CYTK - NASDAQ

Good afternoon, and welcome, ladies and gentlemen, to Cytokinetics Third 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'll 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 focused to SEQUOIA-HCM and FOREST-HCM; Stuart Kupfer, SVP and Chief Medical Officer will provide additional updates for aficamten relating to SEQUOIA-HCM and MAPLE-HCM, and we’ll also discuss our early-stage pipeline, inclusive of CK-586 and CK-136. Andrew Callos, EVP and Chief Commercial Officer will discuss commercial readiness activities for aficamten. 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. And finally, Robert Blum will provide closing comments and review upcoming expected key milestones. 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 third 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. And now I will turn the call over to Robert.

Thank you, Diane, and thanks for joining us on the call today. I'm pleased with the progress we made in the third quarter, particularly focused to aficamten, our top priority and with emphasis on the execution of SEQUOIA-HCM and advancement of its broad development program. Thanks to the diligence and dedication of our teams, we remain on track to share top line results from SEQUOIA-HCM in late December. While this time line is admittedly tight, we're confident due to the superb organization and oversight of SEQUOIA-HCM by our clinical operations and statistical teams, like all of you on the call we're eager to see these top line results. As Fady will elaborate, we have strong conviction that the top line results from SEQUOIA-HCM will meet our high expectations for both safety and efficacy based on the patient population enrolled in SEQUOIA-HCM, as well as the unique attributes of aficamten. If SEQUOIA-HCM meets our expectations on both efficacy and safety, we expect it may contribute to expansion of the cardiac myosin inhibitor or CMI category on both accounts. Simultaneously during the quarter, we continued to build our specialty cardiology franchise by advancing the ongoing clinical trials in the development program for aficamten, as well as earlier stage clinical research with enrollment underway in both MAPLE-HCM and ACACIA-HCM, we foresee a near-term future with multiple catalysts for aficamten. And rounding out our specialty cardiology franchise, our CK-586 a second cardiac myosin inhibitor and CK-136 a cardiac troponin activator, on which Stuart will provide an update. Our cash position at the end of the quarter represents over 18 months of cash runway based on our 2023 net cash burn guidance. Importantly, as is our practice for both financial health and prudent planning, we're gating spending through the readout of top line results of SEQUOIA-HCM and we're judiciously focusing our current spending on activities related to our top priorities again with focus to aficamten and a critical eye towards cost efficiencies. Today, you'll hear about the continued progress we made during the quarter and what to expect through the end of the year, as we approach 2024 and as you heard a few weeks ago at our Investor and Analyst Day, Cytokinetics remains laser focused to delivering on the promise of aficamten as well as to advancing our earlier-stage pipeline, as we build our specialty cardiology franchise for the potential benefit of both patients and shareholders. And with that I'll turn the call over to Fady.

