I'm Diane Weiser, Senior Vice President of Corporate Affairs. I'm pleased to welcome you to our investor event to discuss the results from SEQUOIA-HCM, the pivotal phase three clinical trial of aficamten. Today's event is being hosted in a hybrid fashion, and I'd like to welcome both those in person in Lisbon, as well as those online. Before I continue, 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. We undertake no obligation to update any forward-looking statements after this call.
Today, I'm pleased to introduce from Cytokinetics, Robert Blum, President and CEO, and Fady Malik, M.D., Ph.D., Executive Vice President, Research and Development. I'm also thrilled to introduce four leading experts in hypertrophic cardiomyopathy here with us today: Dr. Marty Maron, Dr. Greg Lewis, Dr. Caroline Coats, and Dr. Perry Elliott. Thank you each for joining us today. Here's a look at the agenda for today. First, Robert will provide brief opening remarks, and next, Doctors Maron, Coats, and Lewis will each provide an encore presentation of the late-breaking clinical trial presentations from the Congress. Then Fady Malik will facilitate a panel discussion and Q&A session. Finally, Fady will provide closing remarks. For those online, today's slides are available for download in the webcast.
You can submit questions for the panel at any point during the event using the Ask a Question tab on the upper right-hand side of the webcast. For those in person, please raise your hand during the panel discussion to ask a question. Now I'll turn it over to Robert.
Thank you, Diane. I'm incredibly pleased to be here today, joined by colleagues, leading experts in hypertrophic cardiomyopathy, as well as the global cardiology community here in Lisbon, as we share the primary results and two additional analyses from SEQUOIA-HCM, our pivotal phase three clinical trial of aficamten in patients with obstructive HCM. Frankly, I believe it may be unprecedented to have three sequential late-breaking clinical trial presentations at a congress such as this, coupled with a publication in the New England Journal of Medicine, and all related to the one clinical trial. But the results of SEQUOIA-HCM warrant that focus.
As we said, upon sharing the top-line results from SEQUOIA-HCM by press release back in December, the results met our already high expectations, and we believe they're consistent with our best-case target product profile that we hope may enable aficamten to become the cardiac myosin inhibitor of choice amongst physicians as well as patients. Since sharing those top-line results, we have been moving swiftly in preparing regulatory submissions for both the FDA and the EMA, which we expect to submit this year, based on the results from SEQUOIA-HCM. Please know that our top priority is to bring this potential new medicines to patients suffering from HCM and the clinicians who treat them. At the same time, we're continuing to execute against our broad clinical development program for aficamten, with the goal of potentially extending the clinical utility of cardiac myosin inhibitors.
Towards that end, we're conducting MAPLE-HCM, evaluating for the potential superiority of aficamten compared to metoprolol, ACACIA-HCM, evaluating aficamten in non-obstructive HCM, CEDAR-HCM, evaluating aficamten in a pediatric population with obstructive HCM, and as you know, also FOREST-HCM, our open-label clinical trial extension. All of this would not be possible without the steadfast commitment of our team, as well as the patients who participated in SEQUOIA-HCM, the investigators, and their study staff, to whom we express our immense gratitude. With that, I'll hand it over now and firstly to Marty Maron, who's gonna present the primary results from SEQUOIA-HCM, much like he just did at this congress here in Lisbon. Marty?
Okay. Thank you, Robert. Appreciate that. Okay. Are we advancing with this? Oh, here we go. Good. Okay, excellent. Okay, great. All right, so, just by way of background, outflow tract obstruction is the most important determinant of limiting symptoms in HCM, particularly exertional dyspnea and reduced exercise capacity, and that's really what we're talking about as the primary treatment aims in HCM, is to improve that. Hypercontractility, cardiac hypercontractility is the primary driver for mitral valve septal contact and outflow obstruction, and we have an unmet treatment need in symptomatic obstructive HCM. Aficamten is an investigational, novel, oral selective myosin inhibitor, which reduces LV contractility and is designed for optimal pharmacodynamic profile. Aficamten works in terms of mechanism of action by reducing the excess number of actin-myosin cross-bridges at the level of the cardiac sarcomere.
By doing that, you decrease contractility, which ultimately has a favorable effect on outflow tract gradients. Aficamten has a distinct pharmacologic profile, which includes the following: relatively short half-life, 3.4 days, and by leveraging that, steady state is achieved by two weeks, allowing for rapid dose adjustments for patients as well as rapid reversibility. Number two, shallow dose-response relationship, wide therapeutic window, and ultimately, that's leveraged here in the following way. In particular, small changes in ejection fraction as the dose of aficamten is increased, and therefore, no need for serum, plasma drug concentration monitoring. And number three, minimal drug-drug interactions with aficamten, including no clinically significant CYP inhibition or induction.
Aficamten was investigated in a phase two study, REDWOOD-HCM, where it was shown to be safe, well-tolerated, substantially reduced outflow gradients by mitigating contractility, leading, of course, to what we're talking about today, which is the phase three SEQUOIA-HCM trial, the design of which I'm showing you here. Major inclusion criteria there in the upper left. Patients randomized then in a 1:1 fashion to aficamten or placebo, plus standard of care. Treatment duration for SEQUOIA was 24 weeks, with a 4-week washout period. Dosing was initiated at 5 mg, could be increased by 5 mg to a maximum of 20 mg. Those dose escalations occurred at week 2, 4, and 6 based on echocardiographic parameters, and a number of clinical efficacy measures were obtained at baseline and throughout the treatment period.
Primary endpoint for SEQUOIA-HCM was change in peak oxygen uptake, peak VO2, by CPET from baseline to week 24. In addition, there were 10 individual secondary endpoints that were assessed in a hierarchical analysis that included changes in how patients felt by KCCQ, as well as NYHA class. Changes in hemodynamics, including post-Valsalva gradients, as well as proportion of patients with gradients post-Valsalva that was less than 30 millimeters of mercury, and duration of eligibility for septal reduction therapy was also assessed at week 24, as well as change in total cardiac workload. Okay, baseline demographics for the study population are shown here. Essentially, the message here, really well-balanced between aficamten and the placebo arms here.
I will make note that this was a particularly symptomatically limited group of obstructive HCM patients with baseline peak VO2s of 18.5, which is about 58% of age predicted. In addition, gradients, as we've mentioned, were high at rest and even higher with provocation, and patients were on the conventional background therapies for obstructive HCM, including 2/3 on beta blockers, a third on calcium channel blockers, and over 10% on disopyramide. So well-treated medically in terms of standard of care. Okay, talking about now some of the results, of course, starting with the primary endpoint, change in peak VO2. I'm showing you to the right here is the mean change in peak VO2 over the treatment period.
