Good afternoon, and welcome to Cytokinetics Second Quarter 2020 Conference Call. I will now turn the call over to Diane Weiser, Cytokinetics Senior Vice President of Corporate Communications and Investor Relations. Please go ahead.

Good afternoon, and thanks for joining us on the call today. Robert Blum, President and Chief Executive Officer, will begin with an overview of the quarter and recent developments. Fady Malik, EVP of R&D, will provide updates related to aficamten focused on SEQUOIA-HCM, REDWOOD-HCM, and FOREST-HCM. Steve, VP of Clinical Research and Therapeutic Area lead in Cardiovascular, is filling in for Stuart Kupfer today and will provide additional updates for aficamten relating to MAPLE-HCM and speak to the expected start of Acacia HCM. Andrew Callos, EVP and Chief Commercial Officer, will discuss commercial readiness activities for aficamten and its market opportunity. Robert Wong, VP and Chief Accounting Officer, will provide a financial overview of the past quarter, and Ching Jaw, SVP and Chief Financial Officer, will discuss our financial outlook and revised spending guidance for 2023. Finally, Robert Blum will provide an update on our early clinical programs in his closing comments and review expected upcoming milestones. 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 2023 financial results filed on Form 8-K that was furnished to the SEC today. We undertake no obligation to update any forward-looking statements after this call. And now I will turn the call over to Robert.

Thank you, Diane, and thanks for joining us on the call today. We made substantial progress in the second quarter, not only by advancing and broadening the development program for aficamten but also by making further strides in our earlier-stage specialty cardiovascular pipeline. As Fady and Steve will elaborate, our comprehensive clinical trial development program for aficamten is firing on all cylinders. During the quarter, we completed enrollment in SEQUOIA-HCM. We began MAPLE-HCM, and we prepared to start Acacia-HCM, the Phase III clinical trial of aficamten in patients with non-obstructive HCM. We have accelerated the timeline for this trial, and we now expect to open the trial to patient enrollment next month. It's notable that very soon we will have three ongoing Phase III clinical trials for aficamten plus the open-label extension, which is a testament to our corporate reprioritization and the excellent work of our dedicated regulatory technical operations, clinical research, and operations teams, as well as the high-level enthusiasm and diligence of our clinical site investigators and their staff. Now that enrollment in SEQUOIA-HCM is complete, study conduct is progressing, and we remain on track to share top-line results by the end of this year. This trial has progressed through the dose escalation phase for all patients, and we're monitoring key metrics in blinded data, such as patients randomized, baseline characteristics, standard deviation around endpoints, early terminations, and missing data, and I'm pleased to report that across all of these measures, SEQUOIA HCM is proceeding well and meeting or exceeding our trial design assumptions. Moreover, alongside our preparations for the reporting on top-line results, our regulatory, supply chain, and commercial readiness teams have been actively engaging in numerous activities, including go-to-market plans that build towards potential approvals and commercialization of aficamten. Andrew will elaborate on some of those plans shortly. While aficamten may be top of mind, in parallel, our clinical research activities continued to push forward on other fronts as well. In the second quarter, we advanced CK-586, a second cardiac myosin inhibitor, into a Phase I study. We continued the Phase I study of CK 136, our cardiac troponin activator, and we continued nonclinical research and IND-enabling activities towards our goal of submitting one to two new INDs over the next one to two years. Moreover, in response to corporate setbacks earlier in 2023, and as we telegraphed on our last earnings call, we have reduced operating spending by approximately 15% relative to our initial 2023 financial guidance with a heightened focus on our priorities and pipeline, including preparations for the potential approval and commercialization of aficamten. That's all going to enable us to further extend our cash runway. Ken will provide more details and updated financial guidance for 2023 later in this call. As you will hear today, we're moving forward with momentum into the second half of the year with a broad early and late-stage pipeline, ongoing research, and a stronger financial foundation, giving us conviction and confidence in achieving our goals for the rest of the year as well as setting us up well afterwards. With that, I'll now turn the call over to Fady.

