Welcome, everyone, to Leerink Global Biopharma Conference. My name's Roanna Ruiz. I'm one of the senior biotech analysts here, and it's my pleasure to introduce Cytokinetics. We have Robert Blum, CEO and President, Andrew Callos, EVP and Chief Commercial Officer, and also Fady Malik, EVP of R&D at Cytokinetics. Thanks, everyone, for joining us. I think, Robert, you have a couple of slides you wanted to go through first.
Thank you. So thank you very much for inviting us to present here an update on Cytokinetics. I'll make some introductory comments, and then we'll get into some Q&A together. I'll be making some forward-looking statements, and I'll refer you to our SEC filings with regard to the caveats to those statements. We don't undertake an obligation to update those statements. Through these first several slides, I'll be laying out how we continue to execute on a mission that we started with, quite some time ago. Fady and I started this company over 25 years ago.
As a company focused to an area of biology, we feel like we're in a very good place to bring forward new medicines that are rooted in that biology and as give rise to potential new treatments that relate to muscle degeneration and muscle weakness and dysfunction, and as could be affording increased health span, especially as it relates to patients with cardiovascular disease. Here you see our pipeline, a pipeline that is rooted in this biology. Nearly all of these compounds that you see here are modulators, either activators or inhibitors, of cardiac myosin, a mechano chemical enzyme involved in the mechanics and contractility of cardiac muscle.
Lead amongst these is aficamten, an inhibitor of cardiac myosin that has recently shown activity in a study called SEQUOIA, as could be hopefully leading to its potential registration and approval for patients with OHCM, a disease of hypercontractility. That study, SEQUOIA, has been toplined in a press release, not yet presented and published. That'll be coming very soon. And we expect to be submitting regulatory applications in the U.S. and also outside the United States in the second half of this year, as we hope to go to market in North America and Europe next year.
Aficamten is the tip of the iceberg in that SEQUOIA represents the beginnings of a series of clinical trials that should be reading out the next study, MAPLE, the next study after that, ACACIA, in OHCM and NHCM respectively, as should be augmenting of the clinical profile for aficamten in a cohesive biology where we think the probability of success is higher and as such, unlocking of shareholder value as could translate to more meaningful enhancements. You see on this slide other pipeline products. I won't go into them today just simply to say, as the pioneer and leader in this space of muscle biology, we believe we're advantaged, as can be unlocking of shareholder value with multiple catalysts this year and beyond. This slide depicts how we think about that from the standpoint of the ambition to build a specialty cardiology company.
We don't take lightly the fact that in biopharma, most companies have embraced a different kind of cardiology business model that, frankly, hasn't yielded success in every instance. We do believe we're in an advantageous position to build a specialty cardiology business with a limited infrastructure built for sales and marketing as can return a higher yield on that investment in North America and Europe, a specialty model but as applied to an innovative cardiovascular pipeline. And here you can see the prevalence of the populations we intend to address in OHCM and NHCM and other indications. But importantly, it's significant to note, it's a relatively few number of cardiologists that treat severe cardiovascular disease, less than 10,000 cardiologists in the United States representing larger than 80% of prescribers for severe cardiovascular.
We can get to those folks with a limited infrastructure built in sales and marketing, and similarly in the United States. We think that lends itself to a high return on shareholder equity. SEQUOIA, as I mentioned, was toplined in a press release at the end of December. We haven't yet had an opportunity to present these data at a peer-reviewed medical meeting. We expect that to be happening mid-May in Q2 and hopefully published. This will be a series of medical and publication events over this year, Q2 and Q3, starting with HFA, a meeting in mid-May in Europe, followed by other meetings in Europe in Q2 and in the United States in Q3. Ultimately, we think this represents a significant amount of news flow, presentations, and publications for aficamten coming out of SEQUOIA.
Together, this enables us, we believe, to enhance shareholder value in a meaningful way. We recognize that there's a narrative that's been circulating around Cytokinetics pertaining to M&A. We don't deny that. At the same time, we also recognize that there are different ways we can maximize shareholder value that don't solely depend on M&A as an exit to reward shareholders. We think we can get to a double and a triple potentially enhancing of shareholder value as could be enabling of those things that we can control ourselves while also recognizing we have an obligation and a fiduciary responsibility to do that which is best serving shareholders. We'll respond to increase, but at the same time, we'll manage those things that we can manage.