Thanks, Robert. In the third quarter, we made significant headway across the development program for aficamten. Recently, we were pleased to present the baseline characteristics of patients enrolled in SEQUOIA-HCM the pivotal Phase III clinical trial of aficamten at the HCM Society Scientific Sessions. The baseline characteristics met our objective for the intended trial population, having enrolled a global diverse and real-world population with a substantial deficit in exercise capacity and significant symptom burden despite existing standard of care. Patients enrolled in SEQUOIA-HCM had an average peak oxygen uptake or peak VO2 of 18.5 milliliters per kilogram per minute at baseline or 56.9% of that predicted for their age and sex which is an objective indicator of the extent of their reduced exercise capacity. Nearly a quarter of the patients were NYHA functional class III, with an average KCCQ score of 74.7 further reflective of a highly symptomatic patient population despite background treatment with guideline-directed medical therapies. Background medical therapy included beta blockers, calcium channel blockers and disopyramide with patients permitted to receive combination background medical therapy. Beta blockers, which were known the blunt maximum exercise capacity due to their effect to slow heart rate, we used in 61% of the patients. We are very pleased to see that our objectives are achieved and that we enrolled the population that we intended. As we approach the readout of SEQUOIA-HCM later this year, we're confident in the completeness of the data and that we're outperforming the design assumptions for the trial. The extent of missing data and the standard deviation of the primary endpoint are all within our assumptions, which should augment the power of the trial to assess the change in the primary end point. I'm also pleased to report that nearly all patients have completed dosing and sites have not reported any patients with an LV ejection fraction less than 40%. We're eagerly anticipating sharing the top line results in late December. Our convictions are high that the results of SEQUOIA-HCM will meet our expectations. These convictions are further reinforced by the long-term efficacy and safety of aficamten that we're observing in FOREST-HCM the open-label extension clinical trial. At our recent Investor and Analyst Day we shared new longer-term data with data available in some patients for greater than two years. More than 200 patients have been enrolled in FOREST-HCM to-date and data from 143 patients with obstructive HCM were available for this analysis. The new data from FOREST-HCM showed that no patient had a treatment-related LV ejection fraction less than 50% during the treatment period - during the titration period and approximately two-third are receiving 15 milligrams or 20 milligrams of aficamten. During the maintenance phase of FOREST-HCM there have been no instances of LVEF plus with 40% which would require treatment interruption and only three instances of LVEF less than 50% that simply required a dose down titration. Of the 579 monitoring echocardiograms completed during the maintenance phase of treatment 99.5% of them did not result in a dose down titration. We also observed in these reported data from FOREST-HCM that the mean resting and LVOT gradients remain reduced and below the diagnostic threshold for obstructive HCM after treatment for more than two years. Patients also experienced sustained reductions in cardiac biomarkers and improved symptoms. Approximately half of patients were NYHA functional class I or asymptomatic and 80% of patients improved by one or more functional class. Furthermore 90% of the SCT eligible patients at baseline were no longer SCT eligible at the time of this analysis. aficamten has been generally well tolerated with no treatment-related serious adverse events as assessed by investigators. Additionally, approximately 30% of patients have reduced doses of background therapy are discontinued entirely, at the discretion of the treating physician and/or by request from the patient. This supports the rationale for MAPLE-HCM which Stuart will discuss next. These new results from FOREST-HCM are quite compelling and we look forward to continuing to gather more longer-term data for aficamten in this open-label extension. Shifting briefly back to SEQUOIA-HCM following the top line readout of the results in late December, we expect to hold a meeting with FDA in the first quarter of next year to discuss the top line results with the goal of potentially submitting a new drug application for aficamten in the second half of 2024. During that initial meeting to review the top line results we'd expect to begin a dialogue about how do the safety and efficacy of aficamten observed in REDWOOD-HCM SEQUOIA-HCM and FOREST-HCM would influence the design of a REMS program. We look forward to these interactions and we'll provide further updates next year. Now, I'll hand it over to Stuart to elaborate on additional progress we made for aficamten and provide an update on our earlier-stage clinical pipeline.

Thanks, Fady. During the third quarter we started ACACIA-HCM a pivotal Phase III clinical trial of aficamten in patients with symptomatic nonobstructive HCM. Enthusiasm among investigators as high as, many of the investigators participating in ACACIA-HCM have prior experience with aficamten from REDWOOD-HCM, FOREST-HCM and SEQUOIA-HCM. Additionally, as you may know patients with nonobstructive HCM have limited treatment options. Standard of care medications; including beta-blockers and calcium-channel blockers are not very effective and therefore patients with non-obstructive HCM often struggle with a high symptom burden. Our hope for this clinical trial is to gather evidence about the potential of aficamten for this important segment of the HCM population, which lacks treatment option. In the third quarter we also continued patient enrollment in MAPLE-HCM the Phase III clinical trial evaluating for the potential superiority of aficamten with monotherapy compared to metoprolol as monotherapy in patients with obstructive HCM. We're pleased to report that enrollment is progressing according to plan. If positive, MAPLE-HCM should support the possibility for aficamten to be considered for first-line therapy in obstructive HCM. Shifting to our earlier stage pipeline. As Robert mentioned, we also made progress advancing both CK-586 and CK-136 during the quarter. We've now completed the single-dose cohorts of the healthy participants in the Phase I study of CK-586, our cardiac myosin inhibitor in development for the potential treatment of a subgroup of patients with heart failure with preserved ejection fraction or HFpEF with hypercontractility. We've now concluded our analyses of the single-dose cohorts, which are supportive of the proceeding to the multiple dose portion of the study, which we expect to start in this fourth quarter. As the Phase I study progresses, we also recently unveiled new preclinical data for CK-586 at our Investor and Analyst Day showing improved diastolic function and reduced cardiac fibrosis in an animal model of HFpEF. These data along with the results observed with aficamten in non-obstructive HCM, which has features similar to that of HFpEF with hypercontractility support the potential benefit of CK-586 in this patient population. Shifting to CK-136 our cardiac troponin activator we completed the single ascending dose cohorts in the Phase I study in healthy participants. And we're now analyzing these data to inform potentially proceeding to the multiple dose cohorts of the Phase I study. With that I'll turn the call over to Andrew.

