CYTK - NASDAQ

Good afternoon, and welcome to Cytokinetics' First Quarter 2025 Conference Call. At this time, I would like to inform you that this call is being recorded. And all participants are in a listen-only mode. At the company's request, we will open the call to questions after the presentation. We will allow for only one question per participant. I will now turn the call over to Diane Weiser, Cytokinetics' Senior Vice President of Corporate Affairs. 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; Andrew Callos, EVP and Chief Commercial Officer will address commercial readiness activities for aficamten; Fady Malik, EVP of R&D, will provide updates related to clinical development program for aficamten; Stuart Kupfer, SVP and Chief Medical Officer, will provide updates on clinical development on omecamtiv mecarbil and CK-586, Isaac Ciechanover EVP Corporate Development and Chief Business Officer will provide update on business development in the context of our corporate development; Sung Lee, EVP and Chief Financial Officer, will provide a financial overview of the past quarter and finally, Robert will review expected key milestones for the remainder of 2025. 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 2025 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 to all for joining us on the call today. The first quarter provided a strong start to the year, laying a solid foundation for the increased momentum we're building as we approach a pivotal step towards potential commercialization. Of course, our principal focus is on our new drug application for aficamten. As we disclosed last week, the FDA extended the PDUFA date for the NDA for aficamten for the oHCM to December 26, 2025 to provide additional time to conduct a full review of our proposed revs. And to be clear, we had a series of three meetings with FDA ahead of our NDA submission for aficamten, during which we discussed a range of topics related to the content of our submission, including safety monitoring and risk mitigation strategies. These included a top-line meeting to review the results of SEQUOIA-HCM, a pre-NDA meeting to cover specific topics related to our submission, and a type B meeting during which we discussed strategies related to safety monitoring and risk mitigation in support of our NDA submission. Attending all three of these meetings were representatives from the Division of Cardiology and Nephrology as well as representatives from the Division of Risk Management within the Office of Surveillance and Epidemiology of FDA. As we previously shared, these interactions provided the opportunity to discuss in detail the data supporting the safety and intrinsic pharmaceutic properties of aficamten and how they may inform approaches to manage risk and gain insight into FDA's perspectives on this matter. Given these interactions, we considered it reasonable to propose a distinct risk mitigation approach specific to aficamten and based on labelling and other tools such as voluntary education materials. However, we understood from FDA that the potential need for REMS would be a focus of the Agency's review. We made the determination to take this approach because under the circumstances we thought it was reasonable given the profile of aficamten. However, as a contingency we developed our distinct REMS proposal and we were well prepared to submit it if necessary during the NDA review. Given the mechanism of aficamten, the FDA requested that we submit a REMS specific to its intrinsic properties, which we promptly provided as we communicated last week. We recently learned from FDA that our subsequent submission of the REMS constitutes a major amendment to the NDA and will now require a standard three-month extension to the original PDUFA Action Date. To remind you please we discovered and developed aficamten with objective to advance it as a potential next in class cardiac myosin inhibitor. Based on its inherent characteristics, we evaluated it in preclinical and clinical studies to understand how its half-life, its rapid onset, its reversibility, as well as an optimized relationship between PK and PD could enable a unique convenient dosing regimen. We extensively studied its DDI profile to similarly ensure that it was enabling of a distinct clinical profile to support potential differentiation. We believe the results of our clinical studies including SEQUOIA-HCM and FOREST HCM support a potential label and risk mitigation profile that if approved by FDA will differentiate aficamten. Nothing has changed in that regard and again to confirm, no additional clinical data or studies were requested by FDA. As we disclosed in an 8-K filing in March, during the first quarter, we completed a mid-cycle review with FDA. During the meeting, FDA confirmed that the Agency does not plan to convene an advisory committee meeting which is consistent with prior communications to us, and that our late cycle meeting is expected to occur in June. While the PDUFA extension does delay the potential approval of aficamten, it does not change our confidence in its distinct benefit, risk and pharmaceutic profile, nor does it change our expectation for a potentially differentiated label and risk mitigation profile upon potential approval. Given the FDA review of the NDA is ongoing, we do not intend to provide further color or detailed updates on our communications with FDA. Moving on during the first quarter and recently we also advanced regulatory activities outside of the US in April we received 120-day questions from the EMA regarding the MAA for aficamten in Europe and we're now working to develop responses. I'm pleased to share that we believe we are on track for potential approval by ema in the first half of 2026. During the quarter, we also worked with Sanofi, our partner in China, to support the NDA review of aficamten with the NMPA, and overall we're encouraged by the steady progress of our regulatory interactions globally. Moving to other activities in the first quarter, we continue to dial up our commercial readiness not only in the US but also in Europe. As Andrew will elaborate during the quarter, we made key strides on all commercial planning work streams. Yes, the PDUFA date extension will shift out certain elements of our commercial readiness, but we are moving forward with launch planning. In the first quarter, we also achieved meaningful milestones in our ongoing clinical trials program for aficamten. We're pleased to share today that we plan to report top line results from MAPLE-HCM this month. If the results are positive, we believe these data may represent a potential label expansion opportunity for aficamten following an initial potential FDA approval in oHCM. In addition to oHCM, we're also focused on nHCM, in which there is a significant unmet need for effective treatments and with increasing recognition and diagnosis of the condition, the market opportunity continues to grow. We're pleased to share today that ACACIA-HCM, our pivotal Phase III clinical trial of aficamten in nHCM, has completed enrollment in the first quarter, months ahead of schedule, enabling us to read out the top-line results in the first half of 2026. Fady will elaborate on this achievement as well as on some additional updates that we made to the trial as guided by global regulatory feedback. As the prevalence rate of nHCM rises, we remain optimistic regarding the promise of aficamten in this population of underserved patients. As you know, aficamten for the treatment of both oHCM and nHCM represents the first potential new medicine arising from our specialty cardiology franchise, which also includes omecamtiv mecarbil and CK-586, each advancing in respective later stage clinical trials in two different forms of heart failure. The progress we made in the first quarter reflects thoughtful planning, disciplined resource management and a steadfast commitment to rigorous clinical research, all of which propel us towards our ambitious Vision 2030. And with that I'll turn the call over to Andrew please.

