A good day, everybody. My name is Ash Verma. Welcome to UBS Biopharma Conference in Miami. Our next company on the stage is Cytokinetics, and with me, we have, Andrew Callos, who is the Chief Commercial Officer, and Fady Malik, who is the EVP of R&D. How are you guys doing today?
Doing well.
Good.
Great. Thanks for joining us. So since Andrew, you're sitting next to me, so maybe I can start out with some commercial questions first. And I, I guess maybe just to preface that, like, if it will be helpful to give or get a little bit of a background about the story. So if you can just give us a high-level outline for people who might not be familiar about Cytokinetics, just a two-minute pitch on, like, what, what is the platform, and what are you trying to do here?
So, our later stage programs are really focused on muscle biology and specifically in cardiovascular. Obviously, our late stage program is aficamten focused on hypertrophic cardiomyopathy. So that's our key platform. I don't know if, Fady, you want to expand on that, given your long history with Cytokinetics.
Well, you said it well. I think, for 20+ years, we've pioneered research in the sarcomere, which is the fundamental unit of muscle contractility, and we've developed activators of the sarcomere, inhibitors of the sarcomere. As Andrew mentioned, right now, I think our most important program is aficamten, which is a cardiac myosin inhibitor, and its focus is to treat hypertrophic cardiomyopathy.
Great. So thanks, thanks for that introduction. Maybe just, talking about the hypertrophic cardiomyopathy or HCM market, in general, I mean, we've seen one drug launch in the space, and the launch hasn't been that exciting, based on, like, pretty much everybody, how most of the investors look at it. So but Camzyos... I guess the question that I get from investors a lot is, like, is this, like, a potential, shortcoming of the drug, or do you think that this market in and, in and of itself might not be, you know, realizable?
So just, just wanted to understand from your perspective, like, you know, like HCM, like, is this something that more cardiologists are just waiting to get a better drug in their hands, or is it, like, any kind of, like, structural issue in the market that might be limiting the uptake of the competitor that you had before you?
Sure. So, the HCM market, overall, there's 300,000 patients that are diagnosed with HCM in the U.S. Two-thirds of those are obstructive. That would be the first indication we're seeking with our clinical trial, SEQUOIA. So the obstructive HCM market of 200,000 patients, the ones that are, say, New York Heart class 2 or 3, meaning they're symptomatic, and therefore, most of them are treated over 90% on beta blockers, calcium channel blockers, yet still symptomatic. So there's a high unmet need. Those symptoms look like not being able to do normal functional things, sometimes walking up a flight of stairs. There's also a high correlation of later disease, heart failure, and AFib. So it, you know, it speaks to longer-term morbidity as well.
So there's unmet need. None of the drugs that are treated before mavacamten came to market were specifically focused on the underlying disease. So we have CMIs that focus on the underlying disease. We're hearing anecdotally that patients are feeling better when they take CMIs. And therefore, when you have 130,000 patients, again, they're the New York Heart Association class 2, 3, of that 200,000, there's a market with a high unmet need that there certainly will be there. Sometimes markets take longer to form. There could be an element of a new mechanism, new drug, how physicians learning how to use it. If you have a REMS program, there's workflow associated with that and safety elements associated with that.
Yeah.
The FDA basically puts REMS programs in place because they say the label itself is not enough to ensure safe use. They want other elements of safety. So I think it's a matter of time. Sometimes it just may take a little longer to form, but I have every bit of confidence that the market size is large, that there's a number of patients who need this therapy, and that the number of physicians that'll move outside the centers of excellence over time and into more general cardiology.
Mm-hmm.
Because right now you see, you know, the first in market, obviously being this is Camzyos' product, is pretty linear, the launch, and we haven't seen a trend change in that linear, you know, revenue and patient projection. But once you start to get into the general cardiology, that's when it'll change. It could be a second agent helping do that as well-
Yeah
... expanding the market and accelerating, but it will happen.
Got it. And just like when you say, expanding the market and trying to go to, like, the community practice, like, is there where the diagnostic expansion element of the market is? Like, you think that, over time, like, you can potentially increase the diagnosis of this disease?
Sure. There's been studies that, based on general population, that show that the true prevalence is probably over a million patients. So the true prevalence is probably three to four times what the number is now. The diagnosis rate is increasing with population, about 1% in OHCM, but there's good reason to believe, with genetic testing now as being part of the guidelines, with two agents, if we get approved, if, if aficamten would get approved,
... 'cause now you're at medical congresses, there's an underlying, you know, drug that can change the underlying course of disease. These things typically will accelerate diagnosis, so we're expecting the diagnosis rate to increase as well beyond that 130.
