Good morning, and welcome, ladies and gentlemen, to Cytokinetics' conference call regarding data presented at the European Society of Cardiology Congress 2024. At this time, I would like to inform you that this call is being recorded and that all participants are in listen-only mode. I will now turn the call over to Joanna Siegall, Director of Corporate Communications and Investor Relations. Please go ahead.
Welcome, everyone, and thanks for joining us on the call. Robert Blum, President and Chief Executive Officer, will begin with a brief introduction. Then Fady Malik, Executive Vice President of R&D, will provide an overview of the data presented this weekend at the European Society of Cardiology Congress in London. Next, Steve Heitner, Vice President, Head of Clinical Research, will lead a discussion with Dr. Ahmad Masri and Dr. Iacopo Olivotto to provide perspective on the data and answer questions we received in advance. Finally, Robert will provide closing remarks. 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, including our current report on Form 8-K that was filed earlier today. We undertake no obligation to update any forward-looking statements after this call. In addition, on today's call, Dr. Masri and Dr. Olivotto will share their professional perspectives on the clinical significance and safety implications of aficamten-related data presented at ESC. These perspectives are solely the opinions of Dr. Masri and Dr. Olivotto and may not reflect the opinions of Cytokinetics or those of other experts who review these data, including those who will review the NDA for aficamten at FDA and applications submitted to other regulatory authorities. Dr. Masri and Dr. Olivotto are here today as contracted consultants with Cytokinetics. Now, I will turn the call over to Robert.
Thank you, Joanna, and thank you to everyone for joining us on the call today. Over the weekend, we presented a tremendous amount of new data related to aficamten in four late-breaker presentations and two oral presentations. These presentations were also accompanied by four simultaneous publications in leading cardiac journals, which is truly unprecedented for Cytokinetics. As Fady will elaborate, these new analyses reinforce the primary results from SEQUOIA-HCM in terms of safety, efficacy, and the potential for disease modification to reflect a profile that may enable aficamten to become the cardiac myosin inhibitor of choice among physicians and patients. The primary analyses from SEQUOIA-HCM form the basis of our rolling NDA submission for aficamten, which is currently underway and expected to be completed during this third quarter.
While the primary results from SEQUOIA-HCM represent the anchor of the submission, these additional analyses expand in meaningful ways on the overall profile of aficamten for the potential treatment of obstructive HCM. Now, I'll turn the call over to Fady.
Thanks, Robert. Our six presentations related to aficamten at ESC were accompanied by four simultaneous publications in top-tier cardiac journals, three in the Journal of the American College of Cardiology and one in the European Heart Journal. All presentation slides, as well as links to each publication, are available on our website. The depth of these analyses and volume of published work collectively reinforces the safety and efficacy of aficamten in these clinical studies. What's been made clear from ESC is that as we dig deeper into the data from SEQUOIA-HCM and FOREST-HCM, the body of evidence continues to help demonstrate the potential positive treatment of benefit of aficamten on clinical outcomes, symptoms, biomarkers, and cardiac structure and function. Starting with the additional results from SEQUOIA-HCM, Dr. Ahmad Masri presented data from the SEQUOIA-HCM CMR substudy, which included 50 patients who underwent cardiac MRI within SEQUOIA-HCM.
The data showed that treatment with aficamten significantly improved LV mass index and resulted in favorable cardiac remodeling, meaning that treatment with aficamten appears to change the architecture of the heart and suggests it has the potential to be disease-modifying. Complementing the CMR substudy was a more extensive analysis of the echocardiographic data from SEQUOIA-HCM, presented by Dr. Sheila Hegde, showing that aficamten improved measures of ventricular structure and function, left atrial volume, and diastolic function. These improvements were each associated with improvements in exercise capacity, symptoms, and biomarkers. As previously reported, treatment with aficamten also significantly improved resting and Valsalva gradients by approximately 60%, with a less than 5% reduction in LVEF. While improvements in cardiac structure and function may provide a means to impact the long-term progression of OHCM, many patients live day to day with substantial symptom burden from which they are seeking relief.