Thanks Robert in the first quarter we continued to execute our commercial readiness planning and implementation with a three-month extension to our Purdue facility. Certain work streams will be adjusted we were not losing our sense of urgency or launch readiness momentum. This year has been focused to building, implementing and executing our go-to-market plans as we intend to keep building this momentum towards our revised December PDUFA date. During the first quarter we initiated our Salesforce recruiting. Given the December PDUFA date, we'll be revising our Salesforce onboarding plan while maintaining current recruiting schedule, which is off to a great start. To date we received several thousand applications, many from highly qualified Salesforce professionals, with the majority possessing abundant cardiology experience and existing relationships, giving us a strong talent base from which to identify top candidates for these positions. In late April, we held a virtual recruiting webinar for sales professional candidates that grew nearly 1,000 attendees. These figures show high level of interest and how well positioned we are to attract top talent and build a standout sales organization. In parallel, our work around sales operational planning continued including analytics, targeting, incentive comp as well as finalizing the sales training curriculum. We are also building our bespoke patient support program by integrating our strategic partners into a seamless patient focused implementation. We also finalized selection of our channel distribution partner and specialty pharmacy partners. During the quarter we continued to refine our promotional launch campaign for HCPs and patients, accounting for the most recent market dynamics, ACP Advisory Boards as well as primary market research testing. At the same time, our ungranted disease awareness campaign ACM beyond the Heart continued. The ACP focused awareness campaign directs haps to consider the broader ACM burden and practice whole person care and likewise, the pacing campaign helps educate people living with HCM not just about the condition but about the holistic burden of HCM. We also maintained our engagement with payers and plan to continue educating them on the data from the clinical development program of aficamten, as well as the clinical and economic burden of HCM. On top of the burden of disease, we expect to have several HEOR presentations at upcoming meetings to further characterize both oHCM and nHCM and deepen understanding of the disease to that point. An exciting milestone during the first quarter was our launch of EARTH-HCM, an online open access interactive public health education tool developed in collaboration with leading academic institutions. Outside of our U.S. commercial planning, we advanced European commercial readiness activities in a gated manner, including hiring key leadership positions for marketing, finance, legal, compliance and human resources. And we set up new regional entities in France and the U.K. with in-country leaders. During the quarter, we also validated our reimbursement strategy and country launch sequence, which as we previously stated, begins with Germany in 2026, pending EMA approval. Finally, we began dossier preparation for HTA submission across multiple geographies. To summarize, we've made progress in our commercial readiness activities over the past quarter, and we'll continue to finalize a robust commercial framework to support the potential U.S. and European launches of aficamten. With that, I'll turn the call over to Fady to share updates on our ongoing clinical trial program for aficamten.

Thanks, Andrew. As Robert mentioned, we plan to report top line results from MAPLE-HCM this month with a presentation of the primary results at a medical meeting later this year. We want to set expectations now for the top line release to be qualitative as we don't want to jeopardize this presentation at a major medical meeting by disclosing details of the results. To remind you, MAPLE-HCM is a rigorously designed trial, randomizing patients to treatment with aficamten or metoprolol each as monotherapy. While beta blockers are standard of care in HCM, their impact on exercise performance, symptoms and LVOT gradients in structural HCM is not well characterized. At the same time, the impact of treatment with aficamten as a monotherapy on the same measures is important to understand to inform the implementation of cardiac myosin inhibitors into the standard of care. We look forward to the results of this head-to-head comparison of MAPLE-HCM as may help differentiate the effect of aficamten on exercise capacity, symptoms and cardiac structure and function as well as safety and tolerability from the long-established standard of care metoprolol. We also have a few important updates to share regarding ACACIA-HCM. First, we're pleased to report that in the first quarter of 2025, nearly 6 months ahead of schedule, we completed patient enrollment for the primary cohort of this trial, which encompasses all sites in North and South America, Australia, Europe, China and Israel. We randomized 516 patients in only 18 months, which was driven by high interest in participation that accelerated screening and enrollment through the end of 2024 and into early 2025. The primary cohort of ACACIA-HCM includes the regions originally designated for enrollment when we initiated the trial in 2023. However, alongside the collaboration and licensing agreement we entered into with Bayer, for aficamten in Japan late last year, we also agreed to expand ACACIA-HCM to Japan, targeting a start in Q2 2025 to support its potential marketing authorization for nHCM. Given the primary cohort completed enrollment months ahead of schedule, we've divided ACACIA-HCM into two parts, the primary cohort and the Japan cohort, an approach supported by regulators in Japan. With the enrollment now completed in the primary cohort, we expect to share top line results from that cohort in the first half of 2026. Early in the first quarter, we also embarked on updating the primary endpoint of ACACIA-HCM from a single primary endpoint of KCCQ clinical summary score followed by a first secondary endpoint of exercise capacity to a dual primary endpoint of change in KCCQ clinical summary score and a measure of exercise capacity, peak VO2, each measured as a change from baseline to week 36. This change was made to align the endpoints of the trial to feedback we received from regulators outside the U.S. and harmonize its interpretation globally. Prior to this change, CPET measurements were already being obtained for all patients, so this change does not alter the conduct of the clinical trial. It only elevates a measure of exercise performance from the first secondary endpoint to an additional primary endpoint. Given the brisk enrollment of ACACIA-HCM, we enacted this change knowing that we could also power the trial adequately by increasing the sample size from 420 to at least 500 patients to ensure each of the primary endpoints had 90% power at an alpha of 0.025 to detect a conservative clinically meaningful change. Compared to placebo for KCCQ, that's 5 points. And for peak VO2, that's 1.0 milliliter per kilogram per minute. To be clear, however, if either clinical endpoint that comprises the dual primary endpoint is statistically significant, ACACIA-HCM will be considered positive. In sum, we believe these changes maximize the chances of the success of this trial and will also satisfy regulatory requirements globally. As a reminder, in Cohort 4 of the Phase II trial, REDWOOD-HCM, we evaluated treatment with aficamten in nHCM in an open-label fashion and demonstrated improvements in KCCQ and NYHA functional class and an average reduction in NT-proBNP of 66%. The majority of patients achieved the highest dose offered at 50 milligrams, and there were no drug discontinuations due to low ejection fraction and few instances of LVEF less than 50%. These findings were replicated when patients transitioned into the open-label extension trial, FOREST-HCM. Importantly, ACACIA-HCM builds on this Phase II experience by using the same dosing approach with rapid attainment of target dose within 8 weeks, refinements of the entry criteria and careful patient selection based on echocardiographic review by HCM specialists. Although nHCM currently accounts for about one third of the HCM population, it's now being diagnosed at a much faster rate than oHCM. And as a result, we anticipate that nHCM will comprise eventually nearly half of all HCM diagnoses. If the results from ACACIA-HCM are positive, this would represent a significant opportunity to help this underserved patient population who currently have limited treatment options. To close out the update on our ongoing clinical trials program, enrollment in CEDAR-HCM is progressing, and we remain on track to complete enrollment in the adolescent cohort in the second half of this year. As you've heard in the first quarter, there's been strong progress advancing the ongoing clinical trial program for aficamten, which we believe will pave the way for multiple opportunities to reach more patients living with HCM worldwide. Now I'll turn it over to Stuart.

