Affords us a corporate development strategy that addresses large patient populations 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. Doctor. Fady Malek 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 Wolf to his left is our Chief Medical Officer. Andy is the newcomer amongst this team having joined us over 14 years ago. Andy is in his 15th year at Sato Kinetics, over 30 years in clinical research in the industry.
Brad, who
you will be hearing from later, he is depicted on this slide, has been at Cytokinetics leading our research, now research and non clinical development. Brad is 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. But it doesn't stop there. We continue to add talent as you will hear in the form of Doctor.
Wick Tingley, who joined us within the last year with a distinguished career preceding his joining us at Cytokinetics leading our research and development programs and 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 2 new INDs in recent weeks and will begin Phase 1 studies as they will elaborate for you. We're also honored today to be joined by leaders in both the neuromuscular and the cardiovascular areas, including Doctor. 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, the Irving Medical Center and Doctor. Gincy Andrews, Assistant Professor of Neurology, Director of Neuromuscular Clinical Trials, also at Columbia University. Jackie and Jinci 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 Doctor. John Tierling, Professor of Clinical Medicine at the University of California, San Francisco. John is Director of Heart Failure at the San Francisco Veterans Affairs 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 preclinical research and having overseen from the academic standpoint, the clinical development of Omecamtiv for all these many years. We'll talk a lot about what is ongoing in Phase 3 as he lends oversight to the conduct of the GALACTIC trial.
We're also joined by Doctor. Gregory Lewis. Greg is Section Head, Heart Failure Medical Director and 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 Wyth and Fady and others, the 2nd Phase 3 clinical trial of omecamtiv mecarbil. We are happy to unveil the design of that study at this R and D Day today.
So 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. It's a singular purpose at our core. We continue to 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. And although we may stumble along the way, we will not fall. We turn obstacles into opportunities, which paves the way for triumph. So why do we fight? Because you are our inspiration.
You are our mission. You are worth fighting for.
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 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 1st in class and potential best in class investigational medicines depicted here. We divide our pipeline into 2 verticals, cardiac muscle and skeletal muscle. And 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 and 2 new compounds that we're announcing today, AMG 594, a first in class cardiac troponin activator discovered under our collaboration with Amgen and CK-two seventy four, a potential best in class cardiac myosin inhibitor, both of which have been in the subject of recently filed INDs, both of which we expect to be entering Phase 1 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, and that's being conducted under collaboration with Astellas and independent of Astellas in our laboratories. And 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-six zero one moving in IND enabling studies under our collaboration with Astellas. Today at this R and D day, we're going to be principally talking about omecamtiv mecarbil, reldesemtiv and these 2 new compounds, AMG 594 and CK-two seventy four. They represent for us 5 development programs in clinical development or in preclinical development, all advancing through to important milestones over the next year. You see them depicted here.
Reldesemtiv, and we'll recap these at the end of the presentation, already the subject of a positive Phase 2 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-six zero one 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 1st interim in that time frame, but also starting a new study that you'll hear about today called METEORIC. That will be the subject of a presentation you'll see in a moment. But also AMG 594 and CK-two seventy four, 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. Fadi, as I mentioned, leads R and D at Cytokinetics, and 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, and good morning, everybody, and 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 1 to Phase 3. 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 of our 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. And 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, apartments that sequester calcium, compartments that produce energy, the tremendous amounts of energy that mussel uses. But at the center of all that is a structure called the sarcomere. And sarcomere is an elegant example of one of nature's bio machines.
It's shown here pulled out of a muscle fiber. And 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, sarcomere. So to start, I'm going to first explain and show you what the sarcomere is. So this protein machine, which 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.
And 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 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. But 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 part 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.
And one of the beauties of muscle is that it is its function is so highly conserved from animals to humans. So 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.
And in this assay, we purify the essential components of the sarcomere that I described earlier, actin, thomycin, troponin, tropomycin. And 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 screened over 17,000,000 compounds over the years in this assay. That's a remarkable number.
It was 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. So 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. And so 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. But all of these things contribute to our understanding of the pharmacology of muscle. Coupled with that are a number of capabilities of 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 the technology platform under which much of this hinges. So this is something that's built over years.
It doesn't come together in a single year or even a single 5 year period. The expertise here is something that comes together over many years. And 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 2 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 HADUS lab, we recently crystallized with Omecamtiv mecarbil bound to it.
And 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 the 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 and in the control setting, it's released much faster. And 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 slow the release of calcium. So fundamental understanding of how these molecules work.
There's an experienced team inside of kinetics. As Robert said, some of the members he introduced today have been with us for a long time. But there's also a broad scientific team with a senior scientific leadership there greater than 10 years across biology, chemistry, pharmacology, DNPK, clinical research and so forth. Today, we're going to talk about the output of that research engine. And there are 5 molecules, as Robert said, in development 3, the 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.
And then 2 activators of skeletal muscle, fast skeletal muscle troponin, reldesemtiv and CK-six zero one. Now 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 PKPD 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. And this is one of the strengths of muscle that the functions that we observe preclinically can be explored in the clinic as well. And I'll give you 2 brief examples of that. In respect to our cardiac programs, we have the tool of echocardiography. So this is an ultrasound of the heart.
And 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. And 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. Now 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. But 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. And then the mitral valve, which is kind of the gatekeeper between the two chambers, you can see on the left, it's hardly opening. And that's because the flow of blood from the left atrium to left ventricle is very little. And on the right, it's opening much more widely as the blood flow has increased, in this case, approximately doubled.
Now flipping the transducer 90 degrees, you see a cross section of the heart and here we call a short axis and you can see again the ventricle contracting, the wall here is not contracting at all. It's getting actually getting pushed around by the other ventricle. But after treatment with omecamtiv mecarbil, you see the ventricle thickening symmetrically and this wall has regained some of its function. So those tools help us characterize how omecamtiv mecarbil works in a tremendous amount of detail in a beating heart, both in humans and pre clinically. 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 and as you stimulate that nerve, the muscle contracts, you stimulate it faster, the muscle contract to a greater extent. And what you can see on the left in the green bars after dosing with reldesemtiv is that there's more forces produced at the lower stimulation frequencies, which is what you would predict based on the mechanism of action. And in fact, plotted in a different way on the right, the 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. Now for 3 molecules that we've taken deep into development, tirasemtiv, reldesemtiv, omecamtiv mecarbil.
We conducted trials around the world. And as you can see there in Phases 1, 2 and 3, 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.
So just in summary, here we are today, a pipeline that we'll talk to you about in more detail now with starting with reldesemtiv, going on to discuss omecamtiv mecarbil and AMG 594 as well as CK-two seventy four. So with that, I'm going to turn it over to my colleague, Andrew Wolf, who will take you through our skeletal muscle program in reldesemtiv.
Thank you, Fady. So Fady has already told you, how reldesemtiv works. It's an activator of troponin selective to troponin in fast skeletal muscle. So 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. And when those calcium concentrations increase in response to neural input, does 2 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. So calcium starts that activity. So 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. And 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 a tightly bound force producing state.
So that's what roldesemtiv 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 ores in the water at any one time. Now 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 is 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. And one of the ways that you tell the muscle how much oops, I didn't want to do that.
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. Not usually trying to produce maximal force with any of our muscles. And 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. So 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. So power is important as well. So not just how much force, but how fast you can produce it. And then finally, a consequence of this mechanism is to delay the onset and reduce the magnitude of fatigue that occurs during repetitive stimulation.
So here you can see and this would be consistent with repeated efforts. So you fatigue, right? If you do something over and over and over, you're going to get tired. And 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. But in the presence of reldesemtiv, the onset of that fatigue is delayed to some degree and the plateau is at a higher level.
So there's a reduction in the magnitude of fatigue and the delay in its onset. So 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 the decline in muscle mass. And to improve fatigue or to reduce fatigue ability 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.