Yeah, yeah. Got it, okay. So I wanted to just talk about the upcoming phase III readout, which we know is happening late December. And there's a lot of debate on just, you know, around the setup of the study, how what are the different endpoints that you're using, even the timeline of the study results disclosure is a topic in itself. So maybe to start off, so just in terms of, like, how you have the study design, like when you're looking at exercise capacity, right? Peak VO2 as the primary endpoint. To my understanding, this is something that you did not study in a previous study in a previous trial rather, and this is the first time that we are looking at it.
Like, what gives you confidence that aficamten can show benefit on this endpoint?
Well, first of all, as you know, aficamten is not the first cardiac myosin inhibitor that's been developed. And so, we have evidence from mavacamten that cardiac myosin inhibition can improve our primary endpoint, which is peak VO2. We have evidence from outside of our trials where the goal of therapy in obstructive HCM has been to remove the obstruction-
Right
... either through surgery or interventional techniques as a means to improve exercise capacity. And so, and we've shown with aficamten that the drug results in a very substantial drop in the pressure gradient and a relief of the obstruction. And so, you know, I think we have pretty strong conviction that the main bad actor, which is the obstruction, is relieved by aficamten.
Mm-hmm.
And that should improve exercise capacity, and we have precedent for it as well. So, all of those things I think give us fairly good confidence. We've also seen data with regards to other metrics of patient symptoms, such as the KCCQ, Kansas City Cardiomyopathy Questionnaire, or NYHA functional class, that all show benefits in the right direction, both in our open label extension studies as well as in the placebo-controlled, phase two study. Biomarkers that head in the right direction.
Right.
And so, you know, I think all of those things give us confidence in the ability of aficamten to improve the primary endpoint.
Yeah, yeah. For this study, right, like, when you think about driving it to a specific endpoint or the clinical profile, I know, like, Wall Street and sell side and buy side seems to be hyper-fixated on, like, whether the efficacy measure is going to be something similar or better than Camzyos. And so the physicians that we have talked to are realizing that there is a fair bit of variability in peak VO2, and it's a very fine measure. So is there something that you think that in the study design there are ways to structurally, like, limit any kind of variability when you are taking these measures so that you are getting to the clinical profile that you want to be at?
Well, we do very careful training of the sites. At our investigator meetings, we actually demo a CPET and show them, you know, how we do it, how they should do it. They have to qualify. Each site has to qualify and send in a qualifying study. The studies are all read centrally. We monitor the variability over time, and so as we said on the last earnings call, the variability is well within our expectations. So I think all of those things go to optimize the fidelity of the test. And you know, variability is inherent to the disease. You know, it's not just the test, but the disease itself is variable from day to day. So there is some variability that, you know, just the patients themselves.
But again, you know, having the benefit of another study conducted in obstructive HCM, it gives you a sense of how to power that endpoint and what the intrinsic variability is in the population.
Right. So you recently highlighted at your investor day how, like, using specific baseline characteristics for your patient population increases the chances of teasing out the treatment effect. If you could elaborate on that a little bit, that would be helpful.
Well, I think the drug itself is what and the way it's dosed, the way the dose can be optimized, is all important to maximize the patient population that we enrolled into Sequoia represents, I think, a real-world population. People that have medical therapies that are deployed in the real world, beta blockers, calcium channel blockers, digoxin, verapamil, or even combinations of those drugs. We work to ensure that beta blockers were not overrepresented because, you know, medical therapy is not overwhelmingly beta blockers in the real world. And we also know beta blockers tend to blunt the increase in heart rate with which comes with exercise, which can also have a, you know, blunting effect on other mechanisms that might improve exercise. So-
Mm-hmm.
You know, we think that's important. Peak VO2, we targeted patients that had objectively reduced exercise capacity. So their peak VO2 at baseline needs to be 80% or less of predicted for their age and sex. And, there again, we see a peak VO2 that indicates a significant exercise capacity deficit-
Yeah.
which gives us headroom for improvement. You know, the main reason for their exercise capacity is the fact that they have this obstruction, this gradient, and it's all cardiac related, then, you know, we have a more headroom by which to improve.
In terms of, like, the expectations for the study on efficacy front, I mean, do you think that you have to surpass the efficacy of your competitor in any way? Like, is that even, or do you think that this has to be, like, independently assessed-
I think-
based on how the clinical profile?
