Good afternoon, and thanks very much to Jefferies for inviting us to present at the conference. I'm going to make a very brief presentation to set some context, and then we'll get into some Q&A. I'll make some forward-looking statements. I'll refer you to our filings for caveats. We're not going to undertake obligation to update the statements. If you know Cytokinetics, you know we've been on a mission over 25 years to get to this place where we've been focused on one area of biology, translating muscle biology into a new pharmacology. This is our pipeline. It's led by our myosin modulators, cornerstone of which is aficamten pending regulatory review and approval in OHCM, obstructive HCM. We have a PDUFA date of December 26. We're also moving towards, we hope, potential China approval in this fourth quarter.
Soon thereafter, early next year, we hope we might be seeing EMA approval. We believe that aficamten could be commercialized across three continents in OHCM relatively soon. We're also moving forward very quickly towards a readout of the ACACIA study in NHCM that we've guided to should be available to us in terms of data in Q2. If positive, the subject of a supplemental NDA by the end of next year for potential commercial launch in NHCM in 2027. We have other myosin modulators. We won't talk about them today, but we are building a franchise strategy around myosin for specialty cardiology. That franchise is described here, with HCM giving rise to severe heart failure, both in terms of reduced ejection fraction and preserved ejection fraction.
Three potential drug candidates launched to the same concentrated customer segment, and where we believe that could be enabling of a sustainable and enduring business. Here you see how that plays out in terms of potential commercial launches. We think, while it's taken us a bit of time to get to this place, as we turn a page onto commercialization, we could be on the cusp of building a very valuable commercial business. You can see how that's described here in terms of icons and metrics for the kind of business we're building, following in the footsteps of companies you probably know well that have done that similarly. It's a rarity in biopharma, but there are examples, and Vertex and CF is one such example. There are others.
We believe we could build a similar kind of business here around specialty cardiology, starting with these launches, as you see described here. Japan would come subsequently based on a partnership with Bayer. As we have already outlined, our mission and our vision 2030, it's consistent with bringing forward medicines across all of these geographies, but again, concentrated to our know-how and expertise in specialty cardiology and muscle biology. Here are the data that supports what could be the first potential approval. This is from SEQUOIA, the first of several phase III studies of aficamten, large magnitude, highly statistically significant effects on a meaningful clinical endpoint in patients with OHCM. The second study, MAPLE, this read out this summer. This demonstrated aficamten superior to the standard of care in that same population, a disease state of OHCM.
You can see here we actually demonstrated that the standard of care first-line therapy is causing harm in patients, and we think that could create a major catalyst for category growth upon the approval of aficamten, hopefully in December. This study, ACACIA, again, due to readout in Q2. This is a study in NHCM, roughly the same size population as OHCM, but growing maybe even faster in terms of rate of prevalence. We think that if this study is positive, we could potentially own this market. BMS, developing another myosin inhibitor, had a near miss with its trial called ODYSSEY that read out this summer, and we think for reasons that may shine a light on why one should be optimistic about ACACIA in the similar population. Here is our balance sheet, as we have recently updated with our strong financial position reported with our recent earnings call.
You can see how we have a fortified capital structure and how we're also thinking about access to additional capital. We expect to end the year with north of $1 billion, closer to $1.2 billion. Given where we're thinking OpEx would be next year, we think that we have a very nice, strong, formidable cash runway to support our business ambitions. That's a very quick brief overview of the company, and now I gather we'll get into some Q&A.
[You want to switch or], stay?
I'll stay.
All right. All right. Thanks so much, Robert, and the rest of the team for joining us. It's a pretty big time for Cytokinetics. I wanted to start off on the launch and expectations and the label. Then we're going to talk about non-obstructive as well. Let's just go into the PDUFA, right? That decision is coming out very shortly. I think it's been like almost six months of thinking about the term differentiated and what it means.
Even longer.
Right. Yeah, to be clear. I feel like when I've talked to investors, it's kind of ossified into three different things. Number one, you don't expect to have maybe the same DDIs because of the pharmacology of aficamten. Potentially more flexibility when it comes to kind of echo monitoring.
