Thank you for standing by, and welcome to Cytokinetics conference call to discuss the top-line results of ACACIA-HCM. This call is being recorded, and all participants are in a listen-only mode. After the speaker's remarks, we will open the call to questions. We will allow for 1 question per participant. If you would like to ask a question during this time, simply press star followed by the number 1 on your telephone keypad. If you would like to withdraw your question, press star 1 again. I would now like to turn the conference over to Diane Weiser, Cytokinetics Senior Vice President, Corporate Affairs. Please go ahead.
Good morning, and thanks for joining us on the call today. Robert Blum, President and Chief Executive Officer, will begin with a brief introduction. Fady Malik, EVP of R&D, will provide an overview of the top-line data from ACACIA-HCM. Stuart Kupfer, SVP, Chief Medical Officer, and Steve Hytner, SVP, Head of Clinical Research and Development, are also here with us to answer questions. Please note that portions of the following discussion, including our responses to questions, contain statements that relate to future events and performance rather than historical facts, and constitute forward-looking statements. These include, without limitation, statements regarding expectations regarding regulatory interactions and the potential for regulatory approval, expectations regarding commercial performance, and statements about our financial guidance and capital allocation. Our actual results might differ materially from those projected in these forward-looking statements.
Additional information concerning factors that could cause our actual results to differ materially from those in these forward-looking statements is contained in our SEC filings, including our current report regarding our first quarter 2026 financial results filed on Form 8-K that will be furnished to the SEC today. We undertake no obligation to update any forward-looking statements after this call. Please note that slides accompanying today's discussion are available for download within the webcast and on our website. Now I will turn the call over to Robert.
Thank you, Diane. This morning, we reported positive top-line results from ACACIA-HCM, the pivotal phase III clinical trial of aficamten in non-obstructive HCM. We are pleased that the trial demonstrated statistically significant improvements in both KCCQ clinical summary score as well as peak VO2, and with robust and consistent effects favoring aficamten versus placebo throughout the treatment period. Moreover, these primary efficacy results were supported by positive effects on key secondary endpoints. Today's results from ACACIA-HCM represent an exciting step towards the potential for aficamten to become the only cardiac myosin inhibitor to address the full spectrum of HCM. Patients with NHCM have no approved therapies to address the underlying hypercontractility associated with this disease, which makes these results impactful for the HCM community as well as for all stakeholders in Cytokinetics.
We are humbled by the consistency and the strength of our pioneering science for patients, and we look forward to sharing the results from ACACIA-HCM more fully with regulators as well as with the medical community in the weeks and months to follow. Now, I'll turn the call over to Fady to please speak to the results.
Thanks, Robert. First, I want to take a brief moment to thank everyone involved in this trial. I'm grateful to the contributions from investigators, clinical site staff, many colleagues at Cytokinetics, and most importantly, patients and their families. Before I get into the results, I want to remind you of the study design. ACACIA-HCM was a phase III multi-center randomized double-blind placebo-controlled clinical trial designed to evaluate aficamten compared to placebo in patients with symptomatic non-obstructive HCM. Participants were randomized in a 1-to-1 fashion to receive either placebo or aficamten. Dose escalation was guided by echocardiography with escalation in dose from 5 to 20 milligrams every 2 weeks, as long as left ventricular ejection fraction was greater than 60%. Participants who did not meet escalation criteria continued on the same dose or were down titrated if their LVEF was less than 50%.
After 36 weeks of treatment, participants continued treatment with aficamten or placebo for up to 72 weeks to evaluate additional secondary and exploratory endpoints, including the time to first cardiovascular event. ACACIA-HCM randomized 516 participants outside of Japan. A cohort of patients enrolled in Japan are continuing in the trial in a blinded fashion to sort approval in Japan and are excluded from the primary results analysis. The dual primary endpoint was a change in KCCQ clinical summary score and change in peak VO2 from baseline to week 36. Secondary endpoints included the proportion of participants with an improvement of at least 1 New York Heart Association functional class and changes in the composite Z-score to cardiopulmonary exercise testing parameters of submaximal exercise performance and which is ventilatory efficiency and peak VO2.
NT-proBNP, left atrial volume index, and baseline to week 36 were other secondary endpoints. As Robert mentioned, the ACACIA-HCM met both dual primary endpoints demonstrating statistically significant and clinically meaningful improvements in both clinical summary score and peak VO2 from baseline to week 36 compared to placebo. Specifically, in participants on aficamten, KCCQ increased by 11.4 points compared to 8.4 points for participants on placebo, resulting in a least-squares mean difference of 3 points with a P value of 0.021.
For peak VO2, participants on aficamten experienced an increase of 0.64 mils per kilo per minute compared to an increase of 0.03 mils per kilo per minute for participants on placebo, with a least-squares mean difference of 0.67 mils per kilo per minute and a P value of 0.003. A reminder, the threshold for statistical significance for each of the dual primary endpoints was set at 0.025, which both endpoints achieved, and there was no recycling of alpha spend necessary. Statistically significant improvements were also observed in key secondary endpoints, including the proportion of patients with improvements in NYHA functional class, the composite Z-score, and cardiac biomarker NT-proBNP. Let me put these results into context. CaCHE HCM.