Thanks, Robert. In the second quarter, we made great progress across the broad development program for aficamten. Most importantly, we completed enrollment and randomization in SEQUOIA HCM, the pivotal Phase III clinical trial of aficamten, with 282 patients randomized, surpassing our enrollment target of 270 patients and making it now the largest randomized clinical trial of an investigational therapy ever conducted in patients with obstructive HCM. The conduct of SEQUOIA-HCM benefits greatly from our growing experience and learnings related to the use of cardiac myosin inhibitors as well as measures employed in the evaluation of their effectiveness, patient and physician preferences. I'm pleased to share that we also met or exceeded our enrollment objectives in terms of geography and patient characteristics. SEQUOIA-HCM enrolled a diverse patient population from the U.S., China, Europe, and Israel. Patients enrolled exhibit a substantial deficit in exercise capacity, a key element of the enrollment criteria, considering that the primary endpoint assesses for a potential increase in exercise capacity. Further to this point, SEQUOIA-HCM employs an individualized dose titration strategy designed to optimize dose selection and maximize the potential benefit-risk profile of aficamten. In fact, at this point, all patients have progressed through at least the eight-week visit, which marks the end of the dose escalation phase. We are accumulating more and more blinded efficacy and safety data that we monitor closely, including things like the standard deviation around the primary endpoint, the completeness of endpoint capture, the number of early terminations, and blinded safety data. Across all these measures, we feel SEQUOIA-HCM is proceeding per plan, certainly matching or exceeding our trial design assumptions. Our development operations and medical teams are working hard to collect and clean the data as it accumulates, as well as this program analysis and tables necessary to report the results expeditiously once we lock the database at the end of the trial. All this work has put us on track to report top-line results by the end of the year. Now that all the patients from SEQUOIA-HCM are randomized, we expect to also present baseline characteristics of these patients at the HCM Society Scientific sessions in early October. Also during the quarter, we presented new data in patients with non-obstructive HCM from Cohort 4 of Redwood HCM at the Heart Failure 2023 Congress, building on initial data presented earlier this year at ACC. The data showed that following only 10 weeks of treatment, aficamten was associated with an average improvement in the clinical summary score of the Kansas City Cardiomyopathy Questionnaire, or KCCQ CSS, of 11 points, with 58% of the patients experiencing a clinically meaningful reduction in symptom burden of 5 points or more. Treatment with aficamten was also associated with improvements in NYHA functional class, angina frequency, high-sensitivity cardiac troponin I, and NT-proBNP. We're pleased to see that most patients were able to achieve the highest available dose of 15 milligrams with no drug discontinuations due to adverse events related to aficamten, no treatment interruptions or down-titration events related to LVEF less than 50%, and no events with LVEF less than 40%. We remain confident in the promise of aficamten in non-obstructive HCM and look forward to starting a Phase III clinical trial in non-obstructive HCM soon. Steve will elaborate on this trial in a moment. Before I hand it over to Steve, I want to also share an update on Forest-HCM, which is the open-label extension study for patients who complete participation in Redwood-HCM, SEQUOIA-HCM, and now MAPLE-HCM as well. We're pleased to see that nearly all patients elect to continue into the open-label extension, and we now have patients who have surpassed two years on aficamten in Forest-HCM. In addition to providing data on the efficacy of long-term use of aficamten in the treatment of obstructive HCM, Forest-HCM is providing data on both safety and efficacy in a very clinically relevant real-world manner with investigators empowered to adjust doses in accordance with their clinical judgment and even discontinue other background medical therapy for HCM to simplify their patients' medical regimen. We'll continue to periodically share data from Forest-HCM, which we expect to factor importantly into the next-in-class profile for aficamten and shed light on its potential ease of use, safety, durability of effects, and tolerability. With that, I'll turn the call over to Steve, who is filling in for Stewart, who's unable to join our earnings call today. Steve will speak to the expanding development program for aficamten.

Thanks, Fady. During the quarter, we announced the start of patient enrollment in MAPLE-HCM, the Phase III clinical trial of aficamten as monotherapy compared to metoprolol as monotherapy in patients with obstructive HCM. And we are pleased to report that the first patients have recently been randomized. While we do not foresee that MAPLE-HCM is a critical path to the potential for first FDA approval, if successful in demonstrating that aficamten is superior to metoprolol with respect to improvement of exercise capacity, heart failure symptoms, and New York Heart Association functional class, we would expect to submit the results from this trial as a supplemental NDA for potential label expansion. MAPLE-HCM has the potential to meaningfully expand how physicians foresee using aficamten as would likely be reflected in the treatment guidelines potentially elevating it to first-line therapy and potentially expanding the commercial opportunity. At the same time, in recent months, we have been continuing preparation for the pivotal Phase III clinical trial of aficamten in non-obstructive HCM based on the favorable data arising from Cohort 4 of Redwood HCM. As noted in today's press release, we're calling this trial Acacia HCM in keeping with our theme of Northern California trees for the program. Acacia HCM stands for the assessment comparing aficamten to placebo on cardiac endpoints in adults with non-obstructive HCM. This pivotal clinical trial of aficamten in patients with non-obstructive HCM is expected to open for patient enrollment next month, which is ahead of schedule, underscoring the high level of enthusiasm for this next trial. In advance, I'd like to share a few key points about its design. The Acacia HCM is a Phase III multi-center randomized double-blind placebo-controlled clinical trial expected to enroll approximately 420 patients with symptomatic non-obstructive HCM. The primary endpoint is the change in KCCQ clinical summary score from baseline to week 36. While the primary analysis will take place at 36 weeks, patients will continue on treatment with aficamten or placebo for up to 72 weeks to evaluate additional secondary and exploratory analyses, including the time to the first cardiovascular event. As previously mentioned, we expect to initiate patient dosing in Acacia HCM in September. With that, I'll turn the call over to Andrew.

