Cytokinetics Q2 2025 Earnings Report

Cytokinetics EPS Results

• Actual EPS: -$1.12
• Consensus EPS: -$1.34
• Beat/Miss: Beat by +$0.22
• One Year Ago EPS: -$1.31

Cytokinetics Revenue Results

• Actual Revenue: $66.77 million
• Expected Revenue: $1.95 million
• Beat/Miss: Beat by +$64.82 million
• YoY Revenue Growth: +26,727.30%

Cytokinetics Announcement Details

• Quarter: Q2 2025
• Date: 8/7/2025
• Time: After Market Closes
• Conference Call Date: Thursday, August 7, 2025
• Conference Call Time: 4:30PM ET

Cytokinetics (NASDAQ:CYTK), a late-stage biopharmaceutical company, focuses on discovering, developing, and commercializing muscle activators and inhibitors as potential treatments for debilitating diseases. The company develops small molecule drug candidates primarily engineered to impact muscle function and contractility. Its drug candidates include omecamtiv mecarbil, a novel cardiac myosin activator that is in Phase III clinical trial in patients with heart failure. The company also develops CK-136, a novel cardiac troponin activator that is in Phase I clinical trial; CK-586, a small molecule cardiac myosin inhibitor, that is in Phase I clinical trial; and aficamten, a novel cardiac myosin inhibitor, which is in Phase III clinical trial for the treatment of patients with symptomatic obstructive hypertrophic cardiomyopathy. Cytokinetics, Incorporated has a strategic alliance with Ji Xing Pharmaceuticals Limited. The company was incorporated in 1997 and is headquartered in South San Francisco, California.

Cytokinetics Q2 2025 Earnings Call Transcript

Key Takeaways

• Neutral Sentiment: FDA has extended the PDUFA date for the aficamtan NDA to December 26, 2025, with the late-cycle review moved to September and GCP inspections completed without observations.
• Positive Sentiment: EMA inspections of clinical sites and Cytokinetics are complete, and the company is on track to respond to day-120 questions, aiming for potential EU approval in 2026 and a first launch in Germany.
• Positive Sentiment: In China, Cytokinetics and Sanofi are progressing through an accelerated NMPA pathway for aficamtan, with potential approval expected in the second half of this year.
• Positive Sentiment: Commercial readiness for aficamtan has advanced with the hiring of a seasoned U.S. sales force, optimization of specialty pharmacy distribution, and development of a patient-centric support program ahead of an early Q1 2026 launch.
• Positive Sentiment: Topline results from the head-to-head Maple HCM trial demonstrated a statistically significant improvement in peak VO₂ versus metoprolol, with full data to be presented at the upcoming ESC Congress.

Presentation

[Operator]

Thank you for standing by. My name is Pryla, and I will be your conference operator today. Welcome to the Cytokinetics Q2 twenty twenty five Earnings Conference Call. This call is being recorded and all participants are in a listen only mode. After the speakers' remarks, we will open the call to questions.

[Operator]

We will allow for one question per participant. I would now like to turn the call over to Diane Weiser, Cytokinetics' Senior Vice President of Corporate Affairs. Please go ahead.

[Diane Weiser, SVP - Corporate Affairs at Cytokinetics]

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.

[Diane Weiser, SVP - Corporate Affairs at Cytokinetics]

Andrew Kalos, EVP and Chief Commercial Officer, will address commercial readiness activities for aficamtan. Fady Malik, EVP of R and D, will provide updates related to the clinical development program and medical affairs activities for aficamtan. Stuart Kupfer, SVP and Chief Medical Officer, will provide updates on the clinical development program for omecamtiv mecarbil and CK-five eighty six, which is now called ulicamten. Tom 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.

[Diane Weiser, SVP - Corporate Affairs at Cytokinetics]

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

[Robert Blum, President, CEO & Director at Cytokinetics]

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 aficamptan for the treatment of patients with OHCM to 12/26/2025. 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.

[Robert Blum, President, CEO & Director at Cytokinetics]

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.

[Robert Blum, President, CEO & Director at Cytokinetics]

And during or rather, despite the extension to the PDUFA date, we remain confident in The U. S. Regulatory position of aficamtan given the quality of our clinical data, perceived alignment on a REMS program and ongoing collaborative dialogue with FDA. We also maintain strong conviction that the data behind afficamtion support its potential FDA approval, its distinct benefit risk and pharmaceutical 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 aficamtan continued during the second quarter in both Europe and in China.

[Robert Blum, President, CEO & Director at Cytokinetics]

In April, we received the day 120 list of questions from EMA regarding the MAA for aficamtan 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 cytokines 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 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 aficamtan with the NMPA, and that's on accelerated regulatory pathway for innovative therapies. We look forward to the prospect of bringing aficamtan to patients in additional geographies, and we continue to expect potential approval in China in the second half of this year.

[Robert Blum, President, CEO & Director at Cytokinetics]

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.

[Robert Blum, President, CEO & Director at Cytokinetics]

During the quarter, we also made important progress in our ongoing clinical trials program for aficamtan. 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 N HCM, 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.