You see here those catalysts, as all rooted in Aficamten and cardiac myosin inhibition this year, next year, and the year after, afford us an opportunity to build uncommon value, for shareholders as relates to our pipeline in this one area of biology. We believe we're uniquely positioned for success. We're leaders in this space. We've got a depth of expertise that starts in the science, extends to the clinical development, and also into the commercial arena. We believe we have key stakeholder relationships that afford us an opportunity to potentially turn next-in-class to best-in-class. And we also think we have multiple levers by which we can access capital and deploy that capital in a capital-efficient way, ungating spending and investment in accordance with regulatory and reimbursement milestones. We recently communicated our Q4 earnings.
Our balance sheet at the time of our earnings call reflected either existing cash or access to cash north of $800 million. Given our 2024 guidance, that represents approximately two years of cash. We can be smart about how we deploy cash without having to do things that would be predatory in terms. We do think our cost of capital has benefited from recent results from SEQUOIA-HCM. We expect to be smart about the different levers we can pull ultimately as could be enabling of us in a principally non-equity dilutive way to continue to build shareholder value. Here are the milestones we've laid out for 2024. I suspect we'll get into some of this conversation here in a minute. Thank you for listening to that introduction. Now we'll proceed to Q&A.
Sounds good. Thanks, Robert. So, maybe just to start off with a bigger picture question. I know you had a great intro over there. We've seen a lot of development in the cardiovascular space, both in the private and public domain. I was curious, maybe just set the tone, what do you believe sets your company apart from other cardiovascular-focused biotechs?
It's a very good question. So I'll start by saying I'm in my 40th year having worked in innovations around cardiology. The two prior companies I was associated with, we went from next-in-class to best-in-class in accordance with those launches. And a lot of the things I learned along the way were employing at Cytokinetics as we ourselves were the innovator associated with the first-in-class compound, but that's now being marketed by BMS. And with a next-in-class compound, I think we're advantaged. We're advantaged in the fact that we have long-term relationships with those key clinical investigators who are the top of the pyramid influencers in terms of product adoption. Those are folks that have known us from the preclinical days through to the clinic. Many of them now we've hired as employees, and they continue to lead the ongoing clinical research.
That translates into commercial adoption in ways that I think we're advantaged for the fact that they represent the ability to go from the centers of excellence, of which there are only roughly 50-100 of those centers of excellence for hypertrophic cardiomyopathy, to the broader cardiology space where ultimately, if we're gonna be successful, we have to demonstrate that aficamten in NHCM should be used by more physicians for more patients than is currently the case for an existing drug and growing the category to the benefit of both the first-in-class and our next-in-class. And this is where Andrew, our Chief Commercial Officer, should elaborate, but for which I think we have a thoughtful, methodical way of thinking about go-to-market that should be enabling of us to become a category leader.
Yeah, certainly. So I think one of the, the key differentiators is the focus on a subset of cardiology. So Robert talked about the 10,000 cardiologists that are the initiators of treatment and diagnosis of nearly 80% of HCM. And, you know, this, this focus on cardiology, focus on payers managing a cardiology space, this is not a managed category. There's over 100 payers, in a rare disease, space. They really just manage to label, which is why MAPLE-HCM will become so important, because, you know, then you get monotherapy as well as a combination therapy. But this year, you know, next year we're looking forward to launch. This year we're really focusing on building all the steps to launch.
whether it's OHCM, NHCM to follow, and some of the other products in the pipeline, it's all focused on the specialty cardiology space, which allows for tremendous cost synergy as well.
Got it. Great. And so you mentioned you plan to present more granular data from SEQUOIA coming up this year at medical meetings and publications, etc. I was curious, what sort of additional information do you think will be most interesting to physicians and investors coming out of these granular data?
Yeah. Well, beyond the top-line data, there's a treasure trove to report. So, really seeing the full extent of the top-line data, the subgroup forest plots, the specific adverse events, their frequencies, the strength of the dosing paradigm, and, you know, obviously the endpoints and things like that will all be laid out in relatively short order. But beyond that, we want to also get out detailed data on the CPET. You know, there are a lot of parameters in the CPET beyond peak VO2 that show improvement. We wanna look at echo. echo, we have a very rich echo dataset that reads on structural remodeling and other things, biomarkers and the like.
you know, we have a very aggressive publication plan that over the course of the next several months, we hope to see, you know, six to eight manuscripts come out and then similarly a number of presentations by the end of the year.