Thanks, Steve. Our commercial readiness team is laser-focused on key work streams in support of the potential approval and commercialization of aficamten in both the United States and Europe. During the quarter, we updated and continue to refine our go-to-market plans executed against activities outlined within them, including development of a disease state education plan, branding, positioning, patient support programs, sales force deployment plans, and pricing assessments. We have also conducted additional market research to gain greater clarity on HCM patient and HCP experiences as well as how HCPs, payers, and patients would respond to our potential product profile. Many of these plans will be augmented once we have results in hand from SEQUOIA HCM, but our research to date is encouraging in terms of payer, patient, and physician interest, as well as enthusiasm for a next-in-class cardiac myosin inhibitor. Our research continues to explore distinguishing characteristics of aficamten, including its potential drug-to-drug interaction profile and dose titration, which will be important to patients and prescribers. We believe there is and will remain a large unaddressed population of patients with obstructive HCM that may benefit from aficamten if approved. We are fortunate to have been able to redeploy members of our commercial team who had previously been focused on omecamtiv mecarbil to now focus on aficamten, a corporate pivot that has enabled the acceleration of our planning and efficient operationalization of our preparations for the potential approval and commercialization of aficamten. Meanwhile, conversations with payers progressed in accordance with compliant pre-payer interactions with productive dialogue and education, not only about the HCM landscape and the potential of cardiac myosin inhibitors but about aficamten specifically, in which they remain highly interested. We look forward to continuing to develop, expand, and hone our go-to-market plans for the potential approval and commercialization of aficamten and simultaneously deliver on stepwise and systematic elements of the pre-commercial runway. Toward that end, turning to the market opportunity in Europe, we are pleased to have made our first new hire in Europe, bringing on our Head of Europe, who has a proven track record in launching new products, delivering growth, and achieving expectations in European and international markets within the rare disease and cardiology space. We are looking forward to having both our European Head of Access and Medical Affairs join us by the end of Q3. We are pleased to be attracting top talent, thanks to our culture and pipeline. And with that, I will turn the call over to Robert Wong.

Thanks, Andrew. We ended the second quarter with $592.6 million in cash and investments. Our revenue in Q2 2023 came from Astellas and is the remaining amount due to us from their $12 million commitment associated with our conduct of COURAGE ALS. Our second quarter 2023 R&D expenses increased to $83.2 million from $57.1 million in the second quarter of 2022, primarily due to increased spending for our cardiac myosin inhibition program, which represents approximately two-thirds of our R&D spend for the quarter. Our second quarter 2023 G&A expenses were $39.7 million, down from $42.7 million in Q2 2022 due primarily to reduced outsourced spending on commercial readiness activities. And now Ching will review our financial outlook and corporate development strategy.

Thanks, Robert. We ended the quarter with approximately $593 million on the balance sheet, which represents nearly two years of cash runway based on our revised 2023 spending guidance announced today, on which I will now elaborate. Previously, we had expected our operating expenses for 2023 to be in the range of $420 million to $450 million and net cash utilization to be approximately $350 million to $375 million. We have reduced our operating expenses to be in the range of $390 million to $410 million in response to our receipt of a CRL from the FDA regarding the NDA for omecamtiv mecarbil and the discontinuation of COURAGE ALS. Our net cash utilization is now expected to be approximately $310 million to $320 million. This reduction represents savings of approximately 15%, which demonstrates initiatives to reduce spending and limit headcount growth in light of these setbacks. I will also remind you that as we have outlined in previous and revised guidance, we also expect to receive a $50 million nonrefundable milestone payment from Royalty Pharma upon the initiation of patient dosing in Acacia HCM, which is expected to start next month. Through this transaction with Royalty Pharma, we also remain eligible for two additional tranches of capital if we choose to take them: $75 million upon potentially sharing positive results from SEQUOIA HCM, and $100 million upon the acceptance of NDA submission for aficamten in the U.S. We view this transaction as equivalent to a line of credit, which we can leverage to add to our balance sheet in 2024 if necessary. Towards that objective, we're in the midst of our annual strategic planning process, which critically evaluates corporate and pipeline scenarios, contingencies, and risk mitigations and informs investment decisions as we calibrate with board and shareholder alignment. And with that, I will turn the call back over to Robert Blum.

