Cytokinetics - Earnings Call - Q1 2025

Transcript

Operator (participant)

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 that 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.

Diane Weiser (Senior VP of Corporate Affairs)

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 the clinical development program for aficamten. Stuart Kupfer, SVP and Chief Medical Officer, will provide updates on the clinical development of omecamtiv mecarbil and CK-586. Isaac Ciechanover, EVP, Corporate Development and Chief Business Officer, will provide an 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. Finally, Robert will review our 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. I will turn the call over to Robert.

Robert Blum (President and CEO)

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 treatment of patients with oHCM to December 26, 2025, to provide additional time to conduct a full review of our proposed REMS. To be clear, we had a series of three meetings with the 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 the FDA. As we've 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 the 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 labeling and other tools such as voluntary education materials. However, we understood from the 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 REMS specific to its intrinsic properties, which we promptly provided.

As we communicated last week, we recently learned from the FDA that our subsequent submission of the revs 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 the 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 the FDA, will differentiate aficamten. Nothing has changed in that regard. Again, to confirm, no additional clinical data or studies were requested by the FDA. As we disclosed in an 8-K filing in March, during the first quarter, we completed a mid-cycle review with the FDA. During the meeting, the 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 pharmacokinetic 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 the FDA. Moving on, during the first quarter and recently, we also advanced regulatory activities outside of the U.S. 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 the 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. 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 U.S. 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. 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. With that, I'll turn the call over to Andrew, please.

Andrew Callos (EVP and Chief Commercial Officer)

Thanks, Robert. In the first quarter, we continue to execute our commercial readiness planning and implementation. With the three-month extension to our PDUFA date, certain work streams will be adjusted, but we're not losing our sense of urgency or launch readiness momentum. This year has been focused on building, implementing, and executing our go-to-market plan, 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 the current recruiting schedule, which is off to a great start. To date, we received several thousand applications, many from highly qualified sales 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 a high level of interest in 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 the 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, HCP advisory boards, as well as primary market research testing. At the same time, our unbranded disease awareness campaign, HCM Beyond the Heart, continued.

The HCP-focused awareness campaign directs HCPs to consider the broader HCM burden and practice whole-person care. Likewise, the patient 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 for 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. 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 will 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.

Fady Malik (EVP of R&D)

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 do not 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 at HCM, their impact on exercise performance, symptoms, and LVOT Gradients for 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 the head-to-head comparison in MAPLE-HCM, as it may help differentiate the effects 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 six 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 its DART 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 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, pVO2, each measured as a change from baseline in 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 five points. For pVO2, 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 four of the phase II trial, REDWOOD-HCM, we evaluated treatment with aficamten in nNHCM 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 mg, 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 the phase II experience by using the same dosing approach with rapid attainment of target dose within eight weeks, refinement 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.

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 updates 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 trials 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.

Stuart Kupfer (SVP and Chief Medical Officer)

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 2 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 re-hospitalization rate that also drives up healthcare 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 enrolling COMET-HF, the confirmatory phase III clinical trial of omecamtiv mecarbil in patients with symptomatic heart failure with severely reduced ejection fraction of less than 30%. We maintain 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 their 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.

Isaac Ciechanover (EVP of Corporate Development and Chief Business Officer)

Thanks, Stuart. In the first quarter, we participated in a Series B financing of Embryo Pharmaceuticals to support the advancement of Ninoraf Foxstat 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.

Sung Lee (EVP and CFO)

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-$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 trials 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 pre-launch 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.

Robert Blum (President and CEO)

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 MABLE-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. 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 NMPA, 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. 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. 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 (participant)

Thank you. As a reminder, to ask a question, please press star 11 on your telephone and wait for your name to be announced. To withdraw your question, please press star 11 again. In the interest of time, we do ask that you kindly limit yourself to one question at this time. Please stand by while we compile our Q&A roster. Our first question will come from Sean McCutcheon from Raymond James. Your line is now open.

Sean McCutcheon (VP of Biotechnology)

Good afternoon.

Hey, guys. Thanks for the—Hi, Robert. Thanks for the question. You know, based on the failure of Odyssey and the BMS verbiage around obstructive HCM being different from non-obstructive, 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 non-obstructive disease given you were able to get the majority of patients on that 20 mg dose in the first non-obstructive cohort? Thanks.

