We're really happy to have Cytokinetics with us here, represented by their CEO, Robert , and their Chief Financial Officer, Sung . Thanks for being here.
Thank you.
I think we'll jump right into things. You know, I think one of the biggest updates lately has been the regulatory discussions around Aficamten and the potential major amendment or the major amendment. I guess, can you talk a little bit more about what led to that, what drove the major amendment, and ultimately the confidence that even with a REMS, you're still going to see a differentiated label?
Sure. I'll go back into 2024 a little bit as well to answer your question. Cytokinetics had multiple meetings, three meetings with FDA. Once we had the results from SEQUOIA-HCM, the pivotal clinical study of Aficamten in patients with oHCM. These three meetings preceded the NDA submission. At all three of these meetings, we had conversations with FDA officials, both from the review division and also from the division that would consider a potential REMS. In those meetings, as they were focused to matters relating to safety, tolerability, risk mitigation, and informed our consideration of submission, in all three of those meetings, which were minuted, we got feedback around how we would approach a potential submission. We considered it reasonable, we deemed it reasonable to submit without a REMS.
Knowing that there were considerations around safety and risk mitigation, we included language within the proposed label that would address those matters. FDA accepted the submission without a REMS, which should tell you something. For, as is reasonable, FDA determined during its review of the application that a REMS should be required. We effectively, knowing that that was a risk, took language that was in the proposed label and moved it to a proposed REMS and submitted with that proposed REMS very promptly after receiving that feedback from FDA. Upon its receipt, FDA considered that and thought it necessary to associate with a major amendment and an extension of the review clock. I would not conclude from any of that that there was anything in terms of shift of strategy or change of meaningful plans.
We've been all along the way referring to our expectation, if approved, that Aficamten would be associated with a differentiated risk mitigation profile. We weren't using the words REMS. Now we know that a REMS is required. We do believe if approved, Aficamten will be associated with a differentiated REMS. I don't consider it to be so different that I would anticipate that will have meaningful effect to the way it's positioned in the marketplace. If approved, I think Aficamten would be approved with a dosing regimen, with a DDI profile, with associated convenience and other aspects of positioning that should be enabling of all of the things we've been talking about all along, which should be good for category growth and category penetration, and hopefully, as could be for Aficamten, preferential share of category.
Understood. You know, there can be a lot of difference between REMS programs. Can you maybe talk about whether we're too narrowly focused on the REMS itself and maybe the differences that REMS programs can have and how even if you have a REMS, there can be a gap between what a REMS for a competitor may look like? I understand you can't go into specifics, but sort of what are some of the differences in how REMSes can be structured that we may not be appreciating that can enable Aficamten to have differentiation?
Thank you for asking that question. It's a very good question. I do think we're over-indexing on REMS because in the marketplace, I think ultimately workflows adapt to REMS. What should ultimately matter is the pharmaceutics profile, the PKPD profile, the clinical safety, efficacy, tolerability profile of drugs in a category with and without consideration of REMS. What do we know so far? We know that Mavacamten, the first-in-class drug in this category, is doing quite well, adding about 1,500 patients per quarter. It's due to generate, I believe, over $1 billion in sales for BMS this year, but for which the use of Mavacamten continues to be somewhat concentrated, mostly in centers of excellence, roughly 600 physicians in the United States accounting for about 80% of the prescription, but with a high adherence and compliance. Patients who are on the drug tend to stay on the drug.
BMS is getting its price. It doesn't look like there's a lot of payer pushback. I think ultimately this category, cardiac myosin inhibitors, are making a meaningful dent in the treatment of patients, but where there's still about 80%-85% of eligible patients not being treated with a cardiac myosin inhibitor today. We see there to be an opportunity where another compound coming into the category can be lifting the tide, as would be enabling of growth of cardiac myosin inhibitors for patients. I think REMS is a component of that. To your question, and I'm sorry, it took me a while to get here, to your question, there are major differences in REMS programs as exist today.
I think if you look at the way Aficamten is studied, the uptitration regimen, the DDI profile, all the things that are now presented and published for benefit of Aficamten to potential patients, what do we know from SEQUOIA? What do we know from FOREST? All of these things point to the possibility that if approved, FDA would approve the drug based on its clinical study in ways that would be differentiated in the marketplace. We think that would be to the advantage of physician convenience, patient convenience, a lot of things that we think ultimately speak to market penetration.
