Thanks, everyone, for being here. Our next presenting company is Edgewise Therapeutics, represented by Kevin, their CEO, and Behrad, their Chief Operating Officer. Thanks for being here. Thank you, Leonid, great. Yeah, so maybe we'll just jump right in. I mean, recently, you guys reported four-week data for EDG-7500 in HCM, and it's got a fairly unique efficacy profile. So maybe can you contextualize the symptomatic benefits you saw in KCCQ and New York Heart Association, what that tells us about 7500? Yeah, so I think at first, we need to point out that one of the questions about this mechanism, were we going to be consistent in seeing no changes in ejection fraction as we increase the concentration of the drug, and actually added patients and went out to 28 days. That was the case in both obstructive HCM and non-obstructive HCM. I think that was a defining moment for the mechanism. Now, the reason why I start with the ejection fraction is maybe a very simple concept on feel and function. Now, think about it. Ejection fraction defines a heart failure phenotype, and going below 50% on ejection fraction, is essentially a heart failure phenotype, where you lose the ability to walk upstairs, you lose your ability, you have fatigue, you have a whole host of comorbidities associated with heart failure. For the CMIs, they tend to lower the ejection fraction in most patients. That can range anywhere from 5%- 15% or 20% in some cases. Why would a drug mechanism that lowers ejection fraction have a patient feel better? What we observe with our drug is a mechanism that affects the pharmacodynamics of the heart without lowering ejection fraction. We are directly addressing the hypertrophy endpoint without changing ejection fraction, and therefore, the patients feel better without the negative of lowering ejection fraction. The second key aspect of our mechanism is that we directly affect diastolic function. The relaxation of the ventricle during diastole, and a stiff ventricle that does not fill with blood and is not able to pump a higher volume of oxygenated blood throughout the body. That ventricle needs to be relaxed, and we directly have that effect. The two aspects of our mechanism, relaxation of the ventricle during diastole, which is what we designed the molecule to do, and no changes in ejection fraction lead to higher levels of improvement on KCCQ scores and New York Heart Association scores. What I think, you know, quantitatively, what we're seeing is 70% of the patients becoming asymptomatic on New York Heart Association. KCCQ scores, on average, without any dose optimization of 20 points or more, it's an astounding result. The KOLs have all noticed this. Not only is it exciting for obstructive, but even more importantly, in non-obstructive and perhaps in areas like HFpEF. The mechanism itself is differentiated because we do not lower ejection fraction. I think the other thing, Leonid, to your question, it's a really important one because if you look at the American Heart Association guidelines, it's very clear in obstructive patients where it says, don't treat patients based on gradients. That shouldn't be the goal because if you look at gradients, gradients are variable. Your target should be treat to feel and function. A lot of the questions we got coming out of the four-week study was, you know, you didn't have a placebo arm. That's a valid point. If you look at the 50 mg and the obstructive, and you look at the 100 mg and the obstructive, both didn't have placebos, but you see a deepening of response between the 50 mg and 100 mg. That tells you that there's a drug effect there because you could have equally seen a placebo effect at the 50 mg, but we did not see it as robustly as we saw it when we dosed folks to 100 mg. I think we feel pretty good that that feel and function is actually translating as a therapeutic benefit of the drug. Got it. Since you mentioned LVEF, I had some questions on how that was measured, whether there's a slight decrease at four weeks, and sort of how that interacts with the PK of 7500. Can you talk about a little bit more about what's really driving the confidence that there's no change whatsoever on LVEF? Yeah, so you look first, you looked at our curves. You looked at the average data across from zero to one or from one week to four weeks, and we saw no changes going from one week to four weeks. The molecule gets to steady state, so the concentration is at its, you know, at its maximum by five days because the drug has a 30-hour half-life. By the first measure, the concentration at day seven is the same as the concentration at day 28. Now, we measure at trough at the lowest amount of the drug. If you look at the concentration curves, and we showed you the ejection fraction changes, and we showed you every point, there is no difference and no change in ejection fraction relative to the concentration. Whether you measure it two hours after you take the drug or 24 hours after you take the drug, there is no difference. If there is no relationship in concentration, there is no relationship or concentration. It does not matter when you take the measure. That is just a talking point from someone who does not know