Welcome, everyone, to the 42nd annual JP Morgan Healthcare Conference. My name is Tess Romero, and I am one of the Senior Biotech Analysts here at JP Morgan. I'm pleased to welcome Cytokinetics as our first presenting company of the conference, and speaking on behalf of the company, we have CEO Robert Blum. Robert, over to you.
Thank you, and thank you for allowing Cytokinetics to present here an update on recent activities and our forward-looking statements and forward-looking views to the company in 2024. I will be making some forward-looking statements. I'll refer you to our SEC filings with regard to caveats to those statements, and we don't undertake any obligation to update with regard to those statements. So as you may know, Cytokinetics has been on a mission, on a mission for now over 25 years, to discover and develop new medicines that read on muscle biology, and in particular, as relate to health span of people suffering from devastated conditions, primarily as pertains to cardiovascular and neuromuscular diseases of impaired muscle function and weakness.
We laid out a few years ago a vision, a vision for what we would accomplish between then and the year 2025, and I would suggest that we're well on our way to executing on this ambitious mission. We expect to achieve regulatory approvals for at least one, if not two, of our new medicines by that year. At the same time, we're building out our commercial business for readiness and to execute on thoughtful, deliberate go-to-market strategies, both in North America and Europe. At the same time, generating sustainable and durable engine for new discovery and innovation as we expect to double our development pipeline, and at the same time, doing things the right way.
Doing things as consistent with our purpose, our values, being that company that's very patient-centric and driving patient access, and for the benefit of being a company that others would want to partner with, as well as join. All that we do from the very beginning, as we committed to muscle biology, is rooted in this biological structure, a structure called the sarcomere. This is the fundamental unit of muscle contractility and mechanics, and it is the cornerstone of our research and development as we have been on a crusade to identify, develop, characterize, optimize, and advance new drug candidates that are small molecule modulators of this structure, either to augment or suppress cardiac muscle performance for the benefit of patients. That has produced a pipeline, a pipeline depicted on this slide, that's divided into two areas: cardiac muscle and skeletal muscle.
As you can see, advanced amongst those are two phase III compounds in particular. Today, we're going to spend time talking about aficamten. Aficamten was recently the subject of a positive phase III clinical trial called SEQUOIA. Those results recently top-lined. I'll highlight them a bit today, but also, as you can see, aficamten represents a pipeline in a pill. At the same time, we're advancing also omecamtiv, as well as other compounds directed to cardiac muscle. Aficamten is a cardiac myosin inhibitor, omecamtiv, a cardiac myosin activator, and you'll learn a bit more about the biology of this pipeline here in a minute. We're building a unique, somewhat unusual company in that we are focused to a segment referred to as specialty cardiology.
Specialty cardiology doesn't exist previously in the biopharma space, we would argue, because the other biopharma companies dedicated to cardiovascular medicines are primarily focused to indications that don't bear certain advantages, we would argue, as do specialty cardiology opportunities. Aficamten is directed to oHCM, but also nHCM, and there are multiple indications that we'll be able to address over time. But at the same time, CK-586 borrows from aficamten in terms of mechanism of action, slightly different, but directed to the same molecular target. And CK-586 moves to what we would argue is an indication very much largely underserved, which is heart failure with preserved ejection fraction. And you can see omecamtiv 136, these are other compounds that also derive from the same biology and opportunities for us to make a big impact in specialty cardiology care.
So now I'll drill down a bit more on these opportunities, primarily with focus to aficamten, our next-in-class cardiac myosin inhibitor. We're developing it for hypertrophic cardiomyopathy. This is an indication characterized by hyperactive contractility, where because primarily of genetic mutations in the sarcomere, these patients develop a worsening of their cardiac performance. The indication is rooted in patients who have shortness of breath, inability to exercise. Ultimately, these are patients who suffer the risk of sudden death and live with a high symptom burden. The prevalence of this disease, tied to a mutation in the sarcomere, is growing, especially now with more awareness and new pharmacotherapies, and you can see it represents a large market opportunity.
