Earnings Call Transcript - CYTK Q3 2024

Operator, Operator

Good afternoon, and welcome to Cytokinetics' Third Quarter 2024 Conference Call. This call is being recorded, and all participants are in a listen-only mode. After the presentation, we will open the call to questions at the company's request. I will now turn the call over to Diane Weiser, Cytokinetics' Senior Vice President of Corporate Affairs. Please go ahead.

Diane Weiser, SVP of Corporate Affairs

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 clinical development program for aficamten; Andrew Callos, EVP and Chief Commercial Officer will address commercial readiness activities for aficamten; Stuart Kupfer, SVP and Chief Medical Officer, will provide updates regarding omecamtiv mecarbil, CK-586 and our earlier stage development pipeline; Sung Lee, EVP and Chief Financial Officer, will provide a financial overview of the third quarter. And finally, Robert will review our corporate development strategies and review expected upcoming milestones. Please note that portions of the following discussion, including our responses to questions, contain statements that relate to future events and performance rather than historical facts and constitute forward-looking statements. Our actual results might differ materially from those projected in these forward-looking statements. Additional information concerning factors that could cause our actual results to differ materially from those in these forward-looking statements is contained in our SEC filings, including our current report regarding our third 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.

Robert Blum, CEO

Thank you, Diane, and thanks to all for joining us today. As we communicated just a few weeks ago at our Investor and Analyst Day, we made significant progress across our pipeline in the third quarter. Most importantly, we completed the rolling submission and submitted our new drug application to the FDA for aficamten. This is an exciting milestone for Cytokinetics as well as the physician and patient communities, and it brings us one step closer to hopefully bringing aficamten to patients suffering from obstructive HCM. It reflects a tremendous amount of work from our colleagues for which we're especially grateful. While we have requested priority review of the submission, our base case is standard review. The next step will be the expected announcement of filing acceptance and assigned PDUFA date. During Q3, we also supported CORXEL, formerly Ji Xing, in filing the NDA in China for aficamten for obstructive HCM, which we're pleased to announce today was recently accepted for filing. Meanwhile, our commercial preparations for the potential approval and launch of aficamten in the United States are ramping up according to plan. As Andrew will elaborate, we're executing pre-launch activities, including recently launching an HCM disease awareness campaign for health care professionals. In addition, we selected third-party external partners to support education, distribution and patient support, altogether forming a tailored patient experience. And we refined sales territory configurations, as well as sales training and recruiting programs in the United States, while we also concurrently hired our initial geographic and functional team leaders in Europe. During the quarter, we continued to present and publish additional data from SEQUOIA-HCM, further strengthening the evidence supporting its potential next-in-class safety and efficacy profile. As Fady will elaborate, the additional analyses show that treatment with aficamten is associated with improvements in exercise capacity, gradients, symptoms, biomarkers, cardiac structure and function, as well as favorable cardiac remodeling. Together, these analyses expand in meaningful ways on the overall profile of aficamten and are enabling of the positioning that we foresee for a next-in-class cardiac myosin inhibitor that we believe can expand the category and activate broader adoption. Beyond aficamten, we prepared to start two new clinical trials from within our emerging specialty cardiology franchise, COMET-HF, the confirmatory Phase III clinical trial of omecamtiv mecarbil, and AMBER-HFpEF, the Phase II clinical trial of CK-586. As Stuart will share, each of omecamtiv mecarbil and CK-586 offers an opportunity to expand our specialty cardiology franchise by targeting underserved populations at opposite ends of the spectrum of heart failure, those with severely reduced ejection fraction and those with supernormal ejection fraction. Finally, while our specialty cardiology franchise remains our top priority, our research dedicated to novel muscle-directed therapies has continued within our labs in South San Francisco, and our long-standing innovation in muscle biology continues with another promising drug candidate called CK-089, readying to begin a first-in-human study. CK-089 is a fast skeletal muscle troponin activator, which we believe may have potential therapeutic applications for a specific type of muscular dystrophy. You'll be hearing more about how we have applied lessons learned from prior fast skeletal troponin activators to our next-level plans for CK-089 as it will soon begin clinical development in this fourth quarter. Where we stand today at Cytokinetics is a reflection of thoughtful planning, strategic positioning and prudent capital deployment, all in service of realizing the full potential of our muscle biology platform. We are not a company expecting to simply build for the success of a single drug candidate. Instead, we're focused on building momentum across our pipeline and planning for our future by prosecuting a portfolio of multiple muscle-directed drug candidates designed to address diseases of high unmet need. By doing so, we hope to impact the lives of both patients as well as return meaningful value to shareholders in enduring ways. With that, I'll turn the call over to Fady, please.