Got it. You know, as you think about the differentiation of the drug and what physicians want to see, are there things that are not necessarily in the label, would not appear in the label, that are properties of Aficamten that may resonate with physicians and help uptake?
Yeah, the ongoing clinical evidence. Our team is doing a superb job of continuing to study Aficamten in ways that should further the knowledge base for how a cardiac myosin inhibitor could ultimately be used. Case in point, we recently announced positive results from MAPLE-HCM, a head-to-head study of Aficamten versus first-line metoprolol in patients with oHCM. Believe it or not, metoprolol and other beta blockers and calcium blockers are used in the treatment of oHCM as first-line therapy, but for which there's scant clinical evidence to support their use, nor is there broad FDA review or approval. Yet the guidelines call for it because these are drugs that have been out there for a long time and they're cheap. For which we've done now the first randomized head-to-head study of Aficamten versus metoprolol, and we announced recently that that study was positive.
I'm looking forward to our presenting and publishing those data, as I think will continue to further the evidence to support Aficamten in ways that this goes beyond a REMS. This goes beyond even what ultimately may be knowable about Aficamten today. I think investing in ongoing studies like MAPLE, another study called ACACIA in NHCM, we recently announced that we concluded enrollment ahead of schedule. You'll see those data in 2026. These are the kinds of things that I think further the evidence to support Aficamten if positive.
Got it. On MAPLE, you know, obviously you're going to present that data. How soon do you think MAPLE can be part of guidelines? Is this something that you can use to interact with payers now? You know, maybe make it a two-part question. Is MAPLE and the data from MAPLE something that you're going to show to the FDA now as part of the review process or for the European regulators?
There's no expectation that we'll be submitting MAPLE as part of the ongoing review. It would be potentially presented and published this year. That's our hope. As to your question about guidelines, that could mean enablement of expansion of guidelines to consider MAPLE in 2026. It will be in the public domain. It should be informing guidelines, but it won't be the subject of our interactions with regulatory authorities, nor do we expect that we'd be promoting in accordance with that until it's ultimately incorporated into label.
Got it. Maybe we can talk a little bit about the commercial strategy for Aficamten. I guess, how are you thinking about how to target physicians where you are with payer outreach? Ultimately, do you think you're going to be targeting mostly new patients? Are you going to be targeting switch patients?
If approved, Aficamten would be available and hopefully in the hands of patients in 2026 because we have a PDUFA date end of 2025. Make no mistake about it, we've been preparing for this for quite some time. Our Head of Sales is in the audience here, and he's been overseeing a group of field managers that have been on payroll for a couple of years now. These are folks that have been thinking about how we go to market. What does that mean for sales learning and development? What does that mean for territories, configurations, incentive compensation? How do we be ultimately optimizing for the best type of commercial launch?
They've been working side by side with other colleagues for several years as we do all of the market analytics, all the segmentation, all the omnichannel planning, all of the work that goes into a successful launch. We've been approaching this not just from the standpoint of a first launch, but what would be for enduring value through multiple launches, label expansion, lifecycle management, and Aficamten as it opens the door onto other products like Omecamtiv mecarbil and CK-586. How we think about a commercial business has been the subject of planning for many, many years at our company, how we incorporate our commercial colleagues alongside of our R&D colleagues into one culture, making it happen.
I think when Cytokinetics shows up in the marketplace, it'll be with a tailored bespoke experience for physicians, payers, and patients that enables, we would hope, somewhat of a differentiated commercial story as well. We've been interacting with payers for a long time. We've got medical affairs colleagues that have been in territory for multiple years, engaging with all sorts of opinion leaders around medical education programs, et cetera. Our plans here have been in the works for quite a while, and I expect that that'll show up in the way we go to market.
Got it. I think investors are probably going to use the Camzyos launch as sort of a benchmark for how Aficamten's launch may go. I'm curious your thoughts. Do you expect the launch of Aficamten to potentially be more rapid because the market's built out? Is there going to be pressure because there's some competitive dynamics? I guess, you know, as you think about how Bristol launched that drug, I mean, are there any learnings that you think you'd, things you'd do differently that you want to take away?