[Robert Blum, President, CEO & Director at Cytokinetics]

Following the first potential approval in OHCM, NHCM represents a clear opportunity for aficamtan and innovation. Beyond aficamtan, in Q2, we continued to advance patient enrollment in COMMIT HF and also in AMBER HFpEF, our two later stage clinical trials evaluating omecamtiv mecarbil and CK-five eighty six, now called ulicamtiv, 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 2025. With that, I'll turn the call over to Andrew, please.

[Andrew Callos, EVP & Chief Commercial Officer at Cytokinetics]

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.

[Andrew Callos, EVP & Chief Commercial Officer at Cytokinetics]

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.

[Andrew Callos, EVP & Chief Commercial Officer at Cytokinetics]

Overall, our new sales colleagues have over twenty one years of industry experience and an average of fourteen years of cardiovascular experience. We expect to have the sales force on board and trained in Q4, so they're ready for early Q1 twenty twenty six U. S. Launch of aficamtan. Additionally, during the quarter, we also made progress in optimizing our distribution network of specialty pharmacies and distributors.

[Andrew Callos, EVP & Chief Commercial Officer at Cytokinetics]

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 touch points 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 eighty percent of eligible obstructive HCM patients will be treatment naive relative to a cardiac myosin inhibitor.

[Andrew Callos, EVP & Chief Commercial Officer at Cytokinetics]

So symptomatic OHCM patients naive to CMIs and primarily in specialty centers for HCM represent an entry point for aficamtan. Our launch strategy is to expand the market, ensure more cardiologists are comfortable with aficamtiv and more patients can potentially benefit from this new therapy. Importantly, according to our market research, nearly eighty percent of HCPs polled in HCM specialized centers are familiar with aficamtiv on a native 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 and 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 ACP 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.

[Andrew Callos, EVP & Chief Commercial Officer at Cytokinetics]

We believe that given the differentiated profile of aficamtan, 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.

[Andrew Callos, EVP & Chief Commercial Officer at Cytokinetics]

And ex U. S. Payer requirements as we approach potential regulatory approval in key U. S. And EU geographies.

[Andrew Callos, EVP & Chief Commercial Officer at Cytokinetics]

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 twenty twenty six 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 twenty twenty six. Overall, I am pleased with where we position relative to the potential upcoming approval of aficamtiv. With that, I'll turn the call over to Fadi to share updates on our ongoing clinical trials program and medical affair activities for aficamtiv.

[Fady Malik, Executive VP - R&D at Cytokinetics]

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 twenty four for aficamtan compared to the standard of care beta blocker metoprolol. Safety and tolerability profile of aficamtan 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 APOL HCM will be presented in a hotline session on Saturday, August 30, at the European Society of Cardiology Congress in Madrid later this month.

[Fady Malik, Executive VP - R&D at Cytokinetics]

A pre specified analysis from the trial on the effect of apicamtin 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? MAPOL HCM reads not only on the treatment effect and safety of aficamtin 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.

[Fady Malik, Executive VP - R&D at Cytokinetics]

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, SKOY HCM, and FORWARD HCM. Atrial fibrillation has been an emerging topic 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 aficamtan, we've observed no difference in the rates of atrial fibrillation between placebo and aficamtan. And in the open label extension trial, FORTAST 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 apocamtin in patients with O HCM.

[Fady Malik, Executive VP - R&D at Cytokinetics]

At ESC, we'll also have an oral presentation on longer term follow-up of patients treated with aficamtin and forest HCM with up to three years of data combined together into an updated integrated safety analysis of the clinical trials program for aficamtin 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 aficamtan 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 aficamtan in non obstructive HCM. As we previously communicated, Acacia completed patient enrollment ahead of schedule earlier this year and in fact exceeded our original target to randomize and randomize a total of five sixteen patient, participants.

[Fady Malik, Executive VP - R&D at Cytokinetics]

During the second quarter, we reviewed the emerging safety data from ACCE-eight Centimeters 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 ACCE HCM, excluding Japan, in the 2026. Speaking of Japan, we recently dosed the first patient in the Japan cohort of the ACCE HCM, and our partner Bayer opened to enrollment CAMMELIA HCM, a Phase III clinical trial in Japanese patients with obstructive HCM, a trial which is intended to support potential marketing authorization in Japan. Now to ongoing clinical trials of aficamtan, during the second quarter, we made progress enrolling CEDAR HCM, which is evaluating aficamtan pediatric obstructive HCM. The trial remains on track to complete enrollment of its adolescent cohort in the second half of this year.

[Fady Malik, Executive VP - R&D at Cytokinetics]

Finally, in addition to progress in our clinical development programs, during the quarter, our field medical affairs team engaged in nearly 600 U. S. HCP include in interactions, including over 200 HCM KOLs as well as over 50 European KOLs. 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.

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

Thanks, Vadi. First, we continued start up activities and enrollment of COMMID HF, the confirmatory Phase III clinical trial of omecamtiv mecarbil in patients with symptomatic heart failure with severely reduced ejection fraction less than thirty percent. 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 ACCOMOD HF through this year and to complete enrollment in 2026.

