Cytokinetics, Incorporated (CYTK) Earnings Call Transcript & Summary

Good afternoon, and welcome, ladies and gentlemen, to the Cytokinetics call announcing the full results of REDWOOD-HCM. At this time, I would like to inform you that this call is being recorded. [Operator Instructions] I will now turn the call over to Diane Weiser, Cytokinetics Senior Vice President of Corporate Communications and Investor Relations. Please go ahead.

Welcome, everyone, and thanks for joining us this morning on the call today, focused on the full results of REDWOOD-HCM, the Phase II clinical trial of aficamten, our next-in-class cardiac myosin inhibitor, for the potential treatment of hypertrophic cardiomyopathy, or HCM. Robert Blum, our President and Chief Executive Officer, will lead us off with an overview of yesterday's announcement. Then Fady Malik, our Executive Vice President of R&D, will discuss the next-in-class properties of aficamten and how it was designed to optimize clinical utility as could be assessed in a trial like REDWOOD-HCM. Then following these introductory remarks, we are honored to have an esteemed physician panel, including Dr. Marty Maron, Director Hypertrophic Cardiomyopathy Center at Tufts University School of Medicine and the Principal Investigator of REDWOOD-HCM, who will present the full results. And Dr. Ahmad Masri, Assistant Professor of Medicine, Division of Cardiovascular Medicine, School of Medicine, Oregon Health & Science University, and Clinical Investigator in REDWOOD-HCM, and he'll discuss the challenges of treating HCM patients and how these results may translate in the clinical setting. Before I turn the call over to Robert, 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. And now, I will turn the call over to Robert.

Thank you, Diane, and thank you to everyone for joining us on the call today. Following our announcement of positive top line results from REDWOOD-HCM just 2 months ago, today marks another hopeful day for the HCM community and the patients living with this severe and challenging cardiovascular disease. As you hopefully saw in our press release yesterday, Dr. Maron presented the full results from REDWOOD-HCM at a late-breaking clinical trial session here at the HFSA Annual Scientific Meetings in Denver. These results build upon the encouraging top line results related to the efficacy and safety of our next-in-class drug candidate in patients with obstructive hypertrophic cardiomyopathy. As Dr. Maron will elaborate the combination of significantly reducing resting and Valsalva left ventricular outflow tract gradients in nearly all patients, improving heart failure symptoms, rapid onset and reversibility of effect and the ability to use precise echo-guided dose titration without treatment interruptions augurs well for the potential clinical utility of aficamten as now should be further tested in a pivotal Phase III clinical trial. As previously discussed with positive top line results in hand, we received constructive feedback from FDA on our recent Type C and end of Phase II meetings supportive of progression into our planned Phase III trial, and we're moving swiftly to get that underway during the fourth quarter later this year. It's extremely gratifying to see how our pioneering leadership in the mechanics of muscle contractility and the precise optimization of cardiac myosin inhibitors is enabling the continued investigation of this next-in-class investigational medicine and in patients struggling with the day-to-day challenges of this severe disease. We know all too well how HCM impacts the physical, the emotional and the mental well-being of patients. And we look forward to the hopeful opportunity to bring this much-needed next-in-class potential medicine to them in the coming years. And with that, I'll turn the call over to Fady to elaborate on what was intended by our advanced design of aficamten and how that set the stage for REDWOOD-HCM.

Great. Thanks, Robert. Turning back to REDWOOD-HCM, it's rewarding to see that the physiochemical properties that we prioritized in optimizing aficamten are translating into clinically meaningful results for patients and advancing the science and evidence supportive of cardiac myosin inhibition in patients with obstructive HCM. To remind you, our scientists prioritized and designed in aficamten the following: onset of action, reaching steady state within 2 weeks, rapid reversibility of effect, minimal drug-drug interactions, favorable tolerability, and ease of titration for personalized dosing. I'd like to now start just by presenting a little background on HCM and the optimization of aficamten. I think as you all know, HCM is a disease characterized by hypercontractility of the ventricle of the heart. As you can see on the right, the heart muscle is thickened. The -- when the heart movie there is moving actually, you see that the outflow tract where the blood leaves the heart becomes obstructed as the mitral valve leaflet and the ventricular septum come together. Outflow tract obstruction is a strong and independent predictor of heart failure symptoms. And as a small molecule selective inhibitor of cardiac myosin, aficamten is directly targeting the underlying cause of HCM, in this case, mutations in the sarcomere in an effort to both decrease and abolish gradients and substantially improve heart failure symptoms. Next slide. The unmet need in obstructive HCM really has to do with patients that still have symptoms, Class II or Class III, despite medical therapy and have resting gradients or exercise-induced gradients in the context of background medical therapy. This constitutes up to 70% of patients with obstructive hypertrophic cardiomyopathy. Aficamten, as I said earlier, was optimized to present itself as a therapy that was able to achieve an optimal effect within 2 weeks of dosing. The drugs half life of 3.4 days allows for that. The reversibility is engineered and directly related to its pharmacokinetics. The molecule was further optimized preclinically with a shallow exposure response relationship. That leads in directly to a therapeutic window that, I think, is wide and it enables us to individually dose adjust treatment on a personalized basis with no need for PK guidance. Finally, the drug has really minimal drug-drug or no drug-drug interactions that we know of to date. And so far, it's been well tolerated in clinical studies. If you go to the next slide, it just shows the Phase I data that we acquired in the program prior to REDWOOD-HCM. The left-hand graph shows the PK profile of 2 doses, 5 milligrams and 10 milligrams. And what you see here is that the steady-state concentrations are reached after approximately 14 days. On the right-hand side are the pharmacodynamics in relation to exposure. The gray dots are experiments done in dogs. The green dots are the data that we acquired in humans. And what it really shows is that the shallow PK/PD relationship we engineered preclinically translated into humans as the 2 PK/PD relationships overlap each other. With that, I'm going to turn it over to Dr. Maron to discuss the results of REDWOOD-HCM.

