Good morning, everyone. Thank you for joining our second day of our Piper Sandler Healthcare Conference. Very excited to be hosting the team from Edgewise Therapeutics here with us this morning. We have 25 minutes and quite a bit to cover. I would like this fireside chat to really be focused on one of your assets that you're developing in HCM. I think a lot of our clients know we follow the HCM space really closely, and I would love to just dig deep onto the program. Sure. First, and then get into the pipeline later. Sure. Team, I think the first place to start for individuals who are new to Edgewise is maybe talk about your lead asset, 7500, that you're developing for HCM. What is the mechanism, or what is the mechanistic advantage for the treatment of HCM? Yeah, great. So we, we're a muscle platform company, so all of our targets are novel targets, targeting muscle. We developed this particular asset, actually, as a counter screen for our skeletal muscle program, and we had a choice. We could create a best-in-class, myosin modulator for cardiovascular treatment. But we also, out of this high-throughput screen, identified a novel mechanism that initially we looked at data, and there was a greater therapeutic index- Mm-hmm. -relative to the CMIs. And so we continued to follow up on that particular mechanism, and we're really pleased to see that, this molecule is not a myosin inhibitor, but does regulate the ability, of the sarcomere, to contract- Mm-hmm ... in a way that has a much wider range of relationship between the concentration of the drug and the change in ejection fraction. Mm-hmm. We knew this very, very early, even one of our first studies with our first- Mm-hmm in vivo molecule. Could you help put into context, like, I think a lot of investors know how the myosin inhibitors work. Obviously, we have a first generation that's approved, a second generation, mavacamten, that's currently in Phase III. So how does the mechanism differ in the myosin inhibition, and what is the advantage by targeting this, the sarcomere? So you can think about the physics and the physiology of the sarcomere complex. So the cardiac myosin inhibitors interact directly with the ATPase. Mm-hmm. Think of them as a kind of an on/off switch. Mm-hmm. You're either binding or you're not binding. Mm-hmm. We bind in an alternative space in the sarcomere- Mm-hmm ... which is distal from the ATPase. So what we're doing is changing the rate- Mm-hmm ... in which the contraction occurs- Mm-hmm ... and in which, if you think about it physically, it's the crawling event- Mm-hmm ... the arm and crawling along the actin filament. We change the rate in which that occurs- Mm-hmm ... both on the contraction side- Mm-hmm ... and the diastolic side- Mm-hmm ... and the relaxation side. So in both cases, we have a slower contraction- Mm-hmm ... which increases the range of the relationship- Mm-hmm ... between concentration and ejection fraction- Mm-hmm ... and we speed the relaxation- Mm-hmm ... so the head coming off of the actin filament- Mm-hmm ... which leads to greater levels of relaxation. Mm-hmm. That's a very unique mechanism. We can see this in the echo studies- Mm-hmm ... both in normal, preclinical species- Mm-hmm ... and also in the disease models. Given this differentiation, could you maybe then kind of tell us how does that change the product profile, right? So with this mechanism, what do you hope to show different than the myosin inhibitors that are approved in the development? So what we've shown so far is... And of course, you know that there's the REMS and the black box- Yeah ... with the cardiac myosin inhibitors because of the narrow therapeutic index- Mm-hmm ... and the requirement to titrate to get to exactly the right exposure- Mm-hmm ... for each individual. So what we've shown is that we have a much wider range. Mm-hmm. Therapeutic index is wider, which would ultimately lead to our ability to have a fixed dose- Mm-hmm ... which is a typical dosing strategy for any patient, perhaps based on weight- Mm-hmm ... but without a titration. And it would provide a much broader safety window and would, then, the physicians would be much more- Mm-hmm ... inclined to provide that drug- Mm-hmm ... given the efficacy all being the same. Yeah. Now, the other thing that's exciting about this particular asset is