Afternoon, everybody. This is Kristen Kluska at Cantor. Thanks so much for being here, day one of the Cantor Global Healthcare Conference. Very happy to be hosting the Kardigan team. Joining me on stage, we have CEO, Tassos Gianakakos, Cheryl Abrams, the VP Global Product Head of ataciguat and Head of Medical Affairs, and then Vesna Ballard, the VP Global Product Head of danicamtiv. Thank you all so much for being here. Appreciate you having us here. Thank you. And congrats on a very successful IPO this year. It's good to be public. Yeah. So maybe to kick things off, do you mind just providing us with a high-level overview of the company, and then we'll dig into some of the programs in more detail? Would love to. You guys are pressed from long timelines, capital-intensive approaches. We're seeing a lot of this even today, recently over the last month or so. As a result, we see generally a lack of investment in the world's number one killer of men and women. So we created Kardigan to address that specifically. We've designed the company in order to focus on the root cause of disease, something that the lack of which leads to these long and costly outcome studies. Also moves you further away from being able to get to actual disease-modifying potential in these therapies, which is ultimately what patients need. It gives us the opportunity to do faster trials, to do them with smaller patients, things we've done before in previous companies, but now we've really started Kardigan up in a way to do this at a much larger scale. We've added technologies and some tools that weren't available to us before, and you'll hear from my teammates here on how exactly we're doing that. A company called Prolaio that we started and looking at adaptive, enriching designs. All of this has resulted in the company now having a pretty robust late-stage pipeline in three areas that are in desperate need of new medicines, dilated cardiomyopathy, aortic stenosis, and acute severe hypertension. We've set up the company in a way to be a real platform to make it easy for investors, in part, to participate in the number one therapeutic segment on the planet, which I think is tricky for people to really lean in hard on, and we're going to try and make that easy for you all. Thank you, Tassos. Not your first rodeo in the cardiovascular space. What can you tell us big picture about how doctors are going about diagnosing patients now as new therapies come about, pipelines are built? Are clinicians becoming more willing to use genetic testing to arrive at a more precise diagnosis? I think generally speaking, in clinical practice in cardiology, we're still leaning very much on clinical history, on symptoms, on imaging, in some instances also on biomarkers. It is changing a bit, I think, relative to at least the last time I was involved in developing new medicines in cardiology. We've seen some successes, both in terms of what we've done with drugs like mavacamten and CAMZYOS, but what we're seeing in the amyloid cardiomyopathy space. A little bit more attention is now being placed on profiling patients. Genetics is an important part of that, but importantly, to moving maybe towards more real-world continuous snapshots rather than single annual snapshots of people's conditions. Imaging is fantastic. The heart is just giving us a wealth of information, both in terms of its heart rate, ECGs, we get step counts, et cetera. We get drugs approved by the FDA on improvements in symptoms and functions. These are things that we can measure much more continuously. If you couple that with genetics where we are seeing upticks, there's been some really great successes, I think. The amyloid space is a great story there about improving diagnosis and really making a difference for patients. We're seeing the trends, but there's more work to be done, and we're going to help kind of push that along a little bit. I think the Prolaio technology's going to be a really critical part to that. Do you mind just walking us through what this technology specifically is, and over time, how can this lead to more accurate diagnoses as well as clinical trial monitoring, considering, again, you're collecting data throughout a journey, not just an exam here or there? Yeah. It's a really cool part of our company. We've developed an organization that is effectively its own entity, owned by Kardigan. But we've got 70 or so data scientists, software engineers, et cetera, who take data from multiple different sources, continuous data, primarily from electronic medical records, from smartphones that patients have, so patient-reported outcomes, and from wearables that are FDA-cleared. We've established now an FDA-grade platform that has five algorithms approved. We've got millions of years of patients' worth of data. We use these to paint a much more higher resolution, comprehensive picture of a patient's journey on an individual basis. How is their disease progressing? What's changing? How do things change with interventions? How we're deploying that kind of tool today. I think this is uniquely exciting to cardiology. I think these things are difficult to do in other disease areas, but in cardiology, we are able to get these data fairly easily that are already correlated to disease risk and benefit. We are using that to enrich our patient populations in our clinical trials. All of our programs are deploying these tools. Study participants get a kit that has this equipment in it. They love it, right? They have a say kind of in their own health condition. The data that we get is really powerful, and it augments the in-clinic data that we have, as well as some other tools that we can use as well. I think if you imagine in