Cytokinetics, Incorporated (CYTK) Earnings Call Transcript & Summary

Good morning, and welcome, ladies and gentlemen, to Cytokinetics conference call announcing the top line results of SEQUOIA-HCM. [Operator Instructions] I would now like to 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 on our call today. which will focus on the top line results of SEQUOIA-HCM, the pivotal Phase III clinical trial of aficamten, our next-in-class cardiac myosin inhibitor. Robert Blum, our President and Chief Executive Officer, will begin with an overview of today's announcement. Then Fady Malik, our Executive Vice President of R&D, will present the top line results. Robert will then provide closing remarks before we open the call to questions. 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 may 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, including our current report on Form 8-K that was filed earlier today. 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. Today is a very special and important day for the HCM community of clinicians and patients who struggle with the treatment of this severe cardiovascular disease and have few options to treat the underlying hypercontractility associated with the disease. Today is also an important day for Cytokinetics and for our shareholders, a day that we know you have been patiently waiting for. In the past several months, leading up to today's announcement regarding the results of SEQUOIA-HCM, we spent a lot of time with equity research analysts and also with investors discussing, what would good look like? Well, these results meet the high expectations that we have been discussing, and are consistent with our best case target product profile. As Fady will elaborate, the top line results from SEQUOIA-HCM align well with our next-in-class aspirations for both efficacy and safety, demonstrating that aficamten added to standard of care therapy had a positive impact on exercise capacity measured by peak VO2, as well as on symptoms and functional class in patients with obstructive HCM. We are extremely pleased to see that these results are consistent with and build on those data observed in REDWOOD-HCM, our Phase II clinical trial of aficamten as well as on FOREST-HCM the ongoing open-label extension clinical trial of aficamten, and reflect a profile that may enable aficamten to become the cardiac myosin inhibitor of choice among physicians and patients. We are grateful to the patients, investigators, and site personnel who have participated in SEQUOIA-HCM and continued to support our ongoing research in MAPLE-HCM and ACACIA-HCM, our additional Phase III clinical trials of aficamten in obstructive and non-obstructive HCM, respectively. I also want to take this moment to commend our Cytokinetics' teams for the quality of the design and conduct of SEQUOIA-HCM as measured by the completeness of the data and the speed with which we move from database lock to reporting these impressive results, particularly given the holidays. We look forward to meeting with the FDA and EMA in early 2024 to review these results from SEQUOIA-HCM, and to continuing our work towards submitting regulatory applications in the second half of the year. And with that, I'll turn the call over to Fady to discuss the top line results of SEQUOIA-HCM.

Thanks, Robert. As we reported this morning, the results of SEQUOIA-HCM show that treatment with aficamten significantly improved exercise capacity compared to placebo, increasing peak oxygen uptake or peak VO2 as measured by cardiopulmonary exercise testing by least square mean difference of 1.74 milliliters per kilogram per minute with a p-value of 0.000002. Also importantly, the treatment effect with aficamten was consistent across all prespecified subgroups reflective of patient baseline characteristics and treatment strategies, including patients receiving or not receiving background beta-blocker therapy. Statistically significant and clinically meaningful improvements with a p value of less than 0.0001 were also observed in all 10 prespecified secondary end points. Including the Kansas City Cardiomyopathy Questionnaire clinical summary score at weeks 12 and 24, the proportion of patients with a greater than or equal to 1 class improvement in New York Heart Association functional class at weeks 12 and 24, change in provoked left ventricular outflow tract gradient and proportion of those patients whose gradients were less than 30 millimeters of mercury at weeks 12 and 24, as well as exercise workload and guideline-eligibility for septal reduction therapy. These positive results at weeks 12 and 24 reflect rapid and sustained effects on symptoms and functional class. It's especially wonderful to see in these results, the consistency across all the prespecified secondary endpoints which elaborate on meaningfulness of the primary efficacy endpoint. To add context of these findings, an increase in peak VO2 of 1.0 milliliter per kilogram per minute has been associated with improvements in mortality and heart failure and patients when the peak VO2 is substantially lower than normal as it was in these HCM patients. Aficamten increased peak VO2, 70% more than that metric. Together with the improvements in patient-reported outcomes and functional status of the secondary endpoints assess, these results truly reflect a sizable impact on the well-being of these HCM patients. Also of note, aficamten was well-tolerated in SEQUOIA-HCM with an adverse event profile comparable to placebo. Treatment emergent serious adverse events occurred in 8 or 5.6% and 13 or 9.3% of patients on aficamten placebo, respectively. Core echocardiographic left ventricular ejection fraction was observed to be less than 50% in 5 patients, 3.5% on aficamten, compared to 1 patient or 0.7% on placebo. Importantly, there were no instances of worsening heart failure or treatment interruptions due to low ejection fraction. We're extremely pleased with these results. And as Robert mentioned, they meet our high expectations for the trial. I want to echo the thanks to all the investigators, study staff, and patients who participated in SEQUOIA-HCM and who continue to support our ongoing clinical trial program. I also want to extend an extra shout out to our clinical data management and biometrics teams as well as our external partners, who have worked tirelessly on the execution of this trial. I'm so proud to be part of the stellar team and so grateful for your dedication to the promise of cardiac myosin inhibition patients -- benefit of patients. And now I'll turn it back over to Robert for closing remarks.

