Hello everyone. I'm Diane Weiser, Senior Vice President of Corporate Affairs. I'm pleased to welcome everyone to our investor event to discuss the primary results from ACACIA-HCM, the pivotal phase III clinical trial of aficamten in non-obstructive HCM. Today's event is being hosted in a hybrid fashion. I'd like to welcome those here in the room with us in Munich, as well as those joining online. I'm pleased to introduce from Cytokinetics, Dr. Fady Malik, Steve Heitner, and Robert Blum. I'm also thrilled to welcome three leading experts in HCM for our panel discussions today, Dr. Marty Maron, Dr. Ahmad Masri, and Dr. Christina Paitazoglou. Today's agenda will begin with, i s it on the slide? We're going to pause for a minute. Turning to today's agenda, Fady Malik will provide some brief opening remarks.
Next, Doctors Masri and Maron will provide an encore presentation of the ACACIA-HCM results that were presented earlier today in the hotline session at the Congress. Then Steve will facilitate a panel discussion and Q&A session. Finally, Robert Blum will close us out providing some remarks. For those online, today's slides are available for download in the webcast. You can submit questions to the panel at any point during the event using the Ask a Question tab on the upper right-hand side of the webcast. For those in person, please raise your hand during the panel discussion to ask a question. Before I continue, as you can see on this slide, today's discussion will include forward-looking statements, which are subject to risks and uncertainties. Please refer to our SEC filings for a discussion of these factors. With that, I'll turn it over to Fady.
Thanks, Diane. I'm very pleased to be here alongside my colleagues and leading experts in HCM and the global cardiology community. Maybe we need to turn the mic off. As we share the primary results from ACACIA-HCM, the pivotal phase III clinical trial of aficamten in patients with non-obstructive HCM. These results were just presented a short while ago in the hotline session at the Congress, and were accompanied by two simultaneous publications, one in the New England Journal of Medicine and one in the Journal Circulation. This is the first ever positive phase III clinical trial in nHCM, and the results show that the treatment with aficamten was associated with statistically significant and clinically impactful improvements in both exercise capacity and symptom burden, as well as cardiac biomarkers.
As we'll discuss today, these results create the potential for aficamten to become the first and only cardiac myosin inhibitor to address the full spectrum of symptomatic HCM, offering the first therapy that may directly treat the underlying disease process of HCM. The response from the HCP community at the Congress today was overwhelmingly positive. It's clear these results are resonating, and there is genuine interest in what they could mean for the future in nHCM. Since sharing the top-line results earlier this summer, we've moved swiftly to preparing a supplemental new drug application that we plan to submit to FDA later this year for aficamten in nHCM. So we're extremely proud of these results and of the exemplary execution of this clinical trial.
To that end, I'd like to express my gratitude on behalf of Cytokinetics to the patients, to the families, investigators, and the study staff who helped conduct ACACIA-HCM. We thank you for your dedication. Now with that, I'll hand it over to Dr. Masri and Dr. Maron to present the primary results from ACACIA-HCM. Dr. Masri.
Thank you, Dr. Malik, and hi, everyone here and online. I'll present the primary results of ACACIA-HCM. All right. Everyone who's been involved in the trial. Non-obstructive HCM is a common condition. It affects a lot of patients with hypertrophic cardiomyopathy, and it leads to reduction in exercise capacity and development of progressive symptoms. There are currently no available therapies that have proven to be effective in this disease. Aficamten, which many of you are aware, is available in obstructive HCM in many jurisdictions, has favorable effects on diastolic function, as well as a whole host of other key areas that are involved in HCM pathophysiology. Aficamten has favorable pharmacological profile, which allows for rapid uptitration and dose adjustment with good tolerability. This is the design of the trial. Probably you've seen this before. Patients with symptomatic non-obstructive HCM were randomized to aficamten versus placebo.
517 total patients, one to one randomization. Aficamten dose range was 5- 20 milligrams. All the patients were followed up to 72 weeks in a blinded fashion with a four-week withdrawal period. The study continued until the last patient crossed week 36. In terms of our study visits and assessments, they are listed up there to the left of the screen. We've conducted for the dual primary endpoint. The KCCQ assessment was done in every visit, but the peak VO2 and cardiopulmonary exercise tests were only done at baseline and at week 36. Here are our endpoints. The primary dual primary endpoint changed from baseline to week 36 in KCCQ Clinical Summary Score, as well as peak VO2.
The secondary endpoints were tested in a hierarchical fashion, going from baseline week 36 in NYHA class, Z-score, which includes both maximal and submaximal exercise metrics, NT-proBNP change, left atrial volume index, and time to first composite cardiovascular event. Safety outcomes typical of a myosin inhibitor trial, where we looked at LVEF heart failure. Something really important to note, which is unique to aficamten at this stage, is that patients who get EF between 40% and 50% due to us pushing the dose higher, they can get down titrated while staying on the drug without a drug holiday interruptions that are mandated. Per protocol, only those with EFs less than 40% have to interrupt the therapy. They can be restarted on it, but they have to interrupt the therapy. These are all baseline characteristics. Again, as I mentioned, one to one randomization, 258 aficamten, 259 placebo.
This is a really, in my opinion at least, well-conducted study. The reason behind that, if you look at how many patients had family history of hypertrophic cardiomyopathy or pathogenic, likely pathogenic variant for the disease, 2/3 of them did. This is different from when you look at any patient with LVH. This was a study conducted to enroll such patients. 75% of them were on beta blockers, and they were highly symptomatic with reduced KCCQ scores. A third of them had NYHA class III. Biomarkers were elevated, and peak VO2 was significantly reduced. Here are the primary results. The first of the dual primary endpoint is KCCQ. The primary endpoint was aligned at week 36 for KCCQ and peak VO2. As you can see, the difference was 3 points at week 36 between aficamten and placebo in favor of aficamten with a P value of 0.021.