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

Second, as we announced in today's press release, we received approval from the INN program of the World Health Organization for ulicamten to be used as a non proprietary name for CK-five eighty six. During the second quarter, we continued conduct of AMBER HEPPEF, the Phase II clinical trial of ulicamten in patients with symptomatic heart failure with preserved ejection fraction of at least sixty percent. 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.

[Sung Lee, Executive VP & CFO at Cytokinetics]

Thanks, Stuart. We're pleased to report our 2025 financial results. Starting with the balance sheet, we finished the second quarter with approximately $1,040,000,000 in cash, cash equivalents and investments compared to $1,090,000,000 at the end of the 2025. In the second quarter, we exercised our option on the tranche four loan provided by Royalty Pharma and received proceeds of $75,000,000 We have an option to draw $100,000,000 on the Tranche V loan prior to November 25. R and D expenses for the second quarter were $112,600,000 compared to $79,600,000 for the same period in 2024.

[Sung Lee, Executive VP & CFO at Cytokinetics]

The increase was primarily due to advancing our clinical trials, higher personnel related costs and medical affairs related activities. G and A expenses for the 2025 were $65,700,000 compared to $50,800,000 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 2025 was $134,400,000 or $1.12 per share compared to a net loss of $143,300,000 or $1.31 per share for the same period in 2024. Turning to our financial guidance.

[Sung Lee, Executive VP & CFO at Cytokinetics]

We are maintaining our full year 2025 financial guidance with GAAP operating expense expected to be between $670,000,000 and $710,000,000 Stock based compensation that is included in GAAP operating expense is expected to be between $110,000,000 and $120,000,000 Excluding stock based compensation from GAAP operating expense results in a range of $550,000,000 to $600,000,000 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 Aficamtan in The U. S. Later this year and continue to advance our pipeline. With that, I'll hand it back to Robert.

[Robert Blum, President, CEO & Director at Cytokinetics]

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 twenty five 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 and 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.

[Robert Blum, President, CEO & Director at Cytokinetics]

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 aficamtan, we expect to advance NDA review activities with FDA to support the potential U. S. Approval of aficamtan in the second half of this year.

[Robert Blum, President, CEO & Director at Cytokinetics]

We expect to advance go to market strategies and to continue launch preparations for aficamtan 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 2026. We expect to coordinate with Sanofi to support the potential approval of aficamtan 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 2026 while we continue enrolling the Japan cohort of Acacia HCM in 2025.

[Robert Blum, President, CEO & Director at Cytokinetics]

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 COMMENT HF throughout 2025 to enable completion of enrollment in 2026. For ulicamten, 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]

Thank you. We will now begin the question and answer session. And with that, our first question comes from the line of Jenna Wong with Barclays. Please go ahead.

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

Hello, Thank you for taking my question.

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

So I have so many, okay, but I will limit my question to one. That's regarding the ESC update. So you did mention the MAPLE data could be potentially guideline change. Can you elaborate a little bit like what kind of magnitude of benefit like you are looking for? What are the key data points that we should be focusing on?

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

And what kind of a magnitude benefit the payer or physician are willing to use first line or switch those patients on beta blockers to aficamtan?

[Robert Blum, President, CEO & Director at Cytokinetics]

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

[Fady Malik, Executive VP - R&D at Cytokinetics]

Hi, Tina. Yeah. You know, I think the data and this is really one of the few comparative efficacy trials that's conducted in cardiology. And, 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 to baseline when these patients start the drug. Right now, cardiac myosin inhibitors are thought of as, last line of treatment after you fail everything else.

[Fady Malik, Executive VP - R&D at Cytokinetics]

And I think when we see the data from Maple HCM, that conversation will be revisited, and hopefully, its guidelines as well will be updated to reflect you know, what we have already announced as a superiority of aficamtan versus metoprolol and exercise tolerance. But I think we'll just have to wait to be able to expand on that once the data are out.

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

Thank you.

[Robert Blum, President, CEO & Director at Cytokinetics]

Thank you, Gina.

[Operator]

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

[Akash Tewari, Global Head - Biopharmaceutical Research at Jefferies]

Thanks So so how's it going? So look, it looks increasingly likely that you're going to get the Kymzius 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 Kymzius wasn't and also would support a clear exposure response relationship in this population? Thank you.

[Robert Blum, President, CEO & Director at Cytokinetics]

Yeah. So I'll take a stab at that and maybe ask Fadi 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 two study and took that into a phase three trial where we, elected to proceed without altering a lot of other things. We took a dose optimization regimen.

[Robert Blum, President, CEO & Director at Cytokinetics]

We took a population. We focused to centers where, we already had experience. And, 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 is 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. Fadi, anything you want to add?