Thanks, Fady. I'm pleased to provide updates on our later-stage development programs. During the quarter, we continued conduct of AMBER-HFpEF, the Phase II clinical trial of CK-586 in patients with symptomatic heart failure with preserved ejection fraction of at least 60%. We continue to progress towards our goal of completing enrollment in the first two cohorts in the second half of this year. Approximately two million people with heart failure in the U.S. have an ejection fraction greater than or equal to 60%. Despite advances in care and broad use of standard of care treatments, these patients often have a poor prognosis following heart failure hospitalization and a high rehospitalization rate that also drives up health care costs. The unmet need to deliver better options for patients is clear, and we believe AMBER-HFpEF will help elucidate whether a cardiac myosin inhibitor may benefit the subset of patients with heart failure and builds on our experience in non-obstructive HCM. We also continue to enroll in COMET-HF, the confirmatory Phase III clinical trial of omecamtiv mecarbil in patients with symptomatic heart failure with severely reduced ejection fraction less than 30%. We maintained progress in activating sites in the U.S. and convened a well-attended U.S. investigator meeting at the end of April. During the meeting, we were pleased to see a high level of investigator engagement, reflecting their recognition of the urgency of developing safe and effective treatments for this high-risk population and our motivation to enroll patients in the trial. Many of these investigators participated in GALACTIC-HF, the first Phase III trial of omecamtiv mecarbil. We expect to continue enrolling COMET-HF this year and complete enrollment in 2026. Our later-stage pipeline represents our next highest opportunity following aficamten with multiple opportunities to positively impact patients with adjacent cardiovascular diseases of high unmet need. With that, I'll pass it to Isaac.

Thanks, Stuart. In the first quarter, we participated in a Series B financing of Imbria Pharmaceuticals to support the advancement of ninerafaxstat, for the treatment of nHCM. This deal represents our first equity investment in which we can participate in and advise on the development of a novel therapy in the cardiometabolic space that may be of interest to us in the future without committing significant financial or operational resources. As we've stated in our Vision 2030, external innovation and business development is a key pillar of our growth strategy. Our current R&D pipeline has arisen entirely from internal discovery, and we see a significant opportunity to complement and enhance this foundation through investments, partnering and licensing opportunities. By engaging selectively and prudently in opportunities to balance our own R&D activities by also externalizing innovation, we aim to gain access to additional novel science, expand into adjacent therapeutic areas and ultimately accelerate the development of new therapies for patients. Importantly, we continue to be open to all strategic levers to remain the partner of choice and continue to be both pioneer and leader in muscle biology. Now I'll hand it over to Sung.

Thanks, Isaac. We're pleased to report our first quarter of 2025 financial results. Starting with the balance sheet. We finished the first quarter with approximately $1.1 billion in cash, cash equivalents and investments compared to $1.2 billion at the end of the fourth quarter of 2024. Cash, cash equivalents and investments declined by approximately $132.2 million during the first quarter of 2025. R&D expenses for the first quarter were $99.8 million compared to $81.6 million for the same period in 2024. The increase was primarily due to advancing our clinical trials and higher personnel-related costs. G&A expenses for the first quarter of 2025 were $57.4 million compared to $45.5 million for the same period in 2024. The increase was primarily due to investments in commercial readiness activities and higher personnel-related costs. Net loss for the first quarter of 2025 was $161.4 million or $1.36 per share compared to a net loss of $135.6 million or $1.33 per share for the same period in 2024. Turning to our financial guidance. We are maintaining our full year 2025 financial guidance with GAAP operating expense expected to be between $670 million and $710 million. Stock-based compensation that is included in GAAP operating expense is expected to be between $110 million and $120 million. Excluding stock-based compensation from GAAP operating expense results in a range of $550 million to $600 million. While the guidance range remains unchanged, there are two dynamics that move expenses within the range meaningfully. First, the range incorporates the U.S. PDUFA date extension for aficamten, which we anticipate will drive a decrease in G&A expense, mainly due to the adjusted timing of launch expenses. Second, the range accounts for the acceleration and increased enrollment of ACACIA, our Phase III trial of aficamten in nHCM, which will increase R&D expense. Given the U.S. PDUFA date extension, we will continue to monitor the pace of prelaunch investments and update you accordingly. Our balance sheet continues to be a source of strength, and we are well-positioned to fund the potential launch of aficamten in the U.S. later this year and advance our pipeline. With that, I'll hand it back to Robert.

