Cytokinetics, Incorporated Price & Performance (CYTK)

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 fourth quarter twenty twenty four 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. Now, I will turn the call over to Robert.

Thank you, Diane, and thanks to all for joining us on the call today. The fourth quarter of twenty twenty four was an exceptionally productive quarter that rounded out a successful year. Most notably, we made major strides towards potential regulatory approvals and subsequent commercial launches of aficamten across multiple geographies. Our NDA was accepted by FDA Our MAA was validated by EMA and our NDA was accepted by the NMPA in China with priority review. Now with regulatory submissions on file in The U. S. Europe and China, we're engaging in parallel regulatory interactions that may deliver afecamfet to patients around the world. With our PDUFA date of 09/26/2025, our commercial readiness activities in The United States are reaching a peak, while we also lay the foundation for our go to market activities in Europe. In the nearer term, expect to continue already ongoing activities with FDA in support of their review of the NDA. We have been responding to questions as well as preparing for clinical site and other inspections. And we recently submitted our one hundred and twenty day safety update to FDA. In March, we expect to participate in a mid cycle meeting with FDA. Ahead of that meeting, I want to level set that we do not plan to share detailed updates following that meeting.

Given that the FDA review of the NDA will still be ongoing. However, we maintain our expectation for a differentiated label and misritigation profile for aficamten were it to be approved by FDA. In both Sequoia HCM and Forest HCM, in patients with OHCM, we observed a favorable overall safety profile, LVEF stability, rapid dose titration, as well as a lack of treatment interruptions related to episodes of episodes of heart failure or heart failure hospitalizations related to LVEF. Nor did we observe any clinically meaningful drug drug interactions. We believe all of these characteristics are consistent with the intrinsic properties of afficamten. Moving on to the regulatory review of avicamten in Europe, Following the validation of our MAA in late December, we expect to continue to engage with EMA during their review by responding to requests for information and preparing for inspections. Our next key mile is is receipt of the day 120 list of questions expected in April? As you know, we plan to commercialize aficamt in ourselves in The U. S. And Western Europe In other key geographies, in the fourth quarter, Sanofi acquired with our participation from Corzell the rights to develop and commercialize aficamten in China.

Additionally, in November, we announced our new collaboration with Bayer that entails a license agreement for Aficamten in Japan These two strong pharmaceutical company partners In the two leading markets outside The U. S. And Europe, both align with Cytokinetics in their commitment to cardiology and each brings great expertise, resources and reach to enable us to hopefully deliver othecamton to a greater number of HCM patients in need. And contribute to our goal to reach patients globally with our medicines. Simultaneously, we're advancing our later stage development program for affucamten with multiple ongoing potential label expansion clinical trials. In the near term, we expect to share top line results from Maple HCM in Q2 and if positive, data from this trial may represent again a label expansion opportunity for avacamten following potential FDA approval. Meanwhile, we continue to expand our specialty cardiology franchise and innovative pipeline advancements. Ensuring that we're more than simply a one product company. In Q4, we started COVID HF, a confirmatory Phase three clinical trial of omecamtiv in patients with heart failure with severely reduced ejection fraction, And more recently, we started Amber HalfPath, a Phase two clinical trial of CK-five eighty six in patients with heart failure and preserved ejection fraction.

Our successes over the past quarter reflect our clear vision, strategic execution and responsible investment in our Muscle Biology platform. This year, we're approaching a defining moment with key milestones ahead that will shape our future. As multiple programs advance in our specialty cardiology franchise, alongside progress in our early stage neuromuscular pipeline as well as continued innovation in our research lab We're poised to drive meaningful progress to positively impact the lives of patients as well as create enduring value for shareholders who support our mission. With that, I'll now turn the call over to Andrew. Thanks, Robert. Our launch preparations for AFFE aficamten are well underway. Significant momentum in 2024 and setting up what is the final stretch towards the potential U. S. Approval and launch of our first medicine in September.

The priorities we are guiding towards for a successful launch are as follows: broadening category awareness and effectively communicating the differentiated after [indiscernible] Galvanizing and activating new cardiologist prescriptions. Securing access and an affordable co pay for people with HCM, and providing exceptional patient support. Of note, we are pleased to see continued category expansion of the number of patients treated with a cardiac myosin inhibitor or CMI, Continued market growth and broad awareness is good news for Cyto as it reflects a growing opportunity for Cytokinetics to capture what is largely still an untapped market. Cytokinetics will be focused on increasing market awareness and category penetration and broader cardiology adoption for CMIs with apicamten. For that objective in the fourth quarter, are proud to drive increased education and awareness of ACM with the launch of ACM Beyond the Heart. An unbranded disease awareness campaign featuring real people with ATM. In October, we launched the campaign directed to HCPs to inspire them to look deeper for ATM and practice whole person care. Initial engagement metrics with the website and e mails are above industry benchmark for our target audience. In January, we expanded HCM beyond the heart inclusive of patients.

Incorporating a website, educational tools and resources focused not just on the condition, but on the impact it has on a patient's lives beyond their heart.

This represents another exciting milestone as we move forward toward the PDUFA date later this year. Meanwhile, we continue developing and refining our branded ATP promotional campaign for epicanthine is currently being tested with ATPs. To support our goal of ensuring product and market access post approval, we have continued our engagement with payers while advancing implementation of our robust patient support program This includes contracting with strategic partners, determining the size and approach of our customer facing Nurse Navigator team and creating a bespoke patient experience offering. We are also advanced operational planning for our sales force including finalizing the sales training curriculum and sales territory configurations and deployment, and we finalized our sales representative recruiting process, which will be initiated in late Q1. Beyond The U. S. Launch, we're also scaling up commercial launch readiness activities in international infrastructure to support a potential European approval of Avastikamstan, At the end of last year, we hired key leadership positions in Europe inclusive of leaders in marketing [indiscernible] human resources and in country leadership in both France and The UK. Following our previous hiring of a leader in Germany earlier in the prior year. Weeks and planning activities are ahead of a potential European approval, including validation of our reimbursement strategy, and initial preparation of dossiers for HTA submission across The UK and Western EU market.

