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 and that all participants are in a listen only mode. At the company's request, we will open the call for questions and answers after the presentation. We will allow up to 2 questions per participant. 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, focus on the full results of Redwood HCM, the Phase II clinical trial of apicamten, 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, Fat Malik, our Executive Vice President of R and D, will discuss the next in class properties of apicamten and how it was designed to optimize Then following these introductory remarks, we are honored to have an esteemed physician panel, including Doctor. Martie Marron, Director, Hypertrophic Cardiomyopathy Center at Tufts University School of Medicine and the Principal Investigator of Redwood HCM, who will present the full results and Doctor.
Ahmad Mazri, Assistant Professor of Medicine, Division of Cardiovascular Medicine, School of Medicine, Oregon Health and 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, Doctor. Marron 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 Doctor. Marron will elaborate, the combination significantly reducing resting and Valsava 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 augers well for the potential clinical utility of afacamten as now should be further tested in a pivotal Phase 3 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 2 meetings supportive of progression into our planned Phase 3 trial and we're moving swiftly to get that underway during the Q4 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 apicamten 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 apacamten 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 enafacamten 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 afacamten. 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. Alpha tract obstruction is a strong and independent predictor of heart failure symptoms. And as a small molecule selective inhibitor of cardiac myosin, apacamten 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. Apikamten, 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 drug's half life of 3.4 days allows for that. The reversibility is engineered and directly related to its pharmacokinetics. The molecule is further optimized preclinically with a shallow exposure response relationship.
That leads directly to a therapeutic window that we think is wide and enables us to individually dose suggest 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 has been well tolerated in clinical studies. If you go to the next slide, it just shows the Phase 1 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 PKPD relationship we engineered preclinically translated into humans as the 2 PKPD relationships overlap each other. With that, I'm going to turn it over to Doctor.
Marron to discuss the results of Redwood HCM.
Good morning. Marty Marron here. So this is the clinical trial design, which was a 2 to 1 structure. So for every 2 patients that were enrolled and randomized to afacamten, 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, apacamten, 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 output track rating. So those two 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. Okay.
So key inclusion criteria and endpoints. There's a randomized and blinded dose finding study. As I said, just previously 2 cohorts with 5 overlapping doses between 5 30 milligrams. And this Phase 2 study was evaluating, of course, 1st 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 alco 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, could be a little bit less than patients that had a family history of HCM.
These were symptomatic obstructive patients with NYHA Class II or III and they had to have the gradients, left ventricular pressure gradients of greater or equal to 50 millimeters of mercury at rest or following provocation with Valsalva maneuver. As we mentioned, as Sadi mentioned, these are hyperdynamic ventricles with ejection fractions of 60 percent 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 2, 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 alpha track 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 apicamten group, which is in blue.
Of note, you can see here a rapid decrease in resting gradients within the 1st 2 weeks of treatment. Over the next couple of weeks with dose adjustment period, gradients then decreased and were obliterated continued to be obliterated through the treatment period at the end of the treatment period during the 2 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 1st 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 pool placebo group up top, really no change over the treatment period in provocable gradients. And then once again in the cohort 1 lower dose apicamten treatment arm, rapid decrease in the 1st 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 two slides kind of together and you define a responder in terms of the hemodynamic outcome here, which is the outflow track 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 over the treatment period. Again, similar scheme as the last the other two 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 apicamten 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 apicamten cohort 2 of about 10% decrease.
And then 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 two 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 one or greater improvement in NYHA class over the end of the treatment period. You can see in cohort 2, the higher dose apicamten 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. 2 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.
1st 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 to afacamten and had exacerbation of pre existing 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 apacamten group versus placebo.
In addition, no patient met the stopping criteria for an injection fraction of less than 40%, no treatment interruptions or discontinuations. Treatment emergent adverse events similar between the two groups, as I mentioned. Talking about 2 patients now with ejection fractions that went below 50%, One patient with a baseline ejection fraction of 58% underwent pre protocol, per protocol, per protocol dose reduction at week 4 or an EF that went slightly below 50% with a return of EF to above 50% continued on drug. The 2nd patient with a baseline EF of 70% is noted to have an EF of 49.3 percent 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, afacamten, novel 2nd generation cardiac myosin inhibitor being evaluated here for the treatment of symptomatic obstructive HCM.