Thanks, Stuart. As we outlined at our Investor and Analyst Day, our approach to commercial readiness in 2023 is centered around understanding the patient journey and the holistic experience of living with HCM. As such, we have been focused on gaining a deep understanding of the HCM market with the intention of designing an optimal physician and patient experience. During the quarter, we continued to conduct market research to assess potential patient profiles and available market segments in obstructive HCM, which have confirmed the symptomatic patient population in need of disease-modifying treatment with a potential next-in-class CMI. By anchoring our commercial strategies to this patient-centric approach we are preparing to address a high unmet customer need with the objective of positively impacting patients and shareholders if aficamten is approved. At the same time, we're learning through our market research that physicians indicate a strong interest in the potential target product profile for aficamten showing that there is room to capture CRM share among newly treated HCM patients and the potential to expand the total CMI market. Furthermore, we expect CMI penetration of eligible -- obstructive HCM patients to be less than 20% at the time of expected launch of aficamten meaning that over 80% of the obstructive HCM eligible patient population will remain untreated with the CMI. We are therefore focusing our commercial readiness strategies to those enabling expanded use of CMIs building on the expected next in-class profile of aficamten arriving from our clinical trials program. We also will strive to design a seamless and patient-friendly CMI experience through a comprehensive patient support program to help address the emotional, financial and educational needs of a patient throughout their journey. With the patient experience in mind, we recently held a mystery theater program at the HFSA Annual Scientific Meeting where we facilitated a discussion surrounding the impact of obstructive HCM, which may have a patient on patient quality of life, mental health and well-being, as well as how cardiologists can better understand and address these concerns. This approach of elevating the holistic and human-centric view of HCM is resonating with HCTs and we hope it may help foster better position patient conversations, and raise more awareness of the myriad impact of HCM. Through the end of the year, we plan to continue our market research and go-to-market planning for aficamten. In 2024, our experienced team will shift focus to the design and build of our commercialization strategies as informed by market research, the results of SEQUOIA-HCM and our deepening market insights. With that, I'll turn the call over to Robert Wong.

Thanks, Andrew. We ended the third quarter with $554.7 million in cash and investments. During the quarter, we received a $50 million milestone payment from Royalty Pharma upon the start of ACACIA-HCM, which is treated as a liability on our balance sheet in accordance with GAAP. In addition, recently, we received a $2.5 million milestone payment from Ji Xing received upon the start of ACACIA-HCM. Our third quarter 2023, R&D expenses increased to $82.5 million from $62.7 million in the third quarter of 2022, primarily due to spending on our cardiac myosin inhibition programs. Our third quarter 2023, G&A expenses were $40.1 million, down from $48.2 million in Q3 2022 due primarily to lower outside service spending. Now I'll hand it over to Ching to review our financial outlook and corporate development strategy.

Thanks Robert. As Robert mentioned, we ended the quarter with approximately $555 million on the balance sheet, which represents over 18 months of cash runway based on our 2023 net cash burn guidance. In the second half of the year, we have reduced our spending and are critically assessing our go-forward spending priorities to help facilitate the best return on our financial commitments. Our main priority remains aficamten, and as we approach 2024 we are being prudent in our spending around preparations for the potential commercial launch of aficamten. Towards that end, we are gaining expenses ahead of our sharing the top line results of SEQUOIA-HCM. Once we have the results and provided they are positive we will be able to refine our assumptions further and on gate spending. As usual, we plan to provide guidance to our 2024 spending during the Q4 earnings call. As for access to capital, I'll remind you that through our transaction with Royalty Pharma we remain eligible for two additional loan tranches under our development funding agreement, including $75 million upon our potentially sharing positive results from SEQUOIA-HCM and 100 million upon acceptance of an NDA submission for aficamten in the US. As it relates to corporate development, over the year we have engaged in a rigorous process in which we met with multiple potential partners. We have noted a high degree of interest in aficamten, both independently and in some cases in concert with potential to include only omecamtiv mecarbil in regions outside of North America. This process has affirmed the value proposition to our go-to-Europe strategies. With that said, we do not expect to enter into a partnering deal prior to announcing the top-line results from SEQUOIA-HCM and will continue to evaluate how we access and deploy capital as we will learn more about aficamten from SEQUOIA-HCM. Now, I will turn the call back to Robert Blum.