pharmacology. Okay, be very clear. If the drug, from a standpoint of efficacy, has a clear concentration relationship, as you go up in concentration, you increase the efficacy of the drug, whether it be gradient or whether it be NT-proBNP. No change in ejection fraction relative to the concentration of the drug, a concentration relationship on the efficacy of the drug. Why are we doing a dose optimization? Patients who have lower drug levels in a particular cohort, if we can get them up to a higher level of drug, they will have greater efficacy. We can optimize the efficacy for each individual patient without worrying about ejection fraction. I think the other thing, Leonid, that's interesting about our data is, and you know this, when we looked at the non-obstructive patients, we actually had a discrepancy between a site read echo, which was the eligibility echoes that we use to recruit and dose a patient, and the core read echoes. We had a group of four patients who actually had an LVEF below 60%, which technically did not meet criteria when we looked at the core. Even in those patients who had LVEFs as low as 52%, we did not drop ejection fraction in those individuals. That tells you that there's something about this mechanism that's unique, that even in patients who are susceptible at low LVEFs to showing a drop in ejection fraction, we had no impact there. That's further substantiated when you go and look at all the healthy volunteer data, right? You've seen the plot, we put every LVEF there. Patients, normal healthy volunteer patients, have LVEFs in the low 60s. Even in that population, within C-dramatic drops in LVEF, you look at those, you isolate those points, and you look at the placebo, it's essentially a flat line. I think we've disassociated the relationship between plasma concentration and drops of LVEF. Got it. I Got it. I think one of the other complexities in the data set were the four cases of AFib. I guess, can you talk about why you think that it's not related to the 7500 mechanism? T hen maybe even more importantly, what steps are you going to take going forward to make sure you're enrolling the right patients? We have preclinically done extensive studies in models where you would expect to see an atrial fibrillation signal. Especially in the non-obstructive pig study, which has an AFib signal within that particular study, it was five months, no signals were observed, and the drug was highly efficacious, and you saw actually improvement in the function of the atria and the atria actually getting smaller, which is what you want to see because the atria is enlarged in that model. Now, if you look at the toxicology studies, we ran extensive toxicology studies in both the dog and the rat, nine months, six months, and we saw no effects that were aberrant in the atria, no effects, no events of AFib, nothing you would expect to see in a long-term study. If there was any electrical sort of effect that you saw in an ion channel, we tested, obviously, every ion channel one could look at, or every GPCR one could look at, for any effect on AFib. Okay? Now you go into the normal healthy volunteers. We had patients at 100 mg for 14 days with holters because you always check, that's one of the first things you do in your healthy volunteers. We saw no signal in the healthy volunteers. In our patients, I think maybe one of the key things that we have not discussed a lot is that four patients in that sub-study, in the obstructive HCM patients, had prior AF and did not have AF in the study. What was the difference? Prior AF is a predictor of future AF. What was the difference? The difference was the patients who got AFib, first, two of them, we do not believe were HCM patients based on their wall thickness and their ejection fraction. Second, the other two patients had very large atrias, very large risk factors, and high diastolic dysfunction. Those are patients that generally would not be enrolled into a Mavacamten study, or the physician said they were too sick to put on Mavacamten. The same thing goes for Aficamten. They were too sick to be involved in Sequoia, generally, these patients. Okay? What are we going to do in the future? First thing, and Behrad spoke to this, we allowed the site read labs to enroll patients on the trial. We think that what we need is a higher level of evaluation of the patients. All the patients were read by a core lab, so a consistent read of the echoes as to whether or not they should be enrolled. We have a second read by the company, the sponsor, of whether or not that patient, the level of certain parameters within that patient, and also the number of comorbidities that patient might have. Third, what we have done is matched the CMIs in their inclusion/exclusion criteria. Now we would look back six months instead of 90 days on prior AF. We are eliminating patients with mitral valve stenosis or calcification. We are also looking at, you know, other comorbidities such that we do not enroll patients who have a high risk of AFib and should only be really enrolled in a controlled study. Now, that's not to say we will not treat these patients eventually, but what you need to do is have a controlled study when you put