What you see here is that aficamten, beyond week 12, consistently improved KCCQ Clinical Summary Score. At each time point, aside from week 36, you have a difference that varies from 4.8 to 7 points, including the end of treatment, which every patient in the trial is supposed to go out at the end of the treatment from the trial, 5.6 points difference. During washout, these scores within four weeks were reduced back to similar to placebo without any difference. The reason behind what you see here is the fact that placebo patients had fluctuations in their benefit as it reflects on KCCQ, which you can see clearly here between, for example, week 24, 36, 48, and end of the treatment. The second dual primary endpoint was peak VO2.
Aficamten influenced positively peak VO2 with a difference of 0.67 ml per kilogram per minute with a P value of 0.003. If you look at many pre-specified subgroup analysis, the treatment effect on both KCCQ and peak VO2 was consistent. We here highlight to you some of the groups that some might feel are important, including beta blockers, intracavitary obstruction, and genotype status. As I mentioned during the presentation, I walked into the trial thinking we might end up having a super responder or a less responder group. The reality is, when you look at the pre-specified analysis here, most of these patients have derived the same degree of benefit, all in favor of aficamten.
In terms of NYHA class, which is the first of the secondary endpoints tested in a hierarchical fashion, throughout the trial, you had more in favor of aficamten improvement NYHA class by one class or more. At week 36, it was 14% difference with a P value of less than 0.001. This is the Z-score. It is a slightly complicated thing to explain, but the bottom line is it is a comprehensive exercise metric where you have one exercise metric for maximal exercise tolerance that the patient can achieve, and one is for submaximal exercise, which is what a lot of the patients do from day to day. They operate at the submaximal level, which is called ventilatory efficiency or VE/VCO2. Aficamten positively affected VE/VCO2 with - 0.91. With VE/VCO2 slope, lower is better. With peak VO2, higher is better.
That translated obviously into a positive result on the Z-score with statistical significance. NT-proBNP was affected favorably from the first visit, follow-up visit that the patient had, continued to decline throughout the titration period, and stayed stable with the washout showing you how there is a quick rebound there. Slides are not advancing. All right. Sometimes the question come, what is the significance of having reduction in NT-proBNP or elevation in NT-proBNP? This is a recent study that we actually have been conducting for more than a decade now. It's an NIH-funded study, HCM Registry or HCMR, showing that a really important predictor of outcomes in hypertrophic cardiomyopathy is NT-proBNP.
If you look at how they essentially reported the log N-terminal natriuretic peptide during follow-up, you can see how by reducing NT-proBNP with the magnitude that was seen in the trial, you're actually shifting those patients on a curve that is different from the natural history curve for NT-proBNP. So that's the message from this is that you end up achieving almost 50% reduction in the hazard ratio if you use that natural history study as your reference study. In terms of other endpoints, aficamten did affect left atrial volume index, but it didn't reach statistical significance with a P value of 0.058. Time to first cardiovascular event was not different between the two groups. In terms of our safety outcome, aficamten was well-tolerated. There were no new safety signals here. Aficamten in this trial was titrated to the maximum tolerated dose.
It's different from our prior trials with aficamten where we used the dose that was required to eliminate left ventricular outflow tract obstruction. This is evident by having 81% of the patients on the maximum doses available, 15 and 20 milligrams. Despite all of that, and despite the non-obstructive HCM population being a special population when it comes to sensitivity for cardiac myosin inhibition, the least square mean difference in LVEF was 4.4%. This is similar to what was seen in the obstructive HCM trials as well with aficamten. Only 3% of the patients on aficamten had to hold aficamten or had treatment interruption because they have reduced left ventricular ejection fraction. A little bit more on the safety outcomes. I'm going to just focus on heart failure here, 4.7% aficamten, 1.2% placebo.
All of these happened during the initiation and titration phase because we had to design a trial in a way that we can get patients to the maximum dose available of the drug. While they're heart failure, these are events where it can be managed by diuretics and outpatient management. 10.5% of the patients had an EF less than 50%, but only two of them had a serious cardiac event of heart failure. Importantly, in my opinion, that this 27 number, 21 of them remained on aficamten, either at the same dose or the lower dose during the trial. So there was no treatment interruption here. One thing that I would like to draw your attention to is new onset atrial fibrillation, which it's becoming a really important metric in HCM trials. There was no difference between aficamten and placebo in the new onset of AFib.
One important reminder as well is that the safety goes through the whole period of the trial up to 76 weeks. In conclusion, aficamten improved exercise capacity, patient-reported health status, and symptoms as compared to placebo. Over 36 weeks, we've shown you that aficamten hit on the dual primary endpoint as well as three of the five secondary endpoints. More than 80% of these patients elected to enroll in FOREST-HCM to look at the longer-term safety and efficacy of aficamten. Thank you.
Okay, great. Thanks, Ahmad. I'm going to just get into some of the additional data here in a second. It's going to touch on some considerations around treatment benefit and safety. But I want to just start maybe if I could just with a couple comments. Some of these comments we'll get back to maybe at the end in the question and answer period. But I'm older than Ahmad, by actually quite a bit. He's obviously a superstar. I'm a little bit older and I've got more gray hair. This gray hair, by the way, I want to tell you, a lot of it comes from having taken care of HCM patients for almost three decades. It's a long time. I've been in the trenches taking care of these patients for that period of time, and I've seen a lot of them.
