Good afternoon and welcome, ladies, and gentlemen, to Cytokinetics First Quarter 2023 Conference Call. At this time, I would like to inform you that this call is being recorded and that all participants are in a listen-only mode. At the company's request, we will open the call for questions and answers after the presentation. We will allow for one question per participant. I will now turn the call over to Diane Weiser, Cytokinetics Senior Vice President of Corporate Communications and Investor Relations. Please go ahead.
Good afternoon, and thanks for joining us on the call today. Robert Blum, President and Chief Executive Officer, will begin with an overview of the quarter and recent developments. Fady Malik, EVP of R&D, will provide updates related to aficamten and other drug candidates comprising our early-stage pipeline. Stuart Kupfer, SVP and Chief Medical Officer, will provide further updates on the development program for aficamten. Andrew Callos, EVP and Chief Commercial Officer, will speak further about commercial preparation activities for aficamten and the market opportunity. Robert Wong, VP and Chief Accounting Officer, will provide a financial overview of the past quarter, and Ching Jaw, SVP and Chief Financial Officer, will discuss our financial outlook and corporate development strategies. Finally, Robert Blum will provide closing comments and review expected key milestones for 2023.
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. 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 2023 financial results filed on Form 8-K that was furnished to the SEC today. We undertake no obligation to update any forward-looking statements after this call. Now, I will turn the call over to Robert.
Thank you, Diane. Thanks for joining us on the call today. While we began the first quarter with a clinical stage program directed to the potential treatment of ALS, we ended the quarter acknowledging that we can no longer commit to that opportunity. In the best interest of the science and the shareholders, we must own that reality and rededicate to that which ultimately holds the greatest promise for patients. Toward that end, I want to emphasize our confidence in and priority commitment to our specialty cardiovascular pipeline of novel cardiac muscle-directed drug candidates. Despite the disappointment related to ALS, in the first quarter of 2023, significant progress was made across our cardiovascular pipeline with particular focus to aficamten and its broad development program.
As Fady and Stuart will elaborate, screening in SEQUOIA-HCM, our pivotal phase III clinical trial in patients with obstructive HCM, is expected to close tomorrow, enabling enrollment to conclude in a few weeks and the readout of results in the fourth quarter of this year as planned. We also recently reported data from cohort 4 of REDWOOD-HCM as well as 48-week data from FOREST-HCM, both providing compelling evidence for our next-in-class cardiac myosin inhibitor. We made progress towards expanding development for aficamten with a plan to soon start MAPLE-HCM, the active comparator phase III trial versus metoprolol, and continued preparations for our planned phase III clinical trial of aficamten in non-obstructive HCM. As you know, during the quarter, we also received a complete response letter from the FDA for omecamtiv mecarbil.
We're continuing to engage with FDA and are planning to meet with FDA this quarter to discuss their feedback and to better understand what may be our options going forward. We expect to provide an update when we have something more meaningful to report. In the meantime, we're pressing forward toward potential international approvals for omecamtiv mecarbil. In Europe, we're engaging EMA in its review of the MAA and are preparing to respond to Day 120 questions. In China, the Center for Drug Evaluation of the National Medical Products Administration is reviewing the NDA submission for omecamtiv mecarbil. As I previously mentioned, during the first quarter, we also announced that COURAGE-ALS, the phase III clinical trial of reldesemtiv, met criteria for futility at the second planned interim analysis.
Our dedication to the ALS community over the last decade has been a hallmark of our commitment to novel muscle-directed medicines, and we're disappointed that we'll not be able to move forward a drug candidate for patients with this grievous disease. Given the data from the interim analysis, we've proceeded to conclude study conduct in COURAGE-ALS, and we're completing closeout activities in both this trial as well as the open-label extension study during this second quarter. We plan to present full results from COURAGE-ALS at a medical meeting later this year. The trial was designed and conducted with scientific integrity and in the interest of people living with ALS, and we hope it may serve as a blueprint for how to conduct rigorous patient-centric clinical research.
We're certainly very disappointed in this outcome for COURAGE-ALS, it affords us an opportunity to realize certain savings in 2023, which we believe can extend our cash runway and enable us to reallocate resources to further increase our focus on aficamten. Previously, over 60% of our R&D budget was already devoted to aficamten, with savings we now expect in 2023, an even higher proportion of our total spending will now be dedicated to aficamten. Ching will elaborate further on our expected 2023 spending in a moment. While the first quarter brought some unexpected setbacks, we remain as committed as ever to our mission to bring forward new medicines for patients with diseases of high unmet need.
Our late stage, as well as our early stage pipeline of potential cardiovascular medicines provide a solid path forward, fortified by our strong balance sheet to support continued execution in the interest of all of our stakeholders. With that, I'll turn the call over to Fady.
Thanks, Robert. In the first quarter, we made substantial progress across a broad development program for aficamten. In March, we presented data from cohort 4 of REDWOOD-HCM at ACC, which showed that treatment with aficamten resulted in significant improvements in heart failure symptoms and cardiac biomarkers in patients with non-obstructive HCM. Cohort 4 was a dose-finding exercise, allowing for two dose titrations with the goal of increasing dose with echocardiographic guidance and evaluating the effects on symptoms and biomarkers. As a reminder, unlike in obstructive HCM, where the goal is to titrate patients to a minimally effective dose necessary to eliminate the LVOT gradient, in non-obstructive HCM, the goal is to titrate to the maximum dose based on ejection fraction. In cohort 4, by week 6, 85% of patients achieved the highest dose of 15 mg of aficamten.
