Okay. I want to thank everyone gathered here today, and also those who have dialed in and are viewing the webcast. Today marks a turning point and the beginning of an exciting new chapter in Cytokinetics' story of initiative and innovation, persistence and promise, productivity, and purpose. We're pleased to have announced this morning the details of an expanding pipeline of first-in-class and potentially best-in-class programs. These novel approaches have been designed to address some of the most devastating and costly diseases of muscle dysfunction, a result of our expertise and pioneering leadership in the pharmacology of muscle biology. My name is Robert Blum, and I'm the President and Chief Executive Officer of Cytokinetics. I'm very happy to have you join us today.
For the webcast, for you.
For those of you who have known us over the years, we hope this is an opportunity to see Cytokinetics in a fresh light. For those who are new to our story, we hope to share with you our pioneering science, and that is producing investigational medicines to modulate the sarcomere. This, combined with our strategic partnerships in which we retain key favorable rights, responsibilities, and economics, affords us a corporate development strategy that addresses large patient populations with great unmet need, as well as severe rare diseases for which few treatment options exist, and that provide altogether a compelling rationale for investment.
As we take you through our robust discovery, translational, preclinical, and early clinical expertise, as well as our advancing late-stage clinical development programs, we ask you today to consider with fresh eyes how you might view the company with these new options, as if we were a new company coming onto the scene that you're reviewing.
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Developing potential medicines, first in class and potential best in class, which represent these significant opportunities. With that in mind, I'm thrilled to introduce my colleagues who will be joining me for this program today and who'll be walking you through our presentations on the agenda this morning. As I go through these presentations today, I'll remind you we'll be making forward-looking statements. We point you to our SEC filings. We don't undertake obligations to update them and refer you to those filings. Cytokinetics is a company with a mission. It's a company developing muscle biology-directed potential medicines to improve the health span of people with devastating diseases of impaired muscle function and conditions of muscle weakness associated with aging. We're going to tell you a lot about that today with this agenda and with these speakers who I'll now introduce.
Dr. Fady Malik to my immediate left is our Executive Vice President of Research and Development. Fady and I started the company 20 years ago. It's his vision that we're prosecuting with the programs that you'll be hearing more about today. Andy Wolff, to his left is our Chief Medical Officer. Andy's the newcomer amongst this team, having joined us over 14 years ago. Andy is in his 15th year at Cytokinetics, over 30 years in clinical research in the industry. Brad, who you'll be hearing from later, he's depicted on this slide, has been at Cytokinetics leading our research, now research and non-clinical development. Brad's in his 17th year at Cytokinetics. There amongst just those first introductions, you get a sense of the pioneering expertise, the commitment, and the conviction amongst our senior leadership team. It doesn't stop there.
We continue to add talent, as you'll hear, in the form of Dr. Whit Tingley. Whit, who joined us within the last year with a distinguished career preceding his joining us at Cytokinetics, leading our research and development programs. Whit and Brad together will share insights in new programs emerging out of our research. As you'll see in the press release at your tables, we filed two new INDs in recent weeks, we'll begin phase I studies, as they'll elaborate for you. We're also honored today to be joined by leaders in both the neuromuscular and the cardiovascular areas, including Dr. John Day, who will be joining us by video. John is Professor of Neurology and Pediatrics at Stanford. He led the recent SMA study that you'll be hearing more about with reldesemtiv.
Here on the panel, Jackie Montes, Assistant Professor of Clinical Rehabilitation and Regenerative Medicine at Columbia University Irving Medical Center, and Dr. Jinsy Andrews, Assistant Professor of Neurology, Director of Neuromuscular Clinical Trials, also at Columbia University. Jackie and Jinsy will be available to answer questions pertaining to the ongoing clinical development of reldesemtiv in both SMA and ALS. They'll share perspectives and insights on the promise of reldesemtiv and other fast skeletal troponin activators in neuromuscular diseases.
We'll also be joined in the 2nd part of the program by Dr. John Teerlink, Professor of Clinical Medicine at the University of California, San Francisco. John is Director of Heart Failure at the San Francisco VA Medical Center. John has been involved with omecamtiv development from his academic perch for over 15 years, getting first exposure to this program when it was in pre-clinical research, and having overseen from the academic standpoint, the clinical development of omecamtiv for all these many years. He'll talk a lot about what is ongoing in phase III as he lends oversight to the conduct of the GALACTIC trial. We're also joined by Dr. Gregory Lewis. Greg is Section Head Heart Failure, Medical Director in Heart Failure Transplant Program, and Director of the Cardiopulmonary Exercise Testing Lab, Massachusetts General Hospital.
Greg will be the PI of an upcoming study that you'll be hearing about today from Whit and Fady and others, the 2nd phase III clinical trial of omecamtiv mecarbil. We're happy to unveil the design of that study at this R&D day today. John and Greg will be led into discussion with Fady, who will discuss opportunities and perspectives for a new generation of muscle biology-directed cardiovascular therapeutics that we are pioneering and leading through clinical trials. Before we dig into the rest of this agenda, perhaps it makes sense for me to share with you a little bit about why we do what we do, and with that, I'd like to play a video.
Why do we fight? We wake up every morning with a mission, a problem that needs to be solved. With a singular purpose at our core, we continue to push forward. Though our outcome is uncertain, as pioneers, we continue to chart our own course. We are dedicated, passionate, morally obligated to serve those in need, not because it's just, but because we're partners, and we are in this together. A journey can be arduous, challenging, and disheartening, but the people who fight every day are resilient, and we are, too. Although we may stumble along the way, we will not fall. We turn obstacles into opportunities, which paves the way for triumph. Why do we fight? Because you are our inspiration. You are our mission. You are worth fighting for.
Video was narrated by that patient you just saw there at the end. Her name is Sarah. She lives in San Francisco. She, like so many other patients with ALS, patients with SMA, patients with advanced heart failure, visit our company weekly, tour our labs, visit with our scientists, discuss programs with us, and their unmet need to elevate the patient voice, not only as an inspiration to the work that we do, but also to inform the best ways to conduct clinical research in order to translate the mechanistic science that we have pioneered into outcomes assessments that make a meaningful difference to patients and caregivers, and can read on the potential efficacy and safety as we move forward for these investigational medicines. On this slide, you see our pipeline.
Make no mistake about it, Cytokinetics has pioneered the area of muscle biology and muscle pharmacology over 20 years of research and development, resulting in a pipeline of first-in-class and potential best-in-class investigational medicines depicted here. We divide our pipeline into two verticals, cardiac muscle and skeletal muscle. As you can see here, this pipeline, this portfolio of drug candidates, is comprised of compounds discovered at Cytokinetics that are advancing in clinical trials. Omecamtiv in phase III, reldesemtiv in phase II, potentially moving to phase III. Two new compounds that we're announcing today, AMG 594, a first-in-class cardiac troponin activator discovered under our collaboration with Amgen, and CK-274, a potential best-in-class cardiac myosin inhibitor, both of which have been the subject of recently filed INDs, both of which we expect to be entering phase I this year, in this current calendar quarter.
We also continue to conduct leading and pioneering research, not only in the contractility of muscle biology, but also as pertains to energetics growth and metabolism of muscle. That's being conducted under a collaboration with Astellas and independent of Astellas in our laboratories. As we have already seen evidence of our ability to move and prosecute programs from research into development, we expect that continuing research to continue to yield new drug candidates. Recently, we announced the advancement of yet another fast skeletal troponin activator depicted on this slide. You can see CK-601 moving in IND-enabling studies under our collaboration with Astellas. Today at this R&D day, we're going to be principally talking about omecamtiv mecarbil, reldesemtiv, and these two new compounds, AMG 594 and CK-274.
They represent for us five development programs in clinical development or in pre-clinical development, all advancing through to important milestones over the next year. You see them depicted here. Reldesemtiv, we'll recap these at the end of the presentation, already the subject of a positive phase II study in SMA, will read out new data in an ALS trial that will be concluding enrollment soon and reading out first half next year. The CK-601 advancing in IND-enabling studies. Later stage omecamtiv mecarbil, the subject of GALACTIC, as you'll hear, concluding enrollment in the first half of next year and moving through a first interim in that timeframe. Also starting a new study that you'll hear about today called METEORIC. That'll be the subject of a presentation you'll see in a moment. Also AMG 594 and CK-274, both advancing in phase I.
You'll hear about all of these today. With that, I'd like to turn it over to my colleague, Fady Malik. Fady, as I mentioned, leads R&D at Cytokinetics, he'll share with you the expertise, the pioneering leadership that brought us to this pipeline and set the stage for how that translates into ongoing clinical research.
Great. Thank you, Robert, good morning, everybody. Thank you again for coming. It's really a privilege to stand here today representing my colleagues, so many of whom are back at home, and our academic collaborators, many of whom we've worked with for many, many years together. Today, we're going to discuss a therapeutic space which we conceptualized, the science we pioneered, and which now has produced a portfolio of development programs stretching from phase I to phase III. It starts with a fundamental premise that muscle is a therapeutic target. It's relevant to a number of diseases that have tremendous impacts on people's lives. We probably take it for granted what our muscles do every day.
Cardiac muscle, which obviously pumps blood to all the different parts of our body, skeletal muscle, which provides us the ability to move and pick up our cups of coffee, and smooth muscle, a muscle type that we don't often think about but is essential for regulating blood pressure, working in our GI tract and in our lungs. All of these basic physiologic functions map onto a variety of therapeutic applications, some of which you'll hear about today as we've advanced modulators of skeletal muscle and cardiac muscle function that may be applied in these areas. Muscle is a complex tissue. It's really a machine that's been elegantly engineered to convert energy into force and movement. It has many different compartments that sequester calcium, compartments that produce energy, the tremendous amounts of energy that muscle uses.
At the center of all that is a structure called the sarcomere. The sarcomere is an elegant example of one of nature's bio-machines. It's shown here pulled out of a muscle fiber. What I'll talk to you today, and many of you have heard this for quite some time really, is what we've done at Cytokinetics to pioneer the application of modern drug discovery and therapeutic application to this biological structure, the sarcomere. To start, I'm going to first explain and show you what the sarcomere is. This protein machine that you can see here in the movie is composed of thin filaments, here in blue, that act as roadways. These thin filaments are decorated, covered with what's called a regulatory complex. That regulatory complex governs the interaction of the thin filament with the thick filament. The thick filament containing the motor myosin.
Myosin is the engine of the sarcomere. It hydrolyzes the energy source ATP and converts it into mechanical movement. As you can see, when calcium is released inside of the muscle cell, either with nerve input or the beginning of a heartbeat, that calcium binds to the troponin complex. It moves out of the way a protein that is blocking the interacting sites for myosin and that thin filament, and myosin can then bind to the thin filament, the actin filament, and pull on it and cause the sarcomere to shorten. That biological structure, as you can tell, is very complicated in the way it's put together and how it functions. It's elegantly been developed into a number of different systems that we've applied to finding novel modulators of sarcomere function. This includes the ability to take the sarcomere apart and reconstitute it from its fundamental protein elements.
We can also study the sarcomere in the context of a native muscle fiber or intact organs or tissues. There are a number of ways we can assay muscle function in vivo. One of the beauties of muscle is that its function is so highly conserved from animals to humans. Biology translates with high fidelity and coherence. We've, at Cytokinetics now for many years, have refined the ability to interrogate muscle to understand not only its function at a basic level, but also how the small molecules that we've discovered, how do we optimize them and modulate the function of the structure in ways that might be therapeutically relevant. It starts with an assay that we developed several years ago. It's a reconstituted sarcomere. In this assay, we purify the essential components of the sarcomere that I described earlier, actin, the myosin, troponin, tropomyosin.
In doing so, we can reconstitute them into a system that allows for interrogating the biology and high density plates, which are filled with compounds that can be potential modulators of its function. As you see here, an activator increases the slope of the bio readout in this well, or another compound that slows the activity and inhibits the function of the sarcomere. We've screened over 17 million compounds over the years in this assay. That's a remarkable number. With very good reproducibility from year to year, and it serves as the engine, not only for discovering novel chemical matter that we can go on to optimize into the pipeline that Robert introduced, but also as the engine for optimization that helps us improve those compounds through iterative medicinal chemistry. It's sensitive not only to activators, but also inhibitors of sarcomere function, and it's complex.
It allows us to look at the function of this structure in a way that is agnostic, if you will, to how the compound may actually work, but gives us many possible modes of activity that we may discover. Biochemistry is great, but you also need to understand how your molecules may work in the context of intact muscle, intact systems, intact hearts, intact skeletal muscles. Again, over the years, we've expanded our range of expertise to measures of skeletal muscle function. Certainly, we're very expert in also measures of cardiac function. All of these things contribute to our understanding of the pharmacology of muscle. Coupled with that are a number of capabilities at Cytokinetics that complement this biology.
A team that you'll see has produced compounds that are well optimized and applicable to exploration in the clinic, a group that looks very carefully at how they might be metabolized in their pharmacokinetics in animals and in humans, as well as a technology platform under which much of this hinges. This is something that's built over years. It doesn't come together in a single year or even a single five-year period. The expertise here is something that comes together over many years. Now, again, as you'll see today, as we have an opportunity to discuss a little more about R and not just D today, has yielded two new molecules in our pipeline. Coupled with this, what we call a drug discovery engine, is also a deep understanding of the way these molecules interact with the proteins that they target.
Here depicted, for instance, is the myosin motor. Its crystal structure, which in collaboration with our academic collaborators in Paris, France, the Houdusse Lab, we recently crystallized with omecamtiv mecarbil bound to it. That gave us an idea, if you will, or gave us a conceptualization of how omecamtiv mecarbil interacts with myosin in a way that is relevant to its function in an intact sarcomere. I won't take you through this complex diagram, but it's just meant to illustrate the power of being able to couple science to what emerges from the clinic in terms of how these molecules are working and integrate them into a functional model. Similarly, for troponin, the structural biology coupled with an intimate understanding of what this molecule does to troponin, which is the calcium sensor in muscle.
It slows the release of calcium from muscle, as shown in the graph on the right, where the release of calcium from troponin, the rate of release, is shown in those curves. In the control setting, it's released much faster. In the green line there, in the presence of a troponin activator, that troponin activator has increased the affinity of troponin for calcium and hence slowed the release of calcium. A fundamental understanding of how these molecules work. There's an experienced team inside of Cytokinetics. As Robert said, some of the members he introduced today have been with us for a long time. There's also a broad scientific team with a tenure, senior scientific leadership there, greater than 10 years, across biology, chemistry, pharmacology, DMPK, clinical research, and so forth. Today, we're going to talk about the output of that research engine.
There are five molecules, as Robert said, in development. Three that target the cardiac sarcomere which an activator of cardiac myosin, an inhibitor of cardiac myosin, and an activator of cardiac troponin, shown there from top to bottom on the cardiac sarcomere vertical. Then two activators of fast skeletal muscle troponin, reldesemtiv and CK-601. It's not just enough to have discovered them, but in translating them into the clinic, you need to couple what you've learned preclinically and try to take advantage of those learnings in the clinic. You want to ensure that you've understood that the mechanism is translated into humans. You want to understand the PK/PD relationship. How does the exposure to the drug, is that related to the effect of the drug? You need to have assays that are relevant in humans as they are in animals.
This is one of the strengths of muscle, that the functions that we observe preclinically can be explored in the clinic as well. I'll give you two brief examples of that. In respect to our cardiac programs, we have the tool of echocardiography. This is an ultrasound of the heart. On the left, you see the beating of, in this case, a dog heart before, on the left, and on the right, after an infusion of omecamtiv mecarbil. I think it's easy to see that the heart on the right is contracting to a greater extent than the heart on the left. On the right set of videos is a picture of a human heart, and this human heart is not healthy. It is contracting very poorly on the left. This is a patient with heart failure in one of our early studies.
On the right, you can see that its function is improved after an infusion of omecamtiv mecarbil. The ventricle, which is at the top, is now contracting to a greater extent. The walls are thickening further. The size of the ventricle is smaller. The left atrium, which is down at the bottom, is also contracting to a greater extent. It's gotten smaller, which is usually an indicator that the pressures in the heart have gotten lower. Then the mitral valve, which is the gatekeeper between the two chambers, you can see on the left, it's hardly opening. That's because the flow of blood from the left atrium to the left ventricle is very little. On the right, it's opening much more widely as the blood flow has increased, in this case, approximately doubled.
