CYTK - NASDAQ

Good afternoon, and welcome, ladies and gentlemen, to Cytokinetics' First Quarter 2024 Conference Call. At this time, I would like to inform you that this call is being recorded [Operator Instructions]. I will now turn the call over to Diane Weiser, Cytokinetics' Senior Vice President of Corporate Affairs. Please go ahead.

Good afternoon, and thanks for joining us on the call today. Robert Blum, President and Chief Executive Officer will begin with an overview of the quarter and recent developments. Fady Malik, EVP of R&D, will provide updates related to aficamten, focus to SEQUOIA-HCM, FOREST-HCM and recent interactions with FDA. Stuart Kupfer, SVP and Chief Medical Officer will provide additional updates regarding the ongoing clinical trials of aficamten, MAPLE-HCM and ACACIA-HCM and will also discuss progression of CK-586 and our emerging pipeline. Andrew Callos, EVP and Chief Commercial Officer, will speak about commercial readiness activities for aficamten. Sung Lee, our new EVP and Chief Financial Officer is with us today, but just listening alongside us as this is his first day at Cytokinetics. Robert Wong, VP and Chief Accounting Officer will provide a financial overview of the past quarter. And finally, Robert Blum will review our corporate development strategies before closing the call by reviewing expected key milestones for the year. 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 contained in our SEC filings, including our current report regarding our first quarter 2024 financial results filed on Form 8-K that was furnished to the SEC 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 thanks for joining us on the call today. In the first quarter, we made substantial progress executing on our muscle biology-focused portfolio, anchored by the broad development program of aficamten. On the heels of positive top line results from SEQUOIA-HCM, our pivotal Phase III clinical trial of aficamten in patients with obstructive hypertrophic cardiomyopathy, we are running at full throttle in preparation for an ambitious set of presentations and publications scheduled to occur over the course of the year. In addition, we are laser-focused on regulatory submissions in the second half of the year, continued conduct of the ongoing clinical trials program, accelerating our commercial readiness activities and further expanding our pipeline. While top line results of SEQUOIA-HCM announced last December included a comprehensive high-level view of the safety and efficacy of aficamten, a priority of ours is to present more fully the results from SEQUOIA-HCM at a major medical meeting. Recently, we announced that, that forum will be the European Society of Cardiology's Heart Failure 2024 Congress in Lisbon next week, Monday, May 13, where we will have 3 late-breaking clinical trial presentations related to SEQUOIA-HCM. Along with the primary results, we have 2 other late-breakers with data from additional analyses from SEQUOIA-HCM on which Fady will elaborate. He will also lay out the steady stream of presentations and publications that we anticipate sharing related to aficamten throughout 2024 as we believe will nicely elaborate on its next-in-class profile. During the first quarter, we also engaged meaningfully with FDA ahead of our planned submission of an NDA for aficamten in the third quarter of this year. We convened 2 meetings with FDA in the month of February, including a first meeting to review the results of SEQUOIA-HCM and a second pre-NDA meeting to cover specific topics related to our submission. We are pleased with the agency's feedback, and we look forward to additional discussions to occur this quarter, which will address specific questions we are posing relating to potential REMS scenarios. We've also been preparing for our planned submission of an MAA with EMA expected in the fourth quarter of this year. Moreover, in 2024, many other work streams and activities were pushed into the next phase of execution, notably commercial readiness activities, which Andrew will speak about in more detail. And while SEQUOIA-HCM represents the forward edge of the Phase III development program for aficamten, we now have 2 other ongoing Phase III clinical trials evaluating aficamten, which each represent additional opportunities to expand the clinical evidence use case and hopefully reach more patients in need. Of course, we're also continuing our ongoing open-label extension study, FOREST-HCM, to collect longer-term data on the safety and efficacy of aficamten. And as Stuart will elaborate, MAPLE-HCM, the Phase III clinical trial of aficamten as monotherapy compared to metoprolol as monotherapy is expected to complete enrollment in the third quarter. This trial will provide an evidence-driven answer to the question clinicians are beginning to ask with the emergence of cardiac myosin inhibitors, that is, which drug do we initiate first? MAPLE-HCM may be an important opportunity for aficamten as we hope it may inform a critical change in treatment practice as could be outlined in emerging guidelines. Stuart will also share an update on ACACIA-HCM, our Phase III clinical trial of aficamten in patients with non-obstructive HCM and he'll also describe a third late-stage clinical trial called CEDAR-HCM, which is now open to enrollment in a pediatric population of patients with oHCM. We are especially pleased to maintain a strong financial position at the end of the first quarter, alongside of our maturing R&D programs. As I'll speak to in more detail later in this call, we believe that we are in an advantaged position in terms of our options for accessing diversified capital to further fuel our science for the benefit of patients and to deliver increasing shareholder value. And lastly, we were pleased to recently announce that we had finalized our search for a new CFO. And as you hopefully saw from the 8-K we issued, I'm pleased to welcome Sung Lee to our team. When we began our search, we had several key criteria for the ideal candidate including previous experience in both large and midsized biopharma companies, global commercial finance experience and a track record of innovative financing deals. Sung brings all of that and more, and we couldn't be happier to have him join our team. Prior to Cytokinetics, Sung was CFO of Vir Biotechnology and also MorphoSys AG and Sangamo Therapeutics. Previously, he built his career expertise over 14 years at Gilead, where he served in various roles obtaining leadership expertise in tax, accounting, operations and IR. You will hear from Sung in our Q2 earnings call. And for those of you who don't already know him, you'll soon have a chance to meet him at our upcoming conferences and one-on-one meetings. And with that, I'll turn the call over to Fady, please.