that we designed it to have a shorter half-life- Mm-hmm ... than the CMI. So our half-life is projected to be one-two days- Mm ... instead of seven or eight days for aficamten- Yeah ... and up to 15 days for mavacamten. So although one would think, "Eh, it's not that big of a deal- Yeah ... with a smaller half-life," realistically, for the vast majority of physicians, being able to remove a drug- Mm-hmm ... is really a competitive advantage- Yeah ... because you don't have to follow them for 6 or 7 or 8 days. Yeah. Mm-hmm. Now, a day later, anything that happens- Yeah ... can be resolved. Yeah. I think that's an underappreciated competitive advantage- Yeah ... for our drug, and we'll be able to demonstrate that- Yeah ... in the clinic, shortly, I hope. No, that's very helpful. Could you maybe talk about the type of preclinical data that you have already generated and whether in these preclinical models you randomized an inhibitor as a comparator? And then if you could maybe allude to, like, what did you show, right? So as, and as a comparison, because I think a lot of investors, you know, know the clinical data and so kind of put it into perspective for the patient. Yeah. So preclinically... And this is-- it's great that we have two of the key in vivo pharmacologists- Mm-hmm ... from MyoKardia. So the person that ran the cat model- Mm-hmm. of obstructive HCM and the person that ran the non-obstructive- Mm-hmm. -pig model, of nonobstructive HCM, they ran mavacamten- Mm-hmm. through those models. Yep. And they also have run our molecule- Mm-hmm. 7500 through those same models. Mm-hmm. What we showed in the obstructive cat model was that we could have a decrease- Mm-hmm. in gradient in that obstructive cat model Mm-hmm. -of 61%- Wow! with only a 2% change in ejection fraction Mm. after oral dosing. Mm. Which I think was really compelling to us- Mm. about the differentiation Mm-hmm. of what you would see with mavacamten, and you would have a fairly- Mm. -dramatic change- Yeah in ejection fraction in that cat model. In the pig model, what we saw was in a nonobstructive HCM, what you see is thickening of the wall. Mm-hmm. You see a contracted volume of the- Mm-hmm ... left ventricle, and you see an enlarged atria. Mm-hmm. What we're able to do, which is quite exciting, is decrease the thickening- Mm-hmm ... of the wall, enhance the volume- Mm-hmm ... of the left ventricle, and decrease the volume of the atria. Mm-hmm. So in that case, we did that all without decreasing the ejection fraction. Mm-hmm. Now, a molecule was not mava itself- Mm-hmm. -it was a related molecule, and this is data that's published in a poster- Mm-hmm in a presentation. Although they do see some effects on- Mm-hmm -diastolic function, they don't report the ejection fraction. Mm-hmm. What is clear is that they can't get the diastolic effect they want- Mm-hmm ... to see and the relaxation- Mm-hmm ... effect you want to see without seeing this concomitant- Mm-hmm ... change in ejection fraction. So I think again, it points to our therapeutic index- Mm-hmm ... on both aspects of- Yeah ... of contraction and relaxation is greater than the cardiac myosin inhibitors, and that's what's unique about this mechanism. Yeah, that's, that's very helpful. Is there, as you guys have been able to overlay the mechanism, clients understand that there's the obstructive population and there's the non-obstructive population. Given this product profile and its unique mechanism, is there, is the likelihood to work more in non-obstructive versus obstructive, or do you expect that it could work equally well, both in both populations? How do you think about that? I think it would work equally well in both populations, and what the true deficit is in non-obstructive- Mm-hmm ...HCM, is this relaxation? Yeah ... so the stiff ventricle. Yeah. I think being able to relax the ventricle to allow for- Mm-hmm ... greater filling is something that's unique in our molecule- Mm-hmm ... that you cannot achieve with the CMIs. Mm-hmm. I think we, from what we've shown pre-clinically, we should have the same or better effects- Mm-hmm ... in obstructive HCM. Mm-hmm. So I think it actually really fits within both- Yeah ... mechanisms. I think, you know, where probably the greatest differentiation would be in non-obstructive. Yeah. But I feel in the obstructive space, it would be very exciting as well. Great. Could you maybe for investors who are new, maybe remind them, when was the IND filed and when was the IND cleared, and we'll go through the design of the phase I study. Yeah ... but maybe just from a- Yeah. Um, perspective. We filed the IND in the summer. We started dosing patients in September. Mm-hmm. These are not... normal, healthy volunteers. So one thing, we have reported the dosing schedule. So it goes from 5-15- Mm-hmm ... to 30, 5 to 15, to 45- Mm-hmm ... to 100- Mm-hmm ... 