Great. Sounds good. And then digging into one of the top debates that I've been fielding around aficamten and thinking about a possible REMS program. So maybe just zooming out a bit, thinking about the class and CMIs, do you think REMS is a thing to stay? Are there other scenarios that could happen for aficamten? I know you've talked about this a lot over the course of the several months, but maybe could you recap some of your main takeaways here of your thoughts here?
Well, I think if one took a step back and looked at the data from SEQUOIA in the absence of history in this area, you know, there's nothing that screams in the SEQUOIA data that there needs to be a REMS program to carefully manage the use of that drug. It's not dissimilar from use of beta-blockers and heart failure and other things that cardiologists are used to using. And there's nothing unusual about its pharmacokinetics, its drug-drug interaction profile, its, you know, safety profile in women and other things that really mirrors that. That said, you know, there is a context into which we are proceeding. And, you know, our objective really is to propose a program that is commensurate with the risks that are associated with aficamten. And we think, you know, the FDA is a data-driven organization.
I think they're open to discussion of what is necessary. They recognize the burden of patients of frequent monitoring and things like that. And if it's not necessary, hopefully we will be able to demonstrate that and you know, achieve something that is for patients, you know, optimizes their benefit-risk ratio.
You know, we've gotten this question quite a bit about, you know, should we expect a class REMS? And there's that which relates to the mechanism of action and that which relates to the intrinsic properties of the compound. Aficamten, we believe, deserves its own, independent review for the fact that it was designed specifically to have physicochemical and ADME and PK properties that should render it, safe and convenient and easier to use, by physicians who manage these patients. And we believe that it's, shorter half-life and other, properties that we designed specifically as could be enabling of a next-in-class profile are substantiated by what we've seen in SEQUOIA.
When we present data in the second quarter and the third quarter and that's presented and published, I think it will be reasonable to assume, like we assume as a base case, that aficamten is meriting of a profile specific to aficamten. I do believe that already in the clinical development of aficamten, we've observed that FDA is accommodating of things that would be perhaps reading on what would be an expectation with regard to REMS.
Interesting. Okay. And I think the one last question on REMS, and I'll move on to other topics. But I think you've alluded to possibly being able to select for higher-risk patients that might need more monitoring. Could you just walk us through some of the thoughts there? You think the FDA's amenable to that as well?
Well, it's too early to really comment on what the FDA thinks. But, I think in the context of, what you might expect is, as we showed in October in an investor event, for all the monitoring that we're doing in the open-label extension, you know, we only had two patients that had a change in their dose as a consequence of that. So, you know, roughly two echoes out of 600. So how can we be more efficient around that? And there aren't, you know, what I would say, analyses that are gonna be very rigorous about predictors 'cause there's so few cases. But some of them are obvious.
If somebody's ejection fraction after you get to a target dose, you know, is 52%, you might be a little more concerned to monitor them more frequently than somebody whose ejection fraction at the end of all that is, you know, 75%. And so it's not dissimilar to many other things that in cardiology we do. We, you know, we give blood pressure medicines. When people's blood pressure is on the low side, you tend to bring them back more frequently to see how they're doing. Similarly, if it's not very effective, you bring people back and see how you can maximize it. So, you know, your frequency of interaction is really driven either by trying to maximize benefit or minimize risk. And those things are generally, you know, fairly obvious for each mechanism of action.
Got it. Okay. Great. And maybe let's switch gears a little bit to commercial readiness for aficamten. So how are you thinking about continually engaging payers and physicians, getting closer to a possible approval in OHCM? And, you know, so what do you plan in terms of investing more into those different pieces?
Sure. So from a payer point of view, once SEQUOIA is published, the second half of this year we'll engage 100-plus payers who really are over 90% of lives, commercial Medicare, in the U.S. will review the clinical data so they understand the primary, the secondary endpoints, and the economic benefit associated with that clinical data, things like reduction in the need for SRT, how some of the secondaries like New York Heart Class speak to outcomes or associated with outcomes. So that's what we'll do from a payer point of view, from a physician point of view. We will be rolling out our disease awareness campaign the second half of this year as well, as we continue to work for our branded campaign and finalize our positioning and messaging. We're engaging specialty pharmacy. We're building our hub. So those kinds of activities we're doing this year.