Thank you, Ching. As we proceed to close out 2023, we're approaching an important inflection point for our company. With aficamten representing the leading edge of our specialty cardiology franchise, the top line results from SEQUOIA-HCM will potentially accelerate our momentum as we plan transitions to become a fully integrated biopharmaceutical company in 2024. In 2023, much was put into motion that is now carrying us closer to our goal of bringing forward new medicines for patients with diseases of impaired muscle function. While our priority remains aficamten and our earlier stage pipeline, during the quarter we submitted a formal dispute resolution request to the FDA's Office of New Drugs regarding the CRL or complete response letter for omecamtiv mecarbil. Our objective is to appeal FDA's conclusion that substantial evidence of effectiveness has not been established to support approval of omecamtiv mecarbil. As I've said before, we do not currently have plans to conduct another clinical trial of omecamtiv mecarbil, and we may not be able to address the deficiencies noted in the CRL. However, we still believe in the science underlying omecamtiv mecarbil and the demonstrated evidence to potentially benefit patients with advanced or worsening heart failure. If our appeal to FDA proves successful, we'll then consider potential next steps for omecamtiv mecarbil, albeit and importantly, as to the lens of a company for which our top priority is aficamten. We also continue to pursue potential approval for omecamtiv mecarbil outside of the US. Regarding Europe, we submitted our responses to the day 120 questions to the EMA and now await their feedback. As relates to China, our partner JI XING submitted a request for voluntary withdrawal of the NDA for omecamtiv mecarbil to the Center for Drug evaluation of the National Medical Products Administration of the People's Republic of China, subject to potential resubmission upon receipt of favorable feedback from EMA or FDA with regard to potential drug approval for omecamtiv mecarbil in the EU or US respectively. Shifting now to business development, As Ching said, and to be clear, we do not expect to partner aficamten leading into the readout of SEQUOIA-HCM. Our focus remains on that, which is under our control and that which is the most meaningful for our company and for patients and shareholders, which is advancing Aficamten. However, it is reinforcing to our corporate strategies to have engaged with potential partners who have expressed a high level of interest in Aficamten and ultimately validate our own planning. We believe that we are doing right by all of our stakeholders to objectively and critically evaluate our own plants. As a result, with the readout of results from SEQUOIA-HCM, we'll be better prepared to execute on our strategies. As we approach the end of 2023, we reflect on a year marked with both ups and downs admittedly. We have faced certain setbacks which tested our company's grit and resilience, but we've also made great progress. Today, we're uniquely positioned for success with a strong specialty cardiology franchise led by our own broad late-stage development program for Aficamten complemented by earlier-stage drug candidates that have arisen from our industry-leading research and leadership in muscle biology and the mechanics of contractility. That plus our relationships with key stakeholders and our access to capital sets us apart as does our passion, our dedication to our mission and are focused on doing right by patients. I look forward to 2024 with optimism and eager anticipation for what's yet to come. Lastly, and before I recap our upcoming milestones, I'd like to also mention that leading into the results and the readout of SEQUOIA top line in late December, we plan to enter a quiet period starting on Monday, December 4. Now our upcoming milestones. For Aficamten, we expect to share top line results from SEQUOIA-HCM in late December and continuing enrollment of patients in Maple HCM and Acecia-HCM and continue to advance our go-to-market strategies for Aficamten. For omecamtiv mecarbil, we expect to continue to pursue potential approval for omecamtiv mecarbil in Europe. And for CK-136, we expect to analyze data from the single ascending dose cohorts of the Phase I study to inform potentially proceeding to the multiple ascending dose cohorts in that Phase I study. And finally, for CK-586, we expect to proceed to the multiple ascending dose cohorts in that Phase I study in this quarter Q4 2023. Operator, with that, we can now open up the call to questions, please.

Thank you. [Operator Instructions] And our first question will come from Joe Pantginis from H.C. Wainwright. Your line is open.

Good afternoon, Joe.

Hi everybody. Good afternoon. Thanks for taking the question. So curious on Fady's comments with regard to the patient populations in SEQUOIA. And specifically, any more color you could provide with regard to the background therapy reductions and more importantly, how these therapy reductions might improve the quality of life and the safety of these patients? And then secondly, just quickly, anything meaningful to discuss with regard to the cost impacts of the formal dispute with the FDA and the EMA filings for afacamtin? Thanks a lot.

Sure. I'll let Fady answer your first question, and I'll take the second.

Thanks Joe. I think with regard to withdrawal of background therapy, the protocol, as we reported back at ACC allows investigators to will solely withdraw beta blockers or other background therapies such as disopirmide or calcium channel blockers based on patient tolerance. And then at the same time, they're also allowed to up-titrate afacamtin as necessary to compensate. And so we see -- I can't give you exact percentages, but we see substantial about two-thirds, I think, withdraw from all background therapy. I think in most cases, they've been able to discontinue disopirmide and also with beta-blockers as well quite successful in terms of withdrawing from those. So, I think from a patient point of view, it simplifies medical therapy. It gets them off of some of the troublesome adverse events that they experience with those drugs and it simplifies their medical regimen.

And to your second question regarding potential costs associated with our submitting the formal dispute resolution. They're really quite minimal. These are costs that relate to internal activities and together with council, no new studies, no new analyses, nothing that would represent a meaningful investment of spending.

Thank you, guys.

Thank you.

Thank you. And our next question will come from Dane Leone from RJS. Your line is open.

Hey, how is it going Robert and team? Yes, we're talking a lot lately. So, really only one question for me that keeps coming up with investors is given the late December nature of the topline SEQUOIA, can you just provide any detail on how you think the team will handle disclosure of the topline data? I think a lot of people point back to some of the early REDWOOD disclosures that your team made around description of some of the key primary endpoints and maybe some detail around left ventricular ejection fraction adverse events. But anything you can tell us of how your team plans to handle, I think, could be really helpful for setting expectations? Thank you.