Importantly, despite uptitrating patients to higher doses, there were no drug discontinuations due to adverse events. As we previously reported, three patients had LVEF drops below 50 at the week 10 visit. However, the LVEF normalized in all three of these patients after the two week washout period. The data from this dose-finding cohort will inform the phase III dosing scheme. In terms of safety, aficamten was well-tolerated. There was one death due to sudden cardiac death unrelated to treatment with aficamten. This patient had a history of sudden cardiac death prior to participation in REDWOOD-HCM. Two days prior to the event, the patient's LVEF was normal, symptoms and biomarkers improved, and the plasma concentration of aficamten was within the expected range. We and the investigator believe the death was unrelated to aficamten and therefore remain confident about the safety and tolerability of aficamten.
Building on the presentation at ACC, later this month, we're pleased to be presenting further data from cohort four in the late-breaking clinical trial session at the European Society of Cardiology's Heart Failure 2023 taking place in Prague. These results will include data from additional patients who are not included in the results presented at ACC due to timing, as well as data related to the Kansas City Cardiomyopathy Questionnaire and other additional findings. To provide some perspective on the goal of cardiac myosin inhibition in non-obstructive HCM, it's important to note that although these patients lack a significant LVOT gradient, their disease burden as measured by NYHA class and KCCQ, as well as biomarkers, including NT-proBNP, is just as severe as those patients with obstructive HCM.
The magnitude of improvement in these markers of disease burden that we've observed with aficamten were substantial, nearly equaling what we observed in obstructive HCM and provide a strong indication of treatment benefit. We're pleased with the initial data from cohort 4. We view them both as supportive of advancing to phase III and highly encouraging of the potential effect of aficamten in this important segment of the HCM population. Additionally, at ACC, we presented 48-week data from FOREST-HCM, the open label extension study, showing the treatment with aficamten was associated with significant and sustained reductions in the average resting and Valsalva LVOT gradient, significant improvements in NYHA class, and significant improvements in NT-proBNP. At 48 weeks, 88% of patients experienced an improvement of at least one NYHA functional class, including many patients who are no longer symptomatic.
In those patients that reached 48 weeks, none remained in NYHA class 3, compared to 47% of patients who were class 3 at baseline. Reducing symptoms can have a profoundly positive impact on patients' lives, these data are quite notable. Treatment with aficamten appeared to be safe and well-tolerated, with no instances of treatment interruption or discontinuation attributed to aficamten. We're encouraged that with longer-term treatment with aficamten, patients are experiencing a sustained treatment benefit. Through these data, we're seeing not only a clearer picture of the potential benefit that aficamten may have for patients, but also how aficamten appears to show potential to optimize both patient and physician experience. During the quarter, we continued conduct of SEQUOIA-HCM, the pivotal phase III clinical trial of aficamten in patients with obstructive HCM.
As Robert mentioned, we expect to complete patient screening tomorrow and randomize the last patient soon afterwards. We're tremendously grateful to all of our investigative sites around the world for working with us to achieve this milestone. Recently, the DMC reviewed safety, efficacy, and biomarkers for SEQUOIA-HCM and recommended that the trial continue as planned. With enrollment nearly complete, we're pleased with the patient population that we enrolled and believe we're achieving our goal of focusing on patients who stand to benefit from aficamten. We met four important targets for enrollment that give us confidence in the results we hope to see. First, the proportion of patients who are taking beta blockers as background therapy, which limit heart rate from increasing and can blunt exercise performance, met our expectations. Second, we enrolled patients with clearly impaired exercise capacity, as evidenced by an average peak VO2 at baseline, well below normal.
The proportion of patients using bicycle or treadmill to perform their exercise test met our expectations. Finally, enrollment in SEQUOIA-HCM took place globally, enrolling a balanced and diverse patient population in the U.S., Europe, Israel, and China. We believe that the way we've designed and conducted SEQUOIA-HCM and the patient population we've enrolled will contribute to a clear read on the potential efficacy and safety of aficamten. Before I hand it over to Stuart, I also wanna touch briefly on our earlier stage pipeline. In the prior quarter, we completed three ascending dose cohorts in the phase I study of CK-136, our cardiac troponin activator in healthy volunteers and expect data in the second half of the year.
Additionally, following our IND submission for our second cardiac myosin inhibitor, CK-586, we received FDA clearance to initiate its phase I study. 586 represents a key new clinical program for the expansion of our pipeline, and we intend to develop it for the potential treatment of heart failure with preserved ejection fraction, another important addition to our growing specialty cardiology business. With that, I'll turn the call over to Stuart to speak more on the expanding development program for aficamten, including MAPLE-HCM and our planned phase III clinical trial in non-obstructive HCM.
Thanks, Fady. In the first quarter, we made progress towards beginning MAPLE-HCM, which we expect to open for patient enrollment in this quarter. As a reminder, MAPLE-HCM is the second phase III clinical trial in patients with obstructive HCM, during which we'll be assessing aficamten as monotherapy compared to metoprolol. The primary endpoint is change in peak VO2 assessed by cardiopulmonary exercise testing from baseline to week 24. Secondary endpoints include change in NYHA class, KCCQ, NT-proBNP, and measures of structural remodeling. Our goal with this trial is to evaluate the potential superiority of aficamten to the standard of care therapy of beta blockers. Beta blockers are used as first-line therapy for the majority of patients with HCM because historically there have been few alternatives.