Good morning. Marty Maron here. So this is the clinical trial design, which was a 2/1 structure. So for every 2 patients that were enrolled and randomized to aficamten 1 to placebo. I'll draw your attention to a couple of things on this slide. You can see at the bottom are the 2 cohorts, Cohort 1 and Cohort 2, and you can see the dosing strategies in both of those 2 cohorts there. In addition, to point out as well, there were 3 time points at which dosing of the drug, aficamten, could be adjusted, including week 2, week 4 and week 6. These dose adjustments were predicated on echocardiographic findings done at that time, which included 2 important parameters on the echo, the ejection fraction and the outflow tract gradient. So those 2 variables are what drove decisions to either up or down titrate drug dosing. You can see it's a 10-week treatment period, at which time there was a 2-week washout period. So key inclusion criteria and endpoints. This is a randomized and blinded dose finding study. As I said just previously, 2 cohorts with 5 overlapping doses between 5 and 30 milligrams. And this Phase II study was evaluating, of course, first and foremost, safety and tolerability of the drug and then a number of important clinical parameters, including resting and provocable gradient, as defined by Valsalva, outflow tract gradient, change in ejection fraction, NYHA class and biomarker of NT-proBNP. Key inclusion criteria for the study, a wide age range of 18 to 85 years, wall thickness of 15 millimeters or more. It could be a little bit less since these patients that had a family history of HCM. These were symptomatic obstructive patients with NYHA Class II or III, and they had to have gradients -- left ventricular outflow tract gradients of greater or equal to 15 millimeters of mercury at rest or following provocation with Valsalva maneuver. As we mentioned -- as Fady mentioned, these are hyperdynamic ventricles with ejection fractions of 60% or greater and patients could continue to stay on background stable doses of either beta blocker or calcium channel blocker therapy. Kind of a typical clinical profile for symptomatic obstructive HCM. In terms of that, the majority were younger patients, less than 65 years of age. The majority were Class II, the wall thickness of about -- average of about 17 millimeters. And again, as we said, hyperdynamic systolic function with high ejection fractions, high resting gradients and gradients that were even higher with provocation. So here's what we found. This is the change in resting outflow tract gradients over the treatment period. I'll just draw your attention first to the top bar line, which is gray, which is showing you the change in resting gradients in the pooled placebo group. You can see really, over that period of time, no change -- no significant change in resting gradients. I'll next draw your attention to the Cohort 1, the lower dose aficamten group, which is in blue. Of note, you can see here a rapid decrease in resting gradients within the first 2 weeks of treatment. Over the next couple of weeks, with dose adjustment period, gradients then decreased and were obliterate -- continued to be obliterated through the treatment period at the end of the treatment period during the -- at the end of the 2-week washout period, I should say, gradients then returned to baseline levels. In green is Cohort 2, showing you a similar finding in terms of rest gradient, obviously, rapid decrease in rest gradients within the first 2 weeks. Gradients remained obliterated through the treatment period in the higher dose cohort. And then again, the end of the washout period, gradients returning to baseline levels. This is a similar graph, of course, showing you though provocable gradients. Now again, the pooled placebo group up top, really no change over the treatment period of provocable gradients. And then once again, in the Cohort 1 lower dose aficamten treatment arm, rapid decrease in the first 2 weeks in provocable gradients, which was maintained throughout the treatment period. And then again, as we just talked about, coming back to baseline at the end of the 2-week washout and a similar reduction in provocable gradients, although a little bit more with the higher dose cohort in green, again, similar -- maintaining really obliteration of those provocable gradients through the treatment period. And again, a statistically significant difference in the gradient reduction in the 2 treatment arms compared to placebo. And then if you kind of pool those last 2 slides kind of together and you define a responder in terms of the hemodynamic outcome here, which is the outflow tract gradient, and that was defined here as -- a responder was defined here as a resting gradient of less than 30 millimeters of mercury and a provocable gradient of less than 50 millimeters of mercury. So that's our responder definition for the hemodynamic response, for which 93% of patients, 13 out of 14, in Cohort 2 achieved that responder definition. 79%, or 11 out of 14 in the lower dose Cohort 1 achieved that hemodynamic response. This is demonstrating the change in ejection fraction over the treatment period. Again, similar scheme as the last -- the other 2 slides in terms of the pooled placebo group in gray, showing you really no significant change in ejection fraction as you would expect over the treatment period. And then with the lower dose aficamten group, a small decrease in ejection fraction of about 5% through the treatment period and a slightly greater decrease in ejection fraction for the higher dose aficamten Cohort 2 of about 10% decrease. And I'll just draw your attention to the reversibility here in terms of ejection fraction coming back to normal or baseline levels at the end of the 2-week washout period. The asterisk here show a statistically significant difference in decrease in EF in the 2 treatment arms compared to placebo. And this is demonstrating biomarker data for the 2 treatment cohorts. You can see here significant decreases in NT-proBNP in both Cohort 2 and Cohort 1. If you pool together both of those treatment cohorts, there is a statistically significant decrease in BNP levels over the treatment period compared to the placebo group. So this is demonstrating clinical efficacy here, and that was defined as a 1 or greater improvement in NYHA class over at the end of the treatment period. You can see in Cohort 2, the higher dose aficamten group, 64% of patients had a 1 or greater improvement in NYHA class over a 10-week period. And 43% of Cohort 1 had a 1 or greater improvement in heart failure class. Two serious adverse events were reported in Cohort 1. There were none in Cohort 2. Here's the profile of those 2 SAEs in Cohort 1. First was a 55-year-old woman who developed what's called a stress cardiomyopathy. But I'll emphasize, as you can see, this patient was assigned to placebo. She recovered after treatment of her cardiogenic shock. The second patient is a 50-year-old who was assigned aficamten and had an exacerbation of preexisting musculoskeletal back pain. Importantly, no SAEs reported here resulted in termination -- early termination. There were no treatment-related serious adverse events, and there was no difference in the adverse events reported in the aficamten group versus placebo. In addition, no patient met the stopping criteria for an ejection fraction of less than 40%, no treatment interruptions or discontinuations, treatment emergent adverse events, similar between the 2 groups, as I mentioned, talking about 2 patients now with ejection fractions that went below 50%. One patient with a baseline ejection fraction of a 58% underwent pre protocol -- per protocol dose reduction at week 4, where he had to went slightly below 50% with a return of EF to above 50% and continued on drug. Second patient with a baseline EF of 70% as noted that have an EF of 49.3% at week 10 with an EF that returned to baseline at the end of the study without requirement of a dose change. So in summary, aficamten, novel second-generation cardiac myosin inhibitor being evaluated here for the treatment of symptomatic obstructive HCM. In this Phase II clinical trial, aficamten over a 10-week period -- 10-week treatment period demonstrated elimination or obliteration of resting outflow gradients in nearly all patients, including 93% in the high-dose cohort. This improvement in hemodynamics was mirrored by improvements -- significant improvements in the reduction of the biomarker NT-proBNP. Reduction in gradient resulted as well translated into a significant improvement in heart failure symptom burden with a substantial number of patients achieving 1 or greater improvement in NYHA class. I think this hemodynamic and clinical benefit can be in some ways perhaps attributed to favorable pharmacodynamics here, which include a relatively short half-life and wide therapeutic window, which enabled rapid and substantial reduction in the gradient, precise echo-guided titration of drug dosing and, in this case, without the need at all for any drug interruption and a rapid reversibility that demonstrated after discontinuation of the drug. And overall, extremely well tolerated, no serious adverse events to the drug in a similar incident of AE with aficamten compared to placebo, began to emphasize no patient discontinued aficamten during the study period. So I think in summary then, these data strongly support investigating further the clinical efficacy and safety of aficamten in a larger prospective Phase III clinical trial, which is intended to begin at some point by the end of the year. Thank you.