In this Phase 2 clinical trial, apicamten over a 10 week period, 10 week treatment period demonstrated elimination or obliteration of resting alpha gradients in nearly all patients, including 90 3% in the high dose cohort. This improvement in hemodynamics was mirrored by improvement significant improvement 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 one greater improvement in NYHA class. And I think this hemodynamic and clinical benefit can be in some ways perhaps attributed to favorable pharmacodynamics here, which include a relatively short path life and wide therapeutic window, which enabled rapid and substantial reduction of the gradient, precise echo guided titration of drug dosing, and in this case, without the need at all for any drug interruption and rapid reversibility that demonstrated after discontinuation of the drug and overall extremely well tolerated, no serious adverse events to the drug and a similar incident of AE with apicamten compared to placebo. And again, to emphasize, no patient discontinued apacamten during the study period.
So I think in summary then, these data strongly support investigating further the clinical efficacy and safety of apacamten in a larger prospective Phase 3 clinical trial, which is intended to begin at some point by the end of the year. Thank you.
Thank you, Doctor. Meron. We're going to have a short panel discussion now with Doctor. Masri and Doctor. Marron.
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 Doctor. 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, mavacamten and now with apacamten.
Based on Redwood HCM results, can you describe how your patients fared? We presented a lot of numbers and 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 afacamten. 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 an assycamten 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 insight that they typically under report how they feel and how things are going for the younger patients. And on the other hand, you have a 70 year old woman who's been busy and light headed for a year before, been toying around with a standard of care background therapy, 3 months invasive options done. And while being rafacamten 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 disease and potentially what the numbers that we've generated here actually translate to in terms of patient benefit. So thanks for sharing those.
Doctor. Marron, a question for you. Can you elaborate on your expectation of how these Phase II results may translate into the clinical setting? Specifically, how do you think the attributes of apacamten 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 apicamten could be an important drug option for symptomatic obstructive patients who are not responding to current first line therapies like beta blocker or calcium gen 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 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 provides them
some Just to make one more comment on that too. I mean, I think just to play that 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 alcoablation. But there are 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, a very important role, I should say, for alternative medical therapy options that could have a benefit, a clinical efficacy that would be as good or maybe in some cases better than the invasive procedures.
Okay. Thanks, Doctor. Mery. Let me turn again to Doctor. 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 and physical exam with an echo. And we do follow them up with echocardiography over time. I think having echo 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 labs. I don't have to wait for other factors that would 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're 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 very important aspect. Well, I think,
and personalize its use. We all know that patient variability is so great and it's always hard to say one dose fits all. And so having a modality like GECO, which as you said in your own hands, you can apply to 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 want to do it. And having a wide range of dosing, you're going to go from 5 to 20, probably in the 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 autocantin.
Well, I think you made an important point there as well that the echo isn't the only thing that you use in your assessments. You listen to the patient, how are they doing, are they feeling better and use that to also temper how what you may implement in clinical practice.
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 a 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. Doctor. Marron, 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 extent of gradient reduction we saw here compares to surgical interventions in patients that you sent to surgery for refractory HCM?
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 apicamten would be comparable to what you would see with surgical intervention.
Now obviously, what we're seeing with apicamten in the Phase 2 study is a short term results, of course. Surgery, to be fair and balanced, obviously, has 40 or 50 years of experience behind it. So we know that those gradient reductions for surgery are maintained. That doesn't mean they're not maintained with avacamten, but at this point, we just don't know the answer to that yet. But in terms of what you asked, the answer is absolutely clear.
The grade A 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 there are other complementary data out there that will inform what's the long term effects of these drugs. Great, thanks. I'll turn it back to Robert for some 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 apicamten. 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 3 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 effective 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.
Your first question is from the line of Carter Gould with Barclays.
Good morning, Carter.
Great. It's Edward on the line for Carter. Thanks for taking our questions. So my first question is for Doctor. Maurer and Doctor.
Masri. If you can kind of give us some color on your impressions of the avacamten data from 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?
So yes, this is Marty Merritt. I'll start and then Doctor. Masri will weigh in as well with 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 apicamten balanced with a very favorable safety profile, okay. So you got gradients, the hemodynamic driver to symptom production in 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 ATM is being exceeded here by these data for apicamten.
There's 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 II 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 or calcium beta blocker. That's the paradigm shift.
Great.
