you'd like.
Okay.
Good morning, and welcome to ACTIVATE, INHIBIT and Power: Changing the Course of Cardiovascular Disease. I'm Diane Weiser, Senior Vice President of Corporate Communications and Investor Relations, 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 sharing 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. Undertake no obligation to update any forward looking statements after this call. So we're going to go through the agenda just having trouble there we go.
We're are going to go through the agenda just really briefly. We've focused today's presentation on 3 sections. The first is ACTIVATE, focused on our cardiac myosin activator, omecamtiv mecarbil. The second is INHIBIT, focused on our cardiac myosin inhibitor, CK-two seventy four. And our final section is EMPOWUR, where we're going to have a patient panel on perspectives 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 and 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 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 and 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 Wolf, SVP, Senior Fellow Clinical Research and Development Steve Heitner, and I can't see this slide, so let me just move it up, 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 from Duke University School of Medicine Larry Allen from the University, Colorado School of Medicine Martie Maran from Tufts University School of Medicine Anjali Owens, Assistant Professor of Medicine and Andrew Wong, Duke University School of Medicine. We also have a panel of patients joining us, as I mentioned earlier: Linda Miskowski, who is living with heart failure and Lindsay Davis has joined us. She is 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 orients 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 and 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' focus to muscle biology for several reasons. One of those reasons is this is a quantitative biology, a biology that we can measure and where 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 1 and Phase 2 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 interests. 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 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 and 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 2,005 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-two seventy four, not a cardiac myosin activator, but 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-two seventy one and even reldesemtiv in the skeletal muscle activation area all tie to our objective to be the leading company focused in 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. 1 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 2,006 as was expanded and then Astellas and more recently as of yesterday our announced deal with RTW and Gxing. 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 2,006, Amgen has contributed many 100 of 1,000,000 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 is 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 in 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 monetized a future royalty under our collaboration with Amgen. In 2017, we sold a piece of our royalty to Royalty Pharma for what was then $100,000,000 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-two seventy four needs to be well positioned to build on that.
And yesterday, we announced a new collaboration comprising 4 different transactions with RTW Investments and Jixing Pharmaceuticals. This additional capital, committed capital of about $250,000,000 enables us to advance CK-two seventy four 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, non obstructive 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 in glove together. Under our Amgen collaboration, we are well positioned with them as a partner to sell and market our own medicines under a co commercialization agreement in North America, where our orientation as you'll hear later will be primarily 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-two seventy four 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 of 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, 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 in smooth muscle regulate blood pressure, tone and pulmonary tone and dysregulation 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 and 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 reproduce 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 in its native context and 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 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 to focus on the heart, it's muscular organ, which beats our entire lifetimes, billions of heartbeats it sustains in order to pump blood over the course of decades, is an elegant structure, a pump that is designed to last, but in its function is balanced in a way that is sometimes leads to where diseases that impact that balance lead to diseases either of reduced cardiac contractility, such as on the left, diseases we call heart failure with reduced ejection fraction and 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 so 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 heart's 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, hypercontractile 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 is 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 binds 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 that actin filament shortens and hence muscle contracts. Now the actin myosin interaction is regulated by a series of proteins called the 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, 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. In 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-two seventy four, CK-two seventy one, these are direct inhibitors of cardiac myosin and they reduce the number of active cross bridges, the number of actin 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 in 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 are ECHOs taken in dogs many years ago as we developed omecamtiv mecarbil.
These were the first glimpses in a dog model of cardiac function of the effect of omecamtiv mecarbil on contractile function of the heart. You can see in that 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 ejecting more blood from that central cavity. Now on the right is a patient. This is one of the patients that was treated at 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 of the 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 it's 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 of omicamtivancarbil, 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 of measures of cardi that can be measured and quantified in many different ways. And Doctor. Wolf later will take you through some of those measurements in our clinical trials. So I'm going to begin and just tell you one of the stories that will proceed with today, the ACTIVATE story, that of omecamtiv mecarbil.
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 the 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 at 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 the selection of a compound that entered the clinic, eventually getting the name omecamtiv mecarbil. We can debate whether that's better than its original name CK-one hundred and eighty two-seven thousand four hundred and fifty two.
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 we did in Atomic HF, 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 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 reduced 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, whichever occurred first. We were, however, interested in understanding the effect of omecamtiv mecarbil on 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 patients' 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 is their safety, what's their potential efficacy and features of omecamtiv mecarbil, which doesn't affect 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 1st 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, 8,256 patients. Without going through the numbers in detail, this 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 entry in the trial. It was required that they either be currently hospitalized or hospitalized within 1 year.
You can see that the median time from hospitalization was only 2 months, again, adding to these enrolling patients have greatest need in terms of new medical therapies since these are the patients at greatest risk. Another marker of risk NT proBNP elevated here in about 2,000. Injection fraction reduced 27%. You saw in those prior pictures I showed you what an injection 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 the patient population starting it at baseline. You can see in the columns 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 DAP HF, which enrolled exclusively outpatients, but not quite so high risk as a recently reported trial VICTORIA HF, which targeted in some ways a 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 a third of the targeted number of heart failure events, 1590. And then second thing in that was concluded in the Q1 this year was to look at both utility and superiority when 2 thirds of the targeted number of events had 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 Q4 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 momekamtiv mecarbil's effect in heart failure.
Steve?
Everybody's attention. So I'll start out by jumping in and try 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 remains 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 experience 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 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, hospitalizations and embedded a KCCQ in order to assess patient symptoms, whereas Medioric, 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 basis for up to 2 weeks. And we feel that that speaks 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 the cardioplmonary 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. And 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 Wolf, 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 ask 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 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 worked 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. 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 the lighter green, the 25 milligram group and in the dark green, the PK dose titration group, which included some patients, about I think a third 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, 2 other measures of systolic function, left ventricular fractional shortening and left ventricular ejection fraction, also increasing relative to placebo ethomecamtiv mecarbil. On the next slide, you can see some real predictive measures that are quite impressed, I think, the heart failure world when we first presented these data, and that's significant declines in left ventricular end 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 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 a reflex withdrawal of sympathetic tone, so that if the heart can inject more blood per beat, it needs to beat fewer times per minute 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 the higher it is, generally the worse the heart failure it is. And you can see that it comes down also during treatment with omecamtiv mecarbil. You may recall from the echoes that Fady presented from our patient who was treated with omecamtiv mecarbil in our Phase 2 program that not only is ventricular function improved, but so is atrial function. The atrial myocardium is of the same composition as the 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 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 wanted 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 20 weeks, has done 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 of the blood the atrial 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, 5 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 subdomains 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 baselines. At the bottom in the table, you can see the median values at baseline and the interquartile ranges. Now 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 the 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 a quarter 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 that informs the potential for omecamtiv mecarbil treatment in GALACTIC HF to result in improved heart failure outcomes. So in the next few minutes, I want to review the evidence base 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 of 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 its origin. So NT proBNP is actually an inactive peptide that is cleaved during the processing of the pro hormone of BNP.