Thank you, Ching. As you've heard, in the second quarter, we made substantial progress across the pipeline. To add to what my colleagues mentioned, during the quarter, we also participated in a Type A meeting with the FDA to understand FDA views related to the CRL for omecamtiv mecarbil. And outside the United States, omecamtiv mecarbil is under review in Europe and in China. And during the quarter, we continued to support these reviews and address questions from regulators. We also made progress with our earlier-stage pipeline. During the second quarter, we advanced CK-586 into a Phase I single ascending dose and multiple ascending dose study, and we're pleased with initial progress to date. CK-586 is a cardiac myosin inhibitor that is mechanistically distinct from aficamten and has potential application for patients with heart failure with preserved ejection fraction or HFpEF, for which there are few treatment options. For some people with HFpEF, their disease in many ways mimics non-obstructive HCM due to their thickened hearts and increased cardiac contractility and symptom burden. Encouraging data from Cohort 4 of Redwood HCM in patients with non-obstructive HCM are potentially a proxy for the therapeutic application of cardiac myosin inhibition in this patient population as we hope to further investigate with CK-586 in 2024. At the same time, our consistent commitment to muscle biology research persists. In addition to the ongoing early-stage programs for CK-136 and CK-586, we expect to file one to two additional INDs for new drug candidates over the next one to two years. Once these INDs are filed, we will have advanced three to four new drug candidates in a relatively short time span, an impressive figure for any biopharmaceutical company, which will enable us to expand our pipeline according to our Vision 2025 goals. There is a great deal of work progressing behind the scenes, and I must thank our diligent and dedicated employees for their commitment to our future. Meanwhile, on the finance and corporate development side, you heard from Ching that we're doing right by shareholders to prioritize company activities and associated spending while also extending our cash runway. Moreover, we are continuing to advance business development initiatives with focus on Japan and Europe as we continue to seek potential partners for omecamtiv mecarbil and aficamten. Since opening the aperture to partnering for aficamten in Europe in Q2, we have been actively engaged with potential partners, and we're pleased with the progress and level of interest that we've received as well as the diligence and deal discussions as they relate to both aficamten and omecamtiv mecarbil. Our future is only made possible by what came before. And this year, we have been celebrating our 25th anniversary with a recent open house held at our headquarters in South San Francisco. We invited our local community of partners, former employees, investors, patients, advocates, and community leaders, and we are honored to have been joined by esteemed local city and county elected officials as well as staff representing California state senators. We were grateful to celebrate this joyous occasion with our long-time supporters and friends, recognizing that while much is the same as it was when we started Cytokinetics in 1998, much has also changed as we've made progress towards our ambitious goals. And still, the best is yet to come when we hopefully bring forward our first approved medicines to the benefit of patients. Now I'll recap our upcoming milestones. For aficamten, we expect to share top-line results from SEQUOIA HCM by the end of the year. We expect to continue enrolling patients in MAPLE HCM and start Acacia HCM in September 2023. We continue to advance our ongoing go-to-market strategy during 2023. For omecamtiv mecarbil, we expect to continue to pursue potential international approvals in Europe and in China. For CK-136, we expect single ascending dose data from the Phase I study in the second half of this year. And finally, for CK-586, we expect to continue to enroll in the Phase I study throughout this year. And operator, with that, we can now open up the call, please, to questions.

And our first question will come from Ashwani Verma from UBS.

It's Tasman on behalf of Ash Warman from UBS. I just have a quick one on CK-586. Just looking at the mechanism, it's very similar. It's distinct from Aficamten, like you noted. What gives you confidence that this mechanism of action will work for patients in HFpEF? And why not pursue this also in obstructive HCM? And just a quick second one, like what would be the benchmark for efficacy and what clinical properties are you looking for in the Phase 1 trial?

Sure. So I'll turn this over to Fady and to Steve. But firstly, before I do, I'll just say that CK-586 is intentionally being advanced to be distinguishable from aficamten, which is being developed, as you know, in obstructive disease and non-obstructive HCM now and were we to have identified any issues or liabilities with aficamten, then perhaps CK-586 could be developed in those same indications, but we are not aware of any such issues and hence why we think 586 should stand on its own in a different disease state. So maybe now I'll turn it over to Fady to speak to why we believe this mechanism is translatable to HFpEF and what we may be looking for, both as it relates to Phase I data and ultimately beyond that in HFpEF.

