Cytokinetics, Incorporated (CYTK) Earnings Call Transcript & Summary

Good morning. I'm Diane Weiser, Senior Vice President, Corporate Communications and Investor Relations. I'm pleased to welcome you to new horizons and 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. [Operator Instructions] 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; and 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 Jacoppi, Vice President, U.S. Marketing, for Aficamten; and Jeff Lotz, Vice President, U.S. Sales and Operations. Next slide. I'm also happy to welcome 3 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 & 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, and who will share with us her experiences living with the disease. Following that conversation will present our commercial readiness activities for Aficamten, which will be followed by our panel discussion with our expert HCM physicians. This concludes 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. And 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. And as over time, we hope that will lay a foundation for other indications for Aficamten to follow including potential to expand the 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 nonobstructive HCM as would be informed by the results from ACACIA. SEQUOIA, MAPLE and ACACIA are all 3 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. And 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 us having precedent in biopharma. Other biopharma companies with interest in cardiology typically focus to a much more diffuse primary care segment. And 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 an investment in Aficamten over different indications ultimately as we build a growing revenue base that we believe starts with oHCM grows within nHCM and ultimately provide significant value and benefit for patients and ultimately for shareholders with a growing revenue base and a higher 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 build 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 Afticamten 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. And 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 focused to competing in highly diffused 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 health care 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 will 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 whose properties we understand through the fidelity of these various different models. Next slide, please. We've approached the contractility to the heart really in two respects. First, addressing both Hypercontractility, there on the bottom with activators that were developed to improve cardiac contractility and diseases of heart failure with reduced ejection fraction. And 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. So hypertrophic cardiomyopathy is a disease that's phenotypically defined by a 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 monogenetic and polygenetic etiologies. Next slide. Mutations in the sarcomere have been fully, seem to have caused the vast majority of hypertrophic cardiomyopathy, where the cause is understood is a monogenetic 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 muscles, as you can see on the right, contrast it to the left, but also a disruption of the cytoarchitecture of muscle with the disarray of myofibrils and the laying down of fibrosis within the myocardium. Next slide. HCM manifests really in 2 major forms, 1 we call the obstructive phenotype and the other is the non-obstructive phenotype. And 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 intraventricular 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 nonobstructive 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 intrinsic contractility back to normal in contractility and HCM that's increased because of mutations within the myosin motor or other elements of the sarcomere that lead to excessive cross-bridge formation an outflow tract obstruction, billing pressures that increase or hearts muscles that thicken and looking to address that path of physiology by the reversal of these effects, effects that I'll note can be measured quantitatively either through echocardiography, the biomarkers or cardiac MRI, all leading we expect to improvements in symptoms, improved exercise capacity, improve functional class and disease stabilization or regression. So this is a therapeutic hypothesis we pursued really since about [ 2008. ] Next slide, please. In designing a cardiac myosin inhibitor, they have 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 has decreased excessively a down titration of the drug or wash out 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, 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. And 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 and binds in a pocket above the ATP binding domain. As you can see in the structure on the right, we're another small molecule called lovastatin binds. lovastatin is a good tool and that it enables us because it fluoresces when it binds to myosin to show that Aficamten in binding can displace lovastatin and thus, the fluorescence decreases, and it identifies that crystallographic site on the myosin as the binding site for aficamten. Interestingly, the other cardiac myosin inhibitor in the clinic mavacamten, you see that it doesn't displace lovastatin and likely it binds in a different spot in cardiac myosin. And thus, these mechanisms are distinguishable, and we think, ultimately, that it contributes to some of the differences between the 2 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 create, to produce a shallow and exposure response relationship as we could find. So this is defined by in this rat model of cardiac function, increasing doses, leading to increasing exposures to aficamten, 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 tenfold in contrast to mavacamten where we found was about a threefold 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 is overlaps or looks identical. And the fundamental property, which was designed into aficamten has translated with fidelity into humans. Next slide, please. So with that, I'm going to 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 prevalent splits between obstructive HCM and non-obstructive HCM. I'm going to 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. So, 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 are, there is a study that has a 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. It's 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 of the 1.5 million based on a more recent study in the journal of the Journal of American Cardiology, the 1.1 million, which you see here to the -- as the upper end range is our planning assumption, and that is based on a syndicated report published by the Cardiovascular Resources Group. The split of HCM is approximately 65% or 2/3 obstructive and 1/3 nonobstructive. We are very confident if you see in the, in kind of the middle circles in each box that diagnosed population of oHCM and nHCM of 300,000 in total, of which 200,000 are for obstructive and 100,000 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 per their medical record. The addressable population is that a circle within kind of the symptomatic HCM patients. 