So our neuromuscular program with reldesemtiv right now is comprised of 2 therapeutic areas, SMA, spinal muscular atrophy and ALS. We've recently announced the data from the SMA study, which is diagrammed above, and the ALS trial is currently ongoing. We have a lot of experience in ALS at Cytokinetics. As you see here, we have done 6 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, but 6 double blind randomized placebo controlled trials, 5 with tirasemtiv, 1 ongoing with reldesemtiv and 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. And 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. Now 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. But 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. And consequently, by the time we got to 24 weeks, particularly at the highest of the 3 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. And you can see that the increase versus placebo was around 5%, which is close to what we saw in the Phase 2b 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 dorsal flexion of the foot, pull your foot up toward your head, measured the force of that dorsal flexion and then expressed it in terms of the stimulation frequency. And we know that the faster you stimulate a muscle, the more contract 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. So 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. And with respect to the tolerability, as I've already mentioned, I thought we have 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. But even 4,000 milligrams was not intolerable. There was just no point in going any higher. So 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 1 to 1 to 1 to 1 to either placebo or to 150 milligrams twice a day excuse me, 300 milligrams twice a day or 4 50 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. And we have enrolled 3 75 patients so far toward our goal of 440.
So we expect to conclude enrollment soon. CY-five thousand and twenty one is a study in older children and adults with spinal muscular atrophy. It was done in 2 cohorts, a lower dose cohort of 150 milligrams twice a day and a higher dose cohort of 4 50 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.
And it was intended to enroll twice as many patients on reldesemtiv as placebo. And 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 high in the upper 20s, about a quarter, the third to a quarter were under 18 years of age. And 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. And you can see, I think most remarkably, the 6 minute walk distance was around 300 meters at baseline. Forest 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. And 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. And the 6 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 6 minute walk distance. You can see that the change from baseline over time was clearly dose related. And the forest plot here shows each individual patient and how they stacked up. And 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. They had several of them actually had a decrease in their 6 minute walk distance over the course of the study.
The change from baseline in 6 minute walk distance was related to the concentration of reldesemtiv. So here on the x axis, you can see the peak concentration. And clearly, as concentration increased, so did 6 minute walk distance. And 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 to 3 microgram per milliliter range in the low dose cohort and about triple that in the 5 to 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. And 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.
And in fact, I think it's interesting that fatigue actually appeared to be less frequent on rodesemtiv relative to placebo. Interestingly, this increase in the 6 minute walk distance persisted beyond treatment with study drug. So the last dose of study drug was at 8 weeks. 4 weeks later, you can see that the dose related increase in 6 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 tirasemtiv 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. So 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. So another thing that we saw is that as 6 minute walk distance increased, disease burden as assessed by the SMA Health Index, which is a patient reported outcome measure, decreased. So for the SMA high, as we abbreviate it, lower scores are better. They indicate less disease burden.
And the correlations for all the domains of the SMA high and the overall total score were negative, which is good, meaning that as patients could walk further, their disease burden fell. So that's a good thing. And you can see that some of those associations actually achieved nominal statistical significance, including the total score.
So
we believe that the results of CY-five thousand and twenty one showed potentially clinically beneficial effects in these adolescents and adults with SMA and primarily as evidenced by increases in the 6 minute walk distance and in maximal expiratory pressure, again, a measure that correlates closely with cost peak flow, which is probably related to the ability to clear secretions and remain free of pneumonia. And 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 plateau in the effect.
There was no dose limiting toxicity to preclude us from going higher. And 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. So 6 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 United States.
And importantly, the magnitude of the effects that were used to approve these drugs is similar to the effector range that we saw with reldesemtiv around 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 6 minute walk in SNM. We'll talk with her about that in just a few minutes. But it clearly captures disease severity and demonstrates the required properties, reliability and validity in order to be used as a primary endpoint.
And I think that we'll go forward, almost surely using 6 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. And so these type 1 babies who would have died before nusinersen survive, but they survive with substantial weakness and other disability.
So 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. And 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. So now we have a video that features our lead investigator on CY-five thousand and twenty one, Doctor.
John Day. And we'll play that now.
People ask, do you have SMA in your dreams? I do. It's a 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. I mean, there's nothing easy about it. The second that your independence is diminished, it compromises a lot about what you're able to do and the mental toughness that you're able to create on a day to day basis.
2 years ago, I really wanted to start exploring what the options were. I've been taking care of neuromuscular patients, patients with problems of nerves and muscles for more than 30 years. And 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 stamina, for instance, so that patients have to exert less energy to generate the requisite force that they need.
I definitely had more stamina and you know 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's a little bit of help here. Having a degenerative disorder your entire life, and you're 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's 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're seeing. I think that we can benefit patients with a top of these different gene modifying treatments. So it's not just improving 6 minute walk distance for patients who are ambulatory. I'm 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. So I do think there's 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 real decentive, 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. I mean, it really is an exciting time.
Okay. Thank you, John. In absentia, we're going to have a little discussion with 2 of our experts who are here, Jackie Montes and Jinzi Anzrouz, both from Columbia University. Let me start with you, Jackie. You just heard Doctor.
Day and the patient talk about the promise of using reldesemtiv in older patients. And I've mentioned that you have written a lot on 6 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. So over the past 10 years, we've had a pretty broad experience with the 6 minute loss test in the SMA community and not only here in New York at Columbia, but worldwide. And what we found is that it's quite a valuable assessment of walking ability or just the functional ability as well as a measure of an endurance. And 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 6 minute walk test. What we found is that not only is it representative of the clinical 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. And this opportunity to quantify that symptom and then potentially measure it with intervention is quite valuable.
Okay, thanks. So 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. And we didn't really see an impact on that scale despite the increases that we did observe in 6 minute walk distance. What do you think about that? And should we have expected to see them go in the same direction?
I don't think so. The Hammersmith scale, while it's there's no ceiling for ambulant patients. Those last few points to achieve at the higher end of the scare are quite difficult to achieve. And in fact, even in the disease modifying therapy therapeutic trials, we didn't see any changes in the ambulance population and the expanded Hammersmith then had to rely on the 6 minute walk test for that. So 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 about a measure of motor function.
Whereas you would agree perhaps 6 Minute Walk is all about endurance.
Yes.
So let's turn to ALS. Jinzi, 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 Cyto Kinetics. Why do you think reldesemtiv may be better than tirasemtiv in patients with ALS?
So I think I have a slightly unique perspective because I did participate as a principal investigator initially back in 20 10 with tirasemtiv in myasthenia and then the Phase 2a study in ALS before becoming the medical monitor for the Phase 2b study benefit ALS and then vitality. I think I should also point out that I was also the medical monitor for the single ascending dose for reldesemtiv in the Phase 1 study in healthy volunteers. And I think the perspective I have is the fact that we have data on the tolerability and it's clearly different profiles compared to, tirasemtiv comparing tirasemtiv and reldesemtiv. So I think in tirasemtiv's case, both tirasemtiv and reldesemtiv have the same mechanism of action. But in tirasemtiv's case, as we saw the data from the Phase 3 study, I think our ability to evaluate the outcome, the primary outcome, which was low vital capacity, was really clouded by the tolerability issue.
As Andy pointed out, I think, in one of the slides, majority of the patients that contributed to that primary endpoint were not on drugs. So the analysis was an intent to treat analysis. And so if we can't keep the patients on drug, then we really can't truly assess the efficacy. So I think this is where reldesemtiv carries an advantage. So it's the same mechanism of action.
In the Phase 1 study in healthy volunteers, I have to say we did write the protocol to dose up to 4,000 milligrams. And even though we were able to go all the way up to the maximum dose, we really didn't have any I don't think we really hit the tolerable maximal tolerated dose. And so, although there were reports of dizziness, I had the ability to talk to the investigator to give me kind of the characteristics. And it really is different than what was reported with tirasemtiv. So patients with tirasemtiv really had a lot of light headedness, 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 light headedness feeling and it wasn't something that bothered them and really was associated with almost kind of moving per se, almost like we were over activating muscles. So I think there's a clear difference in tolerability. So the anticipation is that I think that reldesemtiv would have an advantage in ALS.