Sure. I'll do my best, recognizing that we don't have the data, so it's hard to be as clear as you might want us to be. But our goal is to disclose all of that, which should hopefully convey our ability to have achieved a next-in-class potentially best-in-class profile for afacamtin? How much of that will be quantitative with p-values, primary and secondary endpoints, safety and adverse effects is ultimately going to depend on that which we can consider alongside of, hopefully, the American College of Cardiology, where we would hope to be presenting these data, albeit not for several more months afterwards. So, our goal will be to be communicative as much as we can but knowing we don't want to jeopardize any presentation at a proper scientific forum, so we recognize what is expected if we're going to have a next-in-class potentially best-in-class profile. And those are the things that are top of mind for us as we will think about that which we can disclose. Obviously we've got to disclose that which is deemed material to shareholders.

Excellent. Thank you.

Thank you.

Thank you. Our next question will come from Salim Syed from Mizuho. Your line is open.

Good afternoon, Selim.

Hi. Good afternoon, Robert. I guess a question from me. I'll just follow-up on that on SEQUOIA. I just wanted to maybe hear from you or Fady just so that we are all clear on how we should compare mavacamten to aficamten? They had a 1.4% unit change on peak VO2 and I think there was about a 6% injection fraction sub-50%. Just curious, if you could just frame work for us the bookends low-end and high-end on peak VO2. Like is it a one point change in a 1.8 where it'd be comparable? Or where do you actually start to feel like you can differentiate on efficacy. And the same question just on safety, how much different do you need to be versus mavacamten in order to feel like you can actually differentiate and how that speaks to our REMS et cetera? Thank you.

Sure Salim. So you won't be surprised for me to again emphasize that we're not going to be making comparative statements with mavacamten. The SEQUOIA-HCM study is a different study than was the study EXPLORER-HCM that led to the approval of mavacamten. All I can speak to and all Fady will speak to is that which relates to aficamten and what our expectations are ultimately labelling and positioning and how physicians see those two potential medicines will define what will be our hope of expanding the category and best-in-class. So with that long caveat, maybe I'll ask Fady to try his best to speak to what our expectations are around aficampten in SEQUOIA-HCM.

Yeah. Salim, I think what we will see and hope to see is that the changes are going to be meaningful in magnitude such that the question isn't really one of whether there's a slight difference between one or the other. Both drugs are going to be -- well I should say mavacamten we know is quite effective in patients. We hope to see aficampten be equally or even better effective. I don't think you can judge those types of things just based on comparisons of a single number. You have to really look at the totality of the data across all the endpoints. You have to couple it with the safety profile as again as we might see in the study. And so there's not a simple answer to your question as I know you're hoping me to provide.

Okay. No worries. I wanted to ask the question. But I appreciate the answer. Thank you.

Thank you, Salim.

Thank you. Our next question will come from Jason

Hello, Jason.

Good afternoon. And this is Cameron Rosa from Bank of America Securities on for Jason

Sure. And thank you for the question. I've read some of the research that you guys have published relating to this matter and maybe I could clarify how we think about it. We're looking at data from SEQUOIA-HCM with already having discussed with FDA in the design of SEQUOIA-HCM a protocol that's permitting of down titrations when EF falls below 50% as opposed to dose interruption or dose termination. The consequences of down-titration being well within the norm of cardiology group practices in this area. So we approach the data when it will be available from SEQUOIA-HCM with those same optics, meaning I don't think it's really a question of its 3% or 6% or any number within that range. But how does that really affect patients and physicians? And how likely would FDA feel about what would be the consequence if EF does fall. We're feeling emboldened by the fact that aficamten has a half-life that's enabling of a relatively rapid return to normalcy with an EF such that if EF does drop it may be inconsequential. And in that way a simple down titration would be acceptable by physicians without any concerns and worry. We believe that could be very important for ultimately the profile of aficamten. So I wouldn't dwell on the number. Even though as Fady reported, we've had quite a low number of EF excursions and 99.5% of echos have not resulted in any adjustment to dose but for the fact that these down titrations might occur occasionally, I would think that that will go a long way to be providing hopefully if the data in SEQUOIA bear out like we've seen in FOREST, a profile that will be deemed next in class. Fady anything you want to add to that?

I just might add that cardiologists are really quite adapt at managing drugs that have to be monitored. And if you think about for instance heart failure therapies like mineralocorticoid receptor antagonist – these drugs have long been known to cause rises in potassium even life threatening increases in potassium. And if you read the label of eplerenone for instance in 1% to 4% patients that receive these drugs. And it's not – cardiologist no stranger to drugs that need to be monitored. So I don't think it's ultimately as one becomes familiar with a class that it's not surprising that one begins to see monitoring become changing over time and it becomes as part of standard practice. So I think as Robert said what we've seen to date with aficamten coupled with familiarity with the class would hopefully lead to something that's both reasonable for patients and physicians to execute and maintain patient safety.