Flipping the transducer 90 degrees, you see a cross-section of the heart in what we call a short axis. You can see, again, the ventricle contracting. The wall here is not contracting at all. It's actually getting pushed around by the other ventricle. After treatment with omecamtiv mecarbil, you see the ventricle thickening symmetrically, and this wall has regained some of its function. Those tools help us characterize how omecamtiv mecarbil works in a tremendous amount of detail in a beating heart, both in humans and preclinically. We can also similarly translate the effect of a skeletal muscle drug from the preclinical to the human setting. Here, in an assay where we stimulate a nerve to muscle, as you stimulate that nerve, the muscle contracts. You stimulate it faster, the muscle contracts to a greater extent.
What you can see on the left in the green bars after dosing with reldesemtiv is that there's more force that's produced at the lower stimulation frequencies, which is what you would predict based on the mechanism of action. In fact, plotted in a different way on the right, is a similar assay employed in humans that allows us to understand in great detail the pharmacodynamic/pharmacokinetic relationship and demonstrate that this mechanism of action has translated into humans. This enables the conduct of a very thorough and broad clinical development program. For three molecules that we've taken deep into development, tirasemtiv, reldesemtiv, omecamtiv mecarbil. We've conducted trials around the world, as you can see there, in phases I, II, and III. It's a deep experience the company has in terms of how skeletal and cardiac muscle-directed therapies are capable of being developed in humans.
Much of this work has been published in journals that have high impact. You can see there the logos of a number of journals where we have been fortunate with our academic collaborators to place this work, and I think it's a testament to the quality of work that Cytokinetics and its partners do. Just in summary, here we are today, a pipeline that we'll talk to you about in more detail now starting with reldesemtiv, going on to discuss omecamtiv mecarbil, and AMG 594, as well as CK-274. With that, I'm going to turn it over to my colleague, Andrew Wolff, who will take you through our skeletal muscle program in reldesemtiv.
Well, thank you, Fady. Fady has already told you how reldesemtiv works. It's an activator of troponin selective to troponin in fast skeletal muscle. It binds to troponin C and increases its affinity for calcium, and muscle contraction is associated with a rise in calcium concentrations inside the myocyte. When those calcium concentrations increase in response to neural input, it does two things that are important. It stimulates the enzymatic activity of myosin. You've already seen how the myosin heads pull on the actin filaments to cause the sarcomere to shorten. Calcium starts that activity, the myosin heads hydrolyze ATP into ADP and inorganic phosphate, and that initiates the power stroke, where the myosin heads reach out and grab onto the actin filament.
At the same time, when calcium is bound to troponin C, it causes this ribbon of protein tropomyosin to unwrap from around the actin filament and expose the specific binding site on the actin monomers for the myosin head so that the myosin can bind with actin in a tightly bound force-producing state. That's what reldesemtiv does is it enhances the ability of those actin-myosin cross bridges to form so that, as Fady said, we have more hands pulling on the rope, or another analogy that's frequently made, we have more oars in the water at any one time. The pharmacological consequences of that mechanism of action are at least threefold, and I'll go through them in a little detail. This slide shows one of the ways that you decide how much force your muscle's going to produce.
Obviously, your biceps need to produce more force to pick up a heavy suitcase than they do to pick up your cup of coffee. One of the ways that you tell the muscle how much force to produce is by the stimulation frequency. The faster the nerve fires, the faster the nerve is stimulated in the muscle, the more force will be produced, and you can just see that. In the presence of reldesemtiv, more force is produced at a given stimulation frequency, but in particular, at these low to mid-level frequencies, which is where we live our daily lives.
We're not usually trying to produce maximal force with any of our muscles, it's where patients with SMA and ALS also live their daily lives, at those low to mid-level frequencies, which is where the increase due to the effect of a fast skeletal muscle troponin activator is largest. Another consequence of this mechanism is an increase in power, which is not just how much force the muscle can produce, but how quickly it can produce it. If you're maybe about to fall over because you've been inadvertently shoved or something like that, you need fast production of force in your leg muscles in order to right yourself. Power is important as well. Not just how much force, but how fast you can produce it.
Finally, a consequence of this mechanism is to delay the onset and reduce the magnitude of fatigue that occurs during repetitive stimulation. Here you can see, and this would be consistent with repeated efforts. You fatigue, right? If you do something over and over and over, you're going to get tired. Here you can see in black that if we stimulate a muscle repeatedly, the force that it can produce decays and reaches a plateau at a lower level than the maximum. In the presence of reldesemtiv, the onset of that fatigue is delayed to some degree, and the plateau is at a higher level. There's a reduction in the magnitude of fatigue and a delay in its onset. These three things obviously suggest a variety of potential therapeutic uses for this mechanism.
Amplification of the response to motor neuron input suggests potential utility in diseases where neural input is limited and declining, like SMA and ALS. Increasing muscle power suggests utility in a variety of conditions that result in weakness and frailty, even normal aging, which is associated with a decline in muscle mass. To improve fatigue or to reduce fatiguability suggests utility in a variety of muscle and neuromuscular diseases, such as heart failure, which is associated with skeletal muscle defects, not just defects in the contractility of the heart. Chronic obstructive pulmonary disease, which is also associated with the skeletal muscle myopathy, in addition to the pulmonary consequences of the disease. Our neuromuscular program with reldesemtiv right now is comprised of two therapeutic areas, SMA, spinal muscular atrophy, and ALS. We've recently announced the data from the SMA study, which is diagrammed above.
The ALS trial is currently ongoing. We have a lot of experience in ALS at Cytokinetics. As you see here, we have done six clinical trials in patients with ALS, all of them double-blind, randomized, placebo-controlled. This doesn't even count some open label extension studies that have followed the placebo-controlled studies. Six double-blind, randomized, placebo-controlled trials, five with tirasemtiv, one ongoing with reldesemtiv. Those trials have enrolled almost 2,000 patients from around the world across 12 countries, more than 80 centers in those countries. You will know that our phase III trial of tirasemtiv in patients with ALS, which we called VITALITY-ALS, did not meet its primary endpoint of slowing the decline in slow vital capacity.
You can see that while patients on tirasemtiv did somewhat better with respect to the decline in vital capacity than patients on placebo in the solid line, it was not statistically significant, and the primary endpoint at 24 weeks was not met. This was largely due to the fact that a lot of the patients that were randomized to tirasemtiv did not tolerate it and didn't stay on treatment. Because it was a phase III study, we took, some may say, Herculean efforts to try to keep patients in the study, even if they were no longer on study drug.
Consequently, by the time we got to 24 weeks, particularly at the highest of the three doses, fully 20% of the patients who contributed a vital capacity measurement at 24 weeks for the primary endpoint were no longer on study drug and had not been on study drug for months. Literally months. If we look at the patients who did take the dose to which they were randomized and stayed on it, you can see that in fact, at the higher dose, which was 500 milligrams a day, so this is the average daily dose. Obviously, for someone to have an average daily dose over 437.5 milligrams, they would have had to have been randomized to 500 milligrams a day and to have stayed on it for most of the time, most of the duration of that 24 weeks.
You can see that the increase versus placebo was around 5%, which is close to what we saw in the phase II-B study BENEFIT-ALS, and a P value that was approaching nominal statistical significance. So if you could take the drug and stayed on the drug, you did benefit from the drug. But we really did have tolerability issues with tirasemtiv that I really believe we have solved with reldesemtiv. You've seen this kind of data already before. This is where we took healthy young men and stimulated the nerve that mediates dorsiflexion of the foot. Pull your foot up toward your head, measured the force of that dorsiflexion, and then expressed it in terms of the stimulation frequency.
We know that the faster you stimulate a muscle, the more it contracts, but also the effect of the drug to increase that contraction is greatest in these low to mid-range frequencies. I think one of the points of this slide is that you can see that reldesemtiv was able to increase the force produced relative to placebo to a much greater degree at any given concentration compared to tirasemtiv. So it's intrinsically a more potent drug. We got to about a 25% increase with tirasemtiv at most, but we got over 60% relative to placebo increases in skeletal muscle force production with reldesemtiv. With respect to the tolerability, because I've already mentioned I do believe we have solved the issue of intolerability with tirasemtiv. We have administered single doses as high as 4,000 milligrams, and even that wasn't really intolerable.
We stopped our single ascending dose study at 4,000 milligrams because we could see some mild dizziness that was beginning to increase in frequency. Even 4,000 milligrams was not intolerable. There was just no point in going any higher. We're currently conducting a study in patients with ALS we call FORTITUDE-ALS. The primary endpoint is the change from baseline to 24 weeks, I'm sorry, to 12 weeks, in slow vital capacity. Patients are randomized one to one, to one to one, to either placebo or to 150 milligrams twice a day, excuse me, 300 milligrams twice a day, or 450 milligrams twice a day. We're also measuring muscle strength. We're looking at the ALS Functional Rating Scale, and always, of course, adverse events and plasma concentrations of reldesemtiv. This study is ongoing at numerous sites across North America, Australia, and Europe.
We have enrolled 375 patients so far toward our goal of 440. We expect to conclude enrollment soon. CY5021 is a study in older children and adults with spinal muscular atrophy. It was done in two cohorts, a lower dose cohort of 150 milligrams twice a day, and a higher dose cohort of 450 milligrams twice a day. The design was intended to randomize an equal number of ambulatory and non-ambulatory patients. We didn't quite meet that goal. It was intended to enroll twice as many patients on reldesemtiv as placebo. We roughly did accomplish that, as you can see. Baseline demographics were, I think, typical for this kind of population. We had an average age in the upper 20s. About a third to a quarter were under 18 years of age. The majority of our patients were SMA Type 3.
A few were Type 2. Type 4 patients were eligible. We screened some. None of them actually met the entry criteria to enroll. You can see, I think most remarkably, the six-minute walk distance was around 300 meters at baseline. Forced vital capacity was around 85% predicted. Here you can see the various outcome measures arranged in a forest plot. This is the line of no difference. Point estimates to the right side of the line of no difference favor reldesemtiv. You can see the maximal expiratory pressure, which we believe is related to the cough peak flow, which is important for clearing secretions and potentially avoiding pneumonia, was significantly affected at both the low and the high dose.
The six-minute walk distance was borderline nominally statistically significant with what I will suggest to you is a highly clinically relevant increase of around 25 meters in the high-dose cohort. Here we look further at the six-minute walk distance. You can see that the change from baseline over time was clearly dose-related. The forest plot here shows each individual patient and how they stacked up. You can see that at the higher dose, there were some substantial increases, several moderate increases at the lower dose, and patients on placebo, with the exception of this guy here, didn't do as well. Several of them actually had a decrease in their six-minute walk distance over the course of the study. The change from baseline in six-minute walk distance was related to the concentration of reldesemtiv. Here on the x-axis, you can see the peak concentration.
Clearly, as concentration increased, so did six-minute walk distance. We've seen this before, again. Based on the data that we generated in this study in healthy volunteers, we expected at the low dose to have concentrations in the 1-3 microgram per milliliter range in the low-dose cohort and about triple that in the 5-7 microgram per milliliter range in the high-dose cohort. But as you've just seen, we didn't really get there. We only got to about 5 micrograms per ML at the very highest and on average, really only around 3, a little higher than 3 micrograms per ML in the high-dose cohort.
We believe that's due to a change in the formulation between what was studied in the healthy volunteers and the suspension that we used in the patients with SMA, and we intend to investigate that to see if we can increase exposures in patients with SMA because it would appear that we could have gone higher to potentially greater clinical effect. As you can see here, the drug was very well-tolerated. While there were a lot of adverse events, as is typical, there was really no difference from placebo, and there was no adverse event that was particularly clearly related to treatment with study drug. In fact, I think it's interesting that fatigue actually appeared to be less frequent on reldesemtiv relative to placebo. Interestingly, this increase in the six-minute walk distance persisted Beyond treatment with study drugs.
The last dose of study drug was at 8 weeks. 4 weeks later, you can see that the dose-related increase in six-minute walk distance was persistent to about the same degree. We don't know for sure why this is. We have seen similar effects with risdiplam in BENEFIT-ALS. The slowing of the decline in vital capacity that was evident after 12 weeks was still evident 4 weeks after the last dose of study drug. This isn't the first time we've seen something like this. It may be due to an increase in muscle mass because the patients benefit from the pharmacology to make their muscles stronger, so they do more. So maybe they build some muscle mass, and the effect of that is persistent after 4 weeks. It may also be due to improved recruitment of motor neuron units. We don't know, but the phenomenology is fairly clear.
Another thing that we saw is that as six-minute walk distance increased, disease burden as assessed by the SMA Health Index, which is a patient-reported outcome measure, decreased. For the SMA HI, as we abbreviate it, lower scores are better. They indicate less disease burden. The correlations for all the domains of the SMA HI and the overall total score were negative, which is good, meaning that as patients could walk further, their disease burden fell. That's a good thing. You can see that some of those associations actually achieved nominal statistical significance, including the total score. We believe that the results of CY5021 showed potentially clinically beneficial effects in these adolescents and adults with SMA, and primarily as evidenced by increases in the six-minute walk distance and in maximal expiratory pressure.
A measure that correlates closely with cough peak flow, which is probably related to the ability to clear secretions and remain free of pneumonia. As I've also already mentioned, I think we need to see if we can increase the exposure in patients with SMA by administering higher doses because we saw no evidence of an efficacy plateau. 450 was clearly better than 150. Higher concentrations were better than lower concentrations. We didn't see any evidence of a plateauing effect. There was no dose-limiting toxicity to preclude us from going higher. We know from healthy volunteers that when we were able to achieve higher exposures, we also saw greater pharmacodynamic effects, and those concentrations were also very well tolerated. Six-minute walk distance, I believe, is a validated endpoint. It's clearly an approvable endpoint. It's been used to approve a number of drugs in the U.S.
Importantly, the magnitude of the effects that were used to approve these drugs is similar to the effect range that we saw with risdiplam. We saw 25 meters overall at the high dose, and in fact, if we looked at the highest concentrations, we saw even a greater increase in distance than that on the range of around 40 meters. We have with us today Jackie Montes , who really is an expert on six-minute walk in SMA, and we'll talk with her about that in just a few minutes. It clearly captures disease severity and demonstrates the required properties, reliability, and validity in order to be used as a primary endpoint. I think that we'll go forward almost surely using six-minute walk as a primary endpoint in further studies after we confirm that with regulatory authorities. I'm optimistic they will confirm it.
As you've seen, it's been used before to approve other drugs. I think this is important because, as we've just heard very recently with an advisory board of experts in SMA from across Europe, the number of ambulatory patients is going to increase as more and more patients are treated with SMN-directed therapies like nusinersen. These type 1 babies who would have died before nusinersen survive, but they survive with substantial weakness and other disability. They're not normal, and we heard that loud and clear. They have trouble swallowing. They have trouble doing a variety of different things, but they're alive, and they're going to continue to grow and survive. The need for a muscle-directed therapy that can add to the benefits of nusinersen, I think, is very clear, and you'll certainly hear that from the experts.
Now we have a video that features our lead investigator on CY5021, Dr. John Day, and we'll play that now.
People ask, "Do you have SMA in your dreams?" I do. It is 100% of the time I think about it because I have to. I was diagnosed with SMA type 3 at 12 years old. I knew the outlook wasn't that great. The biggest struggle about having SMA as an adult is every single situation during the day. There is nothing easy about it. The second that your independence is diminished, it compromises a lot about what you are able to do and the mental toughness that you are able to create on a day-to-day basis. Two years ago, I really wanted to start exploring what the options were.
I have been taking care of neuromuscular patients with problems of nerves and muscles, for more than 30 years. A great deal of that was spent involved in clinical trials. In terms of the results of the reldesemtiv trial, what they did show was that when we get to a high enough concentration in patients, we can see some improvement in terms of stamina, for instance, so that patients have to exert less energy to generate the requisite force that they need.
I definitely had more stamina. I travel a lot, and the biggest place I noticed that was when I would walk to my gate. It was exciting to feel like, you know what? There is a little bit of help here. Having a degenerative disorder your entire life, and you are used to losing 5% every year of your strength, to feel physically for the first time that something was actually propelling you just a bit in the other direction, it is a cool feeling.
I would really like to go back into clinical trial with reldesemtiv so that we can explore the dosing, get the concentration up to the level that we know that people can tolerate, and that we can maximize the effect that we are seeing. I think that we can benefit patients with a number of different levels of capability of spinal muscular atrophy by complementing reldesemtiv on top of these different gene-modifying treatments. It is not just improving six-minute walk distance for patients who are ambulatory. I am very excited about the possibility that we can increase the function of patients with all levels of ability, so that they can talk longer without getting tired, so that they can move their hands more, as well as those who can walk longer without getting tired. I do think there is a tremendous potential value for reldesemtiv.