Fady Malik, EVP of R&D

Thanks, Robert. In the third quarter, we presented additional data from SEQUOIA-HCM and FOREST-HCM at three medical congresses, the European Society of Cardiology Congress, the Hypertrophic Cardiomyopathy Society Scientific Sessions and the Heart Failure Society of America Annual Scientific Meeting. These prespecified analyses build on the primary results presented and published earlier this year to dig deeper into the profile of aficamten. The depth and volume of these analyses is truly extraordinary with eight presentations, five being late breakers, plus five simultaneous publications in leading cardiac journals. Each of these analyses exceeded our best-case expectations for aficamten and gives us confidence in the opportunity for aficamten to address the significant unmet need in obstructive HCM. Key amongst the additional data from SEQUOIA-HCM are findings that show that aficamten may be associated with favorable cardiac remodeling and improvements in several measures of cardiac structure and function. Together, these data show that aficamten appears to change the architecture of the heart and its potential to be disease modifying, something that's key to changing the trajectory of HCM. Other analyses from SEQUOIA-HCM presented during the quarter showed that treatment with aficamten improved patient symptoms, quality of life, and cardiac biomarkers. Furthermore, a responder analysis showed aficamten was associated with broad clinical efficacy as the majority of patients who received aficamten in SEQUOIA-HCM achieved one or more clinically relevant outcomes. One of the four prespecified outcomes was a complete hemodynamic response, defined as having a resting LVOT gradient of less than 30 and a Valsalva LVOT gradient of less than 50, which was achieved by two-thirds of patients in SEQUOIA-HCM. These data were complemented by findings from an integrated safety analysis that pulled data from REDWOOD-HCM, SEQUOIA-HCM and FOREST-HCM and reinforced the safety profile of aficamten. Finally, an analysis of open-label data from FOREST-HCM showed that the majority of patients who attempted withdrawal of standard of care medications at the discretion of an investigator were successful, with some patients achieving monotherapy, suggesting that the potential for aficamten to be tolerated and effective as monotherapy in patients with obstructive HCM. This hypothesis is being explored further in the MAPLE-HCM trial, which I'll address in a moment. Five of the recent publications were recently assembled collectively in the November 5 issue of the Journal of American College of Cardiology, nearly an entire issue devoted to aficamten. As we continue to curate the data from SEQUOIA-HCM, each subsequent analysis elaborates on the primary results from SEQUOIA-HCM to reinforce the effect of aficamten on clinical outcomes, symptom burden, cardiac biomarkers and cardiac structure and function. Together, this large and growing body of evidence paints a clear picture of the relevance of aficamten to clinical practice as a next-in-class cardiac myosin inhibitor and potentially the cardiac myosin inhibitor of choice for both physicians and patients. All of these clinical work streams also continue to be supported by our medical affairs organization. During the quarter, our field medical teams met with health care professionals, including many HCM KOLs, hospital and IDN leadership and formulary decision-makers to discuss and educate about the results from SEQUOIA-HCM. Now moving to the ongoing clinical trials program for aficamten. We're pleased to report that during the third quarter, we completed enrollment in MAPLE-HCM. Through the rest of this year, we will continue conducting this important trial, and we expect to share results from MAPLE-HCM in the first half of 2025, ahead of when we hope to launch aficamten commercially. If positive, MAPLE-HCM represents the first potential label expansion opportunity for aficamten with results that may provide the rationale to position it as first-line therapy in practice guidelines. During the quarter, we also continued enrollment in ACACIA-HCM, the pivotal Phase 3 clinical trial of aficamten in patients with symptomatic non-obstructive HCM. We now have activated over 90 sites in 13 countries, ensuring that the results from ACACIA-HCM will be representative of a broad and diverse study population. Enrollment is brisk, and we expect to continue to activate new sites and enroll patients at existing and new sites through this year and into next year towards our goal of completing enrollment in 2025. Additionally, we continued conduct of CEDAR-HCM, evaluating the pediatric population of patients with symptomatic obstructive HCM as well as an additional Phase 1 study of aficamten in healthy Japanese and Caucasian participants that may support development of aficamten in Japan. Altogether, I'm proud of the substantial progress we made across the clinical development program for aficamten in the third quarter. Now I'll turn it over to Andrew.

Andrew Callos, EVP and Chief Commercial Officer

Thanks, Fady. In the third quarter, we continued our commercial readiness activities for the potential approval and launch of aficamten in the U.S. We were pleased to launch HCM Beyond the Heart, an unbranded disease awareness campaign for healthcare professionals. The campaign was borne out of market research and real-world feedback from cardiologists, nurses and patients and highlights the story of five individuals living with HCM to illuminate the multidimensional struggle faced daily by people living with HCM. We are planning to showcase this campaign at the upcoming AHA Scientific Sessions in Chicago next week, and we plan to launch a similar patient-focused unbranded awareness campaign in the first quarter of 2025. The launch of HCM Beyond the Heart also marked the first deployment of our omnichannel digital communication strategies, which has successfully validated our investment in planning and set the stage for broader digital engagement to come ahead of and through the time of potential approval and launch in 2025. During the third quarter, we selected third-party external partners for our bespoke patient experience, which we believe is a key element of differentiation for our potential commercial launch. We also made significant progress towards solidifying our promotional launch campaign. Additionally, we advanced our sales force preparations, including finalizing our customer call list and establishing the geographic boundaries for our planned sales territories. We have also designed a robust recruiting plan and training curriculum for the approximately 125 to 150 reps we expect to bring on board. While we do not plan to hire sales reps until closer to launch next year, we already have hundreds of qualified candidates in our pipeline prior to going out into the marketplace to recruit. From the payer side, we continued pre-approval information exchange with key payers and made progress in developing our payer value dossier for both U.S. and ex-U.S. payers. Our SEQUOIA team was also active in presenting and publishing research highlighting the unmet need in HCM, the associated cost burden given current treatment and the potential value of aficamten in HCM. Moving on to commercial readiness activities in Europe, our plan is to prioritize major markets and gate hiring and capital deployment alongside regulatory and reimbursement milestones at a country level. During the third quarter, we designed our distribution model, refined regulatory and labeling strategies, established country launch sequencing, engaged with European key opinion leaders and progressed development of HTA dossier while continuing to engage with key HTAs for early scientific advice. We also established our initial go-to-market plan for Germany, which is expected to be the first country where we launch aficamten in Europe. We now have a head of Europe in place and are recruiting for key country leadership in the UK and France, as well as functional leadership roles for European operations, again, alongside gated investment. As we get closer to the potential approval of launch of aficamten, our commercial readiness activities are continuing to ramp up. Importantly, what we're building today for aficamten will enable synergies with future potential commercial launches across our specialty cardiology franchise. Shared resources, systems, commercial infrastructure and sales organization will facilitate enhanced efficiencies and effectiveness with each specialty cardiology launch. With that, I will turn the call over to Stuart.