[Fady Malik, Executive VP - R&D at Cytokinetics]

I just might add that when you see the OHDSI data, and we see the OHDSI 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 or trial conduct versus, you know, mechanism of action. And, you know, I think, ultimately, that is what will provide some confidence in terms of Acacia's, potential success. But I think as Robert mentioned, you know, we believe strongly in the case of success just based on the strength of the phase two data we generated and the fact that, you know, case is being conducted in a manner that was very consistent with the way we conducted phase two.

[Robert Blum, President, CEO & Director at Cytokinetics]

Thank you, Akash.

[Operator]

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

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

Hi, good afternoon Robert and team. Thanks so much for taking our question. So what does an ideal label look like for aficamtan in obstructive HCM here?

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

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? Thank you.

[Robert Blum, President, CEO & Director at Cytokinetics]

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 aficamtan 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. You know, we designed into aficamtan features that Fady has spoken of often, and we've studied aficamtan in ways that we believe elaborate on how those features read on benefit risk and the data from our phase two and phase three 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.

[Robert Blum, President, CEO & Director at Cytokinetics]

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 Callos, EVP & Chief Commercial Officer at Cytokinetics]

Sure, Robert. So I think you addressed well that differentiated label really would reflect the results of the clinical trial and the properties of aficamtan. 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, there's a lot of 80% plus of physicians in those centers who are aware of aficamtiv. So very, very high awareness even before we come to market.

[Andrew Callos, EVP & Chief Commercial Officer at Cytokinetics]

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. So ultimately, have to wait to see what that label and REMS looks like from the FDA, but we're pretty bullish given those comments.

[Robert Blum, President, CEO & Director at Cytokinetics]

Thank you, Andrew. Thank you, Tess.

[Operator]

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

[Salim Syed, MD & Senior Biotechnology Analyst - Equity Research Americas at Mizuho Securities]

Hey, guys. Good afternoon. Thanks for the question. 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?

[Salim Syed, MD & Senior Biotechnology Analyst - Equity Research Americas at Mizuho Securities]

And just can you remind us how much of the REMS negotiation here actually happens post the late cycle meeting actually during the labeled negotiations themselves?

[Robert Blum, President, CEO & Director at Cytokinetics]

Celine, 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.

[Robert Blum, President, CEO & Director at Cytokinetics]

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, you know, 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.

[Robert Blum, President, CEO & Director at Cytokinetics]

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.

[Salim Syed, MD & Senior Biotechnology Analyst - Equity Research Americas at Mizuho Securities]

Okay. Got it. Thank you very much.

[Robert Blum, President, CEO & Director at Cytokinetics]

Thank you.

[Operator]

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

[Robert Blum, President, CEO & Director at Cytokinetics]

Hello, Cory.

[Cory Kasimov, Senior Managing Director at Evercore]

Hey, Robert. Good afternoon. So I wanted to ask, go back to Acacia and wondering if you could walk us through how drug interruptions and discontinuation protocols differ versus OddiSY. I guess 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 ODICEY. And maybe you can point out any other significant design differences you would maybe call out between the two studies? Thank you.

[Robert Blum, President, CEO & Director at Cytokinetics]

Yeah. 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 Fadi to comment now that we have Odyssey as published in terms of the design and we know what we're doing with Acacia.

[Robert Blum, President, CEO & Director at Cytokinetics]

I think it's good to highlight some of those distinctions.

[Fady Malik, Executive VP - R&D at Cytokinetics]

Yeah. Hi, Corey. I think, you know, with regards to what happens when LVEF falls below 50, you know, in the nonobstructive, you don't have a left ventricular outflow tract gradient, to buffer you, you know, for that. So you really I I I think of what we do in OHCM is we're tolerating the minimum effective dose, whereas in NHCM, you know, we're tolerating the maximum tolerated dose, which is quite a different concept. And so with EF less than 50, you know, it's nice that in with Acacia, you know, primarily as long as the EF is above 40, patients can just down titrate drug.

[Fady Malik, Executive VP - R&D at Cytokinetics]

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. The so that's a a substantial difference, I think, from OddiSY where patients have to interrupt drug for four weeks and and restart and, you know, leads to a lot of, disruption, if you will, in in the, in treatment. You know, another, aspect of this is that we tested all the doses, if you will, in in phase two, five, ten, fifteen, 20. And primarily, the fifteen and twenty milligram doses were the ones that were most commonly used.

[Fady Malik, Executive VP - R&D at Cytokinetics]

You know, we know that in OHDICEY, the, BMS introduced doses of one milligram and two and a half milligrams. Patients could down titrate to those doses, and, you know, ultimately, we don't know what the dose density, if you will, is in the range that that is known to be what is potentially effective. And and in acacia, we are testing doses where at least we believe we saw meaningful clinical benefit in the phase two, and as we're trying now to replicate in phase three. So I think, you know, with regard to dosing, those are and and ES is less than 50. Those are the major differences.

[Fady Malik, Executive VP - R&D at Cytokinetics]

You know, there are some differences in the entry criteria with regards to thresholds, upper limit for peak VO two or NT proBNP. We, you know, we have a group here that is, highly knowledgeable about HCM and and and really look at every patient echo that came came into the study, and so, you know, trying to maximize, if you will, the appropriateness of the patient population. So I I think there is a number of differences there. And, you know, ultimately, when we see the ODYSSEY data, we can, ask ourselves how which of them might be impactful in terms of of Acacia's, success down the road.