Dr. John Spertus presented results of an analysis from SEQUOIA-HCM on the effect of aficamten on patient symptoms, measured by the Kansas City Cardiomyopathy Questionnaire and the Seattle Angina Questionnaire. Both patient-reported measures from SEQUOIA-HCM. On both patient-reported measures from SEQUOIA-HCM, aficamten resulted in a statistically significant improvement in symptom burden. With nearly 1/3 of patients experiencing improvements in KCCQ and SAQ of 20 points or more. Regardless of a patient's baseline characteristics, including how severe their disease was at baseline, aficamten improved self-reported patient symptoms. Additionally, Dr. Caroline Coats presented data from SEQUOIA-HCM, showing the treatment with aficamten resulted in statistically significant reductions in NT-proBNP and cardiac troponin.
Several interesting findings also emerged in this analysis, suggesting that NT-proBNP may be a useful tool to monitor functional and symptomatic improvements in response to treatment with aficamten, using a sample collected as early as two weeks of drug exposure. Beyond SEQUOIA-HCM, Dr. Masri presented an integrated safety analysis that pooled data from REDWOOD-HCM, SEQUOIA-HCM, and FOREST-HCM, and is reinforcing of the safety profile of aficamten. Across the three clinical studies, 3.9% of patients treated with aficamten experienced LVEF less than 50%, but none were associated with clinical heart failure, and all were successfully addressed by simple dose-down titration. As we've disclosed previously, there have been no dose interruptions and no treatment discontinuations in any of these studies.
What's also encouraging is that the placebo-controlled pool, new onset atrial fibrillation, myocardial infarction, and syncope occurred at similar rates between aficamten and placebo, rates which should not increase in the longer-term follow-up. Finally, Dr. Masri presented data from FOREST-HCM. Using the open label data collected through the time of this analysis and in the setting of a protocol, which is designed to approximate real-world practice, the data showed that the majority of patients who attempted withdrawal of standard of care medications at the discretion of the investigator were successful, with some patients achieving monotherapy with aficamten, with no negative impact observed on the safety or efficacy of aficamten. FOREST-HCM remains ongoing. As Robert mentioned, these analyses are consistent with our aspirational target product profile for aficamten and add to our understanding of the potential real-world application of aficamten for patients with OHCM.
Now I'll turn it over to Steve to lead a discussion with our two esteemed guests to dig deeper into these data. Steve?
Thanks, Fady. I'm very pleased to be joined by two world-leading experts in hypertrophic cardiomyopathy to provide additional insights and perspectives into the data presented at ESC over the weekend. So with me are Dr. Ahmad Masri, the director of the Hypertrophic Cardiomyopathy Center in Portland, Oregon, at the Oregon Health & Science University, and Dr. Olivotto, who is the head of the cardiology unit at the Meyer Children's Hospital, as well as being the head of the cardiomyopathy service at the University of Careggi Hospital, and he's a professor of cardiovascular medicine in Florence, Italy. So thanks both for joining us this morning as expert consultants who work with Cytokinetics. And I'd like to start the discussion off with the additional results from SEQUOIA-HCM.
We'll get to the FOREST and the integrated analyses after that. Note these questions were actually submitted to us in advance by our covering analysts, and we'll do our best to have Dr. Masri and Olivotto address them to the extent that they can. We have excluded any questions that compare aficamten to other compounds or speculate on the effect of these data or potential labeling for aficamten. First, I'll start out with Dr. Olivotto. Iacopo, are you with us?
Yes, I am. Sorry for the delay. I'm here.
No worries, so this is a question that came from Yasmeen Rahimi at Piper Sandler, and she asked: Given the great data at the conference presented, could you please tell us how these data were received during the conference by the cardiology community?
Yes, I think that this particular meeting here sort of marked a different era. So we started talking about myosin inhibitors four years ago, and this year it was really like the maturity of the. It was really established via this wealth of data that this strategy is not going to go away. This is a strategy that's here to stay, both in terms of the efficacy and tolerability, particularly of aficamten, and at this stage. And therefore, really, people are quite eager, particularly as we are now beginning to get some real-world feedback from the strategy of myosin inhibition, which is really confirming all the good things that we know about this strategy.
So I think that we are now entering an era where a lot of cardiologists that have never been into cardiomyopathies are really being attracted to this because we now have a treatment that will probably revolutionize the field.
