Welcome, everyone, and thanks for joining. I'm Diane Weiser, SVP, corporate affairs. We're pleased to be discussing new data presented this weekend at ESC, including the primary results from Maple HCM as well as other data related to aficamtan. I'm joined today by my colleagues Robert Blum, President and CEO Doctor. Fadi Malik, Executive Vice President of R and D and Doctor.
Dan Jacobi, VP of Clinical Research. I'm also pleased to welcome our esteemed HCM experts. With us today are Doctor. Pablo Garcia Pavia, Head, Heart Failure and Inherited Cardiac Diseases Unit at the Department of Cardiology of Hospital Universitario, Puerto de Hierro Doctor Carolyn Ho, medical director of the Cardiovascular Genetics Center and professor of medicine at Harvard Medical School Doctor Ahmad Mazari, cardiomyopathy section head and director at the Hypertrophic Cardiomyopathy Center and associate professor of medicine at Oregon Health and Science University and Doctor. Angelie Owens, medical director at the Center for Inherited Cardiac Disease, Director of the Hypertrophic Cardiomyopathy Center, and Associate Professor of Medicine at the University of Pennsylvania.
Thank you all for being here today. Moving to our agenda. First, Doctor. Fadi Malik will provide introductory comments. Next, Doctor.
Pablo Garcia Pavia will provide an encore presentation of his hotline of HC Maple HCM results from the conference. Then Drs. Malik and Jacobi will lead a discussion with Drs. Garcia Pavia, Ho, Masri and Owens to provide perspective on the data and answer questions. And finally, Robert will provide some closing remarks.
To submit a question during the panel discussion, please type your question into the box in the tab on the right titled ask a question. Please note that portions of the following discussion, including our responses to questions, contain statements that relate to future events and performance rather than historical facts and constitute forward looking statements. Our actual results might differ materially from those projected in these forward looking statements. Additional information concerning factors that could cause our actual results to differ materially from those in these forward looking statements is contained in our SEC filings. In addition, on today's call, Drs.
Garcia Pavia, Ho, Masri, and Owens will share their professional perspectives on the clinical significance and safety implications of aficamtan related data presented at ESC. These perspectives are solely the opinions of Drs. Garcia Pavia, Ho, Masri, and Owens and may not reflect the opinions of Cytokinetics or others other experts who review these data, including those who will review the NDA for aficamtan at FDA and applications submitted to other regulatory authorities. Drs. Garcia Pavia, Ho, Masri, and Owens are here today as contracted consultants with Cytokinetics.
And now I will turn the call over to Fadi.
Thanks, Diane. Over the weekend, we were proud to present four oral presentations and one poster related to aficamtan, accompanied by three simultaneous publications in leading cardiac journals. The depth and breadth of these data adds substantially to the existing body of evidence supporting the potential of aficamtan as a treatment for obstructive hypertrophic cardiomyopathy. To start off, on Saturday, Doctor. Garcia Pavia presented the primary results from MAPLE HCM, the Phase III active comparator clinical trial comparing aficamtan to the standard of care beta blocker metoprolol in patients with OHCM, which was also published in The New England Journal of Medicine.
This study is truly the first of its kind, providing both a direct look at the treatment effect and safety of treatment with a cardiac myosin inhibitor versus a beta blocker and a look at the efficacy, safety and tolerability of metoprolol itself in OHCM. The results in showing the superiority of aficamtan to metoprolol challenged the rationale for the long standing first line approach of treating HCM with beta blockers. As Doctor. Garcia Pavio will elaborate, while aficamtan improved exercise capacity, metoprolol resulted in a meaningful reduction in exercise capacity. Treatment with aficamtan also produced larger improvements in symptoms, gradients and cardiac biomarkers as compared to metoprolol with a similar rate of adverse events.
Additionally, Doctor. Sheila Hechtie from the UT Southwestern Medical Center and Brigham and Women's Hospital presented a prespecified analysis of the echocardiographic data from Maple HCM. The analysis showed aficamtan had a larger impact than metoprolol on measures of cardiac structure and function, improved measures of diastolic function and reduced key contributors to left ventricular outflow tract obstruction. These results were accompanied by a publication in the Journal of the American College of Cardiology. Beyond maple HCM, in a late breaking clinical science section, Doctor.