Sorry, please keep going.
No, I was just going to say that Doctor. Mannion 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 he 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 meet the threshold yet to undergo major invasive procedures.
And so that's how the future might change.
This is Robert. I might just add that yesterday when Doctor. 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 cytokinex perspective. Operator, with that, we can turn to the next question, please.
Your next question is from the line of Jason Butler with JMP Securities.
Good morning, Jason. Hi, thanks.
Hi, Robert. Thanks for taking the questions. Just one for Doctor. Marion and Doctor. Masri again.
Just given what we now know from Redwood and also taking the experience from avacamten, how do you think about the risks for afacamten succeeding in Phase 3? What do you think the company should be considering for the Phase 3 trial design to optimize the chance of success?
Well, I
mean, I think extrapolating from what we know from Mavacamten and Xplore and also what we now know about afacamten in Redwood, I think you have to say that the likelihood of success here in terms of a Phase 3 study with this drug in obstructive HCM is high. So I think there would be no other way to conclude that. And so in terms of success, I think that the favorable, maybe more favorable pharmacodynamic profile of afikamten can be leveraged in a Phase 3 study to demonstrate 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 design of the Phase 3 study is to leverage that differentiating feature between mavacamten and apacamten to show increased efficacy with great safety profile in the Phase III study. Does that answer your question?
Sorry.
Yes. Okay.
Thank you, Jason.
Thanks, Robert.
Was there a follow-up, Jason? I'm sorry.
That was great. Thanks for taking the question, Robert.
Thank you. Operator, next question please.
Your next question is from the line of Salim Syed with Mizuho.
Good morning, Salim. Good morning, Robert, and congrats on the data guys and appreciate the panel's color. Fady actually took all my questions. I'm just going to to excuse myself from the queue. Just kidding.
All right.
I actually had a couple
for the panel here to Doctor. Marin and Doctor. Masri. So Doctor. Marin, 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 80s versus mavacamten sort of in the 50s. And safety, I agree, does look better here. Just curious why you're hesitant here to say that 2 seventy four 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 patients 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 beta blockers? Thank you.
Maybe I'll ask You want to maybe start Doctor. Masri and then?
Sure. This is Ahmed Masri. So when you think about afacamten and any drugs that are being put for HBM, you have a population who are in 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 afacantin 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 afacamten.
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 efficacy into it. 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 Merritt here. Just to expand on that too. I think you're asking too, 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 apacamten, 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 apacamten along with high efficacy that these class of drugs with apacamten leading would replace beta blocker and calcium channel blocker as first line agent, I think that's a reality.
Great. Got it. Thank you.
And Selene, just to your first question, I think it's important for us to focus on the data we're generating with apicamten. 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, thanks, Fadi, 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 Martin 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 by afacamten 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 afacamten an advantage here. Okay, that's my opinion. I mean, that's what I'm that's my interpretation right now where we are in terms of the 2 drugs.
So Eem, it's Robert. I appreciate your 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.
Understood. Super helpful color. Thanks so much.
Appreciate it. Operator, could we now go to the next question, please?
Your next question is from the line of Charles Duncan with Cantor Fitzgerald.
Good morning, Charles.
Yes. Good morning, Robert, Fady. Thanks for hosting the call. I had a couple of questions for the KOLs. Just maybe going back to an earlier question.
I'm wondering if, you know, Fady mentioned several design features of afecamten. And I'm just wondering if there was one in particular that was interesting to you, 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 Ahmed 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 sustains 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 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 afikanta and compare it to the rest of available therapies, I think those are the features that make it stand out.
Okay. Doctor. Marin?
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 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 avacamten. 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. Thank you. 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 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 Ahmed Masri. So yes, there are 2 main things to think about. One is, when you have younger and older patients in YHA 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 you actually relieve their obstruction and lower their gradient, they feel much, much better to the point where in retrospect they will tell you, I realized how symptomatic I were. 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 a gradient. They are 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 NYSE 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 mirrored by the results that you're seeing today.
Very good. Okay. Doctor. Neron, 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 terms of longer treatment period. You're more likely to see an improvement in clinical benefit with longer treatment periods than what we saw in what Redwood was for the reasons that Doctor. Masri explained.
Very good. Thanks for taking my questions.
Thank you, Charles. Operator, next question please.
Your next question is from the line of Dan Leone with Raymond James.
