Cytokinetics, Incorporated Stock

Great. Thank you, everyone, for joining. I'm Max Skor, biotech analyst with Morgan Stanley.

And before we get started, for important disclosures, please see the Morgan Stanley Research Disclosures website at www.morganstanley.com/researchdisclosures.

And I'm very happy to welcome the Cytokinetics team: Robert Blum, CEO; Sung Lee, CFO; Andrew Callos, Chief Commercial Officer; Fady Malik, Research & Development.

Welcome, team. Thank you very much for joining us today.

Thank you.

And maybe just to start off, so Robert, we're in the early stages of the MYQORZO launch. Could you just walk us through key learnings at this point and what we should really focus on going forward into year-end?

So MYQORZO, aficamten, was engineered with certain properties in mind and was developed very much to elaborate on those properties. And I think those are playing well to what we hope ultimately proves competitive advantage in the marketplace: ease of use, flexibility, convenience. These are things that we think matter, especially for a second to entry in a category of cardiovascular medicine.

And I do believe that, as we have projected, we're on track for some pretty ambitious goals. Goals like preferential share of new scripts by the end of the year; goals like parity market access. That's all translating into very solid launch velocity and momentum. Andrew can elaborate. But we reported our full second quarter. And in that quarter, as you should expect, we saw a majority of new scripts coming from velocity accounts, those roughly 700 accounts that represent over 80% of the historical CMI business.

But what was also encouraging, and this is imperative to growing the category, is that there were at least half of prescription -- sorry, half of prescribers coming from either, historically, physicians who had not prescribed a CMI or had not done so in a while. And that speaks to their comfort with MYQORZO, especially given a differentiated REMS risk mitigation and also where we believe the data -- strong data publications support its use.

So we're really optimistic and encouraged coming out of Q2. Q3 continues to look promising. And we're looking forward to sharing results at our next earnings call.

Great. So MYQORZO's new-to-brand share exceeded 40% in June and you're targeting more than 50% CMI new patient preference share by year-end. What are the biggest drivers required to close the gap? And what could allow the share gains to occur more quickly?

So some of that relates to market access where those barriers are being chipped away and we expect parity by the end of the year. But maybe I'll ask Andrew to elaborate on how we get to that goal.

Sure. So from a new-to-brand share of 50%, as you mentioned, end of the second quarter, we were above 40%, and still trending in that direction, over 50%. When we look at what is it going to take to get there, our strategy has always been kind of to the higher we decile physicians, every 10%, and the higher the decile means the most productive physicians, we have the highest share, and it goes down from there. So it continues to get the centers of excellence on board and expand the market.

And as we expand the market, below decile 10% and 9% are the highest, spend more time with our field force, spend more time with those customers, and generally those, as you go down, those deciles are less familiar with the details of the data and the differentiation. So there's an education component as well.

But what we've learned, no surprise, is that differentiation matters, the REMS matters, the experience and the process of getting a patient on therapy and going through the REMS matters, and market access matters. So it's reinforcing those elements as well as you go down. But we remain confident in that goal of greater than 50%. Because when we focus resources, we're seeing the share difference.

Great. And I think, Robert, you touched on this in the opening remarks, but more than half of MYQORZO prescribers have been low-volume CMI prescribers or physicians writing their first CMI prescription. What are you seeing in terms of conversion from initial trialing to repeat prescribing and greater prescribing depth?

So on average, those new-to-CMI prescribing were those that not written a script for Camzyos in quite some time. On average, they are 3 prescriptions already. So it's not like it's one-off. We're seeing repeat prescribing.

And this is a category where we're also very pleased to see a couple of other things coming forward. One is very strong adherence and compliance on the part of patients. Patients, when they get a CMI prescription, and especially for MYQORZO, are staying on it. And I think that's essential to the kind of growth trajectory we're highlighting.

The other thing that's really nice to see is that as physicians are prescribing, the time from prescribing to dispensing, the time from dispensing to revenue, reimbursement is short. At one time upon launch, I think analysts, in general, were assuming it might take at least 60 days to see that conversion from dispensing to reimbursement, where that on average is closer to 3 weeks today. So we're really pleased to see that. I think that speaks volumes to the kind of demand, the quality of the demand that we're seeing with MYQORZO.

And can we just touch on the sales force, and any feedback you're getting from physicians on the early launch? Is the differentiated REMS resonating? Are there any roadblocks right now that you're working on to try and fix and expedite the launch?

Yes, I'll ask Andrew to comment. But with any launch, there's going to be some friction points. What I'm especially proud of is how our team is responding to those and knocking them down in order to accelerate the launch. But Andrew, do you want to speak to that?

Sure. So I think what we're hearing from our field force is kind of what I mentioned before, is that the -- understanding the differentiation is important. We can't assume, especially as you go outside of the centers of excellence, that cardiologists understand the data and the differences in the data, as well as the process, the REMS process, to get a patient enrolled and on therapy. I think they're critical components.

The other key area is when you look at general cardiology, and we didn't have as much focus on general cardiology, those who haven't prescribed, I think we're very pleased to see that 40% of our prescribers were the core what we call velocity accounts, 80% of the market, but then 30% had written very little CMI and 30% were naive to CMI. That 30% were naive to CMI is where the majority of the market growth occurred.

So it validated what our expectation was, was that we do well in the velocity accounts, the 40% of the physicians. But to expand the market, at the same time, we need to do well in expanding the market to really have the category and the brand get into the growth phase that we expect. So really pleased to see that. And when you get into that 30% of the market, again, it's differentiation, process, REMS and access. That's really the thing that we're focused on. And when physicians do understand that, we are seeing a preference share.

Prior to FDA approval and launch, we were projecting that, if approved, we should expect a differentiated risk mitigation profile, a differentiated REMS. The FDA did approve MYQORZO and the REMS is different, and I think it's proof positive as to how that difference is being appreciated by customers that we're seeing category growth, growth in the market, and especially in the community. Where community cardiologists who might not previously have been comfortable writing a prescription, perhaps because they thought a REMS was an insurmountable hurdle, now they feel comfortable with MYQORZO.

And that's even as, admittedly, we launched with a REMS that was more manual, less automated. People don't necessarily all understand that with a REMS, there is a process back and forth with FDA. And as we have evolved the REMS to make it more system-wide and integrated across different personnel within the cardiology office, we've been lowering barriers to wider adoption amongst more cardiologists more comfortable prescribing MYQORZO. So as we get to potentially over 50% preferential share of new scripts, I think it speaks to, again, those REMS that -- treatment experience, patient experience being more and more embraced by more cardiologists.

Can you touch on potentially patients switching from Camzyos to MYQORZO? What feedback? What's driving that at this point? Are physicians comfortable doing that? And how do you expect that to evolve over time?

Yes. So it's roughly 5% to 7% of the sales we've reported to this point. It's not core to our strategy to be encouraging of that switching, but it is organically occurring. And maybe I could ask Fady to comment on what might be prompting that. And there is an investigator-sponsored or initiated study that is evaluating how best to do that.

Yes. I mean there are several reasons for potential switching from one to the other. Perhaps difficulty in up-titrating with residual symptoms or gradients, drops in EF that require treatment interruption, DDIs that had -- that are bothersome to the patient because of a particular medicine they would prefer to be on. All of these things contribute to physicians deciding to switch from one to the other.

And how to do that, we never studied that formally, but there is an ongoing investigator-initiated study to look at a particular means of doing that relatively efficiently, primarily by discontinuing Camzyos for a couple of weeks and then starting MYQORZO at week 2 and titrating as per normal. So we'll see how that looks probably early next year sometime.

Okay. That's helpful. So what are the remaining opportunities to reduce the time from prescription to paid therapy? And how much could improved access contribute to the launch trajectory?

Andrew, do you want to take that?

Sure. I don't think there's a lot more we're going to do to change the time to therapy. We're right around 3 weeks in terms of paid therapy, which is where we're going to see it in steady state. We may improve that by a few days over time as payers and their policies are clearer to physicians.

In terms of access, clearly, anywhere where we still have kind of new-to-market blocks, where we have to go through a medical exception process, that certainly does slow down or speed-bump, if you will, patients getting on therapy. And there are instances where patients can't get on therapy. We do provide free drug. Sometimes those patients get put on a competitive product because of that market access situation.

So nothing outside of the normal ordinary course for a launch, but I think we're quite pleased with where we stand in terms of time to paid therapy and the percentage of patients of over 80% who are on paid therapy.

Okay. And you're also launching in Europe. Could you speak to the opportunity there and when we -- or how should we think about the contribution to the overall revenue picture?

Yes. We believe very strongly that we have an obligation to patients, especially in countries that participated actively in our clinical research. So we did commit to a go-to-Europe strategy, and we have now launched in Germany. Soon we'll be launching in other countries, U.K. by the end of the year, Italy, France, Spain and others next year.

And knowingly, pricing in those countries is not on par with that in the United States. But at the same time, we believe we can build a profitable business with MYQORZO in oHCM by itself, and add to that nHCM, and that can even get more attractive. Maybe I'll ask Sung to comment on where ultimately Europe may line up relative to the U.S. in terms of the total financials picture.

Sure. Happy to do that. So if we look at the total worldwide opportunity for MYQORZO, Europe in the end could represent approximately 15% to 20% of that pie, which would be very significant for us considering this is in a blockbuster category and potentially in a second indication in nHCM. So it's a very valuable opportunity for us.

Okay. That's helpful. And then before moving on to ACACIA and the non-obstructive opportunity, you have several, let's say, layers of development going forward. We have approval in obstructive right now, we have the MAPLE sNDA and PDUFA date coming up, and then potential submission of the non-obstructive label expansion towards the end of the year. Could you talk a bit about how you're investing in these opportunities, the sales force going forward and just positioning as more data you just presented at ESC, but how physicians are responding to this approach?

Yes. So I think one of the hallmarks of Cytokinetics, both past and future, is our science. And we came to market with MYQORZO in oHCM with many dozens of manuscripts published in peer-reviewed journals to be enabling of our commercialization. So science to medical, medical to commercial, we have been enabled in oHCM first with SEQUOIA, then MAPLE, and as you point out, an sNDA pending FDA review and EMA.

Next up is nHCM, and we recently presented the results and published them, of the study called ACACIA. And this speaks to strategy. It's not accidental, it's very much on purpose, that Cytokinetics as a pioneer should be leading and extending this category from oHCM to nHCM, and ultimately, as we build our business, from HCM to heart failure. So while it might have taken us a while as a company to go from R&D to commercialization, we do think we have competitive advantage for our leadership in this space.

So you asked about nHCM. This is a very important opportunity for Cytokinetics in as much as, if approved, MYQORZO would be the only medicine approved across the broad spectrum of HCM, o and n. And it's the same customer segment that's prescribing for nHCM as is targeted for oHCM. So we think we have a cohesive strategy between R&D and medical and commercialization to build on. So one should expect that this should continue, that as we demonstrate our leadership in oHCM and category growth, that should extend to shareholder returns in nHCM.

Great. And based on the ACACIA-HCM trial, which met both primary endpoints showing improvement in symptoms, exercise capacity, following the ESC presentation, what findings do you believe are most important for physicians assessing the clinical relevance of the results and identifying appropriate patients for treatment?

Yes, before I turn it over to Fady to answer, I'll just say that we're especially pleased with the results from ACACIA. Those data underscore a consistency across endpoints, time points, prespecified subgroups, and I believe, very comprehensively and robustly make a compelling case for the approval of aficamten in nHCM. And maybe to specify and elaborate, I'll ask Fady to comment.

Yes. So the presentation and the publication in the New England Journal of the data, I think, underscored their relevance to treating nHCM. As Robert said, when you looked at the endpoints across all the subgroups that we examined, there was a consistency of effect. Not really -- I know people want to somehow identify a population that would be more responsive; I wouldn't say any of the subgroup analyses suggested that. Obviously, I think more symptomatic patients will likely be the patients that end up trying MYQORZO first in that indication if approved. But the benefits were seen widely.

And there was an analysis that was also published in Circulation that showed the majority of patients responded in different domains, whether it was improvement in peak VO2 or NYHA class or what we call a patient global assessment of severity. These metrics together, you saw multi-domain responses in patients with not only symptomatic and functional improvements, but improvements in biomarkers and also cardiac structure.

So there's a consistency but also breadth of effect that you see when you look at the data. And I think as we continue to elaborate the data in more detail, people will appreciate the number of people, for instance, the transition from Class III to Class II, the number of Class I patients that appear, and will appreciate the effects beyond, say, what the numbers were in the primary endpoint.

Maybe if we can just touch on -- or compare and contrast the obstructive opportunity to the non-obstructive opportunity. Is the patient experience different? Are these patients generally taken care of in different facilities or by different centers of excellence, et cetera? Any comment on that?

Well, I think in general, the patients end up being treated, kind of when they get referred, in the same places, by the same physicians. They're seeing both n and o HCM patients. So I think where the opportunity lies is that the nHCM patients are more difficult to identify. And so I think there's an opportunity in the broader cardiology community to raise awareness, to look for the particular phenotype that we're talking about and either to treat them there, ultimately refer them.

In oHCM, there's a murmur. When people do a general cardiac exam, they put a stethoscope on someone's chest, often, they hear a murmur. That leads to an evaluation and the diagnosis. In nHCM, because there's no obstruction, there's no murmur, and patients come to attention in more subtle ways, because of complaints of shortness of breath or difficulty exercising, and eventually they get a workup. But it's more under-recognized compared to oHCM.

I'd just add real quick. We look at claims data when we build our field force and we build our field force for o and n. It is the same physicians, and we know that from claims data. There's a slight difference maybe in that about 60% of oHCM patients who are New York Heart Class II/III, so it's about 120,000, where the nHCM, it's about half, which is maybe about 100,000. The total prevalence is 50-50, but prevalence in terms of those that are symptomatic, it's slightly less for n. And that split is probably 2/3, 1/3 within n Class II versus Class III.

But nobody should take away from that, that the disease burden with nHCM is any less. These are patients that suffer in much the same way. And absent any approved therapy, it's a high unmet need.

Okay. And what advantages do you think you have having potentially both obstructive and non-obstructive on the label? What are you hearing from physicians? And what kind of groundwork do you have to put out or start to lay out to prepare the launch or potential launch?

So now that we have the data presented and published, we can incorporate it into target product profiles and scenarios and do proper quantitative market research. But it's already knowable. It stands to reason that if one product is approved for both oHCM and nHCM, and we know that a REMS program can be a challenge, that physicians are likely going to be adopting one cardiac myosin inhibitor for the benefit of the broader spectrum of their patients.

With that said, we still need to do certain legwork, and maybe I'll ask Andrew to speak to the kinds of activities that are already underway.

Yes. On a large scale, the infrastructure is in place, the people are in place. The brand positioning doesn't really change in terms of the core position. The things we're doing are investing in disease state awareness, understanding the patient, understanding the journey of the patient, how long it takes to get the therapy, what's going to activate them. So there's a lot of market research and understanding both from the physician point of view as well as the patient point of view. Starting to as well interact with payers. So they're the activities.

But the core brand, the infrastructure, the people, there's really not much add there at all. The field force is calling on the right physicians already. The payers already know the category. And the physicians, at least anecdotally, we've talked to, doing ad boards, et cetera, they're pretty excited about the opportunity to have a therapy to provide to patients. This is, I think, the fifth or sixth shot on goal for this category and the first time a trial has been successful. So the physicians we're talking to are very pleased and intend on using, if approved, MYQORZO for nHCM.

I should maybe ask Fady to comment, but we haven't yet spoken about the importance of guidelines, and cardiologists tend to be very closely monitoring and adherent to guidelines when they publish. And SEQUOIA, MAPLE, ACACIA, they may all factor into the way guidelines evolve. Maybe, Fady, you could speak to that.

Yes. The current guidelines were published before those data all came to light. In fact, they came out just before I think SEQUOIA or just right after SEQUOIA was read out and presented. So between the last guidelines and now the data from SEQUOIA, the data from MAPLE, which is the head-to-head trial of metoprolol versus aficamten as monotherapy, and then ACACIA, have all read out, have all published. Guidelines generally look to published data in order to incorporate their use in their deliberations of how to write those guidelines.

Both the U.S. and European guidelines, I think, we'll see updates in 2027, and I expect to be substantially improved, if you will, with respect to the positioning of CMIs in the treatment paradigm. Right now, if you read the guidelines, cardiac myosin inhibitors are positioned basically as the treatment of last resort, and which makes no sense especially given what we've shown with MAPLE and the lack of effectiveness of metoprolol in that setting and the highly effective use of aficamten in that setting. And so I think we're going to see a change in the way they're positioned. And ultimately, I think that will also help drive the category.

Okay. Maybe before moving on to the broader pipeline, could we talk just about the launch curve? What should we expect going into year-end 2027? Any acceleration, I guess, in the fourth quarter?

So I'll ask maybe Andrew and Sung to speak to this. But keep in mind, we're very much in growth phase. We expect that to continue. Andrew, do you want to start?

Sure. So I wouldn't expect any major hockey-stick inflection point. I think we're going to see continuous growth. We'll see the market continuing to grow. A lot of it will depend on getting expansion of prescribing. As well nHCM, if approved, certainly will be a catalyst in the HCM category to expand. And I would expect there would be a halo effect from a speed to launch. My expectation is nHCM will go slightly faster, if not the same as oHCM.

But again, I think this is a category where physicians need to understand the REMS, or it's a whole office treatment, so it's not just a physician prescribing and a patient goes. The nurses, the office staff, the echo techs. There's a kind of a whole team that's involved in patient care. And that certainly is probably an element of why we'll see the growth that we expect.

I think once you get into past '27, and there's a lot of clear understanding and process flows built into practices, as well as expanding prescribers, that's when we can maybe start to see even broader uptake and a faster growth rate.

Yes. I think Andrew said it well. I'll just remind everyone, historically, cardiovascular launches tend to be linear in the early years. And of course, we'd like to be better than that, but it remains to be seen, and we're focused on execution.

Great. So what should we be focused on beyond aficamten? How should we be thinking about the bar for omecamtiv mecarbil? Anything else in your pipeline that we should keep an eye on and start doing work on?

This is the elegance of our corporate development strategy that's been in place for many years. As a pioneer and a leader in sarcomere biology and how that's applied to specialty cardiology, we have a 3-legged stool strategy that starts with HCM and extends to HFrEF and HFpEF. We have, in a confirmatory Phase III study, omecamtiv mecarbil being developed for advanced and severe heart failure.

