Good morning. I'm Diane Weiser, Senior Vice President, Corporate Communications and Investor Relations. I'm pleased to welcome you to New Horizons in Hypercontractility, our 2023 Virtual Investor and Analyst Day. Over the course of the next few hours, we plan to review the broad development program for aficamten and outline commercial readiness for its potential approval and launch in obstructive hypertrophic cardiomyopathy, as well as present new preclinical data for CK-586, a cardiac myosin inhibitor, in development for the potential treatment of patients with heart failure with preserved ejection fraction. Today's slides are available for download on the right side of the webcast. We will be hosting a Q&A session at the end of our program today. You can submit questions at any point during the event using the Ask a Question tab on the upper right-hand side of the webcast. Next slide.
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. Our actual results might differ materially from those projected in these 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 call. Next slide. I'm very pleased to welcome several leaders from our team who will present today.
Robert Blum, President and CEO, Fady Malik, Executive Vice President, Research and Development, Stuart Kupfer, Chief Medical Officer, Steve Heitner, Vice President, Clinical Research and Therapeutic Area Lead, Cardiovascular, Dan Jacoby, Senior Director, Clinical Research, Cardiovascular, Andrew Callos, Executive Vice President and Chief Commercial Officer, John Jacobe, Vice President, US Marketing for Aficamten, and Jeff Lotz, Vice President, US Sales and Operations. Next slide. I'm also happy to welcome three leading hypertrophic cardiomyopathy experts joining us for our panel discussion later today. We have Dr. Ted Abraham, Meyer Friedman Distinguished Professor of Medicine, Division of Cardiology, University of California, San Francisco, Co-director, UCSF HCM Center of Excellence, Director, UCSF Adult Cardiac Echocardiography Laboratory. We have Dr. Caroline Coats, Clinical Senior Lecturer, School of Cardiovascular and Metabolic Health, The University of Glasgow, and Dr. Carolyn Ho, Associate Professor, Harvard Medical School and Medical Director of the Cardiovascular Genetics Center. Next slide.
Here's a look at our agenda for the day. We'll start by walking you through how we're building a specialty cardiology company, followed by presenting the foundation of cardiac myosin inhibition and the mechanism of HCM as a disease. Then we'll move into the broad development program for Aficamten, which will be followed by a quick 5-minute break. From there, we'll dive into the HCM patient perspective with Megan Link, a person living with HCM, who will share with us her experiences living with the disease. Following that conversation, we'll present our commercial readiness activities for aficamten, which will be followed by our panel discussion with our expert HCM physicians. This will conclude the aficamten portion of the program, and then we'll shift gears into HFpEF and the CK-586 development program before moving into the Q&A session.
Finally, Robert will make some closing remarks before we conclude the event. Next slide. With that, I'm pleased to hand it over to Robert Blum, President and CEO.
Thank you, Diane, and thanks to everyone for joining us today. I'd like to set some context for what you're going to be hearing throughout this morning, and that's from a corporate angle, how we're going to be building a specialty cardiology franchise anchored in aficamten. Next slide, please. As you can see on this slide, we've given significant strategic thought to how we want our anchor foundation in aficamten to layer in and build a specialty cardiology franchise over time, and as we'll be welcoming other products into that same business opportunity. Starting with aficamten, with focus to obstructive HCM, based on results from SEQUOIA, expected later this year.
As over time, we hope that will lay a foundation for other indications for aficamten to follow, including potential to expand to first-line treatment, as could come with the addition of the MAPLE-HCM study and data and indication, and followed from that, a potential expansion to include non-obstructive HCM, as would be informed by the results from ACACIA. SEQUOIA, MAPLE, and ACACIA are all three Phase III studies of aficamten already underway. And from there, building to CK-586, borrowing from some of the same biology and pharmacology, an extension to HFpEF, a subset of patients with HFpEF whose hypercontractility resembles that of nHCM.
Over time, expanding further to include cardiac myosin activation, cardiac troponin activation, as would be augmented with additional indications as we might hope to come from omecamtiv, potentially approved in Europe, and ultimately CK-136, directed to specialty segments of advanced heart failure. Next slide, please. Ultimately, we're looking at a specialty cardiovascular model, the likes of which we frankly don't see as having precedent in biopharma. Other biopharma companies with interest in cardiology typically focus to a much more diffuse primary care segment. As you can see, our interests are intentionally focused to those high unmet need opportunities treated by a relatively concentrated segment of cardiologists.
Your classical 80/20 rule, if you will, in particular, where HCM is largely treated by fewer than 10,000 cardiologists, mostly in centers of excellence, and even as diffused beyond that, community hospitals, where we think with a relatively limited customer-focused sales and marketing infrastructure, as depicted on the right, we can build a valuable business, a concentrated investment with a high return on investment for potential shareholder return. Next slide, please. And here you can see illustrated how we layer in a investment in aficamten over different indications, ultimately, as we'll build a growing revenue base that we believe starts with oHCM, grows within HCM, and ultimately provides significant value and benefit for patients and ultimately for shareholders with a growing revenue base and a high return on sales. Next slide, please.
That extends to Europe, and we've been good students of those companies who have preceded us in terms of how and when they've built businesses in Europe. Frankly, it's our conclusion that most biopharma companies, when they go to Europe, get it wrong and oftentimes have to retreat. What we believe instead is aficamten, as layered with different indications, affords us an opportunity to gate investments in Europe, focusing to certain high-value clusters, initially, over time, ungating, as we see regulatory progress and proximity to local reimbursement. Ultimately, we believe the same thing holds true in Europe, as is in the case of North America, a high return on investment for potential returns for the benefit of patients as well as shareholders. Next slide, please. Ultimately, we believe we're going to be building something that's somewhat unprecedented in biopharma.
Most biopharma companies with interest in cardiology focus to competing in highly diffuse markets where they have lesser payer leverage, where ultimately it requires larger investments in sales, marketing, and distribution, oftentimes competing with generics or much larger companies that have advantages. How we foresee Cytokinetics positioned is in the specialty cardiology space, borrowing from lessons learned from other specialty pharma companies and applying it to the biopharmaceutical advantages in cardiology. Here, we're focused to those high unmet need, severely ill patients who may benefit from a novel innovation, where there's a concentrated customer segment, where we can get to it with limited sales and marketing infrastructure, high prescriber interest, limited and specialty distribution models.
We're able, therefore, to attract and retain highly experienced reps who are accustomed to calling on these same customers, and we're thinking about a much more high-touch support services for the benefit of patients and prescribers. Ultimately, we don't see that payers are going to be looking to these categories for high budget impact. Ultimately, it's not going to be a highly managed category and where we believe there's already significant unmet need, those currently being treated, probably the tip of the iceberg relative to the percent undiagnosed, and where the rep interactions with healthcare professionals would likely be much higher value scheduled meetings. So a specialty cardiology business, starting with aficamten, starting with oHCM and building from there. Next slide, please. So that's the context, the background around which I hope you'll be interested in what we're going to be elaborating on today.
It builds on our leadership in muscle biology that has been architected over 25 years of commitment to this space, this area of muscle biology, specifically cardiac muscle biology, where we have built an expertise, a depth that starts with HCM and expands from there. You can see North America to Europe, ultimately from HCM to HFpEF, and ultimately to advanced and severe heart failure. Over these 25 years, we've built very important key relationships with the key stakeholders. That's inclusive of those cardiologists, but also the ancillary network of PAs, nurses, and ultimately payers and the whole institutional context around which we'll be evolving our business from R&D to also include commercial stakeholders. And all along the way, maintaining strong access to capital. We already have a strong balance sheet representing a strong cash runway.
And as I hope you already know, we have architected deals to enable us additional access to capital as that may be warranted, including through Royalty Pharma transactions.... Next slide, please. With that, I'll turn it over to my colleague, Fady Malik, who will provide some education on the biology and ultimately the translation in cardiac myosin inhibition.
Thanks, Robert. In the next few slides, I'm going to give you some background on hypertrophic cardiomyopathy and rationale for developing cardiac myosin inhibitors to treat this condition before diving into the data that my colleagues will present. Next slide, please. Cytokinetics has been a pioneer in the pharmacology of muscle contractility, using the basic biology of the sarcomere that's recapitulated in systems of increasing complexity, such as muscle fibers and intact organs and cells that allow us to begin to discover molecules that modulate the function of the sarcomere and translate them into potential medicines and whose properties we understand through the fidelity of these various different models. Next slide, please. We've approached the contractility of the heart really in two respects.
First, addressing both hypocontractility, there on the bottom, with activators that were developed to improve cardiac contractility in diseases of heart failure with reduced ejection fraction. Today, we'll focus on the conditions where cardiac function is marked by hypercontractility, such as in hypertrophic cardiomyopathy and where we've developed aficamten and CK-586. Next slide, please. Hypertrophic cardiomyopathy is a disease that's phenotypically defined by thickening of the heart in the absence of other cardiac or systemic disease that can produce a similar magnitude of hypertrophy. On the left-hand side, what you see is a normal heart with normal thickness of the walls, filling with blood, pumping with blood with every heartbeat. On the right-hand side, you can see how those walls have thickened, and in fact, the chamber has gotten smaller and can't fill as much with blood.
And in some cases, the hypertrophy is asymmetric so that it blocks the exit of blood leaving the heart into the aorta. This is a disease of the sarcomere that has both monogenic and polygenic etiologies. Next slide. Mutations in the sarcomere seem to have caused the vast majority of hypertrophic cardiomyopathy, where the cause is understood as a monogenic disease. And this consists of really dozens of mutations in the key proteins of the sarcomere that include cardiac myosin, cardiac troponin, tropomyosin, and other elements, structural proteins within the sarcomere. What they lead to is a thickening of the muscle, as you can see on the right, contrasted to the left, but also a disruption of the cytoarchitecture of muscle, with a disarray of myofibrils and the laying down of fibrosis within the myocardium. Next slide.
HCM manifests really in two major forms. One, we call the obstructive phenotype and the other, the non-obstructive phenotype. While they're both marked by thickening of the walls of the left ventricle, in the obstructive phenotype, consisting of about 65 or 2/3 of the patients, you see there that the thickening is asymmetric with thickening in the, what's called the interventricular septum, which interferes with the exit of blood out of the heart into the aorta, creating a left ventricular pressure gradient, an outflow tract pressure gradient, which has been the target for therapy, reducing that pressure gradient in order to improve the outflow of blood in patients with obstructive disease.
On the other hand, patients with non-obstructive disease still have significant issues in terms of their hearts filling and subsequently emptying, because of the thickening and stiffness that develops in the ventricle. Next slide, please. So to address the underlying pathophysiology of hypertrophic cardiomyopathy, one really thinks of how do you reset the sarcomere's intrinsic contractility back to normal? In contractility in HCM, that's increased, because of mutations within the myosin motor or other elements of the sarcomere that lead to excessive cross-bridge formation, outflow tract obstruction, filling pressures that increase or heart muscles that thicken.
Looking to address that pathophysiology by the reversal of these effects, effects that I'll note can be measured quantitatively, either through echocardiography, through biomarkers, or cardiac MRI, all leading, we expect, to improvements in symptoms, improved exercise capacity, improved functional class, and disease stabilization or regression. So this is a therapeutic hypothesis we've pursued really since about 2008. Next slide, please. In designing a cardiac myosin inhibitor, there are certain properties that one, I think, wants to target. First, a rapid onset of action. Patients are highly symptomatic and thus, being able to provide symptom relief relatively quickly upon initiating drug therapy was a goal of ours in developing a cardiac myosin inhibitor.
The other is being able to predictably dose a cardiac myosin inhibitor in a way that can be guided by echocardiography and simply treat it as a drug that you either titrate the dose up or titrate the dose down. We wanted to avoid off-target effects that might be seen in combination with some of the medicines that these patients commonly take. And importantly, we wanted to ensure that should one titrate the drug to a level where cardiac function is decreased excessively, that down titration of the drug or washout of the pharmacodynamic effect similarly occurs rapidly. Next slide, please. Focusing on these properties led us to the discovery of aficamten. Aficamten is a small molecule that binds to the head of myosin, the mechanical-chemical domain that converts ATP into mechanical force.
It stabilizes myosin in a post-power stroke state, where it's unable to undergo further productive power strokes. In essence, it takes what's on the left, which are many active cross bridges, and reduces the number of active cross bridges as seen on the right, with fewer hands pulling on the rope, the rope being the actin filament. Next slide, please. Aficamten is unique in other ways, particularly the way that it binds to myosin. It binds in a pocket above the ATP binding domain. As you can see in the structure on the right, where another small molecule called blebbistatin binds. Blebbistatin is a good tool in that it enables us, because it fluoresces when it binds to myosin, to show that aficamten and binding can displace blebbistatin, and thus the fluorescence decreases.
It identifies that crystallographic site on the myosin as the binding site for aficamten. Interestingly, with the other cardiac myosin inhibitor in the clinic, mavacamten, you see that it doesn't displace blebbistatin, and likely it binds in a different spot on cardiac myosin. Thus, these mechanisms are distinguishable, and we think ultimately that it contributes to some of the differences between the two molecules. Next. One important aspect of aficamten is its therapeutic index, and this was carefully optimized through many rounds of trial and error in order to produce a shallow exposure response relationship as we could find.
So this is defined by, in this rat model of cardiac function, by increasing doses leading to increasing exposures to aficamten, and, and that leads to a fall in cardiac contractility. But the steepness of that curve, the ratio of the IC 50 to IC 10, is about 10-fold, in contrast to mavacamten, where we, we found was about a 3-fold difference. The half-life of aficamten, as we predicted from preclinical studies, was about 3 days, and in humans, turned out to be similar. Next slide, please. This concentration-response relationship, which is really important to the way that aficamten is used in humans, was recapitulated in dogs, in healthy humans, and in humans with hypertrophic cardiomyopathy. As you can see here, the concentration-response relationship plotted in these various studies overlaps or it looks identical.
