Thanks everyone for being here. For our next session, we've got Edgewise, represented by Kevin, their CEO, and Behrad Derakhshan, their Chief Operating Officer. Thanks for being here. Thank you. Great. Good to see you. Good to see you. Yeah. There's a lot of things going on with the company, but I figured I'd start with the HCM side of the business. Maybe just to help set the stage, you've got pretty unique molecule in EDG-7500. Can you talk about what you think may be the key advantages of EDG-7500 versus some of the other modalities that are out there? Yeah, I think it starts mechanistically that we target a different protein within the sarcomere. That's a key differentiating factor. What does that mean towards a therapeutic value? Two things. One is we are a partial modulator of the contraction. For competitor mechanisms like the CMIs, they completely block the contraction. If you think about it, whenever you completely block something, having that come back to normal is slow and challenging, and that you can completely arrest the contraction, which is the heart from contracting. That's generally a bad thing. You need your heart to contract at some level to be functional. That's one thing. We're a partial modulator. The second thing is that the pathology of HCM, and for that matter HFpEF in most of heart failure, is that the ventricle contracts, but then it has to relax to actually fill with blood to pump around the body. The systolic effect is contraction. The relaxation effect is called the diastolic effect, and that's the relaxation of the ventricle. Our mechanism, we are more potent on the relaxation of the ventricle, which allows the ventricle to increase its capacity for oxygenated blood, which is now pumped around the body. That drives the pathology of HCM and HFpEF. Those two pieces, partial modulator and more potent on the diastolic relaxation function of the heart, provides differentiation and greater potential within HCM and HFpEF. Now how that is translated to the clinic is that we've seen no changes in ejection fraction as you increase the dose of the drug and the concentration of the drug. That was data that we put out in December, which is a continuation of the data we put out pretty much this time last year, that we could show profound efficacy in HCM patients without changing ejection fraction, which is highly differentiated from the CMIs. Why is that important? Lowering ejection fraction drives a black box warning and a REMS, meaning that you need to have multiple echos to titrate the CMIs to an efficacious dose. That REMS is capping the ultimate market potential of the CMIs in HCM. For EDG-7500, by not seeing any ejection fraction changes and seeing robust efficacy, the drug will be used across all of the treating physicians, not just in the center of excellences, and will make it easier for the patient and easier for the physician to administer the drug. That's the exciting potential and the differentiation of the mechanism. Together with that lack of drop in ejection fraction, which is a significant safety signal and a predictor of heart failure, we've seen robust effects on the diastolic function of the drug, and that's measured by e' and E/e'. In both cases, we had rapid and robust benefit on that particular metric, which would essentially address the pathology of the disease, which is the relaxation of the heart. Got it. You mentioned no impact on LVEF, but there was at one point some concerns about signal on AFib, which may have been confounded by sort of the natural progression of the disease. Can you talk about how you're thinking about AFib and that adverse event versus LVEF drops, maybe the relative importance and I guess your confidence that there isn't actually an impact on either? The whole AFib story, it's interesting. It's one of the first times I've ever seen the KOLs telling the investment community it's part of the background of the disease, and the investment community not believing the KOLs. I've never seen such a thing. What it is patients with HCM have a high incidence of atrial fibrillation, tachycardias, irregular heartbeats in their background. It can be silent, or it can be transient, where you have it for minutes to hours, but you don't even necessarily go to your doctor for these things. Now when you're in a trial, you're being evaluated and being told, "If you feel anything, call up your doctor." There's a trial bias for how much atrial fibrillation exists. In the real world, atrial fibrillation is 20%-30% of the population will have atrial fibrillation. When you run it in a trial, what you've seen in the placebo group is basically between 2% and 10%. We've been arguing that for the last year that that's all in the background noise of the trial. We expect to see nothing different within our next study, because that's the background patients. Got it. Another point of convenience for EDG-7500 that you touched on is the ability, because of no LVEF impact, to change the way titration works and sort of balance that with routine monitoring. I guess, how are you thinking about, as you think ultimately about this drug being used in the real