Good afternoon and welcome ladies and gentlemen to Cytokinetics Third Quarter 2021 Conference Call. At this time, I would like to inform you that this call is being recorded and that all participants are in a listen-only mode. At the company's request we will open the call for questions-and-answers after the presentation, we will allow for up to two questions per participant. I will now turn the call over to Joanna Siegall, Cytokinetics' Senior Manager of Corporate Communications and Investor Relations. Please go ahead.

Good afternoon and thanks for joining us on the call today. Robert Blum, our President and Chief Executive Officer, will begin with an overview of the quarter and recent developments, then Fady Malik, our EVP of Research and Development, will provide an update on omecamtiv mecarbil including recently presented an additional analyses from GALACTIC-HF as well as an update on our ongoing next steps with the FDA. Next, Stuart Kupfer our SVP and Chief Medical Officer, will provide an update on our development program for aficamten by recapping the results from cohorts one and two of REDWOOD-HCM elaborating on continuing activities and REDWOOD-HCM and reviewing the design of SEQUOIA-HCM our planned Phase 3 clinical trial of aficamten and patients with obstructive HCM. He will also speak to initial progress in COURAGE-ALS our ongoing Phase 3 clinical trial of reldesemtiv in patients with ALS. Then, Andrew Callos, our EVP and Chief Commercial Officer will discuss our go-to-market strategy. For omecamtiv mecarbil, and our cardiovascular franchise development plans for the commercialization of aficamten. Robert Wong, our VP and Chief Accounting Officer, will provide a financial overview for the past quarter and Ching Jaw our SVP and Chief Financial Officer, will discuss strategic planning our financial outlook and corporate development strategies before Robert Blum will provide concluding thoughts and expected key milestones for the remainder of 2021. 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 material from those in these forward-looking statements is contained in our SEC filings, including our current report regarding our third quarter 2021 financial results filed on Form 8-K 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, Joanna. And thanks again to everyone for joining us on the call today. We had a very productive third quarter marked by meaningful progress across all of our later stage programs. Most notably, our sharing positive results from our Phase II clinical trial REDWOOD-HCM which demonstrated the efficacy and the safety of Aficamten our next-in-class drug candidate in patients with obstructive hypertrophic cardiomyopathy. As we've said, these results met our high expectations for this trial and we received positive feedback from the physician community. Stuart will elaborate more on these results in a moment. During the third quarter, we are also pleased to complete enrollment in Cohort 3 of REDWOOD-HCM, which as you'll recall enrolled patients also on disopyramide a medication, often prescribed to patients with more severe HCM. We expect to share the results from Cohort 3 in the first quarter of 2022. Following previous interactions with FDA from which we receive feedback on our planned trial design. We continue to advance activities in preparation for SEQUOIA-HCM the Phase 3 clinical trial of our Aficamten in patients with obstructive HCM as we recently presented in a Stuart will elaborate. This trial was designed to potentially demonstrate a significant improvement in exercise capacity and evaluate safety in a broad population of patients with symptomatic obstructive HCM. We're working with sites around the world, including many who participated in REDWOOD-HCM who are enthusiastic about also participating in SEQUOIA-HCM and we look forward to starting this trial soon. Moving now to our heart failure program, we continued activity supportive of our plans to submit an NDA for omecamtiv mecarbil, and we remain on track towards our goal of submission in this fourth quarter of this year Fady will have more to say about that in a moment. Additionally, as outlined…

Thanks, Robert. As you mentioned, results from additional analyses of GALACTIC-HF presented during the quarter at the Heart Failure Society of America Annual Scientific Meeting reinforce that outcomes with omecamtiv mecarbil in black patients enrolled in GALACTIC-HF were consistent with the overall population and like the overall study results were driven primarily by a reduction heart failure hospitalizations and heart failure events. The treatment effect in black patients was also similar compared to white patients GALACTIC-HF enrolled the most black patients among recent heart failure trials and of patients enrolled in the U.S., 29% were black, which is important, not only because Black patients have historically been underrepresented in clinical research, but also because they have a higher risk of heart failure and suffered worse outcomes. This disparity and outcomes is complex, but it's encouraging to see that the potential benefit of treatment with omecamtiv mecarbil remains consistent in this group. Expanding on the theme of higher risk patients with heart failure three weeks ago a manuscript entitled assessment of omecamtiv mecarbil for the treatment of patients with severe heart failure was published in JAMA Cardiology. Following on the heels of the initial data presentation in late June at Heart Failure 2021 and International Congress of the European Society of Cardiology the analysis by Dr Michael Felker and co-authors looked at the treatment effect of omecamtiv mecarbil. On the primary composite endpoint in patients from GALACTIC-HF classified as having severe heart failure based on modified criteria from the heart failure association of the European Society of Cardiology advanced heart failure physician statement. Patients in this subgroup had NYHA Class III, IV symptoms EFs of less than or equal to 30% and hospitalization for heart failure within the prior six months. Approximately 30% of patients enrolled in GALACTIC-HF met these criteria…

