Earnings Call Transcript - CYTK Q2 2025

Operator, Operator

Thank you for holding. My name is Prilla, and I will be your conference operator today. Welcome to the Cytokinetics Q2 2025 Earnings Conference Call. This call is being recorded. I would now like to turn the call over to Diane Weiser, Cytokinetics' Senior Vice President of Corporate Affairs. Please proceed.

Diane Weiser, Senior Vice President 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 and medical affairs activities for aficamten. Stuart Kupfer, SVP and Chief Medical Officer, will provide updates on the clinical development program for omecamtiv mecarbil and CK-586, which is now called ulacamten. Sung Lee, EVP and Chief Financial Officer, will provide a financial overview of the past quarter. And finally, Robert will provide closing comments and 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 second quarter 2025 financial results filed on Form 8-K that was furnished to the SEC today. We undertake no obligation to update any forward-looking statements after this call. And now I will turn the call over to Robert.

Robert I. Blum, President and Chief Executive Officer

Thank you, Diane, and thanks to all for joining us on the call today. The first half of this year has been defined by solid progress as we continue to deliver on key milestones that bring us closer to realizing our vision, a vision of being the leading muscle-focused specialty biopharma company intent on meaningfully improving the lives of patients through global access to our innovative medicines. During the second quarter, we announced that the FDA extended our PDUFA date for the NDA for aficamten for the treatment of patients with oHCM to December 26, 2025. Our late-cycle review meeting has since been moved to September, consistent with the 3-month PDUFA extension. We believe this timing should have no bearing on the approvability of aficamten, and we look forward to that meeting with FDA as we expect will occur soon and inform our next steps. In the meantime, all activities expected alongside the FDA's ongoing review process continue to timeline. For example, GCP inspections of clinical trial sites and also of Cytokinetics by FDA are now completed with no observations recorded. In addition, we're maintaining a productive dialogue with FDA, and we're answering questions to support their review of the NDA. Also during the quarter, we had a collaborative meeting with FDA on our submitted REMS program following their initial review. Subsequent to the meeting, we promptly submitted an updated REMS package, and despite the extension to the PDUFA date, we remain confident in the U.S. regulatory position of aficamten, given the quality of our clinical data, perceived alignment on our REMS program, and ongoing collaborative dialogue with FDA. We also maintain strong conviction that the data behind aficamten support its potential FDA approval, its distinct benefit-risk profile, and potentially differentiated label and risk mitigation profile as a potential new treatment option for patients with oHCM. At the same time, regulatory reviews for aficamten continued during the second quarter in both Europe and China. In April, we received the day 120 list of questions from EMA regarding the MAA for aficamten in Europe, and we're on track to submit responses soon in accordance with the timeline agreed with the EMA. EMA inspections of clinical sites and of Cytokinetics have also been completed with the overall conclusion that the conduct of the Phase III trial was compliant with regulations and guidelines and data are acceptable and reliable. We remain on track for potential approval by EMA in the first half of 2026, and we're targeting Germany for our first potential launch following approval. We have also been working closely with Sanofi, our partner in China, to support the NDA review of aficamten with the NMPA, which is on an accelerated regulatory pathway for innovative therapies. We look forward to the prospect of bringing aficamten to patients in additional geographies, and we continue to expect potential approval in China in the second half of this year. Moreover, in the past few months, our commercial launch readiness activities have advanced with increased intensity and focus, and we're taking advantage of the extra time to further strengthen our commercial launch and operational strategies in the U.S. As Andrew will elaborate, key progress areas in the second quarter include recruiting a world-class U.S. sales force, fine-tuning our patient-centric treatment experience, and engaging key payers and other important stakeholders. During the quarter, we also made important progress in our ongoing clinical trials program for aficamten. Notably, we announced positive top-line results from MAPLE-HCM. We look forward to expanding on these results and their implications for what standard of care treatment may look like in oHCM following the presentation of the primary results at the upcoming European Society of Cardiology Congress to occur later this month. We also continued conducting ACACIA-HCM, the pivotal Phase III clinical trial in nHCM, which is now fully enrolled and towards our expected top-line readout in the first half of next year. nHCM represents an area of significant unmet need and is growing within the overall HCM population with no approved treatment options that address the underlying disease. Following the first potential approval in oHCM, nHCM represents a clear opportunity for aficamten and innovation. Beyond aficamten, in Q2, we continued to advance patient enrollment in COMET-HF and also in AMBER-HFpEF, our two later-stage clinical trials evaluating omecamtiv mecarbil and CK-586, now called ulacamten, respectively. Each trial addresses a different form of advanced heart failure, and these programs are central to our mission of delivering new medicines to patients suffering from diseases of cardiac muscle dysfunction and also addressing the high unmet needs in heart failure as we progress our specialty cardiology franchise forward. In summary, in the past quarter, we made important progress across regulatory, commercial readiness, and clinical development priorities, and we're building momentum as we approach important milestones expected to occur in the second half of 2025. With that, I'll turn the call over to Andrew, please.

