Welcome again for joining us at the Citi's Life Sciences Conference. Really excited to be joined by Cytokinetics next. Robert Blum, Fady Malik, and Sung Lee from the team here, great to have you all. Clearly, you know, an exciting time. You just got your first drug, Myqorzo, approved, you know, a few weeks ago. Amazingly that's not like, you know, the first question I have today. It's really about the trial that's reading out in non-obstructive HCM and again, in only a few weeks' time from now. With that, Robert, maybe I'll just, you know, ask you to give a quick intro, and then we'll jump into the Q&A.
Sure. Thank you, Jason. Thanks for hosting us, and thanks to all of you for being here. Cytokinetics is on a roll. We're doing things that we've committed to do, and they're going well. We recently had an earnings call. We provided an update. We are expecting clinical trial results from the ACACIA-HCM study in Q2. That's a study of our recently approved drug called Myqorzo, which is approved in obstructive HCM and now being studied also in non-obstructive HCM. That pivotal Phase III study is due to read out in Q2. Why is that important? NHCM represents the other half of the market for HCM. Recent claims data analyses underscore that NHCM represents about 50% of the total diagnosed and symptomatic patient population for hypertrophic cardiomyopathy in the United States.
While Myqorzo is approved for OHCM, and we think there's at least 100,000 patients in the United States who could be eligible for treatment with Myqorzo, there's a similar number available to treat with NHCM. In OHCM, where we are now approved, we are entering a category that is already present with one cardiac myosin inhibitor called Camzyos from BMS. That drug is doing quite well. Last year, over $1 billion in US and European sales and on its way, hopefully, to north of that. We enter that space with Myqorzo, and there's still over 80% of the OHCM population we believe eligible for treatment. BMS conducted a study called ODYSSEY-HCM with Camzyos in NHCM, and it was a near miss.
Unfortunately, that study did not produce positive results, but based on what has been reported, it gives us reason to be optimistic that our study, ACACIA, could be fruitful in the Q2. If positive and FDA-approved, we could have the NHCM market to ourselves in addition to competing in the OHCM market. You begin to understand the importance of not only a successful commercial launch, but this clinical trial readout in Q2 for what could be our business for all stakeholders, including shareholders.
Rob, as you said, Camzyos, the ODYSSEY-HCM trial was a near miss. Maybe take a step back from that. Why should one expect or think a cardiac myosin inhibitor could work in this patient population? Maybe we could talk about it from, you know, the patient perspective. How is the disease pathology different between obstructive and non-obstructive HCM, and what is the reasons why you think that a cardiac myosin inhibitor could work in this population?
There are similarities, and there are important differences, and maybe better for my colleague, Fady, to speak to those.
Yeah, Jason. I mean, the similarities lie in the pathology of the disease. There's thickening of the heart, there's diastolic dysfunction, there's excessive cross-bridge formation and hypercontractility in both the non-obstructive and obstructive forms. There are common elements in terms of what happens when you treat a patient that has either form with a drug like aficamten. You see NT-proBNP, which is a biomarker of cardiac wall stress. It speaks to how high the filling pressures are in the heart and what's the stress on the walls of the heart. You see them go down in both conditions. In OHCM, that's strongly predictive of improvements in exercise function.
You know, drops in NT-proBNP at two weeks in our Phase III trial in OHCM were the most predictive biomarker of an improvement in exercise function at 24 weeks. You see the biomarkers come down in NHCM as well. You see improvements in relaxation of the heart that are measured on echocardiography. You see elements in both diseases that contribute to improvements in function. You don't have the gradient to get rid of in NHCM, so that might mute the treatment effects, meaning you may not have as large an improvement in exercise performance. You know, the PROs measure more than just maximum exercise performance. In general, they tend to be a more holistic measure of overall patient wellbeing.
Great. Thanks, Fady. Can we talk now a little more specifically about the data that you've generated for Myqorzo in NHCM and how that kind of informs your confidence in the ACACIA trial?
Yeah. We were very deliberate about how we conducted phase II. We had two objectives in phase II. The first, really was to understand how to dose the drug in NHCM. In OHCM, you have two measurements that you use to guide dosing. One is the ejection fraction, which is the overall cardiac, a measure of cardiac function. It decreases a little bit in about, you know, 5%-10% with the treatment of a cardiac myosin inhibitor. The other is the gradient in OHCM, and that acts as a guardrail. It comes down first and tells you know, in some ways when to stop titrating drug. The strategy in OHCM is minimally effective dose.