Thanks, Robert. Top of mind for all our late-breaking clinical trial presentations next week at Heart Failure 2024 in Lisbon. The presentations include, of course, the primary results of SEQUOIA-HCM, which will provide a complete view of the results related to the baseline characteristics, the primary and secondary endpoints, subgroup analyses and select exploratory endpoints. There will also be 2 additional late-breakers on other data analyses from the trial, one will elaborate on the dosing and safety experience in SEQUOIA-HCM and another is a deep dive into the improvements in exercise capacity affected by aficamten based on a detailed review of the CPET data. These presentations will not only expand on what was in the top line press release, but go further in providing an in-depth look at this very rich data set and its implications for clinical practice. As Robert mentioned, our presentations next week represent only the beginning of our plan to fully dissect the results from SEQUOIA-HCM and build a comprehensive picture of the differentiated profile that continues to emerge for aficamten. We have an aggressive plan that starts with HFA and lays out over the course of the year, a series of presentations and publications that will further elaborate on the efficacy and safety of aficamten. You can expect presentations at the European Society of Cardiology, The Heart Failure Society of America and the American Heart Association Meeting as well as accompanying publications in leading medical journals. These include deeper dives into the echocardiographic, Kansas City cardiomyopathy questionnaire data, CMR data, cardiac remodeling and biomarker data as well as an integrated analysis of efficacy. We look forward to sharing more as the year progresses. Shifting to FOREST-HCM. Last month at ACC, we shared additional 48-week data from 46 patients with obstructive HCM and FOREST-HCM that showed the treatment with aficamten is associated with sustained improvements in resting and Valsalva left ventricular outflow tract gradient, NYHA functional class, NT-proBNP and measures of cardiac structure and function. Furthermore, occasions of left ventricular -- low left ventricular ejection fraction were very infrequent and were not associated with treatment interruptions or heart failure events. These data continue to reinforce the safety and efficacy of longer-term treatment with aficamten and oHCM. With nearly 300 patients currently enrolled in FOREST-HCM, we look forward to reporting more longer-term data in the future. Importantly, during the quarter, we had many opportunities to engage with KOLs and treating clinicians in the community to discuss the results generated to date from the program for aficamten. Feedback has been incredibly positive, and we believe that once presented and published, the full results will reaffirm this enthusiasm. Specifically, our therapeutic medical science liaisons have interacted with over 500 health care professionals and completed profiling of physician practices with HCM treatment programs. At the same time, our managed health care medical science liaisons engaged integrated delivery networks or IDNs around the results of SEQUOIA-HCM and finalized work to build our payer clinical value narrative. On the regulatory front, as Robert mentioned, during the first quarter, we held 2 meetings with FDA ahead of our NDA submission. During the second quarter, we plan to engage FDA once again, this time for a type B meeting focused specifically on potential risk mitigation. While this is a topic that came up in both of our previous meetings, this next engagement affords us the opportunity to elaborate on the safety and pharmaceutic properties of aficamten, discuss their potential impact on different approaches to manage risk and gain insight into FDA's perspective on these matters. In these discussions with FDA, our position is that the benefit/risk profile of aficamten merits an approach to risk mitigation that's reflective of the safety profile of aficamten as demonstrated in SEQUOIA-HCM and FOREST-HCM. Altogether, we remain optimistic and we believe these discussions will inform our proposal for a differentiated approach to risk mitigation in our NDA. As we've previously shared, we're planning for a rolling submission for the NDA, which will provide FDA the opportunity to begin their review of completed modules. We expect to begin and complete the submission during the third quarter. As I'm sure you'll appreciate, there is a tremendous amount of work that goes into an NDA and our teams are working diligently towards this very important milestone for the company. Meanwhile, we're also preparing our marketing application, which we expect to submit to EMA in the fourth quarter of this year and are coordinating with our partner, Ji Xing in China to support their plans to support an NDA as well. During the quarter, we are pleased to welcome a new Head of Regulatory for Europe will lead regulatory strategy and product registration in Europe and support the launch readiness activities. While SEQUOIA-HCM is taking center stage at the moment, it's followed and supported by additional clinical trials and the development program for aficamten that we believe have the potential to expand the utility of cardiac myosin inhibitors. I'll hand it over to Stuart to elaborate more on these additional clinical trials as well as provide an update on our earlier-stage clinical development pipeline.