Omecamtiv mecarbil has already been the subject of a positive Phase III study in a broader population of heart failure with reduced ejection fraction, and now is in a confirmatory study. Maybe I'll ask Fady to comment on why we're optimistic about that confirmatory study.

Yes. So that's COMET-HF. And in COMET-HF, we had the benefit of a large trial prior to it, GALACTIC-HF, that looked at the effectiveness of omecamtiv mecarbil. That was a positive trial, met its primary endpoint, statistically significant, but where the effectiveness was concentrated in a population of patients that had lower ejection fractions, what we call severely reduced cardiac function.

And so in COMET, as we designed it, we focused more on that patient population via the entry criteria, EF less than 30%, higher biomarkers, which indicator of heart failure severity, NT-pro, of 1,000 versus 400, hospitalization within the last year. And that defines a patient population with a very high event rate. I mean we look -- you see event rates of 30%, 40% per year in populations like that. When you compare that to atherosclerosis where you're talking about 2% or 3% per year, the burden of heart failure hasn't gone away.

And we think with the data that we've generated supportive of the design of COMET, we're very confident in its outcome. And we think omecamtiv will turn out to be a very important medicine for those patients.

So aficamten is a cardiac myosin inhibitor. Omecamtiv is a cardiac myosin activator. And we know a lot about this biology, and that's informing the strategy. In GALACTIC, we had, while a positive study, admittedly, a more modest effect, a hazard ratio of 0.92, P less than 0.05, but only about an 8% relative risk reduction, albeit in important clinical cardiovascular outcomes.

We've seen in recent weeks how difficult it is to see a positive effect in cardiovascular clinical outcomes, with a number of other programs failing to do that. Omecamtiv succeeded in that way in GALACTIC, but where, admittedly, the effect was more modest. And now this confirmatory study, COMET, will go after those sicker patients who, within COMET, we saw a doubling of the overall effect size. So there's reasons to be optimistic and encouraged that COMET could read out positively.

Great. And with a few minutes left, I'd just ask maybe a more -- a broader question. How is the rise of China-origin innovation changing your competitive positioning and your R&D or BD playbook?

So it's a very good question, and it is something that we are actively in tune with. We have, from a corporate development standpoint and a goal with regard to our Vision 2030, to be augmenting of our pipeline. And that speaks to both advancement of organic, but also the in-licensing of inorganic programs. And for those inorganic programs, we're looking at a number of opportunities that are incubating in China.

So I wouldn't say our strategy is exclusive to China, but we're very, very China-centric in thinking about where we might be able to find places where we could identify adjacencies to the things that we ourselves do well. I believe that the world order has shifted. The balance geographically has shifted to the point where any business development team should be looking in China much the way we are.

Great. And I think that's it. We're up on time. Thank you very much, Cytokinetics team.

Thank you.

Welcome again to Citi's Back to School Biopharma Conference. I'm Eric Joseph, senior biotech analyst with Citi. And our session this afternoon is with Cytokinetics, and I'm delighted to be joined by Robert Blum and several members of the Cytokinetics team. Thank you all for joining us today. Rob, maybe, Robert, just before hopping into Q&A, I can have you start out with some high-level remarks, and then we'll go from there.

So thank you, and thanks for inviting us to participate in this Back to School Event. It's our first opportunity to interact with investors in person after returning from Munich, where data from ACACIA-HCM were presented to a very, very large congress hall very, very well attended and positive reception on the part of cardiologists there attending that conference in Munich.

And those results from ACACIA, we believe, provide a very important milestone and catalyst for what could be additional value creation that may come our way as that could be data incorporated into a submission for FDA and other regulatory authorities review and potential approval and ultimately enable MYQORZO to be the first cardiac myosin inhibitor approved across the full spectrum of HCM patients.

Why does that matter? Because we're already demonstrating with our commercial launch of MYQORZO in oHCM that it is rapidly ascending and where we've pointed to by the end of the year, we expect to see preferential share of new prescriptions, something quite unusual for a next product launched in a category that its predecessor had already been for 4 years. But I do think the market is embracing of aficamten for the properties that we engineered into it. And the business is off to a great start with a commercial launch, we're very pleased with that continues to exceed expectations.

So we're nHCM to factor into the label together with oHCM, we believe that redefines the way of treatment of patients with HCM, and we're very excited about that. So I expect we'll talk a lot about aficamten and MYQORZO oHCM and nHCM today. And as time permits, hopefully, we can also speak about our financial picture and our outlook for the pipeline.

Great. Yes. We hope we'll touch on all of those points. But let's pick up from ESC and full presentation of the ACACIA results. Actually, let's take a step back and just think about the nonobstructive HCM market. If we're looking at estimates, the prevalence would seem to be roughly an even split between obstructive and nonobstructive disease if you're looking at the total HCM market. But nonobstructive disease tends to have a lower rate of diagnosis.

Can you speak a little bit to sort of why that's the case and whether that has anything to do with how prominent symptomatology or how symptomatic patients often present with in HCM?

Sure. So to my right are colleagues, Tricia, who leads U.S. marketing and Dan, who oversees clinical research. And maybe I'll ask them both to comment on that. Yes.

Can you hear me? Is this on?

Yes. Thanks. This is Dan Jacoby, Clinical Research here at Cytokinetics. And I'm also a hypertrophic cardiomyopathy physician for many years, I -- this was a major part of my practice. I ran clinical trials, and I still have a small HCM clinic. So I think I can kind of say what we're seeing is an evolution in the understanding of HCM as therapies come online and as the potential for treatment comes online.

In fact, my practice, when I was practicing, I had over 1,000 patients, and I was more 70-30 nonobstructive to obstructive because we didn't have an active myectomy center. I think Tricia can speak more knowledgeably to what we're seeing currently in the community. But I think we're still trying to understand the full scope of how this disease presents. It's been years of collecting data from myectomy centers and specialty centers that have prioritized the evaluation of obstructive patients.

The second part of your question is really an interesting one, which is -- how do you know when an nHCM patient is symptomatic, how do you diagnose them? Are they harder to diagnose? Where are they in the community?

And what we're seeing is that physicians who take care large numbers of cardiology patients have these patients in their practice. They're actually not that hard to diagnose, but because there's no specific treatment right now other than just beta blockers or calcium channel blockers, they're just sitting on them. And these are not the typical patients that end up getting referred to these high-volume practices.

But in fact, there's a number of them. And when you talk to individual practitioners, they say, "Oh, I have 10 in my practice, I have 12 in my practice that I'm just sitting on." And so as we see therapy come online, that's effective, aficamten come online, that's effective for these patients. It becomes available in the commercial setting. There's going to be a shift and these practices are going to start to really look at how they diagnose and treat these patients. And I think that's going to lead potentially to a shift in them wanting to engage more with this treatment rather than refer out. So at that point, I'll hand it over to Tricia and see what your thoughts are.

Yes. I think what Dan really hit on was the evolution that we're anticipating to happen within the marketplace and how HCM is being treated and where HCM is being treated. And we have seen over recent years, there has been a shift even in the epidemiology and the understanding of the diagnosis rates for the -- for HCM for o and for n. I think historically, there was an assumption that there was more oHCM patients, whether that was a 60-40 or 70-30 split.

But in more recent years, with the recent data that we have available to us, we see that it's more of a 50-50 split. And of that 50% that is nHCM, a large proportion of those patients would be viable for a CMI treatment based on what we understand today. So a significant opportunity exists within the nHCM space. I do think we'll continue to see evolution in the space in diagnosis rates as well as how these patients are being treated once there is a medicine that is available for nHCM.

Coming back to the full Phase III data themselves, can you talk a bit about what the clinician feedback has been now since the broader clinical profile has been presented? And has it all been enthusiasm, any reservations? And what is -- what data points, I guess, are resonating most with the treating community?

Yes, we had an opportunity to engage with a number of physicians following the full data readout at ESI -- ESC and the receptivity is largely positive. There's a lot of excitement, a lot of recognition that prior to ACACIA-HCM, there were no trials that successfully demonstrated superiority. So to have the first positive nHCM trial and the hope for the first medicine that could be available for nHCM was largely communicated back to us around the anticipation to be able to treat 50% of their HCM population.

Just as we got to see more of the safety profile at ESC, I want to just pick up on the slight imbalance in heart failure events that were observed in the study. And despite them only occurring in a small minority of subjects, this may have given investors a little bit of pause were there any common characteristics in these patients that might have predicted for their heart failure risk or being at higher risk of heart failure? And more broadly, can you help put these SAEs in perspective? How significant are they? And how would it be managed in the real-world context?

Yes. I think I'll just go ahead and take this. So look, we're going to be looking to bring forward more published data on this cohort so people can better understand it. But in the interim, okay, I think there's a couple of thoughts here.

One is, and I think everybody is familiar with this, a serious adverse event according to clinical trials, does not mean it's a serious medical event. There are criteria around what a clinical trial calls a serious event. It really can amount to a simple escalation of care that most physicians would view as routine. And that's what the majority of these were managed by simple short course of diuretics, as [ Dr. Master, ] I think, pointed out during the investor conference at ESC.

You asked about predisposing factors. We -- I can't comment on whether there were predisposing factors in this population that weren't present in the patients who didn't have these SAEs. But I will tell you that among the patients who did experience this and including the placebo patients, we commonly saw things that would tip off a physician to a potentially increased risk, an underlying history of atrial fibrillation an advanced age, one patient was receiving an infusion of medication to help for a different disease.

And so if you're receiving infusions of fluid, obviously, that predisposes you to developing heart failure symptoms. And then there were a couple of patients who just seem to have advanced disease. Maybe they weren't the most ideal patients for the study and end up having heart transplant. So we'll get some of that data in more detail out. The overall message is that these patients probably did have many of them some comorbidities or risk factors that you would ordinarily identify in the course of clinical practice.

And the reason I point to that is because we showed this data before is that these cases occurred early on in the study during titration, but when you look at the cohort from ACACIA that was in the placebo group that hadn't been exposed to aficamten previously that rolled over into FOREST and then were titrated on to aficamten. So this was new exposure to aficamten. Those -- that cohort only had 2 episodes of heart failure, right, in that whole cohort. So it's a much, much lower incidence of heart failure. And why is that?

Well, there was physician oversight, and it's a constraint of clinical trials that there's blinded characteristics and computer-driven algorithms that drive the titration in the care. And so once you let the physician into that care pathway where clinician judgment can be executed, the rate of heart failure goes way, way down and physicians identify those patients, they want to push titration on more rapidly or not as rapidly or they want to adjust diuretics on and they don't want to adjust diuretics on. I don't have that data for you right now. But what we're seeing in the data overall is that once you introduce clinician judgment, those heart failure episodes essentially go away.

Okay. And actually, once we get time to kind of dig into the data a little bit further, particularly the New England Journal publication it struck us that the patients in ACACIA seemed a little bit sicker than the population that you studied in SEQUOIA-HCM if we were looking at their sort of baseline burden of disease, right?

If you're looking at patients with a history of AFib at baseline or ICD placement, assuming an expanded label for MYQORZO, how should we be thinking about the addressable nHCM population eligible for MYQORZO by their symptom severity or treatment history? I guess is there -- should we think about going to market treating a patient population that looks like what the study indicated? Or is it perhaps a patient cohort much broader than that?

Well, I'm going to hand it over to Tricia in a second, but I just want to comment on what you're observing. This is not unexpected. So -- and you can look at multiple different registries and so on that will support this. But essentially, if you have significant hemodynamic obstruction, you have a high gradient, that will generate symptoms even in the absence of very severe actual myocardial muscle disease, right?

So you can have symptoms just from the obstruction, even if the underlying muscle is actually pretty functional with not very much diastolic dysfunction or fibrosis or whatever the case. However, if you don't have that hemodynamic obstruction, in many cases, you require more severe myocardial disease to generate symptoms. So in general, it is true that patients who have symptomatic nonobstructive disease have -- I'm not going to call it more advanced, but just different or maybe slightly more severe myocardial disease than those patients who have just pure obstruction.

Now there's a tremendous overlap here. We're talking about the same disease with just a different hemodynamic structure, but it's not at all surprising that you would see that. And what that means is that the population that was enrolled in ACACIA really truly does represent that population that people are seeing in their clinics who have symptomatic nonobstructive disease. One caveat to that, who has symptoms and who doesn't have symptoms is always a judgment call.

Do you feel well today? Do you not feel well today? Some of that is highly subjective in terms of what your expectations are. And when you generate a treatment that has the potential to improve people's symptoms, they no longer are satisfied to say it just takes me longer to walk up that hill than my husband. They want to walk up the hill at the same speed as they can walk in the evening. So now they have symptoms whereas before they said they didn't. So it's a moving target, and I'll hand it over to Tricia for additional thoughts.

Yes. I think from a commercial perspective, how we will communicate the viable patient will be largely dependent on how our label and our indication is. If you think about oHCM, it's not specified to a certain NYHA class, it's asymptomatic patients. So to that point, if we would assume a mirrored indication, we would speak to the symptomatic nHCM patients, which is a large proportion of those diagnosed nHCM patient population with all the points that Dan made considered as well.

Okay. Maybe you can talk us through some of the commercial preparations that are underway ahead of a potential expanded approval for nonobstructive disease. I know it's a very forward-looking question given that the sNDA hasn't been filed yet, but maybe you can sort of speak to what commercial prep we should be thinking about in the lead up to a potential expanded launch there.

So maybe I'll start and ask Tricia also to comment. I will emphasize that when we made decisions many years ago to build a commercial business, it was with the expectation that for the work we were doing in research and development, we were going to build a franchise in areas where they would be addressing concentrated markets and where sales and marketing infrastructure would return a high yield on investment.

And when we made a commitment to go to market for aficamten, it was with the expectation that there was high overlap in terms of that customer base across oHCM and nHCM, not to mention between HCM and heart failure where our pipeline is directed. And when we built that commercial organization, the sales team leaders, the medical affairs colleagues and ultimately, the field personnel, both medical and sales, it was with a view that oHCM would beget nHCM and we would be rightsized for the opportunities across all of HCM and frankly, for that matter, in large part, heart failure, at least that which is the more severe form. So none of this should come as a surprise to our investors who have been following Cytokinetics along the way.

With that, I'll ask Tricia maybe to comment more specifically about the transition from oHCM to nHCM.

Yes. So with the positive ACACIA results now in hand, we are doing our full due diligence to ensure that we are maximizing the opportunity with the hopeful future expansion into nHCM. We know that we have the chance to potentially be the first and only available treatment for the entirety of the HCM ecosystem.

So we want to ensure that we're maximizing that through what we're doing today and building out the strategy, building out the messaging, ensuring that we're understanding where the nHCM patients are today in their journey of treatment so that we're appropriately reaching them.

So there's a significant amount of work going on from a commercial perspective to ensure that we are ready at the earliest possible date to launch into the marketplace for both o and nHCM, but also ensuring that the appropriate education is happening around the understanding of nHCM, the symptom presentation that patients are coming in, the understanding of any differences from a pathophysiology perspective. So there's a lot of education work that also has to happen that we didn't necessarily have to undertake a Cytokinetics prior to oHCM approval.

Okay. Okay. I think it's still a reasonable question to ask whether going into a potential expanded -- with the approval of an expanded indication, whether the REMS program would need an update or whether additional REMS training would be needed to support expansion to nonobstructive HCM. But assuming that it's required, but if it were, would that process be more streamlined than the one you're currently navigating for in support of obstructive today with...

So I'll take that. With regard to streamlining, the current REMS for aficamten/MYQORZO in oHCM has potential to be streamlined as we generate more and more real-world evidence. So already, we have our eyes set on how that might occur over time as could be relaxing or even ultimately removing of a REMS. However, to your question about nHCM, our assumption -- base case assumption is that if approved, aficamten will be approved with a REMS covering oHCM and nHCM. So really, we're talking about a single REMS, and we're not aware of any precedent for there being 2 different REMS for 2 different indications for the same drug.

So we're assuming base case REMS, but for where the dosing instructions, whether they be in training or whether they be in label, will address what may be nuances between oHCM and nHCM. The good news is with both oHCM and nHCM, the pivotal clinical trials employ the same up-titration doses, 5, 10, 15 and 20. But how you get there may ultimately speak to what you look to monitor and what you keep an eye out for. That's the purpose of labeling more than REMS. And we would hope that as we engage FDA, we might see language pertaining to monitoring and guidance to dosing reflected in label.

Do you have -- okay, I just wonder whether you kind of have flexibility to depart a little bit from the titration protocol as set forth in the ACACIA study when it comes to the recommended escalation relative to the language that may end up in the label when it speaks to recommended dosing.

Yes. So the label for oHCM speaks to how gradient reduction informs up titration and echo monitoring along the way. It was up-titrated differently in ACACIA and different between that clinical trial and the open-label extension that follows. So maybe I'll ask Dan to remind everyone how we up-titrated in ACACIA versus how up titration is occurring in FOREST.

Yes, sure, Robert. Yes. So the answer to your question is, yes, there's flexibility. There sure is. And you can see also, obviously, SEQUOIA was the pivotal trial upon which oHCM was approved. MYQORZO approved for oHCM. And obviously, there's tremendous flexibility in the label, and it does not reflect exactly what was done in the study.

And that was based on the same kind of thing that we did here with FOREST with nHCM, which is that physicians have oversight. They can integrate clinical judgment, not just physicians, nurses, NPs, whatever is taking the patient. But also, there's not just a flexible window, 2 to 6 weeks also, but they get to decide whether they're going to actually increase the dose or decrease the dose. They don't have to increase the dose even if patient meets the criteria for dose increase, so they can execute on their own judgment.

And that's something that we're actually looking into to see where that clinician judgment is playing out in our studies. And obviously, we're going to discuss that with the appropriate regulators to inform on how best to form the label. So yes, simple answer, absolutely. We are not tied 100% to how the pivotal study was structured, which was a forced every 2-week titration computer algorithm, which unfortunately, is how you have to run clinical trials in order to keep them blinded.

Okay. That's very helpful. Maybe I'll refocus this back to the MYQORZO launch in obstructive disease where you are today. Strong start so far. I know since your 2Q update call, folks will be interested to get a sense of how the cadence of new patient starts is trending as well as dispensations relative to sort of that trend that you were seeing back in May and June. And similarly, how conversion to paid prescriptions has evolved since the 2Q update.