In the United States, in particular, one that's growing faster than the population growth, and where the diagnosed population is somewhere in the range of 200-300 thousand, but the prevalent population is significantly higher. With the advent of new medicines, we expect this to be a large cardiovascular market opportunity, but as you'll hear, one that's very concentrated from the standpoint of the customer base. With aficamten inhibiting cardiac myosin and thereby enabling of a relaxation of the superventricular hypercardiac situation, the goal is here ultimately to suppress cardiac contractility and reduce pressure gradients and other things that contribute to symptoms and clinical burden. Aficamten is a next-in-class cardiac myosin inhibitor. It follows behind a first-in-class compound that we played a hand in the discovery.
We know a lot about it, and we designed aficamten with an aspirational profile to address these opportunities that we believe a next-in-class therapeutic should address. As you can see, they relate in large part to things like convenience, safety, predictability, onset, offset, and other things that actually, actually factor into physician choice. SEQUOIA was designed ultimately to be the pivotal study to read on that possibility. SEQUOIA, a study of 24 weeks of patients randomized 1 to 1, aficamten to placebo standard of care, and we enrolled 282 patients all around the globe. We monitored them closely, and we assessed a primary efficacy endpoint of change in peak VO2, a measure of exercise capacity and endurance. We also looked at 10 other pre-specified endpoints, secondary endpoints, looking at patient function, quality of life, and symptom burden, and other things as well as you'll see.
These results came to us late last year. We announced them by top-line press release at the end of December, and the study was positive. I'll now elaborate a little bit more on the data and speak to that which was already presented in our press release, and we'll be able to hopefully elaborate much, much more when we have full data presentation in second quarter. Here are the baseline demographics from SEQUOIA. These have been already presented, but you can see that these are patient characteristics typifying the diversity, but also what is ultimately defining of the marketplace for a myosin inhibitor. These are patients with high symptom burden despite being on standard of care. You can see age, weight, sex, geography, and other things. In particular, I'll highlight the fact that we enrolled patients both on and off beta blockers.
The results, as I mentioned, were presented by press release, and here they are in a simple slide. These are results that underscore this was a very positive study, one that met with best case scenario and high expectations, and for which we're very, very proud that our science has so nicely translated into patient effects and benefit. We hit on the primary endpoint with a clinically meaningful effect of 1.74. This is a measure of increased exercise capacity around which we believe this is suggestive of a significant effect that will be compelling to physicians. But also we hit on all of the pre-specified subgroups within that primary efficacy endpoint. The homogeneity of the effect, especially patients on and off beta blockers, as you'll see, is important.
We also hit on all 10 of our pre-specified secondary endpoints with high statistical significance, as you'll see in a moment. We saw, in particular, with regard to those improvements in symptoms. From a safety standpoint, this also met with high expectations and best-case scenario. We saw that serious AEs actually leaned in favor of placebo. Numerically, we saw a balance in total AEs, and we saw a low incidence of ejection fractions falling below 50, a measure of increased concern were that to be a larger number or even lower numbers of EF. We saw that none of those resulted in treatment interruption, nor did they lead to coincident heart failure symptoms. This is a very important slide.
It highlights what was in the press release already, but you can get a sense of how pristine these data are, consistent across every one of the pre-specified secondary endpoints, highly statistically significant in each and every one of those instances. I've been in this business for over 40 years. It's been a gratifying and long journey, but I've never seen data as compelling as this and that reads so compellingly on potential patient benefit…. What's so nice, especially, is those results from SEQUOIA also marry very nicely with the ongoing data we're seeing from FOREST, which is the open label extension of our phase II study. And what we've reported as of this cutoff date, September, and as we'll be reporting more updates in 2024, we're seeing durable, enduring effects on reductions in gradient while maintaining ejection fraction.
We're seeing improvements in KCCQ and NYHA Class, reflective of improvement relative to symptom burden. And we're seeing that patients who are coming in eligible for treatments, surgical treatments, are no longer eligible because they're receiving this pharmacotherapy. What we're also seeing is despite doing so many echos to be especially overzealous and diligent in understanding potential effects on echo parameters over a long period of time, none of these, for the most part, with a couple of exception, are having any effect to clinical changes, where a physician may choose to simply down titrate based on a lower EF. We think this will translate well into a potential for a lesser REMS program, ultimately for aficamten. So what are we doing now? With these data in hand, we're preparing for FDA interactions as urgently as we can.