So proBNP is actually released by cardiac myocytes in response to pressure overload in the left ventricle. And 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 has 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. And this is one study called guided 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 showed that decreases of NT proBNP associated with the treatment with secubitrilvalsartan were associated with reductions of LD end diastolic volume and end systolic volume.
And so it's data such as these that inform a plausible mechanism for why secubitrovalsartan treatment and the paradigm HF trial were associated with improved heart failure outcomes. So possibly driven by reversal modeling 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 mortality essentially looking at mortality and remodeling trials.
And this included 90,000 patients with hepref. 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 and diastolic volume. So if 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. Do reductions of NT proBNP that are associated with a new investigational agent, does that predict improved heart failure outcomes?
And the evidence base would suggest that the answer is yes. This is an analysis from the PARADIGM HF trial. And in this study, the investigators focused on a cohort of patients that had elevated NT proBNP at 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 secubitril, valsartan or enalapril.
Those patients experienced more than 50% relative risk reduction for the primary endpoint compared with those patients whose anti proBNP levels stayed above that 1,000 picogram per mL threshold. 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 decrease 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 the 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 omecamtivmacargo.
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 battle the virus that's known as COVID-nineteen. 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 participated, who have been fighting this battle for their courage and their dedication. But health care professionals have always been on the front line 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 $30,000,000,000 and is increasing significantly with the expectation that it will achieve reach a level of $70,000,000,000 by 2,030.
Almost 2 thirds 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 healthcare resources at a much higher rate than others. And as you can see, reducing hospitalization can have a significant financial benefit to the entire healthcare 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 2,030, if we're able to reduce heart failure hospitalizations for HFREF by 20%, we could save the health care system about 5,000,000,000 dollars in one calendar year. But reducing the costs 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 affect change. I remember Doctor. 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 you're a 68 year old grandmother who finds herself 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's not working well, 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 Get With the Guidelines that Doctor. Larry Allen, who's also one of our panelists 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, a 50% level or in the case of ACE and ARBs at a 45% level of prescription, but at discharge, we're moved up to 91% and 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 pre discharge and those who initiated post discharge. And as you can see, those who were initiated pre discharge 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 highlighted 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, Entresta 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 2,000,000,000 to 3,000,000,000 worldwide in 2020. Sales trajectory like this, along with some of the 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 lifestyle 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 half RAF. And we also need to make sure we're cognizant of what payers are interested in. We recognize that 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 Wolf, who will lead a panel discussion with those physicians who are currently on the frontline of treating patients and improving the lives of those who have heart failure. Andy?
Thank you, Scott, and welcome to our 4 panelists, Doctors McMurray, Alan, Hernandez and Malik.
Are they with us?
Yes, I hope so.
We can hear you, Andy.
We're 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, Doctor. McMurray. How would you characterize the probability of success for omecamtiv mecarbil in GALAKIC
HF? Thank you, Andrew. So obviously predicting the future is always difficult, but if I wanted a drug to do
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 improvements in clinical outcomes, those effects would be reduction in ventricular volumes, reduction in theatrizipeptides and indeed that reduction in 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 get that has those effects has been beneficial.
Now you can never be sure. It's always possible to be some off target effect that might cause
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. Adrianne, 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 Arnie's and Entresto.
We have the SGLT2 inhibitors. Now we are soon to have it. It appears 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. 1 is just what we've seen so far as the outcomes for heart failure is still 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 maybe something that will be unique that we'll learn from the GALACTIC trial because there's a significant portion of patients who are starting in the 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 by with patients at risk for having either worsening heart failure or actually significant risk for mortality.
Thank you. Let's talk about this from the patient's perspective now for a little bit. Now 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 slow down 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 prescribe 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 and 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 asked 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 our patients feeling, the change was around 1 to 2 points, which is really non significant. 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 showing improved exercise capacity is a meaningful or 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 is 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 will 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 the recent large
part sellers. Is he? Yes.
Sorry. We do have many questions from the audience. So I'm just going to check here. 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 not happy to. Okay, good.
I
can
answer that. So historically, the FDA has looked for evidence that shows clinical benefits relative to safety and patients with HFREF or hard part 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, but certainly supportive.
Yes. With the Vercinguat HFpEF research trials, the FDA did just allow KCCQ or a health status measure how patients are 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 patients.
Thanks. 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 in plasma troponin with homecamtiv mecarbil and cosmic? Is it part of reverse remodeling or another reason? Fady, maybe?
I can start that and ask others to chime in if they'd like. I think there are growing lines of evidence that troponin can be secreted by myocytes in small vessels called exosomes. That may be a signaling molecule that is part of the parts signaling to the right body what is going on. The you see troponins increase with exercise, for instance, and that again may be that's an activity that provokes increased contractility. And so there may be a link between the increase in contractility and the cycling of the out of the tarkovir into exosomes and its subsequent situation.
The in cosmic, we saw the heart getting smaller over time, the volumes of the heart getting smaller, ultimately, if there's a process of reverse remodeling, the heart has to begin to disassemble sarcomeres as the myocytes actually get bigger in heart failure, they need to be get smaller again. And that disassembly process again may also lead to the secretions 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 as a biomarker of nonpathologic mechanisms.
Great. Maybe Doctor. 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 fail. I mean, the reverse remodeling reduction in atriopic peptides, barring some amazing surprise, those huge translate engine through dark counts. So what could go wrong?
Well, we've talked about the Troponin issue, but a tiny change in troponin probably isn't very significant. Could the drug have some hard obstacles, for example, true arrhythmic effect? We've got no reason to believe that because I would say out of all the many drugs I've been involved in exploring over many years, we probably spent more time doing more studies in an early phase with Omecaptive than with any other drug. So I think we would have probably unearthed surprises like that. We have no particular reason to think it should affect renal function, which would be another reason.
And after that, I really run out of ideas, and it would have to be something extraordinary.
The next question is from James Shin from Citi. Could Doctor. 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 so called 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 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's going to be huge interest in trying to get this best evidence within months.
Just to add to that too, I mean, a lot of the therapies that we're talking about using in combination, they can all lower blood pressure, they all potentially have some side effects. So they 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 greater benefit when used together, but omecamtiv might actually be one of the ways to get people on to therapy quicker. There's 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 the other meds, that could really be a bit of a game changer in terms of the way we think about creating combination therapy that need 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 So the answer is yes, because what will happen in many disease areas and many trials is that the control group because they show more worsening, if the active treatment is better, then in the control group, you'll see more add in of other therapies because clearly more of those patients are 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 therapies affected, more drop in of alternative treatments. But usually, that's I mean, it's such a small effect overall that it doesn't change the difference between the new therapy 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 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. 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 heartworm reduced ejection fraction includes the in hospital phase. And so people will be looking to see how this go across in both inpatient as well 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.