Right now, I'm currently taking SPINRAZA, which I have showed really good results over the past 12 months that I've been on it. If I could accent that with something like reldesemtiv, that would be extremely powerful. Just feeling a little window of hope can make such a tremendous difference, and I want to take that difference and turn it into something really beautiful in this world, in my life, connected to a deep purpose.
There's a lot of hope for the future. This has made a tremendous splash in my world, in the world of neuromuscular disease, and of neurodegenerative disorders more generally. This is awesome. It really is an exciting time.
Thank you, John, in absentia. Now we're going to have a little discussion with two of our experts who are here, Jackie Montes and Jinsy Andrews, both from Columbia University. Let me start with you, Jackie. You just heard Dr. Day and the patient talk about the promise of using reldesemtiv in older patients. I've mentioned that you have written a lot on six-minute walk distance in patients with SMA. Can you comment on the validity and the utility of that measure in these patients?
Sure. Thank you, Andrew. Over the past 10 years, we've had a pretty broad experience with the six-minute walk test in the SMA community, and not only here in New York at Columbia, but worldwide. What we found is that it's quite a valuable assessment of walking ability or just functional ability, as well as a measure of an endurance. In fact, it's so useful it's like taking blood pressure for your cardiac patients. Anybody who walks who comes into an SMA clinic usually does a six-minute walk test. What we found is that not only is it representative of a clinically meaningful activity like Chris had highlighted there, walking in the airport, walking in school, walking in the supermarket. It also happens to capture fatigue, and fatigue is a prominent symptom in SMA, as we all know.
This opportunity to quantify that symptom and then potentially measure it with intervention is quite valuable.
Okay, thanks. We've been asked a lot about the Hammersmith scale, which is commonly used in SMA, and in particular, in the very young patients to assess functionality. We didn't really see an impact on that scale despite the increases that we did observe in six-minute walk distance. What do you think about that? Should we have expected to see them go in the same direction?
I don't think so. The Hammersmith scale, while there's no ceiling for ambulant patients, those last few points to achieve at the higher end of the scale are quite difficult to achieve. In fact, even in the disease-modifying therapeutic trials, we didn't see any changes in the ambulant population, and the expanded Hammersmith then had to rely on the six-minute walk test for that. I'm not at all actually surprised. They're actually quite big jumps to make.
We've heard that Hammersmith is more an assessment of mobility than of endurance.
Absolutely. It is absolutely not a measure of endurance at all. It's a measure of motor function, per se.
You would agree, perhaps six-minute walk is all about endurance.
Yes.
Let's turn to ALS. Jinsy, you've been involved in our neuromuscular program for a while now, both in academia before and after your time as a medical monitor with us at Cytokinetics. Why do you think reldesemtiv may be better than tirasemtiv in patients with ALS?
I think I have a slightly unique perspective because I did participate as a principal investigator initially back in 2010 with tirasemtiv in myasthenia and then the phase IIa study in ALS before becoming the medical monitor for the phase IIb study, BENEFIT-ALS, and then VITALITY. I should also point out that I was also the medical monitor for the single ascending dose for reldesemtiv in the phase I study in healthy volunteers. I think the perspective I have is the fact that we have data on the tolerability, and it's clearly different profiles comparing tirasemtiv and reldesemtiv. I think in tirasemtiv's case, both tirasemtiv and reldesemtiv have the same mechanism of action.
In tirasemtiv's case, as we saw the data from the phase III study, I think our ability to evaluate the primary outcome, which was slow vital capacity, was really clouded by the tolerability issue. As Andy pointed out, I think in one of the slides, a majority of the patients that contributed to that primary endpoint were not on drugs. The analysis was an intent to treat analysis. If we can't keep the patients on drug, then we really can't truly assess the efficacy. I think this is where reldesemtiv carries an advantage. It's the same mechanism of action. In the phase I study in healthy volunteers, I have to say we did write the protocol to dose up to 4,000 milligrams.
Even though we were able to go all the way up to the maximum dose, I don't think we really hit the maximal tolerated dose. Although there were reports of dizziness, I had the ability to talk to the investigator to give me the characteristics. It really is different than what was reported with tirasemtiv. Patients with tirasemtiv really had a lot of lightheadedness, dizziness that contributed to their inability to continue dosing. Whereas some of the very minimal few patients that did report it at the absolute maximum dose at 4,000 milligrams really didn't have that lightheadedness feeling, and it wasn't something that bothered them and really was associated with almost moving per se, almost like we were over-activating muscles. I think there's a clear difference in tolerability. The anticipation is that I think that reldesemtiv would have an advantage in ALS.
Do you think that the relatively encouraging results that we saw in our SMA phase II study portends good things for the outcome of the ALS trial that's currently ongoing?
That's a little bit of a tough question. I think one of the main points we can take from, because the diseases are essentially different. What we can take from the SMA study is that what we saw in the series of phase I studies in terms of safety and tolerability was kind of recapitulated in the SMA study. I think the tolerability aspect we can anticipate that we will see improved tolerability in the ALS study. In terms of efficacy and outcomes, I think it's hard. If we saw an effect on six-minute walk in the SMA study, we can hope that some of the functional assessments like the ALS Functional Rating Scale or the muscle testing might show some signals. One difference is that in the SMA study, we dosed 150 and 450 b.i.d. compared to placebo, but we're testing an additional dose of 300 b.i.d.
I'm hoping that we'll get the upper end of the concentrations and maybe anticipate more of an effect.
In our patients with SMA, we saw an improvement in maximal expiratory pressure, but not in forced vital capacity, while slow vital capacity is our primary endpoint in the ALS trial. What do you think about our chances for seeing a slowing in the decline in vital capacity in the ALS trial, given the data that we have just presented in our patients with SMA?
That's me?
That's you.
If you look at the tirasemtiv data from the phase III study, if you look at the people who completed dosing, you can see at the 500 dose level, there was a difference that looked similar to what we saw in the phase II study. I think the tolerability was an issue. I think maximal expiratory pressure, I've done a lot of work in respiratory measures in neuromuscular disease. You can't expect all of the respiratory measures done in their different ways to behave similarly. Maybe I can have Jackie talk about maximal expiratory pressure versus forced vital capacity in SMA, but I think based on what we saw in the VITALITY study, phase III study in tirasemtiv, I anticipate that if we're able to keep patients on drug and follow them for 3 months, we should see an effect.
Jackie, do you have anything to add?
Sure. In ambulatory SMA, forced vital capacity is normal. I think that's pretty widely accepted. In an ambulant SMA patient, we don't even consider forced vital capacity. The maximal expiratory pressure has to do with muscles, including diaphragm, but also including the core muscles and abdominal muscles, which are uniquely weak in SMA patients, even ambulant SMA patients. I think that the findings that we've had in the phase II trial represent perhaps an impact on those core muscles that are uniquely affected in SMA, but I don't expect FVC necessarily to change in an ambulant population.
Thank you. Before we break, are there any questions for any of us from the audience?
Good morning. Charles Duncan with Cantor. Appreciate all the kind of color this morning on what you're up to. Some pretty interesting things going on. Wanted to ask perhaps the KOLs, Jinsy or Jacqueline, about two things that I'm wondering about. One is about reldesemtiv in SMA, and the other is reldesemtiv in ALS. What I'm really trying to gauge is what should be the next steps in terms of SMA and when you would like to see those next steps. Maybe from a company standpoint, what are the kind of rate-limiting components of those next steps? That's in SMA. In ALS, I'm really wondering whether or not the dosing is sufficient. I know, Jinsy, you suggested that if you can keep patients on and the drug is tolerable.
Do you think that the formulation changes that may have impacted SMA and the ability to really perhaps dose or get to the exposures that you wanted to get to, is that going to be an issue for the ALS study?
Well, I'll start, and then I'll ask my two colleagues to give their views on the questions that you've asked. In terms of rate-limiting steps, one thing we do need to do is to explore how much we can increase exposures with the formulations we have by increasing the dose. We know that the current formulations do not achieve dose proportional increases in exposure, and it appears that limitation of exposure gets a little worse as we go higher and higher. We'll need to explore that. It may be that we'll need to wait for another formulation that is currently being investigated, and we're working on it now, but it won't come as quickly as perhaps we might have liked. We also have to consider our partner, Astellas, and what they want to do with reldesemtiv.
That always adds a little complexity because these are not decisions we can make on our own. We do intend to move forward in SMA. Jinsy?
Yeah.
If I might just add a couple of comments on top of that. As we've guided, next steps will include the potential of exploring higher doses and dose proportionality, dose linearity around exposures with those higher doses, as Andy has pointed out. Also we want to ensure with regulatory inputs that six-minute walk distance, which was seen as having effect with reldesemtiv, is in fact acceptable to FDA as a potential registratable endpoint. We believe that in a hypothesis-generating study, we've seen a compelling dose-related effect on six-minute walk distance. We believe, as you've heard, that it's clinically relevant and meaningful, but we do need to make certain that it also represents a potential regulatory path forward. We and Astellas will be engaging with FDA in those conversations before the end of the year.
I think I can just comment on the dosing and whether we're going to get to the exposures that we need to see some sort of a signal in ALS. I think if you go back to the slide or think back to the slide where you're looking at the concentrations compared in the healthy volunteer study, where we're looking at the tibialis anterior, the dorsiflexion of the foot, the maximal contraction is achieved with reldesemtiv in the five to six and seven range of concentration. The effect that you see is much bigger than in tirasemtiv. Even if we may not get to the optimal exposures or where we want to be, I think even given the doses that we're testing now, we probably will see more pharmacodynamic effect than we would, say, with tirasemtiv at those doses.
If you look at the graph side by side, the effect is much more potent with reldesemtiv at the lower concentration.
I'll just add on. I'll just add to that, as she said, in the mid-range of exposures with reldesemtiv, you see an effect that meets or exceeds what we saw with tirasemtiv. Again, with tirasemtiv in ALS, I think we have a clinical signal there in terms of the slowing of vital capacity. We think both of those things portend well for seeing the primary endpoint be met in FORTITUDE. Obviously, we'll find out when we get to that point. I think the effects or where we are in the concentration response relationship should allow us to see that.
This is one of the hallmarks of Cytokinetics' longstanding and pioneering expertise in the R&D of muscle pharmacology. It's essential to understand
dose exposure and pharmacokinetic pharmacodynamic relationships. That's not something that one could hustle through and move rapidly without understanding those intricate relationships. Throughout all of our programs, not only with respect to fast skeletal troponin activation, but also cardiac muscle, as you'll hear in the next section, we believe that PK/PD relationship is a signpost that affords us the understanding from discovery through preclinical research, translational, and into mid and late-stage clinical trials. With tirasemtiv, there was clearly a signal, albeit confounded by tolerability. With reldesemtiv, we think we've solved for the tolerability issues, and we have an opportunity now for understanding the PK/PD relationship to move higher in the dose response curve, as may afford us an opportunity to maximize an effect on six-minute walk distance. Like any other research, clinical research requires one to take a walk through these kinds of understandings, building on prior observations.
In this particular case, I think in this hypothesis-generating, signal-generating study, we've seen something quite compelling that we believe now requires further testing and amplification.
Jackie, go ahead.
Last question. I'm sorry to just ask a bunch of questions, I guess I really want to know is, at the end of the day, for next year, if you had to guess, as I have to guess, could you be in a pivotal program in SMA with reldesemtiv?
Yes.
Thank you.
Sure. If I could add, being in the trenches and being a clinical researcher and a clinician, and having direct contact with this patient population, they are craving this treatment or a treatment to manage their symptoms. This chronic population is really in need of treatment. At the same time, I think we're very uniquely positioned in SMA with a really extensive experience with six-minute walk test in this population and published literature, and an understanding of it that we're uniquely positioned to test the effect.
Jackie, you've obviously been the leading force in understanding the test-retest reliability and fidelity of different endpoints, especially in adult ambulatory patients. Can you elaborate a bit on what you've found in your research?
Sure. In SMA, since there's no cognitive compromise, these are very intact patients, and the six-minute walk test is highly reproducible and has great test-retest reliability because of that. Certainly, in any test that requires cooperation and understanding, the reproducibility can be compromised, but it's not the case here in SMA.
Yeah. Chad Messer from Needham & Company. One more question on six-minute walk in SMA patients. Is there a characteristic sort of pattern of decline like there is in other indications? If so, what are the implications for designing a trial that would have that as a primary endpoint?
Sure. I imagine your question relates to our ability to capture fatigue. What we know in the six-minute walk test is in a healthy individual, you go out the fastest at your first minute. You realize that six minutes is a little longer than you might have anticipated, and you might slow it down a little bit in the middle. Then inherent in the test, you know the goal is to walk as far as you can in six minutes. When the timer says, "You've done five minutes, you have one minute left," you have the reserve, the capacity to pick it up so that you get your best time. That's the perfect design of a test.
In healthy individuals, and in fact a lot of other diseases, the sixth minute is similar or even faster than the first minute, meaning that you have a reserve, a capacity to go farther. What we find in SMA is that the sixth minute is considerably slower than the first minute. We've reported that time and time again. In fact, we found that it might be disease specific, that we don't see it in other diseases that are diseases of weakness like Duchenne or mitochondrial myopathies and such. What happens in the middle, perhaps is in SMA, there's usually the steepest slope in the beginning, then it continues to get a little bit slower.
Sometimes the fifth minute is slower than the sixth minute, but the sixth minute. That's actually affirming to us because we then understand that the SMA patient understands what the task is. They just don't have the physical capacity to speed it up at the end. I hope that gives you a broader understanding of the six-minute walk test.
Do you normally see the total distance walked decline over time, or does it plateau?
You're talking about the disease progression?
Overall. Yeah.
In fact, we think of SMA as a largely stable disease, but in fact, it slowly declines over time with age. That slope of decline, let's say, over a year period, is dependent on vulnerable age groups. Adolescents, the slope of decline over a year is a bit steeper than in older age. It's still a decline over time. 10 years from today that your patient's going to be worse off on the six-minute walk test.
I think the patient in the video described it quite poignantly in terms of about, he felt like he was losing about 5% per year.
I think as Jackie described, it's really over a year. In a course of a clinical trial that might last three to six months, I don't know if you'd agree, but probably their function is pretty stable over that period of time.
Certainly. We've published that in an adult population, it's 9.8 meters per year. Probably goes to about 5%
Yeah.
A little bit more. An increase of 25 meters is beyond the statistical variability of the test and really is noticeable by patients in our population.
I think that's very helpful, but maybe to expand on that a little bit more, are there sort of baseline six-minute walk values that would be optimal for seeing changes?
I guess that sort of juxtaposed against the Duchenne experience, where you might want an optimal group. I don't think so. I don't think that there I would design a trial with a six-minute walk test criteria. The reason being is that when we start studying large cohorts, everybody's at about 50% of their predicted. There's some issues with normative data sets and comparisons, we take it lightly. In general, a chronic population is not normal, and a chronic population isn't going to lose ambulatory function in a short study. The short answer is no.
Just maybe to tie it to other, what does 300 meters mean? Which is kind of what the average you saw in SMA. When we talk later about our heart failure program, 300 meters is what a patient with Class 3 out of 4 heart failure, for instance, might be able to walk. Or a patient who's had hip surgery, elderly patient recovering from hip surgery, that's three to six months out from their hip surgery. 300 meters represents a significant disease burden, if you will, for these patients.
Fady, if I could tell you that a 5'10", 30-year-old male would likely walk 650 meters. It's just to compare that's a big difference.
I think, again, the video gave you a sense of just seeing how our patient there could move around his house. He was an ambulatory patient, but it clearly was not an easy thing for him just to walk down the hallway in his house or climb that one step that led to his front door. You may have noticed he had to lean against the wall and get one foot up over the threshold and then move over. Small differences in muscle function, we think can accumulate to making their lives easier in a lot of different ways, even than the six-minute walk captures.
Thanks for the illuminating discussion. Just a couple of quick questions. The first question is by George Zvaifler from B. Riley FBR. Your mechanism of action is unique. Are you worried at all in terms of drug interactions combining with any other drugs that are out there that are in development or already approved for either SMA or ALS?
Maybe I'll take that one. Just in regards to reldesemtiv, the drug interactions you can test in a number of different well-established assays preclinically. Reldesemtiv was designed from the get-go to not have any drug interactions because we anticipated it being applied potentially broadly. At this time, we don't think that there are any relevant drug interactions that we need to explore, and it should combine well with most mechanisms of action that we might see.