Stuart Kupfer, SVP and Chief Medical Officer

Thanks, Andrew. I'll start with CK-586, our next cardiac myosin inhibitor for the potential treatment of a subset of patients with heart failure with preserved ejection fraction or HFpEF, and hypercontractility. During the quarter, we presented the full data from the Phase 1 study of CK-586 at the American College of Clinical Pharmacology, which showed that CK-586 was safe and well tolerated. No serious adverse events were observed and no study stopping criteria were met. The half-life of CK-586 was observed to be between 14 to 17 hours. CK-586 demonstrated dose proportional exposure and a PK/PD relationship for left ventricular ejection fraction that appeared shallow and predictable. At the highest single dose of 600 milligrams, the mean decrease in ejection fraction was less than 5%. Together, these data demonstrate pharmacologic properties that may enable once-daily fixed dose administration. Because the data from this Phase 1 study were supportive of advancing to Phase 2, we began start-up activities for AMBER-HFpEF, which is the Phase 2 clinical trial of CK-586 in patients with symptomatic HFpEF with ejection fraction of at least 60%, designed to evaluate the safety, tolerability and pharmacodynamic profile of CK-586 compared to placebo. We're pleased to share that we're on track to start AMBER-HFpEF before the end of the year. Next, let's move to omecamtiv mecarbil, our cardiac myosin activator for the potential treatment of a subset of patients with heart failure with severely reduced ejection fraction. During the quarter, we conducted study start-up activities for COMET-HF, the confirmatory Phase 3 clinical trial assessing the efficacy and safety of omecamtiv mecarbil in 1,800 patients with symptomatic heart failure with severely reduced ejection fraction less than 30%. COMET-HF is designed with pragmatic features to improve efficiency of study conduct and reduce patient burden. We expect to begin this trial during this fourth quarter. Heart failure with reduced ejection fraction or HFrEF represents about half of the population of heart failure. Drilling down further, estimates point to a large and growing population of patients with high-risk heart failure and severely reduced ejection fraction below 30%. These are patients who have recurrent heart failure events. They may have limiting use of guideline-directed medical therapy due to poor tolerability and have very elevated NT-proBNP consistent with severe heart failure. Despite the use of SGLT2 inhibitors with a large residual risk of cardiovascular events in this subset of patients with HFrEF. In GALACTIC-HF, this subset of patients with severely reduced ejection fraction experienced a substantially greater treatment benefit with omecamtiv mecarbil. Whereas omecamtiv mecarbil is targeting patients with HFrEF, CK-586 is designed to address patients with supernormal ejection fraction at the opposite end of the spectrum of heart failure. These patients also have high unmet need and despite advances in care with SGLT2 inhibitors have a poor prognosis following heart failure hospitalization. While the pathophysiology of these two heart failure populations is different, medical need for both patient subgroups remains high despite guideline-directed medical therapy with markedly increased risk of cardiovascular mortality and hospitalization for acute decompensated heart failure. Both omecamtiv mecarbil and CK-586 represent opportunities to expand our specialty cardiology franchise into these populations at either end of the heart failure spectrum. Now looking beyond our specialty cardiology franchise, as Robert mentioned, we're pleased to be renewing our neuromuscular pipeline with a novel drug candidate arising from our research called CK-089. CK-089 is a fast skeletal muscle troponin activator or FSTA, designed to amplify skeletal muscle response to nerve input, extending time to fatigue and increasing muscle force and power with potential therapeutic application to a specific type of muscular dystrophy. Having completed IND-enabling studies, we expect to start a first-in-human Phase 1 study of CK-089 in healthy subjects soon. We look forward to sharing more details of our plans to reinvigorate our neuromuscular development activities as informed by prior learnings very soon. What this means is that by the end of this year, we will have one or more drug candidates in each phase of clinical development from Phase 1 to Phase 3, which conveys the richness of our pipeline in muscle-directed therapies. And with that, I will pass it over to Sung.