So we're going to be much more likely to prescribe something that we know is going to be easily tolerated, someone can take long term. And then there is actually an X factor that's unique, I think, for omecanctive 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 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 some better evidence in terms of how they will function. And then that allows us to translate prescription to what they will 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 before getting to GALACTIC or analyses of drug drug interaction studies, we did a couple prior to GALACTIC and in the during the conduct of GALACTIC, we conducted a number of Phase 1 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 the use of omecamtiv mecarbil.
Excellent. 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, it 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 Doctor. McMurray wants to take that.
So that would in fact be a pretty similar follow-up to paradigm heart failure and longer than DAP HF, which had a median follow-up of 18.2 months. So I can't imagine if this treatment works like every other treatment, if this works 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 high event rates, 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 Kopfer and Laura Robertson, who are going to focus in on CK-two seventy four.
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 base that supports development of CK-two seventy four as well as our vision for its development strategy. So CK-two seventy four is the next in class and we believe best in class cardiac myosin inhibitor. It was discovered by psychokinetics 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 CYP inhibition or induction in order to avoid drug drug interactions and high oral bioavailability. Now we conducted non clinical studies and now we have clinical data in healthy volunteers. And these data indicate that CK-two seventy four has predictable pharmacokinetics and a predictable pharmacodynamic
profile which exposures the
CQ374 has relatively shallow dose response relationship in which we predict a wide therapeutic index. The half life supports once daily dosing and is 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 those patients by individualizing therapy.
With that,
I'm going to turn it over to Laura to summarize our Phase 1 data and our Phase 2 Redwood HCM study design.
Hello. I'd like to go through our Phase 1 data. We were very pleased that CK-two seventy four 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 two figures on the left, that we have excellent exposure at the doses administered. The CK-two seventy four has predictable dose linear pharmacokinetics. And on the right, in the multiple dose studies, you can see that CK-two seventy four reaches 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 in 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 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 highlights 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 study 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 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:one to CK-two seventy four 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 are marked there, doses 1, 23. Each of them will be escalating.
Dose titration will occur based on echocardiographic criteria. We will be looking at ejection fraction and outflow tract radiance. We know from Phase 1 that we have a shallow exposure response relationship and predictable PK. So we were 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-two seventy 4'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've 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 have 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 1 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, Laura. So let's continue to elaborate on the opportunities for clinical development of CK-two seventy four. Now, this is an overview of our clinical plan for development in obstructive and non obstructive HCM. And the results of the Redwood HCM trial that Laura just described will inform dose selection for our pivotal Phase 3 trial in which we'll be focusing on evaluation of CK-two seventy four 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 ACM 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 non obstructive 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 2b, Phase 3 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 3 trial in which we'll also be evaluating patients for exercise capacity. This is an outline of the clinical endpoints we'll be evaluating in our Phase 3 trial in obstructive ACM. We'll be employing cardiopulmonary exercise testing.
And as Steve mentioned previously, this is a very precise objective 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're looking for also improvements in symptoms and physical activity based on NYHA class and other measures, 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 for that are specific to the HCM population. So development of CK-two seventy four then is designed to address multiple dimensions of disease burden in HCM. By reducing the LVFT 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-two seventy four treatment to approach magnitudes of benefit consistent with surgical septomyectomy.
Also in anticipation that a cardiac myosin inhibitor will be beneficial in non obstructive HCM, we plan to evaluate another patient population that could potentially benefit from CK-two seventy four. 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 non obstructive HCM and specific health patients, particularly with respect to increased cardiac contractility and diastolic dysfunction. Also, the profiles of these pressure volume loops are similar between these two patient populations. And that also informs investigation of this HFpEF subgroup.
So in summary, CK-two seventy four 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, non obstructive HCM and a specific subgroup 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 ready the cream of the crop with Doctor. Marty Maran, Doctor. Andrew Wong and Doctor.
Angelie Owens and Doctor. Malik, who you've met on multiple forums already. So I'm going to kick off with a question to Marty. And Doctor. Maran, 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 sense, in particular, you have this world renowned surgeon, Doctor. Rastigar, 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. So 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 the newer, although not brand new, but newer, less invasive, hercutaneous approach with alcohol septalablation. Those are our 2 invasive therapies that change the anatomy to relieve the obstruction and ultimately therefore improve symptoms. And there's 2 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 centers 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 in the second 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. It doesn't 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 replacements 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, when you're talking about less developed countries. And so for that reason, then 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 alco ablation, you should really do everything possible to seek treatment for one of those two 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 want to switch over to you over here and ask, obviously, there's a lot of debate about the place of alcohol septalablation versus myectomy in treating these patients with obstructive HCM who are drug refractory. Could you help define what your personal approach is to identifying which therapy is best 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 in 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 non dihydropyridines calcium channel blockers and disopyrimide really form the basis for treating obstructive hypertrophic cardiomyopathy because of their negative inotropic effects. And then there's 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 wanting 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 III or IV symptoms despite medical therapy, then consideration of septal reduction therapy would be advised or recommended.
Perfect. So Angeline, maybe you can help by answering 2 questions that I have. To paraphrase what Doctor. Wang just said, there's 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?
I think certainly patients would be very happy to start a novel therapy that is one targeted to the underlying problem in HCM. So the fact that the myosin inhibitors modulate contractility and perhaps help with relaxation are critical features in treating patients with HCM and are aspects that we don't have currently in our armamentarium. So I would see a benefit right off the bat in talking to patients about a non invasive way to address the underlying problems with their cardiac function and structure.
Okay, great. Thanks. And the second part of the question or second question that I have for you, Angelie, is differentiating between patients who would best be served with a surgical approach versus alcohol septal ablation. Do you have any words to share with
us? I think it depends a lot on your center. And as Mardi Maron said, what expertise you have in your center. And I think if you are able to have sort of a balanced approach, you have operators that are excellent in both, then we tend to approach it as a multi very team and we will all evaluate the patients who are referred for septal reduction therapy, will take into account their age, their comorbidities, we'll take into account their cardiac anatomy. And obviously, we do share decision making and what the patient preference is.
And that is how we are centered making approach to the sepsil reduction therapy that we think is best. It's very much individualized.
Right. Thanks. So I think I'm getting a sense that therapies are individualized both on the medical side as well as potentially on the septal reduction side. Now Andrew,
could I just
Yes.
Go ahead, Mark.
Could I just make one additional point? Is that okay?
Yes. Yes.