Thanks, Fady. I'll start with our 2 ongoing Phase III clinical trials, MAPLE-HCM and ACACIA-HCM. We believe both of these trials have the opportunity to expand the potential benefit of aficamten to additional patients with obstructive and non-obstructive HCM and to elevate aficamten in treatment guidelines. MAPLE-HCM, which is evaluating the potential superiority of aficamten as monotherapy compared to metoprolol as monotherapy in patients with obstructive HCM is on track to complete enrollment in the third quarter. Over 75% of our global sites are activated, and we're expecting sites in China and South America to join MAPLE-HCM soon. By the end of the second quarter, we expect to be at approximately 50% of target enrollment and foresee a large increase in enrollment in the third quarter. The results from SEQUOIA-HCM have provided a strong tailwind for enrollment in our ongoing trials, including MAPLE-HCM, and we've observed strong enthusiasm from sites for completing the trial and getting us across the finish line. We expect MAPLE-HCM to read out in 2025, around the time when we hope to be commercially launching aficamten, and a positive will provide the evidence base to potentially position aficamten in guidelines for use as first-line therapy in obstructive HCM. ACACIA-HCM, the pivotal Phase III clinical trial of aficamten in patients with symptomatic non-obstructive HCM is also entering what we will expect via rapid phase of site activation and enrollment. During the second quarter, we're meeting with many of our investigators and study staff at their sites around the world, and we recently held a successful investigator meeting in San Francisco. Given positive results from Cohort 4 of REDWOOD-HCM, clinicians are enthusiastic about the promise of aficamten for the potential treatment of patients with non-obstructive HCM. And we look forward to continuing enrollment this year towards a goal of completion in 2025. Turning our attention to another important patient population. Just this morning, we announced the start of yet another clinical trial of aficamten called CEDAR-HCM, a randomized double-blind, placebo-controlled trial and open-label extension evaluating the efficacy of pharmacokinetics and safety of aficamten in a pediatric population with symptomatic obstructive HCM. CEDAR-HCM will enroll 2 cohorts, approximately 40 adolescents aged 12 to 17 years will be enrolled in the initial cohort. A second younger cohort of up to 10 children aged 6 to 11 years will begin enrollment after data from at least 20 adolescent patients supports safety and dose selection in the younger cohort. In the cohort in adolescents, the treatment regimen for aficamten will be the same as that for adults. That is once daily doses of 5 to 20 milligrams individually selected based on echocardiographic parameters. Primary and secondary endpoints will be evaluated after 12 weeks of double-blind treatment. The primary endpoint is change in Valsalva left ventricular outflow tract gradient, and secondary endpoints include change in resting gradient, pharmacokinetic print measures, cardiac biomarkers and symptoms. After 12 weeks of double-blind treatment, all patients will roll over into an open-label extension. While pediatric HCM may be rare, it's associated with a high risk of heart failure and serious arrhythmias. HCM tends to present similarly in children and adolescents as it does in adults and is associated with shortness of breath, fatigue and poor exercise tolerance, impacting overall quality of life. We're optimistic, given the results from SEQUOIA-HCM in adults, that aficamten may prove promising for this key segment of the HCM population. During the second quarter, we'll also be starting a Phase I study to evaluate the pharmacokinetics, safety and tolerability of aficamten in healthy Japanese participants to advance our global clinical program in that geography. Additionally, during the first quarter, we advanced CK-586, another cardiac myosin inhibitor, in development for the potential treatment of a subgroup of patients with heart failure with preserved ejection fraction, or HFpEF. Earlier today, we announced top line data from the Phase I study of CK-586, which showed that CK-586 was safe and well tolerated in healthy participants with generally linear pharmacokinetics. These findings are supportive of advancing the program to a Phase II clinical trial, which we expect to begin in the fourth quarter of this year. We plan to present the data from the Phase I study in more detail at a medical congress in the second half of the year. We believe CK-586, which has a different mechanism of action than aficamten has the potential to further unlock the potential biology of myosin modulation for patients with high unmet need. Finally, further work continued in the past quarter on our earlier stage programs that we expect to mature from our labs into the clinic later this year and next, extending beyond muscle contractility for the areas of muscle metabolism and energetics. These emerging programs are an important part of our long-term vision as we continue to pioneer the field of muscle biology and pharmacology. And toward that end, we're pleased to be sponsoring a dedicated muscle biology symposium here in South San Francisco next Friday called CLIMB, Contemporary Landscapes in Muscle Biology. This 1-day event will bring together scientists, researchers and emerging professionals to share innovative research in the field of muscle biology. The goal of this gathering is to foster collaboration, facilitate networking opportunities and promote scientific and interdisciplinary dialogue with the ultimate goal of driving advancements in the understanding and treatment of muscle-related diseases and disorders. With that, I'll turn the call over to Andrew.

Thanks, Stuart. After sharing top line results from SEQUOIA-HCM at the end of last year, in the first quarter, we began the design and build phases of our go-to-market strategies. We worked to refine our market development campaign, which we plan to launch at HFSA later this year and initiated the design and build of our comprehensive patient support services program as well as our specialty distribution strategy. We continue to strengthen our commercial team with new hires, including a U.S. Patient Marketing Lead and a Head of Germany, which, if approved, is the first European country where we plan to launch aficamten. In 2024, hiring in our commercial organization and in Europe will remain modest with more hiring expected in 2025 and 2026, gated to regulatory milestones in the U.S. and EU and reimbursement levels on a country-by-country basis in the EU. On that topic, we are pleased to continue to see more positive health technology assessment for the CMI class during the last several quarters, including from Germany, France and the U.K., which signals a potentially positive forecast for the future reimbursement of aficamten across key countries, if approved in Europe. During the quarter, we continue to build the value proposition for aficamten for various stakeholders, including payers and HTAs by generating data around health economics and outcomes research or HEOR. In the first quarter in recent weeks, our team published and presented 8 HEOR abstracts on topics including the impact of ethnicity, sex, region and payer health care coverage on outcomes in HCM, medical therapy usage post septal myectomy and long-term cost of care for patients with symptomatic obstructive HCM. Our findings around patient outcomes and costs related to obstructive HCM further underscore the clinical and economic unmet need for this growing patient population. Looking ahead, after we present and publish the primary results from SEQUOIA-HCM next week, we will continue engagement with U.S. payers. Our payer and medical account team began dialogues with every major payer in 2023. And beginning in Q3 of this year, we plan to initiate preapproval information exchange with every major payer to review the results of SEQUOIA-HCM, so the payers understand the clinical meaningfulness of the results as well as the cost and outcome burden of obstructive HCM. I'm pleased with our progress for commercial readiness so far in 2024. As I've spoken to before, the obstructive HCM market has a highly concentrated customer base, which is typical to specialty cardiology. Unlike biopharma companies that have come before us who did not perform to market expectations, we believe our focus on specialty cardiology anchored by aficamten should enable us to successfully reach the subset of cardiology -- cardiologists who treat approximately 80% of the obstructive HCM patients. We believe that we are uniquely advantaged for success, and we're keeping our foot on the gas across our commercial readiness preparations this year. Just as our company successfully build a formidable R&D organization that cultivated the robust pipeline we have discussed today, we're well on our way towards building an equally outstanding commercial organization poised to stand shoulder to shoulder with our highly respected R&D colleagues. Together, we are pioneering new frontiers of success, driven by our shared vision and mission to help patients. And with that, I'll turn the call over to Robert Wong.

