Thank you for joining the H.C. Wainwright 26th Global Investment Conference. My name is Yi Chen. I'm a healthcare analyst with H.C. Wainwright. For this session, I have the pleasure of chatting with Dr. Sandeep Kulkarni, Co-Founder and CEO of Tourmaline Bio. Welcome to the conference. Thank you for hosting. So I know Tourmaline is developing TOUR006 for the treatment of cardiovascular disease. Could you tell us why the anti-IL-6 approach would work for cardiovascular disease? Yeah, it's my pleasure. Yi, thanks for hosting, and to H.C. Wainwright for having us at the conference today. We are developing TOUR006, which is an anti-IL-6 antibody. Our company came together in May of 2022, really, like, focused on, like, a number of interesting areas and compelling clinical data that have only emerged in the last handful of years that we are well-positioned to taking advantage of. TOUR006, formerly TOR006, has very strong properties. Most of the data that we received from Pfizer, who had developed this, was with every eight-week administration. However, we think we can push that out to every quarter, which we're testing now. A lot of the interest in IL-6 has been in the cardiovascular space, where for the last several decades, there's been a recognition that lipids are important. However, inflammation may be an important driver of residual cardiovascular risk. And that's really come to a head now with just dozens of publications implicating inflammation and, more specifically, IL-6-driven inflammation, as being an important predictor of cardiovascular risk here. The marker that most folks have followed is high-sensitivity CRP which there are plenty of publications in large series, tens of thousands of patients looking at longitudinal risk in people with elevated CRP, showing that it is a very, very strong predictor of risk, even more so than LDL or Lp(a) risk factors that certainly get a lot more attention here. And so as we see the space evolving, we're really excited about the idea of going after this disease, not just as one of high blood pressure or as of high lipids, but thinking about a whole new axis to be able to modulate. Mm-hmm. Cardiovascular disease risk. Now, to the extent that CRP is a strong predictor of cardiovascular disease risk, IL-6 inhibition has been shown to deliver very deep reductions in CRP levels. We've seen that across the four hundred and forty-eight patients of data that Pfizer had generated. Others have seen it with IL-6 inhibition. You get deep reductions in CRP here. And so, we think all the lines of evidence are converging on this concept that inflammation matters, and more specifically, IL-6 could be a really important way to go after it. Got it. Well, you briefly touched upon the three biomarkers. So I know there is a recent publication in New England Journal of Medicine that stating that the three biomarkers, including CRP, could be predictive of cardiovascular event for in initially healthy U.S. women. So what is the read-through from that study to the application of pacibekitug in cardiovascular disease? Yeah, I mean, we thought the results of that study are just hugely important and potentially practice changing. Now, those results were presented as a late breaker at the ESC conference about a week and a half ago in London, and then simultaneously published in the New England Journal of Medicine. So, the data come from the Women's Health Study, which looked at 28,000 women who were enrolled in the early 1990s, and then tracked them for their, the rate of development of cardiovascular and other disorders. Now, what the results showed is that based on a random blood draw in the early 1990s, looking at three factors: LDL, Lp(a), and hs-CRP, that these three biomarkers can predict the occurrence of cardiovascular events as defined by MACE. All right, now, of the three, CRP, in fact, was the strongest predictor, outperforming both CRP, sorry, outperforming both LDL and Lp(a) which just speaks to this concept that in otherwise healthy people, that, inflammation is an important driver of cardiovascular risk, with, many important impacts on the, on the vasculature h ere. Mm-hmm We think the results show a few things. First of all, the importance of CRP, even relative to other risk factors, they get a lot more attention and then, two, to really start thinking through, like, a different paradigm here with practice-changing implications where, you know, the field has been very focused on the importance of lipid levels and LDL. However, measuring all three of these things, CRP, LDL, Lp(a), can provide just a much more comprehensive view about what causes risk in your patients. Thus far, the rates of testing for CRP have generally been low, in part driven by the fact that there's not an approved therapeutic specifically that can go after that risk factor here. However, we're starting to see calls for universal screening of otherwise healthy people looking at these three factors here. Mm-hmm. We think this is just a, like, potentially a sea change in how we think about cardiovascular disease, adding on an entire pillar to treating it beyond anti-diabetes medications, lipid-lowering treatments, anti-hypertensives. Mm-hmm. This really could be a brand-new way of treating a disorder that affects tens upon tens of millions of Americans and even more patients worldwide. Got it. Could you comment on the current status of the phase II TRANQUILITY trial? Yep When do you expect to report top-line results? Right. So we met with FDA, November of last year to get alignment on our phase II TRANQUILITY study. This is a dose-ranging PK/PD study in 120 patients, where we're testing both quarterly and monthly dosing of TOUR006 versus placebo. The primary endpoint here is change from baseline in hs-CRP. Mm-hmm. There's a regulatory precedent in place that a trial similar to our phase II study can essentially allow us to