Mazri presented an analysis showing that in forest HCM, the risk of atrial fibrillation was quite low during long term treatment with aficamtan and consistent with expectations from validated prediction models of atrial fibrillation. In those that did develop atrial fibrillation, it did not negatively impact clinical status. These data were published in Heart Rhythm. Given atrial fibrillation is an emerging topic of conversation around the use of cardiac myosin inhibitors, these data suggest long term treatment with aficamtan does not appear to increase the risk of atrial fibrillation in OHCM. Doctor.
Sarah Saberi from the University of Michigan also presented longer term data from FORWEST HCM with a mean follow-up duration of sixty two weeks and a maximum follow-up duration of over three years. As we've previously as you've seen previously from Forest HCM, these data again show that aficamtin is associated with early and sustained hemodynamic clinical benefits along with a low incidence of new onset atrial fibrillation and LVEF less than fifty percent. Adding further to these findings from our updated integrated safety analysis presented by Doctor. Mazri builds on the first integrated safety it builds on the first integrated safety analysis we presented last year, inclusive of Redwood HCM, Sequoia HCM and Forest HCM, now including Maple HCM as well. Combining four sixty three patients and almost seven hundred patient years of experience, aficamtiv was shown to be well tolerated with a low incidence of LVEF less than fifty percent and no occurrences associated with serious events of heart failure.
All in, these data expand the evidence base for aficamtan and deepen our understanding of its potential application in OHCM. Now I'll hand it over to Doctor. Garcia Pavia to present the results of MAPLE HCM.
Thank you very much. So it's my pleasure to present the data of the MAPLE HCM that were presented last Saturday in the late breaking trial session of the European Society of Cardiology meeting. Next. So on behalf of Michael Althors, again, I present this data of the trial Maple HCM. Next.
Here, you can see my disclosures. So stratified HCM is a disease characterized by hypercontract left ventricle hypertrophy and levantograph of tract obstruction resulting in limiting symptoms and reduced exercise capacity. Aficantem is an next in class cardiac myosin inhibitor that targets the underlying pathophysiology of HCM by reducing hypercontractivity. Aficantem has demonstrated already several benefits in patients with obstructive HCM who are symptomatic despite the standard of care therapies. In this study, the well, currently currently, the most common standard of care therapy used in clinical practice is beta blockers.
Beta blockers have been the first line treatment for symptomatic patients with a static HCM for more than sixty years despite very limited evidence. In fact, beta blockers are recommended both by the European and American guidelines with a class one level of recommendation as the first line therapy of choice in patients with symptomatic obstructive HCM. Next. In Maple HCM, we sought to evaluate the safety and efficacy of aficantin in monotherapy compared with one of the most commonly used beta blockers in these patients, which is mono metoprolol in monotherapy. So unlike the previous studies, we are not adding aficantam to a standard of care medication.
Here, we are treated we are comparing aficantam with the standard of care medication. The primary endpoint of the study was exercise capacity assessed through peak b o two, which is a parameter that is captured in cardiopulmonary exercise test. Secondary endpoints include symptoms, Valsalva, left ventricle for tract gradient, so the degree of obstruction under Valsalva, NT pro EMP, which is an which is an accepted biomarker of heart failure, And third time, echocardiographic parameters like left atrial volume index and left ventricular mass index. In this slide, you can see the design of the MAPLE HCM study. We randomized 175 patients to receive either metoprolol plus placebo or Aficant ten plus placebo and follow them during twenty four weeks.
During the initial six weeks, both investigational products were those suggested based on-site echocardiogram parameters and vital signs. Both patients with recently diagnosed or treatment naive obstructive HCM and patients with chronic obstructive HCM on standard of care medications could participate in the trial. If the patients were already taking standard of care medications, they had to undergo a two week washout period of standard of care medications before undertaking the screening visit were qualified for the study. Here, you can see the baseline characteristics of the participants in the study. Overall, had milder phenotype than those patients previously included in previous CMI studies.
The median NT proBNP of patients participating in the study was around 500 picograms per ml. The mean peak v o two value was around 20. And regarding gradients, LBOT gradient at rest or with Valsalva were around 45 millimeters of mercury or and 75 millimeters of mercury, respectively. Of note, we observed that there were more patients with hypertension in the aficantam group than in the metoprolol group. During the trial, the majority of patients were exposed to the highest doses of both of metoprolol and aficantem, as you can see here on the slide.
