Good morning, everyone. Welcome to our Piper Sandler Healthcare Conference. It's day two. My name is Yaz Rahimi. I'm a Senior Biotech Analyst here at Piper Sandler. Thrilled to have the team from Cytokinetics here. What an amazing 2024 in terms of execution and lots that has you guys gotten done. I remember last year sitting here right before SEQUOIA. Imagine the hard work that's behind all the programs and an incredible 2025 ahead of us. So team, thank you for being here. Maybe, Robert, congratulations on yesterday's updates on, you know, European filing, PDUFA date assigned, omecamtiv mecarbil study, so.
It's been.
Give it to you for quick remarks, and then we'll go into our questions.
Thank you. And thank you for inviting us. We love being here and providing an update. It's been an incredible week, much less an incredible year. But just to set the context for the conversation, it was about this time last year that we were awaiting phase III clinical trial results for aficamten in patients with obstructive HCM. Those results we top-lined by press release in December. And then we got caught up in a lot of rumors and volatility around our stock as the company was being tossed around as a potential M&A target. We communicated in May that we were, in fact, in such conversations, but that a party with whom we were engaging chose, for reasons we can't fully know, to step back. In the meantime, we've been executing very well on a strategy to build a specialty cardiology franchise business.
And it starts with aficamten and continues from there across a broader pipeline, three products all directed to the same molecular target, cardiac myosin. And a commercial business that Andrew will lead that is designed around going to market in North America and major markets in Europe and with a concentrated sales and marketing infrastructure that should hopefully produce a high return on shareholder equity. We're one step closer to making that happen as we announced this week that FDA has accepted our NDA for aficamten with a standard review, no AdCom expected, PDUFA date in September 2025. And that goes alongside us having on file a regulatory application in China, as well as, as we announced yesterday, we now are on file with EMA in Europe. So a lot going on from a regulatory standpoint.
That's designed to bring aficamten to market as soon as possible in those major markets. At the same time, we announced a couple of weeks ago a deal in Japan with Bayer, and we'll have the ability now with Dan and others leading those activities, to conduct additional studies in Japan to support potential regulatory applications there in the near term. We've got other clinical trials for aficamten due to read out soon. We announced recently the completion of enrollment in a study called MAPLE. That'll read out in the first half of 2025. We're well into ACACIA, another clinical trial that should complete enrollment in 2025, read out in 2026. Then yesterday, we announced the start of a confirmatory phase III study of omecamtiv mecarbil in patients with heart failure and severely reduced ejection fraction.
Soon we'll be announcing the start of a phase II study of CK-586 on another spectrum extreme in heart failure, heart failure patients with preserved ejection fraction for CK-586. So you begin to see the portfolio emerging. Three drug candidates all directed to cardiac myosin establishing, we hope, a beachhead around which we can build an enduring business. Sung is in the audience. He's our CFO, and he's overseeing our stewardship of investment capital and resources. We recently announced we ended Q3 with over a billion, $1.3 billion in cash and equivalents. And we think that represents over two years of forward cash. Plus, we have access to over $500 million in additional capital from Royalty Pharma and milestones under recent deals. So we think we've done a good job of financial engineering. So with that, I'll turn it to you, and we can have a conversation.
Thank you. Thank you, team. Let's maybe go in sequential order of the catalysts as we go into 2025. I think a lot of investors are very excited around MAPLE. And I think the questions that are coming up is around, channel checks with doctors are very clear. Beta blockers don't work, and CMI could have a big opportunity. The question one is, as we head into the data, what is your expectation? As long as you show superiority, it's good enough to follow. Like, what is the actual bar or bogey for that MAPLE? That's part one. And then part two of the question is the utility, because I think beta blockers are cheap. So people are trying to visualize how do we use MAPLE from a commercial perspective to really bring significant uptake. We'd love to hear your thoughts on it.
