Cytokinetics, Incorporated (CYTK) Earnings Call Transcript & Summary

Good morning, and welcome, ladies and gentlemen, to Cytokinetics' ACC '23 Conference Call. At this time, I'd like to inform you that this call is being recorded. [Operator Instructions] I will now turn the call over to Diane Weiser, Senior Vice President of Corporate Communications and Investor Relations. Please go ahead.

Good morning, and thanks for joining us here in New Orleans and on the call today to discuss the data from Cohort 4 REDWOOD-HCM [indiscernible] FOREST-HCM [indiscernible] treatment of hypertrophic cardiomyopathy. Here with me today are Robert Blum, President and Chief Executive Officer, who will make opening remarks; and Fady Malik, EVP of Research and Development who will lead [indiscernible]. We are honored to have Dr. Ahmad Masri, Director of the Hypertrophic Cardiomyopathy Center at Oregon Health & Science University and Dr. Sara Saberi, Assistant Professor of Internal Medicine at University of Michigan Health and Frankel Cardiovascular Center, here with us to present the data. Please note the following discussion, including our answers 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 and additional risk factors are contained in our SEC filings and [indiscernible] report on Form 8-K was filed today and annual report on 10-K. 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 thanks, everyone, for joining us this morning. We're pleased to be here in New Orleans with all of you and appreciate those participating by phone. HCM remains a challenging disease for the patients who suffer from debilitating symptoms, including chest pain, dizziness, shortness of breath or fainting during physical activity and also for the physicians who treat these patients every day. That said, we're encouraged by the emerging data from our expanding clinical development program for aficamten, our next-in-class cardiac myosin inhibitor being developed for the potential treatment of obstructive and nonobstructive HCM, as you may have seen in the press release that we issued Saturday, as you will hear from Dr. Masri and Saberi. In REDWOOD-HCM, our Phase II clinical trial, treatment with aficamten, is showing to be well-tolerated and associated with significant improvements in heart failure symptoms and cardiac biomarkers among patients with both nonobstructive disease and obstructive disease and demonstrate sustained hemodynamic and biomarker improvement after nearly a year of treatment among patients with obstructive disease. In fact, in this study, the majority of patients with nonobstructive HCM, those patients became symptomatic or mildly symptomatic following the length of treatment with aficamten, as we continue to follow patients over the longer-term treatment for HCM and proceed with [indiscernible] HCM, our Phase III pivotal trial with aficamten in patients with obstructive HCM. We also look forward to beginning 2 additional Phase III trials this year, MAPLE-HCM, evaluating the effectiveness of aficamten versus metoprolol in patients with obstructive HCM as well as an additional Phase III clinical trial of aficamten in patients with nonobstructive HCM expected to occur later this year and given the positive results from Cohort 4 in REDWOOD-HCM. Together, this program will comprise 3 Phase III clinical trials across various patient populations aims to elaborate on the promise of aficamten as a potential treatment that may improve exercise capacity and relieve burdensome symptoms in patients with HCM as well as potential long-term effects with cardiac structure and function. With that, I'll turn it over to Dr. Masri to present the findings from Cohort 4 of REDWOOD-HCM.