Thanks, Fady. During the third quarter, in September we presented the full results from Cohorts 1 and 2 of REDWOOD-HCM the Phase 2 clinical trial of aficamten at the Heart Failure Society of America Annual Scientific Meeting in Denver. As we've mentioned, the results were positive and support our advancing aficamten to Phase 3, which I'll touch on in a moment. As we previously shared in REDWOOD-HCM treatment with aficamten for 10 weeks resulted in statistically significant reductions from baseline, compared to placebo in the average resting left ventricular outflow tract for LVOT pressure gradient and the average post-valsalva at LVOT gradient. The majority of patients treated with aficamten 79% in Cohort 1 and 93% in Cohort 2 achieved the target goal of treatment defined as resting gradient less than 30 millimeters of mercury and post valsalva gradient less than 50 millimeters of mercury at week 10 compared to 8% for placebo. These reductions in LVOT gradient were dose-dependent with patients achieving greater reductions of LVOT gradient with increasing doses of aficamten. Reductions in LVOT gradient occurred within two weeks of initiating treatment were maximized within two to six weeks of the start of dose titration and were sustained until the end of treatment at 10 weeks. Reversibility of LVOT gradient and they'll be ejection fraction reductions were observed after discontinuation of aficamten with levels returning to baseline at the end of the two-week washout period. Patients also experienced statistically significant reductions in NT pro BNP and treatment with aficamten was associated with an improvement in New York Heart Association functional class with a substantial number of patients, improving by at least 1 class. As previously stated treatment with aficamten was well tolerated. The incidence of adverse events was similar between treatment arms. And there were no treatment-related serious adverse…

Thanks Stuart. During the third quarter we advanced our go-to-market strategy for omecamtiv mecarbil, and we were pleased to present at our recent Analyst Investor Day. There are a few highlights to the strategy. I'd like to review on today's call. First, our go-to-market strategy is based on a gated build with a planned total investment to be titrated over time as de-risking events occur such as NDA submission NDA filing and approval by the FDA. To illustrate we have around 10% to 15% of our planned commercial FTEs in place today, but we will have less than 1/3 of the total number of in place post NDA submission this level of commercial hires are sufficient for launch preparation. As Robert mentioned, we hired a seasoned team to implement this go-to-market strategy and we now have our full leadership team in place as well as our account manager team who call and payers and nearly all of our marketing organization. The go-to-market strategy is based on four key pillars insights, education, access and support. Insights speaks to having a very deep understanding of who the worsening heart failure patient is where they are treated and who would the cardiologist are who treat them. Education means that omecamtiv mecarbil is approved, then we need to ensure that cardiologist clearly understand the data supporting our label including the evidence supporting omecamtiv mecarbil potential benefit for the subset of patients who have worsening heart failure. Accessed speaks to our plans to have affordable co-pay for most patients as soon as possible after launch. And finally support and tells the programs that we will have and provide for patients like co-pay support for commercial patients patient assistance program and educational services. To support our goal of commercial - of affordable access our payer account…

Thanks, Andrew. I'll provide an update on cash revenue and spending and then Ching will review our financial outlook and corporate development strategies. More details on our actual results for the third quarter 2021 are included in the press release, which we released earlier this afternoon. We ended the third quarter with approximately $668.9 million in cash and investments. Our revenue in third quarter of 2021 came primarily from our recognizing a $5 million milestone from Ji Xing Pharmaceuticals in anticipation of the start of SEQUOIA-HCM. Our third quarter 2021, R&D expenses increased to $48.4 million from $24.2 million in the third quarter of 2020 primarily due to increases in spending for our clinical development activities for our cardiac muscle inhibitor programs. In addition, we incurred transition costs related to the termination of our collaboration with Amgen and our purchase from Amgen of approximately 7.3 million of materials including manufactured quantities of the active pharmaceutical ingredients for omecamtiv mecarbil, thereby completing our purchase commitment. More than 70% of our R&D expenses were attributable to our cardiovascular programs as expected given activity related to transitions from our collaborations with Amgen the purchase manufactured quantities of active pharmaceutical ingredients ongoing activities associated with METEORIC-HF and also our cardiac myosin inhibitor programs, including the ongoing activities associated with REDWOOD-HCM and start-up activities related to SEQUOIA-HCM. Remainder of our expenses were attributable to our early research and skeletal muscle program activity, our third quarter 2021 G&A expenses were $26.2 million, up from $12.3 million in the third quarter of 2020 due primarily to an increase in outside spending in anticipation of our potential commercial launch of omecamtiv mecarbil in 2022. Personnel-related costs, including stock-based compensation and facilities costs related to our new building. And now Ching will review our financial outlook and corporate development strategies.

