All right, thanks everyone for joining us at the Goldman Sachs Global Healthcare Conference. We're really excited to have the team from Cytokinetics here to kind of walk us through the story. Obviously, heading into a very impactful six months ahead. It's a good time to chat with Robert and Fady. I have a disclosure to read at the beginning. We are required to make certain disclosures in public appearances about Goldman Sachs' relationships with companies that we discuss. The disclosures relate to investment banking relationships, compensation received, or 1% or more ownership. We are prepared to read aloud disclosures for any issuer during the sessions upon your request. However, these disclosures are available in our most recent reports available to you as clients on our firm's portal. In addition, updates to those disclosures are available by ticker on the firm's public website.
Goldman Sachs agrees to host this conference on the basis that no third-party speaker will provide confidential or material non-public information. In addition, by attending this conference, you provide Goldman Sachs the right to record and redistribute the conference information. The views of third-party speakers do not necessarily reflect those of Goldman Sachs. With that, let's hop right in. Obviously, there's an impactful six months ahead. Let's start with your lead drug, cardiac myosin drug, aficamten, or afi for short. Can you please remind us of the rationale for targeting cardiac myosin for hypertrophic cardiomyopathy, or HCM?
It may be better for Fady to take that, since he conceived of this class of mechanism, both aficamten and its predecessor.
Well, in hypertrophic cardiomyopathy, the disease is driven by mutations in the sarcomere, which is the fundamental unit of contractility and muscle. Those mutations have the effect of causing the sarcomere to be hypercontractile, meaning you get, you know, a greater contractile effect with every cardiac cycle. You can imagine how over millions of heartbeats, that that leads to destruction of the muscle, hypertrophy of the heart, just like any muscle when you overwork it. The fundamental issue there is that whatever the mutations are within the sarcomere, they lead to too many myosins, myosin being the fundamental motor unit in the sarcomere. Too many myosins, too many hands on the rope, pulling on the rope.
Aficamten is a cardiac myosin inhibitor, and so it reduces the number of active myosins, the active cross-bridges, fewer hands on the rope and sort of restores some of the balance in the sarcomere to where the contractility is more normal.
The disease of hypertrophic cardiomyopathy is characterized by increased pressure gradients, patients feeling worse, breathless. The idea here is that a myosin inhibitor should reduce those gradients, reduce pressure, reduce symptom burden, and allow those patients to live a more normal life.
Great. Given there's an approved drug already for HCM targeting cardiac myosin, Camzyos from Bristol Myers Squibb, I guess at a high level, how do you think afi differentiates in this treatment landscape?
Aficamten was designed to have what we would characterize as the optimal properties of a cardiac myosin inhibitor. The Phase II data that we have been reporting now for a couple of years would underscore that this myosin inhibitor is translating into patient opportunities that we believe augur well for what we should hopefully recapitulate in Phase III. I'll turn to Fady maybe to speak to what we've seen in Phase II and what was originally designed into this next-in-class profile.
The Phase II was designed to essentially show that aficamten could be titrated safely every two weeks. The benefit there to patients is that within a short period of time, they realize the benefit of the drug, by six weeks or so, every patient had achieved their target dose. Consequently, at the end of a 10-week treatment period, when we withdrew the drug, we wanted to show the effect was reversible. If any patient got into trouble, that decreasing the dose would effectively bring them back to, you know, where they were at the prior dose. We were able to demonstrate reversibility in that context. Shallow onset of effect, so that, you know, you don't have patients that have really large responses to the same increments in dose. The shallow exposure response relationship.
We wanted to understand the range of doses that were effective there, and that was accomplished through kind of two overlapping dose, escalation cohorts. Those data helped us design then the Phase III trial, SEQUOIA-HCM, which is what's ongoing now.
Maybe kind of following from this, a little more granularity. Can you walk through some of the existing clinical data for afi, both in obstructive and non-obstructive HCM?