So we can't here provide an inter-quarter update. But I will say that Q2 was a really strong quarter. You saw how from a standpoint of metrics and outputs, we came out of the gate very strong. We continue to believe that we're on track to do similarly in Q3 and hopefully continue to exceed expectations.

The things you're asking about, for instance, time to paid script from prescription continues to be a hallmark of how we are delivering and executing well on this launch. I think it's true that the Street had expected that, that might take as many as 60 days when, in fact, it's demonstrated in Q2 to be just a few weeks. So we like where we situate there, and we'll continue to manage to that. We're continuing to see the same kinds of things that we think we have pointed the Street to monitor as would be evidence of meeting or exceeding expectations.

Robert, you actually began in your opening remarks talking about how you're expecting by year-end to be the leading or to lead new to brand share by the end of the year. Can you talk a little bit about what is driving physician and patient decision-making when choosing between the 2 first-line CMI options today? And to what extent do you see upside beyond that call it, 50% threshold of new brand share.

So I'll ask Tricia to comment on that, but I'll set it up by reminding folks that we designed into aficamten certain attributes that could, upon approval, hopefully render it a medicine that would be viewed as enabling of convenience, flexibility and other attributes that play to physician and patient experience. And upon approval, we received a label and a REMS that was differentiated in its category. And now I'll ask Tricia to comment on what's driving preferential share of new scripts.

Yes, exactly to that point. I know we communicated prior to launch the 2 areas that we wanted to deliver on are clinical differentiation and REMS differentiation. And we believe based on all of the insights that we've gathered to date from the prescribing community that they are recognizing that differentiation across the brand in regards to the clinical profile, efficacy, safety, but also the differentiation that's enabled with MYQORZO for REMS.

I think what we're excited to see is the points that were raised is we are already driving 40% new-to-brand share coming out of June. We are also seeing that we are deepening the penetration of the prescribing deeper into the community with a large portion of our prescriptions in quarter 2 coming from HCPs that previously were low prescribers of CMIs or had never previously prescribed a CMI. And because of the profile that we're offering in regards to the flexibility that our REMS offered, also the exposure to the MAPLE data, which really calls into question some of the historical behaviors of utilizing beta blockers that MYQORZO was able to show statistical significance versus and really key endpoints is really driving some of that utilization deeper in the HCP prescribing community and leading to the share in the differential share that we're driving towards.

If we fast forward a year from now, how do we think about the scale of your marketing campaign in obstructive HCM and sort of the promotional spend relative to where it's at today? And is DTC part of that longer-term marketing strategy?

So I'll ask Tricia, but also Sung maybe to comment on how we're thinking about dialing up certain activities, but also overall OpEx and where that should be pointing.

You want the Head of Marketing or the Head of Finance to answer that question first?

Sure. Eric, I think it's important as a company. We're early days in launch, and we keep all options open. But with regard to the OpEx trajectory, it is fair to think that SG&A, specifically commercial expenses will continue to increase as we prepare for a potential launch in nHCM. Recall, that was a key driver of our OpEx guidance increase for 2026.

And of course, next year, you would get a full year impact ahead of the launch and for years thereafter. I also want to call out, we have important launches to conduct in Europe. We're just at the very beginnings of this with the launch in Germany over the summer. And of course, the U.K. is next. later in Q4 with other large countries coming online in 2027. So the field force for those countries have not been brought on board yet. So that would be a reason for a further incremental increase in SG&A.

If we look at how we're planning from a commercial perspective, obviously, we have a few things that we're doing right now. We'll certainly resource appropriately into further driving the oHCM launch at the same time as we are planning and preparing for the hopeful entrance of nHCM and the opportunity that we have from a commercial perspective to speak to the entirety of the HCM community.

We are looking and one of the nice opportunities that we have at Cytokinetics is to be really nimble in how we are approaching our business and our business planning, and we're looking at ways in which we can reach the HCPs and the patient community and what would probably be considered some of the more traditional mechanisms, but also innovative ways. We know, especially with our patients, the market is changing, how patients are engaging when their health is changing. So what are those innovative ways in which we can reach our patient community to drive appropriate education.

Can I add an additional comment there? We have a very robust academic publication strategy with our studies. We do that for 2 reasons. One is because we believe that getting the data out to the community in the most transparent way possible is the best way to facilitate appropriate and beneficial use of the medicine for patients.

But the other reason that we're doing it is because we recognize that the way people access information now is a bit different. And with OpenEvidence and ChatGPT and pick your item, a lot of these -- a lot of those engines are integrating evidence themselves. And it's really important to -- it's no longer the story that you can just publish in a big journal and say to everybody, here's the big journal publication and let's just index to that. You have to tell the complete story because people are accessing information that wants to integrate the complete story. And I think we have a very robust team for this. Our academic colleagues are incredible and have published extensively, and we will continue that strategy.

I'll try and fit in a couple of pipeline questions in the time that we have left. I want to pick up on omecamtiv in HFrEF. I think this is an opportunity that's often overlooked in our discussions with investors.

Can you, Robert, maybe just speak to lessons learned from the GALACTIC-HF trial and how your level of confidence in COMET-HF underway right now kind of as you sorry, your level of confidence in COMET-HF being successful in the more narrowly defined population being studied there?

Sure. So for those of you who may not remember, omecamtiv mecarbil is being developed for the potential treatment of advanced heart failure with severely reduced ejection fraction. This is a concentrated customer segment like HCM, and there may be upwards of 1 million or more patients in the United States who are frequent flyers in U.S. hospitals with reduced ejection fraction such as we're studying here EF below 30.

Omecamtiv was a subject of over 30 clinical trials, including GALACTIC, an over 8,000 patient clinical trial that met its hard clinical endpoint in terms of reduced outcomes and with a P less than 0.05. In today's environment, that might have been approved by FDA. But at that point in time, FDA was looking for 2 clinical trials if P is less than 0.05, but not less than 0.01. So FDA has asked us to do a confirmatory study. And this confirmatory study is being conducted. It's called COMET, and it's being conducted in a group of patients with EF below 30 compared to GALACTIC-EF below 40.

In that subgroup prespecified in GALACTIC, we saw a doubling of the treatment effect already in roughly 4,000 patients. And now we're doing a study that may be approximately 2,000 patients to reproduce something we've already seen in a study of roughly 4,000 patients as a subset of a group of over 8,000 patients. So when you look at it that way, hopefully, like us, you can be pretty hopeful that this should deliver like it already has in patients with severely reduced ejection fraction. This is something where I think there's a meaningful potential for dislocation relative to Street expectations. And I do think that omecamtiv, if positive in the COMET study, that study should complete enrollment in 2027, potentially read out in 2028 could generate significant upside potential in terms of maximizing the shareholder value.

So we're encouraged by the study, its current enrollment, already what we know from blinded data, and we're looking forward to that study reading out for what could be a new medicine for patients with advanced heart failure where there is no current treatment that acts directly on heart muscle for those patients.

The screening phase of COMET -- there's a screen in treatment phase, I believe, the COMET-HF. Does that aid in the enrichment of patients that are then followed up in the full...

Excellent question, in particular, because in GALACTIC conducted by Amgen, our partner at that time, there were upwards of 15% to 20% of patients we found out afterwards who were not either compliant with study med or at exposures that would render the drug at its target levels. And that, unfortunately, in retrospect was a mistake and a problem. And in spite of that, the study was positive.

So upon our design and conduct of COMET, and I'll ask Dan to speak of this, we included a run-in phase, and he can speak to what are the objectives of that run-in phase.

Yes. Thanks, Robert. The run-in phase will enable the identification of patients who are not compliant for whatever reason with medication and have those patients not enroll in the study ultimately, number one. And number two, it's actually another very important point is that will allow the identification of nonmodifiable early events, right?

So if someone signs up for the study and 1.5 weeks or 2 weeks later has a heart failure hospitalization, that's not a modifiable event. But that patient will no longer be included in the study and will not contribute to a nonmodifiable event, which would be a bias or an obscuring of actual effect for a treatment effect in the study, if that makes sense.

Great. We've gone over. We'll have to leave it there for time. So thanks so much for your time again this afternoon. Really appreciate it.

Thank you. Appreciate it very much.

Hello, everyone. I'm Diane Weiser, Senior Vice President of Corporate Affairs. I'm pleased to welcome everyone to our investor event to discuss the primary results from ACACIA-HCM, the pivotal Phase III clinical trial of aficamten in non-obstructive HCM. Today's event is being hosted in a hybrid fashion. I'd like to welcome those here in the room with us in Munich as well as those joining online.

I'm pleased to introduce from Cytokinetics, Dr. Fady Malik, Steve Heitner and Robert Blum. And I'm also thrilled to welcome 3 leading experts in HCM for our panel discussions today, Dr. Martin Maron, Dr. Ahmad Masri and Dr. Christina Paitazoglou. Today's agenda will begin with -- is it on the slide? Today's -- we're going to pause for a minute. Turning to today's agenda. Fady Malik will provide some brief opening remarks. Next, Dr. Masri and Maron will provide an encore presentation of the ACACIA-HCM results that were presented earlier today in the Hot Line session at the Congress. Then Steve will facilitate a panel discussion and Q&A session. And finally, Robert Blum will close us out providing some remarks.

For those online, today's slides are available for download in the webcast. [Operator Instructions]

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

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

Thanks, Diane. I'm very pleased to be here alongside my colleagues and leading experts in HCM and the global cardiology community -- maybe we need to turn the mic off. As we share the primary results from ACACIA-HCM, the pivotal Phase III clinical trial of aficamten in patients with non-obstructive HCM.

These results were just presented a short while ago in the Hot Line session at the Congress and were accompanied by 2 simultaneous publications, one in the New England Journal of Medicine and one in the journal, Circulation. These are the first -- this is the first ever positive Phase III clinical trial in nHCM. And the results show that the treatment with aficamten was associated with statistically significant and clinically impactful improvements in both exercise capacity and symptom burden as well as cardiac biomarkers.

As we'll discuss today, these results create the potential for aficamten to become the first and only cardiac myosin inhibitor to address the full spectrum of the symptomatic HCM, offering the first therapy that may directly treat the underlying disease process of HCM.

The response from the HCP community at the Congress today was overwhelmingly positive. It's clear these results are resonating, and there is genuine interest in what they could mean for the future in nHCM. Since sharing the top line results earlier this summer, we've moved swiftly to preparing a supplemental new drug application that we plan to submit to FDA later this year for aficamten in nHCM.

So we're extremely proud of these results and of the exemplary execution of this clinical trial. To that end, I'd like to express my gratitude on behalf of Cytokinetics to the patients, to the families, investigators and the study staff who help conduct ACACIA-HCM. We thank you for your dedication.

And with that, I'll hand it over to Dr. Masri and Dr. Maron to present the primary results from ACACIA-HCM. Dr. Masri?

Thank you, Dr. Malik, and hi, everyone here and online. I'll present the primary results of ACACIA-HCM. [Audio Gap] involved in the trial.

So non-obstructive HCM is a common condition. It affects a lot of patients with hypertrophic cardiomyopathy, and it leads to reduction in exercise capacity and development of progressive symptoms. There are currently no available therapies that have proven to be effective in this disease. Aficamten, which many of you are aware, is available in obstructive HCM in many jurisdictions, has favorable effects on diastolic function as well as a whole host of other key areas that are involved in HCM pathophysiology. And aficamten has favorable pharmacological profile, which allows for rapid titration and dose adjustment with good tolerability.

So this is the design of the trial. Probably you've seen this before. Patients with symptomatic non-obstructive HCM were randomized to aficamten versus placebo, 517 total patients, 1:1 randomization. Aficamten dose range was 5 to 20 milligrams. All the patients were followed up to 72 weeks in a blinded fashion with a 4-week withdrawal period. The study continued until the last patient crossed week 36. In terms of our study visits and assessments, they are listed up there to the left of the screen. We've conducted for the dual primary endpoint, the KCCQ assessment was done in every visit, but the peak VO2 and cardiopulmonary exercise tests were only done at baseline and at week 36.

Here are our endpoints. The primary -- dual primary endpoint change from baseline to week 36 in KCCQ Clinical Summary Score as well as peak VO2. And the secondary endpoints were tested in a hierarchical fashion going from baseline week 36 in NYHA class, Z-score, which includes both maximal and submaximal exercise metrics, NT-proBNP change, left atrial volume index and time to first composite cardiovascular event.

Safety outcomes typical of a myosin inhibitor trial, where we looked at LVEF, heart failure. But something really important to note, which is unique to aficamten at this stage is that patients who get EF between 40% and 50% due to us pushing the dose higher, they can get down titrated while staying on the drug without a drug holiday interruptions that are mandated. And so per protocol, only those with EF less than 40% have to interrupt the therapy. And they can be restarted on it, but they have to interrupt therapy.

These are all baseline characteristics. Again, as I mentioned, 1:1 randomization, 258 aficamten, 259 placebo. This is a really, in my opinion, at least well-conducted study. The reason behind that, if you look at how many patients had family history of hypertrophic cardiomyopathy or pathogenic, likely pathogenic variant for the disease, 2/3 of them did. This is different from when you look at any patient with LVH. This was a study conducted to enroll such patients. 75% of them were on beta blockers, and they were highly symptomatic with reduced KCCQ scores. They had -- 1/3 of them had NYHA Class III, biomarkers were elevated and peak VO2 was significantly reduced.

Here are the primary results. So the first of the dual primary endpoint is KCCQ. The primary endpoint was aligned at week 36 for KCCQ and peak VO2. As you can see, the difference was 3 points at week 36 between aficamten and placebo in favor of aficamten with a p-value of 0.021.

What you see here is that aficamten beyond week 12 consistently improved KCCQ Clinical Summary Score. And at each time point aside from week 36, you have a difference that varies from 4.8 to 7 points, including the end of treatment, which every patient in the trial is supposed to go out at the end of the treatment from the trial, 5.6 points difference. During washout, these scores within 4 weeks were reduced back to similar to placebo without any difference. So the reason behind what you see here is the fact that placebo patients had fluctuations in their benefit as it reflects on KCCQ, which you can see clearly here between, for example, week 24, 36, 48 and end of the treatment.

The second dual primary endpoint was peak VO2, aficamten influenced positively peak VO2 with a difference of 0.67 ml per kilogram per minute with a p-value of 0.003.

If you look at many prespecified subgroup analysis, the treatment effect on both KCCQ and peak VO2 was consistent. And we here highlight to you some of the groups that some might feel are important, including beta blockers, intracavitary obstruction and genotype status. Again, as I mentioned during the presentation, I walked into the trial thinking we might end up having a super responder or a less responder group. The reality is when you look at the prespecified analysis here, most of these patients have derived the same degree of benefit all in favor of aficamten.

In terms of NYHA class, which is the first of the secondary endpoints tested in a hierarchical fashion, throughout the trial, you had more in favor of aficamten improvement in NYHA class by one class or more. At week 36, it was 14% difference with a p-value of less than 0.001.

This is the Z-score, it's a slightly complicated thing to explain, but the bottom line is, it's a comprehensive exercise metric where you have one exercise metric for maximal exercise tolerance that the patient can achieve and one is for submaximal exercise, which is what a lot of the patients do from day to day. They operate at the submaximal level, which is called ventilatory efficiency or VE/VCO2. Aficamten positively affected VE/VCO2 with minus 0.91. So with VE/VCO2 slope, lower is better. With peak VO2, higher is better. And that translated obviously into a positive results on the Z-score with statistical significance.

NT-proBNP was affected favorably from the first visit, follow-up visit that the patient had, continued to decline throughout the titration period and stayed stable with the washout showing you how there is a quick rebound there. Slides are not advancing. All right.

And so what -- so sometimes the question come, what is the significance of having reduction in NT-proBNP or elevation in NT-proBNP. This is a recent study that we actually have been conducting for more than a decade now. It's an NIH-funded study, HCM registry or HCMR, showing that a really important predictor of outcomes in hypertrophic cardiomyopathy is NT-proBNP. And if you look at how they essentially reported the log N-terminal natriuretic peptide during follow-up, you can see how by reducing NT-proBNP with the magnitude that was seen in the trial, you're actually shifting those patients on a curve that is different from the natural history curve for NT-proBNP. So that's the message from this is that you end up achieving almost 50% reduction in the hazard ratio if you use that natural history study as your reference study.

In terms of other endpoints, aficamten did affect left atrial volume index, but it didn't reach statistical significance with a p-value of 0.058 and time to first cardiovascular event was not different between the 2 groups.

In terms of our safety outcome, aficamten was well tolerated. There were no new safety signals here. Aficamten in this trial was titrated to the maximum tolerated dose. It's different from our prior trials with aficamten, where we used the dose that was required to eliminate left ventricular outflow tract obstruction. And this is evident by having 81% of the patients on the maximum doses available 15 and 20 milligrams. Despite all of that and despite the non-obstructive HCM population being a special population when it comes to sensitivity for cardiac myosin inhibition, the least-square mean difference in LVEF was 4.4%. This is similar to what was seen in the obstructive HCM trials as well with aficamten. And only 3% of the patients on aficamten had to hold aficamten or had treatment interruption because they have reduced left ventricular ejection fraction.

A little bit more on the safety outcomes. I'm going to just focus on heart failure here, 4.7% aficamten, 1.2% placebo. And all of these happened during the titration initiation and titration phase because we had to design a trial in a way that we can get patients to the maximum dose available of the drug. And these are -- while they're heart failure, these are events where it can be managed by diuretics and outpatient management. 10.5% of the patients had an EF less than 50% but only 2 of them had a serious cardiac event of heart failure. And importantly, in my opinion, that this 27 number, 21 of them remained on aficamten either at the same dose or the lower dose during the trial. So there was no treatment interruption here.

One thing that I would like to draw your attention to is new onset atrial fibrillation, which is an important -- it's becoming a really important metric in HCM trials. There was no difference between aficamten and placebo in the new onset of AFib. One important reminder as well is that the safety goes through the whole period of the trial up to 76 weeks.

So in conclusion, aficamten improved exercise capacity, patient-reported health status and symptoms as compared to placebo. And over 36 weeks, we've shown you that aficamten hit on the dual primary endpoint as well as 3 of the 5 secondary endpoints and more than 80% of these patients elected to enroll in FOREST-HCM to look at the longer-term safety and efficacy of aficamten. Thank you.