Windows of dosing.
Right. When I step back, you're also thinking in terms of how quickly I can get to my dose. That should be a meaningful improvement from what we've seen with Camzyos. That's at least my interpretation of what would be "differentiated" for aficamten's label. Am I missing anything in terms of how you define differentiation from those three buckets I just laid out?
I think you're capturing it well. We've studied aficamten in ways between the SEQUOIA study and its open label counterpart, Forest, that have produced evidence to support a differentiated risk mitigation profile. I think you've hit on the key points. Maybe I could ask Fady to elaborate on the properties of aficamten and how it should be thought if approved. Maybe Andrew could comment. Fady leads R&D at the company. Andrew's our Chief Commercial Officer. Andrew can speak about current impediments to wider adoption of the first-in-class cardiac myosin inhibitor and how we think a differentiated risk mitigation profile for AFI could open the aperture on wider use.
Yeah, I think just to expand a little bit, Akash, on the points you made. Aficamten, because of its half-life, it can be titrated readily. It can also be down-titrated easily. You do not need to interrupt treatment in order to, if you exceed a therapeutic dose. The exposure-response relationship is also quite shallow. As you increase dose, you do not necessarily see very large changes in the underlying ejection fraction, although you do see sizable improvements in other metrics that relate to improvements in symptoms and gradient reductions. Speed of onset, reversibility, lack of treatment interruptions, and then the DDIs, we have studied this now. The key property of aficamten is it is metabolized through multiple pathways. Blocking one still leaves other pathways for it to be metabolized, and that again reduces variability of its plasma levels over time.
When you look at impediments to prescribing, today there are around 10,000 cardiologists who treat and diagnose HCM. The vast majority are still using beta blockers, calcium channel blockers, and less than 20% are using CMIs. One of the key impediments is the administrative requirements associated with a risk management program or REMS in the U.S. Having a REMS that could maybe release some of that burden would unlock additional prescribers. A second dataset in MAPLE is a head-to-head with beta blockers that shows that beta blockers are not effective in this patient population. Our research shows a more sense of urgency to those who are not using CMIs today who are using beta blockers, either to refer more quickly or they themselves to prescribe.
Our research both shows an increased penetration, meaning more patients on a CMI, as well as an increase in preference share with that second dataset. I think in summary, when you look at a differentiated REMS, a differentiated profile, as well as we believe a differentiated patient services campaign, those three collectively, our belief is, and research also supports a preference share in favor of AFI post-launch.
Akash, you hit on the key pillars of what could be differentiation, but do not lose sleep on the fact that having an EF that might fall below 50% and not having to dose interrupt and rather down-titrate is also considered to be a differentiation.
No, I think that's right.
Okay, now, because in my mind, I think one of the questions I get from investors is like there's a congruence where it's like, okay, there's better data, it seems safer, they have a better REMS. When you think about launch expectations, I think your team has been like, look, slow your roll. It's going to take time for this launch. Look at what happened with Camzyos. We have to build out this market, right? That's where I think sometimes people are like, I think for investors, we're like, what's missing here?
Yeah, I think we're going to be, or there was a question coming.
Yeah, I mean, the broader question is really, why wouldn't this have a meaningfully faster launch than what happened with Camzyos? You've benefited from, you know, Bristol's done a lot of the work in terms of teaching people about this mechanism. I think you're introducing a less burdensome REMS. I think for the people who've done work on the data and we support this, we see this with our KLL work, there's a lot of excitement for your product. Why doesn't that start to have a change just out of the gate, right?
You might be right, but we're not going to guide to that until we have evidence to support it. We're looking at cardiology launches in general that oftentimes take a bit longer, especially when you're talking about the time from free drug to reimbursement. These are things that Andrew can speak to as is not unique to the way we're looking at our launch. Over the course of 2026, I do think that we have certain metrics that we've laid out that we should guide towards.