Thank you, Fady. As I said at the start of the call, this is a great day for patients, for clinicians, and for Cytokinetics and our shareholders. As we close out our 25th anniversary year, it is truly gratifying to see Fady's original vision for our muscle biology platform coming to clear focus with aficamten and the results of SEQUOIA-HCM. We have always believed that cardiac myosin inhibition could change the treatment of this grievous illness. And we're humbled to now have a potential therapy that may hopefully become the treatment of choice to impact the underlying contractility dysfunction associated with the condition. We have been good students of this biology and applied learnings from it to our next-in-class R&D program as is especially fulfilling. As we move forward with FDA and EMA discussions and our plans to file marketing applications in the second half of 2024. We continue the conduct of MAPLE-HCM to elucidate the potential benefit of aficamten versus metoprolol for the treatment of patients with obstructive HCM as well as ACACIA-HCM evaluating aficamten for the potential treatment of non-obstructive HCM. We thank all of you for your support and patience and are getting to this announcement. We know it was a long time coming, and we end 2023 with great optimism for aficamten for the HCM community and for Cytokinetics and our shareholders. And with that, operator, we can now open up the call to questions, please.

[Operator Instructions] The first question comes from Roanna Ruiz with Leerink Partners.

So I had a quick question on the efficacy. Curious what factors possibly contributed to the range that you saw in peak VO2 change, and is this range generally what you expected? And what do you think might have led to the low versus high end of those ranges?

So I'll turn to Fady, but I'll just say, as already communicated, the fact that this effect as large as it was, was consistent across all prespecified subgroups, tells you something already, but maybe I'll ask Fady to elaborate.

Well, I think the baseline characteristics of the patients we enrolled, as we've already published indicated a fairly severely impacted patient population, the echocardiographic data, which we're not in those baseline data, but I can tell you these patients had high resting and peak VO2 gradient -- I mean [indiscernible] gradients. And as we've seen with aficamten, the drug very effectively reduces those gradients. And those gradients are the primary reason for exercise intolerance. So I think it's partly a careful patient selection, dose optimization, as we showed in FOREST, the doses that patients were able to achieve where the majority of them got to the higher doses. And as you would expect, those things were consistent in SEQUOIA. And I think all of those factors contributed really to the magnitude of the peak VO2 that we observed.

And second question for me. I was curious, could you talk about the general trends that you observed in LVEF in those patients that went below 50%? And did they overall return to normal ranges after [indiscernible]?

Well, so the patients -- those were core lab measurements. They were not actually even fed back to the sites, so there were no dose changes associated with those 5 instances. All the patients had normal ejection actions at the end of the study. For the most part, the changes were isolated to one visit or there was an extenuating circumstance such as common infection that's been going around lately as you might guess, confounding one of the cases. So I think for overall, the clinical echo measurements are variable and you have to use clinical judgment really in assessing the whole clinical case. And as we looked into the details, we were very reassured by what we saw.

The next question comes from Carter Gould with Barclays.