[Cory Kasimov, Senior Managing Director at Evercore]

That's very helpful. Appreciate it.

[Andrew Callos, EVP & Chief Commercial Officer at Cytokinetics]

Thanks, Corey.

[Operator]

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

[Analyst]

Hi, this is Anna on for Yasmeen. Thank you for taking our question. I guess mine is, what are your expectations in regards to potential REM differences between The US and EU and implications of that? Thank you.

[Robert Blum, President, CEO & Director at Cytokinetics]

So, 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 gonna be altogether so many differences taking 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 gonna be so much more in common than necessarily would be different.

[Analyst]

Thank you.

[Robert Blum, President, CEO & Director at Cytokinetics]

Thank you.

[Operator]

And your next question comes from the line of David with Citi. Please go ahead.

[Robert Blum, President, CEO & Director at Cytokinetics]

Hello, David.

[Ike L, Biotech Equity Research at Citi]

Hi, there. Thanks for taking our questions. This is Aigle on for David Leveowitz. I wanted to ask about the larger market opportunity and non obstructive HCM, which we all know is there. Presumably, you will need to reach more community doctors is our understanding upon that launch?

[Ike L, Biotech Equity Research at Citi]

So thinking about that, how much larger do you think your sales force is going to be if and when that time comes? Thank you.

[Robert Blum, President, CEO & Director at Cytokinetics]

Yeah. Perhaps I'll ask Fadi 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 Malik, Executive VP - R&D at Cytokinetics]

Yeah. No. You know, NHCM is, really like the tip of the iceberg. You know, I think we're seeing we see NHCM cases in clinics, that are more severe, more obvious on echocardiograms and things. But it's a disease that is difficult to diagnose.

[Fady Malik, Executive VP - R&D at Cytokinetics]

And maybe, Stuart, I'll ask you to comment on, you know, what are the challenges with recognizing it and why it might be far more prevalent throughout the community than we recognize.

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

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 sort of the HCM patients sort of appear like patients with a heart failure preserved ejection fraction. And so it does take some discrimination to identify these patients without sort of assuming they're patients with heart failure with preserved ejection fraction. 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 sort of even more less guidance around treatments in non obstructive HCM.

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

So, clearly, the medical need is even higher, and I think that, I mean, Andrew can address that.

[Andrew Callos, EVP & Chief Commercial Officer at Cytokinetics]

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 fuel force at the launch of NHCM, if a case 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-ten codes. And the physicians we're calling on for OHCM treat both NHCM and OHCM.

[Andrew Callos, EVP & Chief Commercial Officer at Cytokinetics]

And there's a really large overlap with those subspecialties who are advanced heart failure cardiologists as well who treat HCM. So around ten thousand or eighty percent of the HCM diagnosis and treatment is where we're focused. If we learn more about NHCM, which right now it's about a fifty-fifty split between the size of the OHCM patient population and the NHCM population, then we'll certainly expand field force as needed. But at launch, we're not expecting it.

[Operator]

Thank you. And your next question comes from the line of Paul Choi with Goldman Sachs. Please go ahead.

[Analyst]

Hi, this is Colleagues calling in for Paul. Thank you so much for taking our question. Since there's been a lot of questions about regulatory interaction, I guess we'll ask about Afrikaans and commercial. I suppose given the 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 Kymzios on patient access, whether that be commercial age patients or America patients?

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

That would be helpful for us. Thank you so much.

[Robert Blum, President, CEO & Director at Cytokinetics]

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 aficamtan. So I'll ask him to comment.

[Andrew Callos, EVP & Chief Commercial Officer at Cytokinetics]

Sure. So as Robert had mentioned, we've had our account manager, fuel 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.

[Andrew Callos, EVP & Chief Commercial Officer at Cytokinetics]

So really the strategy really 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 rents. When you look at the kinds of programs we'll support, we certainly will have for eligible patients, commercial patients will have co pay assistance, will 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 mAb is. The differentiation again is really going to be focused on the clinical data, the REMS and the patient experience.

[Analyst]

Got it. Thank you very much.

[Operator]

And your next question comes from the line of Jason Butler with Citizens GMP. Please go ahead.

[Jason Butler, MD & Biotechnology Equity Research at JMP Group LLC]

Hi, thanks for taking the question.

[Jason Butler, MD & Biotechnology Equity Research at JMP Group LLC]

Just 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 just maybe speak to some of the similarities and differences of what needs to be done to get ready the European launch.

[Robert Blum, President, CEO & Director at Cytokinetics]

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 to Germany and then from there.

[Robert Blum, President, CEO & Director at Cytokinetics]

So Andrew, in leading those activities with colleagues already domiciled in Europe, are looking at this country by country and where reimbursement is gonna be ungating of some significant investment. But I'll ask him to describe more in detail how we're thinking about this.

