Okay, we started. Great, guys. Well, no. Tessa's here. Thank you, Tessa. You don't have to join, though. And, so a really exciting year we've had, and I really have some more compelling data to provide you. And Edgewise is a leading muscle disease biopharmaceutical company developing novel therapies for the treatment of muscular dystrophies and serious cardiac conditions. And, you know, I'd really like to thank the staff, and here's my forward-looking statements. I'd really like to thank the staff, the patients, and everyone involved with the company. We've had three or two major drugs involved: sevasemten, which has been positioned as a fast type 2 myosin inhibitor for the treatment of Becker muscular dystrophy. That drug is now in Phase III pivotal studies, and we had some nice data just in December to talk about our potential in Becker muscular dystrophy. Sevasemten is also positioned in Duchenne muscular dystrophy. We have a dose-ranging study in Phase II, and we've reported on data from DUNE in the spring in limb-girdle and McArdle's, as well as a Becker study. On the cardiovascular space, we've developed our drug 7500 for hypertrophic cardiomyopathy. It is in two different studies: obstructive and non-obstructive hypertrophic cardiomyopathy. We have an additional drug moving into GLP-tox. We anticipate filing an IND for this second-generation 7500 analog. And then we have—and I want to just note that we have another program in cardiometabolic, which takes advantage of interacting with muscle and providing benefit to patients with obesity and cardiometabolic disease. So what did we do this year? We had positive two-year results in ARCH; this is an open-label Becker study with Sevasemten. I'll talk a little bit about the details of that in a coming slide. We've had positive results in CANYON. CANYON was one of the largest placebo-controlled studies in Becker, especially with a targeted population, which we had positive top-line results on both biomarker and functional data. We had positive DUNE data in a paradigm where we had an exercise challenge and could actually blunt the biomarker response due to exercise. We can report that GRAND CANYON will be fully enrolled, which is the pivotal study for Becker. We'll be fully enrolled in the Q1 of 2025, and we'll actually have over-enrollment. I'll speak a little bit to that. And we've selected the five-milligram and 10-milligram dose to move forward in future exploration in the Duchenne population, and we'll report on that a little bit later this year. In hypertrophic cardiomyopathy, we had really positive, exciting data in the first disclosure of normal healthy volunteers in September and our single-dose data in obstructive HCM. And we initiated our Phase II studies of 28 days in obstructive and non-obstructive. And I can announce today that we've initiated the Part D portion of the study, which is the 12-week studies in non-obstructive HCM and obstructive HCM. And finally, we have a very strong balance sheet. We raised $240 million last year and now have a runway through 2027. So great news for the company, a lot of progress in 2024. So let me tell you a little bit about Sevasemten. So Sevasemten can be positioned in multiple indications in the muscular dystrophy population. Becker and Duchenne muscular dystrophy typically target males. These patients lose function typically in their 30s and 40s. There is currently no treatment for Becker patients. This is the data we saw in the spring. Just let me orient you a little bit about the North Star. So the North Star is a 34-point scale, so it's 17 separate activities measured at 0, 1, or 2, total adding up to 34 points. And what we saw, and what I'll talk about, is it's clinically meaningful to see a one-point change. Now, what's been exciting about this field is that as of about four or five years ago, there was new natural history data talking about the Becker progression of disease. And in three separate studies, what we've seen is that patients decline about 1.2 points per year in Becker. And so in our ARCH study, we had 12 patients open label where we treated them with 10 milligrams of Sevasemten and saw that we had actually disease stabilization and even an improvement in the North Star over a two-year period and in a population that we would expect to decline by minus 2.4 points. So this is really unprecedented for Becker and in muscular dystrophy. This is the first time anyone's shown this kind of delta on prevention and stabilization of the disease. So we're really excited about this work. So we designed the first placebo-controlled Becker study called CANYON. And in this study, we recruited 40 patients, 40 adults, and we recruited 29 adolescents. Now, what we did was very important is that we selected this population. So people always say that Becker is too heterogeneous to run trials. We selected patients that had a North Star between five and 32. And we know from the natural history studies that they progress in a homogeneous way of 1.2 points per year. So this was a 12-month study, 3:1 