Thank you, Sung. The first quarter was marked by meaningful progress across our business. Given the uncertainties of the macro market we are operating within, we're pleased to be in an advantaged position with a strong balance sheet and cash position, reflecting thoughtful planning and preparation in 2024 that will allow us to execute on all of our key priorities in 2025. Looking ahead at the next several months, there's a lot in store for our company, most importantly, the potential FDA approval of aficamten at the end of this year and our full transition then to becoming an integrated commercial biopharmaceutical company, but also the near-term top-line readout of MAPLE-HCM. With all of this moving forward, alongside continued conduct of multiple additional later-stage clinical trials as well as our ongoing research, our prospects remain bright as we advance our Vision 2030 based on our pioneering foundation in muscle biology. We're closer than ever to realizing the benefit of our science as may potentially impact the lives of patients living with diseases of muscle dysfunction. And now I'll recap our upcoming milestones. For aficamten, we expect to advance NDA review activities with FDA to support the potential U.S. approval of aficamten in the second half of this year. We expect to advance go-to-market strategies and prepare to commercially launch aficamten in the United States in the second half of this year, subject to approval by the FDA. We expect to continue go-to-market plans in Germany and expand commercial readiness activities in Europe in 2025 in preparation for potential approval by the EMA in the first half of 2026. We expect to coordinate with Sanofi to support the potential approval of aficamten in China, pending approval by the NMDA, and we expect top-line results from MAPLE-HCM this month. We also expect to report top line results from the primary cohort of ACACIA-HCM in the first half of 2026 and begin enrollment of patients in the Japan cohort of ACACIA-HCM in this quarter. And we expect to complete enrollment of the adolescent cohort in CEDAR-HCM in the second half of this year. For omecamtiv mecarbil, we expect to continue patient enrollment in COMET-HF through 2025 to enable completion of enrollment in 2026. For CK-586, we expect to complete enrollment of the first two patient cohorts in AMBER-HFpEF in the second half of this year. And finally, for preclinical development and ongoing research, we expect to continue ongoing preclinical development as well as research activities directed to additional muscle biology-focused programs. Operator, with that said, we can now open the call up to questions, please.

[Operator Instructions] And our first question will come from Sean McCutcheon from Raymond James. Your line is now open.

Good afternoon. Hey guys, thanks for the…Based on the failure of ODYSSEY and the BMS verbiage around obstructive HCM being different from nonobstructive, getting a lot of questions on what that means for ACACIA. Can you speak to how you designed ACACIA around the properties of aficamten to drive higher probability of success and how you view the importance of pushing the CMI dose higher in nonobstructive disease given you were able to get the majority of patients on that 20-milligram dose in the first nonobstructive cohort?

Sure. I'll speak generally and then ask Fady to answer your specific questions. Firstly, as it relates to ACACIA-HCM, we're very excited about the fact that it completed enrollment as it did ahead of schedule and with such enthusiastic participation around the globe. And at the same time, please also understand that for taking the same dosing regimen forward into Phase III and going to centers where we believe there's already ample experience with aficamten, this gives us optimism for what may be ultimately the results from that study. You heard us referring to nHCM, both with regard to REDWOOD Cohort 4 and how it reads, we believe, in an encouraging way on what we should expect testing the same hypothesis in Phase III. So we maintain our very optimistic views towards ACACIA. With that, I'll turn it over to Fady to answer the specific questions.

Yes. I think the points that Robert made are the important ones. When we designed ACACIA, we were able to base it very closely on what we had experienced in the Phase II study, Cohort 4 of REDWOOD-HCM. So the dosing is essentially the same, although we did implement a higher dose in ACACIA. We've seen that dose be very successfully deployed in FOREST. So those nHCM patients have the availability of the 20-milligram dose and some of them are currently taking it. We've seen in the REDWOOD very few treatment interruptions, no discontinuations for intolerance. And those things, I think, are very important, dosing, getting the right dosing regimen is often one of the most critical things in determining the success of a Phase III trial. Secondarily, I think we have, again, confidence in the data that we saw in Phase II with regards to KCCQ and NYHA class improvement. We didn't look at peak VO2 in Phase II, just as we didn't do that for SEQUOIA as well for the oHCM patients. But we expect, again, with improvement in symptoms and functional class to see some improvement in peak VO2, and we're very well powered to see even a modest change in peak VO2. I think the last thing I'll point out is that we stayed with centers where we had a lot of experience, with whom we had vetted very carefully. We have basically a team that reviews every patient enrolled in the trial to ensure that the patients, not only meet the entry criteria, but that their imaging is consistent with what you would expect in HCM. For all those reasons, we're still very optimistic about the chances of success for ACACIA.

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

Great. Hey, Robert, good afternoon. Thanks for the question and all the color today. So I guess I'll just ask the obvious question here on aficamten. I just want to be clear. So did the FDA initially guide you to not submit the REMS? And then what happened? Was it something internal at the FDA? Or was there something in the package that caused them to change their stance, if you want to call it that, and ask you to actually submit the REMS, if you could provide some color around that.

Sure. I understand you want to get more detail. I'll share with you what I can, but please understand, I may be very selective in my language. As you probably know well, when you have these interactions with FDA ahead of an NDA submission, they give you feedback in response to questions. And as you've probably read the summary basis of approval for mavacamten, you know that FDA guided for the submission of a REMS prior to its occurring. In our case, that did not happen. In our case, we did not receive such guidance. In fact, we discussed safety risk mitigation. And based on that discussion, we believed it reasonable to submit as we did without a REMS. It was not an omission. We understood very well the feedback that we were receiving, and we elected to proceed submission without a REMS. It was accepted by FDA without a REMS. And it was during the review itself that FDA notified us that they would like to see us submit a REMS. We can't know all that was going on within FDA that prompted their want to see a REMS. As you know, there's a lot going on around in FDA. But we do know that we were well prepared for that scenario where FDA to then consider during the review that a REMS would be appropriate, and they did. So it was then that we submitted the REMS and as is distinct as we believe consistent with feedback we received with FDA relating to inherent characteristics or intrinsic properties of aficamten. So I think that's going to have to suffice for what we can share. We don't want to communicate things that would be deemed speculation because, frankly, we don't know all that contributed to FDA's ask of us. But I've shared with you what we know and the determination we made based on the feedback we had received.

Our next question will come from Ang Hu from Barclays. Your line is open.

Good afternoon, this is Gena Wang actually. This is Gena Wang from Barclays. So maybe, Rob, just follow your comments. I don't know if you can comment that can you tell us whether the REMS program you submit to the FDA, was that consistent with the one you shared with the investors that the certain protocol, was that consistent when you share -- when you submit that to the FDA? And also, given this unfortunate event, but can you take advantage of it since there is only onetime extension for the PDUFA and FDA cannot extend twice, can you use the MAPLE data and try to submit the MAPLE data and try to be included in the label for the December 26 approval?

So I'll answer the second question first. We do not intend to submit the MAPLE data as part of this review cycle of aficamten in oHCM. That would constitute a different submission that would likely not be well received by FDA given how far along they are in this review. We do intend if positive MAPLE results are obtained later this quarter, we do intend to move swiftly to the enabling of a subsequent submission but that would follow a potential approval of aficamten in oHCM. As it relates to your first question, I just would like some clarification, please. You asked whether the REMS we submitted is consistent with something we shared with investors.