[Andrew Callos, EVP & Chief Commercial Officer at Cytokinetics]

So I think the the the key thing is obvious is it's a country by country launch in Europe. You get EMA for most of Europe, Switzerland and The UK 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 and then you launch.

[Andrew Callos, EVP & Chief Commercial Officer at Cytokinetics]

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 focus 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.

[Andrew Callos, EVP & Chief Commercial Officer at Cytokinetics]

Risk management is typically handled as part of labeling. So I think they're the key differences. But fundamentally, in terms of the differentiation in aficamtan from the clinical trial and how we communicate that, once we get that access is that's going 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.

[Andrew Callos, EVP & Chief Commercial Officer at Cytokinetics]

S. Will launch all at once hopefully in end of this year, early next year. Europe will launch really over about two to two point five years based on that reimbursement timing.

[Robert Blum, President, CEO & Director at Cytokinetics]

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 derisking milestones.

[Operator]

Thank you. And your next question comes from the line of James Candules with Stifel. Please go ahead.

[James Condulis, VP - Biotechnology Equity Research at Stifel Nicolaus]

Hey, thanks so much for taking my question and 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 three within non obstructive is, to kind of confirm any initial signals there, just kind of given both are driven by diastolic dysfunction? Thanks so much.

[Robert Blum, President, CEO & Director at Cytokinetics]

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 Malik, Executive VP - R&D at Cytokinetics]

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 in Amber. And I'll ask Stuart maybe to draw the parallels between the two conditions and what how we think each, one will be reinforcing of the other.

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

Yeah. Thank you for the question. And, you know, as Vady mentioned, the the nondestructive, HCM patients, do inform potential benefit, and these patients with HFpEF and hypercontractility. And, you know, the endpoints that we're evaluating in our phase two AMBER HFpEF trial, will read on the potential benefit. You know, we're we're evaluating for symptomatic improvement, looking at, endpoints like KCCQ, NYHA class, looking for improve so improvements in symptoms, cardiac biomarkers, like NT proBNP, and troponin.

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

And, you know, 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 three and identifying dose or doses that will result in a favorable benefit risk profile. So, again, we're encouraged by what we observed with non obstructive HCM and the benefits of abacamten and the Phase II REDWOOD trial and the ongoing cohort that's been evaluated in FORUST, our open label extension. So those are some of the key findings that we'll be looking for as well as safety and tolerability.

[Andrew Callos, EVP & Chief Commercial Officer at Cytokinetics]

Thanks.

[Operator]

Thank you. And your next question comes from the line of Leonie Timoshev with RBC Capital Markets. Please go ahead.

[Leonid Timashev, Biotechnology Analyst at RBC Capital Markets]

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, 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?

[Leonid Timashev, Biotechnology Analyst at RBC Capital Markets]

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? Thanks.

[Robert Blum, President, CEO & Director at Cytokinetics]

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 wanna see the label, and, ultimately, we'll be promoting to label in ways that we think will be to the advantage of adoption of aficamtan. But as we've discussed in the way that we've designed aficamtan 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 wanna 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 wanna add.

[Andrew Callos, EVP & Chief Commercial Officer at Cytokinetics]

Yeah. Mean, to your point, we're not going to get into what our messaging is. But 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 then the REMS. So we'll communicate clearly the differentiation. We believe we have differentiation in each of those areas as well as a very, very differentiated positioning.

[Andrew Callos, EVP & Chief Commercial Officer at Cytokinetics]

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]

All right. Thank you. And your next question comes from the line of Deverakonda with Truist Securities. Please go ahead.

[Alexander Xenakis, Research Associate at Truist Securities]

Hi. This is Alex on for Kripa. Given that we might see approval in China at 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.

[Robert Blum, President, CEO & Director at Cytokinetics]

Yeah. So this is somewhat of an uncommon situation, isn't it, that we might could 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 Callos, EVP & Chief Commercial Officer at Cytokinetics]

Are you asking about market sizing and revenue? So is that right?

[Alexander Xenakis, Research Associate at Truist Securities]

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

[Andrew Callos, EVP & Chief Commercial Officer at Cytokinetics]

So like The U. S, China would be Aficampton would be second to market. Kind Like of like Europe, you need to get NRDL listing, National Reimbursed Drug Listing in China that it occurs on an annual basis and you have to file by the June of a given year to have reimbursement the following January. So likely the first period of time reimbursement would be through cash paying market versus say, MABA having NRDL. So I would imagine that the uptake would be slow at start, but it's a large market as you can imagine.

[Andrew Callos, EVP & Chief Commercial Officer at Cytokinetics]

There's over three hundred and fifty thousand patients who are very concentrated into about 1,300 hospitals. Obviously, we have a very sophisticated multinational partner who knows that market extremely well. So I won't comment on the phasing, but I would only say that once reimbursement occurs, would expect an acceleration follow that national drug reimbursement. Hopefully, that answers your question.

[Alexander Xenakis, Research Associate at Truist Securities]

Yes. Thanks and congrats on the progress.

[Robert Blum, President, CEO & Director at Cytokinetics]

Thank you.

