Cytokinetics Inc. (NASDAQ:CYTK)
Business Update Call
March 31, 2008 8:00 am ET
Dr. John R. Teerlink - Associate Professor of Medicine
Dr. Andrew A. Wolff - Senior Vice President of Clinical Research and Development and Chief Medical Officer
Dr. John Cleland - Professor of Cardiology
Andrew A. Wolff
Good morning everybody, thank you for joining us. For those of you joining us here at the West and then for those listening via webcast, we hope this morning’s discussion will be helpful. With two principal objectives in mind; firstly, we hope to summarize our recently announced positive phase IIa clinical trial results for CK452 within the context of our ongoing clinical trials program for this novel cardiac myosin activator. Secondly, with the assistance of two key opinion leaders, both of whom are active participants in our clinical trials, we hope this morning’s program may provide some clinical perspective on measurements of cardiac performance and relatives to morbidity and mortality outcomes in the treatment of heart failure patients.
As you can see from our agenda, we have a lot to cover in the next hour. Before we start, I’d like to emphasize that we’re both pleased and encouraged by the positive interim results from this our first phase IIa clinical trial of CK-1827452 in heart failure patients. As Andy will outline for you in a moment, we believe that the growing body of clinical data supports the ongoing development of CK-452, its novel mechanism, and [inaudible] well for what we may observe going forward as we continue the promising program. I’d like to take the opportunity to introduce our speakers.
To my right is our first speaker, Dr. John Teerlink. He is Associate Professor of Medicine at the School of Medicine and Director of the Heart Failure Clinic and Clinical Echocardiography at the San Francisco Veteran Affairs Medical Center, University of California, San Francisco. John was awarded a fellowship in the American College of Cardiology in 1999, and the American Heart Association in 2002, and the European Society of Cardiology in 2003. He serves on the AHA National Committee on Heart Failure and Transplantation, is a member of the US Food and Drug Administration’s Cardiovascular and Renal Drug Advisory Committee, and is on multiple committees with the Heart Failure Society of America.
John received his postgraduate clinical cardiology and internal medicine training at UCSF after obtaining his medical degree from Harvard. Next to John is Andy Wolff, Cytokinetics Senior Vice President, Clinical Research and Development, and the company’s chief medical officer. Andy has been a member of our executive team since September 2004 and has made a tremendous impact especially in leading and overseeing the implementation of both our cardiovascular and oncology clinical trials programs. Prior to joining the company, Andy was Chief Medical Officer at CV Therapeutics, and prior to that held various clinical positions at Syntex, now Roche. In addition, he holds an employment in the Cardiology Division of the University of California, San Francisco, where he is currently an associate clinical professor. Andy received his MD from Washoe St. Louis.
Next to Andy is Dr. John Cleland, Professor of Cardiology at University of Hull in the UK where he has been and continues to be responsible for an impressive portfolio of international clinical trials in the field of cardiovascular care. He has published over 400 papers and participated in numerous clinical trials. He is a consultant to the World Health Organization, and is the current Chairman of the British Society of Heart Failure. Dr. Cleland is also a member of the editorial board of the Journal of the American College of Cardiology. He received his MD from Glasgow in the UK. I should also mention that John Teerlink was the co-PI for our phase I study, first-time-in-human study of CK-452, and John is the investigator in the phase IIa trial for which you will be hearing the interim results here in a moment.
With that I’d like to remind everyone that we’ll be making forward-looking statements during the presentation and Q&A session, and as a result, I refer you to our publicly filed SEC documents for a complete discussion of our risks and uncertainties.
With that I’d like to turn the program over to Dr. John Teerlink.
Dr. John R. Teerlink
Thanks very much. Good morning. It’s my pleasure to actually have an opportunity to speak on CK-1827452 and put it into the context – a bit on how one evaluates cardiac performance in a contemporary drug development. For centuries it has been recognized that the fundamental or one of the fundamental defects in heart failure is the reduced ability of the heart to pump blood. In that context, much of the drug development in heart failure has been geared toward developing new agents that can improve cardiac performance or attempt to improve cardiac performance. However, unfortunately the currently available drugs that we have do so at considerable costs, and these, I am specifically referring to the beta adrenergic agonists such as dobutamine and the phosphodiesterase inhibitors such as milrinone. While these agents do increase cardiac output, they do so at the expense of increasing myocardial oxygen demand and having the clinical adverse effects of increasing ischemia, increasing arrhythmogenicity, and also contributing to increased mortality. These adverse effects are actually directly related to their mechanism of action such that the whipping of the heart, the increase of intracellular calcium, can directly result in these adverse effects. In addition, these agents work by increasing vasodilation – they open up the blood vessels peripherally. So, up until now we’ve never had an agent that directly affected cardiac performance solely and independently, and it is in that context that this truly novel mechanism of action of CK-1827452, which I from now on will just call CK-452, this novel mechanism of action where one can specifically activate cardiac myosin without all of these other potential adverse effects has been potentially a tremendous advancement in the field.