While beta blockers can improve gradients and lead to mild symptom improvement, a substantial portion of patients do not achieve desired symptom reduction with beta blockers, and they're associated with many undesirable side effects. Additionally, beta blockers do not improve exercise capacity, and when used in combination with a cardiac myosin inhibitor, may attenuate its beneficial effects. If aficamten is shown to be superior to metoprolol, it may simplify the approach to treating HCM by enabling the use of aficamten as first-line monotherapy. We're encouraged by data previously presented from FOREST-HCM demonstrating successful withdrawal from background therapy in patients treated with aficamten.
Hey, Robert, Dane Leone. Just wanted to call.
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Our clinical study sites are enthusiastic about participating in this trial. We look forward to starting enrollment in MAPLE-HCM soon. Additionally, as Fady mentioned, the positive data from cohort 4 of REDWOOD-HCM presented at ACC were encouraging for our plans to further expand the development program for aficamten by starting a phase III clinical trial in non-obstructive HCM. We've recently had productive interactions with FDA to ready for this trial. We're finalizing our planning and preparations and expect this third phase III trial of aficamten to begin in the second half of this year. We look forward to sharing more information relating to the planned trial design later this year. With that, I'll turn the call over to Andrea.
Thanks, Stuart. In quarter one, we continued activities and preparations for the potential approval and commercialization of aficamten, including market research to further expand our understanding and better characterize the market and the opportunity. While the overall prevalence of HCM in the U.S. is estimated to be roughly 700,000 to 1 million, we estimate the diagnosed patient population, inclusive of both obstructive and non-obstructive HCM, to be approximately 290,000. The undiagnosed population is sizable, up to 700,000 patients. We believe currently undiagnosed patients represent a very significant growth opportunity for category growth. Through our market research, we've learned that the vast majority of diagnosed patients are currently being treated with beta blockers, calcium channel blockers, or both.
We believe approximately 2/3 of those patients are symptomatic and may be eligible for a cardiac myosin activator like aficamten if approved. At the same time, we also expect the diagnosed prevalence of HCM to increase over time at a mid-single digit growth rate, driven by evidence generation, commercialized treatment options, escalating patient and physician interest, expanding use of CMIs outside of centers of excellence, and the overall appreciation of CMIs in the treatment of HCM. Additionally, during the quarter, we continued to engage further with payers who expressed interest in both HCM, CMIs generally, and aficamten specifically. Some payers have limited experience with HCM due to the lack of approved therapies until recently, but they are interested in the disease, especially in patients with oHCM who are highly symptomatic. We see this as an opportunity for education and up-leveling of their knowledge of HCM over time.
Our development program for aficamten has been designed to provide ample evidence for how aficamten, if approved, may optimize both patient and physician experience through quick and sustained improvement of symptoms, straightforward dose titration, minimal drug-to-drug interaction, and avoiding dose interruption. Through MAPLE-HCM, we're also attempting to show that aficamten is superior to the standard of care beta blocker to potentially further enhance patient experience by avoiding beta blockers altogether and enabling simple monotherapy. As we explained earlier this year, the majority of the commercial team has been shifted to support aficamten launch readiness activities should it be commercialized, and we plan to continue to assess our resourcing to account for the shift in focus from omecamtiv mecarbil readiness to aficamten readiness.
We are fortunate to have a talented and dedicated team with deep experience in cardiovascular disease markets propelling us forward to become a global specialty cardiology company leading with aficamten. With that, I'll turn it over to Robert Wong.
Thanks, Andrew. We ended the first quarter with approximately $704 million in cash and investments. Our revenue in Q1 2023 came primarily from a milestone payment we recognized from Ji Xing for the expected phase III trial of aficamten in patients with nHCM to occur later this year, as well as earned revenue from Astellas in the quarter. Our first quarter 2023 R&D expenses increased to $79.4 million from $45.9 million in the first quarter of 2022, primarily due to increased spending for our clinical development activities related to our cardiac myosin inhibitor programs and COURAGE-ALS. Our first quarter 2023 G&A expenses were $49.7 million, up from $33.1 million in Q1 2022, due primarily to higher personnel-related costs, including stock-based compensation and pre-commercial launch readiness expenses. Now Ching will review our financial outlook and corporate development strategies.
Thanks, Robert. We ended the quarter with approximately $704 million cash on the balance sheet, which represents two years of cash runway. To be clear, we're not adjusting our 2023 guidance today. We do expect to reduce our overall spending in 2023 by more than 10%, primarily through a reduction in planned outsourced services and headcount growth, thereby resulting in over $50 million in projected savings relative to previously forecasted spending for 2023. By employing these measures, we're able to extend our existing cash runway this year as well as in 2024, during which time we have previously anticipated incurring costs for manufacturing commercial supply, commercial readiness preparations, and medical education activities for reldesemtiv. We expect to provide new financial guidance with our Q2 earnings call.
To further add to our balance sheet this year, I'll remind you that we also expect to receive a $50 million non-refundable milestone payment from Royalty Pharma upon the start of the pivotal phase III clinical trial of aficamten in patients with non-obstructive HCM, which is expected to begin in the second half of the year. Finally, on the corporate development side, to further support our balance sheet and our path forward, this year, we are continuing to seek a potential partner in Europe for omecamtiv mecarbil, as well as in Japan for both omecamtiv mecarbil and aficamten. We also believe that we may need to open the aperture on potential European partnering of aficamten as part of our broader cardiovascular portfolio in light of recent events.
That said, we continue to prepare for U.S. commercialization independently, and as we progress our corporate development for the balance of this year, we will continue to make decisions that are in the best interests of patients and our shareholders. With that, I'll turn the call back over to Robert Blum.