And at week twenty four, we found that ten patients who were receiving metoprolol did not tolerate any dose of this drug as compared to one patient on the Aficante room. At week twenty four, patients receiving metoprolol exhibited a mean decrease of six beats per minute in resting heart rate and a mean decrease of six millimeters of mercury in systolic blood pressure. As compared to a mean decrease of blood pressure of five millimeters of mercury in the Vicente group and no change in heart rate addressed. And here is the slide where we presented the results, the primary endpoint results. After twenty four weeks of therapy among patients receiving metoprolol, we observe a mean decrease in peak VO two of 1.2.
While in patients receiving Aficantam, we observe a mean increase in peak v o two of 1.1. The absolute less square mean difference of Aficantem compared to metoprolol was 2.3, which was statistically significant with a p value of less than 0.001. This difference is way above the minimum threshold of clinical significance in clinical practice, which is considered one ml per kilo per minute. Next. When analyzing the prespecified subgroups regarding the primary endpoint, we observed no heterogeneity including for the diagnostic period of the disease in patients participating in the study.
Regarding secondary endpoints, both improvement in NHK class, change in KCCQ, which is a parameter of quality of life, change in NT proBNP, Valsalva LVOT gradient, and left atrial volume index were all statistically significant in favor of Aficante, while the change in eleven to twelve hour mass index was not statistically significant. Analyzing deeper the parameters of the secondary endpoints, and here you can see the functional class. We observe that at week twenty four, 51 of patients treated with aficantam and twenty six percent of patients treated with metoprolol had one or more improvements in in which classes. Of note, at week twenty four, forty percent of patients receiving Aficantem were asymptomatic in NWCHE class one. While in the metoprolol group, this percentage of patients who were asymptomatic was only nine percent.
Regarding KCCQ, a parameter of quality of life, we observed that among patients who received metoprolol, they did improve in this parameter. But the improvement observed in patients receiving Aficantam was larger with a less square mean difference between groups at week 24 of seven points, again, statistically significant. Surprisingly, during the trial, we observed that metoprolol did not improve resting LVOT gradient or Valsalva LVOT gradient, which is the obstruction that these patients suffer when a systolic ejection of base of blood from the blood. In contrast, patients receiving Aficantem had a sustained early decrease in obstruction as observed in the graphs with a mean LVOT gradient at the end of the trial in both cases for REST and Valsalva gradients below the accepted thresholds in clinical practice that are shown here in the graphs in dotted lines. Next.
Regarding change in NT proBNP and left atrial volume index, which are two parameters of diastolic dysfunction. We observed that those patients who received metoprolol, these parameters increase during the trial, while these parameters decrease in the group of patients receiving Aficantem. Of note, by the end of the trial, NT proBNP values in the Aficantem group was were at the upper limit of normality, as you can see here in the graph, with an 81% reduction compared to baseline. Regarding safety, Aficantem was well tolerated. Three patients had to stop metoprolol during the trial due to adverse event as compared to one patient on Aficantem.
Of total or a total of 26 patients had to reduce the dose of metoprolol during the trial compared to four patients on Aficantene. Consistent with the mode of action of Aficantene, At week twenty four, we observed a mean decrease in 11 degree ejection fraction in the aficantine group of five point three percent compared to our decrease of zero point five percent in the metoprolol group. But only one patient in the Vicente group had 11 tuberoid ejection fraction below 50% as assessed by the Core Lab, and this patient did not have any heart failure symptom or sign. And, actually, the 11 tuber ejection fraction reduction got resolved without stopping aficantem just by decreasing the dose. Next.
So in conclusion, the results of the MAPLE HCM study show that Aficantemi monotherapy was superior to metoprolol immunotherapy in patients with symptomatic obstructive HCM with a statistically significant and clinically meaningful improvement in excess capacity, symptoms, Valsalva Lability ingredients, NT proBNP and late atrial volume index. Despite we had been using metoprolol for more than fifty years to treat patients with obstructive HCM as the first line therapy, and there was a strong evidence of our target hemodynamic effects with metoprolol both in heart rate and systolic blood pressure, we did not observe a decrease in obstruction at rest or with Valsalva in participants receiving metoprolol in this trial. Aficantin treatment was well tolerated. And overall, we consider that these findings support aficantamab therapy as the first line therapy of choice in patients with symptomatic or Structed HCM. Next.