200, 300. Wow! Just looking at that data itself- Yeah ... we have a broad- Mm-hmm ... therapeutic window. Yeah. That's the first set of studies that we're doing. That will be completed sometime this quarter. We'll initiate multiple ascending dose cohorts in normal, healthy volunteers, in the beginning of the first quarter. Mm-hmm. We have a number of different cohorts which will be going all up. Depending on the half-life- Mm-hmm ... we'll calculate the amount of accumulation you'll see. Mm-hmm. We also have a set of patients who are elderly, normal, healthy volunteers with a depressed E prime. Mm-hmm. So they have a decrease in diastolic function. Mm-hmm. So we can enhance the window- Mm-hmm ... in which we can measure the diastolic effect in that- Mm-hmm ... particular population, of normals- Yeah ... so to speak. And then, we have already written the protocol for the p hase I- B. So the way phase I- B is, we think of it in this way. We wanted to demonstrate as early as we can, a differential from the cardiac myosin inhibitors. So what they have shown is with a single dose- Mm-hmm ... a deep decrease in gradient in an- Mm-hmm ... obstructive HCM patient- Mm-hmm ... but with a additional decrease- Mm-hmm ... of over 20%- Mm-hmm ... in the ejection fraction. Mm-hmm. We believe, as we saw in the cat model- Mm-hmm ... that we can decrease the gradient in those obstructive HCM patients. Mm-hmm ... with a single dose- Mm-hmm ... of 60% or more without a change or minor changes in ejection fraction. And that will lead us to try to understand that, yes, this molecule- Mm-hmm ... could be used in a fixed dose regimen. Yeah. Okay? The second part of that phase I-B study will be 28 days of dosing. Mm-hmm ... in both obstructive HCM patients- Mm-hmm ... and non-obstructive HCM patients. Mm-hmm. So there we'll see the accumulative effect- Yeah ... of the mechanism- Mm-hmm ... in the patients. We have 28 days of dosing for the toxicology coverage. Mm-hmm. We were so bullish on the mechanism that we decided to go to chronic tox test. Mm-hmm ... testing immediately. Mm-hmm. Sometime by the end of next year- Mm-hmm ... we'll be able to dose patients indefinitely- Okay ... which will accelerate our phase II and our phase III Wow ... for both different indications. No, that's, that's fantastic. Let's maybe kind of like understand each segment of the design. The first segment is going to be a healthy volunteer study, right? Dose ranging, a SAD, and then a MAD. So as you guys are thinking about, could you maybe remind us, like, what is the size of the cohorts in the SAD and in the MAD? And will you share the SAD and MAD data combined and then go into the data release onto the one, one- I think the goal is, we don't know where we can see this diastolic- Mm-hmm. relaxation effect. Mm-hmm. We have seen it with a single dose. Mm-hmm. It's a higher probability in normal healthy volunteers with multiple dosing- Mm-hmm ... at steady state. But I think optimally, you would look at the package. Mm-hmm. I think the SAD and the MAD will define the safety. Yeah. The HCM studies will define- Mm-hmm ... the therapeutic window and the competitive advantage. Yeah. So providing that entire package- Yeah ... I think is more exciting. It's probably gonna be complete by the third quarter. Okay. So I think that's a good time to put out the entire package- Yeah ... and show distinct, clear differentiation and the potential of the mechanism. Okay. I don't recall going back, and I should have. I should know this, but is there any PD marker that you could track in these healthy volunteers that one could compare to the myosin inhibitors, you know, between-- Just to kind of reemphasize the therapeutic window? Yeah. In the—I think in the nonobstructive HCM, you can look at, certainly look at troponin, the