Thanks, Andrew. We ended the quarter with approximately $634.3 million of cash on the balance sheet, which represents 2 years of forward cash runway, including capital we expect to be available to us under our deal with Royalty Pharma upon satisfaction of conditions. Our first quarter 2024 R&D expenses increased to $81.6 million from $79.4 million in the first quarter of 2023, primarily due to spending on our cardiac myosin inhibitor programs, offset by lower expenses for our skeletal muscle programs in the prior year. Our first quarter 2024 G&A expenses were $45.5 million down from $49.7 million in Q1 2023 due primarily to higher pre-commercial expenses in the prior year. With that, I'll hand it back over to Robert Blum.

Thank you, Robert. As you've heard, our cohesive biology anchored by cardiac myosin inhibition continues to drive shareholder value and growth as we execute on our plan to advance to the next tier of biopharmaceutical companies. In the near term, we remain focused on elaborating on the positive results from SEQUOIA-HCM in presentations and publications as well as preparing for the successful launch of aficamten if approved, in 2025, while also continuing to invest in expanding our promising pipeline directed to our plans to build a specialty cardiovascular franchise. In 2024, we've been focused on parallel opportunities to sustain and grow our company by diversifying access to capital and strengthening our balance sheet, and we're prepared to execute on a series of primarily non-dilutive transactions such as comes with partnering and structured financial engineering. We hope to have more to say about these initiatives as they come to closure and commit to ensure not only access to diversified sources of capital, but that we also focus to capital efficiencies as we deploy capital towards advancing our pipeline and emerging commercial business. Our priority remains our ongoing business development campaign for aficamten in Japan. During the quarter, we continued discussions with multiple parties and with momentum, we hope to consummate a deal. We're also looking at restructuring and expanding current financial instruments and deals to lower our overall cost of capital and potentially monetize additional R&D progress. We expect to remain diligent about the different levers we can pull as could be enabling of us in a principally non-equity dilutive manner to continue to augment shareholder value, and may also consider equity financing at the right time as part of a broader capital access strategy. Shaping our business conduct today and into the future is our pledge to corporate responsibility. And recently, we were proud to release our Second Annual Corporate Responsibility Report, which highlights our actions and progress against our goals of keeping patients at the center of our work, advancing a high-integrity, diverse and inclusive culture and supporting sustainable communities. As we look at our longer-term goals and vision, which will be articulated in our Vision 2030 early next year, the company we aspire to be is a sustainable commercial enterprise with an enduring R&D organization. Our vision is to maintain our pioneering leadership in muscle biology and pharmacology and grounded in financial stewardship and doing what's right for the patients we serve. Now I'll recap our upcoming milestones. For aficamten, we expect to present the primary results from SEQUOIA-HCM at the European Society of Cardiology Heart Failure 2024 Congress next week. We expect to submit an NDA to the FDA in Q3 2024 and an MAA to the EMA in Q4 2024. We expect to complete enrollment in MAPLE-HCM in Q3 2024 and continue enrollment in ACACIA-HCM throughout 2024. We expect to continue enrollment in CEDAR-HCM in 2024 and to begin a Phase I study of aficamten in Japanese healthy volunteers in Q2 2024, and we expect to continue advancing our go-to-market strategies for aficamten. For CK-586, we expect to present primary data from the Phase I study at a medical meeting in the second half of this year and to start a Phase II clinical trial in Q4 2024. And for preclinical development and ongoing research, we expect to initiate clinical development with another muscle-directed compound later this year as well as continue our research on expanded muscle biology activities. Operator, with that, we can now open up the call, please, to questions.

[Operator Instructions] And our first question will come from Charles Duncan from Cantor Fitzgerald.

This is [ Estea ] on for Charles. Congrats on all the progress made in the quarter. So we have one question on CK-586. So based on the Phase I results released this morning, what will be the starting dose and escalation strategy for the Phase II clinical study? And also, how do you plan to monitor first safety and efficacy in the study?

So it's a bit premature in light of the fact that we haven't announced the design for the Phase II study. But maybe Fady and Stuart can speak in general tones about how we think about dose escalation and the types of assessments that we might be considering for the Phase II study.

Yes. I mean, I'll just say that all the doses that were in the press release were well tolerated. We didn't find a maximally tolerated dose. We didn't need to push it that high. We've had a clear pharmacodynamic response, and that was enabling of us to decide on how to proceed to Phase II. I think we'll have more to say on specific doses and things, but you can expect Phase II to be really a dose-finding study in patients with heart failure and preserved ejection fraction, those that will resemble patients that we'll study in Phase III. And right now, in terms of monitoring and the dosing schedule and how we're going about it, I'm going to probably remain quiet on that until we are ready to be more forthcoming with those details.