As you can see in the graph included in today's press release and in the webcast slides, at the end of titration at week 8, the curves begin to separate and clearly remain divergent throughout the duration of the trial. Throughout the treatment period, patients on aficamten experienced a robust and consistent treatment effect. During the washout period, patients on aficamten had a rapid reduction in their KCCQ score, bringing them down to match placebo patients. The increase of 11.4 points for patients on aficamten is remarkably similar to the magnitude increases that we've observed for KCCQ in SEQUOIA-HCM, which was 12 points, in cohort 4 of REDWOOD-HCM, which is 10.6 points, and in FOREST-HCM after 96 weeks in patients with NHCM, which was 11 points. These are large and clinically meaningful improvements.
Improvements of 5-10 points are generally seen as clinically relevant and 10-20 points as clinically meaningful as well. In ACACIA-HCM, patients on placebo also experienced an increase in KCCQ of 8.4 points, which is slightly higher than what we've seen before. For example, the 5-point change we observed in SEQUOIA-HCM. The onset of the placebo effect is early and associated with the initiation of participation in the trial. It may result from an improvement in clinical care, greater compliance with background medical therapy, or other aspects of standard of care patients receive in a clinical trial. As I pointed out earlier, the overall effect on KCCQ on patients treated with aficamten was robust and consistent over the entirety of the conduct of the trial, with a washout effect and loss of treatment benefit when treatment with aficamten was discontinued.
The other primary endpoint, peak VO2, is a measure of exercise capacity. At week 36, peak VO2 increased for patients on aficamten while it remained unchanged for patients on placebo, consistent with prior trials of aficamten. We believe the improvement in peak VO2 by 0.67 mils per kilo per minute represents an important clinically meaningful difference as bolstered by the benefits seen in other patient and physician assessed endpoints. The secondary endpoints were analyzed in rank order beginning with NYHA functional class. NYHA functional class is a measure of symptoms, but unlike KCCQ, it's a physician assessment rather than a patient reported outcome. These two different measures of symptom and functional burden are reinforcing of the overall impact of that aficamten had on how patients feel.
The decrease in NT-proBNP is statistically significant relative to placebo and also consistent with our prior studies of patients with both OHCM and NHCM. Turning to the safety results, importantly, there were no new safety signals identified. The percentage of patients who completed planned dosing in ACACIA-HCM was similar between those receiving aficamten and placebo. LVEF less than 50% occurred in 10% of participants taking aficamten and 1% of participants taking placebo. 2 participants on aficamten experienced a Serious Adverse Event of heart failure associated with LVEF less than 50%. Treatment interruptions due to LVEF less than 40% occurred in 3% of participants taking aficamten. The frequency of these findings is not surprising relative to those with aficamten in OHCM. Given the strategy in NHCM, it's a dose to maximum tolerated dose as opposed to minimum effective doses in OHCM.
The great majority of patients in the ACACIA-HCM have now transitioned into the open-label extension FOREST-HCM, and we anticipate reporting on the longer-term safety of aficamten as they reinitiate and continue therapy. Today's announcements represent only the top-line results for ACACIA-HCM. There's much more granularity and additional detail that we plan to present at upcoming medical meetings. Until such time, we can't share any details outside of what's included in today's press release. We are very enthusiastic about these results and what they could mean for patients with NHCM. With that, I'll hand it back to Robert.
Thank you, Fady. ACACIA-HCM is the first trial to demonstrate a statistically significant and clinically meaningful effect on both exercise capacity and symptoms in this patient population. Given the unmet need in NHCM, this represents an inflection point in what the treatment of NHCM could look like for these patients, an opportunity to improve their symptoms and their functional limitations that restrict them from their everyday activities. We're optimistic about what this may mean for patients and the physicians who treat them. We look forward to presenting the full data set in the future, as well as discussing the results with the U.S. FDA, as well as other regulatory authorities. I, too, would like to extend my thanks to everyone involved in the exemplary conduct of this trial.
I'm grateful to the investigators, their site staff, and of course, patients for their participation, and to the many employees of Cytokinetics who contributed to us reaching this milestone moment. Operator, with that, we can now open up the call to questions, please.
Thank you. We will now begin the question and answer session. Please limit yourself to one question per participant. Your first question comes from the line of Selim Said with Mizuho. Your line is open. Please go ahead.
Good morning, Selim.