Thus, this fundamental property, which was designed into aficamten, has translated with fidelity into humans. Next slide, please. So with that, I'm gonna turn it over to Andrew Callos, who will talk to you about the HCM landscape.
Thank you, Fady. In this section, I will cover the landscape focused on the U.S., the prevalence of HCM, as well as the addressable population and market, the way we view it. Next slide. First, let me start with the potential application for CMIs, or cardiac myosin inhibitors, the mechanism of aficamten. To the left, you see HCM and the prevalence of HCM of around 1.1 million patients, and how that prevalence splits between obstructive HCM and non-obstructive HCM. I'm gonna focus the rest of this presentation on HCM. Later, we will talk about the use of CMIs in a subset of heart failure, a subset of heart failure with preserved ejection fraction, and that population is about 1 million patients. Next slide.
The true prevalence in the U.S. is estimated to be between 700,000 and 1.1 million patients in the U.S., and that is growing at the same rate as the population. There is a study that has the prevalence up to 1.1, I'm sorry, 1.5 million as well. The low end of the range is really based on that 700,000, is based on a published study in Circulation, which was based on an echocardiographic analysis of 4,000 subjects. The principal finding of the study was that HCM occurs in about 0.2% of the general population, and then that 0.2 is then extrapolated to the overall population to get to the 700,000.
Again, there is a top end of the range in the 1.5 million, based on a more recent study in the Journal of the American College of Cardiology. The 1.1 million, which you see here to the, as the right upper end range, is our planning assumption, and that is based on a syndicated report published by the Cardiovascular Resource Group. The split of HCM is approximately 65% or two-thirds obstructive and one-third not obstructive. We are very confident, if you see in the, in kind of the middle circles in each box, the diagnosed population of oHCM and HCM of 300,000 in total, of which 200 are for obstructive and 100 for non-obstructive.
We're very confident in that number, as that's based on a 5-year longitudinal claims analysis of patients who have the diagnosis of HCM, you know, per their medical record. The addressable population is that circle within, kind of the symptomatic, HCM patient. So the total addressable population in 2025, we're assuming to be, around 200,000 patients, and that really is the addressable market. Next slide. So to the left, you see this 300,000 of diagnosed HCM patients in total, obstructive and non-obstructive, and again, growing at the rate of 1%, consistent with the U.S. population. To the right, you see the 5%, which is the increase in diagnosis. That is informed by a 6-year study in the American Journal of Cardiology of actual increase in diagnosis rate.
And there's really good rationale to believe that that diagnosis rate will continue at that rate. Obviously, there's disease awareness, including some direct-to-consumer television, highlighting and building awareness for HCM. There is AI models, including Viz.ai, which looks at electrocardiograph and highlights patients who are suspect of HCM. The guidelines do include the American, t he AHA, and guidelines do include screening tests. So if a patient is diagnosed with HCM, kind of their first-degree family members should also be screened for HCM. And obviously, when there's a disease-modifying therapy, like a CMI on the market and multiple products on the market, that also increases diagnosis and utilization. So we believe by 2033, that diagnosed patient population will be 500,000 overall in the US. Next slide.
So let me just break out obstructive HCM just in terms of demographics and symptom status. Now, HCM is fairly evenly split across gender, and while patients are typically diagnosed in their early 40s, the current average age of an obstructive HCM patient is in their early 60s. To the right is the symptom status. So that status informs the patients that are more likely to seek treatment that would be supported by payers. The focus of clinical studies, anticipated labeling, and reimbursement is on the New York Heart Association Class II and Class III patients, which represent about two-thirds of the obstructive HCM population. These patients have physical activity limitations, where CMIs have the potential to improve symptom status. Next slide.
So while many patients are treated, you can see to the left here, 90% of patients who are diagnosed with oHCM are treated. To the right, you can see the treatment that these patients are on. These are largely non-disease-modifying therapies, such as beta blockers or calcium channel blockers. So despite the vast majority of HCM patients being treated, many are still symptomatic and not well controlled, as evidenced by the previous slide, where you saw the New York Heart classification split. Next slide. So similarly, for non-obstructive HCM, you can see the gender split, where this actually skews a little higher towards male, with the average age again in the early forties. I'm sorry, age of diagnosis in the early forties and the average age in late fifties.
The symptom status again informs where, CMIs could be utilized. There is a range of symptom status, based on varying, publications, somewhere between 35% and 50%. You know, our analysis and, and assumption is it's about a 40% of the non-obstructive HCM patients would be eligible for CMIs. Next slide. Like the OH, oHCM, the vast majority of patients in non-obstructive HCMs are treated with one or more therapies, which you see to the right. The products to the right, are used despite no clinical evidence or indication for the treatment of non-HCM. Should aficamten get approved, our call to action will really be to get obstructive and non-obstructive patients have a, a aficamten added on to their, existing therapy. Next slide. So despite patients being treated, the symptoms limiting function are very burdensome.
So when we speak to the patients living with HCM, this is one view from HCMA, a patient association, and their Voice of Patient report when asked about their most burdensome symptoms. The report also references that about 60% of patients are limited from even moderate activity, and that 50% of patients can't walk one flight of stairs without significant discomfort. Assuming the majority of these patients are treated with non-disease modifying therapy, they're highly symptomatic, as evidenced in this slide. Next slide. So the overall market opportunity, let me orient you to this slide. The diagnosed patient population of 300,000 to the left in 2023, which we see growing to 500,000 in 2033, is the overall population. The purple is those that are symptomatic and eligible for CMIs.
So they would be the New York Heart Association twos and threes. The green are our projections for that subset who are considered for CMIs, actually using CMIs, with the penetration rate between 25%-40%. Our assumption is that when, you know, should aficamten get approved and launch in 2025, that over 80% of those patients in the purple that are eligible for CMI are still available and not on a current CMI therapy. In 2028, when we would potentially launch nHCM, that number would be greater than 90%. So it gives us a large opportunity of market to compete for. The overall market has the potential to be over $5 billion, you know, based on the higher level of 40%. So, a large unmet need for patients and a large opportunity for Cytokinetics.
Next slide. With that, I will turn it over to Stuart Kupfer.
Thanks, Andrew. So, let's begin to review our clinical development program and discuss how we're translating the elegant research that Fady described to help patients with HCM. Next, please. So, based on this schematic overview, I think it's readily apparent that we've planned and executed a very robust clinical development program in obstructive and non-obstructive HCM. I think it's actually quite amazing that we now have 4 ongoing Phase 3 trials with aficamten in HCM. So at the top, there's SEQUOIA-HCM, which is our pivotal trial. In obstructive HCM, we're comparing aficamten to placebo, evaluating exercise capacity, heart failure symptoms, and health status. Another very interesting trial is MAPLE-HCM.
We're comparing aficamten monotherapy to metoprolol monotherapy, and this is to evaluate, I think, a very interesting objective, superiority of aficamten to first-line standard of care beta blocker treatment. Below that is FOREST-HCM. This is our long-term open-label extension. Patients from REDWOOD and SEQUOIA have rolled over into that study, and we have some new and interesting results that Steve Heitner will be presenting in a moment. Finally, at the bottom, we've initiated a Phase 3 trial in non-obstructive HCM, which we're calling ACACIA-HCM. Here we're comparing aficamten to placebo, not only to evaluate heart failure symptoms and functional capacity, but this is a study with the treatment duration approximately 3 times longer than SEQUOIA and MAPLE, and it gives us an opportunity to evaluate clinical outcomes.
So before we discuss these Phase 3 trials, I want to spend a few moments discussing Phase 2 results that inspired the potential benefit of aficamten and inform the study designs of these Phase 3 studies. Next, please. So in our Phase 2 REDWOOD-HCM trial, we conducted 2 dose-finding cohorts, a low dose Cohort One and high dose Cohort Two in obstructive HCM. REDWOOD-HCM was a 10-week, double-blind, placebo-controlled trial in which we enrolled patients with symptomatic obstructive HCM, and these patients had to have both elevated resting and provoked or Valsalva gradients. And aficamten dosing was individualized. So, the dosing was individualized to target achievement of both resting and Valsalva gradients while maintaining, you know, while maintaining a normal ejection fraction, above 50%.
Furthermore, the dose titration or dose optimization was completed in a relatively short timeframe, within six weeks. Next, please. So there was rapid reduction and normalization of gradients in both cohorts, with greater reduction observed in Cohort Two, with availability of the higher 20-milligram dose. After the 10-week treatment period, there was rapid reversibility of gradients, and this paralleled a rapid reversibility of ejection fraction. And so this profile of rapid reversibility informed the potential to manage the drops in ejection fraction by dose down titration rather than treatment interruption. Next, please. So there was a high proportion of responders to aficamten in REDWOOD. You can see that in the middle bar, Cohort One, there was a large proportion of responders in this low-dose cohort, and we defined responders as achieving both resting and Valsalva gradient targets.
And then the high dose Cohort Two on the right, nearly every patient was a responder. These results gave us an indication that aficamten could completely eliminate the outflow obstruction gradient in most patients with HCM. Next, please. So these gradient reductions were associated with very large reductions of NT-proBNP, which is a sensitive biomarker of cardiac wall stress and a predictor of clinical outcomes. And just to give you some context here, these, these reductions of NT-proBNP are almost unprecedented. We're observing 70%-80% reductions of NT-proBNP. And just to give you some idea of that magnitude, typically what you might observe in effective agents to treat heart failure with reduced ejection fraction, it's in an order of 30%. So these are quite, quite amazing results.
They were associated with improvements of NYHA class, indicating some improvement of heart failure symptoms and functional capacity. Next, please. These reductions in NT-proBNP were also associated and corresponded with improvements of cardiac structure and diastolic function. We observed reductions of left ventricular mass index, left atrial volume index, and improvements of parameters of diastolic function. These results suggested there was at least some degree of normalization of cardiac contractility and improvement of left ventricular filling pressure. Next, please. Now, improvements of these efficacy parameters were also associated with good tolerability, and importantly, with continuity of treatment. There were no treatment interruptions or discontinuations. There were no patients who had ejection fraction less than 40%. Only two patients dropped below 50%, and they were asymptomatic, and there was rapid reversibility of ejection fraction.
The adverse event profile was similar between aficamten and placebo. Importantly, in an additional cohort 3 that we conducted in patients receiving disopyramide, which is sometimes used in patients with more severe disease, the pharmacodynamic profile and the safety profile were similar to what we observed in cohorts 1 and 2. In summary, the safety profile, along with the robust efficacy results that we observed, you know, indicated that aficamten potentially has a wide therapeutic index and only perhaps infrequent drops of ejection fraction that could be readily managed by dose down titration rather than treatment interruption. Next, please. With that, I'll turn it over to Steve Heitner to discuss FOREST-HCM.
Thank you, Stuart. Next slide, please. It gives me great pleasure to present an update on the conduct and data that we've been collecting from the FOREST-HCM open- label extension trial. And the way that we're gonna structure this initially is just by first letting you know that we have more than 200 patients that are currently enrolled in the FOREST-HCM trial. We're gonna present data that we analyzed from last month, September fifteenth data cut, on the 143 available patients. I'll let you know that almost every patient that is offered participation in this development program chooses to participate in the open- label extension.
The long-term data that we're gonna show you is gonna demonstrate sustained durability for the duration of treatment, in terms of the symptoms that patients experience, the hemodynamics that we see on echocardiography, the biomarkers that we measure in those patients' plasma, as well as the importance of being able to avoid therapies like septal reduction therapies, which are the most invasive therapies that these patients could potentially be exposed to. Next slide, please. I'm gonna go back to what Andrew was saying a minute ago, about the prevalence and the sorts of patients that we see in our clinic, and I'll point out that the FOREST-HCM trial demographics indicate that the patients that we have in that study are very similar to what one would experience or see in the clinic.
With about 40% of patients in our study being Class III, even split between male and female, and patients taking the whole gamut of available therapies, per guideline recommendations. I'll also point out that the patients in FOREST-HCM have hyperdynamic left ventricles with a mean ejection fraction of almost 70% and high resting and Valsalva left ventricular outflow tract gradients. On the right-hand side, and on the left-hand side of that bar chart, you see how patients are walking through the titration period, where they started on 5 milligrams on day 1, and as they progress through the titration, you can see increasing representation of the higher doses, 10, 15, and 20 milligram dose strengths.
I'll also point out that once patients achieve their target dose, they tend to stay on their target dose through the duration of therapy. Next slide. So a couple of important things to pay attention to over here. The first is that during that titration period, we had no patients drop their ejection fraction below 50%. And once the patients have achieved their steady state, and that occurs with two-thirds of patients receiving the higher dose strengths available, 15 and 20 milligrams. Once they've achieved that steady state, about 30% of patients actually choose to undergo dose reductions of their background medical therapy, either beta blockers, calcium channel blockers, or disopyramide, at their discretion or the discretion of their treating physicians. Next slide.
We just divided the therapeutic periods into two periods. Firstly, we have the titration period, which occurs early on, and then once the patient reaches that steady state dose, we call that the maintenance phase. We looked at almost 600 echocardiograms in the patients that had achieved that. There were almost 100 patients achieving that steady state. And what we found is that firstly, there were no patients who dropped their ejection fractions to below 40%. To go back to what Stuart said, maintaining treatment continuity is incredibly important for these patients. So we had no treatment interruptions because of an exaggerated pharmacodynamic effect.
