Cytokinetics Q1 2025 Earnings Report

Cytokinetics EPS Results

• Actual EPS: -$1.36
• Consensus EPS: -$1.41
• Beat/Miss: Beat by +$0.05
• One Year Ago EPS: -$1.33

Cytokinetics Revenue Results

• Actual Revenue: $1.60 million
• Expected Revenue: $2.77 million
• Beat/Miss: Missed by -$1.17 million
• YoY Revenue Growth: +89.10%

Cytokinetics Announcement Details

• Quarter: Q1 2025
• Date: 5/6/2025
• Time: After Market Closes
• Conference Call Date: Tuesday, May 6, 2025
• Conference Call Time: 4:30PM ET

Cytokinetics (NASDAQ:CYTK), Inc. is a clinical-stage biopharmaceutical company headquartered in South San Francisco, California. Founded in 1997, the company focuses on the discovery and development of small molecule therapeutics that modulate muscle function. Leveraging its expertise in muscle biology and chemistry, Cytokinetics aims to address a range of diseases characterized by impaired muscle performance, including heart failure and neuromuscular disorders.

The company’s lead programs target both cardiac and skeletal muscle. Omecamtiv mecarbil, a cardiac myosin activator, is being developed for patients with chronic heart failure with reduced ejection fraction, while aficamten, a next-generation cardiac myosin inhibitor, is designed for the treatment of symptomatic obstructive hypertrophic cardiomyopathy. In the neuromuscular space, reldesemtiv, a fast skeletal muscle troponin activator, is in clinical evaluation for conditions such as amyotrophic lateral sclerosis (ALS) and other neuromuscular diseases. Cytokinetics also pursues early-stage discovery programs to expand its pipeline into new therapeutic areas.

To advance its clinical programs and broaden its development capabilities, Cytokinetics has established strategic partnerships with global pharmaceutical companies. Collaborations with Astellas Pharma have supported the global development of aficamten, while agreements with Amgen have facilitated the advancement of cardiac muscle activators. Cytokinetics operates clinical trial sites across North America, Europe and Asia, working closely with regulatory authorities to support potential future approvals.

Leadership at Cytokinetics is headed by President and Chief Executive Officer Robert I. Blum, M.D., who brings extensive experience in cardiovascular drug development. Under Dr. Blum’s stewardship since 2016, the company has expanded its pipeline and strengthened its scientific platform. Supporting him is a management team of drug development and commercial veterans who drive Cytokinetics’ mission to deliver first-in-class muscle-directed therapies to patients worldwide.

Cytokinetics Q1 2025 Earnings Call Transcript

Key Takeaways

• FDA PDUFA Extension: The FDA extended the PDUFA date for the aficamten NDA to December 26, 2025 after classifying the REMS submission as a major amendment, delaying potential U.S. approval by three months.
• Global Regulatory Progress: Cytokinetics received 120-day questions from the EMA and is on track for a potential European approval in H1 2026, while supporting NMPA review efforts in China through its Sanofi partnership.
• Clinical achievements include completion of Acacia HCM enrollment over six months ahead of schedule with a dual primary endpoint design, and plans to report top-line results in H1 2026.
• MAPLE HCM Top-Line Data: Top-line results from the head-to-head MAPLE HCM trial against metoprolol are expected this month, which could inform label expansion and broaden aficamten’s positioning in obstructive HCM.
• Financially, the company ended Q1 with ~$1.1 billion in cash, reported a net loss of $161.4 million driven by R&D and commercial readiness investments, and maintained full-year 2025 operating expense guidance.

Presentation

[Operator]

Good afternoon, and welcome to Cytokinetics First Quarter twenty twenty five 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 Vice President of Corporate Communications & Investor Relations at Cytokinetics]

Good afternoon, and thanks for joining us on the call today. Robert Blom, President and Chief Executive Officer, will begin with an overview of the quarter and recent developments. Andrew Callow, EVP and Chief Commercial Officer, will address commercial readiness activities for aficamten. Sadi Malik, EVP of R and 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-five eighty six Isaac Sighanover, EVP, Corporate Development and Chief Business Officer, will provide an update on business development in the context of our corporate development Sun Lee, EVP and Chief Financial Officer, will provide a financial overview of the past quarter.

[Diane Weiser, Senior Vice President of Corporate Communications & Investor Relations at Cytokinetics]

And 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 may 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 twenty twenty five financial results filed on Form eight ks that was furnished to the SEC today. We undertake no obligation to update any forward looking statements after this call.

[Diane Weiser, Senior Vice President of Corporate Communications & Investor Relations at Cytokinetics]

And now I will turn the call over to Robert.

[Robert Blum, President and CEO at Cytokinetics]

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 12/26/2025 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 aficamtan during which we discussed a range of topics related to the content of our submission, including safety monitoring and risk mitigation strategies.