Sung Lee, EVP and CFO

Thanks, Stuart. We're pleased to report our third quarter of 2024 financial results. Starting with the balance sheet. We finished the third quarter of 2024 with approximately $1.3 billion in cash, cash equivalents and investments compared to $1.4 billion at the end of the second quarter of 2024. Cash, cash equivalents and investments declined by approximately $81 million during the third quarter of 2024. Moving on to the income statement. Total revenues in the third quarter of 2024 were $0.5 million compared to $0.4 million for the same period in 2023. R&D expenses in the third quarter of 2024 were $84.6 million compared to $82.5 million for the same period in 2023. The increase was primarily driven by higher personnel-related expenses to progress our pipeline, partially offset by the completion of clinical trials in 2023. G&A expenses in the third quarter of 2024 were $56.7 million compared to $40.1 million for the same period in 2023. The increase was primarily driven by investments for commercial readiness and personnel-related expenses. Net loss for the second quarter of 2024 was $160.5 million or $1.36 per share basic and diluted compared to a net loss of $129.4 million or $1.35 per share basic and diluted for the same period in 2023. Turning to the financial guidance for 2024. We are reiterating all aspects of our prior guidance, which can be found in our press release. As we head towards the end of 2024, our balance sheet remains an asset and positions us well to prepare for the potential launch of aficamten, advance our earlier and later-stage pipeline and invest in our proven muscle biology platform. We stand to realize synergies from the commercial and R&D investments as our potential future medicines and development activities can all leverage the infrastructure and capabilities that we are creating today and in the years to follow. We believe these capital allocation priorities can enable us to become a leader in specialty cardiology with multiple medicines, delivering benefits for patients and sustainable growth for investors. With that, I'll hand it back over to Robert.

Robert Blum, CEO

Thank you, Sung. The third quarter indeed was marked by important achievements, continuing a year marked by substantial progress. By this time next year, we expect that our company will look quite different, and we're building our infrastructure and capabilities to ensure our successes in the years to come. To that end, during the quarter, we further strengthened our executive leadership team with the addition of Brett Pletcher, who joined as EVP, Chief Legal Officer in August. Brett is a seasoned attorney and industry executive with deep experience developing operational reach and capacity and providing practical legal advice, having spent 17 years at Gilead, 13 of those as General Counsel. We're fortunate to have Brett join our team as we look ahead to the next important chapters for Cytokinetics and increased scope and scale as we mature corporate development. Cytokinetics is well-funded and well-positioned for future successes. As we advance towards the potential approval and launch of aficamten in the United States with global launches hopefully to follow, we're approaching an important inflection point for our company. As we look ahead to that point and beyond, we're laying the groundwork for our Vision 2030 and sustained growth and enduring future successes as a premier specialty cardiology company. As you've heard, this business remains anchored in aficamten for the potential treatment of HCM, followed by omecamtiv mecarbil for the potential treatment of heart failure with severely reduced ejection fraction, and then CK-586 for the potential treatment of heart failure with preserved ejection fraction. This franchise design is intentional with common features across these patient populations and the prescribers that treat them, including a limited distribution model, few or ineffective available therapies, and high unmet patient need. Each of these underscore potential for higher return on investment and provide us the ability to realize R&D and commercial synergies. To achieve these objectives, we're committed to investing wisely and maintaining a strong financial foundation to enable both forward motion as well as velocity. Looking back at the quarter, I'm proud of the tremendous progress we've made towards achieving our vision. Now, I'll recap our upcoming milestones. For aficamten, we expect to continue advancing our go-to-market strategies and prepare to launch aficamten in the United States in 2025, of course, subject to FDA approval. We expect to submit an MAA to the EMA in Q4 2024 and coordinate with CORXEL to support the planned launch of aficamten in China in 2025, pending approval. We expect to complete conduct of MAPLE-HCM and share results in the first half of 2025. We expect to continue enrollment in ACACIA-HCM through 2024 with objective to complete enrollment in 2025. And we expect to continue enrollment in CEDAR-HCM, the Phase I as well as the Phase I study of aficamten in Japanese and Caucasian participants. And for omecamtiv mecarbil, we expect to start COMET-HF, the confirmatory Phase III clinical trial in this Q4 2024. For CK-586, we expect to start AMBER-HFpEF, the Phase II clinical trial also in this Q4 2024. And for earlier clinical development, preclinical development and ongoing research, we expect to initiate clinical development of CK-089 by starting a Phase I study in healthy volunteers in this fourth quarter and we expect to continue ongoing preclinical development and research activities directed to additional muscle biology-focused programs through this year. Operator, with that, we can now please open the call up to questions.

Operator, Operator

Thank you. Our first question will come from Akash Tewari from Jefferies. Your line is open.

Unidentified Analyst, Analyst

Hi. Thank you for taking my question. This is Phoebe on behalf of Akash. Looking at the SEQUOIA data, it appears that the most significant reductions in LVF were observed in hypercontractile patients with an LVEF greater than 75. If you had a method that could demonstrate gradient relief benefits without impacting LVF, would it be considered, and would it be clinically beneficial for patients with severe hypercontractility? Additionally, would you still anticipate seeing a benefit on pVO2? Thank you.

Robert Blum, CEO

Thank you. I'll ask Fady to respond to that, please.