All right, excellent. So let's get stuck into some of the data-related questions. The next three questions are gonna be for you, Dr. Masri. The first coming from Roanna Ruiz from Leerink Partners. And the question is: How might the structural changes seen in the CMR study impact the long-term cardiac function and patient survival rates? And what further studies are planned to monitor these outcomes?
Sure. So, the CMR sub-study from SEQUOIA-HCM went for to 24 weeks, and so patients had CMR at baseline and at week 24. And, treatment with aficamten impacted numerous, variables that are known already to be associated with adverse remodeling and with adverse outcomes in hypertrophic cardiomyopathy. Now we know that if something essentially is heading in one direction and trying to regress, it doesn't always translate into, improved long-term survival necessarily. But in this scenario we are seeing consistent effects on multiple different parameters on cardiac MRI, including LV mass, LV wall thickness, left atrial volume, as well as some actually measures of the structure of the myocardium itself, such as native T1, which is a property of the myocardium.
That means that there i s typically less edema and less burden of disease at the myocardial level and myocyte level. And then finally, we also showed the same that happened with some measures of fibrosis, when it's indexed to the mass. And so collectively taken, I think these are robust findings, really reassuring that what we are seeing with aficamten goes well beyond the reduction in LVOT gradients and improving symptoms. It is acting at the structural level as well.
Just one other portion of that question from Roanna is what further studies are planned to monitor these outcomes?
Yeah. So we have the ongoing FOREST- HCM open label trial. This is a five-year trial. It's gonna be a fairly sizable study that has both obstructive and non-obstructive HCM participants. They're getting MRIs over five years. And so as such, this is of course, in addition to the echocardiograms that are being performed. But to focus on the MRIs for a second, this will allow us to glean into these changes in structure and function further up to five years. And then, on top of that, in the ongoing ACACIA HCM trial, which is going to be a longer trial compared to the other obstructive HCM trial. ACACIA is a non-obstructive HCM, and there is also an MRI sub-study of that.
So we're gonna have lots of data and wealth of information to, one, confirm the findings, but two, show the long-term benefits and effect on cardiac structure and function.
Perfect. Thank you. So the next two questions come from Jeff Hung at Morgan Stanley. And he's asked: For the SEQUOIA-HCM CMR sub-study, how were the 57 patients who took part in the sub-study selected? And what were the baseline LV mass index for the placebo and aficamten patients in the sub-study?
Yeah. So, we obviously showed the exact numbers in both the presentation and the paper. So the patients were selected by being invited to participate. It is difficult and also sometimes counterproductive to enforce every patient to undergo MRIs, for example, as part of a clinical trial, looking at a certain investigational product. And as such, we certified many sites to participate in the CMR sub-study, and we invited the patients who are being part of SEQUOIA-HCM already to participate, and that's how the 57 came into the trial. In terms of LV mass , on average, it obviously is significantly elevated. Index mass was about 110g- 115g per square meter.
And obviously, this is again a randomized trial, even though it wasn't randomized at the level of the CMR conduct itself. Still, if you look at the baseline characteristics and if you look at the patients, they look fairly similar at baseline.
Okay, great. And then as a follow-on from Jeff, In the CMR trial, how do you think about the improvement in remodeling, but lack of significance in the difference in the change in peak VO2, despite the improvements that you saw in the wall thickness and the gradient? Obviously, the gradient changes were confirmed from the echocardiographic study. And is the belief that it takes longer to translate the improved physical function, the peak VO2, or was this outcome expected?
Yeah, I know. I mean, I would. This is not my own interpretation. Neither it would be probably the interpretation of many others that were part of our manuscript as well as presentation. So when you look at the treatment effects, it is very consistent with the results of the parent study of SEQUOIA. The peak VO2 essentially is, while it's not statistically significant because it was just simply underpowered. We're talking about here 50 patients or 57 patients, which we are presenting this CMR analysis for, while the overall trial was in 282 patients. And so, it's just simply being underpowered but the point estimate is for sure going in the right direction.