Do you think that relatively encouraging results that saw in our SMA Phase 2 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, right? But what we can take from the SMA study is that what we saw in the Phase 1 series of Phase 1 studies in terms of safety and tolerability was kind of recapitulated in the SMA study. So 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 6 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 signal. One difference is that in the SMA study, we dosed 150450 BID compared to placebo, but we're testing an additional dose of 300 BID. So I'm hoping that we'll get the upper end of the concentrations and maybe anticipate more of an effect.
So 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 Steve. Well, I think so if you look at
the tirasemtiv data from the Phase 3 study, if you look at the people who completed the study, 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 2 study. So I think the tolerability was an issue. I think maximum expiratory pressure, so 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. Maximum, maybe I can have Jackie talk maximum expiratory pressure versus forced vital capacity in SMA.
But I think based on what we saw in the VITALITY study, Phase 3 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.
Shaki, do you have anything to add?
Sure. In SMA, in ambulatory SMA, forced vital capacity is normal. I think that's pretty widely accepted. So in an ambulance SMA patient, we don't even consider forced vital capacity. The maximum excretory pressure has to do with muscles including diaphragm, but also including the core muscles and abdominal muscles and so which are uniquely weak in SMA patients, even SMA patients.
And so I think that the findings that we've had in the Phase II trial and represent perhaps an impact on those core muscles that are uniquely affected in SMA. But I don't expect FVC necessarily to change in ambulatory population.
Thank you. Before we break, are there any questions for any of us from the audience?
Good morning. So Charles Duncan with Cantor. Appreciate all the kind of color this morning. I want you're up to some pretty interesting things going on. Wanted to ask perhaps the KOLs, Jinzi or Jacqueline, about 2 things that I'm wondering about.
1 is about reldesemtiv in SMA and the other is reldesemtiv in ALS. And 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? And then maybe from a company standpoint, what are the kind of rate limiting components of those next steps? So that's in SMA. And then in ALS, I'm really wondering whether or not the dosing is sufficient.
I know, Jinzi, 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 2 colleagues to give their views on the questions that you've asked. In terms of rate limiting steps, I mean, 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 that limitation of exposure gets a little worse as we go higher and higher. So we'll need to explore that.
And it may be that we'll need to wait for another formulation that is currently being investigated and we were 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. So that always adds a little complexity because these are not decisions we can make on our own. But we do intend to move forward in SMA. Jinzi?
Yes.
If I
could just add a couple comments on top of that. So as we've guided, next steps will include the potential of exploring higher doses and dose proportional linearity around exposures with those higher doses as Andy has pointed out. But also we want to ensure with regulatory inputs that 6 minute walk distance, which was seen as having effect with reldesemtiv is in fact acceptable to FDA as a potential registrable endpoint. We believe that in a hypothesis generating study, we've seen a compelling dose related effect on 6 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.
So, 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 dorsi flexion of the foot, the maximal contraction is achieved with reldesemtiv in the 5 to 6 and 7 range of concentration. And the effect that you see is much bigger than in tirasemtiv. So 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 a more pharmacodynamic effect than we would say with tirasemtiv at those doses. So if you look at the graph side by side, the effect is much more potent with reldesemtiv at the lower concentration.
Yes.
And I'll just add to that, that as she said, in the mid range of exposures as well as Esymptiv, you see an effect that meets or exceeds what we saw with tirasemtiv. And again, with tirasemtiv in ALS, I think we have a clinical signal there in terms of the slowing of biocapacity. So 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, but 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' long standing and pioneering expertise in the R and 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 PKPD 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 PKPD relationship to move higher in the dose response curve as may afford us an opportunity to maximize an effect on 6 minute walk distance.
So like any other research, clinical research requires one to take a walk through these kinds of understandings, building on prior observations. And 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.
Last question, I'm sorry to just ask a bunch of questions. But 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.
Thanks. Sure. If I could add, being in the trenches, 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. So 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 6 minute walk test in this population and published literature and an understanding of it that we're uniquely positioned
test the 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. So in SMA, since there's no cognitive compromise, these are very intact patients and the 6 minute walk test is highly reproducible and has great test, retest reliability because of that. Certainly, in any test that requires cooperation and understanding that the reproducibility can be compromised, but that's not the case here in SMA.
Yes. So Chad Messer from Needham and Company. One more question on 6 minute walk in SMA patients. Is there a characteristic sort of pattern of decline like there is in other indications? And if so, what are the implications for designing a trial that would have that as a primary endpoint?
Sure. So I imagine your leading your question relates to our ability to capture fatigue. And so what we know in the 6 minute walk test is in a healthy individual, there you go out the fastest at your first minute, you realize that 6 minutes is a little longer than you might have anticipated and you might slow it down a little bit in the middle. And then inherent in the test, you know the goal is to walk as far as you can in 6 minutes. And so when the timer says you've done 5 minutes, you have 1 minute left, you have the reserve, the capacity to pick it up so that you get your best time.
And so that's the perfect design of a test. And in healthy individuals and in fact a lot of other diseases, the 6th minute is similar or even faster than the 1st minute, meaning that you have a reserve, a capacity to go farther. What we find in SMA is that the 6th minute is considerably slower than the 1st minute. And we've reported that time and time again. And 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.
So what happens in the middle perhaps is in SMA, there's usually the steepest slope in the beginning and then it continues to get a little
bit slower.
Sometimes the 5th minute is slower than the 6th minute, but the 6th minute because and 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. And so I think I hope that gives you a better understanding of the system off task.
Do you normally see the total distance walk decline over time or does it plateau?
So you're talking about the disease progression? Yes. So in fact, we think of SMA as a largely stable disease, but in fact, it slowly declines over time with age. And that slope of decline, let's say, over a year period is dependent on vulnerable age groups. So adolescents, the slope of decline over a year is a bit steeper than in older age, but it's still a decline over time.
So 10 years from today that your patient is going to be worse off on the 6 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. So but I think as Jackie described, it's really over a year. So in a course of a clinical trial that might last 3 to 6 months, I don't know if you'd agree, but probably their function is pretty stable over that period of time.
Certainly. And we've published that in an adult population. It's 9.8 meters per year. So it probably goes to about 5% or a little bit more. So 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 6 minute walk values that would be optimal for seeing changes?
So I guess that's like 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 6 minute walk test criteria. And the reason being is that when we start studying large cohorts, everybody's at about 50% of their predicted. There are some issues with normative data sets and comparisons, so we take it lightly.
But in general, a chronic population is not normal. And a chronic population isn't going to lose ambulatory function in a short study. So 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 III out of IV 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 3 to 6 months out from their hip surgery. So 300 meters represents a significant disease burden, if you will, for these patients.
Patty, if I could, I could tell you that a 5 foot-ten, 30 year old male would likely walk 650 meters. So it's just to compare that. That's a big difference.
And 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. So small differences in muscle function we think can accumulate to making muscle function, we think can accumulate to making their lives easier in a lot of different ways even than the 6 minute walk captures.
Thanks for the illuminating discussion. A couple of quick questions. The first question is George Zavijo from B. Riley FBR. Your mechanism of action is unique.
So 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?
Yes. So maybe I'll take that one. Just in regards to reldesemtiv, so drug interactions you can test in a number of different well established assays pre clinically. And reldesemtiv was designed from the get go to not have any drug interactions because we anticipated it being applied potentially broadly. So 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.
And 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, but 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. So 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. Okay. Then 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? And when they do go off it, what do you see with the decline in function?
Right. So 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. And in fact, even as now what we've transitioned all those patients that want to continue taking drug even as we've suspended development of 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.
But at the time of designing 5,021 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. So 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 ask.
But to your point, it's worth noting that even as we've suspended the development of Tirasumptive, to Fady's point, there are still quite a number of patients who insisted at supporting them some benefit, compassionate access, managed access program indefinitely.
So I can add a little bit of color. So I now am in the clinic and in the trenches, and so I haven't actually shared this with you guys. But the so I wasn't involved. I was the medical monitor. So 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.
But when you're in the clinic, you kind of get the actual flavor for what maybe the patient's experience on study. And so when the press release had come out about the suspension of tirasemtiv 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 3 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 kind of similar feelings where they felt like they were stable and a little disappointed that they are not getting an open label extension. So I'm hopeful that the company would consider that in future development.