I'll start and then ask Dan, and then afterwards Andrew to comment. So firstly, the study is designed as a head-to-head aficamten versus metoprolol. And in some ways, it may be a little stacked in our favor. It's a study that is designed to elaborate on things we already know about each of aficamten and metoprolol. There's already evidence to suggest that beta blockers are neutral to negative on exercise capacity, and that's the primary endpoint. aficamten has already demonstrated with and without beta blockers and Sequoia effects on peak VO2. So, in addition, we think that aficamten has demonstrated a good safety and tolerability profile where beta blockers don't make people feel better. They actually make patients feel worse. So we're looking at this as a study that we hopefully will read out positive.
It will make a place in guidelines for the adoption of aficamten, we hope, in the treatment of OHCM and potentially as a first-line treatment. Maybe I'll ask Dan to comment on the endpoints and how we designed MAPLE-HCM and what we had in mind in power calculations, primary versus secondary endpoints, and then Andrew has got a good idea on how this should be received by payors to answer your question.
Yeah. So thanks a lot, Robert. Well, you know, the MAPLE-HCM study is designed around the primary endpoint of peak VO2, versus metoprolol. We're looking to that study was powered for a 90% power for a 2.0 difference in peak VO2, which really, I mean, to translate that, what is 2.0? I mean, anyone who runs around with a Garmin watch has had the experience of seeing their peak VO2. The amount of effort it takes to improve your peak VO2 by two is massive. You're talking about months of intensive training. Here we're talking about people who function at a really lower exercise capacity. So that improvement of two is even more profound. So it's a very profound difference that we're looking for, and the study's powered to see that. As far as the secondary endpoints go, we're looking at symptoms. We're looking at hemodynamic properties, LVOTG.
But then, quite importantly, we're also looking at remodeling, left atrial volume index, left ventricular mass index. And I think what we're going to see, what we, what we anticipate we might see at least, is that where beta blocker is an off-target therapy, that really has systemic, adverse effects. I mean, I, I sometimes like taking beta blockers when I'm talking to patients as drinking a negative cup of coffee in the morning. It sort of, has that effect. Instead of doing that, what we're hoping to see, what we anticipate, is that we may see some positive remodeling in terms of the direct on-target effect of aficamten. And I think those lineup of primary and secondary endpoints are highly likely to dramatically influence position, opinion, and practice. I would not take the guideline impact lightly with regard to that.
I don't think I can recall a trial about which I've seen people more excited than this.
Yeah.
More so than Sequoia, which was the study that I ran and spent, you know, weeks and weeks of my life talking to people about. This is an exciting study.
We have gotten the same feedback.
I'm sorry. From a—I mean, commercial point of view for payers, the guidelines will really influence payers. Payers at first really won't put restrictions. Right now, there are restrictions in terms of prior auth required for use of a beta blocker prior to using a CMI. I expect that would continue after MAPLE. But once guidelines are updated, then over time, payers would likely adopt. From a physician point of view, we did recent research and discovered that there are a subset of physicians who maybe aren't as informed and feel like beta blockers are the standard of care and good enough, especially since the price point. And when you show them a profile relative to a beta blocker, more physicians get on board. And in addition, having a second study that shows a similar or even better effect, gets more physicians on board.
It increases market penetration. It likely increases share preference, and it gets those apathetic physicians on board with CMI.
Okay. How do you envision sort of the cadence? I think you've, Robert, spoken about, let's say, middle of the year, we get MAPLE-HCM. You're able to wrap that up into an sNDA within, let's say, six months, right? 3-6 months. How soon could that then take for the guidelines? Like, usually, like, would it be then a 2027, 2026 event to think about? Like, or, like, because I think the comments you made are very, very helpful, but just the visualization of the timing it could take to be incorporated is a little challenging or opaque for investors.
Yeah. I'm happy to kind of opine on that. I mean, you know, predictions are hard to make, particularly when you're talking about the future, as they say. So, but, the guideline committees for really all disease states, but in particular, hypertrophic cardiomyopathy, is really committed to every other year updates and interval updates, via the ACC, you know, though, like, for key developments, and I think this field is evolving so quickly. We're going to see a very rapid commentary from guideline-level individuals and then incorporation into subsets of guideline updates. I would say I would be surprised if it takes more than a year for that to happen.