You can see, in brown, the placebo arm, absolutely no change in peak VO2 from baseline to week 24. In contrast, treatment with aficamten associated with a significant improvement in peak VO2 of 1.8 milliliters per kilogram per minute. Next to that is showing you the magnitude of that treatment benefit with aficamten treatment associated with a least square mean difference versus placebo of an increase in peak VO2 of 1.7 milliliters per kilogram per minute. Just to take a second to put that delta change in peak VO2 here with aficamten into clinical context, prior data in HCM has demonstrated that the risk of death or transplant in this disease is reduced by about 18% for each increase in peak VO2 of 1 milliliter per kilogram per minute.
So I think it's pretty fair to then conclude that an aficamten treatment effect of 1.74 in peak VO2 far exceeds the clinically meaningful threshold for an enhancement in exercise capacity. So that treatment effect that I just showed you with aficamten on enhancing exercise capacity was consistent as well across every single one of the pre-specified subgroups that you see here, including patients that were particularly limited at baseline by Class III, as well as being functionally limited by peak VO2s of less than 18. And again, as I mentioned earlier, you know, you know, I and many in this, in the room have been involved in this disease for a long time, and I think it's pretty fair to say that seeing this degree of consistency in HCM, particularly with respect to a treatment effect, is particularly notable.
I'll also make the point that in contrast to mavacamten in the EXPLORER trial, where the benefit of mavacamten was attenuated in those patients who were on beta blocker, in SEQUOIA, treatment with aficamten was similar whether patients were on a beta blocker or not. Okay. High-level overview here, for the secondary endpoints. As you can see, aficamten had a significant benefit versus placebo in each of the 10 secondary outcome measures. Diving down out into that a little bit more in detail, starting first with the change over the treatment period in both rest and Valsalva gradients. I think you can see here with aficamten in green, significant decrease in gradients with aficamten even as soon as week two. By week six, resting gradients essentially obliterated in almost all patients, and that gradient remains obliterated throughout the treatment period.
As you can see as well, emphasizing the reversibility aspect of the drug here, patients had returned to baseline gradients after the four-week washout period. Similar efficacy with Valsalva gradients next to resting, as you can see here. And in fact, the treatment effect with aficamten here was a decrease of 50 millimeters of mercury in Valsalva gradients compared to placebo. Those substantial kind of hemodynamic improvements translated also into significant improvements in how patients felt. Showing you first that assessment by physician-derived NYHA class of vacation. To the bottom left there, you can see in green with aficamten, the improvement in NYHA class over the treatment period.
By week 24, the end of the treatment period, almost 60% of patients on aficamten had an improvement of one or more NYHA class, compared to about 24% in the placebo group. Translated as well. Next, the improvement you can see that parallels NYHA is an improvement in health status assessed by a, a patient-derived KCCQ score. You can see that increase over the treatment period with aficamten, and the treatment effect here was aficamten associated with a 7-point increase in KCCQ score compared to patients on placebo. Okay, additional secondary and exploratory endpoints included taking the subgroup of patients who were eligible with obstructive HCM for septal reduction therapy at the time of entry into the study. And that was based on gradients that were more than 50 millimeters of mercury and class three or four NYHA class.
You can see for those patients, treatment with aficamten was associated with significant decrease in the proportion of patients eligible for SRT during the treatment period. Drawing your attention perhaps to week 12 there, where almost every single patient on aficamten was at week 12, ineligible for septal reduction therapy because of either an improvement in gradient or symptoms or both. That treatment effect remained fairly consistent through the rest of the treatment period. To the right is the change in the important cardiac biomarker of NT-proBNP. You can see, like gradients, an acute reduction in BNP with aficamten that remained very low in terms of serum levels. In fact, treatment with afi associated with an 80% reduction in proBNP from baseline to week 24.
Finally, in terms of exploratory endpoints, this is an endpoint that, as I said, is exploratory of SEQUOIA, but was actually the primary endpoint for Explore, which is a combination of improvement in functional capacity plus symptoms, or in a greater improvement in functional capacity versus no worsening in symptoms. And that combined endpoint in SEQUOIA was achieved in 42% of patients on aficamten versus 14% on placebo. Again, those proportions are higher here than what we saw in Explore in achieving that endpoint for those on aficamten. Common rate difference here for that combined endpoint versus placebo was 28.7, which was highly statistically significant.
To conclude, in patients with symptomatic obstructive HCM, treatment with aficamten over 24 weeks resulted in clinically meaningful improvements in exercise capacity, as measured by the objective test of peak VO2 by cardiopulmonary exercise testing. In addition to enhancing exercise capacity, aficamten was associated with a significant decrease in the burden of limiting symptoms assessed by both patient or physician-derived metrics, KCCQ and NYHA. Those robust functional and symptomatic improvements and relief of obstruction, as I noted, were observed early in treatment and remained durable throughout the treatment period. In totality, SEQUOIA-HCM underscores the clinical efficacy of aficamten in the treatment of patients with symptomatic obstructive HCM. Thank you very much for your attention. Appreciate it. Do we want to... First of all, this is tough to move.
I don't know if there's another clicker, but okay, there we go. Oh, thank you, everybody. Finally, if you're interested in learning more about aficamten and SEQUOIA-HCM, these results are now online in the New England Journal of Medicine. Thank you very much.
Thank you. Thank you, Marty.
Okay.
We'll move on to the-
Move on.
Next presentation. We'll do a panel discussion afterwards. So I'd like to introduce Dr. Caroline Coats, who will discuss dosing and safety in SEQUOIA-HCM.
Thanks, Fady.
... So on behalf of the SEQUOIA investigators, I'm gonna talk you through the dosing and safety profile of aficamten in the SEQUOIA study. As this audience knows, aficamten is a novel cardiac myosin inhibitor with unique physicochemical properties that target the underlying hypercontractility seen in patients with obstructive HCM. We know from previous studies in other myosin inhibitors that this drug class has the potential for excessive reduction in contractile function and, importantly, symptomatic heart failure. Aficamten was engineered with the goal of achieving specific pharmacological properties that would allow for flexible dosing and increased safety. Its short half-life allows for rapid onset, rapid reversibility, speed to optimal dose. It has a predictable and shallow dose-response relationship, no teratogenicity, and no clinically meaningful drug-drug interactions. The design was a randomized controlled trial with 1:1 allocation to placebo and aficamten at a dose of 5, 10, 15, and 20 milligrams.