Robert Blum (President and CEO)

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. 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 four and how it leads, we believe, in an encouraging way on what we should expect testing the same hypothesis in phase III. We maintain our very optimistic views towards ACACIA. With that, I'll turn it over to Fady to answer the specific questions.

Fady Malik (EVP of R&D)

Yeah, 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 phase II study, cohort four 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-HCM. 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 dose, 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 did not look at pVO2 in phase II just as we did not do that for SEQUOIA as well for the oHCM patients. We expect, again, with improvement in symptoms and functional class, to see some improvement in pVO2. We are very well-powered to see even a modest change in pVO2. I think the last thing I will 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 nHCM.

For all those reasons, we're still very optimistic about the chances of success for ACACIA-HCM.

Robert Blum (President and CEO)

Thank you.

Sean McCutcheon (VP of Biotechnology)

Thank you.

Operator (participant)

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

Salim Syed (Managing Director and Senior Biotechnology Analyst)

Hey, Robert. Good afternoon. Thanks for the question and all the color today. I guess I'll just ask the obvious question here on aficamten. I just want to be clear. Did the FDA initially guide you to not submit the REMS? 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. Thank you.

Robert Blum (President and CEO)

Sure. I understand your 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. As you've probably read the summary basis of approval for mavacamten, and 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. 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 and in FDA. 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. They did. It was then that we submitted the REMS. As is distinct, as we believe consistent with feedback we received with FDA relating to inherent characteristics or intrinsic properties of aficamten. I think that's going to have to suffice for what we can share.

We do not want to communicate things that would be deemed speculation because, frankly, we do not know all that contributed to FDA's ask of us. I have shared with you what we know and the determination we made based on the feedback we had received.

Salim Syed (Managing Director and Senior Biotechnology Analyst)

Okay. Helpful. Thank you very much.

Robert Blum (President and CEO)

Thank you.

Operator (participant)

Thank you. Our next question will come from Hang Hu from Barclays. Your line is open.

Gina Wen (Biotech Analyst)

Good afternoon.

This is Gina Wen, actually. This is Gina Wen from Barclays. Maybe, Rob, just following your comments, I do not know if you can comment, but can you tell us whether the REMS program you submitted to the FDA, was that consistent with the one you shared with the investors, that certain protocol, was that consistent when you shared, when you submitted that to the FDA? Also, given this unfortunate event, can you take advantage of it since there is only a one-time 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?

Robert Blum (President and CEO)

I'll answer the second question first. We do not intend to submit the MAPLE data as part of this review cycle of AFI Campus 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, to move swiftly to the enabling of a subsequent submission that would follow a potential approval of AFI Campus 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. We have not.

Gina Wen (Biotech Analyst)

Right. Or like the previous communication that will be like, say, the frequency will be week two until week eight. I'm trying to pull out the actual information that you shared in the past with investors. Just wondering, have you and then also minimal, like the certain monitoring protocol, was that consistent with what you proposed that you think it will be differentiating from CAMZYOS's REMS program?

Robert Blum (President and CEO)

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. I will ask Fady to elaborate in a general way about how we're approaching safety and risk mitigation.

Fady Malik (EVP of R&D)

Yeah. Hi, Gina. I think what we submitted is consistent with what we've said all along are the differentiated properties of aficamten. As we did in FOREST-HCM, we amended the protocol to enable every six-month monitoring to widen the dosing window from every two weeks to every two to six or eight weeks to enable physicians to guide dosing directly. We've been, I think, straightforward and presented those data recently to American College of Cardiology. We don't really have any clinically common drug-drug interactions. 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.

Gina Wen (Biotech Analyst)

Thank you.

Robert Blum (President and CEO)

Thank you.

Fady Malik (EVP of R&D)

Thank you.

Operator (participant)

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

Robert Blum (President and CEO)

Hey, Paul.

Paul Choi (Biotechnology Analyst)

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 label, removing some of the drug-drug interaction warnings as well as the extended monitoring, increasing the monitoring period to six months. 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 slide any additional points here to help clarify that, that would be helpful. Thanks for taking our question.

Robert Blum (President and CEO)

Sure. Again, in a general way, without specifics, please, I will correct a 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. I would answer your question as follows. There remains, we believe, ample opportunity for differentiation based on the REMS that we have submitted.