the future, you can think about more decentralized studies where we can use real-world endpoints. For example, Prolaio has a clearance for something called eVO2, which is a surrogate to peak VO2. If we can avoid the need to go into a clinic, do a cumbersome cardiopulmonary exercise test, by the way, it was an endpoint that we used in hypertrophic CM, it would really be a game changer for patients, participants in our clinical trials, but also just giving us better data on a more continuous basis, moving us away from the snapshot. You will see it in our studies today. As far as endpoints are concerned, it is more exploratory in nature today. We are building towards using those tools for primaries. It is really important from an enrichment standpoint and also from a profiling of patients, particularly in terms of their response to our candidates and their disease condition. Okay, thanks. Let us talk about danicamtiv, sometimes referred to as DANI, for genetic dilated cardiomyopathy. First, how are these patients diagnosed for their specific condition other than echoes that show enlargement of the left ventricle? How do the genetic familial causes of this disease differ in pathophysiology heart biology versus when you are broadly diagnosed with CM? Yeah. I can speak to that. These patients, as you mentioned, they undergo echo that diagnoses their dilation and their drop in ejection fraction. They undergo ECGs to look at their electrical activity. They may get additional imaging. We look at family history and genetic testing is growing in its use in the U.S. That is a really important piece to the puzzle when it comes to DCM and HFrEF in general. The causes of HFrEF can be multifactorial, but those patients with DCM, many of them have a genetic underpinning. Understanding the genetics and really the cause of the disease, not the downstream consequences, which is the HFrEF and those symptoms, but understanding the cause of the disease, even in the absence of approved therapies today, can direct treatment. There can be discussions around devices about how quickly you ramp up GDMT. Understanding that today is important for the future with a drug such as danicamtiv, it is going to be important to understand which patients may benefit. For us in danicamtiv, we are targeting this drug to those patients that have specific gene variants, and we can learn about them through their genetic testing and learn more broadly around the genetic DCM population who else beyond the specific gene variants we are interested in could get benefit. Okay, and given that myosin is the molecular motor that drives the cardiac contraction, why does activating this mechanism work in the context of DCM heart where the ventricle is enlarged, thinned, and stretched? In other words, how does improving contractility translate to better cardiac output? Yeah. Well, it comes back to the root cause of the disease. In those patients with dilated cardiomyopathy where they have gene variants that affect their sarcomere, the contractile unit or the motor of the heart, the downstream consequences are that dilation and that lack of function. By targeting the myosin, we can improve that contractility so there can still be benefit in those patients who are dilated. It is really about force generation to increase that pumping ability. We are also learning that danicamtiv can reverse remodel as well, so it can shrink the heart. With longer-term treatment, we expect to see more reverse remodeling changes, too. There are benefits both on the sort of specific mechanism of action of improving force generation, but also on the downstream remodeling. Okay. How are you ensuring on-targeting effects and that the myosin is turned on properly and interacting with the actin? Mechanistically, how do you avoid excessive activation or the overworking of the heart, particularly where the myosin is already in an on state? Yeah. It comes down to two things. Firstly, danicamtiv was designed specifically to target the myosin and titin deficiencies in patients that have genetic DCM with gene variants in those genes. We are really targeting the cause of the disease. The mechanism of action improves myosin head engagement to form the cross bridges that allow contraction. Importantly, in the DCM population, we are restoring the appropriate amount of myosin head engagement. We are not over revving that system. In a broader HFrEF population where the cause of disease may not be a deficiency in myosin, you may be excessively increasing myosin head engagement and that whole engine function, and that can cause downstream deleterious consequences, troponin leak, myocyte injury, those kinds of things. But in this population, we are getting back to a normal level of myosin engagement and force and contraction. Okay. Before we talk about some of your clinical findings, what are the best measures, either through preclinical models or clinical, to just indicate that the drug is indeed working through its intended mechanism? We have done a lot of work. We have a large research group that understand the mechanisms of danicamtiv across models from in vitro to ex vivo. We have iPSC-generated myofibrils. We have in vivo models, and of course, we have clinical data as well. Everything points towards the appropriate amount of myosin head engagement. We use things like X-ray diffraction, but importantly functional improvement, so contraction of the heart, appropriate relaxation of the heart, so we are not impairing diastolic function. All of that has been seen in our preclinical models and translates to what we see in the clinic. So across echo parameters that we have looked at, looking at biomarkers, this all ties together into a very