Thank you, Robert. Thank you for having me here today. I will present to you on the results of aficamten in REDWOOD-HCM Cohort 4. It is the first evaluation of aficamten in patients with nonobstructive HCM. We presented the data yesterday ACC. Next slide, please. So nonobstructive HCM constitutes a large proportion of patients with hypertrophic cardiomyopathy. At the time of presentation for [ trigger ] evaluation, about 1/3 of patients with HCM have nonobstructive HCM, and this prevalence of nonobstructive HCM among the population increases over the lifetime of patients because of [indiscernible] perform. Other than cardiac transplantation, when there is [indiscernible] end-stage disease, there are no proven therapies for nonobstructive hypertrophic cardiomyopathy. We tried with beta-blockers, calcium channel blockers and diuretics to manage symptoms, but none of these were evaluated or studied in a large randomized patient trial, and from clinical experience, their effectiveness is minimum. In terms of aficamten, it is a small molecule cardiac myosin inhibitor that counteracts the hypercontractility that underlies the pathophysiology of hypertrophic cardiomyopathy. And REDWOOD-HCM, as you are all aware, is a Phase II clinical trial that is dose-finding safety and efficacy that started with cohorts 1 and 2 as well as Cohort 3 in obstructive hypertrophic cardiomyopathy, and today, we'll talk about Cohort 4 in nonobstructive one. Next slide, please. So these are the key eligibility criteria we're presenting to you. Patients have to have symptoms. So NYHA Class 2/3 plus left ventricular ejection fraction was 60% or above and the NT-proBNP was 300 and above. And the patients had no history of the LVEF [indiscernible] 45%. We did safety assessment as well as we look at NYHA class, left ventricular ejection fraction, cardiac biomarkers as well as safety evaluation. And then we're presenting the data, this is all fresh data that study was still ongoing as of a couple of weeks ago. So we're presenting the data on 40 patients up to week 10, which is the on-treatment duration study, and then there were a 2-week washout [indiscernible] presenting data [indiscernible] patients and [indiscernible] later. Next slide. This is the schema of our study. And again, in the top left, patients with symptomatic and obstructive HCM patients. A very important point to point out that the left ventricular outflow tract obstruction or lateral obstruction, we define it as resting and Valsalva as well as [indiscernible]. So these are patients with true nonobstructive HCM, and there are no gradients -- there's no gradient even with Valsalva [indiscernible] for example, which you can see sometimes there is increased [indiscernible] velocity [indiscernible] Valsalva [indiscernible]. Again, 14-week study, 10 weeks on treatment and 4-week washout. We did a couple of assessments, namely Echo, biomarkers, KCCQ and safety assessment. Next slide. So at dose-finding study, we wanted to understand the full range of the dose that we are offering from 5 to 50 milligrams and how patients do on high dose if they are [indiscernible] 12. So the titration criteria was very simple. Ejection fraction above 55%, they increase and uptitrate. Between 50% and 55%, you maintain. And then if it's below, then you reduce and then discontinue below 40%. And so this is important because in general, typically, you also try to look at symptoms, you try to look at sometimes biomarkers. But in this scenario, again, in the dose-finding study, you wanted to see what happens to patients on the high dose, so we have titrated to the maximum dose level according to LVEF. Next slide. These are our baseline characteristics on the 41 patients that we were reporting on. Mean age was 56. 58% of them were women. And then our trial has diversification population. 20% or so were Black or African-American and then 5% were Asian. A little bit -- about half of the patients were NYHA Class 2 and the other half were NYHA Class 3. And then as you can see, these patients have hypercontractility with elevated LVEF with a BMI of 30 as well as the NT-proBNP was significantly elevated at 1,200. This is in my recollection the highest NT-proBNP seen in any of the hypertrophic cardiac trials of this [indiscernible] trial. And this is important because it's not that it [indiscernible] the disease that -- and how patients are doing this also. Also troponin, the high-sensitive troponin is high, was elevated at 28.7. Next slide, please. So I think we did a good job in the study. These are our doses. I remember we started at 5 and we kept at 15. So Day 1 is 5, Week 2 is 10, Week 4 is 15, and then Week 6 is safety follow-up [indiscernible]. You don't have to get to 15 if EF is below 55%, but we try to push patients better. And as you can see, 85% of the patients achieved that maximum dose offered in the study, which is significant. The rest of the patients were at 10 milligrams, one did not uptitrate aficamten. What was the reason? These are not [indiscernible] otherwise, we would have reported it, but these were personal reasons, and no patient remained on 5 milligrams. Next slide, please. This is our left ventricular ejection fraction, titration period. As you can see, the mean is going from 70 to 66, so modest effect was an average of 4. And there was no situation where during the uptitration, we had an LVEF less than 50%. And so we followed the rules and we had patients continue to [ draw ] the study until Week [indiscernible] changes. Next slide. So these are the summary numbers for our treatment emergent adverse events. It's important to highlight that 66% of the patients reported 1 or more treatment-emergent adverse events. And there were no discontinuation during the study itself initiated by [indiscernible] patients. There was one interruption that patients had an upper respiratory tract infection and had those for 2 days, then they were instructed to go back on that medication again after that. And we'll talk more about some more events in the next slide. So this is recapping some of the things that I already mentioned, so I am not going repeat, but there were no drug discontinuations related to AEs. One patient had a dose reduction to 10 milligrams at Week 9 due to fatigue. One patient had dose interruption for 2 days due to an AE that we talked about. And 3 patients had SAEs. These were nonrelated or unrelated to aficamten. These were bronchitis, new onset atrial fibrillation as well as cardiac arrest. The cardiac arrest patient who died has a history of sudden cardiac death or cardiac arrest. And of those [indiscernible] enrolled in the study, they had all their assessments during the study and the trial period, and there was no indication that this is related to aficamten by the PI as well as the [indiscernible]. Three patients had LVEF less than 50%. So that's roughly 7% of the patients enrolled. This happened at the end of the study. So this is a short study where you don't have a lot of times within the study that you can downtitrate at a time point. Remember, by Week 6, you have to make a decision to [indiscernible] staying at same dose or you will titrate. And so 2 of these patients were with permanent Afib and one of whom reported palpitations that required adjustment of their background medical therapy for rate control. There were no clinical heart failure events. And this is very important for us because when we say that someone is on a certain dose, especially when you're pushing the dose in a dose study [indiscernible] to 15 milligram, you [indiscernible] to look at also how they're doing and how they're feeling. And there were no clinical events of heart failure with those patients. And then as you recall, by Week 10, we stopped that drug, and by Week 12, all these patients had returned to the baseline LVEF. Next slide. These are the changes in NYHA class. So this is very encouraging for us. We had the luxury of having many clinical trials now in HCM [indiscernible] reporting on the effects of NYHA class, which is [indiscernible] to 35% or so in those trials. You can see here from baseline, as we mentioned, [indiscernible]. And then as we progress through the study, you can see an increase in the presence of patients who have Class 1 and 2 and a decrease in [indiscernible]Class 3. This translates to a 54% improvement in NYHA [indiscernible] in these patients, which is, again, exciting for us and significant. The other point to highlight is that it's somewhat easier to move patients from NYHA class [indiscernible] than moving from Page 1 or 2 to 1. We provide you get some numbers. They're small numbers, but they're very encouraging because when someone in the NYHA Class 1, they present to you and I have no sense regardless of what I do, and that's not easy to achieve at the [indiscernible] these patients been dealing with this disease condition for many, many years without any treatment [indiscernible]. Next slide. NT-proBNP, which is an important matter for us. It's a matter of increased wall stream, but more importantly, it's been associated also with stability with disease burden and with outcome. As you can see, we're going from a high value of about 1,200 and over the 30 period and the visits, you can see how risk down by about 55% to 56% by week 10, and then there's, of course, a recon that we expect. Next slide. Similarly, for high [indiscernible] your range here is past. So Troponin in the elevation is not as much as [indiscernible] when it comes to patients with nonobstructive tropic cardiomyopathy. And so here, remember the baseline was about 28 or so for Troponin, and you can see a proportionate increase in Troponin over the study period starting from as early as week 2 with the proportionate decrease all the way out to week 1 and then you see that soman these were significant as well. The summary, if I remember of weekend about 21% of that decrease on this line. Next slide. So in conclusion, REDWOOD-HCM Cohort 4 is the first study exploring dosing and tolerability of aficamten patients with nonobstructive HCM. Aficamten was well tolerated. We pushed the drug to 15 milligrams in the majority of the patients. There were more dis-reduction in every year and the response to significant in terms of improvement NYHA class reduction in core biomarkers and burden of [indiscernible]. And FOREST-HCM, we will have an opportunity to look at the 20 milligram these patients that important. And so, these results afford our progression to our larger, longer-term Phase III trial of aficamten in our strategy next year. And now I'll turn it over to Dr. Saberi, who's joining us online, to present data on FOREST-HCM.