Also, as you know, not only in SMA, but also in ALS, there are a number of very exciting new modalities being evaluated that could offer patients great hope but for other mechanisms. In the case of reldesemtiv, we've developed an oral formulation and oral formulations plural, that afford us, we think, not only potential convenience for patients but also nice complementarity.
You mean going from BID to once daily?
I'm referring to BID dosing, I'm referring to the fact that as an oral therapy, whether it's administered as a suspension or a tablet, it should afford advantages for patients.
Some of these patients, over time, swallowing becomes very difficult. Swallowing pills, suspension is very helpful for them to be able to receive drug that way.
Are you looking for an extended release formulation down the line?
Not specifically. I think twice-a-day dosing doesn't usually represent a huge burden to patients' convenience.
I have a question about ALS in particular. There's a certain time limit within the clinical trials that they take the drug. Do the patients on it when they go off it, do you offer compassionate use? When they do go off it, what do you see with the decline in function?
In the VITALITY program, what we did when patients came off the drug is offer them a chance to go into an open label extension. In fact, even as now what we've transitioned all those patients that wanted to continue taking drug, even as we've suspended development tirasemtiv to enable them to continue to receive access to it through a managed access program. In the case of reldesemtiv, we don't have that option available yet. It's something that we certainly are going to consider and move to try to do in later stage development. At the time of designing 5021 and FORTITUDE, we hadn't yet completed all of the preclinical toxicology and so forth you need to do in order to enable chronic dosing.
Down the road, I think it's something that we would want to offer these patients as they transition off and to be able to examine the questions such as you asked.
To your point, it's worth noting that even as we've suspended the development of tirasemtiv to Fady's point, there are still quite a number of patients who insisted it's affording them some benefit, and we've made it available to them under Compassionate Access managed access program indefinitely.
I can add a little bit of color. I now am in the clinic and in the trenches, and so I haven't actually shared this with you guys. I wasn't involved. I was the medical monitor. You see the data, you see the coded terms, and you don't really have a lot of color when you're working in the clinical development side. When you're in the clinic, you get the actual flavor for what may be the patient's experience on the study. When the press release had come out about the suspension of tirasemtiv's development, certainly there were patients that were followed by other clinicians who found me in the hallway and really asked if they were able to continue with tirasemtiv in any way.
In addition, reldesemtiv study is a three-month study, and so I am very much knee-deep in the clinics for ALS, and I see a lot of patients that come from other facilities who may have completed the trials, and they too have similar feelings where they felt like they were stable and a little disappointed that they are not getting an open label extension. I'm hopeful that the company would consider that in future development.
Clearly, as we will commit to further development of reldesemtiv, we will have to address the needs of those patients who have participated in our clinical research and afford them opportunities to have access to reldesemtiv on a go-forward basis. I think what you are hearing is that there is great promise and prospects for reldesemtiv based on the things we know. However, admittedly, there are things that we still need to learn, and that is what we do clinical research to elucidate. We have seen a signal with this mechanism of action in patients with ALS. We have seen a signal with SMA, and there is an opportunity for us now to consider how best to amplify that signal in further clinical study.
Then last question on ALS. SVC is going to be the primary endpoint. Are you also keeping an eye on survival?
We are. Obviously, anytime a patient dies, you record that, you know it. In a 12-week study, it is unlikely that there will be many deaths.
I will also add that I think there has been growing literature and publications on how SVC relationship interplays with some of the other outcomes, including the overall ALS Functional Rating Scale and overall survival and other data sets. I think there is a little bit more understanding of its relationship and importance.
Jinsy, in your new perch at Columbia, overseeing all the clinical research in ALS, you get to see a lot of different mechanism of action and studies across the landscape. Can you put what we're doing with reldesemtiv in ALS in a context of what else is going on in clinical research?
Yeah. I think the first thing to George's question was the drug-drug interactions. I think that was one of tirasemtiv's major handicaps is that it did interact with riluzole, right? Riluzole was standard of care at the time when we were doing clinical trials with tirasemtiv. Reldesemtiv does not have that handicap. A lot of the drugs that we use in standard of care for ALS does not interact necessarily that we know of with reldesemtiv. In the scope of clinical trial landscape, reldesemtiv plays a complementary role to some of the other investigational therapies that are out there. A lot of them are targeting motor neuron degeneration, targeting inflammation. Several investigational therapies are targeting neural inflammation. There are obviously stem cell therapies that are trying to mitigate motor neuron degeneration by secreting growth factors or having neuroprotective mechanisms.
There are some therapies that are targeting gene or genetic mutations, which we're all part of at Columbia. All of these may not necessarily cure the disease or maybe bring somebody to baseline. There's always a complementary role that skeletal muscle activation can play in the setting of all of these other mechanisms targeting motor neuron degeneration and gene-directed therapy.
Thank you very much.
Anyone else?
Thanks. Jeff Hong, Morgan Stanley. Dr. Montes, on the six-minute walk test with regards to fatigue, could you elaborate on the six minute being slower in SMA patients? How much does this vary in patients based on the instructions that they receive?
The mean fatigue that we've demonstrated and published over the years ranges from about 17%, 18% to 20%. There's about a 20% decline in six minutes, the first minute. The test is administered in SMA as per the ATS guidelines. It hasn't been adapted at all, the influence of instructions, I don't believe it impacts the performance. I think that's proven true with the depth of our work that we've done so far.
Great. Thanks. Any other questions? If not, we can break for about 15 minutes. There's coffee outside the room, maybe some other things as well, we'll be back at 10:15.
Could we ask everybody to please grab your seats? We're going to get started again. Those of you on the webcast, we thank you for your patience. We just got caffeinated, and we're going to get started now with the second session. Thank you everybody for your attention during that first session. We're going to make a transition now from what was a discussion pertaining to reldesemtiv and our skeletal muscle vertical, now to what really is our bread and butter, which is the cardiovascular programs at Cytokinetics. The one you know about, and two, you're learning about for the first time today. With that, I'm going to turn it over to Fady.
Fady, as you may know, a cardiologist, a physician scientist, and it's his vision again that has led us to this place where now we're very pleased to be able to not only describe to you progress we're making with omecamtiv mecarbil, but also two new programs that are advancing into phase I this year.
Okay, well, welcome back. Again, it's a great time to talk about our cardiac muscle program. Today we'll be able to talk not just about D, but also about the outputs of R, which really make this an R&D day. Before we go into our new programs, I want to update you on the progress of our most mature program, which is that of omecamtiv mecarbil. To put it in context first, I want to talk about the therapeutic area that we've founded the work and muscle biology on, which is heart failure. I guess it's no coincidence we started in this area given my background and training. Just as an overview, heart failure is a condition where the heart just can't meet the needs of the body in terms of pumping blood.
You might be surprised to learn that there are two kinds of ways that happens. The obvious way, I think is that you have decreased cardiac contractility. The heart's not pumping as well. There are a number of conditions that lead to that. One is a basket of conditions called heart failure with reduced ejection fraction. There are also more specific cases that lead to the decrease in cardiac contractility, either because of genetic mutations that exist within the sarcomere that reduce the function of the sarcomere, or from other conditions such as pulmonary hypertension where the right side of the heart has to pump into the lungs that have a high resistance and can develop what's called right-sided or right ventricular heart failure. Many other conditions as well, they're not all listed here, that the consequence of them lead to decreased cardiac contractility.
On the right-hand side of the slide, you also see that there's heart failure that seems a bit of an oxymoron. If your heart is working well, why would your heart be failing? Sometimes it works in ways that still don't adequately meet the body's need, either because as you'll learn, in hypertrophic cardiomyopathy, where the heart has the difficulty filling or it's pumping blood against an obstruction that's developed in the outflow tract of the heart, or in the most common type of heart failure, with preserved cardiac contractility, what we call HFpEF or heart failure with preserved ejection fraction. Again, there are a number of conditions that lead to that. In total, this is an area that affects millions and millions of people around the world.
A huge area with tremendous consequences both for people as well as our healthcare system. I'll just talk specifically about a couple kinds of heart failure to give you some context about them. HFrEF, or heart failure with reduced ejection fraction, is what is the most common type of classification of heart failure that is used. In the U.S. is maybe about 3 million individuals that are affected with this. About 1 million patients hospitalized every year with heart failure. If you've been hospitalized with heart failure, it is a dire and very potentially important with regards to your prognostic event that has prognostic implications. 30%-50% of patients may die within 60 days after being hospitalized or are re-hospitalized. Obviously, many more of them are re-hospitalized than die because the 1-year mortality is 20%-30%, 5-year mortality 40%-50%.
A very serious medical condition that I think is underappreciated in the general community. Despite the fact that there are many treatments that exist for HFrEF, there still is a huge unmet need here. Hypertrophic cardiomyopathy, or HCM, is a disease of preserved cardiac function or even hypercontractility. It's a disease of the sarcomere. This is a condition that comes about because of mutations in proteins in the sarcomere that lead to an increase in its function, and subsequently a thickening of the heart or asymmetric thickening of the heart, as you'll see later. There are no specific targeted therapies to treat this disease. There are a number of therapies that are applied that have indirect mechanisms of action, but also have systemic side effects.
There are more invasive means of treating it when you have advanced quite a ways with treatment failures being sent to either surgical myectomy or percutaneous ablation. Here again is an opportunity to target this disease at the etiology of where the problem originates, the sarcomere, in a way that might slow its progression, increase exercise capacity, and improve patients' symptoms. In terms of the therapeutics that target the cardiac sarcomere, Cytokinetics and its partners now have a portfolio of 3 molecules. omecamtiv mecarbil and AMG 594, both of which are being developed in collaboration with Amgen, are cardiac sarcomere activators. omecamtiv mecarbil works on the myosin. As you'll hear later, the new mechanism of action in terms of cardiac sarcomere modulation is a troponin activator. You heard about reldesemtiv, which was a skeletal muscle troponin activator.
Together with Amgen, we've optimized and developed now AMG 594, which is a cardiac troponin activator. In the gray box to the right is CK-274, a cardiac myosin inhibitor that may have application to hypertrophic cardiomyopathy or has application in that area as well as potentially others, and targets the myosin here. If you remember earlier when I spoke, we talked about screening an intact sarcomere that has all of these key components present and affords us the opportunity to identify and discover modulators of sarcomere function that may have different targets. This has now led to three molecules with two different targets, three different modes of action, and many others that potentially may emerge from this platform. The first molecule that we put in the clinic as a modulator of sarcomere function was omecamtiv mecarbil.
We'll talk mostly about its development here today. Just to remind you, omecamtiv mecarbil is a cardiac myosin activator. It binds to the motor domain of myosin, which you can see in this movie, binds ATP, hydrolyzes it, undergoes that power stroke, brings the actin filament, pulls on it, and shortens the sarcomere. Omecamtiv mecarbil primes the myosin head in a position that enables it to bind to the actin filament when the cardiac cycle begins. In terms of the biology of that, an intact muscle, it does so without increasing the calcium in the myocyte, which is a trigger for contractility. Subsequently, that's important because it's related to how much energy the myocyte needs to use with every heartbeat, as well as potential arrhythmogenesis. It works by increasing the duration of contraction.
It increases the amount of blood that's pumped out of the heart. It doesn't change blood pressure or decrease heart rate, which are important clinically. Maybe we'll discuss in the panel. We've found it doesn't increase oxygen consumption as well. Omecamtiv mecarbil has been studied extensively in a phase I, II, and now III program. As we've, I think, mentioned now several times, this is a hallmark of the clinical research that we've done and we've done with our partners to very thoroughly understand the mechanism of action, how it translates into pharmacologic effects in the patient populations that later will go on to be studied in clinical outcome studies. Over 3,000 subjects have been dosed with omecamtiv mecarbil in this program. Over 1,000 years of patient exposure.
To me, that's really remarkable considering where this idea came from so many years ago and the years it took us to get here. I'll talk first about GALACTIC-HF, which is the outcome study. It's really the acid test, if you will, of whether this mechanism action can improve clinical outcomes. I'll also introduce a new study that we're going to be conducting to add to this program. Before I do that, what I want to take you through is a little bit of what led us to GALACTIC-HF. There were phase I and phase II studies in healthy volunteers, patients with heart failure, where we examined the effect of various doses, of a broad range of doses that were examined using echocardiography.
I don't have any movies to show you in this section, but you saw earlier a picture of a patient being treated with omecamtiv mecarbil. Echocardiography can be also quantitated, and various numbers derived from those pictures. The ejection time, which is a measure of how long omecamtiv mecarbil, or rather the heart spends ejecting blood, and which has been a signature of how omecamtiv mecarbil changes cardiac function as it increases in very tight relationship to the exposure to omecamtiv mecarbil. Other metrics such as stroke volume, the amount of blood that's pumped, fractional shortening, and ejection fraction, which are related to how much the heart contracts, are both correlated with the increase in ejection time, but also obviously with the increase in omecamtiv mecarbil concentrations.
You can see the number of points on this plot, and what underlies that is a measurement done in patients for each and every point. There are several hundred points on this plot that help us understand the pharmacokinetic and pharmacodynamic relationship of omecamtiv mecarbil. That enabled us to design COSMIC-HF. Many of the studies I showed you on the earlier slide were short-term studies. We looked at short-term dosing and developed that relationship. In COSMIC-HF, we wanted to understand what the consequence was of more chronic dosing, and also obviously develop a dosing regimen that could be employed in phase III. There were a number of formulations that were initially tested in COSMIC-HF before one was selected and studied in what was called an expansion phase.
A phase of 450 patients that were randomized to 3 different arms, placebo, 25 milligrams b.i.d. as a fixed dose, and what we call a PK titration arm, where patients were started at 25 milligrams b.i.d. and then uptitrated to 50 milligrams b.i.d., depending on what their exposure was at two weeks of 25 milligrams a day. This is personalized medicine. If you exceeded a target which was 200 nanograms per mL, there was really no need to further uptitrate you were left on 25 milligrams. Alternatively, if your exposure was lower, you were uptitrated to higher dose to increase your exposure.
Having applied that, both led to pharmacodynamically active exposures, and what's shown here is the measurements of cardiac function and dimensions, as you'll see subsequently, as derived from echocardiograms that were obtained in these patients at baseline 12 weeks and 20 weeks. The patients were dosed for 20 weeks total. Here are the values at 20 weeks and the ejection time, which I told you earlier, goes up in relationship to exposure, also went up here and was sustained over the course of 20 weeks, about a 25-millisecond increase. The total cardiac cycle in these patients is about 800 milliseconds. It represents about a 5% increase in the total ejection time. That increase in contractility, as seen by ejection fraction and fractional shortening, also leads to an increase in stroke volume.
Besides the changes in function, we also had evidence that there were changes in structure. Again, if you remember from the video I showed you earlier, that patient with heart failure had a very enlarged heart. That's a consequence of what happens in heart failure. What we saw in COSMIC was that the ventricular volume began to decrease. Both the volume at the end of contraction, as well as the diastolic volume, which is at just prior to the beginning of contraction, decreased relative to placebo. That's a sign we think of, it's called reverse remodeling. The process of the heart getting bigger, which is a consequence of the disease, you start to see the heart getting smaller, which we hope is a consequence of the therapy. Two other markers that are related to cardiac function.
Heart rate, you can think of heart rate as a measure of cardiac efficiency, really. You know, an athlete's heart rate goes down in well-trained athletes. Similarly, in heart failure, the higher your heart rate is, the worse your outcomes are. We saw here that heart rate declined in concert with treatment over time. A peptide that's released by the heart when it's under stress, that's called NT-proBNP. It's elevated in patients with heart failure, and the higher it is, the worse your outcomes tend to be. You can see here that NT-proBNP also declined over time. Now, NT-proBNP is an interesting biomarker of cardiac function. It is correlated with morbidity and mortality.
The data shown on the left-hand graph here come from the PARADIGM study of Novartis's drug Entresto, where a decrease in NT-proBNP was very tightly correlated with a fewer number of cardiac events, be them cardiovascular death or rehospitalization. On the right, what you see is that BNP, which is the subsequent peptide that is what's processed from NT-proBNP, that it is also tightly correlated with end-diastolic wall stress. End-diastolic wall stress is related to the filling pressures in the heart, how big the heart is, and how thick the wall of the heart is. As you can imagine, less stress is better. That's true across many domains of life. Here, again, what you see is a nice correlation of a decrease in NT-proBNP, in terms of end-diastolic wall stress.
That tells you, I think, that the diastolic function of the heart is preserved or potentially getting better as the NT-proBNP drops and the therapy here is being administered. People have looked at the size of the heart and what's its relationship to potential cardiovascular outcomes. This is derived from a meta-analysis that looked at many studies of LV volume and the decrease in LV size over the course of a therapy that was applied. A plot, really, of the mean change in end systolic volume, the decrease in it, going to the left, and the relationship in terms of the predictive probability of observing a positive effect on cardiovascular mortality. You see a nice relationship here, and the change we saw in COSMIC puts us pretty high up on the curve.