Great. Hey, good morning. Good morning, Robert. Congrats on the data, guys. Really good and very consistent efficacy. I guess just one for us. It's an obvious one here. Just on the placebo movement, obviously we saw similar placebo movement on KCCQ with mavacamten, you know, and people had speculated there, at least, that there was intensive background care. I think, Fady, I think you described it as being in the 99th percentile of placebo movements for KCCQ at one point. Could you just maybe comment a little bit more on the placebo movement here? Was it intensive background care as well, you believe, or was it the, you know, hypertensive patients?
What was it exactly that you think contributed to the 8.4 movement in KCCQ? Thank you.
I'll turn that over to Fady, please.
Yeah. Hi, Selim. You know, I think we still have work to do to understand what maybe drove the placebo effect here. You know, it's just a bit higher than we saw in OHCM. We think NHCM patients may be, you know, a little more similar to heart failure patients in that they respond to certain heart failure therapies like diuretics and things like that. What we'll do in the ensuing weeks is look at that carefully and see if we can understand what the onset of the placebo effect. It's pretty compelling when you look at how quickly the treatment effect comes on. It's right at, you know, basically during the escalation phase of dosing, and then it levels out, and it wobbles around for a little bit.
Importantly, at the end of therapy, it doesn't go away, unlike the treatment effect for aficamten. We'll have more to say about that as we dig more into the data.
Okay. Thanks so much. Congrats again.
Thank you.
Your next question comes from the line of Roanna Ruiz with Leerink Partners.
Good morning.
Hi, everyone. Good morning. Really interesting results. I was curious. In thinking about, you know, the trends both in PVO2 and KCCQ over time, I thought it was compelling that the KCCQ scores seemed to widen the longer the trial continued. Like, what does that underscore in terms of afi's clinical profile to physicians and to patients, and how are you thinking about uptake in non-obstructive HCM, assuming you get approved?
Of course, we still need to have conversations with regulatory authorities, so I won't speculate on that until we do that. In the meantime, I do think you're pointing out something that has us very intrigued, and we'll learn a lot more from still further data analyses, including from substantive work that's being conducted alongside of these primary efficacy review. Fady Malik, Steve, Stuart Kupfer, anything you want to add to that?
Yeah. This is Steve Heidner. Well, I think your point is well taken. Actually, it was part of our therapeutic hypothesis. When we designed the trial, we understood that non-obstructive HCM patients probably needed to be exposed to the drug for a longer period of time before you started to, you know, incur the benefits. I think what you're seeing is, you know, a potential indication that, you know, patients who are on this drug for a longer period of time do enjoy greater benefits. The study was essentially run for 72 weeks to, you know, point to that exact feature. Hopefully, as we dig deeper into the data, we'll be able to kind of unwind that story for you a little bit more.
I do think as you'll learn more about the secondary endpoints that can align and substantiate to some of these same hypotheses that we're testing. Moreover, as we learn more about the anatomy of these patients, we'll learn more about what may be occurring with time. This may be one of those studies for which these not only primary but secondary publications will inform quite meaningfully. As you can appreciate, this being the first such study positive in this patient population, there's a lot of benchmarking that needs to occur.
Makes sense. Thanks.
Thank you.
Your next question comes from the line of Tess Romero with JP Morgan. Your line is open. Please go ahead.
Hey, Robert and team. Congrats on these data from us as well. Thanks so much for taking our question. We acknowledge, of course, that you need to have discussions with regulators, but at first blush, was curious, how are you thinking about the safety profile that you saw in ACACIA and how this might lead ultimately to potential risk management in the indication if approved? Just to double-click a little bit here, how does what you saw compare to what you thought you would see given patient characteristics, et cetera? Thanks so much.
Thank you, Tess. I'll turn it over to Fady and Stuart to address that.
Yeah, let me start. I mean, I think the what we saw in terms of safety in this trial was pretty consistent with what we have seen in our trials of OHCM. We expected a larger proportion of patients who would develop EFs of less than 50. The majority of them were just, asymptomatic and, responded to down titration. The, you know, the safety profile, I think, really is unchanged, as we said. Over time, as we present these data, I think that'll be clear. The risk mitigation, effect on risk mitigation program, I think it's too early to discuss. I think we have to think about how the, you know, how does the impact of dosing in a blinded trial differ from what happens in, you know, real life?
Maybe ask Stuart to comment a little bit on our experience in FOREST where patients have open label or are receiving open label drug.
Thank you. In the FOREST trial, of course, those were we've been following a cohort of patients from our phase II REDWOOD-HCM trial, now for 2 or 3 years. Those patients tolerated aficamten extremely well. That's why we were optimistic about the tolerability profile in ACACIA. I think it's important, you know, to point out that Fady mentioned in his opening remarks, you know, is that in non-obstructive HCM, you know, patients are titrated to the maximally tolerable dose, unlike obstructive HCM where it's a minimally tolerable dose because of the gradient, the target gradient that we're trying to achieve in that patient population.
You know, the important findings that we're describing here is that even though these patients had some drops in ejection fraction, a large majority of them didn't have any sort of clinical consequence. The large majority of them, of course, didn't require treatment interruptions. Were able to continue aficamten, which drove what we observe as a benefit in terms of symptoms and functional improvement.