Thank you, Dr. Masri. Can everybody hear me okay?

Yes.

Okay. Great. I'm assuming that the slide that you see is the first one from the FOREST-HCM Long-Term Efficacy and Safety of Aficamten in Patients with Symptomatic Obstructive Hypertrophic Cardiomyopathy. Is that correct?

Correct.

Great. Next slide, please. The disclosures that I have to report that I have received consultant fees from Bristol Myers Squibb as well as recut grants from BMS, Cytokinetics, Novartis, and Actelion for clinical trials that we are participating in. Next slide, please. So Dr. Masri has already spoken a little bit about hypertrophic cardiomyopathy and everybody in this room is certainly familiar. But just as a reminder, our understanding of hypertrophic cardiomyopathy is a disease process is really expanded in the last 15 years, where we used to think that this was really just a disease of hypertrophy, what our understanding now is that it's really a disease of hypercontractility and that the hypertrophy that we see is just a byproduct of that hypercontractility. It's also noted to be associated with abnormal relaxation myocardial fibrosis and about 2/3 of patients have left ventricular outflow obstruction. Current standard of care first-line therapies for obstructive hypertrophic cardiomyopathy have included beta blockers, calcium channel blockers and disopyramide, none of which actually address the underlying pathophysiology of the disease. Next slide, please. Aficamten is a next-in-class cardiac myosin inhibitor that's in development for treatment of hypertrophic cardiomyopathy. And it does address the underlying pathophysiology. It reduces the hypercontractile that underlies hypertrophic cardiomyopathy. It's been shown to be safe and effective in lowering resting and Valsalva outflow tract gradient, improving heart failure symptoms, improving patient-reported outcomes through the Kansas City cardiomyopathy questionnaire as well as biomarkers of wall stress and myocardial injury. FOREST-HCM, which was the former REDWOOD-HCM is an ongoing open-label extension study for eligible patients with obstructive or nonobstructive hypertrophic cardiopathy who had completed the parent study of aficamten. And here, we're going to report the interim safety and efficacy data of aficamten in patients with obstructive HCM in the FOREST-HCM trial over a 48-week period of time. Next slide, please. This is the study schema. So patients, like I said, who had completed one of the parent -- sorry, not on of. The parent study of aficamten and whose baseline ejection fraction was at least 55%. We're eligible to continue on to screening for the forest study. At day 1, patients were started on aficamten and had an opportunity to have dose changes at weeks 2, 4 and 6 based on echo-guided titration that's managed by the site PIs. And that titration is dependent on ejection fraction assessments as well as assessments of outflow gradients. Patients underwent cardiac MRI at enrollment and undergo cardiac MRI again at week 48, 144 and 240. We do not have that data to share with you at this time, but are excited to find this data in the future. They also underwrite cardiac rhythm monitoring at baseline, and then that also occurs at week 48, 96, 144, 192 and 240. Next slide, please. So patients were initiated on aficamten 5 milligrams a day and the dose was adjusted between 5 and 20 milligrams at 5 milligram increments, -- like I said, based on site-read echo-assessments of ejection fraction and basal gradients. So the dose could be increased if the ejection fraction was maintained at least 55% and Valsalva gradient were at least 30 millimeters of mercury. The dose was decreased if the ejection fraction was less than 50% regardless of the Valsalva gradient and the medication was either discontinued or the dose interrupted if ejection fraction is less than 40%. We'll be talking a bit about septal reduction therapy later. So I just want to let you know that the septal reduction therapy eligibility criteria were what's recommended by the ACC/AHA guidelines, and that's the presence of New York Heart Association Class III symptoms along with a peak gradient in the outflow tract of at least 50 millimeters of mercury, and that's either resting or dynamic. Next slide, please. So from May of 2021 through September of 2022, 45 patients with obstructive HCM were enrolled. And these are some of their baseline characteristics. Mean age is 59. 60% of the participants are women. It's an overwhelming Caucasian study population with 93% white. They are symptomatic and pretty well split between New York Heart Association Class II and Class III. The average time since the initial HCM diagnosis is about 5 years, and the vast majority are treated with what we consider at this point to be standard of care therapies with the majority being treated with beta blockers and then a smaller proportion that are treated with calcium channel blockers and disopyramide. As expected, they are quite hyperdynamic with a mean ejection fraction of 69% at baseline, and they have obstruction. So the rest in gradients are about 50 millimeters of morphine Valsalva about 80 millimeters of mercury. 19 of the 45 patients, so 42% met eligibility criteria for septal reduction therapy at baseline. Next slide, please. This is a presentation of the range of aficamten doses that have been achieved at various times throughout the study so far. So I'd like to just also say that the 20-milligram dose of aficamten was introduced with the protocol amendment that was finalized in December of 2021, about 9 months prior to this data cut. So that was not really available in the first couple of assessments here. But you can see that the majority of patients were already at a 15-milligram dose by week 6. And as that 20-milligram dose became more and more available at sites, we start to see a creep down of the 15-milligram dose and a creep up of the 20-milligram dose. So, by week 48, about 1/4 of patients are on the 20-milligram dose and other roughly 1/4 of patients are on the smaller doses at 5 and 10 milligrams a day and then about just under half or on the 15-milligram dose. Next slide, please. This is a representation of the effect of aficamten on the outflow gradient, so Panel A shows you the resting gradients and Panel B shows you the Valsalva gradients. The green line here is the Core Lab interpretation of the gradients and the black line is the site interpretation. And I would just like to point out that these 2 lines pretty much overlap or mirror each other. There's not a lot of differences between the site red interpretations and the Core Lab interpretation. If you focus just first on Panel A, you'll see that there's a rapid decline in rest ingredients from the initiation of aficamten by 2 weeks and down below 30 millimeters of mercury by 4 weeks of medication initiation and why that 30-millimeter mercury dash line is important because that is the cutoff for defining somebody as having obstructive hypertrophic cardiomyopathy or not. By about 6 weeks of treatment, the rest ingredients are well below 20 millimeters of mercury on average. And you can see that this reduction in resting outflow obstruction is maintained and actually even declined a little bit more through week 48. From baseline, we see about a 32 millimeter mercury reduction rest in gradients, which is huge. Now if we turn our attention over to Panel B, we're looking at the Valsalva gradient on the same thing. So we see that the site lab and Core Lab interpretations of the outflow peak pressure ingredients are really the same. And again, we see a dramatic fall in the Valsalva gradient by the second week of treatment. And this dash line of 50 indicates what that cutoff is for being eligible for septal reduction therapy. And you can see that we really -- the mean gradients really fall down below that 50 millimeter mercury mark within a month of treatment. And those reduced gradients are actually maintained throughout the entirety of the next 40 weeks. There is a nearly 50 millimeter mercury reduction in Valsalva gradient, which, again, is really dramatic. Next slide, please. This is a presentation of the effects of aficamten on the left ventricular ejection fraction. So again, what we're seeing is the green line is the Core Lab interpretation, the black line is the site red interpretation, and there is a small difference between the 2. And interestingly, the site red interpretations are a bit more conservative in terms of the ejection fraction assessments than the Core Lab interpretations was kind of consistently about 5% less in the site red interpretations as compared with the Core Lab interpretations. Again, at baseline, the patients were quite hyperdynamic with ejection fractions right about 70%. And you can see that there is a small reduction in the ejection fraction by about 4 weeks from -- I mean, about 70% down to about 65%, which is still well within normal limits and that, that mean is pretty much maintained through the rest of the study period. Next slide, please. There's a significant improvement in New York Heart Association class through the 48 weeks of study. So you can see that at baseline, like we had said before that the patients are pretty evenly split between New York Heart Association II and Class III symptoms. And by 12 weeks of treatment, 45% of patients were New York Heart Association I. And by 48 weeks of treatment, 60% of patients were in New York Heart Association Class III. And importantly, there were no patients that reported New York Heart Association III symptoms by 48 weeks of treatment. 88% of patients by 48 weeks experienced at least 1 class functional -- sorry, a one functional class -- New York Heart Association improvement and on had worsening symptoms over that time. Next slide please so 19 of our patients, 42%, had been eligible for septal reduction therapy per the guideline criteria and that was despite receiving optimal medical therapy. And by 48 weeks, none of the patients that had reached that time point actually met that criteria. Next slide, please. NT-proBNP decreased significantly, 70% reduction from baseline to week 48, going from a mean of $651 to a mean of 111 during that time. Next slide, please. Aficamten was well tolerated. There were no treatment-related serious adverse events reported through week 48 of treatment. One patient underwent a temporary dose reduction, and this was a site error related to QTC that was interpreted as being prolonged at the site, but the Core Lab interpretation of that EKG actually revealed normal QTC and the patient was resumed on the Aficamten. The other was a temporary dose interruption in a patient who had recurrent alcohol-induced atrial fibrillation, which he had had a history of prior to initiation of the study is ejection fraction in the setting of this clinical instability was 47% and then normalized after dose interruption, he was able to restart on aficamten. Next slide, please. So in conclusion, this is a long-term study that shows that treatment with aficamten patients with obstructive hypertrophic cardiomyopathy could be actually appropriately managed by investigators and was shown to be safe and well tolerated through week 48, and treatment was associated with the rapid and sustained improvements in echocardiographic hemodynamics paralleled by significant improvements in New York Heart Association class. Aficamten was shown to be able to eliminate SRT eligibility in patients who had previously been guideline eligible at baseline. There were no instances of systolic dysfunction with ejection fraction less than 50% that we could attribute to aficamten. So these data really do support the continued development of aficamten, which is currently being investigated in the Phase III clinical trial, SEQUOIA and planned as a head-to-head comparison of aficamten against metoprolol in the future. Thank you for your attention.