One of the challenges has been that when you have something that directly affects solely the heart how do you actually measure those effects. So one of the things I’d like to take a few moments on is discussing how we approach this problem with the CK-452 development program. We wanted a technique that would be noninvasive, that would be reproducible, and that would be able to be done in a serial manner in the same patient. In that context, echocardiography was the obvious choice. Echocardiography has the ability to be used readily in patients, is readily available in most facilities, and it has measures that are understood by most investigators. Consequently, we looked at, and I’m now looking at the slide entitled “Measures of Cardiac Performance,” we used echocardiography to look at two types of measures. An echocardiography uses ultrasound to basically look at blood flows or velocities of tissues as well as create two dimensional images of the heart; and so the measures that we used in this development program are listed in terms of the systolic ejection time, Doppler derived stroke volume, fractional shortening, and ejection fraction. I’d like to describe a bit how we went about measuring each of these to give you a sense of what we did in these trials. So if we go to the next slide which shows the Doppler derived measures of left ventricular function, the first of these is the systolic ejection time, which is abbreviated as SET. Systolic ejection time is actually a well known and well-established measure which has been around for decades and is a measure of how much time the heart is performing flow generating work – how much time the heart is actually ejecting blood from the heart – and it is very accurately measured – it can be measured within milliseconds, it is highly reproducible, and it has the advantage of being directly related to the mechanism of action of CK-452 which we have seen – the mechanism is directly related to prolongation of the systolic ejection time. So that is measured from these Doppler tracings where one looks at the – if you follow the X axis; the X axis is time, the Y axis is velocity, and in this case, the area that is traced – that downward tracing – is the ejection of blood out of the heart; and you can measure on the X axis the duration of time that the heart is ejecting that blood called the systolic ejection time.
In addition, there is the left ventricular outflow tract velocity time integral or LVOT VTI. This is a measurement of its equivalent to stroke volume, and I’ll discuss in a little bit more detail how that is done as well. One can assess the velocity of blood traveling through a specific point and measure how much blood is basically going through that point over time. If one measures the integral of that, you can actually get an estimate of how far the average blood cell is moved with each beat, and you get something call stroke distance. If you look at the tracing, one can see the curve that is going downward – that is traced and labeled as LVOT VTI – and when the aortic valve opens, which is the first green line, you begin having ejection of blood from the ventricle that then proceeds to a peak and then decreases as the flow begins to trail off out of the heart. In measuring this, you get an estimate of how much blood is ejected from the heart with each beat. So, that’s how much the average blood cell is moved per beat. If you then assess how big or the cross-sectional area of the tube through which that blood is being moved, you can actually get a measurement of the volume of blood that is moved with each beat or the stroke volume – the amount of blood that is ejected from the heart with each individual heartbeat or stroke, and that is demonstrated in the next slide where you have the outflow tract area which is measured from the two-dimensional views of the heart, shown in the smaller insert; you use the radius squared and then multiply that by the left ventricular outflow tract velocity time integral, and that gives you the direct measure of the stroke volume. This has the advantage of being very accurate, highly reproducible within each individual patient, and is not as dependent upon imaging quality.
Then if we go to the next slide, another standard measure of ventricular performance is the fractional shortening. Fractional shortening measures how much the heart in one single plane shortens with each beat. It has the advantage of being relatively well known because it was one of first measures used in echocardiography for measuring heart function, but it has multiple disadvantages as well. It is in effect a measurement of what happens to the heart if you stick an icepick through it; and in fact that’s how it was first noted to evolve; in pathology, they stuck an icepick through the heart and did an ultrasound on it, and measured exactly where that icepick was and then validated the measures. This measurement, because it’s only one specific point in the heart, if you have a heart that has marked abnormalities in its shape such as with heart failure, it has marked limitations in truly assessing the overall function of the heart. The next measurement on the next slide is another image-based measure of left ventricular function and this is the left ventricular ejection fraction. The left ventricular ejection fraction is the proportion of blood that is ejected with each beat; so you started out with a certain amount of blood in the heart and you eject a certain percentage of that and that is reflected in the ejection fraction. The way this is typically done in studies currently is to take two views – orthogonal views of the heart – both of which are from the apex or the point of the heart. The first is the four-chamber view and you measure it in both diastole or the largest dimension in the heart and then systole after full contraction, and then you do another measurement that is at a time point slipping the transducer probe at a 90-degree angle and take the two-chamber view, and this measurement also you take measurements in diastole and systole. We take typically three measures in each view and then average them. This methodology is extremely dependent upon the image quality and also on the variability of the tracing, and one can see because this is a divided value, you can actually markedly magnify small changes and small errors in tracing, and this is why ejection fraction actually is not quite as reliable a measure of cardiac performance in the setting of heart failure. One of the other challenges with ejection fraction is that because it’s a proportion it doesn’t really measure directly cardiac performance. It doesn’t measure how much blood is truly being pumped by the heart per beat or per unit time, and these limitations are magnified in the setting of an abnormally shaped heart where it’s difficult or a heart where you have difficult to obtain images.