I got to tell you that with that experience, which is vast, I never actually thought we would see the day that we are seeing today, actually, where we have advanced a treatment for this population of sick, non-obstructive patients. I say that because I thought it was always a very challenging bar to reach. I think the fact that we have shown that today is not just a milestone, but actually a kind of a transformative period. I don't use that term lightly. I'm not just saying that because I'm here talking to you guys. I actually believe that to be true. A lot of it comes down to being able to have the opportunity here to make these patients feel and function better, of course.
A lot of it stems from the enormous amount of frustration that these patients feel because there's nothing available for them. This has met, in a way, one of the greatest unmet treatment needs that we've had in HCM. Okay? It has to be framed, I think, in that context here when we're looking at the numbers and trying to understand them and relate to them. We've got to take a step back. We've got to really understand that this is a pivotal moment. Okay? With that said, I'm going to touch on two additional considerations that I think are on people's minds that have to do with treatment and safety. Okay? Those come out of, as Ahmad alluded to, this sub-study that was done. It's published as well now in Circulation. It's about the global efficacy of the drug in this population.
And again, this is reiterating, but again, huge unmet need in this population related to morbidity. This is a drug that addresses the underlying basis for why these patients are so frustrated, improving diastolic function. We will get to that more in a minute. We talked about the outcomes that were achieved with ACACIA and the primary results. The question then is why did we do this sub-study then? What was the purpose of doing this since you have just seen the primary data? I will just make one important point, and I think it is really important because I see this happen a lot, is that you just saw very elegantly shown the mean changes in ACACIA. The mean changes between the aficamten and placebo arms. But sometimes those mean changes, they are hard to contextualize in terms of clinical meaningfulness. We get that a lot.
What does that mean when you see those mean changes in KCCQ peak VO2? And when we talk about clinical meaningfulness, what does it mean for the patients? And so we addressed that point here. The way we do that is that we contextualize the treatment benefit as it relates to patient. That is the within-patient change within clinical outcomes that are relevant here. I will show you what those are in a second.
That is what we call a responder analysis, because it contextualizes or translates this data that you just saw into how we want to think about it as it relates to a treatment benefit for the individual patient. So that is the purpose here. And if we look at. Sorry. That was just the clinical trial that you just heard that this trial was on, so I will maybe go back over that, but we saw that.
We will skip right to, again, this concept of why we did this. The responder analysis, again, takes the vantage point of what does the treating physician and the patient, for that matter too, want to know if they were in a position to use this drug clinically? First and foremost, because it is the most important treatment goal we have in this disease, a low mortality disease, it is about morbidity. It is about making my patient feel better. I mean, that is the primary and most important thing we can achieve. And we analyze that through two ways. PGIC is just a questionnaire, that is a one-question questionnaire that asks the question, how are you feeling now on treatment compared to before? The same, better, much better, very much better, worse, very much worse, et cetera. And that PGIC metric is important for two reasons.
One, it has been used scientifically by regulatory agencies and others to anchor, to establish what is a meaningful change in health status with other kinds of patient-reported outcome measures like KCCQ. That is number one. And number two, it is elegant in its simplicity. This is how we work. This is what we want to know. This is how we interact with patients. We ask them that question, and we get something back, and that is our bar clinically. And so the PGIC reflects clinical practice in that way. Of course, we also want to know, do my patients function better? That is measured objectively with cardiopulmonary exercise testing. And in this case, we want to be able to support those important clinical changes by demonstrating that the therapy is biologically active in a way that makes sense to support the clinical benefit.
In here, that was looking at measures of diastolic function. NT-proBNP, sort of direct reflection of LV filling pressures, left atrial pressures, cardiac structure, left atrial volume, again, an indirect measure, but very strong one of left ventricular filling pressures, and diastolic function with septal e', a non-invasive measure of LV or left ventricular relaxation. Okay. The way this works is simple. We just take those measures, and these are the endpoints in this sub-study analysis. Okay. Each of these measures, by the way, each of the five, have each been related to adverse outcome in HCM. So they're predictors of bad things happening to non-obstructive patients. So they, in and of themselves, are very important predictors of what happens in the future to patients.
Therefore, they're relevant in that way, and that's how they are defined as. Then we define them as a responder analysis by putting a clinically meaningful threshold of change that we attach or associate to each one of these. Okay. So for improvement of symptoms, it's a one or more improvement in NYHA class, plus a one categorical change in PGIC, a 0.5 or more improvement in exercise capacity, a greater than 10% decrease in left atrial volume, a greater than 10% improvement in septal e', and a greater than 50% reduction in BNP. Okay. So those define a threshold for which that if we achieve, we would consider to be clinically meaningful based on other supportive data for that individual patient. So if we look at that then in terms of what we saw. So that's the responder analysis.
That's what we did, and this is what we found. Okay. If you look at each of those five outcome measures and you look at what the response was, what the treatment benefit was in this symptomatic, functionally limited, non-obstructive population, you see that over 70% of patients achieve the threshold of a clinically meaningful symptom improvement. It's a lot. Then you've got about half the patients achieve a functional improvement in peak VO2 of 0.5 milliliter per kilogram per minute or more. You've got about 1/3 with that improvement in left atrial volume, more than half with the improvement in LV relaxation, and over 63% with a substantial reduction in BNP, again, reflecting a very important and impactful biological effect on the HCM heart with that kind of reduction in BNP as well. Okay?