[Operator Instructions] I'll ask the first question, though, you for questions you'd like to ask, and we'll direct you to Dr. Masri. You enrolled a reasonable number of patients in the NHCM study. I wonder if you can give all sense of what your experience was in this space -- and what they also felt that are perhaps a little harder to discern from [indiscernible] class as another better network product base.

Excellent question. So we've enrolled 11 patients in the study out of the 41 patients for the role. And it's interesting that in nonobstructive HCM, the phenotype and elite are more consistent over time we see them since we have no intervention. And so these patients are seen over and over at the clinic over the years that is consenting reported and what you find in your exercise testing and everything, then you take these patients significant burden and you enroll them in a trial, and they fail to well and they report how to take on the drug during the study and the price expired to them during the all-share that they asked can this be actually short in or kit because they want decision to go back on that [indiscernible] that's so as possible. And I think this is important because in a lot of scenarios, we don't actually have that maturity of knowledge. In many trials, we enroll it. Patients present new diagnosis communication [indiscernible] the first time that you offer the study and your role. And here is the difference where we had large a longitudinal relationship with the patient understood their net history. And then we enrolled. That's why we're excited about the [indiscernible] HCM, I got to say about the effect that we have seen. And we have -- despite the fact that it's a short study with many businesses, we actually have not had any complaints about that, which tells you that patients are [indiscernible].

Thank you Dr. Masri. Questions in the room?

[indiscernible] Thanks for the presentation and [indiscernible] update. So maybe for Dr. Masri, as you think about the rollover of those HCM patients and so forth, do you anticipate that patients could experience added benefits from a higher available dose? And how much of a role do you think based on some of the experience in symptomatic [indiscernible] that the removal of beta-blockers might also help and sort of getting patients maybe to that dose or just receiving greater [indiscernible].

