Cytokinetics, Incorporated (CYTK) Earnings Call Transcript & Summary

Welcome, everyone, and thanks for joining us on the call today, focused on the primary results of GALACTIC-HF. I'm Diane Weiser, Senior Vice President of Corporate Communications and Investor Relations at Cytokinetics. We have a great program planned for you today. 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 us -- 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. So Robert Blum, our President and Chief Executive Officer, will lead us off with an overview of today's announcement. Then Fady Malik, our Executive Vice President of R&D, will discuss the biologically driven approach we've taken in the development of sarcomere-directed therapies and omecamtiv mecarbil, in particular. Following these introductory remarks, we are honored to have an esteemed physician panel including John Teerlink, Professor of Medicine, University of California, San Francisco; Director of Heart Failure, San Francisco Veteran Affairs Medical Center and Executive Committee Chair of GALACTIC-HF. Dr. Teerlink will present the primary results of Galactic. Scott Solomon, Edward Frohlich, distinguished chair, Professor of Medicine, Harvard Medical School and Director of Noninvasive Cardiology, Brigham & Women's Hospital, will shed light on interpreting subgroups. Michael Felker, Professor of Medicine, Vice Chief of Cardiology for Clinical Research, Duke University School of Medicine and Director of Cardiovascular Research, Duke Clinical Research Institute, will provide context on the advanced heart failure patient, and Dr. Nihar Desai, Associate Professor of Medicine, Associate Chief Cardiovascular Medicine, Yale School of Medicine, Center for Outcomes Research and Evaluation will discuss the growing economic burden of heart failure. Following the presentation, we will open the meeting to Q&A. To submit a question, please use the chat box on your screen. And with that, I'm pleased to turn the call over to Robert.

Thank you, Diane. Today is a very important day for Cytokinetics, but more especially for the heart failure community of clinicians and patients. GALACTIC-HF, one of the largest cardiovascular trials ever conducted met the primary composite endpoint of reduction in heart failure events or cardiovascular death and the effect of omecamtiv mecarbil was consistent across most prespecified subgroups, with potentially greater effect in patients with lower ejection fraction and at higher risk. Importantly, the statistically significant reduction in the composite of heart failure events or cardiovascular deaths was observed in one of the broadest and most diverse range of patients enrolled in a contemporary heart failure trial and without significant imbalances in the overall incidence of adverse events across treatment arms. While admittedly, the trial did not meet the secondary endpoints, including reduction in cardiovascular death, we are gratified to have delivered on a positive primary endpoint. And we're looking forward to continue data analyses and next steps, which will include discussions with the scientific community as well as conducting market research and continuing our discussions with our partner, Amgen, as will inform our potential path forward. It's a very exciting time within the heart failure treatment landscape as new therapies are emerging that will potentially better treat patients fighting heart failure with reduced ejection fraction, many of whom have significant comorbidities as data presented at the meeting underscore. Today, we'll be delving into those patients with more reduced ejection fraction who may especially benefit from treatment with omecamtiv mecarbil. As you'll hear, these are patients who are difficult to manage and may not be able to tolerate current therapies due to their risk and comorbidity profile. As many of you know, we've been at this for a long time, so it's rewarding to be with you all today and to share more details around GALACTIC-HF and especially how omecamtiv mecarbil may fit into an evolving treatment landscape. And with that, I'll turn the call over to Fady, please.

Great. Thank you, Robert, and thanks, everyone, for participating. I'm just going to take a few minutes to set the biological context under which this program yielded omecamtiv mecarbil and led to the conduct of GALACTIC-HF and also provide a little history. Next slide, please. So sarcomere is this biological machine, the engine of muscle contractility that here is shown in a cartoon fashion with the myosin heads in Orange and the actin filaments in blue. Myosin hydrolyzing ATP and reaching for the actin filaments to pull on them and shorten the sarcomere. This is a process that occurs in every muscle cell and is the fundamental basis of muscle contractility. Next slide, please. Now at the start of this program many years ago, we laid down the therapeutic hypothesis that's illustrated in the next 3 slides. Fundamentally, in heart failure, people have pursued mechanisms of action to improve cardiac function which is central to the issue of heart failure, at least in patients with heart failure reduced ejection fraction. But prior approaches had really targeted indirect mechanisms, those that activated second messengers and led to increases in calcium concentration. Next slide, please. And had -- while they increased contractility, they also had several adverse effects, including increasing heart rate, lowering blood pressure, increasing oxygen demand and importantly, increasing the incidence of arrhythmias. We first hypothesized and then pursued the following, which is that targeting the sarcomere, in the next slide, would be an advantageous way of improving cardiac function. Increasing contractility in the absence of changes at the level of the plasma membrane or in calcium cycling and thus not affecting heart rate in an adverse way blood pressure, oxygen demand and arrhythmias. And much of the ensuing years led to working to understand how we could discover, optimize and develop small molecules that modulated sarcomere function, in particular, the cardiac sarcomere. Next slide. Omecamtiv mecarbil was the culmination of that research effort as it entered the clinic in 2005. It was -- it is a cardiac myosin activator, as you all know. And fundamentally, it increases cardiac function as we showed in earlier clinical studies, the driver of much of the pathology and heart failure is, in fact, the decrease in cardiac function for a vast number of patients. And here, the central action of omecamtiv mecarbil increased cardiac function, we hypothesized would have benefit in this group. If you go to the next slide, Diane. Early clinical studies show that omecamtiv mecarbil achieved its pharmacodynamic intention, which was at it increased cardiac function. Here's a set of echocardiograms in a patient with severe heart failure. On the left is the baseline echocardiograms, on the right is after 24 hours of infusion of omecamtiv mecarbil and you can see that the upper chamber there, the left ventricle is now contracting, it's thickening to a greater extent, the ventricular chamber has gotten smaller and the left atrium, which is the bottom chamber in that top right picture is also contracting and has gotten smaller. The bottom picture show the hardened cross-section and again, show the increase in wall thickening of the heart and its cardiac function. Next slide, please. Through a series of studies and it started with the first-in-human study, CY 1111, through which many of our panel here participated, in fact, through this entire program, led to COSMIC-HF, which was the penultimate study before Phase III program began. And this journey to get to Phase III involved nearly a dozen Phase I studies, over half dozen Phase II studies in over 1,400 patients to help us understand dosing and where to -- and how best to conduct GALACTIC-HF, which was an ambitious effort to look at omecamtiv mecarbil in a heterogeneous and broad population of heart failure patients. And with that, I'll turn it over to Dr. John Teerlink, who has accompanied me on this journey for nearly 2 decades, and he will present you the results of GALACTIC-HF.