Fady Malik, EVP of R&D

Yeah. I think the underlying point that you made is that this is a disease of hypercontractility. And in some cases and in most cases, it leads to obstruction as well. Having an ejection fraction of 80% is just not normal. It's not normal even in people that have that don't have hypertrophic cardiomyopathy. And so we think one of the targets in treating this disease is to both reduce the contractility to more normal levels so that the tissue remodeling, the myofibral array, the cardiac wall stresses can all begin to decline as well as to reduce the gradient. And so I don't know if just treating obstruction by itself is sufficient. You can do that with septal reduction therapy, for instance, and that does result in substantial improvement in patient symptoms. But often, they go on to develop non-obstructive HCM and issues over time as their disease progresses. So I don't believe that just treating but not decreasing the hypercontractility is potentially a therapeutic benefit.

Operator, Operator

Thank you. Our next question will come from Tess Romero from JPMorgan. Your line is open.

Robert Blum, CEO

Good afternoon, Tess.

Tess Romero, Analyst

Good afternoon, Robert and team. Hope you're all well. Thanks for taking the question. So on the Phase III MAPLE-HCM trial in patients with symptomatic OHCM, how confident are you in a positive trial here? And specifically, could you walk us through the magnitude of change for aficamten over metoprolol you need to hit a p-value that is significant? And relatedly, what can you tell us on how the patients that enrolled aligned with your expectations?

Robert Blum, CEO

Good questions. Obviously, as we approach the readout of MAPLE-HCM expected next year, we believe that this study will play an important role in consideration and adoption of aficamten, hopefully also in line with evolving guidelines. And the study, MAPLE-HCM was specifically designed, if anything, perhaps as would be accelerating what would otherwise be potentially a Phase IV study and could enable label expansion. I'll ask Fady to speak to how we design the study and how we feel about the patients that were enrolled.

Fady Malik, EVP of R&D

Yes. Hi, Tess, this study has been very well received by the investigator community as it addresses a significant question for them. In terms of patient enrollment, we've performed well in enrolling patients who meet the target criteria and show meaningful symptoms and reductions in their exercise capacity. By starting treatment with aficamten or metoprolol, we will be able to evaluate the benefits of each therapy and compare them. For several reasons, we believe aficamten has demonstrated benefits beyond beta blockers. These patients, who were symptomatic and had an inadequate response to beta blockers, subsequently responded well to aficamten. In the SEQUOIA study, we had patients on aficamten not on beta blockers, and patients on beta blockers without any other therapies. This provided insight into what we anticipate here, with results aligning with our hypothesis for this trial. I won’t speculate on what constitutes a meaningful change or how significant that change might be. We have cautiously powered the trial, aiming for a delta peak VO2 of about 2 with sufficient power to detect changes down to approximately 1.5 in peak VO2, which encompasses the area where SEQUOIA showed positive results. We believe we are adequately powered, and we are looking forward to the results.

Tess Romero, Analyst

Great. Thanks so much for taking our question.

Fady Malik, EVP of R&D

Thanks, Tess.

Robert Blum, CEO

Thank you.

Operator, Operator

Thank you. And our next question will come from Salim Syed from Mizuho. Your line is open.

Robert Blum, CEO

Hello, Salim.

Salim Syed, Analyst

Hey, Robert. Thanks for the color and the question. I guess one for me on MAPLE as well. Assuming you guys actually get the result you want here, could you just maybe give us your thoughts on getting those results published and into treatment guidelines? Like how often does the committee meet and when that could potentially happen? Could it happen prior to the supplementary approval? Thank you.

Robert Blum, CEO

Yes. So obviously, we can't commit for what others will be doing, but the guidelines are updated in a continuous way and regularly, not just once a year. And as you've seen already in this year, we've been aggressive about ensuring that data go quickly from presentation to publication. I think we've had a quite uncommon number of presentations and publications this year, underscoring how closely we're working with the academic community to make sure these data get properly peer reviewed and published for consideration. So that won't change next year.

Salim Syed, Analyst

Do you believe it’s possible to complete it before the official approval? I think the key requirement is publication, right?

Robert Blum, CEO

Well, for consideration of guidelines, you're saying?

Salim Syed, Analyst

Yes. Yes, correct. Yes.

Robert Blum, CEO

I would think that that makes a big difference. And it's certainly our goal to get it published as soon as possible next year. I don't think we should be ahead of even having the data committing to whether that would be ahead of potential approval. But knowing that this is our objective, I think you should assume we'll continue to be very aggressive.

Operator, Operator

Thank you. Our next question will come from Roanna Ruiz from Leerink Partners. Your line is open.

Robert Blum, CEO

Good afternoon.

Unidentified Analyst, Analyst

Hi. Good afternoon. This is [indiscernible] on for Roanna. Thanks for taking our questions. Maybe first on MAPLE, I have a question regarding the results for aficamten compared to metoprolol next year. What could the peak VO2 improvement with aficamten look like in this study compared to what you saw in SEQUOIA previously? Also, what is the outlook on the timeline for possible guideline adoption of aficamten in earlier lines of therapy if the MAPLE data are positive?

Robert Blum, CEO

I feel like we might have just answered that, but maybe I'll turn to Fady and see if there's anything more he might want to add.