[Robert Blum, President and CEO at Cytokinetics]

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 the 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've previously shared, these interactions provided the opportunity to discuss in detail the data supporting the safety and intrinsic pharmaceutical properties of apicalmten 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 apicamtan and based on labeling 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.

[Robert Blum, President and CEO at Cytokinetics]

We made the determination to take this approach because under the circumstances we thought it was reasonable given the profile of affecamtin. 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 apicamtin, 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 aficamtan with objective to advance it as a potential next in class cardiac myosin inhibitor.

[Robert Blum, President and CEO at Cytokinetics]

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 FORWARD HCM support a potential label and risk mitigation profile that if approved by FDA will differentiate apicamtiv. Nothing has changed in that regard. And again to confirm no additional clinical data or studies were requested by FDA.

[Robert Blum, President and CEO at Cytokinetics]

As we disclosed in an eight ks 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 apicamten, it does not change our confidence in its distinct benefit risk and pharmaceutic profile nor does it change our expectation for 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 U.

[Robert Blum, President and CEO at Cytokinetics]

S. In April, we received one hundred and twenty day questions from the EMA regarding the MAA for Aficamtan 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 twenty twenty six. During the quarter, we also worked with Sanofi, our partner in China to support the NDA review of alfecamtin with the NMPA. And overall we're encouraged by the steady progress of our regulatory interactions globally.

[Robert Blum, President and CEO at Cytokinetics]

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.

[Robert Blum, President and CEO at Cytokinetics]

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 aficamtan. 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 aficamtan 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.

[Robert Blum, President and CEO at Cytokinetics]

We're pleased to share today that Acacia HCM, our pivotal Phase three clinical trial of aficamtin 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 twenty twenty six. 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 aficamtan in this population of underserved patients. As you know, aficamtiv for the treatment of both O and N HCM represents the first potential new medicine arising from our specialty cardiology franchise, which also includes omecamtiv mecarbil and CK-five eighty six 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 02/1930.

[Robert Blum, President and CEO at Cytokinetics]

And with that, I'll turn the call over to Andrew please.

[Andrew Callos, Executive VP & Chief Commercial Officer at Cytokinetics]

Thanks Robert.

[Andrew Callos, Executive VP & Chief Commercial Officer at Cytokinetics]

In the first quarter, we continued to execute our commercial readiness planning and implementation with a three month extension to our PDUFA meeting. Certain work streams will be adjusted, but we're 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 sales force recruiting. Given the December PDUFA date, we'll be revising our sales force onboarding plan while maintaining current recruiting schedule, which is off to a great start.

[Andrew Callos, Executive VP & Chief Commercial Officer at Cytokinetics]

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 high level of interest and how well positioned we are to attract top talent and build a standout sales organization. In parallel, our workaround 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.

[Andrew Callos, Executive VP & Chief Commercial Officer at Cytokinetics]

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 unbranded disease awareness campaign, HCM Beyond the Heart, continued. The ACP focused awareness campaign directs HCPs to consider the broader HCM burden and practice whole person care. And likewise, the patient campaign helps educate people living with HCM, not just about the condition, but about the holistic burden of HCM.

[Andrew Callos, Executive VP & Chief Commercial Officer at Cytokinetics]

We also maintained our engagement with payers and plan to continue educating them on the data the clinical development program of furafecamtin as well as the clinical and economic burden of HCM. On top of the burden of disease, we expect to have several

[Andrew Callos, Executive VP & Chief Commercial Officer at Cytokinetics]

ATOR presentations at upcoming meetings to further characterize both O and N HCM 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, advanced European commercial readiness and activities in a gated manner, including hiring key leadership positions for marketing, finance, legal, compliance and human resources.

[Andrew Callos, Executive VP & Chief Commercial Officer at Cytokinetics]

And we set up new regional entities in France and The UK 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.

[Andrew Callos, Executive VP & Chief Commercial Officer at Cytokinetics]

And European launches of aficamtan. With that, I'll turn the call over to Fady to share updates on our ongoing clinical trial program for aficamtan.

[Fady Malik, Executive Vice President of Research & Development at Cytokinetics]

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 apocamtin or motocrolol, each as monotherapy. While beta blockers are standard of care at HCM, their impact on exercise performance, symptoms, and LVOT gradient from obstructive HCM is not well characterized.

[Fady Malik, Executive Vice President of Research & Development at Cytokinetics]

At the same time, the impact of treatment with abacamten 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 ACM as it may help differentiate the effects of aflikamtiv 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 twenty twenty five, 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 five sixteen patients in only eighteen months, which was driven by a high interest in participation that accelerated screening and enrollment through the end of twenty twenty four and into early twenty twenty five. The primary cohort of Acacia ACM 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 apokamtin in Japan late last year, we also agreed to expand Acacia HCM to Japan, targeting it start to Q2 twenty twenty five 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 twenty twenty six.

