All right, good morning, everyone. I appreciate you all joining us in beautiful Times Square. My name is Akash Tewari. I'm a pharma and biotech analyst here at Jefferies. I have the pleasure of hosting the Cytokinetics management team. And happy belated birthday to Robert. Robert, why don't I hand it off to you for some brief intro remarks, and then we'll get started.
Thank you, and thanks for inviting us to participate in the conference. Good to see everybody. Very exciting times at Cytokinetics. We've got an application pending review with FDA and also with China and EMA. Expectations are that we'll be in a position to go to market with aficamten for the potential treatment of OHCM, pending FDA and China approval this year, and in Europe, pending EMA approval next year. This is based on the results of SEQUOIA-HCM, which are presented and published, and with many subsequent publications, we think build a strong case for aficamten, as could be a meaningful opportunity for patients with OHCM. Aficamten is a cardiac myosin inhibitor. It's also been the subject of a study called MAPLE, which is not going to be part of the initial labeling. We have top-lined the MAPLE results.
We indicated by press release that the study met its primary efficacy endpoint. We did not include any data in that press release, but we do expect that that data could be presented and published later this year and provide some wind in the sails for potential aficamten as we go to market. Those are two studies, SEQUOIA and MAPLE, in patients with obstructive HCM, which we think represents about half of hypertrophic cardiomyopathy, the other half being non-obstructive HCM. There is a study called Acacia that we recently announced completed patient enrollment, accelerated, and over-enrolled, and we expect to see those data first part of 2026. This is further evidence of the way we roll at Cytokinetics with ample clinical research, providing, we hope, support for the use of ficamten for patients with hypertrophic cardiomyopathy.
Aficamten represents the first of three legs of a three-legged stool, the other two being Omecamtiv and CK-586, also myosin modulators, one an activator, one an inhibitor, the former for potential treatment of heart failure with reduced ejection fraction, the latter heart failure with preserved ejection fraction. You begin to understand how we're thinking about building a business off of our longstanding pioneering innovation in this pharmacology. These are three potential new medicines, all directed to the same customer segment, and where we think we can build an enduring and sustainable business around a specialty cardiology franchise model, both in North America and Europe. I'm joined today by our Chief Commercial Officer, Andrew Callos, as well as Dan Jacoby, who leads cardiovascular clinical research, and we're looking forward to a good conversation about plans and progress and prospects.
Perfect. I always do enjoy our conversations. Robert, why don't we start? You know, scientifically, you guys run the way that you design trials, the way that you think about amplifying certain signals with aficamten. I think it's been impressive. I think the three-month PDUFA delay, that seems out of character for a company that's been on the ball with its development program on aficamten before. The sense I get is you guys took a calculated risk, and whether it paid off or not, A, doesn't mean that your confidence on aficamten getting approved has changed at all. B, help us understand why your team did take that calculated risk to not submit a REMS and the initial interactions with the FDA.
Yes, of course. So aficamten follows behind a drug called mavacamten that was invented in our laboratories, licensed to a company called MyoKardia. B M S bought MyoKardia, and now aficamten is coming in as may open up further opportunity for patients. When the Bristol Myers Squibb application was ultimately approved, in reading the summary basis of approval, it was clear that FDA mandated a REMS program. Even with submission of a REMS, there was a PDUFA extension in order to seek approval for mavacamten, now called Camzyos. We had three meetings with FDA before we submitted our NDA. In all three meetings, we discussed safety, tolerability, and risk mitigation, risk management. Attending those meetings with FDA were representatives of the Drug Review Division, but also the Division of Risk Management that oversees the REMS programs.
In those meetings, we discussed, asked, and answered questions about the potential for a REMS, and it was deemed reasonable, based on minute meetings with FDA, that we could submit without a REMS, and we chose to do that. The FDA indicated to us that that would be something that would be subject to review post-NDA submission and filing. FDA accepted our submission for filing without a REMS, and they certainly did not mandate a REMS. We thought that was a good risk to take, and we incorporated into labeling that which would be enabling of risk mitigation, risk management. Upon acceptance of the NDA and further review, FDA determined that a REMS should be required and asked us to submit one. We were ready to do that. We knew that that was a possibility.