world, how patients would select a dose, how physicians would select the dose, how they'd move through that, and any requirements around that against sort of a background of these patients have to come in for monitoring anyway? Most drugs in cardiovascular are essentially started a dose which is maybe weight-based or it can be at the low dose, and then titrated up to the patient essentially feeling the best they can feel. Basically getting them to they feel relatively normal. Those are the AHA guidelines. What we would like to do and what we have proposed to the agency. Let's take a step back. We had not talked to the agency for 18 months. We had kind of a two-step process with the agency. We reintroduced the drug, gave them a data cut-up of to January, and asked them some questions about the Phase III design. Our Phase III design going in was we will not need an echo measure to titrate the drug. We'll have an echo measure at the beginning of the trial, an echo measure at the end of the trial, and maybe we'll collect an echo somewhere in the middle, which is not associated with any change in dosing. What the physician will be doing is dosing the drug up from a lower dose to an optimal dose for each individual patient based on how they feel and any tolerability measurement, which is basically how they feel. The goal is to get every patient to normal. What does normal mean? Well, at 1 level, normal is New York Heart Association one. If you start, and the inclusion criteria will be either New York Heart Association two or three. If I can get everybody to one, that would be the guideline-driven optimal dose for each individual. A particular physician may look at a measure of stress to the heart called NT-proBNP, which is a blood-based biomarker. Every cardiovascular patient gets that measure. If they want to drive it down more, perhaps they would utilize that. In essence, what we're titrating to is how the patient feels without any echos. Let's talk about how patients feel on the drug. You guys have shown data just four weeks, pretty impressive benefits on feel and function. There's going to be another data set coming up, longer time on drug. How do we think about the efficacy evolving? Well, we've said, without knowing the numbers and without providing any leading information, that we should be seeing equivalent or better data than we saw in the original disclosure and relative to the CMIs. I think it's important to remember, this is a 12-week study we'll be reporting on. As you've seen with some of the CMIs, depending on which trial, you see a deepening of a response on various biomarkers and echo parameters as you go for time, as you get some level of remodeling. I would say that the 12-week data we're going to report is the minimal data that we'll see. We're confident in saying that we'll see data that's as good or better than what we've seen with the CMIs in our prior trials. Got it. In terms of endpoints, you mentioned New York Heart Association class for inclusion, exclusion criteria, normalization. You previously also talked about KCCQs as being important. Those guys are dosing based on NT-proBNP. How do we think about, is there an endpoint we should be focusing on? Is it the totality of the endpoints? Sort of help guide us as we think about the efficacy. We were just out speaking to some investigators how they have slightly different metrics of how they treat their patients, but we're trying to fit into the manifold of how most treating physicians want to get their patients to an optimal dose. I think you want to simplify it to some extent, right? If you think about the goal here, KCCQ, as you know, is a clinical trial tool, right? Your average community guy, even your academics, aren't using a formal KCCQ in their daily practice. If you think about what is the most logical thing for a physician to determine whether a patient is responding or not is you just have to look in the heart failure space, right? A lot of physicians, both at centers of excellence and in the community, use NYHA as a good metric to determine how is my patient feeling, do I need to optimize anything in order to make sure that they're getting their optimal care as well. You're really looking at what is a feel and function measure that is determined by the physician, but then you've got to look at it from a multi-domain standpoint, right? You can easily get lost and obsess yourself on a gradient, for example. Be like, "I'm just going to drive down gradient." If you're driving down gradients but your NT-proBNP isn't changing and your NYHA isn't changing, then what's really happening, right? You can drive gradient relief and maybe not see the feel and function improvements that you expect. You could easily kind of obsess yourself on that one metric. You have to look at it from a combination of elements. Okay, I'm relieving gradient, but am I also impacting NT-proBNP? Can I get people to normal across a number of metrics? Essentially what you're shifting to is a little bit of a responder analysis in the context of a trial, but that gives a framework for the practicing physicians, both in centers of excellence and in the