S o that would be my own interpretation, that what we have provided over twenty-four weeks is, to me, at least at this point in time, enough evidence that all the clinical points are heading in the right direction. The mechanism of action of the drug is clearly shown, even with statistical significance, in this study and combined with the structural changes. So it's just slightly different interpretation, focusing on the realities of the sample size rather than only looking at the p- value.
Exactly. Thanks. So I'm gonna move on to you, Dr. Olivotto, for the next couple of questions. So we also saw in Sequoia that both resting and Valsalva gradients improved without negatively impacting the left ventricular ejection fraction. How might this read through the potential effect of treatment on the hypercontractility that occurs in hypertrophic cardiomyopathy?
Thank you. We definitely have given a lot of thought to this, and it is important to understand this mechanism, that whenever you're targeting hypercontractility, you are also targeting, at the same time, lack of relaxation. These are two sort of inseparable faces of the same coin. The leading hypothesis now is that aficamten may act by reducing chronotropism, so that means the rate at which contraction occurs, or simply just delay the beginning of contraction by a fair amount, therefore allowing, for example, the mitral valve to resume a normal position before systole occurs. But of course, the bulk of what we are seeing in terms of asymptomatic patient probably occurs on the other side of the coin, so improved relaxation.
We have now some experimental data looking at forces occurring in HCM hearts during myosin inhibition. In fact, what you do see that even when ejection fraction does decrease a little bit, but in the the force of ejection is not particularly impaired. This is, I think, adds to the safety profile of the drug, in the sense that you don't need to push for an actual reduction of ejection fraction, which is a crude measure of systolic function, in order to have a benefit. You can stay clear away from that kind of problem and still have the maximum effect. Of course, the final reason is still under exploration, so we don't have a definite answer to the question.
Great. Thank you so much. So the next question actually comes from Sean McCutcheon at Raymond James. And I think I'm going to actually switch this one to Dr. Masri, and the following two to back to you, Dr. Olivotto. And Sean is asking, while we do see an increase, this is regarding the echocardiographic output that Dr. Hegde presented. So while we do see an increase in the proportion of patients with normal LV diastolic function, across the septal E prime and the lateral E prime and the E over E prime, as well as the left atrial volume index, they remain about 50% or greater with abnormal diastolic function by these metrics. It looks like, on a mean basis, these metrics stabilize or level off after about 16 weeks.
And the question is: Can you explain the time to normalization in the patients that did see a categorical improvement and the trajectory of patients that did not? So quite a complicated question. And then also, is there any indication that longer-term exposure would continue to drive normalization of diastolic function beyond what we've seen in the 24 weeks of SEQUOIA-HCM?
Yeah, I think it's probably five questions in one, so I'll try my best, and please remind me if I forget anything. But part of the concept is that these are not. So a singular measure of diastolic function is not the only measure, and it's not essentially the measure of truth for everything that is happening at, in such a complex system. And as such, that's why we try to provide a multi-domain, essentially, analysis and a multi-domain change of what happens across multiple different aspects of the myocardium, including what we consider surrogate measures of diastolic function. And I think from a population perspective, having such an effect size is considered massive.
I mean, you don't expect to know to. In any treatment, in any trial, in any population-average trial, you don't expect to have the same exact treatment effect in every single individual. That's not why we do these trials. We do them to provide an effect size and treatment estimate for the overall population. And as such, we haven't done this analysis. We could potentially look into it, but ultimately, I think the message is the same, is that you have numerous markers that are all going in the right direction. And personally, I put also a lot of weight in what happens to biomarkers such as NT-proBNP, which is a direct measure of wall stress, wall stretch, as well as diastolic function.
This is, I think, the complexity of this. You have to look at the total data presented and all the domains. I know that you are just seeing different ones of them presented individually, but at some point in the future, we might be able to do something that is multi-domain as well, so that you can see more of that. That is from the diastolic dysfunction piece. Now, if you think about the treatment duration, there are two components to hypertrophic cardiomyopathy, as Dr. Olivotto nicely put there, which is you have the LVOT obstruction in obstructed HCM, and then you have the ongoing issues that are there after you release LVOT obstruction. We knew this for a long time from post myectomy.
