Cytokinetics, Incorporated Aktie

Thank you for joining us. We'll continue with the next session. I'm Paul Choi, and I cover the SMID-cap biotech sector here at the firm. It's our pleasure to have the Cytokinetics team with us here on stage. Maybe what I'll do is let Robert kick it off with some high-level comments and just sort of what his strategic priorities are for the rest of the year and going into 2027. We're also joined on the stage by Dan Jacoby and Tricia, I'm going to apologize for butchering you, Ottaviani who can also speak to some other aspects of the Cytokinetics story, both on the marketing and the clinical side. And so I'll turn it over to Robert.

Thank you, Paul. Thank you to Goldman for inviting us back to provide an update. So here in 2026, we're off to a great start, and things are continuing to go very well for Cytokinetics. With our first approval of MYQORZO, formerly known as aficamten, at the end of last year in China and in the United States and more recently this year in Europe, we've launched successfully, and we reported on [indiscernible] as well as some earlier signs of increased momentum in April. And all is continuing to go well for support of MYQORZO in oHCM as that launch continues successfully. And we can talk about some of the metrics of velocity that we continue to monitor as are encouraging for how we think we're off and running there.

We also recently reported results from a study called ACACIA as could be enabling of an expanded label for MYQORZO to include nonobstructive HCM. Those data were positive and will hopefully be presented and published in more detail in the next few months and lend support for our belief that MYQORZO could become ultimately standard of care across all of HCM. So we're encouraged by those clinical trials data that accompany are already pending review of a potential expanded label for MYQORZO in oHCM based on the MAPLE data, which were reported last year. So between SEQUOIA, MAPLE, ACACIA and the open-label extension FOREST that covers all of those studies, we believe that we're doing right by this science for the benefit of patients across all of o and nHCM.

So that's the leading edge of our business and advancing pipeline. But just behind it are other programs, omecamtiv mecarbil in a confirmatory Phase III study, ulacamten in a Phase II study, each, respectively, across different portions of the heart failure spectrum, we think the company is executing well on its R&D as well.

And then lastly, I'll just mention we recently accessed additional capital. We ended Q1 with about $1.1 billion on our balance sheet. We recently raised $800 million, net closer to $760 million. So pro forma in Q2, we have ample financial resources of approximately $1.8 billion to be enabling of us to further invest in the business. So we think we're firing on all cylinders here in 2026 and looking forward to a conversation and questions.

Great. Thank you for that recap, Robert. Maybe starting with the commercial piece, which you began with for either yourself or since we have Tricia here on stage as well, you can maybe address some of the key metrics you're guiding investors towards to help them gauge the success or early days of the MYQORZO launch and other figures that you would direct investors towards.

Sure. So I'll start and then turn it over to Tricia. Coming out of the gate, we felt it was very important to be guiding to the fact that, as a next-in-class compound, MYQORZO should be driving category growth. It's not that we should be, per se, competing with BMS and its drug CAMZYOS, but enabling of more physicians to be comfortable prescribing for more patients. So while there were roughly 700 centers accounting for about 80% of the historical CAMZYOS business, we wanted to, with our direct promotion, focus to those centers, but hopefully be enabling of through some other strategies, including several that Tricia lends oversight to enabling of information, education, awareness to be driving prescriptions from outside.

So we began to see already in just the first several weeks of launch, prescribing as was predominantly in centers of excellence, but also at least 20% of which came from physicians who had never prescribed a cardiac myosin inhibitor. We wanted to ensure parity access, firstly, amongst Medicare accounts, then commercial accounts, Medicare representing about 2/3 of the business. And we believe we're well on track to ensuring parity Medicare access by midyear, commercial parity by end of year. We wanted to see that we were driving from REMS certification to prescribing to dispensing to reimbursement. And whereas we thought that might take months, we were encouraged by the fact that, that was happening in weeks. So that was a good sign.

And lastly, we wanted to ensure that we were driving preferential share of new prescriptions where by the end of the year, we should hopefully accomplish a majority share for new prescriptions exiting on MYQORZO. And as Tricia can elaborate, we began to see at least coming out of Q1 that we're trending towards that end of year goal.

Tricia, can you maybe share with us what your sales force is hearing in the field?

Sure. So we've had our sales force out in the market since January following approvals and obviously, also after we had product availability at the end of January. And the team is continuing to hear very positive feedback from our prescriber base, both those core 700 that drive the velocity or 80% of the CMI prescriptions but also a broader group of physicians. As Robert mentioned, of our quarter 1 sales, 20% of those physicians that wrote in quarter 1 had not previously written a CMI. And we believe that's indicative of the clinical profile that MYQORZO has now brought to market. We see in our surveys that we complete with HCPs favorable differentiation for our clinical profile, both the rapid reduction of obstruction that MYQORZO can deliver as well as the safety profile, but also the differentiation of the REMS profile, the fact that you can titrate dose within 2 to 8 weeks with that echo profile that follows, that there are no DDI calls. We're hearing a lot of favorable feedback from the broader physician community, the 700 Velocity physicians that actively prescribe CMIs, but also the broader community of physicians that there's an appreciation for the clinical profile of MYQORZO.

You talked a little bit about 20% of your early business being from physicians who have never prescribed the CMI previously. Can you maybe tell us a little bit more about the patients that are getting drug? Are you seeing de novo patients mostly? Are you seeing -- can you maybe -- seeing some early evidence of CAMZYOS switches? And just sort of what is driving the prescriber behavior?

Yes. The majority of the prescriptions for quarter 1 were new-to-brand. There were a small subset of patients that were switched from CAMZYOS to MYQORZO, but the majority of those prescriptions were new-to-brand new patients.

Okay. Great. CAMZYOS is currently annualizing at comfortably north of $1 billion already. It's taken a few years to get there, but now it is officially sort of at a blockbuster rate. As you think about the category and the market, how do you think about how MYQORZO might ramp over the coming years? It did take CAMZYOS kind of a few years to get to that status. But Robert or Tricia, as you think about what your aspirations are for MYQORZO here, can you maybe comment on how you might be able to do better or faster than what Bristol experienced?

Yes. So when Bristol-Myers Squibb acquired MyoKardia, they made a public statement that they thought that CAMZYOS could do $4 billion at peak. And I still think they are trending towards that number. We believe that the total addressable market here for oHCM worldwide at peak exceeds $5 billion and could be as much as $10 billion, somewhere in between. And we hope to have a majority of that business in oHCM. We'll talk, I'm sure, about nHCM in a moment.

How we get there depends on how quickly the category grows. So what's nice to see is even as we are trending towards our goal of preferential share of new scripts, so are new scripts growing and the category is growing. And I think as you look at comparable markets, cardiology and non-cardiology, a second to market, ultimately, if it has advantages as it relates to clinical profile can drive category growth and penetration well beyond what would be expected linear with the first. So Cytokinetics is focused to those things that differentiate MYQORZO from CAMZYOS and beta blockers. And I think we can be expecting an acceleration of CMI use ultimately to become first-line standard of care. Whether that happens in an asymmetric way or a more linear way will depend on things that we still need to see in the market.

Maybe speaking to frontline use of CMIs. Maybe we'll bring Dan into the conversation here and talk about, do you have a sense of how familiar cardiologists in the field are with the MAPLE data giving metoprolol or MYQORZO being effective here in frontline?

It's a great question. People are generally very familiar with the MAPLE data. It was a seismic shock to the system when we announced those full data at European Society of Cardiology. And in fact, the impact is worldwide. I was recently in Japan at the Japanese Cardiology Society where they presented an encore of the MAPLE data, and there was no way to get into the room and people bunched out in the hallway. And the reason for that is that for 60 years, we've been using beta blockers as a first-line therapy and thinking that, that might help patients and the MAPLE data shocked everyone into thinking that perhaps it might be minimally helpful or potentially even slightly harmful to patients.

And what that's doing overall is accelerating physicians' enthusiasm around getting to a treatment that they believe in, which is a CMI treatment and one that is readily available. So I think that what we're seeing here is a tremendous amount of enthusiasm. And to be honest, our label already includes language that's very broad and would be generally inclusive of the types of patients that are included in the MAPLE study to begin with. And so those patients can be treated immediately.

Okay. Great. I want to play devil's advocate for maybe just a moment here with you, Dan, and just ask how much of this is generalizable from your perspective or what you're hearing from cardiologists given this is a single study and that the control arm was sort of shockingly underperformed relative to sort of historical understanding of metoprolol. And I guess my second question is, as you speak to cardiologists in the field, how much of this is generalizable to CMIs across the board and not just specifically to aficamten as a molecule?

Yes. I mean I have some personal opinions about the generalizability of data. I'm an evidence-based medicine physician. I grew up in that setting, and I believe that the data needs to be followed. That being said, I don't necessarily think it really matters that much. To speak to Robert's point earlier on, the growing of the overall market, the growing of the overall field is a good thing for patients. And I think in general, what's happening is there's a recognition that people want to move earlier to a CMI therapy. And hopefully, that will be the CMI therapy that is the easiest, most flexible, has the better safety profile and so on.

I will say that there has been a little bit of criticism about the MAPLE study and that there was some [indiscernible] beta-blocker-resistant patient [indiscernible] I don't think that's a widely held view. And even if it is, we're bringing data to bear that may throw that into question, one. And number two, our goal here is not to kill -- the goal is not to kill beta blockers. It's a nice, useful therapy that's cheap and available worldwide. The goal here is to provide evidence to support the general efficacy and usability of aficamten. And I think the MAPLE study really did that. And in a population that was much more mildly affected than the SEQUOIA population, which is a really important point of that. If you look across our studies, look across ACACIA, MAPLE and SEQUOIA, you really have the full gamut, severe obstruction, moderate obstruction and then nonobstructive and including midventricular obstruction. So there is no type of symptomatic HCM patient that MYQORZO has not been able to be shown as an effective therapy to date.

Great. Robert, your sNDA filing based on the MAPLE data has a PDUFA coming up here in November. Can you maybe update us on what sort of the regulatory time lines are there and just your latest interactions with the agency, given we're roughly 6 months out from that -- 5 months out from that PDUFA date?

Yes. So we submitted in early 2026. It was accepted for filing, and we were given a PDUFA date of November, as you point out. We're in the midst of those conversations right now where it's pending review. We tend not to give updates to regulatory interactions except on our earnings call. So with our Q2 earnings call in early August, we should have more to say about that sNDA as well as, and you haven't asked this yet, but an sNDA should be expected for the results relating to ACACIA.

Okay. Great. Given the results of the MAPLE study, can you maybe help investors think about what might be included in a potential label update for MYQORZO here? Is there a goal to seek potentially superiority versus beta blockers in the data section or anything around that? Anything you could speak as to how it compares versus monotherapy? And then I had a follow-up question for how this might affect insurance approvals.

Yes. So Wall Street tends to look at the indication statement and maybe tends to overlook some of the information that's also within the package insert and the label. And the indication statement for MYQORZO as approved in oHCM is already enabling of the MAPLE data in part for the fact that the indication is for the treatment of symptomatic oHCM. It doesn't say anything about beta blockers. And our sales representatives, if asked, can be including MAPLE data in presenting a case for the use of MYQORZO in oHCM. But what's not in the label as informing of benefit risk to clinicians who may prescribe is some of the information pertaining to MAPLE as could be supportive of evidence to use either alongside of or even potentially ahead of beta blockers.

So payers right now naturally for beta blockers being available and inexpensive are oftentimes asking that a physician who wants to use MYQORZO will step through the use of a beta blocker or a calcium channel blocker. When the label is hopefully updated as well as when guidelines are incorporated to reflect MAPLE data, we'll have the benefit of that information. And again, as Dan points out, not so much to substitute for use of beta blockers, but to inform either accelerating through the use of a beta blocker if patients are still symptomatic and in need and where CMI, in particular, MYQORZO would be potentially recommended as first-line treatment. So it has as much to do with guidelines as it does to label. And payers at that point will be perhaps more responsive to the use of MYQORZO earlier and even ahead of beta blockers once incorporated in the guidelines.

Maybe we can bring back Tricia here and just talk about how much beta blockers -- how often beta blockers are typically used as monotherapy. And as you think about the commercial piece, assuming a positive update to the label here later this year, how that might accelerate frontline adoption of MYQORZO for newly diagnosed patients?

Yes. So for those 50% of HCM patients that have oHCM, the large majority of them are on beta blocker or calcium channel blocker standard of care. I think where the opportunity really sits is, as you think about it, only about 20% of oHCM diagnosed symptomatic patients are on the CMI today. I think MAPLE further substantiates the need to drive to earlier use of the CMI for those patients that are still experiencing symptoms.

Okay. Great. I want to turn to your recent news from the ACACIA study where you had a positive top line result in nonobstructive HCM. Maybe, Robert, you can kick it off and share what has the clinical feedback been from the physician community. Dan, if you want to jump in here as well. And just how much did this surprise you? Because I think from the Wall Street perspective, at least based on our conversations, there was a fair amount of hesitancy whether the study would succeed or if it would only succeed on one of the 2 primary endpoints. And so maybe you could share some of your initial feedback ahead of your potential medical conference presentation this year.

So firstly, it's important to understand that nHCM represents based on claims analysis, we believe, at least 50% of the total HCM market and growing, growing at a faster rate perhaps than oHCM. And there are no approved treatments for patients with nHCM. So these data, and we hit not on just one, but on both of our primary efficacy endpoints as well as key secondaries. While they've only been top lined in a press release, they are being met with great enthusiasm and words shared with us by people who have seen the totality of the data, and that includes the steering committee of the study, words like game changer, transformative. These are words that are not that often used in medicine and certainly not in cardiology.

So we foresee that these data when they are fully presented and published, will be met with a very high level of enthusiasm. And we've included certain words in our communications, words like consistent, because we believe not just are the data consistent between the 2 primary endpoints, but so too, are they consistent across the secondary endpoints as well as the prespecified subgroups that were enrolled in the study as is intended to represent a full broad spectrum of nHCM patients. So we believe this is a pivotal study to support the use of MYQORZO (aficamten) in nHCM.

Yes. I mean I think you pretty much covered it. I'll say that we were at the European Society of Cardiology Heart Failure meeting shortly after the top line, and that meeting is filled with heart failure -- not necessarily HCM specialists but heart failure specialists. And if you recall, the ACACIA study really was, in many ways, a heart failure study. It enrolled nHCM patients, but those patients don't have a specific hemodynamic lesion like the obstructive patients do. So it's sort of a heart failure type study.

There has never in history been a study in heart failure that has demonstrated positivity on KCCQ and peak VO2 together. And that's including 5,000 to 10,000 patient studies. Mostly what you see in terms of KCCQ improvement in those studies are a 1 to 1.5 improvement in KCCQ. So this is at least double. And if you look over the span of the treatment, triple in many cases, what you see in heart failure studies that have shown successful impact on outcome. And the community responded incredibly positively to that. People are very excited. They view this as a complete game changer, another word that was used as home run by a very experienced heart failure trialist to describe it as such. So I'm very enthusiastic about it. I think that's reflected in the community [indiscernible] which is a complex over 100 site study globally [indiscernible]

Great. Robert, can you maybe inform us whether you've had your End-of-Phase III meetings either with U.S. or European regulators following the ACACIA top line? And maybe for the team here broadly, given the potential applicability of this data to a broad spectrum of -- now of oHCM and nHCM patients, how does this make you maybe think about driving a switch strategy pending a future label update from this ACACIA study?

So I'll answer the first part. I'm going to resist the temptation and maintain a discipline to what we said before that we'll provide updates on our regulatory interactions on the quarterly earnings call.

From a commercial perspective, we are not focused on a switch strategy and the majority of our patients that we have started on MYQORZO in quarter 1 were new-to-brand. We did have a handful of patients that were switched by their prescribers to MYQORZO. We do know there is interest in the idea of switch. Maybe Dan can speak to there was recently an investigator-initiated research project that was just posted on clinicaltrials.gov, where 2 leading thought leaders within the HCM space are embarking on understanding switch from one CMI to MYQORZO, but it's not actively where we are focused commercially.

Yes. And I think even those investigators honestly, are not really focused on switching patients. When you have a patient who's doing well on CAMZYOS or any therapy, they're doing well, and you generally don't change that. It's more to provide guidance really around when you -- there's going to be some switches. So how do you do it safely? That's really, I think, where these investigators are coming from and trying to explore that.

Robert, earlier, you and I were talking about the ex U.S. market. U.S. investors tend to focus on how the U.S. market is going, but you are also launching internationally. Can you maybe update us on sort of where you are approved and sort of where the launch preparations or launch activities are focused right now?

Yes. So Cytokinetics has, as part of its Vision 2030 [indiscernible] in the United States. So we have a partner in Japan, Bayer. We have a partner in China, Sanofi, and we ourselves are launching in major markets in Europe. The drug is approved and launched in China. We're in advanced clinical studies in Japan, and we launched in Germany last week. And over the course of this year, we hope to be readying to launch in the U.K., France, Italy and Spain and potentially other countries in 2027, 2028. We're seeking to do a partnership in countries where we ourselves don't expect to tee up infrastructure in Latin America, Middle East, Africa and Eastern Europe, for example. So Cytokinetics is taking this very seriously to advance science for the benefit of patients all around the world.

In terms of commercial returns, I don't expect the work that we're doing in Germany or in Europe this year to be moving the needle appreciably, but it speaks to our commitment to patients. Over time, we do believe the work we're doing in Europe can support a profitable business and a meaningfully one at that, especially as we go from oHCM to nHCM and from nHCM to heart failure with the rest of our franchise in specialty cardiology. So we think it's good for science, good for patients, good for business. But I wouldn't be focusing on the German launch as will be meaningfully contributing to commercial revenue this year.

Great. I want to spend a moment just on the competitive landscape. Bristol has recently indicated that they're going to redo the ODYSSEY trial in a potentially accelerated time frame. Investors are carefully monitoring for the upcoming Edgewise CIRRUS-HCM data as well. Could you maybe speak to how you view Cytokinetics' competitive positioning versus some of these other companies, including Braveheart, among others? And then as you think about these companies, what is your outlook for the market over the coming, call it, next 5 years?

So Cytokinetics is the pioneer, and we are the innovator in this space. And it's been, I think, reassuring perhaps to Wall Street, in particular, that there are other companies that have entered the arena and compete here. We remain focused on being the leader in the space. And that means that we tell our story, our narrative and as could be benefiting more science and more patients. BMS seems to be looking at nHCM again. And Braveheart and Edgewise are advancing programs with Phase II data that still warrant doing a proper global Phase III program. In all cases, I guess, imitation is great flattery, but at the same time, it's good for science and good for medicine to have others entering.

I would caution, however, there's nothing that any of these companies are doing that we don't think we have competitive advantage to do at least equal to, if not more so. And we keep a close eye on strategies. We keep a keen focus to what may be enabling of us to consider ways we can even expand our label, if needed, or lessen restrictions on our REMS, if needed, based on real-world evidence. So as a pioneer in this space, having committed over 25 years, shame on us if we're ever going to be ceding leadership to anyone else and instead focusing to more here could be benefiting category growth. We do believe that there are opportunities to continue to innovate, and we'll be doing that.

Okay. Great. I want to turn to omecamtiv mecarbil for a moment. And either Robert or Dan, can you maybe remind us on what is the current status of your Phase III trial? And is there an interim built into that study for potential mid-stage look before you top line the results?

So thank you for asking. I do think that this is one of the greatest opportunities for Wall Street to be refocusing to omecamtiv mecarbil. So omecamtiv mecarbil is a cardiac myosin activator, has already been the subject of an 8,000-patient study in advanced -- in heart failure with reduced ejection fraction, EF below 40 that showed clinically meaningful and statistically significant findings on hard endpoints. But the FDA asked us to do a confirmatory study because admittedly, the overall effect was more modest. And we're focusing to patients within that group of heart failure patients who have more severely reduced advanced heart failure who in the GALACTIC study saw a doubling of the treatment effect relative to the overall. So we're doing a confirmatory study called COMET, which will be roughly 2,000 patients and which will be event-driven. So we're very encouraged by the pace of enrollment in that study. And maybe I'll ask Dan to comment on your question about interim analysis.

Yes. There's no plan for an interim analysis. We're not -- I think your question gets to sort of can you expect any data updates per se before we get to the actual results of the study. And right now, we don't have any plans for that. The study is enrolling nicely. We'd anticipate completion of enrollment in the coming year and hopefully, results soon thereafter. As Robert has pointed out, it's an event-driven study, so I can't really project exactly when we'll get to that, but it shouldn't be too far into the future.

Great. In our last minute here, I want to maybe briefly touch on ulacamten on the HFpEF side and maybe how that study is going.

Yes. So ulacamten, another cardiac myosin inhibitor, is being studied in its first cohort of a Phase II study in patients with heart failure and preserved ejection fraction. We recently announced the expansion of the size of Cohort 1 to match that of Cohort 2 and Cohort 3. The study is enrolling well. This speaks to the third leg of our 3-legged stool as it relates to specialty cardiology and myosin modulators and where we expect to pioneer and innovate there, too.

Great. We're coming up on time. So I want to thank the Cytokinetics team for joining us today, and we'll end it there. Thank you.

Thanks very much.

Welcome, ladies and gentlemen, to the Cytokinetics 2026 Annual Meeting of Stockholders. I'm Diane Weiser, Senior Vice President of Corporate Affairs. At this time, I would like to inform you that this meeting is being recorded. [Operator Instructions].

I will now turn the meeting over to John Henderson, the Chairman of Cytokinetics Board of Directors. Please go ahead.

Many thanks, Diane. Welcome, ladies and gentlemen. I'm John Henderson, Chairman of the Cytokinetics Board of Directors, and I welcome you to our 2026 Annual Meeting of Stockholders. The meeting is now called to order.

Before proceeding to the formal business, let me introduce Robert Blum, the company's President and Chief Executive Officer. Robert will provide a review of our 2025 accomplishments and plans for 2026 after our formal proceedings.

Further, I'm pleased to introduce the other members of the Cytokinetics Board of Directors who are here with us today: Muna Bhanji, Jim Daly, Robert Harrington, Ed Kaye, Bob Landry, Wendell Wierenga and Nancy Wysenski. It's also my pleasure to introduce the other members of the company's Corporate Steering Committee who are joining us in person today. Andrew Callos, Executive Vice President and Chief Commercial Officer; Isaac Ciechanover, Executive Vice President, Corporate Development and Chief Business Officer; Steve Cook, Senior Vice President, Global Supply Chain and Technical Operations; YulyMae DiNapoli, Senior Vice President, Human Resources; Jeff Hessekiel, Executive Vice President, Chief Legal and Administrative Officer; Sung Lee, Executive Vice President and Chief Financial Officer; Fady Malik, Executive Vice President, Research and Development; and Christine Murray, Senior Vice President, Global Regulatory Affairs. I also would like to introduce Dan Coleman of Ernst & Young LLP, the company's independent registered public accounting firm, and he is available to respond to appropriate questions.

Now I would like to turn the meeting over to Jeff Hessekiel to conduct the formal business of today's meeting as set forth in your notice of annual meeting and proxy statement. After the formal part of our meeting, Robert Blum will review the company's recent business activities.

Thank you very much, John. I have at this meeting a complete list of the stockholders of record of the company's capital stock on March 31, 2026, the record date of this meeting. I have proof by affidavit that the company's proxy statement, proxy card and annual report on Form 10-K were deposited in the United States mail commencing on April 17, 2026, to all stockholders of record at the close of business on March 31, 2026. The affidavit, together with copies of the proxy statement, proxy card and annual report, will be filed with the minutes of the meeting.

In addition, Sung Lee, Executive Vice President, Chief Financial Officer, will serve as the Inspector of Election to carry out the duties set forth under the General Corporation Law of the State of Delaware. Mr. Lee has signed an oath of office as Inspector of Election. The oath of Inspector of Election will be filed with the minutes of the meeting. We have present in person and by proxy, holders of a sufficient number of shares to constitute a quorum, so the meeting is duly constituted.

We will vote by proxy and written ballot today. If you are a stockholder attending the meeting today in person and have turned in a proxy and do not intend to change your vote, then it is not necessary that you vote because we will count your votes as expressed in your proxy. Those attending stockholders present in the room today who did not turn in a proxy card or who wish to change your vote and have your proxy card with you, please raise your hand. Are there any additional proxies to be submitted at this time? Is there anyone present whether or not you already submitted a proxy who now wants to vote in person?

The polls are now open for voting this May 27, 2026, at 10:08 a.m. The polls will be closed to voting after we go through the matters to be voted on. We will first present the 5 proposals submitted for approval. Please save all questions related to the proposals for after all of the proposals have been presented, after which we will announce the preliminary results of the voting.

The first item of business is the election of directors. The following 3 directors are nominated by the Board of Directors as Class I directors of the company to serve until our 2029 Annual Meeting: Ed Kaye, Wendell Wierenga and Nancy Wysenski. The Board of Directors recommend that the stockholders vote for these 3 Class I nominees.

The second item of business is the approval of the amendment and restatement of the company's amended and restated 2015 employee stock purchase plan to increase the number of authorized shares reserved for issuance thereunder by 1 million shares of common stock. The Board of Directors recommends that the stockholders vote for the approval of this proposal.

The third item of business is the ratification of the selection by the Audit Committee of our independent auditors. The Audit Committee of the Board of Directors has selected Ernst & Young LLP to serve as our independent registered accounting firm for the fiscal year ending December 31, 2026. The Board of Directors recommends that the stockholders vote for the ratification of this selection.

The fourth item of business is the advisory vote on the executive compensation of the company's named executive officers as described in our proxy statement for this annual meeting. The stockholders have been asked to vote on an advisory basis on the following resolution: Resolved that the company's stockholders approve, on an advisory basis, the compensation of the named executive officers as determined under Regulation S-K and as otherwise disclosed in the company's proxy statement for the 2026 Annual Meeting of Stockholders pursuant to the compensation disclosure rules under the Exchange Act and Regulation S-K, including the compensation discussion and analysis, the related compensation tables and the narrative disclosure to those tables in the proxy statement. The Board of Directors recommends that the stockholders vote for the advisory proposal.

We will now review if there are any questions about the aforementioned proposals before we close the polls. Any questions?

If you have voted in today's meeting, would you please give your ballots to the Inspector of Election? That's all.

It is now 11 minutes after 10 by my watch. And the polls for each matter to be voted on at this meeting are now closed. No additional ballots or votes and no changes or revocations to ballots or proxies will be accepted.

At this time, I would like to report on the results of the preliminary voting as of the close of business yesterday. Regarding Proposal 1, the proposal to elect each of Ed Kaye, Wendell Wierenga and Nancy Wysenski. Ed Kaye received 104,508,714 votes for his election. 3,234,850 votes were withheld. There were 8,305,458 broker nonvotes. Wendell received 85,302,371 votes for his election. 22,441,193 votes were withheld. There were 8,305,458 broker nonvotes. Nancy Wysenski received 104,696,260 votes for her election. 3,047,304 votes were withheld. There were 8,305,458 broker nonvotes. Therefore, the proposal to elect each of Ed Kaye, Wendell Wierenga and Nancy Wysenski is approved, and each of them is hereby reelected.

Regarding Proposal 2, the approval of the amendment and restatement of the company's amended and restated 2015 employee stock purchase plan to increase the number of authorized shares of common stock to be reserved for issuance thereunder by 1 million shares from 1,459,879 to 2,459,879. Votes in favor of the proposal were 107,130,372. Votes against the proposal were 260,746. And 352,446 votes were abstained. And there were 8,305,458 broker nonvotes. Therefore, the proposal is approved.

Regarding Proposal 3, the ratification of the appointment of Ernst & Young LLP by the Audit Committee of our Board of Directors as the company's independent registered accounting firm for the fiscal year ended December 31, 2026. Votes in favor of the proposal were 115,390,120. Votes against the proposal were 269,854. And 389,048 votes were abstained. Therefore, the proposal has been ratified.

Regarding Proposal 4, the resolution concerning the advisory vote on the compensation of the named executive officers as determined under Regulation S-K and as otherwise directed in the company's proxy statement for the 2026 Annual Meeting of Stockholders. Votes in favor of the proposal were 103,992,469. Votes against the proposal were 3,017,487. And 733,608 votes were abstained. And there were 8,305,458 broker nonvotes. Therefore, the proposal is approved.

This concludes the formal business of the meeting, and we would now like to begin our report to stockholders. The meeting is now concluded.

The following discussion and presentation contain forward-looking statements under the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. Our actual results might differ materially from those projected in the statements. Factors that could cause our actual results to differ materially are contained in our SEC filings, including our most recent annual report on Form 10-K, quarterly report on Form 10-Q and current reports on Form 8-K. Copies of these documents may be obtained from the SEC or by visiting the Investor Relations section of our website. These forward-looking statements speak only as of today. You should not rely on them as representing our views in the future, and we undertake no obligation to update these statements.

I will now turn the meeting over to Robert Blum, our President and Chief Executive Officer.

Thank you, Jeff. I'm pleased to be addressing you today at Cytokinetics 22nd Annual Meeting of Stockholders. Thank you to those who are here with us in the room in person and to those listening online. As reflected in our annual shareholder letter, 2025 represented a major inflection point for our company and a culmination of years of disciplined research in muscle biology and dedication to translating that pioneering science into medicine for patients.

2025 was the year that we received our first FDA approval for MYQORZO for adults with symptomatic obstructive hypertrophic cardiomyopathy or oHCM. MYQORZO was also approved in China in 2025 and in Europe in early 2026, positioning us for commercial launches in key geographies around the world. This was an achievement that relied on years of R&D rigor, operational planning and readiness and thoughtful fiscal management.

To meet the moment, we scaled our company in size and in capabilities to enable the U.S. launch of MYQORZO promptly following receipt of FDA approval. And now in 2026, we have launched MYQORZO for patients with oHCM in the U.S., and we expect to launch in Germany as our first European launch in this second quarter. While it's still early, our initial commercial launch is exceeding our internal expectations, and we believe this initial momentum builds a strong foundation for longer-term commercial successes.

In 2025, we also continued to advance our pipeline of muscle-directed therapies. Among those achievements, we presented the primary results from MAPLE-HCM, the Phase III clinical trial evaluating aficamten as monotherapy compared to metoprolol in patients with oHCM and with simultaneous publication in the New England Journal of Medicine. This landmark trial demonstrated that aficamten improved exercise capacity, while metoprolol showed a detrimental effect challenging a long-standing treatment paradigm in HCM and marking an important milestone and turning point in how this disease may ultimately be treated in the future.

We also made progress in nonobstructive HCM, or nHCM, which represents approximately half of the entire population of people with HCM. In 2025, we completed enrollment in ACACIA-HCM, the pivotal Phase III clinical trial of aficamten in nHCM. And more recently, earlier this month, we shared positive top line results from ACACIA-HCM, demonstrating statistically significant improvements from baseline to week 36 in both dual primary endpoints of KCCQ clinical summary score as well as peak VO2, both compared to placebo.

While HCM is the anchor of our emerging specialty cardiology franchise, we also continued our later-stage development programs in heart failure. We continued enrollment and conduct of both COMET-HF, the Phase III clinical trial of omecamtiv mecarbil in patients with heart failure, with severely reduced ejection fraction and AMBER-HFpEF, the Phase II clinical trial of ulacamten in patients with heart failure and preserved ejection fraction. Both of these clinical stage programs represent potential opportunities to extend our expertise in muscle biology to diseases of impaired contractility and to build a robust cardiovascular franchise designed to ensure sustainable growth as well as longer-term shareholder value.

In 2025, we maintained a strong financial foundation and flexibility in accessing additional capital, which set us up well as we started this year. Recently, we also completed a public offering that netted us an additional approximately $760 million on our balance sheet to support the launch of MYQORZO and the continued advancement of our pipeline and ongoing R&D.

Now in 2026, we're proud to be building on this momentum as a global commercial company and to make an impact for patients and to deliver value for all stakeholders, including our shareholders.

In the corporate presentation that will follow, I plan to share some highlights of the progress we achieved in 2025 as well as more recent activities related to our commercial launch of MYQORZO and our ongoing later-stage development programs. I'll now begin my update on the company, and we will be making a presentation that you can find on our website. With that, I'll be making some forward-looking statements. You heard from Jeff earlier about caveats to those statements. And again, we do not undertake obligation to make updates, but instead refer you to our SEC filings.

As you can see on this Slide #3, Cytokinetics' mission, a mission that's been steadfast to our convictions since we formed this company over 20, 25 years ago, is to bring forward new medicines to improve the health span of people with devastating cardiovascular and neuromuscular diseases associated with muscle weakness and impaired muscle function. That hasn't changed. And as we evolve and mature the company, that remains a mainstay of our convictions. But now we're in the advantaged situation to be a commercial enterprise. And with the recent approvals and launches of MYQORZO, aficamten now available, we have our first commercial programs with the FDA approval of MYQORZO for the treatment of adults with symptomatic oHCM. We're very pleased and proud of this progression.

It comes on the heels of a continued advancement of our pipeline you see here on Slide #5. And while MYQORZO with oHCM represents a major achievement for Cytokinetics and with commercialization underway, we never lose sight of our ongoing obligation to continue to innovate and to maintain commitment to research and development and to be enabling the advancement of aficamten in other indications, including expanded label around nHCM built around ACACIA results, but also as we think about CEDAR for pediatric patients ongoing. And that builds a bridge to the way we think about our franchise in specialty cardiology with myosin modulation being a cornerstone and a hallmark to the emerging specialty cardiology franchise.

Omecamtiv mecarbil in COMET-HF advancing in a confirmatory Phase III study and ulacamten in AMBER-HFpEF advancing in Phase II towards potential indication associated with heart failure and preserved ejection fraction. And the hits keep coming as we look beyond our myosin modulators to CK-089 now in Phase I, advancing in healthy volunteers as we consider what could be skeletal troponin activation as another beginnings to a vertical in neuromuscular disease and more in research underneath the hood, so to speak.

Cytokinetics has been built on R&D innovation. Science is in our soul. And that continues to be intentional and a planning for the company as we consider how we advance the business beyond MYQORZO. But MYQORZO, as depicted on this Slide #6, is approved and is indicated for oHCM and the launch in the United States and soon in Europe is encouraging for what may be prospects for all of our stakeholders. Here, you see a snapshot how we're advancing aficamten ahead of omecamtiv and ulacamten and with strong financial backing.

At the end of Q1, we reported cash and cash equivalents of approximately $1.1 billion. We added to that with a significantly large financing more recently gross proceeds over $800 million, net proceeds approximately $760 million. So we proceed this year with a very strong balance sheet, but still very disciplined to how we think about research and development and commercial expansion.

All of this is guided by our Vision 2030. You've seen it before, and it continues to echo through our laboratories and elsewhere within the company. Our Vision 2030 is determined by these pillars: innovation, ignition, impact, inspiration and ingenuity. It's not enough that we advance MYQORZO for patients with oHCM, but we aspire to be advancing at least 2 approved products across 3 indications, hopefully, as well as more and with at least 10 NMEs, new molecular entities, in our advancing pipeline. To get there will require us to continue to do the kinds of innovation that's been a hallmark of our success.

It's not enough that we advanced development programs to commercialization, but that we ensure that those products are available for patients, not just in the United States, but globally, and we have ambition to ensure that we are reaching at least 100,000 patients across 15 countries throughout North America and Europe on our own and through partners in Japan, China and rest of world and that these patients are benefited not just by having access to affordable medicines, but that we play a role in equitable access to our medicines. We're inspired by those patient communities. We want to continue to maintain them and patients as our North Star and that we maintain ingenuity in all of the things that we commit to.

So as we look to the future, Cytokinetics and its product portfolio looks like this, Slide #8. We expect what we'll be able to achieve, all things considered, including risks, is that we manage to the development and commercialization of products associated with multiple launches as depicted here across our emerging specialty cardiology franchise.

Let's dig a little bit deeper into each of these programs, starting with MYQORZO or aficamten. And as you hopefully may remember, MYQORZO inhibits cardiac myosin motor activity, suppressing the hypercontractility associated with hypertrophic cardiomyopathy. We believe that this represents an opportunity not just in oHCM as currently approved in the U.S. and Europe, but also hopefully nHCM, and recent claims diagnoses and analysis would suggest that the market opportunity is split roughly equally between those 2 populations.

How do we get there? We get there by being initially focused to those high-volume cardiac myosin inhibitor prescribers. We call them Velocity accounts, roughly 700 physicians and their offices responsible for about 80% of the volume of cardiac myosin inhibitors to date. Through just the first 9 weeks of commercialization, about 90% of them were detailed by our CAS colleagues, our sales force. But it's not enough that we focus strictly to where the business is.

We also need to ensure that we play a key role in category growth and expansion to those roughly 2,000 CMI prescribers that represent the next 20% of prescriptions as well as roughly 8,000 nonusers of CMIs currently, but who treat HCM, and we believe aficamten or MYQORZO represents a key innovation as could unlock the potential for growth there. And as reported in Q1, 9 weeks, we saw about 40% of those and already are seeing prescriptions coming from unlocking value in those tiers of this onion. So I do believe our commercial strategy driven by our sales force is achieving and reaching the potential customers that will make a difference for these patients.

As we think about key launch drivers to achieve high share and growth, we maintain discipline to those metrics or KPIs, as depicted on this Slide #13. It speaks to how we can communicate what is, we believe, next-in-class properties for aficamten, MYQORZO. And we do believe, as listed here, innovation can be our ticket to what may ultimately be category leadership. That also comes hand-in-hand with ensuring market access. And here, you can see in Q1, our payer mix dominated by Medicare, but with substantial commercial presence. And as you can see here through the progression of quarters, we expect to be achieving by the end of the year, parity access amongst commercial accounts. And already, we're making a big dent in these opportunities. In Q2, we hope we may achieve nearly 90% coverage of Medicare lives. And as you can see in Q3, 50% of commercial lives covered. These are our goals from a market access standpoint to make impact for MYQORZO.

Also metrics associated with breadth and depth of prescribing. Here, you can see how we're measuring that both with respect to number of HCPs, the volume of their prescriptions and also the volume of patients outside of core accounts.

We're already off to an excellent start. And in just the first 9 weeks, you can see some of those metrics depicted on this Slide #16, 275 prescribers of MYQORZO as of March 31. And as you can see also as of March 31, that represents about penetration into 50% of those high-volume accounts I mentioned. Those high-volume accounts already accounting for average 2.6 prescriptions written. But also please note that as of April, we're seeing growth in the numbers of prescribers, and we're seeing growth in the numbers of REMS-certified healthcare professionals as well as coming out of March 31, already we were seeing escape velocity of roughly 30% new-to-brand prescriptions. These are encouraging metrics for first coming out of the gate.

Similarly, with regard to patients, 680 patients prescribed to MYQORZO as of March 31, and those numbers are climbing in this second quarter. We're very pleased with the performance, especially given how we're going so quickly from prescribing to dispensing to reimbursement and exceeding some of our internal expectations for how quickly that can occur.

And it's not happening only in the United States. Our partners are making good progress in China and Japan. We're seeking and expecting, hopefully, regulatory approvals in Canada and Switzerland. And as mentioned, we're going to be launching in Europe in this quarter. Our first country expected to be Germany coming very soon.

All of this is meant to say that based on what we already have with SEQUOIA-HCM is establishing a strong commercial footprint, but that will hopefully expand with incorporation of both MAPLE and ACACIA data as we hope may result in expanded label and in the case of ACACIA, a new indication. ACACIA was presented in top line press release very recently. Here's the study design. I won't go into it in detail. But keep in mind, it enrolled over 500 patients with symptomatic nHCM, and we studied them out to 36 weeks as well as during a washout period, and then they roll into open-label extension. Primary endpoint, a dual primary endpoint of KCCQ and peak VO2.

And as reported by top line press release, the results here, we hit on both dual primary endpoints. Please keep in mind, these are patients who do not have an approved therapy. There is a high unmet need. And what we've seen is aficamten relative to standard of care showed improvements in symptoms and exercise stamina with highly statistically significant findings and consistent over time, as you can see depicted in this graph for KCCQ on the left. We believe that these are encouraging, persuasive and compelling results, and we're looking forward to the full presentation of data as may accompany a concurrent publication, hopefully, as soon as late August.

We believe that these efficacy results were nicely accompanied by good and safe, favorable tolerability and safety data, as also toplined here. We believe this is consistent with what's already known about aficamten in the oHCM population. And I'll highlight here that while there were 2 participants who had a serious AE of heart failure associated with a lower ejection fraction, we believe that, that was well managed by down-titration or dose interruption and one of those patients continued on therapy even into the open-label extension. But as you can see with regard to overall left ventricular ejection fraction excursions, AEs, SAEs, treatment interruptions, we believe these data are consistent with what was already known for aficamten.

So ACACIA added to MAPLE, added to SEQUOIA and other ongoing data from FOREST, we believe, presents for a compelling evidence to support not only the existing commercialization in oHCM, but hopefully potential expansion to nHCM. And that, we believe, opens the door to the franchise we've been talking about for quite some time. The next one up would be omecamtiv, now in Phase III in COMET-HF enrolling quite nicely. And here, you see that design. Please keep in mind, COMET is intended to follow behind already a positive Phase III study called GALACTIC that showed an effect on these same endpoints in a Phase III population of heart failure with reduced ejection fraction. But where admittedly, the results were more modest over the larger heterogeneous population studied in that global study.

And we've now committed and are enrolling a population more severely ill with lower ejection fraction as the GALACTIC data informed those patients did approximately twice as well as the others in GALACTIC. And therefore, we believe with this smaller, more focused study, we can generate confirmatory evidence, perhaps even amplify the results seen in GALACTIC as could be supportive of potential registration. This study is enrolling nicely. We recently expanded its enrollment to include China as well as ongoing North America and Europe.

And who are we targeting with this study? We're targeting those more severely ill heart failure with reduced ejection fraction patients who currently are not benefiting from standard of care. These are patients who are often frequent flyers in hospitals and who do not have good conventional medicines. And we do believe the data underscore the potential for the treatment of these patients which could represent many hundreds of thousands in the United States and also in Europe, who could benefit from a drug candidate whose mechanism of action is unique to those in the standard of care and are designed to improve contractility, enhance systolic function, for those with severely impaired contractility.

Ulacamten is the other side of that same equation of heart failure. There are patients with heart failure and preserved ejection fraction who we believe resemble in many respects patients with nonobstructive HCM. They are large in number with a high unmet need, especially those whose disease is not anchored in metabolic syndromes, but rather the hypercontractility associated with heart failure and preserved ejection fraction. So a subset of patients depicted on this Slide 27, who we do believe could benefit from a cardiac myosin inhibitor, a cousin, if you will, of aficamten called ulacamten.

So we're currently studying ulacamten in AMBER-HFpEF. And here, you see the design of that ongoing Phase II study, we recently announced the expansion of Cohort 1 to study more patients on ulacamten as we peer into the possibility of progression to later-stage study Phase III. So this study is also currently enrolling.

So we're really pleased with the progress we're making, not just in commercialization, but with our R&D pipeline. I've only highlighted those 2 later-stage programs. Suffice it to say, we're also advancing in earlier-stage clinical and nonclinical programs as we continue to invest in pipeline for future growth prospects.

All of that is occurring alongside of a strong balance sheet. Here, you see depicted how we communicated with our Q1 earnings call that we ended March 31 with $1.1 billion on the balance sheet and with access to additional capital given deals we have done previously, but where those are at our option to pull down on tranches of debt loans from Royalty Pharma. In the meantime, we've also added to the balance sheet by doing an equity offering earlier this month and netting $760 million added to that $1.1 billion, consider pro forma approximately $1.8 billion as we entered Q2 and as we are continuing to advance pipeline and business prospects.

So we recently had with our Q1 earnings call, an opportunity to reaffirm guidance for the year. You see it depicted on this Slide 31. Here, you see both GAAP and noncash-based compensation expenses. And as we foresee, we're in a good position, not only with respect to current capital, but how we're thinking about allocating capital to ensure we deliver on important prospects for ambition.

So in summary, here are our 2026 milestones. You see them much as we depicted them in our press release. We continue to want to ensure that we're seeking expanded label for aficamten as we now engage FDA around both the supplemental NDA accepted for filing for MAPLE, but also as we'll meet with FDA and hopefully be submitting a supplemental NDA based on the ACACIA results and at the same time, continuing to execute on U.S. commercial launch ongoing and soon in Germany in Q2. Those are the most important milestones and continuing activities in CEDAR, in COMET and in AMBER.