community, to optimize care. The big psychological barrier that we're hopefully going to be able to overcome for them is you can do that without worrying that you're going to drive down systolic function. That is the key piece to opening up the value proposition. Got it. There's obviously been a lot of interest in some recent nHCM data sets. I guess any takeaways from what we've learned so far in nHCM and then maybe bringing it back to EDG-7500. Do you think the drug's better positioned for obstructive or for non-obstructive and given that the data set we saw in non-obstructive was fairly small, I guess how do we think about the confidence in each of those? Well, in obstructive, I think it's really straightforward what you're observing is that you're changing the, let's call it the biophysics or the geometries of the mitral valve coming over and creating an obstruction by affecting contraction, ejection fraction of the heart. By doing that, as you might imagine, if you increase the flow, if you think of the gradient as a flow of oxygenated blood from the ventricle to the aorta and the rest of the body, you can see how alleviating that biophysical change of that flow obstruction is going to have an immediate benefit on the patient. In a non-obstructive patient, you don't have that effect on flow. What you're really looking at is how do I change the biophysics of the wall of the ventricle which is now thickened and stiff, a much harder metric to affect. Our drug focuses on that particular metric. It can take longer to affect that metric. It also is much more difficult if you don't have a direct effect on the relaxation. For our mechanism, we're directly affecting the non-obstructive phenotype and the pathology of the disease, and that should ultimately have a competitive advantage versus any drug that doesn't affect that primary pathology. I'll give you a good example, Leo. You know we studied fixed doses, right? 50 and 100. You also know we studied 25 because the FDA had asked us to look for a minimally efficacious dose. What was really interesting in the obstructive cohort at 25 milligrams is within a week, you're seeing NT-proBNP drop greater than 30%. It probably happened sooner because you've seen the single-dose data. We saw pretty impressive drops within 24 hours, but we were only measuring a week, two weeks, four weeks. Within a week you're dropping 30%, and then your hemodynamics are not changing. Gradients at the week at 25 are flat. By week two, the gradient's catching up and NT-proBNP is continuing to deepen. That tells you that what we've mechanistically postulated based on the data we have pre-clinically, this molecule works preferentially during diastole, and then the hemodynamic elements pick up later. This really is the proof of principle that we work better in diastole. I think this is a really important piece because to your question, if you go into non-obstructive, which is a diastolic disease, that's a big deal. If our goal is to enhance feel and function, so make the patient feel better, just think about the measure of ejection fraction and what's physically happening. You're ejecting more highly oxygenated blood throughout the body. If you're lowering that amount of blood, how can the patient feel a lot better? If you're inhibiting somebody by 15% or 20%, why would they feel better? Is the enhanced benefit we saw on feel and function in the original disclosure, what is that really based on? I think it's really based on two things. One is mechanistically the diastolic effect, but if you don't lower ejection fraction, you're going to feel better. If you have effects on the biophysics of the heart and you don't lower the ejection fraction, you will feel better because there's more blood flowing, period. When you look at the data from the non-obstructive trials, you saw 20% of the patients going below 50 in ODYSSEY-HCM, and at least 10% of the patients going below 50 in ACACIA-HCM. That's a challenge for those drugs mechanistically. If you take people too low or you drop the ejection fraction to too great of an extent, you actually cap the benefit that you can provide to the patient on feel and function. It poses a practical problem because the beauty of OHCM is that through the echo that they have to perform to kind of monitor or escalate and dose, you can see whether you relieve the pressure gradient or not, right? You can see gradients shifting. In non-obstructive, you really don't have that telltale sign, you're really dosing until potentially LVEF. You can use NT-proBNP, but then the question is, if I drop someone's NT-proBNP by 50%, seems to be like the mark that people are really gravitating to in non-obstructive. Am I getting them to NYHA Class 1 and am I able to do that without dropping systolic function? Now you're trading off risk benefit. Yeah. Can I ask maybe an unfair question, but you talked about the LVEF and echo monitoring requirements. As you think about what a label might look like, would you expect there to be a REMS? Is the label ultimately going to be based on the Phase III design where you'd have sort of the initial echo, the middle echo, then the