We want to to thank all people who have made this trial possible and particularly participants and their families. Next. The results of this trial were published simultaneously on Saturday at the New England Journal of Medicine. Thank you very much.
Thanks, Pablo. To dive deeper, I'd like to shift our shift now to our panel discussion. I'm pleased to be joined by my colleague, Doctor. Dan Jacobi. And alongside Pablo, we also welcome Doctor.
Carolyn Ho, Doctor. Ahmed Mazri and Doctor. Angelie Owens. I'd like to start by discussing the results of MAPLE HCM, including the primary results and the echocardiographic analysis on the effect of aficamtan compared to metoprolol on cardiac structure and function. But first, Pablo, it was quite an exciting weekend. Obviously, lots of over 30,000 people attending the ESC and several thousand of them in the presentation hall where you gave this presentation. Can you just give us your perspective on the impact of the results from Maple HCM? And then perhaps comment on the reactions to your presentation at the congress.
Thank you, Fadi. Yeah. I mean, the presentation was a great success. We have been using a drug that for more than forty year fifty years that actually had very limited evidence to support its use in this disease. And this trial not only brings a new drug to treat these individuals as first line therapy and in monotherapy, but also provides the data to to conclude that the existing therapy that we were using and which is prescribed massively, I will say, has limited efficacy in these patients and potentially even with some of the parameters that we have shown, it could deteriorate the these individuals.
So therefore, this is certainly a game changer as stated by the moderators of the session. And the excitement that I saw in all the people who came to the congress based on these results was massive. It really will help us in having a better drug in order to improve our patients with very limited side effects as shown in the study. So, really, I was delighted to present this data in my hometown of Madrid, and everybody, stated that this was one of the most important presentations of the congress. I mean, actually, the most important congress that is that that there there is in the world based on the number of people attending the congress, which it was around 35,000.
Thanks, Pablo. I'm sure it was truly a special experience for you in doing this in your hometown, and for many of us at Cytokinetics that were there at all to witness it. You know, also participating in that hotline session was doctor Ho, who was a discussant of your presentation. And, Carolyn, do you want to perhaps, just summarize what your comments were and and also maybe add to Pablo's perspective?
Yeah. Absolutely. You know, and I know, just like to build on Pablo's comments about, you know, importance of this trial, mainly in showing us that what we had assumed to be, the the standard of care approach to symptomatic obstructive hypertrophic cardiomyopathy was not nearly as good as we thought it was, and that really highlights the importance of doing proper randomized clinical trials to guide our clinical management. And I think that what people were most shocked by at the Congress was just how poorly beta blockers performed in this population. So this is again the treatment that we have long assumed for decades to be the way to go to try to help improve symptoms and our patients are just being shown with objective evidence, but they really don't achieve any of the objectives that we were hoping they would in terms of gradient reduction, symptom improvement, or, improvement in functional capacity, was, really, very revelatory, I would say.
It's great. Yeah. It, I suspect, did shake people's presumptions about the treatment that they were using for so long. And I even heard in some cases people questioning what they would do when they would go back to their patients that are continuing to take beta blockers. But maybe I can ask also Doctor.
Mazri to comment. You gave several presentations at the congress, and, obviously, you probably also interacted with many of the attendees. Doctor Masri, do you wanna give your perspective as well?
Definitely. Congratulations to everyone here on the call and to, really, our patients because, you know, we delivered on something that really, has been in a way entrenched in the practice. And, you know, we've observed long time ago that once you go, you know, on beta blockers and whatnot, it's not necessarily what everyone believes it to be. So great to have very proper randomized clinical trial data to support that. Aficamten performed as we've expected to.
Correct? We've had now accrued so much data and evidence behind Aficamten. I think, really, the highlight of MAPIL is the fact that metoprolol did not just not do what we wanted it to do, which is affect hemodynamics to improve symptoms and quality of life in a meaningful way beyond what we expect from placebo, but also worsened exercise capacity, which is important for long term outcomes as well, worsened measures of wall stress, diastolic functions, such as NT proBNP, and left atrial volume index. And so these things for me are really important because the the principle is always, you know, for us is we wanna help patients and not harm anyone. Those are the principles.