Those are the outcomes of what we saw with aficamten treatment. Then if you look at that in a little bit more detail. Sorry. Can you go back one? Sorry. This is a little bit hard to advance, so I got it stuck there. Can you go back one?
You're the only driver.
Am I the only driver? Okay. Sorry. Got it. Understood. Okay. If we look at that a little bit more as it relates to the effect of those thresholds over the treatment period and also as it relates to placebo, if we take the two outcome measures, again, that clinically are the most impactful, making patients feel better on the left with that one or more improvement in NYHA, as well as that one categorical improvement in PGIC, you've got on the right the peak VO2 functional there. You can see the red bars are aficamten and the blue bars are placebo. You can see with improvement in symptomatic benefit, first of all, again, that 71% at the end of the treatment period or the end of the assessment period of 36 weeks.
We also see that that improvement in symptom status starts early. It starts at two weeks with a greater proportion of patients on aficamten with an improvement compared to placebo. Okay? It's maintained throughout the treatment period, and you can see that benefit in functional status as well that we talked about of almost half the patients receiving a benefit of an improvement in exercise capacity. Here, if you combine those two measures, feel and function, you see a greater proportion of patients on aficamten achieving that feel and function combination than placebo. In terms of diastolic function, same story here.
Greater proportion of aficamten patients achieving the threshold of improvement in left atrial volume, improving diastolic filling with LV relaxation, and then the BNP, which is probably the most visually impressive performance here, undoubtedly telling us that there is a clear physiological effect here in terms of lowering LV pressures. Again, if you look at the benefit here across the platform, so to speak, across both clinical, structural, and functional measures, if you look at this, you've got more than half the patients on aficamten achieving three or more of those outcome measures versus 13% on placebo. You can translate this. I'm going to finish up here in two seconds. You can translate this data then into a metric that we all can relate to as well, which is number needed to treat.
If you look at the number needed to treat across the five outcome measures, it ranges between 1.7 for BNP and 14 for exercise capacity, and symptom status is 5.5. To give you some context here, the SGLT2 inhibitor drugs, for example, which have mean improvements in KCCQ of 2- 3 in HFpEF and HFrEF, for example, have N number needed to treat to improve KCC and symptom status of 14 to 18. This five, far superior in terms of number needed to treat than a lot of the other traditional heart failure medicines that we have for non-HCM heart failure. Finally, to finish up here. Again, in summary then, over a relatively short period of time, and that's the other point, we are talking about 36 weeks I showed you.
You see here that clinically relevant measures were achieved, three or more achieved much greater in aficamten than placebo, with the number needed to treat that we talked about. Again, this all underscores a broad effect, a broad treatment effect here in this symptomatic function limited population of non-obstructive patients that supports a potential benefit of aficamten in this significantly underserved population. I will finish with just two or three slides about safety for a minute because this is really obviously very important as well. As was probably noted, there was a slight imbalance in serious heart failure events in the aficamten versus placebo groups. The point there is that those low wave events were independent of ejection fraction. Independent of ejection fraction. I will show you why that is in a second. Therefore, titration of aficamten, as we all know, is algorithmic driven, right?
In the trial, you went up on the dose based on ejection fraction. That was a blinded decision that was made, and that was the uptitration strategy. FOREST, the open label extension in which patients could roll over into different story, unblinded look at the echoes. You could include physician judgment in addition to the EF to make decisions about uptitration, and I will show you that FOREST data in just a second. Again, you have seen this, that slight imbalance in serious heart failure events in the afi versus placebo groups of 12 verse 3. Then if we look at that group, the 12 verse 3, here it is in FOREST. So these are patients that were in ACACIA. They roll-
These are still ACACIA.
These were patients that were in ACACIA that rolled over into FOREST.
This is the timing of the patients in ACACIA still.
Yeah. Sorry. I am sorry. I am on the wrong side. This is ACACIA. Sorry. You are absolutely right. This is still ACACIA. Sorry. So I am showing you the 12 serious adverse heart failure events in ACACIA, sorry, where you can see them in the aficamten pink circles. All of them, all 12 correspond to the titration period. All 12. Every single one of them. Again, forced uptitration based on the app. In the placebo group, difference. Okay? So all heart failure events in the ACACIA trial occurred in patients on aficamten in that titration period. All of those patients, by the way, responded very well to minimal heart failure therapy, usually low dose diuretic therapy, and were discharged within a very short period of time. Now, if you look at FOREST then for a minute.
Taking those patients that rolled over into FOREST as part of the long-term extension therapy of aficamten, really important. I think this is compelling here, which is that if you look at these patients, first of all, the patients that were on aficamten in ACACIA who rolled over into FOREST, there are no pink circles. That is because none of those patients had a heart failure event in FOREST. The only heart failure events were those patients, and there were 2, in placebo arm in ACACIA who rolled over into FOREST on aficamten. And those two, which is 1% of the population, occurred during the titration period. Okay.
And I think what this means, to translate this, what this means is that when we look at heart failure events, it appears that these could be significantly mitigated using a strategy of dose titration that is reflective of clinical practice, which is what FOREST titration does. It uses an unblinded assessment of the echo with clinical judgment to make decisions about titration. This is how we practice clinically in the real world. That is what FOREST mimics, and this is what I think we could expect to see based on that experience. All right. My last slide, and then we will open it up, which is a conclusion slide. I think. The advancer, it needs a, okay. So, as anticipated, escalation of dose of aficamten in isolation of clinical data resulted in greater events when compared to dose selection that incorporates clinical judgment and echo assessments.