I think maybe just to add two cents. This study, I think stands out as one that around the original therapeutic hypothesis, when you think about what it was designed and powered for and what we expected in terms of efficacy and safety, hit squarely on the mark. Hopefully, as analysts and investors on this call have come to know this team, they appreciate very well its integrity, its credibility. If anything, I think these data resound profoundly alongside of what we've been expecting and pointing to, including as relates to safety.
Thank you.
Your next question comes from the line of Yasmin Rahimi with Piper Sandler. Your line is open. Please go ahead.
Good morning.
Good morning. This is Dominic on for Yasmin Rahimi. Congrats on the data, and thank you for taking our question. We know that you're still analyzing the data. Do you have any insight, or could you just help us maybe understand what NHCM patients would be ideal for aficamten given today's data? How soon would you envision filing on these results and potentially get it on a label? Thank you so much.
I'll answer the second question first and then turn to my colleagues. We're not gonna comment on timelines yet other than to say we're gonna move as swiftly as possible to make that happen. First things first, we wanna meet with regulatory authorities, understand how they view these data, and then move promptly to a hopefully potential submission. Fady, do you wanna take the first question?
Sure. I think, you know, the trial enrolled a fairly broad population of NHCM patients, and it's premature for me to speculate or even to comment on differences in subgroups and things like that. You know, we think that the efficacy was broad-based and seen really in all the patients in the trial.
Or all types of patients, I should say, in the trial. Frankly, at the end of the day, given the lack of effective therapies in NHCM, this will probably be more a try it and see how it works for individual patients down the road. Some patients will have very large responses, some maybe not so large. You know, whether to continue taking therapy will be a patient and physician choice. I don't think it'll be driven by any specific features of the patients themselves.
Great. Thank you so much. Appreciate it.
Thank you.
Your next question comes from the line of Maxwell Score with Morgan Stanley. Your line is open. Please go ahead.
Good morning.
Great. Thank you very much, and congratulations on these and impressive data. You've cited market research pointing to a 15%-20% halo effect in oHCM prescribing if a case is positive. With the clean dual endpoint win, has this estimate moved up? Can you give us an indication of whether it's kind of pulled forward the sales ramp or maybe this halo effect would be more relevant for 2027? Thank you.
Yeah, I think a halo effect conversation is a very slippery slope. Yes, we did some market research around that. That was prior to having data and that was imprecise. I do think now that we have data, we will do additional target product profile work and more quantitative research. Please keep in mind that this drug is only approved for OHCM. As it may ultimately become approved for NHCM, we would expect that could be enabling of its promotion in that indication. Until then, it would be, I think, improper for us to be trying to quantify a halo effect other than to say it has been noted in comparable markets like this. With that said, I think it's more for the analysts themselves to project what that could look like.
Great. Thank you, and congrats again.
Thank you.
Your next question comes from the line of Mayank Namtani with B. Riley. Your line is open. Please go ahead.
Good morning.
Yes. Good morning, team. Thanks for taking our questions and congrats on spectacular results here. Could you comment on the distribution of patients reaching to the, you know, at the highest dose levels, 15 and 20 mg in ACACIA? If there's any, you know, greater than 5-point KCCQ responded threshold that was cleared, you know, any proportion you can report on. You know, do you expect the titration burden to be in any way impactful in what you're seeing with HCM right now or even in NHCM? You know, 'cause that seems like a thing in the field apparently. We're just curious to get your feedback.
Lastly on the, you know, baseline characteristics, if you could maybe comment on the starting NT-proBNP levels, and if you know, saw the 36-week reductions that were largely comparable to FOREST-HCM. If you would maybe just comment on that would be helpful. Thank you.
You covered a lot of ground in your questions. Hopefully, Fady, you got all that.
I'd take notes, but I've got them all down. you know, we can't, unfortunately, we can't really comment on most of them. you know, the distribution of dosing, I'll just say that there were no surprises there. obviously, we'll show that when we show the full data sets. you know, the same thing goes for the baseline NT-proBNP. No surprises there, the actual numbers and data will have to wait until the data are presented. Titration burden, I think, is, you know, it's very similar to what we have in OHCM in that patients are titrated every 2 weeks. They reach their target dose within 6 weeks or less.
In general, you know, if there was a dose adjustment, it was fairly easily implemented and the patients could continue in the study on their final doses. I don't think that there will be a significant difference between O and NHCM down the road.
Thank you.
for the question.
Your next question comes on the line of Leonid Timashev with RBC. Your line is open. Please go ahead.
Hey, guys. Thanks for taking my questions, and congrats on the data as well. I just wanna ask if you guys can maybe speak to, you know, what you view is, or whether there are any differences in clinical meaningfulness between OHCM and NHCM on KCCQ and peak VO2. I know in particular you guys have done some work on what may be clinically meaningful in peak VO2 and sort of how to contextualize what we saw today with sort of typical thoughts around what's meaningful. Thanks.