BNP. Yeah. You know, if you look at the timing- Mm-hmm ... well, from the prior studies, those molecules with the long half-life and the titration- Mm-hmm ...they, to get the steady state- Mm-hmm ... and maximal efficacy, they have to go six weeks or so, so- Yeah ... to get there. For us, with a shorter half-life- Yeah ... we get the steady state earlier and maximal pharmacology earlier. Mm-hmm. I think you might be able to see- Yeah ... a biomarker response- Yeah ... in the nonobstructive relatively early- Yeah ... within three or four weeks. Okay. That data is coming in the third quarter? Third. Third, probably the 28th day would be- What is the size of the total- The fourth quarter. The total size of both the SAD and the MAD combined, do you recall? Well, they're usually, and this is typical for these SAD, MADs, so they're six treated and two Okay. -placebo. Okay. Yeah, for every cohort. Got it. It'll be quite a few patients. Good. And then once that data is shared, then it will lead into the dose selection going into the 1B. Could you talk about this? The 1B is gonna be focused on the nonobstructive population first? No, the obstructive patients. Sorry, obstructive. Yeah. Obstructive population first. The obstructive population, what's the size of the cohort? How, how much will you try to match this cohort to maybe some of the phase II studies that we've seen with the myosin inhibitors? Yeah. Because I think the natural thing that investors would wanna do is compare your results- Yeah -to the other products that are ahead. So are you guys contemplating to matching them more similarly so that- Yeah -comparing the? That was actually really the goal of this study. We have what we call the n=9. Yeah. Which is 9 obstructive patients. Yeah. three different dose levels. Okay. Right? So, our dose selection would be driven by our results from the SAD. Yeah. So we have a concentration range based on the preclinical models. Mm-hmm ... that we're looking at, and so we'll pick probably the mid dose of that- Okay ... efficacious range- Okay ... from the preclinical models, and look back at the SAD- Okay ... and say, "Is that an effective dose? Yeah. We'd probably start there- Yeah ... and would go up or down- Okay ... based on the results we see. Got it. Then that initial 28-day data for the non-obstructive and the obstructive would be thought really from the single dose result. Got it. also the safety from the MAD. In terms of baseline matching, it will be very much an inclusion/exclusion criteria, similar to what we've- Yeah ... seen with the myosin inhibitor class. Right. Right, exactly. Okay. Yeah, and they, we'll try to match to the extent we can. Okay, good. And then the data would... Basically, they would be nine patients per dose cohort, right? 3 patients per dose cohort. Oh, three patients per dose cohort. Yeah. Okay. Open, essentially open label, no placebo. Okay, got it. Yeah. That data, when do you anticipate being able to share those results? The end of the third quarter, you know. Okay. Sometime in the third quarter, I think. Okay, so that will also- Yeah ... come around the same time. That protocol, that protocol is written and also already through the IRBs. Okay, great. So that could also. So it would be a nice package between the SAD and the MAD and the- Yeah ... first- Right, and then the 28-day data in obstructive and non-obstructive- Yeah ... will come later. Yeah. Probably roughly the first quarter of 2025. Okay, that's very helpful to actually talk about that. And it's also good that your talk package is already ongoing, so by the time 1Q comes, you actually can transition very easily. Yeah ... into a phase II study that would warrant. Right. So I mean, the plan was to have continuous- Mm-hmm ... dosing of the patients. Yeah. Then we can make a cut of the data- Yeah ... along the way- Yeah ... and see the benefit. And because you're largely measuring biomarkers- Mm-hmm ... and echo parameters. Yeah ... I mean, I think the placebo- Yeah. Placebos aren't as- Yeah ... important in that particular- Right ... study design. Yeah. but of course, in the phase II Yeah ... we would have a rigorous, placebo-controlled phase II. Probably very classical- Yeah ... with, three doses- Yep ... and a placebo group. So we would not necessarily- Yeah ... have to titrate. Yeah. No, that's, that's, that's