So with that, I'll conclude my initial comments and open up today's meeting for any questions as there may be here in the room.

Seeing none, hearing none, I want to thank you all. I want to thank you for your continued support of our company. I want to thank you for your continued interest in our prospects, plans and progress. We look forward to updating you in successive quarters. Thank you for all that you do aligned to our vision for Cytokinetics.

And with that, I'm going to turn it back over to John Henderson, please.

We thank you very much indeed, Robert, for the update on the tremendous progress that Cytokinetics has made in the last year as well as more recently. I think it's clear that 2025 was a transformational year for the company that cemented Cytokinetics as a global commercial biopharmaceutical company.

With the launch of MYQORZO underway in the U.S. and expected soon in Europe, a strong pipeline of later-stage programs in adjacent cardiovascular indications and an ongoing R&D engine, the company is delivering on its Vision 2030 to be the leading muscle-focused specialty biopharmaceutical company intent on meaningfully improving the lives of patients through global access to innovative medicines.

I want to thank all of those who participated today in this stockholder meeting, and I now declare the meeting adjourned. Thank you very much, everyone.

Hello, everyone. Thank you for standing by, and welcome to the Cytokinetics Q1 2026 Earnings Conference Call. This call is being recorded. [Operator Instructions]

I would now like to 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 discuss the commercial launch of the MYQORZO in the U.S. and readiness in Europe. Fady Malik, EVP of R&D, will address the results from ACACIA-HCM. Stuart Kupfer, SVP and Chief Medical Officer, will provide updates related to our ongoing clinical development programs. Sung Lee, EVP and Chief Financial Officer, will provide a financial overview for the quarter. And finally, Robert will make closing remarks and review key milestones for the year ahead.

As you can see on this slide, today's discussion will include forward-looking statements, which are subject to risks and uncertainties. Please refer to our SEC filings for a discussion of these factors.

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 first quarter of 2026 has been a remarkable period for Cytokinetics and one that I believe reflects the emerging promise of what we have been building here for over 25 years. Most notably, we launched MYQORZO, our first approved medicine for the treatment of adults with symptomatic oHCM in the United States. This is a milestone many years in the making and that reflects our unwavering dedication to translating our science into impact for patients.

As Andrew will discuss, our initial commercial launch, while representing only a partial quarter, is exceeding our internal expectations with net product revenue of $4.8 million in the first quarter. The level of engagement from prescribers, the pace of REMS certifications and the early demand all reinforce our conviction in the significant opportunity ahead for MYQORZO and based on its clear differentiation. We believe this initial momentum builds a strong foundation for longer-term commercial successes.

Beyond the United States, during the quarter, the European Commission approved MYQORZO for patients with oHCM and we're now moving quickly towards our first European commercial launch in Germany in this second quarter. The global market for MYQORZO is significant, and we're prudently building the right infrastructure to realize its potential.

And then, of course, there is ACACIA-HCM. This morning, we reported positive top line results from this pivotal Phase III clinical trial of aficamten in nonobstructive HCM. We were very pleased to see that aficamten improved both symptoms and exercise capacity with no new safety signals observed. Fady will speak more to the results that we reported, but we're excited by what these results represent for patients living with nHCM who have no currently approved therapies.

And for aficamten, which depending on the results of regulatory review, may now have the opportunity to be the first product approved to treat the full spectrum of HCM. With a statistically significant and clinically meaningful effect on both endpoints, we believe we have a very clear picture of the treatment effect that aficamten has in nHCM. Given the trial results, we plan to meet with regulatory authorities, including the FDA to discuss our plans for promptly submitting a supplemental NDA.

And during the quarter, there were several meaningful regulatory updates for aficamten beyond that. In the United States, our sNDA for MAPLE-HCM was accepted for filing by the FDA, and we were assigned a PDUFA date of November 14, 2026. We believe the results of MAPLE-HCM will be enabling of us to accelerate expansion of the prescriber base, especially with cardiologists in the community setting.

And outside of the United States, we submitted an MAA for aficamten in oHCM in Switzerland. And as a reminder, we also have a marketing application already under review in Canada. Plus our partner, Sanofi, is continuing to progress potential approvals in Hong Kong and Taiwan. Taken together, the progress we made in this first quarter is a testament to what we've built in service of our vision of becoming the leading muscle-focused specialty biopharma company intent on meaningfully improving the lives of patients through global access to our innovative medicines.

As we look ahead, we enter the remainder of 2026 with strong commercial momentum, conviction in our pipeline and a deep sense of purpose. Our priorities remain the continued growth of MYQORZO in the United States, advancing our planned launches in oHCM in Europe, pursuing expansion into nHCM and advancing our muscle biology pipeline, all with disciplined execution and careful attention to capital allocation.

And with that, I'll now turn the call over to Andrew, please.

Thanks, Robert. I'm thrilled to be reporting on our first quarter of commercial performance for MYQORZO. MYQORZO became available to patients on January 27, and we saw HCP prescribing within days. We've had a strong start that exceeded our expectations. Our launch is grounded in the foundation of clinical evidence and differentiation.

The results from SEQUOIA-HCM demonstrate that MYQORZO provides rapid and sustained reduction in obstruction with improvement in symptoms and outcomes that resonate with HCPs. MYQORZO also offers an adaptable monitoring schedule with echoes permitted within a flexible 2- to 8-week window and a REMS that does not require DDI counseling. Over 80% of treating HCPs report awareness that they have seen the prescribing information for MYQORZO on an unaided basis. We're pleased to see continued growth and perceptions of clinical differentiation favoring MYQORZO.

In our most recent HCP survey, we see a higher majority of HCPs favoring the clinical profile of MYQORZO, especially among the high-volume CMI writers surveyed. In addition, HCP survey view MYQORZO favorably across metrics such as dosing flexibility, safety and tolerability profile and REMS program requirements. Beyond the clinical profile, treating physicians are also responding favorably to the practical elements of prescribing MYQORZO across key metrics of ease of prescribing, echo monitoring, flexibility and the absence of DDI restrictions within REMS. HCPs appear to view MYQORZO as differentiated.

Following FDA approval at the end of December, our team of 100-plus cardiovascular account specialists began engaging HCPs in early January, a few weeks ahead of when product became available in late January. Since then, they have reached HCPs at all levels of CMI prescribing. Our initial launch prioritized focusing our promotional and sales force activity on deepening prescribing among the high-volume CMI writers that have historically generated 80% of CMI prescriptions. While our call points span over 10,000 HCPs, we are currently putting greater emphasis and call allocation on the high-volume CMI writers.

In Q1, our sales teams detailed over 90% of these HCPs. We plan to continue this emphasis on high-volume prescribers until we achieve over 50% new-to-brand prescription share among these HCPs, which we anticipate will occur by year-end. Once we see strong share performance in the high-volume CMI writers, we will put greater emphasis on increasing the breadth of prescribing while still maintaining leadership and growth in the high-volume CMI writers. We are already seeing uptake outside the high-volume prescribers.

In Q1, more than 40% of MYQORZO prescriptions are from the combination of low-volume CMI prescribers and first-time CMI writer segments. In Q1, our field force reached an estimated 40% of these HCPs. Beyond personal and nonpersonal promotion, our surround sound approach to reaching HCPs has also delivered strong interest with robust participation in our peer-to-peer physician speaker programs and engagement with our digital advertising. By the end of Q1, over 2,100 people already enrolled in the MYQORZO patient community.

In addition to our clinical profile, we're taking the time to educate HCPs on our REMS program and patient services as they are different from what HCPs have become accustomed to. Since launch, we have moved quickly to release enhancements to these systems that are consistent with HCP feedback and clinical practice. To measure launch performance overall, we have committed to sharing 3 launch metrics, the depth and breadth of prescribing and volume of patients.

Breadth of HCP prescribing is measured by the number of HCPs who have written prescriptions, depth of HCP prescribing is measured by the number of patients each HCP prescribed MYQORZO and the volume of patients is measured by the number of unique patients prescribed MYQORZO. In Q1, we saw strong demand with more than 275 unique HCPs prescribing MYQORZO with over 50% from the high-volume CMI writer segment. Through April, we have seen continued prescriber growth with more than 425 HCPs prescribing MYQORZO.

Overall, these CMI writers that have prescribed MYQORZO have written an average of 2.4 prescriptions per HCP, while the high-volume writers have prescribed MYQORZO to approximately 2.6 patients per HCP. While it's difficult to be precise about our new-to-brand Q1 exit share due to some limitations in data availability, our internal analysis leveraging projected syndicated data suggests that the MYQORZO new-to-brand Q1 exit share was greater than 30%. These are very encouraging numbers at such an early stage of our launch.

We also see positive momentum in the 1,400-plus HCPs who became REMS certified during the quarter, a potential leading indicator of HCPs who plan to prescribe MYQORZO. The differentiated profile of MYQORZO and our targeted HCP engagement since the beginning of the year has resulted in approximately 680 patients prescribed MYQORZO by the end of Q1 2026. And through April, the number of patients have increased to 1,100.

Importantly, in Q1, over 70% of dispensed patients are on a paid prescription. On an average, patients convert to a paid prescription in less than 2 weeks. Both of these metrics exceed our launch expectations. This is particularly due to our limited distribution model with dedicated focus on MYQORZO patients, which has helped us achieve a high percentage of patients on paid prescriptions very early in the launch phase.

As we continue to accelerate our launch, we're also focused on expanding access and reducing barriers to prescribe. As we've shared, we've been engaging with payers for quite some time regarding the clinical evidence from our clinical trial program and the clinical and economic burden of oHCM. We currently have comparable access for nearly 90% of Medicare lives and expect to have parity in Medicare within Q2. We are also building commercial access and expect to reach 50% of commercial lives by early Q3 and remain on target to achieve commercial access at parity by end of Q4.

Simultaneously, we're continuing to expand our commercial readiness and launch planning in key geographies around the world. We secured approval for MYQORZO in the EU in February and continue to move quickly towards our first European commercial launch in Germany planned in the second quarter.

In support of that milestone, we finished hiring and onboarding our full German team, inclusive of sales, marketing, medical and leadership teams. Across the EU, we have also now submitted 6 HTA dossiers with 5 more expected to be submitted this quarter on the path to broaden European patient access. We also submitted an MAA to Swissmedic and beyond Europe, we continue to look forward to receiving a decision in Canada in the second half of this year.

Cytokinetics is now firmly a commercial stage company. And while it's early in our U.S. launch, we're very encouraged by the initial performance. Both in the U.S. and in Europe, our commercial teams are dedicated to delivering excellence in this new chapter of our company's history.

And with that, I'll turn the call over to Fady.

Thanks, Andrew. This morning, we were thrilled to report the top line results from ACACIA-HCM. The trial met both of its dual primary endpoints, demonstrating statistically significant improvements from baseline to week 36 in both KCCQ clinical summary score and peak VO2 compared to placebo. In patients treated with aficamten, KCCQ increased by 11.4 points compared to 8.4 points for patients on placebo, resulting in a least squares mean difference of 3 points with a p-value of 0.021.

Similarly, peak VO2 increased by 0.64 ml per kilo per minute in patients on aficamten, while it decreased by 0.03 ml per kilo per minute for patients on placebo, resulting in a least squares mean difference of 0.67 ml per kilo per minute and a p-value of 0.003. Statistically significant improvements were also observed in key secondary endpoints, including the proportion of patients with improvements in NYHA functional class, the composite Z-score of ventilatory efficiency and peak VO2 and NT-proBNP.

Importantly, there were no new safety signals identified. Percentage of patients who completed treatment in ACACIA-HCM was similar between those receiving aficamten or placebo. The occurrence of LVEF less than 50% with 10% patients taking aficamten, of which 2 patients experienced a serious adverse event of heart failure. LVEF less than 50% occurred in 1% of patients taking placebo.

Treatment interruptions due to LVEF less than 40% occurred in 3% of the patients taking aficamten. The improvement in KCCQ was robust and consistent throughout the treatment period in patients on aficamten. Following washout, KCCQ decreased for patients on aficamten to match the placebo group. At week 36, peak VO2 increased for patients on aficamten while it remained unchanged for patients on placebo, consistent with prior trials of aficamten.

What makes the data particularly compelling is the consistency across what the primary, secondary and other exploratory endpoints capture. The KCCQ is a patient-reported outcome that reflects how they feel and function, their symptoms and their quality of life, while peak VO2 reflects an objective functional measure of exercise capacity.

NYHA functional class, the first key secondary endpoint is also a measure of symptom and functional burden, but is physician assessed to have improved both symptoms and functional capacity in a meaningful way reflects the depth of the potential impact of aficamten in this patient population. This is a historic moment for the HCM community and nHCM is a serious condition for which no therapies have ever been approved.

These results suggest that aficamten has the potential to change and to become a treatment to support the full spectrum of the disease. We cannot be more enthusiastic about what we've seen in these top line results. I want to take this moment to express my gratitude to our team for their relentless conduct of this trial to ensure the quality and robustness of the findings.

Additionally, we could not be more grateful to the patients who participated in ACACIA-HCM, to their families and to the investigators and site staff across the globe who conducted this trial with such dedication and rigor. Our thanks go to all for everything they have contributed to this program and in turn, to the entire HCM community.

Next, we plan to submit ACACIA-HCM for consideration at an upcoming medical meeting and look forward to presenting the results in a more fulsome fashion at that time. Until then, we won't be able to share any additional detail on top of what was reported in today's press release.

As Robert mentioned, we also look forward to discussing these results with the U.S. FDA and other regulatory authorities. It's been an extremely exciting start to the year, to say the least.

And now I'll hand it over to Stuart to speak more about our ongoing clinical trials in both HCM and heart failure.

Thanks, Fady. First, I'll touch on our ongoing global clinical programs for aficamten and HCM. During the quarter, we continued to advance 3 trials that together are building a comprehensive clinical foundation across indications, geographies and patient populations.

In obstructive HCM, our partner, Bayer, advanced conduct of CAMELLIA-HCM, a Phase III clinical trial evaluating aficamten in Japanese patients. And in pediatric patients with obstructive HCM, we continued enrolling CEDAR-HCM, our global clinical trial evaluating aficamten in adolescents and younger children. We expect to complete enrollment in the adolescent cohort by the end of 2026.

In non-obstructive HCM, we continued enrollment of the Japanese cohort of ACACIA-HCM. In fact, Japan represents an important market where aficamten is not yet approved for either obstructive or nonobstructive HCM. Both CAMELLIA-HCM and the Japanese cohort of ACACIA-HCM are designed to support potential marketing authorization for both indications in that country.

To that end, I'm also pleased to note that aficamten received orphan drug designation from the Japan Ministry of Health, Labor and Welfare for the treatment of non-obstructive HCM in adults and for obstructive HCM in pediatric patients, reflecting the unmet need that remains in these populations.

Now I'll move on to our clinical development programs in heart failure. COMET-HF, the confirmatory Phase III clinical trial of omecamtiv mecarbil in patients with symptomatic heart failure with severely reduced ejection fraction less than 30% is progressing well. All sites in the U.S. and Europe are now activated, and we're working to bring on additional trial sites in China. We're pleased with the progress we've made so far this year and plan to continue enrollment through 2026.

We also continued AMBER-HFpEF, the Phase II clinical trial of ulacamten in patients with symptomatic heart failure with preserved ejection fraction of at least 60%. During the quarter, we expanded enrollment in Cohort 1 following the recommendation from the dose level review committee to collect more data at the current doses, and we expect to complete patient enrollment in Cohort 1 in the second half of this year. Across these programs, we remain focused on rigorous execution and are encouraged by the progress we continue to make in building what we believe will be a leading specialty cardiology franchise.

And with that, I'll pass it to Sung.

Thanks, Stuart. Beginning with revenue, total revenues for the first quarter were $19.4 million compared to $1.6 million for the same period in 2025. In the first quarter, we recorded $4.8 million in net product revenues for MYQORZO, which reflects approximately 9 weeks of commercial sales following the U.S. launch near the end of January.

As Andrew stated earlier, we saw strong demand for MYQORZO and the net product revenue is reflective of over 70% of dispensed patients on a paid prescription with the balance receiving drugs through either our 30-day free trial, bridge or patient assistance programs. We expect the majority of patients receiving MYQORZO through free trial and bridge programs to transition to paid prescriptions on a timely basis, and this dynamic is expected to repeat in future quarters.

Other components that contributed to total revenues in the first quarter include $2.6 million in collaboration revenue compared to $1.6 million for the same period in 2025 and $11.9 million from the achievement of a milestone under the Bayer license agreement tied to the first commercial sale of MYQORZO in the U.S. Turning to expenses. R&D expenses for the first quarter were $95.5 million compared to $98.3 million for the same period in 2025. The decrease was primarily due to higher clinical trial activity in 2025, partially offset by higher personnel-related costs in 2026.

SG&A expense for the first quarter were $104.9 million compared to $57.4 million for the same period in 2025. The increase was primarily due to external costs associated with the commercial launch of MYQORZO, the U.S. sales force and higher nonsales personnel-related costs, including stock-based compensation. Cost of goods sold for the first quarter of 2026 was $0.2 million.

Collaboration cost of revenues for the first quarter of 2026 was $2.4 million compared to $1.6 million for the same period in 2025. Collaboration cost of revenues includes cost reimbursement as well as costs incurred in connection with manufacturing drug supplies for collaboration partners. Net loss for the first quarter of 2026 was $206 million or $1.67 per share compared to a net loss of $161.4 million or $1.36 per share for the same period in 2025.

Turning to the balance sheet. We ended the first quarter with approximately $1.1 billion in cash and investments compared to $1.2 billion at the end of the fourth quarter of 2025. Cash and investments declined by approximately $144 million during the first quarter of 2026. Moving on to our financial guidance. We are maintaining our full year 2026 financial guidance with GAAP combined R&D and SG&A expense expected to be between $830 million and $870 million.

Stock-based compensation included in the GAAP combined R&D and SG&A expense is expected to be between $120 million and $130 million. Excluding stock-based compensation from the GAAP combined R&D and SG&A expense results in a range of $700 million to $750 million.

As we have just announced positive top line results from ACACIA-HCM, we will update you accordingly in the future on the potential impact of this development on our financial guidance. Looking ahead, we remain focused on disciplined capital allocation and prioritizing our investments on the launches of MYQORZO in the U.S. and Europe, advancing our development pipeline and investing in our muscle biology platform and research pipeline.

With that, I'll hand it back to Robert.

Thank you, Sung. This was the first quarter we will long remember at Cytokinetics. Our first medicine reached the hands of patients in the United States. We recorded our first product sales revenues. We progressed readiness for future global launches. And more recently, this morning, we reported positive top line results from ACACIA-HCM, results that we believe may open a new chapter for patients living with nHCM. I'm incredibly proud of what we've accomplished so far in 2026, and I'm even more energized by what lies ahead.

The opportunity in HCM has never looked brighter, and we've never been better positioned to deliver. We look forward to keeping you updated as we progress through the year. And now I'll recap our 2026 milestones. For aficamten, we expect to meet with regulatory authorities, including the U.S. FDA to discuss the results of ACACIA-HCM and our potential plans for submitting a supplemental NDA. We expect to launch MYQORZO in Germany in this second quarter 2026.

We expect to potentially receive FDA approval of the supplemental NDA for MAPLE-HCM in Q4 2026. We expect to complete enrollment in the adolescent cohort of CEDAR-HCM in the fourth quarter this year, and we expect to potentially receive approval from Health Canada in the second half of this year.

For omecamtiv mecarbil, we expect to continue patient enrollment in the conduct of COMET-HF through 2026. For ulacamten, we expect to complete patient enrollment in Cohort 1 of AMBER-HFpEF in 2H 2026.

And for CK-089, we expect to begin conduct of a second Phase I study. And finally, for our preclinical development and our ongoing research, we expect to continue those activities directed to additional muscle biology-focused programs through the year.

As a reminder, there will not be a question-and-answer session following these prepared remarks on today's call. We want to thank you all, all the participants on this call today for your continued support and your interest in Cytokinetics.

And operator, with that, we can now please conclude the call.

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

Thank you for standing by, and welcome to Cytokinetics conference call to discuss the top line results of ACACIA-HCM. This call is being recorded. [Operator Instructions] I would now like to turn the conference over to Diane Weiser, Cytokinetics Senior Vice President of Corporate Affairs. Please go ahead.

Good morning, and thanks for joining us on the call today. Robert Blum, President and Chief Executive Officer, will begin with a brief introduction. Then Fady Malik, EVP of R&D, will provide an overview of the top line data from ACACIA-HCM. Stuart Kupfer, SVP, Chief Medical Officer; and Steve Heitner, SVP, Head of Clinical Research and Development, are also here with us to answer questions.

Please note that portions of the following discussion, including our responses to questions, contain statements that relate to future events and performance rather than historical facts and constitute forward-looking statements. These include, without limitation, statements regarding expectations, regarding regulatory interactions and the potential for regulatory approval, expectations regarding commercial performance and statements about our financial guidance and capital allocation. 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 first quarter 2026 financial results filed on Form 8-K that will be furnished to the SEC today. We undertake no obligation to update any forward-looking statements after this call. Please note that slides accompanying today's discussion are available for download within the webcast and on our website.

And now I will turn the call over to Robert.

Thank you, Diane. This morning, we reported positive top line results from ACACIA-HCM, the pivotal Phase III clinical trial of Aficamten in non-obstructive HCM. We are pleased that the trial demonstrated statistically significant improvements in both KCCQ clinical summary score as well as peak VO2 and with robust and consistent effects favoring Aficamten versus placebo throughout the treatment period. Moreover, these primary efficacy results were supported by positive effects on key secondary endpoints.

Today's results from ACACIA-HCM represent an exciting step towards the potential for aficamten to become the only cardiac myosin inhibitor to address the full spectrum of HCM. Patients with nHCM have no approved therapies to address the underlying hypercontractility associated with this disease, which makes these results impactful for the HCM community as well as for all stakeholders in Cytokinetics. We are humbled by the consistency and the strength of our pioneering science for patients, and we look forward to sharing the results from ACACIA-HCM more fully with regulators as well as with the medical community in the weeks and months to follow.

Now I'll turn the call over to Fady to please speak to the results.

Thanks, Robert. First, I want to take a brief moment to thank everyone involved in this trial. I'm grateful to the contributions from investigators, clinical site staff, many colleagues at Cytokinetics and most importantly, patients and their families. Before I get our results, I want to remind you of the study design ACACIA-HCM was a Phase III multicenter, randomized, double-blind, placebo-controlled clinical trial designed to evaluate Aficamten compared to placebo in patients with symptomatic nonobstructive HCM.

Participants were randomized in a one-to-one fashion to receive either placebo or Aficamten. Dose escalation was guided by echocardiography with escalation in dose from 5 to 20 milligrams every 2 weeks as long as left ventricular ejection fraction was greater than 60%. Participants who did not meet escalation criteria continued on the same dose or were down-titrated if their LVEF was less than 50%.

After 36 weeks of treatment, participants continued treatment with Aficamten or placebo for up to 72 weeks to evaluate additional secondary and exploratory endpoints, including the time to first cardiovascular event. ACACIA-HCM randomized 516 participants outside of Japan. Cohort of patients enrolled in Japan are continuing in the trial in a blinded fashion to sort approval in Japan and are excluded from the primary results analysis.

The dual primary endpoint was a change in KCCQ Clinical Summary Score and change in peak VO2 from baseline to week 36. Secondary endpoints included the proportion of participants with an improvement of at least 1 New York Heart Association functional class and changes in the composite Z score to cardiopulmonary exercise testing parameters of submaximal exercise performance and which is [indiscernible] efficiency, and peak VO2, NT-proBNP, left atrial volume index and baseline to week 36 were other secondary endpoints.

As Robert mentioned, the ACACIA-HCM met both dual primary end points demonstrating statistically significant and clinically meaningful improvements in both clinical summary score and peak [indiscernible] on baseline to week 36 compared to placebo. Specifically, and participants on Aficamten, KCCQ increased by 11.4 points compared to 8.4 points for participants on placebo, resulting in a least square mean difference of 3 points with a p-value of 0.021. For peak VO2, participants on Aficamten experienced an increase of 0.64 ml per kilo per minute compared to an increase of 0.03 ml per kilo per minute for participants on placebo. [indiscernible] mean difference of 0.67 ml per kilo per minute and a p-value of 0.003.

As a reminder, the threshold for statistical significance for each of the dual primary endpoints was set at 0.025, which both endpoints achieved and there was no recycling of alpha spend necessary. Statistically significant improvements were also observed in key secondary endpoints, including the proportion of patients with improvements in NYHA functional class in post [indiscernible] score and cardiac biomarker and TPro BNP.

Now let me put these results into context. First, [indiscernible] as you can see in the graph included in today's press release and in the webcast slides, at the end of titration at week 8, the curves begin to separate and clearly remain divergent throughout the duration of the trial. Throughout the treatment period, patients on Aficamten experienced a robust and consistent treatment effect. During the washout period, patients on Aficamten had a rapid reduction in their KCCQ score, bringing them down to match placebo patients.

The increase of 11.4 points for patients on Aficamten is remarkably similar to the magnitude increases that we've observed for KCCQ and SEQUOIA-HCM, which was 12 points and Cohort 4 of REDWOOD-HCM, which is 10.6 points and FOREST-HCM in after 96 weeks in patients with nHCM, which was 11 points. These are large and clinically meaningful improvements, improvements of 5 to 10 points generally seen as clinical relevant and 10 to 20 points as clinically meaningful as well. And in ACACIA-HCM, patients on placebo also experienced an increase in KCCQ of 8.4 points, which is slightly higher than what we've seen before. But for example, the 5-point change we observed in SEQUOIA-HCM.

The onset of the placebo effect is early and associated with the initiation of participation in the trial. It may result from an improvement in clinical care, greater compliance with background medical therapy or other aspects of standard of care patients receive in a clinical trial. As I pointed out earlier, the overall effect on KCCQ in patients treated with Aficamten was robust and consistent over the entirety of the conduct of the trial with a washout effect and loss of treatment benefit when treatment Aficamten was discontinued.

The other primary endpoint, peak VO2 is a measure of exercise capacity. At week 36, peak VO2 increase for patients on Aficamten, while remain unchanged for patients on placebo, consistent with prior trials of Aficamten. We believe the improvement in peak VO2 by 0.67 ml per kilo per minute represents an important clinically meaningful difference as bolstered by the benefit seen in other patients and physician-assessed endpoints.

The secondary endpoints were analyzed in rank order, beginning with NYHA functional class. NYHA functional class is a measure of symptoms, but unlike KCCQ, it's a physician assessment rather than a patient-reported outcome. These 2 different measures of symptoms and functional burden are reinforcing of the overall impact of that Aficamten add on how patients feel. The decrease in NT-proBNP is statistically significant relative to placebo, and also consistent with our prior studies of patients with both o and nHCM.

Turning to the safety results. Importantly, there were no new safety signals identified. The percentage of patients who completed planned dosing in ACACIA-HCM was similar between those receiving Aficamten and placebo. LVEF less than 50% occurred in 10% of participants taking Aficamten and 1% of participants taking placebo. Two participants on Aficamten experienced a serious adverse metal part failure associated with LVEF less than 50%. Treatment interruptions due to LVEF less than 40% occurred in 3% of participants taking Aficamten. The frequency of these findings is not surprising relative to those with Aficamten and oHCM, given the strategy in nHCM is a dose to a maximum tolerated dose as opposed to minimum effective doses in oHCM.

The great majority of patients in the ACACIA-HCM have now transitioned into the open-label extension for ACACIA-HCM and we anticipate reporting on the longer-term saving of Aficamten as they reinitiate and continue therapy. Today's announcements represent only the top line results for ACACIA-HCM. There's much more granularity and additional detail that we plan to present at upcoming medical meetings. Until such time, we can't share any details outside of what's included in today's press release. We are very enthusiastic about these results and what they can mean for patients with nHCM. And with that, I'll hand it back to Robert.

Thank you, Fadi. ACACIA-HCM is the first trial to demonstrate a statistically significant and clinically meaningful effect on both exercise capacity and symptoms in this patient population. Given the unmet need in nHCM, this represents an inflection point in what the treatment of nHCM could look like for these patients, an opportunity to improve their symptoms, and their functional limitations that restrict them from their everyday activities. We're optimistic about what this may mean for patients and the physicians who treat them.

We look forward to presenting the full data set in the future as well as discussing the results with the U.S. FDA as well as other regulatory authorities. I, too, would like to extend my thanks to everyone involved in the exemplary conduct of this trial. I'm grateful to the investigators, their site staff and, of course, patients for their participation and to the many employees of Cytokinetics who contributed to us reaching this milestone moment.

Operator, with that, we can now open up the call to questions, please.

[Operator Instructions]

Your first question comes from the line of Salim Syed with Mizuho. .

Congrats on the data, guys. It's really good and very consistent efficacy. I guess just one for us, it's an obvious one here. Just on the placebo moving. Obviously, we saw similar placebo movement on KCCQ with [indiscernible] and people had speculated there at least that there was intensive background care. Just curious -- and I think that, I think you described it as being the 99th percentile of placebo movements for KCCQ at one d1 point. Could you just maybe comment a little bit more on the placebo here? Was it intensive background care as well, you believe or -- or was it the hypertensive patients? Was it exactly that you think contributed to the 8.4 in KCCQ? .

I'll turn that over to Fady, please. .

Salim, I think we still have work to do to understand what maybe drove the placebo effect here. It's just a bit higher than we saw in oHCM. We think HCM patients may be a little more similar to heart failure patients and that they respond to certain heart failure therapies like diuretics and things like that. But what we'll do in the ensuing weeks is look at that carefully and see if we can understand what the onset of the placebo effect. It's pretty compelling when you look at how quickly the treatment effect comes on. It's right at basically during the escalation phase of dosing and then it levels out and wobbles around for a little bit. And then importantly, at the end of therapy, it doesn't go away, unlike the treatment effect for Aficamten. So we'll have more to say about that as we dig more into the data. .

Your next question comes from the line of Roanna Ruiz with Leerink Partners. .

Really interesting results. I was curious, thinking about the trends both in peak VO2 and KCCQ over time. And I thought compelling that the KCCQ scores seem to widen the longer the trial continued like -- what does that underscore in terms of Afi's clinical profile to physicians and to patients and how are you thinking about uptake in nonobstructive HCM, assuming you get approved? .

So of course, we still need to have conversations with regulatory authorities. So I won't speculate on that until we do that. In the meantime, I do think you're pointing out something that has us very intrigued, and we'll learn a lot more from still further data analysis, including from substantive work that's being conducted alongside of these primary efficacy review. Fady, Steve, Stuart, anything you want to add to that? .

Yes. So this is Steve Heitner. Well, I think on your point is well taken. And actually, it was part of our therapeutic hypothesis. When we designed the trial, we understood that non-obstructive HCM patients probably needed to be exposed to growth for a longer period of time before you started to incur the benefits. And I think what you're seeing is a potential indication that patients who are on this drug for a longer period of time do enjoy greater benefits. The study was essentially run for 72 weeks to point to that exact feature. So hopefully, as we dig deeper into the data, we'll be able to kind of unwind that story for you a little bit more. .

And I do think as you'll learn more about the secondary endpoints that can align and substantiate to some of these same hypotheses that we're testing moreover. As we learn more about the anatomy of these patients, we'll learn more about what may be occurring with time. So this may be one of those studies for which these not only primary but secondary publications will inform quite meaningfully. And as you can appreciate, this being the first such study positive in this patient population, there's a lot of benchmarking that needs to occur.

Makes sense.

Your next question comes from the line of Tess Romero with JPMorgan. .

Robert and team, congrats on these data from us as well. So we acknowledge, of course, that you need to have discussions with regulators. But at first blush, I was curious, how are you thinking about the safety profile that you saw in ACACIA? And how this might lead ultimately to potential risk management in the indication if approved? And just to double-click a little bit here, how does what you saw compared to what you thought you would see given patient characteristics, et cetera. .

Thank you, Tess. I'll turn it over to Fady and Stuart to address that.

Yes. Let me start. I mean, I think the -- what we saw in terms of safety in this trial was pretty consistent with what we have seen in our trials of oHCM. We expected a larger proportion of patients who develop EF of less than 50. The majority of them were just asymptomatic and responded to down titration. The safety profile, I think, really is unchanged, as we said. And over time, as we present these data, I think that will be clear. The risk mitigation -- effect on risk mitigation program, I think it's too early to discuss. I think we have to think about how the -- how does the impact of dosing blinded trial differ from what happens in real life.

And maybe I'll ask Stuart to comment a little bit on their experience in FOREST, where patients have open label are receiving open-label growth. .

Yes. Thank you. So in the FOREST trial, of course, those were essentially we've been following a cohort of patients from our Phase II REDWOOD trial, now for 2 or 3 years. And those patients tolerated Aficamten extremely well. And that's why we are optimistic about the tolerability profile in ACACIA. But I think it's important to point out that, as Fady mentioned in his opening remarks, is that in non-obstructive HCM patients are titrated to the maximally thermal dose unlike obstructive HCM, where it's a minimally tolerable dose because of the gradient, the target grading that we're trying to achieve in that patient population.

But the important findings that we're describing here is that even though these patients had some drops in ejection fraction, a large majority of them didn't have any sort of clinical consequence. And the large majority of them, of course, didn't require treatment interruptions, and we're able to continue Aficamten, which drove what we observe is the benefit in terms of symptoms and functional improvement.

I think maybe just to add two cents, this study, I think, stands out as one that around the original therapeutic hypothesis when you think about what it was designed and powered for and what we expected in terms of efficacy and safety hit squarely, hits squarely on the mark. And Hopefully, as analysts and investors on this call have come to know this team, they appreciate very well its integrity, its credibility and if anything, I think these data resound profoundly alongside of what we've been expecting and pointing to, including as it relates to safety.

Your next question comes from the line of Yasmeen Rahimi with Piper Sandler.

This is Dominic on for Yasmeen Rahimi congrats on the data. We know that you're still analyzing the data. Do you have any insight? Or could you just help us maybe understand what nHCM patients would be ideal for Aficamten given today's data? And how soon would you envision filing on is results and potentially get it on the label?

I'll answer the second question first and then turn to my colleagues. We're not going to comment on time lines yet other than to say we're going to move as swiftly as possible to make that happen. But first things first, we want to meet with regulatory authorities, understand how they view these data and then move promptly to hopefully potential submission.

Fady, do you want to take the first question?

The trial enrolled a fairly broad population of nHCM patients and it's premature for me to speculate or even to comment on differences in subgroups and things like that. We think that the efficacy was broad-based and seen really in all the patients in the trial or all types of patients, I should say, in the trial. And frankly, at the end of the day, given the lack of effective therapies in nHCM, this will probably be more a try it and see how it works for individual patients down the road. Some patients will have very large responses, some maybe not so large. And whether to continue taking therapy, will be a pitch -- patient and physician choice. But I don't think it will be driven by any specific features of the patients themselves. .

Your next question comes from the line of Maxwell Skor with Morgan Stanley. .

Congratulations on these impressive data. So you've cited market research pointing to a 15% to, let's say, 20% halo effect in oHCM prescribing, if ACACIA is positive. So with the clean jewel endpoint win, basically, has this estimate moved up? Or can you give us an indication of whether it's kind of pulled forward the sales ramp? Or maybe this halo effect would be more relevant for 2027?

Yes. I think a halo effect conversation is a very slippery slope. And yes, we did some market research around that. That was prior to having data, and that was imprecise. I do think now that we have data, we will do additional target product profile work and more quantitative research. But please keep in mind that this drug is only approved for oHCM and as it may ultimately become approved for nHCM, we would expect that could be enabling of its promotion in that indication. Until then, it would be, I think, improper for us to be trying to quantify a halo effect other than to say it has been noted in comparable markets like this.

With that said, I think it's more for the analyst themselves to project what that could look like. .

Your next question comes from the line of Mayank Mamtani with B. Riley. .

Congrats on spectacular results here. Could you comment on the distribution of patients reaching to the -- at the highest dose levels, 15 and 20 mg in ACACIA. If there's any greater than 5-point KCCQ responder threshold that was cleared any proposition you can report on? And then do you expect the titration burden to be in any way impactful in what you're seeing on oHCM right now or even in nHCM because that seems like a thing in the field apparently I was just curious to get your feedback.

And then lastly, on the baseline characteristics, if you could maybe comment on the starting NTP levels. And if you saw the 36-week reductions that were largely comparable to FOREST-HCM, if you could maybe just comment on that, that would be helpful.

So you covered a lot of ground in your question. So hopefully, Fady, you got all that .

I'd take notes, but I've got them all down. We can't -- unfortunately, we can't really comment on most of them. So the distribution of dosing, I'll just say that there were no surprises there. We'll -- obviously, we'll show that when we show the full data sets. And the same thing goes for the baseline NT-proBNP, no surprises there, but the actual numbers and data, we'll have to wait until they are presented. Titration burden, I think, is -- it's very similar to what we have in oHCM and that patients are titrated every 2 weeks. They reached their target dose within 6 weeks or less.

in general, if there was a dose adjustment, it was fairly easily implemented and the patients could continue in the study on their final doses. So I don't think that there will be significant difference between and nHCM down the road.

Your next question comes from the line of Leonid Timashev with RBC.

Congrats on the data as well. I just want to ask if you guys can maybe speak to what you view as -- or whether there are any differences in clinical meaningfulness between oHCM and nHCM on KCCQ and peak VO2? I know, in particular, you guys have done some work on what is -- what may be clinically meaningful in peak VO2 and sort of how to contextualize what we saw today with sort of typical thoughts around what's meaningful.

That's a good question and allows us to maybe put these data both for KCCQ and peak VO2 in a context, an ecosystem around which those end points have been measured in other populations. Fady, do you want to take a stab at that? .

Yes, I'll start and maybe ask Steve to comment on some of the analysis we've done in oHCM. And so when you look at KCCQ across a spectrum of heart failure trials, including trials that have very positive impacts on mortality, morbidity, like SGLT2 inhibitors and [indiscernible]you rarely see KCCQ that exceed 1 or 2 points. Here, we have a 3-point delta at 36 weeks at other time points, deltas of 5 and even 7 at the end of treatment. So I think these represent very meaningful changes for patients overall. And there'll be -- once the full data set is revealed, I think one will see how they're bolstered by other endpoints and other measurements in the trial.

With regards to peak VO2, again, I think I can safely say, although I haven't canvased the entire literature, this is the first trial to show positive impact on both KCCQ and peak VO2 in the same study. And so again, when you think about clinical meaningfulness, you ask yourself, how are the endpoints are they consistent? Do you see benefit across multiple domains, multiple aspects of the disease. And I think they reinforce one another.

In HF ACTION, which was the largest trial ever done in heart failure, using peak VO2 is about 2,200 patient trial. The change from placebo is about 0.6. And there, again, it was correlated with patients feeling better and actually fewer hospitalizations. So I think it's safe to say, we believe these are clinically meaningful differences. And maybe I'll ask Steve to comment on our work looking at the deltas in oHCM.

So what we did was we looked at what patients perceived as clinically meaningful. So most people don't exercise to the peak VO2 on a daily basis. And that number doesn't necessarily translate directly to how they feel. But in order to elucidate that, what we did was we linked a patient-reported improvement of minimal but important improvement to a number on that peak VO2. And the number we came up with was anywhere between 0.35 and 0.5. And I think that the important message over there is that while the community has settled on this number of 1.0 as being an important threshold, that might be true when it looks -- when you're measuring things like hospitalization or mortality. But just from a purely logical perspective, patients tend to feel better before they end up in the hospital or having a mortal event.

And therefore, that threshold really should be lower to meet how patients feel on a day-to-day basis. So in obstructive HCM, that number is anywhere between 0.35 and 0.5 million -- and I would be surprised if that was a different number that we came up with in non-obstructive HCM when we do our minimal important difference analysis in this study.

next question comes from the line of [indiscernible] with Truist Securities.

Congratulations on the data. I wanted to ask a little bit about the safety profile. The treatment interruptions, you said occurred in about 3% of patients who had LDF less than 40%. I was wondering if there were any patients that reinitiated therapy after the interruptions or were unable to reinitiate? And what does that imply clinically?

You want want to take that, Stuart?

This is Stuart Kupfer. Well, we can't really get into the details about those patients who required interruption of treatment and the extent to which they resume treatment. So those details will be forthcoming. But in general, what we have observed with Aficamten treatment is that once the treatment interruption occurs, within approximately 1 week, the ejection fraction recovers. For those patients in this trial, again, not only on specific data because we can't discuss that today. And we haven't even gone through all the data in complete detail.

But those variances is where that does occur. The ejection fraction recovers quite rapidly within a few days to a week, patients resume treatment at a lower dose and generally continue treatment and very tolerable manner and experience treatment benefit. So we anticipate a similar type of profile in this in ACACIA.

Yes. Bottom line is we designed healthy Campton originally with certain expectations, and that includes the ability when ejection fraction may fall to be enabling of either down titration or in the rare case of a dose interruption, a pause to be enabling of restoration of treatment. And I do believe in these data in ACACIA that we met those design expectations.

Your next question comes from the line of Ash Verma with UBS.

Congrats from my side as well. I know Bristol commented last week that they're going to restart their non-obstructive program for [indiscernible] which is great for the field, by the way, but just like looking at the results today, what's your sense of how that part inform their study?

And then secondly, on looking at the LVEF rates here in nHCM, I'm wondering if there is an implication that you could draw on what the rems part of the label could look like eventually? Would it be a continuation of the same language that you've had on the oHCM side or anything slightly more stringent given the absolute rates here are a touch above.

So I'll take the first question, maybe ask Fady to take the second. I don't think it's our place to comment on what should do or should not do with regard to our data, I think that's really more appropriate a question opposed to them directly. And with that, I'll turn to Fady to answer the second question. .

Yes. I think it's hard to obviously give strict guidance on rems. But if you think about our open-label experience and Forest, we are following the same protocol that we follow in the oHCM patients and that there's a titration window. There is a follow-up that occurs every 6 months. And obviously, there's no monitoring for drug-drug interactions or anything like that, that none of that really changes. So there may be slight -- some changes. We'll find out as we -- again, as we go through the data and decide what we think support the best safety for patients. So we'll probably have more to say about that as we learn more about these data and as we begin to interact with regulators. .

Your next question comes from the line of Paul Choi with Goldman Sachs.

Congratulations to you and the team on this positive data. My question is with regard to the other secondary endpoints, particularly time to first cardiovascular events that weren't mentioned in the press release, can you clarify if that endpoint was reached or if you're still analyzing that data set and it's being adjudicated, and that's just something that will be clarified at a medical meeting in the future?

Yes, I think you can infer that those last 2 endpoints in the hierarchy were not met in terms of statistical significance, but we'll obviously present those data in full when we come to -- when we come to the presentation of all data set. .

Your next question comes from the line of Carter Gould with Cantor Fitzgerald.

Congratulations to you and the broader team. I wanted to come back to the KCCQ data for a minute. The sort of the pinching of the curves at week 36, is there anything specific going on there? Any explanation? Is that just noise? Were you sort of just unlucky at that specific data point? And I guess specifically the level of import that investors should assign to the overlap of the confidence intervals at that point on KCCQ? .

Yes. I mean the analysis is a prespecified analysis of the KCCQ or week 36, it includes imputation of any missing data. You see that the number in the graph, the 3.1 is really the absolute difference between those 2 points. The LS mean change includes all the aspects of the statistical model. It's basically the same, 3.0. So those other inclusions in the model didn't really affect an end point. And if you look at the placebo curve, it wobbles around. It was much lower at week 24, went up at week 36. So it went back down at week 48. They're approximately the same number of patients at all those time points. So I can't really give you a definitive answer as to why we think the placebo effect changed at that week and maybe we'll come up with something as we dive more deeply into these data. They're pretty fresh, as you can imagine.

But I think overall, once you focus on the whole reason we put a figure in the press release is that looking at the treatment effect overall. And in fact, the loss of treatment effect as you withdraw therapy as to the compellingness of these data.

Your next question comes from the line of James Condulis with Stifel.

