Cytokinetics, Incorporated (CYTK) Earnings Call Transcript & Summary

Good morning, and welcome to activate, inhibit, empower, changing the course of cardiovascular disease. I'm Diane Weiser, Senior Vice President of Corporate Communications and Investor Relations, and I want to thank you all for joining us this morning. We have an exciting agenda to go through with you today. We're going to be showing updates on our cardiovascular pipeline as well as strategies on building a commercial franchise. Before we get to the program, I do have some forward-looking statements, so bear with me. 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. So we're going to go through the agenda, we're just having trouble. There we go. We're going to go with the agenda just really briefly. We've focused today's presentation on 3 sections. The first is activate, focus on our cardiac myosin activator on omecamtiv mecarbil; the second is inhibit focused on our cardiac myosin inhibitor CK-274; and our final section is empower, where we're going to have a patient panel on perspective, living with these diseases that we'll be talking about as well as how we're going to build our cardiovascular franchise. There'll also be panel discussions throughout our session today, and you'll have an opportunity to ask questions. I'll get to that in a moment. On this slide, just some housekeeping about engaging with the platform. For those who aren't familiar with it, you have the opportunity to customize your dashboard however you'd like. There are some features that you can see on the screen, in the lower left box, there's Q&A box. You can find our speaker bios as well as the agenda, so you can follow along. As I mentioned, you do have the opportunity to type in questions in this box at any time throughout the program, and we will do our best to answer everybody's questions. If we don't have time to get to your question, we will , we will definitely follow-up with you after the program has ended. If anybody is experiencing technical issues throughout the program, please just type a message into the Q&A box and our tech support team will help you. Finally, there will be a full recording of our program that will be available on the Cytokinetics website. So I'm pleased to introduce my colleagues from the company who will be speaking today: Robert Blum, President and CEO; Fady Malik, EVP, Research and Development, Stuart Kupfer, SVP, our Chief Medical Officer; Andy Wolff, SVP, Senior Fellow, Clinical Research and Development; Steve Heitner and I can't see this slide, so let me just move it out, Senior Medical Director, Clinical Research, Cardiovascular; Laura Robertson, Medical Director, Clinical Research, Cardiovascular, Scott Jordan, SVP, New Product Planning and Commercial development; and Durga Baba, VP, Global franchise, General Manager Cardiovascular. I'm also very pleased to introduce our panel of speakers who will be joining us today. John McMurray from the University of Glasgow, Adrian Hernandez, Duke University School of Medicine, Mary Allen, from the University, Colorado School of Medicine; Marty Maron from Tufts University School of Medicine, Anjali Owens, Assistant Professor of Medicine; and Andrew Wang, Duke University School of Medicine. We also have a panel of patients joining us, as I mentioned earlier. Linda Moskowsky, who is living with heart failure; and Lindsay Davis has joined us, she's living with hypertrophic cardiomyopathy. And with those introductions, I'm pleased to turn the program over to our President and CEO, Robert Blum.

Thank you, Diane, and thank you to everyone for joining us today. This is an incredibly important and transformative time for Cytokinetics. And it is with great pleasure that I am here today to welcome and orient you to today's program, but also the mission of the company. Our mission -- and many of you have known us for over 20 years, our mission has been to ensure that we are mining the area of biology, in particular, muscle biology in order to bring forward new pioneering medicines to improve the health span of people living with devastating cardiovascular and neuromuscular disease associated with impaired muscle function and muscle weakness. We've been at this for a long time. And as I mentioned, we've been pioneering this new space. But as you talk to us today, we're in a position to execute on a vision, a vision that we put forward for this company over 20 years ago, but now we can articulate specifically in terms of how those investigational medicines come forward to benefit patients and how that's connected with our corporate development strategy and our commercial strategy to building a business that is sustainable and durable. So our Vision 2025 outlined on this slide, articulates that over the next 5 years, we expect to bring forward at least 2, potentially 3 new medicines originating out of our research. We also expect to be able to bring forward a commercial infrastructure built on the backbone of our leading science. And in that way, offering continuity of expertise as we go from an R&D-focused company to a commercial focused company. How we do that matters as I'll articulate in a minute. In doing that, we want to ensure we're building sustainable business and cash revenues, growth and profitability. We want to make sure we're constantly feeding the engine, the soul of ingenuity for our company and in that way, investing in expansion of our platform in biology beyond what is currently focused to the contractility of muscle to then also include energetics growth and metabolism of muscle. And still being true to form muscle biology focus. We want to ensure that we're populating our pipeline today, which comprises 5 programs in development. We expect over the next few years, that's going to be doubled to 10 programs. And every step along the way, we need to make sure we're listening to patients and that we are that company that not only patients want to partner with, but also that employees want to join for this being an authentic value-centric company oriented towards the mission that I outlined. How do we get there? Let's start in the left-hand top portion of this circle, leading with science. Cytokinetics has always been and always will be a science-driven company. We anticipate being able to expand our muscle biology focus but always remain true to the hallmark of what has got us to where we are today. Cytokinetics focused to muscle biology for several reasons, one of those reasons is this is a quantitative biology, a biology that we can measure. And one of those same measurements that guide our thinking in research translate into the in vivo systems, the translational systems in early clinical trials and also through mid-clinical trials that are predictive and high-yield for what we would expect to come out of Phase III trials. That's essential and very important, oftentimes lost in building a new company. We want to have a high fidelity biology that translates importantly into something that we can measure in clinic the same way. Moving to the right, how we assess our clinical candidates is also very important. Cytokinetics will never be accused of being an overnight success. We've been methodically investigating in Phase I and Phase II studies all along the way the properties of our compounds, not just to lead compounds but backup compounds and follow-on compounds. It's that kind of redundancy that builds out success in our high-risk drug development industry. But we also can become profoundly observant to the learnings of pharmacokinetics. All along the way, cytokinetics has ensured that we're understanding the connections between the pharmacokinetics of our small molecule drug candidates and the pharmacodynamics of them in order to assess not only proper dosing and therapeutic window, but how to customize these investigational medicines as could be potential new treatments for patients, who themselves have personalized interest. Now moving to the other corner, think like a patient, all along the way, we need to be engaging patients, elevating their voice understanding what matters to them, ensuring that what we're assessing in clinical trials translates to something that's profoundly important to them in their everyday living and then building a franchise. Cytokinetics from its very beginnings and origins has always been oriented towards pipeline and portfolio. And how we think about this is that as we mature our business, the science begets clinical research, the clinical research begets gets our commercialization and planning. All of that needs to be connected so that it's a science-driven and market-focused orientation to our business in all aspects, enabling us to build on our successes ultimately for the benefit of medicine in patients. So where are we today? Today, we're looking at this pipeline. This is a pipeline that originated from our own research, again, over 20 years. And we divide our portfolio of novel drug candidates into 2 verticals, those that modulate cardiac muscle and those that modulate skeletal muscle. While we have these many compounds in development, early, mid and late stages, today's program is really focused to 2 of these compounds, in particular, omecamtiv mecarbil, a first-in-class cardiac myosin activator that entered clinical trials in 2005, partnered with Amgen since 2006. You're going to learn a lot today about the science underlying this program, the clinical research and why we have reasons to believe that the Galactic results expected later this year can be positive and what that means for us in terms of building out our business. CK-274, not a cardiac myosin activator with a cardiac myosin inhibitor. This is essential to the strategy connecting the dots from the work we're going to be doing together with Amgen in the area of heart failure and reduced ejection fraction and extending our leadership in muscle biology and cardiovascular medicine to those patients suffering from hypertrophic cardiomyopathies. I won't speak to these other programs on the pipeline, but please understand that AMG 594 and CK-271 and even reldesemtiv in the skeletal muscle activation area, all tie to our objective to be the leading company focused to novel medicines rooted in muscle biology and directed to cardiovascular diseases. We've been good students of biotechnology for many years. And what you see on this slide, a corporate development strategy is essential to how we get to where we want to be. We recognize that biotech companies typically have 2 failure modes; one is they're set up to basically pivot on binary risk a product succeeds or fails in the company's fortunes alongside of that, we've, from the very beginning, focused to a biology where we can both pioneer and lead and become a dominant player exploiting that new pharmacology to new medicines. But the corporate development strategy also matters. How do we fund that? We've always felt like it's essential that we'd be able to monetize our leadership in biology in order to be able to generate cash flows and capital, so we don't rely on any one particular source of capital but layer into the company over time different sources of capital to ensure a sustainable growing business. And we've done that through leveraging partnerships. Starting with Amgen in 2006 as was expanded and then Astellas and more recently, as of yesterday, our announced deal with RTW and Ji Xing. These deals together contribute to upfront cash payments. They contribute to sponsored research, sponsored development, milestone payments, ultimately royalties on sales and then as those may become durable and sustainable, Cytokinetics should be able to retain rights, responsibilities and economics to its own programs and build an increasingly profitable and valuable business. I mentioned our deals. These have been pivot points and fulcrums around which the company has matured its strategy. As I mentioned, Amgen in 2006, Amgen has contributed many hundreds of millions of dollars to advance our research and development. We're especially grateful to them for a long standing partnership. Together, we've conducted clinical trials and largely at Amgen's expense in order to be able to tee up what it's a very exciting time this year with Galactic results expected later in Q4. Under our Amgen deal, they're also affording us certain sponsorships as we transition to a commercial entity and as much as they'll be financing our build of our sales and marketing infrastructure, reimbursing us for certain sales force costs. Along the way, we also monetize the future royalty under our collaboration with Amgen. In 2017, we sold a piece of our royalty to Royalty Pharma for what was then $100 million, affording us additional capital to build our business and still retaining a royalty that approximates about 20% of sales upon the first commercialization of omecamtiv mecarbil, which we expect potentially by the end of next year. CK-274 needs to be well positioned to build on that. And yesterday, we announced a new collaboration comprising 4 different transactions with RTW Investments and Ji Xing Pharmaceuticals. This additional capital -- committed capital of about $250 million, enables us to advance CK-274, not only in China, an area outside of our current strategic interest, but also in order to be able to parallel process multiple indications, obstructive HCM, nonobstructive HCM and subsets of patients with heart failure and preserved ejection fraction. Here again, this partnership enables us to leverage our expertise in science and clinical research in order to mature our corporate development. And ultimately, as we see this translating to our commercial strategy, these all go hand and glove together. Under our Amgen collaboration, we are well positioned with them as a partner to sale and market our own medicines under a co-commercialization agreement in North America, where our orientation, as you'll hear later, will be primarily directed to institutional care segments of the marketplace and again will be reimbursed for our cost of sales and that will enable us to proceed to what could be profitability as a company much sooner. But the opportunity with omecamtiv mecarbil being as large as it is, given the high unmet need and high prevalence of heart failure and reduced ejection fraction, affords us cash flows, cash flows that can be invested in our build of our commercial business that will extend with CK-274 and reldesemtiv beyond North America to also include Europe. In all cases, whether it be for omecamtiv mecarbil or the other programs, our focus will be to those concentrated customer segments where a high return on investment is possible, given the tractable sales and marketing infrastructure and resources required to be a player in this space. So that's how the corporate development strategy matches with the commercialization strategy. Moving forward, in order to be understanding how that all is going to be played out over time, it's essential that you understand where we have been and where this science will be taking us. With that, I'd like to turn it over to my colleague, Fady Malik, with whom I've been partnered in building this company for over 20 years. Fady leads research and development, and he'll take you through the biology of modulating contractility and how that can deliver on unmet needs. Fady?