Thank you, Dr. Maron. We're going to have a short panel discussion now with Dr. Masri and Dr. Maron. I'll ask a few questions. We'll have some closing remarks, and then we'll open it up for questions for those on the line.

So first, I'll start with Dr. Masri. You've enrolled more patients in clinical trials with cardiac myosin inhibitors than any physician in the world given your work both in EXPLORER and trials of mavacamten, and now with aficamten. Based on REDWOOD-HCM results, can you describe how your patients fared? We present a lot of numbers in graphs. Maybe you can tell us how your patients actually felt on study drug.

That's a great question. So as you know, we enrolled a lot of patients in REDWOOD. And the thing that you see consistently is rapid response, rapid relief of symptoms and consistent response throughout, essentially, the study for those who are on aficamten. If you think about the study as with all HCM studies, there was a wide range of ages of the patients essentially included. And I can think of 2 qualitative examples of somebody who's on the younger side who thought that they've always with interviews would say they have mild symptoms. But after being on aficamten described that they never realized how symptomatic they were before. Now they're able to work in their farm, do everything without stopping -- ever stopping again. And that gives the patient insights that they typically underreport how they feel and how things are going for them for the younger patients. And on the other hand, you have a 70-year-old woman who has been busy enlighted it for a year before been toying around with the standard-of-care background therapy, once invasive options done. And while being in aficamten, immediately within a couple of days, felt very well with no symptoms essentially. And once she got off the drug, she realized something, and she told me that she never realized how a drug can make somebody feel and the extent of how good the drug made her feel. So I think these qualitative examples are important because they add more to the quantitative data that you've shown. The ease of the use of medication titrating it and using it based on echocardiography, I think, are very important aspects of this medication.

Thank you. Yes. I think you're absolutely right. It's so hard to quantitate those kinds of things that you related. But obviously, they really speak to the burden of the disease and potentially what the numbers that we've generated here actually translate to in terms of patient benefit. So thanks for sharing this. Dr. Maron, a question for you. Can you elaborate on your expectation of how these Phase II results may translate into the clinical setting? Specifically, how you think the attributes of aficamten may translate into clinical use?

Sure. Well, I think what we can say in terms of answering that, based on what I showed here for REDWOOD in terms of the reduction in gradient and translating into the improvement in heart failure burden would be that the translation of that -- those results to the clinical treatment arena would be that you could imagine that aficamten could be an important drug option for symptomatic obstructive patients who are not responding to current first-line therapies like beta blocker or calcium channel blocker. And as you showed in your presentation, there are a substantial proportion of patients who are not achieving the symptom reduction that they want to have with beta blocker or a calcium channel blocker. And so -- and they're also -- and therefore, that's where, obviously, an important role would then be for a new drug to help improve the quality of life in the symptom burden in that situation. And as you noted, there is a substantial number of patients to whom that would be applicable today right now. So I think that's probably most fair to say where the translation of what we just saw from the REDWOOD data would be applicable to the clinical arena.

Perfect. Yes. No, I think, again, the -- providing options to patients. Obviously, they're not fully treated on existing medical therapy and often have to go on to more invasive therapies providing another option, again, maybe provide some with...

Yes. Let's make one other comment on that, too. I mean I think just to play -- to expand on that point, you just said. I mean there are invasive treatments, right? So they've got surgery, which is open heart surgery, and you've got a catheter-based procedure called alcohol ablation. But there are a lots of patients who -- to whom that is not appealing. And -- or in whom their other clinical profile would mean that their risk of that procedure, invasive procedure is high. And so for that reason, too, there is a role and a very important role, I should say, for alternative medical therapy options that could have a benefit of clinical efficacy that would be as good or maybe, in some cases, better than the invasive procedures.

Thanks, Dr. Maron. Let me turn again to Dr. Masri. As you indicated earlier, you've treated a lot of patients with cardiac myosin inhibitors in clinical trials. You've had to initiate them on therapy. Maybe you can tell me how does echo-guided dose titration enable you to optimize target dose in these patients?