Robert and team, congratulations on the data. And again, congrats to the whole team there. I know pulling together this data was challenging. Maybe following on, on the prior question. I guess with the LVEF drops you did see, can you talk about your level of confidence here that you'll end up with a differentiated REMS. And I don't know if there's additional detail either on the magnitude, duration or the dose at which those drops were seeing that gives you confidence that you end up with a differentiated REMS.

Yes. So I'll start and then turn to Fady. Firstly, it's premature to address a potential REMS absent having interactions with FDA, of course, recognizing that we do believe that these results provide solid evidence for the target product profile that we've been discussing, which would be enabling of potentially a less restrictive REMS for the benefit of physicians and patients. And as Fady can now speak, these data, we believe are consistent with our expectations for having performed lots and lots and lots of echos, they didn't necessarily translate to anything that would affect clinical management of these patients. But for where we did have LVEF excursions, they seem to be well addressed simply by dose titration where that occurred down titration based on site reads. What Fady will now speak to is the EF excursions from the standpoint of the core lab, which, again, as he just mentioned, didn't feed to the sites to inform dose down titration. Fady?

Yes. I think, Carter, as we've talked about endlessly, really, and prior to this, it's really a consequence of the number. Echo reads are variable. And in these cases, what you saw for the most part was a single number, it was maybe even out of context with the other numbers that the patients had in their visits, and there was no clinical consequence. You look at biomarkers and you look at patients, they in fact, were all symptomatically improved for the duration of their treatment. So I think the overall data and the strength of the positive effects of the drug on symptoms, the safety, remember, serious adverse events were actually lower on aficamten than they were on placebo. The safety profile here really is excellent and should afford us potentially a REMS program that's favorable to patients and physicians.

[Operator Instructions] The next question comes from Charles Duncan with Cantor.

These data look very nice. It's a great way to start the day. I had a quick question with regard to the regulatory process. I'm wondering if you've yet had an opportunity to ask the FDA for a meeting, and if not, when would you anticipate doing that? And also, what do you see as the next, call it, critical steps to being able to file that NDA in the second half?

Sure. So we'll provide further updates with our Q4 earnings call in February, but we have already arranged for interactions with FDA, and we should be in a good position in Q1 to provide some updates.

Okay. And are there any experimental, call it, clinical trial results that are gating to that NDA submission?

No. We've already, throughout 2023, been readying for these results to be added to the dossier that we've already been organizing writing all of the final study reports and to be enabling of a submission as soon as practical after we have had those interactions with FDA and EMA. So I think these results are reinforcing of those accelerated time lines, again, as we'll be able to elaborate in early 2024.

The next question comes from Yasmeen Rahimi with Piper Sandler.

I just want to say congrats on the stellar data and the tremendous hard work that went into the study. So really just amazing. Just quick question. I think before this data came out, we had spent quite a bit of thinking about how the beta-blocker use and what the impact would be on efficacy. I just wanted to drill down, I think, the way the press release read, it sounded like that PVO2 and efficacy was the same regardless of whether you were on a beta-blocker or not. Could you maybe drill down and comment a little bit more on whether the efficacy was the same regardless of beta-blocker use and whether we saw that consistency not just in PVO2, but maybe also some of the key secondary endpoints, and I'll jump back into the queue.

Yes. In fact, thank you for pointing that out. Good pickup from the press release. That was a very notable observation from these data and reflect the advancing clinical knowledge with aficamten. I'll ask Fady now to elaborate.

Well, as Robert said, indeed, that language was specifically crafted because of the observation that we made in looking at the subgroups that there was no heterogeneity in any of the prespecified subgroups including beta-blockers, which means essentially the effects were similar, whether or not you're on beta-blockers or whether or not any of the other prespecified factors were taken into account. So the treatment effect of aficamten was uniform across all those prespecified subgroups. And I think it's a very, very strong finding of the study. With regards to the other NYHA class or KCCQ, we haven't yet looked at those data. We literally have had these data just for a handful of days and a lot of these tables are still in production. But I wouldn't expect any differences there either. Generally, PVO2 is the one that was most susceptible to differences in the baseline factors.

