Good afternoon. I'm Serge Boulanger, one of the healthcare analysts at NEOM & Company. I want to welcome everybody to our 24th Annual Healthcare Conference. For our next Fireside Chat session, we have the Cytokinetics team with us. From the company, we have the EVP of R&D, Fady Malik, the company's CFO, Sung Lee, and the Chief Commercial Officer, Andrew Callos. Before I hand it over to them to give us an overview of Cytokinetics, I just want to highlight that we can take our Q&A via the portal that you're watching the presentation on. Just submit them through there, and we'll take them as they come. I'll hand it over to the Cytokinetics team here and give us a quick overview of the company for those who aren't familiar with the company or recent developments.
Sure. I can take that. Thanks for having us, Serge. I'm Fady Malik, the head of R&D. I'm joined by Sung Lee and Andrew Callos, our CFO and Chief Commercial Officer, respectively. Cytokinetics is a muscle biology company that has pioneered ways of modulating muscle contractility over the past 25 years, and in particular, contractility of the heart by focusing on the sarcomere, which is the fundamental structural unit of contractility in the heart. We have developed a number of molecules through the clinic. The one that is most advanced now is Aficamten, which is a cardiac myosin inhibitor that was developed to treat hypertrophic cardiomyopathy.
It's a next-in-class molecule that has completed a fairly extensive phase one, two, and three program with other trials ongoing in order to define its place in the context of other therapies, as well as to examine it in an adjacent population to the obstructive HCM population. The NDA has been at the FDA for a while. We've recently put out an 8-K. We've had our mid-cycle review with FDA and believe that we still have a differentiated approach to labeling and risk mitigation, as we've thought all along, really, with no anticipated advisory committee expected. Otherwise, we're looking at now MAPLE, a second trial looking at a monotherapy trial of Aficamten versus beta-blocker reading out in the second quarter and continuing to progress ACACIA-HCM, which is a non-obstructive trial of patients and moving that forward.
Maybe with that backdrop, I'll turn it back over to you, Serge, and we'll take any questions.
Perfect. Great overview. I guess regarding the ongoing review with FDA, like you said, you did put out an 8-K recently. Just curious if the recent FDA changes, if you're aware of it, if they've impacted the division that is reviewing the Aficamten NDA.
We interacted with folks before NDA and during this review and as recently as a mid-cycle. So far, everybody is still the same. No change in the players there, including up to the division reviewers that are in charge of our review. You never know what could change, but so far, we've been pleased to have the same group working with us.
Okay. Otherwise, it sounds like it's gone smoothly. No adcom. Manufacturing site inspections are on schedule. Nothing's changed on that front?
Nothing has changed beyond the course of the normal NDA review, I think, at this point. We're fielding questions. We answer questions. Inspections are scheduled and have been ongoing in some cases. So far, I think we will continue to progress our interactions with them, but we'll probably stay relatively silent on the details, just given it's an always changing field.
I'm sure you field a lot of questions about Aficamten's potential product label and its REMS. So I'll ask the same thing. What are your current expectations for both at this point?
I think I guess maybe I'll answer and just say that, again, we expect a differentiated label and risk mitigation. We know, obviously, BMS has submitted for modification to their REMS, which likely would include moving monitoring echoes from every three months to every six months. That was something that they were able to achieve in Europe. That is not the only, I think, point of differentiation between Aficamten and Mavacamten. I think there are many other features that are intrinsic to Aficamten specifically and are important, I think, to physicians. Maybe I'll ask Andrew to comment on how he thinks the REMS of Mavacamten impacts its use and how Aficamten may be different.
Yeah. Today, based on the syndicated data that we have available, it would indicate that about 80% of MAVA's prescribing is with around 600 physicians, mainly Cardiologists and centers of excellence. There's about 1,000 active prescribers. There have been more prescribers over time, but that, again, is what we see in our syndicated data. From our Market Research , those physicians who weren't prescribing and are aware of the category are referencing two centers of excellence as compared to treating patients themselves with a CMI, mainly because of the administrative activities associated with the ETASU REMS . When you look at the areas of ETASU REMS , again, we hear feedback on it's the ECHO monitoring, the window of when an ECHO is complete to the timing of when a patient can fill a prescription, and the drug-to-drug interaction monitoring. Those three elements.