Clearly, as we may commit to further development of reldesemtiv, we'll 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're hearing is that, there's great promise and prospects for reldesemtiv based on the things we know. But however, admittedly, there are things that we still need to learn and that's what we do clinical research to elucidate. And we've seen a signal in with this mechanism of action in patients with ALS. We've seen a signal with SMA.
And there's an opportunity for us now to consider how best to amplify that signal in further clinical study. And then last question on ALS.
SVC is going to be the primary endpoint. Are you also keeping an eye on survival?
We are. I mean, obviously,
any time a patient dies, you
record that, you know it. But in a 12 week study, it's unlikely that there will be many deaths. I'll
relationship interplays with some of the other outcomes, including the overall ALS functional rating scale and overall survival and other data sets. So I think there's a little bit more understanding of its relationship and importance.
So Jitsi, 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?
Yes. So the first thing to George's question was the drug drug interaction. So I think that was one of Tirasemta's major handicaps is that it did interact with Rilizole, right? And so Riluzole was standard of care at the time when we're doing clinical trials with tirasemtiv. So reldesemtiv does not have that handicap.
And so 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 kind of plays a complementary role some of the other investigational therapies that are out there. A lot of them are targeting motor neuron degeneration, so 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 being having neuroprotective mechanisms.
And then there are some therapies that are targeting gene or genetic mutations, which were all part of at Columbia. And so all of these may not necessarily cure the disease or maybe activation can play in the setting of all of these other kind of mechanisms, targeting the activation can play in the setting of all of these other kind of mechanisms targeting motor neuron degeneration and gene directed therapy.
Thank you very much.
Anyone else?
Thanks. Jeff Hung, Morgan Stanley. So Doctor. Montes, on the 6 minute walk test with regards to fatigue, could you elaborate on the 6 minute being slower in SMA patients? Like how much does this vary in patients based on the instructions that they receive?
So the new fatigue that we've demonstrated and published over the years ranges from about 17%, 18% in the 20%. So there's about a 20% decline in 6 minutes, the first minute. The test is administered in SMA as per the ATS guidelines. It hasn't been adopted at all. And so the influence of instructions, I don't believe to impact the performance.
And I think that's proven true with the depth of our work that we've done so far.
Great. Thanks.
Any other questions? Okay. If not, we can break for about 15 minutes. There's coffee outside the room and maybe some other things as well. And 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. So 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 2 you're learning about for the first time today. So 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 are very pleased to be able to not only describe to you progress we are making with omecamtiv mecarbil, but also 2 new programs that are advancing into Phase 1 this
year. Okay. Well, welcome back. And again, it's really going to be a great time to talk about our cardiac muscle programs. Today, we'll be able to talk not just about D, but also about the outputs of R, which really make this an R and D day.
But 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. But to put it in context first,
I want to
talk about the therapeutic area that we founded the work in muscle biology on, which is heart failure. I guess it's no coincidence we started in this area given my background and training. But just as an overview, their heart failure is a condition where the heart just can't meet the needs of the body in terms of pumping blood. And you might be surprised to learn that there are 2 kinds of ways that that happens. The obvious way I think is that you have decreased cardiac contractility, the heart is 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 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 heart, 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. And many other conditions as well, they're not all listed here, that are as a consequence of the consequence of them lead to decreased cardiac contractility. On the right hand side of the slide though, you also see that there's heart failure that's due to increased or preserved cardiac contractility and that seems a bit of an oxymoron.
If your heart is working well, why would your heart be failing? But 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 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. And in total, this is an area that affects millions and millions of around the world. So 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 of them about them. So half rep or heart failure with reduced ejection fraction is what is the most common type of classification of heart failure that is used in the United States is maybe about 3,000,000 individuals that are affected with this, about 1,000,000 patients hospitalized every year with heart failure. And if you've been hospitalized with heart failure, it is a dire and very potentially important with regards to your prognosis event that has prognostic implications. 30% to 50% of patients may die within 60 days after being hospitalized, 1 year or are rehospitalized, obviously many more of them are rehospitalized and die because the 1 year mortality 20% to 30%, 5 year mortality, 40% to 50%, a very serious medical condition that I think is underappreciated in the general community. So despite the fact that there are many treatments that exist for HFpEF, there still is a huge unmet need here.
Hypertrophic cardiomyopathy or HCM is a disease of preserved cardiac function or even hypercontractility. It also is it's a disease of the sarcomere. This is a condition that comes about because of mutations and 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 myomectomy or percutaneous ablation. But 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, improve patient symptoms. In terms of the therapeutics that target the cardiac sarchemere, 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, our cardiac sarcomere activators, omecamtiv mecarbil works on the sorry, works on the myosin. But as you'll hear later, a new mechanism of action in terms of cardiac sarcomere modulation is a troponin activator. You heard about reldesemtiv, which is a skeletal muscle troponin activator.
Together with Amgen, we've optimized and developed now AMG 594, which is a cardiac troponin activator. And then in the gray box to the right is CK-two seventy four, a cardiac myosin inhibitor that may have application cardiomyopathy or has application in that area as well as potentially others and targets the myosin here. So you remember earlier when I spoke, we talked about screening an intact sarcomere that has all of these key components present and it affords us the opportunity to identify and discover modulators of sarcomere function that may have different targets. And this has now led to 3 molecules of 2 different targets, 3 different modes of action and many others that potentially may emerge from this platform. So the first molecule that we put in the clinic as a modulator of sarcomere function was omecamtiv mecarbil.
And we'll talk mostly about its development here today. But 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 is binds ATP, hydrolyzes it, undergoes that power stroke, brings the active filament to the 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 and intact muscle, it does so without increasing the calcium in the myocyte, which is the trigger for contractility.
And 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 heart rate, which are important clinically, as maybe we'll discuss in the panel. And we found it doesn't increase oxygen consumption as well. Now omecamtiv mecarbil has been studied extensively in a Phase 1, 2 and now 3 program.
And as we've, I think, mentioned now several times, this is a hallmark of the clinical research that we've done and 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 1000 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. So 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, but 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. First, there were Phase 1 and Phase 2 studies in healthy volunteers, patients with heart failure, where we examined the effect of various doses, a broad range of doses that were examined using echocardiography. So I don't have any movies to show you in this section, but you saw earlier a picture of a patient with a being treated with omecamtiv mecarbil. So ECHO can be also quantitated in various numbers derived from those pictures. The ejection time, which is a measure of how long omecamtiv mecarbil, 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.
And in other metrics such as stroke volume, the amount of blood that's 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. So you can see a number of points on this plot and what underlies that is a measurement done in patients for each and every point. There are several 100 points on this plot that help us understand the pharmacokinetic and pharmacodynamic relationship of omecamtiv mecarbil. Now 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 how the what the consequence was of more chronic dosing and also obviously develop a dosing regimen that could be employed in Phase 3. 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 twice a day as a fixed dose. And then what we call a PK titration arm, where patients were started at 25 milligrams twice a day and then up titrated to 50 milligrams twice a day, depending on their exposure of the what their exposure was at 2 weeks of 25 milligrams a day. So this is personalized medicine.
If you exceeded a target, which was 200 nanograms per ml, there was really no need to further up titrate you. And so you were left on 25 milligrams. Alternatively, if your exposure was lower, then you're up titrated the higher dose to increase your exposure. Now, having applied that, both led to pharmacodynamically active exposures and what's shown here is the measurements of cardiac function and dimensions that you'll see subsequently as derived from echo echocardiograms that were obtained in these patients at baseline 12 weeks 20 weeks. So 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 ejection, the total cardiac cycle in these patients is about 800 milliseconds. It represents about a 5% increase in the total ejection time. But that increase in contractility, as seen by ejection fraction and fractional shortening, also leads to an increase in stroke volume. The other besides the changes in function, we also had evidence that there were changes in structure.
So again, if you remember from the video I showed you earlier, that patient with heart failure had a very large enlarged heart. That's a consequence of what happens in heart failure. And 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. And that's the 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, higher your heart rate is, the worse your outcomes are. We saw here that heart rate declined in concert with treatment over time. And then 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 it's 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 marker, 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' drug Entresto, where a decrease in NT proBNP was very tightly correlated with a fewer number of cardiac events, be it in cardiovascular death or rehospitalization. And then 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.