But what you can expect is that we're borrowing from learnings as it relates to aficamten in nHCM for application to CK-586 in HFpEF. And we believe that there are similarities in patient populations as well as endpoints for clinical evidence of effect. So we'll have more to say about that later in the year.

And our next question will come from Paul Choi from Goldman Sachs.

Nice to see Sung again here and to continue working with him. My question is on MAPLE. And with regard to your timing comments with the trial to be enrolled by third quarter this year, you presumably will have access to a cut of the data, let's say, by -- as late as middle of next year. So my question here is -- do you have any plans to submit any interim or partial cut of the data or maybe even the full data as part of either a safety or efficacy set in consideration for your -- as part of your NDA filing either to bolster your case for your proposed REMS and/or label. If you could comment on that, that would be great.

Good question. I'll ask Fady to comment.

Yes. So the trial will remain blinded until it reads out in 2025. But that said, during an NDA review, there's something called a 120-day safety update. And so we'll be submitting aggregate safety data from ongoing trials like MAPLE and ACACIA as well as updated safety and efficacy data from FOREST-HCM. So there will be more data, if you will, to consider and to cement if the safety profile of aficamten during the NDA review.

Our next question will come from Srikripa Devarakonda from Truist Securities.

Aficamten is still in early stages of launch, and I may be jumping the gun here in terms of we have to wait for aficamten to get approved. But just thinking a little bit long term, if approved, aficamten would still have a significant proportion of the market left to penetrate, but I was wondering about the potential of patients to switch from mavacamten to aficamten? If they're either concerned about the safety or not satisfied with the efficacy, that may not be your base case, but I was just wondering if there is a possibility?

So it's interesting. I think analysts have been polling opinion leaders about that very matter, and we'll leave that to the equity research community to make its own conclusions from those surveys. But it's certainly our primary strategy to be expanding the category for aficamten as could be applicable to a broader array of patients and physicians who prescribe for those patients and not otherwise to focus on patient switches, but maybe I could ask Andrew to speak about how he's thinking about the broader category growth and penetration.

Yes. Robert, maybe just to build on what you described. I mean, we're expecting the vast majority of the market -- addressable market to still be available and really just educating physicians and broader cardiology on aficamten, and then so they can inform and make an informed decision around treatment of a patient. We're not going to be communicating or marketing switches at all. If that happens, that would be through the physician-patient dialogue.

We're trying to be good students -- I apologize. We're trying to be good students of other cardiovascular brand launches and next-in-class strategies and how that ultimately serves patients and shareholders. And I think it's incumbent upon us to be focused on where cardiac myosin inhibition still has application to a broader array of patients ultimately in order to be able to fulfill our science and mission.

Our next question comes from Tessa Romero from JPMorgan.

So we saw that you have an upcoming meeting with the FDA this quarter. Curious on your latest thinking on what you will provide us all in terms of how that meeting goes on your interactions around a risk mitigation plan here? And like, will there be a disclosure before you begin the NDA filing or not? And what could that look like? And then second quick question is just on the epidemiology side for HCM. We attended ACC and one of our key takeaways was around the focus on improving diagnosis. Where are you today on the right number, what the patient number is that could be addressable at the time of the launch? And how does this number expand if one includes the pediatric population?

Sure. So I'll tackle the first one. Maybe Fady will add something to that, and then we'll ask Andrew to comment on numbers 2 and 3. As it relates to our strategy, we do not intend to provide feedback on a play-by-play basis with regard to regulatory interactions, especially as it relates to REMS. We do expect to come out of the meeting with FDA with clarity on what we might choose to do in connection with the potential REMS and we'll give some general update with our next earnings call but not otherwise, after the meeting itself. We believe that it's in the interest of transparency to at least provide some general updates, but not so specifically as that may affect the actual review and discussions we're having with FDA. And as you know, ultimately, it won't be until perhaps a mid-cycle review that the FDA gives us a sense of what they're thinking, and that's ultimately what's most actionable. And it will be at that point if this drug, hopefully, will be approvable that we'll be in a negotiation around a potential REMS or other risk mitigation strategies. So I don't think it's in anyone's interest to -- foreshadow that before we've even submitted the NDA. Fady, anything you want to add to that?

Yes. I'll just add, I think that these conversations in general are mostly just directional. They're not -- not commitments in any sense. They are helping FDA get familiar with the data as we see them. They'll obviously need to do their own review. And so any disclosures would not necessarily be that useful because things will change over the course of a review. And I don't think we want to be confusing folks in terms of what direction things are moving.

To be clear, however, we do expect to float different scenarios, different risk mitigation strategies as could read on a potential REMS and it won't be until after that meeting that we make a decision about how to approach that in the course of submitting an NDA in Q3. And with that, maybe I'll turn it to Andrew to answer questions 2 and 3.

Sure. So on the diagnosed, so I'll just stick to obstructive HCM. There's 200,000 patients today diagnosed, of those 130,000 would be eligible for treatment as defined by New York Heart Class II or III. The like most rare diseases, that number in terms of the true prevalence is likely underrepresented where many patients are not diagnosed, but probably the true prevalence is 3 or 4x that number. It's also not uncommon once an available treatment is on the market, guidelines are updated to include that available treatment, there's education and publications by pharmaceutical companies, you'll start to see those rates go up, and we're expecting that to be the case. In terms of the pediatric population, so of the 200,000 obstructive HCM diagnosed patients in the U.S., and Europe is similar, there's around 6,000 to 8,000 pediatric patients with HCM. So I'm assuming that's probably we don't have a breakout of New York Heart Class for the pediatric population. But assuming it's probably 50% to 60% of that population would be eligible for treatment. So hopefully, that answers your question.