I just want to make one additional point to kind of expand on the comments of both Andrew and Angelie too, particularly for the audience that may be a little bit less initiated with HCM and much more familiar with other forms of heart failure like HFrEF. The current drugs for treatment of obstructive ATM, not only are they not, they're not none of them which are FDA approved, but the efficacy of the drugs and they're limited, there's just 3, is low, very low in a way. Remember, these are young patients. We're talking about long exposure times here that differ substantially from other forms of heart failure where patients are a lot older. In this situation, you're talking about young patients who are functionally limited, who have no real good long term drug therapy options currently available for the problem.
That's a huge unmet need.
Just wanted to clarify that.
It differs dramatically from other forms of heart failure that everybody is
much more
familiar with. So Marty, while I've got you engaged over here, you were of the 3 external experts over here were not involved in the EXPLORER HCM study. And I wanted to get your opinion as to what you think about those results. And then further help explain where you see an opportunity exists for a next in class drug like CK-two seventy four?
Yes. So these are my thoughts about EXPLORER that the results were very good, that the mechanism of action of the drug translated into a clinical benefit. It lowered gradients and then that translated into a significant clinical benefit in improvement of limiting symptoms for patients on the drug. So there's no question that that was positive, very positive results. With that said, I will also say that there is room on the table Despite how good those results were, I believe that there is still a lot of room on the table for even more improvement,
okay?
There is opportunity for even greater efficacy that would draw us even closer with drug therapy to the outcomes that we see with surgical myectomy, which really stands as the gold standard for the treatment of obstructive HCM. And I say that in both in terms of maybe even greater improvement in NYHA class with the drug, improvement in functional capacity with VO2, and also as a result improvement in lowering gradients that would result in those 2 clinical efficacy endpoints. So I think it was great, but there's even more room for improvement. And I guess I would expand on that by saying that, yes, I think you asked about how 274 could fit into that discussion and the way it could fit into that discussion by closing the gap or improving the efficacy on EXPLORER relates to the pharmacodynamics of the drug. And it's as you heard earlier in the talk, the more shallow dose response curve and the more forgiving therapeutic window translates, we hope, and this would be the hope here, into the opportunity to more reliably dose patients in a way that would lower gradients better, more effectively than EXPLORER, translating into that better or greater clinical efficacy.
I see Diane has showed up, which means that we have some questions from the analysts on board. So I'm going to take a pause. And Diane, over to you.
Excellent. Thanks. So the first question is from Dopant Dennis from H. C. Wainwright.
Ahead of the EXPLORER study readout, one of the potential risks of failure raised by a physician discussion that they had was whether mavacamten could reach required PK levels through titration quickly enough. Even though the study was positive, why would CK-two seventy four's differentiated PK profile add to its potential clinical impact?
That sounds like a question that Fady can help with.
I can start, but I think the clinicians did contribute. The rationale behind optimizing the profile of CK-two seventy four was intended to facilitate convenient dosing. So with the drug that you want to dose escalate to a point where there's a potential for exceeding an effect on a desired effect, you want a drug that is readily reversible and whose PK allows you to make dose adjustments in a way that we consider our options to do other drug therapies in hypertrophic and dengueopathy. And so the shallow exposure response relationship and the reversibility and time to stay stay of the drug enable hopefully the optimization of target dose and subsequently with better target dose, hopefully optimizing efficacy as well. Maybe turn it over to Marty or the others to think about how do they use current drug therapy and how does that would this fit into
that? Well, I think the way the current paradigm is we start with in symptomatic patients with beta blockers, titrate up to hopefully efficacy or patient have side effects, we come back down. If that doesn't work, sometimes we'll do calcium channel blockers. In select patients who don't respond to AV nodal blocking agents with beta blocker or calcium channel blocker, we may consider Norpace in those situations. Again, it depends.
We have to individualize that decision about NOR PACE. It's not for everybody. And so as you can see at that point then, in a symptomatic patient who doesn't respond to these limited therapies, you really are on to a discussion and recommendation for invasive therapies at that time. And again, that kind of underscores the unmet need for drug for additional drug therapy in symptomatic obstructive HCM. And you could imagine then that with what we're seeing with clinical efficacy of the myosin inhibitors, that they could very quickly become, in fact, perhaps even first line agents for the treatment of symptomatic obstructive HCM for all the reasons we've spoken about.
To add to what Marty said, if I might, there it takes time to get symptom control in patients with HCM and if CK-two seventy four can differentiate itself, with ease of dose titration and achieving efficacy and symptom control safely, faster in a targeted way. I think there could be significant benefit and it depends on the way it acts trial and we'll soon have that information. But it has shorter half life and that may translate some benefit. I think the other important point is that if these agents reach FDA approval, we have to think about dosing in the cardiology community at large. And community cardiologists, some patients with HCM may want to bring this therapy to the patient and they may not be functioning in a large HCM center with a big business or ability for echos and dose titration.
So the simpler the dosing strategy and titration, the better.
Thank you, Doctor. Owens. I think a follow-up on this discussion is a question from Jeff Hung from Morgan Stanley. With the potential for multiple additional drugs available in the coming years, what characteristics would you focus on when deciding between treatment options for patients with OHCM and NHCM? Maybe Doctor.
Wang?
Yes. Doctor. Wang, do you want to take that one?
Yes. Thank you. I think as Anjali had mentioned, the ease of dosing and seeing the pharmacodynamic effect of a dose change in the near future for dose adjustment would be very important. Obviously, echocardiography is going to be our guidance in dosing, both with regard to the safety with possible reductions in left hand trigger ejection fraction as well as efficacy with reduction in the outflow tract obstruction. And so being able to see the effect on both of those parameters in a very short time interval from a dose initiation and then dose change, I think, is very important.
I was involved in the EXPLORER trial and we're all waiting for the readout. But just to remind everyone in that trial, there were only across the 38 week or 30 week on drug treatment period, there were only 2 opportunities for dose changes in that trial across 30 weeks to raise the dose based on pharmacodynamic properties. And I think with a drug that has a shorter half life with multiple different steps in drug dosing, you could see really this being tailored to the specific patient and their response.
Excellent. The next question is from Jason Butler from JMP Securities. In addition to the usability advantages CK-two seventy four has, are there clinical efficacy or safety benefits that you think the compound can show differentiation versus mavacamten in OHCM? And then a follow-up, how should we think about the patient population you will evaluate in the CK-two seventy four program versus mavacamten? Maybe one of our KOLs can take the first part and Fady can take the second.
Angelie, do you want to address the first?
Go ahead, Marty.