And congrats on the data. Maybe one just kind of like big picture looking at all of this data. And I mean, obviously, there's a lot more to come. But I guess as you look at sort of like the commercial picture and think about how docs are going to approach using Aficamten were it to be approved and non-obstructive, do you think docs are going to have to work harder to find sort of the ideal patients that are kind of best suited to respond to a CMI? Or is it in your view, better to think about kind of all symptomatic non-obstructive patients in interiors should be eligible for a drug like Aficamten, again, assuming our work to be approved.

Keep in mind, we have access to data that aren't being top line this morning. That includes baseline demographics, forest plots as well as waterfall plots. What I do think you should perhaps focused to is some of the language we're using in our disclosures, things like consistent and robust and throughout the time period. I mentioned that all because I do believe that these data will provide a compelling case for all patients with nHCM to potentially benefit from this mechanism of action.

And ultimately, a population served would speak to the use of a medicine like this, if approved, as each physician together with his or her patient can determine if that patient is benefiting. But I don't think there's anything in the data that we've seen to date that would suggest limiting the potential for nHCM patients to benefit.

Your next question comes from the line of Jason Butler with Citizens. .

Congrats on the results. Can I just ask a question about part 2 of the trial. Is the goal there to, again, focus on maximally tolerated dose? Or how do you expect dose titration when patients are reinitiated on therapy? .

I'll ask Steve to answer that question. .

So the study itself had a blinded dose titration strategy. So the physicians who were responsible for the patients actually didn't anticipate in the decision as to whether to increase or decrease the dose that was then all in a blinded fashion. In FOREST-HCM, as I mentioned, that physician is actually responsible for making that final decision on the basis of reviewing the [indiscernible] and integrating how the patient is feeling at that time. And what we have seen and reported with our REDWOOD experience is that when you integrate both clinical and echocardiographic information into your decision-making process, you're able to titrate the drug very effectively and safely in order to minimize patient symptoms and hopefully maximize their activity. .

And what we saw with the obstructive experience is that while the titration mechanism was based on the Phase III clinical trial data from the open-label extension did inform how regulators thought about it and put it into that chemical context. And I suspect that that we're going to be looking at a very similar situation when it comes to negotiating with globally -- formally with regulators on this indication .

Your next question comes from the line of Martin Auster with Raymond James.

At the risk of [indiscernible] service, I want to congratulate you on the consistent robust efficacy results across the trial. A great job by the team. I may want to follow up real quick on -- I think it was Paul's question earlier on the safety side. It was encouraging to see a very low rate of SAEs related to congestive heart failure in the trial. Have you just been able to calculate what the total base plus is and whether they're -- that's balanced between the 2 groups at this stage? .

Yes. We've certainly looked at that, and that's why our statement on safety signals were identified is supported, but I can't give you exact numbers. But again, we think that we know that this mechanism can reduce ejection fraction, there's a warning in the label about the risk of heart failure with this mechanism. In general, we've seen it very rarely, almost nonexistent in oHCM and here in nHCM as we reported 2 cases associated with low ejection fraction that were serious adverse events of heart failure. So overall, I think it continues to be a relatively uncommon effect of initiating therapy with Aficamten. .

Were there other measures that had imbalance, such as like hospitalizations for other factors, arrhythmias, things like that that you observed? .

Yes. I can't really, again, give you more color on that beyond what we've already put in the release, what we thought were the most relevant numbers in the release. So I think it should rely on that. .

Your next question comes from the line of Cory Kasimov with Evercore ISI. .

Exciting to see these super impressive results. So I know this trial started with KCCQ as the primary endpoint and added peak VO2 primarily originally for regulatory purposes. But I'm curious, do you believe one will resonate more than the other with docs? Or is this really now at this point more about the totality of the data with the additional stat sig benefit you have on some of the secondary endpoints as well. .

Good question. Obviously, one is subjective to patient interpretation. One is objective to high fidelity measure. And then you haven't seen it yet, but why HA improvements, as is physician assessed together with BNP, which is also quite quantitative, all these things together contribute to a picture. I think regulatory authorities will look at the consistency and the totality. Peak VO2 is not something that most HCM specialists are measuring day-to-day for their patients, but it does have effect to how patients feel and function in the same way that KCCQ does. So I don't know that we could point to one versus the other, but maybe my colleagues can weigh in. .

I might just add that certainly, I think depending on both endpoints, is easier -- an easier case to make than getting on one and not hitting on the other. And regulators like peak VO2 because of objective, we think KCCQ is an important measure of actual patient symptoms. And so we were very excited to see that we have both. I think there was some question whether we might hit both. And as you can see from the data in the release, it's pretty compelling case of both were hit.

And when we, again, see the totality of the evidence from the trial, the meaningfulness of this will be clear.

Maybe if I could add one more point. There are other PROs embedded in the study that regulators requested that we put there. Obviously, we're not going to be talking about those results today. But there are other orthogonal ways of assessing how patients are feeling aside from looking at the the KCCQ, which I'll remind everybody is a measure that was designed to assess heart failure patients that is now being repurposed in hypertrophic cardiomyopathy. So they want us to assess whether it is, in fact, an appropriate metric for these patients. And in order to do that, they have requested additional assessments.

your next question comes from the line of Serge Belanger with Needham. .

I'd like to also offer my congrats on the data. First one, have you selected a medical meeting when we could see more detailed data on ACACIA? And then secondly, regarding the regulatory steps going forward, sounds like you want to meet with regulators before expanding on the time lines and those steps. Just curious what you expect here in terms of the regulatory path, what kind of clarity you'll be seeking and if you need additional data? .

Thank you. So I'll answer the second question first, then turn to my colleagues. Regarding the regulatory path, that's certainly something still to be determined, but it would be our expectation to aim for a meeting to review these data. And then as we've done in the past, have conversations at a subsequent meeting that would be a pre-NDA submission meeting getting those all done as promptly as possible is priority #1 right now. And maybe, Fady, you can speak to a potential venue for these data? .

Yes. I mean the next, I would say, major medical meeting other than the one that's this weekend, which is a little premature is ESC European Society of Cardiology, end of August. So we'll aim for that. Hopefully, we'll get on the program there. We obviously don't have any insight into that at the moment. .

Your next question comes from the line of Jason Zemansky with Bank of America. .

Congrats on the data. I wanted to ask a follow-up to, I think, Carter's question regarding the KCCQ over time. Just curious, at weeks 24 and 60. The delta is similar, about 5.0 with differences at weeks 24 and week 72. So I'm curious, given how lumpy things are, overall, is 5.0 the baseline that you're moving from? And then anything specific happened again in your models with regards to the decline in placebo KCCQ from week 60 to 72?

So I wouldn't characterize these data as lumpy. But I do think your question allows us to point to the consistency of the effect even as measured at week 36. So I'll ask Fady to comment on that, please. .

Yes. I mean, I think, again, I think when you just look overall we see a treatment effect of 3 to 5 points on average across the spectrum of the time points that we measured. I think what's also -- again, I don't want to keep harping on this, but the washout effect, the loss of effectiveness over with just 4 weeks of discontinuation of therapy patients revert back to baseline. And that's also a very compelling indicator of symptom improvement from the therapy. The modeling and other things don't really affect the lumpiness, if you will, of the placebo effect.

You can contrast that with the, I think, the lack of lumpiness in the Aficamten graph as well. So these -- all these data points have confidence intervals around them and the point estimates are within those confidence intervals. obviously, you could smooth them out and come up with something in between. But I think just pointing again to the consistency and overall robustness. And as we stitch together all the other endpoints that one will see the treatment effect of KCCQ is bolstered by simpler assessments of patient reported well-being as well as physician assessed well patient well-being.

The other thing I might add is if you look at the magnitude, of change for patients on Aficamten at all time points relative to their own baseline. And you look at that also for patients in REDWOOD Cohort 4 and those that have continued into FOREST, you see a ruthless consistency of large magnitude increases in KCCQ of double-digit size. That's, I think, going to be viewed very compelling by regulatory authorities and physicians who treat these patients, and where there may be some lumpiness, if at all, is perhaps in the placebo effect as we expected and as we saw also in the other trial of a cardiac myosin inhibitor, ODYSSEY.

So that speaks, I think, to Fady's point earlier that intensification of care in a clinical trial introduces for placebo patients in effect in KCCQ, but we can take, I think, comfort in the fact that patients on Aficamten experienced such a large consistent effect across all time points. So I hope that answers the question.

Your final question comes from Yanan Zhu with Wells Fargo.

I wanted also to focus on KCCQ. I think the 5-point difference is something that a threshold in physicians' mind. And I totally agree with the sentiment that it seems like you achieved a delta and beyond at week 48, which is a similar time point to Odyssey and also beyond. So I was wondering how how mature the data for you in terms of the data point and beyond, can you assign any nominal p-value to those data points. And is there a way for these data to be getting into the label? And lastly, maybe on NYHA, great to hear that you did hit that sick. I thought in REDWOOD study, NYHA improvement was quite significant. Can you comment on whether the magnitude here is similar to REDWOOD?

No, it's Fady here. I think the -- there's no real standard, if you will, for what magnitude of KCCQ represents an approvable or even, frankly, a meaningful impact to patients. The 5 is what is supported by various analyses. Our analysis and oHCM suggests it's somewhat lower than 5%. The -- so I think that there is a meaningful effect here that patients clearly perceive and just based on the majority of them moving into the open-label extension, I'm sure they wanted to stay on therapy because they pursue the benefits to themselves. We'll be, again, triangulating the change in KCCQ with other metrics that we haven't reported.

And as Robert pointed out, the absolute magnitude of change is quite large. So over 10 points. Generally, patients can perceive an improvement with a 10-point change in their KCCQ from baseline. That's in stating, I think you can just look at the error bars and take a guess, but you would probably be accurate in what you've decided there. The other time points, the in REDWOOD and in FOREST has been quite meaningful for us, particularly once seeing now with even longer follow-up that the majority of patients have transitioned to become Class 1. And so again, I think the totality of the evidence here suggests that patients drive an early benefit but a benefit that is steady over time and perhaps increasing as the length of treatment is -- gets longer. .

This concludes the question-and-answer session. I will now hand the call back to Robert Blum for closing remarks. .

Thank you, operator. It's the top of the hour, and we thank all of our participants who joined us for this call today. We appreciate that you share our enthusiasm for these data from ACACIA-HCM. And I do believe your sentiments are echoed by our conversations together with steering committee members for the clinical trial who have used adjectives like transformational and now like home run in best case scenario when speaking to these results. We look forward to elaborating on these data as they will be presented in full. And we appreciate your continued support and interest in Cytokinetics. And operator, with that, we can now conclude the call.

Anyway, since we started a little bit, it's totally on me. I'm Emily Field covering U.S. biopharma here at Barclays, and we are -- that's why I got the whole squad. So CEO, Robert Blum and...

EVP of R&D, Fady Malik, Sung Lee, CFO.

Okay. Great. Well, okay. So 20 minutes, let's go. So obviously, everyone is just really focused on MYQORZO launch. And I think if you are trying to get some sort of early metrics on what you're going to disclose versus not disclosed. So now that, what, maybe 3 weeks in, 4 weeks in, what can you tell us about the launch thus far?

So to underscore, we only launched in late January, so we're really only a month in, but the early signs are encouraging. And as we said on our earnings call, we're looking at a couple of key metrics. We'll get discipline to repeating the same KPIs with our Q1 earnings call and afterwards. But ahead of that, what should we be focused to?

Ahead of that, we're focused on the following: what's the awareness of MYQORZO. So as we went out and did some market research, there's over 90% awareness of MYQORZO amongst the high-volume prescribers for Camzyos, the other cardiac myosin inhibitor. So over 90% of the targeted cardiologists that we've been focused to are already aware of our studies, our product and have been waiting. We were encouraged by the fact that many of them had already been warehousing patients awaiting the approval. And it was very soon after a product was in channel that we already had over 700 cardiologists go through our REMS program. and within days already dispensing MYQORZO to patients who were prescribed it. So that's a very good sign. We saw prescriptions coming not just from the currently 700 cardiologists accounting for over 80% of the Camzyos scripts, but we saw prescriptions coming from cardiologists who had never written a prescription. So that's encouraging.

And then I guess the other early indicator of interest is that we're already getting requests from our medical information hotline for how does one go about switching patients, so that's interesting. I wouldn't make more of that than that it's interesting, not yet compelling. We're certainly not going to move the needle for the overall picture of adoption based on switches but it suggests to me that prescribers who are targets are already aware of differences and can be expected to switch patients who might not be performing at the most optimal levels on the existing cardiac myosin inhibitor, Camzyos. So maybe they're on the 2 to 5 -- 2.5 or 5-milligram dose strength of Camzyos. They're still burdened with symptoms and maybe that cardiologist may be looking to switch that patient.

Yes. Because at least the switch opportunity, I don't think is something that you've emphasized as a near-term opportunity.

Then we won't. We won't. It's not going to drive the business.

Well, I mean, what terms of feedback are you getting from prescribers? Because obviously, there is a difference in the REMS, which is we can just look at full stop. But what sort of feedback are you getting in terms of the switch opportunity from initial prescribers?

So again, I don't want to make more of it than what I did, which is to say that people understand the differences. But I do believe that MYQORZO offers a different experience for physicians from the standpoint of speed of onset of actions, ability to get to target dose and steady state exposures more rapidly. That's enabling of a physician experience, a patient experience that we've been focused to for all the time we've been developing aficamten MYQORZO.

Our promotion strategy is kind of pillared across safety and efficacy as translates into differentiated label and REMS, but also how do we make this a physician and office experience that's unique to this opportunity and a patient experience in getting patients all the way through to reimbursement as promptly and easily as possible. And because this is all we do, and this is what we built our commercial organization around, we think we can build something that's more tailored, accustomed to this opportunity and bespoke to the market opportunity.

Okay. Yes. And then maybe kind of continuing with the launch story before getting into pipeline. From a financial perspective, how are you thinking about investment in both the commercial organization in the U.S. and also in Europe, which I know takes -- I just moved back. So that takes a lot of time. But yes, in terms of just sort of the pushes and pulls from a cash balance perspective versus now being a revenue-generated company?

Maybe I'll start, and then I'll turn it over to Sung. So we're ambitious when we think about mission and purpose, we think about bringing this science and medicine to patients globally. As such, we're now launched in the United States. We're approved in Europe, and we're going to be launching in Q2 in Germany. And our partner, Sanofi, is approved and launching in China soon afterwards, we expect our partner, Bayer, to be getting approval and launching in Japan. So if you think about our Vision 2030, it speaks to global access to this medicine for the benefit of patients globally, and we're committing to do that at least ourselves in North America and Europe.

To that point, how we go about it, we have to be good students of what other companies in front of us have done and what they've learned. And we're investing in Europe on a gated basis, stage to reimbursement as we learn more from Germany, France, Italy, U.K. and Spain. So maybe with that, I'll ask Sung to elaborate.

Yes. So Emily, I would say, well ahead of the launch in the U.S., we did some things on the finance side to really shore up our balance sheet in order to be able to launch in the U.S., but also in Europe, as Robert said. So going back to May of 2024, we expanded our strategic partnership with Royalty Pharma, which has provided some critical funds in terms of the commercial launch.

And then September of last year, we had a very successful convertible notes offering. So we really started this year with a solid balance sheet. We have our capital allocation priorities, and it shouldn't be a surprise, the launch in the U.S. and Europe. But also, as Robert said, investing in our pipeline to advance our ongoing development programs, but also we have a very productive research organization and expect us to do some things additionally in our pipeline in the future.

Okay. Fantastic. Well, yes, maybe then to pivot about catalysts that investors are watching very closely the ACACIA readout. Perhaps it would be helpful to talk about the setup into this and obviously, the ODYSSEY trial was unsuccessful and how your trial is perhaps maybe just from like a structural perspective, tailored a little bit differently. And then we can, I guess, pivot into what are the most important points to look for when we do get that headline.

Yes. So Fady should speak to this in more detail, and I'll just start by saying, this ACACIA study represents an opportunity for aficamten now called MYQORZO to be potentially showing evidence of clinical safety and efficacy in a population of nonobstructive HCM, a population that based on claims data is roughly equivalent in size to the obstructive HCM population.

But the difference being that there are no approved treatments in nHCM and for which you don't have a gradient to pressure gradient to necessarily manage to. So it's a market for which there's high overlap in terms of high-volume prescribers, but for which the market dynamics are slightly different. We've designed a study, the same team that we've had in place for over 5 years that has designed and conducted SEQUOIA, MAPLE, FOREST, CEDAR, and now ACACIA, is in place and lending oversight to the conduct of this trial. And under Fady supervision, we're quite hopeful for what it may read out in results in Q2.

And with that, maybe I'll ask Fady to speak to it in more detail.

Sure. So we went about the process of examining the effect of aficamten in nonobstructive HCM very deliberately. One of the challenges is how do you dose the drug in nHCM. And oHCM, tend to dose to a minimum effective dose because you -- as soon as a gradient comes below a certain threshold, you stop dose escalation. There is no gradient in nHCM that strategy is one more of maximum tolerated dose. And so in that context, you need to understand what doses are well tolerated, what's the right way to titrate dose, what are the right thresholds.

And so in Phase II, we piloted that very deliberately testing doses of 5, 10 and 15 milligrams, escalating dose for ejection fraction of 60 or greater. Holding dose steady if you're between 50 and 60 and decreasing dose, not interrupting those for ES of 40 to 50. And that strategy worked very well. We didn't see any treatment interruptions. We had a couple asymptomatic ES below 50, which responded immediately to down titration. And so going from 40 patient experience to now a 500 patient experience, we're pretty confident in the dosing paradigm that shouldn't lead to treatment interruptions and it shouldn't lead to kind of being stuck on low doses.

When you looked at the ODYSSEY data, that was one of the issues that they had in ODYSSEY. They had about a 20% treatment interruption rate. And there was some evidence that a sizable portion of the population will probably treated with the lowest doses of 1, 2.5 or 5 milligrams and as opposed to being able to escalate to higher doses. So dosing, very important, I think we got it right. We'll know when we unblind the data.

Secondly is conduct of the trial. As Robert said, we've done 6 trials, you forgot REDWOOD in this area. With the same team of experienced physicians that have expertise in HCM, myself included, and then a clinical operations team, Core Labs, that have worked with us through this entire period. We've optimized over that time, how do you train sites in terms of the endpoints, KCCQ, pVO2, echos, acquiring echos, how do you qualify patients for the study, you have entry criteria, but nHCM is kind of a visual diagnosis. And so if you really want to know what you're getting in the trial, you have to look at the echos and we have a team that does that.

So I think from terms of setup and the way the trial is conducted, we feel very confident that there are no methodological issues that should lead to results that are ambiguous. What we saw in terms of Phase II data were encouraging. We saw patients whose biomarkers improve, their echos relaxation parameters improved and their KCCQ and NYHA class improved, and we've seen that now for over 2 years in our open-label extension. So we like the setup going into the trial...

And just to confirm investor expectations because you will hopefully want to present the full data side at a medical meeting, the press release that will come out in Q2 will be mostly qualitative.

I think in general, that's what I would expect. We'll try to see what we can get into it, but it's a negotiation between us and people that hold the cards in terms of the medical meeting. It is important that we get these data out in front of a large medical audience. There's a tremendous amount of press around these large medical meetings, besides the people that are in the audience, which number in the thousands. And so the investment community is important. Obviously, the cardiology community, getting the message to them is also in long term, very important to us.

And then in terms of -- like from a commercial perspective, look, a halo effect if ACACIA were to be successful, like do you see that as having an impact on current MYQORZO sales?

Yes. I think it's legitimate to assume there's some form of halo effect that if we hit on ACACIA that will bleed over to oHCM is simply because it's reinforcing of the clinical safety and efficacy in an adjacent population. Again, I wouldn't put a lot of stock in that until such time that hopefully it's reflected in FDA-approved label, and we can promote to it. And the guidelines will be updated to reflect the use of MYQORZO in that population. But I do know there's high-level interest in ACACIA, and it might translate into some wider adoption, maybe even for the full category in oHCM.

Okay. Great. Well, maybe like taking a step back. So I used to cover Novartis but obviously -- and there was a lot written in the media, and I'm not -- don't want to rewrite history. But -- so maybe now that you're in your first commercial launch, a huge catalysts coming up. Maybe it would be helpful to just maybe you could step back and think about like from a strategic perspective, how you see Cytokinetics and also going in alone in Europe, which I thought was a very interesting decision just because a lot of your competitors that are launching cardio drugs you choose a partner in Europe. So maybe it would be a good talking point just talking about like overall strategic vision and then pipeline beyond MYQORZO?

Yes. So why did we go to Europe? We committed to Europe in part because we can. And I would argue most biopharma companies shouldn't because they don't have the redundancy in the pipeline or the business prospects where they can do that in a way that returns on investment the way we believe we do. So MYQORZO, even as would be priced at $0.15 to $0.20 on the dollar relative to U.S. pricing can be a profitable opportunity in Europe if we do it smartly. And that's an oHCM by itself, add in nHCM, and it's even more so.

But would we have gone to Europe if we hadn't built this company the following way? Fady and I started this company 27-plus years ago, and we've always intended to be a commercial enterprise, always rooted in one area of science and biology that we pioneer and lead and better than anyone else and for which we have a portfolio of programs all directed to the same molecular target, all directed to the same concentrated customer segment, where we have the ability to build a specialty cardiology franchise, the likes of which, frankly, don't otherwise exist in peer group companies.

So we're enabled to go forward and build a very valuable company for science, medicine and patients and also shareholders and do that as an independent autonomous company because, frankly, it's a bit of a mature birth to commercialization as we go forward with MYQORZO in oHCM and hopefully soon afterwards in nHCM, right behind it, we have omecamtiv mecarbil being developed in a confirmatory Phase III study in advanced heart failure, a very high unmet need and ulacamten, another cardiac myosin inhibitor in a subset of patients with advanced HFpEF. So this is, if you will, a somewhat uncommon situation of a franchise pipeline moving forward from clinical research through regulatory sciences and into the marketplace, and we think that can become a very impactful company both for patients and shareholders.

Yes. That's super helpful. Maybe just to touch on the pipeline assets behind aficamten and when we might see additional clinical data on that?

Sure. The most advanced program is the omecamtiv mecarbil program. It's drug that's a cardiac myosin activator is being studied in severely reduced ejection fraction, heart failure. So these are patients, the number in the hundreds of thousands in just the United States. They've kind of exhausted most medical therapies and are still hospitalized, having a very high risk of mortality. So we are executing COMET now, about a 2,000-patient trial. It's enrolling this year. It will enroll through the early part of 2027, event-driven with clinical composite outcome of heart failure events and CV death and a couple of other components.

That trial, talk about setup, that trial was set up by a positive 8,000-patient trial in heart failure that met its endpoint, had an 8% reduction in heart failure events and CV death. And while it didn't lead to a drug approval, it gave us very strong evidence for where the treatment effect was concentrated and ultimately, we designed COMET in that population.

So I think -- when you look at pipeline, we have ACACIA, ACACIA potentially leading to label expansion for aficamten. Following that, we have omecamtiv mecarbil. And again, what you might consider kind of a specialty cardiology population. Behind that, we have ulacamten, which is another cardiac, a different cardiac myosin inhibitor that we're examining in heart failure with preserved ejection fraction, which we think is an adjacent population to some of the nHCM type of patients. And that's in Phase II kind of a dose-finding Phase II study now called AMBER-HF.

Okay. Well, great. I think we're just about at time. So, Robert, if you want to give any last words just because it's such an exciting year for the company, just to conclude.

Yes. I'll just conclude maybe the same way we started. This is a team that's been in place together for a long time. We've committed to an area of biology, we know better than anyone else, and it's yielding great clinical evidence to support therapeutic hypothesis across different specialty cardiology indications.

As that translates to a business, we've now turned the page on to commercialization. We should be measured by how quickly we can grow the top line and do that in a responsible way to our fiduciary obligations, both with regard to the P&L and also shareholder value, and I think we're on our way. This year will be one where not only should we be assessed by how well we commercialize MYQORZO in U.S. and Europe. But how do we grow that opportunity. And hopefully, ACACIA shines a light on a new opportunity for nHCM.

Great. Thank you so much for coming, and thanks, everybody. Well, keep going with the conference. Thank you.

Thank you for standing by, and welcome to the Cytokinetics Fourth Quarter 2025 Earnings Call. This call is being recorded [Operator Instructions].

I would now like to 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 discuss the commercial launch of Myqorzo in the U.S. and readiness in Europe. Fady Malik, EVP of R&D; and Stuart Kupfer, SVP and Chief Medical Officer, will provide updates related to our clinical development programs; Sung Lee, EVP and Chief Financial Officer, will provide a financial overview of 2025 and discuss our 2026 financial guidance. And finally, Robert will then make closing remarks and review key milestones for the year ahead.

Please note that portions of the following discussion, including our response to questions, contain statements that relate to future events and performance rather than historical facts and constitute forward-looking statements. These include, without limitation, statements regarding expected timing, potential outcomes of clinical trials, including ACACIA-HCM expectations regarding regulatory interactions and the potential for regulatory approval, expectations regarding commercial performance and statements about our financial guidance and capital allocation.

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 2025 financial results filed on Form 8-K that was furnished to the SEC today and our annual report to be filed on Form 10-K in the coming days. 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 2025 marked a defining moment for Cytokinetics with the FDA approval of Myqorzo for the treatment of adults with symptomatic obstructive HCM, the first medicine we've advanced from discovery to commercialization. In fact, in the span of a single week Cytokinetics received approvals for Myqorzo in both the U.S. and China, plus a positive opinion from CHMP for Myqorzo in the European Union. That latter milestone preceding last week's announcement of the European Commission's approval of Myqorzo in the EU.

Together, these milestones represent the culmination of years of focused scientific, clinical and regulatory execution and we now turn the page on to a new chapter for Cytokinetics as a global commercial stage biopharmaceutical company.

More importantly, the approval of Myqorzo offers a new treatment option to patients living with obstructive HCM, a serious condition that can profoundly impact quality of life. As Andrew will discuss, since the FDA approval in December, our teams have been focused on executing a disciplined and deliberate commercial launch. Our ongoing priority is to implement the systems, the education, the promotion and market access pathways to support physicians, patients and payers while also building initial and sustainable launch velocity and momentum. While it's still early, we are encouraged by our progress thus far and the initial engagements we're seeing from the cardiology community. In fact, the level of interest in Myqorzo as a new treatment option is high.

With an eye towards the longer-term U.S. commercial launch trajectory during the first quarter, we submitted the supplemental NDA for Maple HCM to the FDA. We expect FDA to conclude its review of the sNDA in Q4 2026. We believe that the potential inclusion of results from MAPLE-HCM into an expanded label for Myqorzo could boost category penetration, depth and breadth. So more patients may ultimately benefit.

Of course, we also anticipate the readout of results from ACACIA-HCM in nonobstructive HCM, and we're on track for a top line announcement in the second quarter of this year. nHCM is a different patient population with significant unmet medical need. Should this trial prove positive it could also represent a potential growth driver for Myqorzo.

Outside the U.S., following the recent approval of Myqorzo in the EU, we've now shifted into full execution of our commercial readiness planning with our first planned launch in Germany expected in the second quarter. Additionally, during the fourth quarter of last year, Health Canada accepted for review the new drug submission for aficamten and a potential approval for aficamten in Canada could come later this year. As we look ahead, we enter this next phase of our corporate development with strong momentum and also solid financials. The progress we delivered last year positions us well for continued growth and value creation while we also keep a close eye on capital structure and capital allocation.

Sung will speak to our financial guidance and position as we ended 2025 and as well as operating expense guidance for 2026. That guidance reflects the priorities of launching Myqorzo and advancing our muscle biology pipeline both with disciplined execution and attention to capital efficiencies. We're confident in the foundation we're building for our specialty cardiology franchise and to deliver for both patients as well as shareholders.

And with that, I'm going to now turn the call over to Andrew, please.

Thanks, Robert. Our U.S. commercial was process began immediately following FDA approval of Myqorzo on December 19 last year. We have built our customer support systems around a team of HCM navigators who serve patients in a one-on-one relationship. These navigators are taking calls within days of approval, ensuring patients and HCPs had support. Immediately following the FDA approval in December, we launched our patient and HCP marketing campaigns, leveraging surround sound assets and activation such as Quick Start guides, patient drugstores, websites and social media advertising to help drive awareness and education.

Our sales representatives, whom we call cardiovascular account specialist began engaging with HCPs immediately following the New Year's holidays and certifications within the Myqorzo label. Within reach of approval, the online porter portal for the Myqorzo -- program went live and Myqorzo became available for prescription. On that same day, we also launched Myqorzo and you, our patient support programming offering personalized support, access and reimbursement assistance and affordability programs for eligible patients, including a free trial program, Ridge program, Coke pay assistance and patient assistance program.

On the first day of product availability in channel, ACPs began to be certified in REMS and patients enrolled in Myqorzo and you. Within days of availability, the first prescriptions from Myqorzo were dispensed.

At the end of January, we also hosted our first national speaker broadcast with strong attendance from across the U.S. This was only the start of what will become an extensive peer-to-peer physician education program, which is a key element of our strategy to ensure HCPs are aware of this new treatment option.

All of these integrated commercial launch programs were synchronized to roll out and support our ambitious plans for Myqorzo in the United States. While we are still early in our launch so far, customer feedback has been positive, as expressed enthusiasm for another cardiac myosin inhibitor as a treatment option for obstructive HCM, with particular interest in the clinical evidence demonstrating sustained reduction in obstruction and improvement in symptoms with no treatment discontinuation due to ejection fraction drops as observed in SEQUOIA-HCM. Our understanding is that a substantial portion of HCPs also appreciate the flexible dosing and ability to rapidly titrate as early as every 2 weeks the adaptable monitoring schedule that allows for echos to be completed within a 2- to 8-week window and that drug-to-drug interaction canceling is not required as part of the REMS for Myqorzo.

While it's still early in our launch, we're encouraged by the initial level of engagement, REM certification and overall demand. Within 3 weeks, we had over 700 HCPs now REM-certified across HCM specialty and nonspecialty senators, a leading indicator of ACT's planning to prescribe Myqorzo. And as mentioned, patients were on therapy within the first week that Myqorzo was available. The level of demand in Repaint enrollments and therapy initiation is so far reinforcing our conviction and the commercial prospects for Myqorzo.

In addition, we have already achieved over 12,000 customer engagements, including our cardiovascular account specialist having engaged over 95% of the 700 HCPs who account for the majority of CMI prescribing today. Our current focus remains on educating HCPs -- prescribing information, preparing them for the REMS requirements, and encouraging them to identify patients for Myqorzo.

From market research conducted post launch, we have learned that on an ad basis, roughly 90% of HCP's surveyed are aware of Myqorzo, the majority of which have stated they plan to prescribe Myqorzo for their obstructive HCM patients. They further state they recognize the potential benefits of the Myqorzo clinical profile for efficacy, safety and tolerability as well as the differentiated REMS and dosing flexibility.

As we've stated, starting with our Q1 earnings call, we will report on 3 key metrics to measure the pace and velocity of Bureau launch. The number of HCPs are actively writing prescriptions, the volumes of prescriptions and HCP rights and the number of patients on Myqorzo, we see this as leading indicators of launch depth and breadth that will read on our overall progress. As we continue this launch, our goal for Myqorzo is to achieve greater than 50% of CMI new patient preference share by the end of 2026. We also intend to engrave the overall MI category. Our confidence is based on 3 launch drivers: clinical evidence are bespoke patient support services and the differentiation of our REMS program. First, the clinical evidence from SEQUOIA-HCM supports that Myqorzo is associated with rapid and sustained reduction in obstruction and improvement in symptoms, that it provides flexibility that type -- really 2 weeks with a flexible monitoring schedule for both patients and HCPs and was not associated with treatment interruptions or clinical heart failure events.

Second, our patient support program called Myqorzo in you, which provides a single point of contact for patients to deliver an experience that balances empathy and individual connection with consistency and seamlessness. And third, the Myqorzo REMS program allows for the flexibility to titrate as early as 2 weeks with Echo monitor required within a 2- to 8-week window following dose initiation and any subsequent dose change with no DDI monitoring. And importantly, a patient's dose may be titrated after each echo with no delay.

These 3 launch drivers are what we believe will fuel the uptake for Myqorzo and preference share. Driving access for patients is also a high priority. We've been engaging with payers for some -- quite some time ahead of FDA approval to educate them on the evidence from our clinical trial as well as the clinical and economic burden of obstructive HCM. We have already met with all key payers earlier this year following approval. Our goal was to have Medicare access comparable to Camzyos in the first quarter and commercial access comparable Camzyos Q4 2026.

In Europe, with DCA approval for Myqorzo now secured in the European Union, we are moving quickly towards our first European commercial launch in Germany planned in the second quarter. Our German medical and commercial teams are hired and launch plans are accelerating. We also now have hired country legion in all EU 4 countries and the U.K. to prepare for subsequent European launches in later 2026 and in '27.

We also continue to advance European commercial readiness activities, including preparing HTA dossiers for all key European markets. It's a privilege to be in the position of launching Micro globally, and it is our priority to deliver, as proven by other launches, the early work of establishing awareness and confidence in access is critical to unlocking long-term momentum and velocity. We're encouraged by initial engagement and are focused on converting these engagements into consistent scalable execution with positive commercial success as the year progresses.

And with that, I'll turn the call over to Fady to address our medical and clinical development activities.

Thanks, Andrew. In support of the launch of Myqorzo, our medical affairs organization continued to expand its engagement with the HCM community ahead of and now during our commercial launch. The field medical affairs team has been in place for several years now working with our clinical trial sites during the conduct of SEQUOIA-HCM and MAPLE-HCM, building deep relationships across the HCM community. Immediately upon approval of Myqorzo, our U.S. field medical teams, including therapeutic medical scientists and managed health medical scientists were fully trained and operational, allowing them to hit the ground running and engage HCPs at the start of 2026.

Since approval, our U.S. TMS team has rapidly scaled scientific engagement, conducting over 500 interactions with HCPs that supported Myqorzo. Our U.S. MHMS team in collaboration with our U.S. payer account managers, have expanded engagement by conducting more than 50 access-related interactions, reinforcing the economic profile clinical profile and safety considerations most relevant to access decision makers.

At the ACC next month, our presence will underscore our leadership in HCM and with accepted oral and poster presentations covering the real-world treatment implications, additional data from MAPLE-HCM and important safety and efficacy analyses drawn from our late-stage clinical programs. Supportive our global development strategy, our partner Bayer completed enrollment to Camelia-HCM, a Phase III clinical trial of aficamten in Japanese patients with obstructive HCM. Additionally, we completed enrollment of the Japanese cohort of nonobstructive HCM patients and ACACIA-HCM, both intended to support potential marketing authorization for aficamten in Japan.

During the fourth quarter, we presented additional data from MAPLE-HCM and 3 late-breaking sessions at the HCM Society Scientific Session and the AHA scientific sessions. Responder analysis show that significantly more patients on aficamten achieved a positive or complete response compared to patients on metoprolol. Additionally, treatment with aficamten resulted in significantly greater improvements to -- on symptoms and cardiac biomarkers. The results from MAPLE-HCM have resonated strongly across the cardiology community, highlighting the evolving thinking around the standard of care treatment in HCM and the need for new therapies.

Now I'll hand it over to Stuart to speak more about ACACIA-HCM and as well as our ongoing development programs in heart failure.

Thanks, Fady. Our next important data readout will come from ACACIA-HCM, the pivotal Phase III clinical trial of aficamten patients with an HCM. We remain on track to share top line results of the primary cohort, which excludes Japan in the second quarter. We anticipate the top line press release will remain relatively high level shows not to jeopardize presentation of the full results at a potential medical congress later in the year.

nHCM is a highly underserved patient population with no approved therapies. We look forward to reporting the results of ACACIA-HCM and to evaluating whether aficamten can demonstrate a clinically meaningful benefit for these patients. As with any pivotal trial, the range of outcomes is possible, and we'll provide a thorough review of the results at an upcoming medical congress following the top line release.

As we previously guided, the conduct of ACACIA-HCM remains within its design parameters and closeout is going according to plan. Given our expertise and experience in designing and managing trials in HCM, we believe that we have successfully executed a well-designed clinical trial. We continue to be confident in ACACIA-HCM and look forward to seeing the results in the second quarter.

Now moving on to our clinical development programs in heart failure. During the quarter, we continued conduct of Code-HF, the confirmatory Phase III clinical trial of omecamtiv mecarbil in patients with symptomatic heart failure which severely reduced ejection fraction less than 30%. We now have 100% of U.S. sites activated and over 90% of European sites activated. We soon plan to expand the trial into China to increase the global footprint of this important clinical trial. We also continued AMBER-HFpEF, the Phase II clinical trial of ulicamten in patients with symptomatic heart failure with preserved ejection fraction of at least 60%.

We continued enrollment in cohort one of AMBER-HFpEF and expect to complete enrollment in this first quarter. After an interim safety review is conducted, we may assess whether to begin to enroll in cohort 2 for a valuation of higher doses. We're encouraged by the continued progress and execution across these ongoing clinical trials, reinforcing our focus on disciplined development and advancing innovative medicines within our emerging specialty cardiology franchise.

And with that, I'll pass it to Sung.

Thanks, Stuart. We're pleased to report our fourth quarter and full year 2025 financial results. Starting with the balance sheet. We finished the fourth quarter of 2025 with approximately $1.22 billion in cash, cash equivalents and investments compared to $1.25 billion at the end of the third quarter of 2025. The 2025 year-end balance includes $100 million in proceeds from the drawing on tranche 5 of the Royalty Pharma multi-tranche loan. Excluding the proceeds from this loan, cash, cash equivalents and investments would have declined by approximately $134 million during the fourth quarter of 2025.

Turning to the income statement. Total revenues in the fourth quarter of 2025 were $17.8 million compared to $16.9 million for the same period in 2024. Total revenues for the full year of 2025 were $88 million compared to $18.5 million in 2024. We Total revenues for the full year 2025 benefited primarily from the successful completion of the technology transfer totaling $52.4 million to Bayer in the second quarter of 2025 and the recognition of $15 million in milestones in the fourth quarter of 2025 related to the approvals of Myqorzo in the United States and China under the Sanofi license agreement. As we announced previously, Myqorzo became available to patients near the end of January. And as such, we expect to report product sales of Myqorzo with our Q1 2026 results.

R&D expenses for the fourth quarter were $104.4 million compared to $93.6 million for the same period in 2024. R&D expenses for the full year of 2025 were $416 million compared to $339.4 million in 2024. The increase from 2024 to 2025 and was primarily due to advancing our clinical trials, higher personnel-related costs, including stock-based compensation and medical affairs activities.

G&A expenses for the fourth quarter of 2025 were $91.7 million compared to $62.3 million for the same period in 2024. G&A expenses for the full year of 2025 were $284.3 million compared to $215.3 million in 2024. The increase from 2024 to 2025 and was primarily driven by investments towards commercial readiness, including the hiring of our U.S. sales force, primarily in the fourth quarter of 2025 and higher nonsales personnel related costs.

Net loss for the fourth quarter of 2025 was $183 million or $1.50 per share compared to a net loss of $150 million or $1.26 per share for the same period in 2024. Net loss for the full year of 2025 was $785 million or $6.54 per share compared to a net loss of $589.5 million or $5.26 per share in 2024.

Turning now to our financial guidance for 2026. As it is our first year of launching Myqorzo, we are not providing product sales guidance at this time. In terms of expense, we expect our GAAP combined R&D and SG&A expense to be between $830 million and $870 million. Stock-based compensation included in the GAAP combined R&D and SG&A expense, is expected to be between $120 million and $130 million.

Excluding stock-based compensation from the GAAP combined R&D and SG&A expense results in a range of $700 million to $750 million. The GAAP combined R&D and SG&A expense do not include the following: collaboration expenses, which can include reimbursed expense expenses and cost of inventory sales of aficamten to partners.

Subject to the results of ACACIA-HCM and regulatory review, potential costs related to commercialization of aficamten and nHCM and the effect of GAAP adjustments as may be caused by events that occur subsequent to publication of this guidance, including, but not limited to, business development activities.

Our capital allocation priorities are as follows: first, launching Myqorzo in the U.S. and funding commercial readiness activities in Europe. Second, advancing our pipeline with important label expansion opportunities for aficamten and ongoing clinical trials of omecamtiv mecarbil and ulacamten; and third, investments in our muscle biology platform and pipeline. We will continue to be disciplined in our approach to capital allocation and remain good stewards of capital as we embark as a global commercial stage company.

With that, I'll hand it back to Robert.

Thank you, Sung. Before we open the call to questions, it's worth pausing to recognize what this moment represents for Cytokinetics. After years of focus, discipline and unwavering commitment to our science, we've crossed an important threshold from pursuing possibilities to delivering impact. The approval of Myqorzo marks the beginning of a new chapter, one for which our work impacts the daily lives of patients and the decisions made in clinics around the world.

This is a moment we've been working towards for nearly 28 years at Cytokinetics and reflects unstoppable resilience, dedication and a rigorous focus on translating our science into medicine, for the benefit of patients. With that transition comes a deeper sense of purpose and dedication to our core values, which define how we do what we do. Chief amongst them is our value of patients or North Star. And during the fourth quarter, we announced our support for a 3-year initiative led by the American Heart Association to address disparities and access to care, diagnosis and treatment for people living with HCM.

Through this long-standing commitment, we hope to help close the gaps between evidence, guidelines, implementation and equities in health care delivery for HCM. Progress at this stage is not only about innovation, but also about our responsibility to show up for patients and the communities we serve. What we discussed today reflects years of focused work across the organization from discovery and development through regulatory, manufacturing and now commercial execution.

What made all of this possible was the enduring dedication and the passions from our employees for which I have endless gratitude. As we enter this next chapter as a commercial stage company, -- our focus remains clear, execute ambitiously, advance our pipeline and deliver meaningful longer-term impact for patients and shareholders.

Now I'd like to share our 2026 milestones. For aficamten, we expect to report top line results from ACACIA-HCM in the second quarter 2026. We expect to launch Myqorzo in Germany in the second quarter 2026. We expect to receive potential FDA approval of the supplemental NDA for MAPLE-HCM and by Q4 2026. We expect to complete enrollment in the adolescent cohort of CEDAR-HCM in Q4 2026, and we expect to receive potential approval from Health Canada in the second half of this year.

For omecamtiv mecarbil, we expect to continue patient enrollment and the conduct of common HCF through 2026. For ulacamten, we expect to complete enrollment in Cohort 1 of AMBER-HFpEF in Q1 2026 and complete enrollment in Cohort 2 of AMBER-HFpEF by the end of 2026. And finally, for our preclinical development and ongoing research, we expect to continue that ongoing preclinical development and the research activities directed to additional muscle biology-focused programs.

Operator, with that, we can now open up the call to questions, please.

[Operator Instructions]. Your first question comes from Tess Romero with JPMorgan.

This afternoon. So one from us on ACACIA. Is it true that the study will be successful, if at least one of the end points reaches statistical significance. And then along these lines, in your study protocol, did you specify which endpoint would be you would need to hit to be claim -- to properly claim success. In other words, either KCCQ or peak CO2 or is either fine?

So I'll start, and I'll turn it over to Fady and Stuart. To define success, you have to also consider with whom you're engaging. And obviously, the clinical community is going to have 1 set of expectations and interest as mid FDA, but also they could diverge. But it is true that as we have designed this clinical trial, it will be deemed positive if it hits on either or both of the prespecified clinical trial end points.

With that, I'll also turn it over to Fady and Stuart, if they want to add anything.

I think the only thing to add is that either endpoint is considered equally positive, but either one is positive, the trial would be considered positive. There's not one is not weighted more heavily than the other.

Your next question comes from the line of Roanna Ruiz with Leerink Partners.

Good afternoon, everyone. So a question for me. I was thinking about Myqorzo and its initial launch in cardiologist engagement. And could you share any color on how long it's taking sites and centers to get through the REMS certification and start to prescribe? And are the field reps noticing anything so far in their detailing?

Yes. So I'll start again and turn it over to Andrew. And we very purposefully are focusing on engagements, inputs, if you will, on this call because it is early in the launch. But we are indeed impressed by how many HCPs have already been REMS certified and the speed at which that happened shortly after product was in channel, and I'll ask Andrew to elaborate.