Thank you, Ching. Today, our company looks different than how we expected to look as we started 2023. However, we're confident in where we stand and in the road ahead of us. We have overcome challenges before during our 25-year history, and we believe that with our foundation of a strong research and development pipeline rooted in muscle biology, we now have an opportunity to build the industry's leading specialty cardiology business. As we look to the future, we're optimistic, and we have strong conviction in aficamten and also our other novel mechanism drug candidates advancing in our cardiovascular pipeline.
Also, last quarter, we were proud to release our inaugural corporate responsibility report. This report reflects our commitment and continued integration of corporate responsibility throughout our organization, as well as decision-making processes and our ongoing commitment to provide transparency and accountability on matters related to corporate responsibility. We intend to release an annual update to this report on our progress and goals, building on the foundation and as we continue to focus on how we can better serve patients, the communities around us, as well as the environment. As Ching mentioned, we're in an advantaged position with the cash that we have, and we're managing it carefully. We're prudently managing our spending, our growth, and our allocation of resources. We have a promising development program with our cardiac myosin inhibitors, aficamten and CK-586.
In addition, we're equipped with an early stage in research pipeline that adds further to our portfolio of muscle-directed therapies. Our intention is to build value for our company through our science, and that has not changed, and we'll continue to balance the needs of both patients and shareholders as we advance forward. Now I'll recap our upcoming milestones. For omecamtiv mecarbil, we expect to continue to pursue potential international approvals for omecamtiv mecarbil, including in Europe and in China. For aficamten, we expect to present additional data from cohort 4 of REDWOOD-HCM at Heart Failure 2023 on May 20 in Prague. We expect to complete patient enrollment in SEQUOIA-HCM in Q2 2023, with results expected in Q4 2023.
We expect to begin MAPLE-HCM, the second phase III clinical trial of aficamten as monotherapy in patients with obstructive HCM in Q2 2023. We expect to begin a phase III clinical trial of aficamten in non-obstructive HCM in the second half of 2023. As well, we expect to advance our U.S. go-to-market strategy during 2023. For CK-136, we expect single ascending dose data from the phase I study in the second half of 2023. For CK-586, we expect to advance that compound into a first-in-human phase I study in this quarter, Q2 2023. Finally, for reldesemtiv, we expect to conclude clinical trial conduct and complete the majority of closeout activities for COURAGE-ALS in Q2 2023, and we expect to share results in the second half of the year. Operator, with that, we can now open up the call, please, to questions.
To ask a question, please press star one one on your telephone and wait for your name to be announced. To withdraw your question, please press star one one again. As a reminder, please limit to one question. Please stand by while we compile the Q&A roster. Our first question comes from Srik ripa Devarakonda. With Truist, your line is open.
Thank you so much.
Good afternoon.
Taking my question. Good afternoon. Thanks for taking my question. For aficamten, it looks like you're on track for enrollment completion in second quarter. I just was wondering how confident are you about the timelines for fourth quarter? Is there any chance that it could spill over into early 2024? As you see Camzyos launch and whatever you're hearing from the ground, has that changed what you think you need to do to prepare for commercialization of aficamten? Thank you so much.
Sure. Two questions really. The first one is around enrollment, we do expect to be completing enrollment, as you heard from Fady, such that randomization and enrollment are both concluding in the month of May, therefore we are confident to see results in the fourth quarter of this year. With regard to a potential commercial launch of aficamten, we're monitoring the uptake in cardiac myosin inhibitors as a class, carefully, we like what we see. We believe that the market is evolving very much as we predicted, we're not expecting that should change the way we think about the commercial uptake. Maybe I'll just turn to Andrew to see if there's anything he wants to add.
No, I would agree, Robert, that BMS recently reported their first quarter earnings and I think showed good momentum. We're hearing very positive things for the category overall from clinicians, so it doesn't change the way we feel about it at all. If anything, we're even more bullish about it than maybe we were before.
Great. Thank you so much. I'll give it back to you.
Thank you. Sure.
One moment for our next question. Our next question comes from Salim Syed with Mizuho. Your line is open.
Hi, Salim.
Hey. Hey, Robert. Thanks for the question. Just one for me on the enrollment of SEQUOIA. I just wanna make sure I understand this correctly. Fady, I'd love to just get confirmation from you or some color on when was the last time you looked at the blinded aggregated standard deviation for peak VO2 in SEQUOIA. Can you confirm that we are indeed sub 3.5 on the standard deviation? That there's no risk of trial increase at this point. Thank you.
Just the answer that there is no risk of increasing enrollment at this point. As I said, we're gonna be done enrolling patients tomorrow, and we'll finish randomization shortly. Standard deviation, I can't tell you exactly the last time I saw, probably in the last week, but it's certainly within the expected parameters.
Super helpful. Thanks so much, guys.
Thank you, Salim.
One moment for our next question. Our next question comes from Tessa Romero with JPMorgan. Your line is open.
Good afternoon, Tess.
Hi. Good afternoon, everyone. Thanks so much for taking our question. One from us on non-obstructive HCM. We're looking forward to the full presentation there later this month on cohort 4. As we recall, KCCQ is one of the key endpoints you're monitoring for health status. Can you quickly orient us briefly to what magnitude of change you are looking for over 12 weeks of treatment on the KCCQ? Like, is there a change that would be considered kind of clinically meaningful there? Kind of what we should be expecting with respect to approximate baseline score? Thanks so much.