randomization, 10 milligrams for the treated group and the placebo group. What we saw was a very safe drug. This drug was well tolerated, did not differentiate highly from placebo. Only thing we did see was what we would call transient and spontaneous resolving dizziness. But other than that particular AE, which subsided early in the study, there are really no AEs of note. So it's a very well-tolerated drug. So what do we see? So when patients move and exercise who are missing dystrophin or had low levels of dystrophin, as in the Becker population, they consistently damage their muscle. And what you see via damage of the muscle is in the plasma compartment, you can measure certain biomarkers. One of those biomarkers is creatine kinase. And actually, creatine kinase is used to diagnose Becker and Duchenne patients. We also saw decreases in TNNI2. Now, TNNI2 is a structural protein within the fast muscle fiber. So we are a selective type 2 FAST myosin inhibitor. So what we noted from this particular work on the biomarkers is we saw a statistically significant decrease in creatine kinase and a statistically significant decrease in the on-target biomarker fast muscle troponin, which to us means that we have picked the correct dose. We have a high level of target engagement, and the biomarker used to actually diagnose patients has been decreased in a statistically significant way. First time in any study that people have shown this. So really exciting result. Even more exciting is that our benefit on the functional endpoint. Now, North Star is the primary endpoint for our GRAND CANYON study, and considered clinically meaningful by the agency. So this is what you can use to approve a clinical trial. What we've seen here is, again, as we saw in ARCH, stabilization of disease, and, based on the placebo, a 1.12 difference from placebo. This is considered clinically meaningful, and let me give you a thought of what is clinically meaningful, so one point is I can't get up out of a chair by myself, or one point is I'm walking across the street and I can't lift my leg up on a curb, so it's obviously clinically meaningful to see this one-point delta in a placebo-controlled study, first time ever in a Becker population, so drug was well tolerated, all doses, no safety concerns. I saw the biomarker response that were statistically significant and saw stabilization of disease as we had seen in the ARCH study, so we think this is very positive for the Grand Canyon readout, and so the Grand Canyon, this is a confirmatory study that is a Phase III pivotal study. I can say same kind of inclusion criteria, 10 milligrams. This is now 18 months, but the powering is quite different. We're 95% powered to achieve statistical significance. You're looking at the North Star endpoint. We've enrolled now 120 patients. We will over-enroll this study probably on the order of 160 patients. Why is that? Because the demand after we put the 24-month data out on ARCH was so great that we felt we should over-enroll this and provide this drug to the patients, so what do we achieve with the Becker studies? The CANYON results really offer us an opportunity to go to the FDA and discuss with them the opportunity for an accelerated approval. There's new guidance out there that actually fits very well with our data package of utilizing a drug endpoint like North Star in a disease population that is considered severe with no drug therapy and that we've completed enrollment of that follow-on study. So I think it's something I'm very interested in talking to the FDA about. We've over-enrolled our Grand Canyon expectations in over 51 sites. 99% of the patients have decided to move on to our open label extension study, which is clearly important. The patients feel like they have benefit from this drug. Otherwise, they wouldn't stay on this drug. And finally, we have increased confidence that Grand Canyon can be successful when we hit statistical significance. Now, it seems like, is this a big market, an important market? Absolutely, this is an important market. There are 12,000 patients in the three major markets, and there are no approved therapies. So I think I'm really excited about the potential of the drug in Becker, be the first drug on the market for Becker. Now, we've also done additional work in the Duchenne space. There's been a number of approvals in the last year or so, but yet there continues to be an unmet medical need in Duchenne for additional therapies. What's novel about our drug is that we can be combined with multiple other modalities because we are preventing the muscle damage associated in what's driving the pathology of the disease. So we think this is a very important mechanism within Duchenne. We talked about it was quite a long trial, and we started off with a dose-ranging and started at 2.5 milligrams and doubled the dose every three to four months. One of the, I think, the issues and challenges with this study is that the FDA decided or asked us to dose escalate each individual patient when we had safety at the next higher