So, that’s a bit of the background in terms of the different modalities, and because of those findings, on the next slide, it has been felt that in assessing the left ventricular systolic function, the Doppler derived stroke volumes may be more reproducible and less variable in the image derived ejection fraction, especially in patients with heart failure.
Andrew A. Wolff
Thanks John for that nice overview, the way in which we assess ventricular function with echocardiography. I’ll now go on to remind you of our findings in our first-time-in-human study in healthy volunteers, and briefly review how we are continuing to go forward to evaluate CK-1827452 for the treatment of heart failure, and then share what I can with you of the data from our ongoing phase IIa study in stable heart failure patients. As you may know, the data from that trial will be presented in a much more complete and quantitative fashion at the Heart Failure 2008 meetings of the European Society of Cardiology in June in Milan, and so prior to that presentation, we are being very careful not to say too much so as not to jeopardize the presentation by Prof. Cleland more on the program – we like it that way – we want to stay there. So we’ll be very top-line today. I’ll remind you of our key findings from our phase I first-time-in-human study. These are data in healthy volunteers, and arranged here along the X axis are ranges of plasma concentration starting from 0 up to 900 ng/mL and above, and on the Y axis, we’re looking at placebo corrected data; so this is the difference from placebo in the change from baseline, in this case, systolic ejection time of parameter which John has described in some detail, and you can see that as the concentration of CK-452 increases, so does the ejection time. This is really the pharmacodynamic signature of CK-452 – a prolongation of ejection time; and if the heart ejects longer, then as a direct consequence of that, it will eject more. If it spends more time squeezing, more blood is going to come out by the time that individual heartbeat is done, and just as we saw clinically meaningful and statistically significant increases in ejection time over the same range of plasma concentrations, we saw a very clearly concentration related increase in stroke volume measured by Doppler at the left ventricular outflow tract using the identical methodology that John has just described to you. In association with those increases in ejection time and stroke volume, we also saw statistically significant, and I think, clinically meaningful increases in two other indices of left ventricular systolic performance, in black fractional shortening, something John has also described to you, and in blue, ejection fraction where the percentage of blood that the heart has in the ventricle at the beginning that it is actually able to eject. So, as he pointed out, it is a normalized variable. It ranges from 0% to 100%. You can see that as we got to the higher concentrations, we were achieving ejection fractions again versus placebo on the order of 8 to 10 percentage points, but even down here at the middle to lower range we were certainly increasing the ejection fraction of these healthy volunteers by about 5 percentage points, and just to remind you, at those same concentrations, we were increasing stroke volume in these volunteers by about 6 or 7 or 8 cc.
Now, to remind you how the phase I data have led into our current phase IIa program in stable heart failure and what else we are doing, the ongoing study that I’ll talk about in just a minute is represented here, the primary objective of course is safety and tolerability, and to understand the pharmacokinetics of the drug in heart failure and the relationship between the plasma concentration and the effect on ventricular function or PKPD relationships. To get there, we’ve done the phase I study that I just briefly described, and we’re also supporting our development program with a variety of other studies in healthy volunteers. I know we’ve talked in the past on various telephone calls about an ongoing drug-drug interaction study in which we are demonstrating a very low potential actually for drug-drug interactions most of which occur because of competition in the liver for the cytochrome P450 enzymes of drug metabolism; and as you may recall, we have announced data a year or more ago on our oral bioavailability study as we moved toward oral formulation development that shows that the drug is essentially completely absorbed from an oral dose. If a drug is completely absorbed on oral dosing, then not very much of it is being chewed up in the liver because anything that comes from the gut into the blood stream has to get through the liver first. So, we’re anticipating that this study will show very very modest potential for drug-drug interaction at two of the key enzymes of drug metabolism. In addition, we understand that while an intravenous formulation will be certainly useful in the treatment of hospitalized patients with acutely decompensated heart failure, the real crying unmet medical need, and therefore consequently the real commercial potential for this compound is in the treatment of outpatients with heart failure who have systolic dysfunction and whose hearts need to pump a little more blood with every beat, and so getting the drug as a pill or a tablet is really the goal. We know the drug is very rapidly absorbed and so we need to slow down its release so that we can develop a very smooth plasma profile with oral dosing without a lot of fluctuation between peak and trough plasma levels, and we’ve made substantial progress in that regard in the healthy volunteer efforts to develop a modified release formulation.