Thank you very much, Fady. And on behalf of the GALACTIC-HF committees, investigators and patients. Thank you for the opportunity to share the results of GALACTIC-HF with all of you today. Next slide, please. These are the relevant disclosures for this presentation. Next slide, please. As many of you know, the fundamental central defect and initiating factor in heart failure with reduced ejection fraction, otherwise known as HFrEF is a decrease in systolic function. And Fady already talked a bit about that as a -- is a primary defect in heart failure. Yet despite extensive investigative efforts over a century, no therapies for chronic HFrEF targeting this systolic dysfunction have improved patient outcomes. And most have actually -- sorry, for the feedback there. And most have actually increased mortality. Omecamtiv mecarbil is a novel selective cardiac myosin activator, a myotrope that directly increases systolic function and has been shown to improve cardiac remodeling and decrease heart rate, and NT-proBNP in patients with HFrEF. The GALACTIC-HF trial tested the hypothesis that specifically improving cardiac performance can result in improved clinical outcomes in patients with HFrEF. Next slide, please. The key inclusion and exclusion criteria are listed here. Participants in GALACTIC-HF had symptomatic chronic heart failure with ejection fractions less than or equal to 35% with elevated natriuretic peptide levels who are receiving standard heart failure therapies. To include the full range of presentations of heart failure patients in patients admitted for heart failure as well as ambulatory heart failure patients were enrolled in GALACTIC-HF. Next slide, please. Patients were randomized 1:1 to pharmacokinetically guided dosing of omecamtiv mecarbil shown throughout this presentation in purple or placebo represented in yellow. Randomization was stratified by the location of enrollment as an inpatient or an outpatient as well as the region. Next slide, please. The primary outcome for GALACTIC-HF was the time to first heart failure event or cardiovascular death, whichever occurred first. Secondary endpoints were evaluated using a hierarchical testing procedure shown in the diagram on the right and included cardiovascular death and the Kansas City Cardiomyopathy Questionnaire total symptom score, tested simultaneously with an unequally split alpha, followed sequentially by heart failure hospitalizations and all-cause mortality. The estimated sample size was approximately 8,000 patients in this event-driven trial designed to -- for a 90% power to detect a 20% reduction in cardiovascular death, which required an accrual of an estimated 1,590 cardiovascular deaths. Next slide, please. 8,256 patients were randomized in GALACTIC-HF, with 4,120 patients in the omecamtiv mecarbil group and 4,112 patients in the placebo group contributing to the full analysis set. As a tribute to the superb operations of this trial, only one patient was lost to follow-up for vital status. Patients were followed for a median of about 22 months. Next slide, please. Participants in GALACTIC-HF represented one of the broadest ranges of heart failure with reduced ejection fraction patients enrolled in heart failure trials. Patients were median at 66 years of age, predominantly male and white race with a mean ejection fraction of 27%, about half with NYHA functional class III or IV and half with ischemic etiology. Systolic blood pressure and renal function were lower and NT-proBNP concentrations were higher than in many heart failure trials, and over 1/3 of the patients had cardiac troponins above the upper reference limit at baseline. Patients in GALACTIC-HF also had among the best heart failure therapies at baseline of any contemporary heart failure trial, with almost 20% of the patients receiving a ARNI or an angiotensin receptor-neprilysin inhibitor. It is now my honor to present the primary results of GALACTIC-HF. Next slide, please. So GALACTIC-HF met its primary endpoint with a significant 8% reduction in the risk of the composite outcome of time to first heart failure event or cardiovascular death, with a p-value of 0.025. For the first time, these results confirm the hypothesis that selectively increasing cardiac function with the cardiac myosin activator, omecamtiv mecarbil, can improve clinical outcomes in patients with heart failure and reduced ejection fraction. Next slide, please. As shown in the upper-left panel, the risk of a first heart failure event, which was the predominant driver of the primary outcome, was reduced by 7% in the omecamtiv mecarbil treatment patients but did not individually reach statistical significance with a nominal p-value of 0.06. In the lower-left panel, the risk of cardiovascular death, another component of the primary outcome as well as a secondary endpoint, was not significantly different between omecamtiv mecarbil and the placebo group. To evaluate the potential impact of omecamtiv mecarbil therapy on patient symptoms, the change in Kansas City Cardiomyopathy Questionnaire total symptom score from baseline to week 24 was assessed, and the results of this are represented in the right-hand panel. The overall joint test statistic p-value of 0.028 did not meet the hierarchical multiplicity-controlled threshold of 0.002. And thus, this secondary endpoint was also not met and further hypothesis testing of other secondary endpoints where is not pursued. However, note that the more symptomatic patients treated with omecamtiv mecarbil, who are as -- enrolled as in patients had a 2.5 point improvement in their KCCQ score with confidence foundries excluding 0. Next slide, please. In general, prespecified subgroup analyses of the primary composite outcome demonstrated a consistent across-the-board beneficial treatment effect of omecamtiv mecarbil. Next slide, please. However, one subgroup, the baseline ejection fraction demonstrates significant heterogeneity in the treatment effect with an interaction p-value of 0.003. Further analysis suggested that this subgroup of over 4,400 patients with an ejection fraction less than or equal to 28%, had a nominal 16% reduction in the primary endpoint. Given omecamtiv mecarbil's mechanism of action of increasing cardiac function, as Dr. Malik outlined for us. There is biological possibility that there may be greater benefit in patients with more severely reduced systolic function. And it suggests that there may be patient populations who might drive even greater benefit from this therapy. Next slide, please. Also consistent with its mechanism of action and evidence from prior studies omecamtiv mecarbil had no significant effect on systolic blood pressure, potassium homeostasis or renal function suggesting that it could be readily incorporated into contemporary heart failure treatment algorithms and would not compete with initiation or dosing of established heart failure therapies. As also seen in prior studies, there was a small reduction in heart rate, consistent with sympathetic withdrawal and reduced natriuretic peptides, consistent with improved ventricular -- left ventricular wall stress and decongestion. A minor increase in cardiac component eye of 0.004 nanogram per milliliter was also noted with an assay that has a limit of detection of 0.006 nanograms per milliliter. Administration -- let's go to the next slide, please. Thank you. Administration of omecamtiv mecarbil resulted in no imbalance of adverse events or serious adverse events including those adjudicated events related to cardiac ischemia or ventricular arrhythmias with an overall adverse event profile similar to placebo. Next slide, please. So in conclusion, in patients with HFrEF, omecamtiv mecarbil statistically significantly reduced the risk of the primary composite outcome of first heart failure event or cardiovascular death, predominantly through a reduction in both urgent visits and hospitalizations for heart failure. The pattern of adverse events including myocardial ischemia and ventricular arrhythmias were similar in the omecamtiv mecarbil and placebo groups. GALACTIC-HF represents the culmination of a journey to increase cardiac function as a means to treat heart failure that started over 1 century ago. It provides evidence that improving cardiac function by selectively targeting the cardiac sarcomere with omecamtiv mecarbil. This first-in-class myotrope is a novel approach to improving cardiovascular outcomes. Clearly, further analyses of GALACTIC-HF will provide greater insight into subgroups of patients who may demonstrate greater efficacy, such as patients with lower ejection fraction and whom improving cardiac function may have a greater benefit. And next slide, please. So for further details, please see the full text article in the New England Journal of Medicine, which is published online now. And then finally, in this forum, I'd still like to thank the committee members, national leaders, the sponsor personnel, which have had phenomenal interactions, site investigators, study coronaries, and most importantly, the patients who participated in GALACTIC-HF. And thank you to all of you for attending this session and learning more about the GALACTIC-HF trial. I look forward to addressing your questions.