Yeah, I'm going to answer that and also ask Sung to speak to it from his perspective. We've been good students of not only the BMS Mavacamten launch, but also many of us come from experiences with cardiology and next-in-class launches that go back decades. We're trying to best take learnings from those and apply them here for Aficamten. A second drug to market typically has for some period of time a similar trajectory, but then what drives launch velocity? Those are the kinds of things that ultimately are informing our decisions. How we as a new commercial entrant come to market speaks to building something that's tailored to our pipeline, our strategy. What does that mean for distribution? What does that mean for how we segment and prioritize the physicians we call upon with what reach and what frequency?
These are all things that you can borrow learnings from next-in-class drugs in cardiology. I think it's reasonable to use a benchmark of the Mavacamten launch, but things should be different. I'm not going to speak today to what would be metrics to measure, not yet. You'll hear those from us in due course. I do think that a second drug in the same category typically deploys a different strategy. We're not going to be focused as much on switches. We may see some, but it's more important for us to drive category penetration beyond centers of excellence to the community and ultimately as will be benefiting the category where there are currently ample opportunities for patients not being presently treated or treated well.
Yeah, Leon, I'll just add to that. We have a PDUFA date obviously ahead of us, and we'd like to see ultimately the label that we arrive at. Based on our clinical data, we certainly have an aspiration to want to do better. As Robert said, in the cardiovascular space, in the early years, certainly you could see a linear pattern.
Yeah, there's, I think, a lot of history around cardiology launches where they typically take longer to get payer traction reimbursement. This is going to be a category where, based on what we know so far, you shouldn't expect a lot of Medicare contracting. This is a roughly 50/50 split Medicare, non-Medicare, but we anticipate that this will all be handled primarily under Medicare exception. Time to reimbursement factors into how quickly we can see the asymmetric phase of revenue generation post-launch. There are other things that we're doing that also should drive launch velocity, and they speak to patient experience. How can we create a patient hub that ultimately is distinguishing of Aficamten in the marketplace? How can we be enabling from the standpoint of positioning and driving where there are pockets of demand to a preferential place?
What strategies might we employ that are bespoke to the Cytokinetics experience? These are things that I'm not going to speak to in detail today, but they're top of mind for us.
That makes sense. I wanted to ask on ACACIA and the non-obstructive market. We saw some data from, or I guess we did not see a lot of data from Bristol, but there was an update. I guess, how are you thinking about ACACIA? You made some changes to the study, to the study endpoints. Were those internally driven? Were those driven by regulators? Were those driven in any way by what you thought may have come out of the Bristol data? Can you talk about that?
Yeah. In the audience, we have the lead from our clinical team who's better suited to do that than I am, but I'll do my best. Firstly, to answer your last question, nothing that we did was driven by any specific knowledge of the Bristol data. For feedback we received to harmonize across regulatory jurisdictions, we wanted to make certain that the endpoints and statistical plans were cohesive across territories. We made minor modifications to the way in which the study design will ultimately be implemented, but for which the same endpoints are being measured. We're just making what was previously the first amongst a hierarchy of secondary endpoints a co-primary. We've altered the statistical plan to be accommodating of that, and we've increased enrollment to increase our statistical power to measure both co-primaries.
All of these things are in line with regulatory feedback and have nothing to do with the BMS study design. For which we do believe it's to our advantage, ACACIA can be positive were we to hit on one or both of the co-primaries. For now, having increased the enrollment, we think we're in a good position to test the hypotheses that are being studied in ACACIA and as could be enabling of something very meaningful for Aficamten if positive in ACACIA. BMS reported that their study ODYSSEY was negative in NHCM, and we don't know why. We have speculations like everybody else, but we can't know until we see the data. We don't think it reads on mechanism.
We don't think it reads on the population, but for which we'll ultimately know the answer based on the study we have designed and are conducting, which is going quite well. If ACACIA is positive, it will be imperative that we move swiftly to get those data submitted to regulatory authorities as promptly as possible because as we're seeing now in claims data, the population of patients with NHCM may represent now about 50% of the total. This is a larger and more rapidly growing segment of the population than we would have expected even a couple of years ago. That could be quite enabling of the commercial profile of Aficamten to be even further differentiated upon a potential approval, but again, subject to ACACIA being positive. We're excited about that possibility.