Thank you. That's a good question and allows us to maybe put these data both for KCCQ and peak VO2 in a context, an ecosystem around which those endpoints have been measured in other populations. Fady, do you wanna take a stab at that?
Yeah, I'll start, and maybe ask Steve to comment on some of the analyses we've done in oHCM. When, you know, when you look at a KCCQ across a spectrum of heart failure trials, including trials that have very positive impacts on mortality, morbidity, like SGLT2 inhibitors and sacubitril/valsartan. You rarely see KCCQs that exceed 1 or 2 points. You know, here we have a 3-point delta at 36 weeks. At other data points, deltas of 5 and even 7 at the end of treatment. I think these represent very meaningful changes for patients overall, and they'll be, you know, once the full data set is revealed, I think one will see how they're bolstered by other endpoints and other measurements in the trial.
With regards to peak VO2, you know, again, I think I can safely say, although I haven't canvassed the entire literature, this is the first trial to show positive impact on both KCCQ and peak VO2 in the same study. Again, when you think about clinical meaningfulness, you ask yourself, Well, how are the endpoints? Are they consistent? Do you see a benefit across multiple domains, multiple aspects of the disease? I think they reinforce one another. In HF-ACTION, which was the largest trial ever done in heart failure using peak VO2, it was about a 2,200 patient trial, you know, the change from placebo was about 0.6. There again, it was correlated with patients feeling better and actually fewer hospitalizations.
I think it's safe to say we believe these are clinically meaningful differences. Maybe I'll ask Steve to comment on our work at looking at the deltas in OHCM.
What we did was we looked at what patients perceived as clinically meaningful. You know, most people don't exercise to their peak VO2 on a daily basis, and that number doesn't necessarily translate directly to how they feel. In order to elucidate that, what we did was we linked a patient-reported improvement of minimal but important improvement to a number on that peak VO2. The number we came up with was anywhere between, you know, 0.35 and 0.5. I think that the important message over there is that while the community has settled on this number of 1.0 as being an important threshold, that might be true when you're measuring things like hospitalization or mortality.
You know, just from a purely logical perspective, patients tend to feel better before they end up in the hospital or having a mortal event. Therefore, that threshold really should be lower to meet how patients feel on a day-to-day basis. In obstructive HCM, that number is anywhere between 0.35 and 0.5. I would be surprised if that was a different number that we came up with in non-obstructive HCM when we do our minimal important difference analysis in this study.
Thank you
for the question.
Your next question comes from the line of Srikripa Devarakonda with Truist Securities. Please go ahead.
Hey, guys. Congratulations on the data. Thank you so much for taking my question. I want to ask a little bit about the safety profile. Treatment interruptions you said occurred in about 3% of patients who had LVEF less than 40%. I was wondering if there were any patients that reinitiated therapy after the interruptions or were unable to reinitiate, what does that imply clinically? Thank you.
You want to take that, Stuart?
Yeah. This is Stuart Kupfer. Well, we can't really get into details about, you know, those patients who required interruption of treatment and, you know, the extent to which they resumed treatment. Those details will be forthcoming. In general, you know, what we have observed with aficamten treatment is that once a treatment interruption occurs, within approximately 1 week, the ejection fraction recovers. For those patients in this trial, again, not calling out specific data because we can't discuss that today, and we haven't even gone through all the data in complete detail. Those rare instances where that does occur, the ejection fraction recovers quite rapidly within a few days to 1 week.
Patients resume treatment, at a lower dose and, generally continue, treatment, in very tolerable manner and, you know, experience treatment benefit. We anticipate a similar type of profile in this, ACACIA.
Yeah. Bottom line is we designed aficamten originally with certain expectations, and that includes the ability when ejection fraction may fall to be enabling of either down titration or, in the rare case of a dose interruption, a pause to be enabling of restoration of treatment. I do believe in these data in ACACIA that we've met those design expectations.
Great. Thank you so much, and congrats again.
Thank you.
Your next question comes from the line of Ashish Verma with UBS. Please go ahead.
Hey, guys.
Good morning.
Congrats from my side as well. Good morning. Thanks, thanks a lot for taking our questions. I know Bristol commented last week that they're going to restart their non-obstructive program for CAMZYOS.
Which is great for the field, by the way. Just, like, looking at the results today, what's your sense of how that might inform their study? Secondly, looking at the LVEF rates here in NHCM, I'm wondering if there is an implication that you could draw on what the REMS part of the label could look like eventually. Would it be continuation of the same language that you've had on the OHCM side or anything slightly more stringent given the absolute rates here are a touch above? Thanks.
I'll take the first question, maybe ask Fady to take the second. I don't think it's our place to comment on what BMS should do or should not do with regard to our data. I think that's really more appropriate a question posed to them directly. With that, I'll turn to Fady to answer the second question.