Very shortly, you’ll hear us announce the initiation of two other phase IIa studies, one other in a patient population quite similar to the ones that we are evaluating in our ongoing study in which we’ll have patients in the cath lab and we will be able to evaluate very precisely with invasive methodologies their ventricular function and simultaneously measure their myocardial oxygen consumption. You may recall that on several occasions we presented preclinical data from dogs that show that in dogs with heart failure, we can increase the stroke volume substantially without really affecting myocardial oxygen consumption translating therefore into a substantial increase in the efficiency of oxygen utilization by the myocardium, and we wanted to be able to make those same statements based on data from actual patients with heart failure. So that will begin very soon as will a safety study in patients whose heart failure is specifically and exclusively due to coronary artery disease and prior myocardial infarctions; so both of those initiations will be announced very soon.
To remind you what we announced recently in our press release, we have completed an analysis of data from the first two cohorts of patients from our ongoing pharmacokinetic/pharmacodynamic trial in patients with stable heart failure. So it is in fact multicentered, double-blind, randomized, and placebo controlled, but as I’ll describe, it is also a dose escalation study so that the subjects or the patients, I should say in this case, do get CK-452 in ascending order or doses; low, medium, high, but there is a placebo treatment randomized and amongst those three; so over the course of four different study days they do get the drug in ascending order, but the placebo is administered on potentially the first, second, third, or fourth day, no one knows, and it maintains the blinding of the study. It’s primarily aimed at evaluating the safety and tolerability of the agent in patients with heart failure, but we are also very careful to establish a relationship between the plasma concentration of the drug and its effects on ventricular function, and of course, we want to understand how CK-452 is handled in the body by patients with heart failure or that is to say the pharmacokinetics of the drug. This is a fairly typical population for study in heart failure; these are patients who are on stable doses of standard therapy in this day and age for heart failure which means a beta-blocker, an ACE inhibitor, or an angiotensin receptor blocker. They may or may not be on diuretics, but if they are, they need to have been administered in a consistent fashion over the prior four weeks, and these folks have ejection fractions less than 40%. I often get [inaudible] say right now there is no New York Heart Association Classification criterion if they have systolic dysfunction to the degree that their ejection fraction is measured to be less than 40%, they are eligible for the study providing they need these entry criteria and that some other ones that I won’t worry you with, but they are fairly standard. We have now begun dosing as you know in the third cohort. In all three of these cohorts, patients are studied four times as I’ve already mentioned. There are 8 patients in each cohort and each of these patients is treated four separate times. The doses of CK-452 are administered in ascending fashion, the placebo is randomized in there across two cohorts as I’ll describe now; we studied five different dose levels if you will A, B, C, in cohort I, and then C, D, and E in cohort II with that middle dose overlapping the cohorts. Cohorts I and II, we looked at a 2-hour infusion. It was primarily to understand the pharmacodynamics of the drug; the first hour was a loading dose to achieve the target plasma concentration, the second hour was a slower infusion to maintain that concentration at a relatively stable place so that we could get the echo on treatment and not have plasma concentrations of the drug fluctuating wildly while we were obtaining that echo, and in the ongoing cohort III now, we’re extending the duration of our experience of treatment with the drug toward a more clinically relevant period of time which is a total of 24 hours.
So this re-capitulates the way the study is done, three different dosing regimens, the loading dose twice as fast as the maintenance dose, so just for simplicity, we have been referring to them based on the first hour’s rate of infusion from 0.125 doubled to 0.25 doubled to 0.5, and maintenance is half that rate targeting plasma concentrations of 90, 175, and 320 ng/mL, and then again, the overlapping dose of 0.5 going to 0.25 and then escalating at a somewhat slower rate, we’re not doubling anymore, we’re increasing in this case by 50%, and then in this case only by 33% as we move toward concentrations that are toward the higher end of the dose response, topping out in the study at a target concentration of 650 ng/mL – and if I can get back there pretty quickly – so we’re studying in the range from about here up to about here; these again are data from healthy volunteers, but these are the effects on these volunteers, that is the range of concentrations that we are now evaluating in patients with heart failure. What we have seen in these first two cohorts over that range of plasma concentrations is a very well-tolerated drug, the heart rate and blood pressure are not moving in directions we don’t want to see them go, the pharmacokinetics are very well behaved, they are generally linear across the range that we studied to date, and in fact we found that the plasma concentrations that we’ve targeted are what we have achieved, we based our dosing on the data from phase I healthy volunteers and so it means that the healthy volunteer data very accurately predicts what we are seeing in the stable heart failure patients and not a lot of difference between the two populations; and in terms of the pharmacodynamic variables of interest, we’ve seen statistically significant, and I suggest to you, when you see the data in Milan quite clinically relevant increases in Doppler derived stroke volume, in fractional shortening, and these parameters increase on the basis of that increase in systolic ejection time which as I have mentioned earlier is really truly a pharmacodynamic signature of the drug. Ejection fraction while it did trend to increase as plasma concentrations increased, it did not yet over these first two cohorts worth of data achieve statistical significance. John has explained the variability inherent in measuring ejection fraction, particularly in patients with misshaped and in diseased ventricles, so while we haven’t achieved statistical significance yet, in some part due to the variability in the measurement, as we acquire additional data from further cohorts, that situation may change over time. Also, in terms of the relationship between the plasma concentration and the effect, we saw statistically significant correlation between an increasing concentration of CK-452 and Doppler derived stroke volume, fractional shortening, and systolic ejection time. So, I’m really looking forward to a couple of months from now when Prof. Cleland and other investigators and those of us from the company can share with you in more detail the data that have come from this exciting study of this novel new agent.