Like the previous communication that will be like, say, the frequency will be week two until week 8. I'm trying to pull out the actual information that you shared in the past with investors. So just wondering, have you -- and then also minimum like the certain monitoring protocol, was that consistent with what you proposed that you think will be differentiating from Camzyos' REMS program?

Yes. Please also understand in the interest of maintaining competitive advantage, we're not going to provide specific information regarding the REMS we did submit, but I will ask Fady to elaborate in a general way about how we're approaching safety and risk mitigation.

Yes. Gena, I think what we submitted is consistent with what we've said all along are the differentiated properties of aficamten. So as we did in FOREST, we amended the protocol to enable every 6 months monitoring to widen the dosing window from every two weeks to every two to 6 or 8 weeks to enable physicians to guide dosing directly. And we've been, I think, straightforward and presented those data recently to the American College of Cardiology, we don't really have any common clinically common drug-drug interactions. And so you can expect all those features would have gone into the design of a REMS program that we think will be distinct and well received by physicians that treat these patients.

Our next question comes from Paul Choi from Goldman Sachs. Your line is open.

Hey, Paul. Good afternoon, everyone. Thanks for taking the question. Robert, earlier, you said aficamten will be differentiated, but maybe just to continue on what Fady was saying, with the recent changes to the Camzyos label, removing the -- some of the drug-drug interaction warnings as well as the extended monitoring, increasing the monitoring period to 6 months. So I guess a lot of investors are just wondering what's sort of left on the table for aficamten to be differentiated here. If you maybe slight any additional points here to help clarify that, that would be helpful.

Sure. Again, in a general way without specifics, please, I will correct the statement you made as it relates to DDIs, and as it relates to echo monitoring, there were modifications made to the existing Camzyos REMS, but still there are limitations as it relates to DDIs. Still, there are limitations as it relates to echo monitoring, certainly during the up-titration phase, but also during the maintenance phase as it pertains to certain patients. So I would answer your question as follows, there remains, we believe, ample opportunity for differentiation based on the REMS that we have submitted.

And our next question will come from Cory Kasimov from Evercore. Your line is open.

Hey, Corey. Hey, Robert. Hey, guys. Thanks for taking the question. My question is, did you submit a REMS as part of your EMA filing? And if not, was that brought up as part of your day 120 list of questions?

So there is no REMS per se as part of an MAA filing with EMA. But obviously, there are ways that one wants to ensure safe use and mitigate risk. I'll turn it over to Fady maybe to elaborate.

Yes, EMEA approaches it differently. They don't have a REMS program per se. They do ask you to submit a risk mitigation program or RMP as a standard part of any submission, which we did. And again, we don't expect any changes, if you will, no additional submissions in Europe relating to that. So very different than the way it's approached in the United States.

But to the point of your question, for now receipt of the day 120 questions and are proceeding to respond, we believe we're well served by what we submitted.

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

Hey, everyone. Afternoon. So a question on the ACACIA trial. Can you talk a bit more about the pros and cons of changing the primary endpoint to a dual primary of peak VO2 in KCCQ? And I was also curious if you could share more details of the current statistical plan for ACACIA, if you're able to share with the dual primary endpoint, that would be really helpful.

Yes. So before I ask Fady to answer, I'll just say, I think as I look at this, this gives us two opportunities to win with ACACIA and building off of what we've seen with aficamten, both in oHCM as well as in REDWOOD Cohort 4 this is encouraging in light of how we proceeded in the design of conduct of ACACIA. And maybe Fady can go into more detail with you.

Yes. When we designed ACACIA, one of the important characteristics was to make it as efficient a trial as possible. We didn't know at the time, nobody really knew at the time how an HCM trial would enroll, how quickly it would enroll. And consequently, the most efficient thing to do is to declare a single primary endpoint and assign all the alpha to it. And your secondary endpoint can be your next most important endpoint. And if the first one is positive, then all the alpha, the 0.05 flows to the second endpoint. That was an approach that was endorsed by FDA. And of course, they -- even if the trials were positive on the first primary endpoint, they wanted to see consistency across multiple endpoints, including exercise performance. And so the design in ACACIA that we originally put forward was really the most efficient at doing that. We're well powered with that 420 patients. Now other regulators just didn't have the same appreciation of that as FDA did. And as we got advice in Europe, we got advice in Japan, they were much more insistent on the imposition of a dual primary endpoint with two components, one being KCCQ and the other being peak VO2. And rather than leaving it to be a review issue, what we also were benefiting of is that towards the end of last year, the enrollment in our trial really began to accelerate, and it became quite feasible for us to enroll more patients and to satisfy regulators around the world by designating a dual primary endpoint without losing any power. They're both powered at 90% and essentially allow us to assess KCCQ and peak VO2 in parallel. And so if we win on both endpoints, then the next secondary endpoint is evaluated at 0.05. If we win on one of the two endpoints, then the secondary endpoint -- the next secondary endpoint, which is NYHA class would be evaluated at 0.025. But again, just to be clear, both endpoints and the secondary endpoints, for that matter, even at 0.025, have more than 90% power based on the increase in enrollment. So we think it puts us in the best possible position to really satisfy regulators around the world when all is said and done. And ultimately, it doesn't change the interpretation of the trial, which requires, I think, or by regulators, which requires both, I think, they want to see both symptoms and exercise performance be consistent. Hopefully, that...

Our next question comes from

Hey, this is actually Akash. So a couple of things. What would you have to show with the FDA in real-world data to potentially get a yearly echo requirement over time? Is that a discussion you've already had with the agency? And then just to be clear, is Cytokinetics confident that a differentiated REMS for aficamten means an educational REMS and not an ETASU one?

Sure. Again, please understand if we won't answer all of the specific questions relating to elements of differentiation within the REMS itself. So your question about the frequency of echo monitoring is the same as how we approach other matters, probably best for us not to address specifically. What I will say is I think it's reasonable for us to be assuming of an ETASU REMS. That's the approach we're taking.

[Operator Instructions] And our next question will come from Charles Duncan from Cantor. Your line is open.