Andrew M. Callos, EVP and Chief Commercial Officer

Thanks, Robert. With the PDUFA date extension, we've adjusted our plans and are leveraging the extra time to finalize U.S. commercial launch readiness activities as well as refine the implementation of our promotional campaign and patient support program. Recently, a key focus has been the hiring of our U.S. sales force. After our highly successful virtual recruiting event in April, we received over 8,800 applications and proceeded to hire a very experienced cardiovascular sales team, with nearly all territories now filled. This exceptional level of interest in joining Cytokinetics has provided a deep and experienced talent pool, enabling us to be highly selective in assembling a best-in-class sales team. We have now hired sales professionals who have existing relationships with cardiologists and possess deep therapeutic and industry expertise, positioning us to execute a highly impactful launch. Overall, our new sales colleagues have over 21 years of industry experience and an average of 14 years of cardiovascular experience. We expect to have the sales force on board and trained in Q4, so they're ready for an early Q1 2026 U.S. launch of aficamten. Additionally, during the quarter, we also made progress in optimizing our distribution network of specialty pharmacies and distributors. This infrastructure will be key in delivering a high-quality patient-centric experience for both patients and providers alike. We also advanced the development of our bespoke patient support program. Taken together, we have a goal to create an integrated, simple, and patient-centric treatment and assistance experience across all touchpoints, both for HCPs and their patients. As we approach potential approval later this year and commercialization, we remain focused and driven by the compelling unmet need. We believe that approximately 80% of eligible obstructive HCM patients will be treatment-naive relative to a cardiac myosin inhibitor. So symptomatic oHCM patients naive to CMIs and primarily in specialty centers for HCM represent an entry point for aficamten. Our launch strategy is to expand the market and ensure more cardiologists are comfortable with aficamten and more patients can potentially benefit from this new therapy. Importantly, according to our market research, nearly 80% of HCPs polled in HCM specialized centers are familiar with aficamten on a needed basis, giving us a strong starting point for initial engagement from which we expect to grow market adoption and to expand to community cardiology. Recently, market research findings that incorporated a target product profile based on MAPLE-HCM resulted in further support, likely expanding prescribing beyond HCM specialized centers. Our promotional launch campaign for both HCP and patients, which are currently in final market research testing and refinement, are designed to evolve in step with our market positioning in key areas of differentiation. We believe that given the differentiated profile of aficamten, these messages will resonate and contribute both to commercial launch as well as category preference. Payer engagement also remains a priority. And in the second quarter, we continued to educate payers on the results from SEQUOIA-HCM, along with the clinical and economic burden of HCM. We also began building foundational health economics and outcomes research models around budget impact, cost effectiveness, and cost comparisons to support both U.S. and ex-U.S. payer requirements as we approach potential regulatory approval in key U.S. and EU geographies. Specifically, in Europe, we are making meaningful progress for commercial readiness. In the second quarter, we added to our EU commercial team, our leadership team, and continued dossier preparation for 2026 submissions to multiple HTAs and progress launch readiness across multiple countries with a focus on our first potential commercial launch in Germany during the first half of 2026. Overall, I am pleased with where we've positioned relative to the potential upcoming approval of aficamten. With that, I'll turn the call over to Fady to share updates on our ongoing clinical trials program and medical affairs activities for aficamten.

Fady Ibraham Malik, Executive Vice President of Research & Development

Thanks, Andrew. During the second quarter, we were pleased to report positive top-line results from MAPLE-HCM, which demonstrated a statistically significant improvement in peak oxygen uptake from baseline to week 24 for aficamten compared to the standard of care beta blocker, metoprolol. Safety and tolerability profile of aficamten was also favorable in comparison to metoprolol. MAPLE-HCM is the only trial comparing a cardiac myosin inhibitor head-to-head with the long-standing standard of care therapeutic approach of beta-adrenergic receptor blockade. As we recently announced, the full results from MAPLE-HCM will be presented in a hotline session on Saturday, August 30, at the European Society of Cardiology Congress in Madrid later this month. A prespecified analysis from the trial on the effect of aficamten versus metoprolol on cardiac structure and function will also be presented on Sunday, August 31. Until then, we can't elaborate on the top-line results, but we look forward to sharing much more detail in a few weeks. Why are these data important? MAPLE-HCM reads not only on the treatment effect and safety of aficamten compared to metoprolol, but also on the impact of metoprolol itself on exercise performance, gradients, symptoms, and biomarkers. As you'll see when the results are presented at ESC, we believe these results may lead to their incorporation into treatment guidelines and may lead to changes in standard of care treatment algorithms in obstructive HCM. We also plan to share other data and analyses of interest at ESC, including a late-breaking clinical trial presentation on the incidence and impact of atrial fibrillation in patients with oHCM via an integrated analysis of REDWOOD-HCM, SEQUOIA-HCM, and FOREST-HCM. Atrial fibrillation has been an emerging topic of conversation around the safety of cardiac myosin inhibitors, but speculation as to whether adverse events of atrial fibrillation are disease-specific or treatment-dependent. As we've previously shared, in completed studies of aficamten, we've observed no difference in the rates of atrial fibrillation between placebo and aficamten. And in the open-label extension trial, FOREST-HCM, the incidence remains similar to historical data. We're looking forward to sharing these data that we believe reinforce a consistent safety profile for aficamten in patients with oHCM. At ESC, we'll also have an oral presentation on longer-term follow-up of patients treated with aficamten in FOREST-HCM with up to 3 years of data combined together into an updated integrated safety analysis of the clinical trials program for aficamten in oHCM, inclusive of MAPLE-HCM. In totality, we expect the data presented at ESC will importantly expand on the safety and longer-term effects of aficamten in patients with oHCM. Moving on to nonobstructive HCM. During the quarter, we continued the conduct of ACACIA-HCM, pivotal Phase III clinical trial of aficamten in nonobstructive HCM. As we previously communicated, ACACIA completed patient enrollment ahead of schedule earlier this year and in fact, exceeded our original target to randomize a total of 516 participants. During the second quarter, we reviewed the emerging safety data from ACACIA-HCM with the Data Monitoring Committee, which recommended continuing the trial without any changes to the protocol or study conduct. We expect to be able to share top-line results of the primary cohort from ACACIA-HCM, excluding Japan, in the first half of 2026. Speaking of Japan, we recently dosed the first patient in the Japan cohort of ACACIA-HCM, and our partner, Bayer, opened to enrollment CAMELLIA-HCM, a Phase III clinical trial in Japanese patients with obstructive HCM, a trial which is intended to support potential marketing authorization in Japan. As to ongoing clinical trials of aficamten, during the second quarter, we made progress enrolling CEDAR-HCM, which is evaluating aficamten in pediatric obstructive HCM. The trial remains on track to complete enrollment of its adolescent cohort in the second half of this year. Finally, in addition to progress in our clinical development programs, during the quarter, our field medical affairs teams engaged in nearly 600 U.S. HCP interactions, including over 200 HCM KOLs as well as over 50 European KOLs. The team also attended key payer conferences, including Asembia, AMCP, and regional AMCP meetings to actively engage with national and regional payers.