Thanks, Robert. It's really my privilege to be here with you today and be representing the scientists at Cytokinetics, the physicians that we've worked with over the years and to serve the patients, some of whom we have with us today. I'm going to take you on a journey from concept through discovery and through development in a few short slides, 20 years of work in 20 minutes. And so with that, let's go ahead and get started. What you see on the first slide here is to appreciate that muscle is at the root of many different diseases. We often think of diseases of the lungs, the heart, skeletal muscle as disease entities of those organs. But underlying all of those, as you can see, is -- are a diversity of contractile functions that in cardiac muscle, power ejection and filling of the heart, skeletal muscle give us mobility and strength and then smooth muscle regulate blood pressure, tone and -- pulmonary tone. And this regulation or dysfunction of contractile tissues can result in an array of diseases that are outlined in the second row of that table. At Cytokinetics, we realized that over 2 decades ago, we began a journey of developing the technology to modulate the function of muscle, either positively or negatively as the disease state demanded by designing assays that -- of increasing complexity that reproduced the function of muscle, either in a biochemical assay that enable us to do high throughput screening and discover modulators of muscle function to assays of muscle and its native context in muscle fibers or other systems, muscle cells, muscle organs and ultimately in vivo models of muscle function. And one of the features of muscle is it's extremely highly conserved. The muscles in our -- in the preclinical setting are virtually identical to those in humans. And so there's a fidelity of translation from the preclinical setting to the clinical setting. Now a focus on the heart, muscular organ, which beats our entire lifetimes, billions of heartbeats sustains in order to pump blood over the course of decades, is an elegant structure, a pump that is designed to last. But it's function is balanced in a way that is -- sometimes leads to where diseases impact that balance lead to diseases either a reduced cardiac contractility, such as on the left, diseases, we call heart failure with reduced ejection fraction, genetic dilated cardiomyopathies or right ventricular failure due to other etiologies, such as pulmonary hypertension. And on the right, conditions of increased cardiac contractility, which are genetically driven often and result in hypertrophic cardiomyopathy or sometimes when they're not genetically driven, it may result in a disease we call heart failure with preserved ejection fraction in certain subsets of that population. The underlying structure in muscle is a sarcomere. It's an elegant structure. It's shown there to the right of each chart. And it's an array of fibers repeated over and over again in muscle, thick filaments there at the center that contain the myosin motor that powers cardiac function and the thin filaments, which act as the ropes on which myosin pulls to cause muscle to shorten. This is all in balance typically, but at times, it becomes unbalanced. And you see sarcomere dysfunction emerge and disease result. Now a normal functioning heart here is displayed in the middle and these images taken with magnetic resonance imaging. You see the left ventricle there sort of at 2'o clock. It's the main pumping chamber of the heart. And this heart is contracting normally. We characterize that by saying it has an ejection fraction, in this case, of 60%, which means it's ejecting about 60% of the volume in that chamber with every heartbeat. Now on the left-hand side, you can see a heart that has got reduced contractility or low contractility. And that left ventricle has dilated. It's gotten bigger. You can see the hearts beating faster. Its intrinsic thickening of the muscle is much less than you see normally. And fundamentally, this heart is not pumping blood as it should. On the right-hand side, what you see, though is a hyperfunctioning heart, hyper contractile heart. This heart is thickened. You see the walls of the ventricle there have begun to occlude the cavity in which blood is filling. In some cases, the thickening of the heart is asymmetric and that thickening blocks the outflow of blood from the heart and this is characterized by high ejection fraction and cardiac thickening. The heart's a visual organ, and we're able to use these technologies often in the translation of the preclinical science to the clinic. Now underlying the contractile function of the heart is this elegant structure, the sarcomere. What's shown below in this diagram is the thick filament, which contains the myosin motor. This elegant protein finds ATP as an energy source. It hydrolyzes it into ADP and phosphate and ultimately grabs the actin filament up above in purple and pulls on it. And then actin filament shortens and hence muscle contracts. Now the actin myosin interaction is regulated by a series of proteins called troponin and tropomyosin complex. This complex enables the actin and myosin interaction to be regulated by calcium. Calcium is released inside the cardiac myocyte at the beginning of every heartbeat. It binds to troponin move -- which moves tropomyosin out of the way, revealing binding sites for myosin on the actin filament and the muscle begins to shorten. In the meantime, calcium is being pumped back out of the myocyte. Calcium levels fall, the tropomyosin falls back into its normal position, blocking the myosin, pushing it off the filament and the muscle begins to relax. This structure is something that we've been able to take apart to screen, find modulators over the years and has led to a number of either activators or inhibitors of the sarcomere. The case of activators, omecamtiv mecarbil, which is a cardiac myosin activator, it works directly on the myosin motor as well as another activator, which works on the troponin complex, AMG 594. And 2 inhibitors, CK-274, CK-271. These are direct inhibitors of cardiac myosin. And they reduce the number of active cross bridges, a number of active myosin heads that can interact with the filament and reduce contractility. And so fundamentally, the premise behind either activating the sarcomere or inhibiting the sarcomere is to try and restore balance to muscle and to take what might be a hypo functioning heart with low contractility and increases contractility towards the center or a hypercontractile heart on the right and reduces contractility. And again, push its function towards the center into a more normal range. Now this is illustrated on the following slide. Here we see translation from the preclinical setting to clinical setting. On the left, our echos taken in dogs many years ago as we developed omecamtiv mecarbil, these are the first glimpses in a dog model cardiac function of the effect of omecamtiv mecarbil on contractile function of the heart. You can see in the left-hand panel, the heart before omecamtiv mecarbil and after an infusion of omecamtiv mecarbil on the right, you can see that the heart there is contracting to a greater extent and injecting more blood from that central cavity. Now on the right, is a patient. This is one of the patients that was treated in our early Phase II trials. This patient, as you can see, has terrible heart failure. The top panels are a cross-section of the heart from the tip of the heart to the base of the heart, the left ventricle, pumping chamber to the heart is -- a main pumping chamber of the heart to the body is at the top of the picture there. On the left-hand is before we infused omecamtiv mecarbil. On the right-hand is after a 24-hour infusion of omecamtiv mecarbil. And what you can see is that the walls of the ventricle are thickening to a greater extent. The ventricle itself has gotten smaller in size. The mitral valve, which sits between the left atrium and the left ventricle there that bright line that transects the void is now opening widely in the right-hand panel because more blood is flowing from the bottom chamber, the left atrium into the left ventricle. Left atrium itself has gotten smaller, and that's a visual indication of lower pressures in the left ventricle, better functioning pump. And you can see the contractile function itself has improved in the left atrium. Now on the bottom panels are the same heart but now shown in cross section. And you can see there the circumference of the heart on the left is, again, poorly contractile. And in fact, the middle wall there is not contracting at all getting pushed around as the rest of the heart contracts. And on the right-hand side, after infusion omecamtiv mecarbil, again, visually, you see the contractile function of the heart's improved, the ventricular walls are thickening in a greater extent and the wall that was not moving before has started to move again. These are visual representations that ultimately measures of cardiac can be measured and quantified in many different ways. And Dr. Wolff later will take you through some of those measurements in our clinical trial. So I'm going to begin and just tell you one of the stories that we'll proceed with today, the activate story, that of omecamtiv mecarbil. And I'm going to start with a bit with its origins. And the fundamental premise for omecamtiv mecarbil began really with thinking about the etiology of heart failure as being central related to reduced cardiac function. You arrive there in many different ways, either through a heart attack or hypertension or genetic disease and fundamentally it results in a number of adaptations body makes try to reduce the work the heart's doing. Many of our treatments for heart failure have targeted these adaptations, which sometimes become over exuberant and continue to drive the heart in its ongoing -- in its path of continuing dysfunction and have been quite successful in improving mortality and morbidity. As you'll see later, though, there's still a tremendous unmet need as patients still have a risk of death every year if they've been hospitalized of up to 40%. Fundamentally, the hypothesis that we pursued was that by directly targeting the sarcomere. We could increase cardiac contractility and blunt these adaptations that occur and potentially modify the course of heart failure. And so as I told you earlier, we began a journey of developing modulators of the sarcomere directly specifically targeting the cardiac sarcomere, not affecting the calcium cycling within the myocyte, which can be energetically expensive and had been a method of improving contractility that proved to not be successful. But selectively and in a targeted way, improving the function of the heart. And this journey began ultimately with developing the technology. We needed to find those modulators to optimize those modulators and subsequently led to the development of omecamtiv mecarbil. You can see the journey here laid out on this arc of development from concept to the left to -- and the first screens that were conducted to selection of a compound that entered the clinic, eventually getting the name omecamtiv mecarbil. You can -- we can debate whether that's better than its original name, CK-1827452. The conduct of a number of clinical trials that led to our understanding of how to dose omecamtiv mecarbil and how to introduce it into larger and sicker populations, such as, as we did an Atomic-AHF, which is a substantial trial of hospitalized patients with heart failure and COSMIC-HF, which was a trial of patients -- outpatients with heart failure. All of these led to the initiation of the clinical outcomes trial, GALACTIC-HF and functional trial, METEORIC-HF, which we'll describe now in a moment. So where are we now? We are now at the precipice of seeing the results of a cardiovascular outcomes trial that we began in 2017 with enrolling the first patient. Together with Amgen, our partner, the conduct of this trial has been a quite a journey. Over 8,000 patients have been enrolled in 1,000 sites in 35 countries. The objective of this trial was to show that omecamtiv mecarbil reduce the risk of cardiovascular death or first heart failure event. And the primary endpoint is a measure of the time to each of those events, which ever occurred first. We were, however, interested in understanding the effect of omecamtiv mecarbil and cardiovascular mortality. And so this trial was powered based on that secondary endpoint. It has 90% power to assess the risk of cardiovascular death. And thus, it's overpowered for the primary endpoint the composite endpoint, which combines cardiovascular death and other heart failure events. Importantly, this trial is also designed to assess the impact of omecamtiv mecarbil on patient symptoms, which is the next secondary endpoint. We've employed a dose optimization rationale that is guided on an individual basis. The dosing of omecamtiv mecarbil is individualized and tied to exposure in each individual patient. We enrolled patients from 2 different settings from the hospital setting as well as the outpatient setting because often physicians are looking to think of how can they improve heart failure therapy when their patients get hospitalized with heart failure. And they frequently lack the data to help them understand how new drugs work in that setting, what's their safety, what's their potential efficacy and features of omecamtiv mecarbil, which doesn't infect blood pressure, doesn't impact kidney function, make it particularly well suited to begin in the hospitalized population. The design is shown here in a straightforward way. Patients were randomized in a one-to-one fashion to active drug, omecamtiv mecarbil or placebo. They went through this dose titration over the first 6 to 8 weeks of clinical trial and then subsequently stayed on omecamtiv mecarbil. And we're seeing regularly over the course. Some of these patients now having been in this trial for up to almost 4 years. A few months ago, we presented the baseline characteristics of patients in GALACTIC-HF. We enrolled, as we said, 8256 patients. And without going through the numbers in detail, I just will highlight a few things that are shown on the left. First of all, 25% of the patients as intended, were enrolled from the inpatient setting. These patients had a short time from hospitalization to entering the trial. It was required that they either be currently hospitalized or hospitalized within 1 year. And you can see that the median time for hospitalization was only 2 months. Again, adding to these -- enrolling patients have greatest need in terms of new medical therapy since these are the patients at greatest risk. Another marker of risk NT-proBNP, elevated here in about 2000. Ejection fraction reduced 27%. You saw on those prior pictures I showed you what an ejection fraction of 35% or 60% looks like. And importantly, they're on excellent background medical therapy including one of the newer therapies Entresto, which was introduced just as this trial was getting underway, but we ultimately had about 20% of patient population starting in a baseline. You can see in the columns that inpatients are a bit sicker than the outpatients as would be expected. This trial in the context of other trials is a -- puts it in higher risk category than, say, PARADIGM-HF or DAPA-HF, which enrolled exclusively outpatients, but not quite so high risk as a recently reported trial VICTORIA-HF, which targeted in some ways, very sick patient population. So we think we hit the sweet spot. The protocol had 2 interim analyses built into it. Those interim analyses included a look at futility after 1/3 of the targeted number of heart failure events, 1,590. And then second thing -- that was concluded in the first quarter this year was a look at both futility and superiority, when 2/3 of the targeted number of events have accumulated. In both cases, the data monitoring committee told us to continue the trial without changes. And now we're looking for the conclusion and the readout of this trial in the fourth quarter of this year. So with that, I'll pass the baton to Stephen Heitner, who joined us a few months ago. He's an expert in heart failure and genetic cardiomyopathies. And he's going to tell you about METEORIC-HF, which is a trial that adds to the body of evidence of omecamtiv mecarbil's effect in heart failure. Steve?