Thanks, Robert. As is our annual practice, we recently conducted a comprehensive, strategic planning process with subsequent presentation and discussion with our Board this year the strategic plan was focus to prioritizing our expanding clinical pipeline to ensure that we focus on R&D programs that leverage our core competencies and competitive advantages in muscle biology and also address high unmet need opportunities that may for high return on investment potential. In addition, we pressure tested plans to enrich our research pipeline with external collaborations that could complement and strengthen our internal innovation. Lastly, we focused in this year strategic planning process to critically evaluating and reformulating our cardiovascular and neuromuscular business franchise strategy that's to continually capitalized on lifecycle management of our most advanced drug candidates omecamtiv mecarbil, Aficamten and reldesemtiv. To recap, our cash position we ended the third quarter with approximately $669 million in cash which includes $297 million raised in Q3 through an equity offering net of expenses. Therefore, our pro forma cash at year-end 2021 is expected to be in the range of $600 million to $610 million which represents more than three years of cash runway using our revised net cash utilization guidance of $195 million to $215 million in 2021. With the potential commercial launch of omecamtiv mecarbil and the funding of 2 Phase 3 clinical trials SEQUOIA-HCM and COURAGE-ALS. We do expect our 2022 and 2023 cash burn rate to increase relative to 2021 spending and we will provide guidance on this in our fourth quarter earnings call and to occurred in early 2022. As we have stated, we continue to seek ways to strengthen our balance sheet and in the third quarter, we have been advanced partnering and structure financing discussions aligned with our corporate development strategy. During the quarter, we continue…

Thank you, Ching. Within our vision, 2025 that we set forth in 2020 we laid out several goals, including achieving regulatory approvals for at least two drugs arising from our pipeline and expanding our discovery platforms. Over the past quarter, in addition to the clinical, regulatory and commercial progress we made, we also engaged in activities to broaden our research footprint in the years to come. Thinking even beyond 2025, we continue to forge ahead as leaders in muscle biology with focus to populations of high unmet need. In the next year, you'll be hearing more about our activities as we've extended our muscle biology focus from the bio-mechanics of muscle contractility to the energetics growth and metabolism of muscle with novel mechanism drug candidates advancing in development. While much of our focus has been on our programs in cardiovascular disease as you heard with our starting COURAGE-ALS, our commitment to the ALS communities remains strong. Along these lines, we also recently donated data from our completed clinical trials in ALS to the PRO-ACT database, which stands for pooled resource open access ALS clinical trials. PRO-ACT is available to members of the research community and it contains over 10,000 de-identified clinical patient records from multiple completed clinical trials, providing a powerful tool to advance research in the ALS field and also together observations related to disease progression and epidemiologic data. We will be donating data from three completed trials in ALS BENEFIT-ALS, VITALITY-ALS and FORTITUDE-ALS which represents data from almost 600 patients. We're pleased to be working with the ALS Association with Price for Life and with the Neurological Clinical Research Institute at Mass General to share these data with the ALS communities to which we are altogether so importantly dedicated. Further demonstrating our commitment to patient communities during the…

[Operator Instructions] Your first question comes from the line of Dane Leone with Raymond James.

Hello, Dane.

Great. Hi, Robert and team. Thank you for taking the questions and congratulations on all the updates. Just two for me if you will. Firstly, can you give us any more color in terms of the scale and scope of the SEQUOIA-HCM study, as we think about one modeling expenses and two time to run the study. Is it fair to use the EXPLORER-HCM study as a similar proxy and scale and scope for the patients required an enrollment? And then my second question would be just to drill down a little bit more on the submission for omecamtiv, I know it's been asked before, but in terms of updating your communications back and forth with the FDA, any additional color in terms of the scope or scale of the label as it relates to baseline left ventricular ejection fraction. Thank you.

Sure. Good questions. So I'll start and turn it over to Fady. He may also ask Stuart to elaborate. I don't think we're going to provide any specific financial guidance with regard to SEQUOIA, it may be premature to do that until we start dosing patients, but certainly we can give you some things to hold on to with regard to your projections. For instance, what might be our expectations in terms of time for enrollment and duration of the study. I hope that could be helpful and certainly you know already the number of patients we aim to enroll. So why don't I turn it over to Fady first to talk to you about how we think it's going to enroll the number of sites, the number of countries, things like that. And then most likely once we start dosing presumably that will be in early 2022 will be at a better position to point to how we think it's going to be affecting our spending, and then we'll come back to your second question.

All right. Thanks, Robert. I think we plan to enroll approximately 270 patients into SEQUOIA, which is a little bit more than was in roles and explore. I think the size and scope are comparable and certainly the number of sites and things like that. We will probably go to a few more sites than they did in explorer nearly a dozen countries and well over north of 80 sites. I think ultimately, when we get study fully up and going. So our plan is to push hard and to enroll this as quickly as possible. But there are certain I think limitations in terms of study startup and things like that, that are hard to press once we have sites up and going, I think it would actually enrolled very rapidly.

