I'm Diane Weiser, Senior Vice President of Corporate Affairs, and I'm pleased to welcome you to Heart Forward: Advancing Cardiac Myosin Modulation, our 2024 Investor and Analyst Day. I'm pleased to be hosting this event in a hybrid fashion, and welcome those here in the room with us in New York, as well as those attending online. Over the course of the next few hours, we plan to provide an update on the company's cardiac myosin modulation programs, as well as commercial readiness activities for aficamten. Before I continue, please note that portions of the following discussion, including our responses to questions, contain statements that relate to future events and performance rather than historical facts and constitute forward-looking statements. Additional information concerning factors that could cause our actual results to differ materially from those in these forward-looking statements is contained in our SEC filings.
We undertake no obligation to update any forward-looking statements after this meeting. So I'm pleased to welcome our team from Cytokinetics. Some of them are very familiar to you, others represent an extended team that we are excited to introduce you to. So of course, we have Robert Blum, Sung Lee, and Fady Malik, as well as several members from Fady's R&D team, including Stuart Kupfer, Stephen Heitner, Dan Jacoby, and Punag Divanj i. We also have Andrew Callos here and his commercial leadership team, including Joseph Dagher, Dan Kates, Genie Dubuk , Sunil Karnawat, John Giacoppi, and Jeff Lotz. I'd also like to extend a warm welcome to John Henderson, Chairman of the Cytokinetics Board of Directors, and Muna Bhanji, member of the Cytokinetics Board of Directors, who are here with us today.
Next, I'd also like to introduce three physician experts who we're very honored to have with us today to join the discussion: Dr. Mariko Harper, Dr. Shepard Weiner, and Dr. Michael Felker, so we have a packed agenda this morning, and here's a look at it. We will start with an introduction about Cytokinetics and the specialty cardiology franchise that we're building, followed by some financial highlights. We'll then move into the broad development program for aficamten, where we're going to synthesize data from clinical trials relating to aficamten, and then tap into our expert HCM clinicians to share their perspectives on the data. We'll then move to commercial preparations for the potential launch of aficamten, showcasing activities and insights from a variety of areas within the commercial organization. This section will be followed by a quick five-minute break.
Following the break, we'll dive into omecamtiv mecarbil and the rationale and trial design for COMET-HF, our confirmatory phase 3 clinical trial of omecamtiv mecarbil, followed by the commercial opportunity and the unmet need in heart failure with severely reduced ejection fraction. Then we'll shift gears to another form of heart failure, HFpEF, and discuss plans for CK-586 and the market opportunity before moving into an open Q&A session. And then finally, Robert will wrap things up with some concluding remarks before we close the meeting. And with that, I'll now turn it over to President and CEO, Robert Blum, to get things started. Robert?
Thank you, Diane, and thanks very much to your team, Joanna and Ava, who have put together a phenomenal program. It's such a joy to see so many people here in New York. This is by far our largest event of this type, and even more people who I know are in the Zoom room. We're grateful for your participation. I hope that you'll see in Cytokinetics today some things that speak to the maturing and evolving company that we are.
A company that is still rooted in the original same science, but for which, especially as you're going to meet so many new colleagues and executives responsible for taking us to the next level, is committed to the translation of that science to the promise of new medicines, and a business that should be rewarding of shareholders the way you would want to see us operating with conviction and discipline. So with that in mind, as one gets to this point in one's career and also for the maturity of the company, you get fewer slides.
So they gave me a few slides today to kind of set the table for what we're going to be doing next, but I think that's exactly what I should be doing as I kind of put forward the original therapeutic hypothesis around myosin modulation and what it means for Cytokinetics today. Myosin. Myosin is that mechanochemical enzyme around which we've built a platform. We talk a lot in our industry about platforms, and myosin has served its own platform. This is the same biology that Cytokinetics has been committed to for over twenty years. You've seen this slide in many of our presentations, but have you taken a moment to think about how one single molecular target has given rise to a portfolio, a pipeline of modulators, new potential medicines around which we can expect transformational change in cardiovascular medicine?...
Myosin, whether you're talking about activating it or inhibiting it, provides a cornerstone for the way we think about medicine, but also business. You'll hear today about progress we've made with aficamten, a next-in-class cardiac myosin inhibitor, as well as CK-586, another cardiac myosin inhibitor, both directed to suppressing the hypercontractility associated with either hypertrophic cardiomyopathy in two forms, obstructive and non-obstructive, as well as certain patients with heart failure and preserved ejection fraction. And of course, we should also underscore the importance of activating cardiac myosin, as has already demonstrated important clinical evidence to support the potential treatment of patients with heart failure and reduced ejection fraction. You'll hear more about our plans and next steps there. And as we will be sharing with you these updates today, please keep in mind how this translates into catalysts and multiple milestones for increased shareholder value.
All of this is intended to suggest how Cytokinetics, by continuing to prosecute this area of science and biology, can reward both patients and medicine, but also shareholders. On this slide, you can see, and I won't go into each of them, but you can see how we start in 2024 to accrue important next-step milestones that will be unlocking value as could be meaningfully rewarding shareholders. We have an abundance of news flow, even still yet this year, but also over the next couple of years, as we'll be advancing this biology towards the build, and you'll hear much more about this and what we mean by it, a specialty cardiovascular franchise. How we think about the business and increasingly our lexicon is being adopted, as you'll hear, by more and more companies, both biopharma and large pharma.
Specialty cardiology, borrowing a page from the playbook of other companies, both in cardiology and in specialty pharmaceuticals, but as should translate into enduring and growing value, and as that can be approached with discipline, discipline and integrity in science and medicine, but also in operations and how we think about capital deployment, capital allocation, and efficiencies. You'll hear more about that today. Starting with aficamten in HCM, you're going to hear today more about how we build a business, a business differentiated in terms of market access and positioning in the market, as well as patient experience, not only in North America, but also in Europe, and how we can be addressing a significant, a highly significant unmet need clinically, but do so in a way that's directed to a concentrated customer segment, where the return on investment, return on shareholder equity, should be rewarding of investment and growth.
But it doesn't stop there. Many of the foundations we'll build for HCM, both obstructive and then non-obstructive, accrue value as we then transition to HFrEF, but not all of HFrEF. Those advanced, severely reduced, ejection fraction patients with worsening disease for which existing standards of care do not serve them well. You'll learn about the unmet need, both clinically and pharmaco-economically, and how the investments in commercial infrastructure then can be also accruing synergy as we expand to address the opportunities in HFrEF, and then ultimately in HFpEF. Again, not all of HFpEF, not the cardiometabolic disease, but those HFpEF patients who have supernormal ejection fractions and where we do believe cardiac contractility is impaired, irregular, and where our myosin modulation affords us a yet further next act.
So across the arc of these three products directed to the same molecular target, we're building a business that we think should be, hopefully, addressing meaningfully what you would be looking for from a company like ours. We use specialty cardiology and not in words like orphan or ultra-orphan, because we're not talking about relatively select small disease areas. We're talking about disease areas with patient numbers, prevalence, but also symptomatic and diagnosed, that refer to hundreds of thousands of patients, and in some cases, approximating upwards of a million patients. So here you can see on this slide that we're addressing with aficamten, both obstructive, then non-obstructive, and then ultimately omecamtiv and CK-586, incidence and prevalence numbers that are sizable, meaningfully large, high clinical unmet need, and not, I underscore, not being well addressed by standards of care.
I hope we can disavow you of the belief that these are largely addressed markets, because what you're going to hear today is the very high unmet need, still high morbidity and mortality associated with these populations in these areas where we're going to be focusing with a myosin-directed strategy. And with that, I'd like to turn it over to Sung, our Chief Financial Officer, who's going to layer in how the financials track with this corporate development and commercial strategy. Sung?
... Great. Thank you, Robert, and good morning, everyone. It's a pleasure to be here. At Cytokinetics, we're focused on creating an enduring business model centered on a specialty cardiology franchise. We believe we have the capabilities and wherewithal to achieve this, starting with, first, a strong balance sheet with $1.4 billion in cash and investments as of mid-year, and access to up to $500 million in further funding. Second, we have the depth and breadth in our pipeline. And finally, we have a proven muscle biology platform. Our capital allocation priorities are clear. Our resources will be focused on preparing for a potential launch of aficamten in OHCM, advancing our pipeline with important label expansion opportunities for aficamten, and clinical trials of omecamtiv mecarbil, and CK-586.
And finally, we'll be making investments in our research platform, specifically our muscle biology platform, which we believe is capable of generating additional drug candidates in the future. As we pursue our strategy, you can bet that we'll be good stewards of capital. We believe the execution of this strategy could lead to sustainable growth, driven by our specialty cardiology franchise and fuel future waves of innovation. In the next few minutes, I'd like to walk you through how the business model focused on specialty cardiology can support sustainable growth. Preparing for the potential launch of aficamten in OHCM is a top priority, but as you know, we have an ambition to become a multiple medicine integrated biopharma company. We want to realize the full potential of our muscle biology platform and capabilities.
To that end, we're making investments in important programs such as omecamtiv mecarbil and CK-586, which could be very complementary to aficamten and drive long-term revenue growth. Because of the investments we're making in our commercial and R&D capabilities, we stand to realize synergies should omecamtiv mecarbil and CK-586 become approved medicines in the future. An important result of this could be the realization of enhanced margins, as the cost of sales of these medicines are relatively low, and from the synergies we expect to realize from the investments in our commercial and R&D capabilities. These margins, in turn, could fuel additional waves of innovation, and we expect to invest part of that growth back into our pipeline. In the end, we have an opportunity to become a leader in specialty cardiology with multiple medicines, delivering clinical benefit for patients and sustainable growth for investors.
So with that, I'd like to hand it over to my colleague, Fady.
Great. Thank you, Sung, and welcome, everybody. Just building on Robert's comments, I guess I've been here long enough, I only got one slide. So, I'll be brief, but I'm fortunate that they'll share this with many of my colleagues, who you'll hear from after, after I'm finished. But what a slide it is. It's kind of humbling, if you think about 25 years ago, a scientist working at Cytokinetics, having a chance observation in a motor protein assay and thinking about how activating myosin could be therapeutically relevant. And then the company building, what you see here, is really the most comprehensive program to leverage this concept in biology and bring it to patients.
Just along the top line are arrayed the clinical trials of aficamten, the cardiac myosin inhibitor that you read this morning we just submitted our NDA for. REDWOOD, SEQUOIA, MAPLE, ACACIA, Cedar, FOREST, all probably consisting of, I shouldn't say probably, but definitely consisting, I think, of the most comprehensive program of studies in this area that should expand our understanding of how this therapy can and this class of therapies, cardiac myosin inhibitors, can treat patients with HCM, can modify the course of their disease, and ultimately, you know, hopefully change the lives of many patients who have access to these therapies.
We continue to progress the last four trials, MAPLE-HCM, our comparator trial of aficamten versus standard of care, metoprolol, ACACIA-HCM, a label expansion study in non-obstructive HCM, CEDAR-HCM, a pediatric study, and FOREST-HCM, which is where we will gain long-term understanding of how this mechanism impacts patients. Along the bottom there, you see the trials that we've completed, some of them, not all of them, but in the major ones, of omecamtiv mecarbil, a cardiac myosin activator, and I'd like to introduce the last trial today, COMET-HF. So COMET-HF is our second confirmatory trial of the benefit of omecamtiv mecarbil, building on what we observed in GALACTIC-HF and other trials that came before it. We'll discuss that in more detail later, and we're fortunate to have Dr. Felker, who is the principal investigator of COMET-HF, with us today.
Lastly, I get to introduce Amber HFpEF. It's our trial of CK-586, and it's a dose-finding trial, a phase II trial in a population, a specific population of HFpEF, that we think builds on what we've learned in HCM, and we're excited to introduce that, and as you can see, that theme of trials to come. We'll be accepting nominations for future trial names after this presentation. But I'm humbled, really, to see what the company's been able to accomplish in 20 years, and over the next several years, we hope to continue to build on what you see there today. Without further ado, I'm going to pass the clicker over to Stuart Kupfer, who will take us first through dosing, efficacy, and ease of use of aficamten.
Thank you, Fady. Good morning, everyone. I'm Stuart Kupfer, Chief Medical Officer. Thanks for joining us. So to begin with... Is it not on? Is it on?
Yeah, it is.
Okay. Good morning, everyone. Thank, thanks for joining us. To begin with, I wanna highlight the features of aficamten's efficacy profile and the dose titration strategy that contributes to that profile. And so, let's focus on SEQUOIA-HCM. This was our pivotal phase III trial in patients with symptomatic obstructive HCM, comparing aficamten and placebo. And, you know, we, in this trial, you know, in the interest of maximizing treatment benefit and minimizing risk, we implemented a, an individualized dose titration strategy, based on achievement of Valsalva gradient, less than 30 millimeters of mercury, and maintenance of a normal ejection fraction. And what we observed was that, you know, with this rather simple dose titration scheme, with a low starting dose of 5 milligrams, was good tolerability, in SEQUOIA.
For example, in the dose titration period, there were no occurrences of ejection fraction less than 50%, despite the fact that the majority of patients were titrated to the two highest doses of 15 and 20 milligrams. During the entire 24-week trial, decreases of ejection fraction less than 50% were uncommon, and none of those occurrences were associated with treatment interruption or heart failure events. This dosing strategy resulted in a robust treatment benefit in the context of good tolerability. Now, the primary endpoint in SEQUOIA was change in peak VO2 by cardiopulmonary exercise testing, and that's this is the gold standard for measurement of, you know, maximal exercise capacity.
The increase of 1.74 mL/kg/min for aficamten versus placebo was highly statistically significant and represented a very substantial improvement in exercise capacity, considering that an increase of 1 mL/kg/min or greater is recognized as clinically relevant. Now, this improvement in peak VO2 was consistent and similar across all the pre-specified endpoints in the SEQUOIA trial, including those patients who were treated with beta blockers at baseline. No difference whether patients were treated with beta blockers or not. This is important because the majority of patients with symptomatic obstructive HCM are treated with beta blockers. Unfortunately, those beta blockers can exacerbate exercise intolerance, you know, by suppressing an appropriate increase in heart rate.
The improvement in exercise capacity was associated with rapid and substantial reductions of you know outflow tract gradients. Both mean resting and Valsalva gradients decreased below the thresholds that define outflow tract obstruction. Also importantly, in that context, the decrease of ejection fraction was quite modest, so less than 5% mean reduction of ejection fraction. Now, on this slide is representing some data from a recent publication evaluating clinically relevant responder thresholds. Dr. Maron and colleagues reported that a remarkable two-thirds of patients were complete responders in SEQUOIA. These are patients who achieved both resting and Valsalva gradient targets of less than 30 and less than 50 millimeters of mercury, respectively.
They also reported meaningful improvements of symptoms, exercise capacity, NT-proBNP based on again clinically meaningful response thresholds. Furthermore, if we evaluate longer-term treatment of aficamten, what we observe is reductions of the resting and Valsalva gradients that are not only sustained but continuing to improve over time. These data suggest that there will be durability of effect, treatment effect, treatment benefit of aficamten with chronic therapy. You know, these are data out to one year, but now we have data out to three years, and we're observing similar results. That's a quick run-through of some of the features of the efficacy profile of aficamten. What I'd like to do now is invite up our panelists.
We're very fortunate to be joined by Dr. Harper, Dr. Weiner, who have extensive experience and expertise in treating HCM. And we look forward to their perspective on, you know, the results of our clinical development program with aficamten. And I'd first like to give the two of you an opportunity to introduce yourselves. And so please, Dr. Harper.
My name is Mariko Harper. I'm the Founding Medical Director of the Hypertrophic Cardiomyopathy Center at Virginia Mason Franciscan Health in Seattle, Washington. For those of you who don't know, that region has a paucity of HCM centers and providing subspecialty care. So we have patients from what we call the WWAMI region, so Washington, Wyoming, Montana, Alaska, and Idaho coming to see us to get that subspecialty care. And so we have a large catchment area. As a clinical cardiologist, I see about 20 to 25 new HCM patients every month, in addition to many dozens in clinical follow-up. And we provide comprehensive HCM care, from clinical trial options to surgery and all the medical therapy that we're talking about today.
Great. Thank you. Thank you.
My name is Shepard Weiner. I'm the Medical Director of the HCM Center at Columbia University Medical Center, so I usually spend my days about 120 blocks north of here. I didn't travel as far. We're an HCM center of excellence, and additionally, have similar experience to Dr. Harper in terms of the numbers of patients that we see with HCM. Want to underscore how COMET HCM is. It's out there. And I always say that it's really an exciting time to be an HCM doctor, just because there is the potential for new therapy that can really help our patients. It's an exciting time to be an HCM patient, but also on the provider side, it's definitely a point of opportunity.