Based on Sequoia and the clinical data at Sequoia, obviously, we're still in negotiation and finalization of label with REMS, as Fady alluded to. Our expectation in base case would be there will be areas of difference around ECHO window, the ability to increase dose after the first ECHO and get the patients to max dose. Based on the number of echoes they need and an ECHO at a time, you can increase dose provided that EF continues to stay above 55% or stabilize dose without the drug-to-drug interaction monitoring and with a broader window. The expectation would be that there is less administrative burden associated with the risk management program, as well as areas of difference that we feel will be from a safety and from an efficacy point of view.
Ultimately, the label will dictate that in terms of what we can prescribe or, I'm sorry, describe to our prescribers around the label and the differentiation.
The lessening of the ECHO requirement that BMS is seeking for Camzyos sounds like it could remove a potential point of differentiation, but still be a positive to increase the overall usage of CMIs. Is that how you're thinking?
Yeah. We don't know what BMS submitted. I think we have to, the analog of Europe would indicate that maybe for most patients, monitoring in the maintenance phase every six months. I believe BMS said that the prior approval supplement PDUFA date is April. We should be finding out soon on what exactly was submitted and if they were successful in getting approved, whatever it is they submitted. When Cytokinetics submitted the 8-K and we talked about differentiated labeling and differentiated REMS, that's with or without that change, if that's what the change is, that six-month monitoring in the maintenance phase. Again, we feel like Aficamten should have the ability in our base case to increase dose after each ECHO if needed or maintain dose. It's not like you have to have multiple echoes before you increase dose.
Aficamten, we're not expecting to have drug-to-drug interaction monitoring, and we're not expecting to have such a narrow window of when an ECHO is done to when a patient can get a prescription filled. Those areas are differentiating. Obviously, we won't make any comparisons in the marketplace, and I'm not making any now. I mean, obviously, we have to understand what that label and risk management program, but we'll basically communicate and educate the Cardiology community on our data and our areas of difference and whatever is needed to ensure safe use.
In your Market Research , how much of a burden was the original REMS that was approved for Camzyos? Was that a burden that was shared by both physicians and patients?
Yeah. I mean, we didn't use the word burden. I mean, Mavacamten works from an efficacy point of view. I think generally, we see in our research that physicians and patients are, for the most part, satisfied with the efficacy. There are those physicians, especially in the community setting, that don't want to learn the REMS, get certified on the REMS. They'd rather refer to those that are more familiar with it and comfortable with it. Those that are comfortable with it, we hear they know how to manage it. They know how to get patients on therapy, and they're growing their prescriber base, although albeit a very concentrated market. The overall REMS program and the administrative resources required to assure safe use is what keeps some cardiologists away from prescribing CMIs, at least based on our research.
Okay. I think since you're coming second to market, you've had the luxury or benefit from learning from the first launch. Just curious what you think you can improve upon or how your approach could be different.
Sure. I mean, one, Bristol-Myers Squibb has done a very nice job of building awareness. I think the DTC TV campaigns, the unbranded work, working with Viz.ai to get diagnosis rates increasing over time. These kinds of things are generating more awareness for the market. When we do our studies, we were pleasantly surprised of how well the market has been seeded. Over time, when you have a second entrant, when you have more publications, education in the community, perhaps even stronger guidelines with additional data sets with Sequoia, hopefully with MAPLE, these things should help grow categories. I think what happens is that the category hopefully will grow, prescribing will expand beyond these 600 or 1,000 C ardiologists. There are about 10,000 Cardiologists who are 80% of Cardiology prescribing or diagnosing of HCM. We're seeing an increase in diagnosis of NHCM.