So then, your second question related to the NDA and how we're approaching what could be that which is contained within the NDA indication statement and otherwise. In particular, around ejection fraction. And as we've stated, we do believe that patients with the EF is less than 30% are seemingly benefiting a great deal of more than other patients in GALACTIC and we do think that it's in the interest of omecamtiv mecarbil in patients with heart failure that's where the label should point. So we are hopeful that data including graphics could be included in the label ultimately upon potential approval, but that's obviously going to be subject to FDA review, but based on conversations we've been having in Fady can elaborate. We do feel encouraged that would be supportive and consistent with other things the FDA has done. Fady anything you want to add?

No, I mean, I think we've had those discussions with FDA obviously what ends up in the label will be the outcome of the negotiations at the time that we negotiate the label. But in general, I think there are supportive of the concept, that the label should indicate where the benefit of the drug is concentrated and that provides physicians with the information needed to best use the drug. And in that context, EF is obviously an important indicator.

And not only the label. I might suspect that could ultimately inform how omecamtiv mecarbil could be incorporated into guidelines also and you got a sense of that from some of the publications that Fady referred to in his statements.

Excellent. Thank you very much and congratulations.

Thanks, Dane.

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

Hi, Joe.

Hi, everybody, good afternoon. Thanks for taking the questions. I wanted to focus my first question and the concept that you guys are really in an important execution and logistics time for the company. So with that said, I'll even go off of, I want to Stuart's comments, and Robert you said it to about drug availability for -- early next year and executing COURAGE as well. Do you feel you've had to plan anything above and beyond for these studies, no matter what it is, including drug availability based on any anticipated issues around the global supply chain problems that we're seeing right now?

Very good question, and I think that might be the first time on one of these earnings call that we really did get a question about the supply chain. It's an area of intense focus for us right now, as we're not only embarking on these large Phase III studies, but we're readying for the supply of omecamtiv into the marketplace and obviously had, we still been partnered with Amgen, that would be something we'd have relied on them for, but now it's our responsibility. And we are executing well on contracts as well as conversion of drug substance to drug product and the like, and the study startup activities for SEQUOIA are proceeding nicely, we moved very swiftly from having completed Cohorts 1 and 2, reading out there results, having meetings with FDA and readying to start SEQUOIA, all of that occurring in a relatively short timeframe. So it seems like things are going well. That way, both in support of clinical trials and also commercialization. But we are building the supply chains. At the same time we're executing on how the delivery of drug product into clinical trials is occurring. So it's something that I think is going to be continuing to be a focus for senior management as that is enabling of our success, and to this point, the good news is, we're working with some of the same contract manufacturing organizations with whom we have long-standing relationships with. And there may also be opportunities to consolidate programs, amongst them so that we're working with them for more than one program. And we're focused to small molecule drug candidates, and that in way, it's not like we're dealing with an incredibly novel way of approaching supply, but at the same time, we have to ensure capacity and deliverable timelines and that's what we're focus towards. Fady, anything you want to add to that?

No, I think you summed it up, but I think we've been able to continue to advance drug supplies for our studies and things like that. I think the real major constraints this has to do with the spare capacity in the supply chain. There is just a lot of it's been squeezed out. So you have to be careful about how you plan things.

And what I might also say as Andrew and his team are very focused to the hand off between the manufacturers and then the logistics associated with distribution and all of the activities in connection with ensuring patients get reliable sources of drug as well and that speaks to potential patient hub services and other things like that. Over time, I expect you'll hear more about that from Andrew too.

That's very, very helpful. Thank you. And then I guess two smaller questions. One maybe for Ching on the financial side. Are you -- we have this $7.3 million cost to pay Amgen for drug product for omecamtiv. Just curious, what might still be outstanding, they're going into the future or if that expense is essentially done? And then second, if I heard Fady, correct when he was discussing the future for omecamtiv as well. I could of sworn I heard him say potential ISTs, so that sounded like an interesting there. So I'm curious what kind of studies you might be looking at. Thank you.

Yes, I mean…

Thanks.

Oh. Got ahead, Ching. You go first.

Yes, I'll go first Fady. So, in regards to e-payment that we pay Amgen, the $7.3 million this quarter is the last of those payments. As we stated in our press release for the nine months ended September 30, 2021, we have pay them $46 million. So that was the total amount, and this was $7.3 million was the last of the payments.

Thanks.

And I think just in regards to investigator sponsor initiated study, we've begun to receive proposals, obviously we'll let them and decide which ones we can support things like that, they fall under a fairly broad range of interest. The people have really outside, some of them outside of the heart failure, population that we studied in GALACTIC, some of them within, but I think we'll elaborate more on those as we begin to see them through.