Here is where we eventually want to go with all of this. It’s nice to look at the data that we have in hand, but it’s also very important to put it into the context of our eventual goal which is to have a new medicine that can be used as we say across the continuum of care in patients with heart failure. So, we’d like to think that any patient with systolic dysfunction who is symptomatic or at risk of death because of that insufficient systolic performance could benefit from CK-452. They could come into the hospital in an acutely decompensated state and begin treatment with the intravenous formulation and be transitioned to the oral or they could be at high risk for re-hospitalization, probably most commonly due to a recent hospitalization – the biggest risk for hospitalization due to heart failure is just having been in the hospital with heart failure – and those patients could go straight onto the oral, and we would intend to demonstrate that either avenue toward the initiation of treatment but in the end resulting on long-term treatment with oral CK-452 will reduce the incidence of death or re-admission due to heart failure in these patients, and we’ll also of course evaluate a variety of other measurements that indicate quality of life in heart failure, performance status in heart failure, physician’s assessment in heart failure, biomarkers of disease severity such as BNP. It will be a treasure trove of heart failure data once we get to the phase III program to enable this kind of treatment paradigm.
So with that I’ll hand it over to my colleague, Prof. Cleland to talk about what these data may actually mean as you see them in Milan.
Prof. John Cleland
Well, thank you very much, and I’m delighted to be involved with this program. I think it’s one of the most exciting compounds out there in cardiovascular medicine and heart failure. I’m really going to pick up where Andy has left off. Our ultimate goal is to get down to improving symptoms, reducing hospitalization partly because it’s unpleasant for patients, partly because it requires a lot of human resources to keep the people in hospital, and of course it’s a major item on the spending bill, and ultimately we’d like to increase longevity. If we can control symptoms, stop people being hospitalized, and substantially reduce premature deaths, then we might start to talk about cardiac remission or even cure a heart failure, and ultimately that’s the goal of any heart failure physician; and indeed physician for any disease is to try and cure it. Perhaps cure is an ambitious target in patients with heart failure but certainly putting the patient into remission is an important and I think achievable task, and rather like cancer – many people described heart failure as cancer of the heart – the oncologists are very happy when they can achieve a remission of disease, and that’s pretty well what we want to do. Now in order to hit these targets, you certainly need thousands of patients in controlled trials, perhaps a few hundreds for symptoms, but certainly when you’re talking about hospitalization and death, you’re usually moving up into thousands of patients, and of course, you want to be wise in the use of financial and human resources to do clinical trials and also even the patients, you don’t really want to involve thousands of patients in a drug program that is unlikely to be successful. So we have to look for surrogates for these important goals of treatment, and still the best surrogate that we’ve got in patients with heart failure is cardiac function and the different ways that we can look at cardiac function, but if we can improve cardiac performance by increasing stroke volume and ejection fraction resulting in an improvement in organ perfusion so that you perfuse your brain, your kidneys, your muscle; all of these organs work better when they have a better blood supply. Also, if you can allow the heart to do its work at a lower filling pressure because that filling pressure determines lung congestion and symptoms like breathlessness. If you can improve these things, the natural consequence of these is to reduce the enlarged heart, so reduced left ventricular volumes and improved remodeling, and we know when that starts to happen that we’re very likely to see a reduction in hospitalization and death. So, that’s the importance of doing these homodynamic studies, and I just like to show you in the next few slides what other programs have achieved with other source of interventions.
