Thank you for standing by. 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, and all participants are in a listen-only mode. After the speaker's remarks, we will open the call to questions. We will allow for one question per participant. If you would like to ask a question during this time, simply press the star, followed by the number one on your telephone keypad. If you would like to withdraw your question, please press the star one again. I would now like to turn the call over to Diane Weiser, Cytokinetics Senior Vice President of Corporate Affairs. Please go ahead.
Good afternoon, and thanks for joining us on the call today. Robert Blum, President and Chief Executive Officer, will begin with an overview of the quarter and recent developments. Andrew Callos, EVP and Chief Commercial Officer, will address commercial readiness activities for aficamten. Fady Malik, EVP of R& D, will provide updates related to 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. 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. Now I will turn the call over to Robert.
Thank you, Diane, and thanks to all for joining us on the call today. The first 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 26th, 2025. Our late-cycle review meeting has since been moved to September, consistent with the three-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 during or rather 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 and pharmaceutic 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 in 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, and that's on 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 our 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 also 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 it's 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 continue 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 also 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.
Thanks, Robert. With the PDUFA date extension, we 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 onboard 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. 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 native basis, giving us a strong starting point for initial engagements 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 prescribed and 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 and 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 continue 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 affair activities for aficamten.
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 a longstanding 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 30th, at the European Society of Cardiology Congress in Madrid later this month. A pre-specified analysis from the trial on the effect of aficamten versus metoprolol on cardiac structure and function will also be presented on Sunday, August 31st.
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, with 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 three 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 non-obstructive HCM, during the quarter, we continued conduct of ACACIA-HCM, pivotal Phase III clinical trial of aficamten in non-obstructive HCM. As we previously communicated, ACACIA completed patient enrollment ahead of schedule earlier this year and, in fact, exceeded our original targets to randomize a total of 516 patient or 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. Now I'll turn it over to Stuart to provide updates on our other late-stage development programs.
Thanks, Fady. First, we continued startup 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 non-proprietary 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, a 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.
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 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 IV loan provided by Royalty Pharma and received proceeds of $75 million. We have an option to draw $100 million on the Tranche V loan prior to November 25 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 toward 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. W e are maintaining our full-year 2025 financial guidance with GAAP operating expense expected to be between $670 million and $710 million. Stock-based compensation that is included in GAAP operating expense is expected to be between $110 million and $120 million. Excluding stock-based compensation from GAAP operating expense results in a range of $550 million- $600 million. We've continued 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.
Thank you, Sung. 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 the 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. 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. 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.
Thank you. We will now begin the question and answer session. If you have dialed in and would like to ask a question, please press the star one on your telephone keypad to raise your hand and join the queue. If you would like to withdraw your question, simply press the star one again. If you are called upon to ask your question and are listening via a loudspeaker on your device, please pick up your headset and ensure that your phone is not on mute when asking your question. Just a reminder, we will allow for one question per participant. With that, our first question comes from the lineup. Gena Wang with Barclays, please go ahead.
Hello, Diane.
Thank you for taking my question. I have so many, but I will limit my question to one. That's regarding the ESC update. You did mention the MAPLE data could be potentially a guideline change. Can you elaborate a little bit? What kind of a magnitude of benefit are you looking for? What are the key data points we should be focusing on? What kind of a magnitude benefit would a payer or physician be willing to use first line or switch those patients on beta blockers to aficamten?
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.
Hi, Diane. Yeah, you know I think the data, and this is really one of the few comparative efficacy trials that's conducted in cardiology. When the data themselves will present a picture not only of the difference between the two, but what is, you know, the absolute benefit of each of the two drugs themselves compared to baseline when these patients start the drug. Right now, cardiac myosin inhibitors are thought of as, you know, last line of treatment after you fail everything else. I think, you know, when we see the data from MAPLE-HCM, that conversation will be revisited and hopefully guidelines as well will be updated to reflect, you know, what we have already announced as the superiority of aficamten versus metoprolol in exercise tolerance. I think we'll just have to wait to be able to expand on that once the data are out.
Thank you.
Thank you, Gena.
Your next question comes from the line of Akash Tewari with Jefferies, please go ahead.
Hey, thanks so much. It looks increasingly like either 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, you know, 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? Thank you.