[Operator Instructions] And our next question will come from Roanna Ruiz from Leerink.

So a follow-up on the CEDAR-HCM trial in pediatric patients. Could you talk a bit about the unmet need there for an agent like aficamten in this particular segment of the HCM market? And how long might it take to actually complete that trial? And do you have any thoughts on the regulatory path forward, assuming that you have positive data from CEDAR?

Yes. So I think the pediatric population is not as large as the adult population, but there's a significant unmet need. You heard Andrew comment on it -- on the size. They don't have generally the same -- they have the same types of treatment options available to them that adults do. But surgery is a much less preferred option in that age group, if you will. The availability of a myosin inhibitor, I think, would be quite meaningful as an option for these patients who, when they manifest disease at an early age like this, it can be quite aggressive. So we may also, over time, be able to generate information that looks at how potentially the disease is stabilized as opposed to progressive -- in this subgroup that may be more amenable because their disease may progress more rapidly. I think when you talk about any pediatric patient population, the FDA in general is very accommodating to trying to move those things as quickly as possible through the review process. We would expect these data to be positive. Just given the main endpoint is reduction of the left ventricular outflow tract gradient, and so once we have these trials done, we're not really guiding yet to how long it will take, but we think it will go fairly quickly, we can file this as part of the supplemental NDA.

Our next question will come from Salim Syed from Mizuho.

And I'd like to all extend my welcome and congrats to Sung. Its good to reconnect, Sung. I guess on 586, if I can, I know you're not -- maybe this is for Fady, providing any details exactly on the Phase II design. But is there anything in particular, Fady, from the Phase I trial that you learned that how this compound could potentially differentiate from the MyoKardia 224 compound and the read across there into how a trial could differentiate from their current Phase II study?

It's a challenging one to answer, Salim, because we don't really know very much about 224 and we haven't told you very much about 586. I guess I'll just say, and maybe I can ask Stuart to expand a little bit, but our goal is to make dosing of 586 simpler than aficamten, and we think it has some unique properties that may enable that as we develop in -- as seen in Phase I. Stuart, do you want to maybe elaborate a little bit?

I think the only thing I'll really add is that CK-586 was designed to target what we consider more vulnerable population. These patients have had many comorbidities, perhaps more at risk of some decreases in ejection fraction, for example. And we think CK-586 has properties that would make these patients more manageable and less prone to that or other risks. And so, again, those details will be more forthcoming.

And our next question will come from Jeff Hung from Morgan Stanley.

Congratulations, Sung, on your new role. For CEDAR, what are the expectations for the dose range that's likely to be sufficient for most pediatric and adolescent patients? If they end up being a similar dose range as the patients from SEQUOIA, would you expect a higher rate of ejection fraction excursion because of the differences related to age?

Stuart, do you want to take that one?

Sure. Thanks for the question, Jeff. So as we mentioned, the doses in adolescent patients are exactly the same as the doses that we're studying in adults, between 5 and 20 milligrams. And again, what's important is that the dose selection is individualized based on achievement of target gradient and maintain -- maintenance of a normal ejection fraction. In terms of younger children, the key question will be really what is the safe starting dose. And the plan will be to, as I mentioned, evaluate doing interim analysis, evaluate 20 patients, adolescent patients, pharmacokinetics and safety and determine for younger children, what is a safe starting dose. And that's the basic strategy. And so with that in mind and individualized dose selection, we don't -- we anticipate that the benefit/risk ratio in children will be just as good as we're observing in adults.

Next question will come from Mayank Mamtani from B. Riley Securities.

Also pleased to see Sung join the team. Just maybe on the next Monday's ESC Heart Failure Congress data, just could you please clarify if you could get the patient level and safety analysis relative to maybe what we saw at the top line? And also obviously curious to see how much of the dose titration and the responder rate of patients staying at higher efficacious doses is helpful to having that peak VO2 number that is -- seems to be on the higher side and not connected to the baseline characteristics that we had initially thought. If you could clarify that, that would be great.

Yes, Mayank. I mean, I think most of your questions will be addressed those presentations. Remember the 3 of them, one will speak a lot about dosing and safety. And so we'll show the characteristics of patients at the various doses and how safety is related to that. With regards to peak VO2, can't really comment. I'm not sure that there is a dose-specific analysis. But you got to remember these patients were not randomized to dose, they were randomized to a dosing strategy, and they achieved a dose based on their individual response to the drug. And so in that way, we, in a lot of ways, consider them just all part of the same dosing strategy.

Our next question will come from Jason Butler from Citizens JMP.

And congrats on all the progress. Just wondering if you could give us an update on regulatory progress for China and what next steps are there?

Jason, I'll take that one. In light of that, we're making very good progress, but we aren't in a position yet to be specific until such time as we and Ji Xing, our partner are aligned on setting those expectations. So I do hope that we'll be able to say something with the next earnings call.

Our next question will come from Jason

This is Cameron Bozdog on for Jason. So you've discussed the potential of a [ novel drug ] and it's based on a risk algorithm. I mean, could you kind of elaborate a little bit on what this could look like? Have you received any feedback from regulators on this point? And then if you could maybe touch on your base case assumptions currently for number of echoes likely to be required in both titration and then in the maintenance setting as well?