Sure. Understood. Thank you very much.

Thank you.

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

Hello, Yasmeen.

Hi, Robert. Thank you so much for taking my questions. But I have two questions for you. Maybe the first place to start is, a lot of our investors have been sort of surprised by the FDA recently by some of the actions that were taken a created sort of a nervous Nellie situation. So I get the question for you is, especially over the last few months as you've been interacting with the FDA. What sort of their tone, their body language, there into towards you. So if you could just elaborate, and how does discussions went, and I think that could be really important. And then I have a follow-up question?

Sure. So what I'll say is oftentimes in these situations, biotech companies’ talk about having a pre-NDA meeting, they submit an NDA, it gets filed or doesn't get filed, and then they await approval. In our case, over the last year, we've had many interactions with FDA both in-person before COVID shut that down and then also subsequently by Zoom interactions and otherwise through written exchange of documents. I found FDA to be very accessible and very interactive with us and providing guidance that informs both the formatting and the content of our planned NDA submission. So I'm very encouraged by the level of engagement and I should hopefully support our submission that would hopefully align with interest for approval. We've had all of our questions satisfactorily answered in order to provide for us now to go through the final mechanics of an NDA submission in order to get that done this quarter.

And thank you, Robert for answer. And maybe a follow-up question is, maybe giving me some insight when you speak with cardiologist whether these are in private practice, whether it is at the hospital setting, and sort of the level of appreciation, they have for omecamtiv in terms of a novel mechanism of action. Does it click right away when they know that it's the first myotropes being able to really, being able to improve cardiac contract. I think that might be really important like how important is the novelty of its mode of action for driving adoption in their enthusiasm beyond obviously the outstanding data form black in nature.

So it's a little too early to talk about adoption of course in that as much as not approved, but certainly based on ad boards and interactions with key opinion leaders that have been driven out of medical affairs and also market research as is driven out of our commercial group. We're getting very positive vibes about how the novelty of the mechanism may translate into potential future adoption, maybe I'll turn it over to Fady first to speak about some of those activities that he is overseeing, and then I'll turn to Andrew as well.

Yes, Yasmeen. I think the physician community certainly understands where this could play a role and it's been a finding a drug that can improve cardiac function safely and have benefit for patients has been a longstanding goal in this field. And if you listen to our Investor Day presentation, I think you might hear some of the enthusiasm in the two discussions we had, but it was similar amongst many ad boards that we conducted both in the U.S. and in Europe. And I think even as we go out to other stakeholders in the process, we're sensing their enthusiasm for something that is new, but on the other hand, we understand how it works and it's rational, it's rationale as to why you might use it.

This is Andrew. The only thing I would add is that when we talk with physicians, they excited by the mechanism enough for the mechanism alone, but it's a reason to believe relative to the data any evidence that we produced. So when they look at the mechanism and the evidence and the unmet need very well aligned, they are running out of options when patients can't tolerate guideline directed medical therapy. They are running out of options when they need products that what could be an add-on that neutral on kidney, neutral on blood pressure in working patients. And when you talk about the add-on and those type of effects think get very excited and a good reason to believe then kind of closing is a mechanism. So we're getting a lot of enthusiasm for a very specific subset of patients relative to the product.

Thank you for the answer.

Thank you.

Your next question comes from the line of Jeff Hung with Morgan Stanley.

Hi, Jeff.

Hi, Robert. Thanks for taking the questions. Previously indicated that meetings with payers on omecamtiv mecarbil has been largely introductory, just curious if you have any updates that you can provide on payer feedback.

Sure, I'll turn it over to Andrew to address that.

Sure. So I appreciate the question. So we've interacted with. As I've mentioned, we've hired all of our account managers, as well as the leader of that team. Many of them have existing relationships with all the major payers. We've interacted with the major payers and it's really more about introduction who is Cytokinetics and then making sure we aligned well on how they think about heart failure, how do they manage heart failure, what are their challenges and what are their needs. So we've had those kind of baseline discussions and then where will go next is per FDA regs is kind of a pre-approval information exchange, we will start doing that incoming weeks. So the feedback has been 12, they do like that we can clearly identify those patients relative to benefit in EF. So then therefore that could indicate where they would target us from a prior authorization point of view, which is acceptable to us, because that gives us access to a very specific population that greatly benefit from omecamtiv. So hopefully the color of our interactions in the third quarter.

The other thing to add is, there is a lot more forthcoming that you'll see in the published literature in 2022 that underscores the economic burden of heart failure, especially for those with worsening heart failure and where there could be opportunity for a new mechanism therapy like omecamtiv mecarbil based on results from GALACTIC to make a dent in that for payers. And payers are clearly aware of the economic burden associated with their management of heart failure patients. They're aware, especially of the high Medicare percentage of these patients for which there oftentimes penalized when these patients are readmitted. So a novel mechanism therapy that could reduce heart failure related events primarily hospitalizations would be something that would catch the retention, and that's something that we'll continue to investigate, this could be supportive of our plans for omecamtiv.

