Good afternoon, and welcome to Cytokinetics' Fourth Quarter 2024 Conference Call. At this time, I would like to inform you that this call is being recorded. And all participants are in a listen-only mode. At the company's request, we will open the call to questions after the presentation. We will allow for only one question per participant. 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; Andrew Callos, EVP and Chief Commercial Officer will address commercial readiness activities for aficamten; Fady Malik, EVP of R&D, will provide updates related to the clinical development program for aficamten; Isaac Ciechanover, EVP Corporate Development and Chief Business Officer will provide an update on the recently announced business development deal in the context of our corporate development; 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 past quarter and discuss our 2025 financial guidance. And finally, Robert will review expected key milestones for the year ahead. 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 fourth 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 to all for joining us on the call today. The fourth quarter of 2024 was an exceptionally productive quarter that rounded out a successful year. Most notably, we made major strides towards potential regulatory approvals and subsequent commercial launches of aficamten across multiple geographies. Our NDA was accepted by FDA. Our MAA was validated by EMA and our NDA was accepted by the NMPA in China with priority review. Now with regulatory submissions on file in the U.S., Europe and China, we're engaging in parallel regulatory interactions that may deliver aficamten to patients around the world. With our PDUFA date of September 26, 2025, our commercial readiness activities in the United States are reaching a peak, while we also lay the foundation for our go-to-market activities in Europe. In the near term, we expect to continue already ongoing activities with FDA in support of their review of the NDA. We have been responding to questions as well as preparing for clinical site and other inspections and we recently submitted our 120-day safety update to FDA. In March, we expect to participate in a mid-cycle meeting with FDA. Ahead of that meeting, I want to level set that we do not plan to share detailed updates following that meeting given that the FDA review of the NDA will still be ongoing. However, we maintain our expectation for a differentiated label and risk mitigation profile for aficamten were it to be approved by FDA. In both SEQUOIA-HCM and FOREST-HCM, in patients with obstructive HCM, we observed a favorable overall safety profile, LVEF stability, rapid dose titration, as well as a lack of treatment interruptions related to episodes of heart failure or hospitalizations related to LVEF. Nor did we observe any clinically meaningful drug–drug interactions. We believe all of these characteristics are consistent with the intrinsic properties of aficamten. Moving on to the regulatory review of aficamten in Europe, following the validation of our MAA in late December, we expect to continue to engage with EMA during their review by responding to requests for information and preparing for inspections. Our next key milestone for these regulatory interactions with EMA is receipt of the day 120 list of questions expected in April. As you know, we plan to commercialize aficamten ourselves in the U.S. and Western Europe. In other key geographies, in the fourth quarter, Sanofi acquired, with our participation from CORXEL, the rights to develop and commercialize aficamten in China. Additionally, in November, we announced our new collaboration with Bayer that entails a license agreement for aficamten in Japan. These two strong pharmaceutical company partners in the two leading markets outside the U.S. and Europe both align with Cytokinetics in their commitment to cardiology and each brings great expertise, resources and reach to enable us to hopefully deliver aficamten to a greater number of HCM patients in need and contribute to our goal to reach patients globally with our medicines. Simultaneously, we're advancing our later stage development program for aficamten with multiple ongoing potential label expansion clinical trials. In the near term, we expect to share top line results from MAPLE-HCM in Q2 and if positive data from this trial may represent again a label expansion opportunity for aficamten following potential FDA approval. Meanwhile, we continue to expand our specialty cardiology franchise and innovative pipeline advancements ensuring that we're more than simply a one-product company. In Q4, we started COMET-HF, a confirmatory Phase 3 clinical trial of omecamtiv in patients with heart failure with severely reduced ejection fraction. And more recently we started AMBER-HFpEF, a Phase 2 clinical trial of CK-586 in patients with heart failure and preserved ejection fraction. Our successes over the past quarter reflect our clear vision, strategic execution and responsible investment in our muscle biology platform. This year, we're approaching a defining moment with key milestones ahead that will shape our future as multiple programs advance in our specialty cardiology franchise alongside progress in our early-stage neuromuscular pipeline as well as continued innovation in our research labs. We're poised to drive meaningful progress to positively impact the lives of patients as well as create enduring value for shareholders who support our mission. With that, I'll now turn the call over to Andrew.

Thanks, Robert. Our launch preparations for aficamten are well underway with significant momentum in 2024 and setting up what is the final stretch towards a potential U.S. approval and launch of our first medicine in September. The priorities we are guiding towards for a successful launch are as follows: broadening category awareness and effectively communicating the differentiated attributes of aficamten, galvanizing and activating new cardiologist prescriptions, securing access and an affordable copay for people with HCM and providing exceptional patient support. Of note, we are pleased to see continued category expansion of the number of patients treated with a cardiac myosin inhibitor or CMI. Continued market growth and broad awareness is good news for Cytokinetics as it reflects a growing opportunity for aficamten to capture what is largely still an untapped market. Cytokinetics will be focused on increasing market awareness and category penetration and broader cardiology adoption for CMIs with aficamten. Toward that objective in the fourth quarter, we are proud to drive increased education and awareness of HCM with the launch of HCM Beyond The Heart, an unbranded disease awareness campaign featuring real people with HCM. In October, we launched the campaign directed to HCPs to inspire them to look deeper for HCM and practice whole-person care. Initial engagement metrics with the website and emails are above industry benchmarks for our target audience. In January, we expanded HCM Beyond the Heart inclusive of patients, incorporating a website, educational tools and resources focused not just on the condition, but on the impact it has on a patient's life beyond their heart. This represents another exciting milestone as we move forward toward the PDUFA date later this year. Meanwhile, we continue developing and refining our branded HCP promotional campaign for aficamten, which is currently being tested with HCPs. To support our goal of ensuring product and market access post approval, we have continued our engagement with payers while advancing implementation of a robust patient support program. This includes contracting with strategic partners, determining the size and approach of our customer-facing Nurse Navigator team and creating a bespoke patient experience offering. We also advanced operational planning for our sales force, including finalizing the sales training curriculum and sales territory configurations and deployment, and we finalized our sales representative recruiting process, which will be initiated in late Q1. Beyond the U.S. launch, we're also scaling up commercial launch related activities in international infrastructure to support a potential European approval of aficamten. At the end of last year, we hired key leadership positions in Europe, inclusive of leaders in marketing, finance, human resources and in-country leadership in both France and the U.K., following our previous hiring of a leader in Germany earlier in the prior year. Recent planning activities are ahead of a potential European approval, including validation of our reimbursement strategy and initial preparation of dossiers for HTA submission across the U.K. and Western EU markets. I'm pleased with the progress we've made to prepare for both the U.S. and European commercial launches of aficamten and where we are positioned today on our commercial readiness roadmap. With that, I'll turn the call over to Fady.