Angela, I'll just quickly, then you can add in too. I'll just say that the answer to the force from my perspective would be that kind of leveraging again the pharmacodynamic properties of 274, the shallow dose response curve, the shorter half life, the translation of that into efficacy, but mostly safety as you as was just alluded to would be that you would hopefully limit or eliminate the safety concern of dropping ejection fraction too much with drug dosing. So we want to try to lower gradient, but not at the expense of decreasing systolic function too low. And I think with more ability to more precisely and reliably dose with a more forgiving therapeutic window will significantly decrease the chances of injection fractions dropping into ranges that we wouldn't want to see for these patients.
The other thing I would add to that is that clinical trials tend to clean the pretty patient, but the cardiology community of the patients at large HCM are varied and HCM affects their heart differently and the patient comorbidities are very different. And as Marty said, there are young patients that have, you know, almost no comorbidities and there are older patients that have hypertension, coronary artery disease and a host of other non cardiac diseases along with HCM. And so the wild card of what might happen to somebody physiologic septic shock or an acute MI or something like that, where all of a sudden they may need a little more effect. If you have a drug that you could withdraw easily or overcome the effect of the financial treatment, if you need, that would be beneficial in the clinical world?
Thank you. We'll do sorry, Fady.
Just to address briefly the patient population. I think as Doctor. Robertson or discussed in the design of Redwood, we're targeting patients that have significant disease at baseline. So resting gradients that are relatively high in the obstructive population certainly help drive the disease and symptoms and potentially more symptomatic patients. If you take the approach that we took in GALACTIC HF, where we targeted a higher risk, higher disease higher patient population with greater disease burden, there I think you have the opportunity to demonstrate some of the largest effects.
And so we'll be thinking about how to design criteria in Phase 3 that will hone to that principle.
Great. Couple of more questions, a lot of interest in this program. So from Gil Blum from Needham, do you feel CK-two seventy four is even more relevant in patients with non obstructive HCM considering surgical intervention is less of an option?
I can start.
Marty, you want to
Yes. I'll start and say, that's a really good observation. Fundamentally, what's driving the disease are mutations of the sarcomere that lead to a hypercontractile state. So addressing that was something that balances aside, maybe they're only up in the long run besides very difficult things like heart transplant or something like that. But that's still to be seen.
I think it's harder because you don't relieve the obstruction immediately or relative with relatively short term treatment. You're looking at a longer term impact on cardiac structure and function that may lead to symptom improvement and patient outcomes. Maybe I'll just ask maybe if Palos want to comment there as well.
Yes, I'll just add I'll expand on that by just also saying that in some ways there's even greater unmet need for the non obstructive patients since the therapies that we have are even less efficacious and even fewer. Surgical myectomy like it is for obstructive ACM does not exist with the non obstructive. The only surgery would be heart transplant and that's obviously complicated. So there's even a greater unmet need for symptomatic non obstructive ATMs in some ways than for the obstructive cohort. And so a benefit these drugs potentially in improving feel and function would be a huge win since we have almost nothing else to provide them to change their natural history in a beneficial way.
I think the key to deploying these agents and patients with a non obstructive HCM were really to be to look at stiff hearts with high filling pressures and some degree of tactile reserve. And sometimes you can assess that clinically imaging, other times you may need to make the key dynamic to really see what the factorial reserve is. But I think subpopulation of a non obstructive HCM stands to benefit, but patient selection is going to be pretty crucial.
Thank you. From Dan Leone from Raymond James. So if mavacamten is already approved, how would Cytokinetics run a larger clinical study and fit into clinical utilization? What clinical endpoints could prove advantageous to those from the EXPLORER study? Fady, do you want
to I
think that, that sounds like a good question for Fady.
I'll start and just see what others think. I think in the context of another therapy, certainly there are ways to develop additional therapies and not all patients will have immediate access to therapy in all regions around the world will have immediate access. As you saw today, we have also announced an initiative to develop CK-two seventy four in China alongside North America and Europe. So there are strategies to enroll patients and I think the availability of CK-two seventy four and participation in this program will be attractive to many. I think we have we still have a lot to learn from as we see more data coming out of the pioneering trial that MyoKardia did in EXPLORER.
But we I think that hewing to the principles that this panel has said, we're going to be focusing on function and symptoms in these patients. Often outcomes are hard outcomes like we're used to using in heart failure with reduced ejection fraction are far more infrequent fortunately. And this is a place where symptoms and functional deficits are what is the tremendous burden to patients.
Great. Okay. This probably will have to be the last question. So this is focused on PK titration schemes and how receptive cardiologists are to personalize PK titration schemes? And do you see any issue with this being a barrier to adoption of the myosin inhibitor class?
So I think before we select a panelist for that, I just wanted to make clear that the intention of the Redwood study is that we are not going to be relying on PK in order to titrate 2 74 doses. We're aiming at using echocardiographic based titration, which may end up being something that differentiates the drug. With that in mind, Andrew, do you want to take a shot at that one?
Yes. I would agree. I think the Phase 2 studies and even the Phase 3 studies are important to understand the pharmacokinetics and dynamics. But ultimately, if the drug is found to be effective, then it's going to be much more of a pharmacodynamic driven dosing approach. Cardiologists, for example, if mavacamten is approved or 274 is approved, we'll rely on the echocardiogram to tell them if there's any concern about safety with a reduced ejection fraction as well as dosing for efficacy in terms of achieving a significant reduction in outflow tractation.
And
so the
I would say the tool the cardiologist is going to use, you can say that we're not smart enough to understand PK relationships, is that we're going to use an ultrasound, something that we can see in front of us to say, oh, the ejection fraction is too low, I'm going to dose reduce it and see the patient back in a week and then dose adjust it after that or the output track gradient is still present and the patient still has some symptoms and I'm going to recommend increasing the dose and seeing them back in a week and seeing how that looks.
Yes. I'll just add. I think cardiologists are well accustomed to using a variety of means to titrate effect. I mean, physiologic parameters are classic, blood pressure, heart rate, simple things that we measure. Echo is becoming a modality that you can now almost access on a smartphone with a transducer and becoming very even more readily accessible.
And so I think personalizing the dose, personalizing the effect to each patient is what's enabled by the person that each other is taking and I think is kind of the essence of personalized medicine.
The other parameter that cardiologists are pretty comfortable with is biomarker. And so trending the NT proBNP and seeing it fall and it starts with uptick that relates with symptomatic heart failure or worsening status, you may then have a red flag of them and see what's going on with the ejection fraction. So there's some
Excellent. Well, with that, I just want to sorry, Marty, go ahead.
30 seconds. I just wanted to add one additional point, which I think is really important and it ties on to what Fady was saying on the last question, the previous one, and I want to make sure we get it in. Stuart had shown a slide making the point that non obstructive HCM stands as a model for pathophysiologically for HFpEF, other forms of non HCM heart failure with preserved EF. So I want to make the point that if we can if CK-two seventy four can show benefit by improving feel and function in the non obstructive HCM population, that makes a really strong argument and opens up the door for further exploration and investigation of these drugs in non HCM HFpEF. I don't know if HCM is an example for all of HFpEF, but it's certainly a large segment of HFpEF has very similar overlap pathophysiologically.