The current algorithm with FOREST essentially mimics clinical practice as well as what we have for aficamten in symptomatic obstructive HCM. And the incidence of serious heart failure in FOREST, including patients never exposed to aficamten before, is substantially lower than that noted in ACACIA. Thank you.
Yeah. Please come up, guys. So thanks, Marty. Thank you, Dr. Masri. And I would like to just welcome Dr. Christina Paitazoglou up to the stage, and we will get the Q&A session on the go now. So I am actually going to start out with you, Dr. Paitazoglou. So you are a HCM doctor and a heart failure doctor here in Germany. Can you just tell us a little bit about yourself, what your practice might involve? And then as a second question, a follow-up, you really were not part of the study, and you saw the results really for the first time just a couple of hours ago. Maybe you can contextualize those results, tell us what you think about them and what they mean for the patients in your clinic.
Yes. Thank you very much. First of all, congratulations to your trial and the results. Very impressive. My name is Christina Paitazoglou. I am a heart failure specialist. I work at a university clinic. I am head of the heart failure department at our clinic, and I am also the lead of the heart failure network for the state department with the Ministry of Health, so we get a lot of referrals to our university clinic. Not only HCM, also other heart failure pathologies, but we see a lot of patients with HCM because in Germany, those patients treated with a myosin inhibitor now, and titrated, is in the university clinic. So we have treated all of our patients. Not all of our patients have obstruction. We get a lot of referrals with patients who do not have obstruction, and there is, as Dr. Maron said, a clear unmet need.
We don't have options for those patients. They are still very symptomatic, and we can only treat them according to the guidelines of heart failure. We did not yet have, so far, a targeted treatment. That's why it's a great milestone. It's the first positive trial in this difficult population. You do not have an obstruction. You give a specific drug, and the patient gets better. So for us, it's a new opportunity. We have a new tool. We can help the patients. We can give them hope for treatment. Your results are, for me, very encouraging because, as I said earlier to you, I was not expecting the same results as an obstructive, because it's a different patient population, the patients with non-obstructive. The symptoms, it's more complex, derived from many factors. It's a diastolic dysfunction. It's microvascular disease. The drug is very specific.
It led to an improvement of the patient, and that is very important. Not only hemodynamically, the patient feels better, and we know the safety profile. I've treated, in Germany, a lot of patients with aficamten in obstructive. I feel very safety with this drug, and now it gives me hope for this patient population. I don't know if it answers exactly your question. It was very widely asked.
Yeah, that was a beautiful description. Maybe just to dig a little bit deeper, you mentioned to me earlier on that you're actually an expert in cardiopulmonary exercise testing.
Yeah.
You've done some advanced training in New York City. You also treat other forms of heart failure. So you have a special understanding of the magnitude of the treatment effect in terms of the peak VO2, for example. Maybe you can just drill down on that a little bit to put some perspective over there.
The CPET training. Yes, we do a lot of CPET in our heart failure patients, and that is not a very common examination for cardiologists. Not many have the expertise in CPET. I did it in New York at Columbia University, also in Heidelberg. We perform CPETs in all of our patients, even advanced heart failure. I know these parameters you presented, the peak VO2, even the slope, they are prognostic parameters for heart failure. Usually in my patients, they go down. Not the slope. The slope goes up, which is bad. In your trial, we saw an improvement, and it is very difficult to change those parameters in the CPET. An improvement in the peak VO2, it is very difficult to achieve even for those patients and exactly for those patients without obstruction.
Maybe they resemble a little bit the more broader patient collective like HFpEF patients. It is, I do not want to say impossible, but it is very difficult to improve them. Many trials have not chosen this parameter as a primary endpoint, I think because they are afraid of the results, and they may have failed. An improvement consistent with an improvement in symptoms and the NT-proBNP going so much down after 36 months is, for me as a clinician, a very great sign and it makes me happy to see that. You have to leave the patient longer on this medication. Maybe this parameter will even get better because the medication targets exactly the disease.
All right. Beautiful. Thank you so much. Maybe moving on to you, Dr. Masri. How would you characterize the overall safety and tolerability of the data that you presented today, and what did you and your investigators actually see and manage over the course of the trial? What do you see in some of the patients that you might actually have now in the FOREST open label extension?
That is a great question. As we alluded to, the numbers that you are looking at, you have to really understand what it means when we say that there was reduction in LVEF. I think of them as kind of almost three buckets. One is what was the average reduction in LVEF throughout the trial or at week 36, for example, and that was 4.4%. The second bucket is we are dosing to titrate to LVEF. Like you do with blood pressure, if you want to dose to blood pressure, you will have instances of reduction in blood pressure. Same with EF. You are dosing to it. There will be instances of reduction. The question is, can you keep the patients on the drug or lower dose? Can you continue without having cycles of stop and start?
Are you causing these patients with the reduced ejection fraction either irreversible issues or something really significant that is having them exit or just say, "I don't want to do this." This is not our experience. We've already shown you the numbers. I'm not going to repeat those. Even our local experience, where we have now more than 40 patients or so with non-obstructive HCM on aficamten as part of these clinical trials in the open label FOREST-HCM study, this is not our experience. Our experience is generally speaking in the blinded period. I don't know anything about what happens to these patients in the blinded trial, but if these patients suffered a significant event or something meaningful per protocol, I would have known about it, for example, and this wasn't the case.
