatory risk typically 2 to 10 milligrams per liter, it tends to be the range. When CRP levels get higher than 10, clinically, there's a question of whether or not there might be an acute process like an infection, mild infection or inflammation that may be driving those higher levels. And so in clinical practice and by prior guidelines, the recommendation is the CRP is greater than 10 to repeat it, just to reexamine the patient and to establish their baseline inflammatory state.

Next question is coming from Alexander Xenakis from Truist Securities.

Do you think you need the quarterly dosing to be attractive over the competition? Or how do you weigh the need for quarterly dosing over every other month dosing in case there is an efficacy difference that we see in the trial?

Alex, thanks for the question. Gerhard, do you want to take that?

Yes, I'm happy to take that. As I mentioned earlier in the presentation, we have a 3-pronged approach differentiation, quarterly administration being 1 of them, development strategy being the second and then having the opportunity to learn fast, generate critical insights that act upon as a third prong. So it is important, but it's not the be all and all. I want to say that the ASCVD total addressable market is very large. We estimate it to be 14 million patients in the U.S. alone. We believe potentially very high MACE risk reduction is possible as we've seen in the cancer sub populations. We are targeting high-risk patient populations and there are still plenty of opportunities for us to further differentiate [indiscernible] through development strategy by going for a broader label than ziltivekimab. And last but not least, currently, there is ziltivekimab and pacibekitub, 2 IL-6 inhibitors in a very large market opportunity. So overall, we believe that the opportunity will remain very large, even though quarterly is helpful, but the monthly will still make us very competitive given the differentiation approach that we have available.

And maybe one more. With all the studies and all the compelling data that you've been presenting, are you aware of any data from a biology standpoint that might show a difference in certain patient populations being more or less resistant to CRP lowering or is it pretty much uniform across all patient populations that you see?

Emil, do you want to take that?

Sure, happy to. So I mean, across populations, it's remarkable how consistent the epidemiological and genetic data have been digesting IL-6 inhibition and lowering CRP would reduce MACE. I would point to there are populations which appear to be even more inflamed where a potential for absolute or relative risk reduction may be greater, and those were some of the populations that Dr. Bonaca had outlined, patients with cardiovascular disease, peripheral artery disease, acute coronary syndrome with additional risk factors. But what's been quite remarkable across now probably over 100 epidemiological studies looking at hsCRP is the consistency of findings across different endpoints, comorbidities, demographics as far as the association from hsCRP and risk.

Yes. Maybe if I can add on to that. I mean I think what's notable is there's been a lot of interest over the last couple of decades in going after inflammation, but what's emerged is mechanisms that lower CRP appear to be the ones that are associated with positive MACE benefit here. And so we're eager to see the results from the Novo trial when that reads out. But overall, I think there's a really strong reason to believe that a mechanism that can lower therapy, especially one as much as IL-6 #10, should be associated with real meaningful benefit. Right, Dr. Bonaca, do you have anything else you want to add to that?

Well, I did agree with everything you said. The one notion that I will raise is that CRP is on nonspecific biomarkers. So in these chronic populations, where it's driven by vascular risk is very tightly linked just as Emil said, do you think there are risk for other programs where it could be raised due to the background inflammation or acuity event. So in the acute coronary syndrome setting for example, how much of the high CRP is driven by risks or other things. And then you may identify a group where you have more or less inflammation. And I think that's really the beauty of this design as we're selecting populations where it is the vascular disease driving the high CRP. And so therefore, you're identifying a group that should be responsive uniformly to the driving. I think that's a risk to some other programs.

Next question today is coming from Etzer Darout from BMO Capital Markets.

Just a couple. Just curious around maybe your observations internally or even externally that have led to sort of the increased enthusiasm on cardiovascular inflammation. How much was the shift may be driven by the 30-year cardiovascular outcome study in women? And do you think that the results of that study shifts physicians' focus to patients on CRP levels? And I have a follow-up.

Sure. You may ask Dr. Bonaca to comment on how we think about that study and maybe how his interest has evolved over the last, call it, a year or so and then I can talk about how we, from the company side, view these evolving?

