Alrighty. Got one minute. So for intro remarks, okay. So good morning, everyone. I hope you're all doing well. Day one of our London Healthcare Conference. I hope everyone enjoyed their red-eye flight, coming here. I know I did. I know Robert did as well. But it's great to see you all. My name is Akash Tewari. I'm a pharm and biotech analyst here, and I have the pleasure of hosting Cytokinetics, including CEO, Robert Blum, Chief... Is it medical or scientific officer? Chief-
Just the head of R&D.
Head of R&D. It's one of those, Fady Malik. Cytokinetics is a topic for us. They obviously have a very big readout coming out, year-end. I'm gonna give it to the team for some intro remarks, and we'll take it from there.
Sure. So thank you for the introduction. Thanks for inviting us to the conference. I'll make some opening remarks just simply using a few slides, and then we'll have mostly conversation. I'll introduce you to the company that Fady and I started 25 years ago. We've pioneered, and we lead in an area of muscle biology, translating that into a new pharmacology. Our pipeline directed to a business model that we think is also unusual, and we'll be able to elaborate more on this. I'll be making some forward-looking statements. I'll refer you to our SEC filings, including our last Q just filed, and that we don't undertake any obligations with regard to those opening or those forward-looking statements. Our mission is a simple one.
We want to translate this area of science, this one area of biology that we know better than anyone else, into a new business, a business that's translating that to medicines that could be available to assist people who are suffering from devastating, mostly cardiovascular conditions of impaired muscle function. By doing so, we start with this structure, the sarcomere, the fundamental unit of the mechanics of contractility of muscle, something that we know better than anyone else. We've pioneered it for it being a cornerstone of how we do drug discovery. All of our compounds in clinical study now are either activators or inhibitors of proteins involved in muscle performance driven by sarcomere biology. Our pipeline is here. Aficamten represents the leading edge of our portfolio. It's a cardiac myosin inhibitor that we're developing as a potential treatment for obstructive and non-obstructive hypertrophic cardiomyopathy.
Aficamten follows behind a compound called mavacamten that we played a hand in discovering as that company, MyoKardia spun out of our research and ultimately was acquired by BMS. Aficamten is intended to be a next-in-class cardiac myosin inhibitor, goal being to expand the category beyond where it's currently being used. Aficamten inhibitor, we've got other activators and inhibitors of our pipeline. We probably don't have time to go into them in much detail today, but pointing out here on this slide, our pipeline and portfolio is comprised of cardiac muscle-directed compounds, and I underscore that because most drugs we use in cardiology don't act directly on the heart, and especially as we're learning more and more about cardiometabolic syndromes and other diseases that read on cardiology, obesity, and diabetes, et cetera.
Having drug candidates directed to cardiac muscle represent the next adjacency, and we think aficamten reflects positively on that and also enables us to build something that we think is unusual for a biopharma company. A lot of companies doing very interesting, compelling things as relates to innovation. None of them focus to building a specialty cardiovasculars business. We think that some of the companies in biopharma that orient towards cardiology are having to build infrastructures and sales, marketing, medical, et cetera, that don't lend themselves to a high return on investment or shareholder equity. What we're doing here by focusing strictly on cardiac muscle and those indications that are managed by a fewer number of customers, enables us to build a lean sales and marketing infrastructure that could afford a high return on sales, ultimately more payer leverage.
These are severe unmet needs where we believe the economics favor a company doing what we do. Aficamten's profile is listed here. We believe it has an opportunity as a next-in-class compound to win on efficacy as well as safety, but where also convenience plays a role ultimately in market adoption, product positioning, and category expansion. Aficamten was designed from the get-go, given we knew a lot about the first-in-class compound, to demonstrate what could be properties that could be reflective of a potential best-in-class profile.
Here you see on this slide some of the things that we've designed into the molecule, all of which have been borne out by current phase II data, as well as the open label extension study of that phase II study, all of which have been already reported and which augur well for the phase III data to follow from SEQUOIA. SEQUOIA is the pivotal study in obstructive disease. It's reflected here by schematic. We over-enrolled it, 282 patients. We're measuring change from baseline in peak VO2 at 24 weeks. We will have these data in late December, and these data, we think, are already...
Benefiting from the fact that, we've reported from the open label extension on patients who have been treated out to two years, and we think that, again, points to why one should be cautiously optimistic about what to expect from the phase III data if those bear out similarly in this pivotal randomized controlled study. There are two other studies that are also underway with aficamten, MAPLE and obstructive disease. Think of it as a potential phase IV study that we've brought into a phase III program, the goal being to publish these data so they're available at the time of launch. That could be enabling of aficamten to move into frontline treatment of patients with obstructive HCM and have that be included in guidelines. We're also studying aficamten in non-obstructive HCM in a pivotal phase III study called ACACIA. It's underway.