Hello Charles. Good afternoon. Hey Robert. Good afternoon. Thanks for taking the question. Congrats on the progress. I do have what I'll call a multipart question, and that is the same subject. And that is regarding MAPLE-HCM, absolutely respect the strategy with regard to the FDA. But are you thinking about the same type of strategy with regard to submitting MAPLE after the fact for the EMEA as well as in China to the NMPA? And if so, why?

Good question. I'll turn that to Fady, please.

Yes. I think, Charles, the answer really is the same in all jurisdictions that adding MAPLE-HCM to an application applications are already well into review would be quite disruptive. And so we don't plan to do that. We'll plan to submit the following approvals in those jurisdictions.

Our next question comes from Tessa Romero from JPMorgan. Your line is open.

Hello, Tess. Thank you. Thank you. Good afternoon. Did the FDA indicate at any point during these three meetings that you outlined before your NDA was filed that they did not think that a REMS would be necessary? And why didn't you disclose that there was no REMS submitted back when you submitted the NDA? And when exactly did the FDA request the REMS?

So I'll do my best to answer the questions. I prefer not to communicate what the FDA told us, as I think that's for the FDA to communicate. What I can communicate is how we determined, based on FDA feedback, what we should do. That's what we're communicating today. If aficamten is ultimately approved, then I expect in a summary basis of approval, this will all be laid out for you then to understand. But I hope you can appreciate that, for the fact that we continue to have ongoing interactions with the FDA, I don't think it would make sense for us to let this play out in a public way in any such way that the FDA might ultimately be concerned. That's number one. Secondly, you asked when did we received this information. We received it very promptly, around the time that we communicated as we did that we made this decision, and we're getting feedback from the FDA regarding the amendment. So it was recently that we submitted the REMS, and recently the FDA came back to us and said, upon review of the REMS, they believe this constitutes a major amendment. Did I answer your questions?

You did. I'm just curious why a disclosure wasn't made back when you submitted the NDA that there was no REMS that was submitted.

Because that would be unconventional, irregular, and certainly, that would be potentially subtracting from downstream competitive advantage. We didn't think that was information that required disclosure. In fact, instead, because we did not submit a REMS, we were very disciplined about what we were saying that we believe, upon approval, that aficamten would carry a differentiated safety and risk mitigation profile. You'll note that we did not say with REMS or we did not say without REMS. But only upon asking for us to submit a REMS, did we then submit the REMS, and we began communicating now differently, so that we expect the differentiation would be within the REMS.

Our next question comes from Maxwell Skor from Morgan Stanley. Your line is open.

Great. Thank you for taking my question. So I'll probably approach this a little bit differently or try to. But given that the Camzyos REMS was updated recently, you submitted a 120-day safety update from the FOREST trial. I'm just wondering whether the REMS you recently submitted to the FDA potentially differs from what you would have submitted with the initial filing or discussed during your pre-NDA meetings.

This is a very fluid situation. What we might have submitted had we submitted a REMS in 2024 is, upon reflection, speculation that I prefer not to go there. What I will say is that we have been monitoring quite closely not only our conversations with the FDA, but also how the FDA approached the modification of the REMS program for Camzyos. And we believe we've submitted a REMS that would be enabling of a differentiated, distinct profile.

Our next question comes from Leonid Timashev from RBC. Your line is open.

Hey, thanks for taking my question. I forgot to give you guys a break from the REMS discussion. I was just curious on nHCM. Obviously, with only one drug potentially going to be approved in the near term, yours, I guess, how are you thinking about what that means for potential uptake of aficamten in nHCM if it's approved? I mean, would you expect more patient warehousing and therefore, more rapid launch? Or would you have preferred someone building out that market? And then I guess on EU versus U.S., and you've talked about 50% of patients ultimately coming from nHCM. Is that dynamic just for the U.S. or both internationally as well?

Good questions. I'm going to turn to Andrew Callos to answer those, please.

Sure. So, from an nHCM point of view, the diagnosis rate is increasing pretty dramatically. I think when you do market development for HCM, it's not restricted to obstructive HCM. It's really broader for the disease. So when we look at uptake for nHCM, I would expect that nHCM uptake would be faster than oHCM because of all the market development work, because of physician utilization of CMIs, as well as expansion beyond the current prescribing base. So we're already thinking with MAPLE with the properties of aficamten, that we have the ability to expand beyond the centers of excellence. I think that would get accelerated with MAPLE and further accelerated with ACACIA, and there'll likely be a halo effect, if you will, in terms of utilization across both obstructive and nonobstructive if both MAPLE and ACACIA are positive as well.

And our next question will come from David Lebowitz from Citi. Your line is open.

Thank you very much for taking my question. Could you characterize the nature of the market opportunity presented by MAPLE, given that while beta blockers might not necessarily be the most effective, they are cheap and they're prescribed by a wider array of doctors?

We've been consistent that we do believe that if MAPLE were positive and ultimately, that's reflected in guidelines, that this would be incremental, but not transformative to what we believe ultimately could be the adoption curve for aficamten and could be enabling of more category penetration, especially amongst cardiologists who may be very comfortable with beta blockers. But you're absolutely right. They are inexpensive. And as payers go, they may likely want to see the guidelines be modified, reflecting of the use of a CMI for patients as first-line therapy. Andrew has done some market research here, and he may have more to add.

Yes. I would only say that, and this is Robert said, that when you have a second data set that, assuming it's positive, MAPL positive, a second data set that confirms efficacy that confirms safety, that as the guidelines generally will increase penetration within use of CMI. So, simply said that more physicians with more patients will use a CMI than would without MAPLE, and then there's an increased share potential for aficamten as well. So you really get all those things collectively when you have a second data set around the same disease area. And I do think from our research, it's going to enable broader penetration into the community cardiology.

If the results are positive, and we hope they are, then we can do further market research around that particular profile, and that may inform how we may communicate down the road. But I think at this point in time, that's the way we see things.

Our next question will come from Mayank Mamtani from B. Riley Securities. Your line is now open.

Good afternoon. Thanks for taking our questions. Two quick process questions really. Could you touch on your confidence level in this newly submitted REMS to be accepted as is? And what sort of communication we can receive from you in this follow-up to the June late-cycle meeting that is coming up? And just high level, like do you sense independent physician feedback, say, in form of an Adcom is something that could be valuable here for the agency and the community, particularly since you'd have the MAPLE-HCM data by then to talk to that clear API differentiation?