Obviously, for the fact that this is an open label study, you recognize that we've seen these data. While we don't want to front run the data ahead of the presentation as a late breaker, later this month, I will ask Fady to try his best to answer your question without being too forward-leading.
Yeah, I don't really want to give quantitative expectations given I know what the quantitative numbers are. I should say that, you know, the baseline data indicate a severely symptomatic population, in terms of a baseline KCCQ score. In general, expectations of an increase of five points or more is what's considered clinically meaningful. I think, you know, that's how I would put that in context as you see the data later this month.
Any other kind of analyses that we should be specifically looking out for beyond KCCQ that we haven't already seen to date?
Yeah. We'll actually be showing data in relation to and the assessment of angina, which is something that hasn't really been assessed in a trial like this before. I think we'll show some of the first data in terms of angina score in nHCM. We'll be looking at some of the echo parameters and, you know, you'll see a greater, you know, more of the KCCQ data than just what the delta was. You'll see the sort of the responders that have smaller or larger responses and a proportion of those people.
Okay. Thanks so much.
Hope that helps, Tess. Thanks.
Thank you.
One moment for our next question. Our next question comes from Charles Duncan with Cantor Fitzgerald. Your line is open.
Charles.
Hey, Robert, and team. Congrats on nearing full enrollment of SEQUOIA, and thanks for taking my questions. I suspect there'll be a lot of questions on AF i-- so I'll ask one on reldesemtiv and the FSTA program. I'm wondering, would that be an out-licensing candidate and ex U.S., what are your plans for it?
Right now.
For reldesemtiv.
Sure. Right now, in light of the fact that we're still conducting study closeout activities, we really can't know for certain how the final data are gonna shape up. Based on the interim analysis, we've seen enough data to suggest that it wouldn't be proper to continue conduct of that study in ALS. We've seen signals of activity of reldesemtiv in other indications in phase II. But in light of this phase III result, we really don't have any current plans for reldesemtiv, but we'll assess those again once we see the final study data, and that's both as it relates to U.S. and ex- U.S. We do have other activities associated with fast skeletal muscle, and we're assessing how they may contribute to our pipeline growth and enhancement going forward.
Obviously, we also have other programs in research that read on skeletal muscle and neuromuscular indications. Similarly, we'll be assessing all of those together in light of this recent development. Probably can't answer your question well enough to your satisfaction right now, but it is something that's top of mind for us.
I guess if I just ask, can I, can I assume that you are very much focused on becoming cardio or becoming known as a premier cardio innovator and not leveraging the platform more broadly?
Wouldn't conclude that, as generally as you stated it, but certainly our clinical pipeline is focused to specialty cardiology, and that's what we're gonna be focused on with regard to a majority of our investment spending. We still have research programs that are directed to other muscle types and other indications, but those are not things that typically our shareholders are privy to. In light of the fact that, they are earlier stage and therefore we keep them still confidential. It relates to what shareholders are mostly focused to, yes, I think you can conclude that our focus is on specialty cardiovascular medicines, of which we have four such drug candidates now in our pipeline.
Yep. Very good. Thanks for taking the question, Rob.
Thank you, Charles.
One moment for our next question. Our next question comes from Carter Gould with Barclays. Your line is open.
Hello, Carter.
Hey, guys. You've got Edward on the line for Carter. Thanks for taking our questions. We've just got one on aficamten. How would you set expectations for how quickly Cytokinetics is planning to turn around an NDA on the back of the SEQUOIA data? Have you already started that process ahead of the data? Then a follow-up housekeeping question. Should we expect a press release announcing the completion of enrollment in SEQUOIA when that does happen? Thanks.
To answer your first question, yes, we've already started that process around which we're looking at timelines, how we might bring them in, what we can be doing ahead of the results of SEQUOIA, and how we can move as quickly as possible to submit not just in the U.S. but also internationally for a potential approval of aficamten. That's very much a priority. Already in recent weeks, we've had many such meetings on that very matter. Your second question related to whether or not we're gonna be announcing completion of enrollment, the answer is no.
With regard to SEQUOIA-HCM, what we've indicated on this call is what we intend to have stand as our communication, which is, we expect to complete screening tomorrow, and we're gonna be completing enrollment and randomization here, in this month of May.
Thank you.
Thank you.
One moment for our next question. Our next question comes from Yasmeen Rahimi with Piper Sandler. Your line is open.
Afternoon, Yasmeen.
Hello, Robert. Thank you so much for always the thoughtful remarks. Team, earlier, this week we saw data from the EXPLORER-HCM study conducted in China. When we benchmarked the data versus the EXPLORER-HCM study, it appears that the treatment response was greater. Maybe, Fady, if you could just comment on, you know, is there anything different in the Asian population, or is it just the baseline demographics that could have led to differences? Then more importantly, I guess the question leads into what percentage of the SEQUOIA population will be in China? Could that also be impacted and maybe boost the results further? Appreciate any color you could give us in that regard, and I'll jump back to you.
Sure. Good questions and good pickup. Certainly, we noted that communication regarding the data in China. I'll ask Fady to comment, and I'm thinking he'll probably also defer to Stuart on some of that too. Between the two of them, hopefully we'll get to your questions well enough.
Yeah. I think, you know, I think the first thing, Yasmeen to note is that the Explorer China trial didn't use peak VO2 in their trial. I don't think you can really speak to larger results per se, since the kind of the primary assessment of function wasn't included in that trial. They certainly had sizable changes in gradients, improvements in KCCQ and NYHA class that were quite substantial. I would be cautious about trying to compare magnitudes of responses between trials that were enrolled at different times, at different geographies and, you know, in different populations. Stuart, do you wanna have anything to add to...