Just to set the context, and maybe I'll ask Fady then to go into it in more detail. We've conducted REDWOOD-HCM, which is a study, a Phase II study, comprising four cohorts. Three of those cohorts, one, two, and three, looked at patients with oHCM. Cohort 4, patients with nHCM. Patients, as they complete the randomized placebo-controlled portion of REDWOOD cohorts 1, 2, and 3 have been rolling into an open-label extension that goes by the name of FOREST-HCM. All of these Phase II cohorts are 10 weeks duration treatment, with a 2-week washout period. Maybe Fady, if you want to speak to sort of what we've observed through those cohorts.
Sure. I'll split it into two parts. One is obstructive HCM. Those are the patients that have a thickening of the heart underneath, where the aortic valve, where the blood exits the heart, they develop a pressure gradient there. The non-obstructive patients, which we studied in Cohort 4. In oHCM, what we observed in the first two cohorts, which were essentially dose-finding cohorts. We studied in the first group, 5, 10 and 15 milligrams. In the second group, 10, 20, and 30 milligrams. We wanted to understand the range of doses that we potentially were gonna take with us into Phase III. In that placebo-controlled, double-blind study of those two cohorts, we found that the gradients, the pressure gradients was, you know, resolved with treatment.
In the higher dose cohort, 9 out of 10 patients resolved their gradients below the diagnostic criteria for obstruction. We saw improvements in functional class, as measured by the NYHA class, to where about 65% of the patients had a one class or greater treatment improvement. We saw a reduction in biomarkers that are, you know, correlated with cardiac stress, like NT-proBNP and troponin. Importantly, we also saw that safety was quite good, and that we didn't have patients who had to either stop the drug because of too exuberant a response or terminate it for other reasons.
Ultimately, we, out of that experience, decided to focus on the first four doses, five, 10, 15, and 20, going forward in our clinical trials program, because with the 30-milligram dose, we only had one patient that ultimately achieved that dose, and so it didn't seem, at least, feel like we'd reached the top of the exposure-response relationship. The third cohort in Redwood was designed to look at patients who had been excluded from all prior development of this mechanistic class. Those were patients on the last line of medical therapy, which is called diazoxide. That was an open-label experience. Relatively small, 13 patients, which showed the same things. Gradients went down. These are patients failing this last line of therapy because they were got into our trial because they had high gradients despite being on diazoxide.
They still had a treatment response. They still improved their New York Heart Association class. Safety also was quite good in that group. That provided the rationale for including them in our Phase III trial, and really providing them potentially with an option down the road for medical therapy. Then the last group, Cohort 4, which we really reported on only in the last few months, these are the non-obstructive patients. These patients have very little in the way of treatment options. They don't respond to beta blockers or calcium channel blockers, kind of the standard of care. Surgery is not really an option for them. As we reported in March and in May, these patients experienced a substantial treatment benefit. Their biomarkers were improved, the NT-proBNP and troponin.
They had a functional class improvement in their NYHA class. They had improvements in their Kansas City Cardiomyopathy Questionnaire, to where about 60% of the patients had a 5 point, which is a kind of a clinically meaningful threshold or greater improvement in their KCCQ. Safety overall was reasonably good. We had, you know, reversible declines in ejection fraction in patients at the end of therapy. That helped us to really define the range of doses that we would take forward. 85% of the patients got to the highest dose, as we've thought about now, the Phase III trial, we understand the range of doses and kind of how to dose the drug in that group.
What's encouraging about all of these cohorts is you're getting patients to their target dose within just a few short weeks, and that's producing symptom burden relief within just a few short weeks, which I think will matter a lot ultimately to patients, if that's borne out by the Phase III data and also as we go to market.
Great. Kind of with all of that in mind, obviously you mentioned SEQUOIA-HCM, the Phase III trial. Can you remind us some of the key aspects of the design of this trial, and then maybe follow up with some discussion about how it roughly compares in terms of design, maybe to the EXPLORER-HCM trial for Camzyos in the same obstructive HCM population?