Certainly. So if you think about how we evaluate these patients, we always start after, of course, the clinical history of disease exam with an echo, and we do follow them up with echocardiography over time. I think having echocardiographic guided dosing enable us to treat these patients well, treat them early and achieve the maximum dose tolerated and needed for their symptoms also early. And I have complete control over that. I don't have to wait for anything else. I don't have to wait for lab. I don't have to wait for other factors that would make influence my decision. I can design my practice if I'm thinking that I need to change something. I can design my practice to have the echo done, seeing the patient on the spot deciding what I want to do. And as you know, the design of the open-label extension is similar. And so you can take that and go and run with it. And I think it's very appealing, not just for physician -- as a physician, but also for the patients. You try to decrease the number of visits. You try to consolidate their treatment also quickly over if there's, for example, severely symptomatic, you can scale it up and do it over a short period of time. If they are less symptomatic and you have time, then you can also do it over a longer duration. So I think that's very attractive, and that's a very important aspect.

Well, I think HCM is quite unique in the disease and that we have a modality by which to measure the effectiveness of the drug and personalize its use. We all know that patient variability is so great, and it's always hard to say 1 dose fits all. And so having a modality like echo, which as you said in your own hands, you can apply the patients is pretty powerful.

Absolutely. And that's what's very attractive is that you can combine both the clinical symptoms as well as an objective measure that you're doing to decide on how you're going to do it. And having a wide range of dosing you're going to go from 5 to 20, probably in a subsequent studies. Having this wide range of dosing is very helpful because you can personalize it as you suggested. And I think it is a powerful property of aficamten.

Well, I think you made an important point there as well that the echo isn't the only thing that you use in your assessment. You listen to the patient, how are they doing? Are they feeling better and use that to also temper what you may implement in clinical practice. So...

And this is especially important with Valsalva gradient. Sometimes you have patients who are completely asymptomatic. They still have some elevation in Valsalva gradient, but you don't have a clinical reason to keep going up on the dose. And when you're looking at the summary data, sometimes you're like, oh, there is this patient or 2 who still had high provoked gradient with Valsalva. But in reality, we want to treat patients to the maximum-tolerated dose that makes them asymptomatic, not only just treat the numbers. So the combination, I think, is what's important and what we should go after.

Good point. Dr. Maron, just for you. You have a lot of experience with surgical intervention and large practice, large history, really maybe one of the largest experiences in the United States. So maybe you can tell me how the extensive gradient reduction we saw here compares to surgical interventions in patients that you send to surgery for refractory HCM?

Yes. Sure. Well, I mean, the answer is clear. I mean the gradient reductions that we reported here are as good as surgery. There's no question about that. Resting gradient, reduction with aficamten would be comparable to what you would see with surgical intervention. Now obviously, what we're seeing with aficamten in this Phase II study is a short-term results. Of course, surgery to be fair and balanced, obviously, has already 40 or 50 years of experience behind it. So we know that those gradient reductions of surgery are maintained. That doesn't mean they're not maintained with aficamten, but at this point, we just don't know the answer to that yet. But in terms of the -- but in terms of what you asked, the answer is absolutely clear. Gradient reduction with the drug is equivalent to what you see following surgery.

Well, I think you're absolutely right. It's early days in the development of what's really a novel therapy. It targets the basis of the disease. And time will tell as we gather more data and as we look at patients on drug for longer periods of time as we're doing in our open-label extension and as there are other complementary data out there that will inform what the long-term effects of these drugs. Great. Thanks. I'll turn it back to Robert for some -- who will give some closing remarks.

Thank you, Fady. And before we open it up to questions on the line, I want to thank our panelists for their very insightful comments today. We're pleased with the results from REDWOOD and how they augur well for the further development of aficamten. We're very committed to rapidly moving this potential next-in-class cardiac myosin inhibitor into a planned Phase III trial before the end of the year. We look forward to elaborating on the design of that trial at our upcoming investor event. Hopefully, folks have received notice about that in the mail. It's going to be on October 7 in person in New York, and virtually also online. In my concluding, I'll also mention that here at HFSA, additional results from GALACTIC-HF, the positive Phase III clinical trial of omecamtiv mecarbil, which is our cardiac myosin activator, which we're developing for the potential treatment of heart failure, they were also presented in the same late-breaking clinical trial session yesterday. Inequities and heterogeneity of clinical trial results is a major theme at this HFSA meeting, and GALACTIC-HF stands out for its higher enrollment of black patients amongst contemporary heart failure studies. The results announced yesterday demonstrated that the effect of treatment with omecamtiv mecarbil in black patients was consistent with the same treatment effect in the overall population, and also as well in white patients. These analyses are particularly important because compared to other racial or ethnic groups, black patients have higher risk of heart failure. They have worse outcomes oftentimes and have historically been underrepresented in clinical research. We were pleased to share these results with the heart failure treatment community yesterday as they further add to the body of evidence in support of omecamtiv mecarbil and hopefully may inform potential patient selection decisions down the road. And with that, we appreciate everyone's interest in the updates on this call today. Operator, we can now open up the call please to questions.

[Operator Instructions] Your first question is from the line of Carter Gould with Barclays.

Great. It's Edwin on the line for Carter. My first question is for Dr. Maron and Dr. Masri. If you can kind of give us some color on your impressions of the aficamten data from the meeting? You talked about this a little bit before, but if you can comment on where you see the treatment paradigm shifting with the addition of new agents. Is there any -- is there an eagerness to treat Class IIs? And has any of the data surprised you?

Look, so yes, this is Marty Maron. I'll start and then Dr. Masri will weigh in as well obviously his impressions. I think you asked me first about my overall impressions of the REDWOOD data. I mean I think that what I would say to that is very impressive. I mean I think there's no other way to conclude other than that. I mean in terms of what you want to see for an effect of a drug in this class of patients, you're seeing that with aficamten balanced with a very favorable safety profile, right? So you got gradients, the hemodynamic driver to symptom production and obstructive HCM, really being eliminated by the drug over the treatment period. And you're seeing that translate into what is the ultimate goal with this treatment initiative, which is a decrease -- a significant decrease in symptom burden. So the sort of the unmet need that we talked about for a therapy in obstructive HCM is being exceeded here by these data for aficamten. There are no other way to conclude that really based on what I showed you. And so for that reason, the answer to your second question would be that I think you can start to see, for that reason, the possibility here, always hard to predict the future, but you can start to see the potential for, as you said, a paradigm shift in terms of perhaps more aggressive treatment of drug therapy in the Class II obstructive HCM patients. And that may also extend to more aggressive drug treatment trials in Class III obstructive patients too as well. So both potentially would represent paradigm shifts in terms of the fact that we would provide patients the option of a drug therapy treatment for their symptoms that were not improved with background treatment with beta blocker and calcium channel blocker. That's the paradigm shift.