The other thing that I'll point out is that 99.5% of patients in the treatment maintenance phase who had an echocardiogram did not result in a dose down titration. There were, in fact, only three patients with an ejection fraction of under 50%, two of whom had modest decreases of ejection fraction to 47 and 49%. Both of those patients were asymptomatic and underwent a per-protocol dose reduction with ejection fractions that returned to above threshold. And there was one patient who developed atrial fibrillation with an ejection fraction of 47%. That patient underwent treatment of his atrial fibrillation, as well as a dose reduction of the aficamten. And in fact, all three patients are currently on study receiving aficamten with relief of their obstruction, improvement of their symptoms, and biomarkers.
Next slide, please. In terms of the hemodynamic effect, the treatment effect, of this drug, this goes back to what Fady was showing really early on and translating it into patients. On the left-hand side, you see the resting gradient. In the middle, you see the Valsalva gradient. And I'll point out that, in the salmon-colored box, that's the titration period. Once the patients have completed their titrations, their gradients are well below the diagnostic threshold for severe obstructive HCM, and that treatment effect is maintained for the duration of treatment exposure. And this is in the setting of maintaining a mean ejection fraction of around 65%, down from that 69% that I showed you in the baseline characteristics, with a safety threshold being 50% for dose down titration. Next slide, please. Next slide.
So we have several ways of looking at efficacy, and on the left-hand side over here, you see the cardiac troponin that Stuart was talking about in the Phase 2 study, and we're detecting about a 30% reduction from baseline in the plasma high sensitivity cardiac troponin levels. This is a marker of myocardial injury and is also associated with cardiovascular outcomes in patients who have high high baselines and high sensitivity cardiac troponin. Next slide. The NT-proBNP shows again a very impressive reduction as patients are exposed to treatment. In this example over here, the mean goes down from about 750 picograms per milliliter at baseline very rapidly to slightly above the normal threshold, which is 100 and is maintained for the duration of therapy exposure.
This represents about a 70% reduction relative to baseline. Next slide. Next slide. And this is what is most important to patients. So how do they feel on our drug? And what we can see over here is that 70% of patients who are started on aficamten in the FOREST-HCM trial report a 5-point improvement in their KCCQ clinical summary score. The minimal clinically important difference is about 5 points or is 5 points, and 70% of patients experience it. And actually, 30% of patients experience a moderate to very large improvement in their KCCQ scores as treatment progresses. Next slide. Their physicians also report that the patients are doing much better.
Over here, you can see that at baseline, about half of the patients are severely symptomatic in Class III, and by a year, half of the patients or more than half of the patients are completely asymptomatic. And that proportion of asymptomatic patients is maintained for the duration of the trial. And in fact, 80% of patients who are started on aficamten report at least 1-point improvement of New York Heart Association class at every visit after treatment initiation. Next slide. In terms of whether they were able to avoid eligibility for septal reduction, you can see that as early as 12 weeks, 90% of patients who were considered SRT eligible at baseline are no longer eligible, and this proportion is maintained in this example over here, for at least 1 year of treatment exposure. Next slide.
I wanted to show you an example, harkening back to what Fady was showing with the cartoons of the HCM. At the top, you can see a baseline echocardiogram of a patient with obstructive HCM, the hyperdynamic left ventricle, which is the chamber towards the top of the screen. The smaller chamber underneath that is the left atrium. And you can see the squeeze of the heart is hyperdynamic. In this case, I would estimate that's about 70%-75%. The middle panel on the top over there indicates color flow Doppler, and that shows a substantial mitral regurgitation as a result of the movement of the mitral valve. And on the right panel at the top, you can see the Doppler indicating a resting gradient of 75 millimeters of mercury.
In this example, after just two weeks of exposure of aficamten, you can see that the left ventricular ejection fraction has been reduced to normal. The degree of obstruction is down to 10 millimeters of mercury, which is normal, and now there is just very mild or trace mitral regurgitation. These hemodynamic features are confirmed in terms of the clinical impact. At the top, you can see the patient started out with New York Heart Association Functional Class III and improved very rapidly to asymptomatic, and that was maintained for the duration. In this case, the patient was exposed to aficamten for 120 weeks. And those clinical features are also confirmed by a very impressive reduction in NT-proBNP from more than 1,000 to actually below the normal threshold of 100.
In this case, it was undetectable, being below the level of detection of 50 picograms per milliliter. Next slide. So in summary, I wanted to point out that almost all patients who are eligible chose to participate in this open label extension, that the patients were actually managed entirely by their treating physicians, who were able to safely titrate these patients in two-thirds of the cases to the higher available doses of aficamten. The patients who completed the titration period did so without experiencing ejection fractions of under 50%, and 99.5% of monitoring echocardiograms have not resulted in a per protocol dose reduction. The efficacy is maintained, and of the patients who are eligible at baseline for septal reduction therapy, 90% or more of them were no longer eligible.
Aficamten is well tolerated in the FOREST-HCM trial, with 60% of patients experiencing at least one treatment adverse event, but no treatment interruptions, no treatment-related SAEs, and no patient deaths. Next slide. And with that, I'm going to hand it over to my colleague, Dan Jacoby, who's going to tell us about the progress of SEQUOIA-HCM. Dan?
Thanks, Steve. Next slide, please. I'll be speaking with you for the next few minutes about the SEQUOIA-HCM Phase 3 trial. As you know, this trial completed enrollment, and we expect top line results by the end of the year. The schema for the trial is here on the slide, on the right-hand side. The key points about this trial study design include a primary endpoint, with it, which is change in peak VO2 by CPET from baseline to week 24 as the sole primary endpoint. The secondary objectives include measuring the change in the KCCQ, Kansas City Cardiomyopathy Questionnaire, and improvement in the New York Heart Association class at both weeks 12 and week 24.
The study enrolled 282 patients treated with standard of care, with at least a resting gradient greater than 30 and post-Valsalva gradient of greater than or equal to 50, New York Heart Association Class I or II at screening and exercise performance quantitatively assessed at less than 80% of predicted by cardiopulmonary exercise test. As in the REDWOOD study and the FOREST study, individualized dose of titration based on echocardiography was conducted with LVEF greater than or equal to 55% and post-Valsalva LVOTG, left ventricular outflow tract gradient, greater than or equal to 30 millimeters of mercury, indicating the opportunity for uptitration to doses of 5, 10, 15, or 20 milligrams per day. Uptitration was optimized by week 8, and follow-up was at week 24, with end of study observation for safety at week 28.
Patients were randomized 1:1, placebo versus aficamten over the course of the treatment period. Next slide, please. Here is the enrollment summary across regions. North America enrolled 94 patients, China enrolled 46, and Europe and Israel enrolled 142 patients combined. On the next slide. Next slide, please.... We have here a summary of the baseline characteristics, which reflect a highly symptomatic patient population with reduced exercise capacity. On the left-hand column of the baseline characteristics, you will see age, sex, ethnicity, region, vital signs, and HCM history, all reflecting a generalizable population. In particular, on the right-hand side, I'd like to point out the significant symptom burden despite background therapy. 61% of patients were on beta blockers, while another proportion were on non-dihydropyridine calcium channel blockers, with 12.8% taking disopyramide.
The baseline peak VO2 in the middle of the right-hand column reflects a patient population with reduced exercise capacity, and that, of course, is by design. As I mentioned on the previous slide, that we required less than 80% predicted peak VO2 for enrollment. It's notable that the predicted peak VO2 in this patient population was approximately 57%, which reflects a relatively impaired, exercise-impaired patient population. As Robert mentioned early on in the presentation and others have commented, our program is designed to study broadly the patients who have hypertrophic cardiomyopathy reflected in general cardiology practices, and I think that's what we have here. An analogy that occurred to me when I saw this data, which I found very exciting, was that in order to create a gourmet dinner, you need gourmet ingredients.
I'd like to think of these baseline characteristics as the right ingredients, the ones that we aimed for, to fulfill that opportunity to demonstrate benefit. Next slide, please. Let me summarize the objectives that we met for this patient population for this enrollment. The target population was successfully enrolled and representative of a very broad group of oHCM patients. I can tell you I still see patients in the HCM clinic. My clinic is next Friday, and many of the patients that I see referred to me in my clinic would be excellent patients for enrollment in SEQUOIA, were we still enrolling. Population is diverse by race and sex. There was objective physical limitation, demonstrated by a high degree of symptom burden.
There is an approximately equal split between CPET modality that favors treadmill slightly, with 55%, and all currently available HCM therapies for North America and Europe are represented. Significant representation of patients not receiving background beta blocker therapy should be noted. All the patients, and here's a very significant point in my view, all the patients in SEQUOIA-HCM have passed through the dose titration period, and there have been no reports of LVEF less than 40%. Reporting is mandatory as it triggers dose interruption and conversation with the medical monitor. Next slide, please. As we review our expected milestones for 2023, we expect top-line results for SEQUOIA-HCM by the end of the year. Next slide, please. I'll now be shifting away from SEQUOIA-HCM into MAPLE-HCM, our Phase 3 clinical trial of aficamten compared to metoprolol. Next slide.
I'll spend a minute now reviewing the background of just why it might be that a study directly comparing aficamten with metoprolol could be expected to yield important results. The use of metoprolol in obstructive hypertrophic cardiomyopathy has a long history, but not necessarily backed by prospective clinical trials. In fact, the use, the usefulness of beta blockers across the field of cardiovascular disease has been augmented and supported strongly in the fields of heart failure, reduced ejection fraction with reduced mortality, and also for reductions in mortality and benefit in post cardiac infarct. However, this medication has many so-called off-target effects.
In a recent study looking at the potential of withdrawal of beta blocker therapy to see what the effect would be in patients with heart failure, preserved ejection fraction, based on a suspicion that perhaps the side effects of beta blocker may be negatively impacting patients' functional capacity or symptoms, it was observed that exercise capacity improved with the withdrawal of beta blocker therapy in patients with heart failure, preserved ejection fraction, and that was mirrored by an improvement in symptom burden. You'll note that, Panel C shows the Minnesota Living with Heart Failure Questionnaire, and a lower score on the Minnesota Living with Heart Failure Questionnaire is a better score. It's the opposite of the Kansas City Cardiomyopathy Questionnaire, so it's worth pointing that out.
You'll see on the bottom a second study that was done recently, which is the only, prospective, randomized, and in this case, crossover, study comparing metoprolol against placebo in patients with symptomatic obstructive hypertrophic cardiomyopathy. This study demonstrated that while there is some improvement in gradients, particularly post-exercise gradient, with the use of beta blockers, and there was also some improvement in symptoms, the filling pressures within the ventricle did not substantially change, and the objectively quantified exercise capacity with peak VO2 did not significantly change. Probably what we are seeing here, it's possible, is that in some way, perhaps because of beta blockers, so-called off-target effects, or in fact, on target effect of lowering the heart rate, particularly during exercise, it may be that patients are unable to realize increased exercise capacity, in many cases, with effective use of beta blocker to reduce gradient.
Next slide, please. This provides ample background and support for a head-to-head study comparing aficamten and metoprolol with a double-dummy design and 1:1 randomization to assess for improvements in exercise capacity for the treatment of symptomatic obstructive hypertrophic cardiomyopathy. The MAPLE study, the MAPLE trial, is planned to enroll approximately 170 patients, with a primary endpoint, again, of change in peak VO2, assessed by cardiopulmonary exercise test, and secondary endpoints, including change in New York Heart Class, change in KCCQ, change in NT-proBNP, and very importantly, measures of structural remodeling by echocardiography. The study is designed to include two different primary types of hypertrophic cardiomyopathy patients with obstruction. In the first case, it includes patients with recently diagnosed disease or patients who are otherwise treatment naive. So patients who have obstructive hypertrophic cardiomyopathy, who have not been chronically on background therapy or are newly diagnosed.
In the second group, patients with a history of obstructive hypertrophic cardiomyopathy who are currently taking standard of care medicines, beta blocker, calcium channel blocker. The reason we're particularly interested in this is because it has never been demonstrated, actually, that early treatment, or first-line, potentially treatment with cardiac myosin inhibitor could potentially be beneficial. And so we are specifically looking at these two groups of patients. Another special design or specific design feature of MAPLE-HCM that differs from SEQUOIA-HCM is that it includes a relatively less sick population. Patients with LVOTG of resting greater than or equal to 30 or post-Valsalva greater than or equal to 50. In the case of SEQUOIA-HCM, it's resting greater than 30 and post-Valsalva greater than or equal to 50. LVEF should be greater than or equal to 60, and patients should have NYHA Class II or III.
The study will be conducted for 24 weeks, and it has already started enrolling, with sites opening across the U.S. and EU soon. Next slide. We believe that MAPLE-HCM will contribute substantively to an evolving treatment paradigm. Pending favorable results, the MAPLE-HCM study trial has the potential to evolve the treatment paradigm, specifically by supporting the rationale for first-line use in HCM treatment guidelines, demonstrating efficacy in earlier diagnosed patient population, demonstrating a more favorable side effect profile of aficamten versus metoprolol. Remember, Dr. Heitner alerted us to the fact that a significant number of patients were coming off of background therapy in the FOREST-HCM study. And demonstrating structural remodeling potentially as a secondary endpoint, which can be interpreted as disease modification. Next slide.
Again, as part of our expected milestones for 2023, we expect to continue enrollment of MAPLE-HCM, the second Phase 3 trial of aficamten in oHCM. With that, I will hand things back over to Steve to review the results from cohort 4 of REDWOOD-HCM and discuss ACACIA-HCM. Thank you.