Sure. It's premature to speak to the second part of your question, the number of echos is a function of conversations that we're still going to be having with FDA. But I think there's no scenario by which we expect a similar REMS. I think in light of the fact that the dosing strategy employed in SEQUOIA-HCM and continuing in FOREST-HCM is itself differentiated. And therefore, that ties to the risk mitigation strategy. It's, I think, going to be clear that there will be a different kind of REMS program. And with that, we expect to have conversations with FDA about what that could look like in a concrete way as will be informed by how we might approach risk mitigation in an NDA submission. And there are different ways to approach risk mitigation, as you know. Some of that can be handled by labeling. Some of that can be handled in an informational REMS. Some of that may require ETASU REMS. And the current cardiac myocin inhibitor is the subject of an ETASU REMS. And our objective is to understand how FDA thinks about risk in light of not just the EF excursions as seems to be the focus of Wall Street, but also as pertains to ADME properties, drug-drug interaction properties, pharmacokinetic properties that speak to half-life and shape of the curve with regard to pharmacodynamics, all these things factor into how one approaches risk mitigation. And I do think we're going to be in a position, as is our base case, to have a differentiated profile for risk mitigation. I think that's the best I can do today, but we do hope to have more to say down the road.

Our next question comes from Carter Gould from Barclays.

I'm going to ask you a bit of an unfair one in that the AHA and ACC HCM guideline just dropped this afternoon. But I'm going to go out on a limb and say that you probably had a good sense of what was going to be in there. So I guess at a high level, is there anything in there that's surprising? And maybe just at the risk of provoking Diane and the operator, when you think of -- I guess, for Andrew, when you think then about the importance of guidelines down the road, conveying that differentiation between mavacamten and aficamten. How important is that based on all the prior kind of case study work you've done?

Yes. So good on you for noting that those guidelines dropped just today. I will ask Fady and Andrew both to comment from their perspectives in light of your questions. And you did get a grin out of Diane, by the way.

Well, I saw the guidelines drop into my inbox 2 hours before this call and actually didn't see that until the middle of this call. So just -- I'll do my best to answer your question, which having scanned them briefly, I think they -- number one, they are referring to a class of myosin inhibitors and -- nothing really surprising, I would say. They followed sort of the same approach that the EMA, the ESC guidelines did kind of placing cardiac myosin inhibitors as following first-line therapy of beta blockers. So these are patients who fail first-line therapy like that that's why we are conducting MAPLE potentially to show that there are advantages to starting cardiac myosin inhibitors first. And hopefully, those data will inform future guidelines. There are some specific things where they conflate issues with cardiac myosin inhibitors that are actually compound-specific and not cardiac myosin inhibitor-specific. I won't delineate those, but I think if you read them, you'll figure that out, and so some of that may, in the future, need to be sorted out, and we'll just have to do our best to ensure that, that information is in the hands of the people who do the guidelines. We certainly weren't aware of what was in the guidelines. We don't participate in that process, but we can make sure that the data is available to them. And I expect...

I'm sorry.

Go ahead, Andrew.

Yes. The only thing maybe I was going to add to your question was around the guidelines. Certainly, that's credibility when talking to physicians around evidence, that certainly adds credibility to payers to cover, especially if it's a first-line therapy. Additional studies certainly give more strength to a guideline as well. And I think probably extremely important is, if a guideline, as an example, talks about, say, first-line therapy because of data like MAPLE, having that data and that evidence and being able to talk to physicians about it as compared to not having that evidence and not being able to talk to physicians about it, I think is a big difference. So I think the guideline helps maybe to summarize with credibility to various stakeholders and probably most importantly lets us as a pharmaceutical company talk to physicians and payers about the evidence relative to aficamten if we get approved.

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

I guess as we're going into the Cardiology Heart Failure Congress here on Monday. You have spoken about how the more you look at the data, the better it gets. Do you think on -- like, I guess, the question that people have going into Monday's data release or full data disclosures around it is will it become even more clear that aficamten wins on efficacy, not only just on its safety product profile? I would love to kind of get your color around that, and I'll jump into -- back into the queue.

So to be clear, we did not conduct a head-to-head comparison of aficamten with mavacamten and it would not be appropriate to imply that we did. With that said, we believe the profile of aficamten in SEQUOIA as it relates to efficacy, safety, convenience and all those things that factor into its next-in-class profile will be supported by the evidence as would be indicative of our belief that aficamten can become the cardiac myosin inhibitor of choice, ultimately, if approved. With that said, that's ultimately for you to determine once you see the data. The results will be available not just in presentations, but in publications and not just at the European Heart Failure meeting, but throughout other meetings later this year. And I do believe that these results are reaffirming of our expectations.

Our next question comes from Akash Tewari from Jefferies.

This is Amy on for Akash. Just one on CK-586. Do you think the drug will need out LVEF monitoring? And what are you seeing in your healthy volunteer data that either supports or doesn't support this requirement?

I'll maybe take that one. I think we developed CK-586 and as potentially the mean to dose this in HFpEF patients without echo monitoring -- routine echo monitoring. That said, we need to produce the data that eventually supports that, and I think it's premature to know for sure whether we'll achieve that or not. The profile that we saw in Phase I was contributory toward that. And so we'll know more as we explore this drug more in Phase II.

Our next question will come from Serge Belanger from Needham.

You've had 2 meetings with the FDA so far and another one coming up, I guess, later this quarter. What are your current thoughts regarding the potential for a priority review or in the AdCom?