With that, we're going to move to Dr. Solomon with his presentation making sense of subgroups. Dr. Solomon.

Thank you, and thanks, John, for taking us through that and leaving us on this journey over the last many, many years. I'm going to be relatively brief because I'm going to focus on a very specific aspect of the data that Dr. Teerlink just showed you, which is the subgroup results in GALACTIC-HF and how we put this into context. Next slide, please. Here are my disclosures. Next slide, please. Well, as you just heard, that overall headline results of GALACTIC, I think, can be summarized as follows. We saw a significant, albeit modest overall treatment effect and clearly, a greater benefit in patients in the lower left ventricular ejection fraction subgroup in a therapy that was quite well tolerated in patients with heart failure and reduced ejection fraction treated extremely well. Next slide, please. And Dr. Teerlink just showed you this slide, which is a forest plot of all the prespecified subgroups. In GALACTIC-HF, I'm sure you're used to looking at slides like this, where we're basically looking at the hazard ratios in each of the subgroups. We see on the -- in the middle here, the hazard ratios for the individual subgroups, absent on this slide primarily because the New England Journal doesn't like us to publish these are the interaction p-values that go with the subgroup interaction testing. Now normally, when we look at subgroups, we do that for a particular reason, and that particular reason is to look for consistency. Move forward, please? As Dr. Teerlink has already shown you, there is one particular subgroup that we're going to pay a tremendous amount of attention to because indeed, we saw evidence of real heterogeneity, and that's the patients who had an LVEF less than or equal to the median under 28%, a group that represents about 4,400 patients, more than half the patients in GALACTIC-HF. And as you can see, there appears to be a difference, a real difference between the benefit in the patients in that lower ejection fraction group and the patients in the higher ejection fraction group. We determine whether that benefit is actually statistically different by looking at an interaction p-value, and you can see here that it is highly significant. Now if you move to the next slide, this is one of the best academic papers about how we look at subgroups in clinical trials. And reminds us that normally, we look at subgroups not to look for differences, but to look for evidence of consistency. And as is written by Janet Woodies in this really important paper, if we're lucky, all the reported subgroups will show essentially the same thing and the summary of the results will include a statement that the findings were consistent across subgroups of interest. Well, that was true for the majority of subgroups of interest in GALACTIC-HF, but not for left ventricular ejection fraction. Next slide, please. So how do we determine if this is a real or a spurious subgroup? And we know of many examples where people can look at a subgroup and say, "Oh, there appears to be greater benefit in one group than another." We have to ensure that, in fact, when we talk about a subgroup result that, that subgroup result is actually not a random and spurious result, but a real one. And there are several criteria that we use to make that assessment. The first is that the subgroup must be prespecified, not post hoc. And clearly, it was here. In fact, we knew that patients in the lower end of ejection fraction might benefit to a greater extent from a drug that works in the way that Fady already showed you by increasing contractile function of the heart. That subgroup should be large. Patients and should have a large number of patients and a large number of events and often we see subgroup results where there might be 10% or 20% of the overall population. As I've shown here, this particular subgroup was greater than 50% of the patients in GALACTIC. It was 4,400 patients. And I will remind you that, that is a larger number of patients than were in the entire DAPA-HF trial and many other trials that we've tested therapies in heart failure. We then have to statistically test this by using a test for interaction. I've already described that. And ideally, also testing for both multiplicity and in a multivariable analysis because some of these subgroups do travel together. And the size of the p-value in this particular subgroup suggests it would hold up to multiplicity testing. We have to examine the architecture of the total data and the adjacent subgroups. Does it make sense? Is their internal consistency? Well, have we seen this result with a greater benefit in patients in the upper ejection fraction group as opposed to the lower ejection fraction group, we would have been scratching our heads and saying, well, that doesn't make a whole lot of sense. So we believe that this makes sense, given what we know about this drug and the disease. And finally, is there biologic plausibility. And I think that as you'll hear from Dr. Felker, there is -- there are lots of reasons to think that a drug that makes the heart contract better will, in fact, work better in patients who have more contractile dysfunction. Next slide, please. Now I'm going to show you an example of a case where, indeed, a trial was positive overall. Just like GALACTIC-HF and where a post hoc review of subgroups demonstrated that indeed, there were patients who did not benefit very much from this therapy and patients who did benefit to a much greater extent. And this was the MADIT-CRT trial, which used cardiac resynchronization therapy in which patients were enrolled who had evidence of a conduction system abnormality. What we didn't realize until the trial was over was that patients who did not have a particular type of conduction system abnormality called a left bundle branch block did not benefit at all from this therapy. And in fact, guidelines now and the indication is for patients who have left bundle branch block. It's a subgroup within the original study, but these were the patients who clearly benefited the most, even though just like GALACTIC, this trial was overall positive. Next slide. So in summary, patients in GALACTIC with the lowest EF benefited clearly to a greater extent, than do patients with higher EF, this benefit occurred on top of very good overall background therapy as Dr. Teerlink has pointed out. This is a subgroup finding that in light of a significant, albeit modest overall benefit, I think, provides a clear road map for omecamtiv mecarbil, becoming a standard of care therapy in patients with advanced heart failure and low ejection fraction. And as Dr. Felker is going to tell you in a few minutes, this is a group with great unmet need. Thanks for your attention.

Thank you, Dr. Solomon. As Dr. Solomon just mentioned, we're now going to turn it over to Dr. Felker to talk about that unmet need in advanced heart failure. Dr. Felker?