And harm doesn't have to actually be that you are leading to an adverse event that you can visually see in front of you. It can also be that, you know, you are reducing their exercise tolerance and their ability to do more aside from its side effects. Now for the longer term data, which I'm sure we'll discuss later on, what what's important from my perspective is that when you use a hemodynamic modulator with a myosin inhibitor, it is really meant not to only focus on the initial duration of the randomized clinical trial. The randomized clinical trial establishes the efficacy and the short term safety. But the long term data are so vital for us, especially as a drug like aficamtan progresses, hopefully, in the next few months to early next year to the commercial stages, that you want to make sure that over a long period of time, this drug performs from an efficacy and safety perspective as you would want it to. Okay.
Great. Thanks, Doctor. Mazer. I think the we got several questions from our people online as well as prior to this call. Let's go through them perhaps, and then I'll get people's opinions on this.
So first question is the level of peak VO2 improvement in Maple was 1.1 for aficamtan, which was slight as a change from baseline for itself in the aficamtan treatment group, which was lower than that of 1.874 that we observed in SEQUOIA. And so the question really is, what do you think contributes to the lower absolute treatment effect for aficamtan relative to baseline and whether can you make this sort of cross trial comparison? So doctor Pavegarci Pablo, you
wanna Yeah. I will address that one. Yeah. I mean, the population of patients included in the study were complete in both studies were completely different. These patients included in in the trial were milder in the sense that these were patients who had better excess capacity at rest.
So if you are starting in a higher point, it's more difficult to go higher than if you
Yes. Absolutely. So it's tricky. Right? Because as as Angelie said, it's not just about, you know, taking therapies in isolation.
We had to consider access, costs, ease of implementation, and all of that. And, also, the MAPLE trial was designed to take people that weren't feeling well on beta blockers, so it was a little bit selective in that way. Think that it's possible that there are some people with very mild manifestations of HCM and mild symptoms that, you know, it it might be practically easiest to initiate beta blockers first and see how how they do on that. But that might be, you know, then the niche for for beta blockers. And beta blockers are also very helpful in treating other issues related to hypertrophic cardiomyopathy, like atrial arrhythmias or, you know, ventricular activity.
So I think that they will, you know, continue to play a role in the management of our patients along those regards. You know, certainly a more targeted therapy like a cardiac myosin inhibitor is far more effective in terms of treating the more pronounced manifestations of disease and and, you know, specifically, outflow tract obstruction and the issues related to outflow tract obstruction.
Pablo, do you want to to add to that?
Yeah. And I think that when I mean, I think the data really support aficantamab first line therapy and monotherapy in these patients. So what it this that this data are gonna do is that they're gonna change the order that we use these medications. In the trial, obviously I mean, people who go into a trial is because of a reason, and there was a group of patients who probably were symptomatic already on beta blockers. They stopped the medication and then went into the trial and received either beta blocker or Aficante.
But there was still a thirty percent of newcomers that were not on therapy before were not taking beta blockers before going into the trial. And and we observed exactly the same findings analyzing the the participants based in previous exposure to beta blockers or not. Moreover, we also undertook an analysis based on the what was the dose of beta blockers that were taken in order to see if that had made any contribution to the results and no interaction with beta blocker dose was found. Moreover, you could say, well, maybe only patients who were intolerant to beta blockers were or who had side effects due to beta blockers went into this study. But that was not possible because there was a clear exclusion criteria to participate in the study, which was intolerance or side effects due to previous beta blocker exposure because we didn't wanted to have somebody into the trial who maybe will have received beta blocker during the trial.
So really, really solid data here. Moreover, even if if we excluded the 10 patients who actually did not tolerate the beta blockers, we got exactly the same results.
Great. Thanks, Pablo. And then lastly, you know, Ahmed, I know you addressed this question in one of your talks. Do you wanna also perhaps briefly comment? I think it's a really important, point.