In FOREST, as Dr. Maron alluded to, we dosed all of these patients in FOREST, and we are not dealing with any of these major issues. Even if you end up seeing a reduction in EF less than 50%, if the patient is asymptomatic, the reason why we go down on the dose is that because we don't know what the long-term meaning of that, so we just want to keep that threshold. To me, essentially, the safety is on par with what I have expected it to be. It's just you have to put into perspective the design of a clinical trial where we're taking 517 patients, randomizing them one to one, and for those 289 patients, we're telling them, "All of you have to go through the same process." This is not clinical practice and not FOREST-HCM design either.
Got it. Thank you. Dr. Maron, so which of the patients in your practice do you think that the results of ACACIA are most applicable to? In other words, do you think that there are patients who would derive more benefit than others? Thinking a little bit more ahead, how do you think the conduct of ACACIA-HCM may translate into future diagnoses of new non-obstructive HCM patients?
Yeah. Great. Thanks, Steve. I'm going to get to that in one second. I want to address one other point that was raised here that I think is important, and this is something I'm kind of seeing and hearing. I think that there was this expectation, I think in some people's minds a little bit, that we would see a treatment benefit here that was similar to the obstructive HCM trials. Right? There was that expectation, I think, psychologically or otherwise. Of course, that was never going to be the case because in obstruction, these drugs so effectively lower acutely that high LV pressure, that it translates into such a magnitude of benefit in how patients feel that you weren't going to ever be able to achieve that kind of degree of improvement in this different population.
That doesn't mean that the clinical benefit that we're seeing in non-obstructive is less significant necessarily, but that to compare the two experiences isn't fair and shouldn't really be done. I think I see a little bit of a psychological thing going on here where people were expecting those same treatment benefit numbers and not seeing them psychologically has created a little bit of consideration. I think that, look, we made the case here, I think, with this responder analysis, that the benefit is clearly there in this population. It's different than non-obstructive. Number two, I'll make the point that, and I'll support that point with this following anecdote, which I think to me tells the whole story almost. If you look simply at the patients that were in ACACIA who rolled over into FOREST, of which there are several hundred.
If you look at those patients, you will see that 99% of them remain in FOREST on aficamten many months later. Almost none have dropped out. I can tell you, there's one thing I can tell you, it is that these patients, if they were not deriving a clinical benefit, would not schlep back in for all of the visits that are necessary for FOREST and everything else if they did not feel that there was a true treatment benefit that they were getting with the therapy. That kind of level of commitment would not happen, and it speaks, I think, essentially to the treatment benefit that we're talking about. If we take that for a minute, then Steve, to answer your question is that, Ahmad showed that there really was no heterogeneity in treatment benefit across all of these different subgroups.
The answer of who would potentially benefit from this drug, it would be nearly all the non-obstructive patients who fit into the criteria of ACACIA. Symptomatic, functionally limited patients would be potential candidates for the therapy. By the way, it's tough to sit across from these patients that are really frustrated with how they're doing, and you know that you've got a therapy that can improve how they feel and function across the non-obstructive spectrum and not potentially think about that option for them. I mean, that is an important principle. I think what we will do in practice is that we will potentially consider all the patients that fit into the ACACIA trial profile as potential candidates for therapy.
All right. Perfect. Thank you. Beautifully said. We're going to switch over to some questions from the audience. Joanna, yep, there you go.
Thank you very much. Cory Kasimov with Evercore. Dr. Maron, I just want to follow up on a point you were making and just ask it a little bit more bluntly. The discussant in the trial, while I think balanced overall, again brought up this point of a modest effect when describing the study. Given the dearth of options for these patients with non-obstructive HCM, in other words having none, are there patients who you think would not be candidates for aficamten assuming approval or perhaps subgroups of patients where you would not want to at least try this product? Thank you.
Well, two things. One is that I think I would push back a little bit on the characterization that came up today about the treatment benefit was modest. I think what I'm trying to say here, based on the data and our experience, is that I don't think that that is necessarily characterizing what's going on here in terms of treatment. I think the treatment benefit is much more than that for the vast majority of patients that are on therapy. Again, it may not reflect as intuitively in mean changes. We saw the benefit that I think supports that with the responder analysis where you've got 70% of patients feeling better by a clinically meaningful change. That's really important. I don't look at it, by the way, by the data or in my own practice as a modest change. I think it's much more than that.
Two is that I think that we don't really have any idea about whether there's any kind of subgroups. We don't really have a good idea about whether there are specific subgroups that would be better responders or not so much good responders in this population yet. I think what we do know is what Ahmad showed from the primary paper, which is that there was no treatment difference among a lot of different pre-specified relevant subgroups here. All of them were getting benefit here, and I think we have to go on that presumption right now that that is the case, and that's how we'll practice clinically.
Hi, Tess Romero from JPMorgan. Thanks so much for having me. Just to piggyback off here, maybe just thinking about how you compare and contrast the treatment effects that you've seen across both of these patient populations. What were the true surprises in the data relative to your expectation? Then how should we be thinking about sort of longer-term treatment effects and sort of where this could go over time?
Take that one.
Great question. One of the things that came up to me is when you look at mean population averages, you actually are not reflecting on the patient experience. As I mentioned, we have substantial number of patients, and in a blinded trial, I cannot tell much, but I have them in the open label extension. The individual patient experiences, there are exceptions, obviously. There are patients who just their heart structure might not be tolerant of a CMI like aficamten. But in general, for the majority of the patient, our patient experience has been very positive. I am not talking about someone just going to the bathroom and not being short of breath. I am talking about actual scenarios where patients essentially were short of breath just walking down the street now to hiking in Oregon, which is not a very easy thing to do.