Clinical assessments were performed at screening and at each visit, and patients had three opportunities at weeks twp, four and six for dose escalation. As you've heard from Dr. Maron, SEQUOIA met its primary endpoint with an improvement in peak oxygen consumption. This pre-specified analysis looks at the study in three phases: in the titration, the maintenance, and the washout phase. We evaluate the safety of implementing a site-based dosing algorithm and also characterize the dose concentration relationship and the stability of plasma drug concentration during the maintenance phase. This is the dosing algorithm. Sites were reading the echocardiogram on the day the patient came in for the visit. An echocardiologist input their own interpretation of the echo to allow dose adjustment. The target was to bring the gradient down to less than 30 while maintaining an ejection fraction above 50%.
On the right, you can see that the dose would increase if the gradient was over 30, provided the ejection fraction was over 55%. If the gradient fell below 30 or the ejection fraction was between 50% and 55%, there was no change, and if the ejection fraction came below 50%, there was a dose reduction. Although not shown on the slide, if the ejection fraction was below 40%, the protocol specified a dose interruption, which did not occur. 80% of patients reached the higher doses of 15 or 20 milligrams of aficamten. If we look at the population by the dose achieved at week eight, we can see that there are no differences in age, sex, ethnicity, body mass index, or comorbidities between the dosing groups.
Not unexpected, patients with a higher gradient at rest required a higher dose of aficamten. Between baseline and week 24, the overall change in ejection fraction was 4.8%. This graph also illustrates nicely that the sites were reading the echocardiograms approximately 5% below the core lab. So they were more conservative, which I think reflects clinical practice. You can see at the end of the 24 weeks of treatment that the ejection fractions recover during the washout phase. In clinical practice, we're much more familiar with using categories of ejection fraction because there's an error in ejection fraction measurement, so a meaningful change in ejection fraction is usually over 5%. We see here that the majority of patients had a small change in ejection fraction.
Although there are some with a large change in ejection fraction, the average ejection fraction in the population was 75% at baseline. So even a reduction in 20% still falls into the normal range. Here we see the stepwise increase in concentration as the dose increases. This was the expected dose concentration relationship. You can see the trough and peak concentrations where there's less than 20% variability. Once a patient achieved their dose at week eight, there was a very stable concentration throughout the remainder of the maintenance phase. These are kernel density plots, which take account of all the echo data from all the patient visits. So the key metrics that we're looking at are ejection fraction on the left, outflow tract gradient in the middle at rest, and Valsalva gradient on the right.
What this illustrates very nicely is that you can make a large reduction in gradient with a small shift in ejection fraction. So when the sites read the echocardiogram, eight people were interpreted to have an ejection fraction of less than 50%. Seven were in the aficamten group, and one was in the placebo group. No treatment interruptions occurred. When the core lab read the echocardiogram, six patients had an ejection fraction of less than 50%, 5 in the aficamten group and one in the placebo group. No heart failure was experienced by any patient treated with aficamten that had an ejection fraction of less than 50% by either the core lab or the site-interpreted data. All aficamten patients with an ejection fraction less than 50% were reversible.
You can see from the Venn diagram that only two patients overlapped, where both core and site interpreted the echocardiogram as less than 50%. The one aficamten patient that overlapped had a COVID infection before that visit. The core lab interpreted the ejection fraction as less than 40%, but the site interpreted the ejection fraction as between 40% and 49%, so there was no treatment interruption. And that patient improved their ejection fraction to 55% simply with a down titration from 15-10 milligrams. This slide illustrates the individual patient data of patients that had either a core laboratory-reported ejection fraction less than 50% or a site-reported ejection fraction less than 50%.
You can see the matching site and core ejection fractions for the individual patients, the background treatment that they're on, and other metrics, which were important to us in clinical practice. Importantly, these were asymptomatic, ejection fraction less than 50%, and in many cases, when the ejection fraction was less than 50%, the symptom score was very high. Importantly, in all cases, at the next visit, the core lab ejection fraction was over 50%. There were no serious adverse events, cardiovascular events associated with aficamten treatment. You can see the overall adverse event profile is similar between the placebo and aficamten group. There was a slightly higher proportion of hypertension and palpitations in the aficamten group.
The occurrence of hypertension with relief of obstruction is a well-recognized phenomenon that's been reported in relief of aortic stenosis and also in septal reduction treatments and, mavacamten. The incidence of new-onset atrial fibrillation was uncommon, one event in each group. So in conclusion, aficamten appeared safe and effective in treating patients with obstructive HCM in the SEQUOIA trial. Importantly, this was... the dosing was done using locally interpreted echocardiograms for both titration and monitoring. Overall, there was a very low frequency of ejection fraction less than 50%, all of which was asymptomatic. There were no treatment interruptions for reduced ejection fraction. The adverse event profile of aficamten was similar to that of placebo, with hypertension and palpitations occurring slightly more frequently in the aficamten group.
I'd like to thank the patients, particularly for their participation in the trial, my co-investigators and site staff, and the sponsor, without whom this would have not been possible. Thanks.
Thank you, Caroline. Last but not least, we have Dr. Lewis, who will recap his presentation on an analysis of the CPET data from SEQUOIA-HCM.
Okay, thank you very much. I'll be discussing enhancing exercise response in obstructive hypertrophic cardiomyopathy on behalf of all of the SEQUOIA investigators. So we know that exercise intolerance is an important clinical feature of obstructive hypertrophic cardiomyopathy, and as you've heard, with aficamten, there's reduction in left ventricular outflow tract obstruction and improvement in exercise tolerance. But there's more to the story here. We know that there's a host of mechanisms that are impaired beyond just the left ventricular outflow tract gradient obstruction in this condition. And collectively, they lead to impairment in cardiac reserve capacity during exercise, and this is manifest as reductions in peak and submaximum oxygen uptake, a decrease in cardiac power, a reduction in chronotropic competence during exercise, as well as inefficient ventilation.
We can capture all of these variables during cardiopulmonary exercise testing, which was performed during SEQUOIA-HCM, and this gives us objective assessments throughout all of exercise. We specifically focused for this analysis on two components of the exercise response. First was the relationship, breath by breath, of minute ventilation to CO2 elimination, which is a marker of the efficiency of breathing during exercise, and this is measured throughout exercise and encompasses the submaximum domain of exercise as well. And then there's maximum exercise as quantified by peak oxygen uptake. Not only is there temporal complementarity between these two variables, but we also know that there's prognostic relevance of both. They independently predict outcomes in patients with obstructive HCM. If we look at one unit change in VE/VCO2, that is associated with a hazard ratio of 0.9.