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 nonobstructive and again, growing at the rate of 1%, consistent with the U.S. population. To the right, you see a 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 a really good rationale to I believe that, that diagnosis rate will continue at that rate. Obviously, there's disease awareness, including some direct-to-consumer television highlighting and on building awareness for HCM there is AI models, including VIS AI, which looks at electrocardiograph and highlights patients who are suspect of HCM. The guidelines do include the American the AHA and guidelines do include screening test. 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 U.S. 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 the early 60s. To the right is a 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 2/3 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 could see the treatment that these patients are on. These are nondisease, 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 nonobstructive HCM, you can see the gender split where this actually skews a little higher towards male with the average age again in the early 40s. I'm sorry, age of diagnosis in the early 40s and the average age in late 50s. The symptom status, again, informs where CMIs could be utilized. There is a range of symptom status based on varying publication somewhere between 35% and 50%. Our analysis and assumption is it's about 40% of the non-obstructive HCM patients would be eligible for CMIs. Next slide. Like the oHCM, the vast majority of patients of nonobstructive HCMs are treated with 1 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 nonobstructive patients having 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 the 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 are 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 Classification IIs and IIIs. The green are our projections for that subset who are considered for CMIs actually using CMIs with the penetration rate between 25% to 40%. Our assumption is that when should aficamten get approved and launched 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 based on a 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 nonobstructive HCM. And I think it's actually quite amazing that we now have 4 ongoing Phase III trials with aficamten at 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 aticamten 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. And 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. And then finally, at the bottom, we've initiated a Phase III trial in nonobstructive HCM, which we're calling ACACIA-HCM. And here, we're comparing aficamten to placebo. Now I would like to evaluate heart failure symptoms and functional capacity. But this is a study with the treatment duration approximately 3x longer than SEQUOIA and MAPLE. And it gives us the opportunity to evaluate clinical outcomes. So before we discuss these Phase III trials, I want to spend a few moments discussing Phase II results that inspired the potential benefit of aficamten and inform the study designs of these Phase III studies. Next, please. So in our Phase II REDWOOD-HCM trial, we conducted 2 dose finding Cohorts, a low-dose Cohort 1 and high dose Cohort 2 in obstructive HCM. REDWOOD 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 a target achievement of both resting and Valsalva gradients while maintaining while maintaining a normal ejection fraction above 50%. And furthermore, the dose titration or dose optimization was completed in a relatively short time frame within 6 weeks. Next, please. So there was rapid reduction in normalization of gradients in both Cohorts with greater reduction observed in Cohort 2 with availability of the higher 20-milligram dose. After the 10-week treatment period, there was rapid reversibility of gradients and this paralleled rapid reversibility of ejection fraction. And so this profile of rapid reversibility and form 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 and REDWOOD. You can see that in the middle bar Cohort 1, there was a large proportion of responders in this low dose Cohort. And we define responders as achieving both resting and Valsalva gradient targets. And then the high dose Cohort 2 on the right, nearly every patient was a responder. These results gave us an indication that aficamten could completely eliminate the outflow obstruction grading in most patients with HCM. Next, please. So these grading 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 reductions of NT-proBNP are almost unprecedented. We're observing 70% to 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 reduced ejection fraction. It's in the order of 30%. So these are quite amazing results. And they were associated with improvements of NYHA Class, indicating some improvement of heart failure symptoms and functional capacity. Next, please. So these reductions in NT-proBNP were also associated and corresponding with improvements of cardiac structure and diastolic function. So we observed reductions of left ventricular mass index, left atrial volume index and improvements of parameters of diastolic function. And these results suggest that 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. So there were no treatment interruptions or discontinuations. There was, there were no patients who had ejection fraction less than 40%. Only 2 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. And 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. So in summary, the safety profile, along with the robust efficacy results that we observed. We 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. So 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 going to 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 going to present data that we analyzed from last month, September 15 data cut on the 143 available patients. I'll let you know that almost every patient that is offered participation in this development program choosed to participate in the open-label extension. And the long-term data that we're going to show you is going to 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. So I'm going to 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 for 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 gradient. 