Yeah. I mean, the only thing I'll say relative to launch trajectory is I think a base expectation would be similar to mava. To your point, I think there are reasons to believe that it could be faster. Obviously we need those data points. If ACACIA is positive, that's certainly going to be an accelerator.
If MAPLE has the impact we think it could have in terms of expanding prescribing, that those that are on the sidelines today start prescribing, and you still have the 10,000 or so patients that are being treated every year as an add-on and those core prescribers. I think there are reasons to believe for an acceleration, but we have to finalize label, finalize REMS, and launch and see if those reasons come to fruition.
Okay. So a few threads from that. I think it's quite interesting. Number one, you mentioned we're going to get some of these metrics and then maybe potentially think about guiding. Just in terms of as we go into JP Morgan next year, could Cytokinetics give guidance for aficamten for year one out of the gate? Is that a discussion that your team is having, or is that probably something more of a 2027 dynamic?
Unlikely. I'll ask Sung maybe to speak to how we're going to more likely approach these matters.
Yeah, I think with launches in the first year, typically, Akash, companies like to see some history, some trends before they provide guidance. I think that's a fair expectation from us as well.
Okay. Now, when we think about metrics that you're looking at that maybe might have been different from what Bristol did, right? Because I can't help but think you're going for a broader set of physicians, not just maybe these centers of excellence. What metrics, let's say in Q1, should we be looking at to feel like, you know what, Cytokinetics is on track to deliver aficamten being a bigger product than what Camzyos could be?
We'll focus to physicians and patients, and maybe Andrew can elaborate to that.
Sure. I mean, I think for externally, we're going to keep it simple. The number of prescribing physicians, the number of new prescribing physicians of the CMI, and the number of patients on product, including those on free drug. Launches usually start, especially on the commercial side with free drug until you convert them through payers, go through the medical exception process. If you look at the most basic, how many patients are on therapy, I think that's probably the most basic, and then the number of prescribers.
Understood. Just kind of remind us, you mentioned free drug, and my guess is the vast majority of patients are going to have to go through medical exemption out of the gate. Landmark me, A, how quick do you expect free drug to convert to paid drug as we go through the medical exemption route? As we think about Medicare, Medicaid, and then commercial reimbursement, what's the cadence of that getting layered on in 2026?
Sure. Medicare coverage will, because of the IRA coverage, is very limited. That's also true of mava, probably 15 or so percent of lives are covered. Medicare, although it's the majority, about 55% of the business, it goes through medical exception. Commercial, our expectation is toward the latter part of the second half of next year, we'll have comparable access from a commercial point of view, probably in the 70%-75% of commercial lives covered. When you first launch, it takes typically around 90 days or so on average to go through medical exception. Usually can accelerate that post-launch to 45-60 days once payer policies get established, once our patient support program understands better what they're looking for beyond what their standard form is. That's how I think you can think about access.
I mean, strategically, we think comparable access, differentiated profile, and differentiated REMS. We're not looking for differentiated access.
Okay. Got it. Now, when we think about MAPLE, and the way I kind of describe with investors is you mentioned that the vast majority of these patients are on beta blockers right now. Is it as simple as MAPLE unlocks that entire 80%, or do you have to kind of stratify it? When you think about patients who are on beta blockers versus patients who are on beta blockers and who aren't well controlled, and you can use the MAPLE data very quickly to justify switching to a CMI like AFI, how do we target that low-hanging fruit? And how big is that market?
I mean, we know the low-hanging fruit because claims data shows who prescribes and what they prescribe for. It won't be binary. The 80% who are using beta blockers that we're calling on that don't use CMIs, it's like any other consumer segment as an analog. There'll be categories of early adopters, later adopters. Usually, if you look at physicians' offices who have more infrastructure, multiple physicians in there, et cetera. We believe it'll unlock in tranches over time. We do have that segmented out in terms of behavioral dynamics as well as prescribing dynamics as a predictor, but we'll obviously know a lot more once we launch.
I think MAPLE data will ultimately make their way into guidelines. That may not be till 2027. In the meantime, early adopters may more likely move patients through beta blockers faster, but payers, there's probably still going to be insistent on a beta blocker before a CMI.