Great. Well, thanks again for joining us. We really appreciate it. So I wanna run through a few questions, and to begin with, I wanted to ask you about the reductions of gradients that I just presented. We specifically, intentionally designed aficamten and this dose titration strategy to achieve pretty rapid and robust reductions of gradients. And maybe I'll start with you, Dr. Harper. If you could sort of give us your perspective on how you think those data would impact management of your patients and, and-
I mean, from a clinical standpoint, a majority of patients come to us having been detected with a heart murmur. So that murmur is that obstruction, and they're coming to their primary cardiologist or their PCP saying, "I don't feel well." And it's that murmur that triggers the echo, that triggers the HCM consultation. But in my experience, that outflow tract obstruction is really what drives those symptoms, that exertional shortness of breath, that chest pain, what we call angina, the fatigue, and all of these symptoms. And it's very predictable how when that gradient goes down, patients feel remarkably better, and very, very quickly. Outside of these medical therapies that we're talking about today, it's really only been surgery, which is not available anywhere, and there's this recovery period as well, where you've had that really rapid drop in gradients associated with clinical improvement.
Great, thank you. Dr. Weiner, would you like to add to that?
Yeah. I mean, I think the data from SEQUOIA, you know, objectively speak for themselves, and whenever I, you know, talk about this subject, I really find that my charge is to try to humanize the data and say, "What does that mean? What does that decrease in gradient mean?" And what it means for me, when I had patients enrolled in SEQUOIA and now rolling over to FOREST, is that those patients hug you every time they see you because they feel so well, and they thank you for giving them the opportunity, to be involved with this and to benefit from this treatment.
Great, thank you. So I'm gonna move on to another topic. The, I presented data on the primary endpoint, change in peak VO2, which, as you know, is a quite, reliable, quantitative, measure of functional capacity. But I think for most physicians, it can be sort of a difficult, measure to interpret. But the two of you have a lot of expertise in this area, and, I'm wondering what you think of those data and how, you think it would impact a patient's functional capacity and quality of life? Maybe start with you, Dr. Weiner.
So as you mentioned, you see that, you know, statistically significant improvement in peak oxygen consumption, and what does that mean? It is significant, but what we wanna convey is how clinically significant that is. So again, it's the patient who can, you know, go out and throw a baseball with their grandson and not get winded, or the patient can go for a walk in a neighborhood park with their spouse that they haven't been able to do in twenty years, but now they can because they have that improvement. And I think it's very important for these trials, you know, initially to include that objective outcome with the peak VO2, because there are placebo effects in the background of clinical trials, and this is really an objective measure which shows us that the science is there.
But what does that really mean? How does that translate to the patient? It's impactful, it's meaningful, and it's really a game changer for these patients.
Great, thank you.
... Yeah, I really echo that. Most patients with obstructive HCM, especially with severe gradients, are not truly asymptomatic. And what we pick up on the CPET and that peak VO2 is exactly how symptomatic they are. But they've been on, you know, and the data shows this, that they've been living with their symptoms, undiagnosed or undertreated for many years. And so to a point, they might be telling you they have symptoms, but they may not really fully appreciate exactly how severe those symptoms are, in fact, until they start feeling better on therapy.
And that really correlates to that improvement, that the peak VO2 is just an objective measure of what we see clinically and what our patients tell us, saying, "Hey, you know, I used to, you know, park here in the hospital, and I have to call someone, a porter up with, to get me a wheelchair because I can't walk, you know, just, you know, across the sky bridge. And my daughter and I, we walked the whole way here, and we're going to go for a walk outside after." So to be able to do that in a very short period of time is just remarkable and the most rewarding part of clinical practice.
Oh, that's great. Yeah, we've heard some amazing stories about how patients have improved with treatment with aficamten. The final question I have for you is, you know, related to the individualized dose titration strategy that we employed in our clinical development program, and, you know, we hear a lot about precision medicine, you know, in an effort to optimize patient management and improve benefit, risk, and outcomes. Maybe you could give us your impression of how this might impact your management of patients and, you know, optimizing their treatment. Maybe start with you, please.
Yeah. I think looking at aficamten and certain properties of aficamten, the short half-life, the easy titration schedule that can be proposed, is that provides patients with that flexibility. It also provides us as clinicians, you know, especially as we expand into providing this as an option for community cardiologists in more, you know, rural areas, maybe who don't have that experience or a tie with a center of excellence. We want to be able to have that conversation with a patient where we rapidly see results, to be able to titrate that so that we have that real-world feedback and our patients do, too, of, "Hey, I feel better," and we're, you know, escalating up to full dose quickly. And if for whatever reason, there needs to be a dose titration down, that's also equally flexible.
That's a very reassuring thing to be able to say, "Okay, that dose is maybe a little high. Let's go back down," and within a very short period of time, be able to get in that sweet zone.
Okay, thank you. Dr. Weiner?
You know, I agree completely. You have an effective therapy, but you can use it safely, quickly, get to a dose that's, you know, maximally effective for your patients, and the real-world implication of that is very significant.
Thanks very much, Dr. Harper, Dr. Weiner. Appreciate your perspective and insights.
Thank you.
Thank you.
With that, we're going to move to the next section of our program, and I'm going to invite Dr. Heitner to the podium. Thank you.
Sure. Good morning, everyone. So Kylie is going to join us up here on the panelists. Good morning, guys. So we're going to be switching gears to the emerging safety profile of aficamten. And firstly, as presented and published in this really fabulous manuscript that Dr. Coats and her colleagues presented initially, we outlined the safety of aficamten in very, very fine detail. And what you see on the slide over here is that the adverse events of special interest and the overall adverse events are not too dissimilar than what you would see in any clinical trial with particular reference to the low EF events that Dr. Kupfer outlined a minute ago of less than 5%.
Next, we published and presented this integrated safety analysis that actually combines the entirety of the experience with aficamten, both in our randomized clinical trials of Redwood and Sequoia, as well as the long-term exposure of patients in Forest for up to three years, actually. What you'll see in the table on the right over there is that the adverse events of special interest in the aficamten versus placebo arms are not dissimilar, and actually in the cumulative exposure for, again, up to almost three years, is very similar to what you would see in the placebo arms. Importantly, there's no difference in atrial fibrillation, and there were no dose interruptions related to low ejection fraction events, and none of the patients in this presentation developed heart failure related to low ejection fraction.
And when you put that into context about the monitoring phase that we've been conducting throughout our clinical development period, you'll see that once the patient has achieved their target dose and is now in the maintenance phase, less than 1%, 0.5% of patients' echocardiograms result in a dose-down titration. So the 3 patients who underwent a down titration because of an ejection fraction between 40% and 50%, did so in the setting of being asymptomatic, no heart failure events and no clinical consequences of those echocardiographic findings.
And then lastly, before we transition to our panelists over here, I wanted to detail that in the setting of a randomized clinical trial, where things are very rigidly controlled by algorithms and such in a blinded fashion, we see an ejection fraction excursion, a rate of below 50% of about 3%-4%. When you transition that into something that closely resembles clinical practice, where the treating physicians are able to integrate their clinical impressions and select the doses on that basis, we see exactly the same thing for a prolonged period of time. Importantly, this is in the setting of no treatment interruptions being related to ejection fraction excursions. All of those excursions that were detected were entirely reversible, and none of them were associated with any clinical consequences of heart failure.
So with that, I'm going to turn to our three panelists now. And I'll preface this by saying, you know, aficamten is a new mechanism of action for treating obstructive HCM, and there's obviously going to be a large emphasis on the associate or understanding the safety aspects of this. So we've collected a whole lot of data, and we've been very dense in our data collection, making sure that we're gonna be treating patients as safely as possible, both in our randomized controlled trials and encouraging patients to transition to the open label extension, FOREST-HCM. And I presented some of the highlights. Obviously, we've got much more data than what I've showed, and I'd like to actually get some of your impressions now. So I'll start with you, Dr. Harper.
What is your overall impression about the safety profile of aficamten?
So safety is paramount. It's the most important thing. It doesn't matter how good a drug works if it's not safe, and aficamten safety profile is really, really great, right? No clinical heart failure. Ultimately, that's really what it comes down to when we're talking about a drug with a mechanism of action that can subtly reduce ejection fraction. Of course, our patients with HCM generally have these hyperdynamic ejection fractions. That's what we want, but the lack of a clinical heart failure, so not just the drop in ejection fraction, but no clinical heart failure is really what drives care. It's what patients care about. It's what we, as clinicians, care the most about, and when we're initiating a new drug, that's the most important discussion point.
Perfect. Thank you. And, Dr. Weiner, anything that you'd like to add to that besides the ejection fraction excursions?
Yeah, I mean, I think you just really cannot overstate that, you know, the importance of when you have a patient in front of you, and you're looking them in the eye, and you're saying, "I have a potential therapy for you," that there's gonna be no clinical interruption of therapy, no clinical heart failure, because you have a drug that has a very safe and robust profile in that regard, that we take an oath when we, you know, become physicians that we're gonna first do no harm. So that's where you start, and you have the data to support the fact that you're not gonna have to interrupt therapy or have any clinical heart failure. That's very important, obviously.
This is a really important time now, a few years into Camzyos. Our patients are much more educated-
-than where they were a few years ago, as are our community clinicians, and this is the number one question that comes up. So patients will come to you with that question. That's really what often the referrals are about is: Hey, can you provide more information about this? How do we keep our patients safe? I'm interested in prescribing a CMI, but these are my concerns. So it's out there, and it's very reassuring to have that data to back it up.
All right. Excellent. So, I mean, you know, just following up on that note a little bit more about now we're gonna focus on our concern about ejection fractions below 50% and try to place that into clinical context. So, Shep, can you kind of explain to me what your feelings are about echocardiographic ejection fraction and the meaning of that in the setting of a CMI?
So, I mean, obviously, ejection fraction is important. It's a number. We all like to kind of be guided by numbers. Ejection fractions can change, but it's really what is that ejection fraction change associated with? If you're less than 50%, but you're not having any clinical heart failure, you're on a steady dose of a medication, which is making you feel better, we know that that's safe. So obviously, ejection fraction is important, and we take seriously any changes in ejection fraction. We know that, you know, CMIs can have an effect, obviously, on contractility, but how does that actually play out, you know, with the patients in front of you?
It's the ability to tell them that you're not gonna have to stop therapy, that you're not gonna have clinical heart failure, that provides that reassurance that they're very eager to get the benefit from medication that's safe.
Dr. Harper?
I echo all of what Shep said, and I think it's important that we have this context of EF of 50%. That's a number, but really, it's just a number. And regardless if it's HCM or any other patient we see in cardiac practice, an EF of 49 versus 51% clinically is the exact same number. And the very next day, that echocardiogram, core lab or whatnot, is gonna. It might change from 49 to 51 and back again with no meaningful clinical change.
So it's really important that we provide that context since our patients come to us saying, "Oh, oh, no, well, that 50% or that 49%." As you see in the trial, most of these ejection fractions, even the few that were low, are all in that high, you know, in the 40-plus range, in the 45-plus range. And there is a margin of error with echocardiography, but the important part is, what's the clinical part? Are the patients feeling better, or are they feeling worse? And they feel better.
Perfect. Thank you so much. So we're going to switch gears a little bit, and, you know, Dr. Kupfer mentioned our study, MAPLE-HCM, which is a head-to-head comparison of aficamten against standard of care. Well, actually, metoprolol, which is the most frequently used first-line beta blocker. And we're in the process of conducting that. So, in your opinion, Dr. Harper, how do you think the results of that study will alter clinical care?
I think this is a really important study. So just to clarify, beta blockers have never been studied in an RCT fashion in HCM, and the vast majority of patients on beta blockers have side effects. That can be weight gain, hair loss, erectile dysfunction, that blunting of heart rate with activity. Most people, especially on those high doses that traditionally we've been using to treat OHCM until this era, have had side effects. So the ability to provide patients with less medications, less side effects, that really gets to the crux of why we're doing this, to help people feel better and live a better quality of life. And beta blockers don't help people feel better. It's just been better than the alternative, which was do nothing until now.
Okay, and
Yeah, I mean, I have the same experience. I mean, patients come to you on the accepted standard of care, but there really is not, you know, a high level of data to support that, and it can't be, again, overstated how important it is to try to balance side effects, and, you know, beta blockers have a lot of side effects, and patients are very happy to come off beta blockers. And, you know, this trial will show us, you know, what that strategy really looks like. But in my clinical experience, you know, having patients on CMI, once they're steady in a maintenance phase, the first thing they ask is: When can I decrease the dose of the metoprolol? When can I come off the metoprolol?
That's a strategy that we've employed, and that alone has, you know, very significant benefit to our patients.
Thank you. Fady, I'm gonna ask you a question. So we recently announced that we had a protocol amendment to the FOREST-HCM study, essentially decreasing the frequency of the monitoring requirements at the clinical interpretation of the treating physician. Can you explain how we got there and what that might read out in terms of how aficamten might ultimately be used if it were clinically approved?
Sure. Well, Steve took you through a little bit of the data, obviously not very deep, but we've generated a lot of information now in patients with HCM about how ejection fraction changes with dosing of aficamten. And, as we intended when we engineered the drug, the change in ejection fraction is relatively predictable. It is, reversible when you change dose, and when you look at the conservative strategy we employed initially, which was echoes every three months, very few, you know, less than 1% of the echocardiograms that we were getting had any clinical impact.
So when you look deeper into that, you also notice that in those very few cases where the ejection fraction fell below 50%, pretty much the patients who you would think would be subject to that possibility, and those are the patients whose ejection fractions were pretty low once they reached target dose. You know, 50, 52, 54, you know, so. And probably a lot of it is, frankly, just variability. And so, in thinking about this, you know, we proposed a strategy of decreasing the frequency of ejection fractions to every six months, based on a deep analysis of the data. But also saying, you know, patients having a low ejection fraction below 55, that we would you could monitor them more frequently until you were satisfied that they basically had reached steady state.
We presented those analyses to FDA in detail at some of the meetings we had with them earlier this year as part of our pre-NDA, a set of meetings. And essentially, they agreed with us in terms of our approach to modifying FOREST-HCM to reduce the frequency of echoes and also to increase the flexibility of dose titration. You know, there was some, I think, misperception that because we uptitrate drug every two weeks, that it has to be uptitrated every two weeks. Doesn't really. It can be uptitrated within a window of time and as might be convenient for the patient and the physician. So, that's now what's being implemented in all sites that are involved in FOREST-HCM.
You know, I think that was an opportunity, if you will, to preface our strategy for what we hope will ultimately be the way the drug is used in the clinic.
All right. Perfect. Thank you so much to all three of you. I'm gonna hand over to my friend and colleague, Dr. Jacoby, who's going to take us through the next section of the presentation.
Hi, good morning, everybody. It's nice to see some familiar faces out here. We'll just plow right ahead here. So I'm gonna go through a couple of slides here, and then we'll get to some further conversation with our panelists. Much of this data you're familiar with, but let me go over it quickly again.
...Here we have the secondary and exploratory endpoints from the SEQUOIA-HCM study. On the left-hand part of the slide here, you can see the greater than or equal to one class improvement in New York Heart Association, achieved by 58% of patients on aficamten by week 24. And similarly, symptom improvement was seen as expressed by the KCCQ overall summary score here, and the Seattle Angina Questionnaire, which measures chest pain, chest pressure, angina-type symptoms. The mean difference between aficamten and placebo was approximately eight points for both of those, with a large minority of patients, 30% or so, achieving very substantial or very large improvements, which represents a massive improvement in symptoms.
Here we show the significant improvement in exercise capacity and symptoms in a composite responder endpoint of improvement in peak VO2 and NYHA, or significantly higher improvement in peak VO2 and no worsening in NYHA, and broken down by group, there you see below, with the overall common rate difference versus placebo of approximately 30%, which breaks down to a number needed to treat of about three to achieve this endpoint. Improvements in biomarkers mirror these improvements in symptoms, with an 80% proportional reduction from baseline to week 24 in NT-proBNP, but that doesn't really tell you the whole story, because you can see the improvement in NT-proBNP begins very early, as early as 2 weeks, and similarly with troponin, which achieves ultimately a 43% reduction, relative reduction in, level over the course of the study.
Again, achieved during predominantly during the titration period, and then stable and durable out to week 24, with a return to baseline after just a 4 week washout period, which is really an important factor that's already been touched on this morning, this, this reversibility. These findings that I've just discussed with you are mirrored in the open label long-term extension study. As you will note, there are 48 weeks of follow-up here, but as has been mentioned already, we are now up to 3 years of follow-up with similar findings, with substantial improvements in KCCQ, NYHA, and NT-proBNP. With, as you can see, very high proportions of patients achieving very substantial symptom improvement, 30% achieving a greater than 10-point increase in KCCQ, for example. Let's now turn to discussion of these with our panelists, and I'm gonna start off by focusing on biomarkers here.