Definitely. I think, ultimately, you know, you have, phase three randomized clinical trial data. Again, this wasn't an easy trial. You know, kudos to all of you and us for, actually, our patients for doing this. But, really, it wasn't an easy trial, and it was done been very you know, conducted very well.
Now the question is, do you now use beta blockers widely as a first line therapy in obstructive hypertrophic cardiomyopathy or or what? And the takeaway for me from this is that, you know, it it becomes on a case by case basis. If you have reasons to go for it, you have reasons to go ahead. But, you know, the big elephant in the room is that, you know, we need, you know, aficamtiv to be available as well to be able to use it as a first line therapy and monotherapy for these these patients. So that's ultimately the goal here.
But the beta blockers would be, in my opinion, case by case basis going forward.
Great. Thanks, everybody. In interest of time, I want to move on to a couple of the other presentations that were made, and, maybe I'll turn it over to Doctor. Jacoby to introduce the next topic.
Hello. Can you hear me?
Yep.
Yes. Thanks very much.
Yeah. Hi. So, we received a number of questions about the results of OddiSY, actually. And, this was presented over the weekend by BMS. And the questions here are the potential read through to our phase three clinical trial of aficamtin in NHCM, Acacia HCM.
Obviously, we we've excluded questions that compare aficamtin to other compounds for obvious reasons, but I I guess I wanna start off really by, asking oh, Achmed's fallen off here. But I guess I wanna ask Carolyn in that case, why do you think OddiSY didn't hit its primary endpoint here over here? Do you have a a perspective on that? And then as a correlate to that, I mean, I guess, can you opine on any particular aspects of the forest plot or the subgroup analysis that might, you know, provide any insights there?
Yeah. Well, I I guess that's a million dollar question. Yeah. And, yes, so much to to think about. For us, he was, you know, the you know, really important in being the first, you know, quite large scale, like, testing of a cardiac myosin inhibitor for symptomatic nonobstructive HCM.
And, you know, we're learning, you know, you know, as we go along. And I think that one of the big things that stood out to me is that nonobstructive HCM is relatively straightforward. We have a good target to go for in terms of drug titration, you know, and improving and resolving obstruction really is associated with clinical improvement, symptomatic improvements, improvement in in function. Non obstructive HCM is much more complex and heterogeneous, and so it might be that a one size fits all approach doesn't work for non obstructive HCM as it does for obstructive HCM. We fundamentally don't know really what the mechanism underlying symptoms are in non obstructive HCM.
We believe that it's they're largely driven by diastolic abnormalities and inefficient myocardial energetics, which may be improved by cardiac myosin inhibitors. But, you know, our you know, I think we're trying to think about, you know, what dose is needed is is important. I mean, it's difficult with nonobstructive HTM because we don't have a clear biologic target to give us, you know, minute by minute readout as to whether we're giving the right dose. With obstructive HCM, we're able to target the minimal effective dose. But, you know, once we relieve obstruction, we can stop dose titration.
But with nonobstructive HCL, we wanna guard against underdosing, particularly in the realm of clinical trials. And so we're really going for the maximum tolerated dose, know, uptitrating as long as LVEF seems to be still tolerating it. So I think, you know, a lot to learn. You know, they were obviously was relatively close statistically to the hitting significance both in peak v o two and KCCQ. And so, you know, I think we're there's still, potential for, non for CMIs to be beneficial in nonobstructive HCM, and we'll just need to await, further, further information as it as it comes through.
Yeah. Thanks, Carolyn. And I what I hear you pointing out here is that, you know, you really need a kind a of drug that can can have a therapeutic window between efficacy and toxicity that's broad enough to be able to titrate the dose there. Pablo, do you have any, thoughts, or did you hear anything in terms of discussions at ESC on this topic?
Well, obviously, it was a big disappointment because we I mean, for obstructive HCM, we thought we had some therapies. But for non obstructive HCM, or at least we still have myectomy and surgery surgical procedures. And but for non obstructive HCM, we did not have anything. So the disappointment was big. And, particularly, there was concern about the number of individuals who had to stop the medication during the trial, the ODC trial, I mean, because that certainly could have had some impact in the results.