We're going to see a couple of data sets read out in NHCM, both for BMS as well as for Cytokinetics. I think all these kinds of activities should fuel market growth and opportunity as there are hundreds of thousands of patients between obstructive and non-obstructive, many that are on the obstructive side that are treated with generics. The expectation is that the categories get expanded and Aficamten gets pretty broad utilization because of the clinical profile.
Did we look at the Camzyos launch as a potential proxy for what AFI could do upon becoming available?
Yeah. I mean, it's hard to say until we get our label and our risk program. I think there's about, from what we can tell, there's about 6,000 new patients per year added to a CMI, maybe about 15% or so of the overall eligible obstructive HCM population currently being treated today. That penetration, there should be more than 80% of the market available, assuming we get approved at our PDUFA from that timing point of view. The ability for us to continue to increase penetration in that market, as well as growing the market from an NHCM point of view, I think will be the critical drivers.
Okay. In terms of timeline, PDUFA is in late September. A 4Q launch is possible. In Europe, I think you have filed, but is it a second half 2025 potential approval?
Probably first half 2026. Some of the clock stops are a little longer. It's a little bit different of a regulatory approval process. There are two clock stops. There are member states. There are two experts, if you will, that give regulatory questions. We started the EMA process a little later than the US process, only by a few months. Our expectation is that we would get approved in first half 2026.
Okay. Going back to the MAPLE-HCM trial, I think that's the next major catalyst you're expecting to read out in the second quarter. Have you given more granularity than second quarter at this point, or?
No. Not yet. Not yet.
Not yet? All right. I had to try. I guess if you can just give us kind of a, well, you've given us an overview. It's a comparison of AFI versus Metoprolol. All. But the purpose of the trial and what you would view success or a positive outcome from MAPL.
Sure. For the group listening, the trial was designed to be a head-to-head trial of Aficamten as a monotherapy versus beta-blocker as a monotherapy. Beta-blocker, metoprolol, is the most commonly used sort of first-line treatment in hypertrophic cardiomyopathy. It's not been very rigorously studied. I think our understanding of what actually it does for patients is not established. While in Sequoia, our completed phase three trial, we enrolled patients who were on beta-blockers as well as those that were not. We showed that Aficamten had similar efficacy in both groups, whether or not they're on beta-blockers. Here, we wanted to look at patients who were being treated only with beta-blockers and to compare that to Aficamten. They're randomized. They're treated with a double-blind, double-dummy drug. Meaning everybody gets either an Aficamten or placebo metoprolol, or they get metoprolol and placebo Aficamten.
They truly can't tell really what they're getting. The other is the treatment duration is similar to Sequoia's 24 weeks. The endpoints are not that different either. It's a peak VO2 at 24 weeks, NYHA class, KCCQ, biomarkers, echo, and so forth. What we hope to see from MAPLE is that Aficamten proves to be superior in terms of efficacy, that it improves symptoms, gradient reductions, peak VO2 to a greater extent than beta-blockers do, and in a statistically significant fashion as well, that the safety of Aficamten is preserved, that we understand what maybe some of the challenges with dosing beta-blockers are in these patients, as it will be more of a qualitative analysis of safety when all is said and done.
The long-term goal is if the trial is positive, and it's to support, elevate, if you will, Aficamten in the guidelines so that it's considered as an option for first-line therapy as opposed to being the therapy of last resort when all other medical therapies have been exhausted.
Okay. The primary endpoint here is exercise capacity based on peak VO2?
Correct.
We've seen what Aficamten can deliver in the Sequoia trial. What are the expectations for metoprolol? I guess, what are you powered for? What difference are you powered for to demonstrate?