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 have, 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 ejection fraction below 50%. And once the patients have achieved their steady state and that occurs with 2/3 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. And 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. And we looked at almost 600 echocardiograms in the patients that have achieved that, here about 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%. And 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 3 patients with an ejection fraction of under 50%, 2 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 return to above threshold, and there was 1 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 3 patients are currently on study receiving aficamten with relief of their obstruction improvement of their symptoms and buyer markets. 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 II 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 baselines and high-sensitivity cardiac troponin. Next slide. And 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. 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. Minimal clinically important difference is about 5 points or is 5 points. And 70% of patients experienced that. And actually, 30% of patients experienced 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. And 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 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 are 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. And 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 arrest gradient of 75 millimeters of Mercury. And in this example, after just 2 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 a very mild or trace mitral regurgitation. So 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 improve very rapidly to asymptomatic and that was maintained for the duration in this case, a patient was exposed to Aficamten for 120 weeks. And those clinical features are also confirmed by a very impressive reduction in NT-proBNP for 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 are able to safely titrate these patients in 2/3 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 1 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 III 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, 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 II or III 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 up-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 30-millimeter greater than or equal to 30 millimeters of mercury, indicating the opportunity for up-titration to doses of 5, 10, 15 or 20 milligrams per day. Up-titration was optimized by week 8 and follow-up was at week 24 with end-of-study observation for safety at week 28. Patients are randomized 1:1 placebo versus aficamten over the course of the treatment period. Next slide, please. Here's 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% in 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. And 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. And 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 represented of a very broad group of oHCM patients. I can tell you, I still see patients in HCM clinic, my clinic is next Friday. And many of the patients that I see refer to me in my clinic would be excellent patients for enrollment in SEQUOIA, where we're 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 topline results for SEQUOIA-HCM by the end of the year. Next slide, please. I'll now be shifting away from SEQUOIA-HCM and to MAPLE-HCM, our Phase III 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 usefulness of beta blockers across the field of cardiovascular disease has been augmented and supported strongly in the field 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, the 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 burn. 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 in support for a head-to-head study comparing aficamten and metoprolol with a double dummy design in one-to-one 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 the 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 2 different primary types of hypertrophic cardiomyopathy patients with obstruction. In the first case, it includes patients with recently diagnosed disease, more 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. And in the second group, patients with a history of obstructive hypertrophic cardiomyopathy who are currently taking standard of care medicines, beta blockers, calcium channel blockers. 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 2 groups of patients. Another special design or a specific design feature of MAPLE-HCM that differs from SEQUOIA 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, 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. Say it 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 in 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 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 III trial of Aficamten in oHCM. And 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 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 aficamten did seem to have what looked like an impressive improvement in patients 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, 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 25% and 20% of those patients experience large to very large and moderate to large increases in the 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 with Class III severely symptomatic. And by 10 weeks, about 1/4 of patients with entirely asymptomatic with about 2/3 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 the setting of 85% of patients titrating to the maximum available dose within this Phase II 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 have 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 the patient's quality of life quite significantly. Next slide. So these data actually form the basis of the design and gave us confidence in moving into Phase III for non-obstructive HCM. So we have designed the ACACIA HCM trial, we presented the study design at the Heart Failure Association 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 will 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 aticamten doses of 5 to 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 actual 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. And that will give us the unique opportunity to measure whether aficamten appreciably impacts cardiovascular clinical endpoints, 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 study and followed after that. Next slide, please. And again, just to distill that into our milestones, we're continuing. ACACIA is open. We've enrolled patients, and we are accelerating our enrollment and site initiation through the remaining part of this year and into next year. Next slide. So with that, we're going to 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. [Break]