We basically took language around risk mitigation that had been submitted in the draft labeling. We moved it into a REMS, and we promptly submitted that REMS. Upon its receipt, FDA accepted it and said, "This constitutes a major amendment and therefore a 90-day extension," which is their prerogative. We think that we did right by this application because, if anything, socializing this risk mitigation underscores differentiation that even as may be within a REMS, we think ultimately will serve our interests as we hopefully will seek approval and gain approval of aficamten, and it may be approved with a differentiated risk mitigation, even within a REMS. We think all this speaks to the same upside as could occur with a differentiated positioning if aficamten is ultimately approved, albeit, unfortunately, now with a 90-day extension.
It makes sense. Now, I know we're going to speculate, but sometimes we have to. This is the way I kind of see it. I am very confident you're going to have less echoes. I'm very confident you're going to be able to get patients to an optimal dose more quickly because, frankly, you've shown that in all of your studies. When I think about no REMS or REMS, and to me, it's not the titration. I think it's more of a theoretical question on durability and echo monitoring there. You know, it's funny. You and I have talked about this with some of your competitors, and it's like one of the things you mentioned is the FDA doesn't just look at the mean or the median. They look at the entire range of exposures with DDIs, et cetera, et cetera.
One of the concerns we've had with Camzyos, and this is a theoretical one, is you can have different levels of drug accumulation for a subset of these patients, and if you can have that accumulation, you can induce a systolic dysfunction. That's a theoretical concern that Bristol answered with more data. You have the FOREST data you submitted here, but you don't have a lot of real-world evidence at this point, right? When I think about what led to one REMS or a REMS or no REMS, is it fair to think maybe we should be thinking about the durability and that theoretical concern rather than anything with the initial titration?
Yes, but, and I'm going to ask Andrew and Dan to weigh in, I think ultimately what will drive commercial adoption is how comfortable are physicians who aren't prescribing mavacamten to be activated to now prescribe aficamten. That's where our strategy is rooted. I do think making that experience a more positive one for physicians and patients is enabling us to move beyond the roughly 600 physicians who are accounting for about 80% of the mavacamten prescriptions today. This is where Andrew and his team have done a lot of market research. They've got good strategy. Dan can speak to about how that's bolstered by data we're seeing from now hundreds of patients in the FOREST-HCM study that are out beyond one year, and maybe I'll ask them to comment on these things.
I can start. I think Robert covered kind of this concentration of the current market around centers of excellence where the vast majority of patients are treated today. For the market to expand, the need for a broader set of cardiologists to treat patients, especially in the community, will be critical for really to move out of this kind of linear growth phase to a high growth phase. When we look at differentiation based on SEQUOIA, that certainly, I think, will bode well based on our research. That preference share will shift towards aficamten. When you look at that as well as a differentiated REMS, and when you add on MAPLE to show that standard of care is not inferior relative to aficamten, that should unlock more community prescribers who feel like beta blockers are good enough for some patients.
I guess that without getting too deep into our strategy, that's really how we're thinking about aficamten. Three to six months into our launch, assuming we get approved at the end of this year based on this revised PDUFA, that's when our non-obstructive trial reads out, which is Acacia, which certainly should expand the market and give even further propulsion if that's a positive study. I'll turn it to Dan for maybe additional comment.
Sure, yeah. I really appreciated what you said, Akash, in terms of your sort of interpretation that we should have fewer echoes and we should be able to get to target dose more rapidly. I think that that is reflected in the data from both our phase 3 study and from FOREST-HCM, which used a real-world approach to titration. Remember, these studies were conducted with site-based echocardiography. The echocardiologist at the site interprets the echo, and the dose titration occurs that day, which is exactly how it will work in the real world. In fact, in FOREST, the investigator themselves can look at the echo and look at the patient and make a determination. That is exactly how clinical care will work. We see in that setting rapid improvement in symptoms, biomarkers, gradient, and that improvement is sustained over the extended period of time.
We have over 250 patients that are out over a year at our last data cut. We are increasingly trying to get this data out for people so they can digest it. I anticipate hopefully bringing some more data into play in the coming months or so. It will reflect, I think, again, what we have been seeing all along that confirms your impression.