Everybody's attention. So I'll start out by jumping in and trying to explain exactly why we chose to do the METEORIC-HF study. And I'm going to draw your attention to the left-hand side over there, you have 3 bullet points. Each of those start with the word despite. And essentially, what we're trying to say is that despite all of the excellent therapies that we have for our patients in 2020 and the tremendous innovation that has gone on over the years, mortality still remained a problem. So there's an unmet need where approximately 50 patients -- 50% of patients over 5 years will experience mortality. And that, as you'll hear later on, is often worse than many cancers. And the main driver of this adverse mortality is the lack of our ability to actually impact the quality of life of individuals. So what we know is that patients who actually feel the worst, irrespective of what their ejection fraction is, those are the individuals that experienced the worst outcomes. And all these amazing therapies that we've developed over the years have focused primarily on the ability to improve mortality and morbidity. But we have shown a little ability to improve the quality of life, which is, first and foremost, for the majority of our patients. So we went into the METEORIC-HF with an idea of rounding out the information that we're getting out of the GALACTIC-HF study. So Fady explained to you beautifully that Galactic is primarily focused on mortality, heart failure, hospitalizations and embedded a KCCQ in order to assist patient symptoms. Whereas METEORIC, on the other hand, looks at both exercise performance. And the way that we do that is with the very best assay in physiology, which is the cardiopulmonary exercise test as well as our ability to utilize technology in the current era with an accelerometer, so patients wear these watches. And we can actually get a very high content of data of what they're doing on a day-to-day business for up to 2 weeks. And we feel that, that speak volumes to how these individuals are doing at home. So METEORIC is, as Fady alluded, is our current Phase III study that's underway. It's an international study. It's being run in both North America and in Europe, with a total of 9 countries planned. And actually, today, we have 5 of those 9 countries up and running. And 92 sites in total with -- as of today, 70 sites that have been activated. And what we're doing is we're looking at the effect of omecamtiv mecarbil on peak VO2, which is measured with cardiopulmonary exercise test over a 20-week period of treatment with omecamtiv mecarbil versus placebo. We have some secondary endpoints that look at finer details of what's happening with these patients exercise capacity. So we're looking at things like cardiac efficiency as well as measurements of activity using the accelerometer. The study itself is randomized 2 to 1. As you can see over here, we assess the CPET at baseline and again at 20 weeks with intervals of actigraphy measured along the way to see where and when these changes happen along the study course. And then we end the study after a total of 24 weeks after a 4-week washout. And with that, I'm going to hand over to my colleague, Andrew Wolff, who's been with the program for a very long time, and he's going to delve into the details from COSMIC-HF and the reasons why we have so much faith on this molecule. Thanks, Andy.