So end diastolic wall stress is related to the filling pressures in the heart, how big the heart is, how thick the wall of the heart is. And as you can imagine, less stress is better. That's true across many domains of life. But here, again, what you see is a nice correlation of a decrease in NTGropinP in terms of end diastolic wall stress. And 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 are what's its relation to potential cardiovascular outcomes. And this is derived from a meta analysis that looked at many studies of LV volume and the decrease in LV size over course of a therapy that was applied and 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. So all of these things together were taken into account as Cytokinetics, Amgen and its partner Servier as well thought about moving forward into Phase 3. Safety was obviously also an important consideration. And here cardiac serious adverse events were relatively balanced between placebo and the various different groups.
There were no significant differences in these 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, 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. And here, we saw a very small increase about 10 times below the 99th percentile, the upper limit, what we call the upper limit of normal. And since it is used as a marker of cardiac ischemia, we look for whether any clinical events were associated with these increases in troponin.
So every time troponin increased, the site was queried about that patient as a potential event. Troponin oscillates in heart failure, goes up and down. And so you generated a lot of these events, 278 total events. Remember, there are only 4.50 patients in the study. And all of them were adjudicated by Central Events Committee for potential ischemia, 0 of them were positively adjudicated.
So I feel like we've maybe put this to rest here, but obviously it's still something that we can only tell whether the balance of this signal versus everything else is positive is by conducting trial that looks at clinical outcomes, which we'll talk about next. Inclusions are here. And as I said, COSMIC was penultimate study that led to the design and implementation of GALACTIC HF. So GALACTIC HF is a cardiovascular outcomes trial. It's a global approach to lowering adverse cardiac outcomes through improving contractility and heart failure.
John Terlingst and 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. And I've had the privilege of working with him over many years now on this program. But 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. So 8,000 patients in 35 countries at about 1,000 sites around the world.
And 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 is 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 of CV death, with 90% power to discriminate an improvement in CV death, which implies it's overpowered for the primary endpoint. But we're also looking at 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.
So we talked earlier about personalized dosing. And here, we've applied that same principle in GALACTIC. We've introduced an intermediate dose. So patients are started at 25. They then may be titrated directly either the 37.5 or 50 depending on their plasma level at 2 weeks.
We also in this study are enrolling patients from both the outpatient setting, but also the inpatient setting. So 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. And 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 8 weeks. And then they go on to be followed. It's an event driven trial. And so we need to accumulate the number of events that will lead to the readout of the study at the end of the day. So 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 twenty nineteen.
We've, I think, enrolled the patients that we intended to enroll, which was a high risk population. The entry criteria produced, on average patient population with an EF of less than 30%, a time from last hospitalization of less than 4 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, and 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.
And there are 2 analyses, 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 twenty nineteen. That really will just tell us to continue or not. And then 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. So today, I'm going to talk about something in more detail that's new, which is METEORIC HF.
And 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 and PeerLink is also involved in the steering committee and a number of others from countries in Europe as well as in several in North America. And the real muscle behind this is Whit Tingley, who is leading has led this study and leads it from cytokinetics perspective. So 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. And, METEORIC is designed to evaluate whether omecamtiv mecarbil improves exercise capacity in patients with heart failure.
So as you might know already, one of the cardinal symptoms or features of heart failure is that people have reduced exercise capacity. And 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. So this study will look at the effect of omecamtiv mecarbil on exercise capacity. And 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. And the primary endpoint will be the change in peak VO2 measured by CPET from baseline to week 20. There are other secondary measures that look at different ways of quantitating exercise capacity with CPET, but 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 2 week period at baseline and then a 2 week period prior to the conclusion of the study. So the trial overview is shown on this slide here. And what we'll be doing again is randomizing patients, but now in a 2:one fashion.
So twice the number of patients will be randomized to omecamtiv mecarbil and the 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 or 5.5 or 50 milligrams depending on their exposure at 2 weeks. There is a screening CPET and that is one of the key entry the their ejection fraction. And as I said earlier, 20 weeks of therapy and 90% power to observe a difference in peak VO2.
So the entry criteria in some ways are similar to 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, but there are some specific changes that are relevant to METEORIC itself. So they need to, what is key here is looking at for patients that have reduced exercise capacity. And so they need to qualify for this study by having on an exercise test a peak VO2 that's 75 percent of predicted normal value.
And 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 3 months because hospitalization has some very acute effects on exercise performance. And then 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 is 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, somebody with less bit compared to more bit as they exercise.
And 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. So 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. And so 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.
So this now begins the R part of our R and D Day. And we're very fortunate to be able to tell you about 2 new molecules that have come out of our labs, 1 here developed in collaboration with Amgen. And I'll turn it over to Brad Morgan, who will take you through that to begin with.
Thank you, Fady.
So Fady spoke eloquently about Cytokinetics' long standing expertise in muscle biology and how we've been able to apply this expertise to discover and develop novel molecules that modulate muscle contractility. Now I'm excited really to share with you how we've been able to extend and expand this cardiovascular franchise to 2 new molecules that are entering clinical development for the treatment of heart disease. Now the first story I'd like to share with you is an extension of our cardiac contractility activation franchise as the result of a 5 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 1st selective cardiac troponin activator.
Now 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. Now turning over to our the base of our pyramid. In this research collaboration, we screened over 1,500,000 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 2 where we took in vivo to optimize both PK and PD of these conferencing, where we selected AMG 594, the first selective cardiac component activator. Now 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. And it's 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.
So what did we end up finding from these optimization efforts? Well, cardiac troponin activators are selective. You can see here in our primary and some of our primary assays, Fady has 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're 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's been reconstituted, 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've lost that activation. And another sarcomere that's 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. Well, as I've mentioned, we need to make sure there's 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. And in these cells, we can show that cardiac component activators can activate or extend the cell length of these cells and the absence of showing any change of cardiac transients measured by FURA ratios in these cells.
These results consistent with direct activation to sarcomere as our mechanism of action. And finally, I've mentioned the biggest component for the optimization of that as ensuring a clear pharmacokinetic, pharmacodynamic relationship. And most importantly, is trying to get a wide pharmacodynamic window and optimizing for that pharmacodynamic window. This shows cardiac component 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've induced a myocardial infarction, these rats have decreased contractility similar to patients with systolic heart failure.
And 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. So hopefully, I've been able to show to you how our 5 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 preclinically. With that, I'll turn the podium over to my clinical colleague, Whit Tingley. Whit's a physician scientist and cardiologist extensive experience in clinical development.
So based on the robust preclinical results that Brad has just described, we are happy to say that Amgen, in collaboration with Cytokinetics, will launch the 1st 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 doses and multiple daily doses up to 7 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, 5 of them followed by 3 multiple ascending dose cohorts. Each cohort will have 8 healthy subjects randomized 6 to 2 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 preclinical results we've seen to date raise the possibility of testing 594 in patients with heart failure to due to distinct varieties of left ventricular or right ventricular systolic dysfunction. So 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 study in Phase II. In summary, we have selected AMG 594 as a next generation cardiac inhibitor from among or more than 1,500,000 compounds in 80 distinct molecular series because of its unique potential and robust preclinical 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 for convenience and compliance.
We will enter clinic this year with the 1st 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. So second story I'd like to share with you is really an expansion of our cardiac sarcomere, a modulation franchise. This story is now the discovery of what I believe to be the best in class cardiac myosin inhibitor, CK-two seventy four. So we've had expertise in myosins for many years at Cytokinetics. Fady has already talked to you about the X-ray of cardiac myosin obecamtiv 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 discovery of various inhibitors. Now, because of the different modes of binding to myosin and the different targets of inhibiting esarcomere, is 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 heads based on the performance in our well established assays over the years. We can target even the we can target either the myosin motor in multiple different modes or we can target the regulatory complex to decrease sensitivity on this. Well, what we've been able to do is to identify distinct classes, distinct chemotypes with multiple mechanisms of action at inhibiting the sarcomere. So from that has arrived CK-two seventy four, potentially the best in class cardiac myosin inhibitor.