Thanks, Dan. I can't wait to see the results of both of those studies. Next slide, please. So cohort 4 of the REDWOOD-HCM trial evaluated non-obstructive HCM on the backbone of the REDWOOD-HCM trial, so the kind of schedule of events and the duration of exposure was exactly the same. The only difference was the nature of the patients that we enrolled were non-obstructive HCM patients. You'll see that the patients were exposed to 3 different dose strengths in this particular study, titrated over the first 6 weeks, and then exposed at steady state for an additional 4 weeks, with a 2-week washout period between week 10 and 12. So nothing really that novel over here other than the patient population being studied. Next slide.
What is novel, however, is that, you know, aficamten did seem to have what looked like an impressive improvement in patient symptoms, with a mean improvement of KCCQ from baseline of almost 11 points over just the 10-week treatment period. And you can see again in that salmon color over there, that's the washout period, where symptoms seem to be drifting down to where they were at baseline after the drug is withdrawn. When you look at this in a categorical way, you know, almost 60% of patients experienced that minimal clinically important difference of 5 points or more in the KCCQ score, something that's very important to our patients. However, I'd like to point out that...
You know, 25% and 20% of those patients experienced large to very large and moderate to large increases in their KCCQ. So these were patients that reported feeling much, much better after treatment with aficamten. And again, their physicians reported that the patients were being were able to do more in terms of a day-to-day function. You'll see on the left-hand side, at baseline, almost 50% of patients were Class III, severely symptomatic, and by 10 weeks, about a quarter of patients were entirely asymptomatic with about two-thirds of patients being mildly symptomatic and just 10% remaining within that Class III. Again, after treatment was withdrawn, you see symptoms starting to return.
And this is in a setting of 85% of patients titrating to the maximum available dose within this Phase 2 dose-finding study. Next slide, please. So these changes were mirrored. The symptom improvements were mirrored by substantial reductions in both NT-proBNP of more than 50% and high sensitivity troponin of about 20% over that short treatment duration of just 10 weeks. And one interesting thing that we did observe in the study is that patients who complained of chest pain as a symptom, and I'll refer back to a slide that Andrew showed earlier on, where a big chunk of patients with HCM do complain of chest pain.
And patients recruited into this non-obstructive trial, who complained of angina at baseline, and these are patients who complained of angina on a daily or weekly basis, they had an improvement in their symptoms over just that 10-week period. That number of 14 points over there actually translates into those patients complaining less frequently, so going from daily to weekly, now moving more to weekly to monthly angina, which really can impact a patient's quality of life quite significantly. Next slide. So these data actually formed the basis of the design and gave us confidence in moving into Phase 3 for non-obstructive HCM. So we have designed the ACACIA-HCM trial. We presented the study design at the Heart Failure Society of America meeting a couple of weeks ago.
And in essence, what we're doing is enrolling about 420 patients at more than 150 sites around the world. These are patients with non-obstructive HCM. And our primary endpoint is actually what is most important to patients, which is how they feel, and that's the change from baseline in their KCCQ scores. That'll be measured at baseline, and again, the endpoint will be the change from baseline to week 36. Patients will have available the full gamut of Aficamten doses of 5-20 milligrams. This will be dosed according to ejection fraction alone. We also have some key secondary endpoints, which are very important.
We have an objective metric of global exercise performance, as defined by both peak exercise, the peak VO2, and the VE/VCO2 slope, which is a heart rate independent metric of exercise performance. We have some structural metrics, the left atrial volume index, as well as biomarkers, NT-proBNP, and of course, New York Heart Association functional class. As Stuart mentioned earlier on, patients enrolled in the study will be followed for a maximum of 72 weeks in the blinded portion until the very last patient crosses that 36-week primary endpoint analysis period. That will give us the unique opportunity to measure whether Aficamten appreciably impacts cardiovascular clinical endpoints, you know, heart failure events, cardiovascular death, stroke, those sorts of important clinical endpoints.
And then patients after that 72-week period will be offered participation in an open-label extension per study and followed after that. Next slide, please. And again, just to you know, distill that into our milestones, we're continuing. ACACIA is open. We've enrolled patients and we're accelerating our enrollment and site initiation through the remaining part of this year and into next year. Next slide. So with that, we're gonna take a 5-minute break and we'll be back for a very important discussion from our patient representative and we'll see you shortly.
Welcome back, everyone. I'm so pleased to welcome Megan Link. She's a patient living with HCM, and she'll be discussing her experience with the disease. Before we begin our conversation, I just wanna make clear that while Megan was a participant in our Phase 2 trial for aficamten, REDWOOD-HCM, and is now part of our open-label extension clinical study, FOREST-HCM, because aficamten is still an investigational drug, from a compliance standpoint, we cannot have Megan speak about her experience with aficamten specifically. So today in our discussion, we'll focus on Megan's experience living with HCM. So thanks again, Megan, for being with us this morning.
Can you start off with giving us a bit of background into your experience with the disease and what your overall journey has been like?
Yeah, my experience is it's just been a learning curve the whole time. I was born with HCM, so I've known since day one. I grew up seeing multiple different providers, not really a specialist, so there was always the questioning of how is this gonna, like, what's the outcome of this? My experience has just been a lot of teaching and learning.
Great. So what was it like being diagnosed at such a young age? I mean, was this something that sort of consumed you? And what sort of emotional impact has it had on you?
Well, since I was diagnosed when I was little, that's really all I've known. So I don't... I wouldn't say it's consumed me, but it definitely. I had a lot of questions growing up, just knowing, not knowing the uncertainty of what this will be when I get older. So I would say, yeah, just growing up was just learning.
What are your most common symptoms now, and did you ever have a major episode?
I mean, the most common symptoms I would have is the shortness of breath, dizziness, fatigue, getting just fatigued really easily. I would get palpitations all the time, and I had one episode when I was younger that scared me. I actually went to the hospital 'cause my mom thought I was having a heart attack, but I wasn't. But I just had this episode where it felt like my heart was beating from, like, here and then just, like, dropping. So if you can imagine your heart just beating like this, and kinda just feeling it in your stomach, and my mom not really knowing the certainty of my condition, she was worried, so she always was, like, sending me to the doctor's or going to the emergency room to get checked out 'cause she just didn't know what could happen.
I've only had one big episode, but the palpitations was almost daily. Going and hanging out with friends, I would get tired if we were just walking, or if it was hot outside, I always told them I, like, I can't do heat. Like, I could be out there for a little bit, and just the heat would make my heart feel like it was overworking. And yeah.
When you think about living with your disease today, how does it affect your day-to-day life? Give us a sense of what that's like from an everyday experience now.
Well, now my day-to-day life is different. But I am very excited for what the future holds for HCM. Yeah.
Great. And then I think the last thing that we're interested in is, you know, what do you think is most important, when it comes to people understanding this disease? What would you like people to know about, people like yourselves and having to manage this disease? Because it's often, you know, what we call kind of a silent disease, 'cause you can't see it. What would you like people to know about it?
I mean, I would like people to be open-minded when patients with HCM are trying to tell them and teach them about it, because a lot of people don't know what it is, and, like, growing up, I would have to teach a lot about, like, if I'm doing PE and I have to stop, and other kids are like: "It's easy, like, keep going." I'm like: "No, I can't." I would have to teach them and tell them: "Actually, I'm pushing myself to the fullest," and, yeah.
I know you can't talk about your experience on the trial, as we mentioned. Clearly, there's a lot of research, you know, going on. What is your overall kind of impression of how things are going to, you know, what, what your future is living with this disease?
I mean, I feel like the future is really bright for patients with HCM. There's a lot of things coming out, to help them kind of live a somewhat normal life. I mean, I know it's not gonna completely 100% cure HCM, but it will help patients feel like they can live a normal life with less limitations. Yeah.
Wonderful. Well, thank you so much for sharing some of your experience with us and spending the time, talking about what you've been through and your outlook. We really appreciate it.
Thank you.
And then at this point in our program, we're now gonna move to the next section of our presentation, which focus on the commercial readiness for aficamten. With that, I'll turn it over to my colleague, John, who'll be presenting new market research and preliminary positioning for aficamten.
Thanks so much, Diane, and thank you, Megan, for sharing your story with us here today. I'm very happy to be here to review our preliminary marketing approach for aficamten. Over the next 10 minutes or so, I'm going to be highlighting some key customer insights that will inform our overall brand positioning and go-to-market strategy. Next slide. You just heard from Megan, and she really did describe some of the issues that folks who suffer from hypertrophic cardiomyopathy feel on a relatively frequent basis. She talked about uncertainty and having to teach others about the disease state. As you know, patient centricity is in our DNA at Cytokinetics. You've heard from our medical colleagues and clinical colleagues about the science and the cardiovascular impact of HCM. But importantly, as you heard from Megan, and we hear constantly from others, this is a devastating condition.
I really wanted to start with two quotes here, one from an individual living with HCM and another from an HCM treater. The patient: "My life was always unraveling, and after a while, you get sick of being sick and weak. I could not even hold my husband's hand and walk on the boardwalk because I could not keep up with him." An HCM treater says: "Patients make their world smaller and don't realize how symptomatic they have been until they feel well." These and many other stories are guiding our overall marketing approach at Cytokinetics. Next slide. As we look at our overall go-to-market approach, I think of it in three distinct phases: learn, design, and build. As you can see here, our focus to date has really been on the learning phase, and I'm gonna be sharing some key highlights with you.
As we approach 2024 and have our SEQUOIA-HCM results, we'll begin to enter our design and build phase. Customer insights are going to be key for us, and we plan to co-create many of our programs alongside our customers, both patients and healthcare professionals. Next slide. We've, over the past 18 months, done a ton of market research because we truly believe that a deep and profound customer understanding will be a key to our future success. We've commissioned market research with almost 850 HCPs and over 160 individuals who suffer from HCM over the past 12-18 months. I'd now like to highlight some of our learning. Next slide. You heard a little bit from Megan around the patient journey, and we have extensively mapped out the HCM patient journey.
Right here, we're just showing a singular, singular aspect around patient presentation and diagnosis. The overall journey to diagnosis is complex and challenging due to the unique symptoms present in each patient, along with limited disease awareness across the broader healthcare system. All of this leads to confusion and complexity for patients and the HCPs who treat them. Next slide. We know there are many complications of HCM, and although relatively infrequent, sudden cardiac death is on patients' minds a lot. And this is something that we hear time and time again in terms of speaking with patients and healthcare professionals in the HCM care. We know that these things are on their minds. Our discussions with these patients and their families highlight what else is impacting them.
On the right-hand side of this slide, you can see HCM impacts physical function, psychological well-being, social involvement, and just many aspects of everyday life. Next slide. CMIs are offering hope for patients, and CMIs are actually now a reality for some, and their use has entered into European treatment guidelines. You can see here the recently published European Society of Cardiology guidelines. We're hopeful that before long, this too will be the case in the U.S. Next slide. We see all around us that CMI have has transformed the patients' lives for those who suffer from HCM. Here you can see a tweet from Dr. Ashley at Stanford that shows he sees CMIs as game-changing. Clinicians are truly seeing results with these new drugs.
However, the next slide shows that when we talk to respondents about CMIs and their experience, we do hear great results, but we also hear another side of things. There are some challenges that exist, and they have impacted adoption of CMIs. You can see burden of monitoring, concerns about drug-drug interactions, down titration challenges, and lack of coverage and established office protocols are paramount when we talk to providers. The quote on the bottom of the slide is very interesting. It talks about a perception of CMIs. "It's revolutionary, in my opinion. I just wish it wasn't so burdensome." And I think this really does capture what we hear from US physicians in a lot of the market research we've done to date. One of the key drivers for this burden is the REMS program. Next slide. I wanna just take a moment to familiarize everybody with REMS.
Now, REMS stands for Risk Evaluation and Mitigation Strategy. There are many different types of REMS, everything from medication guides, communication plans, to an ETASU REMS. ETASU stands for Elements to Assure Safe Use, and an ETASU REMS can include any or all of the following six elements. There's HCP certification, pharmacy certification, limited distribution and dispensing, evidence of safe use for dispensing. Each patient is subject to certain monitoring, and patients are enrolled. Next slide. While we hear in market research that some of these requirements are causing stakeholders to consider CMIs a little bit differently, and some of them have waited to adopt CNIs, CMIs, the three key areas we see are around echo monitoring, pharmacy certification, and process complexity that are really impacting the current uptake of the CMI category.
Now, we're hopeful that we'll have some key attributes that may drive differentiation. As we think about DDI profile and echo frequency and window, these are some areas that we're hoping to potentially see around reducing the risk of or the burden to HCPs in the United States. Next slide. If we look at the full spectrum of attributes that we may have for aficamten, you can see here, and I would refer back to an earlier presentation about the ideal CMI. You see some of those aspects here: rapid onset, rapid reversibility, speed to optimal dose, predictable dose response, titratability , and no clinically meaningful P450 liabilities resulting in drug-drug interactions. This is a profile that we think is very differentiated within the market.
In fact, next slide, in market research, we've looked at the potential patients for aficamten, and what you would expect is it's very much in line with what you've heard earlier. Symptomatic obstructive hypertrophic cardiomyopathy, NYHA Class II, III patients with an ejection fraction above 60%, and those who are not well controlled, contraindicated to, or cannot tolerate beta blockers, calcium channel blockers. At launch, we expect CMI penetration to be less than 20% of that total addressable patient population. Our primary focus will be on patients that have already been diagnosed. Next slide. In market research, we've tested a blinded aficamten product profile. We've asked prescribers how they would utilize the product if it were approved. We're very encouraged by the results, as we're not only seeing high preference share for aficamten, we also see that the availability of aficamten actually expands the entire CMI category.