Sure. So the REM certification, as you're maybe aware, is a quick self-study training and attend question-and-answer that scored, it takes 10 to 20 minutes generally for cardiologists, sometimes even faster. So it's really not been a barrier to be REM-certified. I think the there are many HCPs and cardiologists we were talking to that were waiting for Myqorzo to be approved and had patients that were also waiting. And we've gotten strong engagement across a broad base of cardiologist both in centers of excellence and outside of centers of excellence in -- not only REM certification, but also getting patients REM certified and prescribing.

And also to add, knowing that this is not the first, but now the second cardiac myosin inhibitor. These cardiologists were accustomed to a REMS were awaiting one. And when we did launch and have product in channel I think they were poised, well positioned to move swiftly with REMS certification, and we're seeing evidence of that.

Your next question comes from the line of Mayank Mamtani with B. Riley Securities.

Congrats on a productive recent few months. So ACACIA, if I may. Could you comment on your placebo arm response expectations for both KCCQ and PVO2? And if you'd expect consistency to what we've seen in preceding HCM trials? And if you could also comment on whether you'd expect a similar proBNP reduction that you saw in the earlier Edward experience at the time point that you have here? And if you expect that to be correlated to the exposure that you may have from a dose intensity standpoint?

So I'm going to ask my colleagues to answer your question, but I'll remind you and also them that as we're approaching the conclusion of the study and as we would be expecting to proceed to database lock and unblinding, we should answer your question with regard to what was the original design expectations. And I want to make certain that we're not in any way front-running anything that might be understood regarding the progress of the trial rather it's design and conduct.

Yes, it's important to realize that we are still blinded to the data. So we have really no clue as to what the placebo arms are doing. But based on past experience, the PPO 2 arm, generally, placebo response is close to 0, maybe a little higher, maybe a little lower, but in our prior studies that placebo response, there isn't much of a placebo response to PPO 2.

And again, we based ACACIA design on a placebo response in line with our prior studies, expect 4 to 5 points, perhaps 6 points. But just to emphasize the statistical design of the study doesn't rely on the magnitude of the placebo response. It relies on the difference between the active response and the placebo response. And so that difference in the case of KCCQ, which we powered the study on was 5 points difference between placebo and active.

And then your last thing point was with regards to NT-proBNP, we certainly wouldn't have any expectations that are different from what we observed in the Phase II or the open-label extension with regards to how NT-proBNP has declined during treatment with came but we're blinded to those data as well.

Your next question comes from the line of Joe Pantginis with H.C. Wainwright.

So a question on market uptake, and I'm glad Andrew made an earlier comment as well that I wanted to ask. So with regard to the U.S. first, Andrew, you made some comments about and previously about patients docs have been having in reserve. I wanted to know if there is any uptick there that you thought might have been in line or even quicker than expected.

Secondly, with regard to ex U.S., China, for example, what would you describe as any commercial differences? I know you have started to put a team there or potential headwinds that you could expect versus what you see in the United States.

Andrew, do you want to take that?

Sure. So maybe start backwards. China is partnered Sanofi is commercializing China. We're not doing that. So that's an important element. I think the back to the U.S. patients and reserves I think the demand we're seeing and where we're seeing it from is what we were expecting. So we were not surprised by the patient demand. I think it will reflected in research we were seeing when we were doing primary market research, preapprovals, things like demand studies, things like awareness studies that there was broad awareness the physicians certainly were aware of, not only SEQUOIA, but also MAPLE that were presented at Congresses. So I think we're where we were expecting to be. knowing that we've been in the market with product for about 3 weeks.

But also like just -- sorry.

Maybe I can just add to the point of Andrew's comment market research, but also as equity research analysts from Wall Street have done their own surveys, there was clear evidence that the current cardiac myosin inhibitor category was only penetrated 15% to 20% at most and that there would be a large number of patients still eligible for treatment. What we heard, what analysts heard is that there would be a number of patients that could be started promptly. And the early evidence would suggest that there were patients that were held awaiting a potential approval. And we'll be in a position to comment more about that in time.

Your next question comes from the line of Cory Kasimov with Evercore.

So I had a follow-up on ACACIA and I want to also ask between these 2 primary endpoints of KCCQ and peak VO2. And we think specifically about U.S. investigators. Is there a view from like domestically on whether one of these endpoints is more important than the other? I know the original primary with KCCQ, is that a reflection of how U.S. physicians are thinking about it. And then from that standpoint, I know how it's powered, but what's considered to be a clinically meaningful change, again, from a physician point of view?

So here again, I'm going to remind our colleagues with regard to what were the original design requirements. But I'll also say that the fact that we chose to have co-primary end points was not because we originally thought one was more important than the other, but rather because regulatory authorities wanted to see a harmonization across the study as could be best achieved by putting equal weight and emphasis to the 2 co-primaries. Maybe Fady and Stuart will ask you if you want to say anything else?

Yes. I'll just add. I don't think physicians will lean one way versus the other. I think they will look kind of at the totality of the evidence and not just the primary endpoints, but also the secondary endpoints that include NY class and other metrics of exercise, biomarkers and things like that. So in this field, there are no treatments for nonobstructive physicians are looking for improvements in their patient status and there are many dimensions upon which they can improve. And I think they and also regulators will look at the totality of that.

I'll just add -- to answer your question about minimally important differences, for this being in HCM and to reiterate what Fady said, there is no approved drug for these patients in this population. What's going to be considered important and clinically meaningful is going to be hopefully a function of this trial as we learn what's concordant how the end points move together and what ultimately defines larger magnitude improvements versus what may be otherwise.

So I think we're going to learn a lot from this study that's going to be informing the clinical literature and hopefully what ultimately may be medical guidelines. But we don't have reference standards or benchmarks that we can point to. Instead, this study is intended to test those hypotheses and determine what should be important and meaningful.

Your next question comes from the line of Salim Syed with Mizuho.

One for us just on the disclosure. When you said high level, should we be thinking more along the lines of how Bristol had their press release for Odyssey, which was just completely qualitative, I think it was just 1 sentence like hit on the dual primaries. Or should we be thinking somewhere more along the lines of SEQUOIA. Had you guys did it, which had a lot of numbers in it or somewhere in between? And if it is all qualitative, would you be willing to comment on each of the co-primaries in the press release?

So ultimately, this will be a function of the actual data and what's deemed material and also what would be upon receipt of those data, what can be negotiated with the medical congress. Disclosing more would be an objective if that can be permitting of the full presentation at an important medical meeting. And in the case of Sequoia, we disclosed more but at the expense of being able to present it at the Medical Congress where it would have been more appropriate.

So we'd like to be able to do both of our KCCQ and needed to disclose as much as we can, but still preserve the opportunity to present at the appropriate next level Congress. If it is going to be more qualitative, I imagine we'll have to speak to both endpoints. I don't think we could speak to 1 and not the other. But in terms of what would be contained beyond that, I think it all depends on the data, magnitude of effect, P values and what we can be enabling of at Congress. Fady, anything you want to add?

I'll just add that the presentation of the data is important to the academic community. And in the past, I would say that, if you look at the presentation of MAPLE at the ESC Congress last year was tremendously impactful that way. So there are many considerations and important trade-offs here. in terms of all the stakeholders involved.

We're fully aware of the significance of the importance of these data, both to the medical community as well as to the Wall Street community, and we're going to try to do our best.

Your next question comes from the line of Yasmeen Rahimi with Piper Sandler.

My question is just related to ACACIA also I think 1 of the questions we've been getting is, would -- have you done payer work or uptake work to understand whether the usage would still be strong as you showed a 3-point placebo-adjusted difference in KCCQ or just commentary as long as you have a statistical separation and the magnitude of delta difference in KCCQ is irrelevant. I appreciate color and I'll jump back in the queue.

So maybe that's a question for both Saudi and Andrew. In terms of your specific example of a 3-point difference in KCCQ, I assume you picked that number arbitrarily, but maybe Fady and Andrew, if you want to tackle that?

Let me start by saying that in MAPLE and SEQUOIA, you see a range of strength of response. And while the average response say, in your example of 3 may represent an all-comers average response. You see responses that are far larger than that. And obviously, you see some patients that don't respond very much at all. And so I think in a lot of ways, the average number that's coming out of the trial will certainly color how physicians maybe look at the importance of the results, but we also enrolled 500 patients in the study and many of them will go into open-label extension and many of these investigators will have a chance to evaluate on their own how patients improved.

And I think, ultimately, this will be part of the case -- if you try it, you have a sizable response and it's important to you, then continue therapy. And if you don't, then you don't have to continue therapy and it's a little different than drugs where we treat to lower risk where you don't really know if you're the one that's going to benefit from the drug and thereby absolute differences are far more important to understand potential benefit. So I hope that helps from a medical percent.

And from a demand point of view, provided that the study is statistical and that Myqorzo would be approved for nonobstructive. The care demand is driven significantly higher. We hear things like AAPs being able to use 1 product across all of ATM, not worrying whether it's OEM or nHCM, especially given the profile that you know and we know from SEQUOIA that it would drive up use, both in OEM obviously as well as in HCM. So it has a significant impact on nHCM and maybe not significant, but definitely an impact on OHCM as well.

And I think just to maybe culminate here. Just simply achieving clinical significance is not alone enough. The magnitude of change needs to be meaningful, especially relative to an instrument like KCCQ, where there is a history of a placebo effect. So our goal is to demonstrate with this trial above and beyond a placebo effect a meaningful impact on KCCQ.

Your next question comes from the line of James Condulis with Stifel.

Congrats on all the progress. I actually wanted to ask one about HFpEF. And I was curious in the context of Acacia, how important or meaningful you think in ACACIA win would be helping to kind of risk that broader HFpEF opportunity given some of the overlapping kind of pathology here. And just curious if you could also help frame out kind of when we may see initial data there? And what a win looks like.

Good question, and I'm going to ask Stuart to comment, but I'll also highlight that we learned a lot from what we can glean from those data from Odyssey. And that obviously has impacted implication to what we hope to see with our study, Acacia. But to your point, ACACIA can also inform what we might expect from HFpEF and the translation of this mechanism of a cardiac myosin inhibitor to an adjacent population. That's certainly our objective. And with that, I'll ask Stuart maybe to comment.

Thank you, James. I mean you'll hit upon an important evidence space that really informed this hypothesis about the potential benefit of in patients with HFpEF and more specifically those patients with hypercontractility. So many of the features clinically and structurally are similar between patients with nonobstructive HCM and with HFpEF and hypercontractility. So I think the outcome of ACACIA could further inform the potential benefit of a CMI and HFpEF. With respect to when we expect results from -- from AMBER-HFpEF, I think it's a little bit too soon to say that, but we'll continue updating you in terms of the progress of the trial.

But underscoring what Stuart said around hyper contractility, and ensuring that everybody appreciates that the way we're thinking about FPP is not the entirety of that population, but those whose disease and anatomy is defined by hypercontractility and that's where we believe there's an adjacency to nHCM.

Your next question comes from the line of Jason Butler with Citizens.

Just wondering if you could give us any color on the centers that are signing up in the REMS program right now. Are you getting any health care prescribers that are either not current CMI prescribers or have never precise CMI? Or is it fair to say the majority of all of the sign-ups are current CMI prescribers?

Andrew?

Yes, sure. So thanks for the question. The majority are current CMI prescribers, but we have -- we do have prescribers who are REM-certified who are not CMI prescribers today, and we do have prescribers that are first-time CMI prescribers as well. But as you would think the majority are carrier CMI prescribers.

And then tracks with the ways in which our cardiovascular account specialists are focusing their energies, as Andrew commented in his prepared remarks, our activities are more focused to those targeted cardiologists who are already high-volume prescribers, and that's where he commented on percent engagements. But it's nice to see that already we're seeing outside of that circle use of a cardiac myosin inhibitor where it had not been previous.

Your next question in comes from the line of Maxwell Skor with Morgan Stanley.

So assuming positive ACACIA readout, how should we think about any incremental uplift to the obstructive HCM launch trajectory in 2026? If you can maybe quantify or speculate how that would read through? And also, I'll try. Can we expect ACACIA to read out in the early part of the second quarter or maybe later on in the second quarter?

So I'll tackle that latter question and ask Andrew to do the former. We're not going to guide to when in second quarter. I imagine analysts will do their own math and make their own handicapping and projections, but we're not going to comment on that. And then I'll ask Andrew to speak to your first question.

Yes. I mean I think, obviously, we're not going to be promoting or talking about an HCM or ACACIA, if the product's positive and approved. But given that we would expect that there would be uplift. We have seen in market research that there's a halo effect, if you will, on obstructive HCM probably in the order of magnitude of 15% to 20% uplift.

It -- depends on the data, we'll have to do additional market research to assess how that might inform use in HCM. And what kind of spillover there may be. But underscoring, we intend to be very much by the book compliant with regard to what our cash colleagues would be able to speak to.

Your next question comes from the line of Serge Belanger with Needham.

I'll pile on ACACIA 2 seems to be the topic du jour. So I know you're still blinded to almost all the data, but I think in the past, you've talked about monitoring the variability in the end points. So just curious if there's been any change in that variability in what you can glean from that?

Yes. So I'll turn to Fady, but I'll emphasize yet again that in light of the fact that we're now near to what would be database lock and unblinding. We can't comment on something like what you asked with regard to standard deviation. Rather instead, we can comment on what the study was designed to demonstrate.

Yes. The study was designed to demonstrate a 5-point belt on KCCQ, assuming a standard deviation of 15 and a PF2 of 1 with a standard deviation of 3. 90% power with being able to detect statistically significant differences at the differences that are less than that with less power, obviously. And as I stated in the script, the study remains within its design parameters. And we won't commit to updating those statements going forward.

Your next question is from the line of Jason Zemansky with Bank of America.

This is Jackie on for Jason. Congrats on the progress. So real quick, can you report what you've seen thus far this year in terms of patient start forms? And also about -- how much of your early efforts have involved more community practices? And what has the reception been like specifically within these offices?

Thank you. Andrew?

So we're not going to give numbers. We'll do that in the first quarter relative to start forms. All I can say is what we said in the script, which is our demand in the 3 weeks and the engagement we've seen with physicians is at if not above what we expected internally in terms of community versus centers of excellence, the 700 physicians were 80% of the market. That's where the majority is coming from, but there's also strong engagement from the community. Their strong engagement from new prescribers probably new prescribers who have never prescribed the CMI, those numbers are higher than we were expecting. So I think we're seeing a good balance across all types of prescribers. And the majority, obviously, are the ones that we're calling on and educating. But in our first quarter call, we'll give more color on pages and engage in centers of excellence versus non centers of excellence, prescribing death, et cetera. So more to come, but too early to say with just 3 weeks of data.

Suffice it to say, it's early innings, but we're pleased.

Our next question comes from the line of Crypta Devin Conda with Truist Securities.

This is -- for Crypta. Congrats on the progress. We're very excited to see how Myqorzo's REM can also improve the patient and physician experience A question on the REMS. Could there still be an option to modify the runs requirement in the future? And could Cytokinetics go back to the FDA at some point with updated post-marketing data and get it rereviewed potentially to potentially make it even more favorable?

Yes. So we've already seen that the FDA was accepting of an opportunity to see real-world evidence data in support of a modification of the Camzyos REMS. But for our REMS, we're not guiding to any changes in the near term. But certainly, over a medium to longer term, it's reasonable to expect that real-world evidence could inform changes. What those changes might look like, it would be premature to speak to today. Fady or Stuart, anything you want to add?

Yes. The REM itself is quite straightforward in terms of what's required to execute it. But new real-world data will inform potential future modifications to it. But as Robert said, it's still too early to decide what it is that we may pursue. I think we just need some real-world data to understand what maybe our pinch points and how those real-world data would support all 3 grams at my release those few points.

Your next question comes from the line of Ash Verma with UBS.

This is Natalie on for Ash. So just on ACACIA, could you talk about how the discontinuation rate in Acacia compares to prior studies? And then also for the baseline patient population, could you give us a sense of the percentage of patients that might have the concentric LDH phenotype?

I can talk to discontinuations. And again, study was designed to withstand a 10% discontinuation rate. And I think as I said in the past, we've been within that metric. And in my earlier comments, reaffirm that, but we'll commit to updating that going forward. And then we haven't released any of the baseline characteristics, and so I can't really comment on your last question.

But what I can say is that our group of HCM specialist physicians review every echo of every patient that's enrolled in the trial and unless they feel is an echo consistent with hypertrophic cardiomyopathy, the patient would have a query raised to the site to gather more information that might support the diagnosis.

Your next question comes from the line of Leonid Timashev with RBC Capital Markets.

I just want to go back to the Myqorzo launch and the patients. I guess, can you provide any color on the types of patients that are being started versus what you might expect from the initial Nava camps in the launch? I guess is there anything specific about the patients being put on? Is it just new patients? Are there any switches? Is it patients who may be needed higher efficacy or had lower baseline ejection fraction. I guess I'm just curious how docs are thinking about the initial use of aficamten -- have there the ability to use the drug?

I'm sorry, just keeping in mind we don't always have insights into patient level data, but we only hear things maybe a bit more anecdotally. I think all of the above may be a way of addressing your question. But maybe, Andrew, you have something else you want to add?

No, you said exactly what I was going to say is that we -- patient information is protected. We don't see exactly who was put on in for what reason. The data is too early to see if they're switching, et cetera. But I do think we're seeing all of the above, as Robert said.

And that concludes our question-and-answer session. I will now turn the conference back over to Robert Blum for closing comments.

Thank you, operator, and thanks to all of you for joining us on this call today. Obviously, we reflected on the importance of this moment, I won't repeat those statements other than to say we understand the significance of this as we turn the page on to commercialization and we want to do the right thing by these patients for the benefit of their care and do right by health care professionals who attend to their care.

We also recognize and acknowledge that this is an important milestone for Wall Street as Cytokinetics is now a global commercial company, and we take that very seriously as well. And we look forward to providing you insights as we have more substantial information relating to the launch of Myqorzo in the United States, its expected launch in Germany and other European countries and we'll know more and be able to share more through the remainder of this year. Moreover, as we have access to results from Acacia expected in Q2. We look forward to sharing those with you and we recognize the significance of those 2.

So thank you for your interest and attention to all that we're doing at Cytokinetics. We look forward to keeping you abreast of progress. With that, operator, we can now conclude the call.

Ladies and gentlemen, this concludes today's conference call. Thank you for your participation, and you may now disconnect.

Welcome, everyone, to the 44th Annual JPMorgan Healthcare Conference. My name is Tessa Romero, and I'm one of the senior biotech analysts here at JPMorgan. Our next presenting company is Cytokinetics. And presenting on behalf of the company, we have President and CEO, Robert Blum. Robert, over to you.

Thank you, Tessa, and thank you to JPMorgan for inviting us again this year. This is a very important year for Cytokinetics, as I'll be elaborating as we are turning the page at Cytokinetics after over 20 years and presenting at this conference to now a company that is commercial considering that we just had our FDA approval of -- thank you.

We appreciate that. And here today, we're going to talk about this monumental milestone and how we are prepared to meet the moment. I'll be making some forward-looking statements. I'll refer you to our SEC filings. For caveats to those statements, we don't undertake obligations to update those statements, but rather instead refer you to those filings.

Cytokinetics from the beginning, over 25 years ago has been consistent and disciplined with regard to a focus to one area of biology, and it defines our mission. Cytokinetics is committed to bringing forward new medicines focused to the health span of people with devastating cardiovascular and neuromuscular conditions rooted and anchored in impaired muscle function.

Why we do, what we do is captured in this video, and I'd like to share that with you as hopefully is defining what's next for our company and this next chapter.

[Presentation]

So Cytokinetics is very pleased to now be in front of JPMorgan with Myqorzo approved by the U.S. FDA for the treatment of adults with obstructive hypertrophic cardiomyopathy. Myqorzo is now launched, and I'll be speaking today in some detail to elaborate on our commercial strategy and how it's differentiated and what our goal is in defining of this opportunity to build a specialty cardiology franchise business.

But Myqorzo is the tip of the spear, if you will, and the United States, the first of its frontiers. Myqorzo is also now approved in China. And in December, we were pleased to announce that we received positive CHMP opinion for the approval of Myqorzo in Europe with the expectation that the European Commission will be approving of it in Q1 this quarter, enabling of us to go to market in Germany in Q2.

This is all consistent with everything we've been saying about Cytokinetics and our plans to exploit this business opportunity for so many years, and Myqorzo represents the leading edge in oHCM as will be followed, we expect with a positive, hopeful study in Q2 this year, Myqorzo aficamten being studied in nonobstructive HCM.

Again, results expected in Q2. That's a very meaningful opportunity, as I'll elaborate later in this presentation. And again, that's one leg of the 3 legs of the stool that we've been building at Cytokinetics all along the way. omecamtiv in HFrEF, heart failure with reduced ejection fraction, ulacamten in HFpEF. These are legs 2 and 3 as we build what we hope to be an enduring and sustaining growth business against the backdrop of already a strong balance sheet, north of $1 billion reported at the end of Q3 last year with access to capital, as I'll elaborate more in the coming slides.

I mentioned we're building a specialty cardiology franchise. What's meant by that? This is not an accident. This is very purposeful to the way we exploit this biology. We believe in a commercial rationale that's been defining of our business ambitions for many, many years, addressing concentrated customer segments, high revenue per prescriber, enabling of a high return on investment and at the same time, categories that are not actively managed by payers, rather instead managed to label, where we think we, even as a smaller company with more limited access to capital can build a very valuable growth business.

This is the pipeline that's going to get us there. This is the same pipeline you've been seeing advancing over many years. But now Myqorzo approved in oHCM and with a differentiated risk mitigation profile approved in the United States and in China and with potential expansion of opportunity in nHCM, again, ACACIA data expected Q2 this year.

And you can see how that ripples through the rest of the pipeline. Aficamten being studied in CEDAR, in FOREST, and also omecamtiv, ulacamten and other muscle biology-directed research. As we turn the page for this company on to commercialization, don't sleep on the fact that we've got a pipeline underlying the opportunities here to enable further news flow catalyst growth and a sustainable enduring business.

But today is about Myqorzo. Myqorzo approved in the United States, 5 milligram, 10 milligram, 15 and 20-milligram strengths. And you can see it pictured in the bottles that will soon be in the hands of patients. Myqorzo was approved by the U.S. FDA based on the SEQUOIA-HCM study, data that were top lined in 2024, published, and you can see these data here.

Myqorzo on top of standard of care in patients suffering significant symptom burden demonstrated meaningfully large, clinically relevant increases in peak VO2 out to week 24. Standard of care, no change from baseline. Those patients on Myqorzo, you can see a dramatically large increase in their ability to exercise and sustain that.

But accompanied also by highly statistically significant, large clinically meaningful changes in other secondary endpoints as also reported on the right-hand side of the slide, meaningful changes in grade or pressure as well as relief of symptoms, disease status, significant reductions in biomarkers and all of this accompanied by anatomical changes in heart structure and function that corresponded with clinical benefit.

These results published in the New England Journal of Medicine and accompanied by a safety profile consistent compatible with standard of care and no serious adverse events. This is underscoring of what we believe to be an important feature of the Myqorzo go-to-market strategy.

Our go-to-market strategy is defined by the business opportunity. Consider this an onion, if you will. Currently, there are roughly 700 physicians accounting for over 80% of prescriptions for the cardiac myosin inhibitor class. This represents the low-lying fruit and the most important of the audience to which we're going to direct promotional activity.

But also, there are 2,000 physicians who have previously written a cardiac myosin inhibitor. There are over 8,000 based on claims data that we should be approaching with our promotional activities. Not everybody will get the same reach and frequency, but we'll be focusing to the 10,000 health care professionals who are treating at least 80% of the obstructive symptomatic Class II and III patients out there.

And we believe this is tractable to our focus with a commercial organization hired, trained and certified now in their territories already calling on customers. We hired in 2025 in 2 waves, a sales organization to accompany the 15 or so area business managers and we had over 9,000 applicants for the roughly 100 positions.

We are able to bring on board a highly experienced group of cardiovascular trained, experienced sales professionals. We call them cardiovascular account specialists, and they have, on average, each of them over 5 years of President awards. These are the top of the ladder people that have come to join our company on this next leg of the journey.

And what are the launch pillars? What are the pillars that define the way we're going to go to market? Of course, it starts with efficacy and clinical differentiation. We believe that Myqorzo affords the physician an experience that can be unique, a rapid and sustained symptom improvement and reduction in obstruction, but with flexibility around the way one can dose up titrate and the windows associated with that.

We did not experience any dose terminations in our clinical studies based on EFs below 40 or heart failure hospitalizations. We believe that affords the physician a confidence, a user experience that will be distinctive to how we can grow the business. And it echoes to the REMS program.

We said all along the way, we expected a differentiated risk mitigation profile and how that could be captured in a REMS. And the FDA-approved label in REMS carries forward that expectation now to the marketplace. The REMS program for Myqorzo is different. It affords different features that I'll elaborate on in a moment, and we believe that can be enabling of category growth and penetration, but it also doesn't stop there.

We believe as a company doing this for the first time, it's incumbent upon us to show up in the marketplace with a physician and patient experience that's unique to this opportunity, bespoke to the way we do business and our patient support services, how we engage the office administration staff and the patients will be specific to Cytokinetics and the way we approach a single point of contact, delivering a consistent tailored user experience, enabling a streamlined and seamless engagement and rooted in the values and the purpose-driven convictions of Cytokinetics.

We have already gone live with our health care professional and our patient delivered promotional campaigns. You can see them on the website. Like any good company should be doing, there are hundreds of materials that we'll be going to market with that define the positioning.

With health care professionals, it's about moving forward, moving forward rapidly to get patients to symptom burden relief sooner with more flexibility as should be compatible with a next-in-class opportunity that aspires to be best-in-class. For patients, we recognize what they want. We listen to them. They were involved in the design of our campaign.

They want to be heard, and we believe this campaign addresses what they're interested in and the gratitude associated with how they see their life journey. I mentioned the REMS is distinctive. The REMS for Cytokinetics and Myqorzo is different than the REMS for Camzyos. Listed here are the many ways that it differs.

We believe that these things matter and our market research echoes that. We believe that currently, limitations on the adoption of cardiac myosin inhibitors are based on things like the number of echoes, the complexity of the patient monitoring forms, the number of DBI checks, how that's administered by phone and with whom and ultimately, the number of months required to get to maintenance dose.

These are all things that we think in addition to the amount of drug that can be dispensed, the windows associated with echoes, all of these things are distinctive to the REMS program for Myqorzo as we believe will be enabling of greater category growth and penetration. But again, how do we engage patients, how do the office staff in the physicians' offices, how do they engage around this opportunity. That's where Myqorzo in you comes in.

This is a program that was designed bespoke to this experience. How we think about providing support for reimbursement, how physicians and their office personnel engage with us is defined by a one-on-one relationship with territory managers and nurse navigators, so that there's always the same person with whom one is engaging.

It's not a patient experience that's evolved for this opportunity based on other opportunities, but rather one that was architected and implemented unique to Myqorzo. And here, again, how that is enabling a point of contact is, we think, going to be distinguishing of Cytokinetics in the marketplace, our access colleagues being CEOs of their territories, one-on-one relationships with cardiologists and the same is true for the office staff with our nurse navigators and the patients with the nurse navigator.

We believe in the bespoke experience that will be defining of how Myqorzo is launched. How will it be priced? We've indicated we always thought it would be priced around the same ZIP code. Today, I'm announcing that Myqorzo is going to be priced with a wholesale acquisition cost of $108,400, a parity slight plus, meaning that we're going to be in the marketplace, not so much competing on price, but rather at the same time, as I've been saying, on the clinical and physician patient experience.

That speaks to how we think about market access. Here, you see the business as it is defined by payer mix. Medicare roughly 50% to 60% commercial, 30% to 35%. We do not intend to be competing on access or price, rather instead looking to achieve parity access with coverage criteria consistent with our clinical evidence in 2026.

Our global value and access colleagues have already been in the field for a couple of years engaging with payers, and we believe that's going to confer to us a competitive advantage as we now roll out the Myqorzo launch. And how are we going to communicate to shareholders?

We expect to be sharing with you key metrics that define launch momentum and velocity, focusing on the number of health care professionals who's prescribing Myqorzo, the depth and the breadth amongst those tiers of the onion I shared with you earlier and the volume of patients.

We believe that we're in a good position to grow this category, and you should be holding us accountable to these kinds of metrics throughout the year. What precedents do we have to be defining of how this market can be growing based on a next-in-class that aspires to be best-in-class. Here, borrowing a page from the playbook of Bristol-Myers Squibb, we see how Eliquis in a similar cardiovascular category was able to catalyze and go from next-in-class to best-in-class based on a differentiated clinical and safety profile.

We believe in my 40 years of experience in cardiovascular sales and marketing would indicate that this is not uncommon. It's common that a next-in-class drug becomes a best-in-class in cardiology based on metrics and measures that define a safety and tolerability. We hope that, that can be the case for Myqorzo.

And similarly, you're seeing something like that already playing out in the amyloidosis space. The introduction of Attruby led to a catalytic growth in the marketplace even more amplified based on announcements this morning. And we believe that the same is possible also for Myqorzo entering the CMI category.

You can see on the right hand of the slide, BMS has done a very good job. They will likely eclipse $1 billion in 2025 full year sales. But at the same time, it's been largely linear growth quarter-to-quarter. And we think the introduction of Myqorzo can make a meaningful difference impacting category growth and penetration beyond centers of excellence to also community-based cardiologists, so more physicians feel comfortable prescribing a cardiac myosin inhibitor for more patients.

So Myqorzo advancing globally. I've been talking about U.S. strategy. It's consistent also with how we approach Europe, but in a more gated investment spend. We did recently announce that our partner, Sanofi, was able to get Myqorzo approved in China. We think the same thing will happen in China.

So imagine Cytokinetics now with Myqorzo active in markets as far away as China and ourselves in North America and Europe. And that's the business that we're building and today at JPMorgan turning the page on that narrative. And that forms the anchor, the tip of the spear, if you will, for the franchise strategy that we've been talking about and is now one step closer to reality.

Here, you can see how our specialty cardiology franchise strategy applies to adjacent markets with similar characteristics. And you can see both in terms of HCM, a specialty cardiology market, but also those specialty cardiology patients and opportunities in severe heart failure with reduced ejection fraction as well as heart failure and preserved ejection fraction, Myqorzo followed by omecamtiv followed by ulacamten, and you begin to see how we can build an enduring growth, sustainable business.

I've talked about oHCM, and I want to make sure I also highlight nHCM. We believe recent claims data and soon to be published will be elaborating on how the growing market in HCM is more and more taking a dimension where nHCM represents about 50% of all claims.

And we think that Myqorzo is very well positioned to be the first new medicine approved for nHCM based on what we believe can be the promise of the ACACIA study due to read out in Q2 this year. The ACACIA data is a Phase III study that is going to read out in Q2, and it follows from the REDWOOD Cohort 4 data already presented and published.

Here, you can see the 12-week data, meaningfully large increases in KCCQ and reductions in NYHA functional class, large, almost unprecedented increases in symptom burden relief in this REDWOOD Cohort 4 Phase II data and even out to 96 weeks, demonstrating durability as presented and published.

And we believe that we've designed the right experiment in over 500 patients, monitoring the patients coming into the study. We're monitoring things like standard deviation, safety, all the things you'd expect of us in the blinded data, and we're bullish and optimistic about what could be the promise of Myqorzo or aficamten in this study as we expect its results to be top line in Q2.

And again, ongoing clinical trials, omecamtiv in a confirmatory Phase III study that will continue in 2026, ulacamten in a Phase II study, at least 2 cohorts and possibly data by the end of the year in that study. The hits they keep coming at Cytokinetics as we continue to advance pipeline. At the same time, we're building the commercial business.

How do we do that with our financial resources with thanks to disciplined OpEx and spending in 2025 and also deals we did in 2024 and 2025, largely nonequity dilutive, we've been able to build a balance sheet of over $1 billion and with access to additional capital from Royalty Pharma, as you can see here.

We think we're being prudent and good stewards of shareholder capital as we build the business and turn the page on to the narrative and deliver on the expected milestones you see here on the right-hand side of the slide.

Most important amongst these are a successful U.S. commercial launch with good velocity demonstrating that we can get by the end of the year, at least 50% of new patients, at least parity access and all the metrics that are defining of a strong momentum.

And at the same time, submitting in Q1 this year, the supplemental NDA based on MAPLE data for a potential label expansion by the end of the year, reflecting the MAPLE data. And in Q2, hopefully, a readout of the ACACIA study, opening the gates hopefully, to what could be further expansion of the commercial opportunity on nHCM and all the while, while continuing the other clinical trials with potential readouts to follow.

We believe we delivered on what we promised in 2025. We expect to do the same thing in 2026 and enable the runway to our Vision 2030, already well in hand as we are making Myqorzo available in multiple countries for what will be over 100,000 patients by 2030 and at the same time, augmenting pipeline, expanding pipeline, bringing other potential new medicines to patients, consistent with mission, purpose and values.

With that, thank you. Thank you for following Cytokinetics, your interest all these many years. We're pleased to be able to turn the page on to the important new narrative. And with that, maybe we can be addressing some questions. I'm joined today by our Chief Commercial Officer, Andrew Callos; our Head of R&D, Fady Malik, who -- it's his vision we've been following in this science for over 25 years; and Sung Lee, our Head of Finance, CFO. All 3 of them will join me in answering Tessa's questions. Thank you.

Okay. Terrific. So I thought I might start the conversation here on how you think about what the opportunities are and any potential challenges as you start the launch of Myqorzo? How has the Bristol launch of Camzyos informed your launch plans?

So I'm going to turn it over quickly to Andrew to answer that question. But firstly, I want to say that I think BMS has done a very good job launching Camzyos. And over the last 4 years, as I mentioned, they're going to do north of $1 billion in sales in 2025.

But like any cardiovascular launch, it's been primarily linear and where a next-in-class that aspires to be best-in-class can make a meaningful difference. Andrew has been a good student. He's been with us now over 4 years, thinking about how to go to market, and I think his team is well poised to meet the moment. Andrew?

Yes. Thanks for the question, Tessa. So in terms of opportunity, there's at least 80% of the market available, meaning symptomatic oHCM patients that are not on a CMI. In terms of the Bristol launch and what it's informed, I think first and foremost is that our campaign highlights the areas of difference.

There's 3 that we really will be focusing on. One is around rapid and sustained reduction in obstruction and symptom improvement. Two is the ability and this adaptable titration schedule. And three is that there were no treatment interruptions or symptoms of heart failure in our clinical trial. You saw the campaign move forward. So that's one of the key areas.

The second key area is that our patient support program and our REMS program are -- provide a consistent and positive experience for patients and HCPs. We had patients and patient organizations involved in our campaign, involved in designing our patient support and how we communicate our REMS to make sure it resonates with patients. I think that's another kind of key area of information.

So having a REMS program that's adaptable, automated and provide that good user experience with that clinical differentiation, with that patient support. And then the last is how we designed our model, which Robert alluded to, which is a one-to-one point of contact for a physician and a rep and a one-to-one point of contact for a patient and a navigator. They are the key areas that we were informed in terms of the Bristol launch.

Okay. Great. And as we stand here today, how would you say the level of awareness is around Myqorzo at this point across physicians and institutions? Are there any key gaps you think you need to fill?

So when we looked at an ATU, which looks at exactly that question, our awareness levels, especially with that 700 -- those 700 physicians or 80% of the market are extremely high going into our launch.

We've been in the field for several months. We've had several thousand interactions already. We'll get to those 700 physicians by the end of this month with our field force and medical colleagues. We've already been to about 40% of them in the first week.

And we're already learning that a number of those folks have been awaiting the launch of Myqorzo to be prescribing. They've been following the literature, following the presentations. Fady, you may want to speak to the number of manuscripts that published in 2024 and 2025, adding to the literature for this category.

Over the last 2 years, we've probably published close to 20 papers, I think, not knowing exact numbers, but been very prolific in terms of both expanding on the analysis of SEQUOIA, but also obviously presenting earlier last year, the MAPLE data and subsequent analysis of that.

And then finally, analyses from the open-label extension FOREST, which look both at long-term effectiveness and safety in the o and nHCM populations. Importantly, I think some of that long-term nonobstructive HCM information is relevant to how we think about ACACIA.

A company like Cytokinetics that's both a pioneer and a leader in this area of pharmacology as we have been for so many years, develops relationships with the top of the pyramid influencers, cardiologists and also advocacy groups. And that confers to us a competitive advantage as we go to market. Those relationships, that history, that credibility and report, we expect will serve us well.

So zooming ahead at this time next year, what do you hope to have accomplished with the Myqorzo launch versus what might still be untapped in your kind of year 2 and beyond?

In terms of launch, you saw those 3 metrics that Robert showed, breadth of prescribing, depth of prescribing and number of patients. We'll report on those 3 metrics at our quarterly earnings call longitudinally. Our expectation would be that we increased depth of prescribing, meaning that those 700 physicians and 2,000 that prescribe today, our market share is greater than 50% for new patients.

The second thing would be breadth of prescribing. There's 8,000 existing physicians who treat HCM, but don't use CMIs. So starting to get more prescribers and broadening that prescriber base. And the third thing is that to do at least as well as Bristol did year 1 in terms of number of patients on therapy or greater.

The number, as I recall, is around 3,800. So our expectation that we -- again, we would do that or better. We have MAPLE in the label by the end of the year. And obviously, we'll know ACACIA and whether or not we're in process of filing ACACIA to continue to grow the category and have category leadership in terms of new-to-brand prescriptions.

Okay. Great. And can we talk a little bit about quarterly dynamics when it comes to payer? And can you just remind us in this population, the Medicare and commercial dynamics here? And what percent of the business you expect each of those segments to make up?

So there was a slide in the deck that showed mix of payers. The category right now is about 55% to 60% Medicare. Medicare, our expectation is we will have comparable access in Medicare. Most of Medicare is not formally covered because of the Inflation Reduction Act.

And therefore, although it's almost 60% of prescriptions, that goes through medical exception. We're expecting the same, and we'll provide support as we can through medical exception. About 35% will be commercial. Our expectation is towards the end of the year, we will have comparable access in commercial.

You can support commercial patients with a bridge program up to 12 months of free drug as we're helping support patients get on paid therapy as well as co-pay assistance once they are on paid therapy. Our expectation, again, is that we're differentiating and growing the market and competing on clinical difference, REMS and patient support, and we're not differentiating on pricing and access, meaning that there'll be comparable pricing and access.

Okay. And do you think all institutions will prescribe both Myqorzo and Camzyos? If they don't, why not?

So I mean Camzyos has been on the market for nearly 4 years. There's many patients who have benefited from Camzyos. I think it's too early to tell and answer that question in terms of all, but I certainly expect that having 2 options on the market that many physicians will use both based on what they see fit for physicians.

Many are comfortable with the workflow around Camzyos, and they've kind of learned it. So I would expect that. I also would expect that over time, that Myqorzo would be the market leader.

The flip side to that question is, why aren't more patients on a cardiac myosin inhibitor today still being over 80% of the market eligible for treatment and what's holding them back. And our market research would indicate that the things that we believe Myqorzo can deliver should be enabling of many more patients treated for an experience that would be supportive of more symptom burden relief.

Okay. Just looking at the time here. So I'd love to turn the conversation here and talk a little bit about the expansion potential here in nonobstructive HCM. Fady, maybe this is a question for you. What are all the levers that you're thinking about that drive your confidence that you'll have a successful study here for ACACIA?

I think it's really the careful development that we did from Phase II to Phase III. We started Phase II studying aficamten in a nonobstructive population in the REDWOOD trial, piloting a dosing scheme that we intended to employ in Phase III very successfully. Those patients demonstrated, as you saw on the slide in Robert's presentation, improvements in KCCQ, improvements in NYHA classes as well as improvements in NT-proBNP, a biomarker of cardiac wall stress.

Those patients then went on to the open-label extension and demonstrated the same improvements now sustained over 96 weeks as we've presented recently. In designing ACACIA, we employed the same dosing paradigm, so that we could be confident that patients would tolerate aficamten that we wouldn't have an excessive number of treatment interruptions or discontinuations. We haven't had any patients discontinue from the open-label extension.

The other in terms of conduct is getting to trial sites where we had a lot of confidence based either on their performance in our prior trials or recommendations from some of our experienced steering committee members or site visits ourselves, qualifying those studies in terms of echo and CPET and training them on the endpoint of KCCQ, which is a patient-reported outcome, but actually, you need to carefully train the patients and the physicians in terms of how to administer it.

And then finally, monitoring the conduct of this trial ensuring that every patient that gets in is reviewed by our own medical team. The echocardiograms are consistent with nHCM that the rest of the case history is also consistent and just trying to get the highest quality patients enrolled.

And on a blinded basis, like are you able to tell us what you're seeing from a titration perspective or most of these patients getting up to the high dose?

Well, I can't tell you that because we're blinded to those sorts of data, obviously. I mean what I can tell you is that we monitor the variability in the endpoints because that's one of the aspects of powering the trial.

And we've noted to date, and I've said this before, that the variability remains within our expectations and within what we assumed when we powered the trial. And based on all those things, I think we have a good power to resolve a meaningful change.

How do you think about key risks to the study? Like what keeps you up at night?

Well, there's always unpredictable things that happen in clinical development, unpredictable placebo effects or other things. I think we've tried to minimize all of those things through the course of the trial. And I feel -- I guess, I sleep pretty well, but you never know what can happen.

But I think, again, given our experience now having conducted SEQUOIA, MAPLE, other trials using these endpoints, I think we've become very good at ensuring that these things go smoothly.

Perhaps it's worth noting that the same team has been in place for the design and conduct of all of these studies. So whether you're talking about SEQUOIA or MAPLE or FOREST or ACACIA, all of those studies, and we've already seen very high integrity data coming from the previously reported studies, the same team designed and conducted ACACIA.

I might also note, it's a team of a very high degree of expertise with internationally recognized HCM experts, cardiologists that have been working with nHCM, as Robert points out now for half a dozen years and all of them working together and ensuring best conduct of this trial.

Last question for me is just how does the launch curve look with and without the expansion into the nonobstructive population?

So in our research we've done is that -- the launch curve that I described in our expectation was based on obstructive only independent of ACACIA. So efficacy wasn't positive. ACACIA is positive, there is a halo effect, if you will, even before approval in that a third data set, MAPLE being the second, SEQUOIA being the first, highlighting and reinforcing that safety and efficacy.

So there certainly is a bump in both penetration, i.e., more patients treated as well as share. Once ACACIA would launch, then the patient population overall doubles because, again, it's about a 50-50 mix. And it certainly then learning the label, the safety, assuming that they're similar would reinforce even greater share for Myqorzo as the single agent that would be approved in both obstructive and nonobstructive patients.

All right. Terrific. Thank you so much to the entire Cytokinetics team and everyone for joining.

Good day, everyone. My name is Leila, and I will be your conference operator today. At this time, I would like to welcome you to Cytokinetics conference call for the FDA approval of MYQORZO. [Operator Instructions].

At this time, I would like to 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 today's call to discuss the FDA approval of MYQORZO for symptomatic obstructive HCM. Today, I'm joined by my colleagues, Robert Blum, President and CEO, who will provide introductory remarks; Fady Malik, EVP of R&D, who will review the label, the REMS and the data that support the approval; and Andrew Callos, EVP and Chief Commercial Officer, who will discuss our U.S. commercial launch plans.

Today's presentation is accompanied by slides, which are available to download within the webcast. Please note that portions of the following discussion, including our responses to questions, contain statements that relate to future events and performance rather than historical facts and constitute forward-looking statements. Our actual results might differ materially from those projected in these forward-looking statements. Additional information concerning factors that could cause our actual results to differ materially from those in these forward-looking statements is contained in our SEC filings. We undertake no obligation to update any forward-looking statements after this call.

With that, I'll turn the call over to Rob.

Thank you, Diane. At Cytokinetics, our mission is to bring forward new medicines to improve the health span of people with devastating cardiovascular and neuromuscular diseases of impaired muscle function. With today's news, we've taken an important step forward towards successfully realizing that mission. Today, the U.S. Food and Drug Administration approved aficamten for the treatment of adults with symptomatic obstructive hypertrophic cardiomyopathy to improve functional capacity and symptoms. Aficamten will be available under the brand name MYQORZO. This is indeed an important milestone, first and foremost, for the oHCM community that we serve and for which there is still a high unmet need.