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 the centers where we already had experience. Obviously, here at Cytokinetics, we have an expert team of HCM experts that have been both academic 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 one to the next. Fady, anything you want to add?
I think I just might add that, you know, 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, you know, mechanism of action. I think ultimately that is what will provide some confidence in terms of Acacia's potential success. I think, 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.
Thank you, Akash.
Your next question comes from the line of Tessa Romero with JP Morgan. Please go ahead.
Hi. Good afternoon, Robert and team. Thanks so much for taking our question. What does an ideal label look like for aficamten in obstructive HCM here? 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? How are these updates tracked to your expectations for a differentiated REMS? Thank you.
Yeah. There's a lot in that question that I cannot unpack given that we are in ongoing conversations with FDA. 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. Both are, we believe, enabling of differentiation as could be supportive of our expected profile. You know, 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. 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.
Sure, Robert. I think you addressed well that a differentiated label really would reflect the results of the clinical trial and the properties of aficamten. In terms of market research, I think what we've seen in our research is if the REMS and the label do reflect the properties and the study, that we would be expecting good uptake at the centers of excellence where most of the prescribing is occurring now. There's already, as I mentioned in my remarks earlier, a lot of, you know, 80% plus of physicians in those centers who are aware of aficamten. Very, very high awareness even before we come to market. That expansion into community cardiology and general cardiology supported by that differentiation, further supported by MAPLE, that's what we're finding in our market research leading to a preference here, even adjusted for overstatement in our market research.
Ultimately, we have to wait to see what that label and REMS looks like from the FDA, but we're pretty bullish given those comments.
Thank you, Andrew. Thank you, Tess.
Your next question comes from the line of Salim Syed with Mizuho, please go ahead.
Hey, guys. Good afternoon. Thanks for the question. I guess one for us on the oHCM late cycle meeting. Robert, what exactly are you planning to learn or discuss in that September late cycle meeting? Can you remind us how much of the REMS negotiation here actually happens post the late cycle meeting, actually during the label negotiations themselves? Thank you.
You know, 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. 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 interests.
As such, I would hope that at a late cycle meeting, we get validation that we're all good to go. 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. 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. 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.
Okay. Got it. Thank you very much.
Thank you.
Your next question comes from the line of Cory Kasimov with Evercore ISI. Please go ahead.
Hello, Cory.
Hey, Robert. Good afternoon. I wanted to ask, I go back to ACACIA, and I'm wondering if you could walk us through how drug interruptions and discontinuation protocols differ versus ODYSSEY. I'm particularly curious about how ACACIA differs from the four-week dose interruption that is necessary if LVF drops below 50%, as was the case in ODYSSEY. Maybe you can point out any other significant design differences you would maybe call out between the two studies. Thank you.
Yeah. The design differences are significant. It would appear much like there are design differences in other studies. Again, how ACACIA is conducted in accordance with that design may ultimately prove to matter. 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.
Yeah. Hi, Cory. I think, you know, with regards to what happens when LVEF falls below 50%, you know, and in non-obstructives, you don't have a left ventricular outflow tract gradient to buffer you, you know, for that. I think of what we do in oHCM as we're tolerating a minimum effective dose, whereas in nHCM, we're tolerating the maximum tolerated dose, which is quite a different concept. With EF less than 50%, it's nice that in ACACIA, primarily as long as the EF is above 40%, patients can just down-titrate drug. There is no treatment interruption. For an EF below 40%, they do interrupt drug for about a week, and they would resume drug after that at a lower dose.
That's a substantial difference, I think, from ODYSSEY, where patients have to interrupt drug for four weeks and restart, and it leads to a lot of disruption, if you will, in treatment. Another aspect of this is that we tested all the doses, if you will, in Phase II, 5 mg, 10 mg, 15 mg, and 20mg, and primarily the 15 mg and 20 mg doses were the ones that were most commonly used. We know that in ODYSSEY, the MS introduced doses of 1 mg and 2.5 mg. Patients could down-titrate to those doses. Ultimately, we don't know if the dose density, if you will, is in the range that is known to be what is potentially effective. In ACACIA, we are testing doses where at least we believe we saw meaningful clinical benefit in the Phase II, and as we're trying now to replicate in Phase III.