[Fady Malik, Executive Vice President of Research & Development at Cytokinetics]

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 a change in KCCQ clinical summary score and a measure of exercise capacity, peak VO2, each measured as a change from baseline in week thirty six. 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, CPAP measurements were already being obtained for all patients.

[Fady Malik, Executive Vice President of Research & Development at Cytokinetics]

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 a KHCM, we enacted this change knowing that we could also power the trial adequately by increasing the sample size from four twenty to at least 500 patients to ensure each of the primary endpoints had 90% power and an alpha of 0.025 to detect a conservative clinically meaningful change. Compared to placebo for KCCQ, that's five points. And for peak CO2, that's one point zero milliliter per kilogram per minute.

[Fady Malik, Executive Vice President of Research & Development at Cytokinetics]

To be clear, however, if either clinical endpoint that comprises a dual primary endpoint is statistically significant, AKCEA 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 two trial, REDWAY HCM, we evaluated treatment with apnekampin and NHCM in an open label fashion and demonstrated improvements in KCCQ and NYHA functional class and an average reduction in T ProBNP of 66%. The majority of patients achieved the highest dose offered at fifty milligrams, and there were no drug discontinuations due to low ejection fraction and few instances of LVDF less than 50%. These findings were replicated when patients transitioned into the open label extension trial for SATEM.

[Fady Malik, Executive Vice President of Research & Development at Cytokinetics]

Importantly, KJACEM builds on this Phase II experience by using the same dosing approach with rapid attainment of target dose within eight 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 a KHCM 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 aficamtan, 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, Senior VP & Chief Medical Officer at Cytokinetics]

Thanks, Vaddy. I'm pleased to provide updates on our later stage development programs. During the quarter, we continued conduct of AMBER HFpEF, the phase two clinical trial of CK-five eighty six in patients with symptomatic heart failure with preserved ejection fraction of at least sixty percent. We continue to progress towards our goal of completing enrollment in the first two cohorts in the second half of this year. Approximately 2,000,000 people with heart failure in The US have an injection fraction greater than or equal to sixty percent.

[Stuart Kupfer, Senior VP & Chief Medical Officer at Cytokinetics]

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 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 to roll in COMET HF, the confirmatory phase three clinical trial of omecamtiv mecarbil in patients with symptomatic heart failure with severely reduced ejection fraction less than thirty percent. We maintain progress in activating sites in The US and convened a well attended US investigator meeting at the 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.

[Stuart Kupfer, Senior VP & Chief Medical Officer at Cytokinetics]

Many of these investigators participated in GALACTIC HF, the first phase three trial along with cantamacarbil. We expect to continue enrolling COMMOD HF this year and complete enrollment in 2026. Our later stage pipeline represents our next highest opportunity following aficamtiv, 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, Corporate Development and Chief Business Officer at Cytokinetics]

Thanks, Stuart. In the first quarter, we participated in a Series B financing of Embryo Pharmaceuticals to support the advancement of Ninerifaxtat 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 02/1930, external innovation and business development is a key pillar of our growth strategy. Our current R and D pipeline has risen entirely from internal discovery, and we see a significant opportunity to complement and enhance this foundation through investments, partnering and licensing opportunities.

[Isaac Ciechanover, EVP, Corporate Development and Chief Business Officer at Cytokinetics]

By engaging selectively and prudently in opportunities to balance our own R and 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, Executive VP & CFO at Cytokinetics]

Thanks Isaac. We're pleased to report our first quarter of twenty twenty five financial results. Starting with the balance sheet, we finished the first quarter with approximately $1,100,000,000 in cash, cash equivalents and investments compared to $1,200,000,000 at the end of the fourth quarter of twenty twenty four. Cash cash equivalents and investments declined by approximately $132,200,000 during the first quarter of twenty twenty five. R and D expenses for the first quarter were $99,800,000 compared to $81,600,000 for the same period in 2024.

[Sung Lee, Executive VP & CFO at Cytokinetics]

The increase was primarily due to advancing our clinical trials and higher personnel related costs. G and A expenses for the first quarter of twenty twenty five were $57,400,000 compared to $45,500,000 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 twenty twenty five was $161,400,000 or $1.36 per share compared to a net loss of $135,600,000 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 $670,000,000 and $710,000,000 Stock based compensation that is included in GAAP operating expense is expected to be between $110,000,000 and $120,000,000 Excluding stock based compensation from GAAP operating expense results in a range of $550,000,000 to $600,000,000 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 would drive a decrease in G and 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 three trial of aficamtan in NHCM, which will increase R and D expense.

[Sung Lee, Executive VP & CFO at Cytokinetics]

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 Avnocamtiv in The U. S.

[Sung Lee, Executive VP & CFO at Cytokinetics]

Later this year and advance our pipeline. With that I'll hand it back to Robert.

[Robert Blum, President and CEO at Cytokinetics]

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.

[Robert Blum, President and CEO at Cytokinetics]

Most importantly, the potential FDA approval of apoptimtin 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 02/1930 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 apicamtan, we expect to advance NDA review activities with FDA to support the potential U.