Thanks, Andrew. As Robert mentioned, we recently submitted the 120-day safety update to FDA with an additional ten months of safety data from FOREST-HCM. These longer-term data are consistent with the previously presented data from FOREST-HCM and the safety profile of aficamten as reflected in the NDA submission with, we believe, no evidence of an increased risk of EF excursions or heart failure events. As FDA reviews the NDA, we're continuing to answer their questions and prepare for clinical site and other inspections. As Robert mentioned, we also expect to participate in a mid-cycle meeting with FDA in March. Moving on to our work in the fourth quarter to expand the evidence base for aficamten. At the American Heart Association Scientific Sessions in November, we presented data from two prespecified analyses of SEQUOIA-HCM and one analysis of FOREST-HCM. Expanding on our activities to make data from this program available to the medical community. These presentations included analyses of post-exercise oxygen uptake recovery, patient quality of life and guideline eligibility for septal reduction therapy, all favorably impacted by aficamten. In addition to disseminating data during the quarter, our managed healthcare MSL team continued preapproval information exchange to actively engage national and regional payers in scientific discussions related to obstructive HCM and aficamten and notified payers of our PDUFA date. Scientific engagement with HCM specialists also continued with discussions focused on the results from SEQUOIA-HCM, including the primary results and secondary data analyses. Now shifting to the ongoing clinical trials program for aficamten, having completed enrollment in MAPLE-HCM in the third quarter of last year, we continue to conduct the trial, collect data and progress towards database lock. We're on track to share top line results in the second quarter of this year, which we expect to be followed by a presentation of the full results at a subsequent medical meeting. If the results of MAPLE-HCM are positive, it'll provide an opportunity to elevate aficamten as a potential monotherapy for the treatment of obstructive HCM following approval. Meanwhile, we've continued to conduct ACACIA-HCM, a pivotal Phase 3 clinical trial in non-obstructive HCM, CEDAR-HCM in the pediatric population of patients with symptomatic obstructive HCM, and of course, FOREST-HCM, the ongoing open-label extension clinical study. FOREST-HCM continues to grow with now over 400 patients enrolled, nearly 300 patients have at least a year of follow-up and over 90 have two years of follow-up. We're pleased to report that patient enrollment in ACACIA-HCM has progressed rapidly over the last few months, thanks to our highly engaged sites. We've completed site activations in North and South America, Europe and Israel and are pleased with the baseline characteristics of the population. Results from this trial represent a key future milestone for the potential label expansion trajectory for aficamten into non-obstructive HCM. While today representing about one third of the HCM population, non-obstructive HCM appears to be growing at a faster rate than obstructive HCM in terms of diagnoses, such that we expect it to eventually represent nearly half of HCM diagnoses. So it's an important segment of the population that needs to be addressed, in particular because non-obstructive HCM lacks effective medical or surgical therapy unlike obstructive HCM. Overall from a clinical development perspective, our work in the fourth quarter wrapped up a truly monumental year, highlighted by numerous data presentations and publications in high impact journals. We look forward to building on and publishing that growing clinical evidence in support of aficamten as we approach the potential approval and the launch of aficamten in obstructive HCM this year. Now I'll turn it over to Isaac.

Thanks, Fady. As Robert mentioned, we secured two new partnerships in the fourth quarter, which together will support the development and commercialization of aficamten in critical global geographies. We were pleased to enter into a collaboration and licensing agreement with Bayer for the development and commercialization of aficamten in Japan. This deal stands alone in terms of its favorable economics for a cardiovascular drug: EUR50 million in upfront payments to Cytokinetics, eligibility to receive an additional EUR90 million tied to milestones through the commercial launch, EUR490 million in commercial milestone payments from Bayer upon their achievement of certain sales milestones and tiered royalties on net sales of aficamten in Japan. To support the potential marketing authorization of aficamten in Japan, Bayer will conduct a Phase 3 clinical trial in Japanese patients with obstructive HCM to support SEQUOIA-HCM and FOREST-HCM, while Cytokinetics plans to expand both ACACIA-HCM and CEDAR-HCM into Japan. As you know, we have been pursuing a deal like this in Japan for some time. Bayer, like Cytokinetics, has a deep commitment to cardiology and through this process ultimately rose to the top as the right partner who is well equipped to bring aficamten to patients in Japan. Additionally, during the fourth quarter, Sanofi acquired exclusive rights to develop and commercialize aficamten from CORXEL, formerly Ji Xing, in China. Through this transaction, Cytokinetics remains eligible to receive up to $150 million in development and commercial milestone payments from Sanofi and royalties in the low to high teens on sales of aficamten in China. Cytokinetics is now also eligible to receive additional payments in connection with the execution of the agreement between Sanofi and CORXEL. Over the years, we have enjoyed a highly productive collaboration with CORXEL and now we are pleased to partner with Sanofi, harnessing their expertise in cardiology to bring aficamten to patients in China. Both of these recent deals serve to expand the potential reach of aficamten in key geographies worldwide. Now with partners on board in China and Japan and our own commercial infrastructure scaling in the U.S. and Europe, we're turning our attention to how we may further expand our geographic reach with aficamten and how we may also catalyze external R&D activities and pursue new business objectives to augment our existing pipeline alongside innovation from our own labs. To that end, our goal is to bring additional new chemical entities into clinical development through external innovation, seeking complementary potential therapies to support our late-stage cardiovascular franchise and emerging neuromuscular pipeline. As stated in our Vision 2030, we also seek to expand into new modalities through a combination of both building internal capabilities and identifying external collaborations with industry partners and academic institutions. In the year to come, you can expect more activity on the business and corporate development fronts at Cytokinetics as it relates to bringing aficamten to more patients worldwide, as well as how we may augment our R&D pipeline in more ways that read on progress towards our stated vision. I look forward to sharing more of these matters as they progress. Now I'll hand it over to Stuart.