Great, thanks. And I think I may have misheard, but did you say that you expect enrollment of COURAGE to be completed this year. Otherwise, any updates on this made timing or when you might be better able to gauge the pace of enrollment to estimate that time. Thanks.

Yes, what I would I said are meant to say was that enrollment continues through this year, but also intended next year also. We expect that will enroll patients sufficient to enable a first interim analysis next year, the timing of which is still to be defined. But we expect that were it to pass through that interim analysis, hopefully it will. The study would continue through next year. So, no, it's not intended to complete enrollment this year.

Okay, thank you.

Thank you, Jeff.

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

Hello, Akash.

Hi, Robert. So, thanks so much for taking my questions. Can you talk about what drove your decision to look at exercise capacity as a primary endpoint for - and not the comps that I'd point that ahead why may exercise capacity be a more useful endpoint, both for the agency and clinicians. And additionally, have you heard any feedback from either the FDA or KOLs on the need for long-term outcomes data post-approval for our Aficamten. Thank you.

Why don't we turn first to Stuart to address the first question and then maybe Fady and Stuart the second question.

Thank you, Robert. So, we focused on evaluating functional improvement in patients with obstructive HCM comparing Aficamten versus placebo. And with respect to the fact that these patients have very poor exercise tolerance. We focus on one of the most rigorous objective measurements of exercise capacity and that is clearly peak VO2 as well as other parameters using cardiopulmonary exercise testing. And so we rather than combining this with, say, a more subjective component of the composite endpoint. We really wanted to zero in on what we thought was the most sort of critical and quantitative measurement and objective measurement of exercise capacity. And you said that, we will be evaluating other endpoints as secondary endpoints that evaluate symptomatic improvements such as the Kansas City Cardiomyopathy Questionnaire New York Heart Association functional class et cetera. So those other kind of I'll say more traditional endpoints we will be evaluating in SEQUOIA.

And your second question was -- why do you repeat that for me Akash?

Yes, absolutely. Have you heard any feedback either from the FDA or KOLs on the need for outcomes data post-approval?

Yes. Outcomes, I think that the regulators and KOLs appreciate that outcomes data are very hard to come by in a symptomatic, although very heavily burdened patient population. These patients, unlike traditional heart failure patients don't get hospitalized, there mortality rates are usually quite low and lessen well under 5% per year. So you can't really do outcomes-based trial per se and I think that's well understood based on the event rate. That said, I think that there's also recognition that the therapy that has been developed for these patients is a lifelong therapy. And so, having a good understanding of it safety, long term is important and that's why we're conducting the open label extension in plan at least five years of follow-up in patients that we enroll in that, that rollout of either REDWOOD or SEQUOIA to enable us to better characterize the course of these patients who are being treated with aficamten.

I think the advent of new pharmaceutical is going to drive a better awareness of the outcomes associated with a diagnosis of HCM as could be modified with add-on-therapy of Aficamten or Mavacamten, and you're going to see I think increasingly publication arising out of registries that speak to the real world evidence associated with these longitudinal studies. So we will be in a position to better understand what might be possible. And I do suspect that will play into ultimately the adoption of category, but to your original question is to whether regulators are pushing for it? I don't think that's likely going to factor into the registration of these new medicines at least not from what we've heard from FDA.

That super helpful. And if I may just follow-up here. Can you talk about the importance of showing to the FDA that patients are able to get stabilize on to a safe dose from this class of drugs. Is that something that the agency is focused on from a regulatory perspective? Thanks so much.

It’s certainly something that we think is possible and achievable with Aficamten, and hope to be able to demonstrate that with SEQUOIA. If your question is pointed to, is that something FDA is pushing for, because of their review of another product that would not be appropriate for FDA to be signaling anything like that to us.

Understood. Thanks so much. Appreciate it.

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

Hello Salim.

Good afternoon, Robert and team. And congrats on all the progress. Just a couple from me, one on 274 and one on actually reldesemtiv. So, on 274, looks that Robert obviously the thesis here has gotten a lot more comfortable for a lot of long-only investors, right? And I'm curious in your mind what are the gating factors -- when you think about the story what are the gaining factors here for 274 that are really stopping you from turning on the after burners and starting to develop -- have path, which is it's a large indication more aggressively? And I guess we could also ask the same question for non-obstructive hypertrophic cardiomyopathy. And the second question on reldesemtiv. So as we start to dig in here on the COURAGE design, you guys are enrolling looks like ALSFRS total score 44 or less. But when you look at the Phase 2 data, the slow progressors turtle [ph], which had a score of 41, didn't really show much of a difference between drug and placebo. So I'm curious how you guys are thinking about COURAGE. Are you going to limit somehow the slow progressors that are entering the trial? Or how are you ensuring that when we get to futility that you're having an over-enrolled slow progressors I guess is one way to ask it? Or how are you controlling that you're going to actually have enough medium or fast progressors that would show a larger benefit here potentially according to the Phase 2 data? Thank you.