And I'm deeply sorry and disrespectful towards my colleagues of asking a second question, but I must ask, is there a potential you could use the label could actually allow also without the use of beta-blockers given the efficacy is the same with and without beta-blockers. I'll now jump in the queue. My apologies to my colleagues for asking a second question.

That's a legitimate question, but I wouldn't expect so the study was conducted over the background of beta-blockers. The question you're asking, though, is the one we will be asking in the conduct of MAPLE-HCM, where our hope is that, that next trial may be permitting of a direct comparison as could be affording of a label claim expansion that would be enabling of use absent beta-blocker background therapy.

The next question comes from Joe Pantginis with H.C. Wainwright.

Congrats, very well deserved for the team as well as hopefully a great new drug for patients coming up. So I know this has been discussed a little bit, so I'm going to ask it in a different vein. Obviously, you said everything exceeded your expectations, which is great to hear. I wanted to focus on the titration experience as well as the lack of treatment interruptions. But more specifically, and I know Fady and Robert, you'll present it from a secondhand standpoint. But any early trial investigator feedback with regard to these data, with regard to titration experience and treatment interruptions or lack thereof?

Yes. I think Fady and his colleagues very expertly designed a study to ask and answer that question about the utility of this dose titration schema and I think these results very impressively address the fact that we got it right, and Fady can speak to how that played out in these data.

Yes. I mean, as you know, in the trial, the investigators didn't really controlled dose titration. That was controlled by the [indiscernible] system and then just based on the echo data that were entered. But I would say that the dose titration experience in SEQUOIA is very consistent with what we saw in FOREST, and where the investigators -- FOREST is a more real-life experience. And as we reported earlier this year, about 80% of the patients were reaching doses of 15 and 20 milligrams, the physicians are choosing whether to escalate the patient or not. So they make the measurements, they have the guidance in terms of whether to increase the dose in almost all cases, they do per the guidance every once in a while, they decide to stand pat, because the patients are 100% better and they just apply their clinical judgment in that case. And as we saw in FOREST, there were really, there was really excellent safety of the dose titration protocol and simplicity. So these results are pretty consistent with that. I can't go into the details, obviously, but we will, but the FOREST experience is reflective of what we saw in SEQUOIA.

And just quickly to that, I mean were physicians pleasantly surprised with regard to the experience with the drug?

Well, I would say we haven't spoken yet with the physicians at the sites because the data were blinded -- just announced, obviously. We did speak with the steering committee -- executive committee of the trial ahead of this release and some of them were also investigators, and I can tell you they were extremely enthusiastic and pleased with the results, and they were also in their own experience, very pleased with the use of the drug.

I appreciate all the color and looking forward to some exciting steps for the company coming up soon, hopefully.

The next question comes from Jeff Hung with Morgan Stanley.

Congratulations on results. Can you just talk about if there was an indication of improvement in treatment benefit between weeks 12 and 24?

I think those data will have to wait until they're fully presented. But you can note in our language in the press release what has been the consistency of effects observed at both weeks 12 and 24, I think, to hopefully satisfy your inquiry. We do believe that these effects came on rapidly, and we're sustained.

The next question comes from Akash Tewari with Jefferies.

Congrats on the results today. So a couple of things. When you think about the $13 billion that Bristol paid for MyoKardia and the $4 billion peak sales that they publicly guided for that asset. Maybe just stepping back, do you feel like a best-in-class drug for HCM could actually have that type of commercial opportunity over time? And any thoughts on how Cytokinetics should really be valued commercially, when you think about the relative contributions of obstructive HCM, non-obstructive HCM, and then HFpEF.

Sure. So obviously, we have our own scenario planning, strategic planning, forecasting exercises, et cetera. We've only just received these results, so all of those need to be updated to reflect now having these data to support what could be our go-to-market planning and what would be the implications of that in terms of potential sales around the world. It's premature to talk about all of that until such time as we've done those exercises. And that's what we expect you and your colleagues on Wall Street will be doing as to giving guidance to sales as to what could be a valuation for Cytokinetics, those are things that we'll leave to you. And when we have done the proper work around these results and put that into our go-to-market strategies, we'll have more to say about that down the road.

The next question comes from Srikripa Devarakonda with Truist Securities.