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 want to make clear that while Megan was a participant in our Phase II 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 will focus on Megan's experience living with HCM. So thanks again, Megan, for being with us this morning.

Thank You.

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?

Yes. 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, and I grew up seeing multiple different providers, not really a specialist. So there was always the questioning of how is this going to -- like what's the outcome of this? So 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 now?

Well, I -- since I was diagnosed when I was little, that's really all I've known. So I don't, I want to say it's consumed me, but it definitely 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, yes, 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. Actually went to the hospital because 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 kind of 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 doctors or going to the emergency room to get checked out because she just didn't know what could happen. So 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 him I -- like, I can't do heat, like I can be out there for a little bit and just the heat would make my heart feel like it was over working.

Yes?

Yes.

And 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. Yes.

Great. And then I think the last thing that we're interested in is 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 we call kind of a silent disease because 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 my 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. Yes.

And I know you can't talk about your experience on the trial, as we mentioned. Clearly, there's a lot of research going on. What is your overall kind of impression of how things are going to 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 somewhat normal life. I mean I know it's not going to completely 100% cure HCM, but it will help patients feel like they can live a normal life with less limitations.

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 going to move to the next section of our presentation, which focus on the commercial readiness for Aficamten. And with that, I'll turn it over to my colleague, John, who will 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". And 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 3 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 going to 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 health care 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 to 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 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 health care 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 health care 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 the 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 uses entered into European treatment guidelines. You can see here in 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 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 U.S. physicians and 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 want to 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 guys, communication plans to an ETA SU REMS. ETA SU stands for elements to assure safe use, and an ETA SU REMS can include any or all of the following 6 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 CMIs. The 3 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 & Window, these are some areas that we're hoping to potentially see around reducing the risk 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 early presentation about the Ideal CMI. You see some of those aspects here. Rapid onset, rapid reversibility, speed to optimal dose, predictable dose response, teratogenicity 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 them. Next slide. A few comments. 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 going to 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 will discuss the payer landscape.

Thanks, John. So in this section, I want to 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. 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. 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 plants. 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 and 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. And 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 are a Class II, Class III, and that's how they will manage a 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 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 datesheet would be approved in 2025, which would mean we would bid the Medicare bid processes, say, the end of the year in December, and that bid process would be applicable for 2027. Any Medicare coverage we get in '25 or '26 is considered off cycle, and it's certainly able to be achieved, but largely most Medicare formulary will come on within that formal bid process. If I orient into 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 2 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 I consider the, I'm sorry, if we consider the clinical trial. I can give you a few examples. If SEQUOIA can demonstrate the ability to change a patient 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 onetime procedures for patients in terms of curing obstructive HCM. While there are a few exceptional centers with highly successful SRT outcomes, 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 and health technology assessment reports. The better Aficamten can report, Aficamten can perform in our clinical trial, but 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 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 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 part of the patient's responsibility is during a coverage gap and then 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 prices, which is known as a catastrophic cost. So today, a drug around $100,000 would cost a patient a little over $7,000. You can see 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 the pharmacy. So they will not get the script filled because of the out-of-pocket cost. And pharmaceutical companies cannot support a co-pay 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 in Medicare patients of higher cost drugs. Next slide. So last thing I want to cover in terms of the implications of what John described in terms of the complex patient journey, especially 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 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 the 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 that are shown for illustration. But certainly, we are committed to helping patients along with our journey and helping patients get on therapy should their doctors feel like Aficamten as an 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 going to cover 2 things. First, I'm going to walk you through how we're thinking about our launch preparation. And the corresponding gating of the investment for launch. And then I want to 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 want to 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, in addition to the insight gathering that John talked about, 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 could ultimately develop account-specific launch plans that we believe is a significant competitive advantage and a very innovative approach to approaching the launch. Once we get through the SEQUOIA readout, we'll start, as John mentioned, we'll start the design phase and start to build. And you'll see, 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 preapproval information, planning our final deployment of our custom fixing teams and building the technology that enables them to engage with customers. And then once we're approved, there will be significant investment in communications through media and supporting patients through a variety of programming. Next slide. So now I just want to talk a little bit about some of the insights we've gathered around our potential HCP customers, 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, 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 7,000 to 10,000 treaters, diagnosers and treaters and somewhere, and they're spread that across 500 to 700 health care organizations that represent approximately 75% to 80% of the patient volume. So 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. And Robert shared this graph. And what you can see is that 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 -- our 80% of the patients covered. Next slide. Now when we talk to customers 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 throw people at the problem. And 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. And there are several people visiting practices or health care organizations throughout the day that could be disruptive to patient care. So we've taken these customer insights and put them right into our design principles. And ultimately, we want to create a very efficient, highly impactful and high-quality customer experience and build relationships with our HCPs and ultimately Aficamten patients. And we want to 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 want to fill these positions with people who have 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 going to be in clinic on Friday. And when Dan gets to the clinic, he wants to work with his care team to help as many patients as he can throughout a day. And it becomes disruptive when he has several different people 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. So next slide. As I mentioned, 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. And 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. And 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. And 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 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 1 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 & Women's Hospital in Boston. Welcome today. I'd like to 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 practices 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. Thank you so much. It's a pleasure being here today. And we see a number of different challenges with our patients, some struggling with the impact that HCM has had on their families and trying to understand what the future might hold for them and their children and others dealing with symptoms related to HCM. That impacts their quality of life and their ability to engage in activities that they have enjoyed doing.

Ted, you've been taking care of patients on both coasts, both East and West. How have the challenges of taking these patients changed over the years?

Thank you, Fady. I think very similar to Caroline. We've had, I guess, across both Coasts now close to 5,000 or 6,000 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 nonmedical and more surgical 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.

And Caroline, you practice in the United Kingdom and Scotland, maybe how is your practice there? How it might differ from practices here in the U.S.? Maybe if you can comment on that.