Got it. Now, you know, sometimes you'll hear a no from the agency, and it's definitive, and they're very clear, like, "Hey, this is how we think about a certain drug. This is how we not think about a certain drug." When we look at the Bristol experience, they had real-world data. They submitted that to the FDA. They made an argument, and they went away from the quarterly echo monitoring.
I can't help but think, if there's a theoretical concern about drug accumulation over a longer period of time, and you guys have, one of the things we've noted is meaningfully less PK variability than a lot of your competitor compounds, and there is this kind of consistency in exposure that we see with aficamten, why can't Cytokinetics, let's say a year with real-world experience and you have more real-world data, go back to the FDA and either argue, "Hey, I think it's prudent for us to now go into a 12-month echo monitoring paradigm," or potentially remove the REMS entirely? Are those avenues that the company could explore here?
Yes, although I don't know that it'll happen as rapidly as maybe you're alluding. FDA tends to be more relaxing of REMS programs after several years more than after several months. Yeah, and as I think you and I have discussed in the past, I don't think we'd be even talking about a REMS based on our data alone, but based on the category and the mechanism of action, I think it is our expectation that a REMS is going to be a fact of life, at least for a while. With that said, I think the street is over-indexing on REMS here because ultimately, I think the marketplace is adapting to the existence of a REMS, and workflows and echo capacity are adapting. There's administrative burden, to be sure, but these are patients who didn't have drugs before. Now they do, and they're benefiting greatly.
The adherence and compliance, even with a REMS, is quite high. I think the use of these drugs is underscoring that physicians, their staff, pharmacists, and patients have developed the work streams. It is incumbent upon us within the existing work streams to make it simpler, to make it more convenient, to give more flexibility. That is where I think, and Andrew should comment, that is where I think being new to market, we can design something that is more bespoke and custom that should be welcomed by potential customers.
Yeah, I think Robert covered it well. It really is around differentiation and patient experience distribution, the entire continuum of prescribing to a patient, getting a prescription, and making that less onerous, less administrative for an office staff as well as a pharmacy. That is how we kind of look at the market. It is a specialty market. It is a market where to get more community engagement and involvement, that is going to be required so that their administrative burden, if you will, is relieved relative to what they are perceiving today, and which is limiting the number of prescribers in the CMI category.
Got it. Now, maybe stepping back, this is an angle that we think about REMS and the echoes, but one of the angles we've always thought about is just straight-up efficacy. I mean, read the AMA review. Why did they go with a modified REMS? Because 65% of the patients on Camzyos are on 2.5 and 5 mg. My team, we've worked on this. My suspicion is the pivotal benefit in that lower dose cohort is about one. I mean, I know that's not published. You kind of have to back into it. But I have a pretty strong suspicion there's a meaningful amount of Camzyos patients that aren't actually getting a huge clinical benefit. The way I almost see Camzyos is it's a great drug for patients who need a low dose who thin out the wall.
If you need higher levels of exposure, if you have more impeded exercise gradients, that's where I think aficamten could really differentiate. You guys haven't per se talked about the switch population in your studies, but I know, Dan, you also have some interesting perspectives as a practicing physician. What % of Camzyos patients do you think would be very receptive to switch onto aficamten and the clinical profile they have?
Yeah, I guess I'll, yeah, sorry, I'll take this. You know, we talked last night a little bit about this. You know, I hate to put a number on it. We obviously do think that there's some patients out there that may have, I guess, be undertreated on a certain level. And I guess those patients may be candidates for switching. I think, you know, my personal experience with this is that you do get patients who just don't want to deal with the hassle of potential interruption, have had an interruption before, don't want to take the risk of trying to get up to 10 or 15 mg, are happy with having reduced symptoms, but not necessarily no symptoms.
It is that kind of patient who, if there is an option that seems to be maybe a little bit easier to use, maybe a little bit safer at higher doses, perhaps, that that patient may be interested to kind of investigate that with their physician. There will be people who will bring that forward, but as a team, we are not pursuing that. Andrew can speak to that specifically as a commercial strategy, but that is not a point of an angle for us that we are particularly going after per se.
Yeah, we don't have that data. That's not in our trial. We're going to be pursuing new patients. Over 80% of the market in OHCM should be available in the U.S. when we launch if we get approved at the end of the year. To Dan's point, that will be really a physician-patient dialogue if that switch were to occur, but it's not going to be driven from a strategy point of view.