Robert, as you mentioned, CK-586 has a distinct mechanism of action from aficamten, but it's still a cardiac myosin inhibitor. The distinction is really subtle at the point of where it binds and what form of the motor protein it inhibits. Fundamentally, it does the same thing. It reduces the number of active cross bridges and reduces cardiac contractility. It has a shallow exposure-response relationship, as does aficamten. And so fundamentally behaves very similarly. As Robert said, aficamten is doing wonderfully. We don't really think we need another drug in HCM, but HFpEF is a much different population and a very large population at that. What we're intending with 586 is to focus on the different indication and into a subset of patients with HFpEF whose phenotypes mimic some of our NHCM patients. They have larger hearts, thickened hearts, high filling pressures, higher biomarkers, symptoms, and poor exercise tolerance. So in many ways, they are a phenocopy for those that have genetic non-obstructive HCM. So we'll be advancing 586 in that direction. It's really premature for me to discuss what we'll be doing in Phase III, other than focusing, I think, in that population that most closely mirrors the NHCM population. I hope that's helpful.

And our next question will come from Rohit Bhasin from Needham & Company.

This is Robin on for Serge. Can you just talk about your expectations for the rate of enrollment for both the MAPLE and Acacia trials? And then when do you plan on presenting the new data disclosures at medical meetings?

Sure. So as it relates to both MAPLE and soon to start Acacia, I think it's too early for us to be guiding as to the rate of enrollment. I do understand the question, and we should get you that answer. But let's see how we get out of this startup phase and these initial enrollments before we might start guiding to enrollment rates and conclusion. I don't expect that there will be any data from either of these studies in 2023, of course. As we look to next year, I think it's also premature; we'll be in a better position to point to what to expect next year when we do our Q4 earnings in February.

Thank you. Our next question will come from Jason Butler from JMP.

You said in the prepared comments that all patients in SEQUOIA are now through the titration phase. Just wondering if you could comment on whether you're seeing what you expected to see in terms of the proportion getting to target doses.

So thank you for asking, and that's a notable achievement as you highlight that we now are through that dose escalation phase. Keeping in mind we're blinded to dose, but maybe I'll ask Steve if he wants to elaborate.

Well, Jason, I think Robert just answered your question. This is obviously a blinded study, and we are, in fact, blinded to the actual dose that's administered. So we don't know the proportion of doses that patients are being exposed to in SEQUOIA. But you have already seen some of the data that have been presented with regard to the Redwood study, which is unblinded, where there's a nice bell-shaped distribution in the doses, patients being exposed to 15 and 10 milligrams for the most part with a smaller proportion getting exposed to 5 and 20 milligrams.

And our next question comes from Jason Zemansky from BofA.

Congratulations on the progress. I wanted to circle back to some of your comments regarding MAPLE and the possibility of broadening the label of aficamten to include use in the first-line setting. I'm curious, what do you see as the opportunity here? I mean, obviously, the addressable market is sizable, but it seems like there could be potentially logistical or administrative hurdles thinking about pushback from payers or potential capacity issues from community prescribers. I mean do you see aficamten as a valid option for all comers with obstructive HCM?

Yes, I think we're following the lead of investigators themselves in Forest who are choosing to take patients off of beta blockers for reasons that matter importantly to physicians and patients. And ultimately, I think we'll be welcomed if MAPLE is successful by payers. Maybe I'll ask our clinical colleagues if they want to add anything to that, and maybe also Andrew if he wants to.

Jason, this is Fady. I might just add that in the context of a drug that addresses the underlying cause of the disease, there's obviously an opportunity for disease modification. And so MAPLE is not designed to address that point. But in terms of thinking about drug selection for patients, at least we provide the evidence of which of the current number one choices that's initiated versus the newcomer, the cardiac myosin inhibitors, where might the best efficacy be found. And then over time, we would hope to broaden the case for using cardiac myosin inhibitors early based on the fact that they may slow the progression of the disease or stabilize the progression of the disease. So I think this is the beginning of a strategy to establish cardiac myosin inhibitors as first-line therapy.

Yes. Well, maybe one or two things, Jason. First is that having evidence certainly helps inform guidelines. Guidelines will then help, kind of the second point from a payer point of view, maybe get rid of the step that we have or likely have, I should say, as a category through beta blockers and calcium channel blockers, which from our research seems to be important to physicians as well as patients if there's evidence that aficamten alone can treat the disease effectively, then we think that will certainly be a good strategy commercially as well.

And our next question will come from Joe Pantginis from H.C. Wainwright.