You know, I agree with that. It's always a challenge to compare across studies, generally speaking, but the results certainly look encouraging, continue to build the evidence base for supportive cardiac myosin inhibitors worldwide. As you know, with respect to SEQUOIA, we are collaborating with our colleagues at Ji Xing and enrolling patients in China. Patients from China have definitely contributed to enrollment of SEQUOIA. We'll have a very diverse group of patients, when we have the final results to reflect upon and support, you know, support our regulatory strategy worldwide.
You know, we're not disclosing the specific number or the percentage of patients enrolled in China other than to say that, we believe it should be sufficient to support registration in China.
Great. Thank you so much, team. I'll jump back to you.
Thank you.
One moment for our next question. Our next question comes from Akash Tewari with Jefferies. Your line is open.
Hey, guys. Thanks so much.
Hello, Akash.
Hey. Look, in your view, why would partnering aficamten in Europe be in the best interest for shareholders versus an outright sale of the company, especially before SEQUOIA has read out? I was kind of surprised to hear that on the call today. What could really swing that decision one way or the other? Any thoughts on releasing baseline characteristics for the SEQUOIA population mid-year ahead of the readout for Q4? Thank you.
I'll answer the first and ask Fady to answer the second. The point of that comment that Ching made was not to say that we're committed to partnering aficamten outside of the U.S. other than we think it's in the interest of shareholders that we assess what could be possible. To your question about, you know, whether we should go down that path versus selling the company. Obviously, that's not something that we can address on a call like this, for the fact that those are matters that don't warrant a discussion in light of what could be our corporate development strategy. Our corporate development strategy is very much to maximize shareholders for those matters that are under our direct control.
This is one of those things that we can control as it relates to the best way to enable us to access capital and do the what's best for science, patients, and shareholders. We think it's incumbent upon us to assess what would be possible and the opportunity. To this point, there have been lots of inquiries around aficamten, and we've been relatively close-minded to considering them. In light of recent developments at Cytokinetics, we think it's in our interest and that of shareholders to at least be opening the aperture to what could be those possibilities, and that's what we intend to do. The next question you asked related to baseline characteristics in SEQUOIA, and maybe I'll ask Fady to comment on what might be our plans there.
Thanks, Akash, for the question. I've been asked this before. You know, we're looking to see whether perhaps we can pull together final baseline data and find a venue for presenting them. They won't come, you know, far in advance of probably the final data from SEQUOIA-HCM or rather the top-line data from SEQUOIA-HCM. You know, we'll update folks once we have an idea of what we're planning to do there for sure.
Thanks very much.
One moment for our next question. Our next question comes from Jeff Hung with Morgan Stanley. Your line is open.
Go, Jeff.
Hi. Thanks for taking my question. I know it depends on the SEQUOIA-HCM data, but how do you think about the likely potential scenarios for REMS on the aficamten label? Like, what would you think you need to show to have REMS that are less onerous than those for Camzyos or to not even have REMS? Thanks.
Well, obviously, that's a difficult question to answer until such time as we see data from SEQUOIA and also continue to have good data from the open label extension. It is our hope that we'll have from FOREST-HCM as well as SEQUOIA data that would be enabling of us to make a case to FDA for what might be a lesser REMS or no REMS. In that regard, it's really difficult to speculate until we have the actual data. With the fact that you asked the question, maybe I'll see if Fady or Stuart have anything to add in terms of what they're gonna be looking for that might determine ultimately our regulatory strategy that way.
You know, I think we'll certainly be looking at how dosing was implemented, how tolerated, you know, adverse events related to the need to monitor patients. As was pointed out in FOREST-HCM, where I summarized the 48-week data earlier, we haven't had drug discontinuation due to low ejection fraction or treatment interruptions. You know, we hope that those events are limited to the extent that the monitoring of them can be appropriately gauged, you know, if you will. Maybe there's monitoring during the titration phase then at some interval thereafter, twice a year or something like that. You know, I think it'll depend on the data and it's just difficult to speculate at this time.
Okay. Thank you.
One moment for our next question. Our next question comes from Jason Zemansky with Bank of America. Your line is open.
Hi, Jason.
Good afternoon. Hello. Thank you so much for taking our questions, and congrats on the great progress. maybe going to the earlier stage pipeline. Now that 586 is entering the clinic, can you provide some color over your developmental or development strategy in HFpEF? You know, do you still see this as an opportunity for aficamten as well? maybe conversely, where does HCM fit in plans for 586?
Excellent. Very good questions, and I'll ask Fady to respond. You know, what we're doing in HFpEF has become a central part of our development strategy. CK-586 is a compound that has roots in the same science and biology that gave rise to aficamten, but it comes from a very different chemical class with a different mechanism. As such, we think it may be better suited for our development in HFpEF. Fady can speak about the therapeutic hypothesis and how we see that rolling forward.
Yeah. Hi. You know, CK-586, as we have developed it and has a lot of the same properties of aficamten and that it has a shallow exposure-response relationship. We think it's relatively clear of drug-drug interactions. We think the dosing should be predictable. The PK should be appropriate for something that needs to be titrated and reversible. You know, what we have strategically decided to do was to really separate the development of HCM from HFpEF by using aficamten and, you know, developing that specifically into HCM. There's a lot of...