So with these large reductions in NT-pro and troponin, it can be a complicated thing. How do we interpret these? How does this, what does this mean to you as clinical HCM doctors when you see a patient? How do you discuss this? I'll turn to Dr. Weiner first.
Yeah, I mean, first, I just have to say that you show these graphs, and you see this, you know, very large decrease in proBNP. You know, outside of CMI, you just don't see that. I mean, we now take this for granted that you see these data, and you say, yes, proBNP goes down, it washes out, it comes back up when you stop the aficamten. I mean, that really is unbelievable, you know, at the science level, in terms of saying, well, are we favorably remodeling the HCM heart? We have other markers that go along with that, echo markers, left atrial volume, mass, index, E/E' diastology.
So it all travels together, and it all underscores the fact that we're modifying. We think we're modifying this disease at the level of the sarcomere, and what that does for the patient is that they feel better. And you look at all these outcomes and everything, you know, the company keeps. It all goes in the same direction. So, you know, for us, as people involved in research, yes, the science really is clear, but for the patient is when you see that drop in proBNP from 800 to 100, what does that mean? That means they're getting their life back.
Whenever I first see an obstructive HCM patient, when I start the conversation, the question I ask them is, "When's the last time you felt normal?" And I'm usually met with a blank stare because patients don't even know what normal is. They can't remember the last time they felt normal. They've accommodated their lifestyle to avoid symptoms because the existing or historical standard of care was not really that helpful. And when you see these numbers, what that means is that patients feel normal again, and it's pretty powerful.
Thanks for that. Dr. Harper, we were talking yesterday. You mentioned that you have a routine of checking NT-proBNP.
In your clinical practice. Why do you do that? How does this data reflect on the fact that you're already doing that in your clinical practice?
Yeah. So biomarkers like NT-proBNP and troponin are prognostic markers in HCM. They give us an insight into how far advanced patient's HCM is, and we follow that over time as another measure of their clinical health, beyond what they're just saying to us as far as how they feel and what the obstruction or non-obstruction is. And as Dr., as Jeff was saying, when the obstruction falls when it's a beta blocker or a calcium channel blocker, we don't see these profound changes. So it again speaks to the fact that it's affecting the cardiomyopathy-
Mm-hmm
At the level of the sarcomere, and it's not just a reflection of the obstruction.
Okay. Okay, appreciate that point. So, with Sequoia and Forest together, we saw actually very significant improvements in KCCQ across both studies, across the placebo-controlled study, across the long-term extension. It really is a great tool for assessing symptoms in clinical trials, but we all know that, you know, in general, people don't check KCCQ in their clinical practices. So the challenge here is, can we put these findings into a more clinical context? Is there a way to think about what do these changes that you saw mean? And again, I'll turn to Dr. Weiner first to give his perspective here.
Sure. So I mean, the KCCQ, a great tool, it's been validated. Sometimes you don't necessarily have the time to implement that in the clinic setting. Up in Washington Heights, where we are at Columbia University Medical Center, there's a hill that patients have to walk up to get into the hospital building, and that's kind of our easy KCCQ, that you know, patients when they first see you, they say, "I couldn't walk up that hill. I had to stop ten times," and now they kind of pass right through, have to wait at security, get through everything, and then take the elevator up, but that's our way of kind of operationalizing this on a day-to-day level and saying that, again, that patient's getting that quality of life back.
So the KCCQ is a great tool, but there are so many stories that are consistent with that improvement that we saw in the aficamten trials.
I just wanna say that when I was a fellow at Columbia, I did bike up that hill every day. Thanks so much. And so, Dr. Harper, what have you observed in your practice with regard to can you translate for us, you know, this eight-point change or this 30% of patients who are achieving, you know, a twenty-point change in KCCQ? What does that mean clinically for you?
Yeah. So a clinically meaningful KCCQ change of about five, say five to 10, that in my clinical practice translates from that patient who needed help walking, you know, walking up the across the sky bridge and up a flight of stairs to our cardiology clinic, to being able to walk in. This is somebody who's saying, "I can't keep up with my grandkids. I wanna walk with my husband, but he says I'm too slow, and I'm huffing and puffing and stopping," to being able to not think about their heart and their limitations, and being able to do all of the activities that they want to do without their heart and having to stop or catch their breath, being on their mind all the time.
Okay, and maybe I'm gonna ask you, Fady, since you're an interventional cardiologist, you've dealt with a lot of angina over the years. Can you help us understand the change in the SAQ-7 that we're also seeing?
Yeah, I mean, just like breathlessness can be a limiting symptom, the chest pain that people get with HCM can be very much a limiting symptom. It provokes anxiety, right? I mean, you have this pressure in your chest, you don't know where it's gonna lead to. And we saw that obviously with people that have coronary artery disease, while, you know, in that case, the interventions, they, profoundly improve angina because you are relieving the obstruction. You know, in the case of HCM, the muscle is just ischemic because of its hypertrophy and the improvement in the, the Seattle Angina Questionnaire, is almost of the same magnitude, and probably is the same magnitude, as that we see with, you know, an intervention in PCI so-
Wow, that's powerful!
Again, it takes a real burden off the patients and their ability to just not have that anxiety as they exercise and work themselves.
Okay. Yeah, thanks a lot. So okay, so the last question here, last topic here. Let's talk about NHCM. I didn't show any slides on NHCM, but as everybody knows, the primary endpoint for our pivotal phase 3 ACACIA study is actually KCCQ. So the best question here is, you know, well, how might these results that we're seeing in Sequoia read on the potential effect for a non-obstructive patient? And is there... Well, I'll save the second part for- let me hold off on the second part. Let's just ask that first question. Do these results from Sequoia kind of have bearing on, you know, how we should expect to see the effect in NHCM? And Dr. Harper, you wanna weigh in on that?
Yeah. I mean, NHCM is a really difficult diagnosis to treat because they have these symptoms and there's not a lot else out there, outside of patients for transplant until now, and when we're treating patients, what they come to you with is shortness of breath, effect on their quality of life, this heart failure, and to be able to treat that, and that's what the KCCQ measures: how much better are patients feeling? What is their quality of life? That's really the crux of the issue, and so to have a therapy available to help them feel better rapidly and with a in a sustained fashion, is really what this is all about and what drives most patients to come into a clinical practice to seek care.
Be it angina or shortness of breath, it's what most people see a cardiologist for, and until now, we've been very limited in this particular patient population.
Okay, so if I hear you right, what you're saying is, you know, patients don't know N or O, they just know their symptoms.
Exactly.
Therefore, they should be able to report out those symptoms equivalently.
Absolutely.
Okay, great. Thank you so much. And so, Dr. Weiner, you know, can you translate what we're seeing with Sequoia at all into the world of NHCM and Acacia in anticipation of the results from that study?
Yeah, no, I absolutely think you can. Just to underscore what was said, patients don't feel gradients, they feel symptoms. And if you look at the, you know, the mechanism of action of aficamten, in terms of improved relaxation, I mean, there's biologic plausibility, that it'll be effective in that patient population. And yes, improving symptoms is why we're giving people medication, and using that as an outcome is very, very relevant.
Okay, well, thanks a lot. We just hit zero, zero, zero on our time, so we're perfect, and thank you so much for your expertise and discussion.
Thank you.
Thanks for joining us.
Thank you.
... I'm gonna hand this over to Dan Kates.
Good morning, everyone. I'm very pleased to be here this morning and to be able to represent the medical affairs function at Cytokinetics, and to shed some light on the important role that medical affairs plays in the transition of aficamten from clinical development to clinical practice. For those of you who may not be as familiar with the medical affairs organization, we are primarily comprised of physicians, pharmacists, and nurses. We sit on the R&D side of the company, but we very much are at sort of a crossroads. We help bridge the gap between the R&D side and the commercial side of the company, and between the R&D and the G&A side of the company. While medical affairs has an internal-facing role, where we really deliver importance is in the external-facing role that we play.
We have different field-facing parts of our organization. We routinely meet with healthcare professionals, medical societies, patient advocacy groups, and patients. We are very much a global organization. We have staff on the ground in both the US and in Europe. I wanna focus a little bit today on our two field-based US teams. We have two different field-based medical science liaison or MSL teams in the US. We have our therapeutic MSL team. This team is primarily focused on prescribers and treaters, so they are focused on physicians, pharmacists, nurses, and mid-level practitioners. This group is primarily comprised of doctorate-level pharmacists. It's a very experienced group. On average, our therapeutic MSLs have about 20 years experience in industry, mostly in medical affairs, and most of that in the cardiovascular space.
The second team that we have is the managed healthcare, MSL team. This team focuses primarily on payers and decision-makers, so they are routinely meeting with medical directors, pharmacy directors, and other individuals who are involved in population-based decision making. This team is also comprised primarily of PharmDs, all of whom come from a clinical patient background, as well as the managed care side, and then eventually moved over into industry. And I think most importantly on this slide, you see that in aggregate, this group has launched fifty-eight drugs over the course of their career, so they bring a tremendous amount of launch experience to the aficamten launch. So changing gears here a bit, I wanna talk about another role that medical affairs plays, and that's in helping to support our publication efforts.
After a very successful phase I and phase II program, we've been more recently, of course, focused on our phase III program, with SEQUOIA-HCM being the pivotal trial there, and that has culminated this year, as many of you may know, in the publication of the primary trial results for SEQUOIA-HCM in The New England Journal of Medicine. We are shifting our focus a bit now towards the FOREST-HCM trial. As was mentioned, we've already begun to present and publish data from FOREST, and of course, that is our open-label extension trial for aficamten. We're very excited looking forward to next year, where we will start to present and publish the first results of the MAPLE-HCM trial. MAPLE-HCM being the head-to-head trial of aficamten to metoprolol, metoprolol representing the beta blocker class of drugs.
Medical affairs also plays a very important role in supporting continuing medical education. We do this by providing independent medical education grants to external parties who support these types of activities. You can see on the slide here just some examples over the last twelve months of CME activities that we've supported by providing grants both in the U.S. and in Europe, and we will continue to provide grants to these important activities moving forward. We're also very proud at Cytokinetics of our association with the Hypertrophic Cardiomyopathy Society. Prior to three years ago, there was no medical society dedicated solely to hypertrophic cardiomyopathy.
Cytokinetics played an important role in sitting down with various stakeholders who had an interest in developing a medical society, and ultimately, we ended up providing a founder's grant so that they were able to get operations up and running. Just a few weeks ago, they executed their third annual scientific congress. Each year it has gotten bigger and better than before, and as I said, we're very proud of that relationship, and we will continue to support the efforts of the HCM Society. And then on my last slide here, I just wanna mention that our commitment to aficamten clinical research does not end with our phase III program. We already have plans underway and are developing our ongoing research platform. That can take many different shapes and forms.
It could potentially be additional phase IV clinical trials. It could be collaborative research. We already have existing collaborative partnerships with several external, independent, academic research centers, and we'll continue to evolve that. We're excited to expand our investigator-sponsored study program. This is basically where we provide support to independent external investigators who are interested in doing ongoing clinical research with aficamten. And then lastly, I wanna mention the importance of real-world evidence. It's obviously very important for us to demonstrate the safety and efficacy of aficamten in well-controlled clinical trials. It's also very important that we demonstrate the safety and efficacy of aficamten in the real-world setting. So we already have relationships with two important patient registries, as you see on screen there, the SHARE Registry and the HCM Registry.
These are both independent, multinational, academic patient registries, and we will continue to look for other opportunities to explore other channels for us to develop further real-world evidence. So, I think you can see that medical affairs plays a very important role in this transition of aficamten from clinical development to clinical practice, whether it's in our key opinion leader engagement or ensuring seamless access to our scientific data. We've built a very strong foundation, and we think that this will certainly provide tremendous benefit to both healthcare professionals and patients moving forward. And so with that, I will turn things over to Andrew Callos, who is going to be discussing building a specialty cardiology franchise.
Good morning, everyone. Great to see a lot of familiar faces. So, in this section, members of the commercial leadership team and I will walk through our aficamten launch preparation in the U.S. and Europe. But I'm going to first start by defining what we mean by specialty cardiology franchise as well as the approach, rationale, and strategy. I know you've heard that term a lot today. And then provide an overview of the systematic and disciplined approach we're using for the aficamten launch, and I'll end with kind of the market sizing and opportunity in HCM. So you can see from this slide, over the next five years, we have the potential for four launches across three distinct patient populations and two products.
The element of multiple products is core, and a shared customer base are core to a franchise strategy. Also core are shared resources, a shared commercial infrastructure, shared FTEs and headquarters, shared customer-facing colleagues, a medical organization, a sales organization, account managers who focus on payers. All of these things are shared in a franchise strategy in that common customer base. This gives the potential to provide, you know, enhanced value to customers, enhanced value to patients and shareholders overall. You can see in the last row here, the potential for a fifth product launch in HFpEF in the early twenty-thirties. So there's a lot of financial, physician and stakeholder benefits to a franchise strategy versus a single product. So let me talk a little bit about business models and what we mean by specialty cardiology.
So there's a lot of business models in pharmaceuticals. I think buy and build versus oncology, versus vaccines, ultra orphan. These are all different, different price points and different resources. You think about a primary care business model, which many cardiology products are in, think cholesterol, blood thinners, the first-line heart failure. These things require a lot of resources, large field forces, competitive with payers, large rebates. Generally, the patients are known and diagnosed as compared to a specialty. So if I walk through this slide, I think a key element really is finding the right physicians because there's a subset of them, a focused distribution model, finding patients, and the ability to find patients over time also fuels growth and awareness. And I think you've seen this in new product launch.
Having a seamless customer experience, as well as, you know, a distribution model. So if you look at the first quadrant here, there's about 35,000 cardiologists in the U.S. If you're in, you know, large scale or primary care-driven cardiology, you probably have a field force calling on 70,000, 80,000, 90,000 physicians. HCM, as an example, we're going to focus on 10,000 physicians, and you'll hear more about that later. In terms of revenue per prescriber, generally, these the general cardiology products are under $10,000 list price in the U.S. As an example, the Camzyos on the market now is over nearly $100,000. So a lot less physicians, a lot higher price, and obviously, finding those right physicians and right patients is critical.
The diagnosis I've described, we believe that the true prevalence as compared to diagnosed prevalence, it's about 25% or 30%, that HCM is diagnosed, and you compare that to general cardiology. So finding patients and generating awareness is key. If I go to the patient experience, you can see diagnosis, treatment, education. General cardiology usually focuses on copay and financial assistance, where it's really important to have a differentiated patient experience in a specialty cardiology model. You know, think about, you know, a call center offering copay is really what you would see in general cardiology, but in specialty cardiology, the path to treatment can sometimes be long.
Usually, you'll have a patient-focused colleague called a nurse navigator that really is the point of support for an education path to treatment, emotional support. That moment of diagnosis or considering a treatment is really a big... You know, it's really a big emotional moment for a patient and having someone walk you through that as a nurse navigator, because in a rare disease, it's often difficult to find the physicians who can help you or other patients who share a similar experience. So having a role like that is really critical to the patient experience. Last element is a path to reimbursement. General cardiology, they pick winners and losers. The payers will have products competing against each other.
Rebates go high as compared to general cardiology, where access is usually open, it's not competitive, and payers. We're educating payers on that, and generally, the access is based on the label. So if you're appropriate use based on the label, then you usually get reimbursement. You'll hear more about reimbursement and that from Sunil Karnawat, our VP of Customer Experience. So, you know, the benefits of a cardiology franchise really are across these four quadrants: financial, operational, customer experience, and efficiency. From a financial point of view, obviously, I talked about the shared resources, really, that equates to reduced operating cost both at headquarters as well as across the field base. From an operational point of view, we're really designing-...
Every territory to be custom to where the customers are, then finding those right customers are critical. We have one rep per territory, so there's no overlap. Every rep is a CEO, if you will, of their individual geography. So there's really clear accountability and real clear ownership from a customer point of view, if you will, and no coordination across multiple reps. That obviously increases customer experience. A single point of contact allows a representative to establish a longer-term relationship, follow up on ownership, provide support, provide more value, and there's no, when you go into a customer saying, "Well, somebody from your company was just here." So you'll get that certainly when you have a larger model.
From an efficiency point of view, you can discuss multiple products on every call, and from a customer list, you'll start to expand your customer list a little bit within cardiology, and you'll start to HCM physicians, sometimes treat heart failure and vice versa, so you'll actually pick up more value over time. So a franchise makes us much more accountable, more efficient, less costly, while enhancing value to Cytokinetics, ACP, and shareholders. The leadership team, the commercial leadership team, who is leading the Cytokinetics Specialty Cardiology Franchise initial launch, has really deep expertise across a mix of Big Pharma and biotech. You can see them on the slide there, across business models, across therapeutic areas, across geographies, with nearly 30 years of experience on average.