We knew in NHCM that there is no gradient, so you're really titrating just to ejection fraction, and the only thing you can do there really is titrate to maximum tolerated dose. In piloting our phase II , we enrolled about 40 patients, studied them at doses of five, 10, and 15 using a titration algorithm that only increased dose if the ejection fraction was 60% or above. That was quite successful. We had no treatment interruptions. We didn't have any big drops in ejection fraction. We didn't have patients. We had a couple patients who had to down titrate dose, but nobody developed any, you know, adverse consequences of that. That, you know, maximum tolerated dose strategy worked quite well and fundamentally was. We were able to deploy that in phase three.
Got it. The ODYSSEY-HCM trial, the BMS study for Camzyos that was unsuccessful, essentially provided a benchmark for us to think about trial design. What have you done in ACACIA that is similar and different to that study?
Well, we used similar measures of outcomes. We used KCCQ and peak VO2. We have signs from ODYSSEY-HCM that they both were positively impacted. They were not statistically significant, but there were probably issues in terms of study design that contributed to that. The patient-reported outcome, for instance, in their trial had an unusually large placebo effect. I mean, KCCQ's been employed in hundreds of clinical trials, and I'd probably put their placebo effect at the ninety-ninth percentile. The other issue that they had in ODYSSEY-HCM was they didn't have a chance really to pilot their dosing in phase II . They used a different strategy in phase II that was not that successful. Tried a different strategy in phase three.
They had, you know, roughly 20% of the patients that had to interrupt treatment for low ejection fraction, and that's a month interruption plus down titration to lower dose and several weeks before you get back to an active exposure. You know, issues with consistency in terms of exposure, and then potentially, you know, the types of patients they enrolled were also maybe problematic as well. We've done things. We've had experience and our team has been together conducting trials in HCM since 2019. We've always had measures in place to not fall into those sorts of traps. I think we have a good shot there based on our conduct.
This is where I think oftentimes, Wall Street and analysts and investors may lose sight of what it takes to get to a positive outcome in a clinical trial. There's the design of a clinical trial, and then there's the conduct of a clinical trial. Very often, those things are considered but maybe the conduct taken for granted. I do believe the continuity of our team, the expertise in doing these studies, working with these centers and the investigators, training them on how to assess these endpoints and monitoring a study for what could be outliers, where that needs to be questioned, ensuring that patients are properly screened in that meet with inclusion criteria and the oversight of the study through a core lab and other activities. These are the things that can make a well-designed study either successful or not successful.
I do think Cytokinetics has demonstrated with this team, these centers, the same core lab, the similar levels of oversight, that as it relates to studies REDWOOD-HCM, SEQUOIA-HCM, MAPLE-HCM, FOREST-HCM, CEDAR-HCM, now ACACIA, we're in a good position to conduct these studies much as they were designed. For having reviewed these data from the standpoint of conduct, we're confident that study conduct is aligned to study design. Just one more question on ACACIA. Fady, you mentioned dose. Can you talk about the titration protocol in ACACIA from you know perspective of how straightforward is it, but also how quickly can patients get to their optimal dose, and how long will they be on the optimal dose for the assessment of the primary endpoint and secondary endpoints?
Sure. The treatment algorithm is very simple. You know, you start at the lowest dose, which is 5 milligrams every two weeks. You can escalate dose based on an echo, which measures the ejection fraction. The ejection fraction's above 60, you increase dose. If it's between 50 and 60, you stay on the same dose. If it's below 50, you down titrate. Everyone can probably recite that to me, right? It's pretty simple. You know because we escalate every two weeks, patients get to their target dose within six weeks. The endpoint's measured at 36 weeks, and we expect, you know, 30 weeks of exposure at least on target dose.
That is a bit in contrast to the way ODYSSEY-HCM was designed because mavacamten initiation of drug took three months before you would think about changing dose. They had a higher ejection fraction threshold to increase dose. They increased at 65%. There was a you know sort of a lot more challenges in terms of getting to the dose at the right period.