If we look at changes in peak VO2 per 1 ml per kilogram per minute, it's a hazard ratio of 0.82 for these modest changes in these exercise variables. So in this pre-speci-specified analysis, we hypothesized that aficamten would improve a novel measure of integrated maximum and submaximum exercise performance, and that the changes in peak VO2 would relate to other clinically important endpoints. You've heard about the design of SEQUOIA. Specifically, this analysis focused on a primary endpoint of an integrated measure of exercise performance that combines into a two-component, equally weighted Z-score with peak VO2 and reversed VE/VCO2 slope. We also looked at a host of secondary endpoints that encompass both maximum as well as submaximum responses to exercise that are highly relevant to activities of daily living for these patients. Here are the results of our primary endpoint.
For our integrated exercise performance measure, z-score at 24 weeks was 0.35 higher in the aficamten arm compared to placebo, with a narrow confidence interval that you see here and a p-value that contains nine zeros in it. Notably, this level of significance was greater than that achieved for either individual variable of peak VO2 or VE/VCO2 in terms of the components of this combined endpoint. If we look at the individual patient-level data from SEQUOIA, this is the data on each individual that was enrolled. Shown in green is the aficamten group. You can see in ascending order is the baseline values for peak VO2 and for VE/VCO2 slope. The vertical measures indicate the changes over the course of 24 weeks.
If you focus attention on the aficamten arm, you can see that throughout the spectrum of baseline VO2 values, we see improvements in peak VO2 with aficamten. With the VE/VCO2 slope measure, you can see that as values ascend above 35 for the VE/VCO2 slope, indicative of inefficient ventilation that is potently prognostic, you can see that uniformly there was reduction in the VE/VCO2 slope. In contrast, in the placebo group, both of these cardiopulmonary exercise testing endpoints had no change at all from baseline to week 24 on average, with the individual data shown here. Here is our categorical variable responder analysis. We used large improvement, defined as a greater than 3 milliliter per kilogram per minute increment in peak VO2, and a moderate improvement of greater than 1.5 mls per kilogram per minute.
And you can see here in green that if randomized to aficamten, there was a 13-fold greater chance of having a large increase in peak VO2 compared to a large decrease, which only occurred in 2.3% of the patient population. And then in terms of numbers needed to treat for any improvement, moderate to large improvement or large improvement, they were uniformly below six patients. Here's a cubic spline analysis that relates the changes in peak VO2, which are shown here on the X-axis with the histogram in green, relative to the Y-axis, which are other measures, starting with the Kansas City Cardiomyopathy Questionnaire and the New York Heart Association class, both of which change proportionately to the improvements in peak VO2.
And then we see with both the resting and the Valsalva left ventricular outflow tract gradients, as the gradients decrease to a greater extent, we saw proportionate increases in our peak VO2. We also measured circulating biomarkers and looked at the relationship between change in NT-proBNP, change in troponin, and the proportionate improvements in peak VO2. This is particularly notable because in our multivariate regression analysis, it was a change in NT-proBNP that explained the greatest variance in change in peak VO2. And notably, the NT-proBNP levels fall dramatically, both in obstructive HCM as well as non-obstructive HCM from previous studies with aficamten. Also of note, in the ongoing ACACIA trial, the combined endpoint that I just showed to you of VE/VCO2 and peak VO2 will be the key secondary endpoint in that trial. Here are the remainder of results from our secondary endpoints.
First, starting with peak exercise measures, we can see that there was improvement in peak VO2, improvement in workload, improvement in circulatory power, exercise duration, as well as heart rate reserve. And notably, these improvements were achieved with no difference in the respiratory exchange ratio, which is a barometer of maximum volitional effort that was achieved in both the aficamten and placebo arms at both baseline and at week 24. Submaximum exercise parameters also improved, whether we looked at the efficiency of ventilation during submaximum exercise, all of exercise, the ventilatory power, or importantly, when patients reach their anaerobic threshold in terms of the VO2 at the anaerobic threshold also improved, and this was with no change in the VO2 work relationship.
... So in conclusion, our comprehensive pre-specified analysis of cardiopulmonary exercise testing metrics in SEQUOIA-HCM demonstrated significant improvement in the novel integrated exercise performance metric that combines both maximum and submaximum exercise parameters that are highly prognostic, and this combined metric is again being focused on in the ACACIA-HCM trial. And we also saw improvement in multiple other measures of exercise performance. The enhanced exercise responses correlated with significant improvements in cardiac structure and function beyond just the reduction in the left ventricular outflow tract gradient. These findings offer valuable mechanistic and clinical insights into the beneficial therapeutic effects of aficamten in patients with HCM. I'd like to acknowledge the co-investigators, patients, and sponsor for their critical roles in this work. Thank you.
Okay, thank you. Great set of presentations. I'm Fady Malik, the Executive Vice President of research and development at Cytokinetics.
It's truly an exciting day for those of us here. The reception to the data that you just heard was spectacular. In the lecture hall, as we attended the Heart Failure 2024 meeting here in Lisbon, you know, from concept to clinical effectiveness, it's a remarkable journey, and I'm grateful for all. There are many, many who contributed to making this day possible, including those on the podium with me today. Now that you've heard the presentations, I'm pleased to be moderating a panel with these esteemed physicians sitting next to me, Dr. Martin Maron, Dr. Caroline Coats, Dr. Greg Lewis, and Dr. Perry Elliott, who was the discussant on two of these presentations in the late-breaker session. Thanks for all, all of you for being here.
As Diane mentioned at the beginning, you'll be able to submit questions online via the webcast, and here in the room, if you raise your hand, we'll be happy to bring a microphone to you. While we compile the questions, I wanted to start us off by asking a couple of questions myself. So first, Dr. Maron, I'd like you, if you could, to put in perspective the clinical significance of the improvements in peak VO2 and, and other clinical measures that how they might apply to your daily practice.
Thanks, Fady. Well, you know, let's start first with, you know, I think something really important, which was that the improvement that we saw with aficamten in peak VO2 of 1.74 milliliters per kilogram per minute, to my knowledge, interrupt me if I'm wrong, but I believe is one of the highest change in peak VO2 for medical therapy in any cardiovascular trial that I know of. So that, that alone stands as a, you know, I think a not inconsequential point, and that's telling us something, right? I mean, that's telling us something really, really important about what the drug is doing in terms of pathophysiology.
And what that means in terms of translating that change pathophysiologically is that that is translating ultimately into one of the most important things for patients, which is to impact their limitation from an exercise standpoint, okay? And so for somebody who takes care of these patients and has for more than 20 years, the two most important things that we hear from patients that have obstructive HCM is that they can't exert themselves on a day-to-day basis the way they want, and they don't feel well. They've got limiting symptoms. Both of those, of course, impacting their quality of life.