these patients into the trial. Got it. I think what's interesting even for those AFib cases is AFib aside, they were pretty good respondents. They were efficacious. They had KCCQ improvements. It is just that they also had these underlying comorbidities that made them a high-risk patient. I think moving forward to Kevin's point, it is not that you're going to leave those patients out. It is maybe a complex patient has a different algorithm to get them to an efficacious dose than a more traditional healthy HCM patient. Got it. I guess you're going to be presenting an additional cut of data in the second half. What should we expect from this 12-week data? I mean, were we thinking that we should be seeing deepening of efficacy on biomarkers, stability? Can you talk about what sort of the expectation should be there? Yeah, I think if you look at trends, I think the NT-proBNP can deepen. I think things like the gradient with the obstructives are within the noise of the gradient measure. It's probably likely to be reasonably similar. We had robust efficacy there. It's an open question in non-obstructive, the deepening of the responses. I don't know if there's enough data to know how the response on feel and function. I think from the CMIs, you could surmise that the maximal efficacy on non-obstructive is more like 12 weeks to 6 months. I think the efficacy on feel and function might deepen in the non-obstructives. We'll have to see them. Got it. Earlier you had mentioned the titration scheme that you guys are working with. Can you just talk about the rationale, maybe specifically of the starting dose and why start so low? Given that you have an efficacious fixed dose, that's how you're thinking about the trade-off between getting more patients to maximally effective dose versus maybe what's most convenient to simply use? You know, the key is this guideline from AHA that you're treating to feel and function. We had, at the 50 mg dose, about a quarter of the patients had benefit on feel and function. The question, and the other thing that we've noticed, is that patients who went below a threshold of about 150 pg /mL in NT-proBNP, they turned out to be New York Heart Association 1. I've been thinking, I've probably been saying this for three or four months, that getting a patient to normal is the goal. Normal on feel and function, meaning I'm asymptomatic, or normal on KCCQ, that I'm greater than 90, or normal on NT-proBNP, that I'm less than 150, is the goal. For every patient, can I achieve that goal? How do I do that? How do I create a new paradigm? Actually, what we're thinking about now, especially with looking at the zero change in ejection fraction, is how about we start with thinking about non-obstructive, where there is no gradient, and you do not need to use an echo? How do you get each individual patient to their optimal dose? You have to use a combination of the NT-proBNP and the feel and function to get them to an optimal dose. Now, can you apply that paradigm to the obstructive patients? That would mean you could eliminate all the echoes, even in obstructive, if you can figure out what would predict a patient's feeling better. The goal here is to optimize for each individual patient so that they feel better, and that will create the best outcome for each individual patient and a competitive advantage for the drug. I think the word titration is used in the context of the CMIs because they require an echo to titrate because of a safety concern. I think the fundamental difference between that strategy and what we're proposing is you can start a patient on a dose, and the physician, at their discretion, determines whether they think that dose is efficacious or not, relying on measures that are not echo measures. Then depending on how complex that patient is, the physician can make a decision on when to perform an echo for that individual. If you have a complex patient or you have a pretty simple patient, might put them on the first dose, keep them on that dose. If you're a simple patient, patient's responding, everything's looking good, I'll do an echo in line with your annual echoes when I track your disease progression. If you've got a complex patient, you might put them on a dose and say, maybe I need to do an echo because I want to track gradient as well to see what happens. You're leaving it at the physician's discretion to make a determination on when to do an echo to optimize the dose. That's different to titrating because you're concerned that there's an LVEF liability and because it's pre-prescribed through a REMS that requires you to monitor those patients. Now, your question of why start so low, I said that 50 on feel and function measures did have some benefit for some patients. We also saw robust changes in NT-proBNP. We believe that 25 is a pharmacodynamically active dose, meaning that you are affecting the heart even at 25. The question becomes, and you asked it originally, is there a time component to the benefit of the drug and all of these drugs? I think there perhaps is, and the goal here is to, you know, think of it this way. You have had a heart that has been in a disease state for a decade. What do I want to do to that