Because if you have to stop the medication and then wait four weeks to restart the medication and so on at a lower dose, that could have had some impact in the outcomes of the study. We need to see we need to see that Aficantem in in the following study in the case here because of the pharmacological properties that the that the compound has and the design of the trial, which requires in case that eleven degree exon fraction dysfunction appears, the drug is not stopped, it's reduced. Maybe in those cases, that is critical in order to achieve a good evolution of these patients. We will see what happens.
Thanks. Pablo, maybe I could just ask one question if I can just jump in. You were the second largest enroller in in OHDIESY, and so you had a fair I think you enrolled 20 patients. So what was your, I guess, impression in your patience of
Well, there were 13 patients who did very well. The I I can say that. I mean, there were 13 patients who really improved largely during the trial. And, actually, by looking the data in the study and some of the sub analysis that have been presented during the ESC, the NT pro EMP values and the echocardiographic parameters, I mean, there are large reductions in NT pro EMP in the in the group. So I'm still I still think that CMIs can have a role in non obstructive HCM because there are certain parameters that really improve largely, as we have seen in clinical practice among the patients included in the trial.
So let's see. Let's see. I think we have more hope. I mean, it was a disappointment, but I I don't think this is this is ended. I think the jury is still out and and looking forward to know what happens with the case results.
Yeah. Just to quickly build on that. Yeah. I totally agree with with Pablo. You know, again, the population that we're working with in non obstructive HCM, I think we're learning is, like, much more heterogeneous, and there might be sub cohorts within the overall population that do enjoy benefit from cardiomyocytes inhibitors.
Those are really hyperdynamic, you know, potentially even those with mid cavity obstruction. So, you I think that we just have to, you know, you know, continue to to see where the science, takes us and see where evidence takes us.
So then, I guess, the follow-up to that for for Angelie, there's two two things. One is I think people were a little bit surprised by the amount of, placebo effects seen in the KCCQ, in this study. And I'm I'm sure you don't have a quick answer for that, but, if you have any perspectives. And then I guess, similarly, so tangentially, but similarly, if you have any insights from what you've seen in the long term data that's been published from the forest study in the NHCM population that might, you know, support any read through perspective on whether Acacia might be different, specifically along the lines of what of what Carolyn and Paolo are just talking about?
That's a great question. I wish I had the answer to the KCCQ, improvement in the placebo arm. It's hard to know, exactly why we saw that 10 improvement where in prior studies including the phase two MAVERICK we saw more in line of six point improvement. I think it speaks to the importance of doing randomized controlled trials in this population where we do see a significant placebo effect. Keep in mind, these patients were in close contact and care with their physicians for the forty eight week trial period, which they otherwise would not have been.
So my guess is these patients were getting more intensive care, more recognition potentially of, periods of congestion or periods of AFib, and they were being actively managed. There's always the question of background therapy that's being given for other comorbidities that are quite common in patients with non obstructive HCM, including obesity, and the rise in use of GLP-1s, of SGLT2 inhibitors. I think, you know, that could have potentially played a role. We have to do a deeper dive, as Carolyn and Pablo have said, into the responders. I think the therapeutic hypothesis of myosin inhibition in non obstructive HCM is still very much alive based on the signals that we saw in biomarkers and in evidence of diastolic improvement and structural improvement.
So I, you know, as we said, it is certainly not one size fits all in non obstructive HCM, and it's probably not even one size fits most. You really have to do an individual analysis of where your patient is on the continuum of disease, and it may be that myosin inhibition benefits some and not others. What we've seen in terms of the long term data in Forest, I think is very, good and it speaks to the fact that hopefully we'll get a positive result in acacia. But I think non obstructive HCM in general is a higher risk proposition than obstructive HCM, and we have to be realistic about that and think about really understanding the underlying disease pathophysiology in the nonobstructed state where we don't have the biomarker of obstruction and how we might benefit those patients in the long run. With regard to the subgroup analysis that you, had asked Carolyn and she started to mention, you know, we did see some signals for the patients who were perhaps younger and perhaps less sick, the class two patients.
So there's a possibility that we enriched too much for those that had advanced diastolic dysfunction, and subsequently, probably longer duration of disease in Odysee. So all these things will need to be looked into.
Thanks, Angie. I wanna pass it over to to, doctor Malik here, for a question and then a follow-up.
