Excited to be joined next at the Citizens Life Science Conference by Cytokinetics. Cytokinetics is a specialty cardiology company with a focus on muscle biology. Really exciting time for the company with Aficamten, PDUFA date just several months away now. Obviously, lots of discussion over the last week about the PDUFA extension, so we'll jump into that. Robert and team, just welcome, and maybe I'll just ask you to give a couple of introductory comments.
Thank you. Thanks to Jason, thanks to Citizens for inviting Cytokinetics to provide this update. We may be making some forward-looking statements, so we'll just refer you to our recently filed 10-Q, and we don't undertake an obligation to update those statements. We are in the midst of a very exciting time. As we elaborated on our earnings call yesterday, lots going on at the company, and I'm joined by Fady, who oversees R&D, Andrew, who oversees our commercial organization, and under each of their supervision, many work streams in support of our Vision 2030, starting with our move towards a potential approval for Aficamten in patients with OHCM, as we're hoping for and expecting as could occur by the end of this year. PDUFA date, December 26th this year.
That's based on a study called Sequoia-HCM, and together with its open-label extension called Forest-HCM, we've seen some very significant, clinically meaningful effects of Aficamten overlaid to standard of care for patients with OHCM. Those effects were both on primary and secondary endpoints, and Fady can elaborate on those specifics. We do believe that Aficamten represents some major innovations for patients with OHCM, and that may hopefully be complemented by results from another study called Maple-HCM that's due to read out this month. Maple-HCM and Sequoia-HCM, together with Forest-HCM, we believe sets the table nicely for what could be a new medicine for patients with OHCM. OHCM represents roughly half of HCM, the other half being non-obstructive HCM.
Yesterday we announced an accelerated completion of enrollment of a study called Acacia that's going to read out in the first half of next year in patients with NHCM. Consider those two bookends as could be enabling of Aficamten to be a breakthrough medicine if approved for patients with HCM. Aficamten represents the first of three legs of a stool for our specialty cardiology franchise, the other two being a compound called Omecamtiv Mecarbil, being studied in patients with heart failure and reduced ejection fraction, another compound called CK-586, heart failure with preserved ejection fraction, and those three together form the cornerstone of a business that we're building under Andrew's supervision for what could be go-to-market activities in North America and Europe, for an enduring business in specialty cardiology. We can talk about all of those matters as you may have interest.
Great. Thank you, Robert. Maybe start with the obvious point, the PDUFA extension in the background there. I think one thing that may be obvious, may be lost in the mist here a little bit, is you've had a lot of interactions with FDA, including through the NDA review, including the mid-cycle review meeting. There does not seem to be any pushbacks or major objections or major questions coming out of FDA when it comes in regards to the data that you've submitted and the potential for approval. Can we just maybe start with that focus? Is that the right way to think about this, that, you know, the FDA is not pushing back or does not have strong questions around the Sequoia results?
Correct. On top of that, I'll say we've engaged at very senior levels of FDA, both within the division of cardiology and nephrology, as well as the division that oversees risk mitigation and REMS. They've been present and active in multiple meetings. We had, as we elaborated on our earnings call yesterday, three meetings prior to submitting the NDA between the time we had the Sequoia results and the time we submitted the NDA, and it was accepted for filing, three meetings. We've had interactions since then, both a mid-cycle meeting as well as many other interactions where FDA has asked questions, we've answered them, asked for analyses, we've provided them. There are ongoing inspections and other activities, as you would expect, would be aligned to what could be a regulatory process proceeding as planned, as intended, and as we hope will lead to a potential approval.
All those things suggest that FDA is proceeding in the review as one would expect.
Look, people can go back and listen to the earnings call yesterday for all the details. I think what matters now is where we're at today and what we're thinking about in the future. I think what hasn't changed is that investors were widely expecting you to have a REMS and one that had a potential to be differentiated from Kamzyos, the first-in-class cardiac myosin inhibitor. I know you don't want to give details about the REMS that you've proposed to FDA, so maybe I'll ask it a different way. Can you talk a little bit about where you see the opportunity based on the Kamzyos REMS today and the update, where you see the opportunities to differentiate?