I'm pleased with the progress we've made to prepare for both The U. S. And European commercial launches of avacamten and where we are positioned today on our commercial readiness roadmap. That, I'll turn the call over to Fady. Thanks, Andrew. As Robert mentioned, we recently submitted the one hundred and twenty day safety update to DA with an additional ten months of safety data from FOREST HCM.

These longer term data are consistent with the previously presented data from FORESTACM and the safety profile of avacamten as reflected in the NDA submission. With we believe no evidence of an increased risk of EF excursions or heart failure events. FDA reviews the NDA, we're continuing to answer their questions and prepare for clinical site and other inspections. As Robert mentioned, we also expect to participate in a mid cycle meeting with FDA in March. Moving on to our work in the fourth quarter to expand the evidence base for at the American Heart Association scientific sessions in November we presented data from two pre specified analyses of Sequoia HCM and one analysis of Forest HCM. Expanding on our activities to make data from this program available to the medical community. These presentations included analyses of post exercise oxygen uptake recovery, Patient quality of life, and guideline eligibility for septal reduction therapy. All favorably impacted by avucamten. In addition to disseminating data during the quarter, our managed healthcare MSL team continued preapproval information exchange to actively engage national and regional payers and scientific discussions related to OHM and apicamten and notified payers of our PDUFA date Scientific engagement with HCM specialists also continued with discussions focused on the results from Sequoia HCM including the primary results and secondary data analyses Now shifting to the ongoing clinical trials program for APICI Having completed enrollment in Maple HCM in the third quarter of last year, we continue to conduct the trial, collect data and progress towards database lock on track to share top line results in the second quarter of this year which we expect to be followed by a presentation of the full results at a subsequent medical meeting.

If the results of Maple HCM are positive, it will provide an opportunity to elevate apicamten as a potential monotherapy for the treatment of OHCM. Following approval. Meanwhile, we've continued to conduct Acacia HCM pivotal Phase three clinical trial in non obstructive HCM, CDER HCM and pediatric population of patients with symptomatic OHCM and of course FOREST HCM, the ongoing open label extension clinical study.

Forestate Centimeters continues to grow with now over four hundred patients enrolled. Nearly three hundred patients have at least a year of follow-up and over ninety have two years of follow-up. We're pleased to report that patient enrollment in AKA SHATE [indiscernible] has progressed rapidly over the last few months, thanks to our highly engaged sites. We've completed site activations in North And South America, Europe and Israel, and are pleased with the blinded baseline characteristics of the population. Results from this trial represent a key future milestone for the potential label expansion trajectory for apicamten into non obstructive HCM. While today representing about one third of the HCM population, NHCM appears to be growing at a faster rate than OHCM in terms of diagnosis. So we expect it to eventually represent nearly half of HCM diagnoses. So it's an important segment of the population that needs to be addressed in particular because NHCM lacks effective medical or surgical therapy unlike OHCM. Overall, from a clinical development perspective, our work in the fourth quarter wrapped up a truly monumental year highlighted by numerous data presentations and publications in high impact journals. We look forward to building on and publishing growing clinical evidence in support of fucamten as we approach the potential approval and the launch of apicamten in OHCM this year, I'll turn it over to Isaac.

Thanks, Fadi.

As Robert mentioned, we secured two new partnerships in the fourth quarter, which together will support the development and commercialization of apicamten critical global geographies. We were pleased to enter into a collaboration and licensing agreement with Bayer for the development and commercialization of Efficamten in Japan. This deal stands alone in terms of its favorable economics for a cardiovascular drug.

EUR 50,000,000 in upfront payments to Cytokinetics, eligibility to receive an additional €90,000,000 tied to euros $490,000,000 in commercial milestone payments from Bayer upon their achievement of certain sale milestones and tiered royalties on net sales of apicamten in Japan. To support the potential marketing authorization of apicamten in Japan, Fyra will conduct a Phase three clinical trial in Japanese patients with OHCM to support Sequoia ACM and Forest HCM.

While Cytokinetics plans to expand both Acacia HCM and CDR ACM into Japan. As you know, we have been pursuing a deal like this in Japan for some time, Biotech like Cytokinetics has a deep commitment to cardiology and through this process ultimately rose to the top of the right partner who is well equipped to bring apicamten to patients in Japan.

Additionally, during the fourth quarter, Sanofi acquired exclusive rights to develop and commercialize aficamten from Koraxel, [indiscernible] Through this transaction, Cytochromatics remains eligible to receive up to $150,000,000 in development and commercial milestone payments from Sanofi and royalties in the low to high teens on sales of In China, Cytokinetics is now also eligible to receive additional payments in connection with the execution of the agreement between Sanofi and Coraxel. Over the years, we have enjoyed a highly productive collaboration with CoreCell, and now we are pleased to partner with Sanofi harnessing their expertise in cardiology to bring Aficamten to patients in China. Both of these recent deals serve to expand the potential reach of ficamten in key geographies worldwide. Now with partners on board in China and Japan, and our own commercial infrastructure scaling in The U. S. And Europe, we turning our attention to how we may further expand our geographic reach with apicamten. And how we may also catalyze external R and D activities and pursue new business objectives to augment our existing pipeline alongside innovation from our own labs. To that end, our goal is to bring additional new chemical entities into clinical development through external innovation.