I think, with regard to dosing, those are in EFs of less than 50%, those are the major differences. There are some differences in the entry criteria with regards to thresholds, upper limit for VO2 or NT-proBNP. We have a group here that is highly knowledgeable about HCM and really look at every patient echo that came into the study. Trying to maximize, if you will, the appropriateness of the patient population. I think there are a number of differences there. Ultimately, when we see the ODYSSEY data, we can ask ourselves which of them might be impactful in terms of Acacia's success down the road.
That's very helpful. Appreciate it.
Thanks, Cory.
Your next question comes from the line of Yasmin Rahimi with Piper Sandler. Please go ahead.
Hi. This is Emma on for Yas. Thank you for taking our question. I guess mine is, what are your expectations in regards to potential REMS differences between the U.S. and EU and implications of that? Thank you.
Understanding that in the EU, there is not the same sort of mechanism for a 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. 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.
Thank you.
Thank you.
Your next question comes from the line of David Lebowitz with Cedar. Please go ahead.
Hello, David.
Hi, Robert. Thanks for taking our question. This is Ike Lee on for David Lebowitz. I wanted to ask about the larger market opportunity in non-obstructive HCM, which we all know is there. Presumably, you will need to reach more community doctors, is our understanding, upon that launch. Thinking about that, how much larger do you think your sales force is going to be if and when that time comes? Thank you.
Yeah. 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.
Yeah. No, you know, nHCM is really like the tip of the iceberg. I think we're seeing, we see nHCM cases in clinics that are more severe, more obvious on echocardiograms and things. It's a disease that is difficult to diagnose. Maybe, Stuart, I'll ask you to comment on what are the challenges with recognizing it and why it might be far more prevalent throughout the community than we recognize.
I think as you commented previously, of course, the non-obstructive patients don't have gradients. That's one sort of key criterion that makes it more difficult to diagnose. There are a number of features that make the HCM patients sort of appear like patients with heart failure with preserved ejection fraction. It does take some discrimination to identify these patients without assuming they're 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, there's even less guidance around treatments in non-obstructive HCM. Clearly, the medical need is even higher. I think that maybe Andrew can address that.
Sure. When you look at nHCM versus oHCM, the initial physician target list won't be any different. We're not expecting to increase our field force at the launch of nHCM ACACIA-HCM 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. The physicians we're calling on for oHCM treat both nHCM and oHCM. There's a really large overlap with those subspecialties who are advanced heart failure cardiologists as well who treat HCM. 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 is about a 50/50 split between the size of the oHCM patient population and the nHCM population, we'll certainly expand field force as needed.
At launch, we're not expecting it.
Thank you. Your next question comes from the line of Paul Choi with Goldman Sachs. Please go ahead.
Hi. This is Khalil calling in for Paul. Thank you so much for taking our question. It seems there's been a lot of questions about regulatory interactions. I guess we'll ask about aficamten and commercial. I suppose given some other launches in cardiology recently, there's been this focus on patient access. We're just curious whether you had any strategies in place to differentiate against perhaps Camzyos on patient access, whether that be, you know, commercial age patients or medical patients. That would be helpful for us. Thank you so much.
Yeah. This is an area where I think Cytokinetics has been laser-focused already for quite some time. Andrew and his expert team have been very diligently attending to this from a market development standpoint and what will read on aficamten. I'll ask him to comment.
Sure. 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 in access in Medicare. The strategy really is to have the same access and really have differentiation and support be the differentiators.
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 kinds of programs we'll support, we certainly will have for eligible patients, you know, commercial patients, we'll have copay assistance. We'll have patient assistance programs for those who are uninsured or underinsured. 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 mavacamten is. The differentiation, again, is really going to be focused on the clinical data, the REMS, and the patient experience.
Got it. Thank you very much.
Your next question comes from the line of Jason Butler with Citizens GMP. Please go ahead.
Hi. Thanks for taking the question. I guess an extension of that. When you think about the expansion into Europe and the commercial work that you're doing there, can you maybe speak to some of the similarities and differences of what needs to be done to get ready for the European launch?
Yeah. 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 to Germany and then from there. Andrew, in leading those activities with colleagues already domiciled in Europe, is looking at this country by country and where reimbursement is going to be ungating of some significant investment. I'll ask him to describe more in detail how we're thinking about this.