Stuart Kupfer, SVP and Chief Medical Officer

Thanks, Fady. First, we continued start-up activities and enrollment of COMET-HF, the confirmatory Phase III clinical trial of omecamtiv mecarbil in patients with symptomatic heart failure with severely reduced ejection fraction less than 30%. During the quarter, our first sites in Europe came online, and we continued expanding site activations in the U.S., both of which are driving progress in enrollment. We expect to continue enrolling COMET-HF through this year and to complete enrollment in 2026. Second, as we announced in today's press release, we received approval from the INN Program of the World Health Organization for ulacamten to be used as a nonproprietary name for CK-586. During the second quarter, we continued conduct of AMBER-HFpEF, the Phase II clinical trial of ulacamten in patients with symptomatic heart failure with preserved ejection fraction of at least 60%. Enrollment in the first cohort is progressing, and we're pleased by the progress we've made in activating new clinical trial sites and in engaging investigators in this important trial. Overall, we're encouraged by the clinical trials progress of both of these later-stage pipeline programs, which represent the next strategic pillars in advancing our specialty cardiology franchise. Despite the advances in heart failure care over the years, substantial unmet need persists across the spectrum of the disease and one that we believe our potential medicines may impact. With that, I'll pass it to Sung.

Sung H. Lee, EVP and Chief Financial Officer

Thanks, Stuart. We're pleased to report our second quarter of 2025 financial results. Starting with the balance sheet, we finished the second quarter with approximately $1.04 billion in cash, cash equivalents and investments compared to $1.09 billion at the end of the first quarter of 2025. In the second quarter, we exercised our option on the Tranche 4 loan provided by Royalty Pharma and received proceeds of $75 million. We have an option to draw $100 million on the Tranche 5 loan prior to November 25th of this year. R&D expenses for the second quarter were $112.6 million compared to $79.6 million for the same period in 2024. The increase was primarily due to advancing our clinical trials, higher personnel-related costs, and medical affairs-related activities. G&A expenses for the second quarter of 2025 were $65.7 million compared to $50.8 million for the same period in 2024. The increase was primarily due to investments towards commercial readiness and higher personnel-related costs. Net loss for the second quarter of 2025 was $134.4 million or $1.12 per share compared to a net loss of $143.3 million or $1.31 per share for the same period in 2024. Turning to our financial guidance, we are maintaining our full year 2025 financial guidance with GAAP operating expense expected to be between $670 million and $710 million. Stock-based compensation that is included in GAAP operating expense is expected to be between $110 million and $120 million. Excluding stock-based compensation from GAAP operating expense results in a range of $550 million to $600 million. We continue to monitor the pace of our commercial readiness investments as we move closer to the PDUFA date for aficamten, and we will update you accordingly. With our current balance sheet and access to additional capital, we are well positioned to fund the potential launch of aficamten in the U.S. later this year and continue to advance our pipeline. With that, I'll hand it back to Robert.

Robert I. Blum, President and Chief Executive Officer

Thank you, Sung. So midway through 2025, I'm pleased with the progress we've made and the position we are in ahead of a very important second half of the year. As we approach a significant inflection point, one that has been more than 25 years in the making, our company stands at the cusp of transformative growth. This moment reflects the culmination of decades of scientific innovation, strategic investment in R&D, and a steadfast commitment to delivering potentially meaningful therapies to patients in need. None of this would be possible without the dedication of our teams across the organization whose tireless work is propelling us towards these long-anticipated milestones. With a strong foundation, a clear vision, and the right people in place, we're poised to unlock substantial value for patients and shareholders, ushering in the next chapter of maturation as a fully integrated, high-impact leader in specialty biopharma. 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 to continue launch preparations for aficamten in the United States in the second half of this year. We expect to continue go-to-market planning in Germany and expand commercial readiness activities throughout Europe in 2025 in preparation for the 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 to present primary results from MAPLE-HCM later this month at ESC. We expect to report top-line results from the primary cohort of ACACIA-HCM in the first half of 2026, while we continue enrolling the Japan cohort of ACACIA-HCM in 2025. And we expect to complete enrollment of the adolescent cohort in CEDAR-HCM in the second half of this year. For omecamtiv mecarbil, we expect to continue patient enrollment in COMET-HF throughout 2025 to enable completion of enrollment in 2026. For ulacamten, 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 our ongoing research, we expect to continue ongoing preclinical development and research activities directed to additional muscle biology-focused programs. Operator, with that, we can now open up the call to questions, please.

Operator, Operator

And with that, our first question comes from Gena Wang with Barclays.

Huidong Wang, Analyst

I have several questions, but I will focus on one regarding the ESC update. You mentioned that the MAPLE data could potentially lead to a change in guidelines. Can you provide more details on the magnitude of benefit you anticipate? What key data points should we concentrate on, and how significant do you think the benefit would be for payers or physicians when considering making aficamten a first-line treatment or switching patients from beta blockers?

Robert I. Blum, President and Chief Executive Officer

So obviously, it's difficult to answer your question until you have the data that we have, but I'll ask Fady to do his best.

Fady Ibraham Malik, Executive Vice President of Research & Development

Yes. I think this is one of the few comparative efficacy trials conducted in cardiology. The data will show not only the differences between the two drugs but also the absolute benefits of each drug compared to the baseline when patients start treatment. Currently, cardiac myosin inhibitors are considered a last line of treatment after other options have failed. When we see the data from MAPLE-HCM, I believe that discussion will be revisited, and hopefully, the guidelines will be updated to reflect the superiority of aficamten over metoprolol and exercise tolerance. However, we'll need to wait for the data to be released before we can expand on that.

Operator, Operator

And your next question comes from the line of Akash Tewari with Jefferies.

Akash Tewari, Analyst

So look, it looks increasingly likely that you're going to get the Camzyos ODYSSEY data at ESC. What are the two or three things investors should be looking at in that data that would support the team's hypothesis that ACACIA will be successful where Camzyos wasn't and also would support a clear exposure response relationship in this population?

Robert I. Blum, President and Chief Executive Officer

Yes. So I'll take a stab at that and maybe ask Fady to add. I think it's very important to distinguish between that which is related to clinical trial conduct and that which is related to potential mechanism of action as translates to that patient population. Clearly, with ACACIA, we took what we believe to be an optimized dosing regimen that was verified in a Phase II study and took that into a Phase III trial where we elected to proceed without altering a lot of other things. We took a dose optimization regimen. We took a population. We focused on centers where we already had experience. And obviously, here at Cytokinetics, we have an expert team of HCM experts that have been both academically and industry trained in order to be able to ensure that patients met the criteria. The kinds of things that we'll be focused on are related to from a study conduct standpoint and operations; how much might there have been a change between the Phase II and the Phase III study for mavacamten and how much might that have read on the outcome in Phase III versus where we think we've been quite linear in focus from one to the next. Fady, anything you want to add?