Maybe I'll ask my colleagues, Fady and Andrew, to speak to that because they come at it from different optics. Fady from the standpoint of evidence generated in our clinical studies, but also as was originally intended in the design of Aficamten and has been elaborated preclinically and clinically. Then maybe Andrew from the standpoint of what we know in market research, and where the touch points are for potential distinction or differentiation.
Yeah, when we designed Aficamten, one of the goals was to simplify dosing of the drug in a way that allowed people to rapidly escalate dose, achieve symptom relief in a relatively short period of time, as well as to have confidence that if they exceeded the target dose, that if they lowered the dose, patients would, you know, that the effect would, you know, subside in a relatively short period of time. We demonstrated that through phase two and phase three studies, a fairly straightforward way of escalating the drug, simple, you know, similar to any other titrated drug that people use, guided by echocardiography in this case.
And, importantly, you know, if you do exceed the threshold for ejection fraction, you know, rather than discontinue the drug and wait for it to wear off, you just merely drop the dose and continue on the lower dose that you previously tolerated. You know, that's been successful in Sequoia, that strategy is successful in Forest when the physicians were actually guiding dosing, and it's essentially the same strategy we're using in Maple and Acacia. The other things, you know, have to do with the profile of the drug as it relates to drug-drug interactions. We're very careful about how we designed Aficamten in that regard. We don't expect any common clinically meaningful drug-drug interactions to be an issue. The predictability, you know, I think gives confidence as you escalate that patients will have a predictable response.
and I think that also, you know, gives one confidence in terms of maximizing dose so that you maximize efficacy instead of, you know, treating patients potentially on suboptimal doses. So all of those things were part of how we designed the molecule and then generate the clinical evidence supporting those points.
From a commercial point of view, I guess ultimately it'll depend on our label and the REMS, that final. From a differentiation, there's differentiation in efficacy, safety, as well as the REMS we've submitted. I'm not going to get into the details of it, but if you think of the clinical trial and the properties of Aficamten in terms of speed of onset, the ability to titrate immediately, drug-to-drug interactions, and you have to disrupt existing therapies that patients are on, when you get below an EF of 50%, as Fady had described, downward dosing as compared to interruption of therapy, the ability to start at the lowest dose and then titrate up very quickly. When we do testing, with efficacy, it always starts with efficacy, safety, and REMS.
We're hearing from physicians that these products are differentiated from their point of view. The second thing is Maple further differentiates. Maple should help us expand into general cardiology as well as a differentiated REMS. It won't be all of cardiology. Right now you have about 1,000 that are writing, maybe 600 that are 80% of the market. If we can get that 1,000 into 2,000 or 3,000, that's meaningful. Thirdly, while we're in launch mode, if Acacia reads out positively, now you have Sequoia with a launch, if Maple's positive with Acacia, that's really going to get a lot of momentum as well as kind of a halo effect. To your first comment about moving back PDUFA three months, we would have been launching at the end of October by the time you've implemented the REMS and get supply in.
You're launching during the November-December holiday period, which is not the easiest time to launch. We would have certainly liked to have launched in September or got approved in September. If we do get approved in December, then I think we're off to the races right away without holidays and that kind of interruption from building momentum. Right.
As much as three months is a long time, it's not really a long time at all. Can you just talk, Andrew, about the work you're doing this year and to what extent anything has changed? Obviously, the Salesforce hires get shifted back a few months, but anything else in terms of your approach to the launch that changes because of the PDUFA extension?
Sure. We don't really change a lot, to be honest.
I mean, I think when you look at just OpEx, there's things like media, Salesforce spend, launch meetings, et cetera, that push OpEx out to next year. We do have that. When you actually look at launch activities within, I mean, we're very buttoned up in terms of all the things that have to happen in launch. Within 24 hours, we were able to turn around an entirely new launch plan, with supply, with REMS, with websites, with digital, with Salesforce. We're not changing our Salesforce recruiting process or timeline because we've built good momentum. Again, there's holidays in there. We have over 4,000 recruits right now for, you know, about 125-150 positions. The vast majority, because of all the layoffs that have occurred in pharma, are cardiovascular reps, over 90%. On average, have more than 10 years' experience. That translates to relationships.