All of these things together were taken into account as Cytokinetics, Amgen, and its partner Servier as well, thought about moving forward into phase III. Safety was obviously also an important consideration. Here, cardiac serious adverse events were relatively balanced between placebo and the various different groups. There were no significant differences in those things like cardiac failure, death, angina, and so forth. Importantly, arrhythmias. We saw a small increase in cardiac troponin. This is a biomarker of troponin, as you know, we've been talking about it all morning, is a protein inside the cardiac myocyte that can be released either because of myocyte necrosis or damage, but also because of other processes where troponin is released from the cardiac myocyte. Here we saw a very small increase, about 10 times below the 99th percentile, what we call the upper limit of normal.
Since it is used as a marker of cardiac ischemia, we look for whether any clinical events were associated with these increases in troponin. Every time troponin increased, the site was queried about that patient as a potential event. Troponin oscillates in heart failure, it goes up and down, and so you've generated a lot of these events, 278 total events. Remember, there are only 450 patients in the study. All of them were adjudicated by a central events committee for potential ischemia. Zero of them were positively adjudicated. I feel like we've maybe put this to rest here. Obviously, it's still something that we can only tell whether the balance of this signal versus everything else is positive is by conducting a trial that looks at clinical outcomes, which we'll talk about next.
Conclusions are here, and as I said, COSMIC was penultimate study that led to the design and implementation of GALACTIC-HF. GALACTIC-HF is a cardiovascular outcomes trial. It's a global approach to lowering adverse cardiac outcomes through improving contractility and heart failure. As John Teerlink in part of our panel here is the chair of the executive committee and has led a number of the studies that I've just talked about today. I've had the privilege of working with him over many years now on this program. In addition to John, there are several others that have spent several years collaborating with us Michael Felker, John McMurray, Scott Solomon, and then more recently, as we've expanded into a much larger global program, Rafael Diaz and Marco Metra, whose affiliations you can see here. GALACTIC-HF, as the name implies, is a large study.
8,000 patients in 35 countries at about 1,000 sites around the world. You need a study of that size in order to interrogate the clinical outcome of interest, which is the time to CV death or first heart failure event. We define heart failure event as either being hospitalized for heart failure, but also as coming to an emergency room or some other acute setting for worsening heart failure, where you need to have intensified therapy, usually with intravenous diuretics. The study is powered based on one of those components, which is the time to CV death, with 90% power to discriminate an improvement in CV death, which implies it's overpowered for the primary endpoint.
We're also looking at the effect of omecamtiv mecarbil in the hierarchy on symptoms by examining the effect on the KCCQ, or Kansas City Cardiomyopathy Questionnaire, and then looking at the other components of the primary endpoint. There's some key design points that make this study a bit unique. We talked earlier about personalized dosing, and here we've applied that same principle in GALACTIC. We've introduced an intermediate dose. Patients are started at 25. They then may be titrated directly, either to 37.5 or 50, depending on their plasma level at two weeks. We also, in this study, are enrolling patients from both the outpatient setting but also the inpatient setting. About 25% of the patients will be enrolled from the hospital setting after they've been stabilized and are about ready for discharge.
The study schema is shown here on slide 77. As I said, we're enrolling patients both from the hospital setting and also the outpatient setting. They're randomized in a one-to-one fashion to omecamtiv mecarbil or placebo. They go through a titration phase that lasts approximately eight weeks. Then they go on to be followed. It's an event-driven trial, and we need to accumulate the number of events that will lead to the readout of the study at the end of the day. Where we are today is that over 5,000 patients have been enrolled in GALACTIC, and we anticipate completion of enrollment in the first half of 2019. We've, I think, enrolled the patients that we intended to enroll, which was a high-risk population.
The entry criteria have produced, on average, patient population with an EF of less than 30%, a time from last hospitalization of less than four months, NT-proBNPs, which are significantly elevated, greater than 2,000 picograms per mL, and as we've targeted, obviously 25% of them enrolled from the inpatient setting. The study is monitored regularly by an unblinded data monitoring committee. They've met quarterly and have advised us to make no changes to study conduct. The event rates are consistent with our assumptions at baseline. There are two interim analyses that will be conducted, the first of which is a futility analysis that's conducted by the DMC. It's expected in the first half of 2019. That really will just tell us to continue or not.
An efficacy analysis in 2020 sometime, in the event that we see overwhelming benefit, as we say, that would merit early conclusion of the trial. Today, I'm going to talk about something in more detail that's new, which is METEORIC-HF. This is a study that is being co-led by Greg Lewis, who's here with us today, and Michael Felker are the co-PIs. John Teerlink's also involved in the steering committee, and a number of others from countries in Europe, as well as in several in North America. The real muscle behind this is Whit Tingley, who has led this study and leads it from Cytokinetics' perspective. METEORIC, you can see a theme in the name of our clinical trials in this program, is Multicenter Exercise Tolerance Evaluation of omecamtiv mecarbil related to an Increase in Contractility in Heart Failure.
METEORIC is designed to evaluate whether omecamtiv mecarbil improves exercise capacity in patients with heart failure. As you might know already, one of the cardinal symptoms or features of heart failure is that people have reduced exercise capacity. While obviously improving mortality and morbidity are important objectives, for patients on a day-to-day basis, an important objective for them is to be able to walk further, not get tired when they walk, and feel better. This study will look at the effect of omecamtiv mecarbil on exercise capacity. In this case, we're using cardiopulmonary exercise testing, or CPET, to evaluate its effect. It's a 20-week study, similar to COSMIC. We'll be dosing omecamtiv mecarbil in the same way that we dose in GALACTIC, but over 20 weeks now.
The primary endpoint will be the change in peak VO2 as measured by CPET from baseline to week 20. There are other secondary measures that look at different ways of quantitating exercise capacity with CPET. Also, we're looking at actigraphy or what you might think of as a Fitbit or an Apple Watch type of measurement. How active are these patients on a daily basis, as measured over a two-week period at baseline and then a two-week period prior to the conclusion of the study? The trial overview is shown on this slide here. What we'll be doing, again, is randomizing patients, but now in a 2-to-1 fashion. Twice the number of patients will be randomized to omecamtiv mecarbil than to placebo. The omecamtiv mecarbil patients will be treated in the same way that we're treating patients with GALACTIC.
They'll be started at 25 milligrams twice a day and then titrated directly to either 37.5 or 50 milligrams, depending on their exposure at two weeks. There is a screening CPET, and that is one of the key entry criteria, that you have reduced exercise capacity on the subjective test. They must qualify based also on their ejection fraction and, as I said earlier, 20 weeks of therapy and 90% power to observe a difference in peak VO2. The entry criteria in some ways are similar to GALACTIC-HF. As I said, these patients have to have a reduced ejection fraction, 35% or less, Class II to III. They need to be managed on standard of care therapies at stable doses. They need to have an elevated NT-proBNP. There are some specific changes that are relevant to METEORIC itself.
What is key here is looking for patients that have reduced exercise capacity, They need to qualify for this study by having, on an exercise test, a peak VO2 that's 75% of predicted normal value. While in GALACTIC-HF, we require a hospitalization, in this study, we don't. In fact, we exclude patients that have been hospitalized recently, within three months, because hospitalization has some very acute effects on exercise performance. Finally, just to wrap up, I'm not going to take you through all of these graphs, but these are the various different measures that you can extract out of cardiopulmonary exercise testing. What's shown on these graphs are the difference between somebody that is more fit, in green, or less fit, in black.
Just on the top left, for instance, is the change in oxygen delivery in a patient or somebody that's less fit compared to more fit as they exercise. You can see that despite the fact they reach similar peak VO2s, which is the top of this trace, curves look quite different. The healthier individual is able to deliver oxygen to their tissues. They're able to climb that curve much more rapidly than the patient that is less fit, who climbs it more slowly. It's a rich measurement of exercise performance that is a hallmark of this program, where we've used rich pharmacodynamic measures of patient function as a means to understand the impact of omecamtiv mecarbil on this disease. With that, I'm going to conclude, and I'm going to pass this over to now talk about new molecules coming to the clinic.
This now begins the R part of our R&D Day. We're very fortunate to be able to tell you about two new molecules that have come out of our labs, one here developed in collaboration with Amgen. I'll turn it over to Brad Morgan, who will take you through that to begin with.
Thank you, Fady. Fady spoke eloquently about Cytokinetics' longstanding expertise in muscle biology and how we've been able to apply this expertise to discover and develop novel molecules that modulate muscle contractility. I'm excited, really, to share with you how we've been able to extend and expand this cardiovascular franchise to two new molecules that are entering clinical development for the treatment of heart disease. The first story I'd like to share with you is an extension of our cardiac contractility activation franchise, and it's the result of a five-year research collaboration with Amgen. You've heard previously about omecamtiv mecarbil, the first selective myosin activator. This is really the next-generation cardiac sarcomere activator, AMG 594, the first selective cardiac troponin activator. The basic goal of our collaboration was try to really improve efficacy and ease of use with a sarcomere activator within patients.
To do this, together with Amgen, we explored multiple mechanisms of actions and multiple chemotypes. Turning over to the base of our pyramid. In this research collaboration, we screened over 1.5 million compounds from both the Cytokinetics and Amgen libraries through our proprietary sarcomere assays. We identified greater than 80 different sarcomere activator series from these assays. We ended up exploring these diverse MOAs and chemotypes, shown in the gray box, and selected cardiac troponin activation given its potential to improve efficacy and ease of use for patients. We looked at greater than 15 different chemotypes of cardiac troponin series and activation, optimized down to two, where we took in vivo to optimize both PK and PD of these compounds, where we selected AMG 594, the first selective cardiac troponin activator.
The objectives of this program, as shown here in the black box, were selectivity for cardiac muscle, no PDE3 inhibition, no effect on calcium transients. As has been mentioned by previous speakers, our ability to design clear and concise pharmacokinetic/pharmacodynamic relationships, where we have pharmacokinetics adequate for once-daily dosing and a wide pharmacodynamic window preclinically for ease of use for patients. What did we end up finding from these optimization efforts? Cardiac troponin activators are selective. You can see here in some of our primary assays. Fady's already mentioned that we use ATP hydrolysis as a measure in these assays. ATP produces chemical energy that is directly translated to the force of the sarcomere.
You can see in this graph on the left that cardiac troponin activators selectively increase ATPase in cardiac myofibrils with little to no activity in either slow or fast skeletal, showing selectivity for these. In other assays that Fady's also spoke about, we are able to reconstitute the sarcomere into a well, and we can then what we call mix and match different components of this sarcomere to understand the mechanism of our inhibitors and how we are activating the sarcomere. This is shown here in the graph on the right, where if you look at the entire cardiac sarcomere that has been reconstituted, and now we are looking at the regulatory elements here, the tropomyosin and the troponin in the all-cardiac system, you can see an increase in ATPase activity with a cardiac troponin activator.
When we take one of the components, the troponin, and swap out the cardiac for fast skeletal, you can see this goes back down to normal, where we have lost that activation. In another sarcomere that is all fast skeletal, as you can see on the far right, you can see no activation, just normal activation of the sarcomere. Whereas when we take out the fast skeletal and swap in the cardiac troponin, again, you see robust activation. Data showing select for cardiac and troponin as our target. As I have mentioned, we need to make sure there is no change in calcium transients of these as well. We do this by looking at primary cardiomyocytes, which are just beating cells in a dish.
In these cells, we can show that cardiac troponin activators can activate or extend the cell length of these cells in the absence of showing any change of cardiac transients measured by Fura-2 ratios in these cells. These were results consistent with direct activation of the sarcomere as our mechanism of action. Finally, as mentioned, the biggest component for the optimization of that is ensuring a clear pharmacokinetic/pharmacodynamic relationship. Most importantly is trying to get a wide pharmacodynamic window, and optimizing for that pharmacodynamic window. This shows cardiac troponin activators in a number of different animal models of contractility, and these are measured by echocardiography, the same measurements that is used in the clinic. You can see in healthy rats and in rats where we have induced a myocardial infarction, these rats have decreased contractility similar to patients with systolic heart failure. In normal dogs.
You can see in all these models of contractility a very wide pharmacodynamic window. We hope for this to translate into then ease of use and expanded efficacy in patients. Hopefully, I've been able to show to you how our five-year research collaboration with Amgen, we've been able to explore diverse mechanisms of actions of activating the sarcomere. We've been able to explore diverse chemotypes in order to select AMG 594 as a selective troponin activator to improve efficacy for this mechanism and ease of use in the patients. Most importantly on this, providing a wide pharmacodynamic window pre-clinically. With that, I'll turn the podium over to my clinical colleague, Whit Tingley. Whit's a physician scientist and cardiologist with extensive experience in clinical development.
Based on the robust pre-clinical results that Brad has just described, we are happy to say that Amgen, in collaboration with Cytokinetics, will launch the first-in-human study of AMG 594 by the end of the year. The primary objective is to assess the safety and tolerability of AMG 594 given as single oral doses and multiple daily doses up to seven days. Secondary objectives include assessing the pharmacokinetics and pharmacodynamics of AMG 594, including a detailed analysis of the exposure-response relationship between 594 and left ventricular systolic function as measured by echocardiography. This is a nested SAD and MAD study with single ascending dose cohorts, five of them, followed by three multiple ascending dose cohorts. Each cohort will have eight healthy subjects, randomized six to two active to placebo for a total of 64 patients overall.
The study is intended to identify a safe, tolerated dose that has the desired PD effect of increasing left ventricular contractility, and the results will be used to select doses for the first patient studies. The favorable pre-clinical results we've seen to date raise the possibility of testing 594 in patients with heart failure due to distinct varieties of left ventricular or right ventricular systolic dysfunction. We have the possibility of testing this molecule in HFrEF, heart failure with reduced ejection fraction, but also genetic dilated cardiomyopathy or right ventricular heart failure associated, for example, with pulmonary hypertension. Amgen and Cytokinetics are currently prioritizing patient populations for study in phase II. In summary, we have selected AMG 594 as a next-generation cardiac inhibitor from among more than 1.5 million compounds in 80 distinct molecular series because of its unique potential and robust pre-clinical results.
In particular, the wide pharmacodynamic window is its key attribute, and it will allow us to optimize both safety and efficacy as we select doses in the clinic. In addition, the projected PK supports once-daily dosing, which for convenience and compliance. We will enter clinic this year with a first-in-human study to assess its key attributes. I will now hand the podium back to Brad, and we will transition from this cardiac sarcomere activator to our new cardiac sarcomere inhibitor.
Thanks, Whit. Second story I'd like to share with you is really an expansion of our cardiac sarcomere modulation franchise. This story is now the discovery of what I believe to be the best-in-class cardiac myosin inhibitor, CK-274. We've had expertise in myosins for many years at Cytokinetics. Fady's already talked to you about the X-ray of cardiac myosin, omecamtiv mecarbil, bound to the pre-power stroke of myosin. That really helps to help us to explain the function of our cardiac myosin activators. We've also had experience with inhibitors, such as smooth muscle myosin inhibitors. These bind to a different site on the myosin, a novel allosteric pocket during the recovery stroke transition. This appears to be an induced fit and a way you can inhibit myosin. We've been able to take these and develop homology models to aid in the discovery of various inhibitors.
Because of the different modes of binding to myosin and the different targets of inhibiting a sarcomere, it's one of the primary reasons that our screen is really agnostic to the mechanism. We can pick up all of these types of mechanisms with our screening. We're then able to classify hits based on the performance in our well-established assays over the years. We can target either the myosin motor in multiple different modes, or we can target the regulatory complex to decrease sensitivity on this. What we've been able to do is to identify distinct classes, distinct chemotypes, with multiple mechanisms of action at inhibiting the sarcomere. From that has arrived CK-274, potentially the best-in-class cardiac myosin inhibitor. As shown in the pyramid on the bottom, we screened over 200,000 compounds in our primary screening of the Cytokinetics libraries against inhibition of the sarcomere.
From here, we've identified to date greater than 20 different sarcomere activator series, different chemotypes, different modes of action of inhibiting the sarcomere. We've advanced 15 of these to some optimization studies where we've characterized them extensively in vitro. Taken three of these to optimize and characterize in vivo in efforts that are still ongoing in research, of which we've selected as our first clinical candidate in this area for the treatment of HCM, CK-274. Again, our objectives for an inhibitor are similar to an activator program. We want selectivity for cardiac muscle myosin, especially over smooth muscle myosin. No effect on calcium transients. We want to be able to, again, optimize our pharmacokinetic and pharmacodynamics of this mechanism.