dose. So we had multiple different dose escalations, intrapatient dose escalations along the way. What we ultimately determined is that the 5 and 10 milligram doses were the appropriate doses where we saw disease stabilization and biomarker response over a six to nine-month period. So what we did was essentially a reset, bring everybody, and this is now 80 patients into the 5 and 10 milligram dose group, and then we recruited another set of patients. We just call them a clean set of patients at five and 10 milligrams. So we will have that data by the end of the Q2. It'll include all of the populations that are now being treated in Duchenne, which includes naive patients from steroids and LYNX patients on a steroid background, including exon skippers, and additionally patients in FOX that have had prior gene therapy two years after their actual endpoint. So obviously, a very large patient population continued unmet medical need. Our mechanism would fit across the different patient groups and is agnostic to the mutation associated with the Duchenne. And we're really the only company running combination studies with gene therapy. So let me change gears here a bit and move to EDG-7500, our cardiovascular asset. Hypertrophic cardiomyopathy is a disease. Think of it as a stiff ventricle and an enlarged heart. The heart is hyperactive. The ventricle is stiff. You can't fill up the ventricle to actually pump the blood to the periphery, and patients lose the ability to walk. They lack endurance. It's a horrible quality of life. What we'd like to do is find a drug that would take symptomatic patients who have functional deficits and turn them into asymptomatic patients. Now, let me orient you a little bit with the disease. In this disease, you have an enlarged ventricle that the wall thickness is much thicker than normal going from the left side to the obstructive side. As the blood flows from the atria to the ventricle out through the aorta, you've created what's called a gradient. There's a flow effect. That gradient leads to lack of endurance and morbidity in these patient populations. Now, in the non-obstructive patient population, you don't have that gradient or flow, but you still have a stiff ventricle, and you cannot relax the ventricle to fill the cavity with blood to pump around the circulation. So these are two distinct populations. Both have considerable high unmet medical need, but these are diseases of excessive contraction and impaired relaxation. So what do we do? We developed a novel mechanism that affects the contractile element, the sarcomere. And what we've done is not only change the contraction of the ventricle and the atria, we've actually changed the rate of that contraction. By changing that rate of contraction, we can actually create drugs that don't affect the contractile cycle, which is left ventricular ejection fraction. And it turns out that lowering ejection fraction to too great of an extent leads to a heart failure phenotype. So all the drugs like the cardiac myosin inhibitors, mavacamten and aficamtin have a direct relationship of decreasing the ejection fraction to decrease things like gradient and improve feel and function. So we have a mechanism that has disassociated the ejection fraction change from the gradient reduction. This could provide much greater ease of use, could provide a much wider therapeutic window, and increase the efficacy of this mechanism relative to some of the other mechanisms. So we designed the CIRRUS study. We first provided a single dose to patients. They reported that data in September. We have Parts B and D, which is a 28-day portion of the CIRRUS study. And now we've moved patients into Part D, which is a long-term extension where we provide a CPET early on to the patients and then measure out at 12 weeks a peak VO2 measure. So why is this important? Peak VO2 is the approvable endpoint for this class of drugs in hypertrophic cardiomyopathy. So what we want to tie together is the biomarkers, the gradient reduction, and ultimately peak VO2 to demonstrate the value of this mechanism. So we dosed several patients, I think a total of 11 with obstructive HCM. Compound was very well tolerated. None of the AEs were related or deemed related, and they all resolved spontaneously. We observed a 67% reduction on resting gradient. So this means when a patient is resting, they get an echo, and we had a dramatic effect on their resting gradient. There's sort of a threshold. People look at the efficacy of these drugs. Anything below 30, they start well above 30 is a win for this class of drugs. There's a second way we evaluate the efficacy of these drugs using a Valsalva endpoint, which is a way similar to an exercise challenge, not exactly, but quite similar to that. We saw many of the patients go below the threshold of 30 with just a single dose, with an average of 55% reduction in the 100- and 200-milligram dose groups. This is very exciting, a single dose data, very unusual to see this kind of dramatic response. Our mechanism disassociates ejection fraction