Great. It's my pleasure to try to provide a little bit of clinical context, as Scott mentioned, about just who are these patients we're talking about with advanced heart failure, what are the challenges in managing them? And what potential role might a drug like omecamtiv mecarbil be able to play. So next slide. So advanced heart failure is sort of a broad term, it doesn't have a precise definition, but there's been several consensus statements. This is adapted from the consensus statement from the European Heart Failure Association. Basically patients with advanced heart failure are those who despite already being on excellent medical and device treatment continue to have persistent symptoms. These may be at rest or with modest exertion. And they have objective evidence of severe impairments of cardiac performance. We've talked a lot about ejection fraction today in this document, they defined an EF of less than 30. They have other evidence of objective impairment of hemodynamics at rest, whether those are invasive or noninvasive, they're characterized by recurrent hospitalizations and severe impairment of functional capacity, that is, these are people whose daily life is markedly limited by the symptoms of heart failure. Next slide. So you also may be familiar with the idea of stage D heart failure, and this is from the AHA, ACC staging, which defines 4 stages of heart failure. A and B are really precursors to heart failure, either the presence of risk factors or the presence of asymptomatic structural heart disease. Stage C is groups with symptomatic heart failure what we're used to thinking about sort of NYHA Class II and III patients and that shades gradually into stage D patients with advanced heart failure. And I apologize if you hear a dog barking in the background. Next slide. So the natural history of heart failure, as we all know, is unpredictable. Many patients have long periods of stability, but then interspersed with episodes of decline in performance, often with hospitalization and gradually, heart failure is a progressive disease. What starts out as a disease primarily of more hormonal abnormalities gradually progresses to the point where we call low output symptoms, symptoms like fatigue, very limited functional capacity begin to predominate as the disease progresses. And these patients often are not ideally treated with the medications that we have presently, as I'll describe in a second. Next slide. So when I'm seeing patients at the bedside, there are several things that I can identify that often tell me this patient is progressing. Recurrent heart failure hospitalizations is a big one. After hospitalization, patients returned to their baseline, but over time, that baseline begins to gradually be worse and worse in terms of baseline disease state. A big one is progressive hypotension, which limits the ability to be treated with the nonhormonal drugs that we're familiar with, beta blockers, ACE inhibitors, ARBs, ARNIs and leads to either stopping altogether or reducing the doses of those agents similarly with renal dysfunction and azotemia. And then finally, a common finding is worsening diuretic resistance, where it's taking escalating doses of loop diuretics to maintain clinical stability. Next slide. So -- sorry, next slide, just keep -- there you go. So what are the options for these patients? Well, obviously, we're treating them with optimal medical therapy. Some patients, and Scott mentioned these may be treated with CRT, if they have cardiac resynchronization therapy if they have certain types of electrical abnormalities. But often, we're talking about treatment for these very advanced patients with treatments like heart transplant or mechanical cardiac support with a left ventricular assist device or even the need for palliative care. So where do these more advanced options fit in the armamentarium? Next slide. So even though transplant or LVAD therapy are dramatic benefits for the patients who receive them, they're really very limited epidemiologically. There's about 6,000 patients who are a little bit less in the United States who receive these therapies each year, and that's been more or less stable over time. So even though these therapies can be dramatically beneficial for the groups of patients that receive them, they tend to be not available because of comorbidities or other issues for a variety of the patient population that we're talking about. Next slide. And I think this is an important point because as people are aware, we already have a number of good treatments for heart failure, but those treatments are progressively difficult in patients, the sicker they are. So this is data from Canada, but showing the patients who are higher risk in the green and lower risk in the blue. And what you can see is the highest risk patients tend to be treated the least aggressively with a traditional medical therapy. And that's not because doctors want to do a bad job in those patients. It's simply that as patients get sicker, their ability to tolerate ACE inhibitors, ARBs, beta blockers and the other aspects of guideline-directed medical therapy becomes less and less. So there's clearly a need for alternative strategies for these people. Next slide. And the issue is, as been mentioned by John and others, most of these drugs have overlapping intolerances, that is beta blockers, ACE inhibitors, ARBs, ARNIs, MRAs, they all lower your blood pressure. And as a heart failure patient with a low blood pressure to start with, especially as the disease becomes more advanced, they have limited ability to tolerate and often we're backing down on doses of medication. So there's clearly a need to identify drugs that play better with the other parts of the armamentarium. And are well tolerated even in patients with relative hypotension, as was mentioned by John in his discussion of the results of GALACTIC. Next slide. So I think there's a clear unmet need for these advanced heart failure patients. Again, for drugs that do not overlap and their intolerance that can be used in relatively advanced patients despite low blood pressure or azotemia and again, that directly impact the problem that begins to predominate in the physiology of these patients that is low cardiac output as opposed to nonhormonal abnormalities, next slide. And so as a final slide, I think it's important to think about the paradigms of how we treat chronic diseases. There are a large number of chronic diseases that we manage where there are multiple drugs in our armamentarium. And the way we treat those as we match the drugs to the particular characteristic of individual patients. In heart failure, by contrast, traditionally, our method has been that we give all the drugs to all the patients. And -- next slide. I think it's increasingly clear that as we have more and more drugs in the armamentarium, option 2 is not really sustainable and that we're going to need to be identifying specific subgroups to target a specific therapies based on their characteristics and pathophysiology. And I think that's a unique opportunity for omecamtiv mecarbil to address this unmet medical need. So thank you, very much.

Thank you, Dr. Felker. And concluding the presentations now will be Dr. Desai. To put this all into the context of the growing economic burden of heart failure. Dr. Desai.