Okay. Great. Thanks, Ahmad. So I'm going to just get into some of the additional data here in a second. It's going to touch on some considerations around treatment benefit and safety. But I want to just start maybe if I could, just with a couple of comments. And some of these comments we'll get back to maybe at the end in the question-and-answer period. But I'm older than Ahmad by actually quite a bit. He's obviously a superstar. I'm a little bit older, and I've got more gray hair. And this gray hair, by the way, I want to tell you, a lot of it comes from having taken care of HCM patients for almost 3 decades. It's a long time. I've taken -- I've been in the trenches, taking care of these patients for that period of time. And I've seen a lot of them.

And I got to tell you that with that experience, which is vast, I never actually thought we would see the day that we are seeing today, actually, where we have advanced a treatment for this population of sick non-obstructive patients. And I say that because I thought it was always a very challenging bar to reach. And I think the fact that we have shown that today is not just a milestone, but actually a kind of a transformative period. And I don't think -- and I use that term lightly. I mean I'm not just saying that because I'm here talking to you guys. I actually believe that to be true.

And a lot of it comes down to being able to have the opportunity here to make these patients feel the function better, of course. But a lot of it stems from the enormous amount of frustration that these patients feel because there's nothing available for them. And so this has met in a way, one of the greatest unmet treatment needs that we've had in HCM. And it has to be framed, I think, in that context here when we're looking at the numbers and trying to understand them and relate to them. We've got to take a step back, and we've got to really understand that this is a pivotal moment.

And so with that said, I'm going to touch on 2 additional considerations that I think are on people's minds that have to do with treatment and safety. And those come out of, as Ahmad alluded to, this substudy that was done that's published as well now in Circulation. It's about the global efficacy of the drug in this population. And again, this is reiterating, but again, huge unmet need in this population related to morbidity. This is a drug that addresses the underlying basis for why these patients are so frustrated, improving diastolic function. We'll get to that more in a minute. We talked about the outcomes that were achieved with ACACIA and the primary results.

And so the question then is, so why did we do this substudy then? What was the purpose of doing this since you've just seen the primary data? And I'll just make one important point, and I think it's really important because I see this happen a lot is that -- you just saw very elegantly shown the mean changes in ACACIA, right? The mean changes between the aficamten and placebo arms. But sometimes those mean changes, they're hard to contextualize in terms of clinical meaningfulness. We get that a lot, right? What does that mean when you see those mean changes in KCCQ, peak VO2?

And how does it -- when we talk about clinical mean, what does it mean for the patients? And so we address that point here. And the way we do that is that we contextualize the treatment benefit as it relates to patient that's the within patient change, within clinical outcomes that are relevant here. I'll show you what those are in a second. That's what we call a responder analysis, because it contextualizes or translates this data that you just saw into how we want to think about it as it relates to a treatment benefit for the individual patient. So that's the purpose here.

And if we look at -- sorry, this is -- okay, that was just the clinical trial that you just heard, the trial design. So maybe I'll go back over that, but we saw that. We'll skip right to, again, this concept of why we did this. The responder analysis, again, takes the vantage point of what does the treating physician and the patient, for that matter, too, want to know if they were in a position to use this drug clinically. First and foremost, because it's the most important treatment goal we have in this disease, a low mortality disease. It's about morbidity. It's about making my patient feel better, right? I mean that is the primary and most important thing we can achieve.

And we analyze that through 2 ways. PGIC, it's just a questionnaire. That is a one-question questionnaire that asks the question, how are you feeling now on treatment compared to before? The same, better, much better, very much better, worse, very much worse, et cetera. And that PGIC metric is important for 2 reasons. One, it's been used scientifically by regulatory agencies and there was a -- to anchor to establish what is a meaningful change in health status with other kinds of patient-reported outcome measures like KCCQ. That's number one.

And number two, it's elegant in its simplicity. This is how we work, right? This is what we want to know, this is how we interact with patients. We ask them that question and we get something back, and that is our bar clinically. And so the PGIC reflects clinical practice in that way.

Of course, we also want to know do my patients function better? That's measured objectively with cardiopulmonary exercise testing. And in this case, we want to be able to support those important clinical changes by demonstrating that the therapy is biologically active in a way that makes sense to support the clinical benefit. And in here, that was looking at measures of diastolic function. ProBNP, sort of direct reflection of LV filling pressures, left atrial pressures, cardiac structure, left atrial volume, again, an indirect measure, but a very strong one of left ventricular filling pressures and diastolic function with septal e-prime, a noninvasive measure of LV or left ventricular relaxation.

And so the way this works is simple. We just take those measures, and these are the endpoints in this substudy analysis. And each of these measures, by the way, each of the 5 have each been related to adverse outcome in HCM. So they are predictors of bad things happening to non-obstructive patients. So they in and of themselves are very important predictors of what happens in the future to patients. And so therefore, they are relevant in that way, and that's how they are defined as -- and then we define them as a responder analysis by putting a clinically meaningful threshold of change that we attach or associate to each one of these.

So for improvement of symptoms, it's a 1 or more improvement in NYHA class plus 1 categorical change in PGIC, a 0.5 or more improvement in exercise capacity, a greater than 10% decrease in left atrial volume, a greater than 10% improvement in septal e and a greater than 50% reduction in BNP. So those define a threshold for which that if we achieve, we would consider to be clinically meaningful based on other supportive data for that individual patient.

So if we look at that then in terms of what we saw. So that's the responder analysis. That's what we did, and this is what we found. So if you look at each of those 5 outcome measures and you look at what the response was, what the treatment benefit was in this symptomatic functionally limited non-obstructive population, you see that over 70% of patients achieved the threshold of a clinically meaningful symptom improvement. It's a lot. And then you've got about half the patients achieve a functional improvement in peak VO2 of 0.5 milliliters per kilogram per minute or more. You've got about 1/3 with that improvement in left atrial volume, more than half with the improvement in LV relaxation and over 63% with a substantial reduction in BNP, again, reflecting a very important and impactful biological effect on the HCM heart with that kind of reduction in BNP as well.

And so those are the outcomes of what we saw with aficamten treatment. And then if you look at that a little bit more detail, sorry, can you go back one. Sorry. This is a little bit hard to advance. So I got -- it's there. Can you go back one?

You got the only driver.

Mine, the only driver. Okay. Sorry. Got it. Understood. Okay. And so if we look at that a little bit more as it relates to the effect of those thresholds over the treatment period and also as it relates to placebo, if we take the 2 outcome measures, again, that clinically are the most impactful, making patients feel better on the left with that one or more improvement in NYHA as well as that one categorical improvement in PGIC. And then you've got the -- on the right, the peak VO2 functional there.

And you can see the red bars are aficamten and the blue bars are placebo. And you can see with improvement in symptomatic benefit, first of all, again, that 71% at the end of the treatment period or at the end of the assessment period of 36 weeks. But you also see that, that improvement in symptom status starts early. It starts at 2 weeks with a greater proportion of patients on aficamten with an improvement compared to placebo. And it's maintained throughout the treatment period. And you can see that benefit in functional status as well that we talked about almost half the patients receiving a benefit of an improvement in exercise capacity.

And then here, if you combine those 2 measures, feel and function, you see a greater proportion of patients on aficamten achieving that feel and function combination than placebo.

In terms of diastolic function, same story here. Patients -- the greater proportion of aficamten patients achieving the threshold of improvement in left atrial volume, improving diastolic filling with LV relaxation and then the BNP, which is probably the most visually impressive here performance here, undoubtedly telling us that there is a clear physiologic effect here in terms of lowering LV pressures.

And again, if you look at the benefit here across the platform, so to speak, across both clinical, structural and functional measures, if you look at this that you've got more than half the patients on aficamten achieving 3 or more of those outcome measures versus 13% on placebo.

And then you can translate this -- I'm going to finish up here in 2 seconds. You can translate this data then into a metric that we all can relate to as well, which is number needed to treat. And if you look at the number needed to treat across the 5 outcome measures, it ranges between 1.7 for BNP and 14 for exercise capacity and symptom status is 5.5. To give you some context here, the SGLT2 inhibitor drugs, for example, which have mean improvements in KCCQ of 2 to 3 in HFpEF and HFrEF, for example, have a number needed to treat to improve KCCQ and symptom status of 14 to 18. So this 5 far superior in terms of number needed to treat than a lot of the other traditional heart failure medicines that we have for non-HCM heart failure.

Finally, to finish up here, okay. Again, in summary, then over a relatively short period of time, and that's the other point, we're talking about 36 weeks I showed you. You see here that clinically relevant measures were achieved and 3 or more achieved much greater in aficamten than placebo with a number needed to treat that we talked about. And again, this all underscores a broad effect, a broad treatment effect here in this symptomatic function limited population of non-obstructive patients that supports a potential benefit of aficamten in this significantly underserved population.

And I'll finish with just 2 or 3 slides about safety for a minute because this is really obviously very important as well. And as was probably noted, there were a slight imbalance between in serious heart failure events in the aficamten versus placebo groups. The point there is that those low-AF events were independent of ejection fraction, okay? Independent of ejection fraction. And I'll show you why that is in a second. And therefore, titration of aficamten was, as we all know, is algorithmic driven, right? In the trial, you went up on the dose based on ejection fraction. That was a blinded decision that was made, and that was the up-titration strategy.

FOREST, the open-label extension in which patients could roll over into different story, unblinded look at the echoes, you could include physician judgment in addition to the EF to make decisions about up-titration, and I'll show you that FOREST data in just a second. Again, you've seen this, that slight imbalance in serious heart failure events in the afi versus placebo groups of 12 versus 3.

And then if we look at that group, the 12 versus 3, here it is in FOREST. So these are patients that were in ACACIA. They...

These were, still ACACIA.

These were patients that were in ACACIA that rolled over into FOREST.

But this is the timing of the patients in ACACIA still.

Yes, sorry. I'm sorry. We're on the wrong side. This is ACACIA, sorry, you're absolutely right. This is ACACIA, sorry. So I'm showing you the 12 serious adverse heart failure events in ACACIA, sorry. Where you can see them in the aficamten, pink circles. All of them, all 12 correspond to the titration period, all 12, every single one of them. Again, forced up-titration based on EF. In the placebo group, difference, okay? So all heart failure events in the ACACIA trial occurred in patients on aficamten in that titration period. All of those patients, by the way, responded very well to minimal heart failure therapy, usually low-dose diuretic therapy, and were discharged within a very short period of time.

Now if you look at FOREST then for a minute, taking those patients that rolled over into FOREST as part of the long-term extension therapy of aficamten, really important. I think this is compelling here, which is that if you look at these patients, first of all, the patients that were on aficamten in ACACIA who rolled over into FOREST, there are no pink circles. That's because none of those patients had a heart failure event in FOREST. The only heart failure events were those patients, and there were 2 in placebo arm in ACACIA who rolled over into FOREST on aficamten. And those 2, which is 1% of the population occurred during the titration period.

And I think what this means, to translate this, what this means is that when we look at the heart failure events, it appears that these could be significantly mitigated using a strategy of dose titration that is reflective of clinical practice, which is what FOREST titration does. It uses an unblinded assessment of the echo with clinical judgment to make decisions about titration. This is how we practice clinically in the real world. That's what FOREST mimics, and this is what I think we could expect to see based on that experience.

All right. My last slide, and then we'll open it up, which is a conclusion slide. The advancer, it needs a -- okay. So as anticipated, escalation of dose of aficamten in isolation of clinical data resulted in greater events when compared to dose selection that incorporates clinical judgment and echo assessments. The current algorithm with FOREST essentially mimics clinical practice as well as what we have for aficamten in symptomatic obstructive HCM. And the incidence of serious heart failure in FOREST, including patients never exposed to aficamten before, is substantially lower as we noted than that noted in ACACIA. Thank you.

Please form up, guys. So thanks, Marty. Thank you, Dr. Masri. And I'd like to just welcome Dr. Christina Paitazoglou up to the stage, and we'll get the Q&A session on the go now.

So I'm actually going to start out with you, Dr. Paitazoglou. So you're an HCM doctor and a heart failure doctor here in Germany. Can you just tell us a little bit about yourself, what your practice might involve? And then as a second question, a follow-up, you really were not part of the study, and you saw the results really for the first time just a couple of hours ago. Maybe you can contextualize those results, tell us what you think about them and what they mean for the patients in your clinic.

Thank you very much. First of all, congratulations to your trial and the results, very impressive. My name is Christina Paitazoglou. I'm a heart failure specialist. I work at the university clinic. I am Head of the Heart Failure department at our clinic. And I am also the lead of the Heart Failure Network for the State Department with the Ministry of Health. So we get a lot of referrals to our university clinic, not only HCM, also other heart failure pathologies, but we see a lot of patients with HCM because in Germany, those patients treated with the myosin inhibitor now and titrated is in the university clinic. So we've treated all of our patients. Not all of our patients have obstruction. We get a lot of referrals with patients who do not have obstruction.

And there is, as Dr. Maron said, a clear unmet need. We don't have options for those patients. They are still very symptomatic, and we can only treat them according to the guidelines of heart failure. And we did not yet have so far a targeted treatment. And that's why it's a great milestone. It's the first positive trial in this difficult population. You do not have an obstruction. You give a specific drug and the patient gets better. So for us, it's a new opportunity. We have a new tool. We can help the patients so we can give them hope for treatment.

And your results are for me very encouraging because, as I said earlier to you, I was not expecting the same results as an obstructive because it's a different patient population, the patients with non-obstructive. The symptoms derive from -- it's more complex, derived from many factors. It's a diastolic dysfunction, it's microvascular disease and the drug is very specific. And it led to an improvement of the patient, and that is very important, not only hemodynamically, the patient feels better. And we know the safety profile. I've treated in Germany, a lot of patients with aficamten in obstructive. I feel very safety with this drug. And now it gives me hope for this patient population. I don't know if it answers exactly your question. It was very widely asked.

Yes. I mean that was a beautiful description. Maybe just to dig a little bit deeper. You mentioned to me earlier on that you're actually an expert in cardiopulmonary exercise testing. You've done some advanced training in New York City. So you -- and you also treat other forms of heart failure. So you have a special understanding of the magnitude of the treatment effect in terms of the peak VO2, for example. Maybe you can just drill down on that a little bit to put some perspective over there.

The CPET training, yes, we do a lot of CPET in our heart failure patients, and that is not a very common examination for cardiologists. Not many have the expertise in CPET. I did it in New York at the Columbia University also in Heidelberg, and we perform CPETs in all of our patients, even advanced heart failure. And I know these parameters you presented, the peak VO2, even the slope, they are parameters, prognostic parameters for heart failure. And usually, in my patients, they go down, not the slope, the slope goes up, which is bad.

And in your trial, we saw an improvement. And it's very difficult to change those parameters in the CPET to an improvement in the peak VO2, it's very difficult to achieve, even for those patients and exactly for those patients without obstruction. So maybe they resemble a little bit the more broader patient collective like HFpEF patients, it's -- I don't say impossible, but it's very difficult to improve them. And many trials have not chosen this parameter as a primary endpoint, I think, because they are afraid of the results, and they may have failed.

So an improvement consistent with an improvement in symptoms and the NT-proBNP going so much down after 36 months (sic) [ 36 weeks ] is for me as a clinician, a very great sign, and it makes me happy to see that. And you have to leave the patient longer on this medication, maybe this parameter will even get better. Because the medication targets exactly the disease.

All right. Beautiful. Thank you so much. Maybe moving on to you, Dr. Masri. How would you characterize the overall safety and tolerability of the data that you presented today? And what did you and your investigators actually see and manage over the course of the trial? And what do you see in some of the patients that you might actually have now in the FOREST open-label extension?

That's a great question. So as we alluded to is that the numbers that you're looking at, you have to really understand what it means when we say that there was reduction in LVEF. So I think of them as kind of almost 3 buckets. One is what was the average reduction in LVEF throughout the trial or at week 36, for example, and that was 4.4%.

The second bucket is we are dosing to titrate to LVEF. So like you do with blood pressure, if you want to dose to blood pressure, you will have instances of reduction in blood pressure. Same with EF you're dosing to it. There will be instances of reduction. The question is, can you keep the patients on the drug or lower dose? Can you continue without having cycles of stop and start? And are you causing these patients with reduced ejection fraction, either irreversible issues or something really significant that is having them exit or just say, I don't want to do this. And this is not our experience. We've already shown you the numbers. I'm not going to repeat those.

But even our local experience where we have now more than 40 patients or so with non-obstructive HCM on aficamten as part of these clinical trials in the open-label FOREST-HCM study, this is not our experience. Our experience is, generally speaking, in the blinded period, I don't know anything about what happens to these patients in the blinded trial. But if these patients suffered a significant event or something meaningful per protocol, I would have known about it, for example. And this wasn't the case. And in FOREST, as Dr. Maron alluded to, we actually are not dealing -- we dosed all of these patients in FOREST, and we are not dealing with any of these major issues.

Even if you end up seeing a reduction in EF less than 50%, if the patient is asymptomatic, the reason why we go down on the doses are because we don't know what the long-term meaning of that. So we just want to keep that threshold. And to me, essentially, the safety is on par with what I have expected it to be. It's just you have to put into perspective the design of the clinical trial where we're taking 517 patients, randomizing them 1:1. And for those 289 patients, we are telling them all of you have to go through the same process. This is not clinical practice and not FOREST-HCM design either.

Got it. Thank you. Dr. Maron. So which of the patients in your practice, do you think that the results of ACACIA are most applicable to? In other words, do you think that there are patients who would derive more benefit than others? And thinking a little bit more ahead, how do you think the conduct of ACACIA-HCM may translate into future diagnosis of new non-obstructive HCM patients?

Yes. Great. Thanks, Steve. So I'm going to get to that in one second. I just want to do one -- I want to address one other point that was raised here because I think it's important, is that -- and this is something I'm kind of seeing and hearing. There was -- I think that there was this expectation, I think, in some people's minds a little bit that we would see a treatment benefit here that was similar to the obstructive HCM trial, right? I mean there was that expectation, I think, psychologically or otherwise. Of course, that was never going to be the case because in obstruction, these drugs so effectively lower acutely that high LV pressure that it translates into such a magnitude of benefit in how patients feel that you weren't going to ever be able to achieve that kind of degree of improvement in this different population.