Yes. 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 they get diagnosed with asthma or, so they often come to us at quite a frustrated stage, I would say. And it's, the therapeutic options are limited. The -- it's a big deal to have an intervention, whether that's surgery or alcohol ablation. So, Yes, it's a very similar demographic in patients. 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. I think that there's a spectrum, and there are some patients that tend to be more aggressive and willing to take on big procedures just to kind of move on within and well hopefully have more of a one-and-done strategy that will restore their physical functioning and alleviate symptoms. But I would say that I think most patients are understandably reluctant to take a big step, particularly having open heart surgery to address symptoms. So I think that a lot of patients put up with some amount of functional limitation. So symptoms that may be anywhere from modestly to moderately improved with standardly available medical therapy. To avoid 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 our complication rates, mortality rates were quite low, and we often cited that we did not have a single death, for example. That was not something that we're fully enthusiastic about. So actually, there was more of a resistance in getting to that therapy, and there'll be a lot of questions and lots of delays once that question was popped or once they hit the threshold where we said 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 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 have disopyramide," I say, "let's go for it and we'll do it right now". But once you pull the nonmedical option, there would be lots of delays, lots of having [ a hung ] and a general discomfort in proceeding in that direction.

And Dr. Coats, I guess, with comments of Ted and Carolyn, how do you think -- do you think patients really lived compromised? If you will, and how they might feel in terms of accepting a certain amount of disability given the treatments that were available a couple or 3 years ago?

I think we definitely see that. And I think I'd echo the sort of reluctance to jump 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 yes, there is this kind of acceptance for some people or adjusting their life without really appreciating it. And it's only when they compare themselves have had young people, and it's not until they've gone to university and met other people around them that actually really can't do stuff that I maybe should have. So yes, I think there's definitely a gap in the market for people who aren't, had enough to actually say yes, I want to go for surgery, but they do want to feel better.

That's an important point you made in the sense that people may not really 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 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? 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 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?

Yes. So there's a portion of patients with obstructive HCM that aren't completely asymptomatic and are able to function at a high level, but I would say there's a large number of patients that are limited and have a spectrum of symptoms ranging from mildly to quite substantially limited. And so our approach before has been stepwise, as Ted described, first starting with beta blocker or calcium channel blocker and trying to escalate dose, potentially adding on disopyramide, if people still do not have adequate symptom relief with those measures. So I would say that the standard medical approach is modestly to moderately affected. Some people notice a fairly meaningful improvement. Other people noticed almost no improvement or troubled by side effects of particularly beta blockers. We typically had to escalate medical therapy. And generally, we're still left with the gulf of people not quite feeling as well as they wanted to feel. And could therapy does not -- medical therapy doesn't tend to be durably effective to people that initially had reasonable symptom relief that they have high gradient remaining, and it's pretty predictable that over a period of a year or 2, there symptoms would become really quite limiting, again, on maximum 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 Carolyn and Caroline do the same thing is, we have a lot, especially younger patients with high-grade and just 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 find and sometimes they don't. That's number one. Number two, medical therapy, we found to be more successful in folks who have borderline gradients and not very extremely high gradients. And 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 would we follow the exact same protocol that Carolyn just described at the higher doses, and this 1 patient who was on 200 or 250 milligrams of metoprolol and a pretty healthy dose of disopyramide mostly tolerate the dose, the gradients -- I remember him walking in one day, and we say, "your gradients are completely normal" it's worked. And he said, "Yes, 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.

Yes, I think Ted, 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?

Yes. So that's a huge challenge actually because we really don't have anything to offer. 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 failures 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 is potentially going to impact on that. So 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 as, really not sure how helpful they are being for patients.

Let's maybe turn to cardiac myosin inhibitors. 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 to classes, the treatment option for [indiscernible] has changed your practice from a clinical perspective. Dr. Ho, do you want to go first?

Yes, sure. It's been really transformative in a number of ways. Added so much excitement and enthusiasm and hope that we might have an effective medical therapy that really substantially abolishes symptom burden without adding its own array of side effects, the patient's have by and large, felt really great with clinical trial participation with the commercial introduction of cardiac myosin inhibitors, and it's allowed people to really understand how limited as they were and how much better that they can feel. So it's just, again, the excitement and the enthusiasm, the optimism has been really a great thing to be part of.

Dr. Abraham how have they become 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, "I think I'm on the drug, She was 70 years old, could barely walk up 7 steps up to our apartment in San Francisco, and she said, 2 weeks after the drug, I can go up to my son's apartment on the third floor or 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 uncomfortable not to offer this trial to every single person in our, both ablation and surgical volume, almost ground to 0 that for several years after that. So yes, we tend to have a lower threshold. We start to 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...

Oh sorry. Dr. Coats, we know that CMIs are just 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 clinic?