Yeah. I think it's, you know, hard to obviously give strict guidance on the REMS. If you think about our open label experience in FOREST, we are following the same protocol that we follow in the OHCM patients in that there's a titration window, there is follow-up that occurs every six months. You know, obviously there's no monitoring for drug-drug interactions or anything like that, you know, none of that really changes. There may be, you know, some changes we'll find out as we go through the data and decide what we think support the best safety for patients. We'll probably have more to say about that as we learn more about these data and as we begin to interact with regulators.
Great. Thank you.
Thank you.
Your next question comes from the line of Paul Choi with Goldman Sachs. Please go ahead.
Morning, Paul.
Hi. Good morning, Robert, and congratulations to you and the team on this positive data. My question is with regard to the other secondary endpoints, particularly time to first cardiovascular event that weren't mentioned in the press release. Can you clarify if that endpoint was reached or if you're still analyzing that data set or, and it's being adjudicated and that's just something that will be clarified at a medical meeting in the future? Thank you.
Yeah, I think you can infer that those last two endpoints in the hierarchy were not met in terms of statistical significance. We'll obviously present those data in full when we come to the presentation of the full data set.
Okay, great. Thank you.
Your next question comes from the line of Carter Gould with Cantor Fitzgerald. Please go ahead.
Great. Robert, Fady, congratulations to you and the broader team. I wanted to come back to the KCCQ data for a minute. The sort of the pinching of the curves at week 36, is there anything specific going on there, any explanation? Is that just noise or you sort of just unlucky at that specific data point? I guess specifically the level of import that investors should assign to the overlap of the confidence intervals at that point on KCCQ. Thank you.
Yeah, I mean, the analysis is a pre-specified analysis of the KCCQ at week 36. It includes imputation of any missing data. You see that the number in the graph, the 3.1, is really the absolute difference between those two points. The LS mean change includes all the aspects of the statistical model, and it's basically the same, 3.0. Those, you know, other inclusions in the model didn't really affect a endpoint. If you look at the placebo curve, it wobbles around. It was much lower at week 24, went up at week 36, it went back down at week 48.
There are approximately the same number of patients at all those time points, so I can't really give you a definitive answer as to why we think the placebo effect changed at that week, and maybe we'll come up with something as we dive more deeply into these data. They're pretty fresh, as you can imagine. You know, I think overall one should focus on the whole. The reason we put figure in the press release is that, you know, looking at the treatment effect overall, and in fact, the loss of treatment effect as you withdraw therapy, you know, adds to the compellingness of these data.
Thank you.
Thank you, Carter.
Your next question comes to the line of James Kundelis with Stifel. Please go ahead.
Go ahead.
Hey, thanks for taking my question and congrats on the data. You know, maybe one just kind of like big picture looking, you know, at all this data and, you know, obviously there's a lot more to come. I guess as you look at sort of like the commercial picture and think about how docs are gonna approach using aficamten were it to be approved in non-obstructive, do you think docs are gonna have to work harder to find sort of the ideal patients that are kind of best suited to respond to a CMI? Or is it, you know, in your view, better to think about kind of all symptomatic non-obstructive patients in theory should be eligible for a drug like aficamten? Again, assuming it were to be approved. Thanks so much.
You know, keep in mind we have access to data that aren't being top-lined this morning. That includes baseline demographics, FOREST plots, as well as waterfall plots. What I do think you should perhaps focus to is some of the language we're using in our disclosures, things like consistent and robust and throughout the time period.
I mention that all because I do believe that these data will provide a compelling case for all patients with an HCM to potentially benefit from this mechanism of action. Ultimately, a population served would speak to the use of a medicine like this, if approved, as each physician together with his or her patient can determine if that patient is benefiting. I don't think there's anything in the data that we've seen to date that would suggest limiting the potential for an HCM patients to benefit.
Makes sense. Thank you.
Thank you.
Your next question comes to the line of Jason Butler with Citizens. Please go ahead.
Hey, thanks for taking the question, and congrats on the results. Can I just ask a question about part 2 of the trial? Is the goal there to again, focus on maximally tolerated dose? Or how do you expect dose titration when patients are reinitiating on therapy? Thank you.
Yeah. Let me ask Steve to answer that question.
You know, the study itself had a blinded dose titration strategy. The physicians who were responsible for the patients actually didn't participate in the decision as to whether to increase or decrease the dose. It was done all in a blinded fashion. In far as HCM, as we've mentioned, that physician is actually responsible for making that final decision on the basis of reviewing the echocardiogram and integrating how the patient is feeling at that time. What we've seen and reported with our Redwood experience is that, you know, when you integrate both clinical and echocardiographic information into your decision-making process, you're able to titrate the drug very effectively and safely in order to minimize patients' symptoms and hopefully maximize their activity.
What we saw with the obstructive experience is that while the titration mechanism was based on the phase III clinical trial, data from the open label extension did inform how regulators thought about it and put it into that clinical context. I suspect that we're gonna be looking at a very similar situation when it comes to negotiating with globally with regulators on this indication.
