Hello, and welcome to Edgewise Therapeutics Investor Event. My name is Telepan, and I will be your operator for today's call. I would now like to pass the call over to Mike Carruthers, so please go ahead when you're ready. Thank you.
Thank you. Good morning. This is Mike Carruthers, Chief Financial Officer at Edgewise Therapeutics. Welcome to our call to introduce our new cardiac program, including the lead candidate, EDG-7500, initially targeting hypertrophic cardiomyopathy. You can join this webinar from the Edgewise website at edgewisetx.com. We're using slides to accompany our remarks today, which can be downloaded from the investor relations section of our website. A replay of this presentation will also be available as a webcast on our website. I'd like to introduce our speakers for today's call, which includes Edgewise President and Chief Executive Officer, Dr. Kevin Koch; our Chief Development Officer, Dr. Marc Semigran; our Vice President of Discovery, Marc Evanchik . Our special guest today, Dr. Martin Maron, who is the Director of Hypertrophic Cardiomyopathy Center at Lahey Hospital in Burlington, Massachusetts, will present a clinician's view of hypertrophic cardiomyopathy.
Also available during Q&A are our Chief Scientific Officer, Dr. Alan Russell, as well as our Chief Medical Officer, Dr. Joanne Donovan, and Dr. Behrad Derakhshan, our Chief Business Officer. Before I turn the call over to Kevin, we want to remind everyone of the following Safe Harbor statement: The matters we are discussing today include projections or other forward-looking statements about the future results and research and development goals of Edgewise. These statements are estimates based on management's current expectations and involve risks and uncertainties which could cause them to differ materially from actual results. We refer you to risk factors discussed in our filings with the SEC, including our annual report filed on Form 10-K on February 24th, 2022, and other Edgewise filings with the SEC.
These filings identify important risk factors and could cause actual results to differ materially from those in our projections or forward-looking statements. Edgewise specifically disclaims any obligation to update any forward-looking statements except as required by law. I'll now turn the call over to Edgewise President and CEO, Dr. Kevin Koch.
Hi, all, and thanks for joining. Edgewise Therapeutics is a clinical stage company focused on advancing innovative strategies for the treatment of devastating muscle disorders. We have an experienced management team with deep expertise in muscle physiology and its application to rare disease research. We leverage our discovery and development capabilities to identify novel protein targets to achieve our goals. In our first program, we invented EDG-5506, a first-in-class oral available molecule, and are developing it to become a foundational therapy for the treatment of multiple indications in muscular dystrophy. Our overarching vision is to improve the lives of patients and families suffering from rare debilitating muscle disorders. Today, I'm going to discuss expansion of our pipeline and of precision medicines into the development of novel agents targeting select cardiovascular diseases.
Advances in the understanding of cardiovascular disease has allowed scientists to genetically characterize defined patient populations, allowing targeted precision medicine-driven drug discovery efforts. Edgewise is poised to leverage its knowledge of sarcomeric biology across multiple therapeutic indications to identify unique targets for therapeutic intervention. Building on our success in creating orally active drugs for the treatment of neuromuscular disorders, today we will describe EDG-7500, a potentially new approach to the treatment of hypertrophic cardiomyopathy. We had a very successful 2022, where we initiated three phase II studies in muscular dystrophy targeting Duchenne, Becker, limb-girdle, and McArdle's muscular dystrophy. We are initiating IND-enabling preclinical studies for our first cardiovascular candidate, EDG-7500, this month. Next slide. Mike has already given you an overview of our agenda.
Now I'm gonna pass it over to Martin Maron who's gonna speak to us about the clinician's view of the hypertrophic cardiomyopathy space. Thank you, Martin.
Great. Thank you. It's great to be with everyone this morning, give you the opportunity to give you an overview, from a clinical view of hypertrophic cardiomyopathy. I've been involved with HCM for over 20 years as director of one of the largest referral centers for this disease in the United States, as well as being involved in a number of clinical research initiatives aimed at better defining the natural history, diagnosis, and management of the disease. I'm gonna begin with. There we go. A definition, just to start right at the beginning of the story. Hypertrophic cardiomyopathy, HCM, is defined as increased left ventricular wall thickness, left lower chamber of the heart, increase in thickness, without any other obvious cause to that increase in hypertrophy from either another cardiac or systemic disease. This is what it looks like.
On the right is obviously a schematic of HCM compared to the left, which is a normal heart. I want to make one point here and tell you that the HCM heart or phenotype is characterized by, as we just talked about, increase in left ventricular wall thickness as well as small left ventricular cavity size, smaller than normal, and also a hyperdynamic function to the left ventricle. Expressed clinically as an ejection fraction, which is usually about 5% or 10% higher in HCM than normal hearts. Obviously, this is a still frame. I'm not showing you the contractile properties of the heart here, but you can imagine that it is greater than normal. That's the sort of the triad that defines, in a way, three of the major principles of HCM: increased wall thickness, small cavity size, and increase in heart function.
We'll come back to the relevance of that in a minute. I also wanted to show you that although grossly these hearts are abnormal, based on the features I just showed you, histologically they're abnormal as well. Upper left is just showing you that the heart cells are hypertrophy, bigger than normal, and also arranged in a disarray or chaotic pattern. In addition, in the upper right, the vessels that supply blood to the heart muscle, the thick heart muscle, are abnormal structurally as well. You can see the lumen to these vessels is more narrow than normal, giving supply-demand mismatch to blood supply at the tissue level. That's relevant because that can create over time the production or deposition of scarring or what we call fibrosis. That's evident in the bottom right, stained in red.
That's scar tissue in the heart muscle of an HCM heart. To the bottom left, fibrosis also between the cells stained in blue, called interstitial fibrosis. We've got a very abnormal histology as well to HCM, comprised of fibrosis and myocytes or cells that are abnormal and also small vessel disease. If we take a step back, that's the disease, both grossly and histologically. Why does it matter? Why are we talking this morning about the disease? It's the most common genetic cardiovascular disease in the world. We'll talk about numbers in just a minute. It's the most common cause of sudden death in the young, including competitive athletes.
It's an important cause of atrial fibrillation and stroke for patients of any age with HCM, and also an important cause of heart failure, limiting symptoms that impact quality of life in patients with HCM of any age as well. Focus is really gonna be today on the impact of heart failure on the burden for individual patients by decreasing significantly their quality of life and really representing, in a way going forward, the greatest unmet need in this disease from a therapeutic standpoint. We'll talk about more about that in just a minute. I wanna come back, though, before we talk about heart failure and the unmet needs there. It's important first to really clarify that there are two types of HCM. Without understanding this, it becomes very difficult to understand, you know, the different treatment strategies.
When we talk about HCM, we're really dividing it into those that have an additional pathophysiologic feature called obstruction, which is present in 70% of patients with HCM. If we go to the right here, again, HCM heart, increased wall thickness, small cavity, hyperdynamic function. In the 70% of patients with HCM have this additional feature where the mitral valve, which is structurally normal, but makes an abnormal bend to actually touch the thick muscle, the septum, at the point in time when blood is being ejected out, creating what's called obstruction, a pressure gradient. Higher pressures are generated in the left ventricle than normal based on this mechanism. What is the driver to why the mitral valve is kind of pushed or dragged over and in fact impeding blood flow going out is the hypercontractile nature of the left ventricle.