Thanks for the question. So for your first question about the higher does, we will find that. That's why I really like the design of products that allows the indicators to push the drug to a higher maximum level of 20 million. That would be a lot also on tackle HCM. In general, if you think about it, while we -- in this cohort for Phase 2, it's a [indiscernible]. So we're going to push the drug to stimulate see what's happening. Now as far as there's more flexibility, so you're going to incorporate how efficient is doing, what is going on and how [indiscernible] biomarker that was not. And I already have patients with 20 milligrams [indiscernible] with no structures because there is a rollover fitter, [indiscernible]. And so again, this is important because if the patient still [indiscernible], you want to [indiscernible]. I can tell you, again, from the experience of the trial, and you saw that [indiscernible] graph as well. Patients do start deriving [indiscernible] and again, important because in a way which is taking some of our assumptions that in nonobstructive HCM, you need to do a very long treatment period before you see a [indiscernible]. We didn't see that the [indiscernible] a gradual improvement incentive early and more important [indiscernible]. So the short answer is, yes, I think the 2 milligram would be [indiscernible]. Your second question was about [ data markets ]. Again, as I mentioned, there's no evidence that they actually were in nonobstructive HCM. I can tell you from [indiscernible] experience in at least my patients for patient being on, and we have a large [indiscernible]. When you essentially try them, you keep the patients on them when they feeling okay. But some people don’t [indiscernible] or don't realize they actually are slowed down by the [indiscernible]. That's why exactly we are attempting to withdraw beta-blocker, and [indiscernible] FOREST-HCM. Again, the FOREST-HCM is not empowers the [indiscernible] to decide what they want to do for patients within the [indiscernible] of course, and there are some rules there. So typically, once you're stable with aficamten, we do withdraw the [indiscernible]. And we are already deciding and we've actually done it in some patients with one of takes was already that by the time they cross week 12 and the state goes in parts, we do withdraw their background [indiscernible]. And we have done the [indiscernible] obstructed HCM [indiscernible] we've seen some in on this previously. So I do believe that it's important to intend to do that and see how patients improve as they will like between [indiscernible].

Just maybe one more for Dr. Saberi. You provided some presentations on the longer-term benefits from [indiscernible] at a conference and a duration longer than the sort of RTT studies. When you noted how you didn't expect normalization of the heart with these sort of treatment, how should we then think about cardiac [indiscernible] inhibition as a tool of prevention of heart pace? And what sort of evidence would motivate you to why don't you explore this and maybe a [indiscernible] or even earlier stage disease patients.

Thank you for that question. Yes, I mean, I'll point out again that the [indiscernible] age of the participants here is 60. And while the time since initial HCM diagnosis was about 5 years, we know that HCM is very underrecognized and that there is a significant delay from the time of symptom onset to the time of actual diagnosis. My own kind of observations, and I think it's supported by the literature is that patients who are diagnosed, younger have more advanced or more severe phenotype, and that's really related to the penetrance. And I think the [indiscernible] at least the data that we have seen with mavacamten shows that there are structural changes that occur with mavacamten through the cardiac MR substudy. Even with just a 30-week treatment course and again, in a patient population that already has kind of well-defined left ventricular hypertrophy, other structural changes, such as left atrial dilation. I don't think that we're going to be able to take a 20-millimeter septum and make it 10. I don't think. Now that doesn't mean that it's not going to happen. We're already surprised by the effects of mavacamten just with a few months of treatment that we even saw the structural changes that we did. But the fact that we see those structural changes with mavacamten is what's the most hope filling kind of promise for me and for the future is that, again, it harps back to this understanding of HCM now as a disease of hypercontractility. And I will say that in my patients who are genotype positive phenotype negative, meaning that I don't actually detect left ventricular hypertrophy, either by Echo or by cardiac MRI. A lot of them already have hypercontractility. Their ejection fractions are hovering 70% and above. So while that finding is not within the current definition of hypertrophic cardiomyopathy, my personal belief is that it should be and that these patients are already seeing the effects of the genetic change and that the hypertrophy is a later development than the hypercontractility. And so if cardiac myosin inhibitors can be actually implemented far earlier in the disease process, if we can extrapolate the findings from the CMR sub-study of mavacamten, then it leads me to believe that we may be actually able to prevent and significantly delay the progression of the hypertrophy and all of the other consequences that happened thereafter in terms of myocardial stiffness, diastolic dysfunction, relaxation abnormalities, left atrial dilation. So I actually think it makes the most sense the way that these studies have been laid out. Meaning we have been investigating the effects of these agents in patients who clearly have disease and oftentimes have had disease for a decade plus. But where the -- in my opinion, where the likely biggest impact for patients themselves will be in thinking about how this disease affects them and their families. My hope is actually that these medications can really be implemented in way younger patients and hopefully pediatric age patients in order to prevent everything that I see as an adult cardiologist.

How much [indiscernible] I think Dr. Saberi noted. The earlier recognition of disease provides an opportunity for early intervention. And it ultimately will be up to us to show that that's meaningful. But there is precedent if you think about treatment of hypertension in either the regression of left ventricular seen with certain treatments that lower blood pressure and patients that have established LDH or that goal really is to prevent the development of left ventricular hypertrophy perfect by treating the underlying seamless of it, which in the case of hypertension and high blood pressure. So heart clearly had some capacity in the model, and that's very good. We've seen that where longer-term data are available with mavacamten, and I think it will be an important objective of this program to establish that down to growth. Other questions in the room?

[indiscernible]. My question is, can you talk some about the design characteristics of mavacamten? what's your commercial strategy here? And would you be looking to enter [indiscernible]?