Operator (participant)

Thank you. Our next question will come from Cory Kasimov from Evercore. Your line is open.

Robert Blum (President and CEO)

Hey, Cory.

Cory Kasimov (Senior Managing Director)

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

Robert Blum (President and CEO)

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.

Fady Malik (EVP of R&D)

Yeah. EMA approaches it differently. They do not 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. Again, we do not expect any changes, if you will, no additional submissions in Europe relating to that. Very different than the way it is approached in the United States.

Robert Blum (President and CEO)

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.

Operator (participant)

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

Roanna Ruiz (Senior Research Analyst)

Hey, everyone. Afternoon. A question on the ACACIA trial. Could you talk a bit more about the pros and cons of changing the primary endpoint to a dual primary of peak VO2 and KCCQ? 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.

Robert Blum (President and CEO)

Yeah. 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. 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 and conduct of ACACIA. Maybe Fady can go into more detail with you.

Fady Malik (EVP of R&D)

Yeah. When we designed ACACIA, one of the important characteristics was to make it as efficient a trial as possible. We did not know at the time, nobody really knew at the time how an nHCM trial would enroll, how quickly it would enroll. Consequently, the most efficient thing to do is to declare a single primary endpoint and assign all the alpha to it. Your secondary endpoint can be your next most important endpoint. 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. Of course, even if the trial were positive on the first primary endpoint, they wanted to see consistency across multiple endpoints, including exercise performance. 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. Other regulators just didn't have the same appreciation of that as FDA did. As we got advice in Europe, as 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. Rather than leaving it to be a review issue, what we also were benefiting of is that towards the end of last year, enrollment in our trial really began to accelerate. 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.

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. 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. We think it puts us in the best possible position to really satisfy regulators around the world when all is said and done. Ultimately, it does not change the interpretation of the trial, which requires, I think, by regulators, which requires both. I think they want to see both symptoms and exercise performance be consistent. Hopefully, that's.

Roanna Ruiz (Senior Research Analyst)

Got it. Yep. Helpful. Thank you.

Robert Blum (President and CEO)

Thank you.

Operator (participant)

Thank you. Our next question comes from Zaki Molvi from Jefferies. Your line is open.

Akash Tewari (Global Head of Biopharmaceutical Research)

Hey, this is actually Akash. 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? Just to be clear, is Cytokinetics confident that a differentiated REMS for aficamten means an educational REMS and not an OTATSU one? Thanks so much.

Robert Blum (President and CEO)

Sure. Again, please understand that we won't answer all of the specific questions relating to elements of differentiation within the REMS itself. Your question about 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 OTATSU REMS. That's the approach we're taking.

Akash Tewari (Global Head of Biopharmaceutical Research)

Thanks.

Operator (participant)

Thank you. In the interest of time, we do ask that you please limit yourself to one question. Our next question will come from Charles Duncan from Cancer. Your line is open.

Robert Blum (President and CEO)

Hello, Charles.

Charles Duncan (Managing Director)

Good afternoon. Hey, Robert. Good afternoon. Thanks for taking the question and congrats on the progress. I do have what I'll call a multi-part question, and that is the same subject. That is regarding MAP-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 EMA as well as in China to the NMPA? If so, why?

Robert Blum (President and CEO)

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

Fady Malik (EVP of R&D)

Yeah. I think, Charles, the answer really is the same in all jurisdictions, that adding MAPLE-HCM to an application that applications are already well into review would be quite disruptive. We do not plan to do that. We will plan to submit that following approvals in those jurisdictions.

Charles Duncan (Managing Director)

Okay. Looking forward to that data.

Robert Blum (President and CEO)

Thanks, Charles.

Operator (participant)

Thank you. Our next question comes from Tess Romero from JP Morgan. Your line is open.

Robert Blum (President and CEO)

Hello, Tess.

Tessa Romero (Biotechnology Equity Analyst)

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? Why did you not disclose that there was no REMS submitted back when you submitted the NDA? When exactly did the FDA request the REMS? Thanks.

Robert Blum (President and CEO)

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 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. I hope you can appreciate that for the fact that we continue to have ongoing interactions with 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 FDA might ultimately be concerned. That's number one. Secondly, you asked when did we receive this information?