Thanks, Isaac. I'm pleased to provide updates on the later stage development programs within our specialty cardiology franchise as well as our earlier stage neuromuscular clinical research. I will start with omecamtiv mecarbil, a cardiac myosin activator. During the quarter, we started COMET-HF, a confirmatory Phase 3 clinical trial in patients with symptomatic heart failure with severely reduced ejection fraction less than 30%. Since starting the trial, we've seen a great deal of enthusiasm from our investigators who recognize the considerable unmet need in this high-risk population and are eager to enroll patients. Currently, this trial is enrolling in the United States and regulatory submissions have been completed in Canada, the U.K. and the rest of Europe. Investigators with prior experience with omecamtiv mecarbil have been reaching out to us regularly to inquire about participating in COMET-HF, and our steering committee is now fully seated with the foremost heart failure leaders from countries where the trial will be conducted. Now I'll move on to CK-586, our next cardiac myosin inhibitor. In January of this year, we began AMBER-HFpEF, a Phase 2 placebo-controlled double-blind trial evaluating the safety, tolerability, pharmacokinetics and pharmacodynamic profile of CK-586 in patients with symptomatic heart failure with preserved ejection fraction and LVEF greater than or equal to 60%. AMBER-HFpEF is expected to enroll approximately 60 patients in three 12-week dose escalation cohorts with doses ranging from 160 mg to 600 mg once daily. Potential treatment benefits of CK-586 include increased cardiac relaxation leading to improved diastolic function, improvement of heart failure symptoms and increased exercise capacity, and we expect to build a body of evidence in support of these outcomes through this trial. Our goal is to complete enrollment of the first two cohorts in the second half of the year. Finally, beyond our specialty cardiology franchise, during the fourth quarter, we were pleased to begin a Phase 1 study of CK-089, a fast skeletal muscle troponin activator. The study comprises both single and multiple ascending dose cohorts. CK-089 arose from our pioneering research in neuromuscular disease and was optimized by our prior learnings. CK-089 is designed to amplify skeletal muscle response to nerve input, extending time to fatigue and increase in muscle force and power with potential therapeutic application to a specific type of muscular dystrophy. We expect to complete this Phase 1 study within 2025 and look forward to keeping you updated on our progress in this key area of clinical research as it underscores a second vertical for our company. With that, I'll pass it to Sung.

Thanks, Stuart. We're pleased to report our fourth quarter and full year 2024 financial results. Starting with the balance sheet, we finished the fourth quarter of 2024 with approximately $1.2 billion in cash, cash equivalents and investments compared to $1.3 billion at the end of the third quarter of 2024. Cash, cash equivalents and investments declined by approximately $60 million during the fourth quarter of 2024 and benefited from the receipt of $52.4 million or €50 million payment from Bayer for the exclusive license to develop and commercialize aficamten in Japan. Moving on to the income statement, the revenues in the fourth quarter of 2024 were $16.9 million compared to $1.7 million for the same period in 2023. The revenues for the full year of 2024 were $18.5 million compared to $7.5 million in 2023. Total revenues in the fourth quarter of 2024 and full year 2024 benefited from a $15 million upfront payment from CORXEL in connection with the assignment of CORXEL’s rights for the development and commercialization of aficamten in Greater China to Sanofi. R&D expenses for the fourth quarter were $93.6 million compared to $85 million for the same period in 2023. R&D expenses for the full year of 2024 were $339.4 million compared to $330.1 million in 2023. The increase year-over-year for both the fourth quarter and full year was primarily due to advancing our clinical trials and higher personnel related costs including stock-based compensation. G&A expenses for the fourth quarter of 2024 were $62.3 million compared to $44.1 million for the same period in 2023. G&A expenses for the full year of 2024 were $215.3 million compared to $173.6 million in 2023. The increase year-over-year for both the fourth quarter and full year was primarily driven by investments toward commercial readiness and higher personnel related costs including stock-based compensation. Net loss for the fourth quarter of 2024 was $150 million or $1.26 per share compared to a net loss of $136.9 million or $1.38 per share for the same period in 2023. Net loss for the full year of 2024 was $589.5 million or $5.26 per share compared to a net loss of $526.2 million or $5.45 per share in 2023. Turning now to our financial guidance for 2025, we expect our GAAP operating expense which is comprised of R&D and SG&A expenses to be between $670 million and $710 million. Stock-based compensation included in the GAAP operating expense is expected to be between $110 million and $120 million. Excluding stock-based compensation from GAAP operating expense results in a range of $550 million to $600 million. Our capital allocation priorities remain the same and our resources will be focused on the following. First, on preparing for the potential U.S. commercial launch of aficamten in September of this year, including the hiring of up to 150 sales reps in the U.S. in the third quarter of 2025. Second, on advancing our pipeline with important label expansion opportunities for aficamten and clinical trials of omecamtiv mecarbil and CK-586 and third, on investments in our muscle biology platform. The anticipated year-over-year growth in operating expense will primarily be driven by the investments toward commercial readiness for the potential launch of aficamten for patients with obstructive HCM. Our strong balance sheet and access to further capital position us well to execute on our strategy, which we believe could lead to sustainable growth driven by our specialty cardiology franchise. With that, I'll hand it back to Robert.