We've already scheduled two meetings in February, one to review top-line results, the other, to ready for an NDA submission. Similar interactions with EMA, and we're already leveraging the preparedness from 2023, anticipating this scenario where we did much of the heavy lifting to be enabling of a regulatory submission, not just in the U.S., but counterpart submissions all over the world in the second half of 2024. And at the same time, continuing to advance the science. Aficamten is the subject of two other phase III studies currently underway. This is MAPLE. It's a study similar in duration, a lower number of patients, and here we're asking the question: How does aficamten compare to beta blockers? Beta blockers are used first line in these patients, and because they limit heart rate, they're thought necessarily they could be limiting to exercise duration.
So we want to ask the head-to-head question, should aficamten, in fact, be used even in front of beta blockers in this population? We should have the answer to that question from the trial readout in 2025. We hope concurrent with when we might expect to go to market initially with aficamten. So we think that could be meaningfully informative to guidelines. We're also looking at aficamten in context of nHCM, patients who don't necessarily have the same, gradients or symptom burden, but they still have wall thickening, they still have risk associated with their diagnosis, and this population is deserving of these types of advancements and innovations as well. A lot that we learned from SEQUOIA reads positively on what we expect to see in this study, ACACIA.
Both MAPLE and ACACIA seem to be already benefiting from a boost in screening and enrollment because of the results of SEQUOIA. So we're looking commercially at a population that's growing, a population that's layered based on both o and nHCM, and one where we think there's large commercial market potential. You can see the numbers on this slide. But importantly to my earlier points, it's concentrated. From a sales and marketing standpoint, it's within reach of a company like ours, with more limited access to capital and not wanting to put in place a very large sales and marketing infrastructure.
In fact, we see this as one where a sales organization of roughly 100-150 people focusing for those 10,000 cardiologists in the United States who treat a majority of these patients, we think that can be producing a high return on investment, high return on sales, high reward for all of our stakeholders. We're already underway in building out the readiness strategy. Frankly, we got a head start because we were in place with omecamtiv in earlier 2023. But now we shifted, throughout the year towards a focus to aficamten, and you can see the activities that are underway. But from a standpoint of investment spending, please note that most of the hiring doesn't take place beyond that which is already on the payroll until 2025.
We won't put in place a sales organization until we have a real read-through to approval. But in the meantime, there's market research and other things that inform strategy, positioning, pricing, and other important activities, and that is underway. This market research is exemplifying of what we've already learned, that the target product profile for which we achieved with SEQUOIA would meet with high market acceptance and we think ultimately could translate to aficamten becoming next in class and potentially a category leader. There's a lot of work to do, and you see it laid out in a simple slide like this, but it underscores what we're going to be doing in what order over the next two years to ready to bring this innovation to patients. I'll now very briefly touch on the rest of the pipeline before ending the presentation and inviting Q&A.
CK-586, as I mentioned, is a next-in-class cardiac myosin inhibitor, and as you can see, slightly different in its mechanism of action to aficamten, but also a potent selective inhibitor of cardiac myosin. And we've already seen evidence that it has a mechanism that translates to preclinical effects that we believe warrant follow-up in clinical studies. Here, in particular, in heart failure with preserved ejection fraction from a preclinical model. Here, you see data that augur well for what we hope to see in clinical study. We're also developing CK-136, a first-in-class cardiac troponin activator that has also potential for increasing cardiac performance in select patients with heart failure, where that may be compromised, and you'll hear more from us on CK-136 this year as well.
From a corporate profile, here is a snapshot of the company, summarizing some of the things I've already spoken to. What I'll highlight in particular is our end-of-Q3 cash position, $550 million, approximately. That doesn't include some draws on our ATM. We are active, as you might see in our 10-Q. As designated in the footnote below, we raised about $80 million through to the reporting of that 10-Q, and we'll update on our full end-of-year numbers with our Q4 earnings call, which will be taking place in February. But consider that, based on our 2023 guidance, we expect we entered 2024 with approximately two years of forward cash. As we're building a company, we believe uniquely positioned for success, you see that we're focused and a leader in muscle biology, but with an orientation to specialty cardiology.