Yeah. Metoprolol tends to have a slight negative impact on exercise performance. There was one crossover trial that was done a couple of years ago that showed about a 0.5 mL per kg per minute reduction in peak VO2. Essentially no change or slightly worse exercise performance. In that context, we hope to see Aficamten replicates what we saw in Sequoia. The patient population is a little different. It is not quite as severe as the Sequoia population was. The baseline data are published. That was a little bit intentional because in Sequoia, we enrolled essentially treatment failures, people that had very severe disease. Here, we wanted to enroll the rest of the patient population with obstructive HCM that were not eligible for Sequoia, as well as patients that would have been eligible for Sequoia, but to generate evidence across the whole spectrum of obstructive HCM.
Okay. Do you expect, I know you plan this as part of the regulatory strategy to, I guess, improve the label once Aficamten is approved. Do you also expect that the MAPLE trial could support a change in treatment guidelines and move AFI more upfront to a more upfront role than it could have with the original approval?
I mean, I think if the trial is positive and it wins on comparative efficacy and there are no new safety issues, I would think that in an evidence-based approach, that it should be at least elevated to the same level as metoprolol and that it had shown to be as effective or more effective than metoprolol. Guidelines tend to be very data-driven as opposed to economics and things like that, although I'm sure those will play a part. The class, the indication, if you will, the class of evidence and the level of recommendation is usually based on some fairly strict criteria, including quality of clinical data and number of trials and things like that.
Okay. The ACACIA-HCM trial in non-obstructive HCM, we're still enrolling here to complete. Have you given timelines on when you expect enrollment completion and when we could see a readout?
Yeah. We'll give a more thorough update on our May earnings call in terms of ACACIA-HCM. I think right now we will maintain our guidance of finishing enrollment in the second half, although I will say enrollment has been very strong. I will sort of narrow that in the coming earnings call.
Okay. I guess to complete our Aficamten discussion, just talk about potential competitors. Obviously, there was news last week on a new competitor with their phase two trial. I do not know if you want to comment on the data, but maybe if there is anything we should be paying attention to as we try to compare phase two results from a small patient number trial versus what you have for Aficamten.
Yeah. I don't think I'll comment on it too extensively. I mean, I think there are what you said right there. And with Aficamten, we now have hundreds of patients being treated with Aficamten, hundreds of patient years of experience with Aficamten. I think we have a pretty good picture of what Aficamten looks like. I think the Edgewise data are just still premature, early. Obviously, there are some headwinds from their last data presentation. Time will tell. I think there's a high bar set by Aficamten that its safety profile, both in terms of efficacy, safety, and occurrence of atrial fibrillation that have to be met.
All right. They had a nice slide highlighting that Aficamten was not impacted by atrial fibrillation, so.
Well, the.
Another difference.
Mine was actually an error, actually. It quoted the wrong numbers. It quoted numbers from an open label extension.
Which is actually lower.
Which is our phase two experience. If you restrict yourself to the clinical trial period, as has been published, is that we had zero cases of atrial fibrillation during Redwood. They cited our open label experience, which is after patients had transitioned into the open label extension. You have to somehow adjust for risk, a period of risk. They had four weeks of data. They are now quoting months and months, if not years' worth of exposure. I think anyway, I'll just leave it at that.
All right. I guess let's talk about Omecamtiv mecarbil. I think it was a subject that was a little controversial about a year ago when you announced your plans for it. Just curious if the outlook for that program has changed as people have done more work around it. I guess where you are with the phase three trial.
I think, first of all, comment on the heart failure community. They're tremendously supportive of us conducting this trial because they see strong clinical need in their patients that they treat that ultimately run out of their current treatment options, whose blood pressure becomes too low, who are failing despite being on best medical therapy. This is not a rare population. These are hundreds of thousands of people that end up in this bucket. Very strong support from the heart failure community as well as many of the leaders in heart failure clinical research around the world. The investor community, I think, is starting to understand the potential value of this. I mean, it's still quite a ways off in the future and not something that they've really done a lot of homework around.
As Aficamten gets into its third, fourth year of launch, I'm pretty sure people will be asking us, "Well, what's next?" Omecamtiv will be our what's next. It'll be the next major readout, potentially the next product approval. I think we're well positioned with the data from an 8,000-patient trial to have designed a confirmatory trial that we're conducting now.