Fady Ibraham Malik, Executive Vice President of Research & Development

I just might add that when you see the ODYSSEY data, and we see the ODYSSEY data, we haven't seen them yet, the question will be whether the trial didn't meet its primary endpoint because of specific features of mavacamten or trial conduct versus mechanism of action. And I think ultimately, that is what will provide some confidence in terms of ACACIA's potential success. But as Robert mentioned, we believe strongly in ACACIA's success just based on the strength of the Phase II data we generated and the fact that ACACIA is being conducted in a manner that was very consistent with the way we conducted Phase II.

Operator, Operator

And your next question comes from the line of Tess Romero with JPMorgan.

Tessa Thomas Romero, Analyst

So what does an ideal label look like for aficamten in obstructive HCM here? And Robert, can you just double-click on any specifics you can give us on the updated REMS that it sounds like you submitted versus the original one? And how these updates track to your expectations for a differentiated REMS?

Robert I. Blum, President and Chief Executive Officer

Yes. So there's a lot in that question that I cannot unpack given that we are in ongoing conversations with FDA. But I think what I can say is that an ideal label for aficamten is one that tracks with its engineered properties and the way it's been studied. And both are, we believe, enabling of differentiation as could be supportive of our expected profile. We designed into aficamten features that Fady has spoken of often, and we've studied aficamten in ways that we believe elaborate on how those features read on benefit-risk. And the data from our Phase II and Phase III studies and also as further substantiated in the open-label extension are supportive of what we've argued would be a potential differentiated program in the clinical setting for patients, but also for physicians. I might ask Andrew, our Chief Commercial Officer, to speak to how his market research has been pointing to the unmet need and where we believe a differentiated label could support our expectations and aspirations.

Andrew M. Callos, EVP and Chief Commercial Officer

Sure, Robert. I believe you highlighted that a distinct label would accurately reflect the results of the clinical trial and the properties of aficamten. In our market research, we've found that if the REMS and the label genuinely represent these properties and the study findings, we expect strong adoption at the centers of excellence where most prescribing is happening currently. As I noted earlier, more than 80% of physicians in those centers are already aware of aficamten, indicating very high awareness before our market entry. The potential to move into community cardiology and general cardiology, bolstered by this differentiation and supported by the MAPLE data, is what our market research suggests would lead to a preference for aficamten, even when considering possible overstatements in our research. Ultimately, we will need to see the final label and REMS from the FDA, but we feel optimistic based on these insights.

Operator, Operator

And your next question comes from the line of Salim Syed with Mizuho.

Salim Qader Syed, Analyst

I guess one for us on the oHCM late-cycle meeting. So Robert, what exactly are you planning to learn or discuss in that September late-cycle meeting? And just can you remind us how much of the REMS negotiation here actually happens post the late-cycle meeting, actually during the label negotiations themselves?

Robert I. Blum, President and Chief Executive Officer

Salim, very good questions. I'm not sure I can answer them to your full satisfaction simply because so much has already been discussed between Cytokinetics and FDA. I would hope that come the late-cycle meeting, we're learning that everything we are assuming continues to be tracking towards potential approval and that there's nothing new that gets introduced. But as far as the activities that have occurred, we believe we've addressed them without a lot of difference or distance between what FDA might be interested in and what we could provide with supportive evidence. Case in point, the REMS. FDA and Cytokinetics convened a meeting to discuss the REMS promptly after we submitted one. And the conversation was a very fruitful one. We were able to turn around very quickly revisions that we believe were responsive to FDA's interest. And as such, I would hope that at a late-cycle meeting, we get validation that we're all good to go. But this is somewhat unchartered territory with regard to a REMS conversation, and it may be that we learn something new. I hope not, but we're very much in a position where we think we're aligned together with FDA on what it's interested in. And to that point, it was anticipated very nicely by Cytokinetics, our colleagues here such that when we heard from FDA that they did, in fact, want a REMS, we were ready to submit one right afterwards. So I guess in that regard, to answer your question, at the late-cycle meeting, I'd like to learn that we're proceeding to final label conversations and that we're expecting no other new news.

Operator, Operator

And your next question comes from the line of Cory Kasimov with Evercore ISI.

Cory William Kasimov, Analyst

I wanted to ask about ACACIA and if you could explain how the drug interruption and discontinuation protocols differ compared to ODYSSEY. I'm particularly interested in how ACACIA differs from the four-week dose interruption required when left ventricular function drops below 50%, as seen in ODYSSEY. Additionally, could you highlight any other significant design differences between the two studies?

Robert I. Blum, President and Chief Executive Officer

Yes. So the design differences are significant. It would appear much like there are design differences in other studies. And again, how ACACIA is conducted in accordance with that design may ultimately prove to matter. So I'll ask Fady to comment now that we have ODYSSEY as published in terms of the design, and we know what we're doing with ACACIA, I think it's good to highlight some of those distinctions.

Fady Ibraham Malik, Executive Vice President of Research & Development

Yes, Cory, when LVEF drops below 50%, in the nonobstructive cases, there's no left ventricular outflow tract gradient to help manage that. In oHCM, we are managing the minimum effective dose, while in nHCM, we’re working with the maximum tolerated dose, which is a significant difference. With an EF under 50%, it's beneficial that in ACACIA, as long as the EF stays above 40%, patients can reduce the drug dosage without stopping treatment. For those with an EF below 40%, there is a drug interruption for about a week before resuming at a lower dose. This contrasts with ODYSSEY, where patients must stop treatment for four weeks, leading to considerable disruption. Additionally, in our Phase II testing, we evaluated multiple doses—5, 10, 15, and 20 milligrams—with 15 and 20 milligrams being the most frequently used. In ODYSSEY, starting doses were introduced at 1 milligram and 2.5 milligrams, allowing for down titration to those levels. However, we can't confirm if these doses are in the effective range. In ACACIA, we are examining doses where we believe we previously noticed significant clinical benefits in Phase II, which we’re now trying to replicate in Phase III. Regarding dosing for those with EF under 50%, these are the main differences. There are also variations in entry criteria related to thresholds, peak VO2, or NT-proBNP. Our team is very experienced with HCM and carefully reviews every patient echo that enters the study to ensure we have the right patient population. There are numerous differences to consider, and when we receive the ODYSSEY data, we’ll be able to evaluate which factors may influence ACACIA's long-term success.