So this is Ahmad Masri.

Great. Sorry. Please keep going.

No, I was just going to say that Dr. Maron had the high notes. To add to that just the fact that if you have a therapy that is effective and safe, there is no longer a reason to sit on patients who are symptomatic, even if they're mildly symptomatic. You just -- as you suggested, you have to see the long-term effect and the sustainability. But the reality is, right now, we are sitting on patients who are symptomatic because we call them "mildly symptomatic" or they don't need the threshold there to undergo major invasive procedures. And so that's how the future might change.

This is Robert. I might just add that yesterday, when Dr. Maron presented these results at this late breaker clinical trial session, afterwards, when the program ended, he was surrounded by a lot of his peers who were congratulating him and asking questions and clearly very enthusiastic about these data. It's somehow hard to relate potentially during a pandemic for this being the first scientific congress medical meeting that many of us have been at in over 18 months to remember. But this was a packed ballroom with quite a number of people that were there for other presentations as well. But I think these results were met with a high degree of enthusiasm and support and interest in light of the data and what they may represent in terms of a potential advancement and as you point out potential transformational treatment for these patients who right now don't have any medicine approved for their indications. So this is, I think, being embraced by the Heart Failure Society, both here in person in Denver, but also online, virtually. So we were very pleased with that from the Cytokinetics perspective.

Your next question is from the line of Jason Butler with JMP Securities.

Just one for Dr. Maron and Dr. Masri, again. Just given what we now know from REDWOOD and also taking the experience from aficamten, how do you think about the risks for aficamten succeeding in theory? What do you think the company should be considering for the Phase III trial design to optimize the chance of success?

Well, I mean I think extrapolating from what we know from aficamten and EXPLORER, and also what we now know about aficamten in REDWOOD, I think you have to say that the likelihood of success here in terms of a Phase III study with this drug in obstructive HCM is hot. It's hot. There will be no other way to conclude that. And so in terms of success, I think that the favorable -- maybe more favorable pharmacodynamic profile of aficamten can be leveraged in a Phase III study to demonstrate better -- maybe better efficacy and less concern around safety than the mavacamten EXPLORER trial. And I think that's probably the goal here for -- when we're talking about the design of the Phase III study is to leverage that differentiating feature between mavacamten and aficamten to show increased efficacy with great safety profile in the Phase III study. Is that your question? Sorry again. You're good?

Yes.

Was there a follow-up, Jason, I'm sorry?

No. That was great.

Your next question is from the line of Salim Syed with Mizuho.

Congrats on the data guys, and appreciate the panels color. Fady actually took all my questions. So I'm just going to excuse myself from this, just kidding. I actually had a couple for the panel here, to Dr. Maron and Dr. Masri. So Dr. Maron, you kind of talked about mavacamten a little bit. Just curious here, there does seem to be a decent placebo-adjusted gradient impact here, where 274 is putting up numbers placebo-adjusted again, in the 70s and 80s versus mavacamten sort of in 50s. And safety, I agree, does look better here. Just curious why you're here to say that -- sorry, the 274 is actually the superior drug? And then secondly here, just given that this drug was also used in conjunction with or allowed for beta blockers and calcium channel blockers in the trial, why wouldn't this drug be used in the first line setting? You said -- you mentioned for drug -- for patients who failed first line, then this drug could become that -- the next option here. But why wouldn't this just become the immediate go-to first-line along with calcium channel blockers and the beta blockers?

Maybe I'll ask the panelists to answer the second question first in terms of use of the drug and standard of care where it may ultimately just be positioned. Do you want to maybe start, Dr. Masri, and then...

Sure. This is Ahmad Masri. So when you think about aficamten and any drugs that are being ported for HCM, you have a population who are on standard of care. They are symptomatic on standard of care. So the first step is to treat them on their background therapy, not make them worse when you're enrolling them in a placebo-controlled trial. So you take them on their standard-of-care therapy. You treat them. You're showing the superiority of aficamten, even on the background therapy. And then there will be opportunities in the future to look at this as a monotherapy as trying to decrease or take out these background therapy. But there is no -- clinically, it would be hard to take patients who have symptoms and tell them I'm going to take you off all of your medications and then randomize you to placebo versus aficamten.

I'm saying used in conjunction with the standard of care. So all first line, right, because that's how the trial was conducted, right, with beta blockers and calcium channel blockers.

Correct. And that's how you would envision it. You'd envision that you have patients who are symptomatic on standard of care, and then you would add aficamten, too. But there will be opportunities in the future to think about and study in a different fashion. But yes, you're right. This is the design of the study, and this is what the results are representing.

And I think -- this is, sorry, Marty Maron here, just to expand on that, too. I think you're asking to -- I think a little different question. I think you're asking our opinion about if we kind of looked into the future, knowing what we know today about the efficacy and the safety profile of aficamten, could we imagine a point in time where these would be first-line agents, because why not? Their efficacy seems to be so superior to beta blocker and calcium channel blocker therapy. And you know what? You're right. You're absolutely right. I mean I would say that beta blocker and calcium channel blocker, we use them first today because we don't have a lot of other alternative options, of course, but we use them today. But the reality is their efficacy is really poor, and they have side effects. So could you imagine if the safety profile is as good as we hope it will continue to be with aficamten along with high efficacy, that these cost of drugs with aficamten leading would replace beta blocker and calcium channel blocker as first-line agent, I think that's a reality.

And so just to your first question, I think it's important for us to focus on the data we're generating with aficamten. We're not trying to make any comparative statements. We ran a trial against placebo. We have obviously a Phase III trial to run and see what the clinical benefits are there and ultimately hope to generate a set of data that's very compelling to physicians to use in their patients.