It should also read out, we hope, in 2025, rounding out the picture of aficamten as a potential best-in-class compound in both obstructive and non-obstructive disease. We do believe the company is uniquely positioned for the success as that specialty cardiology business I described. We're a leader here. We've been at it for 25 years. We've established certain credibility and integrity among not only clinical researchers, but they also represent key opinion leaders in adoption of products. And we have a depth here. This is not a one asset, one trial, binary risk company. We've got an enduring business model and pipeline that we think builds longevity into what ultimately will be enabling of us to establish meaningful relationships with customers and in the business.
I think that's afforded us already, uncommon access to capital, both through equity financings, but more importantly and more significantly in terms of magnitude, we've been, I think, demonstrated over 25 years that we rely primarily on non-equity dilutive capital through partnerships, through royalty monetization, ways that we can monetize our expertise in ways that don't come at the expense of shareholders. I think we come into this big event later in December, already with a strong balance sheet representing between 18 and 24 months of forward cash. Here are those expected milestones for the remaining weeks of 2023, the most important of which is obviously the readout of the phase III study, SEQUOIA, in late December. With that, we're ready to maybe have a panel discussion.
All right. Thanks so much. Okay, so, maybe just jumping in here. There is a... There's a really interesting graph in the multidisciplinary review for mavacamten, and basically, the FDA kind of determined it was like 350 nanograms per milliliter to 750 was kind of the sweet spot on PD effect. And they actually looked at the percent of patients for both EXPLORER, this is the mavacamten phase III, and then also I think through PIONEER, that actually got to that sweet spot. And it was really provocative. I think for, EXPLORER, it was about 39% of patients who the FDA determined patients got to that kind of sweet spot, and it, it kind of closely correlates with the response rate. They showed 37%.
Robert or Fady, I'd love to get your take on, do you believe that there is a PD exposure-response relationship when it comes to pVO2? and if you were to guess, based on what you've seen with the PK/PD data with aficamten, what % of patients would be able to get into your own kind of theoretical sweet spot, from a PD perspective?
So I'm gonna turn for the technical part of that to Fady in a moment. Fady can obviously speak to that. He's the one who's most expert as it relates to PK/PD relationships and exposure-response relationships. What I can say is that in EXPLORER, MyoKardia was using both PK-guided dose titration and echo-guided effects to determine up titration of patients to what would be thought to translate to optimal efficacy. But in approving the drug, FDA was permitting of a dose titration regimen that doesn't rely on PK-guided use. There isn't a companion diagnostic assay that's guiding the use of mavacamten. As a result, interestingly, in the real world, many more patients are being down titrated than up titrated as a derivative of the REMS program that's in place, a restrictive REMS program for mavacamten.
We have knowingly adopted a regimen of dose up titration that is simple and that we believe would be enabling of, we hope, a REMS program that would be opening the door, opening the aperture on a wider adoption use of aficamten. And already, we're seeing in REDWOOD and FOREST data to suggest that we're getting patients up titrated using... Now, we have access to 5, 10, 15, and 20 mg doses, getting patients, to where we think that can be optimized. But maybe I'll let Fady elaborate and also address your specific technical question.
You know, there's not a super tight relationship between peak VO2 and plasma concentrations because it's not a one-to-one relationship. Your plasma concentrations will reduce cardiac function. That'll then have an effect on a gradient that may affect the exercise performance, but other factors play in, you know, body weight, general conditioning, other things. So I would view it as a, you know, pretty broad band. I think the issue is really how do you navigate the therapeutic index? And how do you get patients to therapeutic doses without exceeding doses that are potentially harmful to them? And with the open label data, and we have so far seen that about two-thirds of patients get to one of the two higher doses.
We have seen no impact in terms of safety in that, in terms of that dose distribution, and so that should enable us, you know, to sort of maximize exposure and maximize treatment response.
Understood. Okay, that's very helpful. Now, a common investor question I'll get is, you know, why pick peak VO2? We never measured it, blah, blah, blah. You've heard this question a million times. I think the more interesting question is, like, I feel like if you look at the mavacamten data, the question is: Is it a bug or a feature? When you look at on pVO2, patients who are more severe actually did worse on pVO2 improvement. You've talked about enrolling a more severe cohort. So, you know, and this gets into more of a theoretical question, but when I look at that, I think, okay, that is a feature to me because it looks like mavacamten can't adequately treat those patients. They can't get to adequate PD exposure.