That's the predominant driver or mechanism for why two-thirds of patients with HCM develop the obstructive component of the disease. On the left, one-third of patients do not have the propensity with this disease to develop outflow tract obstruction. The valve does not get in the way in systole of blood flow, and therefore, during systole, LV pressures are relatively normal. In these patients, again, muscle's thick, cavity is small. The mechanism driving heart failure here is largely related to diastolic dysfunction, impaired relaxation, small stroke volume, low stroke volume, low LV end-diastolic volume, and therefore low output. It's a low output heart failure syndrome. Patients with obstruction can also have diastolic dysfunction too, so they've got two reasons to have heart failure.
That brings me to this important principle slide here, which is that when we talk about heart failure and the burden it has on patients, we really have to again divide it into two, the two groups of HCM patients. The obstructive patients have heart failure symptoms being driven by two phenomenon. One is a systolic phenomenon of outflow tract obstruction, which is the predominant mechanism of heart failure, and to a lesser degree, but still important in these patients, is diastolic dysfunction, impaired relaxation, low stroke volume, low output situation. Compare that again to those with non-obstructive HCM, which again, don't, by definition, don't have obstruction, and their heart failure is predominantly driven by a diastolic problem. Coming back to heart failure in a second, let's talk about numbers just for a minute 'cause I know that this audience is also very interested in this issue as well.
When we talk about HCM, we talk about it in terms of the most common genetic heart disease in the world. It is in fact a global disease, and we view it now in the global perspective. It's been identified, HCM, on essentially 90% of the world's population. As you can see in the upper half of the slide, prevalence worldwide is between 1 in 200 and 1 in 500. That means you're talking about 15-20 million people globally with hypertrophic cardiomyopathy. If we translate that to the United States specifically, we know that there are about 250,000 clinically identified patients with HCM that are kinda in the healthcare system, identified and diagnosed with this disease based on large insurance claims database studies.
That means that with a prevalence of 1 in 500, there's about 450,000 patients with HCM that are not clinically, that are not diagnosed with the disease. That really represents one of the major unmet needs going forward is better ways of identifying patients reliably and early on with HCM so that they can be provided the same kind of current and novel therapies that may impact natural history that those with diagnoses with HCM have currently. How do patients get diagnosed with HCM? Important, the vast majority is that they become symptomatic with heart failure symptoms, which leads to usually further evaluation with an EKG, which is abnormal, and then an echocardiogram demonstrating the features we talked about in a definitive diagnosis that way.
The most common symptoms that patients experience with HCM, whether it's obstructed or non-obstructed disease, is exertional shortness of breath, by far and away the most common limiting symptom, frustrating for patients that are otherwise healthy. Again, these are intact pump functions of normal systolic function, but they've got exertional shortness of breath, which is very frustrating for them, often on a daily basis. Exertional fatigue, more wiped out and tired for a level of activity that they shouldn't be for. That's also a source of major frustration when it occurs on a daily basis. Chest pain, atypical, usually palpitations. In addition, on routine examination, patients can be identified as having a systolic ejection murmur leading to further testing and diagnosis. A number of other avenues lead to diagnosis including acute event and of course, family screening, given this is a genetic disease.
Diagnosis is made non-invasively with echocardiography demonstrating increased wall thickness, which is again the sine qua non of diagnosis clinically for HCM. MRI advanced imaging can also be used when that echo is uncertain or ambiguous in terms of diagnosis. The EKG in the exam can raise suspicion for HCM, are not pathognomonic or diagnostic themselves for the disease. Obviously, as everyone probably on the call appreciates, HCM genetic heart disease, these are mutations that are in genes encoding the structural apparatus of the heart muscle, the sarcomere. The most common genes responsible for HCM are beta myosin heavy chain and myosin-binding protein C. About seven or so other genes in other structural locations in the sarcomere are responsible for HCM as well.
I think today in 2023, you know, what is the major principle here in terms of the genes, just to kinda go 10,000 foot here, is that we've got a common HCM phenotype that we've just been talking about, increased wall thickness, small cavity, hyperdynamic. That are features across the board for HCM that define the disease and of course two-thirds with obstruction and one-third without. If you look at that common phenotype, it's about 30% today that have a sarcomere mutation identifiable, a pathogenic mutation in the sarcomere genes we just talked about, that is associated with disease for that patient. It's the majority, 70% that, or close to that are sarcomere negative. No clear mutation responsible for disease based on the current comprehensive genetic testing panels.
The emerging, you know, you know, explanation for that is that the, the way that this path or these patients get to the phenom is probably multiple genetic variants, what we call polygenic risk, that ultimately drives pathways that are similar to the sarcomere mutations that lead to a common HCM phenotype. Let's talk about what happens when patients are clinically identified, diagnosed. You know, we typically start out in clinic by first reassuring patients that in the current era with the current therapies that we have, the vast majority of patients with a diagnosis of HCM have the opportunity today to live a normal or near normal longevity. We're really not talking in this disease so much about mortality as the primary or the predominant issue.
We're really talking about the burden of symptoms on quality of life for patients, okay? Once we say that, we also tell patients that, you know, the patients say, "Okay, then what can happen to me if I have HCM as I go through life?" Patients really can, at some point, fall into one or more what we call subgroups, where they could be at risk for adverse disease complications related to their to HCM. Those are sudden death, aggressive heart failure, and atrial fibrillation and stroke. Those are your main adverse disease pathways. Let's discuss real quick sudden death, which of course is the most visible and has been the most visible complication from HCM since its initial clinical description over 60 years ago.
You know, as I said before, HCM remains the most common cause of sudden death in young people in North America, including competitive athletes. Here's an out-of-hospital cardiac arrest on the athletic field. This is, I guess somewhat timely given what happened last night. Many have probably seen the NFL player from the Buffalo Bills who had a cardiac arrest on the field last night requiring on-the-field CPR. I don't know what the cause of that out-of-hospital cardiac arrest for that player was. Nevertheless, HCM is in fact the most common reason for young athletes experiencing sudden death on the athletic field. For all patients with HCM, that increased risk of sudden death obviously is really, really important.
We've developed over, as a HCM community, over the last 30 years, a risk stratification strategy, a method where we identify one or more major risk markers that may be present in a patient's clinical profile that have been associated with an increased risk of sudden death in this disease, and in that case, would potentially justify the presence of one or more of these major risk factors' consideration for a primary prevention ICD to protect against sudden death complication. This strategy, these risk markers, and the therapy of the ICD have worked incredibly well at essentially protecting patients from the most acute adverse complication of this disease, sudden arrhythmic death, over the last 20 to 30 years.
As evidence of that, you know, here's a paper we just recently published just demonstrating sudden death event rates in HCM have really dramatically decreased since the mid-1980s to present, almost a more than half reduction in sudden death event rates over that period of time due to the maturity of that risk stratification strategy and the ICD. I'm showing you this here today because it's relevant because the decrease in sudden death event rates has really resulted in an increase in a way of more patients living longer with the disease and, of course, because of that as well, more advanced heart failure as part of the disease and really has become the most predominant issue in this disease in terms of for individual patients and treatment. Let's talk about heart failure now.
When we do, again, it's really important, we've gotta again divide the population into obstructive versus non-obstructive when we talk about how we approach heart failure. Let's start with obstruction. I showed you an image before, an illustration before of a, of the mechanism obstruction. I thought I'd just take you, take the opportunity to show you, 'cause it's so important, an echo image of obstruction, just really kind of brings alive how mechanical this issue is. Increase in wall thickness, the VS is the ventricular septum, LV is the left ventricle, and the arrows are pointing to, in mid-systole, the acute bend of the mitral valve making contact with the septum, impeding blood flow going out and creating that very high LV systolic pressures that is the, in fact, pressure gradient that we've been talking about. The obstruction is equal to the pressure gradient.