Thanks, Steve. So the first question we asked is what did we learn from COSMIC-HF, and then I'll go into some of the detail that show you how we learned it. But it was the first time that we demonstrated the effectiveness of the PK-guided dose titration regimen that was employed in COSMIC, where we began everybody at 25 milligrams twice daily and then increased to 50 milligrams twice daily, only if their plasma concentration at steady state at trough was below 200 nanograms per ml, that was subsequently revised in GALACTIC-HF to include 3 different potential dosing regimens, 25, 37.5 and 50 bid. But it works very effectively in COSMIC-HF to avoid excessive exposures, which we know can be deleterious. And when we say excessive, we mean over about 1,000 nanograms per ml and we want to operate around 300 to 400 nanograms per ml at which concentrations the drug has been very safe and very well tolerated to date. It also demonstrated improvement in several different measures that tend to predict improved prognosis. And you'll see this decreases in left ventricular volumes in NT-proBNP and in heart rate. And we also demonstrated a favorable tolerability profile over 20 weeks of treatment. So here, we can see dose-dependent increases in cardiac performance. In gray, we have placebo in a lighter green, the 25-milligram group. And then the dark green, the PK dose titration group, which included some patients about I think 1/3 of them were still on 25 and the majority had titrated up to 50 milligrams twice a day. And in the upper left, you can see what has always been the pharmacodynamic signature of omecamtiv mecarbil, an increase in ejection time, a matter of some milliseconds. And next to that, on the upper right, if the heart ejects for longer, then it's going to eject more blood. And consequently, you can see the stroke volume increase. And then down at the bottom, to other measures of systolic function centric -- excuse me, left ventricular fractional shortening and left ventricular ejection fraction also increasing relative to placebo omecamtiv mecarbil. On the next slide, you can see some real predictive measures that quite impressed, I think, the heart failure world when we first presented these data. And that's significant declines in left ventricular and systolic and end diastolic volume along the top. And then at the bottom, we have data from just the PK dose titration group and rather than presenting these data by dose. We're presenting them by -- over time. These are placebo-corrected data, and you can see the heart rate decreasing over the 20 weeks of treatment as did also NT-proBNP. Now we know there is no direct effect of omecamtiv mecarbil on the automatic tissue of the heart, so there's not a direct effect to decrease heart rate. We believe this is reflex withdrawal of sympathetic tone so that if the heart can eject more blood per beat, it needs to beat fewer times permanent and so heart rate comes down. And that has generally been a good prognostic indicator. NT-proBNP, as you probably know, is a molecule that's related to stretch in the atrium and the ventricle. And so higher it is, generally, the worst the heart failure it is, and you can see that it comes down also during treatment with omecamtiv mecarbil. You may recall from the echos that Fady presented from our patient who was treated with omecamtiv mecarbil in our Phase II program that not only is ventricular function improved [indiscernible] atrial function. The atrial myocardium is of the same composition [indiscernible] ventricular. It's just the walls are thinner. But that's not what I'm showing here, I'm sorry. This just shows that these increases in systolic function -- I'm sorry, left ventricular systolic function are maintained over time. So you can see that the systolic ejection time, the increase at 12 and 20 weeks is similar, so is the increase in the stroke volume. And then remarkably, the decrease in end systolic and end diastolic dimensions, which also then relate to the end systolic and end diastolic volumes actually declined more after 20 weeks compared to 12. So that potential reverse remodeling process appears to continue to progress, which would be good news. Here's the left atrial systolic function that I want to talk about. You can see that on the far left, this is the change in the maximum left atrial volume, so it gets much smaller and that is also progressive between 12 and 20 weeks as then the minimum left atrial volume which you see in the middle and something that also progresses from 12 to 20 weeks. And then the left atrial emptying fraction, which is how much is the blood that atrium starts with and then how much does it empty into the left ventricle, that fraction also increases significantly at 12 weeks and even more so at 20 weeks. We also looked at the Kansas City cardiomyopathy Questionnaire. That's a patient reported outcome measure that reflects health related quality of life. And you can see that the change in the PK dose titration group was almost 5 points and reached conventional statistical significance after 20 weeks. Five points is generally considered to be a clinically meaningful increase in the KCCQ. And you can see that this was reflected in some of the sub domains, showing here the symptom frequency and symptom burden domains. We have known that there are very small increases in troponin that occur with omecamtiv mecarbil treatment, but they're not really related to the degree of exposure. There is an increase and then there's a small -- the decrease goes back to baseline. So at the bottom in the table, you can see the median values at baseline and the interquartile ranges. And you probably know that 0.04 is generally considered to be the level for diagnosis of a myocardial infarction. And in all of these treatment groups, the top of the interquartile range is right at about 0.04. And yet none of these patients that had a clinically evident myocardial infarction as they came into this study, that would have been an exclusion criterion. So these heart failure patients we know have elevated troponins a lot of the time. You can see the median change from baseline, then below that, it's extremely small. There's 2 zeros after the decimal place. And there now, if you look at the lower end of the interquartile range, you can see that fully 1/4 of these patients had either a decrease over time in their troponin or no change. We looked at significant increases in troponin, which we defined as an increase to greater than 0.04, if it was undetectable previously, or if it had been detectable previously, an additional increase of 0.03 nanograms per ml. There were 278 of them. All of them went to a clinical events committee to be adjudicated and none were felt to reflect an event of clinically apparent myocardial ischemia. So with that, to talk further about the predictive value of some of these data, I'll turn it over to my colleague, Stuart Kupfer.

Thank you, Andy. So as Andy described in COSMIC-HF, treatment with omecamtiv mecarbil results in reductions of NT-proBNP and also enhances reverse remodeling. And so it's this profile then it forms the potential for omecamtiv mecarbil treatment in GALACTIC-HF and it result in improved heart failure outcomes. So in the next few minutes, I want to review the evidence space that informs the positive predictive value of this COSMIC-HF profile. So let's start with NT-proBNP. Most who are familiar with heart failure research and therapeutics appreciate that increases of NT-proBNP are associated with worsening heart failure and conversely decreases potentially with treatment benefits. And that's because NT-proBNP is a biomarker worsening heart failure. We know that elevations of NT-proBNP are associated with increased cardiac wall stress with adverse cardiac remodeling and also with increased risk of adverse heart failure outcomes, such as hospitalization and cardiovascular death. So in order to better understand the significance of NT-proBNP, it's important to understand it's origin. So NT-proBNP is actually an inactive peptide that is cleaved during the processing of the prohormone of BNP. So proBNP is actually released by cardiac myocytes in response to pressure overload in the left ventricle. In BNP or B-type natriuretic peptide is the active hormone that can have beneficial biological effects in patients with heart failure, such as vasodilation, diuresis and reverse remodeling. So NT-proBNP can be thought of as an indicator that the heart is stressed, often due to worsening heart failure and that is trying to compensate for this worsening cardiac function. So let's go through some of the evidence that essentially demonstrates its relationship between NT-proBNP and cardiac structure and function. So many studies have shown that increases of BNP are associated with worsening cardiac function and heart failure. And this is one of the early studies to evaluate this relationship. In this study, an investigator is measured BNP along with other cardiac parameters in order to try to understand what stimulates BNP secretion. And what they observed was that increases of BNP were associated with increases of left ventricular end diastolic pressure on the left. And on the right panel, there were particularly strong correlations with elevated BNP and end diastolic wall stress. So these results suggested that the altered mechanics associated with worsening cardiac function were actually driving BNP secretion. Now conversely, other studies show that interventions that decreased NT-proBNP correlated with reverse remodeling. This is one study called, GUIDE-IT in which the investigators were evaluating potential use of NT-proBNP as a biomarker to guide intensification of heart failure therapy in comparison to usual care. And what they observed was that interventions or therapeutic strategy that lowered NT-proBNP was not only associated with increases of LV ejection fraction, but also with incremental improvements in left ventricular end diastolic volume and end systolic volumes. And this is another interventional study in patients with heart failure and reduced ejection fraction. And here the investigators show that decreases of NT-proBNP associated with the treatment with sacubitril/valsartan were associated with reductions of LV end diastolic volume and end systolic volume. And so it's data such as these that inform a plausible mechanism for wide sacubitril/valsartan treatment and the PARADIGM-HF trial were associated with improved heart failure outcomes, so possibly driven by reverse remodeling and also predicted by reductions of NT-proBNP. Now these relationships are further strengthened by observations that adverse cardiac remodeling is correlated with increased risk of heart failure mortality. And even more importantly, interventions that enhance reverse remodeling are associated with decreased risk. And so this was a meta-analysis conducted in -- essentially looking at mortality and remodeling trials. And this included 90,000 patients with HFrEF. And in this study, the investigator showed that a decreased risk of heart failure related death was associated with reverse remodeling. And in particular, in this particular graph, it was reduction of left ventricular end diastolic volume. So an adverse cardiac remodeling is associated with increased heart failure mortality and with increases of NT-proBNP then really a key question in clinical drug development is the following. The reductions of NT-proBNP that are associated with a new investigational agent, does that predict improved heart failure outcomes? And the evidence space would suggest that the answer is yes. This is an analysis from the PARADIGM-HF trial. And in this study, the investigator is focused on a cohort of patients that had elevated NT-proBNP baseline above a threshold of 1,000 picograms per ml. And they evaluated for risk of the primary endpoint, which was a composite of hospitalization for heart failure and cardiovascular death. And what they observed was that those patients whose NT-proBNP dropped below this threshold of 1,000 picograms per ml and that was regardless of whether they were treated with sacubitril/valsartan or [ lpril ] those patients experienced a more than 50% relative risk reduction for the primary endpoint compared with those patients whose NT-proBNP levels stayed above that 1,000 picogram per ml threshold. And furthermore, in this meta-analysis of -- this is 16 interventional trials that included 50,000 heart failure patients. And these studies were completed between 1987 and 2013. And in this study, reductions of NT-proBNP correlated with improved heart failure outcomes. And more specifically, there were trends of lower all-cause death associated with decreases of NT-proBNP. And there were significant risk reductions for all-cause hospitalizations associated with lower NT-proBNP levels. So in summary, what we know is that interventions that decreased NT-proBNP and enhanced reverse remodeling, predict lower risk of adverse heart failure outcomes. And so if we put the COSMIC-HF results in this context, the evidence base really indicates potential for improved heart failure outcomes with omecamtiv mecarbil treatment in the GALACTIC-HF trial. And with that, I'll turn it over to my colleague, Scott Gordon, Senior VP of New Product Planning and Commercial Development, who will discuss the commercial opportunity with omecamtiv mecarbil.