Congratulations on the fantastic data. I just wanted to follow up on a previous question. You talked about how aficamten effect was consistent across all the subgroups, just curious, was there something that you expected given we've talked about impact of beta-blockers on PVO2. I'm just wondering how similar the population in SEQUOIA is to the real-world population.

Sure. I'll turn to Fady for that, please.

Yes. When you look at the baseline characteristics by treatment group, they were extremely well balanced, and we stratified on beta-blocker use. So that means they were equally distributed into those that were using it or not using beta-blockers. And I just think aficamten, given the other factors of the patients overcame. It overcame some of the limitations such a way that all patients received a sizable treatment benefit. And I think also contributing to that was how effective the dose could be optimized in these patients. As I said, in FOREST, we found really that the majority of patients made it to one of the 2 higher doses. I think all those factors contributed to not seeing really any heterogeneity in that treatment subgroup.

The next question comes from Ash Verma with UBS.

Yes, the safety data looks pretty good from our perspective. I think just curious to understand, as you look at the drug, like what do you expect the echocardiogram monitoring requirement to look like? And just if you can share any color on how quickly are patients able to reach the optimal dose.

Fady, do you want to take that?

Well, I think it's -- again, it's premature to comment on what labeling and things might look like, but we think that SEQUOIA, but also FOREST and those data we have actually reported in fair detail, are supportive of a monitoring schedule that's convenient for patients and for physicians, incorporates risk factors, things like that, hopefully, to simplify and extend the time between monitoring as compared to what we did -- what we're doing in FOREST currently. And just to remind you, in FOREST, only a couple of the echos out of several hundred had an impact on the clinical journey of the patient. And so that's a lot of extra echos for not -- a lot of extra safety, and we think that they're probably smarter and better ways to implement monitoring. With regards to dosing, again, as I said earlier, the dosing in SEQUOIA reflected what we saw in FOREST. And I think if you go back to our October Investor and Analyst Day, you'll see that those patients in FOREST, 3/4, 80% of them were on either 15 or 20 milligrams. So they got to the 2 highest doses with really no impact to safety.

Next question comes from Tessa Romero with JPMorgan.

Congratulations to all of you on the really nice results here. So what are the additional analyses that we should prepare for at a medical meeting next year. I'm assuming ACC is the goal there. And what drove the decision to not provide the magnitude of change that you saw in the NYHA class, in the placebo and drug arms, -- was that just a function of the data coming into right? And then second efficacy question for me. In the context of the known baseline characteristics, how do you all interpret the magnitude of improvement at 1.74 in SEQUOIA versus the 1.4 that we saw with [ MAVA ] in the EXPLORER-HCM trial. It does seem to us like the p-value here is meaningfully stronger, but how do you interpret or compare those 2 results?

Thank you. So I'll start and turn to Fady. Firstly, I hope you won't be surprised, much like we've said prior to having these results we should not be making comparative statements between SEQUOIA-HCM and its results to any other study, including EXPLORER. We designed SEQUOIA-HCM as could be elaborating on a profile of aficamten specifically. And we were very pleased to see in these data consistency across all of the subgroups leading to the effects we've described today. What I'll underscore is that a peak VO2 change from baseline of 1.7 meets with our high expectations around our target product profile. And we've already been talking about what a next-in-class profile could be enabling. We see 1.7 as a very significant increase and we recognize that Wall Street analysts have already kind of handicapped where they expected comparable data to be or superior data to be. And that's really for Wall Street to do, not for us to do and as much as this is our study, and we'll stay focused to these results. These results will be to your first question, supplemented and complemented with elaboration in particular, around the subgroups and secondary endpoints so that you'll be able to see the magnitude of change in those secondary endpoints in presentations to follow, hopefully, as will all be occurring in the second quarter, whether that's at ACC or also with the European heart failure meetings, we have expectation for several presentations and hopefully also several publications to be enabling of the full data set to be in the public domain in these next few months. Maybe I'll look to you, Fady, if there's anything else you want to add.

Yes. I'll just add -- I think we couldn't put everything in the press release, Tess. I mean, we already, I think, provided more than probably you all expected. But I would just say that all the data are consistent with what we expected, very strong across the board. And the future medical meeting, we'll be elaborating not just only on those data, but also analysis of how the treatment effects were put together. It's not just about a number. It's really about how all the factors come together, how patient symptoms, NYHA class function, all those measure different things and how patients experienced improvement in several dimensions. And we were pretty excited by what we've seen so far, and we look forward to elaborating on it at a future medical meeting.