We’re going to start up with something that I’m sure you must know about if you’ve been involved in cardiovascular medicine, which are thrombolytics for myocardial infarction. The idea here is to preserve myocardium from the infarcting process, help preserve cardiac function, and thereby hopefully improve – make it less likely that the patient is going to develop heart failure – improve symptoms, and improve prognosis. And you can see in this particular study, it’s not the largest study of thrombolytics, but it is one where ventricular function was carefully studied, improved ejection fraction by 6 points, and you can see there was a substantial difference in the morbidity/mortality outcome. ACE inhibitors is one of the standard treatments for patients with heart failure, and here we have data from Solvd study, over 2500 patients in Solvd, not all of them in the sub-study looking at cardiac function, but certainly in the echocardiographic sub-study, several hundred patients. Very modest improvements in ventricular function, you can see that the difference between placebo and enalapril was only 2%, did achieve statistical significance but you need quite large numbers to show those sort of differences, and yet when you look at the long-term clinical outcome, a highly significant 16% reduction in mortality and a larger reduction in the morbidity/mortality outcome of hospitalization or death. Beta-blockers again one of the mainstays of both heart failure and post-infarction care; a large study called Capricorn with almost 2000 patients; there is what is considered by many cardiologists to be substantial improvement in ejection fraction, but is only 3.9%, the improvement in stroke volume, very modest 2.6 mL and you can see a 23% improvement in mortality.
For those of you who are not just interested in drugs but also interested in devices, there are the cardiac resynchronization devices. These are clever pacemakers that pace both the right and the left ventricle. I was fortunate enough to be the PI on this particular study. As you can see with just over 800 patients, at 3 months we were able to improve ejection fraction by about 4% compared to the controlled group by 7% after 18 months. Interestingly, no real change in the stroke volume, but substantial reduction in mortality and morbidity, one of the largest things we see. And there are other studies, another one here comparing upgrade from right ventricular pacing to biventricular pacing or CRT, and you can see improvements in stroke volume and ejection fraction. So this just gives you some idea of the magnitude of change that we’re seeing with some really effective treatments which have become standard of care for patients with heart failure. It also shows you that you often meet quite large numbers to show changes in things like ejection fraction, and as Dr. John Teerlink has pointed out, when carefully measured using the techniques that he has described using Doppler echocardiography, stroke volume is probably a more accurate measure. It has to be said that stroke volume in most of these studies was measured from the change in the ventricular volume which has all the same inaccuracies as trying to measure ejection fraction. So, I suspect that the way that we’re measuring stroke volume in this study is just more accurate and more robust than what has been used in some of these bigger larger pervious studies.
So, I’d just like to summarize by saying that we certainly know there is an association between drugs that improve cardiac function often modestly and substantial improvements in heart failure, morbidity, and mortality. Some of these drugs like ACE inhibitors and beta-blockers might have effect on arrhythmias, might have indirect effects that improve cardiac function, but thrombolytic agents and cardiac resynchronization really just works on the heart – a direct effect – and even when we just limit our attention to these drugs that directly affect the heart, that relationship between improved ventricular function and outcome is maintained and it suggests that there may be a causal link. We don’t know that yet because we’re so early in the program, but it’s very clear from looking at the initial experience that CK-452 improves stroke volume statistically and I think clinically relevant terms, there is a strong trend towards an improved ejection fraction with only eight patients in the top dose group, it would really be quite unlikely knowing the variability of ejection fraction that we would achieve statistical significance at this stage. And of course, this is just the first step on what’s going to be a considerable journey. I think in the next years we’ll see programs which target improvement in symptoms and those will probably contain hundreds of patients and then ultimately the FDA will require a large substantial safety database of many thousands of patients and that will be used to investigate the effects of this drug on morbidity and mortality. Thank you.
Andrew A. Wolff
Thank you to our speakers. With that, I think we’ve got about 15 minutes to make available for questions and answers, and we’ll be taking questions from those of you here in Chicago. George?
Two questions. You talked about stroke volume as one of the [inaudible]. Cardiac output is often [inaudible] as a measure of cardiac function. Why can’t [inaudible] cardiac output?
Andrew A. Wolff
That’s an excellent question. Cardiac output is actually stroke volume times the heart rate. So, it’s really taking how much blood the heart ejects per beat and multiplying it by time factor – usually per minute – so, it’s the liters per minute measurement. We’ve done that as well. In the earlier 11/11 study that showed as well improvements in cardiac output and if you see that there is no change in heart rate in a study, then one gets a commensurate improvement in cardiac output if the stroke volume goes up. So the heart rate stays the same and stroke volume goes up, that does mean the cardiac output goes up as well. In fact, that’s saying the same thing.
Prof. John Cleland
The cardiac output has gone up with higher doses in this study.
Second question is yesterday there was a talk about [inaudible] pharmacologically improved heart failure and they talked about A1 adenosine antagonists, vasopressin antagonists, istaroxime, perhexiline [inaudible] you might comment where those four [inaudible] might play into the continuing of [inaudible].