Yes. So I'll take that question. [indiscernible], for those of you that don't know, is a study that we plan to start in the first half of this year that we'll look at aficamten as monotherapy against beta-blocker is monotherapy, beta-blocker being [indiscernible]. And so it gets to the question, many patients are on monotherapy with beta-blocker. [indiscernible] and Redwood for us and many of them are studied on top of the beta-blocker. But beta-blockers have a number of symptomatic adverse consequences to patients as well as a blood heart rate increase, and so they actually reduce the ability for patients to exercise to a greater extent. And so what we wanted to do is establish quantitative, randomized data that we look at the magnitude of the treatment effect of the cardiac myosin inhibitor, [indiscernible] versus [indiscernible]. So we haven't given a lot of details of the study, but in general, it will be a look at randomization, 24 weeks of treatment using PCO2 as a primary outcome and other symptomatic measures are fairly similar to what you see in SEQUOIA. What we hope is that should the results be supportive of it, then it provides the basis for thinking of cardiac myosin inhibition as first-line therapy, superior results, superior adverse event profile, superior sensitive improvement and so ultimately, with that evidence and perhaps also looking at modeling over time, whether you see that with beta-blockers or whether you only see a mic inhibition may provide the emphasis we're deciding where to position or a physician in inhibition as first line therapy.

Just to follow on, you asked a question about that as it might pertain to commercial readiness strategy. And after we close here, I'll introduce you to our Chief Commercial Officer, sitting in the back of the room. But just to highlight, we see this as consistent with an expectation that aficamten may ultimately contribute to an expanding of what could be deemed the category and ultimately, where this class of medications may be used by experts in the specialty cardiovascular. We not necessarily primary care, as I think to averted, but perhaps where other cardiologists do an outside of HCM centers and they ultimately get comfortable with the use of a myosin inhibitor in particular, aficamten for patients who had presented symptoms.

Okay. Well, no questions in the room. We'll turn to see there are questions on the call. Operator?

[Operator Instructions] and our first question will come from Ash Verma from UBS.

I have 2. First one, so in the cohort 4 data for the 3 patients that you saw the ejection fraction go below 50% at the week 10, like how long did it go? Just curious to understand the dynamic there. And then just like broadly about this nonobstructive side of things, like what percentage of these patients are symptomatic, is symptomatic percentage kind of below where what we've seen obstructive. Is this a market segment that can lend itself to expanding diagnosis over time, like you've described the obstructive market?

Let me get 3 questions. Maybe I'll add a Dr. Masri the first one has to do with the resolution of the less than 50% [indiscernible].

Sure. As we mentioned that there were 3 patients with LDS they were probably obviously in the [indiscernible] range, and they were on the end of study on treatment. These patients were not symptomatic. So which means they were not more symptomatic than they already been so they just showed up for an echocardiogram, as the echocardiogram hey stop the treatment that we can and then it was reported on the [indiscernible]. So this is a numerical [indiscernible] nonclinical presentation from [indiscernible] or systematic presentation. And as we mentioned by week 12, everybody here went back to [indiscernible] accessible range. And one has to realize the evaluability and rejection of action quantification, especially in patients with actual [indiscernible] 2 of these patients with a ratio and that changes your [indiscernible]. We're doing a single assessment time point and it depends on where we choose in the correct between [indiscernible]. So all of this needs to be taken into account. The way I think about this person the patients have spent [indiscernible]? Do they complain? Do they have an adverse [indiscernible] because of that low [indiscernible] number? Or you saw something on an echo and then you adjusted your treatment contain and the ability to be doing well at this or [indiscernible].

I believe we had really no treatment interruptions due to low ejection fraction. It's really, as Dr. Masri said an adjustment of dose sort of the case of these patients or a can study the use drug. Your second question, if I -- comparators correct me if I'm wrong, [indiscernible] really compared symptom burden in the nonobstructive patients for obstructive patients. And maybe I can ask Dr. Masri to comment on that as well.

Sure. So when you think about non- obstructive HCM, it's a largely underdiagnosis even much more than obstructive HCM because you don't have the whole mark that essentially tells the practitioner the finish that is actually a problem. So when someone listens to someone's checks with [indiscernible]to an echo and you have obstruction it is easier [indiscernible] because the obstruction levels, this could be HCM. Nonobstructive you have at particular hypertrophy without obstruction. So you can plan anything you want from hypertension to rise into all other things. And that leads to patients presenting typically after multiple rounds of contactless than complaints. They come and go. You have no treatment and servo condition and there is specifically delayed diagnosis. And so in terms of symptoms, there are some patients who are asymptomatic and there are patients who are chronically symptomatic and debilitated by conditions. So the difference from obstructive HCM is the acuity of the presentation, in obstructive HCM typically patients who are found to have the obstruction with the disease burden of [indiscernible], you find that within months to maybe 1 to 2 years on average by the [indiscernible]. Patients would then also understand has more of a chronic stage of having [indiscernible], and they are typically limited. Now if you look at an outcome of that, obviously, it drops very common in nonobstructive HCM or obstructive HCM for that matter. I think patients are limited exercise capacity, and they have a lot of symptoms that they like that and just how they live accordingly. And so -- and that's actually a reflective of the data that you see as the patients will in that.

Just maybe the interest of time, operator, I'll see if there are other questions on the line.

[Operator Instructions] And we'll take our next question from Rohit Bhasin from Needham & Co.

This is Rohit on for Serge. The cohort 4 results appear compelling, how should we think about potential placebo rates for NYHA improvements based on other studies?

Well, prior to this in prior [indiscernible]. In prior we've seen placebo rates of class improvement of about 30%, 35%. In fact, in the forest data, the poster we calculated the p-values assuming a placebo event rate of about 30%. And so these statistics are calculated against a background placebo rate that we've seen more than one study now that about that range.

Our next question comes from Jeff Hung from Morgan Stanley.

For Dr. Saberi and Dr. Masri, if you want to comment, where does the 100% of patients becoming ineligible for septal reduction therapy rank in importance relative to other aspects of this weekend FOREST-HCM data.

Dr. Saberi, do you want to comment on the resolution, if you will, of these patients needing criteria for septal reduction therapy for us.