They know cardiology. They can get into offices. But we're not really changing. I think it gives us a little more time to test things, to integrate. Patient experience is really important. There's a lot that happens on the back end, if you will. It's a complex process to integrate copay and patient assistance and free goods and medical exception and nurse navigators. So there's a lot to coordinate. I think that gives us a little more time to test and make sure that kind of de-risking the launch and that patient experience even more. But, you know, three months doesn't really change a lot for us.
Yep. Okay. Maybe we move on to the Maple study. It's relatively infrequent to see a head-to-head study versus standard of care at all for a drug, let alone this early in the drug's life cycle.
Can you speak to what drove you to run that study? What gives you confidence that you'll see a monotherapy benefit, in Maple?
I'll start and then maybe ask Fady to elaborate. We've taken to describing this hopefully as would be an unfair fight. We'll find out soon enough. We designed Maple already knowing that in Sequoia, patients on or not on beta blockers similarly saw effects that were clinically relevant in terms of increases in exercise stamina. As they then rolled into the open label extension, their cardiologists were increasingly comfortable taking them off of standard of care beta blockers. We designed what would otherwise be more likely a phase four study comparing Aficamten alone to beta blocker on an endpoint where beta blockers do not really have any evidence to support its use. Maybe with that, I'll turn to Fady.
Yeah, I think as Robert said, in the open label extension, there was a opportunity to withdraw background therapy. Importantly, when people did that, we essentially saw the efficacy did not change, which implies that background therapy was not really doing very much. You know, there is a lot of evidence that beta blockers reduce exercise performance. They have a lot of side effects, not well tolerated in some people. They are very entrenched as a standard of care in this disease, and they are obviously generic and widely available. We felt that for Aficamten and the mechanism, which is potentially disease modifying, in order to elevate it into the standard of care as opposed to being, you know, the drug of last resort, we needed to generate evidence against, direct evidence against, a beta blocker like metoprolol. We designed and conducted Maple.
and it won't only provide, you know, comparative data with regards to exercise and symptoms, but it will also look at what happens to cardiac function structure. What are the relative differences between gradient reductions or between the regression of cardiac hypertrophy, which is a disease modifying effect. We hope to show that, you know, fundamentally a mechanism that addresses the root cause of disease is disease modifying. Beta blockers are not, and then further distinguish them and, you know, ultimately change the standard of care.
Great. And then just very quickly, how should we think about defining success here? What kind of magnitude of benefit do we, do we need to see?
You know, I think it's more complicated than that because it's both just efficacy, but also safety and tolerability. You know, so we'd like to see, you know, the trial was powered to see a 2.0 increase, a pretty sizable difference in terms of peak VO2, because a small difference probably isn't going to win the day. Probably it'll, it would still be positive down to about 1.5 or so, maybe even a little bit less. That's kind of the range we think is meaningful. The other aspect is also going to be safety. How many patients discontinue the drug? We know that with Aficamten, almost nobody discontinues the drug. How does that compare to beta blockers? How does the relative tolerability compare, and all those things?
Great. Another important announcement last night, Robert, as you mentioned, was Acacia-HCM and completing enrollment almost six months ahead of schedule. Can you just speak to what you think drove such a rapid enrollment into that study?
Yeah, before I do, and I'll ask Fady, I think this is a big deal. I think the fact that we were able to bring in Acacia in terms of rapid enrollment and even over-enroll it a bit is a big deal for the fact that within about a year, we should see results for Aficamten in NHCM. From a current value standpoint, I think that eclipses what may be the effect of a three-month delay of OHCM, especially in light of the fact that Aficamten, if positive in Acacia and approved in NHCM, may be the first cardiac myosin inhibitor to get that approval in a population that's growing faster, NHCM growing faster than OHCM and representing at least half the total market opportunity. I think that's a considerable, new development here that hopefully drives investor interest as well.
Maybe to answer your question, I'll turn to Fady to elaborate.
You know, what drove enrollment, I think, is the investigators having a lot of enthusiasm for the mechanism of action, collaboration with our clinical team that works very closely with them. You know, they together identified sites that had patients whose investigators were invested in the mechanism of action. You know, generally trials increase enrollment when investigators perceive some potential benefit to their patients. We hope that that's reflective of this. We saw really enrollment take off broadly globally as, in what was during a holiday period, you know, generally at the end of last year when things tend to slow down. It caught us a little bit by surprise, and it was sustained throughout the last quarter of 2024 and into the first quarter of 2025.