Thanks for all the details and looking forward to the start of Acacia. So Robert, I'm going to give you a bit of a run-on sentence here, if you give me a little patience here. So with regard to the initiatives in cost savings and what have you, would you consider the company rightsized at this point? Or can we expect any potential additional cost savings? And then with regard to aficamten, since this is a broad geographical study, are there any particular geographies that might have enhanced focus by you with regard to clinical trial conduct or a treatment regimen that might be different from other regions? And lastly, with regard to Acacia, are there any external impacts that also assisted with regard to accelerating the start of the study?

You're right, that was a long sentence, and I'm trying to remember the component parts. So let me start with what I remember to be the first part. I do believe, and Ching can comment on this too, if he likes that we went through a very significant cost-cutting exercise, critically assessing what we need to be doing in 2023 to align better with a new reality, a reality that has us focused on aficamten and where omecamtiv mecarbil, because of the CRL, is not part of our near-term future and recognizing that reldesemtiv was not progressing in Phase III. We needed to see where we could redeploy people to have them focused on that, which was now our new priority and that's aficamten first, second, and third. And in order to do that, we looked at outsourced spending, contractors and consultants, and our internal headcount. We also looked at plans to grow headcount, and we set some aggressive targets, and we met those targets. I think the team here at Cytokinetics did a great job pulling all in the same direction to ensure we could very meaningfully reduce operating spending, not just over the long term, but in the nearer term, so as to extend cash runway this year. And that's what we achieved when we gathered for the Q1 earnings call; we knew we had ambitious targets, and we had not yet concluded that exercise. We did conclude that exercise in Q2, and I think people tightened their belt quite substantially. Hence, I think we are rightsized for what are our current priorities and knowing where we are today, recognizing that aficamten is going to be paving the path for this company, and we have to be in the best position to capitalize on that as soon as we know more from SEQUOIA and that will be end of this year. So let me see, firstly, if Ching has anything to add to that.

I think Robert covered it well. The only thing I would add is, as part of our strategic planning process, we're also contemplating different scenarios if SEQUOIA readout does not meet our expectations, then we have scenario planning to address those. But obviously, we'll have to wait for data before executing anything. I think the next part of your sentence related to geographic variability potentially, and were we noting anything or preparing for anything. Maybe I'll turn to Fady or Steve to speak to that.

Sure. So I'll take that one. This is Steve speaking. So your question alluded to whether there are specific geographies that we're targeting. I think the strategy that Cytokinetics has employed has been to cast a wide net and capture all geographies. You're right that there are treatment or strategic differences in how patients are treated in different parts of the world. However, the way that SEQUOIA was designed captures all patients who have symptomatic obstructive HCM independent of what medical treatment they have available to them, whether it includes disopyramide or not. I guess the exception would be Japan, where they have sav3enzaline therapy, and we're not running the study in Japan, as you know. Independent of the availability of septal reduction therapy, whether it be septal myectomy or alcohol ablation, you see that we do have an endpoint that does measure the impact of aficamten on the eligibility of these patients for that. And I think if you take a step back and look at the strategy that we've employed for HCM at large is that we have a development program not only targeting patients with obstructive HCM independent of geography, but all patients with HCM independent of phenotype, including non-obstructive patients, patients with mid-ventricular obstruction that you've seen without Redwood Cohort 4, as well as hopefully in the future other subgroups. And then you had a third part to your sentence, and I can't remember it...

External impacts - I'll take that. I think for MAPLE, there's a lot of enthusiasm giving the question that we were asking in that study. And that patient population is a little different than the other HCM populations that have been studied to date. And obviously, there are no large OHCM studies ongoing. With regards to NCM, we think it's the first time a novel therapy is being studied in NCM. I think investigator and DBS will be high across the board.

Our next question will come from Dane Leone from Raymond James.

This is Sean on for Dan. Can you talk about the strategic logic behind the sole primary endpoint of KCCQ for Acacia given the parallel MAVA study, you have K2 and CO2 as co-primaries? What position in FDA feedback drove that decision? And is the 36-week endpoint versus a 48-week time point in Odyssey, entirely driven by the expected duration of the titration period? And if not, you’ve gone to that decision making?

Sure. I'll ask Steve to speak to those questions, please.