So you could imagine then that there could be a reason, a very strong reason to explore these drugs in what is a huge morbidity and mortality impact with HFpEF as well. So I just wanted to make sure we got that point in because I think it's really important.
Thanks, Mark.
Thank you. Thank you, Steve, for moderating, and thank you to all of our panelists. We are now going to move forward with the 3rd section of our program and that's EMPOWUR. And we're very fortunate to have 2 patients with us living with these diseases, hypertrophic cardiomyopathy and heart failure, and really hear their perspectives because at the end of the day, that's why we all do what we do. That's why the physicians are focused on optimizing therapy, and that's why we at Cytokinetics are working so hard to bring these therapies to market.
So with that, I'm going to introduce Linda Myszkowski and Lindsay Davis. Great. Thank you both, and welcome. Thanks for taking the time. So just to kick things off, I'd love for each of you to just briefly recap your experience with getting your initial diagnosis and what your initial reaction was.
We'll start with Linda in heart failure, please.
Good morning. Thank you for letting me be a part of this program this morning. My cardiac disease dates back to 1989. I had Hodgkin's disease. It was treated with radiation therapy and radiation therapy back in the late '80s was very different from today.
So now let's now that we know the ideology of my heart failure, let's fast forward. About 14 years ago, I had an MI that was secondary not to atherosclerotic disease, but to a clot that was evacuated. So that was my first encounter with a cardiologist for follow-up. We determined at that time that I had mitral valve stenosis, aortic valve stenosis secondary to the radiation. And we really didn't treat me for heart failure at that junction.
I was monitored and then approximately 7 years ago, things progressed. You know, we were doing echoes and things progressed to the point where I needed TAV treatment. Carvedilol Lasix potassium supplement and CoREG. About 5 years ago, I needed to have a because I don't do anything the easy way. So 5 years ago, I had a pacemaker put in.
And then 6 months after that, then I had the aortic valve replaced. So now that they've gotten everything as anatomically correct as they can, It's now just a matter of maintaining and treating me for the heart failure. How has this impacted me? I can't really say I was angry or mad about everything that has transpired. To be honest, I'm grateful that they had the radiation therapy back then.
Otherwise, I would not be having this conversation with you all today. I can, however, relate to something that Doctor. Allen said earlier as far as patients do want to be involved physically and patients do want to be involved in their care, and I think I have done so well. I've not been in the hospital for any heart failure since I was treated, but I'm very anal retentive on my care. You tell me what to do and I will take care of it.
I will do it. You tell me that I need to exercise. You tell me I need to lose weight. It's done Because I feel I need to honor my own self by following your instructions. Plus, I feel I need to honor the medical team that's giving me these recommendations.
Because if you're giving recommendations and your patients aren't following through, then I would imagine as a clinician that that's really frustrating. And I can say that coming from the perspective that I'm a retired nurse And I did a lot of patient instruction and teaching in my career, and I know how that impacted me as a nurse when people took heed to my advice and when they just threw caution to the wind.
Thank you, Linda.
Showed us
where I am today.
Excellent. Lindsay, if you could do the same and focus on how your hypertrophic cardiomyopathy impacts your quality of life.
Good morning. Thank you for having me here. So I was a ballerina my whole life and I kept having these ambiguous symptoms. I was passing out. I had shortness of breath, fatigue.
I couldn't get my heart to calm down after dance routines. And it wasn't until I was a 17 year old ballerina with plans to go to Juilliard that I collapsed after dance practice and was diagnosed with HCM. My initial reaction was, would I have to give up dance? I thought only older people got heart disease. It was a confusing time for me, and my world was rapidly changing, giving up dance, taking a massive cocktail of medication every day that oftentimes didn't give me side effects.
I was implanted with an internal defibrillator that broke and misfired and shocked my heart, that I've had to replace with one that sticks out of my body to manage my symptoms and keep me alive. I went from feeling like a normal teen one day to the next being a child who had more struggles and health concerns than someone twice my age. And as far as that how it impacts my quality of life, I have good days and bad days. Sometimes, I almost feel normal or what I believe to be normal. In other days, I can't even walk across my bed for me, like, being out of breath.
My absolute kryptonite is stairs. I have a hard time ascending stairs, ramps, hills without being out of breath and my heart beating so hard that it's moving my shirt. It's embarrassing as a young person to have to slow down in front of friends and explain why and just feel alienated by the disease.
Thank you, Lindsay. You've heard a lot about new therapies to address the underlying root cause of heart failure and HCM. Linda, as a nurse and a patient, what would it mean to have a therapy like omecamtiv mecarbil available as part of your treatment regimen?
Like Lindsay, I also have physical limitations that I have a hard time dealing with. Historically, I was a long distance cycler and I like to hike. Those have really been on the back burner because of the limitations that I have. Having the ability to feel better on a day to day basis would be golden. And I think any opportunity for research and development where we have better options for quality of life, that to me is a big game changer.
Thank you. Lindsay, what about with managing hypertrophic cardiomyopathy, how do you think a cardiac myosin inhibitor like CK-two seventy four might impact your day to day life and challenges with HCM?
I think it would give my life a bit of normalcy that I haven't really gotten a chance at or I've gotten brief glimpses of on good days. I would love to be able to just walk up a flight of stairs with someone and not have to pause our conversation and catch my breath and explain the complexities of my disease. I'd love to be able to travel and not worry about altitude of the location, not have to think about the temperature of where I'm going to prevent me from possibly passing out or having check scenes because it's too hot. Or I wouldn't have to miss a meeting or an event because I end up in the hospital for my symptoms. I would just like to have a slice of what it truly feels like to not carry this burden.
I've encountered so many HCM patients who are immeasurably ambitious. And I almost think it should be a common symptom, among HCM patients. But we're often held back by limitations of our disease. And I would like to imagine I could accomplish much more if I wasn't constantly experiencing symptoms.
Thank you. The last question that I'd love you guys to address is and I think this was mentioned a bit earlier, sort of the disconnect between the attention that is given to some other diseases like cancer or even ALS and that of heart failure and HCM. It really seems to be disproportionate. Lindsay, you have a platform for education and awareness. What do you believe is needed more to inform the public and other stakeholders about the urgency to innovate and treat heart failure and related diseases?
Truly, I feel patients need to be engaged more, not only in their own treatment, but they need to be sharing their stories more, Whether in media, at medical conferences, at meetings like this, or even medical offices, making them a part of the discussion. We need to be educating more. With the legislation that I passed, health and youth law, we were able to educate coaches, parents, and student athletes on the leading cause of death in student athletes, setting for the FRS. No one typically thinks that that could happen to a young athlete who's literally the epitome of health. But through education and awareness, more of these conditions are being identified.