It is again the hypercontractile, the increase in contractility, the super normal contractility of the left ventricle, which is the major contributor to this mechanism of obstruction. The high pressures are responsible for the symptoms. The major principle in this disease is that interventions that can decrease or modify contractility will lower, or in some cases, completely abolish obstruction, translating to an individual patient significant improvement in potential elimination of heart failure. It's been 20 years, and I was very fortunate to be part of this study in The New England Journal, again, almost now 20 years old. It's hard to believe that.
Anyways, this is the major principle, data demonstrating this idea that if you've got obstruction in HCM, you are in fact almost 4.5-fold greater likelihood of developing heart failure than non-obstructive patients. Non-obstructive patients are still at increased risk for heart failure. We'll talk about that in a minute. Just demonstrating here the immense independent driver that obstruction is in terms of creating limiting heart failure symptoms for patients. This is how we then translate that data into kinda management of patients today with obstructive HCM who've got symptoms that we're seeing in clinic. Again, the symptoms for heart failure obstruction are not the same as non-HCM heart failure, where you often get volume overload. You're often admitting patients for intravenous diuretics. That doesn't happen as much in HCM.
This is mostly day-to-day, very frustrating, limiting shortness of breath, decreased exercise tolerance. We describe it as a significant decrease in the heart failure burden is really about the quality of life that patients really feel is limited because of their disease. When that occurs, we treat the obstruction and the heart failure first with drug therapy. The drugs that we're using here, we're leveraging their negative inotropic properties. We're trying to decrease contractility to lower or abolish the gradient. We start with beta blocker or verapamil. Patients that don't get better with that can have the choice of either stronger negative inotropic drugs. Choices there are now disopyramide, anti-arrhythmic drug, but it also has negative inotropic properties to it.
Of course, the newer first generation myosin inhibitor, mavacamten, approved specifically for treatment of symptomatic obstructive HCM in April of this year by the FDA. We'll spend a little bit of time in a second talking a little bit more about mavacamten. If these drugs don't work, then of course, in terms of symptom improvement, then the gold standard for the relief of heart failure in obstructive HCM is surgery or the less invasive catheter-based alcohol septal ablation. Patients also have the choice, based on the recent HCM guidelines, of going directly to septal reduction invasive therapies before additional drug therapy if they're really symptomatic after beta blocker or calcium channel blocker therapy too. I'll just mention again, septal reduction therapies, surgical myectomy have been around for 60 years. The less invasive catheter-based procedure, alcohol ablation, 30 years. Both very good.
Again, they have to be done, these procedures, which are invasive, including septal myectomy, which is open heart surgery, has to be done really in order to get the results that we want for patients in terms of efficacy and safety in expert centers. There's limited expert surgical centers in the United States that can do this procedure the way that we really want it done for patients. Of course, these procedures also are associated with the risk and morbidity. From my perspective then, what's the unmet need? I mean, where are things sort of falling short then for our patients in the current algorithm for obstructive HCM? Well, let's start first with the fact that the average age for a symptomatic obstructive patient is 50 years. Young.
I mean, you're talking about really young patients who are really frustrated with how they feel, and that really means that drug therapy, if we're gonna start and rely on drug therapy, has to be reliable at reducing symptoms over long periods of time, and also of course with that, has to have a great safety profile with it, given the long exposure that patients will have to therapy. The first point to make then with beta blocker and verapamil is that they are really weak in terms of their efficacy. They're just weak negative inotropic drugs. They just don't do it in terms of relief of symptoms well enough for most patients, particularly over long periods of time, or patients will have side effects, particularly younger patients, in terms of beta blocker side effects like fatigue and sexual dysfunction.
If we move forward then in the algorithm, you know, we've got limitations to disopyramide, an old drug, including the fact that a third of patients that go on disopyramide get no benefit out of the gate with the drug. The two-thirds that get an improvement, that improvement is modest but important, but may not be long-lasting. It can go away over time. We'll spend a little bit more time on mavacamten in a second. Of course, we talked about the limitations to surgery and alcohol ablation, including limited expertise for the procedures, obviously procedural risk, which is small but real, and of course morbidity that can come with invasive procedures as well.
Let's talk a second about mavacamten, and let me just say first that, you know, I'm excited that we have additional drug therapy as an option for patients. It's a, it's a huge move forward in this disease. I think as a community for HCM, we're all very excited about the opportunity for new drug therapy, including the impact that a drug like mavacamten will have for certain patients. In the context that we're talking about today though, I think it's important though to underscore perhaps some of the gaps related to this drug.
Even though it's early in our experience with the drug, I think a number of principles have already emerged which are relevant to the discussion today, including the fact that mavacamten, at least based on the two major trials that led to FDA approval, EXPLORER and VALOR, it's pretty clear that although gradients are reduced in many patients, about 40% of patients on mavacamten still have residual outflow tract gradients, and we'll talk about the significance of that in a second.
The translation to clinical improvement with the drug is good, you know, it's important to underscore that there are still, and this is pretty consistent with the phase III studies I just showed you of mavacamten as well as the phase II studies, as well as the phase II study that was just published with the second generation myosin inhibitor aficamten, all are consistent now in demonstrating that about a third of patients on the myosin inhibitor drugs have no improvement in NYHA Class. A third. That's important. That's an issue that's not getting a lot of attention right now, but is really important, particularly for experts like me, when we're talking to patients and trying to understand the efficacy of these drugs. If you look at health questionnaires, KCCQ, it's about the same.
30% of patients on mavacamten reported no improvement or worsening in their status with KCCQ. In the EXPLORER trial, it was only a third of patients that met the primary endpoint of both symptom improvement and improvement in functional capacity by peak VO2. Of course, you know, I think the question is, why is there this third of patients not getting an improvement on mavacamten? We don't yet clearly know the answer to that, but one of the answers may be that those are patients with residual gradients still driving symptoms in those patients. Of course, as everyone I think on the call is aware, there's certain patients that are what we call super responders.
You know, they metabolize mavacamten in a certain way that causes significant reductions in systolic dysfunction, which puts those patients at risk for heart failure, particularly if they have other comorbidities that may increase heart failure in that situation, like atrial fibrillation. This has led to, you know, a complex FDA-mandated REMS program where patients are required to have really extensive serial longitudinal echo studies. It's fairly burdensome for patients, to be honest with you, to come back every month for an echo, and then every 3 months indefinitely after that. It's not particularly convenient for a lot of patients. That's a limitation as well as what's not shown here, which are drug-drug interactions, which also limit the applicability of the drug, widespread applicability of the drug as well.
I also wanna, you know, mention too that another explanation for the lack of improvement in this one-third on mavacamten, besides residual gradients, may in fact be as well diastolic dysfunction, okay? The drug can lower the systolic component of heart failure in the obstructive case, but you still got diastolic dysfunction that may not be effectively treated or treated at all potentially with mavacamten that may be the driver in those patients to why they're still limited. I'll show you some evidence for why that may be the case, you know, just using surgical data. Here's the myectomy, the gold standard for treatment of heart failure with obstructive HCM, and this is just demonstrating the improvement in heart failure after myectomy, which completely gets rid of gradients.
In 1-year follow-up, none of these patients had outflow gradients anymore, but still about 35% have symptoms of either Class II or Class III with no gradient. The reason they may still be limited, again, is likely, most likely issues related to diastolic dysfunction or diastolic heart failure, and that's what we've always considered to be the reason for residual heart failure post myectomy. Let's finish up with non-obstructive HCM now. Again, here in the absence of obstruction, this is a diastolic heart failure problem, and you're talking about hypertrophy, ischemia, which impact the ability for this thick muscle to relax properly. You've got problems with distensibility related to the pathology as well, the hypertrophy, the disarray, the fibrosis, all those things I showed you earlier.