The team has expertise and learnings across nearly 50 launches, and we often draw on this in references in our discussion and as we're planning on commercializing aficamten. This team represents nearly 80-plus commercial colleagues across the US and Europe and growing, that has knowledge and experience in what it takes to launch a product in the US and the EU, because the vast majority have launched one or multiple products. Launches are challenges, require time, adjustment. The commercial leadership team spent a lot of time together, kind of in the trenches, if you will, building trust, building camaraderie, and I have a tremendous amount of confidence and trust that this team is the right team to launch our cardiovascular franchise, given the passion and fit the culture and experience.
And you'll be hearing nearly from all the senior Cytokinetics commercial leaders over the next 40 minutes. This team is really combining the expertise that I described with a very formal and rigorous program and project management for both our infrastructure and our launch readiness. You can see here just a couple of screenshots of extensive project plans, clear points of accountability, steps, dependencies, timelines, all the classical things you'd see in project management, formal governance process. But this disciplined approach really enables us to make sure that we're sticking to timeline. We can bring in external experts for validation, especially for highly specialized area. And, you know, we know we're very confident and on the path to launch, really due to this collaboration.
We report issues, we're very transparent about it, and that's kind of the culture that we live in. We're hitting milestones, we're solving issues, and we will be ready for launch, if approved, next year. From a milestone point of view, I won't go through these. Obviously, we just started the fourth quarter, but you're going to hear about the market development campaign, from John Giacoppi, our VP of Marketing. In a few minutes, you'll hear about sales planning from Jeff Lotz, our VP of Sales and Sales Ops. I've already talked about, you know, Sunil and Jeanne Dubuc will talk about our customer experience and how important that is. Jeanne is our VP of Customer Experience and Insights. We're doing this in a very cost-efficient way. Most of our...
The pie chart you see, most of our headcount actually occurs in proximity to launch. Once launch is de-risked, we're confident where we're getting the label, we'll hire our field force. It's about 125 to 150 in the U.S., similar number in Europe, maybe slightly smaller. The activities and really that equate to cost, you can see over to the right. Most of the big spend associated with launch is media purchases and patient support. As I kind of outlined earlier, this is specialty cardiology. These aren't large spends overall anyway, but we are taking it very seriously and gating them to these regulatory events. You know, the customer-facing colleagues are obviously the way that most payers and physicians will start to get to learn who Cytokinetics is.
So it's really important that we pick people that is gonna introduce Cytokinetics, because that's exactly how these physicians will understand who we are. The experienced colleagues, and you can see this on the left, the payer account team, they're the ones who actually talk to the key payers, both regional and national. To the right are our sales leaders. But picking the right people, making sure these people are good stewards of our science, of our culture, and represent with established experience and relationships that really can accelerate that ability to trust. And this is what we've done with the team that we have in place. We have our payer account management team. They're talking to payers. You'll hear more about that.
We have our first-line field managers, and, you know, they're the team that's actually going to be hiring the reps. So in summary, we have the science, we have the expertise, we have the relationships, we have a very disciplined process, we have the people and the resources to successfully launch our specialty cardiology franchise, starting with aficamten in twenty twenty-five, if we get approved. In terms of market opportunity. This is the US, Europe is very similar. The blue in the middle is really overall HCM true prevalence, not all that prevalence is diagnosed. If you kind of go through the layers of circles, if you will, the outer layer is the, what is suspected to be the true prevalence of both OHCM and NHCM. NHCM is growing at a much higher rate.
These will maybe get to a 50/50 split over time. The diagnosis, that middle circle, 200 in OHCM, 100 in NHCM, and it's about, you know, 40%-60% of 40% in the NHCM, OHCM that would be appropriate for treatment, meaning they're New York Heart Association class two, three, and symptomatic. This number is growing, you know, about five times the overall. So the diagnosed into the undiagnosed is growing about five times the rate of population. These patients are treated. So you can see over here, over 90% of these patients who are diagnosed are treated. The vast majority are on beta blockers and calcium channel blockers. We expect when we come to market, that at least 80%, if not more, of the Camzyos market for eligible patients will be available.
So the key is for us to activate patients and activate physicians on a disease-modifying Camzyos on top of beta blockers and maybe even instead of beta blockers, post MAPLE. Last slide I have is. So if you take the around 300,000 plus for the US, three hundred thousand for Europe or so, this number is growing at about 25,000 patients per year. That's around the number you get in the US and EU in terms of number of patients, you see in blue. Those that are symptomatic and considered appropriate for treatment for a Camzyos is probably a little over half of that number, and those that could use, really, how many of those patients actually penetrate and use Camzyos.
If you consider the price point in the US is $100,000 and probably growing at CPI, the price point in Europe, list price is around 15%-20%. You can get to a market sizing, if you get into the penetration rates, around 50% or above a $10 billion market in the US and Europe. So a very, very large market, a reasonable amount of resources required, and we certainly feel like we have the ability, knowledge to be able to do very well, both in the Camzyos market as well as in the specialty cardiology market. So with that, I'm gonna turn it over to our VP of Marketing for aficamten, John Giacoppi.
Thank you, Andrew, and good morning, everybody here in New York, as well as those of you here virtually with us. I'm excited to provide an update on the U.S. preparations for the aficamten launch in 2025. I'm really proud to be part of an exceptional team of experienced cross-functional leaders who are laser-focused on its successful aficamten launch. Before I dig in, though, I wanted to start the way we start many of our internal aficamten launch team meetings, and that's with the voice of someone who suffers from HCM.
My name is Eric, and I'm 47 years old. I was diagnosed with HCM in 2023. I finally felt heard. I finally felt like I was being taken seriously, and that something was actually wrong. This discovery that knowing something is wrong, while challenging in its own right, is powerful, you know. It's being able to put a face to a name, being able to understand symptoms and what they really have been, and understanding how they play out in my life.
As you heard from Eric, there's a journey to HCM diagnosis. And as you heard from some of the clinicians today, everybody's journey is different. Our goal, our brand vision, is to elevate the standard of care in HCM treatment. Whether you're a patient, whether you're a loved one, we feel that for us, it's really important for us to help the patient in a holistic fashion. And you'll see today, as I go through, we're doing a lot of things even prior to our branded launch, to make sure that we're doing right by the HCM community. When I spoke, actually, a year ago at the investor meeting, we showed a slide that talked about learn, design, and build. And really, twenty twenty-three was focused on learning. We were doing a lot of marketplace insight gathering.
We were talking to a lot of patients, really understanding HCM, to make sure that we can launch aficamten differently and uniquely. The year 2024 has really been all about design, and you're gonna hear from my colleagues, Jeff and Jeanne, and Sunil, about what we're doing today to prepare for a launch for aficamten. But ultimately, you know, it comes back to. We're not done learning. We continue to go back to the marketplace and better understand the opportunity that we have for aficamten. We've recently completed a demand study that really shows that not only will aficamten do very well in the market in terms of share, but the launch of aficamten will also expand the Camzyos market to more patients, to more clinicians, and we think that's critically important. The other thing that we continue to hear is the unmet need is real.
The unmet need for physicians and the unmet need for patients continues to exist in this marketplace, even though there is a Camzyos on the market, and lastly, our timing is very opportune. We constantly hear that having a Camzyos on the market has actually grown a comfort level, and there are many HCPs who have sat on the sideline, and they're waiting to enter the Camzyos market, but they're really looking for a product like aficamten to expand their comfort level with writing a Camzyos. We have a very unique opportunity to not only launch aficamten in twenty twenty-five, but we really have a unique opportunity to show potential customers who we are as Cytokinetics.
What you see here is the objective for our market development campaign, and it's really to help show the holistic impact of HCM for all treaters, and really, more importantly, how we as Cytokinetics are gonna do this differently, how we're gonna go to the market differently. Really critically important. So without further ado, I'd like to show you our new campaign. HCM is so much more than a problem with my heart. It's my loneliness. It's looking healthy on the outside. It's the years of searching for an answer. At Cytokinetics, we believe HCM is not just a heart problem, it's a human problem. This is Eric. He is one of five ambassadors that we're working with on this campaign. And as you heard from Eric before, everybody's journey is unique.
What we're really proud of is this campaign embodies all of the values of Cytokinetics as an organization, but it's also crafted with real patients, real quotes, and real stories, which we think is critically important to separating us from some of big pharma within this industry. It's not just about an ad, though. This campaign, HCM Beyond the Heart, has already launched. We launched in preparation for HFSA. There is a website, hcmbeyondtheheart.com, that you can go to right now to check it out. But there are multiple channels that we are rolling this campaign out, so that we can hit multiple potential HCM treaters and ultimately make sure that people understand who we are as Cytokinetics and how we're gonna be entering the HCM market. But with that, I'd like to turn it over to Jeff Lotz.
Thanks, John. Good morning. I'm very excited to be able to be here today to talk a little bit about our sales build-out. What I'm gonna cover is how we are defining our customer universe, how we plan to align our sales team to those customers, the structure that we'll launch with, and then also talk about how we're gonna evolve with the specialty cardiology franchise. There's two themes that you'll hear. One is we're building with the efficiency of our investment in mind, and also with creating a differentiated customer experience.
We have an incredibly unique opportunity that we don't have an existing sales structure that we have to fit aficamten or fit a portfolio into, which is, you know, so often the case in pharma launches, and even the situation with our primary competitor, so we're gonna take advantage of that situation with extreme focus, again, on efficiency and customer experience, so this is how we define our universe. Andrew talked about 10,000 HCPs, mostly cardiologists, that diagnose and treat HCM. We've used diagnosis and treatment claims to understand the patient flow in the marketplace, and there's about 35,000 cardiologists that touch an HCM patient at some point in their journey, but the vast majority of those patients, 75% of them, are diagnosed and treated by 10,000 cardiologists.
So that requires a team of about 125 to 150 account specialists to cover that universe. So you can see the concentration curve, here on the left. It just shows how focused and how concentrated this marketplace is from a diagnosis and treatment perspective, and then where these physicians and treatment centers are around the U.S. Highly concentrated on the right half of the country, as well as up the West Coast, and this really helps with our deployment and our alignment so that we can be extremely efficient and not, you know, waste investment in white space. So from a structure standpoint, as Andrew mentioned, we're building our structure to have single point of accountability, and that's the model on the right. One person responsible for every customer.
So the sales colleague pictured here is the CV account specialist. That person will be 100% accountable for the physician's journey and the physician's office staff, their journey with aficamten. Genie is gonna talk to you about how she's working on creating a differentiated patient experience, and she'll have a team of people that work directly with the patients, again, having single point of accountability for the patient journey. That's much different than what traditional pharma deals with, or even our primary competitor in this space, which is more of a model on the left, where there's a lot of inefficiency, and customers have told us that the model is overwhelming.
They don't know who to talk to, depending on the issue that they're dealing with, or their patients are confused or waste a lot of time on the phone, trying to coordinate care across multiple, people at those companies. Our ability to do this from scratch creates a significant competitive advantage in creating that differentiated journey and differentiated experience, and also allows us to use our investment efficiently. Andrew mentioned that the sales team, the sales leadership team, is in place. We are ready. We're ready for launch. We are far along in our launch preparation. I just wanted to highlight a few things here. I mean, I already told you that we built the customer list. We've already done our alignments. We know where our representatives are gonna be, what territories they're gonna be in.
We've done a bunch of training on HCM and the treatment landscape. We have two preceptorships set up with two of the top centers of excellence in the country to further our learning. One of the things that we've been doing with the leadership team is building account-level launch plans, and one of the reasons why that's so significant is because often, pharma companies wait until reps are in place, and until they have approval, to go out and learn about accounts and build those plans. We're doing that now, so we've taken a look at the top accounts across the country. We've defined who the opinion leaders are in those accounts, who the prescribers are in those accounts, who the sonographers are in those accounts, who are the office managers in those accounts? Who are the payers?
What's the treatment journey look like for a patient in those accounts? So we'll have all, all of that planned and ready to be handed off when we hire the reps, which leads me to the next point. That's the next major milestone for us. We'll be staffing our team next year. We already have a partner identified. We have a little over seven hundred candidates in our database already. We've been extremely impressed with the outreach of experienced representatives in the cardiovascular space and in the launch space and in the rare disease space, and their desire to join our team. So we're well-positioned to staff up next year.
So the other thing that we're doing is we're building with the evolution of our pipeline in mind, and you can see here we've already analyzed who the prescribers are. In HFrEF and HFpEF, we've looked at the overlap. So when we build our alignments, and we talk about the growth of the team over time, we have the portfolio in mind, right from the start. And you can see here, we expect that there'll be somewhere around 18-19 thousand cardiology customers across the portfolio, which is about half of the cardiology universe, and is often, you know, in contrast to what other pharma companies may try to cover. So thank you so much for your time, and now I'll turn it over to Genie.
Thank you, Jeff, John, and Andrew. I'm Genie Dubuk. I'm the Vice President of our Customer Experience and Insights team. And it's great to be working with such an organization that is so patient-focused. You've heard a lot about that from John and Jeff and Andrew, and even from our R&D colleagues, and that pulls through in everything that we are doing as we are putting together our treatment experience, our patient support program. As we started to think about the type of patient support program we wanted to build, we first did our due diligence, and we spoke with clinicians and patients and stakeholders, and really wanted to get their experience with Camzyos and learn from them. We heard consistent themes that you see here on this slide. Healthcare providers and clinicians and nurses are frustrated. You've heard that a lot today.
They're frustrated with all the number of phone calls they have to return, the disconnected nature of the current process, the fact that no one individual knows what's happening with that patient once they're starting to initiate therapy. They're looking for answers, and they're getting transferred from multiple places to multiple individuals, and there's no connection between everyone, and the process is challenging for patients as well. Patients explain to us that they spend hours on the phone with their specialty pharmacies, trying to get their drug filled. They are trying to get to that one person who knows what's going on. They're trying to get answers, and they are frustrated and stressed, as you would imagine, when they're just trying to get their refill, and in many times, they may only have a day or two left on their therapy, and they're trying to expedite this.
There's no one there who really understands that full process. There's no one there that can explain to them what the next steps are, and they're looking for answers, and they aren't able to find them. So this feedback was consistent from all. The current Camzyos process is challenging, disconnected, and overwhelming. So as we look to build our treatment experience and our patient support program, we're considering those insights that we gathered from clinicians and patients and stakeholders, and we're creating a strategic framework that's built upon four key pillars. The first is that our support program needs to be knowledgeable and confident, and be able to provide patients with the motivation and the confidence for them to effectively manage their treatment... by approaching them with empathy, ensuring that their unique experiences are heard, validated, and respected.
Understanding that for some patients, they have waited years for a diagnosis, and for others, they may be very concerned on the impact on their family members, and we heard that many from the ambassadors that John's been working with, so they have these concerns, so we have to approach them and understand, and listen to them. Second, we have to create a positive and consistent experience for both patients and providers by offering relevant resources, answering questions, explaining the next steps to them, and helping to navigate the process using a humanistic, empowering, and personalized approach, listening to understand, not working a patient through a queue, but truly listening to them and helping to answer their questions. Third, we have to foster relationships while building these connections to enhance that overall experience.
Having a consistent nurse navigator, that one-to-one connection, that one person who is there with you throughout every phone call, that one person who's also connected to your clinician and your office. Someone who can be with you on the journey, someone who returns your phone calls as promised, engages with you as you would like them to engage with you. Someone who remembers the conversations that you had, and you don't need to repeat yourself every time you speak to a new person. When you call, you get Amy, and Amy's always your person, and Amy's talking to your clinician. So there's this connection and relationship built on trust. And fourth, we have to develop a flexible model that meets the unique needs of patients and healthcare providers by asking them to collaborate and build with us.
Each of the offices and patient needs are going to be different. We have to be flexible. We have to build in optionality. We need to meet everyone where they are and as they're moving along the journey. There's no one single pathway, and we need to understand that, and we need to build with them in this model that goes along with them and their journey, regardless of where their journey goes. So where are we in building this process? So I just talked about the conversations we've had, engaging with patients. We've also done extensive landscape assessments, trying to understand what are the best trends in patient support? Who are the best partners? What's the new technology? How do we simplify? How do we integrate? How do we connect? And bringing all those individuals together. We did a lot of conversations.
We have looked at reputations of individuals and partners. We wanted to make sure that whoever we bring in for specialty pharmacy, which you'll hear a little bit about from Sunil, to our co-pay programs, everyone has that same vision that we have, and they are focused on providing the best experience for that patient in an integrated, connected way. Our next steps are going to be a very detailed design build. And once again, we're gonna take that back to our patients and our clinicians, and we're gonna ask them: How are we doing? Does this meet your needs? What needs to change? And we're gonna build those refinements into the program, so that when we launch, we have a program that meets the needs of the patients and the clinicians throughout their journey. So finally, our critical success factors are very straightforward.