Sure. So this is Steve. The primary endpoint for Acacia, as we mentioned earlier on, is the sole endpoint of the change in KCCQ, and we picked that based on our experience from our Phase II study, the Redwood Cohort 4 that was presented and you've seen the data. We also are aware that the majority of patients who have non-obstructive HCM are receiving therapy with either beta blocker or calcium channel blocker—actually mostly a beta blocker. And as you know, that impacts the potential to achieve a significant change in PVO2. And we felt that if we were to incorporate these two endpoints as a composite to a primary endpoint or dual primary endpoints for that matter, we would hamper the likelihood of success. Obviously, exercise capacity is important, and we have incorporated this as Fady mentioned, as a key secondary endpoint, exercise capacity as measured by cardiopulmonary exercise testing. But in essence, we felt that separating those two would increase the likelihood of technical success for Acacia HCM. There was a second part of the question? And I think we've chosen 36 weeks, and that gives us, I think, plenty of time to get to the maximum effects. We have a relatively short titration period in our study, which is mirrored by what we've executed in SEQUOIA, and we've chosen that. And you'll see, as we mentioned later, patients will be followed up after that primary endpoint for longer, and we'll have the opportunity to see if there's any other accumulating efficacy over time. Thanks for your question.

And our next question will come from Ted Romero from JPMorgan.

I wanted to ask a question on HCM epidemiology today, if I could. You've historically talked about a patient population of 190,000 in the U.S. with diagnosed obstructive HCM with, of course, an undiagnosed patient population on top of that. As I recall, Bristol had talked about 75,000 identified diagnosed obstructive patients that we saw them quote around the time of their launch. Can you help us close what the gap might be there? We just really like to get a better understanding of where your latest thinking is on the epidemiology in obstructive HCM as you think about diagnosed patients here at the time of a potential aficamten launch? And where you might see that evolving with time.

Sure thing. I'm going to turn to Andrew, who is very focused on these matters and also how the literature is evolving here.

Sure. So thanks for the question. So there are multiple publications, some older that speak to lower numbers of epidemiology. We did a five-year longitudinal study on claims data on actual patients that are diagnosed. And then we corroborated that with publications that are more recent around the 190,000 number. I can't speak to where the miscalibrated number is. I can only speak to that we're very confident in that 190,000 number, and that number is growing a little higher than the rate of population on the OHCM. And again, that's based on actual data in claims. So we're going from that number, the 190,000 over that 190,000 from our research. Furthermore, I think it's important to understand that probably around 60% of those patients are not currently optimized with treatment and still having symptoms, and that's really the target of therapy.

And our next question will come from Yasmeen Rahimi from Piper Sandler.

Hi, Robert, first of all, congratulations on the big anniversary and what a wonderful achievement for the entire company. Two questions that are directed to Steve and Fady and maybe also Andrew could comment on it. A question that we're getting from quite a lot of clients right now is what do we want to see from a safety perspective in the upcoming SEQUOIA that could want a differentiated monitoring? And what would be a favorable rent? I think a lot of clients understand the absence of DDI but may want to understand sort of how the SEQUOIA data could maybe just get us really comfortable with a differentiated label. And I really appreciate your thoughtful comments around these questions, and I'll jump back in the queue.

Sure. I'll turn first to Fady, but I'll underscore, of course, that what we're going to share are comments based on what we've seen already in Redwood and Forest and what we hope to and expect to see in SEQUOIA, that that's still to be known. And aficamten remains an investigational compound. So with that, I'll turn to Fady to answer your question.

Yes. I think in terms of monitoring, we hope to see that the data from Forest will support a frequency of echo monitoring that is manageable by patients and their physicians. I'm not going to really make any comparative statements as you asked for differentiation. But you could imagine that we are in Forest now monitoring patients for every three months. We would hopefully, those data would support the lack of treatment decisions or safety events that are driven by all of those echoes. I think everyone recognizes the cardiograms are a burden to the sites and to the medical system. I think there should be a general incentive to minimize the burden on patients and the medical system. We're very happy with how Forest has been proceeding. As I said earlier, we now have patients out to two years, and we hope that, that safety database will lend itself to making a compelling argument for echo monitoring that might be twice a year or even yearly at some point. And in terms of REMS, I don't think we have any meaningful drug-drug interactions and other aspects of the drug that would not require extensive physician education. So stay tuned. As the data evolves, I think we will hopefully have more to say. What's especially reassuring in the clinical trials data that we've seen to date is that we haven't observed any early terminations as a result of ejection fractions unexpectedly falling in patients with obstructive HCM. We'll be looking to see if that may continue with the unblinding of the SEQUOIA results, but that's the kind of thing that may ultimately factor into what would be considered a risk that would be mitigated by a potential REMS program. And that's something that we're continuing to be quite hopeful for.

Thank you for the thoughtful remarks. I'll jump back in the queue.

And our next question comes from Salim Syed from Mizuho.