nice mechanistic story that makes sense for the benefits of danicamtiv in the patient population that we are targeting. Okay. With a clear understanding of the mechanism which you have showcased as well, how should we now think about that correlation between myosin and measures like LVEF based on the myosin acting cycling and ultimately how this impacts ejection fraction? Well, the ejection fraction is driven by that myosin activity and t he sarcomeric function. We are improving force, not at the expense of calcium, not at the expense of ATP. We are improving it in an efficient manner, and again, allowing that appropriate relaxation as well. This fits perfectly with the MOA of danicamtiv. Okay. Fortunately, the patients in the trial did benefit, but there were certain mutations, causes that showed an even more profound effect. Why do the sarcomeric gene mutations matter in the context of myosin function and impact the mechanics? It gets back to the MOA. We have talked a lot about myosin heads. I will touch on titin. Titin is this large protein that senses stretch in the heart. As the heart relaxes, blood is ejected from the left ventricle. As it contracts, I should say. As it relaxes, the heart stretches, and titin senses that stretch, signals back to the myosin heads to recruit the appropriate number for the next round of contraction. That all fits together with the ejection fraction, which is what you see, the amount of blood and the proportion of blood that is ejected from the left ventricle. It makes a lot of sense. Okay. With all the data you've shown, it's been quite robust across several measures. But the question I have is: How do the degree of these changes that you've reported ultimately lower a patient's risk of having heart failure? Yeah. So we have shown benefit with danicamtiv across multiple measures and importantly, across multiple chambers. So we see the benefits in the left ventricle. We see that we're improving contractility, but we also see benefit in the left atrium. So that obviously feeds the left ventricle. It's important for that blood flow. We see reductions in LA size. That is a measure potentially of arrhythmic risk. If we can reduce LA size, we believe that we'll see benefit on arrhythmias. It's something that we're measuring in our current study. And most recently, we've presented data at ESC just over a week ago, showing that we also have potential benefit on RV function as well. So again, in preclinical models as well as post-hoc analysis of data in our last phase II DCM study, everything points towards improvement of RV function. All of that, the reverse remodeling that we see, those improvements in function, all move in the right directions that generally portend better outcomes for those patients. Okay. Next, could you please walk us through the phase IIb trial design that's set to read out in the first half of next year? Yes. This is actually a phase IIb/III adaptive seamless design. It is a randomized control study. We have two cohorts of patients. Those patients who have myosin and titin gene variants, where we expect to see the most benefit, as we have discussed. It is matched to the mechanism of action. But in a previous II-A study, we also saw benefit in patients who had other DCM, so other primary DCM with genetic causes. We saw some benefits there, and we are studying those in the Cohort 2 patients. They may have DCM associated with other genes, non-myosin, non-titin, or they may have a family history of DCM, and they are included in that Cohort 2. That is where we want to learn about the potential benefits of DCM beyond those two sarcomeric genes. We have seen some early signs that there may be benefit there, and we are exploring that in the current study. This trial is called KINSHIP-DCM. We are enrolling 80 patients in phase IIb, split between the two cohorts equally. Patients undergo two weeks open-label of placebo treatment, followed by two weeks open-label of danicamtiv treatment. We can look at that data early on. It is pre-blinding and pre-randomization to see if we are seeing benefits similar to what we have seen in the previous study. Then everyone undergoes essentially six months of treatment, either DANI or placebo, in a blinded, randomized fashion. At the end of phase IIb, the data that we will get will be based on echo measurements and CPET. So we will look at left ventricular ejection fraction. We will look at LVGLS. We look at LA function as well with a measure called LAFI, and that is our primary endpoint for phase IIb. We will also look at peak VO2. So we will look at change from baseline in peak VO2. We will not be powered to see a statistically significant improvement, but we will take this measure, and we will use that to see if we are seeing a directional improvement, and that will help inform phase III, where change in peak VO2 is our registration endpoint. This is an adaptive design, meaning we are running it seamlessly, so we are running phase IIb and phase III at the moment. But what we learn from phase IIb will ultimately inform phase III. So in both phase IIb and III, we are capturing all the echo parameters, peak VO2, but we can make adjustments to phase III from what we learn from phase IIb. So in terms of our size of our population, we might make some adjustments there. Unlikely to make adjustments to our endpoint, but it is a possibility. We are not changing our dose. We have a fixed dose, 50 mg BID, which we feel very good about. But we are learning from phase IIb as we are enrolling phase III. As of today, we have completed enrollment of Cohort 1 of phase IIb, so now we are enrolling patients into phase III Cohort 1, those myosin and titin patients. And what de-risks