Thank you, Stuart. It's nice to be here today. Frontline. It's a term that's normally used in the context of military battles. In 2020, it's become synonymous with health care professionals as they battled the viruses known as COVID-19. Obviously, the reason that all of us are participating in this event safely from our homes rather than in person. And we thank the health care professionals who participate who've been fighting this battle for their courage and their dedication. But health care professionals have always been on the frontline in other diseases, and in particular, heart failure is a good example where they've been fighting to keep patients stable out of the hospital, enjoying their lives and enjoying the quality of their life. And this is a tireless battle that health care professionals have been waging for many years. So today, I'll be telling you about the significant burden of heart failure, the unmet needs, the opportunities to intervene and the activities that Cytokinetics and our partner, Amgen, are taking to prepare for the launch of omecamtiv mecarbil. Today, the heart failure costs over $30 billion, and is increasing significantly with the expectation that it'll achieve -- reach a level of $70 billion by 2030. Almost 2/3 of those costs are due to inpatient treatment. And that is partially because approximately 40% of the heart failure patient will be admitted to the hospital at some point during the next calendar year. And it's not just the cost that we're worrying about as a macro level, these patients represent a disproportionate level of medical spend for the system. Let's take the Medicare population for instance. They represent -- heart failure patients represent 14% of the entire Medicare population beneficiary pool, but they represent 43% of the Medicare spend. Clearly, they're using health care resources at a much higher rate than others. And as you can see, reducing hospitalization can have a significant financial benefit to the entire health care system, especially if we can impact those due to HFrEF, which represent about 55% of the heart failure hospitalizations in any given year. So for instance, in 2030, if we're able to reduce heart failure hospitalizations for HFrEF by 20%, we could save the health care system about $5 billion in 1 calendar year. But reducing the cost for the system is not the only goal. From a patient perspective, following that initial hospitalization for heart failure, the chances of being readmitted or dying are significant. Almost 50% will be readmitted within 6 months. And between 20% to 30% of patients will die within 1 year with almost 50% dying within 5 years. That's a prognosis that's worse than some common cancers that we spend a lot of time focusing on. But hospitalizations are also an opportunity to effect change. I remember Dr. Adrian Hernandez, one of our panelists today, once telling me that hospitalization is that moment of truth for the physician and the patient. Imagine, if you will, that your 68-year-old grandmother who finds yourself in the hospital due to shortness of breath and edema tied to your heart failure. You get tired just playing with your grandkids and tired doing your everyday activities like walking to the mailbox. Your quality of life has started to diminish. Clearly, something is not working well, and you're in the hospital. And frankly, the approach to treating your heart failure is failing and you want to be discharged and get back to your normal life, doing your normal activities. So therefore, the hospitalization becomes a moment when the patient and the physician are really attuned to what's the opportunity for change. If you look first at the chart on the left, this is from a study focused on getting with the guidelines that Dr. Mary Allen who's also one of our panels today, was heavily involved in. And you can see that it was identified that patients when they came into the hospital were at a -- in the case of beta blockers at 50% level or in the case of ACE and ARBs at a 45% level of prescriptions. But at discharge, we're moved up to 91% to 94%, respectively. Clearly, this is an opportunity to get patients onto the guideline directed therapy, but also, clearly, this is a moment when the physician can actually alter and make changes to a patient's therapy. On the right side, you'll see that the data from the impact HF study, where beta blocker use was studied 60 days post discharge. At that point, they focused on patients that were initiated with beta blockers predischarge and those who were initiated post discharge. And as you can see, those who initiated predischarge had a 91% compliance rate at 60 days versus those at 77% for those who were initiated post discharge. So obviously, this is a moment when the physician can make a change and when the patient can become more compliant and more thoughtful about their therapy. The hospital experience is just one of the many stops in the patient journey where we can impact the lives of patients with HFrEF. I highlight it because Cytokinetics has co-promotion rights that relate to the institutional care settings. As Robert alluded to earlier today. Through our co-promotion with Amgen, we expect to conduct a coordinated field deployment strategy, where Amgen and Cytokinetics sales representatives will participate together alongside one another in sales and promotion activities. We anticipate the companies will leverage a reach and frequency approach in these institutional settings in North America. And within the institutional care setting we believe that there's a concentrated number of institutions that account for 70% of the HFrEF patients and approximately 75% of the heart failure prescriptions that are written in the institutional care setting. Upon approval and commercialization, Amgen and Cytokinetics expect to leverage the strengths of both companies and educate the heart failure community on the potential clinical effects and economic benefits of omecamtiv mecarbil and where it may be positioned with appropriately within the continuum of care. Speaking of therapies, Entresto was a very recent launch into the heart failure space, as it was indicated for HFrEF. And while it had a slow start in the early years, it's now on course to achieve $2 billion to $3 billion worldwide in 2020. Sales trajectory like this along with some statistics I laid out earlier point to the continual need for therapies that might change the course of the disease for patients allowing them to do more and have a better life style and quality of life. So we and our partners, Amgen, are working diligently to ready for the launch of omecamtiv mecarbil. We have multiple work streams focused on educating the heart failure community and heart failure marketplace, assessing the impact of our value proposition, differentiating our program for health care professionals and supporting advocacy of patients. For instance, Amgen and Cytokinetics have initiated a disease state education program to educate the heart failure community on the unmet needs in heart failure and the unmet needs of their patients and to explain how contractility drives the cardiac performance in HFrEF. And we also need to make sure we're cognizant of what payers are interested in. We recognize the payers look at value very differently depending on the type of organization they are. We've contemplated that in our trial design and our real-world evidence strategy to support our hypothesis that omecamtiv mecarbil will provide economic benefit to payers across all parameters that are important to their particular organization, whether it be on the budget side, the cost effectiveness side or some sort of quality measures that are important for their organization to succeed. Cytokinetics is collaborating with a diverse set of providers and health care systems to generate real-world evidence regarding the cost burden of heart failure and eventually the potential for omecamtiv mecarbil to impact that cost burden. And at the end of the day, we believe GALACTIC and METEORIC were designed appropriately to demonstrate outcomes that address the significant unmet needs of physicians, patients and payers. It's our hope and our expectation that we'll be able to demonstrate that omecamtiv mecarbil can keep patients alive out of the hospital, feeling better and doing more. With that, I'll turn it over to Andy Wolff, who will lead a panel discussion with those physicians who are currently on the front line of treating patients and improving the lives of those who have heart failure. Andy?

Thank you, Scott. And welcome to our 4 panelists. Dr. Smith McMurray, Allen, Hernandez and Malik. Are they with us?

Yes, I hope so.

Perfect and [indiscernible]?

We are here.

Yes, okay. All right. Well, let's get started then. Stuart presented quite a bit of data regarding the correlation of certain measures that we obtained in COSMIC-HF with eventual CV outcomes. With that in mind, I'm going to start with you, Dr. McMurray, how would you characterize the probability of success for omecamtiv mecarbil in GALACTIC-HF?