Obviously, the patient population there is very different than the HFpEF population, whereas 586 is something that would be developed specifically into HFpEF. Thereby, you know, not sort of confuse one drug versus the other and where to use it and so forth. You know, we look forward to starting the phase I for 586 shortly, then from there, proceeding into what would be a, you know, beginning to look at this study of HFpEF, and we'll, you know, we'll give more details on that as we, as the program progresses.
You know, certainly the work that we've done with aficamten in nHCM reads on what might be the potential for 586 in HFpEF. We see that there's a translation there that lends support for this mechanism and warrants its exploration.
Definitely. Thanks so much for the color.
Thank you.
One moment for our next question. Our next question comes from Jason Butler with JMP Securities. Your line is open.
Hi. Thanks for-
Good afternoon, Jason.
Hi, Robert. Thanks for taking questions, and congrats on the progress. Just what about non-obstructive HCM? Given, you know, the obvious lack of gradients here, can you talk to how you think biomarker monitoring could play into clinical practice here versus just treating, you know, symptoms? You know, is there something? How do you think the practice could emerge here?
Good question. I'll turn to Fady and Stuart to answer that.
Well, I think, you know, in terms of how the drug may be deployed in oHCM, practically speaking, I think symptoms and functional improvement, those are what will guide the physician more so than biomarkers. I mean, I think they certainly will wanna look to see NT-proBNP go down as a sign of biological response. you know, we aren't gonna really have a whole lot of understanding for quite some time in terms of how much it needs to go down and what does that mean in the long run for the patient. I think in a lot of ways this will be guided by how patients feel and whether, you know, there's any continued room for improvement in their symptoms as you escalate the drug. Stuart, do you have anything, any other thoughts there?
I think that's completely right. It just provides more information to profile improvement of symptoms and function and how that relates to these pharmacodynamic markers we expect to improve.
I mean, it is nice to have an objective biomarker, you know, as you're dosing something. It can sometimes be hard to assess symptoms. The biomarker is helpful, but it probably won't drive implementation.
Great. Thank you.
Thanks, Jason.
One moment for our next question. Our next question comes from Rohit Bhasin with Needham & Company. Your line is open.
Good afternoon.
Hi. Good afternoon. This is Rohit on for Serge. Thanks for taking our questions. Can you just talk about your regulatory strategy for aficamten in Europe? Will the trials being run fulfill requirements, or do you expect to run additional studies? Thanks.
Good questions. We do believe that the conduct of SEQUOIA, as is occurring globally, should be satisfactory to requirements throughout Europe and also the rest of the world. It's not just being driven by our U.S. strategy, but a global strategy. Same with the way we're thinking about MAPLE and the way we're approaching nHCM. All of these are intended to be global studies that should be serving our interests globally.
Thank you.
Thank you.
One moment for our next question. Our next question comes from Madhu Kumar with Goldman Sachs. Your line is open.
Hello, Madhu.
Hi. This is Omari on for Madhu. We have a couple questions. First, what do you think you need to see from MAPLE-HCM trial for cardiologists to position aficamten ahead of metoprolol in the oHCM treatment paradigm? Second, are there any considerations to running a phase III trial for aficamten that is comparable to Camzyos' VALOR-HCM trial?
Two part question. One relating to, I guess, effects that would delay the need for septal reduction therapy. That was part B of your question. Part A was what?
Part A is what do you need to see from the MAPLE-HCM trial for cardiologists to position aficamten ahead of-?
Yeah.
metoprolol?
I'll ask Fady to comment on both A and B.
I mean, with regards to, MAPLE, I would say that strong data, showing that aficamten produces sizable increases in exercise performance, KCCQ, NYHA class, you know, relative to beta blockers, would certainly provide a strong rationale in the guidelines for it being considered as first-line therapy. I mean, if SEQUOIA, reads out the way that we hope it does, it'll show that aficamten added to standard of care is better than standard of care. What we hope to show is that aficamten by itself is better than the initial standard of care, and thereby, you know, provide the rationale for using it first. 'Cause physicians really aren't that excited about starting beta blockers in their patients.
They can be hard difficult to tolerate and have side effects that, you know, the patients don't really enjoy. These data would support that. I think the interest in that trial and excitement by the physician community is also a good reflection of the importance of this particular question. You know, with regards to the whether we would conduct a VALOR-like trial with aficamten, you know, we haven't really considered doing that at this point. Certainly something, When you think about the cardiac myosin inhibitor class, it's sometimes to expand the field as opposed to just repeating work that's already been done. If we were to do something in surgical-eligible patients, I think we'd probably ask a somewhat different question and then go from there.
At this time, no plans to do something VALOR-like.
Great. Thank you.
Thank you.
One moment for our next question. Our next question comes from Ash Verma with UBS. Your line is open.
Hello.
Good afternoon.
Hi. For Camzyos, it seems like bulk of the use is coming from the 2.5 and 5 mg doses, and higher doses are not being used. Does that indicate that presumably physicians are not able to titrate up, thus underlining the need for a safer yet effective drug for HCM? On the flip side of the argument, do you think like if the real world incidence of systolic dysfunction is below what was seen in the clinical study, can the FDA relax the REMS at the request of BMS?
I think those, that two-part question is better meant for BMS to answer, not for Cytokinetics. I don't think it's appropriate for us to be commenting on the dosage strengths of Camzyos and what that means for patients, or otherwise what might be necessary for removal of the REMS program. We certainly have our views, but I don't think that's something that we ought to be sharing publicly.
Thanks.
Thank you.
One moment for our next question. Our next question comes from Dane Leone with Raymond James. Your line is open.