Operator, Operator

And your next question comes from the line of Yasmeen Rahimi with Piper Sandler.

Unidentified Analyst, Analyst

This is Emma on for Yas. I guess one is, what are your expectations in regards to potential REMS differences between the U.S. and EU and implications of that?

Robert I. Blum, President and Chief Executive Officer

So understanding that in the EU, there is not the same sort of mechanism for REMS, it would otherwise be addressed in other means. I don't think there's going to be altogether so many differences taken collectively in light of the fact that we conducted an international study and the conversations we're having with FDA and EMA are tracking very similarly. So while there's not a formal REMS in Europe, we should expect and we are anticipating labels that are encompassing from a risk mitigation, drug-drug interaction, pharmacology, and otherwise dosing and indication that there's going to be so much more in common than necessarily would be different.

Operator, Operator

And your next question comes from the line of David Lebowitz with Citi.

Ike Lee, Analyst

This is Ike Lee on for David Lebowitz. I wanted to ask about the larger market opportunity in nonobstructive HCM, which we all know is there. Presumably, you will need to reach more community doctors is our understanding upon that launch. So thinking about that, how much larger do you think your sales force is going to be if and when that time comes?

Robert I. Blum, President and Chief Executive Officer

Yes. Perhaps I'll ask Fady and maybe Stuart, if he wants to add with regard to how nHCM is treated and where and then maybe ask Andrew also to add his perspective to that, especially as it might ultimately read on the size of our commercial group.

Fady Ibraham Malik, Executive Vice President of Research & Development

Yes, nHCM is just the beginning. We are observing cases of nHCM in clinics that are more severe and more apparent in echocardiograms. However, diagnosing this disease can be challenging. Stuart, could you elaborate on the difficulties in recognizing it and why it might be more widespread in the community than we currently acknowledge?

Stuart Kupfer, SVP and Chief Medical Officer

Well, I think as you commented previously, of course, the nonobstructive patients don't have gradients. And so that's one sort of key criterion that makes it more difficult to diagnose. And there are a number of features that make the HCM patients appear like patients with heart failure preserved ejection fraction. And so it does take some discrimination to identify these patients without assuming there are patients with heart failure with preserved ejection fraction. I think another important factor is, unlike obstructive HCM, where there are some more specific guidelines referring to available treatments, and we can debate about the evidence base to support those treatments, but there's even less guidance around treatments in nonobstructive HCM. So clearly, the medical need is even higher. And I think that maybe Andrew can address that.

Andrew M. Callos, EVP and Chief Commercial Officer

Sure. So when you look at nHCM versus oHCM, the initial physician target list won't be any different. So we're not expecting to increase our field force at the launch of nHCM if ACACIA is positive and it gets approved by regulatory authorities. The way we target and look at the cardiologists who are engaged in HCM, both diagnosis and treatment is through claims data and ICD-10 codes. And the physicians we're calling on for oHCM treat both nHCM and oHCM. And there's a really large overlap with those subspecialties who are advanced heart failure cardiologists as well who treat HCM. So the around 10,000 who are 80% of the HCM diagnosis and treatment is where we're focused. If we learn more about nHCM, which right now, it's about a 50-50 split between the size of the oHCM patient population and the nHCM population, then we'll certainly expand the field force as needed. But at launch, we're not expecting it.

Operator, Operator

And your next question comes from the line of Paul Choi with Goldman Sachs.

Unidentified Analyst, Analyst

This is Khalil calling in for Paul. It seems there's been a lot of questions about regulatory interactions. So I guess I'll ask about aficamten and commercial. I suppose given some other launches in cardiology recently, there's been this focus on patient access. So we're just curious whether you had any strategies in place to differentiate against perhaps Camzyos on patient access, whether that be commercial age patients or Medicare patients. That would be helpful for us.

Robert I. Blum, President and Chief Executive Officer

Yes. This is an area where I think Cytokinetics has been laser-focused already for quite some time, and Andrew and his expert team have been very diligently attending to this from a market development standpoint and what we'll read on aficamten. So I'll ask him to comment.

Andrew M. Callos, EVP and Chief Commercial Officer

Sure. So as Robert had mentioned, we've had our account manager field personnel talking to payers for quite some time. We've hit or have interacted with every major payer. When we look at commercial, we expect to have kind of parity of access in commercial. When we look at Medicare, we expect to have parity and access in Medicare. So really, the strategy is to have the same access and really have differentiation and support be the differentiators. And when you look at patient support, we are designing our patient support program around this patient population and the journey they go through and the support that's needed, including REMS. When you look at the kind of programs we'll support, we certainly will have for eligible patients, commercial patients, we'll have co-pay assistance, and we'll have patient assistance programs for those who are uninsured or underinsured. So I think you'll find that the patient support programs, the access, the affordability are really targeted to be at par, if not slightly differentiated positively from where mava is. The differentiation, again, is really going to be focused on the clinical data, the REMS, and the patient experience.

Operator, Operator

And your next question comes from the line of Jason Butler with Citizens JMP.

Jason Nicholas Butler, Analyst

Can you discuss some of the similarities and differences in preparing for the European launch as you expand into Europe and carry out your commercial work there?

Robert I. Blum, President and Chief Executive Officer

Yes. So understand our focus is on the U.S. launch, but we're taking measured and deliberate steps in Europe to prepare for what would hopefully be a launch in the first half of the year with focus on Germany and then from there. So Andrew, in leading those activities with colleagues already domiciled in Europe, are looking at this country by country and where reimbursement is going to be ungating of some significant investment. But I'll ask him to describe more in detail how we're thinking about this.