But is there anything from the panel -- is there anything from the panel that would -- that's bringing particular pause to saying that 274 is the superior compound here. I mean to me, at least seems like the worst case scenario is that they're comparable, worst case, to mavacamten, right?

So yes. So Marty Maron here. Yes. So I mean, I think you said when you first came on -- I mean I didn't -- so I would say that right now, based on what we know, based on what we know about aficamten and mavacamten that -- what you just said is correct. But I would also say that there are a number of features that we're already seeing related again to the more favorable pharmacodynamic profile that would clearly give aficamten an advantage here, okay? That's my opinion. I mean that's what I -- that's my interpretation right now of where we are in terms of the 2 drugs.

Salim, it's Robert. I appreciate you want to follow this line of questioning, but I don't think it's appropriate in light of the fact that this is a call really intended to report on the results of REDWOOD-HCM. And there have not been head-to-head studies. And I really do want to focus on what might be the takeaways from the REDWOOD trial.

Your next question is from the line of Charles Duncan with Cantor Fitzgerald.

Yes. I had a couple of questions for the KOLs. Just maybe going back to an earlier question, I'm wondering if -- Fady mentioned several design features of aficamten. And I'm just wondering if there was one in particular that was interesting to -- especially given the emerging treatment paradigm. Is it, say, the onset of action, timing, this time to steady state, the rapid reversibility? Anything in particular that you want to point to that intrigues you most.

This is Ahmad Masri. I think there are a couple, and you might be asking us to choose from, but I'll tell you that when patients feel good quickly within days, that's important. And when that's sustained, also that's important. The ability to titrate the medication based on echocardiography is very important also as well as clinical symptoms. And then what's most important, I think, is the fact that the medication is safe. And we haven't seen any major instances where there were any major serious adverse events that would lead to the drug, for example, discontinuation. So when you look at this aficamten and compare it to the rest of available therapies, I think those are the features that make it stand out.

Okay. Yes. Dr. Maron?

Yes. So I think that -- I think -- when I'm thinking about this, I'm thinking the goal here is to make patients feel better and that's achieved by lowering the gradient here. So there's a direct relationship between lowering the gradient and clinical improvement, which is dramatic. When you lower the gradient, patients feel, as you've heard, a lot better. And so to achieve -- and so we're trying to do that but not also lower the ejection fraction too much, okay? So there's that balance that we're trying to achieve between gradient lowering and preserving ejection fraction, okay? So that's the -- that's what this -- this is what -- that's the dynamic going on here. And when you've got a more shallow dose response curve where over concentrations of the drug, there's more finite changes to ejection fraction with aficamten, then, to me, that is the -- in particular, a pharmacodynamic strength that would potentially allow this more personalized, more finite dose adjustments in an individual patient to achieve the goal of gradient reduction without sacrificing a decrease in ejection fraction too much. So that's -- if I were to kind of summarize it, that's really the key -- to me, at least the key point in translating the pharmacodynamics to a clinical benefit.

Yes. That makes sense. And just one additional question regarding -- going to the NYHA class observations. I acknowledge relatively small and very rapid -- or very, very short time to make the observation. But when you think about the, I guess, placebo-adjusted NYHA class change, how do you feel about that? And do you think that it would expand, if you will, if the duration of drug exposure was longer, say, out to maybe 30 weeks?

This is Ahmad Masri. So yes, there are 2 main things to think about. One is, when you have younger and older patients, NYHA class, while it's objectively assessed, as I gave you an example, some patients don't realize how symptomatic they are. And despite repeated questioning and asking them this repeatedly, they tell you that they have mild symptoms. But once they -- you actually relieve their obstruction and lower their gradient, they feel much, much better to the point where, in retrospect, they would tell you, I realized how symptomatic I was. So that's one angle. But the second one is what you mentioned also. Some of these patients have been living with limitations for a long period of time. They're deconditioned. It's not just that it's a switch that you turn it on and off with the gradient. They're deconditioned. And it does sometimes take time for people to push themselves more, to exercise more, to do more and recondition themselves to feeling better. And so while there are limitations to NHYA class, this is very exciting to see even with a small number in REDWOOD. This improvement in NYHA class is very important and significant. And this is also what I see in my own patients. And so it's narrowed by the results that you're seeing today.

Very good. Okay. Dr. Maron, anything to add?

No. I was just going to just -- no. In fact, I was going to say that I totally agree with those comments, and I think that you're on the right track in terms of longer treatment period. You're more likely to see an improvement in clinical benefit with longer treatment periods than what we saw -- than what REDWOOD was for the reasons that Dr. Masri explained.

Your next question is from the line of Dane Leone with Raymond James.

Congrats on the data presented over the weekend. Really great to see all the details of the REDWOOD study. So 2 questions for the panel and the team, if I may. First one, could you please discuss once we get into the clinical setting with these drugs, how you would think about using echo-directed guidance on dose titration for the patients? We've had a lot of debate with your peers in the cardiology community and what for this patient population and size of the patient population would be tenable for an institution to take under a regular echo monitoring. And there's been a suggestion that maybe many echoes could be utilized for dose-titration guidance. And that might resolve some of the issues. But maybe go into that a little bit. And then secondly, from the clinical community perspective, what would be kind of the minimum design for an outcome study with these agents, aficamten and potentially mavacamten, that you think could demonstrate a hurdle of clinical plausibility that you could get outcomes that would be on par with surgical intervention, or at least satisfy that question for the clinical community?