For healthcare providers, we have to minimize that administrative burden of Camzyos by connecting all those treatment requirements. For patients, we have to provide them with education and resources, and once again, bring all those partners together to minimize that burden and challenge on them. By doing this, we will successfully build a patient support program designed to provide a differentiated and elevated experience built by those and with those who know best. And with that, I will turn it over to Sunil.
Thanks, Genie. I'm going to take you through the market access journey and what we are doing to prepare the launch of aficamten. But before I do that, we have built an excellent team in market access at Cytokinetics. Many of the team members have come actually from the payer world, and many of us have twenty-plus years of experience launching product in the market access capacity. In my presentation today, I will cover three important topics. The first, I'll walk you through what we are learning with our interactions with the payer, and particularly, the implications of Inflation Reduction Act that is about to take place starting January first, and what is the implication of that for aficamten. Second, we'll describe how we are generating the value proposition when we are interacting with the payer, both on clinical side that we learn, but also on the health economic side.
Because when you talk to the payer, they want to convert the clinical endpoint into: What is the patient outcome? What is the cost offset? What is the health economic savings for the payer? So we'll walk through that. And third, I will talk to you about the tool we are building, which is a public tool online, that will help you understand the prevalence of the disease, the burden of the disease, and it will be in the public domain, and we'll talk a little bit about that. So we are in front of payers. As you know, with the FDAMA 114, FDA allows us to interact with the payer before the approval. So we are interacting with the payer, with the PIE Deck, we call it, Pre-Approval Information Exchange Deck.
We have built a value proposition based on the clinical data, and we are talking to the payers, and in the process, we are learning a lot in terms of how will they manage this particular category and the value of the aficamten for them. We are also in the middle of designing the distribution strategy, as Genie mentioned. We have selected the SP, the specialty pharmacies and specialty distributors. We'll have a very focused, narrow, limited network to make sure that we provide the superior customer service for our patients, and last but not least, with Jeannie's team, we are going to make sure that the sales team, the patient support services team, the account team, all are well-equipped to train and make sure that we support the HCPs and the patient on how to work on the prior authorization and medical exception process.
So let me walk you through what we are learning in the marketplace. As we talked to the payers over the last six months, what we are learning is that this is a rare disease, has a low prevalence, has a low budget impact. So for the most part, this is not on the payer's radar. As you know, they are busy with many other things, including the Inflation Reduction Act. But when we do talk to them, and when we do present them, the aficamten value proposition, they do appreciate that the peak VO2 is a well-established and objective clinical endpoint and predictor of clinical outcomes. They also think that as the product comes in the market, there will be more payer interest in this category.
With today's announcement of the NDA submission, I'm sure the payers are going to be very excited, and they would want to know when we get the PDUFA date. There will be more payer engagement with our account directors team. Last but not least, it's very important that payers, as the second product comes in the market, are very interested in indirect treatment comparison. Our team will be ready to make sure that we are providing that information to the payer. What I just told a minute ago, what is on payers' mind as we talk to them? Let me walk you through the implication of the Inflation Reduction Act on the payers. This is a hypothetical example of $12,000 WAC per month, $144,000 annual cost for the drug.
On the left-hand side, you see the pre-IRA implication, and on the right-hand side, you see the post-IRA implication. Clearly, if you notice, the risk is shifting. Pre-IRA, majority of the risk was taken by CMS. Post-IRA, the risk is shifting. As you can see, majority of the financial risk now is taken by the Medicare Part D plans and the manufacturer. You see, the patient maximum out-of-pocket cost has gone down from almost ten thousand in this example to two thousand. So naturally, we ask payer, "What does that mean to you?
What is the implication of that IRA shift?" When we talk to the payers, they are saying that, "Listen, given that we have to pay 60% of the product cost post-IRA, naturally, the specialty product are going to be not on the formulary." They will have a narrow formulary, and what they're saying is that, "We will cover this product, but through the medical exception process. So it will just create some hurdles for us to overcome." But it's important to understand, coverage and access is very important. Even if we are not covered, we still have access through the medical exception process. And what we have learned throughout this year, that number of these products are on the medical exception, but they are getting approved.
It just requires a lot more due diligence working with our team to educate the doctors, so we can remove these hurdles of the medical exception. Next, we talk to the payers about what could be potential prior authorization criteria for the Camzyos drugs. It's very simple. With the specialty drugs, with the rare diseases, most of the prior authorization will be consistent with the label. We have seen that in the past, and that's what we'll see also for aficamten. This is not new. We have seen many rare diseases where the prior authorization is consistent with the label. Now, it won't have any impact on the eligible patient population because prior authorization is simply a way to make sure that the right patient gets the drug. Now, in the commercial space, we'll have a prior authorization. In the Medicare space, we'll have the medical exception.
Now, why Medicare is important? We think almost 50% of the business will come from Medicare, given the demographics of the population. So it's very important that we continue to educate our team to make sure that they are supporting the offices, so our patient support services, on supporting the prior authorization for commercial payers and medical exceptions for the Medicare payers. So let me switch gear on talking about what are payers asking for. So we heard quite a bit today from our doctors that peak VO2, LVOT gradient, NYHA functional class, KCCQ, really important clinical endpoint. But when it comes to payers... They want to know, convert that to me in health savings. Convert that to me in economic savings. What does that mean to me as a plan? If the patient see the improvement, what is the economic saving for me in the payer?
We are building number of tools to make sure that we are addressing these questions with the payers. We are publishing a number of data points, and we are building the models to address these concerns of the payer. The other important thing, particularly we hear in Europe and in HTA bodies, is the indirect comparison. So when the two drugs are in the market, naturally, payer wants to know which one is better. So we are building the statistical models to demonstrate various ways you can do the indirect comparison of the drugs in the market. And we are also engaging the HTA bodies for the early scientific advice, so we understand exactly what are the inputs important, what kind of modeling is needed, and how are they going to assess the Camzyos class?
Let me quickly talk about the substantial amount of publications we have done this year to address the health economics need for the payers. These publications range from looking at the patient characteristics, the burden of disease, medical burden, pharmacy burden, talking about the different payer types and what is the cost associated with different payer types. We recently published a very good article on implication of higher peak VO2, which predicts fewer adverse events and mortality in cardiovascular patients, supporting its use as a surrogate endpoint in OHCM and economic models. So with that, let me go to my final slide. I. As I mentioned before, we are going to unveil this tool. This is a public online tool which will show...
It's a website-driven, where you can enter the information, and it will show the prevalence of HCM, the disease burden, the treatment paradigm, the disparities in the HCM. It's a real, sort of a online tool with a real-world data that will be updated regularly, and it will be available to the public. So, for example, if somebody wants to know, "Hey, what is the HCM prevalence in California?" You can go into this tool, and you will have that information. So it's a tool that we are going to unveil in Q4, and we'll definitely make it available on our website. So in, conclusion, I want to just remind you the three important things that, from this presentation.
The first and foremost, that we are talking to the payers, and what we are learning is that the IRA is a major impact for the Medicare population going into next year. We do expect a lot more payer engagement once we get the PDUFA date. And then last but not least, we are building tools to address the health economic needs of the payers to make sure that we are looking at the LVOT, peak VO2, NYHA functional class, and connecting those to the health economics outcome. So with that, I'm very excited about the payer launch of aficamten, and I'm going to bring now Joseph to talk about our launch readiness in Europe.
Thank you, Sunil. Good morning, everyone. I'm excited to be here with you to share with you some of the insights we've been gathering in Europe on our understanding of how OHCM patients are managed in Europe, and share with you some of the progress we've been seeing towards our commercialization for aficamten in Europe. Our initial focus will be on EU5. This is where the biggest opportunity resides. We will be setting up entities, we will be recruiting senior managerial role in those EU5 countries, with the plan to expand beyond EU5 towards EU 18 in the coming three years. We will be gating our investment decisions based on pricing and reimbursement, positive outcomes. I'm happy to report that we have just established our German entity out of Munich, with a general manager and a medical director.
We will be concentrating all of our supporting functions out of our European headquarters in Zug, Switzerland. In Zug, we have been fortunate enough to recruit highly experienced, talented people in market access, regulatory, medical affairs positions with a broad experience in orphan, non-orphan disease. Most of them have significant cardiology experience, and most importantly is their ability to design market access strategies, execute on them, and getting successful outcomes. They have a proven track record of securing pricing and reimbursement for multiple drug launches in Europe. In the last 12-15 months, we've been setting up our distribution blueprint in Europe.
We've started building up our quality systems and all the SOPs needed for our importation license, and I'm happy to report that the German team has been doing a fantastic job connecting with most of the OHCM expert centers in Germany, gathering insights, talking about unmet needs, and more importantly, started writing the pricing and reimbursement dossier. So when it comes to Europe, market access, it can be complex and challenging. And to that intent, we have launched several work streams to be able to go and understand what are the unmet needs. Are there any data gaps in our data sets? How to mitigate them. What are the value driver? How we're gonna build our value dossier.
We've been doing market research, we've been doing advisory boards with payers, ex-payers, and experts in order to assess what would be the willingness to pay for our drug when, when we are ready. So when all these work streams will finish, we'll be able to determine our EU launch sequence and our pricing strategy. On top of that, we've been doing market research, trying to understand how the market is structured in EU5. It wasn't surprising to see that right now, as we speak, the market is quite concentrated in countries like the UK and Spain. Less concentrated, on the other hand, in Germany, where we see a mix of OHCM expert centers treating those patients, and a good proportion of office-based cardiologists organized in polyclinics, starting to treating OHCM patients.
We start asking also those, initial Camzyos prescribers about the challenges they've been facing so far in their prescription patterns, and it came as no surprise that genotyping, the requirement for genotyping testing, the echo appointments, the echo slots availability, can be challenging. In some countries, it might take up to six weeks to find a echography appointment, and most importantly, they were mentioning the overall burden, so most of the multidisciplinary teams that are treating OHCM are overwhelmed by the admin, support required. So most of them started recruiting additional nurses and admin support in order to deal with the organization of all the tests and all the, appointments required to treat, those patients. I've gathered on this slide some of the, major publicly available information on, aficamten in EU5.
We can see that aficamten secured a good rating in France and Germany. They were quick to secure reimbursement in the UK. We're still waiting on information from the Italian dossier, which is in progress. The good willingness to pay, they have secured prices beyond our initial forecasting. And I wanna also bring your attention to the size of the opportunity. The health authorities agreed on a sizable portion of the target population, and this speaks to the overall opportunity in Europe when it comes to Camzyos . We will be focusing in the next three months to submit our regulatory marketing authorization application. Our regulatory team in Zug and our US stakeholders are working extremely hard to be able to submit our MAA before the end of the year.
We will be finalizing our EU launch sequence, deciding on our pricing strategy and our pricing governance, and we will continue interacting with the major KOLs in Europe. We've been so far, we have been successfully interviewing more than fifty KOLs in Europe in order to better understand what are the unmet needs, where can we partner and establish long-term relationship with those experts, knowing that we intend to be the specialty cardiology pharmaceutical company going forward. On top of the German entity, we will be setting up in the coming months, entities in France, the UK, Italy and Spain. We'll be putting managerial positions only for the time being when it comes to a general manager, medical director, market access director.
They will be focusing on establishing good relationship with the KOLs, with the patient association, and especially the health authorities. They will be representing Cytokinetics in those five countries. And on the other hand, they will start doing the cost effectiveness assessment that are needed when we are ready to submit pricing and reimbursement dossier at EMA approval. Thank you for your time for... And now we're gonna take a five-minute short break, and we'll be back here in this room.
... Ava, maybe you can round up some folks. Thanks. Okay, I'm pleased to welcome my colleague, Punag, who's going to kick off our discussion about omecamtiv mecarbil and our COMET-HF confirmatory phase III trial.
Thank you, Diane. Welcome back from the break. Welcome back from your Bloomberg terminals. Let's hit the ground running and go through the omecamtiv mecarbil development program together. What we know, what we've learned, and how this informs the path forward. My name is Punag Divanji. I'm a cardiologist, Medical Director for Clinical Research here at Cytokinetics. I wanna frame our discussion today in three ways. One is unmet need, the other is how GALACTIC informs the population we hope to study, and the third is how GALACTIC forms a foundation of a pragmatic, efficient, streamlined clinical trial. Now, you'll see here that there's high unmet need in this population. Patients with high-risk heart failure have continuous hospitalizations, recurrent hospitalizations, and a descent into a highly morbid pathway that, in some cases, leads to LVAD implantation or cardiac transplantation.
We've conducted one of the largest clinical trials on heart failure in GALACTIC-HF, and based on everything we've learned, we have the opportunity to leverage pragmatic trial design and conduct a more streamlined and efficient clinical trial. But we also have prior experience that drives us to explore where the clinical benefit of omecamtiv mecarbil might be in patients with features of high risk. You've seen this before. This is the trial design of GALACTIC-HF. I wanna emphasize a couple of important design features in GALACTIC because it will inform our discussion of COMET-HF. Let me remind you that this included patients with heart failure hospitalization within a year, that GALACTIC-HF allowed patients to have their EF confirmed within a year. I'll also point out that a significant proportion of the patients in GALACTIC were subtherapeutic on their omecamtiv mecarbil levels. Now, this is an important point to make.
This is true in many clinical trials with many medications, but we have a unique opportunity because we measure plasma concentrations of omecamtiv mecarbil, not only to understand who's in the therapeutic range, but this is a key lesson in terms of the design of COMET-HF, an opportunity to improve on the number of folks that are in target, target plasma range. You'll see here the primary results, a significant treatment effect for the reduction in heart failure events and cardiovascular death, but ultimately, not sufficient and not enabling of marketing approval. You'll also see no change in cardiovascular death in the subset in age on this slide. But in pre-specified subgroup analysis, we learned a couple of important things. One is that left ventricular ejection fraction is the most significant treatment effect modifier for patients with heart failure and reduced ejection fraction on omecamtiv mecarbil.
The pre-specified median value here was 28%. You've heard before that a more clinically relevant cut point, because we round when we evaluate LVEF, you heard Mariko Harper talking about this earlier. A more clinically relevant cut point is around 30%, and you'll see that represented on this slide. Patients with a greater baseline decrement in contractility, it turns out, derive greater treatment benefit from omecamtiv mecarbil. Let me say that another way. Patients with a lower LVEF at baseline derive greater treatment benefit. Now, this was a key point because it really does inform the design of COMET and the population we're gonna be looking at. You'll see on this slide represented two things. One is the figure on the left, which looks at the event rates in this population. As LVEF decreases, event rates increase, high unmet need.
These are patients with recurrent hospitalizations and an increased risk for cardiovascular death, and in some cases, again, LVAD implantation and cardiac transplantation, highly morbid procedures. You'll also see the figure on the right, that the treatment effect of omecamtiv mecarbil increases as LVEF decreases, and it turns out it's right around that cut point of an LVEF of 30%. But it's also important to evaluate safety of any drug in this population. Again, as the risk of heart failure increases, so does the risk of events. As LVEF decreases, so does the risk of events. So is this drug safe in patients at higher risk? You'll see that highlighted quite nicely on this slide.
No meaningful difference in serious adverse events, no meaningful difference in adverse events of special interest, including ventricular tachyarrhythmias, and germane to the mechanism of action of this drug, no significant difference in terms of myocardial ischemic events. You'll see a green box highlighted at the bottom of this slide. Let me draw your attention to that for a moment. Stroke was not an efficacy endpoint in GALACTIC, but it was an adjudicated safety endpoint. You'll notice a substantial reduction in stroke in this trial.
Not something we typically pay much attention to in heart failure clinical trials, but a substantial reduction in stroke with mechanistic plausibility in the setting of a drug that increases contractility, reduces chamber size, and thereby increases or improves flow, and results in a potential decrease in the risk of atrial fibrillation. With all of this in mind, we explored subgroups of patients with high risk. You'll see a publication on the left of this slide. This is from Dr. Michael Felker, who you're going to hear from in just a few moments. He looked at patients with more severe heart failure, defined by a lower LVEF, higher NT-proBNP, worse symptoms, and more recent hospitalization. And you can see that ultimately, the result, the conclusion of this analysis was that high-risk patients may indeed be the right population for omecamtiv m e carbil.
The same idea was highlighted by Dr. Chris O'Connor during the advisory committee meeting, that those patients at highest risk may also have the opportunity to derive the greatest treatment benefit from omecamtiv mecarbil. Now, this is a really important slide. We dug deeper into those markers of high risk. You'll see them highlighted on this slide. At the top is all patients from GALACTIC. Absolute risk reduction of 2.1 events per patient year, per 100 patient years. Below that is the group with an LVEF of less than 30%. But let's look at those subcategories. Now, they're not sequentially additive. You'll see that from the number of patients in each group. Instead, individual LVEF less than 30%, plus hospitalization within three months, or LVEF less than 30%, plus systolic blood pressure less than 110. That's an important one.