Seeking complementary potential therapies to support our late stage cardiovascular franchise and emerging neuromuscular pipeline. As stated in our Vision 02/1930, we also seek to expand into new modalities through our combination of both building internal capabilities and identifying external collaborations with industry partners and academic In the year to come, you can expect more activity on the business and corporate development fronts at Cytokinetics as it relates to bringing ficamten to more patients worldwide as well as how we may augment our R and D pipeline in more ways read on progress towards our stated vision.

I look forward to sharing more of these matters as they progress. Now I'll hand it over to Stuart. Thanks, Isaac.

Pleased to provide updates on the later stage development programs within our special [indiscernible] I'll start with omecamtiv macarbil, a cardiac myosin activator.

During the quarter, we started COMIT HF, a confirmatory Phase III clinical trial in patients with symptomatic heart failure we severely reduced ejection fraction less than 30%.

Since starting the trial, we've seen a great deal of enthusiasm from our who recognize the considerable unmet need in this high risk population are eager to enroll patients. Currently, this trial is enrolling in The United States regulatory submissions have been completed in Canada, The U. K. And the rest of Europe.

Investigators with prior experience with omicompromicaribol have been reaching out to us regularly to inquire about participating in Acommod HF And our steering committee is now fully seated with the foremost heart failure leaders from countries where the trial will be conducted. Now I'll move on to CK-five eighty six, our next cardiac myosin inhibitor.

In January of this year, we began Amber Heppet, a Phase two placebo controlled double blind trial evaluating the safety, tolerability of pharmacokinetics and pharmacodynamic profile, of CK-five eighty six in patients symptomatic heart failure with preserved ejection fraction and LVEF greater than or equal to sixty percent. AMBER HFpEF is expected to enroll approximately sixty patients in three twelve week dose escalation cohorts with doses ranging from one hundred and fifty to six hundred milligrams once daily.

Potential treatment benefits of CK-five eighty six include increased cardiac relaxation leading to improved diastolic function, improvement of heart failure symptoms and increased exercise capacity. And we expect to build a body of evidence in support of these outcomes through this trial. Our goal is to complete enrollment of the first two cohorts in the second half of the year.

Finally, beyond our specialty cardiology franchise, During the fourth quarter, we were pleased to begin a Phase one study of CK-eighty nine. A fast skeletal muscle troponin activator. The study comprised of both single and multiple ascending dose cohorts. CK-nine arose from our pioneering research in neuromuscular disease and was optimized by our prior learnings. CKO89 is designed to amplify skeletal muscle response to nerve input extending time to fatigue and increasing muscle force and power with potential therapeutic application to a specific type of muscular dystrophy. We expect to complete the Phase one study within 2025 I look forward to keeping you updated on our progress in this key area of clinical research as it underscores a second vertical for our company. With that, I'll pass it to Sung.

Thanks, Stuart.

We're pleased to report our fourth quarter and full year 2024 financial results. Starting with the balance sheet, we finished the fourth quarter of twenty twenty four with a at the end of the third quarter of twenty twenty four. Cash, cash equivalents and investments declined by during the fourth quarter of twenty twenty four and benefited from the receipt of $52,400,000 or $50,000,000 payment from Bayer for the exclusive license to develop and commercialize apicamten in Japan. Moving on to the income statement, The revenues in the fourth quarter of twenty twenty four were $16,900,000 compared to $1,700,000 for the same period 2023. The revenues for the full year of 2024 were $18,500,000 compared to $7,500,000 in 2023. Total revenues in the fourth quarter of twenty twenty four and full year 2024 benefited from a $15,000,000 upfront payment from Corzell in connection with the assignment of Corzell's rights for the development and commercialization of avacamten in Greater China to Sanofi. R and D expenses for the fourth quarter were $93,600,000 compared to $85,000,000 for the same period in 2023.

R and D expenses for the full year of 2024 were $339,400,000 compared to $330,100,000 in 2023. The increase year over year for both the fourth quarter and full year was primarily due to advancing our clinical trials and higher personnel related costs, including stock based compensation. G and A expenses for the fourth quarter of twenty twenty four were $62,300,000 compared to $44,100,000 for the same period in 2023. G and A expenses for the full year of 2024 were $215,300,000.0 compared to $173,600,000 in 2023. The increase year over year for both the fourth quarter and full year was primarily driven by investments toward commercial readiness and higher personnel related costs, including stock based compensation. Net loss for the fourth quarter of twenty twenty four was $150,000,000 or $1.26 per share, compared to a net loss of $136,900,000 or $1.38 per share for the same period in 2023.

Net loss for the full year of 2024 was $589,500,000 or $5.26 per share compared to a net loss $526,200,000 or $5.45 per share in 2023. [indiscernible] Turning now to our financial guidance for 2025.

We expect our GAAP operating expense which is comprised of R and D and SG and A expenses, to be between $670,000,000 and $710,000,000 Stock based compensation included in the 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 Our capital allocation priorities remain the same. And our resources will be focused on the following: First, On preparing for the potential U. S. Commercial launch of avacamten in September of this year, Including the hiring of up to 150 sales reps, in The U. S. In the third quarter of twenty twenty five.

Second, on advancing our pipeline with important label expansion opportunities for afecamten and clinical trials of omecamten mecarbil CK-five eighty six and third, The anticipated year over year growth in operating expense will primarily be driven by the investments toward commercial readiness, for the potential launch of avacamten for patients with obstructive HCM. Our strong balance sheet and access to further capital position us well to execute on our strategy which we believe could lead to sustainable growth, driven by specialty cardiology franchise. With that, I'll hand it back to Robert.