Ultimately, coming back to answer your question, the change with aficamten that we're seeing, this magnitude of benefit, which is the highest that's ever been seen with any kind of medical treatment in a cardiovascular disease, is translating into substantial improvements on how patients feel and function on a day-to-day basis. And that's translating into patients feeling very happy and will feel very happy with that kind of result. They felt very happy with that in the trial, but they will feel very happy about that, and so will the physicians taking care of them because that is really the primary treatment aim: making patients here feel better and function better.
I think these data, without any question, demonstrate that functional capacity in terms of peak VO2 is changed in a degree with aficamten that is incredibly impressive and will make a huge difference.
Great. Thanks, Dr. Maron. Dr. Coats, I wanted to ask you a question as well. So, you know, people might be confused regarding the LVEF less than 50 data that you presented, data, site versus core, their meaningfulness, you know, whether we should really be focused on treatment interruption and heart failure events. Can you expand on this aspect of your presentation and then put it in your own context?
Yeah, thanks. So I hope I spent enough time explaining, you know, both the ethos behind the design, which I think was important. It was different from the Explorer study. It was, you know, meant to be very patient-centric. It was meant to be implementable and provide us with real-world data. So the metric of 50% is a metric that, you know, we-
... we have to have a cutoff at something. But we all know as clinicians that, is it 52%? Is it 49%? Is it 55%? You know, the error and the challenge, particularly in hypertrophic cardiomyopathy, where you've got a thick cavity, big papillary muscles, measuring that to anything more than plus or minus five is difficult. So that's why I shared the categorical data, 'cause that's what clinicians, you know, would want to see. So what we all you know, what this trial has also given us, really for the first time, is echocardiograms that were read by two independent observers, and that's important data. But I think the message that we've seen is actually whoever read it, the incidence was very low, and it wasn't associated with heart failure, and that's the important thing for patients.
Yeah, I think you shouldn't be adding datasets together. You should be looking at them separately, and separately, basically come up with the same number. And if you wanted to look at them together, you should ask: Well, when, how many cases did they agree? And as you pointed out, they only agreed in two cases. So great. One question for you, Dr. Lewis. Do you mind just elaborating a little bit on why, you know, this novel integrated measure of exercise performance that we developed and analyzed here in SEQUOIA-HCM might be relevant to ACACIA-HCM?
Sure. Be happy to. So you know, I think that the motivation for this measure was that it captures different important aspects of the exercise response pattern. So whether we alleviate somebody's inefficient ventilation, that translates to them being breathless with exercise, or we make them be able to exercise to a higher level, as measured by peak VO2 and corroborated by peak workload and all the other things that we measured, we're going to be essentially enhancing their exercise response pattern. We saw that the results of this combined measurement were highly statistically significant. And we also found that the changes that we saw in peak VO2, the number one explanation for those changes in terms of explaining variance was the change in the NT-proBNP, and that's more of a global readout of cardiac performance.
It is integrating the filling pressure in the heart; it's integrating the diastolic function and the LVOT gradient. That is a measurement that's been seen to go down, whether you're studying patients with obstructive hypertrophic cardiomyopathy or non-obstructive hypertrophic cardiomyopathy. We're encouraged by the fact that the natriuretic peptide levels were explaining a lot of the variance we were seeing and the change in peak VO2, because the next step through Acacia is to translate these findings into a non-obstructive population. The results that we saw with this combined endpoint and with the assessment of peak VO2 alone provided encouragement for that key secondary endpoint that's already been pre-specified for Acacia.
Great, thanks. And Dr. Elliott, you were the discussant for two of these, and I'm wondering if you just might briefly recap your impressions of the data as you shared them with the audience this afternoon?
Sure. So I tried to make the point earlier that, you know, when you're assessing the, the efficacy of a new therapy, you need to define a number of things. It's not just simply about a statistical association of benefit. What is the unmet need that we're trying to meet? And I think even the data from SEQUOIA itself is illustrative of the fact that our current standard of care is suboptimal. So 75% of the patients in this study were not at the level of symptomatic limitation that would require intervention with surgery, but they were on what we would regard as being optimal medical therapy, and yet remained symptomatic. And I think that, that really chimes with our day-to-day practice.
We know that our existing approach to obstruction is suboptimal, and patients end up living for many years accommodating to their symptoms, but still having to live with a significant symptom burden. So I think there's a significant unmet need there. The other point that I tried to explore was, are the changes that we're seeing in this study clinically meaningful as well as statistically significant? And, you know, I, I use the term unprecedented in my, in my assessment. The changes that we're seeing, not only in what you might regard as objective measures of cardiovascular performance, such as peak VO2... Actually, what's much more important to patients is how they feel, what their symptoms are like, how they function on a day-to-day basis.
I think we see complete concordance between the biological effect of this drug and the effect that it's having on patients' daily lives.
Wonderful. Thank you. We have a question in the room here, I think, or any questions from the room? For Paul.
Thank you. Paul Choi with Goldman Sachs. Dr. Coats, my first question is for you, and if you could kindly elaborate on your comments on the hypertension and palpitations. I think you indicated it's sort of a normal occurrence with improvement in heart failure, but could you maybe elaborate a little bit more on the severity of the events and how they were resolved, and if they possibly required any dose interruptions or discontinuations? And my second question for the panelists generally is, as you take a look at the totality of the efficacy and safety data here from this study relative to Explorer, as well as the,
... the pharmacokinetic data that Dr. Coats presented. Could you maybe just speak to, you know, how you think about the ease of use here of aficamten and just sort of your thoughts on the safety, benefit profile relative to mavacamten? Any color there would be greatly appreciated. Thank you.
Great. Caroline, do you want to take the first question?
Start off. So, yeah, this, the higher frequency of hypotension is, we hypothesize, and others have done the same, that by increasing cardiac output, we're essentially unmasking pre-existing hypotension. In answer, neither the palpitations nor the hypotension resulted in any dose interruptions and or hospitalizations.
Dr. Maron?
Yeah, so I was just gonna... I was gonna just then kind of dovetail on the, I think, your second, you know, point. So let me be, you know, let me be clear about that, because I think that's a really critical question, of course, right now. And I'd say that, you know, here's how I look at it, and again, I think you could ask a lot of different cardiologists who will ultimately make their own decisions about that answer to that question, but here's where I'm coming from. If you pull together the totality of the SEQUOIA data shown today, you know, you'd have to come away with that with the following, that there's a incredibly compelling argument to be made, both on efficacy and safety, that aficamten would be the first choice of my, a cardiac myosin inhibitor therapy.