Andrew M. Callos, EVP and Chief Commercial Officer

Sure. So I think the key thing is obvious is it's a country-by-country launch in Europe. You get EMA approval for most of Europe, exclude Switzerland and the U.K. for now. But you get EMA approval, so you get uniform approval across the majority of the European countries, and then you have to get reimbursement on a country-by-country basis. You have free pricing in Germany for six months while you're negotiating price. So that is a key difference in terms of launch by launch and the government is the main payer. You have to go through health technology assessments and assign pricing and reimbursement before you launch. So beyond the regulatory gate, then you have a reimbursement gate. I think the other key difference is once that reimbursement occurs, they're usually occurring in focused centers of excellence, hospital-specific cardiology. So it's more narrow and focused prescribing generally in Europe than in the U.S. And as Robert alluded to, Europe does not have a REMS program. Risk management is typically handled as part of labeling. So I think they are the key differences. But fundamentally, in terms of the differentiation in aficamten from the clinical trial and how we communicate that, once we get that access, is going to be very similar, but again, on a country-by-country basis. Most of our spend does not occur on a country-by-country basis until reimbursement occurs. So we have gated and we're building Europe slowly, where the U.S. will launch all at once, hopefully, in late this year, early next year. Europe will launch really over about two to two and a half years based on that reimbursement timing.

Robert I. Blum, President and Chief Executive Officer

Hopefully, we're being good students of how companies have gone to Europe, some who have done it more successfully, most who have not, frankly. And that's where Sung, working with Andrew, working with others of our executives are taking a very disciplined, deliberate approach to how we think about Europe and doing so as is informed by de-risking milestones.

Operator, Operator

And your next question comes from the line of James Condulis with Stifel.

James Condulis, Analyst

Congrats on all the progress. Maybe just a quick one on HFpEF. Just curious, we'll get those data like early next year and wondering if you can kind of frame out what a win looks like. And kind of in that context, wondering how important you think success in Phase III within nonobstructive is to kind of confirm any initial signals there, just kind of given both are driven by systolic dysfunction.

Robert I. Blum, President and Chief Executive Officer

Yes. Good questions, especially the linkage between what we're doing in nHCM as could read on HFpEF. I'll ask Fady and Stuart both to comment, please.

Fady Ibraham Malik, Executive Vice President of Research & Development

Yes, I believe the discussions we've had about ACACIA provide some insight into our expectations for AMBER. I'll ask Stuart to explain the similarities between the two conditions and how we see them supporting one another.

Stuart Kupfer, SVP and Chief Medical Officer

Thank you for the question. As Fady mentioned, nonobstructive HCM patients indicate potential benefits in those with HFpEF and hypercontractility. The endpoints we are assessing in our Phase II AMBER-HFpEF trial will provide insights into these benefits. We are looking for symptomatic improvement, focusing on metrics like KCCQ and NYHA Class, as well as improvements in cardiac biomarkers such as NT-proBNP and troponin. Additionally, we will evaluate echocardiographic parameters for potential improvements in diastolic function. All of this will help us understand the overall benefit profile and determine if we should advance to Phase III, along with identifying the dose or doses that offer a favorable benefit-risk balance. We are encouraged by our observations with nonobstructive HCM and the benefits of aficamten in the Phase II REDWOOD trial and the current cohort under evaluation in FOREST, our open-label extension. These are some of the key findings we will focus on, along with safety and tolerability.

Operator, Operator

And your next question comes from Leonid Timashev with RBC Capital Markets.

Leonid Timashev, Analyst

I just want to ask, as you approach commercialization, how you're thinking about the message that you're going to lead with in HCM? I guess what I'm getting at is, what do you think really drives physician and patient enthusiasm to use the drug? And is it gradient, which is readily checkable? Is it the symptomatic benefits? Is it cardiac function? You have a lot of data across a lot of these endpoints and obviously, potential convenience advantages. I guess what's the messaging that you're going to lead with to try to drive use?

Robert I. Blum, President and Chief Executive Officer

Yes. I think you probably can appreciate it's not on an earnings call where we're going to be communicating our messaging and our positioning with any kind of specifics, rather instead, you should expect us to want to see the label and ultimately, we'll be promoting to label in ways that we think will be to the advantage of adoption of aficamten. But as we've discussed in the way that we've designed aficamten and the way we've studied it, we do believe there's high levels of differentiation. And it would be reasonable for this being a next cardiac myosin inhibitor for us to want to be focused on how might we be able to grow the category and grow preferential share of the category for the benefit of more patients, more physicians comfortable with cardiac myosin inhibitors. So maybe with that as a bit of a backdrop, I'll ask Andrew if there's anything further he might want to add.

Andrew M. Callos, EVP and Chief Commercial Officer

Yes. I mean, to your point, we're not going to get into what our messaging is. But generally, once the product is approved by the FDA, the physicians really want to understand and lead with the efficacy component, the balance of safety relative to that efficacy, and then in this instance, then the REMS. So we'll communicate clearly the differentiation. We believe we have differentiation in each of those areas, as well as very, very differentiated positioning, but you'll have to wait until we get our launch and approval and our label until that kind of gets unveiled. Thanks for the question.

Operator, Operator

And your next question comes from the line of Kripa Devarakonda with Truist Securities.

Unidentified Analyst, Analyst

This is Alex on for Kripa. Given that we might see approval in China as the first market, can you remind us of the dynamics of the China market and what type of cadence of revenue we can expect in the upcoming quarters?

Robert I. Blum, President and Chief Executive Officer

Yes. So this is somewhat of an uncommon situation, isn't it, that we might expect an approval in China even before an approval in the United States. It's not without precedent, but they are few and far between. With that said, we are working with Sanofi, our partner. And maybe I'll ask Andrew, he's one of the leaders of that collaboration, to speak to your question.

Andrew M. Callos, EVP and Chief Commercial Officer

You asking about market sizing and revenue? Is that right?

Unidentified Analyst, Analyst

Yes. And the rate that we can expect adoption in the market.

Andrew M. Callos, EVP and Chief Commercial Officer

So similar to the U.S., China would be the second market for aficamten. Like in Europe, you need to obtain the National Reimbursed Drug Listing in China. This takes place annually, and you must submit your application by the end of June of a given year to receive reimbursement the following January. Therefore, during the initial period, reimbursement will likely come from cash-paying patients rather than patients with NRDL access. I expect the initial uptake to be slow, but it is a sizable market with over 350,000 patients concentrated in about 1,300 hospitals. We are collaborating with a well-established multinational partner who has extensive knowledge of that market. While I won't comment on the timeline, I can say that once reimbursement is secured, I anticipate a rapid increase in adoption after the national drug reimbursement is granted. I hope that answers your question.