Yeah, I don't like to make... I mean, we're not doing head-to-head studies, and, and-
Sure.
We shouldn't be making comparative statements. But the focus on the degree, you know, cardiac myosin inhibition, as we've seen with mavacamten, is incredibly effective at improving patients' symptoms and function. And it's not really, I think, a question of which one is more. They're both gonna be, I think, on... Mavacamten has the data. We expect and hope to see substantial improvements with aficamten. It's sort of like, you know, you're taking a patient who, at baseline, has trouble walking up one flight of stairs, and after treatment, you know, they might be able to walk up four or five flights of stairs. You know, whether that's four flights or five flights or six flights, I don't know if it really matters, right?
I mean, they've gotten over to where they can, they can, function in a more normal way because they can get over that first flight of stairs. So I think, you know, the focus on how much efficacy you can squeeze out is maybe a little misguided.
Mm-hmm.
We think we'll have very strong efficacy, but also there are other aspects that are important to patients and to physicians, safety, ease of use, convenience, all those sorts of things. And we think aficamten has some benefits in those areas as well, that given its reversibility, given what we've seen in the open label extension in terms of the rarity of low EF events and things like that, that speak to it having some intrinsic advantages.
Well, we've done very robust research. You know, 450 physicians, half of them have used mavacamten, half of them are from centers of excellence, and we show them our profile across a range. Safety is the most important thing, preservation of ejection fraction-
Yeah.
followed by efficacy, things like gradient reduction, New York Heart class change. So we show these physicians a range of where we could wind up on our primary endpoint. Their utilization maybe goes down a little bit, but still, you know, we would get more patients on aficamten than not, if the safety elements wind up being what we're expecting.
Yeah. Yeah, I mean, and to that end, I mean, on the safety front, the LVEF less than 40 and 50 data that you have highlighted from the FOREST study, I mean, that has been pretty remarkable. Like, is there a reason to believe that in the SEQUOIA study, this profile could be any different compared to what we saw in the FOREST study?
Well, we know, we also disclosed in the earnings call, we know that we haven't had any low ejection fraction events below 40%. We're blinded to those between-
Right
... 50 and 40, but the patients in FOREST are the patients that came from SEQUOIA, right? So, you know, we think the data we have in FOREST should be pretty representative of what we're seeing in SEQUOIA, because these patients undergo the same dose titration.
Mm-hmm.
They undergo... They're the same patients. They're more of them, actually, because the placebo patients, you know, are put on drug in the open label extension, where they were on placebo in SEQUOIA. So we think the FOREST open label extension data are fairly compelling, and I don't think you can ask for a better insight into a blinded study than, than-
Right
to repeat the blinded study in an open label fashion.
Yeah. Yeah, absolutely. And then, like, again, like, on this piece as well, just like in terms of the variability between the measurement of LVEF, less than 50 or 40 or 45, like, I mean, like how much of variability is there, between, like, different sites or different investigators making a measure of something like that?
You know, ejection fraction can vary anywhere from 5%-7%, even with the same person and the same site, day to day. Either that's intrinsic. Ejection fraction is not a fixed number. It's not, you know, like measuring somebody's height.
Yeah.
It changes dynamically, depending on loading conditions and dehydration and things. So there's intrinsic variability in ejection fraction, but generally, that's the range of variability you see. You know, so in measuring it, if someone has on one measurement of ejection fraction of 52, you know, it's quite possible variability will have one measurement below 50. They may also have one that's closer to 60.
Mm-hmm.
So, you know, the way our dosing as it's deployed, it kind of accounts for some of that, in that we kind of ignore ejection fractions between 50 and 55. We don't act on them. There's no dosing changes that are made. So you only increase the dose if the EF is greater than 50, and you decrease the dose if the EF is less than 50. And I'm sorry, you increase the dose if it's greater than 55, you decrease the dose if it's less than 50. You don't do anything for whatever's in between.
But it seems like so, on every data card, like, so far on this metric, I mean, aficamten seems to be doing well. So my question really on this is that, like, is this, does this type of a profile will it give the conviction to the physicians that you need to do the echo monitoring on a less frequent basis? And that's been, like, one of the hot button issues with Camzyos. Do you think that, like, with this type of data, and if you're able to replicate that in phase III, there would be less of an onerous monitoring?