Perfect. Thanks very much. I'm delighted to be with you. And I'm going to pull a lot of the themes that Fady, John Teerlink and Scott and Mike kind of have already touched on and try and pull them together. But with a slightly different perspective, more of a wide-angle lens, if you will, providing some perspectives on the broader heart failure landscape and what's happening in the ecosystem around us, which is there's a lot of activity there and this sort of push to value that I'm sure many of you have heard about. Next slide. So how do I sort of see heart failure? I mean, you've obviously seen a lot of data from Mike and Scott about heart failure and unmet need. And I think there are sort of 4 key bullet points, if I was going to sort of summarize where we are. First, it's the #1 cause of hospitalization and 30-day readmission. The 5-year mortality rate is staggering at about 75% for patients that were hospitalized for heart failure. There's been a substantial increase in health care spending associated with heart failure, over 127% increase with expenditures now over $80 billion. And then finally, I think that sort of puts it all together is substantial variation in quality outcomes and payments, a real opportunity to create value and drive value. I think the final sort of piece to this puzzle, if you just hit the next button, is that new therapies don't enter a vacuum, but they actually enter a complex and dynamic ecosystem. And I think that we're entering a period now where the environment is going to evolve or has evolved to such a point where we're really going to see the fostering of adoption of therapies that really drive value. I think that's the framework to sort of evaluate some of the results and very exciting results that you've seen thus far in this presentation. Next slide. So beyond the clinical burden that you've heard about from the other speakers, I think the economic burdens are just staggering here. We sort of talked in the last slide about $80 billion in total spending. And the drivers of that are shown on this slide, which is actually a couple of years old now. But to no one's surprise, the principal driver of health care expenditures, representing about 50% of the total cost of heart failure is in-patient hospitalizations that the hospital and what happens to patients there really is the primary driver of health care spending. So if you put the last couple of slides together here about substantial variation in quality and cost and pretty important opportunities to improve the care of our patients, it's to no one's surprise that we've seen pretty unprecedented amount of activity in the policymaking side to try and improve what's happening in the heart failure landscape. So next slide. So what have policymakers been trying to do? I think there's been a lot that's sort of gone on here. I think it started maybe a couple of decades ago, frankly, with reducing length of stay, improving quality and outcomes. And those are, of course, important policy objectives. But I think what's happened more over the last 7, 10, 15 years is on the top part of this figure, to reduce hospitalizations and readmissions and reducing spending and increasing value that those really have become explicit objectives of policymakers and payers together and really are driving a lot of clinical decision-making that's happening every day in the office as well as in the hospital. But policymakers have relatively few tools available to them despite these very laudatory objectives that they hold. And so on the next slide, you can see sort of what's going on. I think one of the levers that they do have available to them is the payment system, and they have used that payment system. And been very creative with trying to sort of stimulate change on the delivery side, especially in chronic conditions like heart failure. So what's the broad arc that we are traveling on right now. And I think it's sort of summarized on the top part of this slide, they move away from fee-for-service, very transactional volume-oriented medicine to a value-based model of care, where the payment that a provider or a hospital receive is actually tied to the quality of care, the outcomes of that care and actually, the efficiency of that care, what was the cost and utilization of that encounter and how efficient was that care? There have been a number of important national policy programs that have been instituted over the last decade or so. And I'm going to touch on just a couple of them, but we're going to, to no one's surprise, talk about rehospitalizations, readmissions. I'll touch on the bundled payment program. And then finally, the accountable care organizations. But fundamentally, what all of these programs require is that those providing care, those delivering care are taking on some financial risk. They are being held accountable for the quality of care, for the outcomes that those patients are achieving and to the cost and efficiency of that care. And so at the bottom part of this slide, you can see sort of a -- to get us to kind of some objective or empirical definition of value. And I think the way to quantify it is really to think about these 2 elements of quality and cost. And then you can break quality down even further into clinical outcomes and patient experience. And I think that helps frame many of the very important findings that Dr. Teerlink shared with you for omecamtiv mecarbil, seen in the GALACTIC-HF trial. So along both of those domains, outcomes and patient experience, functional outcomes, functional status you've seen very important benefits for clinically definable subgroups, and of course, overall in the trial itself. Next slide. It's also important to remember that there's not a uniform distribution of what happens to patients with reduced EF heart failure. There are many different subgroups and many different trajectories that our patients follow. So this is an analysis, actually looking at Medicare data just looking at how concentrated Medicare spending has become amongst the subsets of patients that have a growing number of clinical comorbidities and a number of chronic conditions. And I would venture to say, I don't have the data available to me for heart failure specifically. But we all know and certainly clinically and intuitively true that the