Hey, Dave.
Hi, thanks. Hey, how's it going? Congrats on the data presented over the weekend. Really great to see all the details of the Redwood study. So two 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 avacamten 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?
Thank you.
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 one echo and making a dose adjustment on one 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 avacamten, 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 3 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 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 NYJ 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 Ahmed Nasri. 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 avacamten and Redwood could have done the surgery. And so you are not dividing necessarily that there's no divide in there.
You're seeing the patient divide 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 it a echocardiography. The nice thing is that the timeline, you can scale it up and down based on your institutions and the settings you practice in and what you want to do. The key concept that I wanted to highlight is you don't have to have an hour 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.
Thank you both. 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? Yes.
Hi, Dane, this is Fady. I think there are parallels to the kinds of questions you're asking in 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 examples enrolled 1,000 patients or more see those outcomes.
So I think, as Doctor. Maran 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.
Great. Thank you so much.
Thanks, Dave. Operator, next question please.
Your next question is from the line of Jeff Hung with Morgan Stanley.
Good morning, Jeff.
Good morning. Thanks for taking the question. For the NOHA data, you looked at least one class improvement. I guess recognizing the sample size and limited duration, what proportion of patients had a 2 class improvement in NOI J? Did that happen for any patients?
Yes. I won't say 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 and 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 3 study here. Our goal being to see if we might be able to enroll a substantial number of Class 3 patients who stand to potentially benefit that much.
I'll just add one thing though. I mean, getting as Doctor. 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 1, 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. It's not there's not a lot of resolution there.
Okay. Thanks.
Thank you, Jeff. Operator, next question please.
Your next question is from the line of Emanuele Brancheti with H. C. Wainwright.
Good morning, Emanuele.
Good morning, Robert, and good morning, everyone, and thanks for taking my question. So for Doctor. Masri and Doctor. 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 tolerance 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 2, it does result in 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 the 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. Thank you. And another question about you show data on the NT, proBNP reduction. And we know that this is an accepted prognostic marker in after failure patients.
But if I'm correct, the DHA guidelines are less focused on DNP in patients with obstructive HCM. Could you provide more color on the relevance of these observations? And could these substantial effects on Wolfrats be predictive of positive remodeling long term for this patient?
I mean, 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 in obstructive HCM. That said, I think that the fact that you see in Redwood is 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.
Thank you, Emmanuella. Operator, next question please.
Your final question is from the line of Greg Savage with Goldman Sachs.
Hello, Greg.
Hey, Robert, Fady and team, thanks so much for taking the questions. Congrats on the data. I've got a couple of questions for the KOLs. 1, in light of the efficacy and safety that we're aware of in terms of the surgical option, alcohol ablation, current oral therapy such as beta blockers and calcium channel blockers. Based on what we know today in terms of the Phase 3 data for MAVA, the Phase 2 data for afacamten, 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 the sopiramide, 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 afacamten relative to perhaps mavacamten? And then my last question is just, if we assume that afacamten generates positive Phase 3 data and gets on the market, given that it will be behind mafacamten or 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? Thanks so much.
So those are 3 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? Let's start there.
So when you this is Ahmed Masri. So when you look at the from today's presentation for Redwood, when you look at the performance of that you can't in and Info Phase 3 is 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 you can position it as compared to background therapy and as compared to other invasive options. In terms of your radiciparumet question, I think you answered it.
We have Cohort 3 ongoing, which is enrolling everybody on disopiramate 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 had been treated with disopyrimid over stable period of time and they're still symptomatic, obstructive and then you're going to see the effect of afacamten. 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 word approved and also mavacamten approved and what might be new patients versus switches. Let's go into the Phase 3 study. Let's see how the Phase 3 results might ultimately read on a profile for afacamten 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 two questions?
Yes. I mean, I'll just add just to expand on it, I could just really briefly. In terms of the disopyrimide that 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 3, but the potential idea there is that those these two drugs could be synergistic, could be in terms of benefit because they're 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, we don't have 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 Doctor. Masri was right. I think we're going to see a lot more patients on drug therapy with these drugs with this drug therapy with mouse inhibitors with symptomatic obstructive HCM that are on drug therapy today. I see a lot more of those patients over longer periods of time. Will it eliminate surgery in the 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 2 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 afacamten now promptly into Phase 3, 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 3 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.