Fady Malik, EVP of R&D

Yes. I mean I just will reiterate in SEQUOIA, we had 1.74 ml per kilo per minute improvement in patients not on beta blockers. That effect was modestly bigger. So we're kind of in that range of peak VO2 improvement. Prior publications of metoprolol use in HCM showed that metoprolol doesn't increase peak VO2. And so you can guess that if we're in the same ballpark, we might see something in that range. This is a smaller study than SEQUOIA was. We're treating patients who are slightly less symptomatic because we wanted to sort of expand the aperture to naive patients and newer patients. So the exact effect size is a little tricky to handicap, but I don't think the exact effect size is really what's important. What's important is that there is a meaningfully different and better effect of aficamten to improve exercise function and symptoms than metoprolol does in these patients, and that should guide its use in therapy. As to the guidelines, I mean, we'll present this. We'll get it published, I think, fairly rapidly. The guideline committees, they don't publish their meeting schedules. They don't publish their timing of updating guidelines, but they are aware that this is a fast-moving field and that they do need to be timely and sort of considering the evidence and revising their guidelines. So leave it at that.

Unidentified Analyst, Analyst

Got it. And then maybe if I may, could you comment about how you're thinking about the European launch dynamics for aficamten if it's approved? And I guess, any learnings that you could apply based on what you're seeing from the competitor launch throughout Europe? Thank you.

Robert Blum, CEO

So we're really just taking one question for analysts right now, but I suspect you'll get to your question answered as we go through what looks to be a very long list of folks who want to ask questions. We'll come back to that. Operator, if we can move to the next one, please.

Operator, Operator

Thank you. Our next question comes from Jason Zemansky from BofA. Your line is open.

Robert Blum, CEO

Hey, Jason.

Cameron Bozdog, Analyst

Hey, good afternoon. This is Cameron Bozdog on for Jason. Congrats on the quarter. And thanks for taking our question. So in terms of leveraging the aficamten profile to warrant a potential pricing premium, I guess, what factors are likely to be critical here? Is it going to be efficacy, safety, the administrative profile? Or I guess, in other words, do you think less frequent LVEF reductions below 50% in SEQUOIA versus EXPLORER is enough to warrant a pricing premium? Or would you need to see the safety benefit reflected in the monitoring protocols or the label to establish a basis for a premium here? Thank you.

Robert Blum, CEO

So first off, your question is kind of presupposing that there'll be a pricing premium, and we haven't spoken to that. But instead, we've referred to pricing within a relative same ZIP code. But maybe I'll ask Andrew to comment, if you will, on what we believe is ultimately going to translate to wider adoption for a next-in-class therapeutic in this category.

Andrew Callos, EVP and Chief Commercial Officer

Yeah. So I think Robert answered the pricing, and I'm assuming you're asking about US pricing where we have the ability to set the price. But in the U.S., we'll be in the proximity of what the established price for the market is. In terms of uptake of payers based on price, we're certainly going to be working and have already been with commercial payers. We're working on medical exception for Medicare payers. I think we addressed IRA challenges, which is an industry challenge, not unique to us, and that's how we'll get access; that we believe will be within parity of competition. So we've really been taking that out of the equation and focusing on educating, promoting and uptake as well as supporting patients.

Robert Blum, CEO

So the market research we've done underscores the importance of risk mitigation and ultimately how that can translate to hopefully more physicians prescribing a cardiac myosin inhibitor for more patients. And we do hope that if approved, aficamten could be accompanied by a risk mitigation profile that fits with next-in-class objectives.

Operator, Operator

Thank you. Our next question will come from Sean McCutcheon from Raymond James. Your line is open.

Robert Blum, CEO

Hey, Sean.

Sean McCutcheon, Analyst

Thank you for taking my question. Regarding CK-586, could you share the insights gained from the EMBARK results? How do you assess the similarities or differences between the target patients and those in EMBARK? Additionally, which pharmacologic properties do you consider most valuable if the mechanism is validated in the sub-segment of HFpEF patients? Thank you.

Robert Blum, CEO

Sure. So that's a good question for Stuart, maybe to pick up on and Fady, if he wants to add anything.

Stuart Kupfer, SVP and Chief Medical Officer

Sure. Thanks for the question. So first of all, we're very encouraged with the potential benefit in this population with CK-586 in large part from the data we observed in non-obstructive HCM with aficamten. And similar results were observed with mavacamten and nondestructive HCM in terms of the pharmacodynamic improvement, symptomatic improvement. But the EMBARK data do inform and encourage a potential benefit of CK-586 in this population of HFpEF patients with hypercontractility. Now, we are enriching a population, of course, with an ejection fraction of at least 60%. We have a lot to learn in terms of the potential dosing range that may be effective and safe and tolerable. And so, this first inpatient study will help us characterize the pharmacodynamic benefits. We'll be measuring cardiac biomarkers such as NT-proBNP, cardiac troponin and as well, of course, evaluating ejection fraction. And what we observed, I think, very favorably in our Phase 1 studies is a very shallow exposure response profile with respect to only small incremental decreases of ejection fraction with increasing doses of CK-586. So I'm not going to go into a lot of speculation about comparing study designs or the data from EMBARK, but the data we've accumulated so far are very encouraging with CK-586 as well as aficamten in non-obstructive HCM. And so we're quite optimistic and look forward to this Phase 2 trial.

Robert Blum, CEO

The EMBARK study was not a large study, and therefore, there's still a lot to be learned from testing a cardiac myosin inhibitor in a larger, longer study. So our goal will be to do a proper development program for CK-586 to inform CK-586.