Operator, Operator

And your next question comes from the line of Joe Pantginis with H.C. Wainwright.

Joseph Pantginis, Analyst

First, for Andrew, as you're preparing with all your commercial plans, what do you feel are some of the necessary components that you will address but may not actually need, depending on how a potential REMS may or may not unfold? Secondly, for Stuart, as you're evaluating COMET and considering the company's extensive experience with omecamtiv, how would you describe the site's enthusiasm regarding enrollment compared to other omecamtiv studies?

Robert I. Blum, President and Chief Executive Officer

So the first question was a complicated one. I'm trying to make sure I understand it, Joe. Your question is the kinds of things we prepared for that we might not need to do. Is that what I heard?

Joseph Pantginis, Analyst

Correct, based on how REMS may or may not play out.

Robert I. Blum, President and Chief Executive Officer

Yes. So we're pretty clear-minded on how this is evolving. And frankly, it's quite aligned to the three meetings we had with FDA even before we submitted the NDA, although you'll remember, we did not submit originally with a REMS; we had already anticipated what we thought mattered to FDA, and we incorporated that into the label. And then FDA indicated it would, in fact, like to see a REMS. So we were already prepared to execute on that in the form of a REMS. So I don't know that there's much in the way of distance between what we expected and where we're at such that we had to prepare something that may not be relevant. I think we've got a pretty good idea as to where this is going. With respect to your next question, maybe I'll ask Stuart to comment on the level of investigator interest in COMET.

Stuart Kupfer, SVP and Chief Medical Officer

Yes. Bottom line is there's a lot of interest in COMET, and we're very pleased to see that, and it's for several reasons. One is recognition of the very high unmet need in these patients with heart failure and severely reduced ejection fraction. They really don't have medical options before on the road to end-stage heart failure. So they recognize that omecamtiv mecarbil is a potential medical option to save off that outcome. Second, they are very well aware of the results of GALACTIC, which, of course, was a positive trial. And in the subgroup of patients we're targeting now in COMET, the treatment benefit was of large magnitude, risk reduction for the heart failure outcome. So there's appreciation that because of the large sample size of the subgroup of patients and the results we observed in GALACTIC, there's a high probability of success. And third, I think they're very pleased to see we're running a very streamlined trial without much burden on investigators and their staff. And so operationally, it's going to be an easier trial to conduct. So overall, a lot of enthusiasm for COMET.

Operator, Operator

And your next question comes from the line of Jason Zemansky with Bank of America.

Unidentified Analyst, Analyst

This is Jackie on for Jason. Congrats on the progress. So now that you've seen more of the MAPLE data, can you comment on your expectations for first-line use? How receptive do you think prescribers and payers are likely to be? And how long do you think it will take before there can be appreciable uptake in this part of the market?

Robert I. Blum, President and Chief Executive Officer

Sure. So I'll start, and I think Fady and Andrew can both respond from their respective viewpoints. What I will say is that we conducted a study head-to-head of aficamten versus metoprolol. And I do believe it will raise some eyebrows as to what is currently guideline-directed first-line therapy. But maybe that shouldn't be too surprising in retrospect because those guidelines were written absent a randomized controlled study of metoprolol in this population. So this is building a body of evidence that didn't exist before. And for having done that, we do believe that aficamten, and you'll understand maybe why we believe this after you see the results, should be part of the conversation about what medicines to reach for in what order for the treatment of these patients. Now granted, metoprolol is a generic drug, and there's ample experience with beta blockers. But I do believe in Cytokinetics fashion, we're doing rigorous clinical research to inform guidelines, and the guidelines will hopefully take into consideration the way in which the study was robustly conducted and the fidelity of the results. With that, I'll ask Fady to speak to that and maybe Andrew, if he wants to also comment on how that might ultimately get reflected and over what time frame in guidelines and how that may afford adoption.

Fady Ibraham Malik, Executive Vice President of Research & Development

Yes. I mean, I think it's going to take a while before beta blockers are displaced as first-line treatment given the cost differential. But I think a study like MAPLE-HCM will facilitate earlier movement and hopefully elevate aficamten in the guidelines. So it's not seen as the last line of therapy before surgery potentially, but instead is seen on par with the other therapies that physicians can consider. And so if patients are only modestly improved, they know that they have an alternative that they can move to more quickly. And with longer time, we hope to be able to develop evidence that there are things beyond just symptom and function relief that aficamten addresses that other therapies don't, given aficamten targets the underlying path of the disease. So with that, I think this is the beginning of a sort of a longer run in terms of changing the standard of care in this disease.

Andrew M. Callos, EVP and Chief Commercial Officer

Yes, I would think, I mean, our expectation is launch in the first several years after launch that first-line therapy is likely not going to occur mainly because of payers. And Robert mentioned beta blockers obviously are generic. But what we do expect to occur is more patients being on aficamten than would have been otherwise without MAPLE. We expect the acceleration of an add-on of aficamten to a beta blocker and maybe weaning off a beta blocker after the start over time. So I think those are the kinds of things you'll see for the first several years. If guidelines are updated, and aficamten is part of first-line therapy, then with broader use, we could see first-line therapy. But again, I think that's several years out. Thanks for the question.

Operator, Operator

Your next question comes from the line of Mayank Mamtani with B. Riley Securities.

Unidentified Analyst, Analyst

This is William for Mayank. I wanted to follow up on ACACIA. You've primarily concentrated on the ODYSSEY study and the transition from Phase II to Phase III, discussing how that might lead to positive results next year. I'm also interested in how new data from the MAPLE study and past SEQUOIA might support ACACIA, and what specific endpoints you would highlight in support of those claims. Additionally, regarding REMS, how should we approach the REMS for oHCM in relation to non-obstructive HCM? Should we consider them to be similar or potentially different based on their profiles?

Robert I. Blum, President and Chief Executive Officer

Yes. So you're asking us to speculate on some things that are pretty far down the road. And obviously, we can't be considering claims. But the MAPLE study was conducted in a population of oHCM where echoes are very informative to how one approaches dose titration. ACACIA is conducted absent that in a very different population. So I'll ask Fady and Stuart to comment, but I can already suggest that we don't think that there's going to be a lot of translation from one to the other. Fady?