That's an important one because in terms of many of the other guideline-directed medical therapies, blood pressure may be restrictive in terms of their dosing and titration. I'll draw your attention to the last group on this page. LVEF less than 30% and an NT-proBNP more than 1,000. 2,800 patients from GALACTIC-HF were in this category, and you see a couple of important things. One is a substantial benefit from treatment with omecamtiv mecarbil, but I also want to draw your attention to the absolute risk reduction. Now, this is important to patients. This is important to the clinicians that care for them. How much are we able to legitimately reduce the risk of heart failure events, and you can see that when we reduce the EF and increase the NT-proBNP, that absolute risk reduction is more than fourfold the overall GALACTIC-HF population.
It's almost twice what we see with just a reduction in LVEF to 30%, a substantial benefit in this group. Now, all of this information comes together to inform the trial design of COMET-HF. This is probably the first time you're seeing this, so let's take a moment to walk through it together. There are a number of unique features that differentiate COMET, the confirmation of omecamtiv mecarbil efficacy trial in heart failure, from GALACTIC-HF. First is the primary endpoint. I mentioned that we're looking at high-risk patients, high-risk patients that have the risk of requiring LVAD implantation or cardiac transplant. We've included that in the endpoint at the behest of clinicians. Every time we have a conversation with a heart failure cardiologist about omecamtiv mecarbil, this is a question they pose to us: Will it impact the risk of these highly morbid procedures?
We've also included stroke based on the information you just saw a few slides ago. Now, the second important feature here is greater precision, greater precision around the patient population that we're enrolling. LVEF within 6 months rather than 12, hospitalization within 6 months rather than 12. We'll have a greater likelihood of knowing that these patients are indeed truly high risk when they enroll in the study. You'll see the key, key characteristics that define this population. An LVEF less than 30%, an NT-proBNP more than 1000, symptomatic as represented by being on a loop diuretic, and a heart failure event, as you see, within 6 months rather than 12. Third, we've included a run-in period. I mentioned to you that a significant proportion of patients in GALACTIC were below the therapeutic plasma concentration.
With the design of this trial, patients will have a higher likelihood of being on the right dose, a dose that leads them into the target plasma concentration before they are randomized. This will give us more precision about those folks that are entering the study, a greater likelihood of benefiting from the drug. Additionally, because of the large database that GALACTIC-HF represents, more than 8,000 patients from whom we have meaningful, critical information, this trial can be smaller, more streamlined, more efficient. That efficiency is represented by remote clinical visits, limited safety labs and ECGs, streamlined eligibility and study conduct, and streamlined AE reporting. And we're happy to say that we've discussed this with the FDA and have gained agreement from them on this trial. You'll also notice that the trial is smaller.
It's only about 1,800-2,000 patients rather than the 8,000 we had in GALACTIC. Part of the reason for that is the very high event rate in patients with high-risk heart failure, with the characteristics that you see mentioned above. Now, with that, I'm happy to hand over to Andrew Callos, who's going to talk us through the commercial opportunity for omecamtiv mecarbil.
Thanks, Punag. I'll first start with the patient population and the target product profile. You can see the 2020 to 2029 estimates at the top is heart failure, including HFpEF, so that's a wide range of heart failure, and the growth rate. 2029 is the year we expect to launch, if things go as planned. The HFpEF is around half of that at 4.3 million. I'm looking at the 2029. Those that are EF less than or equal to 30 or 2.8. The population that Punag just described in the trial you just saw is around 840,000 expected at launch. So they're high-risk patients.
If you look at this, we're really looking at patients that are a subset of overall heart failure, that need an additional therapy because of risk on top of GDMT. The markers of high risk, you saw in the trial criteria, which really talk about a heart failure event within the last twelve months, elevated NT-proBNP, and oftentimes patients have limiting concerns because of GDMT, things like hypotension or renal dysfunction or hyperkalemia. Now, GDMT certainly has increased in the last few years, has been, you know, Entresto added, SGLT2s more recently, and the residual risk has been reduced. But as you can see here, you know, if you see green and blue together, it's both Entresto and SGLT2 use.
If it's just green, then it's Entresto plus generic GDMT, if it's just blue, et cetera, so you see about 20% overall SGLT2 use and growing, and about 30% overall, 35% about either Entresto and/or SGLT2s. But as you can see from the DAPA-HF trial, I think it was around 2018, 2019, despite adding SGLT2s, which certainly reduces risk, there's still a lot of residual risk. This is an overall population, not a subset. The subset population we're describing has even greater risk. When you think about the risk from an event and from a patient point of view, as well, from an economic point of view, I think it makes sense that the lower your EF is, the greater your risk of hospitalization or an event, so we're studying the highest risk group.
This group is less than 20%, but accounts for around 60% of hospitalization, so high event rates. 35 percent of those that are hospitalized in this group are rehospitalized within one year. It cost about a little over $15,000 in a hospitalization for the event. That event, over the course of a year, is about $35,000. So a significant driver, actually, heart failure is the number one driver of Medicare cost in the U.S. So certainly, the reducing events, certainly would have a benefit. The direct cost from rehospitalization, not just hospitalization alone, you can see they're projected to continue to increase. So a clear benefit, to the healthcare system and patients reducing events. The business case, if you will, for why would we pursue omecamtiv.
I talked about a specialty cardiology franchise approach, the overlapping customers, the efficiency. This pricing, and we've done the pricing research already, before we pursued continuing the trial in the business case. So if you look at branded products in this market, it's a smaller subset, high unmet need, really not a lot of competition, premium to market, severely reduced EF. It's around one million patients post-GDMT. We were considering and getting ready for launching omecamtiv, prior, with an EF less than or equal to thirty as a cutoff. That population was a lot larger, still a great unmet need. This is even a greater unmet.
When we actually talk to physicians in a patient share, we get a much higher subset of this patient or a preference share at 50% higher than we did for omecamtiv in the EF less than or equal to 30, which I think really speaks to physicians really, you know, not having a lot of treatment options here. From a cardiology franchise point of view, if we had launched omecamtiv by itself as compared to adding it on to aficamten, there's a 20-point improvement in margin. You think you heard somewhere earlier talk about improvement in margin? So that's very significant from a margin point of view. Cost avoidance, sharing the same infrastructure, the same FTEs, the same customer-facing colleagues.
Had we launched this alone, you know, we're really avoiding 70% of the cost as a standalone, as compared to as part of a franchise. So you start to see, just from an economic point of view, specialty cardiology franchise coming through. So with that, I'm gonna turn it over to Fady to have a conversation with Dr. Felker.
All right. Have a seat, Dr. Felker. Okay, well, it's really a pleasure to have Dr. Felker here with us today. He is, as you heard earlier, he's a professor at Duke University and is at the Duke Clinical Research Institute. He was a member of the COSMIC Executive Committee, and he'll be the lead investigator for COMET-HF. You might recall, he spoke on our behalf at the FDA advisory meeting about unmet need in cardiology. He's a tremendous advanced heart failure specialist and physician researcher. And maybe I can just ask you to kind of introduce yourself a little bit and what your, you know, daily practice and things and interest, research interests are.
Yeah, thanks, Fady. It's great to be here. So, as Fady said, I'm a heart failure cardiologist. Been practicing at Duke University in North Carolina for the last 24 years. We have the largest advanced heart failure program in the United States at Duke. I take care of a lot of patients with all forms of heart failure, but especially more severe forms of heart failure, and work in our transplant and LVAD program. And, on the research side, I lead our cardiovascular group at the DCRI, the Duke Clinical Research Institute, which coordinates both clinical trials and outcomes research, nationally and globally. So, excited to be here.
Well, I think you're a, you know, one person who can speak truly to what the unmet need is in heart failure, since you see a lot of people, probably, who have unmet needs. You know, we have therapies. People know there are lots of exciting developments, but what remains?
Yeah. So we do have a lot of effective therapies, but I think the persistent burden of heart failure is remains huge. I was rounding in the hospital yesterday before I came up here yesterday evening, and I saw twenty-something patients in the hospital, and almost all those patients were on SGLT2 inhibitors, and they weren't in the hospital because they were doing well with their heart failure. They were in the hospital because their heart failure is progressing, and they're decompensated. So I think even though the treatments we have are effective, we still see a huge burden of patients who progress. Obviously, people know the epidemiology, the burden of heart failure continues to grow because of the aging of the population.
So, we are still seeing a huge portion of patients, especially those with more severe forms of heart failure, who continue to have a very high event rate, and they're not well served by most of the therapies we have because they tend to struggle with tolerating those therapies, especially around issues, as was mentioned earlier by Punag, around blood pressure, and renal function. So, clearly, what we need is therapies that can be effective in these more severe patients and that don't have overlapping adverse effects with other therapies we have already.
Maybe you can build on that a little bit. You know, you've worked on omecamtiv mecarbil quite a long time. You've had probably hundreds of conversations with physicians around the world. Just tell me a little bit about what that revolves, what makes people excited, potentially, about this mechanism, should it be effective, and how might it fit into their clinical practice?
Yeah, I think the... In general, there's a huge level of interest and excitement about the idea that omecamtiv development is gonna continue because people who take care of these patients recognize that the drugs that we have, while effective, they really focus on neurohormonal activation, which is an epiphenomenon in heart failure. But as patients get more and more severe, their problem becomes more and more related to hemodynamics and low stroke volume. And so the beauty of omecamtiv is that it actually attacks the main problem that these patients have as their heart failure progresses. And so, and the other thing I mentioned already is we spend a ton of time, as we think about adding on therapies, worrying about overlapping adverse effects and whether a patient could tolerate it.
So the idea of a therapy that targets the fundamental problem and also plays very well with the other therapies we already have is, I think, really exciting for patients, physicians taking care of these patients. I was telling Fady earlier, I was just in Tokyo last week, and I got asked over and over again about whether there was gonna be additional studies of omecamtiv, so I think the community has a huge degree of enthusiasm for this mechanism, especially in these more severe patients like we're gonna be studying in COMET-HF.
You know, I hadn't mentioned already that you're the current president of the Heart Failure Society of America, and you sort of have a unique platform, not just of what the American cardiology community is thinking, but interact with a lot of the international societies. So you mentioned some of your interactions in Japan and other places, in physician excitement about pursuing this next confirmatory trial. But you've also been involved in a lot of our regulatory interactions around this, and you know, how would you characterize sort of those things and how you know regulators have been viewing this next trial?
Yeah, I mean, I think the FDA actually seems extremely enthused about the idea of pursuing a second trial. And they've been very supportive, not just of recognizing the unmet need, which I think, you know, anybody who looks at the data sees, but also the opportunity to leverage the fact that we've already done a large trial, in patients with heart failure, reduced ejection fraction, with omecamtiv mecarbil in GALACTIC. And so how... You know, this is really a somewhat unique situation. We've done a large trial, showed the drug was effective, and also showed that there's a subpopulation, within that pool of patients where the drug seemed to be extremely effective. And I think what's exciting is that same population is the group with the highest event rate and the group least well served by current therapy.
That's really a you know sort of a triple header of identifying the combination of an effective drug and an unmet need and a high event rate. I think and having done a prior trial really will allow us to leverage a lot of the pragmatic elements that Punag mentioned earlier to try to do a more focused streamlined trial. We understand a lot about how to use the drug. We understand a lot about safety, and so I think that's gonna allow for a more pragmatic and streamlined clinical trial in common.
I mean, hypothesis-driven, clinical research in heart failure is kind of a novel concept, right? So maybe, maybe, how, you know, how is this program different than many of the other programs that you've participated in?
Yeah, I mean, one thing people don't often realize is that if you look at all the drugs in our armamentarium for heart failure, none of them were initially developed as heart failure therapeutics. They're all developed for hypertension or diabetes or some other reason. So people who take care of these patients really recognize that, especially as the ejection fraction gets lower and lower and heart disease gets more and more severe, the problem becomes more of a hemodynamic problem, and it needs a hemodynamic solution. That's why we often think about transplant and LVAD in these kind of patients.
So the idea to have a drug that actually targets systolic dysfunction, and Punag mentioned this as well. I think one thing, as somebody who works at a large transplant center, we have a lot of patients who you can sort of see that they're progressing towards needing something like a transplant. But they're not there yet, but they will be there soon, and that's like the perfect patient. If you had something to give them. I mean, I've said before, and people tell me all the time, that you know we see a lot of patients where we really wish we had a tool like omecamtiv to wish for, and hopefully we can generate the evidence to make that happen in the future.
Yeah, I think you rarely have, I think, a hypothesis to pursue, fill a niche in an area in cardiology that's probably not filled by something else that's currently developed. How do you, you know, consider the strength of evidence that we have that underlies, you know, our pursuit of COMET-HF?
Yeah, well, as you know better than anyone, you know, there's been a long development program. We have a lot of experience now with this drug. It's actually pretty unusual to be doing a trial for a drug that you already have a strong sense of that's safe and effective, based on, you know, I mean, GALACTIC was one of the largest heart failure trials ever. So, you know, we have a lot more experience with this drug, and I think a lot more confidence compared to some novel mechanism that nobody's really sure about. We're certainly gonna be leveraging that experience by using many of the same sites who participated in GALACTIC are gonna be participating in COMET.
As I said, you know, so far, just as we're starting up COMET, the enthusiasm both in Europe and the United States for people wanting to get involved has been extremely high. As you know, before there was even a decision to pursue another trial, this was the kind of thing that we were asked about all the time. That just speaks to, again, the clinicians who are taking care of these patients recognize the unmet need and the limitations of the tools they have for patients who really I mean, being in a hospital with heart failure is a terrible experience if you're a patient.
The idea, well, you're just in the hospital for a few days and, you know, it's being in the hospital is really difficult, and being in the hospital once portends future events. We know that once you start down this sort of high-risk road with your heart failure, and your heart failure is progressing, we see recurrent hospitalizations over and over again as patients progress. The idea that we could have something that we can give chronically, that's safe and effective, that interrupts that downward trajectory, is gonna be extremely powerful for a lot of these patients.
I have a lot of patients, when we talk about transplant or other advanced heart failure therapies, they often ask me, "Isn't there a medicine I could take, instead?" Because no one wants to have, you know, a highly invasive surgery and take complicated immunosuppressive regimen for all their life, with all the things that, entails. And traditionally, the answer is we don't have any, you know, other than the heart failure medicines you've already been on, we don't have something, that we think is gonna help change the trajectory of your advanced heart failure. But I think with a drug like omecamtiv, you know, that may be different, so that's exciting.
Yeah, I think you brought up a good point earlier in the sense that heart failure patients have compensatory mechanisms. You know, as their cardiac function gets worse, and they get activated, and we try and take advantage of those or treat them, we didn't really understand where those compensatory mechanisms run out as cardiac function fails. And then, you know, I think GALACTIC taught us, in the sense that there's a failure to compensate, you know, once your EFs get down, and cardiac function becomes more central.
Yeah.
Obviously, when you get to that point, the interventions you're considering are intended to, you know.
Yeah, they're hemodynamic.
Intended to augment cardiac function, whether they be mechanical or transplant. Well, lastly, I just wanted to talk about some, you know, an effort that you and I both participate in, called the Heart Failure Collaboratory. So that for most of you don't know, this is a private-public partnership between academics, biopharma, FDA, and patients, to think about how can we improve the ecosystem of clinical research in heart failure. And, we've been good students of all the discussions that we've had over many years. How do you see some of those discussions reflected in our design of COMET?
Yeah. So as you said, the Collaboratory is really about trying to streamline how quickly we can move from a hypothesis to developing evidence and getting drugs to, effective drugs to market for patients. And one of the... as we all know, the clinical trial enterprise is unwieldy. And, you know, in some ways, this is a perfect opportunity, 'cause as I said, there's a lot of unique aspects here. We already have an effective trial, a trial showing the drug is effective, and we're really doing a confirmatory trial in the patients in whom we think it was most effective, based on what we saw in GALACTIC. So, we're really trying to leverage a number of the things, Punag mentioned, so some remote visits, instead of having to... You know, we wanna try to meet the patient where they are.
One thing we hear from patients all the time is clinical trials are not very patient-friendly. We tell the patient, "You've got to come here and do this and do this. It's all part of the protocol." So we want to meet the patients where they are. We're gonna do more limited safety surveillance and collection of serial labs and those things, because we already have a really good understanding of the safety of omecamtiv mecarbil. We're gonna do the run-in, which is gonna help us maximize, I think, our signals of efficacy and really understand how the drug works. So I think it's a great opportunity to really lead in advancing the science of clinical trials around how to do trials faster, more streamlined, more effective, cheaper and get evidence to patients more quickly.
Yeah, and I've been very pleased how FDA has engaged us in those discussions, so we've had several discussions with them to date, and, we're excited to get this started. I'm sure, you are, very busy at the DCRI, working with our team to launch this trial, and, we'll look forward to updating you on its progress down the road. So thanks for joining us today, Mike.