patients that have the most severe heart failure. Those with the most severe systolic dysfunction. Those that have the greatest symptom burden are the most likely to be driving health care expenditures. And so as you think about this, subset of patients that are really driving utilization and you start thinking about what Mike Felker just talked about in terms of unmet need, what Scott Solomon talked about in terms of subgroups, and then obviously, what John Teerlink showed you with the overall results of GALACTIC and that subgroup of patients that have the most severe systolic dysfunction, the most advanced symptoms and symptom burden and that all sort of comes together around a real value opportunity as we think about omecamtiv mecarbil. Next slide. So with that sort of backdrop, I just want to touch on a couple of things like sort of national programs, if you will, that have really important implications for the way physicians and hospitals are treating heart failure and thinking about heart failure. So the first is around readmissions. And this is a slide actually from about a decade ago from Steve Jencks, looking at Medicare data, just looking at how often patients come back to the hospital. And you can see that numbers are actually quite staggering here that more than 1 in 5 patients are rehospitalized within a month, about 1 in 2 will be rehospitalized out at 6 months. And so as part of the Affordable Care Act, there was a program called the Hospital Readmission Reduction Program, that for the first time, financially penalizes hospitals for having too many readmissions. But there's a lot of subtleties and nuances for how that program is structured and how it's ultimately implemented. But on the next slide, you'll see the financial consequences. And so there's a lot here, but I will just focus your attention to the bottom row, which gives you an estimate of just how much these penalties are. And if you look since the inception of this program in fiscal year 2013, the penalties that have been levied against hospitals, including for heart failure, which has been a diagnosis that's been included in this program since its inception. It's about $3 billion of financial penalties. So it's to no one's surprise that hospitals, providers, everyone is really attuned to reducing rehospitalizations and reducing the burden on our patients with heart failure. Next slide. The other program I just want to touch on quickly, sorry for all the abbreviations, is the BPCI Advanced or the Bundled Payment for Care Improvement Advanced program. And again, there's a lot on this slide, but I just want to focus on the text at the very, very top. So this, again, is a real paradigm shift in the way that we take care of patients. So what this program requires, it's currently voluntary. My own system is actually participating in this program. Is hospitals are now financially accountable for the cost and quality of care provided to Medicare fee-for-service beneficiaries for the inpatient stay and the 90 days that follow thereafter. And so here, readmissions take on a fundamentally different complexion. Now all of those rehospitalizations, all of those costs, all of that utilization is actually on the hospital's checkbook. Medicare is not going to reimburse and pay hospitals all over again for that. And so again, I think it heightens the importance of if there's a clinically definable group of patients where we think there is a substantial benefit for omecamtiv mecarbil and the other heart failure therapies that you've heard about, then all of a sudden, there's now a financial incentive for providers and hospitals to actually deliver those therapies that can reduce rehospitalizations, reduce total utilization and improve symptoms. Next slide. And providers and systems are actually preparing for this. They see the writing on the wall. It might be voluntary right now, but there is also an announcement, actually last month from CMS that they're going to make that bundle program mandatory starting in 2024, and systems are reacting to that. They sense that the ecosystem is evolving and changing in a very, very dramatic way. And so this is some survey data from New England Journal a couple of months ago, just showing how many systems are actively participating in what right now are voluntary programs because they're trying to figure it out. They're trying to build the infrastructure, build the expertise to not just survive in this value-based world. That's really thinking about quality and outcomes and costs in a fundamentally different way, but they are actually preparing for that to thrive in that sort of world that lies ahead of them. Next slide. And again, I don't think it's any secret. CMS has been very clear. Here's a slide of Alex Azar, who is the current HHS Secretary, and this is a speech he gave a couple of years ago actually telling the world that CMS is absolutely going to make these programs mandatory in the future. And I don't think it would surprise anyone that heart failure and cardiovascular conditions would be amongst those at the very, very center of this work, just given the prevalence, the amount of spending that we're talking about and just how much variation there is in these patients. Next slide. So just a couple of kind of summary thoughts for me to wrap up this part. First, that the pressure to move to a value-based model of care in terms of delivery and financing is intense. And will only further intensify. I think cardiology will get a disproportionate amount of focus in these efforts. And I think heart failure will be the principal disease condition for much of this work. In parallel, I think there's an urgent need to reimagine what heart failure care looks like with this sort of move and this push to value. And finally, the therapies and strategies that deliver value to patients, providers and payers, specifically with improved outcomes, better quality of life and reduced costs will thrive in this evolving ecosystem. I think the data that you've seen from John Teerlink and the other contextual information that you got from Scott and Mike really give you a sense that omecamtiv mecarbil can really be part of this new value landscape and the treatment of heart failure for many of our patients. So with that, I'll sort of close out and thank you again.