I believe that was three questions, and I'm going to try to remember now the first one. I think you asked me if I thought that the REMS as submitted would be accepted as submitted. And these things are never exactly as they are submitted. There's always a back and forth. We do believe it's for that reason that FDA chose to make the submission a major amendment, but we believe there's ample time to address those matters within now the extended time. I know your third question related to the Adcom. And because the FDA communicated they don't expect an Adcom, we're not expecting an Adcom. And I don't believe that, that could change based on anything that we're having conversation about today. So you were suggesting that maybe an Adcom could be to our advantage, if I heard you correctly. I don't think that's practical at this point.

I mean you'd have some more data to be shared in a public forum about the drug's profile, especially the treatment initiation phase with the echo monitoring. So, can the agency benefit from having that independent physician feedback in a forum like what's the thought?

As we've stated before, the choice to have an Adcom or not rarely, if ever, I believe, pivots around things that are included in a REMS. They don't typically have expertise amongst advisers who populate an Adcom pertaining to REMS, as they look at risk mitigation at FDA. So that would be, I think, a quite irregular type of Adcom. So I don't foresee that something that investors or analysts should be thinking about. I believe your second question pertained to what was it, Andrew?

Late cycle meeting.

And based on communications we've received from FDA, we're expecting that to occur in this second quarter in June.

[Operator Instructions]. And our next question will come from Kripa Devarakonda from Truist. Your line is open.

Hey guys, thank you so much for taking my question, Robert, sorry to belabor the REMS point, but I just want to make sure I understood it correctly. You said you did not receive any guidance from FDA to submit REMS, whereas mavacamten, they did receive guidance. But you also said that during these meetings, the three meetings that you talked about, they give feedback in response to questions. So, based on what you're saying, is it fair to assume that you asked the FDA if you should submit the REMS? And then, based on the feedback, you concluded that it was fair not to submit the REMS program.

I think that's correct.

Our next question will come from James Condulis from Stifel. Your line is open.

Thanks for sneaking me in. And sorry for one more question on the REMS here. And so it sounds like ask from the FDA kind of came after the mid-cycle review. I guess, is that right? I'm just wondering if there's any color on sort of that mid-cycle review that you can give in terms of discussion around the need for the REMS or lack of that? And just kind of curious if there's any color you can provide.

I think we provided the color that we can provide. And as you know, we did issue an 8-K after the mid-cycle review meeting. We did indicate that we submitted a REMS, and we got the feedback upon receipt that it constitutes a major amendment. I'm thinking that's all that we can communicate at this time. I hope that's good enough. It seems we may be over-indexing a little bit about this matter now. But I do think that we're going to try to stay within consistent language around which we have now made these disclosures.

Our next question comes from Jason

I apologize, I do want to return to the REMS. Just given everything that's happened, I know you are reluctant to discuss what FDA has said, but focusing in on the Cytokinetics side of things, given that the REMS has been such a focal point and it was a big matter in mavacamten's review, why not just include the REMS initially and then work around it? It seems like this was a risk hindsight being 2020 that was sort of always out there.

I would agree with you that it was a risk that was out there. It was a calculated one, and we made a determination based on multiple meetings with FDA. Please understand that we not only have within Cytokinetics, substantial expertise as it relates to such matters, but also we convened with consultants, including ex-FDA officials on this matter. And collectively, we all together concluded that the way we approached the submission without a REMS was reasonable. And we addressed feedback we received as pertains to labeling and risk mitigation absent including a REMS in that submission. The NDA was accepted for filing without a REMS. And as we knew was a possibility during FDA's review, FDA did come back and ask for REMS. So we believed then that we were doing the right thing to be enabling of aficamten as could be differentiated and distinct in its positioning, but for addressing safety and risk mitigation within labeling. FDA has come back and now is asking for a REMS. That's reasonable. FDA, upon its review has determined a REMS is appropriate given the mechanism. But forward, we believe FDA has also communicated that a REMS distinct to the intrinsic pharmaceutics and inherent characteristics of aficamten is appropriate. So we've submitted such a REMS. I don't know that there's much more that we can say. I hope that answers your question.

Our next question comes from Leland Gershell from Oppenheimer, your line is open.

Thanks very much. I'm actually going to ask a non-REMS question. Robert, I just want to ask in terms of any real-world studies that you may be performing after presumptive aficamten approval of the 24-week SEQUOIA data, will you be looking to collect real-world data that may further flesh out or delineate the benefit to septal reduction surgery for patients who are treated?

So the FOREST study continues to enroll, and the conduct of that study continues to support what we believe to be a distinct profile for aficamten. You'll see more of that data this year. And while this wasn't a specific question of yours, I do believe this data is supportive of how we foresee aficamten as could be enabling of us to continue to maintain a distinct profile. Maybe I'll turn to Fady. I think you asked a specific question about septal reduction.

Yes, that's right.

Yes. Well, as you know, in SEQUOIA, we conducted an analysis of patients qualified for septal reduction therapy and showed essentially treatment with aficamten reduces that need by 90% or 90% of patients were no longer eligible for it. That we've seen, again, as those patients roll in the FOREST, same sort of dynamics and what we anticipate as we look at now much longer-term experience in FOREST, even with patients that didn't qualify to start is to get a sense of the natural history of that. You would expect some of those patients would have gone on to begin to qualify their conditions would have worsened. And we can begin to compare those FOREST data to real-world registries and look at the progression of event rates in FOREST versus the progression of event rates perhaps elsewhere, I think what we'll see is that aficamten potentially slowing those rates in the long run, and that will add to the conviction that aficamten is a cardiac myosin inhibitor is a disease-modifying mechanism.

Our next question comes from Jason Butler from Citizens JMP. Your line is open.

Hi, thanks for taking the question. Just wanted to switch gears here at the end and ask a question about CK-586 in the AMBER study. Just I guess, two parts. One, can you give us color on how you plan to disclose data from the first two cohorts. But I guess more importantly, how should we think about these first two doses in terms of being effective doses or when we would expect to see something that's optimally effective out of the study?

Jason. I'll turn to Fady and also to Stuart to answer that question, please.

Yes. I'll let Stuart answer most of this. But just remember, this is a Phase II study. The objectives are really to find dose and to begin to get some sense of effectiveness. And Stuart, maybe you can take it from there.