Maybe I'll start. Firstly, we're gonna avoid making any comparisons of aficamten to mavacamten, but certainly the trial designs, we can describe how they're similar and how they're different. As it relates to SEQUOIA-HCM, it's intended to be as real-world as can be practical, and I say that from a couple of different optics. One of which is the way in which the clinical trial is designed, but also where it's conducted. It's a study that's being conducted truly internationally, throughout Europe, North America, even in the Middle East and Asia. SEQUOIA-HCM is designed to look at patients with obstructive HCM, compared to. It's a comparative study, those on placebo alone, or those on placebo plus aficamten, as would be dosed over 24 weeks, with a washout period of 4 weeks.
The idea here is to assess for changes in peak VO₂, as measured by CPET, for those patients who start with baseline measurements and then over time, and then secondary endpoints, including the KCCQ. Our objective here is to, with SEQUOIA-HCM, read out in a way that could be expanding for potential array of patients and those physicians who treat them, and their comfort for use of myosin inhibitors. Maybe I'll turn to Fady and speak more to the specific design elements, including the statistical objectives.
With SEQUOIA-HCM, our objective was to be able to demonstrate an improvement in exercise capacity, functional class, and symptoms. The endpoints reflect those three objectives. First, being exercise capacity. There, we measure exercise capacity using an objective test, which is a cardiopulmonary exercise test, and the metric of interest there is a change in peak oxygen consumption. The primary endpoint of the trial is the change in peak VO₂. The other endpoints of NYHA class, functional class, and KCCQ have described Phase II data in those, generally, and those are the secondary endpoints. As well as looking at some of the echocardiographic and biomarker changes that occur with treatment with aficamten.
The primary endpoint is really just a continuous measure, a continuous calculation of using the change from baseline at Week 24. It's powered to over 90% power to detect a 1.5 milliliter per kilo per minute change. What does that mean practically? Well, clinicians tend to think of anything above 1.0 as being clinically significant. You know, with what we have in terms of the number of patients we've enrolled and the observed variability so far, you know, we have well over 90% power to see that a 1.5 change or even less than that in this clinical trial. We think in terms of conduct, that that's very, you know, that endpoint should be very stringently assessed.
The, you know, the other objectives have to do with safety, they're looking at the number of patients that have treatment-related safety events, in particular, drops in ejection fraction. The way that we handle those is with a decrease in dose that's handled through a computer system, there's no physician or our intervention. It's only in cases where the ejection fraction drops fairly low that there is an unblinding event. The trial is 24 weeks in duration. There's a 4-week follow-up after the after 24 weeks. They come off drug at 24 weeks, they have a follow-up visit at 28 weeks, at which point then, you know, data can be cleaned and database locked and finally analyzed.
All right. You asked about the comparison to the EXPLORER study. There are similarities and differences. The endpoints are different. The primary efficacy endpoint in SEQUOIA is change in peak VO₂. The primary endpoint in EXPLORER, the pivotal study for mavacamten in obstructive patients, was a combination endpoint that included both peak VO₂ and change in NYHA class. We're measuring both of those things, but we're doing it separately, where our primary endpoint is peak VO₂ by itself. Otherwise, the patients being enrolled are similar. It's possible we'll see in the baseline characteristics some differences.
We can't be sure, but it's possible that we'll be in a position to report on the baseline characteristics in SEQUOIA sometime in Q3, as may occur at either the HFSA meeting or the HCM Society meeting, both of which are in September. You know, our goal here is to advance the category and advance the science, so there are things that we aimed to do that could be enriching for treatment effect and amplifying the magnitude of response. These are things that should be enabling of us to understand whether aficamten should in fact have labeling that may ultimately prove different. For instance, we're looking at patients on and off beta blockers.
We're looking at patients who come into the study with a deficit in exercise capacity and may therefore have potential to see a greater increase in exercise stamina. These are some of the things that might ultimately prove to be different between the two studies, although we can't know that until we see the data.
All right. As far as about all that, can you remind us how enrollment is going in SEQUOIA? And I guess, how confident are you that you're on track for a readout this year?