Thank you so much, Dr. Desai, and thanks to all of our esteemed panelists. So some great presentations. We're now going to open it up for our Q&A discussion. So there are a lot of questions that have come in. So bear with us, we'll do our best to get to them all. If we can't in the time that we have, we'll obviously be able to follow-up with folks to make sure that all your questions are answered.

So the first couple of questions come from Jason Butler from JMP Securities. And I'll kick it off first to Dr. Teerlink. How do you think about the clinical importance of 16% relative risk reduction in the LVEF less than 20% population.

So thank you for that question. I think that we have -- the main point that I've made before in regards to this issue is that the trial as a whole was a very positive trial. So we already had a reduction overall. In that specific group, the 16% reduction is on a level and better than some of the recent trials in terms of its improvement in clinical outcomes. And I would emphasize that this is an opportunity for us to treat a group of patients that as Mike Felker pointed out, is already solely, very poorly treated right now. So it provides a real opportunity, I think, for better -- for advancement in the treatment of these patients.

Great. Thank you. Related to that, what was the representation of LVEF less than 28% between inpatient and outpatient population. In other words, does the data support the lower EF increases, risk of hospitalization and these patients being a greater medical need. Dr. Teerlink?

So as we saw on the baseline manuscript, there wasn't actually a difference in the inpatient and outpatient ejection fractions at the time of enrollment in the trial. However, there's -- if you look at -- and you have to be careful looking at subgroup analyses and the forest plots. But if you look across them, if there are any shifts and changes beyond the ejection fraction, most of them actually favor omecamtiv mecarbil in the setting of a bit more advanced in a sicker patient population.

Great. And then how did the primary endpoint event rate in a placebo arm compare between the overall population versus the LVEF less than 28% subgroup? Dr. Teerlink.

Could you repeat that? I'm confused a bit by the way.

Yes, So am I a little bit. How did the primary endpoint event rate in the placebo arm compare between the overall population versus the less than 28% LVEF subgroup?

So it sounds like they're asking about the event rates in the -- so the overall -- the primary composite overall event rate was at 24.2 events per patient year in the omecamtiv mecarbil group and 26.3 per events per 100-patient years in the placebo group. In terms of splitting it out by the ejection fraction, we haven't gone into those analyses at this point in time. I think that addresses their question.

Thanks. Okay. Moving on a couple of questions from Joe Pantginis from H.C. Wainwright. And maybe we'll ask Fady this question. Can you talk to the underlying muscle biology? Why LVEF under 28 might be better, for example, healthier muscle, not as reactive to omecamtiv?