Sure. Both very good questions. Let's start with your first one around the development program for Aficamten. We've spent quite a bit of time over these last several months once we saw the REDWOOD results, considering what might be our next steps beyond SEQUOIA-HCM for Aficamten. And Fady and Stuart and Steve and others here at Cytokinetics are considering a number of different trial designs as we would be expected to expand the development program in non-obstructive HCM and in hefpath [ph]. It's premature for us to elaborate on them, but you should expect in 2022 to hear more about our plans that way. We intend to be pursuing the development of Aficamten along both those lines and not in a linear way per se, but in parallel ways that would be enabling of us to build on what we know for Aficamten. I'm just not in a position to do that on today's call. But certainly as we plan for budgets for 2022 and goals and considerable resources that we need to align in order to make that happen that's very much in the forefront of our planning. Your second question related to COURAGE-ALS and I'll ask Fady and Stuart to address. I think you might be misunderstanding a bit how we are designing the study. We are going to be prioritizing for those patients who are progressing, but they can elaborate.

Yes. I think it's really an enrichment strategy Salim and so the entry criteria designed in such a way to enrich for the medium and faster progressors. And I can turn over Stuart a little bit to describe how that works. But ultimately it's also something that we can monitor, because you can look at progress -- you can look at the -- calculate the early progression rates in the study and ensure that you're enrolling the right patients in a blinded way. Stuart?

Yes. So Salim, I think you're referring to the post-hoc analyses that were conducted with the FORTITUDE-ALS and database. And why we observed trends of benefit in slow progressors, we observed greater magnitudes of benefit with respect to ALSFRS-R in the medium and fast progressing patients. And what we did was map that progression rate to critical entry criteria particularly a maximum ALSFRS-R of 44, as well as time from symptom onset of two years. And so, if we apply those apply those two main criteria that enriches as Fady mentioned for population, a faster progressing patients, while not excluding slow progressors, but we'll have a larger proportion of medium and faster progressing patients. And with that strategy, we anticipate that this will increase the sensitivity of detecting a beneficial treatment effect with reldesemtiv.

Okay. Got it. So this is more you will be able to in your view do this based on entry criteria not having to calculate during the trial based on blinded data?

That's correct. Exactly.

Okay. Thank you.

Thank you, Salim.

Your next question comes from the line of Jason Butler with JMP Securities.

Good afternoon, Jason.

Hi Robert. Thanks for taking the questions. Just wondering if you could talk a little bit more about the path for Aficamten in China. Is there data that you need beyond the completed PK study to open up the SEQUOIA trial to China? And then, just give us a sense of what proportion of patients in SEQUOIA you think could come from China? And then, could SEQUOIA as a standalone support registration in China? Or would you need additional data or an additional trial beyond that trial? Thanks.

Yes. So, very good questions. We're still learning about what might be required. But it's our assumption that we're going to be in a position to start SEQUOIA in China and based on the Phase 1 data be enrolling China patients into the same study and as could be supportive of registration in China as well as outside of China, U.S., Europe elsewhere. So that's the intention and the plan obviously that's subject to regulatory interactions that are still to be had, but our partner Ji Xing is very much on top of these things and we're working very very well. Stuart is leading much of that activity for Cytokinetics. Stuart, anything more you want to add?

No. I think you've summarized it very well. We certainly rely on Ji Xing for guidance. They have more expertise in China regarding the regulatory requirements. But as you've -- as it has been laid out we expect the Phase 1 data to support enrollment of patients in China in SEQUOIA-HCM and that trial to support registration in China.

Great. Thanks for taking the questions.

Thank you.

Your next question comes from the line of Charles Duncan with Cantor Fitzgerald.

Hello, Charles.

Hello, Robert and team. Congratulations on good year of progress. Thanks for taking my question. I had a couple of questions. One on omecamtiv and then another on reldesemtiv. With regard to omecamtiv NDA filing, I guess I'm wondering are you planning on press releasing the submission or the acceptance for review or filing? And then, I guess, I just need to clarify something. I think it was to Dane's question. Would you be filing for a broad label claim with data pointing to the patient the cohort that had the greatest benefit? Or would you limit the filing claim to that cohort?

Yes. So I'll take those and Fady may want to elaborate. With regard to the communications and the press release, we expect to be submitting an NDA in this quarter and we probably would not be communicating anything until such time as we have a read on its file ability whether it's filed or not filed by FDA. And then as to your second question I'll ask Fady to speak regarding how we might approach the indication statement and where it might be the information containing the patients that benefited the most.