We deployed, in 2022 and 2023, medical affairs colleagues who have been assisting us in a number of ways around clinical research and other things. We hired sales managers, who ultimately will be responsible for configuring and aligning territories and putting in place the bones and infrastructure to support a commercial team when we hire the salespeople in 2025. So we've taken a gated approach, again, to efficiently deploying capital as could be enabling of us ultimately to hit the ground running when we have an approval. And relationships that we're establishing will hopefully pay dividends at that time.
Got it. Great. I know aficamten is also ongoing in two other trials, ACACIA and MAPLE. So maybe could we talk a bit about some of your goals and what you hope to see in those two readouts and how they might be tailwinds for aficamten going into the future?
Yeah. So this is a case where we started some of the lifecycle management associated with aficamten years before might be conventional and thinking about label expansion even before we might ultimately have an approval. So MAPLE, and I'll ask Fady to speak to these studies in more detail in a moment, but MAPLE is a study that should be enabling, we hope, of label expansion and better positioning and guidelines for patients with OHCM. ACACIA is a pivotal study in patients with NHCM that should hopefully afford yet further expansion in a population where the prevalence is growing in such a way that we think ultimately that could even overtake in time OHCM.
So we're looking at this like would be more traditionally a pharma approach, but for a biopharma product innovation where we see out two to three years, and we think, that's unusual in the biopharma space where, you might be able to build a franchise around a molecule, a franchise that, would be enabling of us to continue to have news flow with cardiologists who treat these severely ill patients. And maybe, Fady, you wanna speak to what those studies are designed to show.
Sure. So, MAPLE is a trial of aficamten as monotherapy versus beta-blocker as monotherapy, beta-blocker specifically being metoprolol. It's been the standard of care in HCM for, you know, a couple decades. The goal is to compare them in the absence of other background therapy. You know, we believe aficamten should be superior to beta-blockers. It should reduce gradients to a greater extent. It should improve peak VO2 to a greater extent. It should improve symptoms to a greater extent. It should be absent certain side effects to a greater extent. All of those things in a head-to-head trial, we think, we can demonstrate and provide the rationale for considering elevating it in guidelines as to be considered as first-line therapy, in particular if we're able to demonstrate prognostic things about long-term effects of reduced cardiac mass or reduced certain biomarkers. So that's a trial.
It's ongoing now, randomizing those patients, 1:1 to each treatment arm. We hope to report those data in 2025. Acacia is a trial of non-obstructive HCM patients. These are patients that don't have a pressure gradient of blood leaving their heart. They have really very few treatment options. They, you know, medical therapy doesn't do much for them. They don't have surgical treatment options 'cause there's no obstruction to get rid of. So, we think aficamten, by addressing the fundamental root of those diseases, which is hypercontractility, can afford them improvements in their symptoms and function. We conducted a phase II study in a sizable number of those patients and showed improvements in their symptoms and functional class and biomarkers. You know, we think that that augurs well for how Acacia reads out. ACACIA's a more sizable trial.
Uses the KCCQ, a patient-reported outcome. The Kansas City Cardiomyopathy Questionnaire is its primary endpoint. It's continuing to enroll over the next over this year and part of next and will then likely read out in 2026.
Got it. Great. You, you started to allude to, with some of the data from these trials, aficamten possibly moving earlier line of therapy. I just kinda wanna tag on to that and ask, like, do you think guidelines could change, assuming that results could be positive for both Maple and Acacia for aficamten?
Well, absolutely. I mean, for non-obstructive, if we have a positive trial, there's nothing that's ever had a positive trial for non-obstructive. So it, presumably would become the standard of care in that disease, in that, in that particular type of, HCM. In the, obstructive HCM patients, the European guidelines anyway specifically, said for cardiac myosin inhibitors that no head-to-head trials had been completed, you know, relative to standard of care. And so, you know, it's unknown where it should be positioned in terms of standard of care. We already had Maple ongoing. So it was kinda nice to see a statement like that because I think it supports the rationale for doing Maple, and should lead to, you know, in kind of a, inclusion in the guidelines as those data to, position aficamten appropriately within the guidelines.