[Operator]

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

[Joseph Pantginis, MD & Senior Healthcare Analyst at H.C. Wainwright & Co.]

Hey, everybody. Good afternoon. Thanks First, for taking the I guess maybe for Andrew, it's 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? And secondly, for Stuart, as you're looking at Comet with the company's broad, very broad experience with omecamtiv long term, how would you characterize the, site excitement with regard to enrollment versus all the other omecamtiv studies? Thanks.

[Robert Blum, President, CEO & Director at Cytokinetics]

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

[Joseph Pantginis, MD & Senior Healthcare Analyst at H.C. Wainwright & Co.]

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

[Robert Blum, President, CEO & Director at Cytokinetics]

Yeah. So, you know, we're 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 label.

[Robert Blum, President, CEO & Director at Cytokinetics]

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

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

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 very high unmet need, in these patients with heart failure and severely reduced ejection fraction. They really don't have medical options before, you know, on the road to end stage heart failure.

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

So they recognize that omecamtiv mecarbil is a potential medical option to save off that outcome. Second, they're very well aware of the results of GALACTIC, which, of course, is 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 you know, because of the large sample size of the subgroup of patients and the results we observed in GALACTIC, you know, 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.

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

And so operationally, it's going be an easier trial to conduct. So overall, a lot of enthusiasm for Comet.

[Joseph Pantginis, MD & Senior Healthcare Analyst at H.C. Wainwright & Co.]

Great. Appreciate the clarification and color, guys.

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

Thank you. Thanks, Joe.

[Operator]

And your next question comes from the line of Jason Simanski with Bank of America. Please go ahead.

[Analyst]

Hi, good afternoon. This is Jackie on for Jason. Thanks for taking our question and congrats on the progress.

[Analyst]

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 Blum, President, CEO & Director at Cytokinetics]

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 apicamtan versus metoprolol, and I do believe it'll 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 of a body of evidence that didn't exist before.

[Robert Blum, President, CEO & Director at Cytokinetics]

And for having done that, we do believe that aficamtan, 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.

[Andrew Callos, EVP & Chief Commercial Officer at Cytokinetics]

Now

[Robert Blum, President, CEO & Director at Cytokinetics]

granted metoprolol is a generic drug, and there's ample experience with beta blockers. But I do believe in cytokines 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, Thadde to speak to that and maybe, Andrew, if he wants to also comment on how that might ultimately get reflected and over what timeframe and guidelines and how that may inform, adoption.

[Fady Malik, Executive VP - R&D at Cytokinetics]

Yeah. I mean, I think, you know, it's going to take a while before, beta blockers are displaced as first line treatment given the cost differential. But I think study study like MAPLE HCM will facilitate, earlier movement, and hopefully elevate aficamptan in the guidelines so it's not seen as the last, you know, the last line of therapy before surgery potentially, but, instead, it's, you know, seen on par with the other therapies that physicians can consider. And so, you know, if patients are only modestly improved, you know, 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 apicamtin addresses that other therapies don't, given apicamtin targets, you know, the underlying path of the disease.

[Fady Malik, Executive VP - R&D at Cytokinetics]

So with that, we someday may be able to show that, you know, we reduce the progression of disease, and then it becomes, I think, a much more important question as to which therapy to start. So this is the beginning, I think, of a, sort of a longer longer run-in terms of changing the standard of care in this disease.

[Andrew Callos, EVP & Chief Commercial Officer at Cytokinetics]

Yeah. 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 aficamtan than would have been otherwise without Maple. We expect the acceleration of an add on of aficamtan to a beta blocker and maybe weaning off a beta blocker after the start over time.

[Andrew Callos, EVP & Chief Commercial Officer at Cytokinetics]

So I think those are kinds of things you'll see for the first several years. If guidelines are updated and aficamtiv is part of first line therapy, then with broader use, we could see first line therapy. But again, think that's several years out. Thanks for the question.

[Operator]

Your next question comes from the line of Mumtani with B. Riley Securities. Please go ahead.

[Analyst]

Thanks for taking our question. This is William on 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. But 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?

[Analyst]

And then also just in terms of REMS, how should we think about the REMS in OHCM sort of 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.

[Robert Blum, President, CEO & Director at Cytokinetics]

Yeah. 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, echos are very informative to how one approaches dose titration. Acacia's 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 gonna be a lot of translation from one to the other. Patty?

[Fady Malik, Executive VP - R&D at Cytokinetics]

Yeah. I I think, you know, you asked whether there's anything we've learned in Maple or Sequoia that might inform Acacia. And, you know, we've already published data from Sequoia that that that look at how aficamtin 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. 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.

[Fady Malik, Executive VP - R&D at Cytokinetics]

And so 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, 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, you know, labeling or REMS, things like that. I don't know if there's anything you'd like to add, Stuart.

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

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

[Robert Blum, President, CEO & Director at Cytokinetics]

You didn't ask this, but I'll add, in our Phase II REDWOOD Cohort four, 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. But also and please don't lose sight of the fact that those patients roll over into FORAST. And FORAST is an open label study. And later this year, you'll have a chance to see what we're already seeing in patients who rolled into FORUST with NHCM, and that gives us confidence in what we can expect from Acacia next year. So we remain quite optimistic about Acacia.