Yes. So neither of those are in our base case assumptions, we believe that as a next-in-class profile, it would be more exceptional to assume priority review. It's certainly possible, but that's not something that we're banking on, so to speak. And as it relates to an AdCom, we don't expect one, but one can be surprised by those things. And for the fact that the data are, we believe, quite compelling. There's already very effective cardiac myosin inhibitor on the marketplace that did not have an AdCom. I think it would be unusual to now have an AdCom for a next-in-class compound. But I guess it's theoretically possible, it's not our base case assumption.

Our next question will come from Ash Verma from UBS.

I have 2. So regarding just the presentation on Monday, like from your perspective, what do you think is the bar for the LV at less than 40% event from the SEQUOIA study? What level of LV less than 40% would give you the conviction that the FDA could actually indeed be discerning in viewing your safety profile as differentiated from Camzyos? And then second, on the oHCM market, just in the long run, do you think fundamentally, there is a lot of diagnosis expansion that you could drive? oHCM is sometimes compared to ATTR binders, and that has seen pretty significant diagnosis expansion? Just if you can frame what's the difference between the 2.

So I might ask Fady to speak to the comments about ES below 40%, but recognizing our top line press release already speaks to some of those matters.

Yes. I was going to say that as we said in our top line that we didn't have any treatment discontinuations for EF less than 40%. And the protocol mandated those if they were observed at the site. We'll expand on that in the presentation, I suppose. But again, I don't think n of 0 or 1 is going to be any -- be all that contributory, if you will. Things that don't happen are a good to know, and they're certainly supportive of the safety profile. We've never had an event of heart failure due to aficamten and treatment interruptions have been almost nonexistent. And so I think, overall, those are all very promising things with regards to the potential labeling down the road. And I don't think we understood your second question, which I guess we'll entertain.

Yes. Just like quickly, I mean, in terms of like just the diagnosis expansion of oHCM, right, I mean, one could argue that, yes, it has a high unmet need, but the mortality and mobility burden is not as high as something like ATTR which has seen a significant diagnosis expansion. So do you believe that in the long run, you could potentially drive a lot of diagnosis expansion? I mean, this one has been doing a lot and other marketing campaigns are still not driving any kind of a meaningful inflection on Camzyos. So just trying to understand if this oHCM market is sort of where it is? Or could we see like a material expansion in the long run?

Yes. I don't think the disease burden here is defined by mortality incidents as much as symptom burden and other matters that read on functional life and quality of life. And it's very clear that patients who receive a cardiac myosin inhibitor are very adherent and compliant with their therapy. Look at the data for Camzyos. These are patients who are benefiting substantially from receiving a new therapy and want to stay on that therapy. And I do believe that, that's ultimately going to be defining on what could be the opportunity for category expansion. Andrew, anything you want to add to that?

Yes. I would say that's probably part of the remit of what we're doing in a QoR. If you think about some of the secondary endpoints like improvement in New York Heart Class Association, improvement in KCCq, reduction for the need of septal therapy, and surgery, all those speak to improvement in health outcomes and improvement in cost savings. So I think you'll start to see some more publications and us talking to that and then merging that with large data sets to show the impact it can have on larger populations. So it may be not as obvious as something as [ ATTR ], but it's certainly something I think you're going to see over time that the expertise that we have in [ a QoR] around this area will certainly lead to what you're describing.

And our next question will come from Sean McCutcheon from Raymond James.

Can you comment on the patients you will enroll in the Phase II study for 586 or maybe what subset do you think has the clearest pathophysiologic rationale and how you're thinking about the Phase II in terms of parsing the HFpEF subsets and maybe broad strokes on the size of the opportunity in those restrictive populations?

Yes. Sure. I'll ask Stuart to answer that, but in sort of general terms, I'll just mention ahead of time that as Robert said earlier, the NHCM patients that responded so well in the Phase II study kind of provide a human model of the type of HFpEF patients we want to study with CK-586, and maybe Stuart can expand on those characteristics generally.

Yes. Thanks, Fady. I think that's right. We believe that for a subgroup of patients with severe diastolic dysfunction may be in large part driven by patients with hypercontractility and some of these patients develop ventricular wall thickening just like patients with non-obstructive HCM. And so the outcome in patients we observed in Phase II and the REDWOOD-HCM, but non-obstructive HCM really reads -- informs potential benefit and improvement of diastolic function in the subgroup of patients with HFpEF. And so we'll be looking -- we'll be evaluating patients who have a relatively high ejection fraction, some degree of ventricular wall thickening who are symptomatic and having functional and symptomatic heart failure symptoms related to their disease to see if those patients could benefit from treatment. So that's generally the population we'll be targeting.

Andrew, do you want to speak in general terms approximately around how we're thinking about the subsets of HFpEF from a prevalence standpoint? Andrew, you might be on mute.

Yes. HFpEF, just all probably from our press releases, around half of the overall market. We're describing here is a subset of HFpEF in the upper range of ejection fraction. And I think once we start to learn more in Phase II, we'll probably hone in more of exactly the size of that subset and where the cutoff is.

And I am showing no further questions from our phone lines. I'd now like to turn the conference back to Robert Blum, President and CEO, for closing remarks.

Thank you, operator, and thank you to the analysts for some excellent questions. We're excited to have shared this update with you, especially as it pertains to our expanded focus on the development program for aficamten. And at the same time, we believe that we're being good financial stewards as we think about capital diversification and capital deployment and efficiencies. And we're looking forward to updating you on continued progress including with our presentations next week, Monday, May 13 at the European Heart Failure meetings and afterwards. We thank you for your interest in Cytokinetics and we'll look forward to the next earnings call. Operator, with that, we can now conclude the call.