We received it very promptly around the time that we communicated as we did that we made this decision and were getting feedback from FDA regarding the amendment. It was recently that we submitted the REMS and recently that FDA came back to us and said upon review of the REMS, they believe this constitutes a major amendment. Did I answer your questions?

Tessa Romero (Biotechnology Equity Analyst)

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.

Robert Blum (President and CEO)

Oh, because that would be unconventional, irregular, and certainly that would be potentially subtracting from downstream competitive advantage. We did not 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 believed 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. Only upon asking for us to submit a REMS did we then submit the REMS, and we began communicating now differently that we expect the differentiation would be within the REMS.

Tessa Romero (Biotechnology Equity Analyst)

Thank you.

Robert Blum (President and CEO)

Thank you.

Operator (participant)

Thank you. Our next question comes from Maxwell Score from Morgan Stanley. Your line is open.

Maxwell Skor (VP of Biotech Equity Research)

Great. Thank you for taking my question. I'll probably approach this a little bit differently or try to. Given that the CAMZYOS REMS was updated recently, you submitted a 120-day safety update from the FOREST-HCM 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. Thank you.

Robert Blum (President and CEO)

Yeah. 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 FDA, but also how the FDA approached the modification of the REMS program for CAMZYOS. We believe we've submitted a REMS that would be enabling of a differentiated distinct profile.

Maxwell Skor (VP of Biotech Equity Research)

Great. Thank you.

Robert Blum (President and CEO)

Thank you.

Operator (participant)

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

Leonid Timashev (Biotechnology Analyst)

Hey. Thanks for taking my question. I figured I'd give you guys a break from the REMS discussion. I'm 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? I guess on E.U. versus U.S, I mean, you've talked about 50% of patients ultimately coming from nHCM. Is that dynamic just for the U.S. or both internationally as well? Thanks.

Robert Blum (President and CEO)

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

Andrew Callos (EVP and Chief Commercial Officer)

Sure. 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. 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. 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 There would likely be a halo effect, if you will, in terms of utilization across both obstructive and non-obstructive if both Mle and ACACIA are positive as well.

Operator (participant)

Thank you. Our next question will come from David Lebowitz from Citi. Your line is open.

Robert Blum (President and CEO)

Hello, David.

David Lebowitz (Senior Research Analyst of Biotechnology)

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

Robert Blum (President and CEO)

Yeah. 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. You're absolutely right. They are inexpensive. 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's done some market research here, and he may have more to add.

Andrew Callos (EVP and Chief Commercial Officer)

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

David Lebowitz (Senior Research Analyst of Biotechnology)

Got it. Thank you for taking my question.

Robert Blum (President and CEO)

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

David Lebowitz (Senior Research Analyst of Biotechnology)

Thank you.

Operator (participant)

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

Mayank Mamtani (Senior Managing Director, Group Head of Healthcare Research, and Senior Biotechnology Analyst)

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? What sort of communication can we receive from you in this follow-up to the June late-cycle meeting that is coming up? Just high-level, do you sense independent physician feedback, say, in form of an adcom, as 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 AFI differentiation?

Robert Blum (President and CEO)

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. 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. We believe there's ample time to address those matters within now the extended time. I know your third question related to the AdCom. Because the FDA communicated they don't expect an adcom, we're not expecting an adcom. I don't believe that that could change based on anything that we're having conversation about today. 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.

Mayank Mamtani (Senior Managing Director, Group Head of Healthcare Research, and Senior Biotechnology Analyst)

Yeah. 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. I don't know, can the agency benefit from having that independent physician feedback in a forum like that? What's the thought?

Robert Blum (President and CEO)

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 do not typically have expertise amongst advisors who populate an adcom pertaining to REMS as they look at risk mitigation at FDA. That would be, I think, a quite irregular type of adcom. I do not foresee that is something that investors or analysts should be thinking about. I believe your second question pertained to, what was it, Andrew? Late-cycle meeting. Based on communications we have received from FDA, we are expecting that to occur in this second quarter in June.

Mayank Mamtani (Senior Managing Director, Group Head of Healthcare Research, and Senior Biotechnology Analyst)

Thank you, Robert. Very helpful.

Robert Blum (President and CEO)

Thank you.

Operator (participant)

Thank you. As a reminder, we do ask that you please limit yourself to one question. Our next question will come from Kripa Devarakonda from Truist. Your line is open.