So it shouldn't surprise me that the more severe patients actually did worse on mavacamten on pVO2, not the responder endpoint, but on pVO2. I would love to get your thoughts on how you think about the, you know, severity and exposure relationship with your drug versus mavacamten, and if there's any kind of expectations you have for SEQUOIA.
Yeah. So the way that we achieved a peak VO2 on average of 18.5, it's about 1 point lower than the 19.5 that was seen in EXPLORER, was really by shaving the top. So we prohibited enrollment of patients whose peak VO2 was well above normal or was not functionally impaired. It had to be 80% or less of predicted. And so we didn't necessarily enroll more severe patients. We got rid of the patients whose peak VO2 was already exceeding normal. You know, and so in that sense, I think there's not an adverse impact. But I think that potentially it's more meaningful because you have patients whose exercise capacity is clearly impaired.
You know, you walk a fine line between trying to optimize and enrich your study for maximal treatment effect, but still having something representative of the intended hypothesis that you're testing in real-world clinical practice.
Right.
And I do think we threaded that needle, well, enrolling patients who have a deficit in exercise capacity, but not so severely impaired that they may be unable to demonstrate an improvement. So a slight reduction, where there could be still some headroom to benefit from an investigational treatment, but excluding those outliers that might be not representative of the majority of clinical practice.
Understood. Now, you know, it's funny, I get this question a lot. We even ran a survey because I had no idea. Like, what's, quote-unquote, "the bar" to show differentiated efficacy on peak VO2? I know you guys have powered for 1.5. Our survey says 1.8. I don't know if a doctor draws the line at 1.8. Does he draw a line at one... I'm not sure. But on pVO2, if you were to say, let's say, you know, what threshold do you think you would show that if you can have that on your primary endpoint, that a doctor and the clinicians would actually think this is differentiated on efficacy, right? Is there a bar that maybe you can help us with?
It's funny you say that, because as we've interacted with fund managers, we get different numbers.
Yeah.
Yours is 1.8?
Well, that's actually their conglomerated answer.
From a survey?
Yes.
But I think there's some range there.
Yeah, absolutely.
This morning, we had somebody tell us it could be, you know, north of 2.0 before it might be differentiated. That's quite a large difference from, you know, mavacamten, 1.4 in EXPLORER to 2.0. That's a very large differential. I think anything in cardiology that's 20% better than something else, 20%-30% tends to be viewed as differentiated. I'm actually gonna take maybe a slightly off-angle way of addressing this, and I believe, while I expect Cytokinetics in SEQUOIA is gonna be able to win on efficacy, at the end of the day, I would argue most physicians don't even look at peak VO2 or understand it well enough to appreciate the nuances that drive differentials.
Hmm.
And how it relates to BMI, how it relates to other things, is lost on most physicians who are gonna be treating patients with these drugs. More important to them is likely gonna be convenience and safety, and ultimately, what speaks to patients' recognition of symptom burden relief, and that's measured in terms of endurance, not necessarily activity at peak exercise, and also how it reads on shortness of breath or other things that they experience in a daily way.... more than how they perform at peak exercise.
Understood. Okay, and by the way, for the record, I guess $14.20, that would imply $17-$18. So you're not that different. Okay. Understood. So another question, we're internally thinking about, I know investors ask about as well, is disopyramide. And, maybe just... I know you over-enrolled the study, which always seems to be a good idea. Would you be able to give data, when you top-line press release sometime in late December, where you would show an apple- Right, 'cause mavacamten study did not include these disopyramide patients. Disopyramide is obviously a very applicable treatment. There's issues with the therapeutic index.
But would you be able to give a cut of patients who are not on disopyramide, so we have, you know, kind of an apples-to-apples comparison and then a cut with a full cohort? Would that at least be possible for the top-line data?
I doubt it. I wouldn't expect that level of cut for a top-line press release before data are actually presented at a medical meeting. The most likely one to follow is American College of Cardiology.
Right
- in early April. You didn't ask this, but I'll say, you know, we're looking at that top-line release and knowing that it's ACC, and they tend to be more conservative in terms of what can be included quantifiably. What can we communicate that, obviously, we're gonna communicate that which is deemed material from a legal standpoint, but what can we communicate without jeopardizing the release that is reflective of, whether this drug is meeting our target product profile, which is consistent with next-in-class, potential best-in-class? I'm not sure, people off of disopyramide is gonna rise to that level of materiality, but also, we're not gonna be feeding, any improper comparisons-
Mm-hmm.
of EXPLORER-HCM to SEQUOIA-HCM because they're different studies conducted at different times with different drugs. It's not a head-to-head. We're gonna just be reporting on that which we think is material to pharmacokinetics and meaningful for the study we conducted.