changes from the reduction in gradient. As you can see here, there's no change in ejection fraction based on dose. This is all within the noise of this assay. It's about plus or minus 5% in ejection fraction is in the noise. We're excited about this result, differentiated mechanism. Now, what's really important in these patients, our mechanism not only affects the systolic action of the mechanism, but also is involved in the relaxation of the ventricle and diastole, and so every KOL you speak to will point to that proBNP is a marker of diastolic function and that an elevated proBNP is bad for the patient, and what we had shown is a deep response with just a single dose in proBNP of up to 64% in the 200 milligram dose group. Why is that important? Because in recent studies, it's been shown that the depth of this proBNP response directly correlates with the depth of the Peak VO2 increase, so important aspect of the study, really looking forward to providing this data in the end of this quarter, so the drug was well tolerated, decreases in resting gradient of 67%, decreases of Valsalva gradient of 55%. We saw no concentration-related change in ejection fraction, and we saw deep responses on proBNP, a marker of diastolic function. So exciting data set. We started to recruit the 28-day data in the September timeframe. We will report that data out at the end of this quarter, having 10 patients, a minimum of 10 patients in obstructive, a minimum of 10 patients non-obstructive, two to three dose groups. We'll then take those patients, wash them out, and then give them a CPET, and then over another 12 weeks, measure a second CPET to get a peak VO2 measure, tying together all of the different biomarkers and gradients. So there still is an unmet medical need in obstructive and non-obstructive HCM. It's the most common genetic disease out there. One in 500 people are impacted by HCM. And there still continues to be significant limitations in the HCM population. So what's next? Exciting year for the company. Our milestones are we will report LYNX data and FOX data in Duchenne, controlled dose ranging studies. We'll look at six-month, nine-month, and 12-month data looking at endpoints like stride velocity, 95th percentile, time to rise in North Star to understand, do we have a path forward for Phase III? In In Duchenne, we'll make a commitment to run a Phase III if the data supports making that investment in the second half of 2025. We'll have CANYON feedback from the agency. We're planning to put in a meeting request in the next month or so. That'll lead to a discussion with the FDA in regards to the accelerated approval path for this drug, the CANYON data. Should have feedback from the agency back sometime in the Q2, waiting for the meeting minutes from that discussion. GRAND CANYON will be completed by the end of this quarter, and we expect to have GRAND CANYON results out in the Q4 of 2026. It's an 18-month study and fully recruited at this point. In the cardiac program, we have the CIRRUS-HCM data, 28-day readout, which will include a wide variety of endpoints: resting, Valsalva, gradient, proBNP, feel and function measures like change of New York Heart Association and KCCQ scores over 28 days, and of course, ejection fraction changes, which we anticipate minimal changes in ejection fraction, which will provide differentiation from the CMIs. We'll then have a 12-week readout at the end of the year, which will be a Q4 of 2025. We expect to be able to be enabled to have a discussion with the agency in the Q1 of 2026 and start two Phase III studies in obstructive and non-obstructive HCM by the Q2 of 2026. In the heart failure space, we have a second-generation candidate that we're positioning in heart failure. It still has diastolic effects that would be actually pivotal for putting into areas like HFpEF. We expect to have another cardiometabolic molecule have a candidate by the end of the year. We expect to be able to put out data from our heart failure candidate sometime in the first half of 2026, both normal healthy volunteer data and perhaps even HFpEF data. So exciting year for the company, lots of milestones that are value-generating. We have $493 million in the bank. We have 94 million shares outstanding and a cash run rate through 2027. So well-financed to obtain multiple milestones, an exciting year for Edgewise. With that, I'd like to thank you for your attention and look forward to taking any questions. Hi, everyone. I'm Tessa T. Romero. I'm one of the senior biotech analysts here at J.P. Morgan. The glory of Monday at the healthcare conference. Apologies for being a little bit late. Kevin, I think let's just start a little bit bigger picture here. As we exit 1Q, what are the key takeaways you hope that investors will have about the profile or the emerging profile of EDG-7500? Yeah, so my goal is to, I think the data we've seen so far with single doses is the depth of the gradient response. So we want to show that that gradient reduction is durable over a 28-day period. Obviously, the drug has a