Over 25 years, we've built key relationships, establishing high integrity, high credibility with key stakeholders, including leading cardiologists. We believe that all of this together has produced a company rewarding for shareholders, enabling of us a lower cost of capital and as could be enabling of us the ability to continue to execute well on our corporate strategies. Here's the financials from the end of Q3. I think I've summarized already what are the key points here, but again, you can see our guidance for the year, and we'll be updating how we did against that guidance and also our outlook for 2024 when we convene in February. Key milestones here will also be updated at that time.
We're not updating them for this presentation, but you can see we've already here provided an update with regard to those things we referred to last year and will be elaborating further in a few weeks. With that, I thank you for your interest in Cytokinetics, and I'm going to ask our head of R&D to join me up here, and we're going to address some questions that I know Tess has and maybe also you have in the audience. Before I do that, I do have one other comment to make. Before I answer any questions, I am going to not answer any questions relating to M&A and speculation pertaining to that topic. Because BD also reads on that, I might have to be especially limited in what I can disclose with regard to our BD activities also.
I trust you understand and appreciate the fact that you recognize we can't speak to those matters today. Thank you. With that, I'll turn it to you, Tess.
Thank you, Robert, and thank you, Fady. As Robert mentioned, please wave your hand if you do have a question, and I will flag you. But I thought I would just start with one. We just saw top-line data from the phase III SEQUOIA-HCM trial, which you just articulated for us, Robert. Have you exposed docs to the preliminary profile yet? And if so, what has the physician feedback been here in the early days?
So, with regard to who has had access to these data, it's a very, very limited set of investigators, and I'll ask Fady to elaborate.
Well, so obviously, what we did with these results after we received them was to socialize them with the executive committee of the trial. It consists of really leaders in the HCM world. They, you know, were extremely excited, as I think you can imagine we were. They viewed what we observed in SEQUOIA as fulfilling, really, all the objectives of developing a drug in this space, something that had a very strong safety profile, that had a very strong efficacy profile, that really appeared to, in terms of magnitude of the effects, to make patients feel better. And, you know, they were as excited as we were when we saw those results.
Did it surprise you that there was as much consistency among the patient baseline characteristics and treatment strategies that there was, and what implications might this have in the real world?
Well, the baseline characteristics were extremely balanced among the treatment and active groups. That's not always the case in studies that, you know, have two , 250, 300 patients. But we were really pleased, and some of those differences were forced because there was stratification of the randomization to ensure, for instance, that patients on beta blockers were evenly distributed into the active and placebo groups and patients that were either on treadmill or bicycle. These are two factors we thought might influence treatment. As we pointed out, really none of those assumptions early in the trial bore out. There was no heterogeneity in terms of the subgroup findings, but they did lead to what we think was a very nice, evenly distributed randomization of patients to placebo versus active.
...you showed a table to us just a couple moments ago that had a number of the primary endpoint, but of course, also a number of pre-specified secondary endpoints. Which of these matter most to physicians is, and particularly on NYHA, is that more or less important than other measurements of how patients feel and function?
You know, I think all the measurements truly are important to physicians. They create a picture as opposed to focusing on a single number or a single endpoint. NYHA Class, people focus on that because that's really the integrated physician's feeling of how the patient is doing. But the other numbers substantiate that their assessment is actually accurate. And so ultimately, I think, you know, when, when physicians have a chance to use aficamten, their pain... You know, their, their feeling of how the drug works will just be influenced by their own experience with the drugs.
You know, I might add a couple of things to that. NYHA is a constellation of how patients feel, and it's how the physician can best assess them. And sometimes we get lost in clinical trials data with too much of a singular focus on that, which could be statistically quantified and objective. But what ultimately matters is when a patient shows up at the physician's office, how are they feeling? And the physician is going to respond in large part for that. And that's not lost on payers. As we've done market research, NYHA is one of those things that payers seem to be intently focused on. But that's not also to subtract from what Fady said. It's the consistency of all of this and how it reads on how patients feel that I think drives what will be ultimately adoption.
I do think that, as we are now continuing the MAPLE study, that's another harbinger, hopefully, of good things to come because, you know, beta blockers don't make patients feel great. To the extent you're demonstrating improvements in NYHA Class, I think that augurs well for what we hope to see in MAPLE.