These are all real stories, playing with their grandkids or taking care of them. That is one of the surprises that, back to Dr. Maron's point, is that I personally do not feel that the treatment effect is modest. You have a disease which is more resemblant of a heart failure syndrome than it is of an acute afterload problem. You moved every single domain that you want to move, even the left atrial volume index, which has a lot of shortcomings to it. Even that was marginally positive, essentially. You are moving all of these domains in the right direction, which has never been achieved before in a heart failure syndrome trial. We make people live longer with heart failure, yet we make them feel worse and exercise less.
That to me, essentially, is the important piece here is that there is education to be had and to be done to translate what we saw and what our experience is to allow people like what you reflected on in the conference, for example, understand this as well.
Just one follow-up here. Just to kind of double-click on how we should interpret the heart failure events that were not associated with EF drops below 50%. Can you just provide your thought around this? Thanks.
I am happy to take it. I actually, myself, had patients like that. What happens is when you are using aficamten, your goal is to improve stroke volume and cardiac output. That is your ultimate goal, and that is how you improve peak VO2. You improve how patients feel and how patients do. You have a left ventricle that is stiff, that has been with this disease for decades and decades, and you are acutely changing how the left ventricle and the heart is working. During that titration period when you are introducing that acute change, you will have some fluid imbalance because you are suddenly seeing more blood coming to the left side of the heart, which is stiff and has lived with the same amount for years. Again, when we say heart failure, it is just a broad basket.
Like my patients, you give them few days or even few doses only of an oral diuretic, their legs are no longer swollen, and they keep going. That is, I think, where this requires an effort to show people and explain it to them, is that it is you are acutely changing something over eight weeks that has been there for 20 years. So in very few number of patients, the number is one out of 20. We are talking about such a small number of these patients. One out of 20 patients had to have that. So in my opinion, this is a minor issue. It is addressable, and the beauty of this is that this is not a therapy where you have to give it to everyone and wait until they live or die 10 years later.
This is something you can give it to the patient, talk to them, see how they do and how they feel, and make a decision. Six months later, 12 months later, you make a decision. Are you liking being on this drug? Do you derive benefit from it? What is going on here?
Hey, good afternoon. Serge Belanger from Needham. There was a lot of discussion about titration and dosing. In the trial, you titrated based on max tolerated dose. You mentioned it would be different in the real world. Just curious, if you applied real-world criteria, if it would have had any impact on the efficacy and safety that we saw in this trial? Secondly, for the company, what do you expect the regulators will look for in terms of dosing and titration for this indication?
Maybe I will start with the question for the company, just to get that out of the way. We are in discussion with regulators right now. We do not like to speculate what regulators are going to say, what they want, and what they do not want. We are going to put our best foot forward, and we are going to negotiate in order to get the best outcome for patients, ultimately. Marty, you?
Yes, I will just say so for FOREST. I think the answer to your question is, it has to do with FOREST data. FOREST, the open label extension, and I think we touched on this. Two points is that, number one, FOREST uses a titration scheme that is similar to the one we have for obstructive HCM, but also, again, mimics or incorporates physician judgment. Which is still really important even in the current era we are in. Seeing the patients and making judgments while also looking at the echo. When you do that, at least by the FOREST experience, you do not see those heart failure events like you did in the clinical trial.
I think it does speak to the fact that when we think about real world, we will see, and we do not have any reason to believe it would be different, that experience in terms of heart failure events. Number two is that if you look at FOREST data in the non-obstructive patients now out to more than 96 weeks therapy. If you look at that data, which is published, you see two things. One, that the clinical benefit is maintained. You still continue to see significant improvements in how patients feel, both by NYHA and KCCQ. This benefit that we are seeing in the trial appears by the FOREST experience to be maintained.
Lastly, based on these results, what are your thoughts now on the role of CMIs and aficamten for HFpEF?
Well, maybe we'll all jump in on that one, because there may be different. Here's what I think. I think I'll say that when we talk about HFpEF, and so non-HCM HFpEF, I would say this. This is how I would answer that, and I'll be brief so these others you can jump in. I'd say that the results of ACACIA, to me, open the door, in a way, to the idea that CMIs could have clinical benefit in the HFpEF population. That's principle number one. I think that's true. What I think is going to need to happen, though, is we're going to need to find the right HFpEF population that's going to be benefiting from these therapies. It may not be the entire pie, which as you know, is a big pie, which is a very diverse phenotypic in subgroups in that pie.
I think we're going to have to be a little bit thoughtful about which are the right patients to look at and essentially be following in trials to get the kind of outcomes that we want and like we saw here. So I think it's a possibility, but it's going to require that as, I think, a big step.
Christina, why don't you piggyback off that?
Yes. When you presented your data, my colleague, also cardiology at my department, asked me, "Oh, maybe we can use it also on the other HFpEF patients." Or, "How many of your patients were maybe not HCM or HFpEF patients?" Well, I agree that the HFpEF population is very diverse, and that's maybe why trials in the past were not successful, because they did not address it regularly. If you look at the mode of action of aficamten, it reduces the hypercontractility. We have to find patients in this HFpEF collective who have this hypercontractility, because it reduces the hypercontractility and it may the ejection fraction go down. So you have to find the ideal population in this potpourri of HFpEF patients which may benefit. It will be not easy, but if you find a specific subpopulation, maybe this drug is also good in the HFpEF.
Thanks. Ahmad, I know what you think about this, but we're going to move on to the next question.