Hi, Dane.
Hi. congrats on the progress. I'll keep it short because it's been a really long day. The question I'd be interested in hearing from your team is, as you go into the pivotal results and read out SEQUOIA, how are you thinking of taking those results, which is obviously a very comp study to the predicate that supported the approval of mavacamten and, you know, one, positioning those results, in terms of discussion with FDA and what you would want from a labeling discussion and think is very important to have on the label, to help differentiate, the drug and its clinical utility, versus mavacamten.
Secondly, bring forward to the clinical community to help them understand potential advantages of getting patients through that really grinding 12-month process that, you know, continues to be a headache with Camzyos. Any initial thoughts there? Obviously, we know it's ahead of the study results, but, you know, I think we kinda know where things are going. Thanks.
Here again, it's not for us to be co-commenting on something in a comparative way to Camzyos. What I will say is that we've developed aficamten very much with an eye on demonstrating some of its properties for what could be an optimal cardiac myosin inhibitor as it relates to efficacy, tolerability, safety, and convenience. You know, I'll ask Fady to maybe respond to your questions as to, you know, what we'll be specifically looking for, and maybe Andrew wants to comment as well as to how it might play ultimately into the marketplace.
You know, our goal is to ensure that cardiac myosin inhibition is something that physicians are comfortable reaching for when they think about their patients, obstructive and non-obstructive, and not just those cardiologists who might be in centers of excellence, but cardiologists outside of those centers who might also be encountering those types of patients. Maybe, Fady, you wanna start?
Yeah, sure. I think, you know, obviously, we've, we're hoping that the data from SEQUOIA will support a label that will make the drug easy for patients to use, easy for physicians to use, and maximize its safety and tolerability. Those data will be shared with FDA. Those discussions will be had. We recognize that there's a lot of patient burden here in terms of dose escalation because of the need for echoes and things like that and monitoring. Our goal will be to, if you will, go with the data, what they suggest is necessary, as a means of maximizing safety and minimizing patient burden. I think that's in the interest of patients, and the FDA usually has the interest of patients in mind.
From, a commercial point of view, we certainly won't have comparative data for Camzyos, and we won't be comparing. Our focus will be on our data. How that leads to a label that Fady described, making sure that we educate a broad range of cardiologists, not just centers of excellence, that we get market access, that we support patients through patient services, and that the market landscape and ecosystem payers, treaters and all HCPs are very clear on aficamten and the potential benefits and risk, so they can make an informed choice. That's really what we'll focus on.
Great. Thanks.
Thank you.
Operator?
Next question comes from Justin Kim with Oppenheimer.
Thank you.
Hi Robert and team. Good evening. You know, I'll just add maybe one question on MAPLE-HCM. As this study is sort of more important for answering clinical and commercial questions and not necessarily regulatory ones, are there any specific populations that the team is hoping to treat and see the benefit of aficamten in and that may differ from SEQUOIA-HCM?
I think that is, the purpose of the, you know, expanding the development program to include nHCM, and maybe I'll ask Stuart to comment on how that complements the patient population in SEQUOIA.
He's asking about MAPLE.
I get it, but maybe he's asking about expanding the patient population.
Right. Yeah. In, you know, in SEQUOIA, we're studying patients who are generally later in the natural history of the disease, most of them receiving background therapy, for treatment of HCM. You know, we're considering targeting a patient population that is somewhat earlier in the natural history of the disease. You know, those details will be, you know, discussed, soon. That's sort of generally this general strategy because strategically we're interested, as we mentioned, in determining if aficamten would be appropriate for first line therapy and potentially superior to the current standard of care, beta blocker treatment.
All right. maybe just a follow-up about-
Go ahead, Justin.
I was just gonna ask, I mean, is it right to think about MAPLE as maybe a setting where you hope myosin inhibition might be best optimized because you're sort of preserving EF, just, and that way you could show a benefit in a milder disease patient?
You know, I think in. The question really is, are beta blockers, if you use a cardiac myosin inhibitor, are beta blockers helping or hindering the maximization of patient benefits? MAPLE is designed to help us answer that question. You know, in terms of patient population, you know, MAPLE, Stuart said, will enroll patients, potentially with, somewhat less severe gradients a little earlier in their disease, potentially. You know, if we're trying to enroll patients that are not on beta blockers, you could imagine that patients naive to therapy might be in patients that get enrolled in MAPLE. You know, think of...
If you think of HCM as a whole disease entity, you have patients like in SEQUOIA that represent those that have high gradients, and represent one portion of the pie. Patients with nHCM representing another portion of the pie, and then MAPLE patients kind of representing something in between, and including patients like those in SEQUOIA. You know, and ultimately the goal is to try and generate evidence in the whole pie and not just specific slices of it so that there's really a rationale to use cardiac myosin inhibitors in patients with HCM and not, you know, specific subsets of HCM.
Okay, great.
Yeah.
Thanks for taking the question.
Sure.
Thank you.
I'm showing no further questions at this time. I would now like to turn the conference back to Robert Blum for closing remarks.
Thank you, operator. Thanks to all of our participants on the teleconference today. Thank you for your continued support and interest in Cytokinetics. We're looking forward to keeping you abreast of our progress with regard especially to aficamten, which is slated for quite a lot of news flow this year, and a commitment around our investment spending that I think is very much in the interest of our shareholders. With that, we'll keep you apprised of progress through the remainder of this year. Operator, with that, we can now conclude the call. Thanks very much.
This concludes today's conference call. Thank you for participating. You may now disconnect.