[Robert Blum, President and CEO at Cytokinetics]

S. Approval of apicamtan in the second half of this year. We expect to advance go to market strategies and prepare to commercially launch apicamtan 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 twenty twenty six. We expect to coordinate with Sanofi to support the potential approval of apucanthin in China pending approval by the NMPA and we expect top line results from MAPLE HCM this month.

[Robert Blum, President and CEO at Cytokinetics]

We also expect to report top line results from the primary cohort of Acacia HCM in the first half of twenty twenty six and begin enrollment of patients in the Japan cohort of AKAYCE 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 common HCF through 2025 to enable completion of enrollment in 2026. For CK-five eighty six, 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.

[Robert Blum, President and CEO at Cytokinetics]

Operator, with that said, we can now open the call up to questions please.

[Operator]

Thank you. In the interest of time, we do ask that you kindly limit yourself to one question at this time. Please standby while we compile our Q and A roster. And our first question will come from Sean McCutcheon from Raymond James. Your line is now open.

[Sean McCutcheon, Vice President - Biotechnology Equity Research at Raymond James Financial]

Good afternoon. Hey, guys. Thanks for the hi, Robert. Thanks for the question. Based on the failure of OHDSI and the BMS verbiage around obstructive HCM being different from non obstructive, getting a lot of questions on what that means for Acacia.

[Sean McCutcheon, Vice President - Biotechnology Equity Research at Raymond James Financial]

Can you speak to how you designed Acacia around the properties of avacamten to drive higher probability of success and how you view the importance of pushing the CMI dose higher in non obstructive disease given you are able to get the majority of patients on that twenty milligram dose in the forest non obstructive cohort? Thanks.

[Robert Blum, President and CEO at Cytokinetics]

Sure. I'll speak generally and then ask Patty to answer your specific questions. Firstly, as it relates to a case 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 three and going to centers where we believe there's already ample experience with apicamtan 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 reads we believe in an encouraging way on what we should expect testing the same hypothesis in Phase three.

[Robert Blum, President and CEO at Cytokinetics]

So we maintain our very optimistic views towards Acacia. With that, I'll turn it over to Fadi to answer the specific questions.

[Fady Malik, Executive Vice President of Research & Development at Cytokinetics]

Yes, think the points that Rob will make 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 forests, so those NHCM patients have the availability of the twenty milligram dose, some of them are currently taking it. We've seen in the Redwood very few treatment interruptions, no discontinuations for intolerance.

[Fady Malik, Executive Vice President of Research & Development at Cytokinetics]

And those things I think are very important, you know, 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 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.

[Fady Malik, Executive Vice President of Research & Development at Cytokinetics]

We have basically a team that reviews every patient enrolled in the trial to ensure that patients not only meet the entry criteria, but that their imaging is consistent with what you would expect in a TM. You know, it's for all those reasons, we're still very optimistic about the chances of success for Acacia.

[Sean McCutcheon, Vice President - Biotechnology Equity Research at Raymond James Financial]

Thank you.

[Robert Blum, President and CEO at Cytokinetics]

Thank you.

[Operator]

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

[Salim Syed, Managing Director, Equity Research at Mizuho Securities]

Great.

[Salim Syed, Managing Director, Equity Research at Mizuho Securities]

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 aficamtan. I just want to be clear.

[Salim Syed, Managing Director, Equity Research at Mizuho Securities]

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? Thank you.

[Robert Blum, President and CEO at Cytokinetics]

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. 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.

[Robert Blum, President and CEO at Cytokinetics]

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.

[Robert Blum, President and CEO at Cytokinetics]

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 were 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 aficamtan.

[Robert Blum, President and CEO at Cytokinetics]

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.

[Salim Syed, Managing Director, Equity Research at Mizuho Securities]

Okay, helpful. Thank you very much.

[Andrew Callos, Executive VP & Chief Commercial Officer at Cytokinetics]

Thank you.

[Operator]

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

[Robert Blum, President and CEO at Cytokinetics]

Good afternoon.

[Gena Wang, MD - Biotech Equity Research at Barclays]

This is Wen actually. This is Gina Wen 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, would that consistent with the one you share with the investors, you know, that the certain protocol was that consistent, you know, when you share, when you submit that to the FDA and also, you know, given this unfortunate event, but can you take advantage of it since there is only one time extension for the PDUFA and if you cannot extend twice, do you, can you use the MABLE 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 at Cytokinetics]

So I'll answer the second question first. We do not intend to submit the MAPLE data as part of this review cycle of apocamtiv 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 be enabling of a subsequent submission that that would follow a potential approval of aficamtiv in O HCM. As 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.

[Gena Wang, MD - Biotech Equity Research at Barclays]

Have not heard 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 share in the past with investors. So just wondering, have you and then also minimal, like, the certain monitoring protocol was that consistent with, what you propose that you think it will be differentiating from Kamsiho's REMS program?