Please.
Congratulations, guys, on SEQUOIA. Just had a quick question around when you've kind of gone to this, with this data to docs. What do you think is driving their interest? Is it really kind of possibly the less of echo or the ability to not have to titrate up and down, when taking a patient off?
You know, I think what drives them first is just the consistency and strength of the results across the board. The clarity by which the drug performed in terms of ease of use and the rapidity with which the results, the treatment effects came on with the patients. So, you know, I don't think there's any, again, any one thing nobody just points to. And again, the number of physicians we've shared this with is rather limited to date, but you know, I think it's the whole picture. Efficacy, safety, convenience, all those things matter, and we're really pleased with how the drug performed in SEQUOIA.
What analyses are you still awaiting that you have not been exposed to as of yet? And can you give us a sense of what we should be anticipating as we think about 2Q 2024 this year and a presentation or publication there?
Well, the dataset with SEQUOIA is extremely rich in terms of what we gathered. We gathered a lot of echo parameters. We gathered, in some patients, cardiac MRI. We have, obviously, all of the endpoint data, how they're correlated, the biomarker data. So, you know, seeing how all of that is put together, how it's correlated, thinking about how do patients, not just respond, you know, what's just one endpoint, but how many patients, for instance, responded across the board to all the endpoints that we, assessed there? So, there's a lot of analyses that we have planned and will come out in the coming year.
And to that point, the team had already organized, under Fady's supervision, a wonderful publications plan that will go into great elaboration on these data, and you can anticipate not just presentations at medical meetings, but also manuscripts published, manuscripts published that will fully inform the breadth and the array of these data.
What does an ideal label look like for aficamten?
You know, I think that might be premature to comment on. I don't wanna socialize our regulatory strategy this way. What I, I can say is, it's incumbent upon us in developing a next-in-class opportunity here to ensure that we're enabling for a wider array of physicians to feel comfortable using aficamten on a wider array of patients. You know, you might already be seeing television commercials that underscore HCM as a problem. It's a problem that is you can even watch Sunday Morning Football and see a commercial that speaks to, "Come see your doctor if you have these symptoms." But it's just scratching the surface in terms of those patients currently diagnosed relative to the prevalent population.
I do believe as we think about the opportunity here, we have to be thinking broadly about how to best leverage these data to ensure that any patients with, you know, oHCM suffering symptom burden that could benefit from aficamten get that choice.
How should we think about possibly another cut of FOREST? Do you anticipate a further cut to be included as part of your dossiers to regulatory agencies?
Well, I think the further cuts of FOREST will enable us to look more rigorously at some of the long-term imaging metrics, the cardiac MRI, for instance, which is only being done at a year's interval, the echos in terms of looking at the potential for reverse remodeling, ongoing safety, which I think is important. And FOREST will provide a substantial part of what we include in the dossier for our regulatory filings, because it speaks to the long-term safety as well as what's more or less real-world use of the drug. The way that the FOREST was designed was to, you know, allow physicians to implement dosing with guidance in terms of a dosing regimen, but not necessarily forcing it, as you do in a, you know, in a computer algorithm.
You know, we think it provides a lot of real-world experience with how the drug is used and its safety.
How should we think about a potential launch curve here, assuming approval? And which patients do you foresee taking the drug first? And do you expect a switching dynamic to occur, or rather, to capture new patients that might be naive to a cardiac myosin inhibitor?
So obviously, these data are very fresh, and we're just now getting to the place where we can be, assessing their impact on our market research. But as we think about our go-to-market, we believe that, a potential launch of aficamten is well-timed for where the market itself is hitting an inflection point and potentially getting to that more asymmetric phase of market growth and category penetration opportunity. I think BMS is doing a good job with mavacamten, and I think, you know, as they continue to report sales, they seem to be eclipsing what I think were, subsequently reduced, consensus estimates. And I think they'll continue to outperform as, mavacamten continues to get good traction. But by the time we get to market, we still think there'll be, potentially over 90% of patients eligible for treatment that'll still be untreated.
We do believe that, based on these data, there's an opportunity to not only grow relative to category, but to expand the category meaningfully. You had a follow-on question, I think, relating to... What did I miss? The tail end of that question.