gonna be really important. Do you think the one question that will come up is like, you know, I think placebo in these studies has been very minimal, even though it's an open label. I think investors are gonna get familiar, comfortable with that. Maybe just do you think the three-patient dose cohort is going to give them sufficient information? Like, what was the rationale and why not, and why not upsize it a little bit higher? Well, you know, the thing about a single dose, you're at the, you know, you have the variability of the- Yeah of the individual Right exposure of Yeah - any individual patient. Yeah. Data at steady state- Yeah - is always preferable. Yeah. If you look at the timelines- Yeah you'd be pushing out that data quite a bit if you just- I think wanted to go 14 days and longer. I... So I think how we viewed it as there is clear evidence... Mm-hmm - that, with a single dose, you can see- Mm-hmm a change in gradient and a deep change in ejection fraction. It's, it's a comparator- Yeah - to the CMIs. Mm-hmm. That's the earliest time you can get a comparison. Mm-hmm. It's not ideal- Yeah Because you only have nine patients. Yeah. Yeah. No, that's- You know ... that's helpful. And then, team, I guess, so one of the differentiation, which you made clear, is higher therapeutic window, no need for dose titration, no echoes associated, which we hear is significantly the hurdle for strong adoption both of these products and for this product in the market. The other question, that also we have heard from physician is the DDIs, right? So with mavacamten, there is a significant pharmacy protocol that's in place. Could you maybe talk about if you've done any DDI work and, and what you've seen? Because I think that's the other component on just opening the bottleneck. Yeah. We've done DDI work. We do not have any DDIs. Okay. We do not have any issues in that case. It's very clean molecule- Yeah from a P450 transporter- Yeah - other areas. Maybe, Behrad, let me talk a little bit about the research we've done on uptake of the molecules and, you know, what are the limiting factors- Yeah - for the current, the, for the- Mm-hmm Current market and where we think we have an opportunity? Yeah, I think, you know, you've probably done- Yeah similar research, right? When you speak to physicians. Actually, if you look at script data- Yeah Plainly, right, you see that the majority of patients are on the 5 milligram. Yeah. Then you've got people who are actually downtitrating- Yeah - to 2.5, and 10 is starting to pick up, but still- Yeah The volume isn't there. The reason is I think physicians are concerned around the- Yeah EF drop, right? Yeah. You're seeing a very conservative use of- Mm-hmm - the current CMI that's on the market- Yeah - because, you know, they're getting enough of a gradient relief- Mm-hmm - with the five milligram dose- Yeah - but they're not willing to push- Yeah because, you know- Yeah - the consequence is quite- Yeah quite problematic. And I think once you let people out- Mm-hmm and you don't know if, like, someone gets COVID- Yeah or they go get Paxlovid- Yeah or they have a deep, they take Yeah - a PPI. Yeah. All of a sudden, you've got- Yeah really high levels of drug circulating, and it becomes a problem. Yeah. So, as Kevin mentioned, we don't have that issue. Yeah. You know, when we speak to physicians around the profile that Kevin- Yeah described, there's a lot of enthusiasm Mm-hmm - around what we're doing, even relative to- Yeah You know, both of the CMIs that are out there. Yeah. No, that's, that's very helpful. Is obviously this is a very significant value-driving program for the company, and I'm sure, you know, through our coverage of the space, strategic interest remains very- Mm-hmm ... high on this. So what is your views? At what junction would you be interested in wanting to partner this asset? Sure. How far along- Yeah Do you want? And obviously, you know the capital allocations needed- Yeah as we can map out- Mm-hmm based on other- Mm-hmm - myosin inhibitors and their past studies. Yeah. So the nice thing about the way we've kind of set up- Mm-hmm - the program. Obviously, as you mentioned when you started- Yeah We have two programs. We have the skeletal program. Yeah - but we also have 7500 for HCM. But I think, you know, base, we have $29 million