It's also a major achievement for Cytokinetics as we celebrate the approval of our first medicine, fulfilling our promise to patients to transform our science into medicines to make a meaningful impact on their lives. Today's accomplishment reflects years of dedication to rigorous research and development as well as diligent commercial planning, all underscored by our unwavering commitment to patients and a belief that our innovative science can positively change lives.

I'd like to express my gratitude to the many people who made this possible, our employees, clinical trial investigators and site staff, partners, investors, disease awareness advocates and most importantly, the patients who have supported and inspired us every day on this journey. As we celebrate this achievement, we remain focused on the future, ensuring access, deepening our engagement with the HCM communities and advancing the other programs in our pipeline with the same purpose and the same passion that brought us here today.

I'm pleased that the approved label and REMS reflect the distinct characteristics of MYQORZO with a straightforward, flexible dosing regimen, no requirement for drug-drug interaction monitoring and a predictable safety profile. In designing and developing MYQORZO, we've been purposeful since the start. Our scientists pioneered cardiac myosin inhibition as a therapeutic strategy for HCM, and we designed MYQORZO around certain drug properties intended to maximize its benefit risk profile. Through an extensive preclinical program, we engineered MYQORZO to achieve a predictable exposure response as well as rapid onset of action and reversibility. And our clinical development program elaborated on how these properties contributed to the safety and efficacy of MYQORZO in patients with oHCM. We believe that today, with the FDA-approved label and REMS for MYQORZO, we have delivered an innovative medicine that advances treatment towards these objectives.

Now we're eager to turn the page to bring this medicine to patients with a label that we believe is anchored in flexibility, ease of use and convenience for both physicians and patients and accompanied by a tailored and manageable REMS program based on the inherent characteristics of MYQORZO. Our years of planning and commercial preparations have readied us for this moment, and we're well positioned to bring MYQORZO to patients across the U.S. with oHCM.

All of the work that led us to today and the work still to come has been inspired by people living with oHCM and their loved ones. Their courage in the face of uncertainty, their persistence through challenges and their unwavering hope fuels all that we do. They are our source of strength and our North Star, guiding us toward what matters the most, making a meaningful difference in their lives.

Now I'll hand it over to Fady to speak about the FDA-approved label, the REMS and the clinical trial results that supported this approval.

Thank you, Robert. Today is indeed a historic moment for patients and for our company. I'd also like to extend my gratitude to the patients who participated in our clinical trials as well as the investigators, clinical trial staff, partners and of course, my colleagues who contributed to the discovery and development of MYQORZO.

HCM is the most common inherited heart disease. In HCM, the heart muscle abnormally thickens, which causes the inside of the left ventricle to become smaller, stiffer and less able to relax and fill with blood. In oHCM, the thickened heart muscle and mitral valve narrow the left ventricular outflow tract, limiting the heart's pumping function. Patients experience reduced exercise capacity and symptoms, including chest pain, dizziness, shortness of breath or fainting during physical activity.

MYQORZO is an allosteric and reversible inhibitor of the cardiac myosin motor activity. MYQORZO reduces the force generated by myosin at the cardiac sarcomere, which contributes to the pathophysiology of HCM. In patients with oHCM, myosin inhibition with MYQORZO reduces cardiac contractility and left ventricular outflow tract obstruction.

MYQORZO is now approved for symptomatic adults with oHCM to improve functional capacity and symptoms and is available at 5-, 10-, 15- and 20-milligram tablets. This FDA approval is based on the results of SEQUOIA-HCM, and those results are reflected in our medicines' label. The Phase III clinical trial showed that adults with oHCM treated with MYQORZO for 24 weeks significantly improved exercise capacity, increased peak VO2 by 1.7 mls per kilo per minute compared to placebo with a p-value of 0.000002. This treatment effect was consistent across all prespecified subgroups, including patients receiving beta blockers. Significant improvements, all less than -- p less than 0.001 were observed in each of the 10 secondary endpoints.

Patients treated with MYQORZO also had substantial reductions in symptom burden, including a 7-point improvement in KCCQ, and 34% more patients improving by at least 1 NYHA functional class compared to placebo.

MYQORZO was also associated with substantial improvements in post-Valsalva left ventricular outflow tract gradient with 49% of patients achieving an LVOT gradient of less than 30 millimeters of mercury compared to 4% on placebo as well as an 80% reduction in NT-proBNP, a biomarker of cardiac wall stress. MYQORZO was well tolerated with no instances of clinical heart failure or treatment interruptions due to low ejection fraction.

Treatment-emergent serious events -- adverse events occurred in 5.6% of patients on MYQORZO and 9.3% of patients on placebo. Core laboratory echocardiographic LVEF was observed to be less than 50% in 5 patients or 3.5% on MYQORZO compared to 1 patient or 0.7% on placebo. Hypertension was the only adverse reaction occurring in more than 5% of patients and more commonly on MYQORZO than on placebo, occurring in 8% of patients on MYQORZO compared to 2% of patients on placebo. As described in the label, MYQORZO-associated increases in blood pressure are consistent with the relief of LVOT obstruction and improved cardiac output.

The label for MYQORZO is reflective of the clinical data as well as the intrinsic properties in pharmacokinetics engineered in its development. The label includes a boxed warning for the risk of heart failure. This is consistent with our expectations and aligns with the mechanism of the drug. The risk of heart failure can be mitigated through echo monitoring, which I'll speak to in a minute.

Before that, I want to note what the label does not include. There are no drug interactions included in the boxed warning. The label carries a single contraindication for rifampin, an antibiotic used to treat tuberculosis, and a strong inducer of CYP P450 enzymes known to interact with many commonly used drugs. There's no warning around embryo-fetal toxicity nor are there warnings regarding the use of MYQORZO alongside oral contraceptives.

Dose adjustment of MYQORZO is explained with one straightforward table that's based on our experience with dosing in both SEQUOIA-HCM and the open-label extension, FOREST-HCM. All patients will initiate MYQORZO on the lowest dose, 5 milligrams. Following treatment initiation, patients may titrate dose with an echo assessment within 2 to 8 weeks of initiation or subsequent increase in dose until the patient reaches their target dose.

Depending on a patient's individualized maintenance dose, the number of titration phase echo assessments could range from 1 to 4 following initiation of therapy for a maintenance dose of 5 milligrams or 20 milligrams, respectively. Once the patient reaches their target dose and enters the maintenance phase, echoes are required approximately every 6 months for patients with an LVEF of 55% or above and every 3 months for patients with LVEF between 50% and 55%. We anticipate that the majority of patients will require echo assessments every 6 months after the establishment of their maintenance dose.

Notably, treatment interruption for LVEF less than 50% is not required unless EF falls below 40%, when treatment is interrupted for at least 7 days and can be resumed at 5 milligrams, when LVEF is greater than or equal to 55%. This approach mirrors the protocol in SEQUOIA-HCM and reflects the wide therapeutic window and rapid reversibility of MYQORZO.

As Robert mentioned, the FDA required a REMS to mitigate the risk of heart failure due to systolic dysfunction. The REMS is designed to ensure adequate education, safe use and monitoring for risk of left ventricular systolic dysfunction and heart failure with MYQORZO. The REMS is tailored to the label dosing and administration of MYQORZO and does not include the need to monitor for drug-drug interactions.

Within the REMS for MYQORZO, there are 4 elements to assure safe use, also referred to as ETASU. They are: that prescribers become REMS certified; that patients enroll in the program and comply with echo monitoring requirements; that pharmacies become REMS certified and dispense only authorized patients; and that wholesalers and distributors only distribute to certified pharmacies.

As the REMS is intended to implement labeling, the REMS for MYQORZO follows the dosing and administration instructions in the label, allowing for echoes in the titration phase to occur in a 2- to 8-week window following the initiation or titration of MYQORZO, providing flexibility in scheduling for both patients and their care teams. There's no screening for drug-drug interactions required.

As MYQORZO reflects the latest innovation in this market, its FDA-approved label and accompanying REMS will offer a new treatment experience for physicians and patients. Physicians can escalate dose of MYQORZO with confidence to reduce the LVOT gradient and treat patient symptoms, and every echo informs either a change in dose or entry into the maintenance phase. The only contraindication is to a rarely used drug, rifampin, and there are no clinically common drug interactions complicating the use of MYQORZO.

Overall, we're very pleased with this FDA-approved label as it reflects the bespoke design properties we've carefully engineered when developing MYQORZO, and the REMS has been designed such that it can be incorporated into clinical practice with minimal burden.

Now I'll turn it over to Andrew to review our U.S. commercial launch plans.

Thanks, Fady. I'm excited to review the U.S. commercial launch plans for MYQORZO. As Robert said, this is a major milestone moment for the company and one for which we have been planning over many years. I echo both Fady and Robert in the gratitude for the tremendous contributions and collaborations amongst many stakeholders that enabled us to reach this day.

For me, this moment is personal and speaks to mission and purpose. I joined Cytokinetics nearly 5 years ago to build our commercial organization, capabilities and launch our specialty cardiology franchise led by MYQORZO for many reasons. But one important reason is that I lost a close family member to HCM in 1989. It is extremely meaningful to have the opportunity to bring MYQORZO to patients living with obstructive HCM today, to raise greater awareness, to honor the legacy of my deceased family member and to make a difference in the lives of patients with obstructive HCM.

In the U.S., there's approximately 0.7 million to 1.1 million patients living with HCM. Among those diagnosed with HCM, obstructive HCM, or oHCM, has historically represented over 50% of cases. As diagnosis of non-obstructive HCM or nHCM has increased in recent years, overall prevalence rates for nHCM are now up to 60% with figures varying by region and study design, leading to our current estimate of a roughly even split of diagnosed HCM patients between oHCM and nHCM.

Within the oHCM population, about 200,000 people have been diagnosed, of which 110,000 to 130,000 are symptomatic. HCM diagnosis continues to increase over time, driven by a better awareness, approved CMI products and genetic testing.

Our market research supports our belief that MYQORZO is likely to achieve greater than 50% CMI preference share and grow the cardiac myosin inhibitor category based on 3 launch drivers: clinical evidence; our bespoke patient services and support; and the REMS.

First, the clinical evidence from SEQUOIA-HCM, the pivotal Phase III clinical trial, and FOREST-HCM, the open-label extension showed that treatment with MYQORZO led to rapid and sustained reduction in obstruction and improvement in symptoms, allow for dose titration as early as 2 weeks with an adaptable monitoring schedule and did not lead to treatment interruptions or clinical heart failure events.

Second is our approach to patient support services. Our patient support services program is designed to help patients through their treatment journey. Our program is built on compassion and integrity, and that means striving for equitable access so that no one is left behind when it comes to care.

Our patient support program called MYQORZO & You provides a single point of contact for patients, delivering a consistent but tailored user experience. The program also enables seamless integration with our systems for data analysis. The program is designed to build empathetic connections with patients and providers. In doing so, we believe we will create a positive ecosystem of care to help patients get and stay on treatment. In a moment, I'll speak more about this specific offerings within MYQORZO & You.

The third driver is the REMS. The MYQORZO REMS allows for the flexibility to titrate as early as 2 weeks with echo assessment within the 2 to 8 weeks following dose initiation and any subsequent dose change. Importantly, a patient's dosing may be titrated after each echo with no delay. What this means is that for a patient on 10 or 15 milligrams, they can expect to reach their target dose as quickly as 4 or 6 weeks, respectively. Once the patient is in the maintenance phase, echoes are required every 6 months for patients with LVEF greater than or equal to 55% and no monthly DDI screening calls with pharmacies before dispensing.

Each of these drivers have been extensively researched and designed to help propel our launch and encourage uptake, not only towards motivating the existing oHCM specialists and prescribers, but also in expanding the prescriber base and market penetration of the category. Our commercial launch strategy is designed with all this in mind, and we feel confident in our ability to translate this potential into strong uptake and long-term growth.

As I mentioned, with the approval, we are launching MYQORZO & You, a personalized support program for patients prescribed MYQORZO. The program will offer the following: support with insurance coverage and reimbursement; a free trial offering for government -- for eligible government-insured patients; a bridge program providing up to 12 months of free drug for eligible commercial-insured patients who are facing delays in insurance coverage; a co-pay savings program to provide financial assistance to eligible commercial-insured patients to reduce out-of-pocket costs; and the patient assistance program offering a free supply of MYQORZO for eligible patients meeting certain financial criteria. In providing this bespoke and comprehensive support program, we hope to ease the burden on patients and help them to get the care they deserve.

Another key work stream we began pre-approval, and that continues as our engagement with payers. As we've shared, we've been engaging with payers for quite some time, ahead of this FDA approval, to educate them on the evidence from our clinical trial as well as the clinical and economic burden of obstructive HCM. In fact, through the past few years, we've interacted with every major payer ahead of this approval. Now post approval, we plan to meet again with all targeted payers within the first quarter of the year to discuss the value proposition for MYQORZO.

As we work to secure access, MYQORZO & You will provide support for prior authorizations and medical exceptions for both commercial- and government-insured patients. Our goal is to reach parity access with criteria coverage consistent with our clinical evidence, which we believe we will achieve by the second half of 2026.

Of course, to fuel this launch, we rely on our sales team. We are pleased to have a very experienced team of roughly 125 people. They have an average of over 20 years of industry experience, 14 years of cardiovascular experience. They have brought a great expertise in existing relationships that we're confident will create strong launch momentum and velocity, and they will be fully trained and ready to hit the ground running.

We are pleased to share that MYQORZO will be available in the second half of January. Immediately in the new year, ahead of that date, our cardiovascular account specialists and field-based medical colleagues will be deployed with around 100,000 accounts and initial hire emphasis -- with initial hire emphasis on centers of excellence and existing CMI writers. In advance of product availability in January, we will announce price, which we have previously discussed will roughly be in line with current pricing of the category. We are excited and very well prepared to launch MYQORZO in the United States and redefine the future for people living with obstructive HCM.

Now I'll hand the call back to Robert to close.

Thank you, Andrew. Today, we've demonstrated that we've been able to translate our legacy of innovative science into an FDA-approved medicine for patients. And now we're entering a new era of care for patients with oHCM.

With this approval, Cytokinetics is also beginning a new chapter in our own journey. MYQORZO represents our first approved medicine in our emerging specialty cardiology franchise. However, today is not the finish line. It defines a new starting point as we seek to build an enduring global franchise of cardiac muscle modulators, not only within HCM, but in adjacent and synergistic indications.

As we announced early this week, MYQORZO was also approved in China for the treatment of oHCM. And last week, the CHMP of the EMA adopted a positive opinion recommending marketing authorization in the EU for MYQORZO, and a final decision is anticipated from the European Commission in the first quarter of 2026. As such, we've dialed up our commercial readiness activities in Europe and to enable launch in the second quarter of next year.

All of this is guided by our Vision 2030, which outlines our ambitious goals to become the leading muscle-focused specialty biopharma company intent on meaningfully improving the lives of patients through global access to our innovative medicines. The FDA approval of MYQORZO today marks important progress towards realizing that vision. With this forward momentum, we intend to positively impact patients with oHCM while creating a prosperous future for our company and our shareholders.

Before we open up the call to questions, I'd like to again share my gratitude to those who made today possible, including our investors. I'm deeply appreciative of the dedication that has led us to today and for your continued support as we move forward from here.

Operator, with that, we can now open up the call to questions, please.

[Operator Instructions] First question will come from Akash Tewari with Jefferies.

This is Zaki on for Akash. Congrats so much on the approval. Just a question on the echo window and the flexibility around that. So it looks like 2- to 8-week flexibility. What have you seen or heard from docs who are prescribing Camzyos and the flexibility around that window? And how much is it cutting into adherence for patients when they can't meet their scheduled echo timing?

So thank you for the question. We'll be careful not to make comparative statements as it relates to MYQORZO and Camzyos, but we can speak to market research and where we think there could be an enablement with aficamten now called MYQORZO. Maybe I'll ask Andrew to comment on the market research and Fady to add any color if he likes.

Thanks for the question. So from a -- I'll go backwards. From an adherence point of view, we don't have specific data that fine around adherence rates. I can only say that adherence in this category is much higher than other cardiovascular categories, and we're expecting the same.

And relative to the window, we do know that from our market research that uptake across a broad prescriber base, one of the reasons that it has been somewhat limited, is because of ETASU REMS. The second thing we know of the window is that those that prescribe, especially those that prescribe high volumes, need to create workflow around a more precise schedule, and having a more adaptability will allow easier scheduling ultimately. I think we'll see what that translates to in the real world as compared to market research. I think much of that is intuitive, but that's what we've been hearing.

I don't know, Fady, if you want to add anything?

Yes. I'll just add that scheduling echoes is always something that is resource limiting, and we think this is advantageous that patients essentially have a 6-week window. It not only helps the sites fit patients into their schedule, but also helps patients fit these echoes into their lives. And I think that's something that will be very appealing to patients and physician practices.

Our next question will come from Gena Wang with Barclays.

This is [indiscernible] on behalf of Gena Wang from Barclays. Congrats on the early approval and the strong label.

So for the questions. I want to ask about the drug-drug interactions -- highlighted that there's no -- that drug-drug interaction in the warning box and no monthly screening. So could you further elaborate especially in the initiation phase when physicians first prescribe this drug, is there a required pharmacy drug interaction counseling? So could you just give us more color for the differentiation in this part?

Sure. I can do that. When the physician introduces a patient to a new drug, they should obviously educate them on the label aspects that are relevant to them. And so -- but there's no formal requirement per se, if you will. The pharmacy doesn't need to counsel the patients. It's not a required element of the REMS to either initiation or during maintenance dosing to counsel patients on drug interactions. But it is obviously -- it's important for anybody taking any medicine to be counseled on any relevant drug interactions. We just find -- in the case of aficamten, there are very few drug interactions and really none to common clinically used medicines.

Your next question will come from Tess Romero with JPMorgan.

Congrats, Robert, Fady and to the whole team on this approval and all the work it took to get to here. Can you give us a little bit of a preview of what's in store for us at our JPMorgan Healthcare Conference next month from Cytokinetics? Congratulations.

Thank you. Yes, indeed, it's going to be, I think, a very important conference for us. We're very pleased with already what appears to be our best schedule ever. And what I can say is that we intend at that conference to be showcasing and highlighting a lot of important developments and announcements associated with this approval. We're going to go into some meaningful details that will shine a light on operationally how we expect to go to market, included amongst which will be matters associated with pricing and other activities around building for the patient experience and timing with regard to product availability. So we do believe that we're going to be asking folks to be mindful in paying attention to those communications at the conference. We think it will be showcasing why we think aficamten now called MYQORZO will make a big dent in the universe for patients with oHCM.

Okay. We'll move on to Roanna Ruiz with Leerink.

So for me, I was just curious, could you elaborate on some of the remaining steps that are left for payer engagement now that you have MYQORZO's label in hand? And how quickly could payers update their formularies and decisions to offer coverage of MYQORZO?

Thank you. We'll ask Andrew to comment on that, please.

Thanks for the question. So we will get to the most critical payers in the month of January. As I mentioned, we'll get to all target payers in the first quarter. For the first several months, we will primarily be getting access through medical exception. There will be some payers who will cover immediately, but that will be the minority. And that -- the answer to that, I think, varies based on payer and how quickly they take to review that category. So I think we can give a good update on where we are with that probably in our February earnings call.

Our next question will come from Paul Choi with Goldman Sachs.

Robert, congratulations to you and the team. As we look at the indication statement on the label, there's no specific requirement for prior therapies. And so I'm just curious, as you've engaged in your pre-approval conversations with payers, just sort of what the receptivity to potential frontline utilization is for MYQORZO.

So do you want me to answer that, Robert?

Yes, please.

So the label in the clinical trial section does describe SEQUOIA and beta blocker. Most payers are going to restrict label relative to study design. So it does -- although the indication statement doesn't show that the study itself did include beta blockers, our expectation is that beta blockers will be required, either a patient has tried a beta blocker or can't use a beta blocker, and the physician has attested to that. So that would be our expectation relative to beta blockers for now.

Our next question will come from Salim Syed with Mizuho.

Great. Congratulations, guys. Label looks great. Andrew, one from us on the commercial side. Did I hear you correct? You said a 50% preference. Was that the correct number?

What I said was we believe that we will have over a 50% preference share over time in the CMI category.

Okay. Got it. Just curious, what was that -- when was that market share data calculated? What was it calculated on? Was it based on -- like did the physicians putting in that data have access to a profile that's similar to this label? And just the other piece here that would not be preferred to go to AbbVie, what was the color that you got from there that maybe you can now counter detail? Like, why wouldn't anybody prefer Minerva here?

So the market research actually was done several times with an evolving label. We did do research very specific to this label as well. And in each instance, we were getting a very similar answer of a preference share. I won't give a specific number, but it was a good bit over 50%. And we do show a profile, i.e., like a summary label, if you will, based on -- but blinded relative to products. And that's what we did.

I think in terms of what we heard in the research for Minerva is I think physicians are telling us they're happy with Minerva. They're happy with the clinical profile, the efficacy, et cetera. So I think we'll have to see over time what happens in the real world once physicians truly understand the differentiation. And we were out there with our field sales organization as well as our medical organization. But I certainly expect that Minerva will continue to get -- physicians prescribing patients is certainly a good drug that works well.

Congrats again.

Thank you, Salim.

Our next question will come from Cory Kasimov with Evercore.

This is Josh Chazaro on for Cory. Congrats on getting this over the finish line. The question is, what kind of launch metrics do you expect to give investors with the second half of 2026 -- or second half of January 2026 launch?

Yes. So we're going to echo some things we shared on our last earnings call. And obviously, things evolve more over time. But I'll ask Andrew to reaffirm those things that we're going to be pointing to initially.

So we will certainly share the prescribing breadth, meaning the number of HCPs who are active prescribing and depth, meaning the volume of prescribing as well. Our goal would be to do well in those that are currently writing CMIs, but also to expand prescribing, and that's essentially what we mean by breadth and depth. We'll also talk about the volume of patients or the number of patients on MYQORZO, and we'll share that kind of longitudinally through the year. We'll probably share some metrics as we go quarter-to-quarter, but those 3 metrics, breadth, depth of prescribing, and volume of patients, is what we'll share continuously through 2026.

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

Congrats. Just wondering if you could speak to your plans to now submit the MAPLE data to expand the label and ultimately, what you think that can do to the launch over the midterm?

Thanks, Jason. So we're now with this approval announced today, going to move very swiftly to submit for what could be an expanded label, inclusive of the MAPLE data, a supplemental NDA submission promptly early in 2026. I'll ask Andrew to comment on how he thinks it may factor into commercial adoption.

So MAPLE and the commercial adoption. One is MAPLE, is in the public domain. Our medical colleagues will have MAPLE and be able to answer questions and describe MAPLE to physicians. But essentially, what we learned in our research has been confirmed by kind of anecdotal conversations is that MAPLE really highlights the lack of efficacy of beta blockers if you -- if one looks at biomarkers or relief of obstruction, and MAPLE should -- our expectation is MAPLE will also influence guidelines, if not in '26, then in '27.

And the combination of a second trial, confirming efficacy, safety, showing data that's from a clinical trial that beta blockers are impacting gradients, and if our expectation is correct and that MAPLE or beta -- is added -- or at least the results are added in influencing guidelines, I think the combination of those things, it would increase prescribing beyond the current prescribing base. The current prescribing base from the data we have is about 700 physicians or about 80% of the prescribing today as compared to the over 30,000 cardiologists in the market and 10,000 cardiologists who actively treat and -- existing patients. When you look at claims data, that's about 80% of the market is those 10,000.

Your next question will come from Kripa Devarakonda with Truist.

Congratulations on the approval. In the initial launch, I was wondering if you can help us understand a little bit about what your plan for the distribution footprint is expected to be. [indiscernible] you have at launch, what percent of HCM centers of excellence, for instance, would you expect to cover within the first quarter of launch?

Sure. So you referenced distribution, but I think maybe you're asking more about promotion, coverage, reach and frequency.

One was distribution footprint and the other one was HCM centers of excellence covering -- coverage of centers of excellence. Yes.

So we'll elaborate more on these activities in January. But maybe, Andrew, you can talk about how we're creating a more bespoke distribution channel for the benefit of patients and how we're thinking about coverage.

So associated with the REMS is that pharmacies need to be certified. We have 2 specialty pharmacies that will be certified and able to distribute. We will have a hub to support patients and then large hospital systems or IDNs, integrated delivery networks. Once they have an agreement in place, they'll also have access to distribute product over time. Our expectation is that those 2 specialty pharmacies will be right away, and we'll have well over 20 IDNs probably by second quarter that can also distribute drug. In terms of HCM centers, we will get to every HCM center in the first quarter.

Your next question will come from Joe Pantginis with H.C. Wainwright.

Huge congratulations. So my question is, besides the payers, what do you consider to be the rate-limiting steps with regard to the launch, for example, the rapidity of getting docs certified? Or anything else you'd like to add? Congrats again.

Yes. I think given this label, given this REMS, we believe that this should be enabling of a rapid adoption for aficamten enabled by which we engineered into the product from the beginning, things like we mentioned pertaining to convenience, ease of use and flexibility. But to your specific question, maybe Andrew can comment on those things that ultimately have to be processed and what may be cycle time associated with that.

Yes, Joe, thanks for the question. So one is payer and you -- besides payer, likely, aficamten is differentiated. We have to make sure physicians and their offices understand the differentiation. The workflows associated with the REMS has to be administered as well. So that's probably going to be the biggest rate limiter. I don't think it's going to be a very big rate limiter, but following payers, making sure physicians understand the difference and then putting that workflow in the REMS, giving that adaptability, et cetera, that will probably take a little bit of time. But when I say, "a little bit of time," I'm talking weeks or maybe a month or 2, not much longer than that.

Our next question will come from Martin Auster with Raymond James.

My question has been asked and answered. Congratulations to you.

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

Congrats on that accomplishment. Have you guys -- maybe this question is for Andrew. What is the distribution of HCM patients, obstructive [ blockage ], patients that are under cardiology centers versus centers of excellence? And maybe also your color around this really flexibility and echoes, how that could actually be very helpful when we think about general cardiology practices?

Sure. Thanks, Yas, for the question. So are you asking how many patients are in centers of excellence versus outside of centers of excellence?

Yes, that's exactly right. Yes.

Your first question?

Yes.

Yes. So I don't know that we have that level of precise data. I can say that those patients that are currently treated with a CMI is probably right around 50-50 at this point, maybe slightly higher for non-centers of excellence, but -- and that number has been kind of growing outside that non-center of excellence.

In terms of the flexibility of echo, our market research would tell us. And I think it's fairly intuitive, if you can increase dose at every echo, if they have a little more adaptability of when you can perform an echo relative to a patient scheduling, that should allow for patients to get on the proper level of drug, from an efficacy point of view, very quickly and that very straightforward. Every time you increase dose, you do an echo. Once you're at the maintenance dose, you do an echo in the maintenance phase and for most patients, it's every 6 months. So I think what we heard in our research again is that's very straightforward and easy to understand.

Your next question will come from James Condulis with Stifel, Nicolaus.

Congrats on the approval. Just wanted to clarify something really quick on these echo windows and specifically in the maintenance setting. As I understand it with Camzyos, these echoes need to be done within sort of a 5-day window. For aficamten, including in the maintenance setting, it sounds like it's a 6-week window to get these echoes in. Is that right? Just wanted to clarify that. Congrats again.

Yes. In the maintenance space, the window is not 2- to 6-week thing, plus or minus a month at 6 months. So it gives you latitude on either side to generate some flexibility.

Your next question will come from Serge Belanger with Needham & Company.

Congratulations on the early Christmas present. I guess a question for Fady. I believe in the SEQUOIA trial, about 80% of patients were on the top 2 doses and maybe 50% were on the top dose. Just curious if you expect a similar distribution outside of the clinical trial setting.

Sure. What you commonly see in the clinical setting is that dosing is not as aggressive as is done in the clinical trial. I think we might see somewhat lower doses utilized in the real world. That's, I think, a likely scenario. It doesn't necessarily -- there's no reason not to push the dose as we did in the trials because those high doses -- the highest -- the highest doses were extremely well tolerated and also quite safe, and some patients are necessary to maximize efficacy.

So in the clinical setting, physicians can take more variables into consideration than they can in our clinical trial. I mean the clinical trial was driven primarily by gradient and ejection fraction. But in the clinical setting, physicians will probably take symptoms into account. And so patients that may be just above the thresholds for titration but are completely asymptomatic, they, for instance, may choose not to titrate them because you can't make somebody that's asymptomatic feel better. So I think there are rationale to believe that lower doses will be probably more common in the clinical setting.

Got it. Congrats again.

Thank you.

Thank you.

Your next question will come from Maxwell Skor with Morgan Stanley.

Congratulations, team, on the approval. So based on your conversations with physicians, I was just wondering, do you anticipate that the flexibility in monitoring and the risk mitigation strategy could facilitate broader use or able streamline REM requirement, basically unlock a certain group of patients that maybe physicians were hesitant to put on Camzyos? Are there any qualities or specifics within the label or REMS you'd like to call out?

So yes, most definitely, we believe that aficamten now called MYQORZO is -- with associated label and REMS going to drive not only category penetration more widely for more physicians to be prescribing for more patients, but we also expect that it should be enabling of preferential share. We've highlighted already today where we think those differences lie in attributes of MYQORZO, originally engineered into its design and development. Maybe we could repeat those for you. Would that be helpful?

Yes. Or if there's any you would call out that you think physicians are really focused on or you're excited about it being included.

Sure. So maybe I'll just ask Fady to highlight them again.

I mean I think, again, the label provides use cases for aficamten that will make it easier for physicians to implement. So maybe I'll just pick one in terms of women of child-bearing age. And in the case of women of child-bearing age, there's no contra -- or rather no warning with regards to embryo-fetal toxicity. Aficamten doesn't have to be discontinued prior to pregnancy. There's no pregnancy test prior to administering aficamten.

Those kinds of things, if you are practicing and taking care of those patients, should hopefully broaden access of those patients to aficamten, on a cardiac myosin inhibitor as opposed to where people might have stayed on the beta blocker or something that's clearly less effective. So we think there are -- and there are other things as well, some of this -- DDI, lack of DDIs that are common in terms of clinical importance. Those things, I think, all make aficamten something that can be implemented in patients where perhaps physicians were reticent before.

Maybe I'll just add -- maybe I can just add, rapid and sustained symptom improvement is one we hear a lot from physicians as well as very straightforward and easy-to-understand dosing.

Congratulations again.

Thank you.

Your next question will come from Leonid Timashev with RBC Capital Markets.

Yes. Congratulations again on the approval. I had a similar follow-up question to a few of the others. I guess on the maintenance echoes, patients over -- with an LVEF over 55%, every 6 months but between 50% and 55%, every 3 months. I guess based on your experience in SEQUOIA and FOREST, what percentage of patients fall in that 50% to 55% LVEF category? And then as you move into the real world, you mentioned already maybe less aggressive dosing. I guess, what do you think that percentage might be?

Yes. I mean, in our experience, it's very few patients. I can't give you an exact number in the 50% to 55% range, but probably single-digit percentage of the total number of patients. And so I don't expect it to be a burden, and it's not a requirement that they continue to be monitored at infinitum in that frequency. It's just that you just need to establish that they're stable there, and then you can move on to 6 months.

The other piece of it in terms of -- I'm not going to speculate what range of doses we'll see clinically. I just think that it's -- you see that with almost every medicine that's deployed that the doses tend to be a little less aggressive in the real world than they are in clinical trials. And that may be okay if there are patients who feel perfectly adequately treated. But I think we'll just need to wait to see what the real-world data looks like to be able to speak to that.

Your next question will come from Mayank Mamtani with B. Riley Securities.

Many congrats on the approval in U.S. and China and also the positive CHMP opinion. Sorry if I missed this, could you touch on how the label grant informs sort of your thinking on pricing and your expectation of proportion of patients getting on the patient assistance program within the initial few months?

And Andrew, I know this has been discussed before. Anything you can comment on your expectation for 2026, 2027 market penetration you're sort of working to get to relative to where we are today at the end of 2025?

Yes. So maybe I'll just start and ask Andrew then to elaborate. This label and also this REMS, we believe, are very reflective of what we set out when we designed and developed aficamten, enabling of what we see as an innovation in this marketplace. As such, when we think about our commercial strategy, it's incumbent upon us to be thinking about how we can drive broader adoption and be enabling of more physicians to be comfortable prescribing this cardiac myosin inhibitor for more patients.

So I'm not going to reveal our pricing on this call. You'll hear about that in January. But you should expect everything we're doing reflects that same level of innovation in connection with how we go to market, how we engage physicians and patients ultimately for the benefit of wider adoption.

Andrew, anything you want to comment on specifically?

No. I mean I think you answered the pricing. It's going to be in proximity to the market, and we'll reveal that in January. Penetration, we believe penetration is probably right, in the range of, say, 15% to 20%. Our expectation is, by the end of '26, penetration will be in the mid- to high 20% range.

And -- did you have a third question? Maybe I'm misremembering one or not remembering one of the three you asked.

No, no, you answered it all. Congrats again.

Yes. Thank you.

Your next question will come from Ashwani Verma with UBS.

Congratulations on this big milestone for the company. I had a commercial question. Maybe, Andrew, if you can comment on this. As you're launching the drug, do you have a sense of like how many naive patients are there in play for a CMI every quarter? And how quickly can you penetrate that group?

Did you -- the number of naive in total, you're asking?

Yes, yes. So naive patients in play for either of the CMI every quarter.

Sure. So I mean currently, there's probably in the range of, say, high teens up to, say, 20,000 on a CMI. The market in the U.S. in terms of when you look at claims data longitudinally, there's probably in the range of 110,000, maybe 120,000 patients who are symptomatic and eligible for treatment. So doing the math, the number is probably in the 80% to 85% range that are still available. Now how many of them are actually in the market and seeing physicians, I think that's a tougher number to get to, but my expectation, that's probably about 1/3 to 1/2 of them.

Your final question will come from Jason Zemansky with Bank of America.

Congrats on the approval. You've talked about broadening the market both here and in the past, including moving into the community setting. So when you look at the 4 components of the ETASU, based on your market research, can you speak to how easy this transition is going to be? I mean, how quickly can your average prescriber outside of the center of excellence meet these criteria?

Andrew, do you want to take that?

Sure. So when you look at the components, I think one of the key drivers is that from a REMS system point of view, that -- much of that will be automated, meaning that physicians will be able to put in patient status forms. And when they put that status form in, every status form can correspond to an echo and can correspond to a dose increase until you get to the proper gradient based on the grid that Fady showed.

When you consider the dosing, when you consider MAPLE on top of that dosing and what we hear in our market research is ease of use, so to speak. That's, I think, what speaks to broader utilization, that as well as the class is really well understood or at least well known by cardiologists. So when you look at those that are aware of CMIs, those that are aware of aficamten, the number is very high, much higher than you would typically go into a launch.

So I think the combination of awareness, the combination of the multiple publications that this is more of a focus at meetings when we go to professional medical meetings that there's a second trial of if a case is positive, that's certainly going to accelerate, if guidelines get updated with MAPLE. So I think all these things in combination as well as the REMS that -- it's very straightforward, when you increase your dose, you do an echo. You start at the lowest dose and you have an adaptable window, you can get 2 prescriptions filled without having to get an echo. You don't have to worry about disrupting existing therapies with the exception of a very rifampin, which is not really used all that much.

So I think when you put all these things together, that's what gives us the confidence that the market will expand, and that's what physicians tell us. So I think the time will tell in terms of how long that will take. Probably that will also correspond when we get broader access. So when these things all come together, my expectation, you'll start to see that for the third or fourth quarter of this year -- '26, sorry.

Jason, put another way, I think we're going to resist the temptation to rank order those elements of REMS that might in hierarchy point to enabling a broader category penetration and preferential share. Rather instead, what I would say is it's a collective experience that we're going to be hopefully enabled to create with MYQORZO for physicians and patients. And it may vary depending on the physician or the patient as to which one might ultimately be the most important advantage.

But I do believe that MYQORZO represents an innovation rooted in the attributes that are differentiated and were intentional in its design. And if we are executing properly, then we should be in a good position based on label, based on REMS and based on efficacy, including things like speed of onset to addressing treatment and disease burden that we're in a good position to drive the ambitions of this commercial business. So I hope that answers your question well enough.

It does.

There are no more questions at this time. I'd now like to turn the call back over to Robert Blum for closing remarks.

Thank you, operator, and thanks very much to everybody who participated in the call today. Today, we've entered a new era for Cytokinetics. Again, it's not the end, it's instead a new beginning. And we're going to focus on commercializing MYQORZO alongside of continuing to prosecute our specialty cardiology pipeline, always with a focus to our continued convictions, our innovative science and for the benefit of patients.

With patients as our North Star, [indiscernible] continue to grow shareholder value, and now as a fully integrated biopharmaceutical company, hopefully now deliver on the promise of muscle biology and pharmacology for more and more patients.

Thank you for your continued support. Thank you for your interest in Cytokinetics. Operator, with that, we can now conclude the call, please.

Thank you for standing by, and welcome to the Cytokinetics Q3 2025 Earnings Conference Call. This call is being recorded and all participants will be in a listen-only mode. [Operator Instructions]

I would now like to 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 and medical affairs activities for aficamten. Stuart Kupfer, SVP and Chief Medical Officer, will provide updates on the clinical development program for omecamtiv mecarbil and ulacamten. Sung Lee, EVP and Chief Financial Officer, will provide a financial overview of the past quarter. And finally, Robert will provide closing comments and review our expected key milestones for the remainder of 2025.

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 2025 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.

Now I will turn the call over to Robert.

Thank you, Diane, and thank you all for joining us on the call today.

The past quarter was highly productive and defining for Cytokinetics. We made significant progress across the company's priority objectives as we advance towards the end of the year when we hope to achieve our first potential FDA approval of aficamten for patients with oHCM. Our major accomplishments this past quarter were dedicated to preparing for that milestone, including continuing constructive engagements with FDA, completing key commercial launch readiness activities and fortifying our capital structure.

During the quarter, we held our late-cycle meeting with the FDA. As we previously disclosed during the meeting, we discussed our proposed REMS program, including elements to assure safe use, or ETASU, as well as anticipated post-marketing requirements.

Prior to the meeting, we had received FDA's responses to our proposed REMS and label for aficamten. And based on our exchanges and discussions with FDA to date, we continue to expect a differentiated label and risk mitigation profile for aficamten if approved by the FDA.

We've completed all GCP inspections by the FDA with no observations noted. Moreover, to date, we have not been notified of the intention of FDA to conduct pre-approval inspections. We look forward to continuing our dialogue with FDA ahead of the PDUFA date.

In recent months, we've also leaned further into commercial readiness with the onboarding of our commercial field sales colleagues and the finalization of promotional campaigns and patient support programs, with objective to further differentiate how we show up commercially.

At the same time, in Q3, we achieved an important clinical milestone within the development program for aficamten. We presented the positive primary results from MAPLE-HCM, which demonstrated superiority of aficamten to metoprolol in patients with oHCM, challenging the long-held status quo of treatment in this disease. Our intention is to file a supplemental NDA for MAPLE-HCM following its potential initial FDA approval. But in the meantime, we believe these results may help catalyze certain prescribers and help unlock more of the market upon the initial introduction of aficamten as may result in increased commercial launch velocity.

Following closely behind the potential approval and launch of aficamten in the United States is the expected potential approval of aficamten in the EU. During the quarter, we received the Day 120 List of Questions from the EMA, and we subsequently submitted our responses. More recently, we've continued EMA interactions, and we're preparing Day 180 responses. We're encouraged by ongoing interactions, and we expect a final decision from the European Commission in the first half of next year, even possibly on the earlier side of the year, given the pace of our review to date.

In parallel, our European launch readiness activities are well underway, focused on market access planning, medical education and engagement with the cardiology community and to ensure a strong foundation for a successful introduction of aficamten in Europe.

We also continue to work closely with Sanofi to support the potential approval of aficamten in China to further broaden the global opportunity and reinforce our commitment to making this therapy available to patients worldwide. To achieve all of this, we're fortunate to have a strong balance sheet, which we further bolstered during the quarter through our convertible note offering. As Sung will elaborate, this transaction helps not only to provide additional capital at this important time, but also financial flexibility. And lastly, we continue to build momentum across our broader pipeline at this important inflection point in our corporate development, reflecting our ongoing commitment to sustained innovation and longer term growth.

With that, I'll turn the call over now to Andrew, please.

Thanks, Robert. We continue to make strong progress with commercial readiness activities towards the potential FDA approval of aficamten next month. As Robert mentioned, our interactions with the FDA to date have reinforced our expectations for a differentiated risk mitigation profile anchored in REMS and label, and we have confirmed our go-to-market plans and promotional campaign.

Following anticipated approval in December, our launch process will begin immediately. Within days, our website, patient navigators, patient support services will go live to begin supporting physicians and patients on their treatment journey. Shortly thereafter, in early January, our fully trained cardiovascular sales and medical teams will be in the field engaging healthcare professionals with full commercial launch, inclusive of product availability and REMS operations to follow.

To ensure a seamless and impactful launch, we've invested deeply in assembling the right team and creating the right infrastructure. Over the last several months, we've built a strong and highly experienced cardiovascular sales team with our field sales representatives averaging over 20 years of industry experience and 14 years of cardiovascular experience. These are seasoned sales professionals who understand the nuances of launching a new medicine in a specialized market.

Our sales team is on board and completing training to ensure that our full team will be prepared to begin HCP engagement within days of FDA approval. A subset of our sales team has already been in the field since early September, introducing Cytokinetics to key oHCM HCPs and providing disease education.

Core to our launch strategy and consistent with the value and our vision of a differentiated patient-centric treatment experience, one that has been built from the ground up specifically for aficamten. Our approach is designed to be simple and integrated across all touch points for both HCPs and patients. At the heart of this model is a highly qualified team of patient navigators who will serve as a central point of contact throughout the patient journey. These navigators are also on board and have completed their training or are completing their training and preparations ahead of their anticipated approval to ensure readiness.

We've developed a distinct and compelling promotional HCP campaign that highlights the differentiated characters of aficamten and key attributes of our REMS program. We believe this campaign will clearly communicate the clinical value of aficamten and support broad awareness among cardiologists.

Ahead of launch, we continue to engage with payers to educate them on the evidence from our clinical trial as well as the clinical and economic burden of HCM. We remain confident in our ability to see parity access by the second half of 2026. Importantly, our strategy is comparable access with focus to differentiate based on the clinical profile of aficamten, our REMS program and our comprehensive bespoke patient support services.

As we stand several weeks out from our potential approval, I'm pleased with our commercial preparation and launch readiness, and I'm confident in our ability to execute quickly and effectively if aficamten is approved. As we look ahead to measuring the pace and velocity of our launch after approval, we will focus on a few key metrics.

First, HCP prescribing breadth as measured by the number of HCPs who are actively writing prescriptions. Second, prescribing depth as measured by the volume of prescriptions and HCP writes for aficamten. To achieve rapid uptake, we will quickly engage existing CMI prescribers with an eye to expanding the prescribing universe to those who treat HCM, but have yet to prescribe a CMI. More specifically, our goal for our field-based cardiology account specialists was to reach nearly all of the estimated 650 HCPs or approximately 80% of the HCM prescribing to date within the first few weeks of January.

And third metric is the volume of patients on aficamten. We will be closely monitoring and supporting patient uptake, including time of conversion to commercial drug, adherence, compliance and persistency. These measures will provide us early insights into the speed and trajectory of our launch rate of change and overall strength of our commercial execution focused on category growth and overall preferential share in an expanding market.

Finally, our attention is not only on the U.S., but also in the EU, where we've made meaningful progress in preparing for potential commercial launch of aficamten in that geography. We recently hired a General Manager for Italy alongside colleagues that are already on board in the U.K., France and Germany and also began recruiting and hiring our full German commercial team inclusive of our field sales reps.

In addition, we are preparing dossiers for upcoming discussions with HA bodies across key EU countries, with potential EMA approval expected in the first half of 2026, we remain on track for a launch in Germany in the first half of 2026 with other geographies to follow in '26 and '27.