Yes. Maybe just to put a punctuation point on that, as Fady spoke it's the fuller, the more fulsome data set here that I think is especially impressive. The consistency, making these really pristine data in terms of everything we assessed for and our high expectations were met. When you look at the data across the endpoints, the consistency, the subgroups, the magnitude of effects, the P values, I think these data are being characterized already by others, third parties, not Cytokinetics as a pristine data set that really are extraordinary. And for that, we're grateful and looking forward to being able to share more of these results when it would be better appropriate in a major medical meeting.

The next question comes from Justin Kim with Oppenheimer.

Congrats to the team and truly genuinely highest praise for all efforts to reach this point. I know we're getting a little ahead of ourselves of the top line results by talking about subsets. But just to confirm, the sort of group of patients on beta blockers with disopyramide contacted dose with [indiscernible]. Was that a prespecified upset?

Yes, it was a prespecified subset. All of the background therapies were prespecified subsets.

And then in terms of revisiting the requirement of MAPLE to define treatment in the frontline setting. Just curious, given the absence of evidence to suggest that beta blockers show a PVO2 benefit in these patients. I'm just sort of curious how much uncertainty exists in demonstrating sort of the treatment effect of aficamten here?

I'm sorry, could you repeat that? Sorry, Justin.

So I mean, just with SEQUOIA confirming aficamten profile in a pivotal trial and -- the fact that we know that -- or have not seen a benefit in peak VO2 with beta blockers, the addition of beta blocker, right, in the frontline setting? I'm just wondering like how much uncertainty exists for this study to read out positively and sort of going back to the whole point of the requirement of MAPLE to define that treatment setting?

Well, I think the MAPLE members is monotherapy versus monotherapy. And so we know that beta blockers tend not to improve peak VO2 at all. With aficamten, we've seen this improvement on top of fairly aggressive background therapy. So the expectation would be that it's at least the same, if not greater, and likely that trial should read out quite positively.

Another advantage of having these results now is as MAPLE is in early innings of its enrollment. We expect this to provide a nice boost to the enrollment rates to be affording us an opportunity to have hopefully, those results concurrent with potential approval of aficamten as could be informing guidelines, that was the original expectation and aspiration and I think these results will catalyze that to hopefully become a new reality for us.

Our next question comes from Salim Syed with Mizuho.

Just one question for me, if I can. I noticed there was no placebo figure mentioned for the peak VO2 measure. It was just a difference of 1.74. Could you just clarify for us what the placebo movement was?

Well, with close -- well, it was 0.0. So I'll just leave it at that.

Okay. So no difference. It would still be 1.74 from baseline.

There was no contribution to the aficamten treatment effect from placebo, let's put it that way.

The next question comes from Sean McCutchen with Raymond James.

Congrats on the robust result here, guys. Just one quick clarification from my end on prior commentary on the call. Could you speak to the number of patients that had a down titration mentioned that there are no patients that have down titration due to a central read, but just curious on the exact numbers there.

Yes. I mean the numbers down titrations based on site reads were pretty consistent with what the Core Lab numbers were in terms of Echo. So I think you had a small handful, you could count them on probably a single hand. And as we said that they were really not driven in any way by patient symptoms or anything else.

The next question comes from Paul Choi with Goldman Sachs.

Robert, my question is a commercial one for you, which is, given what you've disclosed in the press release with regard to the P values for both the primary and secondary endpoints, which appear to be differentiated versus the approved therapy on the market currently. Can you maybe comment on how you're thinking about potential premium pricing given what looks like relatively stronger data on all these measurements at least as you've disclosed in the press release?

Sure. So I'm also joined on this call by Andrew Callos our Chief Commercial Officer. And what I'll do is ask him to comment in response to your question. Obviously, for these data being brand new, we have not had a chance to do any of the quantitative market research that might be enabling of informing prompt decisions, but perhaps he can speak to what should be expected going forward.