Sure. I think the key thing is obvious is it's a country-by-country launch in Europe. You get EMA for most of Europe, you know, exclude Switzerland and the UK for now. You get EMA approval, so you get uniform approval across the majority of the European countries. 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. 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, then you launch. Beyond the regulatory gate, 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. It's more narrow and focused prescribing generally in Europe than in the U.S.
As Robert alluded to, Europe does not have a REMS program. Risk management is typically handled as part of labeling. I think those are the key differences. Fundamentally, in terms of the differentiation in aficamten from the clinical trial and how we communicate that, once we get that access, that's going to be very similar. Again, on a country-by-country basis. Most of our spend does not occur on a country-by-country basis until reimbursement occurs. We have gated, and we're building Europe slowly where the U.S. will launch all at once, hopefully, in the end of this year, early next year. Europe will launch really over about two to two and a half years based on that reimbursement timing.
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. 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.
Thank you. Your next question comes from the line of James Condulis with Stifel. Please go ahead.
Hey, thanks so much for taking my question and congrats on all the progress. Maybe just a quick one on HFpEF. Just curious if we'll get those data early next year and wondering if you can kind of frame out what a win looks like. In that context, wondering how important you think success in Phase III within non-obstructive is to confirm any initial signals there, just given both are driven by systolic dysfunction. Thanks so much.
Yeah, 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.
Yeah. I mean, I think the discussions we've had around ACACIA earlier are a good read on what we think we'll, we hope to see in AMBER. I'll ask Stuart maybe to draw the parallels between the two conditions and how we think each one will be reinforcing of the other.
Thank you for the question. As Fady mentioned, the non-obstructive HCM patients do inform potential benefit in these patients with HFpEF and hypercontractility. The endpoints that we're evaluating in our Phase II AMBER-HFpEF trial will read on the potential benefit. We're evaluating for symptomatic improvement, looking at endpoints like KCCQ, NYHA class, looking for improvements in symptoms, cardiac biomarkers like NT-proBNP and troponin. Of course, evaluating echocardiographic parameters, looking for potential benefit in terms of diastolic function.
These will all contribute to the profile of potential benefit that will inform whether we progress to Phase III and identifying dose or doses that will result in a favorable benefit risk profile. We're encouraged by what we observe with non-obstructive HCM and the benefits with aficamten and the Phase II REDWOOD trial and the ongoing cohort that's being evaluated in FOREST, our open label extension. Those are some of the key findings that we'll be looking for as well, as well as safety and tolerability.
Thanks.
Your next question comes from the line of Leonid Timashev with RBC Capital Markets. Please go ahead.
Hey. Thanks for taking my question. I just wanted 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, you know, what do you think really drives physician and patient enthusiasm to use the drug? I mean, 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 these things?
Yeah. 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. 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. 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.
Maybe with that as a bit of a backdrop, I'll ask Andrew if there's anything further he might want to add.
Yeah. I mean, to your point, we're not going to get into what our messaging is. Generally, once a product's 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, the REMS. We'll communicate clearly the differentiation. We believe we have differentiation in each of those areas, as well as very, very differentiated positioning. 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.
All right. Thank you. Your next question comes from the line of Kripa Deverakonda with Truist Securities. Please go ahead.
Hi. 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? Thanks.
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. Maybe I'll ask Andrew, he's one of the leaders of that collaboration, to speak to your question.
You asked about market sizing and revenue. Is that right?
Yes, and the rate that we can expect adoption in the market.
Like the U.S., China would be aficamten would be second to market. Kind of like Europe, you need to get NRDL listing, you know, National Reimbursed Drug Listing in China. That usually occurs on an annual basis, and you have to file by the end of June of a given year to have reimbursement the following January. Likely, the first period of time reimbursement would be through cash-paying market versus, say, mava having NRDL. I would imagine that the uptake would be slow at start, but it's a large market. As you can imagine, there's over 350,000 patients who are very concentrated into about 1,300 hospitals. Obviously, we have a very sophisticated multinational partner who knows that market extremely well. I won't comment on the phasing, but I would only say that once reimbursement occurs, I would expect an acceleration followed by that national drug reimbursement.
Hopefully, that answers your question.
Yeah, thanks. Congrats on the progress.
Thank you.
Your next question comes from the line of Joe Pantginis with HC Wainwright. Please go ahead.