You can see the key drivers that are driving preference share within our studies. LVOT gradient reduction, the change in NYHA functional class, our pharmacodynamics, maintenance of ejection fraction, change in KCCQ, and the absence of DDI. Next slide. When we put this all together, aficamten exists to really elevate the standard of care in HCM, and we're very much looking forward to marketing this brand upon FDA approval. Next slide. I'll close my comments with where I started. Our focus to date has really been learning from our customers. As we enter the new year, we'll shift to our design and build mode. This will involve innovative approaches to meet the needs of HCM patients and those who treat, who treat them. Next slide. A few comments.
For those of us, for those of you who are at HFSA this year, you've seen our overall approach come to life. HCM treatment is a team sport. At HFSA, we had an industry theater where we had a patient and a multidisciplinary panel discuss the holistic treatment of HCM. We're gonna continue to learn and look forward to the results of SEQUOIA-HCM, which will inform our final go-to-market strategy. I'd like to now turn it over to Andrew, who'll discuss the payer landscape.
Thanks, John. So in this section, I wanna describe the focus on the U.S. payer landscape, how we foresee payers managing the CMI category, as well as patient services and support. Next slide. So first, let me just start with the landscape of the payer environment. This chart really describes the payer mix for patients diagnosed with HCM and receiving any drug therapy. You know, Medicare and commercial represent more than 80% of claims. The critical PBMs you see listed on the left and right of the slide are the intermediaries that negotiate and contract the pharmacy benefit on behalf of downstream plans. This also informs where we need to contract to ensure formulary placement and access for patients. Next slide.
We've done 4 waves of research, both from those critical PBMs, national and regional players, that represent over 200 million commercial and Medicare lives. That's over 60% of covered lives in the United States. What we heard, or the top beliefs of payers are, one, that there's a very low interest in restricting branded HCM drug choice. If I kind of go to left to right in kind of the key findings of those studies, one is that payers do recognize there is symptomatic HCM as an obstructive disease that has high criticality and unmet need. The second key point is that there is a low overall budget impact, given the prevalence of disease and that it's a rare disease. The third is that the way that payers will manage is to label.
So if the label suggests that it's a Class II, Class III, as an add-on to a beta blocker, as an example, they will ensure that patients are on a beta blocker or have failed a beta blocker, and that they're a Class II, Class III, and that's how they will manage the category. So, I think the essence of this is we understand the importance of making sure that access is there for patients and how we will contract with payers to ensure that access. Next slide. So first, let me start with, you know, the two critical components of Medicare and commercial. So Medicare bid timing is really the key driver of access to Medicare, where commercial usually varies by plan.
If I orient to the very bottom of the slide, in purple, you see our targeted approval date, should we be approved in 2025, which would mean we would bid. The Medicare bid process is, say, the end of the year in December, and that bid process would be applicable for 2027. Any Medicare coverage we get in 2025 or 2026 is considered off cycle, and it's certainly, you know, able to be achieved, but largely, most Medicare formulary will come on within that formal bid process. If I orient to the slide in terms of the bars, in 2025, should we receive approval, we assume that we'll have initial coverage and higher coverage in commercial, with about 40% of covered lives and 20% of Medicare, respectively.
We'll be building coverage in 2026, with broad coverage in 2027. Our assumption is at least 70% of covered lives in Medicare and 75% in commercial, and our hope is that we will achieve a higher level of coverage. Next slide. Critical to contracting with payers for coverage is an experienced account team with established relationship with key payer customers. Cytokinetics recruited with this in mind and have our entire account team in place. You can see the high experience and collective experience of our account team. Cytokinetics account managers cover over 100 plans that represent greater than 90% of covered lives in our priority segments.
These account managers have interacted with every major payer introducing Cytokinetics, and will engage further in the first half of 2024 with our results from SEQUOIA to ensure payers understand the critical data. I'm sorry, the clinical data, the economic data, and the launch timeline. Next slide. So Cytokinetics also maintains our commitment to health economics research, allowing us to effectively convey the value of aficamten to a broad range of stakeholders. There are two platforms that will generate this value. One would be the clinical trial readout from SEQUOIA, and the second will be related to the clinical attributes of aficamten. So if we consider the clinical trial, I can give you a few examples.
If SEQUOIA can demonstrate the ability to change a patient's surgery eligibility status and no longer requiring surgery, there could be value attributed to aficamten in both cost and complication avoidance. Our observations suggest that SRTs are generally not one-time procedures for patients in terms of curing obstructive HCM. While there are a few exceptional centers with highly successful SRT outcomes, you know, comprehensive national claims data demonstrate a notable correlation between SRT and significant complications, increased use of beta blockers, and onset of new AFib. There is also a strong correlation between peak VO2 change and New York Heart class change. That correlation is with an improvement of mortality and health outcomes, and this has been demonstrated and published in both health technology assessment reports.
The better aficamten can report, the aficamten can perform in our clinical trial, the greater attribute we can, or value we can attribute to aficamten. So Cytokinetics aims to generate, publish, and disseminate this health economics data, in collaboration with, you know, prominent KOLs to ensure we harness the full potential of aficamten's clinical features. Next slide. This slide really speaks to the Inflation Reduction Act and the potential to reduce patient out-of-pocket cost burden for high-cost drugs. So the, the plan design for Medicare is changing and associated with the Inflation Reduction Act. In 2023, that plan design, so this is an illustration of a drug that is around $100,000, and a part of the patient's responsibility is during a coverage gap.
Once a patient passes a catastrophic threshold, which is a little over $7,000 out of pocket today, the patient has to pay 5% of whatever the drug's list price is, which is known as a catastrophic cost. Today, a drug around $100,000 would cost a patient a little over $7,000. You can see pictured in that depicted in that top bar. We do know that patients who have an out-of-pocket cost of over $250 a month over 70% of the time will abandon the script at pharmacy. They will not get the script filled because of the out-of-pocket cost. Pharmaceutical companies cannot support a copay the way they can with commercial paying patients in Medicare.
In 2025, if you look at the lower bar, again, the plan design for Medicare is changing. The coverage gap will go away, and patients will no longer be responsible for any portion of the catastrophic coverage. So, and their out-of-pocket will be capped at $2,000, which should result in a higher utilization and of Medicare patients of higher-cost drugs. Next slide.
So, last thing I wanna cover in terms of, you know, the implications of what John described in terms of a complex patient journey, especially if a, a, if a product has a REMS program associated with it, the coverage delays I described in terms of it taking time to build coverage, how payers will utilize or or manage utilization to a label, and the increase, especially on the commercial side, the increase in copays. So drugs like aficamten to be approved are associated with all of these challenges and hurdles for patients to get on therapy. So in response, Cytokinetics is in process of designing a very comprehensive patient support program to address these challenges and hurdles.
The boxes you see below, in terms of reimbursement support, affordability programs, supporting the patient on their journey, and education resources, are the components that will be included in our patient support programs. We may or may not include all of these components, they're shown for illustration, but certainly we are committed to helping patients along with their journey and helping patients get on therapy should their doctors feel like aficamten is the appropriate therapy if it's approved. So, next slide. With that, I will turn it over to my colleague, Jeff Lotz, to describe our sales strategy.
Thanks, Andrew. Good morning, everyone. I'm really excited and grateful for the opportunity to speak to you today. I'm gonna cover two things. First, I'm gonna walk you through how we're thinking about our launch preparation and the corresponding gating of the investment for launch. Then I wanna talk to you about the insights we've gathered so far, on our HCPs, our potential HCP customer base, and how that's informing our sales strategy and customer-facing deployment. Next slide. So, first, I just wanna cover a little bit about our approach, to the launch and how we've planned it over time, and how we've gated investment with that launch planning.
So whether you look at the left side of this slide and look at the pie chart around hiring or the list of launch activities, launch planning activities on the right, you'll see that the majority of our investment comes much closer to approval in 2025. So on the left, we've hired headquarters positions, we've hired our sales leadership team, and those colleagues are helping us gather insights, design and develop strategy, design and develop processes and systems and tools, and we'll ultimately build them. But you can see that the vast majority of commercial organization is customer-facing positions, and they'll be brought on much closer to approval in 2025.
And then when you look through the right side of activities, you can see that right now, you know, in addition to the insight gathering that John talked about, you know, we're starting to take those insights and formulate strategy. And in the sales organization, we've been doing a lot of work on identifying who our customers are and starting to profile them so we can ultimately develop account-specific launch plans that we believe is a significant competitive advantage and a very innovative approach to approaching a launch. Once we get through the SEQUOIA readout, you know, as John mentioned, we'll start the design phase and start to build.
You'll see, you know, we'll be working on things like our launch campaign, HCM market development communications, building out the commercial training modules, starting to engage with payers with our pre-approval information, planning our final deployment of our customer-facing teams, and building the technology that enables them to engage with customers. Then once we're approved, there'll be significant investment in communications through media and supporting patients through a variety of programming. Next slide. Now I just wanna talk a little bit about some of the insights we've gathered around our potential HCP customers, you know, the data that we've used to do that, and then I'll talk some more about insights we have from engaging with over 800 different HCPs in market research, focus groups, advisory boards, and how that's informing our customer-facing strategy and deployment.
So as Robert mentioned, you know, HCM is a rare disease that's treated by a highly focused group in the cardiology specialty. And we've used secondary data, patient diagnosis data, prescriptions and treatment data, our own knowledge and primary research to identify researchers and opinion leaders and the HCM centers and programs around the country. And what that's shown us is there's approximately 7-10 thousand treaters, diagnosers and treaters and they're spread then across, you know, 500-700 healthcare organizations that represent approximately 75%-80% of the patient volume. So, you know, a very focused group covering the vast majority of patients, and this allows us to design and then deploy a very efficient and highly impactful customer-facing structure. Next.
Robert shared this graph, and what you can see is that, you know, they're highly concentrated in the right half or the eastern half of the country and then up the West Coast. And again, through this very tight geographic concentration, we're still covering 80% of the patients covered. Next slide. Now, when we talk to customers, you know, through focus groups and advisory boards on how they engage with pharma and biotech companies, what we've heard is that the traditional models are overwhelming. And what we mean by that is, especially in the rare and specialty space, because of the complexity of the HCP journey, the complexity of the patient journey, pharma companies have often thrown people at the problem.
What it does is it overwhelms clinics, it overwhelms HCPs and their care teams, because it's often confusing on who they're supposed to engage with for what. There's several people visiting practices or healthcare organizations throughout the day that can be disruptive to patient care. So we've taken these customer insights and put them right into our design principles, and ultimately, we wanna create a very efficient, highly impactful, and high-quality customer experience and build relationships with our HCPs and ultimately aficamten patients. We wanna do that by having a simple design that has one person accountable for the HCP journey in HCM and aficamten, and then another who's responsible for the patient journey for HCM and aficamten.
We also wanna fill these positions with people who have, you know, deep experience in the industry, deep experience in rare disease and specialty therapeutic areas, and also in cardiovascular disease, and working with cardiovascular treaters and their care teams. So just to bring this to life, Dan Jacoby spoke earlier about how he's gonna be in clinic on Friday. When Dan gets to clinic, he wants to work with his care team to help as many patients as he can throughout a day. It becomes disruptive when he has several different people from the same, from the same company, servicing the same product, walking into his practice throughout the day, walking into the clinic throughout the day, and it often causes confusion on who they deal with for what.
So ultimately, we would love Dan to have one person that he interacts with, who will educate him on aficamten and new developments with the product throughout its life cycle. That could be scheduled at a time that's appropriate for him throughout his treatment day, while the rest of his care team works with the patient service specialist to navigate the complexity of the patient journey and also engages with the patient in that model.... Next slide. As I mentioned, we, you know, we're looking to hire very experienced people, and on the first slide that I presented, I talked a little bit about how we have also hired our sales leadership team.
The reason for hiring them was to help us with the generation of insights, the development of the sales processes, the sales systems, the technology that they and their team will ultimately use. You can see here that they have an average of 22 years in industry, 13 years in leadership, 14 years in the cardiovascular therapeutic area. We have a mix of small and big pharma experience, and all of them have launch experience, as well as experience in specialty diseases and/or rare disease. That's the exact same approach we plan on taking when we ultimately hire the account specialists and the patient services specialists. Next slide.
So I know Robert talked to you a little bit about the evolution of our cardio, cardiology franchise over time, and the approach that I just laid out for aficamten and for HCM is the exact same approach we plan to take as our business and our franchise evolve. Whether it be in HFrEF or HFpEF, we know that there's a highly concentrated number of treaters that treat the vast majority of patients, and that we can move forward with a highly efficient customer-facing model that eventually engages around half of the cardiology universe, but still captures the vast majority of patients treated for these diseases. And that's atypical in the cardiology space. As you can see, in a big pharma model, they're generally calling on every one of those 30,000 cardiologists.
Okay, well, thank you so much for your time today, and now I'll turn it over to Fady Malik.
Great. Thank you, Jeff. It's really my pleasure today to introduce our esteemed panel of HCM specialists. We have Dr. Ted Abraham from UCSF, Dr. Caroline Coats from the University of Glasgow, and Dr. Carolyn Ho from the Brigham and Women's Hospital in Boston . Welcome, welcome today.
Thank you.
You know, I'd like to just start off with talking a little bit about how your practice of HCM and the patients that you see, and perhaps if I can start with you, Carolyn. Since you all have practice in HCM, just first, let's hear a little bit how each of your practices differs, and maybe describe the kinds of challenges you see in the HCM patients that you take care of. Carolyn, do you want to go first?