Got it. I want to flip over to Myqorzo on the launch. Before we do that, I think it's really important to talk about the differences in between Myqorzo and Camzyos. I think the really exciting and comforting part was the story has kind of evolved in the way that you expected it to since you designed the drug and since we saw that first preclinical data, right? There were very specific attributes that you looked for, like, that translate into ease of use, and we've said it many times, in our view, a better safety and efficacy profile. Just walk us through the differences between. Or let me ask it this way.
Talk to us about Myqorzo and what the attributes are of the drug that you think are optimized.
Thanks. That's a better way to put it. You want to start?
I'll start just by saying that, we take a lot of pride in the successes of Camzyos for the fact that our scientists were involved in its original discovery before we spun out that research to a company called MyoKardia that developed mavacamten, first conceived during a collaboration between us and MyoKardia before then MyoKardia developed that medicine and was acquired by BMS. We have involvement in the origins of this category by being pioneers to the innovation. With that said, we also, as pioneers in the innovation, think about next improvements and ways that we might be able to further the development of medicines that can address what could be other market opportunities. Our scientists discovered aficamten, optimizing it with certain properties in mind.
With that maybe as context, I'll ask Fady to speak to what were those properties and how have they been translated into clinical research and in support of our FDA-approved label.
Yeah, you know, at Cytokinetics, we invented the field of myosin modulation, both activators and inhibitors. There are certain things you want in a drug that modulates cardiac function, and they were deliberately engineered in aficamten. First being a shallow exposure-response relationship. As you increase dose, you know, you want the effect to come on gradually. You don't want to sort of walk and all of a sudden fall off a cliff and have a very, very marked effect. Because you're titrating drug to an effect. It's like titrating blood pressure. You don't want the blood pressure to go from, you know, 140 to 90 with a single change in dose. That's related to how gradually the effect comes on.
That has to be done almost empirically because we don't have good ways of predicting that. We did a lot of animal studies to help characterize that through different analogs till we got to aficamten. The other is drug interactions. You know, it's. People are on lots of different kinds of medicines. You're talking about a drug that modulates the function of the heart, so you want it to be immune to those sorts of interactions. The third has to do with onset and offset. Again, you know, you're titrating to an effect. Sometimes you overshoot and you want to be able to back off and with Myqorzo, you can do that. You don't have to interrupt treatment. You just simply down titrate the dose. Those were really our major objectives.
As you said, you know, as the data emerged from even phase I and phase II, we knew that we had reached that profile.
FDA approved Myqorzo, and as we had been expecting, with a label and an associated REMS program that speak to differences. How are Myqorzo and Camzyos different? I'd rather not speak so much about Camzyos and more about Myqorzo. Myqorzo was approved with an FDA label and associated REMS that we believe provides for physicians an ease of use, a convenience, a flexibility as it relates to the echoes and the frequency around which those echoes are conducted during an uptitration phase, the windows associated with when those echoes can be performed, as could be convenient to physician and patient. An absence of drug-drug interaction monitoring that we believe lowers the burden on physicians and patients as well as pharmacists. Other things that may be unique to our label and REMS.
Altogether, it enables Cytokinetics to launch Myqorzo, as we did in January, with product and channel in the third week, and as well as enabling of an experience for physicians, their offices, and patients that we believe is bespoke or custom to this opportunity. We've designed all of our services, all of our sales, marketing activities associated with this being the only thing our team is focused on, disciplined to ensuring that that experience is conveyed into the marketplace.
Can you walk us through the first weeks of the launch? How, you know, with the feedback you've heard, how is it going relative to, you know, again, from an operational perspective, how is it going relative to your plans and expectations?
I'd say, even after just a few weeks in the marketplace, we can say that we're very encouraged, and we're looking at certain early signs of commercial uptake and what we call velocity for launch. Firstly, when the REMS program was first made available to, healthcare professionals, cardiologists to register and train, over 700 in just a couple of weeks, as we reported on our earnings call, cardiologists went through that REMS program, and immediately many of them began writing prescriptions. Those prescriptions were processed, and through patient hub activity, patients were dispensed medicine and reimbursed within days. The things that we look for are levels of awareness. We did market research where over 90% scores of awareness and education suggest that, the market was awaiting Myqorzo.