Both those issues come together to basically alter LV diastolic filling, and again, create this low stroke volume, low output heart failure syndrome, which is really frustrating issue for patients since it significantly impacts their quality of life. Here is really how it sort of plays out. It mostly is with exertion, so patients exert themselves with these hearts. They can't fill appropriately, particularly at higher heart rates. You're decreasing stroke volume even more with exertion, and you're getting into even a more lower output heart failure situation. Again, that limits the patient's ability to do even routine exertion the way they want to and, of course, makes them symptomatic. This inability to increase stroke volume is the driver.
I'll just point out to you that, you know, this is perhaps for me, and I think other experts in the disease would agree, and certainly patients in this situation would definitely agree, that this is really, really frustrating and may in fact represent the greatest unmet need in hypertrophic cardiomyopathy are the symptomatic non-obstructive patients for which at any point in time cross-sectionally 30, maybe 35% are really frustrated by limiting symptoms based on the mechanism I've just showed you, despite AV nodal blocking agents, which are being used to try to improve relaxation and filling, but are just not very effective drugs here at all and are very, very low effectiveness here. Again, very frustrating.
These patients develop progression on a 1.5 per year basis, and at any 1 point, 10% have advanced heart failure in non-obstructive HCM, for which the only long-term treatment option in that situation is heart transplant, which no patient, of course, wants to even think about or consider. We've got a real problem in terms of therapy for non-obstructive HCM. We have almost nothing available for these patients. Unmet treatment need, of course, would be therapies directed at improving symptoms in, you know, earlier in the disease and, of course, preventing that heart failure progression and hopefully eliminating in that situation the need for advanced heart failure therapies.
I'll just conclude by saying that in terms of unmet treatment needs, limiting symptoms for obstruction, you know, we've got more and more room here for improvements based on the points I think I hopefully underscored. The non-obstructives, perhaps even a greater unmet need for their symptom burden related to diastolic heart failure and, of course, being able to prevent progression in the non-obstructives to end-stage heart failure, critical, critical unmet need in this disease. Thank you very much for your attention. I'm happy to answer questions at the end. Thank you. I'll turn it over now to Marc Evanchik , who will continue the discussion.
Thank you, Dr. Maron. Dr. Maron's told you about disease. I'm gonna tell you about EDG-7500, which is the new agent that we're developing for folks with HCM. He spoke already about the disease setting and what happens, and he spoke to the importance of the heart function being able to contract, right, systole and to relax and fill with blood which is diastole. I'm gonna tell you a little bit about the tools that we use to characterize heart function because that's gonna become important as we talk about how we measure 7500's drug action and what it's doing and why we think this new aid novel agent could be beneficial for folks with HCM.
One of those tools that we use and can use pre-clinically and even clinically is measuring pressure-volume loops. It's a powerful tool to be able to measure both, as the name implies, volumes of the heart, so how much blood is in the heart or being ejected, and the pressures at which those operate. Dr. Maron really highlighted the importance of, you know, having those things functioning properly and the increased pressures within the heart, within disease. So, you know, having this tool available is extremely important. Let's start with that PV loop, and I'm going to start at, you know, the bottom right-hand side, which is labeled end-diastole. The heart starts squeezing there. You get an increase of pressure without any change in the volume of the blood in the heart.
That's because the aortic valve is still closed. Once that valve opens, the heart continues to pump. Blood moves through the rest of the body, right, ventricular ejection, until it hits end systole, where that aortic valve closes. Those pressures fall dramatically. Then that valve, the mitral valve, opens up, and then new blood comes into the heart, and that's what we call diastolic filling. The reason to walk through this, right, Dr. Maron really talked about the importance of diastole and the impaired relaxation that happens within those HCM hearts. So we've been developing this molecule to specifically focus and have properties, enhanced properties to make the heart relax more.
Let's go to the next slide, where you see an obstructed HCM heart, and you get, and there's a new loop on that right-hand side graph. remember, this is where you have that left ventricular outflow tract obstruction creating really high pressures within the left ventricle, and that's depicted here. Also importantly, the that loop is very narrow now. Those hearts have decreased left ventricular volume. They have decreased stroke volume. They don't pump as much blood, as a normal heart does, and that's why people don't feel and function as well as they should. Lastly, just important to point out that those hearts operate at higher end-diastolic pressures. When the heart is filling with blood, at the end of that filling phase, there's a lot of high pressure.
We haven't talked about it yet, but Marty's graphs really illustrated those left atrias become huge because they feel all the back pressure as they're filling with blood. Next slide shows a non-obstructed HCM heart, and it's really the same without the high, high filling pressures and back pressures that those left ventricles are feeling. Let's go to the next slide. Marty touched on this, right? There's about eight proteins in the sarcomere. This is the molecular unit that's responsible for heart contraction and relaxation. And there's two main proteins that have mutations in them that drive most of the genetic HCM. Those That's myosin heavy chain. That's and myosin-binding protein C. Those are like. Let's flip to the next slide.
Those are like hands on a rope, rows, or, you know, some people think about rows or oars in water, you know, as you're rowing. Or it's a motor, molecular motor. Regardless of whether HCM is being driven by a genetic disease or a non, you know, genetic identified pathway, those hearts are hyperdynamic. They squeeze too hard, and they do that both in systole, when the heart's squeezing, but they also do it during diastole, when the heart is relaxing. When the heart goes to relax and those cross bridges, as we call them, should come off, they don't. They don't come off as effectively. And that's why the hearts remain impaired during relaxation. It's why they don't fill.
That's why they have reduced stroke volume because if you can't fill the heart with blood, no matter how hard you squeeze, you're not gonna have as much blood moving through the body. Next slide. Why develop a novel approach to HCM? Marty talked a lot about it. You know, there's while there's good options now, there remains populations of folks who don't benefit from those options. We've learned a lot about how to treat HCM now. We know the cardiac myosin inhibitors reduce cross bridges. They do that during the entire cardiac cycle, so they're removing them when the heart's squeezing. That sometimes, you know, leads to the discontinuation of the use of those types of molecules.
We've recognized the importance of making hearts perform better when they should be relaxing. Could you make cross bridges come off preferentially and selectively during diastole, and make hearts function better? Of course, you know, those hearts are hyperdynamic, so we wanna be able to preserve some of that beneficial function. That's what we've been working on. You know, I'll start to introduce EDG-7500. What is our approach? Our approach is to develop an indirect myosin modulator. These molecules, I'm gonna tell you these molecules do not bind to the motorhead, but they are sarcomere modulators, so they work on the complex protein-protein interactions that exist within the sarcomere, and that control contraction and relaxation processes within the sarcomere.
The goal there is to reduce the excessive residual actin-myosin cross-bridges, primarily during diastole, which should facilitate improvements in relaxation. It should facilitate improvements in ventricular filling. It does that by changing it's speeding the rate of relaxation, so speeding the rate of cross-bridge detachment, and it slows the rate of cross-bridge attachment or contraction, which we think is gonna be beneficial. It does so without the excessive drop in systolic function. I'm gonna walk through a number of data that supports, you know, the approach that we've just outlined, and it comes from a number of different sources. Told you we have a novel target. This is we believe is gonna be a first-in-class agent.
It targets a new set of proteins within the sarcomere, and it does so and it preserves the myosin motor head function. It does it by slowing contraction. It increases compliance or distensibility, so that relaxation component of the heart. We've done this in a number of models. We're gonna show you some data in validated models of obstructed and non-obstructed HCM. In the obstructed model, we're gonna show you potent gradient reduction. We're gonna show you that EDG-7500 is well-tolerated even at super therapeutic exposure. We're gonna show you activity at low levels, and then we're gonna ramp up exposures and show that they're well-tolerated.