Thank you, Sung. Our progress in the fourth quarter 2024 has set the stage for a pivotal year ahead as we approach the potential U.S. approval and commercial launch of aficamten in 2025. We are strategically aligning our longer-term vision while sharpening our operational focus for near-term milestones and progress. With the right infrastructure, capabilities, partners and team in place, we are confident in our ability to execute and achieve multiple successes within our growing reach. Earlier this year, we laid out our Vision 2030, our five-year strategic objectives designed to propel Cytokinetics to become the leading muscle-focused specialty biopharmaceutical company intent on meaningfully improving the lives of patients through global access to innovative medicines. Vision 2030 serves as an aspirational roadmap made up of five objectives; innovation, ignition, impact, inspiration and ingenuity. These objectives articulate how we want to deliver product approvals, achieve broader access to our medicines, promote more equitable access and advance our pioneering research to benefit patients, shareholders and employees. Aligned with this vision for our future, we recently announced the appointment of Robert Landry to our Board of Directors. Bob brings over three decades of financial and operational expertise in the pharmaceutical industry, most recently serving as Regeneron's Chief Financial Officer for 11 years, during which time he helped guide the company as it scaled and commercialized medicines globally. We're pleased to have him join our Board at this time in our corporate development. Looking at the year ahead in 2025, we will continue to focus on FDA approval and U.S. commercial launch readiness for aficamten and the execution of our ongoing clinical trials programs. Last year, we raised over $1 billion between existing cash and access to new capital which affords us the runway to execute the U.S. launch of aficamten, while also advancing our R&D pipeline and making investments in a fiscally prudent capital efficient way to build enduring value for shareholders. I'm optimistic about what our future holds in 2025. So now I'll recap our upcoming milestones. For aficamten, we expect to advance NDA review activities with FDA to support the potential U.S. approval of aficamten in the second half of this year. We expect to advance go-to-market strategies and prepare to commercially launch aficamten in the U.S. in the second half of this year subject to approval by the FDA. We expect to continue go-to-market plans in Germany and expand commercial readiness activities in Europe in 2025 in preparation for potential approval by the EMA in the first half of 2026. We expect to coordinate with Sanofi to support the potential approval of aficamten in China in the second half of 2025 pending approval by the NMPA. And we expect to report top line results from MAPLE-HCM in Q2 of this year. We also expect to complete enrollment of ACACIA-HCM in the second half of this year and to complete enrollment of the adolescent cohort in CEDAR-HCM also in the second half of 2025. For omecamtiv mecarbil, we expect to continue patient enrollment in COMET-HF through 2025 to enable completion of enrollment in 2026. For CK-586, we expect to complete enrollment of the first two patient cohorts in AMBER-HFpEF in the second half of this year. And for CK-089, we expect to complete the Phase 1 study this year. And finally for our preclinical development and ongoing research, we expect to continue ongoing preclinical development and research activities directed to additional muscle biology focused programs. Operator, with that, we can now open the call to questions, please.

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

Hi, everyone. Good afternoon to you too. This is Kahlil calling in for Paul. I guess our question could be on MAPLE-HCM. If the results are positive, how should we think about the timeline for potential label expansion assuming approval in September? And then how would the positive results fit into the company's marketing strategy in the interim? Thank you so much.

So I'll turn first to Fady to answer the first part and then to Andrew the second part please.

Yes, hi. I think in terms of timing to label expansion, we would certainly be looking at the results and deciding how to proceed. With respect to timing for that, I would expect it to come into 2026 as opposed to 2025, given our PDUFA date right now is September 26, 2025. But I think it all depends on timing and whatever else is going on at that time.

And in terms of the marketing strategy, the second study really offers confirmatory evidence of a primary study, both safety and efficacy, which is reassuring to physicians seeing a lot of the same primaries and secondaries. It opens up a cohort of cardiologists who really treat with beta blockers alone. There's really about 2,000 cardiologists or so who are the majority of prescribers of CMIs today. And per our market research, this would open up more prescribers who may feel that beta blockers are sufficient. It offers that additional evidence and may influence guidelines and move treatment to first line over time, but that certainly takes a lot longer.

Maybe to echo what Andrew is saying, I do believe that MAPLE-HCM were it to be positive could contribute to more category growth as potentially more cardiologists would be more comfortable prescribing a cardiac myosin inhibitor. And on top of that we would hope it would add to more category penetration for aficamten into that larger market. But I would consider it more incremental than transformative to what we would hope would be the label opportunity provided by SEQUOIA-HCM.

Great. Thank you.

Thank you. And our next question will come from Cory Kasimov from Evercore ISI. Your line is open.

Hey, good afternoon. Thanks for taking the question. So following up on Andrew's prepared comments on market expansion, I think it's pretty well established that HCM is a highly underdiagnosed condition. So curious as to your expectations as to how this changes over time when there's two companies on the market educating and promoting the benefits of cardiac myosin inhibitors. If it really is on the order of 70% to even 80% of patients undiagnosed, is there a good proxy of where this rate may get to say three to five years from now? Thank you.