Well, we would hope that the data would support a convenient dosing and maintenance, you know, schedule of echocardiograms. So, I can't really comment on where we'll end up, because ultimately that, you know, ends up being a discussion between us, what we propose, and what FDA wants to see. But I think from just the resource utilization standpoint, echoes are burdensome and they cost the system money. And, as we showed in the FOREST, you know, of the 579 echoes that we've gathered in the maintenance phase, only 3 of them had a treatment impact. And so, you know, what's the right... There's got to be a more efficient way of ensuring patient safety, but not necessarily, you know, getting lots of echoes that contribute no information.
We have a few ideas about how to get there, I think.
Got it. Okay. And so in this case, I mean, yeah, like, we are done, we are looking for the clinical trial data, but eventually, like, what the FDA wants to do in terms of the label will be the key determinant of the value right here. I mean, yeah, like from your perspective, like, if you think that this is the type of profile that is emerging for the drug, do you feel confident that you would not require a REMS? Or even if there is, there will be like a much less onerous REMS as with the Camzyos.
I'll let Andrew say that.
So from a REMS point of view, I think that as Fady outlined, we will suggest a REMS to the FDA, and then it's a negotiation based on what the FDA wants to see to ensure safe use. Once we see the data, then we'll put a REMS program together. You know, I don't want to use less or more, because then we're comparing to something, and I think it's more around what do patients who would be considered for aficamten, and what does the FDA and what do we feel, given the mechanism, needs to be in a REMS program. We do think we're going to suggest a REMS program. It's likely gonna be an ETASU REMS, and we'll, you know, maybe we have, you know, monitoring a dose adjustment, but with a several-week window.
Maybe we have once or twice a year, on stable dose, or maybe it's risk-adjusted based on where the ejection fraction or a patient element is. So I think we're gonna try to put something together that's reasonable for the healthcare system, but assure safe use as informed by our data. So our data will stand on its own, and if we see data like REDWOOD, then I think we have good confidence that we should have a reasonable negotiation with the FDA that gives us a REMS program that could be preferential for treatment. But there's a variability, and at the end of the day, the FDA can decide that they do or don't agree with us.
Right. Right. So and then, just in terms of the timing of the study, top-line disclosure and what data we might expect, I mean, yeah, this is kind of like a topic that has taken a life of its own. I mean, so anything that you can comment to clarify, like, when to as much as the same as you can, like, when are we going to get the top line, and what would the timeline say, what can we expect at the conference next year?
I mean, I think we can be pretty simple. The answer is, well, it's late December. That's as precise as we'll get. The top-line release is still to be determined. We don't expect to be able to give lots of quantitative data in the top-line release because we would like to see the study presented at the American College of Cardiology, and they have rather strict rules about that. But we certainly will hopefully give some qualitative directionality in terms of both efficacy and safety.
Pointing towards 2024, you know, with the American College of Cardiology, one will see, I hope, because it hasn't been submitted nor accepted yet, but we would hope to be presented there as a late breaker and, you know, have the full data set really laid out for consumption.
Good. Good. Okay. So just one, quick, pipeline question before we wrap up. So, for CK-586 program, I just wanted to understand, like, what's the value proposition for HFpEF? There are a bunch of different, options available here. Just wanted to see how you think this would differentiate versus existing options.
I'll start. I'll turn it over to Andrew. But thanks for asking the question. You know, CK-586 is another cardiac myosin inhibitor. It is different from aficamten in the way it works. It's now in phase I, and we have positioned it towards a subset of HFpEF that we think is a mimic of the non-obstructive HCM patient. So kind of extending the population into an adjacent group of heart failure patients. They have thickening of their hearts. They have heart failure symptoms. They have elevated biomarkers. In a lot of ways, they look like NHCM patients, maybe not quite as severe in terms of hypertrophy. So we think that there are hundreds of thousands of those patients, and they similarly could benefit from a treatment that improves their function and their, you know, disease status.
Maybe Andrew can comment a little bit on the research we've done there.
Yeah, I mean, the subset is probably gonna be an ejection fraction that's greater than 65. SGLT2s are used there, generally and indicated, so by the time, if this gets to market, would be on top of SGLT2s, likely. Entresto, from a data point of view, has HFpEF in the label, but from a publication point of view, I think the number starts to, in terms of where benefit wanes, is when you start to hit the higher 50s, like 57, 58. So that's probably not a competitor, per se, Entresto, in that market. But that subset is pretty large. It's a million patients, high unmet need. So, you know, this is an area where we feel like, we could provide benefit on top of what the standard of care would be at that point.
Great. All right. With that, we are just a little bit over time, so thank you so much for this, and good luck, and looking forward to hearing more about the top line.
Thank you, Ash.
Thank you very much. Okay.