Understood. And that makes sense. So, maybe going into safety and, you know, it's... This is one thing I was at AHA, I hosted a KOL, and this is something I did not appreciate was the cost of an echo. It's like $1,000 every single time. So on top of having a very expensive, you know, drug where you could be paying a lot out of pocket, the echoes are a significant financial hurdle for a lot of the patients who have HCM. So, you know, I get the question quite often: What is a differentiated REMS? To me, I think there will be a REMS class effect. That doesn't surprise me. That would be an unreasonable bar. But what would you think of the potential of a yearly echo?
'Cause feedback from doctors suggests an HCM patient would be seeing their doctor on an annual basis. So, A, is that potentially a possibility for aficamten? And then number two, I think the more nuanced question is, we're probably not gonna get enough data with the top-line release of SEQUOIA to maybe paint that picture, right? So if that's not the case for the top-line release, when would we get enough data, maybe on follow-up, to feel confident that that's a possibility?
I mean, I think, you know, there's like anything that we monitor in medicine, there is often a need to monitor more frequently when you initiate and then the taper of monitoring over time as patients are demonstrated to be stable on that therapy. You know, in FOREST, with the open label data, what we have reported is that of, you know, close to 600 echoes, only three of them manifested any clinically actionable result. And so what the right frequency is, clearly, the every three months that we're doing in FOREST it seems to be overkill. I think you can argue for every six months or every year or potentially a risk-based monitoring. So I think there are ways to maintain safety but reduce the burden both for the patients, the sites, and obviously, the medical system.
But as Fady's pointing out, not everybody necessarily needs to be echoed on the same schedule. So, you know, obviously, what you're trying to do by doing these echoes is keep people out of heart failure. And if you've got a higher ejection fraction, maybe you have a different-
Mm
... echo frequency than if you don't. So ultimately, that'll be a derivative and a function of data. And a REMS program is a negotiation between the sponsor and the FDA, and what we're encouraged by is that the FDA's already been permitting of us in clinical trials to do something that is very different from what they put in place, to ensure safe use of mavacamten, which is they're permitting, when an EF falls below 50, of a simple down titration with aficamten, as opposed to a dose interruption. And I think that augurs well for what we would hope will be FDA's, science-driven, data-driven approach to a REMS program when we come before them with our data.
Understood. And just to remind, is there going to be an extension on REDWOOD, where you might be able to follow patients out, let's say, to a year, similar to what you did?
SEQUOIA, you mean.
Sorry, sorry.
Yeah, all those patients in SEQUOIA have been eligible to enroll in the open-label extension. So we now have over 200 patients enrolled in that open-label extension, and they'll be followed for up to 5 years.
Understood.
Already there are SEQUOIA patients in FOREST.
Got it. Got it. Got it. I want to last touch on the IRA. I feel like you guys actually have quietly been one of the biggest winners from the IRA, because it seems like, you know, Bristol might have thought they could take MYK-224 into obstructive HCM. They're gonna have that data Q1 2024. But with the IRA now, they're so excited about their signal in HFpEF that that's really where they're taking that, a molecule that at least descriptively sounds very much like aficamten. Can you talk about the HFpEF opportunity? You know, Bristol made some pretty, you know, encouraging comments at their R&D day. But how do you think about a drug where, you know, it seems like it's more of a proxy on non-obstructive? You have to dose higher, you have to get higher exposure.
You don't necessarily have the biomarker of the obstruction. But what is the potential for this class of drugs in that indication? And, you know, what could we maybe think about from an efficacy perspective there?
Well, you know, about eight years ago, we proposed pursuing this mechanism in HFpEF alongside HCM because the non-obstructive HCM patients are a bit of a proxy for HCM. They have a similar physiology, similar thickening of the heart, just more extreme. So-
Mm
... a certain fraction of the HFpEF patients, we think, behave a lot like the NHCM patients. There are more of them, and what we've decided to do was pursue it. Rather than pursue with aficamten, we developed a second molecule. It's now called CK-586, and we're pursuing that in phase I and plan to advance that into studies of HFpEF, as soon as next year.
Understood. We are out of time. I really did enjoy it. Thanks so much for joining us, and thank you so much, Robert and Fady.
Thank you.