Yes. I can - I think if you look at different indication statements even recent ones there are different approaches, but and generally they reflect the patient population that was studied in the clinical trial at large. You can see in the ENTRESTO label after the PARAGON data were added that there was an additional statement with regards to where the benefit was concentrated i.e. in patients with below normal ejection fraction. So it may be that you could end up with the modifying statement in the indication. You certainly will have data in the clinical trial section that show the pre-specified subgroups, which one of which was ejection fraction as you know, and showed the benefit in the lower ejection fraction group, the NYHA 3-4 group and others -- and across the subgroups that we had pre-specified. So there are different places in the label where the information may be contained and ultimately it's hard to predict where we'll end up until we go through those discussions.

Okay. That's helpful. I consistent with what I kind of thought. Regarding METEORIC, I think you mentioned that you'd complete the conduct of it yet this year. Can you give us some sense on timing to data? Could that be in the first half of the first quarter? And then, can you confirm whether or not you think that that data would then be submitted to the agency and have any potential for impacting the review? It seems like it could be pretty early in the review cycle, so likely not.

Yes. I think what -- we probably aren't going to give guidance with regards to first half or second half of the quarter with regards to METEORIC. Its conduct will wrap up this year, but it's really going to wrap up pretty late in the quarter. And then of course, it's a complicated study because there's a lot of central lab work in terms of the CPET evaluations and so forth. And the data sets are relatively complex to integrate. So time database lock may be not as swift as you might have in an event-based trial.

Okay.

But I think the other aspect of your question that you're going to have to remind me of again now I got a lot of track of it.

Just impact on review cycle timing?

Yes. No. I think having the results in hand and early in the quarter is not going to -- obviously, the FDA will see them as we release them and hope to see them presented, but they won't we think impact review. It will be -- the safety data will be probably part of an update during the review cycle, but that's it.

Okay. And then going on to reldesemtiv, just one quick question regarding the conduct of that trial. And I think you mentioned in the previous set of questions or a couple of before that you're kind of enriching for faster progressing patients. And so I guess I'm wondering are you explicitly asking for more bulbar onset versus limb onset patients seemed like to be consistent with that given that under two years since symptom presentation?

Stuart, do you want to take that?

Yes. We're not seeing that restricted in terms of our enrollment. We're certainly enrolling patients in both categories. But as I mentioned before, major criteria to enrich for faster progressing patients based on that LSAFRS score at baseline and the time since symptom onset.

Okay. Thanks for taking the questions.

Thank you.

Thank you, Charles.

Your next question comes from the line of Rohit Bhasin with Needham and Company.

Good afternoon, Rohit.

Hi. Good afternoon. This is Rohit on for Serge. Thanks for taking my question. Can you talk a bit about how the METEORIC-HF trial fits with the gold market strategy for omecamtiv. Do you expect a label expansion or better payer reimbursement?

Sure. I'll ask Fady to speak to that and maybe Andrew might want to add.

Yes. I think if METEORIC is positive we would at some point submit for a supplemental NDA filing an expansion of the label that would include the results of METEORIC. The clinical benefit there is important patients and certainly would be worth having in the label that wouldn't come until after the primary approval of omecamtiv mecarbil. And I think being -- that improving exercise capacity is something that is rarely shown with drugs that improve heart that would be a unique feature of omecamtiv mecarbil so the trial be positive. Maybe I'll turn it over to Andrew to see if he has anything else he wants to add there.

Sure. And we're going to be negotiating access pre-approval, post-approval and largely we'll be using the data from galactic. If we have a positive METEORIC trial that certainly will enhance the benefit. We could bring to patients especially in capacity. It could enhance our value argument. If patients feel better or could be more productive. So it's really going to depend on how the data read out and what the adjustments are to the label. But I wouldn't expect it to have a major impact on our overall access strategy or access levels.

What it does do is it reinforces the mechanism as provides what could be differentiating benefits to patients beyond outcomes, this being a functional outcome. And in that way it could reinforce the use of omecamtiv mecarbil. But I agree with Andrew. It's not likely to drive a view things. It might very much have the effect of things like adherence and compliance of patients and also how physicians might ultimately view the category.

Great. Thank you.

And there are no further questions in queue at this time. Robert, your closing remarks please.

Thank you. Thanks very much to all the participants on our teleconference today. Thanks for your continued support and your interest in Cytokinetics. We're pleased to be able to provide you updates with respect to our progress as well as our prospects. Obviously, a lot is going on at our company and we're looking forward to continuing to execute well on our key milestones through the remainder of this year. And then peering into next year as mentioned, it could be quite a transformational year 2022. We look forward to sharing with you all of those updates. And with that operator we can conclude the call.

Thank you. This does conclude today's conference call. You may now disconnect.