Thank you, Sung. Our progress in the fourth quarter twenty twenty four has set the stage for a pivotal year ahead, As we approach the potential U. S. Approval and commercial launch of afficamten, in 2025, we are strategically aligning our longer term vision while sharpening our operational focus for near term milestones and progress. With the right infrastructure, capabilities, partners and team in place, we are confident in our ability to execute and achieve multiple successes within our growing reach. Earlier this year, we laid out our Vision 02/1930 our five year strategic objectives designed to propel Cytokinetics to become the leading muscle focused specialty biopharmaceutical company intent on meaningfully improving the lives of patients through global access to innovative medicines. Vision 02/1930 serves as an aspirational roadmap made up of five objectives.

Innovation, ignition, Impact, Inspiration and Ingenuity, These objectives articulate how we want to deliver product approvals achieve broader access to our medicines, promote more equitable access and advance our pioneering research to benefit patients shareholders and employees.

Aligned with this vision for our future, we recently announced the appointment of Robert Landry to our Board of Directors. Bob brings over three decades of financial and operational expertise in the pharmaceutical industry. Most recently serving as Regeneron's Chief Financial Officer for eleven years. During which time he helped guide the company as its scaled and commercialized medicines globally. We're pleased to have him join our Board at this time in our corporate development. Looking at the year ahead, in 2025, we will continue to focus on FDA approval and U. S. Commercial launch readiness for apicamten and the execution of our ongoing clinical trials programs. Last year, we raised over $1,000,000,000 between existing cash and access to new capital, and which affords us the runway to execute The U. S. Launch of apicamten while also advancing our R and D pipeline and making investments in a fiscally prudent capital efficient way to build enduring value for shareholders. I'm optimistic about what our future holds in 2025. So now I'll recap our upcoming milestones. For Aficamten, we expect to advance NDA review activities with FDA to support the potential U. S. Approval of avucamten in the second half of this year.

We expect to advance go to market strategies and prepare to commercially launch afficamten in The U. S. In the second half of this year subject to approval by the FDA. We expect to continue go to market plans in Germany and expand commercial readiness activities in Europe in 2025 in preparation for in the first half of twenty twenty six. And we expect to report top line results from Maple HCM in Q2 of this year. We also expect to complete enrollment of Acacia HCM in the second half of this year and to complete enrollment of the adolescent cohort in CDAR HCM also in the second half of twenty twenty five. For omecamt and mecarbil, we expect to continue patient enrollment in COMIT HF through 2025 to enable completion of enrollment in 2026. For 86, expect to complete enrollment of the first two patient cohorts in AMBERHEF PEF in the second half of this year and for CK089 we expect to complete the Phase one study this year And finally, for our preclinical development, and ongoing research we expect to continue ongoing preclinical development and research directed to additional muscle biology focused programs, Operator, with that, we can now open the call to questions, please.

And our first question will come from Paul Choi from Goldman Sachs. Your line is open.

Good afternoon. This is Hi, everyone. Good afternoon to you too. This is Kalia calling in for Paul. I guess, our question could be on Maple HCM. If the results positive, how should we think about the timeline for a potential label expansion assuming approval in September? And then how would the positive results fit into the Yes. Hi. I think in terms of timing to label expansion, we would certainly be looking to [indiscernible] deciding whether to with the timing for that, I would expect it to come into 2026 as opposed to 2020 given our PDUFA date right now is September twenty six of twenty twenty five. But I think it all depend on timing and whatever else is going on at that time. And in terms of the marketing strategy, The second study really offered confirmatory evidence of a primary study. Both safety and efficacy, which is reassuring to physicians seeing a lot of the same primaries and secondaries, it opens up a cohort of cardiologists who really treat with beta blockers alone There's really about 2,000 cardiologists of 500 or with some vast majority of prescribers of CMIs today. And per our market research, this would open up to more prescribers who many of them feel like maybe beta blockers is good enough.

And and it offers that additional evidence and maybe it didn't influence guidelines move treatment to first line over time, but that certainly takes a lot longer. [indiscernible] Sorry, just to add to comment to Andrew's, I do believe that Maple HCM were to be positive could contribute to more category growth as potentially more cardiologists would be more comfortable prescribing cardiac myosin inhibitor And on top of that, we would hope it would add to more category penetration for Aficamten. Into that larger market. But I would consider it more incremental than transformative to what we would hope would be the label opportunity provided by Sequoia HCM. Great. Thank you. Thank you. And our next question will come from Cory Kasimov from Evercore ISI. Your line is open.

Hello, Cory. Good afternoon, guys. Hey, good afternoon. Thanks for taking the question. So following up on Andrew's prepared comments on market expansion, I think it's pretty well established that HCM is a highly under diagnosed condition. Curious kind of as to your expectations as to how this changes over time when there's two companies on the market educating and promoting the benefit of cardiac myosin inhibitors. If it really is on the order of seventy percent to even eighty percent of patients, as yet undiagnosed, is there a good proxy of where this rate may get to say three to five years from now? Thank you. Thank you. I'll turn to Andrew, please. [indiscernible] I think as you know, when guidelines get adjusted, when studies are out, when us and others are at congresses where physicians go to learn about emerging data Those certainly increased penetration of market and increased diagnosis with awareness and I think what we've seen over the last few years is obstructive ACM has continued to increase diagnosis rates around with population, but the non obstructive is growing at a double digit rate. So I think over time non obstructive maybe even be fifty-fifty or slightly larger than obstructive in terms of overall patient population The estimate we have right now is about thirty percent or so of the population is diagnosed and given these rates and kind of where they're going that certainly could be in the fifty percent range in the next, say, three to five years?