Thank you. This is Robin Roch too. Quick question on the potential halo effect to have a drug that not only works in oHCM but also in HCM, and how that basically plays back into oHCM to have basically one drug that is able to treat both patient populations. A quick follow on.
Maybe Christina, you're not involved in the study, and again, I'm going to pick on you because you have a broader opinion. The question really is, do you think that now that we have some positive data in patients with non-obstructive HCM, that will translate into an increased utilization of aficamten in patients with obstructive HCM, too?
The medication is available in Europe, only in Germany, and it is since June available. We have gained a lot of experience since then, and it is a very safe drug to use. All of the cardiologists who are working with the drug are, and I was talking to them, are feeling the same. It is easy to use, it is safe. You can go back. You have a quick up titration process. You can get patients quickly on target. If they have a good experience in obstructive, and now we have data for non-obstructive, I think it will be very easy, and they are already asking us, "Can we use it? Can we prescribe it?" We say, "No, you have to wait for the label." I think it will be very quickly in the use also for the other collective. It is the only positive trial.
For the other medication, we do not have positive data. With this easiness at use and the positive trial, yes, I think it will be very easy in the translation. The physicians and all of them are waiting to get a drug like this because we have the patients and we could not treat them yet with the medication. We said to them, "Oh, no, you do not have obstruction. Sorry, we cannot treat you, and we have to wait for your results." I have in mind many happy patients now, or patients who would be very happy to hear your results. They are waiting for the treatment.
I think it is a huge point, actually. I will piggyback real two seconds. I think it is a huge point. It is a huge differentiator. You know why? Because the clinical practice and cardiology community does not want to think about, wait a minute, this patient has got obstructive or not. Which drug? This simplifies. If it is approved for non-obstructive, it simplifies the approach to the management of HCM, which is particularly impactful in the general cardiology community here. I think that this will do that. I think it is a really important point that cannot be minimized.
Quick one on the patient deaths in the study. Was there any imbalance that you saw there?
Yeah. There were three deaths in the placebo arm. There were no deaths in the aficamten arm. It is a very small number to make anything out of it, really.
Perfect. Thank you so much.
All right. Any more questions in the audience? We will take one question from online over here. I will just go with the first one, Paul Choi, from Goldman Sachs. He is asking, "Do you envision your non-obstructive HCM patients actively seeking treatment, or will they get on MYQORZO over time as they come in for their periodic checkups?" Ahmad, do you want to take that?
Yeah. We actually have experience from this with the recent approval of aficamten in obstructive HCM patients, where I was on vacation, and it was a day or two before Christmas, I think, when the approval came through from the FDA, and we started getting all these messages. "Hey, I saw this online. Can I please come and talk to you about it?" This is an obstructive HCM, correct? A lot of these patients are limited, and they are significantly limited, and there are a lot of initiatives from patient advocacy group, from societies, supported by sponsors, supported by others, that when you have such a drug becoming available, I expect a lot of patients to reach out to their physicians and say, "Hey, I saw this. I am limited.
I want to be considered or at least talk about it. This happens outside of HCM. It happened also in amyloid when new therapies became available, and I expect the same to be here.
Great. I apologize. We have some other great questions from our online attendees that we are not going to be able to get to. With that, I would like to thank our three panelists. Thank you, guys. I really appreciate you spending your afternoon with us, and Robert is going to say a few words.
Thank you, Steve, and many thanks to our panelists. I very much appreciate you taking the time to share these data and perspectives with us. It is a very exciting time for science and for patients and for us at Cytokinetics here in Munich. We are really proud to have these results shared here at the ESC. ESC is the very largest cardiology conference held globally each year. There are over 30,000 people here, and I have been doing this for over 40 years. I have been coming to these meetings, and I have never been at a scientific session where there were as many people gathered as we saw here today. Not only was the congress hall filled in every chair, but standing room only in the back 15 rows deep.
It was really quite impressive, and it is so nice and gratifying for us at Cytokinetics to see our science presented to an audience and have those results so warmly embraced. At the same time, here we are. We are pleased to be underway here in Germany with the launch of MYQORZO. That occurred in June alongside of the launch in the United States that occurred earlier in the year, also in China. As mentioned recently on our Q2 earnings call, we also received approval from the MHRA alongside of positive guidance from NICE in the U.K. and Wales. MYQORZO is beginning to reach patients all around the world in multiple geographies, and that is truly wonderful to see. We really appreciate the warm embrace, the market access, and the adoption for MYQORZO in oHCM.
Given now these positive results from aficamten in ACACIA-HCM, we're really pleased, and frankly, we're very committed to be moving very swiftly to submit a supplemental new drug application to the FDA for aficamten. We're going to do that in nHCM in the fourth quarter of this year. On our next earnings call, we'll provide an update on our plans with regard to other geographies. We look forward to engaging with the FDA to potentially bring this important medicine to bear on patients with nHCM, for which there is no other treatment. At the scientific sessions today, there was a slide put up that showed that every other study conducted in patients with nHCM was negative. That includes a lot of very commonly embraced drugs in the use of heart failure and another cardiac myosin inhibitor.
We're really pleased that aficamten in this study, ACACIA-HCM, was positive for patients who don't have any other approved treatments. We look forward to the potential of aficamten being approved across the full spectrum of patients with HCM and especially now with nHCM, a very challenging and life-altering disease. We thank all of you for your continued interest and your support of our company. We really mean that. This is especially gratifying for us, and we're glad to have shared this with you. With that, we'll now conclude the event. Thank you.