Understood. By the way, I will say from our own work, I think about 30% of patients. You can do that on LVEF. Let's say you have a baseline LVEF of 80. You can't get reduction with the PK variability Camzyos has. So that's at least us. I don't know. You don't have to bless in our repository.
Akash, you've known us to be conservative in the way we talk about these things. I do think that represents upside. I also understand the street looks to switches as maybe an early biomarker for commercial traction. We anticipate some switches. It's not strategy. Yeah, and you know, there's at least one key opinion leader who's on record publicly for saying he expects to switch two-thirds of his patients, and he's one of the highest volume mavacamten writers. We do foresee that there will be switches, but to Andrew's point.
It's not your stretch.
Over 80% of the market is still available to us, and it's incumbent upon us not to compete with BMS or mavacamten, but rather to expand the market for the benefit of more patients getting a cardiac myosin inhibitor.
Understood. Now, let's talk about launch cadence and expectations there. Bristol has, you know, kind of it seems like there's two buckets, right? If you can get to the community center setting, you can really increase your patient ads. What we've seen with Camzyos is 5,000, 5,000, 5,000 in terms of patient ads in that kind of community center setting. If we're thinking about obstructive HCM out of the gate, that's the big pool. That's the initial pool. Maybe six months, a year down the line, you're thinking about more community center. Andrew, in terms of investors and expectations on the HCM launch, we've been pointing people, it's not going to be worse than the Camzyos launch, but I would comp it to the Camzyos launch as a realistic cadence for the obstructive HCM launch one year out of the gate. Is that fair?
I think that's reasonable based on the number of patients that are in the centers now, that key variable. There's a few of them that could certainly drive that up. One is how long does that community engagement take and how broad is that community engagement? The second is how much of an accelerator does MAPLE provide to that once MAPLE gets added? I guess the third would be if Acacia is positive and we're three to six months into launch, there's likely a halo effect, given you would now have three clinical studies with safety efficacy, especially in a clinical study in a brand new population. I think there's things that could accelerate, but for a base case, I think the way you've outlined it is reasonable.
Got it. Makes sense. Let's hit on Acacia because, you know, the more work we're doing, and it sounds like you guys are the same way, this is a meaningful strategic card flip because there could be, you know, maybe where the biggest increase in diagnosis is going to be in the community center setting for non-obstructive patients. You can have something like that. It really does change the profile. Bristol has, you know, with their top-line press release, it almost sounded like they're saying, and this is just not the right mechanism in this population, like we learned from that. You know, it almost felt to me like, okay, maybe there's a waning of effect. Maybe, you know, there's some issue biologically. There's some type of compensation. When we talked to Bristol about it, it's almost like there is a curve separation. It is durable.
It was simply not statistically significant. Can you talk about some of the differences between, you know, the Bristol study and then Acacia when you think about dose titration, when you think about therapeutic window, and then also your confidence in a dose effect manifesting in non-obstructive, given that you've seen, at least in your clinical data, 80% of your patients can get to higher doses?
I think you're touching on some key points. BMS conducted a study called Odyssey in patients with non-obstructive HCM, and they recently toplined that the study did not meet its endpoints. We hope to see these data presented later this year. We're conducting a study called Acacia. In Acacia, in contrast to Odyssey, we basically took the same dosing regimen that we had studied in phase two, and we moved it into phase three. We added a high dose that wasn't in phase two, as could be permitting of getting more patients to more exposure for longer. The Acacia study also returned to some of the same centers. We didn't introduce any other variables. We also looked at patients as they enrolled and verified that they did, in fact, have non-obstructive HCM by dint of their echoes.
Dan and his colleagues looking at every echo. I do think we did what's more conventional and classical by keeping things more similar, moving from phase two to phase three. Based on our phase two data, we remain very optimistic about what we should see in phase three. That's further buoyed by the fact that those phase two patients have rolled into an open label extension. We're continuing to monitor those patients. They are getting to higher doses. We are seeing consistent effects as we would hope to see also in phase three. In some ways, we're conducting a side-by-side experiment. One is an open label extension. The other is a randomized controlled study. We remain bullish on prospects for Acacia. I'm going to turn to Dan maybe to speak to the things that we're most encouraged by.