In the non-obstructed model, we're gonna show you that we can normalize the hyperdynamic nature of those hearts, and we're gonna show you that we can improve ventricular filling. We're gonna, you know, in these models, we're gonna show you large exposure ranges and show you really that this drug limits the reduction in systolic contractility. Let's go to the next slide and look at some of that data. Here's a biochemical assay that is specifically designed to look at the fuel consumption or ATPase activity, which is of the sarcomere function. Specifically, this is a myosin motor head. It's an S, so-called S1 subfragment.
You can see that that line is completely flat over a large concentration range, showing that activity in this assay is preserved. We're not targeting the same spot on the protein structure or the sarcomere as the cardiac myosin inhibitors, and it's representing this new novel mechanism. Here's some PV loop data. This is that pressure-volume loop. It's the reason I spent some time walking through what that looks like. Marty, Dr. Maron showed that hearts have reduced stroke volume. Those PV loops become narrow. Right in the middle of that graph, you can see the loops. In edgewise green is the drug-treated loop. That shifts to the right, and it also increases in the width, the stroke volume or the end-diastolic volume of those hearts are increased with EDG-7500 treatment.
It does so without increasing end-diastolic pressure. That's a really, really important concept here because you're allowing the heart to fill with more blood without increasing the wall stress that those hearts fill. That is opposite of what HCM hearts look like. You know, this is a pharmacologic event. This is an acute treatment of hearts, and you see this immediately once you administer EDG-7500. It does so by slowing contraction. The graph on the left is what we call pre-ejection period. It's the time from when the electrical stimulation in the heart tells the heart to contract. 7500 is slowing that down.
It's got, you know, this, it's gonna reduce the hyperdynamic nature of the heart, but it does so without stealing the myosin cross-bridges when you need to squeeze. I'm gonna show you some of that data in the next slide. We can measure that in the PV loop. That's this measure, which is the LV pressure development. It's when the heart's squeezing. This is analogous to what could be measured by a different technique, which is echocardiography. It's the left ventricular ejection fraction surrogate. What you see here is that at the doses and exposures where I showed you that we have a slowing of the contraction and improvements in diastolic filling, we have this slight reduction in the rate of pressure development.
You get about an 8% drop in these four animals that we treated. We've continued to increase the dose multiple-fold over that, you can see that we end up getting a self-limiting reduction in the systolic contractility. And we've gone as far as over tenfold increase in exposure here. Really we plateau at a very modest reduction in that systolic contraction. The next set of slides I'm gonna show you is, does this modest reduction in systolic contraction confer benefit? Can we remove obstruction, and can we make hearts fill more efficiently? The first model that we're gonna show data is the myosin-binding protein C mutation in this cat model. This is the only known animal model that gets obstruction. What you see here is an M-mode image, so it's an echocardiography.
It's a non-invasive technique to measure many of the same things that I just showed you in the PV loops. This is imaging the walls of the heart, and you can see that the 2 X's that are circled in the red circle are touching. That thick septum is touching the outside of the wall, and that's where you get that left ventricular outflow tract that was so nicely described by Dr. Maron. That creates a pressure gradient. You actually measure that by measuring the velocity of the blood that comes out, and you convert that to a pressure gradient using an equation that multiplies it by 4 V squared. It's a nonlinear relationship in the measure that's being made there to the gradient. In cats, clinically significant gradient is 10 mm of mercury.
We've driven these gradients to be sort of those exertional gradients, which are really the robust gradients that are hard to remove. We've done this on a number of animals. I'm gonna show you that data next. Let's flip to that slide. You know, let's cut to the chase. We can take that gradient from 13 mm of mercury, and we can reduce it to and ablate that gradient. Really get rid of it, right? Anything below 10 mm is a non-issue anymore. This is a 2.5 mm gradient with a very modest low dose, single dose, all pharmacologically driven by EDG-7500. Let's quantitate that. Let's go to the next slide, and we'll show you a number of cats that we treated. We've treated six cats in this experiment.
Every single one of them is hyperdynamic at start, and every single one of them has a modest drop in left ventricular fractional shortening, it was very similar to ejection fraction. They all remain within the healthy range of a normal cat. We're not dropping systolic function dramatically. That range has been described by Fox et al. and another Maron, Barry Maron, so quite a nice publication there. On the right-hand side with the left ventricular outflow tract gradients, those have all been removed. Every single cat had a gradient to start with. I told you, we drove that to be sort of in this exertional gradient, so very robust. Every single cat has that gradient ablated, so on average, over 60% removal of gradient at the 1 mg per kg level. Next slide, please.
This is showing gradient removal with respect to EDG-7500 free fraction concentration. We've done that same experiment I showed you with the PV loops and where we've ramped up exposures by giving higher and higher doses. We've done that here. We've gone from 0.3 mg per kg in a cat, which removes gradients quite effectively, and we've gone all the way up to over 4 mg per kg in a cat. You can see that gradient removal is very potent. It happens very quickly. As you increase drug exposure and concentration, you can continue to drive down gradients, but it does it in a nonlinear fashion, so in an exponential way. This has never been described before. Quite exciting. It's uncoupled from the systolic change that we see which is quite modest.
Again, this is the 0.3 mg per kg up to the 4 mg, over 4 mg per kg. You see that potent range that's highlighted, that sort of 50%-75% removal of the gradient happens at very low drug concentrations. Even when you go to those doses and exposures that are multiple folds higher, you still get a modest reduction in systolic contractility. We're quite excited by this data. Next slide. Let's cover some of the non-obstructed data. This is the pig model. These have large or normal pig has a normal-sized LV and LA, so left ventricle and left atria. That's depicted there. In the disease state, you get a tiny left ventricle, right? Reduced volume.
You get a huge left atria because they're filling all of this back pressure when the heart is filling. I didn't mention this. This is a myosin heavy chain mutation. It represents the other major protein in the sarcomere that's mutated that causes most of the mutations and causes a non-obstructed HCM phenotype in this animal model. Similar to the cat, we've given 1 mg per kg in this model. What you can see is that we reduce hypercontraction, so we reduce the hyperdynamic nature essentially back to wild type levels. That's the Edgewise green color there, the post-treatment and the R403Q, which is the mutated model. We shave off the edge of contraction there.
We look at a bunch of the parameters that let us assess diastolic function, and we see that we can improve left ventricular filling, and we can reduce the left atrial size, which are all consistent with reduced filling pressures in the heart. E-prime there is early relaxation. We told you that we slow contraction and we improve relaxation, this is a direct measure of that. You can see we have a dramatic statistically significant improvement in early relaxation with single doses of 7500, all pharmacologically driven. The left ventricular wall thickness is a measure of how many of those cross bridges are engaged at end diastole, so end of relaxation. We bring that back down from too many, so too many heads engaged back down to normal levels.
The left atrial size, which is that surrogate of the back pressure, is significantly reduced just with single doses of EDG-7500. Next slide. Let me summarize that preclinical data. First-in-class sarcomere modulator. It's targeting sarcomere protein in and modulating the sarcomere in a new and novel way. It's an oral selective cardiac molecule, normalizing the number of cross bridges selectively in diastole, but also shaving off some of that excess systolic contraction. Really, right, that's the underlying pathophysiology of disease. We've shown you data, preclinical data in both obstructed and non-obstructed models, with minimal changes in LVEF. This novel agent, novel mechanism really we think supports investigating fixed-dose regimens because of that self-limiting mechanism on systolic contraction. I'm going to hand it over to Dr. Semigran to walk you through our clinical strategy.