Sure, Robert. So from a pricing point of view, in the U.S., there's list price and net price. From a list price point of view, I would expect we will be in the neighborhood of the [ MAVA ], which is on the market today, and they kind of established what the list price is. From a net price point of view, given their results, we'll have to look at and speaking with payers, what that really will mean and translate from the net. But I would assume, again, we're going to be in the range. From a European point of view, the ATA agencies, the P-value will really help drive the cost benefit. So I would expect that we would get favorable pricing in Europe as well. But I'll leave it at that until we do more work.

The next question comes from Serge Belanger with Needham.

And congrats to the team on the data, and I'm convincing the [ ACC ] to release this level of data also. I guess the first one, regarding discussions about a potential makeup of a REMS program, does that begin with this upcoming meeting with regulators in early 2024. It's more of a discussion once the NDA has filed and you're talking about the label. And then secondly, I think the ACC won't allow you to discuss this data more than what we have today until the ACC meeting in April. Just curious if that limits you when it comes to discussions with other parties and partners to discuss this data.

Sure. So let me take those one at a time. Firstly, I want to correct an assumption. So we have had discussions with ACC. And based on discussions, we chose to disclose that, which we did in this press release but I cannot speak for ACC. And while we've submitted for potential late-breaker abstracts, it will be for ACC to determine whether in or making these disclosures, we're still eligible for presentation of late-breaker at ACC. And I can't assure you that, that's going to happen. We should be learning from ACC, whether our abstracts will be accepted during the first quarter for that meeting, which occurs in the second quarter. We have a contingency plan if these data preclude presentation at ACC for publication and presentation as would be enabling of the full data to be made available in the second quarter whether that's at ACC or not at ACC. As it relates to your second question on FDA and REMS, the way we would expect to approach matters is to have at least one meeting, if not more than one meeting with FDA during the first quarter. One is may be enabling of a review of these results. And if a second one, then a second one to be focused to a NDA submission, where that could be deemed a pre-NDA meeting. It would be perhaps at that second meeting where we might begin to socialize, at least by or asking of questions what might be acceptable to FDA in connection with the potential REMS, but it's only going to be after submission and upon acceptance or filing, and during the review of that application that we get concrete feedback from FDA pertaining to our recommendation connected to a potential REMS. So those are interactions that will take some time, and we'll be providing updates most likely on periodic earnings calls next year as to how those are going. But it would be unlikely that we'll have any concrete and meaningful feedback on our expectations and plans until the second half of the year.

The next question comes from Jason Butler with JMP Securities.

Congratulations on the results, and I had, I guess, another one for Andrew. Just -- as you think about the next steps over the time that you're prepared for submitting the NDA, what are the investments that a positive outcome from SEQUOIA can trigger? And then just at a high level, we've spoken a lot about ease of use and ease of titration here, how do these results reinforce your thoughts around messaging around that product profile?

Sure. So firstly, I'll address that we had multiple scenarios coming into having these results. And these results put us now in our best case scenario as it relates to planning for 2024 and beyond. What that means, however, is that we'll be making certain investments to your question, in our go-to-market strategies. And I'll ask Andrew to comment not so much on the dollars to be spent, but the activities to be pursued in 2024 and we'll provide actual guidance on investment spending with our Q4 earnings call in February. And then we'll ask Fady to comment on the dose titration question you asked. So firstly, I'll ask Andrew to comment.

Sure. So from a commercial point of view, the data that we're presenting today unlocks certain investments to your question. The key things we'll be looking at really are crafting the payer engagement so we can do pre-approval information exchange with payers and creating those materials, creating the marketing campaign and materials as well as a investment in kind of digital nonpersonal promotion. We'll also be investing more in our value proposition and overall economic data, so we can present those both in the U.S. and in Europe. We're not going to be doing much team expansion, team expansion in terms of field force will occur next year, the majority of the individuals we need to shut up and kind of get the campaign and all the commercial readiness activities done. Most of those individuals are in place and then in '25, that's what we'll hire the field force, which would be the next major investment in people. Fady?