Switch.
Switches. Oh, we haven't yet done the market research pertaining to switches. I think ultimately it'll be a question I can answer when I have the quality of data behind me rather than suppositions. I look at these data, and I think they make a compelling case, but ultimately, it's what physicians think that matters.
Are there any questions from the audience? This is a quiet group. So how is MAPLE-HCM progressing, and when might we expect data? And can you help frame our expectations for this readout a little bit more?
Yeah, MAPLE-HCM is progressing well. I think the SEQUOIA data will certainly push it along as even further. I think the question that we're addressing there is very exciting to physicians to assess because there is a real conundrum with generating evidence in terms of what's the order, which therapies seem to perform better than others? What's the order of initiation? What's their role? These are questions that are so rarely addressed, and this is a very particularly important one because I think the physician community has recognized that beta blockers, while they reduce gradient and do improve symptoms, their effects are limited, and they have substantial downsides for patients. You know, having these data might allow them to recalibrate, you know, what medicines they start and when.
Can you just talk about ACACIA-HCM and what are your thoughts on the subject?
Well, I think the strength of the signaling, and ACACIA-HCM, the KCCQ, is the primary endpoint, the Kansas City Cardiomyopathy Questionnaire, which was assessed in this trial. You know, I think the strength of the effect there now seen, you know, with really two trials, both with mavacamten and with aficamten, also with our open label data that we provided earlier this year or last year, you know, about 40 patients, where there was a substantial impact on the KCCQ, as well as biomarker improvement and things like that, that are all show alignment, if you will, of the therapeutic profile, I think give us, you know, strong confidence that ACACIA-HCM will read out positive down the road.
Okay. So let's talk a little bit about the size of the market here. You talked a little bit about how big you think it is. How, how do you see potential label expansion opportunities in symptomatic, non-obstructive HCM and/or as a first-line treatment option in obstructive HCM as changing those? I think there was a graphic, but perhaps is there any other detail you'd provide on how you see the market?
...So, you know, you're talking about a market that's not been served by pharmacotherapy, but only by some other types of interventions in the case of oHCM septal reduction therapy. And, and there are good case studies for this, whenever you have a new pharmacotherapy, you open the opportunity for where could be therapeutic applications even beyond the currently diagnosed population. I think this is one of those examples. You're asking about symptomatic and asymptomatic nHCM. I think ultimately, having a new medicine like mavacamten, having a new innovation, hopefully, that would be coming soon, like aficamten, it's enabling the physicians to understand their patients a whole lot better.
That means, patients who may have symptom burden also coming in and asking their physicians, you know, "Are there treatments that might apply to my condition?" So we can only report that, which is, you saw it on the slide. That's based on publications, market research, that's based on work that has been presented and published, but for which we tend in our industry to get that wrong. We tend to be precisely wrong when we're predicting these things, and things tend to be substantially more underserved than we oftentimes know. And I think an innovation like a myosin inhibitor will open the aperture on what could be new opportunities, even beyond the things that we're currently monitoring.
Okay. Thank you. Last question from me is, what is your latest thinking on partnering opportunities for aficamten outside of the U.S.? And bigger picture, how do you think about capital allocation priorities over the next few years for the company?
So again, I'm going to be very limited in what I can say about your first question. What I will say is that in 2023, we set out for a strategy to ready our own go-to-market activities in North America and Europe, but to seek a partner, potentially for aficamten, in Japan, much like we've already partnered in China. And as relates to others of our pipeline opportunities, things that read on our ability to continually generate non-equity dilutive capital, as I think Cytokinetics has done very well over many years. So access to capital, I think, is rooted in that matter.
We have, I think in 2023, taken prudent measures, to reduce spending so as to be in a good position as we enter 2024, with substantial capital on our balance sheet and a good cash runway and outlook. So it enables us at a conference like this one, to be engaging with potential partners, to be engaging with investors, to best understand what's the best way we can maximize shareholder value.
Okay, that might be a good place to leave it. Thank you, Robert, Fady, and the rest of the Cytokinetics team for being here, and I hope everyone enjoys the rest of their conference.
Thank you.
Thank you.