[Robert Blum, President and CEO at Cytokinetics]

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 Fadi to elaborate in a general way about how we're approaching safety and risk mitigation.

[Fady Malik, Executive Vice President of Research & Development at Cytokinetics]

Yeah. Hi, Gene. I think what we submitted has been consistent with what we've said all along are the differentiated properties of abacamten. So as we did in Forest, we amended the protocol to enable every six months monitoring to widen the dosing window from every two weeks to every two to six or eight weeks to enable physicians to, you know, guide dosing directly. And, you know, we've been, I think, straightforward and presented those data recently at the American College of Cardiology.

[Fady Malik, Executive Vice President of Research & Development at Cytokinetics]

We don't really have any 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 well received by physicians that treat these patients.

[Gena Wang, MD - Biotech Equity Research at Barclays]

Thank you.

[Robert Blum, President and CEO at Cytokinetics]

Thank you.

[Fady Malik, Executive Vice President of Research & Development at Cytokinetics]

Thank you.

[Operator]

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

[Robert Blum, President and CEO at Cytokinetics]

Hey, Paul.

[Paul Choi, Analyst at Goldman Sachs]

Good afternoon, everyone. Thanks for taking the question. Robert, earlier you said, aficamtan will be differentiated, but maybe just to continue on what Fadi was saying with the recent changes to the CHEMZIOUS label, removing the some of the drug drug interaction warnings as well as the extended monitoring, increasing the monitoring period to six months. Sort of, I guess a lot of investors are just wondering what sort of left on the table for Afrikaans to be differentiated here. So maybe slight any additional points here to help clarify that that would be helpful. Thanks for taking our question.

[Robert Blum, President and CEO at Cytokinetics]

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 Kamsiyos REMS but still there are limitations as it relates to DBI's. Still there are limitations as it relates to echo monitoring certainly during the uptitration phase, but also during the maintenance phase as it pertains to certain patients. So, I would answer your question as follows.

[Robert Blum, President and CEO at Cytokinetics]

There remains we believe ample opportunity for differentiation based on the REMS that we have submitted.

[Operator]

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

[Fady Malik, Executive Vice President of Research & Development at Cytokinetics]

Hey, Cory.

[Cory Kasimov, Senior Managing Director at Evercore]

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? Thank you.

[Robert Blum, President and CEO at Cytokinetics]

So there is no REMS per se as part of a 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 Fadi maybe to elaborate.

[Fady Malik, Executive Vice President of Research & Development at Cytokinetics]

Yeah, EMA approaches it differently. They don't have a REMS program per se. They do ask you to submit a risk mitigation program or an RMP as a standard part of any submission, which we did. And, you know, 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.

[Robert Blum, President and CEO at Cytokinetics]

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.

[Operator]

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

[Roanna Ruiz, Senior Managing Director, Biotechnology Analyst at Leerink Partners]

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 and 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.

[Robert Blum, President and CEO at Cytokinetics]

Yes. So before I ask Patty 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, Aficampton both in OHCM as well as in REDWOOD Cohort four, 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.

[Fady Malik, Executive Vice President of Research & Development at Cytokinetics]

Yeah. 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 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 alphas to it. And your secondary endpoint can be your next most important endpoint. And if the first one's positive, then all the alpha, you know, the 0.05 flows to the second endpoint.

[Fady Malik, Executive Vice President of Research & Development at Cytokinetics]

That was an approach that was endorsed by FDA. And, you know, 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 and was well powered with that four twenty 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.

[Fady Malik, Executive Vice President of Research & Development at Cytokinetics]

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 went on one of the two endpoints, then the secondary endpoint, the next secondary endpoint, which is NYJ class, would be evaluated at point zero two five.

[Fady Malik, Executive Vice President of Research & Development at Cytokinetics]

But again, just to be clear, endpoints and the secondary endpoints for that matter, even at point zero two five, 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.

[Roanna Ruiz, Senior Managing Director, Biotechnology Analyst at Leerink Partners]

That's helpful. It. Yep. Helpful. Thank you.

[Robert Blum, President and CEO at Cytokinetics]

Thank you.

[Operator]

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

[Akash Tewari, Managing Director at Jefferies]

Hey, this is actually Akash. So, 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 apocamtin means an educational REMS and not an a tattoo one? Thanks so much.

[Robert Blum, President and CEO at Cytokinetics]

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 frequency of echo monitoring is 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]

Thanks. Thank you. And our next question will come from Charles Duncan from Cantor. Your line is open.

[Robert Blum, President and CEO at Cytokinetics]

Hello, Charles. Good afternoon.

[Charles Duncan, Analyst at Cantor Fitzgerald]

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 and that is regarding, Maple HCM, absolutely respect the strategy with regards 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?