Great. Thank you.
With that, I'll turn it over to Dr. Kupfer, who will speak about our next clinical program.
Thank you, Fady. Can you hear me? No. What now? All right. Well, it doesn't matter. I'll go back here. So anyway, we're at the bottom of the eighth inning. Appreciate your hanging in there. I have another turn at bat to discuss the strategy for CK-586, our new cardiac myosin inhibitor that we're developing for treatment of a subgroup of patients with heart failure and preserved ejection fraction with associated hypercontractility. Is this on now? No. Okay. So the potential benefit of CK-586 in HFpEF is informed by treatment effects that we've observed with aficamten in patients with non-obstructive HCM, in cohort 4 of our phase 2 REDWOOD-HCM trial, and that we're also observing in FOREST-HCM, which is our open-label extension.
In Redwood, what we observed was improvement of heart failure symptoms in the majority of patients with non-obstructive HCM. We saw clinically meaningful improvements of KCCQ, shown in the graph in the middle, as well as improvements of NYHA functional class. These observations occurred in the context of good tolerability, and there were no patients that discontinued aficamten due to adverse effects. Now, these improvements in symptoms were associated with reductions of cardiac biomarkers in non-obstructive HCM, so decrease of NT-proBNP and cardiac troponin, indicating decreases of left ventricular pressure and decreased myocardial injury. These patients also experienced a lower frequency of anginal chest pain. That's suggesting that aficamten is, you know, reducing myocardial ischemia.
So, we're, you know, we're confident about extrapolating the results of aficamten in non-obstructive HCM to the potential benefit of CK-586 in HFpEF, you know, based on similar features of these populations, particularly focusing on symptoms and pathophysiology. So both populations have heart failure symptoms, such as shortness of breath, exercise intolerance in association with increased cardiac contractility and diastolic dysfunction. So let's talk about CK-586. This is a selective allosteric inhibitor of cardiac myosin, with a mechanism of action distinct from aficamten. Now, you know, approach for developing a cardiac myosin inhibitor for HFpEF has to take into account that it's a population that's generally older and with more comorbidities than non-obstructive HCM, so likely, these patients are gonna be more vulnerable to potential treatment-related adverse effects. And so, we sort of took...
Tried to optimize our discovery efforts to develop a cardiac myosin inhibitor with a shorter half-life than aficamten and an even shallower exposure-response profile. The data that were generated in our first-in-human trial with CK-586 demonstrated that these objectives were achieved. What we observed was a PK profile that was predictable and dose-related, with a half-life of about 14-17 hours, and a PK/PD profile that was shallow based on, you know, evaluating concentration versus ejection fraction, as shown on the right. This profile was associated with very good tolerability. We evaluated a wide range of doses. In fact, you know, decreases of ejection fraction, mean ejection fraction, were less than 5% at the highest tested dose of 600 milligrams. And so...
You know, the pharmacologic features of this profile support the possibility of fixed-dose administration of CK-586 without the need for routine echo monitoring. So that brings us to our phase 2 trial, AMBER-HFpEF, in which we're evaluating CK-586 in a dose-ranging study design versus placebo in these patients with HFpEF and relatively high ejection fractions of at least 60%. So we plan to enroll about 50 patients in three 12-week cohorts with overlapping doses ranging from 150 milligrams to 600 milligrams once daily. We plan to capture endpoints that were similar to those we evaluated in non-obstructive HCM to characterize, you know, heart failure symptoms, diastolic function, safety and tolerability, and looking at the PK/PD relationship. So again, we
There's a lot more to come in terms of the details of the study design, but we wanted to give you kind of a high-level view of the design, and we're planning to start the study by the end of this year. And so a lot more to come with CK-586 and this patient population with a very high unmet need. And I'm going to turn it over to Andrew, who's going to discuss that in more detail.
All right, I'll bring this home in terms of presentation before Q&A. The market opportunity. On the left, you can see guidelines. Recently, SGLT2s, Entresto, up to an EF of 57, has been proven to effective, getting broad use with those new branded medications, especially SGLT2s. You know, around 80% of patients are on this, but still, about a third to 40% of patients are uncontrolled. We've done a lot of research around unmet need, and certainly, physicians are describing unmet need and are excited about the possibility of a different mechanism to help treat these patients and add it to the armamentarium and guidelines overall.
From just a numbers and an HR point of view, if you will, about 75% of patients will die within five years of initial hospitalization due to HFpEF. Eighty-four percent, you heard Dr. Felker talk about this rehospitalization cycle once it starts. The hospitalizations have increased dramatically. You can see in the kind of fourth little icon, there are 200 to nearly 500,000. That's in 2018, and that number obviously continues to increase with a lifetime cost of over $125,000, you can see in that last quadrant. But, you know, so certainly a subset of HFpEF patients could benefit from this, and obviously, that's what our clinical programs will try to you know, see where the evidence lies in terms of who benefits.
I talked about, you know, this takes a 2024 cut based on growth rates. They're pretty consistent across datasets, 50% or so, HFpEF. We're studying, you saw the design of an EF of, greater than or equal to 60. Ultimately, will this be commercialized and studied in EF 60 or 65 as we continue to learn more about the profile and the patient that benefits most? But that population, if it's a 60 above, it's about 2 million patients. If it's 65, it's about 1 million patients, so 10% to 20%, overall, so large patient populations. Our profile, this is a cardiac myosin inhibitor, so certainly, we're looking for hard endpoints, combined endpoints when we, ultimately do our phase 3.
You know, once a day, minimal drug-to-drug interaction, and monitoring based on a biomarker as compared to an echo. So I think that's be an important component, especially when you have a much, much larger patient population. So with that, I will close. I will turn it to Diane, who's going to lead us through our Q&A.
Thanks, Andrew. Yes, thank you. Will my colleagues please join me on the stage?
Coached us well. We knew what to do.
So as you've heard from our presenters, we are literally firing on all cylinders here, furthering the development of aficamten, omecamtiv, and CK-586, and strategically preparing for the global commercial launch of aficamten. We've covered a lot of ground, so before we get into the Q&A, I'm just going to quickly recap to guide our discussion now. So with the help of our HCM experts, we synthesize all our clinical data from aficamten as it relates to what we hope will be a potentially differentiated profile. We went into all the details about our commercial launch preparations for aficamten, including our differentiated approach to market access and the patient experience, and discussed our European go-to-market strategy, all of which we hope will enable us to deliver on our specialty cardiology franchise business objectives.
We also outlined our financial footing, foundation, and business model, which sets the stage to create an enduring business with the opportunity to reinvest in our pipeline, enabling sustainable growth and future innovation. And lastly, we explored the development of CK-586, including the design of AMBER-HFpEF, and discussed the potential market opportunity in that category of heart failure. So with that, we'll begin the Q&A session. We'll take questions both from those in the room as well as those online. We will do our best to get to everyone. If we don't get to your question, we'll try to follow up with you afterwards. We are gonna need to limit questions to one per person as best as we can. So in the room, just raise your hand, we'll bring a microphone over to you.
Please state your name and your firm before asking your question. And to ask a question online, please type your question into the box in the tab on the right, titled Ask a Question. Your question will be sent to us in the room, and we'll relay it to our panelists. Again, if we don't have time, we will follow up with you after. And we will start with those in the room. And I know Yas requested... I don't even see you. Where are you, Yas? Yasmeen.
I'm wearing a coat.
You're all bundled up.
Thank you so much. Thank you, guys. Excellent presentation and really thorough, really showcasing the entire portfolio. I guess you spoke at parts, how you're making the launch very customer-centric and very bespoke. Could you maybe tailor in, like, and I think, Fady, you mentioned how titration could work through the process. Could you maybe provide a little bit more color, how it would look like in the real world, you know, versus in the clinical practice? Like, what would be a best-case scenario? And I'll hand over the mic.
Sure. I'll, you know, emphasize that everything is speculative at this point, but, you know, if you look at how we amended FOREST-HCM, I think it's a good metric for, or a good model for how we might see this happen in the real world, so aficamten, by its properties, it can be reach steady state after a couple weeks, so it can be titrated as quickly as every couple weeks, so when we designed our clinical trials, we designed it with the shortest interval in mind. It maximizes treatment to target dose, and it also proves that it can be safely titrated that quickly, but, you know, it also there are first principles of clinical pharmacology tell you that you can also wait and create more flexibility, particularly at the lower doses.
There's not any urgency to check somebody's echo, so to speak. We had, you know, very safe, they appeared very safe at doses of 5 and 10 milligrams, and at 15 and 25, 15 and 20. But, you know, as you get to the highest doses where you want to maximize the reduction in the gradient, you know, giving patients the opportunity to achieve a maximal treatment effect, you'd want to guide your treatment a little more carefully. So I think in the real world, and, you know, our clinicians could probably opine on this better than I, but, you know, they'll use their judgment as they initiate dose titration. They'll schedule echoes at an interval that makes sense for the patient.
You know, we think in every two to six weeks or something, you know, say, a monthly or less, whatever cadence is appropriate for the patient. Once they get to a target dose, we hope to see that monitoring would be on a six-month basis, you know, potentially even less as time goes on. And it's all really about establishing confidence the patients reached a steady state. And as I mentioned earlier, you know, the only more frequent monitoring is in those with lower ejection fractions when you reach target dose. So, you know, it's a, I think, a very flexible. The frequency of echoes, frankly, is something patients already have as part of the normal care routine. Nobody's gonna stop echoing HCM patients.
You know, just, you wanna know how their gradients are, you wanna know how their disease is progressing, and ultimately, the echoes will be approximately what would be part of normal clinical care.
You know, a corollary to your question can be answered, I think, also in terms of what are the major impediments to the adoption of a cardiac myosin inhibitor today? Maybe I'll ask Andrew to comment on what we've learned through market research, but last week, we had in the office a retired CVS executive, a major payer, who is this patient herself on a Camzyos today. And she was commenting on it's less the frequency of echoes, which I think Wall Street is very fixated on, and more the window associated with when that echo can be performed. That can be a major issue. Meaning, if you don't get your echo within a certain number of days, then you might be forced to down titrate or dose interrupt.
And this particular patient was saying, "My next echo is during the week of Christmas, and if I don't get my echo when I'm expected to, I might have to start all over with the dose up titration and getting to steady state." That could be majorly problematic. We expect that the window of echo, if approved for aficamten, may be more permissible. Andrew, maybe you want to speak to what you've learned.
Sure. I think in the market research, it's always a combination of efficacy, safety, and in the instance of Camzyos , the administrative processes associated with a risk management program. So having a differentiated risk management program certainly does move the needle in terms of preference share, at least in our research with several hundred cardiologists.
Okay, thanks. Saleem? Yeah.
... Saleem Syed, Mizuho. Thanks for all the color today, guys. It's helpful. I guess, one, you know, so I think Wall Street's pretty. I think the base case is you will end up with a lighter REMS, and you've spoken about the $10 billion market number today. You referenced in one of the slides, which I think is a little bit larger than what Wall Street may be modeling. Just curious how you sort of think about the lighter REMS. How does that really open up the OHCM market opportunity? And, like, what sort of cadence should we be thinking about typically, as we talk about cardiovascular launches?
It takes a little bit of time, but this is obviously a mechanism people are familiar with, and there's, you know, is it pretty quick, or are you anticipating more of a traditional CV launch? Thank you.
Yeah. I think from a launch point of view, so, certainly the ability to open up more prescribers to Camzyos as compared to maybe around the 1,500 or so, which 500 are really the vast majority, 80%, based on the available data. Opening that up to the 10,000 that we described, getting more geographic dispersion where the patients are and where the physicians are, certainly could accelerate. Launches, in general, go slower than maybe they did 10, 15 years ago. There's payer uptake that takes a little bit of time. Commercial payers are generally around 6 months. We already talked about Medicare and where that will be, but getting a medical exception process in place at a payer level takes time. Physician utilization of the Camzyos and understanding.
So when we look at analogs for launches, it generally takes, you know, eighteen to twenty-four months before you start to see an inflection point, fairly linear, and once that inflection point does come, then there usually is an acceleration. Ultimately, I think the, as Fady described, the label will matter a lot. The risk management program will matter a lot because that's generally... I mean, that's what we base our education to the physician community, payer community, and patients on. So, that is a big wild card here, so that could accelerate faster or slightly slower based on what that label ultimately looks like. No different in Europe as well.
The existing cardiac myosin inhibitor in the marketplace continues to see pretty linear quarter-to-quarter growth, and as they're getting payer coverage and reimbursement, as a percentage of total is increasing, we're starting to see what we think will be the beginning of the asymmetric phase of product adoption. My colleagues are getting a little bit annoyed with me. I'll let you in on a little secret because I keep pointing to what are we gonna do to increase velocity of commercial launch at the time of launch. So ask the same question of us next year, and hopefully, we'll have an answer to what are the things we're doing that will accelerate commercial adoption sooner.
One last question, point. This is a rare disease. I talked about 25%-30% of patients diagnosed. There's a lot out there now in terms of both for consumers and for physicians to increase awareness. John Giacoppi described our campaign as well, so I certainly think that's going to help accelerate as well as you continue to find more patients.
Great. We'll do Kripa, and then Joe and then Paul.
Thank you so much, and great presentations, a lot of detail. It will take us some time to wrap everything around. So one of the things we've heard from, especially from community doctors and also from doctors that work in centers of HCM excellence, is that they would like doctors from the community centers to refer, and is there anything specifically you're doing to help that happen? Because we feel like you could get a lot more patients treated if that happens. Thank you.
If, I'm sorry, if what happened?
Activating community.
Oh, I see. Got it. So I mean, I think similar to what I just was describing to Saleem, ultimately, the label and how much administrative resource it takes, how many echos do you have to do? What's your weekly ECHO window? Do you have to do drug-to-drug interaction monitoring and phone calls with patients? Can you titrate immediately, or does it take two or three echos before you can titrate? So, all of those steps in our healthcare system, especially when you consider a physician's office, a nurse office, a specialty pharmacy, a patient, the coordination between them, how much effort does that take? The less effort, I think the greater amount of engagement you'll see across cardiology.
We're advantaged. You know, we often get the question from investors and analysts, "How do you compete in a category where there's a large pharma, a company already, present?" I hope you're starting to appreciate, from hearing presentations from my excellent colleagues, how we may have a competitive advantage here with regard to building it, de novo, with focus, with discipline, with a custom bespoke experience for patients, with a fewer number of specialty, distributors, and how the HEOR and other things from a market access standpoint may play to our advantage, with regard to aficamten. But it's incumbent upon us to activate community cardiologists in order to not compete with a company that's doing a reasonably good job, but it's only achieved roughly 8%-10% of penetration into a category.
But how do we think about the remaining 90% and activating community cardiologists to be comfortable using a drug that may have these next-in-class advantages?
Creating a customized patient experience, designing our field force where the customers are, getting out there and publishing HEOR, not being a resource-intensive business model where resources win, share of voice, et cetera. I think this is an advantage for a smaller company as a larger company, when we're talking about specialty cardiology.
... Joe?
Great, thank you. Joe Pantginis, H.C. Wainwright. If I could just squeeze in a quick logistical question first before my main question. I'm just curious, anticipated percentage of overlap of sites for COMET versus GALACTIC. And then second, I would love to ask this question of Dr. Harper, doctors Harper and Weiner, but either way, wanted to ask, you know, since they discussed that, you know, patients and doctors are much more educated now with regard to HCM as well as the REMS burden of mavacamten, at what point, obviously, you'll be targeting new patients first, but at what point do they believe that you could see potential patient switches?
As far as COMET, smaller trial, you know, GALACTIC was 35 countries, 950 sites or so. We're gonna not be going to that many countries and certainly not that many sites. But the size, it gives us an opportunity, if you will, to pick the best sites that participated in GALACTIC. We're going to many of those sites, but, you know, a few other sites as well. The DCRI has a very long experience in conducting heart failure trials, so they have their own database of sites that we can also leverage. I expect a great overlap. I can't give you an exact number, but we can leverage that experience.
Okay, just to address the question about potential Camzyos crossover. Yes, that's something that we think about and potentially look forward to that opportunity. It seems like it would probably start in patients who potentially have issues with potential drug-drug interactions, where a next-in-class Camzyos would offer benefit, as well as patients who maybe had some dose reductions, some intercurrent illness that potentially increase their risk of current Camzyos. So the anticipation is that yes, there probably will be a portion of patients. It's hard to put a number on it at this point. We will be thinking about that as part of our strategy to better improve our patients.
Paul? And then we'll do Charles, and then Leland, you had your hand up.