[Operator]

And your next question comes from the line of Serge Belanger with Needham and Company. Please go ahead.

[Analyst]

Hi, good afternoon. This is John on for Serge today. Thanks for squeezing in my question. Just wanted to touch back on with omecamtiv and the common trial. It seems like you guys have been getting some positive feedback from investigators and KOLs.

[Analyst]

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. Thanks.

[Robert Blum, President, CEO & Director at Cytokinetics]

Stuart, do want to take that?

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

Sure. Yeah. As we sort of indicated in the call today and our press release, the COMMOD HF trial enrollment is on track. We plan to this is an 1,800 patient trial, less than a fourth of the size of GALACTIC. So that certainly makes it easier in terms of the operational scope.

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

However, this is a more severe patient population, so 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. So, things are going according to plan.

[Robert Blum, President, CEO & Director at Cytokinetics]

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. 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 wanna confirm that in this next trial. So that's contributing, we believe, to momentum for the study.

[Operator]

All right. Thank you. And your next question comes from the line of Roana Riese with Leerink Partners. Please go ahead.

[Analyst]

Yes. Thank you. This is Maisie on for Roana. Just more from myself to see. So from a cardiac myosin biology perspective, as you advance apicamtin and more of the HCM phenotypes and develop, ulicamtin 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 Blum, President, CEO & Director at Cytokinetics]

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

[Fady Malik, Executive VP - R&D at Cytokinetics]

Well, so it's really interesting, you know, when we look at the myosin motor protein, after twenty plus years, we've now identified three distinct, binding sites for small molecule modulators of the protein. Apicamtin binds in one place, omecamtiv mecarbil and mavacamten bind in another place. And, lastly, the, CK five a six or olecamtiv bind in even a third place. And each of them has distinct facts of, on how they impact motor function in the sarcomere. You know, you can you can scribe.

[Fady Malik, Executive VP - R&D at Cytokinetics]

I won't really go into, you know, the the details and specifics here. But those differences, I think as we may be seeing in in the clinic, lead to differences in their profiles. And, you know, I think it's still a little early to know exactly how they differ and and which one may be preferred. But, you know, there are, I think, differences that are emerging. With olucanthin olucanthin, we see, potentially a a more shallow, decrease in in ejection fraction, a more shallow PKPD curve than even apicamtin.

[Fady Malik, Executive VP - R&D at Cytokinetics]

And, you know, we think the reversibility of both compounds is is not just a feature of the compound itself, but also potentially, you know, the mechanism where they bind. So I'd say stay tuned, and I hope to, someday write a paper that describes all the various different biology and how it links to clinical.

[Analyst]

Thank you so much.

[Robert Blum, President, CEO & Director at Cytokinetics]

Yes, good question.

[Operator]

And your next question comes from the line of Ash Birma with UBS. Please go ahead.

[Ashwani Verma, Executive Director - SMID Biotech & Biopharma at UBS Group]

Hi. Thanks for taking my question. I wanted to ask like, this late cycle meeting push out from June to September, is that the result of your prior three months belief by extension? Or is this a separate development which can now have a cascading effect on the belief for 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? Thanks.

[Robert Blum, President, CEO & Director at Cytokinetics]

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 PDUFA date. No reason to believe otherwise.

[Ashwani Verma, Executive Director - SMID Biotech & Biopharma at UBS Group]

Great. Good to hear that. Thanks.

[Robert Blum, President, CEO & Director at Cytokinetics]

Thank you.

[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 Blum, President, CEO & Director at Cytokinetics]

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]

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

Participants

Executives

• Diane Weiser, SVP - Corporate Affairs
• Robert Blum, President, CEO & Director
• Andrew Callos, EVP & Chief Commercial Officer
• Fady Malik, Executive VP - R&D
• Stuart Kupfer, Senior VP & Chief Medical Officer
• Sung Lee, Executive VP & CFO

Analysts

• Gena Wang, MD - Biotech Equity Research at Barclays
• Akash Tewari, Global Head - Biopharmaceutical Research at Jefferies
• Tessa Romero, Equity Analyst - Biotechnology at J.P. Morgan
• Salim Syed, MD & Senior Biotechnology Analyst - Equity Research Americas at Mizuho Securities
• Cory Kasimov, Senior Managing Director at Evercore
• Analyst
• Ike L, Biotech Equity Research at Citi
• Jason Butler, MD & Biotechnology Equity Research at JMP Group LLC
• James Condulis, VP - Biotechnology Equity Research at Stifel Nicolaus
• Leonid Timashev, Biotechnology Analyst at RBC Capital Markets
• Alexander Xenakis, Research Associate at Truist Securities
• Joseph Pantginis, MD & Senior Healthcare Analyst at H.C. Wainwright & Co.
• Ashwani Verma, Executive Director - SMID Biotech & Biopharma at UBS Group