Sure. Yeah, thank you so much. It's a pleasure being here today. And we see a number of different challenges with our patients. Some, you know, struggling with the impact that HCM has had on their families and trying to understand, you know, you know, what the future might hold for them and their children. And others dealing with symptoms related to HCM that, you know, impacts their quality of life, their ability to engage in activities that they have, you know, you know, enjoy doing.
Ted, you've been taking care of patients on both coasts, both the East and West. How have, you know, the challenges of taking these patients changed over the years?
Thank you, Fady. I think, very similar to Carolyn, we've had, I guess, across both coasts now, close to 5 or 6 thousand patients, and the impact on their lifestyle, their families, their children, very important. I think over the last 19 or 20 years of practice, the lack of therapy was also very critical. At a certain point, whether it was obstructive or non-obstructive, you got to a level where you had to move the patients over to therapies that were non-medical and more surgical or interventional. So that concerned a lot of patients, and they were hoping that just like hypertension or something else, we would have more options for them at that point, given that the age range is quite wide. Especially on the younger side, they would have preferred a medical therapy.
Caroline, you practice in the United Kingdom, in Scotland. Maybe how is your practice there, you know, how it might differ from practices here in the U.S.? Maybe you can comment on that.
Yeah, sure, Fady. So, I mean, I think we see a similar demographic of patients. Often by the time they get to a specialist, they've had quite a long journey. Sometimes, you know, they get diagnosed with asthma or... So that they often come to us at quite a frustrated stage, I would say. And it's the therapeutic options are limited. It's a big deal to have an intervention, whether that's surgery or alcohol ablation. So, yeah, it's a very similar demographic of patients. You know, this is a global disease, and I think our patients feel the same.
And you both all talked a little bit about surgical interventions or interventional like interventions like septal ablation. I guess how enthusiastic are your patients about pursuing those sorts of treatments previously? Carolyn, do you want to start?
Sure. Yeah, I think that there's a spectrum, and there are some patients that you know, tend to be more you know, aggressive and willing to take on you know, big procedures just to you know, kind of move on within you know, and hopefully have more of a one-and-done strategy that will restore their you know, physical functioning and you know, alleviate symptoms. But I would say that I think most patients are understandably reluctant to take a big step, you know, particularly having you know, open heart surgery to address symptoms. So I think that a lot of patients you know, put up with some amount of functional limitation.
You know, so, symptoms that, you know, may, you know, you know, may be anywhere from modestly to moderately improved with, you know, standardly available medical therapy. You know, that, you know, you know, to avoid the, the big step of, moving towards an intervention.
Ted, do you want to also give us your thoughts on that question?
Sure. I think, not to completely repeat what Carolyn said, but it's a very similar experience, wide range. I would, however, add that a minority of patients would volunteer for either of those procedures, even though, you know, our complication rates, mortality rates were quite low, and we often cited that we didn't have a single death, for example. That was not something they were totally enthusiastic about. So I'd say there was a more of a resistance in getting to that therapy, and there'd be a lot of questions and lots of delays once that question was popped or once they hit the threshold where we said, "You know, we've had, we've had you on 200 or 300 milligrams of beta blockers. We have you on disopyramide. Your gradients are not controlled.
You need something else." And that's where the delay would start. I didn't. I don't think I had a single patient who would say, "Okay, if that's the next step, let's go for it," which is what they would say with the escalation of treatment. They said, "We know we need to add disopyramide." I said, "Okay, let's go for it, and we'll do it right now." But when once you pull the non-medical option, there would be lots of delays, lots of hemming and hawing, and a general discomfort in proceeding in that direction.
Dr. Coats, I guess, you know, with comments of Ted and Carolyn, how do you think... Do you think patients really lived compromised, if you will, on how they might feel in terms of accepting a certain amount of disability, given the treatments that were-
Yeah
Available a couple of 3 years ago?
Yeah. I think we definitely see that, and I think I'd echo this sort of reluctance to jump at the choice of surgery. I think patients feel much more in control when they're taking tablets, and they will accept a degree of limitation. They've often seen other people around them live like that. So it's yeah, there is this kind of acceptance, it for some people, or adjusting their life without really appreciating it, and it's only when they compare themselves.
You know, I've had young people, and it's not until they've gone to university and met other people around them that they think, "Actually, I really can't do stuff that I maybe should have." So yeah, I think there's definitely a gap in the market for people who aren't bad enough to actually say, "Yep, I want to go in for surgery," but they do want to feel better.
That's an important point you made in the sense that, you know, people may not really yet recognize how limited they are, until they are challenged, if you will, in social settings or otherwise. As we heard from our patient earlier today, she had to educate people, you know, around her as to what she could or couldn't do. And I'm sure you all see that in your practices as well. Well, maybe let's talk a little bit about how you approach therapy in your patient population. And so let's think of this, before the availability of cardiac myosin inhibitors. And maybe Dr.
Ho, can you just give me a sense of, you know, what was your approach to medical therapy in your patients with obstructive HCM and generally, what do you feel the impact was of that therapy?
Yeah. So, you know, there, there's a portion of patients with obstructive HCM that are completely asymptomatic and, you know, able to function at a high level. But I would say, you know, there's a large number of patients that are limited and have, you know, a spectrum of symptoms ranging from mildly to, you know, quite substantially limited. And so, our approach before has been, you know, kind as stepwise as, as Ted described, you know, first starting with beta blocker or calcium channel blocker and trying to escalate dose. You know, potentially adding on disopyramide if people still did not have adequate symptom relief with those measures. So, I would say that the standard medical approach is modestly to moderately effective.
You know, some people notice, you know, a fairly meaningful improvement. Other people notice, you know, almost no improvement or are troubled by side effects of, you know, particularly beta blockers. You know, we typically had to escalate medical therapy, and, you know, generally are still left with a gulf of people not quite feeling as well as they wanted to feel. You know, and therapy does not tend, you know, medical therapy, doesn't tend to be durably effective. The people that, you know, initially had reasonable symptom relief, but they have high gradients remaining, and it's pretty predictable that, you know, over a period of a year or two, their, you know, their symptoms would become, you know, really quite limiting.
Again, you know, on maximal medical therapy.
Any differences in your practice, Dr. Abraham?
No, I think pretty similar. The only sort of color I would add to those, and I know both Caroline and Carolyn do the same thing, is we have a lot, especially younger patients with high gradients, who say, "We're feeling just fine." But we do push them. We do exercise them. We do a cardiopulmonary stress test, and sometimes they actually do fine, and sometimes they don't. That's number one. Number two, medical therapy we've found to be more successful in folks who have borderline gradients and not very extremely high gradients. Once they start coming close to 100 millimeters of mercury, either provoked or resting, the chance that medical therapy would work diminishes exponentially. And lastly, I'd say we've had patients who follow the exact same protocol that Carolyn just described.
At the higher doses, I remember this one patient who was on 200 or 250 milligrams of metoprolol and a pretty healthy dose of disopyramide, mostly tolerated dose, the gradients were. And I remember him walking in one day, and we said, "Your gradients are completely normal. It's worked." And he said, "Yeah, everything really is good, but I have difficulty getting up in the morning and going to work." So even when the numbers are good, the quality of life is pretty significantly impaired and affected by the previous medical therapies, especially at the higher doses.
Yeah, I think, Gary, you're right. Sometimes we forget about how the drugs that we have come with their own issues, and they may make the numbers look better, but not the patient feel better. So that's a good point. Let me ask you, Dr. Coats, about non-obstructive HCM. What could you do for those patients? They don't have a gradient to try and reduce. How would you approach them? How are these therapies, medical therapies work in those patients?
Yeah. So that's a huge challenge, actually, because we really don't have anything to offer. You know, we use beta blockers. High doses are not effective. They often make people feel worse. Diuretics, the SGLT2 inhibitors potentially have benefit, but really, we don't have anything that's disease-modifying. And they often have a different symptom burden, so heart failure is common, but so is chest pain, and that is a very, very disabling symptom for patients. It's frightening, and that's something that I really hope this class of drug might address. Certainly from REDWOOD, it's potentially going to impact on that.
I think we've got a whole range of drugs that we might use, that we extrapolate from heart failure or angina drugs, but actually, the practicalities of using them is really not sure how helpful they are then for patients.
Well, let me turn to cardiac myosin inhibitors. You know, it's a dream of anyone that works to discover and develop drugs, that maybe they'll find something that will change the practice of medicine. And maybe tell me a little bit about how the introduction of the cardiac myosin inhibitor classes, a treatment option for oHCM, has changed your practice from a clinical perspective. You know, Dr. Ho, do you want to go first?
Yeah, sure. It's been really transformative in a number of ways. You know, it's you know, added so much excitement and enthusiasm and hope that we might have effective medical therapy that really substantially you know, abolishes symptom burden without adding you know, its own array of side effects. That patients have you know, by and large, felt really great you know, with clinical trial participation, with the commercial introduction of cardiac myosin inhibitors, and it's you know, allowed people to really understand how limited that they were and you know, how much better that they can feel.
So it's, you know, just, you know, again, the excitement and the enthusiasm and the optimism has been really, you know, a great thing to be part of.
Dr. Abraham, have they become a part of your practice?
No, I mean, I agree and completely echo what Carolyn just said. It's been transformative, to borrow that term.
I still remember our first patient in our first CMI trial, and obviously blinded, but she came in and said, "You know, I think I'm on the drug." She was 70 years old, could barely walk up 7 steps up to her apartment in San Francisco, and she said, "Two weeks after the drug, I can go up to my son's apartment on the third floor without using the elevator." She said, "I've never felt like this ever in my life as far as I can remember." And that really prompted us thinking it was really unconscionable not to offer this trial to every single person in our both ablation and surgical volume, almost ground to zero, that the, you know, for several years after that. So yeah, we tend to have a low threshold.
We start a modicum of beta or calcium channel blockers, and we tend not to push them, and we immediately put them on CMIs. So we have an early sort of.
Dr.-
CMI.
Oh, sorry. And Dr. Coats, we know that CMIs are coming to be available in the United Kingdom, and maybe you can tell, are they available in your practice yet? And if so, how are you using them? I know you've been an investigator in many of these trials, but how do you use them in-
Yeah, exactly. So yeah, so we've not yet got them available within our National Health Service. So my experience is in patients within trials, and again, on an individual patient level, it has been game-changing. You know, I've had a conversation about myectomy with a patient, and they're sending me a letter saying, "Can I start jogging again?" Having been on a CMI. So it's for the patients that I've had on the treatment, it really has been very satisfying to be their doctor for once. So yeah, I hope that we will be able to use them in the not-too-distant future.
Yeah, and just to emphasize the patient perspective, I think that's so important to understand, like, you know, how this has, you know, really helped to change the lives of our patients. We've had patients say, you know, "I would pay money to be, you know, to stay involved in this trial." You know, people came in during the pandemic, you know, very reliably, you know, because, you know, everybody was, you know, just so excited about being part of this and so excited about how beneficial these medications seem to be. And it, you know, kind of translates over to our clinical trial team.
Like, the study coordinators and the nurses were all, like, you know, super happy because, you know, they're just seeing the day-to-day impact on study participants being so positive.
Yeah, so it's uncommon in the field of cardiology to have a medical therapy that has such a profound impact on the way patients feel. Let's maybe let me ask a little bit about it to you, Dr. Ho, and you, Dr. Abraham, since you're using these clinically now. What's the administrative impact on using them? And how do you, you know, imagine that might evolve over time? Dr. Ho, do you want to go first?
Yeah. I mean, it's a pretty heavy lift now. You know, I would say that everybody's keen and eager to do it, again, because, you know, people want to have access to these medications. We know that the, you know, the benefit will be pretty substantial. So, you know, everybody's, you know, up for the challenge, but it is, you know, the burden is not inconsiderable. And we are able to do it here because we're lucky at Brigham and Women's Hospital to have a great specialty pharmacy team. So they have largely taken all of the work of the prior authorizations and, you know, sorting out payment and distribution of medications, you know, from the providers, so it's been amazing.
And we also have a nurse practitioner who has, you know, assumed the role of, you know, taking charge of all of the, you know, REMS monitoring visits. And without those two entities, you know, it would be really difficult to absorb into practice. And we, you know, we've talked with our echo lab, and they, they've been very accommodating in terms of, you know, developing a streamlined protocol and accommodating the study with this. So I think it really takes, you know, a decent amount of institutional support and buy-in.
Dr. Abraham, how has that impacted your clinical practice?
Very similar, I would say. You know, I would endorse everything that Carolyn just mentioned. I think it's easy to convince patients. The logistic burden is substantive in the sense that the number of forms, the REMS program, I think, does impede uptake of CMIs in a regular practice. The echoes are not a huge issue. We do 120-140 echoes a day, so adding a couple doesn't make a huge difference. But just the paperwork, the REMS, having to send a patient status form, a pharmacy form. We also have had the good fortune of having an NP, so after trying the first two patients, I gave up, and the NP handles everything. Once I identify a patient, I just hand it over to the NP. They take care of everything else.
We do, just like Carolyn, have a specialty pharmacy to do all the education, the pre-op, and I think right now they've started dispensing as well, locally. So, so that, that part's done, but the provider burden remains, not minuscule.
And Dr. Coats, so how do you imagine they will be implemented in your practice, and what, you know, sorts of, you know, the infrastructure that you have that might help with implementation?
Yeah. So I think we'll have a similar model where we have a kind of streamlined pathway for patients that go on to this therapy. And I think we've drawn up sort of potential pathways similar to monitoring of drugs in oncology, actually, where people are coming for surveillance imaging, very focused data that's needed and education, really. So I think that's critical to educate the sonographers, every person that interacts with the patient, to provide that safety and monitoring that we need at the moment.