Here's what I can say. With our Q1 earnings call, which was conducted on May fourth, we indicated that we would expect to complete screening on May fifth, which we did. We'll give an update on enrollment with our Q2 earnings call, which will be in early August. To answer your other question, we do feel confident that we're on track to see data in Q4, which means we would have needed to meet our objective of completing enrollment in Q2. We're still in Q2, so we'll report on all of this here in the next few weeks. Our objective, as we've commented publicly, was to even over-enroll the study, and we'll be able to provide some thoughts about that too.
The study was designed to enroll 270 patients, and as such, it would be the largest, clinical trial conducted in a population of obstructive HCM patients, and our goal was to over-enroll it. We'll see how we did.
I asked this question because I'm going to get asked this question in the next couple of days. When you say you'll see data by year-end 2023, do you mean you'll see data or we will see data?
Our intention is to top line it by press release in the fourth quarter.
Okay, excellent. Great.
The actual full data presentation may not occur until the next logical medical meeting, which, as we look at the calendar, would likely therefore be the American College of Cardiology meeting in early 2024.
Perfect. To that end, let's get to that point about the top-line versus full medical data. Imagine I'm sitting around watching my favorite holiday movie, bloop, press release, top-line data from SEQUOIA. How should we think about the data we're going to see in the top-line for SEQUOIA, relative to a more complete review of the data at a medical meeting like ACC in next year?
It's a hard question to answer until we actually see the data, but it would be our intention to report that which is deemed material and not have that otherwise jeopardize the presentation of the data at a medical meeting. That's in part a negotiation between us lawyers and the people at the American College of Cardiology. We've done this before, and, you know, it's a dynamic process, but you can expect at least that which reports on the primary efficacy analysis and hopefully a p-value associated with that. As to magnitude of effect, I don't know. Then there's the secondary endpoints, and then there's the safety. I think you should hopefully expect some reporting on those, but again, not enough that it would be deemed front-running the presentation at a medical meeting.
It's some combination of those things that should enable investors, hopefully, to feel confident that the study met its endpoint, as could be enabling of potential approval. As to how much and how it might ultimately read on a REMS program or the product profile or all these kinds of things, that's something that I can't know until we see the data as to how much of that would be included in the press release versus a medical meeting.
That's an excellent transition for us. The REMS is a question we get asked about all the time for this class, right? Given the kind of structure for Camzyos right now on approval and kind of how to think about the transition better over time, how should we think about a potential REMS for afi, based purely on how you design kind of monitoring in SEQUOIA?
Based on how we designed monitoring. We designed monitoring in SEQUOIA so as to be able to collect and analyze data that would inform a flavor of REMS. Meaning, if it is evident that in doing as frequent echo monitoring as we're doing, that there are no value adds for that, no excursions that warrant assessment of ejection fraction or other echo parameters as frequently. One would hopefully be able to make a case for less frequent echo monitoring in the real world than was in the clinical trial. That's the objective. Our base case is that we're doing more monitoring in SEQUOIA than we think should be necessary post-marketing, and we just have to collect the data in order to be able to lend evidence for that base case.
So far, I think you can be encouraged by the fact that we have now dozens of patients beyond 1 year and some patients beyond 2 years in the open label extension of the REDWOOD-HCM Phase II study. We're encouraged by the fact that, you know, we're not seeing dose interruptions, dose discontinuations, drug-drug interactions, or anything that would warrant frequent echo monitoring post-marketing. To the extent that continues, and to the extent that is validated by the SEQUOIA-HCM data, that would lend evidence-... to how we would approach FDA vis-a-vis REMS.
Okay. I mean, following from that, do you think that these are issues that could come up as early as the initial FDA review of aficamten, or is this the kind of thing where potentially 2 years down the road to a commercial launch, you could revisit an existing REMS regime, kind of based upon real-world experience?
I think it's part of our go-to-market strategy. The initial approval should hopefully reflect that, in as much as a REMS can often be proposed by a sponsor, and it becomes part of the negotiation of the label. Our base case is that we should have a form of REMS, but not necessarily one that's very restrictive in terms of frequency of echo monitoring.