That doesn't mean that the clinical benefit that we're seeing in non-obstructive should be -- is less significant necessarily, but that to compare the 2 experiences isn't fair and shouldn't really be done. And I think I see a little bit of a psychological thing going on here where people were expecting those same treatment benefit numbers and not seeing them psychologically has created a little bit of quest -- consideration. And I think that, look, we made the case here, I think, with this responder analysis that the benefit is clearly there in this population. It's different than non-obstructive.

Number two, I'll make the point that -- and I'll support that point with this following anecdote, which I think to me, tells the whole story almost. If you look simply at the patients that were in ACACIA who rolled over into FOREST, of which there are several hundred. If you look at those patients, you will see that 99% of them remain in FOREST on aficamten, months, many months later. Almost none have dropped out. I can tell you -- there's one thing I can tell you, it is that these patients, if they were not deriving a clinical benefit, would not schlep back in for all of the visits that are necessary for FOREST and everything else if they did not feel that there was a true treatment benefit that they were getting with the therapy. That kind of level of commitment would not happen. And it speaks, I think, essentially to the treatment benefit that we're talking about.

And so if we take that for a minute then, Steve, to answer your question, is that Ahmad showed that there really was no heterogeneity in treatment benefit across all of these different subgroups. And so the answer of who would potentially benefit from this drug, it would be nearly all the non-obstructive patients who fit into the criteria of ACACIA, symptomatic, functionally limited patients would be potential candidates for the therapy.

And by the way, I mean, it's tough to sit across from these patients that are really frustrated with how they're doing and you know that you've got a therapy that can improve how they feel and function across the non-obstructive spectrum and not potentially think about that option for them. I mean that is an important principle. And so I think we're going -- what we will do in practice is that we will potentially consider all the patients that fit into the ACACIA trial profile as potential candidates for therapy.

All right. Perfect. Thank you. Beautifully said. We're going to switch over to some questions from the audience, Joanna, there you go.

Cory Kasimov with Evercore. Dr. Maron, I just want to follow up on a point you were making and just kind of ask it a little bit more bluntly. So the discussion in the trial, while I think balanced overall, again, brought up this point of a modest effect when describing the study. Given the dearth of options for these patients with non-obstructive HCM, in other words, having none, are there patients who you think would not be candidates for aficamten assuming approval or perhaps subgroups of patients where you would not want to at least try this product?

So I think -- well, two things. One is that I think I would push back a little bit on the characterization that came up today about the treatment benefit was modest. I think what we're -- what I'm trying to say here based on the data and our experience is that I don't think that, that is necessarily characterizing what's going on here in terms of treatment. I think the treatment benefit is much more than that for the vast majority of patients that are on therapy, okay? Again, it may not reflect as intuitively in mean changes, we saw the benefit that I think supports that with the responder analysis where you've got 70% of patients feeling better by a clinically meaningful change, okay? So that's really important. So I don't look at it, by the way, by the data or in my own practice as a modest change. I think it's much more than that.

Two is that I think that -- look, I think we don't really have any idea about whether there's any kind of subgroups. We don't really have a good idea about whether there are specific subgroups that would be better responders or not so much good responders in this population yet. I think what we do know is what Ahmad showed from the primary paper, which is that there was no treatment difference among a lot of different prespecified relevant subgroups here. All of them were getting benefit here. And I think we have to go on that presumption right now that, that is the case. And that's how we'll practice clinically.

Tess Romero from JPMorgan. So just to piggyback off here, maybe just thinking about how you compare and contrast the treatment effects that you've seen across both of these patient populations. What were the true surprises in the data relative to your expectation? And then how should we be thinking about sort of longer-term treatment effects and sort of where this could go over time?

Do you want to take that one?

So great question. One of the things that came up to me is when you look at mean population averages, you actually are not reflecting on the patient experience. As I mentioned, we have a substantial number of patients. And in a blinded trial, I can't tell much, but I have them in the open-label extension. And the individual patient experiences, there are exceptions, obviously. There are patients who just their heart structure might not be tolerant of a CMI like aficamten. But in general, for the majority of the patient, our patient experience has been very positive. And I'm not talking about someone just going to the bathroom and not being short of breath. I'm talking about actual scenarios where patients essentially were short of breath just walking down the street now to hiking in Oregon, which is not a very easy thing to do.

And these are all real stories, playing with their grandkids or taking care of them. And so those -- that's one of the surprises that back to Dr. Maron's point is that I personally don't feel that the treatment effect is modest. You have a disease which is more resemblant of a heart failure syndrome than it is of an acute afterload problem. And you moved every single domain that you want to move. Even the left atrial volume index, which has a lot of shortcomings to it, even that was marginally positive essentially. And so you're moving all of these domains in the right direction, which has never been achieved before in a heart failure syndrome trial. We make people live longer with heart failure, yet we make them feel worse and exercise less.

And so that, to me, essentially is the important piece here is that there is education to be had and to be done to translate what we saw and what our experience is to allow people like what you reflected on in the conference, for example, understand this as well.

And then just one follow-up here. Just to kind of double-click on how we should interpret the heart failure events that were not associated with EF drops below 50%. Can you just provide your thought around this?

I'm happy to take it. I actually myself had patients like that. And what happens is when you are using aficamten, your goal is to improve stroke volume and cardiac output. That's your ultimate goal. And that's how you improve peak VO2, you improve how patients feel and how patients do. You have a left ventricle that is stiff that has been with this disease for decades and decades, and you're acutely changing how the left ventricle and the heart is working. During that titration period when you're introducing that acute change, you will have some fluid imbalance because you're suddenly seeing more blood coming to the left side of the heart, which is stiff and has lived with the same amount for years. And again, when we say heart failure, it's just a broad basket. Like my patients, you give them a few days or even a few doses only of an oral diuretic. Their legs are no longer swollen and they keep going.

And so that's, I think, where this requires an effort to show people and explain it to them is that it is you're acutely changing something over 8 weeks that has been there for 20 years. So in very few number of patients, the number is 1 out of 20. We're talking about such a small number of these patients. One out of 20 patients had to have that. So in my opinion, this is a minor issue. It's addressable. And the beauty of this is that this is not a therapy where you have to give it to everyone and wait until they live or die 10 years later. This is something you can give it to the patient, talk to them, see how they do and how they feel and make a decision. Six months later, 12 months later, you make a decision. Are you liking being on this drug? Do you derive benefit from it? What is going on here?

Serge Belanger from Needham. There was a lot of discussion about titration and dosing. In the trial, you titrated based on max tolerated dose. You mentioned it'd be different in the real world. Just curious, if you applied real-world criteria, what -- if it would have had any impact on the efficacy and safety that we saw in this trial? And then secondly, for the company, what do you expect the regulators will look for in terms of dosing and titration for this indication?

Maybe I'll start with the question for the company, just to get that out of the way. So we're in discussion with regulators right now. We don't like to speculate what regulators are going to say what they want and what they don't want. So we're going to put our best foot forward, and we're going to negotiate in order to get the best outcome for patients ultimately. Martin?

Yes. So for FOREST, so I think the answer to your question is it has to do with FOREST data, okay? So FOREST, the open-label extension, I think we touched on this at 2 points is that, number one, FOREST uses a titration scheme that is similar to the one we have for obstructive HCM, but also, again, mimics or incorporates physician judgment, which is still really important even in the current era we're in, seeing the patients and making judgments while also looking at the echo. And when you do that, at least by the FOREST experience, you don't see those heart failure events like you did in the clinical trial.

So I think it does speak to the fact that when we think about real world, we will see and we don't have any reason to believe it would be different that experience in terms of heart failure events. Number two is that if you look at the -- if you look at the FOREST data in the non-obstructive patients now out to more than 96 weeks therapy. If you look at that data, which is published, you see that 2 things: one, that the clinical benefit is maintained, okay? So you still continue to see significant improvements in how patients feel both by NYHA and KCCQ. And so this benefit that we're seeing in the trial appears by the FOREST experience to be maintained.

Lastly, based on these results, what are your thoughts now on the role of CMIs and aficamten for HFpEF?

Well, maybe we'll jump in on that one maybe because it may be different. I think here's what I think. I think I'll say that when we talk about HFpEF, so non-HCM HFpEF, I would say this, this is kind of how I would answer that, and I'll be brief so the others can contribute. I'd say that the results of ACACIA, to me, open the door in a way to the idea that CMIs could have clinical benefit in the HFpEF population. That's principle number one. I think that's true. What I think is going to need to happen, though, is we're going to need to find the right HFpEF population that's going to be benefiting from these therapies. It may not be the entire pie, which, as you know, is a big pie, which is a very diverse phenotypic subgroups in that pie. So I think we're going to have to be a little bit thoughtful about which are the right patients to look at and essentially be following in trials to get the kind of outcomes that we want and like we saw here. So I think it's a possibility, but it's going to require that as, I think, a big step.

Christina, why don't you piggyback off that?

Yes, when you presented your data, my colleague also cardiology at my department asked me, oh, maybe we can use it on also on the other HFpEF patients or how many of your patients were maybe not HCM or HFpEF patients? Well, I agree that the HFpEF population is very diverse. And that's maybe why trials in the past were not successful because they did not address the collective -- they did not address it regularly. If you look at the mode of action of aficamten, it reduces the hypercontractility. And we don't -- we have to find patients in this HFpEF collective who have this hypercontractility because it reduces the hypercontractility and the -- yes, and it may the ejection fraction go down. So you have to find the ideal population in this periphery of HFpEF patients, which may benefit. It will be not easy. But if you find a specific subpopulation, maybe this drug is also good in the HFpEF.

Ahmad, I know what you think about this, but we're going to move on to the next question.

A quick question on -- this is [ Robin Rock ]. Two quick question on the potential halo effect to have a drug that not only works in oHCM but also nHCM, and how that basically plays back into oHCM to have basically one drug that is able to treat both patient populations? And then a quick follow-on.

Maybe, Christina, you're not involved in the study. And again, I'm going to pick on you because you have a broader opinion. So the question really is, do you think that now that we have some positive data in patients with non-obstructive HCM, that will translate into an increased utilization of aficamten in patients with obstructive HCM, too?

The medication is available in Europe, only in Germany, and it's since June available. We have gained a lot of experience since then, and it's a very safe drug to use. And all of the cardiologists who are working with the drug are -- and I was talking to them are feeling the same. It's easy to use, it's safe. You can go back. You have a big -- a quick up-titration process, you can get patients quickly on target. So if they have a good experience in obstructive and now it will -- we have data for non-obstructive, I think it will be very easy, and they are already asking us, can we use it? Can we prescribe it? And we say, no, you have to wait for the label. I think it will be very quickly in the use also for the other collective. And it's the only positive trial for the other medication, we do not have positive data.

So with this easiness at use and the positive trial, yes, I think it will be very easy in the translation and the physicians and all of them are waiting to get a drug like this because we have the patients and we could not treat them yet with the medication. We said to them, oh, no, you do not have obstruction. Sorry, we cannot treat you, and we have to wait for your results. And I know -- and I have in mind many happy patients now -- or patients would be very happy to hear your results. They are waiting for the treatment.

I think it's a huge point actually, I'll piggyback, really 2 seconds. I think it's a huge point, it's a huge differentiator. You know why? Because the clinical practice in cardiology community does not want to think about wait a minute, this patient got obstructive or not which drug. I mean this simplifies if it's approved for non-obstructive, it simplifies the approach to the management of HCM, which is particularly impactful in the general cardiology community here. And I think that this will do that. So I think it's a really important point that can't be minimized.

A quick one on patient deaths in the study. Was there any imbalance that you saw there?

Yes, there were 3 deaths in the placebo arm. There were no deaths in the aficamten arm. It's a very small number to make anything out of it, really.

All right. Any more questions in the audience? So we'll take one question from online over here. I'll just go with the first one, Paul Choi from Goldman Sachs. He's asking, do you envision your non-obstructive HCM patients actively seeking treatment? Or will they get on MYQORZO over time as they come in for the periodic checkups? Ahmad, do you want to take that?

Yes. So we actually have experience from this with the recent approval of aficamten in obstructive HCM patients where I was on vacation. And it was 1 day or 2 -- like was 1 day or 2 before Christmas, I think, when the approval came through from the FDA, and we started getting all these messages. Hey, I saw this online. Can I please come and talk to you about it? And so this is an obstructive HCM, correct? And so a lot of these patients are limited and they're significantly limited. And there's a lot of -- there are a lot of initiatives from patient advocacy group, from societies, from -- supported by sponsors supported by others that when you have such a drug becoming available, I expect a lot of patients to reach out to their physicians and say, hey, I saw this, I am limited. I want to be considered or at least talk about it. And this happens outside of HCM, it happened also in amyloid when new therapies became available, and I expect the same to be here.

Great. So I apologize, we've got some other great questions from our online attendees that we're not going to be able to get to. With that, I'd like to thank our 3 panelists. So thank you, guys. I really appreciate you spending your afternoon with us. And Robert is going to say a few words.

So thank you, Steve, and many thanks to our panelists. I very much appreciate you taking the time to share these data and perspectives with us. So it's a very exciting time for science and for patients and for us at Cytokinetics here in Munich. We're really proud to have these results shared here at the ESC. ESC is the very largest cardiology conference held globally each year. There are over 30,000 people here. And I've been doing this for over 40 years. I've been coming to these meetings, and I've never been at a scientific session where there were as many people gathered as we saw here today, not only was the congress hall filled in every chair, but standing room only in the back, 15 rows deep, it was really quite impressive. And it's so nice and gratifying for us at Cytokinetics to see our science presented to an audience and have those results so warmly embraced.

So at the same time, here we are, we're pleased to be underway here in Germany with the launch of MYQORZO that occurred in June, alongside of the launch in the United States that occurred earlier in the year, also in China. And as mentioned recently in our Q2 earnings call, we also received approval from the MHRA alongside of positive guidance from NICE in the U.K. and Wales. So MYQORZO is beginning to reach patients all around the world in multiple geographies. And that's truly wonderful to see. We really appreciate the warm embrace the market access and the adoption for MYQORZO in oHCM.

And given now these positive results from aficamten in ACACIA-HCM, we're really pleased and frankly, we're very committed to be moving very swiftly to submit a supplemental new drug application to the FDA for aficamten. We're going to do that in nHCM in the fourth quarter of this year. And on our next earnings call, we'll provide an update on our plans with regard to other geographies. We look forward to engaging with the FDA to potentially bring this important medicine to bear on patients with nHCM for which there is no other treatment. And at the scientific sessions today, there was a slide put up that showed that every other study conducted in patients with nHCM was negative. That includes a lot of very commonly embraced drugs in the use of heart failure and another cardiac myosin inhibitor. But we're really pleased that aficamten in this study, ACACIA-HCM was positive for patients who don't have any other approved treatments.

We look forward to the potential of aficamten being approved across the full spectrum of patients with HCM and especially now with nHCM, a very challenging and life-altering disease. We thank all of you for your continued interest and your support of our company. We really mean that. This is especially gratifying for us, and we're glad to have shared this with you. With that, we'll now conclude the event. Thank you.

Thank you for standing by, and welcome to the Cytokinetics Q2 2026 Earnings Conference Call. This call is being recorded. [Operator Instructions]

I would now like to turn the call over to Diane Weiser, Cytokinetics Senior Vice President of Corporate Affairs. Diane, please go ahead.

Good afternoon, and thanks for joining us on the call today. The slides accompanying today's webcast can be found on the Investors & Media section of our website at cytokinetics.com, along with today's press release. Robert Blum, President and Chief Executive Officer, will begin with an overview of the quarter and recent developments. Andrew Kallos, EVP and Chief Commercial Officer, will discuss the commercial launch of MYQORZO in the U.S. and Europe. Fady Malik, EVP of R&D, will provide updates related to aficamten. Steve Heitner, SVP and Chief Medical Officer, will provide updates related to our ongoing clinical development programs. Sun Lee, EVP and Chief Financial Officer, will provide a financial overview for the quarter. And finally, Robert will make closing remarks and review key milestones for the year ahead.

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

Thank you, Diane, and thanks to all for joining us on the call today. The second quarter was another solid period of execution for Cytokinetics, marked by strong commercial momentum for MYQORZO in the United States, our first European launch in Germany, progress towards additional market access globally, potential regulatory milestones internationally and continued advancement of our later-stage specialty cardiology pipeline. Just 5 months into the commercial launch of MYQORZO, we are demonstrating increased velocity that's exceeding expectations. As Andrew will discuss, growth in prescribing and dispensing for MYQORZO reflects increasing awareness and physician engagement, expanding patient access and adoption across multiple segments of the targeted prescriber base, all of which reinforce confidence in MYQORZO and its clinical, therapeutic and commercial opportunities.

During the quarter, we also executed well on our global commercialization strategy with the launch of MYQORZO in Germany, the first in a series of European launches expected over the next 6 to 12 months. This is a key milestone for Cytokinetics and for patients in Europe, and it serves as the foundation upon which we will build broader access across Europe and beyond over the coming years.

To that end, more recently, the MHRA granted MYQORZO Marketing Authorization across the United Kingdom for the treatment of symptomatic oHCM in adult patients. And at the same time, NICE issued guidance recommending MYQORZO for use in England and Wales. We're pleased that the concurrent regulatory approval and reimbursement recommendation will help MYQORZO reach patients sooner. We expect drug supply and full launch in the U.K. later this year.

During the second quarter, we highlighted the opportunity for aficamten to potentially treat the full spectrum of HCM and as we shared the top line results from Acacia HCM in patients with nonobstructive HCM showed that the Phase III trial met both of its dual primary end points demonstrating statistically significant improvements from baseline to week 36 in both KCCQ Clinical Summary Score and peak VO2 compared to placebo. These results represent an important scientific achievement for an nHCM patient population with no currently approved therapies and they define a meaningful step toward expanding the potential reach of aficamten beyond oHCM subject, of course, to regulatory review and subsequent potential approval.