Thank you. Paul Choi with Goldman Sachs. With regard to the $10 billion market opportunity you've laid out here for the Camzyos class, can you maybe comment a little bit on how you're thinking of frontline use as a percentage of that, or roughly being a driver of that forecast versus the current-
Frontline use?
post-beta-blocker population and, you know, just kind of some of the numbers that lie behind that. And then secondly, on that note, with regard to sort of thinking about duration over the longer term between first and second line, just kind of what are sort of your high-level assumptions there to get to this sort of a $10 billion opportunity? Thank you.
Duration of treatment?
Yeah.
Sure. The patient population is clear. There are how many patients are diagnosed, that's based on, you know, claims data, in Europe and the US. The growth is really driven by NHCM versus OHCM. OHCM is taking a little longer to get started, as we're seeing in the marketplace. My expectation is NHCM will actually go faster from a launch point of view because the treatment of HCM overall will be better understood. I think the key variable in where that number goes is at $6 billion, is at $8 billion, is at $10 billion, really will be the penetration of Camzyos in eligible patients. That'll certainly be driven by labeling, understanding, safety in the real world, efficacy in the real world.
I think you heard from a few experts treating, or two experts treating patients today and, and what patients are experiencing from an efficacy and a safety point of view. So, ultimately, first line use after MAPLE, when you start to add the guidelines, when guidelines basically say, beta blockers aren't needed and you get increased efficacy, if that's what the clinical trial ultimately shows, that should accelerate first line over time. So generally, what happens is you generate the data, the data generates a guideline, the payers will get on board after guideline, most of them, and patients and physicians are gonna want to treat monotherapy, given the side effect of beta blocker. Many physicians are starting to wean beta blockers off anyway, after approval.
So I would expect all this takes time, but I would expect to start to see a lot more first-line use when you start to look five, six years out. But that penetration rate, how many patients that are eligible, is that 30%? Is it 60%? Ultimately, that's what really will be the determinant and how many of those patients that aren't diagnosed that are 25%-30%, but ultimately get diagnosed. You know, they're the two key variables to look at in terms of market size.
We're still somewhat conservative about what will contribute to adoption and when, with Sequoia more likely being the major catalyst to adoption and MAPLE being incremental to that. Over time, three to five years down the road, it may be more of a fifty/fifty mix, but you're not gonna hear us pounding the table to say that MAPLE will be itself transformational at launch. More likely, that'll take more time to make its way through guidelines and adoption.
Leland?
You've seen in other categories, evidence and adoption, and over time it increases, and that's what we expect.
Thank you for today's comprehensive discussion. Leland Gerschel with Oppenheimer. If I could also sneak in a quick logistic question before the main question. I want to ask if you, what your current expectation is for a specialty distribution model, as is the case for the current Camzyos. But my main question, maybe you could also have Doctors Weiner and Harper chime in, would be, there's been a lot of discussion about echo. At the same time, cardiac MRI is, I think, increasingly involved in the diagnosis of HCM. Want to ask if you could speak to that being a standard part of diagnosis, is it in guidelines? And is that a hurdle or something to work on with respect to increasing diagnosis in the population? Thank you.
... Distribution, I'll take real quick. There's large players in the distribution model that are also in PBMs, that are also kind of vertically integrated, and then there's independents. So the approach we're taking really will be to focus on very few distributors, so those distributors know the flow and what it takes to prescribe, what steps are needed, what safety elements are needed for verification, as compared to if you create five, six, seven distributors and they're pretty diffused because you don't have a lot of patients. You may not get someone on the phone or generating the prescription that understands the patient journey and what's required. So part of the overall experience is having very, very few distributors who really know the product, who are trained. That's ultimately a key element of the patient experience.
Okay, so to address the part of the question about imaging in HCM. Echo really is the cornerstone. I mean, MRI does add more data, but in terms of our day-to-day management of patients with HCM and whether they're on Camzyos or not, that is something that we are accustomed to doing, and it's actually something that patients really don't mind. Echoes are easy tests. They're non-invasive, they're quick, you can get a lot of information from that. And even our patients who are not on Camzyos, maybe we'll see them every six months, you know, do an echo, which is kind of similar to, you know, how things could be done in FOREST-HCM. I don't see that being a barrier.
Patients don't really perceive it as such, and they actually like having that objective information. They say, "Doc, what's my gradient? What's my EF?" and it gives them comfort in taking novel therapy.
Great. Then we're going to do Charles, Tess. Your name is, like, on the tip of my tongue. Michael, sorry.
Thank you. Yeah. Good morning, everyone. Charles Duncan with Cantor. Robert and team, thank you for a very informative and well-organized session. I had a question that was related to health economics outcomes research, really, because Dr. Weiner alluded to this and suggested that there's an opportunity for really reimbursement authorities to rethink obstructive HCM and think about the value. And he, maybe I'm putting words in his mouth, but I'm kind of wondering if you could address where the greatest disconnect is. Is it driven by, you know, call it, the costs of other therapy or a lack of understanding or appreciation of the cost avoidance for improved morbidity and mortality, especially with the longer-term durability of aficamten?
In the first place, it starts from an HEOR point of view, as our endpoint is a peak VO2, exercise capacity. What does that really mean to a payer? So I think you heard Sunil talk about publications that link peak VO2 to clinical outcomes. Obviously, some of the secondaries, New York Heart Association class, is a big predictor of clinical outcomes in New York Heart Association class three, versus a two, and the risk associated with that. There's also a lot of comorbidities. I think there's just a big disconnect. AFib, heart failure, and ongoing comorbidities associated with having the disease that maybe Fady can speak to. Those that get SRT and the cost of SRT over time.
But then there's an element of, you know, which HTAs, like the U.K. or Canada, take in mind, kind of this idea of a quality. There's this element of: Are you making patients feel better? How does it actually affect the patient's quality of life? We have a KCCQ element that can take that into account. So when you put all this together, and we'll be publishing, even more, in 2025 around these elements, and that's the kind of discussions we have with payers in the U.S. and HTA agencies in Europe.
This is where MAPLE-HCM may make a meaningful difference. As hopefully, MAPLE-HCM reads out positively in support of aficamten, and that's included in guidelines, payers will be confronted with a choice. I think it's commonly expected that beta blockers don't contribute to improved exercise capacity and stamina, and there's quality of life implications. And while they are cheap, payers will be confronted with a guideline, hopefully, that will suggest where aficamten can play a role, and payers will have to respond to that. This is not a category that has major budget impact for payers right now. You're not talking about many hundreds of thousands of patients all of a sudden on these drugs, but rather, you know, right now you're talking about thousands.
I think payers are gonna look to these data to inform choice, and it'll be, I think, especially incumbent upon payers to respond to guidelines if MAPLE-HCM, in particular, reads out in our favor.
Yeah-
Ken.
I just, I just might add one brief thought, which is that, you know, beta blockers don't modify the course of the disease. They. And what we hope to contrast is, in Maple, particularly with the head-to-head, some of the imaging that might suggest that there's a real difference in how the structure of the heart changes and, you know, with more data over time. I think the goal here is not. You know, we're really treating, right now, treatment failures, patients who have high gradients on background therapy. For drugs that have the potential to mechanisms that have potential to slow progression of the disease, even reverse it, and you really like to think about implementing them earlier, that will expand the patient pool over time.
It's incumbent on us to, you know, develop data that support that down the road.
... Tess.
Hi, Tess Romero from J.P. Morgan. Thank you so much for having us today. You talked about your aficamten launch preparations extensively, and we appreciated all the details that you shared. You touched a little bit on your four-pillar approach to the potential treatment experience here, which emphasized that you're looking to create a more personalized approach. On the HCP side, based on your market intel, where might there be any gaps or misunderstandings at this point about the profile of aficamten? And how do you really think about filling these with respect to your physician education, particularly for those prescribers that sit outside the key centers of excellence and academic centers that may have less or no Camzyos experience so far? Thanks so much.
I mean, that's essentially the job of our medical affairs organization and our Jeff Lotz's sales organization. Once we have clinical data, I mean, obviously, we can't go out there and talk about that today when we don't have a label, we don't have approval, et cetera. Once there's approval, well, not only will those representatives. We talked about the model difference, each physician having a one-to-one relationship with a representative. When that physician has a question, when that physician has a follow-up, when that physician wants a lunch program or a speaker program, there's always one representative they're dealing with. Peer-to-peer programs will be critical as well, but it's really about generating education and awareness of aficamten as an option for treatment, at the clinical data around aficamten, and then how aficamten differentiates.
So that's where, obviously, John's team comes in from a marketing component as well.
Can you also talk about omni-channel and how that plays a role?
Sure. So you saw a slide that John Giacoppi presented around the surround sound, if you will, of our campaign. You know, digital ads, banner ads, social media ads. You know, physicians like us go on certain websites. They go to certain places to get education. We know where these physicians go, and buying media and educating there as well. So it's not an or, it's an and. So doing these things are typical of what pharmas do. I think the difference here, though, we're going to that focused set of I mean, we know the physicians, based on data, who are diagnosing and treating HCM. Getting them educated and what it would take to prescribe aficamten will be our job at launch.
Michael?
Hi, this is Michael Riad on for Jeff Hung and Morgan Stanley. Thank you for taking our questions and for hosting the event. Circling around the MAPLE HCM discussion and given the beta blocker side effect profile, how... Like, what magnitude of disease modeling is really needed to demonstrate value to payers? And how far into the treatment journey do you expect to go to start to see that, meaningful disease remodeling?
Well, you know, MAPLE is only six months, twenty-four weeks of treatment, so I, you know, what we hope to begin to see is a contrast between the way the heart restructures itself on aficamten versus a beta blocker response to the biomarkers. You heard earlier, NT-proBNP and troponin. That's really just the beginning of the story. I mean, it'll take time. We have, in FOREST, a long-term follow-up and imaging component of it over, we hope, you know, five years with a substantial cohort of patients. So, all those data together are going to inform what is, how's the heart responding over time with these drugs, and are they disease-modifying? And that, I think, will be impactful, you know, to their eventual use and where they're positioned.
Jason?
Hi, Jason Zemansky from Bank of America. Thank you so much for taking my question and for hosting this very thorough, review. I'm curious, how scalable is your, commercial organization and just overall the administrative infrastructure? I mean, as you think of the launch, and especially, MAPLE coming in in 2026, you know, that focus on that, customer-centric model and just the overall number of echos that are necessary, what sort of investment do you envision, you know, necessary to hit that $10 billion target? Thank you.
So, the organization. I'll keep it simple. There's two parts of the organization. There's a headquarters part, and there's field. The headquarters, very scalable, and we can always add resources in any analytics, distribution, pricing, et cetera. We have a fully integrated, headquarters model, and we're building that in Europe. So our systems we're building are certainly scalable as well. So then it really comes down to, do you need to interact with a broader set of customers, and therefore, you need a bigger medical affairs and/or commercial organization. The ability for us to scale that commercial organization, you know, Jeff and his team will be creating roles. They've already done that in territories, and be able to recruit individuals across the U.S. with specific experience, you know, within, like, six or eight weeks.
It's a very, very quick process. So if we get to the point where we say, well, there's only 1,500 cardiologists or so engaged in Camzyos, if it goes beyond that 10,000, we have the ability to scale up very quickly. I think those of us who've been in pharma a long time, especially in the 1990s, when field forces were increasing, have a lot of experience in terms of what does it take to expand a field force? How do you minimize disruption in that one-to-one relationship? So that would be a wonderful problem to have, and I certainly know that we'll be prepared for that when that comes. We certainly expect to do that with omecamtiv mecarbil. I think you saw the slide Jeff showed, which we said we would increase our physician universe.
... But given the importance of aficamten to patients, if it's approved, and given the value, that's something we're gonna keep a close eye on to make sure we got those 10,000 right.
You know, one of the benefits of having some time to prepare for our first commercial launch, and we like to joke, nobody's ever gonna accuse Cytokinetics of being an overnight success. But one of the things we get to do, is we get to understand the failure modes for companies that go commercial, and who's done well and who's not done so well. And here, in particular, as you know better than we do, it's fashionable to short a commercial launch. I hope that'll be a mistake were it to be around Cytokinetics, because we're trying to identify ways that with news flow catalysts, ways that we can scale from one indication of OHCM to NHCM, one product from aficamten to omecamtiv to CK-586.
We're producing a layering and an enduring value growth and operating margins that should be addressing where those relative few companies that go commercial are ultimately able to build a valuable business for the benefit of all shareholders.
I think we're gonna have to just do one more, just we've kept you very long, and Robert has some closing remarks. So Jason?
Thanks, Diane. Jason Butler, Citizens JMP. I guess just a quick one on omecamtiv and the COMET study powering. What gives you comfort or confidence when you think about the expected event rate for incorporating LVAD and transplant into the endpoint? And what data you have from, for example, the GALACTIC study to inform that? Thank you.
Right. Thanks, thanks, a lot for the question. I mean, fortunately, we're in a position where we have this very large, robust database from GALACTIC to inform the sample size for COMET. And so, you know, what we appreciate, and, you know, Punag mentioned this previously in his presentation, is that we can, because of the large sample size, even the subgroups that we're targeting COMET are relatively large. And so based on that sample size and the very high event rate in these patients with more severe heart failure, we can really have a fair amount of confidence in terms of what kind of event rate do we expect. In addition, what type of treatment benefit might we anticipate, you know, in this patient population?
So we've cut the data a lot of ways, and we're quite confident, that we, you know, we will observe about a 20% relative risk reduction, in this population. And, you know, has been mentioned earlier, we're gonna conduct a trial with a sample size of less than fourth the size, of GALACTIC. And again, that's because, these patients have a very high event rate, which also speaks to the fact that there's very high unmet medical need in these patients. So we'll run a more efficient trial.
I might just add one thing in terms of the additional endpoints, stroke and LVAD. You know, we don't really expect them to contribute a lot of power to the study. They're not gonna be tons of those events. We had them in GALACTIC. They all trended favorably. Stroke was a very strong signal, as you know. But the point really is to show, in designing that endpoint, is to emphasize the severity of the population. And you know, those things are things that happen in the population we're enrolling.
Thank you all for your questions. If you didn't get your question answered, you can send us a quick email, and we can try to get back to you, or the team will be available for a few minutes following the program. With that, thank you to my colleagues, and I'll turn it back over to Robert for some brief closing remarks.
So I'll be very brief because we've kept you a little bit longer than planned. If the prior presentation was bottom of the eighth, maybe this is the bottom of the ninth, and I'll just close by repeating. You know, you heard about echoes today, and maybe I'll echo something that we said earlier. This is a company that is thoughtfully and disciplined about how we build. Design, build, and execute. And here on this slide, you see that there are a number of events that should matter to shareholders, a number of events that speak to how we translate science to medicine, medicine to patients, patients to business, and ultimately reward shareholders. You heard today, and with today's announcement, we have submitted the NDA for aficamten.
That occurred on time in Q3, and we expect to be learning in Q4 whether we have standard review or priority review. We asked for priority review, we made a case for it. Hopefully, FDA will respond to that in ways that will be favorable, but that's not our base case. Our base case is a standard review, and as you can see here, there are lots of opportunities for us with aficamten in OHCM, aficamten, and NHCM. Omecamtiv now in COMET, CK-586 entering phase II. Lots of opportunities to demonstrate value, shareholders, and returns, and we expect that we can... If we continue to execute well, and hopefully now that you've met more of our colleagues, you have the similar confidence we do, that we have an excellent team in a position to drive execution and value for shareholders.
Here, here you can see how not over five to 10 years, not over 10 to 20 years, we can take this company to the next level, and you've seen here, on this slide, how we intend to be measured by that, and I trust that you'll hold us accountable. We're building something different. Hopefully, you've heard that we're not just good students of science and biology, but we're good students of business. We're good students of commercial launch. We listen, and we learn. We apply those learnings to ways that we can address a new opportunity, not like other biopharma companies that may have broken their pickaxe in cardiology, but by learning from those companies in specialty markets applied to cardiology, how we can build a business, first in HCM, and then extending to two bookends of heart failure.
Not all heart failure, where Entresto and SGLT2 inhibitors are playing a meaningful role, but on the ends of that spectrum, severely reduced ejection fraction, supernormal ejection fraction, where drugs that modify cardiac contractility ought to play a meaningful role, given the unmet need, given the etiology, given the pathogenesis of the disease, and how that translates, not just science to medicine, but medicine to business in terms of important return on investment, return on shareholder equity. Here's a very busy slide. I'll end on this slide. But you can see here how we are thinking about commercial together with pipeline and the foundations for that, that are rooted, anchored in good financial discipline. You heard from Sung, how we're good stewards of shareholder capital, but that's not sufficient.
We have to be capital efficient, we have to be gated in investment spending, we have to be thoughtful in terms of how we apply our precious shareholder capital to building this business. And these are all the ways that you can track and monitor our progress over the next couple of years. With that, we'll end. Thank you. Thank you for taking so much time this morning to listen and learn from us, and we'll be available, as Diane said, to answer any other remaining questions, and we look forward to keeping you updated on our progress.