With that, I'll turn the call over to Fady.

Thanks, Andrew. During the quarter, we are pleased to have presented new data that further reinforces the differentiation of aficamten and its potential for patients with HCM. Most notably, at the ESC Congress, we presented positive primary results from MAPLE-HCM, which were simultaneously published in the New England Journal of Medicine.

The results which show superiority of aficamten to metoprolol represent a watershed moment in treatment of oHCM. While patients treated with aficamten experienced a significant improvement in exercise capacity, those on metoprolol showed a decline, challenging the long-standing rationale for beta blocker used as the standard-of-care therapy in this disease. This finding has resonated strongly across the cardiology community as we heard firsthand from many healthcare professionals and key opinion leaders on site at ESC.

In addition to improving exercise capacity, aficamten also produced larger improvements in symptoms, gradients and cardiac biomarkers as compared to metoprolol. Improvements were consistent across all prespecified subgroups and confidence of the robustness of the findings. Importantly, adverse events were similar in the 2 groups and the safety of aficamten observed in MAPLE-HCM was consistent with previous studies.

To that end, as the evidence of aficamten expands, so too does our confidence in its consistent safety profile. An updated integrated safety analysis representing nearly 700 patient years of exposure from REDWOOD-HCM, SEQUOIA-HCM, FOREST-HCM and now MAPLE-HCM as well, aficamten was shown to be well tolerated with a low incidence of LVEF less than 50% over extended periods of exposure, with no occurrences associated with a serious event of heart failure. Long-term treatment with aficamten has also been shown to not be associated with an increased risk for atrial fibrillation.

Looking ahead and coming up this month at the AHA scientific session, pleased to have 3 late-breaker presentations with additional data from MAPLE-HCM providing new insights into these results.

With respect to the ongoing clinical trial program for aficamten, the next major data milestone for us will be the readout of ACACIA-HCM, the pivotal Phase 3 trial in nHCM. We completed enrollment of the primary cohort, excluding Japan, in the first quarter of 2025, and we now expect to report the top line results from this cohort of ACACIA-HCM in the second quarter of 2026.

During the third quarter, we completed enrollment of patients in the Japan cohort, closing enrollment of ACACIA-HCM worldwide. If the results of ACACIA-HCM are positive, it represents an opportunity to address the needs of a highly underserved patient population and an important opportunity to expand the therapeutic impact of aficamten.

Our belief in the therapeutic potential of aficamten in nHCM is founded in the existing body of evidence from the nHCM cohort of REDWOOD-HCM and strengthened by their longer term follow-up in the FOREST-HCM trial as recently reported.

At the Heart Failure Society of America meeting in late September, we presented new data covering at least 96 weeks of treatment in these nHCM patients. What you saw, albeit in an open-label setting was that 79% of the patients treated with aficamten improved by at least 1 NYHA functional class. Patients also had a mean increase in their KCCQ Clinical Summary Score of 11.2 points as well as improvements in cardiac biomarkers. Few patients experienced LVEF less than 50 and all instances were reversible after down titration or short treatment interruption. We are hopeful that these data may be replicated in the results of ACACIA-HCM given the similarity in patient populations and dosing scheme involved.

Alongside our clinical research, our Medical Affairs organization has been very active, engaging the HCM community broadly as we prepare for launches in both the U.S. and Europe. They conducted recent advisory board meetings in the U.S. and Europe and met with the HCM community of physicians at ESC and HFSA alongside institutional visits in their territories.

Our team of therapeutic medical scientists in Germany is in place, and we now have medical directors located in Germany, the U.K. and France, supported by our regional group located in Switzerland. Our field team in the U.S. have now also partnered with their newly hired sales colleagues to compliantly conduct introductory meetings with key opinion leaders and healthcare professionals.

Now I'll turn it over to Stuart to provide updates on our ongoing clinical trials in heart failure.

Thanks, Fady. During the quarter, we continued conduct of COMET-HF, the confirmatory Phase 3 clinical trial of omecamtiv mecarbil in patients with symptomatic heart failure with severely reduced ejection fraction less than 30%. These are patients who remain at high risk for frequent hospitalization and mortality despite receiving maximally tolerated guideline-directed therapies.

COMET-HF is designed to confirm the findings of the positive Phase 3 clinical trial of GALACTIC-HF in a more severe HFrEF population in whom we believe this mechanism may be able to deliver greater cardiovascular risk reduction.

In October, we conducted an investigator meeting in Europe, which revealed tremendous enthusiasm for COMET-HF. Many of the investigators had participated in GALACTIC-HF, and it was really wonderful to see their continued enthusiasm for the potential benefits of omecamtiv mecarbil. We now have over 75% of sites in North America and Europe activated and are continuing to activate sites around the world. We expect to continue patient enrollment in COMET-HF into 2026.

We also continue to conduct AMBER-HFpEF, the Phase 2 clinical trial of ulacamten in patients with symptomatic heart failure with preserved ejection fraction of at least 60%. By inhibiting cardiac myosin to attenuate hypercontractility, ulacamten is uniquely positioned to address the underlying diastolic dysfunction in this subgroup of HFpEF patients.

HFpEF represents approximately half of all heart failure cases and remains an area of high unmet need with limited treatment options. Enrollment in AMBER-HFpEF is progressing, and we expect to complete cohorts 1 and 2 in 2026 to inform FDA interactions and the decisions to proceed towards potential registrational studies.

We're pleased with the continued execution of these ongoing clinical trials, each in a different form of heart failure, which reflects our continuing commitment to further advance innovative medicines within our specialty cardiology franchise.

And with that, I'll pass it to Sung.

Thanks, Stuart. We're pleased to report our third quarter of 2025 financial results.

Starting with the balance sheet. We finished the third quarter with approximately $1.25 billion in cash and investments compared to $1 billion at the end of the second quarter of 2025. Our cash and investments increased quarter-over-quarter due to the net proceeds of $327 million received from the issuance of $750 million aggregate principal amount of the convertible senior notes due 2031 and concurrent exchange of $399.5 million aggregate principal amount of our 2027 notes.

These transactions together accomplish our goal of providing the company with financial flexibility ahead of the potential launch of aficamten for oHCM. Excluding the net proceeds received from this transaction, our cash would have declined by approximately $112 million quarter-over-quarter.

In October, we received proceeds of $100 million from the Tranche 5 loan provided by Royalty Pharma, which will enable us to finish 2025 with approximately $1.2 billion in cash and investments.

R&D expenses for the second quarter were $99.2 million compared to $84.6 million for the same period in 2024. The increase was primarily due to advancing our clinical trials and higher personnel-related costs, including stock-based compensation.

G&A expenses for the third quarter of 2025 were $69.5 million compared to $56.7 million for the same period in 2024. The increase was primarily due to investments towards commercial readiness and higher personnel-related costs, including stock-based compensation.

Net loss for the third quarter of 2025 was $306.2 million or $2.55 per share compared to a net loss of $160.5 million or $1.36 per share for the same period in 2024. The net loss for the third quarter of 2025 includes the debt conversion expense of $121.2 million due to the induced exchange of $399.5 million of aggregate principal amount of the 2027 notes.

Turning to our financial guidance. We are narrowing our full year 2025 GAAP operating expense range to $680 million to $700 million from the previous range of $670 million to $710 million. Stock-based compensation that is included in 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 $560 million to $590 million.

As we near the close of 2025, we have taken important steps to add flexibility and strength to our balance sheet. This positions us well ahead of the PDUFA date for aficamten in the U.S., potential approval in the EU in the first half of 2026 and the readout of results from ACACIA-HCM expected in the second quarter of 2026.

With that, I'll hand it back to Robert.

Thank you, Sung. This quarter, we made substantial progress across the company. We reported additional data that continues to validate our pioneering and leading science, and reinforce the differentiated profile of aficamten, while also finalizing our commercial launch readiness and maintaining momentum across our pipeline. These accomplishments underscore the focus, rigor and dedication of our teams as we move closer to the most important milestone in our company's history.

To help us prepare for this pivotal phase in the company's evolution, we were pleased to welcome James Daly to our Board of Directors during the quarter. Jim brings more than 30 years of global biopharma commercial leadership experience including long-standing senior commercialization expertise from his time as Chief Commercial Officer at Incyte and in senior commercial roles at Amgen, alongside now Board roles at leading commercial biopharma companies. We look forward to his guidance and oversight now as a Board member at Cytokinetics.

As we approach our first potential FDA approval at Cytokinetics, I want to thank our employees, our partners and our shareholders for their continued trust and support. We're approaching a pivotal moment in our company's history, standing at an important threshold after many years of disciplined investment in our science, pipeline and infrastructure as well as capital structure, and that will enable our planned transition to a fully integrated commercial company.

At this juncture, we are not spectators, but instead, we are active participants in shaping the next chapter for our company. Our near-term focus remains on potential regulatory approvals and commercial launch and velocity. I'm confident in the strength of our teams and the clarity of our shared vision now translating to execution.

With that, 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 by the end of the year. We expect to advance go-to-market strategies and continue launch preparations for aficamten in the United States. We expect to continue go-to-market planning in Germany and expand commercial readiness activities in Europe in 2025 and in preparation for potential approval of aficamten by the EMA in the first half of 2026.

We expect to continue to coordinate with Sanofi to support the potential approval of aficamten in China, pending approval by the NMPA. And we expect to report top line results from the primary cohort of ACACIA-HCM in the second quarter of 2026 and continue patient enrollment and conduct of the adolescent cohort in CEDAR-HCM into 2026.

For omecamtiv mecarbil, we expect to continue patient enrollment and conduct of COMET-HF through 2026. For ulacamten, we expect to continue patient enrollment and conduct of AMBER-HFpEF through 2026. And finally, for preclinical development and ongoing research, we expect to continue ongoing preclinical development and research activities directed to additional muscle biology-focused programs.

And operator, with that, we can now open up the call to questions, please.

[Operator Instructions] We'll hear first from the line of Gena Wang at Barclays.

I have tons of questions on approval, but I will save that for my peers. So I will ask one question regarding ACACIA data. I think you did mention that the data will be coming out in 2Q '26. So as we remember that you added pVO2 as a dual primary endpoint for regulatory feedback from Europe and Japan. So technically, the drug should receive approval as long as you hit 1 of the 2 primary endpoints. So -- but in the case of missing pVO2, do you anticipate any issue of approval in Europe and Japan? I assume U.S. will be totally okay as long as you're hitting one endpoint.

I'll ask Fady to respond to that.

Gena, I think it's really difficult to know what will guarantee approval or not. Obviously, it depends on the magnitude of the other results. It depends on safety profile, depends on lots of things. But I think the trial will be considered positive based on our statistical analysis plan of either endpoint is positive, but you'd like to see them at least minimally moving in the same direction. You'd like to see magnitudes that we think are clinically meaningful. You like to see consistency across the other endpoints.

So I think all of those things go into regulators' evaluation of whether a trial not only was statistically significant, but represents a clinically meaningful therapeutic in the field.

Our next question today will come from the line of Salim Syed at Mizuho.

I'll also ask one on ACACIA, just given the amount of attention this trial is receiving. And sorry for the granularity around the p-value here. But Fady, so the ACACIA trial p-value is split, as I understand it, between KCCQ and peak VO2, both at 0.025, so equal.

And if one wanted to play devil's advocate for a second here, just curious why is that the better strategy at this point versus what ODYSSEY had, which was weighted to KCCQ at 0.04 and came in with a p-value of 0.06, which was close to hitting and also a better p-value than what we saw with ODYSSEY with the peak VO2 measure. And the trial only needing, again, statically one measure to hit to be successful. And to that point, while the study is still blinded, if you wanted to, could you change the weighting between the 2 endpoints in ACACIA before unblinding the results?

Again, I kind of go through the -- what I said earlier is that any positive result is not necessarily a meaningful result. You could -- I think the ODYSSEY trial missed and the KCCQ delta was 2 or 3, I can't remember the exact number, but pretty modest, and I doubt would -- if you consider the magnitude of effect would be that compelling to regulators. So we powered this trial of 0.025 for each based on what we think is a solid clinical effect at KCCQ that's 5 points and with peak VO2's improved by 1.0.

Now that powering -- the trial is powered at 90% power for each of those magnitudes doesn't mean that the trial is positive only if we reach those magnitudes. The minimum, I guess, positive difference for those endpoints is substantially smaller and gets into the range of where it's probably debatable whether the size of the effect is meaningful or not.

So we think we have adequately powered each endpoint. We think allocating alpha equally provides us an opportunity to win the best on each endpoint. And at this point, I don't anticipate us making any changes to that.

Our next question today will come from Akash Tewari at Jefferies.

This is actually Zaki on for Akash. So just again on Nonobstructive. You've talked about how Bristol's ODYSSEY study had an outlier placebo. And to us, it almost seems like their standard deviation on KCCQ in particular, came in higher than they expected in their protocol. So for ACACIA, you've chosen to keep the trial actually at a similar size of ODYSSEY with an even more aggressive alpha split.

So I just want to know in terms of what you're seeing on blinded variability, what gives you confidence that, one, you're not underpowered versus ODYSSEY and two, that placebo is actually tracking in line with your expectations around that 5-point placebo-adjusted delta on KCCQ?

Well, I think your last point is impossible to answer because we're blinded, so we don't know what the placebo effect is in ACACIA. We do monitor the variability of the combined data set and for now, the variability appears to be within our assumptions. So I think we're adequately powered based on the global variability. And again, I'll just say that the variability that we've observed in the KCCQ and several trials that we run using that metric is generally about 15-point range, which tracked with SEQUOIA, it's tracked with other trials we've done in that area. And I think the indication, it's not really any different at this point.

So I think we're tracking along our assumptions and for now, we'll just let things play out and see how they read out next year.

I might also underscore that variability is a function of a number of factors, including experience in the course of conduct of studies such as this. And please understand that we believe that one way to manage variability as we have done, is to go to centers with ample experience conducting clinical research using aficamten and as has already been historically validated in our prior studies. So we do believe that's something that serves to our favor.

Our next question will come from Carter Gould at Cantor Fitzgerald.

Maybe I'll give ACACIA a break for a minute. Andrew detailed a lot of metrics that you'll be watching. Which of those metrics are you likely to share with the investment community? And any of those I can get you to commit to today? And do you anticipate blocking third-party prescription data during the launch?

Andrew?

So those 3 metrics I talked about in terms of prescribing breadth and depth as well as volume of patients is what we plan on sharing. No, we're not going to give targets and share what those would be.

Relative to data, this is a very limited distribution the REMS drives that as well. The specialty pharmacies or 2 of them will not report data. We will report that on a quarterly basis. There are also pharmacies that will be qualified IDN pharmacies through large healthcare systems. Many of those will be reported through syndicated data, but that will be a very small portion of our overall volume, maybe around 20% to 30% or so.

So if you look at syndicated data from IQVIA or Symphony or one of those sources, you're not going to see anywhere near the complete picture, but we certainly will give that picture on a quarterly basis.

Our next question will come from the line of James Condulis at Stifel.

I'd like to ask one on back to ACACIA and again, on blinded data. I was curious how much of a line of sight do you have on kind of like blinded safety data and maybe what the LVF less than 50% rate looks like? Obviously, not anything specific, but like how it compares to, say, what you saw in SEQUOIA and Obstructive. Just curious if there's any color there.

Yes, I'm going to try carefully here. I'll just say that there's nothing out of the blinded data that are unexpected based on what we've seen so far.

Moving on, we'll hear from Cory Kasimov at Evercore.

So I want to go back to the pending launch. And I'm curious, do you anticipate the implementation of another REMS program at these HCM clinics where they're already prescribing mavacamten is going to be a barrier that we should expect to kind of slow down the cadence of launch in the early days? Or is the process of registering centers relatively straightforward at this point?

So I'll ask Andrew to comment. I might just start by saying we're respectful of the fact that there are existing workflows that have already been adapted. And as Andrew has already highlighted, it's our goal to be enabling a REMS program and implementation that should create for a more flexible and easy experience for physicians, patients and pharmacists within established workflows.

Maybe Andrew can elaborate.

Yes, it's a good question. There's a lot of centers that physicians who are writing today. So part of the goal would be for a differentiated REMS program alongside MAPLE, alongside SEQUOIA to these get more over the line, so to speak, to prescribing. So that would be new workflow for them. Those who have existing workflow.

The workflow in the office really is around echo for titration and monitoring. That is similar. So you're going to have echo monitoring potentially with, say, a different frequency or the ability to titrate up at each point of monitoring. So it's the same kind of workflow, if you will. So we're not anticipating that the workflow around monitoring or the window for monitoring will cause must act, especially among high users and high centers. So we are expecting that a differentiated REMS, the differentiated label and an overall profile will drive differentiated use when physicians certainly understand that. So that's the way we've been thinking about it.

Next, we'll hear from Tess Romero at JPMorgan.

This is Caroline Poacher on for Tess Romero with JPMorgan. Just one from us on aficamten and oHCM. So acknowledging that the late cycle meeting took place on September 15, can you just comment on if the REMS has been finalized yet at this point in the review process? And if not, what are the remaining items of the REMS that need to be finalized? And when would you expect this to be completed?

So we're continuing with interactions with FDA, and we have not finalized those matters. We do anticipate that we're making progress towards enablement of finalization of those in order to meet the PDUFA date. With that said, we've had exchanges and interactions -- and as I've indicated previously, we don't believe that we're engaging around framework, but rather some operational details, things that speak more to things like web pages and that which is administrative. Those are things that we think should come together to be enabling of FDA to review this and hopefully approve it in time for the PDUFA date.

Moving forward, Maxwell Skor with Morgan Stanley.

One more on ACACIA. Could you just confirm whether there are any shared trial sites between ODYSSEY and ACACIA, approximately how many -- the percentage overlap? And if so, what potential impact that might have on, let's say, a placebo response or other factors relevant to interpreting ACACIA results?

Max, I can't give you the exact overlap, but the overlap is not very large. Obviously, sites were conducting 2 trials that were simultaneously in the same patients, it would be a bit problematic. Some trials have finished their commitment and obviously and then became a case of sites later and things. But the overlap, I don't think is very large.

We ended up generally going to sites that we already had experience with or have visited ourselves, either our HCM team or clinical operations group. And so we ended up choosing a cadre of sites in South America, Europe, North America, Australia, China, Israel that represented either our own prior experience or had -- clearly had experience in other HCM trials.

Yasmeen Rahimi with Piper Sandler. You have our next question.

Maybe a question for Andrew. You did such a nice job outlining your commercial strategy. How are you thinking about pricing? It sounded like you're thinking about pricing and parity to mavacamten. Obviously, given the product profile, you may have flexibility to go higher. So I appreciate any color around that.

Sure. So we'll communicate our price what it's set. But I think you can think about when a second product comes out or a category that's already been priced is typically priced in proximity to the initial product. So I would think we're going to be in that same kind of ballpark, plus or minus maybe a small percentage, but we're certainly going to be in that range.

Our next question today will come from Roanna Ruiz at Leerink Partners.

So a quick follow-up of the aficamten potential U.S. launch. Could you share more details about what you expect in terms of time to conversion to commercial drug, patient compliance over time? And anything you're hearing or learning about the possible rate in which early adopters could prescribe aficamten?

Sure. So thanks for the question. So in terms of conversion, in the beginning, we'll have blocks as payers go through reviews, medical exception is certainly the path that, that will go through. Medical exception can be as fast as, say, 2 to 3 weeks or it could take 90 days. So it depends on the plan, depends on the doctor's office, the documentation and if it's in compliance with what the plan wants. But I think you can think in that time frame, we're going to have the patient support programs where we can have them for commercial patients to bridge them through that process.

Medicare patients, of course, we can't do that. We'll provide free drug for those that are appropriate for patient assistance. And so that's how I would think about time to conversion until we have more broader access.

In terms of compliance, we are seeing that at least in this category, compliance and persistency is higher than you see for other cardiovascular drug. I'm guessing likely because of the time frame it takes to get our drug, the commitment of going through echos and the like that you're going to see compliance after 2 years probably still be above 50% or so.

And then your third question was, can you remind me?

Yes. The last part was about early adopter physicians prescribing aficamten out of the gate.

Yes. So this is a very, very focused market, 650 prescribers or so, about 80% of the market. Those prescribers, we know well. We've actually been interacting with many of them already. We will call on the vast majority, if not all of them in the first few weeks of launch.

When you think about those high users, if you will, when we've done even most -- market research even in the last month or so, MAPLE with SEQUOIA increases their urgency to treat. So we're expecting to get high use, if you will, relative to other physicians in those physicians that were early adopters for CMIs, we should see the same for aficamten if it gets approved. So that's our expectation.

We'll go next to Mayank Mamtani at B. Riley Securities.

Productive third quarter. Would love to hear your thoughts maybe for Andrew on what your latest thinking is on peak CMI drug penetration. Maybe if you can also comment on where it stands now and your expectation of scenarios where it could land in the kind of near-term, 1 to 2 years. And like you said about your impact of the MAPLE-HCM data, but also a lot of real-world data coming from your peers, including at AHA. If you could maybe comment on that, that would be helpful.

And a subpart question was around some of the patient navigator training that you're doing that happens around when you have a label in hand. I was just curious if any key FAQs or pushbacks you're preparing for would also be helpful to get color on.

So a lot of questions there, so I'll try to address those. CMI penetration, I think, was your first question. Right now, the penetration is probably in the 15% to 20% range of oHCM, and I'm defining that as the number of eligible patients, those that are Class II, Class III, those that are treated with the CMI. So we are expecting, as we said all along, around 80% or so of the market to be available, meaning patients who are eligible, but not currently on a CMI. The expectation is that, that probably penetration probably increases in the -- around 5 percentage points each year.

So when you look at real-world evidence when you look at additional trials, that certainly will increase penetration. If guidelines are impacted, if MAPLE helps influence guidelines in '26 or '27, that certainly will accelerate penetration. So I think there's things that can change the trajectory of penetration, but that's where it is now.

In terms of training, we did provide the label to the FDA. We've had a few rounds of feedback. I think that we've alluded to. I think we can certainly train on a draft label and then we'll train again on the final. That's pretty typical around how you would train relative to a label and relative to a REMS.

Moving forward, we'll take our next question from Joe Pantginis at H.C. Wainwright.

So curious, just totally switching gears here to omecamtiv mecarbil. Right now, the guidance is moving enrollment continuing into 2026. When do you anticipate providing more visibility as to sites, enrollment numbers? And what levels of clarity can we get, do you think, starting in '26?

We'll ask Stuart maybe to take that, please.

As I mentioned, we are making good progress in terms of site activation. We have 75% of sites activated in North America and Europe. And we're seeing screening picking up, randomization picking up. And I mean we're sort of not at a point where we can sort of start providing those numbers because I think we're going to hold off on that until we have all the sites activated and we have a good trajectory. But so far, so good. Study conduct is going well and so with site interaction and screening.

So Joe, I think as we roll into the new year and have a better sense of how these new sites that have been activated are enrolling, we should be able to tighten some of that guidance to the expectation of when we might complete enrollment. And then from there, as you know, this is a study that's accruing events. It's event-driven, and we can maybe point more generally to when we might expect data.

Our next question will come from the line of Paul Choi with Goldman Sachs.

I want to ask on your partnered CAMELLIA trial and just if you can provide any updates on timing on that and just sort of maybe help us think about when your partner might be able to launch in Japan and just sort of what would be a reasonable assumption there?

And then on the AMBER trial study for HFpEF, would you be in a position to potentially present some initial data on that in 2026?

I'll ask Fady to tackle those, please.

Yes. I mean with regards to the progress of the oHCM trial in Japan, I mean, the strategy in Japan will be a little bit tied more to completion both of ACACIA and CAMELLIA. We expect them really to kind of complete in a similar time frame and both leading to regulatory interactions and ultimately approval there. So I can't really give you specifics yet in terms of where it is, but CAMELLIA is moving along within line of that expectation.

And then AMBER, I think we're still a little too early for us to commit to data in 2026. We should be able to say more about that probably at our next earnings call.

Next, we'll hear from Serge Belanger at Needham.

This is John Gionco on for Serge today. So with the results of MAPLE now in the public domain, curious what your time lines look like in terms of how quickly you'd like to file the sNDA to incorporate that data into API label and whether you think having it in the label will alter in any way prescribing habits for treating physicians?

So I'll take the first part and ask Andrew to address the second part. But our goal is if we see aficamten approved based on the SEQUOIA results by the end of this year that we're moving very swiftly to submitting a supplemental NDA based on MAPLE data promptly in early 2026 to be enabling of a potential expanded label even possibly by the end of 2026.

Andrew can comment on how that may factor into expanded use.

We've tested this several times, including most recently this quarter. Each time we get a top line increased use of CMI, so CMI penetration goes up and increased brand share for aficamten or preferential share, if you will. So a larger market, larger share of that market.

When you segment it, those that are kind of the core users, they're basically saying it's confirmatory of safety and efficacy, and that gives them even more reason in belief. When you look at those that are heavy beta blocker, it really challenges their belief in the efficacy of beta blockers. It increases their urgency to treat or urgency to refer I think that second group is going to take a little longer, some of them and guidelines as well as continued education and promotion will certainly continue to move those. So at a high level, we're expecting a larger market, a larger share, and we're certainly seeing this as one of the expansion strategies we've talked about in terms of a bigger market.

Next, we'll hear from Kripa Devarakonda at Truist Securities.

Alex on for Kripa. Based on your updated late cycle meeting with the FDA and the nature of the day 120 List of Questions for the CHMP, is there anything we should be aware of to indicate that the REMS requirement could possibly be meaningfully different from the U.S. and EU?

Well, there is no REMS requirement in the EU. That's all handled through labeling, as you know. But I do think that to your question, we're expecting that aficamten, if approved in the U.S. and in the EU will be addressed similarly in terms of risk mitigation.

Our next question will come from Ash Verma at UBS. Hearing no response, we'll move forward. We'll hear instead from Jason Zemansky at Bank of America.

Congrats on the progress. Maybe just to switch gears, but in light of your recent balance sheet updates, where do you stand in terms of your ability to support both the U.S. and EU launches? I mean, do you foresee any need for additional capital, especially given your expectations for the launch?

Jason, this is Sung. Thanks for the question. We can't rule out future financing. But with that said, we expect to finish the year with $2.2 billion in cash and investments I'm sorry. $1.2 billion Thank you. I got a little excited there. So that puts us in a very strong position, not only to launch aficamten in the U.S., but also to continue to build out in the EU and importantly, to continue to advance our pipeline.

Keep in mind that we do have access to further capital potentially up to $175 million. This is from the Tranche 7 loan from Royalty Pharma. So we'll continuously weigh our options in terms of capital requirements and capital structure.

And now we'll move to Ash Verma with UBS.

This is Natalie on for Ash. This is Natalie on for Ash Verma at UBS. So we just had a quick question on nHCM. Now I know there's a lot of discussion about the heterogeneity of this patient population. Have you guys been able to identify if there is a specific set of patients that see the most benefit from CMI?

Well, I would say that, that question remains unanswered, maybe perhaps we will require both analyses of the ODYSSEY data, the ACACIA data when they come out. We think enrolling patients that are symptomatic, that have classic HCM -- classic HCM phenotype as evident on echocardiography that have certain biomarker increases. I think all of those things talk about a symptomatic, highly symptomatic and functionally limited patient population. And based on our prior experience in REDWOOD, we think that population should be responsive to aficamten. So I think we'll have more to say when we see the ACACIA data in next year.

I think I would add that we've been following a cohort of Nonobstructive patients for over 2 years now. And the large majority of them are responding well symptomatically and based on cardiac biomarker improvement. So I think what we're observing so far, at least in this cohort in FOREST is a pretty general improvement in response to treatment.

And thank you, ladies and gentlemen. That was our final question from our audience today. Mr. Blum, I'm happy to turn it back to you for any additional or closing remarks you have.

Thank you. I want to thank all of our participants on the call today. I want to thank you for your continued support as well as your interest in Cytokinetics. This will conclude our Q3 earnings call. And my hope is that next time we convene in one of these earnings calls, we'll talk about what could be the first potential approval for aficamten and a product arising out of our long-standing research and development, a very important milestone for our company and all of our stakeholders, including our shareholders.

With that, operator, we can now conclude the call.

Thank you. And ladies and gentlemen, thank you for joining today's Cytokinetics Q3 2025 Earnings Call. You may now disconnect your lines.

All right. Great. I'm Max Skor, a biotech analyst with Morgan Stanley. And before we get started, I'd like to read some quick disclosures. For important disclosures, please see the Morgan Stanley research disclosure website at www.morganstanley.com/researchdisclosures. If you have any questions, please reach out to your Morgan Stanley sales representative.

And with that, I am happy to welcome the Cytokinetics team. With us today is Fady Malik, Head of R&D; Sung Lee, CFO; and Andrew Callos, Chief Commercial Officer. So just from the top, there's a lot of exciting things that have both happened with Cytokinetics this year. And then looking forward, we've got the PDUFA date. But maybe I'll just open it up to the team here if you have any opening comments.

Sure. Thank you, Max, for having us. And I might just start with the forward-looking statement. We'll be making forward-looking statements and refer you to our SEC filings for that. We don't take any obligations to update them.

We're coming here off the European Society of Cardiology Conference over Labor Day weekend, where we presented in full the primary results of MAPLE-HCM, which was our clinical trial of aficamten as monotherapy versus the current first line of therapy, metoprolol. And I think that was quite a watershed moment for the field in that the performance of the beta blocker was much poorer than expected. This is a therapy people have used for decades with very little evidence supporting its use. And we weren't surprised that aficamten outperformed it, but really the basis for the use of the beta blocker as a standard of care was, I would say, undermined by the data that we presented in aficamten.

So lots of people leaving the meeting with questions about what do they do with their patients on beta blockers, how do they adequately maybe think about their treatment paradigms more objectively, potential updates to guidelines in the future and things like that.

On top of that, we saw data from ODYSSEY, which was the BMS trial of mavacamten in nonobstructive HCM with some promising evidence of benefit there, and we can discuss that as well. And as we kind of roll into the last quarter of 2025, we're looking forward to our PDUFA date at the end of the year. Obviously, we have a late cycle meeting this month, and with lots of preparations ongoing for launch and then rolling into next year, other approvals potentially in Europe and maybe China approval coming even before FDA approval this year. So the next 6 to 8 months are shaping up to be pretty exciting and transformative ones for Cytokinetics.

Great. So maybe we just touch on MAPLE first. If you can give kind of the high-level data sets, the fact what struck me, and I think highlighted by KOL feedback is the fact that beta blockers in regards to exercise capacity, it also deteriorated, and it was significant with aficamten. Any highlights there? And maybe if you can call out key KOL feedback, that would be great.

Sure. Well, so in MAPLE, we assessed exercise performance as the primary endpoint, and it was probably not that surprising that beta blockers caused a decrease in exercise performance. That's been seen in other conditions. It's even been seen in a small study of nHCM -- rather of obstructive HCM patients.

What was really more surprising was the lack of effect of beta blocker on reducing the obstruction, the LVOT gradient. There was almost no effect of the beta blocker on that. And that's fundamentally the rationale for using the beta blocker in oHCM. So lack of impact on the underlying cause of symptoms. The increase in BNP was also a bit surprising. Patients reported a fair number of adverse events that were a consequence of the beta blockade. And we pushed the dose in the trial. And so we could say that the beta blockers had a fair shot at it, but it also led to several down titrations and discontinuations of the beta blockers.

So I think when you walk the floor and spoke with KOLs afterwards, this was presented in front of an audience of about 4,000 people on the -- in the most prestigious session of the meeting, you got the sense that they were just questioning the basis for the use of this drug for their first line of therapy and how that might -- ultimately, the standard of care may evolve in HCM.

And potentially, this would be submitted as a supplemental application after the PDUFA date in December. But overall, this is a significant milestone. How is it kind of shaping Cytokinetics' positioning in HCM overall? What's your approach going into the potential launch in December?

So from a commercial point of view, when the sNDA goes in, this is not a new indication, it just further elucidates the effective beta blocker. So it is in the public domain. We're obviously focusing our launch on SEQUOIA. But when we talk to physicians, when we do formal research or anecdotally, when we talk to KOLs, the -- a few takeaways are: One that beta blockers will probably still be used in the near-term first line, more driven by payers, but the call to action to add aficamten a lot sooner than they would have otherwise.

Two, as it gets -- there's many cardiologists who don't prescribe CMIs today. They do use beta blockers, there's around 10,000 cardiologists who are 80% of the market. And about 80% of those 10,000 cardiologists aren't writing CMIs. So this would get more of them on board. So what it does is it increases penetration, i.e., the number of patients who would be on a CMI over time, and it increases our preference share when we've studied a profile of aficamten to include MAPLE data.

So I think it's pretty promising in that we can get a broader set of the cardiology community engaged in treatment, get aficamten, if it's approved, added sooner. It will get added to guidelines. I think that will -- if it does in 2027 is our base case of that. And if it does get added to guidelines, I think that will further propel some of that activity.

And you said 2027.

That's base case.

Base case.

Our best guess. I mean, we don't control that, obviously.

Yes. And any gating factors in regards to getting that on label? Would you -- what would be the bull case in that scenario? Or just...

Timing wise?

Yes.

I mean, I think you can assume we will be filing it quickly after approval, and it's about a 10-month review. So toward the end of 2026.

Okay. That's very helpful. And so moving over to the potential launch, the PDUFA date in December. And so you have a late cycle review this month, is there any expectation that you'll put something out regarding that late cycle review or any commentary around that or expectations?

Well, as we did with the mid-cycle meeting, I mean, we committed to updating on our quarterly earnings call. Next quarterly call will be in November, so I would anticipate a more detailed update at that time. I don't anticipate necessarily anything detailed in the meantime. We haven't -- these are very fluid discussions. And so despite there being a late-cycle meeting, we're always in constant exchange with FDA with regards to different things. And so we'll plan to focus in the quarterly call and give maybe more substantive updates at that time.

Okay. And maybe this is a good opportunity just to ask how are interactions going with the regulators? Or everything consistent? Any changes there?

Yes. I mean the review team has remained pretty constant. We get a lot of questions about that. The review team and their members have been the same throughout the process. They're pretty experienced with the mechanism of action. They're very, very knowledgeable now, obviously, about aficamten and its profile. And so I just would characterize our interactions as productive and have been progressing normally through the course of the last few months.

Okay. And I believe you just said in regards to having fluid discussions, ongoing discussions with regulators. Will this be the first formal meeting where they basically give their response to the REMS that the team submitted?

No. I mean when we submitted the REMS, we got comments back from them that were stylistic and editorial and things like that. The REMS have to kind of follow the label. The label ultimately has to get finalized and if there are any discrepancies, they have to be reconciled at the end. We seem to have good alignment between label and REMS. And what -- as we move forward, as we continue to negotiate a final label, that will finalize itself shortly thereafter. So they're moving together in parallel, probably is the best way to put it, and they'll get finalized in parallel.

Okay. And then in regards to the potential label, the proposed REMS, I don't want to push you too far on details, but I'm just trying to think about how potentially it could be differentiated from Camzyos. I know there's differences in drug-drug interactions, the titration schedule. But anything you'd like to comment there?

Yes. I'm just going to comment on our clinical trial experience and what we've put out in the public domain as a means of thinking about it. When you look at the way that aficamten has been dosed in all of its clinical trials, including MAPLE, including FOREST, including SEQUOIA, this was done in such a way that every -- basically, the patients would start the drug every couple of weeks with some flexibility now in FOREST, where it's every 2 to 6 weeks. They can come in, have an echo, potentially uptitrate. Every echo either leads to a titration or it leads to an entrance into the maintenance phase, if the target dose has been reached. Treatment, down titration is the means by addressing EF less than 50%, above 40%. Treatment interruptions have been very rare.

And we don't expect necessarily any differences when we get to labeling because obviously, the clinical data would inform the label. Drug interactions, we published the -- or we presented those data at the American College of Cardiology some time ago, and the data demonstrated that there are multiple pathways of aficamten metabolism. It's hard to block them all at the same time, blocking any one pathway doesn't lead necessarily to a large increase in aficamten exposure.

And so again, we expect any labeling around drug-drug interactions to be consistent with that profile that we see, which is altogether, we think quite differentiated and should ultimately lead to a differentiated label.

Okay. And based on the fact that Camzyos, the REMS was updated this year, it's been on the market for a bit. What kind of learnings are you taking from that launch and applying to your own launch? Or specifically in the United States, patient demographics you're targeting, physicians, community setting, where can you be differentiated in regards to Camzyos?

So when we look at it from a launch point of view, we have our campaign. We spent the last probably 4 or 5 months finalizing what that campaign would be to communicate that differentiation. I won't get into details of where the differences are. I mean, obviously, Fady just described them from our Phase III study, but we do have differentiation in efficacy, safety, REMS and patient support, assuming that the label and REMS program is finalized the way we're expecting. And that campaign will communicate that very clearly to physicians.

I think what we've learned, and I think we've all been students of launch. I think our commercial team is very experienced in launch. We've all launched many products. And the key is to get a core set of physicians on board first that will be likely the centers of excellence to make sure that they're communicating their experience to the next kind of level of cardiologists.

I think we do have a profile in aficamten that likely can expand the market to a broader set of cardiologists and when I say likely expand the market, it will -- I do believe it will expand the market, likely what I mean in 2026. Can we do it as quickly as in 2026. MAPLE will help a lot with that, especially if guidelines get updated faster than we were expecting. If a case is positive, that will certainly help with that. So I think there's lots of reasons to believe that acceleration could occur beyond what maybe a base case launch could look like.

I think finally, we've been really focused on HCM, aficamten, this patient population, this treatment journey. We've designed a patient treatment program around it. We've been interacting with the KOLs. They know us very well. We know them very well. So I think we have a competitive advantage in that we have that level of focus as an organization and a business model, that specialty that you don't need large field forces and a lot of resources to compete in.

So in many ways, with MAPLE potentially on the label, that's where the inflection could come from expanding beyond centers of excellence to community setting. Do you think that's a reasonable expectation?

Yes, I think that's a very reasonable expectation.

Okay. And then without providing specific guidance or launch metrics, how are you communicating to investors, the investing community in regards to what 2026 looks like in regards to the launch?

So in November at our earnings call, we'll probably describe that better in terms of the metrics, but you can imagine it's going to be things like the number of patients treated. The number of patients that are commercially -- being converted to commercially paying patients, the number of physicians who have been certified in the REMS program. So there'll be a couple of metrics that we talk about that are early indicators of greater launch success.

And I think -- the first year of mavacamten's launch had around 4,000 -- or the first 12 months, I believe, had around 4,000 patients. So I think that would be a minimum that we would expect. I certainly think for reasons around MAPLE, the patient support program, the areas of differentiation, the ability to expand, I certainly believe we could do better than that. But we'll have to see how the label and the REMS play out as well.

Okay. That's very helpful. And so moving on, you noted it, Fady, at the beginning in regards to ODYSSEY, Camzyos, the data in nonobstructive HCM. Is there anything you'd like to call out there before maybe some questions on that program?

Sure. I mean I think the -- what we saw at ODYSSEY was that the underlying basis for believing that a cardiac myosin inhibitor would impact the physiology of HCM in a positive way was confirmed. We saw improvements in echocardiographic measures of cardiac relaxation. We saw decreases in NT-proBNP, which is also a reflection of probably filling pressures of the heart. And so that physiologic basis for believing that there would be a clinical benefit to that was solidified. And in a very large and global population of HCM patients.

The clinical outcomes data were not statistically significant in terms of their statistical testing plan, but there were positive trends on both endpoints that were, again, encouraging. One of the endpoints was confounded by a large placebo effect. And so I think all of those things portend well for ACACIA potentially being positive down the road with certain improvements in the way the study is potentially conducted or the product is dose and things like that.

Could you speak to the patient journey for someone with nonobstructive HCM? What does it look like? What are the diagnostic criteria? My sense from both your presentation and reviewing the ODYSSEY data, it seems like it could be a heterogeneous population, but any commentary around that would be helpful.

Sure. Well, the obstruction in oHCM gives you a very specific and kind of unusual feature by which to say those patients have obstructive hypertrophic cardiomyopathy. The nonobstructive patients don't have the obstruction. So what they have, though, are thickened ventricles, they generally have geometries that are not very normal-looking, asymmetric hypertrophy for instance, or the hypertrophy is concentrated at the apex or they have mid-cavitary obstruction, things like that.

So this is not, in general, something like you see in heart failure with preserved ejection fraction where the hypertrophy is more concentric looking. So it's more of a visual thing. And we have our physicians, that are HCM experts, look at every single echo that is a part of the qualification process and as patients get screened into the study. So we think we have pretty good control of that.

The patient journey is also a bit different because nHCM -- oHCM can be recognized early because of a murmur. You need a stethoscope, listen to somebody's heart, you hear a murmur, even if you don't know what the murmur is, it does suggest that perhaps you should image the heart and see what's going on. And that leads to an echocardiogram and hopefully, the echocardiogram leads to a diagnosis. nHCM is silent. There's no murmur. The symptoms are often mistaken for other things and as other things can present very similarly.

And so it takes -- these patients tend not to get recognized until later in their disease until they've had substantial symptoms for quite some time. And I think that just is a call to action for us to improve diagnostic rates and elevate the diagnosis and the sort of differential diagnosis. And therapies -- available therapies, if aficamten does become available for that, often change that dynamic, and they improve diagnostic rates and recognition of disease.

So just touching again on the inclusion criteria for ACACIA versus ODYSSEY. I know you've noted previously that you have a team that's reviewing echocardiograms. How confident are you that you've enrolled a differentiated patient population compared to ODYSSEY?

Well, I would say -- I wouldn't say that their population was the reason that ODYSSEY didn't reach statistical significance. I mean, I think we've enrolled a population with some more objective measure of exercise intolerance. So we have an upper limit on peak VO2. That was not in the ODYSSEY entry criteria, that people could have normal or even over normal peak VO2s. We both had entry criteria related to KCCQ that required patients to have substantial symptoms, symptom burden. We have maybe a bit higher of an NT-proBNP entry criteria, which is another objective measure of burden of disease.

So I think these things are fine-tuning things. The review of echos is important, obviously. But then probably the biggest difference will be in dosing density, I would imagine. We piloted the dosing of aficamten in nHCM patients in Phase II and then retested it in the open-label extension. We were able to titrate patients, the majority of them to the highest doses. We didn't have patients having interrupt treatment. And generally, we're able to take that same dosing regimen right into Phase III, having road tested it. So hopefully, that will also increase our likelihood of success.

Okay. And then for the nonobstructive patients, how reflective is the enrollment criteria for ACACIA in regards to the overall patient population? I'm trying to get a sense of the TAM here.

When we designed ACACIA, if you think of all of HCM as a pie, [ SEQUOIA ] was really the treatment-resistant population. Patients that were on background therapies still have substantial symptoms. We required a high level of both resting and provoked gradient to get into the trial. MAPLE enrolled patients with obstructive HCM that essentially met just a diagnostic criteria, all-comers that sort of met those diagnostic criteria for obstructive HCM.

So what's left are essentially the patients we enrolled in ACACIA. These are patients that don't have -- they don't meet the diagnostic criteria for obstruction. They have the appropriate wall thickening. They have symptoms, things like that. But we've tried not to exclude a lot of patients from the trial because, again, we wanted to address the whole pie, not just pieces of it.

So would you say the opportunity is larger, but less defined in regards to which patients would go on therapy right away in nonobstructive?

No. I mean I think the patient population, again, people that have HCM, we hope at the end of the day, is that aficamten is a drug indicated for hypertrophic cardiomyopathy, period, end of story. And not obstructive or nonobstructive or cuts in both directions. And so -- and that's the way it should be. This is a disease of hypercontractility. This is a mechanism that addresses hypercontractility across the whole spectrum of HCM. And there shouldn't necessarily be little pockets that are carved out other than patients that don't have symptoms. I mean those are the ones that probably are not needing of therapy until later in their disease.

The overall population size, nHCM is about half the market, and oHCM is obviously, the other half. And from the symptomatic, our expectation is the number is going to be pretty similar, about 130,000, 140,000 that are symptomatic. I think the difference is, obviously, if we are successful there, then there -- none of them would be treated. There's not -- they don't -- beta blockers don't work well. So first-line therapy, really would be the call for -- which could fuel further first-line therapy for oHCM over time as well.