Hey, everybody. Good afternoon. Thanks for taking the question. First, I guess maybe for Andrew, as you're preparing with all your broad commercial preparations, what do you feel are some of the components that you're required to do but won't necessarily need, but needed to go through the motions depending on how a potential REMS may or may not play out? Secondly, potential for Stuart, you know, as you're looking at COMET with the company's broad, very broad experience with omecamtiv mecarbil long-term, how would you characterize the site excitement with regard to enrollment versus all the other omecamtiv mecarbil studies? Thanks.
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?
Correct. You know, based on how REMS may or may not play out.
Yeah. You know, we're pretty clear-minded on how this is evolving. 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 label. FDA indicated it would, in fact, like to see a REMS. We were already prepared to execute on that in the form of a REMS. 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.
Yeah. Thank you. 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 need in these patients with heart failure and severely reduced ejection fraction. They really. They
really don't have medical options before, you know, on the road to end-stage heart failure. They recognize that omecamtiv mecarbil is a potential medical option to stave off that outcome. Second, they're very well aware of the results of GALACTIC, which of course was a positive trial. 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. 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. Third, I think they're very pleased to see we're running a very streamlined trial without much burden on investigators and their staff. Operationally, it's going to be an easier trial to conduct. Overall, a lot of enthusiasm for COMET.
Great. Appreciate the clarification and color, guys.
Thank you.
Thanks, Joe.
Your next question comes from the line of Jason Szymanski with Bank of America. Please go ahead.
Hi, good afternoon. This is Jackie on for Jason. Thanks for taking your question and congrats on the progress. 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'll take before there can be appreciable uptake in this part of the market?
Sure. 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'll raise some eyebrows as to what is currently guideline-directed first-line therapy. Maybe that shouldn't be too surprising in retrospect because those guidelines were written absent a randomized controlled study of metoprolol in this population. This is building a body of evidence that didn't exist before. 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 and 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 timeframe in guidelines and how that may inform adoption.
Yeah, I mean, I think it's going to take a while before beta-blockers are displaced as first-line treatment given the cost differential. 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, you know, the last line of therapy before surgery potentially, but instead is, you know, seen on par with the other therapies that physicians can consider. If patients are only modestly improved, you know, they know that they have an alternative that they can move to more quickly. 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, you know, the underlying path of disease.
With that, we someday may be able to show that, you know, we reduce the progression of disease. It becomes, I think, a much more important question as to which therapy to start. This is the beginning, I think, of a sort of a longer run in terms of changing the standard of care in this disease.
Yeah, I would think it, 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. You know, Robert mentioned beta-blockers obviously are generic. What we do expect to occur is, you know, 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. 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. Again, I think that's, you know, several years out. Thanks for the question.
Okay, thank you. Your next question comes from the line of Mayank Mumtani with B Riley Securities. Please go ahead.
Thanks for taking our question. This is William for Mayank. I just wanted to circle back to ACACIA. Today, you've mainly focused on sort of the ODYSSEY and the Phase II to Phase III transition on how that supports potential positive results when that reads out next year. I was also curious how new data from the MAPLE study, also from past SEQUOIA, how those may, that new data may support ACACIA and what specifically, specific endpoints you may, specifically can highlight that may support those claims. Also, just in terms of REMS, how should we think about the REMS in oHCM to read through to non-obstructive HCM? Should we think that those would be relatively the same or potentially differentiating just based on profiles? Thank you.
You're asking us to speculate on some things that are pretty far down the road, and obviously we can't be considering claims. The MAPLE study was conducted in a population of oHCM where echos are very informative to how one approaches dose titration. ACACIA is conducted absent that in a very different population. 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?
I think, you know, you asked whether there's anything we've learned in MAPLE or SEQUOIA that might inform ACACIA. We've already published data from SEQUOIA that look at how aficamten improves diastolic function, you know, 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. Similarly, you'll see data presented on diastolic function in MAPLE at ESC. That's part of the late breaker that I described earlier. I think both of these data sets will inform the fact that there is a meaningful pharmacologic effect that, you know, we believe impacts the functioning of the heart in nHCM. I think both of those studies are supportive, and those analyses are supportive of ACACIA's potential success.
As to the other questions, I agree it's kind of a little too early to speculate on those, you know, labeling or REMS, things like that. I don't know if there's anything you'd like to add, Stuart.