Sure. I'd I, first of all, I'd just like to ask, Pablo maybe a question with regards to Aficampton. We have Acacia ongoing. What property we've just finished Maple, so you're pretty familiar with what the properties of Aficampton are. What what properties of aficamtan do you think, you know, may enable it to succeed in NHCM?
Well, I think the wide therapeutic window that it has, it's certainly something very positive because it allows us to modify the the dose quickly. And and that really is helpful because when you have one of these patients, what you want is to uptitrate as soon as possible so they start improving. You don't wanna keep the patients under your car several months until you can increase the doses. So that's one of the things. Second, I think it's important the absence of relevant drug to drug interactions.
So I think it's that's very helpful in everyday clinical practice. So those two things are really, really key when selecting the the drug that you wanna use. And and, yep, those are mostly the the things that you really, really want in in in in a drug that you are using in clinical practice. And and really and and also that that it has a good efficacy, obviously. That's that's safety and efficacy.
And and and so far, they have been excellent in the trials that they they have been conducted so far with AFI.
Yeah. Yeah. I agree. I mean, I think the you know, obviously, what we saw in ODYSSEY, I think, was evidence that the underlying impact on on measures of diastolic function improved, biomarkers improved. You saw trends in the endpoints that were positive and but perhaps the measure of measures of efficacy were clinical efficacy were confounded by some of the challenges with obtaining the proper dosing and treatment interruptions and things like that as you as the panel has pointed out.
Let me let's move back perhaps to Maple quickly. And before we wrap up, there was an impactful presentation, impactful study. How do you think the process and timing for updating guidelines is for something like this? And what might you expect or guess? I guess I shouldn't say expect because who knows how the guideline committees will land.
But what what would you guess if it were you and your those in in their shoes?
Well, I can speak by the European Society of Cardiology Guidelines. During this congress, it has been announced that there's gonna be an focus update of the 2023 cardiomyopathy guidelines, and that's gonna take place and be published in 02/1927. So I guess that that will allow plenty of time to know what do regulators and payers also if they approve or not, AFI, for the indications that they have already been filled, and maybe in the future, there will be others. And, certainly, the guideline committee will have to take into consideration the results of Maple and and Acacia in order to incorporate them into the update of the of the guidelines.
K. Carolyn, do you wanna add to that?
Sure. The American guidelines committee haven't, like, met yet about informally to discuss this. It's never a fast process to to update guidelines. You know, you know, the The US guidelines are have moved to what will hopefully be a more nimble and, you know, kind of rapid processing of of guideline updates so you're not waiting, you years and years between, you know, guideline versions. But even with the the more rapid strategy, it took almost two years for the update and the HCM guidelines to come out.
So I I suspect that there would be a pause waiting for Acacia to read out there and thereby being able to handle nonobstructive HCM and the role of beta blockers at the same time. So probably, you know, kind of targeting the same date in 2027 to perhaps have a more formal revision of an updating of the guidelines.
Great. Well, thanks. I want to really thank our panelists for joining us today. Doctor Madri had to leave early for clinic, I think. But, thank you all.
And I want to turn it over to, Robert Blum, our CEO.
Thank you, Fadi, and thank you also to Drs. Garcia Pavia, Ho, Masri and Owens for joining us on this call today. We're especially pleased by the positive feedback that we're receiving from cardiologists related to the results of VAPEL HCM as well as the additional data coming out of ESC relating to aficamtan in OHCM. Having three more high profile and simultaneous publications further reinforces the importance of the growing body of evidence that we believe underscores momentum building within the field and around aficamtan and its potential role in OHCM. However, in the meantime, please understand we continue to work with FDA as it reviews the NDA for aficamtan with a PDUFA date in late December.
Also, understand the NDA was accepted based on efficacy and safety results of SEQUOIA HCM, our first Phase III clinical trial of aficamtan. We're now already preparing the requisite regulatory report for MAPLE HCM, and we expect to submit a supplemental NDA to include trial results into labeling following the potential approval of aficamtan later this year. We also look forward to sharing top line results for Makacia HCM in the 2026 and the primary results at a medical meeting hopefully soon to follow. We very much appreciate your interest in Cytokinetics and our development program for aphecamtin. We're looking forward to keeping you up to date on our progress and thank you for joining on our call today. Operator, with that, we can bring it to a close, please.