Yes. Thanks, Andrew. So with regards to ease of use and titration, the way that struggle was employed in SEQUOIA and has been put in for us is very similar to what physicians expect with any drug that they titrate to effect, whether it's blood pressure or cholesterol medicine or heart failure drugs, you titrate to the desired effect. In this case, it's pretty easy to remember, EF greater than or equal to 55 and a gradient below 30. And -- if you -- EF falls below that, you might stand pat or decrease the dose depending. It's pretty simple. And as we saw in SEQUOIA, as we've shown in other studies, the effects are quite responsive to the change in dose. So whether the effects increase when the dose goes up or they decrease when the dose goes down, it behaves quite predictably. So it should be fairly -- fit fairly well into the normal practice of physicians.

The next question comes from Jason Zemansky, with Bank of America.

Congratulations on the data. Happy holidays. I wanted to circle back on one of your earlier comments regarding the so-called functional and fuel endpoints like NYHA and KCCQ. Appreciating that there's a limit to what you can disclose, I was curious, can you maybe provide a little more color on the relative impact of these endpoints versus the PVO2. Should investors be expecting sort of a -- similar sort of magnitude? I guess, how much did they -- those increases correlate?

Sure. Well, I'll say that I think their magnitudes were equally impressive and not going to be specific. We've already given lots of data in the press release, and we've been pretty sensitive about that for obvious reasons. But I think it's also the analysis of how consistent -- how many patients experienced increases in exercise as well as increases in NYHA class, for instance, a so-called responder, were quite impressive. So those sorts of correlative analyses are underway. A couple of them have been done, and we'll expand on them when -- as the data set are more fully presented, but very pleased with what I've seen so far.

The next question comes from Mayank Mamtani with B. Riley Securities.

Congrats on strong results and a long time coming indeed and I appreciate the level of detail provided here. Sorry if I missed this, what percent of patients got to have remained at the maximal 20 mg dose? And at what median time point -- I asked that because that was a very low number for [ MAVA ]. Also, what proportion of SEQUOIA patients have rolled over to FOREST-HCM? And if you could clarify what additional site or patient level data set could come even at ACC that you anticipate being helpful to your planned regulatory correspondence in early 2024?

Sure. So let's take those one at a time. The first one related to dose. And what we've said is that here in SEQUOIA, much like data we've already presented vis-a-vis FOREST, a majority of patients are getting up titrated. But I wouldn't focus strictly to that number that got to the highest dose because one of the very elegant things that Fady and his team have been able to make happen with aficamten, is a dose titration scheme that's tailored to the individual patient needs. And what we're pleased to see is that we can, with now 4 doses, 5, 10, 15 and 20, get each patient to the right dose for that patient and be enabling, therefore, of dose titration within just a few weeks to get patients to functional and symptom benefits rapidly. So it's less about how many got to 20 mgs and more -- how many patients got to the right dose for seeing that kind of relief. So that was your first question. I'll turn to Fady with regard to the others.

Yes. I mean as I said earlier in the call, I was consistent with FOREST, so you can look back at those data and see how those proportions were. As to the number that have rolled over in FOREST, we still have patients rolling into FOREST, ones that finished the study late are still going through the screening procedure and getting enrolled. But I expect 90% or more to roll into FOREST. And then with respect to data at ACC, I think it's premature for us to comment. Those abstracts are still being reviewed and -- but you'll see, I think, in the next quarter or next probably in Q2 and beyond several analyses of these trial data. We hope to get them out in an expeditious fashion.

I show no further questions at this time from our phone lines. I would now like to turn the call back over to Robert Blum, President and CEO, for any closing remarks.

Thank you, operator, and thank you to all of you for joining us on this call today. Obviously, this is a very important day for Cytokinetics and for its shareholders, but most importantly, we should call out the significance of this milestone for the benefit of patients, patients with HCM who are deserving of another treatment option. And hopefully, these data lend support for aficamten as could be become that next-in-class cardiac myosin inhibitor. It's good when good things happen for good science. And Fady and his colleagues have persevered through over 25 years of commitment to this biology, and it's especially gratifying and fulfilling to see that come home in this impressive way. We look forward to keeping all of you informed of our progress with next steps as we pursue the potential approval of aficamten based on these results. And we'll look forward to further interactions into 2024 and through that year as we're ready for our further corporate development. Operator, with that, we'll bring this call to a close. Thank you very much.

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