Fady Ibraham Malik, Executive Vice President of Research & Development

Yes. I think you asked whether there's anything we've learned in MAPLE or SEQUOIA that might inform ACACIA. And we've already published data from SEQUOIA that look at how aficamten improves diastolic function, the relaxation of the heart, which is probably the primary mode by which patients with nHCM will receive treatment benefit since they don't have a gradient to reduce. And similarly, you'll see data presented on diastolic function in MAPLE at the ESC. That's part of the late breaker that I described earlier. And so I think both of these data sets will inform the fact that there is a meaningful pharmacologic effect that we believe impacts the functioning of the heart in nHCM. So I think both of those studies are supportive, and those analyses are supportive of ACACIA's potential success. And as to the other questions, I agree, it's kind of a little too early to speculate on those labeling or REMS, things like that. I don't know if there's anything you'd like to add, Stuart.

Stuart Kupfer, SVP and Chief Medical Officer

Well, the only thing I'll add is the safety and tolerability profile we've observed in obstructive HCM in SEQUOIA. And that would be the fact that aficamten is a drug with a shallow exposure response profile, a relatively short half-life, and a very quite stable PK profile. I think all that contributes to what we observed in obstructive HCM in terms of its tolerability and expectation that will carry through to nonobstructive HCM.

Robert I. Blum, President and Chief Executive Officer

In our Phase II REDWOOD Cohort 4, we observed significant effect changes that give us confidence that if this continues into Phase III, we should expect a positive outcome for ACACIA-HCM. It's also important to remember that those patients transition into FOREST. Since FOREST is an open-label study, later this year, you will see results from patients who moved into FOREST with nHCM, which reinforces our expectations for ACACIA next year. Therefore, we remain very optimistic about ACACIA.

Operator, Operator

And your next question comes from the line of Serge Belanger with Needham & Company.

John Gionco, Analyst

This is John on for Serge today. Just wanted to touch back on with omecamtiv and the COMET trial. It seems like you guys have been getting some positive feedback from investigators and KOLs. Just wanted to gauge kind of how enrollment is tracking relative to your internal expectations as you're on your way to completing enrollment next year.

Robert I. Blum, President and Chief Executive Officer

Stuart, do you want to take that?

Stuart Kupfer, SVP and Chief Medical Officer

Certainly. As we mentioned in our call today and in the press release, the enrollment for the COMET-HF trial is progressing as planned. This trial involves 1,800 patients, which is less than a quarter of the size of GALACTIC, making it more manageable operationally. However, we are focusing on a more severe patient population, specifically a smaller subgroup of patients with HFrEF. Nonetheless, we still aim to finish enrollment by the end of next year. Most site activations in the U.S. are complete, and we are also on schedule for site activations in Europe. Overall, everything is proceeding as expected.

Robert I. Blum, President and Chief Executive Officer

What's important to note with this study is it's not competing with a bunch of other studies for the same population. This is a population that we don't believe is well served by existing standard of care or other investigational treatments. And instead, we're building off a body of evidence where we've already seen in GALACTIC, a profound treatment effect in these patients, and we just want to confirm that in this next trial. So that's contributing, we believe, to momentum for the study.

Operator, Operator

And your next question comes from the line of Roanna Ruiz with Leerink Partners.

Mazahir Lukman Alimohamed, Analyst

This is Mazi on for Roanna. Just one from us, obviously. So from a cardiac myosin biology perspective, as you advance aficamten and more of the HCM phenotypes and develop ulacamten for HFpEF, with this distinct mechanism, can you discuss the key differentiating factors and how these myosin inhibitors differ and how they interact with sarcomere function?

Robert I. Blum, President and Chief Executive Officer

Sure. Nobody better than Fady Malik to answer that question.

Fady Ibraham Malik, Executive Vice President of Research & Development

Well, so it's really interesting when we look at the myosin motor protein after 20-plus years, we've now identified three distinct binding sites for small molecule modulators of the protein. Aficamten binds in one place, omecamtiv mecarbil and mavacamten bind in another place. And lastly, the CK-586 or ulacamten bind and even a third place. And each of them has distinct effects on how they impact motor function in the sarcomere, you can describe. I won't really go into the details and specifics here. But those differences, I think, as we may be seeing in the clinic lead to differences in their profiles. And I think it's still a little early to know exactly how they differ and which one may be preferred. But there are, I think, differences that are emerging. With ulacamten, we see potentially a more shallow decrease in ejection fraction, a more shallow PK/PD curve than even aficamten. And we think the reversibility of both compounds is not just a feature of the compound itself, but also potentially the mechanism where they bind. So I'd say stay tuned. I hope to someday write a paper that describes all the various different biology and how it links to clinical.

Operator, Operator

And your next question comes from the line of Ash Verma with UBS.

Ashwani Verma, Analyst

I wanted to ask like this late-cycle meeting push out from June to September, is that a result of your prior 3-month PDUFA extension? Or is this a separate development, which can now have a cascading effect on your PDUFA date? What I'm trying to understand is like does the September late-cycle meeting give FDA enough of a runway to now finish up the wrap-up activities on the review before the deadline?

Robert I. Blum, President and Chief Executive Officer

Yes. So as we said in the scripted comments, we believe that the shift in the late-cycle meeting is consistent with the PDUFA date extension, and we don't have any reason to think that there's anything else here. And we believe that based on interactions we've been having in the meantime with FDA that we should consider still this as a hopeful approval consistent with the PDUFA date. No reason to believe otherwise.

Operator, Operator

And I'm showing no further questions at this time. I would like to turn it back to the President and CEO, Robert Blum, for closing remarks.

Robert I. Blum, President and Chief Executive Officer

Thank you, operator, and thanks to all the participants on our call today. We appreciate your continued support. We appreciate your continued interest in Cytokinetics. Lots going on, and we think this midyear check-in is indicative of why we continue to be quite ambitious and hopeful and planning for success with what we hope will be our first medicine to be potentially approved later this year and all that goes with it. With that, operator, we can conclude the call. Thanks very much.

Operator, Operator

Thank you, presenters. And ladies and gentlemen, this concludes today's conference call. Thank you all for joining. You may now disconnect.