And sorry, just going back to the beta blocker dynamic. When do you plan to get feedback from payers? Do you expect the MAPLE data to potentially support shrinking the time patients are on beta blockers to start? Yes, just any commentary around that.

So guidelines are probably the most impactful thing for payers. I think in reality, we're not trying to position MAPLE to fuel first-line therapy in the short term. I think what we're trying to fuel is a call to action for those who have HCM who are not on a CMI, when aficamten gets approved, to be on aficamten. That approval should at least get payers to reduce the time frame, but beta blockers will still be first line. The ability to add a CMI and accelerate use more quickly from a payer is really the response we're looking for and from the community of cardiologists to get more of them to write because of the superiority of beta blockers not working for the gradient.

Okay. And so I'd like to touch on the pipeline also. I know most of the questions have been around aficamten, but you have a pipeline -- expanding pipeline. And is there any highlights or catalysts we should keep an eye out for over the next 12 to 18 months?

Sure. I mean, I think just with even aficamten as a pipeline and a product, right, with ACACIA reading out next year, label updates occurring next year and potentially the year after in terms of ACACIA.

And following that, omecamtiv mecarbil, that trial COMET, which is the trial in severely reduced ejection fraction heart failure patients, we'll have finished up enrolling. And hopefully, in 2028, we'll read out and positively as it's supported by a fairly large -- maybe the largest ever clinical trials program supporting a pivotal trial. And that is a drug that would add nicely to the aficamten launch as that story is beginning to mature. The omecamtiv data and potentially its launch approval, things like that would follow soon thereafter.

AMBER is a trial in heart failure with preserved ejection fraction. This is a kind of a population where we think nHCM is a model of that particular population, thickened heart, symptomatic, a lot of same features in HCM. We'll see early data from the Phase II trial in 2026. And if those data are supportive, launching of a size -- a more sizable trial in 2027.

So I'd say the next 3 years have a lot of exciting changes for Cytokinetics on top of transformation of the company into a commercial powerhouse.

I think that leads in well. Maybe we can just discuss financials. I believe with over around $1 billion in cash at the end of 2Q, additional potential tranches from Royalty Pharma, how are you thinking about capital allocation? And any thoughts on business development?

Yes. So Max, our top priority, obviously, is the launch of aficamten in the U.S. We're also putting up the infrastructure -- commercial infrastructure for launch in Europe later next year as well. So that will be an important priority.

Also, with our capital allocation, advancing our pipeline is very important. As Fady said, we have sort of an abundance of opportunities with aficamten alone, sort of a pipeline and a product. So funding those ongoing studies, taking ACACIA across the goal line. We have the wherewithal to do that and of course, omecamtiv mecarbil and CK-586. So those are our capital allocation priorities.

You mentioned something very important. In addition to the cash balance of $1 billion midyear, we have important options ahead of us in terms of additional access to capital. So starting with a $100 million term loan that we've already qualified for. So I think it's fair to expect us to take that down before the end of the year. And if aficamten is approved before the end of this year, we would qualify for an additional $175 million. So that will be an important source of additional capital.

And as you know, we've retained the vast majority of worldwide rights to aficamten still with the exception of Greater China and Japan, where we have partners. So that could be an additional important source of nonequity source of financing, selling the rights to rest of the world.

Okay. And that leads into a couple of quick questions we've been asking several of our companies. Just with the China's recent rise in biotech innovation, how are you thinking about your competitive position here? And will this influence your R&D or BD strategy at all?

Well, I think like every company out there, we certainly look at the entire landscape in terms of opportunities to externally partner or license things. So I think that, that we're certainly not going to be restricted in our view in that way.

Maybe just to step back a minute, the company is, we think, uniquely positioned not just to launch aficamten and develop that market, but -- and with other clinical and regulatory milestones in the future, but we've maintained a pretty meaningful and productive research group. We have other small molecules that are poised and hopefully will enter development in the near future as our entire pipeline has grown internally from work from our research group. But that doesn't mean that we're only thinking to grow our pipeline with internal discovery because, obviously, there's a lot of opportunities externally as well. We've considered things in China. We consider things anywhere really in order to augment that.

And our long-term vision is to grow our pipeline over the course of the next 5 years and add to those 3 important products that we've talked about today.

And would the opportunity potentially or -- is the China opportunity becoming more significant now, I guess? Or is it equal with anything else you can find across the world?

I think we find innovation everywhere. I mean, I think we've talk to companies in China around potential partnerships. I mean, there are companies in the U.S. we've talked to as well. I don't think there's a tilt necessarily one way or the other, but we'll be as open-minded as anyone else will be.

Okay. And I guess last question. Is there anything I missed? Or is there something you would like to highlight? Or you think are top of mind among investors?

Well, I think it's a confluence of how our first launch is coming together with a field that has developed a lot of enthusiasm for new therapies. We're seeing other products being developed in HCM. We're seeing the standard of care really shift. And so I think of it as a very opportune time for us to launch aficamten, which we hope will be a highly differentiated product first in o and maybe potentially in nHCM.

The company has positioned itself very well financially. We've had a long time to prepare commercially to launch aficamten. And so in many ways, we represent unusual story in how we've come to this point. And hopefully, we'll continue with that momentum going forward.

I mean, maybe just to add that the level of energy and excitement at Cytokinetics is really off the charts. One, we have a very differentiated product that we really believe in, in both the profile, the REMS. We're building a patient support program that's very accustomed to this patient population. Timing is great in that there are many sales representatives on the market or who have recently left organizations who have been focused on cardiology. We have 9,000 applicants for a little over 125 jobs. And we have very deeply experienced representatives who know these cardiologists, who have relationships, who will be in these offices.

So when you combine the commercial team, the know-how, the people on top of the rest of the organization, the differentiation we have in aficamten, the life cycle coming with MAPLE and ACACIA, I think there's a lot to be really bullish about in the short term. And you can feel the energy in the company as it's getting closer and closer to launch.

Great. Well, thank you very much.

Thank you for having us.

Thanks everybody for coming to the Citi Biopharma Conference. Next on the docket, we have with us Cytokinetics. They had some interesting news today. I'm sure we'll discuss it. Before we jump into that, if you could all just introduce yourselves and give us kind of the brief history of Cytokinetics, and then we'll jump in.

So good afternoon. Thanks to the folks at Citi for inviting us to the conference today. It's a big day for us. So I'm joined by an all-star team of our senior executives. I'm Robert Blum. I'm President and CEO of Cytokinetics. I'll ask them to introduce themselves. I'll maybe for just a few minutes, provide some background and then jump into a presentation that we made and try to do all that in about five minutes so that we leave plenty of time for conversation.

So I'm Fady Malik. I'm the Head of Research and Development at Cytokinetics and joined the company when we launched in 1998. I'm a physician scientist and cardiologist and lead our both discovery and development efforts.

I'm Sung Lee. I joined Cytokinetics about 16 months ago as CFO.

Hello there. I'm Isaac Ciechanover. I'm the Chief Business Officer, and I also joined around 16 months ago.

So as mentioned, I'll just provide a quick overview, but then I'll jump into a few slides. So Fady and I started this company 27-plus years ago, and over these many years, we've built out a new pharmacology rooted in one biology, and as he is a visionary and physician scientist has led us all along the way.

Over the course of these many years, we've built out a portfolio. You'll hear about that more in a minute. And we've added to our team, including, as you see here, Sung and Isaac, who joined us within the last year or so. And I think that reflects the maturity and the evolution of the company. There are many of us who have been with the company for 10, 20 or more years, others who have joined more recently, all fit for purpose as we're seeking now to turn a page on the company as we move from R&D to commercialization over the next several months.

So with that as a background, I'll jump into some more detail. I'll be making some forward-looking statements. I'll point you to these slides and also to our SEC filings as it relates to caveats to those statements. We don't undertake an obligation necessarily to update those statements. But I will be talking to you about the company in broad brush strokes.

Our mission has always been to mine this area of biology for new medicines. And in particular, as that biology reads on muscle and translating muscle biology into a new muscle pharmacology, in particular, around diseases of cardiovascular and neuromuscular impairment. And as you can see on this slide, our commitment to that science has translated into a pipeline, a pipeline of potential medicines, all of which have been discovered and developed at Cytokinetics and for which we're quite pleased with progress, including progress announced even just this past weekend at the European Society of Cardiology.

As I mentioned, our focus has been on muscle biology and in particular, the mechanics or machinery that drives the contractility of muscle and where one particular molecular target, cardiac myosin, a mechanochemical enzyme that translates ATP hydrolysis into mechanical force that drives contractility of muscle. And ours is the first company to industrialize research around the sarcomere, the fundamental unit of muscle contractility that we all probably studied in high school, but for which we now have a pharmacology rooted in myosin modulation inhibitors and an activator of myosin that we believe hold great promise to the build of a specialty cardiology franchise.

Lead amongst these compounds is aficamten, a potential next-in-class cardiac myosin inhibitor. It's currently pending FDA review for potential approval in obstructive hypertrophic cardiomyopathy based on a study called SEQUOIA that read out over a year ago. And that study provides, we believe, ample support and evidence for what we hope will be an approval later this year, PDUFA date, December 26.

And at the same time, we're pending regulatory review in China and in Europe based also on SEQUOIA. And that informs the leading edge of our pipeline and go-to-market strategy. This past weekend at the European Society of Cardiology, investigators presented results from a second Phase III study called MAPLE, that study was positive, and we believe that could enable a potential label expansion, but not initially will we go to market based on MAPLE instead on SEQUOIA.

And as you may have questions, the team here, we can respond to how MAPLE factors into our life cycle management plans. A third study is completed enrollment and will read out in first half of 2026. That's a study called ACACIA. ACACIA is a study of aficamten in patients with nonobstructive HCM. So you begin to understand how aficamten is itself a pipeline in a pill, OHCM followed by nHCM, but for which there are 2 other drug candidates in later-stage development, omecamtiv mecarbil, a cardiac myosin activator, already the subject of over 30 completed clinical trials, including one 8,000-patient study called GALACTIC that was positive and for which we're now doing a second confirmatory study and how that may enable us to extend the franchise to advanced heart failure treated by the same physician group.

And then there's another cardiac myosin inhibitor called CK-586. It acts by a different mechanism. It's being developed for the potential treatment of heart failure and preserved ejection fraction. Three drug candidates, molecular target, one strategy oriented towards building an enduring business in specialty cardiology.

We have other compounds in earlier clinical development that are depicted on the pipeline. I won't speak to them today. So you begin to see how this all begins to play out in terms of what could be multiple specialty cardiology launches that could be occurring over successive time, starting with SEQUOIA by the end of this year, followed by MAPLE, followed by Acacia, followed by HFrEF, followed by HFpEF. And there, you begin to understand why we think a specialty cardiology business model, the likes of which really don't exist in biopharma, but for which we believe could build uncommon enduring value for patients and shareholders.

Over the weekend, I mentioned we presented results from MAPLE, this was -- these are the primary efficacy data as they were presented on Saturday in a late-breaking session simultaneously published in the New England Journal. And what you can see here depicted is patients on aficamten did better by the primary efficacy endpoint of peak VO2. This is a measure of exercise capacity.

Patients on the standard of care beta blocker, metoprolol actually did worse. How could that be standard of care? You might ask, this was the first randomized controlled study of a beta blocker in patients with OHCM despite the fact that beta blockers have been a mainstay standard of care in this disease for 60 years. And absent having done a proper study like this, we do believe now that these data are presented and published, they may turn heads and call into question the use of the first-line treatment in this population.

And as I think the cardiology community very enthusiastically embraced these data when presented on Saturday. If you're interested, we also convened an IR webinar this morning and the principal investor -- I'm sorry, principal investigator presented again, and those data and that presentation is archived on our website alongside of the publication.

Here are the design elements of the ACACIA study that I mentioned. As you may have questions, we'll get into that, I'm sure. ACACIA is due to read out in the first half of next year, as I mentioned. This is really interesting. Nonobstructive HCM represents probably half the population with HCM and where the prevalence would suggest it's growing at a faster rate than obstructive HCM.

The first-in-class compound in this category, a compound called mavacamten was recently the subject of a study called ODYSSEY in patients with nHCM. Those data were also presented on Saturday at the same late breaker. Unfortunately, that study was not successful. The study failed to demonstrate an effect on either of the two co-primary endpoints, but with trends that are really quite provocative and for which we believe they may illuminate that aficamten in ACACIA could represent a positive outcome.

And as you may have questions about what was presented and why we remain optimistic, Fady can speak to that in our question-and-answer session. So again, we're building a specialty cardiology franchise. You see here how they all fit together. This is a concentrated customer segment base where we believe with roughly 125 sales professionals in each of the United States and Europe, we can get to the high-volume prescribers who treat these advanced populations where there's a very high unmet need.

We believe we can build a specialty distribution network and with what we believe to be both payer leverage and differentiation amongst products, we believe we can build a very valuable business for shareholders with all of these products.

We have a strong financial position. We recently reported our Q2 earnings over $1 billion, approximately $1 billion in cash. And to the point, given deals we've done, and I do believe Cytokinetics has created a high watermark amongst peer group companies in terms of combining both equity dilutive, but especially leaning into nonequity dilutive capital with partnerships, royalty monetizations and the proper balance of debt, we believe we have access to still additional capital.

We have access to $100 million in a loan from Royalty Pharma that we have already qualified for, another $175 million that we may qualify for if aficamten is approved by the end of the year and an additional $150 million that may be available to us for the development of one of our pipeline programs.

So these are loans that come with deals we've done with Royalty Pharma and for which we believe the cost of capital is competitive and advantageous to us as we continue to hopefully be good financial engineers much in the same way we've developed our R&D pipeline. And Sung can speak to how we're thinking about not only access to capital, but how we can be efficient with regard to deployment of capital.

So with that, as an introduction, I'll turn it back to you for question and answer, and thank you for your interest in Cytokinetics.

Thank you so much for that, and I appreciate the seminar this morning. It was very interesting. I guess to start out, when we look at this space overall, OHCM and nHCM, naturally, people are looking at Camzyos, which is out there, mavacamten, and they're trying to measure that up against the profile of aficamten. Thus far, we can compare them on the actual data in OHCM, which is under the FDA review. But there's also these other emerging data sets with respect to MAPLE and ACACIA coming online, ODYSSEY from there end.

How do you see the profiles of these drugs ultimately being compared? I mean there's the REMS program. Yes, there is the data that will be on label, but they also -- all the doctors know that there's other things going on that differentiate them.

Yes. So that's a very good question. There's a lot to unpack. I'm going to turn it over to Fady, but I'll just start by saying, we played a hand in the discovery of mavacamten as it was discovered in a company that incubated within our laboratories before we spun it out as a separate entity.

So we know that compound quite well. We understand its positives, but also where there could be opportunities to engineer a next-in-class compound as we did. And aficamten was engineered with certain properties in mind, and we've studied it both preclinically and clinically to elaborate on what could be a differentiated profile. And we do believe the clinical studies that we've conducted in later-stage development, REDWOOD, SEQUOIA, now MAPLE elaborate on its profile.

With that, maybe I'll turn it over to Fady to answer your specific question.

Sure. As we -- as Robert said, and we work to discover aficamten, we had a particular profile in mind. We wanted a drug that could be titrated easily, drug that was reversible if you -- like with any drug you titrate to effect, you wanted to be able to down titrate simply, drug that's devoid of significant drug-drug interactions that complicate its use and ultimately, then to take those properties, including a shallow PK/PD relationship and develop a best-in-class data package for them.

And so through the conduct of our Phase II trial, REDWOOD, followed by SEQUOIA, which is now followed by MAPLE in obstructive HCM, we think that the safety profile of aficamten is exemplary with showing essentially that titration works and titrate the drug as needed. You don't have to interrupt treatment. You can down titrate the drug if necessary, patients respond to down titration.

We haven't observed heart failure events, significant heart failure events as a consequence of use of aficamten. And now as was presented at the ESC in addition to MAPLE was some very long-term follow-up data in our open-label extension.

So those -- those attributes have -- that we intentionally designed in aficamten now are manifesting themselves in our development program. And ultimately, we hope that leads to a label and practical everyday experience in using aficamten that make it something that physicians want to choose.

Understanding your REMS program is still in the works, and we don't have a submission. Where do you see given the recent changes that happened on Bristol's and as potential areas of differentiation for your program?

Yes. I think the properties, again, the way that we have employed aficamten in our clinical trials, we hope would be reflected in the label as well as REMS. So titration would occur on a more frequent schedule, so patients could potentially get to target dose within 6 to 8 weeks if they so choose, perhaps maybe longer than that if they decide to go more slowly.

If they don't have to worry about significant drug-drug interaction effects, that's another aspect of REMS that physicians might be educated on the label, but patients don't have to, every month, kind of go through their medication list with a pharmacist because there aren't as many or meaningful clinically significant drug interactions.

All of these things, I think, help, if you will, differentiate a potential REMS from another. And the REMS are reflective of your label. And so -- and the label is reflective of the use of the drug in the clinical trials as well as obviously, the data that you generate with them. And so I think if you look at our clinical data, they support a meaningfully differentiated REMS down the road.

In terms of once it's approved and launches, what's the lift in getting into the new-to-therapy patients versus potentially getting some switches. It strikes me that certainly given some changes regarding for Camzyos, a switch is a higher lift, a much heavier lift than would be new patients -- new to therapy. And towards that end, how penetrated is the market at this point?

Yes. So BMS is doing a nice job educating and building market awareness for the category of cardiac myosin inhibitors. They're adding about 1,500, 1,600 patients per quarter, and they're going to do north of $1 billion worldwide in sales this year, but for which in the United States, there's still about 650 physicians who are accounting for over 80% of the prescriptions, and it's incumbent upon us to work to grow the category and to hopefully have preferential share of category, but to ensure that more physicians are comfortable prescribing a cardiac myosin inhibitor for their patients.

Right now, we believe they've penetrated about 15% of the symptomatic diagnosed population and where there's even more who are undiagnosed and perhaps going to be available ultimately for treatment, and that's in the United States. So we believe that a next-in-class opportunity if aficamten were to be approved, could be opening the aperture on the market in ways that the differentiation could drive wider adoption.

Cardiology launches generally take longer. There's both that period under which you have to go from free drug to revenue-producing drug, but also just adoption takes longer, but they have long tails as well. And we do believe that there's quite substantial TAM here and enduring value that could make this one of the leading cardiovascular categories.

And it's important that Cytokinetics when we go to market, we're not seeking to compete with BMS. That would be perhaps bringing us both down, but rather as could be enabling of more patients to benefit from this innovation. So while there may be some switches, and we're hearing that there are high-volume prescribers who are intending to switch their patients, that's not going to be core to our strategy. Rather instead, what's core to our strategy is building on the momentum and speaking to the integrity of our data, our science and its implication for patients with OHCM.

On the question of the high-volume prescribers, because of the burdensome REMS program, has there been kind of a conglomerate of people who will just pass the patients on because they don't want to deal with the program towards these high-frequency prescribers? And can a drug that gets kind of has a more simple or easier program push beyond that group?

Yes. So we've been out in the field, if you will, for a couple of years seeking to answer that question. And I think we've got a lock on it. We understand referral patterns very well locally, metro area by metro area. And we understand how they translate to payers.

We have had 15 area business managers and many MSL's deployed for a long time readying for our commercial launch. We believe we understand it well enough to know this that right now, a lot of community-based cardiologists are choosing to refer patients to centers of excellence, but reluctantly. And that if there is a potential new medicine that could be available with a less burdensome REMS that they may be more likely interested in prescribing themselves. And we believe we can activate them if aficamten is approved with the differentiated label that we expect of it.

So our strategy will be to focus to centers of excellence and also where there may be low-lying fruit in the peripheral community of cardiologists who also see a lot of HCM patients. And our intention is to be focused to where we can influence both those high-volume prescribers who have themselves already been warehousing patients awaiting the potential of aficamten and as they've told us, and at the same time, grow the category beyond where currently cardiologists are comfortable prescribing.

So you presented details of MAPLE this past weekend, and the data was very, very strong. It was clearly superior. How does that translate ultimately into a market opportunity? Is it -- how difficult is it going to be to move into the first line? How should we think about that when we're building our models? And secondly, do you see as there being a benefit just from optics perspective of eventually having on label that might help after beta blockers, even though the trial is for frontline?

So the question you just asked, I asked that of many opinion leader cardiologists over the weekend. And where I do believe for the fact that beta blockers are a mainstay standard of care and they're cheap, that it's not going to be overnight that we see practice changing.

But to my surprise, many cardiologists indicated that when they get back to their offices today, they will be looking at certain patients differently than they would have last week for knowing these data and that the time that they may remain on beta blockers could be shortened.

At the end of the day, this ultimately has to factor into guidelines. And to be clear, we won't be promoting MAPLE data upon launch. It won't be in our label. We will be compliant to label, but for which we could imagine that there may be some physicians who are more likely going to be looking more skeptically or critically at beta blockers.

And ultimately, this will take some time, but I do think it could be enabling of aficamten to become a first-line therapy for these patients. Fady, I think, has a better insight into this, and maybe he should also comment.

Yes. Obviously, beta blockers have been entrenched for decades and people have a lot of comfort with using them. If our data weren't so compelling, it would be, I think, a long road to displace them. But the fact that aficamten was better than metoprolol was not surprising to me. It was -- I expected that to be the case.

But what was, I think, surprising to the physician community was how ineffective metoprolol was. And obviously, that should cause one to question its use. Now remember, these things can always be tried and one can switch from one to the other. But I think the data over time, as they get incorporated in time lines, as physician practice begins to evolve, you'll begin to see not in year 1, year 2, but out in the outlying years, you'll begin to see a greater proportion of physicians that decide to go straight to CMI's.

Payer practices will probably evolve over time to support that as well. So this is a trend that's been seen not once but many times before a medical practice where the newer therapy displaces something that maybe has been entrenched for quite some time.

It's very interesting. I'd be curious to see how that ultimately evolves. If we move on now to nonobstructive and obviously, Acacia is going on, and there is data presented today with respect to Camzyos from ODYSSEY or presented this past weekend.

Could you run us through what your takeaways from that data is? And what are the deltas that -- from the Camzyos experience that could be different for you because they came close, they just were a little short.

Yes. No, absolutely. We were pleasantly surprised to see that there were positive trends on their endpoints. and that the underlying data, the rationale for using the drug in nHCM was also positively impacted. It reduced NT-proBNP, which presumably reflects improved healing pressures.

It reduced or improved diastolic function and the relaxation of the heart. And then you saw peak VO2 move in the right direction. You saw KCCQ, their other primary endpoint move in the right direction. That one was confounded by an unusually large placebo effect that is not typically observed to that magnitude with KCCQ.

And -- but what was clearly evident is that the way that the drug was dosed confounded the interpretation of the results. So they had upwards of 25% of patients that had to interrupt treatment at some point during study. Some of those went on a discontinued treatment permanently.

We had patients that developed heart failure as a result of some of the EF excursions. Obviously, that impacts patients' assessment of their health status as well as their exercise performance. And there were doses that were utilized that haven't been studied before for their effectiveness like 1 milligrams or 2.5 milligrams.

And so what we put together with that is that perhaps there was a dilution of the treatment effect. And we'll have to wait and see if they publish an on-treatment analysis that excludes patients whose treatment were interrupted. But they indicated as much as that they were planning to do so, and you would think that if that was the case, there's probably something there.

Aficamten, we've -- in our Phase II and open-label extension experience, we've been able to dose aficamten with an EF-guided algorithm that has been well tolerated, hasn't led to discontinuations of treatment or treatment interruptions or severe heart failure events.

In the background of that, we've seen improvements in diastolic function. We've seen improvements in NT-proBNP even to a larger extent than they observed. And so I think at least the fundamental basis for believing that this drug should work in nHCM is still intact and perhaps something that is less prone to confounding will help us get to the right answer.

And obviously, we'll find that out not too far from now. So getting back kind of to a question I had asked earlier. Now if you're a doctor out there and you're prescribing and you're trying to compare the two data sets that are on label, which is always fraught with difficulties and it gets noisy.

But you have a label that one of the therapies has MAPLE on it and does have nonobstructive, assuming the trial works out. What does that mean for the on-label indication right now that eventually it can turn out there? Does that mean that the profile of aficamten in the head-to-head indication right now is actually improved? Or do you think doctors will view them all as completely separate indications?

Well, I think the -- I mean, that remains to be seen, but you invest a lot of time learning how to use a particular drug. And if you can use one for everything, and there's no reason to necessarily pick the other because it's superior in some aspect.

I think the rational thing is that people will simplify their practice of medicine and kind of focus on the one that has the most uses. So Acacia could provide a, if you will, rationale for focusing on the use of aficamten if Acacia were positive. And I think physician practice ultimately might reflect that.

I think there's two ways to answer your question. And it's -- does the properties of the molecule lend itself to the potential approval across different indications? Or do the indications ultimately drive the use of the molecule? And I think they're, in some ways, one of the same. This is a bit of a reciprocal.

So we've designed and engineered into aficamten certain properties that may lend it able to be studied in such a way that it could translate to positive outcomes in OHCM and nHCM. That was the intention. And I believe enabling of flexible dosing, flatter PK/PD relationships and the opportunity to achieve greater dose density is hopefully going to be serving us well not only in OHCM but also in nHCM.

So we've got five minutes left here. What do you think we should -- we could talk about a lot of things we could talk about what your marketing effort will look like or if you want to move into omecamtiv, what do you think that the Street is not paying attention to that we should be?

So maybe I'll answer that real quick, but I also want to make sure that we get a chance for you to learn a little bit more about how we're thinking from a corporate development and a finance standpoint because I think those things matter also to ultimately inform the full picture of Cytokinetics.

To your question, omecamtiv mecarbil is the subject of a study called COMET, which is designed to confirm what we've already seen in GALACTIC. In GALACTIC, 4,000 approximately patients were enrolled in each of two arms. And this was a study of a broader, more heterogeneous group of heart failure patients with ejection fractions below 40, and we saw a statistically significant effect on death and readmission.

But admittedly, it was a more modest effect. But in the more advanced patients with EF below 30, it was more than double. So FDA and EMA have asked us to now go back and do a smaller study just in that population, confirm the effects. And if COMET is positive, which we have every reason to believe it can be, that could be really meaningful for patients who right now don't have a good treatment for the more severe forms of heart failure.

So in effect, we're doing a 2,000-patient study to replicate something we've already seen in an 8,000-patient study, of which 4,000 of those patients match up to the inclusion criteria in the 2,000-patient study. So we hope this is going to be like being on the 5-yard line first in goal and an opportunity to bring this forward to the end zone for patients and shareholders. So that study, COMET is already enrolling. Hopefully, it completes enrollment next year and would be another pillar in our franchise development strategy.

Sure. So we think about business development from two perspectives. Our primary focus is obviously the launch of aficamten and making sure that patients everywhere in the world get access to it. So as you know, late last year, we did a deal in Japan.

We have a partner in China with Sanofi, Bayer in Japan. There's still the rest of world territories. We are obviously building our own franchise in Europe. But there's been considerable interest in being able to work with us in those territories. So that's something that is of great focus to aficamten.

Separate to that, there's in-house expertise, as you can imagine, both from a biology perspective, chemistry in muscle diseases in general, not just cardiac, and we are going to leverage that.

From a business development perspective, we look at multiple programs, both preclinical as well as clinical to augment our pipeline. We'll do that in a cost-effective way, but we really are in a unique situation to bring best of breed.

We did a deal last year from an equity perspective with Imbria, where we think that is a very unique molecule. We continue to do that across the board, and that's something that you should pay attention to and expect from us.

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Sure. So obviously, in building a cardiovascular franchise, we want to make sure that whatever we do, we could use -- we can leverage our sales force. I will say that our focus has been on small molecules. We look to expand outside of small molecules into other modalities, but ones that are already well established, and so skeletal muscle and cardiac are probably the primary focus for us.

None of this happens without a strong balance sheet and good financial discipline. So maybe Sung could speak to sort of how we're approaching those matters.

Sure. Happy to. And just to reiterate what Robert said, we ended quarter 2 with a very solid balance sheet position with $1 billion in cash and investments. Of course, this was made possible through the financings that we did about a year ago. partly equity, but also partly nonequity provided by Royalty Pharma.

I also want to focus you on the capital that lies ahead of us in addition to the $1 billion in cash and investments already on our books. So as Robert mentioned, we're eligible to take down $100 million loan from Royalty Pharma this year. We've already qualified for that. We could further become eligible for an additional $175 million should aficamten be approved this year in the U.S.

So those will be very two important levers for us in terms of adding capital to our balance sheet. Also, we have pipeline funding. Should CK-586 move into a pivotal study, Royalty Pharma has the option to opt in up to $150 million. So that could be potentially an important source of capital to further advance our pipeline.

Excellent. I think we've run up to the end of our time. Thank you so much. Always great and look forward to seeing you again soon.

Thanks very much. Appreciate it.

Welcome, everyone, and thanks for joining. I'm Diane Weiser, SVP, Corporate Affairs. We're pleased to be discussing new data presented this weekend at ESC, including the primary results from MAPLE-HCM as well as other data related to aficamten.

I'm joined today by my colleagues, Robert Blum, President and CEO; Dr. Fady Malik, Executive Vice President of R&D; and Dr. Dan Jacoby, VP of Clinical Research. I'm also pleased to welcome our esteemed HCM experts. With us today are Dr. Pablo García-Pavia, Head, Heart Failure and Inherited Cardiac Diseases Unit at the Department of Cardiology of Hospital Universatario, Puerta de Hierro; Dr. Carolyn Ho, Medical Director of the Cardiovascular Genetic Center and Professor of Medicine at Harvard Medical School; Dr. Ahmad Masri, Cardiomyopathy Section Head and Director at the Hypertrophic Cardiomyopathy Center and Associate Professor of Medicine at Oregon Health & Science University; and Dr. Anjali Owens, Medical Director at the Center for Inherited Cardiac Disease, Director of the Hypertrophic Cardiomyopathy Center and Associate Professor of Medicine at the University of Pennsylvania. Thank you all for being here today.

Moving to our agenda. First, Dr. Fady Malik will provide introductory comments. Next, Dr. Pablo García-Pavia will provide an encore presentation of his hotline of MAPLE-HCM results from the conference. Then Dr. Malik and Jacoby will lead a discussion with Dr. García-Pavia, Ho, Masri and Owens to provide perspective on the data and answer questions. And finally, Robert will provide some closing remarks. [Operator Instructions]

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.

In addition, on today's call, Dr. García-Pavia, Ho, Masri and Owens will share their professional perspectives on the clinical significance and safety implications of aficamten-related data presented at ESC. These perspectives are solely the opinions of Dr. García-Pavia, Ho, Masri and Owens and may not reflect the opinions of Cytokinetics or other experts who review these data, including those who will review the NDA for aficamten at FDA and applications submitted to other regulatory authorities. Dr. García-Pavia, Ho, Masri and Owens are here today as contracted consultants with Cytokinetics.

And now I will turn the call over to Fady.

Thanks, Diane. Over the weekend, we were proud to present 4 oral presentations and 1 poster related to aficamten, accompanied by 3 simultaneous publications in leading cardiac journals. The depth and breadth of these data add substantially to the existing body of evidence supporting the potential of aficamten as a treatment for obstructive hypertrophic cardiomyopathy.

To start off, on Saturday, Dr. García-Pavia presented the primary results from MAPLE-HCM, the Phase III active comparator clinical trial comparing aficamten to the standard of care beta blocker metoprolol in patients with oHCM, which was also published in the New England Journal of Medicine. This study is truly the first of its kind, providing both a direct look at the treatment effect and safety of treatment with a cardiac myosin inhibitor versus a beta blocker and a look at the efficacy, safety and tolerability of metoprolol itself in oHCM. The results in showing the superiority of aficamten to metoprolol challenged the rationale for the long-standing first-line approach of treating HCM with beta blockers.

As Dr. García-Pavia will elaborate, while aficamten improved exercise capacity, metoprolol resulted in a meaningful reduction in exercise capacity. Treatment with aficamten also produced larger improvements in symptoms, gradients and cardiac biomarkers as compared to metoprolol with a similar rate of adverse events.

Additionally, Dr. Sheila Hegde from the UT Southwestern Medical Center in Brigham and Women's Hospital presented a prespecified analysis of the echocardiographic data from MAPLE-HCM. The analysis showed aficamten had a larger impact than metoprolol on measures of cardiac structure and function, improved measures of diastolic function and reduced key contributors to left ventricular outflow tract obstruction. These results were accompanied by a publication in the Journal of the American College of Cardiology.

Beyond MAPLE-HCM in a late-breaking clinical science section, Dr. Masri presented an analysis showing that in FOREST-HCM, the risk of atrial fibrillation was quite low during long-term treatment with aficamten and consistent with expectations from validated prediction models of atrial fibrillation. In those that did develop atrial fibrillation, it did not negatively impact clinical status. These data were published in heart rhythm. Given atrial fibrillation is an emerging topic of conversation around the use of cardiac myosin inhibitors, these data suggest long-term treatment with aficamten does not appear to increase the risk of atrial fibrillation in oHCM.

Dr. Sara Saberi from the University of Michigan also presented longer-term data from FOREST-HCM with a mean follow-up duration of 62 weeks and a maximum follow-up duration of over 3 years. As we've previously -- as you've seen previously from FOREST-HCM, these data again show that aficamten is associated with early and sustained hemodynamic clinical benefits, along with a low incidence of new onset atrial fibrillation and LVEF less than 50%.

Adding further to these findings from our updated integrated safety analysis presented by Dr. Masri builds on the first integrated safety -- it builds on the first integrated safety analysis we presented last year, inclusive of REDWOOD-HCM, SEQUOIA-HCM and FOREST-HCM, now including MAPLE-HCM as well. Combining 463 patients and almost 700 patient years of experience, aficamten was shown to be well tolerated with a low incidence of LVEF less than 50% and no occurrences associated with serious events of heart failure. All in, these data expand the evidence base for aficamten and deepen our understanding of its potential application in OHCM.

Now I'll hand it over to Dr. García-Pavia to present the results of MAPLE-HCM.

Thank you very much. So it's my pleasure to present the data of the MAPLE-HCM that were presented last Saturday in the late-breaking trial session of the European Society of Cardiology Meeting. Next.

So on behalf of Michael [indiscernible], again, I present this data of the trial MAPLE-HCM. Next. Here, you can see my disclosures. So HCM is a disease characterized by hypercontractile left ventricle hypertrophy and left ventricular outflow tract obstruction, resulting in limiting symptoms and reduced exercise capacity. Aficamten is a next-in-class cardiac myosin inhibitor that targets the underlying pathophysiology of HCM by reducing hypercontractivity. Aficamten has demonstrated already several benefits in patients with obstructive HCM who are symptomatic despite standard of care therapies.

In this study, well, currently, the most common standard of care therapy used in clinical practice is beta blockers. Beta blockers have been the first-line treatment for symptomatic patients with obstructive HCM for more than 60 years despite very limited evidence. In fact, beta blockers are recommended both by the European and American guidelines with a Class I level of recommendation as the first-line therapy of choice in patients with symptomatic obstructive HCM.

Next. In MAPLE-HCM, we sought to evaluate the safety and efficacy of aficamten in monotherapy compared with one of the most commonly used beta blockers in these patients, which is metoprolol in monotherapy. So unlike the previous studies, we are not adding aficamten to standard of care medication. Here, we are treated -- we are comparing aficamten with the standard of care medication. The primary endpoint of the study was exercise capacity assessed through peak VO2, which is a parameter that is captured in cardiopulmonary exercise test. Secondary endpoints include symptoms, Valsalva LVOT gradient, so the degree of obstruction under Valsalva, NT-proBNP, which is an accepted biomarker of heart failure and third time, echocardiographic parameters like left atrial volume index and left ventricular mass index.

In this slide, you can see the design of the MAPLE-HCM study. We randomized 175 patients to receive either metoprolol plus placebo or aficamten plus placebo and follow them during 24 weeks. During the initial 6 weeks, both investigational products were dose adjusted based on site echocardiogram parameters and vital signs. Both patients with frequently diagnosed or treatment-naive obstructive HCM and patients with chronic obstructive HCM on standard of care medications could participate in the trial. If the patients were already taking standard of care medications, they had to undergo a 2-week washout period of standard of care medications before undertaking the screening visit were qualified for the study.

Here, you can see the baseline characteristics of the participants in the study. Overall, patients had milder phenotype than those patients previously included in previous CMI studies. The median NT-proBNP of patients participating in the study was around 500 picograms per ml. The mean peak VO2 value was around 20 mls per kilo per minute. And regarding gradients, LVOT gradient addressed or with Valsalva were around 45 millimeters of mercury or -- and 75 millimeters of mercury, respectively. Of note, we observed that there were more patients with hypertension in the aficamten group than in the metoprolol group.

During the trial, the majority of patients were exposed to the highest doses of metoprolol and aficamten, as you can see here on the slide. And at week 24, we found that 10 patients who were receiving metoprolol did not tolerate any dose of this drug as compared to 1 patient on the aficamten group. At week 24, patients receiving metoprolol exhibited a mean decrease of 6 bits per minute in resting heart rate and a mean decrease of 6 millimeters of mercury in systolic blood pressure as compared to a mean decrease of blood pressure of 5 millimeters of mercury in aficamten group and no change in heart rate at rest.

And here is the slide where we presented the results -- the primary endpoint results. After 24 weeks of therapy, among patients receiving metoprolol, we observed a mean decrease in peak VO2 of 1.2 ml per kilo per minute. While in patients receiving aficamten, we observed a mean increase in peak VO2 of 1.1 ml per kilo per minute. The absolute less square mean difference of aficamten compared to metoprolol was 2.3 ml per kilo per minute, which was statistically significant with a p-value of less than 0.001. This difference is way above the minimum threshold of clinically significance in clinical practice, which is considered 1 ml per kilo per minute.

Next. When analyzing the prespecified subgroups regarding the primary endpoint, we observed no heterogeneity, including for the diagnostic period of the disease in patients participating in the study. Regarding secondary endpoints, both improvement in NYHA class, change in KCCQ, which is a parameter of quality of life, change in NT-proBNP, Valsalva LVOT gradient and left atrial volume index were all statistically significant in favor of aficamten, while the change in left ventricular mass index was not statistically significant.

Analyzing deeper the parameters of the secondary endpoints. And here, you can see the functional class. We observed that at week 24, 51% of patients treated with aficamten and 26% of patients treated with metoprolol had one or more improvements in NYHA classes. Of note, at week 24, 40% of patients receiving aficamten were asymptomatic in NYHA Class 1. While in the metoprolol group, this percentage of patients who were asymptomatic was only 9%.

Regarding KCCQ, a parameter of quality of life, we observed that among patients who received metoprolol, they did improve in this parameter but the improvement observed in patients receiving aficamten was larger with a less square mean difference between groups at week 24 of 7 points, again, statistically significant. Surprisingly, during the trial, we observed that metoprolol did not improve resting LVOT gradient or Valsalva LVOT gradient, which is the obstruction that these patients suffer when systolic ejection of blood from the blood.

In contrast, patients receiving aficamten had a sustained and early decrease in obstruction as observed in the graphs with a mean LVOT gradient at the end of the trial in both cases for rest and Valsalva gradients below the accepted thresholds in clinical practice that are shown here in the graphs in the other lines.

Next. Regarding change in NT-proBNP and left volume index, which are 2 parameters of diastolic dysfunction. We observed that those patients who received metoprolol, these parameters increased during the trial, while these parameters decreased in the group of patients receiving aficamten. Of note, by the end of the trial, NT-proBNP values in the aficamten group was -- were at the upper limit of normality, as you can see here in the graph with an 81% reduction compared to baseline.

Regarding safety, aficamten was well tolerated. 3 patients had to stop metoprolol during the trial due to adverse event as compared to 1 patient on aficamten. Of -- a total of 26 patients had to reduce the dose of metoprolol during the trial compared to 4 patients on aficamten. Consistent with the mode of action of aficamten, at week 24, we observed a mean decrease in left ventricular ejection fraction in the aficamten group of 5.3% compared to a decrease of 0.5% in the metoprolol group. But only 1 patient in the aficamten group had a left ventricular ejection fraction below 50% as assessed by the core lab, and this patient did not have any heart failure symptom or sign. And actually, the left ventricular ejection fraction reduction got resolved without stopping aficamten just by decreasing the dose.

Next. So in conclusion, the results of the MAPLE-HCM study show that aficamten in monotherapy was superior to metoprolol monotherapy in patients with symptomatic obstructive HCM with a statistically significant and clinically meaningful improvements in exercise capacity, symptoms, Valsalva LVOT gradients, NT-proBNP and left atrial volume index. Despite we had been using metoprolol for more than 50 years to treat patients with obstructive HCM as the first-line therapy, and there was a strong evidence of on-target hemodynamic effects with metoprolol, both in heart rate and systolic blood pressure, we did not observe a decrease in obstruction addressed or with Valsalva in participants receiving metoprolol in this trial. Aficamten treatment was well tolerated. And overall, we consider that these findings support aficamten monotherapy as the first-line therapy of choice in patients with symptomatic obstructive HCM.

Next. We want to thank all people who have made this trial possible and particularly participants and their families. Next. The results of this trial were published simultaneously on Saturday at the New England Journal of Medicine. Thank you very much.

Thanks, Pablo. To dive deeper, I'd like to shift now to our panel discussion. I'm pleased to be joined by my colleague, Dr. Dan Jacoby. And alongside Pablo, we also welcome Dr. Carolyn Ho; Dr. Ahmad Masri and Dr. Anjali Owens.

I'd like to start by discussing the results of MAPLE-HCM, including the primary results and the echocardiographic analysis on the effect of aficamten compared to metoprolol on cardiac structure and function. But first, Pablo, it was quite an exciting weekend. Obviously, lots of over 30,000 people attending the ESC and several thousand of them in the presentation hall where you gave this presentation. Can you just give us your perspective on the impact of the results from MAPLE-HCM and then perhaps comment on the reactions to your presentation at the Congress.

Thank you, Fady. Yes. I mean the presentation was a great success. We have been using a drug that for more than 40 -- 50 years that actually had very limited evidence to support its use in this disease. And this trial not only brings a new drug to treat these individuals as first-line therapy and in monotherapy, but also provides the data to conclude that the existing therapy that we were using and which is prescribed massively, I will say, has limited efficacy in these patients and potentially even with some of the parameters that we have shown, it could deteriorate these individuals.

So therefore, this is certainly a game changer as stated by the moderators of the session and the excitement that I saw in all the people who came to the Congress based on these results was massive. It really will help us in having a better drug in order to improve for patients with very limited side effects as shown in the study. So really, I was delighted to present this data in my hometown of Madrid, and everybody stated that this was one of the most important presentations of the Congress. I mean, actually the most important congress that is -- that there is in the world based on the number of people attending the Congress, which was around 35,000.

Thanks, Pablo. I'm sure it was truly a special experience for you in doing this in your hometown. And for many of us, it's Cytokinetics that were there at all to witness it. Also participating in that [ highline ] session was Dr. Ho, who was a discussant of your presentation. And Carolyn, do you want to perhaps just summarize what your comments were and also maybe add to Pablo's perspective?

Yes, absolutely. And I would just like to build on Pablo's comments about the importance of this trial, mainly in showing us that what we had assumed to be the standard of care approach to symptomatic obstructive hypertrophic cardiomyopathy was not nearly as good as we thought it was. And that really highlights the importance of doing proper randomized clinical trials to guide our clinical management. And I think that what people were most shocked by at the Congress was just how poorly beta blockers perform in this population.

So this is, again, the treatment that we have long assumed for decades to be the way to go to try to help improve symptoms and our patients are just being shown with objective evidence that they really don't achieve any of the objectives that we were hoping they would in terms of gradient reduction, symptom improvement or improvement in functional capacity was really very regulatory, I would say.

That's great. Yes. I suspect did shake people's presumptions about the treatment that they were using for so long. And I even heard in some cases that people questioning what they would do when they would go back to their patients that are continuing to take beta blockers. But maybe I can ask also Dr. Masri to comment. You gave several presentations at the Congress. And obviously, you probably also interacted with many of the attendees. Dr. Masri, do you want to give your perspective as well?