I guess if the monitoring and safety requirements were to change, do you imagine that implementation of a cardiac myosin inhibitor might facilitate its implementation outside of your specialty care centers?
Yeah, absolutely.
Yeah, it's a bit daunting right now, I would say. So-
But maybe last
That's what we want. You know, we want it to be. We want people to have equal access to it. You know, in Scotland, we have a very rural population, people living on islands, and it's, you know, we really want people to benefit wherever they live.
Yeah. Very good. Maybe lastly, I'll direct this to you, Dr. Abraham. We've just got a minute left, but how do you see the role of cardiac myosin inhibitors in the non-obstructive HCM populations, those trials that are just getting underway?
I think it'd be, you know, completely excited to at least learn more about their potential. I, you know, I agree with, Caroline, and her comments saying, in fact, now, and even prior to CMIs, there were some avenues of advanced therapies with obstructives, but the non-obstructives were really, you were at the end of the road at stage one. You tried the initial therapies, none of them that had evidence to support their use, and, you were stuck. And I think, I'm glad Caroline raised the issue of angina and chest pain. That's disabling, it's disheartening, and it's very frustrating to treat. So I'm hoping that these, ongoing trials will yield some transformative information, just like the obstructive trials did.
Wonderful. Well, with that, maybe I'll close the panel and thank you all for your participation. I'm very grateful for you both at all taking time to join us today. Thanks again.
Thank you.
Thank you.
So we're going to switch gears now and focus on a different patient population, while still focusing on inhibition of cardiac sarcomere as a therapeutic strategy. Next, please. So half the patients with heart failure have preserved ejection fraction. It's referred to as HFpEF and defined as ejection fraction of at least 50%. Now, unlike patients with heart failure with reduced ejection fraction, which is mainly driven by systolic dysfunction, patients with HFpEF primarily have impaired diastolic function. And this is associated with thickened, fibrotic, stiff ventricular walls, which can result in poor ventricular compliance and reduced cardiac output. Now, HFpEF is a heterogeneous disorder. However, there is a more homogeneous group of patients with excessive cardiac contractility, with ejection fractions of at least 65%.
These patients tend to have, they tend to be at higher risk of adverse heart failure outcomes compared to other patients with HFpEF. So on the basis of this underlying pathophysiology, now we developed a hypothesis and asked the question if a cardiac myosin inhibitor could attenuate the hypercontractility in this subgroup of HFpEF patients and improve ventricular compliance and cardiac output, and would that lead to improvement of heart failure symptoms, functional capacity, and clinical outcomes? Next, please. Heart failure is a disease with increasing prevalence, including HFpEF. Currently in the United States, there are about 3.6 million people with HFpEF, and that's expected to increase to 4.8 million by 2033. That includes an increase in prevalence of this subgroup of HFpEF with hypercontractility, estimated to be nearly 1 million by 2033. Next, please.
Now, the recent demonstration of the benefits of SGLT2 inhibitors validates the first evidence-based therapy for people with HFpEF. However, there's an important observation here, and that is that these patients still have very high residual risk, and that's indicated in the recent DELIVER trial with dapagliflozin. And you can see that even in the dapagliflozin group, there is a high cumulative incidence of worsening heart failure or cardiovascular death. So, you know, this clearly indicates that more effective therapies are needed for patients with HFpEF. Next, please. Now, the potential benefit of cardiac myosin inhibitors in this HFpEF subgroup with hypercontractility is informed by a patient profile that's similar to non-obstructive HCM.
So not only do both conditions suffer from similar heart failure symptoms, but both, both patient populations, may have a pathophysiology that's driven by hypercontractility, in a similar manner, and that can drive, you know, increased left ventricular hypertrophy, increased filling pressure, and diastolic dysfunction. And now, having seen the results of aficamten in non-obstructive HCM with, with improvement of heart failure symptoms and cardiac biomarkers that Steve Heitner presented earlier, as well as improvements in diastolic function that were presented at the ESC heart failure meeting earlier this year, I think suggests that treatment with a cardiac myosin inhibitor, could be beneficial in, this HFpEF subgroup. Next, please. So to test this hypothesis, we discovered a new cardiac myosin inhibitor, CK-586, with a mechanism that's distinct from aficamten....
CK-586 inhibits cardiac myosin ATPase at two-headed myosin, in contrast to aficamten, which inhibits both single-headed and two-headed myosin. Next, please. So in vitro data indicate that CK-586 has a shallow concentration-response profile, and this favorable profile is similar to that of aficamten. What's different about CK-586 is that it has a shorter half-life than aficamten, and it's predicted to be approximately 15 hours in humans. So these properties of CK-586 suggest that it will be well-tolerated and safe in HFpEF patients with hypercontractility. Next, please. Now, preclinical models of HFpEF suggest that a cardiac myosin inhibitor may be effective in this subgroup of HFpEF patients. So in this study, treatment with CK-586 in ZSF-1 obese rats showed a decrease in cardiac contractility, as expected.
You know, and this was associated with improvement of diastolic function and reduction of cardiac fibrosis. Next, please. Similar results were observed with another cardiac myosin inhibitor in a different HFpEF model. So treatment with another of our cardiac myosin inhibitors, CK-271, in Dahl salt-sensitive rats, also resulted in improvement of diastolic function and reduction of cardiac fibrosis. Next, please. So the results from these preclinical models of HFpEF and the results of aficamten in non-obstructive HCM informed our decision to embark on a clinical development program, the CK-586, in a subgroup of HFpEF patients with hypercontractility. And we've initiated a first-in-human study in healthy participants with a fairly standard study design, with single ascending doses and multiple ascending dose cohorts.
The interim results support continued development of CK-586, and they will already informing our thinking about studies in patients in this HFpEF subgroup. Next, please. To summarize our approach with cardiac sarcomere inhibition, we've been targeting multiple adjacent patient populations for potential benefit. As you've seen, we have a very robust program in obstructive HCM with multiple ongoing trials in this patient population. We've now initiated a Phase 3 trial in non-obstructive HCM, and we've started the clinical development program, the CK-586, in a subgroup of HFpEF patients with hypercontractility. Next, please. To check off the expected 2023 milestones, we will continue our first-in-human study with CK-586 and begin studies in the multiple ascending dose cohorts. Next, please. Now I'm gonna turn it over to Diane for Q&A.
Thanks, Stuart, and thanks to all our presenters today. Well, we finally made it to our Q&A session. If you'd like to ask a question, please submit your question via the Ask a Question tab on the upper right-hand side of the webcast. Our company management will be participating in this session. If we don't get a chance to answer your question, we'll do our best to get back to you after this event. So, the first question is from Dane Leone from Raymond James, and we'll have Robert take this one. What do you view as the benefits and hurdles of launching aficamten behind Camzyos, and what is your best case for REMS requirements within the US?
Excellent question. So I'll try to start, and if any of my colleagues want to add, please do. We're coming in with expectation that aficamten, if approved, would be entering a category where there's already building awareness, education, and opportunity. I believe BMS is doing an excellent job as it builds the market for CMIs, of which Camzyos is an excellent drug, but for which there are still, as you heard from Andrew, quite ample opportunities, even within the diagnosed population, to, with a second category entrant, demonstrate potential next-in-class and best-in-class properties, depending on SEQUOIA data and upon approval.
We also believe that the market opportunity for CMIs will continue to grow, both as new payers come on board and also as we expect currently undiagnosed patients, like we've seen in other specialty categories, to seek treatments where there's such a remarkable opportunity for function and symptom improvement. So I do believe that we are seeing still a symmetric phase of penetration in the current category that may soon become asymmetric, as is typical 1-2 years following a launch in a cardiovascular space.... And I do hope that by the time aficamten may become available, we'll be in a position to accelerate that asymmetric growth, both in the United States and outside. As it relates to a REMS program, I'll underscore that this all depends, obviously, on continued FOREST data and also our results from SEQUOIA.
But it's our hope that as the FOREST data are already pointing, and as we hope SEQUOIA may underscore, that Cytokinetics with aficamten can win both on efficacy and on safety, and as may be permitting of us to engage FDA in discussions around a potentially less restrictive REMS program. That's ultimately to be determined, but that's certainly our base case and our goal. The FOREST data, I think, are reinforcing of that as an assumption that should be a base case, and ultimately, we'll see next year if that's something that, we can be more planful towards.
Thank you, Robert. Our next question comes from Roanna Ruiz from Leerink. Just want to confirm, I think I heard that... This will be for Fady, please. I think I heard that all of the patients in SEQUOIA, none of them had LVEF less than 40%. Is that as of today's date, post-enrollment completion?
Well, I think when I made that statement on our last earnings call, I also made the commitment that I wasn't going to continue to update that statement. What we stated today is what our current guidance is, but we're very pleased with what we're seeing in SEQUOIA. Obviously, the data that we showed you today in FOREST should be reinforcing that these patients, all of whom came from SEQUOIA, are able to get to high doses of 15, 20 milligrams, and the majority of them had no such excursions below 40%.
Thanks, Fady. Our next question is from Charles Duncan at Cantor, and I will throw this one to Andrew. Does the assumed preference share depend on a differentiated REMS at launch over time or same as the other CMI?
Thanks for the question. The assumed preference share is based on us showing to physicians a profile that that we feel will be the profile of aficamten, given the evidence to date. The preference share is as a result of a combination of the elements that John showed on the slide, which does include, you know, potentially a differentiated REMS program, a support program, efficacy. So there's many elements of it, and those elements in the profile are the elements that we walked through today. So obviously, we'll have to wait for data and get approval, and then see how that plays out.
Thanks, Andrew. Our next question is from Justin Kim from Oppenheimer, and this will go to Steve, please. Can the team remind us... Oops, I just lost my question. Can the team remind us of the titration and monitoring schedule in FOREST, and how that informs expectations on the potential real-world implementation of the drug for oHCM and HCM?
That's an excellent question, and thank you for asking it. So I'll start out by saying that the titration schedule in FOREST-HCM for obstructive HCM is, as I mentioned, entirely driven by the investigator or the prescribing physician, such that what happens is the patient will come in, they'll get an echocardiogram. The treating doctor will read the echocardiogram and then adjust the treatment accordingly. And that's about as close to the real-world scenario as you can get within the bounds of a clinical trial. For obstructive HCM, we're using both the left ventricular outflow tract gradients with Valsalva, and the ejection fraction to adjust the doses. With non-obstructive HCM, we're just using the ejection fraction on its own. The drug is titrated every two weeks until the patient reaches their target dose.
And then, the patients are followed with three monthly echocardiograms once they're at that steady state. And, you know, the data that we showed today basically indicated that once those patients are at the steady state, 99.5% of them don't have any down titrations because of low EF events, you know, subsequent to completing the dose titration. We didn't present any data on non-obstructive HCM, but hopefully, when that becomes more available, we'll be able to disclose that at a scientific meeting.
Thanks, Steve. Our next question comes from Kripa Devarakonda from Truist. Thank you... This will go to Andrew. Thank you for presenting about the Medicare bid timing. You mentioned that you might see some Medicare coverage in 2025 and 2026 as well. Can you give any sense of what % of patients could be covered? Now that the competitor drug has been on the market for several quarters, have you heard anything in terms of Medicare coverage that can help you with your strategy?
Thanks for the question. So, Medicare, a company can get coverage for a product like aficamten in what's considered an off-cycle bid.
... So the on-cycle bid is what I described in the slide, is that if aficamten were to be approved in 2025, and the bid occurs at the end of 2025, the broad coverage and inclusion would occur in 2027. But, you know, we will be interacting with Medicare plans. We already have been. Our assumption is that, there will be probably 1-2 plans that will enable us to, or enable Cytokinetics and aficamten to get on formulary in that off-cycle timeframe. The slide that, that is available for download and I showed is an illustration of what that level of coverage would be in terms of, covered lives.
So it's, it's likely gonna be in, you know, less than 50% of covered lives in Medicare in that off-cycle phase, and then growing to likely greater than 70% of covered lives in 2027.
Thanks, Andrew. Our next question comes from Salim Syed from Mizuho, and this will go to Fady, please. When we speak about aficamten, we typically speak about it as having a better safety profile versus mavacamten. But given we're seeing 80% of patients improve on NYHA class in today's data versus 65% with mava in EXPLORER, so 23% better on a relative change basis, at which point do you believe physicians say that efficacy is also better than mava?
Well, I think it's not our job to make those comparisons. We're not doing a head-to-head comparison. But, you know, I do think when you see the data from SEQUOIA, that it's gonna present some very compelling efficacy data to stand on their own. And as you know, you can't get a lot better than 80% getting to, you know, NYHA Class I. It's really very compelling in the in FOREST and, while certainly that's not a controlled comparison with placebo, you know, we expect the lines that the results in SEQUOIA to be in line with what you're seeing in FOREST.
Great. Thanks, Fady. Our next question is from Jason Zemansky of B of A. We'll ask Steve, please, to take this one. Congrats on the data. Was wondering if you could dive a little bit further into the FOREST data. To the extent that you can, have these effects been observed between both patients with oHCM and nHCM? Can you talk about the enrollment split, and if there is any significant difference in LVEF reduction below 50%?
Thanks for the question. You know, I did mention a minute ago that we didn't disclose any of the data on non-obstructive HCM. I can say, though, that, you know, patients enrolled from cohort 4 in REDWOOD-HCM into the FOREST-HCM program. So we do have non-obstructive HCM patients that are currently receiving aficamten treatment in the investigational environment. But we'll be reporting those data once the patients cross the threshold that enables us to present that at a scientific meeting. And that data will obviously also include the safety data that you're after.