Sure. I think that it's actually very important. If you think about from a patient perspective, what the effect of undergoing an open-heart surgery would mean for them in their lives. And that's not a small bit. We're talking about 2 months of being out of work. We're talking about patients being able to afford the cost of the surgery. And we actually already know that just because a patient undergoes septal reduction therapy does not mean that they're going to be a one and done essentially situation, meaning that there are a significant proportion of patients, and I can attest to this just being in the clinic that undergoes septal reduction therapies with or without mitral valve repairs who years later, will develop recurrence of obstruction, oftentimes, in my experience, it's not necessarily in the outflow track, it's deeper into the ventricle, and it relates to the underlying hypercontractility of the ventricle. That surgery does not actually affect the hypercontractility, the underlying pathophysiology of the disease. So if we can use medications that actually address the underlying pathophysiology of the disease, they may actually be more effective in the long haul for patients than the mechanical dealing with just one section of the heart causing a problem, but leaving the entire heart still diseased.

Our next question comes from Carter Gould from Barclays.

Maybe one for Dr. Saberi. Just going back to your commentary on the structural changes you've seen with the class and you highlighted the CMR data. You do not see really an impact in fibrosis in that study. Is that more a reflection of the amount of fibrosis, the small sample size? And I mean, I guess, a bigger question around the classes effect on reversing fibrosis in this setting. And then maybe cytokinetics can just comment on the imaging component of SEQUOIA, and it sounds like it's Maple as well based in [indiscernible].

Yes. No, we'll definitely have cardiac MRI data to share with aficamten in the future as well. But what I can say is we do not have the capability of turning scar fibrotic tissue back to muscle. So I don't actually expect that we're going to see any regression of fibrosis with these medications. The hope is that with correcting some of the underlying pathophysiology that we would see a decline in the progression of fibrosis. Now in the mavacamten assessment so far, we have seen in the 96-week cohort data that I presented a small in there an absolute [Technical Difficulty].

We're losing your sound [indiscernible] Dr. Saberi.

[Technical Difficulty] For those you in the real apologies for the Wi-Fi challenges, you don't think that people on the line [indiscernible]

Our next question will come from Charles Duncan from Cantor Fitzgerald.

I was going to address this question to Dr. Saberi but I think I'll actually do it for Dr. Masri. But relative to Dr. Saberi's presentation, I'm thinking Slides 26 to 29 really the data slides, I'm kind of -- a picture tells a thousand words, guy. And so when you consider the LVOT NYHA class change and SRT eligibility change? I'm kind of wondering if you can tell us what stands out most to you? Or is it really just the ease of use of aficamten in this cohort versus perhaps other candidates or other drugs that are -- have been developed for this indication.

[Technical Difficulty] Dr. Masri comment on manufacturing the lack of patients [Technical Difficulty] impressions of that.

Thank you for the question. I think when you think about it, [Technical Difficulty] if you think about coming with more and the fact that [Technical Difficulty] being that they're still expected that you don't have significant obstruction anymore. Obviously, it's very that the drug [Technical Difficulty] doing so using, which has been shown over and over here [Technical Difficulty] aficamten. But the second point is, as you mentioned, is of use. This comes into play when the patients are [indiscernible]. It doesn't just mean that you no longer agents that you don't want to [indiscernible]. You could still decide to process [indiscernible] can happen with both drugs. The fact that the patients still continue and want to continue means, one, they have essentially enjoying how they're feeling, 2, they don't see a burden that they would want to withdraw back and change their mind. And to your point is, when a drug becomes commercially available, this comes into play when patients are making their decision and deciding on undergoing [indiscernible] it is not only what the [indiscernible] also how the patients are doing and feeling and also the age use and days of follow-up pay very important [indiscernible]

Our next question will come from Jason Butler from JMP.

Robert, you mentioned the fact that you had studied ECHOs in the study. Can you talk about the importance of those data and when we might see them.

I'm guessing you're referring to Cohort 4 in HCM?

Yes.

Yes. I'll turn that over to Fady. These are the initial data sets from Cohort 4, and you can speak to when we might have additional data coming.

Yes. So I think the as Dr. Masri noted in his presentation, we really have just finished these patients through the site is something that's assessed as a safety metric very quickly. The rest of the metrics takes more time and analysis. So we'll have more detailed echo information percent think of the first half of this year as another medical conference. There's also KCCQ data that was collected in the study that will also be included in the later presentation. So I think you'll see an evolution of the data over the next weeks or a couple of months.

And in parallel with that, we're already, as we noted, proceeding towards ready to start a Phase III study, and you'll get more details on the design and conduct of that Phase III study as we move into the middle part of the year.

Our next question comes from Salim Syed from Mizuho.

I guess one for me on Phase III dynamics here, Fady. When we look at the [indiscernible] proBNP chart that's in the Cohort 4 poster, it looks like you may actually have a faster onset of action on NT-proBNP versus mavacamten and that's in line with what we saw in gradient in OHCM. So just curious if you're thinking about 52 weeks being a relevant time marker on peak VO2 is Bristol's Odyssey study is designed? Or do you think perhaps you'd be able to see something quicker on peakVO2?

Thanks for the question, Syed. I think at this time, probably I'm not going to comment on what we're thinking in terms of duration of study for Phase III. But your point is the most important one is that there is a rapid resolution of biomarkers and also these patients reach their state dose, if you will, approximately 6 weeks. So a factor in for.

Congrats on the data, guys.

Our next question will come from Yasmeen Rahimi from Piper Sandler.

Congrats on both presentations. My questions are directed to Dr. Masri. Did you -- I know in the study measured KCCQ, but it was not reported maybe what did that measure look like? We also didn't see any details on PVO2 cardiac structure and mechanics measurements, such as lobby and lateral inceptual [indiscernible]. Any comments there on those measures? And then also it would be great if you could just put into context how this data compares to what we have seen in mavacamten in the nonobstructive population and I'll jump back into the queue.

Maybe I'll just clarify a couple of things. First of all, we didn't measure PVO2 in this study, yes, we focused on symptomatic changes in biomarkers, including KCCQ. And as I said earlier that KCCQ forthcoming. Dr. Masri, do you want to comment on what you think the ECHO data might show.