Now 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 looked at we've advanced 15 of these to some optimization studies where we've characterized them extensively in vitro, Taken 3 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-two seventy four. Now 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. And again, a wide pharmacodynamic window within these patients. Well, this is research that's still ongoing. We have this is an example of many of the 6 series that we've begun optimization on. These series are different both different chemotypes and multiple mechanisms of action, of which our most advanced series, Series A, we have selected development candidate CK-two seventy four, along with several other compounds who are currently exploring and expanding the range of therapeutic applications of this mechanism.
We are continuing with research to try to look at potential advantages of other chemotypes or other mechanisms of actions of inhibiting the sarcomere. So why did we choose CK-two seventy four as our first development candidate for HCM? Well, 1st and foremost is its favorable pharmacokinetic and pharmacodynamic properties, as well as all the other criteria we go into for candidate selection. It's a selective allosteric inhibitor, 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 amycin and it has favorable properties in ADME and PK.
Now these PK optimization allows us to have projected once daily dosing to rapidly reach steady state in these patients. And pharmacodynamically, it's been optimized to have a shallow dose response curve, which may translate into favorable therapeutic window and broaden the clinical utility of this mechanism. Now some of the characteristics of CK-two seventy four 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 myosin cardiac myosin is indeed our target with these compounds. So how does this really then work within the context of the whole sarcomere?
We've had many years of studying the sarcomere and as shown here in the actin myosin cycle, you have a weekly bound and a strongly bound state. Strongly bound state is when myosin is bound to the actin is the force generating process to the sarcomere. Through stop flow kinetics, we're able to show that CK-two seventy four slows the transition from this weakly bound to strongly bound state, which is the equivalent of having fewer myosins in the strongly bound state. So 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 don't change calcium transients and indeed we're targeting the sarcomere with our activity.
You can see here again in cardiomyocytes, primary cardiomyocytes, we're 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 compounds. And finally, as I've 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-two seventy four. And to put into it, this is really at 5% to 10% is really where we want to be efficacy in our clinical trials.
In 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.
Now in these mice, it takes a normal heart and with the sarcomere 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, and 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.
Now when these mice are treated with our cardiac sarcomere inhibitor, you see initial upswing and then a normalization or decrease in that hypertrophy of these mice, similar to the wild type or the control mice, the wild type with a cardiac myosin inhibitor. Now, in the second model of cardiac hypertrophy, one of the hallmarks of this hypertrophy is also a fibrosis that can happen in the heart. Now we're able to take a model, this is now a rat model, a dull salt sensitive rat model. This is a rat model where when fed a high salt diet, these rats develop hypertension. This hypertension then translates into a cardiac hypertrophy and a fibrosis within the heart.
And you can see here, just based on the histology, the low salt diet and the high salt diet on trichrome staining, you can see much bluer content on the high salt diet in these rats. You can see that these rats when dosed and fed with the cardiac myosin inhibitor look much more like the low salt than the high salt. That can be these images can be quantitated as shown in the graph on the right to show an increase in fibrosis from 1 high salt diet and a normalization of 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. So with that, I hope I've been able to show to you how we've been able to really extend and expand our contractility into what we believe to be the best in class sarcomere 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-two seventy four are very exciting, projected human PK adequate for once daily dosing, rapidly reaching steady state and a wide pharmacodynamic window. Now I've been in the pharmaceutical industry for about 30 years of my life devoted to discovering novel mechanisms of treating disease. And I'm very excited that we have this we filed an IND in this program.
And with Tingley, again, we'll take you through the way we plan to study this in the clinic.
So 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 and they cluster in 11 genes and 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 and interstitial fibrosis, 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.
So 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. Now the feature that stands out most in hypertrophic cardiomyopathy is the thickening of the muscular walls of the ventricles. And 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. Now the hypertrophy of the ventricle is not symmetric in most cases. And in twothree 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. And 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.
So the severity of disease can be quantified by measuring this pressure drop, which can be done by echocardiography non invasively. 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.
1 in 500 Americans are carriers of these mutations. But fortunately, many patients are stable without substantial symptoms. But 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 stroke, 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.
And the dosing of these medications is often limited by systemic side effects. So 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.
And it's only available in a small number of centers in the United States, those centers that have high volumes, so that they can have low complication rates and many patients don't have access to these centers. So we will initiate the 1st in human study of CK-two seventy four this year with a nested sat 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 8 single ascending dose cohorts and 3 multiple ascending dose cohorts. Again 8 healthy subjects per cohort randomized 6 to 2 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 1st in human Phase 1 study, we will do a small Phase 2 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 a pivotal Phase 3 study using cardiopulmonary exercise testing, as Fady has described, to measure exercise capacity and look for improvements in exercise capacity with treatment with CK-two seventy four. 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-two seventy four. And in parallel, we'll run studies in other patients with hypertrophic cardiomyopathy that do not have outflow tract obstruction called non obstructive or NHCM.
So in summary, CK-two seventy four 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 and its PK projections that support potential once daily dosing. And the PK is particularly important here because we want to titrate the dose to the effect using echocardiography. So we can start a dose, get to steady state and then measure that gradient across the LV outflow tract and then change the dose if needed to optimize the effect of the drug and having the appropriate PK to allow efficient titration is critical for this disease.
We're advancing into clinical development. We filed the IND and we have an efficient clinical development plan with robust PD assessments to measure the exposure response relationship in early clinical development. So I'd now like to hand it back to Fady to moderate our discussion with our distinguished
colleagues. Okay. Thank you, Whit. Well done. And we'll go ahead and move on to the Q and A.
We'll invite questions in just a moment. I may start off discussion, but I do encourage you all to think of and contribute to this panel discussion. So maybe I'll start first with METEORIC, METEORIC being a trial of omecamtiv mecarbil effects on exercise tolerance. And Doctor. Lewis, maybe you can just explain based on your experience in exercise capacity trials and why might we expect the mechanism of action of omecamtiv mecarbil to increase exercise capacity in heart failure patients?
Sure. So first of all, 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 a room. So 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 excite tests before and after exposure to the drug. In terms of why we are encouraged by the findings to date and the ability to improve excess 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. And 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. So 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 CF 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 or synchronization 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. So there is historical precedent for improving this endpoint. Johnny, do you want to add?
No. I mean, as someone who sees these patients every day, that when they come in, this is their main concern. They say that they can't do things. And so 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.
So maybe moving to the results of the Phase 2 program and COSMIC. John, you as the leader of GALACTIC HF, our outcomes trial, how does the Phase 2 program, which you had a large part in, contribute to your confidence in terms of the outcome, potential outcome of Lactic HF.
Yes. I mean, I think one of the things that's really been very interesting about the cardiac myosin activator program with omecamtiv mecarbil is it finally provides an opportunity for us to test a hypothesis that has been around for over 100 years since the initial discovery of ADRENALIN. And since that discovery, the hypothesis has been that somehow by improving cardiac performance, we can help patients feel better and live longer. And 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. So the 2 main Phase 2 programs, the Atomic HF study and COSMIC HF provided kind of the bridge between the excellent preclinical work that Doctor.
Morgan and colleagues did at CytokinX towards the GALACTIC HF trial. And so the ATOMIC HF trial looked at over 600 patients with acute heart failure. So these were sick patients hospitalized for heart failure and we administered intravenous omecamtiv mecarbiliz patients and we're able to show that the agent was very safe in that patient population and in the highest dose actually improved their symptoms. So it was able to show that made the patients feel better in a safe setting where they were otherwise hemodynamically and otherwise decompensated. So that provided us a lot of comfort saying, this is an agent that we can give to patients who are hospitalized, who are sick and feel comfortable with that safety profile.
Then when we moved into COSMIC HF, we had the 20 weeks of therapy. And as you alluded to, in this study, we were able to show not only that select a formulation, but also all 6 of the pre specified primary endpoints were met in that trial. And so in that way, we were able to actually show improvements in volumes, improvements in dermal 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. So these all bode very well for the potential success of GALACTIC HF and are some of the strongest predictors.