[Robert Blum, President and CEO at Cytokinetics]

Good question. I'll turn that to Fady,

[Fady Malik, Executive Vice President of Research & Development at Cytokinetics]

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

[Charles Duncan, Analyst at Cantor Fitzgerald]

Okay. Looking forward to that data.

[Robert Blum, President and CEO at Cytokinetics]

Thanks, John.

[Operator]

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

[Robert Blum, President and CEO at Cytokinetics]

Hello, Tess.

[Tessa Romero, Equity Analyst at J.P. Morgan]

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?

[Tessa Romero, Equity Analyst at J.P. Morgan]

And when exactly did the FDA request the REMS? Thanks.

[Robert Blum, President and CEO at Cytokinetics]

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 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 apicamtiv is ultimately approved then I expect in a summary basis of approval this will all be laid out for you then to understand.

[Robert Blum, President and CEO at Cytokinetics]

But 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 we're getting feedback from FDA regarding the amendment.

[Robert Blum, President and CEO at Cytokinetics]

So 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, Equity Analyst at J.P. Morgan]

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 at Cytokinetics]

Oh, 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 believed upon approval that, apocamtion 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 that we expect the differentiation would be within the REMS.

[Tessa Romero, Equity Analyst at J.P. Morgan]

Thank you.

[Robert Blum, President and CEO at Cytokinetics]

Thank you.

[Operator]

Thank you. Our next question comes from Max Wolskoye from Morgan Stanley. Your line is open.

[Maxwell Skor, Analyst at Morgan Stanley]

Great. Thank you for taking my question. So I'll probably approach this a little bit differently or try to. But given that the Kymzios REMS was updated recently, you submitted a one hundred and twenty day safety update from the FORCE 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 at Cytokinetics]

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 KEMZIAOS and we believe we've submitted a REMS that would be enabling of a differentiated distinct profile.

[Maxwell Skor, Analyst at Morgan Stanley]

Great. Thank you.

[Robert Blum, President and CEO at Cytokinetics]

Thank you.

[Operator]

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

[Leonid Timashev, Biotechnology Analyst at RBC Capital Markets]

Hey, thanks for taking my question. I forgot to 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 aficamtin in HCM if it's approved? I mean, you expect more patient warehousing and therefore more rapid launch?

[Leonid Timashev, Biotechnology Analyst at RBC Capital Markets]

Or would you have preferred someone building out that market? And then I guess on EU versus U. S, I mean, you've talked about fifty percent 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 at Cytokinetics]

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

[Andrew Callos, Executive VP & Chief Commercial Officer at Cytokinetics]

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 apicanthin 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 would likely be a halo effect, if you will, in terms of utilization across both obstructive and non obstructive if both MACEL and AKHAR are positive as well.

[Operator]

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

[Robert Blum, President and CEO at Cytokinetics]

Hello, David.

[David Lebowitz, Analyst at Citigroup]

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

[Robert Blum, President and CEO at Cytokinetics]

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 aficamtan 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.

[Andrew Callos, Executive VP & Chief Commercial Officer at Cytokinetics]

Yes, I would only say that and this is Robert said that when you have a second data set that assuming it's positive, Maple's positive, a second data set that confirms efficacy, that confirms safety, that adds to 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 aficamtan as well. So 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, is going to enable broader penetration into community cardiology.

[David Lebowitz, Analyst at Citigroup]

Got it. Thank you for taking my question.

[Robert Blum, President and CEO at Cytokinetics]

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.

[David Lebowitz, Analyst at Citigroup]

Thank you.

[Operator]

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

[Mayank Mamtani, Senior Managing Director at B. Riley Securities]

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.

[Mayank Mamtani, Senior Managing Director at B. Riley Securities]

This high level, like do you sense independent physician feedback same form of an outcome 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 differentiation?

[Robert Blum, President and CEO at Cytokinetics]

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.

[Robert Blum, President and CEO at Cytokinetics]

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 could change based on anything that we're having conversation about today. So you were suggesting that maybe an AdCom be to our advantage if I heard you correctly. I don't think that's practical at this point.

[Mayank Mamtani, Senior Managing Director at B. Riley Securities]

Yeah, I mean you'd have some more data to be shared in a public forum about the drugs profile, especially the treatment initiation phase with the echo monitoring. So I don't know, can the agency benefit from having that independent physician feedback in a forum like that?

[Robert Blum, President and CEO at Cytokinetics]

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 advisors 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's something that investors or analysts should be thinking about. I believe your second question pertained to what was it Andrew?

[Robert Blum, President and CEO at Cytokinetics]

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

[Mayank Mamtani, Senior Managing Director at B. Riley Securities]

Thank you, Robert. Very helpful. Thank you.

[Operator]

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

[Srikripa Devarakonda, Analyst at Truist]

Hey, guys. Thank you so much for taking my question. Robert, sorry to belabor the REMS point, but just wanna make sure I understood it correctly. Now 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.

[Srikripa Devarakonda, Analyst at Truist]

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 not it was fair not to submit the REMS program.