Yes, in terms of Reviewing the landscape as well, and I do believe that the amyloidosis space and the pulmonary arterial hypertension space both afford comps in terms of what a next in class drug could mean in terms of increased diagnosis and also category penetration. We look at those as good proxies All right. Sounds good. Appreciate it. Thanks guys. Thank you. Thank you.

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

Hello, Salim. Great.

Hey, Robert. Thanks for the question. One question we're getting a lot on, I'm sure you guys are as well, I would just love to get your view It's just the upcoming Edgewise data set, the twenty eight day. Just sort of look to see how you're framing it, anything you're looking out for there? And And also just related to that do you think there's any even remote possibility that they If they were to progress come out of this without any REMS at all, Thank you. Based on the preclinical data at least. Yes, it's a very slippery slope obviously that we won't go down to comment on another company's ongoing development program but I still appreciate the question. With that said, it's early days. And I'll turn to Fady to comment on this matter much as he's been asked by others. But I would suggest that we let the data and evidence speak for itself Yes. Hi, Saleem. I think it's still, as Robert said, early in the program, I think in order to understand the safety profile You're going to need hundreds of people's worth of data. And until you understand that, it's premature to comment.

Even if I were to comment on their eventual safety profile and monitoring. So I'll probably just I'll probably just leave it there. We're looking forward to seeing the data Obviously, these data will be telling as to whether there is an opportunity to land a new mechanism treatment in OHCM that would be potentially differentiated we're very pleased with the data we have supporting Aficamten, both as it relates to efficacy as well as safety ease of use and other things that were designed into Opicamten consistent with intrinsic properties [indiscernible] as we look forward to potential approval and potential commercial launch We're very confident that we're situated in a very positive place. With that said, we'll take a look at these data as they may come out later I guess, in the first quarter from what we gather. Okay, perfect. Thank you so much. Thank you.

Thank you. Our next question comes from James Condellus from Stifel. Your line is open. [indiscernible] Good afternoon. Thanks for taking my question and congrats on all the progress. I just want to ask one kind of quick question on the REMS and totally appreciate there's only so much you can say, but wanted to get your thoughts on if you expect Mavacamten's Rims To Be Eased In The U. S. As well and sort of if that happens, like how does that change how you sort of think about the range of scenarios for kind of what Afic Hampton's rents look again sort of like in that scenario, would you you define differentiated REMS is still differentiated in sort of the maintenance setting as well or does that become more about some of the other aspects of the REMS? Curious what you can share there.

Yeah. Here again, I'm going to be careful not to make any comparative statements. But I will say we noted with interest the BMS earnings call and its reporting on the changes as it relates to EMA label, how FDA may respond to an application to ease certain restrictions relating to the existing REMS for mavacamten, CAMZYOS We've done a lot of market research And there are points of differentiation that we continue to believe are quite meaningfully important for afecamten as our consistent with intrinsic An echo frequency is one of those but so are there several others Maybe I'll ask Andrew to comment on the market research we've done and our expectations for a differentiated risk mitigation profile if approved. [indiscernible] differentiation, I mean, maybe we'll just start with the data. The data is should inform the label, which is our guidelines for claims around differentiation. There are many aspects of differentiation that we're exploring and that are going well from a market research point of view. This could be one of them or this could be in parallel, but there's others. I think if this does get relaxed for the whole category, this is actually good for the category.

The vast majority of patients are not treated today with a CMI. If less frequent, monitoring in the maintenance phase gets more patients on board with the CMI, gets more physicians to treat with the CMI. Kind of high tide lifts all both. So we look forward to what the FDA has to say. I believe the date is April.

And we'll certainly go from a differentiation given how our label is informed by the data. But we've said this many times our goal is to ensure that more cardiac myosin inhibitors are used by more cardiologists for more patients and still to our estimates, there are over eighty percent of eligible patients who could stand to benefit from use of a cardiac myosin inhibitor, and with prevalence growing, [indiscernible] number increases We believe strongly that afucamten, if approved, will have a differentiated profile.

Both as it relates to label and risk mitigation, we'll wait and see.

But I hope that answers your question.

Yes.

I appreciate the color. Thank you. Thank you. Our next question will come from Tess Romero from JPMorgan. Line is open. Hey, Tess.

Hi, Robert and team. Thanks for taking our questions tonight and look forward to ACC So do you think based on your physician and KOL interactions, that is it is appreciated that there is not the same pharmacogenomic and DDI liability with aficamten as there is with CAMZYOS due to the way that the drug is metabolized related to a patient's SIP2C19 genotype versus yours. If not, how do you think you will go about educating doctors around this point? And then relatedly to be clear, will any monitoring be needed by the pharmacy around concomitant meds with afecamten? Thanks so much.

Good questions. Maybe I'll ask Fady and Stuart to comment and then Andrew if he wants to add anything.

Well, I think, to your question really ultimately is going to depend on the labeling that we achieve with Abicamten, but the think physicians that we've interacted with even that have conducted our clinical trials recognize a difference that the drug interaction profile of apicamten doesn't involve 2C19, that has a very few meaningful drug interactions and I certainly have been educated to that fact and act accordingly. The monitoring of can come in a medication [indiscernible] There's no drug in the universe that is not susceptible at all to any drug interactions. Even at the camped in, but any drug interactions we have would be reasonably rare and uncommon. And physicians would be educated on those as well. But I doubt that there's necessarily a need Mark, a monitoring program or anything like that. We haven't done that in our clinical trials and have any issues Today, For clarification, you asked about pharma Stuart or Andrew, do you want to comment on that?

Pharmacy I mean we're not expecting I think in our base case that a from any REMS program that pharmacy monitoring would be part of a REMS program where a pharmacy has to call a patient and talk about existing drugs and potential drug interactions.

That is not something that we're anticipating.

Thank you, guys.