Our pharmacokinetics, where we're able to provide once a day dosing, but the ability to rapidly reach steady state with this compound for ease of use in clinicians, for personalized dosing to reach the right dose, and for patients for getting to the right treatment, right doses very quickly. Again, a wide pharmacodynamic window within these patients. This is research that's still ongoing. This is an example of six series that we've begun optimization on. These series are both different chemotypes and multiple mechanisms of action, of which our most advanced series A, we have selected development candidate CK-274, along with several other compounds that we're currently exploring and expanding the range of therapeutic applications of this mechanism. We're continuing with research to try to look at the potential advantages of other chemotypes or other mechanisms of actions of inhibiting the sarcomere.
Why did we choose CK-274 as our first development candidate for HCM? First and foremost is its favorable pharmacokinetic and pharmacodynamic properties, as well as all the other criteria we go into for candidate selection. It is a selective allosteric inhibitor of cardiac myosin with no inhibition of smooth muscle myosin, just as we set out for. Its in vivo pharmacodynamic advantages relate to a distinct binding site on the myosin, and it has favorable properties in ADME and PK. This PK optimization allows us to have projected once daily dosing to rapidly reach steady state in these patients. Pharmacodynamically, it has been optimized to have a shallow dose response curve, which may translate into favorable therapeutic window and broaden the clinical utility of this mechanism. Some of the characteristics of CK-274 biochemically are shown here.
In our simplest system of myosin, which is simply the S1 head unit of myosin that can convert ATP to ADP and PI, we show a nice concentration-dependent inhibition of myosin. Showing that cardiac myosin is indeed our target with these compounds. How does this really then work within the context of the whole sarcomere? We have had many years of studying of the sarcomere, and it is shown here in the actin-myosin cycle. You have a weakly bound and a strongly bound state. The strongly bound state is when myosin is bound to the actin, is the force-generating process to the sarcomere. Through stop flow kinetics, we are able to show that CK-274 slows the transition from this weakly bound to strongly bound state, which is the equivalent of having fewer myosins in the strongly bound state.
You can decrease contractility by really having fewer hands pulling on that rope, is a way to think about it. Again, making sure that we do not change calcium transients and indeed we are targeting the sarcomere with our activity. You can see here, again, in cardiomyocytes, primary cardiomyocytes, we are able to decrease the cell length or decrease contractility in the absence of any change in calcium transients. Again, consistent with direct inhibition of the sarcomere as our mechanism of action for the compound. Finally, as I have mentioned, we want to ensure we have a wide pharmacodynamic window with these compounds, and this is through optimization. You can see now in rat models of contractility, where we show concentration versus fractional shortening, or in dog models, where we show concentration versus ejection fraction, a wide pharmacodynamic window to CK-274.
To put into it, this is really at 5%-10%, is really where we want to be for efficacy in our clinical trials. On addition to all the optimization from the PK and PD parameters, we also want to show that this mechanism translates to disease states that are relevant to human. The first model we went about with our cardiac myosin inhibitors is a model of HCM in mice, and this is an R403Q transgenic mice. This is one amino acid mutation in the myosin of these mice. This is the same amino acid mutation that is present in patients that can develop HCM. In these mice, it takes a normal heart, and with the specific sarcomere mutations, can make these hearts hypertrophic. You can see that by the increase in wall thickness in these mice.
One measure we use of this is the septal wall thickness and how this increases. This can be shown with echocardiography, similar techniques that are used in the clinic. This is a representative M-mode in echocardiography, measuring the septal wall thickness at diastole. When you look at this over time in these mice, as shown in the graph on the right, you can see the wild-type mice being a straight line, whereas the R403Q mutants increasing in septal wall thickness. When these mice are treated with our cardiac sarcomere inhibitor, you see initial upswing and then a normalization or a decrease in that hypertrophy of these mice, similar to the wild type or the control mice, the wild type with a cardiac myosin inhibitor. The second model of cardiac hypertrophy, one of the hallmarks of this hypertrophy is also a fibrosis that can happen in the heart.
We're able to take a model. This is now a rat model, a Dahl salt-sensitive rat model. This is a rat model where when fed a high-salt diet, these rats develop hypertension. This hypertension translates into a cardiac hypertrophy and a fibrosis within the heart. You can see here, just based on the histology, the low-salt diet and the high-salt diet on trichrome staining, you can see a much bluer content on a high-salt diet in these rats. You can see that these rats, when dosed and fed with a cardiac myosin inhibitor, look much more like the low salt than the high salt. These images can be quantitated, as shown in the graph on the right, to show an increase in fibrosis from, one, a high-salt diet and a normalization, a significant decrease of that fibrosis of the high-salt diet when given our cardiac myosin inhibitor.
Again, a second translational model for the efficacy of these compounds. With that, I hope I've been able to show you how we've been able to really extend and expand our contractility into what we believe to be the best-in-class cardiac sarcomere inhibitors. We're continuing research in this area. We're exploring diverse mechanisms of actions and chemotypes to see if we can find any clinical advantages in this mechanism with other chemotypes on this. The properties of CK-274 are very exciting. Projected human PK adequate for once-daily dosing, rapidly reaching steady state, and a wide pharmacodynamic window. I've been in the pharmaceutical industry for about 30 years of my life, devoted to discovering novel mechanisms of treating disease. I'm very excited that we filed an IND in this program. Whit Tingley, again, will take you through the way we plan to study this in the clinic.
Our therapeutic hypothesis is that direct inhibition of the cardiac sarcomere will counteract the pathologic effects of mutations of these same proteins in the sarcomere that cause hypertrophic cardiomyopathy. Hypertrophic cardiomyopathy is the most common monogenic disorder of the heart. It doesn't result from one mutation. In fact, there are thousands of mutations that have been implicated in the disease, they cluster in 11 genes, those genes encode the proteins of the sarcomere, the same structure we've been talking about throughout the day today. At the cellular level, these mutations result in myocyte hypertrophy. The myocytes get bigger with more filaments. Myocyte disarray, which means the myocytes are no longer oriented in the same direction as their neighbors. They are disorganized. Interstitial fibrosis, as Brad was just discussing. At the whole heart level, this results in several pathophysiological consequences.
Hyperdynamic contraction of the heart, which actually can lead to obstruction of blood as it's trying to get out of the heart. I'll show you that on the next slide. Also, it leads to a small cavity, which doesn't fill well, resulting in a small stroke volume, and impaired relaxation of the ventricle, increasing the ventricular filling pressures. This picture of the heart shows a normal heart on the left and an HCM heart on the right. A small green arrow on the left shows the flow of blood from the left ventricle across the left ventricular outflow tract, or LVOT, across the aortic valve to the aorta and out to the body. This actually shrinks the size of the cavity and impairs filling.
It also causes those muscles to be stiff and increases the filling pressure, and this can back up into the lungs and cause symptoms of heart failure. The hypertrophy of the ventricle is not symmetric in most cases. In two-thirds of patients, there is asymmetric or exaggerated thickening of the ventricular septum, and that fills the space where the LV outflow tract is and causes a resistance to blood flow, so that when that ventricle squeezes, blood has to squeeze between this thick septum and that anterior leaflet of the mitral valve here. This resistance results in a pressure drop so that the ventricle is seeing pressures far higher than systolic blood pressure, and that can exacerbate the process of hypertrophy itself.
The severity of disease can be quantified by measuring this pressure drop, which can be done by echocardiography noninvasively, and that can guide our treatment decisions for these patients. It can also be used as a measure of activity in drug studies, as we will do. There is substantial unmet need for patients with hypertrophic cardiomyopathy, in particular for a targeted oral therapy to reduce daily symptoms and stop or ideally even reverse disease progression. These mutations are very prevalent. One in 500 Americans are carriers of these mutations. Fortunately, many patients are stable without substantial symptoms. A subset of people are at high risk for progressive disease with progressive thickening, which can lead to adverse consequences such as atrial fibrillation, which can cause strokes, sudden death due to arrhythmias, and progressive exertional symptoms and limited exercise tolerance.
The current medical armamentarium for this disease is based on repurposed older medications that are not specific or selective to the mutations. These include beta blockers and calcium channel blockers, which have some efficacy in some patients, but the efficacy is variable and often inadequate. The dosing of these medications is often limited by systemic side effects. They lower blood pressure, they lower heart rate, and they can induce electrical heart block. For those patients that remain symptomatic, there's only one option left, which is invasive therapy to physically reduce the thickness of that septum. This can be done surgically with a surgical myectomy or percutaneously with an alcohol ablation of the septum. This is indicated only for the most severely affected patients.
It's only available in a small number of centers in the U.S., those centers that have high volumes so that they can have low complication rates, many patients don't have access to these centers. We will initiate the first-in-human study of CK-274 this year with a nested SAD and MAD study in healthy subjects similar to the one that we described for AMG 594. The primary objective is to assess the safety and tolerability of single and multiple oral doses given daily for 14 days. The study design includes eight single ascending dose cohorts and three multiple ascending dose cohorts. Again, eight healthy subjects per cohort randomized six-to-two active to placebo for a total of 96 healthy subjects. The intention is to find a safe and tolerated dose that has the desired PD effect of reducing cardiac contractility as measured by echocardiography.
After the first-in-human phase I study, we will do a small phase II proof of concept study in obstructive hypertrophic cardiomyopathy patients using a placebo-controlled randomized design and echocardiography endpoint with one objective to be demonstration of reduction of the LVOT gradient. This will be followed by pivotal phase III studies using cardiopulmonary exercise testing, as Fady has described, to measure exercise capacity and look for improvement in exercise capacity with treatment with CK-274. We will also have long-term extension study that will allow us to look at the long-term safety and efficacy of treatment with CK-274. In parallel, we'll run studies in other patients with hypertrophic cardiomyopathy that do not have outflow tract obstruction, called non-obstructive, or NHCM. In summary, CK-274 is a potentially best-in-class cardiac sarcomere inhibitor for the treatment of patients with hypertrophic cardiomyopathy.
It is intended to counteract the pathological effects of mutations in the sarcomere that cause hypertrophic cardiomyopathy. The preclinical results support its potential for best-in-class safety and efficacy, its PK projections support potential once-daily dosing. The PK is particularly important here because we want to titrate the dose to the effect using echocardiography. We can start a dose, get to steady state, then measure that gradient across the LV outflow tract and then change the dose if needed to optimize the effect of the drug. Having the appropriate PK to allow efficient titration is critical for this disease. We're advancing into clinical development. We filed the IND. We have an efficient clinical development plan with robust PD assessments to measure the exposure-response relationship in early clinical development.
I'd now like to hand it back to Fady to moderate our discussion with our distinguished colleagues.
Okay. Thank you, Whit. Well done. We'll go ahead and move on to the Q&A. We'll invite questions in just a moment. I may start off discussion. I do encourage you all to think of and contribute to this panel discussion. Maybe I'll start first with METEORIC being a trial of omecamtiv mecarbil's effects on exercise tolerance. Dr. Lewis, maybe you can just explain, based on your experience in exercise capacity trials, why might we expect the mechanism of action of omecamtiv mecarbil to increase exercise capacity in heart failure patients?
Sure, Fady. First, I do want to start by saying and echoing the importance of exercise capacity of these patients who have heart failure. It's something that they experience their exercise intolerance literally on a daily basis, sometimes multiple times a day, every time they try to climb up a flight of stairs or walk across the room. As a cardinal manifestation of heart failure, it's one of the reasons that we're targeting it, and we want to try to target it with great precision in terms of making measurements of cardiopulmonary exercise tests before and after exposure to the drug.
In terms of why we are encouraged by the findings to date, the ability to improve exercise capacity, you saw from some of the nice studies that have been summarized that cardiac performance significantly improves in these patients in terms of the amount of blood ejected forward, less backflow, shrinking of the heart, attenuation of this heart failure severity. We know that heart failure and exercise capacity are very tightly linked, and we can measure that by measuring the total amount of oxygen consumption during exercise. By virtue of improving cardiac performance, we feel that that's going to translate to improvement in exercise capacity since these patients with heart failure and reduced EF are truly limited by their cardiac performance when they exert themselves. As far as historical precedent, there's certainly other agents that have moved the dial on VO2.
An example from a mechanical perspective of improving the performance of the heart, if you think about something like cardiac resynchronization therapy, has been shown to improve peak VO2. Agents that make the heart easier to pump blood forward, that vasodilate the blood vessels, help to improve peak VO2. There is historical precedent for improving this endpoint.
John, anything you want to add there?
No. As someone who sees these patients every day, when they come in, this is their main concern. They say that they can't do things. To find an agent that can actually improve exercise function and their ability to do their activities will be a major step forward in this arena.
Maybe moving to the results of the phase II program and COSMIC. John, you as the leader of GALACTIC-HF, our outcomes trial, how does the phase II program, which you had a large part in, contribute to your confidence in terms of the potential outcome of GALACTIC-HF?
I think one of the things that's really been very interesting about the cardiac myosin activator program with omecamtiv mecarbil is that it finally provides an opportunity for us to test a hypothesis that has been around for over 100 years, since the initial discovery of adrenaline. Since that discovery, the hypothesis has been that somehow by improving cardiac performance, we can help patients feel better and live longer. One of the surprising things is it has not been until this time, over a century later, that we've actually been able to effectively test this hypothesis. The two main phase II programs, the ATOMIC-AHF study and COSMIC-HF, provided the bridge between the excellent preclinical work that Dr. Morgan and colleagues did at Cytokinetics towards the GALACTIC-HF trial. The ATOMIC-AHF trial looked at over 600 patients with acute heart failure.
These were sick patients hospitalized for heart failure, we administered intravenous omecamtiv mecarbil to these patients and were able to show that the agent was very safe in that patient population and in the highest dose, actually improved their symptoms. It was able to show that it made the patients feel better in a safe setting where they were otherwise hemodynamically and otherwise decompensated. That provided us a lot of comfort saying, "Well, this is an agent that we can give to patients who are hospitalized, who are sick, and feel comfortable with that safety profile." When we moved into COSMIC-HF, we had the 20 weeks of therapy, as you alluded to in this study, we were able to show not only to select a formulation, but also all six of the pre-specified primary endpoints were met in that trial.
In that way, we were able to actually show improvements in volumes, improvements in neuro hormonal activation, and improvements in things that would suggest and hopefully translate into improved outcomes in GALACTIC-HF. In addition to that, we had suggestions of improvements in symptoms as well. These all bode very well for the potential success of GALACTIC-HF, and are some of the strongest predictors. The volumes and the NT-proBNP piece, as you point out, some of the strongest predictors of improved outcomes in patients with heart failure and reduced ejection fraction.
Great. Thank you. Maybe one more question, I'll throw it open to the group here. For Greg, because we've talked about quantitating exercise capacity earlier with regards to using six-minute walk in patients with SMA, and six-minute walk is also applied in heart failure. Can you comment maybe on why selection of CPET in this study, METEORIC, might be more appropriate for this population?
Sure. The exercise capacity is the primary endpoint of this study, we really want to get as high a resolution as possible into exactly what's happening to these patients when they're exerting themselves. For heart failure, there's a long tradition of the application of cardiopulmonary exercise testing based on the close link to the severity of heart failure and the performance during cardiopulmonary exercise testing. It's actually mandated by CMS as one of the tests to be done in patients with advanced heart failure to determine whether they're eligible for therapies such as transplantation or left ventricular assist devices. It's commonly used in patients that have heart failure already, it gives us a lot of information about cardiac performance. We look at how the heart is performing during the early phase of exercise.
As Fady alluded to during one of his slides, how quickly oxygen uptake increases. We also can measure precise volitional effort. There was a couple of good questions before in terms of what the different times of the six-minute walk tests imply about endurance. During cardiopulmonary exercise testing, we subject patients to a graded ramp protocol so we can understand how patients are responding to very low-level exercise, intermediate exercise, and maximum exercise. We can also determine how much volitional effort there was, whether it was a maximum effort study that was limited by their cardiovascular performance. We can focus on those patients that are truly limited by cardiac function as opposed to a musculoskeletal problem, for example, in this population of patients who does accumulate comorbid diseases based on the age and the profiles of these patients. We have other information along the way.
We're monitoring the electrocardiogram, we're monitoring blood pressure responses, and we're truly monitoring every single breath that they take. We have a lot of precision there in this measurement. Fortunately, it's getting easier and easier to do in terms of the modern-day metabolic carts and how they perform. It also permits us to do a smaller study. The test-to-test variability in VO2 measurements is lower than it is in six-minute walk in heart failure patients, and as a result, it can reduce the sample size that we're doing for the trial.