As I explained yesterday, it enabled us to revise how we analyze the study, and I think give us greater, you know, power to hit on now two endpoints.
Robert, you mentioned that, if the study's positive, Aficamten could be the first approved CMI for non-obstructive HCM. We saw a few weeks ago negative results for mavacamten in the same indication, the Odyssey study. What gives you the confidence still that Aficamten is going to work in non-obstructive HCM?
Yeah, we were disappointed to see the results of Odyssey as we hoped, for mavacamten that would represent a win in NHCM. What gives us confidence, in light of that? We look at our Redwood cohort four data as we're encouraging of moving from phase two to phase three as supportive of our optimism. Moreover, the size of that study, the duration of that study, we believe reads well, augers positively for what we should expect in phase three, especially in light of the fact that we're taking the same dosing regimen into phase three that has already shown positive effects in Sequoia and Forest, as well as in Redwood. We are going into centers that already have experience with Aficamten. We're not increasing the number of centers beyond what already we believe should be seasoned in their use of a cardiac myosin inhibitor, in a population such as this.
There are other things that, we think in the design and conduct of Acacia-HCM give us reasons to be optimistic. I'll ask Fady if he wants to add anything else.
Yeah, I think, phase two experience we had was, was really quite positive. We treated 40 patients, in part in an open label fashion, in part to ensure that we could best understand how to dose the drug. You know, in NHCM, you don't have the same guardrail as to when to stop dosing as you do in OHCM with the gradients. We found, you know, that Aficamten was well tolerated up to the highest dose, 15 milligrams. About 85% of the patients got there. Symptom improvements that, you know, were generally much larger than you'd expect from placebo, biomarker response, echo improvements in terms of diastolic function. All of those things in isolation bode well for testing the drug in phase three and enabling the design of the phase three trial, which took advantage of that.
We were able to implement the same dosing scheme in phase three, you know, with fairly good confidence. It's well tolerated. We were able to refine the entry criteria a bit to, to look to maximize, if you will, a treatment effect. We were again very careful about sites that we selected, places we went to, people we engaged with that were real HCM experts. We have our own HCM experts at the company that validated, you know, literally every patient as they entered the trial.
The other thing to note is there's those 40, approximately 40 patients from Redwood cohort four roll into Forest in the open label extension, and that enables us a real-time assessment of how they're doing on an ongoing basis in Forest, and they continue to thrive.
I just want to squeeze in one more here as we think about the broader opportunity set, and that's on CK-586 in heart failure with preserved ejection fraction. You also updated last night that you'll be completing enrollment in the first two cohorts later this year. As we think about, you know, the context of the Acacia-HCM data, you know, roughly 12 months from now, how should we think about the read-through to HFpEF and our confidence there?
This is the beauty of the business model that we set about building quite some time ago. Each of these programs and studies reads and informs on validation for the next. Yes, what we're learning in NHCM, we think has direct relevance to this mechanism in half-path, albeit a subset of patients of half-path. Fady can speak to that.
You know, I think some of the audience know heart failure with preserved ejection fraction is a pretty heterogeneous condition. Some of it is due to obesity and has been addressed very nicely by some of the GLP-1s. Before the obesity epidemic 20-25 years ago, half-path was really marked by people that had normal body weights, normal habitus, hypercontractile cardiac function, and symptoms of heart failure, which is why it was such a puzzling disease. The heart looks like it's working well when you look at it, but they have all the symptoms of heart failure. In many ways, they mimic what an NHCM patient looks like, a heart that looks like it's hyperdynamic, no other real medical issues.
We've designed a study that focuses on a population of high ejection fraction, you know, elevated biomarkers, symptoms of heart failure, and other metrics that help us hopefully recreate that NHCM model, patient model in this adjacent population and see if we are directionally similar with 586.
Great. Fantastic. Robert, Fady, Andrew, really appreciate you being with us this morning and, exciting few months ahead as usual with Cytokinetics.
Thank you.