Okay? I'm not just saying that just to say it, but I mean, let's, let's talk, let's say if you sort of break that down, it comes to your question, that the, the, the breakdown there is you saw, you know, kind of excellent efficacy, both in terms of how patients feel and function. As Perry said, that's incredibly important. But you also saw what has not been achieved before in terms of functional capacity, okay? Those are incredibly impactful efficacy achievements. And then two, that's complemented by a number of other factors, including safety. We heard from, you know, obviously from Caroline, that the incidence of LVEF is very low and not associated with treatment interruptions or heart failure, okay? So that's, you know, incredibly reassuring point from a safety standpoint. And then two-- and then three is the ease of use.
I mean, as you just pointed out, I mean, I think what we, you know, what I'd say there is that you're looking at a short half-life, so you can titrate up quickly, okay? So that by, in some cases, two weeks, but six to eight weeks, patients are already on a dose of aficamten that makes them feel and function really well. That's quick. It's really quick, yeah. So you're gonna have a lot of happy patients, and I don't know if the physicians are taking care of them because of that. So individual dose titration, easily made, steady state with the half-life that allows for rapid dose titration. Okay, so that's unique as well here. Okay?
So I think as well as the rapid reversibility, by the way, too, I mean, that's the other point, is that when you stop it, then, you know, you've got rapid reversibility, which is another important point there, too. So I think if you, you know, if you put all of that together, I think that is a very compelling argument here to weigh on a decision of one over another here.
Any others want to comment?
I mean, you're absolutely right to focus on the practicality. This is a new paradigm, if you like, for cardiac disease to some extent, in that you, we are being ultra-cautious in the use of this new class of drugs, so hence the frequent monitoring during the, particularly the up titration phase. But the idea of frequent monitoring is not new to cardiology. We do this all the time in cardio-oncology, for example. So the notion of having to monitor cardiac function during the initiation and up titration of a drug, I think is not a crazy one. It's one that we already do. It's just we have to adapt it to a disease which we haven't been used to considering that for.
I think the point that Marty makes is that even at a low dose, many patients actually already feel better. I think that what we're going to see as we move along with greater experience with these drugs is a segue into a way of thinking about these drugs, which is much more aligned with routine clinical practice. At the moment, we have these drugs being introduced, they're new class of drugs, so there's an intense focus on safety. As we, as physicians become used to these drugs, then I think we'll be using them in a way which doesn't impose a huge burden in terms of the monitoring that we have to do.
Thank you. We have some questions online. I'd like to go to those. We wanna have a hard stop at the top of the hour. So, let me ask the first question from Joe Pantginis, who asks, you know, "Thanks, all, for the great data. If aficamten is approved, can the physicians give their views on the evolution and learning curve of practice in the real world on the frequency of echoes and dose monitoring, and plus the anticipated impact of thought leaders versus the broader cardiology community in terms of treating these patients?
Yeah, I can take that. So I think, I think you could tell by today when the data was presented, there's real excitement in the, the general cardiology and heart failure community about this, this, treatment. You know, there's still questions to be answered, young people, non-obstructive, hypertrophic cardiomyopathy.... I, I agree it feels a safer drug, and, we don't know yet what the regulators will say, but the-- it, it feels like something that we'll be capable of monitoring in clinical practice with education about echo and, and dosing. We are, as Perry says, familiar with this. We've optimized pacemakers in the past with echo. We do it in oncology to, to monitor treatment, so it's, it's a very familiar concept.
Wonderful. All right, we have a question in the room.
Thanks. Cameron Bozdog here for Jason Zemansky at Bank of America. I wanted to focus on the individuals that had LVEF excursions. I mean, if you look at the baseline levels, they were relatively broad, including one above 80. I'm just curious if there were any similarities between these patients that may help inform a patient's risk profile or, or potentially a risk-based monitoring of, of LVEF in the future? Thank you.
I can-
Yeah.
I can help you.
Yeah.
You want to take that or-
Okay, I mean, we've looked pretty hard at this data to try... You know, 'cause that's what everyone wants to know is: can we find the patient that this is gonna happen to? And we can't. You know, the numbers are too small to do that at the moment. And, so I think, you know, the honest answer is we can't distinguish a patient that's at risk, and as you say, there doesn't appear to be a feature to predict that.
Yeah. Again, I think the number you're referring to is their baseline EF, but what you have to look at is the entire journey, right? So what you see is their, as their EF starts to go down, as their gradient started to get treated, in general, the risk accumulates. It's probably most prominent in those whose EFs are closest to 50% prior to up titrating dose. So most of these patients had EFs, you know, below 55 or so before they got to the next dose. They started higher, but they went down. And then the computer is sort of a, you know, a non-judgmental organism or beast. It doesn't care what the patient thinks or feels or the physician, it just does what the algorithm's programmed.
In real life, as you know, as we've implemented in FOREST, physician would just look at the patient and integrate the whole picture. You have a patient who's feeling well. Remember, so how the patient felt was not part of the dosing algorithm, which it should be in real life, who might be on the lower end of ejection fraction. And essentially, you know, you might make the decision not to uptitrate because you can't make them feel better, because they already feel well, and you don't need to just treat to the numbers. So we keep focusing on the numbers, and it works both ways. Like, you shouldn't treat to the numbers, you shouldn't overreact to the numbers. You should really think about the patient. All right, how about another question from online?
This one is back to maybe the first question, as posed by Salim Syed from Mizuho. Thanks for the question, one for the panelists. Given today's data, in your view, what's the argument that a physician or patient would make at this point to take Camzyos over aficamten, assuming approval? Provocative question. Anyone want to take that?
Yeah, like a simple—I can't find one. I mean, to be honest. I mean, I really—I mean, I'm not—I mean, I think that there isn't really a clear, at this point, based on the data we just saw from SEQUOIA, in my mind, any kind of clear, compelling reason that you wouldn't choose aficamten, as I just said a minute ago, as your first choice for myosin inhibitor.
Greg?
I completely agree.
I'll just lend an additional perspective to what Caroline said before about the audience being excited about this. I oversee a large group of heart failure physicians, and they are eager to embrace this therapy. Most of the medicines we give patients tend to stabilize things. They don't make them function better, they don't make them feel necessarily better, they don't improve their exercise capacity. Here we have an agent, that patients are very happy when they take, and physicians, are happy too when they see that happen with their patients. So I think there will be widespread adoption.
Yeah.
All right. I've got another question here.
No, no.
Oh, Perry-
No, no.
Go ahead.