Thank you, Marc. I'm gonna move relatively quickly to be respectful of people's time. I would like to take a few moments speaking about what we at Edgewise believe to be the unmet needs of HCM patients and how we plan to address them with EDG-7500. Cardiac myosin inhibitors such as mavacamten and aficamten have complex pharmacologies and variable metabolism, often genetically based, which results in potentially excessive reduction in cardiac function. They largely, as Marty has pointed out, only address excessive contractility, which can limit their efficacy in a disease where both contractility and diastolic function are abnormal. These factors lead CMIs to be difficult to initially dose and to reach a safe and efficacious maintenance dose.
Their use is complicated by the need to avoid significant drug-drug interactions with drugs such as omeprazole and esomeprazole, also known as Prilosec and Nexium, as these drugs can markedly increase mavacamten levels and lead to systolic dysfunction and heart failure. In addition, intercurrent diseases that lower cardiac contractility, such as severe COVID and other infections, can be additive to the effects of CMIs on contractility and potentially get a patient into trouble. All of these factors lead to the need for patients to have frequent indefinite follow-up at expert centers accompanied by specialized cardiac imaging.
In addition, as I'll show in a moment, even with CMI therapy, there remain a significant number of obstructive HCM patients that do not respond to therapy, the efficacy of these agents in patients with non-obstructive disease and in whom impaired relaxation and diastolic dysfunction drive symptoms remains to be proven. Next slide. Marty showed you in a slightly different format, this data from his recent perspective paper, authored along with Steve Ommen of the Mayo Clinic on the limited efficacy of the current therapeutic approaches to obstructive HCM. To remind you again, 43% of patients treated with mavacamten had a residual rest or provokable gradient, and 35% had no improvement in NYHA functional class. Next slide, please.
In this slide, and the two following, taken from the mavacamten prescribing information, I'm gonna illustrate the complexity of reaching a safe and efficacious dose in the real world. First, dose titration relies on having a patient perform a Valsalva maneuver, which can be difficult to instruct a patient how to perform and difficult for the patient to execute. However, if performed incompletely or incorrectly, it can lead to erroneous dosing. At several points in this algorithm, you'll see that Valsalva-determined LVOT gradients re-occur repeatedly in these slides and in this algorithm. Secondly, even at the initial dose level, it may be necessary to stop therapy and follow the patient for the development of heart failure.
Thirdly, even after 12 weeks of treatment, the maximal achievable dose is only 5 mg per day, which is less than the overall efficacious mavacamten dose observed in EXPLORER-HCM of 7.44 mg per day. Next slide, please. At week 12 and indefinitely every 12 weeks thereafter, the patients must be seen and evaluated with an echo with Valsalva, both to assess for safety. That is the lack of fall in LV ejection fraction to less than 50% necessitating treatment interruption and for efficacy, that is the persistence of a gradient and the need to uptitrate the medication. You can see the complexity that this really brings to following a patient on mavacamten. Next slide, please. This again, from the prescribing information for clinicians to use in utilizing mavacamten.
We see here the algorithm to be followed at any time should the treatment need to be interrupted, including follow-up with echoes, with Valsalva, again, every 4 weeks. The complexity of this treatment algorithm, the significant number of obstructive HCM patients that do not respond to CMI and other HCM therapies, and the compelling need to identify a therapy for non-obstructive HCM patients that addresses their unique pathophysiologic need lead us at Edgewise to believe that there is an overall pressing need for new agents that address both major underlying pathophysiologies in HCM patients and can be used across the entire spectrum of patients. Next slide. This slide depicts the relationship between EDG-7500 plasma concentration and LV contractility in the validated feline model of obstructive HCM that Marc Evanchik presented a few moments ago. You can see that all of the cats are hypercontractile at baseline.
Treatment with EDG-7500 that results in an IC50 to IC75 removal of clinically significant LVOT obstruction is associated with only a modest decrease in contractility, and that all 7500 concentration studied, LV fractional shortening remained within the normal range. This observation raises the possibility that a fixed dose regimen of EDG-7500 requiring less intense follow-up than current therapies may be possible. Next slide, please. This slide shows an outline of our plan for the phase I study of 7500 in healthy volunteers and in HCM patients that we anticipate will begin in the second half of this year. We will closely observe patients for safety and tolerability in both single ascending dose and multiple ascending dose studies, and also assess the pharmacodynamics of this agent.
This will include assessment of efficacy on rest and provokable LVOT pressure gradients in patients, assessment of functional capacity, and assessment of cardiac biomarkers of wall stress and injury. Next slide, please. In summary, EDG-7500's unique mechanism of action targets both abnormal systolic and diastolic function in HCM patients, suggesting the ability to drive a broad efficacy response at a low risk of decreasing LV ejection fraction below normal. EDG-7500's excellent selectivity, bioavailability, and favorable half-life should make it easy to use by clinicians and patients. We anticipate an efficient pathway for the rapid clinical development of EDG-7500 in a wide range of HCM patients. Kevin, back to you.
Thank you, Marc. Thank all the speakers today. I won't belabor this point. I think we've demonstrated and told you today that there's a still remains a significant unmet medical need for the treatment of hypertrophic cardiomyopathy. In particular, the non-obstructive set of the population really does not have any good therapies at this time. Next slide. Of course, you need to have a drug that has the appropriate properties, and this is a very interesting. Edgewise 7500 is a first-in-class sarcomeric modulator to help fill that therapeutic gap that we see now in the market. We see limited reduction of left ventricular fractional shortening. This molecule has projected human half-life of one to two days, different than some of the other agents that are out there of other mechanistic classes.
We've designed the molecules specifically to eliminate P450 induction or P450 inhibition to eliminate the metabolic liabilities of some of the current agents. We've performed broad off-target profiling and have a very clean profile, very high level of selectivity for cardiovascular tissue and muscle. It is largely a P450 substrate of the 3A4 enzyme, which is the most common enzyme and very difficult to saturate. We're predicting oral 1-daily dosing with an anticipated time to steady state of less than a week. This is easily reversible, rapid onset of action. I think it has very good properties. Next slide. In summary, just to say what we've already said is that this is a molecule and a modulator that preferentially is active and diastolic.
We believe that ultimately this will allow us to avoid the need to have complex echo-guided dose titration because of our minimal effect on ejection fraction. We believe that we will see a robust elimination of the gradient in obstructive HCM, and that will translate directly to a positive impact. The New York Heart Association class increases in peak VO2 in obstructive HCM, and ultimately in the very important market in unmet medical need of non-obstructive HCM. Next slide. Just to point out that this is a organization that delivers on its milestone. We started our Becker study, our phase II/III study this year. We started our Duchenne study in phase II with dose ranging and have dosed our first patient.
We reported out our Becker open label six-month data that positively showed that our drug, improved function in these late stage Becker patients. We initiated our Limb-girdle 2I and McArdle studies in Copenhagen. Now we've shown you today that we've selected and are moving into preclinical IND-enabling tox, our novel clinical candidate. Also, we're very well-funded. We have three years of cash through 2025. With that, like to thank you for your attention, and we'll answer any questions.
Thank you. If you would like to ask a question, please click the Raise Hand button at the bottom of your screen at this time. Our first question comes from the line of Tessa Romero from JPMorgan. Please go ahead. Your line is now open.
Hi, all. Good morning. Really nice to see the progress here with EDG-7500. A couple of mechanistic clarifying questions from us this morning. Can you walk us through how targeting the complex sarcomere protein-protein interactions could potentially decrease LVOT gradient without significantly lowering LVEF? Relatedly, can you further explain to us mechanistically how the reduction in systolic contraction is self-limiting with 7500? One more follow-up from us would just be any safety considerations that could be on target we should be thinking about. It sounded like your comment suggested that the asset has been pretty clean preclinically. Thanks so much.