Thank you, Andy. So obviously, predicting the future is always difficult. But if I wanted a drug to [Technical Difficulty]

I'm not hearing -- here we go.

[Technical Difficulty] Sorry I [indiscernible] Andrew because my video [Technical Difficulty]

Well, unfortunately, frankly, we're not hearing much of what you're saying, John, which is disappointing for all of us. Because I'm sure what you had to say was good.

I don't understand, sorry.

Maybe give it one more try, John.

Yes, we can hear you now.

Okay. Okay. Sorry. So what I was saying was that if you wanted a drug to demonstrate effects that might translate into improvement in clinical outcomes, those effects would be reduction ventricular volumes, reduction in natriuretic peptides and indeed that reduction heart rate that you mentioned is also another very nice additional finding. And I suppose we would have to say that almost everything that we've seen to date that has those effects has been beneficial. Now you can never be sure, it's always possible to be some off-target effect that [Technical Difficulty]

Well, that's frustrating. John, we heard most of that, I think. But right toward the end, we lost you again. I'll move on to another question. And Adrian, I'll direct this one to you. Considering all the new options that we have coming along now in heart failure in addition to we've had for years now, the beta blockers, ACE inhibitors, ARBS, now we have ARNi's Entresto. We have the SGLT2 inhibitors. Now we are soon to have [indiscernible] vericiguat. What do you think the guidelines are going to say about these? They've all been studied over a background of what we've come to call standard of care, do you start them all at once or attempt to start them all as soon as you can? Or do you take a more stepped approach?

Yes. So I guess 2 things here. One is just what we've seen so far as the outcomes for heart failure are so poor and so there is greater thought about how to be more aggressive for patients with heart failure. A nice paper actually with John and others actually showed that a more comprehensive strategy actually was better if you were to do things earlier in terms of the combination of different therapies. One thing to note is that for some of these therapies, we actually don't have great data on when to start, say in the in-hospital setting. And so specifically, for example, the SGLT2 inhibitors, which are really promising therapies for chronic heart failure, we don't have as much evidence in terms of starting in-hospital setting. And so this will may be something that will be unique that we'll learn from the GALACTIC trial because there is a significant portion of patients who are starting in hospital setting. I think a lot of people are going to start thinking about this in a more comprehensive strategy. Also, I think the guidelines will evolve to ensure that we don't let time go buy with patients at risk for having either worsening heart failure or actually significant risk for mortality.

Thank you. Let's talk about just from the patient's perspective now for a little bit. And we're going to hear directly from patients later in the program. But Larry, based on your day-to-day interactions with patients who have to live with heart failure, where do you see the greatest unmet need when it comes to their treatment?

Yes. So as you know, heart failure is not only a deadly disease, but it's highly symptomatic. The symptoms drive hospitalizations, which lead to a lot of the resource use that you touched on. But just day-to-day, even for patients who are stable, they often have a significant symptom burden that keeps them from doing a lot of the things that they want to do, both in terms of activity, but just in terms of energy level. So I think one of the things that stands out to me about omecamtiv, among the many therapies you just mentioned is that a lot of the therapies we've developed so far kind of slowdown and rest the heart. That's the way I think about it. And so in the long term, that can help cardiac function. But what I see in clinic day to day is a lot of the drugs that I prescribed in the near term do not really make people feel better, in fact we kind of struggle to get on therapy because patients aren't feeling good and we're prescribing drugs in the short term, may even slow things down and make them feel a little worse. As was nicely highlighted in the presentation, omecamtiv works a little differently. It works on the efficiency of the heart, the ability to squeeze. And so not only have the preclinical and clinical data to date shown that it improves cardiac function, but I think something that's really impressive is that some of the health status measures how patients are feeling look better. So the Kansas City cardiomyopathy questionnaire really ask patients what they're able to do, what symptoms they're having. And there have been pretty impressive results so far, and we'll see from GALACTIC whether that holds true in a larger population. In contrast, if you look at the PARADIGM trial, where Entresto was tested, there was a run-in phase in that trial, where about 10% of the people couldn't even tolerate the drug and then even though the drug kept people out of the hospital and kept them living longer. When you looked at the changes in Kansas City cardiomyopathy questionnaire data, which really say how are patients feeling, the change was around 1 to 2 points, which is really nonsignificant. So I think when we see the results of GALACTIC, what I'm going to be really interested in is not just what's the magnitude of benefit in terms of death and hospitalization, which I think will be important in comparing to other drugs that are out there, but I really want to see what the symptoms are. And that's important because the other burden that's out there these days is there are so many therapies available to patients, which is great. But that -- there's a burden of complexity, there's a burden of getting people on therapy. And if we have a drug that not only helps people live longer and their heart work better, but it immediately makes them feel better. I think that's really going to distinguish omecamtiv from some of the other things we can start early in the disease.

Do you think that positive data from METEORIC shown improved exercise capacity is a meaningful -- would be a meaningful component of what you just discussed?

Absolutely. I spend a lot of my time on the research side doing shared decision making, how do doctors and other clinicians talk to patients about what their therapies are. And patients are extremely interested in how they're feeling, what they're able to do. A lot of the discussions I have are about unproven therapies because people are kind of so interested in not just what the data shows in terms of hospitalization but are they really feeling better day-to-day and what does it really mean for them when they take a pill. So I think if METEORIC backs up GALACTIC and shows that people can be more active, have greater exercise capacity that, that would be a huge addition. And a lot of studies haven't really looked at that. So I'm really glad the company has gone down that route as well.

Okay. I think we don't have much more time, but hopefully, I think John is back. I know you've been instrumental in designing a lot of recent large...

Sorry. We do have many questions from the audience. So I'm just going -- they have some specific questions for the panelists. The first question is from Gil Blum from Needham. What is the FDA's position regarding NT-proBNP as a surrogate study endpoint, given all the outcomes related evidence?

Does anybody want to take that? Nobody is volunteering.

I'm happy to.

Okay, good.

Yes, I can answer that. So historically, the FDA has a look for evidence, such as clinical benefit relative to safety. And patients with HFrEF, or heart failure with reduced ejection fraction that has relied on clinical outcomes. Although there's interest more around patient-reported outcomes as well, especially across the spectrum of heart failure. So NT-proBNP wouldn't necessarily be the marker that people would look at as a surrogate that's certainly supportive.

Yes, with the vericiguat HFrEF research trials, the FDA did just allow KCCQ or health status measure how patients were reporting, how they're feeling to be a primary endpoint. So I think BNP LV remodeling are super important in the early clinical phase. But I think you're going to have a lot of endpoints coming out of the omecamtiv trials that are going to be of real interest to the FDA as well as the patients.

The next question comes from Jeff Hung from Morgan Stanley. Recognizing that elevated troponin was not associated with myocardial infarction, what is the hypothesis behind the small increases and plasma troponin with omecamtiv mecarbil and COSMIC. Is it part of reverse remodeling or another reason? Fady, maybe?

I can to start that and ask others to chime in if they'd like. No, I think there are growing lines of evidence that troponin can be secreted by myocytes in small vesicles called exosomes that maybe a signaling molecule that is part of [indiscernible] what is going on. The -- you see Troponin's increase with exercise, for instance, that again may be -- that's an activity that for folks increased contractility. And so there may be a link between the increase contractility and the cycling [indiscernible] exosomes and a subsequent secretion. The -- in COSMIC, we saw the heart getting smaller over time, the volumes of the heart getting smaller, ultimately if there's [indiscernible] reverse remodeling, the heart has to begin to disassemble sarcomere as the myocytes actually get bigger in heart failure, they need to beget smaller again. And I think assembly process, again, may also lead to secretion of troponin in a non pathologic way. So I think there's a lot of scientific work that's going on right now in terms of understanding the role of troponin both as a pathologic marker, but also maybe the biomarker of non pathologic regulators.

Great. Maybe Dr. McMurray can address this one from Salim Syed from Mizuho. What are the greatest risks you see to GALACTIC-HF? In other words, if it were to fail, what would those reasons be as to why it failed, not that any of us are assuming that will happen.

Okay. Well, I hope my Internet works this time. I can't think of any particular reason why it should feel. I mean the reverse modeling reduction in natriuretic peptides, borrowing some and losing surprise, those should translate into improved outcomes. So one could go wrong where we've talked about the troponin issue but a tiny change in troponin probably isn't very significant. Could the drug have some part obstacles, for example, through arrhythmic effects. We've got no reason to believe that. Because I would say all the many drugs have been involved in exploring over many years, we probably spent more time doing more studies in an early phase with omecamtiv than with any other drug. So I think we would probably [indiscernible] surprises like that. And with no particular reasons I think it should affect renal functions, which would be another reason. And after that, I really run out of ideas and would have to be something extraordinary.

Thank you. The next question is from James Shin from Citi. Could Dr. Hernandez expand on his "comprehensive approach.” Does he mean simultaneously prescribing these newer treatments?