Appreciate the color. Thank you.

Thank you.

Thank you. Our next question comes from Serge Belanger from Needham. Your line is open.

Good afternoon, Serge.

Good afternoon, Robert. A follow-up on a prior question regarding the data disclosure that we're expecting in late December. ACC has historically been pretty restrictive and what can be disclosed ahead of the late-breaking clinical trial presentation at their meeting. So in some cases we heard nothing more than whether at a primary endpoint. So, just curious if you're confident that you will be allowed to provide more data than that on both the efficacy and the safety side of the trial? Thanks.

Thank you. Again, not having the data it's difficult to be as clear as you might ultimately want. But yes, I'm confident. I think we can communicate what we need to communicate to be satisfying both our objectives to be disclosing that which is deemed material for the benefit of shareholders and ultimately also enabling of a proper presentation at the ACC when it comes. We've been down this path before. Others have to. And I think this is something that can be accomplished. Next?

Thank you. Our next question will come from Ashwani Verma from UBS. Your line is open.

Good afternoon.

Hi. Good afternoon. Thanks for taking our question. Fatima here on behalf of Ash Verma from UBS. Just two quick ones here. We understand that you have low beta blocker use in your study from the baseline characteristics. And that can help tease out the effect size for aficamten. But since data blocker usage is really high in the real world with aficamten effect size in real world potentially be lower than what you will show in the SEQUOIA study. I mean just a second quick one. We want to get your views on what is the relationship between LVOT. It was great in reduction and peak VO2. We have some studies like one from KEM

Sure. So I'll just start and then ask Fady to speak to your questions. We designed and conducted a study SEQUOIA-HCM that we believe is very representative of the population that we hope ultimately aficamten will be available to treat. So it's not an artificial construct. It's not a manufactured population. It's in fact real world. And in that way, we went to great pains to ensure that this was a study that was enabling of physicians ultimately upon the availability of data to apply these results to their own practices. And with that, I'll turn it to Fady.

Yes. Let me remind you that I said 61% of the majority of patients are taking beta blockers. It's not out of line with what it's seen in the real world. Additionally, you look at the use of calcium channel blockers, the allowance for combination therapy of calcium channel blockers and beta blockers or beta blockers and dicoparamide. I would argue that SEQUOIA-HCM provides a very relevant real world experience in terms of aficamten's effectiveness when we have those data. So I think that question is really answered by the baseline characteristics. It showed that there's a high degree of background medical therapy that's employed. I think the second point as we pointed out is that background therapy may not be optimal for these patients. Ultimately some of these background therapies may be holding them back and beta blockers being an example. One of the reasons you see less good correlations between LVOT gradient reduction and peak VO2 is because beta blockers disrupt that correlation in the absence of being able to increase your heart rate during exercise even as you've gotten rid of the gradient you can increase your exercise performance because you can increase your heart rate. And so it's more complicated unfortunately than a clean scientific experiment where you change one variable and measure another variable. But roughly there is a good correlation, reducing the gradient has always been the target of both medical and surgical therapy. And obviously there's precedent in the class that reducing the gradient improves PVO2.

Great. Thanks for taking the question.

Thank you.

Thank you. And our next question will come from Jason Butler from JMP Securities. Your line is open.

Hey, Jason.

Hi. Thanks for taking the question. Hi, Robert. Just wondering, if you could comment on from a commercial planning perspective, how feedback from FDA assuming positive data from SEQUOIA and you meet with FDA in 1Q 2024. How that feedback on a REMS program will impact your commercial planning and scenario there the REMS could be similar to mavacamten or less burdensome the mavacamten? Thanks.

So I just want to make sure I captured your question properly. Could you repeat the first part?

Yeah. Just when you get feedback from FDA on potential of what a REMS program may look like, how that would impact your commercial planning in scenarios where the REMS was similar to mavacamten or less burdensome the mavacamten?

Okay. No I understand. Thank you. I'm going to ask Andrew to speak to some of this but please understand that absent the data right now these are abstract scenarios that we've contemplated in market research. And once we have the data, we'll be able to do more refined market research, and ultimately as we may propose a REMS this is something that is going to be achieved through interactions the sponsor with FDA. So all of this is subject to still a great deal of uncertainty until we have the data around, which it's based. But we do have certain expectations as we have seen REDWOOD data as we've seen FOREST data. And as we've understood what's behind the REMS for the other cardiac myosin inhibitor we have a view to what might ultimately be enabling of a lesser REMS, but that's still quite speculative as you can imagine at this point in time. Andrew, can you speak to how you've approached this from the market research standpoint?