Jason. Thanks for the questions. First of all, you wouldn't expect that we would disclose the results of the first two cohorts independently of having the results of the final study. So we'll look at the totality of the data and then disclose the results. In response to your second question, as Fady alluded to, this is a dose-finding study and a dose titration strategy study in a population with a lot of comorbidities, this is an older population than the nonobstructive HCM patients we're studying in ACACIA. And so we're taking a very careful systematic approach as you would with many dose-finding studies starting with lower doses and titrating up based on what we observed in terms of the pharmacodynamic effect, effects on ejection fraction, safety and tolerability. And with this sort of systematic and safe approach, then we will essentially characterize what is the appropriate dose to take forward in terms of the benefit risk profile.

And our next question will come from Serge Belanger from Needham & Co. Your line is open.

Hi, this is John for Serge. Thanks for taking my question. Just want to underscore the expectations now between both the U.S. and EU with the amendment to ACACIA. Are regulators aligned on what would be considered approvable based on which, if not both endpoints, the trial needs to satisfy? Or is there any disparity on whether KCCQ or pVO2 are looked at in a different light between the two agencies?

I believe that as Fady can elaborate, we've harmonized feedback we received from regulatory agencies, but I'll ask him to comment.

Yes. I think, again, when you don't have a hard endpoint like mortality or hospitalization, regulators on both sides of the Atlantic are looking for consistency across feel and function. And it does no good to improve someone's exercise capacity in peak VO2 if they have no perceptive, they don't perceive any benefit from it and vice versa, people are perceiving benefit, you'd like to understand that, that's because they are receiving some direct benefit from the drug and not something else that might be off target or what have you. So the endpoints need to be consistent. Both sides of Atlantic I think agree in that. The way we approached it is, frankly, we provide that information to both sets of regulators. But I think each of them have a different concept of how to approach that by designating certain endpoints and by upsizing the trial and harmonizing the primary endpoints to include both components, we were able really to satisfy everybody. And ultimately, I think they'll use very similar interpretations of the data at the end of the day.

Our next question comes from Yasmeen Rahimi from Piper Sandler. Your line is open.

Good afternoon, team. Thanks for the updates. I guess what we're trying to figure out is like with all these different varieties of questions around the REMS, is it just a procedural mishap that it wasn't -- they should have asked you to submit it and they didn't and you guys didn't submit it, you wanted to follow with their instruction. Or is there more to read into it? Like I think that's what it comes down to. Like is it just a procedural mishap and now it's in place, it's fine? Or is there more to make sense out of this them coming back and asking. So really, I'm struggling to figure that part out. I understand the sequence of events that occurred, and I think all your remarks were very, very helpful. maybe help us understand which one it is because the stock is trading in a way that makes it thing it's not just procedural, there's more to it. So it would be wonderful if you could comment to the extent you can.

I hear you struggling, and I'll try to address this in a constructive way. But please understand there was no mishap. I read what is causing some consternation amongst certain investors. And please understand we don't believe at all that there was anything to suggest an irregularity to it. This is part of a process by which a sponsor communicates with the FDA, you get feedback. Based on that feedback, you take an action. The FDA is within its reason to be able to make a certain additional request. There's nothing here that would suggest anything new, we believe, in terms of risk and safety. But instead of having this addressed through label, now it's being addressed through a more formal REMS. But the distinction, the differentiation, those things that we believed coming into the submission when the submission was accepted for filing and even now through the review, those things all speak to the same profile of aficamten that has been emerging through its clinical study. There's nothing that FDA has communicated to us to suggest otherwise. We do believe that the REMS program is a form of management of risk that now makes it more structured, but it's still fundamentally as we have been communicating. So I hope that helps address some of the questions and concerns, but you used the word mishap. I would not at all suggest that that's what occurred here.

Our next question will come from Ash Verma from UBS. Your line is open.

This is Natalie on for Ash. So I'm going to switch gears a little bit, and I actually have a question related to Edgewise. And in particular, we want to understand how you view their recent clinical data. And to get even more specific, we're really looking at the numbers here, and we were wondering if the ejection fraction measurements were done at peak like you've done in your program as opposed to doing them at trough, how much of a difference do you think that would have made to their measurements? And just do you have any other broad comments on that data that they put out? Thank you.

Yes. So we did note the data that Edgewise presented, and it's not for us to make comparative statements about aficamten versus an investigational drug that's in its early Phase II. But specifically, you asked about measurement of effect on EF. And as you point out, we have been measuring EF changes in our studies when we believe the drug is having its more maximal effect and that Cmax exposures. I'll ask Fady to address what could be a delta between peak and trough. But as I trust you understand that's determined by each individual drug.

Yes. I mean I think for aficamten, the change in ejection fraction on average is only about 4%. What transpires between peak and trough is maybe one or two points. It's hard to speculate. We didn't make any measurements at those points in time. There's a lot of things that affect ejection fraction, including time of day and diurnal variation, hydration and so forth. So it's very difficult to say exactly what the magnitude would be other than it would have been less. And similarly, I would expect if you measured a drug effect at peak, any drug, edgewise drug or otherwise, if there is a relationship, you would see a bit more of an effect. And that goes for other measurements of efficacy as well. So I think that's about as far as I can really say. I can't really make any comparisons there.

And I am showing no further questions from our phone lines. I'd now like to turn the conference back over to Robert Blum for any concluding remarks.

I want to thank everybody for your participation in this call. I hope you've got clarification to the questions that you were pondering coming into this call. Obviously, we addressed a lot of topics, including a conversation about REMS. And I hope that you can feel comfortable that we took appropriate steps, but for things continue to evolve, and that's fair and reasonable, and we're prepared given that we had a contingency plan that we executed on. With that said, we remain confident in the potential approval of aficamten and upon its potential approval with a label and a REMS program that would provide distinct positioning for aficamten and as could be enabling of us to execute on the commercial readiness program, albeit three months delayed perhaps, but one that we have been aiming forward towards for quite some time. We're optimistic about how that will be received, and we're encouraged by the reception we're getting for candidates for our open commercial positions. And at the same time, we point you to upcoming data from MAPLE and we're excited also about ACACIA, omecamtiv and CK-586. So lots of good things happening in and around Cytokinetics. We look forward to providing you further updates when appropriate. We thank you for your interest in this call. And operator, with that, we can now conclude.