Cytokinetics, Incorporated (CYTK) Earnings Call Transcript & Summary

Everyone, 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 III 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 and 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, MD, PhD, Executive Vice President, Research and Development. I'm also thrilled to introduce 4 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, Drs. 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. And 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 shared the primary results and 2 additional analyses from SEQUOIA-HCM, our pivotal Phase III clinical trial of aficamten in patients with obstructive HCM. Frankly, I believe it may be unprecedented to have 3 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 weren't that focused. 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 and 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. And 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. And 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 is going to present the primary results from SEQUOAI-HCM, much like he just did at this Congress here in Lisbon. Marty?

Okay. Thank you, Robert. Appreciate that. Are we advancing with this? Oh, here we go. 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 names in HCM is to improve that. Hypercontractility, cardiac hypercontractility is the primary driver for mitral valves [indiscernible] and outflow obstruction, and we have an unmet treatment need in symptomatic obstructive HCM, and aficamten is an investigational, novel, oral selective medicine 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 2 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 II study, REDWOOD-HCM, where we've 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 III SEQUOAI-HCM trial, the design of which I'm showing you here, major inclusion criteria there in the upper left, patients randomized then in a one-to-one 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 milligrams could be increased by 5 milligrams to a maximum of 20 milligrams, 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. The primary endpoint for SEQUOIA 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 limited -- symptomatic limited group of obstructive HCM patients with baseline PVO2 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, 1/3 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 it to the right here is the mean change in peak VO2 over the treatment period. And 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. And 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. I think it's pretty fair to then conclude that a 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 prespecified subgroups that you see here, including patients that were particularly limited at baseline by Class III, as well as being functionally limited by peak VO2 of less than 18. And again, as I mentioned earlier, I and many 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 SEQUOAI, treatment with aficamten was similar whether patients were on a beta blocker or not. Okay. High-level overview here for the secondary endpoints. And as you can see, aficamten had a significant benefit versus placebo in each of the 10 secondary outcome measures. Diving down into that a little bit more in detail. Starting first with the change over the treatment period in both rest and Valsalva gradient. And I think you could see here with aficamten in green, significant decrease in gradients with aficamten even as soon as week 2, by week 6 resting gradients essentially obliterated in almost all patients, and that gradient remains obliterated throughout the treatment period. And as you can see as well, emphasizing the reversibility aspect of the drug here, patients had returned to baseline gradients after the 4-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 vacation, to the bottom right -- bottom left there, you can see in green, with aficamten, the improvement in NYHA class over the treatment period. And 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 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. All right. 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 III or IV NYHA class. You can see for those patients, treatment with aficamten was associated with a 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. And that treatment effect remained fairly consistent through the rest of the treatment period. To the right is the -- sorry, 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 remain very low in terms of serum levels, and 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 end point that, as I said, is exploratory, but it was actually the primary endpoint for EXPLORER, 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% versus placebo. Again, those proportions are higher here than what we saw in EXPLORER 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. And 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. The robust and functional -- those robust functional and symptomatic improvements and relief of obstruction, as I noted, were observed early in treatment and remain durable throughout the treatment period. In totality, SEQUOAI underscores the clinical efficacy of aficamten in the treatment of patients with symptomatic obstructive HCM. Thank you very much for your attention. I appreciate it. Do we want to -- first of all, Diane, this is tough to move. I don't know if there's another clicker, but -- okay, there we go. And finally, if you're interested in learning more about aficamten and SEQUOAI-HCM, these results are now online in the New England Journal of Medicine. Thank you very much.

We'll move on the new presentation, we'll do a panel discussion afterwards. So I'd like to introduce Dr. Caroline Coats, who will discuss dosing and safety in SEQUOAI-HCM.

Thanks, Fady. So on behalf of the SEQUOAI investigators, I'm going to 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 contractual function and importantly, symptomatic heart failure. Aficamten was engineered with a goal of achieving specific pharmacological properties that would allow for flexible dosing and increase safety. Its short half-life allows for rapid onset, rapid reversibility, speeds 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 3 opportunities at weeks 2, 4 and 6 for dose escalation. As you've heard from Dr. Maron, SEQUOAI has met its primary endpoint with an improvement in peak oxygen consumption. This prespecified analysis looks at the study in 3 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 echo cardiologist input their own interpretation of the echo to allow dose adjustment. The target was to bring the gradient down to less than 30%, whilst 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%, all the ejection fraction was between 50% and 55% and 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%, though it was the protocol specified 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 weak 8, 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 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 call app. 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 step-wise 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 8, 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. And 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, 8 people were interpreted to have an ejection fraction of less than 50%, 7 were in the aficamten group and 1 was in the placebo group. No treatment interruptions occurred. When the core lab read the echocardiogram, 6 patients had an ejection fraction of less than 50%, 5 in the aficamten group and 1 in the placebo group. No heart failure was experienced by any aficamten patient treated with -- any patient treated with aficamten that had an ejection fraction of less than 50% by either the core lab or the site interpreted data. And all aficamten patients with an ejection fraction less than 50% were reversible. You can see from the Venn diagram that only 2 patients overlapped where both core and sites interpreted the echocardiogram is less than 50%. The 1 aficamten patient that overlapped had a COVID infection before that visit. The site -- the core lab interpreted the ejection fraction is less than 40%, but the site interpreted the ejection fraction is between 40% and 49%, so there was no treatment interruption. And that patient recovered their ejection -- improved their reduction fraction to 55% simply with a down titration from 15 to 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 are 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. And importantly, in all cases, that 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, 1 event in each group. So in conclusion, aficamten appeared safe and effective in treating patients with obstructive HCM in the SEQUOAI 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 the participation in the trial, my co-investigators and site staff and the sponsor without whom this would have not been possible.