strong safety profile in general, but in particular, you don't see any changes in the ejection fraction that are concentration-related within the noise of that assay. So we're excited about that particular result. I think even more important is to generate data on the proBNP endpoint. We want to see the depth of that response, the durability of that response. We will get an initial look at what we would call measures of diastolic effect by echo. So we'll be looking at things like changes in E prime and E over E prime. And then, of course, what everyone should really focus on that, in the end, it's how a patient feels. It's not about the gradient reduction or the BNP reduction. So how many patients have we converted from a symptomatic patient to an asymptomatic patient? So I think it's important to recognize that in the 28-day studies for the CMIs, you did not see robust changes in feel and function. We would hope to see robust changes in things like New York Heart Association or see KCCQ scores going up north of 10 points. So what's clinically meaningful in KCCQ is about a 5-point delta, an improvement. We would hope to see those same changes within our patient population at the target dose. So those are the things to be expected out of the 28-day. Okay. And I mean, I think one of the key questions that we've been fielding here is, which of the efficacy measures do you have confidence will move materially over 28 days in each of these patient populations? What internal data or competitive data underpins your expectations? Yeah, so I think I'm confident that the gradient reduction will be durable and that the lack of changes in ejection fraction will be durable, but it remains to be seen. We don't have the data yet, all the data and all the dose groups. I think it's more speculative to say that you will see the diastolic effect, but you've never seen a drug in 28 days have an effect on the diastolic parameters, and as I said, the feel and function measures, they need to deepen over time. Seeing those effects at 28 days would be an outstanding observation. But remember from our conference call, Anjali Owens, one of our lead investigators, said that one of the patients, this has occurred with more than one of the patients, they received one dose and the patient described that their heart was pumping out of their chest and they took the dose and it disappeared with one dose. So I think it's really important to recognize that this is a drug that may help people immediately, which would be differentiating from a titration that's required for the CMIs to get to the right exposure level. Okay. And then how do you think about what might not be appropriate to be thinking about at 28 days? What would not be appropriate? In other words, I'm trying to sort of tease out what you're going to learn in that further dose ranging work, right, and that you'll complete in 2025. I think you'll give us an update. You said 12-week data sometime this year versus what you could see at 28 days. Because I think there's a bit of confusion in the marketplace around this. So let's just, what's your sense of that? Yeah, I think, well, I always think of it as what does the physician want to see? And the physician wants to see the patient be asymptomatic. They no longer have the disease. And if you can show a trend towards seeing that in 28 days, you should be excited because that's not been shown before. Okay. Kevin, can you talk a little bit about how a dose adjustment could work? And will you explore that in your further dose ranging work before you start a Phase III program? Yeah. Generally, the absorption profile of a drug is you'll have plus or minus 30% or 40% on either side. With any oral drug, you have some variability. We would anticipate that you could treat most of the patients, say it's 70% of the patients with a fixed dose. But then you probably want to optimize the dose for a particular patient. There's always a need to do that. If you take a blood pressure medicine, you don't take a single dose. You take an increased dose based on blood pressure or decreased dose based on blood pressure. If you are taking Lipitor, there's 10-40 milligrams that different individuals respond differently. We'll ultimately have one dose adjustment to get to the optimal dose for each individual patient. But I think we can do that in multiple different ways. You can do that by a gradient reduction with an echo, but you could do that with how the patient feels. Or you might be able to do that with proBNP as a, do you have the maximal response in proBNP? So you're not going to be tied to an echo regimen that is very firm. For instance, perhaps at any time between two and six weeks, you get a second echo when it's at your convenience to come in, get the echo, adjust the dose, and you're done. So that would be the kind of paradigm we're talking about. We'll explore all of these paradigms within 2025, where we'll have 12 weeks of dosing. We can see what happens after 12 weeks. We can adjust the dose on an intrapatient level along the way and