Right. Okay, makes sense. What is your kind of base case expectation of the class recommendation that you would get post-MAPLE? I mean, is this class, it seems like a class two recommendation, but I'm curious.
It's a really good question, and it might vary between the U.S. and Europe. Maybe I'll ask Fady to comment.
I mean, I think those kinds of things are always driven by data. There's rarely class indications given out in the guidelines. The U.S. in general tends to be more specific as to drug-specific drug and the data they've generated. The EU might generalize a little bit more. I think the bottom line is that as opposed to aficamten potentially sitting at the bottom of the treatment, try everything else, and if all else fails, you have these cardiac myosin inhibitors. The evidence for the thing at the top of the pyramid is not very good. Similarly, everything below it is even less good. Elevating something like aficamten to the top should just make people consider implementing it sooner as opposed to trying everything else first.
Right. The only dataset that one can point to in this comparison is an aficamten dataset for MAPLE.
Okay, that's right, but I want to make sure I understand that. Fady, is the expectation in Europe that it will be aficamten and then you might have broad CMIs being considered? And then in the U.S., it's going to be drug-specific? I just want to make sure I understand that.
Yeah, I think just in general, the guidelines usually speak to the molecule that generates the data.
That's the expectation in both Europe and the U.S.?
That would be my expectation in both. Whether there's a statement about this may apply more broadly or not, you might see that in Europe, maybe less so in the U.S.
Okay. Got it. Understood. Now, one of the questions I think we're struggling with is if you look, the Camzyos launch has started to chug along, but it's not like it's accelerated as much as it's just been consistent patient adds. You're converting those patients into paid scripts, but there does seem to be kind of this wall of these treatment centers of excellence simply can't get so many patients on CMIs. It actually seems like a pretty, the number year over year seems about the same. When you think about the introduction of aficamten, should we see net adds for the CMI class expand, or is it more we're going to see 75% of new patient starts trend towards another? I'm putting that word out there. But do you expect patient adds to increase for the class as a result of your entry?
I think both. Maybe Andrew can speak to this.
Yes, I mean, you're exactly right. It's been 10,000 patients a year for the last three years. It's been somewhere between 1,500 and 1,700 patients added per quarter net ads as well. I think that's what I was alluding to earlier. I think base case, you could assume a similar 10,000 unless there's a catalyst. Part of that catalyst could be increased prescribers unlocking patients in the community. Does MAPLE and the differentiated REMS and overall profile of a product unlock? Our research would indicate that it does. Timing is the key question.
Do you think the MAPLE unlock, the true unlock, is a 2026 event or a 2027 event?
That's the key question. I think how long does it take for MAPLE to kind of change behaviors? Guidelines will certainly accelerate that. Base case is probably 2027 for guidelines. We may start to see more acceleration in the second half of next year. I would not expect it at launch. I do think by the end of the year next year, we should be adding more new patients and mava is our expectation. If we can accelerate the market, then even more so.
Got it. Fady, this is a question for you. I was talking with my team, and I remember when the ODYSSEY data came out, I think the simplistic read I think a lot of people had is like, "Oh, you have a better drug than Bristol. You can see that in your obstructive HCM data. Bristol almost hit in non-obstructive. Ergo, there's this kind of read, the ACACIA trial should be successful." Then we started to kind of dig into it. I'm like, "Oh, your alpha split's different." ODYSSEY had a 17-point standard deviation, which is incredible. If you get to that point, your powering it just goes completely haywire.
I remember we were pretty anxious that weekend when we were looking at the data because we said, "I'm not sure if there's a one-on-one read across." I went and I spoke with you and the rest of your team the next day. You're a cool customer, Fady. You're usually pretty relaxed, but you were still very relaxed. I think the thing that stood out to me was that you weren't telling me, "Hey, I'm going to increase my N. I'm going to change my trial design. I'm going to change my alpha split." Why? I think a lot of people, when you look at that ODYSSEY data, you'd say, "Cytokinetics should make XYZ tweaks." Why are you guys sitting pat with your trial design for ACACIA?