Kripa Devarakonda (VP of Biotechnology Equity Research)

Hi, guys. Thank you so much for taking my question. Robert, sorry to belabor the REMS point, but 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. You also said that during these meetings, the three meetings that you talked about, they give feedback in response to questions. Based on what you're saying, is it fair to assume that you asked the FDA if you should submit the REMS? Based on the feedback, you concluded that it was fair not to submit the REMS program.

Robert Blum (President and CEO)

I think that's correct.

Kripa Devarakonda (VP of Biotechnology Equity Research)

Okay. Thank you. I'll stick to one question.

Robert Blum (President and CEO)

Thank you.

Operator (participant)

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

James Condulis (VP of Biotechnology Equity Research)

Thanks for sneaking me in. Sorry for one more question on the REMS here. It sounds like the ask from the FDA kind of came after the mid-cycle review. I guess, is that right? 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. Thanks.

Robert Blum (President and CEO)

Yeah. I think we've provided the color that we can provide. As you know, we did issue an 8K 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. I do think that we're going to try to stay within consistent language around which we have now made these disclosures.

James Condulis (VP of Biotechnology Equity Research)

All makes sense. Thank you.

Robert Blum (President and CEO)

Thank you.

Operator (participant)

Thank you. Our next question comes from Jason Zemansky from Bank of America. Your line is open.

Jason Zemansky (VP of Equity Research, Biotechnology, and Pharmaceuticals)

Good afternoon. Congrats on the quarter, and appreciate you squeezing us in. 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.

Robert Blum (President and CEO)

I would agree with you that it was a risk that was out there. It was a calculated one. 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. Collectively, we all together concluded that the way we approached the submission without a REMS was reasonable. 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. As we knew was a possibility during FDA's review, FDA did come back and ask for a REMS.

We believed then that we were doing the right thing to be enabling of AFI Campus 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. We believe FDA has also communicated that a REMS distinct to the intrinsic pharmaceutics and inherent characteristics of AFI Campus is appropriate. We have submitted such a REMS. I don't know that there's much more that we can say. I hope that answers your question.

Jason Zemansky (VP of Equity Research, Biotechnology, and Pharmaceuticals)

It does. I appreciate the color.

Robert Blum (President and CEO)

Thank you.

Operator (participant)

Thank you. Our next question comes from Leland Gershell from Oppenheimer. Your line is open.

Leland Gershell (Managing Director and Senior Analyst)

Thanks very much. Actually, going to ask a non-REMS question. Robert, just wanted to ask in terms of any real-world studies that you may be performing after presumptive aficamten approval of the 24-week SEQUOIA-HCM 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? Thank you.

Robert Blum (President and CEO)

Yes. The FOREST study continues to enroll. 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. While this was not 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.

Leland Gershell (Managing Director and Senior Analyst)

Yes, that's right.

Robert Blum (President and CEO)

Yeah. 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 the patients were no longer eligible for it. That we've seen again as those patients roll into FOREST, same sort of dynamics. What we anticipate as we look at now a much longer-term experience in FOREST, even with patients that did not 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. We can begin to compare those FOREST data to real-world registries. We will get the progression of event rates in FOREST versus the progression of event rates perhaps elsewhere.

I think what we'll see is that aficamten is potentially slowing those rates in the long run. That will add to the conviction that aficamten is a cardiac myosin inhibitor, a disease-modifying mechanism.

Stuart Kupfer (SVP and Chief Medical Officer)

Great. Thank you very much.

Robert Blum (President and CEO)

Thanks.

Operator (participant)

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

Jason Butler (Managing Director of Biotechnology Equity Research)

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-HFpEF study. Just, I guess, two parts. One, can you give us color on how you plan to disclose data from the first two cohorts? 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?

Robert Blum (President and CEO)

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

Fady Malik (EVP of R&D)

Yeah. I think just I'll let Stuart answer most of this. Just remember, this is a phase II study. Its objectives are really to find dose and to begin to get some sense of effectiveness. Stuart, maybe you can take it from there.

Stuart Kupfer (SVP and Chief Medical Officer)

Thanks, 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. We will 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 non-obstructive HCM patients we are studying in ACACIA. We are 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 observe in terms of the pharmacodynamic effect, effects on ejection fraction, safety, and tolerability.