Yes. Marty Maron here. I'll start. In terms of the answer to your first question. Look, I think, obviously, the requirement of less echoes, the better in general. I think that is kind of obvious that if you have to do less echo follow-up when starting the drug to dose adjust then that's better for patients and physicians and so forth. That's a more favorable situation. What number would be a threshold there? I think that -- I don't know the answer to that. I certainly think that the idea of 1 echo and making a dose adjustment on 1 echo, it makes a lot of sense and would not be a game changer in any way. Perhaps somewhat more of that would not change the landscape very much at all. So it's a hard question to really answer. I'll just say that, again, coming back to the pharmacodynamics of aficamten, there's the possibility here that there may be the need for less echocardiographic guided dose adjustments here. We'll have to see, of course, I think the Phase II will really help inform that. In terms of your second question, the design of a -- I think you're asking about the design of a clinical trial comparing the myosin inhibitors to surgical intervention. And I think the -- there's a -- it's a complicated question. There's a lot of different aspects to it. That's why I'm kind of hesitating. But what ultimately -- the answer to your question would come down to would be -- what you would be looking at for your endpoint, okay? If you're looking at serious cardiovascular events, then it would be very difficult to power a clinical trial that could answer that question because adverse event rates are just incredibly low here in this disease, even on treatment -- and even more on treatment. If you are trying to consider a design where you would be looking at other types of endpoints like NYHA class improvement or improvement with cardiopulmonary exercise testing, there's the possibility that a design like that could work. How to power it? I don't know how to answer that right now. I think that's a difficult question. I'd have to take a look at it. It'd be hard to know that right off the top of my head.

So this is Ahmad Masri. To add to that, if you think about the patients that we are enrolling in the trial, we don't divide patients necessarily those who need surgery and those who don't need surgery. We meet the patients who are NYHA Class II or III. Some of them, if we didn't have aficamten and REDWOOD, could have gone to surgery. And so you are not dividing necessarily that -- there's no divide in there. You're seeing the patient development and offering them the trial, and they're participating in the trial. In terms of the echocardiography question, at this point, we are still doing -- we will need to be doing echocardiography. The nice thing is that the time line you can scale it up and down based on your institution and the settings you practice in and what you want to do. The key concept I wanted to highlight is you don't have to have an hour of echo every time you're trying to do something. You're looking for gradients and for ejection fraction. And so there are protocols for truncated echoes. We can evolve over time to address this question by having -- and this problem by having essentially echoes that are 10 minutes long, and they can assure us of the safety as well as where we want to go next. So hopefully, that answers your questions.

Just maybe one really quick follow-up on that. Do you think a study design for the myosin inhibitors where you're using time to surgical intervention could be an event study that would be plausible, and maybe running that against the control group?

Dane, this is Fady. I think there are parallels to the kinds of questions you're asking on the coronary artery disease world, where you're talking about medical therapy versus surgical therapy or PCI, how much crossover do you have, all those sorts of things. So there do exist paradigms for what you're thinking about. I think the challenge just is the small numbers of patients that -- well, they're not -- this is not an ultra-orphan disease by any stretch of the means. Many of the trials you described -- many of the trials that I just named as the examples enrolled 1,000 patients or more to see those outcomes. So I think as Dr. Masri said, you have to really look carefully at what kind of treatment effect you might see, how much crossover you might expect and then decide, can you really practically enroll something like that in a disease where it's still really an orphan disease and know whether that's practical. So it's sort of the cardiovascular paradigm to do something like that, but most cardiovascular diseases are not orphan diseases where we think about doing that.

Your next question is from the line of Jeff Hung with Morgan Stanley.

For the NYHA data, you looked at, at least 1 class improvement. I guess recognizing the sample size and limited duration, what proportion of patients had a 2-class improvement in NYHA? Did that happen for any patients?

Yes. I won't tell you exactly how many it happened for, but we did see some patients with a 2 class improvement. It's a pretty small study, again. And as you can tell, there are only 14 patients, approximately, in each group. So that's a big change. And the number of Class III patients that we enrolled was also not the majority of the trial. So -- but we did see examples of that. And potentially with a little more focus on larger studies, we'd be able to report those kinds of things out.

That is compatible with how we're thinking about what could be the upside of a potential Phase III study here. Our goal being to see if we might be able to enroll a substantial number of Class III patients who stand to potentially benefit that much. So...

I'll just add one thing, though. I mean getting -- as Dr. Masri stated, getting the Class I totally asymptomatic is very challenging, right? You're taking patients who may be deconditioned, have other comorbidities that may have nothing to do with their hearts, but may contribute to symptoms and other things that exercise intolerance, obesity. You have a hard time deconvolving those things often to get to NYHA class I, which is asymptomatic. And so NYHA class is a pretty crude tool. I mean it seems to be a pretty effective way of looking at things, and that it's dose responsive and treatment responsive and things like that. But it's a 4-point scale, and we exclude the Class IV patients. So it's not -- there's not a lot of resolution there.

Your next question is from the line of Emanuela Branchetti with H.C. Wainwright.

So for Dr. Masri and Dr. Maron, could you share your view around the correlation between gradient reduction and peak VO2 also in light of what demonstrated by mavacamten in the EXPLORER trial? And do you think exercise problems as an endpoint is valid for the Phase III trial?

Yes. So well, I think as you were just kind of alluding to, I mean, I think from -- what we know from EXPLORER and other initiatives -- treatment initiatives in HCM that lowering the gradient significantly translates into 2 important things: improvement in how patients feel their quality of life, which really is our primary goal here in treatment; and then two, it does rose relative improvement in functional capacity as measured by peak VO2. So if you're going to lower the gradient, you will see an improvement in peak VO2 and symptoms. So feel and function will get better. It's harder -- gradient -- I think if you're asking, is there a direct linear relationship, so to speak, between gradient reduction and a magnitude of improvement in peak VO2, that's harder to get at, to be honest. We just don't know enough about that relationship in terms of treatment effect to really tell you. So what I told you is a broad principle that I think absolutely applies. But when you start to get into exactly what the magnitude of change in peak VO2 is related to the magnitude of change in gradient harder to really kind of nail that down.

And if you think about the patients that we enroll, we enroll patients that have an obstructive disease that we think having symptoms because of that obstruction. And so those are the kinds of sorts of patients that we enroll in these trials. There are patients who have obstruction and don't have as many symptoms or as -- or their symptoms might be related to other things. And so your hope is if you're selecting your patients well -- and we'll learn more about the design of the Phase III. But your selection of patients will dictate what you find out from any study that you do.