see how the patients respond, all with the goal of achieving the optimal dose for each individual patient, but making it as physician-friendly as you can provide it and also account for the patients can't come in at the whim of three or four times and having to be adjusted and then having a safety issue. And the goal here is if we don't see the ejection fraction changes, there is not a safety issue. So therefore, it's simply an efficacy argument of why you would have them adjusted. Okay. And any other comments you'd make on where you think there are suitable comparisons that you can make from these initial data to what we've seen with the cardiac myosin inhibitors in each of these patient populations, acknowledging we know the CMIs are titrated up, right? We know you're looking at a fixed dose. How do you think about that? With the 28-day data, I think what we'd be differentiating is seeing significant changes in New York Heart Association and KCCQ scores. I think I would be looking for the depth of the BNP response and the depth of the gradient response. All of those endpoints, so gradient reduction, BNP, those changes directly correlate with the Phase III approvable endpoint. After the 28-day data, I think you can look at that drug and say, "This drug is approvable. This will work in the well-powered Phase III trial. Do you plan to disclose the specific target of the drug? We have discussed that. I don't think there's a burning need for us. The investors have said that, although everyone would like to know the mechanism, we don't need to show the mechanism. There's competitive reasons why we might not show that mechanism. If the clinical data will speak for itself. Okay. And And just on the IP, Kevin, maybe just quickly on 7500, what have you said publicly around that? I think it's on the order of in the late 2030s. Without extension. So how do you think big picture about where the treatment landscape in HCM is going to go over the next 5, 10 years? And where do you see your product fitting in potentially? Well, I think a drug, so we plan to move obstructive and non-obstructive studies in parallel. So you could think about it this way. If patients or physicians had a drug that whatever mode and/or phenotype of HCM that you had, you had a single drug that could be utilized in each one of those distinct populations, that would make it significantly easier. If you had a drug that had a competitive advantage on the safety profile because you did not have to worry about ejection fraction changes, that's where I think that the drug would fit. And then I think the wild card here is we may have the first drug to truly affect the pathology of the disease, which is a stiff ventricle. And so relaxation of a stiff ventricle would drive perhaps additional efficacy across multiple populations. So that would be the go-to drug immediately relative to the current profile of the CMIs. Okay. Switching gears now to Sevasemten and Becker, what are the top questions you need answers on from the regulators at this point? Yeah. So our plan today, and I think so I've spoke to everyone should read the new draft guidance for accelerated approval because what they put in place was what's called an intermediate clinical endpoint. And it's very similar to a surrogate, but it's not a biomarker. It's an actual functional endpoint that can be used perhaps as the accelerated approval endpoint and for full approval. Right? So if you think about the profile of Sevasemten and the Becker population, it's high on medical need. We have fast track. So the agency has decided that they could use a drug for these patients. The drug has been very well tolerated to date with all the patients that have been treated. There seems to be enthusiasm for the drug. 99% of the people have moved from the studies to the open label study. We demonstrated statistically significant changes in muscle damage. One argument is preventing muscle damage should be clinically meaningful for a patient. And then finally, the crux of the discussion will be is the magnitude of the North Star benefits sufficient to provide approval today. And now we will have the GRAND CANYON study will be fully enrolled. It will read out in the Q4 of 2026. But if you want to wait for that study, you're going to keep this drug that has a good investment or a good clinically meaningful benefit. You'll keep patients from this drug for three years. So if the drug is safe and it's clinically meaningful benefit, why would you keep the drug from those patients? So it would make sense to provide an accelerated approval. I think that's kind of the exact argument we're going to use, and we'll see how it goes. Our base case is that we have a well-designed confirmatory study in place and that this drug is approvable and will be approved in 2026 and 2027. But I think the patients would benefit from having this drug in their arsenal. I think we have to leave it there. Thank you so much, everyone, for joining us. I hope everyone has a great rest of the conference, and thank you to the Edgewise team.