I think fundamentally, we believe the design and conduct of Acacia favors why we should remain encouraged by what we hope to see in Acacia.
Yeah, thanks, Robert. I guess I'll just add a couple of data points to just back up what you're saying. In our paper that we published with the 36-week follow-up in FOREST-HCM on non-obstructive hypertrophic cardiomyopathy, 65% of the cohort achieved 20 dosing after titration, which is the highest dose of aficamten available, with another 15% or 17% achieving 15 mg. A total of around 80% achieving the top two dosing. The safety was phenomenal, with only two patients having to have down titrations. The efficacy demonstrated a 56% reduction in NT-proBNP and a 13-point plus increase in KCCQ, all of which speaks very strongly to the fact that at least the therapeutic hypothesis that aficamten as an excellent class cardiac myosin inhibitor could demonstrate efficacy in hypercontractility in HCM is definitely still intact.
I just want to take a pause there on the KCCQ improvements. That is a very large increase in KCCQ. Admittedly, this is open label, so you have to assume there is going to be some placebo effect in phase three. Even if you subtract away the expected placebo effect, you are still talking about one of the largest potential improvements in KCCQ as has been measured in cardiology. If that is borne out again in phase three, and that is way higher than what phase three is powered to demonstrate, we should expect a positive outcome.
I want to hit on two points on that. A, when you think about the Odyssey protocol, there are instances where Bristol could go in almost one-mg increments in terms of increases in doses of Camzyos. That's obviously not what you've seen in your protocol or even FOREST, which is even more aggressive. Can you talk about the importance of that? Number two, placebo is important here. You know, it is open label data that you have right now. How concerned are you about more variability or a higher placebo response? I think in our own work, we're kind of expecting a five-point placebo benefit on KCCQ. Is that reasonable, or are there concerns that that variability might be bigger than expected?
Yeah, obviously, we don't have the data, so this is highly speculative. If you look at the placebo group KCCQ curves from what we see in CMI trials, you tend to see a rise in the placebo response, and then it flattens and maybe even declines a little bit over more exposure. That's consistent with what we know about placebo. There's initial enthusiasm, and then as you start to realize that things haven't changed that much, that kind of deteriorates. I would be surprised if over a 36-week treatment period, we saw a more exuberant placebo response than we saw over 24-week treatment periods in SEQUOIA or even in Explorers. I think we're kind of safe.
The other factor that we have to consider here is that while the therapeutic hypothesis, as I said, is intact, NHCM is a somewhat different kind of clinical course in some ways than OHCM. Over 36 weeks in a non-treat or in a population that's not effectively treated, there could be some deterioration that could occur. Maybe you'll see some of that also in the KCCQ. Again, highly speculative, but I think reasonable to kind of think about those things.
Got it. We're towards the end, and I'm going to stick in my strategic question, which I always do to you, Robert. You always play ball, which I appreciate. The question I get the most right now is non-obstructive seems to be a really important clinical card flip. I think MAPLE, that data to me is going to be solid. You had restrictions in terms of what you could do from getting in a publication, which I think investors understand. Could there be strategic news? Like if an investor says, there's no way there's strategic moves from Cytokinetics ahead of this non-obstructive data, why or why is that not the case?
I trust you're using the word strategic to maybe allude to M&A.
Yes.
What I'll say is we're being quite strategic about how we're thinking about OHCM and as could be further benefited by NHCM in terms of how we're investing in our go-to-market strategies. To your point, I do think the NHCM card flip takes on more significance in light of the Odyssey results being negative and the market showing more prevalence and growth in NHCM. With that said, you know, BMS bought MyoKardia for $13 billion based on expectations that the OHCM opportunity represented, as they said publicly, $4 billion in peak sales. They're on track this year to generate over $1 billion, and I think it's within reach that they'll get to $4 billion based on mavacamten in OHCM. If we execute well, we think that aficamten can do at least that, if not north of that in OHCM. NHCM represents further upside to that too.
We like the way we're situated, and from a strategic standpoint, we're investing like we mean it with the goal to become a meaningful player here commercially in OHCM and hopefully also NHCM.
The way I interpret that is not necessarily we have to look at that paradigm. There could be optionality there. I really appreciate it, Robert. Thanks so much and to the broader team, and thank you so much for the investors for joining us. Really enjoy.