Patients still deal with a lot of issues after as well, related to the stiffness and impaired relaxation. And as such, for the acute effect of relieving LVOT obstruction, you expect to see some changes, essentially, when you relieve that LVOT obstruction and pressure overload but we want to see more and more during the follow-up because we're looking at reverse remodeling, favorable remodeling and that's exactly why we're running the five-year trial FOREST-HCM, so that we can provide further data, that, you know, once you relieve the obstruction, how things are gonna behave after that. And I think that addresses a large portion of that question, but if I missed anything, please remind me.
No, that was great. Thank you. So we're gonna move on to you, Dr. Olivotto. There's a question from Serge Belanger at Needham. And the question is: How do you think about cardiac remodeling as observed by CMR versus what we see with echocardiography?
I would say in a more general standpoint that I have been quite surprised because I was not expecting to see a lot of remodeling at all from short-term studies. On the other hand, this seems to be. I was only expecting to see some atrial remodeling because you know HCM is a lifelong process and what we see when we intervene the patient is the result of decades of structural remodeling. To see a reverse remodeling occur in a short time, I think would have been you know optimistic. Whereas I would expect some atrial remodeling which we did see which is the low-hanging fruit in terms of reduced LV filling pressures and improved hemodynamic balance.
I was actually surprised to see any LV remodeling at all, which is actually being consistent with myosin inhibition in obstructive HCM. And it's even hard to some extent how this can explain. It's probably something to do with reduction in the massive protein synthesis that occurs in hypertrophic hearts when myosins are going at full speed. So to see even a measurable reduction in mass and a measurable increase in the cavity, I think was a striking result. Obviously, MRI is much more accurate, it's the gold standard, and is actually what we would use.
I would say in general, both the direction, as Ahmad was saying, Dr. Masri was saying, the direction of the changes and the amount of the changes is consistent with echo and MRI. Of course, before we can draw the final balance of the benefit of myosin inhibition in terms of long-term remodeling, this will really take long-term studies. And we know that. We know that from Fabry disease, from other models of hypertrophic cardiomyopathies.
Okay, perfect. So really, complementary of each other. And we're gonna switch gears to talk a little bit about the KCCQ output. So again, for you, Dr. Olivotto, Dr. Spertus presented the data on KCCQ from the SEQUOIA-HCM trial, and he showed an average improvement of 7.9 points, with 30% of patients experiencing an improvement of 20 points or more. And in your practice, what magnitude of improvement in KCCQ is meaningful for patients?
First of all, KCCQ is really important because it's really what matters to patients. The patients don't really care about gradients or about category modeling. They care about their quality of life, the things they can do. A clinically important improvement, which means, well, anything above five is relevant. 20 points is huge. It means, for example, in my practical experience, from being unable to play with your little children and play around, or to have any, even a very short walk up hills, trekking on the mountains, to being able to lead a relatively normal life with vigorous exercise. It's something that is, by all means, comparable to surgical myectomy.
This is what you would expect to have in somebody who has a surgical myectomy performed optimally or a TAVI, for example, in aortic stenosis, so it's quite striking and in SEQUOIA, about almost one in three patients with aficamten improved by this amount, which means, again, normalization of the quality of life, and compares to only one in ten in the placebo arm, so it's definitely a striking result. Again, not something you often find in pharmacological trials in cardiovascular medicine.
Okay, great. Thank you. So back to you, Dr. Masri, a question from Paul Choi at Goldman Sachs. While treatment with aficamten suggests structural improvements, why are KCCQ and the Seattle Angina Questionnaire numerically worse than placebo after the washout period?
So, what's happening is that you're giving someone a very effective therapy, as Dr. Olivotto just e xplained, and they feel so much better, and they are able to do so much more. And this is not a trial of six weeks. It is a trial of 24 weeks, and so you have removed already LVOT gradient in a lot of them by six weeks. So they lived all of that time in a way, enjoying their life. And so while the placebo, as you can see, essentially starts to go up initially and then levels off. And so really, that's even a further confirmation, in my opinion, to the effects of the drug and the treatment effects of the drug.
And I wouldn't necessarily view it negatively, because, we talk to patients all the time. We have recruited many patients into these trials, and we understand the behavior. Y ou've taken away a drug that is effective, that has a short half-life in a way. S o you're over these four weeks, you're gonna see these changes happen. And if this is part of the study and development of this investigational product, you could argue that you would want to continue patients on the drug and just roll over to the open-label, for example. But that's not how we develop medicines. And so that, that's my opinion about this, there is nothing really to dive deep into it.