Thank you. Thank you. Our next question comes from Leonid Timoshev from RBC Capital Markets. Your line is open. [indiscernible] Thanks for taking my question.

Wanted to ask on the endpoints for Acacia and maybe some comparison to the competitor NHCM study in don't mean a corner unit commenting on someone else's study, but [indiscernible] Potential differences in KCC-twenty three versus KCC-twelve and maybe why you've settled on a single primary focusing on KCCQ rather than also including PVO2 as a primary and sort of whether that was based on your own diligence of your own data or in consultation with the FDA? Just any thoughts there be appreciated. Thank you.

Sure. I'll ask Fatty and also Stuart if he wants to comment. [indiscernible] [indiscernible] patient reported outcome. We examined its impact, the impact of afucamten on KCC and our Phase two study in NHCM. And while that was an open label experience, there was a meaningful impact on KCCQ. That said, I think that regulators in general would like to see an impact of a drug on more than just KCCQ. They like to see improvements in exercise and in NOI shape class, a consistency, if you will, across functional and symptomatic endpoints And Acacia is currently designed has both. It has an exercise endpoint as a secondary endpoint as KCCQ as a primary endpoint As you pointed out, Odysee has a dual primary endpoint with both peak VO2 and KCCQ in parallel. Assessed as part of a primary I think practically speaking, there's not that much of a difference They both are both designed to assess the strength of the evidence with respect to a patient reported outcome and other functional metrics. And I think regulators clearly want to see consistency across those Both of those domains Hopefully that answers your question, Leo.

That's great. Thank you.

Thank you.

Thank you. And our next question will come from Akash Tewari from Jefferies. Your line is open.

Hello, Akash.

Hi.

This is Zaki on for Akash. Thanks so much for taking the question. So in terms of non instructive HCM, so it looks like Bristol's Odyssey and your Acacia trial, you're both looking to dose patients up to achieve higher exposures And so when I look at REDWOOD Cohort four, it looks like the final proBNP levels are similar to MAVERICK's lower dose cohort.

So I think the key question is, whether you can actually show more efficacy by getting patients onto the twenty milligram dose in Acacia So based on like the SOQUA data you've seen so far, how easily do you think you can actually keep patients on the twenty milligram dose without EF issues for like the whole thirty six week period? And also, is there any sense on whether slower titration like we're seeing in Odysee might be better in the NHCM population?

That's a multi part question. Ask Fady and Stuart to tackle it.

Well, maybe I'll take it. I think just to be simple and concise, The Redwood data, we dosed patients between five and fifteen milligrams, eighty five percent of patients got up to fifteen milligrams. And were there within six weeks of initiation of therapy, many of those patients were still eligible to uptightrate to twenty milligrams. I don't think fundamentally there's any difference between the cardiac function of an NHCM patient and an OHM patient. So So one could expect a similar dose distribution in the two groups perhaps even a bit skewed to the high side. And HCM because you don't stop titrating based on achieving the targets with respect to gradients.

And what we saw in Redwood was that NT proBNP decreased in a dose dependent manner. The higher doses produced greater decrements in NT proBNP, And so I think the strategy that we've adopted in in Acacia Is Built Very Tightly On What We Did In Redwood. It's a one to one. The dosing strategy is almost [indiscernible] the speed of dosing is almost the same and I think all of those things are helpful when you design a Phase three study on the basis of a Phase two study. I think we're pretty confident with how we've addressed dosing in that trial.

Alright. Thank you guys so much. [indiscernible] Hi, this is Ike Lee. On for David Lebowitz. We are wondering you can orient us on expectations for [indiscernible] heading into the Maple HCM readout. Are we looking for a similar level of benefit this time head to head versus beta blockers as we did in Sequoia. Something like 5% to 8%, maybe 10% improvement over baseline exercise capacity. And is there any change the level of clinical meaningfulness for this one as opposed to the trials run before since the endpoint is the same. Good questions.

We'll probably want to answer them in terms of how the study was designed. What it was powered to demonstrate, And I'll ask Fady to comment on that please.

Sure. So Maple was designed as a trial with a To assess the impact of apicamten and metoprolol on exercise capacity and it's powered to about a two point zero difference between the two as we add in Sequoia achieved 1.75 I think that's pretty reasonable expectation, dollars 1.75 was very, very highly statistically significant. I think when you get to questions of clinical meaningfulness, anything above one thought to be clinically meaningful. And certainly the 1.74 that we achieved in Sequoia is we consider that clinically meaningful There are data that show that mortality and morbidity are potentially tied to peak VO2 and then changes in peak VO2 of that magnitude have substantial impacts on long term morbidity and mortality. So I think any of those changes five percent to eight percent, ten percent, would represent clinically meaningful differences between the two. And again, as I said earlier, it's not necessarily just going to be all about what's the difference between peak VO2, but it's going to be a consistent treatment effect across endpoints. It's going to be safety. It's going to be tolerability. All of those things I think are should be considered in considering how apicamten performs as monotherapy compared to Thanks for the question.

Thank you. Thank you.

And our next question will come from Sean McCutcheon from Raymond James. Hello, Sean. Hi, guys. Good afternoon and thanks for taking the question. Maybe to build on the last question. For Maple, you're enrolling patients with percent predicted PCO2 of less than one hundred percent whereas in Sequoia, for the most part, outside of one patient, you are enrolling less than eighty percent [indiscernible] How should we be thinking of this patient population as it relates to obstruction driving exercise capacity deficits And how that contrasts with Sequoia if at all? Thanks. Hi, this is Stuart Kupfer. I think that what we've observed in Sequoia was that that threshold less than 90% or less than 80% did not make a significant difference in terms of the incapacity of these patients. I think it is apparent that because of the degree of instruction And the fact that these patients were significantly symptomatic They already had a significant deficit. In their exercise capacity. So we just realized we could relax that criteria and still enroll patients with quite significant deficit that we believe that that these patients could benefit from avacamten treatment.