Yes. Well, I guess there are 2 things here. One, there isn't any study yet to show if you started off with, call it, all therapies at once, whether that's an added benefit yet, however, the accumulation of evidence does show that in combination or if you were to estimate what would be the longitudinal benefit that starting earlier in a comprehensive strategy would be impactful. So that doesn't mean all at once in one day. But quickly over weeks and months to get to people on the best evidence that's out there from the clinical guidelines. And so as opposed to waiting years, there's going to be huge interest in trying to get this best evidence within months. However, the accumulation of evidence does show that in combination or if you were to estimate what would be the longitudinal benefit that's starting earlier in a comprehensive strategy would be impactful. So it doesn't mean all at once in one day, but quickly over weeks to months to get to people on the best evidence that's out there from the clinical guidelines. And so as opposed to waiting years, there is going to be huge interest in trying to get this best evidence within months.

Yes. Just to add to that, too, I mean, a lot of the therapies that we're talking about using in combination, they all -- they can all lower blood pressure. They all potentially have some side effects. So they're usually added sequentially and increased in their dose gradually. Again, I think one of the things that potentially distinguishes omecamtiv is that because of the mechanism of improving efficiency, it could theoretically, and some of the data would suggest, actually make people feel better right off. So not only do we think that all these drugs in combination are additive and thus, give you bigger benefit when used together. But omecamtiv might actually be one of the ways to get people on to therapy quicker. So a lot of data that people kind of both clinicians as well as patients kind of fatigue in that process of adding and increasing drug. And so if you have a new drug that works well, but also really kind of gets people feeling better, gets them excited about therapy and then makes their blood pressure able to tolerate some of these other meds. That could really be a bit of a game changer in terms of the way we think about creating combination therapy and getting it done quickly.

Great. Lots of questions coming in. So we'll try to get to as many as possible. We have about 5 or so minutes left for this panel. This question comes from Dane Leone from Raymond James. Would there be any reason to think that a positive clinical effect from omecamtiv and GALACTIC could spur higher utilization in the control arm?

Yes. So I can answer this if you'd like. So the answer is, yes. Because what will happen in many disease areas, in many trials is that the control group because they show more worsening, if the active treatment is better than in the control group, you'll see more add in other therapies because clearly, more of those patients deteriorating and their physicians try to add additional treatments to try and prevent that. So in almost all trials in the control arm when the other therapy is affected or drop in of those kinds of treatments. But usually, that's -- I mean, it's such a small effect overall that it doesn't change the difference between the new therapies and the placebo or control therapy.

Excellent. The next question is from Charles Duncan from Cantor Fitzgerald. When thinking about a future world in which omecamtiv may be approved, assuming that the target patient profile is clearly established as envisioned, how would you see it being used within the current treatment armamentarium? What would be the clear efficacy parameter that you would rely on to make a prescribing choice? Or would it be driven by external factors such as reimbursement availability?

Adrian, why don't -- you've been speaking toward that, why don't you take that?

Yes. Yes. Yes. I think there's a couple of unique features for GALACTIC that people will look at. So one is that it is a patient population, patients with heart failure reduced ejection fraction includes the in-hospital phase, and so people will be looking to see how this go across both inpatient as well as outpatient in terms of their profile. The second thing which is definitely depends on different areas of the world, reimbursement or how patients have access to medications also matters. And so we see that certainly in the U.S. And so -- but that is also driven by the evidence that comes out of these trials. The third thing is going to be tolerability. And so like how does someone tolerate. And so we're going to be much more likely to prescribe something that we know is going to be easily tolerate, someone can take long term. And then there is actually an X factor that's unique, I think, for omecamtiv is that because there's also this interest in terms of how it can help someone feel or function. That's a really unique thing because a lot of the -- a lot of therapies that we give patients for heart failure, they don't necessarily feel great immediately or over weeks or months. Long term, they do, but at least, we may have better evidence in terms of how they will function, and then that allows us to translate a prescription into what they actually experience over the coming weeks or months.

Excellent. The next question is from Joe Pantginis from H.C. Wainwright. This might be for Fady. Are there outstanding questions of drug-drug interactions that need to be addressed, cardiovascular or otherwise?

We've done a number of studies in -- before getting to GALACTIC or analysis of drug-drug interaction in these studies. We did a couple prior to GALACTIC. And in the -- during the conduct of GALACTIC, conducted a number of Phase I drug-drug type interaction studies. None of them have uncovered any significant drug-drug interactions that would, I think, need to be taken into account in terms of use of omecamtiv mecarbil.

Excellent. And I think we'll take one more question. And then as I mentioned at the outset, we'll try to follow-up with folks to get their questions answered. But we do want to try to be mindful of time and respectful of everybody's commitment to being here with us today. So let's see, one more question from Salim at Mizuho. Let's see, Salim has a lot of questions. You will likely have a median follow-up of 24 to 25 months, but you wanted something a bit longer at seems. This is also a bit shorter than PARADIGM. Is there a risk here that the arms are still separating and not parallel yet at 2 years? How much do you think this hurts your hazard ratio? Maybe Dr. McMurray wants to take that.

Yes. So that would, in fact, be a pretty similar follow-up to PARADIGM, heart failure and longer than DAPA-HF, which had a median follow-up of 18.2 months. So I can't imagine if this treatment works like every other treatment that has worked in heart failure, we will easily see it in that time frame and with the enormous number of patients in the study and the relatively higher event rate. I mean, I have no concerns that if this is an effective treatment, this trial is really well-designed to demonstrate that.

Excellent. Thank you. I think with that, Andy, we can wrap up this panel. Thank you to all of our expert speakers for joining us today. And as I mentioned, if there are follow-up questions, we can address those following this event. We're now going to move to the next section of our program, inhibit. And I'd like to turn things over to my colleagues, Stuart Kupfer and Laura Robertson, who are going to focus in on CK-274. Stuart?

Thank you, Diane. So we're going to shift from cardiac myosin activation to cardiac myosin inhibition. And Laura and I will review the evidence space that supports development of CK-274 as well as our vision for its development managing. So CK-274 is the next-in-class, and we believe best-in-class cardiac myosin inhibitor. It was discovered by Cytokinetics' scientists, and it was specifically engineered to have features to optimize efficacy, safety and patient management. And these features include high selectivity for cardiac myosin, minimal SIP inhibition or induction in order to avoid drug-drug interactions and high oral bioavailability. Now we conducted nonclinical studies, and now we have clinical data in healthy volunteers, and these data indicate that CK-274 has predictable pharmacokinetics and a predictable pharmacodynamic profile with exposures [indiscernible] contract. The CK-274 has relatively shallow dose response relationship in which we predict a wide therapeutic index. The half-life supports once-daily dosing, and it's consistent with treatment of steady state at 2 weeks, which will support relatively rapid dose titration. And if needed, relatively rapid reversibility. And so the goal essentially is to ensure that we have a good benefit risk profile and enable dose [indiscernible] by individualizing therapy. With that, I'm going to turn it over to Laura to summarize our Phase I data and our Phase II REDWOOD-HCM study design.

Hello. I'd like to go through our Phase I data. We were very pleased that CK-274 study met all of our objectives. It was safe and well-tolerated. All adverse events were mild to moderate, and there were no serious adverse events. The pharmacokinetics were well-characterized and decreases in ejection fraction were readily reversible within 24 to 48 hours. As you can see in the 2 figures on the left, that we have excellent exposure at the doses administered. CK-274 has predictable dose linear pharmacokinetics. And on the right, in the multiple dose studies, you can see that CK-274 reached its steady state at 2 weeks and then readily washes out. Next slide. In the figure on the left, you can see that we characterized fully the PK profile and multiple dosing cohorts. And on the right, you can see that the pharmacodynamics were also well characterized, both in preclinical and human studies. This figure shows the exposure relationship mix between dogs in the gray dots and human data in the green dots. Plasma concentration, the exposure is on the x-axis and ejection fraction the response on the y-axis. And as you can see, the data points overlap, and this shows excellent translation between our preclinical and human data. And I really think these data highlight Cytokinetics' careful development of a cardiac sarcomere inhibitor that has predictable pharmacokinetics and a shallow exposure response relationship. Next slide. And all these data have informed a really streamlined efficient Phase II clinical trial design. We have the schema here. We've named our studied REDWOOD-HCM, in honor of our state tree here in California. This study has the objectives of safety, tolerability and dose-finding so that we can test doses in a population of obstructive hypertrophic cardiomyopathy patients will be similar to those that we will be studying in a Phase III trial. The study will be conducted in 2 sequential dose-finding cohorts of 18 patients per cohort. The patient population, you can see highlighted there on the left of the slide will be a symptomatic obstructive hypertrophic cardiomyopathy patients who still have a significant resting or provoked gradient despite being treated with beta blockers or calcium channel blockers, or both. The patients entering the study will be randomized 2:1 to CK-274 or placebo, plus their background HCM therapy. There will be a 10-week dosing period, you can see that with the green arrow there. There are 6 weeks of dose titration. We will have 3 possible doses. You can see those marked there, doses one, two and three. Each of them will be escalating. Dose titration will occur based on echocardiographic criteria. We will be looking at ejection fraction and outflow tract gradient. We know from Phase I that we have a shallow exposure response relationship and predictable PK. So we are able to do a relatively swift trial with echo-guided dose titration. We'll look at the PK as well, but it's not necessary for dosing decisions. Patients will reach their target dose at 6 weeks. Continue for another 4 weeks of dosing and then have a 2-week washout period. The washout period will help us establish the reversibility of CK-274's effect. So in summary, this study should provide a detailed exploration of our PK and exposure response relationships in obstructive hypertrophic cardiomyopathy patients, and that will inform our Phase III dosing scheme and design. Next slide. So we had great enthusiasm among investigators for REDWOOD-HCM. 27 sites in the U.S. and Europe are going to participate in this study. So with 27 sites, we should be able to enroll 36 patients relatively swiftly. Although, we have had a COVID pause, we are now up and actively screening new patients for the study. 3 patients have been dosing through that COVID pause and completed the study, but now we are ready to accelerate through the summer. We believe that the study will be enrolled by the end of the summer with cohort data being ready probably by the end of the year. And then we will be able to initiate cohort 2 rapidly. I'll turn it back to Stuart to continue discussion of the program.