But I'll just,
Go ahead.
I'll just may remind Jason that the data in cohort 4 from REDWOOD that that Steve presented are very representative, we think, of what's happening in FOREST. It's essentially followed the same protocol, and those patients, you know, for up to 10 weeks, had substantial improvements in symptoms and so forth. So, you know, we're excited to see what the longer-term data show, and we hope to be presenting those soon.
Great. We'll go from one Jason to the other, Jason Butler, and ask Stuart to take this question: Can you discuss the predictive... Jason Butler, sorry, from JMP Securities. Can you discuss the predictive value of HFpEF animal models to clinical impact?
Thank you, Jason. You know, the models that we chose to interrogate, I think could be representative of outcomes in patients. There's always going to be, you know, some questions about translatability to any animal model. But, you know, HFpEF is driven by multiple etiologies. It could be hypertension, insulin resistance, obesity can contribute, and the models that we studied have those features that are driving, you know, diastolic dysfunction in these animals. And so, the features of those models and the improvement with the cardiac myosin inhibitors that we studied give us confidence that there could possibly be some translation into patients. But obviously, you know, we can never guarantee that when we're studying these preclinical models.
Thanks, Stuart. Our next question comes from Jeff Hung, from Morgan Stanley, and I'll ask Andrew to take it. In your market research indicating aficamten may achieve high share, what magnitude of change in peak VO2 drove CMI preference share for aficamten, where respondents prompted with similar or greater peak VO2 change than what was observed with mavacamten?
So the preference share research, again, is there's a profile, think of a label, an aspirational label, you know, should aficamten be approved?
... There's many elements in that profile. Peak VO2 is one, gradient, KCCQ, whether or not there is a clinical meaningful drug-to-drug interaction. So it's a combination of these things collectively that inform the profile. Obviously, the data from SEQUOIA will have to inform the label, as will the negotiation with the FDA, the label and the type of REMS program and the elements of the REMS program. So I don't think we can look at any one element or any one change that would drive that preference. It really is all the elements in totality.
Great. Next question is from Ash Verma, from UBS, and I'll ask Steve to take this, please. For the baseline SEQUOIA characteristics, a lower % of patients are taking beta blockers versus prior study. My question is that, would that be representative of a real-world patient population? Does that raise the expectations for the efficacy that mavacamten can show?
Thanks for the question. So I think, you know, actually, Andrew presented a slide, early on in the presentation that showed the proportion of patients taking beta blockers, calcium channel blockers, and disopyramide in the obstructive, group. And that's real-world data, and I think that the SEQUOIA data or the SEQUOIA baseline characteristics, you know, fairly accurately reflects that. And, you know, myself, having treated, you know, thousands of patients with hypertrophic cardiomyopathy, that's precisely what we see in our clinical practice. The second part of your question was, you know, whether, you know, a larger proportion of patients not taking beta blockers, you know, could impact the peak VO2 difference. And the answer to that is, well, we'll have to wait and see.
I'm not going to predict what the future might hold. However, I will point you to the fact that with the mavacamten treatment program, the largest independent driver of treatment effect was, in fact, whether the patients were receiving background beta blocker therapy or not. So we were happy to see that, you know, we had what we think is a representative proportion of patients who were not receiving beta blockers in our trial.
Thanks, Steve. Our next question comes from Serge Bélanger from Needham. I'll ask Fady to take this, please. Great event, very informative. Thanks, Serge. How important will treatment guidelines be in moving CMIs into frontline roles? Is it possible without the MAPLE-HCM trial? Thanks.
Well, I think it's probably not possible without head-to-head data. The recent ESC guidelines actually came out and made that explicit statement that in the absence of head-to-head data, it's hard to give CMIs a Class I indication. It's a little surprising, frankly, given the amount of randomized controlled data with mavacamten that already exist. But nonetheless, I think it reflects the bias of the community in terms of having hard data to support guideline recommendations. So, as we designed MAPLE, we thought it was very important not to be able to substantiate, I think, what many in the field already feel or know that the CMIs are superior to beta blockers, even as first-line therapy.
They tend not to push the beta blockers anymore, push dose or try and use them extensively, as you heard during our panel discussion. And I think the data from MAPLE, should they be positive, which we expect they will be, will be quite compelling and supportive of a first-line indication for cardiac myosin inhibitors.
Great. Okay, another question from Justin Kim from Oppenheimer, and I'll ask Steve to take this: How have patients with background disopyramide performed in long-term treatment? Are there any identifying features of the 10% of patients who remained eligible for SRT based on guideline criteria?
Thanks for that question. You know, I guess the short answer to the question is, we didn't actually present the individualized patient-level data. I will say, though, that, you know, disopyramide is a drug that is hampered by two main things. The first is it is fraught with side effects, anticholinergic side effects being the most troublesome, and those kind of manifest with, you know, patients complaining of blurred vision, dry mouth, dry eyes, urinary retention, constipation, and so forth. The second one is that it's prone to tachyphylaxis, which is basically the drug loses its effect over time.
So when you put those two things into context, what we've seen in FOREST is obviously patients who are taking disopyramide want to come off that medication as quickly as possible. And that is the most frequently removed therapy from patients' background medical therapy, or actually the first drug that's removed if they're taking, you know, these two. Whether or not it impacts you know the efficacy, I can say I'll you know point you to the phase two data where we did study it at the same dose strength that was in cohort one, and it had the same efficacy profile as the cohort one patients not receiving disopyramide.
So there's no reason to believe that, you know, aficamten in these patients in the FOREST-HCM is going to be any less efficacious than patients not taking disopyramide.
Thanks. Just a couple more, before we wrap up. Kripa has another question that I'll ask Stuart to take. Our KOLs have indicated that slightly lower than 50%, as was seen in FOREST- HCM, is not concerning to them, especially given margin of error in measurement. Is this consistent with what you are hearing?
If you could, just, repeat that, please. I didn't quite, follow.
Our KOLs have indicated that slightly lower than 50%, I guess, reduction in LVEF, she means, as was seen in FOREST, is not concerning to them, especially given margin of error in measurement. Is this consistent with what you are hearing?
Well, thanks for the question. First of all, it's certainly true that there is a fair amount of variability associated with measurement of ejection fraction, so that certainly needs to be taken into consideration. For the most part, the few drops in ejection fraction that we've seen in FOREST are sort of a small decrease, you know, below 50%. And for the most part, these have been asymptomatic and, you know, manageable by dose-down titration. And, you know, again, we're seeing rapid recovery of ejection fraction with that management approach.
So, I think we, I think we'd agree that, you know, that and, and we're learning, as Steve pointed out, with allowing investigators more leeway in terms of managing patients and using more of their discretion in terms of the clinical status of patients, that, you know, these small excursions are not very clinically meaningful and readily manageable.
Robert, did you want to add something?
Yeah, I read the note this morning, and it may benefit from some clarification. I agree with the observation from the KOLs that simply having an EF drop below 50% is, by itself, given variability, not so significantly meaningful. But however, it's the consequence of that that I think could be in the case of a down titration, that's certainly an adjustment KOLs are accustomed to making. To the extent it might contribute to a dose termination and a dose interruption where patients may come off of medicine for weeks to months, I think that could be quite consequential, and I think that's the key distinction.
With FOREST, we're very encouraged by the fact that, with even the relatively few, 0.5% of echoes that led to an EF below 50 in the maintenance phase, and for which that only required a down titration, that's inconsequential, it seems. And we hope that, the data from SEQUOIA will further underscore that were that to happen in any instance, simply a down titration can accommodate and not otherwise a dose interruption.
Great. And the final question I'll ask Steve to take from Charles Duncan. For SEQUOIA, can you clarify implications of measuring CPET on treadmill versus bike?
Great. Thanks. Thanks, Charles. So it has to do with hemodynamics. And you know, essentially, human beings are designed to exercise while upright. And there are impacts of gravity on your vascular system that actually can potentially exacerbate or make your gradients worse. So when you're on a bike, the mode of exercise can independently impact your gradients. And when you're looking at a treatment effect between placebo and an active drug, that can also reduce your gradients, you want to minimize any kind of potential confounders, and you know, I guess, magnify the treatment effect, if possible.
So if you are exercising somebody upright on a treadmill, and they're on placebo, you would expect that their gradients would go higher, whereas if they were receiving a myosin inhibitor that was effective, you would expect that that would reduce the gradient substantially, and the difference between them would be bigger. When on a bike, that difference could potentially be smaller because, you know, the patient is seated. That's all. So we just wanted to make sure that we were not going to overrepresent the bicycle in our baseline characteristics, and potentially blunt a treatment effect in that way.
Great. Thank you. So that's all the time we have. Thank you all for your great questions. Again, if we didn't answer all the questions, we will do our best to get back to you. With that, I'll turn it back over to Robert for some closing remarks.
... Thank you, Diane, and thanks to everybody for joining us for this program today. Next slide, please. I'll try to summarize some key takeaways. We covered a lot of ground, but there are a couple of points that I think are important to emphasize. One, is we're building a different kind of business model, a specialty cardiology franchise that we believe anchored in aficamten affords us an on-ramp to a business that will enable gated, investment, investment that ultimately can produce high returns, both for patients as well as ultimately for shareholders. That starts with aficamten and continues with aficamten, but first amongst those studies will be SEQUOIA, expected to read out later this year.
We're very encouraged by the baseline characteristics of SEQUOIA, indicating that we succeeded with our objectives to identify and enroll those patients who have a meaningfully significant deficit in exercise capacity and a significant symptom burden despite background therapy, enabling of us, we believe, to amplify effects of aficamten ultimately on top of standard of care. Our expectations are this is a study that can win on efficacy as well as safety and tolerability, as reinforced by our having designed and conducted a study that enrolled the right patients and ultimately the FOREST-HCM data that we shared for the first time, really in a meaningfully long duration format today, underscore why we expect to see SEQUOIA meet or exceed expectations by the end of the year.
The FOREST data are underscoring that we seem to be meeting expectations already high for aficamten, both as it relates to sustained and durable effects on clinical efficacy endpoints, and importantly, that the dose titration and the maintenance schemes of dosing are enabling of those durable effects without treatment interruptions. We're not seeing EFs fall below those thresholds, and FDA seems to be, as informed by the design and conduct of SEQUOIA, comfortable enabling of us to simply down titrate if EFs fall below 50, and they did occur in three of those echoes. But in no instances, dose interrupt, dose terminate, no EFs below 40, despite removing the guardrails from the randomized clinical trial and having 143 patients out for such long duration treatment, some of them beyond two years of treatment. For that, we're very encouraged.
The other thing you heard today is that we're doing the same kind of very systematic, thoughtful, methodical, and deliberate planning as relates to our commercial readiness for a footprint in a commercial space, much like we've done in R&D for so long here at Cytokinetics. Much like Fady has hired those people in his organization with excellent background expertise and perspective on how to design the right clinical trials, Andrew is building with his colleagues, those people who have the same kind of very considered perspective on how we can build a valuable commercial business for the benefit of HCPs and patients, of course, but ultimately, as transcends to the benefit of shareholders.
As you're also seeing, and as we've been good students in those relatively few companies that have built sustainable franchises in a commercial space, we, for our expertise in the biology and the pharmacology of cardiac muscle, in particular, cardiac myosin inhibition, have a next act, aficamten SEQUOIA, followed by MAPLE, followed by ACACIA, and ultimately transitioning to 586 in a subset of patients with HFpEF that resemble those with nHCM. So this hopefully provides for shareholders a perspective of how we see a through line for our business, continuing ultimately to build, ultimately more and more value to return for patients, science, and shareholders. Next slide, please. It all starts with a leadership in the science and muscle biology. You know about our pioneering leadership in cardiac muscle biology, as is focused to the CMI space.
Over 70% of our R&D spending is going to aficamten right now. But we have, from that core engine, more to say over time, that we expect will continue to translate into value for shareholders. But with an expertise and a depth in cardiology, as you've heard in quite significant ways today, starting with obstructive HCM and continuing non-obstructive HFpEF, and ultimately to advanced heart failure. We have, over 25 years, developed a credibility and a reputation, a strong one, in clinical science and R&D that enables us to transcend that from science R&D to business. And ultimately, I expect those same relationships with opinion leaders translate to respect and rapport with those who ultimately will be prescribing aficamten and other medicines, hopefully to follow.
And all of this comes with being prudent stewards of shareholder capital, both our strong balance sheet today that represents significant cash runway, but also contingencies and access to non-equity dilutive capital, like with our Royalty Pharma transactions. Next slide, please. So in summary, strong cash, access to additional capital, and it's being gated as we will look at SEQUOIA data, continue to be thoughtful about how we invest, knowing it's shareholder capital we are investing and ultimately translating, we hope, based on the backbone of clinical evidence, to a business franchise that we think can represent something unusual in the biopharma space, a highly concentrated customer segment and a specialty cardiovascular business model. Next slide, please. Here are the milestones for the remainder of this year. Foremost amongst them, we expect top-line results from SEQUOIA by the end of the year.
We will continue our clinical studies, MAPLE-HCM and ACACIA-HCM, continue to seek international approval for omecamtiv mecarbil, and continue the phase I studies of CK-136 and CK-586, as you heard about CK-586 today. Next slide, please. We thank you very much for your interest in this program. We appreciate you spending this time with us today. We'll look forward to keeping you abreast of our progress. Next up will be our earnings call in early November. We'll highlight some other data and outlook prospects in progress, and we will look forward to that and also results from SEQUOIA-HCM by the end of the year. With that, we can now conclude this program. Thanks again for joining us.