Okay. With that, maybe I'll throw it open to questions from the group.
Thanks. Jeff Hong, Morgan Stanley. The first question's for Doctors Teerlink and Lewis. What do you think the bar is for METEORIC to show clinically meaningful differentiation in exercise endurance?
Yeah. Again, we have a lot of data accumulated in heart failure patients. Just to frame this a little bit, I know there was discussion before in six-minute walk. Where we expect these patients to be is somewhere in the range of about 13 or 14 milliliters of oxygen per kilogram per minute. That's a typical exercise capacity in patients with heart failure. What's been shown to be a clinically meaningful improvement is if somebody can increase that exercise capacity by one or more milliliters of oxygen per kilogram per minute. These patients are on the steep of their curve, if you will, and that every single milliliter per kilogram per minute can translate into a significant difference in whether they can climb a flight of stairs, for example, or walk across a room. That's been shown in other clinical trials.
It's also been looked at in the large HF-ACTION study. For every 5% increase in PCO2, which the one ml per kilo per minute would be more than, there's a 6% reduction independently shown to reduce mortality in patients with heart failure, reduced EF. That's a bar that we would like to exceed in terms of an effect size.
Great. Thanks, Jeff.
Maybe just for context, in a healthy individual, what would their PCO2 be approximately? What do you think Lance Armstrong's-
Yeah.
off of EPO would be?
Oh, now that's deep.
Well, I don't know that I can classify the off of the performance-enhancing substances because I don't know that we have too many of those for Lance. No, for an elite level athlete, 70 mLs per kilo per minute, which is, by the way, all of us right now are using about three and a half mLs per kilo per minute, just in terms of the resting state, and that's one metabolic equivalent. An elite athlete can increase that metabolic rate by about 20-fold. In the heart failure patient, it's only four-fold. That 14 mLs per kilo per minute is about the cost of a brisk walk on level ground, and will not permit you to walk up a flight of stairs quickly.
As opposed to a normal individual with the same age range, is more in the mid-20s. There is an age dependence, weight dependence of these measurements, 25 to 30 mLs per kilo per minute, which permits you to conduct activities of daily living. Substantial reduction in peak exercise capacity in these patients, which closely correlates with their quality of life and their total morbidity burden of the heart failure.
Great, thanks. One question for the company. How is CK-274 different from MyoKardia's mavacamten? Given the history, what is your current thoughts on how they might differ clinically?
I think, we developed our drug to keep in mind what would be the optimal properties of a molecule that might be applied in this condition. As you can tell from the presentation, we used our experience really in what PK/PD means, what pharmacokinetics means in these populations, how do you apply these drugs in the clinic. We think, without getting into specifics, that what we did to optimize this molecule will lead to potentially a best-in-class potential. That relates to convenience of use, ability to uptitrate, potentially achieve greater efficacy in the presence of better safety. All those things were part of the calculus that went into selecting 274.
Thanks.
Great. Thank you. Two quick questions for the company, if I may. Firstly, with respect to METEORIC, would that be the second phase III study required for approval following GALACTIC? Would there be other clinical trial requirements for an NDA?
I'll answer that, but also ask John to comment as well. GALACTIC-HF is the only trial that's required for the registration of omecamtiv mecarbil in terms of its efficacy. There are obviously a lot of trials that contribute to its registration. GALACTIC by itself, which is being conducted under a special protocol assessment agreement with the FDA would be sufficient for registering omecamtiv mecarbil. METEORIC is a study that I think adds to articulating the value that omecamtiv mecarbil has to patients and is complementary and expansive, if you will, of the development program.
Thanks. That's very helpful and clear. Secondly, is there any milestones associated with 594 advancing into the clinic under the Amgen collaboration?
Let me just add a comment onto what Fady said. I'll probably not be able to address your question to your satisfaction, your second question. Firstly, with respect to METEORIC and the rationale for it, I'll remind you that under our collaboration with Amgen and Cytokinetics are jointly conducting a development program. All these studies are being conducted under the joint oversight of a joint development committee that Fady co-chairs with a counterpart at Amgen. To reiterate what he said, the GALACTIC study is the pivotal registration study. We, having conducted market research around this area and understanding what we think clinicians, payers, patients may appreciate about a novel mechanism of action, we all agree that there could be other advantages that would be conferred upon this strategy and this development program were we to also see an effect on increasing exercise duration and stamina.
We think that translates into positioning for this new mechanism, especially relative to other heart failure therapeutics. You heard mention of the fact that in the device world, there's evidence that having left ventricular assist can translate into increased exercise duration and stamina. We think a pharmacotherapy that may have also that advantage would play well to the interest and the unmet need. With respect to advancing AMG 594 from preclinical development into now clinical development, we're really not able to comment on what may trigger milestone payments under our collaboration agreement with Amgen. I'll only be able to point you to what will be our financial disclosures over time as both omecamtiv mecarbil and AMG 594 are both advancing under the collaboration. In some of my summary slides, I'll point to what might be expectations for key milestones coming forward.
Hi, thanks. You have two sarcomere activators. I think one of the first things I'd do would be to put them together and see what happens. Have you done that? Strategically, are you thinking of 594 as a follow-on to omecamtiv, or perhaps to be used in combination later on?
We really think of them as separate molecules. I don't think that there is potentially an advantage of combining them. We get sufficient, if you will, increases in contractility with omecamtiv, and we'll learn what magnitude increases we can elicit with 594 potentially may yield greater efficacy as time goes on. I don't think likely that they will be used together in combination, and we haven't really looked at their combination pre-clinically either. Maybe, John, you want to comment on whether you think there would be any role to combine them?
Yeah. It's an intriguing possibility and one that I've also considered. I don't think it's going to be pursued right away. It's more of a business decision as well as the medical decision. We're already seeing quite effective responses to omecamtiv. I think the other perspective I'd want to give with this whole class of agents is that one of the unique aspects of this is, as a heart failure doctor who takes care of these patients, one of the things you always have to balance is when you're trying to do your ACE inhibitors and all these different medicines, you kind of have this spinning function. You have to get rid of heart rate or blood pressure or potassium or kidney function when you add all these different drugs of the previous ones.
Now this whole class of agent has no effect on any of those aspects. Omecamtiv mecarbil and these class of agents can be added in at any time in the patient's clinical course. That's a huge advantage to it, if GALACTIC-HF and METEORIC are positive, not only will we have a new drug available, but it will actually be a drug that we could use. It won't be so complicated to try to fit into the current armamentarium of agents that we have. That.
John, since you mentioned business, and since I'm the only one up here that doesn't have an MD or a PhD. I might address this from a corporate strategy standpoint. We at Amgen look at AMG 594 as different. We don't know necessarily that it's better. We do know that for having studied omecamtiv mecarbil for over 10 years in clinical research, we believe we have a good handle on what may be its PK/PD relationships and how that may translate into potential clinical benefit. Ultimately, we'll learn a lot from a phase III study. What I think you can take away from our advancing AMG 594 now into phase I is this is an opportunity for us together to extend and expand a franchise that we hope to be building in cardiovascular pharmacotherapy tied to muscle biology.
This is an opportunity, I think, for us to look at what may be different physicochemical properties and how they may translate, firstly, in healthy subjects and then potentially in patients down the road, and understand where that may address not only opportunities pertaining to heart failure with reduced ejection fraction, but as we will continue conversations around what else we may do with a mechanism that could enable us to consider beyond those patients with systolic dysfunction to other heart failure patients.
As a follow-on, have you stopped development as an IV formulation in the acute setting? Is it all going to be now oral in the chronic setting?
Right now, we're developing omecamtiv mecarbil orally, obviously. The IV is still something that we keep in consideration in terms of how it might be applied as we understand omecamtiv mecarbil's efficacy in this population. I think one of the most important thing to note in GALACTIC is that we are enrolling patients in the hospital setting. That is, I think, in a very important setting where patients' therapies get optimized and potentially new therapies get added, and it's important to have an understanding of how your therapy behaves in that population since it's a place where decisions are made so frequently. With an IV, we might look at even earlier in the hospitalization how we might intervene. That for now is a later-time thought in the development program.
Yeah. As many of you may know, other programs have had to actually do separate trials to say, okay, they can start drug in-hospital. One of the reasons we started it in-hospital is to provide that as an opportunity. In addition, it's been well known that patients who have their medicines given to them in-hospital are much more likely to continue those medications long-term, as well as to have them up titrated. That is why it's important to try to have included that in the GALACTIC-HF program.
Yeah. I'd say with respect, George, you followed the story for quite a number of years, I would suggest that with regard to the intravenous form of omecamtiv mecarbil, that's something that will be informed by what we learn from these phase III studies and whether that might afford us an opportunity from a lifecycle management standpoint to consider, again, how we could expand the franchise.
Okay. Thank you very much.
Charles?
Hi. Charles Duncan, Cantor. Thanks for taking my follow-up questions. First question for Dr. Teerlink. For GALACTIC, in terms of what you'd like to see out of it, time-to-event, what kind of delta or difference between control and experimental arm would you like to see to consider that clinically meaningful?
What we usually like to see is about a 15% reduction in terms of the relative risk of the combined event of heart failure hospitalizations and cardiovascular death. That's what we're clearly powered to see. In the interim analyses, we'll be looking at effects that are much better than that. I think the other point that needs to be made very clear is that with the second interim analysis, which is for superiority, to which Dr. Malik already alluded to.
That is looking for the really shooting-the-moon-type benefit where we have to stop it. We're looking for about 15% in terms of relative risk reduction in terms of the primary endpoint.
Just to clarify my thinking, for the futility analysis, you need to see some daylight between the curves, or what do you need to see there?
I'll just make a point. It's important to know we won't see anything.
Yeah.
I understand that, what is the assumption?
Yeah. We haven't been very specific intentionally as to how the futility analysis is being conducted. Essentially, what you'd like to ensure at this point in the trial, that there's no cumulative harm to patients.
Yeah
That you certainly don't have your curves diverging in the wrong direction. If that was the case, you wouldn't want the trial to continue indefinitely, and the DMC would want to do something about it. A futility analysis is primarily looking for, not a lack of efficacy, but more of a signal of things moving in the wrong direction at the time.
To quote Dr. Andy Wolff, who uses this expression when thinking about these things, we want to rule out potential badness. In that regard, I think we're doing the responsible thing by doing an interim analysis at that stage of the study.
The other advantage we have with this program is we have just a superb DMC with people who I've worked with for years in other contexts. This DMC has followed the entire omecamtiv program. They have the cumulative safety and have seen all the data from the program, for the main part of the program, all along the way. We feel very comfortable with them championing and sort of shepherding on the program in GALACTIC-HF.
That's a really important point to underscore. This often gets lost in conversations such as this.
Yeah
With Wall Street analysts and investors. Clearly, we're not going to be the overnight success in this space. You've been following us, and Cytokinetics is a story that you've known for quite a long time. omecamtiv mecarbil entered clinical studies in 2005. Over the course of that period of time, now 13 years, we've had the opportunity to engage very actively with the heart failure community, the academic leaders, John and others. When he talks about the DMC and the safety review, it's the same people who have been involved in this program for 10 years and plus 10 years. That's something that you can't reproduce easily. That's fundamentally a function of expertise, insights, intuition, and knowledge that gets generated through the course of a number of clinical trials, over a dozen clinical trials that have led us to this place.
You've heard about the research that underscores the advancement of these compounds into clinical trials and how the mechanistic science translates into potential advantages in clinical trials. Don't underestimate the power of the clinical research and the people who are involved, the continuity of that involvement, and how that can hopefully increase the yield of what will be a positive study at the end of the day.
Yeah, I was going to comment. I think, Dr. Teerlink, you were gracious enough to be on a KOL call that we hosted 12 years ago or so. Something like that.
Well, just to expand a little bit on what Robert said, it's really a commitment by these individuals over-
Yeah
a long period of time, to which I and others, many others, are extremely grateful. We know John's been involved for a long time, but as he pointed out, the members of the DMC have invested several years of time in this program, members of our executive committee similarly.
Clinical Events Committee.
I think in the Clinical Events Committee, it's, I think, a real testament to their interest, and I'm enormously grateful to their commitment.
Potentially differentiate a profile of omecamtiv. Let me just ask you then, as kind of a follow-up, Dr. Teerlink. It would seem like the trial is, and I hate to say overpowered because I don't like to say that. Robustly powered, let's say. That it's a robustly trialed part of the GALACTIC is. What do you think drove the number of patients? Was it a consideration of a desire to rule out badness in terms of safety, or was it a desire to really nail the efficacy endpoint?
I think I'd modify your statement and say that it's appropriately powered, because it's appropriately powered to look at cardiovascular death. Actually, there's a recent trial that was done in another agent with heart failure was about the same size. This is the size that, for better or worse, is where we're at with heart failure outcome trials now. It is appropriately powered to look at cardiovascular mortality. The reason that's the case is I think that's the question that people really ultimately want to have at least some confidence around. Clearly, it's important to reduce heart failure hospitalizations, so we will be able to see whether we do that in conjunction with cardiovascular death.
Even if we reduce the combined endpoint, people will still say, "Well, what's the potential effect on cardiovascular death?
We'll be able to answer that, hopefully appropriately, with this trial. Did that address your question?
Yep. That answers my question. Last question, Robert. 594 composition of matter patent, when does it go to?
We're not yet going to be speaking about that, but we are going to discuss with Amgen what will be permissible with regard to a disclosure on that, and we'll come back to you.
You said it extended the franchise, so I assume it's longer?
Correct.
Okay.
Chad Messer at Needham & Company. Can you discuss the preclinical tox findings a little bit more on 274? What you ran into, is it all related just to cardiac insufficiency or were there other things?
You said it yourself. It's a mechanism of action that reduces cardiac function, and as you could see from the curves of PK/PD that Brad presented, it can have a substantial effect on reducing cardiac function. In our tox studies, what we've observed so far has been consistent with its primary pharmacologic effect. We expect the toxicity of the molecule to be related to its efficacy or an over-application of its efficacy, and that's where you want to be, truly, in a program, being able to titrate the two against each other. We haven't seen anything so far, anyway, that is inconsistent with its mechanism of action. Okay.
Maybe I'll just ask a follow-up question for John and also for Greg to comment, because I think, John, you started to discuss this, but I think it's important to expand on how does omecamtiv mecarbil fit in where it might be used, and what advantages might it have relative to current standard of care as we would think about applying it should GALACTIC be a positive outcomes trial. Yeah. This is where I started, perhaps less eloquently than I should have in terms of the challenge of our current therapies. We have the angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and the angiotensin receptor-neprilysin inhibitors, all of which can decrease blood pressure, increase potassium, and decrease renal function. When you initiate those agents, you have to follow up and you get frequent blood laboratory tests to follow those aspects.
When you try to figure out how are you going to add in the mineralocorticoid receptor antagonists like spironolactone or eplerenone, now you also have to worry about effects on renal function and potassium. You throw in the beta blocker, which is really useful, but decreases heart rate and blood pressure, so it interacts with those agents. If you get this far, now you have to think about ivabradine to try to take care of the heart rate further. In human beings, you only have so many millimeters of mercury to spend before the person passes out or before you ruin their renal function or before the potassium becomes at a critical level. It requires a lot of work for busy physicians.
One of the sad aspects of heart failure therapy is that much of it is not done by cardiologists or by heart failure specialists. Much of it is done by primary care physicians, which is hard for them to try to take all the time that it takes to balance all these things. From a purely pragmatic standpoint, omecamtiv mecarbil, if it is successful in all this program, will be able to fit very easily into this regimen because you won't have to worry, based on what we've seen so far, about those other factors. In addition, in terms of the patient's disease course, one can imagine that if it actually helps reduce ventricular remodeling, as we saw in COSMIC-HF, and improve outcomes, its indication will be through Class II through Class IV patients, which is what we're enrolling in GALACTIC-HF.
We will be able to intervene during almost the entire disease cycle of heart failure. Greg, do you have anything?
Yeah, no, I completely agree. As another heart failure cardiologist that spends a lot of time trying to juggle all these different medications for patients with heart failure, not only is it challenging to layer these therapies on that have similar side effects, you often find yourself not able to get anywhere near the doses that were studied in clinical trials, particularly when they were layered on one at a time. You end up putting on tiny doses of one medication or another. Having agents that don't share the same side effect profiles when it comes to potassium and renal function and so forth is a major advantage in these patients. Then, as John said, these patients are managed by a wide spectrum of physicians, and part of that is because the magnitude of this problem continues to expand.