Prof. John Cleland
The adenosine antagonist I think is a very exciting group of drugs. They are very much targeted at improving renal function and trying to improve cardiovascular function through the kidneys. For any Egyptians in the audience, the Egyptians used to believe that the kidneys were the seat of the soul not the heart or the brain. So, maybe they are right. So, I think I could see adenosine antagonists and this sort of drug working very much in a complimentary fashion. So, I don’t see any competition between these agents.
The AVP antagonists – what we’ve seen is a very large study with a rather neutral outcome. I don’t think it’s the final word on the AVP antagonists and my suspicion is that they will have a future role in the management of heart failure, but they really haven’t achieved a convincing clinical trial beta, and aren’t likely to anytime very soon, but there are still ongoing programs. I think that they will have a role in the difficult to manage hyponatremic recurrent decompensation type heart failure patient. Istaroxime – I’m going to pass to my colleague in case he knows something because I haven’t really been involved with that at all. Perhexilline – a very interesting concept. It’s an old-fashioned drug with problems of toxicity like neuropathy and liver problems. The reason why there has been a resurrection is two-fold; first of all an assay has been developed so that plasma concentration can be easily measured and there is some considerable evidence that if you can avoid high plasma concentrations, you can make this drug relatively safe. It is very much dependent on your acetylator status and some people are genetically just programmed to metabolize the drug slowly and they get most of the toxicity. So, you can’t predict easily who is going to get toxicity because we don’t have an easy genetic test for the acetylator status. So, you really just have to measure the plasma concentration.
There is one study published in circulation; it’s a small single-center study – I think it’s an interesting result, but I wouldn’t have a high degree of confidence in it until it is replicated, and it’s been around for about 30 years. I think one of the major problems is actually finding a financial model to resource the clinical research that needs to be done to bring it to the market. It potentially had problems with Q-T interval as well which is obviously of concern to the FDA. Personally, I think the research programs on this will go ahead because I think they will be investigator led even if they don’t find a major backer for it. So, I think you haven’t heard the last of perhexilline – not an easy drug to use, but these patients are still in dire need. So, we have to explore all the potential mechanisms that are available to us. So, that’s my run then. Istaroxime?
Andrew A. Wolff
I’d second John’s enthusiasm perhaps for the A1 adenosine antagonist in terms of addressing the need in terms of the cardiorenal syndrome; istaroxime has had the Horizon trial which has been presented and is being presented in various forums in different settings. Istaroxime is a digoxin-like compound that supposedly has beneficial lusotropic effects and I think we’re still trying to figure out where it will fit if it in fact has those beneficial effects. From my unbiased I guess – or biased opinion – the two areas of greater clinical need, we have agents that can address… we need something that helps cardiorenal syndrome and we need something that can beneficially affect cardiac performance. We don’t have anything in that area that doesn’t hurt people yet. And so, it’s because of that that I have such enthusiasm for the CK-452 program. In full disclosure, I am also involved with the A1 adenosine antagonist program as well.
Thanks for taking the question. Can you talk about systolic ejection time a little more since that is the primary pharmacodynamic target, I suppose. In some of the heart failure patients, do they have lower systolic times relative to the overall cardiac cycle? Also, obviously we know that cardiac coronary artery perfusion occurs during diastole. Can you talk a little bit about that ratio and how that might affect development of the drug as well as maybe perhaps comment on the predictability of this drug and how that might affect development?
Dr. John R. Teerlink
Sure. So, the systolic ejection time as I mentioned has been around for decades and was originally a way to help diagnose heart failure, but shorter systolic ejection times were considered to be related to worse heart failure. So, the tendency is that patients with worse heart failure will have a trend towards a shorter systolic ejection time or will have shorter to normal systolic ejection times. So, the way that we measured it is very accurate and can be precisely followed. It seems to be very dynamic and directly related to plasma concentrations of CK-452. The measure is the time during which the heart can eject blood and because there is a sort of a 0 some gain in terms of the total cardiac cycle, when one expands systole, one does impinge a bit on diastole. I will remind you that this drug was tested very effectively in dogs which have a heart rate of 120 and up to 200 in the pacing models without adverse effects at the kind of plasma concentrations that we’re looking at here. So, yes – one can get – as with any drug, you can go high and up to a point where one could impinge upon diastole, one could impinge upon cardiac filling, one could impinge upon coronary filling – but by the time you can get plenty of beneficial effects before you even approach those impinging upon functions. Does that answer your question?