Okay. And then, team, I think you have been really prolific in terms of your publication cadence, your visibility at the conference. As soon as Sequoia was completed, I mean, it's very clear. I guess the question that I have is that as you go into the medical meetings and interact with many physicians, what is the feedback that they have? Like, when you ask them a very simple question, how do you view aficamten based on all the publications, differentiation versus mavacamten? What do they say? Like, what is their feedback to you guys in terms of, because I'm sure it's, you know, they're impressed by the depth of the data. Yeah.
Just so everybody knows, we had a concurrent New England Journal manuscript publication of the SEQUOIA results, but then afterwards, six or seven.
About six simultaneous, eight total.
Presentations. There was recently, in publications, an edition of the Journal of the American College of Cardiology that had, I think, six publications on aficamten, and it was like a journal just dedicated to aficamten. So the team has been incredibly prolific in terms of publications, and it goes a long way. This is a very concentrated customer segment where a relative few number of cardiologists influence the adoption of these new medicines. HCM specialists are well versed in the literature. While your question related to aficamten versus mavacamten, I'll say the opportunity here really isn't as relates to mavacamten as much as how do cardiac myosin inhibitors in general become a standard of care for the treatment of these patients for which still over 90% of patients eligible for a treatment like this aren't getting one.
I think that's where the literature is making a big impact already. We're seeing that in terms of education and awareness. Andrew's doing market research around that. There's a high degree of anticipation for aficamten to market.
Yeah. I mean, I think the things that matter most, I mean, ultimately, it's going to depend on the label and the risk management. But based on the profile, we think the, the feedback we get from an efficacy point of view, speed of onset with or without beta blocker from a safety point of view, no episodes of heart failure or heart failure hospitalization, from a, and, and drug-to-drug interactions. We're not expecting those either, in terms of, contraindications or part of a REMS program. And then from a monitoring perspective, let, you know, less echoes, a larger window between when the echo needs to be performed and when a prescription gets filled and, and lack of a DDI monitoring. So those are the things that, drive preference share and the things that we hear physicians talk about that they're most excited about potential areas of differentiation.
Okay. And, team, maybe it would be worthwhile. The next catalyst path to MAPLE-HCM will be, at some time around MAPLE-HCM, we'll be expecting the ODYSSEY-HCM data will be the first registrational readout in a non-obstructive study. And so a lot of investors are wondering, you know, as you're sitting there, obviously, it's not your study, but if you look at the way they designed the study, what is the likelihood of success? And obviously, if it's positive, has a read-through on establishing CMIs. If you could talk about how do you view the study, whether you believe it's a high POS for success, and also talk about if it is negative, why it could have no read-through to aficamten , SEQUOIA-HCM study.
You're asking a tough question because you're right. It's not our study. ODYSSEY-HCM is the study of mavacamten in patients with non-obstructive HCM, and it's designed very differently. It's designed with a different dosing regimen than is currently the practice for use of mavacamten in the marketplace and with inclusion criteria and duration of treatment and measurement of efficacy different than is our study. So I'm hesitant to comment too much on their study as much as to say that I believe that it will hopefully show at best efficacy that will be trending in the direction that we would hope would support the use of mavacamten. I believe that our study is designed more optimally. And maybe Dan, if you want to talk about sort of the ways the studies compare from a design standpoint.
Yeah. I can do that a little bit, although, you know, I don't have access to quite appropriately the ODYSSEY protocol. I think just to kind of double down on what Robert, you know, is saying, the most, you know, important thing here, the best thing for everybody is if ODYSSEY, you know, shows benefit, obviously. The data that the team was working with to design ODYSSEY was limited to the MAVERICK cohort, which had, you know, a mixed population of patients, mixed results, different dosing, across a relatively small number, as everybody knows. It's also very complicated. Mavacamten is a much more complicated drug to dose in this population.