go into any number of CV phase III trials on the other side of it. So we've designed this as a trial that can allow us to pick a dose, confirm we can dose every quarter, and then move into later trials. In our study, we're enrolling people who have CKD stage III and IV as well as elevated markers of inflammation defined by an hs-CRP of two or greater. Mm. Right now, that trial is actively enrolling. We dosed the first patient in May of this year, and we're guiding to having data in first half of 2025. Got it. Well, as you mentioned, the endpoint is measurement of change from baseline levels of hs-CRP. Is that an approvable endpoint in a pivotal trial setting? So not yet. I mean, thus far, in the cardiovascular disease indication, the FDA is, you know, generally preferred to have outcomes trials. Now, there are a couple surrogate markers that can be used for approval. LDL comes to mind, as well as changes in blood pressure. However, CRP is still relatively new here. And so it's an important marker, just given how much evidence there is that CRP levels do track with different degrees of cardiovascular, disease risk. However, we're using our CRP as a marker to, one, confirm what dose we'd want to take forward, confirm we can dose every quarter, and then take that into outcomes trials on the other side of it. Now, that situation could change, you know, down the road when CRP is more established, not just as a biomarker of risk, but also as a predictor of clinical benefit, if you can reduce it. Right. However, we're not there at this point just yet. Right. So if a pivotal trial's endpoint is reduction in MACE, how long would it take for a pivotal trial to complete? Right. So there's a few ways to think about this. I mean, outcomes trials are certainly large, but this is meant to really prove you know the benefit in a very large group of patients on outcomes that are you know hard and clear, ones that are clearly recognized as being clinically meaningful. Given the high-risk nature of the patients we are going into, we think this could allow for fairly efficient trial design. We've seen some examples of other IL-6s going into CV outcomes trials from some of our competitors, where the trial designs are you know in the kind of 6- 10 thousand patient range. So certainly smaller than 15 or 20 thousand patients others have had to do for outcomes trials here. However, you know, in selecting for the high-risk group of patients we think we can potentially do that relatively quickly. Base case is kind of four years to an outcomes trial. However, there are some options to be able to do that sooner. Okay. I'll point out that one thing that's important to note when we look at the different trial designs and degree of risk here is that we're talking about a high-risk group of patients and going after a risk factor that has been poorly addressed today, which we think could potentially, you know, allow for outsized clinical benefit relative to, you know, incremental changes in LDL or other risk factors that are already been managed here. This is really just a ton of white space. Got it, got it. So, with respect to the other indications, thyroid eye disease, what existing evidence make you feel confident that the anti-IL-6 approach should work? Right. So, thyroid eye disease, it's a very different pattern than cardiovascular disease. It is an autoimmune disorder driven by a pathogenic autoantibody associated with Graves' disease, and that's been well established that that tracks with degree of symptom severity for TED. Now, the evidence for IL-6, it comes in many different forms. Like, first, there is good translational evidence showing that IL-6 levels are elevated in patients who have active thyroid eye disease relative to patients who do not have TED or who don't have any autoimmune disease at all. And then second of all, like, we know mechanistically, the IL-6 work is pleiotropic in terms of what it can do, with an important role on B cells, T cells, macrophages, and so can lead to a more kind of broad control of disease than you get with a more limited mechanism here. Now, the thing that we take the most confidence in is looking across the literature, where there are over 50 publications capturing the experience of 350 patients who have received IL-6 inhibitors off-label for the treatment of TED. All the data from these case series, reports, small studies, kind of points in the right direction of a mechanism that is very well tolerated, at least a good durability of disease control, and can lead to benefit, not measured just by a single endpoint, but more holistically gets the disease under control here. Now, TED, at its very core, is an autoimmune disease. There's a very clear inflammatory component. Patients present, you know, hot. They have inflammation, they have swelling, they have redness, they have itchiness, they have pain. So a drug like ours is a direct-acting anti-inflammatory we think can lead to a real benefit for a disease that we know is inflammatory and autoimmune in nature. The history of autoimmune disease is to get control of the inflammation as quickly as possible. It's true with RA, true with psoriasis, any number of indications. A drug like ours, we think, could really help get that disease controlled quickly with a mechanism that has been well validated. To date, IL-6 inhibition has not been tested in a true industry-sponsored, registration-directed clinical trial, so we'll be among the first to generate that dataset, despite the fact that there's just been ample, ample case reports and series out there suggesting that this should work, just has never been formally studied to date. Got it. Have you observed any side effects of TOUR006 in TED patients? So we've, like, of course, track safety across our clinical studies. We've not observed anything that we need to disclose, like, thus far, so we're confident in the