What would be the market opportunity for the target population that you're addressing here?
Yeah. So the market opportunity, I mean, if you look at those with heart failure with an EF less than 30 that are more severe, it's probably around 800,000, maybe up to a million patients in that range. They're the ones that are also the highest cost to the Medicare system, highest rates of hospitalization. So that's a population we'll be serving as an add-on to guideline-directed medical therapy.
Okay.
It's going to be entering a market that'll be our expectation generic by then, SGLT2s, Entresto, as well as the other pillars of guideline-directed therapy at that point in time as well. Given the high unmet need, given the high cost, if we can certainly show reduction of hospitalization and utilization of overall healthcare, I think there's also a good economic argument beyond the clinical argument.
Got it. Your HFpEF program, kind of just getting underway with the Amber trial. Maybe Andrew, if you could highlight that market opportunity and how it differs from within HF, what does HFpEF look like?
It really depends on where we land in terms of our clinical profile. Fady can certainly talk about that as the EF cutoff is 60 or higher, 65 or higher. How big is that number as well? It's kind of the other end of the spectrum relative to Omecamtiv on heart failure. That could be around 1 million patients as well. We do see SGLT2s utilized in HFpEF, Entresto up to a certain level of EF. I think it's around 57 where the clinical data shows benefit. There is certainly a lot of high unmet need, especially in this much higher relative rate of HFpEF from an EF point of view. I think we need to do a little bit more work clinically to determine where we think we're going to land in that profile.
Sung, I haven't forgotten about you. If you can just give us an overview of the financials and give us an idea of where the cash balance is, especially in this kind of market we currently are. I think a lot of it.
Yeah, sure. That's really a strength of the company right now. We started the year with $1.2 billion in cash and investments. Of course, we arrived at that point because of the financing we did last May. The timing is fortuitous given the climate we're in today. In terms of guidance for this year, we've also guided that you can expect about the low $500 million in terms of cash utilization. You can see by the time we get to the end of this year, we would still have a strong balance sheet and the PDUFA date presumably behind us. In addition to the cash and investments, we have access to further capital. This is by way of Royalty Pharma term loans. Up to $350 million, we've already qualified for half of that. The other half is tied to the approval of Aficamten in the US.
All in all, we're in a position of strength here in terms of the balance sheet, and we're able to fund the launch of Aficamten and beyond.
Okay. Maybe just to wrap up, I'll leave it open to all three of you, but anything you feel is misunderstood or underappreciated currently in the story?
I think the catalysts that we have coming up in the future, as we've kind of covered them, when you put the whole picture together, I think we're an uncommon company in these turbulent times. We're well capitalized, as Sung just reviewed. We have several important catalysts coming up, near-term product revenues, and a pipeline that we have established and are committed to expanding over time. It is an exciting time for Cytokinetics and with several near-term value drivers that will hopefully provide some buoyancy to the stock, as well as enable us to deliver on our commitment to patients.
Yeah. Maybe the only thing I would just add to that is if you look over the next four to five years, leading with hopefully approval in September based on Sequoia, a supplemental NDA with MAPLE, probably a year after that, ACACIA for non-obstructive, which likely is going to be a larger population than the obstructive population. Not long after that, omecamtiv mecarbil for heart failure. All of this done on the same infrastructure. And Fuel Force, as well as commercial kind of engine, if you will, around the same prescriber base, but there may be some addition of Fuel Force, but not meaningful. You are really talking about a tremendous amount of synergy as well as added value to a patient and prescriber point of view when you think about three different patient populations across two different molecules in such a short time frame.
All right. I think we'll wrap it up here. We're up on time. I want to thank all three of you for spending time with us this afternoon and telling more about Cytokinetics and some of the exciting catalysts that are upcoming here.
Thanks, George. Appreciate it.
Thank you.
Thank you.
Thanks, Ross.