Stuart Kupfer, SVP and Chief Medical Officer

No. I just want to add that this is a placebo-controlled trial. It will be a much more rigorous assessment of the cardiac myosin inhibitor in this population with HFpEF and hypercontract as opposed to EMBARK.

Robert Blum, CEO

Yes. Thank you, Stuart.

Operator, Operator

Thank you. Our next question will come from Paul Choi from Goldman Sachs. Your line is open.

Robert Blum, CEO

Good afternoon, Paul.

Paul Choi, Analyst

Good afternoon, Robert and team. Thank you for taking our question. I just want to return to the subject of MAPLE and with regard to any sort of clinical efficacy bar that has been potentially discussed with payers as they think about potential guideline changes there. And have they provided any feedback to you or any sort of physician community commentary on just sort of what would be considered clinically meaningful here versus metoprolol as to drive guideline changes here? Thank you very much.

Robert Blum, CEO

Yes. So I'll ask Andrew to comment, but I think it would be premature for us to be talking about MAPLE with payers before we have data from MAPLE and before we have even an approval potentially based on SEQUOIA. But we are gathering insights into how payers think about these things in a general sense. So maybe, Andrew, if you could comment, please?

Andrew Callos, EVP and Chief Commercial Officer

Certainly. As Robert mentioned, our current focus with payers is on SEQUOIA. Strategically, we are exploring how to incorporate MAPLE into conversations with payers and value discussions both in the US and Europe. From a physician's perspective, MAPLE offers two main benefits. It broadens the physician population since some physicians are indifferent to new treatments and prefer to stick with beta blockers due to their lack of experience with cardiac myosin inhibitors. Presenting a direct comparison to their current options can help attract more physicians, thereby increasing market size. Additionally, if we have a secondary study with results similar to our expectations, it can validate our primary study and enhance preference shares. This alignment should facilitate guideline acceptance, market expansion, and strengthen value arguments in both the US and Europe. However, we are not currently engaging with payers about MAPLE.

Paul Choi, Analyst

Okay, great. Thank you.

Robert Blum, CEO

Thank you.

Operator, Operator

Thank you. Our next question comes from Jason Butler from Citizens JMP. Your line is open.

Robert Blum, CEO

Good morning, Jason.

Jason Butler, Analyst

Hi, Robert. Thanks for taking the question. Just a quick one on CK-089. You guys have a long history with this class. Can you just, at a high level, just tell us how 089 differs from the prior candidates? Thanks.

Robert Blum, CEO

Yeah. So 089 comes from a very different chemical scaffold, and for which I'll ask Fady to comment in a moment. But please understand that we've applied learnings to our interest as it relates to 089 and in particular, you'll hear more about how we're developing it going forward, underscoring that we're not going to be pursuing the development of 089 in ALS, but rather in a muscular dystrophy and in fact, a rare form of disease where we think it may play a potential role. Fady, do you want to comment on how it may differ from prior fast skeletal compounds?

Fady Malik, EVP of R&D

Yeah. I mean, CK-089 is a third molecule, and we view each iteration have come to a molecule that is more potent, has better pharmaceutical properties. It's a challenging target, and we think 089 maximizes the efficacy that we can pull out of this mechanism of action, at least in preclinical models and is better suited in terms of its physical properties for doing dosing and dose ranging and so forth. So still early days. We have some very interesting and promising preclinical data, and we'll be looking to see if we can translate that going forward into the clinic.

Robert Blum, CEO

The world has evolved quite a bit around skeletal muscle since we were advancing two prior compounds. And we're borrowing from those learnings, too, in terms of how we think about skeletal muscle force, power, endurance, fatigue, and muscle function. And we do believe that CK-089 has an opportunity to establish a position where some others have been building value for shareholders. And again, you'll hear more about our plans as we roll forward into Phase I and hopefully beyond.

Operator, Operator

Thank you. Our next question comes from Charles Duncan from Cantor Fitzgerald. Your line is open.

Unidentified Analyst, Analyst

Hi team. This is Asiya on behalf of Charles. Thank you for taking our question. We have one question regarding omecamtiv mecarbil. As you approach the initiation of COMET-HF, what is your perspective on its competitive position in the heart failure market, especially as other treatments for heart failure with reduced ejection fraction are being developed?

Robert Blum, CEO

Thank you, an excellent question. I think it warrants being answered by both Fady and Stuart, as well as Andrew may have a perspective on that, and I'll ask our team to comment, starting with Fady, please.

Fady Malik, EVP of R&D

Well, sure. I think in the population that we plan to study omecamtiv mecarbil in people with severely reduced ejection fraction and really severe heart failure, there are a few new options. Many of the drugs that are developed lower blood pressure. They can be challenging to use in these patients because they impact kidney function. And they don't address the core element of why these patients are so symptomatic at this point in their disease process, which is their cardiac function has deteriorated substantially and is now severely reduced. So, I think omecamtiv has sort of a unique place in terms of being used in this area, and it's conceptually easy to understand why it would benefit these patients, to explain to patients why you would use it. And so I think the enthusiasm that we have been met with as we announced the initiation of this trial, rather than announced the intent to conduct COMET in the heart failure community has been quite large. I get emails weekly, frankly, from investigators that are interested in participating. We're grateful that we're continuing to develop omecamtiv mecarbil because it really fills an unmet need for them in terms of what do they do next when the sort of foundational treatments for heart failure are not working.