More or less, you're taking away an effective therapy that makes people feel so much better.
All right. So we're gonna jump to our next question. And actually, Fady, I think that you're probably best equipped to answer this question from Joe Pantginis from H.C. Wainwright. Do you expect aficamten to be able to reduce or even eliminate background standard of care therapy in obstructive HCM patients?
I think certainly in some patients, it should be possible, as was demonstrated by Dr. Masri's presentation on this matter from FOREST-HCM. M any patients were able to completely withdraw from background therapy. Not all, but the majority were able to get to monotherapy. We're doing now the MAPLE-HCM trial, which is looking at head-to-head therapy of aficamten as monotherapy versus the beta blockers monotherapy. And ultimately , if the order of initiation of these drugs is different, that also might yield more patients in whom monotherapy is preferred. So I think time will tell, but certainly I think in many patients, that should be possible to eliminate background therapy.
Great. So, on that note, back to you, Ahmad. This is a question from Tess Romero at J.P. Morgan. And she's asking: In the standard of care withdrawal study, was there any difference between the efficacy or safety of aficamten between those who attempted to withdraw from the various medications, and those who did not?
So no, we delved really deep into this, both in the presentation, and hopefully you're going to see this in an upcoming publication at some point in the near future. But there is not much difference. So everyone responds similarly to aficamten from baseline to the follow-up on maintenance dose of aficamten, the maximum maintenance dose needed. And then when you withdraw or don't withdraw the background therapy, that treatment effect essentially is sustained. And so this is what we set to test, and this is what we essentially were able to find. And this is not just one metric. We're talking about resting LVOT gradient, about pulse LVOT gradient. We're talking about NYHA class, KCCQ as well as biomarkers. And then we also evaluated blood pressure and heart rate and whatnot.
And so as such, these are really significant findings that we have seen, that it appears to be, at least in these patients, that we selected to withdraw the background therapy from, which was totally at the PI's discretion, so there wasn't any guidance provided to these PIs on how you have to do something or not do something. And then with that in mind, I think these are positive, and there was no difference between the two groups.
Great. Thank you. Iacopo , Sean McCutcheon from Raymond James is asking questions also about the background therapy withdrawal presentation. Any additional commentary from the withdrawal study on patient baseline disposition and factors implicated in whether a patient was a good candidate and will be a good candidate for potential withdrawal from standard of care negative inotropes in the future?
Yeah. So, basically, all patients are potentially good candidates for removal of background therapy because none of the background therapies have ever shown any efficacy on outcome and on progression of symptoms or disease. They are known to control some of the symptoms, particularly, they've been studied in the context of acute sub administration but always in a retrospective and very unsystematic manner. So, of course, any unnecessary drug is a potentially harmful drug, and in this respect, to be able to have a pure therapy, just addressing the core mechanism without giving patients anything else, unless there are additional indications, I think it is obviously important.
Of course, you would give sort of a preference to patients that are hypertensive or markedly bradycardic or have other, asthma or any other, or have major side effects from the drug, which are every day limiting, having, forcing us to choose between, trying to control the gradient better, but inflicting side effects, or, treating the gradient, you know, in a sort of less aggressive manner, but having a better quality of life. So from that respect, I think there is no one who would not like to get rid of standard of care, withdrawal background therapy in the absence of any definitive, evidence o f efficacy in this disease.
Got it. So, Fady, I'm gonna come back to you for this one. This is from Salim Syed at Mizuho. Is there more confidence around possibly needing less echo monitoring with aficamten? 0.7% of echo is leading to dose reduction. This is very low. So, does it eliminate the need for constant or more frequent monitoring?
I think the data from FOREST certainly underscore that frequent echo monitoring in the vast majority of cases or occasions doesn't lead to any change in patient management. S o then you have to ask, are there ways to reduce patient burden on the clinical sites and so forth by developing a more cogent and reasonable strategy in terms of monitoring patients on aficamten. I'll also add that in the cases of the few echoes that we saw, as Salim noted, the outcome was just a reduction in dose. There were no adverse symptoms that the patients experienced or declines in their function or worsening of their biomarkers.