the trial design, and how are you thinking about the bar that needs to be achieved as you think about the next part of the study? Yeah. The adaptive design really helps to de-risk. We have these early open-label periods where we can look early at data and see what movement we're seeing on echo parameters. We can look at the phase IIb data while we're in-flight enrolling into phase III. Again, we can adjust sample size. We can look at our endpoint. We'll get peak VO2 and see, are we seeing what we would expect to see? Not statistically powered, but is it moving in the right direction? We can correlate the changes that we're seeing on echo parameters with our predicted peak VO2 improvement. We've set a bar of seeing a clinically meaningful benefit in peak VO2, generally accepted to be a one-unit change. So we can model what we see on the echo changes. We'll have the early read on peak VO2 in phase IIb. Thank you so much, Vesna. Appreciate it. Okay, let's talk about ataciguat for moderate calcific aortic valve stenosis, or CAVS. I love acronyms in biotech. Oh, good. For this condition, there are several factors that put a patient at risk for CAVS. How does this both limit and support the ability to diagnose patients? Yeah. So interestingly, diagnosis on aortic stenosis is really specific to echocardiographic parameters that look at the level of stenosis of the valve and pressure gradients of how the heart is actually pumping blood across a stenotic valve. The comorbidity factors actually do not really precipitate the actual diagnosis itself. The guidelines are very specific, and the actual criteria for diagnosis of disease severity is really set on aortic valve area. The indication for an aortic valve replacement currently is an AVA or an aortic valve area of less than one. Okay. Do we have a good sense as to what level of calcium accumulation becomes dangerous in restricting blood flow? How well does calcification predict stenosis progression and severity? Yes. So aortic valve calcium is very well established in severe disease, where the threshold is very clear, above 2,000 in men and above 1,200 in women is what would be considered severe aortic stenosis. Calcium is used in that specific patient population, particularly when the echo parameters are what we call discordant. They don't always necessarily align because many of them are flow dependent. They can be variable based upon that given day and often are also dependent upon blood pressure. However, when we take a step back into mild to moderate aortic stenosis, calcium is more of an independent risk predictor. So it predicts progression, but it is not necessarily linear to the actual rate of progression. What is linear are things like aortic valve area and other specific parameters, but it is definitely causal. It is a great mechanistic link and is central to the progression of disease when you look at the actual consequence of calcium being deposited on the valve. Okay. As an oral soluble guanylate cyclase activator, where do you see ataciguat fitting in the treatment paradigm? At what stage of aortic stenosis would intervention be most likely to potentially slow down that disease progression? Yeah. Currently we're evaluating ataciguat in moderate aortic stenosis. In reality, everything less than severe is really a continuum of mild to moderate disease. Because ataciguat has a dual mechanism where it works directly on the valve to slow the progression of calcification, likely also to slow the worsening of a parameter like aortic valve area, but it also has a direct effect on the ventricle. We see improvements in systolic and diastolic function, which are important because the consequence of aortic stenosis is valvular heart failure. When you think of that mechanism, that dual mechanism in particular, you can really treat patients across the full continuum. From even aortic sclerosis prior to even the development of calcium, upwards even through post aortic valve replacement, because the progression to heart failure still exists, even post-TAVR, as does calcium. While we're developing it currently in mild to moderate aortic stenosis, I would say, there's significant life cycle expansion opportunities across the full continuum. Okay. What is the importance of increasing cyclic GMP as it relates to all of the aspects of the heart in this condition? How do you minimize the risk of broader systemic effects? Yes. The increase in cyclic GMP in the valve is ultimately what results in the downregulation of calcium signaling, of osteogenic signaling. So that's the effect of cyclic GMP in the valve. The effect of cyclic GMP in the ventricle is actually to improve diastolic relaxation and to improve systolic function. So when you put the two together, that's why we see in the phase II data set a reduction in the deposition of calcium as well as a direct effect on the ventricle. When we think, though, about how that mechanism portrays to off-target effects, what's unique about ataciguat is it preferentially targets the oxidized form of sGC. So that's in the valve and in the ventricle. We do not see stimulation of sGC in the periphery, which would result in stimulation of the nitric oxide pathway. The reason we know that is because we do not see any evidence of hypotension or a drop in blood pressure, which would be the result of stimulation of nitric oxide in the periphery. The last thing I'll say is that would be a very bad thing. You do not want to drop blood pressure in patients with aortic stenosis because they cannot maintain cardiac output through a stenotic valve. So this is a very unique mechanism of action, very deliberately set to this disease, in particularly on the valve and on the