By contrast, what you have with aficamten is the same dosing strategy that we saw in REDWOOD cohort four, which was the non-obstructive cohort, which used five, 10, and 15 milligrams that was extended to 20 milligrams for the ACACIA-HCM study. Really, between SEQUOIA-HCM, MAPLE-HCM, and ACACIA-HCM, you have the same dosing and titration strategy for all the different types of hypertrophic cardiomyopathy. When it comes to potential ease of use and potential applicability in the clinical environment, that is incredibly important. Also makes the study quite easy to run and design. There's no PK monitoring. It's all site-based echocardiography.
I think, you know, if you want to kind of get to the second part of your question, which is what does it mean for the overall field of CMIs if ODYSSEY is less robust in terms of its, results, I think you have to tease that apart a little bit. It may not tell you everything you need to know about the effect, potential effect of a CMI and NHCM. And all you have to do to learn about that is to look at the differences between cohort four and REDWOOD and what you saw in MAVERICK, the results of cohort four showing a very significant KCCQ improvement, NYHA improvement, a couple of, EFs that were dropped but with no heart failure. Most of the patients achieved the highest dose. It was a simple dosing strategy. There's been a publication on it.
You can, I'm sure you're familiar with it. Whereas in MAVERICK, as I've expressed, the results were a bit more complicated, particularly with regards to safety and dosing, so I, I anticipate it's going to be an interesting time. I would be hesitant to extrapolate right away. Let's see what the results show.
We might ask Andrew to comment just on what NHCM were it to be added to the label could mean for aficamten , because I do think, to this point, the street is not yet, assessing the opportunity in NHCM to the extent that, we are. And I do believe that NHCM is increasingly, a vector for value upside that, warrants more attention.
Yeah. When we looked at OHCM versus NHCM split probably two years ago, the data showed it's about a two-thirds, one-third split, meaning two-thirds of HCM patients are obstructive and one-third are non-obstructive. When you kind of dig into the data a bit, there's two ICD-10 codes. One says obstructive. The other one says other HCM. That other HCM you dig into, which we've done a lot of work on, and it looks like it's more like 60/40, but the NHCM is growing at a much faster rate, double-digit rate. So, you know, by 2030, it could be around a 50/50 split, where there's a lot more growth in NHCM. So potentially more of a value driver, especially after SEQUOIA, after MAPLE, ACACIA comes in, if you have a third positive study and a whole new population, that could really open up a lot of value.
Hopefully, the community cardiologist is on board with treatment of an HCM with a CMI by then as well. You'll see hopefully a faster accelerated uptake.
Okay. Perfect. And then past ODYSSEY, we're going to head into September for the PDUFA date. How do you envision between now and PDUFA, how you're going to communicate with your analysts and investors and how, I guess, the communication is progressing with the agency?
I don't think we should be communicating in a public way too much about what we're discussing with FDA until we know something more definitive. So what I can say already is that, you know, in accepting the NDA for filing, it was a very straightforward conversation around the application. Sometimes you get a read on how FDA views things by the number of questions even before they accept the application for filing. In this case, it was very administrative and straightforward, and they accepted it for filing with standard review, which was what was our expectation. On a go-forward basis, we'll start getting questions. FDA will start doing its own analyses and modeling based on data that we've generated. We'll start to get a read on things.
We'll have a mid-cycle review meeting at which time, we'll get, a better calibration of how FDA is viewing risk mitigation, which I think is the key, pivot point around which we expect differentiation in the marketplace. And I'm sure investors would like to know whether we think there's going to be a restrictive REMS or some other form of risk mitigation, but we really can't comment on that based on interactions with FDA in real time, until such time as we hopefully are negotiating labeling and we know where FDA is at. So it'd be misleading, perhaps to be communicating too much, and I certainly don't want to be negotiating something with FDA through public communications. So it's better to assume less is more here.
If there's something that looks materially negative, we'll obviously have to disclose it, but to the extent we're not, we're not communicating, that probably augurs better.