Thank you. I'll turn to Andrew, please.

Sure. It's a great question. I think as you know, when guidelines get adjusted, when studies are out, when us and others are at congresses where physicians go to learn about emerging data, those certainly increase penetration of market and increased diagnosis with awareness and education. I think what we've seen over the last few years is obstructive HCM has continued to increase diagnosis rates, and the non-obstructive segment is growing at a double-digit rate. So I think over time, non-obstructive may even be 50-50 or slightly larger than obstructive in terms of overall patient population. The estimate we have right now is about 30% or so of the population is diagnosed. Given these rates and where they're going, that certainly could be in the 50% range in the next three to five years.

In terms of comparators, we're reviewing the landscape as well. I do believe that the amyloidosis space and the pulmonary arterial hypertension space both afford comparators in terms of what a next-in-class drug could mean in terms of increased diagnosis and category penetration. We look at those as good proxies.

All right. Sounds good. Appreciate it. Thanks, guys.

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

Hello, Salim.

Hey, Robert. Thanks for the question. One question we're getting a lot on, I'm sure you guys are as well, I would just love to get your view, is just the upcoming Edgewise dataset, the 28-day. We just sort of look to see how you'd frame it, anything you're looking out for there? And also related to that, do you think there's any even remote possibility that they if they were to progress come out of this without any REMS at all? Thank you, based on the preclinical data at least. Thank you.

Yes, it's a very slippery slope obviously that we won't go down to comment on another company's ongoing development program. But I still appreciate the question. With that said, it's early days and I'll turn to Fady to comment on this matter much as he has been asked by others, but I would suggest that we let the data and evidence speak for itself.

Yes. Hi, Salim. I think it's still, as Robert said, early in the program. In order to understand the safety profile of a drug that's going to be used in thousands of people, you're going to need hundreds of people's worth of data. Until you understand that, it's premature to comment, even if I were to speculate on their eventual safety profile and monitoring. So I'll probably just leave it there.

We're looking forward to seeing the data. Obviously, these data will be telling as to whether there is an opportunity to land a new mechanism treatment in obstructive HCM that would be potentially differentiated. We're very pleased with the data we have supporting aficamten both as it relates to efficacy as well as safety, ease of use and other things that were designed into aficamten consistent with intrinsic properties. And as we look forward to potential approval and potential commercial launch, we're very confident that we're situated in a very positive place. With that said, we'll take a look at these data as they may come out later in the first quarter from what we gather.

Okay, perfect.

Thank you. Our next question comes from James Condulis from Stifel. Your line is open.

Good afternoon. Thanks for taking my question and congrats on all the progress. I just want to ask one kind of quick question on the REMS and totally appreciate there's only so much you can say, but wanted to get your thoughts on if you expect mavacamten's REMS to be eased in the U.S. as well and sort of if that happens how does that change how you sort of think about the range of scenarios for what aficamten's REMS looks like? Again, sort of like in that scenario, would you define differentiated REMS as still differentiated in sort of the maintenance setting as well? Or does that become more about some of the other aspects of the REMS? Just curious what you can share there. Thanks.

Yes, here again, I'm going to be careful not to make any comparative statements. But I will say we noted with interest the other company's earnings call and its reporting on the changes as it relates to the EMA label and we look forward to learning how FDA may respond to an application to ease certain restrictions relating to the existing REMS for mavacamten. We've done a lot of market research and there are points of differentiation that we continue to believe are quite meaningfully important for aficamten as are consistent with intrinsic properties. Echo frequency is one of those, but there are several others. Maybe I'll ask Andrew to comment on the market research we've done and our expectations for a differentiated risk mitigation profile if approved.

Thanks, Robert. So differentiation—maybe we'll just start with the data. The data should inform the label; the label informs what claims we can make around differentiation. There are many aspects of differentiation that we're exploring and that are going well from a market research point of view. This could be one of them or it could be in parallel with others. If monitoring is relaxed for the whole category, this is actually good for the category. The vast majority of patients are not treated today with a CMI. If less frequent monitoring in the maintenance phase gets more patients on board with a CMI and gets more physicians to treat with a CMI, it lifts the category for everyone. We look forward to what the FDA has to say. The date is in the spring, and we'll see how our label is informed by the data.

We've said this many times that our goal is to ensure that more cardiac myosin inhibitors are used by more cardiologists for more patients. Still to our estimates, there are over 80% of eligible patients who could benefit from use of a cardiac myosin inhibitor and with prevalence growing that number increases. We believe strongly that aficamten, if approved, will have a differentiated profile, both as it relates to label and risk mitigation. We'll wait and see, but I hope that answers your question.

Yes, I appreciate the color. Thank you.

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

Hi, Robert and team. Thanks for taking our questions tonight and look forward to ACC. So do you think based on your physician and KOL interactions that it is appreciated that there is not the same pharmacogenomic and DDI liability with aficamten as there is with the other product due to the way that the drug is metabolized related to a patient's CYP2C19 genotype versus yours? If not, how do you think you will go about educating doctors around this point? And then relatedly, to be clear, will any monitoring be needed by the pharmacy around concomitant meds with aficamten? Thanks so much.

Good questions. Maybe I'll ask Fady and Stuart to comment and then Andrew if he wants to add anything.