The only thing I'll add is the safety and tolerability profile we've observed in obstructive HCM in SEQUOIA. The fact that aficamten is a drug with a shallow exposure response profile, relatively short half-life, and very quite stable PK profile, I think all that contributes to what we observe in obstructive HCM in terms of its tolerability and the expectation that will carry through to non-obstructive HCM.
You know, you didn't ask this, but I'll add, in our Phase II REDWOOD Cohort 4, we saw very large magnitude effect changes that give us confidence that if that translates in Phase III, we should anticipate a good outcome for ACACIA-HCM. Also, please don't lose sight of the fact that those patients roll over into FOREST. FOREST is an open-label study. Later this year, you'll have a chance to see what we're already seeing in patients who rolled into FOREST with nHCM. That gives us confidence in what we can expect from ACACIA next year. We remain quite optimistic about ACACIA.
Appreciate that.
Thank you, Andy. All right, thank you. Your next question comes from the line of Serge Bellajee with Needham and Company. Please go ahead.
Hi, good afternoon. This is John. I'm for Serge today. Thanks for squeezing in my question. I 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's tracking relative to your internal expectations as you're on your way to completing enrollment next year. Thanks.
Stuart, you want to take that?
Sure. As we sort of indicated in our call today and a press release, the COMET-HF trial enrollment is on track. We plan to, you know, this is an 1,800-patient trial, less than 1/4 of the size of GALACTIC. That certainly makes it easier in terms of the operational scope. However, this is a more severe patient population. We are targeting a smaller subgroup of patients with HFrEF. Having said that, the plan is still to complete enrollment by the end of next year. We have site activations, most of them complete in the U.S., and we're on track for site activations in Europe as well. Things are going according to plan.
You know, 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. Instead, we're building off a body of evidence where we've already seen in GALACTIC a profound treatment effect in these patients. We just want to confirm that in this next trial. That's contributing, we believe, to momentum for the study.
All right, thank you. Your next question comes from the line of Rowana Ruiz with Leerink Partners. Please go ahead.
Thank you. This is Maisie on for Rowana. From a cardiac myosin biology perspective, as you advance aficamten in more of the HCM phenotypes and develop ulacamten for HFpEF with its distinct mechanism, can you discuss the key differentiating factors in how these myosin inhibitors differ in how they interact with sarcomere function?
Sure. Nobody better than Fady Malik to answer that question.
It's really interesting, you know, when we look at the myosin motor protein, after 20+ 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. Lastly, CK-586 or ulacamten bind in even a third place. Each of them has distinct effects on how they impact motor function in the sarcomere. You know, I won't really go into the details and specifics here. Those differences, I think, as we may be seeing in the clinic, lead to differences in their profiles. I think it's still a little early to know exactly how they differ and which one may be preferred. There are, I think, differences that are emerging. ulacamten, we see potentially a more shallow decrease in ejection fraction, a more shallow PK/PD curve than even aficamten.
We think the reversibility of both compounds is not just a feature of the compound itself, but also potentially the mechanism where they bind. I'd say stay tuned. I hope to, I'm going to write a paper that describes all the various different biology and how it links to clinical.
Thank you so much.
Yeah, good question.
Your next question comes from the line of Ash Verma with UBS. Please go ahead.
Oh, hi. Yeah, thanks for taking my question. I wanted to ask, this late-cycle meeting push out from June to September, is that a result of your prior three-month relief extension, or is this a separate development which can now have a cascading effect on your relief date? What I'm trying to understand is, there's a September late-cycle meeting. We give FDA enough of a runway to now finish up the wrap-up activities on the review before the deadline. Thanks.
As we said in the scripted comments, we believe that the shift in the late-cycle review meeting is consistent with the PDUFA date extension, and we don't have any reason to think that there's anything else here. We believe that based on interactions we've been having in the meantime with FDA, we should consider this as a hopeful approval consistent with the PDUFA date. No reason to believe otherwise.
Great. Good to hear that. Thanks.
Thank you.
I'm showing no further questions at this time. I would like to turn it back to the President and CEO, Robert I. Blum, for closing remarks.
Thank you, operator. Thank you 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 mid-year check-in is indicative of why we continue to be quite ambitious and hopeful in 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.
Thank you, presenters. Ladies and gentlemen, this concludes today's conference call. Thank you all for joining. You may now disconnect.