Well, I don't know if the underlying effect on cardiac function is what's driving the benefit per se. We know omecamtiv mecarbil works in healthy hearts, it works and parts that have a range of ejection fractions. I think what drives it is the fact that the underlying path of physiology in those more advanced heart failure patients is more central to their pathology is this reduction in ejection fraction. The higher -- patients with higher injection fraction still respond to the drug, but their events, their heart failure condition may not be driven so strongly by the fact that their heart failure, their ejection fraction is less than normal.

Great. Next question from Joe. Maybe Dr. Felker. Would atrial fibrillation would be a valuable subgroup in a sicker population? Also wants to know if increased eGFR may be a valid subgroup analysis.

Yes. So certainly, there's a number of subgroups you can look at. Atrial fibrillation is more common as patients' heart failure gets more advanced -- as patients' heart failure gets more advanced lower EGFR or worse renal function becomes more common. So I think Scott mentioned a lot of these things travel together. There's clearly a lot more to do in examining the data from GALACTIC and trying to tease out how all these things interact together and think about potential benefits?

Excellent. Okay. Lots of questions from many of our analysts about next step. So maybe Robert and Fady can address these. And then some want to be posed directly to our physician panelists. So in terms of next steps with respect to potential NDA submissions, when can we expect to hear an update? And then related to that, people are interested in, what kind of label will we seek and expect to get? Robert?

Yes. So I think it's premature to be speculating on the type of label that we'd be seeking. What I'll say is Amgen conducted an excellent study. You heard from our panelists, how rigorous this study was in terms of ensuring that patients were on standard of care. And we have now data that we need to understand and to Amgen's credit and in collaboration with Cytokinetics, we have a lot of work still to do. To this point, these are data analyses that have been conducted together with the executive committee of the trial but are only now being shared publicly, and that includes with the investigators of the study. There are nearly 1,000 investigative centers and these investigators are just now understanding these data. And we and Amgen are committed to speak with the full investigator collective as well as other opinion leaders who weren't involved in the conduct of the study to understand how they see these data. And there's a lot more data analyses, as you just heard, that are still to be performed. So we and Amgen are going to be diligent about -- going about understanding how they view these data in the context of where the signal may lie with regard to some of the noise, admittedly and where there could be a path forward. In addition to that, we and Amgen are committed to doing certain market research. You've heard now about how we might begin to think about prespecified subgroups and understanding which ones are independent and which ones may be more dependent but understanding that in the context of a potential target product profile or profiles and doing market research around that, not only with physicians and not only amongst those who are like our panelists, the leading academic lights in cardiac care, but also those who may not be an academic medicine but involved more in communities, understanding how they view these data and not only discussing it with physicians, but also with other people in the continuum of care. And also with payers, so understanding how all of those stakeholders might view these data in order to understand what could be the opportunity set here. Only then will Cytokinetics and Amgen, I think, be best served to talk about next steps and whether that might include proceeding to conversations with regulatory authorities and after that. So give us some time, please. There's a lot of work still to be done, including additional data analyses, but other work around the data analyses that we and Amgen are committed to do and as we'll then inform our next steps.

Thanks, Robert. In terms of the addressable population, there's many questions related to this. And I know Cytokinetics and Amgen are continuing to analyze the data and conduct the market research, as Robert mentioned. Let's go to -- and Dr. Solomon in his presentation concluded that omecamtiv mecarbil may be appropriate as standard of care for this particular population of patients with EF below the 28% level. So interested to hear perhaps for Dr. Solomon to try to quantify that population of patients that sits within that level?

So I'm not sure that I can give you a precise number, maybe Nihar knows the exact number of people who live there. I think that, as you've heard today, we're in the very early stages of analysis of the data from GALACTIC-HF. And we know that there is greater benefit in these patients with lower EF. 28% was the prespecified median cutoff. That doesn't necessarily mean that, that is the cutoff that where -- the optimal cutoff if we were to identify a group of patients in whom we think this drug would work well. It may extend beyond that. We will have to look at data in a more rigorous way in -- by looking at ejection fraction, not just cut at the median, but as a continuous measure, we're going to have to look at other things as well. So very early stages here. And we -- I think it's fair to say that there are a lot of patients who live with advanced heart failure with ejection fractions that are in this range. And they're the most challenging patients, as Dr. Felker has already mentioned. And part of that is because every drug that we use pretty much in heart failure, lowers blood pressure, lowers heart rate and has other effects on the kidneys, for example, on potassium, for example, that limit our ability to use these therapies. And the fact that this drug doesn't have those effects, gives it, I think, an advantage over some of the other drugs that we have for which there is a cost to using them.

Maybe Dr. Desai. Just jumping off of your last point, can also adjust that question.

Yes. No, it's a good question. I don't have a number, just like sort of Scott was saying. But I think the key question and sort of what I would suggest the audience and everyone to think about is, what's the role of this therapy amongst the broad population of patients with heart failure. I mean, these patients have significant unmet medical need. They account for substantial amounts of health care costs. And as the world sort of continues to move, it forces us to think differently about quality and cost for these incredibly high-risk patients, that the more that we can sort of come together with additional analyses to really create this sort of narrative about which patients benefit and how do we sort of partner with patients and providers and health systems and payers to really help them sort of tackle the challenges of managing these incredibly difficult patients, I think the better off that we're all going to be.