Great. Thank you, Lauren. So let's continue to elaborate on the opportunities for clinical development of CK-274. Now this is an overview of our clinical plan for development in obstructive and nonobstructive HCM. And the results of the REDWOOD-HCM trial that Laura just described, will inform dose selection for our pivotal Phase III trial, in which we'll be focusing on evaluation of CK-274 and improving exercise capacity. And the results of this trial will support and a submission for an indication or an improvement of exercise performance. And many of these HCM patients, of course, are quite disabled because of their disease. And so we anticipate an improvement in that regard. In parallel, we plan to conduct a development program in patients with nonobstructive HCM. And again, we'll extrapolate the findings from the REDWOOD-HCM trial to inform the study design, and we plan to conduct a seamless Phase IIb Phase III trial in this patient population. So in the first phase, we'll optimize dose selection. And once that is completed, we'll open up enrollment into the pivotal Phase III trial, in which we'll also be evaluating patients for exercise capacity. This is an outline of the clinical endpoints we'll be evaluated in our Phase III trial in obstructive HCM. We'll be employing cardiopulmonary exercise testing. And as Steve mentioned previously, this is a very precise ejective methodology for evaluating exercise capacity. We'll look at peak VO2 and other assessments. And these assessments, these endpoints are important for -- not only for assessing functional capacity, but they also correspond with heart failure outcomes and survival in HCM patients. So we'll be looking for also improvements in symptoms and physical activity based on NYHA class and other measures and using echocardiography to look at improvements in the LVOT gradient and decreases in cardiac contractility. We'll look for improvements in biomarkers of myocardial stress and myocardial injury. And we'll look at quality of life improvements based on patient-reported outcomes, some of which have been previously validated, others are newly developed or that are specific to the HCM population. So development of CK-274 then is designed to address multiple dimensions or disease burden in HCM. By reducing the LVOT gradient and hypertrophy, we expect to see significant improvement in exercise capacity, alleviation of patient symptoms, such as dyspnea and fatigue, normalization of cardiac markers of reverse remodeling. And we also anticipate that patient management can be optimized because dosing will be individualized for each patient in order to achieve target pharmacodynamic effects. Now in the long term, because of the advantageous features and potency, we expect CK-274 treatment to approach magnitudes of benefit consistent with surgical septal myectomy. Also in anticipation that a cardiac myosin inhibitor will be beneficial in nonobstructive HCM, we plan to evaluate another patient population that could potentially benefit from CK-274, and that is a subgroup of HFpEF patients, that is patients with preserved ejection fraction who also have hypercontractility. Now this hypothesis is essentially informed by a constellation of symptoms and pathophysiological features that are similar between nonobstructive HCM and specific HFpEF patients, particularly with respect to increased cardiac contractility and diastolic dysfunction. Also, the profiles of these pressure volume loops are similar between these 2 patient populations and then also informs the investigation of this HFpEF subgroup. So in summary, CK-274 is a unique therapeutic strategy that addresses high unmet needs in multiple patient populations, for which there are no approved therapies in the U.S. or other regions. So these populations include obstructive HCM, nonobstructive HCM and a specific subset of patients with heart failure and preserved ejection fraction. And with that, I'll turn this over to Steve, who will lead a panel discussion on embracing a new era in the treatment of HCM.

Thank you, Stuart. So I'd like to introduce our excellent panelists. We have really the cream of the crop with Dr. Marty Maron, Dr. Andrew Wang and Dr. Anjali Owens. And Dr. Malik, you've met multiple forums already. So I'm going to kick off with a question to Marty. And Dr. Maron, we really appreciate the tremendous work that your center and really your life's work has been, helping with overall success of treating these patients with hypertrophic obstructive cardiomyopathy. And in your center, in particular, you have this world-renowned surgeon [ Dr. Ostergard ], who's really been instrumental in developing the procedure and democratizing it. But my question to you is, what are your thoughts regarding the access challenges that patients face globally. Getting access to these centers of excellence with skilled surgeons. And what advice would you give such folks who seek septal reduction therapies, but perhaps, through less experienced centers?

Yes. All right. Thanks, Steve. So let me -- I'd answer that this way. So just for context, there are 2 invasive septal reduction therapy options for symptomatic obstructive HCM. There is surgical myectomy, open heart surgery. It's been around for about 60 years. And in newer, although, not brand new, but newer less-invasive percutaneous approach with alcohol septal ablation. Those are our 2 invasive therapies that change the anatomy to relieve the obstruction and ultimately, therefore, improve symptoms. And there is two points to make relative to your question, I think, is this: One is that we know that for both of those 2 invasive procedures that outcome is good, excellent when those procedures are performed by really experienced operator that have good multidisciplinary HCM center supporting the procedures. And on the flip side, we know that when those procedures are done with less experienced operators in lower volume centers, outcomes meaning safety and efficacy is much poor for sure. And so the -- and then the second point to that is that these procedures, both of them, even at the expert level, are limited in accessibility, not just in the U.S. but even more -- if you talk about globally, for sure. Does it mean that you can't get access to good centers that do alcohol ablation or surgery, but comparatively speaking to much more visible procedures like coronary artery bypass grafting, valve replacement or percutaneous procedures like stenting, alcohol ablation and myectomy are much more limited in availability at the expert level and that would be both for the U.S. or North America. And certainly, for sure, globally, particularly when you're talking about less developed countries. And so for that reason and coming back to the second part of your question, my advice is -- to patients is that you really should seek treatment if you're looking for an invasive option like surgery or alcohol ablation, you should really do everything possible to seek treatment for 1 of those 2 procedures at an expert high-volume center. And that's what we really recommend for patients to be able to do. If that's not possible, then we have to entertain other options, which can come up as well, but the advice is based on the outcome data is to seek expert care, if possible.

Perfect. Thank you. So on the same vein, Andrew, I think I'm going to switch over to you over here and ask, obviously, there is a lot of debate about the place of alcohol septal ablation versus myectomy in treating these patients with obstructive HCM who are drug refractory. Could you help define what your personal approach is to identify which therapy is bear suited for these patients?

Yes. Steve, thank you. And I think to build on what Marty had just talked about in terms of the role for septal reduction therapies, guidelines and current practice really start with medical therapy for patients with symptomatic obstructive hypertrophic cardiomyopathy. And to date, most of those medicines were not really designed or specifically studied necessarily in randomized trials for obstructive hypertrophic cardiomyopathy, that really taken and used from other cardiac conditions, the beta blockers, the nondihydropyridine calcium channel blockers and disopyramide really form the basis for treating obstructive hypertrophic cardiomyopathy because of their negative inotropic effects. And then there is a big gap, though, between those therapies in patients who have symptoms and may continue to have symptoms on those therapies and the gap toward warning an invasive therapy for improvement of their symptoms and quality of life. And patients will go for many years trying to make the best of these medications that are currently available before deciding that they want to pursue an invasive strategies. And oftentimes, these are in older patients as well where the risk of the procedure may be higher. So I think the guidelines would advise medical therapy initially for patients for symptomatic obstructive hypertrophic cardiomyopathy. And if patients continue to have persistent symptoms, and the guidelines actually recommend fairly advanced symptoms, New York Heart Association Class 3 or 4 symptoms despite medical therapy, then consideration of septal reduction in therapy would be advised or recommend.

Perfect. Thank you. So Anjali, maybe you can help by answering 2 questions that I have. To paraphrase what Dr. Wang just said, there is obviously this treatment gap, as he put it, that's out there. How do you think that these novel therapies that we're working to develop for obstructive HCM would fit in the current treatment paradigm?