Just to make the point, I think that what has been established with SEQUOIA is the principle of myosin inhibition. So that should now be standard of care. The choice of drug is going to be determined by a number of factors, and afi clearly has a number of advantages: the shallow dose response, the fact that there are no drug interactions in the way that we have with Camzyos. So there are a number of things which a physician will consider when they're making that choice about a myosin inhibitor, but I think the principle is that this is now standard of care.
Yeah, may I? You, as you probably know, we're conducting MAPLE-HCM, which is a trial of monotherapy aficamten versus current standard of care, beta-blockers monotherapy. Might you comment on how that might change the equation in your mind? You've already made that statement, but, you know, how might that add to or strengthen your statement?
I mean, it's an interesting starting point, isn't it? Our first-line therapy is beta-blockers, based on virtually no randomized data whatsoever, and it's based on a historical precedent. Here we are with drugs which are backed by, you know, very potent findings from randomized controlled trials, which are showing clear superiority over beta blockade. Is the world ready, the medical world ready yet to say that our first-line therapy should be a myosin inhibitor? It's probably not quite there. But what will happen in practice is that people will see this difference in responsiveness. And so I think the first step is class one for myosin inhibitors, and then following in its trail, and if the trial is positive, I think it won't be long before myosin inhibitors become first line. But that's gonna be a process of persuasion and changing habit, I think.
Yeah. We cardiologists tend to be slow to changing habits.
We do.
So, we have a good question from Charles Duncan of Cantor. This one's for Dr. Coats. Dr. Coats, do you see the dosing and safety data through 24 weeks as notably different from that of the other currently approved cardiac myosin inhibitor? Would you be comfortable incorporating aficamten into clinical practice with less frequent monitoring than required with the REMS of the current CMI? I know you don't use that in the UK, but you might be familiar with it. And if not, what data would you like to see to do so?
Yeah, so I think there are a couple of points. So, you know, there were no treatment interruptions, and that's different from, from mavacamten. There were no heart failure episodes, which we've seen with mavacamten. In FOREST, you know, people are coming in 12 weekly in the maintenance part of that, and that's working well. So I think, you, you know, it is the potential for less frequent monitoring. You know, see them at the start to, to get on the right dose, but then that maintenance phase feels very safe, and I think the, the plasma concentration data backs that up.
All right, another question here from Serge Belanger, from Needham & Company. Great presentation. Do you expect any of these new subset group analyses will be part of the product's approved label? I'll answer that one. And how important is it for them to be included in the label? So, so in general, labels will include a forest plot, such as the one that we presented today. It's because those are all pre-specified subgroups. But perhaps you can comment, Dr. Maron, on how important is it for them to be included in the label.
So if you're talking about the for the-
forest plot of the peak VO2 change.
Yeah. Yeah, no, I, I think, well, I think, you know, yeah, I think it's really important. I mean, I think if we can, for sure. I mean, I think the, the FOREST plot, you know, as I said, you know, today and, you know, twice now, that, you know, I, I was taken aback by the consistency of those results in terms of the aficamten for the primary endpoint. I mean, you know, to see that kind of level, I think, of consistency in this kind of heterogeneous disease for anything, including a treatment effect, is really sort of telling you that what you are seeing in terms of the magnitude of benefit of the peak VO2 is really real and reaches across the entire spectrum of the disease. And so for that reason, super important to, to consider for labeling.
I've got a question here from Carter Gould of Barclays. For the clinicians, how should we interpret the rate of LVEF drops and the discordance between site versus core in the context of historical benchmarks for the class? Or put another way, in the absence of additional information, is there a difference in the risk between a drop of 50%, less than 50% with aficamten and a drop of less than 50% with mavacamten in your mind? Caroline, do you wanna take that?
Yeah. So I think, you know, this correlation with site and core is something that we weren't expecting, you know, to have really only a modest correlation between site and core. So does it translate for both drugs? I think we've seen a similar pattern in the long-term extension data in mavacamten. We've seen exactly the same. The sites are more conservative at reporting ejection fraction. The correlations are not the same. I don't know that you'd interpret an EF the same, regardless of what was causing it, whether it was a cardiotoxic cancer drug or a cardiac myosin inhibitor. The clinician faced with an echocardiogram with an ejection fraction of 40% would take an action.
Does the reversibility of that effect, I guess, weigh in on how you might approach it?
Yeah, absolutely. So I mean, this very convincing, you know, rapid reversibility. And, so yeah, I mean, that's reassuring with, with this.
Okay.
I don't think we should be too concerned about a more conservative approach at the physician level. I mean, I think that's, for me, an appropriate clinical response. And as you said earlier, Fady, it's. You interpret it in the light of the individual patient sitting there in front of you. So I, I, I'm not perturbed by that at all.
Good. Great. Let me ask another question. We presented the responder analysis. You know, that is kind of the combined peak VO2 and NYHA class. I guess, you know, how do you put that in con... We're talking a lot about EF comparisons. Is it worth thinking about how, you know, the responder analysis in SEQUOIA performed?
Yeah, I mean, I'll start with that. I mean, yeah, I mean, I think, you know, here's how I kind of look at that. I mean, I think that responder analysis—again, what we're talking about that is the change in both functional capacity and symptoms, or greater achievement in functional capacity with no worsening symptoms. You know, that's—so, so first of all, that, you know, that endpoint, you know, reflects, you know, really, again, the primary treatment aim in this disease. It's making patients feel and function better, okay? So in some ways, putting those two together, feel and function, you know, is really telling us about the efficacy of the drug in terms of the primary treatment aim.
To put it into perspective, you know, the responder analysis for that endpoint here for SEQUOIA, you know, was higher than what's been demonstrated previously by first-line myosin inhibitors. To sort of, you know, sort of translate it, you know, into sort of other terms, perhaps, than, than what we showed on the slide, is that, you know, for aficamten to, to the-- perhaps the best way to look at this is, to express it, is the number needed to treat. So when you're looking at that, responder analysis, that it's-- I think it was about 3.5 patients number needed to treat for aficamten to achieve that endpoint versus higher than that for other myosin inhibitors, okay? So you're getting, you know, greater efficacy for perhaps the most important endpoints that you want for the drug.
Great. Thanks, Marty. A couple more questions here. So, from Jeff Hung at Morgan Stanley. Again, people seem to be persevering on this: With ejection fraction less than 50% captured by both core and site labs, how should we interpret the overlap being only in 2 patients? Who here reads echoes for a living?