Okay. Kind of following from that, at a high level, assuming SEQUOIA is successful, how do you view the commercial proposition for afi relative to other drugs in the obstructive HCM landscape?
We look at aficamten as a next-in-class compound. If you look at next-in-class compounds, generally speaking, it's incumbent upon those companies commercializing a next-in-class compound to be expanding of a category. A lifting tide, if you will, helps all boats. Our expectation is that aficamten will enter a market that's still in its infancy, with still a vast majority of patients on beta blockers and calcium channel blockers and not a myosin inhibitor. Our goal would be to demonstrate that physicians in HCM centers of excellence, but also outside of those centers, could be comfortable with a profile of aficamten, so as to be able to use that to the benefit of their patients.
We foresee that there's a large market here, upwards of 200,000 patients in the United States, and where that just represents, in some ways, the tip of an iceberg, because there are a lot of patients who are currently symptomatic but not diagnosed, sorry. Therefore, it's incumbent upon us to continue to build education and awareness around the potential benefits a myosin inhibitor could accrue to patients. We're looking at this as a category that's going to grow appreciably, both in obstructive patients and also potentially in non-obstructive patients. This is an area that could be defining of a very large cardiovascular market.
All right. Maybe moving beyond SEQUOIA, can you walk us through the additional planned pivotal studies you all have for afi in obstructive HCM?
You use the word pivotal. There's another study called MAPLE-HCM that I don't consider pivotal, but it should be, if successful, expanding of labeling. Maybe I'll ask Fady to comment on the design of MAPLE-HCM. There's another Phase III study in non-obstructive HCM. MAPLE-HCM's gonna get underway with start this month, and the non-obstructive HCM pivotal Phase III study will get underway in the second half of the year. We haven't commented so much on the design of that study yet, but maybe, Fady, if you wouldn't mind speaking to MAPLE-HCM?
Sure. MAPLE-HCM HCM is intended to evaluate monotherapy of aficamten versus monotherapy of a beta blocker. you know, beta blockers traditionally are first line of therapy in this disease. Many of our patients in SEQUOIA-HCM will be on beta blockers as background therapy. What we saw in the open label extension in FOREST-HCM is that we allowed physicians to titrate background therapy away, and in doing so, they eliminated beta blockers or calcium channel blockers in their patients and saw that the efficacy was maintained with aficamten as monotherapy. We now want to evaluate head-to-head, which of these two therapies is superior. The reasons to think aficamten would be superior, beta blockers tend to blunt exercise capacity. When you look at trials of beta blockers, there's no improvement in exercise capacity.
They have more modest effects on symptom improvement. The real storyline here is, can you establish a cardiac myosin inhibitor as a preferred first-line therapy in this disease because of more, a larger treatment benefits, fewer side effects, and potentially also demonstrate that there is structural, positive structural changes that occur in the heart with a mechanism designed to target the disease as compared to a beta blocker, where they may not exist. MAPLE-HCM is about 170 patients. Patients can either be naive to therapy or they can be on background therapy and withdraw from it. They're then randomized to aficamten or beta blocker, metoprolol in this case, and they undergo titration in a blinded fashion.
They are treated for 24 weeks. At the end of 24 weeks, peak VO₂ is the primary endpoint, you know, of course, we're measuring similar things as we do in SEQUOIA. It's about 170 patients. It's smaller than SEQUOIA. The entry criteria are a bit more relaxed compared to SEQUOIA. We'll see patients that are not necessarily as severely impacted as those in SEQUOIA. You know, that trial is gonna start imminently. It's really enthusiastically embraced by the community. They want an answer to kind of this question and data that support maybe using cardiac myosin inhibitors as first line therapy. The other trial that we are planning to start is in the non-obstructive HCM patients.
As I described earlier, the Phase II data were really quite promising. We've used that to inform the design of a Phase III study that will start the second half of this year. We haven't given many details about that, but you can imagine we'll measure things in that we've measured before. I mean, these patients have the same symptom burden, and so the same issues that they have in terms of exercise capacity, symptoms, and functional class, and we'll look to begin that trial for the in the second half of the year.