heart? You want to slowly re-acclimate the heart to normal function, remodel the heart to normal function. You can do that in a systematic way. I think that's very positive for the patient. I mean, things like Entresto, you look at the label, you're starting at a low dose, and over a period of two months, you're getting to an optimal dose for each individual patient. Now, of course, some of those patients you could have started at the highest dose, but I think for each individual patient, there is an exposure and an optimal amount of drug. We just want to be able to design that into our phase threes because that would provide us a competitive advantage. Got it. I want to shift gears for the last few minutes to Sevasemten and maybe starting with the DMD data that we'll be looking for around mid-year. I guess, can you remind us how many patients we're going to see, what the breakdown is between Lynx and Fox, and how we should think about potential efficacy measures for Lynx and for Fox? Yeah, so it'll be a complicated discussion, and we've explained what we did. Let me go back and re-examine what the strategy was. We ran a placebo-controlled three-month study, dose ranging. The agency asked us that when we had a safe dose, safe higher dose, to move all the patients from the lower dose to the higher dose. We did that multiple times. We started at 2.5 and went up to 30 mg. Each cohort took about four to five months. Okay? We have, in each dose group, roughly 10 patients. Okay? We're going to have patients who are on a background of steroid, and some are on EXONDYS 51. We allowed Exon skippers. We'll have various groups, and you'll have the three-month data looking at biomarker. Then you'll have 9 and 12-month data of some of those patients having functional outcomes. We will look at the differences between those different groups. All of those patients ultimately came back down to 5 mg or 10 mg because that turned out to be the pharmacodynamically relevant dose. We will have a cut of data at that level. We will have a cut of data when those patients have been on a 5 mg or 10 mg dose out to almost a year. I think in Lynx, we are talking about 60-70 patients, and in Fox, roughly 30 patients, 20-30 patients. You know, it is interesting, right? The Fox patients are gene therapy treated patients. I think what is being kind of interesting to watch is Sarepta put out data last year at MDA that showed the two-year benefit of a patient who had received Elevidys. There was a two-point improvement versus a predicted decline of, I think it was 0.6 points or something like that. At three years, they had a five-point drop. They went from +2 at two years to - 2.5, I think, at year three. Natural history declined at the same rate. They went from - 0.6 to - 5.6. That tells you that now you've lost that benefit and now you're declining at the same rate as natural history. What if we could do something similar to what we've done in Becker for the Duchenne kids who've received the gene therapy? I think it's an interesting kind of group of patients. I think it's clear that within two years, you're getting a benefit from the gene therapy, but once you go two years out, you're starting to lose that benefit. This is consistent with the MRI data that Pfizer showed a few years ago that, again, showed, I think, after two years, there was benefit, but then all of a sudden, at the third year, you're losing a lot of it. Got it. And, you know, as we think about that data set, I mean, the original design was CK at three months as the primary. I mean, obviously, mission is a complex set of data. Should we be focused on the three-month CK data being static? Should we be looking at the longer-term NSAA data? Or should we be looking at the longer-term stride velocity data? I would look at, you know, probably NSAA makes sense because that's ultimately the primary endpoint, right? That's what's traditionally been the primary endpoint. I think we can look at biomarkers, and we've talked about biomarkers a lot because it's kind of the target of the molecule, right? We look at TNNI2 specifically and obviously CK. I think ultimately, this data set is going to inform what we do in phase III. I think you have to look at function as the primary measure of what we're going to do. Remember, what we did say is that the depth of the response at nine months actually was increased at lower concentrations and lower drug doses. Different than Becker, where the response was immediate, the depth of the response on the biomarkers increased over time, which is one of the actual criteria for why we went down to the 5 mg and 10 mg, because at nine months, the biomarker response was different than at the three-month time point at the low doses. We're about 30 seconds over, but I had one last important question. You guys are talking to the FDA on accelerated approval for Becker. Has that discussion happened yet? When might we hear the latest update? We're on track for disclosure by the end of the year, or end of the quarter. Let's say end of the year. End of the quarter. We're ready for the end of the quarter to discuss the data from the FDA. Got it. Thank you so much for being here. Thank you, Leonid. Thank you.