That's also evidence from the fact that we learned that many prescribing cardiologists had already been warehousing patients as they put, not ones and twos, but many patients on medicine immediately. The fact that we were able to process so many of them so quickly through the hub and to reimbursement suggests to us that while we still believe that it's prudent to speak to that being an important measure of key performance and where we believe that that's one of the things that cardiology launches oftentimes show that they need to move to faster reimbursement. We're encouraged by the early days of how quickly we're getting patients through, especially commercial pay patients, onto reimbursed medicine. With that said, we do have a free drug program.
We do expect that some lag will occur between prescription and reimbursement, but it's an important velocity metric to be able to move patients through to reimbursement as promptly as possible, and that's working well. The early weeks would suggest that this launch is off to a very good start, and we're not yet reporting on numbers of patients or depth and breadth of prescribing, but we will start to do that with our Q1 earnings call in the Q2.
I think following on from that, one of the things that we took away from the recent earnings update, from a positive perspective, speaking to the fact that this is a different drug, and again, in our view, a better drug, you're seeing prescribers that have not previously prescribed Camzyos starting to prescribe Myqorzo already. Can you talk about the
Yeah
you know, the feedback that you've heard from those type of physicians? To your point earlier, there's still 80% of the OHCM market that hasn't been addressed yet by CMI.
Yeah. We segment the market into those roughly 700 cardiologists who are accounting for 80% of the current Camzyos prescriptions and another 2,000 cardiologists that have written a prescription but maybe aren't regular or they stopped writing. We've had high levels of engagement with both of those segments of cardiologists already in the first few weeks. Over 90% of those 700 we've already engaged with at least once, and they're inviting us into their offices to speak about Myqorzo. To your point, what we're also seeing is even in areas where there hasn't been prior prescriptions written, we're seeing prescribing. Those numbers are small, and it's early innings, but it's encouraging to suggest that perhaps with this differentiated label in REMS, we might see uptake in the community, which is ultimately important for this to take on its full potential.
We have to demonstrate to the roughly 8,000-10,000 cardiologists who are high volume or even low to medium volume prescribers of medicines for HCM that we can grow the category and penetrate broader into the community, and early signs would suggest we're on our way to doing just that.
Great. I know we just have a little over a minute left. I really wanted to touch on a point Fady made before, that you guys truly have been pioneers in the development of cardiac myosin modulators. You have another cardiac myosin inhibitor that's in the clinic, focused on a larger heart failure population with preserved ejection fraction. Can you maybe just speak about, you know, what's different about this next gen compound and the data you've seen so far preclinically, and why the data we'll see, including from ACACIA, will inform us about the potential for that drug in the future?
Right. In heart failure with preserved ejection fraction is the population we're talking about. These are patients that have thickened hearts like patients with NHCM. They have symptoms, heart failure symptoms. They have elevated NT-proBNPs. They are a non-genetic form of essentially a hypertrophic cardiomyopathy. They have a thickened heart and in many ways have features that are similar to our NHCM population. You know, we think that success in ACACIA will help us understand how to apply the mechanism to this adjacent population of heart failure patients. HFpEF is. You know, heart failure is 6 million individuals in the United States, about half of them have the preserved ejection fraction form and a fraction of those, maybe a third to a half, have increased contractility in a way that, you know, leads them to develop heart failure.
We're looking in phase II to help define that population. It's a more heterogeneous population than perhaps you see in NHCM. To understand what features might help us define that, understand the safety of the molecule. It's an older population, a bit more frail, and the drug that we've developed there, ulacamten, mechanistically is distinct from aficamten and that also provides us a new means of looking to see how a different, slightly different mechanism, still a myosin inhibitor, binds at a different location on myosin may translate again into even better pharmacology down the road.
To the point of your question, this is all coherent to strategy, has been in place for many years. In this case, aficamten, Myqorzo, forming a wedge into a marketplace of concentrated customers that we, as an emerging biopharmaceutical company that now has a commercial business, can penetrate with a high return on investment in a limited sales and marketing infrastructure and stamp that out for Myqorzo and OHCM leading to NHCM leading to advanced heart failure, HFrEF and HFpEF. It's consistent with strategy that we've articulated for many years that we intend to build a specialty cardiology franchise rooted in this one area of biology and science and medicine that we both pioneer and lead.
Great. Well, we're out of time, so Robert, really appreciate you and the team being here and, very exciting few months ahead of us for sure.
Thank you very much. Appreciate it.
Thank you, Jason.