I think your question ultimately will depend on the labeling that we achieve with aficamten, but physicians we've interacted with, even those who have conducted our clinical trials, recognize differences—for example, that aficamten's interaction profile does not involve CYP2C19, and that it has very few meaningful drug interactions. Physicians have been educated to that fact and act accordingly. Monitoring of concomitant medications is something that's always done clinically; there is no drug that is completely without the potential for interactions. Any drug interactions we have would be reasonably rare and uncommon, and physicians would be educated on those as well. We haven't found a need for a pharmacy monitoring program in our clinical trials and haven't had any issues to date.

For clarification regarding pharmacy, Andrew, do you want to add anything?

I mean, we're not expecting in our base case that pharmacy monitoring would be part of any REMS program where a pharmacy has to call a patient and discuss existing drugs and potential drug interactions. That is not something that we're anticipating.

Thank you, guys.

Thank you. Our next question comes from Leonid Timashev from RBC Capital Markets. Your line is open.

Good afternoon, guys. Yes. Thanks for taking my question. I wanted to ask on the endpoints for ACACIA and maybe some comparisons to the competitor's HCM study. I don't mean to compare someone else's study, but can you talk about any potential differences in KCCQ-23 versus KCCQ-12? And maybe why you settled on a single primary focusing on KCCQ rather than also including pVO2 as a primary and whether that was based on your own diligence or in consultation with the FDA? Any thoughts would be appreciated. Thank you.

Sure. I'll ask Fady and Stuart if they'd like to comment.

Let me say the KCCQ is a patient-reported outcome. We examined its impact in our Phase 2 study in non-obstructive HCM. While that was an open-label experience, there was a meaningful impact on KCCQ. Regulators generally like to see an impact of a drug on more than just KCCQ; they like to see improvements in exercise and in NYHA class, a consistency across functional and symptomatic endpoints. ACACIA is currently designed to include both: an exercise endpoint as a secondary endpoint and KCCQ as a primary endpoint. As you pointed out, another company's ODYSSEY has a dual primary endpoint with both peak VO2 and KCCQ assessed in parallel. Practically speaking, there's not that much difference between the two approaches; both are designed to assess the strength of evidence with respect to patient-reported outcomes and functional metrics. Regulators clearly want to see consistency across these domains. Hopefully that answers your question, Leo.

That's great. Thank you.

Thank you. And our next question will come from Akash Tewari from Jefferies. Your line is open.

Hi. This is Zaki on for Akash. Thanks so much for taking the question. Regarding non-obstructive HCM, it looks like both companies are looking to dose patients up to achieve higher exposures. Looking at REDWOOD cohort data, the final proBNP levels are similar to MAVERICK's lower dose cohort. I think the key question is whether you can actually show more efficacy by getting patients onto the 20 mg dose in ACACIA. Based on the SEQUOIA data you've seen so far, how easily do you think you can keep patients on the 20 mg dose without EF issues for the whole 36-week period? And is there any sense that slower titration like we're seeing in ODYSSEY might be better in the non-obstructive population?

That's a multipart question. I'll ask Fady and Stuart to tackle it.

Maybe I'll take it. The REDWOOD data dosed patients between 5 mg and 15 mg; 85% of patients got up to 15 mg and were there within six weeks of initiation of therapy, and many of those patients were still eligible to up-titrate to 20 mg. I don't think there's fundamentally any difference between the cardiac function of a non-obstructive HCM patient and an obstructive HCM patient in terms of tolerability. One could expect a similar dose distribution in the two groups, perhaps even skewed to the higher side in non-obstructive HCM because you don't stop titrating based on achieving gradient targets. In REDWOOD we saw that NT-proBNP decreased in a dose-dependent manner; higher doses produced greater decrements. The strategy we've adopted in ACACIA is built tightly on what we did in REDWOOD — similar dosing strategy and speed of dosing — which is helpful when designing a Phase 3 study based on Phase 2 data. So I think we're pretty confident with how we've addressed dosing in that trial.

Thank you, guys so much.

Thank you. Our next question will come from David Lebowitz from Citi. Your line is open.

Hi. This is Ike Lee on for David. Thanks for taking the question. We are wondering if you can orient us on expectations, particularly on the exercise capacity primary endpoint heading into the MAPLE-HCM readout. Are we looking for a similar level of benefit this time head-to-head versus beta blockers as we did in SEQUOIA, something like a 5% to 8%, maybe 10% improvement over baseline exercise capacity? And is there any change in the level of clinical meaningfulness for this one as opposed to trials run before since the endpoint is the same? Thanks.

Good questions. We'll have Fady address how the study was designed and what it was powered to demonstrate.

MAPLE was designed as a trial to assess the impact of aficamten versus metoprolol on exercise capacity and it's powered to about a 2.0 difference between the two. In SEQUOIA we achieved 1.75, which was highly statistically significant. I think that's a reasonable expectation. When you get to clinical meaningfulness, anything above 1 is generally considered clinically meaningful, and certainly the 1.74 we achieved in SEQUOIA we consider clinically meaningful. There are data that show that mortality and morbidity are potentially tied to peak VO2 and that changes in peak VO2 of that magnitude have impacts on long-term morbidity and mortality. So I think changes of 5% to 8% or 10% would represent clinically meaningful differences. And as I said earlier, it's not just about the difference in peak VO2; it's about consistency across endpoints, safety and tolerability. All of those should be considered when evaluating aficamten compared to metoprolol as monotherapies.

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

Hi, guys. Good afternoon and thanks for taking the question. Maybe to build on the last question: for MAPLE, you're enrolling patients with percent predicted peak VO2 of less than 100%, whereas in SEQUOIA, for the most part, you enrolled less than 80% predicted. How should we think of this patient population as it relates to obstruction driving exercise capacity deficits and how that contrasts with SEQUOIA, if at all? Thanks.