in cash. Mm-hmm. That'll get us through 2025, maybe even into the first quarter- Okay - of 26. With that cash, we can get well into the Phase 2s Mm-hmm for obstructive and non-obstructive. Mm-hmm. The nice thing is we've got a really good catalyst calendar- Mm-hmm from both programs Mm-hmm to help us finance to get to that. Yeah. I think... Personally, I think that the company's view is we're going to push these as far as we can- Yeah to key value inflection points, right? Yeah. I think we've all worked at bigger companies. Yeah. We know what the triggers are. Yeah. So what people are gonna be interested in. I think that the hidden aspect about this molecule is the diastolic benefit- Yeah - that this molecule has. So we've talked about obstructive, we've talked about non-obstructive, and then there's a broader category- Mm-hmm - of diseases of diastolic dysfunction. Mm-hmm. If you think about that, you start walking into the HFpEF space- Yeah right? And we've seen a lot of data coming from some of the GLP- Mm-hmm - where, you know, you're seeing Mm-hmm some improvement in patients who have heart failure with preserved ejection fraction. If this molecule- Mm-hmm diastolic benefits plays out, that's an avenue. Yeah that we would like to kind of pursue with the molecule, because clearly that's, that's a big issue. And that's where we would think about, okay, is there a partner who- Mm-hmm - we could work with in order to- That could go broader. That could go broader, right? Yeah. Because you know these trials. Yeah. They're big trials. Yeah. They have pretty hard endpoints. Mm-hmm. I think, you know, if we have conviction, and we can convince a partner- Yeah to work with us, that'll be a good path. Great. No, that's, that's very helpful. And team, I know I, I don't do this fireside justice because we only focus on 7500, but given that we have about a minute left, maybe just the last place is, what are the key catalysts for the muscular programs that are going to be reading out in 2024? Obviously, the HCM data set is going to be a very important data set for many clients who are following the space. Mm-hmm. We're very excited for that. But if you could, Yeah - talk about- There's a- What else is happening? It's a really exciting year for us. We'll have Duchenne data in the first half. Mm-hmm. The first time we'll have Duchenne data. Mm-hmm. It will be controlled data. 6 patients treated, 3 patients placebo- Mm-hmm ... for three months in multiple dose cohorts, and we'll be looking at biomarker changes- Mm-hmm statistically significant biomarker changes, and- Mm-hmm We will be looking at functional benefit- Mm-hmm functional benefit of the drug, and all those patients will go on to an open label. Okay. That's the first half of 2024. We'll also have the 24-month data in Becker patients- Mm-hmm ... open label- Okay - which realistically, I think is exciting because you're seeing what should see a 2.5 point change. Okay. The hope would be that we would continue to stabilize disease… Mm-hmm - which would be really outstanding- Yeah - for those Becker patients. Later on in the year, we'll have our first controlled patient study- Mm-hmm - in Becker. Mm-hmm. 3:1 randomization, 40+ patients. That'll be at the end of the year, and that has the potential of providing us the ability to file for accelerated approval if we see changes in biomarkers. Mm-hmm that are statistically significant. And I think if we're directional- Mm-hmm - with the North Star - Yeah I think we clearly could go to the agency and say, there are no treatments for Becker. Yeah. We have Fast Track designation. Mm-hmm. This is a high, unmet need population. Yeah. We should. This drug should be approved for that population. Yeah, we're seeing a lot of flexibility from regulators in neuromuscular, right? Mm-hmm. Yeah. Yeah. There's some good precedents out there- Yeah with Reata, Amylyx Yeah. Yeah. So we feel pretty good that a totality of data- Yeah - will be supportive of Yeah - of early approval. Yep. No, that's, that's fantastic. Well, team, thank you for a great discussion. We're very much looking forward to a very busy 2024- Yeah excited to work with you. Exciting year for us. Yeah. All right. I want to say thank you- Thank you so much. ... on behalf of all of us here at Piper Sandler. Thank you. Great job, guys. Thank you.