[Robert Blum, President and CEO at Cytokinetics]

I think that's correct.

[Srikripa Devarakonda, Analyst at Truist]

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

[Fady Malik, Executive Vice President of Research & Development at Cytokinetics]

Thank you.

[Operator]

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

[James Condulis, Associate Vice President - Biotechnology Equity Research at Stifel Nicolaus]

Thanks for sneaking me in and sorry for one more question on the REMS here. And so it sounds like the ask from the FDA kind of came after the mid cycle review, I guess. Is that right? And 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 at Cytokinetics]

Yes, I think we've provided the color that we can provide. And as you know we did issue an eight ks 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.

[Robert Blum, President and CEO at Cytokinetics]

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.

[James Condulis, Associate Vice President - Biotechnology Equity Research at Stifel Nicolaus]

All makes sense. Thank you.

[Robert Blum, President and CEO at Cytokinetics]

Thank you.

[Operator]

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

[Jason Zemansky, Vice President, Equity Research, Biotechnology and Pharmaceuticals at Bank of America Merrill Lynch]

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 cytokinetic 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 twentytwenty that was sort of always out there.

[Robert Blum, President and CEO at Cytokinetics]

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.

[Robert Blum, President and CEO at Cytokinetics]

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 a REMS. So we believed then that we were doing the right thing to be enabling of aficamtan 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.

[Robert Blum, President and CEO at Cytokinetics]

FDA upon its review has determined a REMS is appropriate given the mechanism but for, we believe FDA has also communicated that a REMS distinct to the intrinsic pharmaceutics and inherent characteristics of apicalmten 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.

[Jason Zemansky, Vice President, Equity Research, Biotechnology and Pharmaceuticals at Bank of America Merrill Lynch]

It does. I appreciate the color.

[Robert Blum, President and CEO at Cytokinetics]

Thank you.

[Operator]

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

[Leland Gershell, MD & Senior Biotechnology Analyst at Oppenheimer & Co. Inc.]

Thanks very much. I'm actually going to ask a non REMS question. Robert, just just wanted to ask in terms of any real world studies that you may be performing after presumptive, at the Camtam approval of the twenty four weeks of COLI 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 at Cytokinetics]

Yes, 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 aficamtan.

[Robert Blum, President and CEO at Cytokinetics]

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 Affie Camden 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.

[Fady Malik, Executive Vice President of Research & Development at Cytokinetics]

Yeah. Well, you know, in SEQUOIA, we conducted an analysis of patients qualified for septal reduction therapy and showed essentially treatment with dapamcantin reduces that need by ninety percent, or ninety percent of patients were no longer eligible for it. That we've seen again as those patients roll in the fourth, the same sort of dynamics and what we anticipate, you know, as we look at now a much longer term experience in FORCE, even with patients that didn't qualify to start, is to get a sense of the natural history of that. You know, you would expect some of those patients would have gone on to begin to qualify, conditions would have worsened. And we can begin to compare those forest data to real world registries, and we'll get the progression of event rates in forests versus the progression of event rates perhaps elsewhere, I think what we'll see is that africanfins potentially slowing those rates in the long run.

[Fady Malik, Executive Vice President of Research & Development at Cytokinetics]

And that will add to the conviction that abecamtiv and the cardiac myosin inhibitor is a disease modifying mechanism.

[Leland Gershell, MD & Senior Biotechnology Analyst at Oppenheimer & Co. Inc.]

Great. Thank you very much.

[Operator]

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

[Jason Butler, Managing Director & Biotechnology Equity Research at Citizens JMP]

Hi, thanks for taking the question. Just wanted to switch gears here at the end and ask a question about CK-five eighty six 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?

[Robert Blum, President and CEO at Cytokinetics]

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

[Fady Malik, Executive Vice President of Research & Development at Cytokinetics]

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

[Stuart Kupfer, Senior VP & Chief Medical Officer at Cytokinetics]

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. So we'll look at the totality of data and then disclose the results. And Sean, to your second question, It's Fady alluded to, this is a dose finding study, and a dose titration strategy study.

[Stuart Kupfer, Senior VP & Chief Medical Officer at Cytokinetics]

In a population with a lot of co morbidity, this is an older population than the non obstructive 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 observe 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.

[Operator]

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

[Serge Belanger, Senior Analyst at Needham & Company]

Hi, this is Tom for Serge. Thanks for taking my question. Just want to underscore the expectations now between both The US and EU with the amendment to a Caucha. 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? Thanks.

[Robert Blum, President and CEO at Cytokinetics]

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

[Fady Malik, Executive Vice President of Research & Development at Cytokinetics]

I think that 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 and peak VO2 if they have no perceptive they don't perceive any benefit from it. And vice versa, you know, the 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, you know, might be off target or what have you. So, you know, the endpoints need to be consistent. Both sides of Atlantic, I think, agree in that.