Yes. So in terms of the ECHO data in general, this is a heavy study. So you want to keep that in mind as you start evaluating structural change. And so if you start seeing the [indiscernible] structure change, we work on that, although [indiscernible] you're not going to be able to derive under preclusion from what would happen. However, these patients had elevated into kind pressures. And so as you are modulating contractility is coping the [indiscernible] and things you might be something there of some indirect measures of this innovative [ entropatic ] pressure. In terms of your other questions, I think it's always difficult to compare across different studies. I think my focus is mainly related to Cohort 4, showing early and continued improvement [indiscernible] I would have expected personally as being more in all these studies. That's beyond what I had expected to see from a myosin inhibitor over a short period of time. And this is why it's encouraging to me as well as the effect on the biomarkers as well as the safety profile of the drug is also in testing that we're going to be progressing [indiscernible].

Fady, just a clarification. Why is the KCCQ measurement not complete? Is it just because it takes time to get all the answers and analyzed or just didn't make it into the poster and therefore, not like maybe just color on why we didn't have it this morning.

Right. And on the KCCQ, it just requires more analysis. It's a multi questionnaire survey, there are lots of domain. So it takes a fair bit of analysis where NYH class is pretty simple. It's 1, 2, 3 or 4 and it is easier sort of put together. So given the timing of the data, KCCQ will come out a bit later, like the ECHO data, which also are more complicated sale. So we wanted to get you something which we did a little bit some of the more complicated data will come out a bit later.

And our next question will come from Srikripa Devarakonda from Truist Securities.

Congrats on the presentations. Dr. Saberi commented about starting earlier and that having biggest impact in younger patients and constructive CM, Dr. Masri. I was just wondering, based on what you've seen with the nonobstructive patients, does this apply to those patients as well? And what would it take for that to actually happen?

I'll ask Dr. Saberi to answer that question in terms of you made your comments about potentially starting earlier in the course of the disease of OHCM. Do you think it applies to HCM and what do you think we might need to do in order to do that?

Sure. I do think that it would apply to patients with nonobstructive HCM as well. The finding of obstruction versus not is not necessarily defining a different disease process. So it's the same disease process. It's just really a matter of where is the majority of the hypertrophy. And is it basal enough within the ventricle that is actually causing outflow obstruction. So in my mind, it's the same exact disease no matter whether you have obstruction or not. And I expect that the same exact outcome would be seen as the patients with nonobstructive disease that if we were to be able to implement the drug earlier in the disease process, we would see likely less of a hypertrophy burden and left atrial dilation and some of the other kind of complications that occur from the diastolic dysfunction that's a function of the disease itself.

Great. And then in your presentation, you talked about not paying any instances of LVF less than 50%, especially in the longer term 48-week data. I was just wondering if this has changed perspective in terms of potential for REMS program, for aficamten in any way, maybe a tough question to answer at this point, but just wondering if you're seeing this as a safe drug.

Maybe I can just rephrase that because I think it runs programs is really in the regulatory domain. But I think the real question you're getting at is what given you've seen in [indiscernible] do you think ongoing monitoring ejection fraction, things like that to think the necessary from a clinical point of view.

So it's -- I guess, to put it into context, the MAVA-LTE data presentation at the 2021 ACC. So we don't have a manuscript to be able to kind of compare with. But Dr. Rader had presented data through week 60 in at ACC 2021 in patients with obstructive HCM that were treated with mavacamten. And at that point, they had had 4 patients with an LVEF less than 50%. And that range had been 44% to 48%. By contrast, with our data, we actually have seen 0 patients with an ejection fraction less than 50%. So I can't influence regulators and their decision-making in terms of this. But I think this contrast actually is a step in the right direction. And if we continue to see this type of data come in, in terms of safety and a lack of a significant decline in LV systolic function that regulators will actually see that as a defining difference between aficamten and mavacamten and perhaps they'd be more open to a less stringent rent. But it [indiscernible]or them.

And we'll take our last question from Madhu Kumar from Goldman Sachs.

So we just wanted to know what the correlation was between NT-proBNP and cardiac or cone declines in NYHA class improvement? And then what dose were the 3 patients who had left in [indiscernible] below 50% in week.

Okay. So 2 questions there. I think correlations between NT-proBNP [indiscernible] and class improvement, those analyses for alone done yet for this study, but maybe Dr. Masri you want to comment on how you think those might could correlate?

Yes. As you mentioned, more analytics was not coming from the data set. But in general, based on our experience, as you influence patient symptoms and they feel better. You see a reduction in [indiscernible] and you see a reduction in troponin where you started with these biomarkers is very important. I know everyone like summary numbers, but the reality is you need to look at the individual patient data on to [indiscernible] as well and thinking about how they're doing. And these tend to correlate, but also depend on what other comorbid to the patient. Sometimes patients have increased clearance of these biomarkers. You are still doing this over time, but a lot of these things are dynamic, including kidney function can be dynamic in threshold situation exercise intensity. Some of these patients and they see much whether they start sending a lot more. And when they start a lot more some of these biomarkers can actually fluctuate [indiscernible] and in general, they do quarterly fairly well, but the range of -- that you have with NTT correlating with NYH [indiscernible] is a more tight range in terms of pollution because of how wide some of the efficient satiation of [indiscernible], that's a lot more typically than troponin. I can tell you in most practices, people follow more NT-proBNP, a few practices follow troponin, we follow troponin because it helps us tremendously in avoiding unnecessary cap by patients piece. But troponins are very important. They predict outcomes, conditions with HCM. However, there is correlation with [indiscernible] is not as high as of NT-proBNP.

And I'd like to turn the conference back over to Dr. Fady Malik, for any closing remarks.

Great. Well, I'd just like to thank everyone for the dynamic discussion today and all the questions and all the interest. As Robert said at the outset, we're pleased with the data emerging from REDWOOD-HCM and FOREST-HCM, and we look forward to beginning additional Phase III clinical trials in patients with obstructive and not instructive HCM as we continue to elucidate the potential of aficamten in patient engrave need treatment option to address the underlying hypercontractility that is present in this disease. So with that, operator, we can conclude the call.

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