Thank you. And our next question will come from Kripa Devarikanda from Truist Securities. Your line is open. [indiscernible] Thanks. We are excited about the progress in 2025. [indiscernible] One commercial question for us. We've heard with nadacamten that treatment by cardiologists in the practice centers may be limited to insufficient numbers of monitoring equipment to adjust the large volume that they see. And patients have been referred to more specialist centers.

There potential for future treatment with OP2 be administered by a broader range of HCPs? And does your market research highlight bottlenecks related to equipment readiness in target markets outside The U. S? As well as The U. S. So we noted your equity research analyst note to that effect. And where some of the echo perhaps impeding adoption beyond centers of excellence Maybe I'll ask Andrew to comment on what he's learned from market research with regard to that and how that may or may not extrapolate to learnings in Europe, Sure. So we looked at Echo capacity across The U. S. Both within specialized centers, academic centers, city centers as well as community. It is currently not a a burden or a a anything that's kind of reducing the capacity is not allowing patients to potentially get treated? So I think there's other challenges with starting treatment outside maybe academic centers, incentives of excellence it's not related to echo capacity largely When we looked at Europe, Europe is a more concentrated market than U. S. Typically, Europe, you have to start in a hospital, in a community center, it's not as diverse in terms of the number of physicians' offices you have to go to.

Usually going actually to a center. And because Europe has a single payer system generally by country, and they as part of the reimbursement process For a specialty medication, it's pretty typical for It's difficult sometimes to distinguish between what's caused and effect or which the cart and which is the horse we do believe that a majority of Kamsayo's use currently is amongst A concentrated number of prescribers who happen to be in centers of excellence and with more experience [indiscernible] ability to navigate through A REMS program So can you extrapolate that to mean that there's less of an issue outside of centers of excellence We look at this as Experience with cardiac myosin inhibitors in general is correlated [indiscernible] broader and more adoption of the existing cardiac myosin inhibitor Our hope is if ficamten is approved, that we can contribute to more education more awareness more category growth and expansion beyond centers of excellence as could be a rising tide to lift the class. And that could hopefully confer benefit to Aficamten as we hope it becomes a category leader independent of what may be any concerns relating to echo capacity. I hope that helps.

It makes a lot of sense and thanks. We're all looking towards the year ahead.

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

Good afternoon.

Hi, good afternoon everyone. So slightly different question from me. I was curious if you could elaborate a bit more on your future goals for I think you mentioned BD and corporate development in the coming years. It sounds like you're willing to consider augmenting your R and D pipeline, curious if any color on stage of asset mechanisms indications, etcetera that you'd be interested in internally or externally? And how would you balance that with your current cash runway expectations today?

Yes. So I'll ask Isaac to comment first followed by Sung and then I may have a few comments after that. Sure. Thanks so much for the question. The most important thing for us is to make sure that we continue to focus on our expertise in the muscle biology and be able to look at a landscape both of what's being developed externally as well as internally to make sure that we can help advance the most advanced programs that are available. So from a licensing perspective, we have been and are actively discussions with both academics and research centers where there are preclinical programs also looking at early stage clinical development programs where we can use our own expertise to advance these programs forward. We're obviously looking at them being prudent from a financial perspective and where we think we can have the greatest impact Our focus has been on small molecules and as we've made comments earlier, in our talk that being able to look at other modalities is something that is very important to us because we see that happening, within the field and we want to make sure that we are in the forefront.

Yes. And Roanna, in terms of cash runway, we believe we have multiple years of runway as we start the year and this is supported by our starting cash balance of 1,200,000,000.0 Also, we have access to further capital as you know from Royalty Pharma up to $500,000,000 We'll also benefit from some near term milestones from the BD deals we closed last year related to Aficamten ex U. S. [indiscernible] we're in a very strong position here Specific to this year, we expect cash utilization to be in the low 500,000,000 So you can kind of work out the math there that with all the things that I've described in terms of sources of capital we believe we have multiple years on the runway right now.

Yes. And just to elaborate a little bit, our focus to be clear, remains on apicamten and our later stage pipeline and that's where our investment capital is best deployed The things that Isaac was referring to are more intentional to augment complement and provide adjacency to things we're doing in earlier stage of our research And the capital investments alongside of that will be modest relative to the overall spend. So this is more about building training wheels for Cytokinetics as we want to execute on our Vision 2,030 alongside of the things we're doing organically to provide some inorganic complement especially as could be adjacent to things we're already doing where we can mitigate risk and with new modalities enable a transition to some non small molecule approaches Don't confuse that to mean we're going to go into more expensive modalities like gene therapies and cell therapies, that's not our intention.

Understood. Thanks.

Thank you.

Thank you. And our next question comes from Joe Pantginis from H. C. Wainwright. Line is open.

Hello, Joe.

Hey, everybody. Thank you for taking the question. Good afternoon. So I'm not sure if you could discuss this right now because everything is is active, but upcoming to your mid cycle meeting with the FDA, anything you could discuss about key questions that are still outstanding or any potential rate limiting steps And then also with regard to omecamtiv, anything you might be that you can share regarding COMET HF and the enrollment trajectory say related to GALACTIC since there are additional screening Sure. So you answered your own question with respect to ongoing FDA interactions. We can't really comment other than to say that we feel very good about how we're situated in light of the ongoing activities And as we approach a mid cycle meeting, we believe we're in a good position to address any questions we may be getting from FDA As it relates to Comet and enrollment sites relative to GALACTIC, Maybe I could ask Fady or Stuart to comment on that.