Sure. So, I guess, there's two important things to understand. One is, we probably won't have that much clarity in terms of exactly what a REMS program is going to look like early in the review process. That's something that we proposed to the FDA. But relative to our patient support services, independent of what the REMS will look like. There are certain elements of patient support we're going to offer. So we know we're going to offer things like patient assistance and co-paper. We'll look at echo reimbursement. We do we'll help with benefits verification education on disease states. So there are certain things that we know around minimum and that we're going to do. There's other things that based on the complexity of the REMS that we'll do as well. Our assumption going into the planning is that we're going to assume a complex REMS with all elements and it's a lot easier for us to simplify or back down from that once the REMS program comes into view because when it does come into view it's a negotiation as you're negotiating a label near the end and we would not have enough time to react. So hopefully that gives you a sense of how we're thinking about it.

And just to add one more comment. If you read the summary basis of approval, there's a lot that one can learn about what the FDA was seeking to accomplish in putting in place the REMS program that does exist today. And we'll obviously be conditioned based on that prior knowledge to know what we need to glean from the evidence from FOREST and SEQUOIA in order to hopefully enable something that is different. But ultimately, that's something that comes down the road following the acceptance and the review of a new drug application.

Okay. Thank you.

Thank you.

Thank you. And our next question will come from Srikripa Devarakonda from Truist Securities. Your line is open.

Good morning.

Good morning, Robert and the team. Thank you so much for taking my question. And really looking forward to the data in about a couple of months hopefully less than that. I have a question about MAPLE trial. You talked about enrolling patients that are naive to therapy as well as those who were on background therapy but withdrew from it. Can you remind me if there's any restriction in terms of how long these patients could have been on therapy symptomatic and on standard of care? And how that featured into how the trial was powered?

Very good questions. I'll turn to Fady please.

I'll ask Stuart to answer since he discussed MAPLE in his section. But in general, patients could have been on beta blockers for any length of time as long as they could be withdrawn they were considered in certain classes. And depending on the length of time I'll let Stuart elaborate please.

Thank you.

Thank you.

Thank you. Our next question will come from Jeff Hung from Morgan Stanley. Your line is open.

Hi, Jeff.

Hi. Good afternoon. This is Catherine on for Jeff. Thank you so much for taking my question. You mentioned previously that physicians have indicated their interest and excitement in aficamten. We want to ask you either your reader to-date or any feedback that you received what aspects of aficamten profile is the physicians may be finding most compelling?

So Andrew, may I ask you to respond to that please?

Sure. So with our market research when we put an aspirational profile in front of physicians. The things that they mentioned most is excited about are preservation of LVEF function. Obviously, which is the safety element change in New York Heart class or improvement going from a three to a two or three to a one two to a one as an example, change in KCCQ and limited DDIs that really don't need to be monitored relative to dosing. Those are the things they mentioned that are most would drive their preference for aficamten.

Okay. Thank you so much.

Thank you.

Thank you. Our next question will come from Yasmeen Rahimi from Piper Sandler. Your line is open.

Good afternoon, Yasmeen.

Hi, Robert. Thank you so much for all your comments. GI guess with data expected late December and you guys entering a quiet period I guess December 4. Like could you maybe highlight to us what is your definition of late December? And then secondly just maybe comment on how has been this data cleaned up as you guys have been collecting it? Or is it just like do you start like cleaning up the data as soon as things get locked out in early December? Thank you. I appreciate if you could taxable to me?

Sure. So I hope this can be helpful, but please understand as Fady shared with you while nearly all of the patients have completed their maintenance phase not all of them have and there's still some additional visits that must occur from which data collection still must follow in order to be enabling of database lock. So while we're in the very late innings of this project it's not yet done. So we can't be as precise as you might like in asking the question about what do we mean by late December. What we mean is it's going to be in December whether that's towards -- if we thought it was early December we would have said so. Late December probably means, it's as you can imagine weeks into the month and that's ultimately going to be defined by how quickly, can we get two database lock and the enabling of analysis. It's not uncommon where in a study like this it would typically take four to six or more weeks to go from database lock to tables listings and figures from which one could distill, top line results. We're going to try to do that faster and as fast as we can, subject to what are still data to be collected. To this point in time, we feel very good about where we are with data collection enabling of database lock and analysis. And I hope that's helpful to your question.

Thanks, Robert.

Thank you. Our next question will come from Charles Duncan from Cantor. Your line is open

Good question. And I'll say, I've been myself engaging with our colleagues to understand what could be accomplished for our making this a truly international registrational study and what can we learn from prior studies and what do we know? So, I'll ask Fady to speak specifically to your question.