The volumes in the NT Probuium piece, as you point out, some of the strongest predictors of improved outcomes in patients with heart failure and reduced ejection fraction.
Maybe one more question and I'll throw it open to the group here for Greg. Because we've talked about quantitating exercise capacity earlier with regards to using 6 minute walk in patients with SMA and 6 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. So the exoSPESSI is the primary endpoint of this study and 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 cardioplmonary 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. So it's commonly used in patients that have heart failure already and 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 6 minute walk tests imply about endurance. During cardiobromic exercise testing, we subject patients to the 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. And so 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.
So we have a lot of precision there in this measurement. And fortunately, it's getting easier and easier to do in terms of the modern day metabolic hearts and how they perform. It also permits us to do a smaller study. The test to test variability in peak VO2 measurements is lower than it is in 6 minute walk in heart failure patients. And as a result, it can reduce the sample size that we're doing for the trial.
Okay. And with that, maybe I'll throw it open to questions from the group.
Thanks. Geoff Hong, Morgan Stanley. The first question is for Doctors Tier Link and Lewis. What do you think the bar is for METEORIC to show clinically meaningful differentiation in exercise endurance?
Yes. So again, we have a lot of data accumulated in heart failure patients. Just to frame this a little bit, I know there was discussion of 4 and 6 Minute Walk. Where we expect these patients to be is somewhere in the range of about 13 milliliters or 14 milliliters of oxygen per kilogram per minute. That's a typical exercise capacity in patients with heart failure.
And what's been shown to be a clinically meaningful improvement is if somebody can increase that exercise capacity by 1 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. And so that's been shown in other clinical trials. It's also been looked at in the large HF ACTION study and a for every 5% increase in peak VO2, which the 1 ml per kilo per minute would be more than, there's a 6% reduction independently shown to reduce mortality in patients with heart failure, reduce CF. So that's a bar that we would like to exceed in terms of an effect size.
Great. Thank you. Maybe
just for context, in a healthy individual, what would their peak VO2 be approximately? And then what do you think Lance Armstrong's off of EPO would be?
All in all, that's EPO.
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. But no, for an elite level athlete, 70 ml per kilo per minute, which is, by the way, all of us right now are using about 3.5 ml per kilo per minute just in terms of the resting state and that's one metabolic equivalent. So an elite athlete can increase that metabolic rate by about 20 fold. In the heart failure patient, it's only 4 fold. So that 14 ml 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 in the same age range is more in the mid-20s.
There is an age dependence, weight dependence of these measurements, about 25 to 30 ml per kilo per minute, which permits you to conduct activities of daily living. So 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. And then one question for the company. How is CK-two seventy four different from myocardia's mavacamten? And given the history, what is your current thoughts on how they might differ clinically?
Well, I think we developed our drug with to keep in mind what would it be the optimal properties of a molecule that might be applied in this condition. We as you can tell from the presentation, we used our experience really in what PKPD means, what pharmacokinetics means in these populations, how do you apply these drugs in the clinic. And we think without getting into specifics that the what we did to optimize this molecule will lead to potentially a best in class potential. And that relates to convenience of use, ability to up titrate, potentially achieve greater efficacy in the presence of better safety. And all those things are part of the calculus that went into selecting 2 74.
Thanks.
Great. Thank you. Two quick questions for the company, if I may. Firstly, with respect to METEORIC, would that be the 2nd Phase 3 study required for approval following GALACTIC? And would there be other clinical trial requirements for an NDA?
So I'll answer that, but I'll also ask John to comment as well. So GALACTIC HF is the only trial that's required for the registration of omecamtiv mecarbil in terms of its efficacy. I mean, there are obviously a lot of trials that contribute to its registration. But 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. And then secondly, is there any milestones associated Amgen collaboration? Let me just add a comment on to what Fady said and then 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, 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, but 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 where we to also see an effect on increasing exercise duration and stamina. And so we think that translates into positioning for this new mechanism, especially relative to other heart failure therapeutics. You heard mention of the fact that the device world, there's evidence that having left ventricular assist can translate into increased exercise duration and stamina. And we think a pharmacotherapy that may have also that advantage would play well to 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. So 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. And in some of my summary slides, I'll point to what might be expectations for key milestones coming forward.
Hi, thanks. You have 2
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? And strategically, are you thinking of 5
minute 4 as a follow on thalbecamtiv or perhaps to
be used in combination later on?
So 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. But I don't think likely that they will be used together in combination and we haven't really looked at their combination preclinically either. Maybe, John, you want to comment on whether you think there would be any role to combine them?
Yes. It's an intriguing possibility and one that I've also considered, but I don't think it's going to be pursued right away. And 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, there's 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 the spending 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. And now this whole class of agent has no effect on any of those agents of those aspects. And so omecamtiv mecarbil and these class of agents can be added in at any time in the patient's clinical course. And so that's our huge advantage to it.
We'll actually not only 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. And it won't be so complicated to try to fit into the current armamentarium of agents that we have. So that's
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. So 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 PKPD relationships and how that may translate into potential clinical benefit. But ultimately, we'll learn a lot from the 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. So this is an opportunity, I think, for us to look at what may be different physiochemical 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 cystolic dysfunction to other heart failure patients.
As a follow on,
have you stopped development of the IV formulation in
the acute setting? Is it all going to be now
oral in the chronic setting?
So right now, we're developing omecamtiv mecarbil orally, obviously. But the IV is still something that we keep in consideration in terms of how it might be applied as we understand omecamtiv mecarbil 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. So that is I think in a very important setting where patients' therapies get optimized and potentially new therapies get added. 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.
And with an IV, we might look at even earlier in the hospitalization, how we might intervene. But that for now is a later time thought in the development program.
As many of you may know, other programs have had to actually do separate trials to say, okay, they can start drug in And so 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. So that is why it's important to try to have included that in the GALACTIC HF program.
Yes. I'd say with respect and 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 3 studies and whether that might afford us an opportunity from a life cycle management standpoint to consider again how we could expand the franchise. Okay. Thank you very much.
Charles Duncan, Cantor. Thanks for taking my follow-up questions. First question for Doctor. Tierlink. For GLASTIC, 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 be consider that clinically meaningful?
So what we usually like to see is about a 15% reduction in terms of the relative risk of that event the combined event of heart failure hospitalizations and cardiovascular death. And that's what we're clearly powered to see. And we will be having, in the interim analyses, we'll be looking at effects that are much better than that. And so 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 Doctor. Malek already alluded to, that is looking for the really shooting the moon type benefit where we have to stop it.
So we're looking for about 15% in terms of relative risk reduction in terms of the primary endpoint.
And 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. Yes. I understand that,
but what is the assumption?
So we haven't been very specific for intentionally as to how the futility analysis is being conducted. But essentially, what you'd like to ensure at this point in the trial that there's no cumulative harm to patients and that you certainly don't have your curves diverging in the wrong direction. And if that was the case, you wouldn't want the trial to continue indefinitely and EDMC would want to do something about it. So a futility analysis is primarily looking for not a lack of efficacy, but more of a signal of things moving in the wrong direction of harm.
To quote Doctor. Andy Wolf, who uses this expression when thinking about these things, we want to rule out potential badness. And 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. And this DMC has followed the entire omicamtiv program. So they have kind of the cumulative safety and have seen all the data from the program for the main part of the program all along the way. And so we feel very comfortable with them kind of championing the or shepherding on the program in GALACTIC HF.
That's a really important point to underscore. So this often gets lost in conversations such as this with Wall Street analysts and investors. So 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 2,005.
But 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. And 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. And 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.
But don't ever underestimate the power of the clinical research and the people who are involved, 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.
Yes. I was going to comment, I think, Doctor. Terlingk, you're gracious enough to be on a KOL call that we hosted 12 years ago or so.
Well, just to expand a little bit on what Robert said, it's really a commitment by these individuals over a long period of time to which I and others many others are extremely grateful. So we know John has been involved for a long time, but as he points out, the members of the DMC have invested several years of time in this program, members of our executive committee similarly. And I think it's a clinical events committee. It's a I think a real testament to their interest
and I'm enormously grateful to their commitment. And potentially differentiated profile of the omecamtiv. Let me just ask you then as kind of a follow-up, Doctor. Tierling. It would seem like the trial is and I hate to say overpowered because I don't like to say robustly part, let's say, that it's a robustly trial part 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? Out.