Yeah. And then, team, another perspective that just been recently surfacing among investors is making this assumption, and I would love and Dan and I talked about it early this morning, people will say, "Okay, by the time aficamten gets their label, it could be that behind the scenes, the agency will evaluate both CMIs risk mitigation at the same time." And so there is that notion out there, right? And Dan, I would love for you to kind of share your comments that you had to me where you were like you were shocked by my question. Like, yeah, I would love for you to tackle that because there is that strong notion right now and investors saying, "Yeah, both could end up with the same risk mitigation.
Before we ask Dan to comment, I might just suggest here again. I think the street is fixated on aficamten versus mavacamten. And while I expect a BMS strategy is to try to relax the REMS program, I think we should always be more focused on how might CMIs as a general category penetrate the still over 90% of patients who could benefit. And while we do expect a differentiated risk mitigation profile for aficamten versus mavacamten, that's not where the real action is. Both these drugs can be multi-billion dollar drugs, and everybody can be happy about that without necessarily fixating on the differentiating differentiation between label.
With all of that said, I do believe that the REMS program for BMS is working for mavacamten, but despite the REMS program we're seeing in the published literature still heart failure hospitalizations, heart failure episodes, and we've seen none of those with aficamten . And maybe Dan against that you can comment.
Yeah. I mean, that's really the point here. I guess you know there's been a series of publications of long-term data from VALOR-HCM, mavacamten LTE, and from now we finally have some data from the actual post-commercial REMS data. And there was a nice editorial by Lakdawala and Masri on that, which is worth reading that really demonstrates the REMS doing its job, as Robert has said. What does that mean?
That means that we're still seeing those heart failure events and even up until heart failure hospitalization, even up until cardiogenic shock for some of those patients. The small case series that have come out from expert centers, UPenn and otherwise, demonstrate usability of it, but don't demonstrate significant differentiation from what has already been published in the literature. And also, those are in the hands of highly expert individuals. I think what we're seeing is really positive. People are coming out and saying, "Look, once you wrap your head around this, we can figure out how to use it in a way that maintains the safety profile similar to prior to the prospective studies." Well, to me, from a logical perspective, I don't see how that would promote a different way of managing it that could potentially leave open the possibility of a worsened safety profile.
That being said, I think what Robert also said is the key point here, which is that in all of our studies, open-label and blinded studies, we're really not seeing those heart failure events.
Maybe one last quick question. You're right, Robert. Every KOL call I've done, I bring a KOL in who says to me, "I treat 1,500, 2,000, 3,000 HCM patients," and I ask them, "How many do you have on mavacamten?" And the number is usually below 50, right? So the bigger opportunity for us in 2025 is to think about what is BMS going to do to get that big bucket of patients on it? So what I think the hard part we have is we don't know the roadblock that's on there other than the echoes. So how do you envision the world of uptake of mavacamten to really get it to as many patients in need as possible?
It's become.
What is the next?
The comfort upon us, with aficamten , as is not uncommon for a next-in-class drug to open up the category to broader penetration. Maybe Andrew can comment on how, from a commercial standpoint, we're designing a program to do that. I mean, any new category of drug sometimes takes longer for uptake, especially outside of centers of excellence, because especially here where physicians in their offices need to create a workflow. I think that's been really worked out to some extent. The other big factor is, what is the monitoring requirements? Because the monitoring requirements turn into or translate into level of time and workload on a physician office, not just the physician.
So anything that we can do, one, to raise awareness, and I think that's been really done, and we're seeing the data in terms of more and more physicians aware, two, to educate, beyond awareness, and then three, to make the experience of a physician and a patient as seamless as possible, with whatever the monitoring requirements are. And I think over time you'll see the uptake because the drugs work. Now it's a matter of, okay, how do they work for a physician and a patient and getting them to work for a physician and a patient as well, from a resource point of view. And I think that's our next step.
Wonderful. Let's say thank you for the team for the great discussion and an incredible progress and all, obviously, an amazing 2025 ahead of us. So.