Hi, this is Stuart Kupfer. What we observed in SEQUOIA was that thresholds less than 90% or less than 80% did not make a significant difference in terms of incapacity of these patients. Because of the degree of obstruction and the fact that these patients were significantly symptomatic, they already had a significant deficit in their exercise capacity. We realized we could relax that criteria and still enroll patients with quite significant deficits who we believe could benefit from aficamten treatment.

And our next question will come from Srikripa Devarakonda from Truist Securities. Your line is open.

Hi, it's Alex on for Srikripa. Thanks. We are excited about the progress in 2025. One commercial question: we've heard that treatment by cardiologists and their practice centers may be limited by insufficient numbers of monitoring equipment to adjust the large volumes they see, and patients have been referred to more specialist centers. Wanted to know on your end, have you heard this? Is there potential for future treatment with aficamten to be administered by a broader range of HCPs? And does your market research highlight any bottlenecks related to equipment readiness in target markets outside the U.S. as well as the U.S.?

So we noted that concern and we review the topic closely. Maybe I'll ask Andrew to comment on what he's learned from market research and how it may relate to Europe.

We looked at echo capacity across the U.S., within specialized centers, academic centers, city centers and community centers. It is not currently a capacity constraint that is preventing patients from getting treated. There are other challenges with starting treatment outside academic centers and centers of excellence, but it's not largely related to echo capacity. When we looked at Europe, the market is more concentrated; prescribing is often limited to hospitals or designated centers, and those institutions generally have the necessary capacity. So while there are logistical challenges to starting therapy outside of centers of excellence, we do not see echo equipment capacity as the primary bottleneck.

It's difficult sometimes to distinguish between cause and effect. A majority of current use is among a concentrated number of prescribers in centers of excellence. With more experience comes ability to navigate REMS programs. We believe that a majority of adoption is correlated with experience with CMIs. Our hope is, if aficamten is approved, we can contribute to more education and awareness and help drive category growth and expansion beyond centers of excellence, which would benefit the entire class and could help with broader adoption. That said, we do not see echo capacity as the limiting factor based on our research and interactions.

Yes, it makes a lot of sense and thanks. We're all looking towards the year ahead.

Thank you. Our next question comes from Roanoke Ruiz from Leerink Partners. Your line is open.

Good afternoon, guys. Slightly different question: I was curious if you could elaborate on your future goals for business development and corporate development in the coming years. It sounds like you're willing to consider augmenting your R&D pipeline. Curious about any color on stage of asset, mechanisms, indications, etc., that you'd be interested in internally or externally? And how would you balance that with your current cash runway expectations today?

I'll ask Isaac to comment first followed by Sung and then I'll add a few comments.

Thanks. The most important thing for us is to continue to focus on our expertise in muscle biology and to look at the landscape, both external and internal, to advance the most promising programs. From a licensing perspective, we are actively engaging with academics and research centers that have preclinical programs and early-stage clinical development programs where we can use our expertise to advance them. We're looking at this from a financial prudence perspective and where we think we can have the greatest impact. Our focus has been on small molecules, but we are open to other modalities and want to ensure we are at the forefront. We're seeking complementary programs to support our cardiovascular franchise and neuromuscular pipeline.

Roanoke, in terms of cash runway, we believe we have multiple years of runway as we start the year, supported by our starting cash balance of $1.2 billion. We also have access to further capital from Royalty Pharma, up to $500 million. We'll also benefit from near-term milestones from the BD deals we closed last year related to aficamten ex-U.S. So we're in a strong position. Specific to this year, we expect cash utilization to be in the low $500 million. With these sources of capital, we believe we have multiple years of runway right now.

To elaborate, our primary focus remains on aficamten and our later-stage pipeline. That's where our capital is best deployed. The activities Isaac mentioned are intended to augment and complement our efforts and will be modest relative to overall spend. This is about building strategic options that are adjacent to our core programs and could include new modalities, but not necessarily expensive modalities like gene or cell therapies. We're focused on capital efficiency while advancing Vision 2030.

Understood. Thanks.

Thank you. And our next question comes from Joe Pantginis from H.C. Wainwright. Your line is open.

Hey, everybody. Thank you for taking the question. Good afternoon. I'm not sure if you can discuss this before the mid-cycle meeting, but anything you could discuss about key questions that are still outstanding or any potential rate-limiting steps? And then also with regard to omecamtiv, anything you can share regarding COMET-HF and the enrollment trajectory, related to GALACTIC, since there are additional screening criteria? Thanks.

You answered your own question about ongoing FDA interactions; we can't comment much other than to say we're in a good position to address questions. As it relates to enrollment and COMET-HF, I'll ask Stuart to comment.

Thanks, Joe. We began enrollment in COMET-HF late last year. We have the advantage of leveraging information from GALACTIC in terms of identifying the best investigators and sites for the trial. We also have the advantage of a solid data set supporting the hypothesis that omecamtiv mecarbil will be effective in higher-risk patients. Enrollment is proceeding as estimated. We plan to continue enrollment through the year with completion of enrollment targeted for 2026. The study is proceeding according to plan.

We're borrowing many learnings from GALACTIC and believe that places us in an advantaged situation to enroll COMET-HF efficiently. We'll share more as the trial progresses.

Thanks again.

Thank you. Our next question comes from Mayank Mamtani from B. Riley Securities. Your line is open.

Good afternoon, team. Thanks for taking our questions and congrats on the progress. Switching gears to CK-586 HFpEF study: you mentioned the first two cohorts and that completion by the end of this year is expected. Could you talk about the higher dose cohort being contingent on completion of the first two cohorts and what you're looking to learn on tolerability and biomarkers in the HFpEF study?

I'll ask Stuart to address that.