Following our announcement of the top line results from Acacia HCM, we met with the FDA to discuss our next steps. We reviewed the clinical trial results together, and we pose questions to which the FDA responded. Those discussions and the FDA feedback now inform our plan to submit a supplemental NDA for aficamten in HCM in the fourth quarter of this year. We also plan to meet with EU regulators to hold similar discussions in support of future potential regulatory submissions in Europe. In the meantime, we look forward to presenting the full results from Acacia HCM in a hotline session at the European Society of Cardiology Congress to occur later this month. Alongside progress towards making MYQORZO available to more patients with oHCM in the United States and internationally, we're prioritizing potential regulatory approvals for aficamten in patients with nHCM and that could lead to MYQORZO being the only approved therapy for patients across the wider spectrum of HCM.

Moreover, in the second quarter, as you'll hear, we continue to advance our later-stage specialty cardiology pipeline with further progress evidenced in important clinical trials for novel drug candidates that have emerged from our pioneering leadership in innovative muscle biology and pharmacology. And we fortified our balance sheet with a successful financing that supports our plans and objectives. Taken all together, the progress we made the second quarter underscores that Cytokinetics is executing well on a global commercial stage and integrated biopharmaceutical company. We're building commercial growth and velocity, expanding global scale and access, proceeding towards expanded product labeling and advancing pipeline. All with focus and discipline to capital access and allocation. I look forward to sharing more about that now from our colleagues. And with that, I'll turn the call over to Andrew.

Thank you, Robert. In the second quarter, the launch of -- MYQORZO continued to exhibit strong growth. While still early, we are encouraged by the steady progress we're seeing across physician awareness, prescribing activity, patient demand and market access. We believe these early indicators are beginning to demonstrate that the differentiated profile of MYQORZO is resonating well with both health care providers, payers and most importantly, also with patients.

Since our commercial launch at the end of January, MYQORZO has accelerated quarter-over-quarter growth in new-to-brand prescriptions within the CMI category, by 24% in Q1 and 15% in Q2 compared to the single-digit growth rate observed when only a single CMI was available. The introduction of MYQORZO is helping drive increased breadth and depth of new patient starts as well as greater engagement and awareness among a broad range of physicians and prescribers within the category. In fact, in our most recent market research survey, which was conducted during the second quarter, unaided awareness among ATPs increased to 68% compared to 52% in the first quarter.

We're also seeing encouraging engagement among patients. Our patient marketing campaign has driven early and increased awareness, resulting in over 30% awareness among oHCM patients in the United States. In addition, we have generated more than 390 million impressions and 2.1 million social media clicks through our focused and directed digital media campaigns across a broad range of channels and platforms. We're also pleased to see continuing perception of clinical differentiation favoring MYQORZO among HCPs. And our most recent physician survey conducted in May HCPs are continuing to favor the clinical profile of MYQORZO, treating physicians that we surveyed also view MYQORZO favorably across several attributes, including the convenience of dosing flexibility safety and tolerability and the flexibility associated with differentiated REMS requirements.

In this stage of our commercial launch, our emphasis remains on deepening prescribing among high-volume CMI prescribers, Historically, these physicians have generated approximately 80% of CMI prescriptions. While our call universe more than 10,000 health care providers we are prioritizing engagement with high-volume prescribers. And at the end of the second quarter, our sales team had reached more than 90% of these HCPs. We plan to maintain that same priority emphasis to high-volume prescribers until we achieve greater than 50% new-to-brand prescription share, which we believe could occur by the end of this year, if not sooner.

At the same time, we're encouraged by the degree to which adoption is already broadening beyond the historically high-volume CMI writers. In fact, by the end of the second quarter, more than 50% of MYQORZO prescribers were either low-volume CMI prescribers or first-time CMI writers. Our field force reached more than half of these physicians during the second quarter. We see prescribing from this cohort as an important signal that MYQORZO is gaining traction across a wider segment in the OHM treating community something we anticipated based on the differentiated profile of MYQORZO it is validating to see that in actual prescribing.

Importantly, our field-based teams are also bringing the data from Maple HCM to the attention of the oHCM treating community. These important data from our second Phase III trial of time a both support findings from SEQUOIA HCM and further demonstrate that MYQORZO superior to beta-blocker metoprolol, an important point of differentiation that resonates with physicians to further reinforce the safety efficacy and utility of MYQORZO in patients with oHCM.

As we committed at launch, we continue to evaluate performance using 3 key metrics: breadth of prescribing measured by the number of HCPs who have written prescriptions depth of prescribing, measured by the number of patients to which each HCP prescribed MYQORZO and patient volume, which reflects a total number of unique patients prescribed MYQORZO. Across all 3 metrics, we are encouraged by the progress and rate of growth achieved during the quarter. By the end of the quarter, more than 700 unique health care providers in the U.S. have prescribed MYQORZO including approximately 300 physicians from the high-volume CMI rider segment. On average, HCPs prescribed MYQORZO to approximately 3 of their patients, the figure is even higher among the subset of high-volume CMI writers who have now already prescribed MYQORZO at approximately 5 of their patients on average.

Although limitations with syndicated data make it difficult to precisely calculate new-to-brand Q2 exit share in the CMI category, our internal analysis suggests that the exit share for MYQORZO has increased to greater than 40% in the second quarter. We also continue to see encouraging leading indicators of future demand, including more than 25 health care -- 2,500 health care providers who have now completed REMS certification since launch.

Turning to patient demand. In the first quarter, we reported approximately 680 MYQORZO prescriptions, of which 400 were dispensed to patients by end of Q1. By the end of the second quarter, MYQORZO was dispensed to 1,500 patients, approximately nearly tripling the number of new patients dispensed MYQORZO in the quarter. The majority of prescriptions continue to be dispensed within approximately 3 weeks. Once all patient documentation and benefits investigation is complete.

Going forward, we plan to report on patient dispense versus prescriptions to better align with product revenue. In Q2, over 80% of the dispensed prescriptions were paid for with the remainder associated with either free trial, bridge or other patient assistance program. These 2 are encouraging indicators of commercial launch growth and velocity. From an access perspective, we maintain our aspiration of broad coverage across key payer channels. We ended the quarter with nearly 90% parity coverage for Medicare lives. We also continue to broaden our commercial wide coverage achieving over 50% commercial coverage by quarter end and remain on track to achieve parity access by the end of 2026.

Outside the United States, we successfully launched MYQORZO in Germany in June to support expanding access throughout Europe, we have also submitted 10 HTA dossiers across Europe reimbursement approval received effective August 1 in the Netherlands. And in England and Wales, nice published guidance recommending MYQORZO for use as we continue to make progress broadening the pathway to further patient access, in key markets with additional markets anticipated to launch later this year during the first half of 2027.

We are very encouraged by the performance we have seen in our launch markets. The launch velocity we are seeing reflects the differentiated profile of MYQORZO, but also the dedication and execution of our colleagues across the U.S. and Europe were delivering excellence with both integrity and focus. And with that, I'll turn the call over to Fady.

Thanks, Andrew. The second quarter was an important period for our HCM portfolio, most notably with our announcement of positive top line results from Acacia HCM and our pivotal Phase III clinical trial in patients with symptomatic nHCM. As we shared by top line press release in May, Acacia HCM met both dual primary end points, demonstrating statistically significant improvements from baseline to week 36 in both KCCQ Clinical Summary Score and peak VO2 compared to placebo. In addition, statistically significant improvements compared to placebo were observed across key secondary endpoints, and no new safety signals were identified. We believe these findings are particularly meaningful because they demonstrate the potential of aficamten in nHCM, which represents as much as 1/2 or more of the overall HCM population and for which there are no currently approved therapies.

For many years, treatment options for patients with nHCM have been limited despite the significant burden associated with the disease. We believe the results from Acacia HCM represent an important step towards potentially changing that treatment paradigm. Later this month, we look forward to presenting the primary results from Acacia HCM during a hotline session at the European Society of Cardiology Congress. Alongside the presentation of the primary results, which will provide a more comprehensive and detailed look at the results for both primary endpoints, secondary endpoints and of course, safety. We'll also be presenting additional analysis regarding the effect of aficamten on cardiac structure and function separate late-breaker session to help further inform treatment effect of aficamten in this population. At ESC, we also plan to hold an event both in person and online for investors and analysts her perspectives and insights on the results from prominent HCM KOLs.

As Robert mentioned, after we shared the top line results publicly, we then met with FDA to discuss the results of Acacia HCM, and next steps for aficamten, which informed our plan to submit a supplemental NDA expected during the fourth quarter of this year. While we prepare for that filing, we also expect to engage with European regulatory authorities in a similar fashion regarding a potential submission to the European Medicines Agency. There is still much work ahead, but the positive top line results and our regulatory interactions to date reinforce our continued confidence in opportunities for aficamten in nHCM.

In oHCM we continue to support review activities and engage constructively with FDA regarding the sNDA based on Maple HCM that's currently under review with a PDUFA date of November 14, 2026. We continue to believe that the results from Maple HCM have the potential to meaningfully inform treatment guidelines and clinical practice by providing evidence supporting the use of aficamten as an earlier treatment option in appropriate patients. In the meantime, given that the efficacy and safety profile of aficamten observed in Maple H&M are consistent with our labeling, our field medical team have been sharing these results with potential prescribers.

In addition, our field medical team continued to support the launch of MYQORZO. They completed more than 800 scientific exchanges with U.S.-based HCPs across a variety of topics, including questions related to the USPI and our public announcement of the results from Acacia ATM. Our medical science liaisons also supported our cardiovascular account specialists or CAS with introductory ACP meetings. During the quarter, our medical colleagues were pleased to support the initiation of our first ever investigator-initiated research study utilizing aficamten. Studies investigating the feasibility, safety and efficacy of physician seamlessly transitioning patients from mavacamten to aficamten in patients with HCM.

Taken together, the progress made this quarter reinforces our conviction in the potential role of aficamten to address the full spectrum of HCM. With MYQORZO now available for patients and -- I mean, for adults with symptomatic oHCM and the positive results from Acacia HCM supporting a potential expansion into NCM, we continue to see a substantial opportunity to bring this medicine to a broader population of patients in the United States and also around the world.

Next, I'm pleased to hand it over to Steve Heitner, but before I do, I'd like to formally announce that Steve has been promoted to Chief Medical Officer. Steve, who joined Cytokinetics in March 2020, will continue to lead clinical research with responsibility for conception conduct and execution of our clinical trial as well as contributing to the expansion of our pipeline and evolution of our clinical research infrastructure as we move into a new age of artificial intelligence aided R&D.

Experience in treating patients with HCM and deep expertise in this disease, Steve has been an exemplary leader in helping to bring aficamten to patients. The insights and guidance contributed immeasurably to the approvals of MYQORZO in the U.S., EU and China. He's also played major roles in the innovative study designs and quality of conduct of Acacia HCM for aficamten, for omecamtiv mecarbil.

This transition represents a passing of a baton from Stuart Kupfer, who had served as Chief Medical Officer at Cytokinetics since 2020 and who contributed enormously to many of our successes in recent years. Through his seasoned leadership and expert oversight of clinical research, clinical pharmacology and drug safety. We're pleased that Stuart will remain at Cytokinetics as Senior Vice President of Clinical Development; contributing to our clinical programs and external innovation with a special focus on pharmacovigilance. And with that, I'll hand it over to Steve.

Thank you, Fadi. The first, starting with our ongoing programs for African, we continue to advance studies supporting broader availability worldwide. During the third quarter, we expect to complete the conduct of the Japan cohort of Acacia HCM and for our partner, Bayer, to complete the conduct of HCM evaluating the treatment of obstructive HCM patients in Japan. We also advanced CEDAR HCM, a study evaluating aficamten in pediatric patients with obstructive HCM. In fact, during the quarter, we completed enrollment in the adolescent cohort ahead of prior expectations. In addition to the progress for aficamten, we continue to advance the remainder of our cardiovascular pipeline during the second quarter. Starting with omecamtiv mecarbil, the continued conduct of, our confirmatory Phase III clinical trial in patients with heart failure and severely reduced ejection fracture.

We've now enrolled just over 1/3 of patients across North America, Europe and China. With the additional sites from China this past quarter, more than 90% of planned sites are now activated. We are encouraged that the baseline characteristics of patients with heart failure and their severity are tracking very closely with those in the subgroup of heart failure patients from heart data with severely reduced ejection parking the design of this trial. We expect to continue enrollment through 2020.

For, we continue to enroll Cohort 1 of Amber Hedde, our Phase II study in patients with heart failure preserved ejection fracture towards our expected completion of enrollment in the second half of this year. We remain focused on continuing trial conduct and generating data to help define the potential role of cardiac myosin inhibition in heart failure preserved ejection fraction.

Overall, we are pleased with the continued progress across our later-stage specialty cardiology development portfolio and look forward to important milestones over the coming quarters. With that, I'll hand over to Sung.

Thanks, Steve. Beginning with revenue. Total revenues for the second quarter were $28.6 million compared to $66.8 million for the same period in 2025. We Net product revenues of Micorzo reached $25.3 million, serving as the foundational driver of our top line moving forward. Of this amount, U.S. net product revenues were $23 million powered by robust demand and more than 80% of patients on paid prescriptions. Europe contributed $2.3 million in net product revenues, reflecting initial inventory purchased by distributors in Germany.

Other components that contributed to total revenues in the second quarter include $3.3 million in collaboration revenue compared to $2.4 million for the same period in 2025. No licensing or milestone revenues were recorded in the second quarter of 2026 compared to $64.4 million in the second quarter of 2025, which benefited from the achievement of milestones from our collaboration agreement for aficamten in Japan with Bayer.

Turning to operating expenses. R&D expenses for the second quarter were $97.8 million compared to $110.1 million for the same period in 2025. The decrease was primarily due to higher clinical trial activity, supply chain costs and medical affairs activities in 2025, partially offset by higher personnel-related costs in 2026. SG&A expenses for the second quarter were $104.4 million compared to $65.7 million for the same period in 2025. The increase was primarily due to commercial launch costs for MYQORZO, the U.S. sales force and higher nonsales personnel-related costs, including stock-based compensation.

Cost of goods sold for the second quarter of 2026 was $2.7 million driven almost entirely by a nonroutine charge related to drug supply optimization. Collaboration cost of revenues for the second quarter of 2026 was $2.9 million compared to $2.4 million for the same period in 2025, reflecting primarily partner cost reimbursement. Net loss for the second quarter of 2026 was $198.8 million or $1.50 per share compared to a net loss of $134.4 million or $1.12 per share for the same period in 2025.

Turning to the balance sheet. We ended the second quarter with approximately $1.7 billion in cash and investments compared to $1.1 billion at the end of the first quarter of 2026. The increase in cash and investments in the second quarter was primarily driven by our May public offering generating approximately $760 million in net proceeds.

Turning to financial guidance. We are updating full year 2026 GAAP combined R&D and SG&A expense to a range of $860 million to $890 million from the previous range of $830 million to $870 million. Stock-based compensation included in the GAAP combined R&D and SG&A expense is being adjusted to a range of $130 million to $140 million, up from the previous range of $120 million to $130 million. Excluding stock-based compensation from the updated GAAP combined R&D and SG&A expense, results in a range of $720 million to $760 million. This increase in guidance is primarily driven by commercial readiness investments prompted by the positive results from Acacia HCM to support the potential 2027 launch of MYQORZO in nHCM. With that, I'll hand it back to Robert.

Thank you, Sung. As we reflect on the first half of 2026, I believe the progress that we've made demonstrates the strength of our execution and our strategic positioning as a maturing global growth enterprise. In less than 6 months of our commercial launch, we've seen encouraging demand for MYQORZO, growing physician adoption and expanding patient access, the breadth of prescribing increasing depth of use amongst physicians and growth in patient volume all provide evidence that our launch is gaining momentum. We also executed a successful launch in our first European market. And while we're early in our commercial journey, the trajectory we're seeing reinforces our belief that MYQORZO has the potential to become the CMI of choice in oHCM.

Our near-term priorities for aficamten are clear. in OHCM firstly, executing successful global launches for MYQORZO and pursuing additional approvals across Europe. In nHCM, presenting the primary results from Acacia HCM ESC and preparing and submitting an sNDA to FDA later this year as well as planning for the commercialization in nHCM.

Beyond Europe, regulatory reviews for aficamten also remain active in multiple geographies, including Canada, Hong Kong and Taiwan. In parallel, we continue to evaluate opportunities to broaden global access through potential partners in additional regions outside of North America, Europe and Asia where we believe MYQORZO may address meaningful unmet need. Building our specialty cardiology franchise also relies on the promise of both omecamtiv mecarbil and Julian which are pleased are progressing well in respect of later-stage trials.

As we look ahead, I believe our strategic positioning has never been stronger. We're entering this next phase of growth with a strong balance sheet that provides financial flexibility to support the global commercialization of micro and continuing investing across our pipeline to pursue opportunities that can enhance longer-term shareholder value. Together with our growing commercial presence, expanding clinical evidence base, and advancing pipeline, we believe we're well positioned to create meaningful value for patients and shareholders in the years ahead.

Now I'll recap our 2026 milestones. For aficamten, we expect to submit a supplemental NDA in nHCM in Q4 later this year. And we potentially will receive FDA approval of the sNDA for Maple HCM and also in Q4 later this year. We expect to prepare to launch aficamten in the U.K. later in Q4, continued conduct of the adolescent cohort of Cedar HCM throughout the year and potentially receive approval from Health Canada in the second half of 2026. For omecamtiv mecarbil, we expect to continue patient enrollment and the conduct of COMET-HF, we expect to complete patient enrollment in Cohort 1 of Amber HPA in the second half of this year. And for CK-089, we expect to continue the second Phase I study -- and finally, for preclinical development and ongoing research, we expect to continue those activities directed to additional muscle biology-focused programs. And operator, with that, we can now open up the call to questions, please.

[Operator Instructions] Your first question comes from the line of Salim Syed with Mizuho.

Congrats on the great number. Robert, Andrew, maybe just 1 from us on the dispensed versus prescribed. We're certainly getting a lot of e-mails just on the clarification here. Could you -- just so we have the apples-to-apples on the Rx So I think you said it was $400 million dispensed $400 million dispensed versus the $680 million in the 1Q and then 1,500 dispensed this quarter. What's the Rx this quarter, if you could provide that? And is the ratio of 59% consistent between the 2 quarters if you don't want to get too granular?.

Yes. I'll turn that over to Andrew to address. But obviously, it's the dispensing that drives the revenue. So we thought it important to align to that number. But Andrew, could you address the specific prescriptions and dispensing in Q2?