Definitely, congratulations to everyone here on the call and to really our patients because we delivered on something that really has been, in a way, entrenched in the practice. And we've observed a long time ago that once you go on beta blockers and whatnot, it's not necessarily what everyone believes it to be. So great to have very proper randomized clinical trial data to support that. Aficamten performed as we've expected to, correct? We've had now accrued so much data and evidence behind aficamten. I think really the highlight of MAPLE is the fact that metoprolol did not just not do what we wanted it to do, which is affect hemodynamics to improve symptoms and quality of life in a meaningful way beyond what we expect from placebo, but also worsened exercise capacity, which is important for long-term outcomes as well, worsened measures of wall stress, diastolic function such as NT-proBNP and left atrial volume index.

And so these things for me are really important because the principle is always for us is we want to help patients and not harm anyone. Those are the principles. And harm doesn't have to actually be that you are leading to an adverse event that you can visually see in front of you. It can also be that you are reducing their exercise tolerance and their ability to do more aside from the side effects.

Now for the longer-term data, which I'm sure we'll discuss later on, what's important from my perspective is that when you use a hemodynamic modulator with a myosin inhibitor, it is really meant not to only focus on the initial duration of the randomized clinical trial. The randomized clinical trial establishes the efficacy and the short-term safety. But the long-term data are so vital for us, especially as a drug like aficamten progresses hopefully in the next few months to early next year to the commercial stages that you want to make sure that over a long period of time, this drug performs from an efficacy and safety perspective as you would want it to.

Okay. Great. Thanks, Dr. Masri. I think the -- we got several questions from our people online as well as prior to this call. Let's go through them perhaps, and then I'll get people's opinions on this. So the first question is the level of peak VO2 improvement in MAPLE was 1.1 for aficamten, which was slight as a change from baseline for itself in the aficamten treatment group, which was lower than that of 1.74 that we observed in SEQUOIA. And so the question really is, what do you think contributes to the lower absolute treatment effect for aficamten relative to baseline and whether can you make this sort of cross-trial comparison. So Dr. García-Pavia, Pablo, do you want to add...

I will address that one. Yes. I mean the population of patients included in the study were -- in both studies were completely different. These patients included in the trial were milder in the sense that these were patients who had better excess capacity at risk. So if you are starting in a higher point, it's more difficult to go higher than if you

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I think that's a fair point. I mean these are very different populations. One of our questions here is what's the rationale behind including less severe patients in MAPLE as SEQUOIA. Maybe I'll take that. Because -- the -- as we designed the study, when we designed SEQUOIA, we really were focused on treatment failures, patients who had still very high gradients, resting gradients, symptoms despite being treated sometimes with even up to 3 different medical therapies. And in this case, we wanted to expand the population to really understand the treatment effect of aficamten in all comers, anyone who met the criteria for obstructive HCM, which is a gradient, either Valsalva gradient 50 or a resting gradient greater than 30.

In SEQUOIA, that was an and. Patients had to have both. They had to have worse exercise performance and other things at baseline. And so this we thought would apply more generally to clinical practice and the effects would be more generally applicable to what people see as patients come in.

And can I say also that -- given say that the degree of improvement was less than the one shown in SEQUOIA, it was still above the minimum threshold difference considering clinical practice, which is 1 ml per kilo per minute. And we know from retrospective studies that were published that, if you increase the -- as the increase of PPO2 goes more than 1 ml per kilo per minute, the risk of death and heart transplantation gets reduced more than 21%. So I think it's fair to say that was less, but it still was significant.

Yes. No, absolutely. Why don't we go to the next question. And the next question, maybe I'll throw to Dr. Jacoby because he's most familiar with these details. It has to do with 3 patients on aficamten were down-titrated due to LVEF less than 50. Did this happen at the maximum dose? Dr. Jacoby, do you want to take that one?

Yes, sure, sure. Yes, the doses were a range of the upper doses for those patients and the down titrations occurred at different points in the study. There wasn't any real pattern to it. And it was not just at the highest dose that the down titration occurred. So -- which is not completely unexpected. It's what we've seen across our studies. These are individually titrated doses based on echocardiography for that individual patient. And so although there is some relationship between dose and effect, it's not surprising that you would see a range of doses. But these did not occur at the lowest doses, which is important. The lowest doses remain safe without any real incidence of LVF excursions in those groups.

Thanks. This is an interesting one. So on safety, the most common adverse event reported was hypertension for aficamten, is this something that needs to be monitored or treated? And how is this different than what was seen in SEQUOIA? Maybe Dr. Masri, I'll ask you to take this one because I know we've discussed this many times.

Yes. This is a long-term experience with the relief of LVOT obstruction. You're improving cardiac [ stroke ] volume and cardiac output. And when you are relieving LVOT obstruction, you're essentially unmasking. These patients have arterial stiffness and other arterial issues that contribute. And so you're just making them feel better, improving their stroke volume, cardiac output, and that's why you see this blood pressure rise and it can usually be easily treated. This is not really, in a way, thinking of it as an adverse event that the drug actually raises blood pressure because we've seen that across the board from other myosin inhibitors, and we see this also in our experience after you release LVOT gradient using other methods and metrics as well.

It's really kind of unmasking an underlying condition that exists preexisting. Our next question is that given that beta blockers seem to be making patients worse in some aspects, do you think the evidence is strong enough to warrant skipping them as first-line option altogether and using aficamten upfront? And maybe Dr. Owens, I'll ask you to comment on that question.

Sure. Happy to comment. I think that what MAPLE showed us is that using a targeted therapy that addresses the underlying pathophysiology of a disease works better than a nonspecific therapy that was used because, quite frankly, it was the best that we had. And so I think certainly moving towards treating a disease with a targeted therapy is where we're headed. And I absolutely think that this data supports starting a CMI early, if not first. There are other things that we have to take into consideration when we treat large volumes of patients, including access to therapy, implementation of new therapies and, of course, cost of new therapies. So there are other things in the real world that we have to take into account. But I 100% think that this tells us beyond a doubt, move to a targeted therapy when you have one.

I think also there was probably a little confusion maybe about the message in terms of the use of beta blockers in this condition. And we have a question, is there a role left for beta blockers in treating oHCM? And maybe Dr. Ho, I'll ask you to comment on that because I think you did address that in your discussion.

Yes, absolutely. So it's tricky, right? Because as Anjali said, it's not just about taking therapies in isolation, we had to consider access, costs, ease of implementation and all of that. And also, the MAPLE trial was designed to take people that weren't feeling well on beta blockers. So it was a little bit selected in that way. So I think that it's possible that there are some people with very mild manifestations of HCM and mild symptoms that it might be practically easiest to initiate beta blockers first and see how they do on that. And that might be the niche for beta blockers and beta blockers are also very helpful in treating other issues related to hypertrophic cardiomyopathy like atrial arrhythmias or ventricular active.

So I think that they will continue to play a role in the management of our patients along those regards. But certainly, a more targeted therapy like a cardiac myosin inhibitor is far more effective in terms of treating the more pronounced manifestations of disease and specifically alpha tract obstruction and the issues related to alpha tract obstruction.

Pablo, do you want to add to that?

Yes. I think that when -- I mean, I think the data really support aficamten as first-line therapy in monotherapy in these patients. So what this data are going to do is that they're going to change the order that we use these medications. In the trial, obviously, I mean, people who go into a trial is because of a reason, and there was a group of patients who probably were symptomatic already on beta blockers. They stopped the medication and then went into the trial and receive either beta blocker or aficamten. But there was still a 30% of newcomers that were not on therapy before -- were not taking beta blockers before going into the trial. And we observed exactly the same findings analyzing the participants based in previous exposure to beta blockers or not.

Moreover, we also undertook an analysis based on the -- what was the dose of beta blockers that were taken in order to see if that had made any contribution to the results and no interaction with beta blocker dose was found. Moreover, you could say, well, maybe only patients who were intolerant to beta blockers were -- or who had side effects due to beta blockers went into this study. But that was not possible because there was a clear exclusion criteria to participate in the study, which was intolerance or side effects due to previous beta blocker exposure because we didn't want to have somebody into the trial who maybe will have received beta blocker during the trial.

So really, really solid data here. Moreover, even if we excluded the 10 patients who actually did not tolerate the beta blockers, we got exactly the same results.

Great. Thanks, Pablo. And lastly, Ahmad, I know you addressed this question in one of your talks, do you want to also perhaps briefly comment? I think it's a really important point.

Definitely. I think ultimately, you have Phase III randomized clinical trial data. Again, this wasn't an easy trial, kudos to all of you and us for actually our patients for doing this. But really, it wasn't an easy trial and it was been very -- conducted very well. Now the question is, do you now use beta blockers widely as a first-line therapy in obstructive hypertrophic cardiomyopathy or what? And the takeaway for me from this is that it becomes on a case-by-case basis. If you have reasons to go for it, you have reasons to go. But the big elephant in the room is that we need aficamten to be available as well to be able to use it as a first-line therapy and monotherapy for these patients. So that's ultimately the goal here. But the beta blockers would be, in my opinion, a case-by-case basis going forward.

Great. Thanks, everybody. In interest of time, I want to move on to a couple of the other presentations that were made, and maybe I'll turn it over to Dr. Jacoby to introduce the next topic.

Can you hear me? So we received a number of questions about the results of ODYSSEY actually. And this was presented over the weekend by BMS. And the questions here are

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ACACIA-HCM. Obviously, we've excluded questions that compare aficamten to other compounds for obvious reasons. But I guess I want to start off really by asking Ahmad -- Ahmad's fallen off here. But I guess I want to ask Carolyn in that case, why do you think ODYSSEY didn't hit its primary endpoint here? Do you have a perspective on that? And then as a correlate to that, I mean, I guess can you opine on any particular aspects of the FOREST plot or the subgroup analysis that might provide any insights there?

Yes. Well, I guess that's a million-dollar question and so much to think about. ODYSSEY was really important in being the first quite large-scale testing of a cardiac myosin inhibitor for symptomatic nonobstructive HCM. And we're learning as we go along. And I think that one of the big things that stood out to me is that nonobstructive HCM is relatively straightforward. We have a good target to go for in terms of drug titration and improving and resolving obstruction really is associated with clinical improvement, symptomatic improvement, improvement in feel and function.

Nonobstructive HCM is much more complex and heterogeneous. And so it might be that a one size all approach doesn't work for nonobstructive HCM as it does for obstructive HCM. There -- we fundamentally don't know really what the mechanism underlying symptoms are in nonobstructive HCM. We believe that it's -- they're largely driven by diastolic abnormalities and inefficient myocardial energetics, which may be improved by cardiac myosin inhibitors. But I think trying to think about what dose is needed is important. I mean it's difficult with nonobstructive HCM because we don't have a clear biologic target to give us minute-by-minute readout as to whether we're giving the right dose with obstructive HCM, we're able to target the minimal effective dose.

But once we've relieved obstruction, we can stop dose titration. But with nonobstructive HCM, we want to guard against under dosing, particularly in the realm of clinical trials. And so we're really going for the maximum tolerated dose and up titrating as long as LVEF seems to be still tolerating. And so I think a lot to learn. They were obviously was relatively close statistically to hitting significance, both in peak VO2 and KCCQ. And so I think there's still potential for CMIs to be beneficial or nonobstructive HCM, we just need to await further information as it comes through.

Yes. Thanks, Carolyn. And what I hear you pointing out here is that you really need a kind of drug that can have a therapeutic window between efficacy and toxicity that's broad enough to be able to titrate the dose there. Pablo, do you have any thoughts or did you hear anything in terms of discussions at ESC on this topic?

Well, obviously, it was a big disappointment because we -- I mean, for obstructive HCM, we thought we had some therapies. But for non-obstructive HCM or at least we still have myectomy and surgical procedures. But for nonobstructive HCM, we did not have anything. So the disappointment was big. And particularly, there was concern about the number of individuals who had to stop the medication during the trial, the ODYSSEY trial. I mean, because that certainly could have had some impact in the results because if you have to stop the medication and then wait 4 weeks to restart the medication and so on at a lower dose, that could have had some impact in the outcomes of the study.

We need to see. We need to see that aficamten in the following study in ACACIA because of the pharmacological properties that the compound has and the design of the trial, which requires in case that left ventricular ejection fraction dysfunction appears, the drug is not stopped, it's reduced. Maybe in those cases, that is critical in order to achieve a good evolution of these patients. We will see what happens.

Pablo, maybe I could just ask one question, if I can just jump in. You were the second largest enroller in ODYSSEY. And so you had a fair -- I think you enrolled 20 patients. So -- what was your, I guess, impression in your patients of...

Well, there were 13 patients who did very well. I can say that. I mean, there were 13 patients who really improved largely during the trial. And actually, by looking at the data in the study and some of the sub-analysis that have been presented during the ESC, the NT-proBNP values and the echocardiographic parameters, I mean there are large reductions in NT-proBNP in the mavacamten group. So I'm still -- I still think that CMIs can have a role in nonobstructive HCM because there are certain parameters that really improve largely as we have seen in clinical practice among the patients included in the trial.

So let's see. This year, I think we have more hope. I mean, it was a disappointment, but I don't think this is ended. I think the [indiscernible] is still out and looking forward to know what happens with the case results.

Yes. Just to quickly build on that. Yes, I totally agree with Pablo. Again, the population that we're working with in nonobstructive HCM, I think we're learning is like much more heterogeneous and there might be sub cohorts within the overall population that do enjoy benefit from cardiac myosin inhibitors, those that are really hyperdynamic, potentially even those with mid-cap obstruction. So I think that we just have to continue to see where the audience takes us and see what evidence takes us.

So then I guess the follow-up to that for Anjali, there's two things. One is, I think people were a little bit surprised by the amount of placebo effects in the KCCQ in this study? And I'm sure you don't have a quick answer for that, but if you have any perspectives. And then I guess, similarly, sort of tangentially, but similarly, if you have any insights from what you've seen in the long-term data that's been published from the FOREST study in an HCM population that might support any read-through perspective on whether ACACIA might be different, specifically along the lines of what Carolyn and Pablo are just talking about.

That's a great question. I wish I had the answer to the KCCQ improvement in the placebo arm. It's hard to know exactly why we saw that 10-point improvement where in prior studies, including the Phase II MAVERICK we saw more in line of 6-point improvement. I think it speaks to the importance of doing randomized controlled trials in this population where we do see a significant placebo effect. Keep in mind, these patients were in close contact and care with their physicians for the 48-week trial period, which they otherwise would not have been. So my guess is these patients were getting more intensive care, more recognition potentially of periods of congestion or periods of AFib and they were being actively managed. There's always the question of background therapy that's being given for other comorbidities that are quite common in patients with nonobstructive HCM, including obesity and the rise in use of GLP-1s of SGLT2 inhibitors. I think that could have potentially played a role. We have to do a deeper dive, as Carolyn and Pablo have said, into the responders.

I think the therapeutic hypothesis of myosin inhibition in nonobstructive HCM is still very much alive based on the signals that we saw in biomarkers and in evidence of diastolic improvement and structural improvement. So as we said, it is certainly not one size fits all in nonobstructive HCM. And it's probably not even one size fits most. You really have to do an individual analysis of where your patient is on the continuum of disease. And it may be that myosin inhibition benefits some and not others.

What we've seen in terms of the long-term data in FOREST, I think, is very good, and it speaks to the fact that hopefully, we'll get a positive result in ACACIA. But I think nonobstructive HCM in general is a higher risk proposition than obstructive HCM, and we have to be realistic about that and think about really understanding the underlying disease pathophysiology in the nonobstructed state where we don't have the biomarker of obstruction and how we might benefit those patients in the long run.

With regard to the subgroup analysis that you had asked Carolyn and she started to mention, we did see some signals for the patients who were perhaps younger and perhaps less sick, the Class II patients. So there's a possibility that we enriched too much for those that had advanced diastolic dysfunction and subsequently probably longer duration of disease in ODYSSEY. So all these things will need to be looked into.

Thanks, Anjali. I want to pass it over to Dr. Malik here for a question and then a follow-up.

Sure. First of all, I would just like to ask Pablo maybe a question with regards to aficamten. We have ACACIA ongoing. What property -- we've just finished MAPLE, so you're pretty familiar with what the properties of aficamten are. What properties of aficamten do you think may enable it to succeed in HCM?

Well, I think the wide therapeutic window that it has is certainly something very positive because it allows us to modify the dose quickly, and that really is helpful because when you have one of these patients, what you want is to up titrate as soon as possible, so they start improving. You don't want to keep the patients under your car several months until you can increase the doses. So that's one of the things.

Second, I think, is important, the absence of relevant drug-to-drug interactions. So I think that's very helpful in everyday clinical practice. So those 2 things are really, really key when selecting the drug that you want to use. And yes, those are mostly the things that you really, really want in a drug that you are using in clinical practice. And really -- and also that it has a good efficacy, obviously, that's safety and efficacy. And so far, they have been excellent in the trials that have been conducted so far with afi.

Yes, I agree. I mean I think the -- obviously, what we saw in ODYSSEY, I think, was evidence that the underlying impact on measures of diastolic function improved, biomarkers improved. You saw trends in the endpoints that were positive and -- but perhaps the measures of efficacy or clinical efficacy were confounded by some of the challenges with obtaining the proper dosing and treatment interruptions and things like that as you -- as the panelists pointed out.

Let me -- let's move back perhaps to MAPLE quickly. And before we wrap up, it was an impactful presentation, an impactful study. How do you think the process and timing for updating guidelines is for something like this? And what might you expect or guess, I guess I shouldn't say expect because who knows how the guideline committees will land. But what would you guess if it were you in their shoes.

Well, I can speak by the European Society of Cardiology guidelines. During this Congress, it has been announced that there's going to be a focus update of the 2023 cardiomyopathy guidelines, and that's going to take place and be published in 2027. So I guess that will allow plenty of time to know what do regulators and payers also if they approve or not afi for the indications that they have already been filled and maybe in the future, there will be others. And certainly, the guideline committee will have to take into consideration the results of MAPLE and ACACIA in order to incorporate them into the update of the guidelines.

Okay. Carolyn, do you want to add to that?

Sure. The American Guidelines Committee haven't like met yet about informally to discuss this. It's never a fast process to update guidelines. The U.S. guidelines have moved to what will hopefully be a more nimble and kind of rapid processing of guideline update. So you're not waiting years and years between guideline versions. But even with the more rapid strategy, it took almost 2 years for the update and the HCM guidelines to come out. So I suspect that there would be a pause waiting for ACACIA to read out and thereby being able to handle nonobstructive HCM and the role of beta blockers at the same time. So probably kind of targeting the same date in 2027 to perhaps have a more formal revision and updating of the guidelines.

Great. Well, thanks. I want to really thank our panelists for joining us today. Dr. Masri had to leave early for clinic, I think, but thank you all. And I want to turn it over to Robert Blum, our CEO.

Thank you, Fady, and thank you also to Dr. García-Pavia, Ho, Masri and Owens for joining us on this call today. We're especially pleased by the positive feedback that we're receiving from cardiologists related to the results of MAPLE-HCM as well as the additional data coming out of ESC relating to aficamten in oHCM. Having 3 more high-profile and simultaneous publications further reinforces the importance of the growing body of evidence that we believe underscores momentum building within the field and around aficamten and its potential role in oHCM. However, in the meantime, please understand we continue to work with FDA as it reviews the NDA for aficamten with a PDUFA date in late December. Also, please understand the NDA was accepted based on efficacy and safety results of SEQUOIA-HCM, our first Phase III clinical trial of aficamten.

We're now already preparing the requisite regulatory report for MAPLE-HCM, and we expect to submit a supplemental NDA to include trial results into labeling following the potential approval of aficamten later this year. We also look forward to sharing top line results from ACACIA-HCM in the first half of 2026 and the primary results at a medical meeting, hopefully soon to follow.

We very much appreciate your interest in Cytokinetics and our development program for aficamten. We're looking forward to keeping you up to date on our progress, and thank you for joining on our call today. Operator, with that, we can bring it to a close, please.

Thank you for standing by. My name is Prilla, and I will be your conference operator today. Welcome to the Cytokinetics Q2 2025 Earnings Conference Call. This call is being recorded. [Operator Instructions]

I would now like to 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 and medical affairs activities for aficamten. Stuart Kupfer, SVP and Chief Medical Officer, will provide updates on the clinical development program for omecamtiv mecarbil and CK-586, which is now called ulacamten. Sung Lee, EVP and Chief Financial Officer, will provide a financial overview of the past quarter. And finally, Robert will provide closing comments and review our expected key milestones for the remainder of 2025.

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 second quarter 2025 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 first half of this year has been defined by solid progress as we continue to deliver on key milestones that bring us closer to realizing our vision, a vision of being the leading muscle-focused specialty biopharma company intent on meaningfully improving the lives of patients through global access to our innovative medicines.

During the second quarter, we announced that the FDA extended our PDUFA date for the NDA for aficamten for the treatment of patients with oHCM to December 26, 2025. Our late-cycle review meeting has since been moved to September, consistent with the 3-month PDUFA extension. We believe this timing should have no bearing on the approvability of aficamten, and we look forward to that meeting with FDA as we expect will occur soon and inform our next steps. In the meantime, all activities expected alongside the FDA's ongoing review process continue to time line. For example, GCP inspections of clinical trial sites and also of Cytokinetics by FDA are now completed with no observations recorded.

In addition, we're maintaining a productive dialogue with FDA, and we're answering questions to support their review of the NDA. Also during the quarter, we had a collaborative meeting with FDA on our submitted REMS program following their initial review. Subsequent to the meeting, we promptly submitted an updated REMS package and during or rather despite the extension to the PDUFA date, we remain confident in the U.S. regulatory position of aficamten, given the quality of our clinical data, perceived alignment on our REMS program and ongoing collaborative dialogue with FDA. We also maintain strong conviction that the data behind aficamten support its potential FDA approval, its distinct benefit risk and pharmaceutic profile and potentially differentiated label and risk mitigation profile as a potential new treatment option for patients with oHCM.

At the same time, regulatory reviews for aficamten continued during the second quarter in both Europe and in China. In April, we received the day 120 list of questions from EMA regarding the MAA for aficamten in Europe, and we're on track to submit responses soon in accordance with the time line agreed with the EMA.

EMA inspections of clinical sites and of Cytokinetics have also been completed with the overall conclusion that the conduct of the Phase III trial was compliant with regulations and guidelines and data are acceptable and reliable. We remain on track for potential approval by EMA in the first half of 2026, and we're targeting Germany for our first potential launch following approval. We have also been working closely with Sanofi, our partner in China, to support the NDA review of aficamten with the NMPA, and that's on accelerated regulatory pathway for innovative therapies. We look forward to the prospect of bringing aficamten to patients in additional geographies, and we continue to expect potential approval in China in the second half of this year.

Moreover, in the past few months, our commercial launch readiness activities have advanced with increased intensity and focus, and we're taking advantage of the extra time to further strengthen our commercial launch and our operational strategies in the U.S. As Andrew will elaborate, key progress areas in the second quarter include recruiting a world-class U.S. sales force, fine-tuning our patient-centric treatment experience and engaging key payers and also other important stakeholders. During the quarter, we also made important progress in our ongoing clinical trials program for aficamten. Notably, we announced positive top line results from MAPLE-HCM. We look forward to expanding on these results and their implications for what standard of care treatment may look like in oHCM following the presentation of the primary results at the upcoming European Society of Cardiology Congress to occur later this month.

We also continued conducting ACACIA-HCM, the pivotal Phase III clinical trial in nHCM, which is now fully enrolled and towards our expected top line readout in the first half of next year. nHCM represents an area of significant unmet need, and it's growing within the overall HCM population with no approved treatment options that address the underlying disease. Following the first potential approval in oHCM, nHCM represents a clear opportunity for aficamten and innovation. Beyond aficamten, in Q2, we continued to advance patient enrollment in COMET-HF and also in AMBER-HFpEF, our 2 later-stage clinical trials evaluating omecamtiv mecarbil and CK-586, now called ulacamten, respectively. Each trial addresses a different form of advanced heart failure, and these programs are central to our mission of delivering new medicines to patients suffering from diseases of cardiac muscle dysfunction and also addressing the high unmet needs in heart failure as we progress our specialty cardiology franchise forward.

In summary, in the past quarter, we made important progress across regulatory, commercial readiness and also clinical development priorities, and we're building momentum as we approach important milestones expected to occur in the second half of 2025.

With that, I'll turn the call over to Andrew, please.

Thanks, Robert. With the PDUFA date extension, we've adjusted our plans and are leveraging the extra time to finalize U.S. commercial launch readiness activities as well as refine the implementation of our promotional campaign and patient support program. Recently, a key focus has been the hiring of our U.S. sales force. After our highly successful virtual recruiting event in April, we received over 8,800 applications and proceeded to hire a very experienced cardiovascular sales team with nearly all territories now filled. This exceptional level of interest in joining Cytokinetics has provided a deep and experienced talent pool, enabling us to be highly selective in assembling a best-in-class sales team. We have now hired sales professionals who have existing relationships with cardiologists and possess deep therapeutic and industry expertise, positioning us to execute a highly impactful launch.

Overall, our new sales colleagues have over 21 years of industry experience and an average of 14 years of cardiovascular experience. We expect to have the sales force on board and trained in Q4, so they're ready for an early Q1 2026 U.S. launch of aficamten. Additionally, during the quarter, we also made progress in optimizing our distribution network of specialty pharmacies and distributors. This infrastructure will be key in delivering a high-quality patient-centric experience for both patients and providers alike. We also advanced the development of our bespoke patient support program. Taken together, we have a goal to create an integrated, simple and patient-centric treatment and assistance experience across all touch points, both for HCPs and their patients. As we approach potential approval later this year and commercialization, we remain focused and driven by the compelling unmet need.

We believe that approximately 80% of eligible obstructive HCM patients will be treatment-naive relative to a cardiac myosin inhibitor. So symptomatic oHCM patients naive to CMIs and primarily in specialty centers for HCM represent an entry point for aficamten. Our launch strategy is to expand the market and ensure more cardiologists are comfortable with aficamten and more patients can potentially benefit from this new therapy. Importantly, according to our market research, nearly 80% of HCPs pulled in HCM specialized centers are familiar with aficamten on a needed basis, giving us a strong starting point for initial engagement from which we expect to grow market adoption and to expand to community cardiology.

Recently, market research findings that incorporated a target product profile based on MAPLE-HCM resulted in further support likely expanding prescribing beyond HCM specialized centers. Our promotional launch campaign for both HCP and patients, which are currently in final market research testing and refinement are designed to evolve in step with our market positioning in key areas of differentiation. We believe that given the differentiated profile of aficamten, these messages will resonate and contribute both to commercial launch as well as category preference. Payer engagement also remains a priority. And in the second quarter, we continued to educate payers on the results from SEQUOIA-HCM, along with the clinical and economic burden of HCM. We also began building foundational health economics and outcomes research models around budget impact, cost effectiveness and cost comparisons to support both U.S. and ex-U.S. payer requirements as we approach potential regulatory approval in key U.S. and EU geographies.

Specifically in Europe, we are making meaningful progress for commercial readiness. In the second quarter, we added to our EU commercial team, our leadership team and continued dossier preparation for 2026 submissions to multiple HTAs and progress launch readiness across multiple countries with a focus on our first potential commercial launch in Germany during the first half of 2026. Overall, I am pleased with where we've positioned relative to the potential upcoming approval of aficamten.

With that, I'll turn the call over to Fady to share updates on our ongoing clinical trials program and medical affair activities for aficamten.

Thanks, Andrew. During the second quarter, we were pleased to report positive top line results from MAPLE-HCM, which demonstrated a statistically significant improvement in peak oxygen uptake from baseline to week 24 for aficamten compared to the standard of care beta blocker, metoprolol. Safety and tolerability profile of aficamten was also favorable in comparison to metoprolol. MAPLE-HCM is the only trial comparing a cardiac myosin inhibitor head-to-head with the long-standing standard of care therapeutic approach of beta-adrenergic receptor blockade. As we recently announced, the full results from MAPLE-HCM will be presented in a hotline session on Saturday, August 30, at the European Society of Cardiology Congress in Madrid later this month. A prespecified analysis from the trial on the effect of aficamten versus metoprolol on cardiac structure and function will also be presented on Sunday, August 31.

Until then, we can't elaborate on the top line results, but we look forward to sharing much more detail in a few weeks. Why are these data important? MAPLE-HCM reads not only on the treatment effect and safety of aficamten compared to metoprolol, but also on the impact of metoprolol itself on exercise performance, gradients, symptoms and biomarkers. As you'll see when the results are presented at ESC, we believe these results may lead to their incorporation into treatment guidelines and may lead to changes in standard of care treatment algorithms in obstructive HCM. We also plan to share other data and analyses of interest at ESC, including a late-breaking clinical trial presentation on the incidence and impact of atrial fibrillation in patients with oHCM via an integrated analysis of REDWOOD-HCM, SEQUOIA-HCM and FOREST-HCM.

Atrial fibrillation has been an emerging topic of conversation around the safety of cardiac myosin inhibitors, but speculation as to whether adverse events of atrial fibrillation are disease-specific or treatment-dependent. As we've previously shared, in completed studies of aficamten, we've observed no difference in the rates of atrial fibrillation between placebo and aficamten. And in the open-label extension trial, FOREST-HCM, the incidence remains similar to historical data. We're looking forward to sharing these data that we believe reinforce a consistent safety profile for aficamten in patients with oHCM. At ESC, we'll also have an oral presentation on longer-term follow-up of patients treated with aficamten in FOREST-HCM with up to 3 years of data combined together into an updated integrated safety analysis of the clinical trials program for aficamten in oHCM, inclusive of MAPLE-HCM. In totality, we expect the data presented at ESC will importantly expand on the safety and longer-term effects of aficamten in patients with oHCM.

Moving on to nonobstructive HCM. During the quarter, we continued conduct of ACACIA-HCM, pivotal Phase III clinical trial of aficamten in nonobstructive HCM. As we previously communicated, ACACIA completed patient enrollment ahead of schedule earlier this year and in fact, exceeded our original target to randomize -- and randomize a total of 516 patient -- participants. During the second quarter, we reviewed the emerging safety data from ACACIA-HCM with the Data Monitoring Committee, which recommended continuing the trial without any changes to the protocol or study conduct. We expect to be able to share top line results of the primary cohort from ACACIA-HCM, excluding Japan, in the first half of 2026.

Speaking of Japan, we recently dosed the first patient in the Japan cohort of ACACIA-HCM, and our partner, Bayer, opened to enrollment CAMELLIA-HCM, a Phase III clinical trial in Japanese patients with obstructive HCM, a trial which is intended to support potential marketing authorization in Japan.

As to ongoing clinical trials of aficamten, during the second quarter, we made progress enrolling CEDAR-HCM, which is evaluating aficamten in pediatric obstructive HCM. The trial remains on track to complete enrollment of its adolescent cohort in the second half of this year. Finally, in addition to progress in our clinical development programs, during the quarter, our field medical affairs teams engaged in nearly 600 U.S. HCP interactions, including over 200 HCM KOLs as well as over 50 European KOLs. Team also attended key payer conferences, including Asembia, AMCP and regional AMCP meetings to actively engage with national and regional payers.

Now I'll turn it over to Stuart to provide updates on our other late-stage development programs.

Thanks, Fady. First, we continued start-up activities and enrollment of COMET-HF, the confirmatory Phase III clinical trial of omecamtiv mecarbil in patients with symptomatic heart failure with severely reduced ejection fraction less than 30%. During the quarter, our first sites in Europe came online, and we continued expanding site activations in the U.S., both of which are driving progress in enrollment. We expect to continue enrolling COMET-HF through this year and to complete enrollment in 2026.

Second, as we announced in today's press release, we received approval from the INN Program of the World Health Organization for ulacamten to be used as a nonproprietary name for CK-586. During the second quarter, we continued conduct of AMBER-HFpEF, the Phase II clinical trial of ulacamten in patients with symptomatic heart failure with preserved ejection fraction of at least 60%. Enrollment in the first cohort is progressing, and we're pleased by the progress we've made in activating new clinical trial sites and in engaging investigators in this important trial.

Overall, we're encouraged by the clinical trials progress of both of these later-stage pipeline programs, which represent the next strategic pillars in advancing our specialty cardiology franchise. Despite the advances in heart failure care over the years, a substantial unmet need persists across the spectrum of the disease and one that we believe our potential medicines may impact.

With that, I'll pass it to Sung.

Thanks, Stuart. We're pleased to report our second quarter of 2025 financial results. Starting with the balance sheet. We finished the second quarter with approximately $1.04 billion in cash, cash equivalents and investments compared to $1.09 billion at the end of the first quarter of 2025. In the second quarter, we exercised our option on the Tranche 4 loan provided by Royalty Pharma and received proceeds of $75 million. We have an option to draw $100 million on the Tranche 5 loan prior to November 25th of this year. R&D expenses for the second quarter were $112.6 million compared to $79.6 million for the same period in 2024. The increase was primarily due to advancing our clinical trials, higher personnel-related costs and medical affairs-related activities.

G&A expenses for the second quarter of 2025 were $65.7 million compared to $50.8 million for the same period in 2024. The increase was primarily due to investments towards commercial readiness and higher personnel-related costs. Net loss for the second quarter of 2025 was $134.4 million or $1.12 per share compared to a net loss of $143.3 million or $1.31 per share for the same period in 2024.

Turning to our financial guidance. We are maintaining our full year 2025 financial guidance with GAAP operating expense expected to be between $670 million and $710 million. Stock-based compensation that is included in 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. We continue to monitor the pace of our commercial readiness investments as we move closer to the PDUFA date for aficamten, and we will update you accordingly. With our current balance sheet and access to additional capital, we are well positioned to fund the potential launch of aficamten in the U.S. later this year and continue to advance our pipeline.

With that, I'll hand it back to Robert.

Thank you, Sung. So midway through 2025, I'm pleased with the progress we've made and the position we are in ahead of a very important second half of the year. As we approach a significant inflection point, one that has been more than 25 years in the making, our company stands at the cusp of transformative growth. This moment reflects the culmination of decades of scientific innovation, strategic investment in R&D and a steadfast commitment to delivering potentially meaningful therapies to patients in need. None of this would be possible without the dedication of our teams across the organization whose tireless work is propelling us towards these long anticipated milestones. With a strong foundation, a clear vision and the right people in place, we're poised to unlock substantial value for patients and shareholders, ushering in the next chapter of maturation as a fully integrated, high-impact leader in specialty biopharma.

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 to continue launch preparations for aficamten in the United States in the second half of this year. We expect to continue go-to-market planning in Germany and expand commercial readiness activities throughout Europe in 2025 in preparation for the 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, pending approval by the NMPA. And we expect to present primary results from MAPLE-HCM later this month at ESC.

We expect to report top line results from the primary cohort of ACACIA-HCM in the first half of 2026, while we continue enrolling the Japan cohort of ACACIA-HCM in 2025. And we expect to complete enrollment of the adolescent cohort in CEDAR-HCM in the second half of this year. For omecamtiv mecarbil, we expect to continue patient enrollment in COMET-HF throughout 2025 to enable completion of enrollment in 2026. For ulacamten, we expect to complete enrollment of the first 2 patient cohorts in AMBER-HFpEF in the second half of this year. And finally, for preclinical development and our 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 up the call to questions, please.

[Operator Instructions] And with that, our first question comes from the line of Gena Wang with Barclays.

So I have so many, okay, but I will limit my question to one, that's regarding the ESC update. So you did mention the MAPLE data could be potentially guideline change. Can you elaborate a little bit like what kind of a magnitude of benefit like you are looking -- what are the key data points we should be focusing on? And what kind of a magnitude benefit that payer or physicians are willing to use first-line or switch those patients on beta blocker to aficamten?

So obviously, it's difficult to answer your question until you have the data that we have, but I'll ask Fady to do his best.

Yes. I think the data -- this is really one of the few comparative efficacy trials that's conducted in cardiology. And when the data themselves will present a picture not only of the difference between the 2, but what is the absolute benefit of each of the 2 drugs themselves compared to baseline when these patients start the drug. Right now, cardiac myosin inhibitors are thought of as last line of treatment after you fail everything else. And I think when we see the data from MAPLE-HCM, that conversation will be revisited and hopefully, guidelines as well will be updated to reflect what we have already announced the superiority of aficamten versus metoprolol and exercise tolerance. But I think we'll just have to wait to be able to expand on that once the data are out.

And your next question comes from the line of Akash Tewari with Jefferies.

So look, it looks increasingly likely that you're going to get the Camzyos ODYSSEY data at ESC. What are the 2 or 3 things investors should be looking at in that data that would support the team's hypothesis that ACACIA will be successful where Camzyos wasn't and also would support a clear exposure response relationship in this population?

Yes. So I'll take a stab at that and maybe ask Fady to add. I think it's very important to distinguish between that which is related to clinical trial conduct and that which is related to potential mechanism of action as translates to that patient population. Clearly, with ACACIA, we took what we believe to be an optimized dosing regimen that was verified in a Phase II study and took that into a Phase III trial where we elected to proceed without altering a lot of other things. We took a dose optimization regimen. We took a population. We focused to centers where we already had experience. And obviously, here at Cytokinetics, we have an expert team of HCM experts that have been both academic and industry trained in order to be able to ensure that patients met the criteria. The kinds of things that we'll be focused on is related to from a study conduct standpoint and operations, how much might there have been a change between the Phase II and the Phase III study for mavacamten and how much might that have read on the outcome in Phase III versus where we think we've been quite linear in focus one to the next. Fady, anything you want to add?

I just might add that when you see the ODYSSEY data, and we see the ODYSSEY data, we haven't seen them yet, the question will be whether the trial didn't meet its primary endpoint because of specific features of mavacamten or trial conduct versus mechanism of action. And I think ultimately, that is what will provide some confidence in terms of ACACIA's potential success. But I think as Robert mentioned, we believe strongly in ACACIA's success just based on the strength of the Phase II data we generated and the fact that ACACIA is being conducted in a manner that was very consistent with the way we conducted Phase II.

And your next question comes from the line of Tess Romero with JPMorgan.

So what does an ideal label look like for aficamten in obstructive HCM here? And Robert, can you just double-click on any specifics you can give us on the updated REMS that it sounds like you submitted versus the original one? And how these updates track to your expectations for a differentiated REMS?

Yes. So there's a lot in that question that I cannot unpack given that we are in ongoing conversations with FDA. But I think what I can say is that an ideal label for aficamten is one that tracks with its engineered properties and the way it's been studied. And both are, we believe, enabling of differentiation as could be supportive of our expected profile. We designed into aficamten features that Fady has spoken of often, and we've studied aficamten in ways that we believe elaborate on how those features read on benefit risk. And the data from our Phase II and Phase III studies and also as further substantiated in the open-label extension are supportive of what we've argued would be a potential differentiated program in the clinical setting for patients, but also for physicians. I might ask Andrew, our Chief Commercial Officer, to speak to how his market research has been pointing to the unmet need and where we believe a differentiated label could support our expectations and aspirations.

Sure, Robert. So I think you addressed well that a differentiated label really would reflect the results of the clinical trial and the properties of aficamten. In terms of market research, I think what we've seen in our research is if the REMS and the label do reflect the properties and the study that we would be expecting good uptake at the centers of excellence, where most of the prescribing is occurring now. There's already -- as I mentioned in my remarks earlier, there's a lot of 80% plus of physicians in those centers who are aware of aficamten. So very, very high awareness even before we come to market.

That expansion into community cardiology and general cardiology supported by that differentiation, further supported by MAPLE, that's what we're finding in our market research leading to a preference here, even adjusted for overstatement in our market research. So ultimately, we have to wait to see what that label and REMS looks like from the FDA, but we're pretty bullish given those comments.

And your next question comes from the line of Salim Syed with Mizuho.

I guess one for us on the oHCM late-cycle meeting. So Robert, what exactly are you planning to learn or discuss in that September late-cycle meeting? And just can you remind us how much of the REMS negotiation here actually happens post the late-cycle meeting actually during the label negotiations themselves?

Salim, very good questions. I'm not sure I can answer them to your full satisfaction simply because so much has already been discussed between Cytokinetics and FDA. I would hope that come the late-cycle meeting, we're learning that everything we are assuming continues to be tracking towards potential approval and that there's nothing new that gets introduced. But as far as the activities that have occurred, we believe we've addressed them without a lot of difference or distance between what FDA might be interested in and what we could provide with supportive evidence.

Case in point, the REMS. FDA and Cytokinetics convened a meeting to discuss the REMS promptly after we submitted one. And the conversation was a very fruitful one. We were able to turn around very quickly revisions that we believe were responsive to FDA's interest. And as such, I would hope that at a late-cycle meeting, we get validation that we're all good to go. But this is somewhat unchartered territory with regard to a REMS conversation, and it may be that we learn something new. I hope not, but we're very much in a position where we think we're aligned together with FDA on what it's interested in.

And to that point, it was anticipated very nicely by Cytokinetics, our colleagues here such that when we heard from FDA that they did, in fact, want a REMS, we were ready to submit one right afterwards. So I guess in that regard, to answer your question, at the late-cycle meeting, I'd like to learn that we're proceeding to final label conversations and that we're expecting no other new news.

And your next question comes from the line of Cory Kasimov with Evercore ISI.

So I wanted to ask -- go back to ACACIA and wondering if you could walk us through how drug interruptions and discontinuation protocols differ versus ODYSSEY. I guess I'm particularly curious about how ACACIA differs from the 4-week dose interruption that is necessary if LVF drops below 50% as was the case in ODYSSEY. And maybe you can point out any other significant design differences you would maybe call out between the 2 studies.

Yes. So the design differences are significant. It would appear much like there are design differences in other studies. And again, how ACACIA is conducted in accordance with that design may ultimately prove to matter. So I'll ask Fady to comment now that we have ODYSSEY as published in terms of the design, and we know what we're doing with ACACIA, I think it's good to highlight some of those distinctions.

Yes, Cory, I think with regards to what happens when LVEF falls below 50%, in the nonobstructive, you don't have a left ventricular outflow tract gradient to buffer you for that. So you really -- I think of what we do in oHCM is we're tolerating the minimum effective dose, whereas in nHCM, we're tolerating the maximum tolerated dose, which is quite a different concept. And so with EF less than 50%, it's nice that in -- with ACACIA, primarily as long as the EF is above 40%, patients can just down-titrate drug. There is no treatment interruption. For an EF below 40%, they do interrupt drug for about a week, and they would resume drug after that at a lower dose.

The -- so that's a substantial difference, I think, from ODYSSEY where patients have to interrupt drug for 4 weeks and restart and leads to a lot of disruption, if you will, in the -- in treatment. Another aspect of this is that we tested all the doses, if you will, in Phase II, 5, 10, 15 and 20. And primarily the 15 and 20-milligram doses were the ones that were most commonly used. We know that in ODYSSEY, the BMS introduced doses of 1-milligram and 2.5 milligrams. Patients could down titrate to those doses. And ultimately, we don't know if the dose density, if you will, is in the range that is known to be -- is potentially effective.

And in ACACIA, we are testing doses where at least we believe we saw meaningful clinical benefit in the Phase II and as we're trying now to replicate in Phase III. So I think with regard to dosing, those are in EF of less than 50%, those are the major differences. There are some differences in the entry criteria with regards to thresholds, upper limit for peak VO2 or NT-proBNP. We have a group here that is highly knowledgeable about HCM and really look at every patient echo that came into the study. And so trying to maximize, if you will, the appropriateness of the patient population. So I think there is a number of differences there. And ultimately, when we see the ODYSSEY data, we can ask ourselves how -- which of them might be impactful in terms of ACACIA's success down the road.

And your next question comes from the line of Yasmeen Rahimi with Piper Sandler.

This is [ Emma ] on for Yas. I guess one is, what are your expectations in regards to potential REMS differences between the U.S. and EU and implications of that?

So understanding that in the EU, there is not the same sort of mechanism for REMS, it would otherwise be addressed in other means. I don't think there's going to be altogether so many differences taken collectively in light of the fact that we conducted an international study and the conversations we're having with FDA and EMA are tracking very similarly. So while there's not a formal REMS in Europe, we should expect and we are anticipating labels that are encompassing from a risk mitigation, drug-drug interaction, pharmacology and otherwise dosing and indication that there's going to be so much more in common than necessarily would be different.