Got it. We've got a few minutes left, and I wanted to touch on some of the other drugs that Cytokinetics is working on, maybe starting with Omecamtiv . You guys are running a second phase 3 there. Assuming that it ends up reading out positively, I guess I'm curious how you see that drug fitting into the landscape for HFrEF, especially maybe towards the end of the decade as guideline-directed therapy continues to evolve. Are you seeing that drug, is it going to be used primarily in the population that it's studied? Do you think that there's maybe opportunity to expand that, that the study is just sort of a run in that population because that's where it's most likely to show a clinical benefit, but the drug could actually be used more broadly?
Yeah, I think this is one of the great opportunities for our science. We've studied omecamtiv mecarbil six ways from Sunday, and we've done this in over 30 clinical trials. It's apparent that omecamtiv mecarbil has a very profound pharmacodynamic effect that's translated to clinical benefit in phase two and phase three studies. Here, omecamtiv is already the subject of a positive 8,000 patient phase three study where that effect size was doubled in a patient population with more severe disease. The ongoing confirmatory phase three study is a roughly 2,000 patient study meant to replicate a finding from a prior 8,000 patient study. If positive in the ongoing COMET study, I do think it'll be potentially quite meaningful for patients with more severely advanced heart failure with ejection fractions below 30%. These are not patients that are seemingly benefiting from existing standard of care.
The event rate of death and hospitalization for these patients remains unacceptably high. I do think that if positive in COMET, the heart failure specialists tell us that this will be a very meaningful driver of guideline adoption of this new innovation. I think that when we go to cardiology meetings, like was the case just a few days ago at the European heart failure meetings, there's a very high level of enthusiasm for Omecamtiv that frankly is not matched right now with Wall Street interest. I think that could be a mismatch and a potential arbitrage for investors. I think there's a significant opportunity with Omecamtiv that's being largely underappreciated.
Yeah. I also want to touch on CK-586 and the AMBER study.
We should also talk about our financials when we can. I want to make sure that's appreciated too.
We'll make those the last two questions then. You know, 586 for AMBER, can you talk about how recruitment's progressing? I'm also curious on the patient population. I think we hear questions on why you've chosen the patient population with 60% as the LVF cutoff. I guess can you talk about why you think that's the right patient population to go after here?
Yeah. Much like HFrEF, patients with a reduced ejection fraction can be broken into cohorts. We're studying those with more severely advanced systolic dysfunction with Omecamtiv mecarbil. With CK-586, an inhibitor of cardiac myosin, we're looking at a subset of HF patients, patients with preserved ejection fraction. There, those with higher EFs have anatomies that more resemble the NHCM patients that we're studying with Aficamten. The clinical evidence will hopefully support movement into phase three. The preclinical data already demonstrates that these patients are not more likely to benefit from existing standard of care, but a cardiac myosin inhibitor could be addressing that which ails them in ways that could benefit them.
We're looking at the other extreme side of heart failure with a subset of patients with higher EFs, thicker anatomies, and where while they don't have a pressure gradient, we do think that they're different from the other HF patients that maybe are more metabolic. We're not focused to the more obese metabolic patients. We're focused to those with more hyperactive contractility. We think they'll benefit from an inhibitor. The phase two study, AMBER, is enrolling. We hope to have at least two cohorts completed this year, data hopefully next year.
Got it. You guys have a lot going on at the company, gearing up for a launch, a lot of R&D. You wanted to mention something on the financial position. I'd love to hear it.
Yeah, absolutely. We finished quarter one, as you know, with $1.1 billion in cash and investment. We are in a real solid position with regard to the balance sheet. Importantly, we have access to further capital. We could be eligible for up to an additional $425 million. This would be provided to us by our partner, Royalty Pharma. This puts us in a great position to not only launch Aficamten, but also to advance our pipeline and, importantly, the label expansion opportunities for Aficamten.
Appreciate it. I think that's all the time we had. Thank you so much for joining us.
Thanks very much. Appreciate it.
Thank you.