Prof. John Cleland
Also, just say – the heart cycle has actually got four phases – there is the systolic ejection when it is pushing blood out, there is the diastolic filling when it’s filling up with blood, but also two other periods which is that period where it is beginning to relax – it has stopped ejecting, but it hasn’t started to fill and that time when it starts to contract when it has stopped filling but hasn’t started to eject. So this leaves two buffer zones between systole and diastole. And one of the aspects of heart failure is that the heart becomes much more inefficient because those buffer zones get longer. They are called the isovolumic periods. So, the heart is sort of sitting around actually getting ready to do something, but isn’t actually doing anything. And one of the good things about an effective therapy will be to shorten those redundant periods of the cardiac cycle. So, by extending the ejection time it may be that we’re eroding that downtime from the ventricle in between being active. So, it could improve cardiac efficiency that way. As stroke volume goes up, some of that increase in stroke volume is likely to be distributed to the coronary bed. Also, if you reduce filling pressures, the coronary perfusion pressure is the pressure gradient between the ventricle and the aorta, and if you reduce the filling pressures, you actually can improve myocardial perfusion just by dropping the ventricular filling pressure even if the aortic pressure hasn’t gone up. So, it’s a complex situation, and ultimately you do your experiment, you get your results and you then explain it.
May be it’s just an additional question. Given that we have other drugs classified as inotropes that also are used clinically to enhance cardiac performance and cardiac output, can you distinguish between what you are saying here with CK-452 in terms of systolic ejection time?
Prof. John Cleland
We think we’ve worked out what the name of this class of drug should be and we’re going to check this with some of our Greek friends because we’re not sure our Greek is that good, but we think this is a macrotropic agent. It is the first of a new class and the macrotropic basically means that it prolongs systole.
But in terms of those that are inotropes relative to cardiac performance, how might they be expected to affect systolic ejection time and where else are they exerting maybe their more principal effect?
Prof. John Cleland
The inotropic agents are increasing the speed of the cardiac contraction; they are increasing the energy consumption of the heart. They will often prolong ejection time; they often increase heart rates as well. So, it has been likened to taking a horse with a very heavy load and trying to get them to pull that cart up the hill and just whipping the horse faster and that sort of gives you the image of the classic inotropic agent. This is a rather different approach. I am not quite sure of what my cartoon picture of this is in my head, but…
Andrew A. Wolff
The way I’ve presented it has been adding more horses…
Prof. John Cleland
Andrew A. Wolff
So, you can actually have the same load, but you get to actually add more horses because you have more myosin actually working effectively.
Prof. John Cleland
I think I’ll use that one.
How do we know that the prolonging ejection time on the long term is not adaptive or maladaptive? I suppose, let’s say, inotropes in general have improved cardiac performance, let’s say; but ultimately when given chronically it has led to an increase in mortality. How do we know that the same is already miles in the dog model of chronic use with respect to this – you may cause further remodeling of a heart as opposed to reverse remodeling that you may see with ACE inhibitors and beta-blockers.
Andrew A. Wolff
First of all, it’s not clear that the agents that currently exist actually improve cardiac performance. Performance is a sum of the ability to do work at given certain resources, and all of these – the dobutamine and milrinone – increase myocardial oxygen demand, and so may actually decrease cardiac performance. If your question is that how do we know that improving – what we do have here is an ability to improve stroke volume, and one of the main triggers as we saw from Prof. Clelan’s presentation, one of the main triggers for the development of heart failure – the remodeling aspect – is the signal from the rest of the body saying, “I’m not getting enough blood flow.” So it activates all this neurohormonal cascade that result in adverse cardiac remodeling and all of the adverse sequelae that we’ve been trying to deal with for centuries with heart failure. So, the hypothesis is that if you can actually improve cardiac performance – improve that stroke volume – one can actually reduce the adverse remodeling or perhaps reverse remodel. So you actually result with cardiac remission and improve not only the cardiac structure, which we believe is directly related to arrhythmias and subsequent deaths due to pump failure, but also reduce the neurohormonal stimuli that result in the whole syndrome of heart failure which is a total body disease. So, it is a hypothesis. There are animal models suggesting that if we improve cardiac performance you can reduce remodeling. And we have the experience with LVADs; where if you put in an LVAD, if you just improve cardiac output by a mechanical means, you can reverse remodel the heart and you turn off the neurohormones. So this is the first pharmacological chance we have to do that in chronically inpatients without having to implant an LVAD.
And one thing I just might add; going back to an earlier answer to a question is, in heart failure the ejection time is reduced relative to normal. So, I am not sure that what we would be doing with CK-452 is really correctly characterized in heart failure as prolonging ejection time, but rather maybe more accurately re-normalizing ejection fraction.
Prof. John Cleland
That was a point I was going to make. This drug makes the patient’s ejection time the same as yours.
Andrew A. Wolff
On that note we’ll conclude this program. It’s 8 o’clock here at Chicago. We thank you for coming. We are quite pleased and encouraged by the data that we’ve observed now in these first two cohorts with CK-452 in this ongoing phase IIa clinical trial. We look forward to sharing the actual results from this interim analysis with you in Milan in June. Thank you.
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