Yes. Thank you for the opportunity. So I think that paper was very impactful for clinicians, but it's a piece of the puzzle. I think Paul Ricker has worked for hsCRP for a long time describes sort of an association. I think for a lot of clinicians who they want to prove that treating inflammation actually reduces risk that was the CANTOS story that followed. And then the next question was, okay, well, now we can lower LDL to really low levels of PCSK9s and there going to be LP(a) lowering maybe that will work, and we've got rivaroxaban and other antithrombotic drugs. So does it still matter? And that's where I think this most recent paper was really important to show that, that risk is independent and additive. So the reality then as a clinician is that, geez, no matter what I do in terms of lowering LDL or thinning the blood, like I'm never going to be able to address inflammatory risk about a targeted agent. I know from CANTOS, it will work if you have the right agent. And I think that has been really reinvigorated the inflammatory space. And I think then -- we thought we might have had a solution with colchicine that doesn't really lower CRP and the latest trial was a complete null. And so I've stopped using it, and I think a lot of clinicians have too. And so we really need the right drug. But that latest analysis really showed us that we can't ignore inflammatory risk if you want to be the best for our patients.

Yes. Maybe I'll add on that. I think the results that came out in the New England Journal were, of course, important and presented very active, but those results don't stand in isolation, still it builds on just decades of belief the inflammation matters and CRP is a predictor of that risk. So we've been interested in seeing inflammation since when the company was first in your first form, but over the last year you're -- I think it's undeniable that every week, every couple of weeks, there's a new publication coming out, implicating inflammation, implicating IL-6, implicating hsCRP a predictor of risk that we opened that we think is quite exciting. To have a chance to have a seat at the table as this field is really rapidly evolving. So like I would say that the results that came out earlier this year from Dr. Ricker's Group was really important to just further confirmation of the importance of going after this risk factor that I think we as the field have overlooked until now.

Next question is coming from Yi Chen from H.C. Wainright.

My first question is the decision to delay the initiation of the second pivotal trial in TED, simply due to capital availability and prioritization? Or are there other considerations?

I'll take that. It's the former. It really -- we're excited about CV inflammation. We recognize the costs associated with developing drugs within ASCVD and other cardiovascular indications here. And so big call the rationale for gating the Phase III TED trial upon results in Phase II is to reserve our strong financial position so that we keep our options open as we think through what is the right path to take this drug forward into later-stage development.

Okay. And can you comment on the estimated time line to announce partners for TED and ASCVD indications?

So we're not commenting on partnerships right now, as we've discussed before in the past that you see the companies that are interested in the cardiometabolic space right now to a number of them. We have good discussions ongoing with a number of them on any number of potential deals we've done here. I think there's broad recognition from industry that inflammation is an area that has not been well addressed within cardiometabolic disease with a lot of interest being catalyzed by some of the data for the GLP-1 agonist, for example, which do show CRP reduction to some extent, and there's a belief that the cardiovascular benefit that those drugs may be showing could be related to the degree of anti-inflammatory effect here. So I can't give you a time line. We're working off a time line of when we would plan to announce the deal. However, we think we have a lot of good options ahead of us. We're well capitalized to get into 2027 with our current cash year. So there's no rush to do a deal. We'll do with the one that makes the most sense for the company.

We reached the end of our question-and-answer session. I would like to turn the floor back over to Dr. Kulkarni for any further closing comments.

Great. Thank you. As we wrap up today, on behalf of the entire team of Tourmaline, I want to extend a sincere thank you to all of you for attending. I'd also like to thank Dr. Bonaca for his time and for sharing his valuable insights into the massive unmet need that persists within atherosclerosis and other cardiovascular diseases and how we may address this residual inflammatory risk. We believe that we are well positioned at Tourmaline as we head into the new year with 2 potentially transformational opportunities for pacibekitug in cardiovascular inflammation and thyroid eye disease. We look forward to sharing our first data readout in 2025. Happy holidays to all, and we look forward to speaking with many of you at investor conferences in the new year. Operator, you may now end the call.

Thank you. That does conclude today's teleconference and webcast. You may disconnect your line at this time, and have a wonderful day. We thank you for your participation today.