Got it. Got it. And another question about -- you show data on the NT-proBNP reduction. And we know that this is an accepted prognostic market in particular patients. But if I'm correct, the AHA guidelines have less focus on BNP in patients with obstructive HCM. Could you provide more color on the relevance of these observations? And could this substantial effect on Valsalva be predictive of positive remodeling long term for these patients?

I think that in terms of that question, you are right that from a clinical standpoint, we don't, for example, follow longitudinally BNP values and then make adjustments to treatment based on those values or tell patients prognostic information necessarily about outcome in terms of BNP levels and obstructive HCM. That said, I think that the fact that you see in REDWOOD a significant reduction in BNP is really supportive really. I mean I think that's the way I look at it. It's a supportive data finding to the other larger finding of gradient reduction, okay? So lower gradient, lower wall stress, and you see and you would expect to see and you did see a corresponding decrease in BNP. So I think it's -- to me, it's kind of helping support the argument of the benefit of therapy in terms of the hemodynamics. Whether it's telling us something about long-term remodeling? I just think we don't know the answer to that yet. We'll have to see.

Your final question is from the line of Graig Suvannavejh with Goldman Sachs.

Congrats on the data. I've got a couple of questions for the KOLs. One, in light of the efficacy and safety that we're aware of in terms of the surgical option, alcohol ablation, current oral therapies such as beta blockers and calcium channel blockers. Based on what we know today in terms of the Phase III data for mava, or the Phase II data for aficamten. I'd love to ask the KOLs if they could perhaps look in their crystal ball and say, 5, 10 years time from now, how do you think those dynamics will change, if at all, again, based on the existing data we have? So that's my first. My second for the KOLs is just in light of Cohort 3 data with disopyramide. I was wondering what the doctors are expecting to see with that data? And perhaps more importantly for those of us who aren't cardiovascular specialists, what does that data do particularly for the profile of aficamten relative to perhaps mavacamten? And then my last question is just if we assume that aficamten generates positive Phase III data and gets on the market, given that it will be behind mavacamten, at least that's the assumption. Just wanted to get a sense of how they would think about whether it's a switch dynamic or if there's specific patient populations where one would be perhaps considered versus another?

So those are three questions. Maybe we should unpack them. I forgot what the first one was.

So the first one is looking into the crystal ball. How do you see the dynamics of therapy changing in the next 5 to 10 years? Lets start there.

So when you -- this is Ahmad Masri. So when you look at the -- from today's presentation for REDWOOD, when you look at the performance of aficamten and see what's forthcoming, this is showing you that in the future, it's potentially a game changer. And that's what you will potentially be relying on because it was effective in decreasing the gradients while not decreasing the ejection fraction to a degree that worries us. The problem is what you're suggesting is, then what can you do next? And I think we have just to wait and see how the program evolves and how the data comes out from the Phase III and what other data come out to see, how we can position it as compared to background therapy and as compared to other invasive options. In terms of your -- the disopyramide question, I think you answered it. We have Cohort 3 ongoing, which is enrolling everybody on disopyramide, and this is going to be great addition because it would be the only study that is looking at cardiac myosin inhibitors in a group that all have been treated with disopyramide over a stated period of time. And they're still symptomatic, obstructive and then you're going to see the effect of aficamten. So I'm very excited to see the results of that cohort.

And I think it may be premature to address that third question around how to think about this drug were to approved, and also mavacamten approved and what might be new patients versus switches. Let's go into the Phase III study. Let's see how the Phase III results might ultimately read on a profile for aficamten and speculating about the future like that may be just unnecessary or premature at this time. Marty, anything you want to add with regard to those first 2 questions?

Yes. I mean I'll just add -- just to expand on just really briefly. In terms of the disopyramide, since you asked about that, I think I'll just add that. Look, we don't know the answer. Of course, that's why we're going to do Cohort III. But the potential idea there is that these 2 drugs could be synergistic, could be, in terms of benefit because they are acting in a different -- 2 different mechanisms in terms of attacking the outflow gradient and symptom production. So that's why I think we're investigating even on the answer, but the hope would be maybe that it could be synergistic. And so that's going to be something that would be very interesting to see. And I think in terms of the first question, crystal ball, I mean, I think I'll just -- I think Dr. Masri was right. I think we're going to see a lot more patients on drug therapy with these drugs -- with this drug therapy of myosin inhibitors with symptomatic obstructive HCM that are on drug therapy today. We're going to see a lot more of those patients over longer periods of time. Will it eliminate surgery and alcohol ablation? I think it's too premature to say that at this point. That would be unfair. I think there's probably always going to be some select patients that will require additional treatment interventions here. But the number of patients on drug therapy for this issue is going to dramatically increase.

I think, operator, you mentioned that was the last question. So maybe I'll just make some concluding remarks. I want to thank our panelists for participating so actively and candidly with regard to the questions and answers and your commentary. I think this is a very good discussion of our Phase II results, REDWOOD-HCM. And this is another proud moment for Cytokinetics. We were very gratified to see our science showcased in a late-breaker session yesterday. Obviously, these results are very encouraging and lend support for our movement of aficamten now promptly into Phase III, and we look forward to that study getting underway. I'll remind you that we'll have an investor event October 7. Hopefully, you'll all be able to join us. You'll learn not only about the design of the Phase III study, but also, what we're doing with regard to a go-to-market strategy for omecamtiv. And that's maybe where I'll end this, which is, I think, again, this is somewhat of a watershed milestone time for Cytokinetics. Yesterday, for Cytokinetics to have 2 late-breaker clinical trial presentations at this important heart failure meeting underscores the importance of cardiac myosin as a pinch point for the potential treatment of patients with heart failure and reduced ejection fraction as well as for patients with obstructive hypertrophic cardiomyopathy. And I think the quality and the integrity of the science that we've been pursuing here is getting noteworthy attention amongst the investigators and other clinical researchers and clinicians at this important meeting. So we're very pleased for that. We're pleased for your interest as it relates to Wall Street and investor attention to the work that we're doing. If you have any other questions, please reach out to us and follow up. And with that, operator, we can end the call. Thanks very much.

This concludes today's conference call. Thank you for your participation. You may now disconnect.