final echo? Could all of this be even less stringent than what you're seeing in the Phase III? I think it's a good question, right? I think when you and I chatted a couple of weeks, I think I want to say something and then I want to answer your question because I think there's two catalysts for the company this year. Three. As it relates to HCM, there's two. One is obviously the data, and then the second as we discussed is we're obviously going to go to the FDA with our end-of-Phase II data. We're going to get some feedback, and that'll give you a sense of the level of monitoring that we're going to perform in Phase III. That flexibility or that regimen will inform ultimately how the FDA views a potential REMS or not. Right? It's a good surrogate for that. I think where it's going to play out practically is not having to worry about LVEF in the real world gives the physician the discretion to determine when and if they perform an echo. The problem today is the echos, but because they're mandated. You cannot move up in dose unless you perform an echo. As you know well, the bottleneck is echo time and experts in order to get all the patients that they want onto CMIs. I think if you say to the physician, "It's at your discretion," I can't go into a practice and tell them, "Don't do echos." They can do whatever they want. It might be a question of the complexity of a patient. If I have a really difficult patient and I've put him on dose X and they've responded, but they seem to be problematic still, I might want to do an echo, but no one's forcing me to do it. It's my discretion to do it. I think that's where it's going to play out in the real world. I think the hope is that the FDA will give us the baseline end of study, and then if there's one in the intermediate which doesn't inform anything, it's a purely safety echo, that's a really great place to be. In the real world, that translates into the physician use at their own discretion performing an echo, or they could just say, "You know what, I'm going to wait six months, my normal cadence of seeing my patients, in order to do an echo on them." That's the psychological difference. Yeah. You mentioned that there's a few catalysts for the company, and I'm hoping one of the ones implicit there is Grand Canyon. Oh, that's super exciting. I wanted to spend at least the last two minutes on that. A whole two minutes. Yeah, a whole two minutes. I guess you guys sound pretty confident it's going to read out in the 2nd half of the year. You've talked about the powering for the study. Separate from the powering, what's meaningful, and given that dystrophies have historically been challenging to hit? Yeah function endpoints, how much wiggle room is there? You know what's funny? We've almost done things a little bit backwards because a lot of people use a surrogate in these diseases to show efficacy, right? Even in our phase II we used CK, but it was mostly to show target engagement, right? TnI and CK. We've actually done the harder thing, which is show functional improvements relative to placebo and natural history, right? Obviously in phase II it wasn't powered, but if you look at the data, it looked pretty good. Directionally. Directionally it was very positive. I think when you look at the data set, you start to get pretty excited about, okay, what is clinically meaningful to your question? I think if you look at one point on one year and you analyze that over five years, if I tell you you're going to lose five f unctions over five years versus I'm going to keep those functions in place, that's pretty dramatic, right? What we're hearing from physicians now is they're coming and looking at the data and they're saying, "What I'm seeing in your data is fundamentally different than what I'm seeing in my patients in my practice. You've gone out long enough where I can look at my patients and see them declining, and when I look at your drug, you're arresting that decline." That's a pretty powerful statement from physicians. I think for us, we feel really confident that it's powered adequately, and even if we're powered at, I think, it's 1.8 over 18 months or 1.7. That's pretty cool. People should pull our poster from the Muscular Dystrophy Association. I think it was a stark observation. You look out for the patients who have been treated across the study. They are stable over multiple years. Even in the placebo group, they were heading down like the natural history. These are patients who are all blinded. They don't know if they were on drug or placebo. The patients still don't know. The placebos flattened out or even went up over the last year. No one knows who was on drug originally, so why would the placebo go flat and up? The people who are on drugs still are flat. Yeah. Every physician who looked at it said, "I've never seen that before". Gaining a function for Becker patient is almost as important as, or maintaining a function is as important as gaining a function, right? I think we're out of time, but a lot going on. I'm really happy to talk about it with you guys, and thanks for being here. Thanks, Leo. Thank you. Thank Thank you all for joining.