ventricle. Okay. So tying it back in with my earlier question, you were able to show reduced calcium in aortic valve area. How do these findings cement that addressing the root cause of calcium buildup results in clinical benefit? Yeah. The number one factor of clinical benefit is actually valve area. Yeah. Calcium is your mechanistic link. Valve area is what really determines progression to severe disease. It is very linear, as I said, but also it is the predictive marker as to whether or not a patient is eligible for an aortic valve replacement. Physiologically, it makes sense. The more narrow your valve is, the worse you are going to be. The full continuum of all the other parameters that we will be looking at also will portray a clinical benefit because I mentioned these patients have valvular heart failure. You want a drug that is going to improve diastolic function and systolic function equally just as much as slowing the progression of the decline of valve area. How do you think about the long-term potential relative to how patients may progress as they get older? Yeah. Aortic stenosis is a disease of aging, is what people say. Very much like HFpEF. It is more predominant in the elderly. When you think about moving more upstream into mild to moderate AS, there are predictive measures that you could take with a drug like ataciguat to slow the overall progression of disease. The idea would be to hope that patients, as they age, if TAVR is needed, it is done once with a drug like ataciguat, fully modifying disease progression. What are the next steps for this program? This trial is continuing to enroll in the phase IIb study, and then we have a separate phase III trial that will begin sequential enrollment thereafter. We will have data in the first half and second half of next year. The Week 24 primary interim analysis is looking at the effect of ataciguat on aortic valve calcium and all these other echo measures we spoke about, including valve area. The primary analysis is at Week 48, and that's also where we'll look at the direct effect of ataciguat on cardiopulmonary function, going back to the discussion on feel and function. How do these changes on the heart actually translate to an improvement in functional capacity? We'll see that in the second half of next year. Thank you, Cheryl. I know we just have a few minutes left and unfortunately can't spend too much time on TLA, but would love to just close by asking you, clearly you're a new story out there. You just recently became public. What do you think is the most misunderstood or undervalued component to Kardigan's valuation? Why should investors look at your company now? Well, at the highest level, I think investors should not ignore the largest segment on the planet, and it's our job to make it a lot easier for you to get really invested in the space. As it relates to our company, it's going to take time for people to get to know us. We're a complex story in that we've got, in one case, we've got a platform. We're a true platform. We're a cardiovascular platform. There are bona fide synergies across these programs, both in terms of disease biology, in terms of execution, in terms of the tools, whether they're Prolaio tools, et cetera. That is really valuable, and it's hard to get your arms around that. I don't know that there are many companies out there that when you look across their portfolio, you can actually see de-risking between these programs. This is actually really happening here. If you have aortic stenosis, you are going to develop heart failure. If you have dilated cardiomyopathy, you are going to look at AFib, and AFib is a big part of it. All of this is really important, and we are designing the organization to be able to understand that, and there is definite benefit across our programs and building our collective knowledge across the platform. You look at the pipeline. We have three programs. Every single one of these programs, in and of themselves, can be extremely valuable if we deliver. They are first in disease. They are in really important indications. They have the potential to be disease modifying. And we are taking away the thinking that we often hear about binary risk in biotech companies. We have a portfolio. We are very good at understanding how to make decisions around the portfolio. We are experts in this area, and we want you to trust. We want to earn your trust in helping see us as folks who are ruthless executors, really, really good at making portfolio decisions on science and on resource allocations. Last but not least, it is a repeatable approach. We are working on three programs here today. We are developing our own programs internally. We are a fully integrated discovery, research, and development organization, hopefully soon to be commercial as well. And when we look at opportunities out there to externally innovate, we see the application of our expertise. I am really glad you got to meet some of the leaders in this company besides me, because they are really tremendous. Leveraging their expertise and our tools, we do feel that we can do this over and over again. We got to prove it. The first half of 2027 is a critical time for us to start sharing data and talking to you about data and not just our vision, mission, and our aspirations. And hopefully we continue to build credibility with everyone, and we can start seeing momentum and shift back into pushing the frontiers and really reimagining how we do cardiovascular drug development and treating these diseases. Well, thank you all so much. We are certainly rooting for you into these big catalysts next year, and thanks for being at our conference. Thanks for having us here. We appreciate it.