Yes. Thanks for the question, Salim. Happy to clarify. So you're right, $68 million to 400 in Q1 to around 2,000 to 1,500 in Q2, launched to date overall. That difference of pending patients. We described patients in the process. Once a prescription is sent in, I mean, that's really the underlying demand and there has not been a change. Actually, there's a growth in underlying demand as you saw from the market share for new-to-brand that we reported. But there is a process, a REMS enrollment has to occur, a prescription has to occur, signatures, both on physician and patient side, benefit investigation, oftentimes prior off -- so there's a process that takes several weeks. We're getting about 100-plus prescriptions per week. So the majority of the difference is that pending patient in process of getting a prescription filled and dispensed. There is a small mid-single-digit prescriptions that do get canceled, but the vast majority are in process and will wind up as a dispense. Hopefully, that answers your question.

Okay. So about 2,000 Yes, you got it.

Thank you, Salim.

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

So I was curious regarding the different metrics that you're tracking for my Corsa's U.S. launch, just a big picture -- are there any that seem to be accelerating more than others into the quarter? And could you comment on the -- what you can see in terms of number of switches versus new patient starts that proportion holding from last quarter? Or are you seeing some changes there? .

Sure. So maybe I'll turn that also to Andrew, please?

Sure. Thanks for the question. So we are seeing a couple of changes. One, the higher percentage of paid for prescriptions, which is encouraging around the same in terms of how long it's taking that prescription paid. We're seeing acceleration in that low volume to first-time member CMI prescribers from a switching point of view and both of those certainly speak to breadth of prescribing. Switching, we reported very kind of low single digit. We are actually seeing probably in the 5% to 7% of our overall dispenses are from switching. The switching has increased slightly, but not dramatically and not a major driver.

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

Doing a bunch of math on the fly here, but it would seem to suggest that the overall class sort of adds per month or per week are only sort of up modestly and what you're seeing so far is primarily share capture versus growing the pie. Is that sort of a fair characterization? And -- and separately, I guess, a clarification question. Was there any impact from stocking in that $23 million figure?

So Andrew, again, I'll turn to you, please.

Sure. So we are actually seeing an increase in growth. I showed you the new-to-brand prescription growth overall. I think last year, we were seeing at least in syndicated data about 2,000 new prescriptions per quarter. I think in the first quarter, the number was probably around $2,500. In the second quarter, it's starting to approach 3,000. So you're seeing a growth in terms of new patients entering the market. And there really hasn't been a change in kind of compliance and persistency overall. So you're seeing an increase in patients dispensed. And I'll send the question over to Sung around stocking relative to revenue.

Yes. So thanks, Carter. So as demand increases, our distributors would carry higher inventory, but that inventory is commensurate with the demand. So this quarter was demand led.

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

So yes, I have kind of like a similar question just a prescription with the dispense. So I know when you provided the first quarter update, you mentioned about the April prescription. And if I take that 20 number and apply this 60%, I get to 250 dispense during April, versus like when you did it for the full quarter is like 1,500. So 1 month had $250 million. And then for the full quarter, you have 1500, as you're thinking about like month-over-month, are you seeing more of a growth acceleration at this point? And anything that you can share about how July is shaped out to be?

So we will resist the temptation to talk about July, but Andrew, could you speak to the second quarter?

Sure. So you can see from the ratios, we are -- we do see an increase in dispense. I would expect dispenses to level out once managed care and access level out, oftentimes, that time frame of a pending patient. The REM certainly adds to it because of certifications needed, but pending patient often stays impending longer because of the benefits investigation and a prior auth process. So we would look to shrink that time frame down over time, but I would not anticipate that in the near term.

Our next question comes from the line of Tessa Romero with JPMorgan.

So taking a step back, as you think about ESC here coming up in a few weeks, what do you believe will be better understood by physicians and investors on the other side of the conference -- and then secondly, just to double click here, you talked about reaching 50% new-to-brand share by end of the year, if not sooner, for MYQORZO. With that in mind, where do you sit now?

So let's take the first part of your question regarding ESC, what might be elaborated from -- with regard to what has already been disclosed in our top line press release. Firstly, we've been very clear that we believe that when we actually present the fuller data that investors will better understand what we've meant by words like consistent and robust as we now can speak to magnitudes of change across all endpoints, including secondary endpoints and how we believe that tells a very consistent robust story of efficacy measured by those various endpoints. Maybe I'll ask Fady and Steve, if they want to speak more to that before we address your second question, which relates to a proportion of new scripts.

So we have both the top line data, which kind of occurs to the endpoints delineated in the but none are going to be put into both clinical and mechanistic context. So the clinical context will be deliberated by Dr. Masri in his presentation on Friday. And then on the Saturday, you'll see that there is the echo analysis that's being done by Dr. Hegde where we'll be talking about what the mechanism by which these clinical benefits are being enjoyed by patients. And I think that, that's going to be very elucidating to scientists and patients hopefully moving forward.

So I do think that as these data will be fully presented, we'll be able to speak much more completely about the effects how they were observed across time as well as ultimately across endpoints that measure both function and quality of life. With regard to your second question, let's turn to Andrew. I think you may have already addressed it in part by speaking to over 40% proportion of new scripts coming out of second quarter, but maybe Andrew, if there's anything more you want to elaborate?

Yes. I mean that's the number we're reporting at the end of Q2 as an exit share, meaning our share in the month of June was over 40% new to brand share. So we're not going to report July. We'll report the third quarter during that call.

Tessa to the point, if not sooner, the trends are demonstrating that we are seeing a higher proportion of new scripts to MYQORZO than might have been expected. And when we talk about exceeding expectations, we are coming out of the gate very strongly with respect to new scripts, knowing that some of that could be a transient effect. I think we're going to be still conservative with respect to timing on when we might expect majority share. But certainly, it's moving very swiftly in that direction. .

Our next question comes from the line of Akash Tewari with Jefferies.

This is Manoj on for Akash. Just 1 from Alan. Are you hearing any feedback from the prescribers who switched from the can sales, especially like the efficacy with the lower doses? And approximately what percentage of your new patient that are outside the treatment of the center of excellence .

So if I understood your question correctly, are we hearing anything with respect to mavacamten as it relates to lower uses -- and .

Yes, the patent suits from Akamai your efficacy with the lower doses of AI?

Yes. So it's not for us really to comment on Chemdios and lower doses. But Andrew, is there anything you want to say about aficamten and MYQORZO and how doses are being titrated and then perhaps tackle the second question. which relates to prescribing outside of velocity accounts. .

Sure. So in terms of dosing, so we do have a flexible dosing window. A physician can increase a dose and we're seeing that dosing window play out in real world where some patients are being dosed as quickly as 2 weeks and other patients are being increased dose as long as 2 months. And that's really between the logistics of a center of patients and the physicians scheduling. So that window is taking place across every dose change. Relative to breadth and depth of prescribing we have a really good mix in terms of breadth. The majority of our prescriptions and prescribers are in that high CMI category, that's about 40% overall. And then that low volume category is about 30% and the CMI naive, meaning they had not written a CMI until we've entered the market as 30% of our prescribers. So we're doing really well across a broader range of prescribers.

When we talk to those CMI naive prescribers anecdotally, we're really hearing what you saw in that slide around differentiation. It really comes down to the REMS the dosing window, the dosing flexibility, the lack of DDI monitoring as part of the overall REMS program. And there are the reasons we hear from those generally from that CMI naive in terms of why initiation of the CMI at this point. Hopefully, that answers your question.

If you think about what may be auguring well with regard to a exceeding of expectations associated with prescribing down the road, it's going to be the number of prescriptions, repeat prescriptions coming from each of these segments and an expansion of the category. And I think Andrew commented on both of those in his scripted comments. We're especially encouraged to see the high-volume riders writing the number of prescriptions that they are, but also that 50% of the prescriptions are coming from folks who were otherwise new or low-volume prescribers, that suggests to me that we're seeing category expansion, as you should expect of us.

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

Apologies for any background noise. As you think about your commercialization efforts over the coming year, you'll be launching in symptomatic HCM frontline oHCM and then which is a lot of data is put in front of doctors. And as you think about your messaging, maybe clarify for us how you'll sort of think about all these opportunities and presented them to doctors as your sales force in the field. over the next year.

Yes. So maybe I'll ask both Fady and Steve to start because they're obviously on the forward edge of these studies and as they get reported, presented and published, the medical colleagues are already speaking to some of these things. And then Andrew and his commercial team pick up from there. So Fady, do you want to start and then Andrew afterwards?

Yes. I mean it really starts with dissemination of the data through the published literature. And Steve and his team have been strictly productive in terms of not just the primary publications, but secondary publications that expand on the initial findings. With that, our medical affairs team is regularly interacting with the most elite prescribers and physicians taking care of these HCM patients, bringing them the information, help them walk them through it and concise with complete matters.

And finally, through executing a number of educational programs either through CME or industry-sponsored symposia. So pretty complete program from the primary publications through to delivering the information through a variety of channels. And ultimately, our commercial colleagues we'll build on what gets into a label and be able to then also disseminate the information broadly to their customer base. So the question...

Sure, I can -- do you want to add Yes, sorry. Thanks, Matt. I can maybe just add to it from a commercial point of view, it's a great challenge in terms of having so much data in this period of time. When we think about Maple, Maple well we've done a lot of research on this as well. from a physician point of view, it broadens the horizon in terms of who they think an appropriate patient is for a CMI. So we'll certainly highlight that for a physician that's especially true for those low writers and the naive CMI writers meaning they haven't written before where they certainly feel like they have the appropriate patient when you consider them relative to a beta blocker.

Guidelines has certainly feel that more if that were to change in 2027, nHCM then really just broadens the spectrum of the number of patients, a physician and a cardiology office can have with a single agent in my MYQORZO if it's approved for nHCM to treat a broader range of patients. So we have our messaging cascaded. We have our visas, cascaded, et cetera, and I think we'll be ready to take well advantage of that further differentiation should those approvals come in from a regulatory point of view?

Paul, to your question, we aim to keep it simple. And what I especially am pleased to see is how we have great coordination across functions at Cytokinetics. You asked about publications and communications in the field. What I'll also point you to is the abundance of secondary manuscripts and other publications that build off of the primary manuscript. There's a plethora of information that's informing physicians about how best to think about aficamten, MYQORZO. And I do think that that's translated to awareness, significant education and pull-through in patient demand as is enabling of our commercial colleagues to do so well. So hats off to the medical colleagues who make it happen on the publication side and then the commercial folks can keep it simple when they are out there detailing physicians.

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

And congrats on all the progress. Maybe on the non, I'm sure just curious, as you started sort of the sNDA discussions, do you expect any sort of differences on the label or the REMS with the potential approval of nonobstructive? I appreciate any color you can share?

Yes. So it's premature to speak to that. Obviously, we haven't even submitted the sNDA nor had conversations with FDA following their review of a submitted NDA -- but I do expect that for what could be this being a separate trial, there will be some distinctions that will have to reflect nHCM versus oHCM, but maybe we shouldn't front run any of that until we have actually interacted with FDA following the submission.

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

Congrats on the quarter. Robert, can you just walk us through your expectations for the cohort 1 of how are you thinking about what you can learn from that cohort specifically about the safety profile as well as PK/PD?

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

Yes. So I mean I think as we've said before, is a, let's say, a dose-finding trial and to understand how the unique mechanism of ulacamten might play out in heft population. So we'll have initial PK. We'll be looking broadly across cardiographic parameters. Of course, we'll have safety. And we'll also understand the feasibility of enrolling a population focused to where we think the impact might be felt with a mechanism like a canton. So I think over the course of the study that will help inform the continued development of in this indication.

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

What percent of the OHCM market is penetrated by CMS today? And what do you anticipate a peak penetration could be for the class? .

So maybe I'll turn it to you, Andrew, for that, please?

So our guess is around 110,000 to 120,000 -- it's more than a guess based on the analytics we've done from an Epi point of view around that number is the eligible patient population, that's if diagnosis doesn't increase. There's probably in the 20,000 to 25,000 range of treated patients, so you get a penetration in around 20% range. Peak penetration, I think it will depend over time on access, demonstrated safety of REMS programs change, et cetera, but I would anticipate peak penetration in the 60% to 70% range.

Yes. So what Andrew is citing would suggest that we've got a long way to go still to see CMIs penetrate a majority of the patients who are diagnosed and eligible and there could be still others that could be diagnosed now that there's new medicines available to those patients. So this is the beginning of what hopefully will be penetration of MYQORZO into more and more of those patients. But assume we're closer to 20% of the total eligible today, and that number -- hopefully denominator grows.

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

I wanted to ask on comment, just given the pace of enrollment, how are you thinking about the timing of the interim, your expectations for that interim? And then ultimately, what would be clinically meaningful on comment?

Fady, please?

Yes. I mean the pace of enrollment in COMET has been pretty pleasing to us over the last few months, and we're, I would say, not providing specific guidance on when we think it will complete enrollment, but it will be into the beginning of 2027 for sure. The interim analysis has a pretty high bar to stop the trial on the basis of efficacy I wouldn't necessarily -- I mean my expectations for stopping at the end of an analysis are pretty low because it's a very minute bit of alpha that's spent there.

Clinically, we think anything trial was designed and we're always trying to do this, design a trial with a neuro patients you think, to demonstrate a minimally clinically beneficial effect and not overpower it to show de minimis effects, if you will. So this trial was powered what's that in mind, and I think it should be statistically significant around 0.87, 0.88 terms of the hazard ratio for the primary endpoint. But of course, I think when you looked at this treatment effect in GALACTIC, we saw more sizable treatment effects on that, and we hope to see that in comment emerge as well. I hope that addresses your question, Leo.

Our next question comes from the line of Ami Sahale with B. Riley Securities.

Congratulations on the quarter. This is Amin on for Mayank. I just had a question for Andrew, on the greater than 40% exit NBRx share. Can you talk about what gets you to 50 plus by the end of the year? Is that mostly the 300 high-volume docs going deeper? Or do you need kind of the rest of that Velocity group coming on? And then relatedly, when you put the full Acacia data up at what do you think that does to OHCM prescribing near term?

Andrew, do you want to take that? .

So in terms of what gets us there, it's not going to be any 1 segment that gets us there. It really is continuing utilization across all segments. The definition of a velocity account for us was 80% of the market. That is actually shifting in terms of who are the Velocity prescribers as compared to who they were when we launched. So our expectation is that on a physician-by-physician basis, especially the academic centers and centers of excellence where we certainly want to continue to grow share as we have been doing for the majority of them, but also getting on board the CMI-naive segment as well as a kind of a segment who hasn't really written much from a CMI.

Many of them were referring. And with nHCM, getting to your second question, obviously, it's not approved. We're not going to be promoting it or discussing it until it is approved. But the fact that it will be published in the public domain, our expectation, there probably will be some kind of overhang effect, if you will, in terms of increasing prescribing. When you have a third clinical trial, the obstructive HCM 2 trials with Sequoia in Maple and a third 1 with Acacia, the continuous safety evidence, efficacy is very reassuring to a physician as well. So I think all this collectively will have an effect on oHCM.

So we anticipate continuing to grow share over time. And as we've said all along, our aspiration is to have greater than 50% the share by the end of the year. We're certainly on our way to do that.

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

So if we draw on the CEMZYOS experience, how should we think about persistence as the treated base builds -- and could it look different from MYQORZO given that differentiated dosing and titration regimen? And also, if I could ask, any thoughts on seasonality or how we should frame quarterly cadence heading into 2027?

Do you want to take that?

Sure. So from a persistence point of view, I mean, our expectation is that we will be the same, if not slightly better from point of view, just given the profile of the drugs and some of the programs were put in place, but I think it's reasonable to assume they'd be similar, if not slightly improved for my core though. In terms of your second question was around -- can you repeat that part again? I'm not sure if I heard.

Yes. Just in regards to any thoughts on seasonality or how we should think or frame the quarterly cadence heading into 2017?

So I mean, I think it's -- we always see a lag right before right during a holiday week, there is flattening during the summertime. Physicians are on holiday or vacation as our patients. We see an uptick again in the fourth quarter. So the seasonality you'll see it's usually around holidays, which is a minor point, but it's more flattening during that summer time, especially in the months of July and August.

Our next question comes from the line of Yasmeen Rahimi with Piper Sandler Company. Yasmin, your line is open.

This is Dominic on for Yes. Just had a quick question on European launch. How are you envisioning that panning out especially as you continue to progress with U.S. launch and launches in other European countries, do you think that, that will be a driver for subsequent launches.

Yes. So maybe I'll start there and ask Andrew and also Sun maybe to comment. We're very committed to ensuring that MYQORZO is available to patients throughout Europe. Now with our focus on certain countries and in partnering discussions as relate to others, we believe we can make that happen. But at the same time, we're realistic about what moves the needle for the revenue line, and that's going to be more primarily, obviously, the U.S. business. With that said, we're off to a great start in Germany. And we are very pleased with how we got some initial traction there in terms of stocking towards really just the last few weeks of the quarter. And now we've got to ensure that we're going to be enabling a demand and pull through. Andrew, do you want to speak to expectations in Europe and relative to U.S.? And Sung, anything you want to add after that.

Yes, sure. So from a German point of view, it's early. We just launched in June data lags, but the data we've seen beyond the stocking is at, if not above our expectations from a German point of view. Other major markets, we're starting to get reimbursements in. We've talked about the England and Wells. We've talked about the Netherlands.

We have major markets launching probably one at the end of this year, several first half of next year. Europe takes more time to build up over -- from a revenue point of view, pricing is in the 10% to 20% range. So my expectation would be that Europe will be a contribution, but not a driver of growth. And over time, it will probably be in the 15% range of our overall revenue, but maybe Sung wants to add to that.

Yes. I think Andrew characterized the pace in Europe well. The launches are staggered as we go through the process in each country and the next likely country that we will launch in Q4 is the U.K., and we'll have subsequent launches into 2027 all the way to the end of the end of 2027.

We don't underestimate the challenges of going to market in the United States and also in multiple countries in Europe at the same time. But I do believe we're executing very well across all these geographies and setting the table for the kinds of things that matter to shareholders, including the top line growth.

Our next question comes from the line of with Truist. Your line is open.

Congratulations on the quarter. Given the launch curve that you're seeing now and PDUFA date for Maple in November, how are you expecting a potential approval to change this curve? Do you expect it to have an immediate effect? Or do you think it could take time for doctors to be more educated about Maple. And then just a quick follow-up on the doctors that are REMS-certified, it looks like about 1,400 of them are REMS-certified. Can you remind me what percentage of them have prescribed the drug and if you're seeing any bottlenecks going from certification to prescription?