Thanks, Jason.
Your next question comes from the line of Martin Auster with Raymond James. Please go ahead.
Hey, guys. Thanks for taking the question.
Morning.
At the risk of fan service, I wanna congratulate you on the consistent, robust, FC results across the trial. Great job by the team. I think I wanted to follow up real quick on, I think it was Paul's question earlier on the safety side. It was encouraging to see a very low rate of SAEs related to congestive heart failure in the trial. Have you guys been able to calculate what the total MACE is and whether that's balanced between the two groups at this stage? Thanks.
You know, we've certainly looked at that, and that's why our statement of no new safety signals were identified is supported. I can't give you exact numbers. You know, again, we think that we know that this mechanism can reduce heart, can reduce ejection fraction. There's a warning in the label about the risk of heart failure with this mechanism. In general, we've seen it very rarely, almost nonexistent in OHCM, and then here in NHCM as we reported 2 cases associated with low ejection fraction that were serious adverse events of heart failure. You know, overall, I think it continues to be a relatively uncommon effect of initiating therapy with aficamten.
Were there other measures that had imbalance, such as like hospitalizations for other factors, arrhythmias, things like that you observed?
Yeah. I can't really, again, give you more color on that beyond what we've already put in the release. We put what we thought were the most relevant numbers in the release. I think should rely on that.
Gotcha. Thanks.
Your next question comes from the line of Cory Kasimov with Evercore ISI. Please go ahead.
Hey, good morning, guys. Exciting to see these super impressive results. I know this trial started with KCCQ as the primary endpoint and added peak VO2 primarily originally for regulatory purposes. I'm curious, do you believe one will resonate more than others, more than the other with docs? Is this really now at this point more about the totality of the data with the additional stat sig benefits you have on some of the secondary endpoints as well? Thank you.
Good question. Obviously, one is subjective to patient interpretation. One is objective to high fidelity measure. You haven't seen it yet, but NYHA improvements as is physician assessed together with BNP, which is also quite quantitative. All these things together contribute to a picture. I think regulatory authorities will look at the consistency and the totality. You know, peak VO2 is not something that most HCM specialists are measuring day to day for their patients. But it does have effect to how patients feel and function in the same way that KCCQ does.
I don't know that we could point to one versus the other, but maybe my colleagues can weigh in.
I might just add that, certainly I think hitting on both endpoints is an easier case to make than hitting on one and not hitting on the other. Regulators like peak VO2 because it's objective. We think KCCQ is an important measure of actual patient symptoms. So we were, you know, very excited to see that we hit both. I think there was some question whether we might hit both. As you can see from the data in the release, it's a pretty compelling case that both were hit. When we again see the totality of the evidence from the trial, the meaningfulness of this will be clear.
Great. Thank you.
Maybe if I could just add one more point. You know, there are other PROs embedded in the study that regulators requested that we put there. Obviously we're not kind of, gonna be talking about those results today. You know, there are other orthogonal ways of assessing how patients are feeling aside from looking at the KCCQ, which I'll remind everybody is a measure that was designed to assess heart failure patients that is now being repurposed in hypertrophic cardiomyopathy. They want us to assess whether it is in fact an appropriate metric for these patients. In order to do that, they have requested additional assessments.
Awesome. That's very helpful.
Thanks, Cory.
Thank you.
All right.
Operator, next question.
Your next question comes on the line from Serge Belanger with Needham. Please go ahead.
Hi, good morning, and I'd like to also offer my congrats on the data. First one, have you selected a medical meeting when we could see more detailed data on ACACIA? Then secondly, regarding the regulatory steps going forward, sounds like you wanna meet with regulators before expanding on the timelines and those steps. Just curious what you expect here in terms of regulatory paths, what kind of clarity you'll be seeking, and if you need additional data. Thanks.
Thank you. I'll answer the second question first, then turn to my colleagues. Regarding the regulatory path, that's certainly something still to be determined, but it would be our expectation to aim for a meeting to review these data, and then, as we've done in the past, have conversations at a subsequent meeting that would be a pre-NDA submission meeting. Getting those all done as promptly as possible is priority number one right now. And maybe, Fady, you can speak to a potential venue for these data.
Yeah, I mean, the next, I would say, major medical meeting other than the one that's this weekend, which is a little premature, is the ESC, the European Society of Cardiology, end of August. We'll aim for that. Hopefully, we'll get on the program there. We obviously don't have any insight into that at the moment.
Thank you.
Your next question comes from the line of Jason Zemansky with Bank of America. Please go ahead.
Good morning, Jason.