Thank you, Caroline. And last but not least, we have Dr. Lewis, who will recap his presentation on an analysis of the CPET data from SEQUOAI-HCM.

Okay. Thank you very much. I'll be discussing enhancing exercise response in obstructive hypertrophic cardiomyopathy on behalf of all of the SEQUOAI 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 a 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 and gradient obstruction in this condition. And collectively, they lead to impairment in cardiac reserve capacity during exercise. And this is manifested as reductions in peak and sub-maximum 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 SEQUOAI. And this gives us objective assessments throughout all of exercise. We specifically focused for this analysis on 2 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 sub-maximum domain of exercise as well. And then there's maximum exercise as quantified by peak action uptake. Not only is there a temporal complementarity between these 2 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 1 unit change in VE/VCO2, that is associated with a hazard ratio of 0.9%. And 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 prespecified analysis, we have prophesied that aficamten would improve a novel measure of integrated maximum and sub-maximum exercise performance and that the changes in peak VO2 would relate to other clinically important end points. 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 2-component equally weighted Z score with peak VO2 and reverse VE/VC02 slope. We also looked at a host of secondary endpoints that encompass both maximum as well as sub-maximum 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 9 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. And you can see an ascending order is the baseline values for peak VO2 and for VE/VC02 slope. The vertical measures indicate the changes over the course of 24 weeks. And 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 a 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's our categorical variable responder analysis. We used large improvement, defined as a greater than 3-milliliter per kilogram per minute increments 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 a large improvement, they were uniformly below 6 patients. Here's a cubic spline analysis that relates to changes in peak VO2, which is 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 Classes, both of which changed 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 PO2. And notably the NT-proBNP levels fall dramatically, both in obstructive HCM as well as nonobstructive 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 rest for 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. Sub-maximum exercise parameters also improved, whether we looked at the efficiency of ventilation during sub-maximum exercise, all of exercise, the ventilatory power or importantly, when patients reach their anaerobic threshold in terms of the VO2, if the anaerobic threshold also improved. And this was with no change in the VO2 work relationship. So in conclusion, our comprehensive prespecified analysis of cardiopulmonary exercise testing metrics in SEQUOAI-HCM demonstrated significant improvement in the novel integrated exercise performance metric that combines both maximum and sub-maximum exercise parameters that are highly prognostic and this combined metric is, again, being focused on in the ACACIA trial. And we also saw improvement in multiple other measures of exercise performance. The enhanced exercise response is 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, we were -- as we attended at the Heart Failure 2024 Meeting here in Lisbon, from concept to clinical effectiveness, it's a remarkable journey, and I'm grateful for all, and there are many, many who contributed to making the stay possible, including those on the podium with me today. . So 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 discussing on 2 of these presentations in the late breaker session. So thanks to 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, raise your hand, we'll be happy to bring a microphone to you. While we compile questions, I wanted to start us off by asking a couple of questions myself. So first, Dr. Maron, if you could to put in perspective, the clinical significance of the improvements in peak VO2 and other clinical measures that how they might apply to your daily practice?

Sure. Thanks, Fady. Well, let's start first with, 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 the great -- the highest change in peak VO2 for medical therapy in any cardiovascular trial that I know of. So that alone stands as a, I think, not an inconsequential point. And that's telling us something, right? I mean it'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 2 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 emitting symptoms, both of those, of course, impacting their quality of life. And so what 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 seeing 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. And I think these data without any question, demonstrate that functional capacity in terms of peak VO2 has 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 people might be confused regarding the LVEF less than 50 data that you presented data site versus core, their meaningfulness 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?

Yes. Thanks. So I hope I spent enough time explaining both the ethos behind the design, which I think was important. It was different from the EXPLORER study. It was 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 we have to have a cut off at something, but we all know as clinicians that is it 52%? Is it 49%? Is it 55%? The error and the challenge, particularly in hypertrophic cardiomyopathy, where you've got a fit cavity, big papillary muscles measuring that to anything more than plus or minus 5%, is difficult. So that's why I shared the categorical data because that's what clinicians would want to see. So what we -- what this trial has also given us really for the first time is echocardiograms that were read by 2 independent observers. And that's important data. But I think the message that we've seen is actually whoever read it, that the incidence was very low, and it wasn't associated with heart failure. And that's the important thing for patients.