safety profile for what we've seen so far, in part, given how much data we inherited from Pfizer, where they dosed over 400 patients across phase I and phase II. The results of those trials has been made public. It's published. Doses of 50 mg and below, which is the highest dose we're testing, were all very well tolerated, with safety level comparable to placebo. We think we also benefit from how much class experience there has been with IL-6 inhibitors across any number of autoimmune and inflammatory disorders. Over an estimated million patients have been dosed with IL-6 inhibitors in commercial usage, clinical trials. So, this is a safety profile that's been well established, and what we see in our phase I and phase II is very much consistent with the IL-6 field. Now, in TED specifically, like, I'd refer you to the case series looking at use of tocilizumab off-label, where the safety profile almost invariably is referred to as it's easy to give. Safety profile has been quite strong, so we take a lot of confidence looking at those reports. Mm-hmm. Okay. So, can you comment on the current status of the spiriTED trial? Yep And when do you expect to report results? Absolutely. So we've designed our phase II spiriTED study to be our first of two pivotal trials. We met with FDA in May of 2023 and came out with good alignment about what the trial design needs to look like. So we have designed it and are conducting it to be a pivotal trial here. That study started end of 2023. We're guiding to data in 2025. Now, in the trial, we're enrolling 81 patients across three arms. So two active arms versus placebo, and measuring the primary endpoint at week 20, which is changed from baseline in proptosis. This is the FDA's preferred endpoint for regulatory approval, so again, we're following a very clear playbook and precedent, there. Okay. We have introduced some inclusion/exclusion criteria into the trial to ensure that we are getting patients who have active inflammatory disease. Mm-hmm. We've capped the number of months since symptom onset. The patients could have had the disease before coming into the study. We're requiring them to have at least four or greater on the seven-point Clinical Activity Score scale, which is a strong predictor of who has inflammatory disease, and we are requiring patients to have a positive autoantibody test as measured by the TSI. So, so we think these factors really give us strong confidence that we are getting patients in the midst of their first flare of disease, who have active inflammation that could benefit from treatment with an IL-6 inhibitor. We're guiding the data from the study in 2025. Got it, got it. Do you believe TOUR006 has the potential to outperform teprotumumab in efficacy? Right. So let me answer a couple, like, different ways. Like, first of all, when we look across the various case reports for IL-6 inhibition, we think the data there are broadly in line from an efficacy point of view as teprotumumab, whether you measure it on proptosis benefit or on other markers, you know, here. Given that this is an autoimmune disease, we think it makes sense that a drug that can go after the underlying inflammation could lead to just more broad impact on the clinical endpoints here, versus trying to limit it just to proptosis alone. Now, when we speak with prescribers, which we do in our market research, we see this in, you know, KOL presentations that you and your colleagues on the sell side conduct. I think there's very clear recognition that there's a need to treat the disease, like, differently, here, where, teprotumumab, the only approved drug for thyroid eye disease, has good efficacy on proptosis. However, it's not perfect when it comes to other endpoints. We know the safety profile has been a challenge with a number of prominent, side effects, including hearing impairment, that have been, reported, that we think overall gives, physicians pause about, "Is this really the first drug to try here? And so when we look at the space here, we don't think the goal is necessarily to out-proptosis Tepro, but more importantly, to bring benefit on the other markers of the disease that we know matter to physicians, and they matter to patients as well here. Mm. And so when we see the overall market, with Tepro, we think 80% of the active inflammatory patient population is not getting treated with teprotumumab to date. Mm. That's despite it being the only game in town for four years now. And so, we think a different mechanism like ours that more directly goes after the inflammation and can lead to benefit measured by multiple factors, we think will be really preferred and could be an important treatment advance. If TOUR006 is approved in the future and commercialized, do you expect it to primarily seize market shares from teprotumumab, or be primarily prescribed to newly diagnosed patients? I think it's the opportunity is twofold. Like, one is to really make inroads into the 80% of this market where these are patients who get seen by endocrinologists, get seen by comprehensive ophthalmologists. To date, we've not seen meaningful uptake of Tepro in that group just yet, and we hear it from the other companies that that's where they're trying to commercialize, get more into making inroads there. We've just not seen it so far. We think a different tool like ours could be that first preferred treatment option with its every eight-week subQ administration profile, sorry, the safety profile that's been well characterized. And then three, a mechanism action that more directly controls the disease because it is an inflammatory autoimmune disease at its very nature. All right, but then second, we think there is potential here to be a better treatment option, even among the group of patients who'd otherwise get teprotumumab right now. Folks who may be concerned about hearing impairment, maybe folks who already have