Thanks, Joe. So as you know, we began enrollment in COMB HGF late last year.

And we have an advantage of leveraging the all the information we have from GALACTIC in terms of the best investigators to participate in the trial. And have the advantage of a great data set. To draw from demonstrating I think the hypothesis that omecanthamucarbonyl will be even more effective these higher risk patients. And so so enrollment is proceeding as as estimated. We will continue to roll through the year. We plan to complete enrollment next year. And so studies are proceeding according to plan.

To your question, we're borrowing a lot of learnings from Galactik and we believe we're in an advantaged situation for having conducted GALACTIC to know where to go for comment. So that trial can enroll rapidly. We'll have more to say about that through the year.

Thanks again.

Thank you.

Thank you. Our next question comes from Mayank Mamtani from B. Riley Securities. Your line is open. Good afternoon.

Good afternoon, team. Thanks for taking our questions and congrats on the progress. Just maybe switching gears to CK-five 86. [indiscernible] I think you mentioned the first two cohorts low and mid dose level enrolling at in completion by end of this year. Could you maybe just talk to the higher dose cohort is contingent on completion of the first two cohorts and maybe just what you're looking to learn on both the tolerability and obviously the biomarkers there in the hep thanks for taking my question.

Maybe I'll ask Stuart to tackle that please.

Stuart, thank you. So the study is designed intentionally and designed to be flexible. And so as you noted, our intent is to complete the first two cohorts by the end of the year and based on the information that we retrieve from those two cohorts then we would consider we need to proceed with the third cohort or perhaps with a different dose, So it is a flexible design and I think that really strengthens the study. With respect to the endpoints of the trial, first and foremost, we're evaluating safety and tolerability. In this hep hep population. We'll be collecting biomarker data cardiac biomarkers, anti proBNP, as well as assessing pharmacokinetics and evaluating effects on ejection fraction. And so those are some of the key endpoints that we'll be evaluating.

To this is mainly a dose finding type of study. Thank you. Any other hopefully that answers your question.

Yes, it does. Thank you. Appreciate it.

Thank you.

Thank you.

Thank you. Our next question comes from Yasmeen Rahimi from Piper Sandler. Your line is open. Hello, Yasmeen. Hi, Robert. Thank you so much for all the great updates. Guess one of the questions I was wondering about is recently the base line demographics of the Odysee study was published. And I would love to maybe get Fady's thoughts on that study and what stood out to you [indiscernible] Just some commentary. I appreciate the commentary throughout the call that positive days [indiscernible] continue to grow the uptake of C Mites in this big market. I mean, we're talking about a million patients, which is a a big mark of high addressable population. So you could just kind of comment around that I know Akaya is currently fully in enrollment mode. It's But maybe if there are any some differences that stand out to you as you look at that? Baseline population? Be helpful. And I'll jump back in the queue. Thank you, Fady.

Yes. Hi. I mean, I think the baseline characteristics were not on unsurprising and these are people that have significant symptoms, they have elevated biomarkers, reduced exercise capacity, all of those things that we expect to see in a population that is an HCM population. I think what is surprising is as how similar they are to the OHM patient with the exception of a gradient. In the biomarker and other deficits that they have.

So I think that it speaks to the fact that there are a lot of highly impacted patients with NHCM We've seen both their trial enroll very well. We've seen our trial enroll very well. This is a condition that's probably not as uncommon as people originally thought.

And I think it the effectiveness of CMIs and the should we'll be Lucidated by the results but there's similarity in lots of ways to the patients, I think bode well for what we might expect to see Thank you, Patty.

Thank you. And our next question comes from Charles Duncan from Cantor Fitzgerald.

Your line is open.

Hello, Charles. Hey, good afternoon.

Hey, Robert and team. Congrats on a great year of progress. Lots of Lots of good questions asked. So I will send one in, in terms of biz dev. I'm just kind of wondering if you could characterize the kind of work that's Sanofi did In terms of the China market, it seems like obviously could be quite large, Wondering if you could provide any color on call it the unmet need there and how you might see it pace in terms of it being developed And would you anticipate milestones yet this year in terms of cash payments or even early next year? Thanks. Yes. So we've been very impressed by the degree to which Sanofi has jumped in and dialed up and stepped up in meaningful ways. I'll ask Isaac to comment on that. And then Sung to speak to your second part of your question. Sure.

So as Robert said, we've been very impressed with Sanofi and their process To be clear, this was a transaction that was done through But what we understand is there were multiple parties interested. There's a clear understanding of an unmet need in China There are no REMS programs in China. So I think from that perspective, it went into Sanofi's value proposition of being able to go and take advantage of all the benefits of afficamten. And so they stepped into the collaboration I can tell you that since then, we have a very active dialogue with them as part of the the potential approval this year. There are, as you know, milestones associated with the approval, but again, they depend on that event happening in this calendar year. If not, they'll be pushed into 2026.

Yes. And Charles, just extending on the milestone question. We do expect meaningful milestones this year. And I would say these milestones, of course, we have multiple partners here, so I'm not going to be specific to a single partner.

But these milestones are tied to clinical and regulatory milestones. So just to give you some color, we could be eligible up to $35,000,000 in total across our partners.

And then as I mentioned, they've stepped up in some meaningful ways in terms of timelines, forecasts, manufacturing, and supply requirements Maybe I'll ask Andrew to comment on market sizing in China. Andrew, are you on mute? Yes, sorry. Yes, Charles. So in terms of population, China is also a concentrated market. There's around four hundred thousand diagnosed patients and there's a little over 1,000 hospitals where the vast majority, over eighty percent of those There's likely a lot more patients in the rural and community settings that are diagnosed, so that could