I wanna follow up on the discussion of MAPLE-HCM, 'cause I feel like intrinsically, one can get their hackles up that beta blockers are like, they're a multi-decade, inexpensive frontline therapy. Kind of the conventional wisdom is you're gonna step through that before you get to a drug like aficamten. In your discussions, both with the regulators and also with payers, like, what do you need to see in that trial to really make the case that you should take a branded drug ahead of a beta blocker as first line therapy in a disease like this?
Keep in mind that beta blockers tend to make patients feel worse. If you're measuring exercise capacity, as Fady has pointed out, patients on beta blockers don't have the ability to perform with the same endurance, because oftentimes beta blockers blunt heart rate, and you can't get your heart rate up to be enabling of higher exercise stamina. On top of that, they make people feel crappy. I don't think there's gonna be a tremendous obstacle to overcome with physicians, despite beta blockers having been around for a long time, if we demonstrate superiority with aficamten versus metoprolol. Payers are actually encouraging of this study, because right now, you do have to step at it through beta blockers to get to a myosin inhibitor.
The objective would be to demonstrate that that may no longer be necessary, especially if we demonstrate superiority in terms of exercise capacity, an endpoint that matters as well as safety, things that, ultimately the patients complain about the most.
Maybe coming back to non-obstructive. I think the question you get from a lot of people is how to think about the timing for non-obstructive, the timing, the addressable population in non-obstructive HCM relative to obstructive disease. How do you think about that kind of proportionately, the non-obstructive relative to the obstructive population?
The prevalence of non-obstructive HCM is smaller than obstructive HCM.
Diagnosed prevalence.
Diagnosed prevalence. Therefore, one should not expect that the labeled indication will address a treatable market that's considerably larger. It's actually smaller. What's important, though, is that nHCM has read through to other patients who have comorbidities and diagnoses that may ultimately benefit from a myosin inhibitor. We look at nHCM almost as a gateway to how we think about a myosin inhibitor and how it may have application to a subset of patients with heart failure with preserved ejection fraction, of which there are millions of patients, and for which roughly a third to a half of them have thickened walls in their heart and other symptoms and structural abnormalities that are resembling of what you see in nHCM.
Think of it as a continuum, if you will, obstructive patients, non-obstructive patients, HFpEF, all of which ultimately define a very large cross-section of cardiovascular patients growing larger with the aging demographics.
Right. I'll ask you the question we're asking all companies at the end of the conference: Why should someone buy and own Cytokinetics shares in the coming 12 months?
Cytokinetics is a company, now in its 25th year. Fady and I started the company 25 years ago, and we are coming into a period in the second half of this year that is its most important period. We are staring down a pivotal study that could represent a transformational event for the company, as would be enabling of our compound aficamten to be a new potential medicine in the treatment of obstructive HCM. Investors see that, as we understand from them, as a meaningfully important driver for value, in part because there's a predecessor company that we helped launch that developed the first-in-class molecule, and Phase III data prompted that company's acquisition at a premium far north of where we're currently trading today.
That's not why we are doing the study, to be sure, but at the same time, I can't ignore that as a investor value proposition. What I can say is it's a meaningfully important catalyst for Cytokinetics as we mature our business. Being in a position where we can advance our science for the benefit of patients and be in a position where we could go to market with our first medicine next year and build a more enduring, sustainable business, as it would be the leading edge of a specialty cardiovascular business.
You know, we now find ourselves with four potential medicines, drug candidates in our pipeline, aficamten the lead amongst those, and we believe that we've developed in our science and pharmacology what can be a somewhat unique profile, a specialty cardiology company, that with a limited sales and marketing infrastructure, can produce a very high return on investment and return on sales. I think that's a good place to be.
Excellent. Well, thank you so much, Robert and Fady, for joining us this afternoon. Thanks, everyone, for joining us today at the Goldman Sachs Global Healthcare Conference.
Thank you.
Thank you.