What's nice to see is already in the open-label extension studies we're doing, we're seeing physicians choose to take patients off of beta-blockers in order to be able to potentially maximize their clinical effects. So that we think is indicating of what may be a comfort amongst physicians to move a myosin inhibitor to frontline therapy if the MAPLE data do what we expect them to do.
Got it. Great. I think one trial I haven't mentioned yet, but the FOREST-HCM trial, open-label extension there, you recently presented some cardiac MRI data coming from that study. I was curious if you could just give us some of the highlights of, you know, what were some of the key learnings from there and what do you hope to see, as you continue on with the trial?
Well, so that was just really the tip of the iceberg. We presented 16 patients' worth of data that had gone out to a year in FOREST and had gotten a second cardiac MRI. What we saw was what we had hoped to see, which is that you began to see the cardiac structure change. So the thickening of the heart starts to regress a little bit. The left atrium, which is the chamber that receives blood from the lungs, starting to shrink. It sort of begins to grow adversely in HCM. We didn't see any increase in the fibrosis; that's in the myocardial interstitium. So maybe that reflects some disease stabilization. So, you know, overall, a positive picture of how the drug is impacting the structure of the heart.
you know, these data will be augmented with more patients over time as well as longer follow-ups. Some of these patients we hope to follow up to five years.
Got it. Okay. So we've talked a lot about aficamten. Also wanna ask about your earlier pipeline as well. So what should investors keep in mind about your earlier stage assets and how they're differentiated?
So the first thing to note is it's all built around the same biology that we pioneered. From the beginning, our company was focused to the sarcomere, it's a unit of muscle contractility around which there are different ways to modulate it with small molecules, either to activate or inhibit proteins that are involved in the generation of muscle force and power, whether that's cardiac muscle or other muscle types. So everything that we've talked about publicly, is really focused in that space. And I think you should expect to see other, modulators of sarcomere function moving through, from research to development. And in particular, CK-586, which is another cardiac myosin inhibitor that we're developing for heart failure with preserved ejection fraction, which in many ways mimics, NHCM.
So the fact that we have some proof of concept already with aficamten in phase two in NHCM reads positively on what could be the prospects for CK-586 in HFpEF. And that's the way we think about things which lend validation to the space in biology for advancing and broadening the pharmacology. Beneath the hood, so to speak, within research, Fady is overseeing the conduct of a lot of studies with other, potential, programs that, relate not so much to the contractility and the mechanics and the biomachinery of muscle, but energetics and growth and regeneration of muscle. So our focus will remain on muscle biology. We'll maintain that discipline and commitment to muscle biology, but we'll expand potentially as could even include us being a partner of choice with other companies, other modalities working in a similar space adjacent to that which we do.
Got it. Great. So I think maybe just last question. Anything else, Robert and team, that you wanna highlight before we close out the session?
Well, I think, you know, the coming year is gonna be really exciting for us with a lot of great data that'll come to the forefront, the filing of an NDA, the filing of a marketing application in Europe. So, you know, it's really the realization of many hard years of hard work by a large team, and, you know, very excited to hand off our product to Andrew's group and get it to patients.
Yep. It's a very exciting time commercially. You know, in the next three years, we should have a launch, add MAPLE, add ACACIA, expand the market, give further reason to believe in the science of further ways and physicians and patient types to prescribe for, both in Europe and in the U.S. This team has been in place for around two years because we built this team for omecamtiv mecarbil, who got a CRL. So we've already engaged with every major payer. We've built our major systems. We have our analytics department. So we will be ready for launch. And it will be a very exciting time, as we continue to roll aficamten and hopefully broader with expanded label.
You know, bottom line, there's a lot that can be learned from looking out over decades now of biopharma and where certain companies have been successful and, maybe set themselves apart. And we think we've been good students of that both from the standpoint of science and pharmacology, but also as we go to market. And building a franchise model with focus to a specialty care segment where there could be, higher returns on more limited investment and sales and marketing infrastructure should be enabling of us to be counted amongst some of those companies.
Sounds great. Thanks again for coming out and talking about your.