We see scary things all the time in the media, stories of people experiencing things that we think are big risks that we should be scared of. But if you take devastating things like Alzheimer's disease, assault with firearms, breast cancer, cervical cancer, colorectal cancer, diabetes, HIV, house fires, motor vehicle accidents, and suicide and combine them all, you've got how many people we lose each year to sudden cardiac arrest alone. But why do we barely hear about it? Partially, the leading cause of death in the U. S.
This alone affects 1 in a 100 people and some studies even show up to 1 in 200 people. We need to be educating through individual patient narratives, whether it's the general public to bring awareness or to stakeholders to show how important these new treatments are to bettering and prolonging so many lives. Education through personal stories is the most impactful way to create change. Numbers and data can only go so far. That's why I think it's fantastic.
Phytokinetics got Linda and I onboard today to share the side of our patient journey. New candidates for new therapies that could possibly correct our disease instead of just treating symptoms would completely change the world for us.
Thank you so much. I think that's extremely well said and a great place to close this session. Thank you both so much for giving your time and being such great advocates for your disease and for other patients living with heart disease. Thanks again for joining us. Us.
Thank you. We're now going to move on to some of our final presentations, and I'm happy to turn things over to my colleague, Durga Baba, who's going to walk you through how Cytokinetics is building an industry leading cardiovascular franchise. Durga?
Good morning. The commitment to clients and patients that you've heard about this morning, it's real, and that commitment has enabled a robust cardiovascular pipeline that is based on novel breakthrough science. The Cytokinetics cardiovascular franchise strategy translates expertise and muscle biology into the satisfaction of unmet medical need on 3 dimensions. The first dimension is health span. That's a term of art that we use here at Cytokinetics.
And what it means is for patients to do more for longer. The second theme in our cardiovascular franchise strategy is expertise in muscle biology. This morning, you've heard from many experts and there is a common understanding in the lay public that you need 10000 hours to become an expert made famous by the Malcolm Gladwell book. 10000 hours is roughly 5 years. While this company has been on a journey for 22 years and Fady and Robert have been on that journey for the entire time, many others here at Cytokinetic, their tenure is not measured in years or hours, but in decades.
The 3rd dimension is commercialization, how we transition from an R and D company to a fully integrated biopharmaceutical. I love what Lindsay said just a few minutes ago, that heart disease is the number one killer of Americans. It's greater than all cancers combined. I know many of us have heard that. You see that in the left hand panel.
In the middle panel, you see the incredible toll that cardiovascular disease has. It's the largest expenditure of healthcare dollars. And that burden is just not in dollars, but it's an impact to patients, caregivers, families and society. Yet despite the high unmet clinical need and the high cost, 10 products have been approved by the FDA I'm sorry, 43 products have been approved by the FDA in the last 10 years. Let me put that into perspective.
You can see here that we have 4 molecules in development. So if we're lucky enough to move those through in advance and get approvals, Cytokinetics has ability to increase number of approvals by 10%. And if you look a little further on the slide, you'll see that just 4 drugs in the last 10 years have improved have been approved for heart failure against the rich cardiovascular pipeline of cytokinetics has an opportunity to meaningfully impact that. So our cardiovascular franchise is built on science, medicine and patient health span. If I can draw your attention to the left hand side of the panel, the foundation for success.
You've heard a lot today from experts and that we have 4 molecules in development. We firmly believe that success leaves clues. And we've studied very successful organizations. And one of the things that we've learned is, it's not just important to build initial molecules that are novel and are breakthrough, but also to defend franchises to continue to build to come up with follow on molecules. So zonecamtumecarbil becomes 594 and CK-two seventy four becomes CK-two seventy one.
That's part of our franchise. I draw your attention to the right hand panel. For 20 years, we have been focused on using quantitative biodynamic measures to develop novel molecules with the patient in mind. And that's the journey of Omecamtiv Mecarbil. We thought about the patient early, like Linda, and we developed expertise around those needs.
And you can see in the aqua dot here, the insured clinical development captures patient benefits. That's the main reason we did METEORIC, which whose primary endpoint is improvement in peak VO2 or cardiac function. So we have kept the patient in mind through our entire development. And we strive to ensure that our molecules address clinical unmet need from a physician and from a patient standpoint. Our goal is simple.
We want to make sure that the cardiovascular franchise we have today fulfills our promise and also in the future improves patient health span. So today, we're working very closely with our Amgen colleagues on a global collaboration and our near term goal is to successfully launch Omecamtiv mecarbil. And we plan to build a industry leading commercial organization that will do that. Once omecamtiv mecarbil is optimized and launched successfully, we're going to move forward with CK-two seventy four. And while our pipeline advances and our organization develops, we're going to be keeping a keen eye out for other assets.
And we know that the promise of our R and D engine led by Fady Malik is going to develop more than the 4 molecules that we have in the pipeline today. And all this is done with the patient in mind. So we hear Linda and Lindsay very clearly. Let's take a closer look at our pipeline. So for the last 20 years, we've become experts in sarcomere modulation.
We can dial up or dial down. When we dial up, we develop activators like omicamtiv mecarbil, which is in Phase 3. One of the largest heart failure studies ever done and the largest heart failure ever done in North America. And that's followed by AMG 594. In terms of inhibition, when we dial down contractility, CK-two seventy four that you heard a lot about is also followed by CK-two seventy one.
These are big markets that we're playing in. Currently in HFrEF, there are about 3,000,000 patients in the United States. And in HCM, there's about 600,000. And there are no FDA approved products in HCM today. That's going to change.
And so we hope to have next generation HCM molecules and a 1st generation, 1st in class myotrope called omecamtiv mecarbil. And the promise of our pipeline goes beyond those 4 molecules we just talked about. You can see here we have HFrEF, BoxChecked, HCM. We're also going to pursue programs in HFpEF, other cardiomyopathies, RVD. And we have a skeletal muscle vertical, which is unique in the industry.
And we think the convergence of that is going to help cardiovascular patients suffering from comorbidities such as frailty and muscle weakness. So what we're doing is taking the best of medicine, applying our unique quantitative measure approach to develop a rich, robust pipeline to improve patient health span. We firmly believe that the best medicine does not reach its full potential unless we can get it to the patients. And you need a commercial organization to do that. We're lucky enough to be working with Amgen, a world class company.
And our focus today is to build a commercial organization that fully optimizes Omecamtiv Makar bill. There's about 6,000 institutions and centers of excellence in the United States. We're going to focus on top of that pyramid. Those leading accounts, they account for about 75% of HFrEF patients and 78% of HCM patients. Let me state this a different way.