Good morning. Perfect. Thank you so much for squeezing us in, and congrats on the data. I wanted to ask a follow-up to I think Carter's question regarding the KCCQ over time. You know, just curious, at weeks 24, 48, and 60, the delta is similar, about 5.0, with differences at weeks 24 and weeks 72. I'm curious, you know, given how lumpy things are overall, is 5.0 sort of the baseline that you're moving from? Anything specific happen again in your models with regards to the decline in placebo KCCQ from week 60 to 72? Thanks.
I wouldn't characterize these data as lumpy. I do think your question allows us to point to the consistency of the effect even as measured at week 36. I'll ask Fady to comment on that, please.
I mean, I think, again, I think when you just look overall, you see a treatment effect of 3 to 5 points on average across the spectrum of the time points that we measured. I think what's also, again, and I don't wanna keep harping on this, but the washout effect, you know, the loss of effectiveness over with just 4 weeks of discontinuation of therapy, see patients revert back to baseline. That's also a very compelling indicator of symptom improvement from the therapy. The, you know, the modeling and other things don't really affect the lumpiness, if you will, of the placebo effect. You can contrast that with the, I think the lack of lumpiness in the aficamten graph as well.
You know, these data, all these data points have confidence intervals around them, and the point estimates are within those confidence intervals. Obviously, you could smooth them out and come up with something in between. I think just pointing again to the consistency and overall robustness and as we, you know, stitch together all the other endpoints that one will see, the treatment effect of KCCQ is bolstered by, you know, simpler assessments of patient-reported well-being as well as physician-assessed patient well-being.
The other thing I might add is if you look at the magnitudes of change for patients on aficamten at all time points relative to their own baseline, and you look at that also for patients in REDWOOD-HCM cohort 4 and those that have continued into FOREST-HCM, you see a ruthless consistency of large magnitude increases in KCCQ of double-digit size. That's, I think, gonna be viewed very compelling by regulatory authorities and physicians who treat these patients. Where there may be some lumpiness, if at all, it's perhaps in the placebo effect as we expected and as we saw also in the other trial of a cardiac myosin inhibitor, ODYSSEY-HCM. That speaks, I think, to Fady's point earlier that intensification of care in a clinical trial introduces for placebo patients an effect in KCCQ.
We can take, I think, comfort in the fact that patients on aficamten experienced such a large consistent effect across all time points. I hope that answers the question.
Very helpful. Thanks for the color.
Thank you.
Your final question comes from Yanan Zhu with Wells Fargo. Please go ahead.
Morning. Great. Morning. Hi, Robert I. Blum. Thanks for taking our questions and for fitting us in. I wanted also to focus on KCCQ. I think the 5-point difference is something that of a threshold in a physician's mind. I totally agree with the sentiment that, you know, it seems like you achieved a delta of 5 and beyond at week 48, which is a similar time point to ODYSSEY-HCM and also beyond. I was wondering how, you know, how mature the data for you at, you know, in terms of the data point 48 and beyond. Can you assign any nominal P value to those data points? Is there a way for these data to be getting into the label?
Lastly, maybe on NYHA, you know, great to hear that you did hit that sig. I thought at REDWOOD in REDWOOD study, NYHA improvement was quite significant. Can you comment on whether the magnitude here is similar to REDWOOD? Thank you.
Yeah. Hi, Yanan. It's Fady here. I think, you know, there's no real standard, if you will, for what magnitude of KCCQ represents an approvable or even frankly a meaningful impact to patients. The 5 is what is supported by various analyses. You know, our analyses and OHCM suggests it's somewhat lower than 5. You know, so I think that there is a meaningful effect here that patients clearly perceive. Just based on the majority of them moving into the open-label extension, I'm sure they, you know, wanted to stay on therapy because they perceived a benefit to themselves. We'll be again triangulating the change in KCCQ with other metrics that we haven't reported.
As Robert pointed out, the absolute magnitude of change is quite large. Over 10 points, generally patients can perceive an improvement with a 10-point change in their KCCQ from baseline. As in stats sig, you know, I think you can just look at the error bars and take a guess, but you would probably be accurate in what you decided there. The other time points, the NYHA in REDWOOD and in FOREST, you know, has been quite meaningful. FOREST particularly, one's seeing now with even longer follow-up that the majority of patients have transitioned to become Class 1.
Again, I think the totality of the evidence here suggests that patients derive an early benefit, but a benefit that is steady over time and perhaps increasing as the length of treatment gets longer.
Very helpful. Thank you and congrats.
Thank you.
This concludes the question-and-answer session. I will now hand the call back to Robert Blum for closing remarks.
Thank you, operator. It's the top of the hour, and we thank all of our participants who joined us for this call today. We appreciate that you share our enthusiasm for these data from ACACIA-HCM, and I do believe your sentiments are echoed by our conversations together with steering committee members for the clinical trial who have used adjectives like transformational and nouns like home run and best case scenario when speaking to these results. We look forward to elaborating on these data as they will be presented in full, and we appreciate your continued support and interest in Cytokinetics. Operator, with that, we can now conclude the call.
This concludes today's call. Thank you for joining. You may now disconnect.