So Robert, the number one question we get, I want to see I'm sure you get it too, why is the stock back down at $30. I think a lot of people are trying to sort out why exactly it's there, and nobody really thought it would be at any point in 2023, really. And then the reasons that we hear from folks seem to be pointed to your CAMSOS-NRx line and then potential deal risk around aficamten? And I know there's one question. I really want to focus on the deal risk piece here. So given we are four months or so away from the COA readout, just curious in your discussions with potential partners, how that particular aspect of the stores being perceived. Do you think folks will want to see that data? Or can you make a decision to go it alone or partner prior to that data? Just give us, if you can, just set aside some context for us how timing of a potential deal, if any, or go alone or partner decision.

Sure. Any deal that we might do would have to be a deal that met our expectations to be able to go to Europe on our own, but would be supplemented by a partner's involvement. The hurdle is very, very high. We're not looking to do a deal for the sake of doing a deal. And were we to do any deal, it would be as enabling of our continued corporate development with an emphasis on our own to go to Europe. You've already heard Andrew say that we've hired our Head of Europe. We're hiring some other folks there. It's our intention to build out our commercial business in Europe. So with our last earnings call, I did indicate we were opening the apertures to partnering aficamten potentially in Europe, but with a focus on Japan and as would only be done if we could make a case that, that's better than going it alone. While I won't comment on what we've concluded, I will say that we continue to execute on our go-to Europe strategy, and we're looking very critically at what might be any alternatives to that plan. We think it's in the interest of shareholders that we objectively approach that decision. We've done that, we’re doing that, and we continue to execute well on our plans. I hope that answers the question.

Our next question comes from Carter Gould from Barclays.

Pete on the line for Carter. We just have a question on expectations for what you will disclose in the SEQUOIA top-line press release. To what extent does the MyoKardia level disclosure serve as a good benchmark for what to expect? And then as a follow-up to that, considering SEQUOIA is right on the horizon, what should we anticipate from you and/or what will your presence be at the HFSA and AHA meetings this year?

So we're going to be out in full force at HFSA and AHA this year, as well as the HCM Society Meeting in October, which falls in between. What I'll also say is, in as much as we've guided to results for SEQUOIA by the end of the year, it's reasonable to expect that the full-on presentation of those results would occur not at one of those meetings, but perhaps at ACC, which is in April 2024, and ACC has its own guidelines and restrictions as to what would be permitting of a presentation in their scientific sessions, which are different from other meetings. If I recall correctly, when MyoKardia presented its data, it was leading into the ESC meeting that year. ESC has different restrictions than ACC. So I don't know that you can compare what will be our disclosure in a top-line release to theirs. However, what I will say is we will disclose that, which we determine to be material and informative to shareholders without jeopardizing the presentation at ACC. And until we see the data, it's hard to know exactly where that falls.

And our next question comes from Justin Kim from Oppenheimer.

Robert, maybe just as a follow-up there. I just wanted to ask a question with respect to the presence at AHA and maybe just what we might expect from Forest; presumably, you'd have some experience from sort of SEQUOIA completers. I'm just wondering, like, is that something we can expect to see how some of those participants of the pivotal study did once they were off the drug and re-titrated or titrated up from placebo and sort of see that at AHA later this year?

Yes. So we're not guiding to any new data from Forest at AHA, but rather you heard us refer to baseline demographics from SEQUOIA at the HCM Society. As it relates to Forest, it's not been our practice that we would provide updates at every medical meeting. However, we certainly want to provide meaningful updates when there's significant new data to share. That's more likely as we'll be coming at ACC next year.

And our last question will come from Srikripa Devarakonda from Truist Securities.

Good afternoon. Just to follow up on what Robert, you mentioned earlier in terms of the LV drop. I think previously you had mentioned that there could be an unblinding event if the LVEF drop was fairly low. I was wondering if you can help set what is the bar for fairly low. And if we haven't heard about it so far, can you assume that it didn't happen?

Good question. I'll turn it to Fady and maybe, Steve, if he wants to add.

Alright, Brett. I think the protocol is pretty clear that if we see a patient with an ejection fraction fall below 40%, that the investigator and Cytokinetics should be informed. To date, we haven't seen—we haven't been informed of any such events, which is quite reassuring. We're not privy to any other drops in EF. The rest are blinded and will remain so until the study is complete.

Thank you. And I'm showing no further questions from the phone lines. I'd now like to turn the conference back over to Robert Blum, President and CEO, for closing remarks.

Thank you, operator, and thanks to everybody who joined us on this call today. Obviously, quite a lot is going on at our company as we're reprioritizing, focusing on aficamten, reducing spending, and advancing our pipeline. We think we're doing that very well aligned with what shareholders should expect of us as we come forward to these important milestones. We look forward to keeping you abreast of our progress. We welcome your further questions, and we look forward to updating you throughout the remainder of this year. With that, operator, we can bring this call to a close.

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