Well, I do, sadly. But, yeah, I mean, I think it's-- the ones that overlapped were the, you know, the, the, core readers less than 40%, and the site readers 40%-49%. So you can't really get it wrong if you're, you know, if there's a change like that. But it does illustrate the variability in this, in this number, and as, as we've said, it's, you know, we, we don't treat the number, we treat the patient.
Okay.
There's lots of other things when we read an echocardiogram that we look at above ejection fraction and above gradients. There's lots of other really important information, degree of mitral regurgitation, pulmonary pressures, et cetera. I think although we need metrics like this in the trial, in implementation, it would be a different story.
I mean, I think there's a point there that the sites looked at the same echoes and had no concerns. They were instructed to bring concerns to the principal investigator. And the other point potentially to make is that the unique design of having the sites control dosing, but the core lab doing another read, so the core lab found patients, or they identified patients with EFs less than 50, where no dosing changes were made, on that basis, in fact, for several weeks, in some cases, months. And those patients did extremely well. They're, you know, you showed a table there that's very dense. I'm sure people will pick over it, but you might summarize what you thought.
Yeah, I know. And I mean, this phenomenon of, you know, when we report echo and look at echoes, we always say, you know, "What do you think of this echo?" Do you know, this is a common discussion, particularly when it impacts a treatment. And I work in the cardio-oncology arena as well, so every week I'm being asked, you know, "The sonographers reported this as 50%. What, you know, should we interrupt treatment?" So I think as we learn to use these medicines in the real world, this will become something that we learn to do.
All right, so a couple more. One from Roanna Ruiz at Leerink Partners: How are you interpreting the numerical differences in peak VO2 among those with and without beta blocker background therapy as you think about the upcoming MAPLE results? Greg, do you want to take that one?
Sure. I mean, I think that, as Marty said earlier, it was terrific to see the consistency of findings across all of the subgroups, where the beta blocker was obviously a point of interest, but there was also subgroups in terms of what your baseline peak VO2 was, other measures of, you know, obstructive HCM severity. And so we were pleased to see the beneficial effects of aficamten, regardless of whether or not you were on background therapy with beta blockade. And I think that it probably speaks to the fact that there was also a higher total population change in peak VO2. So some of this may have just been essentially all of the values were further to the right of the line of unity here. We don't have a, you know, a absolute explanation yet.
Some of this could be somewhat, somewhat play of chance as well. We did also ensure that patients did achieve maximum volitional effort on their cardiopulmonary exercise test with a high degree of rigor, and we looked at the respiratory exchange ratio to ensure that. There was a very high level of consistency in the testing that was performed in SEQUOIA, which also probably helped in terms of that endpoint.
Great. We have another question online, and this one's from Yasmin Rahimi from Piper. I'm not sure everyone on the panel here will be equipped. I can help with this one, but can you talk about any differences in efficacy and safety in the U.S. versus Asian population across the study? Do you think afi wins on both efficacy and safety? What stands out to you in regards to efficacy differences? So maybe the. I'll answer the first one. You know, the results were very consistent across both U.S. and or I should say Asia, which was China really, versus the rest of world. There were really no meaningful differences there.
And the other two questions just had to do with, is there anything that stands out in terms of the aficamten data in particular, compared to what you know about cardiac myosin inhibition?
I mean, the bit we've not really talked about is, you know, we need in Europe to do CYP genotyping to, you know, pharmacogenomic testing to be able to use mavacamten. I think that's not going to be required for aficamten. Marty can talk to the forest plot, but I mean, there was no difference in efficacy in the Asian group.
The other thing I'd say is that we, these are entirely legitimate questions, whether we're talking about ethnicity, whether we're talking about age, whether we're talking about genotype. These are the sort of things that will only emerge as we start to get large data sets with real-world experience. But this level of scrutiny is extraordinary when you think about what we do in response to other pivotal trials. So what is the response or individual response to Entresto or the individual response to Dapa? There must be similar variability in the response to these drugs, but it's not part of the paradigm of thinking-
Mm-hmm.
When you roll out a new therapy. So it's great that we're being ultra cautious and really inquisitive and trying to work out the response, but it's probably a level of scrutiny we wouldn't, we haven't done with any other major drug class. I think it's partly cultural. I think in that, I think... This is probably not the right forum to have this discussion, but I think you're seeing the merger of two different cultures. So you have the trials heart failure mindset, which is very much driven around sort of a few endpoints, sort of big picture results, and you've got cardiomyopathy, where we've not had effective therapies before. So we've focused on intense detail about phenotyping and so on. And what you're seeing now is the merger of these two worlds in a very interesting way, I think.
There were virtually none, and as you know, in this, but even if it's. But I think it's also because we do fret about small details, maybe more than we need to.
All right, I think we have one last question here. So this is from Tess Romero of J.P. Morgan. On the safety side, how do you interpret as a clinician the placebo-corrected mean change in LVEF over 24 weeks sitting at -4.8%? Could this even be within the noise of the endpoint? Are you able to put in further context the occurrences of palpitations observed between the two arms, and are these clinically relevant changes?
Yeah, so I think, I mean, I've said already today that, you know, in clinical practice, ±5% is the ballpark of how we, you know, would read an echocardiogram. So, you know, it's a definite decline in ejection fraction, but it's small, it's less than 5%, so it's not a large decline at all. We have looked as to whether that was associated with atrial fibrillation events, and it wasn't. So that was an important finding as well, which I haven't presented before, but we've done that analysis.
Great. I mean, I think I'll just reiterate that the mood in the room, you know, in response to the data was really spectacular. There was a lot of enthusiasm for the results that they were seeing. It's not often in cardiology you see data that are that strong with consistency across all the endpoints. But I think more importantly, as Perry made the point, the magnitude of the changes is something that we rarely see, and we don't often, as Greg also made this point, you know, make our patients feel better. But these changes, you know, clearly will make a difference to patients, which is ultimately what we want to achieve. And so I think we'll just wrap up.
I want to thank the panelists and everyone for their questions and their interest in SEQUOIA-HCM. You know, as we move forward towards regulatory submissions for aficamten in patients with obstructive HCM, we're extremely enthusiastic about the promise of bringing this next-in-class potential medicine to patients that struggle every day with the impact of their disease. We know HCM can severely impact patients' quality of life, and it may limit their ability to exercise normally, perform some of their everyday activities, and things that you and I take for granted, such as the walk up the hill from the conference center to the hotel. I guarantee you, most of your, our HCM patients would not be able to have made that hike. So we, you know, we're committed.
We're committed to executing against the broad development plan, as we've discussed briefly today, and as may extend the potential benefit of aficamten across the broadest range of patients. And with that, we'll conclude the event, and thank you again for participating today.