With this sort of systematic and safe approach, we will essentially characterize what is the appropriate dose to take forward in terms of the benefit-risk profile.

Operator (participant)

Thank you. 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 E.U. 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? Is there any disparity on whether KCCQ or pVO2 are looked at in a different light between the two agencies? Thanks.

Robert Blum (President and CEO)

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

Fady Malik (EVP of R&D)

Yeah. I think, again, when you do not have a hard endpoint like mortality or hospitalization, regulators on both sides of the Atlantic are looking for consistency across field and function. It does no good to improve someone's exercise capacity and pVO2 if they have no perceptive, they do not perceive any benefit from it. Vice versa, if people are perceiving benefit, you would like to understand that that is because they are receiving some direct benefit from the drug and not something else that might be off-target or what have you. The endpoints need to be consistent. Both sides of the Atlantic, I think, agree on that. The way we approached it is, frankly, we will provide that information to both sets of regulators.

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 to satisfy everybody. Ultimately, I think they'll use very similar interpretations of the data at the end of the day.

Great. Thank you.

Operator (participant)

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

Yasmeen Rahimi (Senior Research Analyst)

Good afternoon, team. Thanks for the updates. I guess what we're trying to figure out is with all these different varieties of questions around the REMS, is it just a procedural mishap that it was not they should have asked you to submit it, and they did not, and you guys did not submit it. You wanted to follow their instruction. Or is there more to read into it? I think that is what it comes down to. Is it just a procedural mishap, and now it is in place, it is fine? Or is there more to make sense out of this, them coming back and asking? Really, I am struggling to figure that part out. I understand the sequence of events that are occurring. I think all your marks were very, very helpful.

Maybe help us understand which one it is because the stock is trading in a way that makes it think it's not just procedural. There's more to it. It would be wonderful if you could comment to the extent you can.

Robert Blum (President and CEO)

I hear you struggling, and I'll try to address this in a constructive way. Please understand, there was no mishap. I read what is causing some consternation amongst certain investors. 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 is nothing here that would suggest anything new, we believe, in terms of risk and safety. Instead of having this addressed through label, now it's being addressed through a more formal REMS.

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 is 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 is still fundamentally as we have been communicating. I hope that helps address some of the questions and concerns. You used the word mishap. I would not at all suggest that that is what occurred here.

Yasmeen Rahimi (Senior Research Analyst)

Okay. Thank you, Robert. Very helpful.

Robert Blum (President and CEO)

Thank you.

Operator (participant)

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

This is Natalie on for Ash. Thank you guys for your time and for the updates. I'm going to switch gears a little bit. I actually have a question related to Edgewise. In particular, we want to understand how you view their recent clinical data. To get even more specific, we're really looking at the numbers here. 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? Do you have any other broad comments on that data that they put out? Thank you.

Robert Blum (President and CEO)

Yeah. We did note the data that Edgewise presented. It is not for us to make comparative statements about AFI Campus versus an investigational drug that is in its early phase II. Specifically, you asked about measurement of effect on EF. 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 at Cmax exposures. I'll ask Fady to address what could be a delta between peak and trough. I trust you understand that is determined by each individual drug.

Fady Malik (EVP of R&D)

Yeah. 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 percentage 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 and hydration and so forth. It's very difficult to say exactly what the magnitude would be other than it would have been less. Similarly, I would expect if you measured a drug's effect at peak, any drug, Edgewise's drug or otherwise, if there is a relationship, you would see a bit more of an effect. That goes for other measurements of efficacy as well. I think that's about as far as I can really say. I can't really make any comparisons there.

Great. Thank you.

Operator (participant)

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

Robert Blum (President and CEO)

I want to thank everybody for your participation in this call. I hope you 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. I hope that you can feel comfortable that we took appropriate steps, for things continue to evolve. That's fair and reasonable. 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.

We are encouraged by the reception we are getting for candidates for our open commercial positions. At the same time, we point you to upcoming data from MAPLE. We are excited also about ACACIA, Omecamtiv Mecarbil, and CK-586. Lots of good things are happening in and around Cytokinetics. We look forward to providing you further updates when appropriate. We thank you for your interest in this call. Operator, with that, we can now conclude.

Operator (participant)

Thank you. This concludes today's conference call. Thank you for participating. You may now disconnect.