I think it's twofold. One is that when you look at their endpoints, they were close on both. You'd like to see clinically meaningful effects, not just positive effects. These are symptomatic and functional endpoints, and there is no sort of de minimis in survival, for instance, any de minimis improvement is thought of as meaningful. It's not the same in symptoms and function.
Just to interrupt, I'm sorry to interrupt, but clinically meaningful would be what in your mind?
There's never a hard line.
Four on KCCQ?
Huh?
Four points or higher on KCCQ?
Four points or higher, say, on KCCQ, 0.6-0.8 on peak VO2. When I've looked at how we've powered the trial and we monitor the standard deviation of our trials, they're well within the powering assumptions that we've made for a clinically meaningful effect. I think if we miss, it's going to be because the treatment effect is too small, or is small, I shouldn't say too small, but is small. It speaks to an increased hurdle for getting an indication in that if it's not of a significant magnitude. I don't think there's any reason necessarily to change.
Since that weekend you're referring to, we've also had a chance to see additional data secondary and post-hoc from the ODYSSEY study. As Fady and others had predicted, there does appear to be a drug effect for those patients who were able to get to higher doses and stay on them. That is something that we think will be a hallmark of what would hopefully be our success with ACACIA. We haven't seen dose interruptions. We haven't seen the kinds of things that can create vacuums in terms of dose density when you're measuring your primary endpoint. That is certainly true for our phase II experience, but also the ongoing open label extension where we've got patients out beyond two years.
We do believe that by not altering the dose strategy, going back to the centers where we had previously conducted NHCM studies and OHCM studies, we should hopefully expect a higher fidelity, more reliable response in ACACIA.
Understood. Fady, I wanted to just, that's super helpful by the way, Robert, on standard deviation, because I think this is a point that I don't think everyone really appreciates. So you're able to monitor, it almost seems like on a monthly basis, your standard deviation. You had updated non-obstructive data with longer follow-up. Your standard deviation's kind of at 14. I mean, it's right kind of smack in the dab of where you would want it to be. I think that's what Bristol saw.
You're talking about the open-label data.
Right. Is it fair to say a standard deviation of around 14 points is what you would say is a normal amount of variability in this population?
Yeah, I would. I mean, I think we powered ACACIA assuming a standard deviation of 15 for KCCQ and a standard deviation of 3 for peak VO2. When you look at the open label extension data, as you said, the standard deviation is around 14. We've seen that similarly in the OHCM data. I think we designed ACACIA before we had those long-term OLE data. Again, the assumption is around the right point, and we're, I think, tracking towards that.
Understood. Robert, I was sneaking in a cheeky question at the end, and you always end your game. I think was it two or three years ago, I remember being at JP Morgan seeing a Wall Street Journal article and being like, "Okay, at least one's out of the way." And maybe there was a deal, maybe there wasn't. Whatever happened, happened. As you think about the value of Cytokinetics now and the data you've generated, the non-obstructive MAPLE and really your clinical development strategy, how strong of a strategic position do you think you're in now versus a couple of years ago when, again, you were kind of at the center of biotech speculation for a takeout?
I think Cytokinetics continues to execute well on a strategy that's building value for shareholders. We're doing the things that we knew we were capable of doing, and there's more that can follow.
Maybe just last question. In terms of the atmosphere, I mean, I've never seen bidding wars for quite some time, and it's been annoying for me to deal with. It does seem like there is an urgency on the strategic side in a way that I don't think we've seen in the past. Can you kind of comment on just the general atmosphere you're seeing out there? Maybe even for your own strategic discussions, if you're looking to end license things, right? How much more urgency is there from strategics in terms of finding assets that have the value that AFI has?
I think you're seeing that in premiums paid. I think you're seeing that in terms of bidders. You're also seeing it in terms of end licensing deals too. As we're out there considering what we might want to do with our pipeline and partnering it, and as we think about where we might even be on the buy side, definitely there's more urgency and more competition.
Understood. Thank you so much for your time. Seriously, thanks.