The study is intentionally designed to be flexible. Our intent is to complete the first two cohorts by the end of the year and based on the information from those cohorts we will consider whether to proceed with the third cohort or adjust dosing. This is a dose-finding study. We'll be evaluating safety and tolerability in the HFpEF population, collecting cardiac biomarker data such as NT-proBNP, assessing pharmacokinetics, and evaluating effects on ejection fraction. These are the key endpoints for the study.

Yes, it does. Thank you. Appreciate it.

Thank you. Our next question comes from Yasmeen Rahimi from Piper Sandler. Your line is open.

Hi, Robert. Thank you so much for all the great updates. I guess one question we were wondering about is the recently published baseline demographics of the other company's ODYSSEY study. I would love to get Fady's thoughts on that study and what stood out to you. Any commentary would be helpful. I appreciate the commentary that positive data from ODYSSEY or MAPLE continue to grow uptake of CMIs in this market of potentially a million patients. If you could comment on any differences that stand out compared to ACACIA, that would be helpful.

I'll ask Fady to comment.

Hi. The baseline characteristics in the ODYSSEY population were not surprising; these are people with significant symptoms, elevated biomarkers, and reduced exercise capacity—typical of an HCM population. What is notable is how similar they are to obstructive HCM patients, with the exception of gradient differences and some biomarker differences. This highlights that non-obstructive HCM patients are highly impacted. Both trials have enrolled well, suggesting the condition may be more common than initially thought. We'll learn more about effectiveness of CMIs in non-obstructive HCM from the upcoming results.

Thank you, Fady.

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

Hey, good afternoon. Congrats on a great year of progress. A question on business development: can you characterize the work Sanofi did for the China market? It seems like it could be quite large. Any color on unmet need there and how you might see it pace in terms of development? Would you anticipate milestones this year in terms of cash payments or early next year?

We've been impressed by Sanofi's engagement. Isaac, could you comment? Sung, could you address milestones?

We were pleased with Sanofi and their process. To be clear, the transaction was between CORXEL and Sanofi. There were multiple parties interested. There's a clear understanding of unmet need in China. China has no REMS programs as in the U.S., which factors into the value proposition. Since the transaction, we've had an active dialogue with Sanofi about potential approval timing. Milestones associated with approval depend on that event occurring this calendar year; if not, they'll move into 2026.

Charles, on milestones: we do expect meaningful milestones this year from our partners; I won't tie them to a single partner, but they are tied to clinical and regulatory events. To give color, we could be eligible for up to $35 million in total across our partners in the near term.

In terms of market sizing for China, it's a concentrated market. There are around 400,000 diagnosed patients and a little over 1,000 hospitals where the vast majority of patients are treated. Many more patients in rural and community settings are likely undiagnosed, so that could increase over time. The KOL universe is relatively small—less than 500—and that's where market initiation will take place.

I think the opportunity in China could be under-recognized and we're impressed by how Sanofi is embracing this opportunity.

Thank you. And our next question will come from Jason Butler from Citizens JMP. Your line is open.

Hi, Robert. Thanks for taking the question. You mentioned the safety update submitted to FDA had additional data from FOREST-HCM. Can you say how much of that data, in terms of patients or patient-years, is from after the protocol amendment implemented to lower the frequency of echo monitoring? And does the safety profile appear consistent before and after that amendment? Lastly, are there any additional protocol amendments you're considering for FOREST regarding echo monitoring?

Good questions. I'll ask Fady to respond.

Hi, Jason. The protocol amendment was put in place last year, but there isn't a large amount of data yet accumulated from patients who have had six-month monitoring echoes versus three-month monitoring echoes. We have thousands of three-month monitoring echoes and have seen very little impact on dosing changes or patient safety from those. As time goes on, this year we'll see more six-month monitoring accumulate. At the moment, we don't have additional planned protocol amendments for FOREST. The key point is that as we gain more data, the safety profile we've observed for aficamten remains consistent and supportive of our expectations for a differentiated risk mitigation profile. We'll update those data with new cuts in the future and present them publicly.

To underscore Fady's point, whether echo monitoring is every three months or six months, our data to date remain encouraging on safety and tolerability for aficamten. We'll continue to present data publicly as they become available.

Thank you. And our next question will come from Jason Zemansky from BofA. Your line is open.

Afternoon. Congrats on the progress. Appreciate you slipping us in. I was hoping to get additional color on comments regarding expansion into first-line setting: your strategy for moving beyond centers of excellence, challenges getting prescribers who are less comfortable with CMIs, how dependent is this on the REMS itself, and realistically how you expect uptake?

That's a multi-part question. Andrew, would you like to comment?

First-line setting is unlikely to change quickly; guidelines, payer responses and long-term evidence all play roles. Typically, physicians try beta blockers first—these are inexpensive and widely available. Over time, as evidence accumulates and guidelines evolve, first-line use may shift. There are physicians in the community who are less familiar and may be hesitant due to monitoring requirements; education and evidence help overcome that. Cardiovascular launches typically unfold over two to four years as more prescribers adopt the therapy beyond KOLs and specialty centers. We see MAPLE as potentially contributing to this broader adoption over time.

Yes. Appreciate the color. Thanks.

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

Thank you, operator, and thank you to all the participants on our call today. We thank you for your continued support and your interest in Cytokinetics. We believe that 2024 was a very strong year for Cytokinetics and sets the table nicely for 2025, a year in which we hope to be delivering on the promise of our science and over 25 years of commitment to this area of biology now for the potential benefit of patients. We believe that we're executing very well on strategy and we've outlined for you key milestones for this coming year. We look forward to keeping you abreast of our progress. And with that, operator, we can now conclude the call.

Thank you. This concludes today's conference call. Operator Closing Remarks.