some degree of hearing impairment at baseline, folks who have diabetes, may be concerned about side effects on hyperglycemia, as has been seen with blocking that other pathway here. And so I think we can make a compelling case to say, "This is the right option to try first and keep that other mechanism in your back pocket for patients who don't respond well to our drug here." So we see a ton of white space in both going to a treatment-naive population, whether it's people who otherwise get Tepro, but more importantly, the group for whom Tepro has really not been the drug they would otherwise be getting. Okay, great. So when do you plan to start a phase III trial in TED? Will the phase III trial have the same design as the spiriTED trial? Yeah. So, the regulatory precedent in TED is to do two pivotal studies. So it's always been our plan that we would need to do two pivotal trials. We did stagger them in part to make sure we had time to get our phase III manufacturing set, which we've now completed, and so we'll be in a position to start the phase III trial later this year. We did meet with FDA recently, and alignment on the trial design here. So in broad brushstrokes, it looks very similar to the phase II trial. It's slightly larger. Not so much the power for the primary endpoint, more to make sure we have enough patients in the safety database to be able to file for an approval here. So, really no surprises in what the trial design looks like. Now, one nuance is we will include a cohort of patients in the phase III that has seen prior treatment, including steroids. That group won't count towards the primary endpoint, so we won't introduce any untoward uncertainty into the primary endpoint. However, there'll be a really great chance for us to get more experience with how our drug performs in patients who've already seen other treatments. In fact, most of the experience with IL-6 inhibition off-label has been in people who have seen multiple courses of steroids. So we already have good reason to believe that the drug should be effective here, and we think, you know, building out that dataset further could help, you know, from, you know, treatment decisions, in particular for ex-US areas where steroids tend to get used more often for patients with TED. Got it. Got it. Could you discuss the patent portfolio covering TOUR006? Absolutely. So, like, our program is a monoclonal antibody, and so, it's never been approved before. So by virtue of that, on a first approval, we would qualify for twelve years of regulatory exclusivity. In addition, we filed a number of patent applications to cover our methods of use, cover dosing, dosage strategy et cetera. So if any of those claims issue, we'll get coverage into 2043 and beyond. So overall, this is a pretty similar pattern for other licensed antibodies, where base case, 12+ years, we'll be able to add on to that with additional some of the additional patents that we have, applications that we filed. Got it. So could you just give us a brief overview of the upcoming catalysts within the next 12-18 months? Absolutely. So, on the CV side, we're really excited about the data, you know, here. We'll have our data first half of 2025 from our TRANQUILITY study. There are some important external catalysts, including an outcomes trial from Novo Nordisk, looking at their IL-6 program in a similar patient population. That will read out, we think, late 2025, early 2026, based on, like, what Novo has been saying. We have some advantages over that program. We think we can get to every quarter administration, and compared to theirs, which is given every month. On the TED side, we'll have data in 2025 from our program. There are a number of external readouts for competitors in different classes that we're interested to see, and they'll come out later on. We've also guided this to announcing a new indication before end of this year. We are well capitalized to get into 2027. That includes paying for what we're doing in CV, our two TED trials, as well as adding a new indication, which again, we'll announce later this year. Got it. And does the company have sufficient capital to fund two pivotal trials? Right. So we have $334 million in cash on the balance sheet at end of Q2. That does fund us into 2027. In terms of TED, like, we are funded to pay for our two pivotal trials, so we are funded there through phase III. In terms of CV, we're running our phase II program. We know the outcomes trials, you know, can be larger. We'll look at the data and make a decision on how to best pursue that. We're having a number of conversations with strategics. We have some other paths here on how we can pursue that forward, but that will be a data-driven decision in 2025 with our data in hand. Got it. So lastly, what do you think is the key takeaway message for investors, and why should investors pay attention to Tourmaline today? Absolutely. I think we have two very different ways to win big here that are non-overlapping. We think TED has a lot of evidence behind it. CV also has a lot of evidence behind it, so it creates, like, two uncorrelated bets, both of which we think we can, you know, swing, like, balls we can swing out with, with high probability for either one. IL-6 inhibition has worked in a number of disorders here, so we know this is fundamentally important immune biology we are going after, where we can pick indications where there's high unmet need, very clear validation, and we can come in with a drug that we think is truly the best-in-class, you know, has best-in-class potential, in these areas here. So 2024 has been an execution year for us. 2025 is when we'll start to, you know, read out important readouts that I think will be very exciting. Got it. Okay, great. Thank you very much for your participation, Sandeep. Thank you. Thank you. Best wishes for your clinical development. Thanks so much for hosting.