[Fady Malik, Executive Vice President of Research & Development at Cytokinetics]

You know, the way we approached it is, frankly, we'll provide that information information to both sets of regulators, but I think each of them have a different concept of what how to approach that by designating certain endpoints and by upsizing the trial and harmonizing the primary endpoint to include both components, we were able to really satisfy everybody. And ultimately, I think they'll use very similar interpretations of the data at the end of the day.

[Serge Belanger, Senior Analyst at Needham & Company]

Great. Thank you.

[Operator]

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

[Yasmeen Rahimi, Sr. Research Analyst at Piper Sandler Companies]

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, is it just a procedural mishap that it wasn't you know, they 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?

[Yasmeen Rahimi, Sr. Research Analyst at Piper Sandler Companies]

You know, like, think that that's what it comes down to. Like, is it just a procedural mess up 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 are pertinent.

[Yasmeen Rahimi, Sr. Research Analyst at Piper Sandler Companies]

All your marks were very, very helpful. So maybe help us understand which one it is because the stock is trading in a way that makes a thing. It's not just procedural, there's more to it. Would be wonderful if you could comment to the extent you can.

[Robert Blum, President and CEO at Cytokinetics]

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.

[Robert Blum, President and CEO at Cytokinetics]

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 aficamtan 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.

[Robert Blum, President and CEO at Cytokinetics]

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.

[Yasmeen Rahimi, Sr. Research Analyst at Piper Sandler Companies]

Okay. Thank you, Robert. Very helpful.

[Robert Blum, President and CEO at Cytokinetics]

Thank you.

[Operator]

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

[Natalie McArthur, Biotech & Biopharma Equity Research Associate at UBS Group]

This is Natalie on for Ash, and thank you guys for your time and for the updates. 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, you know, 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?

[Natalie McArthur, Biotech & Biopharma Equity Research Associate at UBS Group]

And just do you have any other broad comments on that data that they put out? Thank you.

[Robert Blum, President and CEO at Cytokinetics]

Yes, so we did note the data that Edgewise presented and it's not for us to make comparative statements about aficamtan 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 determinant by each individual drug.

[Fady Malik, Executive Vice President of Research & Development at Cytokinetics]

Yeah. I mean, think for ampicamten, 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.

[Fady Malik, Executive Vice President of Research & Development at Cytokinetics]

There's a lot of things that affect ejection fraction, including time of day and diurnal variation and migration 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's 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.

[Natalie McArthur, Biotech & Biopharma Equity Research Associate at UBS Group]

Great. Thank you.

[Operator]

Thank you. 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.

[Robert Blum, President and CEO at Cytokinetics]

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 aficamtan and upon its potential approval with a label and a REMS program that would provide distinct positioning for aficamtan 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.

[Robert Blum, President and CEO at Cytokinetics]

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 for MAPLE and, we're excited also about Acacia, omecamtiv and CK-five eighty six. 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.

[Operator]

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

Participants

Executives

• Diane Weiser, Senior Vice President of Corporate Communications & Investor Relations
• Robert Blum, President and CEO
• Andrew Callos, Executive VP & Chief Commercial Officer
• Fady Malik, Executive Vice President of Research & Development
• Stuart Kupfer, Senior VP & Chief Medical Officer
• Isaac Ciechanover, EVP, Corporate Development and Chief Business Officer
• Sung Lee, Executive VP & CFO

Analysts

• Sean McCutcheon, Vice President - Biotechnology Equity Research at Raymond James Financial
• Salim Syed, Managing Director, Equity Research at Mizuho Securities
• Gena Wang, MD - Biotech Equity Research at Barclays
• Paul Choi, Analyst at Goldman Sachs
• Cory Kasimov, Senior Managing Director at Evercore
• Roanna Ruiz, Senior Managing Director, Biotechnology Analyst at Leerink Partners
• Akash Tewari, Managing Director at Jefferies
• Charles Duncan, Analyst at Cantor Fitzgerald
• Tessa Romero, Equity Analyst at J.P. Morgan
• Maxwell Skor, Analyst at Morgan Stanley
• Leonid Timashev, Biotechnology Analyst at RBC Capital Markets
• David Lebowitz, Analyst at Citigroup
• Mayank Mamtani, Senior Managing Director at B. Riley Securities
• Srikripa Devarakonda, Analyst at Truist
• James Condulis, Associate Vice President - Biotechnology Equity Research at Stifel Nicolaus
• Jason Zemansky, Vice President, Equity Research, Biotechnology and Pharmaceuticals at Bank of America Merrill Lynch
• Leland Gershell, MD & Senior Biotechnology Analyst at Oppenheimer & Co. Inc.
• Jason Butler, Managing Director & Biotechnology Equity Research at Citizens JMP
• Serge Belanger, Senior Analyst at Needham & Company
• Yasmeen Rahimi, Sr. Research Analyst at Piper Sandler Companies
• Natalie McArthur, Biotech & Biopharma Equity Research Associate at UBS Group