Robert Blum, CEO

Stuart, anything to add from the clinical perspective, before we ask Andrew to comment commercially?

Stuart Kupfer, SVP and Chief Medical Officer

Just add that Fady said, these patients are running out of options. And if you look at the profile of risk in this population, there is a marked inflection point at the threshold of 30% ejection fraction. The risk of mortality and acute decompensated heart failure goes up dramatically, ejection fraction less than 30%. And as Fady was mentioning, these patients are running out of options. They really don't have options withdrawing that guideline-directed medical therapy and heading towards end-stage heart failure. And again, what we observed in GALACTIC-HF is that this subset of patients with severely reduced ejection fraction experienced a substantially greater treatment benefit with omecamtiv mecarbil. Whereas omecamtiv mecarbil is targeting patients with heart failure and severely reduced ejection fraction, CK-586 is designed to address patients with super abnormal ejection fraction at the opposite end of the spectrum of heart failure. These patients also have high unmet need and despite advances in care with SGLT2 inhibitors have a poor prognosis following heart failure hospitalization. While the pathophysiology of these two heart failure populations is different, medical need for both patient subgroups remains high despite guideline-directed medical therapy with markedly increased risk of cardiovascular mortality and hospitalization for acute decompensated heart failure. Both omecamtiv mecarbil and CK-586 represent opportunities to expand our specialty cardiology franchise into these populations at either end of the heart failure spectrum. Now looking beyond our specialty cardiology franchise, as Robert mentioned, we're pleased to be renewing our neuromuscular pipeline with a novel drug candidate arising from our research called CK-089. CK-089 is a fast skeletal muscle troponin activator or FSTA, designed to amplify skeletal muscle response to nerve input, extending time to fatigue and increasing muscle force and power with potential therapeutic application to a specific type of muscular dystrophy. Having completed IND-enabling studies, we expect to start a first-in-human Phase 1 study of CK-089 in healthy subjects soon. We look forward to sharing more details of our plans to reinvigorate our neuromuscular development activities as informed by prior learnings very soon. What this means is that by the end of this year, we will have one or more drug candidates in each phase of clinical development from Phase 1 to Phase 3, which conveys the richness of our pipeline in muscle-directed therapies. And with that, I will pass it over to Sung.

Sung Lee, EVP and CFO

Robert Blum, CEO

Thank you, Sung. The third quarter indeed was marked by important achievements, continuing a year marked by substantial progress. By this time next year, we expect that our company will look quite different, and we're building our infrastructure and capabilities to ensure our successes in the years to come. To that end, during the quarter, we further strengthened our executive leadership team with the addition of Brett Pletcher, who joined as EVP, Chief Legal Officer in August. Brett is a seasoned attorney and industry executive with deep experience developing operational reach and capacity and providing practical legal advice, having spent 17 years at Gilead, 13 of those as General Counsel. We're fortunate to have Brett join our team as we look ahead to the next important chapters for Cytokinetics and increased scope and scale as we mature corporate development. Cytokinetics is well-funded and well-positioned for future successes. As we advance towards the potential approval and launch of aficamten in the United States with global launches hopefully to follow, we're approaching an important inflection point for our company. As we look ahead to that point and beyond, we're laying the groundwork for our Vision 2030 and sustained growth and enduring future successes as a premier specialty cardiology company. As you've heard, this business remains anchored in aficamten for the potential treatment of HCM, followed by omecamtiv mecarbil for the potential treatment of heart failure with severely reduced ejection fraction, and then CK-586 for the potential treatment of heart failure with preserved ejection fraction. This franchise design is intentional with common features across these patient populations and the prescribers that treat them, including a limited distribution model, few or ineffective available therapies, and high unmet patient need. Each of these underscore potential for higher return on investment and provide us the ability to realize R&D and commercial synergies. To achieve these objectives, we're committed to investing wisely and maintaining a strong financial foundation to enable both forward motion as well as velocity. Looking back at the quarter, I'm proud of the tremendous progress we've made towards achieving our vision. Now, I'll recap our upcoming milestones. For aficamten, we expect to continue advancing our go-to-market strategies and prepare to launch aficamten in the United States in 2025, of course, subject to FDA approval. We expect to submit an MAA to the EMA in Q4 2024 and coordinate with CORXEL to support the planned launch of aficamten in China in 2025, pending approval. We expect to complete conduct of MAPLE-HCM and share results in the first half of 2025. We expect to continue enrollment in ACACIA-HCM through 2024 with objective to complete enrollment in 2025. And we expect to continue enrollment in CEDAR-HCM, the Phase I as well as the Phase I study of aficamten in Japanese and Caucasian participants. And for omecamtiv mecarbil, we expect to start COMET-HF, the confirmatory Phase III clinical trial in this Q4 2024. For CK-586, we expect to start AMBER-HFpEF, the Phase II clinical trial also in this Q4 2024. And for earlier clinical development, preclinical development and ongoing research, we expect to initiate clinical development of CK-089 by starting a Phase I study in healthy volunteers in this fourth quarter, and we expect to continue ongoing preclinical development and research activities directed to additional muscle biology-focused programs through this year. Operator, with that, we can now please open the call up to questions.

Operator, Operator

Thank you. Our first question will come from Akash Tewari from Jefferies. Your line is open.