Yeah. Why don't I just take it at a high level, Tessa , is that we believe from a competitive standpoint that we won't go in-depth into the mechanism today, we'll use that for future questions. I think Marc Evanchik can give you his perspective on the mechanistic rationale and without going in-depth in the mechanism. We won't talk about the pre-clinical safety profile, but I would argue that it's probably benign at this point, and anything we see is associated with an on-target effect.
Okay.
Marc, why don't you say. Go ahead.
Yeah. Yep. Yeah, no, just to reiterate what Kevin said, you know, when I'm talking about this, the safety profile referring to that self-limiting contraction on excessive on-target pharmacology, we think, you know, we'll be, we'll be limited from that perspective. Yeah, from a mechanistic standpoint, you know, we know that if you titrate out the myosin heads, then they just do not become available to engage with actin, grab on, right? There are not hands on the rope to grab on. If you modulate. There's a set of proteins that modulate the, you know, sort of the orientation and the ability of the heads to jump on.
You know, if you mess with that system, you know, we're starting to learn now that you can limit the ability of or at least the rate at which you're jumping on to actin and slowing that down, you know, can change the geometry of the heart such that you don't pull over the mitral valve that was so elegantly illustrated with Dr. Maron's slides. If you don't pull over that valve or block that obstruction or that outflow tract, you can prevent the gradient from forming.
Okay, great. Well, thanks so much for taking our questions, and look forward to chatting next week with you guys.
Thanks, Tessa.
Thank you. The next question comes from the line of Joe Schwartz from SVB Securities. Please go ahead. Your line is now open. Mr. Schwartz, your line is now open. Please go ahead. Thank you. The next question comes from the line of Laura Chico from Wedbush. Please go ahead. Your line is now open.
Good morning. Thanks very much. Laura Chico from Wedbush. Can you hear me okay?
Yes, we can.
Okay. Good morning, guys. Thanks very much for taking the question. I actually had one for Dr. Maron. Obviously, Mava's not been on the market that long, but I'm curious how you are actually using it among your HCM patients to date. I have one quick follow-up.
Yeah, sure. It's a great question. As you said, I mean, we got limited experience so far. I mean, we're just a couple months into the clinical approval, so, you know, what I'm saying is very limited in terms of our experience, obviously. The way we're using it is we are, you know, we're taking an individualized patient approach right now. For patients that are frustrated with how they feel with obstructive HCM. Despite first beta blocker or calcium channel blocker therapy, we're offering and discussing mavacamten as an option next in therapy. We also obviously discuss the pros and cons of both mava and disopyramide, as well as the septal reduction therapy options at that point too. That's where we are.
I mean, we're sort of offering the opportunity for patients to consider or go on mava as next line therapy after AV nodal blocking agents if that doesn't, you know, if the first-line drugs don't satisfy the patient in terms of improving the quality of life. That's, that's kind of where we are right now. It's an individualized patient discussion. It's offering them all the opportunities, including disopyramide and septal reduction therapies, as well as mava at that point.
Thank you. Very helpful. Maybe, Dr. Maron, one more.
Yeah.
Are there any other dynamics you see in the next, let's call it 3 to 5 years, where you have that large bucket of unidentified patients with HCM? Anything from a diagnostic perspective or change to the landscape that might be able to help identify more people at an earlier stage prior to symptoms?
Yeah. Yeah, I do. I mean, I, I really do think that, you know, machine learning or AI, and we're hearing a lot about obviously AI, you know, across the board, not just in cardiology, but in medicine in general, you know, where ultimately that technology, that science will, will land across the board in different areas is unclear. I think one area where I can definitely see it having a big impact is, for example, on the ability to interpret the EKG in a way that goes beyond where we are with clinical grounds right now to raise suspicion at the first introduction into the healthcare system with an EKG of the possibility of HCM in that patient based on, again, AI applied to, you know, ECG testing.
I really think that that's probably going to help improve the degree and magnitude, not clear, but I think it's going to improve our ability to detect disease like HCM earlier in the patient journey, perhaps even right away. That's, you know, I think that's where we're at. I mean, I think that, to me, that's the answer is gonna be AI with the ECG, maybe AI in other ways too applied to the echo and imaging. It's more complicated there. I see it having a greater impact when applied to the EKG in terms of improving diagnosis, but there may be other roles of AI as well improving diagnosis. The EKG is gonna be big, I do believe.
Very helpful. Maybe last question for Edgewise. Apologies, I think I missed this in the clinical development plan. Does the target product profile assume both approval in non-obstructive and obstructive HCM? Just from a development perspective, how does that kind of break out in the later studies? Is this doing dual populations? If you could talk a little bit more about that. Thanks.
Yeah. Marc S., why don't you take that?
Sure, thanks for the question. You know, you know, we're relatively early in our planning for the phase I study. You know, I do think, first of all, that non-obstructive HCM is terribly underdiagnosed, perhaps even more so than obstructive HCM, because you don't have, you know, the classic murmur that you do with obstruction. I think if you don't take the time to accurately measure wall thickness on an echocardiogram, you're gonna miss it. First of all, I just wanna, you know, say that one thing we are gonna be working towards is increasing the diagnosis of non-obstructive HCM as well.
I guess, you know, I would also say that, you know, as we go through, given that the clinicians generally see HCM patients, both obstruction and obstructive and non-obstructive, who specialize in this field, that we're likely gonna be, you know, using, you know, sort of perhaps, you know, one study with two parts to allow clinicians who have an HCM patient to be able to refer them into one arm or the other, given, you know, the presence or lack thereof of obstruction.
Thanks very much, guys.
Thanks, Laura.
Thank you. The next question comes from the line of Joe Schwartz from SVB Securities. Please go ahead. Your line is now open. Please unmute yourself.
Great. Thanks. Can you hear me now?
Hi, Joe. Yep, we can hear you.
Awesome. Great. Thanks for the excellent presentation and all the interesting work you're doing in this area. My first question is how cardiac selective is EDG-7500 expected to be given its target is in the sarcomere, which also exists in skeletal muscle? Is EDG-7500 expected to only be active in sarcomeres that have this hyperdynamic phenomenon for the proteins you described today? Do these mutations only happen in cardiac muscle? Have you looked to see whether, you know, there could be any off-target effects in skeletal muscle preclinically?
I'll take that at a high level. Yes, we have looked at skeletal muscle and have seen no effects. Depending on the in vitro profile of the molecule, we do get selective tissue distribution between muscles and different compartments. we're still studying how that at the primary sequence level would drive the distribution of the drug. It is rather novel, interesting, but has not been linked to any adverse effects that we've observed so far, and this is with 2 months of dosing at a therapeutic level in the dog. I think from that standpoint, I'm confident that we have a therapeutic window and that this muscle is, this particular drug is targeting a muscle specifically, and it's not unlike some of the other previous work we've done with EDG-5506 and skeletal muscle.
Yep. Okay. Interesting. Thank you. Is EDG-7500 expected to work any more or less in different patients based on their different sarcomere mutations?
It's quite an interesting question. I think maybe Marty can take that because he's done quite a bit of work in this space.
Yeah. I think, you know, probably what I would say to answer that right now at this point is that I think that, you know, this is a therapy that's intervening on the, you know, on the mechanism of disease that's common to patients whether they have a pathogenic sarcomere mutation or they don't. I would expect to see that the improvements in both systolic and diastolic forms of heart failure related to the intervention of therapy would work as well whether the patient has a sarcomere mutation or doesn't. I think that's at least at this juncture, that's what I would say.