So I think I'd modify your statement and say that it's appropriately powered, because it's appropriately powered to look at cardiovascular death. And so I think one of the questions in regarding and actually, it's there's a more recent the recent trial that was done in another agent with heart failure was about the same size. So this is the size that, for better or worse, is where we're at with heart failure outcome trials now. So it is appropriately powered to look at cardiovascular mortality. And 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 hospitalization. So we will be able to see whether we do that in conjunction with cardiovascular death. But even if we reduce the combined endpoint, people will still say, well, what's the potential effect on cardiovascular death? And so we'll be able to answer that hopefully appropriately with this trial. Did that address your question?
Yes. That answers my question. Last question, Robert, 594 composition, amander patent, when does it go to?
So 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.
Chad Messer at Needham and Company. Can you discuss the preclinical tox findings a little bit more on 2/74? What you ran into, is it all related just to cardiac insufficiency or are there other things?
Well, so you said it yourself. It's a mechanism of action that reduces cardiac function. And as you could see from the curves of PKPD that Brad presented, it can have a substantial effect on reducing cardiac function. So in our tox studies, what we've observed so far has been consistent with its primary pharmacologic effect. And we expect the toxicity of the molecule to be related to its efficacy or I think an over application of its efficacy and that's where you want to be truly in a program being able to titrate the 2 against each other.
But we haven't seen anything so far anyway that is inconsistent with its mechanism of action. Okay. So 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
angiotensin we have the angiotensin converting enzyme inhibitors, angiotensin receptor blockers and the angiotensin receptor nephrolizin inhibitors, all of which can decrease blood pressure, increase potassium and decrease renal function. And so when you initiate those agents, you have to follow-up and you get frequent blood laboratory tests to follow those aspects. And then when you try to figure out how are you going to add in the mineralocorticoid receptor antagonists like spironolactone or plarinone, now you also have to worry about effects on renal function and potassium. And then you throw in the beta blocker, which is really, really useful, but decreases blood decreases heart rate and blood pressure. So it interacts with those agents.
And then if you get this far, now you have to think about evapradine to try to take care of the heart rate further. And so you only have 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. And so it requires a lot of work for busy physicians. And one of the sad aspects of heart failure therapy is that much of it is not done by cardiologists and 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.
So from a purely pragmatic standpoint, omecamtiv mecarbil will be able to fit 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. So we will be able to intervene during almost the entire disease cycle of heart failure. Greg, do you
have anything to add?
Yes. And I completely agree. It's 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 kind of 1 at a time. So you end up putting on tiny doses of one medication or another.
So 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, major advantage in these patients. And 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. So at my hospital that has 1500 beds, there's over 100 patients admitted at any given time that carry the diagnosis of heart failure. And so as heart failure experts, we can't get around to see all of them.
And so 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. And there are a lot of patients who are truly cardiac output limited, particularly as you start to get into later stages of heart failure. And 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. So the idea of an agent that improves cardiac performance that can be taken in toll form right up through the more advanced phases 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. And 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. And 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 one reason why Medicare patients are hospitalized in the United States. 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.
So 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. So 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 is probably a question for Fady and Doctor. Lewis. For agents cardiac remodeling in patients that showed a significant effect on peak VO2 at week 20?
So because there's a close tracking between peak VO2 measurements and heart failure severity and cardiac remodeling is an indicator of that. And I would be not surprised if we saw traction between the remodeling and the peak CO2. So it's a 20 week study, but that also is mirrors what's been done before and demonstrated improvements in LV and dietholic volume and LV stroke volume. And those same hemodynamic improvements are directly embedded within the derivation of what VO2 is. So stroke volume is one of the 3 determinants of VO2.
So if you see a smaller heart with less mitral regurgitation because the heart isn't as stretched and that you're sending more blood forward and you're seeing improvements in stroke volume, then 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 to the panel or is there another question next? Sorry, go ahead. Questions from the floor.
Roy Buchanan, JMP Securities. Just for 2,74 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.
Yes. So I'm not going to comment on exactly where we are there. We've completed what's required for IND filing, which are 4 week studies. And 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 2 portion of their programs. I might add a question with regards to omecamtiv mecarbil.
We have a rather we have a unique way of dosing omecamtiv mecarbil. It's a PK guided dose titration taking, as I explained earlier, with a blood level that we check at 2 weeks and then patients are directly titrated to their target dose. And 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? I'd like maybe both of you can answer that since you both
do a lot of that. I have enough gray here that we started 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 and then we found out that that was bad. And so now we monitor digoxin levels to make sure that they're low enough. And 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 2 weeks, every 4 weeks and then every 1 month to 3 months after that to monitor potassium creatinine and the electrolytes for chronic therapies. So having an agent where you do a 2 week measure and a 8 week whatever we end up doing is actually quite simple. And these patients and we'll not 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, would you? Yes.
I agree. I 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. I mean, 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. So 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. And then 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. So 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.
Okay. Thank you both. Any other questions from the audience? With that, I think I'll transition to Robert to help close the meeting.
So 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 and 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 1 and Phase 2a studies that informed an option they had, an option that they exercised in 2,009. 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. And 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. And as you know, ours is an expensive business. And with this collaboration, we've been afforded not only sponsored development over the many years, but sponsored research. And that sponsored research, as you've heard, led to the discovery of AMG 594 and has 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 $500,000,000 in milestone payments based on progress for this program, omecamtiv, and even more so for AMG 594.
And also, we're afforded other rights, responsibilities and economics. When omecamtiv mecarbil entered Phase 3, that triggered an option we had, an option we had to choose to co fund Phase III clinical trials. And 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 $10,000,000 or $20,000,000 or $30,000,000 or $40,000,000 We chose to co fund at the level of $40,000,000 That enabled us to buy up the royalty economics, and then we turned around and sold that incremental royalty to Royalty Pharma, then for $90,000,000 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. And 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. And 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. So this affords a biopharma company like ours an opportunity to transition from R and 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.
So 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. So this is the way in which we have planned for the migration of Cytokinetics from the R and 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.
And we're very grateful for the long standing 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. But in this case, with focus to the neuromuscular opportunities, we're conducting clinical trials at the expense of Astellas, and we similarly can earn over $500,000,000 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. And 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 the fitting of a company like ours at our stage of corporate development. So 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 and D pipeline. That's all captured in a graphical form on this slide. And you can see, in aggregate, we're eligible for over $500,000,000 in pre commercial milestone payments before we might have the first sales. We're also eligible for over $500,000,000 in sales based milestone payments. That's important to think about when constructing value propositions for an investment such as this.
And 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 And 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 and 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 watermark, 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 $600,000,000 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 2 of their companies, MyoKardia and Global Blood, within our laboratories, myocardia 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.
But 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. And 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. And 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 and 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. So in summary, you see that over 20 years, we've demonstrated leadership in cytoskeletal biology and muscle pharmacology. Our R and 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 physio chemical 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 and 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 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 2nd Phase III study of omecamtiv mecarbil. That should be underway. We're working with Amgen towards the start here before the end of the year.
But also, we expect to initiate Phase I studies for each of CK-two seventy four, 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. And 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 6 minute walk distance for patients with SMA, and 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 the 1st interim analysis, this one being for futility, that to occur in the first half of twenty nineteen for the GALACTIC trial. Were that to proceed smoothly as we hope it should, then we would expect to be completing enrollment also in the first half of twenty nineteen and 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 2 study in this case. And that builds already on a body of evidence we've generated with over 1500 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, and we think it holds great promise for the potential treatment of ALS. And 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 and for whom we draw great inspiration in the work we're doing in SMA.
This is Ryan. He lives with ALS and 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 and that will be meaningful for the purpose we set out in building this company 20 years ago.
So with that, I thank you for your attention to our R and D Day. Hopefully, you've learned a lot about the quality, the integrity and 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. And with that, we'll close the session.