Yes. I think the -- you shouldn't be adding data sets together. You should be looking at them separately and separately, you basically come up with the same number. And if you wanted to look at them together, you should ask, well, how many cases did they agree. And as you pointed out, they only agreed in 2 cases. So, great. One question for you, Dr. Lewis. Do you mind just elaborating a little bit on why this novel integrated measure of exercise performance that we developed and analyzed here in SEQUOAI might be relevant to ACACIA-HCM?

Sure. I'd be happy to. So 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 may then 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 #1 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. And that is a measurement that's been seen to go down, whether you're studying patients with obstructive hypertrophic cardiomyopathy or nonobstructive hypertrophic cardiomyopathy. So we're encouraged by the fact that the natriuretic peptide levels, we're 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 nonobstructive population. So 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 prespecified for ACACIA.

Great. And Dr. Elliott, you were the discussion for 2 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 when you're assessing 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 SEQUOAI is self-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 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 then. 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 I used the term unprecedented 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? So 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 in the room. Paul?

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 require 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 the study relative to EXPLORER as well as the pharmacokinetic data that Dr. Coats presented, could you maybe just speak to how you think about the ease of use here of aficamten and just sort of your thoughts on the safety, benefit profile relative to aficamten? Any color there would be greatly appreciated.

Great. Caroline, do you want to take the first question?

I'll start off. So yes, the higher frequency of hypertension as we hypothesized that and others have done the same by increasing cardiac output, we're essentially unmasking preexisting hypertension. In neither the palpitations or the hypertension resulted in any dose interruptions and all hospitalizations.

Dr. Maron?

Yes. So I was just going to -- I was going to just then kind of dovetail on, I think your second point. So let me be clear about that because I think that's a really critical question, of course, right now. And I'd say that here's how I look at it. And again, I think you could ask a lot of different cardiologists 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'd have to come away with that with the following that there is an incredibly compelling argument to be made, both on efficacy and safety, that aficamten would be the first choice of cardiac myosin inhibitor therapy, okay? I'm not just saying that just to say but I mean, at let's say if you sort of break that down, it comes to your question, that the breakdown there as you saw 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 -- obviously from Caroline, that the incidence of low LVEF is very low and not associated with treatment interruptions or heart failure, okay? So that's incredibly reassuring point from a safety standpoint. And then -- and then 3 is the ease of use. I mean, as you just pointed out, I mean, I think what we -- what I'd say there is that you're looking at a short half-life, so you can titrate up quickly. So that by -- in some cases, 2 weeks, but 6 to 8 weeks, patients are already on a dose of aficamten that makes them feel and function really well. That's quick. It's really quick. You're going to have a lot of happy patients, and I don't know if you anything care of them, because of that. So individual dose titration, easily made the steady state -- sorry, 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've got rapid reversibility, which is another important point there too. So I think 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.

Any others? Would like to comment?

I mean you're -- absolutely your 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 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 form. I think the point that Marty makes is that even at a low dose, many patients actually already feel better. And 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. So the moment we have these drugs being introduced, the 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 don't have a hard stop at the top of the hour. So -- let me ask the first question from Joe Pantginis who asked, 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?

Yes, I can take that. So I think you could tell by today when the data was presented, there's real excitement in the general cardiology and heart failure community about this treatment. There's still questions to be answered, young people, nonobstructive hypertrophic cardiomyopathy. I agree, it feels a safer drug. And we don't know yet what the regulators will say, but the -- it feels like something that we'll be capable of monitoring in clinical practice with education about echo 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 monitor treatment. So it's a very familiar concept.

Wonderful. All right. We have a question in the room?

Cameron Bozdog here for Jason Zemansky, 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 1 above 80. And I'm just curious if there were any similarities between these patients that may help inform a patient's risk profile or potentially risk-based monitoring of LVEF in the future?

I can help you if you want to take that one.

We've looked pretty hard at this data to try -- because that's what everyone wants to know is can we find a patient that this is going to happen too. And we can't -- the numbers are too small to do that at the moment. And -- so I think 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.

Yes. Again, I think the number you're referring to is the baseline EF but what you have to look at is the entire journey, right? So what you see is as their EF starts to go down, as their gradient started to get treated, in general, the risk accumulates is probably most prominent in those whose EFs are closest to 50%, prior to up titrating dose. So most of these patients had EFs 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 nonjudgmental organism or beast. It doesn't care what the patient thinks or feels or the physician, it just does what the algorithm is programmed. In real life, as we've implemented in FOREST, the physician would just look at the patient and integrate the whole picture. You have a patient who's feeling well, number 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 might make the decision not to up titrate 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. How about another question from online. This one is back to maybe the first question is posed by Salim Syed from Mizuho. So 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. Do you want to take that?

Yes, I think 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.