Okay. That kind of led into my last question, which was going to ask how relevant EDG-7500's MOA is to the systolic versus diastolic dysfunction, which you, I think, said that, you know, isn't very well addressed. They're not both equally well addressed by mavacamten.
Right.
I think I.
Go ahead.
Maybe Marc, why don't you take that? I think I would just argue that from the data we've seen, we have a perhaps a greater effect on the diastolic than mavacamten. I mean, Marc, what's your view on that? I think that's how we view what we're observing.
Yeah. Yeah. Yeah, thanks for the question. You know, the molecule works regardless of mutational status, and so we've shown today in two different mutations that, you know, it works. We also have shown that it has pharmacologic effects in normal, so non-mutated systems, you know, living systems. You know, it works across the board regardless of whether you have a mutation or not. Of course, you know, there's 1,000 mutations across all of the sarcomeric proteins that drive disease, so we won't be able to test them all. We will test, and we've tested quite a number of mutations and we see the drug work equally as well across the board to date.
Then in terms of its systolic diastolic balance, you know, we were highlighting the benefits in diastole today 'cause we think that's a really important feature of the molecule. You know, we've shown that it does slow the rate of contraction and, you know, but as measures of with echocardiography, fractional shortening and ejection fraction, you know, we remove the hyperdynamic nature. You know, the question becomes does that confer benefit? It looks like it does very potently in the preclinical models.
Can I just add something to that, Marc? Is that okay? It's Marty.
Yeah.
Yeah. I think that's a really important point to make here, and it's kind of been asked and I think in a number of different ways so far, is that you don't need to drive down contractility significantly to get rid of the gradients here. The principle behind that is just what you said, is that if you can modify early ejection velocity, so the early velocity of blood out of the heart, which can be done without affecting significantly overall contractility, that alone will drive down or abolish gradients in patients with obstructive HCM. 'Cause that's really the most important mechanism leading to the valve coming over and touching the septum is that early ejection velocity issue. Mitigating or modifying that is really the success, leads to the success of getting rid of gradients.
You can do that without having to drive down systolic function significantly. I think that's a key point. It goes to some of the observations you spoke about as well.
Super interesting. Thanks for taking my questions.
Thank you. The next question comes from Leonid Timashev from RBC Capital Markets. Please go ahead. Your line is now open. Thank you.
Hey, thanks for taking my question. I wanted to talk a little bit more about the self-limiting aspect here. I mean, I think it's clear that this potentially has some safety benefits, but can this impact your ability to push efficacy if needed? I guess, do you think that what you're showing now is on track not to push not just the depth of response, like you showed, a 66% reduction in the gradient, but also the actual number of patients that are gonna respond to the mechanism? I guess, do you see this as an easier and safer to take agent that can be used earlier, or do you think that, you know, the efficacy here is gonna be, you know, enough compared to the others? I guess for Dr. Maron, I guess.
Can you talk about how you think about using this and if there are options for polypharmacy in HCM?
Go ahead, Marty.
Yeah. I think you know, you know, I think using it, I think, you know, first of all, I think it, depending, if it's easier and safer to use then, there's gonna be a lower threshold to be using or considering the drug earlier potentially in the course of patients possibly. That's a possibility. In other words, there's already the idea out there that perhaps we should be treating these gradients earlier in the disease than we are right now, because that would potentially have even better benefit in terms of natural history. If we've got a molecule that we can do that very reliably and safely with, I think it really opens up the possibility here for much earlier drug therapy than we currently are doing, for example, with mavacamten.
That's a possibility that could come from a safer, easier to use molecule here. Sorry, what was the other part of the question was, from a clinical standpoint?
Yeah, just curious if there's any options for polypharmacy in HCM?
Yeah.
If these drugs are just used one after the other.
I think the answer to that is that, yes, there is the possibility of polypharmacy here. I think we're very early in that idea here, but I think we've already had some evidence, for example, of aficamten being used with disopyramide in certain ways as dual therapy for select patients that seems to be safe and effective based on a small study that was just presented within the last couple of months. I think that that idea of combination therapy is going to be really important in some patients, both with obstructive and non-obstructive disease.
Thanks, Leonid.
Thank you. The last questions comes from the line of Madhu Kumar from Goldman. Please go ahead. Your line is now open.
Hey, everyone. Thanks for taking our questions, and Happy New Year. I guess our first question is, at a simple level, do you envision EDG-7500 being used as an alternative to myosin inhibitors in the treatment of HCM? Then we'll have a follow-up question.
At a first level, yes. I think as we've shown you the ability to drive the gradient at very low concentrations, perhaps drive more deeper response in the gradient and expanding it into populations that have not responded as maximally to the CMIs, I think is a place where we would be interested in taking it. Of course, I think the real opportunity will end up, because of the nature of the mechanism, being non-obstructive HCM. I think both. You know, I think there's multiple opportunities. We'll see how the market evolves. Marc, do you have any maybe comments on how Marc S, on how this might be used and how we're thinking about it?
Yeah. No, no, I agree, Kevin. You're gonna have to get used to Marc S and Marc E here. Hi, Madhu. Anyway, yes. I mean, if we've got a drug that's targeting both pathophysiologies in obstructive HCM, you know, both the abnormal hypercontractility and the abnormal diastolic function, I mean, yes, we wanna target both of those abnormalities. It would seem to be, you know, preferable to many other agents that are on the market or in development at this time.
Okay. Great. Kind of following from that, I don't know if you guys have performed this study or if kind of what's out there in the literature, maybe Dr. Maron can speak to this. How do kind of CMIs perform in this feline model and porcine model in terms of some of the parameters that have been measured and reported today?
Marc E, do you wanna take that or, you know, I mean. 'Cause when, you know, we published when we were at MyoKardia on the effects of mava in the porcine models.
Yep. Yeah, that's right. Mava shows a very similar benefit that, you know, we illustrated and then, you know, a unique difference. What we showed is increase in end-diastolic volume without increase in end-diastolic pressure. That is the signature with mavacamten. Then, you know, there's a measure that one can make to look for how many myosin heads, you know, engage in contraction, and that is decreased with mavacamten, and relatively preserved with 7500, which is the unique difference and, you know, it's the one that we've been highlighting. It looks like we get the benefits of reducing cross bridges in relaxation. When you need the squeeze, you can recruit it or. That's what's been published with mava that we know about.
I guess an addition to that is that the exposure response on the gradient is quite a bit different, as what we've shown relative to what's known with mava. I think that it's more of a 1-to-1 ratio where we so showed a different relationship between exposure and response.
Marc E, you might wanna comment on the cat data in with mava.
Sure. Yeah. There's a, you know, publication with mava from 2016 showing, you know, linear relationship with the reduction in fractional shortening and drops in gradient. And we've shown that exponential drop in the gradient that really uncouples from fractional shortening. We believe we could drive deeper gradient reduction at lower fractional shortening concentrations, and that's what the preclinical data shows. For less systolic cost, we can drive down that gradient.
Madhu, just for your knowledge, Marc E published the mava data and did it hands-on.
Cool. Awesome. Thank you very much, guys.
Thank you. There are no further questions at this time, I would like to pass the call back over to Kevin Koch for closing remarks. Please go ahead.
Okay. Great. Really like to thank you all for joining the meeting today. We'd like to thank our employees, our patients, all of the scientists and clinicians that work with us, and our families, for all their support. Thank you all for taking the time out of your day. Look forward to speaking to you in the future.
Thank you. That concludes today's webinar. Thank you for all your participation.