So I think as we have now implemented in FOREST and every six-month protocol for monitoring during the maintenance phase, except in patients whose EFs are low after they finish dose titration, with EF less than 55, between 50- 55, is a reasonable strategy, and we certainly might hopefully bring that rationale forward as well, in terms of thinking about how aficamten might be used, if and when it gets approved, in the marketplace.
Thanks, Fady, And before we move on to the integrated safety analysis, I just wanted to note that this discussion is not intended to provide a formal comparative conclusion. O bviously, we have additional clinical studies like MAPLE-HCM, which are being conducted in order to assess the safety and efficacy of withdrawing standard of care medications in the future. So finally, onto the integrated safety analysis. Dr. Masri, since you presented this analysis, I'd like to get your thoughts on aficamten overall, and how it may translate in the real world. It's use might translate in the real world.
Yeah. So, a s we presented, these data are really reassuring that if you look at the total safety events as well as the comparison to placebo, there wasn't really numerically much difference there in the clinical aspects of it. You did have very few events of LVEF below 50%, which were all managed by down titrating the drug. They were largely asymptomatic. No one had heart failure associated with that LVEF less than 50%. With atrial fibrillation, you had something that is comparable to a placebo as well in that blinded duration. Syncope was somewhat similar, all these other issues.
For me, from my perspective, this really provides robust evidence that over this time period that we're presenting this safety analysis on. It really gives us confidence that we are dealing with a drug that has consistent effects, that is over time being viewed to have also consistent safety over that duration. We are continuing to generate more and more data. As you just mentioned, there are multiple studies ongoing using aficamten, and we will develop and have more safety data over longer duration of follow-up and hopefully confirm our findings.
Thanks, thanks, Dr. Masri. The last question that I have is for you, Dr. Olivotto, from Mayank Mamtani at B. Riley. Regarding the integrated safety analysis, while new onset AFib was comparable to placebo, the recurrent AFib rate, and he's given us three numbers over here. The recurrent AFib rate was 2.5%, 1.8%, and 1.3% in the cumulative group, the control group, and the placebo group. Was there any trend or possibility of association of atrial fibrillation recurrences with CMI treatment?
Yes, I mean, this issue has also been raised for the other molecule. However, in the specific case of aficamten, numbers were really very, very low. And, of course, the confidence intervals are really large here because of the sample size. So my feeling is that this is really non-significant. Just to give you a context, these are patients that are very much. They have huge atria, very prone to AFib. You would expect in this population a peri-operative prevalence of AFib of at least 25% in a surgical setting, and approximately a 10% prevalence at five years in operated patients. In non-operated patients, pretty much a little less, because these are again very, very big.
So I think that this is actually a very small number and not significant. Doesn't suggest to me that there is any increase in AFib in this particular population.
All right, perfect. Thank you. So that brings us to the end of the questions, and I'd like to thank both of you for joining us. I know that you're incredibly busy, and we're very grateful for your time, and for providing such a valuable perspective. I'm gonna hand it over back to Robert to provide some closing remarks. Thank you.
Thank you, Steve, and many thanks to Doctors Masri and Olivotto for joining us on the call today. We're very pleased with this substantial amount of data coming out of ESC. However, please understand, we expect also further presentations at upcoming medical meetings later this year, and also other publications arising from both SEQUOIA-HCM and FOREST-HCM. Our approach at Cytokinetics has always been defined by rigorous research and clinical research, and with a high-level commitment to sharing our findings in medical meetings and forums such as these, for the benefit of, analysts and investors. In the meantime, we're moving forward with our rolling NDA submission for aficamten, and we're also preparing for our MAA filing in Q4, and all that while we also conduct the ongoing clinical trials in the ongoing development program for aficamten, MAPLE-HCM, ACACIA-HCM, CEDAR-HCM, and also FOREST-HCM.
We highly appreciate the street's interest in this development program, and we look forward to keeping you up to date on our progress. Operator, with that, we can now close the call, please.
Thank you. This concludes today's conference call. Thank you for your participation. You may now disconnect.