When one of our key account managers drives to a key institution, let's say Duke, where Doctor. Hernandez and Doctor. Wang practice. She will come out of her car and go into Duke Hospital and detail physicians treating Hefrath, then go to a different part of Duke Hospital and detail physicians regarding HCM without ever getting back into her car. That's the nice synergy that we have in our 2 advanced molecules.
And so we're building today to take advantage of our pipeline going forward. Now we've talked a lot about expertise today. And I think our expertise in muscle biology has attracted all the experts that you've heard from this morning. And I mentioned about the 10000 hours. And I'm going to turn this over to Robert Blum, who's been here for all 22 years, who's an expert in leading cytokinetics, but also a wonderful leader.
Robert?
Thank you, Durga. Thank you for those kind words. I will make some closing remarks, and I want to thank our audience members for sticking with us through this program. This is a program that speaks to a lot of science, also how we're thinking about building our business and where we're going from here. And I want to see if I can end in many ways the way we started by connecting the dots for you, connecting the dots for a company that has articulated and has discipline to a vision 2025, a vision that has us over the next several years bringing forward medicines from our innovative R and D that are 1st in class or next in class, but potential best in class opportunities to significantly improve the lives of patients who are suffering from diseases associated with severe cardiovascular weakness or muscle dysfunction.
Again, a reminder that how we do that matters. We need to make certain that we're doing that in the context and within an envelope of building a valuable sustainable pipeline, a durable business relying on cash flows that are predictable and ensuring that we leverage our partnerships, so we don't end up in a be careful what you wish for scenario with approved drugs that we can't afford to commercialize. Also key mantra to how we do this is that we must make certain that we're constantly hearing from the patients what matters to them, how should we be designing our clinical trials to accommodate their interests and also that being a core value of the company, we'll ensure that our patients and our employees are aligned to the mission of the company. And we want to make certain always that we're building that company that people with shared values want to come to work for. So that's the vision.
Now I would like to transition to sort of a way of looking at the company from a snapshot standpoint. We're up to the challenge. If you think about this company and many of you in the audience are investors, if you think about this company from an investment standpoint, one key pivotal clinical trial expected to read out later this year, The results of GALACTIC are expected in Q4. 2 pivotal trials we expect to begin next year in 2021 for other programs. We have the potential for 3 FDA approved medicines from our own research organic to our own discovery over the next 5 years.
Currently, we have 5 clinical stage programs. We hope to double that to 10 over the next few years, continually relying on our ingenuity, our innovation and building out from the mechanics of muscle contractility to the energetics growth and metabolism of muscle and maintaining adherence to our muscle biology focus. We're looking at programs that address high unmet needs in large prevalent populations, populations of patients measured in 1,000,000 in the case of heart failure in this country, the number one reason why people over the age of 65, people on Medicare are hospitalized. We need to do a whole lot better in treating these people and keeping them alive out of the hospital. You heard about HCM and how there are no FDA approved drugs available today.
We hope that will change soon, but there's plenty of opportunity for new innovations, new medicines to expand and to extend the category, not just in obstructive disease, but also in non obstructive disease and how that might translate to patients who are afflicted with hypercontractility associated with FFF. All of these things speak to our continuing investment in research and development. Ours is a company that's up to the challenge. We're only 175 people, so we're small in size perhaps relative to other companies, but we're big on conviction. You see our cash as of the end of Q1.
That cash balance is more than doubling with the access to capital we announced yesterday, over $250,000,000 committed capital that could be available to us for the partnerships we announced yesterday. And still on top of that, we're eligible for over $1,000,000,000 in cash milestone payments based on our existing partnerships as they mature both on pre commercial and post commercial events. And in addition, as you heard, we've retained key rights, responsibilities and economics in collaboration with Amgen, where we earn a roughly 20% royalty on sales of Omecamtiv worldwide, and that's enabling of us to build our business on a solid financial platform around which we'll take forward CK-two seventy four and other products ourselves as we expand our cardiovascular franchise. So putting this all together, what you've heard about is a company that's focused to the faithful recapitulation of biology, the biology of biomechanical muscle function. We're relying on high fidelity quantitative measures of cardiac performance.
We're ensuring very careful methodical approaches to clinical research always anchored in an understanding of the pharmacokinetics and the pharmacodynamics of cardiovascular performance. We're testing for highly predictive clinical trial outcomes in increasing ways as we advance clinical studies. Omecamtiv is the subject of over 18 clinical trials already completed while we now await results from GALACTIC. And we're focused not only on disease burden, but also importantly as you heard from Scott, the economic burden associated with these diseases incredibly important from a societal standpoint. We're striving for things that matter to physicians, but also payers and also very importantly patients.
How we do that, how we move from an R and D focused company to a sustainable commercial business requires that we leverage our partnerships and we do that in a way that produces reliable, sustainable, growing cash flows. We need to avoid, as I mentioned a moment ago, the be careful which you wish for scenario where a company gets an approved drug, it can't afford to commercialize it or can't afford to do that profitably or reliably or sustainably. And that's why we've built out a portfolio that enables a franchise strategy. Organizations like ours need to always be self aware. We have to focus to those things we can do.
It's why we for 20 years focused to one narrow slice of biology, but we know it better than anybody else. And as we extend that from research to development and then to commercialization, we have to be leveraging good science and always continually to innovate to address market driven needs. As Durga said, good companies have done that well and they built franchises that can scale on their science, but address the evolving market needs. And we need to be able to do that not just with our first product and its first indication, but with lifecycle management and with other products that follow behind it. At the end of all of this, it's essential, it's imperative, it is absolutely quintessential to our business that what we do is in the interest of patients.
Marty put it very well when he said that what you can do to improve how patients feel and function will ultimately define category leaders. And we're in a position to do that not only in terms of clinical trial outcomes, but things like exercise, function, capacity, endurance and stamina. And that way it reads not only on things that patients don't necessarily think about, but which could come back to haunt them, but also what they do think about quality of life and activities of daily living. So I'd like to end on that note. I'd like to end on the note that what we do, why we do it is most importantly for the patients that will stand to benefit.
And with that, I'd like to show a quick video. My dad taught me a very significant lesson when I was 7 years old. Whatever you do, you give 100% of that. And I've applied that through my whole life, including when I was diagnosed with heart failure. 50% of the people die within the 1st year of diagnosis and another 50% die within the 1st 5 years of diagnosis.
There is no cure at the present time. So the best you can do is to do everything you need to do to give yourself the best opportunity to continue living. I think that video captures very nicely why we're doing what we're doing and how we'll go about turning that into a sustainable and scalable growing business. I want to thank all of my colleagues from the management team, all of our expert physician and patient panelists and also all of you for attending this program today. Hopefully, you learned a lot about our company and what we're doing and why this might represent for you an important investment opportunity.
With that, thank you. We can take this meeting and call it a close.