Andrew, do you want to tackle those, please?

Sure. So from a -- I'll go backwards from a REMS certification point of view, the ratio is about a 30% ratio in terms of those are prescribed versus those who are certified from a REMS point of view. We continue to get REMS enrollment week after week. It certainly shows an intention to attention to for prescribed overall. Sometimes the certification occurs and prescribing occurs within the institution by another physician -- so it's a good indicator of future prescribing. And again, we're confident that, that growth is going to continue from broad-based prescribing. In terms of Maple, when Maple gets assuming maple gets added to the label, that certainly provides greater ability from a promotion point of view. Probably the 2 things that I discussed earlier that really Maple does is 1 is it paints a picture, especially for low to nonprescribers of appropriate patients for a CMI and it broadens or widens their mind in terms of who that appropriate patient is for.

The other thing it does is it certainly increases preference share and market growth. So there's kind of a multiplier factor there. If guidelines do get updated relative to Maple that certainly would -- as many physicians want to follow guidelines and understand guidelines. So that would be a further accelerator but obviously, that would take more time. So to answer your question specifically, I would expect that we would get some level of impact whether it will be noticeable right at launch or if it's going to take a bit of time, I would expect that it's probably going to take a bit of time more likely than this big bolus of prescribing change.

Our next question comes from the line of Eric Joseph with Citi.

Just wanted to actually follow up on this point about HCD or sorry, REM certified HCPs, given the growth that you saw this past quarter, can you just talk about sort of how that metric contracts with the number of REMS certified writers for and what does that metric look like fully baked?

Are you asking what -- how our REMS certification number compares to the KEMZYO certification number? Is that your question?

Yes, that and sort of what you anticipate the total number of potential REMS certified providers would be in the U.S.

Got it. So I can't comment on the KemZIOSREM certification number. I don't know that number. I don't need to know if that number is reported. I know BMS reported early in their launch, and it stops reporting it at some point in time. In terms of our expectation, so we sized our field force for around 11,000 prescribers. Those 11,000 prescribers are around 80% of the treaters of HCM. Meaning that the majority of them are obviously using beta blockers, calcium channel blockers. So we were going to where we thought the market would go with CMI penetration over time.

So with oHCM, if nHCM could get approved, our expectation is that prescribing base from around 3,000 in total today, will increase to probably in the 7,000 to 10,000 range. So over time, I would expect we'd have greater than 5,000 REM certifications, but we're happy, very happy with the pace. The pace is outpacing the number of prescribers, which is exactly where we want to be.

Talk about exceeding expectations. We're seeing those numbers track in terms of REMS-certified HCPs and how that's converting so promptly to new prescriptions prescribers, especially outside of Velocity accounts.

Our next question comes from the line of Yanan Zhu with Wells Fargo.

Great. And congrats on the quarter. Maybe a question on your FDA interaction for the filing of the nHCM indication. I was just curious, has there been any particular questions or focuses from the agency? And then a quick question on the pattern of the dose -- the final doses patients land on in a commercial setting? And how does -- whether that is similar or different compared with your clinical trial experience?

So I'll ask Fady to comment. But I caution you that it's not our practice to be speaking on a play-by-play basis with regard to ongoing FDA interactions. And then maybe Andrew and Steve can talk about the doses that we're seeing patients relative commercial to clinical?

Sure. I think we presented as we presented the data, the natural questions that anybody would have around reviewing product for potential approval in that indication include the clinical meaningfulness of the endpoints and the results, the safety that was observed, how we might deploy those things in understand the interplay of those with the patient population. I think those are some of the themes of our discussion without getting too granular. And I think we're well placed to be able to address any questions in those areas.

What I can say is we were pleased that there were no surprises. And then, Andrew, do you want to talk about the dose levels that people are achieving already commercially and then Steve can comment about that in the context of clinical research.

Yes, sure. So I mean we are seeing a broad range of dosing all the way up to the 20-milligram I think it's too early to tell exactly where the mix is going to wind up given the number of new patients. We continue to have the dosing window that the physicians and patients are taking advantage of that 2- to 8-week window -- so I think that, that certainly is something we're monitoring and trying to understand exactly where is dosing going to compare to clinical trials. Typically, what I've seen is dosing usually winds up slightly lower in terms of a percentage in clinical trials, but we'll certainly report on that number in the future. Steve, anything you want to add?

Well, I mean, nothing more than say the obvious that the clinical trial did show the preponderance of patients ended up on the 15 and 20-milligram doses, both in Maple SEO and the data that we published out of the forest experience. That gives an opportunity to underscore 1 of the things that we think is important regarding is that 1 can uptitrate and that's enabling of convenience and flexibility for physicians and patients to feel like they can be moving to that dose, which is most likely to be the best balance between efficacy and safety without having to compromise.

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

Maybe the first 1 for Andrew. In your slides, you mentioned about of the sentence marrow June high-volume interest Students are also can Hills users. So -- is there any indication at this point on whether these high-volume prescribers will continue using both products? Or eventually, they'll adopt just 1 -- and then secondly for Robert, was there any discussions in your FDA meeting about a potential priority review for the upcoming HCM sNDA .

Andrew, I'm not sure if you heard all of that question. Did you get it?

I think I got the essence of it at the very beginning of it was very broken up. Serge, thanks for the question. I don't anticipate the majority of the prescribers will go 100% 1 way or the other. There certainly are those that are advocates for 1 product or the other that prescribed that way. The vast majority will use both products over time. Our expectation is that use of micro is greater than that of CEMZYOS for most prescribers, hence, our aspiration in terms of greater than 50% share, but I'm not anticipating that we would have 100% share for the majority of prescribers or anywhere near that.

Your question about the FDA and reasonableness of a priority review. I don't think we'll comment again on any of our specific interactions with FDA -- but as we've stated publicly already, independent of any interactions with FDA, it's not unreasonable. It's reasonable to assume that the priority review might be possible. It's not a base case assumption. -- but it certainly would be great if that happens. And we'll see if we can't make that happen. .

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

Congrats on the quarter and appreciate you squeezing us in. Maybe as a follow-up, potentially the last question. You indicated, I think, that about 5% to 7% of MYQORZO dispenses are for those switching therapies. What are the primary factors driving those switches? And then among those transitioning from mevacamten sort of feedback are you getting regarding the maintenance of symptoms and gradient control? .

Yes. So obviously, there's nothing so systematic about that understanding that we can speak to it with any kind of robust fidelity. But there are anecdotes that we hear. Maybe, Steve, if you want to comment on what might motivate a physician who would switch from CEMZYOS to MYQORZO?

Sure. Before I get to that, I'll just point out that in Maple HCM prior exposure to mavacamten was allowed, and those participants had an expected therapeutic response to aficamten in that setting. Then to Robert's point, there are some pharmacologic benefits that we believe suits certain patients more and those are related, firstly, to the speed of onset and offset. So patients who may have specific indications where they may need to start and stop the drug with a rapid onset and offset. Those are patients who would naturally be selected for aficamten. Individuals who are -- as you might be aware, with the Kansas label, it's a black box warning with MYQORZO the other hand, certainly hasn't been studied but it isn't a black box warning based on our preclinical data. The drug-drug interaction is something that you're well aware of, patients who have had good experiences on therapies for things like gastroesophageal reflex disease may not necessarily want to switch medications in order to start a new medication for their hypertrophic cardiomyopathy. That would be another indication to preferentially use MYQORZO.

Maybe just indicating a bit on what Steve said. It is not fundamentally not our strategy to drive switches. We are observing that there are certain physicians who are asking questions about how to switch and some investigators have chosen to do a study that will inform that practice were that to be of interest. But as Andrew has spoken to prescribing and new prescriptions and share of new scripts, it's a modest percentage of the total that's driven by switches, and that's potentially something for which there was more of a bolus of that activity early on the launch.

And as we get deeper into the launch, we expect that, that may not continue to be a motivating factor for some of those physicians. So all in all, what we're focused on is those patients who are naive to CMI and where they may benefit from the addition of MYQORZO to their regimen. And that's where we're seeing the velocity. That's where we're seeing the growth. and that's where we see ultimately the potential and upside for MYQORZO. So thank you.

We have reached the end of our Q&A session. I will now turn the call back to Robert Blum, CEO, for closing remarks.

Thank you, operator. I want to thank the participants on the call today. I want to thank you for your continued support and interest in how we're doing here at Cytokinetics. I do believe that report here is a very positive one, reflecting on the things that we've indicated matter, that which speaks to how we go commercial and enabling a strong commercial launch momentum and velocity here initially in the United States and hopefully also as we're building the foundation in Europe.

And having that occur at the same time, we're enabling a better information to inform patient and market access and also preparing for what we hope will be an expanded label to include nHCM based on the Acacia data. I'll remind you that we're going to have several presentations, including hotline presentation at ESC later this month. And coming out of that, we'll also have an investor event that we look forward to communicating to you from Munich and at the same time, advancing our pipeline, that's a key tenet and hallmark of how we see our business growing over time for the benefit of patients, science and shareholders. With that, operator, we're going to bring this call to a conclusion, and we thank you very much for all of your time and attention today.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Thanks very much.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

I would now like to turn the call over to Diane Weiser, Cytokinetics Senior Vice President of Corporate Affairs. Please go ahead.

Good afternoon, and thanks for joining us on the call today. Robert Blum, President and Chief Executive Officer, will begin with an overview of the quarter and recent developments. Andrew Callos, EVP and Chief Commercial Officer, will discuss the commercial launch of the MYQORZO in the U.S. and readiness in Europe. Fady Malik, EVP of R&D, will address the results from ACACIA-HCM. Stuart Kupfer, SVP and Chief Medical Officer, will provide updates related to our ongoing clinical development programs. Sung Lee, EVP and Chief Financial Officer, will provide a financial overview for the quarter. And finally, Robert will make closing remarks and review key milestones for the year ahead.

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

And now I will turn the call over to Robert.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Please note that portions of the following discussion, including our responses to questions, contain statements that relate to future events and performance rather than historical facts and constitute forward-looking statements. These include, without limitation, statements regarding expectations, regarding regulatory interactions and the potential for regulatory approval, expectations regarding commercial performance and statements about our financial guidance and capital allocation. Our actual results might differ materially from those projected in these forward-looking statements.

Additional information concerning factors that could cause our actual results to differ materially from those in these forward-looking statements is contained in our SEC filings, including our current report regarding our first quarter 2026 financial results filed on Form 8-K that will be furnished to the SEC today. We undertake no obligation to update any forward-looking statements after this call. Please note that slides accompanying today's discussion are available for download within the webcast and on our website.

And now I will turn the call over to Robert.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

[Operator Instructions]

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

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

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

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

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

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

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

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

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

Makes sense.

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

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

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

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

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

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

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

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

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

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

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

Fady, do you want to take the first question?

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

You want want to take that, Stuart?

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

I'll ask Steve to answer that question. .

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Your final question comes from Yanan Zhu with Wells Fargo.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

I would now like to turn the call over to Diane Weiser, Cytokinetics' Senior Vice President of Corporate Affairs. Please go ahead.

Good afternoon, and thanks for joining us on the call today. Robert Blum, President and Chief Executive Officer, will begin with an overview of the quarter and recent developments. Andrew Callos, EVP and Chief Commercial Officer, will discuss the commercial launch of Myqorzo in the U.S. and readiness in Europe. Fady Malik, EVP of R&D; and Stuart Kupfer, SVP and Chief Medical Officer, will provide updates related to our clinical development programs; Sung Lee, EVP and Chief Financial Officer, will provide a financial overview of 2025 and discuss our 2026 financial guidance. And finally, Robert will then make closing remarks and review key milestones for the year ahead.

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

Our actual results might differ materially from those projected in these forward-looking statements. Additional information concerning factors that could cause our actual results to differ materially from those in these forward-looking statements is contained in our SEC filings, including our current report regarding our fourth quarter 2025 financial results filed on Form 8-K that was furnished to the SEC today and our annual report to be filed on Form 10-K in the coming days. We undertake no obligation to update any forward-looking statements after this call.

And now I will turn the call over to Robert.

Thank you, Diane, and thanks to all for joining us on the call today. The fourth quarter of 2025 marked a defining moment for Cytokinetics with the FDA approval of Myqorzo for the treatment of adults with symptomatic obstructive HCM, the first medicine we've advanced from discovery to commercialization. In fact, in the span of a single week Cytokinetics received approvals for Myqorzo in both the U.S. and China, plus a positive opinion from CHMP for Myqorzo in the European Union. That latter milestone preceding last week's announcement of the European Commission's approval of Myqorzo in the EU.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Andrew, do you want to take that?

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

But also like just -- sorry.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Andrew?

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

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

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

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

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

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

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

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

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

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

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

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

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

Thank you. Andrew?

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

[Presentation]

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

At this time, I would like to turn the call over to Diane Weiser, Cytokinetics' Senior Vice President of Corporate Affairs. Please go ahead.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Our next question will come from Gena Wang with Barclays.

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

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

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

Your next question will come from Tess Romero with JPMorgan.

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

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

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

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

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

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

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

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

So do you want me to answer that, Robert?

Yes, please.

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

Our next question will come from Salim Syed with Mizuho.

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

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

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

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

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

Congrats again.

Thank you, Salim.

Our next question will come from Cory Kasimov with Evercore.

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

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

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

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

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

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

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

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

Your next question will come from Kripa Devarakonda with Truist.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Yes, that's exactly right. Yes.

Your first question?

Yes.

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

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

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

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

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

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

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

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

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

Got it. Congrats again.

Thank you.

Thank you.

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

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

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

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

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

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

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

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

Congratulations again.

Thank you.

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

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

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

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

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

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

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

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

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

Andrew, anything you want to comment on specifically?

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

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

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

Yes. Thank you.

Your next question will come from Ashwani Verma with UBS.

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

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

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

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

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

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

Andrew, do you want to take that?

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

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

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

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

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

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

It does.

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

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

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

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

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

I would now like to turn the call over to Diane Weiser, Cytokinetics Senior Vice President of Corporate Affairs. Please go ahead.

Good afternoon, and thanks for joining us on the call today. Robert Blum, President and Chief Executive Officer, will begin with an overview of the quarter and recent developments. Andrew Callos, EVP and Chief Commercial Officer, will address commercial readiness activities for aficamten. Fady Malik, EVP of R&D, will provide updates related to the clinical development program and medical affairs activities for aficamten. Stuart Kupfer, SVP and Chief Medical Officer, will provide updates on the clinical development program for omecamtiv mecarbil and ulacamten. Sung Lee, EVP and Chief Financial Officer, will provide a financial overview of the past quarter. And finally, Robert will provide closing comments and review our expected key milestones for the remainder of 2025.

Please note that portions of the following discussion, including our responses to questions, contain statements that relate to future events and performance rather than historical facts and constitute forward-looking statements. Our actual results might differ materially from those projected in these forward-looking statements.

Additional information concerning factors that could cause our actual results to differ materially from those in these forward-looking statements is contained in our SEC filings, including our current report regarding our third quarter 2025 financial results filed on Form 8-K that was furnished to the SEC today. We undertake no obligation to update any forward-looking statements after this call.

Now I will turn the call over to Robert.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Turning to our financial guidance. We are narrowing our full year 2025 GAAP operating expense range to $680 million to $700 million from the previous range of $670 million to $710 million. Stock-based compensation that is included in GAAP operating expense is expected to be between $110 million and $120 million. Excluding stock-based compensation from GAAP operating expense results in a range of $560 million to $590 million.

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

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

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

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

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

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

With that, I'll recap our upcoming milestones. For aficamten, we expect to advance NDA review activities with FDA to support the potential U.S. approval of aficamten by the end of the year. We expect to advance go-to-market strategies and continue launch preparations for aficamten in the United States. We expect to continue go-to-market planning in Germany and expand commercial readiness activities in Europe in 2025 and in preparation for potential approval of aficamten by the EMA in the first half of 2026.

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

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

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

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

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

I'll ask Fady to respond to that.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Andrew?

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

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

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

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

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

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

Moving on, we'll hear from Cory Kasimov at Evercore.

So I want to go back to the pending launch. And I'm curious, do you anticipate the implementation of another REMS program at these HCM clinics where they're already prescribing mavacamten is going to be a barrier that we should expect to kind of slow down the cadence of launch in the early days? Or is the process of registering centers relatively straightforward at this point?

So I'll ask Andrew to comment. I might just start by saying we're respectful of the fact that there are existing workflows that have already been adapted. And as Andrew has already highlighted, it's our goal to be enabling a REMS program and implementation that should create for a more flexible and easy experience for physicians, patients and pharmacists within established workflows.

Maybe Andrew can elaborate.

Yes, it's a good question. There's a lot of centers that physicians who are writing today. So part of the goal would be for a differentiated REMS program alongside MAPLE, alongside SEQUOIA to these get more over the line, so to speak, to prescribing. So that would be new workflow for them. Those who have existing workflow.

The workflow in the office really is around echo for titration and monitoring. That is similar. So you're going to have echo monitoring potentially with, say, a different frequency or the ability to titrate up at each point of monitoring. So it's the same kind of workflow, if you will. So we're not anticipating that the workflow around monitoring or the window for monitoring will cause must act, especially among high users and high centers. So we are expecting that a differentiated REMS, the differentiated label and an overall profile will drive differentiated use when physicians certainly understand that. So that's the way we've been thinking about it.

Next, we'll hear from Tess Romero at JPMorgan.

This is Caroline Poacher on for Tess Romero with JPMorgan. Just one from us on aficamten and oHCM. So acknowledging that the late cycle meeting took place on September 15, can you just comment on if the REMS has been finalized yet at this point in the review process? And if not, what are the remaining items of the REMS that need to be finalized? And when would you expect this to be completed?

So we're continuing with interactions with FDA, and we have not finalized those matters. We do anticipate that we're making progress towards enablement of finalization of those in order to meet the PDUFA date. With that said, we've had exchanges and interactions -- and as I've indicated previously, we don't believe that we're engaging around framework, but rather some operational details, things that speak more to things like web pages and that which is administrative. Those are things that we think should come together to be enabling of FDA to review this and hopefully approve it in time for the PDUFA date.