Hi, Charles. I think with regards to exercise performance you're an athlete. If you look at our Olympic level athletes, you see they come from all over the world and performance can be seen in all those populations at an extremely high level. So similarly, I think in studies like this we have the opportunity to see improvements in exercise performance across the board. I'm pleased to really buy the quality of the data that we've received from all of those regions. We have experience in GALACTIC for instance, in terms of response to omecamtiv mecarbil, in all of those regions. And the response to cancer was quite strong particularly in China, in fact. So I don't have any concerns at the moment with regards to regional variability. Obviously, we'll see when the data emerge.

I don't foresee that there's really an analog in biopharma today a company that is a specialty cardiovascular company. Obviously, there are specialty companies in other therapeutic categories like in the areas of CNS, for instance. But what we are focused towards in the build-out of our pipeline and corporate development strategies are those kinds of opportunities that are directed to concentrated customer segments. Where there would be both pricing and payer leverage, where there's limited sales and marketing infrastructure required to get to a high yield, high return on investment strategy. And we don't think the other predecessor cardiology companies in the biopharma space have those advantages in order to be able to compete effectively. We think they do exist in those markets and for those programs where our science directed to cardiac muscle lends itself to a new business model in the biopharma space and one for which we do believe there are elements that translate to maximizing shareholder value. So I hope that answers your question.

Yes it does. You've been a good student of the history of the industry. So I appreciate you providing your perspectives. Thanks.

Thank you.

Thank you. And our next question will come from Roanna Ruiz from Leerink Partners. Your line is open.

Good afternoon.

Good afternoon. Thanks. So a quick one from me. I was curious if you could talk a bit more about the clinical meaningfulness of the 99.5% of monitoring echoes that did not need dose reductions in the FOREST data? And how does it actually compare to what physicians are seeing in clinical practice today with mavacamten?

We'll address that but I hope you'll understand if we don't make a comparative statement to mavacamten. But Fady, could I ask you to take that?

Sure. I think the reason we made that point like I know the reason, we made that point in terms of the number of echoes, the number that don't require a change in management is to give some flavor to what the burden of monitoring it. If you do a test to monitor for something, and it only has a meaningful outcome in less than 0.5% of the measurements that you do. You have to ask yourself are you appropriately deploying resources in a way that is efficient and are there better ways to deploy those resources that can maintain the same degree of safety. But not necessarily burden the system quite as heavily. So, I think incumbent on us to understand what the determinants are of those very infrequent events, how do we anticipate them and to eliminate what our 99% of tests that have no clinical impact, but cost the system a lot in terms of resources time and money. So I think that's ultimately why we made those points in our presentation.

Got it. Thanks.

Thank you.

Thank you. And our next question will come from Justin Kim from Oppenheimer & Co. Your line is open.

Hi, Justin.

Hi, Robert. Good evening, everyone. Sorry, I may have joined a little bit late, but I just had a quick question on the -- I guess the SEQUOIA study and inclusion of patients who are refractory to SRT. Just because of I guess the young women experience was presented a few weeks back, curious like if that experience would be similar to what we saw in EXPLORER? And any color there?

So I think I just want to make sure that we're using the right language. I don't know that refractory to SRT is the right way to put it. What we were pointing out was those patients who were eligible for SRT pretreatment versus post treatment. But maybe Fady you could speak to that.

Yeah. No, that's right. These patients meet the criteria for SRT which is that they have a New York Heart Association class of three or more and that they have a gradient of 50 or more. So in FOREST we a couple of weeks ago looked again at the percentage of those patients who remained eligible for SRT, once they started aficamten treatment and only about 10% of them met those criteria after therapy where of the ones that had met at the time of therapy. So we're not necessarily inclusive of patients that are refractory to SRT. They just meet the criteria for SRT.

Okay. I guess maybe just a clarification. I think there were patients who had residual gradients following surgery. And just wondering if the study includes those patients here just given that these patients do benefit have been shown to benefit?

Yeah. No. And patients that had septal reduction therapy is an exclusion for this particular trial for SEQUOIA.

Okay. Great. And maybe as a segue I mean just on the FOREST presentation, is there a sort of natural timing for the HCM cohort and when we might be able to see any added long-term treatment there?

And with regards to FOREST. Yeah. I mean, I think what we want to see is the NCM cohort to age a little bit, so that we have about at least six months to a year's worth of follow-up before we report those data. So you'll probably see them in 2024.

Okay. We'll look forward to that ICC or ACC.

Thank you.

Thank you. And I am showing no further questions from our phone line. I'd now like to turn the conference back over to Robert Blum, President and CEO for any closing remarks.

Thank you, operator, and thanks very much to everybody for joining us on this call today. We covered a lot of ground. So I won't try to synthesize or summarize that other than to say, we do look forward to the results from SEQUOIA-HCM and top lining them later in this quarter in late December. We thank you for your continued support your interest in Cytokinetics. And operator with that we can now conclude the call.