There are so many patients out there with heart failure, and the number is only growing. At my hospital that has 1,500 beds, there's over 100 patients admitted at any given time that carry the diagnosis of heart failure. As heart failure experts, we can't get around to see all of them. The idea of an agent that's been carefully developed in a way that hopefully will simplify the ability to initiate it
I think is really important. There are a lot of patients who are truly cardiac output limited, particularly as you start to get into later stages of heart failure. We go so far as sending some of these patients home on intravenous preparations of medications that we know don't have particularly favorable impacts on long-term outcomes. The idea of an agent that improves cardiac performance, that can be taken in pill form right up through the more advanced stages of the disease is particularly attractive.
Having been a company involved in the development of investigational medicines for heart failure for a long time, we get to see a lot of things. Every year we go to the Heart Failure Society of America meetings, and every year we hear more and more about not only the clinical burden for heart failure and how it's growing with the increased prevalence of the disease, but also the economic burden. A number of years ago, Cytokinetics decided as a service to the Heart Failure Society of America community that we would sponsor every year a symposium on economic challenges in managing heart failure. I think this is coming home to roost more and more as we see the aging demographics and the number of patients with heart failure only growing. The challenges that heart failure physicians and their institutions are confronting are growing, too.
Heart failure is amongst the single largest line items in the Medicare budget, and being that hospitalization for heart failure is the number 1 reason why Medicare patients are hospitalized in the U.S., this is an economic epidemic. Hospitals being penalized as patients are being readmitted into the hospital. You saw the statistics that Fady shared. This is becoming a bigger and bigger problem where heart failure institutions are really struggling to find ways to keep patients alive and out of the hospital longer. One of our goals with the development of omecamtiv mecarbil through the conduct of clinical research is to hopefully be able to generate evidence that lends support to the economic hypothesis, if you will, that a investigational medicine that can contribute to better outcomes may also afford better economic advantages.
We and Amgen are spending a lot of time on the pharmacoeconomic activities here too, to try to build a similar body of evidence to lend support for the positioning of omecamtiv mecarbil.
Question back there.
Yes. Vernon Bernardino, independent. This probably a question for Fady and Dr. Lewis. For agents like omecamtiv mecarbil that you might study in a study like METEORIC-HF, would you expect to see cardiac remodeling in patients that showed a significant effect on peak VO2 at week 20?
Because there's a close tracking between peak VO2 measurements and heart failure severity, and cardiac remodeling is an indicator of that, I would be not surprised if we saw traction between the remodeling and the peak VO2. It's a 20-week study, but that also mirrors what's been done before and demonstrated improvements in LV end-diastolic volume and LV stroke volume. Those same hemodynamic improvements are directly embedded within the derivation of what VO2 is. Stroke volume is one of the three determinants of VO2. If you see a smaller heart with less mitral regurgitation because the heart isn't as stretched and you're sending more blood forward, and you're seeing improvements in stroke volume, we have every reason to believe that those would translate to improvements in cardiac performance and therefore whole body oxygen uptake.
I'm going to ask one last question of the panel. Is there another question? Oh, sorry. Go ahead. Questions from the floor.
Roy Buchanan, JMP Securities. Just can you, for 274 and 594, can you just tell us what chronic tox studies you've completed? How long are you guys going to be able to dose for? Thanks.
Yeah. I'm not going to comment on exactly where we are there. We've completed what's required for our IND filing, which are four-week studies. In the case of these molecules, we certainly are either planning or conducting longer-term studies so that we can enable chronic dosing in the phase II portion of their programs. I might add a question with regards to omecamtiv mecarbil. We have a unique way of dosing omecamtiv mecarbil. It's a PK-guided dose titration, taken, as I explained earlier, with a blood level that we check at two weeks, and then patients are directly titrated to their target dose. It's different. I wonder if you might comment on how that compares to how other drugs in heart failure are used and titrated and the relative difficulty of doing that.
Yeah.
Maybe both of you can answer that since you both-
Yeah, me, I have-
do a lot of that.
I have enough gray hair that when we were talking about therapeutic drug monitoring, we started with digoxin, where we would measure digoxin levels to make sure that the levels were high enough. We would always increase the levels, then we found out that that was bad. Now we monitor digoxin levels to make sure that they're low enough. That was no problem. That was routine
care. In terms, as I already alluded to, when we start patients on all of our standard care therapies, we will be measuring laboratories every two weeks, every four weeks, then every one month to three months after that to monitor potassium, creatinine, and the electrolytes for chronic therapies. Having an agent where you do a two-week measure and an eight-week measure, whatever we end up doing is actually quite simple. We see these patients that often anyway, particularly when we're starting new medications, so it certainly won't represent any additional burden to the patients. Greg, what do you think?
I agree. I feel like I'm struck by the fact that we don't do more of this in how we take care of patients, given their patient-to-patient variability. We certainly do this in drugs that we use in the hospital for patients. We wouldn't give patients a blood thinner, for example, like heparin, without measuring what their effects of the drug were, the essential equivalent of a level. I think that the monitoring of other side effects of drugs, if you look at the aldosterone receptor antagonist trials, the density with which monitoring took place in studying those was actually quite a bit higher than the frequency that's proposed here. There was literally weekly potassium levels monitored in the clinical trial setting. In the real-world setting, when there was less frequent monitoring, you ended up seeing more adverse effects of not monitoring the potassium so frequently.
I think that it's a sensible strategy and one that certainly can fit within the clinical care of a patient population that are what we consider frequent flyers. These are not patients that are coming in once a year to get their cholesterol levels checked because they had a heart attack several years ago. These are patients that are frequently having monitoring done anyways of their blood profiles.
Thank you both. Any other questions from the audience? With that, I think I'll transition to Robert to help close the meeting.
It's my great privilege to be able to bring this meeting to a close and maybe summarize some of the things you've heard about and also point to the future. I'm going to do that by also putting a bit of a business wrapper around some of the things you've heard regarding our R&D pipeline. I want to start by talking about our collaborations. You've heard us talking a lot about the work we've done together with Amgen. Amgen and Cytokinetics entered into a relationship in 2006. In 2006, we first entered a collaboration around the development of omecamtiv mecarbil, and with that funding provided by Amgen, we were able to conduct certain phase I and phase IIa studies that informed an option they had, an option that they exercised in 2009.
That afforded us the right to go forward together in a co-development collaboration, albeit at that time, the collaboration was limited in its geographic scope to worldwide territories excluding Japan. We expanded the deal to include Japan in 2013. As you know, subsequent to that, Amgen entered into a sublicense agreement with Servier such that Servier has also joined the collaboration, so to speak, in terms of providing support for development and as would be in exchange for commercial rights to omecamtiv in certain territories outside of North America. This collaboration is a powerful force for Cytokinetics. As you know, ours is an expensive business. With this collaboration, we've been afforded not only sponsored development over the many years, but sponsored research.
That sponsored research, as you've heard, led to the discovery of AMG 594 and a function of that enables us and Amgen to go forward now, not only with omecamtiv mecarbil, but AMG 594 for the potential expansion of that cardiac franchise. As we are proceeding now, we're eligible for milestone payments, both pre-commercial payments and post-commercial payments. In aggregate, over $500 million in milestone payments based on progress for this program, omecamtiv, and even more so for AMG 594. Also we're afforded other rights, responsibilities, and economics. When omecamtiv mecarbil entered phase III, that triggered an option we had. An option we had to choose to co-fund phase III clinical trials. As many of you know, we did so exercise that option. We chose to co-fund at the maximum level. We could have co-funded at the levels of 10 or 20 or 30 or $40 million.
We chose to co-fund at the level of $40 million. That enabled us to buy up the royalty economics. We turned around and sold that incremental royalty to Royalty Pharma for $90 million plus an equity investment on top of that. As such, we were able by exercising the option and co-funding at the maximum level. That afforded us the right to proceed with our Amgen collaboration in a more meaningful role as a joint commercialization program partner. We not only have a joint commercialization committee, but we'll be forming a commercial operating team, both of those still accountable to the joint steering committee, much like the joint development and joint research committees have been. This is a very unusual collaboration in many ways, not only with respect to the dollars, but the rights responsibilities.
As we may move forward to commercialization, Cytokinetics has the right to co-promote omecamtiv mecarbil in North America, and on a basis by which Amgen would reimburse certain of our sales force costs. This affords a biopharma company like ours an opportunity to transition from R&D through to commercialization in a way that's befitting and benefiting from the sponsorship of our partner as we migrate to that commercial space. Amgen would be responsible for the cost of goods, cost of marketing, and reimbursing us for certain of our sales force costs. We earn a royalty on potential sales. That royalty would therefore fall more quickly to our bottom line, and we wouldn't be responsible for many of the costs of commercialization that oftentimes become a be-careful-what-you-wish-for scenario.
This is the way in which we have planned for the migration of Cytokinetics from an R&D-centric company to one that's forward integrated into commercialization in a way we consider to be prudent and responsible, recognizing shareholder interest, and as would afforded us, we believe, a high return on investment in sales. That's fundamentally what happens when you're a leader in a space and a pioneer. You're afforded certain advantages in doing the partnerships. We're very grateful for the longstanding collaboration we have with Amgen. It's extremely similar to the deal we architected with Astellas back in 2013. Like our Amgen deal, this deal has also been extended and expanded a number of times. Like our Amgen deal, this deal affords us sponsored research, sponsored development, and joint commercialization rights.
In this case, with focus to the neuromuscular opportunities, we're conducting clinical trials at the expense of Astellas. We similarly can earn over $500 million in milestone payments. Similarly, we can earn royalties that start in the high teens and can eclipse 20 percentage points of sales. Similarly, we have the right to buy up that royalty as could be subsequently monetized and as we may have phase II data to inform that decision-making. In this case, we have co-promotion rights not only in North America, like we have with Amgen, but co-promotion rights in North America and Europe.
That speaks to how we think we can expand our reach and our growth of our commercial business beyond North America for those indications where it makes sense for a company with our access to capital, our bandwidth, to be in a position of leadership where we think there could be a high return on sales and where we think the customer segments are tractable, where the return on sales would be befitting of a company like ours at our stage of corporate development. I hope you understand how, again, being a leader in the space of muscle pharmacology has afforded us deals that we think are unusual, uncommon, relative to other biopharma deals. That's in effect put us in a position where we can continue to innovate, continue to lead, and therefore be in a position today to share with you the expanded R&D pipeline.
That's all captured in a graphical form on this slide. You can see in aggregate, we're eligible for over $500 million in pre-commercial milestone payments before we might have the first sales. We're also eligible for over $500 million in sales-based milestone payments. That's important to think about when constructing value propositions for an investment such as this. That's in addition to royalties that are high. These are not profit-sharing deals. These are not deals where we have to co-fund the commercialization to a large extent in order to get profits, and where those profits can oftentimes be elusive for many years following first commercialization. In these cases, these deals that we have, and we're extremely fortunate to have Amgen and Astellas as our partners, are constructed in such a way that they're responsible for the majority of the spend pre-commercially.
Even post-commercially, they're responsible for the majority of sales and marketing, manufacturing, and other expenses, and we take a royalty off the top line. That's an extremely valuable construct for how to think about shareholder value as the company now matures from R&D through to commercialization. Therefore, in thinking about Cytokinetics' financing history, it's important to drive home a message that's captured on this slide. Unlike most biopharma companies that rely near exclusively on dilutive capital to build their business, Cytokinetics has set a high water mark, we believe, amongst peer group companies in our ability to monetize the innovation, the ingenuity that you've heard about in the deals that we've done in such a way that we've achieved more in the way of already paid-in non-dilutive capital than we've raised through dilutive financings. That's irregular amongst biopharma companies in a pre-commercial state.
We have generated over $600 million already paid into the company in sponsored research, sponsored development, milestone payments, upfront fees. That includes payments we received not only from Amgen and Astellas and Royalty Pharma, but also from Third Rock Ventures as we incubated two of their companies, MyoKardia and Global Blood, within our laboratories. MyoKardia being formed by the spin-out of one of our research programs that led to what is an exciting opportunity for that company in the work that they're doing. In both cases of Amgen, Astellas, and also the work we did with Third Rock Ventures, we have demonstrated that our pioneering expertise, our long-standing leadership in muscle biology and muscle pharmacology, affords us advantages in terms of the way we can monetize this in terms of building our business, and doing it in a fiscally responsible way.
You heard earlier today about how Fady and I have been working together for 20 years, Andy joining us 14 years ago, Brad nearly 17 years ago. The same is true on the business side of our company. Our head of business development, 18 years at the company, our head of corporate development, 16 years at the company. You've heard about our leadership across the senior management. That kind of continuity is essential to build the kind of company that we set out to build a long time ago. Now it's taking root in ways that we believe represent opportunities now from a Wall Street standpoint, as you're hearing from an R&D day, to take a fresh look at this company.
Think about it from the standpoint of the pipeline as presented to you today and the prospects and the promise, not only in early clinical research, but also mid-stage and late-stage clinical research. We're very proud of what we've accomplished by leading this area. In summary, you see that over 20 years, we've demonstrated leadership in cytoskeletal biology and muscle pharmacology. Our R&D team I'd put up against any team in the industry in terms of the ability to prosecute these programs, understand mechanistic biology, translate that into physiochemical properties, evaluating millions of compounds across many different chemotypes and mechanisms of action, understanding the structural biology and how that translates into expertise in the biophysics and the biochemistry of these proteins and these programs, then translate that pharmacodynamically into clinical research. We've conducted many dozens of clinical trials.
We'll have enrolled over 10,000 patients over the course of these next couple of years in clinical trials across over 50 clinical trials to understand how these new mechanisms can translate to potential safety and efficacy. In that way, building what we consider to be an uncommon business with prospects that represent quite significant opportunities for shareholder return. These are the milestones that we've summarized already in presentations to you earlier today, but I'll summarize them here again for you in closing. With regard to 2018, soon we expect to begin patient enrollment in METEORIC, the second phase III study of omecamtiv mecarbil. That should be underway. We're working with Amgen towards a start here before the end of the year.
Also we expect to initiate phase I studies for each of CK-274, what we believe to have potential best-in-class properties, and AMG 594, a we believe novel mechanism, cardiac troponin activator, both enabling study start in Q4 this year. Similarly, we expect Type C feedback from FDA with regard to reldesemtiv as we now have first evidence of a pharmacodynamic effect, a clinically meaningful one we believe, in six-minute walk distance for patients with SMA, we hope to engage FDA in order to understand the tractability of that endpoint for potential registration. In 2019, building on that progress, we expect a first interim analysis, this one being for futility, that to occur in the first half of 2019 for the GALACTIC trial.
Were that to proceed smoothly as we hope it should, we would expect to be completing enrollment also in the first half of 2019, therefore, being in a position to then see how events are accruing such that we might expect a second interim in 2020. If the GALACTIC study goes to its full term, we might expect to see results in 2021. In the meantime, we'll also be looking forward to FORTITUDE-ALS, a study of reldesemtiv in patients with ALS, a study of roughly 445 patients, making it amongst the largest studies ever conducted in ALS, but a phase II study in this case. That builds already on a body of evidence we've generated with over 1,500 patients studied with tirasemtiv or reldesemtiv in ALS.
That puts Cytokinetics in the category of being the company that's conducted more clinical research in ALS than any other company over the last 10 years. We understand this area and its mechanistic translation for fast skeletal troponin activation perhaps better than anybody else, we think it holds great promise for the potential treatment of ALS. I should end the same way that I started. These are patients that we know very well. This is Corey. He has been living with ALS since he was diagnosed in his early 20s, over 10 years with this disease. This is Logan, a patient with SMA who's visited our company. He's toured through our laboratories, met our scientists, for whom we draw great inspiration in the work we're doing in SMA. This is Ryan.
He lives with ALS, he's visited us probably over a dozen times to get to know the company, understand our science, the promise. These are patients who engage with us in very clinically and also personally meaningful ways. This is what inspires us at Cytokinetics. This is the work that we believe ultimately will pay tribute to their courage, the work that we do scientifically, ultimately to accrue benefit, we hope, to these patients, that will be meaningful for the purpose we set out in building this company 20 years ago. With that, I thank you for your attention to our R&D Day. Hopefully, you've learned a lot about the quality, the integrity, the productivity of our scientific platform. We look forward to providing you other updates. We do have boxed lunches outside if you're interested. Please stay if you want.
Otherwise, you can take them with you. We appreciate you spending time with us this morning and also those of you on the webcast. With that, we'll close the session.